key: cord- - dzeebn authors: jonas, richard a. title: rewards, risks, and responsibilities of globalization for the cardiothoracic surgeon date: - - journal: j thorac cardiovasc surg doi: . /j.jtcvs. . . sha: doc_id: cord_uid: dzeebn nan martin, who is co-director of the heart institute and chief of cardiology ( figure ). the relationship between cardiology and cardiac surgery can be a fragile one, particularly in an area of shifting finances and power within the hospital structure. today we are collectively successful in shepherding children with congenital heart disease through even very complex reconstructions with an overall success rate approaching % to %. however, this results in a cumulative pool of patients needing life-long follow-up with cardiology but, ideally, rarely if ever with cardiac surgery. within my professional lifetime, congenital cardiology departments have grown from being equal partners to being up to times as large as surgical departments in terms of numbers of physicians and with increasing financial disparity. this is leading to stresses within congenital cardiac programs. but such stresses can be minimized by an administrative structure such as exists at children's national medical center, where all decisions as well as hospital and professional revenues are managed collectively by the physician and administrative staffs. my journey to this podium has been a long one, but it has also been enormously satisfying and rewarding. as surgeons we are blessed to have families place in our hands the responsibility of caring for their loved ones. we have an opportunity to practice both an art and a science, to enjoy the consummate satisfaction of applying practiced physical skills and the fundamentally humane activity of supporting and encouraging and sometimes grieving with families who are passing through an incredible period of stress in their lives. my journey to this podium would not have been possible without the support of my surgical mentors, to whom i would now like to pay tribute and give thanks by briefly tracing my educational progress halfway around the world. my mentors worked within quite different health care delivery systems. my direct experience with these different systems has no doubt shaped my views of the global challenges and opportunities facing cardiothoracic surgeons that i will share with you this morning. my journey began in adelaide, south australia, best known as the home of the australian wine industry ( figure ). as a medical student at the university of adelaide, i worked within a health care system that in those years was a reasonably successful balance of private and public funding. however, in the tradition of the british model, private and public patients were segregated into private versus govern- ment hospitals. one clear lesson that i took away from that experience was that if ever i was to be undertaking complex surgery in patients who would require intensive care management postoperatively, i would confine my practice to one hospital. this principle was reinforced by my mentor and good friend, dr d'arcy sutherland, who established open heart surgery in adelaide and who set me on the road to this podium ( figure ). d'arcy was a master surgeon, a tremendously successful administrator, and one of the first in the world to recognize the importance of the careful collection of risk-adjusted registry data. at the very first aats meeting that i attended in san francisco in , d'arcy was the honored guest speaker. d'arcy is alive and well in adelaide and sends his best wishes to his many friends in the aats ( figure ). during my medical student years i had the opportunity to work for months in the national health service in the united kingdom. i was surely in the trenches of the national health service in the derby city hospital in the midlands of england treating coal miners and the artisans who crafted royal crown derby china. this was during the winter of discontent in when the heath government was collapsing, the miners were on strike, british rail was on strike, and the national health service was facing major i also had the opportunity in to spend a month in mission hospitals in northern new guinea. new guinea was in a transition phase between colonial government by australia and independence. i worked with a fascinating mix of missionary zealots, kind and humane physician philanthropists, and lunatics. i learned much about human nature and, just as important, i learned about the challenges facing nongovernment organizations that provide care to indigenous populations, the challenge of education versus dependency. in melbourne, australia, miles southeast of adelaide ( figure ), i undertook my general surgical training at the royal melbourne hospital, one of the great academic institutions of australian medicine, where i had the pleasure of working with brian buxton and jim tatoulis (figure ). i began my cardiothoracic training at the melbourne children's hospital, to which d'arcy sutherland had been called in from adelaide to resuscitate a badly ailing congenital cardiac program. d'arcy began by recruiting the great surgical technician dr roger mee ( figure ). this was the first of many opportunities where i witnessed how fragile a congenital cardiac program can be and the care that is needed to build cohesion between surgeons, cardiologists, intensivists, anesthesiologists, and the entire health care team that makes up a congenital cardiac program. figure ). i was extremely saddened by the recent loss of sir brian ( figure ) and extend my condolences to his wife, sarah. working in new zealand allowed me to witness once again the risks inherent in a fully nationalized health system when a country runs into economic difficulty, as was the case in new zealand in the early s. brigham & women's hospital in boston (figure ), the next stop on my journey, was a sharp contrast to the nationalized health care system of new zealand. dr larry cohn and dr jack collins, as well as my peer, richard shemin, who went on to head up the boston university program, all became close friends and mentors and demonstrated the efficiency and superb high standards that the us health care system could achieve. i was particularly impressed to find that there was no distinction between private and public patients. in fact, this concept really did not exist in the united states, and in those days the nonprofit academic health care system in boston was about as egalitarian as one could possibly hope for. drs cohn and collins arranged for me to work at the children's hospital in boston, where aldo castaneda and bill norwood ( figure ) were in the process of building a great regional congenital heart program on the solid foundation laid by robert gross. they achieved this through innovation, courage, and persistence in the face of intense criticism. it was a hugely important experience for me to be a part of the development of the norwood procedure for hypoplastic left heart syndrome and the neonatal arterial switch procedure. i learned a lot about how surgical programs can weather the challenges that arise with innovation. during my years at the boston children's hospital, i worked with many enormously talented individuals. one of my two senior partners, dr john mayer, whom i was fortunate to retain on staff after i became chief of the department in , has made many contributions to congenital coding and reimbursement. dr pedro del nido, whom i recruited from pittsburgh, is currently chair of our aats scientific and government relations committee and is helping to lead the defense against the contraction of funding for cardiothoracic surgical research. this work is vital because there is no question that many forces are at work threatening academic institutions and academic surgeons. it is the role of a professional association such as the aats to advocate for academic surgeons and institutions to protect our mis- sion of advancing the field and training the next generation of cardiothoracic surgeons. there is no question that the teaching of cardiothoracic surgery is a complex task ( figure ). we teach through our personal example, through our mentoring in the operating room, and through the dissemination of new concepts, new techniques, and the introduction of new technology at meetings such as this. we teach through the writing of original journal articles and book chapters, through the editing of books and journals, and through peer review of publications such as the journal of thoracic and cardiovascular surgery. we must reward such activities by mechanisms such as the distinguished reviewer award recently introduced in the journal of thoracic and cardiovascular surgery. but associations such as the aats cannot do it alone. we must work with the collaboration and cooperation of teaching institutions, which must continue to provide incentives and opportunities for adequate instruction of the next generation. this was an easy decision for institutions when there was no limit on the number of hours that a resident could work and reimbursement through the medicare program was generous. however, the current total costs of training are now being carefully factored into the economic analysis of the productivity of clinicians. one of the other great challenges facing cardiothoracic surgical educators is the difficulty predicting the manpower needs for our specialty at the end of a very long training process. how many surgeons should we be training today? like many of you in this auditorium, my surgical training extended over years. what will our manpower needs be in years' time? this is a remarkably difficult question to answer for a host of reasons, but it is a question that we are obliged to answer. cardiothoracic training is still ultimately a mentorship, and there is a fundamental obligation on the part of the mentor to assist the trainee to have a productive and satisfying position at the end of the training process. for many years the aats and the society of thoracic surgeons have collaborated in intramural workforce studies. recently, in addition, we have commissioned the american association of medical colleges to undertake a review to try to help us understand the impact of the many external forces that are likely to influence our manpower needs. these factors include demographic shifts such as the aging of the us population as well as technical innovations in our own and other medical specialties. the relatively recent subspecialization of cardiothoracic surgery into adult cardiac, general thoracic, and congenital has undoubtedly complicated the projection of manpower needs ( figure ). the percentage of female physicians within the specialty has remained less than %. this statistic unique to our specialty has become increasingly important as the percentage of female graduates from medical schools has risen to greater than %. if it is to be truly informative, the manpower study will need to look beyond the shores of the united states. all of us are working within an increasingly interconnected global society. just look at some data that are of great importance to the financial health of this association. more than % of attendees at this meeting over the past years have been non-us physicians ( figure ). in other words, this meeting would be half its size without the international attendees. the same shifts can be seen in the submission and acceptance of manuscripts for our journal (figure ) . the aats has responded to the internationalization of this meeting and the journal in several ways. one of the members of the council is now appointed from among the international members. we thank marko turina for the superb job that he has done in this position. last year, the council voted to eliminate us citizenship requirements for new members. in fact, the membership committee has been charged with increasing the international representation among the membership. the conversion of the journal to an electronic format that is available globally brings distant countries closer to us, such as australia and new zealand, where the journal previously arrived more than months after publication. at this meeting, we have instituted a global session that will be held again this year on wednesday morning, organized by dr philip corcoran, the chief of cardiothoracic surgery at walter reed medical center in washington, dc, with whom i have the pleasure of working. although it is tempting to attribute the growth of the international participation in our meeting and journal to their academic excellence alone, i believe there are other important factors at work. despite its contraction in the united states, cardiothoracic surgery is expanding at a prodigious rate in many areas of the world, particularly in india and china. this is primarily a result of economic development in these and many other countries, development which is being fostered by economic globalization. we need to examine how globalization may affect the manpower needs of our specialty, both within the subspeciality areas and for cardiothoracic surgery as a whole. this analysis will also afford us the opportunity to appreciate how globalization is affecting global health overall and the relevance of those changes to us, not just as cardiothoracic surgeons but also as physicians and as members of the human race. there are many definitions of globalization, but all of them carry the sense that the world is becoming smaller and we are increasingly interconnected economically, socially, and culturally. the epidemic of severe acute respiratory syndrome (sars) and the avian flu threat also remind us that health risks have been globalized. there is a tendency to perceive globalization as a totally new phenomenon, a recent consequence of the internet, the digitization of data, and the establishment of a global hub-and-spoke air-transportation system. however, viewed from a greater distance, globalization is a continuum that has extended over millennia with the gradual breakdown in local tribalism as transportation and communication have evolved. new guinea, as i learned when i was there, is a fascinating study of the consequences of difficult communication and transportation resulting from the dense and mountainous jungle terrain. the isolation of individual tribes has been associated with unique languages among new guinea tribes, which represents the densest concentration of diverse languages of any region of the globe. in contrast, international airline pilots have had to adopt english as a universal global language. there have been important tipping points in the progress of globalization. in fact, some would say that globalization began with the emergence of intercontinental travel by sail ship and the emergence of the capitalist world system in the s. the industrial revolution and the harnessing of power in the th century are cited by others as the origins of globalization. the modern era of economic globalization, however, can be pinpointed with great accuracy both geographically and chronologically. figure shows the mt washington hotel, nestled in the beautiful white mountains of central new hampshire not too far from my own new england home. in july , representatives from the allied nations of world war ii, which was still in progress, sowed the seeds for the establishment of the world bank, the international monetary fund, and the world trade organization. during the cold war years, these three institutions provided the economic armamentarium whereby western countries pursued the objective of containing communism by providing loans to developing countries. after the fall of the soviet union, however, these organizations adopted a new agenda. the underlying goal has been to reduce global poverty and to improve economic opportunity and productivity throughout the second and third worlds by opening markets, removing trade barriers, and through carefully monitored loans from the developed to the developing world. supporters of globalization can produce powerful evidence that these goals are being achieved. , however, there is another side to the story, as i will examine in a few minutes. first, however, let us look at the health consequences of globalization and what these mean for us as cardiothoracic surgeons. in the early s, the world bank commissioned a projected titled the global burden of disease. this was performed in conjunction with the harvard school of public health and the world health organization, the coordinating authority for international public health established by the united nations in . one important outcome of this study was the development of a new metric, the disabilityadjusted life year, which allows assessment of the effect of disease not only on lifespan but also on health span. in essence, a life can be shortened not only by death but also by chronic disability. figure demonstrates that in , communicable diseases such as respiratory infections remained the most common global cause of death and chronic ill health. however, projections by this study suggest that by ischemic heart disease will have become the number disease entity, nearly doubling in less than years. health losses from cancer are also projected to nearly double over the same time frame. economic development carries with it the consequences of an aging population and the hazards of smoking and high fat, high calorie diets. economic progress in the developing world has been accompanied by the replacement of the traditional diet rich in fruit and vegetables by a diet rich in calories provided by animal fats and lower in complex carbohydrates. it has been reflected in a rapid rise of urban obesity. when i first started visiting china in the early s, there were no obese children. there was only one heavy person at our hospital and that was the cook, who determined that i was going to look like her by the end of our visit with a wonderful diet of dumplings. however, the prevalence of obesity in urban children in china aged to years has increased from . % in to . % in . cooking in the developing world has been altered by the availability of microwave ovens and cheap prepared meals with high fat and caloric content. in the united states, the fast food industry spent billion dollars on television advertising in the year . in the same year, the national cancer institute's " a day" program, which encourages the consumption of fruits and vegetables to prevent cancer and other diseases, spent million dollars. there is a tendency to focus any discussion of the aging of the general population of the united states on the baby boom generation, the population bulge that will reach in just years in . however, the situation is significantly compounded by the dramatic increase in life expectancy that has occurred over the past years (figure ). in the year , americans enjoyed a life expectancy of almost years. one hundred years ago life expectancy was close to years. today, individuals who reach age can anticipate a life expectancy of for men and for women. and for those who live to age , the top two causes of death are heart disease and cancer, followed by stroke, emphysema, and pneumonia. all these conditions share a common risk factor: tobacco. trends in the use of tobacco will have important implications for the burden of cardiovascular and thoracic disease that we will face in the coming years. although tobacco use in the developed world is declining slowly by about . %/year, tobacco use in the developing world is rising at nearly . %/year ( figure ) . , today there are more than billion smokers around the globe with numbers projected to rise by more than % in the next years. and although the large american and british tobacco multinational companies take much of the blame for the rapid current expansion of smoking in the developing world, the fact is that china is overwhelmingly the largest producer of tobacco, producing % of the world's cigarettes in contrast to % produced by the united states. in fact, china and its state-run tobacco monopoly produce more tobacco than the next largest producers combined. how will these changing global demographics and practices affect the disease entities most relevant to cardiothoracic surgeons? it is no news to this audience that lung cancer, particularly in american women, has already reached epidemic proportions. between and the death rate from lung cancer among american women increased times. in , there were , more deaths from lung cancer than from breast cancer among women (figure ). unfortunately, efforts to reduce smoking rates have been less successful with women than with men. outside the united states, women are responding to aggressive targeted marketing and joining the ranks of smokers every day. in japan, smoking among women has doubled over a recent -year period from % to %. the dramatic declines in death rates from heart attack and stroke in the united states over the past years have lulled us into a state of complacency and blinded us to a storm that is gathering just over the horizon. the convergence of risk factors, particularly obesity, diabetes, and physical inactivity in the united states and tobacco use, dietary changes, and increased life expectancy globally without question will result in a substantial increase in the global burden of cardiovascular disease. despite regional variations in environmental factors and genetic makeup, the incidence of congenital heart disease around the world remains consistently at approximately . % of live births, thereby making it the most common major congenital abnormality. despite predictions that improved ultrasound methods for fetal diagnosis would result in increased rates of pregnancy termination, the reality is that within the united states and most developed countries fetal diagnosis has not had a large impact on the incidence of congenital heart disease. widespread use of echocardiography, in fact, has resulted in earlier and more complete diagnosis of salvageable heart problems in children. earlier recognition of congenital heart disease is eliminating the scourge of pulmonary vascular obstructive disease, which is making surgery available for a much greater percentage of the world's children with congenital heart disease than in the past. and the cumulative population of adults with congenital heart disease is also increasing the workload for many congenital heart programs. perhaps ultimately an improved understanding of the genetic basis of congenital heart disease will eliminate the specialty entirely, but at this point such an eventuality remains beyond the horizon. how will an increased global burden of cardiovascular disease and cancer affect the manpower needs of our specialty? there is no international organization that has the resources to estimate the total number of cardiothoracic surgical procedures that will be performed globally in , , and years. the world health organization has enough on its plate attempting to define, for example, the risks of a global pandemic of avian flu virus. the question is further complicated by wide disparities in the rates of cardiothoracic surgical procedures performed in various countries as documented by dr jim cox in his presidential address to this association in . in there were open heart surgical procedures per million population in the united states. the only country that approached that level was australia, with procedures per million. and while the rate of per million, which was measured before the impact of coated coronary stents, represents a high-water mark that may never be matched again, it is also clear that many countries in the survey were dramatically underserved. this is an additional factor needed for accurate estimation of the coming expansion of global cardiothoracic services (figure ). let us now examine some of the barriers that inhibit appropriate global distribution of cardiothoracic surgeons, the matching of supply and demand. one of the important efficiencies that is introduced by economic globalization is a rationalization of the distribution of goods and services through elimination of trade barriers. obviously, it would make little sense for each of the states of the united states to be totally self-sufficient and responsible for its own food supply. likewise, we would consider it absurd that surgeons trained in massachusetts could only ever practice within the state of massachusetts. the problem of appropriate matching of supply and demand becomes particularly challenging as a service sector becomes increasingly subspecialized, such as is the case for cardiothoracic surgery. within congenital cardiac surgery, the problem of matching supply and demand on a global scale has resulted in an interesting distribution of surgeons around the planet, often working in locations that are quite remote from their institution of training. my move halfway around the world is not unusual in our subspecialty of congenital cardiac surgery. for example, dr christian brizard from paris, france, is the director of the congenital heart surgical program in melbourne, australia. but as i can personally testify, individuals who have made such moves have done so only with the greatest difficulty because of many bureaucratic barriers related to specialty certification and visas. surely within our tiny subspecialty, which comprises perhaps only in the united states and i would guess no more than dedicated congenital cardiac surgeons globally, it would make sense to establish a system of global certification that would facilitate the movement of congenital heart surgeons from areas of contracting to expanding need. toward this end, the aats council has recently agreed to support my initiative to legally incorporate a global council for the development of educational standards for congenital cardiac surgical training. this is a first step in a process of international certification of congenital cardiac surgeons. and ultimately it is a step that i believe will make sense for the other subspecialty areas within cardiothoracic surgery. what are the implications of a global mismatch of cardiothoracic surgical supply and demand for surgical training programs in the united states? from the perspective of recent graduates of cardiothoracic surgical training programs, we are currently in a state of labor oversupply. we are faced with a drastic reduction in applicants to train to be cardiothoracic surgeons. however, as demand for cardiothoracic services begins to rise in the united states in the near future, and as the supply of graduating surgeons begins to fall in exactly the same time frame, it is quite likely that there will be a considerable undersupply of surgeons in approximately to years. it is important that the extensive us training system that is currently in place not be dismantled because it will soon be needed. and that same system could play a helpful role in supplementing the education of the many surgeons who are already needed in countries like india and china, where demand is already expanding rapidly. however, right now there are considerable visa and licensing challenges for cardiothoracic surgical trainees to come to the united states. surely we in the united states should be welcoming foreign medical graduates who will have plenty of opportunities in their home country when they complete their fellowship. the educational council for foreign medical graduates must expand the sponsoring of non-accreditation council for graduate medical education accredited fellows for j visas, which should be facilitated rather than discouraged by the immigration and naturalization service and us embassies abroad. what implications does globalization have for the personal financial outlook for cardiothoracic surgeons? how will an expanded pool of cardiothoracic surgeons globally affect your hip pocket? according to the economist william baumol, who has formulated the so-called baumol law, service occupations such as medicine, nursing, and surgery are inherently inflationary because they are labor intensive. for society as a whole, a source of increased economic wealth over time is the substitution of capital for labor. this is the very definition of rising productivity. the surgeon who performed procedures in and procedures in expects his real income to at least match the rise in the cost of living. however, since his productivity is unchanged and his real income has increased, he has contributed to inflation. but will an increasing pool of surgeons globally trained and certified to step into any position that becomes available result in falling compensation for surgeons. i believe there is a consensus among the economists that i have read that this is not likely to be the case. in a globalizing world, skills matter more than ever. , while the wages and benefits of unskilled us steel and auto workers are falling toward global norms, in general americans with high skills in contrast are being increasingly highly compensated. globalization allows highly skilled americans and others to offer those skills to the entire world rather than just locally. furthermore, skilled workers in high income nations are paid not just on the basis of their productivity but also on the basis of local living costs and social norms of fairness. americans prize health care greatly and many citizens today will aggressively search out the best health care. as economic conditions improve in second and third world countries, health is likely to become increasingly highly valued, and this will be reflected in the compensation that various societies globally will be prepared to pay for the best in health care. although globalization offers the global cardiothoracic community the potential for generous rewards, there are also important risks and responsibilities that we should be aware of, both as physicians and as human beings. beginning in the s, the international monetary fund and world bank began to rigorously apply "structural adjustment programs" as a condition of supplying loans to developing countries. the basis for the structural adjustment programs is the "washington consensus," appropriately named because there is little doubt that the united states is two of the requirements of the structural adjustment programs promulgated by the international monetary fund and world bank have been reduction of public expenditure and privatization of state enterprises, including public health departments. however, a process of privatization requires strong government regulation as the world bank itself has pointed out. there may also be a minimum population below which such policies are ineffective or even counterproductive. , many smaller countries, such as jamaica, for example, have experienced a deterioration in health care delivery as they were forced to make a decision between taking international loans and continuing governmentfunded public health clinics. there has also been a strong response to the trips agreement, which is now enforced by the world trade organization. trips refers to trade-related aspects of intellectual property rights, which protects pharmaceutical patents for a period of years. the trips agreement, which has led to a substantial increase in the cost of pharmaceuticals as generic equivalents have been eliminated, has become a lightning rod that has united those who believe that the economic benefits of globalization are not being shared equally. in , developing countries paid a combined billion dollars in debt service while receiving only billion in new loans. even individuals from within the world bank, such as nobel prize winner joseph stiglitz, who was chief economist at the bank between and , have argued that current policies of globalization have un-fairly benefited the wealthy nations while making only the most miniscule gains for the poorest nations. although it is true that the number of individuals around the world living on less than $ per day has decreased, the number living on less than $ per day has substantially increased. in other words, current policy has simply taken the excruciatingly poor and made them painfully poor. in contrast, t h e most wealthy third of countries have benefited from tremendous economic expansion over the years between and ( figure ). stiglitz and others would argue that these diverging lines begin to answer the question being asked in the developed world with increasing frequency in recent years: "where does this global unrest come from?" ladies and gentleman, thank you for your attention this morning. thank you for coming to the annual scientific meeting of the american association for thoracic surgery. thank you for coming to the great city of philadelphia, which this year is celebrating the th anniversary of the birth of one of the great founding fathers of this nation, born in boston but living most of his life in philadelphia. benjamin franklin (figure ) was a quintessential american, not only a scientific innovator but also a great business entrepreneur. but in addition, franklin was a globalist. he spent many years living in london and subsequently in paris, where he played a critical role in international diplomacy. and at age , back in philadelphia, benjamin franklin assisted thomas jefferson in writing that great document, the declaration of independence, which as we all know begins: "we hold these truths to be self-evident, that all men are created equal, that they are endowed by their creator with certain unalienable rights, that among these are life, liberty and the pursuit of happiness." as cardiothoracic surgeons, we would all do well to emulate franklin's energy, innovation, and entrepreneurial spirit. and as human beings, we have a responsibility to strive for a reasonable and equitable distribution of the benefits of globalization for all. in defense of globalization why globalization works evidence-based health policy-lessons from the global burden of disease study health politics: power, populism and health globalization and health globalization: a very short introduction presidential address: changing boundaries everything for sale: the virtues and limits of markets the lexus and the olive tree: understanding globalization betrayal of trust: the collapse of global public health health policy in a globalizing world life in debt. a film by stephanie glack. usa. . available from www globalization and its discontents alternatives to economic globalization: a better world is possible the americanization of benjamin franklin key: cord- -lp i o authors: sofat, reecha; cremers, serge; ferner, r.e. title: drug and therapeutics committees as guardians of safe and rational medicines use date: - - journal: br j clin pharmacol doi: . /bcp. sha: doc_id: cord_uid: lp i o nan secondly, the bnf gives information on guidance from the national institute for health and care excellence (nice), but only after the guidance has been formulated. this can take months or years from the time a medicine is licensed. yet, and for clear reasons, pharmaceutical companies are likely to encourage early adoption of novel agents. this explains in part, for example, the very large numbers of patients exposed to rofecoxib (vioxx) in the years from licensing to withdrawal. the time has passed when every practitioner was free to practice medicine in whatever way he or she chose. some unlicensed or offlabel prescribing is supported by strong evidence of efficacy or at least by wide adoption. someone, though, has to sanction the use of medicines outside their licensed indications. for paediatric practice, the bnf for children (bnf-c) covers much of the likely unlicensed prescribing, from acetazolamide ("not licensed for the treatment of glaucoma") to zolmitriptan ("not licensed for use in children"). for off-label or unlicensed use of medicines outside the recommendations of bnf and bnf-c, health care organizations and practitioners are at risk unless the reasons for use are logical and the appropriate safeguards are in place. pharmaceutical companies owe a duty to their shareholders to make profits. they do this by selling medicines that are already licensed and by undertaking research on novel drugs. it is uncertain whether companies spend more on research than on marketing. it is clear that substantial sums are spent on marketing: $ m on medical marketing in , which rose to $ m in . marketing is not always constrained by ethics or self-regulation: between and , there were cases of off-label promotion in the united kingdom, and companies were ruled in breach of the relevant regulation at least once. it is also clear that prescribers are influenced by such marketing. a study in the united states found that "gifts from doi: . /bcp. wileyonlinelibrary.com/journal/bcp pharmaceutical companies are associated with more prescriptions per patient, more costly prescriptions, and a higher proportion of branded prescriptions with variation across specialties. gifts of any size had an effect and larger gifts elicited a larger impact on prescribing behaviors." the favoured solution to the problems outlined above is to control prescribing in the local environment through a committee, variously called a medicines committee, a drug and therapeutics committee, a prescribing and medicines committee, or something similar. the committee's role may vary from one health care organization to another. briefly, the committee would concern itself with the rules and regulations governing the use of drugs in its organization, publish a list of permitted medicines based on efficacy, safety, tolerability and cost, consider any restrictions on their use, and supervise the addition and removal of medicines from the list. [ ] [ ] [ ] when it comes to new or off-label medicines, the committee can help protect patients from poorly founded claims for new medicines, and the organization from the financial burden of a medicine with only marginal benefits but substantially higher costs. an additional task is to guide the judicious use of drugs locally through extensions to the committee's main roles, for example, through antibiotic stewardship, management of demand for intravenous immunoglobulin, and oversight of the switch from originators to biosimilars. the role of formulary committees is evolving. bodies such as nice in the united kingdom now evaluate the evidence for new treatments and make judgements of cost-effectiveness at a national level. nice guidelines influence, and its technology appraisals mandate, the adoption of recommended treatments in both primary and secondary health care. this relieves local committees of the duty to judge medicines considered in a technology appraisal. regional medicines optimisation committees (rmoc), established in england and wales in , aim to provide a single strategic medicines optimization system for england, taking on many of the tasks that currently fall to local formulary committees; this aim has not yet been realized, although the process is still in evolution. local committees have adapted to these changes but continue to face their own substantial challenges. the early access to medicines evidence of efficacy is often lacking, yet access to a medicine can falsely raise expectations; secondly, data on outcomes are not systematically collected, so that information that would help to assess the true value of a drug is lost; and thirdly, the cost of giving early access and potential market share to some drugs is recouped by the pharmaceutical industry after the drug is licensed and the nhs pays the cost. high-cost drugs with little or no evidence on safety or efficacy pose similar problems. individual funding requests made to nhs authorities for exceptional patients who do not fit into a standard evidence-based cohort are often denied. trials on such small groups of individuals will not be possible, but grouped in an observational setting, large treatment effects can inform clinical decisions, and if data are appropriately harnessed with ethical approval, they can also begin to inform the biology of rare and refractory diseases. formulary committees with an allied research arm could then have an enhanced datagathering role embedded into routine care, working effectively as an nhs network for both drug discovery and repurposing, with shorter implementation times. the role of the drug and therapeutics committee continues to evolve. now nice has been established for years, the committee has been largely relieved of the burden of making complex assessments of the effectiveness and cost-effectiveness of newly licensed drugs; regional medicines optimization committees may also remove some of the decisions from local committees. however, there are continued and evolving challenges to ensuring the safe, effective, and cost-effective use of medicines within a single health care facility, and the drug and therapeutics committee needs to continue and to evolve to meet them. clinical pharmacologists have specific knowledge and skills to guide rational therapeutics and improve patient care. as a result, they commonly participate in committees responsible for overseeing the use of medicines in health care organizations, often called drugs and therapeutics committees (dtcs) in the united kingdom and pharmacy and therapeutics committees in the united states. this editorial describes some important aspects of dtcs and how a changing landscape creates both challenges and opportunities. it introduces a bjcp series called "drugs and therapeutics committees" to allow clinical pharmacologists and those participating in dtcs to share data and practices on how best to contribute to dtcs and to adapt to the changing landscape. we encourage contributions from all over the globe so that we can learn and share good practice. we hope to publish articles on topics such as the management of high-cost drugs and how this is applied to individual funding requests; how dtcs manage off-label use of drugs; the relationship between the dtc and the pharmaceutical industry; and how to manage n-of- studies. the first contribution to the series describes an approach to the successful introduction of biosimilars. merck withdraws arthritis drug worldwide pharmaceutical company spending on research and development and promotion in canada pharmaceutical industry off-label promotion and self-regulation: a document analysis of off-label promotion rulings by the united kingdom prescription medicines code of practice authority - influence of pharmaceutical marketing on medicare prescriptions in the district of columbia medical marketing in the united states the hospital formulary system- . l. pharmacy and therapeutics committee, consent and the hospital formulary local formularies the roles of clinical pharmacologists in formulating medicines policy locally we are very grateful to our colleagues past and present who have contributed to our understanding of the work of the drug and therapeutics committee. r.s. is funded by the uclh national institute of health research biomedical research centre. we welcome the submission of original studies or reviews, related to dtcs as part of the series. key: cord- - q ftnd authors: jombart, t; eggo, r m; dodd, p j; balloux, f title: reconstructing disease outbreaks from genetic data: a graph approach date: - - journal: heredity doi: . /hdy. . sha: doc_id: cord_uid: q ftnd epidemiology and public health planning will increasingly rely on the analysis of genetic sequence data. in particular, genetic data coupled with dates and locations of sampled isolates can be used to reconstruct the spatiotemporal dynamics of pathogens during outbreaks. thus far, phylogenetic methods have been used to tackle this issue. although these approaches have proved useful for informing on the spread of pathogens, they do not aim at directly reconstructing the underlying transmission tree. instead, phylogenetic models infer most recent common ancestors between pairs of isolates, which can be inadequate for densely sampled recent outbreaks, where the sample includes ancestral and descendent isolates. in this paper, we introduce a novel method based on a graph approach to reconstruct transmission trees directly from genetic data. using simulated data, we show that our approach can efficiently reconstruct genealogies of isolates in situations where classical phylogenetic approaches fail to do so. we then illustrate our method by analyzing data from the early stages of the swine-origin a/h n influenza pandemic. using isolates sequenced at both the hemagglutinin and neuraminidase genes, we reconstruct the likely history of the worldwide spread of this new influenza strain. the presented methodology opens new perspectives for the analysis of genetic data in the context of disease outbreaks. the most effective strategy to avert infectious disease epidemics is to identify outbreaks at an early stage and identify their transmission routes. for example, wider spread of nosocomial bacteria could be best avoided by rapid identification of colonized medical personnel spreading the infection (albrich and harbarth, ) . early identification of preferential transmission routes could also prove critical for containing wider epidemics, such as sars or avian influenza (cooper et al., ; ferguson et al., ; germann et al., ) . to be most effective, such prophylactic interventions must be implemented early on and will be based on only very preliminary scientific evidence. thus, it is crucial that all sources of useful information be considered. genetic sequence data can now be generated essentially in real time and the analysis of sequence data has already been added to the toolbox of infectious disease epidemiology (rambaut et al., ; russell et al., ; cottam et al., b; garten et al., ; sloan et al., ) . however, the statistical methodologies to harness the full potential of genetic sequence information are currently lacking. in particular there is a need for methods devoted to the reconstruction of the transmission tree of a set of isolates collected during the early stages of an outbreak. current state-of-the-art genetic methods for the reconstruction of pathogen genealogies rely on the phylogenetic paradigm (grenfell et al., ; templeton, ; drummond and rambaut, ; cottam et al., a; lemey et al., a) based on the reconstruction of ancestries between hypothetical common ancestors (most recent common ancestor) and sampled isolates. unfortunately, such approaches may be inappropriate when ancestors and their descendents are both present in the sample analyzed, as is likely during the early stages of an outbreak. phylogenetic methods consider that sampled strains are all tips of an unknown genealogy, making it impossible for a sampled strain to be (directly or indirectly) ancestral to another sampled strain. by definition, these methods are thus unable to uncover ancestries between sampled isolates, and can fail to reconstruct the transmission tree of an emerging pathogen (figures a-c) . to circumvent this problem, we introduce a new methodological approach for the analysis of genetic data collected during disease outbreaks. contrary to phylogenetic methods, we consider that sampled isolates represent a fraction of the genealogy, including internal nodes and tips (figure d ). direct and indirect ancestries can therefore be inferred between the sampled isolates. within this framework, we developed an algorithm called seqtrack, which directly reconstructs the most plausible genealogy of a set of sampled isolates, allowing for a direct assessment of the spatiotemporal dynamics of the epidemic under study. using simple simulations, we illustrate the major difference between phylogenetic methods and our approach, showing the advantage of seqtrack over traditional phylogenetic approaches for inferring transmission trees in densely sampled disease outbreaks. we then evaluate the performance of our method using spatially explicit simulations of outbreaks. finally, we illustrate the novel methodology using sequence data from the early stages of the a/h n influenza pandemic, and reconstruct the likely scenario of worldwide spread of this newly emerged pathogen. seqtrack algorithm our method aims to reconstruct the transmission tree of pathogens during a disease outbreak, using genotypes and collection dates to uncover ancestries between sampled isolates. the fundamental innovation of our approach is to seek ancestors directly from the sampled isolates, rather than attempting to reconstruct unobserved and hypothetical ancestral genotypes. because ancestries are in essence temporally oriented connections between isolates, it seemed natural to tackle the problem of inferring genealogies within graph theory. seqtrack relies on three fundamental, yet simple observations. first, in the absence of genetic recombination, each observed isolate has one, and only one ancestor. second, ancestors always precede their descendents in time. and third, among all possible ancestries of a given isolate, some are more likely than others, and this likelihood can be inferred from the amount of genetic differentiation between the isolates considered. the purpose of seqtrack is to identify the most likely genealogy. technically, this problem translates into finding the optimum branching in a directed graph, where each node is an isolate, and where a given isolate is connected to all isolates occurring strictly later. let g ¼ (s, e, w) be a directed, weighted graph where s ¼ {s ,y, s n } is the set of vertices corresponding to the n sampled isolates, with associated collection dates t ¼ {t ,y, t n }. e is the set of directed edges of g modeling all possible ancestries in s, such that (s i , s j )a e if and only if t i ot j . the weight function w: e-r assigns a weight to each possible ancestry, which reflects how credible each ancestry relationship is. for instance, w could be defined as a genetic distance or similarity, or as the log-likelihood resulting from a probabilistic model of evolution. the weight of a subset a of e is computed as w a ¼ p e a wðeÞ. the 'best' genealogy of the sampled isolates is the spanning directed tree (that is, 'branching' reaching all the nodes) j ¼ (s,b,w) with bde optimizing (that is, minimizing or maximizing) w b . whenever sampled isolates form more than one connected set, the algorithm is applied to each connected set separately (see example in figure b ). this problem has been solved by edmonds ( ) and chu and liu ( ) , who developed an algorithm to find j so that w b is maximum or minimum. the algorithm proceeds by identifying optimum ancestors for each node at the exception of the root (the oldest isolate), and then recursively removes possible cycles. however, in our case, cycles are impossible as ancestries cannot go back in time, which greatly simplifies computations. the entire seqtrack procedure has been implemented in the adegenet package (jombart, ) for the r software (r development core team, ). this implementation allows for specifying any weight w i and for choosing the type of optimization (minimization or maximization of total weight) to take advantage of the method's versatility. maximum parsimony genealogies using seqtrack outbreak genetic data are typically characterized by low genetic diversity, implying that descendents differ from their ancestors by very few mutations. when recombination and reverse mutations are unlikely, the most plausible genealogy is the one involving the fewest mutational steps. such maximum parsimony genealogies can be recovered by seqtrack by weighting edges according to the number of mutations between pairs of isolates, and seeking the branching of minimum weight. the resulting ancestry path connects all the sampled isolates while minimizing the required number of mutational steps, and respecting their temporal ordering. given the low levels of genetic diversity expected during the early stages of disease outbreaks, isolates with identical haplotypes but different collection dates and figure illustration of possible reconstructions of genealogical relations. panel a represents a hypothetical genealogy of six isolates from which three were sampled (highlighted by a blue glow and numbered from to ). panels b and c illustrate phylogenetic reconstructions where the red dots represent inferred nodes; panel b corresponds to a classical phylogenetic reconstruction and c to a tree that accounts for heterochronous sampling (e.g., beast software; drummond and rambaut, ) . panel d illustrates the direct ancestry reconstruction method implemented in seqtrack. locations are likely to occur, resulting in several possible choices for the most parsimonious ancestry. in such cases, seqtrack can use an optional rule to select the 'best' ancestor, and select the closest ancestor according to a given proximity measure. for instance, this approach can be used to select, among all equally parsimonious ancestors, the one being geographically closest. another possibility would consist in favoring ancestors whose haplotype is most frequent in the sampled isolates. by default, seqtrack resolves ties in the choice of ancestors by maximizing the likelihood of the genetic differentiation observed between the ancestor and the descendent. the number of mutations n occurring between two isolates sampled d t time units apart follows a poisson distribution: where l and m are, respectively, the length (in number of nucleotides) and the mutation rate (per nucleotide and per time unit) of the considered dna sequence. note that this likelihood can also be used to assess the statistical support of each ancestry, as we do in figure . individual-based simulations were used to assess the efficacy of our method for reconstructing transmission trees from outbreak genetic data. all simulations were performed using the r software, and procedures that we implemented in the adegenet package. the simulation system is further described in supplementary information. we first used simulations to compare seqtrack to classical phylogenetic reconstruction. because the outputs of both approaches are very different (phylogenies do not provide ancestries between tips), we could not proceed to systematic comparisons over a large number of data sets. however, while not quantitative, the comparisons we performed can be used to show the fundamental differences between both approaches. we simulated two simple genealogies of isolates, using haplotypes of nucleotides and a mutation rate of À mutation per nucleotide and generation, over three and four generations, respectively (figures a and a ). in the second data set (figure ) , only a portion of the genealogy was sampled, so as to show the behaviors of the methods for inferring ancestries with unsampled ancestors. note that the two data sets were chosen randomly, and the results were qualitatively similar in all other simulations we examined. seqtrack was used to obtain maximum parsimony genealogies (figures b and b) . a classical phylogeny was obtained by neighbor-joining using pairwise nucleotidic distances between sampled isolates (figures c and c) . to give the neighbor-joining phylogenetic trees the right direction, trees were rooted using the most ancient isolate sampled. we also analyzed these data using temporally informed phylogenetic reconstruction as implemented in the beast software (drummond and rambaut, ; figures d and d) . we used the exponential growth model with strict molecular clock model, keeping other parameters to their default settings. a consensus phylogeny was computed on the last simulated trees. simulations were also used for a quantitative assessment of seqtrack's performances. data sets were obtained reconstructing disease outbreaks t jombart et al by simulating genealogies of haplotypes evolving stochastically in time and space. a detailed description of these simulations, along with scripts allowing to reproduce them, are provided in supplementary information. two types of simulations, differing in the process governing the spatial spread of the isolates, were performed. the first scheme allowed isolates to disperse on a  spatial grid according to a random poisson process, with identical probabilities to move in all directions (supplementary figure s ). this scheme is later referred to as 'homogeneous diffusion'. the second type of simulations used stochastic dispersal based on predefined connectivity between locations, in which we specified the probabilities of migration between every pair of locations. this allowed us to recreate a spatial dynamic of 'sources' and 'sinks' with some locations seeding many other locations, including distant ones, and other locations attracting migration but hardly seeding other places (supplementary figure s ) . this type of simulation is later referred to as 'heterogeneous dispersal'. for each simulation scheme (homogeneous and heterogeneous dispersal), genealogies of isolates simulated over generations were obtained. ten random samples of isolates were then drawn from the genealogies, yielding data sets that were analyzed. simulations and analyses were performed on the computer cluster of the centre de calcul de l'institut national de physique nucléaire et de physique des particules (ccin p ; http://cc.in p .fr/). genetic data were used to infer the spatiotemporal spread of the early stages of the swine-origin influenza a/h n pandemic. we analyzed all isolates typed for both hemagglutinin (ha) and neuraminidase (na) genes available from genbank (benson et al., ; http://www.ncbi.nlm.nih.gov/genbank/index.html) as of august . genetic sequences and their annotation (including sampling dates and locations) were retrieved and processed using ad hoc scripts in the r language. we only retained isolates for which collection date and location were available. influenza viruses are routinely amplified by serial passaging through cell cultures or chicken eggs before sequencing. duplicate sequences have been submitted for some isolates that were multiply amplified, sometimes resulting in slightly different sequences for the same isolate. in these cases, significantly shorter sequences were discarded, as well as sequences obtained from amplification in eggs because this method is known to induce additional 'artificial' mutations (bush et al., ) . the alignment of all retained sequences was realized using clustalw (larkin et al., ) and refined by hand using jalview (waterhouse et al., ) . ha and na segments were concatenated after verifying that analyses run with either segment yielded similar results (results not shown). the final alignment contained sequences of nucleotides, with collection dates ranging from march to july . accession numbers, alignments, dates and locations of the isolates analyzed are provided in supplementary information. raw pairwise genetic distances (in number of differing nucleotides) were computed using the r package ape (paradis et al., ) . substitution rates for the ha and na segments were based on earlier work by smith et al. ( ) . note that the analyses presented in this paper are largely insensitive to the substitution rate, as this information is only used for the resolution of ties between genetically equally likely ancestors sampled at different dates. flight data were used to assess the role of air traffic in the dispersal of the pathogen. passenger flows between countries were compiled from a list of all commercial flights that occurred between may and april , purchased from oag (http://www.oag.com/). numbers of passengers between countries were then correlated to the number of inferred transmissions, and tested using standard pearson correlation. simulation results showed fundamental differences between the seqtrack algorithm and classical phylogenetic reconstruction (figures and ) . in two randomly chosen examples, seqtrack reconstructed very satisfyingly the transmission tree of the isolates (figures b and b ). when all isolates were sampled, the method perfectly identified the transmission tree ( figure b ). however, results remained very satisfying in the incompletely sampled genealogy (figure b ), in which seqtrack correctly inferred the most recent sampled ancestors, and therefore true branches of the transmission tree. in contrast, phylogenetic trees could hardly be used to draw inferences about the underlying genealogies (figures c and c) . indeed, the phylogenetic trees were not a good match to the transmission tree, and contained some oddities such as several identical internal nodes for a single polytomy (figures c and c ). even when considering tips with zero branch length as internal nodes, the resulting inferred ancestries were largely erroneous. results obtained by beast were somewhat more satisfying, as the tips were ordered according to the sampling time. however, beast failed to identify any of the direct ancestries present in the simulated data set (figures d and d) . further simulations were used to assess quantitatively the performance of our method at uncovering ancestries from genetic outbreak data. most satisfyingly, our results indicated that the true ancestral haplotype was successfully retrieved in % of cases on average throughout all simulations (ci % ¼ [ . - . %]; figure ). the correct location of the ancestor was also inferred in a majority of cases, although more frequently under source and sink dynamics than under homogeneous dispersal ( and %, respectively; t ¼ . , df ¼ , p ¼ .  À ; figure ). having tested the ability of the method at reconstructing transmission trees from outbreak genetic data, we used seqtrack to infer the spatiotemporal dynamics of the early stage of the swine-origin a/h n influenza pandemic. the data set analyzed consisted of nearcomplete ha and na sequences collected between march and july . although no sequences are available for the first confirmed cases (la gloria, february; fraser et al., ) , the time window defined by the collection dates extends from the early stages of the outbreak to the global pandemic, which was officially declared by the who on june . in figure , we present snapshots of the spatiotemporal dynamics of the pandemic reconstructed by seqtrack. overall, most inferred ancestries displayed very few mutations between ancestor and descendent (supplementary figure s ) , suggesting that the actual ancestral haplotype had often been sampled, and was correctly identified by the method. the inferred scenario of the early stages of the pandemic can be split into three main acts: ( ) initial spread in mexico and the united states (figure a ), ( ) sustained transmission within north america and spread to the rest of the world (figure b) and ( ) further worldwide spread and secondary outbreaks outside the americas (figure c ). for a day-by-day reconstruction of the pandemic, see supplementary movie s and supplementary information. details of inferred ancestries are provided in supplementary table s . the initial stage ending around the april is characterized by numerous transmissions from mexico to the united states, as well as some local transmissions within mexico and the united states (figure a ). the fact that two mexican isolates trace their ancestry back to the united states was inescapable as the oldest sequences present in the data set were all sampled in the united states. however, most ancestries of early us isolates point to a mexican origin (figure a ), which gives further support for the a/h n pandemic having originated in mexico. the second stage (ending around may) is characterized by the spread of the virus within north america, with several local transmissions (dots and sunflowers on figure b and supplementary movie s ), indicating the existence of secondary outbreaks and the likely establishment of the pathogen in several cities in the united states and canada. during the same time period, mexico and the united states also started seeding the rest of the world (figure b ). it is worth noting that the first case of within-country transmission outside the americas (france on may, figure b , supplementary movie s ) is observed remarkably early after the spread of the new influenza strain within the united states. in the third and last stage, we observe a considerable number of transmissions inferred from the americas to the rest of the world, alongside with transmissions between countries outside the americas (figure c ). local transmissions with a high statistical support point to multiple secondary outbreaks occurring in several countries, which likely reflect the worldwide establishment of the new influenza strain as a global pandemic. flight traffic is widely recognized as an important determinant for the spread of seasonal and pandemic influenza at large geographic scales (cooper et al., ; ferguson et al., ; germann et al., ; viboud et al., ; wu et al., ) . thus, we evaluated the relationship between air travel passenger-flow and the number of transmissions between countries inferred by seqtrack. both quantities were fairly correlated (r ¼ . ; t-test: t ¼ . ; df ¼ ; p ¼ .  À ), although this correlation was largely driven by the high connectivity of the united states with mexico and canada. we have introduced a new methodological approach called seqtrack for the analysis of genetic data sampled during disease outbreaks. using simulated data, we showed the originality of this method compared to classical phylogenetic reconstruction, and its ability to infer correct genealogies of isolates in densely sampled disease outbreaks. the reconstruction of transmission trees from genetic data has recently received considerable attention (gonzalez-candelas et al., ; hue et al., ; cottam et al., a; cottam et al., b; harris et al., ) . all previous applications we are aware of have been based on the reconstruction of most recent common ancestors. although this body of work has been fairly successful, the simulations presented in this paper suggest that our method outperforms phylogenetic approaches for the reconstruction of transmission trees in intensively sampled disease outbreaks. even when taking temporal information into account, phylogenetic reconstruction seems unable to infer filiations between sampled isolates. this statement does not amount to a criticism of phylogenetics but simply reflects the fact that transmission trees and phylogenies are actually different entities. as such, transmission trees are likely to be inferred more successfully by a dedicated approach. our method is also not meant to supersede phylogenetic approaches but rather to complement them. although seqtrack is better suited for reconstructing the transmission tree during early outbreaks, it does not include some useful features of modern phylogenetic tools, such as the possibility to infer underlying population dynamics parameters. we illustrated our method with a reconstruction of a plausible scenario for the spatiotemporal spread of the a/h n influenza strain during the early stages of the influenza pandemic. this data set might not be ideal for showing the full potential of the new methodology, which may be best suited for the reconstruction of transmission trees in more localized settings. nonetheless, the results suggest that seqtrack can contribute to a better understanding of the spatiotemporal dynamics of emerging pathogens, even at a worldwide scale. the results are largely in line with the general epidemiological understanding of the spatiotemporal spread of the a/h n pandemic. we also recover individual reconstructing disease outbreaks t jombart et al ancestries that seem sensible and correlate with human flight data. it is not entirely straightforward to compare our reconstruction with previous phylogenetic work based on sequence data from the a/h n influenza pandemic (fraser et al., ; parks et al., ; rambaut and holmes ; smith et al., ; lemey et al., b) . these authors used a smaller set of isolates and did not specifically aim to reconstruct the spatiotemporal dynamics with the exception of lemey et al ( b) , who analyzed isolates sequenced for the ha and na genes. they also recovered a strong connection between mexico and texas and multiple instances of transmissions from the united states and canada to outside the americas. in contrast to their results, we infer a larger proportion of direct transmissions from north america to other continents. for instance, although we infer several direct transmissions from north america to china, their reconstruction points to china being only indirectly connected to the united states through either russia, europe or south america. seqtrack is a very versatile approach that allows for weighting the plausibility of individual ancestries in various ways. in this study, we used a maximum parsimony version of the method because the origin of a/h n influenza virus is sufficiently recent for homoplasies (recombination or back mutations) to be very unlikely, and safely ignored. nonetheless, seqtrack genealogies could be optimized on other criteria, such as genetic distances or log-likelihoods based on complex models of sequence evolution. another possible extension of this method relates to the use of heterogeneous genetic information, which occurs when the regions of the genome sequenced vary across isolates. such heterogeneity is likely to occur as soon as the sequencing effort is undertaken independently by a large number of labs, as was the case during the early stage of the a/h n influenza pandemic. as a result, sequence data of the new influenza strain consisted of essentially random combinations of segments, ranging from small fragments of specific genes to whole genomes. in such cases, the analysis of homologous sequences results in a possibly considerable loss of information. this issue could be overcome by averaging genetic differentiation across available segments, using appropriate weights to account for different substitution rates and segment lengths. however, including a large fraction of isolates with heterogeneous sequencing coverage would require accurate estimates of substitution rates, which can be difficult to obtain for emerging pathogens. some other developments would require more effort. in particular, it would be desirable to consider the various parameters of the model from a probabilistic perspective. for instance, the date of probable transmission could be better captured by a distribution of the time during which a specific sequence remains unaltered rather than a fixed collection date for the isolate. moreover, a probabilistic framework would also allow incorporation of information besides genetic sequences and collection dates, such as prevalence data or spatial connectivity between locations. a final possible extension of seqtrack relates to the inference of unsampled ancestral isolates. although phylogenetic methods assume that no isolate in the sample is (directly or indirectly) ancestral to another one, our method considers that ancestries can be inferred between the sampled isolates. in practice, however, the ancestral population of a given isolate may not have been sampled. in such cases, seqtrack is likely to identify the most recent sampled ancestor of the isolate as a substitute for the unsampled direct ancestor (figures d, b, and b) . in other words, the algorithm is likely to retrieve an actual branch of the transmission tree by overlooking unsampled intermediate nodes. the possibility of inferring unobserved intermediate nodes based on a probabilistic model for sequence evolution and spatial dispersal (lemey et al., a) would represent an additional significant improvement in the present approach. understanding the underlying factors behind the spread of diseases is one of the core objectives of infectious disease epidemiology. by reconstructing the transmission tree of an outbreak, our method creates new opportunities for testing how various features of the connectivity between hosts shape transmission patterns. for instance, despite limited genetic information available for the early stage of the swine-origin a/h n influenza pandemic, we observed a positive association between flight traffic and the routes of transmissions inferred by seqtrack, in line with previous works on both seasonal and pandemic influenza (brownstein et al., ; cooper et al., ; ferguson et al., ; germann et al., ; viboud et al., ; fraser et al., ) . the versatility of the presented methodology makes it applicable over a wide range of scales, from localized outbreaks of a nosocomial infection within a hospital to the global spread of a newly emerged pathogen. in not requiring extensive genetic polymorphism, the method should prove effective in bacteria and fungi, in addition to viruses. we hope that the performance of the method, together with its wide applicability, flexibility and computational speed will convince infectious disease epidemiologists to adopt it as an integral part of the toolkit for infectious disease outbreak analysis. health-care workers: source, vector, or victim of mrsa? empirical evidence for the effect of airline travel on inter-regional influenza spread in the united states effects of passage history and sampling bias on phylogenetic reconstruction of human influenza a evolution on the shortest arborescence of a directed graph delaying the international spread of pandemic influenza integrating genetic and epidemiological data to determine transmission pathways of footand-mouth disease virus transmission pathways of foot-andmouth disease virus in the united kingdom beast: bayesian evolutionary analysis by sampling trees optimum branchings strategies for mitigating an influenza pandemic pandemic potential of a strain of influenza a (h n ): early findings antigenic and genetic characteristics of swineorigin a(h n ) influenza viruses circulating in humans mitigation strategies for pandemic influenza in the united states molecular epidemiology and forensic genetics: application to a hepatitis c virus transmission event at a hemodialysis unit unifying the epidemiological and evolutionary dynamics of pathogens evolution of mrsa during hospital transmission and intercontinental spread genetic analysis reveals the complex structure of hiv- transmission within defined risk groups adegenet: a r package for the multivariate analysis of genetic markers clustal w and clustal x version . reconstructing the initial global spread of a human influenza pandemic: a bayesian spatial-temporal model for the global spread of h n pdm bayesian phylogeography finds its roots ape: analyses of phylogenetics and evolution in r language tracking the evolution and geographic spread of influenza a r: a language and environment for statistical computing. r foundation for statistical computing the early molecular epidemiology of the swine-origin a/h n human influenza pandemic the genomic and epidemiological dynamics of human influenza a virus the global circulation of seasonal influenza a (h n ) viruses ecogeographic genetic epidemiology origins and evolutionary genomics of the swine-origin h n influenza a epidemic nested clade analyses of phylogeographic data: testing hypotheses about gene flow and population history synchrony, waves, and spatial hierarchies in the spread of influenza jalview version -a multiple sequence alignment editor and analysis workbench hedging against antiviral resistance during the next influenza pandemic using small stockpiles of an alternative chemotherapy we are most grateful to all our colleagues who sequenced isolates from the influenza a/h n pandemic and made them publicly available. we feel particularly indebted toward nancy cox, mark greenway, naomi komadina, andreas nitsche, john pasick, tomas pumarola and pilaipan puthavathana for their willingness to provide additional information on sequences they submitted on genbank. we address many thanks to vicente acuñ a for providing insights about graph theory, and to vincent daubin for interesting discussions. we are thankful to simon penel and the centre de calcul de l'institut national de physique nucléaire et de physique des particules (ccin p , http://cc.in p .fr/) for providing access to the computer resources used to run and analyze simulations. we finally thank three anonymous reviewers whose comments allowed us to greatly improve the paper. the authors declare no conflict of interest. key: cord- -t ffey authors: chen, jing; nie, xiaoyan; yao, peng; shi, luwen title: trips-plus and access to medicines in china date: - - journal: j public health policy doi: . /jphp. . sha: doc_id: cord_uid: t ffey ample evidence shows that trade-related aspects of intellectual property rights (trips)-plus provisions have seriously affected access to and availability of drugs in the developing countries. in recent years, developed countries have pressured many developing countries to implement trips with stronger intellectual property (ip) protection than required by the trips agreement. the stronger provisions are called trips-plus provisions. this article focuses on ip and the health implications of limited access to medicines in china, explores the trips-plus arrangements in chinese ip laws and regulations, and makes suggestions for china's negotiation strategy in resisting pressure from developed countries to tighten ip laws and regulations. in recent years, high-income countries have been arguing for stronger (trips-plus) provisions in intellectual property (ip) protection as part of bilateral, regional, and multilateral negotiations. trade-related aspects of intellectual property rights (trips) is a world trade organization (wto) multilateral agreement that established minimum global standards for ip protection. trips-plus refers to provisions that either exceed the requirements of trips or eliminate flexibilities in implementing trips. some studies , forecast that trips-plus would result in: delayed entry of generics into developing countries; significant price increases, and reduced access to medicines, thus posing serious threats to public health. china faces great pressure to tighten ip provisions, with a potential for negative health impact on the population of . billion. projections show china's population greater than years old increasing from per cent of the total population in to more than per cent of the total population by . the incidence and prevalence of chronic diseases are increasing substantially and non-communicable conditions -diabetes, heart disease, and cancer -are expensive to treat. estimates for to indicate china will have lost us$ billionalmost one per cent of gross domestic product (gdp) -as a result of heart disease, strokes, and diabetes. the hiv/aids epidemic also challenges china, with an estimated hiv infected people at the end of , of whom have progressed to aids. in , there were an estimated new hiv infections. government data released in show hiv/aids was the leading cause of death from communicable diseases. patent protection of hiv/aids drugs has impeded availability. china also has the greatest burdens of hepatitis b and liver cancer in the world. a national survey found an hbsag carrier rate of . per cent in the total population, indicating that more than one-third of the world's hepatitis b virus (hbv) carriers lived in china. control of infectious diseases remains a major problem in china, creating a great need for medicines at affordable prices. even with rapid economic development, china's healthcare expenditures remain relatively low at per cent of gdp compared with an average of . per cent in the member countries of the organization of economic cooperation and development (oecd). with per cent of the world's population, china accounts for less than per cent of the global drug market. payment for pharmaceuticals constitutes nearly per cent of china's total healthcare expenditures, a sharp contrast to the average of per cent in countries belonging to oecd. in , a new round of healthcare reform in china sought to lower pharmaceutical expenditures while increasing affordability of drugs. despite expansion of medical insurance coverage after , patients' co-payments remain very high. government financial contributions to total health expenditures had increased from . per cent in to . per cent in . the percentage of total health expenditure paid by individuals also increased, from . per cent in to . per cent in , peaking at per cent in . high out-of-pocket payments expose individuals to the risk of catastrophic expenditure, which in affected . per cent of households. according to china's national healthcare service survey, . per cent of patients who needed hospitalization did not get it; . per cent of these did not enter hospitals for financial reasons. patents keep medicine prices sufficiently high that unaffordability constitutes the main barrier to availability in china today. three recent case studies [ ] [ ] [ ] illustrate the severity of the problem: medicine prices, particularly for brand named drugs, remain significantly higher than international reference prices published at the management sciences for health website (http://www.msh.org/resource-center/international-drugprice-indicator-guide.cfm). although the government has taken many steps to reduce drug prices, results are not optimal. drug expenditures in hospitals increased rapidly even after implementation of price controls. the average annual per hospital drug expenditure in china's general hospitals tripled from f . million in to f . million in ($ . ¼ f . ). the chinese government has allowed doctors and hospitals a per cent profit margin on drug sales. as doctors' incomes are greatly influenced by profits from drugs they have prescribed, they tend to aggravate the problem by prescribing more expensive drugs. hiv/aids-related problems are most prominent as government sponsored treatment programmes (free to patients) have been hindered by an inadequate drug supply. as china has provided patent protection for drugs since , most antiretroviral (arvs) drugs are protected. glaxosmithkline's (gsk) patent exclusivity on lamivudine ( tc), for example, makes it unaffordable in china, at $ per patient per year. with increasing burdens of non-communicable diseases in many developing countries, increasing the availability of affordable cancer drugs is a key challenge. china has more than million new cancer cases every year; the numbers are growing and cancer is now the leading cause of death. some cancer drugs are available only in branded versions with patent protection and at high prices. average per patient expenditures on gleevic (imatinib mesylate), a relatively new drug for several cancers (that has turned chronic myelogenous leukaemia, previously deadly, into a chronic disease), amounts to about f per month in china. a generic version in india (without patents or royalties) costs about f per month per patient. although the chinese pharmaceutical industry has been growing rapidly for a few decades, it is still small and lacks product innovation. most of china's approximately drug companies focus on manufacturing generic drugs. in , the state food and drug administration of china (sfda) approved domestic drug registration applications, including for generic drugs ( per cent). on average, research and development (r&d) spending of chinese pharmaceutical companies accounts for only per cent of sales revenue, much less than the - per cent of leading global pharmaceutical companies. ip protection is by no means the only barrier to availability of medicines in china, but it does prohibit production and marketing of generics. although the chinese government has devoted substantial effort to enacting ip protection laws and regulations, critics decry the lack of effective law enforcement. in , the united states sued china at the who for ip infringement. for years, the office of the us trade representative and multinational pharmaceutical companies pressed demands on the chinese government for stronger pharmaceutical ip protection. therefore, china added trips-plus provisions within its ip laws and updated its drug regulatory framework. on march , china enacted the patent law -its first -but excluded pharmaceuticals from patent protection. after threats of sanctions by the united states, china signed a memorandum of understanding on the protection of intellectual property with the united states agreeing to strengthen ip protection. the first amendment ( ) added pharmaceuticals as patentable subject matter and increased the patent term for inventions from to years (from the date of filing an application). trips required developing countries to extend patents to pharmaceuticals before . the chinese patent law amendment provided -year patent protection on pharmaceuticals even before the introduction of trips to the wto ( ). india did not implement pharmaceutical protection until , thus china has been more protective of ip, even as its own pharmaceutical industry has lagged. india has many more pharmaceutical patents, drug master files (dmfs) that are submissions to the united states fda, and plants in the united states than does china. a higher standard of patent protection could result in losses for pharmaceutical industries in developing countries; china has lost public health advantage as compared with india -higher drug prices, lower drug availability, and underdeveloped domestic innovation capacity. six years of data exclusivity . data exclusivity refers to protection of clinical test data that must be submitted to a regulatory agency to prove the safety and efficacy of a new drug, and prevents generic drug manufacturers from relying on these data in their own applications. this protection term is longer than that set out in trips and in bilateral free trade agreements signed by the united states and other nations. although protection of 'undisclosed data' against 'unfair commercial use' for years is enshrined in china's law, there is a divergence of opinions between china and developed countries about certain key concepts such as 'new chemical entities' and 'unfair commercial use'. in china, the definition of 'new drug' is broader than nces, and the chinese government has agreed only to protect undisclosed data of class new drugs, those not marketed in china and abroad. the united states and eu want higher standards of data exclusivity; to expand the interpretation of 'new chemical entities'; and to redefine 'undisclosed data', so that the protection can cover class new drugs (those that are marketed outside of china but not within). new estimates suggest that data exclusivity will increase china's health expenditure by . per cent on average per year from to , while reducing the accessibility to types of medicines by . per cent -a great negative impact on public health in china. policy makers should further investigate the potential impact of data exclusivity on the public health and on access to medicines. patent linkage is the practice of linking marketing approval for generic medicines to the patent status of the original product. the united states first established this system in drug price competition and patent term restoration act (known as the hatch-waxman act, ). patent linkage in the united states involves publication of patent information in the usdaf (the united states food and drug administration) publication, 'orange book', which notifies a patent holder of any generic medicine application. there is then an automatic stay of drug registration approval, and any patent challenge incentive. in china, articles and of the drug registration regulation ( ) set a foundation for patent linkage. for filing a registration application, drug administration authorities require the manufacturer to declare that the drug does not infringe any third-party patent. amendments to china's drug registration regulation in add that a patentee may, on the basis of an infringement judgment, request that the sfda revoke an approved drug registration. patent linkage in the united states has no post-registration revocation rules. for years the sfda and chinese courts have been in conflict over post-registration revocation. the intricacy of patent disputes and lack of legal basis for sfda's revocation led to amendments to drug registration regulation in . these deleted a provision related to sfda's revocation of registration of an approved drug on the basis of an infringement judgment. since , sfda has been posting patent related information from applications, including generic applicants' assertions of non-infringement, on an accessible website. such publication served as a notice, even though chinese patent linkage regulation does not require the sfda or the drug applicant to notify the patent holder of these guarantees. although chinese linkage regulations do not provide an automatic stay period, the threat of infringement litigation delays the entry of generic drugs. pfizer's viagra patent dispute strongly illustrates this: sfda withheld approval of generics based on patent disputes. china's patent linkage system can neither reduce infringement litigation nor the risks of infringement. increasing criticism focuses on patent linkage, that it has exceeded the scope of the sfda's competence. compulsory license and parallel import why has no compulsory license been issued in china? causes are many: low profits for generic drugs, few channels for appeals by patients, and government caution about trade frictions. in , the not-for-profit hepatitis community and the hiv/aids community in china jointly published a letter appealing to the government to issue a compulsory license for gsk's antiviral drug, lamivudine. in , baiyunshan pharmaceutical co. ltd submitted an application for compulsory licensing of genetech's tamiflu. china refused to grant such licenses in order to prove the government's determination to protect the rights of patent holders. a third amendment to the patent law ( ) might change this situation. this amendment grants a compulsory license for patented pharmaceuticals in china public health purposes, no longer limited to for the treatment of infectious diseases. it applies to products made in china as well as exports to qualified countries. it theoretically opens up a broad range of pharmaceutical therapies to compulsory licensing. the new patent law mentions compulsory license to specify the applicability. it may signal the beginning of compulsory licenses. parallel importation is another flexibility that helps developing and least-developed countries have access to less costly drugs. parallel importation generally allows countries where drugs are more expensive to import lower cost drugs from another country. before the revision of the patent law, chinese laws did not address the issue of parallel importation, mainly because prices were low. article of the new patent law ( ) provides for domestic and international exhaustion of patent rights and for parallel importation of the patented products without the patentee's consent, thereby ending the debate over the legitimacy of parallel importation. the new patent law does not clarify how exhaustion will apply to imported products sold outside of china under contractual restrictions. new issues will require judicial interpretation. we expect the relevant departments to clarify implementation of parallel importation, as it can be another important tool to improve access to medicines in china. china is strengthening enforcement of ip rights, but as in other developing countries, many challenges remain for establishing an ip system and for meeting demands of developed countries. for years, china has been on the priority watch list (special report) that identifies countries with insufficient ip protection. the united states has brought a complaint to the wto dispute settlement mechanism over china's ip protection measures. for years, developed countries have shifted their focus to ip enforcement and advocated trips-plus enforcement measures: increased criminalization, higher damages, intermediary liability, and border protection. proponents of trips-plus ip enforcement have also sought to expand the definition of counterfeit products. the term 'counterfeit' has been used in many different ways resulting in confusion about the meaning of the term. correa has observed that the debates about counterfeiting, especially those related to medicines, 'are often obscured by inappropriate use of the concept of "counterfeiting" or piracy to describe situations in which legitimate generic versions of medicines are introduced without the consent of the originator of the drug'. the term 'counterfeit' in china includes a range of pharmaceutical quality and safety problems. most developing countries, including china, have argued that infringing on ip rights should not be confused with sub-standard products. they have expressed concern about redefining 'counterfeit' medicines in a way that will impede access to affordable pharmaceuticals. although china has not yet signed bilateral ftas (free trade agreements) with the united states or the eu, in recent years, pressure from the international community has grown. the watch list designation trips-plus and access to medicines in china (by the united states) and grievances (by the eu) have been directed at china's insufficient implementation and enforcement of national ip legislation. the complaints mention specific articles of the amendment and suggestions for extending patent protection terms on pharmaceutical products. trips-plus obligations go far beyond those imposed by the wto. they may delay entry of generics into the market, increase medicine prices, reduce the accessibility of medicines, and thus threaten public health in china. 'generics' are crucial for the health reforms announced by the chinese government in april . k allowing a compulsory license under some special circumstances, perhaps during a data protection term. k allowing for exceptions for public health emergencies or when duplicating test data would be unethical. k confirming the bolar provision, a research exemption that allows applications for marketing approval even during the period of data exclusivity. patent-registration linkage is a new and relatively complex concept for china, which lacks expertise for implementation. many developed countries including those in the eu have avoided creating a patent linkage mechanism. the us-style patent linkage provisions may provide excessive protection for foreign medicine patents, encourage 'evergreen' patents through repeated small modifications to extend patent term, and delay entry of generic drugs. caution is called for when introducing us-style linkage system. the following principles should be applied: k carry out examination and registration of drugs separately, away from the influence of patent disputes. private patent rights that depend on the owner's desire to enforce should not be transformed into public rights for enforcement by regulatory authorities. k promote transparent and open examination and approval information and procedures. sfda could list all drug applications on its website for the patent holders to track information and bring a timely infringement action. k strengthen the judicial remedies for patent infringement, particularly in response to the patent holder's use of judicial channels. china should emphasize judicial procedures, intensify punishments upon patent infringements, and increase violation costs for patent infringements. extending the life of a drug's patent reinforces monopoly. the hatch-waxman act is a complex regulatory regime that balances fostering innovation with accelerating generics entry. with no generics promotion policy in china, the country is vulnerable to excessive protection for research-based pharmaceutical companies. the sfda has already accelerated the drug approval process and released special drug registration rules to speed the registration for genuinely innovative drugs. china should reject proposals to extend patent terms. the doha declaration affirms the right of all wto members to use the safeguards and flexibilities in trips to protect public health and enhance access to medicines. key factors determining the success of trips flexibilities include their incorporation in domestic laws, manufacturing capability, and the political will. china has lacked the will to issue any compulsory license. thus, patients suffer for lack of generic versions of some important drugs, including those for hiv/aids that appear on the who 'essential drug list', as most arv drugs retain patent protection in china and remain unaffordable. compulsory licenses, even if not issued, can offer leverage to reduce prices to 'acceptable' levels. china's large generic drug manufacturing capacity strengthens its bargaining position -as does its enormous population. the chinese government should encourage and support local generic drug companies to enhance their r&d and manufacturing capabilities. as indian arv drugs cost less in china than those now available, the government can use parallel importation when generics cost less than drugs already available in china. evidence indicating negative impact of trips-plus rules on public health and access to medicines abounds. their impact is potentially grave, as china has a large market for generic drugs and lacks adequate basic health services for the poor. the chinese government, therefore, will have to resist trips-plus pressure and make full use of the trips flexibility to protect the public's health. beyond avoiding 'negative' trade agreements with other countries, it could be helpful for china to form positive relationships with countries, including india and brazil, to promote affordable medicines. although ip laws and policies affect access to medicines, there are a number of other approaches to improve accessrefashioning pharmaceutical innovation, increasing sustained financing, and promoting the appropriate use of medicines. trips was never enough: vertical forum shifting, ftas, acta, and tpp all cost no benefit: how trips-plus intellectual property rules in the us-jordan fta affect access to medicines impact on access to medicines from trips-plus: a case study of thai-us fta population division, desa, united nations global status report on noncommunicable diseases the estimation of hiv/aids in china in statistics report on epidemic situation of legal communicable diseases in china in management of hepatitis b in china ministry of health of china. ( ) china health statistical yearbook oecd health data -frequently requested data growth of the asian health-care market: global implications for the pharmaceutical industry a generic drug policy as cornerstone to essential medicines in china. washington dc: the world bank trends in access to health services and financial protection in china between and : a cross-sectional study trips-plus and access to medicines in china the fourth national health services survey a survey of medicine prices, availability, affordability and price components in shandong province a survey of medicine prices, availability and affordability in shanghai medicine prices, availability and affordability survey in shaanxi province technology development through pooling arv drug patents: a vision from china untangling the web of antiretroviral price reductions: th edition responses from hu yuanqiong, china access to medicines research group. speech to informal interactive hearings of the general assembly with non-governmental organizations, civil society organizations and the private sector yearbook of statistics annual report on drug registration approval chinese pharmaceutical enterprises association is product patent protection necessary in developing countries for innovation? higher standards of patent protection and pharmaceutical industry -a comparative study on china and india impact of medical data protection on drug expenditure and accessibility in china fighting poison with poison? the chinese experience with pharmaceutical patent linkage solving patent problem in the registration and approval of drugs the global debate on the enforcement of intellectual property rights and developing countries linkage' pharmaceutical evergreening in canada and australia china-arv access fact sheet key: cord- - v brjf authors: nicholson, felicity title: infectious diseases: the role of the forensic physician date: journal: clinical forensic medicine doi: . / - - - : sha: doc_id: cord_uid: v brjf infections have plagued doctors for centuries, in both the diagnosis of the specific diseases and the identification and subsequent management of the causative agents. there is a constant need for information as new organisms emerge, existing ones develop resistance to current drugs or vaccines, and changes in epidemiology and prevalence occur. in the st century, obtaining this information has never been more important. population migration and the relatively low cost of flying means that unfamiliar infectious diseases may be brought into industrialized countries. an example of this was an outbreak of severe acute respiratory syndrome (sars), which was first recognized in . despite modern technology and a huge input of money, it took months for the agent to be identified, a diagnostic test to be produced, and a strategy for disease reporting and isolation to be established. there is no doubt that other new and fascinating diseases will continue to emerge. infections have plagued doctors for centuries, in both the diagnosis of the specific diseases and the identification and subsequent management of the causative agents. there is a constant need for information as new organisms emerge, existing ones develop resistance to current drugs or vaccines, and changes in epidemiology and prevalence occur. in the st century, obtaining this information has never been more important. population migration and the relatively low cost of flying means that unfamiliar infectious diseases may be brought into industrialized countries. an example of this was an outbreak of severe acute respiratory syndrome (sars), which was first recognized in . despite modern technology and a huge input of money, it took months for the agent to be identified, a diagnostic test to be produced, and a strategy for disease reporting and isolation to be established. there is no doubt that other new and fascinating diseases will continue to emerge. for the forensic physician, dealing with infections presents two main problems. the first problem is managing detainees or police personnel who have contracted a disease and may be infectious or unwell. the second problem is handling assault victims, including police officers, who have potentially been exposed to an infectious disease. the latter can be distressing for those involved, compounded, in part, from an inconsistency of management guidelines, if indeed they exist. with the advent of human rights legislation, increasing pressure is being placed on doctors regarding consent and confidentiality of the detainee. therefore, it is prudent to preempt such situations before the consultation begins by obtaining either written or verbal consent from the detainee to allow certain pieces of information to be disclosed. if the detainee does not agree, then the doctor must decide whether withholding relevant details will endanger the lives or health of those working within custody or others with whom they may have had close contact (whether or not deliberate). consent and confidentiality issues are discussed in detail in chapter . adopting a universal approach with all detainees will decrease the risk to staff of acquiring such diseases and will help to stop unnecessary overreaction and unjustified disclosure of sensitive information. for violent or sexual assault victims, a more open-minded approach is needed (see also chapter ) . if the assailant is known, then it may be possible to make an informed assessment of the risk of certain diseases by ascertaining his or her lifestyle. however, if the assailant is unknown, then it is wise to assume the worst. this chapter highlights the most common infections encountered by the forensic physician. it dispels "urban myths" and provides a sensible approach for achieving effective management. the risk of exposure to infections, particularly blood-borne viruses (bbvs), can be minimized by adopting measures that are considered good practice in the united kingdom, the united states, and australia ( ) ( ) ( ) . forensic physicians or other health care professionals should wash their hands before and after contact with each detainee or victim. police officers should be encouraged to wash their hands after exposure to body fluids or excreta. all staff should wear gloves when exposure to body fluids, mucous membranes, or nonintact skin is likely. gloves should also be worn when cleaning up body fluids or handling clinical waste, including contaminated laundry. single-use gloves should only be used and must conform to the requirements of european standard or equivalent ( ) ( ) ( ) . a synthetic alternative conforming to the same standards should also be available for those who are allergic to latex. all staff should cover any fresh wounds (< hours old), open skin lesions, or breaks in exposed skin with a waterproof dressing. gloves cannot prevent percutaneous injury but may reduce the chance of acquiring a bloodborne viral infection by limiting the volume of blood inoculated. gloves should only be worn when taking blood, providing this does not reduce manual dexterity and therefore increase the risk of accidental percutaneous injury. ideally, a designated person should be allocated to ensure that the clinical room is kept clean and that sharps containers and clinical waste bags are removed regularly. clinical waste must be disposed of in hazard bags and should never be overfilled. after use, the clinical waste should be doublebagged and sealed with hazard tape. the bags should be placed in a designated waste disposal (preferably outside the building) and removed by a professional company. when cells are contaminated with body fluids, a professional cleaning company should be called to attend as soon as possible. until such time, the cell should be deemed "out of action." there is a legal requirement in the united kingdom under the environmental protection act ( ) and the control of substances hazardous to health regulations to dispose of sharps in an approved container. in the united states, the division of health care quality promotion on the centers for disease control and prevention (cdc) web site provides similar guidance. in custody, where sharps containers are transported off site, they must be of an approved type. in the united kingdom, such a requirement is contained within the carriage of dangerous goods (classification, packaging and labelling) and use of transportable pressure receptacles regulations . these measures help to minimize the risk of accidental injury. further precautions include wearing gloves when handling sharps and never bending, breaking, or resheathing needles before disposal. sharps bins should never be overfilled, left on the floor, or placed above the eye level of the smallest member of staff. any bedding that is visibly stained with body fluids should be handled with gloves. there are only three acceptable ways of dealing with contaminated bedding: the bbvs that present the most cross-infection hazard to staff or victims are those associated with persistent viral replication and viremia. these include hbv, hcv, hepatitis d virus (hdv), and hiv. in general, risks of transmission of bbvs arise from the possible exposure to blood or other body fluids. the degree of risk varies with the virus concerned and is discussed under the relevant sections. figure illustrates the immediate management after a percutaneous injury, mucocutaneous exposure, or exposure through contamination of fresh cuts or breaks in the skin. hbv is endemic throughout the world, with populations showing a varying degree of prevalence. approximately two thousand million people have been infected with hbv, with more than million having chronic infection. worldwide, hbv kills about million people each year. with the development of a safe and effective vaccine in , the world health organization (who) recommended that hbv vaccine should be incorporated into national immunization programs by in those countries with a chronic infection rate of % or higher, and into all countries by . although countries had achieved this goal by the end of , the poorest countries-often the ones with the highest prevalence-have been unable to afford it. in particular these include china, the indian subcontinent, and sub-saharan africa. people in the early stages of infection or with chronic carrier status (defined by persistence of hepatitis b surface antigen [hbsag] beyond mo) can transmit infection. in the united kindgom, the overall prevalence of chronic hbv is approx . - . % ( , ) . a detailed breakdown is shown in table . the incubation period is approx weeks to months. as the name suggests, the virus primarily affects the liver. typical symptoms include malaise, anorexia, nausea, mild fever, and abdominal discomfort and may last from days to weeks before the insidious onset of jaundice. joint pain and skin rashes may also occur as a result of immune complex formation. infections in the newborn are usually asymptomatic. * in the united kingdom, written consent from the contact must be sent with the sample, countersigned by the health care practitioner and, preferably, an independent police officer. the majority of patients with acute hbv make a full recovery and develop immunity. after acute infection, approx in patients develop liver failure, which may result in death. chronic infection develops in approx % of neonates, approx % of children, and between and % of adults. neonates and children are usually asymptomatic. adults may have only mild symptoms or may also be asymptomatic. approximately - % of chronically infected individuals (depending on age of acquisition) will develop cirrhosis over a number of years. this may also result in liver failure or other serious complications, including hepatocellular carcinoma, though the latter is rare. the overall mortality rate of hbv is estimated at less than %. a person is deemed infectious if hbsag is detected in the blood. in the acute phase of the illness, this can be as long as months. by definition, if hbsag persists after this time, then the person is deemed a carrier. carriers are usually infectious for life. the degree of infectivity depends on the stage of disease and the markers present table . the major routes include parenteral (e.g., needlestick injuries, bites, unscreened blood transfusions, tattooing, acupuncture, and dental procedures where equipment is inadequately sterilized), mucous membrane exposure (including mouth, eyes, and genital mucous membranes), and contamination of broken skin (especially when < hours old). hbv is an occupational hazard for anyone who may come into contact with blood or bloodstained body fluids through the routes described. saliva alone may transmit hbv. the saliva of some people infected with hbv contains hbv-dna concentrations / - / , of that found in their serum ( ) . this is especially relevant for penetrating bite wounds. infection after exposure to other body fluids (e.g., bile, urine, feces, and cerebrospinal fluid) has never been demonstrated unless the fluids are contaminated with blood. intravenous drug users who share needles or other equipment are also at risk. hbv can also be transmitted through unprotected sexual contact, whether homosexual or heterosexual. the risk is increased if blood is involved. sexual assault victims should be included in this category. evidence has shown that the virus may also be spread among members of a family through close household contact, such as through kissing and sharing toothbrushes, razors, bath towels, etc. ( ) ( ) ( ) . this route of transmission probably applies to institutionalized patients, but there are no available data. studies of prisoners in western countries have shown a higher prevalence of antibodies to hbv and other bbvs than the general population ( ) ( ) ( ) ; the most commonly reported risk factor is intravenous drug use. however, the real frequency of transmission of bbvs in british prisons is unknown owing to the difficulty in compiling reliable data. hbv can be transmitted vertically from mother to baby during the perinatal period. approximately % of babies born to mothers who have either acute or chronic hbv become infected, and most will develop chronic hbv. this has been limited by the administration of hbv vaccine to the neonate. in industrialized countries, all prenatal mothers are screened for hbv. vaccine is given to the neonate ideally within the first hours of birth and at least two more doses are given at designated intervals. the who recommends this as a matter of course for all women in countries where prevalence is high. however, the practicalities of administering a vaccine that has to be stored at the correct temperature in places with limited access to medical care means that there is a significant failure of vaccine uptake and response. in industrialized countries, hbv vaccination is recommended for those who are deemed at risk of acquiring the disease. they include the following: . through occupational exposure. . homosexual/bisexual men. . intravenous drug users. . sexual partners of people with acute or chronic hbv. . family members of people with acute or chronic hbv. . newborn babies whose mothers are infected with hbv. if the mother is hbsag positive, then hepatitis b-specific immunoglobulin (hbig) should be given at the same time as the first dose of vaccine. . institutionalized patients and prisoners. ideally, hbv vaccine should be administered before exposure to the virus. the routine schedule consists of three doses of the vaccine given at , , and months. antibody levels should be checked - weeks after the last dose. if titers are greater than miu/ml, then an adequate response has been achieved. in the united kingdom, this is considered to provide protection for - years. in the united states, if an initial adequate response has been achieved, then no further doses of vaccine are considered necessary. vaccine administration after exposure varies according to the timing of the incident, the degree of risk involved, and whether the individual has already been partly or fully vaccinated. an accelerated schedule when the third dose is given months after the first dose with a booster year later is used to prevent postnatal transmission. where risks are greatest, it may be necessary to use a rapid schedule. the doses are given at , , and - days after presentation, again with a booster dose at - months. this schedule is currently only licensed with engerix b. hbig may also be used either alone or in conjunction with vaccine. the exact dose given is age dependent but must be administered by deep intramuscular injection in a different site from the vaccine. in an adult, this is usually into the gluteus muscle. hbig is given in conjunction with the first dose of vaccine to individuals who are deemed at high risk of acquiring disease and the incident occurred within hours of presentation. it is also used for neonates born to mothers who are hbeag-positive. between and % of adults fail to respond to the routine schedule of vaccine. a further full course of vaccine should be tried before deeming the patients as "nonresponders." such individuals involved in a high-risk exposure should be given two doses of hbig administered mo apart. ideally, the first dose should be given within hours after exposure and no later than weeks after exposure. other measures include minimizing the risk of exposure by adopting the safe working practices outlined in subheading . any potential exposures should be dealt with as soon as possible. in industrialized countries blood, blood products, and organs are routinely screened for hbv. intravenous drug users should be encouraged to be vaccinated and to avoid sharing needles or any other drug paraphernalia (see subheading . . .). for staff or victims in contact with disease, it is wise to have a procedure in place for immediate management and risk evaluation. an example is shown in fig. . although forensic physicians are not expected to administer treatment, it is often helpful to inform persons concerned what to expect. tables and outline treatment protocols as used in the united kingdom. detainees with disease can usually be managed in custody. if the detainee is bleeding, then the cell should be deemed out of action after the detainee has left until it can be professionally cleaned. contaminated bedding should be dealt with as described in subheading . . if the detainee has chronic hbv and is on an antiviral agent (e.g., lamivudine), then the treatment course should be continued, if possible. hcv is endemic in most parts of the world. approximately % ( million) of the world's population is infected with hcv ( ) . for many countries, no reliable prevalence data exist. seroprevalence studies conducted among blood donors have shown that the highest prevalence exists in egypt ( - %). this has been ascribed to contaminated needles used in the treatment of schistosomiasis conducted between the s and the s ( ) . intermediate prevalence ( - %) exists in eastern europe, the mediterranean, the middle east, the indian subcontinent, and parts of africa and asia. in western europe, most of central america, australia, and limited regions in africa, including south africa, the prevalence is low ( . - . %). previously, america was included in the low prevalence group, but a report published in ( ) indicated that almost million americans (i.e., . % of the population) have antibody to hcv, representing either ongoing or previous infection. it also states that hcv accounts for approx % of acute viral hepatitis in america. the lowest prevalence ( . - . %) has been found in the united kingdom and scandinavia. however, within any country, there are certain groups that have a higher chance of carrying hcv. these united kingdom figures are given in table . after an incubation period of - weeks, the acute phase of the disease lasts approx - years. unlike hepatitis a (hav) or hbv, the patient is usually asymptomatic; therefore, the disease is often missed unless the individual has reported a specific exposure and is being monitored. other cases are found by chance, when raised liver enzymes are found on a routine blood test. a "silent phase" follows the acute phase when the virus lies dormant and the liver enzymes are usually normal. this period lasts approx - years. reactivation may then occur. subsequent viral replication damages the hepatocytes, and liver enzymes rise to moderate or high levels. eighty percent of individuals who are hcv antibody-positive are infectious, regardless of the levels of their liver enzymes. approximately % of people develop chronic infection, one-fifth of whom progress to cirrhosis. there is a much stronger association with hepatocellular carcinoma than with hbv. an estimated . - . % of patients with hcv-related cirrhosis develop liver cancer ( ) . less than % of chronic cases resolve spontaneously. approximately % of cases are parenteral (e.g., needle-stick, etc.) ( ) . transmission through the sexual route is not common and only appears to be significant if there is repeated exposure with one or more people infected with hcv. mother-to-baby transmission is considered to be uncommon but has been reported ( ) . theoretically, household spread is also possible through sharing contaminated toothbrushes or razors. because the disease is often silent, there is a need to raise awareness among the general population on how to avoid infection and to encourage high-risk groups to be tested. health care professionals should also be educated to avoid occupationally acquired infection. an example of good practice blood or blood-stained body fluids need to be involved for a risk to occur. saliva alone is not deemed to be a risk. the risk from a single needlestick incident is . % (range - %). contact through a contaminated cut is estimated at %. for penetrating bite injuries, there are no data, but it is only considered a risk if blood is involved. blood or blood-stained body fluids have to be involved in transmission through mucous membrane exposure. this may account for the lower-than-expected prevalence among the gay population. follow the immediate management flow chart, making sure all available information is obtained. inform the designated hospital and/or specialist as soon as possible. if the contact is known and is believed to be immunocompromised and he or she has consented to provide a blood sample, it is important to tell the specialist, because the antibody tests may be spuriously negative. in this instance, a different test should be used (polymerase chain reaction [pcr] , which detects viral rna). the staff member/victim will be asked to provide a baseline sample of blood with further samples at - weeks and again at weeks. if tests are negative at weeks but the risk was deemed high, then follow-up may continue for up to weeks. if any of the follow-up samples is positive, then the original baseline sample will be tested to ascertain whether the infection was acquired through the particular exposure. it is important to emphasize the need for prompt initial attendance and continued monitoring, because treatment is now available. a combination of ribavirin (antiviral agent and interferon a- b) ( ) or the newer pegylated interferons ( ) may be used. this treatment is most effective when it is started early in the course of infection. unless they are severely ill, detainees can be managed in custody. special precautions are only required if they are bleeding. custody staff should wear gloves if contact with blood is likely. contaminated bedding should be handled appropriately, and the cell cleaned professionally after use. this defective transmissible virus was discovered in and requires hbv for its own replication. it has a worldwide distribution in association with hbv, with approx million people infected. the prevalence of hdv is higher in southern italy, the middle east, and parts of africa and south america, occurring in more than % of hbv carriers who are asymptomatic and more than % of those with chronic hbv-related liver disease. despite the high prevalence of hbv in china and south east asia, hdv in these countries is rare. hdv is associated with acute (coinfection) and chronic hepatitis (superinfection) and can exacerbate pre-existing liver damage caused by hbv. the routes of transmission and at-risk groups are the same as for hbv. staff/victims in contact with a putative exposure and detainees with disease should be managed as for hbv. interferon-α (e.g., roferon) can be used to treat patients with chronic hbv and hdv ( ) , although it would not be practical to continue this treatment in the custodial setting. hiv was first identified in , years after the first reports were made to the cdc in atlanta, ga, of an increased incidence of two unusual diseases (kaposi's sarcoma and pneumocystis carinii pneumonia) occurring among the gay population in san francisco. the scale of the virus gradually emerged over the years and by the end of , there were an estimated million people throughout the world living with hiv or acquired immunodeficiency syndrome (aids). more than % of the world's population lives in africa and india. a report by the joint united nations programme on hiv/aids and the who in stated that one in five adults in lesotho, malawi, mozambique, swaziland, zambia, and zimbabwe has hiv or aids. there is also expected to be a sharp rise in cases of hiv in china, papua new guinea, and other countries in asia and the pacific during the next few years. in the united kingdom, by the end of , the cumulative data reported that there were , individuals with hiv, aids (including deaths from aids) reported, though this is likely to be an underestimate ( ) . from these data, the group still considered at greatest risk of acquiring hiv in the united kingdom is homosexual/bisexual men, with , of the cumulative total falling into this category. among intravenous drug users, the overall estimated prevalence is %, but in london the figure is higher at . % ( , ) . in the s, up to % of users in edinburgh and dundee were reported to be hiv positive, but the majority have now died. individuals arriving from africa or the indian subcontinent must also be deemed a risk group because % of the world's total cases occur in these areas. the predominant mode of transmission is through unprotected heterosexual intercourse. the incidence of mother-to-baby transmission has been estimated at % in europe and approx % in africa. the transmission rates among african women are believed to be much higher owing to a combination of more women with end-stage disease with a higher viral load and concomitant placental infection, which renders it more permeable to the virus ( , ) . the use of antiretroviral therapy during pregnancy, together with the advice to avoid breastfeeding, has proven efficacious in reducing both vertical and horizontal transmission among hiv-positive women in the western world. for those in third-world countries, the reality is stark. access to treatment is limited, and there is no realistic substitute for breast milk, which provides a valuable source of antibodies to other life-threatening infections. patients receiving blood transfusions, organs, or blood products where screening is not routinely carried out must also be included. the incubation is estimated at weeks to months after exposure. this depends, to some extent, on the ability of current laboratory tests to detect hiv antibodies or viral antigen. the development of pcr for viral rna has improved sensitivity. during the acute phase of the infection, approx % experience a seroconversion "flu-like" illness. the individual is infectious at this time, because viral antigen (p ) is present in the blood. as antibodies start to form, the viral antigen disappears and the individual enters the latent phase. he or she is noninfectious and remains well for a variable period of time ( - years). development of aids marks the terminal phase of disease. viral antigen reemerges, and the individual is once again infectious. the onset of aids has been considerably delayed with the use of antiretroviral treatment. parenteral transmission included needlestick injuries, bites, unscreened blood transfusions, tattooing, acupuncture, and dental procedures where equipment is inadequately sterilized. risk of transmission is increased with deep penetrating injuries with hollow bore needles that are visibly bloodstained, especially when the device has previously been in the source patient's (contact) artery or vein. other routes include mucous membrane exposure (eyes, mouth, and genital mucous membranes) and contamination of broken skin. the higher the viral load in the contact, the greater the risk of transmission. this is more likely at the terminal stage of infection. hiv is transmitted mainly through blood or other body fluids that are visibly blood stained, with the exception of semen, vaginal fluid, and breast milk. saliva alone is most unlikely to transmit infection. therefore, people who have sustained penetrating bite injuries can be reassured that they are not at risk, providing the contact was not bleeding from the mouth at the time. the risk from a single percutaneous exposure from a hollow bore needle is low, and a single mucocutaneous exposure is even less likely to result in infection. the risk from sexual exposure varies, although it appears that there is a greater risk with receptive anal intercourse compared with receptive vaginal intercourse ( ). high-risk fluids include blood, semen, vaginal fluid, and breast milk. there is little or no risk from saliva, urine, vomit, or feces unless they are visibly bloodstained. other fluids that constitute a theoretical risk include cerebrospinal, peritoneal, pleural, synovial, or pericardial fluid. management in custody of staff/victims in contact with disease includes following the immediate management flow chart (fig. ) and contacting the designated hospital/specialist with details of the exposure. where possible, obtain a blood sample from the contact. regarding hbv and hcv blood samples in the united kingdom, they can only be taken with informed consent. there is no need for the forensic physician to go into details about the meaning of the test, but the contact should be encouraged to attend the genitourinary department (or similar) of the designated hospital to discuss the test results. should the contact refuse to provide a blood sample, then any information about his or her lifestyle, ethnic origin, state of health, etc., may be useful for the specialist to decide whether postexposure prophylaxis (pep) should be given to the victim. where only saliva is involved in a penetrating bite injury, there is every justification to reassure the victim that he or she is not at risk. if in doubt, then always refer. in the united kingdom, the current recommended regime for pep is combivir ( mg of zidovudine twice daily plus mg of lamivudine twice daily) and a protease inhibitor ( mg of nelfanivir twice daily) given for weeks ( ) . it is only given after a significant exposure to a high-risk fluid or any that is visibly bloodstained and the contact is known or is highly likely to be hiv positive. ideally, treatment should be started within an hour after exposure, although it will be considered for up to weeks. it is usually given for weeks, unless the contact is subsequently identified as hiv negative or the "victim" develops tolerance or toxicity occurs. weekly examinations of the "victim" should occur during treatment to improve adherence, monitor drug toxicity, and deal with other concerns. other useful information that may influence the decision whether to treat with the standard regimen or use alternative drugs includes interaction with other medications that the "victim" may be taking (e.g., phenytoin or antibiotics) or if the contact has been on antiretroviral therapy or if the "victim" is pregnant. during the second or third trimester, only combivir would be used, because there is limited experience with protease inhibitors. no data exist regarding the efficacy of pep beyond occupational exposure ( ) . pep is not considered for exposure to low-or no-risk fluids through any route or where the source is unknown (e.g., a discarded needle). despite the appropriate use and timing of pep, there have been reports of failure ( , ) . unless they are severely ill, detainees can be kept in custody. every effort should be made to continue any treatment they may be receiving. apply universal precautions when dealing with the detainee, and ensure that contaminated cells and/or bedding are managed appropriately. cases of this highly infectious disease occur throughout the year but are more frequent in winter and early spring. this seasonal endemicity is blurring with global warming. in the united kingdom, the highest prevalence occurs in the -to -years age group. ninety percent of the population over the age of is immune ( ) . a similar prevalence has been reported in other parts of western europe and the united states. in south east asia, varicella is mainly a disease of adulthood ( ) . therefore, people born in these countries who have moved to the united kingdom are more likely to be susceptible to chicken pox. there is a strong correlation between a history of chicken pox and serological immunity ( - %). most adults born and living in industrialized countries with an uncertain or negative history of chicken pox are also seropositive ( - %). in march , a live-attenuated vaccine was licensed for use in the united states and a policy for vaccinating children and susceptible health care personnel was introduced. in summer , in the united kingdom, glaxosmithkline launched a live-attenuated vaccine called varilrix. in december , the uk department of health, following advice from the joint committee on vaccination and immunisation recommended that the vaccine be given for nonimmune health care workers who are likely to have direct contact with individuals with chicken pox. any health care worker with no previous history of chicken pox should be screened for immunity, and if no antibodies are found, then they should receive two doses of vaccine - weeks apart. the vaccine is not currently recommended for children and should not be given during pregnancy. following an incubation period of - days (this may be shorter in the immunocompromised), there is usually a prodromal "flu-like" illness before the onset of the rash. this coryzal phase is more likely in adults. the lesions typically appear in crops, rapidly progressing from red papules through vesicles to open sores that crust over and separate by days. the distribution of the rash is centripetal (i.e., more over the trunk and face than on the limbs). this is the converse of small pox. in adults, the disease is often more severe, with lesions involving the scalp and mucous membranes of the oropharynx. in children, the disease is often mild, unless they are immunocompromised, so they are unlikely to experience complications. in adults (defined as yr or older), the picture is rather different ( ) . secondary bacterial infection is common but rarely serious. there is an increased likelihood of permanent scarring. hemorrhagic chicken pox typically occurs on the second or third day of the rash. usually, this is limited to bleeding into the skin, but lifethreatening melena, epistaxis, or hematuria can occur. varicella pneumonia ranges from patchy lung consolidation to overt pneumonitis and occurs in in cases ( ) . it can occur in previously healthy individuals (particularly adults), but the risk is increased in those who smoke. immunocompromised people are at the greatest risk of developing this complication. it runs a fulminating course and is the most common cause of varicella-associated death. fibrosis and permanent respiratory impairment may occur in those who survive. any suspicion of lung involvement is an indication for immediate treatment, and any detainee or staff member should be sent to hospital. involvement of the central nervous system includes several conditions, including meningitis, guillain-barre, and encephalitis. the latter is more common in the immunocompromised and can be fatal. this is taken as days before the first lesions appear to the end of new vesicle formation and the last vesicle has crusted over. this typically is - days after onset but may last up to days. the primary route is through direct contact with open lesions of chicken pox. however, it is also spread through aerosol or droplets from the respiratory tract. chicken pox may also be acquired through contact with open lesions of shingles (varicella zoster), but this is less likely because shingles is less infectious than chicken pox. nonimmune individuals are at risk of acquiring disease. approximately % of the adult population born in the united kingdom and less than % of adults in the united states fall into this category. therefore, it is more likely that if chicken pox is encountered in the custodial setting, it will involve people born outside the united kingdom (particularly south east asia) or individuals who are immunocompromised and have lost immunity. nonimmune pregnant women are at risk of developing complications. pneumonia can occur in up to % of pregnant women with chicken pox, and the severity is increased in later gestation ( ) . they can also transmit infection to the unborn baby ( ) . if infection is acquired in the first weeks, there is a less than % chance of it leading to congenital varicella syndrome. infection in the last trimester can lead to neonatal varicella, unless more than days elapse between onset of maternal rash and delivery when antibodies have time to cross the placenta leading to either mild or inapparent infection in the newborn. in this situation, varicella immunoglobulin (vzig) should be administered to the baby as soon as possible after birth ( ). staff with chicken pox should stay off work until the end of the infective period (approx - days). those in contact with disease who are known to be nonimmune or who have no history of disease should contact the designated occupational health physician. detainees with the disease should not be kept in custody if at all possible (especially pregnant women). if this is unavoidable, then nonimmune or immunocompromised staff should avoid entering the cell or having close contact with the detainee. nonimmune, immunocompromised, or pregnant individuals exposed to chickenpox should seek expert medical advice regarding the administration of vzig. aciclovir (or similar antiviral agent) should be given as soon as possible to people who are immunocompromised with chicken pox. it should also be considered for anyone over years old because they are more likely to develop complications. anyone suspected of severe complications should be sent straight to the hospital. after chicken pox, the virus lies dormant in the dorsal root or cranial nerve ganglia but may re-emerge and typically involves one dermatome ( ) . the site of involvement depends on the sensory ganglion initially involved. shingles is more common in individuals over the age of years, except in the immunocompromised, when attacks can occur at an earlier age. the latter are also more susceptible to secondary attacks and involvement of more than one dermatome. bilateral zoster is even rarer but is not associated with a higher mortality. in the united kingdom, there is an estimated incidence of . - . per -person years ( ). there may be a prodromal period of paraesthesia and burning or shooting pains in the involved segment. this is usually followed by the appearance of a band of vesicles. rarely, the vesicles fail to appear and only pain is experienced. this is known as zoster sine herpete. in individuals who are immuno-compromised, disease may be prolonged and dissemination may occur but is rarely fatal. shingles in pregnancy is usually mild. the fetus is only affected if viremia occurs before maternal antibody has had time to cross the placenta. the most common complication of shingles is postherpetic neuralgia, occurring in approx % of cases. it is defined as pain lasting more than days from rash onset ( ) . it is more frequent in people over years and can lead to depression. it is rare in children, including those who are immunocompromised. infection of the brain includes encephalitis, involvement of motor neurones leading to ptosis, paralysis of the hand, facial palsy, or contralateral hemiparesis. involvement of the oculomotor division of the trigeminal ganglion can cause serious eye problems, including corneal scarring. shingles is far less infectious than chicken pox and is only considered to be infectious up to days after lesions appear. shingles is only infectious after prolonged contact with lesions. unlike chickenpox, airborne transmission is not a risk. individuals who are immunocompromised may reactivate the dormant virus and develop shingles. people who have not had primary varicella are at risk of developing chickenpox after prolonged direct contact with shingles. despite popular belief, it is untrue that people who are immunocompetent who have had chicken pox develop shingles when in contact with either chicken pox or shingles. such occurrences are merely coincidental, unless immunity is lowered. staff with shingles should stay off work until the lesions are healed, unless they can be covered. staff who have had chickenpox are immune (including pregnant women) and are therefore not at risk. if they are nonimmune (usually accepted as those without a history of chicken pox), they should avoid prolonged contact with detainees with shingles. pregnant nonimmune women should avoid contact altogether. detainees with the disease may be kept in custody, and any exposed lesions should be covered. it is well documented that prompt treatment attenuates the severity of the disease, reduces the duration of viral shedding, hastens lesion healing, and reduces the severity and duration of pain. it also reduces the likelihood of developing postherpetic neuralgia ( ) . prompt treatment with famciclovir (e.g., mg three times a day for days) should be initiated if the onset is d ays or less. it should also be considered after this time if the detainee is over age years. pregnant detainees with shingles can be reassured that there is minimal risk for both the mother and the unborn child. expert advice should be given before initiating treatment for the mother. this tiny parasitic mite (sarcoptes scabiei) has infested humans for more than years. experts estimate that in excess of million cases occur worldwide each year. the female mite burrows into the skin, especially around the hands, feet, and male genitalia, in approx . min. eggs are laid and hatch into larvae that travel to the skin surface as newly developed mites. the mite causes intense itching, which is often worse at night and is aggravated by heat and moisture. the irritation spreads outside the original point of infection resulting from an allergic reaction to mite feces. this irritation may persist for approx weeks after treatment but can be alleviated by antihistamines. crusted scabies is a far more severe form of the disease. large areas of the body may be involved. the crusts hide thousands of live mites and eggs, making them difficult to treat. this so-called norwegian scabies is more common in the elderly or the immunocompromised, especially those with hiv. after a primary exposure, it takes approx - weeks before the onset of itching. however, further exposures reduce the incubation time to approx - days. without treatment, the period of infectivity is assumed to be indefinite. with treatment, the person should be considered infectious until the mites and eggs are destroyed, usually - days. crusted scabies is highly infectious. because transmission is through direct skin-to-skin contact with an infected individual, gloves should be worn when dealing with individuals suspected of infestation. usually prolonged contact is needed, unless the person has crusted scabies, where transmission occurs more easily. the risk of transmission is much greater in households were repeated or prolonged contact is likely. because mites can survive in bedding or clothing for up to hour, gloves should also be worn when handling these items. bedding should be treated using one of the methods in subheading . . professional cleaning of the cell is only warranted in cases of crusted scabies. the preferred treatment for scabies is either permethrin cream ( %) or aqueous malathion ( . %) ( ) . either treatment has to be applied to the whole body and should be left on for at least hours in the case of permethrin and hours for malathion before washing off. lindane is no longer considered the treatment of choice, because there may be complications in pregnancy ( ) . treatment in custody may not be practical but should be considered when the detainee is believed to have norwegian scabies. like scabies, head lice occur worldwide and are found in the hair close to the scalp. the eggs, or nits, cling to the hair and are difficult to remove, but they are not harmful. if you see nits, then you can be sure that lice are also present. the latter are best seen when the hair is wet. the lice bite the scalp and suck blood, causing intense irritation and itching. head lice can only be passed from direct hair-to-hair contact. it is only necessary to wear gloves when examining the head for whatever reason. the cell does not need to be cleaned after use, because the lice live on or near skin. bedding may be contaminated with shed skin, so should be handled with gloves and laundered or incinerated. the presence of live lice is an indication for treatment by either physical removal with a comb or the application of an insecticide. the latter may be more practical in custody. treatment using . % aqueous malathion should be applied to dry hair and washed off after hours. the hair should then be shampooed as normal. crabs or body lice are more commonly found in the pubic, axillary, chest, and leg hair. however, eyelashes and eyebrows may also be involved. they are associated with people who do not bath or change clothes regularly. the person usually complains of intense itching or irritation. the main route is from person to person by direct contact, but eggs can stick to fibers, so clothing and bedding should be handled with care (see subheading . . .). staff should always wear gloves if they are likely to come into contact with any hirsute body part. clothing or bedding should be handled with gloves and either laundered or incinerated. treatment of a detainee in custody is good in theory but probably impractical because the whole body has to be treated. fleas lay eggs on floors, carpets, and bedding. in the united kingdom, most flea bites come from cats or dogs. the eggs and larvae fleas can survive for months and are reactivated in response to animal or human activity. because animal fleas jump off humans after biting, most detainees with flea bites will not have fleas, unless they are human fleas. treatment is only necessary if fleas are seen. after use, the cell should be vacuumed and cleaned with a proprietary insecticide. any bedding should be removed wearing gloves, bagged, and either laundered or incinerated. bedbugs live and lay eggs on walls, floors, furniture, and bedding. if you look carefully, fecal tracks may be seen on hard surfaces. if they are present for long enough, they emit a distinct odor. bedbugs are rarely found on the person but may be brought in on clothing or other personal effects. bedbugs bite at night and can cause sleep disturbance. the detainee does not need to be treated, but the cell should deemed out of use until it can be vacuumed and professionally cleaned with an insecticide solution. any bedding or clothing should be handled with gloves and disposed of as appropriate. staphylococcus aureus is commonly carried on the skin or in the nose of healthy people. approximately - % of the population is colonized with the bacteria but remain well ( ) . from time to time, the bacteria cause minor skin infections that usually do not require antibiotic treatment. however, more serious problems can occur (e.g., infection of surgical wounds, drug injection sites, osteomyelitis, pneumonia, or septicemia). during the last years, the bacteria have become increasingly resistant to penicillin-based antibiotics ( ) , and in the last years, they have become resistant to an increasing number of alternative antibiotics. these multiresistant bacteria are known as methicillinresistant s. aureus (mrsa). mrsa is prevalent worldwide. like nonresistant staphylococci, it may remain undetected as a reservoir in colonized individuals but can also produce clinical disease. it is more common in individuals who are elderly, debilitated, or immunocompromised or those with open wounds. clusters of skin infections with mrsa have been reported among injecting drug users (idus) since in america ( , ) , and more recently, similar strains have been found in the united kingdom in idus in the community ( ) . this may have particular relevance for the forensic physician when dealing with idus sores. people who are immunocompetent rarely get mrsa and should not be considered at risk. the bacteria are usually spread via the hands of staff after contact with colonized or infected detainees or devices, items (e.g., bedding, towels, and soiled dressings), or environmental surfaces that have been contaminated with mrsa-containing body fluids. with either known or suspected cases (consider all abscesses/ulcers of idus as infectious), standard precautions should be applied. staff should wear gloves when touching mucous membranes, nonintact skin, blood or other body fluids, or any items that could be contaminated. they should also be encouraged to their wash hands with an antimicrobial agent regardless of whether gloves have been worn. after use, gloves should be disposed of in a yellow hazard bag and not allowed to touch surfaces. masks and gowns should only be worn when conducting procedures that generate aerosols of blood or other body fluids. because this is an unlikely scenario in the custodial setting, masks and gowns should not be necessary. gloves should be worn when handling bedding or clothing, and all items should be disposed of appropriately. any open wounds should be covered as soon as possible. the cell should be cleaned professionally after use if there is any risk that it has been contaminated. during the last decade, there has been an increasing awareness of the bacterial flora colonizing injection sites that may potentially lead to life-threatening infection ( ) . in , a sudden increase in needle abscesses caused by a clonal strain of group a streptococcus was reported among hospitalized idus in berne, switzerland ( ) . a recent uk study showed that the predominant isolate is s. aureus, with streptococcus species forming just under one-fifth ( % β-hemolytic streptococci) ( ) . there have also been reports of both nonsporing and sporing anerobes (e.g., bacteroides and clostridia species, including clostridia botulinum) ( , ) . in particular, in , laboratories in glasgow were reporting isolates of clostridium novyi among idus with serious unexplained illness. by june , , a total of cases ( definite and probable) had been reported. a definite case was defined as an idu with both severe local and systemic inflammatory reactions. a probable case was defined as an idu who presented to the hospital with an abscess or other significant inflammation at an injecting site and had either a severe inflammatory process at or around an injection site or a severe systemic reaction with multiorgan failure and a high white cell count ( ) . in the united kingdom, the presence of c. botulinum in infected injection sites is a relatively new phenomenon. until the end of , there were no cases reported to the public health leadership society. since then, the number has increased, with a total of cases in the united kingdom and ireland being reported since the beginning of . it is believed that these cases are associated with contaminated batches of heroin. simultaneous injection of cocaine increases the risk by encouraging anerobic conditions. anerobic flora in wounds may have serious consequences for the detainee, but the risk of transmission to staff is virtually nonexistent. staff should be reminded to wear gloves when coming into contact with detainees with infected skin sites exuding pus or serum and that any old dressings found in the cell should be disposed of into the yellow bag marked "clinical waste" in the medical room. likewise, any bedding should be bagged and laundered or incinerated after use. the cell should be deemed out of use and professionally cleaned after the detainee has gone. the health care professional managing the detainee should clean and dress open wounds as soon as possible to prevent the spread of infection. it may also be appropriate to start a course of antibiotics if there is abscess formation or signs of cellulites and/or the detainee is systemically unwell. however, infections can often be low grade because the skin, venous, and lymphatic systems have been damaged by repeated penetration of the skin. in these cases, signs include lymphedema, swollen lymph glands, and darkly pigmented skin over the area. fever may or may not be present, but septicemia is uncommon unless the individual is immunocompromised (e.g., hiv positive). co-amoxiclav is the preferred treatment of choice because it covers the majority of staphylococci, streptococci, and anerobes (the dose depends on the degree of infection). necrotizing fasciitis and septic thrombophlebitis are rare but life-threatening complications of intravenous drug use. any detainee suspected of either of these needs hospital treatment. advice about harm reduction should also be given. this includes encouraging drug users to smoke rather than inject or at least to advise them to avoid injecting into muscle or skin. although most idus are aware of the risk of sharing needles, they may not realize that sharing any drug paraphernalia could be hazardous. advice should be given to use the minimum amount of citric acid to dissolve the heroin because the acid can damage the tissue under the skin, allowing bacteria to flourish. drugs should be injected at different sites using fresh works for each injection. this is particularly important when "speedballing" because crack cocaine creates an anerobic environment. medical help should be requested if any injection site become painful and swollen or shows signs of pus collecting under the skin. because intravenous drug users are at increased risk of acquiring hbv and hav, they should be informed that vaccination against both diseases is advisable. another serious but relatively rare problem is the risk from broken needles in veins. embolization can take anywhere from hours to days or even longer if it is not removed. complications may include endocarditis, pericarditis, or pulmonary abscesses ( , ) . idus should be advised to seek medical help as soon as possible, and should such a case present in custody, then send the detainee straight to the hospital. the forensic physician may encounter bites in the following four circumstances: a detailed forensic examination of bites is given in chapter . with any bite that has penetrated the skin, the goals of therapy are to minimize soft tissue deformity and to prevent or treat infection. in the united kingdom and the united states, dog bites represent approximately three-quarters of all bites presenting to accident and emergency departments ( ) . a single dog bite can produce up to psi of crush force in addition to the torsional forces as the dog shakes its head. this can result in massive tissue damage. human bites may cause classical bites or puncture wounds (e.g., impact of fists on teeth) resulting in crush injuries. an estimated - % of dog bites and - % of human bites lead to infection. compare this with an estimated - % of nonbite wounds managed in accident and emergency departments. the risk of infection is increased with puncture wounds, hand injuries, full-thickness wounds, wounds requiring debridement, and those involving joints, tendons, ligaments or fractures. comorbid medical conditions, such as diabetes, asplenia, chronic edema of the area, liver dysfunction, the presence of a prosthetic valve or joint, and an immunocompromised state may also increase the risk of infection. infection may spread beyond the initial site, leading to septic arthritis, osteomyelitis, endocarditis, peritonitis, septicemia, and meningitis. inflammation of the tendons or synovial lining of joints may also occur. if enough force is used, bones may be fractured or the wounds may be permanently disfiguring. assessment regarding whether hospital treatment is necessary should be made as soon as possible. always refer if the wound is bleeding heavily or fails to stop when pressure is applied. penetrating bites involving arteries, nerves, muscles, tendons, the hands, or feet, resulting in a moderate to serious facial wound, or crush injuries, also require immediate referral. if management within custody is appropriate, ask about current tetanus vaccine status, hbv vaccination status, and known allergies to antibiotics. wounds that have breached the skin should be irrigated with . % (isotonic) sodium chloride or ringer's lactate solution instead of antiseptics, because the latter may delay wound healing. a full forensic documentation of the bite should be made as detailed in chapter . note if there are clinical signs of infection, such as erythema, edema, cellulitis, purulent discharge, or regional lymphadenopathy. cover the wound with a sterile, nonadhesive dressing. wound closure is not generally recommended because data suggest that it may increase the risk of infection. this is particularly relevant for nonfacial wounds, deep puncture wounds, bites to the hand, clinically infected wounds, and wounds occurring more than - hours before presentation. head and neck wounds in cosmetically important areas may be closed if less than hours old and not obviously infected. • dog bites-pasteurella canis, pasteurella multocida, s. aureus, other staphylococci, streptococcus species, eikenella corrodens, corynebacterium species, and anerobes, including bacteroides fragilis and clostridium tetani • human bites-streptococcus species, s. aureus, e. corrodens, and anerobes, including bacteroides (often penicillin resistant), peptostreptococci species, and c. tetani. tuberculosis (tb) and syphilis may also be transmitted. • dog bites-outside of the united kingdom, australia, and new zealand, rabies should be considered. in the united states, domestic dogs are mostly vaccinated against rabies ( ) , and police dogs have to be vaccinated, so the most common source is from racoons, skunks, and bats. • human bites-hbv, hbc, hiv, and herpes simplex. antibiotics are not generally needed if the wound is more than days old and there is no sign of infection or in superficial noninfected wounds evaluated early that can be left open to heal by secondary intention in compliant people with no significant comorbidity ( ) . antibiotics should be considered with high-risk wounds that involve the hands, feet, face, tendons, ligaments, joints, or suspected fractures or for any penetrating bite injury in a person with diabetes, asplenia, or cirrhosis or who is immunosuppressed. coamoxiclav (amoxycillin and clavulanic acid) is the first-line treatment for mild-moderate dog or human bites resulting in infections managed in primary care. for adults, the recommended dose is / mg three times daily and for children the recommended does is mg/kg three times daily (based on amoxycillin component). treatment should be continued for - days. it is also the first-line drug for prophylaxis when the same dose regimen should be prescribed for - days. if the individual is known or suspected to be allergic to penicillin, a tetracycline (e.g., doxycycline mg twice daily) and metronidazole ( mg three times daily) or an aminoglycoside (e.g., erythromycin) and metronidazole can be used. in the united kingdom, doxycycline use is restricted to those older than years and in the united states to those older than years old. specialist advice should be sought for pregnant women. anyone with severe infection or who is clinically unwell should be referred to the hospital. tetanus vaccine should be given if the primary course or last booster was more than years ago. human tetanus immunoglobulin should be considered for tetanus-prone wounds (e.g., soil contamination, puncture wounds, or signs of devitalized tissue) or for wounds sustained more than hours old. if the person has never been immunized or is unsure of his or her tetanus status, a full three-dose course, spaced at least month apart, should be given. penetrating bite wounds that involve only saliva may present a risk of hbv if the perpetrator belongs to a high-risk group. for management, see subheadings . . . and . . . hcv and hiv are only a risk if blood is involved. the relevant management is dealt with in subheadings . . . and . . . respiratory tract infections are common, usually mild, and self-limiting, although they may require symptomatic treatment with paracetamol or a nonsteroidal antiinflammatory. these include the common cold ( % rhinoviruses and % coronaviruses), adenoviruses, influenza, parainfluenza, and, during the summer and early autumn, enteroviruses. special attention should be given to detainees with asthma or the who are immunocompromised, because infection in these people may be more serious particularly if the lower respiratory tract is involved. the following section includes respiratory pathogens of special note because they may pose a risk to both the detainee and/or staff who come into close contact. there are five serogroups of neisseria meningitidis: a, b, c, w , and y. the prevalence of the different types varies from country to country. there is currently no available vaccine against type b, but three other vaccines (a+c, c, and acwy) are available. overall, % of the uk population carry n. meningitidis ( % in the - age group) ( ) . in the united kingdom, most cases of meningitis are sporadic, with less than % occurring as clusters (outbreaks) amongst school children. between and , % of cases were group b, % were group c, and w and a accounted for %. there is a seasonal variation, with a high level of cases in winter and a low level in the summer. the greatest risk group are the under year olds, with a peak incidence under year old. a secondary peak occurs in the -to -year-old age group. in sub-saharan africa, the disease is more prevalent in the dry season, but in many countries, there is background endemicity year-round. the most prevalent serogroup is a. routine vaccination against group c was introduced in the united kingdom november for everybody up to the age of years old and to all firstyear university students. this has since been extended to include everyone under the age of years old. as a result of the introduction of the vaccination program, there has been a % reduction of group c cases in those younger than under years and an % reduction in those under year old ( , ) . an outbreak of serogroup w meningitis occurred among pilgrims on the hajj in . cases were reported from many countries, including the united kingdom. in the united kingdom, there is now an official requirement to be vaccinated with the quadrivalent vaccine (acwy vax) before going on a pilgrimage (hajj or umra), but illegal immigrants who have not been vaccinated may enter the country ( ). after an incubation period of - days ( , ) , disease onset may be either insidious with mild prodromal symptoms or florid. early symptoms and signs include malaise, fever, and vomiting. sever headache, neck stiffness, photophobia, drowsiness, and a rash may develop. the rash may be petechial or purpuric and characteristically does not blanche under pressure. meningitis in infants is more likely to be insidious in onset and lack the classical signs. in approx - % of cases, septicemia is the predominant feature. even with prompt antibiotic treatment, the case fatality rate is - % in meningitis and - % in those with septicemia. ( ). a person should be considered infectious until the bacteria are no longer present in nasal discharge. with treatment, this is usually approx hour. the disease is spread through infected droplets or direct contact from carriers or those who are clinically ill. it requires prolonged and close contact, so it is a greater risk for people who share accommodation and utensils and kiss. it must also be remembered that unprotected mouth-to-mouth resuscitation can also transmit disease. it is not possible to tell if a detainee is a carrier. nevertheless, the risk of acquiring infection even from an infected and sick individual is low, unless the individual has carried out mouth-to-mouth resuscitation. any staff member who believes he or she has been placed at risk should report to the occupational health department (or equivalent) or the nearest emergency department at the earliest opportunity for vaccination. if the detainee has performed mouth-to-mouth resuscitation, prophylactic antibiotics should be given before receiving vaccination. rifampicin, ciprofloxacin, and ceftriaxone can be used; however, ciprofloxacin has numerous advantages ( ) . only a single dose of mg (adults and children older than years) is needed and has fewer side effects and contraindications than rifampicin. ceftriaxone has to be given by injection and is therefore best avoided in the custodial setting. if the staff member is pregnant, advice should be sought from a consultant obstetrician, because ciprofloxacin is not recommended ( ) . for anyone dealing regularly with illegal immigrants (especially from the middle east or sub-saharan africa) (e.g., immigration services, custody staff at designated stations, medical personnel, and interpreters), should consider being vaccinated with acwy vax. a single injection provides protection for years. detainees suspected of disease should be sent directly to the hospital. human tb is caused by infection with mycobacterium tuberculosis, mycobacterium bovis, or mycobacterium africanum. it is a notifiable disease under legislation specific to individual countries; for example, in the united kingdom, this comes under the public health (control of disease) act of . in , the who declared tb to be a global emergency, with an estimated - million new cases and million deaths occurring each year, the majority of which were in asia and africa. however, these statistics are likely to be an underestimate because they depend on the accuracy of reporting, and in poorer countries, the surveillance systems are often inadequate because of lack of funds. even in the united kingdom, there has been an inconsistency of reporting particularly where an individual has concomitant infection with hiv. some physicians found themselves caught in a dilemma of confidentiality until , when the codes of practice were updated to encourage reporting with patient consent ( ) . with the advent of rapid identification tests and treatment and the use of bacillus calmette-guérin (bcg) vaccination for prevention, tb declined during the first half of the th century in the united kingdom. however, since the early s, numbers have slowly increased, with some cases reported in ( ) . in , % of reported cases were from people born outside the united kingdom and % were associated with hiv infection ( , ) . london has been identified as an area with a significant problem. this has been attributed to its highly mobile population, the variety of ethnic groups, a high prevalence of hiv, and the emergence of drug-resistant strains ( . % in ) (phls, unpublished data-mycobnet). a similar picture was initially found in the united states, when there was a reversal of a long-standing downward trend in . however, between and , the number of cases increased from , to , ( ) . there were also serious outbreaks of multidrug-resistant tb (mdr-tb) in hospitals in new york city and miami ( ) . factors pertinent to the overall upswing included the emergence of hiv, the increasing numbers of immigrants from countries with a high prevalence of tb, and perhaps more significantly, stopping categorical federal funding for control activities in . the latter led to a failure of the public health infrastructure for tb control. since , the trend has reversed as the cdc transferred most of its funds to tb surveillance and treatment program in states and large cities. from to , the annual decline averaged by . % ( ) , but the following year this was reduced to %, indicating that there was no room for complacency. the who has been proactive and is redirecting funding to those countries most in need. in october , a global partnership called stop tb was launched to coordinate every aspect of tb control, and by , the partnership had more than member states. a target was set to detect at least % of infectious cases by . the acquisition of tb infection is not necessarily followed by disease because the infection may heal spontaneously. it may take weeks or months before disease becomes apparent, or infection may remain dormant for years before reactivation in later life especially if the person becomes debilitated or immunocompromised. contrary to popular belief, the majority of cases of tb in people who are immunocompetent pass unnoticed. of the reported cases, % involve the lung, whereas nonrespiratory (e.g., bone, heart, kidney, and brain) or dissemination (miliary tb) are more common in immigrant ethnic groups and individuals who are immunocompromised ( ) . they are also more likely to develop resistant strains. in the general population, there is an estimated % lifetime risk of tb infection progressing to disease ( ) . there has been an increase in the number of cases of tb associated with hiv owing to either new infection or reactivation. tb infection is more likely to progress to active tb in hiv-positive individuals, with a greater than % lifetime risk ( ) . tb can also lead to a worsening of hiv with an increase in viral load ( ) . therefore, the need for early diagnosis is paramount, but it can be more difficult because pulmonary tb may present with nonspecific features (e.g., bilateral, unilateral, or lower lobe shadowing) ( ). after an incubation period of - weeks, symptoms may develop (see table ). the main route is airborne through infected droplets, but prolonged or close contact is needed. nonrespiratory disease is not considered a risk unless the mycobacterium is aerosolized under exceptional circumstances (e.g., during surgery) or there are open abscesses. a person is considered infectious as long as viable bacilli are found in induced sputum. untreated or incompletely treated people may be intermittently sputum positive for years. after weeks of appropriate treatment, the individual is usually considered as noninfectious. this period is often extended for treatment of mdr-tb or for those with concomitant hiv. patient compliance also plays an important factor. the risk of infection is directly proportional to the degree of exposure. more severe disease occurs in individuals who are malnourished, immunocompromised (e.g., hiv), and substance misusers. people who are immunocompromised are at special risk of mdr-tb or mycobacterium avium intracellulare (mai). staff with disease should stay off work until the treatment course is complete and serial sputum samples no longer contain bacilli. staff in contact with disease who have been vaccinated with bcg are at low risk of acquiring disease but should minimize their time spent in the cell. those who have not received bcg or who are immunocompromised should avoid contact with the detainee wherever possible. detainees with mai do not pose a risk to a staff member, unless the latter is immunocompromised. any staff member who is pregnant, regardless of bcg status or type of tb, should avoid contact. anyone performing mouth-to-mouth resuscitation with a person with untreated or suspected pulmonary tb should be regarded as a household contact and should report to occupational health or their physician if no other route exists. they should also be educated regarding the symptoms of tb. anyone who is likely to come into repeated contact with individuals at risk of tb should receive bcg (if he or she has not already done so), regardless of age, even though there is evidence to suggest that bcg administered in adult life is less effective. this does not apply to individuals who are immunocompromised or pregnant women. in the latter case, vaccination should preferably be deferred until after delivery. detainees with disease (whether suspected or diagnosed) who have not been treated or treatment is incomplete should be kept in custody for the minimum time possible. individuals with tb who are immunocompromised are usually too ill to be detained; if they are, they should be considered at greater risk of transmitting disease to staff. any detainee with disease should be encouraged to cover his or her mouth and nose when coughing and sneezing. staff should wear gloves when in contact with the detainee and when handling clothing and bedding. any bedding should be bagged after use and laundered or incinerated. the cell should be deemed out of action until it has been ventilated and professionally decontaminated, although there is no hard evidence to support that there is a risk of transmission from this route ( ). on march , , the who issued a global warning to health authorities about a new atypical pneumonia called sars. the earliest case was believed to have originated in the guandong province of china on november , . the causative agent was identified as a new corona virus-sars-cov ( , ) . by the end of june , cases had been reported from different countries, with a total of deaths. approximately % of cases occurred in china (including hong kong, taiwan, and macao). the case fatality rate varied from less than % in people younger than years, % in persons aged - years, % in those aged - years, and more than % in persons years or older. on july , , the who reported that the last human chain of transmission of sars had been broken and lifted the ban from all countries. however, it warned that everyone should remain vigilant, because a resurgence of sars is possible. their warning was well given because in december , a new case of sars was detected in china. at the time of this writing, three more cases have been identified. knowledge about the epidemiology and ecology of sars-cov and the disease remains limited; however, the experience gained from the previous outbreak enabled the disease to be contained rapidly, which is reflected in the few cases reported since december . there is still no specific treatment or preventative vaccine that has been developed. the incubation period is short, approx - days (maximum days), and, despite the media frenzy surrounding the initial outbreak, sars is less infectious than influenza. the following clinical case definition of sars has been developed for public health purposes ( ) . a person with a history of any combination of the following should be examined for sars: • fever (at least °c); and • one of more symptoms of lower respiratory tract illness (cough, difficulty in breathing, or dyspnea); and • radiographic evidence of lung infiltrates consistent with pneumonia or respiratory distress syndrome or postmortem findings of these with no identifiable cause; and • no alternative diagnosis can fully explain the illness. laboratory tests have been developed that include detection of viral rna by pcr from nasopharyngeal secretions or stool samples, detection of antibodies by enzyme-linked immunosorbent assay or immunofluorescent antibody in the blood, and viral culture from clinical specimens. available information suggests that close contact via aerosol or infected droplets from an infected individual provide the highest risk of acquiring the disease. most cases occurred in hospital workers caring for an index case or his or her close family members. despite the re-emergence of sars, it is highly unlikely that a case will be encountered in the custodial setting in the near future. however, forensic physicians must remain alert for the sars symptoms and keep up-to-date with recent outbreaks. information can be obtained from the who on a daily basis from its web site. if sars is suspected, medical staff should wear gloves and a surgical mask when examining a suspected case; however, masks are not usually available in custody. anyone suspected of sars must be sent immediately to the hospital, and staff who have had prolonged close contact should be alerted as to the potential symptoms. the most consistent feature of diseases transmitted through the fecaloral route is diarrhea (see table ). infective agents include bacteria, viruses, and protozoa. because the causes are numerous, it is beyond the remit of this chapter to cover them all. it is safest to treat all diarrhea as infectious, unless the detainee has a proven noninfectious cause (e.g., crohn's disease or ulcerative colitis). all staff should wear gloves when in contact with the detainee or when handling clothing and bedding, and contaminated articles should be laundered or incinerated. the cell should be professionally cleaned after use, paying particular attention to the toilet area. this viral hepatitis occurs worldwide, with variable prevalence. it is highest in countries where hygiene is poor and infection occurs year-round. in temperate climates, the peak incidence is in autumn and winter, but the trend is becoming less marked. all age groups are susceptible if they are nonimmune or have not been vaccinated. in developing countries, the disease occurs in early childhood, whereas the reverse is true in countries where the standard of living is higher. in the united kingdom, there has been a gradual decrease in the number of reported cases from to ( , ) . this results from, in part, improved standards of living and the introduction of an effective vaccine. the highest incidence occurs in the -to -year-old age group. approximately % of people older than years have natural immunity, leaving the remainder susceptible to infection ( ) . small clusters occur from time to time, associated with a breakdown in hygiene. there is also an increasing incidence of hav in gay or bisexual men and their partners ( ) . an unpublished study in london in showed a seroprevalence of % among gay men (young y et al., unpublished). the clinical picture ranges from asymptomatic infection through a spectrum to fulminant hepatitis. unlike hbv and hcv, hav does not persist or progress to chronic liver damage. infection in childhood is often mild or asymptomatic but in adults tends to be more severe. after an incubation period of - days (mean days) symptomatic infection starts with the abrupt onset of jaundice anything from days to weeks after the anicteric phase. it lasts for approximately the same length of time and is often accompanied by a sudden onset of fever. hav infection can lead to hospital admission in all age groups but is more likely with increasing age as is the duration of stay. the overall mortality is less than %, but % of people will have a prolonged or relapsing illness within - months (cdc fact sheet). fulminant hepatitis occurs in less than % of people but is more likely to occur in individuals older than years or in those with pre-existing liver disease. in patients who are hospitalized, case fatality ranges from % in - years olds to nearly % in those older than years ( ). the individual is most infectious in the weeks before the onset of jaundice, when he or she is asymptomatic. this can make control of infection difficult because the disease is not recognized. the main route is fecal-oral through the ingestion of contaminated water and food. it can also be transmitted by personal contact, including homosexuals practicing anal intercourse and fellatio. there is a slight risk from blood transfusions if the donor is in the acute phase of infection. it should not be considered a risk from needlestick injuries unless clinical suspicion of hav is high. risk groups include homeless individuals, homosexuals, idus, travellers abroad who have not been vaccinated, patients with chronic liver disease and chronic infection with hbv and hcv, employees and residents in daycare centers and hostels, sewage workers, laboratory technicians, and those handling nonhuman primates. several large outbreaks have occurred among idus, some with an epidemiological link to prisons ( , ) . transmission occurs during the viremic phase of the illness through sharing injecting equipment and via fecal-oral routes because of poor living conditions ( ) . there have also been reports of hav being transmitted through drugs that have been carried in the rectum. a study in vancouver showed that % of idus had past infection of hav, and they also showed an increased prevalence among homosexual/bisuexual men ( ). staff with disease should report to occupational health and stay off work until the end of the infective period. those in contact with disease (either through exposure at home or from an infected detainee) should receive prophylactic treatment as soon as possible (see subheading . . .). to minimize the risk of acquiring disease in custody, staff should wear gloves when dealing with the detainee and then wash their hands thoroughly. gloves should be disposed of only in the clinical waste bags. detainees with disease should be kept in custody for the minimum time possible. they should only be sent to the hospital if fulminant hepatitis is suspected. the cell should be quarantined after use and professionally cleaned. any bedding or clothing should be handled with gloves and laundered or incinerated according to local policy. detainees reporting contact with disease should be given prophylactic treatment as soon as possible (see subheading . . .). contacts of hav should receive hav vaccine (e.g., havrix monodose or avaxim) if they have not been previously immunized or had disease. human normal immunoglobulin (hnig), mg, deep intramuscular in gluteal muscle should be used in the following circumstances: • has the detainee traveled to africa, south east asia, the indian subcontinent, central/south america, or the far east in the last - months? • ascertain whether he or she received any vaccinations before travel and, if so, which ones. • ask if he or she took malaria prophylaxis, what type, and whether he or she completed the course. • ask if he or she swam in any stagnant lakes during the trip. • if the answer to any of the above is yes, ask if he or she has experienced any of the following symptoms: a fever/hot or cold flushes/shivering. diarrhea ± abdominal cramps ± blood or slime in the stool. a rash. persistent headaches ± light sensitivity. nausea or vomiting. aching muscles/joints. a persistent cough (dry or productive) lasting at least weeks. • take temperature. • check skin for signs of a rash and note nature and distribution. • check throat. • listen carefully to the lungs for signs of infection/consolidation. staff at higher risk of coming in to contact with hav should consider being vaccinated before exposure. two doses of vaccine given - months apart give at least years of protection. there is no specific treatment for hav, except supportive measures and symptomatic treatment. although the chance of encountering a tropical disease in custo dy is small, it is worth bearing in mind. it is not necessary for a forensic physician to be able to diagnose the specific disease but simply to recognize that the detainee/staff member is ill and whether he or she needs to be sent to the hospital (see tables - ) . this is best achieved by knowing the right questions to ask and carrying out the appropriate examination. tables - should be used as an aide to not missing some more unusual diseases. guidance for clinical health care workers: protection against infection with blood-borne viruses; recommendations of the expert advisory group on aids and the advisory group on hepatitis guidelines for hand hygiene in health care settings. recommendations of the healthcare infection control practices advisory committee and the hicpac/ shea/apic/idsa hand hygiene task force national model regulations for the control of workplace hazardous substances. commonwealth of australia, national occupational health and safety committee good practice guidelines for forensic medical examiners and the hospital infection control practices advisory committee. guideline for infection control in health care personnel report from the unlinked anonymous surveys steering group. department of health a strategy for infectious diseases-progress report. blood-borne and sexually transmitted viruses: hepatitis. department of health universal precautions for prevention of transmission of human immuno-deficiency virus, hepatitis b virus and other bloodborne pathogens in health-care settings risk factors for horizontal transmission of hepatitis b in a rural district in ghana familial clustering of hepatitis b infection: study of a family intrafamilial transmission of hepatitis b in the eastern anatolian region of turkey hepatitis b outbreak at glenochil prison during european network for hiv/aids and hepatitis prevention in prisons. second annual report. the network prevalence of hiv, hepatitis b and hepatitis c antibodies in prisoners in england and wales; a national survey the epidemiology of acute and chronic hepatitis c the role of the parenteral antischistosomal therapy in the spread of hepatitis c virus in egypt chronic hepatitis c: disease management. nih publication no. - . february department of health hepatitis c virus: eight years old laboratory surveillance of hepatitis c virus in england and wales: - last update aids/hiv quarterly surveillance tables provided by the phls aids centre (cdsc) and the scottish centre for infection and environmental health hiv and aids in the uk in . communicable disease surveillance centre. an update mode of vertical transmission of hiv- . a metanalysis of fifteen prospective cohort studies vertical transmission rate for hiv in the british isles estimated on surveillance data hiv post-exposure prophylaxis after sexual assault: the experience of a sexual assault service in london guidance from the uk chief medical officer's expert advisory group on aids. uk health department failures of zidovudine post exposure prophylaxis seroconversion to hiv- following a needlestick injury despite combination post-exposure prophylaxis department of health, immunisation against infectious disease. united kingdom: her majesty's stationery office chickenpox-disease predominantly affecting adults in rural west bengal prevention of varicella: recommendations of the advisory committee on immunization practices varicella-zoster virus epidemiology. a changing scene? use of acyclovir for varicella pneumonia during pregnancy outcome after maternal varicella infection in the first weeks of pregnancy outcome in newborn babies given anti-varicella zoster immunoglobulin after perinatal maternal infection with varicella zoster virus varicella-zoster virus dna in human sensory ganglia epidemiology and natural history of herpes zoster and post herpetic neuralgia clinical applications for changepoint analysis of herpes zoster pain treatment of scabies with permethrin versus lindane and benzoyl benzoate treatment of ectoparasitic infections; review of the english-language literature nasal carriage of staphylococcus aureus: epidemiology and control measures centers for disease control and prevention. community-acquired methicillinresistant staphylococcus aureus infections-michigan methicillinresistant staphylococcus aureus, epidmiologic observations during a community acquired outbreak emergence of pvl-producing strains of staphylococcus aureus bacteriology of skin and soft tissue infections: comparison of infections in intravenous drug users and individuals with no history of intravenous drug use outbreak among drug users caused by a clonal strain of group a streptococcus. dispatchesemerging infectious diseases bacteriological skin and subcutaneous infections in injecting drug users-relevance for custody wound botulism associated with black tar heroin among injecting drug users isolation and identification of clostridium spp from infections associated with injection of drugs: experiences of a microbiological investigation team greater glasgow health board, scifh. unexplained illness among drug injectors in glasgow embolization of illicit needle fragments right ventricular needle embolus in an injecting drug user: the need for early removal departments of emergency medicine and pediatrics, lutheran general hospital of oak brook, advocate health system. emedicine-human bites prevention and treatment of dog bites human bites. department of plastic surgery guidelines for public health management of meningococcal diseases in the uk planning, registration and implementation of an immunisation campaign against meningococcal serogroup c disease in the uk: a success story efficacy of meningococcal serogroup c conjugate vaccine in teenagers and toddlers in england quadrivalent meningoimmunisation required for pilgrims to saudi arabia risk of laboratory-acquired meningococcal disease cluster of meningococcal disease in rugby match spectators immunisation against infectious disease. her majesty's stationery office ciprofloxacin as a chemoprophylactic agent for meningococcal diseaselow risk of anaphylactoid reactions joint formulary committee - . british national formulary notification of tuberculosis an updated code of practice for england and wales statutory notifications to the communicable disease surveillance centre. preliminary annual report on tuberculosis cases reported in england, wales, and the prevention and control of tuberculosis in the united kingdom: uk guidance on the prevention and control of transmission of . hiv-related tuberculosis . drug-resistant, including multiple drug-resistant, tuberculosis. department of health, scottish office control and prevention of tuberculosis in the united kingdom: code of practice epidemiology of tuberculosis in the united states nosocomial transmission of multi-drug resistant tuberculosis among hiv-infected persons-florida the continued threat of tuberculosis tuberculosis-a clinical handbook the white plague: down and out, or up and coming? a prospective study of the risk of tuberculosis among intravenous drug users with human immunodeficiency virus infection influence of tuberculosis on human immunodeficiency virus (hiv- ): enhanced cytokine expression and elevated b -microglobulin in hiv- associated tuberculosis the chest roenterogram in pulmonary tuberculosis patients seropositive for human immunodeficiency virus type coronavirus as a possible cause of severe acute respiratory syndrome epidemiological determinants of spread of causal agents of severe acute respiratory syndrome in hong kong alert, verification and public health management of sars in post-outbreak period age-specific antibody prevalence to hepatitis a in england: implications for disease control phls advisory committee on vaccination and immunisation. guidelines for the control of hepatitis a infection control of a community hepatitis a outbreak using hepatitis a vaccine seroprevalence of and risk factors for hepatitis a infection among young homosexual and bisexual men outbreaks of hepatitis a among illicit drug users identifying target groups for a potential vaccination program during a hepatitis a community outbreak multiple modes of hepatitis a transmission among metamphetamine users past infection with hepatitis a among vancouver street youth, injection drug users and men who have sex with men implications for vaccination programmes key: cord- - ycwmyg authors: richardson, jacques g. title: the bane of “inhumane” weapons and overkill: an overview of increasingly lethal arms and the inadequacy of regulatory controls date: journal: sci eng ethics doi: . /s - - - sha: doc_id: cord_uid: ycwmyg weapons of both defense and offense have grown steadily in their effectiveness—especially since the industrial revolution. the mass destruction of humanity, by parts or in whole, became reality with the advent of toxic agents founded on chemistry and biology or nuclear weapons derived from physics. the military’s new non-combat roles, combined with a quest for non-lethal weapons, may change the picture in regard to conventional defense establishments but are unlikely to deter bellicose tyrants or the new terrorists from using the unlimited potential of today’s and tomorrow’s arsenals. the author addresses the issues that are raised by this developing situation with the intent of seeking those ethics that will enable us to survive in a future and uncertain world. progress in military medicine, often even setting the pace for civil applications ,a contrasts fiercely with warlike preparations devoid of unredeeming motives. in the endless spiral of staying ahead in retaliatory capability, some governments continue to a. the great reforms in hospital organization and medical treatment resulted from the revolutionary and napoleonic wars of - and the crimean conflict of - : see richardson, j. ( ) . develop weapons with a destructive force well beyond the needs of national defenseand coincidentally make them available to the new terrorism. when the iberian conquistadores explored the new world, one of their many discoveries was the use by the peoples of central and south america of toxic substances to raise the effectiveness of their bow-and-arrow armories. parreira brava (pareira, or chondodendron tomentosum) is the portuguese designation of a vine found in the southern hemisphere, the source of a traditional diuretic treatment. curare, another derivative term in portuguese (from kurari, in carib), and pareira are the sources of a strychnine-like substance capable of arresting motor-nerve reactions in physiological experimentation. they can, in sufficient dosages and with much accompanying pain, kill human beings. strychnine, an alkaloid, is found in the seeds of a tree native to india, strychnos nux vomica. strychnine was long used as a tonic and as a stimulant of the respiratory and cardiovascular systems. but its effects on the overall human organism, highly toxic, finally excluded the substance from modern therapeutic use. poisons of this category were at the root of the formulation in of the treaty of strassburg (today strasbourg, france), a protocol designed to ban poisoned projectiles. this pact became part of the-nearly-persistent western taboo on the use of toxic weapons, a proscription finally broken in the th century with the episodic uses of "poison gas". then came the brash use in of toxic agents by russia's alpha anti-terrorist team to overcome the seizure of hundreds of hostages in a moscow theater by breakaway ethnic chechens. this violent action took the lives of nearly innocent theatergoers. moral repugnance is an attribute that public opinion often confers on the scientistinventor, the boffin or "mad scientist", who designs means of human destruction increasingly destructive and massive in effect. this revulsion dates from the th century's enlightenment, when "natural philosophers"-today, scientists and engineers-became increasingly active and could be identified by laypersons as those contributing to knowledge and the progress of civilization. in the closing months of the th century, when a cash-hungry robert fulton presented his plans for the submarine nautilus to napoleon's directory, the american inventor went to great pains to deal with the moral dimension of a novel instrument of injury and death. conscious of the historic abhorrence of stealth on the part of an enemy (at least in many of the western cultures), fulton sought to cope with the element of furtiveness during his blandishments for a contract from the french naval ministry in . according to biographer cynthia owen philip, the american inventor delivered to the french navy in july of that year, along with a letter of petition to do business, an essay on "observations on the moral effects of the nautilus should it be employed with success". fulton's twofold purpose was "to defend the submarine as a humane weapon and enhance his reputation as a humane inventor". (p. ) this justification for military submersibles "exude[d] suppressed rage and frustration at the [french] government for not having accepted his magnanimous and humanitarian scheme"… . (p. ) if the french should not adopt his plan for an undersea vessel, fulton foresaw the british and americans quickly bringing their own submarines to perfection-as could lesser nations such as denmark and sweden. the latter would thus dispense with the large costs of building surface navies, ran his argument, simply by equipping themselves with underwater craft. after napoleon's return from his first italian campaigns he named pierre forfait navy minister, and it was thus forfait's charge to deal with fulton. although fulton arranged a demonstration for "the scientific and naval establishment and the general public" in june along the seine near the invalides, forfait himself was of a mind that "the nautilus infringed on the laws of war". (p. ) the show went on, but napoleon would not let himself be persuaded that fulton's submersible was meant for the french sea arsenal. this denial by napoleon of an opportunity to gain a military advantage by the admission of a novel device into his armory is not unlike the chinese denial of the use of gunpowder for warlike purposes; a decision taken in the th century: an option that cost them dearly when faced with gunpowder-based british sea power in the th century and thereafter. the lacedaemonians in southern greece are supposed to have used, as early as b.c., wooden faggots covered with flaming pitch and sulfur as offensive weapons. not until the early th century, however, is there record of broader use of harsh agents. in prussian troops under general count friedrich w. von bülow engaged units under the command of french marshal michel ney, replacing their bayonets with brushes soaked in hydrocyanic acid. cyanide is a weak acid but one of the most highly toxic of all chemicals. then, in the s, french and british specialists devised respectively an incendiary and asphyxiating shell for artillery and a shell filled with an arsenic derivative. lieutenant yamamoto yoshinaka, a -year old twice-wounded in china, watched as "boats emerged from boats" (landing craft) in the united states armada, disgorging on okinawa four divisions of young americans. forty-three of the fifty-one men in yamamoto's unit died, the lieutenant himself wounded by shell fragments all over his body. fearing that gangrene would set in, he amputated part of his left arm: wedged against a tree, he wielded his saber by using his good right arm. yamamoto survived. neil mccallum, an american marine eighteen years old, was in the detachment that finally recaptured the island's "sugarloaf hill" in june of the same year, . as he and his comrades made way for a relieving column, mccallum took part of an incoming japanese shell in his right leg. handicapped and in pain for much of the rest of his life, the former marine met the former japanese lieutenant when the two participated in the opening of the peace memorial on okinawa in . "we need a better way," said mccallum to an american journalist, "to settle disputes." while the search for this 'better way' is in hand it seems that we are doomed to be locked into an escalating spiral of increases of harmful capabilities followed by inadequate treaties and conventions to prevent the use of such novel armaments. a participant in the second world war would recall afterwards that "[t]he protracted, wailing sigh of japanese soldiers burned alive [by american flamethrowers] in the caves of okinawa is the worst sound i have ever heard". this was the reminiscence of a former member of the united states marine corps when interviewed in a documentary film on okinawa produced in by the france television channel. the modern flamethrower-no longer a burning arrow or flung bucket of flaming pitch-was invented in by a berlin engineer named richard fiedler. he may have taken his idea from traditional pleasure pyrotechnics such as the chandelle romaine (roman candle) or fusée volante (flying rocket). fiedler devised a small model of his notion of a flammenwerfer, capable of spurting a flame of burning petroleum product (most often oil) a distance of m, and a larger model intended to be vehicle-borne-and with twice the range. german ground forces tested and adopted the new weapons in the years preceding the first world war. the german army used the flamethrower "live" for the first time in against allied troops in belgium. the french and british armies retaliated after a short delay entailed by hurriedly designing and fabricating an equivalent device. both sides intended the new weapon to be largely an instrument of momentary terrorism on the battlefield, although when its victims survived their third-degree burns they were inevitably maimed. at verdun in , flamethrowers added another dimension of horror to the veritable holocaust that dragged on there for nearly eleven months. in the second world war the british and americans added a jellied chemical mixture, napalm, in both backpack and vehicular versions of the flamethrower that transformed fiedler's weapon into a truly demonic arm. the viscous mixture of napalm, clinging to targets and burning slowly with intense heat, is often a soapy aluminum salt of acids such as the aliphatic hydrocarbons. typical hydrocarbons of this type are butane, propene (or propylene) and acetylene, whose carbon chains and rings are synonymous with high combustion. when these compounds are mixed with gasoline, they may be stored easily in flamethrower reservoirs, artillery shells or aerial bombs until ignited by a priming flash or spark. the arm is used against camouflage materials, obstructing underbrush, gunports of concrete or earthen bunkers, and against human beings (whether soldiers or terrorists) in caves, caverns or cellars. flamethrowers were used extensively during the pacific conflict of - , the korean hostilities in - , and during the wars in vietnam from the s to the s. high-concussion explosives did cave-and tunnel-cleansing work in afghanistan, - . both are thoroughly vile weapons, overkilling when not overwounding their intended human targets-and leaving surviving victims permanent, costly wards of society. in the government of the united states announced that it would rid itself of all remaining stocks of napalm: . million kg of the highly flammable jelly stored since the mid- s in , aluminum canisters at the fallbrook naval weapons station in california. the navy was required by local authorities to present, in public hearings, an explanation of the disposal procedure. the disposal operation, requiring five years and $ million-a net cost of a little more than $ per pound-involved having a contractor extract the liquid from its canisters and selling the product as a fuel for kilns in cement factories. how did the treaty of strassburg stand up to the evolution of science and technology? how did the scientifically based haber's constant-the product of the concentration of a substance as parts per million in a fixed volume multiplied by time in minutesbecome, during the first world war, the measure of effectiveness of chemical agents as weapons? b, (p. ) visitors to the national gallery in ottawa are vividly reminded of the human sequel to the work of the german chemist, fritz haber, against canadian and other infantry in belgium (april ) by william roberts' painting, "the first german gas attack at ypres". a comparable work by john singer sargent, "gassed" ( ), is on display at the imperial war museum in london. in the first world war the canadians found themselves adjacent to the troops hardest hit by the gas, a french territorial division and a division of algerian infantry, all of them deployed north of the small belgian rural community of ypres. at hours on april came a german bombardment, "... as sudden as it was severe". the attack proved to be "a dramatic forewarning of the enemy's power to upset preconceived ideas". fritz haber, a leading industrial researcher in germany, was among the many scientists and engineers working for his country during the first world war. he obtained his doctorate at the technical university of karlsruhe, where he became professor of physical chemistry in . at that time a colleague described haber as of lively spirit, impulsive, even capricious, a good lecturer who could discuss amicably almost any subject. haber achieved his place in the pantheon of research, before the conflict, by co-developing the haber-bosch process for the synthesis of ammonia from its elements-and for which he would win the nobel prize in chemistry awarded in . his wife, clara immerwahr, was the first woman to obtain a doctorate of science from the university of breslau. haber was able to synthesize, with the aid of his young british assistant robert le rossignol, ammonia from hydrogen and nitrogen by resorting to new laboratory conditions: a temperature of ° c. and pressure exceeding atmospheres, using osmium (a rare metal-later supplanted by cheaper iron combined with aluminum, calcium and potassium oxides) as catalyst. in july haber and le rossignol produced some seventy drops/minute of synthetic ammonia in the presence of directors of the world's largest chemical producer, badische anilin und soda fabriken (today's basf). four years later, on the eve of the great war, basf was producing commercially about tonnes of synthetic ammonia daily. in the blockade of german ports by the british navy cut off chile as germany's source of nitrates for both fertilizer and munitions. the germans were able to confiscate , tonnes of chilean saltpeter found in antwerp. germany of industrial nitrates could have caused her to negotiate a peace during the first year of the conflict, but this was not to be. with war declared, haber was appointed a reserve captain and worked to the point of exhaustion to develop toxic gases for use in the field: chlorine, for example, delivered not by projectile (the hague conventions of and outlawed this) but released from thousands of -kg containers deployed near the enemy's trench system. here we have the epitome of dual use: scientifico-technological processes capable-through minor adjustments in production-of application to either civil or military/terroristic ends. haber appears to have fancied himself a technical superstar of the war, explaining to scientific colleagues such as otto hahn that imperial germany's use of gas was justified by the first use of (tear) gas by the french against german troops in december . first use by the french was not true, according to his principal biographers, dietrich stolzenberg and son ludwig f. haber. a few weeks later russian troops on the rawka river west of warsaw were attacked by a non-lethal lachrymatory gas, xylyl bromide, known to german military engineers as t-stoff. ambient temperatures caused the t-substance to solidify, however, neutralizing its effectiveness. haber's operational aim on the western front was to pierce, with gas, the front lines over a distance of km, allowing german infantry to break through the british-french trenches. all german troop commanders refused to take part in this assault with the exception of prince albrecht of württemberg, who faced the allies in fierce combat at ypres. german observers of the initial gas attack included, besides hahn, james franck and gustav hertz-on whom nobel prizes not related to the war would also be conferred later. max born, a future nobelist too, refused to be present. after delays in launching the first attack on the western front by german pionierkommando (combat-engineer) troops, the fifth alert occurred the afternoon of april . one-hundred fifty tonnes of chlorine were released from , pressurized cylinders in ten minutes over a sector , m wide, near langemarck outside ypres. the franco-algerian units were routed, but the germans advancing (and still lacking promised masks) were impeded by pockets of gas. nightfall came, as it were saving the day for the allies, despite , killed and easily three times as many injured by the toxic clouds. (pp. - ) in actions that followed along this front, french and british forces retaliated in kind. surviving soldiers were invalided, many of these men finally coughing themselves to death. the wartime occupation of chemist haber, who was back in berlin by may to receive friends at dinner, was the direct cause later the same night of his wife's suicide. fourteen-year old ludwig haber (whose mother was haber's first wife), awakened by a gunshot, found his stepmother in a pool of blood in the family's garden. immerwahr had used her husband's service pistol to do away with herself. "haber was, without a doubt, the originator of chemical warfare", the nobelwinning biologist max perutz maintains. (p. ), the earliest chemical-warfare assaults were primitive and risky maneuvers, therefore, with the gases used likely to be blown back by shifting winds literally into the faces of those launching them. chlorine was the first agent used, unreliable in the pathological sense but with enormous psychological impact on french, british and (in poland) russian troops. the idea was to have "gas clouds" enter the respiratory system and deprive the organism of oxygen by inflaming the bronchi and the pulmonary air sacs. this caused a strain on the heart and, within hours, pulmonary edema would follow with a drowning of the lungs. if the victim survived a gas attack, he became almost always a chronic invalid, society's charge. by winter - the chlorine clouds discharged towards the adversary consisted of percent phosgene (cocl ), a relatively simple compound, one that would be used devastatingly by austro-german forces in october , in the last of the dozen assaults against the italian army along the isonzo river in the limestone heights of the julian alps, between austria and the junction of italy and slovenia. c german forces also tested hydrogen cyanide as a field gas, but it proved too light to manipulate. antidotes and anti-gas defenses were quickly developed, as was a gaswarfare potential among the allied forces; but gas cases remained an additional burden in the evacuation of casualties. escalation of chemical warfare continued, with the allies favoring mustard or blistering gas (dichlorodiethyl sulfide) and phosgene, whereas the germans preferred diphosgene (trichloromethylchloro-formate)-all of these, by now, packed in special artillery shells for more pinpointed delivery than had been possible by simply opening cylinders of compressed gas and pointing the jets towards enemy formations. among all the belligerents, the gas mission was entrusted to engineers or artillery until specialized chemical units could be organized and trained. these troops reached a maximum, on all sides, of perhaps , in . in the following year when the united states joined the allies, the u.s. army created the st gas regiment (commanded by an engineer, colonel amos fries), the genesis of the ultimate chemical warfare service (cws) headed by another engineering officer, major-general w. l. sibert. one of the university chemists recruited into american chemical warfare in was james b. conant of harvard, who would serve again his country's scientificmilitary effort in the second world war, participate actively afterwards in the administration of occupied western germany, and become u.s. ambassador to the german federal republic. the cws was to be the provenance, by the second world war, of the american bacteriological-warfare potential based at fort detrick, maryland. the use of shells and cartridges to facilitate gas delivery, likely first fired by the french at verdun, was a violation of the hague conventions signed in and . but the fat was in the fire for the rest of the -month conflict as both sides also experimented with chloropicrin-a reagent having, like diphosgene, both a high boiling point and a high vapor-density relative to air. tear gas, which may have seen first use against criminals by french police to combat the violent jules bonnot gang in , found applications on the battlefield, especially after trench warfare appeared, and helped stabilize the main line of resistance between foes. the lachrymatory gases used were based initially on ethyl bromoacetate but, because bromine proved scarce in c. today's kaporid, in slovenia, saw the austro-germans under von bülow break through the italian front on october and take prisoner , officers and men, together with more than , artillery pieces. the austro-germans used phosgene in this campaign. wartime (it was available only in germany and the united states), the french military switched to chloroacetone. otto hahn, who would ultimately head the radiochemistry laboratory at the kaiser wilhelm institute of chemistry in berlin where residual radioactivity was found when uranium absorbs neutrons, was one of fritz haber's coworkers in gas warfare, a "gas officer" in belgium. so were were james franck and gustav hertz, who later divided the nobel prize in physics ( ) for discovering the laws governing the impact of an electron on an atom. these scientists did not always get along with the military; producing a dilemma because many chemists believed that science was a force for good and that it ought not be diverted to what they saw as inhumane purposes. that is how hermann staudinger, hahn's contemporary, looked at the problem. chemists, he argued, were not only scientists but also communicators and among their duties was the education of people in the effects of modern scientific warfare. for many years after staudinger's death his widow, magda (also a researcher, with whom the author often conversed in the s), carried forth her husband's message with the belief that the world has faith in science, that research should be used only for social advance. chemical warfare continued throughout the first world war and proved to be a monstrously diversified form of armament. german offensive capabilities peaked in august . british gas casualties numbered about , per week as late as september-october . the german military machine, meanwhile, progressively deteriorated because of generalized attrition and a massive breakdown in morale. according to l. f. haber in a chapter called " : reality and imagination", it was the casualties from mustard gas used by the allies that "contributed to the running down of the machine." if available in sufficient application, in other words, mustard gas can kill... and does-as saddam hussein's action against the kurdish village of halabja showed again in , as discussed further on. that gas can and does kill extensively was in little doubt when a major international newspaper headlined, in , a front-page article, "britain to advise public on surviving gas warfare." shortages of rubber and cotton fabric weakened furthermore the gas defenses of german troops, and it was the german side that brought trench warfare to an end. toxic agents, besides sowing terror on the opponent, neutralized allied artillery and incapacitated both machine-gun crews and infantry, and contaminated the ground beneath them to discourage the bringing up of reinforcements. (pp. - ) a war of movement was never really resumed, and armistice came for all the belligerents on november . wartime nazi germany is not known to have used chemical warfare, perhaps for the singularly personal reason that adolf hitler was gassed during the first world war. d d. a strategic reason may be that a chemical-defense general of the wehrmacht, johann albrecht von blucher, advised against the use of gas because of germany's inferior air-power. in november american brigadier-general alden waitt revealed nevertheless that a vast store of a quarter-million tonnes of toxic products was discovered in western germany, a testimonial to the extent of german preparedness for war with chemicals. waitt added, also publicly, that the united states itself was at that time turning out the most powerful military gases known. the use of chemical and other weapons corroding the human organism was never admitted publicly during the second world war, although unconfirmed uses of chemicals by japan's invasion forces in china crept periodically into the news. the chinese government even claimed that japanese chemical weapons were used more than , times in china against both military and civilians, taking the lives of , civilians. one may conclude that japan had no intention to exercise strategic restraint on china's mainland. indeed, the japanese military in had established a factory on the island of okunoshima, paradoxically only km from the ill-fated city of hiroshima. this facility eventually produced "mustard" and similar vesicant, or liquidproducing and blister-raising, agents, and phosgene and other asphyxiating substances. at the end of the pacific conflict, arriving allied troops found okunoshima and proceeded to dump some , tonnes of its lethal products into the pacific ocean. in addition, more than two million japanese poisonous shells were left at the war's end in munitions dumps in china. at the end of the th century's second major conflict, accumulated stores of german and allied toxic agents and their packaging were dumped-about , tonnes by -into the north and baltic seas by the soviet union and its erstwhile partners in war against the third reich. the united states went so far as filling wartime liberty ships with the deadly substances and then scuttling the vessels at sea, far from coastlines. afterwards commercial fishermen occasionally suffered injuries from toxic projectiles or storage containers brought up in their nets. in , over half a century after the war's end, shells at the bottom of these waters continue to ooze poisonous gels. russia announced in the late s that it would no longer produce a gas called novichok (newcomer) that reacts on the human nervous system. the agent, according to russian chemist vil mirzayanov, is percent more potent than any substance known. mirzayanov, born in , worked for many years in the soviet union's program of biological and chemical warfare. in he published an article in the moscow news in which he declared that he had participated in the development of novichok. russian authorities considered this a violation of five (unspecified) russian laws, and the chemist was jailed first at the lefortovo, then at the matrosskaya tishina, prisons. mirzayanov's case came to trial in before the moscow district court, where it was found that the scientist had been unfairly prosecuted. russian agencies were ordered to pay a total of million rubles [$ , at the prevailing exchange rate] in restitution: million by the government, million by the institute of organic chemistry. mirzayanov and his attorney declared that their victory was the first in contemporary russian history that awarded damages in compensation for arbitrary action by the state. despite the judicial decision, mirzayanov remained without passport and permission to travel abroad. we note, however, that one of the instigators of the trial, retired general anatoli kuntsevich, chairman of the committee on problems of chemical and biological disarmament, was dismissed from his post immediately following the court's decision. continued research and development of this kind would make a farce of both russia's obligations to the chemical weapon convention and of the initialing by presidents boris yeltsin and bill clinton in of an agreement to begin destroying both countries' remaining stocks of chemical and biological weapons. mirzayanov contended that russia, instead of having a reduced stockpile of , chemical arms, had in fact a total of , . the new russian constitution prohibits, furthermore, secret legislation. in reaction to the secret trial of the russian chemist, jo husbands of the national academy of sciences in washington advanced her opinion that "either the russians have a nerve-agent program they deceived us about or they don't, and there are [therefore] no grounds for prosecuting mirzayanov." and there this matter stands. neutralizing existing stores of chemical arms is possible via chemical means. the united states army is committed, for instance, to the destruction by of stockpiles of chemical agents and munitions using them. nerve agents are stored in bulk containers at newport, indiana. there the military pilot-tested one neutralization process by using either water or sodium hydroxide to break offensive molecules into simpler compounds which can then be safely released in the environment. remaining trace compounds require further treatment, however, in order to meet ecological norms. for this, a process called supercritical water oxidation is used: dissolving the noxious compounds with extreme water pressure at high temperatures. the process is being constantly improved. once the new international law on chemical weapons came into force, the pact automatically created the statutory organization for the prohibition of chemical weapons, opcw. opcw (a) supervises the destruction of chemical weapons and their associated facilities among the signers and (b) manages an inspection system to ensure compliance by the military and civil chemical industries. in this way we should be able to foresee, if not the scrapping of chemicals as agents of hostile action, at least some limits to death by chemical weapons. russia's experience with the design, manufacture and storage of chemical arms (first produced in in moscow) dogged president boris yeltsin during much of the s. chemist lev fedorov, who presided over the independent union for chemical safety, stated in that "our preparations for chemical war had disastrous consequences". charging the post-ussr government with not being forthcoming about medical and environmental damage resulting from the handling of chemical arms throughout the soviet decades, fedorov judged that many thousands of factory workers died, especially before the mid- s. production plants lacked proper means of protection, dumping contaminated water into streams, "not filtering gaseous discharges, and burning lethal materials at open sites," the chemist charged. the burning of mustard gas at kambarka caused soldiers there to develop cancer. vladimir uglev, another scientist once associated with the soviet chemical-weapons program, said that his birthplace of sikhany had the highest cancer rate of its region; sikhany once produced chemical arms. the towns of novocheboksarsk and cheboksary, in russian chuvashia some km southeast of moscow, were confronted with a problem of their own. first exploited as centers for the manufacture of nerve gas, cheboksary and novocheboksarsk were then expected to rid themselves of their lethal stockpiles- , tonnes of it-by burning them in the plants whence they had emerged. with the radioactive terror of chernobyl still fresh in the public mind in russia and ukraine, combined with a petition carrying , names, a local legislator by the name of venera a. pechniyakova wanted her community to have no part in the burning of toxic substances. so the legislature simply banned the transport of chemical weapons throughout chuvashia. this effort was crippled, however, by insufficient funds, a bureaucratic posture by the national arms control authority, and little interest by the russian military-badly in need of cash to house and feed a diminished force. the perplexing situation in chuvashia, when combined with analogous problems in so many other places in russia, added to the peril that extant weapon systems might fall into the wrong hands. in , the national academy of sciences in washington recommended to the american government a policy of collaborative research between russia and the united states on "pathogens that can pose serious threats" to public health. the policy sought to exploit the availability of trained but underused scientists in russia and, one can presume, to deter them from more lethal activities. nato, too, stepped in frequently to lend a hand in dealing with the environmental aftermath of using specialized weapons. at a workshop held in poland in , specialists adopted specific actions to solve problems posed by arsenic compounds left in the natural environment by old arms systems: • determine what chemical products form when reagents escape from munitions into surrounding soil and water, what further chemical transformations occur, and their effects on living organisms; • develop a mobile reactor for using detoxifying agents (sodium sulfide, sodium hydroxide) to mix with 'lewisite-mustard'; • examine the practice of adding adamsite (a harassing agent based on arsenic) to concrete mixtures so as to immobilize concrete once it has set. (do arsenic compounds leach from hardened concrete, for example, into ambient water?) the military have the funds to undertake such actions, an effort that would not have been envisaged in the less environmentally-conscious s or s. when south africa's truth and reconciliation commission ferreted out what some of the country's military suppliers had purveyed during the worst years of racist oppression, it found exaggerated applications of r&d to "do in" people, brutalizing them at the individual level: anti-apartheid persecution. hearings of the commission in revealed that the chemical and biological program functioned as late as the s under the direction of a cardiologist, wouter basson, who once served as personal physician to former president p.w. botha. bioengineer jan lourens ran a south african firm called protechnik whose main product, at first, was protective clothing but which soon developed sidelines such as explosives concealed within boxes of soap, poison-tipped umbrellas, and a walking stick capable of firing toxic pellets. the virility and fertility of the country's black population was a specific target of such companies working under governmental contract. this paramilitary application of official apartheid policy aimed, quite clearly, at the selective injury or death of native blacks-while leaving the white part of the population untouched: governmental terrorism in a failing state. when the united nations' special commission on iraq (unscom) was forced by that country's leader to abandon in december its monitoring of what iraq might be developing as weapons of mass destruction, the international inspection group determined that iraq had progressed in terms of developing • biological weapons: culturing enough anthrax bacteria to produce , liters of infectious agent to be held in reserve, • chemical arms including a supply of artillery shells filled with mustard gas, together with at least one and a half tonnes of the nerve reagent vx, and • what may be a long-term missile project, spread among twelve different national facilities. the inspections were resumed in the winter of - , brought to an abrupt halt in february at the instigation of the united states, without having found newly incriminating weapon systems. nor were such systems found by the time of this writing (march ) following the occupation of iraq by coalition forces. whether such systems ever existed, were hidden with great expedition or were removed to another country remain unsolved questions. in an age when pragmatic technological fallout is a measure of the dual-use value of military innovations and their acceptance by the public, one of the few positive results of the development of chemical warfare has been a series of marked improvements-beginning with the use of charcoal e -in the development of the respirator or gas mask. numerous peaceful applications have saved many lives among miners, firefighters, divers and "frogmen", and other specialists coping with toxic-substance accidents. the experience acquired in the first world war may have had an important role in the decision by both sides in the second world war to forgo the use of toxic chemicals. whether this was due to the mutual stand-off in cost-effectiveness calculations or a result of hitler's experiences in the trenches can be debated. the limited use of toxic chemicals by the japanese was of limited significance in the direction of the war in the eastern hemisphere. economically speaking, overkill overcosts. the chemical or biological toxins stockpiled for destruction in the united states, for example, are spread among nine different depots-the major one being the tooele army depot chemical demilitarization facility in utah. during the last decade of the th century, secure storage and inspection cost the taxpayers $ billion, pending complete incineration by specially designed furnaces in order to destroy safely the various agents stored. once the agents and their delivery systems (the integral weapons) have been destroyed, it is hoped by the year , the military will then incinerate the facilities themselves. "only water vapor, carbon-dioxide smoke, and some grainy ashes will remain." (pp. - ) this, at any rate, is the plan. in january chemists, biologists, medical experts, engineers, and specialists in the destruction of arms, representing germany, great britain, latvia, the netherlands, norway, poland, russia, sweden and the united states, met to lay plans for the further identification and neutralization of this contaminating vector. plans included developing a methodology and timetable for the destruction of abandoned weapons, under the guidance of both the north atlantic treaty organization and the chemical and biological arms control institute. it was important, said kyle olson, director of the institute, "to decide how much we want to spend now for having done the expedient thing in the past." funds were duly allocated by various governments; the work is expected to take some years to accomplish, while french farmers still plough up unexploded high-detonation shells dating from - . since the major conflagrations of the first half of the th century, there has been both the development and deployment of a range of toxic chemicals. many of these have been used on the battlefield while others have been liberated in unsuspecting communities that were ostensibly at peace with their fellow citizens. "dioxin" is a generalized label identifying a family of chlorinated hydrocarbons. an isomer within this group, known as tcdd or dibenzodioxin tetrachloride e. the chinese, koreans and japanese still use charcoal as an air purifier/dehumidifier and to make "india" ink. (c h cl o ), is the main culprit: a substance produced collaterally in the manufacture of pesticides and herbicides. even in trace quantities, it can be teratogenic-producing acute deformities-as well as carcinogenic among some animals, humans in particular. dioxin compounds were introduced in the indochinese peninsula by americans in as spray defoliants in order to deny to the communist side the cover provided by plant verdure in tropical forests. in all, some million liters of herbicides were sprayed on vietnam ( million liters between and ), leaving about one-tenth of the country and some neighboring over-the-border areas devoid of greenery. at least percent of the herbicides used was "agent orange", so called because of the identifying orange stripes used by the american military to mark the metal drums bearing the chemical. in july , the south china morning post of hong kong reported that as many as , people were still gravely ill from the effects of the chemicals used more than a quarter-century earlier. the officer who gave the order for their use was an admiral, elmo zumwalt jr., who revisited the region twenty-five years later. there, retired admiral zumwalt met (among others) two sisters of ten and eight years of age, neither of whom was more than cm tall; both had congenital deformities of the legs. during this visit in , zumwalt toured thanh xuan village, a rehabilitation center for retarded and deformed children. of the seventy children housed there, forty-nine had fathers who fought in southern vietnam, according to nguyen my hien, the school's director. zumwalt's own elder son served as a young officer in the mekong river delta, later dying of cancer that may have been caused by exposure to agent orange. not only were there probably many thousands of victims among the vietnamese; veterans of the american forces also claimed compensation for a variety of ills ascribed to the spraying of agent orange. the environmental protection agency (epa) of the united states issued, simultaneously with zumwalt's voyage to vietnam, a report stating that dioxin could be more likely a cause of cancer than previously believed. zumwalt commented that the epa declaration was "ample evidence to add significant other diseases" to the list of those in the compensable category. an american journalist covering zumwalt's trip to southeast asia added that, since the naval officer's retirement, zumwalt had made redressing the human damage inflicted by agent orange his personal mission. he campaigns for compensation for war veterans suffering from exposure to the chemical, and he is in vietnam to urge the government to cooperate in research on the herbicide's health impact... zumwalt and the american managers of the war had no idea at the time of its use that agent orange is a carcinogen. "it's the kind of tragic decision," zumwalt declared to the journalist, "that has to be made in warfare. we desperately needed something to reduce the casualties. we used agent orange to save lives. under the same circumstances, with no other alternatives.., i would do the same." in april the institute of medicine in washington released a preliminary report that some children of u.s. veterans of the vietnam war have a higher morbidity than usual among victims of leukemia. cause-and-effect remains, however, to be proved. in late the institute of medicine announced, in a judiciously worded report, that the "possibility of association" also exists between the chemicals used during the vietnam war as herbicides and the type of diabetes known as adult-onset type . a reevaluation of these agents (orange included) caused the institute's experts to establish "limited or suggestive" evidence of such association. this enquiry, not finished, is long-lasting. sarin, invented in germany in by gerhard schrader at the ig farben chemical trust, is combined from materials easily obtainable in the chemical industry. it is also far less complicated to fabricate than a thermonuclear bomb: a single human being can be done in by one ten-millionth of his/her weight of the compound. when inhaled as a gas, sarin reacts with an enzyme called acetylcholinesterase which, in turn, breaks down the neurotransmitter called acetylcholine, an enzyme normally carrying signals between muscles and nerves. sarin thus interrupts the orderly transmission of electrical signals within the nervous system. the product causes an overstimulation of muscles, the eyes are afflicted by spasms, and the bronchial tubes fill with mucus-leading to intense perspiration, uncontrolled defecation and vomiting, convulsions and paralysis, ending in respiratory failure: all this within minutes of inhalation. when absorbed through the skin, the reactions take hours but they are identical with those resulting from inhalation. unlike the heavier nerve gases (tabun, soman and vx), however, sarin evaporates readily and is thus quite hard to handle. depending on how sarin is manufactured, its shelf life can remain more than percent effective for decades. sarin produced by iraq for use against iran in the s, on the other hand, retained between and percent of its effectiveness after only two years of storage. therapy for an attack by sarin is possible, and modern armies have equipped their troops with kits of antidotes that are activated simply by slapping them against the thigh. atropine closes down the overly stimulated nerves, but this sedation can bring new risks; oxime drugs, on the other hand, can separate sarin from acetylcholinesterase so that this enzyme can resume its normal functions. another counter-agent is ricin, made from the castor bean. dissipated as a liquid or in aerosol form, however, ricin is toxic to the blood, leading to slow death by circulatory collapse. (the french police immobilized, early in , a terrorist-equipped laboratory near paris producing ricin and found another batch stored in a pay-locker at the gare de lyon.) the cure for sarin works chemically-but the patient dies. inadequate financing and weapons conventions were not problems confronting the illegal users of sarin gas when they attacked simultaneously five different subway trains making their morning rush-hour runs towards kasumigaseki in downtown tokyo on monday, march . the users of the deadly substance proved to be members of a secretive sect, aum shinrikyô. a trial run had occurred nine months earlier in the mountain town of matsumoto, with several dead. the toll in tokyo was twelve dead and , injured, including hundreds of hospitalized victims. controls on manufacture and stocking of sarin, involving about countries, should be facilitated and improved by the chemical weapons convention already cited. , , by the s an international accord came into existence that was intended once and for all to banish chemical arms and (the even worse) nerve gases that annihilated the kurdish population of halabja, iraq, in march . one-hundred thirty nations signed the chemical weapons convention (cwc) in in paris, and more within the two years following. the ratifications required for the convention to become international law had to wait, however, until . on the pathological side of the halabja genocide, membranes of the nose, throat and lungs as well as eyes and skin were attacked by a combination of mustard, sarin, tabun and vx. what happens if one survives such onslaught? a medical geneticist, christine gosden of the university of liverpool, visited surviving victims a decade later. she found that they suffered an incidence of such anomalies as infertility and congenital malformation (including breast and childhood cancers) three to four times that of unexposed populations nearby. neither chemotherapy nor radiotherapy was available in the region, a full decade after the attack. national-interest postures are sometimes difficult to fathom in the ruthless task of creating new weapons, at some point finding that they are unusually destructive, then seeking international agreement to limit their use or ban them outright. in president ronald reagan signed a law effectively removing the united states from the world of chemical arms, a unilateral effort by the americans to rid themselves of these devices by . remaining stockpiles, a half-century old, endangered their warehousing environments with leaking substances, and were in many cases unusable. yet the americans had still not ratified the cwc. despite the executive action by washington, it was a soldier, brent scowcroft, and a scientist-engineer, john m. deutch, who felt constrained to urge publicly the united states senate to go a step further and validate the chemical convention. they did not want their country to be categorized among the "pariahs", iran, iraq, libya and north korea. the convention took effect on april , and the united states senate at last ratified the cwc in the same year. a weapon in the generic group of mines, with hidden charges of explosives often supplemented by flying fragments of metal, the land mine is a product of th-century mass production. by the start of the st century, a land mine typically cost less than dollars, sometimes as little as $ . removing the device during the s involved expenses of between $ and $ , per mine, with the number of mines still buried around the world exceeding perhaps million-of which million are in africa alone. "i don't think i have ever worked with a group as sad as this," said magne raundalen, a norwegian psychologist and unicef consultant who has interviewed more than a thousand child victims of war around the world. he had just finished a group-therapy session with a dozen children who had stepped on land mines. for an excruciating hour, the visiting psychologist tried to strike some emotional chord with them. at first he offered soothing questions. later he tried jarring questions. it did not seem to matter. he could not connect. somebody once called land mines the devil's seed. if so, he planted one big crop in angola. the country is home to an estimated , land-mine amputees-nearly percent of the population. [the mines] were laid with minimal record-keeping during years of a civil war in which both sides... made civilians their primary targets. paul taylor of the washington post as with other potentially lethal devices, a land mine's "principal purpose is to maim rather than kill, since an injured infantryman is more burdensome to military support... than a dead one." (p. ) these inexpensive weapons are notorious for the toll they take of the side simply stepping on, or trying to neutralize, them. but their lethality takes no account of the numerous civilians falling victim to them, dead or maimed, even decades after the conflict in which the mines were laid-not to mention the enduring grief and demoralization experienced by the victim's family and friends. by the end of the th century a land mine killed or wounded someone, worldwide, every minutes. these buried weapons now kill more than , people yearly, percent of whom are civilians. the ottawa treaty ( ) banning landmines became effective on march . conspicuous by their absence as signatories were china, russia and the united states of america. the effort to ban land mines as weapons of mass destruction, according to kenneth anderson of human rights watch (a winner of the nobel prize for peace), brands them with "the same stigma we attach to chemical and biological weapons." in , president bill clinton's government volunteered to extend a one-year ban on the export of land mines for three years. when the restriction came up for decision again in the government in washington pleaded an exception to the use of mines-not their production or commerce-in order to protect its forces in the korean peninsula, a position that it maintains in . in commenting on a report issued by the pentagon on the use of land mines, a former commandant of the united states marines corps, general alfred gray, observed: "we kill more americans with our own mines than we do anyone else." the original, multi-nation mine-banning proposal, strongly urged by canada, was tendered in the context of the un's missile technology control regime. funds were sought to enable the secretary-general of the un to encourage mine-clearing operations where these have been "laid without maps in areas designed to protect economic targets or to instill fear in opposition soldiers and civilians", as stated in a study made by the united states department of state. there remains hope, nevertheless. with the united nations mine action service (unmas) as point of focus and the collaboration of several non-governmental bodies, the survey action center has set out to map mine dispositions universally and eliminate or otherwise control these by . the survey action center is managed by the vietnam veterans of america foundation, working closely with handicap international (based in belgium and france), the geneva international center for humanitarian de-mining, the land mine survivors network, medico international, the mines advisory group, the norwegian people's aid, and unmas itself. once president of the international committee of the red cross, cornelio sommaruga, regrets that "humanity has only once succeeded in banning the use of weapons considered unnecessary before they were ever used" until the end of the th century. he referred to the abolition, in , of exploding bullets. the icrc has successfully brought into force a ban on blinding laser weapons, too-after blinding laser rifles and other similar devices made the jump from science fiction to frightening reality-via protocol iv of the convention on certain conventional weapons of . sommaruga explained that "the beam of an antipersonnel laser strikes the retina and, in a fraction of a second, in most cases burns it beyond repair. there are no devices that offer protection...". the horrors of war are not limited to the action of humans on humans. during the first world war, according to the director of microbiological research at britain's chemical and biological defense establishment (cbde) in porton down, "several hundred thousand soldiers died of gas gangrene", exacerbated by their exposure to toxic agents. director richard titball has explained that gas gangrene, a serious infection developing in grave injuries that gives off putrid odors-from infected tissue deprived of any oxygen circulating in the wounds-has probably killed millions of soldiers, and civilians too: overkill, over time, via over-wounding. the bacterium causing most such infections is called clostridium perfringens, producing a protein known as alpha toxin. this toxin is also the active ingredient integrated purposely within some biological weapons. if limbs are affected, members will turn a necrotic black within a few hours. bacteria in one locale spread quickly throughout the body, however, and stop-gap amputation is followed nonetheless by death in most cases. seventy-five years after the end of the first world war, the cbde genetically engineered a vaccine against the natural agent that causes gas gangrene. the vaccine acts by inciting the immune system to make antibodies that counter the toxic bacteria (tests were first made on laboratory animals). the british ministry of defense filed patent applications worldwide to cover the innovation, while seeking partners to finance a scaling up of the vaccine's production. biological warfare goes back to the dumping of plague infected bodies over the walls of fortified cities such as kaffa (now feodissia, ukraine) in and the infamous use of smallpox against the american indians during the french and indian war of - by sir jeffrey amherst. probably the first case of biological warfare in the modern world dates from an incident occurring in august near a village in coastal zhejiang province, china, when a japanese aircraft was seen flying low over surrounding rice fields. a peasant woman named jin xianlan related that smoke poured from the rear of the aircraft over the community of congshan, and that a fortnight later rats began dying. the rats' fleas had infested humans by then, and within two months of the , villagers and farmers were dead. the japanese had sprayed bubonic-plague germs, taken from their extensive stocks in china of the microorganisms of anthrax, typhoid and bubonic fever. the use of such weapons was meant to terrorize, and it did. in november the japanese moved into congshan and burned the infested dwellings, "as the villagers were herded to a nearby slope to watch and wail as their possessions were incinerated." at the war's end, perhaps as many as million chemical projectiles remained in manchuria, or northeastern china. whereas the living germs stored in biological weapons have long since become extinct, chemical ammunition (loaded mainly with mustard gas) remains potent and perilous. the chemical weapons convention requires that such stockpiles be destroyed by . in december the chinese and japanese governments agreed to a combined effort to clean up the residual mess in manchuria. anthrax bacteria, which kill victims within a week by induced pneumonia, require only one hundred-millionth of a gram per individual to be effective. in nature, cattle and sheep are the usual victims. but the germs are easily made and used: they can be ground into minute particles for inhalation or produced for storage in dry form; the spores are stable enough to keep their viability after many years in water or soil. the u.s. department of defense considers, even after the attacks of anthrax through american postal channels in , anthrax treatable only by vaccine. between and a mass-immunization program for . million military and civilians (costing $ million) is administering a six-dose vaccination, followed later by annual booster inoculations. during the fighting on the korean peninsula in the early s, some american troops were stricken by an influenza-like illness-usually terminating in kidney failure-caused by an infectious agent called the hantavirus, named after korea's hantaa river. how the troops may have been infected remains unexplained. four decades later ( ), sixteen mysterious deaths in the southwestern united statesnear the decommissioned army post of fort wingate, new mexico-were attributed by medical authorities to hantavirus, a disease until then unknown in the united states. the normal vector of hantavirus is an airborne particle derived from the feces or urine of rodents. in the same year scientific american observed that the sixteen deaths, known as the four corners victims, could have originated in chemical and biological experiments launched during the decades after the second world war from dugway proving grounds, utah, to the north. fort wingate had been used at that time as an impact area for missiles fired from dugway and other army installations. a cause-and-effect link was not confirmed. yet the suspicion remained, and at least one historian of biological warfare, leonard a. cole of rutgers university, called for public disclosure by the department of defense. indeed, during the same year the united states congress called for the department of health and human services "to examine the feasibility of shifting some biological defense research from the army to the national institutes of health". it is remarkable that physician, army colonel and biological-weapons builder named kanatjan alibekov (he calls himself a bioweaponeer), deserted in kazahstan in from the russian-directed biological-weapons program, where he was its first deputy-director. alibekov has maintained, after establishing himself in the united states, that russian stockpiling of anthrax bacteria and smallpox and plague viruses has not been interrupted-and that research on these agents continues under the guise of defensive readiness against biological attack by an adversary. now known as ken alibek, the former soviet specialist warned the world that the threat of biological terrorism, in either combat or civil strife, cannot be mitigated. even if vaccination against every possible agent were feasible, alibek prefers that the world of research concentrate on (a) preventing disease that might occur after exposure, and (b) treating diseases that do occur. work of this type would also succor those contracting any dread malady under natural conditions. the specter of death or agonizing injury by unconventional weapons is inevitably evoked by the universal apprehension that many different countries might stock chemical and biological agents for surprise use. in the early s five nations officially held stocks of biological weapons: china, iraq, iran, russia and syria. three others (egypt, libya, taiwan) were suspected of possessing them, and north korea figured on some analysts' lists. two specialists at the australian national university in canberra, kevin clements and malcolm dando, estimated that while "chemical weapons are really a tactical threat, biological arms could be used in a first strike with devastating results over a wide area". clements and dando, citing a study published earlier by the un, compared the probable effects of nuclear, chemical and biological weapons as follows. the convention on biological weapons, first opened to ratification by its signatory nations in , lacked sufficient measures for verification of adherence to a treaty designed to ban the manufacture, storage and use of biological arms. new studies of the problem under way since the early s are beginning to throw some light on the problem. what happened to a friendly, totally unaware population near a weapons-testing center after the first soviet nuclear device was exploded in summer came to light only decades later. leonid ilyin, director of the russian public health ministry's institute of biophysics, told the journal new scientist in of the extent of human and material damage caused in a remote corner of the former soviet union. the altai region's uglovskiy district and its , inhabitants, living somewhat to the northeast of the test area, received on that occasion a dose of millisieverts (msv). this is times today's recommended annual limit ( msv) for workers in the nuclear industry, and times the dosage ( msv) for the public at large. some individual exposures to radiation, however, went as high as , - , msv. scientists at the university of munich's radiological institute have cautioned that a dose exceeding , msv can easily induce vomiting, diarrhea, hair loss, and infertility. the initial soviet test may have resulted, according to ilyin, in as many as , more cases of cancer than normal for the altai population sample. valery kiselev, director of the medical research institute for regional medical and ecological problems at barnaul, reported that two-thirds of the baby girls less than a year old exposed to more than , msv died before the age of five from pneumonia or other infectious ailments. this rate is . times higher than for infant girls not subjected to radiation. to make matters almost unimaginably worse, the area in question was the site of nuclear-bomb explosions until . of these, took place underground. among the remainder (and before the partial test-ban treaty of ), tests took place a few meters above ground level and were tested high in the atmosphere. ilyin noted that now "we have also to study the health of [the victims'] children, their grandchildren, and their great-grandchildren." a diabolical sidelight to the left-hand column of our table of comparative effects is to be found in richard rhodes' the making of the atomic bomb. in a passage discussing the real casualty rates at hiroshima and nagasaki, rhodes reviews the calculus of destruction adapted by yale pathologist averill a. liebow from a british method called the standardized casualty rate. working at the army institute of pathology in washington, liebow computed that "little boy [the uranium bomb dropped on hiroshima] produced casualties, including dead, , times more efficiently than a normal, high-explosive bomb" [emphasis added]. another use for uranium, this time in its depleted form, was found during the first gulf war when the radioactive metal was finely elaborated into a particularly lethal antitank device. depleted uranium (du) burns in air-is pyrophoric-and burns upon impact, thus burning its way through a target. it is du's very small particles which, upon being absorbed, cause potential problems. arnold kramish, nuclear physicist depleted uranium, more than nineteen times the density of water, is used to tip "darts" about m long. once fired, the darts cut through an armored vehicle's steel, according to one specialist, leaving a neat hole about the diameter of a golf ball. once inside a tank, "the uranium darts rattle around, killing the crews and battering apart the cabin." is this overkill, or merely a method to assure a disheartening effect on the crews' compatriots nearby? we have concentrated on overkill weapons as they have been, or might be, used against human beings as individuals or relatively small populations among military or civil targets in a hostile encounter. the horizons are much broader if similar means are used against populations of a major town or city, a region, or an entire national economy. water is often singled out as an effective vehicle for the contamination of a large target: from the poisoned well of old, it is easy to imagine the contamination of dammed volumes stored for mass consumption or irrigation. rivers crossing borders from one nation to another are often cited as causes for grave trouble should the flow of water be slowed, stopped or poisoned. the tripartite problem of water shared by israel, syria and turkey is the contemporary archetype. overkill through economic weapons is a specter awesome enough, but its extension to the food and water supply of an entire country terrifies. karl simpson, an anglo-german molecular biologist who has directed several european initiatives in industrial biotechnology, warns that, "in today's era of agriculture often dominated by monoculture, it is not infrequent that an entire harvest may be wiped out by a biological pest entirely natural in origin. this happened to the united states' maize harvest in ". simpson stresses, "i do not believe strongly in the reality of human biological menace. madmen and terrorists might well deploy simple biological weapons (anthrax, smallpox); sovereign nations do not present a real risk. i am much more concerned," very much as ken alibek has cautioned (see p. ), "about mother nature's worrying capability of throwing up new agents such as aids or ebola fever. when nature does get round to pulling something nasty from her toolbox, i hope that the military will be poised to provide a coherent response by providing medical and societal infrastructure." simpson's words virtually foresaw the outbreak of sars in the winter of - . the use of agents intended specifically to affect edible crops, such as using wheatsmut fungus to replace the wheat plant's flowering part, might appear as nothing more than a disease occurring quite naturally. but when used purposely as a weapon, the results would be tantamount to an imposed famine: "apparently anodyne.., with no explosions, bullets, mines or shrapnel". it could be "terrifyingly effective in causing mass casualties". a poor nation whose citizens rely on a staple such as rice, and "in which that rice crop is seriously damaged by a deliberate anticrop attack, could well experience famine that would be at least as costly... as an anthrax attack on a city." so karl simpson and others have reason to worry that, because these pests proliferate naturally, if they are "planted" deliberately the ensuing destruction would be calamitous. in the case of "military adventures", adds simpson, "the deliberate destruction of plants and livestock may threaten a nation with starvation and eliminate in weeks the capability" of a food-production program that took months or years to plan. not only would a population be decimated, but the resulting ecological imbalance could require years to restabilize itself and make human life viable again. despite the terms of international accords governing special weapons, the american department of defense took its precautions in the event that implementation of the chemical pact "fell short during the gulf war, [because] u.s. troops searching for iraq's scud missiles were inadequately equipped with vaccines in the case of attack with 'germ' weapons"… in the pentagon again stressed the need for its forces to be properly protected against poison gas, biological weapons and nuclear arms. two years later, the first face-off with north korea over its nuclear potential exacerbated fears of being unable to locate that country's caches of plutonium. the chief of staff of the u.s. air force, general merrill mcpeak, indicated that eventual attacks with conventional bombs on the north's graphite-core reactor could cause radioactive contamination of the region. an american senator charged that some of the mysterious illnesses experienced by servicemen returning from the gulf war of - could be attributable to biochemical substances provided to iraq by the americans themselves. donald w. riegle, jr., of michigan, contended that between and the department of defense-still stinging from iran's actions against the united states in teheran in -shipped, with presidential approval, toxic agents to iraqi forces, substances including e. coli, salmonella and other infectious bacteria. (press enquiries made in revealed that iraq's main sources of 'culture collections' in the s were a virginian laboratory and france's pasteur institute.) authorities representing military-medical and veterans' interests investigated, the senator said, hundreds of cases. in a special panel of the national academy of sciences' institute of medicine in washington announced that it could not confirm the complaints. this group of physicians, specialists in environmental health together with epidemiologists, stated that it "could find absolutely no reliable intelligence, and no medical or biological" substantiation of claims that poison gas had been employed against coalition forces in the winter of - . the panel further dissociated the so-called gulf war syndrome (disturbances of sleep, changes in mood, persistent aches and pains) from origins in "chemical, biological or toxin warfare, or accidental exposures to stored weapons or research material" in the iraq-kuwait zone. these facts notwithstanding, british and american coalition forces entered iraq during the second gulf war physically equipped to meet toxic agents head-on. in other words, simpson estimates that "the best thing to emerge from biowar scares is enhanced military preparedness to deal with a natural outbreak of new disease". colonel erik henchal, commanding america's army medical research institute of infectious diseases told the new york times in january that, while his goverment is taking steps to inoculate troops and some civilians, terrorists "could well turn to other agents". armed conflict and its seemingly unstructured companion, universal terrorism, became increasingly perilous as the industrial revolution emerged into the globalized information-and-communication revolution. wounds, disability and death are as increasingly daunting to modern military commanders as is management of logistics and communications. although such attrition affects terrorist leaders much less at present, it is only a matter of time before they too will seek to conserve their human and material resources. the hague and geneva conventions, some of them well over a century old, invoke the need for reinforcement and more universal application. the so-called fourth convention, assuring the protection and proper treatment of non-belligerent civilians as victims of war, was put to sore test during the second gulf war. the worldwide antiviolence and peace-research movements such as the pugwash conferences call for proactive roles by scientists, engineers and technicians in addition to ordinary citizens and the military themselves. in washington the naval studies board of the national research council (note the proactive juxtaposition of scientists and military) completed in , shortly before the outbreak of the second gulf war, a -page analysis of the need to develop non-lethal weapons. risk aversion-and even the precautionary principle-are today major constraints on formal strategists, operational and tactical officers of contemporary military services-not to mention their commanders-in-chief. the same inhibitions do not apply, obviously, to the world of terrorism. threats of destruction today and tomorrow, whether by terrorists or the military, will continue to menace the human race. whether collectively or individually, overkill is unlikely soon to become underkill. whether or not an updated version of the united nations can acquire the kudos and the power to keep order in the world is a matter that remains to be resolved. this may not be the time for such an evolution to occur. yet there is no doubt that, as each of our societies has been through periods of barbarism and tension to come out the other side somewhat improved and safer, we have yet a way to go before we can imagine the worldwide evolution from the semi-anarchy we have to a global society that is both ordered and fair. paris television channel fr war, science and terrorism from laboratory to open conflict collision at cajamarca" for the advent in the th century of firearms and toxic combat to the civilizations of central and south america strychnine" in: sybil p. parker, mcgraw-hill concise encyclopedia of science & technology veterans recall the horror of world war ii battle pentagon plans to destroy remaining napalm stocks : a technical research effort by haber's son to place his father's work in perspective in terms of the evolution of chemical engineering both citations from liddell hart's foch, the man of orléans le cabinet du docteur haber the first world war le service de santé des armées face aux armes chimiques durant la guerre de - global population and the nitrogen cycle recollections of nuclear war international herald tribune japan's poison gas plant: guilt symbol exposing a devilish gas using supercritical water oxidation to treat hydrosylate from vx neutralization (report), cited in nas reports & events, february, p. . . national academy ( ) national academy of sciences aftemath, the remnants of war deep-sixed chemical weapons ex-admiral returns to a tragic scene nas, media release deadly gas in terrorist attack is easily made but rarely used north vs south: politics and the biological weapons convention dilemma of dual-use technology: toxins in medicine and warfare as cited in footnote ; see also war-torn nation faces foe for years to come survey action, undated. the survey action center is based in washington; its website is www.vvaf.org . letter to editor ( ) international herald tribune vaccine against gangrene could save limbs china, , in the time of the plague were four corners victims biowar casualties published by the nas press for the national research council industrial aspects of technical cooperation in microbiology and biotechnology the day the sky caught fire the making of the atomic bomb e-mail to the author biological warfare against crops karl simpson, while director of the european association of the plasma products industry (eappi), in a letter to the organization for security and cooperation in europe (osce) in an e-mail message to the author u.s. officer sees gaps in biowar vaccines an assessment of non-lethal weapons science and technology (report) key: cord- -bhlxglyd authors: olival, kevin j.; hoguet, robert l.; daszak, peter title: linking the historical roots of environmental conservation with human and wildlife health date: - - journal: ecohealth doi: . /s - - - sha: doc_id: cord_uid: bhlxglyd we examine the historical and philosophical roots of environmental stewardship and how they relate to conservation and human health. concern for the environment in the united states derives from two distinct historical ideologies that we term “green” and “brown” environmentalism. we propose a modern-day synthesis of these ideologies that recognizes that environmental degradation and the emergence of zoonotic and epizootic diseases, affecting both humans and wildlife (i.e., pathogen pollution), are interconnected. this interconnection provides a compelling new reason to protect and preserve biodiversity. on this th anniversary of the endangered species act, it is appropriate to look at the historical roots of environmental protection and conservation in the united states, particularly as they relate to ecology and to health. modern-day environmental stewardship in the united states is derived from two distinct historical threads. the first, which we refer to as ''green'' environmentalism, focuses on preserving and maintaining natural ecosystems, habitats, and specific sites for the purpose of maintaining biodiversity. the second arena of environmental stewardship, which we call ''brown'' environmentalism, focuses on limiting and mitigating pollution that is generated by human activities-principally industry and agriculture-that affect human health. ''green'' conservation in the us was inspired by the nineteenth-century transcendental writings of thoreau, emerson, and the preservationist john muir, who ascribed an intrinsic value to nature. according to this philosophy, nature should be protected, not because it has current or future quantifiable value for society, but rather, because of what we don't know about it. at the core of these ideals is a belief that natural, pristine places have a spiritual and magical grandeur, and that we should respect them out of childlike wonder (emerson ) . this philosophy laid the groundwork for early environmental policy at the end of the nineteenth century and for the protection of large tracks of land for conservation. john muir was instrumental in lobbying congress to enact the national parks bill in and protect yosemite valley from development. he formed the sierra club in based on these preservationist ideals. muir and colleagues believed in the physical and psychological healing properties of nature and justified the conservation of wilderness, in part, by its link with human health and well-being. ''everybody needs beauty as well as bread, places to play in and pray in, where nature may heal and give strength to body and soul alike'' (muir ) . us environmental policy was additionally shaped by an anthropocentric thesis derived from english utilitarian philosophers jeremy bentham and john stuart mill. gifford pinchot, the first chief of the us forest service ( ) ( ) ( ) ( ) ( ) ( ) , famously championed the idea that forests and wild lands should be managed for their maximum utility to man. pinchot implemented a policy of ''multiple'' or ''wise use'' for federal lands-a policy still in effect today. pinchot summed up the mission of the forest service, which has stewardship of million acres-an area the size of texas-as ''providing the greatest amount of good for the greatest amount of people in the long run'' (www.fs.fed.us). similarly, the mission of the federal bureau of land management, which administers over million ''surface'' acres in the u.s. and million subterranean acres, is ''to sustain the health, diversity, and productivity of america's public lands for the use and enjoyment of present and future generations'' (www.blm.gov). at the same time that emerson and muir were forming their romantic ideals about the preservation of american wilderness, public health officials in the united kingdom were trying to mitigate water pollution to control cholera outbreaks. in the process, they developed the early makings of ''brown'' environmentalism. john simpson, the first medical health officer in london and less well-known contemporary of john snow, the ''father of modern epidemiology,'' emphasized the need for improvements to water quality to combat disease. in he described the thames in london as ''…contaminated with the outscourings of the metropolis, swarming with infusorial life, and containing unmistakeable molecules of excrement'' (simpson ) . his reports led to the first real attempt to improve sanitation and river quality in the uk-an early example of the ''brown'' approach to environmental stewardship in which restoring freshwater ecosystems was a means to protect human health (ashby ). such ''brown'' environmentalism was the primary impetus behind much of the significant environmental legislation enacted in the united states during the early s. hazardous environmental and health impacts in the united states from toxic pollution were first brought to the public's attention by rachel carson, a marine biologist and now famous environmental whistle-blower. in her book silent spring ( ), carson highlighted the cascading ecological and health effects of ddt, arguing that pollution was the primary scourge against humanity: only yesterday mankind lived in fear of the scourges of smallpox, cholera, and plague that once swept nations before them. now our major concern is no longer with the disease organisms that once were omnipresent; sanitation, better living conditions, and new drugs have given us a high degree of control over infectious disease. today we are concerned with a different kind of hazard that lurks in our environment-a hazard we ourselves have introduced into our world as our modern way of life has evolved. (carson ) after carson, public awareness of pollution emerged very rapidly as an issue in the united states. in , few people considered pollution important; five years later, it ranked second only to crime among the public's concerns (graham ). carson's health-centric political lobbying, combined with major pollution events resulting from some highly visible industrial accidents, such as the santa barbara oil spill in , led to the establishment of the us environmental protection agency in and to the subsequent adoption of two of the most important and pioneering environmental health laws in us history: the clean air act ( ) and the clean water act (reorganized in ). these are fundamentally ''brown'' acts that seek to protect the environment as a way to safeguard human health, rather than to care for the environment for its own sake. during this era, heightened public awareness of the environment combined with the well-publicized plights of some charismatic species, such as whooping cranes and whales, provided the setting against which the endangered species act, an essentially ''green'' piece of legislation, became law in . the act's preamble emphasizes that wildlife and plants have intrinsic value and ''are of esthetic, ecological, educational, historical, recreational, and scientific value to the nation and its people''. what have we learned from these historical origins of the environmental stewardship movement in the us, and how can we better reconcile these ''green'' and ''brown'' antecedents? we emphasize a few key points: first, in retrospect, carson was only partially correct. while pollutants remain an insidious threat to health and the environment, there is now a growing acceptance that emerging infectious diseases (eid's) are on the rise and are having dramatic impacts on both global health and conservation (daszak et al. ; karesh et al. ) . the public health optimism of the late s that led carson to dismiss the threats from ''disease organisms'' and william stewart, then the u.s. surgeon general, famously to ''close the book'' on infec-tious diseases (lederberg et al. ) , is over. today the impact and threat of pandemic zoonoses is real and looms large over humanity (morse et al. ) . over % of human infectious pathogens are zoonotic, the majority from wildlife. the list of deadly or debilitating agents includes sars, hiv, nipah virus, lyme disease, rocky mountain spotted fever, west nile virus, and salmonella. further, eids have increased in frequency since the s (jones et al. ) . second, infectious diseases are now recognized as a significant threat to wildlife conservation and to the broader environment (daszak et al. ) . for example, the introduced pathogen, geomyces destructans (cause of white nose syndrome), has spread rapidly in just over five years, killing six million bats from species in north america (whitenosesyndrome.org). several bat species are now threatened with extinction, an event that could have substantial downstream ecological and economic effects (frick et al. ; boyles et al. ; langwig et al. ). anthropogenically introduced pathogens have already caused species extinctions-from gastric-brooding frogs in australia (chytrid fungus), through to around a third of hawaiian honeycreepers (introduced malaria and pox virus). the distribution of eids in nature is pan-global, with antibodies to chicken viruses found in antarctic penguins, and the spread of west nile virus and whirling disease reaching from europe across the us continental divide. we now have a new phrase to bring to the conservation lexicon-'pathogen pollution' (daszak et al. ) . in this play on carson's text, we consider the pathogens that people unwittingly spread around the planet as we alter landscapes, expand agriculture, and travel to new regions. this form of pollution can be as insidious as ddt and may have already had a higher impact on our environment. third, and perhaps most relevant to our premise, a growing body of disease ecology research (emphasized by the quality and quantity of articles published in ecohealth over the past decade) has demonstrated that the same factors that cause environmental destruction and subsequent global declines in biodiversity also drive the emergence of infectious diseases. these anthropogenic ''drivers'' include deforestation, agricultural expansion, natural resource exploitation, bushmeat hunting, and global travel and trade (morse ) . these drivers, which are primarily associated with land-use change, facilitate the emergence of zoonotic diseases by disrupting 'natural' host-pathogen dynamics and/or by exposing humans to a novel pool of pathogens from wildlife reservoirs (jones et al. ; murray and daszak ) . the emergence of nipah virus in malaysia is a good example of how environmental drivers, including the industrialization and expansion of pig farms into bat habitat, led to pathogen spillover and a subsequent human outbreak (daszak et al. ; pulliam et al. ) . scientific recognition of the connection between damage to the environment and the emergence of harmful zoonotic and epizootic diseases provides a compelling new reason to protect and preserve biodiversity. while we recognize that it is neither feasible nor desirable to stop environmental change or the global forces that cause it, we advocate looking for sustainable solutions that will mitigate both ecological damage and disease risk. this search should include working with industry and governments to develop more ''ecohealthy'' alternatives to current practices starting with systematic assessments of emerging disease risk concomitant with environmental impact statements. by emphasizing disease prevention as a reason to preserve intact ecosystems and the creatures that live within them, we bring together critical elements of ''brown'' and ''green'' conservation and provide a simple message: both humans and the environment will be better off from setting aside protected areas (as muir did); adopting best practices for extractive industries (per pinchot); and, like carson, blowing whistles when those practices seem too risky. economic importance of bats in agriculture emerging infectious diseases of wildlif: threats to biodiversity and human health the emergence of nipah and hendra virus: pathogen dynamics across a wildlife-livestock-human continuum an emerging disease causes regional population collapse of a common north american bat species the morning after earth day zoonosis emergence linked to agricultural intensification and environmental change global trends in emerging infectious diseases zoonoses ecology of zoonoses: natural and unnatural histories sociality, density-dependence and microclimates determine the persistence of populations suffering from a novel fungal disease, white-nose syndrome emerging infections: microbial threats to health in the united states prediction and prevention of the next pandemic zoonosis the century company murray ka, daszak p ( ) human ecology in pathogenic landscapes: two hypotheses on how land use change drives viral emergence agricultural intensification, priming for persistence and the emergence of nipah virus: a lethal batborne zoonosis report on the last two cholera-epidemics of london, as affected by the consumption of impure water, london: the general board of health we thank an anonymous reviewer for valuable comments on this essay. kjo and pd were supported by the usaid emerging pandemic threats program predict project cooperative agreement number (ghn-a-oo- - - key: cord- - xp nc authors: crook, paul; smith-palmer, alison; maguire, helen; mccarthy, noel; kirkbride, hilary; court, bruce; kanagarajah, sanch; turbitt, deborah; ahmed, syed; cosford, paul; oliver, isabel title: lack of secondary transmission of ebola virus from healthcare worker to contacts, united kingdom, december date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: xp nc in december , ebola virus disease (evd) was diagnosed in a healthcare worker in the united kingdom after the worker returned from an ebola treatment center in sierra leone. the worker flew on flights during the early stages of disease. follow-up of contacts showed no evidence of secondary transmission of ebola virus. in december , ebola virus disease (evd) was diagnosed in a healthcare worker in the united kingdom after the worker returned from an ebola treatment center in sierra leone. the worker flew on flights during the early stages of disease. follow-up of contacts showed no evidence of secondary transmission of ebola virus. m ore than , cases of ebola virus disease (evd) were reported during the epidemic in west africa in - ( ) . international healthcare workers (hcws) responded, and a number subsequently became infected with evd, including those given a diagnosis after their return travel ( ) . there is international guidance for followup of aircraft contacts of case-patients with evd ( ) ( ) ( ) . we report contact tracing after evd was diagnosed in an hcw in the united kingdom who had worked in an ebola treatment center in sierra leone. this worker had become ill while traveling back to the united kingdom via morocco. for this investigation, a multiagency incident control team and contact tracing teams were established with staff of public health england (phe) and health protection scotland. we undertook a risk assessment that included interviewing the case-patient about symptoms, travel, and contacts. we used preexisting guidance ( ) to classify classified contacts according to their degree of exposure to the case-patient and to other persons with evd on the basis of the degree of infectiousness and physical contact (table) . the degree of public health follow-up of contacts was formulated according to their exposure category (table) . we asked airlines to provide passenger manifests; advanced passenger information (nationality, passport numbers, date of birth); and contact details. if contact details were missing or incorrect, we sought additional information from her majesty's passport office, the uk border agency, phe port entry screening and returning workers information, the national health service patient demographic service, and online social networks. for contacts with uk addresses, we conducted a home visit if telephone contact was unsuccessful. for foreign national contacts, phe also contacted the national focal point of the relevant country as per international health regulations. public helplines were established to provide a contact point for those potentially affected. phe provided public health advice to united kingdom airline staff, and moroccan authorities provided public health advice to morocco airline staff. moroccan authorities led contact tracing for the flight to morocco, which is not reported in this article. the case-patient was a uk national hcw ( -yearold woman) who had worked in an ebola treatment center in sierra leone and had direct patient contact. on december , , she flew from sierra leone to glasgow on flights and aircraft of airlines: from freetown, sierra leone, to casablanca, morocco ( h, min); casablanca to london, england ( h, min); and london to glasgow, scotland ( h, min). during exit screening before boarding in freetown and casablanca, the case-patient was reported to have been apyrexial. symptoms of fever and malaise began during the casablanca to london flight. at london heathrow airport, several readings of temperatures < . °c were made by screening staff before onward travel. in glasgow, after the case-patient took a taxi home, her symptoms worsened, and she telephoned local health services. the case-patient did not report vomiting, diarrhea, or bleeding before diagnosis and admission. contacts had not been exposed to body fluids. the case-patient was admitted to a hospital in glasgow and given a diagnosis of evd on december , . the patient was subsequently transferred by military plane to a specialist infectious diseases hospital in london on december , . she survived her illness. aircraft passengers in the same seat row and rows in front of and behind the case-patient were classified as category contacts. all other passengers and crew were classified as category contacts. border force staff, health author affiliations: public health england, london, uk screeners, and hcws were classified as category contacts, and a community contact was classified as category contact (table) . a total of persons, including category contacts and category contacts, were assessed as having sufficient exposure to the case-patient to warrant further public health follow-up (table) . although no contacts were classified as being category (direct contact with high exposure risk) because of exposure to the case-patient, contacts were classified as category because of other ebola exposures, including healthcare work in sierra leone. all non-flight-related contacts were successfully followed up. passengers on the casablanca to london flight represented nationalities, and ( %) of had non-uk passports. we successfully contacted all passengers on both flights, except for category passengers who had non-uk passports ( / , %); a total of ( %) passengers were contacted within h of diagnosis for the case-patient. we provided information for the passengers we could not contact to their respective countries through their national focal point. two persons in the united kingdom required home visits. all flight crew were contacted. no additional cases of evd were identified among contacts. we report no evidence of secondary transmission of ebola virus to contacts of a case-patient who contracted evd during the ebola epidemic in west africa in - and who was given a diagnosis in the united kingdom. there have been few reports of symptomatic evd case-patients traveling by commercial airline, and secondary transmission has not been documented ( - ). the case-patient we report was probably in the early stages of illness, and there was no evidence of high-risk exposure to body fluids on board the aircraft. a precautionary approach was taken regarding classification of contacts on the aircraft. we used a wider definition for the closest contact category than that recommended by international guidance ( seat in either direction of the case-patient) ( - ) but consistent with that used for the response to a case diagnosed in the united as for category plus provided written advice and a temperature monitoring kit, advised to take their temperature twice a day and to contact the local public health team if they had a fever or symptoms consistent with evd in the d after their most recent exposure; advised to delay any nonessential healthcare treatment until after the -d period; local public health teams assessed the contact after d and reported their completion of public health follow-up as for category plus required to contact the local public health team daily to report their temperature and advised not to undertake healthcare activity; if contact was not made, the local public health team contacted them na *in england a home visit was attempted if no telephone contact was possible. evd, ebola virus disease; lhr, london heathrow airport; na, not applicable; phe, public health england. †includes cabin staff and land customer services staff. ‡includes doctors and nurses who provided dedicated care to the patient while in the specialist infectious diseases unit. §reflects overall number of persons categorized according to their highest category, including those categorized because of their healthcare work contact in sierra leone. numbers in each category do not represent a sum of a column. ¶ contacts who flew casablanca-lhr were classified as category because of their healthcare-related activity in west africa. states ( ) . the decision to contact all persons on the affected aircraft was taken to inform and reassure contacts, not just to prevent transmission. the limited information on passengers initially available hampered the ability to make contact promptly and resulted in extensive efforts to trace persons. furthermore, flight manifests included passengers who had not flown. issues with flight information have arisen before in the united kingdom related to contact tracing ( ) . the need for airlines to collect personal rather than agency contact details should be stressed. to ensure a rapid response, public health agencies need to work with airlines and other international organizations to ensure access to a minimum dataset that would support rapid notification of contacts. in the united kingdom, the national health service patient demographic service was essential for obtaining contact details and identifying whether contacts were likely to be uk residents. in addition, the ebola port entry screening and returning workers scheme provided rapid information on contacts whose journey originated in ebola-affected countries. temperature screening while the case-patient transferred through heathrow airport did not confirm fever, and the patient was allowed to continue the journey. in the presence of exit screening, airport entry screening might not detect imported evd ( , ) . however, one purpose of this screening has been to ensure that persons receive information to enable them to seek care quickly and in a manner that helps prevent transmission. advice provided during airport screening and healthcare deployments aims to ensure that when symptoms develop, exposed persons contact health services early and by telephone, enabling responders to take appropriate measures to reduce transmission. in this instance, early contact with health services resulted in only a small number of contacts outside the flights. an evaluation of evd port entry screening and a scheme for returning workers in the united kingdom is under way. this study provides support for the conclusion that there is low risk for transmission of ebola virus on aircraft from evd case-patients in the early stages of disease. providing information and advice to contacts can be a helpful public health intervention in minimizing virus transmission. ebola virus infection among western healthcare workers unable to recall the transmission route european risk assessment guidance for infectious diseases transmitted on aircraft-the ragida project guidance for contact tracing of cases of lassa fever, ebola or marburg haemorrhagic fever on an airplane: results of a european expert consultation world health organization. travel and transport risk assessment: interim guidance for public health authorities and the transport sector advisory committee on dangerous pathogens public health england. management of hazard group viral haemorrhagic fevers and similar human infectious diseases of high consequence human infection due to ebola virus, subtype côte d'ivoire: clinical and biologic presentation ebola virus disease outbreak-nigeria transmission dynamics and control of ebola virus disease outbreak in nigeria public health response to commercial airline travel of a person with ebola virus infection-united states on behalf of the incident managemen c; incident management team. public health response to two incidents of confirmed mers-cov cases travelling on flights through london heathrow airport in : lessons learnt airport screening for ebola advantages of airport screening for ebola london rd, london se lh, uk; email: paul.crook@phe.gov.uk • transmission of mycobacterium tuberculosis beijing strains • foodborne transmission of bovine spongiform encephalopathy to nonhuman primates • populations at risk for alveolar echinococcosis, france • who international standard to harmonize assays for detection of hepatitis e virus rna we thank the staff at the royal free london national health key: cord- -l c x n authors: singh, amandeep; moayedi, siamak title: clinicopathological conference: fever, productive cough, and tachycardia in a ‐year‐old asian male date: - - journal: acad emerg med doi: . /j. - . .tb .x sha: doc_id: cord_uid: l c x n nan were appreciated. his abdomen was soft, nontender, and nondistended, with normal bowel sounds. no abdominal masses were palpated. he had no peripheral edema. he was alert and oriented, without any focal neurologic deficits. his skin was mildly diaphoretic, without any rashes or lesions. upon arrival to the ed, the patient was triaged to a telemetry bed. intravenous (iv) access was established and an electrocardiogram (ecg) was obtained ( figure ) . a -l bolus of iv normal saline was started, and appropriate blood work was collected. a portable chest radiography (figure ) was obtained. after reviewing the radiograph, a bedside echocardiogram was requested ( figure ) . laboratory values returned as follows: sodium, meq/l; potassium, . meq/l; chloride, meq/l; bicarbonate, meq/l; bun, mg/dl; creatinine, mg/dl; glucose, mg/dl. white blood cell count was . ( /l), hemoglobin was . g/dl, and platelets were ( /l). creatine kinase was u/l with a normal mb fraction, and troponin i was . ng/ml. additionally, blood cultures were pending, and a urine drug screen was negative. the patient's heart rate remained around beats/ min despite the iv fluid bolus. after reviewing the echocardiogram, appropriate consultation was made and the patient was admitted to the intensive care unit. a -year-old man who recently entered the united states from indonesia presented to the ed with four weeks of intermittent fever and a productive cough. his pcp saw him three weeks earlier and treated him with cephalexin for seven days, but his symptoms persisted despite treatment. upon presentation to the ed, he was found to have a heart rate of beats/min, a temperature of . f, and a pulse oximetry reading of % on room air. his physical examination revealed a well-developed and wellnourished male in mild respiratory distress, with bibasilar pulmonary rales, distant heart sounds, and mild diaphoresis on examination. no dermatologic, ophthalmic, gastrointestinal, genitourinary, musculoskeletal, or neurologic signs or symptoms were reported. his electrolytes, renal function, and cardiac markers were normal, as well as his leukocyte count and hemoglobin. no information regarding his prior immunization status was reported. a chest radiography ( figure ) was ordered, presumably to see if an infiltrate was present, and serendipitously showed enlargement of the cardiopericardial silhouette. additionally, a -lead ecg ( figure ) was obtained and revealed a sinus tachycardia, diffuse t-wave flattening, and low qrs-wave voltage. on the ecg, there was no st-segment elevation, pr-segment depression, or t-wave inversion to suggest early or resolving acute pericarditis. an echocardiogram was performed to evaluate the enlarged cardio-pericardial silhouette and electrocar-diographic findings, and revealed a large hypoechoic fluid collection surrounding the heart indicative of a pericardial effusion ( figure ). to generate the appropriate differential diagnosis in this case, there are several key features of the patient's history and physical examination that aid in the understanding of his pathologic process: ) symptom development occurred soon after emigration from indonesia, ) the patient's primary symptoms were pulmonary in origin, and ) secondary cardiac involvement resulted in a large, initially asymptomatic pericardial effusion. although several disease processes are possible explanations for this patient's pathology, one likely diagnosis will become clear through our discussion. travel from southeast asia. with over million people crossing international borders each year, the potential for emerging pathogens to be spread from other geographic regions is greater than ever. over a decade ago, the institute of medicine identified travel as one of six major factors related to the emergence and re-emergence of tropical disease. several years later, the centers for disease control and prevention (cdc) released addressing emerging infectious disease threats: a prevention strategy for the united states; in this doctrine international travelers, refugees, and immigrants are targeted as a priority group for infectious disease surveillance. the updated document from the cdc entitled preventing emerging infectious diseases: a strategy for the st century continues to identify international travelers as a high-risk population that has contributed to the spread of these diseases. the cdc recommendations are in part the result of the concern that many tropical and developing countries contain infectious pathogens not common to the united states. these diseases, such as malaria, plague, dengue fever, and yellow fever, have explosive potential if introduced in this country in sufficient quantity. for symptomatic patients who recently have immigrated to the united states, the potential for diagnosis of these unusual pathogens is significant. new emigrants from developing countries are at particular risk for infectious disease. this population frequently does not utilize appropriate pretravel medical care, may not be appropriately or completely vaccinated, and may experience living or working conditions that place them at higher risk for virulent infectious diseases. additionally, genetic variations in the immune system of immigrants and lack of exposure to antigens on indigenous infectious organisms can contribute to the development of an infection soon after entering a new country. a significant number of immigrants who develop medical complaints will seek primary medical care through the ed. these patients are particularly challenging because of language barriers, atypical presentations of diseases, self-medication with atypical treatments before arrival, and a lack of physician familiarity of indigenous infections from the country of origin. upto % of individuals will complain of fever in the period immediately after travel. the evaluation of the febrile immigrant begins with a thorough pretravel history regarding the living conditions in the country of origin, the patient's vaccination history, and any pretravel health care. specific questions regarding medical history and risk factors for common enteric, respiratory, neurologic, dermatologic, and hematologic infections should be made. in the post-travel period, fever most often indicates an underlying infection; however, other causes of fever should be simultaneously explored (table ). many infectious diseases will have characteristic clinical features that distinguish them from other illness. our patient entered this country from indonesia five months before presentation to the ed. assuming that he became symptomatic with intermittent fever and productive cough three to four weeks before his presentation (i.e., when seen and treated by his pcp), one can assume that one of two possibilities occurred. he either became infected with an organism in the united states four months after entering this country or he harbored an occult, slow-growing infection with a long incubation period from indonesia. in this type of patient, it is useful to generate differential diagnoses for each of these possibilities. a listing of potential pulmonary pathogens is seen in table . pulmonary infection. if we assume that this patient developed his infection in the united states, then we are most likely dealing with a common pulmonary pathogen such as those on the left side of table . the clinical presentation and description of these organisms can be found in most emergency medicine textbooks. it is more likely that this patient harbored a pulmonary infection from indonesia. many of the common pulmonary pathogens from indonesia are similar to those found in the united states; however, many unusual pathogens are found with increasing frequency in this developing country (see right side of table ). mycobacterium tuberculosis is a slow-growing aerobic rod with characteristic acid-fast staining properties. infection with tuberculosis continues to be a worldwide problem, with approximately one-third of the world population currently infected. indonesia has the dubious distinction of having the third largest tuberculosis organism burden in the world. individuals throughout portions of asia are given bacille-calmette-guerin (bcg) vaccination as children; however, the overall efficacy and duration of protective immunity using the bcg vaccine remain unclear. tuberculosis is transmitted primarily through inhalation of aerosolized bacilli. initially, patients often are asymptomatic following primary infection, although the organism may remain viable and dormant for years. in these individuals, the only indication of primary infection is a positive tuberculin purified protein derivative (ppd) skin test. reactivation of the disease is highest in the first two years following exposure, and is highest in young adults. typically, reactivation occurs in the lungs and should be considered in any patient who presents with a cough of more than three weeksÕ duration, intermittent fever, night sweats, hemoptysis, weight loss, and anorexia. although any patient may be at risk for developing tuberculosis, patients with an immunocompromising illness such as hiv infection, prior institutionalization, travel to an endemic region, a positive ppd placed in the past, or known exposure to tuberculosis are especially at increased risk. this patient came from a region known to be endemic for tuberculosis and presented with typical signs and symptoms of reactivation of the disease. the failure of his symptoms to respond to cephalexin also is consistent with a diagnosis of tuberculosis because this antibiotic has little effect against these slowgrowing bacilli. infection with tuberculosis may exhibit extrapulmonary manifestations of this disease that can occur during primary infection or during reactivation of the disease. dissemination can result in infection spreading to any organ system, including the heart and pericardium. q fever is a self-limited infection seen in about % of people infected with the obligate intracellular rickettsial pathogen coxiella burnetii. transmission is primarily through inhalation and is generally seen in farmers as a result of exposure to livestock, through ingestion by drinking unpasteurized milk, or uncommonly via a tick bite. acute infection begins with sudden onset of one or more of the following: high fevers (up to - f), severe headache, general malaise, myalgia, confusion, sore throat, chills, sweats, nonproductive cough, nausea, vomiting, diarrhea, abdominal pain, and chest pain. , fever usually lasts for one to two weeks, and abnormalities on liver function testing can be seen. symptoms of pneumonia occur in % to % of symptomatic patients. the chest radiograph typically shows rounded segmental lower-lobe densities, but may show lobar consolidation. in general, most patients will recover to good health within several months without any treatment. only % to % of people with acute q fever die from the disease. the chronic form of q fever is much more serious, and as many as % of persons with chronic q fever may die from the disease. endocarditis, most commonly involving the aortic valve, can occur in up to twothirds of patients with chronic q fever. our indonesian patient reported no farm-exposure history and did not complain about the typical headache seen in c. burnetii infection. additionally, the typical incubation period of q fever ranges from to days, much longer than the four-month asymptomatic period our patient would have had to experience if he was infected in indonesia. psittacosis and tularemia are caused by infection with chlamydia psittaci and francisella tularensis, respectively. pet shop workers and bird handlers, especially parrot and pigeon handlers, are especially at risk for acquiring psittacosis. the clinical presentation of psittacosis includes high fever associated with a relative bradycardia, severe headache, nonproductive cough or hemoptysis, and hepatic and spleen enlargement. chest radiography reveals patchy perihilar or lower-lobe infiltrates. hunters and trappers of rabbits and those exposed to ticks and rodents contaminated with f. tularensis are at risk for development of tularemia. depending on the route of exposure, the tularemia bacteria may cause skin ulcers, swollen and painful lymph glands, inflamed eyes, sore throat, oral ulcers, or pneumonia. an acute infection presents with the abrupt onset of fever, chills, headache, muscle aches, joint pain, dry cough, and progressive weakness. persons with pneumonia can develop chest pain, difficulty breathing, bloody sputum, and respiratory failure. chest radiography reveals bilateral patchy infiltrates. treatment with streptomycin or gentamycin is highly effective and reduces the mortality rate from % to \ %. although uncommon, pericarditis can be seen in both psittacosis and tularemia. our patient had no avian or rabbit exposure and did not have any of the laboratory or physical examination findings consistent with psittacosis or tularemia. infection with bordetella pertussis is characterized by three distinct phases: the catarrhal phase, the paroxysmal phase, and the convalescent phase. the catarrhal phase begins after an incubation period of seven to ten days. symptoms last one to two weeks and are indistinguishable from an upper respiratory tract infection with cough. the paroxysmal phase lasts two to four weeks and is characterized by paroxysms of coughing followed by a forceful inspiration producing the characteristic ''whoop'' sound. a residual, irritating cough lasting weeks to months is seen in the convalescent phase. whooping cough has seen an increase in worldwide incidence as a result of a reduction in the use of its vaccine. it is unlikely that our patient had whooping cough. although pertussis is seen in any age, it is predominately a pediatric illness. additionally, pericardial effusion is not a known complication of whooping cough. although diphtheria has been nearly eradicated in the united states, endemic infection still occurs in areas throughout the world, including southeast asia. corynebacterium diphtheriae is a gram-positive, club-shaped bacillus that presents as an infection involving the respiratory tract or skin. systemic involvement of the cardiovascular and nervous system may occur. following a short incubation period, patients present with signs of a typical upper respiratory tract infection. on oropharyngeal examination, a grayish-white pseudomembrane adherent to the posterior pharynx can be seen in infected individuals. c. diphtheriae releases a powerful exotoxin that directly injures myocytes, producing a myocarditis, congestive heart failure, and conduction blocks. the exotoxin's disruption of protein synthesis produces a peripheral neuropathy manifesting as muscle weakness. the typical symptoms and signs of diphtheria infection were absent in our patient. hantavirus and the pneumonic plague are endemic in many parts of southeast asia, including indonesia. whereas hantavirus occurs with exposure to rodent excrement, infection with yersinia pestis is transmitted by flea bites from infected rodents. hantavirus infection occurs after a one-to five-week incubation period and initially presents with fever and myalgias. symptoms of cough and shortness of breath herald the development of a rapidly aggressive bilateral pneumonia, often requiring mechanical ventilation within hours. , hematogenous spread of y. pestis leads to a highly contagious and rapidly fatal pneumonia. , without a history of rodent or flea exposure and as a result of the slowly developing symptoms seen in our patient, it is unlikely that our patient was infected with hantavirus or pneumonic plague. lassa virus and lymphocytic choriomeningitis virus are members of the arenaviridae viruses. lassa fever is transmitted person to person and through contact with infected rodent urine. a gradual onset of fever and malaise begin after an incubation period lasting up to three weeks. severe headache and retrosternal chest pain may accompany the development of pneumonitis and respiratory distress. lymphocytic choriomeningitis virus begins as an influenza-like illness after a one-to three-week incubation period. aseptic meningitis may ensue, but even severe cases are associated with good recovery. melioidosis, or whitmore's disease, is caused by infection with burkholderia pseudomallei. a handful of cases are confirmed in the united states each year, seen exclusively in travelers and immigrants, especially from southeast asia, where it is endemic. transmission occurs through either direct person-to-person contact, direct contact with contaminated soil and surface water, or inhalation. acute infection with melioidosis can produce fever and general muscle aches, and may progress rapidly to infect the bloodstream. the acute, localized form of infection presents as a nodule and results from inoculation through a break in the skin. the pulmonary form of the disease presents with symptoms consistent with a mild bronchitis to severe pneumonia. the onset of pulmonary melioidosis is typically accompanied by a high fever, headache, anorexia, and general muscle soreness. chest pain is common, but a nonproductive or productive cough with normal sputum is the hallmark of this form of melioidosis. bacteremic spread of this organism leads to septic shock with microabscesses found throughout the body, including pus-filled skin lesions. numerous fungal and parasitic organisms endemic to southeast asia have potential pulmonary involvement. the acute phase (invasion and migration) of paragonimus westermani may be marked by diarrhea, abdominal pain, fever, cough, urticaria, hepatosplenomegaly, pulmonary abnormalities, and eosinophilia. during the chronic phase, pulmonary manifestations include cough, expectoration of discolored sputum, hemoptysis, and chest radiographic abnormalities. echinococcus granulosus infections remain silent for years before the enlarging cysts cause symptoms in the affected organs. hepatic involvement can result in abdominal pain, a mass in the hepatic area, and biliary duct obstruction. pulmonary involvement can produce chest pain, cough, and hemoptysis. rupture of the cysts can produce fever, urticaria, eosinophilia, and anaphylactic shock, as well as cyst dissemination. ascaris lumbricoides, strongyloides stercoralis, schistosoma haematobium, and several other less common parasites also can present with pulmonary findings. it is unlikely that one of these organisms infected our patient, because the majority of symptoms listed were not present in our patient. additionally, our patient lacked information regarding eosinophilia, which is classically seen in parasitic infections. with these possibilities in mind, let us turn to the last piece of critical information in this case: the development of a large pericardial effusion. pericardial effusion. the normal pericardium is composed of two layers and a potential space that exists between them. the two layers of the pericardium include a thin, visceral layer closely applied to the epicardium and a dense, outer parietal layer. the parietal layer is attached to the sternum, diaphragm, and mediastinum by fibrinous extensions and adventitia. between and ml of fluid normally is contained in the space between the visceral and parietal pericardium. the pericardium is thought to maintain the heart's position, lubricate the heart's surface, prevent the spread of infection from adjacent thoracic structures, prevent cardiac overdilatation, augment atrial filling, and maintain the normal pressurevolume relationships of the cardiac chambers. a minimum of ml is needed to fill the pericardial reserve volume sufficiently to detectably increase the cardio-pericardial silhouette by chest radiography. our patient had multiple imaging findings consistent with a large pericardial effusion. his chest radiograph showed enlargement of the cardio-pericardial silhouette. common etiologies for cardiopericardial enlargement include pericardial effusion, valvular heart disease, cardiomyopathy, and congenital heart disease. our patient did not carry a congenital heart disease diagnosis and did not have a cardiac murmur to signify valvular heart disease. an echocardiogram is needed to investigate these possibilities and in this patient showed a large hypoechoic area surrounding the myocardium. finally, his -lead ecg showed sinus tachycardia, low voltage in the precordial leads, and diffuse t-wave flattening, all of which are consistent with a pericardial effusion. notably, there was no st-segment elevation, prsegment depression, or t-wave inversion to suggest the early or resolving stages of acute pericarditis. the causes of pericardial effusion are numerous and parallel the etiologies of acute pericarditis (table ) . large pericardial effusions are most common with tumors, tuberculosis pericarditis, cholesterol pericarditis, myxedema, vasculitis/connective tissue disease, uremic pericarditis, and parasitoses. an effusion is often asymptomatic but should be suspected in the appropriate clinical setting. pericardial effusions can present with vague chest symptoms such as a feeling of chest pressure and chest ache. a very large effusion can manifest as dyspnea on exertion (compression of lung parenchyma), dysphagia (compression of esophagus), cough (compression of pulmonary bronchi), hiccups (compression of vagus and phrenic nerve), or hoarseness (compression of recurrent laryngeal nerve). classic physical examination findings of distant heart sounds and jugular venous distension are generally unreliable and difficult to detect in the ed. cardiovascular changes occur as fluid within the pericardium accumulates. tachycardia occurs commonly, but many patients may have heart rates of to beats/min or lower in hypothyroidism or uremic patients. significant cardiac tamponade produces absolute or relative hypotension. chest radiography and -lead ecg can suggest the diagnosis of pericardial effusion, but are neither sensitive nor specific enough to confirm the diagnosis. the diagnostic criterion standard is two-dimensional echocardiography in the diagnosis of pericardial effusion. in our patient, the most likely cause of the pericardial effusion was infection with tuberculosis. tuberculous pericarditis is estimated to occur in % to % of patients with pulmonary tuberculosis and is one of the leading causes of pericarditis in nonindustrialized countries. associated pericardial effusions typically are slowly accumulating, and several hundred milliliters of fluid may develop before symptoms become apparent. in many patients, the chest radiography film shows an enlarged cardiac silhouette, but a pulmonary infiltrate often is absent, as was seen in this patient. special cultures of pericardial fluid are needed to diagnose tuberculous pericardial effusion. yields may be increased with biopsy of the pericardium or culturing the precipitant after centrifugation of pericardial effusion. in addition to the development of a constrictive pericarditis, or myocarditis, complications of tuberculous pericarditis includes impairment of cardiac function either directly or through cardiac tamponade. probable diagnosis: large pericardial effusion secondary to tuberculosis infection. to summarize, this patient's recent immigration, symptoms of intermittent fever and of chronic cough that failed to respond to outpatient antibiotics, and development of large pericardial effusion all are consistent with a diagnosis of tuberculosis. suggested management includes admission to a monitored setting and ap- the ecg revealed sinus tachycardia and low voltage. the chest radiography revealed a large cardiac silhouette consistent with either cardiomegaly and or a pericardial effusion. the echocardiogram confirmed a large pericardial effusion and global hypokinesis. cardiovascular surgery was consulted and the patient underwent a pericardial window. six hundred milliliters of bloody fluid was drained from the pericardium. a biopsy of the thickened pericardium revealed necrotizing granulomas consistent with tuberculous pericarditis. m. tuberculosis was isolated from the pericardial specimen. postsurgical serial echocardiograms revealed persistent moderate-to-severe global hypokinesis. five days following surgery, the patient remained stable and was transferred to a telemetry unit. an asymptomatic tachycardia persisted throughout his hospital stay. the patient was discharged days after admission with a four-drug tuberculosis regimen (pyrazinamide, isoniazid, rifampin, and ethambutol). follow-up was arranged with cardiology and infectious disease specialists. tuberculosis is a lethal infectious disease with diverse manifestations. the incidence of tuberculosis has been rising over the past decades. according to the world health organization, approximately million new cases occur annually. it is reported that more than % of these cases are in developing countries such as indonesia. in the united states, more than , cases are reported annually. tuberculous pericarditis is thought to occur in % of all instances of pulmonary tuberculosis. worldwide, tuberculosis is the leading cause of pericarditis. in the united states, it is the leading cause of immunodeficiency-related pericarditis. the typical symptoms of this disease are cough, dyspnea, and chest pain. additionally, night sweats, orthopnea, and weight loss are common. cardiomegaly, pericardial rub, fever, and tachycardia are frequent signs. the mycobacterium spreads to the pericardium either by direct extension from the lungs or by a hematogenous route. the resultant effusion is thought to be caused by a hypersensitivity reaction to the tuberculoprotein. proinflammatory cytokines are implicated as the etiology of symptoms such as fever, weakness, and weight loss. cardiomegaly caused by pericardial effusion frequently is evident on chest radiography. however, fewer than half of the patients may have radiographic evidence of pulmonary tuberculosis. characteristic ecg findings of tuberculous pericarditis are lowvoltage qrs waves and inverted t waves. however, these findings are present only in a minority of cases and are not diagnostic. similarly, echocardiogram findings are nonspecific. evidence of pericardial effusion with possible pericardial thickening is suggestive of the diagnosis. rarely, there may be evidence of cardiac tamponade. definitive diagnosis of tuberculous pericarditis requires isolation of m. tuberculosis. a positive tuberculin skin test may increase the suspicion for the diagnosis; however, a negative test does not exclude it. given the difficulty of isolating the bacteria, pericardial fluid culture is neither reliable nor timely. in fact, culture of the fluid reveals the diagnosis in only % of the cases. a pericardial tissue specimen has a higher yield for isolation of the bacteria. when a large pericardial effusion is present, an open biopsy along with a pericardial window serves as both a diagnostic and a therapeutic procedure. antibiotic therapy mimics the same dose and length as that of pulmonary tuberculosis. resolution of the pericarditis is expected within three months in % of patients. before the advent of modern antituberculosis drug therapy, mortality rates of up to % were noted. with current therapy, the mortality rate has decreased to %. constrictive pericarditis develops in % to % of patients despite medical therapy. thus, the placement of a pericardial window generally is recommended in the treatment of tuberculous pericarditis. travel and the emergence of infectious diseases d www.aemj.org . institute of medicine. emerging infections: microbial threats to health in the united states addressing emerging infectious disease threats: a prevention strategy for the united states centers for disease control and prevention. preventing emerging infectious disease threats: a strategy for the st century travel medicine illness after international travel the global tuberculosis situation and the new control strategy of the world health organization efficacy of bcg vaccine in the prevention of tuberculosis. meta analysis of the published literature rosen's emergency medicine concepts and clinical practice rosen's emergency medicine concepts and clinical practice coxiella burnetii (q fever) pneumonia the chest film findings in ''q'' fever-a series of cases chlamydia psittaci (psittacosis) francisella tularensis (tularemia) bordetella pertussis and chronic cough in adults viral hemorrhagic fevers and hantavirus infections in the americas pseudomonas species (including melioidosis and glanders) emerging infectious diseases and risk to the traveler fever in the returned traveler heart disease: a textbook of cardiovascular medicine should pericardial drainage be performed routinely in patients who have a large pericardial effusion without tamponade? rosen's emergency medicine: concepts and clinical practice harrison's principles of internal medicine, th edition cardiac tamponade as a manifestation of tuberculosis tuberculous pericarditis human immunodeficiency virus-associated pericardial effusion: report of cases and review of the literature tuberculous pericarditis: optimal diagnosis and management tuberculous pericarditis: ten years of experience with a prospective protocol for diagnosis and treatment key: cord- - lf vn authors: biggerstaff, matthew; reed, carrie; swerdlow, david l.; gambhir, manoj; graitcer, samuel; finelli, lyn; borse, rebekah h.; rasmussen, sonja a.; meltzer, martin i.; bridges, carolyn b. title: estimating the potential effects of a vaccine program against an emerging influenza pandemic—united states date: - - journal: clin infect dis doi: . /cid/ciu sha: doc_id: cord_uid: lf vn background. human illness from influenza a(h n ) was identified in march , and candidate vaccine viruses were soon developed. to understand factors that may impact influenza vaccination programs, we developed a model to evaluate hospitalizations and deaths averted considering various scenarios. methods. we utilized a model incorporating epidemic curves with clinical attack rates of % or % in a single wave of illness, case hospitalization ratios of . % or . %, and case fatality ratios of . % or . %. we considered scenarios that achieved % vaccination coverage, various starts of vaccination programs ( or weeks before, the same week of, or or weeks after start of pandemic), an administration rate of or million doses per week (the latter rate is an untested assumption), and levels of vaccine effectiveness ( doses of vaccine required; either % or % effective for persons aged < years, and either % or % effective for persons aged ≥ years). results. the start date of vaccination campaigns most influenced impact; – hospitalizations and – deaths were averted when campaigns started before a pandemic, and < – hospitalizations and – deaths were averted for programs beginning the same time as or after the introduction of the pandemic virus. the rate of vaccine administration and vaccine effectiveness did not influence campaign impact as much as timing of the start of campaign. conclusions. our findings suggest that efforts to improve the timeliness of vaccine production will provide the greatest impacts for future pandemic vaccination programs. factors, including the size, speed, and number of waves of the pandemic outbreak, the number of doses administered, the timing of the vaccination program relative to the spread of the novel influenza virus, and the vaccine effectiveness (ve) [ ] . to help public health officials and policy makers evaluate the impact of a hypothetical vaccination program against a future influenza pandemic, we developed a spreadsheet-based model that allowed quick exploration of the number of hospitalizations and deaths averted in the united states under various vaccination scenarios. we adapted a spreadsheet model (excel, microsoft corporation, redmond, washington) that was originally created to estimate the effects of a vaccine program against influenza a(h n ) pdm [ ] . the model user enters an epidemic curve (the number of persons becoming ill by time) and other variables that define the impact of both the pandemic and the vaccination campaign. these variables include the timing of the vaccination program relative to the introduction of no. of initial cases [ ] cumulative attack rate, % or [ ] case hospitalization ratio, % [ , ] all cases into the united states, the number of doses administered per week and the allocation by age group, the clinical attack rate, and the ratios of health outcomes to the number of cases (eg, the case hospitalization and case fatality ratios) ( table ) . we adjusted calculations to account for individuals who were naturally immunized through infection but who may still be vaccinated. to estimate the number of infections prevented by the vaccination program, we took [the number of persons fully vaccinated weeks prior to the current week in the model] × [the probability of not having been previously infected with influenza before being fully vaccinated and having developed immunity] × [ probability of becoming infected with influenza after being fully vaccinated and having developed immunity] × [ve] [ ] . we utilized standardized epidemic curves, using % and % clinical attack rates in wave of illnesses and different levels of clinical severity and assumed that the pandemic began with persons initially infected [ ] (table ) . for our model, we assumed that doses of vaccine administered weeks apart would be needed to be fully effective, based on data indicating that previous h and h influenza vaccines have low immunogenicity [ ] [ ] [ ] . we further assumed that, during a pandemic with moderate or high mortality, demand for vaccine would be such that % of the us population would receive doses of vaccine. we prioritized persons returning for their second dose of vaccine over persons who were receiving their first dose. we also assumed that vaccine was allocated in a pattern similar to the doses administered among age groups ( months- years, - years, - years, and ≥ years) during the - influenza season [ ] (table ) . once % of an age group was fully vaccinated, we assumed vaccination would end in that age group. remaining vaccine would then be allocated to other age groups until they reached % coverage. we allowed for a -week delay in protection against the virus after administration of the second dose of the vaccine [ ] . we ran multiple scenarios to explore the effects of the quantity of the doses administered, the timing of the vaccine program, and the ve of the first and second doses. we first assumed that the program would administer either million doses per week (approximating the maximum number of doses administered per week during seasonal influenza programs [ ] ) or million doses per week; the latter has yet to be achieved during seasonal influenza vaccination programs. to explore the effects of timing of the vaccine program, we modeled programs starting at different time points, separated by -week intervals: weeks before, weeks before, the same week as, weeks after, and weeks after the first cases of the novel influenza virus were introduced into the united states. we also assumed that dose of vaccine was % effective for figure . the estimated epidemic curve without vaccination and the cumulative number of persons protected by an influenza vaccination program with the following assumptions: an overall clinical attack rate of the influenza pandemic of % or %; administered million (left) or million (right) vaccine doses; vaccination programs that begin or weeks before, the same week, or or weeks after the first cases of a novel influenza virus occur in the united states (us); and the vaccine effectiveness (ve) equivalent to the h n pmd monovalent vaccine. h n -like ve: doses of vaccine administered weeks apart required to be fully effective ( % for persons aged < years and % for persons ≥ years) in protecting against subclinical and clinical cases, hospitalizations, and deaths. we assumed dose of vaccine to be % effective for all age groups. all age groups and doses of vaccine were % effective in protecting against subclinical and clinical cases, hospitalizations, and deaths for persons aged < years and % for persons aged ≥ years (table ) . these values were based on the ve of the monovalent, inactivated, nonadjuvanted influenza a(h n )pdm vaccine [ ] . for the second scenario, we clinical attack rate of the influenza pandemic is % and the overall case fatality ratio is . % (high-severity scenario); million doses (left) or million doses (right) of vaccine are administered each week; the vaccination program begins weeks after, weeks after, the same week as, weeks before, and weeks before the first cases of a novel influenza virus occur in the united states; and the efficacy is "h n pmd monovalent vaccine-like." h n -like vaccine effectiveness: doses of vaccine administered weeks apart required to be fully effective ( % for persons aged < years and % for persons ≥ years) in protecting against subclinical and clinical cases, hospitalizations, and deaths. we assumed dose of vaccine to be % effective for all age groups. assumed a high ve due to the use of higher concentrations of hemagglutinin antigen [ ] or the addition of an adjuvant to the vaccine [ ] . in the high ve scenario, we assumed some ve with dose ( % ve for persons aged < years and % for persons ≥ years) and higher ve with doses ( % effective for persons aged < years and % for persons ≥ years) ( table ) . clinical attack rate of the influenza pandemic is % and the overall case fatality ratio is . % (low-severity scenario); million doses (left) or million doses (right) of vaccine are administered each week; the vaccination program begins weeks after, weeks after, the same week as, weeks before, and weeks before the first cases of a novel influenza virus occur in the united states; and the efficacy is "h n pmd monovalent vaccine-like." h n -like vaccine effectiveness: doses of vaccine administered weeks apart required to be fully effective ( % for persons aged < years and % for persons ≥ years) in protecting against subclinical and clinical cases, hospitalizations, and deaths. we assumed dose of vaccine to be % effective for all age groups. to calculate the number of vaccine-associated averted outcomes (hospitalizations and deaths), we assumed that % of infected cases were symptomatic and either . % of symptomatic cases were hospitalized and . % of symptomatic cases would die (low-severity scenario) or . % of symptomatic cases were hospitalized and . % of symptomatic cases would die (high-severity scenario) ( table ) . we adjusted the risk of hospitalization and death by age group ( table ) . the values for hospitalizations and deaths were based on estimates predicted for a pandemic with high clinical severity, and the adjustments for age were based on historic pandemics [ , ] . for the scenario with a cumulative clinical attack rate of %, without any other intensive interventions, the simulated pandemic peaked in the united states weeks after the introduction of the first cases and resulted in infections, clinical cases, and hospitalizations and deaths in the low-severity scenario or hospitalizations and deaths in the high-severity scenario (figures - ) . for the scenario with a cumulative clinical attack rate of %, the simulated epidemic peaked weeks after the start and resulted in infections, clinical cases, and hospitalizations and deaths (low-severity scenario) or hospitalizations and deaths (high-severity scenario) (figure ). vaccination programs distributing million doses per week would take weeks to achieve % coverage of a -dose vaccine series among all age groups, whereas programs distributing million doses per week would take weeks (figure ). for an influenza pandemic with a % overall cumulative attack rate and high clinical severity, we estimated that a vaccination program beginning weeks before the pandemic started in the united states and that administered million doses of vaccine with the moderate ve per week could avert hospitalizations and deaths ( % reduction relative to no vaccine). starting the vaccination program weeks before the pandemic started would avert hospitalizations and deaths ( % reduction) (tables and ; figures and ) . a vaccine program administering million doses per week that started or weeks before the pandemic would avert hospitalizations and deaths ( % reduction) (tables and ; figures and ) . assuming that the ve would be % and % for persons aged < years and ≥ years, respectively (compared with the base assumption of % and % for persons aged < years and ≥ years, respectively) would further reduce hospitalizations and deaths by at least an additional % relative to no vaccine for both the and million administration scenarios (tables and ) . for an influenza pandemic with a % overall cumulative attack rate and high clinical severity, we estimated that a vaccination program beginning weeks before the pandemic started in the united states that administered million doses of vaccine with the moderate ve per week could avert hospitalizations and deaths ( % reduction relative to no vaccine). starting the vaccination program weeks before the pandemic started would avert hospitalizations and deaths ( % reduction) (tables and ; figures and ) . a vaccine program administering million doses per week that started weeks before the pandemic would avert more than hospitalizations and deaths ( % reduction), whereas one that started weeks before the pandemic would avert hospitalizations and deaths ( % reduction) (tables and ; figures and ). using the high ve would further reduce hospitalizations and deaths relative to no vaccine for both the and million administration scenarios by at least an additional % (tables and ) . for an influenza pandemic with a % overall cumulative attack rate and high clinical severity, we estimated that a vaccination program beginning the same week as the pandemic started in the united states that administered million doses of vaccine with the moderate ve per week could avert hospitalizations and deaths ( % reduction). a vaccine program administering million doses per week that started the same week as the pandemic would avert hospitalizations and deaths ( % reduction) (tables and ; figures and ) . using the high ve would further reduce hospitalizations and deaths by at least an additional % relative to no vaccine for both the million and million administration scenarios (tables and ) . for an influenza pandemic with a % overall cumulative attack rate and high-severity scenario, we estimated that a vaccination program beginning the same week as the pandemic started in the united states that administered million doses of vaccine with the moderate ve per week could avert hospitalizations and deaths ( % reduction) (tables and ; figures and ) . a vaccine program administering million doses per week would avert hospitalizations and deaths ( % reduction) (tables and ; figures and ) . using the high ve would reduce hospitalizations and deaths by at least an additional % relative to no vaccine for both the million and million administration scenarios (tables and ). for an influenza pandemic with a % overall cumulative attack rate and high clinical severity, we estimated that a vaccination program beginning weeks after the pandemic started in the united states that administered million doses of vaccine with the moderate ve per week could avert hospitalizations and deaths ( . % reduction relative to no vaccine). beginning the vaccination program weeks after the pandemic started would avert hospitalizations and deaths ( . % reduction) (tables and ; figures and ) . a vaccine program administering million doses per week that started weeks after the pandemic would avert more than hospitalizations and deaths ( % reduction), whereas one that started weeks after the pandemic would avert hospitalizations and deaths ( . % reduction) (tables and ; figures and ) . using the high ve would reduce hospitalizations and deaths by at least an additional % relative to no vaccine for both the million and million administration scenarios (tables and ) . for an influenza pandemic with a % overall cumulative attack rate and high clinical severity, we estimated that no vaccination program that began or weeks after the pandemic started in the united states would avert more than hospitalizations and deaths (< % reduction), regardless of whether million or million doses of vaccine per week with the moderate ve were administered (tables and ; figures and ) . using the high ve would reduce hospitalizations and deaths by no more than % relative to no vaccine for the vaccination programs beginning weeks after the pandemic started in the united states. for the high ve scenarios starting weeks after the pandemic started in the united states, no additional reductions in hospitalizations or deaths were observed (tables and ) . in our analysis, the clinical attack rate and case hospitalization and case fatality ratios had the greatest impact on the number of severe outcomes averted in the united states, whereas the vaccination program factor with the greatest impact was the timing of the start of vaccination relative to the start of a pandemic. for example, under the % clinical attack rate and million doses per week scenario, a vaccination program starting weeks before the start of the pandemic in the united states results in a % reduction in hospitalizations and deaths. delaying the start of vaccination to the same week as the pandemic starts in the united states drops the reductions to %. the number of vaccine doses administered each week is also very important. decreasing the doses administered to million per week causes the impact of vaccination in the above scenarios to decline to % and % reductions, respectively. the assumptions related to ve of the first and second doses were relatively less important. this study highlights several key components to pandemic influenza preparedness, especially for a severe pandemic, including the importance of ensuring readiness to initiate large-scale vaccination programs as early as possible and ideally before the introduction of a novel influenza virus into the united states [ , ] . factors that may impact vaccine dose availability include how soon we develop an appropriate vaccine virus candidate, growth characteristics of vaccine virus candidates, influenza vaccine production capacity, efficiency of vaccine allocation and distribution, and vaccine administration capacity. increased investment and research in vaccine production technologies, including the use of cell-derived recombinant proteins [ ] , virus-like particles [ ] , or adjuvants (by conserving the use of hemagglutinin antigen), have the potential to increase the speed with which the number of vaccine doses can be produced. also important is the need to identify ways to invest in improvements that will notably increase the capacity to administer large number of doses of pandemic influenza vaccine. currently, the peak administration rate for seasonal influenza in the united states is between and million doses per week. the cdc is working with state and local health officials and vaccine providers to identify means to enhance vaccination administration capabilities. in addition to exercising large-scale b two doses of vaccine administered weeks apart required to be fully effective ( % for persons aged < years and % for persons ≥ years) in protecting against subclinical and clinical cases, hospitalizations, and deaths. we assumed dose of vaccine to be % effective for all age groups. c two doses of vaccine administered weeks apart required to be to fully effective ( % for persons aged < years and % for persons ≥ years) in protecting against subclinical and clinical cases, hospitalizations, and deaths. we assumed dose of vaccine is % effective for persons aged < years and % for persons ≥ years. mass vaccination clinics, this includes increasing partnerships with nontraditional vaccine providers, such as pharmacies, supermarket chains, and other community vaccine providers including diverse health, faith, and community based-organizations that reach vulnerable, at-risk, hard-to-reach, and minority populations [ , ] . we evaluated a wide range of vaccine program initiation times relative to disease introduction in the united states in this article. although this information cannot be known in advance, beginning vaccination weeks prior to the introduction of disease in the united states might be possible if the pandemic virus was identified, a stockpiled influenza vaccine were available and appropriate for use, officials were prepared to administer vaccine, and the decision to vaccinate was made at least weeks before the establishment of the virus in the united states (based on current estimates of weeks to fill and finish and begin distribution of stockpiled pandemic vaccine) [ ] . this timeline is dependent on robust novel influenza virus surveillance that can identify influenza viruses with pandemic potential before widespread transmission has occurred. during the h n pandemic, however, the first cases were identified in the united states after widespread transmission had already occurred, and no stockpiled vaccine or vaccine candidate seed viruses were available. in this example, the first doses of vaccine became available weeks after identification of the first case in the united states and weeks after the start of the main wave of pandemic illness in the fall of [ ] . this situation is demonstrated by the scenarios beginning or weeks after the introduction of the virus into the united states [ ] . this study has several limitations. most important, because infections with influenza a(h n ) so far have been rare [ ] , the modeled number of pandemic-related hospitalizations and deaths, and the numbers of such that would be prevented by a vaccination program, can only be considered as illustrative and are not based on the current epidemiology of h n or other novel influenza virus illnesses. these results, therefore, should not be interpreted as a prediction of the impact of a widespread outbreak of h n or any other novel influenza a virus with pandemic potential. additionally, we did not account for the effects of other interventions (eg, nonpharmaceutical interventions such as canceling mass gatherings or closing schools), the seasonality of when a novel virus might be introduced into the united states, or "waves of illness," which are thought to have occurred in modern pandemics [ , ] . these factors could slow the course of the pandemic and thereby increase the amount of time to initiate and complete a vaccine program, increasing the number of hospitalizations and deaths averted. for ease of estimation, we also did not account for any adverse events associated with vaccination or for the indirect effects of vaccination (eg, herd immunity). theoretically, accounting for indirect effects would likely increase the number of hospitalizations and deaths averted for those vaccination programs assumed to start before the pandemic; this effect would likely be lower for those programs assumed to start the same time as or after the pandemic. another important assumption is that % of the population would want to be vaccinated. this is distinctly different from recent seasonal influenza coverage estimates of approximately % [ ] . we do not know the precise correlation between severity of an influenza pandemic and public demand for vaccination, but % coverage may be an overestimate. another potential limitation is that no data are available on the ve of a possible h n vaccine. thus, we based our estimates of ve of either an nonadjuvanted influenza vaccine, using data from the h n pandemic, or a hypothetical vaccine with high ve based on data from adjuvanted h n vaccine ve estimates. limited data indicate that h vaccines have lower immunogenicity than seasonal influenza vaccines, which may result in lower ve [ , ] . the population coverage or the effectiveness of a h n or other future pandemic vaccine may be lower than what is assumed here, leading to a smaller number of averted outcomes. historically, influenza pandemics have been largely unpredictable events, and it is likely that the set of assumptions used in this study will vary from the actual events seen in the next pandemic, even if influenza a(h n ) is the virus involved. however, the finding that variations in the timing of vaccination administration yield the greatest effect on the reduction in hospitalizations and deaths than do variations in rate of vaccine administration or effectiveness would likely remain consistent. continued research and investment in work that improves the timeliness of vaccine production and administration will have the greatest benefits in the event of another influenza pandemic. global epidemiology of influenza: past and present epidemiology of pandemic influenza a (h n ) in the united states human infection with a novel avian-origin influenza a (h n ) virus clinical findings in cases of influenza a (h n ) virus infection human infection with avian influenza a (h n ) virus-update receptor binding by an h n influenza virus from humans biological features of novel avian influenza a (h n ) virus population-level antibody estimates to novel influenza a/h n emergence of avian influenza a(h n ) virus causing severe human illness-china effects of vaccine program against pandemic influenza a(h n ) virus, united states standardizing scenarios to assess the need to respond to an influenza pandemic novel framework for assessing epidemiologic effects of influenza epidemics and pandemics sensitivity and specificity of serologic assays for detection of human infection with pandemic h n virus in u.s. populations fluvaxview influenza vaccination coverage h n avian influenza: preventive and therapeutic strategies against a pandemic a randomized clinical trial of an inactivated avian influenza a (h n ) vaccine a phase i clinical trial of a per.c cell grown influenza h virus vaccine influenza vaccination coverage: how well did we do in - randomized, double-blind controlled phase trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults years of age and older and pandemic vaccines, to prevent influenza hospitalizations during the autumn influenza pandemic wave in castellon, spain. a test-negative, hospital-based, case-control study final estimates for - seasonal influenza and influenza a (h n ) monovalent vaccination coverage-united states protective efficacy of a trivalent recombinant hemagglutinin protein vaccine (flublok(r)) against influenza in healthy adults: a randomized, placebo-controlled trial virus-like particle (vlp)-based vaccines for pandemic influenza: performance of a vlp vaccine during the influenza pandemic vaccinations administered during off-clinic hours at a national community pharmacy: implications for increasing patient access and convenience public health and faith community partnerships: model practices to increase influenza prevention among hard to reach populations news release: hhs boosts national capacity to produce pandemic flu vaccine surveillance for influenza during the influenza a (h n ) pandemic-united states report to the president on reengineering the influenza vaccine production enterprise to meet the challenges of pandemic influenza low immunogenicity predicted for emerging avian-origin h n : implication for influenza vaccine design a recombinant viruslike particle influenza a (h n ) vaccine disclaimer. the findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the centers for disease control and prevention (cdc).supplement sponsorship. this article appears as part of the supplement titled "cdc modeling efforts in response to a potential public health emergency: influenza a(h n ) as an example," sponsored by the cdc.potential conflicts of interest. all authors: no reported conflicts. all authors have submitted the icmje form for disclosure of potential conflicts of interest. conflicts that the editors consider relevant to the content of the manuscript have been disclosed. key: cord- - wfyaxcb authors: ubokudom, sunday e. title: physical, social and cultural, and global influences date: - - journal: united states health care policymaking doi: . / - - - - _ sha: doc_id: cord_uid: wfyaxcb in chap. , we examined the technological environment of the health care policy-making system. specifically, we examined the classification, evolution, and diffusion of medical technology; the effects of medical technology on medical training and the practice of medicine; effects on medical costs, quality of care, and quality of life; effects on access to care; the ethical concerns raised by medical technology; and the practice of technology assessment. we concluded the chapter by observing that the growth of technology, as well as other human endeavors, affects other important aspects of our lives, most notably, the air we breathe, the food we eat, the generation of radioactive by-products and toxic chemicals, the manufacture of illicit drugs, and the generation of natural and man-made hazards. in other words, in addition to their effects on the health care system, technology and other human activities affect many other aspects of our lives that are associated with health. the who's defi nition of health as "a complete state of physical, mental, and social well-being, and not merely the absence of disease or infi rmity" (who ) , is primarily based on the wellness model. in this defi nition, emphasis is put on the fact that health is not merely the absence of disease, but also involves a social dimension. therefore, it also emphasizes the social and fi nancial support systems identifi ed in table . of chap. . this defi nition of health, as involving the combination of physical, mental, and social well-being led to the concept of the "health triangle." the health triangle left out the spiritual dimension of health, which has recently gained signifi cant attention in the literature due to a growing interest in the notion of holistic health. holistic health stresses the importance of all the things that make a person whole and complete. in addition to the three dimensions of the health triangle, of his analysis (szreter , p. ) . subsequent studies revealed that the cessation of the large-scale redistribution of income and wealth from the very rich to the poorest in society had adverse effects on the health of the population. for example, when unhealthy behaviors and lifestyles were held as constant as possible, studies showed that people of lower socioeconomic status were more likely to die prematurely than were people of higher socioeconomic status (isaacs and schroeder , p. ; smith et al. , p. ; davey smith et al. , p. ) . the relationship between physical, social and cultural, and global environmental factors and health status is very well documented. in a letter to the editor of the jama , winkelstein ( winkelstein ( , p. argues that curative medical care, or those practices that are used for the care and rehabilitation of the sick, which involve most of the physical and designed social technologies listed in table . of the previous chapter, is not the same as health care. medical care, as he defi nes it, makes only modest contributions to the health status of the population. on the contrary, the health status of the population is largely determined by a different set of factors that involve important physical, social, and economic components. these include preventive medicine, genetic predisposition, social and economic circumstances, environmental conditions, lifestyles and behaviors, and medical care (mckeown ; kannel et al. ; belloc and breslow , p. ; bunker et al. ; bunker et al. , p. ; marmot et al. marmot et al. , p. bell and standish , p. ; mcginnis et al. , p. ; wilkinson wilkinson , p. . we briefl y examine each of the identifi ed determinants of health below. preventive medicine seeks to minimize the occurrence of illness and disease. unlike the medical model that is reactive and seeks to contain disease and ill-health after they have occurred, preventive medicine is proactive and seeks to minimize the likelihood of the occurrence of disease and ill-health. generally, there are three areas or types of preventive measures, namely: primary prevention, secondary prevention, and tertiary prevention. primary prevention seeks to stop or minimize the development of disease or ill-health before it occurs. primary prevention may involve counseling against smoking, in order to prevent the development of chronic emphysema or chronic obstructive pulmonary disease (copd) and lung cancer. other primary interventions may include the promotion of an active lifestyle or exercise program, in order to minimize the likelihood of excess body fat and heart disease; driver education and mandatory seatbelt and motorcycle helmet laws, in order to reduce motor vehicle accidents and accidental head injuries; vaccinations for various forms of diseases and illnesses, such as measles and rubella, which can minimize the occurrence of early childhood diseases and mortality; and water purifi cation and sewage treatment programs that can minimize the occurrence of typhoid, cholera, and other waterborne diseases. secondary prevention involves the early detection and treatment of disease. health screenings and periodic and regular health examinations, such as hypertension screenings, mammograms, and pap smears, serve as examples of secondary prevention measures. these examples fall under the broad category of health promotion discussed in chap. . the benefi ciaries of these programs are currently healthy people who are targeted to improve their health-related behaviors in order to minimize their chances of developing catastrophic and expensive illnesses. as was discussed in chap. , secondary prevention measures are some of the most cost-effective steps employers take to lower their health benefi t costs ( coffi eld et al. , p. ) . tertiary prevention measures involve steps taken to reduce the complications of diseases or illnesses, or to prevent further illnesses. they involve rehabilitative practices and the monitoring of the process of health care delivery. the infection control practices in hospitals and other improvements in the methods of health care delivery discussed in chap. , under the postindustrial period of the evolution of the health care system, which are intended to reduce the occurrences of nosocomial infections and iatrogenic illnesses, are practical examples of tertiary prevention measures. other examples include patient education, nutrition counseling, and behavior modifi cation programs that seek to prevent the recurrence of disease and illness (timmreck , p. ) . since the mid- s in the united states, there have been signifi cant reductions in heart disease, stroke, personal injury, and non-tobacco-related death rates foege , p. ; banta and jonas , p. ) . similarly, the data presented in table . of chap. show signifi cant declines in death rates related to heart disease, cancer, stroke, infl uenza and pneumonia, chronic liver disease or cirrhosis, human immunodefi ciency virus (hiv) disease, suicide and homicides, from to . these particular declines appear to be the result of preventive health measures, such as early screening, detection and treatment of hypertension, the provision and utilization of pneumonia and infl uenza vaccinations, moderate alcohol intake or abstinence, safe sex practices, suicide prevention and anger management programs, increased use of seatbelts and reductions in driving-underthe-infl uence episodes, smoking cessation, and the lowering of dietary fat and cholesterol. if, at least, some of the declines in mortality discussed above are due to preventive measures, the preventive strategy has yielded signifi cant gains in health. perhaps, it is this recognition of the importance of preventive services that led to the establishment of the us preventive services task force (uspstf) in . most likely, it was the recognition of the crucial role that preventive medicine plays in enhancing population health that led to the convening of the uspstf in by the us public health service. the task force is a leading independent panel of nationally recognized nonfederal experts in prevention and evidencebased medicine. programmatic responsibility for the task force was transferred to the agency for health care research and quality (ahrq) in (uspstf procedure manual ). the uspstf is assigned the responsibility of making evidence-based recommendations that address primary and secondary preventive services targeting conditions that represent a substantial burden in the country, and that are provided in primary care delivery settings or made available through primary care referrals. the task force's recommendations are intended to improve clinical practice and promote the public health. tertiary prevention measures are outside the scope of the uspstf. even though the main audience for task force recommendations is the primary care provider, the recommendations are also used to guide programmatic, funding, and reimbursement decisions by policy-makers, managed care organizations, public and private payers, quality improvement organizations, research institutions, and consumers. beginning at the end of may , the uspstf changed the grades it assigns to its recommendations. it assigns one of fi ve possible letter grades, a, b, c, d, or i, to each of its recommendations, including "suggestions for practice" associated with each grade. the agency also defi nes the levels of certainty regarding the net benefi t of each of its recommendations. the task force's reduction of the grade given for evidence quality from "b" to "c" for routine mammograms in women under the age of years generated signifi cant controversy among health professionals and politicians (kinsman ) . in addition to the mammography recommendations stated above, the uspstf has recently recommended against screening for testicular cancer in adolescent or adult males (grade d recommendation) (uspstf , p. ) . it has also concluded that there was insuffi cient evidence to assess the balance of benefi ts and harms of screening for bladder cancer in asymptomatic adults (moyer , p. ) , and that prostate-specifi c antigen (psa) screening was associated with psychological harms, while its potential benefi ts remained uncertain (lin et al. , p. ) . table . shows the approach adopted by the agency in june , to rank its recommendations. health is dependent upon biological factors. our predispositions to health or disease begin to take shape at the moment of conception. these predispositions are embedded in our genetic code. the genetic code guides the development of the proteins that determine our phenotypes (sizes, shapes, personalities, hair color, etc.) and genotypes or those aspects of our genetic codes that we cannot see, such as the biologic limit of our life expectancies (mcginnis et al. , p. ; khoury et al. ; bell and standish , p. ; starfi eld , p. ; blum ; centers for disease control and prevention (cdc) ) . genetic factors predispose individuals to certain diseases. but although an individual may have a strong likelihood of developing a particular disease, this propensity to develop the disease is signifi cantly enhanced by environmental factors. for example, some studies demonstrate that there is a genetic basis for alcoholism (reich ) . but a person who has never taken a drink will not become an alcoholic. some triggers, in this case, the availability and consumption of alcohol, are necessary for the individual to progress from being genetically predisposed to alcoholism to actually (berkman and breslow ; burnett ; banta and jonas , p. ; davis and webster , p. ) . these examples suggest that the interaction between genetic factors and the environment in producing a particular disease is complex. while people have little or no control over their genetic makeups, the lifestyles and behaviors they freely choose and the surroundings where they live can have signifi cant infl uences on the likelihood of developing a particular disease to which they are genetically predisposed. to further the discussion of the infl uence of genetics on health, mcginnis et al. ( , p. ) cite studies which show that although only about % of deaths in the united states may be attributed to purely genetic diseases, about % of late-onset disorders, such as diabetes, cardiovascular disease, and cancer, have some genetic component. for example, the brca gene accounts for only between and % of breast cancers in the united states; only about % of colon cancers may be explained by genes, and only about % of elevated serum cholesterol levels may be explained by familial hyperlipidemia. similarly, studies of identical twins focusing on the occurrence of schizophrenia, and other twin studies examining the occurrence of dementia in older people, have found that about half of each might be explained by genetic factors. further, while about two-thirds of the risk of obesity might be genetic, the risk is expressed only with exposure to controllable lifestyle factors (baird , p. ; muller , p. ; panjukanta et al. , p. ; kendler kendler , p. rowe and kahn ) . the institute of medicine (iom) ( , p. ) reported that americans in , compared with those who lived in , were healthier, lived longer, and enjoyed lives that were less likely to be marked by injuries, ill health, or premature death. but the gains in health reported by the iom were not shared equally among the population of the united states. at the moment, as was also the case in , gains in health status are not shared fairly or equally by all americans. americans with a good education, those who hold high-paying jobs, and those who live in serene and comfortable neighborhoods live longer and healthier lives than those with lower levels of education and income, and those who live in crime infested, overcrowded, and less comfortable and cohesive urban areas (isaacs and schroeder , p. ; bell and standish , p. ; lantz et al. lantz et al. , p. navarro , p. ; satcher , p. ; williams , p. ; metzler , p. ; kilbourne et al. kilbourne et al. , p. berkman and lochner , p. ) . there are several pathways through which social and economic circumstances affect health. those with good educational achievements are more likely to attain higher socioeconomic status than the poorly educated (angel et al. ; barr ; bartley ; mirowsky and ross , p. ) . people of lower socioeconomic status die earlier and are more susceptible to undesirable life events than people on higher socioeconomic levels, a pattern that holds true in a progressive fashion from the poorest to the richest (mcleod and kessler , p. ; adler et al. , p. ; adler and newman , p. ; guralnik et al. , p. ; mcdonough et al. mcdonough et al. , p. . this trend also holds whether one looks at education or occupation (national center for health statistics , p. ; kaplan and keil , p. ). these differences are said to be due to the fact that people of higher socioeconomic status have healthier behaviors and lifestyles than those of lower socioeconomic status. people of higher socioeconomic status are less likely to smoke, and are far more likely to eat healthier foods and to engage in leisure-time physical exercise (national center for health statistics , p. ; pratt et al. , p. s ; giles-corti and donovan , p. ). according to isaacs and schroeder ( , p. ) , as a result of "a sedentary lifestyle and unhealthy eating habits, obesity and the diseases it fosters now characterize lower-class life." poor eating habits and a sedentary lifestyle alone do not explain the differences in health between high and low socioeconomic people. rather, another explanation for the differentials lies in the distribution of income or the income gradient between the low and high socioeconomic groups. in a study of white americans using census data, undertaken by smith et al. ( , p. ) , men earning less than $ , per year were . times as likely to die prematurely as were those earning $ , or more. a similar study of british civil servants conducted about years before the american study showed that when smoking and other risk factors were controlled for, those who were in the lowest employment category were more than twice as likely to die prematurely of cardiovascular disease as were those in the highest employment category (davey smith et al. , p. ) . the fi ndings of these studies have led to the theory that inequitable distribution of income and wealth, or the socalled income and wealth gradient, causes poor health (sen (sen , p. , daniels et al. ; deaton , p. ). as noted above, the relationship between health and income is referred to as a gradient. this terminology emphasizes the gradual relationship between the two variables. health improvements are directly related to improvements in income throughout the income distribution, and poverty has more than a "threshold" effect on health (deaton , p. ) . the us national longitudinal mortality study (nlms) published by the national institutes of health (nih) ( ) showed that the proportional relationship between income and mortality was the same at all income levels, implying that the absolute reduction in mortality for each dollar of income was much larger at the bottom of the income distribution than at the top. apart from income, mortality is also known to decline with wealth, rank, and with social status (marmot et al. (marmot et al. , p. (marmot et al. , (marmot et al. , p. . similarly, studies also show marked differences in life expectancy by race and by geography or people's places of residence. for example, there is a -year gap in life expectancy between white men who live in the healthiest counties or localities and black men who live in the unhealthiest counties (murray et al. , p. ; gittelsohn , p. ; marmot marmot , p. kawachi and berkman ) . the brief discussion in this section points to the effects of numerous, and possibly interrelated, social and economic factors on health. income might affect health just as health might affect income; the distribution of income and wealth might affect health. similarly, education, race, minority status, geography, employment, housing, discrimination and social isolation, nutrition, lifestyle, stress, health practices, and coping skills might affect health. it does not appear to matter very much which of the above factors is stressed, especially since they are more likely to be interdependent than independent. disease risks exist, most often, along a continuum (rose ) . risks are rarely dichotomous. according to lochner ( , p. ) , there is no clear division between risk and no risk with regard to, for example, levels of blood pressure, cholesterol, alcohol or tobacco use, physical activity, diet and weight, etc. this gradient of risk also exists for many social and environmental conditions, such as socioeconomic status, social isolation, occupational and environmental exposure, and air quality. put differently, the numerous studies on the determinants of health that we are unable to fully summarize individually here for lack of space, point to the fact that even though the human and material resources at our disposal, the foods we eat, our levels of education, the houses we live in, the quality of the environments where we live and work, to name but a few, affect every person's health, the effects may vary in direction and scope from person to person, depending on the differences in their unique circumstances. improvement in environmental conditions is an important goal of the us government, as can be inferred from the emphasis on environmental quality outlined in healthy people . that document clearly states that factors in the physical and social environment play major roles in the health of individuals and communities. the physical environment is operationalized to include the air, water, and soil through which exposure to chemical, biological, and physical agents may occur. the physical environment can harm individual and community health, especially when individuals and communities are exposed to toxic substances, irritants, infectious agents, and physical hazards in homes, schools, and work sites. the physical environment can also promote good health, for example, by providing clean and safe places for people to work, exercise, and play ( healthy people , p. ). therefore, the physical environment is perhaps one of the most important factors that should be considered when classifying the health status of an individual (wikipedia ) . environmental factors, such as air and water quality, exposure to pesticides and toxic waste, and housing conditions, have major effects on health and human development. for example, substandard air and water quality have been directly associated with diseases such as cancer, asthma, certain birth defects, and some neurological disorders (grant makers in health , p. ) . similarly, many forms of cancer are associated with dioxin, polychlorinated biphenyls (pcbs), and mercury (friis ) . also, airborne particulate matter, tobacco smoke, and ground-level ozone, have been known to cause asthma attacks in children. exposure to lead, which can be found in peeling paint or in the soil and air in many poor communities, has been associated with impaired cognitive and behavioral development and low birth weight among children born to exposed mothers, and is also known to cause kidney damage (friis ) . in recognition of the danger of environmental contamination, bell and standish ( , p. ) urge communities to act on their behalf to make changes in the policies that affect their physical, social, and economic environments. they state, plausibly, that "policy, place, and community" matter. combined, policy and community can alter or ameliorate the underlying forces that lie at the heart of the determinants of health. for example, they argue that policy determines the behaviors or things that are allowed, encouraged, discouraged, and prohibited. policy also determines whether industrial facilities will be sited near residential neighborhoods, how industrial facilities treat their neighbors; how dense neighborhoods will be; what materials can be used to build houses; who will live in a neighborhood; whether businesses can locate in a neighborhood; and whether there are tax or other incentives available for locating in a neighborhood (bell and standish , p. ). in the developed communities or countries, environmental epidemiologists are concerned about such things as gene-environment interactions, environment-environment interactions, particulate air pollution, nitrogen dioxide, ground-level ozone, environmental tobacco smoke, radiation, lead, video display terminals, cellular telephones, and persistent organic pollutants (pops) that act as endocrine disruptors. exposure to these downstream or proximate environmental vectors (exposures that are closely related in time and space to the ill-effects they cause) affect both health and well-being (encyclopedia of public health ) . in the developing communities, the primary environmental determinants of health are said to involve biological agents in the air, water, and soil that account for most deaths. for example, diarrheal diseases acquired from contaminated food or water, malaria, intestinal parasitic infections, respiratory diseases caused by biological and chemical agents in both indoor and outdoor air, wreak havoc in the developing countries. these environmental hazards take a far greater toll on human life and suffering in absolute terms compared to those environmental vectors of concern in the developed countries (encyclopedia of public health ) . the above environmental vectors that cause havoc in the developing countries also abound in the poor localities of the united states and other developed countries. wealthy people are more likely to live in better homes and locations where they are less exposed to environmental risks than poor people (friis ; mcleod and kessler , p. ; giles-corti and donovan , p. ; shi and singh , p. ; grant makers in health , p. ) . for example, although the rates of asthma have been rising in the country, the disease affects low-income people disproportionately. whereas the national prevalence rate of childhood and adult asthma is put at about %, some african-american communities report about % of children suffering from asthma. also, puerto rican children are reported to have the highest prevalence of active asthma of any us ethnic or racial group. in california, latino children are reported to be hospitalized for asthma at a rate that is % greater than that of white children. obviously, environmental hazards are some of the reasons for these disparities ( healthy people ; joint center for political and economic studies and policylink , p. ; flores et al. , p. ) . despite the gains in environmental quality since the advent of the environmental movement in the s, mainstream environmental policies neglected the problems identifi ed in low-income communities because the inhabitants of those areas lacked the political and economic resources to press for environmental justice. however, since its start around , the environmental justice movement has resulted in the cleanup of hazardous waste sites, the redevelopment of brown-fi elds, the shutdown of incinerators, and the establishment of parks and conservation areas in low-income communities. additionally, in low-income communities, local pollution problems are being addressed, cleaner and more accessible means of public transportation are made available, and wild lands and unique habitats are being protected (faber and mccarthy ) . these changes are due to interest group pressure, the recognition of the externalities associated with environmental degradation, and the value of a clean environment to the health and well-being of all persons, rich and poor. mcginnis et al. ( , p. ) contend that behavior choices constitute the single most important domain of infl uence over health prospects in the united states. lifestyle and behaviors involve many dimensions, including dietary choices, engagement in physical activity, sexual behavior and recreation, including the choice to smoke and to ingest alcohol, the wearing of motor vehicle seatbelts and motorcycle helmets, and other responsible behavior when operating motor vehicles. because lifestyle and behavioral factors are under the control of individuals, the public is very likely to defi ne lifestyle and behavioral health problems as being self-induced. the choices we make with regard to the many dimensions of lifestyle and behavior enumerated above have signifi cant impacts on personal and population health. for example, dietary factors have been associated with coronary heart disease and stroke; colon, breast, and prostate cancers; and diabetes (us department of health and human services ) . similarly, a sedentary lifestyle has been associated with increased risk for heart disease, osteoporosis, dementia, diabetes, and colon cancer (us department of health and human services ) . furthermore, research shows that diets rich in fruits and vegetables, low-fat dairy foods with reduced saturated and total fat, and low sodium diets can lower blood pressure (appel et al. (appel et al. , p. svetkey et al. , p. ; sacks et al. , p. ) . the primary differences between how we perceive behavioral change now from much earlier perceptions is the great awareness that individual behavior occurs in a social context (berkman and lochner , p. ) , be it the place of work or abode, the family, the place of worship, the peer group, the school system, the stage of development, etc. for example, the results from the national youth risk behavior survey (yrbs) demonstrated that numerous high school students engaged in behaviors that increased their chances of dying from motor vehicle crashes, other unintentional injuries, homicide, and suicide. specifi cally, the survey results showed that . % of those surveyed had rarely or never worn a seatbelt during the days preceding the survey; . % had ridden with a driver who had been drinking alcohol; . % had carried a weapon during the days preceding the survey; . % had drunk alcohol during the days preceding the survey; . % had used marijuana during the days preceding the survey; and . % had attempted suicide during the months preceding the survey (grunbaum et al. , p. ) . the authors of the yrbs concluded that "priority health-risk behaviors, which contribute to the leading causes of mortality and morbidity among youths and adults, are often established during youth, extend into adulthood, are interrelated, and are preventable." the examination of the main causes of death in the united states, which we shall shortly discuss in the next section of this chapter, will shed further light on behavioral risk factors. meanwhile, suffi ce it to say that lifestyle and behavioral factors constitute some of the important determinants of health that health policy must seek to address. even though it is agreed that the contribution of medical care to improved health is not as pronounced as the other factors just examined, curative medical care-those practices, technologies, and organizations that society and the medical profession use to cure and rehabilitate the sick-is nonetheless a key determinant of health (blum ; cdc ) . the centers for disease control and prevention (cdc) estimate that only about % of premature deaths in the united states can be attributed to inadequate access to medical care, while the remaining % can be accounted for by individual lifestyle and behaviors ( %), genetic profi les ( %), and social and environmental conditions ( %) (cdc ) . the reason why medical care is the least important determinant of health is because it is reactive, not proactive-it waits for disease and illness to occur before intervening, so to speak. in other words, while individual and population health are somehow associated with having access to curative care, access to preventive services is of greater signifi cance. therefore, health can improve signifi cantly, and the prevalence of disease can decline dramatically, without effective medical care, due to the other determinants of health (sigerist , p. ; mckeown , p. ; banta and jonas , p. ). this knowledge is very likely the reason why williams and jackson ( , p. ) and isaacs and schroeder ( , p. ) advocate the broadening of the concept of health policy to include the other determinants of health that were not usually seriously considered when discussing health policy. this knowledge, too, is the primary reason for this chapter of the book. we can elaborate further on the importance and relevance of the determinants of health by linking them to the ten leading causes of death in the united states. where possible, the analysis will link the incidences of mortality reported in the country that are associated with each, some, or combinations of the determinants of health. table . shows the ten leading causes of death in the united states for and . we present, below, the ten leading causes of death in the country for and in order to attempt to link some of them to treatable or preventable behaviors and exposures. in other words, we shall attempt to show that most of the deaths can be associated with factors that mainly fall under the social, economic, environmental, and lifestyle and behavioral determinants of health that we have just discussed. most of the ten leading causes of death presented above are nongenetic and can be prevented or treated. diseases of the heart, cancers, cerebrovascular diseases or strokes, chronic lower respiratory diseases, unintentional injuries, diabetes, infl uenza and pneumonia, and infection-and high blood pressure-induced nephritis can be curtailed, prevented, or treated. for example, cigarette smoking is linked with an increased risk of heart disease, chronic lower respiratory disease, and cancer; obesity is a major health risk for diabetes, hypertension, coronary heart disease, and some forms of cancer; alcohol causes a wide variety of accidents and injuries, increases the risks for high blood pressure, irregularities of the heart, and stroke; fl u vaccines can minimize infl uenza deaths; and seeking treatment for infections can prevent septicemia. additionally, although there is a genetic basis for nephrosis and nephrotic syndrome, the conditions can occur as a result of infection (such as strep throat, hepatitis, or mononucleosis), use of certain drugs, and diabetes. furthermore, although age and family history are important risk factors for alzheimer's disease, longstanding high blood pressure and a history of head trauma are suspected risk factors for the disease as well mcginnis and foege ( , p. ) identifi ed and quantifi ed the major external or nongenetic factors that contributed to deaths in the united states in . deaths associated with socioeconomic factors and access to medical care, although important contributors to the total deaths recorded in the country, were not included in the study because of the diffi culty quantifying them independent of the other factors reported in the study. about years after the mcginnis and foege study, mokdad et al. ( mokdad et al. ( , p. ) used a similar methodology to quantify the nongenetic factors that contributed to deaths in . the results of the two studies cited above showed that about half of all deaths that occurred in the united states in both and could also be attributed to a small number of largely controllable behaviors and exposures, including tobacco, diet and activity patterns, alcohol, microbial and toxic agents, fi rearms, sexual behavior, motor vehicle accidents, and illicit drug use. the results of the causes of death studies reported by mcginnis and foege and mokdad and his colleagues are consistent with the fi ndings of the national yrbs cited earlier in this chapter. the survey results showed that in the united states, . % of all deaths among youth and young adults aged - years were due only to four causes: motor vehicle crashes, other unintentional injuries, homicide, and suicide. the deaths attributable to these causes among the identifi ed population group were . , , . , and . %, respectively (grunbaum et al. , p. ) . furthermore, substantial morbidity and social problems were said to result from the approximately , pregnancies that occurred each year among women - years (ventura et al. , p. ) , and from the estimated million cases of sexually transmitted diseases (stds) that occurred each year among persons - years (institute of medicine ; eng and butler ) . similar to the studies on the actual causes of death in the united states in and , the yrbs also found that the leading causes of mortality and morbidity among all age groups in the country were related to behaviors that contributed to unintentional injuries and violence, tobacco use, alcohol and other drug use, sexual behaviors that contributed to unintended pregnancies and stds, including hiv infection, unhealthy dietary behaviors, and sedentary lifestyles. in , almost years after the yrbs discussed above, the cdc quantifi ed the death rates among teenagers aged - years between and . not surprisingly, the ten leading causes of death for the teenage population remained constant throughout the period. they were as follows: accidents or unintentional injuries, % of deaths; homicides, % of teenage deaths; suicide, %; cancer, %; and heart disease, %. further analysis showed that motor vehicle accidents accounted for almost three quarters ( %) of all deaths from unintentional injury; and that non-hispanic black males had the highest death rate among all teenagers, with homicide being the leading cause of death for them (minino ) . the determinants of health that have occupied our attention up to this point are not only affected by the broad national and personal factors we have identifi ed but are also affected by broad global or international factors (shi and singh , p. ) . therefore, the rest of this chapter is devoted to examining the infl uences of global factors on the health care system and the health policymaking process. foreign policies involve the political relationships between countries and the outside world. foreign policy development generally concerns the protection of a country's national interests, usually defi ned in terms of security, economic prosperity, and ideological goals (lee et al. , p. ) . increased globalization has led to the broadening of foreign policy concerns to include health. conversely, it is now recognized that international trade and fi nance, migration and population mobility, environmental change or global warming, the emerging and reemerging infectious disease paradigms, natural disasters, and global insecurity or terrorism have clear and observable consequences for human health (kassalow ; mcinnes and lee , p. ; lee et al. , p. ; katz and singer , p. ; campbell-lendrum et al. , p. ; fidler , p. ; macpherson et al. , p. ; labonte et al. ) . we shall briefl y examine how these components of globalizationinternational trade, population mobility, infectious diseases, global warming or climate change, and natural disasters and terrorism-affect countries' health care and policymaking systems generally, and the united states' health care and policymaking systems in particular. we begin with international trade. the principal agents of global international trade and fi nance include such international agencies as the world bank, the international monetary fund (imf), and the world trade organization (wto). it has been reported that the market-biased or effi ciency-oriented austerity policies these organizations promote or sponsor have resulted in reduced expenditures for social programs in developing countries, thereby impairing population health and slowing the advances in literacy, fertility reduction, and improved reproductive health of the women of the developing countries (kinnon , p. ; gray ; watts ) . some specifi c examples of international trade and fi nance policies include the following: trade liberalization or the lowering of tariffs and other barriers to imports that has led to the doubling of the value of world trade from % of world gdp in to % in (world bank ; the reorganization of production and service provision across multiple national borders by multinational or transnational corporations, such as outsourcing or the pursuit of integration into global value chains, resulting in a global labor market (world bank , p. woodall ) ; the conditions attached to world bank and imf loans, and to the rescheduling of loan payments, including structural adjustment programs (saps); fi nancial liberalization, which exposes national economies to the uncertainties created by large and volatile short-term capital fl ows; the signifi cant growth in the world's urban population caused by transnational economic integration; the promotion of export-oriented agricultural development that does not consider the social and environmental consequences of such actions, which result from the pressures on governments around the world to increase export earnings (stonich and bailey , p. ) ; and the promotion and reinforcement of a market-oriented concept of health sector reform that strongly favors private provision and fi nancing (petchesky ; koivusalo and mackintosh , p. ). critics of the above international trade and fi nance policies argue that it is not at all clear that globalization leads to substantial poverty reduction. they point to the large-scale and extreme unequal distribution of wealth and income in the countries that have been identifi ed as "globalizers" witnessing rapidly growing economies. it is argued that even a little redistribution of income through progressive taxation and targeted social programs would go farther in terms of poverty reduction than many years of solid economic growth (jubany and meltzer ; paes de barros et al. ; de ferranti et al. ) . further, it is argued that as countries compete for foreign direct investment and outsourced production, the need to appear business-friendly may limit their ability to adopt and implement labor standards, occupational safety and health regulations, and other redistributive programs (cornia ) ; global integration of production may cause a sharp decline in the wages of, and demand for, low-skilled workers; large amounts of debt limit the ability of many developing and developed countries to meet other human needs related to health, education, water, public safety, sanitation, nutrition, etc.; globalization may lead to an intensifi cation of worldwide social relations which link distant localities in such a way that local happenings are shaped by events occurring many miles away, and vice versa (giddens , p. ) ; much of the urbanization caused by international fi nance and trade policies occurs in countries that have limited resources to provide urban infrastructures; and the emphasis on private fi nancing and provision of health care leads to large-scale underinsurance and uninsurance in both the developed and developing countries (labonte and schrecker , p. ) . globalization and the quest for exports are also blamed for increased smoking and tobacco-related mortality in the developing countries (murray and lopez , p. ) . also noteworthy is the escalation in the sale of weapons, much of it facilitated by western governments. the wars that have raged on and off in sub-saharan africa, latin america, and asia are tragic examples of the ill effects of aggressive weapon sales to these places (mcmichael and beaglehole , p. ) . although the adverse effects of globalization discussed above tend to affect developing countries more than the united states, there are signifi cant adverse consequences of globalization for the united states as well. some of these include the perpetuation and exacerbation of the gap between the rich and the poor, a large public debt profi le that puts signifi cant pressure on social and other safety net policies and programs, the prevalence of uninsurance and underinsurance, job insecurity and reduced wages, the collapse of large manufacturing businesses, increased availability and demand for illicit drugs, and the emergence of new infectious diseases that spread more easily due to increased migration and population mobility (ubokudom and khubchandani , p. ) . for example, american labor unions complain that the north american free trade agreement (nafta) with canada, mexico, and the united states, which came into force on january , , has led to the loss of american jobs. job loss causes stress, loss of income and the fi nancial means to pay for medical care. from the onset, health issues were not at the heart or margins of foreign policy theory or practice for two reasons. first, the protection and promotion of population health did not factor into world leaders' calculations of what "competition in anarchy" (the condition from which foreign policy dynamics fl ow) required of their countries, nor was health for all seriously (as opposed to rhetorically) considered a pathway to a better world. second, those who were engaged in public health did not participate signifi cantly in discussions of foreign policy (fidler , p. ) . therefore, there were only small and nonsubstantial linkages between health and foreign policy (harris , p. ) . actions linking health issues or problems with foreign policy have been strongest when the potential impact on economic prosperity, national security, the environment, and development is severe. this has resulted in attention to health threats that are acute and severe, those that are projected to result in mass casualties, and those that are believed to be geographically widespread. in contrast, long-term health risks, or health risks that cause minor health problems, affect a limited number of people, or are not geographically widespread, attract little attention in relation to foreign policy. in other words, acute epidemic infections and major public health emergencies, such as natural or human-induced disasters, bioterrorism, and chemical and radiation accidents, have received signifi cant attention (fidler , p. ; lee et al. , p. ; katz and singer , p. ) . a few specifi c examples of "attention-receiving" public health problems include the previously unknown human immunodefi ciency virus/acquired immunodeficiency syndrome (hiv/aids) which appeared in the united states in the early s; the hantavirus, believed to have originated in korea; eastern equine encephalitis, which is found in the eastern and north-central united states, canada, parts of central and south america, and the caribbean islands; western equine encephalitis, which occurs primarily in the western and central united states, canada, and parts of south america; the polio virus that is believed to have originated in india in ; the spread of severe acute respiratory syndrome (sars) from china in ; and the outbreak of the deadly h n -swine flu-infl uenza believed to have originated in mexico (cdc ; shi and singh , p. ; friis , p. ) . in summary, many health problems, particularly infectious diseases, are widely recognized as global concerns that cross national and international boundaries. consequently, countries frequently include in their foreign policies strategies on these diseases that have the potential to threaten their domestic interests. this is likely to lead to higher prioritization, more attention, greater political support, and more funding. for example, in the united states, projections of the impact of hiv/ aids on the workforces of many countries, and the prevalence of hiv among military personnel in several regions of the world, contributed to the determination that hiv/aids was a security issue. similarly, awareness of the havocs caused by previous infl uenza pandemics and the economic impact of the small and short outbreak of sars led to serious preparations by the who and its member states for the next infl uenza pandemic (katz and singer , p. ) . this understanding has led to many international agreements covering health and the environment, including the agreement on sanitary and phytosanitary measures, the international standards organization's classifi cation system for food labeling, the un framework convention on climate change, and the kyoto protocol, to name a few. data from the national aeronautics space administration (nasa) show that the earth's surface has warmed by about . °c between january and november . that period was reported to be the warmest january-november in the nasa goddard institute for space studies (giss) analysis, which covers years. the period was only a few hundredths of a degree warmer than , so it is possible that the fi nal giss results for the full year, , would be warmer or in the same range as . further, the available data also show that the earth's surface has warmed by more than . °c over the past century and by about . °c in the past decades (nasa ) . therefore, contrary to frequent assertions that global warming has slowed in the past decade, global warming has proceeded in the decade that ended in just as fast as it did in the prior decades (nasa ) . the health hazards posed by climate change and global warming are inequitable, diverse, global, and probably irreversible over human time scales (patz et al. , p. ; campbell-lendrum et al. , p. ) . they include increased risks of extreme weather, such as fl oods and storms, fatal heat waves, long-term drought conditions in many areas of the world, surface water pollution and groundwater contamination, the melting of glaciers that supply freshwater to large population centers, salination of sources of agricultural and drinking water, increased rates of water extraction that may precipitate declines in supply, and creating a conducive environment for the global killers that are very sensitive to climatic conditions, such as malaria, diarrhea, and protein-energy malnutrition (campbell-lendrum et al. , p. ; friis , p. ) . as we noted under the actual causes of death, these three global killers cause many deaths in the united states; they are also said to account for about three million deaths worldwide each year (who ) . the relationship between migration, population mobility, and health is receiving renewed attention due to the emerging and reemerging infectious diseases that were discussed previously in this section. the health of both legal and illegal migrants to any country are affected by the determinants of health discussed earlier in this chapter, as well as by the risks that are present in their country of origin or that arise from the migration process itself (macpherson and gushulak , p. ) . this is very true of the united states where a signifi cant portion of the annual population growth is due to migration. the effects of population mobility and migration on the country's health care system and the provision of health services are reported daily in the pages of newspapers. first, there is likely to be increased demand for services due to population growth, whether that growth is due to increased fertility rates or migration. for example, the exponential growth in medicaid expenditures in states that border mexico are said to be due to the increased demand for medical services by illegal immigrants as well as by the medical needs of an aging population. second, offi cials of the states that share boundaries with mexico complain about increased violent crimes committed by illegal immigrants, crimes that take a heavy toll on population health and health care expenditures. third, increased migration compels more health services planning, infrastructure maintenance, development and training of a diverse medical workforce to cater for the increasingly diverse population, and the establishment of public health programs for health promotion, health protection, and disease prevention (macpherson et al. , p. ; cohen et al. , p. ) . and, fourth, the opinion pages of newspapers carry citizens' letters that attribute the success of previous terrorist campaigns to the nearly open border policy the united states maintained prior to september , ( / ). since the / attacks, border security and entry visa requirements have been tightened. border control measures are now centered on inspecting and excluding goods, vessels, and people that pose serious health or terrorist threats to the united states. other countries have similar measures. the world has changed. indeed, the world has changed signifi cantly. while most people are actively planning on how to make their lives better, a few others are actively planning on how to destroy lives and settle political and ideological differences through acts of violence. no place and people are immune from the threats of violence, terrorism, and natural disasters. in the past or years, the united states has experienced disasters that have led to a rethinking of how to keep the population safe. the terrorist attacks in the united states on september , , an unsuccessful attempt to initiate an anthrax epidemic in october , and the devastation caused by hurricane katrina of the atlantic hurricane season led to signifi cant loss of lives and property and revealed defi ciencies in the public health and emergency response systems in the country. because of both underfunding and understaffi ng, and perhaps because the changes that have taken place in the world were not anticipated, the public health system was unable to develop or implement a comprehensive program of preparedness, prevention, response, and recovery (us general accounting offi ce ) . following the disasters, state, local, and federal public health agencies began to identify weaknesses in the nation's public health infrastructure and to reevaluate existing disaster response plans (baker and koplan , p. ). the shortcomings revealed in the nation's disaster response plans elevated public health to an important national instrument for anticipating and dealing with terrorism, infectious disease outbreaks, and natural disasters. the guidance on responses to chemical, biological, radiological, nuclear, and explosive threats provided by the cdc, and by other national organizations and universities, helped individual state governments to develop statewide policies that took their unique concerns into account (ziskin and harris , p. ; shah shah , p. gebbie and turnock , p. ) . public health plans to deal with terrorist threats, infectious diseases, and natural disasters now involve public health agencies at the federal, state, and local levels of government; other government and private agencies, such as the departments of justice and defense; the food and drug administration; private, public, and nonprofi t hospitals, clinics, and nursing homes; private and public practitioners, such as nurses and physicians; blood supply organizations, such as the american red cross; police and fi re departments; and individuals and groups throughout the country. as would be expected, expenditures for government public health activities, while still low relative to expenditures for medical care, rose from $ billion in to about $ . billion in , an increase of . % from (centers for medicare and medicaid services (cms) ) . it remains to be seen if this enthusiasm for public health, demonstrated by increased funding since , can be sustained. the law that is used as the basis for most of the new emergency preparedness measures is the homeland security act of . in addition to the strengthening of the public health infrastructure, the law also called for improved inspections of food products entering the united states. it calls for better measures to contain attacks on food and water supplies, to protect vital infrastructures, such as nuclear facilities, and to track biological materials anywhere in the country. further, the provisions of the law have been used to justify tough and controversial interrogation techniques, such as waterboarding. similarly, presidential executive order , signed by george w. bush on april , , authorizes the apprehension, detention, or conditional release of individuals with suspected communicable diseases, such as sars, cholera, diphtheria, infectious tuberculosis, plague, smallpox, yellow fever, and viral hemorrhagic fevers such as ebola (the free dictionary ) . in summation, international trade and fi nance, infectious disease epidemics, global warming and climate change, population mobility, and natural disasters and terrorism signifi cantly affect the united states health care delivery and policymaking systems. in addition, medical technology and us health care professionals and consumers are also affected by global factors. for example, because the united states is widely believed to be the world leader in the development and utilization of high-technology medical protocols, foreign dignitaries come here for specialty care. also, nurses and foreign medical school graduates (fmgs) move to the united states to acquire licenses to practice in the country. this so-called brain drain causes shortages of medical practitioners in the developing countries and alleviates some of the shortages in the health professional shortage areas of the united states. furthermore, telemedicine allows us physicians to transmit radiological images to other countries where they are analyzed at lower costs. on the other hand, us consulting pathologists and radiologists provide their services to other parts of the world. also, advanced medical equipment and supplies that are abandoned here a few years after deployment are shipped to the developing and less technology-intensive developed countries at low costs. the high costs paid by us consumers are used to subsidize the low costs paid by the developing countries (ubokudom and khubchandani , p. ) . this chapter has identifi ed the impacts of physical, social, cultural, and global factors on health and health policymaking. health can be defi ned under the medical or wellness models. the health status of the us population, or the population of any other country for that matter, is largely determined by factors that have important physical, social, and economic dimensions. these include preventive medicine, genetic disposition, social and economic circumstances, environmental conditions, lifestyles and behaviors, and medical care. these determinants of health are associated, in various degrees, with the real or actual causes of death in the country. research demonstrates that most of the deaths in the country are attributable to a small number of largely controllable behaviors and exposures, or due to factors that fall under the preventive, social, economic, environmental, and lifestyle and behavioral determinants of health. these determinants of health are not only affected by the broad national and personal factors identifi ed in the chapter, they are also affected by global or international factors, including trade and fi nance, outbreaks of infectious diseases, climate change, natural disasters, and the threats of terrorism and population mobility. but even though most of the deaths in the country are the result of social, cultural, economic, environmental, and global factors, medical care is also an important determinant of health that cannot be ignored. an insurance card is one of the important factors that infl uence access to medical services. consequently, the next chapter examines demographic factors, most especially americans' ability to access medical services, and the disparities in health among segments of the population. socioeconomic inequalities in health: no easy solution socioeconomic disparities in health: pathways and policies poor families in america's health care crisis a clinical trial of the effects of dietary patterns on blood pressure in why are some people healthy and others not? strengthening the nation's public health infrastructure: historic challenge, unprecedented opportunity in jonas's health care delivery in the united states health disparities in the united states: social class, race, ethnicity and health unemployment and ill health: understanding the relationship communities and health policy: a pathway for change relationship of physical health status and health problems health and ways of living: the alameda county study social determinants of health: meeting at a crossroads planning for health pathways to health: the role of social factors the role of medical care in determining health: creating an inventory of benefi ts genes, dreams, and realities global climate change: implications for international public health policy healthy people: the surgeon general's report on health promotion and disease prevention national health expenditure projections priorities among recommended clinical preventive services the case for diversity in the health care workforce policy reform and income distribution is inequality bad for our health explanations for socioeconomic differentials in mortality: evidence from britain and elsewhere the social context of science: cancer and the environment policy implications of the gradient of health and wealth inequality in latin america & the caribbean: breaking with history? the hidden epidemic: confronting sexually transmitted diseases green of another color: building effective partnerships between foundations and the environmental justice movement the health of latino chindren: urgent priorities, unanswered questions, and a research agenda essentials of environmental health the public health workforce, : new challenges the consequences of modernity socioeconomic status differences in recreational physical activity levels and real and perceived access to a supportive physical environment on the distribution of underlying causes of death social determinants of health false dawn: the delusions of global capitalism youth risk behavior surveillance-united states educational status and active life expectancy among older blacks and whites marrying foreign policy and health: feasible or doomed to fail? united states department of health and human services (usdhhs) deaths: leading causes for institute of medicine (us) committee on health and behavior: research, practice, and policy. health and behavior: the interplay of biological, behavioral, and societal infl uences class-the ignored determinant of the nation's health breathing easier: community-based strategies to prevent asthma the achilles' heel of latin america: the state of the debate on inequality , fpp - . ottawa, canada. canadian foundation for the americas (focal) regional obesity and risk of cardiovascular disease: the framingham study socioeconomic factors and cardiovascular disease: a review of the literature why health is important to u.s. foreign policy health and security in foreign policy neighborhoods and health overview: a current perspective on twin studies of schizophrenia fundamentals of genetic epidemiology advancing health disparities research within the health care system: a conceptual framework world trade: bringing health into the picture statement on the politicization of evidence-based clinical research in commercialization of health care: global and local dynamics and policy responses globalization and the social determinants of health: the role of the global marketplace (part of ) socioeconomic factors, health behaviors, and mortality: results from a nationally representative prospective study of u.s. adults bridging health and foreign policy: the role of health impact assessments religion and health: is there an association, is it valid, and is it causal? benefi ts and harms of prostate-specifi c antigen screening for prostate cancer: an evidence update for the u.s. preventive services task force health and foreign policy: infl uences of migration and population mobility human mobility and population health: new approaches in a globalizing world health inequalities among british civil servants: the whitehall ii study inequalities in death-specifi c explanations of a general pattern the spiritual history religion and depression: a review of the literature religious involvement and mortality: a meta-analytic review income dynamics and adult mortality in the united states the case for more active policy attention to health promotion actual causes of death in the united states health, foreign policy and security the role of medicine: dream socioeconomic status differences in vulnerability to undesirable life events the changing global context of public health septicemia social determinants of health: what, how, why, and now social patterns of distress mortality among teenagers aged - years: united states actual causes of death in the united states screening for bladder cancer: u.s. preventive services task force recommendation statement hereditary colorectal cancer: from bedside to bench and back patterns of mortality by county and race: - . cambridge, ma: harvard center for population and development studies alternative projections of mortality and disability by cause - : global burden of disease study (phs) - ), - . national institutes of health. . a mortality study of . million persons by demographic, social, and economic factors: - follow-up what we mean by social determinants of health meeting the millennium poverty reduction targets in latin america and the caribbean letter: linkage of familial combined hyperlipidaemia to chromosome q -q impact of regional climate change on human health global prescriptions: gendering health and human rights levels of physical activity and inactivity in children and adults in the united states: current evidence and research issues nephrotic syndrome: nephrosis alzheimer's disease; senile dementia-alzheimer's type (sdat) retrieved biologic-marker studies in alcoholism factors infl uencing the view of patients with gynecologic cancer about end-of-life decisions the strategy of preventive medicine successful aging effects on blood pressure of reduced dietary sodium and the dietary approaches to stop hypertension (dash) diet commentary: include a social determinants of health approach to reduce health inequities development as freedom the formation of the emergency medical services delivering health care in america: a systems approach socioeconomic differentials in mortality risk among men screened for the multiple risk factor intervention trial: i. white men resisting the blue revolution: contending coalitions surrounding industrial shrimp farming health services research: a working model effects of dietary patterns on blood pressure: subgroup analysis of the dietary approaches to stop hypertension (dash) clinical trial rethinking mckeown: the relationship between public health and social change severe acute respiratory syndrome (sars) poor diets, little exercise leading cause of preventable illness and deaths world development report : workers in an integrating world an introduction to epidemiology the ecology of health policymaking and reform in the united states of america united states department of health and human services (usdhhs). . the surgeon general's report on nutrition and health physical activity and health: a report of the surgeon general bioterrorism: public health response to anthrax incidents of section : overview of u.s. preventive services task force structure and processes trends in pregnancy rates for the united states, - : an update epidemics in history: disease, power and imperialism unhealthy societies: the affl iction of inequality social sources of racial disparities in health socioeconomic differences in health: a review and redirection men's health: chronic lower respiratory diseases world health organization (who). . preamble to the constitution of the world health organization as adopted by the international health conference state health policy for terrorism preparedness key: cord- - q ufu authors: linday, linda a. title: nutritional supplements and upper respiratory tract illnesses in young children in the united states date: - - journal: preventive nutrition doi: . / - - - - _ sha: doc_id: cord_uid: q ufu key points: in the united states, children have lower blood levels than adults of eicosapentaenoic acid (epa), an important ω- fatty acid that helps decrease inflammation; vitamin a, the “anti-infective” vitamin; and selenium (se), a trace metal that is an intrinsic part of glutathione peroxidase, an important free-radical scavenging enzyme. epa, vitamin a, and se are important in controlling inflammation and can be supplied by oral nutritional supplements. cod liver oil contains epa (and other important ω- fatty acids), and vitamin a as well as vitamin d. fish oil contains ω- fatty acids (including epa) but no vitamins. our clinical research demonstrates that daily supplementation with a flavored cod liver oil (which meets european purity standards) and a children’s multivitamin-mineral with trace metals, including se, can decrease morbidity from upper respiratory tract illnesses, otitis media, and sinusitis in young children living in the united states. these supplements can be used by practitioners on an individual basis, when clinically indicated; the supplements can be purchased in the united states without a prescription. socioeconomically disadvantaged children are at risk for micronutrient deficiencies. however, their families may not be able to afford to purchase these supplements, which are not available through medicaid, the special supplemental nutrition program for women, infants and children, or the food stamp program. if our results are confirmed in larger studies, a system change will be needed to provide these supplements to nutritionally vulnerable, socioeconomically disadvantaged children living in the united states. key element in the pathophysiology of these disorders. this chapter discusses the role of essential fatty acids, vitamins, and trace metals in the pathophysiology of inflammation; reviews our clinical research on the use of a lemon-flavored cod liver oil (which meets european purity standards) and a children's chewable multivitamin-mineral with se for the prevention and adjunctive treatment of these disorders; reviews the history of cod liver oil, including its importance in the discovery of vitamin d and the anti-infective properties of vitamin a; and discusses the current clinical use of these supplements. if additional research confirms the utility of these supplements in improving the health of young children, the problem of access to these supplements by socioeconomically disadvantaged children in the united states will need to be addressed. children under age yr had an average of . million ambulatory care visits per year for upper respiratory conditions in the united states from to , with another . million visits per year for om during the same time period ( ) . in addition to their cost, unnecessary health care visits for the treatment of colds generate a significant number of inappropriate antibiotic prescriptions ( , ) , although the situation is now improving ( , ) . bacterial antibiotic resistance is considered to be a major public health problem in the united states, and an interagency federal action plan has identified the decrease of unnecessary antibiotic prescriptions as critical to combating antimicrobial resistance ( ) . in , gates ( ) estimated that the total annual cost of treating om with effusion in the united states was $ billion, including both direct and indirect costs. this estimate included the cost of surgical placement of tympanostomy tubes (ventilation tubes placed in the tympanic membrane of the ear), a procedure that is commonly performed for the treatment of this disorder ( ) . frequent om with effusion in early childhood may be associated with later speech and language problems, although causative relationships have not been definitively established ( , ) . sinusitis also is a common and costly condition ( ) ; in , overall health care expenditures for sinusitis in the united states were estimated to be $ . billion, of which $ . billion was for children age yr or younger. the primary treatment of sinusitis in children is medical management. adenoidectomy may be helpful ( ) , although endoscopic sinus surgery is reserved for chronic, refractory cases ( , ) . chronic sinusitis has a major negative impact on the quality of life of children whose disease is sufficiently severe to require endoscopic sinus surgery ( ). viral illnesses usually are brief and self-limited conditions. however, viral infections produce inflammation, enhance nasopharyngeal bacterial colonization and adherence, alter the host's immune defenses, and are associated with bacterial complications, including acute om ( ) , sinusitis, and pneumonia ( , ) . acute om occurs in about % of children with viral upper respiratory infections ( ) . although viral vaccines are in development, the use of vaccines to prevent upper respiratory tract infections is hampered by the large number of different viruses causing these infections ( ) . the us advisory committee on immunization practices voted to recommend influenza vaccination for children ages to mo for the coming influenza season of to ; the impact of this recommendation remains to be seen ( ) . despite the fact that streptococcus pneumoniae is the most common cause of bacterial acute om, the heptavalent pneumococcal polysaccharide conjugate vaccine only produced a % reduction in the overall number of episodes of acute om from any cause ( ) . of inflammatory eicosanoids ( ) . the level of ω- fatty acids and other pufas is largely determined by diet, unlike proteins, whose structure is genetically determined ( , ) . changes in dietary habits in the united states in the last to yr have markedly increased the amount of ω- efa consumed (as in vegetable oils), whereas the amount of consumed ω- efa (as in cod liver oil and fish oil) has decreased ( , , ) . the optimal ratio of ω- /ω- efa in the diet is to : ; in the united states, it is currently to : . this abnormal ratio has been linked with numerous disease states, especially those associated with inflammation. ω- fatty acid levels can be increased by eating more fatty fish and by consuming nutritional supplements such as cod liver oil, algalderived long-chain fatty acids, or fish oils ( , , ) . free radical-induced lipid peroxidation may play a role in the acute ( ) ( ) ( ) and chronic inflammation ( ) of a guinea pig model of acute, unilateral om caused by infection with s. pneumoniae. inflammatory mediators have been demonstrated in both experimental and human middle ear effusions; these mediators include leukotrienes and prostaglandins, which are metabolites of aa and are derived from phospholipids in cell membranes. treatment with specific inhibitors of these mediators has prevented the development of om in some animal models of om ( ) . free radicals are significant components of the inflammatory response, which is part of the pathophysiology of pneumococcal infections ( ) and the influenza a virus ( ) ; the latter are important causes of om. reactive oxygen species (ros) ( ) have also been implicated in sinusitis. the association between respiratory virus infections and acute om in children is well-established ( , ) . oral supplementation with efas ( ) and zinc ( ) has been shown to decrease the incidence of respiratory infections in children. trace elements (including zinc and se) have been shown to have important effects on the regulation of immune responses ( ) . supplementation with ω- fatty acids has been reported to be beneficial in preventing infection in surgical patients ( ) . the importance of ω- fatty acids and trace metals (including zinc and se) is already recognized in the relatively new field of "immunonutrition" ( ) ( ) ( ) . the clinical efficacy of antioxidants in the treatment of om has been reported by two groups of russian investigators ( , ) . of interest is the work of ginsburg ( ) , who proposed that the main cause of tissue damage in infectious and inflammatory conditions is synergistic interactions among ros, microbial hemolysins, enzymes, and cytokines. antibiotics may have anti-inflammatory actions in additional to their antibacterial effects ( , ) . macrolide antibiotics, effective in the treatment of adults with chronic rhinosinusitis ( ) , have anti-inflammatory properties that contribute to this effect. however, the overuse of antibiotics is associated with the development of bacterial antibiotic resistance. in finland, the prevalence of macrolide-resistant group a streptococci diminished after the heavy use of macrolide antibiotics decreased ( ) . in this age of antibiotic resistance, it is preferable to use antibiotics for their antibacterial effects rather than as anti-inflammatory agents. in our first study ( ) , we obtained blood samples from children undergoing clinically indicated ambulatory surgery at the new york eye & ear infirmary (nyee). there were subjects in the tympanostomy tube group (tt); these children were undergoing placement of tympanostomy tubes for frequent ear infections and/or persistent middle ear effusion, with or without concomitant adenoidectomy and/or tonsillectomy. their mean (± standard deviation [sd]) age was . ± . yr; % were male; approximately half were hispanic and half were white; approximately half were private patients; and almost half were taking vitamin supplements. the comparison group (comp) was composed of children undergoing eye-muscle surgery as well as those undergoing ear, nose, and throat procedures such as bronchoscopy or laryngoscopy that did not involve the ears, adenoids, or tonsils. these subjects were slightly older, with a mean age of . ± . yr, and there was a lower percentage ( %) of private patients. no demographical information was available for the six adults in the adult control group (ac), supplied by ann moser of the peroxisomal disease section of the kennedy krieger institute genetics laboratory (baltimore, maryland). data regarding red blood cell (rbc) fatty acids, trace metals, and vitamin a were available for subsets of these subjects. the rbc fatty acid data are summarized in table . the mean values for epa were lower in both groups of nyee children than in the acs supplied by kennedy krieger. the mean rbc epa values were: (a) tt = . % ± . % (standard error [se]), (n = ); (b) comp = . % ± . % (se), (n = ); and (c) ac = . % ± . % (se), (n = ). these differences were statistically significant when analyzed by both parametric (anova, p < . ; f[ , ] = . ) and nonparametric (kruskal-wallis anova by ranks, p = . ; h[ , n = ] = . ) tests. no other significant differences in rbc fatty acids were noted among the three groups, although additional differences might become apparent with larger sample sizes. in , japanese investigators reported lower plasma levels of ω- fatty acids in young normal and atopic children than in adults ( ) . they ascribed these findings to dietary changes in japan in the yr prior to the study. data for plasma se, zinc, and copper for the children in the tt group are summarized in table ; data from the published literature for children ( ) and adults ( ) for these parameters is also included, as are international system units. there was no statistically significant difference between the mean plasma se for study subjects (tt = ng/ml ± . sd; n = ) and the published values for children. both groups of children had lower se levels than published values for adults (p < . , anova; f = . ; f[ . ] = . ) ( ). statistical analyses were performed only for se because only the variances for se were homogeneous (bartlett's test for homogeneity of variances ( ). the mean plasma vitamin a (retinol) level for the tt group was . μg/dl ± . (sd); (range: . - . μg/dl; n = ). (multiply conventional units by . to convert to international units [ ] ). ballew ( ) defined an inadequate vitamin a level as less than μg/dl and a suboptimal vitamin a level as less than μg/dl. the upper limit of the pediatric reference range for vitamin a is μg/dl ( ) . therefore, overall, the values for our subjects were within the reference range. russell ( ) stated that a vitamin a level of μg/dl predicted normal dark adaptation % of the time; % ( / ) of our subjects had vitamin a levels less than or equal to μg/dl, although parents denied symptoms of night blindness for all children. our finding is consistent with ballew's ( ) report that the th percentile for serum retinol levels in children ages to yr was . μg/dl. in addition, % ( / ) of our sample had suboptimal levels (< μg/dl), although none were inadequate ( ) . in this suboptimal group, five of six children were not taking vitamin supplements, five of six children were hispanic, five of six children were general service patients, and four of six children were female (all of whom were hispanic). the overrepresentation of hispanic children in the subgroup of children with suboptimal vitamin a levels was also consistent with previous reports ( ) . on a group basis, there was no statistically significant difference in the mean vitamin a levels between the subgroup of children whose families reported that they were taking vitamin supplements ( . μg/dl ± . sd; n = ) and the subgroup of children whose families reported that they were not taking vitamin supplements ( . μg/dl ± . sd; n = ). our subjects took a variety of prescription and over-the-counter vitamin preparations; no children were receiving or had taken cod liver oil; only one child in the fatty acid subgroup had a history of fish oil ingestion. of the eight different children's vitamin preparations examined, all contained vitamin a palmitate, vitamin a acetate, and/or β-carotene. the blood-level data ( ) revealed that (a) study children had lower levels of rbc epa than adult controls; (b) % of study children had plasma vitamin a (retinol) levels in the lower reference range, with % in the suboptimal range; and (c) study subjects, like other children, had lower levels of plasma se than adults. therefore, for our clinical studies, we chose cod liver oil as a source of both vitamin a and epa and used it in conjunction with a marketed children's chewable multivitamin/mineral preparation containing se. we specifically chose cod liver oil as a source of vitamin a on the basis of our blood-level data, which revealed no significant difference in the vitamin a levels between the subgroups of children who were taking vitamin supplements and those who were not. although we could have used fish oil as the source of epa, fish oil does not contain vitamin a or d. the detailed contents of these supplements are shown in table . the vitamin a content of cod liver oil used in our initial pilot study on om was to iu/teaspoon ( ml); in the subsequent two studies, the vitamin a content was decreased to to iu/ ml. to explore the clinical utility of these supplements, we then performed an open-label secondary prevention study, in which each child served as his or her own control ( ) . we studied one om season, from september , to march , ( ) . all children were patients of the soho pediatrics group, a private group practice in lower manhattan, new york. children were required to have had at least one episode of om from september to november , (the early portion of om season under consideration). children with a known allergy to fish were excluded. eight children were enrolled, ranging in age from . to . yr; seven were caucasian, half were female, and all families were english-speaking. after enrollment, subjects received teaspoon of lemon-flavored norwegian cod liver oil and one-half of a tablet of carlson's scooter rabbit chewable multivitamin-mineral (mvm) tablet per day (see table ). mothers were instructed to crush the mvm tablet, measure the cod liver oil, and mix both in a small amount of food (such as applesauce, yogurt, or rice cereal) to administer the supplements to their children. parents were informed verbally and in writing that supplements were to be given only in the amounts required by the study and that study supplements were to be kept out of reach of children. of the eight children who entered the study, one could not tolerate the taste of cod liver oil. the remaining seven children received antibiotics for om for . ± . (p < . ; mean ± sd) fewer days during supplementation than before supplementation during the om season under study (see fig. ). five of seven subjects had no additional episodes of om during supplementation, although it had no apparent effect on established serous middle ear effusions in two children. however, because our study lacked a randomized, parallel control group, we could not exclude the possibility that the decreased antibiotic usage we found might have occurred without the use of study supplements. based on our prior research (discussed in ref. ) and the historical studies on cod liver oil and upper respiratory illnesses ( ), we hypothesized that use of the study supplements by young children would decrease their doctor visits for upper respiratory illnesses during the late fall, winter, and early spring. we studied the effect of daily use of these supplements on the number of pediatric visits by young, inner-city, latino children from late autumn to early spring ( ). we did not have a matched placebo for liquid cod liver oil. although adults and older children can swallow capsules, infants and toddlers cannot. furthermore, if capsules were cut open to administer the contents, the distinctive odor and taste of cod liver oil would immediately become apparent ( ) . the absence of a matching placebo for liquid cod liver oil precluded our performing a classical double-blind, placebo-controlled study. lack of a placebo coupled with the fact that cod liver oil can be purchased without a prescription by interested parties ( , ) led us to choose a study design in which we randomized pediatric sites, rather than individual patients. this type of design has been used in the worldwide studies of vitamin a supplementation, which are discussed in subheading section . , that have included randomization by ward, household, village, or district ( ) . it was also used in a food-consumption study to avoid changes in food habits resulting from knowledge of the other treatment ( ) . randomized site design is commonly used in behavioral and educational studies where no placebo is possible ( ) ( ) ( ) ( ) ; a recent study of herd immunity and the pediatric heptavalent pneumococcal vaccine also used a randomized site design ( ) . to minimize the influence of the study on the behavior of the participating families ( ), we used a "no-contact" control group ( , ) , which has also been used in behavioral and educational studies. the study was performed at pediatrics , a multisite, private, pediatric group practice in new york city. two of the offices with similar demographics (low-income latino families), located . miles apart in upper manhattan, were randomized to a supplementation site and a medical records control site. study participants were children ages mo to yr of either gender and any race, religion, or nationality who were patients enrolled at the two offices where the study was being performed. study participants were required to be in new york city from enrollment through april (with the exception of brief vacations), and to have some type of medical insurance. patients who routinely received additional health care at other practices or medical centers were excluded; children with known fish allergy, a chronic, life-threatening condition (such as hiv/aids or cancer), feeding disorders, and epilepsy were also excluded. study materials were available in both english and spanish. per practice routine, two professional coders reviewed all charts from both sites, coded the visits, and entered the data into a computer with ndc medisoft™ network professional . software ( ) . participants in the medical records control group were enrolled from october to november , ; those in the supplementation group were enrolled from november to december , . we were unable to randomize enrollment at the two sites because the lemon-flavored cod liver oil used in the study (which was manufactured in norway) had been reformulated with less vitamin a ( ) and was delayed in the us customs office. the study follow-up/supplementation period ended on may , . a total of children ( at each site) were enrolled in the study. the mean age of the supplementation group was . yr (± . sd), and the mean age of the control group was . yr (± . sd). there were no statistically significant differences in the demographical characteristics of the study participants in the two groups: most were latino children from low-income families (as indicated by health insurance), and their mothers were predominantly unmarried immigrants from the dominican republic whose first language was spanish. children of at least yr of age received teaspoon of carlson's lemon-flavored cod liver oil per day and one-half tablet of carlson's scooter rabbit chewable mvm, the same doses used in our previous research administered in the same manner ( ) . however, the vitamin a content of the cod liver oil was approximately half that used in our first pilot study of om (see table ). thus, the full dose of supplements provided a total of iu of vitamin a and iu of vitamin d per day. however, in the current study, the starting dose of supplements was halved for children ages mo to yr .visits were classified as upper respiratory visits, other illness visits, or visits not analyzed on the basis of the icd- visit code ( ) . the primary outcome measure was upper respiratory visits during the follow-up/supplementation period; other illness visits during the same time period were considered as secondary outcome measures. as shown in figs. and and table , the supplementation group had a statistically significant decrease in the mean number of upper respiratory visits over the course of the follow-up/supplementation period (p = . ; r = . ; r = . ; y = . − . x), whereas the medical records control group had no change in this parameter (p = . ; r = . ; r = . ; y = . + . × - x). there was no statistically significant change in the mean number of other illness visits for either study group during the same time period. although there was a significant difference in the pattern of decreasing upper respiratory visits over time in the supplementation group, there was no difference in the total number of visits made by the two groups. data were analyzed on an intention-to-treat basis. as reported by their parents, % of our subjects completed a -to -mo course of lemon-flavored cod liver oil. by comparison, only % of families reported compliance with antibiotic prophylaxis for om in a study of latino children who attended an otolaryngology clinic ( ) . our favorable compliance rates may partly result from the fact that young children in the dominican republic are often given cod liver oil or similar supplements, although families rarely continue this practice after moving to the united states. inflammation and edema of the sinonasal mucosa are important in the pathophysiology of sinusitis. based on our previous research and the similarities between om and sinusitis ( ), we hypothesized that these nutritional supplements would also be effective adjunctive therapy for the treatment of children with chronic and/or recurrent sinusitis. therefore, we performed a -mo, open-label, dose-titration study in which each patient served as his or her own control ( , ) . study participants were private pediatric otolaryngology outpatients of jay n. dolitsky, md, who resided in the new york metropolitan area and had a clinical diagnosis of chronic and/or recurrent sinusitis as well as symptoms of at least mo of duration that were refractory to treatment with antibiotics. subjects were between ages and yr, of either gender and any race, religion, or nationality. children with known allergy to fish; chronic, life-threatening condition (such as hiv/aids or cancer); feeding disorder; seizure disorder; known cystic fibrosis; aspirin-intolerant asthma; and family plans to move outside the metropolitan area during the course of the study were excluded. subjects were enrolled from late january to early march and received supplements for mo from the time of enrollment. primary endpoints were the number of doctor visits for acute respiratory illnesses and the child's sinus symptoms, which were quantified using a pediatric sinusitis symptom questionnaire ( ) . the starting dose of supplements in the current study was the same as in our previous research ( ): teaspoon ( ml) of carlson's lemon-flavored cod liver oil and one-half of a tablet of carlson's scooter rabbit chewable multivitamin-mineral per day (providing a total of iu of vitamin a and iu of vitamin d per day). the vitamin a content of the cod liver oil was lower than in our first pilot study of om ( ) but was the same as that used in our study of latino children ( ; see table ). supplement doses could be doubled to an intermediate dose (providing iu of vitamin a and iu of vitamin d per day) within to wk . if higher doses were needed, cod liver oil was discontinued and fish oil was administered instead (fish oil does not contain vitamin a or d). the maximum dose of fish oil was g/d, and the maximum dose of multivitamin-minerals was four half-tablets per day (providing , iu of vitamin a and iu of vitamin d per day). the titrated doses of vitamins a and d were higher than those used in our previous study ( ) but were well-below the lowest daily toxic doses of these vitamins ( ) ( , iu/d for vitamin a and iu/d for vitamin d). the us food and drug administration (fda) considers fish oil at dosages up to g per day as safe for adults and children ( ) . our four subjects were caucasian males, ranging in age from . to . yr, with chronic/recurrent sinusitis for at least yr prior to entry in the study. three subjects had a positive response; one subject dropped out for administrative reasons. the responders had decreased sinus symptoms, fewer episodes of acute sinusitis, and fewer doctor visits for acute illnesses at , , and wk after beginning study supplements. their parents reported that they had begun to recover from upper respiratory illnesses without complications, which was unusual for these children, as was improvement in springtime; their improvement had previously been limited to the summer months or periods of home-schooling. our findings are consistent with prior work by other clinical investigators. in a study of upper respiratory tract infections in young children, wald and colleagues ( ) noted that an inflamed respiratory mucosa may not completely recover between episodes of infection. parsons ( ) hypothesized that inflammation and edema of the sinonasal mucosa was the primary event in sinusitis, with bacterial infection as a secondary phenomenon. chronic/recurrent sinusitis is a debilitating disorder that may require treatment with intravenous antibiotics and/or endoscopic surgery. use of these supplements as adjunctive therapy for children with chronic/recurrent sinusitis is an inexpensive, noninvasive intervention that clinicians can use for selected patients, pending the outcomes of definitive, large, well-controlled studies. in the s, during the pre-antibiotic era, lipoid aspiration pneumonia was reported with cod liver oil, mineral oil, and egg yolk, which were used at that time to treat sick and debilitated infants ( ) . in , caffey ( ) reported vitamin a toxicity in children who were mistakenly treated with high-dose, long-term vitamin a administered in highly concentrated fish liver oil preparations that were available at that time. however, none of caffey's patients had received cod liver oil, and the highly concentrated fish liver oil preparations they received are no longer available in the united states. in our clinical studies, parents were instructed to crush the half-tablet of mvm, measure the cod liver oil, and mix both with a small amount of food (such as applesauce, yogurt, or rice cereal) before administering the supplements to their child. additionally, parents were informed both verbally and in writing that supplements were to be given only in the amounts required by the study and that study supplements were to be kept out of reach of children. the principal investigator spoke spanish, and all parental study materials were available in both spanish and english. to date, we have not encountered problems with aspiration or overdose in our studies. there is a clear association between viral respiratory infections and acute exacerbations of asthma in both children and adults ( ) . there is also a link between sinusitis and asthma ( , ) , with rhinovirus infections linked to both sinusitis and exacerbations of asthma ( ) . additionally, latino children have a high incidence of asthma ( ) . in view of the results of our studies ( , , ) , we believe that these supplements could be clinically useful for young children (particularly latino children) with asthma, and we are currently beginning to organize research in this area. similarly to other countries worldwide ( ) , socioeconomically disadvantaged children in the united states are at risk for micronutrient deficiencies ( , , ) . although the supplements used in our research can be purchased in the united states without a prescription, their cost may pose an excessive financial burden to lowincome families. cod liver oil does not have a national drug code number, it is not available through medicaid in new york, and the children's vitamins we have located that are available through this system do not contain se or other trace metals. additionally, cod liver oil is not available through the united states department of agriculture (usda) special supplemental nutrition program for women, infants and children (wic); our request for such availability can be found online at http://www.fns.usda.gov/wic/anprmcomments/ ihp- .pdf. furthermore, purchase of vitamins with us food stamps is not permitted (see http://www.fns.usda.gov/fsp/faqs.htm# ). if our results are confirmed in larger studies, a system change will be required to provide these supplements to nutritionally vulnerable, socioeconomically disadvantaged children living in the united states. egyptian and greek physicians may have understood the value of liver (high in vitamin a) for the treatment of night blindness, an early ocular manifestation of vitamin a deficiency ( , ) . the use of fish oils in medicine was mentioned by hippocrates, and pliny discussed the use of dophin liver oil for the treatment of chronic skin eruptions ( ) . however, these classical physicians did not appear to know about the use cod liver oil. the coastal fishermen of northern europe apparently used cod liver oil for many years for the treatment of aches and pains ( , ) . however, the first recorded use of cod liver oil by physicians was from the manchester infirmary in england during the s ( , ) , where it was found to be very effective for "old pains" and "rheumatism," which were probably cases of osteomalacia (a bone disease of adults) ( ) . the pattern of discovery was that the use of cod liver oil by fishing folk and peasants was accidentally observed by a physician, who then tried it and made it known to the medical profession ( ) . guy ( ) states that there was no further mention of cod liver oil in the english medical literature until its revival in by bennett, who had observed its use in germany. bennett reported that in holland, cod liver oil had obtained a wide reputation as a cure for rickets (a bone disease of children) "long before its remedial properties were acknowledged by physicians" (see ref. , p. ) . in the s, schenk and schuette published independent reports in the german literature regarding the value of cod liver oil for curing rickets ( ) , and schuette reported that he used cod liver oil successfully for yr. cod liver oil for the treatment of rickets was introduced in france by trousseau in the s ( ) . the demand for cod liver oil was so great that all types of substitutes were used, and reports of failure, contamination, and substitutes for cod liver oil began to appear in the literature before the middle of the th century. vitamin a was discovered as the result of a long, incremental process with contributions by numerous investigators ( , ) . at the end of the th century and the beginning of the th century, nutritional theories were tested under well-controlled laboratory conditions through the administration of experimental diets to animals, and specific factors necessary for their growth and survival began to be identified. during this time, frederick hopkins, at cambridge university, proposed that there were "accessory factors" in foods that were necessary for life but that had not been previously identified; casimir funk named these factors "vital amines" or "vitamines" ( ) . in , in the same issue of the journal of biological chemistry, two groups independently reported the existence of a fat-soluble factor that was essential for the growth of rats ( , ( ) ( ) ( ) . mccollum and davis of the university of wisconsin ( ) demonstrated that after a certain age, the growth of rats was dependent on an ether extract from eggs or butter. using a different experimental diet, osborne and mendel ( ) , of yale university, found that there was an "essential accessory factor" in butter needed for the normal growth of rats. this fat-soluble growth factor, originally termed "fat-soluble a," soon became known as "vitamine a" ( ). the discovery of vitamin d was closely tied to work on the prevention and treatment of rickets. during the industrial revolution, rickets spread rapidly throughout europe, particularly among the urban poor, who lived in the sunless alleys of factory towns and urban slums ( ) . in , mellanby ( ) , an english physician and professor of pharmacology, reported the first animal model of rickets, which he developed in puppies. in a simple, two-page report to the physiological society, he noted that the daily administration of foods such as butter, cod liver oil, or cc of milk (among others) was effective in preventing rickets in his model, whereas casein and linseed oil were among the substances that were ineffective. mellanby felt that rickets was a deficiency disease and stated that "the anti-rachitic accessory factor has characters related to the growth accessory factor [vitamin a], although it is not identical with the latter …" (ref. , p. xi) . however, mellanby was not able to distinguish these two factors; this was accomplished by mccollum and his new collaborators at johns hopkins university. in the s, mccollum and his colleagues developed a rat model of rickets that could also be cured with cod liver oil. they were then faced with the same question that perplexed mellanby: was the anti-rachitic factor vitamin a, or was it another substance with a similar distribution as fat-soluble vitamin a ( )? it was known that the vitamin a-deficient animals in these studies often developed ocular abnormalities, including dryness of the eyes, corneal ulceration, and blindness, similar to xeropthalmia in humans ( ) . additionally, hopkins demonstrated that oxidation destroyed fat-soluble a ( ) . using these facts, in , mccollum and his colleagues ( ) reported that when cod liver oil was oxidized for or h, it could no longer cure xerophthalmia, although it could prevent rickets. therefore, they concluded that the anti-xerophthalmic and the anti-rachitic properties were a result of two distinct substances, and that the antirachitic factor, which specifically regulated bone metabolism, was the more heat-stable factor. because this was the fourth vitamin to be discovered, mccollum's group named it vitamin d in ( ) . the fact that both exposure to sunlight and cod liver oil could prevent or cure rickets was perplexing and controversial ( ) . careful experiments by chick and coworkers ( ) , working in vienna from to , confirmed the value of both cod liver oil and sunlight in the prevention and treatment of rickets in young infants. in , huldschinsky ( ), a pediatrician in berlin, used light from a mercuryvapor quartz lamp (which includes ultraviolet [uv] wavelengths) to cure four cases of advanced rickets in children with up to mo of treatment. when huldschinsky exposed one arm of a rachitic child to the uv irradiation, he found that the rickets in the child's other arm was cured to the same degree as in the exposed arm. therefore, he concluded that phototherapy was not a local effect and speculated that as a result of exposure to uv light, something was formed in the skin that was then carried to other sites, where it had its anti-rachitic effect ( ) . in , hess and weinstock ( ) reached similar conclusions based on experimental work in animals. these theories were confirmed in , when windaus, working in germany, demonstrated that skin contains the natural prehormone of vitamin d, which is converted to vitamin d when the skin is exposed to uv irradiation (including light from a mercury-vapor lamp) ( ). historical investigators were well-aware of an association between rickets and respiratory diseases. in their paper on rickets, hess and unger stated that "rickets is a predisposing cause of these respiratory diseases (pulmonary tuberculosis, pneumonia, and whooping cough)" (ref. , p. ). in her paper on community control of rickets, eliot stated that "susceptibility to upper respiratory infections, such as colds, bronchitis and pneumonia, is greatly increased in infancy and early childhood by rickets" (ref. , p. ). based on prior animal studies and clinical work by german investigators, ellison discounted the contribution of vitamin d in the efficacy of cod liver oil for measles. nonetheless, he acknowledged that "it is possible that some adjuvant effect was obtained from the co-operation of the two factors [vitamins a and d]" (ref. , p. ). in a study of vitamins a and d (individually or combined) for children hospitalized with measles, mackay noted "there is much to indicate that resistance to infections is reduced in children suffering form an overt deficiency of either of these vitamins [vitamin a or d]" (ref. , p. ). semba noted that cod liver oil, a rich source of vitamins a and d, was used as a treatment for tuberculosis for more than yr ( ) . in the s, charlotte brontë, the author of jane eyre, suffered from tuberculosis, and her treatment included cod liver oil ( ) . a textbook on tuberculosis, although recognizing that there was no specific treatment for tuberculosis at that time, stated that "one of the oldest and best established remedies for the treatment of tuberculosis is cod liver oil" (ref. , p. ); however, the mechanism of action of cod liver oil was unknown. the situation had changed little by , when goldberg's textbook stated that cod liver oil "has been used empirically for many centuries in the treatment of pulmonary tuberculosis without any definite knowledge of its action" (ref. , p. c- ). however, the use of cod liver oil for tuberculosis faded as specific treatments were developed, and "cod liver oil" is not listed in the index of a modern textbook on tuberculosis ( ). mellanby (see section . .) had a large colony of dogs that were maintained on experimental diets. in , mellanby reported, "at one period in the course of my experimental investigations on dogs, the work was greatly hampered by the development of an inflammatory condition of the lungs" (ref. , p. ), which was bronchopneumonia. on postmortem examination, the pneumonia was largely restricted to the vitamin adeficient dogs, and he speculated that this might be relevant to respiratory illness in children ( , ) . in , green and mellanby reported that a deficiency of vitamin a, but not vitamin d, caused increased infections in a rat model, leading them to call vitamin a an "anti-infective" agent; they speculated that this was related to the epithelial changes caused by vitamin a deficiency ( ) . in , ellison ( , ) reported the results of a study of concentrated cod liver oil for children who were hospitalized with measles. ellison was aware of mellanby's work on the anti-infective properties of vitamin a and also knew that vitamin a deficiency damaged epithelial cells in the respiratory tract ( , ) . ellison specifically chose to study measles because it was "a disease which attacks epithelial defences and whose incidence is greatest in those members of the community who are most likely to be suffering from various grades of vitamin deficiency…the children of the poorest classes" (ref. , p. ). he studied children under age yr who were admitted to the grove hospital (london) with measles. the cases were randomized by ward to treatment with a highly concentrated cod liver oil preparation or a control treatment of standard treatment (no placebo was used). treatment with cod liver oil reduced measles mortality by approximately one-half, from . % in the control group to . % in the treated group ( , ) . based on animal studies and german clinical work, ellison attributed the efficacy of cod liver oil to vitamin a, although he did concede that some adjuvant effect could have been obtained from the cooperation of the two factors ( ) . a subsequent study published in ( , ) reported that neither vitamins a and d together nor vitamin d alone had an effect on reducing the mortality rate from measles. however, the control mortality rate in this later study decreased to . %, making it difficult to demonstrate an improvement. by , numerous studies had been conducted to evaluate the ability of vitamin a (usually given as cod liver oil) to decrease the incidence of respiratory infections. the results were mixed, with about half showing a positive impact and the rest demonstrating no effect ( ) . however, cod liver oil did have a significant impact on decreasing industrial absenteeism ( ) . in a study of cod liver oil for the prevention of the common cold in school children, the investigator was not able maintain a control group given no supplements because enthusiastic families purchased cod liver oil for their children outside of the study ( , ) ; this finding is relevant to our current work. with the introduction of sulfa antibiotics and penicillin in the s to s ( ), as well as the improvements in diet in industrialized countries in the late s, interest in anti-infective therapy shifted to antibiotics and away from vitamin a ( ). in the mid- s, uv radiation of food and a variety of other substances was demonstrated to produce anti-rachitic properties ( ) . steenbock patented the addition of provitamin d to foods followed by uv irradiation to produce anti-rachitic activity. in the s, the addition of provitamin d to milk followed by uv irradiation was widely practiced in the united states and europe. rickets was eradicated as a significant public health problem in the countries that used this vitamin d fortification process ( ) . in the late s, otto isler and his collaborators in basel reported the synthesis of all-trans-vitamin a from the inexpensive precursor β-ionone ( ) . in the same time period, arens and van dorp ( ) reported the synthesis of retinoic acid. within a few years, the price of vitamin a fell -fold, and it became economically feasible to add vitamin a more generally to foods. during the latter part of the th century, cod liver oil was rarely used in america, although the reason for this lack of use is not clear ( , ) . however, there was a resurgence in interest, and in , hess and unger wrote, "for many years cod liver oil has been regarded as the sovereign remedy for rickets" (ref. , p. ) . they successfully prevented rickets with cod liver oil in susceptible african-american babies in a lowincome neighborhood in new york city ( , ) . hess urged officials to dispense cod liver oil at the baby health stations at cost, but they declined because it would be too expensive, and they thought that additional milk would be preferable to cod liver oil ( ) . cod liver oil and sunlight were highly valued for the prevention of rickets, and nurses taught mothers of infants how to use these remedies for their infants ( ) . from the s to the s, many children in the united states were given cod liver oil each day ( , ) with orange juice (which was know to prevent scurvy). however, older preparations of cod liver oil had an unpleasant taste, the quality of different preparations was erratic ( ) , and medical professionals became concerned about lipoid aspiration pneumonia ( ) and vitamin a toxicity ( ) . by the s, cod liver oil had been largely replaced by synthetic vitamins in the united states; however, the latter do not contain ω- fatty acids, which have anti-inflammatory properties ( ) and important effects on immune function ( , ) . in norway, the norwegian nutrition council continues to recommend supplementation with cod liver oil beginning at age wk, because it provides ω- fatty acids in addition to vitamin d ( ). before columbus made his first voyage to america, basque fisherman were secretly fishing the massive stocks of cod and other groundfish off the new england coast ( , ) . their salt cod was a staple in mediterranean markets, and cod was a staple of the european diet for more than yr ( ) . although fishermen exploited cod for centuries, the technological innovations of the th century led to the collapse of cod stocks in north america. motorized boats dragged the ocean floor with massive trawl nets, destroying both cod fish and their habitat. factory ships with refrigeration have almost erased the limit to the amount of cod that can be caught and sold internationally without spoiling ( ) ; increasingly powerful and accurate sonar produces detailed readouts of nooks where schools of fish may lurk; and shipping fleets can position themselves precisely through use of the satellites of the global positioning system ( ) . despite growing regulations on allowable catches and fishing equipment, cod stocks have continued to decrease across the north atlantic. in , the canadian government declared a temporary moratorium on cod fishing; the moratorium was extended in . in , with cod stocks showing no sign of recovery, the canadian government banned all cod fishing off its eastern provinces and identified some cod populations as endangered. the us government also imposed restrictions on cod fishing ( ) . however, it is unclear whether north atlantic cod stocks will recover. the level of polychlorinated biphenyls (pcbs) and dioxins in fish and fish oils has become a concern as oceans have become progressively contaminated with industrial waste. this issue was addressed in the united kingdom and europe by purity standards ( ) , which were revised and made more strict in ( ) . in the same year, the uk food standards agency reported that exposure to dioxins had decreased by % over the previous yr and that the levels of dioxins and pcbs found in most of the samples in their most recent fish oil survey were lower than in previous surveys that were performed in and ( ) . mercury contamination of fish is also a concern, and the fda advises that young children and women of childbearing age should avoid tilefish, swordfish, shark, and king mackerel because of their elevated levels of mercury ( ) . however, an analysis of us fish oil supplements revealed no detectable mercury, with a limit of detection of . μg of mercury per gram ( ). after a -yr hiatus, interest in the anti-infective properties of vitamin a was rekindled in the s by the observation of increased mortality in indonesian children who had vitamin a deficiency and xerophthalmia ( , ) . the first symptom of eye disease from vitamin a deficiency is night blindness; at this stage, bitot's spots (superficial, foamy gray, triangular spots) may be present on the conjunctiva ( , ) . this is followed in later stages by xerophthalmia (dryness of the conjunctiva), keratomalacia (corneal ulceration), and blindness ( ) . since the s, numerous studies have been performed regarding the effect of vitamin a supplementation on the health of children in developing countries. for a complete review of this subject, the reader is referred to chapter , as well as reviews ( , , ) , and meta-analyses ( , , ) . for the purpose of this chapter, the findings are summarized to provide a basis of comparison to the status of vitamin a in the developed world as well as to provide a perspective on the results of our research. vitamin a supplementation of children in developing countries decreased overall childhood mortality by about % ( , ) . community-based studies of vitamin a supplementation have indicated that it may decrease the severity, but not the incidence, of diarrhea ( ) . in children hospitalized with measles in the developing world, vitamin a supplementation decreased mortality by an average of % ( , , ) ; the decrease in mortality from measles-related pneumonia was particularly noteable ( ) . the modern studies are consistent with the results of ellison's historical study of cod liver oil for children who are hospitalized with measles (see section . .). the role of vitamin a supplementation in measles is also consistent with the fact that infectious diseases that induce the acute-phase response transiently depress serum retinol concentrations, that vitamin a deficiency impedes the normal regeneration of mucosal barriers damaged by infection, and that it also diminishes the immune function of white blood cells ( , ) . however, several placebo-controlled trials have demonstrated that high-dose vitamin a supplementation is not effective in decreasing the severity of pneumonia in hospitalized children in developing countries and that large doses of vitamin a may be harmful when given to well-nourished children in these areas ( , ) . additionally, vitamin a supplementation is not effective for children who are hospitalized with pneumonia caused by respiratory syncytial virus, which is a paramyxovirus similar to measles and an important cause of infantile bronchiolitis and pneumonia ( , ) . in a multicenter study performed in the united states, patients who received vitamin a actually had longer hospital stays than those who received placebo ( ) . infection with hiv has become increasingly prevalent in many developing countries. vitamin a supplementation of children younger than age yr who are hiv-positive decreases aids-related deaths as well as total mortality and morbidity from diarrhea ( ) . small, frequent doses of vitamin a may be more protective than large, periodic doses. additionally, adequate dietary vitamin a intake is associated with a significant decrease in mortality ( ) , diarrheal and respiratory infections ( ) , and stunting ( ) . new strategies in vitamin a supplementation in developing countries include targeting at-risk populations, improving dietary sources of vitamin a, using horticultural approaches, fortifying food, and addressing multinutrient deficiencies ( ). modern studies of vitamin d indicate that calcitriol ( , dihydroxyvitamin d), the active form of vitamin d, has important nonclassical effects beyond the regulation of calcium metabolism. these include the modulation of hormone and cytokine production and secretion as well as the regulation of proliferation and differentiation ( ) . calcitriol, a potent inhibitor of human t-lymphocyte proliferation ( , ) , and vitamin d analogs have been shown to be effective in the prevention and treatment of some models of autoimmune disease in rodents-particularly autoimmune diabetes in mice ( , , ) . in , muhe and colleagues ( , ) reported the importance of nutritional rickets in the development of pneumonia in developing countries. this is consistent with the work of historical authors discussed earlier, who were also aware of this association. vitamin a deficiency that is severe enough to cause blindness is uncommon in the developed world ( ) . however, some segments of the us population, particularly socioeconomically disadvantaged children ( ) as well as african-and mexican-american children ( ), may have suboptimal levels of vitamin a. in , ellison recognized that children from lowincome households were the most likely to have vitamin deficiencies (see section . .) ( ) . consistent with these reports, in our original study, five of six children with suboptimal levels of vitamin a were hispanic general-service patients ( ) . additionally, young children in the united states-particularly those in the toddler and preschool age groups-may not have adequate dietary intakes of vitamin a ( ) . in developed countries, high intakes of vitamin a (but not β-carotene) by pregnant women have been associated with teratogenesis ( ), leading to recommendations that prenatal vitamins should contain no more than iu of preformed vitamin a ( ) . additionally, high intakes of vitamin a by postmenopausal women in the united states ( ) and -to -yr-old men in sweden ( ) have been associated with a higher risk of hip fractures. as a result, vitamin a supplementation and fortification of food with vitamin a in western countries has been questioned ( ) . as discussed under section . ., the amount of vitamin a in norwegian cod liver oil has been reduced. nonetheless, the norwegian nutrition council continues to recommend supplementation with cod liver oil beginning at age wk, because it provides ω- fatty acids in addition to vitamin d ( ). numerous investigators have stated that vitamin a deficiency rarely exists alone and that it is usually accompanied by variety of other nutritional deficiencies ( , , , , ( ) ( ) ( ) ( ) . in a review, mejía ( ) noted that vitamin a deficiency primarily affects the world's most underprivileged populations, which, because of their limited socioeconomic condition, also lack a variety of other essential nutrients. he emphasized the importance of the interaction between nutrients and reviewed the established relationships of vitamin a status to protein, dietary fat, vitamin e, zinc, and iron ( ) . mejía also mentioned the more controversial links of vitamin a to iodine metabolism; vitamins c, k, and d; calcium, and copper. realizing that the relationships might be direct or indirect, he emphasized the importance of considering these interactions when "treating or preventing vitamin a deficiency both at the clinical and at the population levels" (ref. , p. ) . olson ( ) reported that deficiencies of various other nutrients, including protein, α-tocopherol (vitamin e), iron, and zinc, adversely affects the transportation, storage, and utilization of vitamin a. he also noted that the absorption of vitamin a and carotenoids is markedly reduced when diets contain very little fat (< g/d). more recently, villamor and fawzi ( ) stated that supplementation with vitamins and minerals in addition to vitamin a is likely to "reduce the burden of adverse health outcomes," because of the physiological interactions between nutrients and overlapping micronutrient deficiencies, including iron and zinc. semba ( ) noted that antenatal supplementation with multivitamins reduced fetal deaths and low birthweight in pregnant women who were infected with hiv, but vitamin a alone had no significant effect. semba ( ) also discussed the role that other deficiencies of vitamin d ( ) and zinc ( ) may have in susceptibility to respiratory infections. we agree with semba, who stated that "further studies are needed to address the use of vitamin a in multi-micronutrient supplements, as there is increasing evidence that other coexisting micronutrient deficiencies may limit the efficacy of vitamin a" (ref. , p. ). our work is consistent with the historical uses of cod liver oil, vitamin a as the "antiinfective" vitamin, the link between rickets and respiratory tract infections, the modern understanding of immunomodulatory effects of vitamin d, the importance of ω- fatty acids and trace metals in decreasing inflammation, the clinical observation that inflamed respiratory mucosa may not completely recover between episodes of infection, and the current concept of the importance of multiple micronutrient deficiencies. we have demonstrated that use of flavored cod liver oil (which meets european purity standards) and a chewable children's multivitamin-mineral with trace metals, including se, can decrease morbidity from upper respiratory tract illnesses, om, and sinusitis in young children living in the united states. these supplements were particularly wellaccepted by latino families from the caribbean, where use of cod liver oil is a cultural tradition. currently, there is adequate information for practitioners to recommend the use of these supplements, when indicated, to their individual patients; information for practitioners and families is available online at http://www.drlinday.com. the supplements can be purchased in the united states without a prescription. further research is needed to evaluate the effect of the supplements on antibiotic prescription for these illnesses and to explore their role as adjunctive therapy in asthma. additionally, our findings need to be confirmed in larger studies to facilitate large-scale, policy decision making. use of these supplements has the potential to improve children's health and decrease the cost of their health care. however, cod liver oil does not have a national drug code number and is not available through medicaid in new york, and the children's vitamins we have located that are available through this system do not contain se or other trace metals. also, cod liver oil is not available through the usda wic program; our request for such availability can be found online at http://www.fns.usda.gov/wic/anprmcomments/ ihp- .pdf. furthermore, purchase of vitamins with us food stamps is not permitted (see http://www.fns.usda.gov/fsp/faqs.htm# ). socioeconomically disadvantaged children living in the united states are at risk for micronutrient deficiencies. although the supplements used in our research can be purchased in the united states without a prescription, their cost may pose an excessive financial burden to low-income families. if our results are confirmed in larger studies, a system change will be needed to provide these 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respiratory infections among rural guatemalan children heights, il) donated the nutritional supplements used in this research but had no other role in the design or conduct of the study. information for practitioners and families regarding this research is available at http://www.drlinday.com. key: cord- -qww pe authors: blumenshine, philip; reingold, arthur; egerter, susan; mockenhaupt, robin; braveman, paula; marks, james title: pandemic influenza planning in the united states from a health disparities perspective date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: qww pe we explored how different socioeconomic and racial/ethnic groups in the united states might fare in an influenza pandemic on the basis of social factors that shape exposure, vulnerability to influenza virus, and timeliness and adequacy of treatment. we discuss policies that might differentially affect social groups’ risk for illness or death. our purpose is not to establish the precise magnitude of disparities likely to occur; rather, it is to call attention to avoidable disparities that can be expected in the absence of systematic attention to differential social risks in pandemic preparedness plans. policy makers at the federal, state, and local levels should consider potential sources of socioeconomic and racial/ethnic disparities during a pandemic and formulate specific plans to minimize these disparities. t he threat of pandemic infl uenza has generated concern among politicians, policy makers, healthcare professionals, and the general public. for the past several centuries, major infl uenza pandemics have occurred every to years ( ); it is widely believed that a new pandemic is "inevitable" ( ) . the possibility of an imminent infl uenza pandemic has been heightened by the appearance and spread of avian infl uenza a (h n ), which has a case-fatality ratio of > % ( ) . although the assumption has been that avian infl uenza viruses could not directly infect humans, the transmission of infl uenza virus (h n ) directly from chickens to humans in caused experts to reconsider that assumption ( ) . genetic changes in infl uenza virus subtype h n in resulted in a new strain of the virus, which spread to multiple countries in east and southeast asia ( ) , as well as europe and africa. whether the avian infl uenza virus (h n ) develops human pandemic potential, its spread from birds to humans and the severity of the resulting disease have heightened concerns about a possible future infl uenza pandemic. considerable fi nancial resources have been devoted to pandemic infl uenza preparedness planning at the federal and state levels ( , ) ; however, resources at state and local levels may be inadequate to implement a robust preparedness plan ( , ) . past experience with natural disasters and current socioeconomic and racial/ethnic disparities in healthcare in the united states ( , ) raise questions about the adequacy of plans to address the needs of disadvantaged populations. for example, in responding to hurricane katrina, planners apparently failed to consider that many low-income persons might lack private modes of transportation and would depend on institutional help for evacuation. although the evacuation was successful overall ( ), deaths, injuries, and illness occurred disproportionately among low-income persons in new orleans because of economic and logistic constraints on their ability to respond to government recommendations to leave the city. low-income and disadvantaged persons often suffer disproportionately during natural disasters and epidemics, and historical evidence demonstrates that low-income persons fared considerably worse than high-income persons during the pandemic in the united states ( ) . in this article, we describe ways in which different socioeconomic and racial/ethnic groups might fare differently in an infl uenza pandemic, on the basis of current knowledge of social factors that shape exposure and vulnerability to infl uenza virus and that infl uence the timeliness and adequacy of treatment among those who become ill. we also discuss policy decisions, made either before or during a pandemic, which might differentially affect risk for illness or death for those of low income and of specifi c racial/ethnic groups. our purposes are to ) call attention to potentially major and avoidable social disparities in suffering and death during an infl uenza pandemic and ) highlight the importance of including in pandemic preparedness plans targeted strategies for minimizing or avoiding these social disparities. the following discussion is not meant to be exhaustive; rather, it is meant to provoke refl ection about how potential disparities in the effects of an infl uenza pandemic might be reduced or eliminated through appropriate planning and implementation of clinical and public health activities. using a conceptual framework adapted from diderichsen et al. ( ) , we systematically considered possible sources of disparities during an infl uenza pandemic by examining the following levels at which underlying socioeconomic or racial/ethnic differences could lead to disparities in illness or death: ) likelihood of being exposed to the infl uenza virus; ) likelihood of contracting infl uenza disease, if exposed; and ) likelihood of receiving timely and effective treatment after infl uenza disease has developed. to explore socioeconomic and racial/ethnic disparities at each level, we searched the literature for relevant fi ndings based on population-based national data (figure, table) . regardless of which strain of infl uenza virus causes the next pandemic, it will be highly transmissible between humans. transmission of infl uenza is primarily airborne, through aerosolized respiratory tract secretions expelled during coughing and sneezing, although transmission by direct and possibly indirect contact may occur. transmission can be expected to occur in various settings, including homes, healthcare facilities, schools, work sites, public transportation, and other settings at which people gather for social, commercial, or entertainment purposes. higher exposure risk among particular population groups as a result of factors such as crowding and occupation could contribute to health disparities among socioeconomic and racial/ ethnic groups during an infl uenza pandemic. crowding, an established risk factor for many infectious diseases, can increase the likelihood of pathogen transmission. in the united states, urban poverty and hispanic and asian ethnicity are correlated with domestic crowding; even at higher income levels, hispanic and asian households are relatively more crowded than white and african-american households ( ) . in addition, in the united states, low-income persons, african americans, and nonwhite hispanics are more likely than persons in other groups to obtain regular medical care at emergency departments and publicly funded clinics ( ) , where airborne transmission of infectious agents has been documented. because these locations typically do not segregate sick and well patients and are becoming increasingly crowded ( ) , patients waiting for care in these settings are likely to have greater exposure to infl uenza viruses and other respiratory pathogens. another source of increased exposure to infected persons is public transportation, where persons from low-income and minority households account for % of users ( ) . occupational factors are also likely to lead to differential exposure risk during an infl uenza pandemic, particularly in terms of adherence to strategies that aim to limit case-patient contact with others ( ) . staying home may not be economically feasible for persons in lower wage occupations; these persons are less able to afford losing income as a result of missed work and often lack the job fl exibility that would permit them to work at home. in addition, their jobs may be necessary because they provide essential goods and services. for these reasons, parents in lower wage/lower status occupations may be more likely to keep their children in communal childcare settings-where exposure risks are relatively high-during an infl uenza pandemic, placing everyone in the family at greater risk for exposure. among persons who have been exposed to infl uenza virus, the likelihood of contracting disease may be modifi ed by underlying host factors and medical conditions, such as age, smoking status, nutritional status, stress levels, and cardiopulmonary disease. the infl uence that most host factors will have on the development of infl uenza during a future pandemic is uncertain; some evidence suggests that the factors affecting disease severity and death may differ from those typically observed during annual infl uenza epidemics ( ) . however, given overwhelming evidence that low-income persons are generally more susceptible to infectious diseases, it is reasonable to plan on the basis of well-documented annual epidemic patterns, in which infl uenza disease development is infl uenced by factors that are differentially distributed across socioeconomic and racial/ ethnic groups. these patterns, as well as patterns of many other diseases, indicate that socially disadvantaged groups are likely to be at higher risk for infl uenza disease, particularly severe disease. the inability to predict which infl uenza virus will cause a future pandemic, together with the very limited national and global capacity to produce infl uenza vaccine in massive quantities in a short time, almost ensures that an effective vaccine will be unavailable to most or all of the population during the early stages of a pandemic and in very short supply thereafter. even so, current plans assume that local and state public health agencies will have a primary role for distributing pandemic infl uenza vaccine. in general, however, these plans do not adequately address preventing or minimizing socioeconomic or racial/ethnic disparities in vaccine distribution and acceptance, despite evidence that such disparities have been the rule for the annual infl uenza vaccine, even among persons > years of age ( ) . in the united states, routine use of annual infl uenza vaccine in preschool children has only recently been introduced; information focusing on school-age children is limited ( ) . nevertheless, african american/black children and children from lower income families, who are at higher risk of contracting infl uenza ( ) in this country, are less likely to be up to date with other routine immunizations ( ) . it is possible that, in the context of an infl uenza pandemic, vaccine-seeking and acceptance behavior and resultant coverage patterns may differ from those observed during routine vaccination efforts; however, the weight of available evidence indicates that social disparities in vac-cine coverage are likely to occur in the absence of careful planning to prevent them. among those who contract infl uenza, subsequent illness and death may be infl uenced by underlying factors and conditions and by the timeliness and effectiveness of various treatment modalities. most infl uenza illnesses are self-limiting, and most infected persons during both annual infl uenza epidemics and infl uenza pandemics (including that of - ) recover with only supportive care in the community. even so, current planning efforts recognize the potential importance of reducing disease during a pandemic, through early treatment with antiviral drugs and through other forms of treatment such as respiratory support and antimicrobial agents to treat secondary bacterial pneumonia, among those with more severe disease. in the united states, the likelihood of substantial disparities in access to timely and appropriate care under infl uenza pandemic conditions is high, given long-standing and persistent disparities in access to medical care. for example, persons with low income are ≈ × as likely as those with higher incomes to lack a usual source of healthcare ( ) . similarly, non-hispanic black and hispanic persons are signifi cantly less likely than non-hispanic white persons to report having a usual primary care provider ( ). among persons who do report having a usual source of care, those who are poor or near poor and those who are non-hispanic black or hispanic are . - × as likely as their relatively higher income and white counterparts to rely on a hospitalbased source of primary care ( ) . these same groups are also more likely to report having diffi culty obtaining timely appointments for illness or injury, which suggests problems with access to care even among those with a usual source of healthcare ( ) . language and cultural barriers to seeking and receiving medical care also may contribute to disparities. in emergency departments, for example, interpreters are frequently unavailable or underused, which has potentially adverse implications for patients' understanding of their disease or treatment and for clinical decision making emerging infectious diseases • www.cdc.gov/eid • vol. , no. , may table. factors that could contribute to health disparities among socioeconomic and racial/ethnic groups during an influenza pandemic differences in exposure to influenza virus crowding in households, medical facilities, public transportation occupational factors such as inability to work from home, dependence on childcare outside of the home differences in susceptibility to influenza disease, once exposed to the virus host factors, including preexisting immunity, age, other underlying diseases or conditions, smoking, nutritional status, stress vaccination status, reflecting differences in vaccine seeking and acceptance and in vaccine availability differences in timely effective treatment, once influenza disease has developed access to outpatient and inpatient medical care care-seeking attitudes and behavior financial obstacles, including lack of adequate insurance coverage logistic obstacles, including transportation, language quality of care availability of antiviral treatments appropriate inpatient treatment and quality of care ( ) . in addition, the large numbers of persons who lack health insurance, as well as those who lack documentation of us citizenship, often delay seeking care because they are concerned about paying for the care or encountering legal diffi culties. evidence from previous outbreaks suggests that antiviral drugs may be effective for treatment ( ) and prevention ( ) of pandemic infl uenza, and current antiviral drugs seem to be biologically effective against and like viruses ( ) . because vaccine may not be available when a pandemic begins, experts have suggested that the antiviral drug oseltamivir should be stockpiled for use during a pandemic infl uenza outbreak. recent models suggest that early use of oseltamivir may contain outbreaks if certain criteria regarding transmissibility and compliance are met ( ) . however, experience with nonpandemic infl uenza indicates that oseltamivir must be given early during symptom development for it to have any substantial biological effect ( ) ; modest delays may vitiate the treatment effectiveness ( ) . although plans for release and distribution of antiviral drugs are still being fi nalized, overcoming long-standing disparities in access to timely treatment by socioeconomic status, race/ethnicity, ability to speak english, and legal status will present numerous challenges to ensuring equal access to such drugs during a pandemic. reasons for concern about disparities in the timeliness and appropriateness of the care received by infl uenza patients who might benefi t from in-hospital care are similar. given the predicted insuffi cient supply of hospital beds and staff during a pandemic ( ), a person's access to potentially lifesaving therapies such as respiratory support and antimicrobial treatment of secondary bacterial pneumonias in an inpatient setting is likely to depend on factors that include usual source of care, citizenship status, and ability to speak english. disparities may also occur in the quality of care received by persons who are hospitalized. earlier us studies of persons hospitalized for pneumonia have found that blacks and "other minorities" are % and % as likely, respectively, as non-hispanic whites to receive antimicrobial agents within hours of arrival at the hospital ( ) and signifi cantly less likely to have blood cultures obtained before receiving antimicrobial therapy ( ) . such disparities in quality of care would likely persist during an infl uenza pandemic. although reducing or eliminating socioeconomic and racial/ethnic disparities in health and healthcare has been an offi cial federal and state policy priority for decades ( ), such disparities remain prevalent and may inadvertently become wider when not explicitly addressed by policies designed to improve the health of the population as a whole and of disadvantaged persons in particular ( ) . given the current limitations of our public health infrastructure and the disparities in healthcare, a pandemic infl uenza outbreak in the united states is likely to disproportionately affect persons from socially disadvantaged groups. explicit, systematic, and detailed plans are essential for overcoming the social barriers that are predicted to result in socioeconomic and racial/ethnic disparities in pandemic infl uenza illness and death. saunders and monet also have called for pandemic infl uenza planning that appropriately considers the needs of disadvantaged populations ( ) . the pandemic infl uenza plan of the us department of health and human services (hhs) ( ) does not adequately address potential social disparities in exposure, vaccination, or treatment; the possible effects of such disparities; or strategies for minimizing or eliminating them. the hhs plan ( ) , the federal guidance on vaccine allocation ( ) , and the recent centers for disease control and prevention (cdc) guidelines for community-level mitigation strategies ( ) should be credited for calling for community engagement and inclusion of a wide variety of stakeholders in planning at the local level. outreach to providers, community leaders, and organizations, particularly in disadvantaged communities, will be an important component of any strategy for addressing disparities during a pandemic. however, the available versions of offi cial plans do not call attention to the need for special efforts to overcome the greater barriers likely to be faced by socially disadvantaged groups. on a us government website for pandemic infl uenza (www.pandemicfl u.gov), a question asks which groups would be especially vulnerable during an infl uenza pandemic. the answer notes that people may be vulnerable for a variety of reasons, including limited access to healthcare; limited profi ciency in english; or being disabled, homeless, economically disadvantaged, or a single parent. the response calls for faith-based and community-based organizations to develop plans "to care for dependent populations" and to "provide fi nancial aid to the poor who are unable to work and are in need of emergency income for housing, medicine, or other essential needs" (www.pandemicfl u.gov/faq/pandemicinfl uenza/pi- .html), which implies that attention to the needs of economically or socially vulnerable persons is not primarily a public-sector responsibility but is more a matter for private charity. the hhs plan ( ) itself acknowledges that some groups may need fi nancial assistance if they are unable to work but does not indicate how that assistance would be provided or who would provide it. those who are still formulating plans should consider likely differences in infl uenza exposure and identify potential strategies for mitigating such disparities. mathematical models have demonstrated that community-based interventions, such as quarantine and individual isolation, may be important for reducing infl uenza attack rates and overall incidence ( ) . most pandemic plans call for limiting public gatherings and closing schools to slow the spread of infl uenza, without adequately taking into account how implementing these strategies could differentially affect disadvantaged groups. recent recommendations from cdc go further in recognizing the differential effect of socialdistancing measures on vulnerable communities ( ) . although cdc advocates fl exible work arrangements, income replacement, and job security to minimize the negative effects of social-distancing measures, it pays inadequate attention to those whose jobs will not accommodate these interventions. more specifi c solutions should be outlined in pandemic preparedness plans to address the economic effects of quarantine on low-income persons, who by staying home may be at risk wage loss, job termination, or both. job security and income replacement are key components to limiting the effects of potential quarantine measures on disadvantaged persons ( ) and should be extended to all persons, regardless of their type of work. important decisions also will need to be made concerning access to vaccination and treatment in the event of a pandemic. the federal government's draft guidance on allocating and targeting pandemic infl uenza vaccine ( ) provides a basic framework for allocating vaccine during the pandemic. an appendix to that document mentions (on p. ) that the principles of "fairness and equity (recognizing that all persons have equal value, and providing equal opportunity for vaccination among all persons in a priority group)" were considered when drafting the guidelines. although the proposed schema very reasonably fi rst defi nes groups of different priority levels according to occupation and then, within the general population, according to age and pregnancy status, it does not provide explicit attention to groups who are vulnerable because of social disadvantage. nor does it note the need for explicit attention to vulnerable social subgroups, for example, low-wage workers in prioritized occupational fi elds and low-income and minority pregnant women, infants, and toddlers. we are not questioning the rationality of defi ning major priority groups according to occupation or of using biological criteria to further prioritize within the general population. rather, our concern is with the absence of attention to both biological and social risk factors, which must be addressed to overcome the many social barriers to equal opportunity for vaccination. well-documented evidence of existing healthcare disparities suggests that during a pandemic shortages of infl uenza vaccine, antiviral drugs, inpatient services, and healthcare staff will disproportionately affect persons in socially disadvantaged groups. to limit the crowds that might occur at hospitals and clinics, plans for the release of stockpiles of vaccines, medications, or both could include distribu-tion from private pharmacies or doctors' offi ces. however, because private pharmacies and private practitioners are less likely to be located in lower income neighborhoods, plans to make access to potentially lifesaving vaccines and drugs speedier and more equitable might, in fact, exacerbate disparities. distribution plans may need to include mobile community health centers (staffed by nurses and nurse practitioners) that can travel to low-income areas, along with a variety of community medical and other service providers and nontraditional sites like soup kitchens, sheltered workshops, and transit points, which have become popular places for administering yearly infl uenza vaccine ( ) . other factors, such as the availability of transportation to a hospital, might also become more important during a pandemic. access to a private car may be a major determinant of who is able to obtain care, presenting constraints like those that led to disparities in evacuation from new orleans before hurricane katrina. to ensure that disadvantaged communities are reached and that resources are equitably allocated during an infl uenza pandemic, preparedness plans can and should involve community-based providers and organizations that are familiar with vulnerable groups. social group disparities in exposure, susceptibility, and access to timely and effective treatment for a variety of diseases have been well documented in the united states. infl uenza pandemic preparedness plans that fail to explicitly provide guidelines on how to mitigate these issues could lead to decisions that may, on the surface, seem reasonable, but that are likely to exacerbate social group disparities in health outcomes. given the existence of major disparities in health and healthcare, we cannot expect pandemic preparedness and response planning to eliminate the deep divides that exist between socioeconomic and racial/ethnic groups. these disparities can, however, be minimized through careful planning that considers and proactively addresses vulnerability at each level: exposure to disease, susceptibility to disease if exposed, and treatment of disease. public offi cials should systematically consider the additional barriers faced by socially disadvantaged groups at each of these levels and then actively seek ways to address those barriers. local service providers, leaders of community-based organizations and other organizations working with socially vulnerable groups, and leaders of labor unions representing low-wage service workers are likely to have valuable insights and should be included in the planning process. plans calling for stakeholder involvement without explicitly emphasizing the need to involve representatives of socially disadvantaged groups are unlikely to be effective at minimizing social disparities during an infl uenza pandemic. we have focused here on the united states, but similar fundamental principles-the need for systematic and concrete planning to minimize the social disparities that can be expected to occur in the face of natural disasters such as an infl uenza pandemic-apply worldwide. countries with universal fi nancial access to healthcare and strong social safety nets will be best positioned to minimize such disparities. countries in which large proportions of the population are impoverished or otherwise socially excluded and countries that have more limited resources and weaker public health and social welfare infrastructures will face the greatest challenges. the framework used here-considering and proactively addressing social vulnerability in exposure to pathogens, susceptibility to disease once exposed, and consequences of illness-should be applicable across national and subnational settings. pandemic infl uenza, - : a study in historical epidemiology world health organization. world is ill-prepared for "inevitable" fl u pandemic. geneva: the organization epidemiology of who-confi rmed human cases of avian infl uenza a (h n ) infection the threat of an avian infl uenza pandemic genesis of a highly pathogenic and potentially pandemic h n infl uenza virus in eastern asia state preparedness for bioterrorism and public health emergencies. issue brief (commonw fund) public health preparedness: mobilizing state by state. atlanta: the centers national plan for pandemic fl u unveiled working group on pandemic infl uenza preparedness: joint statement in response to department of health and human services pandemic infl uenza plan us department of health and human services unequal treatment: what healthcare providers need to know about racial and ethnic disparities in healthcare. washington (dc): the institute the incidence of infl uenza among persons of different economic status during the epidemic of challenging inequities in health: from ethics to action the changing problem of overcrowded housing emergency department overcrowding in the united states: an emerging threat to patient safety and public health socioeconomics of urban travel: evidence from the interim pre-pandemic planning guidance: community strategy for pandemic infuenza mitgation in the united states-early, targeted, layered use of nonpharmaceutical interventions. atlanta: the centers pandemic versus epidemic infl uenza mortality: a pattern of changing age distribution infl uenza vaccination levels among persons aged > years and among persons aged - years with high-risk conditions-united states a pilot study of the effectiveness of a school-based infl uenza vaccination program prevalence and characteristics of children at increased risk for complications from infl uenza, united states insurance status and vaccination coverage among us preschool children prenatal care in the united states, - . national center for health statistics use and effectiveness of interpreters in an emergency department successful treatment of naturally occurring infl uenza a/ussr/ h n prevention of russian infl uenza by amantadine existing antivirals are effective against infl uenza viruses with genes from the pandemic virus strategies for mitigating an infl uenza pandemic use of the selective oral neuraminidase inhibitor oseltamivir to prevent infl uenza early administration of oral oseltamivir increases the benefi ts of infl uenza treatment surge capacity associated with restrictions on nonurgent hospital utilization and expected admissions during an infl uenza pandemic: lessons from the toronto severe acute respiratory syndrome outbreak patient and hospital characteristics associated with recommended processes of care for elderly patients hospitalized with pneumonia: results from the medicare quality indicator system pneumonia module us department of health and human services disadvantage, inequality, and social policy eliminating injustice toward disadvantaged populations during an infl uenza pandemic us department of health and human services. hhs pandemic infl uenza plan draft guidance on allocating and targeting pandemic infl uenza vaccine encouraging compliance with quarantine: a proposal to provide job security and income replacement adult immunization programs in nontraditional settings: quality standards and guidance for program evaluation key: cord- -lcog authors: pimentel, david; pimentel, marcia; wilson, anne title: plant,animal, and microbe invasive species in the united states and world date: journal: biological invasions doi: . / - - - - _ sha: doc_id: cord_uid: lcog approximately , plant, animal, and microbe invasive species are present in the united states, and an estimated , plant, animal, and microbe invasive species have invaded other nations of the world. immediately, it should be pointed out that the us and world agriculture depend on introduced food crops and livestock.approximately % of all crops and livestock in all nations are intentionally introduced plants, animals, and microbes (pimentel ). worldwide, the value of agriculture (including beneficial non-indigenous species) is estimated to total $ trillion per year. other exotic species have been introduced for landscape restoration, biological pest control, sport, and food processing, also contributing significant benefits. calculating the negative economic impacts associated with the invasion of exotic species is difficult.for a few species, there are sufficient data to estimate some impacts on agriculture, forestry, fisheries, public health, and the natural ecosystem in the us and worldwide. in this article, we estimate the magnitude of the economic benefits, and environmental and economic costs associated with a variety of invasive species that exist in the united states and elsewhere in the world. some impacts on agriculture, forestry, fisheries, public health, and the natural ecosystem in the us and worldwide. in this article, we estimate the magnitude of the economic benefits, and environmental and economic costs associated with a variety of invasive species that exist in the united states and elsewhere in the world. the value of the us food system is more than $ billion per year (uscb (uscb - , and the value of the world food system is estimated at more than $ trillion per year. according to the world health organization (pimentel a) , the world's food system is not providing adequate amounts of food for all people on earth, more than . billion of the current population of . billion being malnourished. in addition, food production per capita has been declining each year for the past years (faostat (faostat - . this assessment is based on cereal grains, since cereal grains provide about % of the world's food. clearly, more needs to be done to increase food production per capita, at the same time significantly reducing the rate of growth of the world population . most plant and vertebrate animal introductions in the us and world have been intentional, whereas most invertebrate animal and microbe introductions have been accidental. during the past years, the total number of introductions of all species has nearly doubled in the world. the rate of introductions of exotic species has increased enormously because of high human population growth, rapid movement of people, and alteration of the environment everywhere in the world. in addition, significantly more goods and material are being exchanged among nations than ever before, creating greater opportunities for unintentional introductions (uscb (uscb - . some of the estimated , species of plants, animals, and microbes that have invaded the us, and , species of plants, animals, and microbes that have invaded the total world ecosystem provide significant benefits but also many types of damage to managed and natural ecosystems, as well as public health. most exotic plant species now established in the united states and elsewhere in the world were introduced for food, fiber, or ornamental purposes. an estimated , introduced plant species have escaped and now exist in us natural ecosystems (morse et al. ) , compared with a total of approximately , species of native plants (morin ) . in florida, of the approximate , alien plant species (mostly introduced ornamental species), more that have escaped and become established in neighboring natural ecosystems (frank et al. ; simberloff et al. ). more than , plant species have been introduced into california, and many of these have escaped into this natural ecosystem as well (dowell and krass ) . worldwide, an estimated , species of exotic plants have been intentionally introduced as crops, and have escaped to become established in various natural ecosystems. most of the non-indigenous plants that have escaped and become established have adapted well to the favorable living conditions characteristic of moist tropical regions in countries such as india, brazil, and australia. some of the invasive plants established in the us and world have displaced native plant species. in the united states, introduced plant species are spreading and invading approximately , ha of us natural ecosystems per year (babbitt ) . for instance, the european purple loosestrife (lythrum salicaria), which was introduced in the early th century as an ornamental plant (malecki et al. ) , has been spreading at a rate of , ha per year, strongly altering the basic structure of the wetlands that it has invaded (thompson et al. ) . stands of purple loosestrife have reduced the abundance of native plant species, and endangered many wildlife species, including turtles and ducks (gaudet and keddy ) . loosestrife is present in states, and about $ million are spent each year for control of the weed (attra ). many of these exotic species have become established in national parks. in the great smokey mountains national park, for example, of the , vascular plant species are exotic, and of these are currently displacing and threatening native plant species (hiebert and stubbendieck ) . the problem of introduced plants is particularly serious in hawaii, where of the total of , plant species on the island are non-indigenous (elredge and miller ) . in some cases, one exotic plant species may competitively overcome an entire ecosystem. in california, the yellow starthistle (centaurea solstitalis), for example, dominates more than million ha of northern grassland in the state, resulting in the total loss of this once productive forage system (campbell ) . in addition, the european cheat grass (bromus tectorum) is dramatically altering the vegetation and fauna of many natural ecosystems in the western us. cheat grass is an annual that has invaded and spread throughout the shrub-steppe habitat of the great basin in idaho and utah, predisposing the altered habitat to fires (kurdila ) . before the invasion of cheat grass, fire burned once every to years, and shrubs in the region had a chance to become reestablished. currently, fires occur once every to years, and this has led to a decrease in shrubs and other vegetation, and the occurrence of monocultures of cheat grass on more than million ha in idaho and utah. the reason that the alteration of original vegetation is so significant is that all the animals and microbes that were dependent on the original vegetation have been reduced or totally eliminated. insufficient information exists concerning invasive plants in the united states and other countries. this is true even in countries that are dominated by invasive plants, such as the british isles. for example, of the , total plant species on the british isles, only , species are considered native (crawley et al. ) . more than % of alien plant species in the british isles are established in disturbed habitats (clement and foster ; crawley et al. ) . one group of agriculturalists introduced species of plants as potential forage species in australia (lonsdale ). only species of this group of plant species turned out to be beneficial, many others had little impact, but several became serious pest weeds in australia. in india, weeds are estimated to cause a % loss in potential crop production each year (singh ) , amounting to about $ billion in reduced crop yields. assuming that % of the weeds in crops are alien (nandpuri et al. ), the total cost associated with the alien plants in india is about $ . billion per year. about mammal species have been intentionally introduced into the united states, including dogs, cats, horses, cattle, sheep, pigs, and goats (layne ). several of these mammal species escaped into the wild, and have become pests by preying on native animals, grazing on native vegetation, or intensifying soil erosion. goats (capra aegagrus hircus), for instance, introduced on san clemente island, california, have caused the extinction of endemic plant species and have endangered others (kurdila ) . several small mammal species, especially rodents, have been introduced into the united states. these include the european rat (rattus rattus), the asiatic rat (rattus norvegicus), the house mouse (mus musculus), and the european rabbit (oryctolagus cuniculus; layne ). some of the introduced rats and mice have become particularly abundant and destructive on farms. on poultry farms, there is about rat per chickens (smith ; d. pimentel, unpublished data) . using this ratio, it is estimated that the rat number is more than . billion on farms in the us. another million rats are estimated to be in homes and stores in cities and towns. if it is estimated that each rat causes $ in damages each year, then the damage per year would be about $ billion. although the cost of the impact of invasive mammals is relatively high, the percentage of alien mammals introduced into the united states is relatively low, or %; in the united kingdom, the percentage is relatively high, or % . the uk introduced mammals include those species recorded in the us, plus many others. australia is another nation that has a large number of alien mammals. in australia, pigs native to eurasia and north africa were introduced and now number from to million (emmerson and mcculloch ) . feral pigs cause soil erosion, damage agricultural crops, fences, native plants and animals, and are a threat to livestock and humans; they also spread various animal diseases, including tuberculosis, brucellosis, rabies, and foot-and-mouth disease (lever ) . the estimate of pig damage in australia is more than $ million per year (emmerson and mcculloch ) . rodents, including the european and asiatic rats and the house mouse, have invaded all countries in the world. in addition, domestic dogs, cats, and european rabbits have been introduced into all nations of the world. in australia, feral cats are a serious problem, killing native bird, mammal, marsupial, and amphibian populations. the estimate is that there are million pet cats, and million feral cats in australia (anon ) . the cats are considered responsible for having exterminated native australian species of animals (low ) . assuming that each bird has a minimum value of $ in the us (pimentel et al. ) , then the total impact from cats in australia is $ million per year. in the us, it is estimated that cats kill an estimated million birds per year, with an estimated damage of $ billion (pimentel et al. ) . of the , species of birds in the united states, nearly are exotic (temple ) . approximately % of the introduced birds are beneficial, such as the chicken. one of the bird pest species is the english sparrow (passer domesticus), introduced in into the us for the control of canker worm and other pest caterpillars (roots ) . by , english sparrows were reported to be a pest, consuming wheat, corn, and the buds of fruit trees (laycock ). in addition, they harass native birds, including robins, baltimore orioles, and the yellow-billed and black-billed cuckoos, and they displace bluebirds, wrens, purple martins, and cliff swallows (long ) . english sparrows are also associated with the spread of about human and livestock diseases (weber ) . one of the most serious bird pests is the common pigeon (columbia livia), which has been introduced to all cities in the world (robbins ) . pigeons present a nuisance because they foul buildings, statues, cars, and sometimes people, and they feed on grains (smith ) . it is estimated that pigeons cause an estimated $ . billion in damages per year in the united states. they also serve as reservoirs and vectors of more than human and livestock diseases, including parrot fever, ornithosis, histoplasmosis, and encephalitis (long ) . another serious bird pest in the us is the european starling (sturnus vulgaris), a species that in some cases occurs at densities of more than one per hectare in agricultural regions (moore ) . they are capable of destroying as much as $ , worth of cherries ha - in the spring (feare ). they also destroy large quantities of grain crops (feare ) . the estimate is that they are responsible for damages amounting to $ million per year (pimentel et al. ) . information on other bird species that have invaded other nations is not as abundant as one would expect. of the other nations, the uk has some of the best data. of the species of birds in the uk, are alien (gooders ) . pigeons in the uk are as serious a problem as they are in the us. in the uk, pigeons are estimated to cause more than $ million in damages each year (alexander and parsons ; bevan and bracewell ). about species of amphibian and reptile species have been introduced into the united states. these species invasions have all occurred in the warmer regions. for example, florida is host to species (lafferty and page ) . the negative impacts of these invasive species have been enormous. the brown tree snake (boiga irregularis) is one of the worst. it was introduced into the us territory of guam immediately after world war ii, when military equipment was transferred to the island (fritts and rodda ) . the snake population reached high densities of snakes ha - , and dramatically reduced populations of native bird species, small mammals, and lizards. a total of bird species and lizard species were exterminated from guam (rodda et al. ) . the brown tree snake also eats chickens, eggs, pet birds, and causes major problems to farmers. in some cases, the snake enters houses and bites small children in cribs and playpens (ota ) . another costly impact is that the snake is causing power failures by damaging electric transformers. the estimate is that the brown tree snake causes more than $ million in damages per year on guam.a major worry is that the snake will invade hawaii, and cause major extinctions of birds, mammals, and amphibians on the island. an estimated species of reptiles and amphibians exist in australia (fox ) . however, only two of these are exotic. one of the introduced species is the cane toad (bufo marinus), introduced from south america for insect con-trol in cane fields. however, it was soon reported to be a serious pest (fox ) . the cane toad is poisonous to dogs, cats, and other mammals (sabath et al. ) . in south africa, there have been species of reptiles and species of amphibians introduced (siegfried ). one of the invasive species is the red-eared slider (chrysemys scripta elegans) that was introduced from north america. this invasive turtle has become a major threat to the native turtle species (boycott and bourquin ) . a total of invasive fish species have been introduced into the united states (courtenay et al. ; courtenay ) . most of the invaders are found in the warmer regions such as florida, which has at least of these species (courtenay ) . introduced fish species frequently alter the ecology of aquatic ecosystems. in the great lakes, for instance, nearly invasive species are found, and these invaders are causing an estimated $ billion in damages to the fisheries per year (pimentel ) . in addition, most of the alien fish species in south africa are regarded as pests (bruton and van as ) . in total, alien fish species are responsible for the reduction or local extinction of at least species of fish in south africa (bruton and van as ). an estimated , arthropod species (more than , species in hawaii alone, and more than , in continental us) have been introduced into the united states (ota ) . approximately % of these introductions were accidental, the remainder being intentional for purposes of biological control and pollination. about , invasive species of insects and mites are crop pests in the us. introduced insects account for % of the crop insect pests in hawaii (beardsley ) . approximately % of the insect and mite pests in crops in continental us are pests of agricultural crops. the major group of pests consists of native insects and mites that switched from feeding on native vegetation to feeding on crops (pimentel et al. ) . pest insects are estimated to destroy $ billion worth of crops per year. one ant species, the red imported fire ant, is alone causing $ billion in damages and control costs (linn ) . of the species of invasive species in us forests, about % are now serious pests in these forests (liebold et al. ) , causing about $ billion in losses each year (hall and moody ) . a new introduction, the asian longhorn beetle, is threatening maple and ash trees in new york and illinois (hajek ) . of the , species of insects, and , species of spiders and numerous other arthropod species that exist in south africa, several invasive species are causing problems (south africa ). one of the most serious invaders is the argentine ant (linepithema humile), which is destroying native vegetation, including endangered plants (macdonald et al. ). this ant species is also negatively affecting native ants and other beneficial arthropod species. in addition, the argentine ant is a serious pest in agriculture. a total of about species of mollusks have been introduced and established in united states aquatic ecosystems (ota ). the two most serious pest species introduced are the zebra mussel, dreissena polymorpha, and the asian clam, corbicula fluminea (see also chaps. and ). the zebra mussel was introduced from europe, and probably gained entrance via ballast water released into the great lakes by ships traveling from europe (benson and boydstun ) . the mussel was first noted in lake st. clair, has spread into most of the great lakes and most aquatic ecosystems in the eastern united states, and is expected to invade most freshwater habitats throughout the nation. large mussel populations (up to , m ; griffiths et al. ) reduce food and oxygen for the native fauna. zebra mussels have been observed covering native mussel, clams, and snails, and threatening the survival of these and other species (benson and boydstun ; keniry and marsden ) . in addition to ecological effects on other aquatic organisms, the zebra mussel also invades and clogs water intake pipes in water infiltration and electric power plants. it is estimated that the mussels will cause $ billion in damages and associated control costs in the us. in the great lakes alone, they are reported to cause $ billion in damages and control costs (pimentel ) . although the asian clam grows and disperses less quickly than the zebra mussel, it also causes significant damage to native organisms and damage to water filtration plants and electric power plants. costs associated with this animal are estimated to be more than $ billion per year (ota ) . in various us coastal bay regions, the introduced shipworm (teredo navalis) is estimated to cause from $ million to $ million in damages per year (cohen and carlton ; d. and m. pimentel, unpublished data) . unfortunately, there are not data available on mollusk invaders in other nations. this is due to the general lack of knowledge concerning the ecology and systematics of mollusks in the world; they appear to be causing a relatively small amount of damage to aquatic ecosystems in other regions worldwide, and/or few biologists have investigated these organisms. for a start, it should be pointed out that the majority of livestock worldwide are introduced species. for example, in the united states more than % of the livestock species are introduced (pimentel b ). microbial and other parasitic organisms have generally been introduced when the livestock species have been introduced. in addition, to the more than species of pest microbes and other parasitic species that have already invaded the united states (pimentel ) , there are more than additional microbes and other parasitic species that could easily invade the united states and become serious pests of us livestock (pimentel ) . a conservative estimate of the losses to us livestock from exotic microbes and other parasitic species is more than $ billion per year. australia already has several species of alien diseases infecting and causing losses to livestock. in addition, there are an estimated exotic diseases in other regions of the world that could infect australian livestock, if they were introduced (meischke and geering ). at present, alien insect and mite species already cause $ million per year damage to the wool and sheep industry (slater et al. ) . in india, there are more than exotic species of disease and parasitic organisms that are causing major problems for the introduced livestock and native wildlife. already present in india is the serious foot-and-mouth disease. recently, it was reported that there were more than , cases of footand-mouth disease (foot-and-mouth disease leak ), treatment costs being about $ , per year. south africa also reports problems with introduced livestock pests. the exotic diseases include tuberculosis, brucellosis, east coast fever, anthrax, and rinderpest. estimates are that brucellosis alone is causing livestock losses of more than $ million per year (coetzer et al. ) . in brazil and other latin american countries, imported bovine tuberculosis has become a serious threat to the beef and dairy industry. these losses are estimated to be about $ million per year (cosivi et al. ). various influenza virus types, originating mostly in the far and near east, have quickly spread to the united states and other nations in the past. recent disease epidemics have been associated with sars, and now there is the major threat of bird flu that is infecting some people in the far and near east. the current influenza strains are responsible for nearly % of all human deaths in the us (uscb (uscb - . the costs of hospitalization for a single outbreak of influenza, such as type a, can exceed $ million per year. one of the most notorious of all alien human disease is hiv/aids. the pathogen is reported to have originated in east africa, probably from some species of monkey. the disease now occurs in all parts of the world. the costs of treatment of hiv/aids in the world today are estimated to be $ billion per year. in addition to influenza and hiv/aids, there are numerous other diseases infecting humans in various parts of the world. these include syphilis, lyme disease, and tuberculosis. these diseases are causing an estimated $ billion in losses and damages per year. new influenza strains in the uk are reported to cause from , to , deaths per year (kim ) . in total, both influenza and hiv/aids claim the lives of more than , people per year. the treatment costs are in excess of $ billion per year. influenza and tuberculosis in india are reported to cause more than million deaths per year (kim ) . several non-indigenous human diseases threaten people in south america. these diseases include hiv/aids, influenza, malaria, cholera, yellow fever, and dengue. more than million people are infected per year, associated with more than $ billion in damages and treatment costs per year. the number of invading species worldwide has been increasing rapidly, an estimated tenfold increase having been recorded in the past years. some countries with a rapidly increasing population, growing population movement, and increasing global trade, such as the united states, are suffering a greater problem from invaders than is the case for other nations. approximately , species of plants, animals, and microbes have invaded the nations of the world, with about , in the us alone. it must be pointed out that, for all nations combined, about % of all these species were intentionally introduced as crops and livestock. unfortunately, an estimated - % of the introduced species are, or have become, pests and are causing major environmental problems. although relatively few of these species become really serious pests, some species do inflict significant damage to natural and managed ecosystems, and cause serious public health problems. various ecological factors help exotic species become abundant and emerge as serious ecological threats in their new habitat. these factors include exotic plant and animal species being introduced without their natural enemies (e.g., purple loosestrife); the existence of favorable predator-prey conditions in the new habitat (e.g., for house cats); the development of new associations between alien parasites and hosts (e.g., hiv/aids and humans); the occurrence of disturbed habitats that promote invasion by some species (e.g., crop weeds); the occurrence of favorable, newly created artificial habitats for invasives (e.g., cheat grass); and the occurrence of species-specific traits promoting invasion by highly adaptable alien species (e.g., the water hyacinth and zebra mussel). this investigation reports on various economic damages associated with invasive species in various nations of the world that total more than $ . trillion per year (pimentel ) . this amounts to about % of the world gnp (uscb (uscb - . unfortunately, precise economic costs associated with some of the most ecologically damaging species of invasives are not available. for example, cats and pigs have been responsible for the extinction of various animals, and perhaps some plants. for these invasive animals, however, only minimal cost impact data are available. in addition, it is impossible to assess the value attached to various species that have been forced to extinction. if economic values could be assigned to species forced to extinction, then in terms of losses in biodiversity, ecosystem services, and esthetics, the costs of destructive invasive species would be extremely high. the value of $ . trillion cited above already suggests that exotic species are extracting major environmental and economic tolls worldwide. as mentioned above, - % of all crop and livestock are introduced species. these alien crops (e.g., corn and rice) and livestock (e.g., cattle and poultry) are vital to maintaining world agriculture and the food system. the food system has an estimated value of $ trillion worldwide. however, these benefits do not compensate for the enormous negative impacts of exotic pest species. a real challenge lies in preventing further damage from invading exotic species to natural and managed ecosystems of the world. this is especially true in view of rapid population growth and increasing global trade. the united states has taken a few steps to protect and prevent the invasion of exotic species into the nation. many governments of other nations have taken, and are taking, additional steps to combat non-indigenous species. evidently, it is being increasingly recognized that investing a few million dollars to prevent future introduced species from invading a country, where they might cause billions of dollars worth of damage and control costs, is worthwhile. specific laws are needed in all nations to diminish or prevent invasive species introductions. all introductions of exotic species of plants, animals, and microbes -for whatever purpose -should be strictly regulated. in addition, governments should make efforts to inform the public concerning the serious environmental and economic threats that are associated with the invasion of exotic species. introducing a new species into a nation for the control of a plant, animal, or microbe pest invasive species is sometimes criticized as being a hazardous technology. in the past, where vertebrate species such as mammals, amphibians, birds, and fishes were introduced for biological control, several became pests themselves (chaps. and ). for instance, the indian mongoose, introduced for rat control in the west indian islands and hawaiian islands, and the english sparrow, introduced into the us for caterpillar control, have both turned out to be disasters. however, introductions of insect species, such as the vedalia beetle rodolia cardinalis into the us, and of a virus species for the control of the european rabbit in australia, have been notable successes. controls of cacti in australia, knapweed in the us, and the cassava mealy bug in africa, all employing biocontrol insects, have also been successful. the first response after detecting an invasive pest in a country should be to immediately travel to the country of origin of the pest, and attempt to introduce natural enemies of the pest. this is sometimes successful, but not always. there have been almost as many successful biological controls employing new associated biocontrol agents. in new associated biocontrol, the biological control agents are sought from a related species of the pest invasive in another country. the new association biocontrol agent offers an ecological advantage because the biocontrol agent has never interacted with the invasive pest species, and often this advantage makes the new biocontrol agent highly pathogenic to the invasive pest species. the advantage of biological controls is that they reduce the invasive pest species without the need for using pesticides in the new ecosystem, and with minimal or no damage to the new ecosystem (hokkanen and pimentel ) . details on the pros and cons of biological control are given in chap. . pathogenicity for chickens of avian paramyxovirus type i isolates obtained from pigeons in great britain - rare plants protect cape's water supplies purple loosestrife: public enemy # on federal lands statement by secretary of the interior on invasive alien species introductions of arthropod pests into the hawaiian islands our living resources: a report to the nation on the distribution, abundance, and health of u.s. plants, animals, and ecosystems chlamydiosis in birds in great britain. . isolations of chlamydia psittaci from birds sampled between and faunal invasions of aquatic ecosystems in southern africa, with suggestions for their management killer pigs, vines, and fungi: alien species threaten native ecosystems alien plants of the british isles cape town cohen an, carlton jt ( ) nonindigenous aquatic species in a united states estuary: a case study of the biological invasions of the san francisco bay and delta zoonotic tuberculosis due to mycobacterium bovis in developing countries nonindigenous fishes appendix . exotic fishes of the united states and canada. in: robins cr (ed) a list of common and scientific names of fishes from the united state and canada comparative ecology of the native and alien floras of the british isles exotic pests pose growing problem for california numbers of hawaiian species: supplement , including a review of freshwater invertebrates queensland's introduced plants and animals. queensland parliamentary library, brisbane faostat ( - ) quarterly bulletin of statistics. fao, rome feare cj ( ) the economics of starling damage conserving biodiversity: impact and management of exotic organisms immigration and introduction of insects our living resources. a report to the nation on the distribution, abundance, and health of us plants animals and ecosystems predicting competitive ability from plant traits: a comparative approach collins british birds distribution and dispersal of the zebra mussel (dreissena polymorpha) in the great lakes region forest depletions caused by insects and diseases in canada - . forest insect and disease survey information. forest insect and disease survey asian longhorned beetle: ecology and control. in: pimentel d (ed) encyclopedia of pest management new associations in biological control: theory and practice our living resources: a report to the nation on the distribution, abundance, and health of us plants, animals, and ecosystems world exotic diseases. in: pimentel d (ed) biological invasions: economic and environmental costs of alien plant, animal and microbe species the introduction of exotic species into the united states: there goes the neighborhood predation of the endangered tidewater goby, eucyclogobius newberryi, by the introduced african clawed frog, xenopus laevis, with notes on the frog's parasites nonindigenous species naturalized animals: the ecology of successfully introduced species ant warfare: science fights fire with flies: natural enemy central to effort to limit spread of the insects. usa today (nation) introduced birds of the world: the worldwide history, distribution, and influence of birds introduced to new environments feral future: the untold story of australia's exotic invaders ecology and management of biological invasions in southern africa biodiversity: man is one among million species bird problems in agriculture. the british crop protection council our living resources: a report to the nation on the distribution, abundance, and health of us plants, animals, and ecosystems our living resources: a report to the nation on the distribution, abundance, and health of us plants, animals, and ecosystems harmful non-indigenous species in the united states biological invasions: economic and environmental costs of alien plant, animal, and microbe species agriculture: changing genes to feed the world livestock production and energy use aquatic nuisance species in the new york state canal and hudson river system and the great lakes basin: an economic and environmental assessment in: dorf r (ed) technology, humans and society: toward a sustainable world environmental and economic costs of non-indigenous species in the united states ecological and economic threat of alien plant, animal, and microbe invasions in the world update on the environmental and economic costs associated with alien-invasive species in the united states our living resources: a report to the nation on the distribution, abundance, and health of us plants, animals, and ecosystems the disappearance of guam's wildlife easteal s ( ) expansion of the range of the introduced toad bufo marinus in australia - preservation of species in southern africa nature reserves strangers in paradise years of crop science research in india. indian council of agricultural research an investigation into the effects of redlegged earth mite and lucerne flea on the performance of subterranean clover in annual pasture in s producers need not pay startling "rodent tax" losses books in soils, plants, and the environment: stored-grain ecosystems south africa government online exotic birds, a growing problem with no easy solution spread, impact, and control of purple loosestrife (lythrum salicaria) in north american wetland. us fish and wildlife service, and fish and wildlife research united states statistical abstracts health hazards from pigeons, starlings and english sparrow: disease and parasites associated with pigeons, starlings, and english sparrows key: cord- -p b jtf authors: ijaz, m.k.; alharbi, s.; uduman, s.a.; cheema, y.; sheek-hussen, m.m.; alkhair, a.r.a.; shalabi, a.g.; ijaz, s.s.; bin-othman, s.a.; sattar, s.a.; liddle, l.f. title: seasonality and prevalence of rotavirus in al-ain, united arab emirates date: - - journal: clin diagn virol doi: . / - ( ) - sha: doc_id: cord_uid: p b jtf background: rotaviruses are the single most important causative agent of acute neonatal enteritis in most avian and mammalian species including humans. rotaviruses infections have also been shown to be associated with the elderly, immunocompromised individuals and more recently with epidemic diarrheal illness in adults. objectives: to study the incidence and the effect of seasonality on the prevalence of rotaviruses in al-ain, united arab emirates. study design: a total of stool samples submitted to the laboratories of two university teaching hospitals (al-ain and tawam) and a private hospital (oasis) were examined for the presence of rotaviruses from january –december, , using a commercially available latex agglutination assay. the meteorological data (temperature, relative humidity and rainfall) recorded during the sampling period was analyzed statistically to examine the effect of seasonality on the prevalence of rotavirus cases in al-ain, united arab emirates. results: rotavirus was detected in . % of the samples examined. the predominant number of positive cases ( %) were in the – months age group. it was interesting to find rotavirus-positive cases in as low an age group as < months ( . %) and as high as years ( . %). there was no significant difference on infection rates between male and female groups in the study. however, there was a significant difference between the national ( . %) and non-national children ( . %). the higher rate of the latter may be due to import of infections. there appeared to be a seasonal pattern of rotavirus occurrence in the cases studied, with a marked increase in the number of positive cases during the months when the relative humidity was low ( – %) and there was no rainfall. conclusions: rotavirus was detected in all age groups with a predominance in – month age groups, and a higher incidence in non-nationals. there was a marked increase in the number of positive cases during the months when the relative humidity was low ( – %) and there was no rainfall. these findings are discussed in relation to the epidemiology and prophylaxis of rotavirus infections. to study the incidence and the effect of seasonality on the prewllence ot" rotaviruses in a -ain, united arab emirates. teaching hospitals (a -ain and tawam) and a private hospital (oasis) were examined for the presence of rotaviruses from january -december, , using a commercially available latex agglutination assay. the meteorological data (temperature, relative humidity and rainfall) recorded during the sampling period was analyzed statistically to examine the effect of seasonality on the prevalence of rotavirus cases in ai-ain, united arab emirates. results: rotavirus was detected in . % of the samples examined. the predominant number of positive cases ( %) were in the - months age group. it was interesting to find rotavirus-positive cases in as low an age group as < months ( . %) and as high as years ( . %). there was no significant difference on infection rates between male and female groups in the study. however, there was a significant difference between the national ( . %) *corresponding author. fax: (+ ) - ( . - ,, ,$ . :'-', elsevier science b.v. all rights reserved ssdi - ( ) i -k and lion-national children ( . ')<,t. the higher rate o " the latter may be duc to import of infections. there appeared io bc a seasonal pattern of rolavirus occtlltence ill the cases studied, with a marked increase in the number of positix, e cases during the inonths whe the relative humidity was low ( <){,) and there was no rainfall. conclusions: rotavirus \~as detecled in gill age groups with a predominance in month age groups, and a higher incidence in ilon-natiol als. there was a lllarkcd increase in the number o " positive cases during ttle months \~hen the relative humidity was low ( '!;,i ;.lild there was no rainl'all. these findings ;_ire discussed in relation to lhc epidemiolog) ~.ll-ld prophylaxis of rotaxirus infecticms. t:ollowing the discovery of rotavirus in the feces ot" calves sufl'eril g from diarrhea ( mebus et al.. ) , and in biopsy specimens of an infant's intestinal tissue ( bishop et al., ) , it has been reported that rotaviruses are ubiquitous animal and human pathogens that cause significant diarrheal diseases in most lnammalian and avian species (flewett et al., : flewett and babiuk, : estes and cohen, : kapikian et al., : kapikian and chanock, : middleton et al.. . more recently, rotaviruses have been shown to be involved in causing extra-intestinal infections in immunodeficient children (gilger el al., t . they have been associated with enteritis particularly in young ammals (under one month of age) and in infants (six months to two years). epidemics of rotavirus among adults ( l h'dy. , tlung. ) and the elderly havc also been described (kapikian and chanock, ) . it has been estimated that oxer × " cases el'diarrhea occur ammally in humans, resulting either directly or indirectly in approximately × " deaths, of which approximately x '> deaths have been attributed to rotaviruses ( dezoysa and feachem, ; and ratalia, { ) . despite their significant involvement in pcdiatric diarrhea, the role played by, thesc viruses remained undetermined in human populations in the united arab emirates ((iae). the present prelect, therefore, was designed to detine the role of rotaxiruses in pediatric hospitalized diarrheal cases. this information has shed some light on the role of thcsc viruses in acute xiral enteritis in the local population. in addition it defined the eft'cot of seasonaliiy on the prewilence of rotavirus in this part (ai-ain)of tile t!ae. stool samples were collccted from tile pediatric wards of hospitalized children sult'ering fl'om diarrhea in tile a -ain medical district. the ai-ain medical has three main hospitals serving a population of approximately two hundred thousand. ai-ain hospital (serving mainly expatriates but uae nationals arc also served here) and tawam ttospital (serving mainh: uae nationals but a limited number o " expatriates, mainly hospital employees or cases referred from a -ain hospital are also served here) are the large teaching hospitals with beds and beds respectively. the third hospital, oasis hospital is a private hospital which serves both populations and has beds. stools or rectal swabs were collected in sterile containers and sent immediately to the laboratories of the respective hospitals for rotavirus analysis. these samples underwent routine bacteriological or parasitological examination. the samples were examined for the presence of rotavirus using commercially available latex agglutination assay (rotazyme, abbott laboratories, il usa or rotalex, orion diagnostica, espoo, finland). the statistical analysis was performed using different computer software. z-test was applied to determine the significant difference between the two populations. the data was processed on dos . editor for statistical analysis on statistical package for social sciences (spss) software. harvard graphics software was used for the graphical presentation of both clinical and meteorological data. between january, to december, , a total of stool samples were analyzed for the presence of rotavirus. rotavirus was detected in a total of ( . ' ,,) of the samples submitted to the three hospitals. it was interesting to note that none of the samples which were positive for rotavirus were positive for any other infectious agent. rotavirus was detected in all age groups under study ( fig. ) a under three months as well as in the group of over years of age. the rotaviruspositive cases were analyzed statistically to determine if there was any significant difference between different sex groups (rotavirus was detected in % of male and % of female stool specimens) and no significant difference between the two groups was observed. the rotavirus-positive cases were also analyzed to determine if there is any difference between the local (nationals) [ . %] and expatriate [ . %] populations and a significant difference (p < . ) between the two populations was observed. to determine the effect of seasonality on the prevalence of rotavirus in diarrheal cases, the meteorological data o temperature, relative humidity (rh) and rainfall (rf) during the sampling period (january, december, ) was obtained from the division of meteorology. department of agriculture, a -ain, united arab emirates. rotavirus was detected throughout the year with its predominance durmg the months with low rh and no rainfall, and during the months with relatively low temperature ( fig. rotaviruses remain an important pathogen-inducing diarrhea in infants and young children in both developed and developing countries of the world. in ai-ain the population is mixed, i.e., locals and expatriates representing the middle east, south east asia, the subcontinent, north america, australia and europe. therefore, the presence of rotavirus in the a -ain population was not a surprise. rotavirus was detected in all age groups under study and predominately in the months age group. it was interesting to note that rotavirus was also recovered in the group of less than months of age. this agreed with the age incidence observed in nigerian (oyejide and fagbami, ) , native american indians in the united states (santosham et al., ) and mexican children (velazquez et al., ) . the increasing incidence of rotavirus in children after the age of months coincided with the age weaning usually begins and with the age at which maternally derived antibodies start to decline. rotavirus have been reported in adults and the elderly (bourgeois et al., ; hrdy, ; pryor et al., ) . in the present study we also observed rotavirus in older children (> years). the importance of rotavirus in this age group and in adults needs further investigation. the role of seasonality in rotavirus dissemination is poorly understood. in our study rotavirus was detected throughout the year, with its predominance during the months with low rh, no rainfall and with relatively low temperature. cook et al. ( ) have analyzed the data from global studies to investigate the seasonal patterns of rotavirus gastroenteritis and considered their implications on the transmission of the virus. according to their report the global pattern of rotavirus is quite distinct, with its predominance in the cooler months only in the americas. most of the world the virus is present throughout the year, which suggests that a low level of transmission occurs all the year round and that humans are a suitable reservoir. the results of our study taken together with the findings of cook et al. ( ) suggest that temperature alone does not account directly for this broad seasonal pattern and that other environmental factors like rh probably play a significant role in the dissemination of rotaviruses (ansari et al., ; ljaz et al., : a ,b, sattar and ljaz, ) . al-ain is located km east of the capital city of abu-dhabi and is meters above sea level. it is a traditional oasis with a climate ranging between a relatively cool, dry winter and a hot, dry summer. the percentage incidence of rotavirus infection during all the years of study revealed that it peaks in the months of march, april, may, october, november and december (fig. ) . a comparison of meteorological data with rotavirus percentages throughout the year revealed a significant relationship of the monthly temperature, rh, and re with rotavirus frequency. more rotavirus-positive cases occurred when there was low temperature, low rh and no rf. fewer cases occurred in the months with high temperature, rh and rainfall. in conclusion, our observations point towards an endemicity of rotavirus infection in the area studied. the infection was more frequent during the cooler, less humid months and in the periods of low rf. further studies are indicated to extend this to the other regions of the country, particularly those situated on the coast where rh is much higher throughout the year than in a -ain. the virus appears to be responsible lk)r inducing enteritis in the age groups studied (< months to > years). rotavirus has been recovered in diarrheal cases among adults and the elderly {bourgeois et al., ; hrdy, : hung, : kapikian and chanock, {) ). further studies need to be done to look into the possible involvement of rotavirus infections in similar age groups here in al-ain and other parts of the uae, with particular reference to the involvement of different rotavirus serotypes. the information obtained from such studies should be helpful in designing a rotavirus vaccine to control these infections. survival and vehicular spread of human rotaviruses, possible relation to scasonality of outbrcaks virus particles in epithelial cells of duodenal mucosa from children v, ith acute non-bacterial gastroenteritis. lancet it etiology of acute diarrhea among tmited states military personnel deployed to south america and west africa global seasonality of rotavirus inli~ctions } interventions for the control of diarrheal diseases among children, rotaxirus and cholera immunization rotavirus gene structure and l'unction relationship between virus from acute gastroenteritis of children and newborn calves prospects for rotavirus vaccines in humans and animals ) extra-intestinal rotavirus infections in children with ilnmunodeficiency epidemiology of rotaviral infections in aduhs airborne survival of rotaviruses and coronaviruses, implications for disease transmission comparison of the airborne survival of calf rotavirus and poliovirus type i (sabin) aerosolized as a mixture effect of relative humidity, atmospheric temperature and suspending medium oll the airborne survival of human rotavirus development of methods to study the survival of airborne viruses reovirus-like agent in stool, association with int:antile diarrhea and development of serological tests rotavirases. in fields calf diarrhea (scours): reproduced with a virus from a field outbreak orbivirus acute gastroenteritis of inl;ancy. lancet i i ) an epidemiological study of rotavirus diarrhea in a cohort o " nigerian infants. incidence of diarrhea in the first two years of life acute diarrhea in adults, a prospective study worldwide opportunities in genetically engineered vaccines epidemiology of rotavirus diarrhea in prospectively monitored american indian population transmission of viral infectious through airborne route cohort study of rotavirus serotype patterns in symptomatic and asymptomatic infections in mexican children we are grateful to the laboratory staff of a -ain, oasis and tawam hospitals for analysis of stool samples initially. the technical assistance of mr. z. babarindae is highly appreciated in carrying out part of this work. we also acknowledge the support of the faculty of medicine and health sciences, united arab emirates university and the ministry of health, united arab emirates. key: cord- -hqs hfa authors: simpson, william m. title: pesticides date: journal: agricultural medicine doi: . / - - - _ sha: doc_id: cord_uid: hqs hfa nan before discussing individual chemicals, a few principles of pesticide poisoning management should be addressed. the most important issue is proper diagnosis. without it, all other interventions are potentially ineffective and possibly harmful. whenever possible, get the label of the suspected poison. it will contain principles of management and contact information for the manufacturer. the local poison control center and the national pesticide telecommunications network ( - - - monday to friday : a.m. to : p.m.) are also available for further advice. if coworkers have not been able to identify the suspect chemical, cooperative extension service agents may also serve as a resource for commonly used chemicals at particular times of the year on specific crops. remember that careful decontamination of the patient is necessary to prevent possible further injury to the patient and possible injury to emergency department staff. physical decontamination by removing clothing that has been in contact with the chemical, washing the skin with soap and water, and copiously irrigating the eyes is important. recent evidence-based position statements from the american academy of clinical toxicology and the european association of poisons centres and clinical toxicologists suggest that gastric lavage, activated charcoal, cathartics, and ipecac should not be used routinely in poisoned patients. they can be considered within minutes of presentation if a potentially life-threatening amount of poison has been ingested. even in this circumstance, contraindications exist for the use of each: lavage is contraindicated in hydrocarbon ingestion; cathartic in volume depletion, hypotension, electrolyte imbalance, or ingestion of a corrosive substance; activated charcoal in an unprotected airway, a nonintact gastrointestinal (gi) tract or hydrocarbon ingestion; and ipecac in a nonalert patient or with ingestion of a hydrocarbon or corrosive substance ( ) . the most widely used pesticides in the world, herbicides are designed to kill plants and attack plant metabolic pathways that do not exist in humans and other animals. therefore, in general, they have relatively low animal toxicity. there are hundreds of herbicides and herbicide mixtures on the market in the united states and throughout the world. seven of the top pesticide active ingredients (by amount used) are herbicides. chlorophenoxy herbicides are plant growth regulators. they are commonly used for broadleaf weed control on cereal crops and pastures. common chlorophenoxy herbicides include , -d; dicamba; and silvex. many products available to consumers include a mixture of salts in a petroleum base. most toxicity from contact with skin or eyes or ingestion involves mucous membrane irritation. very high dose exposure may result in neurological symptoms including muscle twitching, seizures, and coma. renal and hepatic dysfunction may occur with large ingestions. long-term health effects of low to moderate exposure include alleged, but not confirmed, carcinogenicity, teratogenicity, and reproductive abnormalities. although no specific antidote is known, alkaline diuresis has been reported to be of value in severe overdose. otherwise, aggressive supportive care including protection of the airway, correction of hypotension, and treatment of arrhythmias, hyperthermia, and seizures may be required ( ) . atrazine and glyphosate, triazine, and phosphonate herbicides are also widely used for weed control. glyphosate was developed specifically as a much safer alternative to paraquat (discussed in a subsequent paragraph). mucous membrane irritation is the most common adverse reaction to exposure to these chemicals and their many relatives. gastrointestinal tract erosions were the primary adverse events in large-volume ingestions (all accidental or intentional), but renal, hepatic, central nervous system, and pulmonary involvement was sometimes noted. since no antidote is known, supportive care is also indicated for these groups of agents ( , ) . carbamate herbicides, unlike carbamate insecticides, do not produce inhibition of cholinesterase enzymes or the "all faucets on" cholinergic syndrome. toxicity is uncommon. common generic names for carbamate herbicides include asulam, terbucarb, butylate, pebulate, triallate, and thiobencarb. mucous membrane irritation is the most common adverse effect. after removal of the chemical by soap and water, flushing the eyes, and increased fluid intake, treatment is supportive. urea-substituted herbicides are photosynthesis inhibitors, mainly used for weed control in noncrop areas. chemicals in this class have names ending in "-uron" or "-oron"-e.g., chlorimuron, diuron, siduron, tebuthioron, and tetrafluoron. urea-substituted herbicides have low systemic toxicity based on animal feeding studies; they may, however, produce methemoglobinemia with heavy ingestion. methemoglobin and sulfhemoglobin levels should be measured in patients with dyspnea or cyanosis and a history of urea-substituted herbicide ingestion. otherwise treatment of these ingestions is decontamination and supportive care. the most dangerous group of herbicides is the bipyridyls. paraquat is the most important of the bipyridyl group. others in the group include diquat, chlormequat, and morfamquat. bypyridyls exert their herbicidal activity by interfering with reduction of nicotinamide adenine dinucleotide phosphate (nadp) to reduced nicotinamide adenine dinucleotide phosphate (nadph) during photosynthesis, producing superoxide, singlet oxygen, and hydroxyl and peroxide radicals. this eventually destroys lipid cell membranes, including those in the lungs, leading to late and irreversible pulmonary fibrosis. major local effects of paraquat are due to its caustic properties. corneal ulceration has been reported after paraquat concentrate was splashed in the eyes. gastrointestinal tract ulceration including esophageal ulceration with perforation has occurred. after ingestion of > mg/kg of paraquat concentrate, pulmonary, cardiac, renal, and hepatic failure can occur within hours. ingestion of ml/kg or more may cause renal failure, resulting in impaired paraquat excretion and higher serum concentrations. pulmonary involvement is the major target of ingested paraquat with an adult respiratory distress syndrome (ards)-like syndrome developing to days after ingestion, progressing to pulmonary fibrosis in a few days. treatment of paraquat ingestion is aimed at several points along the toxicity pathway-removing toxin from the gi tract, increasing excretion from the blood, and preventing pulmonary damage with anti-inflammatory agents. cautious aspiration with a nasogastric tube is appropriate if the patient presents within the first hour after ingestion. because of the possibility of severe toxicity, some authorities still recommend activated charcoal ( to g/kg) if the patient is seen within to hours, repeated hours later. hemodialysis is effective for removing paraquat from the blood. pulmonary damage is increased by oxygen supplementation, so low-oxygen breathing mixtures are recommended. immunosuppression has been attempted with corticosteroids and cyclophosphamide or other similar agents, with limited success. deferoxamine and n-acetylcysteine have been used as antioxidants. prospective studies supporting immunosuppressive and antioxidant therapies are lacking. diquat is felt to have much less pulmonary toxicity, but pulmonary fibrosis may also occur, especially if oxygen supplementation is used. chlormequat toxicity resembles organophosphate toxicity but should not be treated as such (see the discussion of organophosphate pesticides in the next section). treatment is by gi decontamination and supportive care. morfamquat is rarely used. no human or animal toxicity has been reported with morfamquat, but poisoning with the chemical should probably be treated initially as a paraquat poisoning ( ). organophosphates are still the most widely used insecticides in the united states and the world, but botanical insecticides and insect growth regulators are becoming much more widely used, due to their lower toxicity. also included in this category are the organochlorines (such as ddt), the carbamates, and insect repellants (deet and p-dichlorobenzene). organophosphates (ops) are the most common cause of insecticide poisoning and cause a few deaths each year in the united states. ops are used for suicide in both the united states and particularly in the third world, where more than , people per year are estimated (by the world health organization) to take their own lives using this group of chemicals. organophosphates are so widely used because of their effectiveness against a wide variety of insects and their lack of persistence in the environment (compared to organochlorines). the toxicity of ops varies greatly-a drop of the op nerve agents vx, soman, or sarin may be lethal, while malathion has an oral median lethal dose (ld ) of approximately g/kg. most of the ops are rapidly absorbed by all routes. they may be classified as direct (the nerve gases) or indirect (most commercially used crop, animal, and home products) cholinesterase inhibitors. metabolism, primarily by the cyp system, is required to activate the indirect inhibitors. direct inhibitors may have almost immediate effects, or up to to hours delay after dermal absorption. indirect inhibitors may not produce symptoms until to hours after exposure. the toxicologic effects of ops are almost entirely due to inhibition of acetylcholinesterase in the nervous system, which causes acetylcholine to accumulate in the synapses and myoneural junctions. muscarinic, central nervous system, and nicotinic effects are produced as outlined in table . , usually in that order. the most common clinical presentation is a patient with an odor similar to garlic, with miosis, increased airways secretion, lacrimation, bradycardia, and gi complaints ( ). this constellation of findings should be managed as op poisoning until proven otherwise ( ) . serum and red blood cell (rbc) cholinesterase levels should be obtained early, but therapy should not be delayed pending laboratory confirmation. treatment should include attention to the airway and adequate oxygenation with atropine administered until secretions dry. the initial dose of atropine should be to mg for adults and . mg/kg for children, administered intravenously if possible, and repeated every to minutes until signs of atropinization develop (flushing, drying of secretions, and dilation of pupils, if they were miotic at presentation). atropine may be required for hours and should be tapered, rather that abruptly stopped. pralidoxine ( -pam) is a specific op antidote. it should be administered as soon as possible in all ( , ) . carbamates are also cholinesterase inhibitors, producing the syndrome of cholinergic crisis as described for ops. the syndrome is of shorter duration and more benign than with ops because carbamates dissociate from the cholinesterase much more readily than ops, producing a reversible inhibition. carbamates also poorly penetrate the central nervous system (cns), rarely producing seizures, ataxia, and central depression of the respiratory and circulatory centers. red blood cell and serum cholinesterase levels return to normal within hours of exposure. treatment of carbamate poisoning is also with atropine (in doses identical to those used for ops but for only to hours because of the shorter duration of enzyme inhibition) and oxygen supplementation. pralidoxime is not indicated in pure carbamate poisoning, but if the poison is not known for certain and cholinergic symptoms exist, it can be used, pending identification of the poison. because of their persistence in the environment, organochlorine insecticides are in limited use in the united states. they are, however, used around the world in mosquito control. lindane is still used in the united states as a general garden insecticide, for control of ticks, scabies, and lice and for extermination of powderpost beetles. it is absorbed by inhalation and ingestion and less well by dermal contact, unless the skin is abraded or treated repeatedly. lindane interferes with normal nerve impulse transmission by disruption of sodium and potassium channels in the axon membrane, leading to multiple action potentials for each stimulus. clinically this may result in confusion, apprehension, tremors, muscle twitching, paresthesias, dizziness, seizures, or coma-usually in the face of a history of repeated treatment for scabies or lice. wheezing, rales, or cyanosis may be found if hydrocarbon (a frequent vehicle) aspiration has occurred. diagnosis is based on a history of exposure or intentional ingestion with physical manifestations of cns hyperexcitability. treatment is decontamination with supportive and symptomatic care. seizures may require lorazepam or diazepam. arrhythmias should be treated with lidocaine. commonly used botanical insecticides include pyrethrum, nicotine, rotenone, and bacillus thuringiensis. other botanicals are used in small quantities but are rarely associated with adverse health effects. pyrethrum is the oleoresin extract of dried chrysanthemum flowers. it contains about % active insecticidal ingredients known as pyrethrins. synthetic derivatives of these compounds, called pyrethroids, are much more widely used today. most insecticides containing pyrethroids also contain piperonyl butoxide, a synergist that increases their effectiveness by retarding enzymatic degradation of the active ingredient. pyrethrum-based insecticides are considered to have low toxicity, but they can produce nausea, vomiting, diarrhea, tremors, muscle weakness, and paresthesias. very high levels of exposure can produce temporary paralysis and respiratory failure. treatment is supportive. allergic reactions to the pyrethroids are more common, with about % of patients sensitive to ragweed, and cross-reacting to pyrethrum. pyrethrum and the pyrethroids are well absorbed from the gi tract and minimally absorbed from dermal exposure. they are rapidly metabolized by the liver, leading to their relative lack of systemic toxicity in humans. persons exposed to prolonged contact with high concentrations of pyrethroids report paresthesias in unprotected skin. vitamin e oil has been reported to relieve these paresthesias, by an unknown mechanism. otherwise treatment of toxicity is symptomatic and supportive. allergic symptoms are treated as with other allergens, by avoidance and antihistamines for mild symptoms, and corticosteroids and epinephrine for severe bronchospasm ( ) . nicotine, usually derived from tobacco, was used as an insecticide in the past. now rarely used, most nicotine poisoning is as a result of ingestion of tobacco products or incorrect use of nicotine patches, gum, or nasal sprays. decontamination is the treatment of choice. care is supportive, since there is no specific antidote for nicotine. severe hypersecretion or bradycardia may be treated with atropine. rotenone, prepared from the roots of derris, lonchocarpus, and tephrosia plants, is used as a household and horticultural insecticide. piperonyl butoxide is also used as a synergist with this compound. toxic to fish, bird, and insect nervous systems, it has produced little human toxicity in decades of use. however, fresh derris root from malaya has been used for suicides. numbness of mucous membranes has been reported in exposed workers, along with dermatitis and respiratory tract irritation. treatment of these symptoms is with decontamination and supportive care. several subspecies of bacillus thuringiensis (bt) are pathogenic to some insects. the product is used both as a spray to be applied to certain food crops and, incorporated into the genetic material of certain plants as a "builtin" insecticide. infections of humans with these organisms is extremely rare. one volunteer ingesting a bt variety not used as a pesticide developed fever and gi symptoms. a single corneal ulcer has been associated with a splash of bt suspension in the eye. the gi symptoms resolved spontaneously; the ulcer resolved with antibiotic treatment ( ) . insect repellants are intended for human use and are therefore designed to be nontoxic in routine use. two insect repellants have produced poisoning syndromes: deet (n,n-diethyltoluamide) and p-dichlorobenzene. deet is minimally absorbed through the skin and is rapidly eliminated, primarily in the urine. excessive use of high concentrations of this compound has been associated with a idiopathic toxic encephalopathy, particularly in girls and female infants. symptoms may include lethargy, anxiety, opisthotonos, athetosis, ataxia, seizures, and coma. ingestion of ml of high concentration deet ( % to %) has produced coma, seizures, and hypotension within an hour of ingestion and death in at least two cases. irritant contact dermatitis and conjunctivitis have also been reported, as has an anaphylactic reaction in one case. there are no characteristic physical findings. treatment is symptomatic and supportive. originally used as a moth repellant and insecticide, p-dichlorobenzene is now more commonly used as a deodorizer. ingestion is fairly common when children eat a part of a deodorant cake in a toilet bowl or diaper pail. it is a mucous membrane irritant and can produce allergic symptoms. massive ingestions may produce tremors and hepatic or renal injury. there are no characteristic features on physical examination or laboratory studies. diagnosis is by history of ingestion, and treatment is supportive. widely used in industry, agriculture, home, and garden, fungicides are used for many purposes-protection of seed grain during storage, transport, and germination; protection of crops, seedlings, and grasses in the field, in storage, and during shipment; suppression of mold; control of slime in paper processing, and protection of carpets and fabrics. fungicides, used properly, rarely cause severe poisonings. most have inherently low mammalian toxicity and are absorbed poorly (at least partly because they are formulated as suspensions of wettable powders or granules). most are applied using methods that intensively expose only a few individuals. irritant injuries to skin and mucous membranes are relatively common in heavily exposed individuals, however ( ) . of the substituted benzene herbicides, only hexachlorobenzene has produced systemic toxicity. this occurred when hexachlorobenzene-treated seed wheat was used instead for human consumption. in years, approximately persons developed porphyria due to impaired hemoglobin synthesis. most affected individuals recovered, but some infants nursed by affected mothers died. thiocarbamates, unlike the n-methyl carbamates, have little insecticide activity. instead they are used to protect seeds, turf, ornamentals, vegetables, and fruit from fungi. bisdithiocarbamates, represented by thiram, are structurally similar to disulfuram. with heavy exposure an antabuse-like reaction can be produced if alcohol is ingested subsequently. this reaction is characterized by flushing, sweating, headache, tachycardia, and hypotension. other thiocarbamates-ziram, ferbam, and metam-sodium-should theoretically predispose to the antabuse reaction, but no occurrences have been reported. metam-sodium decomposition in water yields methyl isothiocyanate, a gas that is extremely irritating to mucous membranes. inhalation of the gas may cause pulmonary edema. metam-sodium is considered a fumigant and should be used in outdoor settings only. persons caring for a victim with metam-sodium ingestion should avoid inhalation of evolved gas. treatment of exposure is with skin and gi decontamination, oxygen supplementation, fluid support, and avoidance of alcohol. ethylene bisdithiocarbamates (ebdc compounds) are another group of fungicides that may irritate skin, respiratory tract, and eyes. maneb, zineb, nabam, and mancozeb represent this class. treatment of the irritant effects of these chemicals is by decontamination. thiophthalimides, represented by captan, captafol, and folpet, are agents used to protect seed, field crops, and stored produce. all of these fungicides are moderately irritating to the skin, eyes, and respiratory tract. they may produce skin sensitization. no systemic poisonings have been reported with these chemicals. copper compounds, both inorganic and organic, are irritating to skin, respiratory tract, and eyes. soluble copper salts, such as copper sulfate and acetate, are corrosive to mucous membranes and the cornea. systemic toxicity is low, probably due to limited solubility and absorption. treatment of poisoning is with gi and skin decontamination. ophthalmologic consultation should be obtained if eye irritation persists after flushing the eyes with saline. intentional ingestions of large volumes of these compounds may result in hemolysis with circulatory collapse and shock, with renal and hepatic failure. in these severe cases, fluid replacement, alkalinization of the urine, chelating agents, and hemodialysis may be required. organomercury compounds have been used primarily as seed protectants. toxicity has occurred primarily when methyl mercury-treated grain intended for planting was consumed in food. poisonings have also occurred from eating meat from animals fed mercury-treated seed. organic mercury is efficiently absorbed from the gut and is concentrated in the nervous system and red cells. early symptoms of mercury poisoning are metallic taste, distal paresthesias, tremor, headache, and fatigue. further symptoms target the cns with incoordination, slurred speech, spasticity, rigidity, and decline in mental status. treatment is by skin and gi decontamination and chelation. cadmium has been used to treat fungal diseases of turf and bark of orchard trees. cadmium salts and oxides are very irritating to mucous membranes of the respiratory and gi tracts. inhaled cadmium dust or fumes can produce a mild, self-limited respiratory illness with fever, cough, and malaise, similar to metal fume fever. more severe symptoms with labored breathing, chest pain, and hemorrhagic pulmonary edema are associated with heavier exposure and resemble chemical pneumonitis. cadmium ingestion may produce severe nausea, vomiting, diarrhea, abdominal pain, and tenesmus. chronic obstructive pulmonary disease (copd), renal and hepatic injury, and pathological fractures have been associated with chronic cadmium exposure. treatment is skin and gi decontamination, respiratory support, and chelation therapy (for severe, acute poisoning, though the possibility of inducing renal failure with a large load of cadmium exists). a long list of miscellaneous organic fungicides is in use in many crop, ornamental, and turf applications. reports of adverse effects on humans are rare or absent entirely. as with all pesticides, following label directions for use is the key to prevention of adverse events, even with these low-risk chemicals. rodenticides are designed to kill nuisance rodents such as rats, mice, moles, voles, ground squirrels, gophers, and prairie dogs. these animals may damage crops in the field or in storage and can transmit disease to humans and other animals through their droppings or bites. a wide variety of organic and inorganic chemicals have been used to control rodents. plant-derived materials such as strychnine and red squill or inorganic compounds such as thallium or arsenic trioxide were among chemicals used early for rodent control. newer agents tend to be synthetic organic compounds. all pose particular risks for accidental poisonings. since these agents are designed to kill mammals, their toxicity is often similar for the target rodents and for humans. also, since rodents often share environments with humans and other mammals, the risk of accidental exposure to the rodenticide is high because of their placement in those environments. as rodents have become resistant to some chemicals, more toxic chemicals have been developed, exposing those applying them and those living in areas where they are used to increased risk of toxicity. there are over trade name rodenticides in the united states alone, many with very similar names. while important for all poisonings, in rodenticide poisoning, having the label to guide therapy is critical. long-acting anticoagulants are responsible for nearly % of human rodenticide exposures reported in the united states. introduced in the s, they have essentially replaced warfarin-based products. they have the same mechanism of action as warfarin but are more potent and have longer halflives. they are effective in a single feeding (or a limited number of feedings) and in animals that have developed resistance to the older anticoagulants. treatment of superwarfarin ingestion depends on the dose. a child who ingests a few pellets or grains of the material can be observed at home for the development of bleeding. a person with a bleeding disorder or who takes an anticoagulant is at much greater risk of excess bleeding, even with a small exposure. patients with large ingestions (> . mg/kg) should have gastric decontamination if they are seen within an hour or two of the ingestion. if there has been a longer delay, activated charcoal is indicated. prothrombin time (pt) and partial thromboplastin time (ptt) should be measured at and hours after a significant ingestion. if any value is elevated, phytonadione (vitamin k ) should be started ( to mg for children and to mg for adults) by subcutaneous injection and repeated as necessary. critically ill adults can be given to mg via slow intravenous infusion ( . mg/min). the pt and ptt should be checked every hours until stable and then every hours. once the pt and ptt are stable, the phytonadione may be switched to the oral form ( to mg daily for adults, to mg for children), tapering the dose as the pt levels decline to normal (over a period sometimes as long as months). warfarin-based products are still available, but single exposures, unless large amounts (> . mg/kg) are ingested, can be observed without therapy. recent large exposures should be treated with activated charcoal. the pt and ptt should be measured at and hours. if the pt is two times normal or more, phytonadione should be given ( to mg for children, mg for adults orally or intramuscularly and repeated as necessary. the pt should be measured every hours until stable, then every hours until normalized ( ) . bromethalin, a relatively new rodenticide introduced in , is a neurotoxin that produces its effect by uncoupling mitochondrial oxidative phosphorylation. this results in increased intracranial pressure, decreased nerve impulse conduction, paralysis, and eventual death. no human exposures have been reported. its effectiveness as a rodenticide is based on the rodent's consuming a relatively larger dose per kilogram than other larger animals. there is no antidote, so treatment of poisoning would be symptomatic and supportive. cholecalciferol (vitamin d ) takes advantage of the fact that rodents are sensitive to small percentage changes in calcium levels in their blood. cholecalciferol increases serum calcium by mobilizing calcium from bone, resulting in calcium deposition in tissues and nerve and muscle dysfunction and cardiac dysrhythmias. ingestion of several bait pellets or treated seeds should not be toxic, and no treatment is necessary. larger ingestions should be treated with gastric lavage if recognized early and activated charcoal in several doses if after to hours of ingestion. serum calcium should be checked at and hours and treatment initiated if hypercalcemia develops. forced diuresis with furosemide and a low-calcium diet should be initiated along with prednisone ( to mg every hours). calcitonin and/or mithramycin may be necessary for patients unresponsive to above measures. red squill is a botanic rodenticide derived from the red sea onion (urginea maritima). it contains two cardiac glycosides that produce effects similar to digitalis. treatment of ingestion is the same as for digitalis toxicity, including the use of digibind. strychnine is another botanical, found in seeds of strychnos nux-vomica, a tree native to india. used in germany in the th century as a poison for rats and other animals, it is still available in many rodenticides. it is a neurotoxin, producing twitching of facial (risus sardonicus) and neck muscles, reflex excitability and generalized seizures. treatment should include activated charcoal and anticonvulsants (diazepam, phenobarbital, or phenytoin if unresponsive to diazepam). stimulation of the patient should be minimized; respiratory support including intubation and mechanical ventilation may be required. thallium rodenticides are not used in the united states, but are available around the world. treatment of poisoning is difficult. gastric decontamination should be attempted with lavage and activated charcoal. fluid support with potassium chloride theoretically displaces thallium and increases its excretion. zinc and aluminum phosphides are used to protect stored grains from rodents and other pests. on contact with moisture, phosphides release phosphine gas, which is the primary cause of toxicity. oral exposures to phosphides occur as a result of intentional ingestion for suicidal purposes. phosphine inhibits oxidative phosphorylation, leading to cell death, manifested by severe gi irritation, hypotension, and cardiac and respiratory dysfunction. management is by activated charcoal and gastric lavage. intragastric sodium bicarbonate and/or potassium permanganate have been suggested to decrease phosphine gas release. oxygen should be supplemented ( % via rebreather). treatment is otherwise symptomatic and supportive ( ) . the fifth edition of recognition and management of pesticide poisoning, edited by drs. routt reigart and james roberts of the medical university of south carolina, contains a table that lists manifestations caused by specific pesticides, which may be useful in evaluating possible pesticide exposures and toxicities. the entire textbook is available on the environmental protection agency web site at http://www.epa.gov/pesticides/safety/healthcare/ handbook.htm (see "index of signs and symptoms" or pages to ) by request from the environmental protection agency, office of prevention, pesticides, and toxic substances at - - . the liquids in which pesticides are dissolved and the solids on which they are adsorbed are chosen by the manufacturers to make handling and application easy and to achieve maximal stability and effectiveness of the active ingredient. the most commonly used solvents are petroleum distillates. the petroleum distillate may produce toxicities in itself in large-volume ingestions. most adjuvants (emulsifiers, penetrants, and safeners) are potentially skin and eye irritants but with very low or no systemic toxicity. about pesticides. u.s. epa - pesticide market estimates european association of poisons centers and clinical toxicologists. position statements herbicide safety relative to common targets in plants and mammals safety evaluation and risk assessment of the herbicide roundup and its active ingredient, glyphosate, for humans acute poisoning with a glyphosate-surfactant herbicide: a review of cases paraquat and the bipyridyl herbicides the role of oximes in the management of organophosphorus pesticide poisoning diagnosis in an acute organophosphate poisoning: report of three interesting cases and review of the literature the organophospates and other insecticides pyrethroid insecticides: poisoning syndromes, synergies, and therapy skin reactions to pesticides anticoagulant rodenticides non-anticoagulant rodenticides key: cord- -dyjpfvvf authors: gardner, anthony luzzatto title: foreign aid and humanitarian assistance date: - - journal: stars with stripes doi: . / - - - - _ sha: doc_id: cord_uid: dyjpfvvf together the us and eu provide two-thirds of global humanitarian assistance for the alleviation of emergencies arising from natural and man-made disasters and % of global foreign aid for longer-term development assistance programs. it is therefore vital that they continue their close partnership to ensure their dollars and euros are spent as effectively as possible in an era of increasingly tight budgetary constraints. the outbreak of ebola in west africa in is a good example of how the us and the eu successfully addressed (albeit belatedly) a major health crisis that could have turned into a global pandemic. in many areas in africa, they are collaborating closely on the foundation of shared priorities, including on food security, resilience, and electrification. they are also among the largest donors to the global fund to fight hiv/aids, tuberculosis, and malaria and to the global alliance for vaccines and immunisation. us and the eu to undertake repeatedly costly emergency measures to respond to disaster. indeed, some short-term solutions can be counterproductive: the dumping of food aid in local markets to address urgent food needs, for example, can undermine the ability of poor countries to develop sustainable farms and functioning markets. during my diplomatic post, i witnessed first-hand how the us and the eu work together in several areas of both humanitarian assistance and foreign aid. there are notable differences in how they pursue their agenda, including their degree of willingness to partner with the private sector and the military, but these have not prevented frequent and deep collaboration. in the fall of , my wife and i found ourselves in a large, abandoned field in downtown brussels to visit the training site of médecins sans frontières (msf), also known as doctors without borders, a non-profit and non-governmental international medical organization of french origin best known for its projects in conflict zones and in countries affected by endemic diseases. we were impressed by the explanations about how the modular kits in the large containers lying in a storeroom could be rapidly shipped to humanitarian disaster zones around the world and assembled on site within hours to provide functioning power generators, water purification, lodging for aid workers, medical treatment, and waste disposal. the logistical know-how and deep experience of msf made it the first, and sometimes most significant, responder to major medical emergencies. although the logistics were interesting, what really grabbed our attention was the sight of several of the organization's instructors training staff on how to put on and take off protective clothing to avoid contamination. the eight-piece clothing, entirely covering the human body, looked like a space suit but was more ominous because it was being worn on land to respond to the outbreak of the ebola virus in west africa in march . the scene reminded me of outbreak, a film released in starring many hollywood icons, including dustin hoffman, kevin spacey and morgan freeman. the film was about the public panic and response by military and civilian agencies in the wake of a fictional outbreak of an ebola-like virus in zaire, and later in a small town in california. a reallife outbreak of the ebola virus was ongoing in zaire when the film was released. the film contained exaggerations to enhance its shock value but wasn't too far from fact. we were transfixed by the demonstration. our guide told us that medical staff could only wear the space suit for several hours in real-world conditions on the ground because temperatures inside the suits can easily reach up to degrees centigrade (nearly degrees fahrenheit). the suit takes a long time to put on in order to ensure that the body is entirely protected from contamination. taking off soiled suits requires even longer (up to twenty minutes) because of a meticulous and rigorous twelve-step process that healthcare workers must repeat three or more times per day. it was clear that there is no margin for error. we were also shown disinfection routines, sample containment wards for infected patients, and the incineration units for soiled clothing and used equipment. during the first months following the detection of an ebola outbreak in march, msf was the most effective response of the developed world. msf remained on the ground throughout the crisis, even when staff members contracted the virus and died. on top of this risk of infection, msf workers also faced angry opposition from villagers suspecting that the treatment facilities were spreading the disease. msf had to close one facility in southern guinea after being attacked in april by a stone-throwing mob. villagers later killed eight african members of an msf team trying to raise awareness of ebola in the region. despite these risks, msf had nearly international workers and local employees fighting the outbreak by the time my wife and i were touring the facility in brussels. by contrast, the eu and its member states struggled to come up with a coherent and decisive response in the early months of the crisis. this was disappointing in light of the eu's deep partnership with africa, europe's proximity to the continent and greater vulnerability to a spread of ebola, and the history of france and britain as former colonial powers in guinea and sierra leone. similarly, the initial us response was slow and focused on domestic preparations. it took until the fall of for the us and the eu to respond in a coordinated fashion. our joint response should have been more effective. as i toured the msf facility i recalled how, as a young director for european affairs in the white house in - , i had played a role in the us-eu new transatlantic agenda that had specifically flagged the importance of transatlantic cooperation on infectious diseases: we are committed to develop and implement an effective global early warning system and response network for new and re-emerging communicable diseases such as aids and the ebola virus, and to increase training and professional exchanges in this area. together, we call on other nations to join us in more effectively combating such diseases. we did not make as much progress on this key challenge as we would have liked in the subsequent twenty years. our msf guide explained that an ebola outbreak starts when a human has direct contact with the blood, body fluids, or organs of infected animals, such as bats, chimpanzees, monkeys, or gorillas. the transmission of the virus from that human to other humans occurs through personal direct contact either with the patient's blood or other body fluids (including sweat and saliva) or through contact with objects, such as needles and syringes, that contain these fluids. transmission of the virus often occurs through caregivers such as family members or medical personnel in homes or healthcare environments where infection-control practices are weak. ebola crises, such as the one in zaire that occurred when outbreak was playing in movie theaters, can be amplified by the transmission of the virus in overcrowded hospitals and burial practices in which highly infectious corpses are washed or touched by family and members of the community in a sign of love for the deceased. ebola is a disease from one of the deeper circles of dante's hell. fortunately, it is not transmitted through the air, like influenza or tuberculosis, or transmitted before symptoms appear, like measles or hiv. nonetheless, it can result in terrible consequences for its victims and can spread quickly if not brought under control. in its early phase, victims of ebola can be misdiagnosed because it is relatively rare and because some of the symptoms, including fever, fatigue, muscle pain, and headache, are difficult to distinguish from those of other infectious diseases, such as malaria and typhoid fever. victims often subsequently experience vomiting, diarrhea, rashes, and hemorrhages resulting in internal and/or external bleeding. the dysfunction or collapse of multiple body organs leads to severe injury and often death. the fatality rate varies from to %, depending on the strain. the ebola outbreak in west africa in was first reported by the world health organization on march in a remote, forested region of south-eastern guinea bordering liberia and sierra leone. multiple chains of transmission of the virus had gone unrecognized for months. by the end of the year, the virus had claimed lives and had infected , persons; by march , the numbers were dead and , sick; and by the time the crisis had been brought under control in march , the dead numbered , . the number of infections and deaths far exceeded those in approximately twenty previous outbreaks since the s in central and eastern africa; in each of those outbreaks, the number of reported cases never exceeded . there were many reasons for the severity of the crisis. like the remote areas of central and eastern africa where prior outbreaks occurred, the virus appeared in a remote area of guinea. normally, this might have helped contain the disease, but in an unfortunate twist of geographic fate the region lay at the junction of guinea with sierra leone and liberia where people regularly move across borders. the region's lack of rudimentary public health infrastructure, partly because of its recent history of civil war and violence, and its lack of experience with a previous outbreak of the virus compounded the problem. as the virus spread to urban areas and expanded into an epidemic, the number of cases quickly overwhelmed the capacity of diagnostic and other healthcare facilities. at the onset of the outbreak, there was a very small number of experienced healthcare workers to deal with it, including in europe and the united states. even at msf, involved in most of the prior outbreaks, there were only "veterans." medical teams were simply not prepared to deal with a disease that kills at least % of its patients and for which no treatments existed. had ebola been a first world disease, there would have been a vaccine. but there wasn't because, in the eyes of the major pharmaceutical companies, the numbers of patients are small, and nearly exclusively in the third world. the business case for the recovery of significant upfront research and production costs had simply not been present. some ebola treatment units (etus) were filled beyond capacity, requiring the facilities to turn away people suspected of having the disease, thereby fostering new chains of transmission. one of the critical factors in bringing an ebola outbreak under control-an exhaustive tracing of contacts between victims and others with whom they had been in contact-was absent. moreover, poor infection control in hospitals led to many infections and deaths among healthcare workers and a rapid collapse of the region's healthcare system. the control of other devastating viruses, such as malaria, and even the provision of routine medical services declined. i had seen reports from our embassies that people who collapsed from heart attacks were sometimes left to die because no one wanted to touch them for fear that they had contracted ebola. children started missing out on education because of school closures. generalized fear and even panic threatened to devastate the region's economies, especially by reducing agricultural output and trade, while driving up prices. my friend and former colleague samantha power, us ambassador to the united nations during president obama's second term, visited brussels several times to brief and coordinate with eu officials on the ebola crisis after her trips to the infected region. on one of those trips, she relayed reports that farming communities were "eating their seeds," indicating not only that current harvests were poor but warning that future harvests and even food security were in danger. a total collapse of civil society was imminent as governments lost control of the situation. in the early days of the crisis, the eu allocated extra emergency funding to msf and other humanitarian organizations, such as the red cross and red crescent, the international medical corps, save the children and the international rescue committee. the aid contributed to the faster deployment of doctors and nurses and the purchase of diagnostic equipment and medical supplies. disaster assistance response teams of the us agency for international development (usaid) and teams from the atlanta-based centers for disease control and protection (cdc) were deployed to the region to carry out an assessment of what needed to be done. the us airlifted significant amounts of personal protective gear, generators, and medical equipment. by early summer, it seemed that wiring funds and providing assistance from a distance would be enough as the number of reported cases leveled off and then dropped, suggesting the outbreak could be contained as in the previously reported outbreaks in africa since . instead, the virus spread. by late july it reached, for the first time in history, densely populated metropolitan areas, not only in the three countries of origin but further afield. a traveler with ebola had flown from monrovia, liberia, to lagos, nigeria, africa's most populous city (with million inhabitants) where he had contact with multiple people who later contracted the illness. a massive effort by the nigerian government, assisted by the cdc, managed to contain the outbreak to just cases in two cities. by early august, the world health organization categorized the outbreak as a "public health emergency of international concern," a declaration that caught media headlines and unlocked significant new funding. claus sorensen, an old friend and the director-general of european civil protection and humanitarian aid operations (echo), conceded that in an ebola crisis "speed is of the essence, and there is a feeling that all of us have been behind the curve." the decisive factor in galvanizing action in the eu and the us was a series of shocking announcements regarding the ebola infections outside africa. in late july and early august, two us citizens, including a doctor with samaritan's purse, were repatriated to atlanta, where they (successfully) underwent treatment for ebola in a specialized isolation ward in emory university hospital. they were the first two patients ever to receive such treatment in the united states. in early october, two spanish priests died in madrid after contracting the virus in sierra leone; a nurse who had treated them also tested positive (but later recovered), the first person to have been infected outside of west africa. shortly thereafter a liberian national who had recently returned from liberia to the united states died of ebola in a dallas hospital. the nurses who had cared for him contracted the virus but recovered. on top of the shock of ebola infections appearing in europe and the united states, public health authorities on both sides of the atlantic conducted modeling about the potential spread of the virus. the results were sobering: in september, the cdc estimated that approximately , ebola cases ( . million cases when corrected for under-reporting) could occur in west africa by january , , if approximately % of all persons with new cases were not effectively isolated. the world health organization projected that new ebola cases could reach , per week by december. when respondents to a telephone poll were asked in october whether they were concerned that there would be a large outbreak of ebola in the united states within the next months, % reported that they were "very" or "somewhat" concerned. the initial us response (before october) was largely domestic because the country was not prepared for an epidemic of this magnitude. when the crisis broke out, only one facility in the united states (the cdc laboratory in atlanta) was qualified to test for ebola and there were only three facilities that could treat ebola patients; by january there were laboratories in states that could do so and by october there were treatment centers in states. during that period, , healthcare workers received instruction on how to identify, isolate, diagnose, and care for patients under investigation for ebola. the cdc and customs and border protection implemented intensive screening of air passengers arriving from west africa. there was significant public support for cutting off all air links with west africa and quarantining anyone who had recently been in the region. while generalized measures of this kind were avoided, the defense department did impose a -day quarantine for all personnel returning from ebola-affected areas, regardless of risk, because of political rather than scientific considerations. the presidential commission established to review the government's response to the ebola crisis was scathing in its final report. it criticized federal, state, and local unpreparedness to cope with the threat of an epidemic and the government's focus on the political implications of public reactions rather than on the underlying health concerns. by the end of the year, the us government's response started shifting decisively toward attacking ebola at its source. president obama was clear about the stakes: this is an epidemic that is not just a threat to regional security -it's a potential threat to global security if these countries break down, if their economies break down, if people panic. that has profound effects on all of us, even if we are not directly contracting the disease. the united states and the eu (as well as its member states), together and in parallel, supported by the african union and several african countries, finally undertook a major and highly successful effort to bring the crisis under control. washington focused on liberia, while paris focused on guinea and london on sierra leone. speaking at the cdc in mid-september, president obama announced that the us military had recently dispatched personnel to monrovia to establish a base under the control of us africa command. its main objectives were to build etus, including new isolation spaces and more than beds, and to recruit and train more than medical personnel to staff them. the department of defense built seven mobile laboratories in west africa that cut turn-around times for testing blood samples from five to seven days to between three and five hours, thereby freeing up bed space in overcrowded clinics and hospitals. the uk and france quickly followed the us example with similar military missions of their own to sierra leone and guinea to build hospitals and diagnostic centers; our experts often singled out the uk effort as being rapid and effective in bringing down new infection rates. in addition to these efforts, thousands of cdc employees and government-supported civilians were deployed in all of west africa, partnering with national governments to train healthcare workers, treat patients, staff field laboratories, trace contacts of patients to identify chains of transmission, develop border and airport-screening programs, promote safe burials, and educate communities. the united states was to airlift more than metric tons of personal protective equipment and other medical and relief supplies during the subsequent months. in the fall of , the white house announced major efforts to accelerate the development of vaccines (to prevent new infections) and therapeutics (to treat those already infected). and in december the us congress overwhelmingly supported legislation providing $ . billion in emergency funding for the cdc and other health services, the state department, and usaid; much of this funding was earmarked for the prevention, detection, and response to the ebola crisis in west africa, as well for efforts to assist in the region's recovery. the eu made an important contribution as a coordinator and donor. the european centre for disease prevention and control, headquartered in sweden, coordinates the work of health experts in different countries but does not have its own emergency-response teams. similarly, eu member states, rather than the european commission, dispose of their own medical personnel, hospitals, labs, and stock of specialized equipment. but as the only european body with a global picture of the fast-moving epidemic, the european commission successfully played the role of "traffic cop" to ensure that europe's response was consistent and effective. that role included the identification of the type and destination of emergency supplies for west africa, providing a clearinghouse of information about the crisis and the disease, and the creation of a list of available member state assets relevant for the treatment of ebola in europe. the european commission also played a key role in identifying european assets and trained personnel that could be deployed for the medical evacuation of patients back to europe and in negotiating a us-eu agreement about when us and european patients could call on their respective emergency medivac "air bridges." ensuring that international healthcare workers could be airlifted to equipped facilities in europe within hours was critical to the ability of the us and eu to recruit such workers. in october, the eu appointed christos stylianides, commissioner for humanitarian aid and crisis management, as eu ebola coordinator to ensure that the eu institutions and member states acted in a coordinated manner with each other and with international partners. in addition to the directorate-general for humanitarian aid, other commission departments were involved in the response to the ebola crisis: these were principally the directorate-general for international cooperation and development (devco), the counterpart to usaid and responsible for foreign aid, and the european external action service (the eu's diplomatic service with delegations in most countries around the world). the role of other departments also had to be coordinated: the directorate-general for health identified facilities in member states that were willing and able to accept ebola patients; the directorate-general for internal affairs (including justice and law enforcement) coordinated entry and exit procedures at airports in case of travelers suspected of having ebola; and the directorategeneral for research worked to promote vaccines and therapies. the eu was also an important donor to help combat ebola in west africa. the european commission and eu member states contributed almost e billion (without counting the value of in-kind contributions from many member states such as personal protective equipment, vehicles, and field hospitals). of this total, the european commission contributed e million out of the eu budget for emergency measures, financial support for the african union's own medical mission to the region, and long-term relief (such as budgetary support for the restoration of vital public services and the strengthening of food security). moreover, the european commission announced substantial funding from the eu budget to promote projects on ebola research, including immediate largescale clinical trials of potential vaccines and tests of existing and novel compounds to treat ebola. the european commission also partnered with the european pharmaceutical industry in launching a e million longer-term research program involving clinical trials of new ebola vaccines, the development of fast diagnostic tests, and new approaches to manufacture, store and transport vaccines. in summary, while the us and eu were both slow in responding to the ebola crisis, by the fall of they had significantly scaled up their efforts and were working very closely together to provide an effective series of measures that brought the crisis under control by the summer of . the lessons learned from that dramatic experience-including european commission coordination of eu member state activities and intensive us-eu coordination to combat epidemics-are important for coping with future humanitarian disasters. the lessons enabled the us and eu to respond to an outbreak of ebola in the democratic republic of congo (drc) in may , the second worst in history and the longest and deadliest of the nation's nine previous outbreaks. us-eu cooperation will be equally important in dealing with the outbreak of coronavirus. while ebola and other epidemics are just one area where the us and eu have worked well in humanitarian assistance, they are emblematic of the many other examples of how they are indispensable partners in alleviating suffering around the globe. one example is their delivery of aid to those suffering from the syrian civil war that has displaced over million people and killed , . the war has been catastrophic, but it would have been far worse without us and eu efforts. under the eu's - multi-annual financial plan, the european commission's annual humanitarian assistance budget averaged e billion per year and is projected to rise under the - budget cycle. in addition to the formal budget, the eu has drawn from other sources to spend hundreds of millions of euros annually to respond to unforeseen events and major crises, including the humanitarian disaster caused by the syrian civil war and the refugee crisis in - . several eu member states-especially the uk, germany, and sweden-are generous donors of humanitarian assistance as well. together with the eu, they provide roughly the same amount of funding as the united states ($ billion per year as of ). us funding, largely administered through a specific bureau within usaid (the office of us foreign disaster assistance), has responded to the same emergencies as the eu-not only the ebola outbreak, but also the syrian civil war and many other crises concentrated in the middle east and africa. both the us and the eu contribute significant amounts through united nations agencies such as the un high commission for refugees, unicef, and other non-governmental organizations such as the world food program and the international red cross. the predominance of the us and the eu as humanitarian assistance actors means that their practices shape those of other donors, including states, ngos, and multilateral organizations. when we join forces to minimize overlaps or inconsistent approaches, we ensure that our dollars and euros have maximum impact, leading to real improvements in the lives of millions of people affected by humanitarian assistance. as one study rightly pointed out: failure by these two parties to enhance their cooperation…would result in additional, yet avoidable, human death and suffering…and could lead to increased insecurity and instability across the globe., threatening us and eu strategic interests. us administrations of both political parties have recognized the importance of this partnership and for good reason. the george h. w. bush administration launched an annual strategic dialogue on humanitarian assistance with the eu at senior levels in usaid, the state department and echo, supplemented with regular contacts on the ground among field officers. in the new transatlantic agenda concluded in under the clinton administration, the us and the eu set forth an extensive list of areas where they should work closely, including improving the effectiveness of international humanitarian relief agencies, and urged the creation of joint missions whenever possible, greater operational coordination, staff exchanges, and information sharing. close dialogue has continued since then, despite the turbulence of us-eu relations during the presidency of donald trump. the us and the eu provide an even larger share of total foreign aid than they provide of total humanitarian assistance. the united states is the largest single provider of foreign aid, accounting for one-quarter of the $ billion disbursed worldwide every year. but the eu, together with its member states (especially germany, the united kingdom, and france), provides over half the total foreign aid disbursed. while the us contribution appears generous, it represents only slightly more than % of the us federal budget and about . % of us gdp, far below the equivalent percentages of many eu member states. the us-eu partnership on foreign aid has worked well, in part because the two are the biggest players globally. an even bigger reason for the successful partnership is that they share values and objectives such as the promotion of human rights, democracy, good governance, gender equality, and open markets. nonetheless, their policies occasionally reflect different outlooks and priorities. us foreign aid policy is often shaped by national security concerns, especially during major wars, and devotes significant resources to military and non-military security assistance (concentrated in afghanistan, israel, egypt, and iraq). moreover, us foreign aid is sometimes used as a tool to open global markets to us exports and is often tied to the purchase of us the united nations has urged countries to spend at least . % of their gdp on foreign aid, a target met by sweden, luxembourg, norway, denmark, the netherlands, and the united kingdom. according to an opinion poll conducted in the united states in , americans on average think that % of the federal budget is spent on foreign aid; given this misconception, many believe that the us should reduce its spending (unlike their european counterparts who support giving generously). see bianca dijulio, jamie firth, and mollyann brodie, "data note: americans' views on the u.s. role in global health," kaiser family foundation, january , . https://www.kff.org/globalhealth-policy/poll-finding/data-note-americans-views-on-the-u-s-role-in-global-health/. goods and services (especially food). some us aid is explicitly made conditional on the recipients' agreement to take certain actions. for example, the millennium challenge corporation, a foreign aid agency established by but independent from the us government, provides large five-year grants to countries that meet certain political and economic criteria and sign up to "compacts" detailing the domestic policies they will pursue. by contrast, the eu's commitment to development assistance is grounded in a widely shared feeling among the european public that the eradication of extreme poverty is a moral obligation and an investment in europe's long-term security. unlike the united states, that has the luxury of large oceans on either side, europe is far more exposed to instability on its borders. without development assistance, significant migration flows into europe from northern africa and the eastern mediterranean are certain. while the eu's development assistance is not shaped by military considerations or the desire to promote exports, the eu has recently moved closer to the us view that aid should be subject to strict conditions about the behavior of recipients, especially their willingness to undertake economic reforms. most us presidents have considered foreign aid as an investment in global and us security and prosperity, and a significant pillar of us foreign policy, rather than a gift to undeserving foreign countries. president trump has departed from that consensus by considering foreign aid wasteful and ineffective unless given to allies. in his speech before the un general assembly, president trump made the latter point in stark terms: "moving forward, we are only going to give foreign aid to those who respect us and, frankly, are our friends." his white house now appears to see africa largely as a playground of big-power rivalry, where chinese and russian influence is on the rise. other than as a destination for growing us exports and investment, africa appears to be of little inherent interest. the president's budgets have regularly proposed massive cuts in foreign aid. his budget has called for % cuts in the foreign aid budget-a target that is not only immoral but geo-politically nonsensical in light of the growing influence of china and russia in africa and other parts of the developing world. fortunately, congress has maintained most of the programs, partly in sympathy with the argument that deploying diplomats and development experts today is cheaper than deploying troops tomorrow. in an open letter to congress in , more than retired admirals and generals argued cogently: we know from our service in uniform that many of the crises our nation faces do not have military solutions alone…[the] state department, usaid…and other development agencies are critical to preventing conflict and reducing the need to put our men and women in uniform in harm's way…the military will lead the fight against terrorism on the battlefield, but it needs strong civilian partners in the battle against the drivers of extremism -lack of opportunity, insecurity, injustice and hopelessness. as with humanitarian assistance, the new transatlantic agenda also tried to introduce greater structure around us-eu cooperation on foreign aid, especially in their joint efforts to "help developing countries by all appropriate means in their efforts towards political and economic reforms." but efforts at a structured dialogue suffered from disagreements in other areas and were only revived when the us and eu launched a development dialogue in . although the annual meetings at ministerial level have not always occurred as envisioned by the dialogue, regular meetings at senior levels and continuous technical exchanges between staff, at headquarters and especially in the field, have enabled the parties to exchange information on policies and programs, as well as to promote greater policy consensus and coordination. the us-eu annual summit in that i attended several weeks after i arrived in brussels issued an ambitious set of targets for the parties' development agenda. some of the objectives were aspirational, such as delivering on the "unfinished business" of the millennium development goals, a set of eight extremely ambitious international development goals for (including the eradication of extreme poverty and hunger) that had been established by the united nations in . these goals have been replaced by the un's global goals for sustainable development, an agenda of social and economic development objectives for that the us and the eu support. us-eu cooperation on foreign aid is not always easy because each party has different budgetary cycles, implementation systems, and measures to ensure accountability. much of the "real" day-to-day work occurs in the field in dozens of countries, making coordination from headquarters in washington and brussels rather complex. even when coordination is successful, moreover, it can be overtaken by fast-moving events. representatives of usaid often observed to me that they preferred to deal with eu member states-such as the uk, the netherlands, sweden, and denmark-because they were less bureaucratic and nimbler than the eu. nonetheless, the constant dialogue between the us and the eu has enhanced their mutual trust and the effectiveness of their foreign aid programs. one example is how each party has increasingly relied on the other's geographic expertise: usaid relies on france and the eu in francophone africa where the us has a relatively more modest presence; the eu relies on the united states in the horn of africa where the former lacks the latter's resources and expertise. during my diplomatic mission, usaid and devco evidenced their mutual trust and intent to specialize by signing an agreement enabling each to fund the other's projects. an important by-product of the us-eu dialogue on development is that it has forced each side to coordinate better among its own government departments. in the case of the eu, that means devco, the european external action service and also the directorate-general for neighbourhood and enlargement negotiations (that implements assistance programs in the western balkans, turkey, the former soviet union, and the maghreb). in the case of the united states, that means not only usaid, but also includes the state department and even the defense department, the department of health and human services, the us treasury, and the department of agriculture. this internal coordination can sometimes be more challenging than transatlantic coordination, as i witnessed many times. the us and the eu development dialogue has covered a wide range of topics. one of the areas of focus has been the challenge of how to improve the "resilience" of developing countries. in the development context "resilience" means the ability of people, households, communities, countries, and systems to mitigate, adapt to and recover from shocks and stresses in a manner that reduces chronic vulnerability and facilitates economic growth that is fairly distributed across society. resilience can be strengthened in many ways: for example, with cash transfer programs to provide a safety net to the poorest households in drought-prone areas; by vaccinating livestock and planting crops that are more resistant to pests and drought; through early warning systems and insurance against extreme weather, plagues, and earthquakes; and with budget support for countries to maintain vital state functions, including policing and health care services. the dialogue has also covered topics such as the effectiveness of aid in achieving economic or human development, adaptation to climate change (especially developing countries' implementation of low-carbon growth strategies and adaptation to harsher weather), improving the availability and accessibility of food ("food security"), the interplay between security and development, electrification (with a focus on rural areas in sub-saharan africa), and health. the last four areas merit further elaboration. at the g- summit in l'aquila, italy, members of the g- and other donors, including the eu, pledged $ billion to support food security over a three-year period. that initiative led to the launch at the g- summit at camp david in may of a new alliance for food security and nutrition between the donors and ten african countries suffering chronic food shortages. the purpose of the initiative is to attract private investment in agriculture, to complement public investment and create the right conditions for the recipient countries to increase agricultural productivity, adopt improved production technologies (including improved seed varieties), and improve their post-harvest management practices to reduce their dependency on food imports and food aid. under the "cooperation frameworks" signed with the donor countries, the recipients agree to implement reforms in a wide variety of areas, including infrastructure improvements, regulatory and tax reforms, and easier conditions for the marketing and trade in farm products. another important example of us-eu cooperation to promote food security in the developing world was the agreement by the bill and melinda gates foundation and the european commission to provide $ million each to fund agricultural and climate-change research during - to assist farmers with crop improvement, protection, and management. the us and the eu have both focused on the importance of providing security as a precondition for effective long-term development. their common views have translated into practical consequences on the ground. for example, the eu and the us ambassadors to south sudan, working with the united nations, averted a military confrontation between two tribes a few years after the country achieved its independence in . the lou nuer and murle tribes had been fighting each other for decades over cattle, with revenge killings occurring frequently. the ambassadors traveled together by helicopter to remote and dangerous areas to negotiate with the tribe's leadership and local elders to mediate an end to the impending conflict. as major providers of aid, the eu and especially the us were successful because they insisted that peace was a precondition for continued aid. electrification is another focus of us-eu cooperation on development. two-thirds of the population of sub-saharan africa, around million people, lacks access to power. that number is growing as rapid population growth creates demand that outstrips increased supply from investments in electrification. the remaining one-third cannot consume as much power as it would like because of blackouts and brownouts. in rural areas, the average electrification rate is only %. the main reasons for this situation include droughts that affect hydropower capacity, aging infrastructure and poor maintenance, unreliable fuel supply and inadequate transmission and distribution capacity. lack of electricity has numerous dramatic effects: for example, it stunts industrial growth and agricultural yields, hurts healthcare services (such as hospital care and the delivery of drugs requiring refrigeration), impedes digital connectivity that is increasingly essential to participate in the knowledge economy, and increases the number of premature deaths, especially among women and children, because of household air pollution caused by the use of solid biomass for cooking and of candles and kerosene lamps for indoor lighting. electrifying africa, especially sub-saharan africa, is therefore crucial to progress; at the same time, electrification using cleaner fuel sources, such as natural gas and renewable energies, will be key to avoid major harm to the environment from meeting the energy needs of a rapidly growing population with dirty coal or oil. ensuring that all people in sub-saharan africa have access to electricity by , one of the un's sustainable development goals, will require a major effort by the region's governments and the international community, above all the united states and the european union. according to various estimates, the region will need to increase its electrical capacity by about gigawatts and invest at least $ billion per year to achieve this goal. attracting that investment from the private sector is a huge challenge because almost none of sub-saharan electric utilities are currently financially sustainable due to artificially low tariffs, low operational efficiency due to losses during transmission and distribution, and poor bill collection. wasteful subsidies incentivize inefficient forms of energy, disincentivize maintenance and investment, and overwhelmingly benefit higher income groups. political patronage, corruption, and a poor regulatory environment present further challenges. investments in the electricity sector are overwhelmingly in the traditional fossil fuel sector generating power on the grid rather than in the renewables sector generating power off the grid. the latter, especially in the form of solar photovoltaic, small hydropower and small wind turbines, are especially relevant for the three-fifths of the population that lives in rural areas. even despite ongoing technological improvements that increase efficiency, renewable energy projects require significant upfront capital commitments and high transaction costs relative to the amount of power produced and the return on investment. sub-saharan africa will only be able to substantially increase electrification rates, especially with renewable energy projects in rural areas, through energy sector reform and international public-private partnerships that mobilize private capital. there are dozens of international initiatives originating in asia, the middle east, europe, and the americas to improve access to power in africa. china is increasingly active, including in sub-saharan africa where chinese contractors (the vast majority of them state-owned) were responsible for % of new electrical capacity between and . the us and the eu are working closely to align their initiatives to promote electrification in sub-saharan africa. in , they signed a memorandum of understanding that outlined their cooperation to reduce energy poverty and increase energy access in sub-saharan africa. although the mou is non-binding and does not require either party to make financial commitments, it establishes a structure for cooperation in several areas, including joint financial support, stimulating private sector investment, and the alignment of technical assistance and reform efforts. as of , there were separate initiatives originating from the member states and the eu institutions. while it is understandable that various member states wish to have separate initiatives to promote national political and commercial interests, it appears rather inefficient for the eu institutions (the european commission and the european investment bank) to have numerous ones as well. nonetheless, during the five years ending in , the eu budget alone allocated more than e . billion in grants to support sustainable energy in sub-saharan africa; those grants enabled the private sector to commit several times that amount in equity and debt capital as well. together with the member states, the eu has supported projects that have brought electricity to more than million people in the region. one of the key projects is the european commission's electrification financing initiative (electrifi) to support the adoption of renewable energy, with an emphasis on decentralized energy solutions in rural areas around the developing world, principally in sub-saharan africa. usaid not only assisted the european commission to structure the program but also approved a us investment of e million in electrifi. that investment represented a crucial "seal of approval" that enabled the european commission to access a far larger pool of capital than would otherwise have been possible. electrifi provides financing and technical support, even at an early stage and in partnership with other funders, to enable projects to overcome gaps in available market financing and achieve maturity in order to attract private long-term capital. the united states has also been active in promoting the electrification of sub-saharan africa. power africa, announced by president obama in , is the largest public-private partnership in history, involving many agencies of the us government, african governments, more than memorandum of understanding between the united states and the european union for reducing energy poverty and increasing energy access in sub-saharan africa, signed july , . https://www.usaid.gov/sites/default/files/documents/ /eu% signed% mou% from% july% % .pdf. private sector partners and international organizations like the african development bank and the world bank. power africa was underpinned by the us electrify africa act of , passed with overwhelming bipartisan support to promote african developments, as well as to assist us exports and counter chinese influence. power africa was one of the few obama-era executive decisions that president trump did not cancel upon entering office; indeed, his administration supported it as a model for how governments can leverage private capital to build infrastructure. the aim of the initiative has been to finance by gigawatts of electricity capacity and million new domestic electricity connections, especially from renewable projects in rural areas, by unlocking sub-saharan africa's substantial wind, solar, hydropower, natural gas, and geothermal resources. by the end of , power africa had attracted over $ billion in commitments and had catalyzed about $ billion in investment into power projects and over gigawatts of capacity. these projects connected about million homes and million people. most of these connections are from solar lanterns that power a single light and enable the charging of a mobile phone. as basic as that may sound, even such connections can result in dramatic improvements in livelihood. power africa is moving beyond these connections to include larger, more on-grid power projects using non-renewable sources. in addition to the power sector, both the us and the eu are actively engaged in the promotion of global health. for example, they are the main contributors to the global fund to fight hiv/aids, tuberculosis and malaria and to the global alliance for vaccines and immunisation (gavi). they sit on the governing boards and closely align their policies. founded in as a partnership among governments, nongovernmental organizations, and the private sector, the global fund raises and invests the world's money-about $ billion per year-to support programs in more than countries that combat the three deadliest infectious diseases. the eu (the european commission and eu member states combined) and the united states provide roughly and % of the global fund's financing, respectively. the health programs supported with this money have reduced the number of deaths caused by hiv/aids, tb, and malaria by one-third since and have saved million lives, the majority of these in sub-saharan africa, as of the end of . the global fund has enabled millions to be on antiretroviral therapy and therefore to be spared the death sentence that hiv/aids used to represent. of the million people living with hiv, million are on antiretroviral therapy ( . million of these thanks to the global fund). improved access to hiv treatment has cut the number of aids-related deaths in half since the peak in , from . million to under million in . however, hiv infections remain very high and especially among adolescent girls and young women who are up to eight times more likely to be hiv positive than young men in some african countries. on the current trajectory, the global fund is unlikely to meet its goal of reducing new infections to , globally by . in addition to the terrible human cost of the disease, the economic impact of hiv/aids is estimated to be over $ billion in lost earnings in . the global fund provides more than % of all international financing to combat tb. the global fund has disbursed about $ billion in the fight against tb by the end of . much of this has focused on expanding molecular diagnostic technology which delivers faster and more accurate results, supporting programs that identify those living with the disease without treatment, and enabling millions to be treated. progress is being made: the mortality rate for tb fell by % between and . but tb remains a serious threat to global health security because it is highly contagious, airborne and increasingly drug resistant. it remains the leading cause of death from infectious disease, with . million deaths per year, not including hiv co-infections. deaths from drug-resistant tb are responsible for about one-third of all deaths due to antimicrobial resistance worldwide; if trends continue, . million people will die of drug-resistant tb by , costing the global economy trillions of dollars in lost output. the global fund is also the leading provider of funding to combat malaria, a disease transmitted to humans by mosquitoes. malaria is a major killer: in , there were million infections and , deaths from malaria (most of them children under age ). in africa alone the economic impact of malaria is estimated to be $ billion per year, including the costs of healthcare, absenteeism, days lost in education, decreased productivity, and loss of investment. but thanks to the support of the global fund, hundreds of millions of insecticide-treated mosquito nets have been distributed and over million cases of malaria have been treated by . as a result, global malaria deaths have dropped by % since . unfortunately, progress has stalled in the past few years due to drug and insecticide resistance. some countries are even losing ground to the disease. launched in with the help of a $ million five-year pledge from the bill and melinda gates foundation, gavi is an international organization that brings together the public and private sectors in the shared goal of creating access to new and underused vaccines for children living in the world's poorest countries. the us and the eu are among gavi's six original donor countries; as with the global fund, they are the largest donors, providing roughly $ million each per year. gavi estimates that it has helped treat over million children and has prevented more than million future deaths in the first years of its existence. looking to the future demands on foreign aid and humanitarian assistance are certain to grow in the future, principally because of population growth and climate change, causing extreme weather patterns (including heat and drought), pests, disease, and rising oceans. some studies predict that of the . billion increase in world population between and . billion will be in africa. the oecd estimates that by half a billion people may be living in "fragile states," defined as countries that are incapable of exercising basic functions, because of climate change and conflict. every year hundreds of millions of people require humanitarian assistance, largely because of natural disasters and conflicts. hunger is one of the main urgent challenges: the food and agriculture organization estimates that over million people suffer from food insecurity, of which over million (roughly half of them children) face acute hunger, even starvation. only one-fifth of children affected by severely acute malnutrition receive adequate care, with the result that many become ill and suffer impaired growth and cognitive development. there are nearly million people around the globe-principally in syria, turkey, lebanon, palestine, yemen, afghanistan, south sudan, somalia, and myanmar-requiring protection, shelter, food, and other basic services due to forced displacement, often lasting a decade or more. very often these people lack access to water, sanitation, and hygiene, resulting in heightened risk of epidemic outbreaks. the world bank estimates that % of land area worldwide, home to approximately % of the world's population, is exposed to drought. at the same time, rapid population growth and urbanization are contributing to a steady increase in the demand for water. as a result, the number of people without access to safe drinking water is expected to double by to billion. in light of increasing demand for urgent humanitarian assistance and longer-term development aid, the us and the eu, including its member states, need to build on their cooperation as the world's leading donors to coordinate more frequently and deeply than ever before. this coordination is not only necessary to make the dollars and euros stretch further, but also to ensure that their common values shape the global development agenda despite the rapid rise of new state donors (especially china) that are focused almost exclusively on the expansion of political power and economic ties, rather than the promotion of democracy, human rights, and good governance. the us and the eu also need to work together to ensure that their activities in foreign aid and humanitarian assistance are consistent with the growing role of private development assistance coming from ngos, foundations, and corporations in the oecd. it will be more challenging, but important, for the us and eu to reconsider some of their policies that undermine their joint objectives to promote more stable economic and political conditions in the poorest countries. in the case of the us, that means its practice of tying aid to the purchase of us agricultural commodities. in the case of the eu, that means its practice of dumping into african markets the cheap surplus food that results from generous european production subsidies; and it also means its opposition to genetically modified food and feed that prevents african countries from accepting some food aid and planting more resilient crops. the signature of a cooperation agreement between the us and the eu in on the sharing of data received from the eu's copernicus constellation of earth observation satellites will assist joint efforts to manage and mitigate natural disasters the new alliance for food security and nutrition in africa the invaluable assistance of dr. emmanuel de groof in the preparation of this chapter is gratefully acknowledged. key: cord- -o ssggit authors: cummings, brian m.; mercurio, mark r.; paris, john j. title: a review of approaches for resolving disputes between physicians and families on end-of-life care for newborns date: - - journal: j perinatol doi: . /s - - - sha: doc_id: cord_uid: o ssggit nan in a commentary in the new england journal of medicine (nejm) on a ruling of the texas supreme court in miller v. hca [ ], george annas, the nejm legal analyst, observed, "one bioethical issue is as intractable today as years ago when the topic was first publicly discussed: the extent of parental authority to refuse life-sustaining medical treatment for an extremely premature infant" [ ] . the case involved the resuscitation of a -week g infant over parental objections. it took years to resolve the case in the legal system. nearly two decades later, we might inquire whether neonatologists and other critical care practitioners have greater comfort in dealing with the issue of parental objection? looking for guidance in the american legal community is not particularly enlightening. left unresolved in physician-parent conflicts are such issues as who decides and on what standard? societal norms over the past half a century on who is to make treatment decisions, and on what standard, have shifted [ ] . it is now agreed within the bioethical and medical communities in the united states that where the risk of mortality is significant and the prospect of benefit to an infant is suffused in ambiguity and uncertainty, the decision on whether or not to initiate treatment belongs to the parents. that position is best summarized in the american academy of pediatrics (aap) guidelines on "nonintervention or withdrawal of intensive care for high risk newborns," published in and reaffirmed in . we find the aap's position spelled out in three brief statements: ( ) when early death is very likely and survival would be accompanied by high risk of unacceptably severe morbidity, intensive care is not indicated. ( ) when survival is likely and risk of unacceptably severe morbidity is low, intensive care is indicated. ( ) there may be cases that fall [outside] these first two categories…parental desires should determine the treatment approach [ ] . although the term "unacceptably severe" is ambiguous and allows for considerable "wiggle room," the aap guidelines mark a decided shift from the tradition that medical treatment decisions are the domain of the physician. that standard prevailed from the dawn of medicine until kubler-ross' landmark book on death and dying [ ] . her contribution to bioethics was not only psychological insight into the stages of dying, but also her insistence that physicians listen to the voices and values of dying patients. with the aap guidelines as our starting point and left to our own individual practices, how do providers build trust between clinicians and families? is "futility" a helpful framework? futility is not a helpful terminology for families or providers. paul helft et al.' article on "the rise and fall of the futility movement" [ ] established that for nearly a decade in the s and s the concept of "medical futility" was an important aspect in the resolution of physician-family conflicts. its significance faded when it became clear that there was no agreement in the medical community or society in general on the meaning of the term. the focus shifted to the importance of so-called "family autonomy." the prolonged debate on autonomy was first raised in a opinion by justice benjamin cardozo of the new york court of appeals in schloendorff v. society of the new york hospital [ ] . in that case, the state's court of final jurisdiction ruled that the term "autonomy" should be confined to the value choices of a competent adult patient. subsequently, new york's highest court recognized the validity of proxy assessment for the nondecisionally capable patient's wishes as well as the known values of the once competent adult [ ] . "best interest" of the patient, not the determination of a family's values, emerged as the standard for minors and those who never possessed decision-making capacity. that standard is articulated in the aap's guidelines on decision-making for newborns, as well as for infants and children [ ] . a decided shift in the right of parents to make medical decisions for their child born with a severely compromised medical condition occurred in a legal case entitled, maine medical center v. baby boy houle [ ] . the child, sidney houle, was born with multiple medical problems. her parents and treating physician agreed to forego invasive surgical treatment. some at maine medical center objected. they brought suit in maine superior court. there judge david roberts began his analysis of the case by stating "while there may be some doubt about the rights of the unborn child, once born the most basic right enjoyed by every human being is the right to life itself." judge roberts ruled that if a patient has medical needs and a medically feasible response is available that intervention must be utilized regardless of the patient's future quality of life. the surgery was performed. sidney died soon thereafter. the court's "life-at-any cost" ruling occasioned a criticism in a jama article by mccormick entitled, "to save or let die?" [ ] . mccormick asked, "granted the life can be saved, what kind of a life are we saving?" he went on to note that there was no moral obligation to impose treatment on a dying patient or one who is totally dependent on medical measures to sustain life. nor is there an obligation to do so for a patient whose potential for relationships never existed or is exhausted. his final point on the fundamental importance of "relationships" was mccormick's major contribution to the topic. his article has since become a landmark in medical ethics, one cited with approval by nearly every professional group that has attempted to design standards for end-of-life care [ ] . a year earlier than mccormick's commentary on aggressive interventions, duff and campbell's article in the nejm brought the topic of ethical dilemmas in the newborn nursery to the public's attention [ ] . the authors reported that of deaths in the special care nursery at yale new haven hospital between and , ( %) were associated with discontinuation of medical treatment. if the parents and physicians agreed that prognosis for "meaningful life" was extremely poor for a child born with multiple abnormalities, trisomy, cardiopulmonary crippling, or a central nervous system disorder, often no further treatment was provided. in those authors' perspective the decision to withhold or withdraw treatment belonged to those who bore the responsibility for the consequences of the decision-the family. in a subsequent article paris and mccormick criticized that approach as "normless" [ ] . it provided no guidelines, no standards, no norms other than the wishes of the parents on which to decide whether to withhold or withdraw medical treatment. under that schema a decision could equally well be based on a concern for "family convenience" as on the "best interests" of the child. what their approach failed to understand is that even good, caring, loving parents-acting out of fear, ignorance or a misreading of the clinical situation-can and do make choices antithetical to the child's interests [ ] . physicians, as seen in the well-known stinson case [ ] , can also err in their judgments on the value of medical interventions for a seriously compromised newborn. the changes in standards and norms on medical decisionmaking are observable in the different approaches to decision-making on end-of-life cases in british and american courts [ ] . although both share the common law tradition, the way courts in those countries decide cases is different. in the english tradition, if one party in a family-physician conflict seeks judicial resolution, the court -and the court alone-will determine the "best interests" of the patient. the arguments of the physicians and the family will be heard and considered. the rationale provided by either side, however, is not dispositive. clear guidelines have been formulated by the courts in the united kingdom that the decision is to be based not on the personal predilections of the judge, physician, or family, but on an independent assessment by the court of the "best interests" of the patient. the decision is not necessarily what the judge would personally choose. nor is it to be based on what the judge believes is the stronger argument. the assessment in the english system is to be made exclusively on the court's judgment of the patient's "best interests." that standard is far different from the tradition of "the doctor knows best" that prevailed from the dawn of medicine through the mid-twentieth century in the united states and the united kingdom. that older standard continues to this day in much of the non-anglo-saxon world. in the united states, years of legal wrangling are a norm. the case of terri schiavo is illustrative of this reality. the dispute among the family on who should decide went to a florida trial court, the florida court of appeals, florida's supreme court, a federal district court, a federal circuit court of appeals, and the united states supreme court. the case also involved the florida legislature, the governor of florida, the united states congress, and the president of the united states, with further commentary from italian parliament, the vatican, and the pope. all were, at one time, involved in this dispute on medical decisionmaking [ ] . the schiavo case, as did the british cases of charlie gard and alfie evans, demonstrated that the public and the media can be highly vocal, influential, and militant advocates for a particular position on end-of-life medical decision-making. such intrusions make the role of bedside caregivers ever more difficult [ ] . the preferred approach to resolution of physician-family conflict: shared decisionmaking rather than litigation or seeking third party resolution, john lantos in the nejm recently summarizes todays generally accepted approach of shared decision-making by the physician and family as the preferred solution [ ] . listening to the patient's family and assisting them in meeting their goals has proven successful in resolving what can seem to be intractable parent-physician conflict. the potential for conflict between parents and physicians, however, has not been fully resolved, nor is it easily dissipated [ , ] . how can we best implement shared decision-making in the clinical setting? recent studies provide an important context for physicians navigating the complexity of building trust and incorporating parental values in difficult decisions. families want to be involved. in a study recently published in this journal, parents of nicu patients were surveyed on their decision-making as well as their regret at the decisions that were made during their child's nicu stay [ ] . the vast majority of parents preferred active or shared decisionmaking. they wanted to be involved in critical decisions. most importantly, being involved was associated with less parental regret. one potential barrier to shared decision-making is a perception that parents could impede clinician autonomy on medical decisions. clinicians do not want to have to get into the weeds for everything. a recent study refutes this concern and does not show parents want to undermine a physician's professional expertise [ ] . in this study of nicu parents, parents reported preferences to defer to caregivers for decisions that were technical in nature, that had high potential for benefit, that required medical expertise or where urgent. parents, however, wanted to be involved when "big picture" goals or when significant risks were at stake. they believe their values and choices should be seriously considered in these matters and gives providers clear guidance on what is the ideal scope of shared decision-making. from the provider perspective, investigators recently interviewed physicians in pediatric and neonatal intensive care concerning end-of-life decision-making. the investigators highlight how different perspectives on best interests could prevail based on the unequal power and authority of physicians, clinical uncertainty, and the complexity of balancing child and family interests [ ] . given the subjective nature of quality of life assessments, physicians should be clear about who is establishing the goals for the child. they should also reflect on their own potential biases and values. regardless of the physician's certainty regarding outcome, physicians should offer noncoercive recommendations that are informed by the patient's and families' values and that incorporate the interests of the parents, siblings, and family as a whole. those recommendations ought not be based exclusively on the physician's values. listening to the concerns of the family about the "big picture" issues is the key to framing shared decision-making. such a process takes time and empathy on the part of providers. in an earlier article, we provided a case of an experienced neonatologist who successfully utilized shared decision-making to resolve a potential conflict between the nicu staff and the family [ ] . he began by acknowledging the father of a nicu patient was confronted with a nearly unimaginable scenario -his wife, who was pregnant with twins, had undergone an emergency c-section after one twin's heart rate was no longer detectable. the father, who just lost one daughter and whose wife and second daughter were critically ill, was understandably overwhelmed. this was not an ideal time to ask him to make an important medical decision. rather what he needed was empathy and above all time to adjust to the new situation. given the opportunity of support, time and the opportunity of discussion with the attending physician and nicu staff, the father noted that despite this being a much-desired pregnancy neither he nor his wife would want to impose a life of unremitting suffering on their child, or worse, a life without consciousness. the decision to limit further aggressive measures for his daughter became the shared choice of the physician and the parents. here modern medicine was adhering to the wisdom not to attempt medical interventions on a patient "overmastered by disease" [ ] . a key aspect of shared decision-making is spending the time to elicit values of the patient's family and culture. many perceived conflicts are a failure to understand one another. this requires meeting, and meeting, and meeting again, sometimes with other clinicians. but always with curiosity and an openness to understand the parent's point of view. seemingly obvious, but sometimes elusive, establishing trust remains crucial. this model of using time to lead to a shared decisionmaking resolution is seen in the case of a compromised newborn with a partial trisomy abnormality [ ] . the parents were young, foreign born individuals who insisted the infant was a "normal child." further the parents believed the medical care was harming their child. multiple family conferences including a neonatologist, a geneticist, a bioethicist, a social worker, and an interpreter allowed the parents to understand the genetic implications and the staff to understand the family's values. although initially there was an "ethos of mistrust," after much discussion, the parents eventually proposed a pathway acceptable to them and to the clinicians. the nicu team supported the parents' decision to omit aggressive inpatient medical interventions for their seriously compromised infant and the parents' decision to have the baby go home. the parents understood and accepted that doing so in the united states would require regular nursing visits to the home to support ongoing medical care. patient listening to the parents' expectations and values and the careful laying out to the parents of the differing cultural requirements on end-of-life care in the united states from those that prevailed in their native country, convinced the parents that the hospital, the attending physician, and the entire nicu team wanted to do whatever was legally permissible to effectuate the parents' desire to take their infant home. a trusting relationship was established. the parents brought their infant to their home where, after a brief time, the baby no longer required a ventilator or a feeding tube. once the child was free from the medical machinery, the parents brought him back to the middle east. shortly thereafter, he died. that the parents developed a trusting relationship with the attending physician and the nicu staff is seen in their returning to the medical center for genetic testing to establish that they were not carriers of a genetic abnormality that might impact a future pregnancy. the parents also thanked the attending neonatologist and the nurses for their understanding and support during their child's hospitalization. the ability to build a trust-filled relationship, which took perseverance and time, ultimately proved helpful in working through a difficult and trying shared decision-making process. shared decision-making, utilizing the aap framework, is possible and the most practical means for resolving parental and provider conflicts. conflict of interest the authors declare that they have no conflict of interest. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. extremely preterm birth and parental authority to refuse treatment-the case of sidney miller from the johns hopkins baby to baby miller: what have we learned from four decades of reflection on neonatal cases? committee on fetus and newborn. noninitiation or withdrawal of intensive care for high risk newborns on death and dying: what the dying have to teach doctors, nurses, clergy and their own families the rise and fall of the futility movement committee on bioethics, section on hospice and palliative medicine, committee on child abuse and neglect guidance on forgoing lifesustaining medical treatment - . cumberland city to save or let die? the dilemma of modern medicine the hastings center guidelines on life sustaining-treatment and care near the end of life moral and ethical dilemmas in the special care nursery saving defective infants: options for life or death brain death the long dying of baby andrew. boston: little brown and company the charlie gard case: british and american approaches to court resolution of disputes over medical decisions the case of terri schiavo: ethics at the end of life alfie's last days: a little boy's life and death stoked a furious debate that will not soon end ethical problems in decision making in the neonatal icu disputes between physicians and family on surgical treatment for an infant with ultra short gut syndrome: the perspectives of an ethics committee conjoined twins separation leading to the death of one twin: an expanded ethical analysis of issues facing the icu team the importance of shared decision-making in the neonatal intensive care unit characteristics associated with preferences for parent-centered decision making in neonatal intensive care physicians perceptions of shared decision-making in neonatal and pediatric critical care approaches to end-of-life discussions with parents of a profoundly compromised newborn decision making for seriously compromised newborns: the importance of explaining cultural differences and unanticipated consequences key: cord- -p sq yg authors: bales, connie watkins; tumosa, nina title: minimizing the impact of complex emergencies on nutrition and geriatric health: planning for prevention is key date: - - journal: handbook of clinical nutrition and aging doi: . / - - - - _ sha: doc_id: cord_uid: p sq yg complex emergencies (ces) can occur anywhere and are defined as crisis situations that greatly elevate the risk to nutrition and overall health (morbidity and mortality) of older individuals in the affected area. in urban areas with high population densities and heavy reliance on power-driven devices for day-to-day survival, ces can precipitate a rapid deterioration of basic services that threatens nutritionally and medically vulnerable older adults. the major underlying threats to nutritional status for older adults during ces are food insecurity, inadequate social support, and lack of access to health services. the most effective strategy for coping with ces is to have detailed, individualized pre-event preparations. when a ce occurs, the immediate relief efforts focus on establishing access to food, safe water, and essential medical services. the most common issues impacting on the nutritional well-being of elderly persons are comprehensively addressed in the preceeding chapters of this edition of the handbook of clinical nutrition and aging. this chapter focuses on a different type of concern, one that can overshadow all other threats to health when a serious disaster strikes. that subject is the welfare of aged persons when catastrophic events pose a direct (or indirect) threat to nutrition and health ( , ) . while there is a large body of literature on the health impact of natural and man-made disasters (e.g., droughts, floods, military conflicts) and associated long-term food shortages in the third world, surprisingly little information is available about the short and intermediate-term consequences of emergency situations in developed countries. in these situations, high population densities and heavy reliance on power-driven devices for day-to-day survival (e.g., electrical power for mass transit, elevators to reach living quarters, medical devices, and refrigeration of foods and medicines) can accelerate the speed with which a catastrophic, health-threatening situation develops. in , the plight of the elderly evacuees from new orleans (pre-storm population approaching , ) following hurricane katrina provided a dramatic demonstration of how essential services can rapidly deteriorate in a well-developed, highly populated urban environment following a major disaster and place older individuals in eminent mortal danger. in order to lay the foundation for this discussion, we begin with some definitions (see table . ). while terms like ''disaster relief'' and ''humanitarian crisis'' may be any of a number of crisis situations that greatly elevate the health risk of individuals in the affected area; examples are natural disasters like floods and earthquakes; urban health emergencies like fires, epidemics, and blackouts; and terrorist acts like massive bombings or poisonings of food or water supplies. resolution of these emergencies requires collaboration between multiple groups. acute protein/calorie malnutrition (pcm) pcm or ''wasting'' is associated with recent rapid weight loss, i.e., as in emergency situations (as opposed to chronic malnutrition). chronic energy deficiency (ced) an intake of energy that is below the minimum requirement for a period of several months or years. in order to achieve energy steady state, the energy expenditure must drop to match the low intake, ultimately leading to underweight and low levels of physical activity. nutritional rehabilitation restoration of weight and healthy nutrition through the provision of appropriate foods based on established protocols. food rations a shelf-stable pre-packaged dry ration that meets minimum daily intake recommendations for calories and other nutrients. used to temporarily meet critical nutritional needs when food supply is inadequate. examples: meals ready to eat or mres ( , kcal) are often distributed in complex emergencies in the united states; general food rations or gfrs ( , kcal) are distributed in many countries in sub-saharan africa. (continued ) more familiar, the most broadly acceptable term for these threatening situations is ''complex emergency'' ( ) . complex emergencies (ces) can occur anywhere and are defined as any of a number of crisis situations that greatly elevate the risk to nutrition and overall health of individuals in the affected area. examples include natural disasters like floods and earthquakes, urban health emergencies like fires, epidemics and blackouts, and terrorist acts like massive bombings or poisonings of food or water supplies (see table . ). ces were originally associated with wars, genocide, and political strife, where innocent civilians were forced to endure loss of access to shelter, food, appropriate clothing, and timely medical care. such emergencies have traditionally been associated with populations in developing nations, not those in the so-called developed countries. however, with increasing a complementary ration to the general food ration is sometimes provided. typically, it consists of fresh fruit and vegetables, condiments, tea, etc. it is especially appropriate when the population of concern is completely reliant on food assistance. ''wet'' feeding food rations prepared and cooked on-site as opposed to rations that are taken home for preparation in the household (dry rations). typically, fortified foods have had supplemental vitamins and/or minerals added. hunger the uneasy or painful sensation caused by lack of food. malnutrition the medical condition caused by an improper or insufficient diet that can refer to undernutrition resulting from inadequate consumption, poor absorption, or excessive loss of nutrients. malnutrition results from an inappropriate amount or quality of nutrient intake over a long period of time. the inability to obtain nutritionally adequate and safe food; or the inability to obtain it in socially acceptable ways food insufficiency inadequate amount of food intake due to a lack of food. epidemics and pandemics an epidemic is a disease outbreak that affects numbers of the population in excess of what would normally be expected in a defined community, geographical area, or season. a pandemic refers to this type of disease outbreak that is occurring over a wide geographic area and affecting an exceptionally high proportion of the population. source: borrel, a. addressing the nutritional needs of older people in emergency situations in africa: ideas for action. helpage international africa regional development centre, westlands, nairobi, . globalization of the world's societies and economies and news coverage documenting world events, it has become clear that ces can and do occur in both developed and developing world locations. nutritional risk is commonly elevated in ces and is most likely to occur when the crisis is protracted or recurrent. table . includes definitions for factors related to inadequate food intake (e.g., food insecurity, hunger), the resulting nutritional problems (e.g., malnutrition, acute protein/calorie malnutrition), and terms used to discuss interventions for undernutrition (e.g., food rations, nutritional rehabilitation). even in the absence of a crisis, older persons are well recognized to be at greater risk than the remainder of the adult population for food insecurity and hunger. some of the many factors that contribute to increased nutritional vulnerability of older adults are listed in table . . in , food insecurity and hunger affected at least . million households in the united states that contained older members ( ) . people in % of those households also experienced hunger, in addition to food insecurity. most of these older persons are suffering from food insecurity due to lack of income or due to their place of residence. residents of the south are more apt to experience food insecurity, as are residents of cities and all elders who live alone ( ). recognizing the day-to-day nutritional vulnerability of its poor and elderly citizens, the u.s. government has a number of programs in place to provide assistance to elders at risk for food insecurity and hunger. mandated by the older american's act, the elderly nutrition program (enp) provides a minimum of onethird of the daily calories required by recipients through daily meals and nutrition services to people aged or older in group settings, such as senior centers and churches, or in the home, through home-delivered meals. the enp provides an average of million meals per day to older americans. these meals are targeted toward highly vulnerable elderly populations, including the very old, people living alone, people below or near the poverty line, minority populations, and individuals with significant health conditions or physical or mental impairments. on an average the meals generously meet the rda requirements, supplying more than % of the recommended dietary allowances (rdas) for key nutrients, thus significantly increasing the dietary intakes of enp participants. the meals are also ''nutrient dense'', that is, they provide high ratios of key nutrients per calories. the most recent evaluation of the enp program occurred in and was conducted by mathematica policy research, inc. (www.mathematica-mpr.com/nutrition/ enp.asp). the resulting report clearly confirms that the enp program recipients are at nutritional risk. it was found that between and % of participants had incomes below % of the poverty level (twice the rate for the overall elderly population in the united states). more than twice as many title iii participants lived alone, compared with the overall elderly population. approximately, twothirds of the participants were either overweight or underweight, placing them at increased risk for nutrition and health problems. title iii home-delivered participants had more than twice as many physical impairments, compared with the overall elderly population. although (and perhaps because) the success of the enp program is well recognized, % of title iii enp service providers have waiting lists for home-delivered meals, suggesting a significant unmet need for these meals. it would appear that even in times of relative calm and prosperity for most americans, there are elderly citizens who are persistently in a state of nutritional crisis. when nutritionally and medically vulnerable older persons encounter a complex emergency, there is an increase in morbidity and mortality rates. this is due to both short-term insufficient nutrition and the resulting long-term increased mental stress and disability, decreased resistance to infection, and exacerbation of chronic diseases ( ), all of which make obtaining proper nutrition more difficult in a cyclic pattern. many different types of ces produce similar challenges. the consequences of a shortage of edible food and/or potable water, regardless of the type of emergency that produced that shortage, are multifold and can lead to increased physical and mental harm to older people ( ) . reduced access to essential medical care heightens the immediate risk. a more extensive listing of the immediate impact of various complex emergencies and the resulting nutritional and health consequences is shown in table . . the likelihood of having to provide care for older persons during a ce is greater than one might think at first. as previously noted, table . provides a list of common ces that have the potential to cause nutrition-related health risks. the impact of these crises on the nutritional state and overall health of older adults is discussed in more detail in the following sections. the hurricane season in the united states, most notably hurricanes rita and katrina, left no doubt that older persons continue to be disproportionately affected by hurricanes ( , ) just as they were with hurricane andrew in ( ). older floridians who were affected by hurricane charley in found that the hurricane not only disrupted their quality of life but also disrupted their medical care ( ) . persons with pre-existing conditions such as diabetes mellitus, heart disease, and physical disabilities were especially affected. approximately onethird of the older residents in the area had a worsening of their conditions posthurricane, including a lack of access to prescription medicine and loss of routine medical care for pre-existing conditions. medically related deaths were linked to the loss of power (resulting in loss of access to oxygen) and to exacerbation of cardiac disease. hurricane iniki in hawaii and the great hanshin-awaji earthquake in japan were associated with an increase in the rate of diabetes mellitus-associated deaths for a year following the disaster ( , ) . in a study of residents in the high-impact area of hurricane andrew, one-third of persons had high levels of ptsd ( ) , which was attributed to variables such as property damage, exposure to life-threatening situations, and injury. tornadoes, while typically more limited in the size of the area affected than a hurricane, are often even more physically destructive. although no research has been published on their specific effects on physical and mental health, it is well recognized that tornadoes can lead to many of the same dangers noted for hurricanes; the disruption of home care services and meal delivery to homebound elderly persons are of concern. the situation can become life threatening not only to the older persons who are critically dependent on these services but also to their dedicated care providers who often risk much to ensure the delivery of food and medical care to their clients (personal communication from area agency on aging of southwestern illinois grantees to nt). floods are a relatively common disaster and are often associated with earthquakes or hurricanes. besides trauma and drowning, the most common conditions associated with floods are an increase in gastrointestinal symptoms. increased preventable conditions following the crisis include gastroenteritis ( ), acute respiratory infections including asthma ( ), and increased post-traumatic stress which can persist for years after the event ( ). in the aftermath of an earthquake, as with the other natural disasters already mentioned, access to basic life-sustaining nutrients and hydration as well as to basic and specialized medical care may be partially or completely disrupted. due to the magnitude and scope of the destruction that occur with a major earthquake, the restoration of infrastructure to fully support the inhabitants of the region may take months or even years to be accomplished. earthquakes result in a three-fold increase in deaths from myocardial infarction, a doubling of the frequency of strokes, increased blood pressure levels, and increased coagulability of blood ( , ) . increased rates of cardiac arrests occurring after loss of power ( ) and deaths due to increased incidence of coronary heart disease ( ) and myocardial infarctions ( , ) are also reported. deterioration of mental health occurs and post-traumatic stress is also prevalent ( , ) . emotional stress can persist for months ( , ) . in particular, the displacement of elderly persons from their places of residence and their social and medical supports can have a dramatic negative effect on health and quality of life (see fig. . ). displacement following a ce has been linked with a significant increase in mortality rates ( , ) . the confusion of the displacement, as well as loss of access to appropriate diet and medications, prevents older individuals from monitoring and treating their medical conditions. inappropriate diet has been directly linked to decreased glycemic control and increased mortality in diabetic patients following an earthquake ( ). the type of naturally occurring ce that is most threatening for older persons in terms of numbers affected each year comes during periods of temperature extremes, especially heat waves, claiming about lives annually in the united states alone, more than the deaths caused by all other disasters combined. at greatest risk are poor persons who live in inner cities, those with chronic illnesses, and those homebound. heat disasters are often aggravated by power outages, which prevent people from keeping cool, bathing properly, and storing food at proper temperatures ( ) . in the heat wave in philadelphia, there was a % increase in total mortality, with a % increase in cardiovascular deaths, particularly in those persons over years of age ( ) . in france, during the period - , there were six major heat waves, resulting in thousands of deaths; the mortality ratios increased with age after years and in the over age years cohort; the death rate was higher for women than for men ( ) . although little research has been published about the health effects of ice storms and blizzards, the loss of power leaves older persons stranded at home, increasing the risk for ingestion of inadequate calories and inappropriately prepared food and/ or spoiled food. the risk of exposure combined with the risk of house fires or carbon monoxide poisoning due to use of unsafe heating devices pose serious threats at a time when emergency services may not available due to the extreme weather conditions. fires increase the extent of cardio-respiratory problems, which results in exacerbation of chronic diseases ( ) . people who already suffer from mental health problems or medically unexplained physical symptoms ( ) and gastrointestinal morbidity ( ) can develop an exacerbation of these problems ( , ) once they become a victim of a fire. even when no injuries result, fires almost certainly force displacement of their victims, adversely affecting quality of life and manifestation of chronic diseases. a serious infectious global pandemic is one of the most threatening of all complex emergencies, and calls back memories of the most devastating infectious disease outbreak on record, the great flu epidemic of - , which killed an estimated - million people worldwide. the spread of this epidemic was linked to the trans-global transportation of soldiers during world war i. today, world travel and the importation of foods and other products are very common. thus, in the event of a serious epidemic in one country, there is a high likelihood of quick transmission to others. the outbreak of sars, a severe acute respiratory illness caused by a coronavirus, was first reported in asia in february and spread to more than two dozen countries in north america, south america, europe, and asia (sickening , and killing ) before the global outbreak was contained (http://www.cdc.gov/ncidod/sars/factsheet.htm). in recognition of the severe strain that a major disease outbreak can place on health systems, the world health organization (who) advocates for an ''integrated global alert and response system for epidemics and other public health emergencies'' that allows for ''a collective approach to the prevention, detection, and timely response'' for these emergencies (http://www.who.int/csr/en/). the who is currently coordinating the global response to human cases of h n avian influenza (bird flu) with regards to the threat of a future influenza pandemic. a widespread illness or intoxication from a food source could also threaten nutritional and overall health. while these outbreaks are typically limited in scope and short lived, the potential for more widespread and dangerous effects exists due to the centralized nature of the us food distribution chain and the clustering of very large populations into a small geographical area. (see more on this topic in section . . . .) while other complex emergencies produce far more damage and deaths each year than are caused by terrorism, the destruction of the twin towers in new york city and a portion of the pentagon in washington dc on september , , focused the attention of americans upon the potentially devastating effects of an intentional man-made disaster. the development of the department of homeland security was a tangible product of the national response to implied threats of bio-terrorism. a terrorist attack such as one causing explosions and collapse of buildings would result in the interruption of basic living functions in a manner similar to previously discussed emergencies like earthquakes, tornadoes, or fires. disruptions to necessities of daily living and loss of power and access to medical care would be major concerns. a bioterrorist attack would have very different potential consequences for the well-being of the elderly, potentially causing widespread illness and/or hunger and dehydration. the propagation of an illness over a wide geographical area could be lethal for a substantial number of older adults, who are typically among the most medically vulnerable. during the anthrax attacks in , all emergent cases involved adults over years old, with the one fatal case affecting a -year-old woman ( ) . intentional contamination of food or water supplies with a toxin or infectious agent also has the potential to cause an outbreak of poisonings or illness over a wide geographical area. in this situation, the outbreak could be slow and/or diffuse and the cause difficult to ascertain, delaying the recognition and treatment of the problem. for example, in , bagged spinach contaminated (unintentionally) by escherichia coli infected over americans (killing three) in states before the strain was isolated and eradicated. similarly, intentional waterborne diseases or toxins would be difficult to detect and could impact a vulnerable population more severely than a healthy population, due to delayed recognition and reporting of the contamination ( ). in the case of deliberate food/water contamination, nutritional health is affected directly (by reducing the availability of safe food and water) as well as indirectly (by the symptoms of illness and the reduced access to an over-burdened medical care system). in fact, the deliberate poisoning of food has already occurred in the united states, when in members of the rajneesh religious cult contaminated salad bars in the dalles, oregon, with salmonella typhimurium. though it was only a trial run for a more extensive attack that was planned to disrupt local elections later that year, the contamination caused people to develop salmonellosis in a -week period. other isolated examples of intentional food contaminations have also been reported in the united states and canada ( ) . coping with complex emergencies due to terrorism is for the most part a new challenge, at least in the united states. despite considerable effort to prepare for these scenarios, our experience in dealing with the aftermath is limited, yet, unfortunately, our experience is likely to grow in the future. experts warn that a major terrorist attack on the united states is very likely ( - %) to occur within the next years (cfr online debate). heat, cold, hurricanes, tornadoes, floods, fires, illness, terrorism, and other disasters endanger health and claim elderly lives. sometimes the effects are immediate, but more often an increase in morbidity and mortality occurs progressively after the disaster as survivors experience a continued decrease in the quality of life and increased nutritional risk due to displacement and a loss of basic resources. these events result in increased disability, which further impairs the ability of older persons to maintain access to safe food and water and sustain proper nutrition and hydration, and so the spiral continues downward. recovery from food insecurity and poor nutrition is more difficult for persons who are poor, socially isolated, cognitively impaired, and/or old. the more risk factors people possess, the faster their decline. all of the disasters described in this chapter threaten nutritional and metabolic health because they disrupt access to food, water, and vital medical treatment ( ) . older persons with pre-existing chronic conditions are particularly vulnerable to these disruptions. preparation for and resolution of the aftermath of these emergencies require collaboration between multiple stakeholders and takes time. there are no easy fixes to ces. the underlying causes of malnutrition in older adults during ces are ( ) insufficient household food security, ( ) inadequate social and care environments, and ( ) poor public health and inadequate health services ( ) . the basis for current governmental and humanitarian responses to nutritional crises builds on lessons learned in the earliest organized relief efforts (circa - ) . during the s, guidelines began to be published following experiences with relief efforts in places like biafra and ethiopia ( ). in the subsequent decades, the experiences of various crises have progressively shaped what are, today, the characteristic challenges, and avenues of support available to older adults who are caught in ce situations in any given country. with increasing recognition that the elderly are uniquely vulnerable to ces, efforts are underway to develop specific recommendations and resources for this population group. table . lists some of the resources available, along with web links. helpage international (www.helpage.org) is a global network of more than not-for-profit organizations in countries who are working for improvements in the lives of older people. this group has published a manual of guidelines for best practice during disasters and humanitarian crises (see table . ). the sphere project minimum standards in disaster response project (http://www. sphereproject.org/content/view/ / ) advocates for the use of community-based systems to implement the care of older individuals in these circumstances. in the united states, a number of national organizations, including the federal emergency management agency (fema), the american red cross, and various branches of the military take responsibility for rescue and relief efforts following a major ce but the contribution of the private sector to the relief effort is traditionally also a substantial one. this type of broad-based support is necessary but makes it more difficult to consistently implement age-related guidelines for relief efforts once they are in the field. coordinating the advance preparation efforts for ces, however, is a more tangible goal. as is true for almost all health issues, the best way to address the nutritional and related health risks that accompany ces is to take preventive measures. in the case of nursing homes and assisted living facilities, many states require that these institutions have a substantial reserve food and water supply and that they have a welldelineated disaster and evacuation plan. the specifics of these requirements vary on a state-by-state basis. however, attention to the development of specialized parish, louisiana, due to a failure to comply with evacuation orders during hurricane katrina, and the bus accident in which houston, texas, nursing home residents being evacuated from hurricane rita died in a fire that was sparked by mechanical problems and fed by the explosions of the passengers' oxygen tanks. beyond the obvious need for institutions and organizations like long-term care and hospice agencies to have detailed plans for evacuations and emergency conditions, there is also a need to identify ''at risk'' older adults living in the community. this would involve developing registries of ''vulnerable populations'' of elders based on degree of factors like contact need, predominant special impairment, and predominant life-support supply need, if any. by doing so, vulnerable elders could be easily identified in the event of a disaster and better supplied with assistance. such registries are currently implemented in some instances (examples are available in california, www.aging.ca.gov, and florida, www.broward.org/atrisk), but a more systematic approach has yet to be employed. these registries will most likely need to be local in origin and maintenance in order that control of sensitive health data would remain confidential. however, it would be preferable for the structure of the databases to be developed in a uniform format in order to facilitate the sharing of important data across local and regional entities. once successful programs and examples are created, their implementation by all interested parties should then be straightforward. emergencies require flexibility and the ability to survive changes in regular routines. this flexibility can be easier to achieve if people have a few necessary and familiar objects with them to assist with performing certain everyday chores, such as eating properly, taking medications, and changing into clean clothes. in order to assist people in getting prepared for the disruptions that inevitably occur during an emergency, the fema and the american red cross recommend that every family have an emergency preparedness kit that contains food, water, clothing, medical supplies, flashlight, and other supplies that will aid their survival for - days. by the time recommended objects are placed in a backpack, the entire kit weighs between and pounds. this is clearly too much weight for an older person to handle safely. of emergency kits for elders the health resources and services administration (hrsa) provided funding to the gateway geriatric education center of missouri and illinois (grant number d hp ) for train-the-trainer programming to teach health-care professionals in the spring of how to create an emergency preparedness kit that was light, compact and specific for older adults. this kit consisted of a small satchel, a flashlight, a photo album (to store copies of prescriptions, insurance cards, evacuation plans, contact phone numbers, and family pictures), a pill box and a pamphlet introducing the fema web site. the trainees were then taught what other materials should be added to the kit to make it appropriate for a particular individual (table . ). upon completion of this training each of the trainees received two complete kits, one to use as an example during their subsequent training sessions of other health-care providers and the other to be given to a disadvantaged older person whom they deemed at risk during an emergency. each participant provided an e-mail address in order to be contacted year following their training to determine the outcomes of their training. one year after training, the trainees were contacted by e-mail. twenty-three of the e-mail addresses were no longer valid. of the remaining trainees, filled out and returned the survey within weeks ( % response rate). an additional surveys were returned after a second e-mail blast ( / , for a final response rate of %). the survey asked if, as a result of their training, had the trainees: . given the extra kit to an older adult? . determined if that kit had been used during an emergency? . used their own emergency kits for training, and if not, why? . used their own emergency kits during an emergency? responses to the quality improvement survey are summarized in table . . the majority of the trainees ( %) had given the extra kit to an older person and many ( ) ( ) of the respondents indicated that the person was either an older relative or a neighbor. however, few respondents ( %) had provided any training to other health-care providers on how to create these kits. barriers cited included lack of money to purchase kit contents, lack of commitment or permission from supervisors, lack of time to provide the training, and lack of time for their colleagues to receive training. the percentage of older adults that were reported to have used their emergency kits by the time of the end point survey was higher than expected ( %), especially given that only % of the (younger) trainees reported using their kits. however, a review of the disruptive weather patterns in the counties in eastern missouri and southwestern illinois where the trainees (and therefore, presumably of the older adults receiving the extra kits) lived, indicated that three area-wide power outages had occurred between august and january . all of these three power failures lasted - weeks, with the rural areas in southwestern illinois being the last to get power restored each time. each of these power failures affected at least a half million citizens each time. numerous cooling or heating stations were set up for older adults, thereby allowing them to evacuate from their homes during the days in august and to receive warm meals during the november and january power failures. multiple public service announcements encouraged people to evacuate their homes completely until power was restored, so many older adults either moved in with relatives who did have power or went to hotels. under those conditions, it is reasonable to expect older persons to take their emergency kits with them. many of the health-care provider trainees reported that they had gone to work daily. a brief second query to trainees who had used their kits and trainees who had not used their kits indicated that both sets had gone to work daily and returned home at night, even if they had no power at home. (these health-care providers worked in facilities with working generators.) several of those that took their kits with them indicated that the kits provided them with some measure of safety while traveling icy roads in november and january. those that had not used their kits indicated no perceived change in their normal safety. this quality improvement study shows that emergency kits for older adults are used during an emergency. community-dwelling older adults appear to be more vulnerable to weather emergencies than are the health-care providers who care for them, as evidenced by the differences in usage rates of the kits by both groups through three lengthy power outages. upon review of the barriers that prevented trainees from providing training to other health-care providers, it is possible that it would have been more appropriate to provide train-the-trainer programs to older adults rather than to health-care providers. peer-to-peer training might have had the added advantage of motivating trainers to find community funding to make kits for distribution because of a greater perceived personal need for the kits. because every emergency event presents a unique challenge, this section offers general information about coping with the major nutritional concerns, namely shortages of food and water and overall loss of access to social support and health-related resources. optimal public health and nutrition relief includes a broad range of interventions and needs to utilize strong programmatic interconnections to meet the aforementioned needs. in the immediate aftermath of a ce, the supplies of food and water may be extremely limited. in this event, food can be more safely rationed than water. a general guideline is that the minimum adult ration be one well-balanced meal per day, with the utilization of vitamin/mineral supplements, protein drinks, ''power bars'', or other fortified foods as meal extenders if available. however, water should not be rationed due to the very rapid effects of dehydration. individuals are advised to drink what is needed today and search for more water on a daily basis. indicators of dehydration in the elderly differ from those in younger individuals; increased thirst, reduced skin turgor are not reliable markers. better indicators include tongue dryness, longitudinal tongue furrows, dry mucous membranes of the nose and mouth, eyes that appear sunken, upper body weakness, speech difficulty, and confusion ( ) . when there is a loss of power to the home, perishable foods are to be consumed first, followed by foods from the freezer. frozen foods should be safe to eat for at least days following the power loss. at this point, nonperishable, staple foods would be the only safe source of nutrients. as conditions stabilize, food aid will begin to become available. the recommended actions to be facilitated for older adults include ( ) achieve/improve access to food aid (rations, supplemental feeding programs, etc.); ( ) ensure that the rations are easy to prepare and consume; and ( ) assure that the rations being used meet the nutritional requirements of older adults ( ) . the usda's food and nutrition service (fns) coordinates with state, local, and voluntary organizations to provide food for shelters and also distributes food packages and authorizes states to issue emergency food stamp benefits to individuals. as part of the national response plan, fns supplies food to disaster relief organizations such as the red cross and the salvation army for mass feeding or household distribution. these organizations, along with other private donors, support the supply of water and food rations to affected areas. there are several concerns related to the access and appropriateness of food aid for elderly individuals (again, see resources listed in table . ). access to the aid is a concern because disabilities and medical problems may prevent elderly individuals from reaching the distribution centers. another concern is the composition of the food rations, which may not be appropriate in consistency for persons who have dentures or who lack teeth and that may not be adequate in nutritional composition. food rations vary in composition; not all are developed for the primary purpose of post-ce relief. in the united states, the meal, ready-to-eat (mre), although first developed for use in the space program and now widely used by the armed forces, is one form of ration that is commonly distributed to civilians who need food following ces. having been designed for soldiers in a high activity situation, the mres are much higher in sodium ( , g) and fat ( g) than is optimal, especially for older adults ( ) . likewise, the texture, packaging, and preparation of mres were not developed with the intention of use by older adults. in an effort to supplement the nutritional needs of elderly citizens and to meet federal recommendations for increased emergency preparedness, the administration on aging (aoa) sought and received special funding to provide shelf stable meals that could be delivered to participants of the home-delivered-meal programs. these meals, which have a shelf life of approximately months, are delivered with instructions to consume them during emergencies when regular home-delivered meal service is disrupted. the program is new so, to date, no evaluations have been done to determine what becomes of those meals (e.g., are they saved for emergencies or eaten to supplement other meals). no policy has been created to determine liability for any sickness caused by consumption of meals that are beyond their expiration date (personal communication from area agency on aging of southwestern illinois and the mideast area agency on aging to nt). obtaining adequate food and water is only one step on the road to recovery where elderly persons are vulnerable to food insufficiency. once food is obtained it must then be stored properly, prepared properly, and then ingested without health risk. in each of these steps, older persons are also at increased risk, compared to the rest of the population. this is because these older persons have additional risk factors for poor nutrition such as functional impairments, social isolation, reduced ability to regulate energy intake, greater susceptibility to depression, decreased ability to taste and smell, poor dentition, and poor health. all of these items (listed in table . ) can lead to malnutrition, if not starvation, in older persons. following a ce, the speed with which basic services such as heating/cooling, shelter, and water supply can be restored will be a major factor in the recovery of older persons. past experience has shown that cold, loss of mobility, access to services, and psychological stress and trauma are some of the most important factors contributing to undernutrition in older people following a ce ( , ) . in particular, the loss of social networks and support systems increases the vulnerability of these individuals ( ) and needs to be corrected as soon as possible to prevent further deterioration as the days following the event go by. the best approach is to utilize programming strategies that address the needs of older adults without undermining their independence and discouraging their ability to support themselves ( , ) . the restoration of medical facilities and the provision of transportation to appropriate medical facilities in unaffected areas are not under the control of the individual clinician or caregiver. these efforts are usually dependent on the local police and military forces who take charge post-ce. additionally, medical facilities will vary in their ability to handle the ce, depending on the type of emergency. for example, the response to a ce such as a hurricane (which would probably slow down access to the facility) would be very different than that required for an infectious disease epidemic (when admissions might very quickly exceed capacity) ( ) . the challenge for the clinician on the front line is to stabilize the older patient until access to more formal support can be restored. thus, the aforementioned preparedness efforts are key in preventing the acceleration of medical conditions from chronic to life threatening. the availability of medical records and prescription medicines, as recommended for the evacuation kits of older adults, can play a critical role in this regard. in summary, the long list of complicated and threatening ces that can affect the nutritional status and overall medical welfare of older adults underscores the fact that all older adults and their care givers, as well as administrators of structured living facilities, should plan for and be physically and psychologically prepared for the event of a serious ce. . home-dwelling elders should be prepared for a ce by stocking a -week safety supply of food, water, and medications, having a carry-away disaster pack with medicines and other essential supplies, and 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earthquake acknowledgments the authors thank caroline friedman for researching the historic and current events cited here. key: cord- - e u authors: paploski, igor adolfo dexheimer; corzo, cesar; rovira, albert; murtaugh, michael p.; sanhueza, juan manuel; vilalta, carles; schroeder, declan c.; vanderwaal, kimberly title: temporal dynamics of co-circulating lineages of porcine reproductive and respiratory syndrome virus date: - - journal: front microbiol doi: . /fmicb. . sha: doc_id: cord_uid: e u porcine reproductive and respiratory syndrome virus (prrsv) is the most important endemic pathogen in the u.s. swine industry. despite control efforts involving improved biosecurity and different vaccination protocols, the virus continues to circulate and evolve. one of the foremost challenges in its control is high levels of genetic and antigenic diversity. here, we quantify the co-circulation, emergence and sequential turnover of multiple prrsv lineages in a single swine-producing region in the united states over a span of years ( – ). by classifying over , prrsv sequences (open-reading frame ) into phylogenetic lineages and sub-lineages, we document the ongoing diversification and temporal dynamics of the prrsv population, including the rapid emergence of a novel sub-lineage that appeared to be absent globally pre- . in addition, lineage was the most prevalent lineage from to , but its occurrence fell to . % of all sequences identified per year after , coinciding with the emergence or re-emergence of lineage as the dominant lineage. the sequential dominance of different lineages, as well as three different sub-lineages within lineage , is consistent with the immune-mediated selection hypothesis for the sequential turnover in the dominant lineage. as host populations build immunity through natural infection or vaccination toward the most common variant, this dominant (sub-) lineage may be replaced by an emerging variant to which the population is more susceptible. an analysis of patterns of non- synonymous and synonymous mutations revealed evidence of positive selection on immunologically important regions of the genome, further supporting the potential that immune-mediated selection shapes the evolutionary and epidemiological dynamics for this virus. this has important implications for patterns of emergence and re-emergence of genetic variants of prrsv that have negative impacts on the swine industry. constant surveillance on prrsv occurrence is crucial to a better understanding of the epidemiological and evolutionary dynamics of co-circulating viral lineages. further studies utilizing whole genome sequencing and exploring the extent of cross-immunity between heterologous prrs viruses could shed further light on prrsv immunological response and aid in developing strategies that might be able to diminish disease impact. porcine reproductive and respiratory syndrome virus (prrsv), the etiological agent of prrs, is one of the most important endemic viruses affecting the swine industry in the united states (holtkamp et al., ) and globally (stadejek et al., ; vanderwaal and deen, ) . the economic impact of the disease in the united states has been estimated at $ million annually (holtkamp et al., ) . clinical signs in affected farms vary by viral variant and according to the farm's production stage (e.g., breeding or growing herd), herd management, immune status, and other factors (goldberg et al., ) . premature farrowing can occur in - % of sows in an affected farm, and up to % of piglets are stillborn during an outbreak (christianson and joo, ) . piglets may be born with low weight and can present with lethargy and anorexia, which can lead to a mortality of more than % among piglets (pejsak et al., ) . prrsvinfected pigs are also susceptible to secondary infections leading to poor average daily gain and feed conversion, further increasing production loss (solano et al., ; xu et al., ) . up to % of united states breeding herds experience outbreaks annually (tousignant et al., a) and control of the disease in the united states, europe, and globally is challenging due to high levels of antigenic variability and its rapidly expanding genetic diversity (frossard et al., ; brar et al., ; guo et al., ; smith et al., ) . porcine reproductive and respiratory syndrome virus was first recognized almost simultaneously in europe (wensvoort et al., ) and north america (collins et al., ) in the late s and early s, but genetic differences suggested a much earlier evolutionary divergence between the north american and european viral types. thus, prrsv is divided into two major phylogenetic clades, prrsv type (more prevalent in europe) and type (more prevalent in north america) (shi et al., a,b; stadejek et al., ) . within each clade, high levels of genetic and antigenic diversity exist and cross-protection is only partial (roberts, ; kim et al., ; correas et al., ) . genetic similarities between prrsv isolates have been used as a tool to understand disease transmission and epidemiology (kapur et al., ; wesley et al., ) , and several different strategies have been used for classifying isolates of prrsv into epidemiologically meaningful groups. for prrsv type , the most commonly used classification system is based on restriction fragment length polymorphisms (rflp) and sequencing, both of which are typically based on the open reading frame (orf ) portion of its genome (kapur et al., ; wesley et al., ) . the orf gene encodes for the major envelope protein (gp ), which plays a role in inducing virus neutralizing antibodies and cross-protection among prrsv variants (dea et al., ; kim et al., ) . rflps have been broadly adopted by the u.s. swine industry despite shortcomings, such as the fact that the genetic relationship between different rflp types is unclear, the potential for two distantly related viruses to share the same rflp type, and the instability of rflp-typing when assessing isolates related to each other by as few as animal passages (cha et al., ) . in , a classification system based on the phylogenetic relatedness of the orf portion of the virus's genome was proposed (shi et al., a,b ). this classification system aggregates isolates into phylogenetic lineages based on the ancestral relationships and genetic distance among isolates. using this system, nine different lineages were described within prrsv type , each of which was estimated to have diverged between and (shi et al., b) . phylogeny-based classification of organisms is seen as the most powerful and robust instrument for distinguishing between variants of a viral population (hungnes et al., ) and has been used in the study of other viral diseases (liu et al., ) . phylogeny-based classification of prrsv, rather than rflp profiling, is expected to provide fewer ambiguities and more insight into the evolutionary relatedness amongst different variants. while the existence of prrsv lineages is well established, the dynamics of their cocirculation within a given region has not been well documented. vaccination is often used as a tool to mitigate clinical impact and viral shedding (holtkamp et al., ) . although specific practices vary across farms, gilts are typically vaccinated before entering the herd, and sometimes the sow herd is mass vaccinated during the year. most commercial prrsv vaccines currently sold in the united states are considered "modified live vaccines" (mlv), which means that the vaccine is an attenuated live virus. vaccines against prrsv show different degrees of protection against homologous and heterologous challenges (cano et al., ; díaz et al., ; geldhof et al., ) ; the exact definition of what constitutes a homologous or heterologous challenge is often not clear, especially taking into consideration the genetic diversity existing within prrsv type (shi et al., b) . five major prrsv vaccines are commercialized in the united states, each developed using a different wild prrsv isolate (lineages , , , and , with the lineage vaccine being the most widely used historically). porcine reproductive and respiratory syndrome virus is known to possess a high mutation rate (hanada et al., ; brar et al., ) . genetic mutations for prrsv are thought to result from rna polymerase errors (murtaugh et al., ) and from the lack of proofreading (kappes and faaberg, ) . coupled to that, genetic recombination events can contribute to prrsv diversity (forsberg et al., ) . thus, the emergence of new variants of prrsv is expected to occur potentially through both mutation and recombination. viral variants can quickly emerge in animals (goldberg et al., ) even after inoculation with a single variant (chang et al., ) . thus, the viral population within an animal can be referred to as a viral cloud or swarm (lauring and andino, ) , which suggests that mutation has a considerable impact in virus diversification even on short time scales. in addition, it is assumed that the immune response removes genetic variants of the virus that it recognizes with high specificity, potentially creating selection pressure favoring antigenically divergent prrsv variants (murtaugh et al., ) . hypervariable portions of the viral genome may be subject to immune selective pressure (chen et al., ) ; variation in proteins coded by those sites may play a role in evasion of host immune defenses (ansari et al., ; darwich et al., ) . prrsv vaccines are known to diminish the severity of clinical signs once an infection occurs, but not to prevent an infection from occurring (lyoo, ) . at the population scale, it can be expected that most animals have some level of immunity because of the high prevalence of natural infection and widespread use of vaccine. this creates the potential for immune-mediated selection to be a driver of prrsv diversification and evolution (murtaugh et al., ) . the identification of point mutations that are undergoing positive selective pressure is often interpreted as evidence of increased evolutionary fitness (kryazhimskiy and plotkin, ) . one way to identify such sites is to evaluate dn/ds ratios, which measure the rate at which substitutions at non-synonymous sites (dn) occur relative to substitutions in synonymous sites (ds). substitutions in synonymous sites are thought to be mostly neutral, but a higher occurrence of substitutions in nonsynonymous sites can be interpreted as evidence of selective processes that favor changes in the protein sequence (kosakovsky pond and frost, ) . positive selective pressure in sites that code for epitopes recognized by the host immune system are of special interest, because they suggest that the origin of such selective pressure, if present, could be driven by the host immune response. the rapid evolution of prrsv coupled with the periodic emergence of new and sometimes more virulent viral variants creates a need to continually update our knowledge on circulating prrsv variants. reports that show the waxing and waning of different viral types in the whole north america (shi et al., b) are helpful when understanding continent-wide status of prrsv lineages. however, understanding viral dynamics on a regional scale could provide important insights into local evolutionary and ecological dynamics of prrsv, including an improved understanding of how often new variants emerge or re-emerge within the region. here, we describe the temporal dynamics of prrsv occurrence in a swine-dense region of the united states, characterizing these patterns according to orf genetic lineages and sub-lineages. we quantify the contemporary occurrence of each lineage, investigate the temporal dynamics and turnover of lineages, identify emerging sub-lineages, and examine evolutionary patterns for evidence of positive selective pressures. monitoring project (mshmp) were used for this analysis. briefly, mshmp is an ongoing voluntary producer-driven nation-wide monitoring program for endemic swine diseases that affect the u.s. swine industry. based at the university of minnesota (umn), this program collects weekly reports on the infection status of sow farms from participating swine-producing companies, veterinary practices, and regional control programs, which serves to capture the occurrence of infectious diseases in the country (tousignant et al., a,b; perez et al., ) . infection status data classifies farms into the following categories (holtkamp et al., ) : status : positive-unstable, status : positive-stable, either through use of live virus inoculation ( lvi) or use of vaccines ( vx); status : provisional negative; and status : negative. the main difference between positive-unstable (status ) and positive-stable (status vx or lvi) is that unstable herds have an active clinical outbreak and are weaning prrsv rt-pcr positive piglets. in contrast, prrsv may be still present in positive-stable herds (through use of field virus inoculation or modified live vaccine) but clinical disease is controlled and piglets weaned from such farms are prrsv-negative as a result of herd immunity, decreased shedding, and maternal antibodies (holtkamp et al., ) . mshmp collects farm-level data from approximately . million sows, which represents approximately . % of the united states breeding herd population (national agricultural statistics service [nass] , agricultural statistics board, and united states deparment of agriculture [usda], ). specific production systems (companies involved in pig production) participating in the project also share the orf prrsv sequences identified on their farms as part of routine veterinary management. for example, samples may be submitted by veterinary practitioners to determine if circulating prrsv on the farm is the same or different from the vaccine virus or a previous variant present on the farm. for this analysis, we analyzed , sequences reported between and from mshmp participants located in a relatively isolated swine-dense region in the united states with an approximate area of thousand square kilometers. production systems operating in this region account for ∼ % of the united states sow population. approximately % of farms within this region participate in mshmp and in this project in particular. sequences used in this study came mostly from sow ( . % of sequences), nursery ( . %) and finisher farms ( . %), followed by boar stud farms ( . %) and sequences without a description of their origin ( . %). sequences shared with us by project participants were sequenced according to standardized protocols adopted by laboratories at sdsu (animal disease research and diagnostic laboratory et al., ), isu (zhang et al., ) and eurofins genomics. of the orf gene sequences used in this analysis, seven had fewer than nucleotides. these were deemed incomplete and were excluded from further analysis. we also included orf gene sequences previously classified into nine different genetic lineages (shi et al., a,b) and added these to the collection of mshmp sequences. these sequences, assembled from a database of sequences that spanned from to , were used as guides to classify the mshmp sequences into the previously described genetic lineages, and will be referred to here as "anchor" sequences. we also obtained the orf gene sequences for five vaccines (ingelvac prrsv atp -genbank id dq . , ingelvac prrsv mlv -genbank id af . (both from boehringer ingelheim), fostera prrsv from zoetis -genbank id kp . , prime pac prrsv rr from merck -genbank id dq . , and prevacent, from elanco -genbank id ku . ). the ingelvac prrsv atp and fostera vaccines use isolates belonging to lineage , while ingelvac prrsv mlv uses a lineage isolate, prime pac a lineage isolate and prevacent a lineage isolate. we also obtained two prrsv prototypes (lelystad -genbank id nc_ . , and vr -genbank id ef . , which represent the prototypical european type and north american type viruses, respectively). the sequence dataset used here is sequences were aligned using the muscle algorithm implemented in aliview (larsson, ) using default settings. the alignment was then examined for the presence of recombinants using the recombinant detection program version (martin et al., ) , followed by removal of potential recombinants. in addition, duplicated sequences (with % nucleotide similarity) were identified and set aside for the allocation of sequences into lineages. the aligned and cleaned dataset was imported into mega (kumar et al., ) , where the genetic pairwise distance was measured as a percentage nucleotide difference. using stata (statacorp, ), each of the mshmp sequences were assigned to the lineage that had the smallest genetic distance to an anchor. after sequences were classified into lineages, the duplicated sequences were allocated to their respective lineage group according to the sequence with % similarity that was kept in the lineage classification process. a flow-chart of these steps can be seen in figure . a maximum likelihood phylogenetic tree illustrating genetic relatedness of sequences was constructed based on , bootstraps, adopting the tamura-nei model for substitution of amino acids (tamura and nei, ; kumar et al., ) . clusterpicker software was used to further stratify the most abundant lineage into sub-lineages (ragonnet-cronin et al., ) , in a matter that seemed consistent with the tree main branches while still returning epidemiological meaningful sublineages. the phylogenetic tree was then colored according to the lineage classification and source of sequences (anchor versus mshmp) using microreact (argimón et al., ) . traditional bootstrap support is estimated based on resampling and replication, which tends to yield low support particularly on deep branches and in large trees with hundreds or thousands of sequences (lemoine et al., ) . branch support on the phylogenetic tree thus was evaluated using the bootstrap support by the transfer method (lemoine et al., ) . this method circumvents issues of traditional bootstrapping by assigning a gradual "transfer" index to each clade within the tree rather than a binary presence/absence index for the presence of a clade in each bootstrap (i.e., a clade is considered absent in the bootstrap replicate if the sequences found within the clade is different by even a single member). temporal changes in the frequency of different lineages was tabulated by quarter of the year. graphs representing the relative frequency of prrsv lineages over time were constructed using stata . the frequency with which each lineage occurred over different years was compared using trend analysis for proportions (using the ptrend command) in stata (statacorp, ) . for this test only, lineages with fewer than sequences overall were grouped. the ratio of synonymous to non-synonymous mutations (dn/ds) for all sites in the orf gene region was calculated using the single-likelihood ancestor counting protocol (kosakovsky pond and frost, ) , implemented on the datamonkey webserver . because the analysis can only be performed on sequences at a time, the analysis was repeated on ten random subsets of sequences (after removal of % identical sequences). sites were considered under positive selective pressure if the p-value associated with a higher rate of non-synonymous versus synonymous mutations was smaller than . . the dn/ds (re-scaled for branch length) of all sites from different runs were averaged and the percentage of runs in which each codon was identified as under significant positive selection was calculated. after removal of the seven inadequately sized and two recombinant sequences from the mshmp data, the remaining , mshmp sequences were classified in five different lineages. . % ( , sequences) were classified as lineage , . % ( ) as lineage , . % ( ) as lineage , . % ( ) as lineage , and . % ( ) as lineage . a group of . % ( ) of the mshmp sequences were genetically closer to the european prototype (lelystad) reference, and were thus classified as type prrsv sequences. lineage was further separated into five sub-lineages (a to e). out of the total , sequences in lineage , . % ( ) were classified in lineage a, . % ( ) in lineage b, . % ( ) in lineage c, . % ( ) in lineage d and . % ( ) in lineage e. the phylogenetic tree with all sequences used in the analysis can be seen on figure . using the booster method (lemoine et al., ) , branch support on main branches (lineages and sub-lineages) was above %. the within-and between-lineage nucleotide pairwise genetic distance is shown in table . in general, between lineage/sub-lineage distances are higher than within lineage variation. the distances between sublineages of lineage seem to be smaller between them than between other lineages. broad tree topology was similar when the tree was constructed using nucleotides or amino acids alignment (supplementary figure s ) . on average, the total number of sequences reported to mshmp increased by each year (supplementary table s ), and there was a clear seasonal pattern (figure b ). the first quarter of each year (january -march) was the one with highest number of sequences reported in all but year. the relative frequency of each lineage changed through time ( figure a and supplementary table s ), and specific patterns are noteworthy. first, the absolute and relative occurrence of lineage decreased over time from . % ( sequences) in to < % ( sequences) in the years - . as lineage occurrence to determine whether changes in sampling effort across time impacted general patterns observed here, we repeated the analysis five times, each time randomly sampling orf sequences per quarter. general patterns of lineage occurrence did not change, suggesting that patterns of lineage occurrence were not affected by sampling effort in each quarter (supplementary figure s ) . the visual patterns and turnover of lineages apparent in figure a were shown to be statistically significant. the increase in the frequency of lineages a, , , and type (p < . ) was significant, and changes in the grouped frequency of other lineages (a sum of lineages d, e, and , p = . ) was also significant, but with a difficult interpretation since this is an aggregate of several uncommon lineages. lineages b and c increased in frequency and then decreased (p < . ). lineage frequency decreased over time (p-value < . ), while lineage occurrence remained unchanged (p-value = . ). a total of sites were identified as under positive selection in at least one single-likelihood ancestor counting run (figure ) . some sites were identified as under positive selection in all runs, while others were only identified in some runs. those identified in all runs (with the largest p-value across all runs), were sites (p-value = . ), (p-value = . ), (pvalue < . ), (p-value < . ), (p-value < . ), (p-value < . ), (p-value = . ), and (p-value = . ). a list of all sites identified as under positive selection in at least one run can be found in the caption of figure . most of the sites positively selected were located in the first third of the prrsv orf . the infection status of farms part of mshmp in the studied area over the study time span is shown in figure . this data show two periods in which vaccine usage increased, the first one in mid- , and a second in approximately mid- . not all farms that reported its status to mshmp contributed to sequences to this analysis. we documented the circulation, emergence and sequential turnover of multiple prrsv lineages in a single united states swine-producing region over a span of years ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . by classifying over , prrsv orf contemporary sequences into phylogenetic lineages based on pre- data (shi et al., a,b) , we illustrated the continual diversification and temporal dynamics of the prrsv population. through further stratifying lineage into three main sub-lineages, we also describe the rapid emergence of a sub-lineage ( a), which was absent in the pre- analysis even though that dataset was based on > sequences from across the world (including the region in which we collected our samples) (shi et al., b) . we also identified sites within prrsv orf gene and resultant orf protein that showed evidence of positive selective pressure, indicating that non-synonymous mutations that lead to amino acid changes in the protein at these sites are favored. from to , lineage was the most prevalent genetic group observed in our dataset. shi et al., a,b showed that lineage was rapidly increasing in genetic diversity, which is a proxy for the effective population size of the virus, from to , and reached a peak from to . our data suggests that, at least for our study region, the occurrence of lineage peaked pre- , after which it rapidly declined and was replaced mostly by lineage variants. from to , three different major sub-lineages within lineage emerged, two of those being the most prevalent lineage in certain years ( c from to , a from to ). the emergence of sublineage a, beginning in and peaking in was perceived by veterinarians in the studied area as being a noteworthy event coinciding with the spread of the - - rflp-type. in our dataset, . % of the sequences belonging to the a sub-lineage were rflp-typed as - - (followed by . % of sequences with rflp - - and less than % of - - , - - , - - , - - and several others with less than % -see supplementary table s ) . while the failure to achieve consistent and reliable prrsv control and prevention through vaccination demonstrates gaps in our understanding of prrsv immunology (murtaugh, ) , based on current understanding, prrsv vaccines are expected to better protect against wild viral variants that have a higher degree of similarity to the original parental isolate used for vaccine development (cano et al., ; díaz et al., ; geldhof et al., ) . despite our limited understanding of heterologous cross-protection for prrsv, the emergence and sequential dominance of different variants leading to lineages and sub-lineages is consistent with the theory of multi-strain dynamics (gupta et al., ; kucharski et al., ) . immune responses, whether originating from human interventions or accumulation of immunity toward wild variants, can exert selective pressure that can ultimately lead to the emergence of new pathogen sub-populations (gupta et al., ) . as a virus evolves, immune responses generated against a past variant are expected to become less effective, resulting in a highly complex system, with different lineages interacting through the partial cross-immunity that they generate in the host population (gupta et al., ; kucharski et al., ) . theory predicts that due to frequency-dependent selection amongst co-circulating viral variants, rare antigenic variants are expected to spread more widely in the host population but then subsequently decline as herd immunity rises. such dynamics have been more thoroughly understood for influenza a (webster et al., ; mccullers et al., ; ferguson et al., ; nelson et al., ) and hiv (mcmichael et al., ) . for prrsv, recent research demonstrates that antibodies can exert a strong selective pressure to viral pathogens by targeting specific viral sub-populations, while allowing for the establishment of other sub-populations (wang, ) . when comparing prrsv genetic diversity before and after vaccine adoption in south korea, prrsv vaccination was suggested to increase viral genetic heterogeneity and the emergence of new glycosylation sites in viral populations (kwon et al., ) . however, the extent in which prrsv immunity, whether from natural infection or vaccination, can potentially drive the evolution of the virus in the field remains largely unanswered. our data does show a dominance of non-vaccine related lineages over time, which leads to speculation that these lineages have partially escaped the immunity induced by commercial vaccines or natural infection by variants in other lineages. prrsv vaccines do not protect against infection (scortti et al., ) , but diminish clinical signs and improve animal performance (cano et al., ) . since our project did not evaluate clinical signs of animals, it is difficult to assess the effects of vaccination in that regard. however, despite high region-wide vaccine usage from onward (figure ) , lineage a spread widely in the studied region, suggesting that vaccination and other biosecurity measures were insufficient to limit the transmission of lineage a. lineages shown (figure ) and discussed here and elsewhere are based on phylogenetic relationships in the orf region, and might not be predictive of cross-protection and immunological responses developed by hosts when faced with viruses belonging to different lineages. despite that, the lineage classification protocol used in this study did reveal temporal patterns consistent with what is expected based on epidemiological theory related to the spread of disease in immunologically naive populations. for example, epidemic-shaped curves of occurrence of different prrsv populations were seen, a pattern consistent with the spread of new pathogens (or subtypes) within a naive population. new (sub-) lineages may potentially be able to become the dominant prrsv in the population if they are sufficiently immunologically distinct to overcome herd immunity, and herds with different levels of immunity induced by pre-exposure protocols or natural infections might create selective pressure that changes how fast a new viral variant is selected in that population. for prrsv, it is apparent that protection against homologous prrsv is more robust than against heterologous variants, though the definition of what constitutes a heterologous virus is highly variable (cano et al., ; díaz et al., ; geldhof et al., ) . at the same time, genetic distance has not been shown to correlate with cross-protection, perhaps because pairwise nucleotide identity fails to capture key mutations that impact cross-protection. studies that further explore the immunological cross-reactivity among prrsv lineages are needed. with the data available in this study, it was not possible to investigate the occurrence of specific lineages with vaccination use and more precisely to which vaccine each farm/system used or to which virus was circulating previously on a specific farm. mshmp data of farms from systems that contributed sequences to this paper ( figure ) show two periods in which vaccine usage increased. the first increase in mid- , and a second in approximately mid- . the second spike in vaccine usage coincided with when lineage a began spreading in the study area. it is possible that this second spike in vaccine usage was a reaction to the shift in circulating lineages (more specifically, to the emergence of lineage a prrsv). it is also possible that the increased use of vaccines onward (shown on figure ) and the occurrence of lineages b and c (shown on figure ) immunologically selected sequences in a manner that allowed for the emergence of lineage a in . by mid- , a proportion of farms began using live virus inoculation (lvi). this strategy refers to the use of controlled exposure in gilts through inoculation with live virus isolated from recent clinical outbreak(s) at the farm (desrosiers and boutin, ) . the rationale is that by exposing gilts to virus found in a farm, gilts will mount "homologous" immunity to that specific wildtype virus and contribute to herd immunity and thus stability. according to veterinarians in the area, the increased use of lvi was due to the circulating virus being "different enough" from the viruses used in commercial vaccines. the practice of lvi in the systems here reported began primarily in (figure ). it is difficult to assess the impact that lvi might have on immunologically selecting for specific viral populations within specific lineages, especially with the aggregated data used in this analysis. while the inability of vaccination to control the spread of prrsv lends credence to immunological selection as a driver of prrsv diversification (murtaugh et al., ) , the impacts that immune-driven selection could have on long term prrsv evolution remain unknown. recording exposure procedures (lvi or vaccine use) within farms is crucial when trying to interpret longitudinal patterns of occurrence of prrsv. in future research aimed at more robustly testing hypotheses about immunity as a driver of evolutionary change, this crucial information would allow for investigation of frequencies in which specific lineages occur in farms pre-and post-vaccine/lvi adoption. within orf , we found sites under positive selective pressure within or near two hypervariable regions (figure ; hanada et al., ; delisle et al., ) located near the principal neutralizing epitope (pne). the pne is located between amino acids - and forms an ectodomain which triggers antibodies development during prrsv infection (plagemann et al., ; hanada et al., ) . the flanking hypervariable regions can be linked to the development of an immune response that block accessibility of antibodies to the pne (popescu et al., ) , including n-linked glycosylation sites such as n , n , and n (ansari et al., ) . in general terms, glycosylation may modulate protein-protein interactions, whether these proteins involve the humoral or cellular immune response of the host (lisowska, ) . in prrsv, there is evidence that these glycosylation sites play a role in glycan shielding, which is an important mechanism by which the virus evades neutralizing immune responses (vu et al., ) . while our findings do not explicitly explain the change in lineage, it does raise one hypothesis of the mechanism behind such change. further studies on how specific portions for the genome, both within orf and the whole genome, modulate immune recognition and possibly selective pressure are needed. we also consistently identified positive selective pressure within the pne region, specifically for amino acid . the identification of positive selective pressure in this region suggests that viral variants with different amino acid composition in that region may experience higher fitness and thus are favored. since this region seems to be the primary binding site of neutralizing antibodies developed during prrsv infection (plagemann et al., ; kim et al., ) , this suggests that the reason for such selective pressure could be immune in nature. such a scenario has been considered as a possible explanation for long-term evolution of rna viruses (domingo et al., ; pérez-sautu et al., ) . additional in vitro research is necessary to further clarify the immunological importance of sites identified in our analysis. however, our results suggest the plausibility of a scenario where prrsv variants with mutations in key immunological regions are able to evade immune responses and thus persist and spread within host populations with partial immunity (figure ) . further studies to investigate the role of an incomplete immunity on the evolution of prrsv are required. other mechanisms that might change the ability of the virus to infect hosts have also been proposed. non-muscle myosin heavy chain (myh ) is a molecule that has been shown to be an essential host factor for prrsv infection (gao et al., ) . myh interacts with prrsv glycoprotein (coded for by orf ), changing cell susceptibility to infection. further studies that investigate the contribution that molecules such as myh have on the infection of different orf prrsv variants are needed. additionally, non-neutralizing antibodies can delay the induction of neutralizing antibodies (ostrowski et al., ) in prrsv infection. indeed, the mean level and duration of viremia in pigs was greater among animal injected with sub-neutralizing prrsv-specific igg antibodies (yoon et al., ) , suggesting the existence of an antibody-dependent enhancement (ade) effect in prrsv. the extent in which prior exposures to the virus can elicit such effect, and how this may relate to emergence of new viral variants, also remains uncertain. as an epidemiologic study relying on secondary data generated at the population level, this study has several limitations. our sequence data were generated by different production systems that differ in number of farms, number of samples submitted, management practices, and health monitoring protocols. because of that, information may be incomplete and interpretation of data might not always be straightforward. for example, the reason for sample collection (clinical outbreak or routine monitoring), sample composition (single versus pool of animals) and type of sample (serum or tissues) is not always clear. the lack of a denominator (total amount of animals sampled in a farm, total number of farms tested) does not allow for the calculation of risk indicators for disease occurrence. data contribution by each system also varies with time. however, restricting the data to only the periods in which all systems contributed to the dataset would limit our ability to visualize long-term trends. additionally, the production system that was responsible for % of all sequences was present in the study for the entire study period. therefore, we believe that biases introduced by this issue were likely small and would not have changed the conclusions of our work. in this united states region, systems that participate in the mshmp represent approximately % of the swine farms. the remaining % of farms belong to smaller systems in the area or independent farmers. by having data from systems that represent the vast majority of farms in this region, we expect our data to be reasonably representative of prrsv occurrence in the region as a whole. additionally, despite the shortcomings mentioned above, the usage of mshmp data allows us to work with data directly from the systems, which might suffer less bias toward diseased animals than usual veterinary diagnostics laboratories data do. another limitation of this analysis involves the data generation process for the sequences analyzed here. production systems usually collect samples and send them to different diagnostic laboratories. laboratory details on quality of sequence reads were not available. these sequences most likely represent a consensus of viral sub-populations present within the host (goldberg et al., ; lauring and andino, ) , but further information that could help in assessing the quality of the read and the variability of sub-populations is not available. the sequences used here are from the orf gene alone and may not fully represent evolutionary dynamics elsewhere in the genome, since the orf gene represents approximately % of the whole genome of prrsv. studies that further explore whole genome sequencing as a tool to understand prrsv epidemiological and evolutionary patterns are required. factors affecting prrsv dynamics in specific farms are not clearly understood. we show overall temporal dynamics of prrsv in a swine-producing region of the united states, however, we have limited farm-level information. thus, we have limited ability to track turnover of viral variants within farms, though we expect this to be influenced by management practices, such as the vaccination protocol adopted by farms, the movement figure | we hypothesize that prrsv evolution is partially driven by immune-mediated selective pressure. immune-mediated pressure (either within an animal or during transmission between animals/farms) selects for escapee viral variants (inset). over time, the selection of escapees may allow for emergence of a heterologous viral populations (i.e., strains, genetic groups, or lineages) which are able to spread within the host population. in scenarios in which some method of pre-exposure is adopted, prevalence of immunity against specific types of prrsv is high (often artificially through vaccination or live virus inoculation) despite high population turnover, possibly favoring the occurrence of immune-mediated selection. of animals and personnel to and between farms, the proximity to other swine producing farms, how neighboring farms manage their animals, etc. pig production in the u.s. swine industry is characterized by multi-site pig production, which refers to segregating the breeding herd from the growing herd such that animals in each stage of production are housed at separate locations. multi-site production results in the movement of animals between different production sites, which can be located in different states within the united states (valdes-donoso et al., ; kinsley et al., ) . the role of animal movement in shaping the temporal dynamics of prrsv lineages is outside the scope of this study, but is an area of active research. in addition, the commingling of animals from different sources, which might have been previously exposed to different viral populations, may allow for the introduction of viral types prevalent in other parts of the country and also exacerbate the potential for recombination of viral populations. still, in our dataset we found evidence for recombination in only two mshmp sequences. immune interaction between infections of differing prrsv isolates remains poorly understood in swine. the vast adoption of control protocols that rely on imperfect immune response aimed mostly at reducing severity of upcoming infections (such as pre-exposure protocols with commercial vaccines or with lvi) suggests that a better understanding of the cross-immunity generated by infection with different isolates of the virus would be valuable to the industry as a whole. prospective studies that obtain sera from sow farms under different pre-exposure regimens and follow the farms through time recording prrsv occurrence would provide valuable information of potential cross-immunity in field conditions. of interest also is the better understanding of how the spread different lineages/sublineages are related to epidemiological data, for example, animal movement data and farm proximity. this might allow for a better comprehension of drivers for prrsv transmission while allowing for the evaluation of the effectiveness of practices aimed at reducing prrsv risk (dead animals disposal, manure composting, filtering the air of farms, to name a few). this study reflects data from a single united states region, which possibly does not reflect prrsv diversity and temporal dynamics of the whole swine industry in the country (shi et al., b) . that being said, the data presented here reflects a substantial portion of the u.s. swine industry in a region that is relatively spatially discontinuous from other swine producing regions in the united states. in addition, the general pattern of emergence and turnover of different lineages over time observed here describe an evolutionary phenomenon that is expected to also occur in other united states regions. a better understanding of the natural history of prrsv can provide insights that can potentially aid in mitigating the impact of the emergence of new viral variants as well as serving as a basis for further work exploring the evolution of prrsv and the effect this has on disease control, management and impact on the industry. here, we describe the occurrence of prrsv over years in a single united states region. we identified the emergence and turnover of different lineages and sub-lineages in the commercial pig population. such rapid turnover in the dominant lineage through time suggests that temporal patterns of prrsv occurrence are characterized by multi-strain dynamics, where different prrsv variants potentially interact through immune-mediated competition or selection. however, cross-immunity between different prrsv lineages elicited by natural or intentional infection is not fully understood, which hinders the effectiveness of disease control. more research is needed on drivers of evolution and emergence of new sub-lineages in order for the industry to be able to predict, prevent, and mitigate the impacts of prrsv. ongoing surveillance for prrsv using molecular epidemiological methods is invaluable to characterize the evolution of the virus but also to identify recent and historical trends that help understanding the natural history of prrsv in the united states. the sequence dataset used here is available in genbank under the accessions numbers mn -mn . ip and kv analyzed, conceptualized, and designed the study. cc, js, cv, and kv contributed to acquisition of the data. ip, cc, ar, js, cv, ds, and kv interpreted the data. mm aided in early interpretation of data. all authors but mm were involved in drafting the manuscript and revising it critically for intellectual content and have given final approval of the version to be published. dna sequencing of prrsv using orf influence of n-linked glycosylation of porcine reproductive and respiratory syndrome virus gp on virus infectivity, antigenicity, and ability to induce neutralizing antibodies microreact: visualizing and sharing data for genomic epidemiology and phylogeography genomic evolution of porcine reproductive and respiratory syndrome virus (prrsv) isolates revealed by deep sequencing evolutionary diversification of type porcine reproductive and respiratory syndrome virus effect of vaccination with a modified-live porcine 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the united states temporal and spatial dynamics of porcine reproductive and respiratory syndrome virus infection in the united states using machine learning to predict swine movements within a regional program to improve control of infectious diseases in the us global trends in infectious diseases of swine role of animal movement and indirect contact among farms in transmission of porcine epidemic diarrhea virus immune evasion of porcine reproductive and respiratory syndrome virus through glycan shielding involves both glycoprotein as well as glycoprotein immunological selection as a driver of porcine reproductive and respiratory syndrome virus evolution and ecology of influenza a viruses mystery swine disease in the netherlands: the isolation of lelystad virus differentiation of a porcine reproductive and respiratory syndrome virus vaccine strain from north american field strains by restriction fragment length polymorphism analysis of orf secondary infection with streptococcus suis serotype increases the virulence of highly pathogenic porcine reproductive and respiratory syndrome virus in pigs antibody-dependent enhancement (ade) of porcine reproductive and respiratory syndrome virus (prrsv) infection in pigs high-throughput whole genome sequencing of porcine reproductive and respiratory syndrome virus from cell culture materials and clinical specimens using next-generation sequencing technology we gratefully thank the contributions that emily smith and andres perez made on early stages of the project. we would like to acknowledge the industry partners who contributed to data for this analysis and to shic and mshmp in general, especially to emily geary, involved in the mshmp data curation. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/ . /fmicb. . /full#supplementary-material key: cord- - aflv ly authors: uhr, joshua h.; governatori, nicholas j.; zhang, qiang (ed); hamershock, rose; radell, jake e.; lee, jun yeop; tatum, jasmine; wu, albert y. title: training in and comfort with diagnosis and management of ophthalmic emergencies among emergency medicine physicians in the united states date: - - journal: eye (lond) doi: . /s - - -x sha: doc_id: cord_uid: aflv ly background/objectives: patients with ophthalmic emergencies often present to emergency rooms. emergency medicine (em) physicians should feel comfortable encountering these conditions. we assessed em physicians’ comfort working up, diagnosing, and managing ophthalmic emergencies. subjects/methods: em physicians participated in this cross-sectional multicentre survey. questions inquired about the amount, type, and self-perceived adequacy of ophthalmic training. likert scales were used to assess confidence and comfort working up, diagnosing, and managing ophthalmic emergencies. results: participants recall receiving a median of and h of ophthalmic training in medical school and residency, respectively. few feel this prepared them for residency ( . %) or practice ( . %). only . % feel confident with their ophthalmic exam. most ( . %) feel confident in their ability to identify an ophthalmic emergency, but . % feel well prepared to work them up. responders feel more comfortable diagnosing acute retrobulbar hematoma ( . %), retinal detachment ( . %), and acute angle closure glaucoma ( . %) than central retinal artery occlusion ( . %) or giant cell arteritis ( . %). only . % feel comfortable determining if canthotomy and cantholysis is necessary in the setting of acute retrobulbar hematoma, and . % feel comfortable performing the procedure. there was a trend towards attending physicians and providers in urban and academic settings feeling more comfortable diagnosing and managing ophthalmic emergencies compared to trainees, non-urban, and non-academic physicians. conclusions: many participants do not feel comfortable using ophthalmic equipment, performing an eye exam, making vision or potentially life-saving diagnoses, or performing vision-saving procedures, suggesting the need to increase ophthalmic training in em curricula. delayed care for ophthalmic emergencies can lead to irreversible vision loss or blindness [ ] [ ] [ ] [ ] , which decreases quality of life for patients and leads to significant personal and societal costs [ , ] . much of the responsibility to recognize the emergency and initiate prompt and appropriate care falls on emergency medicine (em) physicians, as ocular complaints represent a substantial proportion of emergency department (ed) visits [ ] [ ] [ ] [ ] [ ] [ ] . in the united states (us), from to , , , ed visits were for ophthalmic complaints, averaging nearly million eyerelayed ed visits and costing approximately $ . billion annually [ ] . as em physicians are often the first members of the healthcare system to encounter a patient with an ophthalmic emergency, it is important that em physicians feel confident diagnosing and managing these cases. however, research outside of the us suggests that em physicians may not be adequately trained in ophthalmology [ ] [ ] [ ] [ ] [ ] [ ] . prior research in the united kingdom has demonstrated that the majority of senior house officers have "little or no confidence" in handling ophthalmic cases, and emergency departments there may be poorly equipped to manage ophthalmic emergencies [ ] [ ] [ ] [ ] . in london, ontario, canada, em physicians have been reported to have a diagnostic accuracy rate of only % for ophthalmic conditions [ ] . as far as we are aware, no such similar research has been published in the united states. the aim of this study is two-fold: to better understand how much ophthalmic training is incorporated into emergency medicine residencies across the us, and to assess how comfortable emergency physicians in the us feel managing emergent ophthalmic disease. this study was determined by the institutional review board (irb) of wills eye hospital to be irb-exempt. a link to an anonymous and confidential survey hosted on a common online platform, google forms, was distributed by email to the council of emergency medicine residency directors (cord). cord is composed of residents and educators in emergency medicine, including program directors, assistant program directors, clerkship directors, and departmental chairs. to increase participation, personalized emails containing the survey link were later sent to residency program directors or department chairs of emergency departments across the us. the survey was then distributed to faculty and residents at their discretion. as there was significant overlap between recipients of this email and cord membership, this served as a follow up notification for most recipients. survey questions assessing participant comfort level with certain situations or extent of agreement with particular statements were asked on a likert scale from to , with representing "very uncomfortable" or "strongly disagree" and representing "very comfortable" or "strongly agree". in our results, we report the proportion of responders who answered or , indicating feeling comfortable (comfortable/very comfortable) or agreement (agree/strongly agree) with the statement in question. summary statistics are reported on a participant level. comparisons between groups for categorical variables were tested with chi-square test or fisher's exact test for categorical variables, depending on the expected cell count. since the continuous variables were not normally distributed, differences between groups for these variables were tested with the rank sum test. a two-sided alpha level of . was used to determine significance. all p-values regarding the likert scale data are for comparisons of the combined scales (i.e., very uncomfortable/comfortable, neutral, and comfortable/very comfortable) between groups. summaries were computed using sas . . table summarizes basic demographic information about participants. in brief, the majority of responders were male ( . %, / ), trainees (residents or fellows) ( . %, / ), work primarily in an urban setting ( . %, / ), and work primarily in an academic medical centre ( . %, / ). most responders report that training in diagnosis and management of ophthalmic disease was a formal part (including lectures, didactics, and skills sessions) of their medical school ( . %) and residency curricula ( . %). participants recall receiving a median of and h of formal training in medical school and residency, respectively. only . % ( / ) feel that medical school prepared them well for encountering ophthalmic emergencies during residency, and just over half ( . %, / ) feel that their residency training is or was adequate for practice after residency. accordingly, . % ( / ) and . % ( / ) wished they received more training in ophthalmic disease during medical school and residency, respectively. overall, . % ( / ) of responders have access to an on-call ophthalmologist in the setting in which they work. most ( . %, / ) have access to a functional slit lamp, although . % ( / ) have not had formal or dedicated teaching in how to use one and only . % ( / ) feel comfortable/very comfortable using one. fewer ( . %, / ) have access to a direct ophthalmoscope, and . % ( / ) have not had formal or dedicated teaching in how to use one. only . % ( / ) feel comfortable/very comfortable using a direct ophthalmoscope. almost all ( . %, / ) responders have access to a device to measure intraocular pressure, most commonly a tonopen ( . %, / ), followed by an icare rebound tonometer ( . %, / ). the remainder use a schiotz tonometer, goldmann applanation tonometry, finger tension, a combination of methods, or did not know. figure summarizes participant responses to general questions regarding comfort identifying and workup up ophthalmic emergencies. in general, most responders ( . %) feel they know which eye diseases are emergent and which are not, and . % feel confident in their ability to identify an ophthalmic emergency. even so, only . % feel wellprepared to work up patients with these emergencies, and . % feel comfortable generating a differential diagnosis for ophthalmic emergencies. approximately half ( . %) feel confident with their ophthalmic exam. figure summarizes the proportion of responders who feel comfortable diagnosing patients with specific diseases: retinal detachment (rd), acute angle closure glaucoma (aacg), central retinal artery occlusion (crao), giant cell arteritis (gca), and acute retrobulbar hematoma (arbh). most participants ( . %, / ) feel comfortable/very comfortable using ultrasound to evaluate the status (attached vs. detached) of the retina. most ( . %) also feel comfortable diagnosing arbh and determining (comfortable/very comfortable: . %, / ) if orbital decompression by lateral canthotomy and inferior cantholysis (lcc) is necessary in the setting of arbh, but few feel comfortable (comfortable/very comfortable: . %, / ) performing the procedure. almost half ( . %, / ) have never performed one, and the same number have only performed or . the remainder have performed to ( . %, / ), to ( . %, / ), or or more ( . %, / ). providers in urban settings were more often female ( . % vs. . %, p = . ) and in a higher post-graduate year (for residents, p = . ). the urban providers were more often also in academic settings ( . % vs. . %, p < . ) with access to an on-call ophthalmologist ( . % vs. . %, p < . ). more urban providers reported having training in diagnosis and management of ophthalmic disease as part of their residency curriculum ( . % vs. . %, p = . ) and less wished they received more training in ophthalmic disease during medical school ( . % vs. . %, p = . ) and residency ( . % vs. . %, p = . ) compared to the non-urban group. the urban group felt more confident than the non-urban group in their ability to identify an ophthalmic emergency (agree/strongly agree: . % vs. . %, p = . ) and communicate exam findings when calling an ophthalmology consult (agree/strongly agree: . % vs. . %, p = . ). they also felt more comfortable diagnosing patients with suspected arbh ( . % vs. . %, p = . ). the urban and non-urban groups had a difference in proportion for comfortability diagnosing patients with suspected gca, with more urban providers reporting neutral ( . % vs. . %) and less reporting uncomfortable or very uncomfortable ( . % vs. . %, p = . ). more urban providers felt comfortable determining if orbital decompression is necessary in the setting of arbh (comfortable/very comfortable: . % vs. . %, p = . ). they also performed more (> performed: . % vs. . %, p = . ) and felt more comfortable performing lcc (comfortable/very comfortable: . % vs. . %, p = . ). all other survey responses were similar between urban and non-urban providers. academic vs. non-academic (including community/ hybrid/county hospital) (n = ) the distribution of residency locations differed between providers in an academic vs. a non-academic setting, with almost half of the academic group being in the northeast ( . %) compared to . % of the non-academic group (p = . ). providers practicing in an academic setting were also primarily in an urban setting ( . %) compared to . % of providers in the non-academic group (p < . ). the academic group reported having more access to an oncall ophthalmologist ( . % vs. . %, p < . ). this group also feels more comfortable (comfortable/very comfortable: . % vs. . %, p = . ) using a slit lamp. non-academic providers wished they received more training in ophthalmic disease during medical school more often than academic providers did ( . % vs. . %, p = . ), although both groups had an equal proportion of providers ( . % vs. . %, p = . ) wishing they received more training in ophthalmic disease during residency. the academic group felt more confident in their ability to identify an ophthalmic emergency (agree/strongly agree: . % vs. . %, p = . ) and communicate exam findings when calling an ophthalmology consult (agree/strongly agree: . % vs. . %, p = . ). the academic group felt more comfortable determining if orbital decompression is necessary (comfortable/very comfortable: . % vs. . %, p = . ) and more comfortable performing a lcc (comfortable/very comfortable: . % vs. . %, p = . ). all other survey responses were similar between providers in an academic and non-academic setting. attending physicians were less likely to wish they received more training in ophthalmic disease during medical school ( . % vs. . %, p < . ) and residency ( . % vs. . %, p = . ), received more hours of formal ophthalmology training/teaching (median vs. , p < . ), and more often felt that this training was adequate for practice after residency ( . % vs. . %, p = . ). they also were less likely to feel more formal teaching in eyerelated emergencies would be beneficial (agree/strongly agree: . % vs. . %, p = . ). attendings more often had formal teaching or dedicated teaching time in how to use a slit lamp ( . % vs. . %, p < . ) than residents and fellows and feel more comfortable using a slit lamp (comfortable/very comfortable: . % vs. . %, p < . ). they also had more formal teaching or dedicated teaching time in how to use a direct ophthalmoscope ( . % vs. . %, p = . ) and feel more comfortable using a direct ophthalmoscope (comfortable/very comfortable: . % vs. . %, p < . ). attendings more often felt like they know which eye diseases are emergencies (agree/strongly agree: . % vs. . %, p < . ), felt confident in their ability to identify an ophthalmic emergency (agree/strongly agree: . % vs. . %, p < . ), felt well-prepared to work up patients with ophthalmic emergencies in the emergency room setting (agree/strongly agree: . % vs. . %, p < . ), and felt comfortable generating a differential diagnosis for ophthalmic emergencies in general (agree/strongly agree: . % vs. . %, p < . ). they also felt more confident with their ophthalmic exam (agree/strongly agree: . % vs. all other survey responses were similar between attendings and residents/fellows. since eye complaints are common in emergency departments across the united states [ ] [ ] [ ] [ ] [ ] [ ] , and since prompt and appropriate care is important for visual prognosis [ ] [ ] [ ] [ ] ] , it is important that em physicians are well prepared to encounter these cases. however, in this study, a substantial proportion of responders report not feeling comfortable using basic ophthalmic equipment, performing an eye exam, making vision or in some cases potentially life-saving diagnoses, or performing vision-saving procedures. the vast majority of responders have access to basic ophthalmic equipment in their daily practice, including a slit lamp ( . %), direct ophthalmoscope ( . %), and device to measure intraocular pressure ( . %). this is superior to reported access in the uk, where a survey found that only . % of accident and emergency (a&e) departments (equivalent to an american ed) had a slit lamp, although this increased to . % by [ , ] . most ( . %) responders in this study report having had formal training on the slit lamp, but only . % feel comfortable using one (compared to . % who received training and . % who felt comfortable in the uk) [ ] . even fewer ( . %) received formal training for the direct ophthalmoscope, which only . % feel comfortable using. since ophthalmic emergencies in the us often present to general emergency departments-in contrast to the uk, where many large hospitals have separate eye causality departments-it is particularly important for em physicians in the us to have access to ophthalmic equipment for thorough ocular evaluation. however, these tools are difficult to use and their utility is limited by user proficiency. as most responders feel uncomfortable using these devices, it is perhaps unsurprising that only half ( . %) feel confident in their ophthalmic exam, implying a need for increased emphasis on equipment training during em residency. em physicians indicated that they feel more comfortable diagnosing arbh ( . %), rd ( . %), and aacg ( . %) than crao ( . %) or gca ( . %). however, the latter two are particularly important diagnoses to be able to make, as both have features which may be more debilitating than arbh, aacg, or rd in the absence of timely diagnosis. arbh and aacg quickly lead to vision loss or blindness in the affected eye when management is delayed [ ] [ ] [ ] . rd also leads to monocular vision loss, but optimal time to repair depends on multiple factors beyond our scope [ ] . unlike these usually unilaterally vision-impairing emergencies, delayed diagnosis and treatment of gca may lead to rapid bilateral blindness [ ] [ ] [ ] . fortunately, gca is uncommon; the estimated age-adjusted and sex-adjusted prevalence is per , people aged ≥ in the us [ ] , % to % of which may develop permanent vision loss [ ] . even so, as vision loss may be preventable with early initiation of treatment, and since vision loss is associated with substantial personal and societal costs, early recognition is crucial. in contrast, there is no evidence-based therapy available to reverse vision loss in crao [ ] . nevertheless, timely diagnosis is critical as crao has serious systemic health implications. there is increasing awareness in the medical community, including by the american heart association and american stroke association, that acute ischemic retinal cell death is a stroke equivalent [ ] . as such, acute crao constitutes a medical emergency warranting immediate systemic work up [ ] . moreover, recent metaanalyses suggest that thrombolysis (intravenous or intraarterial) appears to be a promising therapy, although safety and efficacy data from randomized clinical trials are needed [ , ] . if thrombolysis does become the standard of care, the window for administration will likely be a matter of hours [ ] , further heightening the need for rapid diagnosis in the ed. although em physicians feel relatively comfortable diagnosing arbh, a minority ( . %) feel comfortable/ very comfortable performing lcc, and almost half ( . %) have never performed lcc. ocular trauma is the most common ophthalmic complaint encountered in the ed and the most common cause of unilateral vision loss worldwide [ , , ] . the reported incidence of arbh in the setting of ocular trauma varies but ranges from < % to . % [ , ] . immediate orbital decompression, most commonly by lcc, is required to optimize visual potential in the setting of orbital compartment syndrome secondary to arbh [ , , , ] . since a strong correlation between preparedness for various procedural skills and confidence of em physicians performing those procedures has been demonstrated [ ] , em physicians should feel comfortable performing this vision-saving procedure. in the united states, em training includes a three or four year residency in emergency medicine following medical school graduation. some physicians may choose to pursue further sub-specialization by completing a fellowship following residency (fig. ) . in our analysis, we consider both residents and fellows to be trainees. attending physicians (who have completed training) in general felt more comfortable diagnosing and managing ophthalmic emergencies than trainees (except for the use of ultrasound), which likely reflects cumulative experience and continued learning after residency. there was also a trend in our data towards urban and academic providers feeling more comfortable diagnosing and managing ophthalmic emergencies. as our data are skewed towards academic ( % of responders) and urban ( % of responders) providers, our results therefore likely overestimate em physician comfort and confidence in the diagnosis and management of ophthalmic emergencies nationwide. although is it a limitation to our study that our sample may not be representative of all em physicians in the united states, this probable overestimation only further strengthens our conclusion that there is a need for increased ophthalmic training in em residencies. there are several other limitations to our study. first, we are unable to determine the response rate. as described, we emailed our survey link to emergency department administrators nationwide, but it was distributed at their discretion and we lack a mechanism by which to determine how many physicians received the link. second, as we asked physicians to retrospectively estimate the amount of teaching received during various periods of training, some aspects of our results may be subject to recall biases. finally, the relationship between confidence and competence is complex and not perfectly correlated [ ] . although it is desirable for physicians to feel confident and comfortable with the diseases they manage, high or low confidence may not always translate into good or bad clinical outcomes, respectively. we cannot determine from our data what proportion of ophthalmic emergencies are correctly diagnosed or managed in the ed setting. this might be an interesting topic for future research. in summary, em physicians surveyed report feeling inadequately prepared by their medical school and residency training to encounter ophthalmic emergencies. concordantly, fig. medical education in the united states. the figure describes the process of becoming a physician in the us, including the general educational steps required for all physicians, as well as the subspecialty training requirements for ophthalmologists and emergency medicine physicians. most desire more training. responders also report low levels of comfort in multiple areas: using basic ophthalmic equipment, performing an eye exam, making certain vision or potentially life-saving diagnoses, and performing visionsaving procedures. taken together, these findings suggest the need to increase ophthalmic training in emergency medicine curricula. considering that the majority of responders have on-call access to an affiliated ophthalmology department, and that most responders desire more ophthalmic training, increased educational collaboration between ophthalmology and emergency medicine departments may be one practical approach to accomplish this. what was known before • timely treatment for these ophthalmic emergencies is important to ensure the best visual prognosis for patients. since patients with eye emergencies often present to emergency rooms, emergency medicine physicians should feel comfortable encountering these cases in order to diagnose them and provide appropriate and prompt initial management. • prior studies have shown that emergency medicine physicians in the united kingdom are underprepared to encounter eye emergencies. this has not been studies in the united states. description of us ophthalmic training: in the united states, ophthalmology training after medical school graduation consists of completing a four-year ophthalmology residency. although there are variations across training programs, the first year of residency usually consists of predominantly general medicine or general surgery rotations. the following three years focus exclusively on ophthalmology. upon completion of residency, trainees are prepared to practice comprehensive ophthalmology. sub-specialty training (retina, oculoplastics, glaucoma, etc.) typically entails completion of an additional one or two-year fellowship program. emergency medicine training in the united states consists of, depending on the specific program, a three or four-year emergency medicine residency. • this is the first study to show that emergency medicine physicians in the united states report generally low levels of comfort using basic ophthalmic equipment; performing an eye exam; making vision saving or, in some cases, potentially life-saving diagnoses; and performing vision-saving procedures. these findings underscore the need to increase ophthalmic training in emergency medicine curricula in the united states. 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nhs competent in managing ophthalmic cases in the emergency department? management of eye emergencies in the accident and emergency department by senior house officers: a national survey national survey of the management of eye emergencies in the accident and emergency departments by senior house officers: years on-has anything changed? can general a&e doctors manage common eye emergencies? accuracy of referral diagnosis to an emergency eye clinic acute retrobulbar haemorrhage: an ophthalmologic emergency for the emergency physician retrobulbar hematoma: a systematic review of factors related to outcomes why does acute primary angle closure happen? potential risk factors for acute primary angle closure ocular emergencies fovea-sparing retinal detachments: time to surgery and visual outcomes simultaneous bilateral posterior ischemic optic neuropathy secondary to giant cell arteritis: a case presentation and review of the literature giant cell arteritis: ophthalmic manifestations of a systemic disease ocular manifestations of giant cell arteritis contemporary prevalence estimates for giant cell arteritis and polymyalgia rheumatica giant cell arteritis: early diagnosis is key central retinal artery occlusion-a new, provisional treatment approach management of acute retinal ischemia: follow the guidelines! ophthalmology is intravenous thrombolysis safe and effective in central retinal artery occlusion? a critically appraised topic intra-arterial thrombolysis for acute central retinal artery occlusion: a systematic review and meta-analysis ocular trauma and other catastrophes incidence of retrobulbar hemorrhage in the emergency department orbital compartment syndrome: the ophthalmic surgical emergency procedural skills training during emergency medicine residency: are we teaching the right things? a qualitative study of self-evaluation of junior doctor performance: is perceived "safeness" a more useful metric than confidence and competence? acknowledgements the authors acknowledge the support of the biostatistics consulting core, vickie and jack farber vision research center, wills eye hospital. conflict of interest the authors declare that they have no conflict of interest.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -cwhmm f authors: nan title: challenges to the european exception: what can s&t do? date: journal: a new deal for an effective european research policy doi: . / - - - - _ sha: doc_id: cord_uid: cwhmm f nan a quick review of the available evidence shows, however, that, while great strides have been made over the past few decades towards the achievement of these goals, europe is facing significant challenges in most if not all of these areas. economic growth is slow. europe's competitive position is feeble. there are not enough jobs, and not enough of them are high-level. europe is still characterised by significant poverty and regional inequality. an important demographic challenge is emerging. europeans' health is affected by serious lifestyle and contagious diseases. and the environment is being degraded. this is undermining what europeans are most proud of and turning europe into a negative exception at global level. the term "european exception" is most often used to refer to a european country not acting in accordance with what most other european countries are doing, whatever the field. sometimes, however, the vocabulary is also used to refer to how europe behaves differently from other advanced world economies. usually, reference to the european exception has a positive tone to it. europeans are proud of their commonly held values, their social model based on egalitarianism and solidarity, their high level of environmental awareness and protection and so on. however, europe appears to be the only advanced economy suffering from chronic low growth and high unemployment, and an unceasing lack of dynamism. its levels of poverty and of individual and regional income inequality are not that far removed from us levels. and this makes europeans feel anxious, and unsure of themselves, their future and further european integration. significant change has characterised the world economy over the past few decades. world trade has been liberalised as both formal and informal trade barriers have been reduced significantly, or disappeared altogether. capital roams the planet freely in search of the best investment opportunities as barriers to capital mobility have been eliminated. global communication and transportation networks have become denser and better integrated through a combination of technological and organisational innovation. the speed of technological change has accelerated while technologies are standardised more rapidly and use is made of modular production systems. as the combination of these factors has made it possible to locate the production of goods and services anywhere on the planet and still serve global markets, the global production system is in the process of being reconfigured. the new international division of labour not only provides both developing and developed countries with ample opportunities, it also has shady sides. on the one hand, low-, medium-and to an increasing extent high-technology manufacturing and services industries are under threat from delocalisation or so-called off-shoring and outsourcing, resulting in at least short-term disruption and unemployment. employment is also under threat from rapid process innovation leading to productivity increases. on the other hand, rapid product innovation provides developed countries with opportunities to improve competitiveness and serve global markets by fleeing forward as it were. the race to upgrade the economy is never-ending, however, and innovation-based advantages are fleeting and unsustainable as rapid standardisation and modular production techniques quickly allow the production process to move partially or completely to developing countries. as reflected in its lacklustre economic growth performance, europe has not yet adapted to the rules of this new game. in the first half of the post-war period, the european economy grew as fast as the world economy ( fig. . ) . in the second half of the post-war period, however, the decline in economic growth was more pronounced in europe than in the united states, japan and other oecd economies (figs . and . ) . in the last years or so, europe has done worse than the united states, while japan has once again started to outperform europe, and the large bric (brazil, russia, india, china) economies and smaller east asian economies continue to grow rapidly. the growth of output amounted to . per cent in the euro area in , substantially lower than the . per cent in the united states and the . per cent in japan, and the . per cent at world level. output is projected to grow by a higher . per cent in the euro area in , still economic growth in the euro area has been lagging that of the best performing oecd countries since the mid- s. it should be acknowledged, however, that some eu countries have performed rather well economically in the past decade. this group includes the member states formerly classified as cohesion countries (especially ireland), as well as finland, the netherlands and the uk. year cumulative growth gap fig. . . slow european economic growth in the second half of the post-war period compared to other industrialised countries (cumulative economic growth gap between the eu and the other industrialised countries (current prices and current ppps)) source: dg research data: oecd note: for both the eu- and the non-eu- oecd countries, gdp at current prices and current ppps (billions of dollars) was taken as . for all following years, gdp growth in percentages relative to the amount was calculated. then the series for the non-eu oecd countries (australia, canada, iceland, japan, korea, mexico, new zealand, norway, switzerland, turkey, us) was set to and the difference with the series for the eu- calculated. significantly lower than the . per cent in the united states and the . per cent in japan, and the . per cent at world level. whenever europe has been able to increase productivity in the past it has suffered in the field of employment, and vice versa, pointing to the existence of structural barriers to growth. underlying europe's lacklustre economic growth performance is its weak competitive position. the most common definition of competitiveness refers to the overall capacity to improve standards of living in a sustainable way. states during the s and s. but since the s, european standards of living have not increased relative to the united states ( fig. . ) . labour productivity is another common measure of competitiveness. though, except for a few countries, the productivity gap was never closed in the end, for most of the post-war period the eu somehow caught up on average with the united states. this catch-up has now stopped and is even being reversed. since , for the first time in three decades, growth in us labour productivity has outstripped that of the union (fig. . ) . this eu productivity downturn is of a structural nature and mainly due to an outdated and inflexible industrial structure slow to adapt to the intensifying pressures of globalisation and rapid technological change. deindustrialisation is often taken as a further sign of europe's deteriorating competitiveness. the fear is that slow labour productivity growth, high labour costs, year gdp per capita (us= ) eu euro area fig. and short and inflexible working hours drive entire industries to low-cost, hightech countries in eastern europe and asia. the evidence for deindustrialisation is not clear-cut. some analyses point out that industry still accounts for the same important share of gross domestic product in terms of volume as in the past, while the declining share in terms of value added and employment is due simply to decreasing prices because of productivity gains and exposure to competition higher than that for services. should it occur, the impact of deindustrialisation would indeed be worrying: the existence of many services depends on the presence of industry; industry pays better wages than services, even for low-skilled jobs; industry accounts for most innovations and technological revolutions; and industry has an important strategic role. europe's feeble competitive position is also clear from its weak trade performance, especially that at the high-tech end. europe's most dynamic export products are generally not those one would closely associate with the knowledge-based economy. the top three products with the fastest growing market share are floor coverings, pork and poultry fat, and hemp. on the other hand, if one looks at products for which market share is in major decline (> per cent loss in market share), the eu has many more ( product groups) than the united states ( ) or japan ( ). what is more, in europe many technological products are among them (e.g. air launchers, turbines, insulating glazing, drugs containing alkaloids or hormones, telephones, photographic film). high-tech manufacturing exports represent a much smaller proportion of total manufacturing exports in europe than in the united states or japan (in , . per cent vs. . per cent and . per cent respectively). europe's share of global high-tech manufacturing exports, though increasing, is lower than that of the united states (in , . per cent vs. . per cent respectively). and europe runs a structural deficit in high-tech manufacturing trade, whereas the united states and japan run surpluses. the european employment input is significantly lower than that in the united states. first, though apparently catching-up, the european employment rate is still substantially lower than that of the united states ( fig. . ). in , the eu- employment rate was . per cent and the eu- one . per cent, so to percentage points below the target under the lisbon agenda, compared to . per cent in the united states. this is mainly due to the limited participation of women, the young, and the elderly in the labour force. at . per cent and . per cent, the female and older people's employment rates were about and percentage points below the lisbon targets for . second, europe also scores lower than the united states in terms of the number of hours worked annually per employee ( fig. . ). for a long time, the low employment rate and number of hours worked annually per employee were explained with reference to the european emphasis on work-life balance. a growing number of authors draw attention to the existence of disincentives to work, however, the main one being the lack of employment opportunities. this lack of employment opportunities is clear from the high unemployment rates. in , about . million europeans were out of work. this equalled . per cent of the labour force, some percentage points higher than the rates in the united states and japan ( fig. . ) . the proportion of high-level jobs is also considerably lower in europe than in the united states. though europe likes to pride itself on its superior social model, poverty rates are rather high, and regional inequality is substantial. in , the at-risk-of-poverty year eu- the gini coefficienta number between and used to express the degree of income inequality, where corresponds to perfect income equality and corresponds to perfect income inequality -was . in both the eu- and the eu- ( fig. . ) . the share of children living in households with income below the poverty line ranges from per cent in slovenia and per cent in denmark to per cent in slovakia. the eu is also marked by substantial inequality in income levels. in , gross domestic product (gdp) per capita was below per cent of the eu- average in out of nuts regions examined in the eu- . the highest eurostat. at the beginning of the s, eurostat set up the 'nomenclature of statistical territorial units' (nuts) as a single, coherent system for dividing up the european union's territory in order to produce regional statistics for the community. nuts subdivides each member state into a whole number of regions at nuts level. each of these is then subdivided into regions at nuts level , and these in turn into regions at nuts level . leaving aside regional gross domestic product per capita (inner london -united kingdom) was about times the lowest one (lubelskie -poland). enlargement, for the european union, is at one and the same time a challenge and an achievement, a "raison d'être" and a "façon d'être". it is a continuation of the historical process that started over years ago with the communities' inception, developed through several steps (in , , , , ) , and reached a high point -albeit not an end-point -with the enlargement of the european union to countries of eastern and southern europe on may . preparation for that enlargement took several years and by the time they joined, the eu- had successfully transformed their economies from centrally planned to functioning free market ones. compliance with the copenhagen criteria for accession served as a powerful catalyst for change. this assessment is detailed in a recent stock-taking exercise in which the commission services have provided strong evidence and analyses indicating that the enlargement constitutes an economic success for the "old" and the "new" member states alike. it has to be noted that enlargement has been a dynamic process rather than a discrete event and that its effects will become visible over time. figure . shows that convergence and catching up in real income have been at work throughout the period since the late s. per-capita incomes are now much closer to eu- levels than they were in , the year in which enlargement prospects crystallized in the commission's agenda . after the output collapse in the early years of transition, growth rates in the eu- have been higher than in the eu- , but also more volatile. the key contributors to actual and potential economic growth in the eu- have been capital accumulation and technical progress (the so-called total factor productivity, tfp), while the contribution of labour has been mostly negative (that being a reflection of weak employment growth and, to a lesser extent, of an ongoing decline in hours worked per employee). in general, and consistent with the convergence hypothesis, member states with lower initial ( ) per capita income tended to grow faster in the intervening years. birth rates continue to be low in europe. everywhere, the fertility rate is below the threshold needed to renew the population (around . children per woman), the local level (municipalities), the internal administrative structure of the member states is generally based on two of these three main regional levels. this existing national administrative structure may be, for example, at nuts and nuts levels (respectively the länder and kreise in germany, or at nuts and nuts (régions and départements in france, comunidades autónomas and provincias in spain). of aids deaths was estimated at . million. in europe, the number of newly reported hiv infections is increasing, while that of newly diagnosed aids cases is decreasing. in the eu countries with data available for and for both hiv infections and aids cases, the number of newly reported hiv infections increased by almost per cent (from to , ) while the number of newly diagnosed aids cases fell by over per cent (from to ). europe is also affected by other communicable diseases including sars and avian influenza. one of the most worrying challenges for europe, and indeed for the whole world, concerns the deterioration of the environment. european citizens overwhelmingly agree that the state of the environment influences their quality of life ( per cent), that policy-makers should consider the environment to be just as important as economic and social policies ( per cent), and that policy-makers should take into account environmental concerns when deciding policy in other areas such as the economy and employment. "a high level of protection and improvement of the quality of the environment" is a european community objective (see above). europe has been implementing environmental action plans and pursuing sustainable development strategies at both national and european level for quite some time now. it plays a leading role in the fight against global warming. and it occupies a strong position in the field of environmental technologies. yet, because of population growth; consumption patterns; market, policy and political failures; features of existing technologies; and world views and values, europe and the world at large are still far removed from a development trajectory that is truly sustainable, that is, which satisfies the current needs of society (growth, competitiveness, employment, etc.) without compromising the needs of future generations. european citizens worry most about water pollution (of seas, rivers, lakes, underground sources, etc.) ( per cent); man-made disasters (major oil spills, industrial accidents, etc.) ( per cent); climate change ( per cent); and air pollution ( per cent). the sixth environment action programme of the european community - ( th eap) identifies four priority areas for urgent action: ( ) climate change; ( ) nature and biodiversity; ( ) environment and health and quality of life; and ( ) resources and waste. the environmental objectives of the eu sustainable development strategy include: ( ) addressing climate change; ( ) better management of natural resources; and ( ) making transport more sustainable. a review of nine recent comprehensive analyses of global environmental problems (table . ) showed near-unanimous agreement that the three problems posing the greatest threats to the global environment and continuing economic development include: ( ) water quality and access; ( ) climate change; and ( ) loss of biodiversity. climate change forecasts indicate that, if the level of emissions is not curbed, the temperature level will rise and risks such as water shortage, malaria and hunger will increase and affect millions of people by ( fig. . ). addressing such environmental problems is highly complex. one of the premises of sustainable development is that environmental problems interact with each other, as well as with economic and social issues. climate change affects agriculture, forestry, water availability, marine systems, terrestrial ecosystems, health and, last but not least, the economy. forests and oceans act as climate regulators but also harbour a wide diversity of species. decisively tackling the issue of biodiversity will require i.a. making forestry sustainable, addressing pollution, and dealing with climate change. pollution negatively affects health, from allergies and infertility to cancer and premature death. in the mid- s damage costs to the eu caused by air pollution originated in the eu (see table . ) were calculated to be around per cent of eu gdp (ranging from . to . per cent) and damages to eu and non eu countries caused by air pollution originated within the eu were estimated to be . per cent of eu gdp (with ranges between . and . per cent), with health damages accounting for the largest share. an animal and human health problem like aviary flu also constitutes a threat to biodiversity. environmental degradation contributes to the increase recorded in the number of disasters and, in relation to this, to a heightened sense of vulnerability (see fig. . in the last section of this chapter). disasters can be man-made or natural and include wildland fires, earthquakes, volcanic eruptions, landslides/debris flows, floods, extreme weather, tropical cyclones, sea and lake ice, coastal hazards including tsunamis, pollution events, and so on. during the period - , disasters killed , people and caused billion dollars of damage. throughout history, the relation between science and society has been marked by both continuity and change. the continuity is situated in the tension between the c h a p t e r philosophical and intellectual pursuit of and search for knowledge on the one hand, and the desire of researchers and their supporters to make scientific knowledge useful and apply it on the other hand. this tension was first recognised by the ancient greek philosophers, and has been reflected in recurring calls from philosophers and scientists throughout history, including today, for more "research for its own sake". within the context of this tension, the change has been located in what has constituted or better what has been considered useful knowledge in each age, in other words in "the changing social expectation of science": "what counts as useful knowledge differed from patron to patron and society to society, so that cosimo de medici and the united states department of energy looked for quite different 'products' to be created by their clients, but both traded support for the potential of utility". from century to century, societal expectations of s&t have not just changed. they have also increased. in the era of the ancient greek philosophers, societal expectations of s&t were rather low. s&t was a highly controlled activity carried out by a small elite group of people for philosophical or religious objectives. at present, however, it is considered a powerful tool for political, economic, and social change. in between, s&t helped exploit worldwide resources as trade empires and colonies expanded ( th century); helped expanding and consolidating trade empires and colonies, and turn their natural resources into wealth, or make up for the lack of trade empires and colonies ( th century); helped fight wars (first world war and second world war); and helped producing consumer goods, consumer medicines, exploring space, addressing environmental challenges, exploring the human genome, and so on (post-war period). it is no exaggeration to say that as a result today societal expectations of s&t have never been higher in industrial countries. in the united states, the carnegie commission on science, technology, and government listed in no less than major societal goals to which s&t can contribute (table . ). and a national academies report noted in that "the nation increasingly looks to the scientific and engineering communities for solutions to some of its most intractable problems, from chronic disease to missile defence, to transportation woes, to energy security, to ensuring clean air and clean water. expectations for s&t are perhaps higher than at any other time in our history and are placing unprecedented demands on leadership". needs of society as they change over time, or in other words, to become a 'science and technology for society' ". things are no different in europe. in , the european commission remarked that "expectations of science and technology are getting higher and higher, and there are few problems facing european society where science and technology are not called upon, one way or another, to provide solutions". out of the challenges europe is facing, and recommendations have been made on how to address them. time and again the same wide range of urgently to be addressed challenges is identified. the reports are also near-unanimous in the key role assigned to s&t in this respect, as will be seen in chapter . in other words, great expectations are held of s&t as regards the tackling of the multitude of challenges europe is facing. this will be developed in chapter as part of the new policy context that enabled the genesis of the lisbon strategy as well as of the th framework programme. the role that s&t can play in addressing all these challenges is expected to be substantial. this section will show that s&t indeed has the potential to contribute to a range of economic, social and environmental challenges: it can improve economic performance, promote employment, improve public health, tackle demographic, cohesion and environmental challenges, and so on. modern mainstream economic theory -whether neoclassical, endogenous or evolutionary -has recognised for quite some time now that technological progress and innovation are the main engines of economic growth. according to baumol, innovation explains much of the extraordinary economic growth record under capitalism. the reason is that in important parts of the economy, competition is based on innovation rather than price. firms are therefore forced by market pressure to support innovative activity systematically and substantially. according to romer, productivity growth is driven by innovation resulting in the creation of new though not necessarily improved product varieties. and under the schumpeterian paradigm, growth results from "quality improving innovations that render old products obsolete, and hence involves the force that schumpeter called 'creative destruction' ". even basic research generates several direct economic benefits. it is a source of useful new information; it creates new instrumentation and methodologies. those engaged in basic research develop skills which yield economic benefits when individuals move from basic research carrying codified and tacit knowledge. through participation in basic research, access is granted to networks of experts and information. those there is also empirical support for the contribution of s&t to economic performance (see tables and sources in annex). estimates of private returns to firms' own investment in r&d still produce varying figures, but there is an emerging consensus that gross returns between and per cent are common and plausible (table . ) . microeconomic studies confirm the existence of significant spillovers of knowledge from the firms that perform the r&d to other firms and industries. taking account of measured spillovers typically raises the estimated gross rate of return on business investment into the range of to per cent (tables . - . ) . macroeconomic studies, which by definition cover all sectors of the economy, also find significantly higher returns to r&d in oecd countries, with estimates ranging from per cent to over per cent. a recent austrian report found that the rise of corporate spending on r&d from . per cent to . per cent of gross domestic product in the second half of the s produced a boost of three tenths of a per cent in growth. both microeconomic and macroeconomic studies find that an important source of productivity growth in all oecd countries comes from the international diffusion of technology. a country's ability to absorb those foreign technologies is enhanced by investment in education and by investment in own r&d. the economic literature is not conclusive on the employment effects of innovation, since process innovation (the introduction of labour-saving technologies) is likely to have a negative effect on employment, assuming all other factors remain constant, while product innovation creates new markets and employment opportunities. but empirical evidence suggests that technological change promotes employment. such evidence includes a recent study of the directorate-general employment which found that the rate of growth of total factor productivity (due to improvements in the efficiency of production or to pure technological progress) has a positive impact on the employment rate, with a one-year lag, and that both in the short-and long-term, countries with higher than average total factor productivity growth tend also to have higher than average growth in employment. clear evidence exists that more computerised or r&d-intensive industries increased their demand for college-educated workers at a faster rate in the s. such high-skilled workers also command higher wages, as the consensus is that the increase in the schooling wage premium and the rise in wage inequality are driven by technological change. support also comes from the observation that all member states saw employment levels in the high technology sector rise between and , leading to an increase of almost million for the union as a whole, with employment in high-tech services accounting for . million of this total (fig. . ) . through its contribution to product, process and service innovation, productivity growth, and the creation of more and higher paid jobs, research and innovation can also help meet the challenges of ageing and cohesion. higher employment rates and levels of productivity -to which s&t can contribute -would allow for maintaining or increasing living standards, and for the absorption of increasing medical and pension costs. doubling the growth of productivity over the next few decades would allow for maintaining current levels of industrial production and average per capita income with some million elderly in the eu. the best solution to poverty is investing in education. for instance, in general the lower the illiteracy rate, the higher per capita income. higher levels of educational attainment enhance the chance of finding work and enjoying a decent standard of living. however, education is not yet accessible for everyone and often only to those who can afford it. improving access to educations takes time and effort. education is, therefore, in its own right not powerful enough to solve the poverty problem. in the meantime, contributions to a solution to poverty can also be expected from science and technology. besides investing in education and developing skills, this means dedicating research programmes to find ways to fight inner-city poverty, to relieve the effects of urbanisation, to diminish the impacts of ever increasing mobility on our environment, and to improve the quality of life of the vulnerable groups in society, such as the handicapped and the ill, the elderly and the young. in developing countries this can take the form of helping to improve the productivity of natural and physical assets, for example, by protecting farmland against erosion and desertification, preserving an area's natural resources, building easy-tomaintain water storage facilities and de-salinisation installations, and strengthening farmers' diagnostic capabilities in relation to livestock diseases, to name a few. that these advances have important impacts on farmers' income levels has been repeatedly demonstrated by the different targeted activities across the framework programmes. science and technology can also make a large contribution to the improvement of public health. it can assist in prevention (e.g. through the development of vaccinations), it can play an important role in the quicker and more reliable diagnosis of diseases (e.g. through the further development of medical imaging), and it can find treatments for diseases or, in the absence of treatments, it can help finding ways to control them (e.g. hiv/aids retroviral drugs). s&t can also help to lessen the impact of disease. furthermore, s&t can help to find new ways to deliver treatment (e.g. ambulant rather than hospital treatment) and can provide better tools for health care system management. a good illustration of the way in which science and technology can make a positive contribution to public health is the article edctp initiative referred to in chapter . it is also useful to take a step back here. globalisation in this regards also means the globalisation of infection transmission. as travel of people (and goods) intensifies, communicable diseases constitute challenges which it is increasingly difficult to confine. interconnectedness is a defining feature of our modernity. as a case in point, healthcare systems are indeed organised as systems -which can lead to catastrophic failures such as the consequences of hiv-infected blood supplies that took a particular prominence in france but did in fact strike many countries. ours is a vulnerable society. while that vulnerability is most strikingly epitomized by ebola-type viruses, with diverse profiles of outbreaks, it is also revealed through world bank, world development report / . the international s&t cooperation with third countries (inco) is one of those programmes which have been developed around the idea that poverty can be overcome by successfully developing human and institutional resources. european and developing countries clinical trials partnership. the rise of nosocomial infections (i.e. ills originating in the very places which are devised to heal). these further illustrate the flipside -or paradoxical unanticipated consequences -of healthcare as interconnected systems. yet, while avian flu and sars together with the above examples represent the globalisation of infection transmission, they also point to the globalisation of the means to tackle public health challenges. the relative containment of avian flu and sars, and even more so the eradication of smallpox (the variola virus), constitute inspirational successes in that regard. there is no doubt that the solution to the environmental challenge has to come first and foremost from elsewhere than from new technological development. available technological best practices should first of all be disseminated as widely as possible. a change of mentality is also required leading to less consumption of more carefully selected resources and increased reuse and recycling within the limits of the current technological frontier. yet it does not seem unjustified to expect a contribution from new technological development. technology is already used in a variety of ways when it comes to the environment, and everywhere there is great scope for improvement. technology in the form of satellites is used to monitor the global environmental situation and change therein. technology in the form of super computers is used to develop climate models and make predictions. technological development has made industrial production less resource intensive. it has also reduced the energy consumption of machinery (e.g. cars). s&t has been successful at developing alternatives for harmful substances (e.g. within the context of fighting ozone depletion). technological development has increased the extent to which a larger variety of goods can be recycled. the production of green energy is wholly dependent on technological development. and s&t is needed to mitigate the impacts of environmental degradation. this need for a joint undertaking -combining existing technologies, technological innovations, as well as political innovations -is illustrated in fig. . in the case of climate change (the fight to curb greenhouse gas emissions, that is). as the next chapter will further examine, s&t is not only an indispensable source for the evidence base on challenges such as environmental degradation, they are also taken to be one of the causes of such predicaments. one can undoubtedly point to the lack of societal controls on the use of s&t, to environmentally harmful production and consumption patterns, and to other types of failures in this regard. nonetheless, the outlook can change fundamentally if one can conceive of s&t as part of the solution rather than the problem. the "precautionary principle" is a useful notion to mark that double perspective. it can first be taken as stifling innovation in the name of environmental protection; but more interestingly, it can be understood as promoting innovations that take account of social and environmental difficulties, taking account of risks as well as benefits, taking account of less tractable, longer-term consequences. its emphasiseven with its origin in german environmental legislation in the s -was as much on environmental protection as on gaining a competitive advantage through innovations on the backdrop of environmental regulation. indeed, although this remains a fiercely debated question, a recent survey of the literature indicates that a transparent and non-discriminatory regulatory framework, coupled with high environmental standards, is an engine for innovation and business opportunities. this engine functions notably through the creation of lead markets. the story of the catalytic converters provides a compelling example of such r&d-based win-win. a first step in that perspective consists in acknowledging the need to sever the link between economic growth and environmental degradation. the endeavour of a duly responsible polity -with a concern for the quality of life of present and future generations -is then to optimise the effects of its economic activity, that is to minimise adverse externalities without sacrificing part of its material well-being or endangering economic growth. a second step consists not in ignoring the above "limits to growth" understanding, but in researching other links between development and sustainability. this move is at the heart of the role of s&t in relation to the environment -and is indeed at the heart of the lisbon strategy as underscored in the conclusions of the göteborg summit. the potential of technology to create synergies between environmental protection and economic growth was emphasised by the october european council. that well-established premise is taken to its most fruitful operational conclusions in the environmental technologies action plan. more recently, the benefits of s&t for the economy and environment alike were further examined in the "towards a more sustainable eu" report for the dutch presidency and indeed in the kok report of november . in fact europe occupies a strong position in the field of environmental technologies. of course this also relates to the fragile but powerful synergies, introduced above, between environmental promotion/protection, s&t, and growth and competitiveness. these potential benefits can also be of great importance for developing countries. with appropriate technology transfer they can provide these countries with affordable solutions for reconciling their desire for strong economic growth with the need to do so without increasing the pressure on the local -or the globalenvironment. this north-south dimension highlights the sustainable development predicament as differentiated yet common. the question of sustainable development can be posed along two main lines: a question of adapting -or otherwise innovating -appropriate "clean" technologies, and a question of redefining needs and lifestyles. now it is interesting to re-consider the climate change issue in the light of the above remarks. the european union has taken a leading role in the international process to tackle global warming so as to promote environmentally responsible choices by all actors. the eu has ratified the kyoto protocol early on, joined by almost all of its international counterparts on this course -most recently russia. its successes are also the planet's successes. the eu is committed to meet its kyoto emissions reduction targets and continues to show leadership on this issue. the role of s&t is set to become even more central in the post-kyoto (post- ) regime, for which negotiations are starting now. the need for new and cleaner technologies as an indispensable means to tackle energy demands and co emissions was the main message of the latest yearly report of the more widely, s&t plays an important part in the eu's capacity to shape -and implement -international agreements. by way of conclusion, it is worthy of note that the answers which science and technology can bring to environmental problems are increasingly judged with reference to the changes they bring in society. they demand choices of policies and governance, the impact of which on economic and social groups must be measured in terms of effectiveness and efficiency, the spread of costs and benefits, and social or regional equity. this is only possible if research also seeks to develop the knowledge-base and methodologies needed by such analyses. the ultimate answer? the ultimate challenge? as the previous discussion of the contribution of s&t to employment or environmental challenges has shown, it is not always clear-cut where problems start and where solutions end. or to put these tangled matters even more simply in this case: the role that s&t can play is manifold. and nowhere is this manifoldness better encapsulated than in the predicament of the "knowledge society". here the challenges, the expectations, and indeed the role of s&t in eliciting and addressing them, are brought together in ways that it is most illuminating to examine. first, this section probes the mutual shaping of science and culture. second, it foregrounds some collateral features of the knowledge society, and in particular the vulnerability that accompanies its emergence. this will lead up, in chapter , to a discussion of our modernity -or modernities -as characterised by a distribution of goods but also of ills or risks, and of knowledge or claims thereon. indeed, in this subsequent chapter, the problematic and ambivalent relations between s&t and the public at large will be considered in the perspective of the weaknesses of european s&t. but firstly we must examine the crucial place of s&t within our knowledge society in the making. the mutual shaping of culture and s&t the examples in this chapter have already shown how profoundly our culture is marked by s&t developments. at the same time as s&t shapes our society, they are themselves produced, taken up, reconfigured, shaped by society. that is one (double) way in which culture is decidedly scientific culture, and thus in which s&t is at the heart of this nearly eponymic "knowledge society". but to allow all sections of society to benefit from those advances -as well as to take part in that shaping process -individuals need to be provided with the appropriate equipment, in terms of education, skills, awareness, and appreciation for the stakes in s&t endeavours. vital for a democratic society in this day and age, such demands point towards another crucial sense for scientific culture, also exposing the acute need for it to be developed. actions to foster a thorough public grasp of what is science and how it contributes to society are thus sine qua non to a full-fledged democratic society. importantly, s&t developments accompany and affect lifestyle changes in societies. in this respect the taking up of mobile phones or gsm provides interesting illustrations. the gsm has strikingly changed the way people communicate with their loved ones, organize their work and outings, and live everyday. as regards research, innovation, and competitiveness, the rise of the gsm standard provides an inspiring example of european leadership. in effect, new information and communication technologies open up opportunities for new lifestyles and new ways of working. remote working or online trading decouples economic activity from a particular geographic location (be it the office, capital cities or structurally favoured regions). moreover, such technologies can facilitate access to employment -and other forms of social inclusion/participation -among sections of society (people with physical disabilities, the elderly) who may otherwise be excluded. key to achieving those benefits is ensuring that people are equipped with the necessary skills to get involved. much information society literature also hypothesises that "ework" (remote working) may contribute to environmental sustainability as, in addition to other dematerialisations, travelling to work is reduced. on the other hand, transport technologies themselves -from the wheel through to the airplanecontinue to have a central role in society, for example in enabling communication. the quality of human life is made up of many more components than the ones already mentioned: greater access to knowledge, better nutrition and health services, more secure livelihoods, clean air to breathe, security against crime and physical violence, satisfying leisure hours, political and cultural freedoms and sense of participation in community activities. s&t can contribute to improvements and bring lasting solutions in each of these areas. for example, investment in research and new technologies to achieve sustainable transport solutions generates desirable impacts on the quality of life worldwide: less energy consumption; fewer air pollution; less respiratory diseases; lower noise levels; increased space and security for pedestrians and cyclists resulting in more friendly cities for children and older people; less congestion; fewer road accidents; and so on. besides, it is s&t which makes possible the novel lifestyles -and indeed the novel societydiscussed above. it may be that, in solving some age-old problems, s&t has created the possibility for new problems to emerge. yet even to address these new problems we can hardly do without s&t. but we can -and rightfully do -concern ourselves with the consequences of the solutions we devise. the vulnerable society and the knowledge society s&t has brought a mix of benefits and risks. in the modern world heightened wellbeing and security are accompanied by increased vulnerability and insecurity. this vulnerability can take many forms, from loneliness or travelling accidents to industrial disasters or the twisting of human rights in a totalitarian state. fig. . provides an illustration of the rising challenge represented by disasters. here "disasters" include both technological and natural events. the dramatic increase shown on the graph may be due not only to the consequences of concentrated urbanisation, climate change, and so on, but also to a heightened sense of vulnerability and risk, together with a better ability to measure disasters. hence the emerging knowledge society will have its problems too. besides, it will not depend solely on s&t but also on governance and on the citizens who will make up our society -and shape it. yet it is characterized by an increasingly pivotal role for s&t. the knowledge society requires a revolution in our understanding of knowledge: not only with regard to s&t researchers, but also concerning a democratisation or broadening of knowledge production. this has profound implications for decision-making, for the lay-expert divide, for the handling of risks and uncertainties, and indeed for the relations between citizens and institutions of governance, as every individual should be recognized as -and given the means to be -a person of knowledge. europe finds itself in a peculiar situation in this regard, and the following chapter will unpack the paradoxical relations between s&t and its citizen. this chapter has explored in greater detail some important economic, social and environmental challenges europe is facing, the expectations held of s&t in addressing these challenges, and the role that s&t could potentially play. the th framework programme was designed against the background of europeans feeling anxious because the continent is experiencing a number of important economic, social and environmental challenges -or indeed against the background of a europe turning from a positive into a negative "exception" at global level. economic growth is slow. europe's competitive position is feeble. there are not enough jobs, and not enough of them are high-level. europe is still characterised by significant poverty and regional inequality. an important demographic challenge is emerging. europeans' health is affected by serious lifestyle and contagious diseases. and the environment is being degraded. as will be further examined at the end of chapter and in chapter , expectations of s&t have never been higher than they are now. such expectations held of s&t are partially justified. s&t can indeed play an important role in addressing societal economic, social and environmental challenges. s&t is the engine of economic growth and competitiveness. the employment effects of s&t are positive. s&t can play a major role in addressing the consequences of ageing, and the cohesion and public health challenges. s&t can play a key role in addressing environmental challenges. s&t is part and parcel of our lives, be they framed in a knowledge society or otherwise, and they are the linchpin of the latter's emergence. however, as will be seen in the next chapter, for s&t to be able to realise its potential, some serious s&t weaknesses will have to be addressed. united nations research institute for social development, information and communication technologies and social development in senegal: an overview/les technologies de l'information et de la communication groupe spécial mobile" hosted by the european conference of postal and telecommunications administrations, and its specifications where defined by the european telecommunications standards institute in the late s. commercial operation began -and the world's first gsm phone call was made european foundation for the improvement of living and working conditions & prest european commission, dg jrc -institute for prospective technological studies impact of ict on sustainable development key: cord- -tt p uue authors: xue, lan; zeng, guang title: global strategies and response measures to the influenza a (h n ) pandemic date: - - journal: a comprehensive evaluation on emergency response in china doi: . / - - - - _ sha: doc_id: cord_uid: tt p uue as an infectious respiratory disease, influenza is prone to cause pandemics for its fast mutation, easy dissemination, susceptibility to humans, and its elusive nature in terms of treatment. three influenza pandemics occurred in the th century which caused huge losses worldwide. analysis by the who, after the global peak in the winter of , there were no signs of any further widespread dissemination of the virus, thus proving the end of the influenza pandemic. nevertheless, the organization warned that entering the post-pandemic period didn't mean the influenza a virus would disappear completely, as epidemic outbreaks were still likely to occur in some regions. additionally possibilities of virus variation were evident and so countries were advised to be on alert during this time. in response to the threat of a global influenza pandemic, the who as per the international health regulations (ihr ) , put a large amount of work into global prevention and control efforts, and also adjusted prevention and control strategy priorities to fall in line with this global influenza outbreak. countries worldwide have been proactive in their responses to the who's strategies and recommendations. in order to tackle possible influenza pandemics and minimize losses, in the who published its official guidance, the influenza pandemic plan: the role of the who and guidelines for national and regional planning, which was then later revised in and , respectively. in the revised who global influenza preparedness plan, an influenza pandemic was divided into six different phases: phases - are interpandemic, i.e., no new influenza viruses have been detected in humans but an influenza virus subtype is circulating among animals and could potentially pose a threat to humans; phases - consist of the pandemic alert phases where a new influenza virus has been detected in humans but its spread among humans remains limited; phase is the warning phase, declaring that the new influenza virus has spread widely across human populations. in its revision of the pandemic influenza preparedness and response, the who retained the use of a six-phase approach, but made some changes to the criteria. phases - are characterized by the transmission of an influenza virus among animals and few humans, and correlate with preparedness, including capacity building and response planning activities. phase is characterized by sustained human-to-human transmission of an influenza virus, while in phases - the virus becomes widespread and prevalent among humans. phases - clearly signal the need for response, prevention, and control measures. during the post-peak period, pandemic activity drops, but there are still possibilities of recurrent outbreaks, before levels finally return to those seen in seasonal influenza periods. these plans from the who were made mainly based on the threat levels from the highly pathogenic avian influenza (h n ), which are much different from the threats posed by influenza a (h n ) in , and which are not likely to be the same as future influenza threat levels. these documents have nevertheless played a crucial role in pandemic response efforts and have provided some basic guidance that can be utilized in the outbreak of any infectious disease. the pandemic influenza preparedness and response also summarized the lessons learned from coping with sars and the highly pathogenic avian influenza, which will be a great asset in responding to future outbreaks of infectious diseases. on may nd, , the who published its first ever list of countries and laboratories with the capacity to perform pcr (polymerase chain reaction) testing used to diagnose the influenza a (h n ) virus in humans, which was updated and re-published on may th, . the who's criteria for diagnostic capabilities are: "scoring % in the last two or more who external quality assurance programme panels (eqap) received by the laboratory; or scoring % in the last panel and having a history of consistent results for earlier panels." on the list published were institutions in countries which were able to perform pcr to diagnose the influenza a (h n ) virus in humans. in response to the outbreak and spread of influenza a, in the initial stages of the pandemic, the who began working on various alert and preparedness plans. on april th, , the who held an emergency meeting, swiftly determining the severity of the pandemic situation and announced that it constituted a public health emergency of international concern. on the evening of april th, , the who raised the influenza pandemic alert level from phase to phase , and again to phase on the evening of april th. level was raised to phase , the highest level the who has declared in the past years-signalling the onset of a global influenza pandemic. on august th, , based on its global assessment, the who removed the phase alert level and announced that the world was moving into the post-pandemic period. while adjusting pandemic alert levels, the who proposed that countries stay flexible in tailoring their specific response measures to their local epidemic situations, and warned that influenza a (h n ), as highly infectious as it is, would continue to do harm in the infected countries and could potentially spread to more countries. as the virus continued to spread in the southern hemisphere, which was at that time entering winter, the risk of its combination and mutation with other local epidemic influenza viruses increased, and so the international community was still required to closely monitor the situation. in the early days of the pandemic, the who's influenza pandemic assessment team published its assessment results on may th, , in which a comparison was made with the and pandemics. the assessment came to the following conclusions: this was a new subtype of the influenza a virus; the influenza a (h n ) virus was likely to become more contagious than seasonable influenza viruses; differences in clinical symptoms were related to the patient's overall health situation; young people were more susceptible to the virus; the mortality rate was expected to be far lower than the pandemic; and there were still many uncertainties surrounding the pandemic. after the pandemic tapered off, on april th, the international health regulations review committee held its first meeting in geneva to assess the global response and the functioning of the ihr in relation to the pandemic, as well as to summarize related experiences and lessons learned. the assessment work is still under way and completion is expected in may . in addition to its preparation and alert efforts, the who also strengthened pandemic monitoring and introduced a series of strategies and measures relating to pandemic response, treatment, vaccine development, inoculation, and distribution. director-general's opening statement at virtual press conference. h n in post-pandemic period. beginning on april th, , when it first published information on the outbreak of human swine influenza in the u.s. and mexico, the who continually released pandemic and epidemiological information to the globe with the intention of facilitating international communication and sharing. from april th through july th, , during the early days of the pandemic, every day or every other day, the who published new laboratory-confirmed cases and deaths in affected countries, and at the same time it closely tracked the global transmission of influenza a (h n ). as the pandemic developed, who experts considered that as far as pandemic risk monitoring and response strategies were concerned, continued laboratory virus testing to all patients was no longer necessary, as it could overburden laboratories and thus influence their capacity in caring for critically ill patients and other unusual circumstances. on july th, , the who announced that countries affected by the epidemic were no longer required to report new confirmed cases, and recommended that attention be placed on monitoring influenza viruses and unusual epidemic events. but countries where influenza a was not present still needed to report cases as they were discovered. after april , although the increasing rates of the fatality were on the decline and the pandemic activity remained relatively low, the who continued the monitoring of the pandemic and remained in close contact with public health experts in countries across the globe in order to determine whether the virus activity had returned to levels and patterns normally seen for seasonal influenza. global pandemic activity had remained low over the past few months, and there was little evidence of higher pandemic influenza activity than what was normally caused by the seasonal influenza. the transmission of the influenza a virus still persisted in the southern hemisphere, but it was still impossible to determine if countries there had transitioned to levels and patterns expected for seasonal influenza. therefore, the who continued conducting epidemiological monitoring of the global pandemic situation and reported on relevant information. zhang ( after the outbreak of influenza a (h n ), the who consulted related pharmaceutical manufacturers about developing vaccines, encouraging worldwide support of influenza a (h n ) vaccination production. the organization also collaborated with drug authorities in related countries ensuring that newly developed influenza a vaccines met as many safety standards as possible. meanwhile, the organization helped china in efficiently obtaining live strains of the influenza a (h n ) virus, which accelerated the country's research and development of relevant vaccines and drugs. while ensuring an adequate amount of seasonal influenza vaccines were available, the who also initiated research and development for influenza a (h n ) vaccinations in the early stages of the pandemic. given that global limited production capacity for antiviral drugs and influenza vaccines could never meet the healthcare needs of . billion people, the who recommended governments to have clear and targeted prevention and control measures to avoid waste of resources. on july nd, , a meeting of the world's health ministers was held in mexico to assess the influenza pandemic and discuss countermeasures and inoculation distribution. at the meeting, who director-general margaret chan called for international collaboration and solidarity, while stressing that special attention must be paid to high-risk groups like pregnant women and patients with chronic diseases. the who also called on vaccine manufacturers to provide them a certain amount of free vaccines so as to help developing countries better cope with their epidemics. in response to the ongoing global pandemic, the who stressed the importance for countries to carry out inoculations and to set forth three goals for their vaccination strategies, i.e. ensuring the normal operation of national healthcare systems, lowering morbidity and mortality, and minimizing possibilities of community-level outbreaks. to ensure continued normal operations of healthcare systems, the who recommended medical workers first be vaccinated, then pregnant women, patients aged six months and older with such chronic illnesses like asthma and obesity, healthy people aged - , healthy children, healthy people aged - , and people aged and older-in that exact order. the who also urged pharmaceutical manufacturers to produce vaccines at full capacity, to ensure fair distribution among developed and developing countries. countries such as china, italy, france, the united states, germany, the united kingdom, norway, sweden, finland, australia, and japan took steps to vaccinate domestic residents, based on their own epidemic situations, healthcare resources, and ability to acquire vaccines. some of the countries placed orders for more vaccines in order to cope with potential outbreaks. , response strategies varied widely across countries (see a detailed description in the next section) because each was faced with outbreaks and developments with different characteristics, in addition to political, economic, and cultural dissimilarities, especially in their public health systems which varied in both management and operation. while developed countries already had fairly effective response measures in place thanks to their advanced economic and social development as well as robust healthcare systems, some developing countries with poor economic foundations and weak public healthcare had a much harder time dealing with public emergencies. therefore, they had an even harder time in dealing with influenza a (h n ). after the pandemic broke out, countries showed varied responses to the who's recommended response strategies and measures; in particular developing countries that had greater reliance on these strategies and measures as well as technical assistance from the who, were much more proactive. there is no doubt that the who played a crucial role in helping countries worldwide-especially developing ones-in coping with the pandemic, whether it is pandemic monitoring, clinical diagnosis and treatment of the virus, or vaccine development and distribution. however, because this pandemic originated in north american countries, taking into account the political, economic and cultural differences between countries as well as their different response capabilities, the who was also faced with new challenges like how to provide tailored guidance to developed and developing countries. the purpose of this guidance was to increase the effectiveness of related strategies and measures, mitigate and contain the spread of the pandemic, and minimize the negative effects of the virus on society and populations. such targeted guidance was not particularly prevalent in their guidance regarding response strategies and measures as the requirements placed on developed countries were quite low, resulting in an overall devaluation of said proposed strategies and measures. therefore, when confronting similar public health emergencies in the future, the who should present more pertinent strategies and tailored measures which could play greater roles in pandemic preparation and response. the outbreak in late april of influenza a (h n ) in several north american countries quickly attracted attention in related countries. responding promptly to the crisis, government agencies and related departments in multiple countries immediately initiated public health emergency mechanisms and put into action a wide range of prevention and control strategies and measures. considering the serious economic, social, and public health consequences that could happen due to the outbreak, coping with the pandemic would demand participation, coordinated preparation, and enhanced collaboration from governments and different departments. some countries specifically established unified leadership bodies and related mechanisms to deal with the pandemic, while others did so through existing government bodies or departments. for example, countries like the united kingdom, india, japan, and mexico set up a special coordination and management mechanism, and established an emergency decision-making, command and coordination body which was directed by the heads of government with the guidance and participation of relevant agencies. the british government specifically established a ministerial committee consisting of related government departments to strengthen inter-departmental communication and coordination and ensure the formulation and execution of preparation and response policies. the indian ministry of health and family welfare established the inter-ministerial task force and joint monitoring group for ai/pandemic to direct and coordinate the national response to the pandemic. france's public health emergency mechanism was run by the "inter-ministerial risk group" with dr. shashi khare. pandemic influenza a h n : preparedness & response in india. cdc new delhi. http:// . . . /linkfiles/rce_day _h n _india-dr_shashi_khare.pps. the responsibility of decision making, situational tracking, and publicity, and the minister of the interior acted as the lead and was responsible for approving and initiating such decisions. japan established the new influenza response headquarters directed by the prime minister, and transformed the risk management center's information liaison office under the prime minister's official residence into the official residence's liaison office for directing and coordinating national pandemic response efforts. mexico, whom in the past responded to public health emergencies mainly through direct government interventions and temporary emergency groups, established the national committee for health security (cnhs) for analyzing, monitoring, and assessing the security issues of national health policies and for proposing relevant policies. the united states, australia and some other countries didn't specifically establish a governing body in response to the pandemic. after its incorporation in into the united states department of homeland security (dhs), the federal emergency management agency's (fema's) responsibilities were expanded from natural disaster response to counter terrorism and pandemic diseases. the fema director, appointed by the president, reports directly to the secretary of homeland security and may, in response to a crisis, be summoned by the president to attend ministerial-level meetings and take part in the decision-making process. after the influenza pandemic outbreak in , the united states launched its standard emergency response procedures, which included close collaboration and coordination among the federal, state and local governments along with the private sector. the u.s. congress was charged mainly with funding public health efforts at the federal, state, and local levels, while it was the responsibility of the federal government to update response plans, strengthen the development and revision of community-based plans, and enhance response capabilities. the dhs oversaw the distribution of antiviral medications and the dissemination of pandemic information to the public. the u.s. department of health and human services (hhs), the executive body of pandemic preparation and response, was in charge of deploying, directing, and overseeing various response efforts, and they also completed the following: issued guidance on the influenza pandemic, provided technical, financial, and medical support to states, and based on pandemic analysis announced a national state of emergency. as the national public health institute under the hhs, the center for disease control and prevention (cdc) played a crucial role in virus monitoring, prevention, and control. similarly, australia established a mechanism in which an inter-agency committee under the leadership of the prime minister and the cabinet was in charge of determining the federal government's preparation and weissman ( . national and regional response strategies and measures response strategies as well as pandemic countermeasures, with state governments making and implementing relevant policies under the guidance of the federal government. whether or not a governing body was established for management of the pandemic, countries worldwide attached great importance to collaboration among government institutes and departments. for example, interim pandemic assessment reports by u.s. departments all mentioned that the timely response to, and rapid progress made in coping with the influenza pandemic, were due in large part to the clear divisions of labor and close collaboration among federal government institutes, departments, and state, and local governments. , the indian government also stressed that pandemic responsibilities did not fall solely on the health department, and that it was necessary for multiple departments to collaborate with one another; the following departments of india were involved in pandemic preparation and response: the ministry of finance which provided cash, budgets, risk management, and insurance; the ministry of commerce and industry which provided medical equipment; the ministry of road transport and highways which was charged with handling relevant transportation and communication issues; the ministry of defense and related military departments which was charged with public services, laws and regulations, security, and human rights; the ministry of information and broadcasting which guaranteed the transparency of strategic communication, the dissemination of information, etc.; the ministry of environment and forests and the ministry of health and family welfare which ensured biosafety, sanitation, wildlife conservation, etc. to effectively curb the transmission of the pandemic and its negative effects on society, many countries formulated a national strategy or plan against possible influenza outbreaks from - , outlining the duties and division of labor among government departments as well as their preparation and response strategies. their policies on influenza a (h n ) were generally built on these strategies. in , pursuant to the pandemic preparedness guidance published by the who, the united states developed the hhs pandemic influenza plan and the national strategy for pandemic influenza, according to which preparation and response strategies and measures would be chosen based upon phases that measured the pandemic's development. included in the documents are detailed provisions about the duties along with preparation and response strategies of related government departments and mechanisms, i.e.: inter-departmental collaboration, council of australian governments/working group on australian influenza pandemic prevention and preparedness. national action plan for human influenza pandemic. . sebellus ( a) . sebellus ( b). public risk communication, vaccine production and distribution, and the stockpiling of antiviral medications. in accordance with the who pandemic preparedness guidance, the united kingdom published their influenza pandemic contingency plan in , and their national framework for responding to an influenza pandemic in , which stipulated that strategies and measures for both preparation and response would be selected based upon pandemic phases. in , australia formulated the australian heath management plan for pandemic influenza and later revised it in , and it remains as the country's national-level health plan for an influenza pandemic. india formulated the influenza pandemic preparedness and response plan in , which was used as a foundation for prevention and control policies against influenza a (h n ). in , the mexican government issued the national preparedness and response plan for pandemic influenza, on which the country's prevention and control policies against influenza a were built. on may th, , the japanese government swiftly issued the action plan for measures against influenza a (h n ) to curb its domestic transmission. this plan contained response measures formulated according to four phases of distinct pandemic phases, i.e. occurrence overseas, early occurrence at home, infection expansion-spread-recovery, and stabilization. for countries across the globe, central governments primarily provided the funds for prevention and control efforts against influenza a (h n ), and these funds were made available to related departments in the different pandemic phases. during the initial period and at the peak of the pandemic, these funds were mainly used for stockpiling antiviral drugs; purchasing relevant equipment, facilities, protective supplies and other materials; establishing points of distribution for antiviral drugs; providing patients with free antiviral drugs; and carrying out pandemic monitoring. during post-peak periods, funds were mainly utilized to purchase unified influenza a vaccines from manufacturers, which were then distributed to the public with no charge. some developed countries also specifically established foreign assistance funds that provided developing countries both monetary and material assistance in combatting the pandemic. the united states congress invested heavily in pandemic prevention and control. in , the congress provided an appropriation of more than seven billion u.s. dollars (usd) for implementing the pandemic preparedness strategy. on april th, , the u.s. president received another appropriation of . billion usd from congress which was specifically designated for combatting the swine flu. in july of that year, congress provided . billion usd to be used as funds for emergency resource deployment and an additional . billion usd for emergency preparation and response against the influenza pandemic. in september, the congress went on to make million usd available to states and hospitals for carrying out vaccination programs. meanwhile, the united states agency for international development (usaid) provided mexico with five million usd in emergency aid funds, , sets of personal protective equipment for virus monitoring personnel, and tamiflu for , courses of treatment. additionally, the hhs provided countries with laboratory diagnostic kits, and donated to the pan american health organization (paho) medications for , courses of treatment in aid of latin american and caribbean countries. in australia, funds for prevention and control against influenza a (h n ) originated mainly from the federal government, which was used specifically for monitoring pandemic development, stockpiling and distributing antiviral drugs, training medical personnel, providing free vaccinations for citizens, and assisting developing countries with prevention and control efforts. the federal government spent million usd on antiviral drugs, . million usd on the purchasing of automatic detection equipment for the national influenza center and other public health laboratories, million usd on training general practitioners across the country, and million usd on a donation to the who which was used in aiding developing countries, especially those neighboring australia, with pandemic monitoring, detection, preparation and response. in the united kingdom, funds for responding to influenza a (h n ) came mainly from the british government; by january th, , the department of health had dispensed to the nation . million doses of pandemrix, an influenza vaccine developed by glaxosmithkline, and , doses of a baxter-developed vaccines. the indian government established a one billion rupee disaster response fund in accordance with the disaster management act, which was administered by the ministry of home affairs, and this disaster fund accepted donations from individuals and organizations. in addition, a national disaster fund was specifically established to finance disaster relief and recovery efforts. state governments also william corr ( established disaster response funds and relief funds in accordance with the law at the state and regional levels. mexico invested a total of million usd in influenza a (h n ) preparation and response, including the purchasing of drugs and vaccines, and the adoption of other prevention and control efforts. declaring a state of emergency helped the hhs prepare for and respond to the influenza pandemic, and prompted the food and drug administration (fda) to issue emergency use authorizations (euas) for the use of antiviral drugs and therapeutic tools-i.e. they approved the use of relenza and tamiflu as stockpiled antiviral drugs for prevention and control of the virus, rt-pcr for virus detection, and n masks, which protected pandemic-affected communities. on april th, , in light of the who's pandemic alert phases and its national pandemic situation, singapore raised their alert level in its five-level disease warning system from green to yellow, and again to orange the next day. to prevent the influenza virus from spreading into and circulating within their territories, many countries adopted strict inspection and quarantine measures in the early days of the pandemic. baggage and raw meat products from epidemic affected areas-were strictly quarantined; many airlines required their service staff to observe and question passengers suspected of illness, and when necessary, have them examined. american border officials between the united states and mexico also were required to examine the physical condition of travelers crossing the border and be prepared to take necessary measures. additionally, citizens were asked to stop all unnecessary travel into epidemic areas. australia also implemented strict border control, requiring all flights from the americas to report the health status of passengers on board before landing; any individual with influenza-like symptoms had to be assessed by australian quarantine authorities in order to determine if further treatment was required; eight major airports across the country were equipped with body temperature measuring instruments, and every incoming passenger was required to complete a health declaration card. india adopted pandemic monitoring measures at airports, sea ports, and inland ports across the country; all incoming passengers to the twenty two international airports were screened, especially those from epidemic areas or with influenza symptoms, who were then quarantined and treated for at least three days. medical personnel were trained in advance, and were required to wear masks, gloves, and protective clothing at work. influenza a (h n ) inspection standards and operational rules were formulated and implemented national widely at that time. japan's ministry of health, labor and welfare required all flights from mexico, united states, and canada arriving at the narita, kansai and chūbu centrair international airports be inspected while aboard the plane. local airports not included on the list of airports for quarantine measures, for example in niigata, akita and hiroshima, also decided to follow suit and expanded the scope of quarantine to include flights from south korea, hong kong, and some other countries and regions. japanese border inspection and quarantine authorities screened people from mexico, the united states and had cargo strictly quarantined, especially baggage and raw meat products from epidemic areas. while applying strict control measures against the importation of the virus, in the early days of the pandemic countries also began strengthening preparation capacity building. for example, in the united states, during the initial stage of the outbreak, the hhs dispensed medication from the strategic national stockpile enough to treat three million people, the department of defense (dod) separately readied enough medication for seven million soldiers, and the cdc allocated antiviral drugs, protective equipment, and testing kits. at the same time, the hhs provided training for medical personnel with the goal of enhancing their abilities in treating and handling the pandemic. the german government required each state to stockpile enough antiviral drugs to use for % of their populations. south korea increased budget spending so that by the end of october the country's had enough drugs stored for % of its population. in an effort to mitigate the spread of the virus, the indian government designated specific hospitals to treat influenza a (h n ) cases. to increase public awareness of the pandemic, countries developed large scale health education and communication projects. the u.s. cdc provided health recommendations to society, communities, clinical workers and other professionals, and launched an online live-broadcast health education program, "know what to do about the flu," to help strengthen the public's abilities in protecting themselves against the virus. the united kingdom updated pandemic situations and work priorities on a regular basis via an official government website, and provided technical support relating to virus prevention and treatment. india published a "public notice' through national media channels with the aim of disseminating knowledge and increasing public awareness of influenza a (h n ) prevention and control. the government also set up a toll-free service hotline to answer questions about the influenza pandemic. in japan, an information, education and communication campaign was launched targeting high-risk groups of people arriving at and departing from the country's international airports, and the ministry of health, labour and welfare opened an information window to answer questions from the public. as the pandemic developed and more cases emerged, it was found that the majority of cases were coming from local communities instead of from abroad. at this point in time, the continued use of containment strategies had been ineffective, and medical personnel were having to dedicate more time and energy to the increasing number of patients. according to the national response framework, the hhs in the united states needed to stockpile enough antiviral drugs for one-fourth of the country's population during the pandemic, and to prepare at least six million treatment courses during the pandemic's initial phase. in the spring of , the hhs allocated eleven million treatment courses that could be used for rapid response against the pandemic. the cdc and the fda also worked together to address potential options for treatment of severely hospitalized patients. in october, the hhs shipped an additional , bottles of the antiviral oseltamivir in oral suspension formula to anna schuchat ( a). . national and regional response strategies and measures states in order to mitigate a predicted national shortage. the fda worked closely with the cdc, the office of the assistant secretary for preparedness and response (aspr), manufacturers, and others to increase production and availability of personal protective equipment such as gloves, masks, and respirators. at the same time, the influenza (h n ) consumer protection team, established by the fda, put in place an aggressive strategy to combat fraudulent influenza products. the british secretary of state for health declared on july nd, , that the united kingdom's response efforts were transitioning from a "containment phase" to a "treatment phase." in order to cure patients more efficiently, the british government created a national stockpile by the purchasing of more antiviral drugs, and drug distribution centers were also established across the country, with the national health service (nhs) playing a leading role in treatment provisions. to relieve pressure on medical institutions, on july rd, , the british government launched the national pandemic flu service (npfs). the npfs was a self-help healthcare system which, through a dedicated website and call centers, provided people worried about flu-like symptoms with professional assessment services, including the suggestions on whether they should receive treatment or contact a general practitioner, etc. a person, if assessed as indeed having influenza a (h n ) symptoms, would be given an authorization number by the system, which he or she could use to pick up antiviral drugs from one of local distributions centers. the launch of this system effectively mitigated the pressure on primary healthcare institutions and allowed general practitioners to dedicate their attention to critically ill patients. in order to quickly detect and treat critically ill patients, and also to ensure an adequate number of hospital beds as the number of cases increased, the japanese government readjusted its guidelines on pandemic response efforts, and discarded the practice of classifying regions according to rate of transmission in that area. according to the revised guidelines, regular hospitals received patients infected with influenza a (h n ); all mildly ill patients were instructed to medicate and rest at home, rather than being hospitalized. for patients with asthma or other illnesses whom had contracted influenza a (h n ) and whose conditions were likely to worsen, a pcr (polymerase chain reaction) test or other influenza a virus test was performed, and effective antiviral drugs were administered as early as possible. when necessary, decisions would be made to get them hospitalized. japan gradually used the confirmed cases reported from a certain number of hospitals as estimations and predictions for that area's infected population. australia used antiviral drugs from their national medical stockpile to treat moderately and critically ill patients, especially those with severe breathing difficulties or those whose conditions were rapidly worsening. all medical personnel, who contracted influenza a (h n ) and developed moderate symptoms of jesse goodman ( infection, or were more prone to develop serious symptoms, were eligible for antiviral treatment. patients with fairly mild symptoms were encouraged to self-medicate. india issued clinical management guidelines, where the indian committee on infectious diseases published guidance on the screening and clinical treatment of laboratory-diagnosed cases of influenza a (h n ); the ministry of health and family welfare issued guidelines on family isolation, clinical examinations, and hospitalization by categories of influenza a (h n ) cases-where categories a/b patients were asked to be isolated and reduce contact with their family and others and category c patients required immediate hospitalization. all suspected cases were tested at the national institute of communicable diseases (nicd) in new delhi, or at the national institute of virology in pune, and then examined further at relevant laboratories. india currently has forty four laboratories dedicated to the early management of controlling confirmed cases. given the dynamic nature of the pandemic, involving each and every citizen in its mitigation became a very important part of global response efforts. to contain the pandemic, mexico mobilized a large force of police officers and soldiers to execute the following: distribute masks among citizens for free, shut down public places, cancel or delay large-scale events, halt teaching activities in all schools-including universities, primary and secondary schools, and kindergartens -in mexico city and in the state of mexico. on april th, , the mexican government declared a suspension of all nonessential public affairs and economic activities from may st through may th. moreover, the mexican government also adopted a wide range of measures to strengthen pandemic information communication and sharing, i.e.: reporting pandemic developments via media channels, setting up hotlines, launching influenza prevention websites, giving out leaflets on pandemic information that called for personal hygiene and increased public awareness of the virus. in the united states, the hss launched a one-stop influenza information website (www.flu.gov), which gathered information from regular media briefings conducted by the hhs and other federal agencies, and provided the public with scientific and effective information services. in collaboration with federal, state, and local partners, the hhs also developed a wide range of community-based intervention guidelines which were being evaluated simultaneously. the cdc and the dhs provided specific recommendations targeted to a wide variety of groups, including the general public, people with certain underlying health conditions, infants, children, parents, john and moorthy ( ) . national and regional response strategies and measures pregnant women, seniors, health care workers, workers in relevant industries, laboratory workers, and homeless people. with these recommendations, people were equipped to take appropriate action in reducing the transmission of the virus, especially in early autumn before vaccines were widely disseminated. the cdc also provided, and updated on a regular basis, scientific guidance on influenza prevention and control to schools, daycares, universities, large and small businesses, and federal agencies. these comprehensive guidelines provided not only advice on how individuals and institutions could protect themselves against the virus and mitigate its spread, but also recommendations for healthcare providers about the appropriate use of anti-viral drugs, especially in treating patients who were at the highest risk of suffering complications from the influenza. , in japan, after the alert level transitioned from an "overseas pandemic" phase to the heightened "early onset of a domestic pandemic" phase, the local governments of osaka and hyōgo prefectures required the following for areas where infections had occurred: gatherings and collective recreational activities be suspended, entertainment venues be temporarily closed, social service workers be required to wear masks, teaching activities of varying levels at more than one thousand educational institutions be suspended for one week, citizens avoid trips and gatherings, and business activity be reduced for the time being. in australia, patients with mild symptoms were allowed to stay at home as a means of isolation. with the rapid spread of the pandemic, the united states didn't take stock in counting cases, but instead focused on the evolution process of the virus. the united states' advanced and unique monitoring system for bacteria and viruses uses dynamic and standardized methods to collect data related to virus occurrence, virus developments, and basic medical trends, and employs national demographic data to compute virus incidence and describe its epidemiological characteristics. this system brings together and facilitates cooperation within the cdc, state health authorities, academic partners, hospitals and infection control centers. moreover, it contains special research platforms, i.e., socio-economic evaluations of disease risk factors, effects of the disease and vaccinations, data on resources for vaccine research and development, and data on approved vaccines. in australia, laboratory testing focused on critically ill patients, high-risk groups with severe diseases, and personnel in relevant institutions. monitoring was also conducted to see if any resistance or mutations of the virus had occurred. understanding that vaccinations were the best means for combatting the virus, countries focused a large amount of resources on vaccination development and inoculation methods. in its influenza pandemic preparedness and response plan, the hhs in the united states set two objectives for vaccine preparation : to stockpile twenty million vaccinations for key personnel, and to increase manufacturing capacity to cover the population in the united states, in other words, produce million doses within six months of the pandemic outbreak. immediately following the outbreak, the national institute of allergy and infectious diseases (niaid) subordinate to the u.s. national institutes of health (nih) began its research on the virus and vaccination development. in july , the niaid initiated a series of clinical trials on the effectiveness of newly developed vaccines. in september, the fda approved manufacturing for four vaccination types, which were then made available for distribution among the states. the federal government then identified priority groups for vaccination and formulated an inoculation policy. starting on october th, a national influenza a (h n ) voluntary inoculation program begun targeting high-priority groups including pregnant women; people between the ages of months through years of age; people aged years or older with chronic health disorders like asthma, diabetes and heart disease; and healthcare and emergency services personnel. during the two months that followed, vaccine manufacturers provided - million vaccination doses each week, an amount which reached roughly million by the end of . , according to statistics, the federal government ordered a total of million doses of the vaccine with the plans of vaccinating million people, and in the end million people were actually inoculated. on october st, , the united kingdom launched its national influenza a (h n ) inoculation program. the first phase of the plan provided the vaccine to the high risk population of fourteen million people, including critically ill patients, pregnant women, and healthcare personnel working in hospitals. soon afterwards, general practitioners across the country began encouraging people with health disorders or immunity problems, and pregnant women to get vaccinated. on december th, , the british government went on to include children ages six months to five years old in the vaccination program. in august , australia approved a national vaccination program and began providing free vaccinations to healthcare workers, pregnant women, and individuals with chronic health disorders who were susceptible to the virus. on september th, the australian government announced that all adults and children aged ten years and older could also receive free vaccinations. in may , the mexican government announced an appropriation of . million usd for the establishment of a dedicated committee composed of authoritative medical experts, and this committee's mission was to mobilize and coordinate research efforts for carrying out etiological, epidemiological, diagnostic reagent and vaccine research relating to influenza a (h n ). it was also responsible for providing policy recommendations on pandemic prevention and control and medical treatment options to the government. in july japan began distributing permits authorizing the utilization of influenza a (h n ) vaccines, and they also launched a national vaccination program. the first groups to receive it included healthcare personnel, police officers, as well as high-risk groups like pregnant women, patients with chronic diseases, and seniors. as influenza a (h n ) cases gradually declined, some countries readjusted their pandemic response levels as well as their measures for virus prevention, control, and treatment. countries set about making summaries and conducting evaluations while continuing their pandemic monitoring and information sharing. in , most regions across the globe saw a decline in influenza a (h n ) activity, and though in some regions the virus still sustained its intensity (level), the overall virus transmission dropped. additionally, it was discovered in most cases that the influenza a virus only caused mild infections, and that its virulence had not increased since it was first reported in april . effective vaccinations had been in circulation since november . it was for these reasons that the singaporean ministry of health decided on february th, , to downgrade its alert level from yellow to green. beginning in february , the united kingdom deactivated the national pandemic flu service (npfs), an act done in line with ensuring the operational response was appropriate to the threat level posed by the virus and also because general practitioners and primary care trusts could now manage the clinical mexico sets up special committee for influenza a (h n ) research. xinhuanet.com, may , . http://news.xinhuanet.com/world/ caseload by themselves. anyone concerned about flu-like symptoms were advised to contact their doctor for assessment, who could then issue an antiviral authorization voucher if needed. the npfs would be reactivated should the pandemic virus regained its virulence. starting on april st, , free antiviral medication from the national stockpile was no longer available to patients with influenza a (h n ). normal treatments and prescription charges were reinstated for those suffering from influenza. in june , the united states declared the end of the public health emergency. as confirmed cases declined and the spread of the virus continued to slow, the u.s. federal, state, and local health authorities began to readjust their response strategies. in addition to continued efforts in strengthening public health education and inter-agency collaboration, other measures included bolstering the vaccination campaign, strengthening virus monitoring, and continuing focus on virus mutations. as the pandemic developed in the united states, especially after the wide distribution of vaccinations to the public, some u.s. agencies and institutions evaluated the results of a range of their prevention and control measures. the purpose of these evaluations were to identify problems that existed in the national pandemic response measures, and correct them to better the response in the future. (upmc's) center for biosecurity held a conference to summarize important lessons learned from pandemic responses and raised policy suggestions in mitigating future infectious disease emergencies. on may - th, , the cdc, the national association of county and city health officials (naccho), and other stakeholders met to review the federal, state and local policies that had an impact on local health departments' pandemic detection, response, and recovery efforts. while modernized health care systems, antiviral drugs and vaccines represented the advantages of global response efforts this time around, factors like globalization and urbanization allowed the fastest transmission of any pandemic ever witnessed. after outbreaks occurred in multiple countries, governments worldwide immediately adopted a wide variety of proactive containment measures. while there were many successful responses, shortcomings were also exposed which incited doubt and controversy surrounding the pandemic. in regards to prevention and control measures, governments in most of the affected countries did not look lightly upon the pandemic, and they played leading roles in policy making, resource collection and allocation, as well as organization and coordination. firstly, governments identified and allocated prevention and control organizations and accountability mechanisms at the national level. as mentioned before, some countries such as the united kingdom and india specifically established bodies for comprehensive coordination in response to the influenza pandemic, while others like the united states-where established emergency response agencies were already in existence-launched their emergency response efforts upon the outbreak of the pandemic. the u.s. government then oversaw an organized response from varying agencies. secondly, countries developed national-level pandemic strategies or response plans as general outlines for prevention and control efforts. thirdly, funds for response efforts in most cases originated from the central government, where the capital was then allocated to appropriate departments based upon their responsibilities. lastly, central governments were in charge of across-the-board organization and coordination in all aspects of the response efforts, especially in the provision of services, drug supplies, and vaccinations, while at the same time playing a crucial role in communication and coordination with other social service organizations, businesses, and the general public. in the course of global responses to the sudden outbreak of the influenza pandemic, the who made good use of its expertise and networking strengths. with a global approach, the organization disseminated information, pushed coordination, and strengthened guidelines. it played an important role in coordinating and guiding countries' efforts to raise awareness, develop technical guidance, release pandemic information, develop vaccines, etc. most countries possessed an influenza prevention and control system comprised of a variety of collaborative relationships, i.e.: partnerships between central, provincial (state), and local governments, the private sector, and individuals, as well as international partnerships established through bilateral or multilateral collaboration. each party within this system had its function and standard operating procedures, with the division of labor already institutionalized; and in implementing specific prevention and control measures, these parties were expected to fulfill their expectations and duties as stakeholders. each stakeholder understood their role to play during the preparation, prevention, and control of the pandemic, and no major changes occurred in that respect during the pandemic. at the same time, capacity building and positioning was constantly being improved according to the different functions of each party. in addition to inter-departmental coordination and collaboration, countries like the united states also called upon the public for participation and global collaboration, which expanded collaboration as it brought in community and societal involvement. during different phases of the pandemic, countries emphasized the integration of comprehensive measures and key response issues, and efforts were adjusted according to the development of the pandemic. in the early phases, prevention and control strategies were "strict," as they focused largely on containment with inspection and quarantine measures. cases diagnosed early were treated in a timely manner to better the odds of developing a successful vaccination. at the spreading period of the pandemic, the focus shifted to clinical treatment of patients, alongside strengthening virus monitoring. during the post-peak period, while some countries quickly revised alert levels which reduced social impact, others had no readjustment mechanisms for policy changes in place which resulted in inefficient prevention and control. during this time, most countries recognized the importance of international collaboration. firstly, faced with the grim situation of a pandemic gripping the globe, affected countries followed the who's pandemic strategies and recommendations. combining the domestic situation with who's proactive policies and recommendations, most countries adopted relevant response measures. however, there were many countries that didn't adopt all of the who's policies and recommendation, nor did they follow all of the policy readjustments. instead in light of their domestic situation, governments formulated their own response strategies and measures. secondly, relatively close collaboration between countries did occur. due to the many uncertainties surrounding the occurrence and development of the influenza a (h n ) pandemic, the level of "appropriateness" of response strategies -i.e. were they considered "lax" or "strict," "ineffective" or "overreacting"became a major controversial point surrounding the pandemic prevention and control policy. on the one hand, based on their own pandemic situations, their preparation evaluation, and cost-benefit analyses, developed countries such as the united states, canada, the united kingdom, and france, adopted policies that focused more on treatment than on control. the united states, for example, in the early days of the pandemic considered influenza a (h n ) no bigger a threat than the seasonal influenza, so the government failed to take strict response measures, like quarantine and medical observation, which resulted in a spike in domestic infections. on october rd, the united states declared a national health emergency, sparking questions about the government's response efforts. while some critics questioned whether there indeed existed such an emergency, others argued that a state of emergency should have been declared from the very beginning. an article published in the new york times in early january , gave full recognition to the country's response strategy, insisting that apart from luck, the federal government's appropriate, rapid, and conservative response successfully contained the virus and minimized potential harmful effects it could've had on the economy. on the other hand, some countries began with strict measures and relaxed them later on, causing difficulties in latent response efforts. for example, countries like mexico declared a state of high alert immediately upon the outbreak, leading to a certain extent, a public panic. but after the who elevated the pandemic alert phase, the mexican government rushed to lower its domestic alert level in order to ease public anxiety. thus the public became careless, causing the increased transmission rate. moreover, media in japan, france and other countries exaggerated pandemic situations that embellished "the widespread transmission" of the virus in home countries through imported cases. people became panic-stricken and it became increasingly difficult to implement proper response measures. japan and other countries failed in resource management as they placed too much emphasis on border control and quarantine, and not enough on domestic control and detection, thus making it difficult to contain the spread of the pandemic. these actions also led to widespread criticism of government response efforts. though the who's role in the global pandemic response efforts was widely recognized, the organization also suffered criticism as there were varied opinions about the timeliness of alert level changes and their investments in personnel and equipment. reuters reported on april th, , that the who admitted to having problems in their response efforts, including its failure to communicate the uncertainty of the new virus before it swept the globe. some critics held that from the perspective of pandemic development, the influenza a (h n ) pandemic was not as dreadful as it was initially anticipated, and it was the who that created a global panic in its response-which caused an excess in vaccination stockpiling among some countries. some even suspected that the ihr emergency committee might have had an "affair" with some drug manufacturers and was suspected of helping them seek profit by deliberately exaggerating pandemic situations so that the who would raise its pandemic alert to the highest level. in response, on april th, , the who commissioned a panel of external experts to conduct an overall evaluation of the global response to the influenza pandemic in the hope of providing lessons for the future, and simultaneously to assess the global implementation of the ihr . the who's policy evaluation comprised three main parts, i.e. capacity and preparedness, pandemic alert and risk assessment, and response. on june th, , the who officially responded to and clarified such issues as to the influenza a (h n ) virus met the criteria for a pandemic, the severity of the pandemic, and related conflicts of interest. central people's government of the people's republic of china. who experts warn global h n pandemic still not over yet. http://www.gov.cn/jrzg/ - / /content_ .htm. who. the international response to the influenza pandemic: who responds to the critics. http:// www.who.int/csr/disease/swineflu/notes/briefing_ /en/index.html. there are no international standards for vaccine allocation in mitigating the global burden of disease. while the united states began vaccinating its citizens in early october after the fda approved on september th the marketing of influenza a (h n ) vaccines produced by csl, medimmune, novartis vaccines and diagnostics, and sanofi pasteur, mexico, which had been suffering a severer pandemic situation, was unable to launch a vaccination program until january . building a powerful global vaccine production infrastructure for influenza pandemics where countries and regions in need could acquire adequate vaccines at affordable prices became one of the hot international topics at this time. the who stated that although antiviral drugs used at that time to combat influenza enjoyed complete patent protection, the organization proposed that these drugs be acquirable in the cases of public health crises. the use of antiviral drugs was hit heavily upon in the who's guidance documents, but, given cost issues, the use of such drugs and vaccines had little operability in most middle and low-income countries. moreover, some international media held that the outbreak in the united states brought to the forefront the many flaws in their healthcare system, most notably the use of old-fashioned vaccine technology and excessive reliance on vaccine manufacturers abroad. a highly controversial event also occurred during vaccination distribution: the new york city department of health and mental hygiene decided to give the small amount of vaccine available in the early phases of the pandemic to big corporations on wall street such as goldman sachs and citibank, an act which experts believe only exacerbated public relation issues. vaccine production and distribution became a controversial focal point during prevention and control of the pandemic as it involved multi-faceted issues such as vaccine patents, mass psychology, and social justice. h n preparedness: an overview of vaccine production and distribution u.s. global health response to a novel -h n hhs' effort to provide science-based pandemic influenza guidance for the u.s. workforce lessons from previous influenza pandemics and from the mexican response to the current influenza pandemic h n preparedness: an overview of vaccine production and distribution pandemic influenza in india who director-general margaret chan says international community cannot afford to take influenza a (h n ) pandemic lightly preparing for the - influenza season h n influenza: monitoring the nation's response protecting the protectors: an assessment of front-line federal workers in response to the -h n influenza outbreak global surveillance during an influenza pandemic. version , updated draft assessing the severity of an influenza pandemic -h n influenza: hhs preparedness and response efforts characteristics of the india's public health emergency management system: from a perspective of influenza a (n h ) preparedness and response. global science, technology and economy outlook influenza a pandemic moves into a new phase, who changes way of epidemic reporting key: cord- -f mzwhrt authors: aggrawal, anil title: agrochemical poisoning date: journal: forensic pathology reviews doi: . / - - - - _ sha: doc_id: cord_uid: f mzwhrt a general increase in the use of chemicals in agriculture has brought about a concomitant increase in the incidence of agrochemical poisoning. organophosphates are the most common agrochemical poisons followed closely by herbicides. many agricultural poisons, such as parathion and paraquat are now mixed with a coloring agent such as indigocarmine to prevent their use criminally. in addition, paraquat is fortified with a “stenching” agent. organo-chlorines have an entirely different mechanism of action. whereas organophosphates have an anticholinesterase activity, organochlorines act on nerve cells interfering with the transmission of impulses through them. a kerosene-like smell also emanates from death due to organochlorines. the diagnosis lies in the chemical identification of organochlorines in the stomach contents or viscera. organochlorines also resist putrefaction and can be detected long after death. paraquat has been involved in suicidal, accidental, and homicidal poisonings. it is mildly corrosive and ulceration around lips and mouth is common in this poisoning. however, the hallmark of paraquat poisoning, especially when the victim has survived a few days, are the profound changes in lungs. other agrochemicals such as algicides, aphicides, herbicide safeneres, fertilizers, and so on, are less commonly encountered. governments in most countries have passed legislations to prevent accidental poisonings with these agents. the us government passed the federal insecticide, fungicide and rodenticide act (fifra) in and the indian government passed the insecticides act in . among other things, these acts require manufacturers to use signal words on the labels of insecticides, so the public is warned of their toxicity and accompanying danger. a general increase in the use of chemicals in agriculture has brought about a concomitant increase in the incidence of agrochemical poisoning. organophosphates are the most common agrochemical poisons followed closely by herbicides. many agricultural poisons, such as parathion and paraquat are now mixed with a coloring agent such as indigocarmine to prevent their use criminally. in addition, paraquat is fortified with a "stenching" agent. organochlorines have an entirely different mechanism of action. whereas organophosphates have an anticholinesterase activity, organochlorines act on nerve cells interfering with the transmission of impulses through them. a early humans are believed to have started agriculture around bce. as the knowledge of chemistry grew, so did the use of chemicals in agriculture. today, chemicals are used in agriculture for three main purposes: to increase farm production (fertilizers and related chemicals), to kill pests (pesticides), and to preserve farm products (preservatives). unfortunately, all three classes of chemicals can cause serious poisoning in humans, mainly through improper labeling, storage, or use. most poisonings with agrochemicals occur in predominantly agricultural economies where a lack of hygiene, information, or adequate control creates unsafe and dangerous working conditions. cases of such poisonings also occur in small factories where pesticides are manufactured or formulated with little respect for safety requirements. accidental poisonings may also take place at home when pesticides are mistaken for soft drinks or food products, and often the victims are curious children who can easily reach pesticides if they are not kept safely away from them. then, there are the intentional poisonings, where compounds, such as phosphorus, arsenic, paraquat, organophosphates, and strychnine, are used as agents for suicidal or even homicidal purposes. this may happen because these chemicals are easily available, relatively cheap, and almost certainly cause death. poisoning occurring as a result of improper use of chemicals used in agriculture has been termed "agrochemical poisoning." agrochemical poisoning can be classified as shown in table . agrochemical poisoning remains one of the major causes of morbidity and mortality around the world today ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , and a review of this relatively untouched subject seems to be justified. experience has shown that above the wide range of chemicals a vast majority of poisonings occur because of pesticides only. the annual report of the american association of poison control center's (aapcc) toxic exposure surveillance system listed a total of , , human exposures to poisons occurring in the united states during the year alone ( ) . out of these, there were , exposures to pesticides ( % of all exposures) and , exposures to fertilizers ( . % of all exposures); a total of fatalities caused by pesticides and one caused by fertilizers were reported. the break-up for pesticide exposure is shown in table , and the fatalities caused by pesticides are given in table . two categories in which deaths were not reported at all were fungicides and repellants. most deaths (n = ) were to the result of insecticides. herbicides and rodenticides accounted for five deaths each, and one death was caused by fumigants. a comparison of poisoning data for the years to ( ) ( ) ( ) ( ) indicates that, although the absolute number of pesticide exposure has been increasing, it is more or less stable at around % of all exposures to poisons; fatalities owing to pesticide poisoning amount to . to % of all fatalities resulting from poisons (table ). in the following sections, those agrochemical poisons that are important from a medicolegal and pathological point of view will be discussed. organophosphorus insecticides are derivatives of phosphoric acid (h po ) or phosphonic acid (h po ) in which all h atoms have been replaced by organic moieties (figs. - ) . l represents the so-called "leaving moiety" and is the most reactive and most variable substituent. it is called so because this moiety "leaves" the organophosphate molecule after it is attached to the esteratic site of the acetylcholinesterase (ache, also known as true cholinesterase type che). r and r are less reactive moieties. most commonly they are poisonous plants (used as green manure, e.g., ricinus communis). . chemicals used to kill pests (pesticides) (i) acaricides (used to kills mites and ticks, also known as miticides, e.g., avermectins, azobenzene, benzoximate, bromopropylate, dofenapyn, nikkomycins, tetranactin). (ii) algicides used to control growth of algae in lakes, canals, and water stored for agricultural purposes (e.g., cybutryne, hydrated lime [component of bordeaux mixture]). (iii) aphicides (used to kill aphids, e.g., triazamate, dimethoate, and mevinphos). (iv) avicides (used to kill birds harmful to agriculture, e.g., -aminopyridine, -chloro-p-toluidine hydrochloride). bactericides (e.g., bronopol, nitrapyrin, oxolinic acid, oxytetracycline). (vi) fumigants (gas or vapor intended to destroy insects, fungi, bacteria, or rodents, used to disinfect interiors of buildings, as well as soil, before planting, e.g., carbon disulfide, sulfuryl fluoride, methyl bromide). (vii) fungicides (e.g., sodium azide, various compounds of copper and mercury, thiocarbamates, captan, captafol). (viii) herbicide safeners (e.g., benoxacor, cloquintocet, cyometrinil, dichlormid, dicyclonon). these compounds basically protect crops from herbicide injury by increasing the activity of herbicide detoxification enzymes, such as glutathione-s-transferases and cytochrome p- . (ix) herbicides/weed killers (e.g, paraquat, diquat, - dichlorophenoxyacetic acid, mecoprop). (x) insecticides (e.g., organophosphorus compounds, organochlorine compounds, carbamates). (xi) microbial pesticides (those pesticides whose active ingredient is a bacterium, virus, fungus, or some other microorganism or product of such an organism, e.g., bti which is made from the bacterium bacillus thuringiensis var. israelensis and used to control mosquito and black fly larvae, bacillus sphaericus and laegenidium giganteum, a fungal parasite of mosquitoes). (xii) molluscicides (used to kill molluscs, such as snails and slugs, e.g., metaldehyde). (xiii) nematicides (used to kill nematodes that feed on plant roots, e.g., , dichloropropene, , -dibromoethane, ethylene dibromide, diamidafos, fosthiazate, isamidofos). (xiv) ovicides (used to kill eggs of insects and mites). (xv) pesticide synergists (e.g., piperonyl butoxide, n-octyl bicycloheptene dicarbozimide, piprotal, propyl isome, sesamex, sesamolin). (xvi) rodenticides (used to kill rodent pests, e.g., strychnine, vacor, antu, cholecalciferol, anticoagulants and red squill). (xvii) virucides (e.g., ribavirin, imanin). (xviii) miscellaneous chemical classes including contaminants and adjuvants of some pesticides which are toxic on their own (e.g., dioxins, present as contaminants of some herbicides produce toxicity of their own). . chemicals used to disturb the feeding/growth/mating behavior etc. of pests, or used for other miscellaneous agricultural purposes (i) bird repellents (e.g., anthraquinone, chloralose, copper oxychloride). (ii) chemosterilants (e.g., , -dibromo- -chloropropane, apholate, bisazir, busulfan, dimatif, tepa). (iii) desiccants (chemicals which promote drying of living tissues such as unwanted plant tops or insects). (iv) defoliants (chemicals which cause leaves or foliage to drop from a plant, usually to facilitate harvest). feeding deterrents or antifeedants (chemicals having tastes and odors that inhibit feeding behavior, e.g., pymetrozine, azadirachtin a). (vi) insect attractants (substances that attract or lure an insect to a trap, e.g. brevicomin, codlelure, cue-lure, dominicalure, siglure). (vii) insect growth regulators (chemicals which disrupt the action of insect hormones controlling molting, maturity from pupal stage to adult, or other life processes, e.g., hexaflumuron, teflubenzuron and pyriproxyfen). (viii) insect repellents (e.g., butopyronoxyl, dibutyl phthalate, diethyltoluamide). (ix) mammal repellents (e.g., copper naphthenate, trimethacarb, zinc naphthenate, ziram). mating disrupters (e.g., disparlure, gossyplure, grandlure). (xi) plant activators (a new class of compounds that protect plants by activating their defense mechanisms, e.g., acibenzolar, probenazole). (xii) plant growth regulators (substances [excluding fertilizers or other plant nutrients] that alter the expected growth, flowering, or reproduction rate of plants through hormonal rather than physical action). . chemicals used for preservation of grains (i) aluminum phosphide. (ii) nitric oxide. available as dusts, granules, or liquids, organophosphorus insecticides are among the most popular and widely used insecticides throughout the world. they began to be synthesized first around with the esterification of alcohols to phosphoric acid. the earliest synthesis of an organophosphate, tetraethyl pyrophosphate, was reported by phillipe de clermont at a meeting of the french academy of sciences in ( ) . many different organophosphorus compounds were synthesized in the early s, but their toxicity was first recognized by lange in . lange stated that inhalation of the vapor of dimethyl or diethyl phosphofluoridate produced a choking sensation and dimness of vision. as nations started looking for lethal gases with the start of world war ii in , interest in these compounds was rekindled. by , schrader in germany and saunders in england and their study groups had synthesized a number of highly toxic organophosphates for possible use in warfare. most notable among these were soman, sarin, and tabun. currently, about organophosphorus compounds are in use as insecticides worldwide. of these, parathion is the most effective for insecticidal use. tetraethyl pyrophosphate enjoys two distinctions among organophosphates: it was the first organophosphate to be synthesized in and is the organophosphorus insecticides are basically ache inhibitors allowing the accumulation of excess acetylcholine at various nicotinic and muscarinic receptors throughout the body including the central nervous system (cns). this essentially results in acetylcholine toxicity. the main symptoms can be remembered by either of the two acronyms sludge (salivation, lacrimation, urination, defecation, gastrointestinal distress, emesis) or dumbels (diarrhea, urination, miosis, bronchospasm and bradycardia, emesis, lacrimation, salivation). rarely, there is chromolachryorrhoea (shedding of red or bloody tears) ( ) because of a disturbance in porphyrin metabolism and its accumulation in lacrimal glands. ld (lethal dose; the amount of a material, given all at once, which causes the death of % of a group of test animals) of these compounds varies from to mg/kg (extreme toxicity) to more than mg/kg (slight toxicity). compounds that are extremely toxic are chlorfenvinphos, diazinon, and methyl parathion, whereas those that are slightly toxic are malathion, acephate, and trichlorphon ( ) . most patients who have ingested a fatal dose will die within hours of ingestion. organophosphorus toxicity has recently been reviewed extensively by rousseau and co-workers ( ). signs of asphyxia are commonly found in fatal intoxications with organophosphorus insecticides. there is congestion of the face and cyanosis of the lips, nose, fingers, and acral parts of the extremities. one of the most remarkable findings is the characteristic odor emanating from the corpse: it has been described as garlic-or kerosene-like and is due to the fact that organophosphates are dissolved on a kerosene base. there is often frothy, bloody staining at the mouth and nostrils, and the pupils may be constricted. a coloring agent, indigocarmine, is added to parathion (e ® ) to prevent its accidental ingestion or criminal use as a poison. this gives rise to a bluishgreenish discoloration of the lips and oral mucosa. the addition of indigocarmine, however, is not a general practice worldwide. for instance, in india and several other asian countries, this practice is not followed. an interesting sign to be observed (albeit only in somewhat less modern mortuaries) is the death of bluebottles and others insects and flies dying immediately after they alight on an opened cadaver at autopsy ( ). the gastric mucosa is congested and may appear hemorrhagic (fig. ) and the stomach contents often contain an oily, greenish scum. the mucosa of the respiratory tract is congested and the airway passages contain frothy hemorrhagic exudate. the lungs show congestion, hemorrhagic pulmonary edema, and subpleural petechiae. the brain is swollen and there is generalized visceral congestion. parathion (e ) has been studied most extensively for histopathological lesions and these are considered to be representative of other organophosphorus insecticides, too ( ) . in the kidneys, there is epithelial necrosis in the straight sections of the renal tubules. in the epithelia of the remaining renal cortical sections, there is pronounced plasma granulation, nuclear wall hyperchromatosis, and clumping and reduction in the chromatin and marginal nucleoli. epithelia in loops of henle and collecting tubules appear swollen. the liver is more resistant to the effects of organophosphates, partly because of its ability to manufacture serum cholinesterase on its own. hepa- tocytes show opaque swelling and glycogen depletion; there are destructive changes in the liver cell strands, detached hepatocytes, and perivascular edema. myocardium, medulla oblongata, and vagal nuclei of the brain show fine, maculate perivascular hemorrhages. limaye has described a type of toxic myocarditis that he had observed in autopsy cases ( ) . kiss and fazekas described focal myocardial damage with pericapillary hemorrhage, micronecrosis, and patchy fibrosis in victims of organophophorus poisoning ( ) . pimentel and da costa ( ) have described the following myocardial ultrastructural changes in fatal poisonings with organophosphorus: multiple circumscribed necroses are found in the skeletal musculature. the oolemma is damaged and sometimes even necrotic. the glomus caroticum shows an increase in the number of dark-cell nuclei, perhaps as a consequence of increased nuclear metabolism owing to augmented demand. ache and butyrylcholinesterase (bche, also known as pseudocholinesterase or type che) levels are depressed in deaths owing to organophosphorus insecticides. the measurement of their levels can assist in the determination of the cause of death ( ) . ache is found mostly in red blood cells, motor endplates, and gray matter, whereas bche is found mostly in plasma, white matter, liver, heart, and pancreas. the physiological function of bche is unknown ( ) , but it is established that bche hydrolyzes suxamethonium (succinylcholine), and for this reason it is of interest to anesthesiologists as well. postulated functions of bche include its role in transmission of slow nerve impulses, lipid metabolism, choline homeostasis, permeability of membranes, protection of the fetus from toxic compounds, and degradation of acetylcholine and in tumorneogenesis ( ) . the plasma cholinesterase (pseudocholinesterase) is more sensitive and levels fall more rapidly than those of the red blood-cell cholinesterase. red blood-cell cholinesterase levels are more satisfactory for the diagnosis of organophosphorus poisoning because they represent the true cholinesterase levels. sample collection and storage (time and temperature) are critical to the catalytic stability of che and thus influence the quality and interpretation of results of the toxicological analysis. fluids and tissues that should be collected at autopsy are blood, cerebrospinal fluid (csf), semen, muscle, brain, liver, heart, and pancreas. the recommended procedures for collection and storage of biological fluids are as follows: . blood must be collected in heparinized tubes. . the samples must be collected and stored in glass rather than plastic containers to avoid contamination by leachates from plastic. . sample contamination with acid or alkali must be avoided. . samples must be immediately refrigerated because che catalytic activity is temperature dependent. . fluid and cellular components of blood, csf, and semen have to be separated. . determine enzyme activity as soon as possible. if enzyme activity is not determined immediately, samples can be stored for several days at °c. if tissues are intended to be stored for longer periods, the storage temperature should be - °c or below. . tissue should be homogenized at ph . to . using a sonicator or nonmetallic homogenizer and then should be stored as indicated above. che activity in blood, serum, and tissues can be measured by a number of methods. one of the most popular is the ph method by michael ( ), whereby a change in ph is measured when che acts on acetylcholine. the principle is that cholinesterase hydrolyzes acetylcholine, thus producing acetic acid, which in turn decreases the ph of the reaction mixture. electrometric determination of the change in ph from . for a definite period of time (e.g., hour) at a specific temperature (e.g., °c) represents the enzyme activity. normal values of che activity as measured by this method (in Δph/hour/ . ml red blood cells or plasma at °c, mean ± standard deviation) are given in table ( ) . in deaths owing to organophosphorus insecticides, the values will be much lower. a % or greater depression of the red blood-cell che level is a true indicator of poisoning. death occurs when levels have decreased by more than %. blood and urine should be preserved for toxicological analysis of che levels. samples from lung, liver, kidney, skeletal muscle, brain, and spinal cord, as well as gastric contents, must similarly be preserved for toxicological analysis of cholinesterase levels ( ) according to the precautions detailed in steps - in section . . . . paranitrophenol is a metabolite of many organophosphates. it is excreted in urine and its presence in urine is characteristic of organophosphorus poisoning. organophosphates usually resist putrefaction and can be detected in the viscera for quite some time after death. wehr ( ) studied five exhumations where the decedents were suspected having been poisoned with parathion. he could detect the degradation products of parathion (aminoparathion and p-nitrophenol) up to years after burial, but after years, neither parathion nor any of its degradation products were detectable. pohlmann and schwerd found evidence of parathion in a corpse exhumed after months ( ) . more recently, karger and co-workers ( ) described a case where they detected paraoxon, the main conversion product of parathion, from the abdominal cavity of a -month-old boy, months after his death. his mother had poisoned him with parathion; her deed was detected when, several months later, her second child-a -year-old girl-also suffered the same fate and parathion was detected in her blood. carbamates (fig. ) are derivatives of carbamic acid. their structure is similar to that of organophosphates (fig. ) . the first recognized anti-che was in fact a carbamate, physostigmine (also called eserine), obtained in pure form in by jobst and hesse from the calabar bean ( ) . some common carbamates used as insecticides today are aldicarb, carbaryl, γ-benzene hexachloride, triallate, propoxur, methomyl, carbofuran, and carbendazim. like organophosphates, carbamates are inhibitors of ache, but instead of phosphorylating, they carbamoylate the serine moiety at the active site. this is a reversible type of binding, and therefore, their toxicity is less severe and of lesser duration ( ) . because they do not penetrate the cns to any great extent, the cns toxicity of carbamates is relatively low. signs and symptoms are the same as those seen in poisoning with organophosphates/organophosphorus insecticides but they are milder in nature. convulsions are not seen in carbamate poisoning. postmortem findings in carbamate poisonings are mostly similar to those found in organophosphates. a bluish discoloration of the mucosa of the mouth and stomach is not seen because the blue green dye indigocarmine is usually not mixed with carbamates. determination of cholinesterase levels is not of much help because these are restored very rapidly in carbamate poisoning. organochlorine pesticides are nonselective insecticides. they are cyclic in nature, have molecular weights between and d, are cns stimulants, and have limited volatility. they are poorly soluble in water but readily soluble in organic solvents and fats, which is the way how they accumulate in the human body. they are very stable, both in the environment and in the body tissues, and can be demonstrated in the bodies of most people born since . based on their chemical structures, organochlorines can be divided into four categories ( fig. ) ( ): (a) dichlorodiphenyltrichloroethane (ddt) and related analogs, such as methoxychlor, (b) hexachlorocyclohexane or lindane, (c) cyclodienes and related compounds (e.g., aldrin, dieldrin, endrin, endosulfan, chlordane, chlordecone, heptachlor, mirex, isobenzan), and (d) toxaphene and related compounds. the best known organochlorine, ddt, was synthesized by the german chemist othmar zeidler in , but he failed to realize its value as an insecticide. it was the swiss paul hermann müller ( - ) who recognized its potential as an effective insecticide. in , ddt was tested successfully against the colorado potato-beetle by the swiss government. the united states department of agriculture used it successfully in . in january , ddt was used to quash an outbreak of typhus carried by lice in naples, italy; this was the first time a winter typhus epidemic could be stopped. so revolutionary was his work that müller was awarded with the nobel prize in medicine in . it is ironic that just years later, in , ddt was banned in the united states. it is perhaps a unique example in the history of science that a nobel prize-winning work was banned within such a short period of time. the main driving force behind this ban was the ecologists' concerns about the persistence of ddt in the environment and its resulting harm to the habitat-humans are equally affected by persistent ddt in the environment. it was rachel carson's book silent spring, published in , which brought the problem to everyone's notice. endrin, one of the cyclodienes, is chiefly used against insect pests of cotton, paddy, sugarcane, and tobacco. it is active against a wide variety of insect pests, and hence is commonly known as plant penicillin. it has been banned in most western countries, but unfortunately continues to be used in several agrarian economies. the mechanism of action of organochlorines is entirely different from that of organophosphates and carbamates. organochlorines act on axonal membranes affecting the sodium channels and sodium conductance across the neuronal membranes. organochlorines also alter the metabolism of acetylcholine, noradrenaline, and serotonin. lindane and cyclodienes appear to inhibit the γaminobutyric acid-mediated chloride channels in the cns. therefore, not very surprisingly, the main symptoms induced by poisoning with organochlorines are cns-related and include vertigo, confusion, weakness, agitation, hyperesthesia or paresthesia of the mouth and face, myoclonus, rapid and dysrhythmic eye movements, and mydriasis (in contrast to organophosphates and carbamates, where miosis is found). other symptoms include nausea, vomiting, fever, aspiration pneumonitis, and renal failure. the fatal dose of ddt and lindane is to g, whereas that of aldrin, dieldrin, and endrin is to g ( ). the conjunctivae are congested and the pupils are dilated. there may be a kerosene-like smell emanating from the mouth and nostrils. this is because most organochlorines are poorly soluble in water and are dispensed as solutions in organic solvents that may have a kerosene-like smell. fine white froth, which may or may not appear hemorrhagic, can be seen around the mouth and nostrils; this is a general effect of pulmonary edema coupled with respiratory distress and therefore, signs of cyanosis are seen on the face, ears, nail beds, etc. the mucosa of the respiratory tract appears congested and the respiratory passages contain frothy mucus which may or may not be tinged with blood. subpleural and subpericardial petechial hemorrhages are common. the lungs appear large and bulky, showing pulmonary edema. the mucosa of the esophagus, stomach, and bowel is congested owing to the irritating effect of organochlorines on the gastrointestinal tract. the stomach contents smell kerosene-like. the visceral organs are congested. hepatic necrosis may be found on cut sections of the liver. in animals killed by ddt, vacuolization around large nerve cells of the cns, fatty change of the myocardium, and renal tubular degeneration can be detected histologically ( ). feces, urine, and subcuatenous adipose tissue (placed in a glass-stoppered vial or a vial with a teflon-lined cap [ ] ) should be collected for toxicological analysis. samples must be frozen before onward transmission to the toxicology laboratoy. nicotine salts, such as nicotine sulfate, were very popular pesticides in the s and s. these compounds generally contained % nicotine (fig. ). now, because most countries have banned nicotine-based insecticides, less than % of home garden insecticides are nicotine-based. these are usually available in powder form. main among these is black leaf- (manufactured by black leaf products company, elgin, il). when nicotine-based insecticides come in contact with moist skin, fatal doses of nicotine may be absorbed through the skin ( ) . apart from occupational exposure to nicotine spray, other methods of fatal exposure include careless storage and inadvertent mixing with foodstuffs, fruits, and vegetables. these insecticides have also been used successfully with suicidal or homicidal intention. brownish froth around the mouth and nostrils is a frequent finding in nicotine poisoning. there is a characteristic odor of stale tobacco emanating from the gastric contents. the esophageal and gastric mucosa is intensely congested, showing a brownish discoloration. liver and kidneys show considerable acute congestion ( ). the liver shows plaque-like granulations in the cytoplasm of centrilobular and intermediary hepatocytes. intrapulmonary hemorrhages and pulmonary edema are typical and there often is detachment of the alveolar epithelium. in the kidneys, there is necrosis and detachment of the epithelia in the straight and convoluted renal tubules. a variety of arterial wall lesions, including lacerations of the elastic interna, are seen that have been connected with extreme fluctuations in blood pressure from the effects of nicotine ( ). an estimated % of all plant species are weeds, with a total of some , species. chemicals, such as common salt, have been used for centuries for weed control. the era of chemical weed control is generally recognized as starting in . bonnet in france found that the bordeaux mixture, already being used on vines to control powdery mildew, also provided control of specific weeds. by the s, farmers were still using simple chemicals for this purpose; for example, copper sulfate (blue vitriol), which was first used for weed control in , was still in use at this time. in the early th century, scientists in europe started using the salts of heavy metals to control weeds but when this was attempted in the united states, the low humidity in the western states prevented these chemicals from being absorbed by the weeds. other chemicals were tried, but most of them had drawbacks. for instance, carbon bisulfide used to control thistles and bindweeds smelled like rotten eggs and was, therefore, quite understandably unpopular. most chemical weed killers of those times (such as sodium arsenate, arsenic trioxide, and sulfuric acid) were highly toxic to humans and had to be used in large quantities (several kilograms per hectare), which was another serious drawback. the first synthetic organic chemical for selective weed control was introduced in . its chemical name was -methyl- , -dinitrophenol, and it could control some broadleaf weeds and grasses in large seeded crops, such as beans. more modern herbicides are now available. these have to be sprinkled in very low doses (grams per hectare) in order to kill weeds and the crop is spared. herbicides are categorized as selective when they are used to kill weeds without harming the crop and as nonselective when the purpose is to kill all vegetation. killing of all vegetation is generally not intended in an agricultural setting. it is required more often in places such as recreational areas, railroad embankments, irrigation canals, fence lines, industrial sites, roadsides, and ditches. both selective and nonselective herbicides can be applied to weed foliage or to soil containing weed seeds and seedlings depending on the mode of action. the term true selectivity refers to the capacity of an herbicide, when applied at the proper dosage and time, to be active only against certain species of plants but not against others. selectivity can also be achieved by placement, such as when a nonselective herbicide is applied in such a way that it reaches only the weeds but not the crop. herbicides can also be classified as contact or translocated. contact herbicides kill the plant parts to which the chemical is applied. translocated herbicides are absorbed either by the roots or the above-ground parts of plants and are then circulated within the plant system to distant parts. timing of herbicide application regarding the stage of crop or weed development forms another basis of classification. a preplanting herbicide is sprinkled on the farm before the planting of the crop. a preemergence herbicide is sprinkled after planting but before emergence of the crop or weeds. finally, a postemergence herbicide is used after the emergence of the crop or weed. herbicides can be applied to weeds in a number of ways. a band application treats a continuous strip, such as along or in a crop row. broadcast application covers the entire area, including the crop. spot treatments are confined to small areas of weeds. directed sprays are applied to selected weeds or to the soil to avoid contact with the crop. in the more recent overthe-top-application, herbicides are applied "over the top" of the crop and weeds shortly after germination. the crops in these instances are naturally tolerant to the specific herbicide or have been genetically engineered to be tolerant to the herbicide used. from a toxicological point of view, the following herbicides are the most important. dipyridyl weed killers include paraquat, piquat, and morfamquat ( fig. ). paraquat is the most important of these three. paraquat ( , ′dimethyl- - ′bipyridylium dichloride) is an important agricultural chemical from a toxicological viewpoint. out of the deaths caused by pesticides reported by the aapcc annual report ( ) , two were the result of paraquat poisoning. paraquat was first synthesized in , but its herbicide activity was discovered very late. its use as an herbicide was first reported in , and paraquat was introduced commercially as a nonselective herbicide in . the introduction of paraquat caused an agricultural revolution because it has some unique properties. it can be sprayed from the ground level or the air and is totally denatured when it comes in contact with the earth. thus, it cannot harm the seeds or young plants that will be placed in the same ground a short time later. indeed, the crop can be planted within days, if not hours, after herbicidal treatment with paraquat. an additional advantage is that plowing is unnecessary aggrawal in many cases with much less soil erosion. paraquat is therefore of immense value in an economic sense ( ) . in countries like sri lanka, its use has resulted in three crops, instead of two, per year being taken off the same field ( ) . paraquat is highly soluble in water and is marketed most commonly as a concentrate containing g paraquat dichloride per liter ( % wt/vol); this is an odorless brown liquid. a "stenching" agent (a pyridine derivative) is added to prevent accidental or criminal poisoning; a bluish-greenish dye is also added for the same reason, and an emetic may be added as well. paraquat is sometimes sold in combination as a mixture with diquat and other herbicides. the liquid concentrate is known as gramoxone (not to be confused with gammexane, which is the trade name for lindane); a weaker, granulated preparation for horticultural use, known as weedol, is also available ( % wt/vol). the solution may be decanted in soda bottles and left unlabelled. because it looks like a cola drink, accidental ingestion may occur. it may be mistaken for vinegar as well; one patient is reported to have sprinkled it on his french fries. wesseling and co-workers ( ) reported that paraquat is the pesticide most frequently associated with injuries among banana workers in costa rica; the injuries involve mostly the skin and eyes. although most fatalities caused by paraquat occur from ingestion, absorption through the skin can also cause fatalities. wohlfahrt ( ) reviewed paraquat poisoning in papua new guinea from to and found that out of fatalities caused by paraquat, six were the result of transdermal absorption. diquat ( , ′-ethylene- , ′-dipyridylium dibromide) is less commonly used than paraquat. it has the same indications and mode of action as paraquat. diquat is, however, used additionally for the control of aquatic weeds. jones and vale ( ) compiled all cases of diquat poisoning published between the years and and found that only cases were reported in detail in the literature, of which ( %) were fatal. conning et al. showed that out of the three dipyridyl weed killers, it was only diquat that produced bilateral cataracts ( ) . diquat was introduced in as a fast-knockdown, contact herbicide and plant desiccant. diquat-only formulations manufactured by syngenta (formerly imperial chemical industries) or its subsidiaries do not contain the dye, "stenching" agent, or emetic added to paraquat ( ). the symptoms include intense pain in the mouth and pharynx, with inflammation and even ulceration of the oral mucosa. esophageal ulceration may lead to perforation with all its attendant risks. renal and hepatic failure develop within to days. the most important effect is on the lungs (pneumotropism), where massive, irreversible pulmonary fibrosis is seen. pulmonary fibrosis is thought to be the result of an increase in the pulmonary concentrations of prolyl hydroxylase, an enzyme which promotes collagen formation. paraquat is one of the few poisons that may produce necrosis of the adrenal glands, possibly leading to hypotension. the fatal dose is to g (about a mouthful of gramoxone). subcutaneous injection of just ml of gramoxone has shown to be fatal ( ) , with death occuring after to weeks as a result of respiratory failure caused by pulmonary fibrosis; greater doses can kill a human within hours. why does paraquat show such remarkable pneumotropism? it has been postulated that inside the pneumocytes, the paraquat dication pq + accepts one electron from reduced nicotinamide adenine dinucleotide and becomes the monocation pq + . (pyridinyl-free radical) (fig. ). the monocation pq + . is unable to cause any injury on its own, but in the presence of molecular oxygen (o ) in the lungs, it is oxidized once again to its dication form (pq + ). in this process, it passes on its electron to the molecular oxygen (o ), which, in turn, becomes the superoxide anion radical (o -. ). this process, known as redox cycling, is sustained by oxygen in the lungs. the superoxide anion radical o -. (reactive oxygen species) generated as a result of this cycle is responsible for cell death. this also explains why oxygen enhances the toxicity of paraquat and should never be administered during paraquat intoxication; by administering oxygen, one is supplying the "raw material" for the formation of the damaging superoxide radical. formation of free radicals is implicated in injuries caused by at least two other poisons-myocardial injury caused by doxorubicin and liver injury by carbon tetrachloride. the related bipyridylium compounds, such as diquat and morfamquat, do not affect the lung as seriously, but rather cause liver damage ( ). there is ulceration around lips and mouth, although it is not as bad as is seen after ingestion of inorganic acids, such as nitric or sulfuric acids. the oral and esophageal mucosa is reddened and desquamated. a unique feature of paraquat ingestion is the formation of pseudomembranes in the pharynx resembling to that seen in diphtheria ( ). patchy hemorrhages in the stomach mucosa are a frequent finding. the liver is pale, showing fatty changes. the kidneys may exhibit pallor of the cortex. the most striking findings are found in the lungs. both type and type alveolar epithelial cells accumulate paraquat and are thereby destroyed. this destruction is followed by inflammatory cell infiltration and hemorrhages; fibroblast proliferation then leads to fibrosis and impaired gas exchange. the lungs are congested, appear stiffened, and retain their shape during evisceration. each lung is typically approx g or more in weight. teare ( ) reported a case of paraquat poisoning (a -year-old man dying of suicidal ingestion of paraquat after days of illness), with the left lung weighing g and the right lung weighing g. blood-stained pleural effusions and fibrinous pleurisy are other typical autopsy findings. cut surfaces of the lungs reveal edema and fibrosis. subendocardial hemorrhages may accompany the aforementioned pathological findings. the pathological features of paraquat poisoning have been reviewed in detail by vadnay and haraszti ( ) . at the beginning of the toxic process, severe degenerative changes appear in the pneumonocytes with fatty infiltration, desquamation, necrosis, and detachment ( ) . later, there is splintering of the basement membranes, fragmentation, aneurysma formation, and multiple ruptures. fibrinous edematous fluid is seen in the interstitium and within alveoli and hyaline membranes can be observed. there is a large-scale dissolution of the pulmonary structure. there may be active proliferation of the bronchial epithelium, forming small adenomata within the pulmonary parenchyma. marked proliferation of fibroblasts with an increase in macrophages in the alveoli (these two mechanisms obliterate the alveolar spaces) can be seen. acute tubular necrosis is a frequent finding in the kidneys. extensive renal cortical necrosis is also seen at times. in the liver, centrilobular hepatic necrosis, cholestasis, and giant mitochondria with paracrystalline inclusion bodies can be detected ( ) . in the myocardium, there is edematous disaggregation of the sarcoplasm and sporadic fragmentation of the myofibrils. paraquat-type herbicides in aqueous solutions have traditionally been determined by colorimetric methods. these involve measurement of the complex formed with some chemical (α-dipicrylamine hexanitrodiphenylmethane). plasma paraquat levels can be assayed by spectroscopy, high-performance liquid chromatography ( ) or radioimmunoassays; levels greater than . μg/ml confirm death by paraquat intoxication. urine paraquat levels can be deter-mined using spectrophotometry, too; levels greater than μg/ml confirm death by paraquat intoxication ( ) . berry and grove introduced an ion exchange and colorimetric method in for the determination of paraquat in urine ( ) . diquat (reglone) is selectively concentrated in the kidneys and causes marked renal tubular damage. in a case of fatal diquat poisoning, mccarthy et al. found esophagitis, tracheitis, gastritis, and ileitis ( ) . autopsy findings and toxicokinetic data in diquat poisoning have been described in detail by hantson et al. ( ) . morfamquat is used far less commonly than the other two bipyridyls, paraquat and diquat. conning et al. have shown that rats that fed on morfamquat developed renal damage ( ). chlorophenoxy herbicides (fig. ) are growth regulators or auxins. they cause abnormal plant growth, thereby ultimately destroying the plant. chlorophenoxy herbicides are commonly used for control of broadleaf weeds in cereal crops and pastures ( ). - dichlorophenoxyacetic acid ( , -d; trimec) has been and continues to be one of the most useful herbicides developed; it is frequently applied to lawns to control broadleaf weeds and is often found in fertilizer products along with other phenoxy herbicides, such as dicamba, mecoprop, and ( -chloro- -methylphenoxy)acetic acid. , -d is easily absorbed through the skin and lungs ( ). on ingestion, , -d causes peripheral neuropathy, muscle weakness, cheyne-stokes respirations, hyperthermia, acidemia, and coma ( ) . the patient is hypotonic, hyporeflexive, hypotensive, and comatose ( ) , and nasogastric aspirate may be guaiac-positive ( ). , -d earned a notorious reputation during the vietnam war as an ingredient of agent orange sprinkled by united states troops over vietnam (see subheading . ). suicidal ingestions of , -d are occasionally reported ( , ) . postmortem findings in deaths caused by chlorophenoxy herbicides are nonspecific. the gastrointestinal mucosa may be intensely congested and/or hemorrhagic. all internal organs are usually congested. confirmatory tests of suspected poisonings with chlorophenoxy herbicides are the demonstration of these herbicides in plasma and urine,which can be detected by radioimmunoassay ( ) and gas liquid chromatography ( ). this category comprises mainly dinitrophenol (dnp), dinitro-orthocresol (dnoc), and pentachlorophenol ( ) . these substances are used in agriculture mainly as selective weed killers for cereal crops. the effects of dnp in stimulating metabolism have been known since , and dnp was used at one time for "slimming." dnp (fig. ) is a potent "uncoupler" of oxidative phosphorylation, causing the energy obtained from the oxidation of nicotinamide adenine dinucleotide and reduction of o to be released as heat. it has been demonstrated that these compounds are dangerous to humans and thus, they are no longer used for medicinal purposes. the principal risk of poisoning is in the agricultural use of concentrated solutions for spraying crops aggrawal (as weed killers). dinitrophenol (dnp) is also used in agriculture for the control of mites and aphids ( ) . absorption occurs by inhalation and thus, breathing apparatus are a must for those who are exposed to this poison. absorption also occurs by ingestion and through the skin. excretion of dnp is extremely slow, so the poison accumulates in the body gradually. the symptoms are fatigue, insomnia, restlessness, excessive sweating, weight loss, and thirst. clinical signs include tachycardia, increase in the rate and depth of respiration, rise in temperature (up to °c and higher) and some yellow discoloration of the sclera. in severe cases, body temperature may keep rising and just before death, it may reach °c. when death occurs, the onset of rigor mortis is rapid. sodium chlorate is a nonselective herbicide. it acts as a soil sterilant at rates of lbs/acre. it is also used as a foliar spray at lbs/acre as a cotton defoliant. it was once avidly advocated as a weed killer, not only because it is effective, but also because it was considered safe. this fallacy was so prevalent that containers of sodium chlorate used to be marked as "nonpoisonous." however, chlorates cause methemoglobinemia. severe hemolysis is a constant clinical feature in sodium chlorate poisoning, with presence of heinz bodies in the red blood cells. acute renal failure and anuria sets in later. anuria occurs because of (a) a direct damaging action of chlorates on the renal tubular epithelium, and (b) mechanical obstruction of the renal tubules by the hemoglobin set free by hemolysis. the fatal dose of sodium chlorate is to g with death occuring within to days. poisoning with sodium chlorate can occur accidentally, suicidally, or even homicidally. accidental poisoning is probably the most common. a -year-old gardner was severely poisoned in a curious way. he was using a concentrated solution of sodium chlorate in an atomizer while a strong wind was blowing. consequently, spray was blown onto his face and he inhaled and ingested some of the solution. symptoms of poisoning started the same evening. he was saved with some heroic effort on the part of the doctors, yet he could only return to full-time work after about year ( ). the skin has a distinctive chocolate-brown color. blood smears may show evidence of hemolysis and heinz bodies. the kidneys are enlarged and their principal change is a brown streaking of the cortex; microscopical examination reveals acute renal tubular degeneration with blockage of tubules by broken red blood cells and brown pigment granules (released hemoglobin owing to hemolysis). glyphosate is an important agricultural chemical from the toxicological viewpoint. out of the deaths caused by pesticides reported by the aapcc annual report ( ) , one was caused by glyphosate. glyphosate is a broad-spectrum, nonselective, systemic herbicide used for control of annual and perennial plants including grasses, sedges, broad-leaved weeds, and woody plants. it can be used on non-cropland as well as on a great variety of crops. although glyphosate itself is relatively harmless, its chemical formulations (e.g., roundup ® , rodeo ® , touchdown ® , gallup ® , landmaster ® , pondmaster ® , ranger ® ) have been used successfully for committing suicide. this is because glyphosate invariably is formulated in a surfactant (polyethoxylated tallow amine), which is quite toxic ( , ) . glyphosate is generally distributed as water-soluble concentrates and powders. mild poisoning results only in gastrointestinal symptoms, such as vomiting, abdominal pain, diarrhea, and nausea, which usually resolve within a day or two. severe poisoning results in intestinal hemorrhage and ulceration, acid base disturbances, renal failure, hypotension, cardiac arrest, pulmonary dysfunction, convulsions, coma, and death. postmortem findings are nonspecific. glyphosate and the concomitant surfactant are demonstrated by toxicological analysis in the gastric contents and other visceral organs. glyphosate levels of mg/ml or more can be detected postmortem in blood, liver, and urine in less than a minute by using p nuclear magnetic resonance ( ). among the several arsenical herbicides available are cacodylic acid, calcium hydrogen methylarsonate, disodium methylarsonate, hexaflurate (asf k), methylarsonic acid, monoammonium methylarsonate, monosodium methylarsonate, potassium arsenite, and sodium arsenite. cacodylic acid (fig. ) is also known as dimethylarsinic acid. cacodylic acid is a white crystalline substance, readily soluble in water and alcohol, and is still used as an herbicide. when it unites with metals and organic substances, it forms salts known as cacodylates. cacodylic acid contains . % of arsenic. fungicides, or antimycotics, are toxic substances used to kill or inhibit the growth of fungi that cause economic damage to crop or ornamental plants. most fungicides are applied as sprays or dusts. seed fungicides are applied as a protective covering before germination. systemic fungicides, or chemotherapeutants, are applied to plants, where they become distributed throughout the tissue and act to eradicate existing disease or to protect against possible disease. bordeaux mixture (cuso cu[oh] caso ) was one of the earliest fungicides to be used ( ) . bordeaux mixture is a liquid composed of hydrated (slaked) lime, copper sulfate, and water. it was accidentally discovered in in the modoc region of france, where farmers, tired of schoolboys pilfering their grapes, sprayed their grapevines with a poisonous-looking mixture of lime and copper sulphate; it was a desperate idea meant just to deter schoolboys from stealing their grapes. however, in , pma millardet from the university of bordeaux observed that the very same mixture effectively controlled the downy mildew of grapes as well. burgundy mixture is a mixture of copper sulfate and disodium carbonate. both bordeaux mixture and burgundy mixture are still widely used to treat orchard trees. copper compounds and sulfur have been used on plants separately and together. synthetic organic compounds are now more widely used because they give protection and control over many types of fungi. cadmium chloride and cadmium succinate are used to control turfgrass diseases. mercury(ii)chloride, or corrosive sublimate, is used as a dip to treat bulbs and tubers. mercury salts used as fungicides include mercurous chloride, mercuric chloride, mercuric oxide, phenylmercury nitrate (fig. ) , tolylmercury acetate, and ethylmercury bromide. organophosphorus fungicides include ampropylfos, ditalimfos, edifenphos, and fosetyl (fig. ) . carbamate fungicides include benthiavalicarb, furophanate, iprovalicarb, and propamocarb (fig. ) ; the toxicity of organophosphates and carbamates has been dealt with earlier. among the most important inorganic fungicides are potassium azide, potassium thiocyanate, sodium azide, and sulfur. other substances occasionally used to kill fungi include chloropicrin, methyl bromide, and formaldehyde. many antifungal substances occur naturally in plant tissues. creosote, obtained from wood tar or coal tar, is used to prevent dry rot in wood. the most important fungicides-from the toxicological viewpoint-aside from organophosphorus and carbamates, are sodium azide and compounds of copper and mercury. copper compounds are also especially important because they are used in agriculture as insecticides and algicides. somerville discussed the metabolism of several fungicides including maneb, mancozeb, zineb, captan, chlorothalonil, benomyl, triadimefon, triadimenol, and cymoxanil ( ). sodium azide is important because it is a potential intentional or accidental poison. aside from being used in agriculture, sodium azide is also used widely in hospitals where it is used as a component chemical in the fluid used to dilute blood samples. sodium azide, like dnp, is an "uncoupler" of oxidative phosphorylation; it also inhibits the enzymes catalase and cytochrome oxidase. ingestion of sodium azide results in nausea, vomiting, diarrhoea, hypotension, and cns symptoms, such as headache, hyporeflexia, seizures, and coma. postmortem findings include edema of the brain and lungs. edema of the myocardium with myocardial necrosis has also been reported ( ) . fig. . fosetyl, an organophosphate fungicide. salts of copper, although mostly used as fungicides, are used for a large number of other purposes in agriculture as well. copper acetate, copper carbonate, cupric -quinolinoxide, copper silicate, and copper zinc chromate are used as fungicidal agents only; copper arsenate is used as insecticide and copper sulfate as algicide, fungicide, herbicide, and molluscicide; copper acetoarsenite is employed as insecticide and molluscicide; copper hydroxide is used as bactericide and fungicide; copper naphthenate is used as fungicide and mammal repellent; copper oleate as fungicide and insecticide; and copper oxychloride as bird repellent and fungicide. chronic exposure to bordeaux mixture in vineyard sprayers causes the socalled "vineyard sprayer's lung." observed mainly in portugal, the disorder includes pulmonary fibrosis ( ) and may lead to lung cancer ( , ) . bordeaux mixture is the only other significant pesticide aside from paraquat that induces significant pulmonary fibrosis with organophosphates coming in a distant third ( ) . the radiological picture in vineyard sprayer's lung resembles that of silicosis with micronodular features in the early stages of the disease ( ) . only in later stages does a picture of massive fibrosis emerge with continuing development of respiratory insufficiency. plamenac et al. ( ) examined the sputum of rural workers engaged for years in spraying of vines. sputum specimens were tested for copper by rubeanic acid. macrophages containing copper granules in their cytoplasm were found in % of the workers engaged in vine spraying compared with none in a control group. other abnormalities, such as eosinophils, respiratory spirals, respiratory cell atypia, and squamous metaplasia, were also found in the sputum. atypical squamous metaplasia was observed in % of vineyard workers who were also smokers ( ). eckert et al. ( ) exposed mice to copper sulfate aerosol for a longer period of time and were able to replicate these changes in the animals' lungs. the authors concluded that the changes seen in vineyard sprayer's lung are a result of copper sulfate toxicity. pimentel and menezes studied the liver of vineyard sprayers by percutaneous biopsy and also at autopsy ( ) . they found histiocytic and noncaseating granulomas containing inclusions of copper as identified by histochemical techniques. they also found that the affected individuals were prone to liver fibrosis, cirrhosis, angiosarcoma, and portal hypertension ( ) . copper sulfate is a popular suicidal poison in india ( ) and copper sulfate was once a very popular homicidal poison ( ) . although no reports of suicide and homicide with bordeaux mixture exist, this is certainly possible. quite possibly such cases did, and still do, occur but have never been reported. mercury is widely used as a fungicide in agriculture. both inorganic and organic salts are used. inorganic mercury fungicides being used as fungicides include mercuric chloride, mercuric oxide, and mercurous chloride. organomercury fungicides include ( -ethoxypropyl)mercury bromide, ethylmercury acetate, ethylmercury bromide, ethylmercury chloride, ethylmercury , -dihydroxypropyl mercaptide, ethylmercury phosphate, n-(ethylmercury)-ptoluenesulphonanilide (fig. ) , hydrargaphen, -methoxyethylmercury chloride, methylmercury benzoate, methylmercury dicyandiamide, methylmercury pentachlorophenoxide, -phenylmercurioxyquinoline, phenylmercuriurea, phenylmercury acetate, phenylmercury chloride, phenylmercury derivative of pyrocatechol (fig. ) , phenylmercury nitrate, phenylmercury salicylate, thiomersal (fig. ) , and tolylmercury acetate. the ingestion of wheat and barley seed treated with methyl mercury fungicides for sowing by a largely illiterate population in iraq led to a major poisoning with mercury in to with a high fatality rate ( ) . the seed-about , tons of it-was intended for spring planting; there had been ample warning that the seed was unfit for consumption, but this warning was disregarded. there was a latent period of several weeks after which pares- thesias began to appear in several victims. paresthesias involved lips, nose, and distal extremities. more serious cases progressed to ataxia, hyperreflexia, hearing disturbances, movement disorders, salivation, dementia, dysarthria, visual field constriction, and blindness. in the most severe cases, individuals remained in a mute rigid posture altered only by spontaneous crying, primitive reflexive movements, or feeding efforts. there were victims with deaths ( ) ( ) ( ) ( ) . seven children remained permanently incapacitated both physically and mentally. this was the second major mercury disaster after the minamata bay disaster in japan occurring between and , when about people were poisoned and died ( ) . phenylmercury acetate has been found to be embryotoxic and teratogenic ( ). in deaths caused by acute mercury poisoning, the mucosa of the mouth, throat, esophagus and stomach is greyish in color showing superficial hemorrhagic erosions; a softened appearance of the stomach wall is characteristic. in cases where the patient survived a few days, the large bowel may show ulcerations. the kidneys appear pale and swollen owing to edema of the renal cortex. microscopically, the kidneys usually demonstrate necrosis of the renal tubules ( ). sperhake et al. ( ) reported the case of a -year-old chemist who died of mercury poisoning. an autopsy carried out hours postmortem revealed unspecific signs of intoxication including severe edema of the lungs and brain, dilatation of the bowel, and marked congestion of the parenchymatous organs. the stomach contained ml of a reddish fluid. between the gastric folds, the mucosa appeared highly preserved with a brownish discoloration, but streaklike erosions in the exposed parts. the mucosal surface of the oral cavity and esophagus also appeared brownish and discolored. histologically, the pre-served areas of the gastric mucosa were totally unaffected by autolysis with an intact epithelial layer, whereas the eroded areas showed loss of mucosal lining with infiltrates of polymorphonuclear granulocytes and lymphocytes. mercury was detected in the epithelial layer of the gastric mucosa in situ using , diphenylcarbazone staining ( . % in % ethanol). tubular necrosis was present in the kidneys. a case of chronic arsenic poisoning in a -year-old man has been described; the man used a sodium arsenite-based fungicide for cultivating his vine yard ( ). methyl bromide (ch br), also known as bromomethane, monobromomethane, embafume, or iscobrome, is mainly used as a gas soil fumigant against insects, termites, rodents, weeds, nematodes, and soil-borne diseases ( , ) . it has been used to fumigate agricultural commodities, mills, grain elevators, ships, furniture, clothes, and greenhouses. its main advantages are its effective penetrating power and absence of danger of fire or explosion hazards. methyl bromide acts rapidly, controlling insects in less than hours in space fumigations, and it has a wide spectrum of activity, controlling not only insects but also nematodes and plant-pathogenic microbes ( ) . about % of methyl bromide produced in the united states goes into pesticidal formulations. pure methyl bromide is a colorless gas that is heavier than air. odorless and tasteless in low concentrations, it has a musty, acrid smell in high concentrations. occupational exposure to methyl bromide also occurs frequently. it is estimated that about , american workers are occupationally exposed to this gas annually. its toxicity is severe and, despite safeguards, cases of acute and chronic intoxication occur, mainly in the fruit and tobacco industries. the maximum allowable concentration of methyl bromide is ppm. concentrations of ppm or less are considered safe. death has been reported to occur at ppm ( ) . methyl bromide can enter homes through open sewage connections, thus causing fatalities. lagard et al. ( ) reported an interesting case of methyl bromide poisoning where methyl bromide caused toxicity in this manner. the sewage pipes serving two houses (one house was fumigated and in the other the poisoning occurred) had been sucked empty only to hours prior to the start of fumigation. because it depletes ozone into the atmosphere ( ) , methyl bromide has been banned in several industrialized countries, except for exceptional quarantine purposes. phosphine, sulfuryl fluoride (see subheading . .) , and carbonyl sulfide are considered viable alternatives. the mucosa of trachea and bronchi is congested and shows petechial hemorrhages. the lungs show subpleural hemorrhages and pulmonary edema. bilateral bronchopneumonia may also be present. the brain is edematous with necrosis of cortical cells, especially in the frontal and parietal lobes. multiple perivascular hemorrhages may be detected throughout the brain and small subarachnoid hemorrhages may be seen in some cases. circumscribed hemorrhages may also be present in stomach, duodenum, myocardium, spleen, and retina. the kidneys are acutely congested and show tubular necrosis on the micromorphological level; the proximal tubules are most commonly affected. in severe cases, the loops of henle and the distal tubules are also affected. the liver is also congested, but liver cell necrosis is not a common feature ( ) . methyl bromide can be detected and quantitatively determined in various biological samples by headspace gas chromatography ( ). sulfuryl fluoride (f o s) is an important agricultural fumigant. according to the annual report of the aapcc ( ), the only death that occurred as a result of fumigants was caused by sulfuryl fluoride (fig. ) . it is an inorganic gas fumigant used in structures, vehicles, and wood products for control of drywood termites, wood-infesting beetles, and certain other insects and rodents. it is also used as a gas fumigant for postharvest use in dry fruits, tree nuts, and cereal grains. it is available under the trade name vikane™ gas fumigant. because methyl bromide has now been graded as an ozone-depleting substance and is being gradually phased out, sulfuryl fluoride is taking its place. because sulfuryl fluoride is an inorganic material, as opposed to the organic methyl bromide, it does not bind onto items being protected and therefore, less quantities of gas are required for the same insecticidal effect. sulfuryl fluoride is a colorless and odorless gas. it does not cause tears or immediately noticeable eye irritation and lacks any other warning property. chloropicrin is added to products containing sulfuryl fluoride to serve as a warning indicator; chloropicrin is a gas that causes eye and respiratory irritation and vomiting. sulfuryl fluoride acts as a cns depressant. symptoms of poisoning include itching, numbness, depression, slowed gait, slurred speech, nausea, vomiting, stomach pain, drunkenness, twitching, and seizures. inhalation of high concentrations may cause respiratory tract irritation and respiratory failure. skin contact with sulfuryl fluoride normally poses no hazard, but contact with liquid sulfuryl fluoride can cause pain and frostbite-like lesions owing to rapid vaporization. occupational sulfuryl fluoride exposure may be associated with subclinical effects on the cns, including effects on olfactory and some cognitive functions ( ) . the oral ld for sulfuryl fluoride in rats and guinea pigs is mg/kg. scheuerman has reported two cases of suicide by sulfuryl fluoride ( ). according to scheuerman, toxicological analysis should include a plasma and urine fluoride level because the toxic effects of sulfuryl fluoride are probably related to this ion. concentrations of fluoride in his cases were and . mg/l, respectively. however, all values have to be interpreted in the light of all information available (kind and length of exposure, symptoms, autopsy findings, etc.) in a given case. aluminum phosphide (alp) is an ideal grain preservative for a number of reasons. it is highly toxic to almost all stages of insects with remarkable penetration power. alp dissolves well in water, oil, and fat. it is considered an ideal seed fumigant since the seeds' viability is not affected and is practically free from residual toxic hazards-provided the seeds have less than % water content. alp is minimally absorbed and easily desorbed from the treated commod- ity, such as wheat grains. it is inflammable at the prescribed dosage and devoid of tainting on fumigated stock. it has a distinct odor, which has been described as a fishy odor. because of this and also because of delays in evolving, phoshine provides considerable safety in handling this fumigant. safety in handling is due to both these reasons. because it has an odor, it is difficult for handlers to accidently ingest it. because the tablet generates the predetermined weight of gas, it is very convenient to administer the exact dose. cost of fumigation is low and its effects on the fumigated stock last longer. alp is easy to transport and handle. unfortunately, no specific antidote to alp is known. alp is used very extensively throughout agrarian economies like india. on exposure to moisture it releases the poisonous phosphine, which percolates through the grain: alp+h _ al(oh) +ph . as long as the grain is stored in airtight godowns, the liberated phosphine remains in the environment, repelling all pests. when the grain is to be used, it is brought out and aerated. this releases phosphine, leaving behind virtually no or only nontoxic residues. alp is generally available as tablets (alphos ® , celphos ® , fumigran ® ), which are dark brown or grayish in color, g in weight, and measuring mm in diameter and mm in thickness. they come in an aluminum container containing ten tablets. alp is also available as . -g pellets. the tablets are composed of pure alp (the active ingredient) and ammonium carbamate/carbonate (the inert ingredient). the ratio of the active and inert ingredient is generally about : . on contact with moisture, each -g tablet evolves about g of phosphine along with carbon dioxide and ammonia, which prevents self-ignition of phosphine gas. this is why it is also called a "protective gas." carbon dioxide and ammonia are liberated by combination of water with other inert ingredients in the tablets. the main function of the inert ingredients is to produce these gases, so phosphine may not ignite easily. the phosphine gas, once liberated, spreads quickly and kills insects and rodents almost in all stages of their development. after complete decomposition of the tablet, alp is left behind as a harmless and nontoxic grayish white residue, which is less than % of the original tablet weight. alp is the leading cause of accidental and suicidal deaths in india ( ) ( ) ( ) ( ) ( ) . it has been implicated in several homicides including dowry deaths (deaths of newlywed brides occurring in relation to dowry and covered under section b of the indian penal code). the mortality rate for poisoning with alp is almost % ( ) . there is an intense garlic-like odor emanating from the mouth and after opening of the stomach at autopsy. all internal organs are congested and show petechial hem-orrhages. pericarditis may be present ( ) . the stomach contents are hemorrhagic and the mucosa shows detachment. residues of alp may be demonstrable in the stomach contents, but rarely can alp itself be detected because it readily reacts with acid and water within the stomach. misra et al. ( ) described eight cases of alp poisoning after ingestion of alp tablets for attempting suicide; the mean age of the patients was years (age range - years). six of the patients died; the mean hospital stay was hours (range - hours). an autopsy was carried out in two patients, revealing pulmonary edema, congestion of the gastrointestinal mucosa, and petechial hemorrhages on the surface of liver and brain. anger and co-workers ( ) reported the case of a -year-old man who committed suicide by ingestion of alp. autopsy revealed signs of asphyxia with marked visceral congestion. the authors also toxicologically analyzed peripheral blood, urine, liver, kidney, adrenal, brain, and cardiac blood. phosphine gas was absent in peripheral blood and urine but present in the brain ( ml/g), the liver ( ml/g), and the kidneys ( ml/g). high levels of phosphorus were found in the blood ( . mg/l) and liver ( . mg/g). aluminum concentrations were highly elevated in peripheral blood ( . mg/l), brain ( μg/g), and liver ( μg/g) compared with the reference values. histopathological findings in alp poisoning have been described in detail by chugh et al. ( ) . various viscera show congestion, edema, and inflammatory cell infiltration. in the myocardium, there are patchy areas of necrosis, whereas the liver shows fatty changes and the lung parenchyma displays gray/red hepatization. the adrenal cortex shows complete lipid depletion, hemorrhage, and necrosis. chugh et al. assumed that the changes in the adrenal cortex could be both a sequel of shock and/or a cellular toxic effect of phosphine. in out of the patients studied by chugh and associates, there was a significant rise in the plasma cortisol level (> nmol/l). in the remaining patients, the adrenal cortex was critically involved and the cortisol level failed to rise beyond normal levels (< nmol/l). pillay ( ) noted that in alp poisoning the heart shows features of toxic myocarditis, necrosis may be seen histologically in both liver and kidneys, and the lungs may demonstrate evidence of adult respiratory distress syndrome (ards). ards has also been reported by chugh et al. ( ) . the dose of the intoxicant in chugh's cases varied from two g) to three tablets (corresponding to and g, respectively). all patients were in shock at admission and developed ards within hours after ingestion of alp. according to these authors, the exhalation of phosphine (which they detected by a positive silver nitrate paper test) was the possible noxious triggering factor in developing ards. in misra at al.'s series ( ) , histopathological changes included pulmonary edema, desquamation of the lining epithelium of the bronchioles, vacuolar degeneration of hepatocytes, dilatation and engorgement of hepatic central veins and sinusoids, as well as hepatocytes showing nuclear fragmentation. in anger's single case ( ) , microscopic examination revealed congestion of inner organs and pulmonary lesions that were attributed to asphyxia. silo filler's disease is another disorder associated with agrochemical poisoning during preservation. corn used for silage is usually grown under conditions of heavy sunlight and drought and its nitrate content is usually very high. when this silage is stored in a silo, the nitrates are fermented into nitrites, which in turn combine with organic acids to form nitrous acid. nitrous acid decomposes into water and a mixture of nitrogen oxides. these are nitric oxide (no), nitrogen dioxide, and dinitrogen tetroxide. the decomposition starts within approx hours of putting the crops into the silo and continues for about days. when entering these silos (which virtually turn into a kind of gas chamber), farm workers may suffer acute poisoning from these gases, and many such deaths have occurred. this type of death in a silo was first described in , but at that time it was wrongly attributed to asphyxia ( ). nos, being relatively poor soluble in water, can reach the terminal bronchioles and even alveoli. within the lungs, the nos react with water to form nitrous and nitric acids, which cause extensive lung damage, resulting in chemical pneumonitis and profuse pulmonary edema. nos trigger histamine release, which causes bronchoconstriction resulting in increased airway resistance. douglas and colleagues ( ) examined patients of silo filler's disease between and . all exposures had occurred in conventional top-unloading silos. acute lung injury occurred in patients, one of whom died. in the fatal case, autopsy findings included early diffuse alveolar damage with hyaline membranes, hemorrhagic pulmonary edema, and acute edema of the airway walls. poisoning with and fatalities owing to fertilizers are rarely encountered but do occur. the annual report of the aapcc toxic exposure surveillance system reported one death caused by fertilizers ( ) ( table ). used as a fertilizer, anhydrous ammonia is a respiratory irritant, which, in high doses, causes pulmonary edema ( ) . exposure most often occurs during transfer operations. ammonia reacts with water to form the strong alkali ammonium hydroxide, which causes severe tracheobronchial and pulmonary inflammation with bronchiolitis obliterans. normally, the peculiar odor of ammonia warns the potential victim. during world war ii, in london, a brewery cellar having ammonia-carrying condenser pipes was temporarily converted into a bomb shelter. during a bombing, a bomb fragment pierced one such pipe resulting in a mortality rate of the affected individuals as high as % ( ) . saito et al. ( ) described the case of a -year-old male who presumably consumed water contaminated with a nitrate fertilizer. on admission to hospital, the man showed drowsiness, deep cyanosis, and dyspnea; the patient died hours later. at autopsy, no particular morphological changes were noted except for the blood being a chocolate-brown color. postmortem toxicology of the blood revealed a methemoglobin concentration of % and the concentrations of nitrate and nitrite were . and . μg/ml, respectively. in deaths caused by nitrate fertilizers, methemoglobinemia and the presence of appreciable quantities of nitrites and nitrates may be demonstrated in cardiac blood and gastric contents (stored at - °c until toxicological analysis) ( ) . capillary gas chromatography-mass spectrometry and capillary gas chromatography with a nitrogen-phosphorus detector can be used to detect nitrates and nitrites in blood. sato and colleagues ( ) described the case of an -year-old woman who supposedly consumed agricultural fertilizer containing ammonium sulfate. she was found lying dead on the ground outside her house. a thorough autopsy could not determine the cause of her death. a beer can was found next to her, and when it was examined, it was found to contain ammonium sulfate. subsequently, ammonium and sulfate ions were detected in her serum samples and gastric contents. the cause of her death was determined as poisoning by ammonium sulfate. in order to further confirm that this death was indeed a result of an ammonium sulfate fertilizer, the authors administered a total dose of mg/kg of ammonium sulfate to three rabbits. the animals developed mydriasis, irregular respiratory rhythms, and local and general convulsions until they came into respiratory failure with cardiac arrest. electroencephalogram showed slow, suppressive waves and a high-amplitude with a slow wave pattern that is generally observed clinically in hyperammonemia in humans and animals. there was a remarkable increase in the concentration of ammonium ions and inorganic sulfate ions in the animals' serum and blood gas analysis showed severe metabolic acidosis. the authors suggested that when the cause of death can not be clearly determined and the previous history is suggestive of ammonium sulfate intake, measurement of ammonium ions, inorganic ions, and electrolytes in blood, as well as in stomach contents, are a prerequisite for the diagnosis. villar and co-workers reported poisoning and death in animals who drank fertilizer-contaminated water ( ) . the water had been hauled in tanks previously contaminated with a nitrogen-based fertilizer. in udaipur, india, chronic fluorotic lesions in cattle and buffalo have been described following consumption of fodder and water contaminated by the fumes and dusts emitting from superphosphate fertilizer plants ( ) . similar lesions have been reported from australia where the main source of fluoride appeared to have been gypsum that was included in a feed supplement and also ingested from fertilizer dumps on paddocks ( ) . gypsum fertilizers have caused several deaths in animals ( ) . similar morbidity and mortality may be seen in humans who drink contaminated water either intentionally or out of ignorance as well. the latter situation is quite possible among the uneducated farmers of agrarian economies. adrian ( ) drew attention to a very unique situation of poisoning related to fertilizers. in several countries, sewage sludges are used on farms as fertilizers because they do contain these materials. however the sewage-not surprisingly-also contains industrial wastes, such as chromium, lead, zinc, cadmium, and mercury. when this sewage is used as fertilizing material, plants tend to concentrate these heavy metals, especially chromium. ingestion of such farm produce may lead to heavy metal poisoning. several other cases of fertilizer poisoning, especially among animals, have been reported, too ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . in several countries, poisonous plants, such as castor, are used as green manure which can cause poisoning of both humans and animals. soto-blanco and colleagues from the university of sao paulo, brazil, described a case of canine poisoning where castor bean (ricinus communis) cake was used as a fertilizer ( ) . the authors stressed that these cakes may be accidentally ingested by humans as well, and recommended that cake production should include heat treatment to denature the poisonous proteins. nematicides can cause poisoning in banana plantations. wesseling and co-workers, studying pesticide-related illness and injuries among banana workers in costa rica, reported that workers at highest risk per time unit of exposure were nematicide applicators ( ) . slugs are major pests of oilseed rape that are poorly controlled by conventional bait pellets. therefore, compounds, such as metaldehyde and methiocarb, are used as seed dressings to control slugs ( ) . metaldehyde is a popular molluscicide that can cause fatal poisoning; the aapcc annual report ( ) mentions as many as cases of exposure to this agent. kiyota ( ) reported the case of a -year-old mentally retarded man suffering from pica, who ingested about . g of metaldehyde. despite medical treatment, he developed acute lung injury and died after days; he was found to have ascites and splenomegaly. high-performance liquid chromatography revealed . μg/ml metaldehyde in the serum. jones et al. ( ) developed a method to detect metaldehyde in samples of stomach contents by gas chromatography-ion trap mass spectrometry for forensic toxicology investigations. a suicide attempt using metaldehyde was reported by hancock and co-workers ( ) . a case of homicide using metaldehyde has been described by ludin ( ) . detailed overviews of metaldehyde toxicity have been provided earlier by booze and oehme ( ) and longstreth and pierson ( ) . avermectins used as acaricides (avermectin acaricides), insecticides (avermectin insecticides), and nematicides have been used for suicidal poisoning. chung and co-workers ( ) from taiwan studied the clinical spectrum of avermectin poisoning reported to a poison center from september to december . eighteen patients with abamectin (agri-mek; % wt/wt abamectin) exposure and one with ivermectin (ivomec; % wt/vol ivermectin) ingestion were identified ( males, females; age range - years). fourteen out of the patients had been exposed as a result of attempted suicide; one patient died days later as a result of multiple organ failure. algicides have not been reported to cause fatal poisoning in humans; minor ailments owing to algicide exposure include, e.g., contact dermatitis ( ) . aphicides are known to persist in crops ( ) ; their toxicity in house sparrows has been described in detail by tarrant and co-workers ( ) . bird repellants are trigeminally mediated avian irritants ( ) . toxic effects to humans have apparently not been reported so far. chemosterilants are chemicals that aim at destroying the fertility of pests. , -dibromo- -chloropropane is used to induce infertility in rats ( ) . the chemosterilant bisazir is extremely hazardous. ciereszko and co-workers ( ) have recommended that special safety measures are necessary when handling this chemical. however, toxic effects to humans have not been reported in the medical literature so far. antifeedants are chemicals having tastes and odors that inhibit feeding behavior. several chemicals, such as silphinene sesquiterpenes ( ), , , oxadiazoles ( ) , and ryanoid diterpenes ( ) , are used as antifeedants; again, toxic effects to humans have not been reported so far. herbicide safeners are compounds protecting crops from herbicide injury by increasing the activity of herbicide detoxification enzymes such as glutathione-s-transferases ( ) ( ) ( ) and cytochrome p- s. several herbicide safeners are used in agriculture such as benoxacor ( ) and dichloroacetamide ( , ) ; there toxicity in humans has not been reported so far. insect attractants attract or lure an insect to a trap. several of them are available, such as boll weevil attract and control tubes ® (plato industries, houston, tx) ( ), imidacloprid ( ) , and gf- fruit fly bait ( ) . their toxicity has been studied in detail by beroza et al. ( ) . the secondary effects of conventional insecticides on the environment, vertebrates, and beneficial organisms have caused a move to the use of more target-specific chemicals, such as insect growth regulators (igrs) ( ) . igrs are chemicals disrupting the action of insect hormones controlling molting, maturity from pupal stage to adult, or other insect life processes. several igrs are known, such as halofenozide ( ), s-methoprene ( , ) , buprofezin ( ) , tebufenozide ( ) , the chitin synthesis inhibitors teflubenzuron, diflubenzuron ( ) , and hexaflumuron, as well as the juvenile hormone mimic pyriproxyfen ( ) . halofenozide (rh- ) is a novel nonsteroidal ecdysteroid agonist that induces a precocious and incomplete molt in several insect orders ( ) . the antifeedant , , -oxadiazoles also show a considerable amount of igr activity ( ) . the toxicity of these antifeedants to animals has been studied by wright ( ) . pesticide synergists are chemicals that, although they do not possess inherent pesticidal activity, they nonetheless promote or enhance the effectiveness of other pesticides when used combined (synergism). synergists usually increase the toxicity of a pesticide so that a smaller amount is needed to bring about the desired effect. this may reduce the cost of application. an example of a synergist is piperonyl butoxide, often used with pyrethrin, pyrethroid insecticides, rotenone, and carbamate-containing pesticides. piperonyl butoxide is a liver toxicant and a possible human carcinogen ( , ) ; it also inhibits t-cell activation and function ( ) . -chloro-p-toluidine hydrochloride (cpth) is an aniline derivative registered as a selective, low-volume-use (< kg/yr) avicide. rice baits are treated with cpth to cause poisoning in birds harmful to crops ( ) . cpth may be mutagenic. stankowski et al. ( ) conducted three in vitro mutagenicity tests of cpth according to methods recommended by the united states environmental protection agency, e.g., the ames/salmonella assay, the chinese hamster ovary (cho)/hypoxanthine-guanine phosphoribosyl-transferase mammalian cell forward gene mutation assay, and the cho chromosome aberration assay. they found that cpth did not display mutagenic activity using the ames/salmonella or cho/hypoxanthine-guanine phosphoribosyl-transferase assays. however, cpth induced statistically significant, concentration-dependent, metabolically activated increases in the proportion of aberrant cells. the authors concluded that the results were suggestive of minimal mutagenicity effects associated with exposure to cpth ( ) . stahl and co-workers draw attention to the consumption of cpth treated rice baits by nontargeted bird species, such as pigeon (columbia livia) and house sparrow (passer domesticus). cpth can persist in the breast muscle tissues of both targeted and nontargeted birds which may be a potential secondary hazard to scavengers and predators ( ) . toxicity of cpth both in humans and animals has been discussed by several other authors as well ( ) ( ) ( ) ( ) ( ) . if a particular agrochemical poison has been banned in a country, it is not necessarily that poisoning with this agent will not be seen in that particular country. for example, in japan, production of azomite emulsion (an acaricide) has been stopped since . however, moriya et al. in ( ) described a recent azomite-related fatality. poisoning with azomite was confirmed when aramite and azoxybenzene, two effective components of azomite emulsion, were detected in the patient's serum when qualitatively analyzed with gas chromatography-mass spectrometry. the authors concluded that even if an agrochemical poison is banned, the pathologist must still keep the possibility of its ingestion in mind. many times, it is not the active agricultural chemical that is responsible for poisoning but impurities (such as dioxin), surfactants (e.g., polyethoxylated tallow amine used with glyphosate) and adjuvants used along with the chemical. these adjuvants, or "inert" ingredients, could be solvents, stabilizers, preservatives, sticking or spreading agents, or defoamers ( ) and may constitute petrochemical solvents, such as acetone, fuel oil, toluene, and other benzene-like chemicals. these could sometimes be more toxic than the active ingredient. rubbiani drew attention to several of these adjuvants and clinical syndromes produced by them ( ) . according to harry ( ) , toxicity is often due to solvents or surfactants included in the composition of a formula used as an agricultural chemical. when the obligatory declaration on the label about identity and concentration of some of these substances is not provided by the actual legislation in a particular country, the problem becomes more acute. it is also often difficult to determine if the cause of the poisoning is the actual agricultural chemical itself or its adjuvants. metabolites are breakdown products that form when a pesticide is exposed to air, water, soil, sunlight, or living organisms and often the metabolite is more hazardous than the parent compound. an estimated three million cases of agrochemical poisoning are reported from around the world every year, making it one of most serious toxicological problems of the present times. an overwhelming majority of these-more than %-are reported from developing countries, such as india, presumably because these are predominantly agrarian economies. in the united kingdom, pesticides are responsible for only about % of deaths ( ) , whereas in united states, as seen in table , the figure varies between and %. the equivalent figures in india have been reported to be as high as % ( ) . figure shows some common pesticides used in india. accidental poisoning may occur in a number of ways. accidental poisoning can occur if the insecticide is stored inadvertently with foodstuffs ( ) . one of the most shocking cases of mass agrochemical poisonings occurred in the indian state of kerala in (known popularly as the "kerala food poisoning case of ") when bags of foodstuffs, such as wheat and sugar, were inadvertently stored together with those of folidol (parathion) in the same cabin on a ship ( ) . the insecticide leaked and contaminated the foodstuffs; more than people were accidentally poisoned when they consumed these contaminated foodstuffs. out of these, more than people died. mixing of pesticides with foodstuffs may be intentional, albeit entirely because of ignorance and without any criminal intent. such a case came to notice in the late s in lakhmipur in kheri district, in the indian state of uttar pradesh. farmers in this state were found to be preserving food grains with benzene hexachloride. a severe convulsive epidemic broke out among several hundred people because of this ignorance and more than people died. in , improper use and application of benzene hexachloride in the town sunser in the indian state of madhya pradesh resulted in many people falling ill. fortunately, no human died, but there were reports of several bird casualties. in march , a case of agricultural poisoning from india was reported where an entire family was poisoned owing to leakage of pesticides into cereal (sorghum/jowar) stored in the same room ( ) . the indian state of kerala is a major cashew growing region. there have been attempts at aerial spraying of this cash crop with endosulphan. because these areas are close to local residential areas, deleterious effects occurring in humans have caused a major controversy in recent times ( ) . pillay ( ) suggests that accidental poisoning due to pesticides can occur in four different scenarios: (a) occupational exposure among agriculturists and those engaged in the task of pesticide spraying, (b) contamination of foodstuffs on account of negligence, (c) inadvertent ingestion by children, and (d) reusing pesticide containers for storing food or drink (the latter is very common among third-world countries). instances of fatalities among agricultural workers due to accidental exposures have been reported from time to time ( ) . accidental poisoning owing to some pesticides, such as paraquat, occurs in a number of scenarios, e.g., when the mouthpiece of fumigation equipment is sucked by the operator while cleaning and it is suddenly cleared of obstruction, confusion under the influence of alcohol, consumption of contaminated water or foods, accidental ingestion by children, and accidental cutaneous exposure or oral topical application for toothaches by ignorant persons ( ) . robert g. book of bloemfontein, south africa, reported a unique case of accidental poisoning with paraquat: a young woman tried to "achieve a high" by spiking her coca-cola with paraquat. she died after a few days of hospitalization. at the time of her admission she had told the doctor that her husband had maliciously put paraquat in her drink a few days before; however, only days later she changed her version as just mentioned ( ) . it is noteworthy that in india it is very common for married women at the time of their death to shield their murderous husbands by making such statements. whether the woman's first or second statement was correct is anybody's guess. according to harry ( ) , accidental pesticide intoxications are mainly caused by ingestions of diluted fertilizers, low-concentration antivitamin k rodenticides, ant-killing products, or granules of molluscicides containing % metaldehyde, whereas voluntary intoxications are mostly by chloralose, strychnine, organophosphorus or organochlorine insecticides, concentrated antivitamin k products, and herbicides, such as paraquat, chlorophenoxy compounds, glyphosate, and chlorates. suicidal poisoning with agrochemicals, especially organophosphates and alp, is very common in countries like india. one of the main reasons is the easy availability of these agrochemicals. many companies now add an emetic to dangerous agrochemicals, such as paraquat and alp. addition of a "stenching" agent to paraquat has apparently not deterred suicidals from consuming this poison. homicidal poisoning with organophosphorus compounds is possible and from time to time, one gets to hear or read about cases of a homicide commit-ted with these substances. svraka and colleagues have described four cases of homicide with organophosphorus compounds ( ) . however, homicidal poisonings with organophosphorus compounds are rare because of the unpleasant taste of most agrochemicals, especially of organochlorines, such as endrin, but they have been mixed with alcohol, especially toddy (a strong liquor that is very popular in india), which masks its smell and has been used with organophosphorus compounds for homicidal purposes in this way. homicidal poisoning with parathion is much easier ( ) ( ) ( ) ( ) . to prevent this, a coloring agent, such as indigocarmine, is added to parathion. this is, however, not a universal practice. in india for instance, addition of indigocarmine to parathion is not practiced. the commonly used herbicide paraquat is odorless and gives rise to symptoms mimicking viral pneumonitis. these two properties-classically hailed as the properties of an ideal homicidal poison-make it very attractive as a homicidal poison. paraquat is supposed to have a burning taste, but this can be masked in hot liquids or spicy foods ( ) . several homicide cases with paraquat undoubtedly must have gone unnoticed. teare and teare and brown ( , ) described five cases of paraquat poisoning, of which, two were homicidal in nature. the first is a well-documented case (reg vs kenyon and roberts) in which a -year-old man, keith william kenyon, was killed by his wife jennifer kenyon and her friend, david roberts, a consultant on the effects of agricultural chemicals. she purchased gramoxone along with her friend olive hemming (who turned out to be the chief prosecution witness) from a farm shop, and most likely administered it to her husband in repeated small doses. kenyon was taken ill on november , and died days later, on december . during his illness, he displayed all the classical symptoms and signs of paraquat poisoning. postmortem examination confirmed death by paraquat intoxication. mrs. kenyon was convicted of murder, whereas david roberts was acquitted because of lack of evidence against him ( ) . the second case occurred only month later. after christmas , on the falkland islands, four local agricultural workers had been having a boxing day party when some gramoxone was slipped for some unknown reason into one of their beers. the man died after displaying typical symptoms of paraquat poisoning. autopsy confirmed poisoning by paraquat. criminal charges against the other three laborers were contemplated, but eventually it was decided to drop them. paul ( ) described the case of a -year-old woman who killed her husband by mixing paraquat in his steak-and-kidney pie twice. when he developed a sore throat and was prescribed medicine for treatment, she mixed paraquat in the medicine as well. the husband died on june , after suffering a day illness. the cause of death was attributed to cardiac arrest in combination with renal failure and bilateral pneumonia and it was only by a curious chain of circumstances that paraquat was detected in the young man's tissues preserved in the mortuary in a bucket, months after the man's death. his wife and her paramour were found guilty and sentenced. stephens and moormeister from the medical examiner's office of san francisco, ca, reported four cases of homicidal poisoning by paraquat ( ) . of these, the first three murders were perpetrated by one man against members of his immediate family, and the fourth case was equivocal-it could either have been suicide or homicide. the first three murders were committed by a man who had been married five times. his first three wives were alive and healthy. when the fourth wife threatened to divorce him, she found herself ill and died days after the onset of her illness ( days after hospitalization). eight years later, when his fifth wife threatened divorce, she suffered the same fate, and a few months later, his -year-old mother also died. all three showed typical symptoms of paraquat poisoning. the postmortem findings seemed to suggest natural disease of the lungs. although a suggestion of paraquat poisoning was made in all three cases, the concerned pathologist was reluctant to sign death certificates as paraquat poisoning. toxicological analysis in the second and third cases revealed the presence of paraquat in the victims' tissues and this resulted in conviction of the murderer. it was found that the defendant worked as a mechanic on a large agricultural ranch and had easy access to paraquat; his thumb print was found on one of the opened paraquat containers, although he had earlier denied having to do anything with those containers. the fourth case involved a -year-old man, a registered herbicide and pesticide user, who had marital difficulties with his aggressive, "shrew-like" wife who also stood to benefit from a large insurance policy upon his death. while in hospital, the victim denied suicidal ingestion; he died days after the start of his illness. no testing of toxic effects from the compounds he worked with was ever performed, nor was any consideration given to this possibility. the case did not result in court charges for anyone. stephens and moormeister concluded that the reason why such cases will often go unnoticed is because of the reluctance on the part of both clinicians and forensic pathologists to even think in the direction of paraquat poisoning when they see such a clear and typical picture of "viral pneumonia." in their opinion, the clinician should suspect paraquat ingestion in all cases in which there is progressive pulmonary involvement with no features of viral infection ( ) . the pathologist conducting the postmortem would do well to go through the clinical history, if available, in detail to rule out the possibility of paraquat poisoning. in all doubtful cases, a full toxicological analysis should be done and the tissues should be particularly analyzed for paraquat. daisley and simmons from the university of the west indies in trinidad reported two cases of homicide by paraquat poisoning ( ) . both cases occurred in children and the common clinical presentations were gastrointestinal ulceration and acute respiratory distress with pneumomediastinitis. at autopsy, the most prominent finding was bullous lung emphysema. the authors stress that pathologists should be aware of this finding because they feel that if this autopsy finding is seen combined with the typical clinical presentation mentioned in sections . . . and . . ., it is almost diagnostic of acute paraquat poisoning. da costa et al. have dealt with the medicolegal aspects related to paraquat poisoning in detail ( ) . another weed killer that has been used commonly for homicidal purposes is sodium chlorate. in reg vs hargreaves, hampshire (winchester) assizes, april , a -year-old woman was charged with the murder of a -year-old man whom she had known for the last years as an uncle. in august , he made his last will, written out by the accused in her favor. on january , the accused bought the weed killer sodium chlorate apparently for a friend who was a gardener. on january , , the old man died and the postmortem examination showed signs of death from sodium chlorate poisoning. the victim had consumed beer and the remaining beer in the mug contained some mg of sodium chlorate. the jury found the woman guilty of manslaughter and sentenced her to months of imprisonment ( ) . one of the biggest and most well-known medicolegal controversies in connection with herbicides has been that of agent orange. agent orange is the name given to a mixture of herbicides that united states military forces sprayed in vietnam from to during the vietnam war for the dual purpose of destroying crops that might feed the enemy and defoliating forest areas that might conceal viet cong and north vietnamese forces. the defoliant consisted of approximately equal amounts of the unpurified butyl esters of , -d and , , -trichlorophenoxyacetic acid ( , , -t). agent orange also contained small, variable proportions of , , , -tetrachlorodibenzo-p-dioxin-commonly known as dioxin-which is a byproduct of the manufacture of , , -t and is toxic even in minute quantities; dioxin is considered one of the most toxic compounds synthesized by humans. agent orange was delivered in -gallon drums with an orange stripe to distinguish the drums visually from those containing other chemical agents (hence the name). about million liters of agent orange were sprayed over vietnam from low-flying aircrafts. among the vietnamese, it is considered to be the cause of an abnormally high incidence of miscarriages, skin diseases, cancers, birth defects, and congenital malformations (often extreme and grotesque). alterations in manufacturing procedures had reduced the dioxin content in agent orange later to minimal levels. today, , , -t registrations have been cancelled and agent orange was voluntarily removed by the manufacturers in . many united states, australian, and new zealand servicemen who suffered long exposure to agent orange in vietnam later developed cancer and other health disorders. a class-action lawsuit was brought against seven herbicide makers that produced agent orange for the united states military. the suit was settled out of court with the establishment of a $ , , fund to compensate some , claimants and their families. separately, the united states department of veterans affairs awarded compensation to about veterans. agent orange has now been replaced by agent white, a mixture of , -d and picloram, which is longer lasting and more effective. in the united states, the federal insecticide, fungicide and rodenticide act (fifra) was passed in (amended in , , and [ ] ). this act divides all pesticides in four broad classes depending on their toxicity. the label of each pesticide has to contain a signal word depending on its toxicity. the criteria established by the fifra are given in table . according to the fifra, toxic category i pesticides must have the signal words danger and poison (in red letters) and a skull and crossbones prominently displayed on the package label. the spanish equivalent for danger, peligro, must also appear on the labels of highly toxic chemicals. toxic category ii pesticides must have the signal word warning (aviso in spanish) displayed on the product label. toxic category iii pesticides are required to have the signal word caution on the pesticide label. toxic category iv pesticide products shall bear on the front panel the signal word caution on the pesticide label. pesticides formulated in petroleum solvents or other combustible liquids must also include the precautionary word flammable on the product label. this was obviously done to prevent cases of accidental poisoning, and similar acts exist in almost all countries. in india, a predominantly agricultural country, handling of insecticides is governed by the insecticides act and the insecticide rules, (amended in ) ( ) . section of the insecticide rules, classifies insecticides on a similar basis. section also insists on affixing a label to the insecticide container in such a manner that it cannot be ordinarily removed. among other things, it must contain a square, occupying not less than onesixteenth of the total area of the face of the label, set at an angle of °(diamond shape). this square is to be divided into two equal triangles, the upper portion of which shall contain the signal word, and the lower portion the specified color. the classification of insecticides, signal words to be used, and the color of the identification band on the label according to the insecticide rules, of india are given in table . if a pesticide is misused in any way, the person who bought and stored the pesticide may be legally responsible. in the united states, the food quality protection act was passed in as a complementary set of regulations, which, among other important features, specifically recognizes the special situations and usages of pesticides for public health. these laws regulate the registration, manufacture, transportation, distribution, and use of pesticides. the regulations are administered by the environmental protection agency. more than , bright green ld : lethal dose in % of the exposed subjects intoxications caused by plant protection chemicals in forensic toxicology in urban south africa patterns and problems of deliberate self-poisoning in the developing world pesticide poisoning agricultural and horticultural chemical poisonings: mortality and morbidity in the united states effects of chemical factors on health of the population in various regions of russia green revolution agriculture and chemical hazards human poisoning caused by agents for plant protection in human poisoning caused by chemicals for plant protection in an epidemic of pesticide poisoning in nicaragua: implications for prevention in developing countries agrichemical hazards in the south african farming sector chemical hazards to agricultural workers acute pesticide poisoning: a major global health problem agrochemical poisoning in sri lanka annual report of the american association of poison control centers toxic exposure surveillance system annual report of the american association of poison control centers toxic exposure surveillance system annual report of the american association of poison control centers toxic exposure surveillance system annual report of the american association of poison control centers toxic exposure surveillance system annual report of the american association of poison control centers toxic exposure surveillance system goodman & gilman's pharmacological basis of therapeutics clinical and experimental toxicology of organophosphates and carbamates carbamate insecticides acute neurotoxic organophosphate poisoning: insecticides and chemical weapons knight's forensic pathology forensic histopathology acute organophosphorus compound poisoning organophosphate poisoning and complete heart block clinical and experimental toxicology of organophosphates and carbamates biochemical determination of cholinesterase activity in biological fluids and tissues pseudocholinesterase deficiency and anticholinesterase toxicity biochemical and toxicological investigations related to op compounds an electrometric method for the determination of red blood cell and plasma cholinesterase activity handbook of pesticide toxicology ( vols.) handbook of autopsy practice detection of e several years after burial concerning evidence of parathion (e ) in an exhumed corpse after months analysis of consecutive forensic exhumations with emphasis on undetected homicides clinical and experimental toxicology of organophosphates and carbamates pocketbook of pesticide poisoning for physicians. cbs publishers and distributors goldfrank's toxicologic emergencies modern medical toxicology dreisbach's handbook of poisoning-prevention acute nicotine poisoning the bipyridylium herbicides poisoning by paraquat pesticide-related illness and injuries among banana workers in costa rica: a comparison between and paraquat poisoning in papua new guinea mechanisms of toxicity, clinical features, and management of diquat poisoning: a review paraquat and related bipyridyls death from paraquat after subcutaneous injection reduction of paraquat and related bipyridylium compounds to free radical metabolites by rat hepatocytes morphologic lesions in paraquat poisoning simultaneous determination of paraquat and diquat in human tissues by high-performance liquid chromatography the determination of paraquat ( , ′dimethyl- - ′bipyridylium cation) in urine diquat intoxication a case of fatal diquat poisoning: toxicokinetic data and autopsy findings pesticides studied in man extoxnet pesticide information profile: , -d fatal suicidal poisoning due to , -d fatal human ingestion of , -d, a common herbicide radioimmunoassay for , -dichlorophenoxyacetic acid simultaneous gas chromatographic determination of , -d and dicamba in human blood and urine classes of toxic chemicals clinical management of poisoning and drug overdose sodium chlorate poisoning complicated by acute renal failure acute poisoning with a glyphosatesurfactant herbicide safety evaluation and risk assessment of the herbicide roundup and its active ingredient, glyphosate, for humans rapid determination of glyphosate in postmortem specimens using p nmr bordeaux mixture the metabolism of fungicides three fatal sodium azide poisonings vineyard sprayer's lung": a new occupational disease vineyard sprayer's 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injury caused by methyl bromide, an insecticide fumigant a fatal case of acute methyl bromide poisoning alternatives to methyl bromide treatments for storedproduct and quarantine insects halogenated hydrocarbons fatal accident resulting from methyl bromide poisoning after fumigation of a neighbouring house; leakage through sewage pipes death following intentional methyl bromide poisoning: toxicological data and literature review health effects associated with sulfuryl fluoride and methyl bromide exposure among structural fumigation workers suicide by exposure to sulfuryl fluoride cardiovascular manifestations of aluminium phosphide intoxication aluminium phosphide: worse than bhopal epidemic aluminium phosphide poisoning in northern india lal-mm ( ) occupational phosphine exposure in indian workers aluminium phosphide poisoning adrenocortical involvement in aluminium phosphide poisoning acute pericarditis in aluminium phosphide poisoning acute phosphine poisoning following ingestion of 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acute, fatal illness in cattle exposed to boron fertilizer suspected superphosphate poisoning in calves forensic pathological studies on autopsy of a patient who died after ingesting the liquid fertilizer hyponex nitrite poisoning in herring gulls (larus argentatus) and ringbilled gulls (larus delawarensis) accidental ammonia exposure to county fair show livestock due to contaminated drinking water ricinus communis cake poisoning in a dog seed dressings to control slug damage in oilseed rape case report-fatal snail bait (metaldehyde) overdose presenting aspiration pneumonia determination of metaldehyde in suspected cases of animal poisoning using gas chromatography-ion trap mass spectrometry attempted suicide with a pesticide mixture murder by metaldehyde poisoning metaldehyde toxicity: a review metaldehyde poisoning from slug bait ingestion agricultural avermectins: an uncommon but potentially fatal cause of pesticide poisoning -chloro- , -dinitrobenzene as an algicide. report of four cases of contact dermatitis aphicide persistence on spinach and mustard greens biochemical and histological effects of the aphicide demeton-s-methyl on house sparrows (passer domesticus) under field conditions bird repellents: interaction of chemical agents in mixtures (dbcp)-induced infertility in male rats mediated by a post-testicular effect efficacy of animal anti-fertility compounds against sea lamprey (petromyzon marinus) spermatozoa silphinene sesquiterpenes as model insect antifeedants the toxic and anti-feedant activity of h-pyridazin- -one-substituted , , -oxadiazoles against the armyworm pseudaletia separata (walker) and other insects and mites selective insect antifeedant and toxic action of ryanoid diterpenes tissue-specific expression and localization of safener-induced glutathione s-transferase proteins in triticum tauschii structure of a tau class glutathione s-transferase from wheat active in herbicide detoxification partial characterization of glutathione 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selective pesticides against the storage mite tyrophagus putrescentiae (acari: acaridae) pulse-exposure effects of selected insecticides to juvenile australian crimson-spotted rainbowfish (melanotaenia duboulayi) laboratory evaluation of selected larvicides and insect growth regulators against field-collected culex quinquefasciatus larvae from urban dhaka inter-regional differences in baseline toxicity of bemisia argentifolii (homoptera: aleyrodidae) to the two insect growth regulators, buprofezin and pyriproxyfen significance of penetration, excretion, and transovarial uptake to toxicity of three insect growth regulators in predatory lacewing adults cytotoxic effects of two antimolting insecticides in mammalian cho-k cells persistence and residual activity of an organophosphate, pirimiphosmethyl, and three igrs, hexaflumuron, teflubenzuron and pyriproxyfen, against the cowpea weevil, callosobruchus maculatus (coleoptera: bruchidae) environmental and toxicological aspects of insect growth regulators mechanistic study on liver tumor promoting effects of piperonyl butoxide in rats piperonyl butoxide technical fact sheet cuprizone and piperonyl butoxide, proposed inhibitors of t-cell function, attenuate experimental allergic encephalomyelitis in sjl mice poisoning with -aminopyridine: report of three cases -aminopyridine poisoning of crows in the chicago area stabilization of the avicide -chloro-ptoluidine as the beta-cyclodextrin adduct -chloro-p-toluidine hydrochloride: in vitro mutagenicity studies for human health hazards determinations improved method for quantifying the avicide -chloro-p-toluidine hydrochloride in bird tissues using a deuterated surrogate/gc/ms method toxicity of the avicide -chloro- -acetotoluidide in rats: a comparison with its nonacetylated form -chloro-p-toluidine the role of renal aromatic n-deacetylase in selective toxicity of avicide -chloro-p-toluidine in birds effects of an acutely toxic dose of the avicide -chloro-p-toluidine in chickens toxicologic studies on the avicide -chloro-p-toluidine tissue distribution and binding of radioactivity in mouse after intravenous administration of [ c] -chloro-p-toluidine a case of suicide suspected of poisoning from taking some agricultural chemicals label review manual chapter : ingredient statement. office of pesticide programs the problem of the presence of dangerous adjuvants in pesticide preparations used in agriculture or households textbook of forensic medicine and toxicology foodborne outbreak of organophosphorus compound poisoning food poisoning due to organophosphorus compounds investigation of a fatality among parathion applicators in california paraquat poisoning in children: survival of three cases homicidal poisoning by paraquat four cases of murder with organophosphorous compound a case of homicidal parathion poisoning six homicides by means of e- committed by a minor criminal poisoning by means of administration of parathion mixed with a medicinal substance a case of murder by parathion (e ) which nearly escaped detection homicidal poisoning by paraquat poisoning by paraquat murder under the microscope-the story of scotland yard's forensic science laboratory homicide by paraquat poisoning the forensic medical aspects of paraquat poisonings sodium and potassium compounds fifra- , glp, and qa: pesticide registration the insecticides act, with the insecticide rules, , as amended by the insecticide (amendment) rules, . delhi law house acknowledgment i wish to thank my wife marygold gupta, a chemist, and my son tarun aggrawal for their whole-hearted support during the writing of this chapter. marygold was especially helpful in making me comprehend the chemical structures of several pesticides. tarun drew several chemical structures and figures on his computer. key: cord- -in r ww authors: nan title: the way forward: prevention, treatment and human rights date: journal: global lessons from the aids pandemic doi: . / - - - - _ sha: doc_id: cord_uid: in r ww there now is a considerable body of evidence to support the view that an effective hiv/aids strategy integrates prevention, treatment and human rights. in this chapter, we emphasize the importance of each of these aspects and draw upon the conclusions reached in previous chapters to map out the future of hiv/aids. while medicine and science have a crucial role to play in addressing pandemics, whether slow-moving (like hiv/aids) or fast-moving (like influenza), the social, legal, political, financial and economic ramifications of pandemics can not be ignored. well-considered social, legal, political and financial strategies are essential in order to address any pandemic effectively. united kingdom kingdom - source: global hiv prevention working group ( ) in chap. , we discussed how integrated prevention-treatment-human rights strategies aimed at high-risk groups have proved effective in countries like brazil. in chap. , we explained that limited resources need to focus on high-risk groups and locations to achieve the best possible results. however, as we showed in the sex workers, who are the source of almost % of hiv infections, a negligible amount of funding for hiv/aids is targeted at this group. the mismatch between the most affected group and the allocation of funding in ghana highlights the importance of matching funding to prevailing prevalence and transmission patterns in a given country or region. as we saw in chap. , an hiv prevalence rate above % is a key threshold for an hiv epidemic to run out of control unless funding for prevention efforts is targeted at high-risk groups, such as commercial sex workers, men who have sex with men, injection drug users and prisoners. however, in chap. we saw that pepfar -the largest bilateral donor of funding for hiv/aids programs in developing countries -prohibits the use of funding for programs for commercial sex workers and needle exchange programs. in chap. , we saw that african-americans make up % of hiv/aids patients, even though african-americans account for less than % of the us population. moreover, black men who have sex with men (msm) have the highest rates of unrecognized hiv infection, hiv prevalence and incidence rates and aids mortality rates among msm in the united states. in five us cities, % of african-american msm are infected with hiv. hiv and aids prevalence rates have affected black msm disproportionately since the beginning of the epidemic. black msm are the only group in the united states with hiv prevalence and incidence rates that are comparable to those in the most affected developing countries. however, the vast majority of hiv prevention intervention for african-americans does not target homosexual men and for homosexual men does not target black msm (millett and peterson ) . thus, the need to focus prevention efforts on the most vulnerable groups remains an issue not just in developing countries. while prevention strategies need to be tailored to the sources of hiv infections in specific contexts, there are several proven prevention strategies that need to be scaled up. the resources for prevention need to be focused according to the specific nature of the epidemic in different settings, as we showed in chap. . figure . shows the source of new hiv infections by region. table . summarizes the coverage levels of several essential prevention strategies and fig. . shows their deployment by region. it is important to emphasize that prevention and treatment are mutually supportive and need to be addressed simultaneously. access to treatment supports prevention by reducing risky behaviors, increasing disclosure of hiv status, reducing stigma and reducing infectiousness (global hiv prevention working group ) . prevention supports access to treatment by reducing the number of people that require treatment, thus making universal access to treat- group ( ) order to enhance the effectiveness of both. ment more affordable. hiv treatment and prevention should be integrated, in hiv prevention strategies fall into four general categories: ( ) prevention of sexual transmission; ( ) prevention of blood-borne transmission: ( ) prevention of mother-to-child transmission; and ( ) social strategies. the strategies for preventing sexual transmission are: ( ) behavioral change programs (to increase condom use, to delay the initiation of sexual behavior in young people and to reduce the number of sexual partners); ( ) condom promotion; ( ) hiv testing (knowledge of hiv status decreases risky behavior); ( ) diagnosis and treatment of sexually transmitted infections (which significantly increase the risk of hiv acquisition and transmission, particularly in the case of genital herpes); and ( ) adult male circumcision (which reduces the risk of female-to-male transmission by about %) (global hiv prevention working group ) . the effectiveness of these strategies varies. the promotion of condoms has been largely successful with respect to commercial sex and casual sex, but condom use remains low within marriage. as we noted in chap. , increasing life expectancy, in areas where it is low due to diseases like malaria, is a cost effective strategy for enhancing behavioral change to lower the risk of hiv infection. a survey by the who, on behalf of the global fund, reviewed anti-malaria operations in ethiopia, ghana, rwanda and zambia. in ethiopia, childhood malaria declined by % and the death rate was cut in half within years of the beginning of the mass distribution of mosquito nets. within a single year, both cases and deaths dropped by twodeaths by a third. in many cases, the distribution of free nets was accompanied by free drugs based on artemisinin, a substance to which the malarial parasite has yet to develop widespread resistance, and spraying ddt inside people's houses. free nets and malaria drugs would bring malaria under control in most of africa at a cost of usd billion (economist ) . these promising results also bode some studies suggest that treating sexually transmitted infections may not rediseases. moreover, as we noted in chap. , oster ( ) argues that the explanation for the substantial difference in the transmission rates between the united tions, which leave open sores from chlamydia, syphilis and gonorrhea that facili-there is significant evidence that male circumcision significantly reduces hiv a similar picture is seen in south and south-east asia, where overall hiv prevalence is much lower, but the countries with highest hiv prevalence have little thirds, in rwanda, and one-third in zambia. in ghana cases fell by an eighth and based on these results, the who believes that a -year campaign that distributes well for hiv prevention. association between the risk of infection with hiv and other sexually transmitted prevent as many as % of new infections over a decade duce hiv transmission significantly (halperin ) . however, there is a strong transmission. box . discusses the relationship between circumcision and hiv/ tate hiv transmission. thus, treating bacterial sexually transmitted infections could states and sub-saharan africa is due to other untreated sexually transmitted infec-male circumcision (papua new guinea, cambodia and thailand) . conversely, hiv prevalence is extremely low in those countries where most men are circumcised (pakistan, bangladesh, indonesia and philippines). there is ecological evidence that prevalence of circumcision is negatively correlated with prevalence of hiv/aids. specifically, there is a strong inverse correlation between the prevalence of circumcision in countries and the prevalence of hiv in those countries. all the highest hiv prevalence countries are those where circumcision is little practiced. in fact, no country with nearly universal circumcision coverage has ever had an adult hiv prevalence higher than %, including higher risk than that in countries with prevalence of around %. this fact is illus- fig. . ecological relationship between circumcision and hiv prevalence. source: bailey ( ) a large, randomized controlled trial in , men between the ages of and years showed that circumcision resulted in a significant % reduction in hiv vulnerability to hiv varies considerably from one epidemic to the next, as do the issues facing vulnerable groups. for example, in a concentrated epidemic, such as in asia and latin america, hiv transmission occurs primarily among vulnerable groups and prevention programs targeted at vulnerable groups would reduce infection (auvert et al., ) . these results were confirmed by two other trials. the way forward prevention, treatment and human rights trated in fig. . . countries such as cameroon, where a survey found sexual behavior to be overall infection. however, in a generalized epidemic, such as in several countries groups, halperin ( ) argues that transmission would continue unabated despite prevention programs targeted at vulnerable groups. however, as we noted in chap. , research regarding the relationship between trade routes, truckers, sex workers and hiv propagation contradicts this idea. in a generalized epidemic, where hiv is spread along trade routes, prevention programs targeted at truckers and sex workers would be effective in bringing down the growth rate of the spread of the disease. having multiple sex partners increases the risk of hiv infection in both concentrated and generalized epidemics, but the impact of this factor on hiv prevalence rates can vary considerably. for example, even though the united states and uganda have similar rates of multiple sex partners, and the number of sexual partners that men and women had over a -year period were much higher in the united states than in uganda, uganda's hiv/aids prevalence rate was about times higher than that of the united states (halperin ). however, as we noted in chap. , a recent study indicates that abstinence-only programs are as effective as providing no information at all when it comes to preventing pregnancies, unprotected sex and sexually transmitted diseases. abstinence-plus interventions, which promote sexual abstinence as the best means of preventing hiv, but also encourage condom use and other safer-sex practices, are more effective than the proven strategies for preventing blood-borne transmission are: ( ) to supply injection drug users with clean injection equipment; ( ) methadone or other substitution therapy to reduce drug dependence; ( ) blood safety programs, including screening of donated blood; and ( ) infection control in health care settings, including injection safety and antiretroviral treatment following exposure to hiv. as we noted in chap. , the risk of aids infection through the use of blood products was recognized as early as , but countries were slow to adopt measures to ensure the safety of the blood supply and the world health organization (who) passed a resolution on blood products that made no mention of aids as late as january . in the s, chinese health authorities promoted bloodselling by poor farmers to commercial blood collection centers, despite warnings from the who, spreading hiv/aids through the blood fractionation and reinjection process. in , new hiv infections through hospital blood transfusions continued to be reported in china, and illegal underground blood collection centers have continued to operate. box . recounts the story of the libyan scandal over blood-borne transmission to children. in southern africa, where hiv transmission occurs primarily outside vulnerable abstinence-only programs (underhill et al., ) . on december , , sixth sense productions, inc., an independent holly-snezhana dimitrova, valentina siropulo) and a palestinian medical intern (ashraf ahmad djum'a al-hadjudj) who were jailed in libya and faced the death penalty for allegedly infecting children with hiv. this news item is a postscript to a long international drama that began to unfold in when the medics were arrested on charges of injecting libyan children with hiv-tainted blood while at a benghazi hospital. of them, over had died by the end of . one important report was submitted by luc montagnier and vittorio colizzitwo leading experts on hiv/aids. their report concluded that the infection at the infections began before the arrival of the nurses and doctor in . through hospital records, and the dna sequences of the virus, they traced it to patient n. who was admitted times between and in ward b, iso and ward a. the first cross-contamination occurred during that patient's admission. montagnier and colizzi both testified in person at the trial of record for the defense. on that the strain of virus was already present before the arrival of the six accused. the accused were tried and retried. the libyans had signed confessions from them -which the accused said were extracted under torture. the final verdict in sentenced them to death by firing squad. the libyan president likened the scotland for the bombing of pan am flight over lockerbie, scotland, on and political favors in exchange for the release of the six. in the end, bulgaria, qatar and a group of european countries funneled usd million into the international fund benghazi to finance the treatment of the hiv-infected children and the improvement of the libyan health care system. france played a pivotal role in the final release of the accused. in exchange for the release, france agreed to sell antitank missiles and nuclear technology to libya. it was a win-win deal for france: they did multi-million dollar business with libya and got publicity for helping the release of the accused. when the nurses returned to bulgaria, the government endorsed a , leva reimbursement for each of the nurses. a bulgarian mobile telephony provider donated an apartment for each nurse. the way forward prevention, treatment and human rights december , nature ( , - ) published a report that also concluded wood producer, announced plans to make a usd million movie about five event to the case of abdel basset ali al-megrahi, who is serving a life sentence in hospital resulted from poor hygiene and reuse of syringes. they concluded that the bulgarian nurses (kristiyana vulcheva, nasya nenova, valya chervenyashka, december . thus, it became clear that libya was trying to extract economic the proven strategies for preventing mother-to-child transmission are: ( ) general hiv prevention for women of child-bearing age; ( ) a brief course of antiretroviral treatment in advance of delivery (which can reduce transmission by %, but is only received by an estimated % of women in need); ( ) prevention of undesired pregnancy in hiv-positive women; ( ) breast-feeding alternatives; and ( ) cesarean delivery where the mother has a high viral load (global hiv prevention working group ) . in developing countries, a small but growing number of children are dying of hiv/aids. as fig. . shows, some % of children died of hiv/aids in . hiv infected mothers carry additional risks for the baby. in table . , we indicate some of the major risks. some risks like stillbirth or high infant mortality have been found only in developing countries but not in developed countries. for these additional risks, it has been suggested that one way of eliminating vents mother-to-child transmission by %. thus, family planning could also help to reduce mother-to-child transmission: o t h e r ( % ) mother-to-child transmission is not to have the baby in the first place. this pre-another often neglected aspect of hiv prevention -one prohibited from funding by the bush administration's international aids programinvolves expanding family planning services, including for hiv-positive women who do not want to conceive. reducing unintended pregnancies could greatly decrease the number of infected infants as well as the number of children who eventually become orphans (halperin ). if an hiv-positive woman gives birth to a child, there is a risk of transmission of hiv itself, in addition to the other risks listed in table . . however, the transmission risk of hiv from mother to child is not %. it can be minimized through drug treatment of the mother and careful birthing. figure . clearly demonstrates this fact, using the data from the united states. the introduction of zidovudine (for the mothers before childbirth) has dramatically reduced the risk of hiv infection of the baby. since , most countries have applied a regimen of zidovudine from weeks, with nvp administered during labor and to the baby, and the addition of a day zidovudine/lamivudine postpartum regime. the result has been a dramatic reduction of infected newborns (see fig. . ). note that the reduction has been evident in europe and the united states since , when this regime was introduced. in thailand, the regime was introduced in and in most parts of africa years later. once a child is born, the question is whether the infected mother should breastfeed the child. on the one hand, unaids estimated that globally there are , babies infected through breastfeeding. on the other hand, the unicef estimates that , , children die every year from lack of breastfeeding by the breastfeed the baby. key factors that increase vulnerability to hiv include: ( ) gender inequality (which reduces women's access to information and services, reduces power to negotiate safe sex with partners, increases the risk of sexual violence and may create the need to depend on sex for economic survival); ( ) institutionalized discrimination against vulnerable groups (such as criminalizing drug use and needle possession, commercial sex work and sex between men); ( ) poverty (which reduces access to information and services and access to prevention tools, such as condoms); ( ) hiv stigma (which discourages individuals from seeking testing, disclosing their status, seeking hiv-related services or using alternatives to breast-feeding); and formation and social support by displacing populations and increase the risk of sexual violence) (global hiv prevention working group ). as we noted in chap. , there is no clear evidence that reducing poverty and income inequality will necessarily reduce hiv/aids prevalence. moreover, povcondoms and circumcision. significant percentage of men who have sex with men are hiv-infected in many africa; % in guyana; % in st. petersburg, russia; and % in urban ethiobetween vulnerable groups and the general population in bangladesh. the linkages between vulnerable groups, and between vulnerable groups and the general social strategies that address the factors that increase vulnerability to hiv innities and hiv-positive individuals in hiv/aids programs; ( ) visible political leadership; ( ) engaging a broad range of sectors in hiv awareness and prevention the way forward prevention, treatment and human rights hiv/aids prevention strategy. thus, if poverty reduces access to information and parts of the world ( % in bangkok; % in phnom penh; . % in urban sene-vulnerable groups are not compartmentalized. people infected through injection drug use can infect their sexual partners. a significant percentage of men who their clients, who in turn may infect their spouses or other sexual partners. in would be to find innovative ways to improve access to information, provide funding measures; ( ) gender equity initiatives to empower women; ( ) involving commution working group ). human rights are the core of most social strategies to gal; and % of african-american men in five us cities). sex workers can infect many areas, sex workers have very high rates of hiv infection ( % in south have sex with men also have sex with women (for example, % in asia) and a ( ) conflict and humanitarian emergencies (which reduce access to services, inerty reduction is too broad a goal to constitute what might be considered a concrete programs; and ( ) legal reforms to support hiv prevention strategies, such as laws clude: ( ) hiv awareness campaigns, including in the mass media; ( ) anti-stigma services and access to prevention tools, such as condoms, a concrete policy response to enhance access to services and provide free access to prevention tools, such as pia) (global hiv prevention working group ). figure . shows the linkages decriminalizing needle possession and anti-discrimination laws (global hiv preven-population, make effective prevention strategies for vulnerable groups essential. awareness of hiv status has a significant impact on rates of hiv transmission. when unaware of hiv seropositivity, the transmission rate is estimated at . - . the transmission rate to an estimated . - . % (holtgrave ). however, inorder to balance the need for more testing with the need to respect human rights, it has been recommended that health care providers offer and recommend hiv testing, in conjunction with counseling (the opt-in approach), rather than rely on the client to initiate this process. however, mandatory hiv tests and routine hiv testand confidentiality (jürgens ). the major barriers to increasing hiv prevention are: ( ) failure to target limited funding where it will have the greatest impact, due to ing unless the client opts out risk violating individuals' rights to informed consent lack of information on the nature of the epidemic or ideological, non-scientific creasing access to hiv testing and counseling also raises human rights issues. in increases in funding; ( ) failure to integrate hiv prevention in schools, workplaces and other health care programs, such as tb and reproductive health; and ( ) stigma and discrimination against hiv-positive people and vulnerable groups, which deter people from seeking testing and prevention services and discourage political leadership (global hiv prevention working group ) . we analyze the problems and solutions regarding stigma and discrimination against hivpositive people and vulnerable groups later in this chapter. we analyzed the issues of inadequate financing, targeted financing and donor coordination in chap. . as we noted in chap. , a lack of donor coordination is an obstacle to expanding treatment and prevention programs, due to the administrative burden that it imposes on recipients. as we noted in chap. , the us government's foreign aids program, pepfar, devotes only % of funding to prevention and requires that two-thirds of that amount be spent on abstinence-only programs that do not promote condom use, despite evidence that this approach to prevention is not effective and undermines best practices. pepfar guidelines also undermine hiv/aids prevention by further stigmatizing sex workers and prohibiting funding of needle exchange programs, despite evidence that such harm reduction programs are effective. the pepfar approach assumes that vulnerable groups do not interact with the rest of society. pepfar is perhaps the best example of ideological, non-scientific restrictions on the use of donor funding, although it also serves as an example of two of the other significant barriers to hiv prevention, due to its promotion of stigma and discrimination against vulnerable groups and the percentage of funding that it allocates to prevention. however, it is important to emphasize that pepfar has done more than any other bilateral funding program to address the need for adequate financing. the key point is that the money that has been made available through pepfar could be better spent. on december , us president bush signed legislation that lifted a ban that had made washington, dc the only us city barred by federal law from using municipal money for needle exchange programs. officials of the district of columbia health department planned to allocate usd million for such programs in (urbina ) . extending this change in policy to pepfar would enhance the effectiveness of prevention programs in the countries that receive pepfar funding. in chap. , we provided an overview of the history of drug developments to treat hiv/aids and saw the dramatic impact on survival of triple combination therapy. without this treatment, the chance of surviving years was about %. with this treatment, patients have a % chance of living another years. in the early s in the united states, the leading causes of death among - old year men come the leading cause of death in this group. following the introduction of universal access to triple combination therapy, deaths from aids fell to fourth place, behind accidents, cancer and homicide. as a result, whereas % of americans considered hiv/aids to be the most urgent health problem facing the united ents became so important, as we saw in chaps. and . this is also why access to there are five classes of anti-hiv drugs, which are known as antiretroviral verse transcriptase inhibitors (nnrtis), which began to be approved for use in , stop hiv from replicating within cells by inhibiting the reverse transcriptase protein. ( ) fusion or entry inhibitors prevent hiv from entering human immune sert its genetic material into human cells (http://www.avert.org/introtrt.htm). hiv-positive people are prescribed antiretroviral therapy once the number of cd cells falls below a certain threshold or when they develop clinical aids , an international panel of experts continued to recommend these guidelines in low-and middle-income countries, which represents % of those in need (who/unaids progress report on universal access to treatment). the " by lion people on arv therapy by the end of . during this period, the number of people in low-and middle-income countries receiving arv treatment increased from , to . million (who ) . and human resources, management capacity and the ability to identify new patients through testing and counseling (chai ) . in chap. , we examined multilateral funding programs that address these capacity constraints in developing ing treatment are just that -estimates. as we have noted, unaids hiv/aids estients that have been identified as requiring treatment. the reluctance of the united states to allow pepfar funding to be spent on who-approved drugs has also been criticized as an obstacle to expanding treatturer, cipla, created a triple-combination drug in a single pill (triomune) that could be taken twice daily, which it offered to sell for about usd per patient per year in . cipla's triomune offer made the by initiative a realizable goal and cipla has the production capacity to produce four million doses of triomune per day. the who approved triomune in december as a first-line treatment for hiv/aids (hamied ) . the pepfar restriction on the use of who-approved drugs had the effect of preventing the use of pepfar funding to buy triomune. moreover, the majority of pepfar funds have been used to purchase patented versions of hiv/aids drugs, rather than generic versions (see chap. ). figure . shows how generic competition has lowered the cost of triple combination antiretroviral therapy. between and , the price of the generic drugs has brought down the price of the originator substantially -from over usd , to under usd . at the same time, the generic prices have stayed in the - % range of the originator price. pepfar funds can be used to purchase other low-cost generic equivalents of several patented hiv/aids drugs, including some produced by cipla. pepfar requires that generic drugs be approved by the us fda, canada, japan or western europe to be eligible for funding (see chap. ). if us fda approval is sought for fixed dose combinations of previously approved antiretrovirals for the treatment of hiv, if one or more of the approved drug components are covered by a patent, the fda cannot approve an application until the patent expires. however, the application can receive tentative approval (which recognizes that at the time the tentative approval action is taken, the application meets the technical and scientific requirements for approval, but final approval is blocked by patent or exclusivity). products that receive tentative approval are eligible for procurement under the table . . lists the generic versions of hiv/aids drugs that have been approved by the fda for purchase with pepfar funds, along with the generic companies that own the patents for the specific generic formulations and the country of manufacture. the fact that the patents for hiv/aids drugs are owned by different companies has delayed combining different hiv/aids drugs in a single pill in markets protected by patents. one such pill, atripla, was created through a joint venture between merck and bristol-myers squibb with gilead sciences and combines efavirenz (bristol-myers squibb, merck) with emtricitabine and tenofovir (gilead sciences) (ib times ). atripla was approved for sale in the united states in , several years after the indian generic manufacturer, cipla, had started manufacturing a triple-combination pill and years after cipla's pill was approved by the who. approval to market atripla in the european union was sought in december . gilead sciences and merck have formed a joint venture to market atripla in developing countries (ib times ). table . shows the us patents, patent owners and patent expiry dates for selected hiv/aids drugs. zidovudine was the first drug to be approved for treatment of hiv infection. as table . shows, the patent for zidovudine expired in and the patent for lamivudine expires in . however, glaxo extended the life of these patents to by combining the two drugs into one pill (called combivir). while the new combination reduces the number of pills that a patient needs to take, it did not involve the invention of any new chemical entities. the patent history of zidovudine has been cited as a classic case of "evergreening" -the use of the patent system to extend drug monopolies far beyond the term of the original patent (hamied ). box . discussed evergreening. zidovudine was originally synthesized in , as a potential cancer treatment. research in showed that it was effective against hiv/aids, which formed the basis for glaxo's patent application. following clinical trials, the us fda approved zidovudine in march for advanced hiv disease in adults and the patent for zidovudine as a treatment for hiv/aids was granted in february (cochrane ) . while zidovudine alone only extended life by a matter of months, once it was combined with two other classes of hiv/aids drugs, it extended life for years. the fda expanded zidovudine approval in to include evergreening is a mechanism by which pharmaceutical and other companies can keep extending patents on drugs after the initial patents expire. over a fixed period of time. the intention of providing a monopoly is to provide an incentive to innovate. granting a patent requires three elements: ( ) novelty of the product. product; ( ) non-obviousness of the new product; and ( ) demonstrated utility of the the role of patents is to give exclusive rights to manufacture the patented product less-advanced stages of hiv disease (coffey and peiperl, ) . to understand evergreening in the united states, we need to examine the drug price competition and patent term restoration act, informally known as the "hatch-waxman act" . it is a united states federal law which established the modern system for generic drug approval. hatch-waxman generic. section ( j)( )(b)(iv), the so-called paragraph iv, allows -day exvolume). for pharmaceutical companies, the hatch-waxman act has created a perverse drugs by making marginal changes than to try the risky strategy of inventing completely new chemicals. thus, the two decades following its passage, the hatch-waxman act has resulted in more me-too drugs than drugs with new chemical case of prilosec -the so-called "purple pill" of astrazeneca (usd billion/year global blockbuster drug), the patent for which expired in only to be reincarnated as a new patented drug nexium. however, on april the supreme court of the united states issued a ruling in ksr international co v. teleflex et al., which raises the bar for patent holders to prove that their invention is not obvious, and therefore patentable. this ruling will make many existing patents more vulnerable, make it harder to gain approval for new patents and make evergreening more difficult in the future. if the patent claim extends to what is obvious, it is invalid. for example, a patent's subject matter can be proved obvious if there existed at the time of invention a known problem for which there was an obvious solution encompassed by the patent's claims. the supreme court noted that, "granting patent protection to advances that would occur in the ordinary course without real innovation retards progress and may, in the case of patents combining previously known elements, deprive prior inventions of their value or utility." it is worth quoting in full the court's description of the reason that patents are only granted for non-obvious innovations: "we build and create by bringing to the tangible and palpable reality around us new works based on instinct, simple logic, ordinary inferences, extraordinary ideas, and sometimes even genius. these advances, once part of our shared knowledge, define a new threshold from which innovation starts once more. and as progress beginning from higher levels of achievement is expected in the normal course, the results of ordinary innovation are not the subject of exclusive rights under the patent laws. were it otherwise patents might stifle, rather than promote, the progress of useful arts." the way forward prevention, treatment and human rights ents for branded counterparts. the hatch-waxman act encouraged the growth of generic industry, whose market share rose from % in to % in (by amended the federal food, drug, and cosmetic act. section ( j) sets forth clusivity to companies that are the "first-to-file" an anda against holders of pat-the process by which would-be marketers of generic drugs can file abbreviated incentive. it has given them more incentive to try to extend the life of existing abbreviated new drug applications (andas) to seek fda approval of the compounds. the most famous documented case of evergreening occurred in the who guidelines for arv treatment regimens provide a basis for a range of treatment protocols in individual countries. in individual countries, factors such as prices, drug efficacy and side effects are also taken into account. stavudine (d t) recommended that d t no longer be used, due to toxicity. instead, countries should switch to tenofovir (tdf) or zidovudine (azt). of these two, tdf is preferable, because of its efficacy and safety and because it can be taken only once a day. emtricitabine (ftc), in one, triple-combination pill that can be taken once a day. patients are more likely to adhere to this once-a-day regimen, thereby reducing azt and tdf, compared to d t, has delayed the shift to the new regimen in many below), the clinton foundation hiv/aids initiative (chai) has negotiated price reductions for several hiv/aids drugs for use in low-and middle-income countries (see table . ). the clinton foundation is discussed in chap. . as of may , , people were benefiting from medicines purchased under chai agreements in countries (chai ). table . . first, the prices are generally higher for middle-income countries than for low-income countries. thus, the pharmaceutical companies are pursuing a price discrimination strategy across different markets, selling drugs at a price that the markets can bear. therefore, there is clear room for generic products in these markets, especially for the low-income countries. compulsory licensing is a distinct possibility (see, however, our discussion in chap. about the difficulties many developing countries faced importing drugs under compulsory license from canada). some companies have used the world bank's country income index or the human development index as their criteria for setting prices. in chap. , we developed a much more comprehensive index that takes into account not just the level of development of the country but also level of prevalence of hiv/aids explicitly. second, the price of hiv/aids drugs in many cases in many developing countries is not necessarily lower than in developed countries. for example, in guatemala, between and , prices of most hiv/aids drugs were consistently higher than in the united states (hellerstein ). according to chai, in , , ( %) of those receiving arv treatment in low-and middle-income countries were taking second-line treatment. the reason that relatively few are on second-line treatment is that most only began treatment within the last years. as a result, relatively few have experienced treatment failure, which is defined as ( ) virologic failure (a viral load of more than copies per milliliter), ( ) immunologic failure (a declining cd cell count in spite of treatment) or ( ) clinical failure (progression to aids evidenced by weight loss or the appearance of opportunistic infections). another reason is that poor diagnostic and laboratory capacity in many countries has made treatment failure difficult to diagnose. by , chai estimates that close to , people will require second-line treatment in low-and middle-income countries (chai ) . the higher cost of second-line treatment means that access requires further funding. however, patents are not expected to be an obstacle to acquiring affordable second-line treatments in the most affected low-income countries, due to the delay of trips patent rules on pharmaceuticals to , although patent rules may affect affordability in middle-income countries (chai ) . in chap. we analyzed trips rules on patents for pharmaceuticals in developing countries. however, as we noted in chap. , the problem of regulatory capture in free trade agreements can undermine trips rules so that patents create obstacles to affordable treatment in some lowincome countries and political pressure on low-and middle-income countries can discourage the use of trips flexibilities to increase access to treatment. unitaid is a global health initiative for hiv/aids, tuberculosis and malaria that is funded by several national governments. with respect to hiv/aids, unitaid funding is focused on pediatric and second-line treatment and the prevention of mother-to-child transmission. unitaid will finance a free supply of second-line hiv/aids treatment in countries for months, after which the reduced prices achieved by chai will enable other funding sources, such as the global fund (discussed in chap. ) and pepfar (discussed in chap. ), to fund the purchase of second-line treatments at lower prices (chai ) . while high-income countries and middle-income countries with low prevalence rates are in a position to pay for hiv/aids treatment, middle-income countries with high prevalence rates and most low-income countries are not. low-income countries with high prevalence rates in particular will have to depend on external funding sources, such as pepfar and the global fund, to expand access to treatment and then to maintain treatment. medical care for people with hiv/aids in developing countries costs about usd , a year, in drugs and support facilities. the economist estimated that it would cost usd - billion a year to provide treatment for the - million people with hiv/aids in low-income countries that were in need of treatment in . however, expanding treatment means that fewer people will die. moreover, millions more will become infected, and even more so if prevention efforts are not improved. thus, universal treatment in lowincome countries could cost usd billion by the end of the next decade. this highlights the need to ensure that external funding is both increased and sustained and the importance of prevention in making universal access to treatment affordable (economist ). scientists have been trying to develop an hiv vaccine for more than years, although some have suggested that an effective aids vaccine may be a biological impossibility (epstein ) . in , about experimental hiv vaccines were being tested in clinical trials. most viral vaccines work by generating antibodies that neutralize or inactivate the invading virus. however, unlike other viruses, hiv- evades the antibody response, which, together with the large genetic variety found in hiv- strains, has made the development of an hiv- vaccine difficult. to date, antibody-based hiv- vaccines have only succeeded in neutralizing a minority of the copies of the virus that are found in a given patient. hiv- antibodies target the mechanism that hiv- uses to bind itself to the host immune cells in order to prevent hiv- from entering the cell. however, hiv- uses shielding mechanisms to prevent the antibodies from recognizing the virus, including a dense coating. current hiv- vaccine research therefore seeks to find vulnerabilities in these shielding mechanisms, but this requires research for multiple genetic subtypes of hiv- (montefiori et al., ) . for example, one recent study identified a place on the outside of the human immunodeficiency virus that could be vulnerable to antibodies that could block it from infecting human cells, which might be targeted with a vaccine aimed at preventing initial infection (dunham ) . a new class of hiv vaccines was designed to trigger cell-mediated immunity to create an extended immune defense. however, in , merck reported that its hiv vaccine, v , had failed. v was being tested by merck and the us national institutes of health in a clinical trial involving , people in highrisk groups in australia, brazil, canada, the dominican republic, haiti, jamaica, peru, puerto rico and the united states (associated press ). v used the common cold virus (the adenovirus) to transport three synthetic hiv genes into the body's cells (park ) . merck halted the trials after of volunteers who got the v vaccine later became infected with hiv, while only of participants that received a placebo also became infected (associated press ). the v vaccine was one of only two aids vaccine candidates in advanced human trials, the other being tested by sanofi-aventis sa (dunham ) . other approaches are also being explored. david ho (the inventor of triple combination therapy) and his team at the aaron diamond aids research center are researching the use of different vectors, or not using vectors at all, to produce stronger immune responses. scientists at the international aids vaccine initiative are studying the use of crippled, live strains of hiv and ways to stimulate a special class of antibodies that appear to be able to defuse hiv. the global hiv vaccine enterprise, which is funded by the gates foundation (discussed in chap. ), wellcome trust, the us national institutes of health and the european union, is seeking to accelerate research on hiv vaccines by linking together independent organizations so that researchers can learn from each other, rather than work in isolation (park ). as we noted in chap. , there are many subtypes of hiv- (the most commonly occurring hiv infection in humans). the major hiv- subtypes accounting for most infections in africa are subtype c in southern africa, subtypes a and d in eastern africa, and circulating recombinant form _ag (crf _ag) in westcentral africa (peeters and sharp ) . the most commonly occurring form of hiv- in north america and in europe is subtype b. the first hiv/aids vaccine ever to reach phase iii trial was for subtype b. the gp vaccine was not effective. however, what vaccine trials have indicated thus far is that, in the case of hiv/aids, there is pattern of development of potential vaccines not in the subtypes where the needs are the greatest but in the area where the biggest monetary rewards are expected. the economics of hiv/aids vaccines suggest that funding for vaccines for the worst-effected countries are unlikely to come from the private sector (see box . ). hiv/aids affects hundreds of millions and kills several million people every year. the disease was identified several decades ago. two nobel prizes have been awarded in the past two decades for identifying the cause and the transmission mechanism of hiv/aids. yet we still do not have a vaccine for hiv/aids. kremer and snyder ( ) have developed an argument as to why the private sector is very unlikely to develop a vaccine for aids. here, we illustrate the argument with one example. imagine there are people in the world. there are people (type l) who have a small chance of % of contracting hiv/aids. there are another ten people (type h) who would develop hiv/aids with a % chance. let us suppose that the harm from hiv/aids is usd for each person. let us also assume that for each usd decrease in harm, a consumer is willing to pay usd (technically, each consumer is risk neutral). suppose the drug is perfectly effective, has no side effects and is costless to produce. how much revenue will a pharmaceutical company generate in each of the following scenarios? ( ) it develops a drug d that cures hiv/aids (forever). ( ) it develops a vaccine v that prevents hiv/aids from developing. we show that under the assumption that the pharmaceutical company cannot distinguish between type h and type l, it is more profitable for the drug companies to produce the drug rather than the vaccine. if the pharmaceutical company develops the drug d, it will be able to sell it to all the people who get hiv/aids. by assumption, all the type h people will develop hiv/aids. thus, there will be ten people from type h who will get hiv/aids. in addition, nine people of type l will also develop hiv/aids. in total, there will be people with hiv/aids, including both types. by assumption, each person contracting hiv/aids will be willing to pay usd to reduce the effects of hiv/aids by %. therefore, the pharmaceutical company will be able to earn usd , in revenue from the entire population. given our assumption of zero cost of production, usd , will also be the profits of the pharmaceutical company. the vaccine has to be sold before hiv/aids strikes. for type l, there is a % chance of hiv/aids. thus, they will be willing to pay the average loss of ( / ) = usd for the vaccine. if the pharmaceutical company cannot distinguish between type l and type h, it can only charge usd to all. in that case, it will generate usd = usd , profits by selling the vaccine to all people. the other possibility is the following. the company sets a price of usd for the vaccine. in that case, no person of type l will buy the vaccine ex-ante (as their expected benefit before hiv/aids strikes is usd but the cost is usd ). the only people who will buy the vaccine will be of type h. since there are ten of type h, the profits will be usd = usd , . thus, in either price strategy, the profits of the company will be usd , . therefore, the profits of the company are bigger in the case of the development of drug d instead of the vaccine v. this argument is extremely general as long as the probability of the type l does not get close to the probability of type h getting the disease and the company cannot distinguish between the types. at the beginning of this book, we highlighted the need to integrate three interrelated issues into any comprehensive aids strategy -prevention, treatment and human rights protection. as we showed in chap. , each of these issues must be considered in the context of specific countries or regions, in order to take into account variations in cultural values, affected groups, infection rates, legal systems, economic resources and human resources. in this chapter, we have analyzed prevention and treatment issues in greater detail. the preceding discussion shows that great progress has been made on these two fronts and that greater progress is possible. our analysis of prevention issues in particular has shown the need to integrate prevention, treatment and human rights strategies. the primary reason that human rights need to be addressed is because discrimination keeps people away from both prevention and treatment programs (gruskin et al., ) . changing social attitudes in order to overcome stigma and discrimination is not an easy task, particularly given deep-seated fears and prejudices surrounding sex, blood, disease and death and the wide-spread perception that hiv/aids is closely supportive and enabling environment for women, children and other vulnerable to change attitudes of discrimination and stigmatization associated with hiv/aids variations in cultural values and legal systems make hiv/aids-related human rights particularly difficult to tackle on a global basis. however, hiv/aidsrelated human rights are the area where the least progress has been made and need to become a central focus in the global fight against hiv/aids (jürgens and cohen ) . in this section, we focus on three categories of laws: ( ) laws that discriminate against vulnerable groups; ( ) laws that discriminate against hiv-positive people, such as those that criminalize hiv transmission; and ( ) laws that prohibit discrimination against vulnerable groups, including hiv-positive people. we review the united nations international guidelines on hiv/aids and human rights and provide examples in each category. the way forward prevention, treatment and human rights to understanding and acceptance (united nations ). groups. the guidelines also recommend that states promote the wide and ongoing distribution of creative education, training and media programs explicitly designed united nations international guidelines on hiv/aids and human rights redialogue, specially designed social and health services and support to community commend that states, in collaboration with and through the community, promote a groups by addressing underlying prejudices and inequalities through community tied to deviant or immoral behavior (jürgens and cohen, ) . in this regard, the the law plays different roles with respect to infectious diseases. some health risks, such as poor access to sterile injection equipment, can be directly attributed to law, and laws have been used to change unhealthy behaviors, such as smoking and drunk driving. both international and national laws are used in disease control. in addition to the law's role as a source of disease control authority for government, the law has a countervailing role as a source of protection against excessive and unnecessary regulations (burris ) . the united nations international guidelines on hiv/aids and human rights acknowledge the inherent limitations in using law reform to enhance human rights. the effectiveness human rights laws depend on the strength of the legal system in a given society and on the access of its citizens to the system, both of which vary considerably from one country to the next. moreover, the law cannot serve as the only means of educating, changing attitudes, achieving behavioral change or protecting people's rights. nevertheless, since laws regulate conduct between the state and the individual and between individuals, they can either support or undermine the observance of human rights, including hiv-related human rights (united nations ) . for these reasons, we first consider laws that support human rights. while social attitudes may take time to change, an important first step is to reform laws, policies and practices that institutionalize discrimination against the groups of people who are most vulnerable to hiv/aids: women and girls; men who have sex with men; commercial sex workers; and injection drug users. the united nations international guidelines on hiv/aids and human rights recommend consistent with international human rights obligations and are not targeted against vulnerable groups (united nations ). laws in this category include those that prohibit sexual acts between consenting adults in private, laws prohibiting sex work that involves no victimization and laws prohibiting measures such as needle exchange that can reduce the harm associated with illicit drug use (elliot ). the united nations international guidelines on hiv/aids and human rights recommend the enactment of anti-discrimination and protective laws to reduce human rights violations against women and children in the context of hiv, to reduce the vulnerability of women and children to hiv infection and to the impact of hiv/aids. with respect to women, the guidelines recommend law reforms to ensure the equality of women regarding property and marital relations and access that states reform criminal laws and correctional systems to ensure that they are have a negative impact on hiv-related human rights and then consider laws that to employment and economic opportunity, such as equal rights to own and inherit property, to enter into contracts and marriage, to obtain credit and finance, to initiate separation or divorce, to equitably share assets upon divorce or separation and to retain custody of children. in addition, laws should ensure women's reproductive and sexual rights, including the right of independent access to reproductive and sexual health information and services and contraception, the right to demand safer sex practices and the right to legal protection from sexual violence. with children against sexual abuse and provide for their rehabilitation if abused and ensexual abuse by their husbands. when the husband is hiv-positive or engages in unsafe sex or drug use, this increases the risk of infection for women. child cusdren make it difficult for women to leave abusive relationships. while statutes allow property ownership regardless of sex, in practice women only have user rights under customary laws, not ownership. under inheritance laws, property remains in the man's family after he dies. thus, if a woman wants to leave an abusive husband or her husband dies, she cannot take any property with her, leaving women economically dependant upon their husbands or, as widows, their families. new laws have created inheritance rights for dependants, but are ignored by the man's family and not enforced. as a result, women and children widowed and women must either rely on their in-laws for support or become commercial sex workers (kelly ) . laws and cultural traditions thus increase women's vulnerability to hiv/aids, either within marriage or by forcing them to support themselves and their children as sex workers. recommend the enactment of anti-discrimination and protective laws to reduce discriminatory property, divorce and inheritance laws for same-sex relationships. the way forward prevention, treatment and human rights tody laws, customary practice and traditions that favor paternal custody of chil-sure that they are not subject to penalties themselves. protection under disability human rights violations against men having sex with men, including in the context orphaned by aids are left without adequate resources for medical treatment, and the united nations international guidelines on hiv/aids and human rights of hiv, including penalties for vilification of people who engage in same-sex respect to children, laws should provide for children's access to hiv-related inlaws, inheritance laws, and child custody laws. in many african countries marital rape does not exist as a legal concept, leaving women with no recourse against formation, education and means of prevention, govern children's access to volcontext of orphans, including inheritance and/or support. laws should also protect untary testing with consent, should protect children against mandatory testing, particularly if orphaned by aids, and provide for other forms of protection in the in sub-saharan africa, laws of particular concern include marital rape, property laws should also be ensured for children (united nations ). one key purpose of such anti-discrimination laws is to reduce the vulnerability of men who have sex with men to infection by hiv and to the impact of hiv/aids. the guidelines also recommend that the age of consent to sex and marriage be consistent for heterosexual and homosexual relationships and that laws and police practices relating to assaults against men who have sex with men ensure adequate legal protection (united nations ). in a internet-based survey of sexually active msm in new york city, % reported being hiv-positive and % reported being hiv-negative. the majority were white, college-educated and in their s. the race of the respondents was white ( %), latino ( %), black ( %) and other ( %). in the previous months, % had more than ten male sex partners, % had engaged in unprotected anal sex and % had used non-injection drugs. fifty percent of the hiv-positive men had unprotected anal sex in the previous months and % of the hiv-negative men had unprotected anal sex in the previous months (nyc health ). in a survey of black msm in new york city, % were hivhigh school education, % were unemployed and % had an annual income of less than usd , . fifty-six percent identified themselves as homosexual, % as bisexual, % as heterosexual and % as other. sixty-five percent had previously been diagnosed with a sexually transmitted infection and % had been raped ( % before they were years old). eighty-four percent knew that they were hiv-positive. of the % that were unaware that they were hiv-positive, % reported having been tested for hiv previously. of those who had never been tested for hiv, the reasons they gave were: ( ) being afraid to learn that they had the perception of not being at risk because they practiced safe sex ( %); and ( ) being afraid that results will be reported to the government ( %). fifty percent reported unprotected anal sex with a man in the previous months and % had exchanged sex for drugs, money or a place to stay in the same period. among those who had unprotected anal sex with a man in their last sexual encounter, % of the hiv-positive men had an hiv-positive sex partner and % of the hivnegative men had an hiv-negative sex partner (nyc health ). according to the unaids guidance note on hiv and sex work, despite high hiv prevalence among sex workers, only one in three receive adequate hiv prevention services and even fewer receive adequate treatment and health care (unaids ) . the unaids guidance note focuses on the reduction of hiv vulnerability among sex workers, who are defined as adults over the age of years in order to take into account that sexual exploitation of children under years of age is prohibited under international law. the key factors that lead people into sex work include poverty, gender inequality, indebtedness, migration, criminal hiv ( %); ( ) being worried that others might treat them differently ( %); ( ) positive. the median age of the respondents was years, % had less than a coercion, humanitarian emergencies, drug use and dysfunctional families. laws, policies and practices that drive sex work underground make hiv/aids prevention and treatment for sex workers and their clients more difficult. discrimination against sex workers among the police, health care services and other social services impede access to prevention and treatment. the unaids guidance note organizes its recommendations into three categories: ( ) reducing vulnerabilities and addressing structural issues; ( ) reducing risk of hiv infection; and ( ) building supportive environments and expanding choices. the strategies in the first category are to: ( ) address poverty and gender inequality by providing alternatives to sex work through micro-finance programs and reforms to property rights; ( ) address the demand for paid sex by seeking to changes men's behavior; ( ) expand access to education for girls and women; ( ) provide alternative job opportunities through employment growth and vocational training; and ( ) provide employment and education opportunities and access to social services for refugees, internally displaced persons and economic migrants. the strategies in the second category are to: ( ) involve sex workers in hiv prevention and treatment programs; ( ) make male and female condoms available for free or at low cost; ( ) increase access to antiretroviral treatment; ( ) address the specific needs of sex workers in sexual and reproductive health programs, taking into account the different needs of female, male and transgender sex workers; ( ) make hiv prevention information and condoms readily available to clients; ( ) seek to eliminate violence against sex workers by clients, managers, police and other government officials; ( ) seek to change attitudes towards sex workers to reduce stigma and discrimination; ( ) promote initiatives to enable sex workers to negotiate safe sex practices; and ( ) promote access to drug addiction treatment programs and harm reduction programs, such as needle exchange. the strategies in the third category are to: ( ) address sex work stigma and discrimination to reduce economic, cultural and social marginalization in families and communities; ( ) improve access to health care, education and training, microfinance and credit, social services, housing support and legal services; and ( ) promote community organizations that work with sex workers. the unaids guidance note on hiv and sex work has been criticized for emphasizing alternative livelihoods without offering concrete examples, rather than emphasizing the right to engage in sex work and workplace safety and national laws that undermine sex workers' rights, particularly criminal prohibition of sex work and related activities. the guidance note's strategy of reducing demand for sex work has been criticized as implicitly supporting the criminalization or repression of sex work, which can increase the risk of hiv infection by driving sex work underground, limit sex workers' choices regarding working conditions and clients and increase stigmatization. the guidance note was further criticized for not advocating enhanced human rights protection for those engaged in sex work -as women, men, transgender persons and workers. the process used for preparing the document was criticized for not meaningfully engaging sex workers. unaids' response to criticism of this document -to withdraw it as a public document and restrict it to internal use -was also criticized (canadian hiv/aids legal network b) the united nations international guidelines on hiv/aids and human rights recommend that criminal law prohibiting sexual acts (including adultery, sodomy, fornication and commercial sexual encounters) between consenting adults in private should not be allowed to impede provision of hiv prevention and care services and should be repealed. with regard to adult sex work that involves no victimization, the international guidelines on hiv/aids and human rights recommend de-criminalizing and legally regulating occupational health and safety conditions to protect sex workers and their clients, including support for safe sex during sex work. more generally, criminal law should not impede provision of hiv prevention and care services to sex workers and their clients and should ensure that children and adult sex workers who have been coerced into sex work are not prosecuted for such participation but rather are removed from sex work and provided with medical and psycho-social support services, including those related to hiv (united nations ). in eastern europe and central asia, unaids ( ) estimates that the use of contaminated injection equipment accounts for more than % of hiv/aid cases and accounts for about % of new infections outside sub-saharan africa. the united nations international guidelines on hiv/aids and human rights recommend that criminal law not be an impediment to measures taken by states to reduce the risk of hiv transmission among injecting drug users and to provide them with hiv-related care and treatment. they further recommend that criminal law be reviewed to consider: ( ) the authorization or legalization and promotion of needle and syringe exchange programs; and ( ) the repeal of laws criminalizing the possession, distribution and dispensing of needles and syringes (united nations ) . in saint petersburg, russia, a study found that % of injection drug users had shared needles in the days prior to their first use of a needle exchange program. in early , there were four syringe exchange facilities in saint petersburg -one mobile service (a bus) and three fixed facilities. however, the most important source of sterile syringes for injection drug users was drug stores. human rights watch found that state-supported impediments to access to both needle exchange points and drug stores were important barriers to hiv prevention, including: ( ) police patrols of drug stores, which deterred injection drug users from purchasing syringes; ( ) police patrols of needle exchange bus stops; and ( ) arrests, fines or bribes for possession of syringes, even though carrying syringes is not illegal in the russian federation. however, while police interference with the syringe exchange bus was a problem in the late s, it lessened in the early s. humanitarian action, an ngo that delivers syringe exchange services in saint petersburg, visited with police chiefs to talk about the importance of syringe exchange for hiv prevention and organized a training session in for police officers that included the participation of former drug users and people living with hiv/aids. however, due to past incidents, the fear of apprehension by the police kept some drug users from using fixed as well as mobile syringe exchange facilities (human rights watch ) . table . shows the dramatic increase in hiv prevalence among injection drug users in saint petersburg from to . a survey of injection drug users (idus) in new york city found that % had obtained a syringe from an exchange program in the previous year, % at a pharmacy, % from a medical provider, % from a friend or sexual partner and % from a drug dealer. the self-reported hiv prevalence rate in the group was %. idus who obtained syringes from sterile sources (exchange, pharmacy or provider) were less likely to share syringes than those who obtained them from non-sterile sources (friends, relatives or the street). those who obtained syringes from exchange programs were significantly less likely to share syringes. nevertheless, % of idus had shared a syringe at least once in the previous months and % had engaged in unprotected sex. idus that had shared a syringe were . times more likely to engage in unprotected sex (nyc health ). another category of laws discriminates directly against people with hiv/aids, such as laws that criminalize hiv transmission and travel restrictions based on hiv status. there is a concern that the criminalization of hiv transmission will discourage people from seeking testing (tarantola and gruskin ) . there is evidence that knowledge of hiv status results in behavioral changes that reduce transmission. in addition, where knowledge of hiv status leads to antiretroviral treatment, treatment also reduces transmission by reducing the amount of virus in the body. thus, the criminalization of hiv transmission may have the effect of increasing, rather than reducing, hiv transmission. one possible response is mandatory hiv testing in health care settings (that is, testing without the informed consent of the patient). however, this policy, too, may be self-defeating if it discourages people from nations international guidelines on hiv/aids and human rights recommendation that public health legislation ensure that hiv testing of individuals should several studies have concluded that the criminalization of hiv transmission is unlikely to serve the goals of public health policy or the goals of criminal law, and ommended that governments and the judiciary take into account the following principles in determining policy regarding the use of criminal sanctions under modes and risk of hiv transmission to rationally determine when and if conduct should attract criminal liability; ( ) the primary objective should be to prevent public health and conform to international human rights norms, particularly nondiscrimination and due process; and ( ) policy makers should assess the impact of law or policy on human rights and prefer the least-intrusive measures possible to achieve a demonstrably justified objective of preventing disease transmission. with respect to the four functions of criminal law (harm prevention through response to the epidemic: ( ) imprisoning an hiv-positive individual does not prevent transmission through conjugal visits or high-risk behavior with other prisoners; ( ) criminal penalties are unlikely to change sexual activity and drug use, due to the complexity of these human behaviors; ( ) punishment/retribution do not achieve the goal of hiv prevention and risk reinforcing prejudice and discrimination against already stigmatized hiv-positive people; and ( ) criminal sanctions are unlikely to act as a deterrent, given that drug use and sexual activity persist even with the risk of criminal prosecution and are more likely to be driven underground when prosecuted, hindering hiv prevention. moreover, overly broad use of criminal laws risks spreading misinformation regarding how hiv is transmitted. in an empirical study conducted in the united states, burris et al. ( ) found that laws prohibiting unsafe sex or requiring disclosure of infection do not influence people's normative beliefs about risky sex and did not significantly influence sexual behavior. the study concluded that criminal law is not a clearly useful in-moreover, given concerns about possible negative effects of criminal law, such as stigmatization or reluctance to cooperate with health authorities, criminal law should be used with caution as a behavioral change mechanism for hiv-positive people. seeking health care. moreover, mandatory hiv testing runs counter to the united thus may do more harm than good. in a unaids policy paper, elliot ( ) bution; and deterrence), elliot ( ) concluded that criminal law is an ineffective imprisonment; prevention of future harm through rehabilitation; punishment/retri-hiv transmission in common law countries. in some cases, courts have applied existing criminal laws to cases involving hiv, where the laws themselves do not refer specifically to hiv. in this context, law reforms could come from the legislature, through amendments that clarify the application of relevant criminal laws to cases involving hiv, or through the evolution of precedents in the courts. the united nations international guidelines on hiv/aids and human rights recommend the reform of criminal laws and correctional systems to ensure that they are consistent with international human rights obligations and are not misused in tization of the judiciary, in ways consistent with judicial independence, on the legal, ethical and human rights issues relative to hiv, including through judicial education and the development of judicial materials (united nations ). criminal laws should not include specific offences against the intentional transmission of hiv but rather should apply general criminal offences to these exceptional cases. such application should ensure that the elements of foreseeability, intent, causality and consent are clearly and legally established to support a guilty verdict and/or harsher penalties (united nations ) . in the united states, a series of cases involving spitting have gone in different directions. in ohio v. bird ( ) , an hiv-positive man was convicted of felonious assault, which requires the knowing attempt to harm by use of a weapon capable of inflicting death, after spitting in a police officer's face, even though all medical and scientific evidence demonstrated that saliva does not transmit hiv. in state v. jones ( ) , another case of an hiv-positive individual accused of spitting on an officer, the new mexico court of appeals ruled that criminal liability for battery could not be based upon the victims' subjective and unsubstantiated fears that they could develop a disease, and reversed the lower court on this issue. in weeks v. state ( ) , the texas court of appeal sustained the attempted murder conviction of an hiv-positive inmate who spat in a guard's face. the spitting cases show how the application of criminal laws to hiv-positive individualswhen based on hiv status, stigma and discrimination rather than on medical or scientific evidence -can undermine genuine efforts to reduce hiv transmission by spreading misinformation and increasing stigma and discrimination. in cases involving behavior that does carry a risk of hiv transmission, such as unprotected sexual intercourse or sharing drug injection equipment, the central issue is consent. in r v. cuerrier ( ) the supreme court of canada established that there is a duty to disclose one's hiv status before engaging in any activity that poses a "significant risk" of hiv transmission. failure to do so legally invalidates a sexual partner's consent to sexual intercourse. the lack of consent to have intercourse with a partner that is hiv-positive converts the sexual intercourse into a criminal assault. in that case, the complainants did not become infected with hiv as a result of the unprotected sex. however, if the complainants believe that their partner is hiv-free and the accused puts the complainants at significant risk to their health, failure to disclose hiv status vitiates consent to sexual intercourse. the way forward prevention, treatment and human rights there have been numerous cases in which criminal laws have been applied to the context of hiv/aids (united nations ). they also recommend the sensi-this decision suggests that there might not be a duty to disclose hiv status prior to engaging in activities that do not pose a significant risk of transmission, such as kissing and oral sex, or where an hiv-positive individual uses a condom. in r v. edwards, a lower court judge ruled that there is no duty to disclose hiv status prior to engaging in unprotected oral sex because it is a low risk activity (canadian aids society ) . on november , the defendant learned that he was hiv-positive, but did not reveal his status to the complainant and continued to have unprotected sex with her. the supreme court of canada ruled that the defendant was not guilty of the act itself, but rather the consequences of the act. because it was likely that the defendant had infected the complainant before he learned of his hiv status, it could not be proved beyond a reasonable doubt that he had endangered the life of the complainant. however, the defendant was guilty of attempted aggravated assault for continuing to have unprotected sex with the complainant after having learned of his hiv status. the court ruled that there is sufficient criminal intent for a conviction on a sexual assault charge if a person acts "recklessly". in canadian law, a person acts "recklessly" if they know that their conduct risks committing a crime but they commit the act nevertheless. in this case, the supreme court ruled that criminal recklessness is established once an individual becomes aware of a risk that he or she has contracted hiv, but continues to have unprotected sex without disclosure of hiv status, thereby creating a risk of further hiv transmission. in this case there was no evidence before the court regarding the defendant's awareness of the risk that he might be hiv-positive, prior to november , other than the fact that he had been asked to take an hiv test. this aspect of the ruling raised the issue of whether there is a duty to disclose the mere awareness of a risk that one might be hiv-positive before having unprotected sex. the court also suggested that an hiv-positive person might be held criminally liable for failure to disclose hiv status before having unprotected sex with another hivpositive individual, where this results in the transmission of a different strain of hiv or a drug-resistant strain of hiv. the supreme court of canada cases have been criticized, on the one hand, for discouraging people from seeking testing in order to avoid the possibility of a criminal conviction based on knowledge of hiv status and, on the other hand, for risking undesirable invasions of privacy if courts are required to determine whether an individual was aware that their past activities put them at risk of hiv infection (canadian hiv/aids legal network ) . however, in r v. williams, the fact that the defendant had been asked to take an hiv test, because he was on a list of former partners provided by an individual who had tested hiv-positive, was not sufficient to establish that he was aware that his past activities had put him at risk in r v. williams ( ) , the defendant began a sexual relationship with the comthe complainant". what distinguishes aggravated assault from mere assault is not plainant in june , in which they had unprotected sex on numerous occasions. requires that the assault "wounds, maims, disfigures or endangers the life of aggravated assault under section ( ) of the canadian criminal code, which of hiv infection. nevertheless, the decision has been criticized for extending the without defining the nature of the awareness that might be required. more generally, the use of criminal law to prevent hiv transmission has been criticized for stigmatizing all hiv-positive people because of the conduct of a few individuals, for discouraging those most at risk from seeking testing and for being unlikely to stop people from having risky sex or sharing needles and syringes. moreover, all of the hiv-related criminal prosecutions in canada have occurred in the context of heterosexual intercourse, rather than homosexual intercourse or injection drug use, creating a perception of discriminatory application (or non-application) of the laws (betteridge ). sion of hiv/aids between and , in which eight accused pleaded guilty, two were convicted and one was acquitted (klein ) . a new zealand court has ruled that people living with hiv/aids are not required to disclose their hiv status if they use condoms during vaginal sex (klein ) . in particular, the use of criminal laws to prevent hiv transmission also has been criticized for not taking into account that hiv-positive individuals living in abusive relationships may fear the consequences of disclosing their status to partners and may not be able to use a condom or insist that their partner use a condom (canadian aids society ) . in a literature review of hiv/aids and genderbased violence, the harvard school of public health program on international health and human rights ( ) found that gender-based violence (which is not limited to violence against women) can interfere with safe sex practices and access to treatment. not only is gender-based violence a risk factor for acquiring hiv/ in summary, the use of criminal laws to prevent hiv transmission may undermine overall public health initiatives by: ( ) reinforcing hiv/aids-related stigma; ( ) spreading misinformation about hiv/aids; ( ) creating a disincentive for hiv testing; ( ) hindering access to counseling and support services; ( ) creating a false expectation that criminal laws eliminate the danger of unprotected sex for people who believe that they are hiv-negative; ( ) creating the risk of selective prosecution of marginalized groups; ( ) criminalizing behavior that results from gender inequality, in the case of hiv-positive people living in abusive or economically dependent circumstances; and ( ) invading privacy through the disclosure of medical records and hiv status in public court proceedings (elliot ) . however, the use of criminal laws may be warranted in some circumstances, where hiv status is an aggravating or otherwise relevant factor in cases involving physical assault that would constitute criminal behavior even in the absence of hiv, such as rape or the use of needles as weapons (elliot ) . finally, a distinction should be made between criminal laws and public health laws that are quasi-criminal in nature, particularly those regarding quarantine. while quarantine laws, such as isolation, detention or quarantine, may be suitable the way forward prevention, treatment and human rights criminal law beyond cases where individuals know that they are hiv-positive, in the united kingdom, there were eleven prosecutions for reckless transmis-aids, but hiv/aids is also a risk factor for gender-based violence. for casually communicable and curable diseases, such laws run the same risk of misuse as do criminal laws (elliot ) . in this regard, the united nations international guidelines on hiv/aids and human rights recommend that public health law provisions applicable to casually transmitted diseases not be applied inappropriately to hiv/aids and that they be consistent with international human rights obligations (united nations ). some countries have restricted the entry of people living with hiv/aids, for shortterm or long-term stays, through mandatory testing or a requirement to declare one's hiv status. as we saw in chap. , the who international health regulations also contain provisions regarding health measures applied to travelers. these provisions encourage states to base their determinations upon scientific principles, available scientific evidence of a risk to human health and any available specific guidance their dignity, human rights and fundamental freedoms and minimize any discomfort or distress associated with such measures. governments cite two main reasons for imposing travel restrictions on people living with hiv/aids -public health protection and reducing demand on health care and social services (unaids/iom ) . in the united kingdom, another source of demands for hiv screening of migrants has been a concern over "health tourism" -hiv infected migrants from developing countries that go to europe to receive health care. however, research shows that access to treatment is rarely the after having arrived in the host country, and there is no uniform policy in european union countries regarding screening of migrants for hiv (carballo ) . hiv/aids is not considered to be a condition that poses a threat to public health in relation to travel because hiv/aids is already present in virtually every country in the world and hiv is not transmitted through casual contact. unlike highly contagious diseases with short incubation periods, such as sars, cholera and plague, hiv transmission can be prevented through safe sex and safe drug injection, which can be used by both the infected and the non-infected to prevent transmission. there is no evidence to support the assumption that both the infected and the non-infected will engage in unsafe practices. as a result, the presence of hiv-positive individuals, by itself, does not pose a risk to public health. in addition, travel restrictions are not effective in preventing the entry of hiv-positive individuals, since hiv tests do not detect the virus in newly infected people and nationals that are returning from travel abroad (who may have been infected while outside the country) are not subject to hiv/aids-related travel restrictions and are not prevented from entering their own country. moreover, travel restrictions can undermine hiv/aids-related public health initiatives by increasing stigma and discrimination and mislead the public into thinking that hiv/aids can be or advice from the who. they also require states to treat travelers with respect for reason for migration to europe, since most migrants only learn of their hiv status prevented through border measures, rather than through proven prevention strategies (unaids/iom ) . unaids and the international organization for migration (iom) recommend that exclusion on the basis of possible costs to health care and social services only occur on an individual basis, where the following considerations are shown: ( ) the person requires the health care and social services and is likely to use them in the near future; ( ) the person has no other means of meeting those costs (for example, through private or employment-based insurance or personal resources); and ( ) these costs will not be exceeded by the benefits of the person's skills, talents, contribution to the labor force, payment of taxes, contribution to cultural diversity and capacity for revenue or job creation (unaids/iom ) . they also recommend that countries treat similar conditions alike, rather than singling out hiv/ aids. one study showed that the -year economic impact of admitting immigrants with asymptomatic hiv infection would be similar to admitting immigrants with asymptomatic coronary heart disease (zowall et al., ) . the canadian immigration and refugee protection act provides that foreign nationals can be deemed "medically inadmissible" based on a medical condition, danger to public health or public safety; or ( ) they might reasonably be expected to cause excessive demand on health or social services. since , canadian danger to public health or public safety by virtue of their hiv status. the issue of excessive demand on health or social services is mainly a consideration in cases of immigration or stays that exceed months, is determined on a case-by-case basis permanent residents (spouses and children). demand on health or social services of health or social services for the average canadian resident; or ( ) the demand the united states has had a travel and immigration restriction in place for people living with hiv/aids since (human rights watch ) . under the united states are inadmissible if they have "a communicable disease of public high level meeting on aids a "designated event" for which an hiv waiver would be available. visitors entering the united states on the visa waiver program (which waives the requirement to apply for a visa prior to traveling to the united the way forward prevention, treatment and human rights government policy has been that people living with hiv/aids do not represent a and therefore denied a visa or entry at the border, if: ( ) they are likely to be a would add to existing waiting lists for those services and would increase the rate us immigration and nationality act, applicants for a visa or for admission to the health significance", which includes hiv infection, although waivers are available ces by canadian citizens or permanent residents. the social or economic contribu-and does not apply to refugees or close family members of canadian citizens or tions the individual is expected to make to canada are not taken into account. or mortality and morbidity in canada by denying or delaying access to those servi- hiv status or to be tested for hiv (canadian hiv/aids legal network a) . on a case-by-case basis. for example, the us attorney general named the people entering canada for less than months are not required to disclose their is considered excessive if: ( ) the anticipated costs would likely exceed the costs states, for certain countries) must fill out an i- w form, which asks, "have you ever been afflicted with a communicable disease of public health significance." if the visitor answers yes to the question or the us border authorities suspect a visitor to be hiv-positive the person may be: ( ) placed into secondary inspection; ( ) questioned by an official of the us department of homeland security; ( ) placed into deferred inspection; ( ) asked to withdraw the application for admission into the united states; ( ) placed into the expedited removal process; or ( ) placed into an us department of homeland security detention center and detained until the case is heard by an immigration judge (gmhc ) . hiv-positive non-immigrants seeking to enter the us on a temporary basis for business, pleasure, or education are eligible for a waiver under which they can be allowed to enter the united states. in practice, a waiver is granted in most cases if: ( ) they are not symptomatic; ( ) it is a short visit; ( ) they have insurance or other assets sufficient to pay medical expenses; and ( ) they don't appear to be a public health risk. permanent residency and immigration applicants can also apply for a waiver, but they are usually rejected. to receive a waiver as an immigrant, the person must be the spouse, unmarried son or adopted child of a united states citident as their son or daughter. in addition, an hiv-positive immigration applicant must prove that: ( ) he will not be a danger to public health; ( ) the possibility of spreading the disease is minimal; and ( ) there will be no cost incurred by any level of government without its prior consent (tarwater ) . june the us public health service added aids to the list of excludable conditions, noting that the exclusion was not based on any new scientific knowledge and that aids is not spread by casual contact, which is the usual public concept of contagious. in july , republican senator jesse helms also added hiv infection to the exclusion list, through the us congress, together with a prohibition on funding from the us centers for disease control for aids programs that "promote, encourage or condone homosexual activities" (koch ; aids treatment news ) . senator helms accompanied the introduction of his amendments with the following statement: "we have got to call a spade a spade, and a perverted human being a perverted human being" (koch ) . in july , senator jesse helms advocated spending less money on hiv/aids, because it resulted from "deliberate, disgusting, revolting conduct" and was "a disease transmitted by people deliberately engaging in unnatural acts" (associated press ). ten years later, he had this to say: "it had been my feeling that aids was a disease largely spread by reckless and voluntary sexual and drug-abusing behavior, and that it would probably be confined to those in high-risk populations. i was wrong" . in , the us centers for disease control (cdc) recommended that all diseases except active tuberculosis be removed from the list of excludable conditions. hiv was left on the list because it had been put on the list by congress. in november the political history of the us hiv travel restrictions is an interesting story. in zen or permanent resident or have a united states citizen or lawful permanent resi- , the immigration reform act of directed the cdc to establish a new list of excludable conditions, based solely on current epidemiological principles and medical standards. in january , the cdc again proposed that only active tuberculosis remain on the list of excludable conditions. religious leaders campaigned to maintain the ban and the us house of representatives opposed removing the hiv ban (aids treatment news ) . in august , democratic representatives barbara lee and hilda solis introduced the "hiv nondiscrimination in travel and immigration act". the proposed legislation would restore the authority of the secretary of health and human services to determine whether hiv status is a communicable disease of public health significance. the decision to maintain or remove the ban would then be based on public health analysis instead of a formal ban made by congress (latino commission on aids ). in november , the us department of homeland security proposed a new rule that would allow short-term visas to be granted to hiv-positive people by us consulates in their home countries. however, applicants would have to agree to conditions, including ceding the right to apply for longer stays or permanent residency in the united states. democratic members of the us house of representatives objected that the changes would only shift decision-making authority to local consular officers, who may lack the appropriate medical expertise. moreover, there would be no appeal process (werner ) . the united states and canada are similar societies, both culturally and economically, but have adopted very different approaches to hiv/aids travel restrictions. the hiv prevalence rate in the united states is higher than in canada. this suggests that the us travel restriction has not been effective in preventing hiv transmission in the united states, and that the lack of such a restriction in canada has not had the effect of increasing hiv prevalence. health care costs, measured as a percentage of gdp, are also higher in the united states than in canada. while this difference is attributable to many factors, making it difficult to determine the impact of the different travel restriction policies on health care costs without further study, it is an indication that the canadian approach has not led to a significant increase in health care costs compared to the american approach. in , americans spent usd , per capita on health care, compared with usd , in canada. americans spent . % of gdp on health care compared with . % of gdp in canada. interestingly, this gap was not always there. in , both countries spent exactly . % of their respective gdp on health care (oecd ) . another factor that suggests that us travel restrictions are unlikely to prove successful is illegal immigration. there are several million illegal entries into the united states each year. they are obviously not screened. thus, from a practical point of view, travel and immigration restrictions for hiv-positive individuals are unlikely to be effective in preventing the entry of many hiv-positive individuals and may provide additional incentives for some individuals to migrate illegally. the united nations international guidelines on hiv/aids and human rights recommend that states enact or strengthen anti-discrimination laws that protect vulnerable groups, people living with hiv/aids and people with disabilities from discrimination in both the public and private sectors, and provide for speedy and effective administrative and civil remedies (united nations ). human rights laws in many jurisdictions prohibit discrimination against vulnerable groups or against people with hiv/aids, as well as providing other rights that are relevant to hiv/aids, such as the right to life and the right to health. human rights laws fall into two categories. the first category applies to governments, prohibiting governments from passing discriminatory laws or requiring governments to uphold certain human rights. the second category of human rights law prohibits discrimination on the part of private actors, for example with respect to employment practices or rental of housing. while it is not possible to eliminate individual or societal prejudices with legislation, human rights laws provide victims of discrimination with legal recourse against acts of discrimination and create economic disincentives through fines or other legal remedies, thereby contributing to social change. canada provides one example of the sources and functioning of human rights laws. section of the canadian charter of rights and freedoms, which is part of the constitution of canada, guarantees equality rights in the following terms: the equal protection and equal benefit of the law without discrimination and, in particular, without discrimination based on race, national or ethnic origin, colour, religion, sex, age or mental or physical disability. canadian courts have interpreted the term "disability" to include hiv/aids, which means that people living with hiv/aids have constitutional protection listed, but also covers analogous grounds, such as sexual orientation. any law that is inconsistent with constitutional provisions may be struck down or interpreted by courts to make it consistent with the constitution. the charter applies to all levels and branches of government, all government acts, government corporations and ment government policies or programs. however, the charter does not otherwise apply to acts by private citizens. instead, discrimination by an employer, a landlord or a private business is addressed under other federal and provincial human rights laws, such as the canadian human rights act, which apply to both the public and private sectors. by virtue of a policy of the canadian human rights commission and decisions of canadian courts and tribunals, the prohibition against disability-based discrimination in the every individual is equal before and under the law and has the right to against discrimination by the state. section is not limited to the grounds that are private persons or bodies that exercise authority granted by a statute or that imple-canadian human rights act and its provincial counterparts cover discrimination based on hiv/aids status (elliott and gold ) . the remainder of this section provides an overview of court cases in a variety of countries that have applied constitutional law, international law and other legislation to uphold the rights of people living with hiv/aids with respect to employment and access to hiv-related medical care and treatment. in march , mexico's national supreme court of justice ruled that a provision in article of the social security institute law for the armed forces (issfam) that required hiv-positive individuals to be discharged from the military was unconstitutional, because it was not based on an individual assessment of the pering people living with hiv/aids. the court ordered that three soldiers be reinduty, which would include an obligation to reinstate their social security benefits with respect to hiv/aids, laws in south africa and latin america that provide a action campaign used this provision to challenge the government's program that limited the use of nevirapine to prevent mother-to-child hiv transmission to test sites. the court ruled that the government's restriction on the use of nevirapine was unreasonable and that the policy should be reformed to meet the government's constitutional obligation (singh et al., ; elliot et al., ) . in argentina, five court cases between and repeatedly ordered the argentine ministry of health to supply antiretroviral treatment to people living with hiv/aids, in accordance with the right to health set out in international treaties, which had been incorporated into domestic law. the failure of the ministry of health to act in a timely fashion, which led to interruptions in the supply of antiretroviral drugs, ultimately led to a court order that would fine the ministry of health usd , per day (funds which would then be used to implement the national aids plan) until it complied with the courts' previous orders, and the threat right to health care have been used to induce governments to provide access to and equality and was inconsistent with mexico's international obligations regardvides a right to health care that is binding on the government. the treatment mexico's national supreme court of justice ruled for a fifth time that this provision was unconstitutional, thereby creating jurisprudence that is binding on all federal son's ability to work, violated constitutional protections of non-discrimination judges in mexico (avilés allende ). table . summarizes several other antiretroviral treatment (gruskin et al., ) . the south african constitution pro-cases involving hiv-related discrimination in employment from various juris- (pearshouse ; medina and reyes ; scjn a, b) . in september , dictions around the world. stated until medical certificates were issued to determine whether they were fit for (elliot et al., ) . an argentine court also relied on the right to health set out in international treaties to order the government to produce and administer a vaccine within a set period of time, in order to protect people living in a region affected by argentine haemorrhagic fever (singh et al., ) . the constitutional court of ecuador relied on the right to health set out in international treaties to rule that the ministry of health had failed to meet its obligations when it suspended its hiv treatment program (singh et al., ; elliot et al., ) . in costa rica, the supreme court ruled in that the costa rican social security fund could not argue that financial constraints justified failure to comply with its very reason for its existence, which is to provide coverage for necessary medical care. shortly after this ruling, the supreme court ordered the social security fund to develop a plan to provide coverage to all persons living with hiv/aids that were in need of antiretroviral treatment. a few weeks later, costa rica became the first central american country to include cov- ) . in india, the courts have interpreted the right to life in the indian constitution to sources to uphold the right to health in a variety of cases (singh et al., ) . table . summarizes several other cases from various jurisdictions around the world where litigation has increased access to hiv-related medical treatment. these cases suggest that human rights laws can be instrumental in promoting health care reforms through litigation, provided that judicial authorities are independent and competent and governments respect the rule of law (singh et al., ) . in addition to laws that institutionalize or prohibit discrimination, institutional policies and practices can represent an important force with respect to stigma, discrimination and access to health care. the united nations international guidelines on hiv/aids and human rights recommend that states ensure that government and the private sector develop codes of conduct regarding hiv/aids issues that translate human rights principles into codes of professional responsibility and practice, with accompanying mechanisms to implement and enforce those codes. in many jurisdictions, the courts have the power to order changes in policies and practices of both governmental and non-governmental institutions. however, litigation is an expensive and time-consuming process that creates additional stress for the people living with hiv/aids who choose to litigate. thus, it is important to promote the voluntary adoption of appropriate policies and practices. one example in this category is the policies and practices of health care institutions. for example, in the mid s, in british columbia, canada, all hospitals refused to treat aids patients, with the exception of st. paul's hospital, which adopted appropriate policies based on the commitment of the founding sisters of include a right to health, and have obliged the indian government to dedicate re-erage for antiretroviral drugs in its national health insurance plan (elliot et al., another example in this category is the policies and practices of employers. as we showed in chap. , hiv/aids affects the productivity of workers substantially, making it cost effective for companies to have prevention programs and to provide treatment for employees, from a purely financial point of view. business leaders have an economic incentive to invest resources in fighting the epidemic. moreover, as we saw in chap. , firms can have a tremendous impact in promotment. however, it is important to have an overarching framework that ensures the adoption of best practices by individual firms and to minimize overlap between the private sector and the other players that are involved in addressing the pandemic. in this regard, the global business coalition on hiv/aids has provided leadership, particularly in its efforts to identify ways to improve the global business community's response to hiv/aids, including through leadership to dispel myths and stigma, break down workplace barriers and influence community change. given the economic and legal incentives, an effective hiv/aids response the way forward prevention, treatment and human rights providence to care for all who were in need, regardless of financial or social standing (gratham ) . in , the city of philadelphia agreed to resolve a complaint regarding the refusal of emergency medical services personnel to touch or lift a patient because of his hiv status, by paying monetary compensation and agreeing to implement a mandatory paramedic/emt training program on hiv and infectious diseases (john gill smith and united states v. city of philadelphia ) . ironically, "philadelphia" was the name and setting of the first high-profile hollywood film to take aids seriously, in . we can think of hiv/aids as a disaster from the point of view of a country as a whole. unlike other disasters (such as an outbreak of an influenza pandemic), this kind of risk, we need to measure the severity and the frequency of occurrence of that risk. once we measure the risk, we need to find ways of managing the risk in a dynamic way. that means putting a risk management plan in place, monitoring the plan and modifying the plan as events unfold. most often, at the national level, hiv/aids is seen as a public health problem and is managed as such. thus, various measures are taken to reduce the incidence of hiv/aids by taking steps against the main channels through which the disease strikes: ( ) actions to reduce the contamination of the blood supply; ( ) special steps to promote health care for key groups, such as sex workers; ( ) needle exchange programs; ( ) promoting safe sex through the use of condoms; and ( ) minimizing hiv transmission from infected mothers to newborns. disaster unfolds over many years. however, the standard operating procedure for ing prevention among employees and their families and providing access to treatdisaster management also applies to managing hiv/aids risk. for managing any must be a core component of an overall business strategy. another approach to risk management is risk avoidance. at the country level, risk avoidance could imply two extreme actions: quarantining people who are already infected and preventing infected people from coming into the country. neither of these policies is feasible for most countries, as they directly go against human rights. thus, extreme forms of risk management and the respect for human rights pose a tradeoff for a country. cuba provides a striking example of how containment of hiv/aids can be conducted at a national level. cuba started promoting public health messages against hiv/aids in , years before the first hiv case was reported in the country. between and , cuba undertook a massive testing exercise, which tested more than % of the adult population. those who were seropositive were quarantined indefinitely in sanitariums. over the years, cuba has relaxed the rule. today, anybody found seropositive is required to attend an week course. after that, they are free to leave. nearly half the people choose to stay in the sanitariums, where they get free food and a place to stay, along with retraining if they choose to help with the logistics of the sanitariums. such a curtailment of freedom of movement without committing a crime is unprecedented anywhere in the world. it has been criticized by many. it did produce a result that is also unprecedented. cuba has an hiv incidence rate of . %. in the neighboring island of haiti, the rate is times as high, at . %. it should be noted that quarantine of individuals who have committed no crime is not unheard of. there was the case of mary mallon in the united states in better known as the "typhoid mary" -who carried typhoid without every showing any symptoms. she was quarantined against her will for a number of years. similarly, during the outbreak of influenza in the united states in , many families were quarantined on public health grounds. individuals with sars were also quarantined in toronto. the future of hiv/aids presents a mixed picture. while hiv/aids incidence has begun to level off in some high-prevalence countries, new infections have increased in many developed countries. while several science-based prevention strategies need to be scaled up significantly, the increase in mother-to-child prevention has dramatically reduced infections among newborns and male circumcision is a promising new prevention strategy. while millions still lack access to treatment, there has been a large increase in funding, drug prices have dropped dramatically, several key drug patents will expire in the near future and efforts to develop new treatments continue. while stigma and discrimination remain obstacles to effective prevention and treatment, human rights laws have proved to be an effective vehicle for addressing discrimination and increasing access to treatment around the world. thus, while hiv/aids continues to pose a significant threat to public health, there are many signs that progress in fighting this pandemic can and will continue, as knowledge gradually replaces ignorance. travel/immigration ban: background senator jesse helms: cut aids funding experimental aids vaccine falls short randomized, controlled intervention trial of male circumcision for reduction of hiv infection risk: the anrs trial amplía corte protección a militares con vih male circumcision: the road from evidence to practice. division of epidemiology, school of public health, university of illinois at chicago betteridge g ( ) criminal law and hiv transmission or exposure: new cases and developments law as a structural factor in the spread of communicable disease the way forward prevention, treatment and human rights do criminal laws influence hiv risk behavior? an empirical trial hiv disclosure & the criminal law in canada supreme court of canada decision in r v canada's immigration policy as it affects people living with hiv/aids a human rights-based commentary on unaids guidance note: hiv and sex work communicable diseases: challenges for health in the age of migration c fe c/ /chpt eu.pdf. accessed a% human% rights-based% commentary% on % unaids % guidance % zidovudine's patent history look to the future: the war against aids. the economist net benefits: giving bed nets and drugs away free may be the way to deal with malaria criminal law, public health and hiv transmission: a policy options paper protection against discrimination based on hiv/aids status in canada: the legal framework the effect of pregnancy on survival in women infected with hiv: a systematic review of the literature and meta-analysis global hiv prevention working group ( ) bringing hiv prevention to scale: an urgent global priority history, principles and practice of health and halperin d ( ) evidence-based behavior change hiv prevention approaches for sub-saharan africa harvard school of public health program on international health and human rights hamied yk ( ) trading in death lessons not learned: human rights abuses and hiv/aids in the russian federation family, unvalued: discrimination, denial, and the fate of binational same-sex couples under memoir, jesse helms says he was no racist a salute to the sisters. promise fall/winter literature review increasing access to hiv testing and counseling while respecting human rights reasons why human rights should occupy the center of the global aids struggle. open society institute the way forward prevention, treatment and human rights conspiring to kill: gender-biased legislation, culture, and aids in sub-saharan africa new hiv cases drop but rise in young gay men. www.nytimes senator helms's callousness toward aids victims the latino commission on aids supports the hiv nondiscrimination in travel and immigration act discriminación por vivir con vih: fuerzas armadas, a punto del revés, letra s the known hidden hiv/aids epidemic among black men who have sex with men in the united states plos medicine : nyc health ( ) hiv epidemiology and field services research unit report accessed november human rights watch ( ) family, unvalued: discrimination, denial, and the fate park a ( ) assessing a failed aids vaccine mexico: supreme court rules discharge of hiv-positive troops unconstitutional genetic diversity of hiv- : the moving target seeds of change in rwanda sesión pública núm the tuberculosis & hiv debate in immigration law: critical flaws cuerrier ( ) scr , supreme court of canada new mexico court of appeals, nm ohio state court appellate amicus brief us food and drug administration ( ) guidance for industry fixed dose combina antiretrovirals for the treatment of hiv /nr/rdonlyres/ ef e-cf - abb-ab f- adf / / demarzode do human rights matter to health? lancet marde state ( ) texas court of appeal united states academic anti-exclusion arguments. georgetown immigration law journal hivlawandpolicy.org /resources /partial % case % &resource % list-lambda packaged drug products, and single-entity versions of previously approved tarantola d, gruskin s ( ) new guidance on recommended hiv testing and hiv_data/ globalreport/default.asp. accessed the way forward prevention, treatment and human rights consolidated version new law allows needle exchanges in washington modeling health care costs attributable to hiv infection and hiv prevention programs in high-income countries systematic review of abstinence-plus aids epidemic -planning, policy and predictions limited setting: treatment guidelines for a public health approach scaling up antiretroviral therapy in resouurce lawmakers, gay-rights groups protesting new hiv/aids travel unaids/iom ( ) statement on hiv/aids-related travel restrictions international guidelines on hiv/aids and human rights key: cord- -kugh y c authors: de sanctis, fausto martin title: civil and criminal legislation regarding money laundering and the protection of cultural heritage date: - - journal: money laundering through art doi: . / - - - - _ sha: doc_id: cord_uid: kugh y c the aim of this chapter is to understand how states combat money laundering and its possible links to organized crime and other financial crimes. the illegal flow of capital poses a great threat to states. through international joint actions, states can fight crime and curtail the enjoyment of property illegally acquired through criminal activity, particularly with respect to the acquisition of works of art on the black market. money laundering was at first linked to drug trafficking. recognition of the crime of money laundering traces its origins, in europe, to a recommendation by the council of europe. the united nations convention against illicit traffic in narcotic drugs and psychotropic substances (vienna convention of ) is considered the international milestone that paved the way for worldwide political and criminal analysis of the subject. all efforts to categorize money laundering as a crime on its own were closely associated with the international traffic in narcotics. two separate aspects appear to have been decisive in bringing about an international mobilization to punish the conversion of the proceeds of criminal drug trafficking into apparently legal wealth. the first is the predictable inefficacy of the methods used in the war on drugs. the second factor stems from the economic impact that the movement of so-called "narcodollars" has on the economies of many countries-enough to interfere greatly with the normal course of production, competition and consumption. thus, there was a strong international push for the adoption of a means to combat money laundering. the united nations vienna convention of provided an international legal framework, although it was specifically organized to battle the traffic of narcotic drugs and psychotropic substances. the failure of traditional legislation to deal with these new issues was well known. it was a constant concern in many countries in their struggle against serious crime because permitting the flow of illegal capital poses a threat to everyone and undermines the confidence in law enforcement institutions. mireille delmas-marty and geneviève giudicelli-delage assert that "beginning in the late s, the international community became aware of the shortcomingsif not futility-of national rights when faced with increasingly effective international crime prospering precisely because of the disparities between, and lack of harmony among, national legislative bodies…. the un convention signed at vienna on december , , was the first response to bring harmony to enforcement." it is important to take into account that criminalizing money laundering emerged as a measure to inhibit the use and benefit of illegally acquired assets. thus, it is a crime derived from another, and could not exist without the antecedent crime having been previously committed. it is, in the words of jean larguier and philippe conte, a "consequential crime," as opposed to behavior preceding or concurrent with the primary act or attempt. to confidently benefit from its illegal income, organized crime has protected itself well, much like the government, causing the latter to turn to the most modern mechanisms for combating crime. francisco de assis betti adds that it is not always "easy for a criminal to use the proceeds of crime." profligate spending and the eccentricities that always accompany the easy acquisition of money, and immediate purchases way above one's standard of living, are outward signs of wealth which give rise to suspicion, and are conducive to investigations by either police or internal revenue authorities. experienced criminals therefore try to come up with arrangements for investing their criminal proceeds and work with others inclined to conceal these assets and obliterate the money trails in order to avoid enforcement efforts. to the extent that society has realized that serious crime can encompass more than just violent crime, more and more states have ratified international regulatory instruments without restrictions, demonstrating that they are no longer willing to tolerate open-ended criminality within their borders. the links between money laundering and organized crime necessitated immediate and aggressive intervention by governments, not least to ensure their very survival. article of the vienna convention of requires that each signatory take all necessary steps to fight drug trafficking and to establish as criminal offenses under domestic law all of the practices enumerated therein. the practices in question are divided into three groups within section of article . the first group (item "a" of article , section ) refers to the drug trafficking itself as it describes production, manufacture, extraction, preparation or sale [ ( )(a)(i)], cultivation [ ( )(a) (ii)], possession or purchase for any of the above purposes [ ( )(a)(iii)], transportation and distribution [ ( )(a)(iv)], and the organization, management or financing of any of the offenses enumerated above [ ( )(a)(v)]. the second group (item "b" of article , section ) deals with money laundering whereby all signatory states agree to outlaw the conversion or transfer of property that is derived from offenses provided in item "a" [ ( )(b)(i)] and the concealment or disguise of the true nature, location, disposition or ownership of said property [ ( )(b)(ii)]. finally, the third group (item "c" of article , section ) addresses other types of contact in connection with narcotics trafficking or money laundering, such as the acquisition, possession or use of the proceeds of narcotics trafficking [ ( )(c)(i)], possession of materials or equipment related to narcotics trafficking [ ( )(c)(ii)], inciting or inducing others to commit the offenses therein enumerated [ ( )(c)(iii)], and aiding or abetting the commission of any of the offenses therein enumerated [ ( )(c)(iv)]. observe that money laundering is in essence a derivative crime because the offense is contingent upon an antecedent crime. in , in the bahamas, the oas general assembly passed and adopted model regulations on money laundering offenses related to drug trafficking, which define, in article , behavior considered unlawful. this led to the drafting of numerous laws in latin america, including colombia (law no. of ) , chile (law no. / ), paraguay (law no. / and venezuela. money-laundering legislation was already in place in argentina, ecuador, mexico and peru before the model regulations were adopted in the bahamas, but after the vienna convention. when the money-laundering law was promulgated in brazil, the crime in question had already lost its characterization as a crime derived solely from drug-trafficking crimes, as was the case in many of the countries that make the offense illegal. for example, spain, switzerland, austria, the united states, canada, australia and mexico no longer classify money laundering as a mere appendage of drug trafficking. given the evidence that the money-laundering problem is not exclusively a drug trafficking issue, and faced with the deleterious consequences of the entry of the proceeds from certain types of crime into a nation's economy, many legislative bodies began to extend the concept of money laundering by associating it with other types of antecedent crimes. the crime of money laundering had to be separated from drug trafficking because there was no justification for legislating against only that particular form of illicit enrichment. however, this presented serious questions of legal doctrine, such as the question of what legal interest is actually being protected. indeed, when money laundering was a crime exclusively in connection with drugs, it could be argued that the legal justification-albeit in an indirect and reflexive manner-was the same as that for drug trafficking. this is clearly the case in the vienna convention, which makes no formal distinction between drug trafficking per se and enrichment therefrom. argentine legislation, originally under article of law no. / and currently under article of law no. / , provides a penalty of two to ten years for all who engage in money laundering even without having participated or cooperated in the predicate crime from which the money was obtained. thus, if a prerequisite for liability for money laundering is the absence of some antecedent narcotics violation, we may infer that this is a case of violation of one and the same criminal legal interest, so as to avoid bis in idem. with the shedding of this exclusive link with the originating crime, many questions emerged as to the legal justification for criminalizing money laundering. today there is no question that the crime of money laundering falls within the category of financial crimes because of the great effect it has on socio-economic order. there is no doubt that introducing large sums of money that originated in crime into the market interferes with the normal course of production, consumption and competition. another difficulty with money laundering is that it is not simple to accomplish, nor does it follow any preset rule. the commission of the crime involves processes that are often complex and sophisticated, with actions taken in a concatenated or scattered manner, all in an effort to make dirty money look legal. one could indeed simply define money laundering as a procedure whereby one transforms goods acquired through unlawful acts into apparently legal goods. however, overriding considerations of legality and legal security do not permit us to make use of such a simple definition. the crime of money laundering, classically speaking, involves three stages of conduct, namely: concealment or placement, in which goods acquired by unlawful means are made less visible; monitoring, dissimulation or layering, in which the money is severed from its origins, removing all clues as to how it was obtained; and integration, in which the illegal money is reincorporated into the economy after acquiring a semblance of legality. added to this is the recycling stage, which consists of wiping out all records of those previous steps completed. faced with the complexity of the various forms of conduct and processes comprising money laundering, one is struck by the almost complete impossibility of imposing legal restraints other than through combined means, by proscribing more than one form of conduct, and open-ended means, since the large number of activities described in the vienna convention and adopted by most countries calls for intervention for full classification within the limits therein imposed. additionally, money laundering is always a derivative crime, so that it must necessarily be connected, to a greater or lesser extent, to its antecedent crime. all of these issues give innumerable peculiarities to the crime of money laundering, peculiarities that must be gradually sorted out by jurisprudence or case law. in brazil's case, money laundering was not typified in the main body of the criminal code, as was done, for instance, in the united states (in u.s.c. § ). this poses an undeniable difficulty, for if the crime in question were codified, it would have to be promptly adapted to the principles and rules of the criminal code. because this system is integrated and hierarchical, there would be no margin for unjustifiable exceptions. such is the case in france, italy, switzerland and colombia. created in december of by the seven richest countries in the world (g- ), the financial action task force (fatf, or groupe d'action financière sur le blanchiment des capitaux-gafi), organized under the aegis of the organization for economic cooperation and development (oecd), has a mandate to examine, develop and promote policies for the war on money laundering. it initially included twelve european countries along with the united states, canada, australia, and japan. other countries joined afterward (including china in ), as well as international organizations (the european commission and the gulf cooperation council). brazil joined, initially as an observer and later as a full member, at the xi plenary meeting, held in september of . the oecd is an intergovernmental agency organized to promote measures for the fight against money laundering. its list of forty recommendations, drafted in , was revised in . another eight recommendations were drawn up in (on financing of terrorism) and a ninth in (also about financing of terrorism). on february , , all forty-nine recommendations were revised, improved and condensed into forty. these recommendations are not binding, but they do exert strong international influence on many countries (including nonmembers) to avoid losing credibility, because they are recognized by the international monetary fund and the world bank as international standards for combating money laundering and the financing of terrorism. in the version, they were adopted by countries. in the - version, they were adopted by over countries. it is important to mention that the idea of improving and condensing the recommendations to avoid distortion and duplication, and to also incorporate the nine special recommendations on the financing of terrorism into the basic text (forty recommendations), originated in brazil when it presided over the fatf between and . some initial resistance to altering wording that had already become assimilated was overcome. no substantial changes were offered, and all focus was on fine-tuning the recommendations to make them clearer and more objective, and as a result more easily enforceable. all of this changed and facilitated matters, including the member nations' methods of evaluation. the following are relevant provisions contained in the version of the recommendations: countries should identify, assess, and understand the money laundering and terrorism financing risks of the country, and take action to mitigate them (risk-based approach-rba, recommendation no. ). countries should ensure cooperation among policy-makers, the financial intelligence units (fius) and law enforcement authorities, and domestic coordination of prevention and enforcement policies (recommendation no. - , , in pirenópolis in the state of goiás, to develop a joint strategy for the fight against money laundering. to monitor progress toward the goals set forth in the objectives of access to data, asset recovery, institutional coordination, qualification and training and international efforts and cooperation, an integrated management office for the prevention of and fight against money laundering (ggi-ld), was created in compliance with target of encla/ . this office is composed of the primary government agencies, as well as the judicial branch and attorney general's office, conducting both breakout sessions and plenary meetings on various occasions. every year they define new actions (formerly targets), in hopes that the conclusions arrived at during their work sessions will be transformed into substantive outcomes. money laundering should apply to predicate offenses, which may include all serious offenses, any of a long list, or any offenses punishable by a maximum penalty of more than one year, and criminal liability should apply to all legal persons, irrespective of any civil or administrative liabilities (recommendation no. ) . no criminal convictions should be necessary for asset forfeiture. furthermore, with reference to the vienna convention ( ), the terrorist financing convention ( ) , and the palermo convention (transnational organized crime, ), the burden of proof on confiscated goods should be reversed (recommendation no. ) . countries should criminalize the financing of terrorism (recommendation no. ) . countries should implement financial sanction regimes to comply with un security council resolutions on terrorism and its financing (recommendation no. ) , and on the proliferation of weapons of mass destruction and its financing (recommendation no. ). countries should establish policies to supervise and monitor non-profit organizations, so as to obtain real-time information on their activities, size and other important features, such as transparency, integrity and best practices (recommendation no. ) . financial institution secrecy laws, or professional privilege, should not inhibit the implementation of the fatf recommendations (recommendation no. ). financial institutions should be required to undertake customer due diligence and to verify the identity of the beneficial owner, and be prohibited from keeping anonymous accounts or those bearing fictitious names (recommendation no. ) . financial institutions should also be required to maintain records for at least five years (recommendation no. ) and closely monitor politically exposed persons (peps), that is, persons who have greater facility to launder money, such as politicians (in high posts) and their relatives (recommendation no. ). the version expanded the definition of peps to include both nationals and foreigners, and even international organizations. other provisions worth mentioning include: financial institutions should monitor wire transfers, ensure that detailed information is obtained on the sender as well as on the beneficiary, and prohibit transactions by certain people pursuant to un security council resolutions, such as resolution of and resolution of , for the prevention and suppression of terrorism and its financing (recommendation no. ) . designated non-financial businesses and professions (dnfbps), such as casinos, real estate offices, dealers in precious metals or stones, and even attorneys, notaries and accountants, must report suspicious operations, and those who report suspicious activity must be protected from civil and criminal liability (recommendation no. , in combination with nos. through ) . countries should take measures to ensure transparency and obtain reliable and timely information on the beneficial ownership and control of legal persons (recommendation no. ), including information on trusts-settlors, trustees and beneficiaries (recommendation no. ) . financial intelligence units (fius) must have timely access to financial and administrative information, either directly or indirectly, as well as information from law enforcement authorities in order to fully perform their functions, which include analysis of suspicious statements on operations (recommendations nos. , , and ) . casinos must be subject to effective supervision and rules to prevent money laundering (recommendation no. ) . countries should establish the means for conducting freezing and seizure operations, even when the commission of the predicate crime may have occurred in another jurisdiction (country), and implement specialized multidisciplinary groups or task forces (recommendation no. ) . authorities should adopt investigative techniques such as undercover operations, electronic surveillance, access to computer systems, and controlled delivery (recommendation no. ) . the physical transportation of currency should be restricted or banned (recommendation no. ) . proportionate and dissuasive sanctions should be available for natural and legal persons (recommendation no. ). there should be international legal cooperation, pursuant to the vienna convention (international traffic, ), palermo convention (transnational organized crime, and mérida (corruption, ) (recommendation no. ) . countries should provide mutual assistance to facilitate a quick, constructive and effective solution (recommendation no. ), including the freezing and seizure of accounts, even with no prior conviction (recommendation no. ) . countries should quickly execute extradition requests (recommendation no. ) , and spontaneously take action to combat predicate crimes, money laundering, and terrorism financing (recommendation no. ) . thus, as of the revision, the recommendations set forth general guidelines, with details given in interpretative notes. the glossary has made it easy to place the standards adopted in proper perspective and also provides important clarifications. the interpretative notes are best described as a sort of common ground made to fit both common law and civil law countries. one important innovation, albeit not the purpose of the february review, was pointing out the need for countries to adopt the risk-based approach (rba). in other words, before applying certain measures, standards must be established to guide public policies for preventing and combating money laundering, terrorism financing and (this is new) the proliferation of weapons of mass destruction. with regard to politically exposed persons (peps), what was once a simple requirement to monitor certain foreign nationals or authority figures now refers to domestic entities, understood to include international organizations. the fatf pressed for the creation of similar agencies known as fatf-style regional bodies (fsrbs), intended to integrate the global network for the war on money laundering, including: the purpose of these groups is to promote the adoption and effective implementation of the forty recommendations, requiring member nations to accept multilateral oversight and mutual evaluations. the fatf does not appear particularly concerned with art, for in recommending the compulsory reporting of suspicious operations on the part of designated nonfinancial businesses and professions (dnfbps), at no time did it mention that sector. it went no further than to include casinos, real estate offices, dealers in precious metals or stones, attorneys, and notaries and accountants, suggesting that they be subject to internal controls, and recommending protection of whistleblowers from civil and criminal liability (recommendation no. , . despite estimates running into the billions for the underworld dealing in works of art, the financial action task force has not addressed the problem. see - annual report for the financial action task force/groupe d'action financière. www.fatf-gafi.org. accessed may , . cf. robert spiel jr. places the annual amount involved in global theft of artworks at $ . billion (in art theft and forgery investigation, pp. and - ). the fbi estimates that the international traffic in artworks amounts to some $ billion annually, while unesco reportedly claims the amount is in excess of $ billion a year (cf. the united nations educational, scientific and cultural organization (unesco) drafted a convention on the means of prohibiting and preventing the illicit import, export and transfer of ownership of cultural property on november , . it sought to prevent the illegal traffic in artwork by requiring special export licenses and an administrative control system to enable member states to prevent illegal importation and exploitation of artworks. the bureau of educational and cultural affairs of the united states department of state provides important support to the claims of states for violations of the aforesaid unesco convention. in , it allocated $ million for article reads: the states parties to this convention undertake: (a) to introduce an appropriate certificate in which the exporting state would specify that the export of the cultural property in question is authorized. the certificate should accompany all items of cultural property exported in accordance with the regulations; (b) to prohibit the exportation of cultural property from their territory unless accompanied by the above-mentioned export certificate; (c) to publicize this prohibition by appropriate means, particularly among persons likely to export or import cultural property. article reads: (a) to take necessary measures, consistent with national legislation, to prevent museums and similar institutions within their territories from acquiring cultural property originating in another state party which has been illegally exported after entry into force of this convention, in the states concerned. whenever possible, to inform a state of origin party to this convention of an offer of such cultural property illegally removed from that state after the entry into force of this convention in both states; (b) (i) to prohibit the import of cultural property stolen from a museum or a religious or secular public monument or similar institution in another state party to this convention after the entry into force of this convention for the states concerned, provided that such property is documented as appertaining to the inventory of that institution; (ii) at the request of the state party of origin, to take appropriate steps to recover and return any such cultural property imported after the entry into force of this convention in both states concerned, provided, however, that the requesting state shall pay just compensation to an innocent purchaser or to a person who has valid title to that property. requests for recovery and return shall be made through diplomatic offices. the requesting party shall furnish, at its expense, the documentation and other evidence necessary to establish its claim for recovery and return. the parties shall impose no customs duties or other charges upon cultural property returned pursuant to this article. all expenses incident to the return and delivery of the cultural property shall be borne by the requesting party. article reads: (a) to restrict by education, information and vigilance, movement of cultural property illegally removed from any state party to this convention and, as appropriate for each country, oblige antique dealers subject to penal or administrative sanctions, to maintain a register recording the origin of each item of cultural property, names and addresses of the supplier, description and price of each item sold and to inform the purchaser of the cultural property of the export prohibition to which such property may be subject; (b) to endeavor by educational means to create and develop in the public mind a realization of the value of cultural property and the threat to the cultural heritage created by theft, clandestine excavations and illicit exports. the conservation of artworks (not just within the united states) and another $ million for training government agencies, including federal prosecutors. another important international convention likewise intended to combat the illegal trade in artworks is the un convention on stolen or illegally exported cultural objects (unidroit). its preamble addresses the concerns over the illegal trade in cultural objects, and requires member states to establish common rules for restitution or repatriation for the return of the property illegally removed. observe that the convention requires the return even of articles acquired in good faith. in the wake of recommendations contained in the convention concerning the protection of the world cultural and natural heritage, drafted at the unesco general conference on october -november , , and dated / / , it became important for governments to confer upon artwork "a function in the life of the community" (article ). it is indeed incumbent upon all to protect the cultural heritage of mankind, as provided in the convention concerning the protection of the world cultural and natural heritage, specifically: article : each state party to this convention recognizes that the duty of ensuring the identification, protection, conservation, presentation and transmission to future generations of the cultural and natural heritage… situated on its territory, belongs primarily to that state. it will do all it can to this end, to the utmost of its own resources and, where appropriate, with any international assistance and cooperation, in particular, financial, artistic, scientific and technical, which it may be able to obtain. article : to ensure that effective and active measures are taken for the protection, conservation and presentation of the cultural and natural heritage… each state party to this convention shall endeavor… d) to take the appropriate legal, scientific, technical, administrative and financial measures necessary for the identification, protection, conservation, presentation and rehabilitation of this heritage. article - : every state party to this convention shall, in so far as possible, submit to the world heritage committee an inventory of property forming part of the cultural and natural bureau of educational & cultural affairs. united states department of state, meeting with margaret g.h. maclean, senior analyst, on / / , at pm, in sa , fifth floor; and exchanges.state.gov/heritage/culprop/review.html. accessed june , . "deeply concerned by the illicit trade in cultural objects and the irreparable damage frequently caused by it, both to these objects themselves and to the cultural heritage of national, tribal, indigenous or other communities, and also to the heritage of all peoples, and in particular by the pillage of archaeological sites and the resulting loss of irreplaceable archaeological, historical and scientific information." article : ( ) the possessor of a cultural object which has been stolen shall return it. ( ) for the purposes of this convention, a cultural object which has been unlawfully excavated or lawfully excavated but unlawfully retained shall be considered stolen, when consistent with the law of the state where the excavation took place. heritage, situated in its territory and suitable for inclusion in the list provided for in paragraph of this article. this inventory, which shall not be considered exhaustive, shall include documentation about the location of the property in question and its significance. article - : on the basis of the inventories submitted by states in accordance with paragraph , the committee shall establish, keep up to date and publish, under the title of 'world heritage list,' a list of properties forming part of the cultural heritage and natural heritage, as defined in articles and of this convention, which it considers as having outstanding universal value in terms of such criteria as it shall have established. an updated list shall be distributed at least every two years. article created the fund for the protection of the world cultural and natural heritage called "the world heritage fund," and article provides, in addition to voluntary contributions, a pledge to deposit contributions to the fund every two years. finally, article requires the state parties to prepare reports for the general un educational, scientific and cultural organization, which are then brought to the attention of the world heritage committee. such measures were adopted to thwart ordinary crime against works of art (robbery, theft, receiving, forgery), but were not thought out in terms of money laundering and terrorism financing. commission of ordinary crime sometimes constitutes a single element in money laundering, and the art used for this crime is only for appearances of legitimacy and legal activities. then, the united nations convention against transnational organized crime was convened in palermo on / / , following the united nations convention against illicit traffic in narcotic drugs and psychotropic substances of / / (article ). both global regulatory guidelines require the state parties to make laundering the proceeds of crime itself a crime (article ), and provide for the confiscation of "proceeds of crime derived from offences covered by this convention or property the value of which corresponds to that of such proceeds" [article ( )(a)]. parallel to that is the united nations convention against corruption held at mérida in (article , item -confiscation and seizure of money in an amount equivalent to the proceeds of crime). items , and of article of the united nations convention against transnational organized crime held at palermo correspondingly assert that "state parties shall adopt such measures as may be necessary to enable the identification, tracing, freezing or seizure of any item referred to in paragraph of this article for the purpose of eventual confiscation; if the proceeds of crime have been transformed or converted, in part or in full, into other property, such property shall be liable to the measures referred to in this article instead of the proceeds; if proceeds of crime have been intermingled with property acquired from legitimate sources, such property shall, without prejudice to any powers relating to freezing or seizure, be liable to confiscation up to the assessed value of the intermingled proceeds." such provisions accurately depict the new world order with respect to combating organized crime, including narcotics trafficking and corruption. it is sometimes alleged by defendants that the property seized has no links to the crime. it is then up to the judge to properly estimate the amount that flowed from the proceeds of the unlawful conduct imputed, mindful of the need to enforce the requirements set forth in the foregoing conventions, as well as article , section iv, of the brazilian code of criminal procedure, which requires that the sentence be fixed at the "minimum amount required for reparation of damages caused by the infraction, taking into account all losses suffered by the aggrieved party," in order to put the confiscation into effect-that is, to secure definitive forfeiture of that amount for the injured party or to the state as indemnification for damages caused by unlawful conduct. under article k. of the treaty of maastricht ( ), european union member states agreed to adopt a common policy in their domestic efforts, and the joint action ( / /jha) sought to include money laundering as a type of organized crime. this was revoked in part by the framework decision of the european union council dated / / , whereby member states agreed not to make reservations on articles and of the european convention of (including the rule that provides for money laundering resulting generically from criminal conduct), since only serious infractions can be at issue, and provided measures for confiscation and criminal action on the proceeds of crime having a maximum penalty of greater than one year, or crimes considered serious (article ). the framework decision of / / ( / /jha) on forfeiture of products, instruments and property related to the crime, allows "extended powers of confiscation" aimed not only at forfeiture of assets of all those found guilty, but also assets acquired by their spouses or companions, or whose property may have been transferred to some company under the influence or control of the guilty parties-for organized criminal practices such as counterfeiting, trafficking in persons or assisting illegal immigration, sexual exploitation of children and child pornography, traffic in narcotics, terrorism, terrorist organizations and money laundering, provided they be punishable by a sentence of a maximum of at least five to ten decision and framework decision (title vi of the european union treaty): with the entry into force of the treaty of amsterdam, these new instruments under title vi of the european union treaty ("provisions on police and judicial cooperation in criminal matters") replaced joint action. framework decisions are used to bring together the legislative and regulatory provisions of member states. they are proposed on a motion by the commission or by a member state, and must be unanimously adopted. they are binding on member states as to results to achieve, and leaves it to national courts to decide on the manner and the means of achieving them. decisions address all other goals besides the conference committee work on legislative and regulatory provisions of the member states. decisions are binding and all measures necessary to carry out the decisions within the scope of the european union are adopted by the council through qualified majority vote. years of imprisonment, or, in the case of laundering, with a maximum penalty of at least four years of imprisonment, and by their nature generating financial income (article , sections - ). note that the palermo convention provides for international cooperation on matters of confiscation [article ( )], and expressly provides that the proceeds of crime be allocated to finance a united nations organizations fund, so that it may assist member states in obtaining the wherewithal with which to enforce the convention [articles ( )(a) and ( )(c)]. artworks could well be included in the scope of this convention if one could point to convincing evidence that they might be related to the commission of antecedent crimes and to money laundering. if the art market were indeed being used for purposes of money laundering, those circumstances would justify judicial search and seizure, and possibly confiscation as well. in the united states, legislation fully supports confiscation of property in both administrative and criminal proceedings. the united states code, title § a (c), establishes customs forfeiture by providing that "[m]erchandise which is introduced or attempted to be introduced into the united states contrary to law shall be treated as follows: ( ) the merchandise shall be seized and forfeited if it… (a) is stolen, smuggled, or clandestinely imported or introduced." there is a "failure to declare" law in the united states, u.s.c. § , which provides for forfeiture of any article not declared or mentioned orally or in writing. the u.s. cultural property implementation act of march ( u.s.c. § § - ), provides a series of administrative measures. section (a) of the act establishes that "[a]ny designated archaeological or ethnological material or article of cultural property which is imported into the united states in violation of section of this title or section of this title shall be subject to seizure and forfeiture." the u.s. criminal code ( u.s.c.) establishes as a crime: § (entry of goods by means of false statements) whoever enters or introduces… into the commerce of the united states any imported merchandise by means of any fraudulent or false invoice, declaration, affidavit, letter, paper, or by means of any false statement, written or verbal,… or makes any false u.s.c. § : (a) in general ( ) ( ) whoever, knowing that the property involved in a financial transaction represents the proceeds of some form of unlawful activity, conducts or attempts to conduct such a financial transaction which in fact involves the proceeds of specified unlawful activity-(a) (i) with the intent to promote the carrying on of a specified unlawful activity; or with intent to engage in conduct constituting a violation of section or of the internal revenue code of ; or knowing that the transaction is designed in whole or in part-(i) to conceal or disguise the nature, the location, the source, the ownership, or the control of the proceeds of specified unlawful activity; or to avoid a transaction reporting requirement under state or federal law, shall be sentenced to a fine of not more than $ , or twice the value of the property involved in the transaction, whichever is greater, or imprisonment for not more than twenty years, or both. (…) ( ) whoever transports, transmits, or transfers, or attempts to transport, transmit, or transfer a monetary instrument or funds from a place in the united states to or through a place outside the united states-(a) with the intent to promote the carrying on of specified unlawful activity; or (b) knowing that the monetary instrument or funds involved in the transportation, transmission, or transfer represent the proceeds of some form of unlawful activity and knowing that such transportation, transmission, or transfer is designed in whole or in part-(i) to conceal or disguise the nature, the location, the source, the ownership, or the control of the proceeds of specified unlawful activity; or (ii) to avoid a transaction reporting requirement under state or federal law, shall be sentenced to a fine of not more than $ , or twice the value of the monetary instrument or funds involved in the transportation, transmission, or transfer, whichever is greater, or imprisonment for not more than twenty years, or both (…). § (engaging in monetary transactions in property derived from specified unlawful activity). whoever, in any of the circumstances set forth in subsection (d), knowingly engages or attempts to engage in a monetary transaction in criminally derived property of a value greater than $ , and is derived from specified unlawful activity, shall be punished as provided in subsection (b ( ) "knowing that the property involved in a financial transaction represents the proceeds of some form of unlawful activity" means that the person knew the property involved in the transaction represented proceeds from some form, though not necessarily which form, of activity that constitutes a felony under state, federal, or foreign law, regardless of whether or not such activity is specified in paragraph ( ); ( ) through this legislation, the united states attorney's office for the southern district of new york was able to seize, confiscate or repatriate many works of art either stolen or fraudulently sent to the united states under false or defective documentation. (footnote continued) described in paragraph ( ) ( ) the term "criminally derived property" means any property constituting, or derived from, proceeds obtained from a criminal offense; and ( ) the terms "specified unlawful activity" and "proceeds" shall have the meaning given those terms in section of this title. the chief prosecutor for the asset forfeiture unit, sharon cohen levin, provided the author with substantial and pertinent information (in her office at one saint andrews plaza) as to claims filed for recovery of goods, among them: in brazil, bill no. / , converted into law no. of / / , which amended law no. of / / , was hotly debated by many agencies that take part in the national strategy for the fight against corruption and money laundering (enccla). the enccla comprises over sixty members, including many government agencies, such as brazil's federal revenue department, the central bank, the ministry of justice, state and federal attorneys' offices, the federal police, and state and federal courts. the enccla strives to honor all international commitments entered into by brazil, and keeps up with all countries that are members of the financial action task force on money laundering (fatf). among its recommendations is a need to close the loopholes that make money laundering feasible. another recommendation is to require individuals in significant levels of trust (auditors, bank managers, insurance, real estate and capital goods brokers, etc.) to submit suspicious activity reports to financial intelligence units, which are key to all crime fighting systems. in closing with a set list of antecedent crimes, it attempted to fine-tune and update the law to the most modern standards of money-laundering legislation, and thus provided preemptive asset forfeiture. just as positive was the change requiring suspicious activity reports from boards of trade, recordkeeping entities and all those involved in mediating, brokering or negotiating the trade of athletes. it was lax, however, in not including, for example, notification requirements on the part of sports clubs, sports federations and sports confederations. by the new language imparted by law of / / , the crime of money laundering is now defined as: art. concealing or disguising the nature, origin, location, disposition, movement or ownership of goods, securities or money derived directly or indirectly from a criminal offense. penalty: three to ten years of imprisonment and a fine. § the same penalty shall apply to anyone who, in order to conceal or disguise the use of goods, securities or money arising directly or indirectly from a criminal offense: i -converts them into legal assets; the most recent argentine anti-money-laundering law (law no. of / / ), in addition to including self-laundering, increases the minimum sentence from two years to three years (while keeping the maximum at ten years), requires the laundered money to have originated from a "criminal act" instead of a "crime," adds language to the criminal code making corporations subject to criminal liability, and establishes forfeiture of assets with no need for criminal conviction, provided illegal origin can be established, including cases of bankruptcy, flight, statutory limitations or the existence of any reason for suspending or terminating criminal proceedings, or when the defendant acknowledges the illegal source of the goods. ii -acquires, receives, trades, negotiates, gives or receives them in guarantee or in bailment, keeps them on deposit, negotiates or transfers them; iii -imports or exports goods at a price other than their true value. § the same penalty shall also apply to anyone who: i -makes use -in financial or business dealings -of goods, securities or amounts they know or have reason to know are the proceeds of crime; ii -is a member of any group, association or office while aware that its primary or secondary activity involves the commission of crimes as provided herein. § such attempts are punishable pursuant to the sole paragraph of article of the criminal code. § the penalty shall be increased by one-third to two-thirds if the crimes established in this law are committed as repeat offenses or through a criminal organization. § the penalty may be reduced by one-third to two-thirds, and may be served under a work-release or similar program, or the judge may suspend the sentence or instead sentence the defendant to curtailment of rights if the first principal, second principal or accomplice freely cooperates with the authorities, and provides information to assist in the investigation of the crimes, identifies the perpetrators or identifies the whereabouts of the goods, securities or monetary proceeds of the crime. brazil's national institute of historic and artistic heritage (iphan) is a federal agency under the ministry of culture. its mandate is to oversee and protect the stewardship of archaeological collections that are federal property (under article , x of the federal constitution, and article of law no. of / / ) and may not be preserved by private entities. it also extends protection to property having historical, artistic and cultural value. the brazilian constitution establishes, in article , section x, that all archaeological and prehistoric sites belong to the union, and in article , sections iii and iv, that all governing bodies (the union, the states, the federal district and the municipalities) shall be responsible for the protection of "documents, works and other assets of historical, artistic or cultural value (…) and archaeological sites" and also must "prevent the loss, destruction, or changing of the characteristics of works of art and other goods of historical, artistic and cultural value. vii -protection of the historical, cultural, artistic, touristic, and scenic patrimony; viii -liability for damages to the environment, consumers, property and rights of artistic, aesthetic, historical, touristic, and scenic value; ix -education, culture, teaching and sports; (…) (added by constitutional amendment no. , of ) iv -democratization of access to cultural assets; (added by constitutional amendment no. of ) v -valorization of ethnic and regional diversity. (added by constitutional amendment no. , of ) art . brazilian cultural heritage includes material and immaterial goods, taken either individually or as a whole, that refer to the identity, action, and memory of the various groups that form brazilian society, including: iforms of expression; making, and living; artistic, and technological creations; objects, documents, buildings, landscape, artistic, archaeological, paleontological, with the collaboration of the community, shall promote and protect brazilian cultural heritage by inventories, registries, surveillance, monument protection decrees, expropriation, and other forms of precaution and preservation. § -it is the responsibility of public administration, as provided by law, to maintain governmental documents and take measures to make them available for consultation by those that need to do so. § -the law shall establish incentives for production and knowledge of cultural property and values. § -damages and threats to the cultural patrimony shall be punished, as provided by law. § -all documents and sites bearing historical reminiscences of the old hideouts for fugitive slaves are declared to be historical monuments. § -states and the federal district may bind up to five-tenths of one percent of their net tax receipts from the state fund for cultural development for financing cultural programs and projects, but these resources may not be used for payment of: (added by constitutional amendment no. of / / ) i -personnel expenses and payroll charges; (added by constitutional amendment no. of / / ) as provided by federal law. chapter v social communication. art. the expression of thoughts, creation, speech and information, through whatever form, process or vehicle, shall not be subject to any restrictions, observing the provisions of this constitution. § -no law shall contain any provision that may constitute an impediment to full freedom of the press, in any medium of social communication, observing the provisions of art. , iv, v, x, xiii and xiv. § -any and all censorship of a political, ideological and artistic nature is forbidden. § -it is the province of federal law to: i -regulate public entertainment and shows, and it is the responsibility of the government to advise about their nature, the ages for which they are not recommended and the locales and times unsuitable for their exhibition; ii -establish legal measures that afford individuals and families the opportunity to defend themselves against radio and television programs or schedules that contravene the provisions of art. , as well as against commercials for products, practices, and services that may be harmful to health and the environment. § -commercial advertising of tobacco, alcoholic beverages, pesticides, medicine, and therapies shall be subject to legal restrictions, in the terms of subparagraph ii of the preceding paragraph, and shall contain, whenever necessary, warnings about harms caused by their use. § -the media of social communication may not, directly or indirectly, be subject to monopoly or oligopoly. § -publication of printed means of communication shall not require a license from any authority. art. production and programming by radio and television stations shall comply with the following principles: i -preference for educational, artistic, cultural and informational purposes; ii -promotion of national and regional culture and fostering any independent production aimed at its dissemination. iii -regionalization of cultural, artistic and journalistic production, according article of legislative decree (decreto-lei) no. of / / , which organized the protection of historical and artistic patrimony of brazil, requires that "the union maintain-for the preservation and exhibition of historical and artistic works-in addition to the national historical museum and the national museum of fine arts, other national museums as may become necessary, and shall also make provisions to promote the establishment of state and municipal museums having similar purposes." there is also a provision for administrative seizure (of illegally exported national heritage works ), and for forfeiture arising from crime (generic provision for all proceeds from or instrumentalities of crime; and a provision in brazil's and confiscation of the proceeds from crime and on the financing of terrorism (warsaw, , article ) all recommend that consideration be given to the adoption of confiscatory measures absent prior criminal conviction, or measures shifting the burden of proving the legal source of assets onto the accused. to increase the likelihood of recovering assets of criminal origin, states are urged to draft laws instituting civil forfeiture actions for illegally acquired assets as a means of fighting money laundering by interrupting the usufruct of the proceeds of crime. for example, on september - , , judicial authorities of the office of the federal prosecutor, the attorney general's office, and the justice ministry's asset recovery and international legal cooperation department (drci), met to discuss the project, given the participation of kimberly prost, un specialist on drugs and crime. the meeting was again taken up on october of that same year and then again on march , , to finalize the project and conclude the discussions. the primary focus was on establishing quicker means of recovering illegal assets-means that did not require a decision on the defendant's criminal liability, but rather, a judicial recognition restricted to proof of the illegal origin of the assets, absence of proper title for their acquisition, or a mismatch between income level and assets acquired. leaving illegally obtained money in the hands of criminals-especially members of organized criminal gangs-encourages the reentry of those monies into the underworld, or back into the original illegal business practices occurring prior to, or even after serving a sentence, with the potential for serious harm to society. enccla target no. of , foreseeing the need to confiscate illegal goods, highlighted the importance of a law to enable the taking of urgent measures in administrative proceedings. the office of the attorney general then agreed to draft a bill which, if passed, could apply to both administrative proceedings and lawsuits charging administrative dishonesty, irrespective of the civil actions addressed here. civil action opens up new inroads for obtaining assets that would end up financing organized crime, inasmuch as they are derived from it. they allow the state to deal with the proceeds of crime. they must also be clearly regulated so as on the one hand to not offend fundamental rights of the individual, and on the other to serve as a quick and effective tool for the recovery of illicit assets. the civil action in question would indeed be an extension of state powers regarding illegal assets, inasmuch as it would allow definitive forfeiture while dispensing with a final decision by a court and still respecting the rights of the individual. the rights of those who received the property in good faith, or of third parties in a similar situation, must be protected. they must therefore be assured the right to answer the civil charges, and even assured payment of minor expenses (like living expenses) during discussion of their situation. one could prove, for example, having rented the house in good faith without knowing that it was used for illegal purposes (such as prostitution). it would not be appropriate, however, for the defense to argue adverse possession, because it would be too easy to deflect the purpose of the action if, for instance, the owner were to pay someone to allege uninterrupted possession. we should mention that the burden of proof as to the illegal origin of the assets and monetary amounts does, in principle, fall on the state and includes not only the proceeds of the crime, but also its instrumentalities, such as cars, boats, houses and businesses. to be clear, it is only if the assets are included in an income tax return that the burden of proof is on the state, as opposed to the owner, possessor or bearer. note that criminal sanctions are oftentimes perceived as a temporary setback (even when penalties are severe), whereas the compulsory transfer of valuable assets to the state, such as cars, mansions and luxury items, causes more trouble to criminals because of its irreversible nature. but civil action is not intended as a means of giving the state yet another punitive instrument. yet it does have this effect, to the extent that those accustomed to having illegal assets value them very highly, even when compared to their own individual freedom. hence, civil action to terminate ownership does indeed become a valuable instrument in fighting crime and is also more effective in the recovery of illegal assets. it is much more difficult to obtain a satisfactory outcome in serious and complex crimes, especially money laundering, because criminals have made use of qualified professionals to enable them to distance themselves from the crime. civil action is quite useful here because the value judgment involved is different. what must be proven is a link. it is not a judgment of merits as in a criminal procedure, but rather a determination of the probabilities that the assets are the product of illegal activity. indeed, the cost involved in gathering evidence of a crime such as money laundering, coupled with the difficulty of obtaining a favorable outcome, even in the presence of strong suspicion of criminal activity, has caused governments to rethink the entire system in terms of adopting less costly methods-methods more closely hedged in with the necessary guarantees-as a strong ally in the recovery of illicit assets. it is important to the success of the action that specific cooperative agreements between states be entered into, thereby opening up a broad avenue for the recovery of illegal assets. due to its autonomous nature, the action under consideration may be brought concurrently with criminal prosecution, provided it does not jeopardize criminal investigations, which are often secret. if during the course of bringing civil action it is found that criminal prosecution can feasibly be quickly resolved, the civil suit should be suspended pending the outcome of criminal proceedings. one must, however, be mindful of the absolute autonomy of civil action. situations such as the death of a defendant or subject of an investigation, statutory limitations, insufficient evidence, criminal immunity or obtaining of evidence from abroad may burden, if not thwart, recovery of illegal assets. civil action could be improved by permitting preventive seizure or impoundment prior to definitive forfeiture, thus allowing the appointment of a custodian of property, but without preemptive alienation (before the decision becomes final), which could be risky because the judgment of merits is different from that in criminal courts, except in cases of deterioration. should a settlement occur in civil proceedings, the effect in criminal court would favor reducing the sentence, whether by acknowledgment of subsequent repentance (cpb-brazilian criminal code, article ), or by mitigating circumstances, such as voluntary cooperation (cpb article , section iii, item b), or by plea bargaining. to avoid improper management of such actions (purely personal or political filings), specific rules of procedure must be established, such as, for instance, rejection of filings once ten or fifteen years have elapsed following possession or holding, prior analysis of the history of the ownership of the assets through forensic examination, and a preliminary hearing with the defendant-all to preclude arbitrary or baseless filings. civil action for termination of ownership is accepted procedure in the united kingdom, iceland, italy, the united states, colombia (through law no. of / / ), australia and south africa. in the united states, the treasury department's office of the comptroller of the currency (occ) requires that all banks file suspicious activity reports (sars) with the financial crimes enforcement network (fincen), also a treasury department agency. this must be done whenever any violation is known or suspected, and also whenever a suspicious transaction involves money laundering or any violation of the rules made pursuant to the bank secrecy act (bsa). note that the occ has received requests to amend the expression "known or suspected violation" because of its breadth of scope. the conclusion was made, however, that attempted crimes, or the potential for the same, must be reported in order to bolster the effectiveness of efforts to combat money laundering. there was, however, more clarity provided on the requirement that banks report suspicious activities "for any reason" because critics considered the expression overly broad and rendered meaningless the $ , threshold for suspicious activity reports. the occ decided that reporting was required on any operation involving $ , or more, provided the banks know, suspect, or have reason to suspect that the operation involves money derived from illegal activities; there is some intent to conceal or disguise the money; colecionadores afirmam que sonegação continuará sendo praxe no meio enquanto carga tributária não diminuir. folha de são paulo, / / , ilustrada supplement publication by internal revenue service. department of the treasury. market segment specialization program branqueamento de capitais: reacção criminal. estudos de direito bancário princípios básicos de direito penal crime organizado e proibição de insuficiência. porto alegre: livraria do advogado lavagem de dinheiro. comentários à lei pelos juízes das varas especializadas em homenagem ao ministro gilson dipp. porto alegre: livraria do advogado perito propõe estratégias de inteligência financeira no cjf lavagem de capitais e 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activos: análisis de los tipos penales previstos en la ley no. . . magazine of the office of the public prosecutor of peru calmon nogueira da temas de direito penal e processo penal: em especial na justiça federal. rio de janeiro: renovar são paulo: max limonad, . garcia, josé Ángel brandariz. el delito de defraudación a la seguridad social arbítrio e inconstitucionalidade na lei de lavagem de dinheiro ou bens do crime de "branqueamento" de capitais: introdução e tipicidade. coimbra: almedina ed crime organizado e seu tratamento jurídico penal direito penal -parte geral crime organizado: que se entende por isso depois da lei no. . / ? -apontamentos sobre a perda de eficácia de grande parte da lei para ministro, há cultura de crimes. folha de são paulo. são paulo, / / . caderno brasil sources of information in a financial investigation comentários ao código penal -arts. a , a , a buenos aires: departamento de prensa, ministerio de justicia y derechos humanos/presidencia de la nación suspicious activity reports disclosure and protection. united states attorney's bulletin criminal prosecution of banks under the bank secrecy act. united states attorney's bulletin crimes econômicos e mercados financeiros. revista brasileira de ciências criminais força-tarefa: conceito, características e forma de atuação rio de janeiro: forense, . machado, agapito. crimes do colarinho branco e contrabando/descaminho. são paulo: malheiros ed a propósito da revisão do decreto-lei no. / , de de janeiro (infracções antieconômicas) direito penal: introdução e parte geral dos crimes contra o sistema financeiro nacional: anotações à lei federal no. . / . são paulo: malheiros ed são paulo: malheiros ed., . malheiros filho, arnaldo. crimes contra o sistema financeiro: as "triangulações" e a "doutrina da estrada de santos curso de direito penal tratado de direito penal lisboa: verbo, . messineo, francesco. máfia e crime de colarinho branco: uma nova abordagem de análise. novas tendências da criminalidade transnacional mafiosa. organizers: alesandra dino and wálter fanganiello maierovitch crime de lavagem de dinheiro: consumação e tentativa. ultima instância: revista jurídica. www.ultimainstancia.com.br ultima instância: revista jurídica. www.ultimainstancia.com.br derecho penal -parte general (fundamentos y teoría del delito) introducción a las bases del derecho penal moraes filho, antônio evaristo et al. habeas corpus -crime de gestão fraudulenta de instituição financeira presunção de inocência no processo penal brasileiro: análise de sua estrutura normativa para a elaboração legislativa e para a decisão judicial são paulo: saraiva, . nucci, guilherme de souza. manual de direito penal -parte geral -parte especial leis penais e processuais penais comentadas. nd rev. ed. são paulo: ed. revista dos tribunais curso de direito constitucional direito e processo penal na justiça federal: doutrina e jurisprudência crimes de gestão fraudulenta e gestão temerária em instituição financeira lavar dinheiro com gado é muito fácil lei de lavagem de capitais crimes contra o sistema financeiro nacional e o mercado de capitais direito penal dos negócios: crimes do colarinho branco crimes contra o sistema financeiro nacional: comentários à lei . , de / / . são paulo: ed curso de direito penal brasileiro -parte geral crimes de colarinho branco it's all about money: advancing anti-money laundering efforts in the u.s. and mexico to combat transnational organized crime rider, barry. the financial world at risk: the dangers of organized crime, money laundering and corruption / e o concurso aparente de leis. direito federal. revista da ajufe criminalidade financeira: contribuição à compreensão da gestão fraudulenta. porto alegre: livraria do advogado entidades buscam aperfeiçoamento normativo. formular leis que garantam o efetivo combate à lavagem de dinheiro e a recuperação dos ativos é a principal meta da encla para este ano de capitais e outros produtos do crime: contributos para o estudo do art. .º do decreto-lei no. / , de de janeiro, e do regime de prevenção da utilização do sistema financeiro no "branqueamento" (decreto-lei no. / , de de setembro) o crime de colarinho branco (da origem do conceito e sua relevância criminológica à questão da desigualdade na administração da justiça penal). coimbra: coimbra ed and sponsored by the oas and the justice ministry for brazilian judges and prosecutors. simpÓsio sobre direito dos valores mobiliários. série cadernos do centro de estudos judiciários do conselho da justiça federal, nos. and financial regulations and tax incentives with the aim to stimulate the protection and preservation of cultural heritage in spain. art and cultural heritage: law, policy, and practice el delito de cuello blanco -white collar crime -the uncut version white-collar crime -the uncut version trends, tips & issues. published under the auspices of the bsa advisory group, issue fincen the relationship between tax deductions and the market for unprovenanced antiquities. colum são paulo: saraiva, . tourinho filho, fernando da costa. curso de direito constitucional les travaux du conseil de l'europe. revue internationale de droit pénal temas relevantes no direito penal econômico e processual penal derecho penal alemán: parte general moderna dogmática del tipo penal. lima: aras editores manual de direito penal brasileiro -parte geral tratado de derecho penal. parte general. buenos aires, . zanchetti, mário. il ricciclaggio di denaro proveniente da reato key: cord- -dd gw t authors: armbruster, walter j.; roberts, tanya title: the political economy of us antibiotic use in animal feed date: - - journal: food safety economics doi: . / - - - - _ sha: doc_id: cord_uid: dd gw t this chapter examines the evidence for antibiotic resistance in the united states and globally, the public health implications, and the impact of—and related industry and political responses to—antibiotic use in animal feed. in , the swann report in the united kingdom noted a dramatic increase in antibiotic-resistant bacteria in food animals receiving low levels of antibiotics in their feed. while the food and drug administration of the united states sought to control antibiotics in animal feed as far back as , only in were such regulations fully implemented. the farm-level costs of such controls are estimated by the us department of agriculture’s economic research service to be minimal, while the centers for disease control and prevention’s estimates of the public health costs of antibiotic resistance without implementing controls are $ billion annually. the complex interactions which exist between economic interests, regulatory policy, and human and animal health are explored in this chapter. antibiotic resistance has been widely recognized as a serious public health problem. hence, there is a major public good to be realized in safeguarding the effectiveness of existing antibiotics and creating new ones. antibiotics are used to treat human infections and used in animal agriculture. while many drugs are dual-use, others are animal-or human-use specific. the production benefits of sub-therapeutic levels of antibiotics in animal agriculture have been recognized since the late s (cast ) . in animal agricultural production, antibiotics are used at therapeutic levels to treat infections and at sub-therapeutic levels to prevent infections and promote animal growth (sneeringer et al. ; van boeckel et al. ; who ) . as the organizational complexity of the animal agricultural supply chain increased, the number of economic stakeholders in on-farm antibiotic use has also increased. the major stakeholders include pharmaceutical companies, production integrators, feed suppliers, farm groups, producers, restaurants, food retailers, the public, the medical community, the scientific community, government regulators and policy makers. each of these stakeholders faces a different set of incentives and disincentives related to on-farm use of antibiotics in animal agriculture. knowledge of these incentives and disincentives has evolved with the accumulation of scientific and economic research. to understand the regulatory outcomes governing antibiotic use in agriculture, it is important to recognize the political economy context in which they are developed. the various stakeholders are driven by the relative benefits they receive under policies as they affect their industry segment (zilberman et al. ). alexander fleming, who discovered penicillin, warned that "…misuse of the drug could result in selection for resistant bacteria" (rosenblatt-farrell ) . antibiotic resistance (ar), a term sometimes used interchangeably with antimicrobial resistance, occurs when bacteria change in ways that make antibiotics less effective in treating infections, thereby allowing the bacteria to survive, multiply, and cause additional harm. ar has been recognized as a serious public health problem among the medical and scientific communities. antibiotics are used to treat human infections and used in animal agriculture. particularly concerning is resistance for those antibiotics that are of value in treating human health issues, the so-called medically important antibiotics. the use of antibiotics along with other advances in agricultural technology has facilitated the concentration of animal production on farms in the united states (us) and elsewhere. for example, in , % of all us sales of hogs and pigs were by the % of farms with , or more head, and % of all layers were produced on the less than % of farms that sold , or more to egg producers (nass ) . the majority of the production of hogs, broilers, and eggs occurred under contractual arrangements between growers and integrators, with the integrators prescribing certain production practices, including the use of antibiotics for treating infections, for disease prevention and for promoting growth. many of the antimicrobial drugs administered to food-producing animals are also important in treating humans, worldwide. domestic sales of medically important antimicrobial drugs for use in food-producing animals in the united states accounted for % of the domestic sales of all antimicrobials approved for use in food-producing animals. and, % of domestic sales of all medically important antimicrobials approved for use in food-producing animals are labeled for therapeutic use only . importantly, animal drug sales data represent products sold or distributed by manufacturers through various outlets for intended sale to the user. since veterinarians and others in the supply chain may have substantial inventory on hand for possible use, these numbers do not accurately reflect the amount of product ultimately administered to animals. given the number of humans versus a much larger number of animals in each of the species, as well as other confounding factors, no definitive conclusions from any direct comparisons between the quantities of antimicrobial drugs sold for use in humans versus animals can be drawn (fda a) . there are obvious situations where antibiotics are required to treat sick animals in agriculture, but the proper therapeutic use versus prophylactic use remains in question among stakeholders. farm groups and others in the food animal supply chain recognize that antibiotics in animal feed keep animals healthy and meat costs down. but over medical doctors and other healthcare providers signed petitions to congress asking for new legislation to reduce non-therapeutic antibiotic use in food animals (miller ) . the animal health industry is very concerned that needed preventative use will be threatened by the recent fda ban on use of medically important antibiotics for growth. fda classifies as therapeutic those antimicrobials targeted for treatment, control, and prevention of bacteria or disease identified on the product label. fda explicitly states that the use of antibiotics in animal feed for growth promotion is not allowed. those who characterize preventative use as routine overlook the difference between treating animals versus humans. if preventative measures are not taken and a disease outbreak occurs and spreads rapidly within a flock or herd, it risks large numbers of animals developing a deadly, high mortality disease. waiting until a disease is clearly evident makes successfully treating the active infections very difficult due to the large number of animals involved. by contrast, a human patient can generally be quickly diagnosed and treated. while some are concerned that producers will continue to use antibiotics for growth under the guise of prevention, the fda-approved label is specific about dose and duration for a specified bacterium or disease. off-label use of antibiotics in animal production is illegal, and fda only allows a veterinarian to decide whether to use or not to use a preventative treatment based on their judgment of a disease threat (carnevale ) . in an economic framework, antimicrobial resistance can be considered as an unwanted side effect, or externality, associated with the use of antibiotics. the efficacy of antibiotics can be considered as a public good that must be managed with government involvement. this is because the costs of overuse by any single individual are borne by society and, in the case of antibiotics, globally. hence, not only is there a role for government involvement with the animal agriculture industry in managing the stock and use of antibiotics as an important public good, but it must be done cooperatively across countries. in , the united kingdom's (uk) parliament received the swann report, which concluded that using antimicrobials at sub-therapeutic levels in food-producing animals created risks to human and animal health (joint committee on the use of antibiotics in animal husbandry and veterinary medicine ). it noted a dramatic increase in numbers of animal-origin bacteria strains which showed resistance to one or more antibiotics and that these strains could transmit resistance to other bacteria. it recommended that only antimicrobials that are not medically important for humans should be used without prescription in animal feed and that antimicrobials should only be used for therapeutic purposes under veterinary supervision. the primary reason that producers were using these sub-therapeutic doses of antibiotics was to promote faster weight gain in the animals. in , a us food and drug administration (fda) task force was charged to do a comprehensive review of antibiotic use in animal feed (fda ). its report found that sub-therapeutic use of antimicrobials in food-producing animals was associated with development of resistant bacteria and that treated animals might provide a reservoir of antimicrobial-resistant pathogens capable of causing human disease. the task force recommended that medically important antimicrobial drugs meet certain guidelines they identified or be prohibited from growth promotion or other sub-therapeutic use by certain dates. further, antimicrobials not meeting the guidelines should be limited to short-term therapeutic use only under veterinarian control. in the s, the animal health institute (ahi), a us trade association for the animal drug industry, funded an on-farm study to determine the impact of adding low-dose antibiotics to chicken feed. within week of adding tetracycline, the intestinal flora in the chickens "…contained almost entirely tetracycline-resistant organisms" (levy et al. ). the antibiotic resistance was not located in the dna of the bacteria which is hard to transfer among bacteria but in plasmids located on the outside surface of the bacteria. plasmids are easily exchanged among bacteria living in the intestine. importantly, the tetracycline-resistant bacteria in the chicken's intestines were resistant to multiple antibiotics. furthermore, some members of the farm families began to harbor these same antibiotic-resistant bacteria in their intestines within months. in , the fda proposed withdrawing the new animal drug approvals for the sub-therapeutic uses of human medically important penicillin and tetracycline in animal feed based on lack of evidence to show they were safe. however, the us congress intervened and asked for more research first. the ahi was one of the groups advocating in congress to delay regulation pending additional research, then and now. in congressional testimony, richard carnevale, vice-president at ahi, testified that while it is possible for human antibiotic resistance to be caused by antibiotic use in farm animals, "…it does not happen enough that we can find it and measure it" (carnevale ) . this statement contradicted the data produced by the ahi-funded study by levy (levy et al. ) that was published in the prestigious new england journal of medicine in . richard carnevale also mentioned in his testimony that prior to joining ahi he was deputy director of new animal drug evaluation in fda and had worked at usda in the food safety and inspection service (fsis). his testimony illustrates two points in the political economy of food production: ( ) how industry has an opportunity to influence regulators' decision-making via the revolving door of employment and ( ) how industry carefully selects its facts to present a point of view that bolsters their profits, namely, for drug companies in this case (oreskes and conway ) . another example of the political economy in action involved usda prohibiting an agency research microbiologist from talking about the significant levels of antibiotic-resistant bacteria detected in the air near midwest hog confinement operations (union of concerned scientists ). a third element of the political economy is shown by industry efforts to influence policy makers through campaign contributions and strong lobbying of proposed legislation which may affect their bottom line. pharmaceutical companies spent at least $ million and agribusiness companies another $ million during , in large part to fight possible limits on antibiotic use in animal feed (mason and mendoza ) . in response to congressional pressure in the late s, fda withdrew its proposal and instead funded three studies to determine the impact of using low levels of antibiotics in animal feed (industry won this round, obtained a delay in regulations, and funded more reports): . in , the national academy of sciences reported that there was limited epidemiological research on the topic. available evidence at that time did not prove nor disprove dangers of seven therapeutic antimicrobials in animal feed, but that did not preclude the existence of hazards (national academy of sciences ). . in , the fda funded the seattle-king county department of public health to analyze salmonella and campylobacter, which were chosen as models to estimate the flow of potentially pathogenic bacteria from animals to humans through the food chain. their report was based on sampling retail meat and poultry and investigating salmonella and campylobacter enteritis cases in humans. isolates from human illness cases and retail foods were analyzed for antibiotic resistance of these pathogens, using plasmid analysis and serotyping. the report found that campylobacter was a more common cause of enteritis than salmonella and appeared to flow from chickens to humans through consumption of poultry products, with tetracycline resistance being plasmid-mediated (seattle-king county department of public health ). . in , the institute of medicine (iom) undertook a fda-requested independent quantitative risk assessment of human health impacts from sub-therapeutic use of penicillin and tetracycline in animal feed. based on a risk-analysis model of salmonella infections that resulted in human death, the iom did not find substantial direct evidence that sub-therapeutic use in animal feed posed a human health hazard. however, they found a considerable body of indirect evidence implicating both sub-therapeutic and therapeutic use of antimicrobials as a potential health hazard and strongly recommended additional study of the issue (institute of medicine ). numerous research results quantifying the extent of the antimicrobial resistance problem have been published in the scientific literature and indicate a growing and serious threat to human health. the many channels for ar to affect humans are shown in fig. . . the two main channels for food animals are ( ) ar bacteria in the food animal's gut can contaminate the meat or poultry eaten and ( ) environmental contamination, such as manure used to fertilize fields that contain ar bacteria, may contaminate the environment and some of the food crops grown on these fields. consumer reports (cr) tested products sold in us supermarkets and found resistance to multiple antibiotics in the following percent of samples: beef %, shrimp %, turkey %, and chicken % (consumer reports ). cr also found that ground beef from conventionally raised cows was twice as likely to contain antibiotic-resistant pathogens as ground beef from cows raised without antibiotics. like other threats to human health, ar is best managed across national boundaries. increasing international trade may spread antibiotic resistance through imported food products as more trade agreements are approved. this scenario could be exacerbated to the extent fsis approves additional international facilities, local regulations, and inspections as "equivalent to the united states." future trade agreements will need to include provisions which address reduced use of medically important antibiotics in producing food animals. numerous trusted institutions from the united states (us) and the united kingdom (uk) as well as international organizations such as the world health organization (who), the united nations' food and agriculture organization (fao), and the world organization for animal health (oie) have acknowledged the threat of antibiotic resistance related to use in producing food animals. the fol- lowing excerpts from a few recent reports highlight the role that low-dose antibiotic use in animal feed plays in spreading ar. the centers for disease control and prevention ( b) reported that: each year in the united states, at least million people acquire serious infections with bacteria that are resistant to one or more of the antibiotics designed to treat those infections. at least , people die each year as a direct result of these antibiotic-resistant infections. many more die from other conditions that are complicated by an antibiotic-resistant infection. antibiotic-resistant infections add considerable and avoidable costs to the already overburdened u.s. healthcare system. in most cases, antibiotic resistant infections require prolonged and/or costlier treatments, extend hospital stays, necessitate additional doctor visits and healthcare use, and result in greater disability and death compared with infections that are easily treatable with antibiotics. the total economic costs of antibiotic resistance to the u.s. economy has been difficult to calculate. estimates vary but have ranged as high as $ billion in excess direct healthcare costs. adding on the costs for lost productivity brings the total societal costs (sic) for ar to $ billion a year ( dollars). (cdc a, p. ) this cdc report also indicates that foodborne cases are responsible for % of human ar infections ( fig. . ). thus, societal costs of these ar foodborne illnesses could total $ billion annually of the $ billion/year total costs to the us economy. these societal costs could be prevented if the foods were free of contamination with ar pathogens. there may be additional costs associated with environmental pathways of human contamination from use of antibiotics in meat production, such as exposure to contaminated water. in , who stated: "antimicrobial resistance (ar) is an increasingly serious threat to global public health. ar develops when a microorganism (bacteria, fungus, virus or parasite) no longer responds to a drug to which it was originally sensitive. this means that standard treatments no longer work; infections are harder or impossible to control; the risk of the spread of infection to others is increased; illness and hospital stays are prolonged, with added economic and social costs; and the risk of death is greater-in some cases, twice that of patients who have infections caused by non-resistant bacteria. the problem is so serious that it threatens the achievements of modern medicine. a post-antibiotic era-in which common infections and minor injuries can kill-is a very real possibility for the st century" (who , p. ) . in , oie noted: "today, in many countries, including developed countries, antimicrobial agents are widely available, directly or indirectly, practically without restriction. of countries recently evaluated by the oie, more than do not yet have relevant legislation on the appropriate conditions for the import, manufacture, distribution and use of veterinary products, including antimicrobial agents. consequently, these products circulate uncontrolled like ordinary goods and are often falsified." to date, there is no harmonized system of surveillance on the worldwide use and circulation of antimicrobial agents. that information is necessary, however, to monitor and control the origin of medicines, obtain reliable data on imports, trace their circulation, and evaluate the quality of the products in circulation. it is in this context that the oie was mandated by its member countries to gather that missing information and create a global database for monitoring the use of antimicrobial agents, linked to the oie's world animal health information system (wahis). that mandate is also supported by fao and the who within the framework of the who's global action plan on antimicrobial resistance. the database will form a solid basis for the three organizations' work to combat antimicrobial resistance (oie , p. ) . in , a uk evaluation of academic, peer-reviewed research articles addressing antibiotic use in agriculture determined that only % found no link and % found a positive link between antibiotic use in animals and antibiotic resistance (ar) in humans (o'neill ) . taken to evaluate proposals to ban the use of growth-promoting or sub-therapeutic levels of antibiotics in food animals, usda's economic research service (ers) economists added questions on antibiotic use to the agricultural and resource management survey (arms). arms is a nationally representative survey of farms administered jointly by ers and usda's national agricultural statistics service (nass). hog producers were surveyed in and , and broiler producers were surveyed in and . ers also drew upon their research using data in the national animal health monitoring system (nahms) to develop a model to estimate the impacts of withdrawing antibiotics for other than therapeutic use in food animals. using monte carlo simulations, ers estimated the impacts of eliminating antibiotic use for growth promotion of poultry and pork, not just the fda-specified "medically important" antibiotics (table . ). simulation results showed less than . % reduction in output and an approximate . % increase in wholesale prices, netting pork producers greater total revenue of . % and poultry producers . %. ers concluded that these small effects were not statistically significant (sneeringer et al. ) . these ers results are consistent with research studies post- indicating that productivity gains from using antibiotics for growth promotion were lower than earlier research had found (teillant and laxminarayan ) . another report suggested that phase out of growth promotion use in food animals over a -year period would avoid most of the % projected global growth in such use and cost agricultural sectors a small portion of the costs of ar in each country. further, reduced infection risk and costs of medications would cover most farm-level costs of improving animal husbandry practices to offset loss of antimicrobials for production purposes (laxminarayan and chaudhury ) . presuming that any new antibiotic classes probably will not be made available for veterinary medicine, it is important to preserve the effectiveness of existing antibiotics which are necessary for treatment of infectious diseases to maintain animal health (teillant and laxminarayan ) . an alternative to encourage development of new antibiotics would be to delay or not approve drugs which mimic others, but for which the applicant company has not performed antibiotic research (amábile-cuevas ). even better, several production practices may be used to enhance animal health in the absence of using antimicrobials for growth or for prophylactic disease prevention (sneeringer et al. ; who ; macdonald and wang ) . these include: • improved management practices, such as more space per animal and better control of the housing environment • tightened biosecurity to prevent diseases and improve productivity by avoiding introduction of infectious agents by wild animals, domestic pets, and nonessential workers or other humans; through increased cleanliness of production facilities; and from timely removal of dead animals • optimized nutrition to increase growth and mitigate stress-related factors and provide vitamin and mineral supplements to reduce disease susceptibility • improved gut microflora to improve feed efficiency by providing enzymes, organic acids, prebiotics, probiotics, and immune modulators • vaccinations to prevent some diseases • hazard analysis critical control point plans to improve productivity in the absence of using sub-therapeutic antibiotics in animal production generally, these practices may raise production costs modestly at the farm level because of the need for more resources required to successfully manage them. since ers found no statistically significant evidence that antibiotics reduce the costs of producing pork or broilers, we conclude that there are small or no costs to producers from withdrawing growth-promoting or prophylactic uses of antibiotics in production of food animals. in contrast, the public health benefits of withdrawing these antibiotics from agriculture are significant. as reported above, cdc estimates that the medical costs and productivity losses of ar illnesses attributed to agriculture are $ billion us dollars annually. the benefit/cost analysis becomes $ billion in public health protection benefits vs. the very small costs to animal production from withdrawing antibiotics from non-therapeutic use. in other words, the protection of the public health will come at little or no cost to agriculture. furthermore, this benefit/cost analysis provides a conservative estimate of public health protection benefits. the cdc public health protection benefits do not include estimates for protection from an increasing number of "superbugs" that would be created if low-level antibiotics would continue to be used. and cdc does not include the costs of long-term health outcomes caused by foodborne pathogens (see chap. ). aside from costs to agricultural producers, there are also other societal costs related to ar and connected to antimicrobial use in animal production, both in their production and use/misuse, affecting human and environmental health. in economic terminology, these costs are considered negative externalities to society from the individual use of antibiotics. moreover, since the science of ar is unfolding, there may be additional unknown human health and environmental risks associated with the use of antibiotics in food animal production. pharmaceutical production. a major issue involved with manufacturing of active ingredients for antibiotics and the effluent from factories producing them is the potential to contaminate nearby water systems. pharmaceutical factories often contaminate the environment, since guidelines for pharmaceutical waste discharge focus on chemicals used in manufacturing, rather than active pharmaceutical ingredients. this is a primary concern in countries outside the united states, but international trade makes it a worldwide problem. use and misuse. worldwide, antibiotics are used heavily in animal agriculture. this practice has created resistance problems transmissible from animals to humans. for example, china has mrc- colicin resistance in pork and salmonella resistance to cephalosporins at higher levels than in the united states (zhang et al. ) . their practice of applying human waste on fields and the closeness of population centers to agriculture contribute to cross-mixing of pathogens in china. parasites are common in chinese soil and can contaminate pork. and low levels of chlorine in chinese water supplies allow accumulation of biofilms containing antibiotic-resistant pathogens in water pipes. in india, manufacturing of pharmaceuticals and waste disposal practices lead to contamination of water and soil. further, over-the-counter antibiotics are available and heavily used there. farm antibiotic use is of concern in india and china in poultry and pigs (apua newsletter ). the threat of superbugs via food is worldwide, due to the distribution of animal food products from china (zhang et al. ; zhu et al. ) . rosenblatt-farrell ( ) drew upon existing literature to identify additional environmental paths to exposure to antibiotic resistance. veterinary antibiotics are frequently excreted intact from food animals (table . ). for the widely used tetracycline, - % of the antibiotic is excreted in the feces or urine and not metabolized by the food animal. the transfer of this animal waste to croplands may transfer antibiotics and possibly ar pathogens. in one study, ar genes in soil increased fourfold after manure from hog and dairy farms was applied to the soil (moyer ) . runoff from farms, feedlots, or cropland can lead to antimicrobial resistance problems in soil, surface water runoff, and groundwater. animal waste held in lagoons allows birds and insects to become contaminated with antibioticresistant bacteria, and flies around food animal facilities can carry antibioticresistant enteric bacteria which increases potential human exposure. migratory birds and seagulls which become infected with antibiotic-resistant bacteria or viruses can widely transmit resistance to other birds as well as marine life. others note that antibiotics should never be used to compensate for poor hygiene and husbandry practices or conditions in livestock production (van boeckel et al. ) . veterinary medicine should only use antibiotics to treat diagnostically determined bacterial infections not otherwise treatable and only those antibiotics authorized for the diagnosed pathogenic indication and the specific bacteria involved. further, given the potential for acute diseases that require immediate treatment, it is important that routine testing (surveillance) be carried out for farm-specific pathogens for all relevant antibiotic classes (silley and stephan ) . who also emphasizes the need for surveillance and monitoring antimicrobial use in food-producing animals to evaluate the extent to which their guidelines are implemented. fda has increased regulation of antibiotic use in food animals. as noted in sect. . above, fda attempted to withdraw new animal drug approvals for subtherapeutic uses of human medically important penicillins and tetracyclines in animal feed based on lack of evidence to show they were safe. after industry opposition and congressional intervention to require further study, this early policy response was withdrawn. subsequently, the us congress gave something to each group when it enacted the animal drug availability act (adaa) in . this act both table . , fda in recent years issued three core documents to implement a policy framework for judicious use of medically important antimicrobial drugs in food animals: on january , , fda announced that it had completed implementation of the guidance for industry # . this means that medically important antimicrobials provided to food-producing animals may no longer be used for growth promotion purposes and may be used to treat, prevent, or control animal illnesses only under direction of a veterinarian. fda worked with industry participants to implement this voluntary compliance to slow development of antimicrobial resistance and preserve effectiveness of medically important antibiotics. more than percent of new drug applications subject to gfi # were converted from over-the-counter to prescription status, applications were withdrawn, and all applications indicating production use withdrew that specified use. fda also indicated plans to work with industry stakeholders to support antimicrobial stewardship in food animal production and to evaluate the effectiveness of strategies to reduce antimicrobial resistance development under the allowed uses (fda ). some industry stakeholders in the supply chain are actively engaged in responding to consumer and general public health concerns about ar in the food supply chain amidst mounting scientific evidence, but responses vary considerably by country, place in the supply chain, and individual company. aside from farm groups, stakeholders include feed companies, pharmaceutical companies, integrators or meat processors, restaurant chains and other retail outlets, and consumer and other interest groups. pharmaceutical companies. in the case of pharmaceutical companies, little evidence exists that they are responding to the ar problem yet. as described earlier, most antibiotics are produced in india and china, and their production has resulted in significant risk, especially environmental risk. regulators need to set minimum standards for the treatment of manufacturing waste before it is released into the environment. other industries which purchase these pharmaceuticals need to establish higher standards through their supply chains to help correct this environmental pollution (o'neill ). furthermore, the drug companies are not required to compensate victims who become ill or die from either the environmental or food exposure. the drug companies and their trade associations have resisted more regulation to prevent misuse of antibiotics. the companies therefore have been getting a "free ride" at the expense of the ill consumers and the general public. integrators and meat processors. some chains and food retailers have recently responded to customer concerns by restricting the use of antibiotics in their food supply chains. large meat processors committing to judicious use of antibiotics have already led many producers to eliminate the use of antibiotics for production enhancement purposes. in a case study of voluntary labeling in the broiler industry, "raised without antibiotics" (rwa) label claims by tyson foods and by perdue farms in , respectively, numbers one and three in total broiler production, resulted in mixed outcomes. at that time, usda fsis had not published a standard for such claims, nor was a clear definition established. perdue and tyson developed their own standards and submitted the label claims to fsis for approval along with supporting documentation. after initially approving both firms' label claims, fsis determined in september that tyson's claim was false and misleading and gave them the opportunity to submit a revised label claim. however, tyson continued their advertising of the rwa claims. the diverse label claims in which tyson and their competitors were using different standards for their claim resulted in consumer confusion, and eventually court challenges were filed jointly by sanderson farms, the fourth largest producer, and perdue against tyson. the suit was upheld in court in april . tyson was found not to have delivered the rwa attribute promised to the marketplace and to thereby have harmed competitors, while tyson profited from introducing a false and misleading claim. in june , fsis rescinded tyson's qualified rwa label claim and required its removal within weeks, after the claims and advertising had continued for more than a year. the authors found no evidence that the events had any impact on tyson's brand, suggesting that companies may have incentives to introduce misleading label claims since the size of penalties is uncertain (bowman et al. ) . perdue farms inc. was the only major chicken producer to eliminate all medically important and animal-specific antibiotics from use in its chicken production as of . by replacing antibiotics with vaccines and improving its production facilities and practices, it has been able to produce chicken at virtually the same cost as when using antibiotics. perdue estimates that its conventional chicken sales are increasing by not more than % annually, while sales for product raised without antibiotics are growing - % annually (bunge ) . gnp company, a leading provider of premium natural chicken products, is adopting antibiotics-free production of chicken products. its gold'n plump brand will feature a "no antibiotics-ever" claim. this will go well beyond what many companies are currently focusing on-eliminating the use of medically important antibiotics, rather than all antibiotics. usda regulations allow this label claim only for chicken never having received antibiotics, even inside the egg. the company will continue to treat flocks for illness as necessary, but not market them under their premier gold'n plump brand. the company plans extensive media and in-store support to educate consumers about the transition to its chicken products raised totally without antibiotics (gnp company ). tyson foods, a leading producer of chicken, pork, and beef and products thereof, adopted a position to eliminate the use of human-use antibiotics in broiler production by september . they stopped the human antibiotic use in their hatcheries and reduced usage in producing broilers by % since . they also have worked with farmers and others in the beef, pork, and turkey supply chains to explore ways to reduce human antibiotic use at the farm level. tyson is employing alternative husbandry strategies such as use of probiotics and essential oils, improved housing, and selective breeding to offset the potential impact of eliminating the use of the antibiotics. they are also interacting with the food industry and other involved supply chain participants, as well as academics, to increase research on disease prevention and alternatives to replace antibiotics (tyson foods ). feed companies. the feed companies are also getting into the discussion to address public health concerns about antibiotic resistance and the relationship to livestock production uses of antibiotics. phibro animal health corporation recently launched a website animalantibiotics.org to "…provide accurate and credible information while still creating open dialogue about animal agriculture in the use of antibiotics." it will address all issues involving animal antibiotics and changes underway within the industry to promote responsible use of antibiotics in livestock (johansen ) . this is very consistent with the historical pattern of the animal agriculture industry making its case in the political economy in reaction to the strong push to limit use of antibiotics to help quell rising antibiotic resistance of medically important drugs. restaurant chains. an interesting example of restaurant chains and poultry producers working together is provided by panera bread co. and perdue farms inc. panera is one of the restaurant companies for which perdue supplies chickens raised without antibiotics. when panera pioneered antibiotic-free chicken in its restaurant products over years ago, they paid a % premium versus chicken produced using antibiotics. with improved production practices, the cost differential has virtually disappeared (bunge ) and is thus consistent with the ers estimates cited earlier. consumer and other interest groups. in the process of developing these new fda regulations, activist groups petitioned the federal courts. for example, in may , the natural resources defense council (nrdc), center for science in the public interest (cspi), food animal concerns trust (fact), public citizen, and union of concerned scientists (ucs) filed a case against the fda. they charged that fda failed to ban penicillins and tetracyclines used at low doses in animal feed for growth promotion, despite evidence fda put forth in that penicillin and most tetracyclines were not shown to be safe and may pose a risk to human health (apua ). in , the federal court ruled in favor of these petitioners. in a later ruling in , the federal court directed fda to reexamine its decision on five other classes of "medically important drugs" used as growth promoters addressed in two citizen petitions (filed in and ) to ensure the safety and effectiveness of all drugs sold in interstate commerce (ibid). given that most governments have neglected to acknowledge and address the problem of increasing antibiotic resistance, international organizations with a role in health issues have been stymied from doing so. it will take more concerted action by societies around the globe to successfully address this cross-border issue (amábile-cuevas ). us consumers, in general, have much less information about the product than does the seller (chaps. and ). this asymmetric information can offer opportunity for the selling firm behavior that is detrimental to the interests of the consumer, as when a product is labeled as containing or not containing certain desirable or undesirable attributes. in the case of many products known as credence goods, it is impossible to determine whether the attributes are as stated, even when the product is used or consumed. this market failure can be addressed either through government regulations or through voluntary steps by the sellers to assure that the stated attributes are factual. the latter could be accomplished through advertising to build and maintain the firm's brand and reputation, and competition with other sellers could result in consumers having increased variety of product choices. however, some consumers may not trust private companies' word about product attributes and prefer certification programs which monitor products against some standard established either by the private sector or by government agencies. lusk (lusk ) argues that voluntary labels are dynamically efficient in responding to changes in market conditions and encouraging innovation more than mandatory labels implemented through regulations, since the latter are more subject to manipulation by those with vested interests. further, usda's agricultural marketing service (ams) process-verified and certification programs are very effective in helping to assure the credibility of voluntary labeling, while accommodating innovation from the private sector. gnp's adoption of antibiotics-free production discussed in . is an example of dynamic market efficiency through use of voluntary labeling to innovate in response to changing consumer demand usda's food safety inspection service (fsis) currently employs an animal production claims protocol for evaluating and allowing or denying labeling claims. labeling applications must provide supporting documentation such as operational protocols detailing production practices and affidavits or testimonials about production practices. fsis then evaluates whether protocols support the accuracy of the proposed label. also, feed formulations must be provided and reviewed to ensure they do not include substances not permitted by the claim. commonly approved claims relevant to the use of antibiotics include "raised without added hormones" (only allowed for use in beef cattle and lamb production) and "raised without antibiotics." claims not allowed include that animal products are antibiotic-, hormone-, or residue-"free" (fsis ) . given the current trend among meat producers, restaurants, and retail livestock product marketers, it can be anticipated that there will be increasing attention to labeling the lack of antibiotic use for other than therapeutic purposes. this will likely result in animals that have been raised with antibiotics to promote growth and uniformity of size consistent with processor contract agreements being diverted to marketing outlets where such promises do not exist. the impact of labeling in this manner will vary according to how much consumers know about the use of antibiotics in livestock production and their ability to currently purchase antibiotic-free livestock products (lusk et al. ) . o'neill and his british colleagues emphasize improving transparency as a major step in addressing antimicrobial resistance related to the livestock production. recent attention by companies such as food retailers, wholesale producers, and fastfood chains, as well as investors, for reducing antibiotic use in their supply chains, has been in response to consumer pressure. providing greater transparency through voluntary approaches is helpful in the short term, but it may be necessary to mandate transparency requirements about how antibiotics are used in the supply chains to have longer-term impacts. labeling that refers to antibiotic use could improve consumer knowledge to allow them to make better informed decisions. they also argued that third-party validation of support from independent institutions to monitor progress may be beneficial (o'neill ). improved transparency by food producers about antibiotics used in producing meat could help consumers make better informed purchasing decisions. but there are large gaps in data needed to allow monitoring of types and quantities of antibiotics used in animal agriculture and their impacts (cfi ), as well as on emergence and spread of resistance in animals. the who also identified major gaps in surveillance and data sharing on emergence of antibiotic resistance in bacteria and its impact on animal and human health. who called for integrated surveillance systems harmonized across countries to enable better comparison of data from foodproducing animals, food products, and humans (who ). in the united states, fda requires drug companies to voluntarily submit data on drugs sold for use in food animals. the publicly available data are not detailed, and % of the sales of medically important antimicrobials are over-the-counter (otc). tetracyclines are primarily added to feed and accounted for % of domestic sales of animal drugs that are "medically important" to human medicine in (fda b) . from to , domestic sales and distribution of tetracycline products approved for use in food-producing animals increased by %. while levy et al. ( ) discovered how rapidly tetracycline created antibiotic resistance in the gut of chickens, years later, the public does not have access to information on what antibiotics are used in which food animals at what stage of life. this will change somewhat in fda implementation of gfi # (fda ) that will identify whether the sales are intended for use in cattle, sheep, hog, or poultry. fda ( b) issued a final rule amending an existing requirement that sponsors of drug products containing antimicrobial active ingredients report annually the amount of each such ingredient in the drug products sold or distributed for use in food-producing animals. effective july , , drug sponsors were required to submit species-specific estimates of product sales as a percent of their total sales. additional reporting requirements are expected to facilitate better understanding of antimicrobial drug sales for specific food-producing animal species and the relationship between such sales and antimicrobial resistance. as reported above, drug sponsors have all adopted voluntary revision of fda-approved labels for use of new medically important antimicrobial animal drugs administered through feed or water. under this rule, sponsors all voluntarily removed the growth promotion and feed efficiency uses and brought the remaining therapeutic uses under veterinarian oversight by the end of december . the rule makes it illegal to use medically important antibiotics for production purposes. despite the scientific and economic evidence, many comments to the proposed final regulation reflected ongoing resistance to the elimination of food animal production use of medically important antibiotics. data available on antibiotics used in the us livestock industry is derived primarily from two nationally representative surveys of farms conducted by the usda's economic research service (ers) and national agricultural statistics service (nass). the agricultural and resource management survey (arms) is designed to collect information on farm finances, production practices, and resource use focuses on three commodities annually, livestock included. different types of livestock are resurveyed every - years and represent commercial producers in states producing % of production for that livestock type. some questions have been included in these surveys on antibiotic use for hogs and broilers. the hog surveys ask about use of antibiotics in feed or water for growth promotion, disease preven-tion, and/or disease treatment in breeding, nursery, and finishing hogs. given the widespread use of hog production contracts under which farm operators may receive feed from integrators, the surveyed operators may not know if antibiotics are included in it. for broilers, there is only a single question about whether they were raised without antibiotics in feed or water other than for therapeutic treatment of illness. production contracts dominate the broiler industry, so surveyed farm operators are in a similar situation as hog producers in not necessarily knowing whether antibiotics are included in the feed provided. a further complication is that arms does not separate traditional antibiotics and ionophores, which are not used in human medicine (sneeringer et al. ) . the national animal health monitoring system (nahms) consists of national studies to provide essential information on livestock and poultry health and management. major food livestock species are surveyed about every years to provide current and trend information important to industry participants, researchers, and policy makers. each study includes states that represent at least % of the targeted animal population and at least % of the farm operations involved and provides statistically sound information for decision-making. a nahms study is a collaborative, voluntary, confidential, scientifically sound product. descriptive reports are prepared along with information sheets which briefly address very specific topics, such as biosecurity practices (aphis ). the nahms focuses on animal health and management, providing information on disease occurrence and disease prevention practices, as well as more detailed information on antibiotics used in production, including by specific purpose. however, the information collected on antibiotics varies greatly across commodities, as well as over time with the same commodities. further, arms focuses on hog production operations with or more head versus nahms focus on or more head. this complicates comparison of statistics across surveys, assuming smaller operations may have different characteristics than larger ones (sneeringer et al. ) . to track antimicrobial resistance changes over time, the national antimicrobial resistance monitoring system-enteric bacteria (narms) was established by cdc in . the program is a collaboration between state and local public health departments and three federal agencies to monitor changes in antimicrobial susceptibility for certain enteric bacteria from ill people (cdc), retail meats (fda), and food animals (usda) in the united states. it provides information about emergent bacterial resistance, the ways resistance is spread, and how resistant infections differ from susceptible ones (narms ). the world organization for animal health (oie) plans to address antimicrobial resistance as a major risk to the international community, in the face of concern about agriculture's role in increased antimicrobial resistance. the goal is to preserve effectiveness of antimicrobials used in animal medicine, protect animal welfare, and help maintain important antimicrobials for use in human medicine. oie has already developed international standards, most recently revised in . the new strategy introduced at the th oie general session in may outlines plans to help nations improve legal frameworks to preserve antibiotics, communicate about the ar problem, train animal health workers, and monitor antibiotic use in animals. they are currently working to create a database of information on the use of antimicrobial agents in animals and develop performance indicators to assist countries by increasing information flow and transparency in their use of antimicrobials. further, the oie expert network is working to reinforce scientific knowledge about new technologies and replacement solutions for current antimicrobials (mitchell ) . the eu has banned the use of antimicrobials in food animal production, other than by veterinarian prescription for specific therapeutic use. some other countries have adopted similar bans, and, as discussed above, the united states fully implemented voluntary guidelines in requiring current drug sponsors to withdraw antibiotics for growth promotion. however, the animal health institute's carnevale has said that the new fda guidance on antibiotics may not decrease the total quantities of antibiotics used in animal food production (moyer ) . generally, variations among countries in implementing regulations have resulted in the spread of resistance. there is ample evidence to support the need for global coordination to prevent continued spread of antimicrobial resistance, and elements of a framework to make such global coordination effective have been posited (so et al. ) . the uk review on antimicrobial resistance final report proposes three broad steps to deal with reducing unnecessary use of antibiotics in animals. first, establish -year targets for reduction in use, with milestones to support progress consistent with countries' economic development. this could encourage farmers to reduce non-therapeutic use to be able to allocate the resulting reduced amounts of antibiotics to treating sick animals. second, implement restrictions or bans on certain types of highly critical last-line antibiotics for humans from being used in agriculture. this would require a harmonized approach to identify the most important human health antimicrobials across countries and good systems of veterinarian oversight to assure compliance. third, improve transparency from food producers on antibiotic use in meat production to allow consumers to make better informed buying decisions. voluntary industry efforts may be one of the most practical approaches to reduce antibiotic use in the near term, but third-party validation to monitor progress would be beneficial (o'neill ) . generally, voluntary industry approaches require monitoring by an outside party to assure both industry participants and consumers that standards are being met as required. the uk medical research council (mrc) recently made three large grants focused on antimicrobial resistance through an initiative established in to address the growing ar issue. the projects will use new technology to exploit natural compounds, develop a better and faster diagnostics tool, and study how the body's immune system can be harnessed to better fight infections. the goal is not only to develop antibiotics but also explore alternatives to antibiotic use, working with other uk research councils to bring to bear a wide range of disciplines to tackle ar (mrc ). the need to focus increased attention to developing new antibiotics is supported by cdc data which shows that many of the most widely used drugs have developed resistance. the number of years to develop resistance varies greatly but never extends more than a couple of decades, and more recent antibiotic introductions have been resistant for only a year or two. for example, the widely used tetracycline was introduced in and developed resistance to shigella by . this is near the midrange of years to resistance reported (cdc a). given this scientific fact, the slow pace of adopting policies to proscribe use of human-use antibiotics in animals and to encourage greater investment in developing newer antibiotics or alternatives is unacceptable. increasing detection of bacteria resistant to last-resort drugs has driven stakeholders to countenance accelerating government efforts to increase surveillance of drug use and to develop new antibiotics (fda week ). promising approaches which provide more rapid assessment utilizing newer technologies such as genomics are now being utilized by scientists. microbiologists are embracing high-throughput genomics to quickly examine individual organisms or entire microbial communities. a project underway at the university of california, davis, the k foodborne pathogen genome sequencing project, will sequence , foodborne isolates for the most important worldwide foodborne illness outbreak organisms. it involves a consortium of academic, government, and industry to create a massive database of genome signatures for the most significant foodborne disease-causing microbes. the goal is to allow public health agencies and the food industry supply chain to trace any foodborne illness outbreaks to their source. by comparing the pathogen genome to the database which includes millions of pieces of information on previously detected strains, including their exact location, the contamination source will be positively identified. bioinformatics and the analytics involved can be used to turn the vast amount of genomic information into actionable knowledge. these event sequencing approaches will enable new diagnostic and public health approaches to manage foodborne disease to facilitate improved public health. the database will increase ability to detect and mitigate pathogenic organisms in food, the environment, and livestock. that capacity is now constrained by continual genetic evolution of pathogens which hinders the ability to defend the food supply. this project will facilitate speedy testing of raw ingredients and finished products from outbreak investigations with precision and accuracy unparalleled using existing methods of analysis. genomics enabled diagnostics with molecular tools will allow surveillance, risk assessment, and diagnosis of foodborne pathogens directly throughout the global food chain. the result will be a genetic catalog for some of the most important outbreak organisms impacting human health. the database will provide insights into molecular methods of infection and drug resistance for use in creating new vaccines and therapies. and importantly, it will assist in systematic definition of biomarker gene sets associated with antibiotic resistance (weimer ). a recent innovative metagenomics study also provides new insights on possible impacts of antibiotic use in food animal production and ar in humans. the research investigated antimicrobial resistance potential-the resistome-by tracking specific pens of intensively managed cattle from feedlot through slaughter to market-ready beef products. study results found no antibiotic-resistant determinants (ards) in the beef products beyond the slaughter facility. this suggests that intervention during slaughter minimizes potential for antibiotic-resistant determinants passing through the food chain. the results also highlight potential risks through indirect environmental exposures to the feedlot resistome through wastewater runoff, manure application on cropland, and wind-borne particulate matter. the insights provided can be used to better inform future agricultural and public health policy. however, this first of its kind study suggests the scientific community must develop a better understanding of the risk of different resistomes and resistance genes. it also identifies a pressing need to standardize ard nomenclature so that databases and analyses are comparable across studies (noyes et al. ) . the world health organization has recently developed guidelines to mitigate human health consequences from use of medically important antimicrobials in food-producing animals (who ). the guidelines are evidence-based recommendations and include best practices for use of medically important antimicrobials in food-producing animals, especially antimicrobials deemed critically important to human medicine. they also can help preserve effectiveness of antimicrobials for veterinary medicine. the recommendations include: • an overall reduction in use of all classes of medically important antimicrobials in food-producing animals. • complete restriction for use in growth promotion. • complete restriction of use to prevent infectious diseases that have not yet been clinically diagnosed. • antimicrobials designated as critically important for human medicine should not be used to control spread of clinically diagnosed infectious disease identified within a group of food-producing animals, nor for treatment of food-producing animals with a clinically diagnosed infectious disease. • for best practices, any new class of antimicrobials for use in humans will be considered critically important for human medicine unless otherwise categorized by who. further, medically important antimicrobials not currently used in food production should not be so used in the future. these guidelines apply universally, and improved animal health management can be used to reduce the need for antimicrobials including improvements in disease prevention strategies, housing, and husbandry practices as noted in sect . above. economic incentives in regulations were addressed in a recent article. in some european countries, capping total antimicrobial use per animal through regulations has been successful in reducing use by more than half while maintaining competitive livestock sectors. the second option was to impose user fees on veterinary antimicrobials, applied at the point of manufacture or wholesale purchases for imported products, which could also reduce use significantly. as a policy option, some combination of these two strategies would significantly reduce antimicrobial use in food animal production (van boeckel et al. ) . finally, as discussed in chap. , sweden does not allow use of antibiotics in broiler production. if there is the political will, strong regulations can provide strong economic incentives to control antibiotic use. to promote the understanding and implementation of the fda's new veterinary feed directive, the farm foundation and the pew charitable trusts sponsored a series of meetings with livestock and farming communities throughout the united states. twelve educational workshops provided livestock producers, feed suppliers, veterinarians, and support service organizations information and insights on the new policies. the workshops also provided opportunity for participants to interact with fda and usda's animal and plant health inspection service (aphis) personnel about implementation challenges. among livestock producers attending the workshops, small-and medium-sized operators, as well as many veterinarians, were unaware of the pending requirements. lack of understanding about responsibilities under the revised vfd rule means that producers and veterinarians need education. some land grant university extension services are now offering balanced education programs to inform these audiences about their obligations going forward, rather than having interested parties in the food animal industry be the primary source of information to producers and veterinarians about the requirements. while seeing positives of improved public perception and livestock management as result of the new rules, workshop participants were concerned about increased costs in animal health due to restrictions on access to antibiotics and lack of veterinary services. perhaps the biggest challenge is that many small producers do not have established relationships with veterinarians needed to establish a veterinarianclient-patient relationship (vcpr). this may be particularly challenging in remote rural and urban fringe areas where fewer veterinarians are available to treat foodproducing animals. in sum, workshop participants saw a need for education and outreach; continuing dialogue between industry representatives, consumers, and state or federal regulators; and the need to provide better access to veterinary services for food animals. there is widespread agreement that the scientific evidence indicates a global human health and environmental crisis due to antibiotic resistance, in part resulting from production practices in animal agriculture. government action in regulating the animal agriculture industry, to date, has done little to slow the advance of ar. most countries still need to pass legislation to establish appropriate conditions for the import, manufacture, distribution, and use of veterinary products, including antimicrobial agents. continued easy access to antimicrobial drugs for use on the farm is not acceptable. important stakeholders in the animal production industry include pharmaceutical companies, feed companies, livestock production integrators, and some farm groups, each with their own set of incentives and supporters. they must be engaged in the effort to reduce agriculture's role in contributing to development of ar, which cdc estimates at % (fig. . ) . even so, other major industry groups must be engaged to significantly reduce their % contribution to resistance development. in the united states, some progress was made with the passage of the animal drug availability act in and its very gradual implementation through various regulations over the past two decades. however, there are serious gaps in these regulations. given the gridlock that has prevailed in the us congress and the power of the pharmaceutical lobby at the national level, state actions are leading the way to responsive regulation in the public interest. for example, california is the first us state to prohibit all human antibiotic use in food animal production. in contrast to the halting actions of governments and industry, consumer and interest group actions are being at least partially successful in getting fast-food and retail establishments to not market animals fed human-use antibiotics for growthpromoting purposes. this suggests that a productive approach may be finding ways to provide information to and educate consumers about the risks of antibiotic resistance to enable them to make better informed decisions. there is an important role for educators to extend scientific information in a nontechnical way to the lay public. the drive to use antibiotics more responsibly and in the public interest may be facilitated by recent economic results that show that reducing antibiotic use in animal production need not come at a significant economic cost to producers or consumers. since the benefits of using antibiotics for livestock growth promotion appear to have resulted in increasingly smaller productivity gains, independent producers where input mix is a farmer-driven choice based on farm-level economics may be better off to substitute good management practices rather than using antibiotics for prophylactic disease prevention. however, much of meat animal production on us farms is produced under contract, where the integrator provides inputs, often including antibiotics, that the grower is required by contract to use. recent actions by integrators and meat processors to reduce antibiotic use and substitute alternative strategies to protect animals from diseases and maintain productivity are an important development, especially since production-purpose use of antibiotics is now prohibited. presuming that any new human-use antibiotic classes will probably not be made available for veterinary medicine, it is important to preserve the effectiveness of existing antibiotics. some policy makers and industry now recognize the urgency to identify new antibiotics. this will require increased antibiotic research funding and judicious use of existing antibiotics. the ban of human-use antibiotics in animals for production purposes is expected to help slow the growth of antimicrobial resistance, giving more time to discover new antibiotics for animal uses and for human health uses. to the extent they can be developed and used separately, the potential for animal antibiotic use leading to antimicrobial resistance for important human antibiotics will be mitigated. the ban on antibiotics used for humans also being used for animal production purposes will necessitate adopting improved cultural practices to reduce the poten-tial for disease and to increase feed efficiency. this calls for research on best management practices to accommodate today's supply chain requirements for food safety, production efficiency, and attribute verification. moreover, there is a need to educate producers-for example, through the usda-state cooperative extension service-about safe production practices for managing ar. this will allow producers to maintain efficiency in their operations and assure that they comply with current regulations to address the growing concern about antimicrobial resistance in the food supply chain. improved data collection and analysis to allow tracking of potential antimicrobial resistance development are essential to facilitate the food animal industry implementation of cultural practices to reduce the potential for contributing to antimicrobial resistance. it would also allow policy makers to better understand the need for any necessary interventions. these investments in the public good can be very cost-effective, though not without additional public investment or internal agency budget reallocation. increasing international trade may spread antibiotic resistance through imported food products as more trade agreements are approved. this scenario could be exacerbated to the extent fsis approves additional international facilities, local regulations, and inspections as "equivalent to the united states." in many developed and developing countries, antimicrobial agents are readily available. policies need to be implemented establishing appropriate conditions for use of veterinary products, including antimicrobial agents. future trade agreements will need to include provisions which address reduced use of medically important antibiotics in producing food animals. to date, there is no harmonized system of surveillance on the worldwide use and circulation of antimicrobial agents. that information is necessary to monitor and control the origin of medicines, obtain reliable data on imports, trace their circulation, and evaluate the quality of the products in circulation. the oie initiative to create a global database for monitoring the use of antimicrobial agents is an important step that can provide valuable information for private sector and public policy leaders worldwide. the serious implications of growing antibiotic resistance require a concerted effort across all stakeholders and society generally. increased attention to this issue is emerging in the medical community where overuse of existing drugs and inadequate sanitary precautions account for % of the resistance. lack of development of new antibiotics 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reducing antimicrobial use in food animals veterinary feed directive a rule by the food and drug administration on / / . illustrative examples of probable transfer of resistance determinants from food animals to humans: streptothricins, glycopeptides, and colistin weimer bc k genome project . veterinary medicine, uc davis antimicrobial resistance: global report on surveillance. summary. world health organization who guidelines on use of medically important antimicrobials in food-producing animals. geneva: world health organization ctx-m- producing salmonella enterica serotypes typhimurium and indiana are prevalent among food-producing animals in china diverse and abundant antibiotic resistance genes in chinese swine farms political economy of biofuel acknowledgments we deeply appreciated the conversations with and review comments from mary ahearn in developing and writing this chapter. any remaining errors, mistakes, or omissions are of course ours. w. j. armbruster and t. roberts key: cord- -awivedxp authors: diaz, james h. title: ticks, including tick paralysis date: - - journal: mandell, douglas, and bennett's principles and practice of infectious diseases doi: . /b - - - - . - sha: doc_id: cord_uid: awivedxp nan ticks are the most competent and versatile of all arthropod vectors of zoonotic infectious diseases for several reasons. first, ticks are not afflicted by most of the microorganisms that they may transmit or the paralytic salivary toxins that they may transfer during bloodfeeding. second, and unlike mosquitoes, ticks can transmit the broadest range of infectious microbes among all arthropods, including bacteria, viruses, and parasites. in addition, tick-transmitted coinfections appear to be increasing and complicate differential diagnosis and antimicrobial treatment. third, ticks can vertically transmit infectious microorganisms congenitally to their offspring of both genders (transovarian transmission) and then disseminate carrier state infections among all generational growth stages (trans-stadial transmission). tick-borne infectious diseases can also be transmitted to humans by blood transfusions and organ transplants, and babesiosis, a tick-borne infection caused by malaria-related parasites, can be transmitted congenitally. fourth, ticks have capitalized on many competitive advantages afforded them by evolving changes in climate and human lifestyle, including the following: wider geographic distributions and longer active breeding and blood-feeding seasons as a result of increases in global mean temperatures and humidity; greater abundance of wild animal reservoir hosts no longer effectively controlled, especially deer, rabbits, and rodents; greater residential construction in recently cleared woodlands adjacent to pastures and yards frequented by wildlife, domestic animals, and humans; and more vacation and leisure-time activities enjoyed by humans and their pets during prolonged tick host-questing and blood-feeding seasons from earlier springs through later falls and milder winters. in short, ticks of all ages and both genders may remain infectious for generations without having to reacquire infections from host reservoirs and environmental and behavioral changes now place humans and ticks together outdoors for longer periods for tick breeding, blood-feeding, and infectious disease transmission. with the exception of toothed hypostomes for blood-feeding and clawless palps, adult ticks resemble large mites with eight legs and diskshaped bodies. there are four stages in the tick life cycle-egg, six-legged larva, nymph, and adult. ticks are classified into three families: the ixodidae, or hard ticks; the argasidae, or soft ticks; and the nuttalliellidae, a much lesser known family, with characteristics of both hard and soft ticks. ixodid ticks have a hard dorsal plate or scutum, which is absent in the soft-bodied, argasid ticks. ixodid ticks also exhibit more sexual dimorphism than argasid ticks, with both genders looking alike. however, all blood-fed ticks, especially females, are capable of enormous expansion and engorged ixodid females are often confused with engorged argasid females. although ticks from all families may serve as disease vectors, the ixodid or hard ticks are responsible for most tick-borne diseases in the united states. ixodid ticks have mouth parts that are attached anteriorly and visible dorsally. they live in open exposed environments, such as woodlands, grasslands, meadows, and scrub brush areas. argasid ticks are leathery and have subterminally attached mouth parts that are not visible dorsally. argasid ticks prefer to live in more sheltered environments, including animal nests, caves, crevices, woodpiles, and uninhabited rural cabins. all ticks feed by cutting a small hole in the host's epidermis with their chelicerae and then inserting their hypostomes into the cut, with blood flow maintained by salivary anticoagulants. ticks are attracted to warm-blooded hosts by vibration and exhaled carbon dioxide. ixodid ticks actually "quest" for hosts by climbing onto vegetation with their forelegs outstretched; waiting to embrace passing hosts ( fig. - ). ticks spend relatively short periods of their lives mating and blood-feeding on hosts: soft ticks feed rapidly for hours and then drop off, whereas hard ticks blood-feed for days ( to ) before dropping off for egg laying. • ticks can transmit the broadest range of infectious microbes among all arthropods, including bacteria, viruses, and parasites. • gravid ticks may also transmit paralytic salivary toxins during blood-feeding. • ticks are among the most competent and versatile of all arthropod vectors of infectious diseases. • tick-transmitted lyme borreliosis or lyme disease is now the most common arthropodborne infectious disease in the united states and europe. • most tick-borne infectious diseases can also be transmitted to humans by blood transfusions and organ transplants, and babesiosis can be transmitted congenitally. • ticks of all ages and both genders may remain infectious for generations without having to reacquire infections from host reservoirs. • new tick-transmitted pathogenic species are constantly being described in the united states. • ticks can transmit several pathogens during one blood-feeding, resulting in coinfections that can complicate differential diagnosis and treatment. • the diagnosis of tick-transmitted infectious diseases is based on combinations of tick-bite history and characteristic lesions, such as erythema migrans and eschars, microscopic identification of pathogens in blood and tissue biopsy specimens, serologic and immunocytologic tests, and nucleic acid serotyping. • most tick-transmitted bacterial diseases remain sensitive to doxycycline, amoxicillin, and chloramphenicol. • the tick-transmitted viral diseases can be managed only supportively. • babesiosis is caused by a malaria-like parasite and must be treated with combinations of antimalarial agents and azithromycin or clindamycin. • combinations of immunization, prophylactic antibiotics, personal protective measures, landscape management, and wildlife management are all effective strategies for the prevention and control of tick-borne infectious diseases. • a single -mg dose of doxycycline administered within hours of a tick bite is more than % effective in preventing lyme disease. short view summary keywords anaplasmosis; argasid ticks; babesia; babesiosis; borrelia; borreliosis; ehrlichiosis; francisella; ixodid ticks; lyme disease; rickettsialpox; rocky mountain spotted fever; tick paralysis; tick-borne coltiviruses; tick-borne encephalitis viruses; tick-borne hemorrhagic fever viruses; tick-borne relapsing fever viruses; tick-borne rickettsioses; ticks; tularemia by the s and s, the causative agents of the ehrlichioses were stratified as newly emerging, rickettsia-like species, and later ( ) were completely reorganized into separate genera, ehrlichia and anaplasma. , in , kirkland and colleagues described a new erythema migrans-like rash illness in north carolina, a nonendemic region for lyme disease, transmitted by the lone star tick, amblyomma americanum (see fig. - ) . this new borreliosis would soon be named the southern tick-associated rash illness (stari) or masters' disease, but its causative agent, b. lonestari, a new borrelia species, would not be identified until (see fig. - ). , by , ticks were recognized as the most common vectors of all arthropod-borne infectious diseases in europe, five new spotted fevercausing rickettsiae were described, four new subspecies of the lyme disease-causing b. burgdorferi complex were identified, a new relapsing fever borrelia species was isolated, and anaplasmosis was exported to europe from the united states. in a seemingly unending era of new discoveries in tick-transmitted diseases, another new and unanticipated vector for rmsf, rhipicephalus sanguineus, the brown dog tick, was identified in the united states in ( fig. - ) . in , the first human cases of relapsing fever caused by ticktransmitted borrelia miyamotoi were reported from russia, and by , % to % of surveyed residents of new england states where lyme disease is endemic were seropositive for prior b. miyamotoi infection. in , a new pathogenic ehrlichia species in addition to endemic ehrlichia chaffeensis and ehrlichia ewingii was identified in four febrile patients in minnesota or wisconsin and presumed to be related to ehrlichia muris. because most tick-borne diseases are caused by obligate intracellular organisms, many of which infect erythrocytes, granulocytes, or vascular endothelial lining cells, many tick-borne infections may also be transmitted congenitally (e.g., babesiosis) and by blood product transfusions and organ transplants. blood product-transmitted infections have now been described for the tick-borne rickettsial diseases (including q fever), babesiosis, and ehrlichiosis. in , the centers for disease control and prevention (cdc) reported the first case in which transfusion transmission of anaplasma phagocytophilum, the tick-borne causative agent of anaplasmosis (formerly, human granulocytic ehrlichiosis [hge]) was confirmed microscopically and serologically by testing of both the recipient and donor. today, the seroprevalence of tick-borne diseases is increasing significantly among blood and organ donors in the united states, tick-borne infectious diseases have challenged researchers and physicians since dr. howard t. ricketts identified the wood tick, dermacentor andersoni, as the vector of rocky mountain spotted fever (rmsf) in and firmly established the insect vector theory of infectious disease transmission. the emergence and recognition of lyme disease in the early s in the united states, whose causative agent, the spirochete borrelia burgdorferi, was not identified until , sparked renewed interest in tick-borne diseases in the united states and europe ( fig. - ) . by the early s, lyme borreliosis had become the most common arthropod-borne infectious disease in the united states and europe. since the s, every decade now describes emerging or rediscovered tick-borne infectious disease and new vectors for previously described tick-borne diseases, such as rmsf. these latest discoveries have been spawned by new immunodiagnostic technologies, especially by nucleic acid identification technologies, particularly the polymerase chain reaction (pcr) assay. states and has been exported to europe, most cases of lb in europe and northern asia are caused by b. afzelii and b. garinii (see table - ) . collectively, the three borrelia species are often referred to as b. burgdorferi (sensu lato). ticks usually acquire borrelia infections as larvae or nymphs by blood-feeding on small reservoir hosts, most commonly birds and rodents, and may transmit lb to humans during blood-feeding, which may go unnoticed (see fig. - ) . borrelia organisms are further maintained in nature as infected adult ixodes ticks blood-feed on larger mammals, especially deer. unlike argasid or soft ticks, ixodes ticks prefer temperate ecotonal zones of canopied forests abutting cleared scrub or grasslands and transmit b. burgdorferi to humans during outdoor exposures in such habitats. because borrelia spirochetes must migrate from the tick's midgut to the salivary gland during blood-feeding, tick attachments for less than hours rarely result in lb in humans. after an incubation period of to weeks, the hallmark of spirochete transmission manifests as solitary erythema migrans, a maculopapular erythematous rash with a bull's eye pattern, at the site of tick attachment . erythema migrans also occurs in stari at the site of amblyomma americanum or lone star tick attachment and results from the subcutaneous centrifugal movement of the spirochetes from the bite sites to the central circulation and target organs (see fig. - ) . in a meta-analysis of longitudinal studies of lb in the united states and europe, tibbles and edlow have reported that many patients do not recall a tick bite ( % in the united states, % in europe), constitutional symptoms of low-grade fever (< ° c [ . ° f]) and headache are common but nausea and vomiting are rare, and a solitary erythema migrans lesion is the most common initial presentation of lb ( % in the united states, % in europe). although deaths from lb are rare, the greatest morbidity from target organ damage in lb occurs in patients with prolonged or untreated infections, with % to % developing cardiac manifestations, % to % developing neurologic manifestations, and % to % developing chronic arthritis. [ ] [ ] [ ] however, if lb is recognized and treated early in the erythema migrans stage, cure rates will exceed %, late manifestations of chronic arthritis will be avoided, and outcomes will be excellent (see table - ). combined tick-transmitted coinfections have been described in regional u.s. populations, and an unexplained increase in the virulence of tick-borne infectious diseases has been described in the united states (rmsf), europe, and north africa (mediterranean spotted fever) and australia (queensland tick typhus). several tick-borne infectious diseases have now been reclassified by the cdc as potential biologic terrorism agents, including the following: francisella tularensis (tularemia), a category a agent (highly likely microorganism to be weaponized); coxiella burnetii (q fever), a category b agent (less likely to be weaponized); and the tick-borne encephalitis and hemorrhagic fever viruses, category c agents (least likely to be weaponized). in the future, the tick-transmitted infectious diseases will increase in prevalence over wider distributions at higher altitudes in a warmer world. unexpected tick vectors of emerging infections caused by obligate intracellular microorganisms will continue to be discovered as people spend more leisure times outdoors in temperate climates in tickpreferred ecosystems. the borrelioses are a large group of tick-borne spirochetal diseases caused by several species of borrelia, with unique geographic distributions, tick vectors, and host animal reservoirs ( lyme borreliosis (lb) or lyme disease is now the most common tick-borne infectious disease in the northern hemisphere and the most common arthropod-borne infectious disease in the united states. , in the united states, lb is caused by borrelia burgdorferi (sensu stricto), first identified as a novel bacterial spirochete in , and transmitted to humans by ixodes spp. hard ticks in u.s. regional pockets, specifically the northeast and co-workers have now dispelled the former concept of chronic persisting b. burgdorferi infections and have demonstrated that repeat episodes of pathognomonic erythema migrans in appropriately treated lb patients were due to reinfections and not to recurrences. , the jarisch-herxheimer reaction (jhr), an inflammatory cytokinemediated reaction to dying spirochetes with a worsening of presenting symptoms, vasodilatation, and myocardial dysfunction, may occur during antibiotic treatment for lb but is more common after antibiotic therapy for tick-borne relapsing fevers. , there have been no reported deaths from jhr during antibiotic therapy for lb, and the very rare case fatalities from lb have been attributed to cardiac conduction abnormalities from myocarditis in untreated cases. first recognized in , stari manifests initially as erythema migrans, as in lb, but occurs in regions in which b. burgdorferi is not endemic and follows the prolonged attachment of blood-feeding lone star ticks, amblyomma americanum, more abundant in the southeastern and south central united states (see figs. - and - ). , patients who are bitten by lone star ticks may develop lb-like erythema migrans rashes and occasionally develop milder constitutional symptoms than in lb, including fever, headache, fatigue, and generalized myalgias. however, unlike lb, stari is not a reportable infectious disease and has no diagnostic serologic tests, such as enzyme-linked immunoassays (elisas), immunofluorescent assays (ifas), and western immunoblot assays. in addition, a microbiologic analysis of skin biopsy specimens obtained from the rashes of patients in missouri with clinical diagnoses of stari failed to detect b. lonestari, suggesting that stari could be caused by other pathogens. because some patients have recovered from stari without antibiotic treatment in lb-untreated patients, recurrent attacks of chronic arthritis were formerly referred to as chronic lb. , later, as all patients in whom lb was diagnosed were treated with antibiotics, synovitis persisting for months to years after initial treatment was renamed "antibioticrefractory arthritis. " antibiotic-refractory arthritis was attributed to a combination of retained spirochetal antigens and postinfectious autoimmune reactions. however, recent investigations by nadelman tbrf is defined clinically by the sudden onset of two or more episodes of high fever (> ° c [ . ° f]) spaced by afebrile periods of to days, with the first febrile episode lasting to days and the relapsing episodes lasting to days each. , , the first episode ends with a -to -minute "crisis" with tachycardia, hypertension, hyperpyrexia (as high as ° c [ . ° f]), and rigors, followed by diaphoresis and defervescence. , , all febrile episodes are accompanied by nausea, headache, neck stiffness, myalgia, and arthralgia. the relapsing febrile episodes result from the growth of new spirochete populations in the blood to replace those killed by macrophages and cytokines. most patients have splenomegaly, % will have hepatomegaly, and most will have elevated aminotransferase levels, unconjugated bilirubin, and prolonged prothrombin and partial thromboplastin times. , direct neurologic involvement is more common than in lb and may include cranial nerve neuritis (especially cranial nerves vii and viii), radiculopathy, and myelopathy. myocarditis is also more common than in lb; may be complicated by adult respiratory distress syndrome (ards), pulmonary edema, and cardiomegaly; and is often fatal. diagnostic and treatment strategies for tbrf are outlined in table the jhr is much more common, although rarely fatal, during treatment of tbrf than during treatment of lb and occurs in % to % of patients with tbrf. at present, no prophylactic strategies to reduce the severity of the jhr have proved beneficial or have been adequately tested in multiple clinical trials, including therapy with antipyretics, corticosteroids, or naloxone. treatment with penicillin instead of tetracycline has a slightly lower risk for causing jhr during antibiotic therapy for tbrf. the family rickettsiaceae contains two genera, the spotted fevercausing genus rickettsia and the typhus-causing genus orientia (see chapters and ). the rickettsiae may be further stratified clinically into the tick-borne spotted fever group and mouse mitetransmitted rickettsialpox caused by rickettsia akari (see chapter ). the rickettsiae are obligate intracellular, gram-negative bacteria that thrive in ixodid tick salivary glands and are transmitted during bloodfeeding. once injected into the host, rickettsiae are initially distributed regionally via lymphatics, with some species causing marked regional lymphadenopathy (e.g., rickettsia slovaca). within to days (mean, days), rickettsiae are disseminated hematogenously to vascular endothelial lining cells of target organs, including the central nervous system (cns), lungs, and myocardium. rickettsiae gain entry into host endothelial cells in a trojan horse-like manner by using their outer membrane proteins (ompa and ompb) to stimulate endocytosis. once within phagosomes, rickettsiae escape to enter the cytosol or nucleus for rapid replication by binary fission, safe from host immune attack. the tick-borne rickettsial diseases that cause spotted fevers (sfs) are compared in a descending order of clinical severity of infection by preferred tick vectors and wild animal reservoirs in table - the global epidemiology of the tick-borne sf-causing rickettsiae has dramatically evolved since the transmission cycle of rmsf was first described by ricketts in with the following: emerging new strains and diseases (r. slovaca-associated lymphadenopathy); greater understanding of the highly conserved genome of several related species (r. africae-r. parkeri and the r. conorii subspecies); wider geographic distribution and greater virulence of existing strains (r. rickettsii, r. conorii subspecies, r. australis); unanticipated new tick vectors for some sfs (rhipicephalus sanguineus for rmsf in the united states); cluster outbreaks of tick-borne rickettsioses in returning travelers (r. africae causing african tick-bite fever); and regional clusters and epidemic cycles of more severe sfs worldwide (rmsf in the united states, mediterranean sf [msf] in europe, and queensland tick typhus [qtt] in australia).* the reasons for such changes in rickettsial sf epidemiology are unclear and may include warming temperatures and increasing humidity, more frequent drought-rain cycles, residential development in preferred tick ecosystems, more competent tick vectors given competitive advantages by environmental and and there have been no long-term sequelae reported in stari cases, some have questioned whether antibiotic therapy is indicated in stari. because distinguishing stari from lb may be difficult, wormser and co-workers have recommended that the differential diagnosis rely on a combination of regional exposures, clinical presentations, serologic results, and potential for long-term sequelae based on their comparison of lb cases from new york and stari cases from missouri. the investigators noted that the timing of rash onset was shorter ( days) in stari compared with lb ( days) and that stari patients were less likely to be symptomatic than lb patients. in addition, the stari rash was more often circular with central clearing than the lb rash. most authorities recommend antibiotic therapy for stari with oral doxycycline or amoxicillin following the same regimen as for lb to cover any missed diagnoses of lb with potential for chronic arthritic and cardiac sequelae (see table - ). the tick-borne relapsing fevers (tbrfs) comprise a worldwide group of serious bacterial infections by borrelia spirochetes after brief, painless, and usually unnoticed bites by ornithodoros spp. argasid or soft ticks. these ticks prefer indoor living-in cabins, caves, and crevices-and quickly abandon warm-blooded rodent hosts for egg laying (see table - ). , unlike the ixodid ticks, ornithodoros ticks feed very briefly, usually for less than minutes, and at night. , adults can live for as long as to years and survive without blood meals for several years. transovarian transmission of the tbrf spirochetes occurs commonly among all species and, unlike lb-causing borrelia species, tbrf spirochetes are already present in the salivary glands at the onset of blood-feeding and do not need time to migrate from the gut to the mouth parts. the wild animal host reservoirs of tbrf are maintained in birds and several mammals, most commonly rodents. the bite of a tbrf-infected tick is painless, and the bite site is marked after a few days by a small red to violaceous papule with a central eschar. , one spirochete is sufficient to initiate tbrf, and the infection rate after a single bite by an infected tick is more than %. the incubation period to onset of the first febrile episode is to days. evolving to petechial rash in % to % of cases in to days. the pathognomonic rash starts distally on the wrists and ankles and then spreads centripetally up the limbs (see fig. - ). the pathophysiologic mechanisms of petechial rashes and target organ system damage (cns, lungs, heart) in the sf rickettsioses include vascular endothelial cell damage by microbial replication, vascular inflammation (vasculitis), and increased widespread vascular permeability, which may result in hypovolemic shock, oliguric prerenal failure from acute tubular necrosis, cerebral edema, and noncardiogenic pulmonary edema. distal, digital skin necrosis may occur in severe cases of rmsf and qtt from hypoperfusion. cardiac vasculitis may manifest as myocarditis with intraventricular conduction blocks. aside from petechial rash and thrombocytopenia, other hemorrhagic manifestations in rmsf and other sfs are rare. cns complications in rmsf and other severe sf infections may include ataxia, photophobia, transient deafness, focal neurologic deficits, meningismus, meningoencephalitis, seizures, and coma. pulmonary complications may include cough, alveolar infiltrates, interstitial pneumonitis, pleural effusions, pulmonary edema, and ards. , [ ] [ ] [ ] initially, msf caused by r. conorii was thought to be a more benign disease than rmsf. in , severe cases of msf with multiple eschars and multisystem disease similar to rmsf with cns, renal, and pulmonary complications were first reported and now appear to be increasing across europe. in a outbreak of msf in portugal, case-fatality rates (cfrs) of % were recorded and exceeded those of untreated rmsf of %. qtt, african tick bite fever (atbf), and r. slovacaassociated lymphadenopathy are generally milder diseases than rmsf and msf. however, severe cases of qtt with rmsf-like complications, including renal insufficiency and pulmonary infiltrates, were recently reported from australia. although atbf caused by r. africae, a similar tick-bite fever in north america caused by r. parkeri, and r. slovaca infections may all cause multiple necrotic eschars and painful regional lymphadenopathy, these sf infections are often spotless (≥ %) and follow typical rickettsial sf prodromes. , a history of tick bites, eschars, and painful regional lymphadenopathy helps to establish the correct diagnosis, especially in the absence of adequate diagnostic laboratory services. the precise laboratory diagnosis of tick-borne rickettsial sfs may be established by microbiologic isolation of the causative organisms from skin biopsy specimens or blood cultures, nonspecific immunofluorescent antibody tests that cross react with many sf antigens, other immunocytologic techniques to demonstrate intracellular rickettsiae, and pcr assay to identify and speciate rickettsial dna or rna. genetic changes, more frequent contact between ticks and humans outdoors, and international trade and travel distributing tick vectors and their preferred animal hosts quickly and widely. the tick-borne sf rickettsioses share many common features in clinical presentations, including incubation periods of approximately week, flulike prodromes of fever, headache, myalgia, nausea, vomiting, and abdominal pain (that may mimic acute appendicitis in rmsf), spotty rashes within to days of fever onset, and necrotic eschars at tick-bite sites (fig. - ). some sf rickettsial diseases may be "spotless, " including rmsf in % to % of cases, complicating early differential diagnosis. the tick-borne rickettsial infections that can cause spotty rashes include r. rickettsii (rmsf), r. conorii (msf), r. australis (qtt), and r. africae-r. parkeri (african-north american tick bite fever) in about % of cases (see fig. - ) . , the tick-borne rickettsial infections that are associated with one or more necrotic eschars at tick-bite sites include r. conorii, r. australis, r. africae-r. parkeri, r. japonica, r. slovaca, r. aeschlimannii, and r. honei. the sf rickettsioses may vary in severity from causing multisystem organ failure (rmsf, msf) to painful lymphadenopathy (r. africae-r. parkeri, r. slovaca) to mild to subclinical disease (r. aeschlimannii). , , after an average incubation period of week, rmsf starts with a flulike, febrile prodrome followed by a characteristic maculopapular tularemia, also known as rabbit fever or deer fly fever, was first described as a zoonosis in squirrels in tulare county, california, in . its causative agent, francisella tularensis, was later identified as a gram-negative coccobacillus by dr. edward francis during an investigation of deer fly fever in utah in . tularemia occurs in regional pockets worldwide, has a very large wild and domestic animal reservoir, and is seasonally transmitted to humans by ixodid tick and deer fly bites and by contact with infected animals, especially rabbits and muskrats. the primary tick vector of tularemia in the united states is the american dog tick, dermacentor variabilis ( fig. - ) . ticktransmitted tularemia is most commonly reported during the spring and summer (may to august) worldwide. tularemia transmitted through contact with an infected animal occurs more often during the fall through hunting and trapping seasons, especially among male hunters who field-clean infected animal carcasses. f. tularensis is an extremely stable microorganism in nature, surviving in soil, water, and animal carcasses for months to years. in addition to fecal or vomit contamination of tick bites and direct inoculation of intact skin or mucosal surfaces when crushing ticks or skinning animals, tularemia may be transmitted by ingesting raw or undercooked infected game or bush meats, drinking contaminated water, or inhaling aerosolized microorganisms. [ ] [ ] [ ] in , a cluster outbreak of primary pneumonic tularemia in patients (with one fatality) was reported from martha's vineyard, massachusetts. a case-control investigation of the outbreak implicated aerosolized exposure to f. tularensis during summertime brush cutting and lawn mowing as significant (odds ratio [or], . ; % confidence interval [ci], . to . ) risk factors for pneumonic tularemia. concerns about inhalation transmission and potential biologic weaponization of f. tularensis led to the reinstatement of tularemia as a nationally notifiable infectious disease in . , the cdc reported a total of cases of tularemia from states from to (period prevalence, cases/yr; range, to cases/yr), with most cases occurring in males during may to august in regional pockets, antibiotic treatment mainstays for the tick-borne rickettsial sfs remain the tetracyclines for most cases and chloramphenicol for severe multisystem disease and during pregnancy. although the quinolones, azithromycin, and clarithromycin may be as effective as tetracyclines and chloramphenicol for rapidly managing some sfs, they are not recommended for initial therapy at this time. although short, -to -day courses of doxycycline have been reported to be as successful as -day courses in some sf infections (e.g., msf), such treatment strategies have not been tested in randomized controlled trials in other sf infections and are also not recommended at this time. most authorities now recommend that tetracycline, chloramphenicol, or ciprofloxacin for tetracycline-allergic patients be continued for a minimum or days or until the patient has been afebrile for at least hours and is improving clinically. q fever q (query) fever was first described in australia in , and its causative organism, coxiella burnetii, was isolated shortly thereafter. c. burnetii is a gram-negative, intracellular, spore-forming bacterium that is the sole species of its genus. c. burnetii is genetically related to legionella pneumophila and, like l. pneumophila, c. burnetii is usually transmitted to humans by inhalation of contaminated aerosols. q fever is a zoonosis with worldwide distribution and extensive domestic animal (cattle, sheep, goats, cats, dogs), wild animal (birds, rabbits, reptiles), and arthropod (ticks) reservoirs. in most cases, humans are not infected by tick bites but by inhaling spores or bacteria in aerosols contaminated with infectious particles in dried animal feces, milk, or products of conception. , q fever may also be transmitted by ingestion of contaminated milk, by vertical transmission from mother to fetus, by contaminated blood product transfusion, and even percutaneously by crushing infected ticks near breaks in the skin barrier. c. burnetii is reactivated during pregnancy and multiplies extensively in the placenta, exposing abattoir workers, veterinarians, researchers (especially those working with parturient sheep), and domestic pet owners (especially of cats) to highly infectious aerosols during delivery. , recently, several cases of q fever were reported among u.s. military personnel deployed to iraq and afghanistan and in travelers returning from asia, latin america, and sub-saharan africa. , c. burnetii has long been considered a potential bioterrorism weapon for several reasons, including its environmental stability, spore-forming capability, ease of aerosolized dispersal, and high pathogenicity, with an ability to initiate infection with a single microorganism. after an average -week incubation period (range, to days), q fever may manifest as a wide variety of illnesses in humans, including the following: acute q fever, a self-limited febrile illness with severe headache, retro-orbital pain, and nonproductive cough; q fever pneumonia with consolidated opacities, pleural effusions, and hilar lymphadenopathy on chest radiographs; q fever granulomatous hepatitis, usually after ingestion of contaminated milk; cns q fever with protean manifestations ranging from aseptic meningoencephalitis and transient behavioral and sensory disturbances to cranial nerve palsies and hemifacial pain mimicking trigeminal neuralgia; and chronic q fever endocarditis, especially in predisposed patients with congenital valvulopathies, prosthetic heart valves, aortic aneurysms, or vascular grafts. , , patients who are immunocompromised by pregnancy, congenital immunodeficiency disorders, cancer, hiv infection/aids, organ transplant antirejection therapy, renal dialysis, or prolonged corticosteroid therapy are at greater risk for acquiring more severe and chronic q fever infections. because the isolation of c. burnetii requires biosafety level , most diagnostic laboratory strategies for q fever rely on microscopic detection on giemsa-stained smears of blood or sputum or tissue biopsies (liver, excised heart valves), on antibody detection by immunofluorescent assays, or on dna detection by pcr assay. , the prognosis is usually excellent in the acute q fever illnesses, and mortality is rare after appropriate antibiotic therapy with tetracyclines (doxycycline is preferred- mg po twice daily for days) or fluoroquinolones. chronic q fever endocarditis will require prolonged treatment with two antibiotics, either rifampin ( mg po twice daily) and genera that are tick-borne bacterial infections of many mammals, including humans, ehrlichia and anaplasma (fig. - ) . , like rickettsiae, the anaplasmataceae attach to molecular ligands on phagocytic cells to gain trojan horse-like entry into leukocytes and then trick intracellular phagosomes into releasing them into the cytosol for replication (see fig. - ) . , the tick-borne anaplasmataceae are now endemic in the united states and have preferred geographic distributions, tick vectors, and wild and domestic animal reservoirs (table - ). they spread from the infected tick's gut to its salivary gland, are inoculated over to hours into the host's dermis, and cause subclinical (especially in children) to severe and potentially fatal infections (especially in immunocompromised adults) within to weeks. because transovarian transmission in ticks has not been observed, the major reservoirs of the anaplasmataceae in nature are wild and domestic animals. , although the presenting clinical manifestations are similar among anaplasmataceae infections, the potential multisystem complications and resulting cfrs from these diseases are ultimately determined by the immunocompetence of human hosts (see table - ). the human anaplasmataceae are resistant to fluoroquinolones but remain susceptible to tetracyclines, which are now recommended for children and adults. because there are no vaccines for the tick-borne ehrlichioses and anaplasmosis, the best preventive measures are tick avoidance and control and rapid removal of blood-feeding ticks by hours or less. , including arkansas and missouri, eastern oklahoma and kansas, southern montana and south dakota, and martha's vineyard. there are two biovars of f. tularensis, with biovar a (f. tularensis biogroup tularensis) causing % to % of tularemia cases in north america and biovar b (f. tularensis biogroup palearctica) causing a milder disease throughout europe and asia. , , the presenting clinical manifestations of infection depend on the virulence of the biovars (a > b), route of entry of microorganisms, multisystem infections, and immunocompetence of infected hosts. the portal of entry of f. tularensis has historically been used to classify the clinical manifestations of tularemia, with untreated pneumonic tularemia having the highest cfrs of % to % (table - ) . [ ] [ ] [ ] , the differential diagnosis of ulceroglandular tularemia, the most common presentation, is extensive and includes other arthropod bites, bacterial and viral infections, and fungal diseases capable of causing skin ulcers with painful regional lymphadenopathy. diagnostic strategies for tularemia include the following: microscopic identification or culture in biosafety level facilities of microorganisms from blood, sputum, gastric lavage fluid, lung biopsy, or lymph node aspirates (sensitivity, % to %); acute and convalescent serology comparing antibody titers (sensitivity, > %); direct immunofluorescent antibody testing; and antigen detection by pcr assay (sensitivity, % to %). frequently accompanying laboratory abnormalities in tularemia include significant elevations in the erythrocyte sedimentation rate (esr), significant leukocytosis (> , /µl), often with normal differential counts, and thrombocytosis. the recommended treatment strategies for tularemia have evolved considerably from historical treatments with painful intramuscular injections of streptomycin to oral therapy with the aminoglycosides and fluoroquinolones, which are effective in % of cases and may result in resolution of ulcers within hours. most cases in adults, including pneumonic tularemia, may be managed with fluoroquinolones alone (ciprofloxacin, mg iv or mg po twice daily for to days, or levofloxacin, mg iv or po twice daily for to days), with aminoglycosides (gentamicin or amikacin, to mg/kg/day for to days) reserved for pediatric infections and widely disseminated systemic infections. relapse rates are highest with oral tetracyclines, including doxycycline, and chloramphenicol, which may still be indicated for cases with cns dissemination despite its potential for bone marrow toxicity. the human ehrlichioses and anaplasmosis (formerly known as human monocytic and human granulocytic ehrlichiosis, respectively) are classic examples of emerging tick-borne infectious diseases. since , four new tick-borne bacterial species have been identified and classified into a new family, anaplasmataceae. the four genera of anaplasmataceae comprise obligate, intracellular, gram-negative bacteria, closely related genetically to the family rickettsiaceae. the anaplasmataceae include two genera that are synergistic parasites of flatworms (neorickettsia sennetsu) and filarial worms (wolbachia spp.) and two cases, usually in elderly, immunocompromised, or splenectomized human hosts, massive hemoglobinuria may be associated with severe anemia, jaundice, acute renal failure, and increased cfrs. babesiosis is now reemerging as an arthropod-borne parasitic disease, as confirmed by increasing numbers of reported cases in the northeast united states and increasing seroprevalence rates there and in california. [ ] [ ] [ ] human babesiosis may be divided into two epidemiologic and clinical patterns based on the causative babesia species, their regional endemicity, and the immunocompetence of their human dead-end hosts (see table - ). the first pattern is caused by babesia divergens and related species or subspecies and occurs in immunocompromised, and often splenectomized, human hosts. it includes b. divergens babesiosis, first in eastern and now in western europe, a b. divergens-like babesiosis in the midwest caused by a babesia species designated mo- , and a babesiosis along the pacific coast caused by b. divergenslike species designated as wa- and as ca types (e.g., ca- , ca- ). [ ] [ ] [ ] [ ] [ ] babesiosis is a tick-borne, malaria-like zoonosis that usually causes subclinical infections with prolonged parasitemias in humans and can be transmitted vertically in utero and horizontally by blood product transfusion. [ ] [ ] [ ] [ ] [ ] babesiosis was initially described in cattle with red water (hemoglobinuric) fever in , when victor babes observed inclusions within bovine erythrocytes. theobald smith later identified the causative agent of bovine red water fever in as babesia bigemina, accurately described the parasite's life cycle, and demonstrated for the first time the arthropod-borne transmission of an infectious disease to a mammal. although more than species of babesia have now been identified as zoonoses in domestic and wild mammals, only a few species can cause babesiosis in humans, a disease characterized by fever, intravascular hemolysis, and hemoglobinuria (table - ). in severe for specific igm antibodies in acute infections and pcr-based assays to detect babesia dna and species-specific dna sequences. quinine ( mg orally three times daily) and clindamycin ( . g iv twice daily or mg orally three times daily), continued for week or until parasitemias are in remission, can be used to treat babesiosis caused by all species. quinine and clindamycin are preferred therapies for wa- babesiosis and for severe b. microti infections, especially the b. divergens-related species are maintained in tick vectors by transovarial and trans-stadial transmission of the parasites, and most infections are transmitted by diminutive and usually unidentified and unnoticed nymphal ticks. the human b. divergens-like cases occur primarily in cattle-ranching regions during the summer months, when tick vectors are most active and the incidence of bovine red water fever is greatest. these are the more severe cases of babesiosis, with hemolytic anemia, hemoglobinuria, and renal failure, usually in splenectomized persons. the second and more common pattern of babesiosis in the united states occurs in regional pockets on the northeast coast (new york, massachusetts, rhode island, connecticut, new jersey, and offshore islands [block island, long island, nantucket]) and upper midwest (minnesota, wisconsin) and is caused by babesia microti, a rodent babesia species transmitted to humans by the same ixodid ticks (blacklegged deer ticks) that transmit lyme disease (see fig. - ) . thus, b. microti babesiosis in the united states parallels the distribution of lyme disease and its tick vectors, occurs in clusters in the same regional pockets as lyme disease, and may coexist with lyme disease in an increasing number of cases. , , , b. microti-induced babesiosis occurs during the warmest months, with % of cases reported between may and august, when deer ticks are most active. humans are usually infected by unnoticed bites by nymphal deer ticks from rodent reservoirs in mice, especially the white-footed mouse (peromyscus leucopus), rather than deer. diagnostic strategies for babesiosis include the demonstration of characteristic intraerythrocytic and extraerythrocytic organisms on giemsa-stained thin smears and subinoculation of human blood samples into hamsters for suspected b. microti infections or into gerbils for suspected b. divergens-related infections (fig. - ) . , , the serologic methods, especially useful when microscopic methods fail in low parasitemias, include indirect immunofluorescent antibody testing in older adults and splenectomized or immunosuppressed individuals. , for non-life-threatening b. microti infections, a -week course of oral atovaquone ( mg twice daily) and azithromycin ( mg on day , followed by to mg/day for week) cleared parasitemias as effectively as quinine and clindamycin, with fewer side effects. for coinfections with b. burgdorferi, patients should be treated specifically for lyme disease with doxycycline ( mg orally twice daily for weeks) and with antimalarial agents for babesiosis. , , the tick-borne viral infections are caused primarily by flaviviruses and may be divided into two separate clinical presentations, each with preferred tick vectors and wild animal reservoirs-the viral encephalitides and viral hemorrhagic fevers (table - ) . the tick-borne viral infections share several common clinical and epidemiologic characteristics, including the following: incubation periods of approximately week; biphasic illnesses separated by symptom-free periods beginning with flulike viremic stages and ending with cns or hemorrhagic manifestations with increased cfrs; nonspecific serodiagnosis by comparing acute and convalescent sera for increased antibody titers or by hemagglutination inhibition; specific serodiagnosis by enzymelinked immunosorbent assay (elisa) and antigen detection from blood or cerebrospinal fluid (csf) by reverse-transcriptase (rt)-pcr; no specific treatments other than supportive therapy; and significantly increased postinfection morbidity. from a global distribution perspective, the tick-borne encephalitis viruses (tbevs) are separated into the old world (eastern hemisphere) and new world (western hemisphere) strains, with the old world strains having significantly higher cfrs ( % to %) and permanent neurologic morbidity rates ( % to %) than the new world strains (cfr, % to %; morbidity rate < %). although additional old world flaviviral strains have now been discovered in sheep reservoirs, the most common old world tbevs have been further stratified regionally into three major subtypes-european or central european (tbev-eu), siberian or russian spring-summer (tbev-sib), and far eastern (tbev-fe; see table - ) . except for the old world tbevs with sheep reservoirs, all the tbevs are transmitted by the injection of infected saliva from viremic ixodid ticks. during blood-feeding, viruses in tick saliva increase up to -fold and render early removal of the feeding tick ineffective in preventing disease. the preferred wild animal reservoirs for tbevs include rodents, insectivores, medium-sized mammals, deer and other ungulates, birds, and, less often, domestic animals (see table - ) . powassan encephalitis, first isolated in , typifies a new world tbev with a confined regional distribution in the new england states and eastern canada, several ixodid tick vectors, primarily ixodes spp., an extensive wild animal reservoir in rodents and medium-sized mammals, especially woodchucks and skunks, and a seasonal occurrence. cases occur from may to december and peak during june to september, when ticks are most active. patients with powassan encephalitis present with somnolence, headache, confusion, high fever, weakness, ataxia, and csf lymphocytosis. transient improvement may be followed by neurologic deterioration, evidence of ischemia or demyelination on magnetic resonance imaging, and slow recovery, often with permanent deficits including memory loss, weakness, ophthalmoplegia, and lower extremity paraparesis. unlike the old world tbevs, powassan encephalitis is uncommon, with only confirmed cases reported by the cdc from to . because there is no vaccine or specific therapy for powassan encephalitis, the best means of prevention is protection from tick bites. since , powassan encephalitis cases historically confined to the northeastern united states and canada have been increasingly confirmed farther westward in minnesota and wisconsin, with fatal cases reported in the elderly. the old world tbevs remain common causes of permanent neurologic morbidity from scandinavia to eastern japan, with more than , cases reported per year, a third of which result in permanent neurologic deficits. in addition to tick bites, the old world tbevs may occasionally be transmitted by ingestion of unpasteurized milk products from viremic livestock (especially goats), breast-feeding, and slaughter of viremic animals. old world tbev is typically biphasic in over % of cases, with an initial febrile flulike presentation followed by a -week (range, to days) symptom-free interval. this honeymoon or recovery period is followed by meningoencephalitis with csf pleocytosis, with or without myelitis, and a poliomyelitis-like flaccid paralysis that targets the arms, neck, and shoulders. magnetic resonance imaging and electroencephalographic abnormalities are common but nonspecific. other acute neurologic complications may diagnoses for the tick-borne coltiviruses are other tick-borne febrile diseases, most commonly rmsf in north america, which may be distinguished from ctfv and srv infections by its characteristic rash and leukocytosis. serologic diagnostic methods to detect anticoltivirus antibodies include complement fixation, seroneutralization assay, immunofluorescence assay, elisa, and western immunoblot. the most specific and confirmatory laboratory diagnostic methods include rt-pcr assays to identify ctfv-rna (or the rna of its crossreacting serotypes, ctfv-ca and srv) or the isolation of coltiviruses after intracerebral inoculation of infected human blood into suckling mice. treatment of all tick-borne coltivirus infections is entirely supportive, and long-term complications are rare in uncomplicated cases. first described in in australia, canada, and the united states, tick paralysis is a rare, regional, and seasonal cause of acute ataxia and ascending paralysis with an incubation period of to days after female tick attachment, mating, and blood-feeding. [ ] [ ] [ ] [ ] although species of ticks have been implicated in tick paralysis cases worldwide, most cases occur in the united states and canadian pacific northwest (washington state and british columbia) and in australia. in the u.s. pacific northwest, tick paralysis is caused by the american dog tick, d. variabilis, or the rocky mountain wood tick, dermacentor andersoni, during april through june, when dermacentor ticks emerge from hibernation to mate and to seek blood meals (see fig. - ) . [ ] [ ] [ ] [ ] [ ] [ ] the mechanism of neurotoxic paralysis in dermacentor tick paralysis is unknown, but neuroelectrophysiologic studies have suggested that sodium flux across axonal membranes is blocked at the nodes of ranvier, leaving neuromuscular transmission unimpeded. in australia, the marsupial ixodid tick, ixodes holocyclus, can cause a more severe form of ascending neuromuscular paralysis by producing a botulinum-like neurotoxin that blocks neuromuscular transmission by inhibiting the presynaptic release of acetylcholine. most cases of tick paralysis in north america have occurred sporadically in young girls with long hair concealing ticks feeding on the scalp or neck. however, a four-patient cluster of dermacentor tick paralysis, including a -year-old girl with a tick on her hairline, and three adults with ticks on the neck (n = ) and back (n = ), was reported from colorado in . although botulism causes a descending neuromuscular paralysis with a preserved sensorium, tick paralysis, guillain-barré syndrome, acute poliomyelitis, and spinal cord tumors may all cause acute ascending paralysis with preserved mental status and must be differentiated from each other (table - ) . [ ] [ ] [ ] because poliomyelitis has been nearly eradicated by vaccination worldwide, tick paralysis is frequently misdiagnosed as guillain-barré syndrome, and the correct diagnosis is made accidentally by finding an engorged, usually female, tick on the scalp, head, or neck during hair combing or when applying electroencephalographic electrodes (see table - ) . before , postmortem examinations of persons who died suddenly of unexplained paralytic illnesses demonstrated attached ticks on their heads and necks. in a review of canadian tick paralysis cases in the s before the widespread availability of mechanical ventilation in intensive care units, rose reported a cfr of % to % without tick removal. in a review of tick paralysis cases in washington state over the period to , dworkin and co-workers reported a cfr of up to %, with most deaths occurring in the s. in a -year meta-analysis of confirmed tick paralysis cases in the united states, diaz reported a cfr of % in the first years, a seasonal pattern of case clusters in children and adults in urban and rural locations, and a significant increase in initial misdiagnoses of tick paralysis as guillain-barré syndrome in more recently reported cases. in addition, the misdiagnoses of tick paralysis cases as guillain-barré syndrome often directed unnecessary therapies, such as central venous plasmapheresis with immunoglobulin g, and delayed correct diagnosis and treatment by tick removal. in all cases, the diagnosis of tick paralysis was later established when attached ticks were either discovered by caregivers or by cranial neuroimaging studies. the cfr from tick paralysis has steadily declined over the past years, with almost all deaths in canada and the united states reported in the s and s. [ ] [ ] [ ] include altered consciousness, seizure activity, cranial nerve palsies, and an often fatal bulbar syndrome with cardiorespiratory failure. because no specific treatments other than supportive therapy exist, tick avoidance and immunization remain the best preventive measures. effective vaccines have now been developed for the three subtypes of old world tbevs, and some have been shown to even provide crossprotection among the subtypes in experimentally infected animals. the tick-borne hemorrhagic fever (tbhf) viruses are maintained in nature in extensive wild and domestic animal reservoirs and are transmitted by infected ixodid tick bites, squashing infected ticks, creating infective aerosols, direct contact with blood or tissues from infected animals or humans, or nosocomial spread among medical personnel. tbhfs may be caused by flaviviruses and bunyaviruses, which are distributed throughout eastern europe, africa, and asia. they are characterized clinically by biphasic illnesses that present as febrile flulike symptoms and end as hepatomegaly and hemorrhagic manifestations (petechiae, purpura, subconjunctival and pharyngeal hemorrhage, thrombocytopenia, cerebral hemorrhage, disseminated intravascular coagulation) separated by a few afebrile days. cfrs range from % to over %, with most deaths occurring within to days of symptom onset during hemorrhagic stages. diagnoses may be confirmed by immunologic techniques, such as antibody increases in paired sera and elisa, and by molecular techniques, such as rt-pcr. although ribavirin can inhibit crimean-congo hemorrhagic fever (cchf) virus replication in animal models, it has not been tested in clinical trials in humans with cchf. nevertheless, if tbhf is suspected in the tropics and laboratory confirmation is unavailable, intravenously administered ribavirin ( mg/kg initially, followed by mg/kg four times daily for days, and then mg/kg three times daily for days) is recommended for severe cases, and oral ribavirin is recommended for high-risk contacts. all patients with tbhfs should be placed in isolation, and strict universal precautions should be practiced by all medical personnel. a mouse brain-derived cchf vaccine has been developed in bulgaria but is not available elsewhere. in the absence of a universal vaccine, the best preventive measures for the tbhfs are tick avoidance and control, rapid burial of dead animals, and personal protective equipment for abattoir workers and medical personnel. the tick-borne coltiviruses of the family reoviridae are all doublestranded rna viruses of the genus coltivirus and include colorado tick fever virus (ctfv), which is endemic in the united states and canadian rocky mountain regions; the california tick fever virus (tfv) of rabbits (ctfv-ca); the salmon river virus (srv) of idaho, a serotype of the ctfvs; and the european eyach virus (eyav). the ixodid or hard ticks are the only vectors of the coltiviruses, with dermacentor ticks (mainly d. andersoni) being the principal vectors of ctfv and srv in the rocky mountains and ixodes ticks (i. ricinus, i. ventalloi) being the only vectors of eyav throughout europe. among the coltiviruses, ctfv has the widest host range, which includes squirrels, other rodents, rabbits, porcupines, marmots, deer, elk, sheep, and coyotes. the remaining coltiviruses have fewer, more specific wild animal hosts, including the black-tailed jackrabbit (lepus californicus) for ctfv-ca and primarily the european rabbit (oryctolagus cunniculus) but also rodents, deer, domestic goats, and sheep for eyav. the coltiviruses are maintained in nature by ixodid ticks that blood-feed on wild animal hosts with prolonged viremias and then transmit coltiviruses trans-stadially but not transovarially. infected nymphs hibernate over winter, and previously infected nymphs and newly infected adults then transmit coltiviruses to human dead-end hosts during spring-summer blood-feeding. ctfv has also been transmitted by blood transfusion and congenitally. both ctfv and srv can cause biphasic to triphasic febrile illnesses that mimic mild cases of rmsf without rash. leukopenia and thrombocytopenia are common laboratory manifestations of coltivirus infections. complications are rare but may include meningoencephalitis, orchitis, hemorrhagic fever, pericarditis, and myocarditis. eyav infections are more often complicated by cns manifestations than american strain coltivirus infections. the most common differential performing regular tick checks. wearing long pants tucked into socks, long-sleeved shirts, and light-colored clothing can help keep ticks off the skin and make them easier to spot on clothing. impregnating clothing with permethrin, routinely performed by the military on maneuvers, is a highly effective repellent against ticks and other insects. the topical application of insect repellents containing % to % formulations of n,n-diethyl-meta-toluamide (deet) directly on the skin is another effective and recommended measure. most patients with lyme disease, tbrf, babesiosis, ehrlichioses, and anaplasmosis will not recall tick bites because these diseases are often transmitted by diminutive nymphal ticks. nevertheless, tick localization and removal as soon as possible, preferably within hours, remain recommended strategies to prevent the rickettsial and viral ixodid tick-borne diseases and to reverse tick paralysis. ticks should always be removed with forceps (or tweezers), not fingers (because squashing ticks can transmit several tick-borne diseases across dermal barriers or create infectious aerosols), and in contiguity with their feeding mouth parts, rather than burning ticks with spent matches or painting embedded ticks with adhesives or nail polishes. landscape management strategies to prevent tick-borne diseases include widespread application of acaricides over tick-preferred ecosystems, removal of vegetation and leaf litter near homes and recreation sites, and creation of dry barriers of gravel, stone, or wood chips between forested areas and yards or playgrounds. wildlife management strategies to prevent tick-borne diseases include encouraging the development of better veterinary vaccines for tick-borne diseases with large domestic animal reservoirs, applying acaricides actively to domestic animals and passively to deer and cattle at baited feeding and watering stations or salt licks, and setting out acaricide-baited rodent houses for rodents to occupy or acaricide-baited cotton balls for rodents to adopt as nesting materials, especially in crawl spaces under homes and near playgrounds. most emerging infectious diseases today, such as west nile virus and severe acute respiratory syndrome, arise from zoonotic reservoirs, and many are transmitted by arthropod vectors. because ticks are the most common insect vectors of zoonotic diseases, ticks have become common arthropod vectors of emerging zoonotic diseases, including lyme disease, ehrlichiosis, and anaplasmosis. ticks are highly competent and versatile vectors of infectious diseases because ticks of all ages and both genders may remain infectious for generations, without having to reacquire infections from host reservoirs. recent environmental changes and human behaviors now place the treatment of dermacentor tick paralysis simply requires removing the tick with forceps (or tweezers) to restore neuromuscular function within hours. although i. holocyclus tick paralysis is also treated by tick removal, transient neuromuscular deterioration may occur for - hours after tick removal. the administration of i. holocyclus antitoxin before tick removal and prolonged observation for hypoventilation have been recommended. there are a number of strategies that can be used in the prevention and control of tick-borne infectious diseases, including immunization, personal protective measures, landscape management, and wildlife management. in the s, a lyme disease vaccine was developed for the united states, but it was withdrawn from the market in because of poor sales. immunization strategies to prevent tick-borne infectious diseases have proved far more effective in europe and asia than in the united states, where neurologic complications from tbevs are second only to japanese encephalitis as causes of permanent paraparesis. current immunization programs for tick-borne viral diseases now provide primary prevention of tbev-eu in europe, tbev-sib in russia and the middle east, tbev-fe in china and the far east, and cchf in bulgaria. a canine antitoxin for i. holocyclus-induced tick paralysis has been used to reverse tick paralysis in animals and humans in australia. in addition to immunization, antibiotic therapy after presumed ixodid tick bites with erythema migrans has been recommended as a prophylactic therapeutic strategy for the primary prevention of some tick-borne infections. a randomized clinical trial found that a single -mg dose of doxycycline administered within hours of a tick bite was % effective in preventing lyme disease. finally, because most tick-borne infectious diseases may also be transmitted by blood product transfusions, screening blood product donors in high seroprevalence areas for lyme disease and other borrelioses, babesiosis, ehrlichioses, and anaplasmosis would eliminate transfusion-transmitted cases. physicians are encouraged to order leukocyte-reduced blood components for blood product transfusions to potentially reduce the risks for ehrlichiosis and anaplasmosis, especially in regions that are highly endemic for leukocytotropic tick-borne infectious diseases. personal protective measures to prevent tick-transmitted diseases include wearing appropriate clothing, using insect repellents, and -transmitted microorganisms reassort their nucleic acids with their hosts and develop antimicrobial resistance (especially to tetracyclines) or superpathogen capabilities, either by nature's own design or human terrorist intent humans and ticks together outdoors for longer periods in welcoming ecosystems for breeding, blood-feeding, and infectious disease transmission. better prevention and treatment strategies for tick-borne diseases are indicated, before the highly conserved genomes of key references the complete reference list is available online at expert consult. . dumler js, walker dh. rocky mountain spotted feverchanging ecology and persisting vigilance rocky mountain spotted fever from an unexpected tick vector in arizona human borrelia miyamotoi infection in the united states emergence of a new pathogenic ehrlichia species, wisconsin and minnesota southern tick-associated rash illness: erythema migrans is not always lyme disease does this patient have erythema migrans? a critical appraisal of "chronic lyme disease reinfection versus relapse in lyme disease failure to isolate borrelia burgdorferi after antibiotic therapy in culture-documented lyme borreliosis associated with erythema 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a six-year-old girl with tick paralysis tick paralysis: electrophysiologic studies a review of tick paralysis tick paralysis: human cases in washington state a -year meta-analysis of tick paralysis in the united states: a predictable, preventable, and often misdiagnosed poisoning clinical and neurophysiological features of tick paralysis prophylaxis with single dose doxycycline for the prevention of lyme disease after an ixodes scapularis tick bite key: cord- -zjr csla authors: hillman, john r.; baydoun, elias title: food security in an insecure future date: - - journal: water, energy & food sustainability in the middle east doi: . / - - - - _ sha: doc_id: cord_uid: zjr csla food security in the middle east is directly affected by a challenging combination of ongoing destructive conflicts, a global economic downturn, widespread poverty, high population growth, corruption, intolerance, and the potentially damaging consequences of climate change. many arab countries demonstrate nearly all the features of those countries classified as poor, less developed, or failing to achieve the eight millennium goals. even the economies of the richer oil-exporting countries in the region have been seriously damaged by the downturn in oil and gas prices as new sources come on stream elsewhere and demand falls as a result of renewable sources of energy becoming available. in a previous article , we considered definitions of food security in the modern era of rising global populations, discussing how food security might be attained in terms of security of water and fossil-fuel-derived energy supplies, climate change, rapid urbanisation, changing dietary trends, and modification of the natural environment leading to depleted natural resources, increasing environmental pollution, and the need to introduce modern technologies. the concepts of sustainable agriculture and uncertainty were also addressed, notably in respect of fresh thinking about key components of agricultural systems. these included (babu and blom ) vertical and horizontal integration of farming-related businesses to allow adequate capitalisation for enhanced efficiency measures; (bardshaw and brook ) policy shifts to remove market-distorting subsidies, tariffs, import and export bans, and excessive bureaucracy; improved crop and livestock breeding, including entirely new species; (bolukbasi et al. ) automation in agriculture and horticulture; (breisinger et al. ) protected cropping; (cong et al. ) new-generation agrochemicals; (elasha ) new agronomic practices; (fan et al. ) novel foodstuffs; (fao ) habitat reconstruction and land renovation; (fao ) biofuels and biodiesel; (garland et al. ) periurban and urban agriculture; (grebner et al. ) industrial biotechnology; (grivetti and ogle ) farming the seas and oceans; long-term carbon storage; and (hillman and baydoun ) new ways of thinking about carbon trading. more recently, we reviewed mitigation and adaptation processes and strategies to address the impacts of climate change on food, water, and energy security in the arab middle east (hillman and baydoun ) . here, we consider potential adaptations to an insecure global future generally, and to the concerns in the arab middle east specifically, in the light of the economic realities of wide disparities in wealth, competition for resources, and widespread poverty in many parts of the globe, coupled to a relatively high population growth, on-going conflicts, attempted cultural genocides, potential conflicts, endemic corruption and nepotism, and epidemics of infectious diseases. most arab countries are classified as poor, less developed, or failing to achieve the eight millennium goals of the united nations, and these arab countries share several undesirable features (table ) . even the much richer oil-exporting arab nations are under pressure. after a decade of relatively high oil prices, these nations have accumulated more $ . trillion in sovereign assets reinforced by substantial infrastructural investments supplemented by high levels of spending on imported military hardware. now, however, oil prices are under pressure as global oil and gas prices slumped in and remain depressed, possibly for the medium to long term as new sources of oil and gas come from hydraulic fracturing (fracking) and from iranian exports as the economic blockade on iran is being relaxed, coupled to greater energy efficiency in industry and new sources of renewable energy. this price depression has exposed the degree to which the economies of these arab oil exporters are dependent on oil and their failure in most instances to diversify their economies as their populations continue to expand alongside public expectations of continuing governmental largesse. nearly all of the immediate adaptations arab countries must undertake in order to adjust to a raft of severe insecurity issues require strategic planning and value-for-money infrastructural and civil-society improvements, and any preparatory changes in rural and urban areas will differ in scale and design. longer-term adaptations will be reliant on more stable conditions and a stepwise improvement of educational standards and attitudes. at the time of writing, no arab country is deemed to have acceptable levels of budget transparency according to the latest open budget index released by the international budget partnership (see www.internationalbudget.org). the future is especially insecure because of the persistence in the region of a combination of incompatible political and economic ideologies, religious and ethnic groupings overtly intolerant of others, introvert nationalism and disrespect of others, disconnection from democratic principles, profound cultural divides, ignorance -some wanton, inability to adapt to modernity, and malevolent community and national leaders. from a noble history of toleration, hospitality, and learning, arab society is fragmenting, defiled by the actions of relatively few. arabs are killing arabs either directly or indirectly; arabs are inflicting as-yetuntold horrific crimes on other arabs either directly or indirectly. attacks on arab countries by their neighbours might be used as an excuse to divert attention from their own failing donor-dependent economies or social structures, or most often to steal resources and ensure that the neighbouring country is suppressed from developing normally. at the global level, many would say that future conflicts and insecurity in much of the world are inevitable, simply because of the impacts of expanding global populations and the obvious competition for limited resources. the intensity of this competition must be analysed in context of the alarming table fourteen features of countries classified as poor, less developed, or failing to achieve the eight united nations millennium goals. the listed features are closely interrelated . poverty common in both the urban and especially the rural poor, poverty is sometimes concentrated in regions, often in marginalised ethnic or religious groups, and may relate primarily to girls and women. many of the urban poor operate in the unofficial economy. the rural poor tend to be land-constrained, dependent on rain-fed, low-yield subsistence agriculture with little or no access to modern technology (modern cultivars and livestock breeds, fertilisers, pesticides, automation, agronomy advice, veterinary support), and usually do not own their land. the rural poor encounter barriers to trade (e.g. transport, storage) and are unable to meet quality assurance standards. with no or limited access to social benefits (primarily pensions, child support, education, training, and healthcare), the poor may be hungry, thirsty, suffer ill health and low standards of accommodation, and die early. the poor are susceptible to exploitation. . hunger and thirst access to food and potable water may involve substantial travel on foot, and the basic requirements may only be met wholly or in part by humanitarian assistance. food quality and safety are usually low, and cooking is often dependent on wood for fuel. symptoms of malnutrition are prevalent. . disease slum dwellings, insanitary conditions, poverty, and hunger lead to a vulnerability to pandemics, made worse by poor or no public health provision. high maternal and child mortality and low general life expectancy characterise poverty and there is a reliance on traditional and/or herbal medicine. crops and livestock are subject to catastrophic attacks by pests and diseases. . poor environmental management poor countries suffer a depletion of their natural resources, including freshwater supplies and native flora and fauna. mineral and fossil-fuel resources are extracted to be exploited by industries in other more-developed countries. land, water, and the atmosphere may be polluted with few or no remediation efforts. national, regional, and international environmental regulations are not properly implemented. agricultural soils tend to be subject to erosion, salination, solarisation, desertification, and nutrient depletion. even without climate-change predictions, the general anthropogenic environmental degradation currently taking place increases the vulnerability to flooding, sand storms, ill health, and displacement of peoples. most poor countries are enduring adverse climate trends, and climate-change predictions point to even harsher conditions (erratic rainfall with rising temperatures, heat waves, hot extremes, and storms; rising sea levels and acidification of seas and oceans; increased desertification with effects on agriculture as well as the natural flora and fauna; socio-economic and health implications). . poor infrastructure quantity and quality of the built infrastructure tends to be low, or even absent (e.g. roads, ports, airports, telecommunications and access to the internet, hospitals and clinics, reliable power and fuel supplies, potable water sources, sanitation systems and sewage disposal, protected natural environments, cold and pest-free storage of agricultural and horticultural produce). the cost of living is worsened by relatively high overland transport costs. facilities may be inadequate to meet demand and maintenance neglected. rapid urbanisation and conflicts exacerbate infrastructural deficiencies. . corruption political autocracy coupled to a lack of transparency in government and public services, a weak judiciary, lack of consultation on major issues, and suppressed media enable a climate of corruption and nepotism to permeate all areas of society, including schools, colleges, and universities. a low regard for human rights, democratic processes, health and safety measures, and international law, is made worse by an overburdensome bureaucracy (staffed by poorly paid civil servants and police) dependent on bribery to function. corruption allows laws to be broken with impunity, and protests ignored. in most areas of society, a lack of altruistic leadership and (continued) poor countries manufacture few value-added products, offer little or no advanced training, and lack participation in the global knowledge economy. there is little or no foreign direct investment and free trade is constrained. financial assistance from donor countries is increasingly being audited to ensure compliance with attempts to prevent unauthorised expenditure. many poor countries have not managed to have constructive relationships with potential donor countries, and some try to align themselves with one of the main international political power blocs. unrelieved debt burdens have led to high interest rates on loans and difficulty of obtaining credit. private savings are minimal and the country may be subject to periodic flights of capital. their economies are grossly imbalanced with little spent on healthcare, education, and other social benefits compared with defence and vanity projects. the economy may be damaged by previous and/or ongoing conflicts, and may in any case have limited absorptive capacity properly to manage additional resource inflows and outflows. agriculture, unofficial transactions, and remittances from those working abroad contribute disproportionately to the real economy. . poor education limited or no access to free schooling accounts for a general low level of literacy and numeracy, especially of females. this is reflected in the absence of high-grade internationally competitive universities, colleges, and research institutes, despite a high level of parental financial sacrifice to secure a supposedly good education for their children. science and technology tend to be poorly taught and there is undue influence of religions with regressive attitudes to modernity. a lack of investment in research and development (r&d) and a lack of a critical mass of scientists, engineers, and technologists impede industrial development, and prevent those that remain from joining international consortia, participate in learned societies, access essential literature and training programmes, and have the opportunity to use state-of-the-art instrumentation, software, and laboratory consumables. the best educated and the most talented and entrepreneurial usually emigrate, leading to a brain drain. intellectual property rights are often ignored and little benefit is derived from traditional knowledge and its products tend to be exploited in other countries. crucial demands and needs of less-developed countries are rarely the targets of major international r&d projects. . gender inequality low educational attainment in most girls and women is reflected in female political, economic, and social representation and participation failing to match their proportion of the general population. cultural and religious influences often lead to females being regarded as inferior to males. family planning is limited, and in the absence of social security and reasonable incomes, large families are the norm. . high population growth this is a feature of the poorest social groups, and correlates with low life expectancy and gender inequality. in some countries high population growth may exceed the economic capacity of the country to feed itself, leading to a propensity to generate refugees, displaced persons, and terrorists. . vulnerability to transnational terrorism terrorism often relates to a combination of one or more of the following: poverty, hunger, poor educational attainment, disconnection from democratic principles, susceptibility to indoctrination by intolerant religious ideologies, criminal activities, and psychiatric disorders. poor countries are usually unable to defend themselves from terrorists, and groups of terrorists may receive covert support from other countries and agencies. poor countries may form the battlefield for fighting between different groups of terrorists. recovery from terrorism and conflicts in general may take several generations, and lead to psychological and physiological after-effects in the survivors and their progeny. projected changes and options for adaptation as well as mitigation (curbing emissions) detailed in the latest fifth assessment report of the international panel on climate change (ipcc, www.ipcc.ch/). the immediacy of food security during social instability in the arab region forms the backdrop to this article, rather than the longer-term infrastructural and social transformations needed to mitigate and adapt to climate-changing emissions, transformations that demand political stability and sophistication. the global population is estimated to be around . billion at present and there is an % probability that it will increase to between . billion and . billion in (garland et al. ) , so stabilisation of the population is highly unlikely this century. moreover, human population reduction is not a quick fix for environmental problems, and even a catastrophic event that killed billions of people would have relatively little effect on the overall impact of humans on the environment . weak public sector low salaries, complex and inefficient bureaucratic processes, poor educational attainment, incompetence, widespread acceptance of corruption through bribery and political interference, and the lack of an investigative free media, account for the justifiable lack of confidence in the public sector. a low regard for human rights, legal processes, and justice undermines societal advancement. there is also poor custodianship of cultural heritage and essential infrastructure. . neighbouring countries many poor countries have reliance on and vulnerability to neighbouring countries for access to water, transport and communication networks, foodstuffs, energy, control of environmental issues (e.g. desertification, flooding, biodiversity protection, pollution etc.), and security. neighbouring countries may (a) create security problems by aiding terrorists and insurgents, (b) provide an uncontrolled source of refugees, (c) invade, (d) steal water or other natural resources, and/or (e) issue mendacious media releases or operate diplomatically to undermine the confidence of donor countries, aid agencies, and investors. the more-developed countries rarely understand the sheer difficulty of managing a poor country facing inter-ethnic conflict, and terrorism and poverty. . international agencies, non-government organisations, international media and the united nations poor countries are monitored by a plethora of international and national bodies, and extensive reports generated, but the necessary actions -political and military -to solve the main issues and problems are rarely carried out. unwarranted aggression inflicted on other countries -poor or not, or the suppression of their populations or specific parts of their populations by nation states eventually must be counteracted by military intervention. sadly, poor nations are oftentimes regarded as pawns in international power struggles, and remain either exploited for their resources, or ignored. moreover, economic downturns in donor countries reduce the level of aid and absorption of refugees, made worse by certain countries cynically failing to meet their initially well-publicised aid pledges. (bardshaw and brook ) . population increases could undermine attempts to ameliorate attempts to reduce climate-modifying emissions. climate-change predictions for the arab region are deeply concerning. most scientists support the conclusions of the latest fifth assessment report of the ipcc. formed in by the united nations environment programme (unep) and the world meteorological organization (wmo), and relating closely to the un framework convention on climate change -the main multilateral forum for addressing climate change, ar comprises three working group reports and a synthesis report with its summary for policymakers. the main issues are covered in detail: observed changes and their causes; future climate changes and their risks and impacts; future pathways for adaptation, mitigation and sustainable development; and a more detailed analysis of adaptation and mitigation including policy options, technology and finance. in the arab human development report authored by balgis osman elasha, ( ), the impacts of climate-change projections in the arab region are given in stark detail. in the coming decades, arab societies and their industries will be profoundly and adversely affected by projected temperature increases in excess of c and severely reduced rainfall, threats of increasing frequencies of impacts originating from el nino events, changes in the seasonal distribution and predictability of rainfall, depleted aquifers, reduced river flows, rising sea levels, flash floods, in addition to increased numbers of dust storms and hurricanes. as the arab region itself is a relatively small direct contributor to global greenhouse-gas emissions, although its fossil-fuel exports and its importation of goods that took energy to create are substantial contributors to them, adaptation must be a crucial factor in policy developments in more settled times that will themselves be dependent on stable and peaceful arab countries. questions arise as to whether organisations such as those overseen by the united nations, multilateral groups such as the european union, individual nations and several charities will be capable of initiating and then maintaining peaceful conditions and food security. food and other forms of aid are likely to face increasing demands at a time when the economies of many donor countries are enduring continuing austerity and recessionary conditions, and when there is growing but unjustified cynicism about the effectiveness of these aid organisations. irrespective of the many estimates that total global food production can readily meet the needs of the present global population, political reality is that all countries and people are patently not equal and are unlikely to be so for the foreseeable future. aid can assist in partially rebalancing the inequalities, not least where several countries in the arab region are currently in turmoil and others are deeply troubled. some regard most of the arab world as regressing, out of synchrony with, and lacking sympathy from, the world at large. food costs and poverty are primary concerns, exacerbated by insecurity of energy and water supplies as well as rampaging insurgents and those wishing to impose unacceptable regimes and suppression of minorities, denying their citizens proper democratic freedoms. wars and conflicts are all too easily incited in the absence of strong democratic civil society involvement and usually quickly bankrupt countries; destroy nearly all parts of their economies; ruin infrastructure including homes, businesses, transport and communication networks; disrupt family life and social interactions; generate displaced people and refugees; and attract foreign interference, including active participants. war crimes are commonplace. psychological aftereffects are noted in civilians and combatants long after fighting has died down. populations in the arab middle east have endured asymmetric warfare between countries with vastly different military capabilities, provoking guerrilla tactics, chemical warfare, civil war, and even unconventional warfare through acquiescence, capitulation, and clandestine support for long-term insurgencies. wherever they occur, warfare and conflicts are always associated with the participants having distorted views of history -some drawing on ancient history -with widely diverse concepts of ethics, and complicated by ethnic and profound religious differences. little consensus exists on triggering factors, theories, and outcomes. prodigious sums of money have been expended in the arab middle east on armaments and defence forces to the exclusion of adequate investments in social welfare, education, and research and development. political instability for whatever reason usually leads to food insecurity and conflict. during social disturbances and the onset of widespread conflict, the normal mechanisms underpinning food production, importation, storage, processing, transport and retailing are profoundly disrupted, creating conditions that promote the formation of ghettos, and further stimulate corruption, robbery, and the black market. normal policing and social order collapse, social behaviour degrades, and criminal activities dominate. as the economy collapses, the terms of trade are transformed. disease epidemics become manifest. the restoration of domestic and business normality takes years and may never be achieved within one or more generations. food insecurity itself may lead to political instability, not least in a world of global intercommunications when citizens of a poor country or region can view with understandable envy the lifestyles of those in rich countries or communities. it is therefore a basic duty of political and community leaders to ensure that food security is a foremost priority for those people within their sphere of responsibility. insecurity of food supplies can be created by adverse weather conditions; the depredations of pests, weeds, and diseases; and salt contamination that can be caused by poor irrigation and agronomic practices. around million hectares of hitherto fertile land on earth have been damaged by salt. according to economics of salt-induced land degradation and restoration (qadir et al. ) , only tree planting, deep ploughing, and growing salt-tolerant crops coupled to digging drains and dykes around the affected area can address the problem. neglecting the health of africa's soils, many of which suffer almost irreversible degradation and nutrient deficiency, will lock the continent into cycles of food insecurity for generations to come, according to the montpellier panel report. indeed, was designated the 'international year of soils' by the th un general assembly. since the s, there are particular issues relating to selection pressures on destructive pests, weeds, and diseases in the vast monocultural single-cultivar agricultural systems that are also the present-day main sources of global food aid. many of these main producing areas are experiencing irregular rainfall patterns and failing irrigation arrangements. crop failures in these areas have quick knock-on effects on volatility of the global agricultural commodity markets; this is a situation likely to get worse as the population inexorably increases and demands more food. moreover, the world has yet to experience the sort of dramatic harvest failures that occurred in the s and before. another aspect of the agriculture sector (generally accepted to include crops, livestock, fishing, and forestry) in the developing world is that it absorbs circa % of the economic impacts caused by medium-and large-scale natural hazards and disasters. between and , these events in developing countries affected more than . billion people and caused more than $ billion, but agriculture only received about . % of all humanitarian aid (fao www.fao.org/emergencies/how-we-work/resilience/en/). delegates from fao at the conference announced the launch of a facility that will focus on bringing together technical expertise and financial resources with the aim of building greater resilience of agriculture to natural extreme weather events. the combination of advanced crop and livestock breeding, agrochemicals, automation, better agronomy and livestock husbandry, increases in the land area farmed, and efficient larger-scale better-capitalised production units have collectively prevented malthusian disasters. since , food production has more than quadrupled, using less than % more cultivated land, allowing civilisation to proceed and expand. food security is no longer an issue in many countries, and the global economy, human health, and societal development have been, for the most part, positively influenced by agricultural advancement. in the period - , when the global population increased from around . billion to around billion, average agricultural commodity prices decreased by an average of . % p.a. because supplies rose faster than demand (unpublished presentation by prof. ingo pies in to biennial development meeting of pottinger). nonetheless, feeding any substantial increases in the global population will only be possible by technological innovations because of the ecological limitations on increased water and fertilizer supplies and increasing the area farmed. likewise, various climatechange predictions amplify justifiable concerns about global agricultural productivity. supply and demand market dynamics are complex and ultimately resilient to political interference, although many countries and trading blocs try to manipulate production by tariffs, export bans, subsidies, inhibiting technological developments and market processes. the spikes in prices of traded wheat, rice, maize, and soya in and were initially blamed on speculation, especially the index tracking funds and derivatives markets. yet this type of speculation does not trade physical goods but price risks, and is therefore a form of insurance market. in addition, speculation would be expected to be associated with high stocks as farmers opt for storage rather than sales. in and , however, stocks were very low and caused the price rises. even so, government policy failures, including protectionist export bans and inadequate promotion of agricultural efficiency, contributed to panic buying, as exporters reduced their offer and importers increased their demand in response. calls by civil society groups to ban speculation by index-tracking funds and derivatives markets were always and continue to be profoundly misguided. all countries should have policies to sustain and constantly review food production and supply, especially if there is a significant dependence on food imports. reasonably substantial reserve food stocks are essential cushions to prevent price bubbles and food shortages, but excessive stocks can distort markets such as when they are released in large quantities as general food aid and undermine the operation of normal agriculture markets in developing countries. some price volatility is an essential component of healthy competitive markets, driving adaptation, risk taking and innovation. debates about the environmental costs of different kinds of agriculture, not least in terms of water and energy security in respect of the arab middle east, and in terms of the destruction of natural habitats and loss of biodiversity, as well as cultural and other changes, have stimulated possible strategies to address these concerns. one approach is for each country to have a "roadmap" for its agricultural development, and these roadmaps might be aggregated into a regional roadmap. the us report: a science roadmap for agriculture -cited as task force on building a science roadmap for agriculture, national association of state universities and land-grant colleges, experiment station committee on organisation and policy, "a science roadmap for the future", november (www.nasulgc.org/comm_food. htm) http://agsci.oregonstate.edu/files/main/roadmap .pdf pioneered a way to define the needs of agriculture and help shape the future direction of the various strands of agriculturally relevant science. this impressive us-specific study followed a conceptual framework of needs to (a) be competitive in a global economy; (b) add value in future harvests; (c) adjust agriculture to a changing climate; (d) be good stewards of the natural environment and natural resources; (e) make agricultural enterprises profitable; (f) make families and communities strong; and (g) modify foods for improved health and safety. one important relevant outcome of this work is the obvious requirement to grow crops and practice livestock husbandry in the most appropriate environments, enabling different environmental zones to have a critical mass of expertise and facilities. for the water-constrained arab middle east, this would mean increased reliance on food imports that could also be regarded as a form of water importation. but this would be possible only if there were formal agreements between food-producing and food-recipient countries, and these agreements were economically and politically stress-resistant. to this caveat would be questions of how to pay for imports, and acquiring resources required to redirect the agricultural workforce into other wealth-creating activities. introduction of a logical, science-led agricultural roadmap in the region may be impossible at present but needs to be initiated. on a global level, food commodity and non-food agricultural commodities prices have declined by - % in the period mid-september to mid-september (see the economist commodity-price index ( ) in www.economist.com/indicators), reflecting relatively clement weather conditions in most of the producing areas, greater production efficiency, balance sheets strong enough to bear losses, competition to gain market share, and continuing investments. importing countries, however, are affected by the strength of their currencies amongst other factors, such as social upheaval. unlike other commodities whose prices direct reflect industrial demand, prices of foodstuffs reflect the effects of weather, pests and diseases, the demands of a rising global population, and many kinds cannot be readily stockpiled. a further factor operating at the global level is the domination of farm supplies by six international companies: monsanto (the largest seed producer), syngenta (the largest agrochemical producer), bayer, basf, dow chemical, and du pont). all of these companies have been active in acquiring other companies and patents, thus reducing competition, and potentially reducing innovation as they robustly defend their intellectual property. in this era of low commodity prices and developing resistance to older-type herbicides, farmers are constrained by input costs of fertilisers, seeds, agrochemicals and veterinary medicines that have steadily risen in over the past decade, only partially alleviated by the recent reduction in fuel and lubricant costs. pandemics -epidemics of infectious or contagious disease that have spread through populations across a large region, crossing international boundariesdrastically curtail food production and distribution, aggravating poverty in both the rural and urban poor. pandemic-causing diseases include the ever-present cholera, influenza such as the and h n outbreaks, typhus, smallpox, measles, tuberculosis, plague (yersinia pestis), leprosy, malaria, human immunodeficiency virus infection and acquired immune deficiency syndrome (hiv/aids), viral haemorrhagic fevers (ebola, marburg, crimean-congo, lassa, rift valley, dengue, yellow fever, etc.), and now there are new diseases such as severe acute respiratory syndrome (sars). vaccine development is necessarily slow, and treatment of bacterial diseases is hampered by the rapid development of antibiotic resistance. the propensity of diseases to mutate, acquire new vectoring capabilities, have reservoirs in wild animals, and even persist in spore form, mean that there must be constant vigilance. as one of the major global food-producing bloc of nations, and as one of the major food importers and donors of food and other forms of humanitarian aid, the european union (eu) bears crucial responsibility for the deleterious effects of its complex and highly bureaucratic common agricultural policy. its massive subsidy regimes impact adversely on global markets and its well-meaning but often poorly thought-through environmental regulatory decisions are not based on sound scientific evidence. so-called "greening" policies are being introduced that may be deemed to enhance the environment but are likely to decrease profitable production. social measures to support small-scale inefficient producers also distort the global marketplace. likewise, the series of restrictions being introduced on the use of a wide range of agrochemicals within the eu and for imported commodities, without carrying out proper impact assessments and fast-tracking alternatives, imperil production. in the medium to long term, a more serious issue is the virtual ban in genetically modified (gm)) crops, inhibiting their uptake in countries intending to export to the eu as well as suppressing state-of-the-art research and development and associated investments in eu countries. of particular relevance in this regard is the recent and largest statistically rigorous review of the agronomic and economic effects of the current range of commercially available gm crops on farming (klümper and qaim ) . in examining publications between and march , it is therefore a near-complete survey. in essence, the two main types of gm crop -resistance to insect pests and tolerance to the wide-spectrum weedkiller glyphosate -conferred considerable yield improvements and much higher profits than conventional crops. gm crops and related products in the development pipeline were not considered, and these promise great advances in nutrition enhancement, environmental clean-up, new medicines, new products for manufacturing industries, and improved crop and forest species. moreover, existing gm crops have greater impacts in poorer countries than in richer countries because their insect pests and pernicious weeds are more difficult to control. by including non-peer-reviewed papers (book chapters, working papers, conference papers etc.) as well as peer-reviewed papers for the meta-analysis, it was possible both to correct for academic bias in focusing just on the most dramatic effects, and include data for many ancillary effects, such as the effects of fertilisers. the eu ban on gm crops is therefore denying poor exporting countries from reaping the full benefits in yield, profitability, and commodity quality, in addition to reducing potential eu food-aid exports. one positive feature of the eu is the bureaucratic system to improve and monitor the quality and safety of foodstuffs, from raw ingredients through to ready-meals, and gm crops have been found to be safe. that for many years most of the feed protein in the eu comprises imported gm maize and soya bean, the issue of gm crops should not be ignored for much longer. opposition to the processes of modern genetic modification and ownership of the processes (often deeming them to be "unnatural"), and disregarding the quality, safety, and valuefor-money of the product, actually condemns conventional agricultural practice, and demonstrates ignorance of naturally occurring mutations and horizontal gene transfer. even so, in early november , the newly elected president of the european commission, j-p juncker, in what is widely regarded as a blatant act of appeasement to greenpeace and other so-called "environment" pressure groups, sacked the eu's chief scientific advisor, professor anne glover, for her support of gm technology, compounding this regressive stance with abolition of the post. all countries and trading blocs should have influential and competent teams of chief scientific advisors. research and development in gene identification, construction, insertion, editing, and expression, coupled to high-throughput phenotyping are collectively revolutionising agricultural, horticultural, and forestry sciences. gm technology is not simply the insertion of genes using various technologies from a similar or different species into a recipient organism. it includes the concept of gene silencing -the prevention the reduction of expression of certain genes -a process that can take place at either the transcription or translation cellular processes. it is not the equivalent of gene knockout but is essentially gene knockdown because the methods to silence genes do not completely eliminate the expression of a specified gene. the methods to silence genes include rna interference (rnai or posttranscriptional gene silencing), small interfering double-stranded rna (sirna), and crispr. of special interest is the crispr (clustered, regularly interspaced, short palindromic repeats) toolkit that is derived from research on prokaryotic antiviral systems and currently involving the cas and cpr endonucleases (jinek et al. ; cong et al. ; bolukbasi et al. ) . as viruses constantly evolve to escape from these antiviral systems, bacteria probably evolve new systems. crispr technology is able to recruit heterologous domains that can regulate endogenous gene expression as well as label specific genomic loci in cells, so that is feasible to engineer germ lines and thus the path of evolution. this technique is replacing methods using mutagenic agents, virus vectors, zinc-finger nucleases and transcription activator-like effector nucleases (talens). its relative simplicity and evolutionary significance for all life forms, including humans, means that internationally agreed regulatory frameworks are essential. the technology does not involve implanting genes from one organism into another, and is not therefore creating transgenic organisms; it is gene editing. there is now realistic expectation of new perennial cereals; incorporation of c- photosynthetic characteristics in existing c- crops; enhancement of nitrogen fixation by free-living soil microorganisms in the vicinity of crop roots; tolerance and resistance to biotic and abiotic stresses; and modification of lignification, texture and endogenous components (such as vitamin content, acrylamide in potatoes, antinutritionals, toxins, proteins, oils, and carbohydrates) of a wide range of existing and potential crop species (see www.isaaa.org/kc/cropbiotechupdate). besides the present-day generation of improved livestock species and new forms of husbandry, the use of balanced diets based on competitively priced synthetic amino-acid and fatty-acid products will lessen the need for large-scale soya and maize production. ancillary advances are taking place in mechanisation; diagnostics; predictive modelling and decision-support systems; remote sensing; protectedcropping systems; and weed, pest, and disease control. diminution of abiotic and biotic stresses in the field and under protective cropping is now the focus of major research initiatives. of the circa , species of angiosperms, according to the food and agriculture organisation of the united nations (fao ) , only species provide % of human energy needs and only four species (rice, wheat, maize, and potato) account for % of energy intake, and % of crop diversity was lost in the last century. around % of human calorie intake comes from crop species (grivetti and ogle ) and % comes from just three grasses -wheat, maize and rice (see www.knowledgebank.irri.org/ericeproduction/importanceofrice.htm) dependency on such a narrow genetic base is a threat to food security and is only partially alleviated by investments in in situ and ex situ plant gene/seed banks, germplasm collections, and dna libraries. just species of angiosperms and gymnosperms have been cultivated for human consumption in human history, with around , angiosperm species yet to be discovered. in theory, most angiosperms should be capable of being biotechnologically modified for food and non-food uses. will scientists in the arab middle east fully participate in these exciting developments? valuable collections in the arab region are inadequately respected for their worth under peaceful conditions but are now extremely vulnerable during this period of war-like conditions and enduring financial pressures. coming into force in , the international treaty on plant genetic resources for food and agriculture (international seed treaty) was designed to complement the convention on biological diversity (cbd) and was designed to guarantee food security by (a) conservation, exchange, and sustainable use of all types of plant genetic resources; (b) offering fair and equitable benefit-sharing; and (c) recognition of farmers' rights. critics of the international seed treaty point to great variability across countries of access to collections and interpretation and implementation of farmers' rights. moreover, in adopting the cbd's outlawing of biopiracy -the uncompensated commercialisation and profiteering of seeds, propagules, growing plants, and their products from source areas -has severely inhibited the acquisition and exchange arrangements in collections until better processes come into force. gap analyses are methods to identify gaps in ex situ collections of wild-plant relatives of agriculturally relevant species as a means to guide efficient and effective collection strategies (villegas et al. ) . a gap analysis by the international center for tropical agriculture managed by the global crop diversity trust and the millennium seed bank in kew examined priority gene pools of the globally most important food crops and their wild relatives. most at risk were eggplant, potato, apple, sunflower, carrot, sorghum, and finger millet (see www.cwrdiversity. org/conservation-gaps/). ongoing conflicts and disorder in the arab region justify an independent review of a regional red list index based on the list of threatened species released by the international union for the conservation of nature (www. iucn.org) in order to evaluate the extinction risk of species and subspecies of the natural flora and fauna. certain individual countries in the eu are important donors of humanitarian aid in their own right. according to a recent report (november , ) from the organisation for economic co-operation and development, economic stagnation especially in the eurozone portion of the eu poses a major risk to world growth. if the stagnation were to continue or even get worse, humanitarian assistance would inevitably be reduced, and countries that hitherto were willing donors would become increasingly introverted. as evidenced by growing problems of graft, corruption and authoritarian government in certain (but not all) members of the eu that were formerly dictatorships or in the sphere of influence of the former soviet union, democratic norms (human rights, respect for minorities, tolerance, free press, independent judiciary and rule of law, active civil-society groups, transparency of accounting for taxpayers' money etc.) take time to become bedded into the fabric of society. in considering the medium-to-long-term future of the eu, it is sobering to note that throughout european history, confederations between its diverse nations and subsets have rarely persisted unless full political, legal, monetary, and more profoundly, cultural fusion had taken place. all governments worthy of the title must ensure that there are relief mechanisms to enable the provision of basic food supplies and fresh water together with functioning standby electricity-generating equipment in unsettled times caused by natural or man-made disasters. surely governments have the ultimate responsibility to attend to the needs of their people and not themselves. rarely observed, governments need genuine food, nutrition and agricultural experts as an integral part of the decision-making hierarchy. such experts must have a proper understanding of the pre-conflict or pre-disaster food, fresh-water, and energy supplies and their distribution systems, and how they can be safeguarded, modified and employed to proper effect, and how alternative mechanisms can be deployed. sadly, this aspect seems to be neglected at the present time in the chaotic condition of certain countries in the middle east. much can be learned from countries in europe during the wars that raged in the nineteenth and twentieth centuries. simply standing by and watching the population adapt slowly to acquiring barely adequate water and food supplies inflicts untold misery on innocent people. all governments should have readily accessible emergency supplies (reserve stocks) and transport systems, and be willing to introduce rationing if need be. special protection measures are needed for water supplies and farms to make sure production can continue no matter the degree of impairment. in more settled times, each government should establish a group of experts to construct interactive databases as the foundation of an agriinformatics and metrics organisation. this would collate information on supply and demand changes, supply-chain details, imports, crop and livestock genetics, commodity production levels, labour-force composition, pricing, inputs, availability of decision-support systems, advisors and research bodies, grant funding, biotic and abiotic stress factors, natural resource constraints, predictive modelling of shocks to the agricultural system and disruptive events, etc. other research organisations would interact with this organisation to ensure best practice and enhance agricultural resilience, demonstrate efficient use of inputs, exploit wastes, optimise the use of mechanisation, and foster skills. arab countries still have to utilise fully the international capabilities and potential of (international centre for agricultural research in the dry areas -currently based in beirut given the conflicts in syria) and other members of the cgiar consortium (formerly the consultative group on international agricultural research). the plethora of aid agencies offering humanitarian and development aid encompass those that are organised by a single government, multilateral donors, non-governmental organisations, philanthropic and charitable organisations, businesses, and individuals. reliefweb (www.reliefweb.int) provides a relatively comprehensive directory of humanitarian organisations. fragmentation of the total aid effort is becoming a worrisome issue. the international committee of the red cross, part of the international red cross and red crescent movement along with international federation of red cross and red crescent societies and national societies, is mandated internationally to uphold the four treaties and three additional protocols of the geneva conventions. these conventions are rules that apply in times of armed conflict both within and between countries, and define the rights of civil and military prisoners and protections for wounded people and for civilians. weapons of war are dealt with by the hague conventions and the biochemical warfare geneva protocol. enforcement of the conventions is through the un security council but is rarely invoked, primarily because of profound ideological differences about democracy and human rights between the five permanent members of the security council with veto powers, so there tends to be diplomatic reliance on regional treaties and national laws. parenthetically, there are ten non-permanent members of the security council without veto powers that are elected by the general assembly of the united nations for a two-year period. on november , the un security council pledged to counter the global terrorist threat and increase cooperation to address the perils posed by foreign terrorist fighters such as those that are a notable feature of conflicts in the arab region. the un office on drugs and crime is also involved in this initiative. other international related treaties include the united nations multilateral treaty referred to as the geneva protocol or convention relating to the status of refugees as well as the declaration on the protection of women and children in emergency and armed conflict adopted by the united nations in . humanitarian aid is distinguished from humanitarian intervention, which involves armed forces protecting civilians from violence or genocide. the united nations office for the coordination of humanitarian affairs is mandated to coordinate humanitarian responses, usually in concert with the international committee of the red cross. valuable reference material can be found in (a) grebner et al. ( ) , the state of hunger in developing countries as a group has improved by % since . even so, the level of hunger is still serious with an estimate of million people continuing to go hungry. the highest levels are south of the sahara and south asia. in the ifpri global nutrition report , evidence is summarised to show that improvements in nutrition status will make large contributions to sustainable development goals, namely poverty, food, health, education, gender, and employment investment in nutrition has a highest benefit ratio. projections from the world health organization (who) and unicef demonstrate that the world is not on track to meet any of the six world health assembly (wha) nutrition targets (reducing child stunting, reducing anaemia in women of reproductive age, reducing low birth weight, reducing the number of overweight children, increasing exclusive breast feeding, and reducing child wasting), although many countries are making good progress in meeting nutrition outcomes. the manifestation of malnutrition is changing as countries are now facing complex, overlapping, and connected malnutrition burdens. three of the chapters in the ifpri publication resilience for food and nutrition security (fan et al. ) are germane to this article. breisinger et al. ( ) briefly mention the arab spring and uses egypt, somalia, sudan, and yemen as case studies of conflict-affected countries. mabiso et al. ( ) have specific reference to the syrian refugee crisis, and take a global overview of the complex relationships between refugees and host countries. babu and blom ( ) introduce a model that seeks to delineate the key capacity components of a resilient food system, considering a country's capacity to create, manage, and utilise human resources for a resilient food system. significant challenges to aid provision include (a) harnessing the necessary stream of funding when grandstanding promises by countries are often never met; (b) establishing and coordinating the basic support network; (c) ensuring the logistics arrangements are effective, including communication networks; (d) prevention of resource misappropriation; (e) protection for officials and support workers on the ground; (f) protecting the vulnerable people needing aid; (g) operating with transparency and integrity; and (h) laying the structural and procedural foundations for self-reliance. effective lines of communication with donors and international agencies and charities are pivotal so that emergency arrangements can be established without delay and hindrance. these bodies need to deal with those individuals in the recipient countries truly knowledgeable about the capacity and specific problems facing food and water security, and fast-moving internal developments. the experts in the recipient countries must have the authority to be able to (a) quantify the levels of demand, (b) direct supplies, (c) recommend the siting of depots and distribution centres, and (d) highlight points of accessibility and vulnerability. in poorly governed countries, experts must be prepared to deal directly with these donors, agencies, and charities, difficult as that might be. the complexities of globalisation extend beyond food and water security (lerche ) . when people are deliberately persecuted, and honest law enforcement collapses, then non-partisan protection must be afforded, usually with outside security forces. unfortunately, ideological differences mean that the international community has often been shown to be ineffective in bringing about rapid termination of conflicts by imposing observers or armed forces, although thanks to relatively few major international donors, humanitarian relief has been forthcoming, albeit frequently late and inadequately funded. dealing with refugees and displaced people requires expertise and sympathetic support. housing provision together with monitoring and combatting infectious diseases, usually run in parallel with the issuance of food supplies. governments that prepare for worst-case scenarios are to be commended. even the distribution of authoritative guidance for populations in stress would represent a small step in the right direction, as would reinforcing the institutions that bind civil society, such as voluntary rescue and care organisations. networks of low-temperature clean and secure depots with associated distribution centres should be set up at the outset of disasters and conflicts. even in peaceful times, a marked cut in food waste helps food security. according to m. m. rutten (rutten ) around a third of the food for humans produced annually (about . billion tonnes) is either lost or wasted, and in developing economies the situation tends to be worse, with in excess of % lost during harvesting, processing and storage (fao. . global food losses and food waste -extent, causes and prevention (see www.go. nature.com/um vga). basic needs of refugees, as recommended by the unhcr and related organisations, are modest but are directly applicable to those displaced or besieged in their own country. unhcr recommends each refugee receive more than calories per day, recognising that a lack of food variety and inadequate supply of fruit and vegetables lead to deficiencies in essential vitamins and minerals. calorific intake can be reduced if the provided foodstuffs do not conform to traditional diets, or if the rations are traded to acquire other non-food goods and services. encouragement is needed to set up temporary gardens. fresh-water provision is of primary importance, with a minimum of litres per person. a greater volume is needed, though, to prevent public-health problems of diarrhoea, cholera, and even polio. thus, clean-water sources and pumps are required along with taps within walking distance. vessels are needed for transfer and storage of water. water-purification tablets should be provided. sanitation systems are essential for hand washing and the safe disposal of urine, faeces, sanitary towels, wound dressings, infected and contaminated materials, and for the disposal of dead bodies. monitoring of faecal contamination is recommended. housing refugees and displaced people at short notice demands special expertise to avoid overcrowding and give adequate protection against inclement conditions. overlaying the fundamental needs for food, water, and shelter are meeting basic medical needs, particularly of the young, women, and the old and frail. in addition, within a short time, children require to be educated. host communities and host countries sometimes resist integration of forcibly deracinated people and can grow resentful at the costs incurred, especially if the host economy is weak. most financial assistance from donor countries is given to aid agencies rather than host countries. large-scale influxes of refugees can soon overwhelm the host country's infrastructural resources (chiefly fresh water, energy, housing, hospitals and healthcare systems, education, and waste disposal). other problems arise from combatants embedded in refugee cohorts, spreading the conflict and increasing policing costs. cultural incompatibilities between refugees and the host population create hostilities. refugees can suffer the dire consequences of being rendered stateless. in general, it is fair to say that humanitarian care is not able to sustain basic needs in the medium to long term. as a consequence of a funding crisis for humanitarian aid in the arab middle east, the world food programme was forced to suspend its desperately needed food-aid-voucher scheme for more than . million syrian refugees at the beginning of december , the onset of winter. this suspension meant that refugees were less welcome in host countries and border closures are already being implemented in the immediate area as well as in the european union. axiomatically, just as responsible governments must be alert to and prepared for civil and other forms of unrest, they should always promote food production and remove any impediments to the uptake of improved technologies so that their economies have inbuilt resilience to dreadful events. likewise, governments should have in their ranks, or instantly available for consultation, competent scientists, technologists, and engineers able to advise on food, water, and energy resource distribution and allocation. over the past few decades, public-sector agricultural research and development in virtually all countries have suffered financial reductions and financial resources have been switched to activities regarded as more exciting and with greater wealth-creating potential; history shows this to be monumentally misguided. the urban disregard for agriculture is likely to continue as urbanisation increases, until the point food security threatens social stability. active or benign neglect of food-producing, food-processing, and food-distribution industries as well as of the scientists, technologists, and engineers underpinning its productivity, improvement and efficiency reveal incompetent governance. as an aside, the dearth of scientists, technologists, and engineers in active politics accounts for numerous policy failures. graduates in the arts (such as history and politics) and social sciences dominate politics and the upper echelons of the machinery of government (civil service) worldwide, people with little understanding or appreciation of business let alone of the "hard" sciences and engineering and their essential utility (and limitations) for mankind. perhaps this explains the growing dissatisfaction with the prevailing political classes. the scientific approach is that of the quest for knowledge by constantly questioning, developing and testing hypotheses by experimentation so that opinions change as "facts" change, oftentimes undermining policies that are not evidence-based, whereas many political parties are founded on inflexible belief systems, as are almost all religions. one aspect of food security in times of conflict and community disharmony has been the remarkable resilience of researchers to continue their studies or just maintain libraries, databases, records, laboratories, and genetic resources under the most trying conditions. the pursuit of knowledge is a fundamental feature of humans, as is the search for improvement. when there is blatant disregard of national constitutions as well as united nations treaties, protocols and conventions, and universities, colleges, schools, and research institutes become targets of malevolent forces, then the rest of the world must have no other option than to intervene, regardless of diplomatic niceties, in order to restore at least the vestiges of societal normality. as a first step, food security and the provision of fresh water for the besieged people must be a priority. if and when particularly large, heavily populated countries become embroiled in conflicts and/or major natural disasters, the existing international support efforts are likely to fail. this, in turn, may lead to a series of related conflicts, as opposing ideological pressures culminate in outright wars, invasions, and suffering on a huge scale. throughout the world, history has shown that unless they are relatively rich (and that may not be enough), smaller or militarily weak larger countries are influenced, for good or ill, by their more powerful and sometimes aggressive neighbours. as recent events demonstrate, conflicts in smaller countries rarely bring about rapid corrective measures from the international community, and adverse and damaging propaganda actively promoted in donor countries can prolong the suffering. ultimately though, food and fresh-water security are a prerequisite and eventually underpin stability, peaceful and thriving economies. today, much of the arab world is poorly governed and insecure for its citizens; they urgently deserve a better life. many of the most talented arabs seek a better life elsewhere. the warfare must be ended forthwith. grossly and unfairly misunderstood by much of the rest of the world, arabs demonstrate admirable resilience and stoicism yet retain their sense of humour tempered by understandable cynicism and justifiable suspicion of conspiracies. enemies of the arabs subject them to a tirade of insults and demeaning innuendos, often designed to deny them basic rights and international support. nonetheless, arabs must not be the continuing authors of their own misfortune, and a first step would be an end to internal conflicts followed by an effective region-wide clampdown on corruption at all levels. remember -it is the victor who determines the writing and shape of history. if the level of insecurity in the region were to get worse, then not only the arabs but also the rest of the world would pay a high price, so it is in everybody's interest to help restore peace. bluntly, the solution to their problems lies in the actions of the arabs themselves. in fully grasping the opportunities available through top-quality education , high standards of integrity and tolerance can be demanded from those in leadership roles in communities, organisations, businesses, and local and national government. ignorance can be reduced, even if not eliminated. essential components of democracy can be established, including independent and diverse news media, an autonomous judiciary operating to high standards of justice and unaffected by pressure groups and politicians, freedom of speech, and dynamic humanities and artistic sectors. wealth, and security of food, water, and energy, can and must be assured through the knowledge economy. harmony can be restored to communities suffering deep-seated divisions. furthermore, countries in the arab middle east will then be in a position to interact much more effectively and comprehensively in the international arena so that, if needed, external support and assistance can be fully and timeously harnessed. despite all the odds, this transition must be accelerated from the current dangerous condition to a much more enlightened and prosperous existence. education throughout society has proved to be a slow process, and can be resisted by regressive forces and indolence, so responsible leadership is a prerequisite. arab scientists, technologists, and engineers must contribute actively to this transition, thereby securing a safe, healthy, and buoyant future for all arabs. research and development priorities must be reassessed in the light of worsening nexus of water, food, and energy insecurity, and the desperate need to return to peaceful conditions. in legal jargon: time is of the essence. finally, a buoyant growth potential for the arab middle east is dependent on the fundamentals of demography, education, access to capital, technology, careful custodianship of its natural resources and environment, and social stability; all are threatened by this insecurity nexus. building capacity for resilient food systems human population reduction is not a quick fix for environmental problems the future of universities in the arab world. arab academy of science creating and evaluating accurate crispr-cas scalpels for genomic surgery food security policies for building resilience to conflict multiplex genome engineering using cripr/cas systems mapping of climate change threats and human development impacts in the arab region ( pp.) food-and-nutrition-security food and agricultural organisation of the united nations action to build resilient livelihoods. prepared by the food and agricultural organization of the united nations (fao) for the world conference on disaster risk reduction world stabilization population unlikely this century global hunger index: the challenge of hidden hunger ( pp.) value of traditional foods in meeting macro-and micronutrient needs: the wild plant connection overview of the roles of energy and water in addressing global food security an overview of mitigation and adaptation processes and strategies to address the impacts of climate change on food, water, and energy security in the arab middle east a programmable dual-rna-guided dna endonucleases in adaptive bacterial immunity a meta-analysis of the impacts of genetically modified crops the conflicts of globalization resilience for food security in refugee-hosting communities international budget partnership. www.internationalbudget.org organisation of economic co-operation and development economics of salt-induced land degradation and restoration what economic theory tells us about the impacts of reducing food losses and/or waste: implications for research, policy and practice. agriculture and food security national association of state universities and land-grant colleges, experiment station committee on organization and policy, a science roadmap for the future. www.nasulgc.org/comm_food.htm the economist commodity-price index a gap analysis methodologhy for collecting crop genepools: a case study with phaseolus beans key: cord- -gmitz gg authors: clemens, john d.; ochiai, r. leon title: sequential stages of clinical trials and overview of issues to be considered date: journal: the grand challenge for the future doi: . / - - - _ sha: doc_id: cord_uid: gmitz gg nan we live in an exciting era in which the fruits of molecular biology and biotechnology are yielding a profusion of new and improved candidate vaccines, delivery systems, and adjuvants that have the potential to control many of the infectious disease scourges of the developing world. indeed, it has been estimated recently that there are over vaccine candidates currently under development against nearly infectious diseases [ ] . discovery of a new vaccine candidate and demonstration of its safety, immunogenicity, and protectivity in animal models are, however, only the first steps toward licensure and introduction of the vaccine into public health practice. the longest phase of development for most vaccines before licensure, and arguably the most uncertain, laborious, and expensive phase, comprises clinical testing of the vaccine in humans [ ] . at a minimum, this clinical testing must demonstrate the vaccine to be acceptably safe and suitably protective in the population that will ultimately be targeted for the vaccine in public health practice [ ] . over the years, regulatory agencies have adopted a standard paradigm for the manner in which new vaccines are tested in humans. a key feature of this paradigm is the phased fashion in which the testing occurs. this chapter describes the phases of vaccine evaluations in humans, including several considerations for the phased testing of vaccines in developing countries. vaccines have had a remarkable track record of safety. nevertheless, even when manufactured flawlessly, some vaccines have caused serious sideeffects [ ] . the mechanisms for these side-effects are diverse and are sometimes related to such problems as vaccine-induced immunopathology, as occurred with early-generation measles and respiratory syncytial virus vaccines [ , ] . at times the mechanism may be obscure, as was the case for sequential stages of clinical trials and overview of issues to be considered intussusception induced by quadrivalent rhesus reassortant vaccine against rotavirus diarrhea [ , ] . whatever the mechanism, the point to be noted is that such severe side-effects are not always predictable. to minimize potential injuries to subjects caused by vaccine side-effects during re-licensure trials, vaccines are tested in a phased manner. in this phasing, early evaluations are conducted in small numbers of subjects, so that if reactions are observed, they will affect a minimum number of volunteers. and early evaluations are typically conducted in the least vulnerable subjects, often healthy adults, so that if the reactions occur, their severity will be minimized. successive evaluations of a particular vaccine are then conducted in progressively larger numbers of volunteers, and, as confidence in the safety-profile of the vaccine increases, in subjects in the ultimate target group, including persons who are more vulnerable (e.g., infants). with these successive studies, the complete ensemble of information about the vaccine's safety, immunogenicity, protectivity, and sometimes additional characteristics (e.g., transmissibility) is accrued. moreover, the large number of subjects ultimately studied ensures estimation of these features in a statistically precise fashion, and, for sideeffects, in a way that enables detection of relatively rare events. clinical trials for licensing a new vaccine candidate are generally planned in three phases. in the code of federal regulations (usa), the phases of clinical trials are described by using arabic numerals (phase , phase , phase ), while in world health organization publications, roman numerals are generally used (phase i, phase ii, phase iii). in this paper, we use roman numerals to describe the phases of clinical trials. phase i trials of experimental vaccines are the first human studies to be conducted after preclinical studies have demonstrated suitable safety, potency, immunogenicity, and, when possible, protectivity. the primary purpose of a phase i trial is to rule out the possibility of frequent vaccine sideeffects. additional goals include preliminary assessment of vaccine immunogenicity, determination of an appropriate dose and regimen, and, for live vaccines, measurement of vaccine shedding. phase i trials are typically small, often on the order of - subjects, usually enroll healthy adults, and may be done with preliminary formulations of the vaccine. depending on whether there are concerns about potential severe sideeffects and the need for biological containment of excreted vaccines, such studies may be done on an inpatient or an outpatient basis. for example, a genetically attenuated, live oral vaccine candidate might well be tested initially on an inpatient basis with containment if there is concern about transmission of fecally excreted vaccine organisms, or about the genetic stability of the candidate during the course of fecal shedding [ ] . often, phase i studies are designed in an uncontrolled fashion. for vaccine candidates that are found to yield promising findings in phase i trials, phase ii trials may be undertaken. the primary goals of phase ii trials are to evaluate vaccine safety and immunogenicity in larger numbers of subjects, and ultimately in the target population for whom the vaccine is intended. for live vaccines, phase ii trials may also be designed to evaluate vaccine shedding and transmissibility. phase ii trials may also further evaluate different vaccine doses and regimens. a frequently used strategy for phase ii trials of vaccine candidates intended for infants is to initiate the studies in an older age group, often adults, and to conduct successive studies in progressively younger age groups, with the transition to each younger age group contingent on satisfactory results from the study of the previous age group. in contrast to phase i trials, which are often done with preliminary formulations, phase ii trials typically evaluate the final formulation of the vaccine, since data from studies of preliminary formulations are not usually eligible for consideration by regulatory authorities in their deliberations about vaccine licensure. phase ii trials are typically larger than phase i trials, sometimes enrolling or more subjects. by the time that a vaccine candidate has reached phase ii, concerns that would mandate testing it on an inpatient basis have typically been resolved, and outpatient studies are the norm. in contrast to phase i trials, phase ii trials are conventionally designed as randomized, controlled trials, and control groups typically receive a placebo or an active agent to permit blinding. for live vaccine candidates, there may be a concern about unintended transmission of the vaccine strain from vaccinees to non-vaccinees with whom they are in contact. special phase ii trials are sometimes conducted to assess the transmissibility of such vaccine candidates. for example, a phase ii study of the live oral cholera vaccine, cvd -hgr, in jakarta, indonesia, randomly allocated pairs of sibling children within households to either vaccine or placebo, and judged transmissibility of the vaccine candidate by the rate of fecal excretion of the vaccine strain and seroconversion to the vaccine in placebo recipients [ ] . phase ii trials may also be done to address environmental concerns about genetically engineered, live vaccine candidates. for cvd -hgr, for example, open sewers outside the jakarta homes of children who had received the vaccine were sampled to evaluate whether there was any detectable persistence of the vaccine strain during the - hours after vaccination [ ] . a recent trend in vaccine evaluation is to use phase ii trials to obtain initial data on the level of vaccine protection against targeted, naturally occurring infections. what distinguishes these phase ii trials from conventional phase iii trials (vide infra) is that they are smaller in size (although usually larger than phase ii trials geared only to the assessment of safety and immunogenicity) and less able to evaluate vaccine protection with suitable statistical precision than well-designed phase iii trials. also in contrast with phase iii trials, such phase ii trials may be used to evaluate vaccine prototypes that will be later modified or augmented into final vaccines for licensure (e.g., a vaccine against a single serotype, when a multi-serotype vaccine will be required for the final vaccine), and may attempt to obtain estimates of vaccine protection based on prevention of a surrogate endpoint (e.g., the use of hiv viral load as a surrogate for the rapidity of hiv disease progression). for certain vaccines, studies are done in volunteers to evaluate the clinical protection against an intentional challenge with the target pathogen. such studies are sometimes termed phase iib trials. in these studies volunteers are typically allocated at random to receive the vaccine or a comparison agent, usually a placebo, and are then challenged at a defined interval after vaccination with an inoculum of the pathogen predicted to cause the target disease in nearly % of the control group. the comparative attack rate of the target disease in vaccinees versus controls provides an estimate of the conventional measure of vaccine protective efficacy (pe) = ( minus the relative risk of the disease in vaccinees versus controls) × %. estimates of vaccine protection in phase iib studies, which are typically small, often conducted in ca. - subjects, may be helpful in triaging vaccines that are deserving of study in larger and more expensive phase iii trials [ , ] . in addition to providing estimates of vaccine protection, phase iib trials can serve to provide data on vaccine safety, vaccine immunogenicity, vaccine shedding and transmissibility (for live vaccines), and preliminary assessments of immunological responses that correlate with protection. because such studies entail intentional challenge with pathogens, subjects for the studies should always be healthy adults. the intentional challenge also limits phase iib trials to infections for which there is no risk of severe acute complications, significant sequelae, or chronic infection if appropriate therapy is administered promptly upon recognition that the challenge has resulted in infection. examples of pathogens for which phase iib studies have been successfully carried out include cholera, diarrheagenic escherichia coli, shigella, rocky mountain spotted fever, malaria, and influenza [ ] . it is imperative that such studies be carried out by staff who are highly skilled in the diagnosis and treatment of the infections under study, and it is usually desirable to conduct the challenge phase of these studies under inpatient conditions. for vaccine candidates found to be suitably safe and immunogenic in phase ii trials, phase iii trials may be done to provide rigorous evidence about vaccine protection against naturally occurring infections, and to provide additional data on vaccine safety in larger numbers of vaccinees. phase iii studies are designed as randomized, controlled trials with clear hypotheses, and are conducted in the target group for whom vaccine licensure is desired and in a population that normally experiences the target infection. these studies thus constitute pivotal evaluations that provide the basis for decisions about whether to license a vaccine for use in public health practice [ ] . figure diagrammatically depicts the design of a phase iii trial comparing two groups. in such a trial participants are recruited from a target population and are enrolled for the study after acquisition of informed consent and ascertainment of eligibility. prior to the trial, a formal randomization scheme is developed to allocate subjects to an experimental vaccine group or a control group, and this randomization scheme is used to allocate the compared agents to consenting subjects who are eligible for participation. to ensure blinding of investigators and subjects to the identities of the compared agents, controls may receive an inert placebo or an active vaccine. if the latter is chosen, it is typically an agent that is identical in appearance to and given with the same regimen as the experimental vaccine, but does not elicit immune responses that are known to protect against the pathogen targeted by the experimental vaccine. after randomization, subjects in the compared groups are followed concurrently with uniform surveillance procedures to detect target infections and adverse events, and the target infections adverse events immune responses figure . a simplified schematic of a phase iii vaccine trial designed as a two-group, randomized, controlled trial. in such a trial, the study population is assembled from a target population and is then randomized to receive an experimental vaccine or a control agent. the experimental and control groups are followed longitudinally and concurrently to detect the comparative occurrence of target infections, adverse events, and immune responses in the two groups to assess vaccine protection, vaccine safety, and vaccine immunogenicity, respectively. comparative rates of these events in the two groups form the basis for the assessment of vaccine pe and safety. similarly, participants, or a subsample of participants, are assessed immunologically at baseline and at a defined interval after dosing. because phase iii trials must provide statistically meaningful estimates of vaccine pe (calculated in the same way as described above for phase iib trials) and because the target disease outcomes to be prevented by vaccination in the trials are typically rare in occurrence, phase iii trials are often quite large, sometimes enrolling tens of thousands of subjects. in addition, because it may be necessary to measure vaccine pe over several years following vaccination in order to provide information necessary to convince regulatory and public health authorities, phase iii trials may entail maintenance and follow-up of study populations for long durations. the large size, lengthy duration, prospective conduct, and extensive quality control and quality assurance procedures needed for phase iii trials make them extremely expensive, often costing millions of dollars. measurement of immune responses in phase iii trials is done for two purposes. first, it is necessary to document that the vaccine tested in a phase iii trial elicited the level of immune response expected on the basis of earlier studies. comparison of immune responses in the vaccine and control groups permits estimation of the proportion of immune responders among the experimental vaccine group that can be attributed to receipt of the vaccine. if vaccine pe proves unexpectedly low in the trial, this assessment will be crucial in helping to explain these results. assessments to assess whether immune responses were as robust as expected usually require evaluation only of a small subsample of subjects participating in the trial. second, it is often desirable that a trial define an immunological correlate of vaccine protection -a level of short-term immune response to vaccination that demarcates vaccinees who are protected against the target infection. immunological correlates of protection are best defined by comparing immune responses to the vaccine in vaccinees who develop the target infection (breakthroughs) versus vaccinees who do not. definition of immunological correlates of vaccine protection is very important because such correlates permit assessments of the protection of the tested vaccine and ones suitably similar to it in small, short-term studies with immunological endpoints, without resort to full-scale, phase iii efficacy trials with clinical infection endpoints. phase iii trials usually provide the only opportunity before licensure for determining an immunological correlate of protection. unfortunately, determination of immunological correlates within phase iii trials can be logistically demanding and costly. these problems result from four considerations: ) it is necessary to contrast short-term immune responses in vaccinees who develop the target infection versus those who do not in order to determine an immunological correlate of protection; ) at the time of vaccination and collection of specimens for immunological assessments it is unpredictable which vaccinees will acquire the target infection ("breakthrough events"); ) most phase iii trials have very few breakthrough events; and ) blinding of phase iii trials prevents knowledge of who received the vaccine and who received the control agent. the implication of these considerations is that it may be necessary to obtain suitable specimens from virtually every participant in the trial to ensure that immunological assessments will be available for a large enough number of vaccine breakthroughs to enable statistically meaningful assessments. moreover, even when arrangements are made to collect the necessary specimens from the required number of subjects, measurement of immune responses in these specimens may not necessarily yield an immunological correlate of the vaccine protection observed in the trial, sometimes for obscure reasons [ ] . experience has demonstrated that the performance of a vaccine in affluent populations in industrialized countries cannot be assumed to generalize to persons living in developing-country settings. examples of vaccines that performed less well in developing-country than in industrialized-country populations have included oral polio vaccine, certain live oral rotavirus and cholera vaccines, and parenteral, polysaccharide-diphtheria protein conjugate haemophilus influenzae type b (hib) vaccine [ ] [ ] [ ] [ ] . it is therefore important that new vaccines be tested in developing countries prior to their licensure in these settings. this raises the question, for vaccine candidates developed in the industrialized world, of when in the phased sequence the candidate should be tested in the developing world. traditionally, it has been argued, partly over concerns about using poor populations in the developing world as "human guinea pigs", that trials in the developing world should commence only when a vaccine has been fully evaluated and licensed in the industrialized world. recent changes in thinking have challenged this view. it is now recognized that deferring trials in developing countries to this extent carries the unwanted consequence of significantly delaying the availability of vaccines to populations in developing countries. for example, polysaccharideprotein vaccines against hib, which have been licensed for over a decade in the united states and other industrialized countries and have nearly eliminated invasive hib disease in children in many of these settings, are used only to a limited extent today in the developing world [ ] . this inequity in use of new-generation vaccines has elicited calls for parallel testing, rather than sequential testing, of new vaccines in industrialized-and developing-world populations. parallel-testing of new vaccines in the industrialized and developing worlds is now being pursued for both experimental hiv and rotavirus vaccines [ , ] . another important trend affecting the testing of vaccines in developingcountry populations is the emergence of highly qualified vaccine producers in the developing world, some capable of developing innovative new vaccines. clearly, it is appropriate that the initial groups for testing of an experimental vaccine developed by such producers be selected from the population of the country in which the vaccine is developed. conventional descriptions of phased trials often portray a seamless progression of trials from phase i to phase ii, and from phase ii to phase iii. in reality, the vast majority of vaccine candidates that are tested in phase i studies do not progress all the way through phase iii testing, because of disappointing findings or because of a lack of sufficient resources to support the increasingly expensive studies in successive phases [ ] . while unwelcome findings at any stage may lead to termination of the clinical development of a vaccine, this need not always be the case. for example, the live-attenuated, oral cholera vaccine, cvd -hgr, was shown to be safe and highly immunogenic when given as a single dose of × organisms in an extensive series of studies in north american volunteers. however, when the vaccine was subsequently tested in thai adult volunteers, it proved erratically immunogenic [ ] . to address this problem, the vaccine developer raised the dose by one log, to × organisms, and found the vaccine to be suitably immunogenic but still safe in a variety of settings in developing countries [ ] . the cvd -hgr experience illustrates that successful vaccine development may require detours in the phased sequence of clinical trials in order to accommodate necessary adjustments in vaccine dose, schedule, or even formulation in response to findings that emerge during the course of clinical studies. however, because vaccines that appear promising in developed countries not infrequently fail to perform as well in developing countries, and because such detours can greatly increase the expense of clinical development, completion of clinical testing of vaccines for developing countries may be exceptionally challenging. the conventional sequence of phases usually culminates in one or more phase iii trials that are designed to provide pivotal evidence on the clinical protection conferred by the vaccine against the targeted, naturally occur-ring, infectious disease. sometimes, however, proof of clinical efficacy in a phase iii trial may not be necessary for licensure of a vaccine. for example, cvd -hgr vaccine against cholera was licensed in europe for use in travelers on the basis of phase i-ii studies, together with phase iib trials showing a high level of protection against experimental cholera in north american volunteers [ ] . however, it is unlikely that phase iib evidence from industrialized countries will be taken as a basis for licensure of vaccines in developing countries, in part because of the discrepancies between vaccine performance in developed versus less-developed settings and in part because of the uncertainties about whether protection in phase iib studies predicts the performance of a vaccine in populations experiencing endemic disease. in addition, if there is an accepted correlation between a certain immune response (e.g., a serological antibody titer) to vaccination and clinical protection, this immune response may sometimes be used as prima facie evidence for judging whether the vaccine is likely to be sufficiently protective to warrant licensure. for example, prp-crm diptheria toxin and prp-neisseria meningitidis outer membrane protein (omp) conjugate vaccines against hib were licensed for infants on the basis of phase iii evidence of clinical protection against invasive hib disease. subsequently, prp-tetanus toxoid conjugate vaccine was licensed for infants in the united states largely on the basis of proven safety and the attainment of protective serum antibody titers to prp, without corresponding evidence of clinical protection from a phase iii trial [ , ] . serological endpoints are also commonly used as a basis for licensure of combination vaccines for which the component vaccines have already been licensed and seroresponse criteria for these components have been established [ ] . some vaccines of public health importance are directed to diseases that cannot be reliably predicted in populations at risk and that cannot be ethically studied in phase iib trials. examples include vaccines against some bioterrorism agents such as anthrax and plague, and vaccines against certain epidemic diseases such as sars and ebola. in these situations, decisions about licensure will have to depend on pre-clinical data, demonstration of safety in humans, and assessments of immune responses in humans (even if such immune responses are not known with certainty to be correlated with clinical protection of humans against the target disease). in recent years, considerable attention has been devoted to the ethics, scientific quality, conduct, documentation, and reporting of clinical trials. several organizations have produced guidelines for these activities, which are subsumed under the rubric of "good clinical practice (gcp)". guidelines for gcp have been published by the world health organization, the united states food and drug administration, and the international conference on harmonization (ich), among others [ ] . table presents the essential elements of gcp in guidelines issued by the international conference on harmonization [ ] . the promulgation of gcp has had several implications for vaccine trials in developing countries. increasingly, the world of vaccines is becoming globalized. vaccines targeted for a global market may be tested in developing countries to provide initial licensure. for example, a live oral human rotavirus vaccine developed by a major multinational vaccine producer has recently received its initial licensure in mexico. moreover, vaccines produced by manufacturers in developing countries are now being used throughout the world. indeed, the majority of all doses of measles vaccines now administered to children in the world are produced in india. with the trend toward globalization of vaccines, increasing emphasis has been placed on conducting clinical trials in developing countries in a manner that conforms to international gcp standards. while the benefits of gcp trials are unquestionable, rigid adherence to gcp standards can be a double-edged sword. the expense of clinical trials has risen rapidly in recent years [ ] . a portion of this increased expense arises from the extensive documentation and auditing requirements demanded by regulatory agencies as a component of gcp, together with the expense of proprietary products developed to ensure compliance with regulatory requirements, such as proprietary computer software for data management and electronic reporting of trials. while this increased expense can be borne by producers anticipating major markets for their vaccines in affluent markets, it constitutes a disincentive to the clinical testing of vaccines against "orphan diseases" affecting developing countries, for which lucrative markets are not foreseen. the ethical guidelines for clinical trials in developing countries have been the subject of recent controversy. the ethical principles of respect for persons, beneficence, and justice, which underlie modern clinical trials, are well accepted [ ] . nevertheless, several issues continue to be debated, of which three are touched on here [ ] [ ] [ ] . one issue concerns the threshold for the risk/benefit ratio for a vaccine to be tested in developing countries. for example, a live oral, quadrivalent rhesus rotavirus-reassortant vaccine was licensed and then withdrawn from the united states market by its manufacturer because of an association between vaccination and the rare occurrence of intussusception [ , ] . understandably, this action had a chilling effect on the testing of this vaccine in developing countries. a meeting of experts organized by the world health organization acknowledged the rationale for the company's withdrawal of this vaccine in the united states, where rotavirus diarrhea is a cause of morbidity but not of significant mortality. nevertheless, there was agreement among participants in the meeting that the burden of mortality of rotavirus in developing countries provided an ethical justification for continued evaluation of this vaccine in these settings [ ] . a second controversy over the ethics of trials in developing countries has focused on the use of placebos. as stated in the declaration of helsinki, "the benefits, risk, burdens, and effectiveness of a new method should be tested against the best current prophylactic, diagnostic, and therapeutic methods" [ ] . there is agreement that a placebo would be inappropriate as a control agent for a trial if a locally licensed standard alternative vaccine exists; there is also general agreement that if such an alternative does not exist, it would be preferable to use for the control group an active vaccine against a different target infection, provided the active control does not cross-protect against the target pathogen and that use of the active vaccine maintains blinding in the trial [ ] . however, it remains controversial whether a placebo can be ethically administered to the control groups in trials for which there is no suitable alternative active control vaccine and in which a licensed alternative vaccine against the target infection exists, but the alternative is not licensed in the country for the trial [ ] . yet a third controversy concerns what is owed to the participants at the conclusion of a vaccine trial. the declaration of helskinki states that: "at the conclusion of a study, every patient entered into the study should be table . principles of good clinical practice (gcp). from [ ] . clinical trials should be conducted in accordance with the ethical principles that have their origin in the declaration of helsinki and that are consistent with gcp and the applicable regulatory requirement(s). . before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. a trial should be initiated and continued only if the anticipated benefits justify the risks. . the rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. . the available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. . clinical trials should be scientifically sound and described in a clear, detailed protocol. . a trial should be conducted in compliance with the protocol that has received prior institutional review board (irb)-independent ethics committee (iec) approval-favorable opinion. . the medical care given to and medical decisions made on behalf of subjects should always be the responsibility of a qualified physician or when appropriate, a qualified dentist. . each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). . freely given informed consent should be obtained from every subject prior to clinical trial participation. . all clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification. . the confidentiality of records that could identify subjects should be protected, respecting privacy and confidentiality rules in accordance with the applicable regulatory requirement(s). . investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (gmp). they should be used in accordance with the approved protocol. . systems with procedures that assure the quality of every aspect of the trial should be implemented. assured of access to the best proven prophylactic, diagnostic, and therapeutic methods identified by the study" [ ] . few would disagree that if the vaccine tested in a trial is found to be beneficial, it should be provided to all participants in the trial. however, controversy surrounds the boundaries for the group of persons entitled to receive the investigational vaccine at the conclusion of the study -only participants in the trial, all persons living in the same region, or all persons living in the same country? and for how long are these beneficiaries entitled to receive the vaccine? increasing expectations for demonstration of vaccine safety before licensure because vaccines are administered in public health practice to healthy individuals, most commonly children, there is a higher expectation of safety for vaccines than for many therapeutic agents. in the past, pre-licensure phase iii trials were often designed merely to evaluate the safety profile of a vaccine observed in previous studies. accordingly, the focus of such trials was on evaluating events that were expected on the basis of earlier studies, that occurred during an interval immediately following vaccination, and that were seen with appreciable frequency. indeed, a common tactic in older phase iii vaccine trials was to evaluate adverse events only in a small subsample of the total trial population, obviating the possibility of detecting rare but potentially significant side-effects. modern regulatory agencies now usually require that surveillance for adverse events be undertaken for the total study population rather than for a subsample, at least for events that can be detected passively (e.g., among persons presenting to health care centers for treatment), and that this surveillance be maintained for the duration of the trial. increasing concern about vaccine safety has also led to other changes in the design of phase iii trials. formerly, calculation of sample sizes for such trials was usually geared to enable detection of a certain level of vaccine protection against the target illness, with an acceptable level of statistical power. detection of rare side-effects was not a typical goal of such calculations. the recent experience with the live oral, quadrivalent rhesus rotavirus reassortant vaccine, which was withdrawn from the united states market because of an association with a small but statistically significant risk of intussusception [ , ] , has led to more stringent regulatory requirements for pre-licensure trials of newer-generation, live oral rotavirus vaccines. the united states food and drug administration, for example, has required that these newer-generation vaccines be tested in numbers of infants sufficiently large to be able to detect whether intussusception is a vaccine side-effect. current trials of these newer vaccines have therefore enrolled samples of infants many times the number enrolled in pre-licensure trials of the live oral, quadrivalent rhesus rotavirus reassortant vac-cine, resulting in greatly increased clinical development costs. whether the experience with rotavirus vaccines portends regulatory requirements for substantially larger phase iii trials for other new-generation vaccines remains to be seen. the experience in the united states with the live oral, quadrivalent rhesus rotavirus reassortant vaccine illustrates yet another issue confronting pre-licensure trials. data from pre-licensure trials of this vaccine showed a suggestive but non-significant elevation of the risk of intussusception [ ] . the united states food and drug administration licensed the vaccine with the proviso that the occurrence of this potential side-effect be scrupulously monitored post-licensure. this was possible because of the well-developed systems for post-licensure surveillance for vaccine side-effects established in the united states [ , ] . unfortunately, post-licensure surveillance systems capable of detecting and evaluating rare but serious vaccine adverse reactions are absent in most developing countries. the weaknesses of post-licensure surveillance systems in developing countries place an even greater onus upon pre-licensure trials in these settings to provide reassurance that a vaccine will not cause rare but serious side-effects. however, the large size and great expense of trials capable of detecting rare side-effects present a major dilemma, especially for vaccines against diseases that are primarily limited to the developing world, for which resources for clinical trials are scarce. clearly, there is an urgent need to develop improved systems of post-licensure surveillance capable of detecting rare but significant vaccine adverse reactions in developing countries. recently work has begun to evaluate the methodological challenges and practical feasibility of establishing large population-based, dynamic computerized databases for evaluating potential vaccine side-effects in developing-country settings. such databases link vaccination histories to severe disease outcomes in defined cohorts, and have been used successfully in industrialized countries for rapid and credible evaluations of putative vaccine adverse reactions [ ] . one such database has been successfully established on a pilot scale in vietnam [ ] . overcoming the challenges of establishing such databases in the diverse settings of the developing world remains a significant but important research agenda. the basic phases of testing of vaccine candidates are relatively straightforward and widely accepted. the successive phases of clinical evaluation of vaccine candidates allow for acquisition of critical information about vaccine safety, immunogenicity, excretion, transmission, and protection in an incremental fashion, while minimizing the risks to subjects who volunteer to participate in these studies. in recent years we have seen a burgeoning of vaccine candidates against diseases of developing countries, creating breathtaking possibilities for disease prevention in these settings. at the same time, this profusion of vaccine candidates for the developing world has added a layer of complexity to the seemingly straightforward phased sequence of trials. the factors underlying this complexity are multiple, and include considerations about when in the phased testing sequence a vaccine developed in an industrialized country should begin testing in developing countries; about whether and how to pursue the clinical development of a vaccine when disappointing clinical results are observed in developing countries; about how to meet the scientific, financial, logistical, and ethical challenges of conducting clinical trials in developing countries that conform to contemporary international standards of good clinical practice; and about how to ensure that a vaccine is acceptably safe before and after licensure. the manner in which these issues are addressed in the future will have a great bearing on the success of efforts to accelerate the introduction of new-generation vaccines into programs for the poor in developing countries. the jordan report: accelerated development of vaccines. the institute vaccine economics: from candidates to commercialized products in the developing world long-term evaluation of vaccine protection:methodological issues for phase iii and iv studies the hazards of immunization an epidemiological study of altered clinical reactivity to respiratory syncytial (rs) virus infection of children previously vaccinated with an rs virus vaccine measles immunization with killed virus vaccine, serum antibody titers and experience with exposure to measles epidemic intussusception among infants given an oral rotavirus vaccine population-based study of rotavirus vaccination and intussusception safety, immunogenicity, and efficacy of recombinant live oral cholera vaccines, cvd and cvd -hgr the safety, immunogenicity, and transmissibility of single-dose live oral cholera vaccine cvd -hgr in - month old indonesian children the ethical challenge of infection-inducing challenge experiments infectious disease experimentation involving human volunteers initial clinical evaluation of new vaccine candidates: investigators' perspective of phase i and phase ii clinical trials of safety, immunogenicity, and preliminary efficacy evaluating new vaccines for developing countries: efficacy or effectiveness? protective effect of two acellular pertussis vaccines in a double-blind, placebo-controlled trial factors affecting the immunogenicity of oral polio vaccine in developing countries: a review trial of an attenuated bovine rotavirus vaccine (rit ) in gambian infants limited efficacy of a haemophilus influenzae type b conjugate vaccine in alaskan native infants. the alaska h. influenzae vaccine study group efficacy of a single dose of live oral cholera vaccine cvd -hgr in north jakarta, indonesia, a cholera-endemicarea global reduction of hib disease: what are the next steps? designing hiv vaccines for developing countries the future of rotavirus vaccines: a major setback leads to new opportunities safety and immunogenicity of different immunization regimens of cvd -hgr live oral choleravaccine in soldiers and civilians in thailand randomized, double-blind, placebo-controlled, multicentered trial of the efficacy of a single dose of live oral cholera vaccine cvd -hg-r in preventing cholera following challenge with vibrio cholerae el tor inaba three months after vaccination the efficacy in navajo infants of a conjugate vaccine consisting of haemophilus influenzae type b polysaccharide and neisseriae meningitidis outer-membrane protein complex efficacy in infancy of oligosaccharide conjugate haemophilus influenzae type b (hiboc) vaccine in a united states population of , children. the northern california kaiser permanente vaccine study center pediatrics group prelicensure evaluation of combination vaccines international conference on harmonisation expert working group ( ) international conference on harmonisation guideline for good clinical practice. e . the conference the future of vaccines: an industrial perspective the national commission for the protection of human subjects of biomedical and behavioral research ( ) the belmont report: ethical principles and guidelines for the protection of human subjects of research. the commission the ethics of clinical research in the third world ethical issues in the design and conduct of clinical trials in developing countries ethical complexities of conducting research in developing countries the future of research into rotavirus vaccine declaration of helsinki: ethical principles for medical research involving human subjects. the association joint united nations programme on hiv/aids ( ) ethical considerations in hiv preventive vaccine research when are placebo-controlled trials ethically acceptable? public health considerations for the introduction of new vaccines against rotavirus: a case study of the rhesus rotavirus-reassortant vaccine the vaccine adverse event reporting system (vaers) vaccine safety datalink project: a new tool for improving vaccine safety monitoring in the united states the vaccine data link in nha trang, vietnam: a progress report on the implementation of a database to detect adverse events related to vaccinations key: cord- -annn qn authors: menitove, jay e.; tegtmeier, gary e. title: other viral, bacterial, parasitic and prion-based infectious complications date: - - journal: blood banking and transfusion medicine doi: . /b - - - - . - sha: doc_id: cord_uid: annn qn nan during the last decade of the th century, diagnostic advancements dramatically reduced the transmission of human immunodeficiency virus (hiv), hepatitis c virus (hcv), and hepatitis b virus (hbv) by transfusion. however, simultaneously, the emergence of additional pathogens as potential blood contaminants gained attention. some of these agents represented newly discovered entities (e.g., severe acute respiratory syndrome [sars-coa]). others were known sources of transfusion complications that expanded into the united states (e.g., chagas disease). additionally, some agents demonstrated species jumping from animal hosts to humans (e.g., variant creutzfeldt-jakob disease [vcjd] , asian influenza, and west nile virus). increasing globalization through commerce, travel, and social interaction requires that many infectious agents, once thought exotic or of remote significance, must be considered as potential blood-component contaminants. , alternatively, new information may reduce some concerns. for example, porcine endogenous retrovirus (perv), previously linked to humans undergoing xenotransplantation, currently appears less threatening. this chapter addresses agents endemic to the united states and those emerging in other parts of the world that have been transmitted or are theoretically capable of transmission by transfusion, and approaches to reduce the associated risks. babesiosis, a zoonosis caused by the rodent-borne piroplasm protozoan, babesia microti, is transmitted by ixodes scapularis, the deer or black-legged tick. i. scapularis also transmits the agents of lyme disease and human granulocyte ehrlichiosis (discussed later). [ ] [ ] [ ] [ ] [ ] [ ] [ ] the white-footed mouse (peromyscus leucopus) is the natural reservoir for b. microti; once infected, a mouse remains parasitemic indefinitely. i. scapularis transmits the piroplasm most frequently during the nymphal stage when the tick is . mm long. tick bites, at this stage, often go unnoticed despite the -to -hour feeding time during which infection occurs. b. microti is the agent most frequently associated with clinical illness; mo -type, wa -type, and ca -type also cause clinical disease. , endemic areas include coastal and island areas of new england and new york as well as parts of california, washington, missouri, wisconsin, and minnesota. , , , , ticks coinfected with b. microti and borrelia burgdorferi (the agent of lyme disease) transmit b. microti less frequently than b. burgdorferi because the tick is a less competent host for b. microti. the intraerythrocytic localization of b. microti, however, favors transfusion transmission of this agent over that of b. burgdorferi. in humans, circulating b. microti dna persists, on average, for days in asymptomatic patients and in those not given specific treatment. co-infection with lyme disease does not alter the duration of parasitemia. parasites circulate for only days in persons who are treated with clindamycin and quinine; alternative antibiotic regimens include atovaquone and azithromycin. silent babesia infections occur commonly. some infected individuals develop a chronic carrier state lasing months to years. in others, recrudescence occurs spontaneously or after splenectomy or immunosuppression. , the parasite retains infectivity in red blood cell (rbc) components at refrigerated or frozen temperatures and in the residual rbcs contained in platelet concentrates stored at room temperature. , to date, more than post-transfusion cases involving b. microti and other babesia species have been reported. , , , , several reports involve donors who transmitted infections through multiple donations given up to months apart. , the overall risk of acquiring transfusion-associated babesiosis is low, but varies regionally. in connecticut, . % of seronegative donors became seropositive on a subsequent donation. in another study, . % of donors in endemic and nonendemic areas of connecticut had confirmatory indirect immunofluorescence assay (ifa)-positive test results for babesia infection; the prevalence rates peaked in july when . % of donors were seropositive. this represents a relatively high potential threat in an endemic area because of recipients became seropositive after receiving blood from ifa-positive blood donors. asplenia, older age, immunodeficiency, organ transplantation, and liver disease increase the risk of severe babesia illness. in acute symptomatic cases, fatigue, malaise, weakness, and fever occur in more than % of the patients. shaking chills, diaphoresis, nausea, anorexia, headaches, and myalgia occur frequently. heart murmurs, hepatomegaly, and splenomegaly are found in % to % of patients; jaundice occurs less frequently. renal failure, disseminated intravascular coagulation, and adult respiratory distress syndrome have been reported. the average hemoglobin concentration was . g/dl in a review of hospitalized patients with community-acquired babesiosis. examination of blood smears for intraerythrocytic ring forms and maltese cross-like tetrads (including more than two parasites per cell, contorted shapes, vacuoles, and budding), antibabesial antibody assays, and polymerase chain reaction (pcr) assays for babesial dna provide laboratory evidence of infection. , most transfusion-associated babesia cases involve rbc transfusions, although frozen-deglycerolized rbc and platelet units have been implemented. , , transfusion-acquired cases have an incubation period of to . weeks. , , , , blood-collection agencies ask all prospective donors whether they have ever had babesiosis. those answering affirmatively are deferred. however, donors are not asked about a recent history of tick bites or geographic residence because of the low predictive value associated with these questions. for example, . % of donors in connecticut reporting tick bites were seropositive for babesiosis antibodies compared with . % in those not reporting tick bites. serologic or pcr testing is impractical at this time. the absence of specific interventions to interdict donors capable of transmitting babesia infections relegates clinical awareness and prompt antibiotic therapy as the primary modality for treating this infrequent complication of transfusion therapy. the borrelia burgdorferi spirochete causes lyme disease, a tick-borne zoonosis present in mice, squirrels, and other small animals. more than , human lyme disease cases occur annually in the united states, although none has been associated with transfusion. endemic areas include the northeastern, mid-atlantic, and upper north-central regions of the united states. , ixodes scapularis, the black legged deer tick, transmits b. burgdorferi in the northeastern and north-central parts of the united states. i. pacificus, the western black-legged tick, transmits the infection along the pacific coast. the ticks feed predominantly in the late spring and early summer during their nymphal stage, and lyme disease usually results from bites of infected nymphs. deer do not become infected but rather transport and maintain the ticks. patients with lyme disease typically present with a characteristic erythema migrans rash accompanied by fever, malaise, headaches, myalgia, arthralgia, or bell's palsy. the rash occurs to days after a tick bite. b. burgdorferi spirochetes disseminate from the entry site via cutaneous, lymphatic, and blood-borne routes. in one study, spirochetes were isolated from the blood of % of patients with symptomatic lyme disease. b. burgdorferi has also been isolated from erythema migrans lesions. the diagnosis of lyme disease is based primarily on characteristic symptoms, physical examination findings, and a history of possible tick exposure. , [ ] [ ] [ ] [ ] serologic tests, including enzyme-linked immunoassays and ifa tests, become positive to weeks after infection. western blot testing is used to confirm the results of reactive screening tests. treatment with antibiotics clears the infection, but additional treatment to relieve symptoms is prescribed when arthritis persists after two antibiotic courses and for post-lyme disease syndrome. [ ] [ ] [ ] [ ] despite documentation that the spirochete survives routine rbc and frozen plasma storage, testing blood donors is not under consideration because no reports exist of transfusion-associated lyme disease. of note, transfusion of rbcs or platelets collected during peak deer tick activity to patients undergoing cardiothoracic surgery resulted in no serologic or clinical evidence of lyme disease. individuals with a history of lyme disease are accepted as blood donors provided they have been treated and are asymptomatic months after the last dose of antibiotics. the rickettsial agents human monocytic ehrlichiosis (hme) and human granulocytic ehrlichiosis (hge) are intracellular organisms that survive in stored blood and cause mild to severe illnesses. ehrlichia chaffeensis causes hme and is transmitted to humans through the bite of the lone star tick (amblyomma americanum) previously infected by contact with deer or possibly dogs. , most of the reported cases have occurred in the south-central and southeastern united states. anaplasma phagocytophila causes hge and is related closely to species infecting horses (ehrlichia equi) or ruminants (ehrlichia phagocytophila). this illness occurs predominantly in the northeastern, upper midwestern, and northwestern areas of the united states and is transmitted to humans by i. scapularis or i. pacificus ticks. , , [ ] [ ] [ ] fifty percent of ticks examined in one study in connecticut were infected with the hge agent, but none was infected with e. chaffeensis. patients with hme and hge present similarly, with fever, headache, myalgia, thrombocytopenia, leukopenia, and elevated liver enzyme concentrations. a rash occurs in one third of patients with hme but in fewer patients with hge. membrane-bound intracytoplasmic ehrlichia aggregates, or morulae, are present in monocytes. complications include respiratory distress, renal failure, neurologic disorders, and disseminated intravascular coagulation. septicemia, vasculitis, and thrombotic thrombocytopenic purpura should be considered in the differential diagnosis. , , , doxycycline is the treatment of choice. because ehrlichia are present in blood, transfusion transmission must be considered. one case of transfusionassociated hge occurred days after an rbc transfusion donated by an asymptomatic donor who had been exposed to extensive deer ticks months previously. the infected rbcs were stored for days before transfusion. an in vitro study suggested that leukocyte reduction may not be completely effective at preventing e. chaffeensis transmission because some pathogens are found in the cell free plasma fraction. an extensive epidemiologic study in arkansas involving military trainee blood donors who had been exposed to tick bites and unknowingly infected with the agents of ehrlichiosis and rocky mountain spotted fever (rmsf) found no clinical illness among the recipients of rbcs and platelets donated by these soldiers. however, possible seroconversion to rmsf occurred in one of the recipients. a single case report has been published of clinical illness associated with transfusion-transmitted rmsf infection. the donor developed symptoms of rmsf days after donation and died days later. the recipient, who developed fever and headache days after receiving the implicated rickettsia rickettsii-infected transfusion, was notified about the donor's illness and was treated effectively. other tick-borne agents implicated in transfusionassociated cases include colorado tick fever virus and tick-borne encephalitis virus. although the risk of transfusion transmission of these agents is low, clinical suspicion is important as a mechanism for determining infection by these organisms. malaria is a protozoan disease caused by four species of the genus plasmodium: p. falciparum, p. vivax, p. ovale, and p. malariae (table - ) . these protozoa are transmitted to humans by the bite of an infected female mosquito of the genus anopheles. infection of the human host, absent treatment, results in a chronic intraerythrocytic infection that can be transmitted by blood transfusion. the two-host life cycle of the malaria parasite is diagrammed in figure although the signs and symptoms of malaria are variable, most patients are febrile, and many also manifest headache, chills, sweating, nausea, vomiting, diarrhea, back pain, myal-gia, and cough. a diagnosis of malaria should be considered for any patient with these symptoms who has a history of travel to a malaria-endemic area or recent blood transfusion. given the periodic reports of local mosquito-borne transmission, malaria should also be considered in the differential diagnosis of patients who have fever of unknown origin regardless of their travel history. malaria is diagnosed microscopically by finding intraerythrocytic parasites on giemsa-stained peripheral blood smears. properly prepared thick and thin smears must be examined by trained laboratory personnel to make an accurate laboratory diagnosis. patients with negative smears suspected of having malaria should have additional smears examined daily for days. pcr can be a useful adjunct in cases in which serial testing of smears yields negative results. malaria is a huge global public health problem with an estimated annual incidence of to million cases and million deaths per year. malaria-endemic areas include parts of africa, asia, central america, hispaniola, north america, oceania, and south america. during the early part of the th century, specifically , an estimated , cases of malaria occurred in the continental united states, but since the s, improved socioeconomic conditions, water management, vector control, and case management have prevented endemic malaria transmission. ongoing malaria surveillance in the united states by the centers for disease control and prevention (cdc) continues to identify cases in immigrants and in residents and travelers to areas of the world where malaria transmission still occurs. additionally, each year, a few cases are reported that might represent local mosquito-borne transmission. for example, seven cases of locally acquired, mosquitotransmitted p. vivax malaria were reported in palm beach county, florida. multilocus genotyping of the ribosomal rna of the isolates from the seven patients revealed that they were infected by the same strain. congenital infections and transfusion-acquired infections round out the sources of malaria cases diagnosed each year in the united states. of cases of malaria in the united states with onset of symptoms in , one was due to transmission of p. malariae by blood transfusion. of cases reported in , one was due to transmission of p. falciparum after a blood transfusion. the overwhelming majority of reported cases in both years were imported (i.e., acquired outside the united states). data from through showed that cases were more frequently identified in foreign civilians than in u.s. civilians. however, since , the situation has reversed. cases in united states civilians are now reported at . to times the number in foreign civilians, most likely due to increased travel by u.s. civilians to endemic areas and decreased immigration since . from % to % of the cases among u.s. civilian travelers occurs in persons who failed to take prophylactic drugs, had not taken cdc-recommended drugs, or were noncompliant with a recommended drug. mosquitoes of the genus anopheles, with few exceptions, feed between dusk and dawn. the exceptions are daytime feedings in densely shaded woodlands or dark interiors of houses or shelters. therefore, travelers who visit malarial areas during bright daylight hours are at little or no risk for acquiring malaria if they return to a nonmalarial area before dusk. transfusion-transmitted malaria occurs at an estimated rate of . cases per million blood units collected. because of this low incidence and the lack of a laboratory test approved by the u.s. food and drug administration (fda), prevention of transfusion-transmitted malaria continues to depend solely on the donor-deferral guidelines established by the fda and most recently updated in . currently, prospective donors who are residents of countries where malaria is not endemic but who have traveled to a malaria-endemic area are temporarily deferred until year after their departure from the endemic area if they have remained free of symptoms suggestive of malaria. immigrants, refugees, citizens, and residents of malaria-endemic areas are deferred for years after can persist in the liver and cause relapses by invading the bloodstream weeks, or even years later.) after this initial replication in the liver (exo-erythrocytic schizogony), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony). merozoites infect red blood cells. the ring-stage trophozoites mature into schizonts, which rupture, releasing merozoites. some parasites differentiate into sexual erythrocytic stages (gametocytes). blood-stage parasites are responsible for the clinical manifestations of the disease. the gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested by an anopheles mosquito during a blood meal. the parasites' multiplication in the mosquito is known as the sporogonic cycle. while in the mosquito's stomach, the microgametes penetrate the macrogametes, generating zygotes. the zygotes in turn become motile and elongated (ookinetes) and invade the midgut wall of the mosquito where they develop into oocysts. the oocysts grow, rupture, and release sporozoites, which make their way to the mosquito's salivary glands. inoculation of the sporozoites into a new human host perpetuates the malaria life cycle. ( their departure from the endemic area if they have remained free of symptoms suggestive of malaria. prospective donors who were diagnosed and treated for malaria are deferred for years after becoming asymptomatic. between and , three cases of post-transfusion malaria due to p. falciparum, two of which were fatal, were diagnosed in the united states, prompting a review by the cdc of all cases of transfusion-transmitted malaria reported between and (see table - , which has been updated to include reported cases in and , ). in total, cases ( . per year) were reported through . thirty-four ( %) cases were caused by p. falciparum, ( %) by p. vivax, ( %) by p. malariae, ( %) by p. ovale, ( %) by mixed species, and ( %) by an undetermined species. p. falciparum cases increased in frequency over the period to , accounting for ( %) of cases during that interval, compared with ( %) of cases reported between and . of ( %) fatal cases overall, were associated with p. falciparum, with p. vivax, and with p. malariae. the incubation period in these cases ranged from to days, with p. falciparum having the shortest time (mean, days; range, to days) and p. malariae having the longest (mean, days; range, to days). the period between onset of symptoms and the time of diagnosis ranged from to days, with a median of days. ninety-four percent of the cases were associated with transfusion of whole blood or rbcs; % were platelet-associated. implicated donors were defined as having met one or more of the following criteria ( ) a blood smear that demonstrated malaria parasites, ( ) a positive result on malaria serology, and ( ) being the only donor. ninety-three donors were implicated in the cases. the median number of donors per case was seven (range, to ). donors were overwhelmingly male ( %) and ranged in age from to years (median, years). foreign-born donors accounted for % ( % of those from africa); % were born in the united states. of donors implicated in the cases for which epidemiologic follow-up was complete, serology was the most effective tool for identifying transmitting donors ( %); only % were identified by a positive blood smear. serology and blood smear were both positive in %, and % were implicated as the only donor to a case. analysis of all cases using current donor deferral guidelines revealed that ( %) cases occurred despite proper application of the guidelines. when reviewed against the guidelines in place at the time they occurred, cases could not be evaluated because their dates of onset were before when guidelines were vague; of the remaining cases would still have occurred, but would have been prevented if then-current guidelines had been applied properly. not surprisingly, most ( %) of the cases that occurred despite following guidelines were caused by p. malariae. the continued occurrence of cases in the face of current history questions highlights the reality that malaria risk from transfusion, although low, cannot be fully prevented by questioning of donors. although the deferral guidelines currently in place are based on the biology of the four species of plasmodia that cause malaria, they represent a balance struck between maximizing safety and minimizing donor loss. p. vivax and p. ovale, species that give rise to relapsing infections, rarely persist longer than years. however, some infections do persist, and individuals with these prolonged infections will transmit malaria if their blood is transfused. likewise, disease caused by p. falciparum, a nonrelapsing species, manifests within year after departure from a malarious area % of the time, but a report of falciparum malaria occurring years after departure from a malarious area has been published. the well-known ability of p. malariae to persist asymptomatically for decades in some individuals further highlights the difficulty of eradicating the risk of post-transfusion malaria through questioning of donors. the aabb has advocated the use of uniform donor screening questions to elicit malaria risk from prospective donors, including questions that inquire about a history of malaria and about the prospective donor's travel history within the past years. a "yes" answer to travel outside the united states and canada triggers further inquiry to pinpoint travel destinations in malarious areas. the fda is in the process of revising its guidelines for deferral of blood donors because of risk of malaria. however, it is unclear when the agency will issue the new guidelines. the proposed guidelines were discussed at the fda's blood products advisory committee meeting in june . in addition to retaining the provisions for donor deferral outlined in the fda memo of july , , the revised guidelines recommend adding the following question sequence to the donor history form: ( ) "were you born in the united states?" if yes, ask: ( ) "in the past years, have you been outside the united states or canada?" if the answer to ( ) is no, ask: ( ) "when did you arrive in the united states, and, since your arrival, have you traveled outside the united states or canada?" if the answer to question ( ) or the second question in ( ) is yes, follow-up questions will be asked of the donor to determine when and which country or countries were visited. the impetus for revision of the guidelines includes the increased number of imported malaria cases in the united states, the large number of postdonation events related to malaria reported to the fda, and the recognition that eliciting an accurate donor history is the only currently available defense against transfusion-transmitted malaria. from time to time, proposals to test donors for evidence of malaria have been advanced, but no fda-approved tests or policies for screening donors are currently in place. selective screening of high-risk donors has been suggested as an alternative to universal screening. blood-smear diagnosis is both impractical and insensitive as a donor-screening technique. the ifa test is useful diagnostically but is unsuitable for large-scale donor screening, although it could be used to test high-risk donors and to determine their suitability. although antibody assays detect most individuals with parasitemia, they also are positive in treated persons who are no longer parasitemic. hence, noninfectious donors would also be deferred if selective antibody screening were implemented. pcr is a promising approach that may have the required sensitivity and specificity, but it is currently not standardized and not available outside research laboratories. american trypanosomiasis, or chagas disease, is a zoonosis caused by the hemoflagellate protozoan parasite trypanosoma cruzi. the life cycle of t. cruzi involves transmission from insect vectors to mammalian hosts including humans. t. cruzi infects humans when triatomid (reduviid) or kissing bugs ingest a blood meal from the host and deposit infected feces into the wound or when contaminated feces contact the mucosal surface of the eye or mouth. hematogenous spread occurs subsequently. in addition, t. cruzi crosses the placenta and can cause congenital disease [ ] [ ] [ ] [ ] [ ] (fig. - ). acute chagas disease is associated with fever, facial edema, generalized lymphadenopathy, and hepatosplenomegaly. symptomatic myocarditis and meningioencephalitis can occur, and fulminant illness can develop in immunologically immature children or immunocompromised adults. however, in more than % of patients, the illness is mild and symptoms resolve in to weeks. if untreated, hosts then enter an indeterminate phase. ten percent to % of patients progress from the indeterminate asymptomatic phase to a chronic symptomatic phase associated with cardiac enlargement, apical aneurysms, mural thrombi, megaesophagus, or megacolon, appearing years to decades after infection. [ ] [ ] [ ] [ ] epidemiology an estimated to million people are infected in south america, central america, and mexico, where chagas disease is endemic and, historically, triatomid insects reside in cracks of rural and suburban houses with adobe walls. in the united states, an estimated , to , persons and in , blood donors may be infected with t. cruzi. almost all are immigrants from central and south america. chagas disease is responsible for , deaths worldwide annually. lifelong low-grade parasitemia persists in approximately % of those infected, and up to % of seropositive blood donors have parasitemia. this presents a risk of transfusion transmission and of vertical transmission to infants. between % and % of recipients of parasitemic blood become infected. estimates of risk for transfusion-associated chagas disease are related to immigration patterns from endemic regions. during the mid- s, . % of nicaraguan and salvadorian immigrants living in washington, d.c., had serologic evidence of t. cruzi infection. parasites were isolated from half. in the early s, . % of a selected blood-donor population in california and the u.s. southwest was seropositive for t. cruzi antibodies. at least % of these donors were of hispanic origin. during the mid- s, . % of donors at a hospital in los angeles responded affirmatively to questions inquiring about birth in chagas disease-endemic areas or residing in dwellings constructed of palm leaf-thatched roofs or walls made of mud, and . % tested positive for t. cruzi antibodies. in a study conducted in the mid-to-late s involving more than . million blood donors, in in los angeles and in in miami were t. cruzi seropositive. although a correlation exists between the percentage of immigrants from endemic areas and the percentage of blood donors with serologic evidence of t. cruzi infection, investigators have also identified seropositive blood donors who were born in the united states. congenital transmission may explain infection in these individuals. in addition, autochthonous transmission has been reported in the united states, and an infestation of triatomines has been reported in texas. since , seven cases of transfusion-associated chagas disease have occurred in the united states and canada. [ ] [ ] [ ] [ ] [ ] symptoms developed approximately to months after transfusion. in at least six of the cases, platelets were the implicated blood component; however, in the seventh case, the implicated unit was not identified. centrifugation may sediment t. cruzi into the platelet layer during component preparation, accounting for the association with platelet transfusions. whereas room-temperature storage of platelets may favor parasite survival, t. cruzi has been shown to survive in refrigerated rbcs and whole blood for at least to days. in six of the north american transfusion-associated cases, a donor emigrating from a t. cruzi-endemic region (bolivia, mexico, paraguay, chile) was identified. four of the donors emigrated between and years before the implicated donation. given this small number of cases, transfusion transmission of chagas disease may be inefficient. in a study of patients receiving blood from blood donors subsequently found to be t. cruzi seropositive, none of the recipients became seropositive after transfusion. however, only two received platelet transfusions. a report of chagas disease also has been reported after transplantation involving an organ donor who emigrated from central america appeared in . the recipient of a kidney and pancreas died of acute chagas myocarditis months after transplant. the recipients of the other kidney and the liver were both also infected with t. cruzi. interventions to reduce the risk of transfusion-transmitted chagas disease include questioning donors about geographic location of birth, extended stay or transfusion in areas endemic for chagas disease, and serologic testing. , , donor history questions may be only % effective. at least one candidate serologic screening assay has undergone clinical trials in the united states and is currently under review at the fda. the u.s. fda has indicated that it will require testing for chagas disease if an appropriate screening assay achieves licensure. this decision reflects the reported transfusion-and organ transplant-associated cases and the concern that up to transmissions may occur annually in the united states. leukocyte reduction by filtration is modestly effective, reducing t. cruzii transmission by % to % in a mouse transfusion model. serologic testing of blood donations for syphilis was instituted in and required by regulation in . no cases of transfusion-associated syphilis have occurred in the united states since . multiple factors-improved donor selection, uniform serologic testing, lack of spirochete viability in blood stored at refrigerated temperatures, and widespread antibiotic use-apparently contribute to the current absence of transfusion-transmitted syphilis cases. [ ] [ ] [ ] in , the aabb standards committee deleted the requirement for syphilis testing, and an fda advisory panel proposed eliminating the requirement for serologic syphilis testing in . however, these changes were not made because of the belief that such testing might identify those at risk of transmitting the hiv. subsequently, observational data did not support this assumption. nonetheless, a national institutes of health consensus statement, issued in january , recommended continuation of syphilis testing because its role in preventing transfusion-transmitted syphilis was not "understood." a lack of complete laboratory data also supports test retention. although spirochetes survive to hours at refrigerated temperatures, , viability at room temperature (e.g., in platelet concentrates) has not been studied. furthermore, loss of viability during storage is an incomplete protection mechanism. no single optimal laboratory test exists for syphilis. the infectious agent, treponema pallidum, is an anaerobic organism that cannot be cultured in vitro. during treponema infection, nontreponemal and treponemal antibodies are produced. the nontreponemal antibodies (reagin antibodies) react against phospholipid isolated from beef heart or cardiolipin. these antibodies are detected by the venereal disease research laboratory (vdrl), rapid plasma reagin (rpr), and other tests in response to the interaction of infected host tissue with t. pallidum. they parallel the pathologic course but have no relation to immunity. treponema-specific antibodies have a higher serologic sensitivity in the early stages of syphilis but are less effective indicators of disease activity. during the first weeks after primary infection, the vdrl is positive in % of cases, and the fluorescent treponemal antibodyabsorption (fta-abs) test is positive in %. other treponemal antibody tests, often used to confirm nontreponemal tests, include t. pallidum particle aggregation (tp-pa) and recombinant antigen tests. an automated test for treponemal antibodies, pk (tm) treponema pallidum (pk-tp), performed on the olympus pk , is widely used. [ ] [ ] [ ] reaction patterns characterized by positive rpr or pk-tp tests and negative fta-abs reactions (socalled false-positive reactions) may be caused by hepatitis, mononucleosis, viral pneumonia, chickenpox, measles, immunizations, pregnancy, or laboratory error. persistent false-positive reactions have been reported in patients with rheumatoid arthritis, cirrhosis, ulcerative colitis, vasculitis, and older age. [ ] [ ] [ ] among pk-tp-and fta-abs-positive blood donors, approximately half give a prior history of a treated syphilis infection. a history of lupus, rheumatoid arthritis, and diabetes did not provide an explanation for nonconfirmed pk-tp results. the typical first sign of syphilis, a chancre, appears to days (average, days) after exposure. the exact timing of spirochetemia and t. pallidum dissemination from the chancre and of seroconversion is not known. secondary syphilis, characterized by a disseminated rash and spirochetemia, occurs to weeks after infection. serologic tests are almost universally positive. if patients remain untreated, recurrent fulminant secondary syphilis recurs within years in approximately %. subsequently, patients become immune to reinfection and become noninfectious. vdrl titers decrease over time. unless patients are treated in the primary stage, treponemal antibodies persist in both treated and untreated patients. tertiary syphilis develops after a variable length of time. reactivation is clinically and serologically noticeable via anticardiolipin and treponemal antibody detection. , , currently, donations with reactive syphilis screening tests are unsuitable unless nonreactive in a confirmatory test. if the confirmatory test is positive, donors are deferred for year; they are then allowed to donate again, provided that they have undergone adequate treatment for syphilis, and a nontreponemal assay is negative. human parvovirus b was discovered serendipitously in human plasma during blood-donor screening for hepatitis b surface antigen in . initially, parvovirus was linked causally with transient aplastic crises in patients with sickle cell anemia and subsequently in patients with other inherited hemolytic diseases, as a result of severe reticulocytopenia and anemia. b was later found to be the etiologic agent of fifth disease or erythema infectiosum, a common childhood illness that manifests as an erythematous rash. , the rash occurs less often in infected adults than children. fever and nonspecific symptoms precede the rash and arthralgia, both of which probably result from immune complex deposition in the skin and other organs. hepatitis, myocarditis, vasculitis, and the gloves-and-socks syndrome have also been linked to b infection (fig. - ) . b infects only humans, and transmission occurs most commonly via the respiratory route. in addition, transplacental transmission of parvovirus b occurs in % of women infected during pregnancy. in women infected during weeks to of pregnancy, hydrops fetalis and fetal death occur in approximately %. the virus is highly tropic for erythroid progenitor cells, gaining access to cells through the blood group p antigen, or globoside, which has been identified as the virus receptor. , , the viral genome consists of single-stranded dna that codes for three proteins. the nonstructural protein, ns , is cytopathic to host cells. viral protein and viral protein code for α-helical loops that appear on the capsid surface. neutralizing antibodies recognize vp . the nonenveloped virus consists of symmetric particles mm in diameter. b infection is ubiquitous in human populations and is already prevalent in pediatric age groups. seroprevalence studies show antibody frequencies of % in high schoolage children and up to % in older adults. , epidemics and sporadic infections may occur at any time of year, with major outbreaks of erythema infectiosum occurring every to years. persistent parvovirus infection, including pure rbc aplasia, occurs in those not developing neutralizing antibodies to vp . the virus circulates at high titer, greater than genome copies per milliliter. , patients receiving cytotoxic chemotherapy, immunosuppressive drugs, organ transplant recipients, and patients with immunodeficiency and the acquired immunodeficiency syndrome (aids) are at higher risk of developing chronic infections. the therapeutic approach for persistent parvovirus infection involves discontinuing immunosuppressive therapy, administering intravenous immunoglobulin (ivig) preparations, instituting antiviral therapy for aids patients, and giving repeated courses of ivig as needed. , the transient -to -week, high-titer viremia accompanying acute asymptomatic b infection allows virus transmission by blood, blood derivatives, and organ transplantation. , , the infrequent recognition of transfusion-associated cases reflects the short viremic phase and the high frequency of immunity among transfusion recipients. in contrast to recipients of blood transfusions, almost all recipients of plasma-derived factor viii and ix concentrate are at risk for b . parvovirus circulates in the blood of approximately in plasma donors. fourteen percent had titers between and genome equivalents per milliliter, and in , had greater than genome equivalent per milliliter. not surprisingly, in plasma derivatives prepared from large-scale plasma pools, pcr testing detects parvovirus b in most lots. in observational studies, recipients of solvent/detergent-treated plasma seroconverted after infusion of products with high-titer parvovirus dna, . to . genome copies per milliliter, suggesting that the presence of anti-b antibodies was not protective against large viral loads. seroconversion did not occur among recipients of lots with viral titers between . and . genome copies per milliliter. the virus is resistant to viral-inactivation steps such as solvent/detergent treatment and heat after lyophilization or in the vapor stage. heat may reduce infectivity if applied in the liquid state. children receiving plasma-derived factor viii concentrates were at least . -to . -fold more likely to be b seropositive than were those receiving no product or recombinant-derived anti-hemophilic factor. parvovirus seemingly becomes concentrated in the plasma fraction used in factor viii preparations. despite the high frequency of parvovirus exposure, long-term sequelae appear subtle. , for example, parvovirus b -seropositive hemophilic children had an -degree loss in joint range of motion, a . % difference, compared with seronegative children. unlike factors viii and ix, albumin has not transmitted parvovirus b . [ ] [ ] [ ] [ ] [ ] [ ] [ ] one report implicated parvovirus transmission by ivig based on detection of viral dna by pcr. however, no documentation showed the same viral genotype in the recipient and the immunoglobulin preparation. in light of these data, in , regulatory agencies and manufacturers of plasma derivatives sought to reduce b dna levels below genome copies per milliliter in plasma pools containing to plasma donations. however, subsequent reports showed that parvovirus transmission occurred in a recipient of solvent/detergent-treated antihemophilic factor containing . × genome equivalents per milliliter and a recipient of a dry-heat-treated factor viii product containing × genome equivalents per milliliter. in these cases, smaller plasma batches with high viral loads were combined to form larger pools used in manufacturing the antihemophilic factor concentrates. currently, manufacturers conduct "in-process" testing to eliminate plasma donors with high-titer b levels. for example, "recovered plasma" (plasma obtained from wholeblood donations) that is intended for fractionation into plasma derivatives undergoes b dna testing via nucleic acid amplification testing (nat) assays on aliquots from pooled samples. subpool analyses are performed to determine which of the samples contained the high-titer donor. these high-titer units, approximately per , donations, are withheld from product manufacture. because the infection is transient and a carrier states does not exist, the infected donor is not identified specifically or permanently deferred. because whole-blood donations rarely transmit parvovirus infections, testing of single unit rbcs, platelets, or plasma for parvovirus b is not under consideration in the united states. transmissible spongiform encephalopathies (tses) occurring in humans include kuru, cjd, gerstmann-sträussler-scheinker disease (a phenotypic variant of cjd), fatal familial insomnia, and variant cjd (vcjd). tses occurring in animals include scrapie (sheep and goats), wasting disease of deer and elk, transmissible mink encephalopathy, and bovine spongiform encephalopathy. [ ] [ ] [ ] the tse infectious agents are classified as prions, or proteinaceous infectious particles that lack nucleic acid. tses resist inactivating agents such as alcohol, formalin, ionizing and ultraviolet irradiation, proteases, and nucleases but are disrupted by autoclaving, phenols, detergents, and extremes in ph that affect proteins. the normal host membrane prion protein prp (designated prp c ), whose function is unknown, is protease sensitive, soluble, and has a high α-helix content. all prion diseases appear to involve conformational modification of prp c to a protease-resistant altered isoform that forms amyloid fibrils (designated prp sc ). the conversion of prp c to prp sc results in refolding of a portion of the α-helical and coil structure of prp c into β-sheets. neuronal loss and vacuolization leads to a spongioform appearance in the brain cortex and deep nuclei. cjd occurs at an incidence of . to . cases per million population worldwide. this rate has increased slightly over the past decade presumably on the basis of improved diagnostic accuracy and greater numbers of older individuals. , fewer than cases per year are reported in the united states. sporadic cjd, causing approximately % of cjd cases, occurs in persons to years of age (average age at onset is years) and is manifested by disordered sleep and decreased appetite, behavioral or cognitive changes or focal signs such as visual loss, cerebellar ataxia, asplasia, and motor deficits. the mean survival time is months. the mode of infection for sporadic cjd is uncertain. approximately % to % of cjd cases occur in patients with a family history of cjd, suggesting an autosomal dominant inheritance pattern and mutations in the prmp gene that codes for the prion protein. more than mutations in this gene, located on the short arm of chromosome , have been identified, but point mutations at codons , , , and occur in % of familial cases. approximately % of cjd cases involve iatrogenic transmission. for example, cjd was transmitted by a corneal transplant from a patient with undiagnosed cjd, whereas stereotactic electroencephalographic silver electrodes previously implanted in a patient with cjd subsequently resulted in two iatrogenic cjd cases. , more than young adults have died to years after receiving intramuscular human growth hormone injections prepared from cadaveric pituitary glands from donors with unsuspected cjd. , cadaveric dura mater grafting with a commercial product prepared by batch processing resulted in at least cjd cases worldwide, some occurring years after graft placement. , in sporadic and iatrogenic cases of cjd, a polymorphism involving codon in the prp gene appears to affect susceptibility. normally % of the population are methionine/methionine homozygous, and % are valine/valine homozygous at codon . the remaining % are heterozygous. homozygous individuals represent almost % of sporadic and iatrogenic cjd cases. , those homozygous for methionine are at risk for fatal familial insomnia, whereas those homozygous for valine are at risk of clinical cjd. in experiments involving mice infected with a strain of gerstmann-sträussler-scheinker disease, blood-component infection was demonstrated. in contrast, no evidence of transfusion-associated cjd was documented in case-control studies involving more than patients with cjd or in recipients of blood from persons who subsequently developed cjd. [ ] [ ] [ ] examination of brain tissue from deceased hemophilia patients showed no evidence of cjd. , , no transfusion-associated cjd cases have been reported to date. nonetheless, the occurrence of iatrogenic cases and the theoretical risk of cjd transmission by blood led the fda to issue a recommendation to defer donors if they have one or more blood relatives with cjd or if they have received human pituitary-derived growth hormone injections or a dura mater transplant. all in-date products from donors with these risk factors must be quarantined and destroyed, and the previous recipients of blood from implicated donors, with the exception of those who have only one family member with cjd, must be notified. in the spring of , several dairy cows in the united kingdom displayed aggressive behavior, ataxia, and falling. these "mad cows" were found to have spongiform lesions in brain tissue resembling scrapie that was subsequently termed bovine spongiform encephalopathy (bse). more than , cattle succumbed to bse, but almost million may have been infected. because the mean incubation period for bse is years and most cows were slaughtered between and years of age, most cattle did not manifest disease. [ ] [ ] [ ] approximately , bse-infected cattle entered the food chain before the first bse case was recognized in . subsequently, the onset of the bse epidemic was traced to a meat-and-bone cattle feed made from sheep, cattle, and pig offal. the rendering process presumably resulted in the feeding of scrapie-infected material to cows. use of sheep offal or other tissues from ruminant animals as feed for other ruminant animals was banned in . the annual incidence of clinical cases in cattle peaked in . after march , only animals younger than months were eligible for food preparation. surveillance for human cjd cases heightened in the united kingdom after recognition of the bse epidemic. ten of cjd patients in and had unusual neuropathologic changes. , they had predominantly psychiatric and sensory symptoms, ataxia, dementia, and myoclonus. all were younger than years, a distinctly unusual characteristic for cjd. electroencephalographic features were not typical of cjd, and florid prp plaques were seen on neuropathologic examination. median survival time was months, in contrast to months for cjd. these cases were considered a new variant of cjd (vcjd). the median incubation period for food-borne vcjd is years. extensive investigations using animal models provided evidence that the same prion strain causes bse and vcjd. ingestion of british beef, therefore, was identified as a risk factor for bse. as of june , cases of vcjd have been reported in the united kingdom, in france, in ireland, each in portugal, spain, italy, the netherlands, saudi arabia, japan, and canada, and in the united states. the latter three plus one irish patient were thought to result from exposure in the united kingdom. the japanese patient spent only days in the united kingdom. all patients tested were homozygous for methionine at prp codon . by , the incidence of human vcjd cases peaked, suggesting that clinical manifestations among methionine/methionine homozygotes may be less than anticipated after extensive exposure to cattle with subclinical disease. , , concern about transfusion transmission of vcjd increased because prp sc is found consistently in the lymphoreticular system of vcjd patients, the possibility that circulating prions transfer the infection from the gut to the brain, and eventually because of animal studies. , , in animal model experiments, sheep were fed aliquots of brain obtained from bse-infected cattle. subsequently, the sheep underwent phlebotomy at periodic intervals. among sheep receiving blood from iatrogenically infected donor sheep, given blood from donors in the preclinical bse phase developed bse, and receiving blood from clinically affected sheep showed clinical signs of bse. among sheep transfused with blood from natural scrapie-infected animals, demonstrated clinical signs of scrapie. , an active investigation to determine whether transfusion associated-vcjd transmission occurs in humans began in the united kingdom in by identifying vcjd patients who donated blood before illness. eventually, recipients of blood from donors with vcjd were identified. three of the recipients, to date, have evidence of vcjd. one, at age years, received non-leukocyte-reduced rbcs from a year-old donor who developed vcjd . years after the blood donation. the transfusion recipient developed vcjd . years after transfusion. the second patient received a transfusion of non-leukocyte-reduced rbcs in . the donor developed vcjd months later. the asymptomatic recipient died of a ruptured abdominal aortic aneurysm years after transfusion. at autopsy, protease-resistant prions were present in the spleen and cervical lymph nodes. prions were not detected in the brain. the recipient, found to be heterozygous (methionine/valine at codon ), did not have clinical vcjd, raising concern that the incubation period may be longer in codon heterozygotes. in animal studies, a primary challenge with vcjd prions resulted in a significantly reduced transmission rate in mice with valine at codon compared with that in animals homozygous for methionine. additional data are needed to confirm whether the incubation period varies among methionine homozygous and heterozygous individuals. the third case developed vcjd approximately years after receiving non-leukocyte-reduced red cells from a person who developed vcjd months postdonation. a the u.k. national blood service also determined that approximately people donated blood to four patients who subsequently showed clinical signs of vcjd. these donors were notified that they may be at higher risk of developing vcjd despite the uncertainty of whether the patients contracted vcjd through food or blood transfusion. in addition, uk authorities notified recipients of factor xi concentrates that donors of these components developed vcjd after donation on the ethical tenet of transparency. the united kingdom currently imports plasma from the united states for patients younger than years and uses apheresis-derived platelets in these patients to reduce donor exposures. , the identification of presumed transfusion-associated vcjd cases appears to validate the steps taken in response to the precautionary principle to decrease the risk of transmitting vcjd by transfusion. donors who visited or resided in the united kingdom for a cumulative period of months or longer between and are deferred indefinitely. donors who spent years or more in europe before and the present are also deferred. in addition, donors are indefinitely deferred if they injected bovine insulin after , received transfusions in the united kingdom and france between and the present, or served in the military on bases in europe for months or more between and . this geography-based donor-deferral protocol evolved in various phases beginning in . approximately . % of potential donors in the united states have been deferred as a result of this policy. the impact was higher in canada. in-date blood components and plasma intended for derivative production from these donors must be recalled, quarantined, and destroyed. ongoing surveillance of vcjd cases, which increased after identification of a texas cow with bse, is currently being conducted, including a recommendation to notify the cdc about all patients younger than years who are diagnosed with cjd. in addition to geographic exclusion policies, other strategies for preventing vcjd transmission include removal of the infectious agent and testing. in the united kingdom, all blood components undergo leukocyte reduction by filtration, based on observations that prions associate with leukocytes. leukocyte reduction, however, is only partially effective, removing only % of total prion infectivity. filters that specifically remove prions and laboratory tests that detect infectious prions are currently being developed and evaluated. the latter, if implemented, will be accompanied by significant ethical concerns. visceral forms of leishmaniasis result from infection with leishmania donovani or leishmania infantum. cutaneous lesions occur in persons infected with leishmania braziliensis or leishmania tropica, the cause of old world cutaneous leishmaniasis. however, at least eight soldiers returning from eastern saudi arabia after operation desert storm developed visceral leishmaniasis that was attributed to l. tropica. , the leishmania organisms, transmitted primarily by bites from infected sand flies, are endemic in the tropical and subtropical regions of the sudan, eastern india, bangladesh, nepal, brazil, and the mediterranean. after transmission by sand fly bite, parasites reside intracellularly in monocytes, which circulate before taking up residence in internal organs. in the most severe manifestation of visceral leishmaniasis, kala-azar, patients have marked hepatosplenomegaly, pancytopenia, hypergammaglobulinemia, and cachexia. the incubation period is approximately months. anti-l. donovani antibodies form shortly after infection. in studies conducted in brazil, seropositive asymptomatic blood donors were found to have positive pcr results for l. donovani, demonstrating the ongoing potential of transfusion transmission in endemic areas. at least transfusion-associated cases of leishmaniasis attributed to l. donovani have been reported in endemic regions. most of those infected were young children or neonates. a probable case of platelet transfusion-transmitted leishmania was reported recently. transfusion-transmission also appears to occur in dogs receiving transfusions of rbcs from seropositive dog-blood donors. veterans of operation desert storm who served in the persian gulf region between august and december were deferred from blood donation for year, after the report of l. tropica-related viscerotropic leishmaniasis. the patients had nonspecific clinical manifestations, including prolonged fever, malaise, abdominal pain, and intermittent diarrhea, which occurred up to months after they returned to the united states. l. tropica was found in the bone marrow of seven patients and in a lymph node in one patient. intracellular amastigotes were seen in the peripheral blood of the one patient in whom this was studied. after reports of hundreds of cases of cutaneous leishmaniasis and two cases of visceral leishmaniasis in troops involved in the iraq war, a similar -year deferral after departure from iraq was instituted in october . l. tropica within human monocytes survives in blood stored at ° c to ° c, in frozen rbcs, and in platelet concentrates stored at room temperature. however, l. tropica has not been detected in relatively cell-free fresh frozen plasma. animal studies demonstrate transmission by contaminated blood. no cases of transfusion-transmitted leishmaniasis have been reported in the united states to date. for this reason, surveillance and targeted donor deferral appear to be appropriate. use of leukocyte filters to reduce leishmania transmission is under investigation. toxoplasma gondii is a ubiquitous parasite whose usual host is the domestic cat. infection sometimes results in lymphadenopathy, malaise, fever, headache, sore throat, splenomegaly, hepatomegaly, and rash. retinopathy and lethal infections occur in immunocompromised hosts. transfusion transmission was reported in . however, the cases occurred among leukemia patients given granulocyte transfusions obtained from other leukemic patients. another case report suggested that a patient undergoing chemotherapy for a leukemic relapse years after receiving an allogeneic marrow transplant developed toxoplasma pneumonitis. a person with serologic evidence of recent toxoplasma infection donated one of the units of blood transfused to the patient. in addition, a -year-old woman with drug-induced thrombocytopenia developed toxoplasma retinochoroiditis, presumably related to a platelet transfusion. a case further emphasizing the importance of nontraditional routes of infection in immunocompromised patients involved a renal transplant recipient who developed toxoplasmosis. the infection was presumably transmitted by a kidney obtained from a seropositive organ donor. dengue, transmitted by aedes mosquitoes, has infected at least u.s. travelers to caribbean islands (including puerto rico and the u.s. virgin islands), pacific islands, asia, central america, africa, and hawaii between and . , the incubation period is to days. infections cause either no symptoms, mild illness, or severe disease including hemorrhagic manifestations and shock. transmission by bone marrow transplantation and several reports of transmission after needle-stick injuries involving symptomatic patients raise the possibility of transfusion transmission by asymptomatic travelers returning from endemic areas. [ ] [ ] [ ] more than % of nonhuman primates in zoos or in animal research facilities are infected with simian foamy virus (sfv), an endogenous, cell-associated retrovirus found in new and old world primates. surveillance studies indicate that approximately % of zoo and biomedical research personnel working with chimpanzees and baboons are infected with sfv. evaluation of archival samples documented infection for to years (median, years). all subjects remained healthy, and each of three spouses undergoing testing for sfv were nonreactive. in addition, % of bush hunters in central africa and % of those exposed to free-ranging nonhuman primates in asia tested positive for sfv. , presumably, those infected were inoculated through exposure to saliva from bites or close contact through exposure to body fluids. only limited information is available about transfusion transmission. one occupationally exposed sfv-infected individual donated blood times during an interval when sfv test results, conducted retrospectively, were positive. none of the tested recipients of rbcs, leukocyte-reduced rbcs, or platelets was sfv positive. three of these blood components were stored for less than days. infections with lymphocytic choriomenigitis virus (lcmv), a rodent-borne arenavirus, usually cause mild, self-limited illness or aseptic meningitis in nonimmunosuppressed patients. human infections typically follow exposures to body fluids or infected animal excretions. vertical transmission occurs, but lcmv is not considered to be communicable from person to person. lcmv has been transmitted to four organ transplant recipients via an asymptomatic organ donor who had a cerebrovascular accident and subsequent brain death. the donor apparently became infected by exposure to a pet hamster. within weeks of transplantation, the recipients of the liver, lungs, and two kidneys developed fever, rash, or diarrhea; three of the four recipients died. a previous case also involving four transplant recipients was unrecognized until this case was reported. transfusion transmission has not been reported but is a possibility, given transmission by solid-organ transplantation. the avian influenza a/h n virus has spread epidemically among birds and poultry since emerging in hong kong in . since that time, more than million birds and poultry have died or been culled to prevent epidemic progression via bird migration in cambodia, china, indonesia, japan, laos, south korea, thailand, vietnam, malaysia, turkey, romania, and russia. transmission to humans via contact with infected poultry or contaminated surfaces has resulted in more than deaths. to date, human-to-human transmission has occurred infrequently. however, concern exists that mutations, reassortments, or recombinant rearrangements of the virus with pathogenic human influenza viruses could produce a virus capable of jumping the species barrier and causing a worldwide pandemic. influenza viremia is infrequent, although highly pathogenic avian influenza can be transmitted via blood. although transfusion transmission is a theoretical risk, a more likely impact would be large-scale donor illness and blood shortages. sars, caused by a novel enveloped rna coronavirus, infected more than patients in countries in february and march . this highly contagious illness dominated worldwide public health attention, resulting in rapid identification, travel advisories, patient quarantine, and eventual eradication of the epidemic. the -week asymptomatic incubation period fostered spread of the virus through close person-to-person contact and raised the possibility of blood-borne infection. for this reason, the u.s. fda issued a guidance document in april requiring blood-collection agencies to defer anyone from donating blood for at least days after possible exposure to sars. those with a suspected sars illness were deferred for at least days after recovery. notices were posted in blood centers apprising donors about sars-affected areas, and donors were asked about recent travel history. those traveling to affected areas, including transit in an airport at these locations, were deferred from blood donation. the epidemic subsided within months. no reports of transfusion-associated sars exist. west nile virus (wnv) is a mosquito-borne, lipid-enveloped, rna virus in the japanese encephalitis flaviridae complex. the viral genome codes for capsid, membrane, envelope, and nonstructural proteins. the virus, transmitted from bird to bird by mosquito vectors, infects humans as incidental hosts. the virus was identified in the west nile district of uganda in . outbreaks occurred subsequently in the mid-east, south africa, and europe. the first north american cases were recorded in new york city in . in addition, viremic blood donors were identified. wnv activity in birds and mosquitos occurs throughout the year, especially in warmer regions. the virus becomes detectable in blood to days after a mosquito bite, followed by an increase in viral loads. however, peak titers are relatively low (median of copies per milliliter) compared with hiv and hcv ( to per milliliter). rna levels decrease markedly to days after infection when immunoglobulin m (igm) antibodies, and subsequently igg anitibodies, appear. igm antibodies persist for more than days in approximately two thirds of those infected. the mean duration of viremia is days. however, wnv rna was detected up to days after infection in one blood donor. [ ] [ ] [ ] [ ] [ ] [ ] approximately % of persons infected with wnv remain asymptomatic. the % with symptomatic infections report abdominal pain, chills, fever, generalized weakness, headache, joint pain, muscle weakness and pain, new macular rash on the trunk and extremities, new difficulty thinking, painful eyes, and swollen glands. one in infected persons develops meningitis, encephalitis, or asymmetric flaccid paralysis. fatal outcomes occur in % to % of those with severe disease. wnv transmission in four recipients of organ donations was reported in . the organ donor, in turn, received blood transfusions from donors, one of whom subsequently was found to be wnv infected. a sample from the organ donor subsequently tested wnv rna positive, but wnv igm negative. initial reports of transmission by blood transfusion in eventually resulted in confirmation of cases of transfusion-associated wnv infection. the interval between transfusion and symptom onset was days (median interval range, to days). nine of implicated blood donors reported wnv-associated symptoms before donation. after intense collaboration among u.s. public health authorities, test manufacturers, and blood-collection agencies, nat for wnv rna was implemented before the wnv season. as a direct result of testing, more than donors were found to be wnv rna positive in , preventing wnv transmission to approximately recipients of rbcs and components prepared from these donations. , , during the summer months, approximately per units was wnv rna positive. in high wnv endemic areas, in approximately donors was wnv viremic. in , six transfusion-associated wnv cases were reported. all of the implicated donors had extremely low-level viremia that escaped detection by routine testing in minipools containing aliquots from to donations. testing of individual samples in high-incidence areas increases test sensitivity by approximately % and was introduced in when incident cases exceeded preestablished thresholds (approximately wnv-positive donor per donations). only one confirmed transmission occurred in . among the confirmed transfusion cases, all implicated donations were wnv igm antibody negative. , a second transplant-associated incident involving three of four organ recipients who developed wnv infection after transplant was reported in . of note, the organ donor (infected through mosquito bites) was wnv rna positive and igm antibody positive. this report raises concern that organ-transplant recipients and other heavily immunosuppressed patients are at extremely high risk for severe wnv complications and that the virus remains viable in organ/ tissue reservoirs despite a humoral immune response. overall, the rapid implementation of wnv testing within months of the initial transplant and transfusion-associated cases resulted in dramatic reduction of further transfusiontransmitted cases. assuming that rna-positive, igm antibody-positive donors do not transmit wnv through blood transfusion, 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nile virus rna screening and supplemental assays available in transmission of west nile virus through blood transfusion in the united states in and investigations of west nile virus infections in recipients of blood transfusion and organ tranplantation insights on donor screening for west nile virus problem solved? west nile virus and transfusion safety nile virus infections in organ transplant recipients: new york and pennsylvania cdc. investigation of rabies infections in organ and transplant recipients key: cord- -obvk d e authors: slater, margaret r. title: the welfare of feral cats date: journal: the welfare of cats doi: . / - - - - _ sha: doc_id: cord_uid: obvk d e nan for over four thousand years, cats have closely accompanied the development of human society, both as real and as symbolic creatures. often associated with evil, witchcraft, devil worship or simply bad luck, they have at times been used as scapegoats for natural disasters or personal misfortunes (tabor ; serpell ) . while some of these negative stereotypes persist to the present day, ever since the th century there has been a rapid evolution towards a far more favourable perception of cats. in many countries the welfare of all cats, and in particular feral cats, has become a focus of public concern. feral cats are likely to be found wherever humans have traveled, either as escapees from domestication or as deliberately introduced controllers of rodents or other pests (figure ). the interest in feral cats may focus on animal control, especially in countries where the free-roaming dog problem no longer is a major concern, or on issues such as predation, public health or the well-being of the cats themselves. feral cats are still viewed by many as creatures living on the borders of civilized communities. this view reinforces the peripheral status of cats and emphasizes their wild or natural propensities. there are also those who argue that feral cats do not belong in the wild, because they are introduced predators of more valued species. i hope to throw some light on the discussion about where feral cats belong, and how to deal with them, by examining selected english language publications, particularly those from the past fifteen years. i have used the scientific literature when it is available but for some types of information, lay publications and personal communication are the only available sources. the reliance on humans for food and shelter (strays) or independence of humans (ferals) (hugh-jones et al. ; dickman b) . i have not defined feral cats in the usual biological sense, which views them as having "escaped" domestication and gone wild, or as having populations which reproduce in the wild. my definition of a feral cat is a pragmatic one, based on the status of an individual cat at a particular point in time. a feral cat is one that cannot be handled and is not suitable for placement into a typical pet home, that is, a cat that is unsocialized. socialization is defined as the process by which an animal develops appropriate social behaviour toward conspecifics (turner ) . however, the term is commonly used to describe the relationship between cats and humans, in the context of "socialization to humans". i use the term socialized rather than tame, as it is a more accurate description of those cats that are adoptable. the socialized or unsocialized (feral) status must be determined, recognizing that there is considerable variability among cats which may be modified by the situation and change with time. the experience, knowledge and type of interaction of the observer may have a great influence over the gestalt assessment of each cat's sociability. many factors have been shown to affect the socialization of cats, and are discussed in chapter . in general, the sociability of a cat relates to its comfort when handled by a person. the sociability index is a spectrum, ranging from cats that are completely unfamiliar with humans, are terrified of them and cannot be handled (feral cats), through cats that have some limited interaction with familiar caretakers, to cats that are very social and friendly. a stray cat is an owned cat that is lost, or has been abandoned by an owner. stray cats are usually considered to be socialized since they were in a household in the recent past. ownership level refers to the degree of care and commitment provided by people towards cats. at one end of the spectrum are cats considered by their owners as members of the family, and whose social, environmental and health needs are provided for. at the other end are cats that are not cared for by humans, and in between are cats that receive some level of care from a specific person or household, or receive regular but limited care by caretakers. another concept is the confinement level of the cat. confinement ranges from completely indoor cats, to cats confined to the owners' property, to cats that are allowed to roam some or all of the time. generally feral cats are not confined. cats that roam freely, at least for part of the time, are those that usually cause problems and concerns. terms such as barn cat, alley cat, doorstep cat, etc. are used to refer to the locations of the cats. these terms should only be used to describe the location of the cats and not to imply their sociability or ownership status. a colony is a group of three or more sexually mature cats living and feeding in close proximity. a queen and her nursing kittens are not a colony as the kittens are still dependent on the mother and immature. this situation has been described as a "proto-colony" since, in time, the kittens and queen will likely become a colony. a managed colony is a colony that is controlled by a trap, neuter and return approach (see section . ). feral cats may be the offspring of existing feral cats, lost or abandoned cats that have become unsocialized or the offspring of owned, intact cats allowed outside. the relative importance of each source will vary widely from location to location and has rarely been studied. data on cat ownership in different countries are presented in chapter . data on the proportion of owned cats that are allowed to roam are not available, and probably vary widely between countries. there may be many stray cats that could potentially become feral. studies in the united states found that about % of owned cats were acquired as strays (new, jr. et al. ) . another study of a single community found that % of owned pets were former strays and % of cats entering a shelter were impounded strays (patronek et al. ) . litters from owned cats are another potential source of feral cats. one study in massachusetts reported that over % of all cats (male and female) were sterilized. in spite of this high sterilization rate % of currently sterilized female cats had previously had litters, with a similar number of total litters per female for intact and sterilized cats (manning & rowan ). own (haspel & calhoon ; johnson et al. ; johnson & lewellen ; luke ; levy et al. b) . it has been suggested that in the united states the number of free-roaming cats equals the number of owned cats (holton & manzoor ) , but others believe that the number ranges from to million (patronek ) . in warmer climates there may be larger numbers of free-roaming unowned cats, since females are able to produce two to three litters in a prolonged warm season and mild winters will result in lower mortality. the number of free-roaming cats will also depend upon the popularity of cats as pets, the beliefs of the owners regarding cats' need to go outdoors, the sterilization rate, the availability of food and shelter and the existence of other predators (see chapters and ). the proportion of free-roaming cats that are feral will vary with the location. anecdotally, between and % of the total cat population taken in by animal control facilities in the united states are feral. management programs using trap, neuter and return, often find that between and % of cats in colonies are feral. based on my experience, i estimate that the number of feral cats in the united states is about one third to one half the number of owned cats. cats have a social structure that lies between the larger pack-hunting carnivores like lions and the solitary territorial leopard and wild cat (fitzgerald & karl ) (see chapter ). free-roaming cat populations appear to be controlled by the resource dispersion hypothesis, suggesting that availability of food is the primary limiting resource for female cats and drives their dispersion (macdonald et al. ) . food-driven dispersion may itself be mediated by other resources such as shelter or resting places, and by competition with other animals (calhoon & haspel ; liberg et al. ; macdonald et al. ) . thus, the presence of a localized, stable and large food source appears to be the primary reason for group living in domestic cats (smith & shane ; liberg et al. ) . for male cats, another limiting resource for group living will be access to females (macdonald et al. ) . the "wait and see" or "do nothing" approach to controlling cat populations has been used historically, and is still applied in some locations. the hope is that "nature will take its course" and cats will be killed or move away. in reality, doing nothing is a poor choice for the cats and is not a solution to the problem. therefore, methods for dealing with populations of free-roaming and feral cats have been developed, and can be divided into three main approaches. the first is to kill cats on site, the second is to trap and remove cats for euthanasia or relocation, and the third is to trap, neuter and return cats to the original location. human perceptions of cats influence the selection of methods used to control them. a review of the factors that influence the way humans perceive cats are discussed in chapter . cats have been accidentally or deliberately introduced to a broad range of locations, including islands . since cats are very adaptable, they have survived and reproduced, accommodating to different food sources. they are also fecund, giving birth to one to three litters per year of two to six kittens. since cats are sexually mature at five or six months of age, this can result in a substantial number of cats in a short period, even with very high mortality rates. moreover, if they die from disease or human intervention, other cats move in to take advantage of the newly available space and food supplies (tabor ) . this is especially the case in locations that are not geographically isolated. these facts suggest that wholesale slaughtering is not a practical solution to permanently eliminating a colony. methods of killing cats on location are generally not popular with the public. they are usually used in locations without human habitation, and are often chosen by local governments because they are perceived to be permanent, relatively inexpensive solutions to feral cat problems. poisons are not specific and may endanger other animals and humans as well as causing a painful death for the cats, so they should only be used in very specific settings (dowding et al. ) . increasingly, the public views cats as domestic animals for whom it has a responsibility, and does not accept the killing of cats as a solution to a problem that, in many instances, is due to people introducing cats to the location in the first place. this view arises from the change in the perception of non-human animals from property, incapable of feelings or thoughts, to animals as companions that experience pain, hunger and other emotions. an example of this change and how it affects animals occurred in april , in the cities of mataro and barcelona, spain. these cities prohibited shelters from destroying stray cats and dogs that were not severely ill, injured or dangerous (www.aldf.org). this change appears to have been due to actions by several animal welfare and rescue organizations, one of which recently took over the government shelter in barcelona. in italy, a law prohibited the abuse or removal of feral cats from their colonies and made provision for the public veterinary services to sterilize the cats (natoli et al. ). the trap, neuter and return method (see section . ) has become widespread in italy. more recently, the cats of rome were given the status of "patrimonio bioculturale" that is, that they are a bio-cultural heritage (www.romancats.de/romancats/news/article.php?id= ) ( figure ). when determining the best option for controlling feral cat populations in natural settings, particularly islands, well-designed studies are required to provide reliable data on the effects of feral cats on wildlife and to devise appropriate management programs (dickman b) . all other non-native species must also be monitored, and native species at highest risk should be identified. other factors that are likely to interact with feral cat predation should be considered, such as habitat fragmentation, clearing of trees and brush and direct human impacts. eradication of cats is not a practical approach for mainland areas; eradication from islands has been achieved at great cost and requires a variety of methods as well as considerable time. most baiting methods have been ineffective due to cats failing to ingest the bait . several small studies using secondary poisoning of predators with agent (sodium monofluoroacetate) or brodifacoum (a second-generation anticoagulant) via poisoned prey species suggest that this may be a more effective method to kill all predators present, including feral cats, stoats and ferrets gillies & pierce ; alterio ) . for example, feral cats and rats were eradicated on fregate island in the seychelles using brodifacoum bait drops (shah ) . this was possible because there were no native mammal species and all endemic birds at risk of accidental poisoning were caught and held in captivity during the baiting, since the island was so small. cats on marion island were originally introduced in to control house mice (bester et al. ) . by the mid 's they were believed to be causing a decrease in bird populations, so an eradication program was devised. it included biological control with feline panleukopenia virus, hunting, trapping and poisoning during a -year period following four years of study and planning (bester et al. ; bester et al. ) . this demonstrates the intense effort required to eradicate cats, even in a closed population. eradication of cats on little barrier island, new zealand was carried out from to using cage traps, leg-hold traps, dogs and poison (girardet et al. ) . only leg-hold traps and poison were found to be effective; cats were killed, as were some birds and rats. eradication of cats on gabo island included shooting, trapping and poison bait programs (twyford et al. ) . only the poison bait was considered to be effective, and cats were eradicated from the island after four years. on dassen island, south africa, cats were studied to determine the effects of their predation on native birds (apps ) . following culling, cat numbers rapidly rebounded because some breeding cats remained, leading to re-population of the island with young cats. models to evaluate the efficacy of eradicating cat populations on islands using feline leukaemia virus (felv) and feline immunodeficiency virus (fiv) have suggested that the former could be effective if the natural immunity of the population is low . however, there are many considerations when introducing a disease into an environment, such as the susceptibility of non-target species, the performance of the pathogen in the field and host susceptibility. a virusvectored immuno-contraception approach for controlling cat populations has been modeled using parameters appropriate for islands (courchamp & cornell ) . control or eradication of the cats was deemed to be possible, if the assumptions in the model were correct regarding baiting rate, transmission rate, mortality, and determinants of population growth. concerns about virus-vectored approaches include effects on non-target species, public acceptance of genetically-engineered organisms, spread of the vector outside the targeted location, irreversibility, genetic changes in the target species or vector, rate of response to exposure and limited knowledge of potential vector candidates (courchamp & cornell ) . in the united states, canada, and europe, feral cats are most often trapped and removed. what happens to them after removal varies widely and is a matter of debate. usually, they are destroyed since they cannot be placed as companion animals. most animal control agencies (government-run organizations) euthanize feral cats that enter their facilities. some have mandatory holding periods while others determine that the cat is feral on arrival and euthanize it shortly thereafter. a few have programs that place cats with local feral cat organizations. many non-profit (non-governmental) organizations do not accept feral cats unless they have a special program to deal with them. euthanasia may be the best option for feral cats that are injured or very ill, since long-term veterinary care is usually not possible. intensive removal programs, with adoption of kittens and socialized adults and euthanasia of feral cats that cannot be relocated or socialized, may be an option in geographically isolated areas where predation clearly threatens native species in decline, or in areas that are unsafe for cats. this type of program must have a strong educational component and commitment to adoption in order to be accepted by residents, and must also include ongoing monitoring for the immediate removal of new cats. in the past decade in north america, there has been an increasing tendency to recommend removal and relocation of cats to another property, often a rural home, farm or sanctuary. sanctuaries are facilities that hold animals, often for the rest of their lives, and they may also have adoption programs. they are expensive to run well and require careful planning to provide for the needs and health care of cats throughout their lives. in the united states and other countries, there is limited oversight of the quality of care and housing provided for animals in sanctuaries and the conditions in some may be poor (see chapters and ). while relocation to a farm setting or placement in a high quality sanctuary are attractive solutions, they are not practical as the sole solution due to the large numbers of feral cats and the limited funding available. in special circumstances, well-run sanctuaries coupled with ongoing trapping may provide a local solution. relocation may also be one component for the control of feral cat populations in conjunction with other approaches. trap, neuter and return (tnr) programs in their simplest form include the humane trapping of feral cats, sterilization by a veterinarian, vaccination for rabies in countries where that is appropriate, and return to the site of trapping. before release back into the colony, the ear of the cat should be tipped or notched to indicate that it has been sterilized (cuffe et al. ) (figure ) . the aim of a tnr program is to create a stable population where cats can no longer reproduce; natural attrition will eventually decrease numbers or at least maintain a stable number of cats. since cats are returned to the original habitat, a vacuum is not left to encourage cats from nearby areas to move in or remaining intact cats to repopulate. because there is always the potential for cats to join the colony, the program must continue to trap new cats that migrate into the area. an aggressive adoption program for tame adults and kittens under about eight weeks of age will reduce the numbers of cats in the colony more quickly (levy et al. ) . sterilization decreases roaming of male cats, improves body condition and tends to make cats more interactive with their caretakers (scott & levy ) . thus, tnr together with adoption and monitoring programs are the most effective and humane options for the long-term control of feral cat colonies. tnr also retains the positive aspects of the presence of cats in specific locations. these include rodent control, especially in cities and around houses and barns, the opportunity to learn about cat behaviour and social interactions, the aesthetic benefits of cats in the urban environment and the relationships between the cats and their human neighbors and caretakers (natoli ) (figure ). i am aware of three locations, two in the united states and one in england, where tnr programs and coordinated efforts to address the sources of feral cats led to the disappearance of colonies. although about ten years was required for this to occur, this demonstrates that tnr is a humane and successful management technique for the feral cat population (remfry ) . extended programs are referred to as ttvar-m: trap, test (the cat is blood tested for a range of diseases), vaccinate (often against a number of diseases), alter (neuter), return (to the original location) and monitor (including regular feeding by a caretaker). cats are blood tested to see if they are infected with felv or fiv. this testing is controversial, as costs are high and cats positive for these viruses are usually euthanized or placed in sanctuaries. placing virus-positive feral cats in sanctuaries is difficult, as most sanctuaries have so many healthy socialized cats needing homes that it may not be practical to spend resources on these feral cats. testing should not be performed if no action is to be taken for virus-positive cats. there are also other reasons not to test. the prevalence of felv and fiv in feral cats is usually quite low, as low or lower than that found in owned cats (lee et al. ) . felv is spread by prolonged close contact between cats and from mother to kittens, and is not highly contagious. fiv is spread by biting during fighting, particularly among males, and its transmission is curtailed when cats are sterilized. fiv infection has a different natural history than felv in that infected cats can often live for a normal lifespan (see chapter ). control programs usually decide to test based on the opinion of their veterinarians and on the trade off of costs and benefits. whether cats are vaccinated for disease other than rabies will depend on the program. most feral cats are likely to have been exposed to the common infectious diseases. vaccination may be performed in order to protect the organization from negative comments, since their feral cats will be as well protected against viral diseases as pet cats. tnr appears to have originated in south africa and denmark well over two decades ago (kristensen ; tabor ) . it was then imported into england and from there to the united states, canada, europe and many other countries (remfry ) . because many programs are small and local, it is impossible to quantify the extent and success of tnr in most locations. using networks of animal protection contacts and web sites, as well as published studies, i have collected some information to give a sense of what is happening internationally in several locations. this is not a comprehensive listing but is based on expert opinion shared with me. in the united states, tnr has become an established approach in some locations and has been on the national and regional agenda of governmental and non-profit organizations since the early 's. in the late 's, most of the large animal-protection organizations, as well as the national veterinary organization, acknowledged the usefulness of tnr, at least under certain specified circumstances. at the same time many bird, wildlife and public health organizations developed policy statements against tnr, primarily because of concerns regarding predation, rabies and lack of data on efficacy. because laws governing cats are usually made at the local city level, general statements about the acceptance of tnr are not possible. several large programs in the northeast and west have become increasingly high profile in animal welfare and animal protection conferences and web sites, indicating a growing awareness, if not always acceptance, of tnr as a humane method for the control of feral cats. alley cat allies is a national organization dedicated to tnr for feral cats with over , donors and supporters in . an early study of a tnr program was conducted on hospital grounds in louisiana and reported on both efficacy (control of cat numbers) and longevity of cats (zaunbrecher & smith ) . of the cats present at the start of the study, were returned to the site. during three years of followup, five cats died, five disappeared and six joined the colony. litters of kittens were not reported during the study, and two cats became more social with the people feeding them. beginning in , the efficacy of tnr in the unites states began to be described in the scientific literature. one was a campus tnr program in texas where the first two years of data were presented . during that period cats were trapped ( figure ), were returned and kittens and tame adults were adopted. the number of kittens trapped decreased significantly between the first and second year, as did the number of complaints to the university pest control service. during the following three years, the number of trapped cats continued to decrease. totals for the five years of the program were: cats trapped, returned to campus (slater ) . of those returned, were eventually adopted and seven were killed or died. no kittens were born on campus after the second year and fewer than cats were trapped in each of the last two years of the program, with almost half being tame cats or kittens. another campus program in florida documented the effect of tnr with an adoption program during an -year period (levy et al. a) . a total of cats were recorded during this period. after the first five years, cats were present on campus and six years later were present. the final disposition of all cats was: % were adopted (including more than % of cats that were initially considered feral), % remained on campus, % disappeared, % were euthanized, % died and % moved to nearby woods. no kittens were found after the first five years of the program. a study of colonies in florida found that the total population of cats decreased from to after tnr . median colony size was initially four cats (range one to ), and was reduced to three (range zero to ) following tnr. the greatest source of new cats was births, and adoptions led to the greatest decrease in numbers. an animal control agency serving a large county in florida initiated a tnr program in collaboration with a local feral cat organization in . six years of data before and after the implementation of tnr for feral cats demonstrated that there was no increase in complaints or impoundments by the animal control agency. figure . humane box-traps are commonly used to capture feral cats. cats will usually become very agitated after the trap closes, so the door should be securely latched and the trap covered immediately to reduce the cat's stress level during the study period, the human population increased by a third, which should have led to one third more cats, cat-related complaints, impounds and euthanasias. in fact, euthanasia rates and complaints decreased during the last five years. numbers of sterilizations increased dramatically in the six years after tnr and low cost sterilization programs were instituted for feral and owned cats. the relationship between the agency and the public improved, as did the morale of the animal control officers. in addition, tnr provided concerned citizens with the option to take action and make a difference to the numbers and the well-being of feral cats in their neighborhoods. some of the earliest published studies come from england, and focus on the longevity and behavioural impact of tnr programs. the behaviour and stability of the groups were studied and found to be "satisfactory on both counts" (neville & remfry ) . seventeen other neutering programs were followed for five years (remfry ) : a total of cats were trapped, were returned to their original site and were still present five years later. in canada, several organizations dealing with feral cats exist and some research interest in the area has developed. as of early there was no national organization, but the no-kill movement (which embraces the idea that euthanasia of healthy animals is not a viable solution to overpopulation) is picking up momentum. the first national conference on the subject took place in the early summer of and attracted participants from canada and the united states. part of their activity was the formation of a national organization of groups and individuals working toward a no-kill policy ("let-live canada"). the summary of the situation in israel is based on two reports from the cat welfare society of israel (personal communication rivi mayer, may , ; personal communication, adi nevo, may , ) . although the feral cat population is much in evidence, feral cats are not a common concern of the public or the government. in general, cats as pets and companions are not highly valued or commonly kept (personal communication, rama santschi, dvm, july , ) . cats primarily come into the public and government awareness as nuisances or concern about rabies. feral cats have been rounded up and destroyed for years without making any difference to numbers. however, the cat welfare society of israel has been active since , and members have made strong efforts to network and learn from existing programs about controlling feral cat populations and implementing spay/neuter programs. recently, the society has sterilized about , cats a year and provides a trapping and transportation service. several cities have begun tnr programs but most have not persisted with them due to a combination of limited funding, lack of commitment by the government and shortage of structural support. added to the complexity of the situation is the fact that, on the one hand, the ministry of environment administers animal rights and protection and also supports tnr, both philosophically and financially. on the other hand, the department of veterinary services is part of the ministry of agriculture and tends to promote lethal methods to control cat populations. city-employed veterinarians are in charge of municipal animal activities and tend not to understand or become involved in tnr or subsidized sterilization programs. nationally, the supreme court determined in that the mass killing of dogs and cats was not permitted, and that each animal-related complaint must be evaluated. the court also declared that non-lethal solutions, including tnr, should be sought, and refined the rules regarding the control of rabies. unfortunately, this has not stopped some private trappers from continuing to trap and kill cats under regulations from the ministry of agriculture. although the situation has improved with more sterilization programs, less killing of cats and increasing awareness of tnr as a solution to the problem, funding and veterinary support continue to be limiting factors. a recent article describes how the existing literature on free-roaming cats can be applied to the situation in israel (gunther & terkel ) . the conclusions of the authors were to promote trap, neuter, identify and return programs in conjunction with community level solutions like keeping garbage cans securely covered, education and dealing with specific problems. they recommended trap and euthanasia only for cats in very poor condition. in germany, a recent dissertation on feral cat populations in a ha study area in berlin was completed by beate kalz (edoc.huberlin.de/abstract.php /dissertationen/kalz-beate- - - ).in her opinion, feral cats are not a highly visible group and are generally well tolerated by the public. german animal welfare organizations usually promote tnr as a control method, with a strong emphasis on the sterilization of cats. the dutch society for the protection of animals has been in operation for years. the shelters in holland are all associated with the society. between and , the numbers of stray cats in the shelters increased by nearly one third, to , . in , , owned cats, , feral cats and all cats in shelters were sterilized (a total of , cats). in the late 's a national sterilization campaign was developed and implemented. this information would suggest that tnr is practised fairly widely and successfully in holland, and that its administration has benefited from the long history of animal welfare activities in that country. an estimated , stray cats live in singapore. in may , singapore's agri-food and veterinary authority (ava) used the sudden acute respiratory syndrome (sars) outbreak as a reason for the intensified culling of stray cats, especially in areas with nuisance problems (the straits times, singapore, may , ). the society for the prevention of cruelty to animals and other welfare groups countered this with a call to end the culling of cats. the following day, the ava reversed its position and denied a link between the culling and sars, and indicated that it was for other public health reasons. in , ava's stray cat rehabilitation scheme had sterilized about , cats through their own cat welfare society, but with the initiation of culling this sterilization program was put on hold. animal welfare organizations continue to seek to relocate cats to sanctuaries and end the culling of cats. while tnr had been implemented in singapore, it has not been adopted at a level to decrease cat-related complaints significantly. furthermore, singapore's example illustrates that even when there is a government program for tnr, its position may revert to old methods of removal and euthanasia in large numbers without good reason. no government office oversees animal welfare at the national level in japan (oliver ) . free-roaming dogs and cats are collected and disposed of by the department of health & hygiene. cats have only recently begun to be regarded as companion animals rather than as working hunters. following the control of free-roaming dogs japan, like many other countries, now has more obvious colonies of feral cats but tnr is rarely practised. one colony of feral cats has been extensively studied, for example see izawa ( ) , yamane et al. ( ) and ishida et al. ( ) . in , a staff member of the hong kong spca introduced tnr to hong kong (garrett ) . in just over three years, , street cats have been sterilized and cared for (about cats a month in ), with registered cat carers and part-time carers. the spca provides free spay and neuter, vaccination and flea control services, and also has a mobile clinic that provides similar services to villages and islands. in august , it declared its intentions to make the city of hong-kong adopt a "no-kill" policy. these examples demonstrate the range of views about killing and caring for cats, as well as differing perceptions of what the feral cat problem, and its control, entails. they also support the slowly evolving view that feral cats are worthy of our concern and compassion. in the previous section, i briefly reviewed the methods of controlling free-roaming cat populations. particularly because of public health and wildlife concerns, the choice of control method can be controversial. when one has considered the financial costs, the welfare of the cats, the need for solutions tailor-made for each location, and a shortage of data on the efficacy of different methods, the choice may not be obvious. nevertheless, the sources of these cat populations also need to be addressed. one often hears the phrase "responsible pet ownership". it implies that a certain level of care is due to companion animals. responsible pet ownership includes the provision of suitable food and shelter, health care and social interaction, and, i believe, the permanent identification of the animal (a tattoo or microchip), the provision of a safe environment and a life-long commitment to the animal's care. the community should view abandonment not only as a failure of individual responsibility but also as an antisocial and immoral act. there are a number of approaches to reducing the number of cats entering the feral cat population. firstly, stray cats need to be reunited with their families; in the united states, only to % of all cats entering shelters are returned to their owners (zawistowski et al. ; wenstrup & dowidchuck ) . the reunification rate is improved substantially in locations where major microchipping and identification programs of cats have been implemented (slater ) . secondly, cats allowed outside should be sterilized and thirdly, owners should seek help for behavioural, medical or pet selection problems. many owners do not keep their cats long-term because of a lack of knowledge about normal cat behaviour and social needs (new, jr. et al. ) . they may relinquish a cat to a shelter after living with its behaviour problem for years, rather than seeking help early on when the situation could be improved (digiacomo et al. ) . subsidized sterilization should be available for those who cannot afford full-cost services, and owners should be helped to find homes for cats they cannot keep. leadership at both national and local levels is needed (christiansen ) . components of community-based programs should include: ) public education from pre-school to adult; ) improving the quality of animal control; ) developing expertise in urban animal management; and ) understanding companion animal population dynamics (murray ) . there may also be a role for legislation to prevent owned cats from becoming part of the feral cat problem. however, some forms of companion animal legislation may have drawbacks. a law against abandoning cats seems logical, but would be very difficult to enforce. such a law could be construed to include tnr programs, that is, caretakers returning sterilized cats to colonies could be accused of abandoning them. while legislation, if thoughtfully written and enforceable, is likely to be beneficial, it should be adapted to enable tnr programs to continue. when considering the management of feral cat populations, the effects of predation of wildlife by feral (and non-feral) cats, public health issues (such as zoonotic disease) and the welfare of the cats themselves are major concerns that should be addressed. the effect of predation of wildlife (mammals and birds) is probably the most controversial issue regarding feral cats. unfortunately, the discussion about cats and wildlife is often polarized and couched as pro-cat versus anticat, or as pro-cat versus pro-wildlife. this division is inaccurate, misleading and counterproductive; in fact, there are many points in common and much overlap between the "cat" groups and the "wildlife" groups. for example, suggestions for reducing predation of wildlife by cats that is often espoused by both cat and wildlife organizations includes keeping cats indoors or confined, sterilizing cats, improving the environment for birds and bats with nesting boxes and carefully considering bird feeder placement (gray ) . there are several themes that arise in discussions of feral cats and wildlife. the first is based on a philosophical belief that since cats are a domestic species, they should not be allowed to hunt wildlife but should be confined indoors, to an enclosure or yard or on a leash (arguably for the cats' welfare as well as for that of wildlife).the second theme is that cats are an introduced, non-native species and therefore should be removed from the environment. there are several assumptions underlying this argument: firstly, introduced or non-native species are harmful and native species should be protected from them. however, cattle and sheep are routinely protected from coyotes, foxes and wolves, despite the latter being native species that are killed because they may prey on domestic species (cohen ) . in some locations, native mountain lions, northern harriers and kestrels have been killed to prevent them from preying on rare species (cohen ) . the second assumption is that if we remove cats from the environment, the ecosystems will return to "normal" or to the pre-cat situation. however, ecosystems are complex and have often been heavily influenced by the effects of human habitation including construction, changes in fire control and water movement, pollution and the introduction of livestock. there are often other introduced plant and animal species (starlings or rats) that affect the balance of the ecosystem. for example, removing cats in certain locations may cause serious problems from the resulting increases in rodent populations. the third theme is the actual impact of cats on wildlife, largely through predation but also through competition or disease. while competition is commonly cited as a concern, little evidence is available to support this claim (george ) . predation is generally considered to be the most serious problem, especially predation of birds. again, the interaction between cats and wildlife varies widely from location to location, and is heavily influenced by other environmental factors such as variety of prey species, the reliance of cats on garbage or being fed, other pressures on local species, climate and the biology of threatened species. predation is often studied by examining the diet of cats in different locations; an excellent review of such studies can be found in fitzgerald & turner ( ) . methods of quantifying the diet of feral or free-roaming cats include examining intestinal samples from cats that are killed, scat (faeces) analysis, recording prey brought home by owned cats and examination of dead or partially eaten prey found in the environment. the results of diet studies do not provide evidence of the impact on a species unless prey species abundance is also monitored, as well as the species' reproductive capacity and other sources of predation and mortality (churcher & lawton ; martin et al. ; risbey et al. ; edwards et al. ) . while predation patterns in a given location are unique, there are some generalizations that can be made. on continents mammals are the main prey eaten by cats, with birds forming about % of the diet (fitzgerald & turner ) . the amount of household food available to cats will depend on the density of the human population. australian cats living near refuse dumps and towns were found to have food scraps as a high proportion of their diet, while the diet of those living distant from human habitation contained few food scraps (risbey et al. ) . relatively few species of mammal commonly form most of the diet. birds are a less frequent component of the diet, but usually many more species are eaten. the number and species of reptiles as food items will vary widely among locations. some believe that to allow owned cats loose to hunt, or to maintain freeroaming cat populations in the natural environment, places more value on the life and needs of the cat than on the life of the prey the cat kills. this argument is a personal ethical belief about the relative importance of different non-human animals, rather than concern over reductions in prey species. cats sometimes precipitate this belief by presenting their owners with prey (dunn & tessaglia ) . sweeping generalizations are often made about cat predation and are not always based on the offered evidence (gray ) . additionally, data are often extrapolated inappropriately (dunn & tessaglia ) . studies that count the number of prey returned to owners are subject to many kinds of biases. owners of cats that are better hunters are more likely to volunteer for prey studies (fitzgerald & turner ) . relatively few cats bring in very large numbers of prey, skewing the results and artificially inflating the mean number of prey; using the median would be a more suitable measure. one example is a commonly discussed one-year study of prey brought home by owned cats in an english village (churcher & lawton ) . there was an average of prey per cat (range zero to ), the median was not presented but, based on a graph, seemed to be eight. mammals comprised most of the prey (mainly wood mice, voles and shrews) and birds about % (mainly the house sparrow). the age of the cat (older cats brought home less prey) and their location in the village influenced prey numbers. cats were estimated to account for at least % of sparrow deaths in the village and were considered to be the major predator of house sparrows. however, there was an unusually high density of sparrows in the village and other predators were not assessed. in addition, there was no indication that this level of predation had caused the sparrow population to decline. in a questionnaire study involving , rural residents in wisconsin (coleman & temple ) , a fifth of the respondents did not have cats. the remaining owned between one and , with an average of five cats per farm or rural residence. they reported prey captures on the to farms and residences in the study area, with mammals making up % and birds % of the prey. these figures were used as the basis for an article with the headline "cats kill millions of small mammals and birds every year" (harrison ) . even some who value wildlife over cats will acknowledge that there are certain wildlife species that are pests which could be controlled by predation, and that using cats to control rodent populations around barns or stables is generally acceptable. endangered species are rarely encountered in urban environments, and there are often large numbers of introduced prey species. in these settings, feral cats may be useful in controlling rodents and introduced species, and are likely to have little impact on endangered or declining species. the large population of some birds and pests in urban environments has been attributed to a variety of factors including a reduced number of predators, favourable microclimates and/or food availability (sorace ) . studies of three italian parks found high prey (including pest species such as pigeons, starlings, mice and rats) and high predator (birds of prey, crows, cats, dogs, rats and foxes) densities compared to the nearby countryside (sorace ) . the numbers of nest predators such as blue jays, raccoons and opossums, and of bird species that lay their eggs in nests of other species, often grow in urban environments due to a proliferation of food supplies (terborgh ) . in addition, current "garden" or suburban birds may be under less predation pressure from cats than they would be from the range of native predators that no longer co-exist close to human habitation (mead ) . invasive or introduced species are a growing concern in many countries, including the united states (dinsmore & bernstein ) and australia (burbidge & manly ) , and cats are considered to be an introduced species. introduced carnivores can affect the local species by competition, predation, interbreeding or disease (dickman a; macdonald & michael ) . while these processes affect individuals, effects at the population or community level may or may not occur (dickman a) . usually cats are only one of many introduced species including rats and the dogs, mongooses and weasels that were released to control them (jackson ) . in addition, the livestock species that were brought in such as pigs, sheep, cattle and goats may also cause serious changes in the environment, especially in the large numbers associated with industrial farming (jackson ) . being an introduced species, cats are often targeted for control measures even when there is little evidence to support this. for example, on socorro island, mexico, the socorro mocking bird had declined in numbers (martinez-gomez et al. ) . habitat destruction was considered to be the primary cause, since northern mockingbirds and cats arrived after much of the decline had occurred. nevertheless, cat control was still a major focus of the authors. reports blamed cats for the disappearance of three petrel species on little barrier island, new zealand (veitch ), yet no evidence exists that these species were ever present (girardet et al. ) . only in the past few years have predators other than cats, such as ferrets and stoats, been considered in studies of predation in new zealand (moller & alterio ; gillies et al. ; norbury ) . habitat destruction by humans generally takes three forms: overexploitation of resources, pollution and introduction of exotic species (macdonald & michael ) , and is generally considered to be the most important cause of species extinctions (lawren ; terborgh ; hall et al. ; dinsmore & bernstein ; macdonald & michael ) . water quality deterioration, drainage of wetlands, agricultural use of prairies, fertilizers, pesticides and herbicides are all responsible for changes in the environment of a variety of bird habitats, which lead to declines in populations (terborgh ; robinson ) . it is crucial to view cat predation within the context of habitat destruction, since cats have not been shown to be the primary cause of the loss of native species on mainland continents (mead ; mitchell & beck ) . unfortunately, evidence regarding extinctions is often anecdotal, circumstantial or historical (dickman a; macdonald & michael ; read & bowen ) . islands have less species diversity, a scarcity of predators and a higher concentration of individuals relative to similar mainland environments (sorace ) . islands with introduced cats differ enormously in climate, size and native species, but generally have relatively few native mammals (fitzgerald & turner ) . the same set of introduced species is common: house mice, rats and european rabbits. where rabbits are present, they tend to be the main prey of cats. predation on rats and mice varies between locations. cats survive on islands without mammals by eating seabirds on small islands and land birds on larger islands. australia is arguably the best studied and most high profile country when it comes to feral cats and predation, and is considered to be an example of the serious threat that feral cats pose to wildlife. however, as of , there were "no critical studies of the impact of feral cats on native fauna in australia" (dickman b) . what has been documented is the association between rainfall, species' habitat and dietary preferences, and the decline and extinction of species (burbidge & mckenzie ) . european settlement led to a reduction in vegetative cover, increased human settlements and introduced species, including livestock, and changes in control of fires in the environment. exotic predators likely exacerbated the situation, depending on the protective habitat of the prey species. feral cats are not recorded to have had a significant impact on any species of reptiles, amphibians, fish or invertebrates (dickman b) ; however, they may have localized effects on populations of native vertebrates. despite much publicity, the role of feral cats in the decline and extinction of australian mammalian species remains unclear (burbidge & manly ) finally, in addition to direct predation, there have been concerns about diseases that could be spread from cats to wildlife. the 'alala bird in hawaii became endangered possibly due to disease, loss of genetic diversity, introduced predators or habitat loss (work et al. ) . reintroduction programs were limited by the presence of the microorganism toxoplasma gondii (for whom the cat is the main host) in four of captive-reared birds due for re-introduction. it is unclear if these particular birds or 'alala birds in general are especially susceptible to toxoplasmosis, perhaps due to a genetic predisposition. toxoplasmosis was suggested to be a contributing factor to local decreases in eastern barred bandicoots in australia (dickman b) . in order to understand their role in predation, it is crucial to recognize that cats are one of a large group of predators, both native and introduced, (fitzgerald & turner ) . other introduced species, such as rats and mice, can have substantial impacts on amphibians, mammals and birds . many factors affect the impact of cats on prey species, such as the density of cats, the density and distribution of prey, the fecundity of native species, the habitats and habits of native species, and the presence of other predators. assumed relationships may not be correct when studied over long periods of time (fitzgerald & gibb ) . because the relationship between different predators and a variety of prey species is complex, removal of cats may have much more widespread effects than are immediately obvious. this is illustrated by a mathematical model including birds, rats and cats, which showed that removing all cats led to a surge in rat numbers, resulting in the extinction of the bird species (prey) . another model examined the relationship between birds (prey), rabbits (an introduced prey species) and cats (the predator) in an island setting . based on field observations, rabbits provide food for other predators and, in times of plenty, are the primary diet of cats. this allows for a larger population of cats than could ordinarily be sustained if rabbits were scarce or not present. when rabbit populations are reduced, cats are able to switch to other prey species (such as birds). similarly, the widespread availability of cat food could lead to larger populations of cats than would otherwise be possible if only local prey were available. despite the eradication of cats on marian island, lesser sheathbill populations remained less abundant and had different habits than birds on neighboring prince edward island (huyser et al. ) . these differences were believed to be due to a decrease in the birds' macro-invertebrate prey (especially weevils and flightless moths), which may have been due to increases in house mice as a result of the cat eradication, decreases in burrowing petrels (which promote invertebrate species), and climate warming, which also increases mouse populations. this example illustrates that the removal of cats may not result in the recovery of a threatened species. most of the agencies charged with public health issues are concerned with the possibility of disease rather than with the actual probability, particularly in regard to cats. this is partly due to the lack of data regarding frequencies of zoonotic diseases and the risk of transmission. rabies in cats is often the chief concern of public health authorities, especially in countries where the disease is common. there are many other zoonotic diseases where cats are implicated (tan ; patronek ; olsen ) . some of them are region-specific, such as plague in the western united states (orloski & lathrop ) and others may affect cats as well as many other mammalian species (riordan & tarlow ) . while any free-roaming or owned cat may carry or transmit a variety of diseases to humans, the frequency of these diseases and their severity will fluctuate widely depending on the geographic location, climate and the health status of the human population. proper handling of feral cats, using traps and other equipment, will reduce the likelihood of bites and scratches, thereby reducing the risk of disease transmission (slater ) . although cat bites in the united states are less common than dog bites, they are more likely to become seriously infected because of the micro-organisms present in cat saliva (tan ) . in southern africa, parts of the caribbean, north america and europe, wild carnivores are the primary vector for rabies, while in asia, parts of latin america and most of africa, dogs continue to be the major source (who a) . the united states is the only country where cats were the most commonly diagnosed domestic species in recent years, yet cases of laboratory-confirmed rabies in skunks, raccoons and bats in the united states far exceeded the numbers of all domestic animal species combined (who b) . historically, measures such as quarantine (restricting animal movements), removing free-roaming animals and vaccinating susceptible animals have been used to control rabies (beran & frith ) . originally, susceptible animals included only domestic species but in the 's wildlife species also began to be vaccinated, using oral bait systems. relatively little research has been done on cat populations and the control of rabies, although dogs have been studied in a number of countries and some solutions have been devised (who expert committee ; meslin et al. ; who expert committee ) . cat population dynamics are likely to parallel those of dogs in many locations, so similar solutions will be effective. feral cats should be vaccinated for rabies in locations where rabies occurs, and vaccination of colonies will result in a herd immunity effect. herd immunity is the point at which the proportion of immune individuals in the group is so high that the disease agent cannot enter and spread (hugh-jones et al. ) . a level of % immunity among dog populations is sufficient to break the transmission cycle of rabies (who a). in , health officials in ontario, canada, incorporated the vaccination of freeroaming cats into their emergency response to outbreaks of rabies in raccoons (rosatte et al. ) . all cats within ten km of the initial raccoon rabies case were trapped and vaccinated. during this outbreak about cats were vaccinated instead of killed, and provided a partial barrier to disease spread. toxoplasmosis is another widely-occurring disease in cats that is transmissible to humans. the acute infection is generally self-limiting in immuno-competent humans, but may cause serious disease in immunocompromised humans (aids patients in particular) or to the foetus during pregnancy (schantz ; olsen ). an additional concern is environmental, with microorganisms contaminating water or feed. the prevalence of toxoplasma infection in feral cats appears to be similar to that in owned cats (defeo et al. ) . cat scratch disease, caused by bartonella henselae, has a wide range of prevalence in owned and feral cats, from zero in norway to over % in the united states and philippines (barnes et al. ; bergh et al. ) . there is also variable prevalence in feral cats in the united kingdom, from to % depending on location (barnes et al. ) . this disease is primarily a problem in immuno-compromised humans (hugh-jones et al. ) , and requires a scratch or bite for transmission. zoonotic diseases are also described in chapter . only in recent decades has the welfare of feral cats themselves emerged as an important issue. in a few countries it is the primary concern, while in others it remains the focus of small groups or individuals concerned with animal welfare. concern for the well-being of feral cats should consider not only their health but also their need for some interaction with humans. cats in managed colonies appear to be in good health and are able to obtain whatever level of interaction they need with their caretaker. caretakers themselves often have a strong bond with their feral cats (haspel & calhoon ; natoli et al. ) (figure ) . a study in hawaii of colony caretakers found that most were female, middle-aged, married and welleducated, owned pets, and were employed full-time (zasloff & hart ) . the caretakers spent considerable time and money caring for these colonies because of their love of cats and the opportunity to nurture them. they also experienced enhanced feelings of self-esteem. a second study in florida of caretakers of cats in colonies found that % were female . the median age was years (range to years) and % owned pets (two-thirds of them owned cats). more than half the caretakers were married. the most common reason reported for caring for the cats was sympathy or ethical concern followed by loving animals or cats. felv and fiv viruses are the infectious diseases most frequently studied in cat populations, both because of their impact on cats' health and the risk of transmission to other felines. a total of stray cats ( were classified as tame and as feral or semiferal) entering an animal shelter and veterinary hospital in birmingham, england, between august and december , was tested for felv and fiv (muirden ) . in all cats, the prevalence of felv antigen was . % and of antibodies to fiv was . %. the prevalence of felv in semiferal or feral cats ( %) was similar to that in tame cats ( . %), while the prevalence of fiv was . times higher ( . versus . %). there were also higher rates of fiv antibody-positive status in males, cats over two years of age and cats with non-traumatic health problems. multivariate analysis indicated that sex, age and non-traumatic illness were independently associated with fiv antibody-positive status but feral status was not. figure . caretakers may spend hours traveling to their colonies to feed, nurture and interact with the cats. another study of felv and fiv in veterinary practices in istanbul, turkey, included indoor cats, cats allowed outside and feral cats (yilmaz et al. ) . the latter two groups were combined for analysis, which makes reaching conclusions about the feral cats difficult. prevalence of fiv in both groups was % ( / indoor and / outdoor cats) and of felv was % in indoor and % in outdoor cats. fiv was more common in male cats; the high prevalence may be related to the fact that most cats were not neutered. the indoor cats may have been previously outdoor cats or from the same household as some of the outdoor cats, which could bias the infectious disease frequency, but no data were given. these studies demonstrate the variability of disease prevalence in different populations of owned and feral cats, and the difficulty in making comparisons between studies that define cat populations differently. among cats trapped during five years of a texas university campus program, % were positive for felv and % for fiv (slater ) . none of the cats trapped were euthanized for other serious health problems. in the florida university campus program, % of cats were euthanized for serious illness (levy et al. a) . of these, % were positive for felv or fiv. operation catnip, a high-volume spay/neuter program for feral cats ( figure ) in florida and north carolina found that % of cats were positive for felv or for fiv (lee et al. ) . fiv was more common in males. among a larger sample ( , ) of cats from operation catnip, nine cats were euthanized for serious health problems (other than fiv and felv) and died from apparent anesthetic complications (nine had physical abnormalities that may have contributed to their deaths), giving a mortality rate of . % (williams et al. ) . a program on prince edward island, canada, trapped and tested cats and kittens during a -week period (gibson et al. ) . prevalence of felv was %, of fiv was % and three cats were positive for both viruses; as in previous studies, fiv was more common in males. these diseases tended to occur within specific colonies, with other colonies being clear of infection. these studies demonstrate that colonies undergoing tnr tend to have few health problems and a low prevalence of fiv and felv, suggesting that feral cats in managed colonies, at least, pose limited health risks to other cats. figure . this female cat is being prepared for surgery at a high-volume spay and neuter clinic. in this type of clinic, over cats can be sterilized in one day. other diseases are occasionally studied in feral cats. for example, rural feral cats from a shelter near zagreb, croatia were examined for lungworms (aelurostrongylus abstrusus) at necropsy (grabarevic et al. ) . the prevalence was %, much higher than the prevalence in cats seen at the veterinary college ( . %). these populations probably differed greatly in the level of care and nutrition they received. weight and body condition are good clues to general health in cats. a study of body condition in adult feral cats found they were lean ( on a scale from to ) but not emaciated at the time of surgery for neutering . one year later, cats were reevaluated and all of them had a substantial increase in falciform fatpad area and depth and body weight, and an increase of one level in the body condition score. caretakers judged that their cats were friendlier, less aggressive, less inclined to roam and had improved health and coat condition. critics of managing colonies by ttvarm argue that feral cats live to less than five years of age and die from car accidents, disease, poisoning, abuse and attacks from other animals (clarke & pacin ). yet the alternative for these cats is euthanasia, and the evidence presented here suggests that feral cats in managed colonies can be kept in reasonably good health and enjoy a good quality of life. over the past few decades and in many parts of the world, the welfare of feral cats has become a matter of great concern. this is largely due to the development of sensitivity toward animal welfare and a shift in how animals, particularly cats, are perceived. all those concerned have a common goal: fewer feral and free-roaming cats. there is often intense conflict, however, over what to do with these cats and who is responsible for them. increasingly, there is resistance to 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of the anesthetic combination of tiletamine, zolazepam, ketamine, and xylazine for neutering feral cats fatal toxoplasmosis in free-ranging endangered 'alala from hawaii factors affecting feeding order and social tolerance to kittens in the group-living feral cat (felis catus) prevalence of fiv and felv infections in cats in istanbul attitudes and care practices of cat caretakers in hawaii neutering of feral cats as an alternative to eradication programs population dynamics, overpopulation and the welfare of companion animals: new insights on old and new data key: cord- - hlwwdh authors: quarantelli, e. l.; boin, arjen; lagadec, patrick title: studying future disasters and crises: a heuristic approach date: - - journal: handbook of disaster research doi: . / - - - - _ sha: doc_id: cord_uid: hlwwdh over time, new types of crises and disasters have emerged. we argue that new types of adversity will continue to emerge. in this chapter, we offer a framework to study and interpret new forms of crises and disasters. this framework is informed by historical insights on societal interpretations of crises and disasters. we are particularly focused here on the rise of transboundary crises – those crises that traverse boundaries between countries and policy systems. we identify the characteristics of these transboundary disruptions, sketch a few scenarios and explore the societal vulnerabilities to this type of threat. we end by discussing some possible implications for planning and preparation practices. disasters and crises are as old as when human beings started to live in groups. through the centuries, new types have emerged. for instance, the development of synthetic chemicals in the th century and nuclear power in the th century created the possibility of toxic chemical disasters and crises from radioactive fallouts. older crisis types did not disappear: ancient types such as floods and earthquakes remain with us. the newer disasters and crises are additions to older forms; they recombine elements of old threats and new vulnerabilities. the literature on crisis and disaster research suggests that we are at another important historical juncture with the emergence of a new distinctive class of disasters and crises not often seen before (ansell, boin, & keller, ; helsloot, boin, jacobs, & comfort, ; tierney, ) . in this chapter, we discuss the rise of transboundary crises and disasters. we seek to offer a heuristic approach to studying these new crises and disasters. we offer a heuristic approach to understanding the disasters and crises of the future. it is presented primarily as an aid or guide to looking further into the matter, hopefully stimulating more investigation on conceptions of disasters and crises in the past, the present, and the future. unlike in some areas of scientific inquiry, where seemingly final conclusions can be reached (e.g., about the speed of light), the basic nature of the phenomenon we are discussing is of a dynamic nature and subject to change through time. the answer to the question of what is a disaster or crisis has evolved and will continue to do so (see perry' s chapter in this handbook). human societies have always been faced with risks and hazards. earthquakes, hostile inter-and intra-group relationships, massive floods, sudden epidemics, threats to take multiple hostages or massacre large number of persons, avalanches, fires and tsunamis have marked human history for centuries if not eons. disasters and crises requiring a group reaction are as old as when human beings started to live in stable communities. the earliest happenings are attested to in legends and myths, oral traditions and folk songs, religious accounts and archeological evidence from many different cultures and subcultures around the world. for example, a "great flood" story has long existed in many places (lang, ) . as human societies evolved, new threats and hazards emerged. to the old there have been added new dangers and perils that increasingly have become potentially dangerous to human groups. risky technological agents have been added to natural hazards. these involve chemical, nuclear and biological threats that can accidentally materialize as disasters. intentional conflict situations have become more damaging at least in the sense of involving more and more victims. the last years have seen two world wars, massive air and missile attacks by the military on civilians distant from battle areas, many terrorist attacks, and widespread ethnic strife. genocide killed one million persons in rwanda; millions have become refugees and tens of thousands have died in darfur in the sudan in africa. while terrorism is not a new phenomenon, its targets have considerably expanded. some scholars and academics have argued that the very attempt to cope with increasing risks, especially of a technological nature, is indirectly generating new hazards. as the human race has increasingly been able to cope with such basic needs as food and shelter, some of the very coping mechanisms involved (such as the double edged consequences of agricultural pesticides), have generated new risks for human societies (beck, ; perrow, ) . for example, in , toxic chemicals were successfully used to eradicate massive locust infestations affecting ten western and northern african countries. those very chemicals had other widespread negative effects on humans, animals and crops (irin, ) . implicit in this line of thinking is the argument that double-edged consequences from new innovations (such as the use of chemicals, nuclear power and genetic engineering) will continue to appear (tenner, ) . we cannot say that the future will bring more disasters, as we have no reliable statistics on prior happenings as a base line to use in counting (quarantelli, ) . at present, it would seem safer to argue that some future events are qualitatively different, and not necessarily that there will be more of them in total (although we would argue the last is a viable hypothesis that requires a good statistical analysis). societies for the most part have not been passive in the face of these dangers to human life and well-being. this is somewhat contrary to what is implicit in much of the social science literature especially about disasters. in fact, some of these writings directly or indirectly state that a fatalistic attitude prevailed in the early stages of societal development (e.g., quarantelli, ) . this was thought because religious beliefs attributed negative societal happenings to punishments or tests this seems to have occurred about five to six thousand years ago (see lenski, lenski, & nolan, ) . however, recent archeological studies suggest that humans started to abandon nomadic wanderings and settled into permanent sites around , years ago (balter, ) so community recognized disasters and crises might have an even longer history. by supernatural entities (the "acts of god" notion, although this particular phrase became a common usage mostly because it served the interests of insurance companies). but prayers, offerings and rituals are widely seen as means to influence the supernatural. so passivity is not an automatic response to disasters and crises even by religious believers, an observation sometimes unnoticed by secular researchers. in fact, historical studies strongly indicate that societal interpretations have been more differentiated than once believed and have shifted through the centuries, at least in the western world. in ancient greece, aristotle categorized disasters as the result of natural phenomena and not manifestations of supernatural interventions (aristotle, ) . the spread of christianity about , years ago helped foster the belief that disasters were "special providences sent directly" from "god to punish sinners" (mulcahy, , p. ) . in the middle ages, even scholars and educated elites "no longer questioned the holy origins of natural disasters" (massard-guilbaud, platt, & schott, , p. ) . starting in the th century, however, explanations started to be replaced by "ones that viewed disasters as accidental or natural events" (mulcahy, , p. ) . this, of course, also reflected a strong secularization trend in western societies. perhaps this reached a climax with the lisbon earthquake which dynes notes can be seen as the "first modern disaster" ( , p. ). so far our discussion has been mostly from the perspective of the educated elites in western societies. little scholarly attention seems to have been given to what developed in non-western social systems. one passing observation about the ottoman empire and fire disasters suggests that the pattern just discussed might not be universal. thus, while fire prevention measures were encouraged in cities, they were not mandated "since calamities were considered" as expressions of the will of god (yerolympos, , p. ) . even as late as an ottoman urban building code stated that according to religious writing "the will of the almighty will be done" and nothing can and should be done about that. at the same time, this code advances the idea that nevertheless there were protective measures that could be taken against fires that are "the will of allah" (quoted in yerolympos, , p. ) . of course, incompatibility between natural and supernatural views about the world are not unique to disaster and crisis phenomena, but that still leaves the distinction important. even recently, an australian disaster researcher asserted that in the southwestern asian tsunami most of the population seemed to believe that the disaster was "sent either as a test of faith or punishment" (mcaneney, , p. ). or as another writer noted, following the tsunami, religiously oriented views surfaced. some were by: "fundamentalist christians" who tend to view all disasters "as a harbinger of the apocalypse". others were by "radical islamists" who are inclined to see any disaster that "washes the beaches clear of half-nude tourists to be divine" (neiman, , p. ) . after hurricane katrina, some leaders of evangelical groups spoke of the disaster as punishment imposed by god for "national sins" (cooperman, ) . in the absence of systematic studies, probably the best hypothesis that should be researched is that at present religious interpretations about disasters and crisis still appear to be widely held, but relative to the past probably have eroded among people in general. the orientation is almost certainly affected by sharp cross-societal difference in the importance attributed to religion as can be noted in the religious belief systems and practices as currently exist in the united states and many islamic countries, compared to japan or a highly secular western europe. apart from the varying interpretations of the phenomena, how have societies behaviorally reacted to existing and ever-changing threats and risks? as a whole, human groups have evolved a for an interesting attempt to deal with these two perspectives see the paper entitled disaster: a reality or a construct? perspective from the east, written by jigyasu ( ) an indian scholar. variety of formal and informal mechanisms to prevent and to deal with crises and disasters. but societies have followed different directions depending on the perceived sources of disasters and crises. responses tend to differ with the perception of the primary origin (the supernatural, the natural or the human sphere). for example, floods were seen long ago as a continuing problem that required a collective response involving engineering measures. stories that a chinese emperor, centuries before christ, deepened the ever-flooding yellow river by massive dredging and the building of diversion canals may be more legend than fact (waterbury, , p. ) . however, there is clear evidence that in egypt in the th century bc, the th dynasty pharaoh, amenemher ii completed southwest of cairo what was probably history's first substantial river control project (an irrigation canal and dam with sluice gates). other documentary evidence indicates that dams for flood control purposes were built as far back as b c in greece (schnitter, , p. , - ) . such mitigatory efforts indicate both the belief that there was a long-term natural risk as well as one that could be coped with by physically altering structural dimensions. later, particular in europe, there were many recurrent efforts to institute mitigation measures. for example, earthquake resistant building techniques were developed in ancient rome, although "they had been forgotten by the middle ages" (massard-guilbaud et al., , p. ) . the threats from floods and fires spurred mitigation efforts in greece. starting in the th century, developing urban areas devised many safeguards against fires, varying from regulations regarding inflammable items to storage of water for firefighting purposes. in many towns in medieval poland, dams, dikes and piles along riverbanks were built (sowina, ) . of course, actions taken were not always successful. but, if nothing else, these examples show that organized mitigation efforts have been undertaken for a long time in human history. there have been two other major behavioral trends of long duration that are really preventive in intent if not always in reality. one has been the routinization of responses by emergency oriented groups so as to prevent emergencies from escalating into disasters or crises. for example, in ancient rome, the first groups informally set up to fight fires were composed of untrained slaves. but when a fire in a.d. burned almost a quarter of rome, a corps of vigiles was created that had full-time personnel and specialized equipment. in more recent times, there are good examples of this routinization in the planning of public utilities that have standardized operating procedures to deal with everyday emergencies so as to prevent them from materializing into disasters. in the conflict area, there are various un and other international organizations, such as the international atomic energy agency and the european union (eu), that also try to head off the development of crises. in short, societies have continually evolved groups and procedures to try to prevent old and new risks and threats from escalating into disasters and crises. a second more recent major trend has been the development of specific organizations to deal first with wartime crises and then with peacetime disasters. societies for about a century have been creating specific organizations to deal first with new risks for civilians created by changes in warfare, and then improving on these new groups as they have been extended to peacetime situations. rooted in civil defense groups created for air raid situations, there has since been the evolvement of civilian emergency management agencies (blanchard, ) . accompanying this has been the start of the professionalization of disaster planners and crisis managers. there has been a notable shift from the involvement of amateurs to educated professionals. human societies adjusted not only to the early risks and hazards, but also to the newer ones that appeared up to the last century. the very existence of the human race is testimony to the social coping mechanisms of humans as they face such threats. here and there a few communities and groups have not been able to cope with the manifestations of contemporary risks and hazards (diamond, ) . but these have been very rare cases. neither disasters nor crises involving conflict have had that much effect on the continuing existence of cities anywhere in the world. throughout history, many cities have been destroyed. they have been: "sacked, shaken, burned, bombed, flooded, starved, irradiated and poisoned", but in almost every case they have phoenix-like been reestablished (vale & campanella, , p. ) . around the world, from the th to the th century, only cities were "permanently abandoned following destruction" (vale & campanella, , p. ) . the same analysis notes that large cities such as baghdad, moscow, aleppo, mexico city, budapest, dresden, tokyo, hiroshima and nagasaki all suffered massive physical destruction and lost huge numbers of their populations due to disasters and wartime attacks. all were rebuilt and rebounded. at the start of the th century, "such resilience became a nearly universal fact" about urban settlements around the world (vale & campanella, , p. ) . looking at these cities today as well as warsaw, berlin, hamburg and new orleans, it seems this recuperative tendency is very strong (see also schneider & susser, ) . in the hiroshima museum that now exists at the exact point where the bomb fell, there is a -degree photograph of the zone around that point, taken a few days after the attack. except for a few piles of ruins, there is nothing but rubble as far as the eye can see in every direction. there were statements made that this would be the scene at that location for decades. but a visitor to the museum today can see in the windows behind the circular photograph, many signs of a bustling city and its population (for a description of the museum see webb, ) . hiroshima did receive much help and aid to rebuild. but the city came back in ways that observers at the time of impact did not foresee. early efforts to understand and to cope with disasters and crises were generally of an ad hoc nature. with the strong development of science in the th century, there was the start of understanding the physical aspects of natural disasters, and these had some influence on structural mitigation measures that were undertaken. however, the systematic social science study of crises and disasters is about a half-century-old (fritz, ; kreps, ; quarantelli, quarantelli, , schorr, ; wright & rossi, ) . in short, there is currently a solid body of research-generated knowledge developed over the last half century of continuing and ever increasing studies around the world in different social science disciplines. to be sure, such accounts and reports are somewhat selective and not complete. there are now case studies and analytical reports on natural and technological disaster (and to some extent on other crises) numbering in the four figures. in addition, there are numerous impressions of specific behavioral dimensions that have been derived from field research (for summaries and inventories see alexander, ; cutter, ; dynes, demarchi, & pelanda, ; dynes & tierney, ; farazmand, ; helsloot, boin, jacobs, & comfort, ; mileti, ; oliver-smith, ; perry, lindell, & prater, ; rosenthal, boin, & comfort, ; rosenthal, charles, & 't hart, ; tierney, lindell, & perry, ; turner, ) . what are the distinctive aspects of the newer disasters and crises that are not seen in traditional ones? to answer this question, we considered what social science studies and reports had found about behavior in disasters and crises up to the present time. we then implicitly compared those observations and findings with the distinctive behavioral aspects of the newer disasters and crises. one issue that has always interested researchers and scholars is how to conceptualize disasters and crises. there is far from full agreement that all disasters and crises can be categorized together as being relatively homogeneous phenomena (quarantelli, ; perry & quarantelli, ) . this is despite the fact that there have been a number of attempts to distinguish between, among and within different kinds of disasters and crises. however, no one overall view has won anywhere near general acceptance among self-designated disaster and crisis researchers. to illustrate we will briefly note some of the major formulations advanced. for example, one attempt has been to distinguish between natural and technological disasters (erikson, ; picou & gill, ) . the basic assumption was that the inherent nature of the agent involved made a difference. implicit was the idea that technological dangers or threats present a different and more varying kind of challenge to human societies than do natural hazards or risks. most researchers have since dropped the distinction as hazards have come to be seen as less important than the social setting in which they appear. in recent major volumes on what is a disaster (quarantelli, ; perry & quarantelli, ) , the distinction was not even mentioned by most of the two dozen scholars who addressed the basic question. other scholars have struggled with the notion that there may be some important differences between what can be called "disasters" and "crises". the assumption here is that different community level social phenomena are involved, depending on the referent. thus, some scholars distinguish between consensus and conflict types of crises (stallings, tries to reconcile the two perspectives). in some research circles, almost all natural and most technological disasters are viewed as consensus types of crises (quarantelli, ) . these are contrasted with crises involving conflict such as are exemplified by riots, terrorist attacks, and ethnic cleansings and intergroup clashes. in the latter type, at least one major party is either trying to make it worse or to extend the duration of the crisis. in natural and technological disasters, no one deliberately wants to make the situation worse or create more damage or fatalities. now, there can be disputes or serious disagreements in natural or technological disasters. it is almost inevitable that there will be some personal, organizational and community conflicts as, for example, in the recovery phase of disasters, where scapegoating is common (bucher, ; drabek & quarantelli, cf. boin, mcconnell, & 't hart, ) . in some crises, the overall intent of major social actors is to deliberately attempt to generate conflict. in contrast to the unfolding sequential process of natural disasters, terrorist groups or protesting rioters not only intentionally seek to disrupt social life, they modify or delay their attacks depending on perceived countermeasures. apart from a simple observable logical distinction between consensus and conflict types of crises, empirical studies have also established behavioral differences. for example, looting behavior is distinctively different in the two types. in the typical disaster in western societies, almost always looting is rare, covert and socially condemned, done by individuals, and involves targets of opportunity. in contrast, in many conflict crises looting is very common, overt and socially supported, undertaken by established groups of relatives or friends, and involves deliberately targeted locations (quarantelli & dynes, ) . likewise, there are major differences in hospital activities in the two kinds of crises, with more variation in conflict situations. there are differences also in the extent to which both organizational and community-level changes occur as a result of consensus and conflict crises, with more changes resulting from conflict occasions (quarantelli, ) . finally, it has been suggested that the mass media system operates differently in terrorism situations and in natural and technological disasters (project for excellence in journalism, journalism, , . both the oklahoma city bombing and the - world trade center attack led to sharp clashes between different groups of initial organizational responders. there were those who saw these happenings primarily as criminal attacks necessitating closure of the location as a crime for a contrary view that sees terrorist occasions as more or less being the same as what behaviorally appears in natural and technological disasters (fischer, ) . scene, and those who saw them primarily as situations where priority ought to be on rescuing survivors. in the - situation, the clash continued later into the issues of the handling of dead bodies and debris clearance. all this goes to show that crises and disasters are socially constructed. whether it is by theorists, researchers, operational personnel, politicians or citizens, any designation comes from the construction process and is not inherent in the phenomena itself. this is well illustrated in an article by cunningham ( ) where he shows that a major cyanide spill into the danube river was differently defined as an incident, an accident, or a catastrophe, depending on how culpability was perceived and who was doing the defining. still other distinctions have been made. some advocate "crisis" as the central concept in description and analysis (see the chapter of boin, kuipers and 't hart in this handbook). in this line of thinking, a crisis involves an urgent threat to the core functions of a social system. a disaster is seen as "a crisis with a bad ending" (boin, ) . this is consistent with the earlier expressed idea that while there are many hazards and risks, only a few actually manifest themselves. but the crisis idea does not differentiate among the manifestations themselves as the consensus and conflict distinction does. this is not the place to try and settle conceptual disagreements and we will not attempt to do so. anyone in these areas of study should acknowledge that there are different views and different proponents should try to make their positions as explicit as possible so people do not continue to talk past one another. it is perhaps not amiss here to note that the very words or terms used to designate the core nature of the phenomena are etymologically very complex with major shifts in meaning through time. we are far from having standardized terms and similar connotations and denotations for them. a conceptual question that has come increasingly to the fore in the last decade or so is the question: have new kinds of crises and disasters began to appear? we think it is fair to say that there are new types of risks and hazards. there are also structural changes in social settings. together, they raise the prospect of new types of disasters and crises. for example, we have seen the breakdown of modern transportation systems (think of the volcanic ash crisis that paralyzed air traffic in ; kuipers & boin, ) . there have been massive information system failures either through sabotage or as a result of technical breakdowns in linked systems. there have been terrorist attacks of a magnitude and scale not seen before. we are living with the prospect of widespread illnesses and health-related difficulties that appear to be qualitatively different from traditional medical problems. we have just lived through financial and economic collapses that cut across different social systems around the world. many of these "new" disruptions have both traditional and non-traditional features: think of the heat waves in paris (lagadec, ) and chicago (klinenberg, ) , the ice storms in canada (scanlon, ) , but also the genocide-like violence in africa and the former yugoslavia. the chernobyl radiation fallout ( ) led some scholars and researchers to start asking if there was not something distinctively new about that disaster. the fallout was first openly measured in sweden. officials were mystified in that they could not locate any possible radiation source in their own country. later radiation effects on vegetation eaten by reindeer past the arctic circle in northern sweden were linked to the nuclear plant accident in the soviet union. the mysterious origins, crossing of national boundaries, and the emergent involvement of see safire ( ) who struggles with past and present etymological meanings of "disaster", "catastrophe", "calamity" and "cataclysm"; also see murria ( ) who looking outside the english language found a bewildering set of words used, many of which had no equivalent meanings in other languages. many european and transnational groups was not something researchers had typically seen together in other prior disasters. looking back, it is clear that certain other disasters also should have alerted all of us to the probability that new forms of adversity were emerging. in november , water used to put out fire in a plant involving agricultural chemicals spilled into the river rhine. the highly polluted river went through switzerland, germany, france, luxembourg and the netherlands. a series of massive fire smog episodes plagued indonesia in and . land speculations led to fire-clearing efforts that, partly because of drought conditions, resulted in forest fires that produced thick smog hazes that spread over much of southeast asia (barber & schweithelm, ) . these disrupted travel, which in turn affected tourism as well as creating respiratory health problems, and led to political criticism of indonesia by other countries as multi-nation efforts to cope with the problem were not very successful. both of these occasions had characteristics that were not typically seen in traditional disasters. in the original version of this chapter, we spoke about "trans-system social ruptures". this term was an extension of the earlier label of "social ruptures" advanced by lagadec ( lagadec ( , . the term "transboundary" has since become the more conventional way to describe crises and disasters that jump across different societal boundaries disrupting the social fabric of different social systems (ansell et al., ) . the two prime and initial examples we used in the original chapter were the severe acute respiratory syndrome (sars) and the sobig computer f virus spread, both of which appeared in . the first involved a "natural" phenomenon, whereas the second was intentionally created. since there is much descriptive literature available on both, we here provide only very brief statements about these phenomena. the new infectious disease sars appeared in the winter of . apparently jumping from animals to humans it originated in southern rural china, near the city of guangzhou. from there it moved through hong kong and southeast asia. it spread quickly around the world because international plane flights were shorter than its incubation period. at least infected persons died. it hit canada with outbreaks in vancouver in the west and toronto far away in the east. in time, persons died of the several hundred that got ill, and thousands of others were quarantined. the city's healthcare system virtually closed down except for the most urgent of cases with countless procedures being delayed or cancelled. the result was that there was widespread anxiety in the area resulting in the closing of schools, the cancellation of many meetings and, because visitors and tourists stayed away, a considerable negative effect on the economy (commission report, , p. ) . the commission report notes a lack of coordination among the multitude of private and public sector organizations involved, a lack of consistent information on what was really happening, and jurisdictional squabbling on who should be doing what. although sars vanished worldwide after june , to this day it is still not clear why it became so virulent in the initial outbreak and why it has disappeared (yardley, ) . the sobig computer f virus spread in august (schwartz, ) . it affected many computer systems and threatened almost all computers connected to the internet. the damage was very costly. a variety of organizations around the world, public and private, attempted to deal with the problem. initially uncoordinated, there eventually emerged in an informal way a degree of informational networking on how to cope with what was happening (koerner, ) . what can we generalize from not only these two cases, but also others that we looked at later in may , the so-called wannacry virus affected millions of computers across the world with ransomware. many hospitals were affected. (ansell et al., ) ? the characteristics we depict are stated in ideal-typical terms; that is, from a social science perspective, what the phenomena would be if they existed in pure or perfect form. first, the threat jumps across many international and national/political governmental boundaries. it crosses functional boundaries, jumping from one sector to another, and crossing from the private into public sectors (and sometimes back). there was, for example, the huge spatial leap of sars from a rural area in china to metropolitan toronto, canada. second, a transboundary threat can spread very fast. cases of sars went around the world in less than hours with a person who had been in china flying to canada quickly infecting persons in toronto. the spread of the sobig f virus was called the fastest ever (thompson, ) . this quick spread is accompanied by a very quick if not almost simultaneous global awareness of the risk because of mass media attention. third, there is no known central or clear point of origin, at least initially, along with the fact that the possible negative effects at first are far from clear. this stood out when sars first appeared in canada. there is much ambiguity as to what might happen. ambiguity is of course a major hallmark of disasters and crises (turner, ) . it is more pervasive in transboundary crises as information about causes, characteristics and consequences is distributed across the system. fourth, there are potentially if not actual large number of victims, directly or indirectly. the sobig computer virus infected % of email users in china, that is about million people and about three fourths of email messages around the world were infected by this virus (koerner, ) . in contrast to the geographic limits of most past disasters, the potential number of victims is often open ended in disruptions that span across boundaries. fifth, traditional "solutions" or approachesembedded in local and/or professional institutions will not always work. this is rather contrary to the current emphasis in emergency management philosophy. the prime and first locus of planning and managing cannot be the local community as it is presently understood. international and transnational organizations must typically be involved very early in the initial response (boin, ekengren, & rhinard, ) . the nation state may not even be a prime actor in the situation. sixth, although responding organizations and groups are major players, there is an exceptional amount of emergent behavior and the development of many informal ephemeral linkages. in some respects, the informal social networks generated, involving much information networking, are not always easily identifiable from the outside, even though they are often the crucial actors at the height of the crisis. in this section, we sketch several future scenarios that most likely would create transboundary disasters. even though some of the scenarios discussed might seem to be science fiction in nature, the possibilities we discuss are well within the realm of realistic scientific possibilities. the most obvious scenario revolves around asteroids or comets hitting planet earth (di justo, ) . this has, of course, happened in the past, but even more recent impacts found no or relatively few human beings around. there are two major possibilities with respect to impact (mcguire, ; wisner, ) . a landing in the ocean would trigger a tsunami-like impact in coastal areas. just the thinking of the possibility of how, when and where ahead of time coastal population evacuations might have to be undertaken, is a daunting thought. statistically less likely is a landing in a heavily populated area. but a terrestrial impact anywhere on land would generate very high quantities of dust in the atmosphere, which will affect food production as well as creating economic disruption. this would be akin to the tambora volcanic eruption in , which led to very cold summers and crop failures (post, ) . the planning and management problems for handling something like this would be enormous. the explosion of space shuttle columbia scattered debris over a large part of the united states. this relatively small disastercompared to a comet or asteroid impactinvolved massive crossing of boundaries, a large number of potential victims, and could not be managed by local community institutions. the response required that an unplanned effort coordinating organizations that had not previously worked with one another and other unfamiliar groups, public and private (ranging from the us forest service to local red cross volunteers to regional medical groups), be informally instituted over a great part of the united states (beck & plowman, ; donahue, ) . a second scenario is the inadvertent or deliberate creation of biotechnological disasters. genetic engineering of humans or food products is currently in its infancy. the possible good outcomes and products from such activity are tremendous (morton, ) and are spreading around the world (pollack, ) . but the double-edged possibilities mentioned earlier are also present. there is dispute over genetically modified crops, with many european countries resisting and preventing their use and spread in their countries. while no major disaster or crisis from this biotechnology has yet occurred, there have been many accidents and incidents that suggest that this will be only a matter of time. for example, in , starlink corn, approved only for animal feed is found in the food supply, such as taco shells and other groceries. the same year farmers in europe learned that that they had unknowingly been growing modified canola using mixed seed from canada. in , modified corn was found in mexico even though it was illegal to plant in that country. that same year, experimental corn that had been engineered to produce a pharmaceutical that was found in soybeans in the state of nebraska. in several places, organic farmers found that it was impossible for them to keep their fields uncontaminated (for further details about all these incidents and other examples, see pollack, ) . noticeable is the leaping of boundaries and uncertainty about the route of spreading. it does not take much imagination to see that a modified gene intended for restricted use, could escape and create a contamination that could wreak ecological and other havoc. perhaps even more disturbing to some is genetic engineering involving human beings. the worldwide dispute over cloning, while currently perhaps more a philosophical and moral issue, does also partly involve the concern over creating flawed human-like creatures. it is possible to visualize not far-fetched worst-case scenarios that could be rather disastrous. it should be noted that even when there is some prior knowledge of a very serious potential threat, what might happen is still likely to be as ambiguous and complex as when sars first surfaced. this can be seen in the continuing major concern expressed in to mid- about the possible pandemic spread of avian influenza, the so called "bird flu" (nuzzo, ; thorson & ekdahl, ) . knowledge of the evolution and spread of new pandemics, their effects and whether presently available protective measures would work, may well be very limited. knowledge that it might occur provides very little guidance on what might actually happen. it is possible to imagine the destruction of all food supplies for human beings either through the inadvertent or deliberate proliferation of very toxic biotechnological innovations for which no known barriers to spreading exists. these potential kinds of global disasters are of relatively recent origins and we may expect more such possibilities in the future. the human race is opening up potentially very catastrophic possibilities by innovations in nanotechnology, genetic engineering and robotics (barrat, ; joy, ; makridakis, ) . a potential is not an actuality. but it would be foolish from both a research as well as a planning and managing viewpoint to simply ignore these and other doomsday possibilities. the question might be asked if there is a built-in professional bias among disaster and crisis researchers and emergency planners to look for and to expect the worst (see mueller, for numerous examples). in the disaster and crisis area, this orientation is reinforced by the strong tendency of social critics and intellectuals to stress the negative. it would pay to look at the past, see what was projected at a particular time, and then to look at what actually happened. the worldwide expectations about what would happen at the turn of the century to computers are now simply remembered as the y k fiasco. it would be a worthy study to take projections by researchers about the future of ongoing crises and disasters, and then to look at what actually happened. in the s, in the united states, scholars made rough analyses about the immediate future course of racial and university riots in the country. their initial appearances had not been forecasted. moreover, there was a dismal record in predicting how such events would unfold (no one seemed to have foreseen that the riots would go from ghetto areas to university campuses), as well as that they rather abruptly stopped. we should be able to do a better job than we have so far in making projections about the future. but perhaps that is asking more of disaster and crisis researchers than is reasonable. after all, social scientists with expertise in certain areas, to take recent examples, failed completely to predict or forecast the non-violent demise of the soviet union, the peaceful transition in south africa, or the development of a market economy in communist china (cf. tetlock, ) . a disaster or crisis always occurs in some kind of social setting. by social setting we mean social systems. these systems can and do differ in social structures and cultural frameworks. there has been a bias in disaster and crisis research towards focusing on specific agents and specific events. thus, there is the inclination of social science researchers to say they studied this or that earthquake, flood, explosion and/or radioactive fallout. at one level that is nonsense. these terms refer to geophysical, climatological or physical happenings, which are hardly the province of social scientists. instead, those focused on the social in the broad sense of the term should be studying social phenomena. our view is that what should be looked at more is not the possible agent that might be involved, but the social setting of the happening. this becomes obvious when researchers have to look at such happenings as the southeast asia tsunami or locust infestations in africa. both of these occasions impacted a variety of social systems as well as involving social actors from outside those systems. this led in the tsunami disaster to sharp cultural clashes regarding on how to handle the dead between western european organizations who came into look mostly for bodies of their tourist citizens, and local groups who had different beliefs and values with respect to dead bodies (scanlon, personal communication with first author). the residents of the andaman islands lived at a level many would consider "primitive". at the time of the tsunami in southeast asia, they had no access to modern warning systems. but prior to the tsunami, members of the tribal communities saw signs of disturbed marine life and heard unusual agitated cries of sea birds. this was interpreted as a sign of impending danger, so that part of the population got off the beaches and retreated inland to the woods and survived intact (icpac report, ) . there is a need to look at both the current social settings as well as certain social trends that influence disasters and crises. in no way are we going to address all aspects of social systems and cultural frameworks or their social evolution, either past or prospective. instead, we will selectively discuss and illustrate a few dimensions that would seem to be particularly important with respect to crises and disasters. what might these be? let us first look at existing social structures around the world. what differences are there in authority relationships, social institutions and social diversity? as examples, we might note that australia and the united states are far more governmentally decentralized than france or japan (bosner, for example, rees ( ) , a cosmologist at cambridge university, gives civilization as we know it only a - chance of surviving the st century. schoff, ) . this affects what might or might not happen at times of disasters (it is often accepted that top-down systems have more problems in responding to crises and disasters). but what does it mean for the management of transboundary disruptions, which require increased cooperation between and across systems? will decentralized systems be able to produce "emergent" transboundary cooperation? as another example, mass media systems operate in rather different ways in china compared with western europe. this is important because to a considerable extent the mass communication system (including social media) is by far the major source of "information" about a disaster or a crisis. they play a major role in the social construction of disasters and crises. for a long time in the former soviet union, even major disasters and overt internal conflicts by way of riots were simply not openly reported (berg, ) . and only late in did chinese authorities announce that henceforth death tolls in natural disasters would be made public, but not for other kinds of crises (kahn, ) . another social structural dimension has to do with the range of social diversity in different systems (bolin & stanford, ) . social groupings and categories can be markedly different in their homogeneity or heterogeneity. the variation, for instance, can be in terms of life styles, class differences or demographic composition. the aging population in western europe and japan is in sharp contrast to the very young populations in most developing countries. this is important because the very young and the very old incur disproportionately the greatest number of fatalities in disasters. human societies also differ in terms of their cultural frameworks. as anthropologists have pointed out, they can have very different patterns of beliefs, norms, and values. as one example, there can be widely held different conceptions of what occasions disasters and crises. the source can be attributed to supernatural, natural, or human factors as indicated earlier. this can markedly affect everything from what mitigation measures might be considered to how recovery and reconstruction will be undertaken. norms indicating what course of action should be followed in different situations can vary tremendously. for example, the norm of helping others outside of one's own immediate group at times of disasters and crises ranges from full help to none. thus, although the kobe earthquake was an exception, any extensive volunteering in disasters was very rare in japan (for a comparison of the us and japan, see hayashi, ) . in societies with extreme cross-cultural ethnic or racial differences, volunteering to help others outside of one's own group at times of disasters or crisis is almost unknown. social structures and cultural frameworks of course are always changing. to understand future disasters and crises, it is necessary to identify and understand trends that may be operative with respect to both social structures and cultural frameworks. in particular, for our purposes, it is important to note trends that might be cutting across structural and cultural boundaries. globalization has been an ongoing force. leaving aside the substantive disputes about the meaning of the term, what is involved is at least the increasing appearance of new social actors at the global level. with respect to disaster relief and recovery, there is the continuing rise of transnational or international organizations such as un entities, the european union, religiously oriented groupings, and the world bank (boin et al., ) . with the decline of the importance of the nation state (guéhenno, ; mann, ) , more and new social actors, especially of an ngo nature, are to be anticipated. the rise of the information society has enabled the development of informal social networks that globally cut across political boundaries. this trend will likely increase in the future. such networks are creating social capital (in the social science sense) that will be increasingly important in dealing with disasters and crises. at the cultural level, we can note the greater insistence of citizens that they ought to be actively protected against disasters and crises (beck, ) . this is part of a democratic ideology that has spread around the world. that same ideology carries an inherent paradox: the global citizen may not appreciate government interference in everyday life, but expects government to show up immediately when acute adversity hits. finally, there has been the impact of the / attacks especially on official thinking not just in the united states but elsewhere also. this happening has clearly been a "focusing event" (as birkland, uses the term) and changed along some lines, certain values, beliefs and norms (smelser, ; tierney, ) . there is a tendency, at least in the us after / , to think that all future crises and disasters will be new forms of terrorism. one can see this in the creation of the us department of homeland security, which repeated errors in approach and thinking that over years of research have shown to be incorrect (e.g., an imposition of a command and control model, assuming that citizens will react inappropriately to warnings, seeing organizational improvisation as bad managing, see dynes, ) . these changes were accompanied by the downgrading of fema and its emphasis on mitigation (cohn, ) . valid or not, such ideas influence thinking about transboundary disasters and crises (and not just in the united states). the ideas expressed above and the examples used were intended to make several simple points. they suggest, for instance, that an earthquake of the same magnitude in france to one in iran will probably be reacted to differently. a riot in sweden will be a different phenomenon than one in myanmar. to understand and analyze such happenings requires taking into account the aspects just discussed. it is hard to believe that countries that currently have no functioning national government, such as somalia and the democratic republic of the congo or marginally operatives ones such as afghanistan, will have the same reaction to disasters and crises as societies with fully functional national governments. different kinds of disasters and crises will occur in rather different social settings. in fact, events that today are considered disasters or crises were not necessarily so viewed in the past. in noting these cross-societal and cross-cultural differences, we are not saying that there are no universal principles of disaster and crisis behavior. there is considerable research evidence supportive of this notion. we would argue, for example, that many aspects of effective warning systems, problems of bureaucracies in responding, the crucial importance of the family/household unit are roughly the same in all societies. to suggest the importance of cross-societal and cross-cultural differences is simply to suggest that good social science research needs to take differences into account while at the same time searching for universal principles about disasters and crises. this is consistent with those disaster researchers and scholars (e.g., oliver-smith, ) who have argued that studies in these areas have badly neglected the historical context of such happenings. of course, this neglect of the larger and particularly historical context has characterized much social science research of any kind (wallerstein, ) ; it is not peculiar to disaster and crisis studies. one trend that affects the character of modern crises and disasters is what we call the social amplifications of crises and disasters. pidgeon, kasperson, and slovic ( ) described a social augmentation process with respect to risk. to them, risk not only depends on the character of the dangerous agent itself but how it was seen in the larger context in which it appeared. the idea that there can be social amplification of risk rests on the assumption that aspects relevant to hazards interact with processes of a psychological, social, institutional, and cultural nature in such a manner that they can increase or decrease perceptions of risk (kasperson & kasperson, ) . it is important to note that the perceived risk could be raised or be diminished depending on the factors in the larger context, which makes it different from the vulnerability paradigm which tends to assume the factors involved will be primarily negative ones. we have taken this idea and extended it to the behaviors that appear in disasters and crises. extreme heat waves and massive blizzards are hardly new weather phenomena (burt, ) . there have recently been two heat waves, however, that have new elements in them. in , a long lasting and very intensive heat wave battered france. nearly , persons died (and perhaps , - , in all of europe). particularly noticeable was that the victims were primarily socially isolated older persons. another characteristic was that officials were very slow in accepting the fact that there was a problem and so there was very little initial response (lagadec, ) . there was a similar earlier happening in chicago not much noticed until reported in a study seven years later (see klinenberg, ) . it exhibited the same features, that is, older isolated victims, bureaucratic indifference, and mass media uncertainty. at the other temperature extreme, in , canada experienced an accumulation of snow and ice that went considerably beyond the typical. the ice storm heavily impacted electric and transport systems, especially around montreal. the critical infrastructures being affected created chain reactions that reached into banks and refineries. at least municipalities declared a state of emergency. such a very large geographic area was involved that many police were baffled that "there was no scene", no "ground zero" that could be the focus of attention (scanlon, ) . there were also many emergent groups and informal network linkages (scanlon, ) . in some ways, this was similar to what happened in august , when the highly interconnected eastern north american power grid started to fail when three transmission lines in the state of ohio came into contact with trees and short circuited (townsend & moss, ) . this created a cascade of power failures that resulted in blackouts in cities from new york to toronto and eventually left around million persons without power, which, in turn, disrupted everyday community and social routines (ballman, ) . it took months of investigation to establish the exact path of failure propagation through a huge, complex network. telecommunication and electrical infrastructures entwined in complex interconnected and network systems spread over a large geographic area with multiple end users. therefore, localized disruptions can cascade into large-scale failures (for more details, see townsend & moss, ) . such power blackouts have occurred among others in auckland, new zealand in (newlove, stern, & svedin, ) ; in buenos aires in (ullberg, ); in stockholm in and in siberian cities in (humphrey, ; in moscow in (arvedlund, ; in brazil in (brooks, ); in bangladesh in (al-mahmood, , and in sri lanka in (lbo, ). all of these cases initially involved accidents or software and hardware failures in complex technical systems that generate severe consequences creating a crisis with major economic and often political effects. these kinds of crises should have been expected. a national research council report ( ) forecast the almost certain probability of these kinds of risks in future network linkages. blackouts can also be deliberately created either for good or malevolent reasons having nothing to with problems in network linkages. employees of the now notorious enron energy company, in order to exploit western energy markets, indirectly but deliberately took off line a perfectly functioning las vegas power plant so that rolling blackouts hit plant-dependent northern and central california with about a million residences and businesses losing power (egan, ) . in the earliest days of electricity in new york city, the mayor ordered the power cut off when poor maintenance of exposed and open wires resulted in a number of electrocutions of citizens and electrical workers (jonnes, ) . one should not think of blackouts as solely the result of mechanical or physical failures creating chain-like cascades. most disasters are still traditional ones. for example, four major hurricanes hit the state of florida in . we saw very little in what we found that required thinking of them in some major new ways, or even in planning for or managing them. the problems, individual or organizational, that surfaced were the usual ones, and how to successfully handle them is fairly well known. more important, emergent difficulties were actually somewhat better handled than in the past, perhaps reflecting that officials may have had exposure to earlier studies and reports. thus, the warnings issued and the evacuations that took place were better than in the past. looting concerns were almost non-existent and less than ten percent indicated possible mental health effects. the pre-impact organizational mobilization and placement of resources beyond the community level was also better. the efficiency and effectiveness of local emergency management offices were markedly higher than in the past. not everything was done well. long known problematical aspects and failures to implement measures that research had suggested a long time ago were found. there were major difficulties in interorganizational coordination. the recovery period was plagued by the usual problems. even the failures that showed up in pre-impact mitigation efforts were known. the majority of contemporary disasters in the united states are still rather similar to most of the earlier ones. what could be seen in the hurricanes in florida was rather similar to what the disaster research center (drc) had studied there in the s and the s. as the electronic age goes beyond its birth and as other social trends continue, new elements may appear creating new problems that will necessitate new planning. if and when that happens, we may have rather new kinds of hurricane disasters, but movement in that direction will be slow. as the famous sociologist herbert blumer used to say in his class lectures a long time ago, it is sometimes useful to check whatever is theoretically proposed against personal experience. in , an extensive snowstorm led to the closing of almost all schools and government offices in the state of delaware. this was accompanied by the widespread cancellations of religious and sport events. there was across the board disruption of air, road and train services. all of this resulted in major economic losses in the millions of dollars. there were scattered interruptions of critical life systems. the governor issued a state of emergency declaration and the state as well as local emergency management offices fully mobilized. to be sure, what happened did not fully rival what surfaced in the canadian blizzard discussed earlier. but it would be difficult to argue that it did not meet criteria often used by many to categorize disasters. what happened was not that different from what others and we had experienced in the past. in short, it was a traditional disaster. finally, at the same time we were thinking about the florida hurricanes and the delaware snowstorm, we also observed other events that many would consider disasters or crises. certainly, a bp texas plant explosion in would qualify. it involved the third largest refinery in the country. more than a hundred were injured and persons died. in addition, there was major physical destruction of refinery equipment and nearby buildings were leveled. there was full mobilization of local emergency management personnel (franks, ) . at about the same time, there were landslides in the state of utah and california; a stampede with hundreds of deaths in a bombay, india temple, train and plane crashes in different places around the world, as well as large bus accidents; a dam rupture which swept away five villages, bridges and roads in pakistan; recurrent coal mine accidents and collapses in china; recurrent false reports in asia about tsunamis that greatly disrupted local routines; sinking of ferries with many deaths, and localized riots and hostage takings. at least based on press reports, it does not seem that there was anything distinctively new about these occasions. they seem to greatly resemble many such prior happenings. unless current social trends change very quickly in hypothetical directions (e.g., marked changes as a result of biotechnological advances), for the foreseeable future there will continue to be many traditional local community disasters and crises (such as localized floods and tornadoes, hostage takings or mass shootings, exploding tanker trucks or overturned trains, circumscribed landslides, disturbances if not riots at local sport venues, large plant fires, sudden discoveries of previously unknown very toxic local waste sites, most airplane crashes, stampedes and panic flights in buildings, etc.). mega-disasters and global crises will be rare in a numerical and relative sense, although they may generate much mass media attention. for example, the terrorist attacks in european cities (madrid in ; london in ; paris in ; brussels, nice, munich berlin in ; stockholm and manchester in ) were certainly major crises and symbolically very important, but numerically there are far more local train wrecks and car collisions everyday in many countries in the world. the more localized crises and disasters will continue to be the most numerous, despite the rise of transboundary crises and disasters. what are some of the implications for planning and managing that result from taking the perspective we have suggested about crises and disasters? if our descriptions and analyses of such happenings are valid, there would seem to be the need for new kinds of planning and preparation for the management of future crises and disasters (ansell et al., ) . non-traditional disasters and crises require some non-conventional processes and social arrangements. they demand innovative thinking "outside of the box" (boin & lagadec, ; lagadec, ) . this does not mean that everything has to be new. as said earlier, all disasters and crises share certain common dimensions or elements. for example, if early warning is possible at all, research has consistently shown that acceptable warnings have to come from a legitimately recognized source, have to be consistent, and have to indicate that the threat or risk is fairly immediate. these principles certainly pertain to the management of transboundary disruptions. actually, if traditional risks and hazards and their occasional manifestations were all we needed to be worried about, we would be in rather good shape. as already said several times, few threats actually manifest themselves in disasters. for example, in the , plus tornadoes appearing in the united states between and , there were casualties in only of them, and of these occasions accounted for almost half of the fatalities (noji, ) . similarly, it was noted in that while about . million people had been killed in earthquakes since , over % of them had died in only occurrences (jones, noji, smith, & wagner, , p. ) . we can say that risks and hazards and their relatively rare manifestations in crises and disasters are being coped with much better than they ever were even just a half-century ago. for example, there has been a remarkable reduction in certain societies of fatalities and even property destruction in some natural disaster occasions associated with hurricanes, floods and earthquakes (see scanlon, for data on north america). in the conflict area, the outcomes have been much more uneven, but even here, for example, the recurrence of world wars seems very unlikely. but transboundary crises and disasters require some type of transboundary cooperation. for example, let us assume that a health risk is involved. if international cooperation is needed, who talks with whom about what? at what time is action initiated? who takes the lead in organizing a response? what legal issues are involved (e.g., if health is the issue, can health authorities close airports?)? there might be many experts and much technical information around; if so, and they are not consistent, whose voice and ideas should be followed? what should be given priority? how could a forced quarantine be enforced? what of ethical issues? who should get limited vaccines? what should the mass media be told and by who and when? at a more general level of planning and managing, we can briefly indicate, almost in outline form, a half dozen principles that ought to be taken into account by disaster planners and crisis managers. first, a clear connection should be made between local planning and transboundary managing processes. there usually is a low correlation between planning and managing, even for traditional crises and disasters. but in newer kinds of disasters and crises, there are likely to be far more contingencies. planning processes need to be rethought and enhanced to help policymakers work across boundaries. second, the appearance of new emergent social phenomena (including groups and behaviors) needs to be taken into account. there are always new or emergent groups at times of major disasters and crises, but in transboundary events they appear at a much higher rate. networks and network links have to be particularly taken into account. third, there is the need to be imaginative and creative. the response to hurricane katrina suggests how hard it can be to meet transboundary challenges. but improvisation can go a long way. a good example is found in the immediate aftermath of / in new york. in spite the total loss of the new york city office of emergency management and its eoc facility, a completely new eoc was established elsewhere and started to operate very effectively within h after the attack. there had been no planning for such an event, yet around , persons were evacuated by water transportation from lower manhattan (kendra & wachtendorf, ; kendra, wachtendorf, & quarantelli, ) . fourth, exercises and simulations of disasters and crises must take into account transboundary contingencies. most such training and educational efforts along such lines are designed to be like scripts for plays. that is a very poor model to use. realistic contingencies, unknown to most of the players in the scenarios, force the thinking through of unconventional options. even more important, policymakers need to be explicitly trained in the management of transboundary crises and disasters. fifth, planning should be with citizens and their social groups, and not for them. there is no such thing as the "public" in the sense of some homogenous entity (blumer, ) . there are only individual citizens and the groups of which they are members. the perspective from the bottom up is crucial to getting things done. this has nothing to do with democratic ideologies; it has instead to do with getting effective and efficient planning and managing of disasters and crises. related to this is that openness with information rather than secrecy is mandatory. this runs against the norms of most bureaucracies and other organizations. the more information the mass media and citizens have, the better they will be able to react and respond. however, all this is easier said than done. finally, there is a need to start thinking of local communities in ways different than they have been traditionally viewed. up to now, communities have been seen as occupying some geographical space and existing in some chronological time. instead, we should visualize the kinds of communities that exist today are in cyberspace. these newer communities must be thought of as existing in social space and social time. viewed this way, the newer kinds of communities can be seen as very important in planning for and managing disasters and crises that cut across national boundaries. to think this way requires a moving away from the traditional view of communities in the past. this will not be easy given that the traditional community focus is strongly entrenched in most places around the world (see united nations, ) . but "virtual reality communities" will be the social realities in the future. assuming that what we have written has some validity, what new research should be undertaken in the future on the topic of future disasters and crises? in previous pages, we suggested some future studies on specific topics that would be worthwhile doing. however, in this section we want to outline research of a more general nature. for one, practically everything we discussed ought to be looked at in different cultures and societies. as mentioned earlier, there is a bias in our perspective that reflects our greater familiarity with and awareness of examples from the west (and even more narrowly western europe, the united states and canada). in particular, there is a need to undertake research in developing rather than only developed countries. and that includes at least some of these studies being undertaken by researchers and scholars from the very social systems that are being studied. the different cultural perspectives that would be brought to bear might be very enlightening, and enable us to see things that presently we do not see, being somewhat a prisoner of our own culture. second, here and there in this chapter, we have suggested that it is important to study the conditions that generate disasters and crises. but there has to be at least some understanding of the nature of x before there can be a serious turn to ascertaining the conditions that generate x. we have taken this first step in this chapter. future work should focus more on the generating conditions. a general model would involve the following ideas. the first is to look at social systems (societal, community and/or organizational ones), and to analyze how they have become more complex and tightly coupled. the last statement would be treated as a working hypothesis. if that turns out to be true, it could then be hypothesized that systems can break down in more ways than ever before. a secondary research thrust would be to see if systems also have developed ways to deal with or cope with threatening breakdowns. as such, it might be argued that what ensues is an uneven balance between resiliency and vulnerability. in studying contemporary trends, particular attention might be given to demographic ones. it would be difficult to find any country today where the population composition is not changing in some way. the increasing population density in high risk areas seems particularly important. another value in doing research on this topic is that much demographic data are of a quantitative nature. we mentioned financial and economic collapses cutting across different systems. how can financial collapse conceivably be thought of as comparable in any way to natural disasters and crises involving conflict? one simple answer is that for nearly a hundred years, one subfield of sociology has categorized, for example, panic flight in theater fires and financial panics as generic subtypes within the field of collective behavior (blumer, ; smelser, ) . both happenings involve new, emergent behaviors of a non-traditional nature. in this respect, scholars long ago put both types of behavior into the same category. although disaster and crisis researchers have not looked at financial collapses, maybe it is time that they did so. these kinds of happenings seem to occur very quickly, are ambiguous as to their consequences, cut across political and sector boundaries, involve a great deal of emergent behavior and cannot be handled at the community level. in short, what has to be looked for are genotypic characteristics not phenotypic ones (perry, ) . if whales, human beings, and bats can all be usefully categorized as mammals for scientific research purposes, maybe students of disasters should also pay less attention to phenotypic features. if so, should other disruptive phenomena like aids also be approached as disasters? our overall point, is that new research along the lines indicated might lead researchers to seeing phenomena in ways different than they had previously seen. finally, we have said little at all about the research methodologies that might be necessary to study transboundary ruptures. up to now, disaster and crisis researchers have argued that the methods they use in their research are indistinguishable from those used throughout the social sciences. the methods are simply applied under circumstances that are relatively unique (stallings, ) . in general, we agree with that position. but two questions can be raised. first, if social scientists venture into such areas as genetic engineering, cyberspace, robotics and complex infectious diseases, do they need to have knowledge of these phenomena to a degree that they presently do not have? this suggests the need for actual interdisciplinary research. social scientists ought to expand their knowledge base before venturing to study certain disasters and crises, especially the newer ones. there is something here that needs attention. in the sociology of science there have already been studies of how researchers from rather different disciplines studying one research question, interact with one another and what problems they have. researchers in the disaster and crisis area should look at these studies. our view is that the area of disasters and crises is changing. this might seem to be a very pessimistic outlook. that is not the case. there is reason to think, as we tried to document earlier, that human societies in the future will be able to cope with whatever new risks and hazards come into being. to be sure, given hazards and risks, there are bound to be disasters and crises. a risk free society has never existed and will never exist. but while this general principle is undoubtedly true, it is not so with reference to any particular or specific case. in fact, the great majority of potential 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authors: martin, susan f. title: forced migration and refugee policy date: - - journal: demography of refugee and forced migration doi: . / - - - - _ sha: doc_id: cord_uid: yvx gyp this chapter focuses on international, regional and national legal norms, policies, organizational roles and relations and good practices that are applicable to a broad range of humanitarian crises that have migration consequences. these crises and the resulting displacement differ by their causes, intensity, geography, phases and affected populations. the chapter examines movements stemming directly and indirectly from: persecution, armed conflict, extreme natural hazards that cause extensive destruction of lives and infrastructure; slower onset environmental degradation, such as drought and desertification, which undermine livelihoods; manmade environmental disasters, such as nuclear accidents, which destroy habitat and livelihoods; communal violence, civil strife and political instability; and global pandemics that cause high levels of mortality and morbidity. demographic trends are themselves drivers of displacement in conjunction with other factors. this can play out in two ways—demography as a macro-level factor and demographic composition as a micro-level driver of movement. the chapter compares the paucity of legal, policy and institutional frameworks for addressing crisis-related movements with the more abundant frameworks for addressing the consequences of refugee movements. the chapter discusses the policy implications of the findings, positing that state-led initiatives such as the nansen and migrants in countries in crisis initiatives are useful mechanisms to fill protection gaps in the absence of political will to adopt and implement more binding legal frameworks. it also argues that, in the context of slow onset climate change, in particular, there is a need for better understanding of how population density, distribution and growth as well as household composition affect vulnerability and resilience to the drivers of displacement. since , the international refugee regime has faced dozens of both traditional and non-traditional challenges in identifying and implementing policies for the protection of refugees and displaced persons. the massive displacement in and from syria has garnished the most attention but large scale movements in the context of conflicts in south sudan, central african republic, ukraine and elsewhere merit consideration as well. earlier in the decade, the famine and long-term conflict in somalia sent hundreds of thousands across the border into kenya and ethiopia while the crisis in libya and political instability throughout north africa caused more than one million to flee across international borders, some seeking asylum while others (mostly contract workers) tried to get to their own home countries as violence erupted in their destination countries. typhoon haiyan in the philippines displaced millions in , leaving many in a situation of protracted upheaval. migration resulting from these natural and man-made events may correspond to current international, regional and national frameworks that are designed to protect and assist refugees-that is, persons who flee across an international boundary because of a well-founded fear of persecution-but often, these movements fall outside of the more traditional legal norms and policies. yet, they have many characteristics in common with refugee movements. for example, they often take place in the context of political instability, countries of origin may not have the capacity or political will to protect their citizens from harm, an international response may be needed because of the scale of the migration, and the need for humanitarian assistance will likely overwhelm local capacities. s.f. martin (*) school of foreign service, georgetown university, washington, th and o streets, n.w, washington, dc , usa e-mail: susan. martin.isim@georgetown.edu this chapter focuses on international, regional and national legal norms, policies, organizational roles and relations and good practices that are applicable to the broader range of humanitarian crises that have migration consequences. the chapter examines movements stemming directly and indirectly from: persecution, armed conflict, extreme natural hazards that cause extensive destruction of lives and infrastructure; slower onset environmental degradation, such as drought and desertification, which undermine livelihoods; manmade environmental disasters, such as nuclear accidents, which destroy habitat and livelihoods; communal violence, civil strife and political instability; and global pandemics that cause high levels of mortality and morbidity. these crises lead to many different forms of displacement, including internal and cross border movements of nationals, evacuation of migrant workers, sea-borne departures that often involve unseaworthy vessels, and trafficking of persons. while the majority of those displaced from humanitarian crises move internally, a significant portion migrates cross borders to other countries. the chapter will compare the paucity of legal, policy and institutional frameworks for addressing these other crises with the more abundant frameworks for addressing the consequences of refugee movements. part introduces the concepts of the chapter, defining the types of humanitarian crises that have migration consequences. it will have subsections discussing briefly the range of crises referenced above, describing the types of forced migration that occur as a result of each category of crisis. part focuses on the legal frameworks and policies available at the international, regional and national levels for addressing the migration consequences of these crises. part will discuss institutional arrangements for addressing the types of migration under review. part will present the conclusions of the chapter and discuss the policy implications of the findings. it also discusses the important role that demography can play in helping to improve responses to forced migration in the context of humanitarian crises. this section presents a typology for analyzing the nature of forced migration. the migration consequences-and the resulting policy frameworks-will differ along five principal dimensions: the precipitating drivers or causes of forced migration, the intensity of these drivers, the geography of the displacement, the phase of displacement, and the affected populations ( fig. . ) . first, forced migration-producing events differ by their causes. some are primarily generated by natural causes whereas others are human made. in most cases, however, a governance failure is at the heart of the crisis whether the trigger is natural or human. among examples of the drivers of displacement are: • persecution, torture and other serious human rights violations. the precipitator of forced migration that, as we will see, fits best into current legal and policy norms involves persecution of individuals or groups on the basis of such factors as race, religion, nationality, membership in a particular social group (often used to address gender), and political opinion. persecution can affect individuals or it can affect groups of people as defined by what are often referred to as immutable characteristics shared by large numbers of people. it often occurs in contexts in which there are no safeguards to protect racial, ethnic, religious, and other minorities who may be targeted by other groups. persecution can involve serious physical or psychological harm (e.g., rape or torture), deprivation of one's liberty (e.g., imprisonment), forced removal or ethnic cleansing, severe economic deprivation, and other mechanisms that result in serious harm to the individual. • armed conflict. one of the principal drivers of forced migration is armed conflict. although most displacement today occurs in the context of internal armed conflict, significant levels of forced migration accompany international armed conflict as well. displacement may be a form of collateral damage as civilian populations get out of harm's way but in many conflicts forcing the relocation of civilians is an overt aim of one or another of the warring parties. • political instability and violence. the recent events in north africa and the middle east fit into this category, with millions fleeing violence perpetrated by the islamic state (isis) and other terrorist and insurgent groups. violence following contested elections in kenya ( ) , zimbabwe ( ) and cote d'ivoire ( ) is another example of political instability that has generated violence that has resulted in large-scale displacement. communal violence that does not rise to the situation of armed conflict, but nevertheless displaced large numbers, has occurred in and from the karamoja region of uganda, bangladesh, ethiopia and elsewhere. the violence can be between clans, ethnic groups, economic fig. . typology of forced migration competitors, religious groups or pastoralists claiming the same land. violence can also be the product of drug cartels and gangs that fight each other or government authorities. • natural hazards. recent examples of crises resulting from extreme natural hazards that have had migration impacts include hurricanes/cyclones (e.g., hurricanes mitch and stan in central america and cyclone nargis in burma/ myanmar), tsunamis (e.g., indonesia, sri lanka and somalia in and japan in ), flooding (e.g., pakistan in ), earthquakes (e.g., haiti in ); and prolonged droughts (somalia in ). generally, the hazard itself does not cause the crisis; a lack of national and local governance, lack of emergency preparedness, lack of adequate building codes, high levels of poverty and similar weaknesses in local and national capacity lead to crisis conditions. experiences with mass displacement after hurricane katrina show that even very wealthy countries are not immune to such disasters, but stable, more economically advanced countries generally have greater capacity to assist their citizens. the differences in deaths and displacement from earthquakes in haiti and chile in are indicative. although the seismic level of the chilean earthquake was much greater than that in haiti, the level of destruction was much greater in haiti, which is one of the poorest countries in the world and suffered from decades of political instability. the earthquake in mexico is another case in point. an albeit more intense earthquake in led to tens of thousands of deaths, but the recent experience demonstrated that new building codes, emergency preparations and timely response could reduce casualties to a handful. • man-made environmental crises. man-made crises include nuclear/chemical/ biological accidents and attacks, accidental or deliberate setting of fires, and similar situations that make large areas uninhabitable and cause displacement. the accident at the chernobyl nuclear plant in , for example, resulted in the evacuation of more than , people within days. the earthquake and tsunami in japan led to further crisis when nuclear power plants lost their capacity to cool reactors, forcing the evacuation of thousands. this classification system, though useful in understanding the causes of crises with migration impacts, is not composed of pure types because there are often overlaps among the factors that create disasters. for example, an acute natural hazard and political instability may intersect to drive people from their homes. in fact, as stated above, an absence of good governance is almost always one of the factors that is present when forced displacement occurs. demographic trends, while not usually directly linked to displacement, also intersect with each of these causes to increase or decrease a population's vulnerability or resilience. the demographic composition of the affected population also helps determine whether specific households or individuals will need to migrate. these may differ, however, depending on the causation. for example, adolescent and young men may be at particular risk of forced recruitment in conflict situations, necessitating flight if they do not wish to participate in the fighting. on the other hand, the elderly and young children may be at higher risk of starvation in the case of protracted drought, as discussed below. a second dimension of the typology is the intensity of the driving factors. the division is broadly between acute crises and slow-onset emergencies. the former often lead to emergency displacements that are readily defined as "forced migration" because conditions in home countries or communities are seen as the primary reasons that people leave. by contrast, the displacement generated by slow-onset situations is often seen as voluntary and often anticipatory migration and may have elements of labor migration. slower-onset crises arise in a number of different contexts. prolonged drought is a principal cause of displacement for millions who are reliant on subsistence agriculture and pastoralist activities. recurrent droughts undermine livelihoods when crops fail and livestock are sold or die because of inadequate rain and depletion of other water sources. when markets do not function in a manner that allows a redistribution of food to drought-affected populations, migration becomes one of the principal ways to cope with losses caused by the environmental change. since many of the affected populations resemble others who migrate to obtain better economic opportunities, it may be difficult to distinguish those whose loss of livelihood is environmentally-related. in worse case examples, when (for example) drought combines with conflict or other political factors to preclude food distribution in communities of origin, famine may be in the offing. when affected populations have exhausted all of their other coping capacities, they may be forced to migrate or suffer starvation. often, children, the elderly and those with pre-existing illnesses are among the first to succumb to famine in the absence of alternatives. they are also the least likely to be able to migrate without assistance. the third dimension is geography-where and how the displacement takes place. in almost all of the situations that are discussed above, most migration is internal or into neighboring countries that share a contiguous border. a smaller proportion of the movements are to countries outside of the immediate region of the crisis. currently, those who cross international borders are designated as 'refugees ' or 'international migrants' whereas those who remain within their national borders are 'internally displaced persons' or 'internal migrants. ' how migrants leave their own countries, pass through transit countries, and enter destination countries also affect designations. some migrants may have received permission to enter another country while others travel without documentation or otherwise on an "irregular" basis. sea-borne migrants, particularly those in small, unseaworthy boats, face dangers not only from variability in the weather but also from pirates and others who prey on them. migrants using smugglers may be routed through multiple countries before reaching their final destination. those crossing difficult land terrains may find themselves endangered as they attempt irregular entry across deserts and mountains. while these irregular means of transit may be common when there is political instability or natural disasters, pandemics present another geographic challenge. airports and seaports often become the focal point for action, especially when governments establish policies to quarantine those who may be carrying the disease. the fourth dimension relates to timing. the migration consequences of crises take different forms and must be addressed through different mechanisms depending on the phase of displacement or movement and its duration. some of the causes discussed above produce protracted crises whereas others lead to more temporary dislocations. for example, some cases of political instability are quickly resolved and new governments put in place but others drag on for years with no resolution in sight. similarly, reconstruction after some extreme natural hazards moves ahead quickly and people are able to return to their homes with little loss of livelihoods, but in other cases, return is delayed or impossible because governments have too little capacity to implement reconstruction programs, there is such great likelihood of recurrence of the same type of natural hazard, and/or the home community has been damaged beyond repair. in extreme cases, an entire country may become uninhabitable (for example, montserrat after the volcano and potentially, small island states as a result of climate change). in these cases, return may be impossible. these phases may play out differently for different populations affected by the same triggering event depending on their personal or household circumstances. they are also not necessarily linear; for example, those who return may find themselves engulfed in new crises and experience new displacements. needs and frameworks differ depending on the stage of the crisis. the first stage is pre-crisis, when actions to prevent, mitigate and help individuals adapt to the causes that may force them to move take place. of particular importance is disaster risk reduction, which involves "systematic efforts to analyse and manage the causal factors of disasters, including through reduced exposure to hazards, lessened vulnerability of people and property, wise management of land and the environment, and improved preparedness for adverse events" (unisdr ). disaster risk reduction does not prevent the extreme natural hazard from occurring but it helps communities to cope with their damaging effects. in some worse case examples, the only option to reduce the risk of disaster may be relocation from fragile areas. identifying and addressing demographic and socio-economic vulnerabilities is essential since the "characteristics and circumstances of a community, system or asset … make it susceptible to the damaging effects of a hazard" (unisdr ). meeting the sustainable development goals would have positive impact in enhancing the ability of people to cope with crises in situ. more broadly, economic, social and human development-with the aims of reducing poverty, increasing access to livelihoods, education and literacy, improving health outcomes, maintaining sustainable environments, etc.-will reduce long-term emigration pressures while giving people increased human security. appropriate interventions will depend on the demographics of the affected populations. equally important, given the highly political nature of many of these emergencies, are efforts to improve governance in countries that are prone to crises. effective governance not only helps mitigate the risks associated with natural and human made hazards (through such preventive actions as earthquake-resistant building codes or public health measures to lessen pandemic risks) but it also helps reduce tensions that can escalate into conflict. early warning mechanisms can help trigger conflict resolution and mediation processes to reduce the potential for communal or political violence. the second stage is the migration itself, with rights and needs differing depending on the form and stage of migration as well as the demographic and socioeconomic composition of those who move. those who have recently migrated will generally have greatest need for such basics as housing, employment, orientation to the social, cultural and political norms of the destination, and some knowledge of the host country's language. over time, those who remain in the destination may have need for assistance to integrate more fully into the host community-for example, skills training to move up the economic ladder, language training and civics education if required for citizenship, services for their children, etc. those who return to their home countries or communities may have needs very similar to what they had at the early stages of their movement. the decision as to whether return is possible involves a range of variables, including the extent, for example, to which the causes-either direct or through other channels-are likely to persist. policies in the receiving communities and countries, depending on whether the migration is internal or international, will also affect the likelihood for return or settlement in the new location. in addition to immigration policies, the policies affecting return and settlement include land use and property rights, social welfare, housing, employment and other frameworks that determine whether individuals, households and communities are able to find decent living conditions and pursue adequate livelihoods (brookings institution ) . the final stage of the life cycle involves (re)integration into the home community or new location. the issues outlined above regarding the potential for solutions will be key determinants of integration, influencing the access of displaced populations to housing, livelihoods, safety and security. these needs will vary depending on the demographic and socio-economic composition of the groups returning home or settling in new locations. integration is also affected by plans and programs to mitigate future dislocations from the hazards that caused the movements, coming full circle on the life cycle to a focus on prevention, adaptation and risk reduction. the fifth dimension of this typology refers to the affected populations. responses may differ in terms of scale-that is, how many people are affected by the crisis. they also differ by the demographic and socio-economic characteristics of the affected populations. generally, those most vulnerable to the harms associated with crises of the type described are already in difficult economic situations, with few financial resources to get them through the crisis. unaccompanied and separated children, women at risk of gender and sexual based violence, adolescents at risk of forced recruitment into gangs and insurgencies, ill and disabled persons, the elderly and other vulnerable groups may require specific approaches to ensure their safety. trafficking in persons is often associated with crises, with criminal elements preying on the desperation of people who have lost their homes and livelihoods. this section focuses on laws and policies for addressing the migration consequences of the types of crises discussed previously. the section focuses on frameworks governing migration across borders, including general human rights instruments as well as migration-specific instruments. it also discusses legal frameworks for protection and assistance of internally displaced persons as they provide useful guidance for issues related to protection and assistance for those who move across international borders (fig. . ). states possess broad authority to regulate the movement of foreign nationals across their borders. although these authorities are not absolute, states exercise their sovereign powers to determine who will be admitted and for what period. the authority of states is limited by certain rights accorded foreign nationals in international law. the principal constraints on state authority are the non-refoulement provisions of the un convention relating to the status of refugees and its protocol and the convention against torture. some migrants in the scenarios described above may be covered under these instruments. the refugee convention defines refugees as persons who were unable or unwilling to avail themselves of the protection of their home countries because of a "well-founded fear of persecution based on their race, religion, nationality, political opinion or membership in a particular social group." states have no obligation to admit refugees, but they do have an obligation not to refoule (return) a refugee to "frontiers of territories where his life or freedom would be threatened on account of his race, religion, nationality, membership of a particular social group or political opinion." in each of the crises discussed above, a subset of migrants may meet the refugee definition although the majority are unlikely to be able to demonstrate that they fear persecution on account of a protected characteristic (that is, race, religion, nationality, membership of a particular social group or political opinion), rather than a more generalized harm. the refoulement provision of the convention against torture applies to persons who face "any act by which severe pain or suffering, whether physical or mental, is intentionally inflicted on a person for such purposes as obtaining from him or a third person information or a confession, punishing him for an act he or a third person has committed or is suspected of having committed, or intimidating or coercing him or a third person, or for any reason based on discrimination of any kind, when such pain or suffering is inflicted by or at the instigation of or with the consent or acqui-escence of a public official or other person acting in an official capacity." particularly in the situations in which political instability and violence precipitate displacement, a subset of migrants may well meet this definition even if the majority does not have a well founded reason to fear torture upon return. in africa, the scope of coverage for refugees is greater because the oau (now au) refugee convention includes those who, "owing to external aggression, occupation, foreign domination or events seriously disturbing public order in either part or the whole of his country of origin or nationality (emphasis added), is compelled to leave his place of habitual residence in order to seek refuge in another place outside his country of origin or nationality." the cartagena declaration (a non-binding agreement) offers a similar expanded definition of refugees in latin america: "persons who have fled their country because their lives, safety or freedom have been threatened by generalized violence, foreign aggression, internal conflicts, massive violation of human rights or other circumstances which have seriously disturbed public order." to the extent that a crisis involves generalized violence, massive violations of human rights or seriously disturbs public order, persons forced to leave their homes because of the crises described above may be covered under the au and cartagena instruments, while they would not be under the convention. the new au convention on internally displaced persons goes even further in specifying that those displaced by natural and human made disasters are covered. those who are forced to migrate, but who are not considered to be refugees or potential torture victims, have certain basic rights even if they are not covered under these specific instruments. the universal declaration of human rights, the international covenant on civil and political rights and the international covenant on economic and social rights, for example, define certain rights that accrue to all persons, not just citizens. importantly, the universal declaration article , which is enshrined in article of the international covenant on civil and political rights, declares that "everyone has the right to leave any country, including one's own, and to return to one's own country." the universal declaration article states that "everyone has the right to seek and to enjoy in other countries asylum from persecution." in neither situation, however, is there a corresponding obligation on the part of states to admit those who exercise their right to leave or to seek asylum. other applicable human rights conventions include the international covenant on social, economic and cultural rights, the convention on the rights of the child, the convention on the elimination of all forms of discrimination against women, the convention on the elimination of all forms of racial discrimination, and the convention on the rights of persons with disabilities. these instruments and relevant articles of the geneva conventions on armed conflict form the basis for the guiding principles on internal displacement. although not legally binding, the guiding principles provide a critical framework for defining and promoting idp protection. under the guiding principles, idps are described as: persons or groups of persons who have been forced or obliged to flee or to leave their homes or places of habitual residence, in particular as a result of or in order to avoid the effects of armed conflict, situations of generalized violence, violations of human rights or natural or human-made disasters, and who have not crossed an internationally recognized stated border. the guiding principles identify the rights and guarantees relevant to the protection of idps in all phases of displacement. they provide protection against arbitrary displacement, offer a basis for protection and assistance during displacement, and set forth guarantees for safe return, resettlement and reintegration. they also establish the right of idps to request and receive protection from national authorities, and the duty of these authorities to provide protection. african leaders adopted the au convention for the protection and assistance of internally displaced persons (idps) in africa at a summit in . it went into force in . forced migrants who use irregular means of exit or entry may be covered under the protocol to prevent, suppress and punish trafficking in persons, especially women and children and the protocol against the smuggling of migrants by land, sea and air, both of which supplement the united nations convention against transnational organized crime and went into force in december and january , respectively. within a few years of their adoption, the trafficking and smuggling protocols have garnered considerable support, with more than signatories and and parties, respectively. these instruments apply respectively to "the recruitment, transportation, transfer, harbouring or receipt of persons, by means of the threat or use of force or other forms of coercion, of abduction, of fraud, of deception, of the abuse of power or of a position of vulnerability or of the giving or receiving of payments or benefits to achieve the consent of a person having control over another person, for the purpose of exploitation" and "the procurement, in order to obtain, directly or indirectly, a financial or other material benefit, of the illegal entry of a person into a state party of which the person is not a national or a permanent resident." trafficking requires coercion or deception as well as exploitation of the labour of the trafficked person, whereas smuggling is usually a voluntary agreement between the migrant and the smuggler in which the migrant gains irregular entry and the smuggler gains a financial benefit. under certain conditions-for example, when the smuggled migrants is placed in bondage to pay off his or her smuggling fees-smuggling may turn into trafficking. those affected by crises are often more vulnerable to exploitation by both smugglers and traffickers, particularly if they are desperate to leave dangerous places with few options to support themselves and their families. the un convention on the law of the sea has provisions applicable to persons in distress at sea, which can include sea-borne migrants. under the convention, "state shall require the master of a ship flying its flag, in so far as he can do so without serious danger to the ship, the crew or the passengers: (a) to render assistance to any person found at sea in danger of being lost; (b) to proceed with all possible speed to the rescue of persons in distress, if informed of their need of assistance, in so far as such action may reasonably be expected of him; (c) after a collision, to render assistance to the other ship, its crew and its passengers and, where possible, to inform the other ship of the name of his own ship, its port of registry and the nearest port at which it will call." the convention also has provisions that outlaw piracy, defined as "any illegal acts of violence or detention, or any act of depredation, committed for private ends by the crew or the passengers of a private ship or a private aircraft, and directed: (i) on the high seas, against another ship or aircraft, or against persons or property on board such ship or aircraft; (ii) against a ship, aircraft, persons or property in a place outside the jurisdiction of any state." the rights of those displaced by natural hazards have not been spelled out in international or regional law as has been the case with those affected by political events. nevertheless, un guidance provided to state authorities regarding displacement due to natural disasters, while not binding international law, is relevant to the issues covered in this chapter. conversely, those who are internally displaced by natural disasters (who have freedom of movement within their borders) should not be required to return to areas in which their safety may be compromised: "persons affected by the natural disaster should not, under any circumstances, be forced to return to or resettle in any place where their life, safety, liberty and/or health would be at further risk" (brookings-bern project ) . also relevant are the provisions of the sendai framework for disaster risk reduction: - that encourages greater cooperation in reducing the risks associated with disasters. the disaster risk reduction (drr) strategies adopted in the sendai framework do not provide great specificity with regard to displacement from disasters aside from recommending that development actors include displaced persons in efforts to "promote the incorporation of disaster risk management into post-disaster recovery and rehabilitation processes, facilitate the link between relief, rehabilitation and development, use opportunities during the recovery phase to develop capacities that reduce disaster risk in the short, medium and long term." (unisdr ) . nevertheless, the overall concept of disaster risk reduction would significantly lessen displacement by providing the tools with which people could remain in situ or return quickly when acute natural hazards strike. progress was made in and in filling some of the protection gaps. in , the conference of the parties (cop) of the un framework convention on climate change (unfccc) authorized establishment of a task force with its processes to identify ways to mitigate and respond to displacement. the state-led nansen initiative on cross-border disaster displacement issued an agenda for protection that spells out actions that governments can take today to provide humanitarian relief to persons requiring either admission or non-return in these contexts. its successor, the platform for disaster displacement, funded by the german government, is helping willing states adopt some of the proposed policies and programs. another state-led process, the migrants in countries in crisis (micic) initiative adopted principles, guidelines and effective practices to respond to the needs of non-nationals who are displaced by natural disasters and conflict. the un high level meeting on large-scale movements of refugees and migrants acknowledged the nansen and micic initiatives, recommending them as models for filling other gaps in protection for vulnerable migrants. taken together, however, the provisions in international law do not constitute a comprehensive framework for addressing forced migration that does not fit within the refugee context. they are particularly weak in reference to those who cross international borders during crises. rather, each displacement tends to be addressed on a case-by-case basis. whether there should be a stronger international legal framework to address non-refugee forced migration is a point that would certainly generate debate. there are a number of reasons that such a framework would be difficult to achieve. trying to identify legal standards for a broad range of potential drivers of forced migration which may have little in common with one another would present challenges, particularly in setting out appropriate criteria for determining who among forced migrants would merit specific forms of protection. see conclusions for further discussion of these issues. the immigration policies of most destination countries are not conducive to receiving large numbers of forced migrants, unless they enter through already existing admission categories or meet refugee criteria. typically, in non-crisis situations, destination countries admit persons to fill job openings or to reunify with family members. employment-based admissions are usually based upon the labour market needs of the receiving country, not the situation of the home country. family admissions are usually restricted to persons with immediate relatives (spouses, children, parents and, sometimes, siblings) in the destination country. at the same time, most overtly humanitarian admissions are generally limited to refugees and asylum seekers. many, if not most forced migrants, however, will be unlikely to meet the legal definition of a refugee since their lives are endangered for reasons that do not involve persecution on the basis of a protected characteristic such as race, religion, nationality, membership in a particular social group or political opinion. despite these limitations, there are both legislative and ad hoc policies that do permit governments to respond when there are crises that provoke migration. they fall into three categories: ( ) policies that permit migrants already on the territory of the destination country to remain for at least a temporary period; ( ) policies to respond to new movements of people leaving either directly or indirectly as a result of the crisis; and ( ) evacuation of citizens and selected others from crisis affected countries. some countries and the european union have established special policies that permit individuals whose countries have experienced natural disasters, conflicts, pandemics or other severe upheavals to remain at least temporarily without fear of deportation. the united states, for example, enacted legislation in to provide temporary protected status to persons "in the united states who are temporarily unable to safely return to their home country because of ongoing armed conflict, an environmental disaster, or other extraordinary and temporary conditions." environmental disaster may include "an earthquake, flood, drought, epidemic, or other environmental disaster in the state resulting in a substantial, but temporary, disruption of living conditions in the area affected." in the case of environmental disasters, as compared to conflict, the country of origin must request designation of temporary protected status ("tps") for its nationals. those granted tps are eligible to work in the united states. they are not considered to be residing under color of law, however, for purposes of receiving social benefits and they are not able to bring family members into the country to join them. importantly, tps only applies to persons already in the united states at the time of the designation. it is not meant to be a mechanism to respond to an unfolding crisis in which people seek admission from outside of the country. it also only pertains to situations that are temporary in nature. if an environmental disaster has permanent consequences, for example, a designation of temporary protected status is not available, even for those presently in the united states, or it may be lifted. when the volcano erupted in montserrat in , tps was granted to its citizens and was extended six times. in , however, it was ended. us citizenship and immigration services in the department of homeland security explained "that the termination of the tps designation of montserrat is warranted because the volcanic activity caus-ing the environmental disaster in montserrat is not likely to cease in the foreseeable future. therefore, it no longer constitutes a temporary disruption of living conditions that temporarily prevents montserrat from adequately handling the return of its nationals. similarly, the conditions are no longer "extraordinary and temporary" as required by section (b)( )(c) of the act." another significant factor is that the designation is discretionary, to be made by the secretary of homeland security in consultation with the secretary of state. countries or parts of countries are designated, allowing nationals only of those countries (or affected regions within them) to apply. a further issue is the difficulty of ending the status. although some early proponents of tps argued that it was temporary in the sense that it would allow time to determine whether those granted the status could return or should be granted legal permanent residence, the legislation makes it difficult for them to remain permanently with full rights of immigrants. if individuals granted tps otherwise meet the criteria for legal admissions as an immigrant, they are eligible to obtain permanent residence without leaving the united states. if it were determined, however, that as a group they cannot return home, special legislation would be needed to allow them to remain permanently. the legislation specifies that such legislation would require a super-majority (threefifths) of senators for passage. tps has proven to be a flexible mechanism for responding to a range of crises, from conflict (somalia, sudan, south sudan, syria and yemen) to acute natural disasters (el salvador, haiti honduras, nepal and nicaragua) to pandemics (guinea, liberia and sierra leone). at the same time, lifting temporary protected status has proven to be very difficult as well. tps was originally triggered by the earthquakes in el salvador ( ) and hurricane mitch ( ) in honduras and nicaragua, meaning that some of the beneficiaries have been in 'temporary' status for almost years. canada may declare a temporary suspension of removals "when a country's general conditions (for example, war or a natural disaster) put the safety of the general population at risk." according to regulation, "the guiding principle of generalized risk is that the impact of the catastrophic event is so pervasive and widespread that it would be inconceivable to conduct general returns to that country until some degree of safety is restored. the suspension order is lifted when country conditions improve and the public is no longer in danger." for example, the suspension of removal was lifted in for nationals of burundi, rwanda and liberia. recognizing that some had been in canada for an extended period, these nationals were given the opportunity to apply for humanitarian and compassionate consideration for permanent residence in canada. such considerations as the best interests of any child directly involved, establishment in canada, integration into canadian society, and other factors put forward by the applicant are taken into account in determining if an applicant will be permitted to remain in canada. canada also undertakes a pre-removal risk assessment in determining if persons denied asylum would be at risk of other serious harm if removed to their country of origin. a number of other countries provide exceptions to removal on a group or case by case basis for persons whose countries of origin have experienced significant disruption because of natural disasters, conflict and violence. after the tsunami, for example, switzerland, the united kingdom and malaysia suspended deportations of migrants from such countries as sri lanka, india, somalia, maldives, seychelles, indonesia and thailand. a number of governments announced similar plans after the earthquake in haiti (martin ) . germany uses the "duldung," a toleration permit when emergent conditions preclude immediate return (schönwälder and vogel ) . these actions are generally ad hoc, allowing governments to respond differentially to crises. the decisions to trigger such responses is based on a combination of factors, including the intensity of the crisis, geographic proximity, the assessment of whether stays of removal will become a magnet for new arrivals, the presence of a strong constituency group within the destination country that calls for stays of removal and other similar factors. return of migrants granted temporary stays of removal remains problematic in many crises. protracted crises are common, particularly in countries without the fiscal resources and governance structures necessary to reintegrate their citizens after an emergency. moreover, over time, migrants begin to integrate into the new destination country, developing equities and ties that make the decision to return difficult. this is particularly the case when migrants granted temporary stays have children who attend school, learn the host country language and develop friendships and ties with local populations. some efforts have been made to facilitate or assist return when conditions permit. after the dayton peace accord, for example, a number of countries offered aid to bosnians who had been granted temporary protection if they chose or were required to repatriate. for example, denmark and sweden funded bosnians to take 'look and see' visits home to determine if conditions had improved sufficiently to return permanently. these countries and other eu members provided financial assistance to help those who voluntarily returned and provided information services about the right to remain or return. similar programs were used in assisting kosovars to return home. at the european union level, the temporary protection directive dated july establishes temporary protection during "mass influxes." with crises in bosnia and kosovo freshly in mind, the european council meeting in tampere urged swift action in addressing the issue of "temporary protection for displaced persons on the basis of solidarity between member states." the directive itself notes that "cases of mass influx of displaced persons who cannot return to their country of origin have become more substantial in europe in recent years. in these cases, it may be necessary to set up exceptional schemes to offer them immediate temporary protection." the purpose of the directive is twofold: to establish minimum standards for giving temporary protection and "to promote a balance of effort between member states in receiving and bearing the consequences of receiving such persons." temporary protection applies to persons who have fled areas of armed conflict or endemic violence and persons at serious risk of, or who have been the victims of, systematic or generalized violations of their human rights. member states may apply temporary protection more broadly to other categories of persons affected by crises. unlike tps in the united states, temporary protection in the eu is envisioned as a mechanism to address mass influxes, not to protect already resident migrants from removal. it can apply to those who spontaneously arrive as well as to those who are evacuated from situations in which they face serious harm. it is seen as a substitute for asylum in cases when "the asylum system will be unable to process this influx without adverse effects for its efficient operation." since its adoption in , temporary protection has not been invoked, at least in part because of different views among member countries concerning what constitutes a mass influx and of concerns about whether it will be practicable to return those granted this status when it expires. on april , , the european commission set out criteria under which it would ask for its use: "the commission would also be ready to consider proposing the use of the mechanism foreseen under the temporary protection directive ( / /ec), if the conditions foreseen in the directive are met. consideration could only be given to taking this step if it is clear that the persons concerned are likely to be in need of international protection, if they cannot be safely returned to their countries-of-origin, and if the numbers of persons arriving who are in need of protection are sufficiently great." however, in the context of the mass movements in from syria, afghanistan, iraq and elsewhere, the eu refrained from triggering a response under this directive and sought, often unsuccessfully, to negotiate responsibility-sharing agreements outside of the framework (akkaya ) . nevertheless, some of the provisions of the directive are worth considering for future policymaking. individuals who would be granted the status are to receive a residence permit for the duration of the grant. member states are to ensure access to suitable accommodations, social benefits and education. those granted temporary protection are eligible to work or be self-employed but states may give priority for employment to eu citizens, citizens of the european economic area and legally resident third country nationals who receive unemployment benefit. there is also access to family reunification as long as the family relationship predated the grant of temporary protection. while the temporary protection directive addresses mass influx situations, asylum law and policies govern individual applications for protection. eu directive allows for subsidiary protection for a person who does not qualify as a refugee but in respect of whom "substantial grounds have been shown for believing that the person concerned, if returned to his or her country of origin … would face a real risk of suffering serious harm." serious harm includes situations in which there is a serious and individual threat to a civilian's life or person by reason of indiscriminate violence in situations of international or internal armed conflict. those granted subsidiary protection have a less secure status than those granted convention protection (for example, their residence permit is for one instead of three years). the eu-wide provisions do not explicitly address crises caused by natural or human made hazards but individual countries have adopted legislation that protects some categories. sweden includes within its asylum system persons who are unable to return to their native countries because of an environmental disaster. the decision is made on an individual, not group basis. although many recipients of this status are presumed to be in temporary need of protection, the swedish rules foresee that some persons may be in need of permanent solutions. similarly, in the finnish aliens act, "aliens residing in the country are issued with a residence permit on the basis of a need for protection if […] they cannot return because of an armed conflict or environmental disaster." finnish law also allows use of transit centres for a fixed term, not to exceed three months, if the number of displaced persons entering the country is exceptionally high, to give time to conduct thorough processes for registration. this provision has not yet been invoked. governments often anticipate departures during crises and establish policies to deter or intercept migrants leaving countries of origin or transit countries. a common response has been to impose visa requirements on nationals of countries in crisis. visas help to screen out those who purport to be coming as tourists or business travellers but who intend to stay for longer periods. air and other carriers have the responsibility to check that international travellers have proper documentation before they are permitted to board the plane or ship. in numerous cases, migrants attempt to enter destination countries clandestinely, across land borders and by sea. the united states, australia and countries in the european union have intercepted boats that were headed for their shores during crises. in many cases, the boats are unseaworthy and the interception is justified on humanitarian as well as border control bases. what to do with those who are intercepted, particularly those who are rescued at sea, can be a complicated issue. bringing these individuals to the territory of the states that interdict the migrants can serve as a magnet that encourages still more people to risk dangerous crossings. returning them to dangerous situations in their home country could have equally deleterious humanitarian ramifications. obviously, leaving them on unseaworthy vessels would be inhumane. one option that governments have tried is off-shore protection for those who are intercepted. the united states, for example, used guantanamo naval base in the s to provide temporary protection to haitians and cubans, rather than returning them into unsettled conditions. in the case of haiti, most of those provided temporary safe haven returned home when the elected president of haiti was returned to office. by contrast, most of the cubans were eventually resettled into the united states, but cuba and the united states signed a migration agreement that provided alternative mechanisms for legal immigration from cuba and a commitment from the cuban government to curb boat departures. australia has established off-shore processing centres in nauru and papua new guinea with the aim of curtailing access to asylum in australia. those found to have valid refugee claims would remain in those countries or be resettled elsewhere. the un human rights council, among others, has criticized the policy, especially for the harsh treatment and poor living conditions of asylum seekers in these other countries (millar ) . a further range of policies pertain to people who are endangered in the countries in crisis or in neighbouring countries and who are evacuated to other states for safety. the most common form of evacuation is of citizens who are caught in the middle of a crisis. in recent cases, governments have evacuated their citizens from earthquake, tsunami, cyclone and flood affected areas (e.g., japan, haiti, pakistan and indonesia) or conflict zones (e.g., cote d'ivoire, lebanon, libya, syria and yemen). when governments evacuate their nationals, decisions must be made about accompanying family members who are not citizens of the evacuating country. although many countries will evacuate non-national spouses and minor children of citizens, they will not necessarily feel a similar obligation to parents, siblings and other relatives of citizens. nor do they necessarily evacuate persons such as household servants who may be highly dependent on the citizens for their protection and support. immigration authorities use various ad hoc measures to admit the nonnational family members to their territory. in some cases, migrants are working in such countries and an international effort is made to evacuate them to their home countries, either from the country in crisis or a nearby location that they have reached. the evacuation of thousands of migrant workers from libya and cote d'ivoire and their bordering countries are such examples. while the majority of these migrants were able to return safely to their home countries, a minority were unable or unwilling to return because of concerns about their safety in the country of origin. the evacuations share many similarities with other forced migration situations. migrants evacuated home may face problems of reintegration and lost income. those who are unable to repatriate because of unsafe conditions at home will be in need of relocation to other countries. if they do not meet convention refugee criteria (that is, the unsafe conditions do not involve their own fear of persecution), neighbouring countries may be unwilling to provide asylum and there may be limited opportunities for resettlement in third countries. in rare cases, evacuations of large groups of vulnerable persons have been supported by the international community. the clearest case was the humanitarian evacuation of kosovars in . in order to convince the countries of first asylum to keep their doors open to kosovars, other countries agreed to bring some of them to their countries at least temporarily. with the assistance of the un high commissioner for refugees, more than , kosovars were evacuated to countries. many of the participating countries set up reception facilities for the evacuees. when the fighting ended and serb forces withdrew from kosovo, many of the evacuated returned to their homes. the kosovars were admitted without determining if they individually met the refugee definition, distinguishing this program from refugee resettlement initiatives that have been used to support first asylum in other contexts. there are fewer mechanisms for permanent admission of people during nonrefugee crises. a number of countries accelerate or facilitate processing of visas during crises so that those who otherwise would be admissible for permanent residence are able to enter. canada, for example, gave priority to processing visas for persons directly and significantly affected by the haitian earthquake. it also established a satellite office in the dominican republic and sent additional visa and control officers to the region. the united states, canada, the netherlands, and france put in place special provisions that accelerated the entry of haitian orphans who had been approved for adoption prior to the earthquake. in the context of the syrian refugee crisis, the eu has been considering a humanitarian visa through which asylum seekers could enter a member state and have the application heard in situ (neville and rigon ) . finally, a number of governments have permanently resettled discrete categories of vulnerable persons for humanitarian purposes. australia, for example, introduced the locally engaged employee policy, which enabled the permanent resettlement of iraqis and afghans who had been employed by the australian government in their home countries. the united states instituted similar programs that permitted resettlement without regard to whether the employee met refugee criteria. australia and canada also consider applications for humanitarian visas from other persons who consider themselves to be at risk. in australia's program, the individual must show that they are subject to substantial discrimination. just as the legal frameworks for addressing forced migration in all of its manifestations are weak, so are the institutional roles and responsibilities at the international level. with the exception of the refugee regime, in which clear responsibility is given to the un high commissioner for refugees, there is no existing international regime for managing international movements of people. this is not to say that there is a total absence of governance. there are a plethora of international, regional and national organizations that have some responsibilities related to forced migration. the mandates and effectiveness of these institutions in addressing forced migration varies greatly. at the international and regional levels, there is a lack of clear authority for addressing new forms of displacement that do not fit into existing mandates. the institutional arrangements differ somewhat based on whether the displacement is internal and can be addressed within the territory of the affected country or is cross border and affects other countries. as discussed above, most displacement is internal. to the extent that institutional arrangements within countries affected by crises fail to provide adequate protection and assistance, cross-border movements may increase. institutional arrangements to mitigate crises in situ are thus highly relevant to understanding how forced displacement might be mitigated. at present, the international response to humanitarian crises is based on the cluster approach. the un high commissioner for refugees is the cluster lead for protection (focusing on conflict-induced displacement) as well as for the emergency shelter and camp management clusters. the international organization for migration has responsibility for camp management in the context of natural disasters. the situation is less clear cut with regard to protection of those displaced by natural disasters. unhcr, the office of the high commissioner for human rights (ohchr) and unicef have all been designated as having protection responsibilities in natural disasters (global protection cluster ). in practical terms, iom often takes on this responsibility because of its role in camp management. cluster leads have relatively little authority over other international organizations during these crises. the interagency standing committee (iasc) guidance note on using the cluster approach explains; "the role of sector leads at the country level is to facilitate a process aimed at ensuring well-coordinated and effective humanitarian responses in the sector or area of activity concerned. sector leads themselves are not expected to carry out all the necessary activities within the sector or area of activity concerned. they are required, however, to commit to being the 'provider of last resort' where this is necessary and where access, security and availability of resources make this possible" (iasc ) . the note recognizes that "the 'provider of last resort' concept is critical to the cluster approach, and without it the element of predictability is lost" (iasc ) . for agencies with technical leads (e.g., health, nutrition, water and sanitation), the ability of the lead agency to take on responsibility is straightforward. however, the note is more circumspect regarding the leadership for cross-cutting areas such as protection, early recovery and camp coordination: "the concept of 'provider of last resort' will need to be applied in a differentiated manner. in all cases, however, sector leads are responsible for ensuring that wherever there are significant gaps in the humanitarian response they continue advocacy efforts and explain the constraints to stakeholders" (iasc ) . the cluster approach has had mixed results in filling gaps in the institutional framework for addressing the full range of issues pertaining to those who are internally displaced by the type of drivers discussed above. certainly, the willingness of unhcr to be the 'provider of last resort' in the protection of conflict induced idps is a critical issue. the numbers demonstrate a clear increase in unhcr's involvement with idps. unhcr reported that it helped . million of an estimated . million internally displaced persons in , as compared to only . million out of an estimated million in (unhcr ; internal displacement monitoring centre ). nevertheless, there are continuing concerns about the nature of the response. for example, a brookings institution report concluded: "while humanitarian reform has improved operational short-term response, it has had little effect on either protecting people from new displacement or in finding solutions for those displaced. questions of access and staff security continue to be the major limitations in protecting and assisting idps" (brookings institution ). the report called for reinvigoration of efforts to protect idps. during this period, unhcr also began responding, albeit in an ad hoc way, to forced migration stemming from causes other than persecution or conflict. although unhcr has limited its cluster leadership to conflict-induced internal displacement, it has nevertheless been drawn into providing assistance during several notable natural disasters. in the state of the world's refugees, unhcr explained its involvement in tsunami relief: "the sheer scale of the destruction and the fact that many of affected populations were of concern to the organization prompted the move. responding to requests from the un secretary-general and un country teams, unhcr concentrated on providing shelter and non-food relief. in sri lanka, unhcr's presence in the country prior to the tsunami allowed for a comparatively swift and sustained humanitarian intervention -including efforts focused on the protection of internally displaced persons" (unhcr , ) . unhcr also assisted tsunami victims in somalia and aceh, indonesia, pointing out: "the protection of displaced populations was especially urgent in areas of protracted conflict and internal displacement in aceh, somalia and sri lanka. furthermore, there was concern for some affected populations whose governments declined offers of international aid, such as the dalits (formerly known as untouchables) of india and burmese migrant workers in thailand; it was feared they might be discriminated against and their protection needs compromised" (unhcr , ) . unhcr was also involved in the international response to cyclone nargis in burma and china and haiti's earthquakes, providing shelter and supplies. unhcr is the lead international agency with responsibility for refugees who have crossed international borders. founded in , unhcr was charged from the beginning to find solutions for refugees, generally in the form of voluntary repatriation when conditions permitted, integration into a country of asylum, or resettlement to a third country. because those solutions were often not forthcoming, unhcr's day-to-day activity was generally to provide assistance to those who were unable to return, integrate or resettle. unhcr's responsibility for cross-border displacement has grown since its founding, from a focus on refugees and displaced persons from world war ii and the emerging cold war to a focus on delivering humanitarian aid to refugees in developing countries affected by international and internal conflicts. it continued to advocate for protection and solutions for refugees throughout the world. its role has been limited, however, in addressing the situation of those who migrate internationally because of non-persecution or non-conflict reasons. unhcr has, however, demonstrated increased interest in mixed migration. as stated in its point plan, unhcr recognizes that situations "in which people with different objectives move alongside each other, using the same routes and means of transport or engaging the services of the same smugglers, can raise serious protection concerns." the concept of mixed migration seems to be rooted in the assumption that the mix is between refugees and economic migrants and deals very little with other forced migrants. the point plan does not address situations in which people are migrating for a mix of reasons that include extreme natural hazards, except for one mention of migrants from aceh in malaysia, or political or communal violence, except for one mention of mexican migrants leaving because of domestic or other violence. in effect, it does little to help address situations in which crises precipitate movements that do not fit into the refugee framework but raise serious humanitarian considerations. the potential for mass displacement from climate change is also an issue that occupied the then high commissioner antonio gutteres' attention: "when we consider the different models for the impact of climate change, the picture is very worrying. the need for people to move will keep on growing. one need only look at east africa and the sahel region. all predictions are that desertification will expand steadily. for the population, this means decreasing livelihood prospects and increased migration. all of this is happening in the absence of international capacity and political will to respond" (guterres ) . then assistant high commissioner for protection, erika feller, summarized the dilemma before the executive committee: "new terminology is entering the displacement lexicon with some speed. the talk is now of "ecological refugees", "climate change refugees", the "natural disaster displaced". this is all a serious context for unhcr's efforts to fulfill its mandate for its core beneficiaries…. the mix of global challenges is explosive, and one with which we and our partners, government and non-government, must together strike the right balance" (feller ) . thus far, however, there has been no inclination on the part of the executive committee for unhcr to become involved with those who cross borders because of natural disasters or climate change. instead, following the commemoration of the th anniversary of unhcr, the governments of switzerland and norway established the nansen initiative to generate further discussion. the international organization with the longest and most sustained focus on international migration is the international organization for migration. iom's constitution sets out its role as a service organization operating on behalf of states. its first two purposes and functions pertain to its original role in making arrangements for the transfer of migrants, refugees and displaced persons. iom provides, at the request of and in agreement with the states concerned, migration services such as recruitment, selection, processing, language training, orientation activities, medical examination, placement, activities facilitating reception and integration, advisory services on migration questions, and other assistance as is in accord with the aims of the organization. it also assists in voluntary return migration, including voluntary repatriation. iom's constitution also gives it a role to provide a forum to states as well as international and other organizations for the exchange of views and experiences, and the promotion of co-operation and co-ordination of efforts on international migration issues, including studies on such issues in order to develop practical solutions. in respect to this last function, it has launched a policy dialogue with governments on policy issues. importantly, the organization has expanded significantly in terms of both staff and membership, which includes more than member states and observers. iom has been a focal point for discussion of forced migration since when it co-hosted a series of consultations on the interconnections between the environment and migration, in the context of the united nations conference on environment and development (unced) in rio de janeiro. as discussed above, iom has also taken on lead responsibility for camp management in natural disasters. in the area of pandemics, iom's health program offers travel health assistance to manage conditions of public health concern as individuals move across geographical, health system and epidemiological boundaries. these include pre-embarkation checks and pre-departure medical screenings to assess a migrant's fitness to travel and/or to provide medical clearance. these measures also ensure that migrants are linked to and given appropriate referrals to medical services once they have arrived in their destination countries. migrants who need medical assistance and care during travel are escorted by health professionals to avoid complications during transit. iom works in collaboration with the world health organization (who), whose work is guided by resolution . on the health of migrants, adopted by the world health assembly in (world health organization ). the resolution encourages who to improve understanding and capabilities to address issues related to the health needs of migrants. finally, iom takes the lead role in the evacuation of migrants in countries that fall into crisis, as seen in its role in evacuating migrant workers stranded on the libya-tunisian border, cote d'ivoire, yemen and elsewhere. it played a similar role in evacuating migrants from kuwait and iraq in and lebanon in . as discussed above, in the majority of cases, iom assists the migrants to return to their home countries, but it works with unhcr in the relocation of those unable or unwilling to repatriate because of unsafe conditions in the country of origin. until , iom operated outside of the united nations. in the context of the un high level meeting on refugees and migrants in september , iom joined the un as a related organization (that is, in a capacity similar to that of the world trade organization). as a result, iom will now be more fully integrated into the decision-making on migration issues within the un. operationally, the organization was already a member of un country teams and followed most un security and other protocols. there are a number of other international organizations that have responsibilities regarding migration. among the more significant, the ilo has a specialized office, the international migration program, which "provides advisory services to member states, promotes international standards, provides a tripartite forum for consultations, serves as a global knowledge base, and provides technical assistance and capacity-building to constituents." the un population division in the department of economic and social affairs (desa) is responsible for collecting data on international migration and took the lead within the un secretariat for organizing the high level dialogue on migration and development. the division also hosts an annual meeting for coordination of data and research on international migration. the office of the high commissioner for human rights (ohchr) supports the mandates of the un special rapporteur on the human rights of migrants and the un special rapporteur on trafficking and services the committee on migrant workers, the treaty body supervising compliance with the international convention on the protection of the rights of all migrant workers and members of their families. the un office for drugs and crime (unodc) coordinates activities related to human trafficking and human smuggling, as the key agency responsible for implementation of the un convention against transnational crime and its smuggling and trafficking protocols. none of these agencies have evidenced a particular interest in the interconnections between climate change and the areas of their specific responsibilities. the un maritime organization has responsibilities regarding the suppression of piracy at sea as well as the safety of persons rescued at sea. recognizing the complex set of organizational responsibilities, the global migration group (gmg) was established to promote coordination and identify gaps in the international system. the gmg grew out of an existing inter-agency group, the "geneva migration group", established in april by the heads of the ilo, iom, ohchr, un conference on trade and development (unctad), unhcr and unodc. in membership in the geneva migration group was expanded to include desa, un development program (undp), un population fund (unfpa) and the world bank. following a recommendation by the global commission on international migration for strengthened coordination, the group was renamed the "global migration group" that same year and expanded to include the un regional commissions, unesco, unicef and unitar. other agencies have since joined. while some participants in the gmg have noted that the group has too large and diverse a membership to be effective, the gmg is missing repre-sentatives that would be useful in gaining progress on issues related to forced migration. for example, the office for the coordination of humanitarian affairs is not actively engaged. forced migration has not been a prominent issue on the agendas of regional organizations or regional consultative processes (rcps), except in the area of refugees and asylum-seekers. the european union is a notable exception, particularly in regard to the temporary protection directive. several regional groups have discussed related issues. the inter-governmental authority on development regional consultative process on migration (igad-rcp), established in , includes mixed migratory flows, environmental migration, and movements of pastoralists on its agenda. the dialogue on mediterranean transit migration (mtm) has also focused attention on mixed migration. the inter-governmental asia-pacific consultations on refugees, displaced persons and migrants (apc) was established in to "provide a forum for the discussion of issues relating to population movements, including refugees, displaced or trafficked persons and migrants." the aim of the consultations is to "promote dialogue and explore opportunities for greater regional cooperation" (apc ). although not regional, the intergovernmental consultations on migration, refugees and asylum (igc) brings together participating states , the united nations high commissioner for refugees, the international organization for migration and the european commission to discuss forced migration, among other issues. generally, the rcps are not forums for discussion of emerging crises, even when these crises are within the region of the consultative body. although libya, egypt and tunisia are members along with european countries of the mtm, it does not appear that a meeting was called to discuss the evacuation of migrant workers or the increase in boat departures that corresponded with political events in libya. a expert meeting in malta did address issues related to irregular migration. addressing forced migration at the national level generally requires a 'whole of government' approach because of the complexities involved. often, institutional responses are ad hoc, designed for a specific crisis. they may differ significantly depending on geographic considerations (e.g., the extent to which migrants are likely to reach the shores of the destination countries), the causes of the crisis (e.g., natural hazards versus political instability), the domestic political and economic climate, the extent of humanitarian need, and other similar factors. this presents challenges, particularly related to coordination across ministries and departments that do not necessarily have ongoing reasons to communicate or cooperate in managing movements of people. policies on and responsibilities for implementation on immigration issues generally fall to interior or homeland security ministries or dedicated immigration or border security agencies in destination countries although foreign ministries play important roles. a much wider set of government agencies become involved in responding to humanitarian crises. which ministries are involved depends largely on the type of crisis, but it is not unusual for large scale crises to bring defense, foreign ministry, development, health, emergency response and other ministries into the process. again depending on the nature and scale of the crisis, governments may establish a taskforce within the prime minister or president's office to coordinate actions across multiple ministries. situations vary but the ministries responsible for immigration issues may not initially be part of these taskforces, particularly if the migration ramifications are not clear at the start of a crisis. for immigration ministries that are addressing the impacts of pandemics, natural disasters, and political instability, gaining needed information about, for example, the need for quarantine of travelers or need for temporary protection can be difficult. similarly, migration ministries may not be part of discussions taking place on climate change adaptation funding even though there is increasing recognition that migration is an age-old way in which people adapt to environmental changes. forced migration is unlikely to disappear in the future. in fact, the number and frequency of crises that generate large scale displacement may well increase substantially in the years ahead. climate change is expected to generate substantial internal and international displacement from increases in the intensity and frequency of natural hazards, rising sea levels, persistent drought and desertification, and, potentially, new conflicts over scarce resources. at the same time, recent events demonstrate that the process of political change taking hold in many parts of the world can be destabilizing, causing new movements of people. increased mobility also means greater potential for pandemics to spread quickly throughout the world, as was seen in the sars and h n cases, and for governments to make decisions regarding non-return, as seen in the ebola crisis in west africa. all of these trends mean that governments will likely be facing recurrent crises that spark migration and accompanying humanitarian needs. although much of this forced migration will be internal to countries facing emergencies, movements across borders are likely as well. this review of laws, policies, practices and institutions reveal weaknesses and challenges in the current capacities to respond effectively, efficiently and humanely to the challenges presented by forced migration. although many countries have advanced and tested systems to respond to refugees and asylum seekers, responses to migration emanating from other crises-natural disasters, political instability and violence, pandemics, human made disasters-are ad hoc and, in many cases, untested. most countries have mechanisms to provide temporary suspension of removal if conflicts or natural disasters preclude immediate return. with little underpinning from international and, sometimes, national law, the application of these provisions tends to be uneven and often dependent on factors that have little to do with immigration or humanitarian considerations or the balancing of these two factors. crises that generate greater visibility, such as the earthquake in haiti or ebola pandemic in west africa, may result in suspensions of removal whereas less known but potentially equally dangerous situations may not yield this response. when taken into account, immigration issues can work in different directions in determining whether to suspend removals or provide temporary protection. in some cases, concern that temporary protection may spur new movements of people is determinative in not granting suspension or triggering temporary protection, whereas in others, flow of remittances to countries in crisis may push a government towards the decision to grant the status and provide work authorization. once granted, temporary protection and suspension of removals have proven to be problematic vehicles to manage forced migration. once granted, it is very difficult to lift the designation even if conditions change sufficiently in home countries to permit return. often, the conditions do not change and the temporary grant of protection becomes a protracted one. in the absence of durable solutions, the forced migrants may end up in limbo for many years. as the stay prolongs, return becomes even harder as those granted permission to remain develop equities and connections to the country in which they are residing. temporary protection is an especially weak policy instrument when the conditions that cause flight are permanent. this may be the situation that arises in the context of climate change. nationals from some low-lying island countries may be unable to return to their home countries if some of the projections of rising sea levels prove to be accurate and their countries are submerged. even weaker than policy frameworks for temporarily suspending removals of migrants already in the country are those for dealing with mass migration resulting from crises. as discussed, the european union passed a directive on temporary protection with new flows in mind but it has never been used. the united states had experience with such movements from haiti and cuba in the s, using guantanamo naval base to house the migrants until a determination could be made on their status. the aim of policies adopted in was to provide safe haven but no access to u.s. territory. mixed migration is a challenge in handling mass movements in the context of humanitarian crises. some of those leaving may be bonafide refugees deserving of asylum, others may have serious reasons to fear for their safety though they do not meet the refugee criteria, but still others may be leaving to seek better economic opportunities. distinguishing among these groups is always challenging and, in the context of a mass migration emergency, even more difficult. the absence of effective policy tools is especially troubling because these crises have implications that go well beyond immigration and touch on basic humanitarian and human rights interests. just as refugees are at risk of serious harm if returned to their home countries, migrants from countries experiencing crises may face life threatening situations. they may also have immediate need for humanitarian assistance, including shelter, health care, food and other basic items. the promulgation of guidelines and the development of policies to respond to forced migration will require new modes of international cooperation. given the potential for significant increases in such migration, efforts to build an effective toolkit should begin now. whether a new convention on forced migration is desirable, or, for that matter, is feasible, are questions that beg easy answers. the history of international conventions related to migration is a mixed one. while the refugee convention and trafficking protocol are widely ratified, the conventions on labour migrants have had very low levels of ratification. because the complex categories of forced migration discussed herein will likely have elements of both forms of migration, depending on whether the trigger is slow or rapid onset, the future of such a convention would be questionable. beyond feasibility, a number of other issues would need to be addressed before determining that a new convention is the best way to improve policies to respond to forced migration. first, to what extent can existing legal frameworks be stretched to include a wider range of people who are forced to move? how should forced migrants be defined? for that matter, what term should be used in categorizing this form of migration; this paper has used forced migration and displacement as short hands. in other contexts, the terms crisis migrants and survival migrants have been used to describe those who do not fit current legal categories. even more important, a new framework for protection-whether a new convention or stretching of existing ones-would need to specify who among forced migrants are deserving of international protection-as distinct from those who can rely upon the protection of their own countries. and, the list goes on. in the end, though, international agreements-whether binding or soft law-will not be a substitute for national action. states should prepare for future crisis responses by preparing a menu of policy options that they could choose to implement in the event of large scale displacement that does not fit into current refugee frameworks. this process is already underway with the nansen and micic initiatives and the similar state process on other vulnerable migrants recommended by the high level meeting. these are forms of what sir peter sutherland, the former special representative of the secretary general on international migration has called mini-multilateralism, that is, initiatives by a small set of representative governments to build norms and identify good practices to be adopted more universally. a further opportunity is negotiation of a global compact on safe, regular and orderly migration, an outcome of the high level meeting. sir peter sutherland, in his final report as the special representative of the secretary general, stated that a principal aim of the compact should be to identify mechanisms for "managing crisis movement and protecting migrants in vulnerable situations." (sutherland ) . in developing an appropriate set of policies for responding to forced migration, consideration needs to be given to the following questions: • what policies and practices are needed to address the situation of migrants already in destination countries when return to home countries may be lifethreatening or otherwise inadvisable? what are the criteria for determining to suspend removals? for how long should the suspension be granted? what criteria should determine if the suspension should be renewed or revoked? what information is needed and from whom to make these determinations? • what policies and practices are needed to address individuals arriving from countries in crisis? should individual determinations be made as to whether to allow them to enter or should decisions be made on a group basis? • what policies and practices are needed to address mass migration flows? under what circumstances is interdiction appropriate? what criteria should be used in determining whether to return or relocate interdicted migrants? what criteria should be used in determining whether to admit such persons on to the territory of other countries? what information is needed and from whom to make these determinations? • if new policies are put in place for forced migration, how should these intersect with established refugee and asylum policies and systems? • if there is a determination that conditions have changed and forced migrants can return safely, what if any assistance should be provided? if there is a determination that return will not be possible for an extended period, what steps should be taken to find durable solutions? should third country resettlement, for example, be part of a policy toolkit for addressing the broad range of forced migration discussed herein? if so, what criteria should be used in determining who should be eligible for resettlement? • should forced migrants be granted work authorization? should they have access to social benefits? under what circumstances should authorities use reception centers or camps to provide initial or longer term accommodation? what forms of documentation and registration are needed in managing forced migration? • how should authorities address potential for fraud and security risks resulting from forced migration? • which agencies within government need to be involved in decision making on forced migration? which international and regional organizations should be involved? • what forms of responsibility sharing among countries would be appropriate in managing forced migration? what are the appropriate forums for negotiating such arrangements? finally, governments should also be reconsidering the ways in which they conceptualize, fund and implement programs to help vulnerable populations adapt to changing conditions that may trigger large scale displacement. in these contexts, migration is not just a problem to be addressed. it may also be a solution for many of those who are affected by climate change and other problems. too often, migration is forced because there are no alternatives for those who anticipate future harm but are unable to move in a safe and orderly fashion. they may lack the financial, human and social capital to relocate to where there may be greater long-term opportunities, or government policies do not accommodate their movements. as governments consider national adaptation plans and disaster risk reduction strategies, more attention is needed to ways to incorporate migration as a potentially positive response to pending emergencies. demography can play an important role in improving responses. too little is known about the determinants of forced migration, especially beyond traditional refugee flows. there is consensus among researchers that no one factor-economic, social, political, environmental or demographic-is determinative but how the various drivers interact to produce one form of movement versus another is largely unknown. in this context, demography is important in two respects. first, demographic trends are themselves drivers of displacement in conjunction with other factors. this can play out in two ways-demography as a macro-level factor and demographic composition as a micro-level driver of movement. for example, in the context of slow onset climate change, there is need for better understanding of how population density, distribution and growth as well as household composition affects vulnerability and resilience to environmental change (martin and bergmann ) . understanding the ways in which these demographic and environmental factors intersect with each other and with political and economic drivers would be useful in assessing likely need for planned relocation as environmental conditions worsen. second, the demographic profile of forced migrants often affects the efficacy of policy and programmatic responses. data on demographic as well as socio-economic characteristics of forced migrants are weak in general and, in the case of many types of forced migrants, non-existent. while some progress has been made in compiling aggregate numbers of persons who are displaced by natural disasters (see, for example, idmc's data (idmc )), there are no comprehensive sources of data broken down by age or sex. even in the case of refugees and conflict idps, the demographic breakdowns are lacking, particularly when they spontaneously settle and may not register with unhcr. unhcr reports that it has sex disaggregated data on % of those persons of concern, with sex disaggregated data on refugees at %, idps at % and stateless at only %. age disaggregated data were available for % of the population of concern; while it was available for % of refugees, it was available for only % of idps of concern (unhcr ). improving sex and age disaggregated data on all forms of displacement would help ensure that policies and programs are appropriate for all of those who are forced to move. it is difficult to plan for protection or assistance programs in the absence of such data. this is true in both acute and protracted phases of displacement. an absence of such data is particularly harmful with regard to needs linked to gender and age, including those related to health, education, food distribution, access to livelihoods and gender and sexual violence. demographers could play an extremely important role in helping governments, international organizations and ngos to collect basic data on forced migrants and thereby, improve protection and assistance for some of the world's most vulnerable persons. why is the temporary protection directive missing from the european refugee crisis debate? harvard humanitarian initiative iasc framework on durable solutions for internally displaced persons ten years after humanitarian reform human rights and natural disasters: operational guidelines and field manual on human rights protection in situations of natural disaster statement by unhcr assistant high commissioner for protection, ms. erika feller. the nd meeting of the standing committee available at global estimates : people displaced by disasters inter-governmental asia-pacific consultations on refugees, displaced persons and migrants (apc) environmental change and migration: legal and political frameworks environmental change and human mobility: reducing vulnerability & increasing resilience humanitarian crises and migration: causes, consequences and responses australia's asylum seeker policies heavily criticised at un human rights council review towards an eu humanitarian visa scheme? policy department for citizens' rights and constitutional affairs, european parliament giuseppe sciortino migration and illegality in germany report of the special representative of the secretary-general on migration presidency conclusions, and october global report. geneva: unhcr united nations international strategy for disaster risk reduction (unisdr) united nations international strategy for disaster risk reduction (unisdr) united nations high commissioner for refugees (unhcr) termination of tps for nationals of montserrat the state of the world's refugees : human displacement in the new millennium key: cord- -qfhmwqgg authors: edgell, david l.; allen, maria delmastro; smith, ginger; swanson, jason r. title: political and foreign policy implications of tourism date: - - journal: tourism policy and planning doi: . /b - - - - . - sha: doc_id: cord_uid: qfhmwqgg nan exchange earnings. this chapter describes tourism agreements among nations, intergovernmental organizations and regional industry associations, as well as international tourism facilitation and tourism as a policy for peace. while the reason for tourism agreements is the promotion of trade through tourism, these agreements also serve additional national policy objectives, such as encouraging international understanding, friendly relations and goodwill. in the past years, the united states has negotiated tourism agreements with many countries. using those made by the united states with other nations as an example, tourism agreements generally focus on the following specific criteria: • increasing two-way tourism, • supporting efforts by the national tourism organization travel promotion office(s), • improving tourism facilitation, • encouraging reciprocal investments in the two nations' tourism industries, • promoting the sharing of research, statistics and information, • recognizing the importance of the safety and security of tourists, • suggesting mutual cooperation on policy issues in international tourism, • providing for regular consultations on tourism matters, • acknowledging benefits from education and training in tourism, • enhancing mutual understanding and goodwill. two prominent examples of international tourism agreements involving the united states and its trading partners are those with the united mexican states and with the republic of venezuela. both agreements accredit tourism officials as members of a diplomatic or consular post and facilitate the exchange of tourism statistics and information between the two nations involved in the agreement. interestingly, these and other agreements state that the united states will participate in the united nations world tourism organization (unwto), although, as stated in the following section, the united states is not a member of that august organization. the tourism agreement entered into by the united states and mexico in october , which superseded an april agreement, assists in facilitating motor carrier and other ground transport across the international border and calls for the nations to share information about automobile liability with one another. understanding policies involving ground transportation is critical for visitors, as many cross the border in private vehicles. the agreement includes provisions for developing bi-national cultural events to strengthen ties and promote tourism, waiving applicable visa fees for teachers and experts in the field of tourism, promoting travel to regions and developing and improving tourist facilities and attractions in regions which contain examples of native culture in each country, and conducting joint marketing activities in third countries. the us-mexican agreement explicitly states that the nations 'will endeavour to facilitate travel of tourists into both countries by simplifying and eliminating, as appropriate, procedural and documentary requirements'. this will conflict with the border crossing policy outlined in the western hemisphere travel initiative (whti), which will require all citizens to provide a secured passport when entering the united states or mexico. this is, of course, in response to acts of terrorism in the united states. this situation is a good example of the need for fluidity in tourism strategy and policy, so that it is not only reactive but also proactive as market conditions and foreign policy change. an interesting aspect of the tourism agreement entered into by venezuela and the united states on september is that it calls for complementary agencies in the two countries to enter into their own agreements with each other. for example, the us national park service and venezuela's instituto nacional de parques are encouraged to pursue cooperative policies related to tourism development and facilitation. the agreement is specific about exchanges and mutual assistance, including efforts to identify tourism experts for short-term exchange assignments and identifying volunteer private-sector executives and professors of tourism who are eligible for sabbatical leave. this arrangement promotes cross-cultural understanding and has increased the body of knowledge in the field of international tourism development. organized associations of governments and tourism organizations comprised of groups at the national, regional and local levels can have a particular influence on the politics and foreign policy implications of tourism. there are a number of such intergovernmental organizations designed specifically to handle international tourism policy issues. two organizations at the world level are the unwto and the world travel and tourism council (wttc). regional organizations include the organisation for economic cooperation and development (oecd), the organization of american states (oas), the asia-pacific economic cooperation (apec) and the caribbean tourism organization (cto). an important regional organization within the united states is the southeast tourism society (sts), which consists of twelve member states. while there are many other organizations that cannot be described here due to space limitations, these seven groups are examples of proactive organizations working to advance tourism in their jurisdictions. the unwto, as part of the united nations, is the leading international organization in the field of travel and tourism and is headquartered in madrid, spain. originally established as the international congress of official tourist traffic associations in , it was renamed the international union of official travel organizations after the second world war, before restructuring occurred in . in , in lusaka, zambia, a unwto budget formula and statutes were adopted allowing for the unwto to become an official organization the following year. its first general assembly was held in madrid in may , and the intervening years have seen its emergence as the key world organization for tourism. in , the unwto achieved status as a un-specialized agency. its current mission statement summarizes its primary responsibility as '. . . (providing) a central and decisive role in promoting the development of responsible, sustainable and universally accessible tourism, with the aim of contributing to economic development, international understanding, peace, prosperity and universal respect for, and observance of, human rights and fundamental freedoms'. unwto offers national tourism administrations and organizations the machinery as a clearing house for the collection, analysis and dissemination of technical tourism information, developing partnerships between the private and public sectors, and supports the global code of ethics for tourism. activities include facilitating international dialogue and implementation of worldwide conferences, seminars and other means for focusing on important tourism development issues and policies. the official languages of the unwto are english, spanish, french, russian and arabic. membership includes roughly member countries, associate members and about affiliate members composed of private sector companies, educational institutions, tourism associations and local tourism organizations and authorities. one country that is not a member of unwto is the united states. as part of the downgrading of the us national tourism office in , its membership in unwto was cancelled; however, there is new political momentum to have the united states rejoin unwto. the structure of unwto is multipartite. at its core is the general assembly, which meets every two years to discuss its budget, programme and policy. the executive council, the governing board for the unwto, is composed of members as elected by the general assembly and meets biannually. the secretariat, located in madrid, is made up of officials who are entrusted with implementing unwto's programmes and responding to members' needs. there are six regional commissions (africa, the americas, east asia and the pacific, europe, the middle east and south asia) who meet annually. nine committees of unwto members advise on management and programme content. these are the programme committee, the committee on budget and finance, the committee on statistics and macroeconomic analysis of tourism, the committee on market intelligence and promotion, the sustainable development of tourism committee, the quality support committee, the unwto education council, the unwto business council and the world committee on tourism ethics. (part of the reference for this section was obtained from www.worldtourism.org/aboutwto.) the world travel and tourism council (wttc) is unique in its structure as it is the only organization representing the private sector in the global context of the travel and tourism industry. it is comprised of business leaders from around the world who are presidents, chairs and ceos of of the world's foremost travel and tourism companies representing almost all sectors of the industry. according to wttc, their mission 'is to raise the awareness of the full economic impact of the world's largest generator of wealth and jobs -travel and tourism'. wttc was established in by a group of chief executives from major companies within the industry to convince governments concerning travel and tourism's strategic importance. over the past decade and a half, wttc has worked with governments to increase understanding of the industry's economic benefits and to persuade them to re-evaluate the role of travel and tourism in their overall policy priorities. an executive committee resides in wttc's headquarters in london, england, and hosts the administration of its programmes. in july , wttc revealed its blueprint for new tourism that proffered the statement 'which issues a call to action for both government and the industry to make several long-term commitments to ensure the prosperity of travel and tourism -one of the world's largest industries, responsible for over million jobs and over per cent of global gdp (gross domestic product)'. the reasoning for this action stems from recovery measures necessitated by recent set backs experienced in the industry as a result of terrorism, war, economic slowdown and sars. the president of wttc, speaking at the global travel and tourism summit, stated, 'there is now a new consciousness amongst governments that they cannot leave the growth of travel and tourism to chance. what is needed is a new vision and strategy involving a partnership between all stakeholders -public and private to turn future challenges into opportunities. the blueprint for new tourism spells out how that can be achieved'. the guiding principles of 'new tourism' recognize global consciousness of the importance of tourism, takes a fresh look at the opportunities and partnerships it produces and the delivery of commercially successful products that provide benefits for everyone -not just the traveller but also the local people and communities with respect to their natural, social and cultural environments. in response to recent acts of terrorism and to prepare for the possibility of future attacks, the wttc formed a crisis committee. the crisis committee has been charged with producing an immediate forecast of the impact of such events on travel and tourism so that the industry and government leaders can make informed planning decisions. a model was developed based on the real effects of catastrophic events including the gulf war ( ), croatia peace ( ), luxor attack ( ), hurricane george ( ), september th usa ( ), september th world ( ), bali bombing ( ) and hong kong sars ( . the london underground bombing on july , allowed the global tourism industry to showcase its new proactive preparedness. the wttc crisis committee was convened within hours to forecast impact and propose strategies. in this case, historical non-peace has made the tourism industry more proactive. (part of the reference for this section was obtained from www.wttc.org.) the organisation for economic cooperation and development (oecd), located in paris, france, is bipartite in its structure. it serves as a forum in which governments work together to focus effectively on the challenges of interdependence and globalization through economic, social and environmental segments. in its efforts to 'underpin multilateral cooperation', oecd produces global research data, analyses and forecasts to enable economic growth and stability, strengthen trading systems, expand financial services and cross-border investments and promote best practices on the international forefront. it was started after the second world war as the organisation for european economic cooperation to coordinate the marshall plan, and in , adopted its current name in order to address trans-atlantic and, ultimately, its global reach. there are member countries and more than developing and transition economies working in partnership with oecd who share a 'commitment to democratic government and the market economy'. the mission of oecd is as follows: • to achieve sustainable economic growth and employment and rising standards of living in member countries while maintaining financial stability, hence contributing to the development of the world economy. • to assist sound economic expansion in member countries and other countries in the process of economic development. • to contribute to growth in world trade on a multilateral, nondiscriminatory basis. the oecd's tourism committee, headed by an executive-level bureau, has taken a leadership role in identifying and working towards the reduction of barriers to travel in its member countries. in view of the major importance of tourism among the principal service industries, the oecd trade committee in , and again in addressed updating and revising the code of liberalization of current invisible operations by carrying out a survey of obstacles to international tourism and reporting its findings in a comprehensive report to the oecd council. in , a milestone was achieved in efforts to reduce impediments to travel with the approval of a new instrument on international tourism policy, which reaffirmed the importance of tourism to the political, social and economic wellbeing of the member countries and agreed to set up formal procedures to identify travel impediments and to take cooperative steps to eliminate them. the oecd tourism instrument recommended minimum amounts for the import and export of national currency, for travel allowances, and for duty-free allowances for returning residents and for non-residents. it also made recommendations concerning travel documents and other formalities that strive towards facilitation of tourism. a finding then was that the most numerous and highly rated concerns among the countries responding were those impediments related to market access and the right of establishment. this reflects the importance of reaching customers in the country of residence in order to attract tourist and travel business. without a local branch or subsidiary, travel agents, tour operators, airlines and other tourist companies are unable to market their services adequately, placing them at a competitive disadvantage. today, the oecd is involving itself with emerging issues dealing with sustainable tourism and new directions in rural tourism. (part of the reference for this section was obtained from www.oecd.org.) the organization of american states (oas), headquartered in washington, dc, is currently composed of the following countries: antigua and barbuda, argentina, the bahamas, barbados, belize, bolivia, brazil, canada, chile, colombia, costa rica, cuba (by resolution in , the current government of cuba is excluded from participation in the oas), dominica, the dominican republic, ecuador, el salvador, grenada, guatemala, guyana, haiti, honduras, jamaica, mexico, nicaragua, panama, paraguay, peru, saint kitts and nevis, saint lucia, saint vincent and the grenadines, suriname, trinidad and tobago, the united states of america, uruguay and venezuela ( figure . ). this organization actually had its beginnings in the s, stemming from simón bolivar's vision of a region 'united in heart'. in , the nations of the inter-american region formed the commercial bureau of american republics, which later evolved into the pan american union, and finally became the oas. in it expanded into the english-speaking nations of the caribbean and canada, encompassing the hemisphere. the oas is committed to democracy for the people (all people have a right to democracy) and governments (government has an obligation to promote and defend democracy) in the member countries of the western hemisphere. 'building on this foundation, the oas works to promote good governance, strengthen human rights, foster peace and security, expand trade and address the complex problems caused by poverty, drugs and corruption. through decisions made by its political bodies and programmes carried out by its general secretariat, the oas promotes greater inter-american cooperation and understanding' (www.oas.org). the oas promotes 'peace, justice, and solidarity in the americas' as titled in their organizational heading. sustainable tourism is of major concern to the oas. the inter-american travel congress (iatc) was established in to develop travel and tourism in the americas by conducting studies that maintain dialogue between governments and the private-sector. the organization also provides technical and research support for tourism development initiatives. today, this focus still prevails. the purposes and functions of the iatc are: • to aid and promote, by all means at their disposal, the development and progress of tourist travel in the americas; • to organize and encourage regular meetings of technicians and experts for the study of special problems related to tourist travel; • to foster the harmonization of laws and regulations concerning tourist travel; • to take advantage of the cooperation offered by private enterprise through world and regional organizations concerned with tourist travel which hold consultative status with the united nations or maintain relations of cooperation with the oas; • to promote cooperative relations with similar world or regional organizations, either governmental or private, and to invite them to participate as observers at the meetings of the congresses; • to serve as advisory body of the organization and its organs in all matters related to tourism in the hemisphere. within this organization is the inter-sectoral unit for tourism. this branch promotes sustainable tourism practices and the importance of tourism as an economic development tool, in recognition of tourism's role as the world's number one growth industry. recent activities have 'focused on tourism development programmes and projects aimed at encouraging cooperative and operational ties at the internal, regional and international levels'. it utilizes the internet and websites to promote its findings. (part of the reference for this section was obtained from http://www.oas.org/main/english/.) convening its activities in , the asia-pacific economic cooperation (apec), headquartered in singapore, was formed as the 'premier forum for facilitating economic growth, trade and investment in the asia-pacific region'. the general philosophy is that strong, vital economies cannot be supported by government alone, thus the need for melding government and the key stakeholders in the business sector, academia, industry, policy and research institutions and interest groups within the community. apec is consistent in its approach to ensure open dialogue and equal respect among its member economies, which are australia; brunei darussalam; canada; chile; people's republic of china; hong kong, china; indonesia; japan; republic of korea; malaysia; mexico; new zealand; papua new guinea; peru; the republic of the philippines; the russian federation; singapore; chinese taipei; thailand; united states of america and vietnam ( figure . ). these member economies account for more than . billion people and per cent of world trade. its uniqueness is that it is 'the only multilateral grouping in the world committed to reducing trade barriers and increasing investment without requiring its members to enter into legally binding obligations'. under this umbrella, there are eleven working groups focusing on agricultural technical cooperation, energy, fisheries, human resources development, industrial science and technology, marine resources conservation, small and medium enterprises, telecommunications and information, tourism, trade promotions and transportation. the tourism working group (twg) has set four policy goals to support its function of creating jobs, promoting investment and development, and improving the tourism industry across the region. these policy goals are . removal of impediments to tourism business and investment; . increase mobility of visitors and demand for tourism goods and services; . sustainable management of tourism outcomes and impacts; . enhance recognition and understanding of tourism as a vehicle for economic and social development. the focus for the apec twg is on public and private partnership for facilitating tourism investments in the apec member economies and exploring best practices of e-commerce application to the small and medium tourism enterprises in the apec region. (part of the reference for this section was obtained from www.apec.org/about.) in , the caribbean tourism organization (cto) emerged from its predecessors, the caribbean tourism association founded in and the caribbean tourism research and development centre founded in . the cto, headquartered in barbados, is an international development agency and the official body for promoting and developing tourism throughout the caribbean. this organization provides information and assistance to its member countries and non-governmental members in order to achieve sustainable development. according to the cto, the organization and its members work together to encourage sustainable tourism that 'is sensitive to the economic, social and cultural interests of the caribbean people, preserves the natural environment of the caribbean people, and provides the highest quality of service to caribbean visitors' (figure . ) . cto also has offices in the united states, canada, the united kingdom, with smaller chapters in france, germany, holland, across the united states and in the caribbean. its composition is not only destination countries, but also private companies including airlines, hotels, cruise operators and travel agencies. membership is open to all caribbean countries and currently consists of english, french, spanish and dutch speaking nations and territories including the following member countries: anguilla the central thrust of the cto is to promote the caribbean as a 'vacation destination'. over time, the cto has produced high-quality websites, which, in turn, address travellers' quests to make better decisions regarding destination choices. the cto has successfully and efficiently utilized database marketing as a promotion tool. the organization supports sustainable tourism practices, development of tourism education and awareness programmes, financial guidelines and technical assistance to its members. (part of the reference for this section was obtained from www.onecaribbean.org.) the southeast tourism society (sts), headquartered in atlanta, georgia, is just one example of a regionally based tourism organization found in the united states as well as in other countries. sts is a non-profit membership organization, which started in and represents the interests of tourism industry members in twelve states: alabama, arkansas, florida, georgia, kentucky, louisiana, mississippi, north carolina, south carolina, tennessee, virginia and west virginia ( figure . ). membership includes state travel offices, convention and visitor's bureaus, destination marketing organizations, accommodations, attractions, advertising, media, educational institutions, product suppliers, travel writers and other related industry segments. sts goals are (a) to develop, market and promote domestic and international travel to the member states; (b) to have a governmental relations programme to serve as advocate of the tourism industry; (c) to develop tourism accreditation criteria to certify professionals in the tourism management field who want to dedicate their careers to the tourism industry; (d) to provide for an annual tourism marketing college with a curriculum that will further the education in marketing expertise of the members and others; (e) to provide programmes and services to the membership as identified by the board of directors. sts continues its dedication to promoting and developing tourism and travel by leading regional and national organizations in innovative programmes and research. in sts formed the southeast tourism policy council (stpc), which interfaces with united states federal agencies and members of congress. the stpc is featured as a case study of this chapter. (part of the reference for this section was obtained from www.southeasttourism.org.) a number of political, economic, and social factors influence the government actions and regulations affecting tourism facilitation. travel bans are imposed from time to time for political reasons. it is not unusual, for example, for a government to prohibit travel of its citizens to war zones or to territories of hostile nations where it has no means of protecting their lives and property. the us department of state through the auspices of the bureau of consular affairs, american citizens services, issues travel warning and consular information sheets, which are travel advisories to warn americans about adverse conditions in specific countries or territories. following the terrorism attacks of september , the us department of homeland security was established to serve this purpose and to provide other safeguards for us citizens and international visitors. in the past, visas were issued freely for travellers and other entry requirements were held to a minimum to avoid discouraging potential visitors. in the aftermath of worldwide terrorist attacks and actions in recent years, safety and security have become high priorities, and governments are readdressing their regulations. as this book goes to print, new policies are being formulated, as discussed below, which will have a major impact on tourism facilitation. in the united states, as well as other countries, the biometric chip (integrated chip) is being considered as a way of ensuring the proper identification of travellers. the biometric identifiers most commonly used for identification are face imagery or electronic fingerprint impressions. the accuracy of identification registers above per cent when both are used. this technology is now being applied to travellers from nations who previously enjoyed easier access to the united states through the visa waiver programme (vwp). residents from countries participating in the us vwp are allowed to travel to the united states for stays of less than days without obtaining a visa. participating nations, include andorra, australia, austria, belgium, brunei, denmark, finland, france, germany, iceland, ireland, japan, luxembourg, the netherlands, new zealand, norway, portugal, san marino, singapore, slovenia, spain, sweden, switzerland and the united kingdom. this programme began in to facilitate travel and promote better relations between the united states and the participating countries. despite the previous ease of travel, as of october , all new or renewed passports of travellers from these countries attempting to enter the united states are required to have a machine-readable passport with an integrated chip (the united states is mandating two index-finger scans). at the same time, transportation carriers will be fined up to $ per violation for transporting any visitor travelling under the visa waiver programme to the united states who does not meet these requirements. another screening process utilized by the united states began in aimed at securing our borders, facilitating entry/exit processes, enhancing the integrity of our immigration system, and protecting the privacy of visitors. the us visitor and immigrant status indicator technology (us-visit) programme implemented by the department of homeland security also employs biometric chip technology. its purpose is to facilitate legal trade and travel across the borders of the us and is in place throughout selected airports, seaports and land ports of entry. this programme is administered by the departments of homeland security and state. new technology is being introduced using radio frequency identification (rfid) technology for land ports in conjunction with heavy reliance on the machine-readable passport and the biometric chip for other ports of entry; but implementation has not been well thought-out, timely or efficient. in a similar measure to facilitate travel while maintaining homeland security, the department of homeland security also experimented with a registered traveler program (rtp). the rtp allowed selected frequent airline travellers to have priority in airport security lines in exchange for providing more personal information. the programme operated with several thousand frequent travellers hand picked by the airline companies, and was implemented at six airports. although the transportation security administration (tsa) suspended the programme while evaluating its success, it is expected to be fully implemented and expanded because of strong support from the travel industry and major airports. currently, there is considerable discussion arising about the determination of security measures. uppermost in the tourism industry's debate is determining the most effective and efficient methods of security inspections without overly disrupting travel. as shown by the examples of the vwp, rtp and us-visit programmes, careful consideration and cooperation with all participatory countries must occur to bring about desired policy outcomes. added to this, governments are also seeking ways to stimulate the construction of needed tourist infrastructure, access roads, communications, airport facilities and the many other supply-side requirements for supporting tourism. efforts are being devoted to conserving areas of natural beauty and developing and maintaining resort areas and sightseeing attractions. local and national governments often encourage special festivals, sports-related events, entertainment and cultural activities to entice tourists to the area. as a result of increased visitation, other government services, such as police protection and crime control, maintenance of proper health and sanitary conditions and good communications are also necessary to support tourism. together, the tourism industry and government must work to ensure that the best practice is used in providing these services for the traveller. special precautions in facilitating travel must also be taken when episodes of contagious diseases occur, as evidenced by the outbreaks of sars (severe acute respiratory syndrome) and west nile virus or potential outbreaks such as avian influenza a, also denoted as 'h n '. on april , the world health organization reported an outbreak of h n affecting humans in egypt, which was the ninth country to report laboratory-confirmed human cases after the first case in vietnam in december . food handling and preparation require special precautions to reduce intestinal illnesses and/or exposure to life-threatening epidemics. information can be found on the websites of international travel organizations addressing warnings and advisories. while these measures may result in discouraging or inconveniencing travellers, they are necessary to not only ensure enjoyable tourism experiences at the destination but also to decrease the chance of global epidemics. as the model for travel safety and security, the airline industry has introduced the most noticeably burdensome practices (exhaustive inspections of luggage and restrictions on items in carry-on bags and one's person). many travellers may perceive these measures as a hardship which they choose not to endure. they may alter their destination choice and stay closer to home, which allows the selection of alternative modes of travel, such as trains, buses or private cars. others may see it as part of the travel adventure and will not be deterred. the outcome depends, of course, on the motivations of individual travellers. a continuing concern of many governments is immigration control. nearly all countries strictly control the entrance of immigrants and enforce laws against illegal entry. of particular concern are social pressures created by the need to care for jobless immigrants, and opposition expressed by the local labour force when jobs are scarce. governments, entrusted with safeguarding their homelands must address the veracity of immigrants' paperwork. to admit foreign visitors and to facilitate their travel within a nation's borders is a political action. therefore, the method by which a nation's international tourism is regulated becomes an aspect of its foreign policy, as well as its economic and commercial policy, and requires careful planning. in the fall of , the united states bureau of customs and border protection issued an advance notice of proposed rulemaking for the implementation of the whti. the whti would require passports as identification for travellers to the united states from mexico and canada. an encumbered entrance is likely to have a negative impact upon these two important feeder markets for the united states. tourism industry leaders have expressed concerns over the reliance on passports as the only acceptable form of identification and have encouraged the government to develop a robust and focused public communications campaign to keep domestic and international travellers informed. many countries sponsor extensive exchanges, cultural programs, lecture services and other events to make people of the world aware of their customs and standards of living. the knowledge gained from contact between persons of different cultures can lead to increased understanding and a relaxation of tensions between nations. the adage mentioned in chapter , 'when peace prevails, tourism flourishes', bears repeating here. (we examine this concept in depth later in this chapter.) international organizations, such as people to people and rotary international, recognize this truth and support the exchange of people and culture. the implementation of glasnost in the s led to the doors being opened in russia in the s, thereby increasing travel into the country, and the dramatic demise of the berlin wall had a profound effect upon east-west travel and continues to do so. the result is a deeper understanding among people of the world, increased commerce, and a greater step towards international cooperation. today, a different climate prevails in which russian relations with the rest of the world are shifting back to more centrist governmental functions. one positive effect of this change may be seen in the field of education. east carolina university in greenville, north carolina, usa, for example, has recognized the contributions of russian scholars and has supported hiring faculty and promoting visits by its faculty members to russia as well as hosting russian visitation on its campus. jean-maurice thurot, noted for his research in tourism advertising, suggests that tourists create an economic dependence by the host country on tourist-generating countries. this dependence can influence the foreign policy of the host country towards that generating country. this is especially true in nations needing foreign exchange, or hard currency, for economic development. nations in the process of economic development need to buy key items, especially capital equipment and technology, from the industrial nations in order to speed their own growth. they, in turn, can sell these tourism products to the developed nations. a country must be made safe for residents and visitors. civil strife and disorder, such as that occurring in northern ireland and england, have had a detrimental impact on tourism. the military discord in the former republic of yugoslavia, a country that used to welcome over million visitors a year, has brought tourism to a virtual standstill. the current political problems in venezuela and other parts of the world discourage tourism. using sri lanka and the israeli/lebanese conflict as examples, the effects of war on tourism are described in detail later in this section. in addition to war, the constant threat of terrorism weighs heavily on international tourism in the united states. travelling contributes to '. . . interchange between citizens which helps to achieve understanding and cooperation', according to ronald reagan, a leading historical international peacemaker (reagan, ) . can tourism be a generator of peace in today's society or is tourism simply a beneficiary of peace? using democratic peace theory as a foundation in light of recent world conflicts and non-peace events, the answer to both queries could be yes. the democratic peace theory is founded upon the premise that democracies rarely enter into war or militarized disputes with one another because of their common values. although there are several examples of disputed cases, the claim that democracies do not engage each other is generally accepted as empirical fact by democratic peace theorists (rosato, ) . however, debate continues on the legitimacy of the theory. the american revolution, the second world war (in which great britain and the united states were pitted against, among other nations, the democratic nation of finland) and the border war in (in which peru fought ecuador) are three examples of nearly two dozen commonly debatable democratic wars. the list of disputable battles dates back to the greek wars of the fifth and fourth centuries bc (white, ) . since democracies do not generally engage each other, then democratic states are motivated to spread global democracy because it will enhance national security and promote world peace -true even though it may involve engaging in war to create sustainable peace. this is a distinguishing characteristic of the democratic peace theory. the democratic peace theory is based on the principles immanuel kant laid out in his essay entitled project for perpetual peace in (kant, ) . in the essay, he proposed that the three definitive articles for perpetual peace are . the civil constitution of every state should be republican. . the law of nations shall be founded on a federation of free states. . the law of world citizenship shall be limited to conditions of universal hospitality. a republican civil constitution ensures representation and requires citizen consent for the declaration of war. as citizens are the bearers of the financial and human burdens of war, they are less likely to support the declaration of unnecessary wars. democratic leaders will typically not engage in a conflict that is unpopular among constituents for fear of being removed from office. through a federation of free states, nations would be under a set of parameters that would transcend the laws of any one nation. if that set of laws ruled out war, then countries would be legally bound to settle disputes in peaceful ways. as the federation is extended, so too would be the principles of peace. universal hospitality implies the right of a visitor in a foreign land to be treated hospitably -not as an enemy. because of the finite size of the earth, its inhabitants must peacefully coexist for humanity to be sustainable. as the theory has evolved since kant's original work more than two centuries ago, the following are the three generally acceptable reasons that could lead democracies to engage in war: ( ) self-defence in protection of the homeland; ( ) prevention of blatant human rights violations in other states and ( ) to bring about conditions in which democratic values can take root abroad (rosato, ) . the theory also provides at least two reasons why democracies do not compromise peace with other democratic states. they are norm externalization and mutual trust and respect. this foundation of democratic peace is illustrated in figure . . norm externalization democratic peace theory under the assumption that peace can be achieved through the spreading of democratic ideals, and if two countries share similar democratic norms and values, then there are no norms that must be externalized upon other nations. therefore nations with similar values will not fight with each other. mutual trust and respect connotes that when conflict arises between democracies they will be inclined to accommodate each other or refrain from engaging in hard-line policies. democracies trust the judgment of nations that believe similarly. the expansion of democracy in the former soviet states lent credence to kant's theory of democratic states seeking pacific relations with one another. in other words, once democratic, the soviet union (or its remnants) was no longer the enemy of the united states. international tourism is the world's largest export earner, making it vital to global trade. tourism growth is also positively correlated to growth in global gdp. as global economies grow, disposable income typically also rises. the growth of international tourism arrivals generally outpaces gdp. however, because of the elasticity of demand for travel, if the economic situation tightens, spending on tourism will also typically decline (wttc, ) . the absence of peace disrupts global trade and investment. and when global trade is disrupted, travel declines, which compounds the decline in global gdp. therefore, tourism benefits from peace and the global economy benefits from tourism development. when safety and security is endangered by expansionist policies of others, it is an occasion for democracies to jeopardize peace (rawls, ) . the democratic peace theory implies that democracy will bring about political stability. political stability leads to safety and security in democratic nations. when safety and security is threatened, war will be engaged to ensure future safety and security. kant explicitly states that the visitor to a foreign land has the right 'not to be treated as an enemy when he arrives in the land of another'. in principle, the visitor must not be treated with hostility, as long as the visitor acts peacefully within the destination, but visitors to foreign countries today, and in the future, may not find this to be the case as a growing number of countries experience terrorist attacks. heightened suspicion towards outsiders can lead to less than hospitable conditions where such attacks have occurred. travellers rank safety and security as key factors in planning a vacation or convention. sixty-three per cent of international travellers to the united states report a destination's safety and security as extremely important. without safety and security in the destination, both business and leisure travel will be negatively affected. in a study conducted by one of the authors of this book, 'safety and security' occupies the number one position in the ten important world tourism issues for (edgell, ) . once again, tourism benefits from peace. an excellent example of the effects of war on a nation's tourism industry is sri lanka, which was involved in civil war from to . the conflict stemmed from the desire of the liberation tigers of tamil eelam to create an independent state in the northeast region of the island, and resulted in fatalities estimated at , people. while the clash officially ended in , the august assassination of the lankan foreign minister has threatened to revive it ( figure . ). during the years leading up to the war, the island nation had played host to a steadily increasing number of international visitors. as shown in figure . , international visitor arrivals decreased by . per cent in , visitor arrivals , tovah pinto, director general of the israel hotel association, reported after the conflict that crisis was looming, as the war had stifled months of growth in israel's tourism sector. the organization expected demand to fall by per cent in the year following the conflict. inbound international tourism to israel is expected to decline by $ . billion, and its contribution to the gdp is expected to drop by $ . billion, according to the israel hotel association. the israeli government contributed to recovery efforts by compensating northern israeli hotels for per cent of their losses during the conflict. in lebanon, as the israeli army entered, tourists naturally fled. despite tourism development plans put in place before the conflict, the lebanese minister of tourism stated the conflict will negatively affect tourism in lebanon for years afterward. upon certainty of a cease-fire, the lebanese tourism ministry planned a us $ . million marketing campaign to revitalize the image of the war-torn nation. tourism is often promoted by industry organizations as a vehicle for cultural understanding. the unwto, states its position on the matter as, 'intercultural awareness and personal friendships fostered through tourism are a powerful force for improving international understanding and contributing to peace among all the nations of the world'. indeed, an entire subset of tourism has developed around the concept of promoting peace through travel. the international institute for peace through tourism was founded in to foster and facilitate tourism initiatives that create a peaceful and sustainable world through travel. in addition to tourism industry organizations endorsing tourism's awareness-creating abilities, world leaders throughout modern history have also realized the benefits of tourism. mahatma gandhi said, 'i have watched the cultures of all lands blow around my house and other winds have blown the seeds of peace, for travel is the language of peace' (cited in theobald, ) . in , john f. kennedy stated, 'travel has become one of the greatest forces for peace and understanding in our time . we are building a level of international understanding which can sharply improve the atmosphere for world peace' (kennedy, ) . us secretary of state condoleezza rice, addressing the global travel and tourism summit breakfast in april, , celebrated the power of tourism by stating, 'travel fosters understanding. it builds respect. the knowledge and experience that citizens gain in their private travels is vital to the cause of diplomacy and international understanding in the twenty first century'. tourism cannot flourish without political stability and safety, which are restricted when peace is absent. without peace, tourism is diminished; therefore, tourism is a beneficiary of peace. through creating cultural awareness, tourism can be a stimulus for peace (assuming peace can be incremental). unfortunately, tourism through intercultural awareness can also be used to impart violence or any other ideal closely held by either the traveller or host. as indicated in figure . , peace can lead to political stability, which can lead to safety and security in the destination, which facilitates tourism. depending upon the motivation of the traveller and the structure of the destination, tourism can create cultural understanding. understanding of the people of other nations is a key ingredient leading to norm externalization and mutual trust and respect -critical components that lead to peace among nations, according to the democratic peace theory, as previously discussed in this chapter. tourism development -demand creation through marketing and supply expansion through investment -can be part of a strategy for geopolitical stability that includes the promotion of peace, economic development and cultural awareness. however, a sound governmental strategy for peace must be based on more than just tourism. the prospective economic benefits of tourism frequently influence the internal and foreign policies of governments. in some corners of our globe, inbound tourism is used to showcase the accomplishments of the government or party in power and to increase understanding abroad of the government's policies. sometimes this approach is successful; sometimes it is not. in terms of foreign policy, the response by governments to the impact of terrorism on tourism surpasses any prior attentions to security. the global tourism industry has been generally unprepared to deal with increasingly sophisticated acts of violence that use elements of the industry as weapons or targets, such as attacks against passenger trains in madrid in march , the october night-club bombings in bali and the use of commercial airliners as missiles in the us in september . as security becomes more important, organizations such as the wttc have measures in place to proactively handle crises as they happen. private sector groups have conducted training sessions to deal with potential terrorism in light of recent attacks. the aftermath of such devastation has raised the awareness of service organizations, the medical community and the individual. such efforts help, but for many pleasure travellers the worry, strain and inconvenience exact too much of a toll. it will take a strongly concerted effort of global cooperation, through policy, if the terrorism of the past three decades and its effects on travel and tourism are to be avoided in the future. this will facilitate international trade and development and contribute to efforts to foster peace and understanding. one means to facilitate this cooperation is through the work of intergovernmental tourism organizations such as those described, and many other proactive and productive groups throughout the world. the mou led to the creation of the federal interagency team on public lands tourism, which consists of representatives of each agency. these representatives regularly attend stpc meetings and serve as liaisons between their agencies and the stpc. the signing of the mou gave the stpc significant credibility in washington, dc and leverage when working on issues with the federal interagency team and other federal agencies. in an effort to maintain visibility in washington, dc the stpc arranges the sts/stpc congressional summit on travel and tourism each spring. the conference is an opportunity for any sts member who chooses to participate to hear about current policy issues from members of the federal interagency team and members of the stpc. attendees are also able to schedule appointments with members of congress and their staff. this is an excellent opportunity for sts members to push stpc issues as well as other policy issues that are important at the local level. listed below are the issues the stpc was actively involved with in december . following the list is a description of each issue, as supplied by bill hardman, jr, president and chief executive officer of the sts. the house adopted a proposal by resources committee chairman richard pombo (r-ca) and energy and mineral resources subcommittee chairman jim gibbons (r-nv) that would permit the sale of national forests and bureau of land management (blm) and corps of engineers lands that contain minerals. this would not apply to the national parks, refuges, wild and scenic rivers, national trails or conservation and recreation areas. the provision was included in h.r. , the deficit reduction act of . although the provision refers explicitly only to "mineral development lands available for purchase", it would apparently not preclude the purchased land to be used for straightforward development purposes, including residential and commercial development. environmental organizations have strongly objected to it, and at this time, it has not received much support in the senate, where it was not included in the senate deficit reduction act. in subsequent discussions with members of the senate and key staff following the october senate hearing described below, sts has been told that no further congressional legislation regarding the recreation fee program is likely until next year at the earliest and probably not until . at this point, congress seems willing to wait for the agencies to complete their protracted implementation process. on october , sts testified before the us senate subcommittee on public lands and forests regarding the new recreation fee program. in this testimony, sts supported the recreation fee program and the work done by the federal land agencies to implement it, although it was urged that implementation be expedited. sts urged that the new fee program be viewed as much more than another source of revenue, and should instead be regarded as part of a new, more innovative, flexible, visitor-focused way of managing the federal lands and as encouraging closer partnerships between the federal land agencies, state park and tourism agencies, the private sector and gateway communities. sts continues to work with the federal land agencies as they are developing guidelines for implementation of the -year new recreation fee authority passed by congress in as the federal lands recreation enhancement act (rea). several interagency working groups have been formed to develop implementation guidelines for the new fee program. at a february department of interior "listening session" with the interagency working group developing the newly authorized america the beautiful pass, sts urged the agencies to recognize the potential for this fee program as more than just a source of revenue, but also as a public information and marketing tool. sts also emphasized the importance of developing regional, intergovernmental passes and of working closely with state tourism offices and gateway communities in developing coordinated marketing campaigns combined with administration of the fee program. in a march communication to department of the interior director of external and intergovernmental affairs kit kimball, arvc joined three other allied tourism and recreation organizations in urging that all interagency fee working groups meet with private and intergovernmental organizations to discuss the potential promise and ramifications of the new fee program. at a june "listening session" in dc on the recreation resource advisory committees (rracs) mandated by the rea, sts recommended state-based rracs instead of national or broad regional ones. sts was assured in august by senior officials at the department of interior that a "state-centred" rrac program will be established, and it has now been announced that existing state blm resource advisory committees would be relied upon to perform the rrac role through special recreation subcommittees. sts questioned this approach in its october senate testimony because it is not clear whether the blm rac or the rrac subcommittee would have greater authority. senate forests subcommittee chairman larry craig (r-wy) agreed with this sts concern. the forest service has announced that it will discontinue entrance fees at relatively undeveloped sites (while retaining fees at sites). the agency hopes this will mitigate continuing strong opposition to the fee program as evidenced by the passage by six state legislative chambers of resolutions condemning the program and demanding congressional repeal. congress is not expected to pass such repeal legislation but may hold further hearings on fee implementation by the agencies. gateway community businesses, outfitters and concessionaires are closely following reported plans to allow discounts to holders of america the beautiful passes for recreational activities such as camping. the concern is that such discounts will reduce net revenue for those private businesses. hurricane katrina and, to a lesser extent, hurricane rita have obviously inflicted severe human suffering and devastating property losses in the gulf coast. they are also having an enormous impact on congress and the federal government. response and recovery to these two "storms of the century" have dominated debate and discussion on capitol hill. with overall projected costs in the $ billion range, pressure is being exerted on every agency budget and general rescissions of - per cent are possible in already approved fiscal year budgets. the public lands agencies and international tourism marketing will not be exempted from such rescissions. proposals have been made to cut back on the federal highway program authorized by congress just a few months ago, although this seems unlikely to happen. the public lands agencies have also suffered considerable direct damage to their park and forest lands located in the gulf coast, with the cost of repair and replacement creating additional budget pressures. in november , sts president bill hardman toured the coastal areas ravaged by katrina to see the level of damage and how the travel and tourism industry is recovering in those areas. the dollar amounts for the overall -year reauthorization and for specific programs are confusing because we are already years into this reauthorization cycle, which will end september . nonetheless, we can conclude that not only is the overall $ . billion nearly $ billion more than tea- , but also, with one notable exception, that programs directly beneficial to tourism and recreation fared reasonably well compared with tea- , with the following amounts not subject to appropriations: • transportation enhancements goes from $ million annually to $ million. supporters of recreational trails and sportfishing and boating were especially pleased with the outcome of safetea-lu. recreational trails will receive effectively a per cent increase over tea- and sportfishing and boating are rejoicing because the entire federal tax of . cents per gallon collected on fuel used by motorboats and small engines will now go into the wallop-breaux fishing and boating trust fund. previously, only . cents went into that fund. this means the allocation for sportfishing and boating should increase from $ million per year to about $ million. unfortunately, attempts to establish a new categorical program of recreational roads with funding of $ million, of which per cent would have been allocated to forest highways and the balance to the blm, corps of engineers and bureau of reclamation, was not included in safetea-lu because of fiscal constraints. very few new programs were authorized because there was not enough money to satisfy existing programs. controversy continues to rage over the wisdom of more than earmarked projects, or "set-asides", in safetea-lu that absorb nearly billion dollars in highway funds. it should be borne in mind, however, that many of these set-asides, including visitor centres, bridges, trails enhancements and restoration of historic sites, will directly benefit tourism and recreation, including many projects in western states. western hemisphere travel initiative (whti). on october, sts president bill hardman submitted comments to the bureau of customs and border protection regarding the advance notice of proposed rulemaking for the implementation of the whti. in his comments, he • urged greater attention to the economic impact of any changes in border inspection and control procedures; • expressed concern over reliance on passports as the only or de facto acceptable means of identification for travellers from canada or mexico; • proposed that closer collaboration between the public and private sectors be institutionalized and made permanent; • recommended that a robust and focused public communications campaign be developed to inform domestic and international travellers of any changes. biometric passports for visa waiver countries. on june, dhs secretary chertoff announced that the united states will accept the production of digital photographs to satisfy the october , requirement of biometric identifications on passports for travellers from the countries in the visa waiver program. by october , the vwp countries will have to begin issuing passports with integrated circuit chips, or e-passports. (on october , vwp countries must present an acceptable plan to begin issuing e-passports by october .) there is concern that france and italy will not be able to comply with this new digital photograph requirement. registered traveller program. after more than a year's experience, the department of homeland security's transportation security administration (tsa) on september announced it would suspend a test program on october that speeds airline travellers to the front of airport security checkpoints in exchange for providing more personal information. the "registered traveller" program operated at six airports and the participants were a few thousand frequent travellers hand-picked by the airlines. because of strong support for the program from the travel industry and major airports, it appears now that the tsa will soon reinstate and expand the program following full assessment of the test program. gateways bill. h.r. is expected to come up for a floor vote in the house of representatives this fall. representative george radanovich (r-ca) reintroduced h.r. , the gateway communities cooperation act, in the first business week of the th congress. the sts supports this legislation, while urging that state governors be given authority to designate communities as gateways. in order to get h.r. on the "consent calendar" in the house, which would mean prompt voice vote approval, revisions have been made in the legislation so that it will not be classified as creating a "new program" that would not qualify for the consent calendar. the main change has been to drop the small $ million grant program from the bill. there has been no further action with regard to the national outdoor recreation policy act. sts continues to work with the american recreation coalition and other recreation industry organizations to draft and advocate a national recreation policy act. this would establish for the first time a national commitment to development of a recreation policy for the country. the bill itself would make no substantive changes in recreation policies or programs, but it could result in a sea change in the emphasis given to recreation on the federal lands. it would accomplish three major goals: (a) it would "declare a national policy regarding the management and use of lands and waters administered by federal agencies to provide the american public with abundant, high-quality and diverse recreational opportunities to enhance ( ) public health and welfare, ( ) appreciation of natural resources and the environment, and ( ) economic benefits associated with outdoor recreation for gateway, rural and other communities"; (b) it would direct the secretary of the interior to lead an interagency effort to prepare within months "a national recreation strategy that identifies statutory and regulatory impediments to providing and facilitating a diversity of recreational opportunities on federallymanaged lands and waters, and appropriate means to increase the quantity and quality of recreation opportunities available to the public"; and (c) it would establish an ongoing federal recreation inter-agency coordinating council, with state and local government officials and others from the industry as advisors, to improve coordination of recreation programs and policies and implement the national recreation strategy. sts joined other industry organizations in explaining this significant legislation to key staff on capitol hill. resistance is expected from environmental organizations that will object to the emphasis given to recreation in this legislation and perhaps from some federal land agencies that do not see recreation as a major part of their mission. the draft bill is supported by at least recreation trade associations although some have expressed concern that it would favour some modes of recreation over others. most environmental and conservation organizations have not endorsed it. the department of the interior apparently has reservations about the need for national legislation and would prefer solving any problems through administrative actions. the forest service has drastically lowered its estimate of the economic impact of recreation on the national forests from $ billion, which had been the figure for nearly a decade, to $ . billion. the agency maintains that this is a much more valid estimate because it is based on actual head counts of visitors and interviews of visitors to determine their spending patterns. recreation industry organizations point out that this estimate only applies to visitor expenditures within miles of national parks and that it does not include billions of dollars in expenditures made farther away for recreation supplies and expensive "durables" such as boats, snowmobiles, skis and other durables, even though those purchases are made with the clear intent of using them on national forests. concerns that the lower impact estimate will be used to justify a lower priority for recreation in the forest service budget are rejected by the agency, which points out that recreation is still the largest generator of revenue of all activities on the national forests. the validity of the fs economic impact estimates has been supported by a new study of the economic impact of wildlife refuges by the us fish and wildlife service. although a much smaller impact of $ . billion is found for , the economic assumptions and methodology are the same and the estimated impact is comparable to the fs when the smaller acreage of the national wildlife refuge system and fewer visitors to wildlife refuges are considered. on october , the national park service proposed a new comprehensive policy for managing the national parks, which is embroiled again in a conflict between those who see the agency's mission to be the unimpaired preservation of the natural resource and those who defend the right of the public to use and enjoy the parks. in , in the closing hours of the clinton administration, the last comprehensive parks policy was issued, over the opposition of recreation user groups who saw it as reducing access and use. environmental groups are now concerned that the proposed plan will exalt use over protection of the parks. a draft proposal written last summer by paul hoffman, deputy assistant secretary of interior for fish and wildlife and parks especially stirred opposition from environmentalists. the comment period for this new proposed management policy has been extended until february . the sts participated in a november listening session at the department of the interior on the new policy on and is reviewing the proposed policy before deciding whether to submit comments. in , the interstate highway system will be years old. this , mile network is arguably the most significant public investment in the history of the nation, if not the world, and it has never cost the federal treasury a dime since it has been entirely financed through the federal motor fuel tax. certainly, the tourism industry in america today has been dramatically shaped and boosted by the interstate system. sts and the national tourism and recreation coalition for surface transportation are joining with the american association of state highway and transportation officials (aashto) to plan an appropriate national celebration of the th anniversary of the interstate system in . one project being considered is a reenactment of the military convoy across america led by then-colonel dwight d. eisenhower, which left a lasting impression on the young colonel of the need for a modern national highway system, and resulted in president eisenhower's signing into law the legislation and creating what became known as the dwight eisenhower national defense highway system. although the coast-tocoast convoy spent months traversing eleven states and the district of columbia, next year's -week reenactment would feature participation from all fifty states. the travel and tourism industry and state transportation departments are being urged to work together to plan this celebration in every state. at the same time, sts is working with the transportation research board, aashto, and other travel and tourism and transportation organizations to develop a substantive strategy to promote better relationships between travel and tourism and state transportation departments in every state and to broaden support for future federal highway policies. there is growing concern over the future of the national scenic byways program. although the program fared modestly well in the tea-lu highway reauthorization bill earlier this year, it is expected that it will come under increasing pressure in the next reauthorization bill in , as fiscal resources diminish. sts participated in a november meeting at the american recreation coalition to begin to develop strategies to strengthen political support for national scenic byways. in the fall of , the stpc surveyed members of sts, the people and organizations for whom the stpc serves as an advocate. the survey was conducted by jason r. swanson, a member of the stpc and one of the authors of this text. the survey had multiple purposes, including • soliciting the input of sts members in developing the agenda for the stpc; • creating a mechanism to periodically collect input from sts members; • providing a guideline for prioritizing policy issues; • proactively identifying emerging policy issues; • generating information for policy makers regarding what is important to their tourism constituents. the survey validates the issues the stpc has chosen as being consistent with the needs or desires of the sts membership. however, several new categories of policy issues came out of the survey that should considered by the organization: • coastal land and sea issues: off-shore drilling, beach re-nourishment, coastal wetlands restoration; • federal per-diem rates for travel expenses; • third-party intermediaries (expedia, travelocity, etc.) and collection of occupancy taxes; • small business development; • cultural preservation, job creation, and environmental quality issues, which are important to mountain areas and cities could be expanded upon; • other "other" responses from the survey (summarized): • fuel prices; • health insurance; • motorcoach regulations; • proposed fair tax law; • federal flood insurance; • improved federal system for tracking international visitation; • eligibility for federal grants for tourism development projects; • border crossing between canada and us; • government competing with private sector; • federal money to promote niche tourism markets, such as agritourism; • fair competition. as previously stated, one of the purposes of the survey was to generate information for policy makers regarding various aspects of tourism. specifically, the survey identified outdoor recreation as being extremely important to the tourism industry in the southeast as evidenced by the following: many of the high-priority policy issues involve areas far beyond economic impact, such as outdoor recreation, cultural preservation, and environmental quality. however, not as much non-economic impact research is being done by dmos, as shown in figure . . with a broader research spectrum, the tourism industry would be better able to provide information that is meaningful to a wider array of policy makers. a future hurdle for the stpc is conducting more rigorous policy analysis. policy analysis is important for at least two reasons: ( ) to decide on how stpc resources should be allocated based on those issues that may have the largest positive impact on the tourism industry and ( ) to provide information that can be communicated in a meaningful way to the political decision makers, the media, and members of the tourism industry. one way in which issues have been prioritized has been based on the likelihood that there will be success in achieving the objective of the particular policy stance. for example, if the political environment indicates the outcome on a particular issue is highly likely to be favourable to the stpc stance, then that issue is pursued. this approach does increase stpc's effectiveness, but the strategy may also take away consideration from other issues that may be more important to sustainable development. conducting valid policy analysis will help decide which side of an issue to be on when various members of the tourism industry may have competing agendas. of course, it is often worthwhile in instances of conflicting views within the industry to pursue other issues that can serve to pull together, rather than polarize, the industry; or, alternatively, to come to a meaningful compromise. one example of the tourism industry having conflicting views on an issue is funding for hurricane relief. subsequent to the severe human suffering and devastating property losses sustained in the gulf coast region during the hurricane season, the us congress proposed funding the expected $ billion recovery by cutting the budgets of many of the programs that the stpc supports. the budgets of international marketing, federal highway reauthorization and public land agencies were among those programs targeted for budget cuts. on the one hand, stpc was interested in rebuilding an important tourism market; while at the same time, the organization did not want other programs it had supported to lose funding as a result. there was a significant federal appropriation towards the rebuilding of the gulf coast states and agency budgets were affected, however, a sort of compromise resulted. the economic development administration within the department of commerce awarded sts a $ , grant program for a tourism marketing campaign focused on the gulf coast states of louisiana and mississippi, including the city of new orleans. undoubtedly, sts would have been far less likely to be awarded this grant had it not been for the relationships established through the stpc. while it may not be in the current mission of the stpc, there could also be an opportunity for this organization, or similar organizations, to affect public policy at the state and local level. through its policy analysis efforts on federal issues, the organization may also be able to offer policy analysis services, through dedicated policy professionals, to members of sts at the state and local levels. in another means of affecting tourism at state and local levels, the stpc and its mou could be a model for state tourism organizations to follow when trying to coordinate the efforts of various agencies in the state. the same can be true for tourism policy development at the local level. capitalizing on tourism's increasing economic and political importance, the stpc is now one of the most respected tourism advocacy groups in the united states and serves as a model for other regional policy advocacy organizations. more information on the stpc, including the organization's charter, can be found at http://www.southeasttourism.org/ south_t_policy_council.html. appropriation, $ . billion • nps operations maintenance: appropriation, $ . million. president bush's budget, $ . million • nps construction: appropriation, $ million. president bush's budget, $ . million • nps recreation and preservation: appropriation, $ million. president bush's budget, $ . million • forest service recreation: , $ . million • forest service trails: , $ . million. president bush's budget, $ . million • blm recreation management: , $ . million. president bush's budget, $ . million • fish and wildlife refuge management: , $ million. president bush's budget, $ million • forest service fire fighting: , $ . billion interior department fire fighting: , $ million. president bush's budget, $ . million • if there are agency wide rescissions because of katrina/rita recovery costs, the preceding figures will be lowered national parks national scenic byways program . cultural preservation . transportation national heritage areas legislation . cultural preservation . national parks earth island cases and categorical exclusions think nature-based outdoor recreation attractions help motivate travellers to visit the area: • per cent believe the majority of their visitors choose their destination because of its nature-based outdoor recreation attractions • per cent report the majority of their visitors participate in naturebased outdoor recreation during their visit to the destination • per cent indicate the majority of nature-based outdoor recreation attraction nature-based outdoor recreation accounts for per cent of total economic impact from tourism, according to survey respondents references the ten important world tourism issues for project for a perpetual peace the saturday review a theory of justice correspondence to th session of the executive council of the world tourism organization. the white house the flawed logic of democratic peace theory annual statistical report of sri lanka tourism global tourism, the next generation democracies do not make war on one another or do they? the web-based survey was sent to all members of the sts, of which tourism professionals responded. sts member organizations of all sizes and geographic locations were represented.respondents were asked to rank the importance of several policy issue categories, based on a five-point scale ranging from " not important" to " very important". the following list shows the average importance score for each of the policy issues.outdoor recreation ( . ) cultural preservation ( . ) environmental quality ( . ) transportation ( . ) federal highways ( . ) job creation ( . ) public lands ( . ) homeland security ( . ) national tourism office ( . ) national parks ( . ) international visitation ( . ) eminent domain ( . ) this priority of importance can be considered when new issues are selected or when deciding on how to allocate resources for work with current issues. accordingly, the priority can be applied to the december stpc issues, as shown below in table . . key: cord- -dnnkor o authors: georgiev, vassil st. title: tick-borne bacterial, rickettsial, spirochetal, and protozoal diseases date: journal: national institute of allergy and infectious diseases, nih doi: . / - - - - _ sha: doc_id: cord_uid: dnnkor o approximately tick species exist worldwide, parasitizing a broad array of mammals, including humans, and thereby playing a significant role in the transmission of infectious diseases ( ). in the united states, tick-borne diseases are generally seasonal and geographically distributed. they occur mostly during the spring and summer but can occur throughout the year. approximately tick species exist worldwide, parasitizing a broad array of mammals, including humans, and thereby playing a significant role in the transmission of infectious diseases ( ) . in the united states, tick-borne diseases are generally seasonal and geographically distributed. they occur mostly during the spring and summer but can occur throughout the year. these blood-feeding arthropods that parasitize all vertebrates can be classified into three families: (i) ixodidae (hard ticks) comprising approximately species and genera; (ii) argasidae (soft ticks), which consists of approximately species and genera; and (iii) nuttaliellidae, which is composed of only one species and is found only in africa ( , ) . ticks are major vectors of arthropod-borne infections and not only can transmit a wide variety of pathogens, such as rickettsia and other bacteria, viruses, and protozoa, but also may carry more than one infectious agent and thus transmit one or more infections to humans at the same time ( ) . infections transmitted by the ixodidae family (hard ticks) include (i) lyme disease (borreliosis); (ii) human ehrlichiosis; (iii) rocky mountain spotted fever; (iv) tularemia; (v) southern tick-associated rash illness; and (vi) babesiosis. infections transmitted by the argasidae family (soft ticks) include the tick-borne relapsing fever ( ) . ticks of the ixodidae family that transmit infections to humans are most often associated with the genera amblyomma, ixodes, dermacentor, and rhicephalus. they live in diverse but relatively humid habitats, and the infections they transmit are usually seasonal and geographically distributed. the hard ticks can attach securely to their hosts and feed slowly for prolonged periods, which will facilitate the transmission of infectious pathogens ( ) . in contrast, the only important disease-transmitting soft ticks belonging to the argasidae family are those of the genus ornithodoros, and they transmit spirochetes throughout their life cycle. ornithodoros feed rapidly, typically at night, and may transmit disease in as little as seconds ( ) . in the united states, ticks have been found in all regions of the country, and the incidence rates of tick-borne diseases have increased steadily over the past decade or so (http:// www .niaid.nih.gov/research/topics/lyme/introduction/htm). although lyme disease and rocky mountain spotted fever are well known to the general public, recently emerging infections, such as ehrlichiosis and anaplasmosis (formerly known as human granulocytic ehrlichiosis), have now also been firmly established in the country. the increasing reports of tick-borne diseases likely reflect improved awareness, surveillance and diagnosis, but the growing u.s. population and the spread of human communities into previously undeveloped environments also increase the regions of tick-human contact. since the identification of borrelia burgdorferi as the causative agent of lyme disease in , tickborne human bacterial pathogens have now been described throughout europe. these include five spotted fever rickettsiae, the etiologic agent of human granulocytic anaplasmosis (hga), four species of b. burgdorferi complex, and a new relapsing fever-causing borellia ( ) . if left untreated, the tick-borne infections can be associated with significant morbidity and even mortality. lyme disease (borreliosis) is the most prevalent tick-borne infectious disease in the united states. the disease is caused by a spiral-shaped bacterium borrelia burgdorferi and is spread by the deer tick ixodes scapularis. the likelihood for a person to be bitten by a deer tick is greater during the times of the year when ticks are most active. young deer ticks, called nymphs, are active from mid-may to mid-august and are approximately the size of poppy seeds. adult ticks, which are approximately the size of sesame seeds, are most active from march to mid-may and from mid-august to november. both nymphs and adult ticks can transmit lyme disease at any time when the temperatures are above freezing. during - , cdc received reports of , lyme disease cases from states and the district of columbia ( ); % of cases occurred among residents of the healthy people reference states (see table and the average annual rate in these reference states for the -year period was . cases per , population: . in , . in , and . in ( ) . not all deer ticks are infected with lyme disease. ticks can become infected only if they feed on small animals that are infected. in most cases, the tick must stay attached to humans for hours or more before the bacteria can be transmitted. there is no person-to-person spread of lyme disease. in extremely rare cases reported, the bacteria may be transferred from an infected pregnant woman to the fetus. even if successfully treated, a person may become re-infected if bitten later by another infected tick. the complex life cycle of b. burgdorferi, which passes through ticks and various intermediate hosts (mice and deer) before infecting humans, is still not completely understood ( , ) (http://www .niaid.nih.gov/research/topics/lyme). the outer surface protein a (ospa) of b. burgdorferi has been extensively studied, leading to a number of hypotheses regarding its role in conjunction with other cell surface proteins (ospb and ospc) in transmission of lyme disease ( ) . although b. burgdorferi depends on ixodes ticks and mammalian hosts for its life cycle, the search for the borrelial genes responsible for its parasitic dependence on these diverse hosts has been hindered by the difficulties in genetically manipulating virulent strains of the pathogen. nevertheless, there is strong evidence indicating that the inactivation and complementation of a linear plasmid- -encoded gene, bpta (formerly known as bbe ), is essential for the persistence of b. burgdorferi in i. scapularis ticks, and therefore, it must be considered to be a major virulence factor that is critical for b. burgdorferi's overall parasitic strategy ( ). early symptoms of lyme disease usually appear within to days after the bite of an infected tick. in % to % of cases, a rash resembling a bull's eye or solid patch (about inches in diameter) will appear and expand around or near the site of the bite. occasionally, multiple rash sites may also appear. in the early stage of the lyme disease, one or more of the following symptoms will appear: chills and fever, headache, fatigue, stiff neck, muscle and/or joint pain, and swollen glands. if not recognized or left untreated, symptoms become more severe, and include fatigue, a stiff aching neck, and tingling or numbness in the arms and legs, or facial paralysis. the most severe symptoms can occur even weeks, months, or years after the tick bite and include severe headache, painful arthritis, swelling of the joints, and heart and central nervous system problems. some evidence points to an autoimmune disease, perhaps triggered by the initial infection ( , ) (http://www .niaid.nih.gov/topics/ lymedisease/research/autoimmune.htm). early treatment of lyme disease involves the use of antibiotics, which in nearly all cases results in a complete cure. however, the likelihood of a full cure will decrease if treatment is delayed. and whereas in most infected individuals lyme disease can be easily treated with antibiotics, in a small percentage of patients it may lead to debilitating symptoms that may continue for years after treatment. as a result of dissemination through the bloodstream, b. burgdorferi can invade the central nervous system within days to a week after the initial skin infection. once in the central nervous system, the spirochete may affect the brain, most commonly causing a disturbance in thinking (cognition), known as lyme encephalopathy. other symptoms may include headache, mood swings, irritability, depression, and a high degree of fatigue. these symptoms comprise the typical features of neuropsychiatric lyme disease in adults (http://www.columbia-lyme.org/ flatp/lymeoverview.html). many of these symptoms are common manifestations in other disorders, such as mood or anxiety disorders, collagen vascular or autoimmune diseases, spinal cord compression, multiple sclerosis, metastatic diseases, endocrinologic disorders, fibromyalgia, chronic fatigue syndrome, and residual damage from past brain trauma or toxin exposure. nevertheless, knowing the typical cluster of symptoms can be helpful in diagnosing this condition. the majority of patients with lyme encephalopathy will not present with joint problems at the time that their cognitive symptoms have been recognized. it is important to emphasize that bedside neurologic examination does not usually disclose neurologic findings, and standard office-based cognitive screening test may not detect cognitive impairment. to detect cognitive disturbance, a more comprehensive neuropsychological examination would be needed. in addition, lumbar puncture, even though important in the differential diagnosis, should not be used to exclude neurologic lyme disease, as approximately % to % of patients with confirmed neurologic lyme disease may test negative in routine cerebrospinal fluid (csf) assays (http://www.columbia-lyme. org/flatp/lymeoverview.html). in general, the majority of patients who undergo early antibiotic therapy will not incur long-term central nervous system problems. the typical time course of the manifestations of lyme encephalopathy (http://www.columbia-lyme.org/flatp/lymeoverview.html) is as follows: (i) very early: erythema migrans (a red, round, expanding rash). (ii) one to months after infection: cardiac or early neurologic involvement (meningitis, encephalitis, cranial neuropathies) with mild to marked neuropsychiatric symptoms. (iii) six to months after infection: arthritis of multiple joints. (iv) two to years after infection: chronic cognitive problems. typical symptoms among adult patients with neuropsychiatric lyme disease (http://www.columbia-lyme.org/flatp/ lymeoverview.html) include: (i) mild to severe fatigue (a need for prolonged sleep), lowgrade fevers, night sweats, migrating arthralgias (joint pains) or arthritis (joint inflammation or swelling), muscle pains, sleep disturbances, and frequent and severe headaches. (ii) cranial nerve disturbance. though either facial nerve palsy or optic neuritis is not frequently manifested, patients may more commonly present with facial numbness and/or tingling. (iii) sharp, stabbing, deep/boring, burning, or lancinating (shooting) pains, as well as signs of peripheral neuropathy (multifocal numbness or tingling in hands or feet). (iv) cognitive problems may include problems of attention, memory, verbal fluency, and thinking speed. some patients may experience what is otherwise a normal environmental stimulation to be excessive, resulting in a cognitive "short-circuiting" (cognitive overload) where patients may start to feel confused, lose focus, stutter, or panic. (v) "brain fog," a term frequently used by patients with lyme disease to describe a syndrome characterized by lack of clarity in their cognitive processes similar to "depersonalization or derealization" in which the person's sense of self and place are altered. (vi) sensory hyperacuities characterized by heightened sensitivity to sound or to light, particularly in the early stages of neurologic lyme disease. (vii) spatial or geographic orientation problems where a patient may bump into the door jambs; try to place an object on a table only to have it fall to the floor due to a misjudgment of spatial distance; or get lost in a familiar place. (viii) less common neurologic syndromes include partial or complex seizures, multiple sclerosis-like illness, dementia-like illness, guillain-barré syndrome, strokes, and tullio phenomenon. most common symptoms of neuropsychiatric disorders in children suffering from lyme disease include headaches, disturbances of behavior or mood, fatigue (falling asleep in class), and problems with auditory and visual attention (some children could be mistakenly diagnosed as having attention deficit disorder). they may have fluctuating symptoms: worse on some days, remarkably better on others, without a clear cause (http://www.columbia-lyme.org/flatp/lymeoverview.html). as noted among adults, when lyme disease is treated early, few children will develop long-term cognitive or neuropsychiatric problems. prior vaccination with the licensed recombinant outer surface protein a (ospa) vaccine reduces the risk of developing lyme disease associated with tick bites ( ). administration of doxycycline ( mg, twice daily) or amoxicillin ( mg, times daily) for to days is recommended for the treatment of early localized or early disseminated lyme disease associated with erythema migrans, in the absence of neurologic involvement or third-degree atrioventricular heart block ( ) . in prospective studies, these two drugs have been shown to be effective in treating erythema migrans and associated symptoms. doxycycline has the advantage of being effective also for treating human granulocytic anaplasmosis (hga), another tick-borne infection that may occur simultaneously with lyme disease. however, doxycycline may be relatively contraindicated for pregnant women, during lactation, and for children aged years or younger (see also section . . . ). because of its higher cost, cefuroxime axetil ( mg orally, twice daily), which is as effective as doxycycline in the treatment of erythema migrans, should be reserved as an alternative agent for those patients who can take neither doxycycline nor amoxicillin ( ) . for children, the recommended dose of amoxicillin is mg kg − day − , divided into doses per day (maximum, mg/dose). cefuroxime axetil is an acceptable alternative given at a dose of mg kg − day − , divided into doses daily (maximum, mg/dose). macrolide antibiotics (azithromycin, erythromycin, and clarithromycin) are not recommended as first-line therapy for early lyme disease; when used they should be reserved for patients who are intolerant of amoxicillin, doxycycline, and cefuroxime axetil ( ) . intravenous ceftriaxone ( . g daily), although effective, is not superior to oral agents and is not recommended as a first-line agent for treatment of lyme disease in the absence of neurologic involvement or third-degree atrioventricular heart block. however, ceftriaxone is recommended for acute neurologic disease manifested by meningitis or radiculopathy ( ) . for children, the recommended dose of ceftriaxone is to mg kg − day − , in a single daily intravenous dose (maximum, . g), or cefotaxime ( to mg kg − day − ) divided into or doses (maximum, . g/daily) for to days ( ) . patients with first-or second-degree atrioventricular heart block associated with early lyme disease should be treated with the same antimicrobial regimens as patients with erythema migrans without carditis. the recommended treatment for patients with a third-degree atrioventricular heart block is parenteral antibiotics such as ceftriaxone in a hospital setting ( ) . although antibiotic treatment does not hasten resolution of seventh cranial nerve palsy associated with b. burgdorferi infection, antibiotics should be used to prevent further sequelae ( ). lyme arthritis usually can be treated successfully with antimicrobial agents administered orally or intravenously. thus, administration of oral doxycycline ( mg, twice daily) or amoxicillin ( mg, times daily), in each instance for days, is recommended for patients without clinically evident neurologic disease ( ) . for children, the recommended dose of doxycycline ( . to . mg/kg, twice daily; maximum, mg/dose) could be given to children age and older, or amoxicillin ( mg kg − day − , divided into doses per day; maximum, mg/dose) for days ( ) . whereas oral therapy is easier to administer than intravenous antibiotics, is associated with fewer adverse effects, and is significantly less expensive, its disadvantage is that some patients treated with oral antimicrobials have subsequently developed overt neuroborreliosis, which may require intravenous therapy for successful resolution ( ). the recommended therapy for patients with late neuroborreliosis affecting the central or peripheral nervous system is treatment with intravenous ceftriaxone ( . g, once daily for to weeks) ( ) . response to treatment is usually slow and may be incomplete. however, unless relapse is shown by reliable objective means, repeat treatment is not recommended ( ) . for children, the recommended treatment is a -to day course of ceftriaxone ( to mg kg − day − , in a single daily intravenous dose; maximum, . g) ( ). after an episode of lyme disease that is treated appropriately, some patients have a variety of subjective complaints, such as myalgia, arthralgia, or fatigue. such patients may then be classified as having either chronic lyme disease or post-lyme disease syndrome. however, both conditions are poorly defined because these patients represent a heterogenous group. because there have not been any randomized, controlled studies of patients who remain unwell after standard courses of antibiotic therapy for lyme disease, there are no convincing published data demonstrating that repeated or prolonged courses of either oral or intravenous antimicrobial therapy are effective for such patients ( ). the niaid has had a long-standing commitment to conduct research on lyme borreliosis, or lyme disease, beginning more than years ago when the cause of the disease was not yet known (http://www .niaid.nih.gov/ research/topics/lyme/research/). in , niaid-funded research efforts resulted in identifying borrelia burgdorferi, a spiral-shaped bacterium, or spirochete, as the causative agent of lyme disease ( r diagnosis, including the development and application of new technologies for rapid and sensitive diagnostic assays, as well as assessment, refinement, and standardization of improved diagnostic procedures. r treatment and prevention, including the development, application, and evaluation of novel and safe therapeutic approaches, as well as identification and characterization of candidate vaccines. r immune mechanisms, including understanding the development of protective immunity, characterizing the immunomodulatory properties of microbial antigens and evaluating their role in the pathogenesis, and characterizing the response of the host's immune system both during infection and after deliberate immunization. r pathogenesis, including the identification and characterization of virulence factors and the molecular basis for damage to host tissues during infection, and defining the role of cytokines and other immunomodulatory agents in the expression of disease. r epizootiology/ecology, including defining potential and established vectors and reservoirs, assessing the role of ticks and other vectors in transmitting the disease and maintaining virulence, relating the role of genetic variation in the incidence of disease in endemic areas, and defining effective measures for significantly reducing or eliminating populations of infected ticks in endemic areas. other developments of niaid-supported lyme borreliosis and tick-borne rickettsial disease research include: r the transmission of lyme disease r diagnostic procedures r co-infection r antibiotic therapy r the role of autoimmune reactivity r vaccine production lack of evidence of borrelia involvement in alzheimer's disease. because various published reports have suggested the possibility that b. burgdorferi may play a role in the etiology of alzheimer's disease, niaid intramural scientists have examined this issue in greater detail. the results of these studies, using a very sensitive polymerase chain reaction (pcr) assay capable of amplifying a borrelia-specific dna target sequence from all strains of b. burgdorferi sensu lato species known to cause disease in humans, have provided no evidence to indicate the presence of b. burgdorferi in the brains of patients with alzheimer's disease ( ). whereas early acute lyme borreliosis is easily cured by conventional antibiotic therapy, some patients who have been correctly diagnosed initially as having lyme disease may experience serious neurologic and musculoskeletal symptoms several months after receiving what appeared to have been successful antibiotic therapy. because it is unclear whether such symptoms are due to long-term persistent infections or other causes, the term posttreatment chronic lyme disease (ptcld) is often used to describe this condition, so as not to impose any judgment on the actual mechanism(s) that might be involved (see also section . . . ) . over the years, niaid has supported research regarding ptcld as well as other clinical issues (http://www . niaid.nih.gov/research/topics/lyme), including: this study, which was carried out in nemc in boston and completed in , was aimed at studying the clinical efficacy of antibiotic therapy for treating ptcld. it involved randomized, double-blind, placebo-controlled, multicenter trials to examine the safety and efficacy of ceftriaxone and doxycycline in patients with either seropositive or seronegative chronic lyme disease. the trials compared treatment with days of intravenous ceftriaxone followed by days of oral doxycycline to treatment with intravenous placebo followed by oral placebo for the same duration in patients who were either seropositive or seronegative at the time of enrollment. preliminary results from the trials showed that after days of continuous antibiotic therapy, there were no significant differences in the percentage of patients who felt that their symptoms had improved, gotten worse, or stayed the same between the antibiotic treatment and placebo groups in either trial ( ) . other results from the trials indicated that patients with ptcld did not show objective evidence of cognitive impairment and that days of continuous antibiotic therapy was not more beneficial for these patients than was administering a placebo ( ) . r state university of new york (suny) clinical study. in another placebo-controlled study conducted at suny at stony brook, patients with pctld were treated with either intravenous ceftriaxone or a placebo for days. they were then evaluated to determine whether there was significant improvement with respect to fatigue, cognitive function, and the clearance of ospa antigen that was present in the spinal fluid of only % of all enrolled patients. the results of the trial have shown that ceftriaxone therapy was associated with improvement in fatigue but not with the other primary outcome markers considered ( ) . because fatigue, which is a nonspecific symptom, was the only primary outcome measure affected and because the treatment examined was associated with adverse events, the results of the suny study do not support the use of additional antibiotic therapy with parenteral ceftriaxone in posttreatment, persistently fatigued ptcld patients (http://www .niaid.nih.gov/research/topics/lyme). r animal models. appropriate animal models also have provided considerable information on the transmission and pathogenesis of lyme borreliosis, as well as on the mechanisms involved in the development of protective immunity. niaid, in collaboration with the national institute of neurological disorders and stroke (ninds), has broadened these efforts to include comprehensive studies on non-human primate animal models for experimental research on the neuropathology associated with chronic lyme borreliosis ( ) . a major goal of these studies is to optimize the rhesus model of lyme borreliosis as well as to determine the pathogenesis of the disease with a focus on the neurologic manifestations. it is anticipated that these studies will expand the knowledge of those factors that contribute to the pathology associated with persistent infection of the central nervous system by b. burgdorferi and ultimately will enable scientists to devise more effective clinical approaches for treating chronic lyme borreliosis in humans. these studies will also supplement and enhance the results of current clinical research on the efficacy of antibiotic therapies for treating chronic lyme disease and provide precedents for use in designing future clinical studies and will ultimately enhance the results of current clinical studies on chronic lyme disease. inflammation of skeletal muscle is a consistent feature of lyme borreliosis, both in humans and in experimental animal models of infection. although several cytokines are expressed in muscle tissue, proinflammatory cytokines commonly associated with inflammation are not upregulated in borrelia-infected muscle. however, the expression of blymphocyte chemoattractant (blc), a chemokine implicated in the trafficking of b cells to tissues, is increased in borreliainfected muscles of non-human primates ( ) . using protein expression profiling, it has been shown that blc is upregulated in the spinal fluid of patients with neuroborreliosis but not in patients with noninflammatory and various other inflammatory neurologic diseases ( ) . because the upregulation of blc was found in every neuroborreliosis patient examined, it may be a valuable diagnostic marker for neuroborreliosis. other studies have shown that b. burgdorferi can be detected in mice for at least months after treatment with therapeutic doses of various antibiotics (ceftriaxone, doxycycline, or azithromycin). these surviving spirochetes could not be transmitted to healthy mice and some lacked plasmid genes associated with infectivity. by months, antibiotictreated mice no longer tested positive for the presence of b. burgdorferi, and even cortisone immunosuppression failed to alter this result; that is, it failed to activate infection. nine months after antibiotic treatment, low levels of borrelia dna still could be detected in some, but not all of the mice. these findings ( ) have indicated that noninfectious b. burgdorferi can persist for a limited time after antibiotic therapy. the implications of these findings to persistent infection and the nature of chronic lyme disease in humans remain to be assessed. results from recent studies have indicated that t cells from patients with chronic lyme disease were reactive not only against b. burgdorferi-specific antigens but also against various host (self) antigens ( ) . such antigenic mimicry might generate autoimmune inflammatory reactions that could be responsible for arthritic as well as neurologic symptoms associated with chronic lyme disease (http://www . niaid.nih.gov/research/topics/lyme/research/autoimmune/). in other studies, antibodies against the ospa epitopes of b. burgdorferi have also been shown to cross-react with neural tissue ( ) as well as myocin ( ) . such antigenic mimicry may have the potential to generate autoimmune inflammatory reactions that could be responsible for the neurologic symptoms associated with chronic lyme disease. in this context, it is interesting to note that homologies between proteins of b. burgdorferi and thyroid antigens have also been reported ( ) . in niaid-supported clinical studies, case subject patients with ptcld were compared with control subjects without such symptoms for the presence of several human leukocyte antigen (hla) class ii (drb and dqb ) genetic markers, some of which are known to be associated with the expression of autoimmune reactivity. the results obtained did not support the involvement of an autoimmune mechanism in ptcld ( ) . however, because not all autoimmune diseases are associated with specific hla haplotypes, these findings do not necessarily exclude that possibility. definitive proof would clearly involve demonstrating the presence of significant levels of relevant autoimmune antibodies and/or autoreactive t cells in patients with ptcld but not in treated control subjects without such symptoms. a greater frequency of drb * , which has been reported to be associated with antibiotic-treatmentresistant arthritis, was noted in the case subject patients; although this finding appeared to be nominally significant (p < . ), its biological significance is ambiguous because none of the case subjects considered had symptoms of inflammatory arthritis (http://www .niaid.nih.gov/ research/topics/lyme/research/autoimmune/). co-infection could represent a major potential problem, mainly because the ixodes ticks that transmit b. burgdorferi often carry-and simultaneously transmit-other emerging pathogens, such as anaplasma (ehrlichia) species, the causative agent of human granulocytic ehrlichiosis (hge), and babesia microti, which causes babesiosis (http://www .niaid.nih.gov/research/topics/lyme/ research/co-infection/). in europe and asia, ixodes ticks also are known to transmit tick-borne encephalitis viruses. fortunately, this tick-borne viral infection has not yet been reported in the united states, although co-infections with powasan virus and deer tick virus have been reported. co-infection by some or all of these other infectious agents may interfere with the clinical diagnosis of lyme borreliosis and/or adversely influence host defense mechanisms, thereby altering landmark characteristics of the disease and the severity of infection ( ) . niaid-supported studies have indicated that co-infection with hge increases the severity of lyme borreliosis ( ) . by contrast, when mice were co-infected with b. microti and b. burgdorferi, neither agent influenced the course of infection induced by the other as evidenced by the percentage of parasitemia, spleen weights, and hematologic and clinical chemistry parameters ( ) . in niaid-supported clinical studies on chronic lyme disease, patients with persisting symptoms were examined to determine if they might have been co-infected with other tick-borne infectious diseases at the time of their acute episode of lyme disease. among the tick-borne infectious diseases considered were babesiosis (babesia microti), granulocytic ehrlichiosis (anaplasma phagocytophilum), and tick-borne encephalitis virus infection. the seroprevalence rates for b. microti and a. phagocytophilum were found to be . % and . %, respectively, and no patient examined was found to be positive for tick-borne encephalitis viruses ( ) . thus, the persistence of symptoms in patients with "post-lyme syndrome" could not be attributed to co-infection with one of these pathogens. an examination of pathogen distributions in the tissues of mice infected with both b. burgdorferi and a. phagocytophilum, the bacterium that causes hge in humans, showed an increase in the numbers of b. burgdorferi in the ears, heart base, and skin of co-infected mice; however, the numbers of a. phagocytophilum remained relatively constant. the serum antibody response to a. phagocytophilum (but not to b. burgdorferi) decreased as a result of co-infection. these findings suggest that co-infection can influence not only pathogen burden but also host antibody responses ( ) . niaid intramural and extramural research programs have initiated clinical studies on chronic lyme disease. the intramural research program is conducting a comprehensive clinical, microbiologic, and immunologic assessment of patients with lyme disease. this involves multiple lines of investigation with emphasis on (i) defining various biological markers of infection; (ii) assessing clinical course and outcomes of patients with lyme borre-liosis; and (iii) characterizing the immune response generated in response to b. burgdorferi (http://www .niaid.nih. gov/research/topics/lyme/research/co-infection/). niaid is supporting various efforts to evaluate and improve existing diagnostic procedures. approximately % of its extramural lyme disease research portfolio is devoted to developing novel and more sensitive diagnostic procedures (http://www .niaid.nih.gov/ research/ topics/ lyme/ research/ diagnostics/). in , the fda granted approval to chembio diagnostic systems to market the wampole prevue borrelia burgdorferi antibody detection assay. the assay is a single-use, unitized immunochromatographic test that uses recombinant b. burgdorferi antigens for the qualitative presumptive (first step) detection of igg and igm antibodies to b. burgdorferi in human serum or whole blood. this test is to be used only in patients with history, signs, and symptoms that are consistent with lyme disease. it is intended for use in clinical and physicians' office laboratories. in collaboration with cdc, niaid is also playing a major role in encouraging the development of novel approaches to improve the diagnosis of lyme borreliosis in humans with various co-infections (e.g., ehrlichiosis or babesiosis), as well as in immunized people (http://www .niaid.nih. gov/research/topics/lyme/research/diagnostics/). for example, it has been shown in niaid-supported research that a synthetic peptide composed of amino acid residues (c ) derived from a variable surface antigen (vlse) of b. burgdorferi can be used in a new, rapid, and extremely sensitive elisa test (the c elisa) for diagnosing lyme disease. because this diagnostic test for lyme disease, which has been approved by fda, does not detect antibodies specific for recombinant ospa, it can be used even for those who have been immunized with the licensed ospa-based lymerix vaccine ( ) . although the lyme urinary antigen test (luat) is one of several diagnostic tests used routinely in niaid's clinical studies on chronic lyme disease, the results of independent quality control assessments of tests conducted by extramural and intramural scientists showed the luat to be unreliable because it yields an unacceptably high percentage of falsepositive reactions ( ) . a critical evaluation of urine-based pcr assays for the diagnosis of lyme borreliosis likewise affirmed that urine is not a suitable material for the diagnosis of lyme borreliosis ( ) . by contrast, the similar assessments confirmed a high degree of reproducibility and concordance (virtually %) for the results obtained using elisa and western blot assays ( ) . of great importance is the fact that decreases in the titer of antibodies against c can be used as an indicator of the efficacy of antibiotic therapy for patients with localized or disseminated lyme disease, but not for chronic lyme disease ( ) . this is indeed a major advancement, because no other laboratory test enables one to obtain such information ( ) . the results obtained with the c elisa assay are consistent with those obtained with other diagnostic tests and may eliminate the time and expense of conducting additional laboratory tests to confirm the diagnosis of lyme disease ( ) . niaid-supported investigators are now working closely with the cdc to determine if the c elisa can eventually replace the traditional two-tiered conventional elisa and western blot assays. the results of other studies confirmed that a decline in the anti-c antibody titer coincides with the efficacy of antimicrobial therapy in patients with early localized or early disseminated lyme borreliosis ( ) (see also . . ) . the b. burgdorferi-specific immune complex (ic) test in which polyethylene glycol (peg) is used to isolate ics from serum has been advocated by some investigators as an approach for the early diagnosis of active borreliosis. however, recent findings indicate that it may not be more effective in detecting early and active infections than other conventional tests in which unprocessed serum specimens are used ( ) . there is a great need to develop additional simple, sensitive, and rapid procedures to distinguish those persons who are actively infected with b. burgdorferi from those who have either recovered from a previous infection or have been immunized previously. because the genome of b. burgdorferi has now been completely sequenced, greater advances toward this goal are anticipated as this information is used in conjunction with microarray technology and proteomics to improve diagnosis, as well as to provide new insights on the pathogenesis of this disease and pathogenspecific host response mechanisms (http://www .niaid. nih.gov/research/topics/lyme/research/diagnostics/). there is no clear understanding about the molecular basis of how b. burgdorferi maintains itself in nature via a complex life cycle that involves passage through ticks and various intermediate hosts, such as mice and deer, before infecting humans. the outer surface protein a (ospa) of b. burgdorferi has been well studied, and there is much speculation about its role-in conjunction with other cell surface proteins (ospb and ospc)-in transmitting lyme disease ( ) . although b. burgdorferi depends on ixodes ticks and mammalian (rodent) hosts for its persistence in nature ( ), the search for borrelial genes responsible for its parasitic dependence on these types of diverse hosts has been hampered by limitations in the ability to genetically manipulate virulent strains of borrelia. despite this constraint, there is evidence to indicate that the inactivation and complementation of a gene (bbe ) encoded by a linear plasmid (lp ) plays a major role in the virulence, pathogenesis, and survival of b. burgdorferi during its natural life cycle ( ) . this gene, which has been renamed bpta (for borrelial persistence in ticks-gene a), potentiates virulence in mice and is essential for the persistence of b. burgdorferi in ixodes scapularis ticks. although bpta appears to be a lipoprotein expressed on the outer surface membrane of b. burgdorferi, the molecular mechanism(s) by which bpta promotes persistence within its tick vector remains to be elucidated. because bpta appears to be highly conserved (> % similarity and > % identity in amino acid sequence) in all b. burgdorferi sensu lato strains examined, it may be widely used to promote persistence in nature. given the absolute dependence on-and intimate association with-its tick and rodent hosts, bpta must be considered to be a major virulence factor that is critical for b. burgdorferi's overall infectious strategy ( ). strategies designed to block the synthesis or expression of bpta could be of great value in preventing the transmission of lyme disease. the potential role that differentially upregulated surface proteins play in the transmission of borreliosis and lyme disease pathogenesis have prompted investigators to conduct a comprehensive gene expression profiling analysis of temperature-shifted and mammalian host-adapted b. burgdorferi. the combined microarray analyses revealed that many genes encoding known and putative outer surface proteins are downregulated in mammalian host-adapted b. burgdorferi. however, at the same time, several different genes encoding at least seven putative outer surface proteins were found to be upregulated during the transmission and infection process. all seven proteins are immunogenic and generate the production of bactericidal antibodies in infected baboons ( ) . this suggests that these outer surface proteins might be excellent second-generation vaccine candidates. the above findings have been consistent with the results of published studies ( ) in which a novel experimental technique (xenodiagnosis by ticks) was used to determine whether b. burgdorferi can persist in mice long after antibiotic therapy. in these studies, an immunofluorescence assay and the pcr assay were used to demonstrate that b. burgdorferi could be detected in doxycycline-and ceftriaxonetreated mice for at least months (if not longer) after antibiotic therapy. however, the resulting surviving spirochetes were unable to infect other naïve mice because they lacked those linear plasmids (lp and lp ) that are essential for their ability to transmit infection ( ) . it is noteworthy that lp also encodes for a gene product (pnca or bbe ) that is essential for the survival of b. burgdorferi in a mammalian host ( ) . niaid-supported investigators have now been able to create various mutant strains of b. burgdorferi and have shown that although ospa and ospb are not required for infection of mice, they were essential for the colonization and survival of b. burgdorferi in ticks (http://www .niaid.nih.gov/ research/topics/lyme/research/transmission/). ixodes scapularis ticks have a receptor on the inner wall of their intestines to which b. burgdorferi is able to bind tenaciously by means of ospa, a cell surface protein. this receptor is called the tick receptor for ospa (trospa). attachment to trospa will enable b. burgdorferi to persist in the gut from the time they were ingested by ticks through a subsequent molt, thereby avoiding elimination; this would allow borrelia to be injected into a new host when the ticks take their next blood meal ( ) . when ticks take a blood meal, the production of ospa is downregulated in favor of the increased production of ospc. this results in gut-bound spirochetes becoming detached, which enables them to migrate to the salivary glands, where they can be injected into mammalian hosts. thus, trospa, in addition to other bacterial cell surface components, such as ospa, appears to play a key role in the transmission of lyme disease to humans. other studies have shown that if ticks are permitted to feed on mice that have been immunized previously with ospa, or have been treated with the antibody specific for ospa, the attachment and subsequent colonization of ticks by b. burgdorferi would be significantly impaired, if not prevented. this suggests the feasibility of developing oral-or vector-expressed transmission-blocking vaccines that involve the immunization of the intermediate hosts upon which ticks feed ( ) . several niaid-supported investigators are now examining and testing this approach under controlled laboratory conditions (http://www .niaid. nih.gov/research/topics/lyme/research/transmission/). results from other studies conducted by niaidsupported investigators ( ) have demonstrated that b. burgdorferi uses an immunosuppressive tick salivary protein (salp ) to facilitate the transmission of infection to mammalian hosts. this finding is based on observations that (i) the level of salp expression is enhanced by the presence of b. burgdorferi in infected ticks; (ii) salp adheres specifically to spirochete surface ospc both in vivo and in vitro, thereby increasing the ability of b. burgdorferi to infect mice; and (iii) the binding of salp protects b. burgdorferi from antibody-mediated killing in vitro, a factor that confers marked survival advantage. all of these observations suggest that salp and/or other tick salivary proteins might be excellent candidates for vaccines to block the transmission of lyme disease ( ) . in this context, prior and repeated exposure of experimental animals to uninfected ticks-and presumably their salivary proteins-has been shown to limit the capacity of infected ticks to transmit lyme disease ( ). two large pharmaceutical companies [glaxosmithkline (skb) and pasteur merieux connaught (pmc)] have devoted considerable effort to developing a vaccine for lyme disease. double-blind, randomized, placebo-controlled clinical trials, involving more than , volunteers from areas of the united states where lyme disease is highly endemic, have been completed for each of two b. burgdorferi recombinant ospa vaccines manufactured by skb and pmc. these vaccines were found to be % to % effective in preventing lyme disease after two injections and % to % effective in preventing lyme disease after three injections. the duration of the protective immunity generated in response to the skb vaccine (lymerix), which was licensed by the fda in december , is not known. consequently, the need for yearly booster injections remains to be established. researchers and health experts anticipate that the use of these vaccines in endemic areas would likely result in a significant reduction in the incidence of lyme disease in the future. niaid was not directly involved in the design and implementation of these particular vaccine trials; however, patents for cloning the genes used for the expression of recombinant ospa, as well as knowledge of the role of antibodies against ospa in the development of protective immunity, were derived from basic research funded by niaid (http://www . niaid.nih.gov/research/topics/lyme/research/vaccine/). in april , glaxosmithkline announced that even with the incidence of lyme disease continuing to increase, sales for lymerix declined from about . million doses in to a projected , doses in . although studies conducted by fda failed to reveal that any reported adverse events were vaccine-associated, glaxosmithkline has discontinued manufacturing the vaccine for economic reasons ( ) . niaid-funded investigators have developed an experimental bait delivery system for an ospa-based vaccine against b. burgdorferi in which mice were immunized orally (via gavage or bait feeding) with a strain of escherichia coli expressing the gene for ospa, which resulted in the appearance of serum antibody specific for ospa. when mice were exposed to ixodes nymphs carrying multiple strains of b. burgdorferi, oral vaccination was found to protect % of the mice from infection, and the resultant serum antibody response confirmed the presence of igg a/ b antibody specific for ospa (http://www .niaid.nih. gov/topics/lymedisease/research/vaccine.htm). this vaccination approach is able to generate a significant protective immune response against a variety of infectious strains of b. burgdorferi, thereby indicating that it can eliminate b. burgdorferi from a major host reservoir. it suggests that the broad delivery of an oral vaccine to wildlife reservoirs in an endemic area is likely to disrupt the transmission of lyme disease ( ) . these findings are consistent with the results reported by other investigators ( ) , thus affirming the utility of this approach. in other niaid-supported studies, scientists have developed a murine-targeted ospa vaccine using the vaccinia virus to interrupt the transmission of disease in reservoir hosts, thereby having the potential to reduce the incidence of human disease. oral vaccination of mice with a single dose of vaccinia virus expressing ospa resulted in high antibody titers to ospa, % protection of vaccinated mice from infection by b. burgdorferi, and a significant clearance of b. burgdorferi from infected ticks fed on vaccinated animals ( ) . these findings indicate that such a vaccine may effectively reduce the incidence of lyme disease in endemic areas. niaid is also funding preclinical studies to develop and test other candidate vaccines (e.g., decorin-binding protein a, or dbpa) for lyme disease. thus, medimmune, inc., and sanofi-aventis pharmaceuticals have reported that a combination vaccine composed of the dbpa and ospa of b. burgdorferi was more effective than either one given alone in preventing the development of borreliosis in experimental animals. on the basis of these encouraging findings, both companies have entered into an agreement to develop a new, more effective second-generation vaccine to prevent lyme disease in humans. although the results of previous studies indicate that dbpa induces the development of protective immunity in a murine model of lyme borreliosis when mice have been challenged (needle-inoculated) intradermally with in vitro-cultivated b. burgdorferi, such mice were not protected from infection transmitted by ticks carrying virulent b. burgdorferi. the principal mission of niaid is to study infectious diseases and host immune defense mechanisms; therefore, the institute conducts and supports most of the basic and clinical research on lyme disease funded by the national institutes of health (nih). however, because lyme disease affects different tissue and organ systems of the body, it is also a matter of great concern to other nih institutes and centers (http://www .niaid.nih.gov/research/topics/lyme/centers/). the national institute of arthritis and musculoskeletal and skin diseases (niams) is funding research on chronic lyme-induced arthritis, including the role of the immune system and genetic factors in contributing to its development. the national institute of neurological disorders and stroke (ninds) is funding research to characterize the neurologic, neuropsychological, and psychosocial manifestations of early and late lyme disease in both adults and children, as well as to characterize pathogenic mechanisms associated with the neurologic symptoms of chronic lyme disease. the national center for research resources (ncrr) provides resource support (non-human primates) for basic and clinical studies on both acute and chronic infection, as well as support for testing and developing candidate vaccines for lyme disease. in addition, the fogarty international center (fic) is funding research on lyme disease abroad, and the national institute on aging (nia) and the national institute of mental health (nimh) have focused on those aspects of lyme disease that relate to their specific missions. to facilitate cooperative interactions as well as to ensure that the research activities of all nih components are complementary, an nih lyme disease coordinating committee (ldcc) was established in . ldcc meets annually to review the results of current studies and recent advances in research on lyme disease. because the fda is responsible for evaluating the efficacy and safety of vaccines against lyme disease (e.g., the lymerix vaccine) and the cdc is especially interested in developing new and improved diagnostic procedures, representatives from fda and cdc have been invited to serve on the ldcc and to provide updates on their activities related to lyme disease. r c elisa diagnostic procedure. it has been shown that a synthetic peptide comprising amino acid residues (c ) derived from a variable surface antigen (v se) of b. burgdorferi can be used in a new, rapid, and extremely sensitive elisa test (the c elisa) for diagnosing lyme disease ( ) . the c elisa test is sensitive only to antibodies generated during an active infection (both early and late stages of lyme disease). another advantage of the test is its ability to detect antibodies specific for both north american and european strains of borrelia. of great importance is the fact that decreases in the titer of antibodies against c can be used as an indicator of the efficacy of antibiotic therapy for patients with localized or disseminated lyme disease, but not for chronic lyme disease. because the c elisa test would not detect antibodies specific for recombinant ospa, it can be used even for those patients who have been immunized with the licensed ospa-based lymerix vaccine ( ) . this is a major advance, because except for the c elisa no other laboratory test is capable of obtaining such information ( ). r an ecologic approach to preventing lyme disease. in a recently developed, ecologic approach to lyme disease prevention, researchers have intervened in the natural life cycle of b. burgdorferi by immunizing the wild whitefooted mouse (peromyscus leucopus), a reservoir host species, with either a recombinant antigen (ospa) of the spirochete or a negative control antigen in a repeated field experiment with paired experimental and control grids stratified by site ( ) . ospa vaccination significantly reduced the prevalence of b. burgdorferi in nymphal black-legged ticks (i. scapularis) collected at the sites the following year in both experiments. the magnitude of the vaccine's effect at a given site correlated with the prevalence of tick infection found on the control grid, which in turn correlated with mouse density. these data, as well as differences in the population structure of b. burgdorferi in sympatric ticks and mice, indicated that non-mouse hosts contributed more toward infecting ticks than previously expected. thus, where non-mouse hosts play a large role in the infection dynamics, vaccination should be directed at additional species ( ). r variable nature of antibodies specific for ospc influence virulence. the outer surface protein c (ospc) of b. burgdorferi, the spirochete that causes lyme disease, has been studied for its potential in the development of a vaccine ( ) . of the ospc types currently identified, a surprisingly large number (types a, b, c, d, k, n, and ) are associated with invasive disease. because a detailed knowledge of the antigenic structure of ospc would be essential for vaccine development, the antibody response against several different recombinant ospc proteins was examined in detail. the results have revealed a high degree of specificity, indicating that the immunodominant epitopes of ospc reside in the variable regions of the protein. to localize these epitopes, ospc fragments were generated and screened against serum collected from infected mice, thus allowing the identification of previously uncharacterized epitopes that define the type specificity of the ospc antibody response. the reported findings have provided valuable insights into the antigenic structure of ospc, as well as a basis for understanding the variable nature of the antibody response to this important virulence factor. the lyme disease spirochete, b. burgdorferi, is maintained in a tick-mouse cycle. evidence has demonstrated that the spirochete usurps a tick (i. scapularis) salivary protein, salp , to facilitate the infection of mice ( ) . the level of salp expression was selectively elevated by the presence of b. burgdorferi in i. scapularis. the salivary protein was shown to adhere to the spirochete and to specifically interact with b. burgdorferi's outer surface protein c. the binding of salp protected b. burgdorferi from antibody-mediated killing, thereby providing the spirochetes with a marked advantage when they were inoculated into naïve mice or mammals previously infected with b. burgdorferi. lyme disease. it has long been known that immunization of mice with outer surface protein a (ospa) will protect against transmission of b. burgdorferi infection and will reduce the carriage of this pathogen in feeding ticks. in a recent study, the development of a murine-targeted ospa vaccine using vaccinia virus to interrupt the transmission of disease in reservoir hosts has been reported ( ) . thus, oral vaccination with a single dose of the ospa-expressing vaccinia virus construct resulted in high antibody titers against ospa, % protection against infection by b. burgdorferi, and a significant clearance of b. burgdorferi from infected ticks that fed on immunized mice. the reported findings indicated that such a vaccine was effective and may provide a means to lower the incidence of human disease in endemic areas. acquisition and transmission of lyme disease by ticks. b. burgdorferi strains exhibit various degrees of infectivity and pathogenicity in mammals, which may be due to their relative ability to evade initial host immunity. innate immune cells recognize b. burgdorferi by toll-like receptors (tlrs) that use the intracellular molecule myeloid differentiation factor- (myd ) to mediate effector functions ( ) . in a mouse model of lyme disease using mutant strains of mice, the absence of myd was found to facilitate tick-transmission of strains of b. burgdorferi of both low and high infectivity ( ) . the reported data will broaden the understanding of factors that contribute the degree of pathogenicity observed between different clinical isolates of b. burgdorferi, as well as the genetic basis for host resistance or susceptibility to infection. tick-borne rickettsial diseases (tbrds) are caused by pathogens of the second main group (the spotted fever group) of the genus rickettsia (the other being the typhus group; see chapter ). tbrds continue to cause severe illness and death in otherwise healthy adults and children despite the availability of low-cost, effective antimicrobial therapy, and the reported incidence of tbrds has increased during the previous decade. the greatest challenge to clinicians is the difficulty of diagnosing these illnesses early in their clinical course when antibiotic therapy is most effective-early signs and symptoms are often nonspecific or mimic benign viral diseases, making diagnosis difficult ( ) . although clinically similar, the tbrds are epidemiologically and etiologically distinct diseases. in the united states, they include (i) human monocytotropic (or monocytic) ehrlichiosis (hme); (ii) human granulocytotropic (or granulocytic) anaplasmosis (hga; formerly known as human granulocytotropic ehrlichiosis or he); (iii) rocky mountain spotted fever (rmsf); (iv) ehrlichia ewingii infection; and (v) other emerging tbrds ( ) . additional diseases caused by the pathogenic members of the spotted fever group of rickettsia are the african tick typhus and rickettsial pox. it is interesting to note that the pathogenic tick-borne r. rickettsii, r. parkeri, and r. sibirica are phylogenetically distinct from the nonpathogenic species r. rhipicephali and r. montana. other species, such as r. felis and r. helvetica, are early diverging within the spotted fever group. the difference at the molecular level between the pathogenic and nonpathogenic species has not yet been completely elucidated. genome sequence of rickettsia conorii. complete genome sequence data has been generated for only one species of the spotted fever group, r. conorii ( ) . the genome of r. conorii is very small, only . mb, and similar to that of r. prowazekii (see chapter ) . the overall architecture of these two rickettsial genomes is essentially the same, with the exception of a few rearrangements near the terminus of replication. symmetric dna inversions at the regions surrounding the origins of replication and termination have been observed also in chlamydia ( ) . the symmetric nature of these rearrangements is thought to be the outcome of recombination events at the open replication forks. such translocation and inversion events have since been identified in a variety of genomes, suggesting that the replicating dna at the open replication fork is particularly vulnerable to recombination events ( ). appropriate antibiotic treatment should be initiated immediately after diagnosis is made based on clinical, laboratory, or epidemiologic findings ( ) . any delay in treatment may lead to severe disease and even a fatal outcome. because any of the tbrd pathogens is susceptible to tetracycline antibiotics (especially doxycycline), these drugs are considered the therapy of choice in nearly all clinical situations. fever typically subsides within to hours after doxycycline treatment is initiated during the first to days of illness ( ) . doxycycline is bacteriostatic against rickettsiae and is active in both children and adults. the recommended dose for adults is mg, twice daily (orally or intravenously). for children weighing less than lb ( . kg), the recommended dose is . mg/kg body weight, twice daily (orally or intravenously). intravenous administration is frequently indicated for hospitalized patients. the length of antibiotic therapy would be at least days after the fever subsides and until evidence of clinical improvement is noted (typically to days) ( ) . the tetracycline antibiotics are generally contraindicated for use in pregnant women because of risks associated with malformation of teeth and bones in the fetus and hepatotoxicity and pancreatitis in the mother ( , ) . however, tetracycline has been used successfully to treat hme in pregnant women ( ) , and its use may be warranted during pregnancy in life-threatening situations where clinical suspicion of tbrd is high. nevertheless, therapeutic choices for pregnant women with ehrlichiosis should be weighed cautiously, even when the benefits of doxycycline therapy generally outweigh its risks ( ) . chloramphenicol (no longer available as an oral formulation) is an alternative drug that has been used to treat tbrds such as rocky mountain spotted fever (rmsf) ( ) . however, the drug is associated with various side effects and may need monitoring of the patient's blood indices. moreover, epidemiologic studies using cdc case report data have suggested that patients with rmsf treated with chloramphenicol have a higher risk of dying than do patients who receive tetracycline ( , ) . whereas chloramphenicol is typically the preferred treatment for rmsf during pregnancy, care must be used especially when administering the drug late in the third trimester of pregnancy because of the risk of gray baby syndrome ( ). only the tetracycline antibiotics have demonstrated in vitro susceptibility and in vivo activity toward ehrlichia species. in spite of in vitro susceptibility against ehrlichia, the clinical effectiveness of rifampin is unknown ( ) . ehrlichia chaffeensis has demonstrated resistance to gentamicin, ciprofloxacin, penicillin, macrolides, and sulfacontaining drugs ( ). a substantial number of patients with tbrds may require hospitalization because of severe manifestations, including prolonged fever, renal failure, disseminated intravascular coagulopathy (dic), hemophagocytic syndrome, meningoencephalitis, and acute respiratory distress syndrome (ards) ( ) . a notable exception is anaplasmosis (hga), which has not been associated with meningoencephalitis. rocky mountain spotted fever frequently presents as a severe illness, during which patients commonly require hos-pitalization. up to % of untreated cases and % of treated cases have a fatal outcome, making rmsf the most often fatal rickettsial disease in the united states ( ) . host factors associated with severe or fatal rmsf include advanced age, male gender, black race, chronic alcohol abuse, and glucose- -phosphate dehydrogenase (g pd) deficiency ( ) . deficiency of g pd is a sex-linked genetic condition affecting approximately % of the u.s. black male population ( ) . deficiency of g pd is associated with a high proportion of fulminant cases of rmsf ( ) . fulminant cases follow a clinical course that is fatal within days of the onset of infection. long-term health effects of severe, life-threatening rmsf that may persist for more than year include partial paralysis of the lower extremities, gangrene requiring amputation (fingers, toes, arms, or legs), hearing loss, blindness, loss of bowel or bladder control, movement disorders, and speech disorders ( ) . similarly to rmsf, hme and hga can also cause serious or fatal illness, although at a lower frequency than that observed with rmsf. clinical conditions that may require hospitalization may include immunocompromised state, pain (headache, myalgia), mental confusion, cough, infiltrate in chest radiograph, abnormal spinal fluid findings, or specific acute organ failure ( ). it must be emphasized that during diagnosis, clinicians should be aware of the overlap of early symptoms of invasive meningococcal infection and tbrds. these conditions are difficult to distinguish early in the course of the illness. in patients for whom both conditions are included in the initial differential diagnoses, after performing blood cultures and lumbar puncture, empirical treatment for both diseases would be appropriate. such treatment could be accomplished by adding an appropriate parenteral penicillin (or cephalosporin) that has activity against neisseria meningitides to doxycycline therapy ( ). r. rickettsii, e. chaffeensis, e. ewingii, and a. phagocytophilum have specific and distinct cell tropism ( ) . r. rickettsii infects endothelial cells and, more rarely, underlying smooth muscle cells, where it multiplies freely in the cytoplasm. the rickettsiae cause a small-vessel vasculitis resulting in a maculopapular or petechial rash in the majority of patients. vasculitis, when occurring in organs (brain or lungs), could cause life-threatening complications ( ) . rickettsiae are not evident in blood smears and do not stain with the majority of conventional stains. ehrlichiosis and anaplasmosis are characterized by infection of leukocytes where the causative pathogens multiply in cytoplasmic membrane-bound vacuoles to form microcolonies known as morulae. e. chaffeensis most frequently infect monocytes, whereas a. phagocytophilum and e. ewingii demonstrate a predilection for granulocytes ( ) . morulae can be stained with conventional wright or giemsa stains and are occasionally observed in leukocytes in smears of peripheral blood, buffy coat preparations, or cerebrospinal fluid. although a routine blood smear can provide a presumptive clue for early diagnosis because of the visualization of morulae, still a confirmatory testing for ehrlichia or anaplasma species is required by serology, pcr, or immunostaining methods. also important to note is that the available methodology to demonstrate morulae in blood smears is not very sensitive, and a case of ehrlichiosis or anaplasmosis might be missed if the diagnosis relies solely on detecting morulae on blood smears. although the diagnostic sensitivity of blood smears is greater for hga than for hme, blood smears might only be positive in up to % of patients with hga ( ). since , the cdc has been tracking reported cases of several diseases collectively called human ehrlichiosis. however, the term "ehrlichiosis" is somewhat misleading, because when studied in detail it became clear that the etiologic agents of these emerging tick-borne infections are two different bacterial genera, ehrlichia and anaplasma. geographically, they have occurred primarily east of the rocky mountains ( , ) . in the united states, infections caused by ehrlichia spp. are typically transmitted by tick species of the genera amblyomma (a. americanum) and ixodes (i. scapularis and i. pacificus). both genera use small mammals and birds as their primary reservoirs ( ). morphologically, ehrlichia spp. are small intracellular gram-negative cocci that infect different hematopoietic cells, causing two etiologically and epidemiologically distinct forms of ehrlichiosis: human monocytic ehrlichiosis (hme) and human granulocytic anaplasmosis (hga). in the united states, most cases of both hme and hga occur in the spring and summer (april to september for hme, and may to august for hga), when ticks are at their peak ( ) . recently, the cdc has described a new group of diseases called "other and unspecified" human ehrlichiosis. these infections include diseases caused by a second ehrlichia species as well cases of previously mentioned illnesses that could not be definitely diagnosed as either hme or anaplasmosis ( , ) . the etiologic agent of human monocytic ehrlichiosis (hme) is ehrlichia chaffeensis (lone star tick), which infects the macrophages and monocytes. the pathogen is transmitted primarily by amblyomma americanum, but dermacentor variabilis (american dog tick) can also transmit the disease. the major reservoir for e. chaffeensis is the white-tailed deer, with most cases being reported in the south central and southeastern regions of the united states. hme has been mainly associated with males ( times more often than females), the elderly (over years of age), and immunocompromised hosts (hiv/aids patients, and those with asplenia or down's syndrome, and patients receiving immunosuppressive therapy) ( , , ) . clinical manifestations of hme include fever, headache, and rash presented as part of a prodrome consisting of abrupt, high-grade fever (> % of patients) often with an associated headache ( % to %), malaise ( % to %), nausea ( % to %), myalgia ( % to %), arthralgia ( % to %), lower back pain ( % to %), and gastrointestinal disorders ( % to %). the rash (on the trunk, extremities, and face, but rarely on the sole and palms) may be petechial, macular, maculopapular, or erythematous ( ) . the prodrome typically manifests itself to days (median days) after exposure to a tick. neurologic manifestations (symptoms of meningitis and encephalopathy) have been observed in approximately % of patients. laboratory findings of hme are characterized by reduction in the multiple hematopoietic cell lines (occurring early in the course of the disease), thrombocytopenia, and leukopenia. a large decline in the total lymphocyte count is often seen in the early stage of the disease, whereas lymphocytosis occurs later, during the recovery phase of hme. elevated liver enzyme levels (aspartate aminotransferase and alanine aminotransferase) are another characteristic laboratory finding of the disease and occur in % to % of patients ( ) . the manifestations of hme are typically moderate to severe and would require hospitalization of at least % of infected patients. if left untreated, hme may be fatal within the first weeks, especially in men, the immunocompromised, and the elderly ( ). the black-legged tick (ixodes scapularis) is the vector for anaplasma phagocytophilum in the new england and north central regions of the united states, whereas the western black-legged tick (ixodes pacificus) is the principal vector in northern california. because these ixodes species also transmit borrelia burgdorferi (the causative agent of lyme disease) and various babesia species, the preponderance of cases of hga occur in the same states that usually report high incidence of lyme disease and human babesiosis ( ) . simultaneous infection with a. phagocytophilum and b. burgdorferi has been reported ( , ) , and discerning such a mixed infection is vital because it might affect the choice of antimicrobial medication; whereas amoxicillin can be used to treat early stage of lyme disease, it is not effective against hga ( ) . in the absence of tick exposure, other modes of hga transmission have also been reported-butchers cutting fresh deer carcasses had contracted the disease ( ). this suggests blood as a potential source of transmission and represents a risk of occupational exposure. at-risk populations include the elderly, patients with chronic diseases (e.g., diabetes, collagen-vascular diseases), and patients on immunosuppressive therapy. hga is manifested as a constellation of nonspecific symptoms that occur after an incubation period of to days after tick exposure; generally to days elapse before a patient will seek medical care ( ) . the disease is commonly characterized by high-grade fever (over • c), rigors, nonspecific myalgia, severe headache, and malaise ( ). other symptoms may include nausea, nonproductive cough, arthralgia, and anorexia. although less common, % of patients with hga will present with rash ( ) , which is thought to be due to coinfection with lyme borreliosis ( ) . though associated with less morbidity and mortality than is hme, % of patients with hga will require hospitalization ( ). unlike patients with hme, those with hga may have normal blood cell counts ( ). nevertheless, approximately % of patients will have leukopenia and thrombocytopenia. increased levels of liver enzymes, in particular, hepatic transaminases and c-reactive protein, are also commonly observed. in general, laboratory abnormalities will reach their peaks within week after the onset of symptoms. during acute hga, morulae can be visualized (with microscopy) in the cytoplasm of leukocytes. this finding, if present, is diagnostic of hga. however, the absence of morulae does not exclude the diagnosis of hga ( ) . typically, the nonspecific disease presentation, lack of morulae, and the transient nature of the blood cell counts would make the diagnosis of hga difficult. as a result, the consensus approach for ehrlichiosis (cafe) society has developed a set of definitions to help clinicians with the diagnosis of hga ( , ) . although hme and hga are two distinct forms of human ehrlichiosis, the treatment is the same for both infections ( ). doxycycline is the primary agent recommended for treat-ment of hga. however, similarly to hme, doxycycline is contraindicated for pregnant women and children younger than age , posing a dilemma for clinicians treating these patients. data demonstrating the efficacy of rifampin in the treatment of ehrlichiosis in pregnant women are limited to just case reports ( ) . therapeutic choices for pregnant women with ehrlichiosis should be weighed cautiously, but the benefit of doxycycline therapy generally outweigh its risks ( ), and according to recommendations by the american academy of pediatrics and the cdc, doxycycline should be used in the treatment of children ( ) and neonates ( ) . it is recommended for children to start with oral doxycycline ( . mg/kg in divided doses) on day , followed by a single dose of . mg kg − day − ; the cdc is recommending the use of doxycycline . mg/kg in divided doses for children weighing less than kg, and mg twice daily (adult dose) for children weighing kg or more (http://www.cdc.gov/ncidod/dvrd/rmsf/treatment). in , rickettsia rickettsii was described in the blood vessels of infected patients and later identified as the etiologic agent of the rocky mountain spotted fever (rmsf). the rocky mountain spotted fever has long been established in the united states. in spite of its common name, it is relatively rare in the rocky mountain region but far more prevalent in the southeastern regions of the united states. most often the infection is transmitted by ticks of the genus dermacentor, which include the american dog tick (d. variabilis) in the eastern, central, and pacific coastal united states, and by the rocky mountain wood tick (d. andersoni) in the western united states. in , the common brown dog tick (rhipicephalus sanguineus), a vector in mexico, was also implicated in an arizona outbreak ( ) . the cayenne tick (amblyomma cajennense) is a common vector of rmsf in central and south america, and its range has extended into the united states in texas ( ) . a case report of rickettsia parkeri infection was recently published ( ) . the organism was first discovered in texas in amblyomma maculatum (gulf coast tick); before that, the disease had not been reported in humans. the main reservoirs for d. variabilis are small animals, such as mice and voles, and dogs and other large animals; and for d. andersoni, both small and large animals, typically wild rodents ( ). ticks become infected by feeding on infected animals, by transtadial and transovarian passage. humans are not a primary reservoir for r. rickettsii but are merely secondary hosts that enter the organism's life cycle tangentially through contact with arthropods. for humans to become infected with rickettsiosis, a tick may need to be attached for as little as to hours. however, attachment of hours or more is generally needed for transfer of the disease ( ). human infection may also result from contact with contaminated tick fluid and tissues during tick removal or from laboratory contact during culture and isolation. in cases reported to the cdc, approximately % occurred from april to september and % during the may to june period, although infections have occurred in every month ( ) . today, if left untreated, rmsf is the most fatal tick-borne infection in the united states, with an overall mortality of % ( ) . however, treatment with antibiotics has reduced the mortality rates to % to %, and this, in most cases, may be due to delay in the diagnosis of the disease. the causative agent of rmsf, r. rickettsii, has been included as a niaid category c biodefense priority pathogen. dogs are susceptible to rmsf, and they frequently develop the disease concurrently with other household members in an endemic area ( ) . the clinical and laboratory manifestations of rmsf are similar to those of hme and hga and generally appear within to days after a tick bite ( , ) . in rmsf, a rash typically appears to days after the onset of fever and will occur earlier in children than in adults; it is eventually observed in approximately % of children. the exanthema typically will begin with the appearance of small, blanching, pink macules on the ankles, wrists, or forearms that evolve to maculopapules. the classic centripetal spread of rash is typically not noticed by the patient and might be difficult to elicit from the clinical history ( ) . although the rash may expand to involve the entire body, its presence on the face is usually limited. patients with petechial rash are often severely ill, and although fever and organ dysfunction may resolve quickly with treatment, complete recovery can take longer. the rash progression of rmsf includes several critical exceptions and considerations as follows ( ): (i) a rash on the palms and soles is not pathognomonic and may occur in illnesses caused by drug hypersensitivity reactions, infective endocarditis, and a diverse group of other pathogens, including treponema pallidum, streptobacillus moniliformis, e. chaffeensis, and especially neisseria meningitides, as well as certain enteroviruses. (ii) the rash might be evanescent or localized to a particular region of the body. (iii) a rash might be completely absent or atypical in up to % of patients with rmsf. in certain cases, patients with rmsf (or ehrlichiosis) may seek medical attention for a febrile illness that mimics viral meningoencephalitis. focal neurologic deficits, including cranial or peripheral motor nerve paralysis or sudden transient deafness, may also be observed ( ) . laboratory findings, especially the complete blood cell count (cbc), are essential for the diagnosis of rmsf ( ) . the total white blood cell (wbc) count is typically normal in patients with rmsf, but increased numbers of immature bands are generally observed. thrombocytopenia, mild elevation in hepatic transaminases, and hyponatremia may be observed with rmsf. by comparison, leukopenia (up to % of patients), thrombocytopenia (up to % of patients), and modest elevation of liver transaminase levels are particularly suggestive for hme and hga ( ) . patients with rmsf may have various signs and symptoms that differ in degree of severity ( , ) . orally given antibiotics are adequate in cases of mild illness, whereas severely ill patients should be hospitalized and treated with intravenous antibiotics. in a retrospective study, information based on multivariate analysis has shown that only increased serum creatinine levels and neurologic symptoms were associated with mortality ( ) . the clinical outcome of rmsf is apparently strongly dependent on the time span between the patient's first visit and the start of therapy; if therapy had begun more than days after the first visit, the outcome is significantly poorer than if treatment had been initiated earlier. the tetracyclines are the cornerstone of therapy for rmsf, with doxycycline being the drug of choice ( , ) . however, as with ehrlichiosis, the use of doxycycline in pediatric and pregnant patients again poses a problem. generally, short courses of doxycycline may be administered in children younger than years of age. however, according to the guidelines of the american academy of pediatrics and the cdc, the empiric use of doxycycline in children and pregnant women, although possible, should be applied with caution and with careful consideration for maternal hepatotoxicity and permanent tooth discoloration. chloramphenicol has long been recommended as an alternative therapy for rmsf and is considered a suitable choice for patients who are pregnant or allergic to tetracyclines ( ). however, the adverse effects of chloramphenicol are well known: aplastic anemia, reversible bone marrow suppression, and gray baby syndrome ( ) . moreover, the chloramphenicol concentrations and reticulocyte counts should be monitored when the treatment exceeds days. clearly, the administration of either doxycycline or chloramphenicol in pregnant women is not without risks. amblyomma americanum is also the principal vector of the ehrlichial pathogen ehrlichia ewinglii ( ) . the ecologic features of e. ewinglii are not completely known. however, dogs and deer have been naturally infected. cases of granulocytotropic ehrlichiosis caused by e. ewinglii have been reported primarily in immunocompromised hosts. human infections with this pathogen have been reported throughout the range of the lone star tick ( ) . early clinical presentations in patients with e. ewinglii include fever, headache, myalgia, and malaise, and they are difficult to distinguish from other tbrds and noninfectious diseases ( ) . as in patients with hga, rash is rare in patients with e. ewinglii infection, and blood smears are useful for identifying patients with e. ewinglii. furthermore, evaluation of csf in patients with e. ewinglii has shown neutrophilic pleocytosis ( ) . appropriate antibiotic treatment should be initiated immediately when a diagnosis of e. ewinglii is made. doxycycline is the drug of choice for both children and adults, and as with the treatment of other tbrds, caution must be applied when doxycycline is used for the treatment of e. ewinglii ( ) . the first report of tularemia in the united states occurred in , in tulare county, california ( ) . one year later, the pathogen responsible for this outbreak was isolated and named bacterium tularense ( ) . the first report of tularemia in humans occurred in in two patients bitten by deerfly ( ) . the infection is transmitted by ticks and is passed transovarially among ticks. in , the organism was renamed francisella tularensis. f. tularensis is a highly contagious organism, which, in the context of biological weapons defense, is considered to be a potential threat. in fact, a tularemia outbreak in before the battle of stalingrad was the result of weaponized f. tularensis. there is no person-to-person transmission, but tularemia delivered as an aerosol could infect a large number of people. ecologically, tularemia is a disease of the northern hemisphere (north america, northern asia, scandinavia, europe, japan, and russia). in addition to transmission by ticks and other arthropods, f. tularensis can be transmitted by inhalation, ingestion of contaminated food or drinking water supplies, and animal bites ( ) . more than animal species are implicated as carriers of f. tularensis. consequently, in different regions of the world the disease is known by different names (rabbit fever, hare fever, deerfly fever, and lemming fever). in the united states, when transmitted by ticks, f. tularensis is primarily transmitted by a. americanum, d. andersoni, and d. variabilis ( ) . except for hawaii, all states have reported cases of tularemia, with the highest rates coming from arkansas, missouri, south dakota, and oklahoma. the disease has a predilection for males, especially native americans and alaskan natives, and children age to and adults age or older. most human outbreaks occur in spring and summer, which correlates with arthropod transmission ( , ). the bacteriology and taxonomy of f. tularensis is complex ( ) . it is a small, pleomorphic, aerobic, gram-negative coccobacillus that can be found both inside and outside of cells. the genus francisella is divided into three major biovars. biovar a (biogroup tularensis) predominates in north america and is the most virulent. biovar b (biogroup holarica) is found primarily in europe and asia, but also exists in north america. biovar c (biogroup novicida; formerly known as f. novicida) is found in parts of north america and has very low virulence ( ). the clinical course of tularemia is quite diverse, ranging from asymptomatic disease to septic shock and death ( ) . typically, tularemia is divided into six forms, reflecting the mode of transmission: (i) ulceroglandular; (ii) glandular; (iii) oculoglandular; (iv) oropharyngeal; (v) pneumonic (pleuritic); and (vi) typhoidal. tularemia is characterized by abrupt but nonspecific symptoms, such as fever, chills, headache, vomiting, fatigue, and anorexia, which make the disease difficult to diagnose. pulse-temperature disparity in which the patients may exhibit a high temperature without reflexive increase in pulse is a hallmark manifestation of the disease ( ) . ulceroglandular tularemia is the most common syndrome, accounting for % to % of f. tularensis infections. the pathogen enters through a scratch, abrasion, or tick and spreads via the proximal lymphatic system. as few as organisms can cause disease. this syndrome usually appears as a papule at the tick-bite site and progresses to a pustular, ulcerated lesion called an inoculation eschar ( ) . glandular tularemia is a relatively rare syndrome ( % of patients) with no ulcer present. the organism causes regional lymphadenopathy and is presumed to have gained access to the host through clinically unapparent abrasion ( ) . diagnosis may be difficult because the patient presents one or several enlarged lymph nodes with no skin lesion. oculoglandular tularemia occurs in approximately % of patients and results from inoculation of the eye by tularemiacontaminated fluids or fingers, perhaps after removal of the tick ( ). the clinical manifestations of oculoglandular tularemia are conjunctivitis with adjacent lymph node involvement, periorbital edema, and erythema. oropharyngeal tularemia accounts for less than % of all cases. this syndrome is not acquired by contact with ticks but results from ingestion of infected raw meats or contaminated water supplies ( ). symptoms include fever, exudative pharyngitis, or oropharyngeal ulcerations. because the manifestations mimic those of other upper respiratory infections, the diagnosis of oropharyngeal tularemia is based on exclusion from lack of response to antibiotics given for bacterial pharyngitis. pneumonic tularemia, the most severe form of the infection, may not be directly associated with tick exposure, but rather can develop through inhalation or secondarily by hematogenous spread ( ) . disease mortality is estimated to be around % ( ) . typhoidal tularemia is a rare syndrome ( ) manifested by fever, chills, and local findings to culture-negative septic shock. the syndrome may also be accompanied by pneumonia, elevated transaminase levels, and rhabdomyolysis, which leads to renal failure ( ) . the diagnosis of tularemia is confirmed when an antibody response occurs approximately weeks after the onset of disease. the preferred serologic methods are agglutination (latex or tube agglutination tests) or pcr. the latter is highly sensitive and safer, but its specificity is dependent on the dna sample and its purity ( ). treatment of tularemia is based solely on case reports and anecdotal experience. based on the latter, aminoglycosides, especially streptomycin and gentamicin, are regarded as the cornerstone of therapy ( ). a meta-analysis found that streptomycin was successful in % of patients, whereas gentamicin was successful in % ( ) . in addition, gentamicin was associated with a % relapse rate and an % failure rate. however, despite these drawbacks of gentamicin, its cure rate was equal to or greater than that of other classes of antimicrobials, thus making it an acceptable alternative to streptomycin. results from tetracycline therapy of tularemia have shown % success and no treatment failures; however, it was associated with % relapse rate ( ) . the high relapse rate of tetracycline may be the result of its bacteriostatic mode of action. in addition, tetracycline can be given only orally, which limits its use in patients with severe tularemia-the drug levels achieved with oral administration only minimally exceeded the minimum inhibitory concentration (mic) for f. tularensis. in patients treated with chloramphenicol, the success rate was % with a % relapse rate ( ) . like tetracycline, chloramphenicol is bacteriostatic. however, when compared with aminoglycosides and tetracycline, one advantage of chloramphenicol is its enhanced penetration into the central nervous system. this feature makes chloramphenicol a therapeutic option for treatment of meningeal tularemia. the fluoroquinolones are another therapeutic option for treating tularemia. ciprofloxacin and levofloxacin have been used in the treatment of pneumonic tularemia, with the former showing a low failure rate and fewer adverse effects ( ) , and no relapses (levofloxacin) year later. although data describing the efficacy of fluoroquinolones in the treatment of tularemia are still evolving, these agents have been as successful as other treatments of the disease ( ). in vitro data demonstrated that f. tularensis isolates have shown resistance to β-lactams and therefore they should not be recommended for treatment of tularemia ( ). erythema migrans, the characteristic rash associated with lyme disease, has been reported in patients living in the south central and southeastern united states. typically, it is associated with the bite of amblyomma americanum. however, the spirochete that causes lyme disease in north america, borrelia burgdorferi sensu stricto, has not been confirmed in these regions of the united states by culture from clinical specimens, and serum antibodies rarely indicate exposure ( ) . although amblyomma americanum is apparently not a vector for b. burgdorferi sensu stricto, the same ticks carry another spirochete, borrelia lonestari. in a case report ( ), a patient was described with erythema migrans and amblyomma americanum attachment. importantly, borrelia lonestari was identified both in the patient and the tick, and serology for b. burgdorferi sensu stricto was negative. therefore, this observation strongly suggested that amblyomma americanum can transmit the spirochete to humans, and the resulting rash, which resembled that seen with lyme disease, has become known as southern tick-associated rash illness (stari). borrelia lonestari (family treponemataceae) is a spirochete that has been detected in amblyomma americanum by dna analysis. unlike ixodes scapularis, a vector for lyme disease, amblyomma americanum is less likely to be infected with a spirochete, with only % to % of amblyomma americanum infected ( ) . in contrast, % to % of nymph stage ticks and % to % of the adult-stage ticks of i. scapularis are infected with a spirochete. the natural reservoir for b. lonestari has not been identified even though it was detected in white-tailed deer. in the only published case report of stari, the patient showed only mild symptoms, such as fatigue, cough, and right shoulder discomfort ( ) . fever and headache were absent, and results of musculoskeletal, neurologic, pulmonary, and cardiac examinations were normal. two erythematous lesions were also noted. the only abnormal laboratory finding was a slightly elevated serum alkaline phosphatase level. there is no specific serologic test for exposure to b. lonestari ( ) . in the only case reported, the patient underwent antibiotic therapy with doxycycline for weeks ( ); the skin lesions resolved in days, and the patient returned to health about days after therapy was initiated. babesiosis, a malaria-like disease caused by intraerythrocyte protozoa named babesia bigemina, was first described in ( ) . the parasite is also the cause of the texas cattle fever ( ). the first case of babesiosis in humans was reported in the former republic of yugoslavia in and in the united states in the late s ( ). the babesia protozoa may vary in size ( to μm) and can be oval, round, or pear shaped ( ) . more than different species have been identified, but only four have been reported to be pathogenic in humans. in the united states, infection is caused primarily by b. microti, and two new strains of babesia that can cause infection are designated as wa- and mo- . although human infections in the united states caused by b. divergens have not been reported, this protozoa is the primary cause of babesiosis in europe ( ). in the northeastern united states, the primary vector for b. microti is ixodes scapularis, and the primary reservoir is the white-footed mouse. although all stages of i. scapularis feed on humans, the nymph-stage tick is typically responsible for transmission of b. microti in humans. vectors and reservoirs for wa- and mo- have not been identified ( ) . while babesiosis infections have been observed in patients of all ages, it appears that the occurrence is higher in men, and persons older than years are prone to more severe infection. the infection is contracted most commonly during the summer (june to august) ( ). like malaria, the babesia species reproduce within the red blood cells and produce hemolysis, which is responsible for the clinical presentation of babesiosis ( ) . manifestations of the disease are diverse and may range from asymptomatic to fulminant, leading to prolonged illness and even death. although in the united states most cases of babesiosis are subclinical, when patients become symptomatic, manifestations usually appear after an incubation period of to weeks. the most common symptoms include fever ( % of patients), fatigue ( %), chills ( %), and headache ( %). less often, myalgia, anorexia, cough, nausea, vomiting, arthralgia, emotional liability, depression, sore throat, abdominal pain, conjunctival injection, photophobia, and weight loss have been reported ( ) . physical findings are generally nonspecific (high fever, mild splenomegaly, and hepatomegaly). unlike other tick-borne infections, rash is not common in babesiosis. the most common complications in patients with severe babesiosis are acute respiratory failure ( % of patients), disseminated intravascular coagulation ( %), heart failure ( %), coma ( %), and renal failure ( %). babesiosis is fatal in % to % of cases ( ) . laboratory findings may include a decreased hematocrit value, thrombocytopenia, and a normal or decreased white blood cell count. elevated levels of hepatic transaminases, bilirubin, and lactate dehydrogenase have also been observed. urinalysis may reveal proteinuria and hemoglobinuria ( ). most cases of human babesiosis in the united states are mild and may resolve without treatment ( ). however, therapy is required in those patients who have undergone splenectomy, are immunosuppressed, are elderly, or have significant symptoms. historically, the cornerstone of babesiosis therapy is a combination of clindamycin and quinine given for period of to days ( ). however, even though effective, the combination clindamycin-quinine has been associated with significant drug-related toxicities, such as hearing loss, tinnitus, vertigo, and diarrhea. atovaquone, an antiprotozoal drug, has been studied in combination with azithromycin for the treatment of b. microti infections ( ) . the atovaquone-azithromycin combination was compared with a -day oral treatment with clindamycin-quinine in immunocompetent adults with nonlife-threatening babesiosis ( ) . resolution of parasitemia and symptoms was similar in both groups; however, the adverse reactions were significantly less in patients receiving atovaquone-azithromycin ( %) than in those receiving clindamycin-quinine ( %). another drug combination found effective in the treatment of babesiosis was clindamycin-doxycycline-azithromycin in an aids patient who developed an allergy to quinine ( ) . the combination of sulfamethoxazole-trimethoprimpentamidine has been used successfully in the treatment of b. divergens ( ) . exchange transfusions, administered concurrently with antibiotic therapy, may be necessary for patients with severe babesiosis showing significant parasitemia (more than %), coma, hypotension, heart failure, pulmonary edema, or renal failure ( ) . exchange transfusions reduce parasitemia and will facilitate the removal of babesia-, erythrocyte-, and macrophage-produced by-products ( ). in , tick-borne relapsing fever (tbrf) was first described in west africa where it was transmitted by ornithodoros moubata soft ticks ( ) . tick-borne relapsing fever (tbrf) is a systemic borrelia infection caused by a group of closely related species of spirochetes: b. hermsii, b. turicatae, and b. parkeri. ( ) . tbrf is endemic in the western united states. it occurs sporadically, but several common source epidemics have been reported. as with other tick-borne diseases, tbrf is a seasonal illness; % of reported cases have occurred during the june to september period. however, in texas most episodes occur during the late autumn and early winter, with % reported from november to january ( ). this difference in seasonality may be related to differences in both organisms and habitats; in texas, cases typically represent b. turicatae infections acquired in caves, whereas in the northwestern united states, cases are generally b. hermsii infections acquired in mountainous regions ( ) . these spirochetes possess the unique ability to change outer surface proteins under pressure from the host immune system in a process known as antigenic variation, a phenomenon responsible for the recurring nature of the disease ( ) . thus, borreliae will sequester themselves in internal organs during afebrile periods and then will reappear with modified surface antigens to evade eradication. as borrelia organisms invade the endothelium, this can produce a low-grade, disseminated intravascular coagulation and thrombocytopenia. the relapse phenomenon occurs because of the antigenic variation-a genetically programmed shifting of outer surface proteins of borrelia that allows a new clone to avoid destruction by antibodies directed initially against the majority of the original infecting organisms. as a result, the patient will improve clinically until the new clone multiplies sufficiently to cause another relapse. the tick-borne illness tends to have more relapses (average of ) than does the louse-borne variety (often just one relapse). relapsing fever (rf) is an infectious disease transmitted to humans by two vectors, ticks and lice. the human body louse, pediculus humanus, is the specific vector for borreliae. pediculus pubis is not a vector. louse-borne relapsing fever is a more severe form than the tick-borne variety. regardless of the mode of transmission, a spirochetemia will develop. the louse-borne relapsing fever is caused by borrelia recurrentis. no animal reservoir exists. the lice that feed on infected humans acquire the borrelia organisms, which then multiply in the gut of the louse. when an infected louse feeds on an uninfected human, the organism gains access when the victim crushes the louse or scratches the area where the louse is feeding. b. recurrentis infects the person through either abraded or intact skin (or mucous membranes) and then invades the bloodstream. because ornithodoros ticks feed so rapidly, patients with tbrf are often unaware of the tick bite. a pruritic eschar may develop at the soft tick attachment site ( ). symptoms will appear abruptly on average days after tick exposure ( ) . common manifestations include fever, headache, myalgia, arthralgia, nausea, and vomiting. the primary febrile period when the temperature can rise as high as • f (or even higher) lasts about days (range, hours to days). patients then experience an afebrile period lasting about week, during which time they may experience malaise before symptoms suddenly recur. without treatment, several (three to five) relapses can be expected. however, the length and severity of the illness will typically decrease with each relapse ( ) . less common symptoms of tbrf include abdominal pain, confusion, dry cough, eye pain, diarrhea, dizziness, photophobia, and neck pain. rash (petechial, macular, or popular) occurs in about % of patients and develops as the fever subsides. other physical findings can be splenomegaly and hepatomegaly ( ) . neurologic complications (neuroborreliosis) will occur predominately in patients infected with b. turicatae ( % to %), but much less in patients infected with b. hermsii ( %). the most common manifestations of neuroborreliosis are cranial nerve palsies and meningisms ( ) . rare complications of tbrf are ocular disorders, myocarditis, and ruptured spleen ( ) . the most common hematologic abnormalities are thrombocytopenia ( % of patients), proteinuria ( %), and hematuria ( %). most patients with tbrf have a normal white blood cell count. no controlled studies have been published regarding treatment of tbrf. based on clinical experience, the tetracycline antibiotics have been the treatment of choice ( ( , ) . oral doxycycline, mg every hours for to days, is the typical treatment. in addition, penicillin, chloramphenicol, and erythromycin have all been used successfully to treat tbrf. tetracycline, erythromycin, and chloramphenicol are usually administered at dosages of mg every hours ( ) . patients with meningitis should receive intravenous therapy with penicillin g, cefotaxime, or ceftriaxone for days or more ( ). the jarisch-herxheimer reaction is a serious consequence of tbrf treatment. it is manifested as an acute exacerbation of the patient's symptoms that can occur with the start of the antibiotic treatment. it has been reported in more than % of patients treated for tbrf ( ) . the pathophysiology of the jarisch-herxheimer reaction has been studied most extensively in patients with louse-borne relapsing fever. the reaction is associated with transient increases in plasma concentrations of tumor necrosis factor-α (tfn-α), interleukin- , and interleukin- ( ) . anti-tnf-α antibodies prevented this reaction in patients with louse-borne relapsing fever ( ) . furthermore, meptazinol, an opioid partial agonist, reduced the severity of symptoms, whereas naloxone was ineffective ( ) . tick-borne bacterial, rickettsial, spirochetal, and protozoal infectious diseases in the united states: a comprehensive review ticks and tickborne bacterial diseases in humans: an emerging infectious threat tick-borne bacterial diseases emerging in europe lyme disease-united states the emergence of lyme disease temporal changes in outer surface proteins a and c of the lyme disease-associated spirochete borrelia burgdorferi, during the chain of infections in ticks and mice bpta (bbe ) is essential for the persistence of the lyme disease spirochete, borrelia burgdorferi, in its natural tick vector iii ( ) neuropathy and cognitive impairment following vaccination with the ospa protein of borrelia burgdorferi practice guidelines for the treatment of lyme disease evaluation of the c peptide enzyme-linked immunosorbent assay for individuals vaccinated with the recombinant ospa vaccine lyme disease-a tick-borne spirochete? lack of evidence of borrelia involvement in alzheimer's disease two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of lyme disease cognitive function in post-treatment lyme disease: do additional antibiotics help? study and treatment of post lyme disease (stop-ld): a randomized double masked clinical trial genotypes determine phenotype in experimental lyme disease increased expression of b-lymphocyte chemoattractant but not pro-inflammatory cytokines, in muscle tissue in rhesus chronic lyme borreliosis the chemokine cxcl (blc): a putative diagnostic marker for neuroborreliosis detection of attenuated, noninfectious spirochetes of borrelia burgdorferi-infected mice after antibiotic treatment identification of candidate t-cell epitopes and molecular mimics in chronic lyme disease antibodies against ospa epitopes of borrelia burgdorferi cross-react with neural tissue evidence of borrelia autoimmunity-induced component of lyme carditis and arthritis homologies betwen proteins of borrelia burgdorferi and thyroid autoantigens a case-control study to examine hla haplotype associations in patients with posttreatment chronic lyme disease increased arthritis severity in mice coinfected with borrelia burgdorferi and babesia microti coinfection with borrelia burgdorferi and the agent of human granulocytic ehrlichiosis alters the murine immune responses, pathogen burden, and severity of lyme arthritis controlled trials of antibiotic treatment in patients with post-treatment chronic lyme disease, vector borne zoonotic dis cytolethal distending toxin is essential for colonization of helicobacter hepaticus in outbread swiss webster mice characterization of a borrelia burgdorferi vlse invariable region useful in canine lyme disease serodiagnosis by enzyme-linked immunosorbent assay intralaboratory reliability of serologic and urine testing for lime disease critical evaluation of urine-based pcr assay for diagnosis of lyme borreliosis pretreatment and post-treatment assessment of the c test in patients with persistent symptoms and a history of lyme borreliosis comparison of western immunoblotting and the c lyme antibody test for laboratory detection of lyme disease a decline in c antibody titer occurs in successfully treated patients with culturecontrolled early localized or early disseminated lyme borreliosis detection of immune complexes is not independent of detection of antibodies in lyme disease patients and does not confirm active infection with borrelia burgdorferi a plasmid-encoded nicotinamidase (pnca) is essential for infectivity of borrelia burgdorferi in a mammalian host identification of borrelia burgdorferi outer surface protein tro-spa, and ixodes scapularis receptor for borrelia burgdorferi an ecological approach to preventing human infection: vaccinating wild mouse reservoirs intervenes in the lyme disease cycle the lyme disease agent exploits a tick protein to infect the mammalian host and the tick-borne infection study group ( ) hypersensitivity to ticks and lyme disease risk adverse event reports following vaccination against lyme disease protective efficacy of an oral vaccine to reduce carriage of borrelia burgdorferi (strain n ) in mouse and tick reservoirs demonstration of ospc type diversity in invasive human lyme disease isolates and identification of previously uncharacterized epitopes that define the specificity of the ospc murine antibody response toll like receptors: molecular structure and functional role in innate and adaptive immunity myd deficiency enhances acquisition and transmission of borrelia burgdorferi by ixodes scapularis ticks diagnosis and management of tickborne rickettsial diseases: rocky mountain spoted fever, ehrlichioses, and anaplasmosis-united states obligate intracellular pathogens genome rearrangement by replication-directed translocation rickettsia rickettsii human monocytic ehrlichiosis presenting as acute appendicitis during pregnancy rickettsia rickettsii and other spotted fever group rickettsiae (rocky mountain spotted fever and other spotted fevers) analysis of risk factors for fatal rocky mountain spotted fever: evidence for superiority of tetracyclines for therapy clinical and laboratory characteristics of human granulocytic ehrlichiosis in vitro antibiotic susceptibility of the newly recognized agent of ehrlichiosis in humans, ehrlichia chaffeensis rocky mountain spoted fever in the united states long-term sequelae of rocky mountain spotted fever human granulocytic ehrlichiosis human ehrlichiosis in the united states ehrlichia chaffeensis: a prototypical emerging pathogen simultaneous human granulocytic ehrlichiosis and lyme borreliosis exposure to deer blood may be the cause of human granulocytic ehrlichiosis diagnosing human ehrlichiosis: current status and recommendations rocky mountain spotted fever: a clinician's dilemma perinatal transmission of the agent of human granulocytic ehrlichiosis rickettsia parkeri: a newly recognized cause of spotted fever rickettsiosis in the united states family cluster of rocky mountain spotted fever predictors of prognosis and risk of acute renal failure in patients with rocky mountain spotted fever rocky mountain spotted fever and pregnancy: a case report and review of the literature ehrlichia ewingii, a newly recognized agent of human ehrlichiosis tularemia: a -year experience with cases ulceroglandular tularemia in a nonendemia area tularemia and q fever tularemia: united states streptomycin and alternative agents for the treatment of tularemia: review of the literature tularemia epidemic in northwestern spain: clinical description and therapeutic response borrelia lonestari infection after a bite by an amblyomma americanum tick borrelia lonestari dna in adult amblyomma americanum ticks severe babesiosis in long island: review of cases and their complications atovaquone and azithromycin for the treatment of babesiosis treatment of transfusion-transmitted babesiosis by exchange transfusion tick-borne relapsing fever in north america antigenic variation of a relapsing fever borrelia species relapsing fever: a clinical and microbiological review tick-borne relapsing fever in the northwestern united states and southwestern canada the spectrum of relapsing fever in the rocky mountains neuroborreliosis during relapsing fever: review of the clinical manifestations, pathology, and treatment of infections in humans and experimental animals detection of plasma tumor necrosis factor, interleukins and , during the jarisch-herxheimer reaction of relapsing fever prevention of jarisch-herxheimer reactions by treatment with antibodies against tumor necrosis factor meptazinol diminishes the jarisch-herxheimer reaction of relapsing fever key: cord- - zbe qmd authors: abeyratne, ruwantissa title: the epassport — new technology to counter security threats date: - - journal: nan doi: . /s - - -z sha: doc_id: cord_uid: zbe qmd the epassport is the culmination of a sustained process of development of technical specifications for machine readable travel documents (mrtd). it introduces a new dimension to aviation security in that, within the conventional machine readable passport with its machine readable zone, an additional layer of verification of information contained in an electronic chip is placed, which verifies the information in the passport’s machine readable zone by the use of a special reader. much research has gone into the areas of the technology and verification in the development of the epassport. at a symposium held at the international civil aviation organization in early october , the epassport was subjected to much discussion by the various experts gathered from across the globe. this article discusses these deliberations and places them against the backdrop of the privacy of the individual and aviation security law. over states are currently producing and using epassports and there are approximately million in circulation. this accounts for % of all passports used globally. the additional feature that the epassport carries in the conventional machine readable passport is a chip containing biometric and biographic information which have to be validated accurately, efficiently and quickly while retaining the security and integrity of the information. ideally, an epassport should be issued in accordance with the technical specifications approved by the international civil aviation organization (icao). however, this does not happen in all cases of issuance of epassports. this lapse could seriously compromise global security. the nuances of this threat are described and discussed in this article against their legal background. at a recent symposium on machine readable travel documents, biometrics and security standards held at icao on to october , experts addressed icao machine readable travel documents (mrtd) standards and specifications, identity management best practices and related border security issues. foremost among these discussions was the epassport, which is defined by icao as a passport which has a contactless integrated circuit (ic) chip within which is stored data from the machine readable passport page, a biometric measure of the passport and a security object to protect the public key infrastructure (pki) cryptographic technology, and which conforms to the specifications of doc part . the icao facilitation manual defines the epassport as a machine readable passport that has a contactless integrated circuit embedded in it and the capability of being used for biometric identification of the machine readable passport holder in accordance with the standards specified in the relevant part of icao document (machine readable travel documents). epassports are easily recognised by the international epassport symbol on the front cover. it is important to note that the operative terms in the definition of the epassport are "biometric identification" and "public key infrastructure (pki) cryptographic technology". biometric technology involves a measurable, physical characteristic or personal behavioral trait used to recognize the identity, or verify the claimed identity of a person. biometric identification has been defined as "a generic term used to icao is the specialized agency of the united nations handling issues of international civil aviation. icao was established by the convention on international civil aviation, signed at chicago on december (chicago convention). one of the overarching objectives of icao, as contained in article of the convention is to foster the planning and development of international air transport so as to meet the needs of the peoples for safe, regular, efficient and economical air transport. icao has member states, who become members of icao by ratifying or otherwise issuing notice of adherence to the chicago convention. see icao doc / ninth edition . machine readable travel documents part volume icao doc sixth edition: , at page ii- at paragraph . , definitions. see the facilitation manual, doc , icao: montreal, first edition , definitions at x. icao has been working on the development of passports since . the seventh session of the icao facilitation division in recommended that a small panel of qualified experts including representatives of the passports and/or other border control authorities, be established: to determine the establishment of an appropriate document such as a passport card, a normal passport or an identity document with electronically or mechanically readable inscriptions that meet the requirements of document control; the best type of procedures, systems (electronic or mechanical) and equipment for use with the above documents that are within the resources and ability of member states; the feasibility of standardizing the requisite control information and methods of providing this information through automated processes, provided that these processes would meet the requirements of security, speed of handling and economy of operation. http://www.dhs.gov/xtrvlsec/programs/content_multi_image_ .shtm to "verify" means to perform a one-to-one match between proffered biometric data obtained from the holder of the travel document at the time of inquiry with the details of a biometric template created when the holder enrolled in the system. describe automated means of recognizing a living person through the measurement of distinguishing physiological or behavioural traits". biometrics target the distinguishing physiological or behavioral traits of the individual by measuring them and placing them in an automated repository such as machine encoded representations created by computer software algorithms that could make comparisons with the actual features. physiological biometrics that have been found to successfully accommodate this scientific process are facial recognition, fingerprinting and irisrecognition which have been selected by icao as being the most appropriate. the biometric identification process is fourfold: firstly involving the capture or acquisition of the biometric sample; secondly extracting or converting the raw biometric sample obtained into an intermediate form; and thirdly creating templates of the intermediate data is converted into a template for storage; and finally the comparison stage where the information offered by the travel document with that which is stored in the reference template. biometric identification gets into gear each time an mrtd holder (traveler) enters or exists the territory of a state and when the state verifies his identity against the images or templates created at the time his travel document was issued. this measure not only ensures that the holder of the document is the legitimate claimant to that document and to whom it was issued, but also enhances the efficacy of any advance passenger information (api) system used by the state to pre-determine the arrivals to its territory. furthermore, matching biometric data presented in the form of the traveler with the data contained in the template accurately ascertains as to whether the travel document has been tampered with or not. a three way check, which matches the traveler's biometrics with those stored in the template carried in the document and a central database, is an even more efficacious way of determining the genuineness of a travel document. the final and most efficient biometric check is when a four way determine is effected, were the digitized photograph is visually matched (non electronically) with the three way check described above. in this context, it is always recommended that the traveler's facial image (conventional photograph) should be incorporated in the travel document along with the biometric templates in order to ensure that his identity could be verified at locations where there is no direct access to a central database or where the biometric identification process has not entered into the legal process of that location. machine readable travel documents part volume , supra note at page ii- at paragraph . . the chicago convention, supra, note , defines, in article , "territory of a state" as the land areas and territorial waters adjacent to the state under the sovereignty, suzerainty, protection and mandate of such state. api involves exchange of data information between airlines and customs authorities, where an incoming passenger's essential details are notified electronically by the airline carrying that passenger prior to his arrival. the data for api would be stored in the passenger's machine readable passport, in its machine readable zone. this process enables customs authorities to process passengers quickly, thus ensuring a smoother and faster clearance at the customs barriers at airports. one of the drawbacks of this system, which generally works well and has proven to be effective, is that it is quite demanding in terms of the high level of accuracy required. one of the major advantages, on the other hand, is the potential carried by the api process in enhancing aviation security at airports and during flight. see abeyratne ( a, b) issuing states must ensure the accuracy of the biometric matching technology used and functions of the systems employed if the integrity of the conducted checks are to be maintained. they must also have realistic and efficient criteria regarding the number of travel documents checked per minute in a border control situation and follow a regular biometric identification approach such as facial recognition, fingerprint examination or iris identification system. public key infrastructure (pki) cryptographic technology pki cryptographic technology uses a brand new technique known as quantum cryptography, designed to eliminate the terrifying vulnerabilities that arise in the way digitally stored data are exposed to fraudulent use. this new technique uses polarized photons instead of electronic signals to transmit information along cables. photons are tiny particles of light that are so sensitive that when intercepted, they immediately become corrupted. this renders the message unintelligible and alerts both the sender and recipient to the fraudulent or spying attempt. the public key directory -designed and proposed to be used by customs and immigration authorities who check biometric details in an electronic passport, is based on cryptography -and is already a viable tool being actively considered by the aviation community as a fail-safe method for ensuring the accuracy and integrity of passport information. in order to assure inspecting authorities (receiving states) that they would know when the authenticity and integrity of the biometric data stored in the mrtd, which they inspect, are compromised and tampered with, the public key infrastructure (pki) scheme was developed by the tag/mrtd, which has been pioneering work on the mrtd for over a decade. the scheme is not calculated to prescribe global implementation of public key encryption, but rather acts as a facilitator enabling states to make choices in areas such as active or passive authentication, antiskimming and access control and automated border crossing, among other facilitative methods. the establishment of a public key directory, through means of public key cryptology and in a pki environment, is consistent with icao's ultimate aim and vision for the application of biometric technology on the fundamental postulate that there must be a primary interoperable form of biometric technology for use at border control with facilities for verification, as well as by carriers and the issuers of documents. this initial premise is inevitably followed by the assumption that biometric technologies used by document issuers must have certain specifications, particularly for purposes of identification, verification and the creation of watch lists. it is also icao's vision that states, to the extent possible, are protected against changing infrastructure and changing suppliers, and that a technology, once put in place, must be operable or at least retrievable for a period of ten years. the story of the passport-the precursor of the epassportstarts with the birth of an individual and his birth certificate, which records the event of birth and time and place thereof. the civil registry is able, with this document to primarily establish the icao's terms of reference in the development of specifications for machine readable passports stem from the chicago convention which provides for icao's adoption of international standards and recommended practices dealing, inter alia, with customs and immigration procedures. chicago convention, supra note , article (j). it is interesting that, although passports apply to other modes of international travel as well, icao has been singly recognized as the appropriate body to adopt specifications for mrtds. this alone speaks for the uniqueness of icao's facilitation programme. see machine readable travel documents, icao doc / sixth edition , - to - . identity of the person at birth and inform his country of his details for purposes of maintaining census and vital statistics. the passport, which uses this information, gives a person a name and natonality that is required for him to travel internationally. the passport is a basic document in the transport by air of persons. its use therefore is of fundamental importance as a travel document, not only because it reflects the importance of the sovereignty of a state and the nationality of its citizens but also because it stands for the inviolability of relations between states that are linked through air transport. the key consideration of an epassport is global interoperabilitythe crucial need to specify a system for biometrics deployment that is universally interoperable. a logical data structure (lds) for epassports required is for global interoperability. it defines the specifications for the standardized organization of data recorded to a contactless integrated circuit capacity expansion technology of an mrp when selected by an issuing state or organization so that the data is accessible by receiving states. this requires the identification of all mandatory and optional data elements and a prescriptive ordering and/or grouping of data elements that must be followed to achieve global interoperability for reading of details (data elements) recorded in the capacity expansion technology optionally included on an mrp (epassport). the other considerations are uniformitythe need to minimize via specific standard setting, to the extent practical, the different solution variations that may potentially be deployed by member states; technical reliabilitythe need to provide guidelines and parameters to ensure member states deploy technologies that have been proven to provide a high level of confidence from an identity confirmation viewpoint; and that states reading data encoded by other states can be sure that the data supplied to them is of sufficient quality and integrity to enable accurate verification in their own systems; practicalitythe need to ensure that specifications can be operationalized and implemented by states without their having to introduce a plethora of disparate systems and equipment to ensure they meet all possible variations and interpretations of the standards; and durabilitythe requirement that the systems introduced will last the maximum -year life of a travel document, and that future updates will be backward compatible. the major components of a biometric system are: captureacquisition of a raw biometric sample; extractconversion of the raw biometric sample data to an intermediate form; create templateconversion of the intermediate data into a template for storage; and comparecomparison with the information in a stored reference template. in terms of security and privacy of the stored data, both the issuing and any receiving states need to be satisfied that the data stored on the ic has not been altered since it was recorded at the time of issue of the document. in addition, the privacy laws or practice of the issuing state may require that the data cannot be accessed except by an authorized person or organization. accordingly icao has developed specifications in section iv regarding the application and usage of modern encryption techniques, particularly interoperable public key infrastructure (pki) schemes, to be used by states with their machine readable travel documents as made in accordance with the specifications set out in doc . the intent is primarily to augment security through automated means of authentication of mrps and their legitimate holders internationally. in addition, ways and means are recommended to implement international epassport authentication and to provide a path to the use of epassports to facilitate biometric or e-commerce applications. annex to the convention on international civil aviation (facilitation of air transport), in standard . requires icao member states to regularly update security features in new versions of their travel documents, to guard against their misuse and to facilitate detection of cases where such documents have been unlawfully altered, replicated or issued. recommended practice . suggests that member states incorporate biometric data in their machine readable passports, visas and other official travel documents, using one or more optional data storage technologies to supplement the machine readable zone, as specified in doc , machine readable travel documents. the required data stored on the integrated circuit chip is the same as that printed on the data page, that is, the data contained in the machine-readable zone plus the digitized photographic image. fingerprint image(s) and/or iris image(s) are optional biometrics for member states wishing to supplement the facial image with another biometric in the passport. member states incorporating biometric data in their machine readable passports are to store the data in a contactless integrated circuit chip complying with iso/iec and programmed according to the logical data structure as specified by icao. the basic legal issues encompassing the issuance of epassports are privacy of the individual ; and the internal security of a state. ensuring both these are intrinsically and exclusively the responsibility of the state. as for privacy, the chicago convention, which established the regulatory framework for international civil aviation, underscores the fundamental aim of states in the context of civil aviation to exchange privileges which friendly nations have a right to expect from each other. in his message to the conference in chicago, president roosevelt said: "the conference is a great attempt to build enduring institutions of peace, which cannot be endangered by petty considerations or weakened by groundless fears" (the department of state ). the chicago convention, in article of the convention provides that the laws and regulations of a contracting state as to the admission to and departure from its territory of passengers, crew or cargo of aircraft, such as regulations relating to entry, clearance, immigration, passports, customs and quarantine shall be complied with by or on behalf of such passengers, crew or cargo upon entrance into or departure from, or while within the territory of that state. this provision ensures that a contracting state has the right to prescribe its own internal laws with regard to passenger annex to the convention on international civil aviation, th edition, . see (abeyratne a, b) . also by the same author, the exchange of airline passenger information -issues of privacy, communication law, vol. , no. ; : p. - , and also by abeyratne, profiling of passengers at airports -imperatives and discretions, european transport law, vol. xxxviii, no. ; : p. - supra, note . clearance and leaves room for a state to enact laws, rules and regulations to ensure the security of that state and its people at the airport. however, this absolute right is qualified so as to preclude unfettered and arbitrary power of a state, by article which makes each contracting state agree to adopt all practicable measures, through the issuance of special regulations or otherwise, to facilitate and expedite navigation of aircraft between the countries. the above notwithstanding, there are three rights of privacy relating to the display and storage and use of personal data: . the right of an individual to determine what information about oneself to share with others, and to control the disclosure of personal data; . the right of an individual to know what data is disclosed, and what data is collected and where such is stored when the data in question pertains to that individual; the right to dispute incomplete or inaccurate data; and . the right of people who have a legitimate right to know in order to maintain the health and safety of society and to monitor and evaluate the activities of government. [hoffman ( )] it is incontrovertible that the data subject has a right to decide what information about oneself to share with others and more importantly, to know what data is collected about him. this right is balanced by the right of a society to collect data about individuals that belong to it so that the orderly running of government is ensured. the data subject, like any other person, has an inherent right to his privacy. the subject of privacy has been identified as an intriguing and emotive one. the right to privacy is inherent in the right to liberty, and is the most comprehensive of rights and the right most valued by civilized man (warren and brandies - ) . this right is susceptible to being eroded, as modern technology is capable of easily recording and storing dossiers on every man, woman and child in the world. the data subject's right to privacy, when applied to the context of the full body scanner is brought into focus by alan westin who says: privacy is the claim of individuals, groups or institutions to determine for themselves when, how, and to what extent information is communicated to others. [westin ( )] the role played by technology in modern day commercial transactions has affected a large number of activities pertaining to human interaction. the emergence of the information superhighway and the concomitant evolution of automation have inevitably transformed the social and personal life styles and value systems of individuals, created unexpected business opportunities, reduced operating costs, accelerated transaction times, facilitated accessibility to communications, shortened distances, and removed bureaucratic formalities. [orwell ( ) ] progress notwithstanding, technology has bestowed on humanity its corollaries in the nature of automated mechanisms, devices, features, and procedures which intrude into personal lives of individuals. for instance, when a credit card is used, it is possible to track purchases, (abeyratne (young ) . as far back as in it was claimed that ten reels, each containing , m of tape . cm wide, could store a twenty page dossier on every man, woman, and child in the world. see (jones ). discovering numerous aspects about that particular individual, including, food inclination, leisure activities, and consumer credit behaviour. in similar vein, computer records of an air carrier's reservation system may give out details of the passenger's travel preferences, inter alia, seat selection, destination fondness, ticket purchasing dossier, lodging keenness, temporary address and telephone contacts, attendance at theatres and sport activities, and whether the passenger travels alone or with someone else. in similar vein, does it follow that a full body scanning exercise would reveal imperfections of the human body which person would desire to keep private? this scheme of things may well give the outward perception of surveillance attributable to computer devices monitoring individuals' most intimate activities, preferences and physical attributes, leading to the formation of a genuine "traceable society". the main feature of this complex web of technological activity is that an enormous amount of personal information handled by such varied players from the public and private sector, may bring about concerns of possible "data leaks" in the system, a risk that could have drastic legal consequences affecting an individual's rights to privacy. at the international level, privacy was first recognized as a fundamental freedom in the universal declaration of human rights. thereafter, several other human rights conventions followed the same trend, granting to individuals the fundamental right of privacy. the pre-eminent concern of these international instruments was to establish a necessary legal framework to protect the individual and his rights inherent to the enjoyment of a private life. privacy represents different things for different people. the concept per se has evolved throughout the history of mankind, from the original non-intrusion approach, which defended an individual's property and physical body against unwanted invasions and intrusions, then manifesting in whom to associate with, later for a detailed analysis of the implications of credit cards with respect to the right of privacy see (nock ) . the paramount importance of airline computer reservation system records is reflected in the worldrenowned cases libyan arab jamahiriya v. united kingdom and libyan arab jamahiriya v. united states of america regarding the panam accident at lockerbie, scotland in , where the international court of justice requested air carriers to submit to the court the defendants' flight information and reservation details. see (international court of justice ). in a similar vein, arthur r. miller describes the significance of airline computer reservation system records when dealing with federal, state, local, and other types of investigations where these dossiers could provide valuable information. see also (miller ) . see scott ( ) ; burnham ( ) at . a contrario to the argument supported in this thesis that the advancement of technology directly affects the intimacy of individuals. u.s. circuit judge richard posner favours the idea that other factors, such as urbanisation, income, and mobility development have particularly weakened the information control that, for instance, the government has over individuals: this denotes that individuals' privacy has increased. see posner ( ) . the text reads: "no one shall be subjected to arbitrary interference with his privacy, family, home or correspondence, nor to attacks upon his honor and reputation. everyone has the right to the protection of the law against such interference or attacks". see universal declaration of human rights. enlarging its scope to include privacy as the individual's decision -making right, and culminating in the control over one's personal information. thus, the conceptual evolution of privacy is directly related to the technological advancement of each particular period in history. the right of privacy, as enunciated by the united states judge thomas m. cooley, was the right "to be let alone" as a part of a more general right to one's personality. this idea was given further impetus by two prominent young lawyers, samuel d. warren and louis d. brandeis, in . before this idea was introduced, the concept of privacy reflected primarily a somewhat physical property or life. the foundations of "information privacy", whereby the individuals would determine when, how, and to what extent information about themselves would be communicated to others, inextricably drawing the right of control of information about oneself, is a cornerstone of privacy. with the development of computer capabilities to handle large amounts of data, privacy has been enlarged to include the collection, storage, use, and disclosure of personal information reidenberg ( ) . the notion of informational privacy protection, a typically american usage, has been particularly popular both in the united states and europe, where the term "data protection" is used. self-determination in the right to protect one's privacy was first judicially embraced by the german bundesverfassungsgericht in . the us supreme court followed this trend by adopting the principle of privacy self-determination in doj v. it must be borne in mind that privacy is not an absolute, unlimited right that operates and applies in isolation (simmel ) . it is not an absolute right, applied unreservedly, to the exclusion of other rights. hence there is frequently the necessity to balance privacy rights with other conflictive rights, such as the freedom of speech and the right to access information when examining individuals' rights vis-à-vis the in this case, the us supreme court acknowledged the right of women to have abortions based on the grounds that the federal government could not interfere within her "decisional privacy" sphere. see roe v. wade, u.s. ( ) . see also cate ( ) . see also zelermyer ( ) . in a remarkable case concerning the legality of a national census scheduled by the authorities, the german constitutional court connected the individual's liberty and the personal data processing of the intended census, to rule that if the individuals do not know for what purposes and who is collecting the data, that situation will eventually create an abdication of the individual's rights to the processor's command, "which cannot be tolerated in a democratic society". see simitis ( ) . see also hoffer ( ) ; gavison ( ) . see cooley ( ) , as cited in warren and brandeis ( ) . the definition of privacy as the "right to be alone" is often erroneously attributed to warren and brandeis. see warren & brandeis. see cooley ( ) as cited in warren and brandeis ( ) . additionally the concept of privacy as "the right to be let alone", and "the right most valued by civilized man: was embraced by us courts in the landmark dissenting opinion of justice louis d. brandeis in olmsted v. united states. see olmsted v. united states, u.s. , ( ) [hereinafter olmstead.] see westin ( ) . for a similar conceptualisation of privacy, see fried ( ) . the former privacy commissioner of british columbia, canada, has asserted that privacy was originally a "non-legal concept". see flaherty ( ). the term "data protection" has been translated from the german word datenschutz, referring to a set of policies seeking to regulate the collection, storage, use, and transfer of personal information. see c.j. bennet, regulating privacy (ithaca. new york: cornell university press, ) at . supra, note . interest of society. this multiplicity of interests will prompt courts to adopt a balanced approach when adjudicating on a person's rights, particularly whose interests of a state are involved. since the data contained in equipment such as body scanners may be subject to trans-border storage, there is a compelling need to consider the introduction of uniform privacy laws in order that the interests of the data subject and the data seeker are protected. although complete uniformity in privacy legislation may be a difficult objective to attain (as has been the attempt to make other aspects of legislation uniform), it will be well worth the while of the international community to at least formulate international standards and recommend practices (in the lines of the various icao annexes) to serve as guidelines of state conduct. after all, as collin mellors pointed out : under international agreements, privacy is now well established as a universal, natural, moral and human right. article of the universal declaration of human rights, article of the united nations covenant on civil and political rights and article of the european convention for the protection of human rights and fundamental freedoms, all specify this basic right to privacy. man everywhere has occasion to seek temporary "seclusion or withdrawal from society" and such arrangements cannot define the precise area of the right to privacy. it is such a definition that is now needed so that the two requirements of ensuring respect for information about individuals and their privacy on the one hand, and the encouragement of free and open dissemination of trans-border data flows on the other, are reconciled. in the provision of biometric data, the provider of the information and the receiver thereof are both under obligation to ensure that the data is not used for any purpose other than clearance of the owner of the information through customs barriers. this information may not later be used for commercial or other gain for instance for advertising purposes (such as using the physical profile of a prominent actor or actress whose biometric information originally given for customs clearance). the protection of human rights is the most significant and important task for a modern state, particularly since multi ethnic states are the norm in today's world. globalization and increased migration across borders is gradually putting an end to the concept of the nation state, although resistance to reality can be still seen in instances where majority or dominant cultures impose their identity and interests on groups with whom they share a territory. in such instances, minorities frequently intensify their efforts to preserve and protect their identity, in order to avoid marginalization. polarization between the opposite forces of assimilation on the one hand and protection of minority identity on the other inevitably causes increased intolerance and eventual armed ethnic conflict. in such a scenario, the first duty of governance is to ensure that the rights of a minority society are protected. see halpin ( ) at . see also foschio ( ) . for a comprehensive study on the conflictive interest on privacy and the mass media and the freedom of speech, see pember ( ); prowda ( ) . see also j. montgomery curtis memorial seminar ( the foregoing discussion addressed the right of privacy of the individual which is paramount over most legal considerations. the only factor that would override this would be the security of state. inherent to the concept of security of state is state responsibility to its citizens and others who are in its territory. the fundamental issue in the context of state responsibility for the purposes of this article is to consider whether a state should be considered responsible for its own failure or non-feasance to prevent a private act of terrorism against civil aviation or whether the conduct of the state itself can be impugned by identifying a nexus between the perpetrator's conduct and the state. one view is that an agency paradigm, which may in some circumstances impute to a state reprehensibility on the ground that a principal-agent relationship between the state and the perpetrator existed, can obfuscate the issue and preclude one from conducting a meaningful legal study of the state's conduct. security it is incontrovertible that in issuing an epassport, the state concerned ensures aviation security not only in its own territory but also in the territory of the state to which the epassport holder travels. new and emerging threats to civil aviation are a constant cause for concern to the aviation community. grave threats such as those posed by the carriage of explosives and dangerous pathogens on board, are real and have to be addressed with vigour and regularity. the leakage of dangerous pathogens from laboratories also presents an ominous analogy to the aviation sector in that the same could well occur in the carriage of such dangerous goods by air (abeyratne ) . although past instances of the escape of dangerous pathogens are small in number, nonetheless their occurrence and the threat posed to the wellbeing of humanity cannot be underestimated. in when anthrax spores escaped from two military laboratories in the united states, the authorities agreed that the leakage was due to a security lapse. in a string of such leakages occurred in asia, this time of the sars virus. icao has been addressing these threats for some time and continues to do so on a global basis, particularly with regard to the impact of unpredictable security measures on passenger confidence in aviation security. there has been much support for this approach because of its value as a deterrent. it has been suggested that states adopt an approach providing for a baseline regime, but with the addition of unpredictable measures, thus achieving a balance between certainty and unpredictability. for an in-depth discussion of state responsibility see abeyratne ( ) . caron ( ) cited in becker ( . pathogens are microorganisms (including bacteria, viruses, rickettsia, parasites, fungi) or recombinant microorganisms (hybrid or mutant) that are known or are reasonably expected to cause infectious disease in humans or animals. an year earlier, a covert event occurred in october when anthrax spores were sent through the mail exposing persons in the eastern usa to contaminated mail resulting in deaths, illnesses and identified exposures to anthrax. overt, announced events, in which persons are warned that an exposure has occurred, have taken place in the united states, although most of these were determined to have been hoaxes, that is, there were no true exposures to infectious agents. the security ensured by the introduction of the epassport undoubtedly has its genesis in the maintenance of international peace and security is an important objective of the united nations, which recognizes one of its purposes as being inter alia: to maintain international peace and security, and to that end: take effective collective measures for the prevention and removal of threats to the peace, and for the suppression of acts of aggression or other breaches of peace, and to bring about by peaceful means, and in conformity with the principles of justice and international law, adjustment or settlement of international disputes or situations which might lead to a breach of the peace. it is clear that the united nations has recognized the application of the principles of international law as an integral part of maintaining international peace and security and avoiding situations which may lead to a breach of the peace. liability of the manufacturer of the electronic chip, often a private entity, and the state is a significant factor in this equation. ultimately, even though the chip incorporated in the epassport is the creation of a public or private entity, is so incorporated in a state documenti.e. the passport, and therefore the state is ultimately liable for defects in the passport. state liability under administrative law can in turn be divided into two limbs: liability for acts of instrumentalities of state; and liability for privatized service providers for whose acts, relating to the provision of technical services, the state would still bear responsibility. the traditional model of administrative responsibility and accountability of the administrative state is based on the premise that parliament controlled the executive but was in turn controlled by the people. added to this, the fundamental postulate lay in the overarching principle that the judiciary played its role in keeping instrumentalities and agencies of the state intact. accountability of the state for its agencies' actions was two fold: one stemming from a statutory power given to that agency by the state; and the other arising from delegation of authority by the state to the agency concerned. in the latter instance, however, the legislature could intervene and share some control of the agency. this gave rise to the inexorable principle that administrative law and judgments of courts on such agencies could be involved only in the former instance, when the state had provided a statutory base for a private agency or entity. in the british case of o'reilly & mackman, the house of lords limited the circumstances in which a public law remedy, such as a declaratory judgment or injunction, could be brought outside of section of the supreme court act of , which prescribed instances of legal actions to be brought against the state for an act of its statutory agent. this is notwithstanding the fact that section of the crown proceedings act allows the court in civil proceedings to issue a declaratory order against the state, although there could be no injunction specific performance orders against a state. furthermore, a later case established that although the claim for judicial review might be brought against the crown, the crown's involvement is merely nominal and the ultimate dispute would be between the claimant and the defendant. in the instance of a privatized service provider, the situation calls for a discussion of the reasons for privatization leading to the legal nature of a privatized entity. the reasons for privatization could well range from improvement of efficiency to reducing government involvement in industrial decision making. the corollaries to privatization are often the widening of share ownership; encouraging share ownership by employees; providing more flexibility to pay policies; and enhancement of economic freedom. there could be two types of privatized service providers: the first being large companies which were once instrumentalities of state, which, even after privatization, do not possess potential for undue competition in the market. these would easily transit to a position in which large companies had been private in the first place, and would not be subject to principles of public law. the second category of the privatized service provider is one which has market power and consequent potential for untrammelled competition. in such cases, the state may regulate the provider by bringing it under the administrative purview of a state agency. these privatized bodies may be vulnerable under public law through the agencies having administrative control over them. one of the analogies in the united kingdom of a privatization of a utility can be observed in the legislative initiative of with the adoption of the telecommunications act which brought about the privatization of a major public utility. the legislation privatized the public corporation british telecom (bt) and abolished bt's monopoly in providing telecom services, thus opening the doors to competition. the director general of telecommunications, established by the act, can grant licenses to operators of telecom systems. the director general is also empowered to refer a matter to the monopolies and mergers commission, particularly on issues related to public interest such as pricing. if this particular feature were to be applicable to a privatized air navigation service provider appointed under statute, there would be the interesting consideration under public law whether that provider complied with article of the chicago convention on charges for services. the operation of the administrative process in a state becomes somewhat complex when viewed in the context of competition policy where the state takes measures to curb the ill-effects on society of monopolies and cartels. an initial difficulty that arose was the th century control of trade, which was aimed at promoting competition proved counter productive, resulting in controlling competition. this difficulty was compounded by the early twentieth century state policy of reluctance r. v. secretary of state ex parte factorframe ltd. [ ] a.c. . for a detailed discussion of the legal liability of states and of a privatized service provider see abeyratne ( ) . from until telecommunications were the responsibility of the post office. the legislation represented telecommunications from kp. services and established british telecom as a public corporation. article provides that every airport in an icao contracting state which is open to public use by its national aircraft shall likewise be open under uniform conditions to aircraft of all other contracting states. the like uniform conditions shall apply to the use, by aircraft of every contracting state, of all air navigation facilities, including radio and meteorological services, which may be provided for public use for the safety and expedition of air navigation services. article also provides that charges applicable to a foreign carrier for the provision of the air navigation services shall not be higher than those imposed on a carrier bearing the service provider state's nationality. to interfere with citizens striking bargains for their benefit. however, after world war , some british governmental measures introduced comprehensive control of market power. british legislators can be proud of three legislative stages of unfair competition control. the first came in the form of the monopolies and restrictive practices (inquiry and control), act which devolved regulatory responsibility on an agencythe monopolies and restriction practices commission (mrpc) -a body outside the normal departmental framework. the second stage commenced with the restrictive trade practices act which addressed the competitive threat of cartels and the restrictive practices court was established to adjudicate an anti-competitive and privy issues. the third stage took on with the expansion of the monopolies commission which investigates monopolies issues. merger irregularities were added to the jurisdiction of the commission with the monopolies and mergers act of . the competition act which followed gave the commission power to investigate particular anti-competitive practices. the final stage of the evaluation demarcates choice of institutions to investigate and adjudicate on anti-competitive practices. from an administrative perspective, the citizen has been known to challenge these state instrumentalities, the most notable of which has been the challenge offered to the various governmental institutions created under statute to define their extent of duty to give reasons for competition legislation. a government's approach to regulation of a public utility, whether public or privatized, is usually based on the public interest rationale where individual consumer choice will determine the demand and supply for goods and their pricing and quantity (ogus ) . in the united kingdom, these factors are intrinsically related to transparency, accountability, proportionality, consistency and targeting. the foremost necessity is to establish a strong security culture in every state. for this, there must be a clear definition of state responsibility and accountability brought to bear by a close and unbreakable link between government and industry stakeholders. a security culture would make states aware of their rights and duties, and, more importantly, enable states to assert them. those who belong to a security culture also know which conduct would compromise security and they are quick to educate and caution those who, out of ignorance, forgetfulness, or personal weakness, partake in insecure conduct. an epassport must necessarily be the result of efficient and fail-safe organizational arrangements. it should be tested at border control by trained professionals. egovernment and eid are the bare essentials for state security. the digital economy has also brought much facilitation that helps the world move to paperless processes which result in greater economy and streamlined processes. however, there must essentially be global harmonization in this process. in this regard icao has made remarkable progress in advancing its mrtd programme to the level it is at now. if harmonization means ensuring consistency between global practices, standardization means compliance with international standards. there is no room for doubt that both harmonization and globalization are needed in this context. mcgregor gow [ ] a.c. . see also sorrell v. smith [ ] a.c. . committee on trusts cmd monopolies and mergers commission exp. elders xl ltd secretary of state for trade industry ex parte lonrho plc see better regulation guide the exchange of airline passenger information -issues of privacy intellectual property rights and privacy issues: the aviation experience in api and biometric identification privatization of hong kong international airport: some legal and economic issues the safe carriage of dangerous pathogens by air: legal and regulatory issues principles of responsibility for private acts of terrorism terrorism and the state, hart monographs in transnational and international law the rise of the computer state. random house the basis of responsibility: attribution and other trans-substantive rules privacy in the information age ) a treatise on the law of torts, nd edn. callaghan, chicago doj v. reporters comm. for freedom of the press motor vehicle records: balancing individual privacy and the public's legitimate need to know privacy: one concept or many privacy: economics and ethics a comment on posner privacy and the limit s of the law rights & law analysis & theory world cyberspace law questions of interpretation and application of the montreal convention arising from the aerial incident at lockerbie some threats of technology to privacy, privacy and human rights curtis memorial seminar ( ) the public, privacy and the press: have the media gone too far? the costs of privacy charter orwell g ( ) nineteen eighty-four. clarendon, oxford pember dr ( ) privacy and the press a layer's ramble down the information superhighway: privacy and security of data legislating privacy. the university of north caroline press data protection law and the european union's directive: the challenge for the united states: setting standards for fair information practice in the u.s. private sector mind your own business -the battle for personal privacy from the market to the polis: the ec directive on the protection for personal data privacy is not an isolated freedom proceedings of the international civil aviation conference the right of privacy - ) the right to privacy privacy and freedom invasion of privacy key: cord- -j trahab authors: loo, may title: select populations: children date: - - journal: complementary and alternative medicine doi: . /b - - - - . - sha: doc_id: cord_uid: j trahab nan the majority, usually seeking cam therapy as an adjunctive management for pain and other discomforts related to the oncologic illness or to medications. in the general pediatric population, chiropractic is the most common form of cam treatment used by children. reports indicate that children made up % of chiropractic patients in and % in . a survey of the boston metropolitan area revealed that an estimated , chiropractic visits were made by children in . childhood disorders being treated include pain, respiratory and gastrointestinal tract problems, ear infection, enuresis, and hyperactivity. homeopathy was the second most popular form of cam therapy used by children in spiegelblatt's report. in , however, the university of pittsburgh found that homeopathy was the most common cam therapy used by children who visited an emergency department (ed). also, in a survey of homeopathic practitioners in massachusetts, children constituted one third of patient visits. homeopathic remedies are highly diluted substances that induce self-healing. these remedies are readily available from a variety of sources, including some grocery stores. although homeopathy may be safe and effective in many childhood conditions, many practitioners believe that homeopathic remedies are best used as adjunctive therapy to conventional medicine in chronic conditions and in acute disorders that respond poorly to conventional therapy. , acupuncture is the third most common therapeutic method used in children but has the largest body of scientific data compared with other cam therapies. a harvard survey of patients with a median age of years who received acupuncture treatment, which included needle insertion, moxa/heat, cupping, and magnets, reported that % of patients rated the therapy as pleasant and % thought treatment helped their symptoms. electrical stimulation, laser, heat, magnet methods, and acupressure or acumassage are effective alternatives to needles for treating children with needle phobia. acupuncture and traditional chinese medicine (tcm) have been used in asia and europe to treat a wide spectrum of childhood illnesses. their use in the united states has been recent but is growing rapidly in popularity. naturopathy ranks with acupuncture as the third most common complementary therapy used by children, although scientific data are sparse. currently, evidence-based information is limited about safety and efficacy of herbal remedies, especially in terms of dosage and application in infants and children, who may be more susceptible to some of the adverse effects and toxicities because of differences in physiology and immature metabolic enzyme systems. , other cam treatments used in children include touch therapy (therapeutic touch), osteopathy, oligotherapy, and hypnosis. religious practices such as prayer have also become prevalent in the pediatric population. children have reported the ability to readily feel energy field from touch therapy. the increasing support for therapeutic touch (tt) , has been anecdotal with little scientific data. approximately % of children receiving treatment with cam therapies seek osteopaths, who claim success in treating many common childhood conditions, including colic and otitis. approximately % of pediatric cam visits are to oligotherapists, who administer poorly absorbed trace elements such as copper, manganese, and zinc to improve health. relaxation training and imagery are forms of hypnosis that have also been effective in children. in fact, children seem to be able to learn relaxation training better and faster than adults. table - summarizes the cam therapies most often used to treat various pediatric conditions. box - lists additional and recent surveys and reviews of cam therapies used to treat pediatric conditions. vaccination is an essential component of pediatric well-child care and has both public health and educational ramifications because up-to-date vaccination is required for vaccine safety is monitored closely. adverse events are reported to the vaccine adverse event reporting system (vaers), administered by the centers for disease control and prevention (cdc) and the u.s. food and drug administration (fda). approximately , adverse cases are reported each year. data are shared internationally by independent scientific experts on the joint committee on vaccination and immunization and committees of the medicines control agency. surveillance results in product withdrawal when there is clear evidence of a safety issue. currently, several serious pediatric conditions are controversially attributed to vaccination: immune compromise, neurologic sequelae, autism, and crohn's disease. the medical community has expressed concern about the effects of vaccination on an immature immune system, especially in neonates. controversial debates are ongoing regarding the possible connection between vaccination and autoimmune illnesses, such as the association between measles and anti-hepatitis b virus (hbv) vaccines with multiple sclerosis. tetanus toxoid, influenza vaccines, polio vaccine, and others have been related to autoimmune phenomena ranging from autoantibody production to full-blown illness, such as rheumatoid arthritis and guillain-barré syndrome. recent evidence suggests that autism may be related to the immune system. the mechanism of autoimmune reactions after immunization has not yet been elucidated. one possibility is molecular similarity between some viral antigen (or other component of the vaccine) and a self-antigen. this similarity may be the trigger to the autoimmune reaction. , before , whole-cell pertussis vaccine was used, composed of a suspension of formalin-inactivated bordetella pertussis b cells. convulsions occurred in case to doses administered, and acute encephalopathy occurred rarely, at . cases per million doses administered. sudden infant death syndrome (sids) and infantile spasms have also been suggested to be associated with diphtheria-pertussis-tetanus (dpt) vaccination. in the s, reports linking pertussis vaccine with infant brain damage attracted media attention, which in turn caused great parental and professional anxiety; the immunization rate fell from % to %. between and , three major pertussis epidemics occurred in the united states, resulting in more than , hospitalizations and at least deaths. in countries such as sweden, japan, united kingdom, ireland, italy, and australia, antivaccine movements targeted pertussis whole-cell vaccines. opponents to the pertussis vaccine have argued that the risks of vaccination outweigh the benefits. the largest study to date conducted by the national institute of child health and human development at the national institutes of health (nih) revealed that sids was actually less likely to occur in recently vaccinated infants. another large study showed that the permanent neurologic sequelae due to pertussis vaccine are so rare as to be unquantifiable. nevertheless, concerns about brain damage led to the development of acellular pertussis vaccine (dtap) that contains purified, inactivated components of b. pertussis cells. this form is associated with a lower frequency of adverse events and is more effective in preventing pertussis disease. dtap was first licensed for the fourth and fifth doses of the pertussis series in and for the primary series in . several studies conducted in europe and africa revealed that u.s.-licensed dtap vaccines have efficacy ranging from % to %. currently, only acellular pertussis vaccine is used. no encephalopathy has been reported. hypotonic hyporesponsive episode (hhe) is the sudden onset of hypotonia, hyporesponsiveness, and pallor or cyanosis that occurs within hours of vaccination, usually after pertussis vaccine administered to children under years of age. hhe occurred in approximately of every dta vaccinations. the largest published report of , cases concluded that although hhe does occur after the administration of dtap and other non-pertussis-containing vaccines, it is generally benign, self-limited, and nonrecurrent. the connection of encephalopathy with pertussis vaccine was biologically more plausible than the proposed link between pertussis, measles vaccines, and autism. the incidence of autism has increased from in , in to in in in some u.s. communities. a study of autistic children suggests that autism may be caused by a pertussis toxin found in the dpt vaccine. the toxin separates the g-alpha protein from retinoid receptors, which are critical for vision, sensory perception, language processing, and attention-characteristic problems of autism. those children most at risk have at least one parent with a preexisting g-alpha protein defect, presenting clinically with night blindness, pseudohypoparathyroidism, or adenoma of the thyroid or pituitary gland. natural vitamin a may reconnect the retinoid receptors. in recent years, discussion has increasingly centered on the controversy concerning the possible association of the measles-mumps-rubella (mmr) vaccine with autism and crohn's disease.* the chinese were among the first populations to vaccinate, beginning with smallpox vaccine, which was injected intranasally. tcm considers most childhood illnesses to occur at superficial levels, and vaccination actually introduces pathogens, still considered energetically active, into deeper blood levels of the body. in addition, tcm also posits that the body can usually effectively handle only one process at a given time. when two separate processes occur at the same time, the human system could become overwhelmed, especially the tender system of an infant or a young child. therefore, although multiple vaccines given at the same time are less traumatic for children and save nursing time, they can easily overwhelm an immature immune system and make the child weak and deficient. although the fear of epidemics motivates the chinese to vaccinate all their children, tcm practitioners in the west often advise against immunization. there is discrepancy among the homeopaths regarding recommendation of conventional vaccines. a german questionnaire survey reported that homeopathic physicians generally do not refuse vaccinations but show a preference for the dpt vaccines. a british survey conducted between and reported that preference for homeopathic remedies for illnesses and religion were the most common reasons parents refused immunization; % believed the risk of diseases to be less than the risk of vaccination and would seek homeopathic treatment if any illness developed in their children, and % believed that children "are protected by god and not by vaccines." a u.s. cross-sectional descriptive survey of homeopathic practitioners and naturopathic practitioners in massachusetts revealed that the majority of the practitioners did not actively recommend immunizations. many homeopaths recommend homeopathic vaccines, which are not yet supported by scientific data. a random sample survey by mail of % of american chiropractors revealed that one third believe there is no scientific proof that immunization prevents disease, that vaccinations cause more disease than they prevent, and that contracting an infectious disease is safer than immunization. a reported % believed that immunization should be voluntary and that spinal adjustment is a viable alternative. a crosssectional, descriptive survey of chiropractics in the boston metropolitan area reported that only % actively recommended childhood immunization. the decision of whether or not to immunize a child is difficult for both parents and practitioners. the advantages of vaccination are difficult to refute, but the temporal relationship between immunization and side effects and the controversies surrounding potential risks are disconcerting. although data are insufficient on cam approaches to vaccination today, practitioners should be aware of the slow yet steady trend toward alternatives and should properly address parental concerns and questions regarding immunization. each practitioner needs to inform parents of the most up-to-date pros and cons of vaccination, be as objective as possible, put aside personal belief systems, and be supportive and understanding of whichever decision the parents make. parents need to become as informed as possible, consider all the pros and cons, weigh the risks and benefits, and realize that ultimately they must live with the outcome of their decision. the common cold is the most frequent infection in children in the united states and throughout the industrialized world. a preschool-aged child has an average of to colds per year. the clinical symptoms vary greatly without any correlation with specific viruses. , the majority of the symptoms are mild, consisting of rhinorrhea, sneezing, nasal congestion and obstruction, postnasal drip, and cough. there may often be additional symptoms of low-grade fever, sore throat, clear eye discharge, digestive discomfort, and general malaise. , , some common viruses that cause upper repiratory tract infections (uris) include rhinovirus, coronavirus, adenovirus, respiratory syncytial virus (rsv), influenza virus, and parainfluenza virus. , , transmission varies with different viruses. for example, rsv spreads primarily through contact with symptomatic children and contaminated objects, whereas influenza spreads mainly through airborne droplets. the precise route of transmission for rhinovirus remains controversial. the virulence of rhinovirus is maximum in infants before year of age (median age . months) and in immunocompromised children. wheezing is associated with rsv in children younger than years of age and with rhinovirus in those over age . simultaneous infection by more than one virus, such as rsv and adenovirus together, can also occur frequently in the pediatric population. many children may also have associated bacterial infection, such as haemophilus influenzae conjunctivitis. the viruses gain entry into host cells through specific viral surface proteins, which cause tissue injury and result in clinical disease. recent studies suggest that the host's response to the virus, not the virus itself, determines the pathogenesis and severity of the common cold. proinflammatory mediators, especially the cytokines, appear to be the central component of the response by infected epithelial cells. , specific viral diagnosis is not necessary because of the benign, self-limiting nature of the disease and the prevalence of different viruses overlapping from fall to spring, which makes it difficult to determine precisely which virus or viruses are causing the symptoms. current medical management of uri remains symptomatic, controversial, and in most cases, ineffective. fluid, rest, humidifier, and saline nose drops constitute the mainstay of nonpharmacologic treatment. topical adrenergic agents do not have systemic side effects, but overuse can result in rebound congestion. , antihistamine and combinations of antihistamine with decongestants are the ingredients in at least over-the-counter (otc) cold remedies. the majority of studies have concluded that antihistamines are of marginal or no benefit in treating cold symptoms. , , , , dextromethorphan is an antitussive that is abundant in otc formulations. although this medication is reportedly safe when taken in the recommended dosages, there have been cases of "recreational" use by teenagers, and deaths by overdose have been reported. codeine is ineffective in controlling uri cough. medications are often overprescribed, leading to higher health care costs and dangerous side effects, such as greater antibiotic resistance. more steroids are prescribed, which leads to a myriad of complications. although interferon has been shown to produce good protection against infection, the high doses necessary to produce a prophylactic effect are often associated with serious undesirable side effects, including nasal stuffiness, bloody mucus, and mucosal erosions, and the trauma of daily intramuscular injection makes it an unlikely remedy for children. research for new medical therapies for the common cold is directed toward increasing resistance to or immunity against the viruses. histamine antagonists are not indicated in the common cold. antiinflammatory mediators and specific antiviral agents may be promising. development of an effective vaccine against the common cold is unlikely because of the large number of viral serotypes. rhinovirus, for example, has at least different immunotypes. although viral uri is a benign illness of short duration, it can lead to bacterial complications such as otitis media, sinusitis, lower respiratory tract infections, mastoiditis, and even meningitis. scientific data on cam treatment for the common cold are surprisingly sparse. in , linus pauling carried out a meta-analysis of four placebo-controlled trials and concluded that vitamin c alleviates cold symptoms, but subsequent reviews indicated that the role of vitamin c in uri is still controversial. [ ] [ ] [ ] although breast-feeding has been believed to protect against infection in infants, studies have been inconsistent in demonstrating its efficacy. in a -year prospective study that actively tracked breast-feeding and respiratory illnesses in healthy infants, breast-feeding was found to reduce significantly the duration of respiratory illnesses during the first months of life. a retrospective review from saudi arabia of randomly selected charts revealed that a direct correlation exists between duration of breast-feeding and frequency of uri in the first years of life. a hospital-based descriptive recall study from sri lanka examined the relationship between breastfeeding and morbidity from respiratory illnesses in infants. of the infants, were admitted and were controls. an inverse relationship was found between the length of breast-feeding and incidence of respiratory illnesses. a nutritional study of healthy newborns followed for months demonstrated that breast-feeding lowers frequency and duration of acute respiratory tract infection compared with formula feeding. a more recent japanese study examined the incidence of pathogenic bacteria isolated from the throat of healthy infants fed with different methods. no pathogens were detected in breast-fed and mixed-fed infants, while h. influenzae and moraxella catarrhalis were isolated from the oropharynx of formula-fed infants. the investigators suggest that breast milk may inhibit the colonization by respiratory bacterial pathogens of the throat of infants. the mechanism was thought to be enhancement of mucosal immunity against respiratory tract infection. in addition to the presence of secretory immunoglobulin a (iga), another mechanism may be the presence of complex carbohydrates in human milk. these glycoconjugates may exert various antipathogenic effects, such as inhibiting the binding of pathogens to the receptors and reducing the production of bacterial toxins. however, a u.s. study that examined nasopharyngeal swabs from infants at month of age and swabs from of these infants at months of age (keeping environmental parameters similar, e.g., number of children in household, number of siblings in day care, proportion with recent uri) revealed that the exclusively breast-fed (n = ) and exclusively formula-fed (n = ) infants did not differ significantly in the number of pathogens. a multicenter randomized trial was conducted in hospitals in the republic of belarus. evaluation within the first year revealed that breastfeeding had no significant reduction in respiratory tract infection compared with the control group. a survey from singapore of breast-feeding mothers at months postpartum revealed no significant differences in the rates of uri between breast-fed and non-breast-fed infants. data are sparse on acupuncture, herbal, and homeopathic remedies for treatment of uri, especially in children. most data are uncontrolled, clinical reports. current information on adults supports efficacy of acupuncture for treating the common cold. , , , acupuncture has been shown to increase the velocity of the nasal mucociliary transport in chronic rhinitis patients. one possible use of acupuncture in uri is its potential effect on the immune system. when chinese herbs were pasted onto acupoints for treating rhinitis and bronchitis in infant, serum immunoglobulin m (igm), igg, complement c , and especially iga levels increased. acupuncture has also been shown to increase t lymphocytes. even massaging local acupoints was effective in relieving symptoms and in enhancing immune functions, with increases in immune indices that persisted for at least months. one report of acu massage of only one point for just seconds resulted in clinical relief from nasal congestion, even though there was no change in nasal airway resistance or airflow. these reports are encouraging for parents because acupressure can be easily learned by nonprofessionals, is well tolerated by children of all ages (including infants), has no side effects, and costs nothing. a clinical trial administering a nontoxic chinese herbal mixture to infants demonstrated more than . % effectiveness in treatment of uri. in a single-blind trial using a chinese herb for acute bronchiolitis with serologic evidence of rsv, hospitalized children were randomized into three treatment groups: herbs, herbs with antibiotics, and antibiotics alone. herbal treatment was found to decrease symptoms and duration of illness without adverse effects. in a randomized, controlled trial using an herbal mixture, children in the treatment group demonstrated % efficacy versus % of children in the control group. there was no description in the abstract (original article in chinese) of what constituted control (e.g., placebo herb, no treatment, conventional drugs) or what constituted efficacy (e.g., improvement in symptoms, duration, of illness). further rigorous studies are needed to demonstrate safety and efficacy of herbal treatment. a recent clinical trial that included children over age years and used a fixedcombination homeopathic remedy for a mean . days of treatment reported that . % reported subjective feelings of being symptom free or significantly improved without complaint of any adverse side effects. a randomized, double-blind, placebocontrolled study from great britain of children with a starting median age of . years in the experimental group and . years in the placebo group concluded that individually prescribed homeopathic remedies seem to be ineffective in reducing symptoms or decreasing the use of antibiotics in pediatric patients with uri. otitis media (om) represents a continuum of conditions that include acute om, chronic om with persistent effusion, chronic suppurative om, recurrent om, unresponsive om, and om with complications. acute otitis media (aom) is most prevalent in young children to months of age. approximately two thirds of all children will have had at least one episode of aom before age years, and half of them will have recurrences or chronic serous om with effusion into early elementary school years. by the time the child reaches adolescence, aom occurs infrequently. almost one third of pediatric office visits are for treatment of aom. the most common etiologic factors are allergic rhinitis , and ascending bacterial or viral agents from the nasopharynx attributable to eustachian tube dysfunction. the most common viral culprits are rsv, influenza virus, and adenovirus. two thirds of middle ear infections are caused by bacteria. the predominant organisms are pneumococci, h. influenzae, m. catarrhalis, , , , and group b streptococcus. bacterial pathogens adhere to mucous membranes, and colonization ensues. the severity of infection or the response to the invading bacteria depends on the health of the child's immune system. the humoral system is especially significant in protecting the middle ear cavity from disease, and the nasopharyngeal lymphoid tissues are the first line of defense against bacterial colonization. , the sterility of the eustachian tube and tympanic cavity depends on the mucociliary system and on secretion of antimicrobial molecules, such as lysozyme, lactoferrin, and betadefensins. evidence indicates that a number of children with recurrent episodes of aom have minor immunologic defects. pneumococcus is by far the most virulent of aom bacteria. it causes approximately million cases of om annually in the united states. uncontrolled pneumococcal otitis can lead to meningitis. the incidence of aom is higher in winter and early spring. clinically, the child with aom presents with earache and fever, usually accompanied by upper respiratory symptoms such as rhinorrhea. on otoscopic examination the tympanic membrane varies from hyperemia with preservation of landmarks to a bright-red, tense, bulging, distorted appearance. in advanced stages of suppuration the tympanic membrane ruptures with a gush of purulent or blood-tinged fluid from the ear. because viral or bacterial om usually cannot be distinguished by otoscopic examination, aom is usually treated empirically, using antibiotics such as amoxicillin that have a high concentration in the middle ear fluid. , however, the widespread use of antibiotics has resulted in increasing resistance to the more common medications. , currently, % of children with aom are recalcitrant to antibiotic therapy. the prevalence of resistant organisms tends to increase in the winter months. economically, treatment failure due to drug resistance has been responsible for further escalating the billions of dollars spent treating aom. in addition, antimicrobials suppress normal flora, which is beneficial to the host because the antibiotic can interfere with and therefore prevent pathogenic infections and may enhance recovery from uris. on the other hand, since the advent of antibiotics, complications such as mastoiditis and intracranial infections have significantly decreased. the current focus is on prevention of aom. breast-feeding confers lifesaving protection against infectious illness, including otitis. , pneumococcal conjugate vaccine (pcv), approved in for use in the united states, covers the seven serotypes that account for about % of invasive infections in children younger than age years. pcv was demonstrated to have more than % efficacy and has resulted in a modest reduction of total episodes of aom. the goal of pcv is to prevent symptomatic infections in the middle ear and prevent colonization of the pneumococci that can cause subsequent middle ear infections. pcv may eliminate nasopharyngeal carriage of pneumococci. however, because pcv only prevents disease caused by the most common serotypes, there is concern that the nonvaccine serotypes will become more common, especially in children less than years of age. an effective rsv vaccine for the infant and young child could greatly decrease om disease. intranasal spray of attenuated viruses is currently under investigation, in the hope that early antiviral therapy would reduce the risk of om after uri. , chronic otitis media with effusion (ome) is one of the most common diseases in childhood. ome is associated with infection, eustachian tube obstruction, allergic or immunologic disorders, and enlarged adenoids. the serous fluid still contains bacteria, such as h. influenzae and pneumococci. ome has been implicated to be an immune-mediated disease because immune complexes have been demonstrated in the middle ear effusion, and highly organized lymphatic tissue has been found in the middle ear mucosa. the rationale for treating ome is prevention of recurrence of aom. currently, a once-daily antibiotic regimen is the recommended prophylaxis. the benefit is also weighed against the increasing risk of emergence of resistant bacteria. when antibiotics fail to control recurrent om, a short trial of prednisone may be prescribed. surgery is recommended when medical treatment fails, especially when the child has hearing loss. tympanostomy tubes appear to be beneficial in ome but are of less value in chronic suppurative otitis. increase in hearing loss has been reported with insertion of ventilation tubes. adenoidectomy is sometimes recommended, especially after tympanostomy tube failure. any safe and effective cam therapy for om would be an important contribution to the pediatric population. large-scale, randomized, controlled studies for cam treatment would need medical collaboration, especially for otoscopic examination and tympanometry. in addition, since aom has a high rate of spontaneous resolution, any clinical study must also prove that treatment effect is faster than natural improvement. although breast-feeding has been found to reduce uri, data concerning its association with frequency or duration of om have been conflicting. epidemiologic reports consistently provide evidence of protection of young children from chronic otitis with prolonged breast-feeding. a u.s. study that followed infants at well-baby visits in two suburban pediatric practices reported that the cumulative incidence of first om episodes increased from % to % between and months of age in infants exclusively breast-fed versus % to % in infants formula-fed from birth. there was a two-fold risk of first episodes of aom or ome in formulafed babies in the first months. a danish study that evaluated infants using monthly questionnaires reported no statistical difference in the breast-fed versus formula-fed infants in incidence of om. an earlier jewish study comparing infants visiting a pediatric ed with healthy infants found that breast-feeding significantly reduced infectious diseases, including om in infants under months of age. a study from switzerland evaluated children with aom by administering individualized homeopathic medicine in the pediatric office. if there was insufficient pain reduction after hours, a second (different) homeopathic medicine was given. antibiotics were given if there was lack of response to the second dose. pain control was achieved in % of the patients after hours, with another % after hours. the resolution rate was . times faster than in placebo controls. no complications were observed in the study group. in a u.s. double-blind, placebo-controlled pilot study, children ages months to years with ome and ear pain and/or fever for more than hours were randomized into individualized homeopathic medicine or placebo group. no statistically significant results were noted. a british nonblinded, randomized pilot study was done with children ages months to years who had ome and hearing loss greater than db and an abnormal tympanogram. the results revealed that the homeopathy group had more children with a normal tympanogram, fewer referrals to specialists, lower antibiotic consumption, and a higher proportion with a hearing loss less than db at follow-up. however, the differences were not statistically significant. further research with larger groups is needed for a definitive trial. in a prospective, observational study carried out by one homeopath and four conventional ear-nose-throat (ent) physicians, a single (nonindividualized) homeopathic remedy was compared with nasal drops, antibiotics, and antipyretics. children between months and years of age were included in the study. homeopathic treatment was given to children and conventional treatment to children. homeopathic remedies were found to be significantly more effective in reducing duration of pain and in preventing relapses. because om tends to affect predominantly young children, it would be more appropriate for studies to compare results in children of similar age rather than a wide range of ages, from infancy to preadolescence. a retrospective, nonrandomized study of children under years of age receiving weeks of treatment from a single chiropractor reported a decrease in om symptoms. the limitations to this study included retrospection and a lack of comparison with the natural course of ear infections. an israeli controlled clinical trial examined the efficacy and tolerance of ear drops made with naturopathic extracts in the management of aom pain. ranging in age from to years, children were randomized into the treatment group and control group using a conventional anesthetic ear drop. there was statistically significant improvement in both groups, indicating that the naturopathic ear drops were as effective as the anesthetic ear drops. the university of arizona has initiated a study of the use of echinacea, a dietary supplement, in the prevention of recurrent om. acupuncture data are lacking on treatment of om in children. the theoretical potential benefit of acupuncture would appear to be its effect on the immune system, as discussed in the section on uri. allergic rhinitis affects % to % of children. perennial rhinitis is related to allergens that children are exposed to continuously, such as animal dander, house dust mites, mold, and feathers. seasonal rhinitis is related to seasonal pollenosis and rarely affects children under age or years. allergic diseases are major causes of morbidity in children of all ages, , , and allergic rhinitis is a significant cause of middle ear effusions. , , , conventional therapy usually consists of avoidance of allergens, use of air-clearing devices, desensitization shots, and medication with antihistamines and at times steroids, both of which are frequently abused. , antihistamines may be beneficial when sneezing and itching are present. cam therapy is common among children with allergic diseases in sweden and is becoming more popular in the united states, although scientific data specifically on children are still lacking. physicians have become more aware of the importance of nutrition , and environmental factors in the development of allergic symptomatology in childhood. , , a prospective, longitudinal study of healthy infants followed from birth to years of age concluded that recurrent wheezing is less common in nonatopic children who were breast-fed as infants. hypnosis has been reported anecdotally to be effective in hay fever. homeopathic efficacy has received increasing attention in recent years, but data consist of adult studies. an international multicenter study involving investigators in four countries and patients with three diagnoses, including upper and lower respiratory tract allergies, concluded that homeopathy appeared to be at least as effective as conventional medicine. another multicenter study using a randomized, double-blind, placebo-controlled parallel group design also demonstrated that homeopathic preparations differ from placebo for allergic rhinitis. homeopathic remedies for allergic children are unsupported by scientific studies at this time. an adult study using changes in conductance of specific acupuncture points for diagnosis and treatment demonstrated statistically significant changes that correlated with clinical improvement. in a randomized study of patients that included older teenagers, desensitization was compared with specific acupuncture treatment for allergic asthma, allergic rhinitis, or chronic urticaria. the study was ridden with multiple, tedious variables. the conclusion that acupuncture was significantly more effective than desensitization in improving symptoms and in reducing recurrence in all three conditions did not give a breakdown in age groups. in a clinical report of chronic allergic rhinitis cases that included three cases in children to years of age and cases in -to -year-olds, two different acupuncture treatments were administered according to tcm diagnoses. there was a cumulative % cure rate without age differentiation. asthma is the most common cause of chronic illness in childhood, with approximately % of children in the united states carrying the diagnosis. , , a significant number of school days are lost because of asthma. a wide variation of incidence is found in different countries, with the highest rates in the united kingdom, australia, and new zealand and the lowest rates in eastern europe, china, and india. , in recent years, prevalence of asthma is increasing worldwide, especially in children under years of age. , although asthma can have onset at any age, % to % of asthmatic children have their first symptoms before to years of age. children up to age years have distinct symptoms and require special consideration. they have increased health service utilization, including a higher annual rate of hospitalization, which has almost doubled in the united states from to for children to years of age. the same trend is observed by other nations worldwide. , among american children ages to years, asthma death rates almost doubled from to . new zealand and canada have observed a similar increase in severity and mortality. , asthma is a diffuse, reversible, obstructive lung disease with three major features: bronchial smooth-muscle spasm, edema and inflammation of the mucous membrane lining the airways, and intraluminal mucus plugs. during the last two decades, chronic airway inflammation, rather than smooth muscle contraction alone, has been recognized as playing the key role in the pathogenesis of asthma in adults. , although this association is less well established in children, recent guidelines for managing asthma in the pediatric population still have emphasized that treatment be directed toward the inflammatory aspects of the disease. , , chronic inflammation is caused by the local production of inflammatory mediators and an increase in recruitment of inflammatory cells, predominantly eosinophils and mast cells. studies in young adults suggest that the chronic inflammation may be responsible for longterm pulmonary changes, including bronchial hyperresponsiveness, airway remodeling, and irreversible airflow obstruction. because of difficulties in conducting studies in infants and young children, pediatric information is incomplete. limited studies have detected increases in inflammatory cells and thickening of the lung basement membrane in infants and young children and have found that asthmatic children have significantly lower lung function at years of age compared with nonwheezers when both groups of children began with the same baseline at age months. these data support the possible presence of an asthmalike inflammation at a very early age that is associated with nonreversible impairment of lung function. the excessive inflammatory changes indicate that asthma is caused by a poorly regulated "immunologic runaway response" that, instead of protecting the host, destroys normal structure. increased concentrations of proinflammatory mediators, such as histamine and leukotrienes, are found in the airways as well as the blood and urine of asthmatic patients during an acute attack and after allergen and exercise challenge. strong evidence correlates asthma with rsv infection; children who enter day nursery before age months and who are exposed to viruses early in life have built up immunity, with decreased development of allergies. in most children, whose asthma is triggered mainly by respiratory infections at a younger age, asthma symptoms appear to remit by the adolescent years. in older children and teenagers, emotions play a significant role both as the cause of symptoms and as the result of interplay of a chronic illness affecting the child's self-image and family dynamics. the latest asthma management guidelines classify pediatric asthma into four groups of severity: mild intermittent, mild persistent, moderate persistent, and severe. mild intermittent asthma can be typified by exercise-induced asthma, a common pediatric condition. status asthmaticus, defined as progressive respiratory failure that does not respond to conventional management, is becoming more prevalent in american children. conventional treatments for pediatric asthma vary from allergen avoidance to state-of-the-art biochemical therapy. avoiding allergens has been a successful management of asthma since the sixteenth century. asthma is a much more complex problem today because of the increasing number of pollutants and chemicals in the environment that are potential allergens for children. parental education, especially in regard to smoking, can reduce hospital admissions. because infections that trigger asthma attacks are mostly viral, antibiotics are not routinely indicated. medication consists primarily of bronchodilators and inhaled steroids, which are now justified as first-line therapy, both as long-term management and for acute attacks. because growth suppression due to inhaled corticosteroids has been well documented, it is important to distinguish infants with early-onset asthma from those with transient wheezing. recently, the fda has also approved leukotriene receptor antagonists for use in asthmatic children under years of age. these agents counteract the hyperimmune response, resulting in diminished airway inflammation and decreased eosinophilia in the airway mucosa and peripheral blood. parents turn to cam for their asthmatic children because of drug side effects or fear of taking long-term medication, especially steroids. , a recent survey from texas of multicultural parents of children with asthma reported the usage of a variety of cam therapies, including homeopathy, herbal therapy, vitamins, and massages. hispanic parents were more likely to use herbal and massage therapies, whereas african-american parents often turned to prayers. the relatively abundant studies on cam therapy in asthma are on adults and often have flaws in methodology. significant improvement , , and even complete cure have been demonstrated with hypnosis, although most studies had weak designs. hypnosis was recommended for children because they were found to be more hypnotizable, but it is unclear whether the efficacy of hypnosis in asthmatic children is a reflection of children's greater suggestibility or a result of a more reversible disease process. in a recent preschool program, children ages to years received treatment with seven hypnotherapy sessions. the number of physician visits was reduced, and parental confidence in self-management skills increased. tcm has been used to treat asthma for centuries. asthma epitomizes the chinese medicine concept of "winter disease, summer cure," which means the best treatment for asthma should be given during the summer, when the child is symptom free. in china, many asthmatic children who were treated with herbal patches applied to acupoints during the summer had minimal or no symptoms during asthmatic seasons. , , although several recent adult studies used herbs for asthma, only two involved children. a controlled study comparing herbal treatment of children with penicillin and aminophylline treatment of another children revealed no significant difference in the response from the two groups. a multicenter doubleblind, placebo-controlled clinical herbal study from taiwan evaluated asthmatic children using tcm diagnoses. the children were randomized into three different herbal and placebo groups. although both groups showed improvement, the herbal groups showed greater improvement in symptomatology and in biochemical changes, such as increase in total t cells and decrease in histamine. an animal experiment using a -herb concoction revealed . % efficacy in easing bronchial spasm. another animal study with an herbal preparation demonstrated strong smooth muscle relaxation through inhibition of histamine and acetylcholine. from the pediatric standpoint, it would be worthwhile to follow the development of external tcm approaches and noninvasive acupuncture. one clinical obser-vation of pasting chinese herbs to acupuncture points in infants with acute bronchitis showed high cure and improvement rate, especially in infants. humoral immune substances, especially iga, were found to be increased after treatment. another clinical observation reported % efficacy in children treated with external application of plasters made of herbal mixtures with antitussive and antiasthmatic properties and % efficacy in children treated with antiasthmatic herbal patches. success was also reported with a different herbal patch for acute attacks. the patches were well received by the children. improvement from acupuncture treatment has been reported in asthmatic adults. , , , despite methodologic weaknesses, it still seems that acupuncture may help asthma, especially drug-induced or allergic asthma. in some european countries, almost a fourth of general practitioners believe in the efficacy of acupuncture in the treatment of asthma. its role in the united states is still controversial; some physicians accept acupuncture's effectiveness, whereas others criticize data based on poorly conducted studies. the few current studies and clinical reports on acupuncture treatment of children with asthma are generally favorable. , a german practitioner reported good results treating asthmatic children using a simple acupuncture regimen in uncontrolled clinical experience. one study demonstrated that although acupuncture did not affect the basal bronchomotor tone, when administered minutes before exercise, acupuncture was shown to be effective in attenuating exercise-induced asthma, which is common in children. one possible mechanism of acupuncture is in reducing the reflex component of bronchoconstriction, but not in influencing direct smooth muscle constriction caused by histamine. for children who are fearful of or who cannot tolerate needles, safe and painless treatments such as cupping and auricular press pellets, laser acupuncture, , and massage of acupuncture points have also been found to be effective. the most interesting future role for acupuncture in asthma lies in its potential both in stimulating an immune response and, more importantly, in regulating or modulating a hyperimmune response. at this time, ample biochemical data in the literature support the theory that acupuncture activates both the humoral and the cellular immune systems to protect the host.* studies have also demonstrated that acupuncture can modulate the synthesis and release of proinflammatory mediators. , , current hypotheses suggest that this is most likely mediated through a common pathway connecting the immune system and the opioids, , , which has been well known to be associated with analgesic effects of acupuncture. homeopathic remedies have been reported to be remarkably effective in asthma in adults, , , and homeopathic doses of allergens have been shown to alleviate allergic symptoms and desensitize patients to allergens. however, there is paucity of scientific data on homeopathy in both children and adults, as well as a lack of consensus among homeopaths as to the appropriate treatment, administration regimen, or potency for asthma. homeopathic practitioners believe that in chronic conditions such as asthma, homeopathic remedies can stimulate the child's innate healing ability, thereby leading to improvement. , two recent large reviews on the role of homeopathy in clinical medicine concluded that, except for the occasionally demonstrated benefit, little scientific evidence exists to support the use of homeopathy in most clinical settings. , the availability of homeopathic, nutritional, and herbal remedies without a prescription is appealing to the asthmatic adolescent's desire for independence. in a number of european countries, chiropractic is often used for treatment of asthma. one of the many difficulties in evaluating chiropractic efficacy lies in the varying abilities of the manual therapy practitioners. natural human differences exist in manual applications and techniques. the practitioners have various training backgrounds, including physiotherapy, respiratory therapy, chiropractic, and osteopathy. a danish questionnaire survey of families with children up to age years reported that % of parents who sought chiropractic help considered the treatment beneficial for their children. , an australian survey reported that the most common cam visits were to chiropractors. a u.s. prospective, observer-blinded, clinical pilot evaluated children from to years of age with mild to moderate persistent asthma for chiropractic treatment in addition to optimal medical management. children were randomized into treatment and sham spinal manipulative therapy (smt) for months. the children with combined smt and medical treatment rated their quality of life substantially higher and their asthma severity substantially lower, and their improvements were maintained at -year follow-up. however, there were no significant changes in lung function or hyperresponsiveness. further research is needed to determine which components of the chiropractic encounter are responsible for the improvements. a controlled, patient-blinded trial of chiropractic manipulation for children with mild or moderate asthma randomized the children into an active or a simulated chiropractic manipulation for months. each subject was treated by of participating chiropractors, selected by the family according to location. no significant benefit was observed in the treatment group. a few studies in adults generated statistically insignificant data. one study found subjective but not objective improvements in individuals with asthma who received treatment in a chiropractic clinic. a systematic review revealed that the majority of the studies on smt had poor methodology; the two good studies did not demonstrate significant differences between chiropractic smt and sham maneuver. the reviewers concluded that the evidence is still insufficient at this time to support the use of manual therapies for patients with asthma. a german pilot study of children ages to years with bronchial asthma combined relaxation using various techniques, including progressive muscle relaxation, autogenic training, fantasy travels, mantras, and periodic music, and demonstrated significant improvement in a number of pulmonary function parameters. however, it is difficult to interpret the results because of the variety of techniques used. a u.s. review of anecdotal reports indicated that massage therapy can improve asthmatic symptoms. [ ] [ ] [ ] diarrhea acute diarrhea is a common occurrence in the pediatric population and a significant cause of pediatric morbidity and mortality in both developed and underdeveloped countries. , , each year an estimated , to , u.s. children are hospitalized for diarrhea, and more than million infants and young children worldwide die of acute infectious diarrhea. infants under months of age have the highest risk for hospitalization and mortality. children under age years have an average of approximately . episodes of gastroenteritis per year in the united states. , internationally, the average is approximately . episodes annually. both diagnosis and treatment continue to be problematic in the pediatric population. the infectious pathogens that cause acute diarrheal episodes in children include viruses, bacteria, and parasites. transmission is most likely through the fecal-oral route, from ingesting contaminated food or water, or in infants and toddlers, by mouthing contaminated toys. the nature of food-borne diseases is changing as more mass-produced, minimally processed, and widely distributed foods result in nationwide and international outbreaks of diarrheal disease instead of just a few individuals who shared a meal. a majority of the cases are caused by viral infections. rotavirus is the most prevalent, and human astrovirus (hastv) is a significant cause of diarrheal outbreaks. frequently, children are co-infected by several viruses. viral diarrhea tends to involve the small bowel, producing large, watery, but relatively infrequent stools. these illnesses usually have short, self-limiting courses, typically lasting to days. however, the diarrheal bouts can be devastating to children with compromised immune systems or structural abnormalities of the gastrointestinal tract. the most common bacterial agents are enteropathogenic escherichia coli, shigella/salmonella, and campylobacter. , these are much more virulent pathogens that usually cause mucocal injury in the small and large intestines, producing frequent, often bloody stools containing leukocytes. e. coli has become an important public health problem in recent years, causing more than , cases of infection and up to deaths per year in the united states. , transmission of infection is most often linked to consumption of contaminated meat, water, unpasteurized milk, leafy lettuce, alfalfa sprouts, and goat's milk, , and exposure to contaminated water in recreational swimming sites. the most common parasitic infection is giardia lamblia, which often causes secretory diarrhea without blood and frequently leads to chronic diarrhea. diagnosis and treatment are still inconsistent. because most acute diarrheal conditions are self-limited, physicians often do not obtain stool cultures or examination for ova and parasites because the results are not available sometimes for several days. stool culture can identify different types of bacteria, but detection of specific enteropathogenic strains of e. coli requires specific serotyping that is not performed in routine stool cultures. it is expensive, time-consuming, and often not sufficiently specific or sensitive and therefore is not recommended for routine diagnosis. the primary treatment focus is on correction of dehydration, which is the most important cause of morbidity and mortality in acute diarrhea. oral rehydration treatment (ort) with solutions containing appropriate concentrations of electrolytes and carbohydrates is recommended by the world health organization (who) and has significantly reduced mortality. , , after rehydration, early refeeding with a lactose-free or normal, age-appropriate diet is important for reducing diarrheal duration, severity, and nutritional impact. supplementation with specific dietary ingredients that are lost in diarrhea, such as vitamin a, zinc, and folate, is also recommended. because most of the acute infectious diarrheal conditions are viral, patients do not require antimicrobial therapy. , the rotavirus vaccine was put on the market in the united states in october . this vaccine, as the natural infection, decreases the risk of acute rotavirus diarrhea by % and the risk of severe diarrhea with dehydration by more than %. improving hygiene such as handwashing is also important, especially in day care. breast-feeding is one of the most important preventive measures. continuation of breast-feeding has been found to control acute diarrheal episodes and lower the frequency and duration of acute diarrhea, especially in infants under months of age. a large-scale randomized trial was conducted in hospitals in the republic of belarus. evaluation within the first year revealed that breast-feeding significantly reduced the risk of gastrointestinal tract infection compared with the control group. however, a survey from singapore of breast-feeding mothers at months postpartum revealed no significant differences in the rates of diarrheal diseases between breast-fed and non-breast-fed infants. treatment with antimicrobial therapy must be instituted carefully and only with specific identification of pathogen and drug sensitivity. with the increasing frequency of antibiotic resistance, common antibiotics may be ineffective in patients with acute diarrhea. , , treatment of salmonellosis with antibiotics can prolong the carrier state and lead to a higher clinical relapse rate. injudicious antimicrobial therapy may also lead to susceptibility to other infections, enhance colonization of resistant organisms, , and disrupt the normal intestinal flora, the body's natural defense against infection. homeopathy has the most convincing evidence of efficacy in treating diarrhea in children. a randomized, double-blind clinical trial comparing homeopathic medicine with placebo in the treatment of acute childhood diarrhea was conducted in nicaragua in . eighty-one children months to years of age were given treatment with individualized homeopathic medicine. standard ort was also given. there was a statistically significant decrease in the duration of diarrhea in the treatment group. although criticisms of the study include homeopathic theory being inconsistent with scientific belief and possible toxicity of the dilute homeopathic remedies, the report was also praised for being an impressive, well-designed study that paves the way for future research into the efficacy of homeopathy and other cam therapies. using the predefined measures based on the study, the same group of researchers more recently carried out a similar study and replicated the same findings of decrease in the duration of diar-rhea and number of stools in children in nepal, ranging in age from months to years. a few studies have demonstrated effectiveness of acupuncture in pediatric diarrhea. the treatment protocols in point selections generally depend on tcm diagnoses, with the majority of points chosen on the two major digestive channels. , , , , acupuncture has also been shown to induce favorable anatomic and biochemical changes in improving intestinal peristaltic function and in enhancing both humoral and cellular immunity. a randomized study comparing shallow acupuncture treatment (needles inserted superficially and withdrawn swiftly) with drugs in children ages to months reported significantly higher therapeutic effect in the acupuncture group. the diagnosis and subsequent choice of points were based on tcm principles, not on stool culture results. unlike the homeopathy study, this investigation grouped together patients with acute and chronic diarrhea. in a clinical trial using one chinese herbal formula for treatment of acute diarrhea, there was significant reduction of symptoms and duration of diarrhea. a clinical report of years' application of a seven-herb concoction in children demonstrated . % improvement and % cure rate. this nonrandomized, nonblinded report used tcm diagnoses that encompassed a variety of diarrheal conditions, including acute, chronic, infectious, and noninfectious diarrhea. the mechanisms were hypothesized as eliminating pathogenicity, improving immunity, accelerating intestinal digestion, and inhibiting intestinal peristalsis. in a clinical report comparing chinese herbs to western medicine in children with diarrhea due to rotavirus, the herbs were reported to be superior and had a viral inhibitory rate of . %, but no mention was made of the efficacy of conventional medicine. chronic nonspecific diarrhea of childhood differs from acute diarrhea in that it is not associated with significant morbidity. once potentially serious causes are excluded, appropriate diet can be instituted to minimize complications, and reasonable time is then allowed for spontaneous resolution. in a nonrandomized clinical trial involving children ages months to years with chronic diarrhea of to months' duration that was unresponsive to western medicine and tcm, individualized acupuncture treatment eliminated symptoms and normalized stools. infantile colic is estimated to affect % to % of all infants under months of age and remains a medical enigma of nature versus nurture. colic may represent a heterogeneous expression of developmental variance, unmet biologic needs, psychologic or emotional distress from poor parent-infant interaction, intrinsic temperamental predisposition, colonic hypermotility, or milk allergy.* although colic is selflimiting by to months of age, treatment is mandated because the psychologic consequences may result in a disturbed mother-infant relationship. , evidence suggests that uncontrollable crying is the precipitating factor in many cases of infant abuse. , because the precise etiology is not understood, the therapeutic goal of western medicine is not aimed at "curing" colic but at containment of the crying. removing cow's milk protein from the mother's diet, changing formula, and prescribing antispasmodic medications are the mainstays of conventional treatment and may be helpful. treatment is often directed toward behavioral changes in mothers. parents may be referred for therapy to learn parenting and coping skills. cam treatments yield inconsistent results. herbs have not yet been proven to be efficacious, although a survey of hispanic mothers in an urban neighborhood in texas revealed that herbal teas were commonly used for colic. evidence is controversial for chiropractic treatment of colic. a multicenter prospective, uncontrolled study of colicky infants involving chiropractors in clinics in the united kingdom for months demonstrated efficacy with chiropractic smt in controlling colic, as reported by mothers in % of cases. a retrospective questionnaire study in revealed satisfactory results of chiropractic treatment in % of infants. a randomized, blinded, placebo-controlled clinical trial of infants with typical colic reported that chiropractic manipulation was no more effective than placebo. however, a randomized, controlled, -week trial comparing smt with the drug dimethicone demonstrated significantly better results in the chiropractic treatment group. craniosacral therapists empirically claim success in treatment of colic. massage therapists have also found empirically that touch therapy can decrease severity of colic. in a finnish clinical trial, infants less than weeks of age perceived as colicky by their parents were randomized into an infant massage group (n = ) and a crib vibrator group (n = ). over weeks there was no difference in the reduction of colicky crying between infants receiving massage and those with a crib vibrator, leading the investigators to conclude that the decrease of crying reflects more the natural course of early infant crying and colic than a specific effect of intervention. therefore infant massage is not recommended as treatment for colic. enuresis is defined as inappropriate or involuntary voiding during the night at an age when urinary control should be achieved. enuresis is a complex disorder with poorly understood pathogenicity and pathophysiology. it affects children worldwide, with about to million children affected in the united states and as many as % of school-age children in italy. the condition is classified as primary nocturnal enuresis (pne) when the child has never been dry at night or secondary nocturnal enuresis (sne) when wetting follows a dry period, usually after an identifiable stress. , by age years, % to % of children should have nighttime dryness. in % of pne patients, bedwetting is monosymptomatic, with a spontaneous remission rate of % per year of age. both the etiology and the pathophysiology of enuresis are still not well understood. multiple factors may interplay: genetic and psychologic predispositions, delayed maturation of the central nervous system, sleep disorders, urinary reservoir abnormalities, detrusor-sphincter incoordination, and urine production disorders. although enuresis is benign, treatment is warranted because of adverse personal, family, and psychosocial effects. , nocturnal enuresis delays early autonomy and socialization because of a decrease in self-esteem and self-confidence and a fear of detection by peers. the child may be at increased risk for emotional or even physical abuse from family members. , the conventional treatment modalities are still controversial. because the vast majority of pne cases resolve spontaneously with time, treatment should carry minimal or no risk. the moisture alarm is both safe and inexpensive and should be the treatment of choice in most cases , , but is often the one least prescribed. , the medications imipramine and ddavp were frequently chosen as first-line treatment choices. adjunctive therapy may include bladder-stretching exercises, which have a success rate of %, and behavioral conditioning. numerous cam therapies are available for childhood enuresis; the most common are hypnosis, acupuncture, and biofeedback. less common cam therapies are chiropractic and nutrition management. hypnotherapy has been recognized by conventional practitioners as a potentially effective therapy. , uncontrolled studies have reported high rates of success. , , , , in one comparative study of imipramine and direct hypnotic suggestion with imagery for functional nocturnal enuresis in -to -year-old patients, % of the imipramine group and % of the hypnosis group had positive response. after termination of treatment, the hypnosis group continued practicing self-hypnosis. at -month follow-up, % of the hypnosis group maintained dryness compared with only % of the imipramine group. hypnosis and self-hypnosis were found to be less effective in younger children (ages to years) compared with imipramine treatment. hypnotherapy has the added advantage that nonphysician health care professionals, such as nurse practitioners, can easily learn the technique to help children. a recent review of controlled studies reported promising findings for hypnosis in children with enuresis, but none of the interventions can currently qualify as efficacious. a major limitation is the lack of treatment specification via a manual of its equivalent. the requirement that the child practice the self-hypnosis technique several times a day limits compliance with the program. acupuncture has been used as an effective treatment for enuresis since at least the s. current worldwide literature in general demonstrates its viability as either a primary or an adjunctive therapy for the enuretic child.* a turkish clinical study on subjects treated with electroacupuncture therapy reported a success rate of . %. acupuncture has been found to be successful both in decreasing the occurrence of enuresis during treatment and in exerting a long-term effect after treatment. , , parents also report a decrease in sleep arousal threshold. although the precise mechanism of acupuncture is still unknown, a multidisciplinary approach that included acupuncture demonstrated on electroencephalography (eeg) that treatment normalized activities of the cerebral cortex. data from china usually consist of clinical reports of large sample populations. results in one study of patients treated with acupuncture on only two body points demonstrated cure in patients ( %), improvement in , and no response in patients. number of treatments ranged from one to three in patients and four to six in . another study of enuretic children ages to years ( over years; oldest years) used tcm diagnosis of organ imbalance and different combinations of acupuncture points, with treatments constituting one course. the results showed that patients were cured, showed marked improvement, and were "effectively" treated. treatment using scalp acupuncture has also been reported to be successful. in one clinical study, children ages to years were treated for to sessions, and some needed a second course. cure was obtained in children, marked improvement in , improvement in , and no response in children. in all these clinical reports, subjects of a wide range of ages were included in the same study; the discussions were short and generalized, giving very few or no details about the children (e.g., types of enuresis, duration of enuresis, number of wet nights, types of improvement); the methods of treatment were laden with numerous variables (e.g., number of points, treatment courses). a clinical study from italy of children with bladder instability due to uninhibited contractions of the detrusor muscle reported that acupuncture treatment was successful in gradual elimination of enuresis in and improvement of symptoms in children. the mechanism was not clarified. a russian clinical trial of using acupuncture specifically for enuresis due to neurogenic bladder dysfunction demonstrated that acupuncture was beneficial in of children. in a clinical report of enuretic children, short-term success in reducing wet nights was % with acupuncture versus % with ddavp, whereas long-term success rates were % and %, respectively. a zagreb report of a clinical trial of acupuncture treatment on children with mean age of years who failed psychotherapy demonstrated a statistically significant decrease in enuresis even at months after treatment. a self-controlled regulating device operating on the principles of acupuncture was found to be effective in the treatment of nocturnal enuresis attributable to neurogenic bladder dysfunction. a controlled clinical study of children between and years of age randomly selected into four groups of : treatment with ddavp alone, acupuncture alone, combined ddavp with acupuncture, and placebo. efficacy of treatment, expressed as a percentage of dry nights, was high in both ddavp and acupuncture groups, but the combined-treatment group had the best results. a scandinavian clinical trial used traditional chinese acupuncture for treatment of primary persistent pne in children ranging in age from to years. the response rate was monitored at -week, -week, and -month intervals. within months, ( %) of children were completely dry and ( %) were dry on at least % of nights, leading the clinicians to conclude that acupuncture is effective, with stable results. another scandinavian study investigated the efficacy of electroacupuncture in treating children ranging in age from to years. twenty treatments were administered over weeks. the number of dry nights consistently increased when the children were reevaluated at weeks, months, and months after treatment. five children had more than % reduction of wet nights at months, and % had more dry nights at the -month follow-up. a recent teaching round at the china academy of traditional chinese medicine in beijing discussed successful acupuncture treatment of a complicated case of enuresis in a -year-old student who had previously failed both western and chinese medicines for his physical and emotional sequelae. using tcm diagnosis of organ imbalances, the treatment combined body acupuncture, scalp acupuncture, and auricular acupressure seed. the patient began improving after three treatments in the first week. he received more weeks of treatment, with no recurrence of enuresis at month follow-up. children are often unwilling to undergo needle acupuncture because of fear of pain, prompting researchers to use noninvasive forms of acupuncture. simple acumassage has been previously reported to be beneficial to the enuretic child. an austrian prospective, randomized trial evaluated efficacy of laser acupuncture versus desmopressin in children over age years with pne. at -month follow-up, the desmopressin-treated group had % success rate with complete resolution of symptoms, an additional % had a more than % reduction in wet nights, and % did not respond. the laser acupuncture group had %, %, and % rates, respectively. the results were not statistically significant. therefore laser acupuncture should be considered as an alternative, noninvasive, painless, cost-effective, and short-term therapy in children with normal bladder function and high nighttime urine production. worldwide reports have demonstrated efficacy in treating enuresis with biofeedback, , , , which aims at learning or relearning of influence of involuntary functions. a clinical study from italy treated boys and girls ages to years with detrusor-sphincter dyssynergy. biofeedback was successful in all the children, with sne resolving significantly sooner than pne and girls responding better than boys. two-year follow-up still revealed an . % success rate, with % at years. in a french study, children with three predominant urinary disorders that included nocturnal enuresis were treated with biofeedback. detrusor-sphincter discoordination was diagnosed in children. pelvic floor biofeedback produced excellent results in these children. belgian investigators reported a clinical biofeedback study of children with median age of . years who did not respond to anticholinergics. seventeen subjects had complete resolution of enuresis, six had a decrease in symptoms, and one child did not respond. at -month follow-up, two children in the cured group had recurrence of enuresis. another study from belgium also reported success in using biofeedback in children with pseudo-detrusor-sphincter dyssynergy; were completely cured, and improved considerably. a spanish study used biofeedback to treat unstable detrusor in enuretic children; complete disappearance of symptoms was seen in . %, with improvement in . %. in a u.s. report of boys and girls ages to years who underwent an average of hours of biofeedback for nocturnal and diurnal enuresis, improvement was noted in % of nocturnal enuresis and % of diurnal enuresis. another u.s. clinical study used biofeedback for children with dysfunctional voiding; ( %) had an excellent response, ( %) had a fair response, and ( %) was too inconsistent to rate. the average number of sessions to achieve a consistent urodynamic response was . (range to ). average follow-up was months (range to months). the investigators recommended biofeedback as an effective method that requires only a short period for treating dysfunctional voiding. all these worldwide studies were clinical reports, not randomized, controlled, blinded studies. the efficacy of chiropractic manipulation in enuresis has been inconsistent. one clinical report identified an -year-old boy with functional enuresis who had successful treatment with manipulation. in an uncontrolled study of children ages to years, with responses monitored by parents, chiropractic manipulation resulted in only . % success. however, a randomized, controlled clinical trial of children demonstrated that % of the treatment group had % or more reduction in enuretic symptoms, although the pretreatment to posttreatment change in wet night frequency was not statistically significant, and there was no long-term follow-up. a comprehensive review of the literature revealed that smt was no more effective than the natural regression of enuresis with age. food allergy as a cause of enuresis has been in the literature for several decades. a recent study of children with severe migraine or attention deficit disorder (add) included children with enuresis. oligoantigenic diets were successful in curing children and improving enuresis in other children. relapse of wetting occurred when foods were reintroduced; the substances implicated most often were chocolate, citrus, fruits, and milk from cows. although no studies are available on naturopathic approaches, which focus on natural remedies (e.g., corn silk and tea, tea and honey), physicians should not dismiss parental opinion that these remedies may be safe and effective. the future of treatment for enuresis should combine various methods to increase the probability of treatment success and minimize risk to the child. atopic dermatitis affects almost % of all children and % of children ages to years. , it accounts for more than % of outpatient pediatric visits. most children with atopic dermatitis typically come to medical attention with cradle cap and facial and extremity rashes by age to months. despite considerable research, the etiology of allergic disease remains poorly understood. allergic dermatitis can be thought of as an inherited skin "sensitivity" that reacts to various external allergens and changes in psychologic states. food causes atopic dermatitis in % of infants, % to % of young children, and % to % of children after puberty. topical steroids remain the main therapeutic method. dermatologists tend to prescribe antibiotics and use potent topical steroids, which are more readily absorbed in children and can result in hypothalamic-pituitary-adrenal axis suppression. new immune modulators have shown promise in severe atopic dermatitis. , cam therapies are increasingly used for dermatitis, although most of the information is in clinical reports, and research data are limited. a database review of randomized clinical trials of atopic eczema covering at least different interventions revealed that evidence is still insufficient to make recommendations on maternal allergen avoidance for disease prevention, herbs, dietary restrictions, homeopathy, massage therapy, hypnotherapy, or various topical cam therapies. a multicenter randomized clinical trial conducted in hospitals in the republic of belarus reported that breast-feeding significantly reduced the risk of atopic eczema compared with the control group in the first year of life. psoriasis was found to worsen with cam treatments such as herbs, dietary manipulation, and vitamins. dietary management with evening primrose oil, rich in gamma-linolenic acid, has been found to be inconsistently effective in small studies. fish oil supplements (enriched in n- polyunsaturated fatty acids) have also been used. various herbs offer relief for eczema. a placebo-controlled, double-blind trial used a chinese herbal prescription specifically formulated for widespread nonexudative atopic eczema. thirty-seven children were randomly assigned to -week active treatment and placebo, with an intervening -week "washout" period. the response to active treatment was significantly superior to placebo, without evidence of hematologic, renal, or hepatic toxicity. the same investigators monitored the children over the following months. eighteen children had at least a % reduction in eczema, and five showed lesser degrees of improvement. two randomized, double-blind placebo-controlled trials from singapore revealed that a concoction of chinese herbs was efficacious in the treatment of atopic dermatitis in both children and adults, and that the mechanism may be through the beneficial immunosuppressive effects. toxicity is a concern, however, because exact dosing of the active derivatives is difficult to achieve. acupuncture treatment of acne has been reported to be successful in as many as . % of adolescents given treatment. other tcm techniques have also been reported to be helpful. a clinical trial treated children with severe, resistant atopic dermatitis with hypnosis. nineteen showed immediate improvement, maintained improvement in itching, and maintained improvement in sleep disturbance months after treatment. homeopathy is frequently used to treat dermatitis. in one homeopathic clinic in israel, more than % of the patients expressed satisfaction with treatment. however, the authors of the survey believed that homeopathic medicine complements conventional medicine and is not an alternative. chiropractic treatment has also been sought by children for allergic problems. a small british study tested the hypothesis that massage with essential oils (aromatherapy) used as a complementary therapy in conjunction with normal medical treatment would help to alleviate the symptoms of childhood atopic eczema. eight children were randomized into the treatment group, who were massaged with oil, and the control group, massaged without essential oil. no significant difference was found between the two groups. there was a later deterioration of eczema in the oil massage group, suggesting allergic contact dermatitis provoked by the essential oils themselves. attention deficit-hyperactivity disorder (adhd) is the most common neurodevelopmental disorder of childhood, with a prevalence rate between % and %, averaging about %. , , the road constellation of hyperactive, inattentive, and impulsive symptoms combined with the multiple comorbid conditions makes the definition and adhd controversial and the diagnosis flawed. adhd is a chronic, heterogeneous condition with academic, social, and emotional ramifications for the school-age child. the disabling symptoms persist into adolescence in approximately % of children and into adulthood in approximately %. , there is a developmental pattern in the primary symptoms of the disorder; hyperactivity diminishes while attentional deficits persist or increase with age. the precise etiology of adhd is still unknown, and assessment and management remain diverse. medication continues to be the mainstay of treatment, with methylphenidate (ritalin) the treatment of choice. the tricyclic antidepressants were added as an alternative medication in the s, with clonidine, buspirone (buspar), and other antidepressants and neuroleptics added to the list in the s. , although it is generally agreed that drugs are beneficial on a short-term basis, there is a paucity of data on the long-term efficacy and safety of medications, especially in children younger than years of age. these drugs have not been shown to produce long-term gains academically or socially. besides pharmacotherapy, a multimodal approach using a combination of drugs and other methods, such as cognitive-behavioral therapy (cbt), psychotherapy, social skills training, and school interventions, is frequently prescribed for adhd. cbt represents the most widely used alternative to pharmacotherapy, although previous studies have shown disappointing results. , , , in the national institutes of mental health (nimh) began a -month, multisite clinical trial, the multimodal treatment study of adhd (mta). , the results indicated that high-quality medication management (with careful titration and follow-up) and a combination of medication and intensive behavioral therapy were substantially superior to behavioral therapy and community medication management. there is slight advantage of combination of medication and behavioral therapy over medication alone. psychotherapy can be an effective adjunct to medication , but usually requires a long-term commitment to several years of treatment. concerns about side effects of medication, , treatment acceptability, , and compliance are additional factors that complicate management of the adhd child. clearly, there is room to explore safe, acceptable, and relatively easy alternatives. interest is increasing in more natural, holistic integrative approaches to adhd. studies using cam therapy for treating adhd encompass more than the usual research difficulties because of the complexity and heterogeneity of the disorder, as well as subjective evaluation by parents and teachers of a wide range of characteristics that may qualify for several different diagnoses. a majority of the cam therapies to date continue to have mostly anecdotal and empiric evidence. the few welldesigned studies include biofeedback, herbal medicines, dietary modifications or supplements, and acupuncture. studies have demonstrated that there is a significant difference in baseline eeg measurements in children with attention deficit disorder (add) compared with normal-achieving preadolescent males. these differences occur mainly in the parietal region for on-task conditions and in the cortex and corticothalamic excitatory and inhibitory interactions. , biofeedback or neurofeedback is a technique for modifying neurophysiology for learning. in a critical review of studies in which biofeedback was used as a treatment for hyperactivity indicated that biofeedback alone had not been effectively evaluated, and methodologic problems limit generalizations that it may be applicable to the entire hyperactive population. a review continues to indicate that although anecdotal and case reports cite promising evidence, methodologic problems coupled with a paucity of research preclude any definitive conclusions as to the efficacy of enhanced alpha and hemisphere-specific eeg biofeedback training. some recent studies using more sophisticated technology claim that neurofeedback can improve attention, behavior, and intellectual function in the child with add, , , with measurable eeg improvement in the frontal/central cortex. its stabilizing effect has also been found to last as long as years after treatment. hypnotherapy and biofeedback do not appear to alter the core symptoms of adhd but may be helpful in controlling secondary symptoms. these methods allow children to become active agents of their own coping strategies. a mailed questionnaire survey of children with adhd with a % response rate reported that % were using stimulant medication and that % of the respondents used or were using a nonprescription therapy. diet therapies constitute the most common cam therapy ( %). one review of cam therapy lends support to individualized dietary management and specific trace element supplementation in some children with adhd. nutritional management of add includes elimination diet, megavitamins, , supplements, and trace element replacement. simple sugar restriction seems ineffective. the well-known feingold diet eliminates natural salicylates, food colors, and artificial flavors. studies have demonstrated mixed results. megavitamins were demonstrated to be ineffective in the management of add in a two-stage study with clinical trial and double-blind crossover. potential hepatotoxicity is a major concern with use of megavitamins. in a recent longitudinal, nonrandomized clinical trial, adhd children were given a glyconutritional product containing saccharides known to be important in healthy functioning and a phytonutritional product containing flash-dried fruits and vegetables. five children were not receiving methylphenidate (ritalin), six children were taking prescribed doses of methylphenidate, and the remaining six children had their medications reduced by half after weeks. the glyconutritional supplement was administered for the entire weeks, and the phytonutritional supplement was added after weeks. the teachers and parents rated behavioral items for adhd, oppositional defiant disorder, and conduct disorder. the conclusion was that the glyconutritional supplement decreased the number and severity of adhd, associated odd and cd symptoms, and side effects of medications during the first weeks of the study; there was little further reduction with the addition of the phytonutritional supplement. the three groups did not differ statistically in degree or reduction of symptoms. this -week study had too many variables and too few subjects without control for a definitive conclusion, although the concept of simple nutritional supplement is important to explore. there is increasing interest in abnormality of fatty acid metabolism as the etiology of at least some features of adhd. these abnormalities can range from genetic abnormalities in the enzymes involved in phospholipid metabolism to symptoms that were reportedly improved after dietary supplementation with long-chain fatty acids. in a randomized, double-blind, placebo-controlled trial of docosahexaenoic acid (dha) supplementation, children ages to years receiving stimulant medication were randomly assigned to receive dha supplementation or placebo for months. there was no significant improvement in the treatment group. oligotherapy focuses on deficiency of trace elements in children with add. , in a polish controlled clinical trial, magnesium deficiency was found in blood and in hair of hyperactive children. fifty -to -year-old add children were given a magnesium supplement of mg/day for months while the control group of children continued on their medical regimen. increase in magnesium contents in hair correlated with a significant decrease of hyperactivity in the treatment group, whereas hyperactivity actually intensified in the control group. the same investigators also found deficiencies of copper, zinc, calcium, and iron, with magnesium being the most common deficiency, in children with adhd. a thorough literature review of alternative treatments for adhd identified cam therapies and reported that chinese herbal treatment has promising pilot data. a clinical trial using chinese herbs in the treatment of children with a diagnosis of hyperkinesia based on the american psychiatric association's diagnostic and statistical manual of mental disorders, ed revised (dsm-iiir) criteria demonstrated . % effectiveness in ameliorating hyperactivity and improved attention and school performance. the herbal remedy was prepared according to the tcm diagnosis of common energetic (qi) imbalance found in these children. clinical observations were substantiated by laboratory findings of significant increase in urinary content of norepinephrine, dopamine, dihydroxyphenylacetic acid, cyclic adenosine monophosphate, and creatinine. in a randomized study, chinese herbal treatment was found to be comparable to methylphenidate but had fewer side effects. research is currently being conducted to investigate the efficacy of herbal and homeopathic remedies because current evidence is inconsistent or lacking. in a prospective, randomized, double-blind pilot study funded by nih that integrated dsm-iv diagnostic criteria, conventional theories of frontal lobe dysfunction, and neurotransmitter abnormalities with traditional chinese theories of energetic imbalances, laser acupuncture was used in the treatment of adhd in -to -year-old children. preliminary data on the six children in the treatment group showed promise in reducing signs and symptoms of adhd. using conners scale as a weekly follow-up measure, improvement in classroom behavior was reflected by substantial drops in the teachers' scores before and after treatment in five of six children. the parents' scores dropped in three children but did not change in the other three children (figures - and - ). one child was promoted to the gifted program, and another demonstrated marked improvement in learning disabilities. there are no data at this time on homeopathic or chiropractic treatment of adhd, although many practitioners claim anecdotal success with the use of homeopathic desipramine (norpramin) and manipulation. pediatric use of cam therapies continues to increase. it is therefore advisable for physicians who treat children to take a thorough history of cam use, especially in those with chronic disorders, to become knowledgeable about the various alternative therapies that can complement conventional care. this allows practitioners to consider possible adverse effects or interactions of cam with conventional therapy, to open lines of communication with cam providers, and even to consider integrating effective cam therapy into their medical regimen. although cam therapy is in general considered safe, there have been a few reports of significant side effects. , continuous research is needed to investigate the safety and efficacy of cam therapies for children; to address explicitly the tremendous heterogeneity between and among the practices, beliefs, and providers of professional and lay services; and to study how cam may enhance the quality of mainstream health services. although children are entitled to new therapies, pediatric research in cam is further complicated by children's vulnerability to violation of their personal rights and to risk exposure. in children of the same age, varying cognitive capacity can be required for informed consent. , differences in physiologic maturation can change the kinetics, end-organ responses, and toxicity of therapy, so data from adult studies cannot be extrapolated for children. even in conventional medicine, children are often rendered "therapeutic orphans" because of history of abuses in pediatric research, a heightened sensitivity to risks in children-especially since the thalidomide disaster-and a limited market potential. in the united states, % of drugs have age limits or contain disclaimers for pediatric use. therefore protecting children by giving them only scientifically proven therapies is counterbalanced by denying them access to possible safe and effective treatment that may not be proven for many years to come. a frequently expressed concern is that visits to cam practitioners may cause delay in diagnosis. a more serious concern is the lack of formal pediatric training in many cam therapists so that they may fail to 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evaluative research a clinical case: asthma and staphysagria and homeo-mesotherapy the effect of acupuncture on bronchial asthma a randomized, double-blind, placebo-controlled trial of docosahexaenoic acid supplementation in children with attention-deficit/hyperactivity disorder national vaccine information centre: first international public conference on vaccination ileal-lymphoid-nodular hyperplasia, non-specific colitis and pervasive developmental disorder in children viral respiratory infections the homeopathic treatment of asthma and allergies role of astroviruses in childhood diarrhea clinical therapy and etiology of viral diarrhea in children potential diagnostic aids for abnormal fatty acid metabolism in a range of neurodevelopmental disorders worldwide variations in the prevalence of atopic symptoms: what does it all mean? psychosocial implications of nocturnal enuresis the role of alternative therapies in the treatment of allergic diseases pharmacotherapy of asthma in children, with special reference to leukotriene receptor antagonists treatment of infantile colic with diclyclomine hydrochloride status asthmaticus in children : a review upper respiratory tract infections in adolescents the short-term effect of spinal manipulation in the treatment of infantile colic: a randomized controlled clinical trial with a blinded observer alternative/complementary medicine: wider usage than generally appreciated environmental control in the prevention and treatment of pediatric allergic diseases prospects for the prevention of allergy in children atopic disease, rhinitis and conjunctivitis, and upper respiratory infections allergen avoidance: does it work surveys of complementary and alternative medicine. i. general trends and demographic groups relationship of infant feeding to recurrent wheezing at age years current treatment of allergic rhinitis and sinusitis cases of enuresis treated with acupuncture treatment of acne with ear acupuncture-a clinical observation of cases cases of child bronchial asthma treated by auricular plaster and meridian instrument acupuncture of guanyuan (ren ) and baihui (du ) in the treatment of cases of enuresis effect of acupuncture on bronchial asthma acupuncture treatment of chronic rhinitis in cases immediate antiasthmatic effect of acupuncture in cases of bronchial asthma preliminary study of traditional chinese medicine treatment of minimal brain dysfunction: analysis of cases clinical and experimental study on yifei jianshen mixture in preventing and treating infantile repetitive respiratory infection clinical investigation on massage for prevention and treatment of recurrent respiratory tract infection in children pneumococcal conjugate vaccine for young children prevention of asthma morbidity: recent advances key: cord- -cvawdes authors: darling, robert g.; noste, erin e. title: future biological and chemical weapons date: - - journal: ciottone's disaster medicine doi: . /b - - - - . - sha: doc_id: cord_uid: cvawdes nan robert g. darling and erin e. noste biological and chemical weapons have been used throughout history. for millennia, indigenous south american peoples deliberately used plant-derived arrow poisons such as curare and toxins from poison dart frogs, although these preparations were used mainly for hunting. similar toxins were used in africa. the ancient greeks, for whom toxikon meant "arrow poison," tipped arrows with winter aconite, and this practice continued into medieval europe, persisting into the seventeenth century in spain and portugal. soldiers in india used smoke screens, incendiary weapons, and toxic fumes as early as bce, and the sung dynasty in china employed a wide variety of arsenical smokes and other poisons in battle. the military use of toxins dates from at least the sixth century bce, when assyrian soldiers poisoned enemy wells with ergotcontaminated rye. in bce, during the peloponnesian war, thracian allies of sparta captured the athenian fort at delium by using a long tube and bellows to blow poisonous smoke from coals, sulfur, and pitch into the fort. greek fire (likely composed of rosin, sulfur, pitch, naphtha, lime, and saltpeter) was invented in the seventh century ce and proved to be a very effective naval weapon. various poisons saw battlefield use during medieval times, and the use of poisons for murder (including assassinations) became widespread. other examples before the twentieth century include the contamination of water by dumping the corpses of dead humans or animals into wells, the use of snakes and other creatures as poisonous vectors, and occasionally, fomites to transmit infections such as smallpox to unsuspecting victims. this latter technique was used with remarkable success during the french and indian war ( - ), when sir jeffrey amherst was alleged to have given "gifts" (blankets) harboring the pus and scabs from smallpox victims to unsuspecting native americans. the indians possessed no immunity against smallpox and thus experienced very high rates of infection and mortality as smallpox swept through the local tribes. during the late nineteenth and early twentieth centuries, the science and technology necessary for the development of sophisticated biological and chemical weapons proceeded apace. world war i saw the first large-scale use of "poison gas," including lacrimators, chlorine, phosgene, arsenicals, cyanide, and sulfur mustard. by the end of the war, nearly one in every three rounds was a chemical munition. dr. shiro ishii and other japanese scientists in the infamous unit worked on the weaponization of anthrax, plague, smallpox, and tetrodotoxin as well as a variety of chemical agents during world war ii. there are even suspicions that the bomb used in the assassination of reinhard heydrich in czechoslovakia in contained botulinum toxin. after world war ii, ricin was used as an injectable assassination weapon, and in the s and s t- toxin, a trichothecene mycotoxin, was alleged to have been the toxic component of the "yellow rain" employed against h'mong refugees from laos. more recently, iraq and iran both used chemical weapons against each other in the iran-iraq war of the s, and iraq had a weapons program that included the development of sulfur mustard, nerve agents, "agent " (an anticholinergic incapacitating agent), botulinum toxin, epsilon toxin from clostridium perfringens, and aflatoxin. militia groups in the united states and terrorist groups throughout the world have used ricin for political purposes. american scientists started developing chemical weapons as a response to the use of chemical warfare in europe during world war i and conducted both offensive and defensive research on biological and chemical weapons. however, in the united states unilaterally renounced the first use of chemical agents, halted chemical-agent production, and terminated its offensive biological weapons program. in the biological weapons and toxins convention was created; it was signed by representatives from nations, including the united states (which ratified the convention in ), the soviet union, and iraq, although many signatories did not consider toxins to be biological weapons and did not consider the treaty binding on toxin use. since that time, at least nations have either signed or ratified this treaty. however, the soviet union and iraq began violating the treaty in short order. in the soviet union, weapons scientists stepped up research and development of numerous biological and chemical weapons as part of one of the largest and most comprehensive biological-weapons programs in history. soviet scientists created large stockpiles of weaponized anthrax, plague, smallpox, tularemia, nerve agent, mustard, and other biological and chemical agents. in the world was put on notice of the devastating potential that biological weapons pose to humanity. in that year, a small quantity of weapons-grade anthrax was accidentally released from a manufacturing plant located in the former city of sverdlovsk (now yekaterinburg) in russia, resulting in cases and deaths. dr. matthew meselson, a harvard scientist, was permitted to study the event many years later and reported the results of his work in a science article. meselson determined that the majority of the deaths had occurred among victims living in a narrow, -km-wide band downwind from the plant. animal deaths were confirmed as far as km downwind. meselson further concluded that less than g of weapons-grade anthrax had been released from the plant. if his calculations are accurate, weaponized anthrax possesses staggering potential as a biological weapon given its stability, its relative ease of production, and its ability to be dispersed in a clandestine manner over great distances. in march , after having unsuccessfully attempting to deploy biological agents, members of the aum shinri kyo cult executed a coordinated attack with the nerve agent sarin (gb) on the tokyo subway system. more than people sought medical treatment, and a dozen died. the aum shinri kyo had used sarin in matsumoto months earlier in an attack that had exposed more than people and killed in an attempt to assassinate judges unfavorable to their cause. , the anthrax attacks in the fall of involved the use of letters containing weapons-grade anthrax mailed through the u.s. postal system. five people died, and became ill with either cutaneous or inhalational anthrax. buildings contaminated with spores included the hart senate office building and the brentwood postal facilities in washington, dc. it cost millions of dollars to rehabilitate these buildings. the anthrax used in the attacks was determined to be extremely potent and could have caused far greater numbers of casualties had it been dispersed more widely. , the use of chemical weapons also occurred in recent history. in september the united nations (un) released their investigations on the use of chemical weapons in syria. the un concluded that sarin gas was used on august , , in the ghouta area of damascus against "civilians, including children, on a relatively large scale." these findings were based on interviews with survivors and other witnesses, documentation of munitions and their components, collection of environmental samples for subsequent analysis, assessment of symptoms of survivors, and collection of hair, urine, and blood samples. according to dr. ken alibek, former deputy director of biopreparat, the soviet union's nominally civilian medical research institute, soviet scientists and physicians spent large sums of money and manpower during the s and s developing the most lethal and potent biological weapons known to man. in addition to weaponizing the etiologic agents of anthrax, smallpox, marburg fever, and others, they created antibiotic-resistant strains of yersinia pestis (plague), francisella tularensis, and other pathogens. furthermore, by applying genetic engineering techniques, the soviets are also alleged to have created pathogens with novel characteristics and strains of several organisms capable of defeating certain vaccines. as we enter the biotechnological revolution of the twenty-first century, our understanding of molecular biology, genetics, and biochemistry is exploding. the human genome has been sequenced, and it is now possible to manipulate genes from disparate organisms to create new and novel pathogens. scientists are also able to synthesize and weaponize a number of different endogenous biological-response modifiers including cytokines, hormones, neurotransmitters, and plasma proteases. but even nature continues to surprise us. new, naturally occurring infections with the potential to cause large-scale human diseases and death continue to emerge at an ever-increasing rate throughout the world, and it is conceivable that these pathogens could also be weaponized by enterprising scientists. this chapter briefly reviews the future of chemical and biological weapons as we enter this new era of explosive growth in our understanding of the life sciences. we are presented with an extraordinary opportunity to solve a host of human afflictions or to create new classes of biological and chemical weapons that have the capacity to destroy our civilization as we know it today. the appearance of a new or reemerging infectious disease has global implications. during the past years, more than new lethal pathogens have been identified. a classic example of this emerging threat is pandemic influenza. in , as world war i was coming to an end, the spanish flu struck with devastating consequences. in less than year, this virus was able to circumnavigate the globe and kill an estimated million people. more recently, the emergence of severe acute respiratory syndrome (sars) in southeast asia resulted from a coronavirus that jumped species from animals to humans and rapidly spread to countries in less than days. finally, the outbreak of ebola in western africa, still raging as of this writing, is an example of how devastating these agents can be when they emerge in a region previously naïve to them. novel and dormant infectious agents such as sars, influenza, and ebola appear to be emerging or reemerging with increasing frequency and with greater potential for serious consequences. many factors contribute to the emergence of new diseases: environmental changes, global travel and trade, social upheaval, and genetic changes in infectious agent, host, or vector populations. once a new disease is introduced into a suitable human population, it often spreads rapidly and has a devastating impact on the medical and public health infrastructure. if the disease is severe, it may lead to social disruption and have a profound economic impact. outbreaks of emerging or reemerging diseases may be difficult to distinguish from outbreaks resulting from intentional introduction of infectious diseases for nefarious purposes. as scientists develop more sophisticated laboratory procedures and increase their understanding of molecular biology and the genetic code, the possibility of bioengineering more virulent, antibiotic, and vaccineresistant pathogens for military or terrorist uses becomes increasingly likely. it is already theoretically possible to synthesize and weaponize certain biological response modifiers (brms) as well as to engineer genomic weapons capable of inserting novel dna into host cells. the potential to cause widespread disease and death with any of these weapons is incalculable and concerning. scientists and policy makers have begun to address the issue with a robust research agenda to develop medical countermeasures. ebola hemorrhagic fever, as of december , , had caused deaths among , confirmed cases in western africa. scientists have debated whether ebola could be weaponized into a weapon of mass destruction by terrorists. the consensus seems to be that this would be a very difficult undertaking because of the knowledge and laboratory skills that are required. moreover, the biology of the virus does not lend itself well to weaponization. of course, nefarious individuals could use ebola in a number of ways, in much the same way that a suicide bomber straps on a vest laden with explosives. in theory a person could deliberately infect themselves with the virus and then attempt to infect others once they become symptomatic. important existing biological agents with the potential for weaponization for military or terrorist use include the following: another way to view the relative importance of the above list of agents and diseases list is to consider the centers for disease control and prevention (cdc) strategy. the cdc categorizes bioterrorism agents or diseases as category a, b, or c. category a agents pose the highest risk to the public and are characterized as follows: • easily disseminated or transmitted from person to person • can cause high mortality rates and possess the potential for profound public impact • could cause public panic and social disruption • require special preparations for adequate public health preparedness diseases and agents • anthrax (bacillus anthracis) • botulism (clostridium botulinum toxin) • plague (yersinia pestis) • smallpox (variola major) • tularemia (francisella tularensis) • viral hemorrhagic fever: filoviruses (e.g., ebola and marburg) and arenaviruses (e.g., lassa and machupo) category b agents are the next highest priority and are characterized by • Μoderately easy to disseminate • cause moderate morbidity and low mortality • require specific enhancements of cdc's diagnostic capacity and enhanced disease surveillance diseases and agents • epsilon toxin of clostridium perfringens • food safety threats (salmonella species, escherichia coli o :h , • ricin toxin (ricinus communis-castor beans) • staphylococcal enterotoxin b • typhus fever (rickettsia prowazekii) • viral encephalitis (alphaviruses: venezuelan equine encephalitis, eastern equine encephalitis, western equine encephalitis) • water safety threats (vibrio cholerae, cryptosporidium parvum) category c agents form the third highest priority and include emerging pathogens that could be engineered for mass dissemination in the future because of the following: • availability • ease of production and dissemination • potential for high morbidity and mortality rates and major health impact agents • emerging and reemerging infectious diseases such as nipah virus, hantavirus, human influenza, avian influenza, sars and sarsassociated coronavirus (sars-cov), and middle east respiratory syndrome (mers) because emerging diseases are so diverse and endemic to different geographic locations, their complete description is beyond the scope of this chapter. however, some of these infections may become future threats as agents of biological warfare or terrorism. the most worrisome emerging infectious disease may well be the one we do not know about. recent experience with hiv, ebola hemorrhagic fever, sars, monkey pox, west nile fever, and hundreds of other "new" diseases reveal that we will continue to be surprised. avian influenza, or highly pathogenic avian influenza, has periodically caused human infections primarily through close contact with avian species, most often through occupational contact at chicken or duck farms in southeast asia. a large outbreak of avian influenza involving the h n strain and human cases occurred in and originated in two countries from this region. no sustained human-to-human transmission was reported, but there is some evidence that isolated episodes did occur, and the potential exists for genetic reassortment between avian and human or animal strains of influenza. a recent report in the journal science linked the influenza virus responsible for the epidemic to a possible avian origin. if true, avian influenza may pose a much greater danger to human populations than previously reported. the disease presents in humans in a fashion similar to other types of influenza viruses. it usually begins with fever, chills, headaches, and myalgias and often involves the upper and lower respiratory tract with development of cough, dyspnea, and, in severe cases, acute respiratory distress syndrome. laboratory findings may include pancytopenia, lymphopenia, elevated liver enzymes, hypoxia, a positive reverse transcriptase-polymerase chain reaction (rt-pcr) test for h n , and a positive neutralization assay for h n influenza strain. in vitro studies suggest that the neuraminidase (na)-inhibitor class of drugs may have clinical efficacy in the treatment and prevention of avian influenza infection. the threat for pandemic spread of human influenza viruses is substantial. the pathogenicity of human influenza viruses is directly related to their ability to alter their eight viral rna segments rapidly; the new antigenic variation results in the formation of new hemagglutinin (ha) and na surface glycoproteins, which may go unrecognized by an immune system primed against heterologous strains. two distinct phenomena contribute to a renewed susceptibility to influenza infection among persons who have had influenza illness in the past. clinically significant variants of influenza a viruses may result from mutations occurring in the ha and na genes and expressed as chapter future biological and chemical weapons minor structural changes in viral surface proteins. as few as four amino acid substitutions in any two antigenic sites can cause such a clinically significant variation. these minor changes result in an altered virus able to circumvent host immunity. moreover, genetic reassortment between avian and human or avian and porcine influenza viruses may lead to the major changes in ha or na surface proteins known as antigenic shift. in contrast to the gradual evolution of strains subject to antigenic drift, antigenic shift occurs when an influenza virus with a completely novel ha or na formation moves into humans from other host species. global pandemics result from such antigenic shifts. influenza causes in excess of , deaths and more than , hospitalizations annually in the united states. pandemic influenza viruses have emerged regularly in -to -year cycles for the last several centuries. during the last century, influenza pandemics occurred times: in ("spanish influenza," an h n virus), in (asian influenza, an h n subtype strain), and in (hong kong influenza, an h n variant). the - pandemic caused , excess deaths, and the pandemic caused , excess deaths in the united states. the influenza pandemic illustrates a worst-case public health scenario; it caused , deaths in the united states and to million deaths worldwide. morbidity in most communities was between % and %, and the case-mortality rate averaged . %. a reemergent -like influenza virus would have tremendous societal effects, even in the event that antiviral medications were effective against this more lethal influenza virus. sars-associated coronavirus (sars-cov) emerged as the cause of sars during . that year, sars was responsible for approximately deaths and more than infections in people from at least countries worldwide. before a case definition had been clearly established, chinese authorities reported to the world health organization (who) more than cases of an atypical pneumonia with related deaths, all originated from guangdong province in china during february . the infection quickly spread as infected patients traveled to hong kong and from there to vietnam, canada, and other locations. only eight laboratory-confirmed cases occurred in the united states, but there is concern that the u.s. population is vulnerable to a widespread outbreak of sars such as the one that occurred in china, hong kong, singapore, toronto, and taiwan in . a sars case definition evolved from this initial report to the who by chinese health authorities in february . a case was initially defined by clinical criteria; a suspected or probable case was defined as an illness that included potential exposure to an existing case and fever with pneumonia or respiratory distress syndrome. in april , a confirmed case was defined as a case from which sars-cov was isolated from culture. sars-cov infections have an incubation period of to days. systemic symptoms such as fever and chills followed by a dry cough and shortness of breath begin within to days. patients may develop pneumonia and lymphopenia by days to of the illness. most patients with sars-cov have a clear history of exposure either to a patient with sars or to a setting in which sars-cov is known to exist. laboratory tests may be helpful but do not reliably detect infection early during the illness. sars-cov should be suspected in patients requiring hospitalization for radiographically confirmed pneumonia or acute respiratory distress syndrome of unknown etiology and one of the following risk factors during the days before the onset of illness: ( ) travel to china, hong kong, or taiwan, or close contact with an ill person having a history of such travel; ( ) employment in an occupation associated with a risk for sars-cov exposure; or ( ) inclusion in a cluster of cases of atypical pneumonia without an alternative diagnosis. a "respiratory hygiene/cough etiquette" strategy should be adopted in all sars-affected health care facilities. all patients admitted to the hospital with suspected pneumonia should receive the following measures: ( ) they should be placed in droplet isolation until it is determined that isolation is no longer indicated (standard precautions are appropriate for most community-acquired pneumonias; droplet precautions for nonavian influenza); ( ) they should be screened for risk factors of possible exposure to sars-cov; and ( ) they should be evaluated with a chest radiograph, pulse oximetry, complete blood count, and additional workup as indicated. if the patient has a risk factor for sars, droplet precautions should be implemented pending an etiologic diagnosis. when there is a high index of suspicion for sars-cov disease, the patient should be treated in terms of sars isolation precautions immediately (including airborne precautions), and all contacts of the ill patient should be identified, evaluated, and monitored. although ribavirin, high-dose corticosteroids, and interferons have been used in treatment, it is unclear what effect they have had on clinical outcome. no definitive therapy has been established. empiric antibiotic treatment for community-acquired pneumonia following the current american thoracic society/infectious diseases society of america guidelines is recommended pending etiologic diagnosis. diagnostic tests for sars-cov include antibody testing using an enzyme immunoassay and rt-pcr tests for respiratory, blood, and stool specimens. in the absence of known sars-cov transmission, testing is recommended only in consultation with public health authorities. testing for influenza, respiratory syncytial virus, pneumococcus, chlamydia, mycoplasma, and legionella should be conducted, as the identification of one of these agents excludes sars by case definition. clinical samples can be obtained during the first week of illness with a nasopharyngeal swab plus an oropharyngeal swab and a serum or a plasma specimen. after the first week of illness, a nasopharyngeal swab plus an oropharyngeal swab and a stool specimen should be obtained. serum specimens for sars-cov antibody testing should be collected when the diagnosis is first suspected and at later times as indicated. an antibody response can occasionally be detected during the first week of illness, is likely to be detected by the end of the second week of illness, and at times may not be detected until more than days after the onset of symptoms. respiratory specimens from any of several different sources may be collected for viral and bacterial diagnostics, but the preferred specimens of choice are nasopharyngeal washes or aspirates. mers-cov is a disease caused by a coronavirus and results in severe acute respiratory disease including fever, chills, cough, and dyspnea. some patients also develop nausea, vomiting, and diarrhea. it has a % mortality rate. most patients who have died had underlying comorbidities and developed pneumonia or renal failure. the illness was first reported in saudi arabia in september ; most cases appear to be limited to the arabian peninsula. the incubation period ranges from to days. the illness can spread from person to person but it requires close contact, and no sustained transmission had been reported by late . the virus could evolve and lead to sustained transmission, but this cannot be predicted with certainty. there is no vaccine for mers-cov and there is no specific treatment, but there is ongoing research by the national institutes of health (nih) and other entities to fill this gap. the nipah and hendra viruses are closely related but distinct paramyxoviruses that compose a new genus within the family paramyxoviridae. the nipah virus was discovered in malaysia in during an outbreak of a zoonotic infection, now called nipah virus encephalitis, involving mostly pigs and some human cases. hendra, the causative section vii topics unique to terrorist events and high-threat disaster response agent of hendra virus disease, was identified in a similar outbreak involving a single infected horse and three human cases in southern australia in . it is believed that certain species of fruit bats are the natural hosts for these viruses and remain asymptomatic. horses and pigs act as amplifying hosts for the hendra and nipah viruses, respectively. the mode of transmission from animal to humans appears to require direct contact with tissues or body fluids or with aerosols generated during butchering or culling. personal protective equipment including gowns, gloves, and respiratory and eye protection is advised for agricultural workers culling infected animal herds. thus far, human-to-human transmission of these viruses has not been reported. in symptomatic cases, the onset of disease begins with flu-like symptoms and rapidly progresses to encephalitis with disorientation, delirium, and coma. fifty percent of those with clinically apparent infections have died from their disease. there is currently no approved treatment for these infections, and, therefore, therapy relies heavily on supportive care. the antiviral drug ribavirin has been used in past infections, but its effectiveness remains unproven in clinically controlled studies. although no person-to-person transmission is known to have occurred, barrier nursing and droplet precautions are recommended because respiratory secretions and other bodily fluids are known to harbor the virus. the clinical laboratory should be notified before specimens are sent as these may pose a laboratory hazard. specimens for viral isolation and identification should be forwarded to a reference laboratory. requests for testing should come through public health departments, which should contact the cdc emergency operations center at - - before sending specimens. brms direct the myriad complex interactions of the immune system. brms include erythropoietins, interferons, interleukins, colonystimulating factors, granulocyte and macrophage colony-stimulating factors, stem cell growth factors, monoclonal antibodies, tumor necrosis factor inhibitors, and vaccines. a growing understanding of the structure and function of brms is driving the discovery and creation of many novel compounds including synthetic analgesics, antioxidants, and antiviral and antibacterial substances. for example, brms are being used to treat debilitating rheumatoid arthritis by targeting cytokines that contribute to the disease process. by neutralizing or eliminating these targeted cytokines, brms may reduce symptoms and decrease inflammation. brms may also be used as anticarcinogens, with the following goals: ( ) to stop, control, or suppress processes that permit cancer growth; ( ) to make cancer cells more recognizable, and therefore more susceptible, to destruction by the immune system; ( ) to boost the killing power of immune system cells, such as t cells, natural killer cells, and macrophages; ( ) to alter growth patterns in cancer cells to promote behavior like that of healthy cells; ( ) to block or reverse the processes that change a normal cell or a precancerous cell into a cancerous cell; ( ) to enhance the ability of the body to repair or replace normal cells damaged or destroyed by other forms of cancer treatment, such as chemotherapy or radiation; and ( ) to prevent cancer cells from spreading to other parts of the body. , more of these promising new drugs are currently in development. it can be readily theorized that research to develop various brms can be subverted to a malicious end. that is, instead of using brms to suppress cancer growth or to decrease disease susceptibility, researchers could develop compounds to cause illness and death. other drugs could be designed to alter certain metabolic processes or to alter brain chemistry to affect cognition or mood. the opportunity for mischief is limited only by the imagination of the person with ill intent. the field of synthetic biology had its beginnings near the turn of the millennium with the idea that basic engineering principles could be applied to biological systems at the cellular and genetic levels to create new and improved organisms. synthetic biology is the "engineering of biology." the goal and end products of the engineering are conventionally to be used for the benefit of humankind. however there has been increasing concern that synthetic biology could be used for nefarious purposes. [ ] [ ] [ ] [ ] a precise definition of synthetic biology has not yet been established; however, a consensus is building that synthetic biology is defined as the use of molecular biology tools and techniques to forward the engineering of cellular behavior. there is disagreement among scientists whether the new field of synthetic biology will allow terrorists to create biological agents with more lethal characteristics or create completely novel pathogens with enhanced pathogenicity and weaponization potential in an easier fashion. some argue that synthetic biology causes "de-skilling" of biological techniques and allows laboratory processes to become easier for less experienced scientists or even laypeople to master. others maintain that the tacit or unwritten laboratory skills that only a few highly trained scientists possess and which are very difficult to transfer and very difficult for a terrorist to acquire. social scientists have carefully studied these tacit skills and argue that these techniques are very difficult to pass on from scientist to scientist without considerable effort that is often impossible even under the most ideal circumstances. this difficulty was historically present in both the u.s. and soviet biological weapons programs each of which were extremely well funded and staffed with competent scientists. nevertheless, the rapid advance of synthetic biology has the potential to alter the present and future threat of biological weapons. , , already, complete or partial genomic sequence data for many of the most lethal human pathogens (such as anthrax, plague, and the smallpox virus) have been published and are widely available via the internet. in addition to the enormous explosion in our knowledge of human pathogens, there is a parallel increased understanding of the complexities of the human immune response to foreign agents and toxins. such knowledge has led to a deeper understanding of the development of basic immunity to a variety of different human infectious diseases. with this increase in scientific knowledge has come the power to manipulate the immune system at its most fundamental level. as we prepare for future threats, we must not ignore the potential quantum leap that synthetic biology offers to terrorists for developing new biological-warfare threats. examples of biological threats that could be produced through the use of synthetic biology include the following: ( ) microorganisms resistant to antibiotics, standard vaccines, and therapeutics; ( ) innocuous microorganisms genetically altered to produce a toxin, a poisonous substance, or an endogenous bioregulator; ( ) microorganisms possessing enhanced aerosol and environmental stability characteristics; ( ) immunologically altered microorganisms able to defeat standard threat identification and diagnostic methods; ( ) genetic vectors capable of transferring human and foreign genes into human cells for therapeutic purposes ; and ( ) combinations of these with improved delivery systems. [ ] [ ] [ ] the threats associated with the use of chemical weapons as battlefield or terrorist weapons are not easy to assess. , risk assessment of use must take into account national laws, international treaties and chapter future biological and chemical weapons conventions, and the likelihood of adherence to these legal obligations. loopholes in existing agreements can be exploited to develop weapons that are technically not prohibited by international law. goals and objectives may vary depending on whether military use is planned at the strategic, tactical, or operational level and whether the developer is a national government, a breakaway republic, a kidnapped or recruited scientist, or a terrorist cell. risk of use may also depend on whether the targets are military versus civilian, human versus nonhuman (animals or plants, including livestock and crops), or individual (as in assassinations) versus large groups, and on whether the aim is death versus incapacitation. risk also depends on agent availability and on the technology available for production, storage, and dissemination; current advances in technology are associated with a higher risk of weaponization. two examples from the twentieth century and one from the twenty-first can illustrate the fallibility of intelligence: . during most of world war ii, the allied perception of risk from possible chemical agent use by axis powers focused on those agents, primarily pulmonary agents and vesicants, known from world war i. in fact, germany had developed a new kind of chemical-warfare agent, the compounds later to be called g-series nerve agents. their existence came as a complete surprise to western governments when, in the waning days of the european campaign, allied soldiers advancing into germany discovered buried nerve-agent munitions and entire nerve-agent factories. why these agents were never used on the battlefield is a topic of much speculation, but in retrospect they clearly posed the most lethal, yet unrecognized, threat from germany. report was released and reported that "while a small number of old, abandoned chemical munitions have been discovered, isg judges that iraq unilaterally destroyed its undeclared chemical weapons stockpile in ." although the initial intelligence proved to be wrong, it does not invalidate the argument that the risk from these agents, if possessed, would be very concerning. chemical agents originally used during world war i are sometimes considered obsolete, especially in comparison to the more potent nerve agents and incapacitating agents. however, agent potency is only one part of the story. to deliver the μg that represents an estimated lethal dose for half of an exposed group (ld ) of the nerve agent vx would seem to be easier than delivering the to g that constitute the ld of sulfur mustard and more difficult than delivering the much smaller lethal doses of toxins such as botulinum toxin. in fact, sulfur mustard is easier to synthesize than is a nerve agent and is easy to disseminate in a clandestine manner to create delayed effects. thus mustard still lays claim to being the "king of gases," and it has allegedly been used in a variety of venues since the end of world war ii. most known chemicals with toxicities equal to or greater than that of ammonia could theoretically be used as chemical warfare or terrorism agents. existing chemicals capable of weaponization for military or terrorist use include the following: existing chemicals remain candidate agents for future use. some compounds not developed to cause injury or incapacitation nevertheless can be very dangerous; hexachloroethane (hc) smoke, for example, can cause the same type of pulmonary damage induced by phosgene, a chemical weapon used in world war i. the cdc lists nearly separate chemicals, including a variety of toxic industrial chemicals and poisons, as potential agents for terrorism. these include osmium tetroxide, long-acting anticoagulants, heavy metals, toxic alcohols, and white phosphorus. the april , , morbidity and mortality report included an even longer list of chemical agents that might be used by terrorists. pyrolysis, the thermochemical change of an organic material in the absence of oxygen by heat, and products from explosions and conflagrations may release large quantities of cyanide and other toxicants that, although different from the original chemicals present, may still cause death. industrial chemicals are readily available in large quantities as preformed compounds and should be considered high on the list of potential terrorist agents. , toxins that are chemicals produced within biological organisms also represent high-threat agents. new chemicals are currently being synthesized on rigid three-dimensional molecular skeletons, the most promising of which are the norbornanes. norbornane is a bicyclic crystalline hydrocarbon (c h ). building on norbornane geometry allows for a modular enhancement of the number of functional sites on a given molecule. many norbornane derivatives, such as the mixture of chlorobornanes known as the toxaphenes, are persistent and have significant acute and chronic toxicity. these norbornane derivatives have been considered as potential candidates for new agents. novichok - (russian for "newcomer") refers to the alleged russian development of a highly toxic binary nerve agent or generation of nerve agents (sometimes called "fourth-generation" agents). only sketchy and unverifiable information is available in the unclassified literature, but the existence of these agents would demonstrate the possibility of creating new section vii topics unique to terrorist events and high-threat disaster response chemical compounds toxic enough to be used as chemical warfare or terrorist agents. one of the sources of unclassified information is from a dissident russian scientist who wrote newspaper articles and published a book about the novichok program and the types of chemical agents that were produced. so-called gv analogs combining some of the properties of g-series and v-series nerve agents have also been suggested as potential new agents. the use in of an incapacitating gas in the siege of a moscow theater taken over by chechen rebels was evidence of use of a chemical aerosol. , the russian health minister at the time, after significant international pressure identified the aerosol as a fentanyl derivative and then stated that use of a fentanyl derivative was not prohibited by the chemical weapons convention. further investigations of survivors have suggested that carfentanil and remifentanil were possibly used in the siege. organofluorines have been investigated because of their reported ability to defeat protective-mask or chemical-filtration systems. other incapacitating agents under development exert primarily physical rather than chemical effects and include immobilizing agents ("stickums"), antitraction gels ("slickums"), and malodorants. , an effective incapacitating agent must be highly potent and reversible. it also must have rapid onset, short duration of action, and a high safety margin. nontraditional agents (ntas) are chemicals that do not fall in the traditional chemical weapons category but have been reportedly researched or developed for use as chemical weapons. "ntas are novel chemical threat agents or toxicants requiring adapted countermeasures," according to homeland security presidential directive/ hspd- . developing defenses against ntas is a listed priority for the u.s. department of defense. ways in which existing or future battlefield chemical agents and delivery systems could be modified to improve performance must be considered. these modifications include the following: . agent thickening . binarization . micronization: "dusty agents" . developments in delivery systems a. dual-use cyberinsects and biorobots b. nanotechnology small quantities of thickening agents, such as acrylates, can be added to chemical agents to increase their viscosity. thickened agents are more persistent in the environment and in wounds than are nonthickened agents, and they are less easily decontaminated. although no nation is currently known to stockpile thickened agents, the technology for their production is relatively simple and requires only standard chemical-warfare agents and the right proportion of a thickener. many industrial chemicals and other poisons could theoretically be rendered more effective as battlefield or terrorist agents by thickening. in the s, the u.s. army began to investigate the then-new technology of binarization, although production did not accelerate until the s and deployment was not widespread until the s. a binary chemical weapon did not employ a new kind of agent but rather represented a novel way of producing and storing an already existing type of agent. the idea was to make storage of chemical rounds safer by stopping the production process at the penultimate synthetic step, resulting in two precursor compounds that when mixed would create the desired agent. these two precursors could then be stored separately. just before use, one component could be inserted into a round, where it would be separated from the other precursor by a thin membrane. the impact and momentum of the launch of the projectile would burst the membrane to allow for mixing of the components and in-flight production of the chemical agent. in practice, this process was often not complete, but the % or so of ancillary reaction product was often extremely toxic by itself. binarization or some similar production-arrest method could theoretically be used by a clandestine terrorist cell to help evade detection and to decrease the risks associated with the production, transportation, and use of chemical agents. micronization is a type of particularization involving the production of extremely fine particles onto which a chemical agent can be adsorbed. during world war ii, germany explored particularization of sulfur mustard onto small carrier particles of silica (silicon dioxide), although other powdered silicates (e.g., talc, diatomite, and pumice) and clays (e.g., kaolinite and fuller's earth) can also be used. the advantages of such "dusty agents" are increased volatility, facilitation of the movement of relatively nonvolatile agents such as sulfur mustard and the persistent nerve agent vx into the alveoli, and increased penetration of clothing and chemical protective equipment. iraq used a "dusty mustard" composed of % sulfur mustard adsorbed onto silica particles ranging in diameter from . to μm during its war with iran. micronization of a variety of chemical, biological, and toxin agents requires a certain degree of technological sophistication that is becoming increasingly easy to acquire. agent delivery can potentially be modified in a variety of ways in addition to thickening and micronization. the jordanian government released a report in of the discovery of an elaborate plot by al qaeda terrorists for a two-stage attack using a massive vehicle-borne improvised explosive device followed by the release of toxic chemicals to include acetones, nitric acid, and sulfuric acid. similarly, enhancedfragmentation munitions could be used in combination with chemical agents to drive the agents more effectively into the body. innovative new delivery systems taking advantage of advances in robotics include the proposed use of cyberinsects and biorobots to deliver biological agents, chemical agents, or toxins. engineering on an even smaller scale is the purview of nanotechnology, also called "micromechanical engineering" and "micro-electromechanical systems." nanotechnology takes advantage of the unique properties of materials on the scale of about a nanometer ( to m) and deals with the molecule-by-molecule or even atom-by-atom assembly of materials. nanoparticles behave in unusual and unpredictable ways, are small enough to enter cells easily, and in fact are being developed to provide not only better storage and dispersal of pharmaceutical products but also more efficient transport of both biological organisms (e.g., viruses) and chemical compounds into the body. in some cases they may be surprisingly toxic, partly because of the ease with which they can cross membranes, including the blood-brain barrier, and enter cells. this toxicity could be exploited by governments or terrorist organizations interested not only in small-particle delivery of chemical agents but also in the ancillary and perhaps synergistic effects of the carrier materials themselves. nanomaterials can be encapsulation compounds such as fullerenes, or buckyballs, which are hollow -carbon geodesic shells; nanoshells (e.g., a gold shell surrounding an inert silica core); a "self-assembled, polyamino acid nanoparticles system" under development in france; or dendrimers, which are onion-like layers of shells surrounding a biologically active core. any of these materials could be used to deliver existing or new chemical agents. other nanomaterials include selfassembling liquids composed of cylindrical nanofibers (each to nm in diameter) that solidify upon injection to form structured scaffolds capable of presenting ordered peptide signals to cells. a ferrofluid such as a colloidal suspension of nanoscale ferrous oxide can be coupled chapter future biological and chemical weapons with antibodies in a laboratory to detect and concentrate rare human cells in a diagnostic setting, but this technology could easily be adapted to target those cells in vivo. quantum dots are nanoscale semiconductor crystals that show promise in the in vitro and in vivo diagnosis of a variety of conditions; although their main use is projected to be in the laboratory, animal experimentation involving injected quantum dots has demonstrated successful targeting of lymph nodes and of prostate-cancer xenografts in mice. adverse health effects from any of these kinds of nanoparticles could represent a primary goal for military or terrorist operatives in addition to the toxicity of any other chemicals delivered by the nanoparticles. for example, water-soluble fullerenes (or buckyballs) have caused brain damage in largemouth bass. also, dendrimers can cause osmotic and membrane damage and can activate the clotting and complement systems. quantum dots composed of selenium, lead, and cadmium could release those metals into cells, depending on the composition of the surface coating of the dots, and cause damage. "designer" chemicals from biotechnological processes biotechnology refers to "any technological application that uses biological systems, living organisms, or derivatives thereof, to make or modify products or processes for specific use." biotechnology includes such time-honored practices as the baking of bread and the brewing of beer, but in the twenty-first century refers in particular to genetic engineering, that is, the artificial transfer of genes from one organism to another and the consequent alteration of the genetic structure of a cell. it is founded on the basic sciences of genomics (the study of the genetic composition of an organism) and proteomics (the study of the expression of the genome by means of protein synthesis). "designer" chemicals could be produced from biotechnological processes. these processes include the following: ( ) combinatorial chemistry and ligand modification; ( ) genomics and target identification; ( ) microarrays, proteomics, and rational agent design; and ( ) toxicogenomics, database mining, and the prediction of toxicity. these developments, if used for chemical warfare agents, would be considered "dual-use technology." this is technology that can be used for both peaceful and military aims. combinatorial chemistry is the production of complex sets, or socalled libraries, of related compounds, as in the case of the norbornane derivatives previously described. automated screening techniques to select for library elements with desired toxic effects on specified target organs can process several hundred thousand compounds a day against several dozen different proteins. this obviously accelerates tremendously the development of new chemical agents. genomics has benefited enormously from three modern scientific efforts: the human genome project, the human genome diversity project, and gene therapy. identification and cataloging of hundreds of single-nucleotide polymorphisms (individual sequence variations) allow for the selection of genomic sequences to be mass-produced for insertion into cells to create a specific effect. targeting unusual sequences of high prevalence in certain populations raises the specter of genomic, or ethnic, weapons, as previously described. less appreciated is the potential for genomics to be used to develop drugs and chemical or toxin agents that can also be targeted to specific variants within a population of humans, animals, or crops. the widespread availability of genome libraries on the internet makes it nearly impossible to control or restrict access to the already published genomic libraries on over a hundred microbial pathogens. proteomics complements genomics by characterizing the protein expression of segments of the genome and by making it easier to develop compounds that target or produce a specific protein. direct gene insertion, genetic delivery via virus or bacteria, or drug tailoring to affect a given protein can be used. for example, a scorpion toxin has been successfully engineered into a virus that acts as a pesticide against caterpillars. protein sequences in toxins are partly responsible for resistance to light, oxygen, moisture, and desiccation; the insertion of genes to create altered proteins or the introduction of chemical agents engineered to cause structural changes in expressed proteins could significantly alter the toxicity of a given compound. furthermore, the widespread use of dna microarrays (glass slides or chips imprinted with thousands of specific single-stranded dna sequences) allows for fast-automated screening of candidate compounds. scientists involved in the selection and evaluation of specific chemical agents can now use toxicogenomics (the study of genetic variation of response to toxins) and data mining (the computerized analysis of databases of drug and chemical information via sophisticated neural nets) as tools to eliminate less likely candidates and to algorithmically predict compounds with high toxicity or with other desired characteristics relating to environmental persistence, toxicokinetics (absorption, distribution, biotransformation, and elimination), and toxicodynamics (mechanism of action). such tools will undoubtedly lead to the development not only of new pharmaceutical agents but also of designer toxins for military or terrorist use. if history is any guide, new biological and chemical weapons and novel "mid-spectrum" agents (e.g., toxins, bioregulators, synthetic viruses, and genocidal weapons) will be developed in the future, and new modifications will be found to improve the production, weaponization, storage, delivery, and action of existing agents. , [ ] [ ] [ ] naturally occurring emerging infectious diseases provide examples of newly identified pathogens with weaponization potential, and midspectrum agents such as toxins and bioregulators will undoubtedly assume more prominence with the accelerating pace of synthetic biology. agents of any category can theoretically be engineered to target specific genes or proteins with differential population prevalence to produce genomic or ethnic weapons; and advances in proteomics, toxicogenomics, and computerized database mining could be used for the rapid and efficient development of not only new drugs but also new chemical agents for terrorism. , , synthetic biology has now advanced to the point that no special equipment is required beyond that available to any modern molecular-biology laboratory, and the scale of operations is also well within the means of governments and terrorist groups. the threats from future modification of existing agents and from the development of new agents, new agent-development technologies, and innovative delivery systems should not 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scientist say gorbachev's regime created new nerve gas in ' the chemical weapons convention: implementation challenges and solutions center for nonproliferation studies history of chemical and biological warfare: an american perspective state secrets: an insider's chronicle of the russian chemical weapons program chemical weapons: documented use and compounds on the horizon incapacitating chemical weapons: a year after the moscow theatre siege analysis of clothing and urine from moscow theatre siege casualties reveals carfentanil and remifentanil use incapacitating biochemical weapons introduction to chemical and biological weapons homeland security presidential directive/hspd- . medical countermeasures against weapons of mass destruction medical aspects of chemical and biological warfare, part i the chemical warfare threat and the military healthcare provider the danger to the chemical weapons convention from incapacitating chemicals. first cwc review conference paper no. . strengthening the chemical weapons convention was chemical bomb target biological warfare, bioterrorism, biodefence and the biological and toxin weapons convention news: nanotechnology: the potential for new wmd. available at the ups and downs of nanobiotech nanotechnology precaution is urged: miniscule particles in cosmetics may pose risk, british scientists say manufactured nanomaterials (fullerenes, c ) induce oxidative stress in the brain of juvenile largemouth bass the free encyclopedia united nations environment program. governments to advance work on cartagena protocol on biosafety the plague makers: the secret world of biological warfare nrc wants genome data unfettered the threat of mid-spectrum chemical warfare agents the future of weapons of mass destruction: their nature and role in bioregulators as prototypic nontraditional threat agents the authors gratefully acknowledge the previous contributions of james m. madsen. key: cord- -f wwn z authors: douglas, r. gordon; samant, vijay b. title: the vaccine industry date: - - journal: plotkin's vaccines doi: . /b - - - - . - sha: doc_id: cord_uid: f wwn z nan the vaccine industry is composed of companies that are engaged in any of the following activities: research (including that performed in industry and biotech), development, manufacture, or sales, marketing, and distribution of vaccines. they receive their revenue chiefly from sales of vaccine products or expectations thereof. the vaccine industry is relatively small, compared to the pharmaceutical industry, but growing. we estimate that total infectious disease vaccine sales in were more than $ billion worldwide and expected to grow to about $ billion by . although components of the vaccine industry are found in countries worldwide, the large vaccine companies are primarily u.s.-or european-based and have the dominant share of vaccine business on a revenue basis; but regional companies are gradually growing their market share on a dose basis (table . ). in the past years, the vaccine business, a former laggard in the pharmaceutical business, has shown remarkable growth powered by new innovative vaccines coupled with superior pricing strategies ( fig. . ). specifically contributing to this spectacular growth were the varicella, hepatitis a, pneumococcal conjugate, shingles, rotavirus, meningococcal conjugate for a, c, y, w, and human papillomavirus (hpv) vaccines, as well as myriad combination vaccines. this projected growth may plateau in the early s unless the vaccine industry continues to introduce new innovative products targeting diseases that impact the western world. sustaining this growth will be a challenge because of dwindling numbers of high-value vaccine targets for which the biology of protection is well understood (see table . ). the vaccine business is a capital-intensive business that requires considerable ongoing investment in manufacturing assets, facilities, and people to maintain compliance with everincreasing regulatory directives. the recent departure of baxter and novartis from the vaccine industry is an ominous sign that reflects the continued financial pressure on the remaining four major vaccine makers. further consolidation of this business is likely. in addition, new alliances will be formed between the big four manufacturers and emerging companies in india, china, and brazil, to take advantage of increasing immunization rates in those countries as well as growth of their private markets. the united states has been extraordinarily successful in vaccine research and development (r&d). , in the past years, most new vaccines approved worldwide were developed in the united states. approximately new vaccines were approved in the united states between and . , since then, combinations of existing vaccines have been introduced for simplified pediatric vaccination resulting in a wider adoption of acellular pertussis vaccination. a polyvalent pneumococcal conjugate vaccine for infants introduced by wyeth (now a subsidiary of pfizer) has been widely adopted and has made pfizer a major force in the vaccine business. since , several new vaccines have been licensed, including a combination of measles, mumps, and rubella (mmr) and varicella, as well as new vaccines against rotavirus, herpes zoster, hpv, meningococcus, influenza, and others. the hpv vaccines developed by merck and glaxosmithkline significantly expanded the field of adolescent vaccines and confirmed market acceptance of premium pricing. in the last years, the vaccine industry in the united states and europe has considerably improved its reliability as a supplier. chronic shortages are a thing of the past; this turnaround has primarily been achieved by modernization of vaccine manufacturing and distribution infrastructure supported and funded by the profitability of the vaccine business. the centers for disease control and prevention (cdc) stockpiling of pediatric vaccines has alleviated some concerns of critical shortages in case of supply interruptions. but the industry's vulnerability because of dependence on singlesourced vaccines continues to be an unresolved concern. the regulators and the industry must proactively develop a solution to this critical challenge and avoid any future public health crisis resulting from vaccine shortages during a prolonged supply interruption. vaccine development is difficult, complex, highly risky, and costly, and includes clinical development, process development, and assay development. the risk is high because most vaccine candidates fail in preclinical or early clinical development and less than in vaccine candidates entering phase ii achieves licensure. the high failure rate is the result of a variety of reasons: . not fully understanding the biology of protection. . lack of good animal models to predict vaccine behavior in humans. . unpredictability of human immune system reactions to antigens as it relates to immunogenicity or safety. . the unpredictability of the impact of combining multiple components in a vaccine. vaccine development requires strong project management systems and controls and requisite skill sets among scientists and engineers. a key strategic document that guides the stakeholders in vaccine development is the "target product profile" (tpp). the tpp summarizes the desired characteristics and features of the product under development, the key attributes of the product that provide competitive advantage, and, finally, a topline roadmap of nonclinical and clinical studies required to evaluate the products efficacy and safety in the target population. a well-defined tpp provides all the stakeholders, including research, process development, manufacturing, clinical, regulatory, and senior management, with a clear statement of the desired outcome of the product development program. process development involves making preparations of the test vaccine that satisfy regulatory requirements for clinical testing including clinical lots, preclinical toxicology testing, and analytical assessment, and finally, scale-up methods that lead to a consistent manufacturing process at one-tenth of full scale. usually three consecutive lots are tested in the clinic for immunogenicity. assay development involves the definition of specific methods to test the purity of raw materials, stability and potency of the vaccine product, and immunologic and other criteria to predict vaccine efficacy. go/no-go decisions must be made at each stage of clinical and process development and the vaccine industry r. gordon douglas and vijay b. samant must be data driven. clinical, process, and assay development tasks must be closely integrated. clinical development involves studies of the effects of vaccines on patients for safety, immunogenicity, and efficacy through a staged process: phase , early safety and immunogenicity in small numbers; phase , safety, dose ranging, and immunogenicity in to individuals; sometimes phase b, nonlicensure, proof-of-concept trials for efficacy; and phase , safety and efficacy trials that permit licensure, which generally require thousands of subjects. "process" can be broadly divided into two categories: bulk manufacturing and finishing operations. bulk manufacturing includes cell culture and/or fermentation-based manufacturing followed by a variety of separation processes to purify the vaccine. the finishing operations include formulation with adjuvant/stabilizer followed by vial or syringe filling (including lyophilization in the case of live viral vaccines) followed by labeling, packaging, and controlled storage. process development may be as costly as clinical development and is critically important to the overall success of a vaccine development program. as development proceeds toward licensure, costs escalate as clinical studies become larger, manufacturing scales up, and facilities must be built. postlicensure studies of safety and efficacy (phase ) of vaccines are essential and represent a large additional cost. it is important to note that, unlike pharmaceuticals, vaccines that pass early proof-of-concept studies in humans have a very high probability of achieving licensure. clinical activities are more visible than bioprocess development and clearly drive the go/no-go decisions that direct progress. the two are interwoven and each has rate-limiting steps, so they must be done in concert. the first stage of vaccine development involves acceptance of a candidate from a basic research laboratory and development of a small-scale process and formulation to make material for phase i study, analytical release assays, preclinical toxicology, immunological assays to evaluate clinical responses, an investigational new drug (ind) filing, and well-designed phase i/iia studies. the second step is to complete the definition of product and process prior to initiation of phase ii dose-ranging studies, which may take a year or more. product definition includes methods of synthesis/bioprocess steps, number of components, and stability/formulation. stability, release, and raw material assays must be in place. immunologic and other assays must be established to support dose-ranging studies, and a regulatory plan for vaccine process and product submissions must be written. the third step is to define the clinical dose and arrive at the appropriate manufacturing scale, which may take years or more. it results in the identification, manufacture, filling, and release of clinical-grade vaccine-usually in a pilot plantdemonstration of safety and a dose response in a phase ii clinical study; validation of critical assays to support phase iii clinical studies; consistency of lot manufacture (ability to produce three or more consecutive production-scale lots that meet all product specifications based on validated analytical methods); and completion of technology transfer to final site material manufactured in the commercial factory. this is especially difficult if immune studies are not highly reproducible, as is the case with most cellular immune assays. such decisions pose large financial risks if the product in development fails and requires access to large amounts of capital, an attribute usually restricted to large pharmaceutical companies. estimates of cost of development of a new drug or vaccine have risen from $ million in , to $ million in , to $ billion in . [ ] [ ] [ ] these estimates take into account all costs, including r&d costs of products that fail, postlicensure clinical studies, and improvements in manufacturing processes. approximately % of the cost is for construction; the remainder is the cost of capital interest. these numbers have been debated (others estimate $ million to $ million); however, the higher estimates have been validated in two ways. first, the number of new vaccines brought to licensure annually by a company or the industry is very small compared with other products, and correlates with r&d expenditures of $ million to $ million for each new product. thus, if a company spends $ million annually for vaccine r&d, one might expect one new product every to years, and this appears to hold true. second, biotechnology companies that are focused on one vaccine and have successfully brought it to market have spent $ million to $ million on r&d as exemplified by the development of the live attenuated influenza vaccine by aviron, now medimmune. in summary, vaccine development from concept to licensure is a lengthy process as illustrated by timelines for some of the currently licensed vaccines (table . ). to understand the predominant role of major pharmaceutical companies in the development of vaccines, one must examine the role of a vaccine development company in relation to its of manufacture of full-scale lots, including process and analytical procedures. for vaccine targets for which animal studies are not predictive of efficacy in humans, such as hiv, malaria, and tuberculosis (tb), small phase iib proof-of-concept studies based on adaptive clinical trial designs may be used to gain confidence before committing significant resources for process development, analytic development, and factory construction. in general, the analytical and release assays are particularly difficult to develop because, in most cases, vaccines are considered "not well-characterized" biologicals by regulatory agencies. the release assays initially involve functional potency assays such as animal immunogenicity prior to acceptance of more robust and precise in vitro assays that correlate with these functional potency assays. in general, variability of biological assays is a major hurdle in achieving process scale-up and manufacturing consistency. the fourth stage is the completion of phase iii pivotal clinical studies and corresponding consistency lot studies, which requires to years. keys to successful phase iii clinical studies are an accurate estimate of sample size based on disease incidence, low dropout rates, precise clinical end point definitions related to future label claims, and rigorous data management to the highest standards. in addition to clinical studies, scale-up and manufacture of consistency lots, including transfer to the facility of all assays, facility validation, demonstration of consistency and real-time stability are needed to support adequate shelf-life claims. the final stage is biologics license application (bla) preparation, licensure, and vaccine launch, which requires . to years. thus the total elapsed time for development is to years, assuming all activities proceed as planned. manufacturing plants are very expensive to construct, ranging from $ million to $ million depending on the size (dose requirements) and manufacturing complexity, with an additional expenditure of approximately % of that cost for cleaning and process validation activities that are now required under the current good manufacturing practices regulations. with few exceptions, each vaccine requires a different plant because of unique manufacturing requirements and the regulatory difficulties associated with changing over to a different product. some processes are scalable, such as bacterial or yeast fermentation, so that increasing the size of the manufacturing unit (i.e., fermenter) will greatly increase the yield; unit cost will decrease with volume increase. other manufacturing processes, for example, those dependent on viral growth in embryonated hen eggs or cell lines, are not scalable. additional plants or modules within plants must be built to increase the throughput, so unit costs do not appreciably decrease with volume increases. despite the complexity of bulk vaccine manufacturing, to years post-product launch, the fully burdened bulk cost of production for most of the older vaccines declines to as little as $ . to $ . per dose, and significant elements of product cost are primarily driven by activities related to filling, vialing, and packaging (table . ). established vaccines with a limited number of suppliers can generate very high profit margins over the product life cycle. the commitment to build a plant must be made early ( to years before expected licensure) including a -to -month finished goods inventory build-up to expedite product to the market. otherwise a gap of to years between licensure and product launch will occur. furthermore, it is far better to produce consistency lots in the final vaccine production factory to demonstrate the ability to manufacture the vaccine reliably and to use those lots in the phase iii efficacy trials. otherwise, immune studies will be required for "bridging" the product used in the efficacy trial to bioshield for the procurement of advanced medical countermeasures for biological as well as other threats and has successfully developed medical countermeasures against smallpox, anthrax, and botulinum toxin. in addition, barda is funding a variety of early stage novel vaccine approaches for pandemic influenza. barda essentially is intended to overlap with and close the gap between nih-funded preclinical or initial phase i trials and the more advanced project bioshield programs that are in late stage phase iii or licensure stages of development. the u.s. agency for international development (usaid) supports limited r&d targeted toward those vaccines that potentially will have the greatest impact on children younger than age years in developing countries. the center for biologics evaluation and research (cber), a division of the u.s. food and drug administration (fda), is responsible for licensing new vaccines. cber establishes standards for manufacturing processes, facilities, and pre-and postlicensing clinical studies to ensure that licensed vaccines are safe and effective (see table . ). these standards have a profound partners. the relative contributions of the various partners to the delicate fabric of vaccine r&d is shown in table . . several branches of the u.s. government play major roles in vaccine r&d. the u.s. national institutes of health (nih) is the major funding source via intramural and extramural (largely academic) programs of fundamental research (e.g., gene-based vaccines or t-cell memory studies) and directed research on pathogens (e.g., hiv), which may lead to new vaccine candidates. the nih, through its vaccine trials network, has increased its role in clinical development domestically and internationally. in addition, the dale and betty bumpers vaccine research center at the nih was established in primarily to pursue the development of hiv vaccines. the centers for disease control and prevention (cdc) is the primary government agency responsible for epidemiological monitoring of disease trends. the cdc conducts disease surveillance and epidemiological studies to ascertain the prevalence and incidence of specific diseases; this information provides a rationale for prioritizing vaccine development. these studies by the cdc are performed in addition to studies conducted by the vaccine companies, such as phase iv studies. through the advisory committee on immunization practices (acip), the cdc recommends usage of vaccines, and is responsible for most of the public purchases (directly through the vaccines for children program for approximately %, and indirectly through other federal, state, and local government purchases for approximately %, together totaling approximately % of all childhood vaccines in the united states), thereby playing a major role in determining the demand and potential profit associated with vaccines. professional organizations such as the american academy of pediatrics and the american academy of family physicians also make recommendations for vaccine usage. there is no federal vaccine program for adults, although medicare does reimburse for influenza and pneumococcal conjugate vaccines. historically, many adults with private insurance were not covered for immunizations. however, the affordable care act of requires health plans to cover vaccines recommended by the acip prior to september with no copayments or other cost-sharing requirements when those services are delivered by an in-network provider. the department of defense (dod) does targeted vaccine r&d to help it perform its mission of protecting deployable impact on the nature and direction of vaccine development and its costs. in addition, cber maintains a strong research base internally, so it is better positioned to evaluate data from various studies. cber remains the premier vaccine regulatory agency in the world. nongovernmental organizations (ngos) are playing an increasing role in vaccine research. the bill and melinda gates foundation supports several organizations including the international aids vaccine initiative, the malaria vaccine initiative, aeras (dedicated to developing tb vaccines), and others with significant funding for development of vaccines that would have the greatest impact on diseases of developing countries. in addition, a related organization, programs for appropriate technology in health (path), is a nonprofit group that forges private sector partnerships to develop vaccine technologies suitable for the developing world. these product development partnership organizations (pdps; essentially not-for-profit biotech companies) bring together specialized knowledge, animal models, immunologic assays, and field sites for vaccine testing as well as early capital investment to reduce the scientific technical risks, opportunity costs, and financial risk to their biotech and large pharma industrial partners. they also provide opportunities for validation of novel vaccine technologies and platforms. the role of large, full-service vaccine companies ( in some limited basic research and significant amounts of targeted research regarding specific organisms, but the preponderance of activity is in clinical and process development. sufficient personnel and expertise in process development and chemical engineering reside almost exclusively in these companies; there is no other resource for such development. clinical development that will satisfy fda standards is also done mostly by the large companies, performed by academia and contract research organizations. personnel and expertise in clinical research, regulatory affairs, data management, statistics, project management, and all other required disciplines also exist within the large companies. perhaps most importantly, their management is structured to make rapid go/no-go decisions required to minimize risk and assess efficient vaccine development. many smaller organizations, often referred to as biotechnology companies, are engaged in vaccine research. they are often started by university scientists, supported by venture capitalists, and are capable of basic research on a vaccine idea. at this early stage, they usually have limited capacity in process development, manufacturing, and clinical development, and none in distribution, sales, or marketing. if research results are favorable, capacity in process engineering, clinical studies, and manufacturing must be enhanced or obtained by partnering. because of the large cost of adding new capacities and expertise, many biotech companies in advanced product development will opt to partner with large, full-scale companies. although or so small companies claim engagement in vaccine r&d, only about a dozen or so consider it a major activity, and only a very few, such as medimmune, have made it to the market or close to the market on their own. more have licensed their products or technology platforms to larger companies that have then completed development, yielding new vaccines such as those for hepatitis b and haemophilus influenzae type b. for example, the hepatitis b innovation came from the research laboratories of chiron corporation that succeeded in making hepatitis b surface antigen in yeast, and thus enabling merck and glaxosmith-kline to commercialize the modern hepatitis b vaccines. in the case of h. influenzae type b (hib), praxis biologics and connaught laboratories pioneered the development of hib polysaccharide and conjugate vaccines. these companies were eventually acquired by sanofi and wyeth-lederle, respectively. the greatest contributions of the biotechnology companies have been the introduction of multiple ideas into early vaccine development, and testing them to determine if they should be rejected or carried forward. these small companies are dependent on several factors for their success: . a vibrant basic research environment that allows for creation of new ideas, an environment that exists in wellfunded (nih) academic research programs. . a strong venture capital and investment community that views vaccine companies as potentially financially rewarding as other investment opportunities. . strong patent laws providing the intellectual property protection that is essential for commercial success. funding sources for vaccine r&d include government, profits from sales of product, risk capital, and charitable foundations. the nih competes with other federal agencies and programs for taxpayer support, and, in general, has been more successful than most. similarly, vaccine r&d sponsored through the dod, fda, cdc, and usaid is competitive with other public needs as determined by the executive and legislative branches of government. risk capital from private investors is the primary source of funds for small companies. investors are attracted to the potential profits of a new vaccine, a forecast determined in part by sales of current vaccines. large vaccine companies, which are divisions of much larger pharmaceutical companies, seek a profit by selling products. on average, pharmaceutical companies reinvest approximately % of their profits from product sales into r&d, and this proportion applies to vaccine sales as well as other pharmaceutical products (pharmaceutical research manufacturers association, personal communication, ). because vaccine companies are subsidiaries of large companies, vaccine r&d and manufacturing must compete with other product areas for resources. comparisons of the economics of the vaccine industry with the pharmaceutical industry in europe, and separately in the united states, were performed by the mercer consulting company in (fig. . ) . these studies in the united states showed that the in terms of technical feasibility, strong patent protection, and potential market size will be taken forward into development (post-phase i). in addition, other candidate vaccines might be licensed from small companies. even in the largest companies, only a few products can be in development at the same time. thus, go/no-go decisions must be made and market size is a major determinant of the choice between two candidate vaccines, otherwise equal in technical feasibility and likelihood of success (table . ). this system works extremely well for vaccines with large potential markets in the developed world when technical feasibility is demonstrated. it does not work for vaccines for diseases that exist predominantly in the poorer regions of the world (e.g., tb); it works imperfectly for diseases of the developed world that affect relatively few persons because of geographic restriction (e.g., lyme disease) or diseases limited to specific risk groups (e.g., cytomegalovirus [cmv] in transplant recipients), and it does not work when technical feasibility has not been demonstrated (e.g., hiv). the last problem has to be solved by a strong basic program in vaccine-related sciences, particularly for hiv, staphylococcus aureus, malaria, and other challenging targets. niche vaccines for developed-world markets are much more attractive to biotech than to large pharmaceutical companies as evidenced by recent biotech vaccine efforts for west nile virus, japanese encephalitis virus, the cmv-transplant indication, and dengue. to involve large companies in development and manufacturing of vaccines to meet needs such as biodefense or health needs of poorer countries, incentives must be established to convince these companies that they should develop and manufacture such products. such incentives might take the form of guaranteed purchase of certain volumes of a vaccine if specified standards are met, direct contracting by a government agency, or some other publicly funded mechanism. , the use of advanced market commitments to create a funding mechanism for vaccines needed in the developing world has been endorsed by the g and pilot projects may be starting soon. this will not solve the problem of the high technical risk and opportunity costs associated with such vaccines, but it may contribute to the solution if combined with early investment. companies may be willing to engage in such work. indeed, they may already have donated or sold vaccines at very low prices to poorer countries. however, such practices alone will not solve the enormity of the health problems worldwide. without special incentives, it is unrealistic to expect companies to engage in r&d on diseases that only, or predominantly, affect the poorer regions of the world. manufacturers in developing countries (initially in india and china, and more recently in brazil) are playing an increasing role in meeting these needs. indeed, they already supply the majority of doses of older vaccines for such countries. as their expertise and capacity in vaccine r&d increases they will perhaps evolve into major participants in supplying new vaccines to the developing world. there are numerous manufacturers in these emerging countries, but a few truly stand out. the vaccine industry has slowly mushroomed in india with several key companies emerging including bharat biotech, biological e., panacea biotec, and others, but the largest one is the privately held serum institute of india. the indian vaccine industry has significantly benefited from technology transfer from the west. despite the industry's success, the available estimates suggest that r&d spending remains relatively low as a percentage of sales. serum institute of india is the world's largest producer of vaccines by number of doses, producing . billion doses contributions to r&d, interest, taxes, and earnings after expenses were similar for the two industries ( % vs. %, respectively). however, the expenses were quite different. significantly more was spent on production and distribution ( %, which includes production, distribution, and returns of product) in the vaccine industry compared with the pharmaceutical industry ( %), whereas the pharmaceutical industry spent more than the vaccine industry on sales, marketing, and administrative expenses ( % vs. %, respectively). consequently, within companies, there is an expectation that sales-to-expense ratios for vaccines will be similar to those of other pharmaceutical products, and that revenues will increase every year. although some of this increase may be accomplished with sales volume, prices stabilize as vaccine products mature, and increased revenues are no longer possible; hence, the requirement for a steady rollout of new products. however, unlike pharmaceuticals, old vaccines continue to be profitable for a variety of reasons, including: . the absence of a regulatory pathway for generic vaccines deters potential entrants from engaging in a complex and expensive approval process. . in most cases, access to knowhow, such as proprietary cell lines, virus strains, and internally developed processes, is far more valuable than patent protection. . the birth cohort is renewable, providing an ongoing unmet need for vaccines. as a result, sole-sourced vaccines, manufactured in fully depreciated assets, are profitable for pharmaceutical companies. one such example is the mmr vaccine, which after years still has no competition in the united states. a typical vaccine company will have several vaccine candidates in early development, defined as all r&d through phase i clinical testing (table . ). [ ] [ ] [ ] [ ] those that are most promising tuberculosis productivity estimated at -to -fold higher than the measles vaccines made by merck and glaxosmithkline. this privately held vaccine company has relentlessly invested in production facilities/infrastructure that surpasses some of the best biotech manufacturing facilities in the united states. so powerful has its growth been that one out of every two children immunized worldwide get at least one vaccine produced by the serum institute. vaccines recently developed by the serum institute are nasovac (live attenuated trivalent influenza vaccine), menaf-rivac (meningococcal a conjugate vaccine), pentavac (dtp hepatitis b-hib vaccine), and inactivated polio vaccine. the institute continues to invest in r&d and is currently working on a rotavirus vaccine, a polyvalent meningococcal conjugate vaccine, a pneumococcal conjugate vaccine, and hpv vaccine, combination vaccines containing acellular pertussis, and others. china ranks as the world's largest vaccine consuming and manufacturing country, with an estimated annual output of billion doses. the original six government-owned regional biological institutes are now part of the china national biotec group (cnbg) consolidated under the china national pharmaceutical group corporation (sinopharm group co., ltd.). cnbg has a large r&d center in beijing that maximizes the synergies of the six affiliated institutions. today, cnbg/ sinopharm supplies % of the doses of the chinese national immunization program vaccines. china's vaccine manufacturing capabilities are currently intensely focused on supplying their own domestic needs for the pediatric birth cohort of million newborns annually. there are registered vaccine manufacturers in china and licensed vaccines. several of the manufacturers are members of the developing countries vaccine manufacturers' network (dcvmn). in , the world health organization prequalified the chinese-made japanese encephalitis virus vaccine made by the chengdu institute for biological products in collaboration with path. china became the first country ever a year; its products are used in more than countries. serum institute is also one of the largest suppliers of measlescontaining vaccines and the diphtheria-tetanus-pertussis (dtp) vaccines to u.n. agencies (unicef and pan american health organization [paho]). the institute makes its measles vaccine in mrc- cells instead of chick embryos and has although the first two of these factors have been consistently present in recent years, downward pressure on price is a major threat to current companies and a disincentive to new companies. freedom to price vaccines is restricted to the private market. less than % of the vaccines for children sold in the united states are sold in the private market; the rest are sold to the federal or state governments at reduced prices. controls are even greater in western europe and japan, and internationally there is strong downward pressure on prices as one moves from well-developed to less-developed regions of the world. in addition to the burden of partial price controls, the vaccine industry is subject to intense regulation. it cannot sell products until the vaccine and the facility in which it is manufactured are approved by the fda or other regulatory authorities; each batch must be released by the appropriate regulatory agency; and the usage, and therefore market size, is largely determined in the united states by the cdc and in europe by national regulatory authorities. thus, the vaccine industry does not operate in a free-market environment, and its behavior reflects these constraints. vaccine business growth in the future will have three important drivers: . new vaccines for cmv, herpes simplex virus (hsv), respiratory syncytial virus (rsv), norovirus, clostridium difficile, enterotoxigenic escherichia coli (etec), "improved influenza," and others that will gradually shift the focal point of immunization activities from the pediatric sector to the adolescent and adult sectors. . private market expansion in india and china driven by "high-income family" birth cohorts of million and million, respectively. this birth cohort roughly equals the combined birth cohort of million in the united states and europe. these high-and even middle-income individuals have shown the desire and ability to pay for vaccines at relatively high prices in relation to their incomes in these and other countries. to approve a hepatitis e vaccine, which was developed by xiamen innovax biotech. brazil has four notable vaccine manufacturing companies. bio-manguinhos/fiocruz is a government-owned entity that supplies the full demand for most vaccines under the brazilian national immunization program (nip). they also have a r&d collaboration with glaxosmithkline for a dengue vaccine. butantan institute is another government-owned institution that supplies the full demand for a smaller number of vaccines under the brazilian nip. ataulfo de paiva foundation is nonprofit private institution that primarily supplies the bcg vaccine for the brazilian market. ezequiel dias foundation (funed) is a public institution and part of minas gerais state. since , it has supplied the meningococcal conjugate vaccine after transferring the technology from novartis. the indian vaccine industry is the most advanced among these three developing countries, and is already providing a significant portion of the world's vaccine supply as well as developing new vaccines. china is on the verge of the transition from a domestic-only provider to a vaccine exporter, and is demonstrating solid progress in vaccine innovation. brazil is approaching the point of supplying its own domestic needs, largely with technology transferred from the developed world. together, these emerging players from middle-income countries will have increasing influence in the global vaccine industry during the coming years. pricing is a critical component of success for large companies and for venture funding of small companies since potential sales determine the desirability of an investment decision. the public expectation is for low vaccine prices, although this has changed somewhat in recent years with the introduction of several new, higher priced vaccines, such as varicella, rotavirus, pneumococcal conjugate vaccine, zoster vaccine, and hpv vaccine ( fig. . ) . large companies believe that vaccines should be priced according to value to society such as reduction in health care and related costs, relief from pain and suffering, and/or prevention of death, and that they should be rewarded for taking the enormous risks inherent in early vaccine development. such prices far exceed manufacturing costs, but are essential to produce the revenue streams that allow vaccines to be competitive for r&d and manufacturing resources within large pharmaceutical companies or that make biotech companies attractive investment opportunities. in general, vaccine prices have declined when more than two companies have competed in a single vaccine market and profitability has fallen sharply. the influenza vaccine market highlights this cyclical ebb and flow of competitors, most recently with the h n outbreak and shortages in leading to expanded competition and a vaccine surplus, followed by lower prices in . a vigorous large-company vaccine industry is dependent upon several factors: . a rich research environment sponsored largely by the nih and mostly carried out in academia, as the source for new creative ideas. . strong patent laws and protection of intellectual property. . freedom to price products at fair levels related to value of product to society. . well-implemented immunization practices. u.s. vaccine price evolution polio vaccine grows in developing countries, alternative approaches for local production will be explored, including access to bulk injected polio vaccine, tech transfer by big pharma as a part of their strategic alliances in developing markets, and potential introduction of alternative injected polio vaccine strains such as the sabin strain. another key driver will be the expansion of vaccine markets in india, china, and brazil. vaccine uptake rates in india, china and brazil are still low compared with western countries (e.g., india's flu vaccine uptake in was . million doses vs. million doses in the united states). , the immunization rates are also expected to increase in other low-income countries, which will increase vaccine dose requirements substantially. most of this demand in low-income countries is expected to be met by manufacturers of dcvmn network. as the dcvmn expands its role, one would expect significant downward pressure on vaccine prices. the delicate balance between innovation, government support, industrial expertise, and market forces has led to the establishment of a robust vaccine industry that will continue into the future. the industry is changing, however, with the growth of new markets in emerging economies and with the pressing need for new vaccines for the developing world. the current efforts of pdps and public creation of markets in response to this need will be successful if lessons learned from the industrial vaccine effort are incorporated into these government and philanthropically driven expectations. estimates of the total worldwide vaccine market revenue are $ billion. the top four western suppliers (see table . ) account for approximately % of these sales; the remainder comes from regional vaccine companies, the largest of which are located in middle-income countries such as india, china, and brazil (see table . ). the top four companies are slowly losing market share in doses to the dcvmn sourced doses and when polio eradication is achieved their dose share will drop to less than % of worldwide dose volume. in the coming years, as the eradication of polio becomes a reality, the developing country manufacturers will phase out their oral polio vaccine production. however, the need for inactivated polio vaccine will grow as developing countries adopt it into their pediatric immunization plans. as the demand for injected assuming such vaccines become reality, there is little doubt that the international donor community, working through organizations such as the global alliance for vaccines and immunization, will provide adequate funds for purchase of effective malaria, hiv, and tb vaccines, all of which are cost-effective references . company year-end earnings releases from evaluate pharma new scientific opportunities and old obstacles in vaccine development immunizing children: can one shot do it all? in: medical and health annual public health: u.s. vaccine supply falls seriously short lessons learned from a review of the development of selected vaccines. national vaccine advisory committee vaccine development: the long road from initial idea to product licensure cost of new drug development spending on new drug development united states vaccine research: a delicate fabric of political and private collaboration. national vaccine advisory committee influenza vaccine manufacturers testimony on vaccine policy before the u.s. house of representatives committee on commerce vaccine advance-purchase agreements for low income countries: practical issues improving vaccine supply and development: who needs what? vaccines market in india china's growing biomedical industry china's emerging vaccine industry special thanks to andrew hopkins for compositional support. key: cord- -yqu ykc authors: nan title: early warning systems a state of the art analysis and future directions date: - - journal: nan doi: . /j.envdev. . . sha: doc_id: cord_uid: yqu ykc nan united nations' international strategy for disaster reduction (isdr), it integrates (united nations, ) : . risk knowledge: risk assessment provides essential information to set priorities for mitigation and prevention strategies and designing early warning systems. . monitoring and predicting: systems with monitoring and predicting capabilities provide timely estimates of the potential risk faced by communities, economies and the environment. . disseminating information: communication systems are needed for delivering warning messages to the potentially affected locations to alert local and regional governmental agencies. the messages need to be reliable, synthetic and simple to be understood by authorities and the public. . response: coordination, good governance and appropriate action plans are key points in effective early warning. likewise, public awareness and education are critical aspects of disaster mitigation. failure of any part of the system will imply failure of the whole system. for example, accurate warnings will have no impact if the population is not prepared or if the alerts are received but not disseminated by the agencies receiving the messages. the basic idea behind early warning is that the earlier and more accurately we are able to predict short-and long term potential risks associated with natural and human induced hazards, the more likely we will be able to manage and mitigate a disaster's impact on society, economies, and environment. environmental hazards can be associated with: ongoing and rapid/sudden-onset threats and slow-onset (or ''creeping'') threats: . ongoing and rapid/sudden-onset: these include such hazards as follows: accidental oil spills, nuclear plant failures, and chemical plant accidents -such as inadvertent chemical releases to the air or into rivers and water bodies -geological hazards and hydro-meteorological hazards (except droughts). . slow-onset (or ''creeping''): incremental but long-term and cumulative environmental changes that usually receive little attention in their early phases but which, over time, may cause serious crises. these include such issues as deteriorating air and water quality, soil pollution, acid rain, climate change, desertification processes (including soil erosion and land degradation), drought, ecosystems change, deforestation and forest fragmentation, loss of biodiversity and habitats, nitrogen overloading, radioactive waste, coastal erosion, pressures on living marine resources, rapid and unplanned urban growth, environment and health issues (emerging and re-emerging infectious diseases and links to environmental change), land cover/land changes, and environmental impacts of conflict, among others. such creeping changes are often left unaddressed as policy-makers choose or need to cope with immediate crises. eventually, neglected creeping changes may become urgent crises that are more costly to deal with. slow-onset threats can be classified into location-specific environmental threats, new emerging science and contemporary environmental threats (table ) . rapid/sudden-onset and slow-onset events will provide different amounts of available warning time. fig. shows warning times for climatic hazards. early warning systems may provide seconds of available warning time for earthquakes to months of warning for droughts, which are the quickest and slowest onset hazards, respectively. specifically, early warning systems provide tens of seconds of warning for earthquakes, days to hours for volcanic eruptions, and hours for tsunamis. tornado warnings provide minutes of lead-time for response. hurricane warning time varies from weeks to hours. the warning time provided by warning systems, increases to years or even decades of leadtime available for slow-onset threats (such as el niñ o, global warming etc., as shown in fig. ). drought warning time is in the range of months to weeks. slow-onset (or creeping) changes may cause serious problems to environment and society, if preventive measures are not taken when needed. such creeping environmental changes require effective early warning technologies due to the high potential impact of incremental cumulative changes on society and the environment. (golnaraghi, ) . the graph shows the timeliness of early warning systems for hydrometeorological hazards and the area of impact (by specifying the diameter of the spherical area) for climatic hazards. early warning systems help to reduce economic losses and mitigate the number of injuries or deaths from a disaster, by providing information that allows individuals and communities to protect their lives and property. early warning information empowers people to take action prior to a disaster. if well integrated with risk assessment studies and communication and action plans, early warning systems can lead to substantive benefits. effective early warning systems embrace the following aspects: risk analysis; monitoring and predicting location and intensity of the disaster; communicating alerts to authorities and to those potentially affected; and responding to the disaster. the early warning system has to address all aspects. monitoring and predicting is only one part of the early warning process. this step provides the input information for the early warning process that needs to be disseminated to those whose responsibility is to respond (fig. ) . early warnings may be disseminated to targeted users (local early warning applications) or broadly to communities, regions or to media (regional or global early warning applications). this information gives the possibility of taking action to initiate mitigation or security measures before a catastrophic event occurs. when monitoring and predicting systems are associated with communication systems and response plans, they are considered early warning systems (glantz, ) . commonly, however, early warning systems lack one or more elements. in fact, a review of existing early warning systems shows that in most cases communication systems and adequate response plans are missing. to be effective, warnings also must be timely so as to provide enough lead-time for responding; reliable, so that those responsible for responding to the warning will feel confident in taking action; and simple, so as to be understood. timeliness often conflicts with the desire to have reliable predictions, which become more accurate as more observations are collected from the monitoring system . thus, there is an inevitable trade-off between the amount of warning time available and the reliability of the predictions provided by the ews. an initial alert signal may be sent to give the maximum amount of warning time when a minimum level of prediction accuracy has been reached. however, the prediction accuracy for the location and size of the event will continue to improve as more data are collected by the monitoring system part of the ews network. it must be understood that every prediction, by its very nature, is associated with uncertainty. because of the uncertainties associated with the predicted parameters that characterize the incoming disaster, it is possible that a wrong decision may be made. two kinds of wrong decisions may occur : missed alarm (or false negative), when the mitigation action is not taken when it should have been or false alarm (or false positive), when the mitigation action is taken when it should not have been. finally, the message should communicate the level of uncertainty and expected cost of taking action but also be stated in simple language so as to be understood by those who receive it. most often, there is a communication gap between ew specialists who use technical and engineering language and the ews users, who are generally outside of the scientific community. to avoid this, these early warnings need to be reported concisely, in layman's terms and without scientific jargon. an effective early warning system needs an effective communication system. early warning communication systems have two main components (second international conference on early warning (ewcii), ): communication infrastructure hardware that must be reliable and robust, especially during the disaster; and appropriate and effective interactions among the main actors of the early warning process, such as the scientific community, stakeholders, decision-makers, the public, and the media. redundancy of communication systems is essential for disaster management, while emergency power supplies and back-up systems are critical in order to avoid the collapse of communication systems after disasters occur. in addition, to ensure the communication systems operate reliably and effectively during and after a disaster occurs, and to avoid network congestion, frequencies and channels must be reserved and dedicated to disaster relief operations. many communication tools are currently available for warning dissemination, such as short message service (sms) (cellular phone text messaging), e-mail, radio, tv and web service. information and communication technology (ict) is a key element in early warning, which plays an important role in disaster communication and disseminating information to organizations in charge of responding to warnings and to the public during and after a disaster (tubtiang, ) . today, the decentralization of information and data through the world wide web makes it possible for millions of people worldwide to have easy, instantaneous access to a vast amount of diverse online information. this powerful communication medium has spread rapidly to interconnect our world, enabling near-real-time communication and data exchanges worldwide. according to the internet world stats database, as of december , global documented internet usage was . billion people. thus, the internet has become an important medium to access and deliver information worldwide in a very timely fashion. in addition, remote sensing satellites now provide a continuous stream of data. they are capable of rapidly and effectively detecting hazards, such as transboundary air pollutants, wildfires, deforestation, changes in water levels, and natural hazards. with rapid advances in data collection, analysis, visualization and dissemination, including technologies such as remote sensing, geographical information systems (gis), web mapping, sensor webs, telecommunications and ever-growing internet connectivity, it is now feasible to deliver relevant information on a regular basis to a worldwide audience relatively inexpensively. in recent years, commercial companies such as google, yahoo, and microsoft have started incorporating maps and satellite imagery into their products and services, delivering compelling visual images and providing easy tools that everyone can use to add to their geographic knowledge. ews: decision making procedure based on cost-benefit analysis. to improve the performance of ews, a performance based decision making procedure needs to be based on the expected consequences of taking action, in terms of the probability of a false and missed alarm. an innovative approach sets the threshold based on the acceptable probability of false (missed) alarms, from a cost-benefit analysis . consider the case of a ews decision making strategy based on raising the alarm if a critical severity level, a, is predicted to be exceeded at a site. the decision of whether to activate the alarm or not is based on the predicted severity of the event. a decision model that takes into account the uncertainty of the prediction and the consequences of taking action will be capable of controlling and reducing the incidence of false and missed alerts. the proposed decision making procedure intends to fill this gap. the ews will provide the user with a real-time prediction of the severity of the event,ŜðtÞ, and its error, e tot ðtÞ. during the course of the event, the increase in available data will improve prediction accuracy. the prediction and its uncertainty are updated as more data come in. the actual severity of the event, e tot , is unknown and may be defined by adding the prediction error to the predicted value,Ŝ. the potential probability of false (missed) alarm is given by the probability of being less (greater) than the critical threshold; it becomes an actual probability of false (missed) alarm if the alarm is (not) raised: referring to the principle of maximum entropy (jaynes, ) , the prediction error is modelled by gaussian distribution, representing the most uninformative distribution possible due to lack of information. hence, at time t, the actual severity of the event, s, may be modelled with a gaussian distribution, having mean equal to the predictionŜðtÞ and uncertainty equal to s tot ðtÞ, that is the standard deviation of the prediction error e tot ðtÞ. eqs. ( ) and ( ) may be written as : where f represents the gaussian cumulative distribution function. the tolerable level at which mitigation action should be taken can be determined from a cost-benefit analysis by minimizing the cost of taking action: where c save are the savings due to mitigation actions and c fa is the cost of false alert. note that the tolerable levels a and b sum up to one which directly exhibits the trade-off between the threshold probabilities that are tolerable for false and missed alarms. the methodology offers an effective approach for decision making under uncertainty focusing on user requirements in terms of reliability and cost of action. information is now available in a near-real-time mode from a variety of sources at global and local levels. in the coming years, the multi-scaled global information network will greatly improve thanks to new technological advances that facilitate the global distribution of data and information at all levels. globalization and rapid communication provides an unprecedented opportunity to catalyse effective action at every level by rapidly providing authorities and the general public with high-quality and scientifically credible information in a timely fashion. the dissemination of warnings often follows a cascade process, which starts at the international or national level and then moves outwards or downwards in scale to regional and community levels (twigg, ) . early warnings may activate other early warnings at different authoritative levels, flowing down in responsibility roles, although all are equally necessary for effective early warning. standard protocols play a fundamental role in addressing the challenge of effective coordination and data exchange among the actors in the early warning process and it aids in the process for warning communication and dissemination. the common alerting protocol (cap), really simple syndication (rss) and extensible markup language (xml) are examples of standard data interchange formats for structured information that can be applied to warning messages for a broad range of information management and warning dissemination systems. the advantage of standard format alerts is that they are compatible with all information systems, warning systems, media, and most importantly, with new technologies such as web services. cap, for example, defines a single standard message format for all hazards, which can activate multiple warning systems at the same time and with a single input. this guarantees consistency of warning messages and would easily replace specific application-oriented messages with a single multihazard message format. cap is compatible with all types of information systems and public alerting systems (including broadcast radio and television), public and private data networks, multi-lingual warning systems and emerging technologies such as internet web services and existing systems such as the us national emergency alert system and the national oceanic and atmospheric organization (noaa) weather radio. cap uses extensible markup language (xml), which contains information about the alert message, the specific hazard event, and appropriate responses, including the urgency of action to be taken, severity of the event, and certainty of the information. for early warning systems to be effective, it is essential that they be integrated into policies for disaster mitigation. good governance priorities include protecting the public from disasters through the implementation of disaster risk reduction policies. it is clear that natural phenomena cannot be prevented, but their human, socio-economic and environmental impacts can and should be minimized through appropriate measures, including risk and vulnerability reduction strategies, early warning, and appropriate action plans. most often, these problems are given attention during or immediately after a disaster. disaster risk reduction measures require long term plans and early warning should be seen as a strategy to effectively reduce the growing vulnerability of communities and assets. the information provided by early warning systems enables authorities and institutions at various levels to immediately and effectively respond to a disaster. it is crucial that local government, local institutions, and communities be involved in the entire policy-making process, so they are fully aware and prepared to respond with short and long-term action plans. the early warning process, as previously described, is composed of main stages: risk assessment, monitoring and predicting, disseminating and communicating warnings, and response. within this framework, the first phase, when short-and long-term actions plans are laid out based on risk assessment analysis, is the realm of institutional and political actors. then ew acquires a technical dimension in the monitoring and predicting phase, while in the communication phase, ew involves both technical and institutional responsibility. the response phase then involves many more sectors, such as national and local institutions, non-governmental organizations, communities, and individuals. below is a summary of recommendations for effective decision making within the early warning process (sarevitz et al., ) . prediction efforts by the scientific community alone are insufficient for decision making. the scientific community and policy-makers should outline the strategy for effective and timely decision making by indicating what information is needed by decision-makers, how predictions will be used, how reliable the prediction must be to produce an effective response, and how to communicate this information and the tolerable prediction uncertainty so that the information can be received and understood by authorities and public. a miscommunicated or misused prediction can result in costs to society. prediction, communication, and use of the information are necessary factors in effective decision making within the early warning process. wishing not to appear ''alarmist'' or to avoid criticism, local and national governments have sometimes kept the public in the dark when receiving technical information regarding imminent threats. the lack of clear and easy-to-use information can sometimes confuse people and undermine their confidence in public officials. conversely, there are quite a few cases where the public may have refused to respond to early warnings from authorities, and have therefore exposed themselves to danger or forced governments to impose removal measures. in any case, clear and balanced information is critical, even when some level of uncertainty remains. for this reason, the information's uncertainty level must be communicated to users together with the early warning . resources must be allocated wisely and priorities should be set, based on risk assessment, for long-and short-term decision making, such as investing in local early warning systems, education, or enhanced monitoring and observational systems. in addition, decision-makers need to be able to set priorities for timely and effective response to a disaster when it occurs based on the information received from the early warning system. decision-makers should receive necessary training on how to use the information received when an alert is issued and what that information means. institutional networks should be developed with clear responsibilities. complex problems such as disaster mitigation and response require multidisciplinary research, multi-sector policy and planning, multi-stakeholder participation, and networking involving all the participants of the process, such as the scientific research community (including social sciences aspects), land use planning, environment, finance, development, education, health, energy, communications, transportation, labour, and social security and national defence. decentralization in the decision making process could lead to optimal solutions by clarifying local government and community responsibilities. collaboration will improve efficiency, credibility, accountability, trust, and costeffectiveness. this collaboration consists of joint research projects, sharing information and participatory strategic planning and programming. because there are numerous actors involved in early warning response plans (such as governing authorities, municipalities, townships, and local communities), the decision making and legal framework of responsibilities should be set up in advance in order to be prepared when a disaster occurs. hurricane katrina in showed gaps in the legal frameworks and definition of responsibilities that exacerbated the disaster. such ineffective decision making must be dealt with to avoid future disasters such as the one in new orleans. earth observation (eo), through measuring and monitoring, provides an insight and understanding into earth's complex processes and changes. eo includes measurements that can be made directly or by sensors in-situ or remotely (i.e. satellite remote sensing, aerial surveys, land or oceanbased monitoring systems, fig. ), to provide key information to models or other tools to support decision making processes. eo assists governments and civil society to identify and shape corrective and new measures to achieve sustainable development through original, scientifically valid assessments and early warning information on the recent and potential long-term consequences of human activities on the biosphere. at a time when the world community is striving to identify the impacts of human actions on the planet's life support system, time sequenced satellite images help to determine these impacts and provide unique, visible and scientifically convincing evidence that human actions are causing substantial changes to the earth's environment and natural resource base (i.e. ecosystems changes, urban growth, transboundary pollutants, loss of wetlands, etc.). by enhancing the visualization of scientific information on environmental change, satellite imagery will enhance environmental management and raise the awareness of emerging environmental threats. eo provides the opportunity to explore, to discover, and to understand the world in which we live from the unique vantage point of space. the following section discusses the potential role of eo for each type of environmental threat. . . ongoing and rapid/sudden-onset environmental threats . . . oil spills earth observation is increasingly used to detect illegal marine discharges and oil spills. infra-red (ir) video and photography from airborne platforms, thermal infrared imaging, airborne laser fluorosensors, airborne and satellite optical sensors, as well as airborne and satellite synthetic aperture radar (sar) are used for this purpose. sar has the advantage of also providing data during cloud cover conditions and darkness, unlike optical sensors. in addition, optical-sensor techniques applied to oil spills detection are associated to a high number of false alarms, more often cloud shadows, sun glint, and other conditions such as precipitation, fog, and the amounts of daylight present also may be erroneously associated with oil spills. for this reason, sar is preferred over optical sensors, especially when spills cover vast areas of the marine environment, and when the oil cannot be seen or discriminated against the background. sar detects changes in sea-surface roughness patterns modified by oil spills. the largest shortcoming of oil spills detection using sar images is accurate discrimination between oil spills and natural films (brekke and soldberg, ) . to date, operational application of satellite imagery for oil spill detection still remains a challenge due to limited spatial and temporal resolution. in addition, processing times are often too long for operational purposes, and it is still not possible to measure the thickness of the oil spill (mansor et al., ; us fig. . illustration of multiple observing systems in use on the ground, at sea, in the atmosphere and from space for monitoring and researching the climate system (wmo, ). interior, minerals management service, ) . existing applications are presented in the section . chemical and nuclear accidents may have disastrous consequences, such as the accident in bhopal, india, which killed more than and injured about , and the explosion of the reactors of the nuclear power plant in chernobyl, ukraine, which was the worst such accident to date, affecting part of the soviet union, eastern europe, scandinavia, and later, western europe. meteorological factors such as wind speed and direction, turbulence, stability layers, humidity, cloudiness, precipitation and topographical features, influence the impact of chemical and nuclear accidents and have to be taken into account in decision models. in some cases, emergencies are localized while in others, transport processes are most important. eo provides key data for monitoring and forecasting the dispersion and spread of the substance. geohazards associated with geological processes such as earthquakes, landslides, and volcanic eruptions are mainly controlled by ground deformation. eo data allows monitoring of key physical parameters associated with geohazards, such as deformation, plate movements, seismic monitoring, baseline topographic, and geoscience mapping. eo products are useful for detection and mitigation before the event, and for damage assessment during the aftermath. for geohazards, stereo optical and radar interferometry associated with ground-based global positioning system (gps) and seismic networks are used. for volcanic eruptions additional parameters are observed such as temperature and gas emissions. ground based measurements have the advantage of being continuous in time but have limited spatial extent, while satellite observations cover wide areas but are not continuous in time. these data need to be integrated for an improved and more comprehensive approach (committee on earth observation satellites (ceos), ; integrated global observing strategy (igos-p), ). earthquakes are due to a sudden release of stresses accumulated around the faults in the earth's crust. this energy is released through seismic waves that travel from the origin zone, which cause the ground to shake. severe earthquakes can affect buildings and populations. the level of damage depends on many factors, such as the intensity and depth of the earthquake, and the vulnerability of structures and their distance from the earthquake's origin. for earthquakes, information on the location and magnitude of the event first needs to be conveyed to responsible authorities. this information is used by seismic early warning systems to activate security measures within seconds after the earthquake's origin and before strong shaking occurs at the site. shakemaps generated within five minutes provide essential information to assess the intensity of ground shaking and the damaged areas. the combination of data from seismic networks and gps may help to increase reliability and timeliness of this information. earthquake frequency and probability shakemaps based on historical seismicity and base maps (geological, soil type, active faults, hydrological, and dems), assist in the earthquake mitigation phase and need to be included in the building code design process for improved land use and building practices. for responses, additional data are needed, such as seismicity, intensity, strain, dems, soil type, moisture conditions, infrastructure and population, to produce post-event damage maps. thermal information needs to continuously be monitored. this is obtained from low/medium resolution ir imagery from polar and geostationary satellites for thermal background characterization (advanced very high resolution radiometer (avhrr), atsr, modis and goes) together with deformation from edm and/or gps network; borehole strainmetres; and sar interferometry. landslides are displacements of earth, rock, and debris caused by heavy rains, floods, earthquakes, volcanoes, and wildfires. useful information for landslides and ground instability include the following: hazard zonation maps (landslides, debris flows, rockfalls, subsidence, and ground instability scenarios) during the mitigation phase, associated with landlside inventories, dem, deformation (gps network; sar interferometry; other surveys such as leveling, laser scanning, aerial, etc.), hydrology, geology, soil, geophysical, geotechnical, climatic, seismic zonation maps, land cover, land use, and historical archives. forecasting the location and extent of ground instability or landslides is quite challenging. landslides can be preceded by cracks, accelerating movement, and rock fall activity. real-time monitoring of key parameters thus becomes essential. the observed acceleration, deformation or displacement, exceeding a theoretical pre-fixed threshold is the trigger for issuing an alert signal. an alternative approach is based on hydrologic forecasting. it should be said that for large areas site-specific monitoring is not feasible. in this case, hazard mapping associated with monitoring of high risk zones remains the best option for warning. local rapid mapping of affected areas, updated scenarios and real-time monitoring (deformation, seismic data, and weather forecasts) assist during the response phase. a tsunami is a series of ocean waves generated by sudden displacements in the sea floor, landslides, or volcanic activity. although a tsunami cannot be prevented, the impact of a tsunami can be mitigated through community preparedness, timely warnings, and effective response. observations of seismic activity, sea floor bathymetry, topography, sea level data (tide gauge observations of sea height; real-time tsunami warning buoy data; deep ocean assessment and reporting of tsunamis (dart) buoys and sea-level variations from the topex/poseidon and jason, the european space agency's envisat, and the us navy's geosat follow-on), are used in combination with tsunami models to create inundation and evacuation maps and to issue tsunami watches and warnings. volcanic eruptions may be mild, releasing steam and gases or lava flows, or they can be violent explosions that release ashes and gases into the atmosphere. volcanic eruptions can destroy land and communities living in their path, affect air quality, and even influence the earth's climate. volcanic ash can impact aviation and communications. data needs for volcanic eruptions include hazard zonation maps, real-time seismic, deformation (electronic distance measurement (edm) and/or gps network; leveling and tilt networks; borehole strainmeters; gravity surveys; sar interferometry), thermal (landsat, aster, geostationary operational environmental satellites (goes), modis); air borne ir cameras; medium-high resolution heat flux imagery and gas emissions (cospec, licor surveys); satellite imagery (i.e., aster) and digital elevation maps (dem). as soon as the volcanic unrest initiates, information needs to be timely and relatively high-resolution. once the eruption starts, the flow of information has to speed up. seismic behaviour and deformation patterns need to be observed throughout the eruption especially to detect a change of eruption site ( - seismometers ideally with -directional sensors; a regional network). hydro-meteorological hazards include the wide variety of meteorological, hydrological and climate phenomena that can pose a threat to life, property and the environment. these types of hazards are monitored using the meteorological, or weather, satellite programs, beginning in the early s. in the united states, nasa, noaa, and the department of defense (dod) have all been involved with developing and operating weather satellites. in europe, esa and eumetsat (european organisation for the exploitation of meteorological satellites) operate the meteorological satellite system (us centennial of flight commission). data from geostationary satellite and polar microwave derived products (goes) and polar orbiters (microwave data from the defense meteorological satellite program (dmsp), special sensor microwave/imager (ssm/i), noaa/advanced microwave sounding unit (amsu), and tropical rainfall measuring mission (trmm)) are key in weather analysis and forecasting. goes has the capability of observing the atmosphere and its cloud cover from the global scale down to the storm scale, frequently and at high resolution. microwave data are available on only an intermittent basis, but are strongly related to cloud and atmospheric properties. is key for monitoring meteorological processes from the global scale to the synoptic scale to the mesoscale and finally to the storm scale. (scofield et al., ) . goes and poes weather satellites provide useful information on precipitation, moisture, temperature, winds and soil wetness, which is combined with ground observation. floods are often triggered by severe storms, tropical cyclones, and tornadoes. the number of floods has continued to rise steadily; together with droughts, they have become the most deadly disasters over the past decades. the increase in losses from floods is also due to climate variability, which has caused increased precipitation in parts of the northern hemisphere (natural hazards working group, ) . floods can be deadly, particularly when they arrive without warning. in particular, polar orbital and geostationary satellite data are used for flood observation. polar orbital satellites include optical low (avhrr), medium (landsat, spot, irs) and high resolution (ikonos) and microwave sensors (high (sar-radarsat, jers and ers) and low resolution passive sensors (ssmi). meteorological satellites include goes and , meteosat, gms, the indian insat and the russian goms; and polar orbitals such as noaa (noaa ) and ssmi. for storms, additional parameters are monitored, such as sea surface temperature, air humidity, surface wind speed, rain estimates (from dmsp/ssmi, trmm, ers, quikscat, avhrr, radarsat). trmm offers unique opportunities to examine tropical cyclones. with trmm, scientists are able to make extremely precise radar measurements of tropical storms over the oceans and identify their intensity variations, providing invaluable insights into the dynamics of tropical storms and rainfall. epidemics such as malaria and meningitis are linked to environmental factors. satellite data can provide essential information on these factors and help to better understand diseases. as an example, the esa epidemio project, launched in , utilizes data from esa's envisat or the french space agency's spot, and field data to gather information on the spread of epidemics, helping to better prepare for epidemic outbreaks. geo, with who and other partners, are working together on the meningitis environmental risk information technologies (merit) project to better understand the relationship between meningitis and environmental factors using remote sensing. wildfires pose a threat to lives and properties and are often connected to secondary effects such as landslides, erosion, and changes in water quality. wildfires may be natural processes, human induced for agriculture purposes, or just the result of human negligence. wildfire detection using satellite technologies is possible thanks to significant temperature difference between the earth's surface (usually not exceeding - c) and the heat of fire ( - c), which results in a thousand times difference in heat radiation generated by these objects. noaa (avhrr radiometer with m spatial resolution and km swath width) and earth observing satellites (eos) (terra and aqua satellites with modis radiometer installed on them with , and m spatial resolution and km swath width) are the most widely used modern satellites for operative fire monitoring (klaver et al., ) . high-resolution sensors, such as the landsat thematic mapper, spot multispectral scanner, or national oceanic and atmospheric administration's avhrr or modis, are used for fire potential definition. sensors used for fire detection and monitoring include avhrr, which has a thermal sensor and daily overflights, the defense meteorological satellite program's optical linescan system (ols) sensor, which has daily overflights and operationally collects visible images during its nighttime pass, and the modis land rapid response system. avhrr and higher resolution images (spot, landsat, and radar) can be used to assess the extent and impact of the fire. smog is the product of human and natural activities, such as industry, transportation, wildfires, volcanic eruptions, etc. and can have serious effects on human health and the environment. a variety of eo tools are available to monitor air quality. the national aeronautics and space administration (nasa) and the european space agency (esa) both have instruments to monitor air quality. the canadian mopitt (measurements of pollution in the troposphere) aboard the terra satellite monitors the lower atmosphere to observe how it interacts with the land and ocean biospheres, distribution, transport, sources, and sinks of carbon monoxide and methane in the troposphere. the total ozone mapping spectrometer (toms) instrument measures the total amount of ozone in a column of atmosphere as well as cloud cover over the entire globe. additionally, toms measures the amount of solar radiation escaping from the top of the atmosphere to accurately estimate the amount of ultraviolet radiation that reaches the earth's surface. the ozone monitoring instrument (omi) on aura will continue the toms record for total ozone and other atmospheric parameters related to ozone chemistry and climate. the omi instrument distinguishes between aerosol types, such as smoke, dust, and sulphates, and can measure cloud pressure and coverage. esa's schiamachy (scanning imaging absorption spectro-meter for atmospheric chartography) maps atmosphere over a very wide wavelength range ( - nm), which allows detection of trace gases, ozone and related gases, clouds and dust particles throughout the atmosphere (athena global, ) . the moderate resolution imaging spectroradiometer (modis) sensor measures the relative amount of aerosols and the relative size of aerosol particles-solid or liquid particles suspended in the atmosphere. examples of such aerosols include dust, sea salts, volcanic ash, and smoke. the modis aerosol optical depth product is a measure of how much light airborne particles prevent from passing through a column of atmosphere. new technologies are also being explored for monitoring air quality, such as mobile phones equipped with simple sensors to empower citizens to collect and share real-time air quality measurements. this technology is being developed by a consortium called urban atmospheres. the traditional methods of monitoring coastal water quality require scientists to use boats to gather water samples, typically on a monthly basis because of the high costs of these surveys. this method captures episodic events affecting water quality, such as the seasonal freshwater runoff, but is not able to monitor and detect fast changes. satellite data provide measures of key indicators of water qualityturbidity and water clarity -to help monitor fast changes in factors that affect water quality, such as winds, tides and human influences including pollution and runoff. geoeye's sea-viewing wide field-ofview sensor (seawifs) instrument, launched aboard the orbview- satellite in , collects ocean colour data used to determine factors affecting global change, particularly ocean ecology and chemistry. modis sensor, launched aboard the aqua satellite in , together with its counterpart instrument aboard the terra satellite, collects measurements from the entire earth surface every - days and can also provide measurements of turbidity (bjorn-hansen, ) . overall, air and water quality monitoring coverage still appears to be irregular and adequate and available in real-time only for some contaminants (global earth observation system of systems, ). . . . . droughts. noaa's national weather service (nws) defines a drought as ''a period of abnormally dry weather sufficiently prolonged for the lack of water to cause serious hydrologic imbalance in the affected area.'' drought can be classified by using different definitions: meteorological (deviation from normal precipitation); agricultural (abnormal soil moisture conditions); hydrological (related to abnormal water resources); and socio-economic (when water shortage impacts people's lives and economies). a comprehensive and integrated approach is required to monitor droughts, due to the complex nature of the problem. although all types of droughts originate from a precipitation deficiency, it is insufficient to monitor solely this parameter to assess severity and resultant impacts (world meteorological organization, ) . effective drought early warning systems must integrate precipitation and other climatic parameters with water information such as streamflow, snow pack, groundwater levels, reservoir and lake levels, and soil moisture, into a comprehensive assessment of current and future drought and water supply conditions (svoboda et al., ) . in particular, there are key parameters that are used in a composite product developed from a rich information stream, including climate indices, numerical models, and the input of regional and local experts. these are as follows: ) palmer drought severity index (based on precipitation data, temperature data, division constants (water capacity of the soil, etc.) and previous history of the indices). ) soil moisture model percentile (calculated through a hydrological model that takes observed precipitation and temperature and calculates soil moisture, evaporation and runoff. the potential evaporation is estimated from observed temperature). ) daily stream flow percentiles. ) percent of normal precipitation. ) standardized precipitation index, and ) remotely sensed vegetation health index. additional indicators may include the palmer crop moisture index, keetch-byram drought index, fire danger index, evaporation-related observations such as relative humidity and temperature departure from normal, reservoir and lake levels, groundwater levels, field observations of surface soil moisture, and snowpack observations. some of these indices and indicators are computed for point locations, and others are computed for climate divisions, drainage (hydrological) basins, or other geographical regions (svoboda et al., ) . a complete list of drought products can be found on noaa's national environmental satellite, data, & information service (noaanesdis) web page. . . . . desertification. desertification refers to the degradation of land in arid, semi-arid, and dry sub-humid areas due to climatic variations or human activity. desertification can occur due to inappropriate land use, overgrazing, deforestation, and over-exploitation. land degradation affects many countries worldwide and has its greatest impact in africa. in spite of the potential benefits of eo information, the lack of awareness of the value and availability of information, inadequate institutional resources and financial problems are the most frequent challenges to overcome in detecting desertification (sarmap, ) . in , through a project called desertwatch, esa has developed a set of indicators based principally on land surface parameters retrieved from satellite observations for monitoring land degradation and desertification. desertwatch is being tested and applied in mozambique, portugal, and brazil. the un food and agriculture organization's global information and early warning system (giews). these provide information on food availability, market prices and livelihoods. the observations of climate-related variables on a global scale have made it possible to document and analyse the behaviour of earth's climate, made available through programs as follows: the ioc-wmo-unep-icsu global ocean observing system (goos); the fao-wmo-unesco-unepicsu global terrestrial observing system (gtos); the wmo global observing system (gos) and global atmosphere watch (gaw); the research observing systems and observing systems research of the wmo-ioc-icsu world climate research programme (wcrp) and other climate relevant international programs; and wmo-unesco-icsuioc-unep global climate observing system (gcos). the intergovernmental panel on climate change (ipcc) periodically reviews and assesses the most recent scientific, technical and socio-economic information produced worldwide relevant to the understanding of climate change. hundreds of scientists worldwide contribute to the preparation and review of these reports. according to the recent ipcc report, the atmospheric buildup of greenhouse gases is already shaping the earth's climate and ecosystems from the poles to the tropics, which face inevitable, possibly profound, alteration. the ipcc has predicted widening droughts in southern europe and the middle east, sub-saharan africa, the american southwest and mexico, and flooding that could imperil low-lying islands and the crowded river deltas of southern asia. it stressed that many of the regions facing the greatest risks are among the world's poorest. information about the impacts of climate variability impact information is needed by communities and resource managers to adapt and prepare for larger fluctuations as global climate change becomes more evident. this information includes evidence of changes occurring due to climate variability, such as loss of ecosystems, ice melting, coastal degradation, and severe droughts. such information will provide policy-makers scientifically valid assessment and early warning information on the current and potential long-term consequences of human activities on the environment. (i.e., ecosystem changes, loss of biodiversity and habitats, land cover/land changes, coastal erosion, urban growth, etc.). landsat satellites (series - ) are extensively used to monitor location-specific environmental changes. they have the great advantage of providing repetitive, synoptic, global coverage of high-resolution multi-spectral imagery (fadhil, ) . landsat can be used for change detection applications to identify differences in the state of an object or phenomenon by comparing the satellite imagery at different times. change detection is key in natural resources management (singh, ) . central to this theme is the characterization, monitoring and understanding of land cover and land use change, since they have a major impact on sustainable land use, biodiversity, conservation, biogeochemical cycles, as well as land-atmosphere interactions affecting climate and they are indicators of climate change, especially at a regional level (igos-p, ) . the united nations environment programme's (unep) bestselling publication one planet, many people: atlas of our changing environment, which shows before and after satellite photos to document changes to the earth's surface over the past years, proves the importance and impact of visual evidence of environmental change in hotspots. the atlas contains some remarkable landsat satellite imagery and illustrates the alarming rate of environmental destruction. through the innovative use of some satellite images, ground photos and maps, the atlas provides visual proof of global environmental changes -both positive and negative -resulting from natural processes and human activities. case studies include themes such as atmosphere, coastal areas, waters, forests, croplands, grasslands, urban areas, and tundra and polar regions. the atlas demonstrates how our growing numbers and our consumption patterns are shrinking our natural resource base. the aim of this report is to identify current gaps and future needs of early warning systems through the analysis of the state of the art of existing early warning and monitoring systems for environmental hazards. among existing early warning/monitoring systems, only systems that provide publicly accessible information and products have been included in the analysis. for the present study, several sources have been used, such as the global survey of early warning systems (united nations, ) together with the online inventory of early warning systems on isdr's platform for the promotion of early warning (ppew) website, and several additional online sources, technical reports and scientific articles listed in the references. for each hazard type, a gap analysis has been carried out to identify critical aspects and future needs of ews, considering aspects such as geographical coverage, and essential ews elements such as monitoring and prediction capability, communication systems and application of early warning information in responses. below is the outcome of the review of existing early warning/monitoring systems for each hazard type. details of all systems, organized in tables by hazard type, are listed in the appendix. the current gaps identified for each hazard type could be related to technological, organizational, communication or geographical coverage aspects. to assess the geographical coverage of existing systems for each hazard type, the existing systems have been imposed on the hazard's risk map. for this analysis, the maps of risks of mortality and economic loss were taken from natural disaster hotspots: a global risk analysis, a report from the world bank (dilley et al., ) . to detect operational oil spills, satellite overpasses and aerial surveillance flights need to be used in an integrated manner. in many countries in northern europe, the ksat manual approach is currently used to identify oil spills from the satellite images. ksat has provided this operational service since , and in europe, use of satellites for oil spill detection is well established and well integrated within the national and regional oil pollution surveillance and response chains. operational algorithms utilizing satellite-borne c-band sar instruments (radarsat- , envisat, radarsat- ) are also being developed for oil-spill detection in the baltic sea area. releases of a hazardous substance from industrial accidents can have immediate adverse effects on human and animal life or the environment. wmo together with iaea provides specialized meteorological support to environmental emergency response related to nuclear accidents and radiological emergencies. the wmo network of eight specialized numerical modelling centres called regional specialized meteorological centres (rsmcs) provides predictions of the movement of contaminants in the atmosphere. the inter-agency committee on the response to nuclear accidents (iacrna) of the iaea, coordinates the international intergovernmental organizations responding to nuclear and radiological emergencies. iacrna members are: the european commission (ec), the european police office (europol), the food and agriculture organization of the united nations (fao), iaea, the international civil aviation organization (icao), the international criminal police organization (interpol), the nuclear energy agency of the organization for economic co-operation and development (oecd/nea), the pan american health organization (paho), unep, the united nations office for the co-ordination of humanitarian affairs (un-ocha), the united nations office for outer space affairs (unoosa), the world health organization (who), and wmo. the agency's goal is to provide support during incidents or emergencies by providing near real-time reporting of information through the following: the incident and emergency centre (iec), which maintains a h oncall system for rapid initial assessment, and if needed, triggers response operations; the emergency notification and assistance convention website (enac), which allows the exchange of information on nuclear accidents or radiological emergencies; and the nuclear event webbased system (news), which provides information on all significant events in nuclear power plants, research reactors, nuclear fuel cycle facilities and occurrences involving radiation sources or the transport of radioactive material. the global chemical incident alert and response system of the international programme on chemical safety, which is part of who, focuses on disease outbreaks from chemical releases and also provides technical assistance to member states for response to chemical incidents and emergencies. formal and informal sources are used to collect information and if necessary, additional information and verification is sought through official channels: national authorities, who offices, who collaborating centres, other united nations agencies, and members of the communicable disease global outbreak alert and response network (goarn), internet-based resources, particularly the global public health intelligence network (gphin) and promed-mail. based on this information, a risk assessment is carried out to determine the potential impact and if assistance needs to be offered to member states. . . . geological hazards . . . . earthquakes. earthquake early warning systems are a relatively new approach to seismic risk reduction. they provide a rapid estimate of seismic parameters such as magnitude and location associated with a seismic event based on the first seconds of seismic data registered at the epicentre. this information can then be used to predict ground motion parameters of engineering interest including peak ground acceleration and spectral acceleration. earthquake warning systems are currently operational in mexico, japan, romania, taiwan and turkey (espinosa aranda et al., ; wu et al., ; wu and teng, ; odaka et al., ; kamigaichi, ; nakamura, ; horiuchi et al., ) . systems are under development for seismic risk mitigation in california and italy. local and national scale seismic early warning systems, which provide seismic information between a few seconds and tens of seconds before shaking occurs at the target site, are used for a variety of applications such as shutting down power plants, stopping trains, evacuating buildings, closing gas valves, and alerting wide segments of the population through the tv, among others. on the global scale, multi-national initiatives, such as the us geological survey (usgs) and geo-forschungs netz (geofon), operate global seismic networks for seismic monitoring but do not provide seismic early warning information. today, the usgs in cooperation with incorporated research institutions for seismology (iris) operates the global seismic networks (gsn), which comprises more than stations providing free, real-time, open access data. geofon collects information from several networks and makes this information available to the public online. usgs earthquake notification service (ens) provides publicly available e-mail notification for earthquakes worldwide within minutes for earthquakes in us and within min for events worldwide. usgs also provides near-real-time maps of ground motion and shaking intensity following significant earthquakes. this product, called shakemap, is being used for post-earthquake response and recovery, public and scientific information, as well as for preparedness exercises and disaster planning. effective early warning technologies for earthquakes are much more challenging to develop than for other natural hazards because warning times range from only a few seconds in the area close to a rupturing fault to a minute or so (heaton, ; allen and kanamori, ; kanamori, ) . several local and regional applications exist worldwide but no global system exists or could possibly exist for seismic early warning at global scale, due to timing constraints. earthquake early warning systems applications must be designed at the local or regional level. although various early warning systems exist worldwide at the local or regional scale, there are still high seismic risk areas that lack early warning applications, such as peru, chile, iran, pakistan, and india. the international consortium on landslides (icl), created at the kyoto symposium in january , is an international non-governmental and non-profit scientific organization, which is supported by the united nations educational, scientific and cultural organization (unesco), the wmo, fao, and the united nations international strategy for disaster reduction (un/isdr). icl's mission is to promote landslide research for the benefit of society and the environment and promote a global, multidisciplinary programme regarding landslides. icl provides information about current landslides on its website, streaming this information from various sources such as the geological survey of canada. this information does not provide any early warning since it is based on news reports after the events have occurred. enhancing icl's existing organizational infrastructure by improving landslide prediction capability would allow icl to provide early warning to authorities and populations. technologies for slopes monitoring has greatly improved, but currently only few slopes are being monitored at a global scale. the use of these technologies would be greatly beneficial for mitigating losses from landslides worldwide. . . . . tsunamis. the indian ocean tsunami of december killed people and left . million homeless. it highlighted gaps and deficiencies in existing tsunami warning systems. in response to this disaster, in june the intergovernmental oceanographic commission (ioc) secretariat was mandated by its member states to coordinate the implementation of a tsunami warning system for the indian ocean, the northeast atlantic and mediterranean, and the caribbean. efforts to develop these systems are ongoing. since march , the indonesian meteorological, climatological and geophysical agency has been operating the german-indonesian tsunami early warning system for the indian ocean. milestones, such as the development of the automatic data processing software and underwater communication for the transmission of pressure data from the ocean floor to a warning centre, have been reached. these systems will be part of the global ocean observing system (goos), which will be part of geoss. the pacific basin is monitored by the pacific tsunami warning system (ptws), which was established by member states and is operated by the pacific tsunami warning center (ptwc), located near honolulu, hawaii. ptwc monitors stations throughout the pacific basin to issue tsunami warnings to member states, serving as the regional centre for hawaii and as a national and international tsunami information centre. it is part of the ptws effort. noaa national weather service operates ptwc and the alaska tsunami warning center (atwc) in palmer, alaska, which serves as the regional tsunami warning center for alaska, british columbia, washington, oregon, and california. ptws monitors seismic stations operated by ptwc, usgs and atwc to detect potentially tsunamigenic earthquakes. such earthquakes meet specific criteria for generation of a tsunami in terms of location, depth, and magnitude. ptws issues tsunami warnings to potentially affected areas, by providing estimates of tsunami arrival times and areas potentially most affected. if a significant tsunami is detected, the tsunami warning is extended to the pacific basin. the international tsunami information center (itic), under the auspices of ioc, aims to mitigate tsunami risk by providing guidance and assistance to improve education and preparedness. itic also provides a complete list of tsunami events worldwide. official tsunami bulletins are released by ptwc, atwc, and the japan meteorological agency (jma). regional and national tsunami information centres exist worldwide; the complete list is available from ioc. currently, no global tsunami warning system is in place. in addition, fully operational tsunami early warning systems are needed for the indian ocean and the caribbean. initial steps have been taken in this direction. in , noaa established the caribbean tsunami warning program as the first step towards the development of a caribbean tsunami warning center. since , steps have been taken to develop an indian ocean tsunami system, such as establishing tsunami information centres and deploying real-time sea level stations and deep ocean buoys in countries bordering indian ocean. in , the united states agency for international development (usaid) launched the us indian ocean tsunami warning systems program as the us government's direct contribution to the international effort led by the ioc. since then, there are ongoing activities, such as germany's -year german-indonesia tsunami early warning system program with indonesia, the tsunami regional trust fund established in , and the united kingdom's tsunami funds reserved for early warning capacity building. nevertheless, on july , only one month after the announcement that the indian ocean's tsunami warning system was operational, a tsunami in java, indonesia, killed hundreds of people. on that day, tsunami warnings were issued to alert jakarta but there was not enough time to alert the coastal areas. the july tsunami disaster illustrates that there are still operational gaps to be solved in the indian ocean tsunami early warning system, notably in warning coastal communities on time. . . . . volcanic eruptions. volcanic eruptions are always anticipated by precursor activities. in fact, seismic monitoring, ground deformation monitoring, gas monitoring, visual observations, and surveying are used to monitor volcanic activity. volcano observatories are distributed worldwide. a complete list of volcano observatories is available at the world organization of volcanic observatories (wovo) website. however, there is still a divide between developed and developing countries. in particular, a large number of observatories and research centres monitor volcanoes in japan and the united states very well. most central and south american countries (mexico, guatemala, el salvador, nicaragua, costa rica, colombia, ecuador, peru, chile, trinidad, and the antilles) have volcano observatories that provide public access to volcanic activity information. in africa, only two countries (congo and cameroon) have volcano monitoring observatories and they do not provide public access to information. only a small number, probably fewer than , of the world's volcanoes are well monitored, mostly due to inadequate resources in poor countries (national hazards working group, ) . there is a need to fill this gap by increasing the coverage of volcanic observatories. currently, there is no global early warning system for volcanic eruptions except for aviation safety. global volcanic activity information is provided by the smithsonian institution, which partners with the usgs under the global volcanism program to provide online access to volcanic activity information, collected from volcano observatories worldwide. reports and warnings are available on a daily basis. weekly and monthly summary reports are also available, but these only report changes in volcanic activity level, ash advisories, and news reports. the information is also available through google earth. this information is essential for the aviation sector, which must be alerted to ash-producing eruptions. there are several ash advisory centres distributed worldwide, in london, toulouse, anchorage, washington, montreal, darwin, wellington, tokyo, and buenos aires. however, there is a need to coordinate interaction and data sharing among the approximately volcano observatories that make up wovo. esa is developing globvolcano, an information system to provide earth observations for volcanic risk monitoring. . . . . wildfires. early warning methodologies for wildfires are based on the prediction of precursors, such as fuel loads and lightning danger. these parameters are relevant for triggering prediction, but once the fire has begun, fire behaviour and pattern modelling are fundamental for estimating fire propagation patterns. most industrial countries have ew capabilities in place, while most developing countries have neither fire early warning nor monitoring systems in place (goldammer et al., ) . local and regional scale fire monitoring systems are available for canada, south america, mexico and south africa. an interactive mapping service based on google maps and eo imagery from inpe, the brazilian space research institute, has been available since september . individuals can contribute with information from the ground; in only months the service has received million reports on forest fires and illegal logging, making it one of the most successful web sites in brazil; it has had real impact through follow up legal initiatives and parliamentary enquiries. wildfire information is available worldwide through the global fire monitoring center (gfmc), a global portal for fire data products, information, and monitoring. this information is accessible to the public through the gfmc website but is not actively disseminated. the gfmc provides global fire products through a worldwide network of cooperating institutions. gfmc fire products include the following: fire danger maps and forecasts, which provide assessment of fire onset risk; near realtime fire events information; an archive of global fire information; and assistance and support in the case of a fire emergency. global fire weather forecasts are provided by the experimental climate prediction center (ecpc), which also provides national and regional scale forecasts. noaa provides experimental, potential fire products based on estimated intensity and duration of vegetation stress, which can be used as a proxy for assessment of potential fire danger. the webfire mapper, part of fao's global fire information management system (gfims), initially developed by the university of maryland and financially supported by nasa, provides near real-time information on active fires worldwide, detected by the modis rapid response system. the webfire mapper integrates satellite data with gis technologies for active fire information. this information is available to the public through the website and e-mail alerts. the european forest fire information system also provides information on current fire situations and forecasts for europe and the mediterranean area. although global scale fire monitoring systems exist, an internationally standardized approach is required to create a globally comprehensive early fire warning system. integration of existing fire monitoring systems could significantly improve fire monitoring and early warning capabilities. an information network must be developed to disseminate early warnings about wild-fire danger at both the global and local levels, to quickly detect and report fires, and to enhance rapid fire detection and classification capabilities at national and regional levels. the global early warning system for wild-fires, which is under development as part of the global earth observation system of systems (geoss) effort, will address these issues. . . . . floods. among natural hazards that are currently increasing in frequency, floods are the deadliest. this study shows there is inadequate coverage of flood warning and monitoring systems, especially in developing or least developed countries such as china, india, bangladesh, nepal, west africa, and brazil. at the local scale, there are several stand-alone warning systems, for example, in guatemala, honduras, el salvador, nicaragua, zimbabwe, south africa, belize, czech republic, and germany. however, they do not provide public access to information. the european flood alert system (efas), which is an initiative by ec-jrc, provides information on the possibility of river flooding occurring within the next three days. efas also provides an overview of current floods based on information received from the national hydrological services and the global runoff data center in germany. floods are monitored worldwide from the dartmouth flood observatory, which provides public access to major flood information, satellite images and estimated discharge. orbital remote sensing (advanced scanning microradiometer (amsr-e and quickscat)) is used to detect and map major floods worldwide. satellite microwave sensors can monitor, at a global scale and on a daily basis, increases of floodplain water surface without cloud interference. the dartmouth flood observatory provides estimated discharge and satellite images of major floods worldwide but does not provide forecasts of flood conditions or precipitation amounts that could allow flood warnings to be issued days in advance of events. noaa provides observed hydrologic conditions of major us river basins and predicted values of precipitation for rivers in the united states. noaa also provides information on excessive rainfall that could lead to flash-flooding and if necessary warnings are issued within h in advance. ifnet global flood alert system (gfas) uses global satellite precipitation estimates for flood forecasting and warning. the gfas website publishes useful public information for flood forecasting and warning, such as precipitation probability estimates, but the system is currently running on a trial basis. at a global scale, flood monitoring systems are more developed than flood early warning systems. for this reason, existing technologies for flood monitoring must be improved to increase prediction capabilities and flood warning lead times. . . . . severe weather, storms and tropical cyclones. at the global level, the world weather watch (www) and hydrology and water resources programmes coordinated by wmo provide global collection, analysis and distribution of weather observations, forecasts and warnings. the www is composed of the global observing system (gos), which provides the observed meteorological data; the global telecommunications system (gts), which reports observations, forecasts and other products and the global data processing system (gdps), which provides weather analyses, forecasts and other products. the www is an operational framework of coordinated national systems, operated by national governments. the tropical cyclone programme (tcp) is also part of the www. tcp is in charge of issuing tropical cyclones and hurricanes forecasts, warnings and advisories, and seeks to promote and coordinate efforts to mitigate risks associated with tropical cyclones. tcp has established tropical cyclone committees that extend across regional bodies (regional specialized meteorological centres (rsmc)), which, together with national meteorological and hydrological services (nmhss), monitor tropical cyclones globally and issue official warnings to the regional meteorological services of countries at risk. regional bodies worldwide have adopted standardized wmo-tcp operational plans and manuals, which promote internationally accepted procedures in terms of units, terminology, data and information exchange, operational procedures, and telecommunication of cyclone information. each member of a regional body is normally responsible for its land and coastal waters warnings. a complete list of wmo members and rsmcs is available on the wmo-tcp website. wmo then collects cyclone information and visualizes it on world maps. the university of hawaii collects information from wmo and provides online information on cyclone categories, wind speed, and current and predicted courses. although comprehensive coverage of early warning systems for storms and tropical cyclones is available, recent disasters such as hurricane katrina of have highlighted inadequacies in early warning system technologies for enabling effective and timely emergency response. there is a pressing need to improve communication between the sectors involved by strengthening the links between scientific research, organizations responsible for issuing warnings, and authorities in charge of responding to these warnings. while the www is an efficient framework of existing rsmc, nmhss and networks, national capacities in most developing countries need improvements in order to effectively issue and manage early warnings. action plans must also be improved. epidemics pose a significant threat worldwide, particularly in those areas that are already affected by other serious hazards, poverty, or under-development. epidemics spread easily across country borders. globalization increases the potential of a catastrophic disease outbreak: there is the risk that millions of people worldwide could potentially be affected. a global disease outbreak early warning system is urgently needed. who is already working in this field through the epidemic and pandemic alert and response, which provides real-time information on disease outbreaks, and goarn. the who member countries, disease experts, institutions, agencies, and laboratories, part of an outbreak verification list, are constantly informed of rumoured and confirmed outbreaks. the who constantly monitors anthrax, avian influenza, crimean-congo hemorrhagic fever (cchf), dengue haemorrhagic fever, ebola haemorrhagic fever, hepatitis, influenza, lassa fever, marburg haemorrhagic fever, meningococcal disease, plague, rift valley fever, severe acute respiratory syndrome (sars), tularaemia, and yellow fever. a global early warning system for animal diseases transmissible to humans was formally launched in july by the fao, the world organization for animal health (oie), and who. the global early warning and response system for major animal diseases, including zoonoses (glews) monitors outbreaks of major animal diseases worldwide. a malaria early warning system is not yet available and the need for system development is pressing, especially in sub-saharan africa where malaria causes more than one million deaths every year. the iri institute at columbia university provides malaria risk maps based on rainfall anomaly, which is one of the factors influencing malaria outbreak and distribution, but no warning is disseminated to the potentially affected population. in addition, the malaria atlas project (map) supported by the wellcome trust, the global fund to fight aids, tuberculosis and malaria, the university of oxford-li ka shing foundation global health programme and others, aims to disseminate free, accurate and up-to-date information on malaria. the map is a joint effort of researchers from around the globe working in different fields (from public health to mathematics, geography and epidemiology). map produces and makes available a range of maps and estimates to support effective planning of malaria control at national and international scales. air pollution affects developing and developed countries without exception. for this reason, air quality monitoring and early warning systems are in place in most countries worldwide. nevertheless, there is still a technological divide between developed and developing countries; in fact, these systems are most developed in the united states, canada, and europe. there are several successful cases to mention in asia (taiwan, china, hong kong, korea, japan, and thailand), a few in latin america (argentina, brazil, and mexico city) and only one in africa (cape town, south africa). most of the existing systems focus on real-time air quality monitoring by collecting and analysing pollutant concentration measurements from ground stations. satellite observation is extremely useful for aviation and tropospheric ozone monitoring, which is done by nasa and esa. air quality information is communicated mainly through web services. the us environmental protection agency (epa) provides an e-mail alert service (epa airnow) only available in the us and the ministry of environment of ontario, canada, also provides e-mail alerts. the epa airnow notification service provides air quality information in real-time to subscribers via e-mail, cell phone or pager, allowing them to take steps to protect their health in critical situations. while current air quality information is provided by each of the air quality monitoring systems listed in the appendix, few sources provide forecasts. the following agencies provide forecasts, which are fundamental for early warning: us epa, esa, prev'air, and the environmental agencies of belgium, germany, and canada (see the appendix). prediction capability is an essential component of the early warning process. existing air quality monitoring systems need to be improved in order to provide predictions to users days in advance so they can act when unhealthy air quality conditions occur. . . . . drought. drought early warning systems are the least developed systems due its complex processes and environmental and social impacts. the study of existing drought early warning systems shows that only a few such systems exist worldwide. on a regional scale, the fews net for eastern africa, afghanistan, and central america reports on current famine conditions, including droughts, by providing monthly bulletins that are accessible on the fews net web page. for the united states, the us drought monitor (svoboda et al., ) provides current drought conditions at the national and state level through an interactive map available on the website accompanied by a narrative on current drought impacts and a brief description of forecasts for the following week. the us drought monitor, a joint effort between the us department of agriculture (usda), noaa, the climate prediction center, the university of nebraska lincoln and others, has become the best available product for droughts (svoboda et al., ) . it has a unique approach that integrates multiple drought indicators with field information and expert input, and provides information through a single easy-to-read map of current drought conditions and short notes on drought forecast conditions. for china, the beijing climate center (bcc) of the china meteorological administration (cma) monitors drought development. based on precipitation and soil moisture monitoring from an agricultural meteorological station network and remote-sensing-based monitoring from cma's national satellite meteorological center, a drought report and a map on current drought conditions are produced daily and made available on their website. the european commission joint research center (ec-jrc) provides publicly available drought-relevant information through the following real-time online maps: daily soil moisture maps of europe; daily soil moisture anomaly maps of europe; and daily maps of the forecasted top soil moisture development in europe ( -day trend). at a global scale, two institutions (fao's global information and early warning system on food and agriculture (giews) and benfield hazard research center of the university college london) provide some information on major droughts occurring worldwide. the fao-giews provides information on countries facing food insecurity through monthly briefing reports on crop prospects and food situations, including drought information, together with an interactive map of countries in crisis, available through the fao website. benfield hazard research center uses various data to produce a monthly map of current drought conditions accompanied by a short description for each country. in addition, the wmo provides useful global meteorological information, such as precipitation levels, cloudiness, and weather forecasts, which are visualized on a clickable map on the wmo website. existing approaches for drought early warning must be improved. due to the complex nature of droughts, a comprehensive and integrated approach (such as the one adopted by the us drought monitor) that would consider numerous drought indicators is required for drought monitoring and early warning. in addition, for large parts of the world suffering from severe droughts, early warning systems are not yet in place, such as in western and southern africa, and in eastern africa where fews net is available but no drought forecast is provided. parts of europe (spain, parts of france, southern sweden, and northern poland) are characterized by high drought risk but have no system in place. india, parts of thailand, turkey, iran, iraq, eastern china, areas of ecuador, colombia, and the south-eastern and western parts of australia also require a drought warning system. . . . . desertification. the united nations convention to combat desertification (unccd), signed by governments in , aims to promote local action programs and international activities. national action programmes at the regional or sub-regional levels are key instruments for implementing the convention and are often supported by action programmes at sub-regional and regional levels. these programs lay out regional and local action plans and strategies to combat desertification. the unccd website provides a desertification map together with documentation, reports, and briefing notes on the implementation of action programs for each country worldwide. currently no desertification early warning system is fully implemented, despite their potential to mitigate desertification. . . . . food security. the fao's giews supports policy-makers by delivering periodic reports through the giews web page and an e-mail service. giews also promotes collaboration and data exchange with other organizations and governments. the frequency of briefs and reports -which are released monthly or bimonthly -may not be adequate for early warning purposes. the wfp is also involved in disseminating reports and news on famine crises through its web service. no active dissemination is provided by wfp. another service is fews net, a collaborative effort of the usgs, united states agency for international development (usaid), nasa, and noaa, which reports on food insecurity conditions and issues watches and warnings to decision-makers. these bulletins are also available on their website. food security prediction estimates and maps would be extremely useful for emergency response, resources allocation, and early warning. the food security and nutrition working group (fsnwg) serves as a platform to promote the disaster risk reduction agenda in the region and provides monthly updates on food security through maps and reports available on its website. fewsnet and fsnwg were instrumental in predicting the food crisis in - in the east african region in a timely manner. nevertheless these early warnings did not lead to early action to address the food crisis. if they had been used adequately, the impacts of the serious humanitarian crisis in the horn of africa could have been partially mitigated (ververs, ) . nearly all efforts to cope with climate change or variability focus on either mitigation to reduce emissions or on adaptation to adjust to changes in climate. although it is imperative to continue with these efforts, the on-going pace of climate change and the slow international response suggests that a third option is becoming increasingly important: to protect the population against the immediate threat and consequences of climate-related extreme events, including heat waves, forest fires, floods and droughts, by providing it with timely, reliable and actionable warnings. although great strides have been made in developing climate-related warning systems over the past few years, current systems only deal with some aspects of climate related risks or hazards, and have large gaps in geographic coverage. information exists for melting glaciers, lake water level, sea height and sea surface temperature anomalies, el nino and la nina. the national snow and ice data center (nsidc)-ice concentration and snow extent provides near real-time data on daily global ice concentration and snow coverage. the usda, in cooperation with the nasa and the university of maryland, routinely monitors lake and reservoir height variations for approximately lakes worldwide and provides online public access to lake water level data. information on sea height anomaly (sha) and significant wave height data are available from altimeter jason- , topex, ers- , envisat and gfo on a near-real time basis with an average -day delay. this information is provided by noaa. additionally, near real-time sea surface temperature (sst) products are available from noaa's goes and poes, as well as nasa's eos, aqua and terra. the international research institute (iri) for climate and society provides a monthly summary of the el nino and la nina southern oscillation, providing forecast summary, probabilistic forecasts, and a sea surface temperature index. however, these systems are still far from providing the coverage and scope that is needed and technically feasible. large parts of the world's most vulnerable regions are still not covered by a comprehensive early warning system. most systems only deal with one aspect of climate-related risks or hazards, e.g., heat waves or drought. finally, most systems do not cover the entire early warning landscape from collection of meteorological data to delivery and response of users. recently, the world meteorological organization proposed a global framework for climate services, which aims to strengthen the global cooperative system for collecting, processing and exchanging observations and for using climate-related information (wmo, ). early warning technologies appear to be mature in certain fields but not yet in others. considerable progress has been made, thanks to advances in scientific research and in communication and information technologies. nevertheless, a significant amount of work remains to fill existing technological, communication, and geographical coverage gaps. early warning technologies are now available for almost all types of hazards, although for some hazards (such as droughts and landslides) these technologies are still less developed. most countries appear to have early warning systems for disaster risk reduction. however, there is still a technological and national capacity divide between developed and developing countries. from an operational point of view, some elements of the early warning process are not yet mature. in particular, it is essential to strengthen the links between sectors involved in early warning, including organizations responsible for issuing warnings and the authorities in charge of responding to these warnings, as well as promoting good governance and appropriate action plans. it is generally recognized that it is fundamental to establish effective early warning systems to better identify the risk and occurrence of hazards and to better monitor the population's level of vulnerability. although several early warning systems are in place at the global scale in most countries for most hazard types, there is the need ''to work expeditiously towards the establishment of a worldwide early warning system for all natural hazards with regional nodes, building on existing national and regional capacity such as the newly established indian ocean tsunami warning and mitigation system'' ( un world summit outcome). by building upon ongoing efforts to promote early warning, a multi-hazard early warning system will have a critical role in preventing hazardous events from turning into disasters. a globally comprehensive early warning system can be built, based on the many existing systems and capacities. this will not be a single, centrally planned and commanded system, but a networked and coordinated assemblage of nationally owned and operated systems. it will make use of existing observation networks, warning centres, modelling and forecasting capacities, telecommunication networks, and preparedness and response capacities (united nations, ) . a global approach to early warning will also guarantee consistency of warning messages and mitigation approaches globally thus improving coordination at a multi-level and multi-sector scale among the different national actors such as the technical agencies, the academic community, disaster managers, civil society, and the international community. the next section provides an analysis of existing global early warning/monitoring systems that aggregate multi-hazard information. this section presents the results of a comparative analysis of multi-hazard global monitoring/ early warning systems. the aim of this analysis is to assess the effectiveness of existing global scale multi-hazard systems and define the set of needs suggested by comparing existing services. it assesses existing monitoring/early warning systems (singh and grasso, ) , chosen to be multi-hazard with global coverage, such as wfp's (the un food aid agency's) hews; alertnet, the humanitarian information alert service by reuters; reliefweb, the humanitarian information alert service by un-ocha; gdacs (global disaster alert and coordination system), a joint initiative of the united nations office for the coordination of humanitarian affairs (un-ocha) and the ec-jrc; and usgs ens. these systems have been analysed for the type of events covered, variety of output/ communication forms and range of users served. these systems cover a range of hazards and communicate results using a variety of methods. usgs ens only provides information on earthquakes and volcanic eruptions through the volcano hazards program (vhp) in collaboration with smithsonian institution. reliefweb focuses on natural hazards (earthquakes, tsunamis, severe weather, volcanic eruptions, storms, floods, droughts, cyclones, insect infestation, fires, and technological hazards) and health; alertnet additionally provides information on food insecurity and conflicts. gdacs provides timely information on natural hazards (earthquakes, tsunamis, volcanic eruptions, floods, and cyclones). hews informs users on earthquakes, severe weather, volcanic eruptions, floods, and locusts. existing systems, such as hews, post the information on a website, provide mobile phone and rss services, and gdacs sends emails, sms and faxes to users. the gdacs notification service mostly addresses humanitarian organizations, rescue teams or aid agencies. alertnet provides information to users through a web service, e-mail, sms and reports. reliefweb uses web services, e-mail and reports to disseminate information to users. reliefweb and alertnet also use new communications tools (facebook and twitter). ocha's virtual on-site operations coordination centre (virtual-osocc) enables real-time information exchange by all actors of the international disaster response community during the early phases following disasters. this service has been integrated within gdacs but is restricted to disaster managers. the only natural event notification provided by usgs e-mail service is earthquakes. hews offers no e-mail notifications for natural events. alertnet and reliefweb inform users on natural hazards and on health, food and security issues. usgs, reliefweb, alertnet and gdacs serve a wide a variety of users such as international organizations, humanitarian aid, policy/decision-makers, and civil society (fig. ) . the optimal global coverage multi-hazard system has to be as comprehensive as possible in terms of content, output and range of users. it will enhance existing systems by streaming data and information from existing sources and it will deliver this information in a variety of user-friendly formats to reach the widest range of users. by building on existing systems the multi-hazard system will inherit both the technological and geographical coverage gaps and limitations of existing early warning systems. the review analysis performed in the section ''inventory of early warning systems'' has shown that for some hazards (such as droughts and landslides) these technologies are still less developed and for tsunamis these systems are still under development for areas at risk. the analysis has shown that there is still a technological and national capacity divide between developed and developing countries. from an operational point of view, the links and communication networks between all sectors involved (organizations responsible for issuing warnings and the authorities in charge of responding to these warnings) need improvement. similarly, good governance and appropriate action plans need to be promoted. overcoming these gaps and enhancing, integrating, and coordinating existing systems is the first priority for the development of a global scale multi-hazard early warning system . early warning technologies have greatly benefited from recent advances in communication and information technologies and an improved knowledge on natural hazards and the underlying science. nevertheless many gaps still exist in early warning technologies and capacities, especially in the developing world, and a lot more has to be done to develop a global scale multi-hazard system. operational gaps need to be filled for slow-onset hazards both in monitoring, communication and response phases. effective and timely decision making is needed for slow onset hazards. below are some recommendations: ( ) fill existing gaps: the section identified the weaknesses and gaps in existing early warning systems. technological, geographical coverage, and capacity gaps exist, in addition to operational gaps for slow-onset hazards. in particular, actions need to be taken to improve prediction capabilities for landslides hazard aimed at developing a landslides early warning system. likewise, there is a pressing need to improve existing prediction capabilities for droughts. a global early fire warning system is not yet in place, the tsunami early warning systems for the indian ocean and the caribbean are not yet fully operational and a desertification early warning system has not been developed yet. there are ongoing efforts to develop these systems, such as the gfmc effort for the global fire ews, the indian ocean tsunami warning system operated by indonesia and a noaa led effort in the caribbean. a malaria early warning system is mandatory for africa, where one million deaths occur every year due to malaria. climate variability impacts need to be monitored within a global and coordinated effort, and the global framework for climate services needs to be further elaborated and operationalized. local earthquake early warning systems applications are needed in high seismic risk areas, where early warning systems are not yet in place. air quality and flood systems require improvements in prediction capabilities. dust storms and transboundary early warning systems do not yet exist. a coordinated volcanic early warning system that would integrate existing resources is also needed as well as an increase in coverage of volcanic observatories. particular attention should be paid to fill gaps in decision making processes for slow-onset hazards. their extent and impact are challenging to quantify. for this reason, actions and response are far more difficult tasks for slow-onset hazards than they are for other natural hazards. an institutional mechanism to regularly monitor and communicate slow-onset changes is needed to keep changes under review and to enable rational and timely decisions to be taken based on improved information. ( ) build capacity: the evaluation study of existing early warning systems (the section ) highlighted that a technological divide between developed and developing countries still exists. it is critical to develop basic early warning infrastructures and capacities in parts of the developing world most affected by disasters; it is also important to promote education programs on disaster mitigation and preparedness and integrate disaster mitigation plans into the broader development context. poor countries suffer greater economic losses from disasters than rich countries. development plays a key role and has a significant impact on disaster risk. almost percent of the people exposed to the deadliest hazards, earthquakes, floods, cyclones and droughts live in the developing world. the impact of disasters is mostly influenced by previous development choices. by integrating disaster mitigation strategies into planning and policies, the effects of disasters can be sensibly reduced and managed. ''disaster risk is not inevitable, but on the contrary can be managed and reduced through appropriate development actions'' (united nations development programme-undp, ) . it is through ''risk-sensitive development planning that countries can help reduce disaster risks''. key targets for capacity building include the following: . developing national research, monitoring and assessment capacity, including training in assessment and early warning. . supporting national and regional institutions in data collection, analysis and monitoring of natural and man-made hazards. . providing access to scientific and technological information, including information on stateof-the-art technologies. . education and awareness-raising, including networking among universities with programmes of excellence in the field of the emergency management. . organizing of training courses for local decision-makers and communities. . bridging the gap between emergency relief and long-term development. ( ) bridge the gaps between science and decision making, and strengthen coordination and communication links: scientific and technological advances in modelling, monitoring and predicting capabilities could bring immense benefits to early warning if science were effectively translated into disaster management actions. bridging the gap between scientific research and decision making will make it possible to fully exploit capacities of early warning technologies for societal benefit. the major challenge is to ensure that early warnings result in prompt responses by governments and potentially the international community. this requires that information be effectively disseminated in an accessible form down to the end user. this is achievable by adopting standard formats and easy-to-use tools for information dissemination, such as interactive maps, emails, sms, etc. the adoption of standard formats (such as the common alerting protocol cap) for disseminating and exchanging information has to be promoted. the advantage of standard format alerts is their compatibility with all information systems, warning systems, media, and most importantly, with new technologies such as web services. the adoption of standard formats guarantees consistency of warning messages and is compatible with all types of information systems and public alerting systems, including broadcast radio and television as well as public and private data networks, with multi-lingual warning systems and emerging technologies. this would easily replace specific application oriented messages and will allow the merging of warning messages from several early warning systems into a single multihazard message format. finally, it is critical to strengthen coordination and communication links by defining responsibility mechanisms and appropriate action plans. more often, time-sequenced warning messages are released in early warning processes, implying a decrease in warning times available for action and in reliability of the information. this trade-off needs to be addressed. the content and views expressed in this publication are those of the authors and do not necessarily reflect the views or policies, or carry the endorsement of the contributory organizations or the united nations environment programme (unep). the designations employed and the presentation of material in this publication do not imply the expression of any opinion whatsoever on the part of unep concerning the legal status of any country, territory or city or its authorities, or concerning the delimitation of its frontiers and boundaries. reference to a commercial company or product in this publication does not imply the endorsement of unep. & maps, photos, and illustrations as specified. this publication may be reproduced in whole or in part and in any form for educational or non-profit purposes without special permission from the copyright holder, provided acknowledgement of the source is made. unep would appreciate receiving a copy of any publication that uses this publication as a source. no use of this publication may be made for resale or any other commercial purpose whatsoever without prior permission in writing from unep. applications for such permission, with a statement of purpose and intent of the reproduction, should be addressed to the director, division of communications and public information (dcpi), unep, p.o. box , nairobi , kenya. the use of information from this publication concerning proprietary products for publicity or advertising is not permitted. citation: unep ( adaptation: ( ) actions taken to help communities and ecosystems cope with changing climate conditions (unfccc). ( ) genetically determined characteristic that enhances the ability of an organism to cope with its environment (cbd). aerosols: a collection of airborne solid or liquid particles, with a typical size between . and mm, that resides in the atmosphere for at least several hours. aerosols may be of either natural or anthropogenic origin. air quality: smog is the product of human and natural activities such as industry, transportation, wild-fires, volcanic eruptions, etc. and can have serious effects on human health and the environment. us epa uses and air quality index (aqi) which is calculated on five major air pollutants regulated by the clean air act: ground-level ozone, particle pollution (also known as particulate matter), carbon monoxide, sulfur dioxide, and nitrogen dioxide. for each of these pollutants, epa has established national air quality standards to protect public health. groundlevel ozone and airborne particles are the two pollutants that pose the greatest threat to human health in this country. biodiversity: the variety of life on earth, including diversity at the genetic level, among species and among ecosystems and habitats. it includes diversity in abundance, distribution and in behaviour. biodiversity also incorporates human cultural diversity, which can both be affected by the same drivers as biodiversity, and itself has impacts on the diversity of genes, other species and ecosystems. biofuels: fuel produced from dry organic matter or combustible oils from plants, such as alcohol from fermented sugar, black liquor from the paper manufacturing process, wood and soybean oil. biomass: organic material, both above ground and below ground, and both living and dead, such as trees, crops, grasses, tree litter and roots. capacity: the combination of all the strengths, attributes and resources available within a community, society or organization that can be used to achieve agreed goals. comment: capacity may include infrastructure and physical means, institutions, societal coping abilities, as well as human knowledge, skills and collective attributes such as social relationships, leadership and management. capacity also may be described as capability. capacity assessment is a term for the process by which the capacity of a group is reviewed against desired goals, and the capacity gaps are identified for further action. capacity building: process of developing the technical skills, institutional capability, and personnel. climate change: change of climate, which is attributed directly or indirectly to human activity that alters the composition of the global atmosphere and which is in addition to natural climate variability observed over comparable time periods. climate variability: variations in the mean state and other statistics (such as standard deviations and the occurrence of extremes) of the climate on all temporal and spatial scales beyond that of individual weather events. variability may be due to natural internal processes in the climate system (internal variability), or to variations in natural or anthropogenic external forcing (external variability). common alerting protocol: the common alerting protocol (cap) provides an open, nonproprietary digital message format for all types of alerts and notifications. it does not address any particular application or telecommunications method. the cap format is compatible with emerging techniques, such as web services, as well as existing formats including the specific area message encoding (same) used for the united states' national oceanic and atmospheric administration (noaa) weather radio and the emergency alert system (eas). cost-benefit analysis: a technique designed to determine the feasibility of a project or plan by quantifying its costs and benefits. cyclone: an atmospheric closed circulation rotating counter clockwise in the northern hemisphere and clockwise in the southern hemisphere. deforestation: the direct human-induced conversion of forested land to non-forested land. desertification: degradation of land in arid, semi-arid and dry sub-humid areas, resulting from various factors, including climatic variations and human activities. disaster: a serious disruption of the functioning of a community or a society involving widespread human, material, economic or environmental losses and impacts, which exceeds the ability of the affected community or society to cope using its own resources. comment: disasters are often described as a result of the combination of: the exposure to a hazard; the conditions of vulnerability that are present; and insufficient capacity or measures to reduce or cope with the potential negative consequences. disaster impacts may include loss of life, injury, disease and other negative effects on human physical, mental and social well-being, together with damage to property, destruction of assets, loss of services, social and economic disruption and environmental degradation. disaster risk: the potential disaster losses, in lives, health status, livelihoods, assets and services, which could occur to a particular community or a society over some specified future time period. comment: the definition of disaster risk reflects the concept of disasters as the outcome of continuously present conditions of risk. disaster risk comprises different types of potential losses which are often difficult to quantify. nevertheless, with knowledge of the prevailing hazards and the patterns of population and socio-economic development, disaster risks can be assessed and mapped, in broad terms at least. disaster risk reduction: the concept and practice of reducing disaster risks through systematic efforts to analyse and manage the causal factors of disasters, including through reduced exposure to hazards, lessened vulnerability of people and property, wise management of land and the environment, and improved preparedness for adverse events. comment: a comprehensive approach to reduce disaster risks is set out in the united nations-endorsed hyogo framework for action, adopted in , whose expected outcome is ''the substantial reduction of disaster losses, in lives and the social, economic and environmental assets of communities and countries.'' the international strategy for disaster reduction (isdr) system provides a vehicle for cooperation among governments, organisations and civil society actors to assist in the implementation of the framework. note that while the term ''disaster reduction'' is sometimes used, the term ''disaster risk reduction'' provides a better recognition of the ongoing nature of disaster risks and the ongoing potential to reduce these risks. droughts: a period of abnormally dry weather sufficiently prolonged for the lack of water to cause serious hydrologic imbalance in the affected area. early warning system: the set of capacities needed to generate and disseminate timely and meaningful warning information to enable individuals, communities and organizations threatened by a hazard to prepare and to act appropriately and in sufficient time to reduce the possibility of harm or loss. comment: this definition encompasses the range of factors necessary to achieve effective responses to warnings. a people-centred early warning system necessarily comprises four key elements: knowledge of the risks; monitoring, analysis and forecasting of the hazards; communication or dissemination of alerts and warnings; and local capabilities to respond to the warnings received. the expression ''end-to-end warning system'' is also used to emphasize that warning systems need to span all steps from hazard detection through to community response. earth observation: earth observation, through measuring and monitoring, provides an insight and understanding into earth's complex processes and changes. eo include measurements that can be made directly or by sensors in-situ or remotely (i.e. satellite remote sensing, aerial surveys, land or ocean-based monitoring systems, fig. ), to provide key information to models or other tools to support decision making processes. earthquakes: earthquakes are due to a sudden release of stresses accumulated around the faults in the earth's crust. this energy is released through seismic waves that travel from the origin zone, which cause the ground to shake. severe earthquakes can affect buildings and populations. the level of damage depends on many factors such as intensity of the earthquake, depth, vulnerability of the structures, and distance from the earthquake origin. ecosystem: dynamic complex of plant, animal, microorganism communities and their non-living environment, interacting as a functional unit. ecosystems are irrespective of political boundaries. el niñ o-southern oscillation: a complex interaction of the tropical pacific ocean and the global atmosphere that results in irregularly occurring episodes of changed ocean and weather patterns in many parts of the world, often with significant impacts over many months, such as altered marine habitats, rainfall changes, floods, droughts, and changes in storm patterns. comment: the el nino part of the el nino-southern oscillation (enso) phenomenon refers to the well-above average ocean temperatures that occur along the coasts of ecuador, peru and northern chile and across the eastern equatorial pacific ocean, while la nina part refers to the opposite circumstances when well-below-average ocean temperatures occur. the southern oscillation refers to the accompanying changes in the global air pressure patterns that are associated with the changed weather patterns experienced in different parts of the world. emergency management: the organization and management of resources and responsibilities for addressing all aspects of emergencies, in particular preparedness, response and initial recovery steps. comment: a crisis or emergency is a threatening condition that requires urgent action. effective emergency action can avoid the escalation of an event into a disaster. emergency management involves plans and institutional arrangements to engage and guide the efforts of government, non-government, voluntary and private agencies in comprehensive and coordinated ways to respond to the entire spectrum of emergency needs. the expression ''disaster management'' is sometimes used instead of emergency management. extensible markup language: a markup language that defines a set of rules for encoding documents in a format that is both human-readable and machine-readable. e-waste: a generic term encompassing various forms of electrical and electronic equipment that has ceased to be of value and is disposed of. a practical definition of e-waste is ''any electrically powered appliance that fails to satisfy the current owner for its originally intended purpose.'' false alarm: in the context of early warning systems, a false alarm is defined as the situation in which an alarm is activated when it should not have been. fine particle: particulate matter suspended in the atmosphere less than . mm in size (pm . ). floods: an overflow of water onto normally dry land. theinundation of a normally dry area caused by rising water in an existing waterway, such as a river, stream, or drainage ditch. ponding of water at or near the point where the rain fell. flooding is a longer term event than flash flooding: it may last days or weeks. floods are often triggered by severe storms, tropical cyclones, and tornadoes. food security: when all people at all times have access to sufficient, safe, nutritious food to maintain a healthy and active life. forecast: definite statement or statistical estimate of the likely occurrence of a future event or conditions for a specific area. comment: in meteorology a forecast refers to a future condition, whereas a warning refers to a potentially dangerous future condition. forest: land spanning more than . ha with trees higher than m and a canopy cover of more than percent, or trees able to reach these thresholds in situ. it does not include land that is predominantly under agricultural or urban land use. gaussian distribution: the gaussian (normal) distribution was historically called the law of errors. it was used by gauss to model errors in astronomical observations, which is why it is usually referred to as the gaussian distribution. geological hazard: geological process or phenomenon that may cause loss of life, injury or other health impacts, property damage, loss of livelihoods and services, social and economic disruption, or environmental damage. comment: geological hazards include internal earth processes, such as earthquakes, volcanic activity and emissions, and related geophysical processes such as mass movements, landslides, rockslides, surface collapses, and debris or mud flows. hydrometeorological factors are important contributors to some of these processes. tsunamis are difficult to categorize; although they are triggered by undersea earthquakes and other geological events, they are essentially an oceanic process that is manifested as a coastal water-related hazard. within this report, tsunamis are included in the geological hazards group. geographic information system: a computerized system organizing data sets through a geographical referencing of all data included in its collections. the potential for earthquake early warning in southern california oregon department of environmental quality. water quality credit trading in oregon: a case study report disaster management support group (dmsg) ceos disaster management support group report. the use of earth observing satellites for hazard support: assessments & scenarios. final report of the ceos disaster management support group natural disaster hotspots: a global risk analysis mexico city seismic alert system environmental change monitoring by geoinformation technology for baghdad and its neighboring areas geoss -year implementation plan reference document early warning systems early warning of wildland fires usable science: early warning systems: do's and don'ts automated decision procedure for earthquake early warning automated decision procedure for earthquake early warning a model for a seismic computerized alert network an automatic processing system for broadcasting earthquake alarms global observations of the land, a proposed theme to the igos-partnership-version probability theory: the logic of science jma earthquake early warning real-time seismology and earthquake damage mitigation global forest fire watch: wildfire potential, detection, monitoring and assessment oil spill detection and monitoring from satellite image on a rational strong motion index compared with other various indices the role of a new method of quickly estimating epicentral distance and magnitude from a single seismic record prediction, science, decision making and the future of nature university of valencia,eos.d c. chinese academy of forestry effective early warning -use of hazard maps as a tool for effective risk communication among policy makers and communities -session organized by the government of japan global environmental alert service digital change detection techniques using remotely sensed data the drought monitor ict in pre-disaster awareness and preparedness. presented at the apt-itu joint meeting for ict role in disaster management early warning systems for natural disasters reduction undp-united nations development programme bureau for crisis prevention and recovery united nations convention to combat desertification the east african food crisis: did regional early warning systems function climate knowledge for action: a global framework for climate services-empowering the most vulnerable quick and reliable determination of magnitude for seismic early warning a virtual sub-network approach to earthquake early warning key: cord- -hwg rqnq authors: oldstone, michael b.a.; rose oldstone, madeleine title: ebola’s scorecard: failure of the who and the international community date: - - journal: ebola's curse doi: . /b - - - - . - sha: doc_id: cord_uid: hwg rqnq ebola’s curse: – outbreak in west africa, a timely, needed and well-presented book by michael oldstone and madeleine rose oldstone, unlocks the mysteries of the largest outbreak of one of the world’s most fearsome viruses. what is ebola? why did this happen? here you will find the answers to these questions, while meeting fascinating people thrust into a situation as dramatic as any that could be imagined in a blockbuster novel or movie. by reading this book you will come to understand why the world was unprepared for the outbreak of such a deadly pathogen as ebola virus and why it still is. you will gain intimate knowledge of a pathogen that spread like a tsunami over a region of the world that lacked the resources to fight it. you will meet a group of people that by chance were already there to fight another deadly virus. you will find out how in a matter of weeks this small group of doctors, nurses, and scientists were overwhelmed and why this matters. you will meet people that fought with limited resources at hand and became heroes that put the possibility of saving their patients ahead of their own lives. in the end you will gain insights into steps that must be taken to ensure that such a horrific virus outbreak never happens again anywhere in the world. the who has its share of blame and rightly so. its chartered role is to protect the health of our world's human populations, and its task is to live up to that purpose. it's major malfunction in the ebola epidemic was its failure to understand the public health disaster as it was unfolding and thus not acting early enough to limit the spread of ebola virus infection. during the initial months of ebola's debut, the who was slow in acknowledging that a unique infectious disease was advancing and killing people. throughout this indolent period, ebola continued to spread from guinea across neighboring countries, primarily sierra leone and liberia. with optimal public health control, the numbers of infections and deaths might have been -fold fewer or less, i.e., , to and , to . compared to the who's successes in handling prior epidemics of h n and h n influenza and severe acute respiratory syndrome (sars), the ebola epidemic was largely ignored and handled poorly. the major cause of this failure by the who was likely its administration at that time. neither their personnel nor that of the international disease control community was sufficiently decisive in understanding, acting, or supervising the outbreak. "we can mount a highly effective response to small and medium-size outbreaks, but when faced with an emergency of this scale, our current systems À national and international À simply have not coped," stated who director-general margaret chan, deputy director-general anarfi asamoa-baah, and the organization's regional directors in a joint statement on april , . but, of course, the earlier an infection is contained, the less likely it will spread from a small to a large problem. the who admitted it was ill prepared. "we have taken serious note of the criticisms that the initial who response was slow and insufficient, we were not aggressive in alerting the world . . . we did not work effectively in coordination with other partners, there were shortcomings in risk communications and there was confusion of roles and responsibilities". in contrast, the who led by a different administration in À acted forcefully and correctly when faced with the outbreak and possible pandemic effect of sars. the who was also defective in monitoring the ebola outbreak. a critique by a group of experts from the harvard global health institute and the london school of hygiene and tropical medicine found that "the lack of capacity in guinea to detect the virus for several months was a key failure, allowing ebola eventually to spread to bordering liberia and sierra leone, underscoring inadequate communication and arrangements between governments and the who to share, validate, and respond robustly to information on outbreak." indeed, after ebola was initially identified, it still spread through the capital cities of guinea and liberia, and within months appeared in other major cities and their international airports. without protocols in place for identification of ebola, the virus rapidly spread. the rt international report of november , stated, "without any approved drugs, vaccines or rapid diagnostic tests, health workers struggled to diagnose patients and provide effective care. without sufficient protective gear, and initially without widespread understanding of the virus, hundreds of health workers themselves became ill and died." in summary, early in the course of the ebola infection, before its massive outbreak, doctors without borders warned the who about the potential threat. this evaluation, despite its highly qualified source, was originally disputed by the who. as a result, actions to fight the infection and arrange for humanitarian aid were delayed. not until august , a good months after the initial ebola cases emerged in guinea, did the who begin to take action. the harvard global health institute's report called for greater accountability and transparency within all global health institutions and remarked that the who should respond to freedom of information requests. in the west african countries, consistently poor health care and lack of adequate infrastructure were major factors in the increasing difficulty of addressing public health concerns and medical emergencies. by comparison, in boston, at peter bent brigham hospital-part of harvard's medical complex, more physicians worked on the second floor alone than in all of liberia. most of the healthcare staff in countries overrun with ebola virus infections were not sufficiently trained to respond. they often lacked even the basic materials required for treatment and had insufficient knowledge or equipment to protect themselves from contamination. the exceptions in some areas included kenema government hospital (kgh) in sierra leone and centers where doctors without borders were located. for example, dr. mariano lugli, a deputy director of operations for doctors without borders, did respond to an early incidence of ebola virus infection. working in remote forests of guinea during march, , when the outbreak spread to guinea's capital, conakry, lugli set up a healthcare receiving and treatment clinic. although lugli was met by a foreign medic and logistician sent by the un health agency, he never saw or met a who official who was responsible for handling this escalation of the outbreak. lugli elaborates, "in all the meetings i attended, even in conakry, i never saw a representative of the who. the coordination role the who should be playing, we just didn't see it. i didn't see it the first three weeks and we didn't see it afterwards." because so many patients and their healthcare providers had already died and those not yet infected feared the same fate, many hospitals were shut down and abandoned. hundreds of patients remained waiting in front of nonfunctional hospitals in the hope of being admitted and treated. the who received extensive criticism for taking too long to provide and organize the flow of physicians, healthcare workers, protective clothing, and even fluids. without leadership by the who in pursuing outside governments and philanthropies to establish isolation centers, surveillance, and laboratory capacity in west africa, the local governments turned school classrooms into holding centers for those suspected of carrying the viral disease. even so, neither bedding nor basic medical equipment were available. for the most part this effort turned out to be useless. in similar straits, dr. melvin korkor, in charge of phebe hospital in liberia, spoke of repeated delays in receiving much needed materials, none of which was available in the region. many patients did not receive basic medications. supplies of test tubes, gowns, and fluids were depleted. medical staff lacked basic safety equipment and sterile latex gloves, without which their hands were unprotected while treating patients exposing these frontline health providers to the virus. the end result was a high mortality rate among the care givers. dr. korkor considered himself "reborn" after surviving ebola infection. the lack of doctors and trained medical workers in west africa played a role in the spread of ebola. liberia has only one doctor for every , people, whereas sierra leone has two. in comparison, the united states has doctors per , individuals. as hundreds of local doctors died in african communities, the ebola outbreak escalated. yet the who knew about the lack of health infrastructure in these countries, and one of their priorities should have been to plan support and enhancement of the healthcare network. their responses should have been more vigorous. failing to notify the global community about the rapid spread and danger of the ebola outbreak was a major error. ashish jhna, director of the harvard global health institute, stated "people at who were aware that there was an outbreak that was getting out of control by spring, and yet it took until august to declare a public health emergency." the harvard institute also accused the who of enabling "immense human suffering, fear, and chaos" as a result of their delayed response to the epidemic. a vivid example of poor management was the handling of early blood samples taken from infected patients to determine if they had ebola. some samples were shipped to laboratories where they were not examined immediately. others sent to paris, france, could not be tested at the recipient institution due to technical difficulties and had to be re-routed to lyon, miles away. thus, analysis of whether an individual was infected and should be quarantined was delayed, another administrative failure. what was the reason for the problems encountered by who and for its delayed actions? according to the who, one major obstacle was their concerns about political opposition from west african leaders. many were cautious about taking aid because they mistrusted the source, a reflection of past exploitation by the west. the who, instead of working vigorously to resolve this difficulty, providing education, and reinforcing communication, became politically correct. when they should have announced that a major infectious outbreak from a deadly virus would hurt these countries' economies, the who did nothing to improve those relationships. sensitive cultural differences made the who leery of disrupting any country's governance without a consensus. unfortunately, regional culture most often trumps science and reason. the who bowed primarily to political pressure rather than health concerns. critics have said, and we concur, that the who should have understood that traditional and natural practices in the region stood in the way of effective mechanisms to contain the virus, and the who had a moral obligation to act as educators, to organize teachers, and to share scientific knowledge of what the outcome would be not only to political leaders of government but most importantly to local tribal leaders. inadequate funds and, when available at all, poorly used were part of the problem. the leader of doctors without borders, ebola response team, christopher stokes, said it was "ridiculous" that volunteers working for his charitable group were bearing the brunt of care in the most severely affected countries and that international efforts will not have any effect for more than a month. as a defense for not arranging to provide sufficient funding to control ebola' destruction, director-general margaret chan of the who explained that the who is not an implementation agency for outbreak response: "first and foremost, people need to understand who. who is the un specialized agency in health. and we are not the first responder. you know, the government has first priority to take care of their people and provide health care. who is a technical agency. so this is how we provide services. we are not like international national government organizations (ngos), for example doctors without borders, red cross, red crescent or local ngos who are working on the ground to provide, you know, direct services". however, the who has the pulpit on the world stage to organize international efforts. in this it was negligent. who should have been crisp in effective decisions to fight ebola. it was not. it was wishy-washy, as its consensus-building approach and political correctness show. instead, a bureaucracy that wishes to be admired and retained did not stir the pot by being decisive. we believe that the who should act aggressively once the science is known during potential major health disasters. they should be on the frontline to mobilize world support for control of such infectious diseases. previously, they followed that kind of aggressive policy to combat the first st century pandemic, sars, but that was at a different time and under different leadership. a safe political bureaucracy should not be the game plan for setting up and funding the who. additional problems had hindered any effective response to ebola. bureaucracies of many countries blocked or delayed responses to the outbreaks by denying visas to scientists, doctors, and healthcare workers who tried to cross their borders to help the victims. the world bank, an international agency that provides loans to developing countries, also made errors during the ebola outbreak. predominant was its delayed response and poor cooperation with the who. the world bank had opportunities early during the outbreak to meet the requests of scientists and government officials for finances to cover basic, necessary operations but chose to respond later. oxfam, an international confederation of ngos working with partners in over countries, criticized the world bank for its failure to invest enough in the region's healthcare infrastructure. jim kim, president of the world bank, admitted his institution's failures, "we should have done so many things. healthcare systems should have been built. there should have been monitoring when the first cases were reported. there should have been an organized response." many critics have pointed out that the delay in response to spreading ebola virus infection was caused, in large part, by the lack of cooperation and disagreement between the who and world bank on a plan of action. kim admitted that failure and stated, "the most important thing is to stop arguing about what is or is not possible and to get on with doing what is needed." the african development bank played a large part in contributing funds to the beleaguered communities. this contribution was supported by other ngos, international organizations, and countries. in , the african development bank provided a total of million us dollars to guinea, liberia, and sierra leone. that bank additionally collaborated with the who to supply additional resources including medicines, equipment, and emergency training. in addition to the promised and paid contributions, the african development bank also established two new post-crisis operations to lessen and prevent the instability and chaos caused by the ebola outbreak. these operations included the establishment of an african centre for disease control, and a post-ebola livelihoods restoration project. an important goal of the un is to provide humanitarian aid in times of famine and natural disasters. however, this time, the un did not live up to its responsibilities. according to doctors without borders, the un had minimal impact on the epidemic regardless of their international pledges and deployments of staff. however, david nabarro, a medical doctor who organized and led the un mission to alleviate ebola, disagreed "i am absolutely certain that when we look at the history, this effort that has been put in place will have been shown to have had an impact, though i will accept that we probably won't see a reduction in the outbreak curve until the end of the year." all told, doctors without borders was the frontline team in the fight against ebola despite their frustration with the lack of support in terms of action and supplies they needed during the epidemic. that organization ran the majority of ebola treatment facilities across the region, providing over of the beds available. the un was not the source of frontline defenders fighting the epidemic. the international community of nations was also deficient in the humanitarian effort it should have supplied to west africa. many countries failed to commit needed medical or financial resources toward alleviating the outbreak. large and wealthy countries such as china, russia, and saudi arabia barely contributed anything. in contrast, a smaller country such as cuba and a rich country such as sweden participated in larger, prominent, and more effective ways. the majority of donations provided came from the united states, united kingdom, and germany. the united states funded over a third of the un relief fund. several banks and philanthropists were also active contributors. the united states and united kingdom provided the most support. shamefully, responses from the rest of europe and the european union were limited and quite unsatisfactory. for example, france pledged $ . million; $ . million in direct bilateral aid and $ . million to multilateral institutions, a meager contribution from its $ . trillion economy. northern european countries donated a significant amount more than germany, which has one of the largest economies in europe. germany agreed to donate $ . million, contributed to international aircraft and to building a field house with beds in guinea. the netherlands contributed the most among its regional neighbors. canada generously pledged over $ million and sent supplies. although possessing a small economy, cuba played a significant role in providing medical staff. cuba sent substantial human resources in that more than doctors and medical staff went to ease the crisis in west africa. other south american countries also donated: brazil pledged $ , to the who along with donating five supply kits, each of which can protect workers from ebola. chile and columbia have also donated funds. to better understand contributions and commitments of countries, it is critical to examine how much countries donated relative to their economy. that is donations by gdp. although the united states and united kingdom have pledged the most funds among all countries, some smaller countries surprisingly pledged more money relative to their gdp. along with the united kingdom and united states, canada as well as australia and japan stand out as having contributed the most relative to their economy. other countries such as china, russia, italy, france, and germany were poor donors, and why they were not more involved is unclear. the world food program (wfp), in particular, lashed out at beijing's wealthy. "where are the chinese billionaires and their potential impact? because this is the time that they could really have such a huge impact," said brett rierson, wfp representative in china. private donors as well as the government of china afforded only meager responses, considering that china is a major investor in africa. although it was in that nation's political interest to expand their influence and potential contacts among the african countries, the government and private sector in china contributed a total of only $ . million to the un main ebola relief fund (compared to more than $ million from the united states). of that $ . million, only $ . million came from the chinese government. however, china did expand its medical staff in sierra leone to laboratory members and promised to contribute another $ million, but as of this writing has yet to fulfill that obligation. beijing announced that it would donate up to $ million to the who. in addition to governments, some ngos, multinational corporations, and other international organizations played a smaller than expected role during the ebola crisis. however, other ngos, specifically philanthropists and wealthy individual charities, made considerable funding available. over ngos, foundations, and charities have provided much needed funding for equipment and supplies. among the major contributors were the bill and melinda gates foundation, oxfam, save the children, paul g allen family foundation, silicon valley community foundation, and the ikea foundation. multinational corporations, also known as corporate enterprises, were slow to respond. during past natural disasters, multinational corporations responded far more quickly and generously. many companies that rely on natural resources in west africa offered little to no help. for example, the cocoa industry relies heavily on west africa products. seventy percent of the world's supply comes from this region. large multinational corporations like nestle, mars chocolate, and hershey's have donated a meager $ , to their cocoa foundation to support the effort against ebola. in past natural disasters and global emergencies, the international community also responded far more magnanimously than recorded for the À ebola epidemic. similarly, international organizations such as the who, world bank, and un appeared to do too little. at the end of the day, it seems that everyone insisted something should be done, but few took action. according to the internal who report, "nearly everyone involved in the outbreak response failed to see some fairly plain writing on the wall. a perfect storm was brewing, ready to burst open in full force." if all this went wrong, then how can the world community plan so this disaster does not happen again? put another way, "those who fail to learn from history, are doomed to repeat it." further, as populations in west africa increase and more humans breach the forest area, in all likelihood a new ebola epidemic will occur. so a storm is brewing; if so, what recommendations are needed for preparations, devising a system for global warning, and implementing a response system? the stated purpose of the foregoing review is to contemplate the management of global health crises, and our suggestions follow. first, better cooperation and communication among international agencies, governments, and ngos are required. to accomplish this task, the development, commitment, and use of a single global institution with the responsibility for natural and environmental epidemics may be essential. would it be more effective to create a new institution, rather than giving the authority to an existing global institution such as the cdc, who, or un? certainly these and other currently operational institutions can and have played important roles in the past. the best argument for a new institution is to generate one with a single focus. the current global institutions have multiple responsibilities and priorities. creating a solely "nonpolitical" and lean institution whose primary goal is for the prevention and recovery of global and natural health disasters would eliminate the lengthy and bloated bureaucratic process so that action would be taken quickly and efficiently. one new institution currently being put in place to meet these responsibilities and could be up to the task is the global virus network (gvn). gvn represent centers of excellence in medical virology. it's work is to understand, prevent, and eradicate viral disease threats to mankind. gvn or a similar type of focused institution might also have full authority over the distribution of raised assets and a reserve fund. the last category brings us to the second recommendation, setting up an emergency fund. acquiring a fund that already has pledged donations and resources would allow immediate action. a rapid action plan would impact future outbreaks of disease by quickly downmodulating their spread. this fund would be used for emergency preparation, recruitment, shipping, doctors and healthcare workers, as well as training populations in third-world areas where outbreaks are likely to occur. also, necessary medicines and medical equipment should be stocked, stored safely, and available. funds for research and facilities should be pre-arranged. one would have to gather international support and trust in creating a new global institution for this goal. the need is to convince the world's sources of wealth to fund an enterprise that manages epidemic-specific activities and to allocate part of their gdp to this effort. the world is getting smaller. diseases like ebola, zika, yellow fever, and lassa are more easily transported by air flight than ever before. thus, the threats of these epidemics are today's reality not only in countries where outbreaks occur, but in all countries engaged in global trade. the third recommendation is the need to expand global investment toward international health and natural disasters. sadly, only a few countries have met their commitments under the international health regulations created by the un after the sars outbreak. realistically, the interests of many countries and institutions are best served by allocating assets toward elimination/control of epidemics despite the fact that they usually occur far from western countries. the global community must recognize that these "exotic" african diseases readily arrive to distant shores of non-african countries carried by travelers incubating the infectious agent. this is not theoretical but actually occurred in the united states, united kingdom, and elsewhere with the transport of ebola, lassa, and currently zika viruses. further, there is the possibility of spread of viruses like ebola and lassa by bioterrorism. in the past ( À ) an influenza epidemic infected over % of the world's population and killed approximately % (over million people). the world bank projected that the cost of inaction of a worldwide influenza epidemic would reduce global wealth by over $ trillion. a fourth issue is represented by the failure of ebola containment. this was, in large part, due to the lack of a universal and robust disease surveillance system. ideally, such surveillance systems would be part of a global public health network. the ability to perform in-depth, rapid sequencing to identify the virus in question in hours or at least a day is now available. this sequencing of individual blood samples during ongoing epidemics is now possible even in remote areas, where the majority of outbreaks occur. surveillance helps increase effective communication among global institutions, countries, and citizens and would greatly decrease the impact of any epidemic. in the past, self-serving politics and flawed policies were the cause of delays that killed thousands; therefore, the fifth issue of reforms in global health care is to avoid bureaucratic issues that prevent the speedy and worldwide release of data that forecast epidemics. the essential mandate is that, once data are obtained and verified, they are released immediately, not withheld for personal gain or credit or by countries wishing to mislead travelers and businesses. the fifth recommendation in this world health plan is that essential investments should be made to train teams of doctors, medical staff, healthcare workers, and researchers. during the À ebola outbreak there was an enormous demand for doctors, nurses, and medical staff that was never met. training in global health should be a component of infectious disease training not only in ebola-susceptible countries but also in the medical schools and residencies of european, american, canadian, south american, and asian countries. the west african countries where ebola infection prevailed still lack doctors. the dearth of basic equipment in ebola-afflicted west africa contributed to the large number of deaths and unsafe medical practices among healthcare workers. in addition, protective equipment-uniforms, gloves, and headgear-should always be available. having trained individuals would speed up the control process and limit the spread of the infecting agent. during the À ebola outbreak, medical volunteers did not step forward in force to help until À months after the ebola outbreak. an enhanced medical team could have prevented escalation of the epidemic. the bill and melinda gates foundation suggests, "we need to invest in better disease-surveillance and laboratory-testing capacity, for normal situations and for epidemics. routine surveillance systems should be designed in such a way that they can detect early signs of an outbreak beyond their sentinel sites and be quickly scaled up during epidemics. . .and the data derived from such testing need to be made public immediately. many laboratories in developing countries have been financed by the polio-eradication campaign, so we will have to determine what capacities will be needed once that campaign is over." finally, an improved education plan is an absolute requirement. public understanding of how a virus spreads, the value of quarantine, and basic public health measures could stop the spread of an ongoing epidemic. an important lesson taught by the À ebola outbreak is that the susceptible populations must be educated in what and why public health measures are needed. the local heads of countries, districts, and most importantly village leaders, must understand how the disease travels, so that they can lead and guide their population in turn. surveillance in all areas including rural sites should be unrelenting along with acceptance of quarantines, appropriate treatments, and safe burial practices. along with these recommendations, courage, grit, and prayer should provide the format and strength to complete the goals of successful medical control of future epidemics. lastly, what have we learned from the ebola outbreak in west africa À ? the science and the underlying advances, management successes, along with the cultural and bureaucratic difficulties and failures come clear. but more than that, the numerous tales of humanity, the human story of native and foreign influx of healthcare workers, the role of kgh staff, drs. khan, sabeti, and garry, doctors without borders, cdc, missionary hospitals as well as volunteers to fight the epidemic and care for the ill stand out front. their stories reaffirm that all people are connected to other people and dependent on other people. these events in west africa in À resonate with lines written over years ago by the english poet john donne in his devotions upon emergent occasions no man is an island, entire of itself. each is a piece of the continent, a part of the main. if a clod be washed away by the sea, europe is the less. as well as if a promontory were. as well as if a manor of thine own or of thine friend's were. each man's death diminishes me, for i am involved in mankind. therefore, send not to know for whom the bell tolls, it tolls for thee. who acknowledges failings of ebola response. time world health organization admits it failed in handling ebola severe acute respiratory syndrome (sars): the first pandemic of the st century. viruses, plagues, & history who 'failed to alert' global community about ebola outbreak allowing virus to spread further À panel ebola aid workers shocked by who's 'amateurism' in response to outbreak ebola virus: for want of gloves, doctors die ebola takes big toll on already poor health care an indictment of ebola response ebola crisis: no impact from pledges of help leader describes the agency's ebola operations ebola crisis: global response has 'failed miserably', says world bank chief global 'failure' to grip ebola crisis criticised by world bank president | world news | african development bank group ebola crisis: un envoy rejects criticism of agency's response action taken by the netherlands and the international community to tackle ebola latin american health officials prepare to fight ebola china's companies, billionaires must step up to fight ebola what countries have pledged to fight ebola organizations responding to ebola un asks $ billion for ebola, gets $ million so far ebola outbreak: who admits it botched early attempt to stop disease international development policy revue internationale de politique de développement the next epidemic lessons from ebola-nejm oldstone mba. viruses, plagues, & history the evolution of ebola virus: insights from the À epidemic further reading what countries have pledged to fight ebola. . . and how much they've paid into the fund key: cord- - m ig authors: duncan, coley b.; falsey, ann r. title: viral infections date: - - journal: infectious disease in the aging doi: . / - - - - _ sha: doc_id: cord_uid: m ig although influenza remains indisputably the most significant viral pathogen in adults, other viruses such as respiratory syncytial virus, parainfluenza viruses, and human metapneumovirus are now recognized as significant pathogens in older populations. oseltamivir and zanamivir are antiviral agents that are effective for the treatment and prophylaxis of influenza a and b. for treatment and for optimal effect, therapy should be initiated within h of symptom onset. infection with hepatitis viruses may be more severe in older adults with more fulminate disease as observed with acute hepatitis a and a more rapid progression to cirrhosis with hepatitis c. outbreaks of viral gastroenteritis are common in long-term care facilities, and infection may lead to death due to dehydration and oliguria. the incidence of herpes zoster increases with advancing age and carries with it a significant risk of post herpetic neuralgia. the use of antiviral medications and corticosteroids may reduce the incidence and severity of chronic pain. parainfluenza viruses (piv), human metapneumoviruses (hmpv), coronaviruses (co-v), and rhinoviruses may cause severe disease in adults and result in hospitalization ( ) . together pneumonia and influenza comprise the fifth leading causes of death in persons aged years and older. influenza viruses are enveloped ribonucleic acid (rna) viruses that are classified as a, b, or c, based on stable internal proteins ( ) . the virus contains two major surface proteins: hemagglutinin (h) and neuraminidase (n), which can undergo minor antigenic changes leading to yearly epidemics or major changes resulting in influenza pandemics. currently, there are two circulating influenza a viruses, h n and h n , in addition to influenza b, present in the united states. h n viruses do not appear to cause serious problems in older persons, possibly due to previous immunity. in , influenza a (h n ), which was previously seen only in birds, crossed the species barrier and human infection occurred in southeast asia ( ) . this highly pathogenic avian influenza has spread in bird populations throughout asia and into europe. to date, human infection has been rare and transmission has occurred primarily by direct contact with infected birds. unlike seasonal influenza, illness due to avian influenza is more severe in young children as compared to older adults. in a community, peak influenza activity typically lasts - weeks, with attack rates highest in preschool and school-aged children and lowest in older persons ( ) . despite lower attack rates, mortality from influenza rises dramatically with age and the presence of underlying medical conditions. the presence of one high-risk medical condition (cardiovascular, pulmonary, renal, metabolic, neurologic, or malignant disease) increases the risk of death from influenza -fold. despite increasing vaccine coverage, current centers for disease control and prevention (cdc) data indicate increasing influenza-related morbidity and mortality over the past decade ( ) . in the united states, approximately , hospitalizations and , deaths occur each year in persons age years and older ( , ) . the devastating impact of influenza is most dramatically seen in long-term care facilities (ltcfs) where explosive epidemics may occur. during outbreaks, rates of pneumonia and hospitalization are as high as % and %, respectively, with case fatality rates of %. the classic presentation of influenza is an abrupt onset of fever, chills, headache, and myalgias (see table ). dry cough, sore throat, and ocular pain are also common ( ) . fever remains a common finding in the elderly, although the height of the fever may be lower compared with young persons. although many elderly adults have classic symptoms, a substantial number may have more nonspecific presentations such as fever and confusion or worsening of chronic medical conditions. in contrast to young healthy persons, the triad of fever, cough, and acute onset of symptoms has a positive predictive value of only % in elderly adults. given the protean manifestations of influenza in older persons, it is always important to consider influenza in the differential when evaluating an acutely ill elderly adult during the winter. influenza lower respiratory tract involvement increases steadily with advancing age with the rates of pneumonia - % in persons aged - years and rising to % in persons over age ( ) . secondary bacterial pneumonia following acute influenza also occurs more frequently in older persons. although the rates of pneumonia rise with age, hospitalization most frequently results from exacerbation of chronic medical conditions. in addition to the immediate complications of influenza, residents of nursing homes who survive influenza experience a significant functional decline in activities of daily living. although many physicians use clinical features to make a diagnosis of "the flu," laboratory confirmation is best, especially if therapeutic decisions are needed because influenza may be difficult to distinguish from other respiratory viruses. winter-spring - non-specific none rsv, respiratory syncytial virus. * mg daily for severe hepatic dysfunction, renal failure (crcl ml/min) and for elderly nursing home patients. **dosage should be reduced in persons with creatinine clearance of < ml/min ***ribavirin is not fda approved for use in adults. bid twice a day; po orally older persons typically shed the virus for - days, although shedding up to days has been documented in hospitalized patients ( ) . rapid antigen testing may be done directly on nasopharyngeal specimens using an enzyme immunoassay (eia) ( ) . although not as sensitive as viral culture, rapid tests offers quick turnaround times and may be useful for infection control and treatment decisions. sensitivity of rapid testing in adults is estimated to be - % for influenza a strains and - % for influenza b ( ) . when available, rt-pcr offers rapidity while retaining excellent sensitivity. as of this writing, zanamivir or rimantadine can be used for the treatment or prophylaxis of influenza a h n strains (*). for influenza a h n or influenza b, oseltamivir or zanamivir can be used. if the strain of influenza is unknown, currently, zanamivir by itself or a combination of oseltamivir and rimantadine is appropriate coverage ( ). resistance to zanamivir remains rare. zanamivir is not recommended for patients with reactive airway disease, because it may exacerbate bronchospasm. future influenza treatment and prophylaxis recommendations for influenza will need to be guided by close monitoring of cdc reports on influenza resistance patterns. treatment should begin < h after onset of symptoms (table ). in practice, physicians are often faced with the question of whether to treat patients who present outside the -h period. at present, only one observational study addresses this question in hospitalized adults ( ) . in adults hospitalized with influenza, mortality was significantly lower in those who received antiviral treatment as compared to those who did not receive antiviral treatment. of the patients who were treated, only % had symptoms < h. the cornerstone of reducing the morbidity and mortality of influenza in the elderly is vaccination (see also chapter "vaccinations"). although the degree of protective efficacy for current inactivated vaccines in the elderly has recently become a subject of controversy, older adults clearly benefit from vaccination ( ) . a multi-layered approach for protecting the elderly from influenza is needed and includes vaccinating elderly persons, their close contacts and care givers, and providing oseltamivir if exposure to influenza has been documented ( , ) . when staff was highly vaccinated, several studies have demonstrated a benefit to elderly residents of ltcfs ( ) . the recommendations of the advisory committee on immunization practices (acip) relating to the elderly, include vaccination of all persons ³ years, vaccination of residents of nursing homes and chronic-care facilities, vaccination of healthcare personnel, and vaccination of healthy household contacts (including children) and caregivers of adults ³ years ( ) . * http://emergency.cdc.gov/coca/ppt/antivirals_update_ _fiore.pps at the present time, only trivalent inactivated virus (tiv) vaccine, which contains killed h n , h n and b strain influenza, is recommended for use in persons years and older ( ) . mild acute local reactions occur in approximately one-third of vaccines and systemic reactions such as fever, and myalgias are uncommon in older persons. influenza vaccine may be safely given simultaneously with pneumococcal vaccine, and the only contraindications to vaccination are anaphylactic hypersensitivity to eggs or other components of the vaccine and a history of guillian-barré syndrome. by using adjuvants and higher doses of antigens, active research continues to improve the immunogenicity and efficacy of inactivate influenza vaccine. live attenuated influenza virus vaccine is not approved for persons over age ; however, it may be given to healthcare workers and close household contacts of older adults. antiviral prophylaxis is recommended for all residents of nursing homes and chronic care facilities and to unvaccinated healthcare providers once influenza a has been documented in the institution ( , ) . chemoprophylaxis is given regardless of vaccination status and is continued until week after the onset of the last influenza case. rsv has long been recognized as the leading cause of lower respiratory tract disease in children; however, recently, it has been recognized as a serious adult pathogen ( ) . it is estimated that rsv results in approximately , hospitalizations and , deaths annually in the united states yielding healthcare costs in excess of $ billion. a number of epidemiologic studies and mathematical models indicate that rsv is second to influenza as a cause of serious viral respiratory disease in adults ( ) . rsv was initially recognized as a pathogen in older persons when several outbreaks were described in long-term care facilities ( ) . attack rates are variable and may be as high as % during outbreaks, but more commonly they range from to % when residents are followed prospectively. in published reports, rates of pneumonia range from to % and death from to %. rsv appears to cause serious disease in community-dwelling older persons as well. in a -year prospective study of elderly persons in the united kingdom (uk) nicholson et al., identified rsv in % of illnesses using serology for diagnosis ( ) . with the advent of sensitive molecular testing, a more accurate assessment of the true incidence of rsv has emerged. in a -year study from the united kingdom by zambon et al., rsv was identified by rt-pcr in - % of adults age years and older who were visiting a general practitioner during the winter for a respiratory illness ( ) . in comparison, during the same period, influenza a was identified in - % of subjects. in a prospective study from rochester, ny, using a combination of viral culture, rt-pcr and serology for diagnosis, rsv infection was documented in - % of healthy elderly and - % of adults with chronic cardiopulmonary conditions over four winter seasons ( ) . serious disease was more common in high-risk patients: % visited the emergency room, % required hospitalization, and % died. finally, a large study of community-acquired pneumonia in adults found rsv to be the third most commonly identified pathogen at . % compared with . % due to streptococcus pneumoniae and . % due to influenza ( ) . manifestations of rsv infection can be difficult to distinguish from other viral respiratory infections, particularly influenza. most individuals with rsv have nasal discharge, cough, sputum production, and constitutional symptoms. although overlap exists, there are some helpful clues to differentiate rsv from influenza. high fever, sore throat, myalgias, and gastrointestinal complaints are more characteristic of influenza, whereas rhinorrhea, dyspnea, sputum production, and wheezing are more frequently associated with rsv infection . unfortunately, because of the labile nature of the virus and low titers of virus in nasal secretions in adults, diagnosis of acute rsv by standard testing is difficult. under ideal circumstances, viral culture is only % sensitive when compared with serology using eia. commercial rapid antigen tests also have poor sensitivity in adults ( ) . rt-pcr offers the best combination of sensitivity and specificity for the diagnosis of acute rsv in adults but is not widely available to most clinicians. the treatment of rsv infection in adults is largely supportive. supplemental oxygen and bronchodilators may be useful, and antibiotics should be considered if bacterial super-infection is suspected. ribavirin is a nucleoside analogue, which has broad antiviral activity, including rsv. anecdotal experience suggests it may be beneficial in selected cases, particularly in persons with immunosupression. however, due to lack of data in the elderly, general recommendations on its use cannot be made ( ) . the major problems with ribavirin are its high cost and difficulty with administration. the recommended - h/day of aerosol at mg/ml concentrations may be quite difficult for the elderly adult to tolerate. higher concentrations ( mg/ml) given three times a day may also be effective and more tolerable ( ) . in healthy elderly patients and in adults with chronic pulmonary disease, low serum neutralizing antibody titers are associated with increased risk of hospitalization with rsv infection suggesting a vaccine may be beneficial. although research is ongoing, an effective rsv vaccine has yet to be developed. rsv is spread primarily by large droplet inoculation and fomites, and handwashing is the single most important measure in the control of rsv. the parainfluenza viruses (piv) are most commonly thought of as the etiologic agents of croup, bronchiolitis, and pneumonia in young children ( ) . four serotypes and two subgroups of piv are recognized ( , , , a, and b); piv- is endemic throughout the year, whereas piv- and piv- tend to occur during the fall. although piv infections are not commonly documented in older adults, several studies of community-acquired pneumonia and chronic obstructive pulmonary disease (copd) exacerbations implicate piv as a cause in - % of cases ( , ) . the piv- and serotypes account for the majority of isolates in older persons, with piv- being relatively uncommon ( ) . similar to rsv, outbreaks of piv infections in nursing homes have been described ( , ) . variable morbidity and mortality has been reported. clinical characteristics of piv infection are not distinctive and include rhinorrhea, sore throat, hoarseness, and cough with high rates of pneumonia ranging from to %. in an institutional outbreak of piv- , the attack rates among residents and nursing staff were % and %, respectively. antecedent parainfluenza infection in long-term care residents has been linked to outbreaks of pneumococcal pneumonia. in clinical practice, a diagnosis of piv infection is usually made by viral culture, although rt-pcr is available in some settings ( ) . diagnosis can also be made serologically; however, piv- and infections result in cross-reactive antibody responses and cannot be distinguished. no antiviral agents have been approved for the treatment of piv infection. in , human metapneumovirus (hmpv) was first identified in the netherlands from archived respiratory cultures collected from infants and young children in whom other pathogens could not be isolated ( ) . it is an enveloped rna virus closely related to rsv and piv. since its discovery, infection has been widely reported each winter in young infants with an illness similar to rsv and characterized by wheezing and bronchiolitis ( ) . however, as with many pediatric respiratory viral pathogens, hmpv infection induces incomplete immunity and reinfections occur later in life at all ages ( , ) . in a -year study, hmpv infection was identified in . % of elderly and high-risk adults, using rt-pcr and serology for diagnosis ( ) . impact was greatest in subjects with cardiopulmonary diseases, who were ill twice as long as healthy elderly. in a study of adult pneumonia, % of subjects were diagnosed by rt-pcr with hmpv ( ) . seventy-five percent of those infected were years of age and older. such hmpv outbreaks can also occur in ltcfs. in a recent outbreak of severe hmpv illness in an ltcf in quebec, canada, % of those infected had pneumonia and % died ( ) . autopsy material from an elderly woman with an extensive right middle and lower lobe pneumonia confirmed the presence of virus in the lower airways by immunohistochemical staining. the clinical characteristics of hmpv pneumonia in older adults do not appear to be distinctive from the other wintertime respiratory viruses. cough is universal and wheezing, dyspnea, and sputum production are common symptoms ( ) . in part due to its fastidious growth characteristics, hmpv remained undetected for many years. although isolation by viral culture is possible, this method of diagnosis is not practical, and rt-pcr is the diagnostic method of choice ( ) . rapid tests have been developed for direct antigen detection in respiratory secretions; however, there are little data regarding sensitivity in the elderly. currently, there is no known effective antimicrobial therapy against this virus. therapy is primarily symptomatic, supportive, and managing any complications. rhinoviruses are the most commonly identified cause of the "common cold," accounting for - % of upper respiratory infections ( ) . rhinoviruses circulate at all times of the year, but peak activity tends to be during the spring and fall. because the virus does not replicate well at °c, infection of the lower airways was previously considered rare. however, recent studies utilizing experimental challenge and specimens obtained at bronchoscopy clearly demonstrate rhinovirus infection of the lower respiratory epithelium ( ) . a prospective study from the united kingdom indicates that rhinoviruses are an important cause of debility and lower respiratory disease in elderly people in the community ( ) . rhinoviruses accounted for % of respiratory illnesses in a cohort of persons over a -year period. although death and hospitalization rates were low, the mean length of illness was days, and % of people were unable to perform their normal household activities. the presence of chronic medical conditions and smoking increased the likelihood of lower respiratory tract complications. because of the frequency of rhinovirus infection, the overall burden of disease in the elderly may approach influenza. rhinovirus has also been identified as the cause of . %- . % of copd exacerbations ( ) . lastly, outbreaks of severe respiratory illness due to rhinovirus have been described in nursing homes with attack rates as high as % and a mortality as high as % of those affected ( , ) . in elderly persons, nasal congestion ( - %), cough ( - %), constitutional symptoms ( - %), and sore throat ( - %) characterize illnesses. rhinoviruses are now appreciated as a common trigger for asthma exacerbations and, therefore, in persons with preexisting lung disease, the dominant symptom may be wheezing ( ) . the diagnosis of rhinovirus is usually made by a viral culture of nasopharyngeal secretions. if available, the use of rt-pcr greatly increases detection rates ( ) . treatment is supportive and care should be exercised when prescribing "cold" medications to elderly persons because many of these "cold" medications contain combinations of sympathomimetics and antihistamines. coronaviruses are rna viruses of which two are major serotypes: human coronavirus e (hco- e) and hco-oc , which, for decades, have been known to cause respiratory disease in humans ( ) . two recently discovered coronaviruses (hco-nl and hco-hku ) cause lower and upper respiratory tract infections with similar frequency ( ) ( ) ( ) . in temperate climates, peak viral activity occurs in the winter. reinfections with coronaviruses are common throughout life, and, similar to rhinoviruses, illnesses are generally mild upper respiratory infections in healthy adults; symptoms include malaise, headache, sore throat, and nasal congestion. exacerbations of chronic obstructive pulmonary disease have been linked to coronavirus infections in several studies. coronavirus infections have been evaluated in the community-dwelling elderly and have, in one prospective study from the united kingdom, accounted for . % of the respiratory illnesses ( ) . coronavirus's were associated with lower respiratory tract symptoms in more than % of cases; infections have also been documented in ltcfs and in frail elderly people attending daycare centers ( ) . coronaviruses have also been implicated in severe respiratory infections requiring hospitalization in older adults ( ) . rt-pcr is now available for diagnosis of coronavirus infection but frequently a specific viral diagnosis is not made ( ) . no antiviral agents are available, and treatment is supportive. hepatitis a virus (hav) is an rna virus in the picornavirus family (see table ). the virus is easily transmitted by the fecal-oral route. in countries where the virus is endemic and sanitation is poor, most people become infected in early childhood when the disease is mild and life-long immunity results ( ) . recently, a shift in the prevalence of cases from childhood to adulthood has occurred, presumably due to improved living conditions. the incidence of hepatitis a in the united states has fallen % from a peak in to an all-time low of presently . cases per , persons ( ) . the prevalence of anti-hav antibodies increases with advancing age ( ) . in a study from colorado, the prevalence of anti-hav antibodies at ages , , and was %, %, and %, respectively ( ) . an acute hepatitis a, advancing age correlates with more severe clinical manifestations, higher bilirubin levels and increased hospitalization rates ( ) . liver failure and death are also more common with increased age ( ) . in the united states, the overall case fatality rate for hav infection is . %; however, it rises to . % in persons years or older ( ) . an inactivated hepatitis a vaccine has been available since , and clinical studies have shown the vaccine to be safe, very well tolerated, and highly immunogenic in all age groups. immunization of toddlers in israel resulted in a > % reduction of hepatitis a in the general population ( ) . although the benefit was least for ages ³ years, a . % reduction in cases was observed in this age group. immunogenicity in frail elderly persons such as residents of long-term care has not been reported. although disease may be more severe in older adults, current vaccination policies do not specifically target the elderly. however, vaccination is recommended for older travelers who plan to visit countries endemic for hav. hepatitis b virus (hbv) is a complex deoxyribonucleic acid (dna) virus transmitted by percutaneous and mucous membrane exposure to infectious body fluids. serum, saliva, and semen have been shown to contain hepatitis b surface antigen (hbsag). since , the incidence of acute hepatitis b has declined in all age groups with the largest decline ( %) being in children < years ( ) . because the primary risk group in the united states and europe is intravenous drug abusers, acute infection is not common in the elderly. transfusion-related hbv infection is now an uncommon event with risk estimated to be in , transfusions ( ) . when several outbreaks occurred during the s- s, ltcf's were thought to be a risk area for hbv ( ) . however, recent surveys of geriatric hospitals indicate the prevalence of hbsag is similar to the general geriatric population (< %) ( ) . acute hbv in older adults is usually mild, and many cases are subclinical or presents with manifestations of cholestasis. in addition to the typical symptoms of jaundice, anorexia, and fatigue, diarrhea is a common complaint in elderly persons. complaints reflecting immune complex disease such as myalgias and arthalgias are rare in older adults. although acute hbv is generally not a severe disease in older adults, the mortality from fulminant hbv increases with age ( ) . in a multivariate analysis of prognostic factors in patients with hbv, age was an independent predictor of survival ( ) . mortality for persons over age years was . % compared with . % for persons ages - . when individuals are infected at older ages, chronic carriage rates also increase. compared with a % carriage rate in young adults, approximately % of older persons become chronic carriers ( ) . in addition to cirrhosis from chronic active hepatitis, one of the major complications of hbv infection is hepatocellular carcinoma (hcc). the length of time infected is an important factor in the development of cancer, and, thus, elderly persons who have been infected for many years are at the greatest risk. the rate of hcc rises from per , in -to -year olds to per , in -to -year-old chronic hbv carriers ( ) . most cases of acute hepatitis b clear spontaneously and do not require treatment. in young patients with compensated disease, alpha-interferon is primarily used in the treatment of chronic hepatitis b. those who respond favorably may see suppression of viral replication and a decrease in the risk of progression to cirrhosis or to cancer. side effects of therapy are frequent and increase with advancing age ( ) . therapy should be reserved for patients in overall good health, except for their liver disease, and who have evidence of active viral replication. five nucleotide/nucleoside analogs (lamivudine, adefovir, entecavir, tenofovir, and telbuvidine) are currently approved by the food and drug administration to treat chronic hepatitis b ( ) . these drugs are usually better tolerated than interferon, although they have not been studied specifically in the elderly. patients with chronic hepatitis b should be tested for immunity to hepatitis a and, if seronegative, should be vaccinated against hepatitis a to prevent acute decompensation that could occur with hepatitis a superinfection. in addition, patients should be counseled to abstain from alcohol, to maintain a healthy body weight, and to use condoms to protect their sexual partners from infection. the currently licensed hepatitis b vaccine is a genetic recombinant vaccine; it is very well tolerated and highly immunogenic with excellent protective efficacy in children and young adults. however, response rates to hbv vaccine diminish significantly with increased age. ninety percent of persons under age achieve an adequate seroresponse compared with only % in persons over age . hepatitis c virus (hcv) is an rna virus in the flavivirus family. exposures to contaminated blood, either through occupation or through intravenous drug abuse, may transmit hcv. although - % of community-acquired hcv cases do not report a parenteral exposure, nonparenteral transmission of hcv is not well understood. sexual transmission, if it occurs, is not efficient. the major risk factor for hcv in older persons is transfusion, and most became infected prior to routine screening of the blood supply in ( ) . for southern europe and japan, the peak era of transfusion-associated hcv was between and whereas in the united states and northern europe, the peak transmission was between and . the current risk of acquiring hcv from transfusion in the united states is approximately in , , ( ) . in southern europe, numerous population-based studies have shown that the prevalence of hcv is - % in persons over years and - % in those over years; infection is extremely rare in subjects < years ( ) . the seroprevalence of . - . % in ltcf residents is approximately that of the general elderly population ( ) . the clinical manifestations of acute hcv are generally mild and nonspecific. in a series of older people with acute non-a non-b hepatitis, approximately - % had fever, abdominal pain, and jaundice ( ) . fulminant hepatitis is rare with hcv, but development of chronic liver disease is very common ( ) . virtually all persons become chronically infected, and a significant number develop chronic liver disease. on average, years after initial infection, chronic active hepatitis or cirrhosis develops in - % of persons. age affects the rate of progression to cirrhosis in two important ways: the younger a patient is when hcv is acquired, the slower the rate of progression to cirrhosis; however, the longer one is infected, the greater the risk of development of cirrhosis and hcc ( ) . hepatocellular carcinoma is clearly associated with chronic hcv infection, and the relative risk of cancer from hcv may be even greater than that from hbv. in a study of older persons with hcv in the united kingdom, % developed hcc ( ) . chronic hcv infection is currently treated with pegylated interferon alpha and oral ribavirin. goals of therapy include clearance of viremia and prevention of decompensated cirrhosis and hcc. persons with high viral load and viral genotype have a low response rate to a -interferon, and, many patients who initially respond, relapse when therapy is discontinued ( ) . most studies of interferon treatment of hcv have not included older participants. in one study from japan, interferon was administered to patients aged and older with hcv, and the response rate was % compared with % in younger persons ( ) . of note, the older subjects had higher hcv-rna titers and more severe fibrosis on their liver biopsy as compared to their younger subjects. response rates in elderly persons correlated with lower hcv-rna titers. because older persons have more side effects and a lower response rate to interferon, treatment should be carefully considered on an individual basis; it should be proposed only in patients up to years who have a significant risk of progression of liver disease, no serious co-morbidities, and an otherwise good life expectancy ( ) . patients with chronic hepatitis c should be tested for immunity to hepatitis a and b and, if seronegative to either, they should be vaccinated to prevent acute decompensations that could occur with hepatitis a or b superinfection. they should be counseled to abstain from alcohol, to maintain a healthy body weight, and to use condoms to protect their sexual partners from infection. although deaths related to diarrhea have traditionally been thought to be a problem of young children in developing countries, in the united states from to , % of the , diarrhea-related deaths occurred in adults over the age of as compared to % in children < year old ( ) . the odds ratio of dying during a hospitalization involving gastroenteritis was . for adults over the age of as compared with children less than years of age. residents of nursing facilities are at particular risk for infectious diarrhea illness because of the outbreaks that can occur in closed populations. the majority of nursing facility outbreaks of gastroenteritis are probably viral and include rotavirus, enteric adenoviruses, norovirus, snow mountain agent, and small round structured viruses (srsv) ( , ) . rotaviruses are small rna viruses in the retrovirus family and are the most important cause of gastroenteritis in infants and young children worldwide. the mode of transmission is assumed to be fecal-oral, and the virus is relatively resistant to common disinfectants and facilitating nosocomial dissemination. several outbreaks of rotavirus infection in elderly residents of ltcfs have been reported with attack rates ranging from to % and mortality rates of - % ( , ) . a typical illness lasts - days and includes voluminous vomiting and watery diarrhea with low-grade fever. death may result from dehydration progressing to oliguria and acidosis ( , ) . in an analysis of specimens from gastroenteritis outbreaks in aged care facilities in australia, rotavirus was detected by electron microscopy in of individuals in out of outbreaks ( ) . although rotavirus infections are most common in winter, outbreaks can occur at other times of the year ( ) . rotavirus serum antibody titers offer some protection against severe disease and tend to diminish with increasing age ( ) . two rotavirus vaccines were released in for use in children, a pentavalent human-bovine reassortant rotavirus vaccine called rotateq ® and a live-attenuated human rotavirus vaccine called rotarix ® . no data on safety or immunogenicity in the elderly exists; however, given the mortality rates in this age group, further study would be reasonable. norovirus (formerly called norwalk-like virus) is also a frequent cause of diarrhea in adults including the elderly (see also chapter "infectious diarrhea"). in a study of gastroenteritis outbreaks in maryland, % of stool samples were positive for norwalk-like virus (nlv) ( ) . the median duration of symptoms with nlv gastroenteritis is - days ( ) . varicella-zoster virus (vzv) is a dna virus and a member of the herpes virus family. it causes two distinct clinical syndromes: primary disseminated infection (chickenpox) and reactivation of latent virus in the dorsal root ganglia, leading to herpes zoster or "shingles" ( ) . herpes zoster is a painful, vesicular exanthem that erupts in one to two dermatomes after a prodrome of days to weeks and may take up to a month to heal. most patients report a deep aching or burning sensation, altered sensation to touch with paresthesias, dysesthesia, or hyperesthesia. herpes zoster is a common condition with a cumulative lifetime incidence of - % with most of the risk concentrated in older age. the overall incidence is . - . per , personyears, but rates rise sharply with increasing age to . per , , for persons age years and older ( ) . chapter "herpes zoster" is devoted to the topic of herpes zoster, and the reader is referred to this section for further details. the epstein-barr virus (ebv) is a herpes virus that establishes lifelong infection. primary infection may occur in childhood when infection is asymptomatic or during adolescence when the symptoms of classic mononucleosis are most often observed ( ) . although primary infection is uncommon in old age, the manifestations may be different than those in youth, which makes diagnosis challenging. seroepidemiologic studies indicate that - % of older adults are at risk for primary infection ( ) . diagnosis is also often delayed because symptoms may be misleading. lymphadenopathy, pharyngitis, and splenomegaly are significantly less common and jaundice is more common in older persons as compared with the young persons ( ) . fever is more common and often lasts more than weeks ( , ) . the neurologic manifestations of ebv infection are protean, and acute ebv encephalitis has been described ( ) . adding to the difficulty of making a correct diagnosis, development of atypical lymphocytosis may be absent or delayed in the elderly. diagnosis of primary ebv is made by the presence of heterophile antibodies or ebv-specific igm. although acyclovir has in vitro activity against ebv, no benefit has been demonstrated in the treatment of acute ebv infection. trends in hospitalizations for pneumonia among persons aged years or older in the united states improved diagnosis of the etiology of community-acquired pneumonia with real-time polymerase chain reaction prevention and control of influenza. recommendations of the advisory committee on immunization practices (acip) current concepts: avian influenza a (h n ) infection in humans impact of influenza vaccination on seasonal mortality in the us elderly population influenza-associated hospitalizations in the united states mortality associated with influenza and respiratory syncytial virus in the united states lung involvement in influenza duration of influenza a virus shedding in hospitalized patients and implications for infection control rapid tests for influenza . current opinions in pediatrics performance of six influenza rapid tests in detecting human influenza in clinical specimens antiviral therapy and outcomes of influenza requiring hospitalization in ontario, canada effectiveness of influenza vaccine in the community-dwelling elderly antivirals and the control of influenza outbreaks effects of influenza vaccination of health-care workers on mortality of elderly people in long-term care: a randomised controlled trial respiratory syncytial virus infection in elderly and high-risk adults respiratory syncytial virus infection in adults acute viral infections of upper respiratory tract in elderly people living in the community: comparative, prospective, population based study of disease burden contribution of influenza and respiratory syncytial virus to community cases of influenza-like illness: an observational study respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults lack of sensitivity of rapid antigen tests for the diagnosis of respiratory syncytial virus infection in adults ribavirin therapy of adult respiratory syncytial virus pneumonitis high-dose, shortduration ribavirin aerosol therapy compared with standard ribavirin therapy in children with suspected respiratory syncytial virus infection parainfluenza viruses impact of respiratory virus infections on persons with chronic underlying conditions parainfluenza virus infection among adults hospitalized for lower respiratory tract infection parainfluenza infections in the elderly - influenza-like illness in residential care homes: a study of the incidence, aetiological agents, natural history, and health resource utilization a newly discovered human pneumovirus isolated from young children with respiratory tract disease human metapneumovirus . seminar respiratory critical care medicine an outbreak of severe respiratory tract infection due to human metapneumovirus in a long-term care facility human metapneumovirus infections in young and elderly adults human metapneumovirus pneumonia in adults: results of a prospective study rhinovirus and coronavirus infections quantitative and qualitative analysis of rhinovirus infection in bronchial tissues risk factors for lower respiratory complications of rhinovirus infections in elderly people living in the community: prospective cohort study effect of interactions between lower airway bacterial and rhinoviral infection in exacerbations of copd rhinovirus outbreak in a long term care facility for elderly persons associated with unusually high mortality two outbreaks of severe respiratory disease in nursing homes associated with rhinovirus human coronaviruses: what do they cause? a prospective hospital-based study of the clinical impact of non-severe acute respiratory syndrome (non-sars)-related human coronavirus infection the novel human coronaviruses nl and hku human coronavirus oc causes influenza-like illness in residents and staff of aged-care facilities in melbourne spectrum of clinical illness in hospitalized patients with "common cold" virus infections history and epidemology of hepatitis a virus surveillance for acute viral hepatitis -united states viral hepatitis in older adults hepatitis a epidemic in the elderly acute hepatitis a virus infection: a review of prognostic factors from years experience in a tertiary referral center incidence of hepatitis a in israel following universal immunization of toddlers current prevalence and incidence of infectious disease markers and estimated window-period risk in the american red cross blood donor population liver disease in the elderly new drugs for chronic hepatitis b: a review hepatitis c virus infection in the elderly: epidemiology, natural history and management prevalence of hepatitis b surface antigen, hepatitis c antibody, and hiv- antibody among residents of a long-term care facility hepatitis c virus infection in the elderly interferon therapy for patients more than years of age with chronic hepatitis c approach to acute diarrhea in the elderly outbreaks of gastroenteritis in elderly nursing homes and retirement facilities associated with human calciviruses rotavirus infection in a geriatric population an epidemic of rotavirus-associated gastroenteritis in a nursing home for the elderly rotavirus detection and characterisation in outbreaks of gastroenteritis in aged-care facilities report of a rotavirus outbreak in an adult nursing home population a predominant role for norwalk-like viruses as agents of epidemic gastroenteritis in maryland nursing homes for the elderly clinical manifestation of norovirus gastroenteritis in health care settings epstein-barr virus and the elderly host clinical and laboratory evaluation of elderly patients with heterophil-antibody positive infectious monoculeosis infectious mononucleosis in middle age infectious mononucleosis in patients aged to years: report of cases, including without heterophil-antibody responses epstein-barr virus causing encephalitis in an elderly woman hepatitis c virus infection in the elderly: epidemiology, natural history and management recommendations for the management of herpes zoster antiviral therapy and outcomes of influenza requiring hospitalization in ontario, canada key: cord- -hprwqi n authors: löscher, thomas; prüfer-krämer, luise title: emerging and re-emerging infectious diseases date: - - journal: modern infectious disease epidemiology doi: . / - - - - _ sha: doc_id: cord_uid: hprwqi n emerging infectious diseases (eids) are characterized by a new or an increased occurrence within the last few decades. they include the following categories emerging diagnosis of infectious diseases: old diseases that are newly classified as infectious diseases because of the discovery of a responsible infectious agent. europe including great britain as well as in india, china, and japan. emerging vector-borne disease events concentrated in densely populated subtropical and tropical regions mostly in india, indonesia, china, sub-saharan africa, and central america (see figs. . , . , and . ). the identification of new infectious agents in old diseases with unknown etiology is still the basis in many epidemiological studies. such newly detected bacteria and viruses in the last few decades are listed in table . . since the detection of helicobacter pylori in , this infection has been identified as the causative agent in % of b-gastritis cases. the risk of duodenal ulcer is increased by - -fold in patients with helicobacter-associated gastritis. who declared h. pylori as a carcinogen of first order because of its potential to enhance the risk of stomach carcinoma and malt lymphoma in long-term infection. in highprevalence regions for h. pylori, the frequency of stomach carcinoma is significantly higher compared to low-endemic areas (correa et al. ). the identification of h. pylori facilitates curative treatment of most associated diseases in individuals. but the most important epidemiological effect on associated diseases is attributed to increased hygienic standards in industrialized countries with a substantial reduction of h. pylori prevalences in younger age cohorts. transmission of h. pylori occurs mainly in childhood. in western developed countries the overall prevalence is around %, higher in older age groups due to a cohort effect, and this increases with low socioeconomic status (rothenbacher et al. ). in countries with low hygienic standards the prevalences are still high in younger age groups and reach % in developing countries. in developed countries, migrant subpopulations from less-developed regions show significantly higher prevalences in comparison to the nonmigrant population (mégraud ). since the early th century, a characteristic expanding skin lesion, erythema migrans (em), and an arthritis associated with previous tick bites were known. borrelia for many decades. increased outdoor activities facilitated contacts between humans and ticks in the s and the s and increased transmission of borrelia to humans at the northeastern coast of north america, leading to the discovery of borrelia burgdorferi in by willy burgdorfer. three different stages of the disease that describe the stage of infection and the involvement of different organ systems are known: stage , early localized infection; stage , early but disseminated infection; and stage , late stage with persistent infection. lyme disease is endemic at the east coast and in minnesota in the united states, in eastern and central europe, and russia. seroprevalence rates that reflect about % of nonclinical infections vary between and % in the general population in germany (hassler et al. ; weiland et al. ) . in high-risk groups like forest workers in germany the prevalences reach - % (robert koch institute a). in ticks (ixodes) the prevalences are between and % depending on the geographical area and the testing method used [immunofluorescence test, ift and polymerase chain reaction (pcr)]. in most studies the main risk factors of infection are age (children: - years, adults - years), outdoor activities, skin contacts with bushes and grass, and the presence of ticks in domestic animals (robert koch institute b) . the probability of infection (seroconversion) after a tick bite in germany is - % and the probability of a clinical disease is . - . %. the probability that the bite of an infectious tick leads to infection in the host is - %. this depends on the time duration that the tick is feeding on the human body. since the detection of the etiologic infectious agent and the subsequent development of laboratory diagnostic tests in the s, the number of reported cases of lyme disease has increased from to , per year, indicating that it is an "emerging diagnosis." the reported numbers vary depending on the reproduction of the hosting rodents for ticks as well as the contacts between humans and nature (spach et al. ) . ticks may live for several years and their survival, reproduction rate, and activity are directly affected by changes in seasonal climate through induced changes in vegetation zones and biodiversity, hence causing local alterations of the tick's habitat and in the occurrence of animals that are carriers of different pathogens (like small rodents). several studies in europe have shown that in recent decades the tick ixodes ricinus, transmitting lyme borreliosis and tick-borne encephalitis (tbe), has spread into higher latitudes (e.g., sweden) and altitudes (e.g., czech republic, austria), and has become more abundant in many places. such variations have been shown to be associated with recent variations in climate. as a result, new risk areas of both diseases have recently been reported from the czech republic. climate change in europe seems likely to facilitate the spread of lyme borreliosis and tbe into higher latitudes and altitudes, and to contribute to extended and more intense transmission seasons. currently, the most effective adaptive strategies available are tbe vaccination of risk populations and preventive information to the general public (danielova et al. ; lindgren et al. ; materna et al. ). an effective vaccine was licensed for b. burgdorferi in . in europe, where different variants of borrelia are present (mostly b. afzelii and b. garinii), this vaccine is not protective. trivalent vaccines for europe are in clinical trials. in recent years, norovirus infections are increasingly recognized as the cause of large outbreaks of diarrheal diseases in the general population, school classes, nursing homes, hospitals, and cruise ships in western countries with peaks in colder seasons (winter epidemics) (centers of disease control ; verhoef et al. ; robert koch institute a) . this is a typical example for emerging diagnosis due to increasing availability of routine pcr testing for these viruses in stool samples. noroviruses (family caliciviridae) are a group of related, single-stranded rna viruses first described in an outbreak of gastroenteritis in a school at norwalk, ohio, in . five genogroups are known. immunity seems to be strain specific and lasts only for limited periods, so individuals are likely to get the infection repeatedly throughout their life. it is estimated that noroviruses are the cause of about % of all food-borne outbreaks of gastroenteritis. for several years there has been an ongoing epidemic in several european countries due to drift variants of a new genotype (gg ii. jamboree) previously unknown to this nonimmune population (robert koch institute a). as a result of an analysis of outbreaks in the united states between and , direct contamination of food by a food handler was the most common cause ( %), person-to-person transmission was less prevalent ( %), and even less frequently waterborne transmission could be proved ( %) (centers for disease control ). vomiting is a frequent symptom of norovirus enteritis and may result in infectious droplets or aerosols causing airborne or contact transmission. this may explain the difficulty to stop outbreaks in hospitals, nursing homes, and similar settings despite precautions to prevent fecal-oral transmission. also on cruise ships, person-to-person transmission is most likely in those closed settings, and drinking tap water is a risk factor as well (verhoef et al. ). searching for an agent which causes large outbreaks of enterically transmitted non-a hepatitis in asia and other parts of the world, the hepatitis e virus (hev) was first described in and cloned and sequenced in (reyes et al. ). meanwhile, hev has been shown to be a zoonotic virus circulating in pigs and other animals. it is implicated in about % of sporadic cases of acute hepatitis in developing countries and associated with a high case fatality rate in the third trimester of pregnancy ( - %). hev is a major cause of large epidemics in asia, and to a lesser extent in africa and latin america, typically promoted through postmonsoon flooding with contamination of drinking water by human and animal feces. recent data show hev also to circulate in european countries and to be associated with severe and fatal disease not only during pregnancy but also in the elderly and in patients with chronic liver conditions. in patients with solid organ transplants, hev may even cause chronic hepatitis and liver cirrhosis (kamar et al. ) . a recombinant hev vaccine candidate has demonstrated a high protection rate of approximately % during clinical trials in nepal (shrestha et al. ). for years, specific human papillomaviruses have been linked to certain human cancers and have been identified as causative agents of malignant proliferations. in the s the detection of papillomavirus dna from cervical carcinoma biopsies were published, showing that hpv types and are the most frequent (dürst et al. ; boshart et al. ) . the relation of hpv infections and cancer is further discussed in chapter . definition: only infections that are newly discovered in humans are listed in this chapter: hiv, new variant of creutzfeldt-jakob disease (vcjd), hemorrhagic uremic syndrome (hus) caused by enterohemorrhagic escherichia coli, viral hemorrhagic fevers like hanta, lassa, ebola, and marburg fever, nipah virus encephalitis, monkeypox, human ehrlichiosis, severe acute respiratory syndrome (coronavirus infection, sars), and avian influenza (h n ) (see fig. . and table . ). these infections mostly have their origin in zoonotic wildlife (e.g., avian influenza, monkeypox, hantavirus, nipah virus, and filoviruses) or livestock (e.g., vcjd). factors promoting the spread of these infections in humans are contacts with wildlife, mass food production of animal origin, and globalization (migration, transportation of goods and vectors) (see fig. . ). in addition, new strains or variants of well-known pathogens have emerged showing increased or altered virulence such as clostridium difficile ribotype or staphylococcus aureus strains expressing the panton-valentine leukocidin (see also chapter ). the epidemiology of hiv is treated in chapter and that of avian influenza and new influenza h n in chapter . in the year , years after the peak of the bse epidemic in the united kingdom, with an annual incidence rate in cows of . per million bovines aged over months, the first mortalities in humans with a new variant of creutzfeldt-jakob disease were observed in the united kingdom. until , smaller incidence rates of bse cases had been reported by other european countries in indigenous bovines and up to more than , per million in in ireland. from , bse started to increase in switzerland and portugal, from in spain and in recent years has spread to eastern european countries (organisation mondiale de la santé animale ). the infectious agent is a self-replicating protein, a "prion." the source of infection for cows is infectious animal flour. the transmission to humans occurs through oral intake of cow products, most likely undercooked meat and nerval tissues as well as transplants of cornea, dura mater, contaminated surgical instruments, or the treatment with hypophyseal hormones extracted from animal tissues. after a statuary ban on the feeding of protein derived from ruminants to any ruminant and the export ban of all cow products from england, the epidemic of bse in cows and the occurrence of human infections decreased in the united kingdom since . by june the total number of deaths in definite/probable cases of vcjd in the united kingdom was (the national creutzfeldt-jakob disease surveillance unit ). only a few numbers of vcjd were reported from other european countries and the united states (who ). nipah virus encephalitis was first observed in / in malaysia. the disease was transmitted by pigs to laborers in slaughterhouses and showed a lethality of %. the infectious agent was detected in (chua et al. ; lam and chua ) . since then, several outbreaks of nipah virus infections have been observed in asian countries: singapore in , india , and bangladesh since (who a harit et al. ) . the virus has been isolated repeatedly from various species of fruit bats, which seem to be the natural reservoir (yob et al. ). west nile is a mosquito-borne flavivirus that was first isolated from a woman with a febrile illness in uganda in . from the s, west nile fever endemicity and epidemics started being reported from africa and the middle east. severe neurological symptoms were thought to be rare. more recent epidemics in northern africa, eastern europe, and russia suggested a higher prevalence of meningoencephalitis with case fatality rates of - %. in , west nile virus was identified as the cause of an epidemic of encephalitis at the east coast of the united states (nash et al. ) . a seroepidemiological household-based survey showed that the first outbreak consisted of about , infections of which about , developed fever and less than % experienced neurological disease ). since then, epidemics occur during summer months in north america each year, with an estimated , febrile illnesses and over , encephalitis or meningitis cases in the united states in (centers for disease control ). age above years is the main risk factor for developing severe disease. the virus is transmitted mainly by culex mosquitoes, but also by sandflies, ceratopogonids, and ticks, with birds as reservoir hosts and incidental hosts such as cats, dogs, and horses. efforts are made to reduce the transmitting mosquito population and to prevent mosquito bites through personal protection as well as to prevent transmission through blood donations by screening (centers of disease control ). the first case of sars occurred in guangdong (china) in november of , leading to an outbreak with cases in china and hong kong ( cases worldwide) until july . the case fatality rate was . %. a new coronavirus (sars-cov) was identified as the causative agent (drosten et al. ) , being transmitted first by infected semidomesticated animals such as the palm civet and subsequently from human to human. some cases were exported to other countries, causing smaller outbreaks there, canada being the most affected country outside asia with cases, before control of transmission was effective. eight thousand and ninety-six cases were reported worldwide, until july , then further transmission stopped (besides one more case of laboratory transmission in ), indicating an efficient international cooperation in disease control (who b) . recently, sars-cov has been found in horseshoe bats, which seem to be the natural reservoir of the virus. about , - , cases of hemorrhagic fever with renal syndrome (hfrs) caused by hantaviruses are reported annually worldwide, with more than half in china, many from russia and korea, and numerous cases from japan, finland, sweden, bulgaria, greece, hungary, france, and the balkan with different death rates depending on the responsible virus, ranging from . % in puumala to - % in hantaan infections (schmaljohn and hjelle ) . hantaviruses are transmitted from rodent to rodent through body fluids and excreta. only occasionally do humans get infected. different types of hantaviruses are circulating in europe and the eastern hemisphere, predominantly puumala virus, dobrava virus, and tula virus, adapted to different mouse species. depending on the virus type the case fatality rate is between and %. as an example, the annual rate of reported cases in germany was about cases per year from onward. this started to change in with reported cases and rose dramatically to cases in . that year, hantavirus infections were among the five most reported viral infections in germany. reasons for the rise in human infections were an increase in the hosting rodent population due to a very mild winter / and an early start of warm temperatures in spring which led to favorable nutritional situations for the mice influencing their population dynamics. in addition, favorable climatic conditions enhanced the outdoor behaviors of humans facilitating transmission in rural areas (robert koch institute b; hofmann et al. ) . since , a previously unknown group of hantaviruses (sin nombre, new york, black creek canal, bayou-in the united states and canada; andes, in south america) emerged in the americas as a cause of hantavirus pulmonary syndrome (hps), an acute respiratory disease with high case fatality rates (approx. %), causing a new, significant public health concern. a total of cases had been reported until march in states, most of them in the western part of the united states (centers for disease control ). lassa virus was detected for the first time in during an outbreak affecting nurses in a missionary hospital in lassa, nigeria. however, the disease had previously been described in the s. lassa virus is enzootic in a common peridomestic rodent in west africa, the multimammate rat mastomys natalensis, which is chronically infected and sheds the virus in urine and saliva. human infection through direct or indirect contact with rats or their excretions is rather common in some west african countries and estimates from seroepidemiological and clinical studies suggest that there are several hundred thousand cases annually. however, only a minority of infections seems to progress to severe hemorrhagic disease with a case fatality rate of - % in hospitalized cases. the virus can be transmitted by close person-to-person contact and nosocomial spread has been observed under poor hygienic conditions. marburg and ebola viruses, which were first detected during outbreaks in and , respectively, have so far been observed only during several limited outbreaks and a few isolated cases in certain countries of sub-saharan africa. however, very high case fatality rates ( - %), the occurrence of outbreaks that were difficult to control in resource-poor settings, and the obscure origin of these viruses have attracted considerable public interest worldwide. recently, evidence was found for both marburg and ebola viruses to occur in certain species of bats that probably constitute the natural reservoir of these filoviruses (towner et al. ). although the disease burden of these viral hemorrhagic fevers is low, they gained considerable international attention due to -their high case fatality rates, -the risk of person-to-person transmission, -several imported cases to industrialized countries, and -fears of abuse of these agents for bioterrorism. as a consequence, considerable resources have been invested, even in nonendemic countries, in the setting up of task forces and high containment facilities for both laboratory diagnostic services and treatment of patients using barrier nursing. this highly virulent strain of c. difficile expresses both cytotoxins a and b and, in addition, the binary toxin cdt, an adp-ribosyltransferase. due to a deletion in the regulatory tcdc gene, the synthesis rates of toxin a and b are increased by -and -fold, respectively. this strain was detected in for the first time in pittsburgh, usa. since then it has spread to canada, and in it reached europe causing multiple outbreaks in hospitals and nursing homes (warny et al. ) . c. difficile -associated colitis has shown high case fatality rates ( - %) and an increased relapse rate. containment of outbreaks in hospitals and other institutions necessitates isolation of patients or cohorts and strict hygienic measures. during recent decades, a large variety of well known infectious diseases has shown regional or global re-emergence with considerable public health relevance (table . ). globally, tuberculosis is probably the most important re-emerging infectious disease. in developing countries, tb infection still is extremely common and, in the wake of the hiv pandemic, the percentage of those developing overt disease has increased dramatically. worldwide, tb is the most common opportunistic infection in patients with aids. the significance of tb and hiv/tb coinfection is reviewed in chapters and . the re-emergence of some infectious diseases is closely related to the lack or the breakdown of basic infrastructures as seen in periurban slums and in refugee camps in developing countries, or as a consequence of war, breakdown of the civil society, or natural or man-made disasters. cholera is a formidable example for both re-emergence and epidemic spread under those conditions. another important group of re-emerging infectious diseases is caused by various vector-borne infections, such as malaria, dengue fever, and yellow fever. these major vector-borne diseases are treated in more detail in chapter . in addition, there are a variety of re-emerging infections transmitted by arthropod vectors such as various arboviral diseases and some protozoal diseases other than malaria (i.e., leishmaniasis, human african trypanosomiasis). the reasons for the emergence of several vector-borne diseases are rather variable and may range from climatic factors (e.g., global warming, rainfall), lack or breakdown of control, to changes in agriculture and farming and in human behavior (e.g., outdoor activities). these factors are usually quite specific for each of these diseases and largely depend on the specific ecology of the agent, its vectors, and reservoirs. cholera, an acute diarrheal infection transmitted by fecally contaminated water and food, had been endemic for centuries in the ganges and brahmaputra deltas in the th century before it started to spread to the rest of the world. since , six pandemics caused by the classical biotype of vibrio cholerae were recorded that killed millions of people across europe, africa, and the americas. it has been a major driving force for the improvement of sanitation and safe water supply. the seventh pandemic was caused by the el tor biotype, first isolated from pilgrims at the el tor quarantine station in sinai in . it started in in south asia, reached africa in , and is still ongoing. after more than hundred years, cholera spread to the americas in , and beginning in peru, a large epidemic hit numerous latin american countries with . million cases and more than , fatalities reported within years. out of the serogroups of v. cholerae, only o and o can cause epidemics. the serogroup o , first identified in bangladesh in , possesses the same virulence factors as o and creates a similar clinical picture. currently, the presence of o has been detected only in southeast and east asia, but it is still unclear whether v. cholerae o will extend to other regions. since , the re-emergence of cholera has been noted in parallel with the everincreasing size of vulnerable populations living in unsanitary conditions. cholera remains a global threat to public health and one of the key indicators of social development. while the disease is no longer an issue in countries where minimum hygiene standards are met, it remains a threat in almost every developing country. the number of cholera cases reported to the who during rose dramatically, reaching the level of the late s. a total of , cases were notified from countries, including , deaths, an overall increase of % compared with the number of cases reported in . this increased number of cases is the result of several major outbreaks that occurred in countries where cases had not been reported for several years such as sudan and angola. it is estimated that only a small proportion of cases -less than % -are reported. the true burden of disease is therefore grossly underestimated. the absence or the shortage of safe water and sufficient sanitation combined with a generally poor environmental status are the main causes of spread of the disease. typical at-risk areas include periurban slums where basic infrastructure is not available, as well as camps for internally displaced people or refugees where minimum requirements of clean water and sanitation are not met. however, it is important to stress that the belief that cholera epidemics are caused by dead bodies after disasters, whether natural or manmade, is false. on the other hand, the consequences of a disaster-such as disruption of water and sanitation systems or massive displacement of population to inadequate and overcrowded camps-will increase the risk of transmission. chikungunya virus, an arbovirus belonging to the alphavirus group, is transmitted by various mosquitoes. the virus was first isolated in tanzania in and since then has caused smaller epidemics in sub-saharan africa and parts of asia with low public health impact. in , the largest epidemic ever recorded started in east africa, spread to réunion and some other islands of the indian ocean, and then spread further to asia, with more than . million cases in india alone so far. characteristics of the disease are high fever and a debilitating polyarthritis, mainly of the small joints that can persist for months in some patients. now, for the first time, severe and fatal cases have been observed that may be due to certain mutations of the epidemic strain (parola et al. ) . the asian tiger mosquito aedes albopictus has proved to be an extremely effective vector in recent epidemics causing high transmission rates in big cities and leading to epidemics with high public health impact. this southeast asian mosquito species has been shipped by transport of used tires and plants harboring water contaminated with larvae to other continents and, since , ae. albopictus has successfully spread in italy and other parts of southern europe. in august , an outbreak of chikungunya fever occurred in northern italy with more than confirmed cases. the index case was a visitor from india who fell ill while visiting relatives in one of the villages and further transmission was facilitated by an abundant mosquito population during that time, as a consequence of seasonal synchronicity (rezza et al. ). ross river virus (rrv) is another arbovirus of the alphavirus group that causes an acute disease with or without fever and/or rash. most patients experience arthritis or arthralgia primarily affecting the wrist, knee, ankle, and small joints of the extremities (epidemic polyarthritis). about one-quarter of patients have rheumatic symptoms that persist for up to a year. the disease can cause incapacity and inability to work for months. it is the most common arboviral disease in australia with an average of almost , notified cases per year. rrv is transmitted by various mosquito species and circulates in a primary mosquito-mammal cycle involving kangaroos, wallabies, bats, and rodents. a human-mosquito cycle may be present in explosive outbreaks which occur irregularly during the summer months in australia and parts of oceania. heavy rainfalls as well as increasing travel and outdoor activities are considered as important factors contributing to the emergence of rrv epidemics. this flavivirus is transmitted by certain culex mosquitoes and is a leading cause of viral encephalitis in asia with , - , clinical cases reported annually. it occurs from the islands of the western pacific in the east to the pakistani border in the west, and from korea in the north to papua new guinea in the south. only in - infections will lead to encephalitis, which is, however, often severe with fatality rates of - % and with a high incidence of neurological sequelae. despite the availability of effective vaccines, je causes large epidemics and has spread to new areas during recent decades (e.g., india, sri lanka, pakistan, torres strait islands, and isolated cases in northern australia). je is particularly common in areas where flooded rice fields attract water fowl and other birds as the natural reservoir and provide abundant breeding sites for mosquitoes such as culex tritaeniorhynchus, which transmit the virus to humans. pigs act as important amplifying hosts, and therefore je distribution is very significantly linked to irrigated rice production combined with pig rearing. because of the critical role of pigs, je presence in muslim countries is low. crimean-congo virus is a bunyavirus causing an acute febrile disease often with extensive hepatitis resulting in jaundice in some cases. about one-quarter of patients present hemorrhages that can be severe. fatality rates of . - % have been reported in hospitalized patients. cchf is transmitted by hyalomma ticks to a wide range of domestic and wild animals including birds. human infection is acquired by tick bites or crushing infected ticks, and also by contact with blood or tissue from infected animals that usually do not become ill but do develop viremia. in addition, nosocomial transmission is possible and is usually related to extensive blood exposure or needle sticks. human cases have been reported from more than countries in africa, asia, southeastern europe, and the middle east. in recent years, an increase in the number of cases during tick seasons has been observed in several countries such as russia, south africa, kosovo, and greece. in turkey, where before no human cchf cases had been observed, a total of , confirmed cases, including deaths, were reported between and june . the emergence of cchf has been associated with factors such as climatic features (temperature, humidity, etc.), changes of vector population, geographical conditions, flora, wildlife, and the animal husbandry sector. rvf is a mosquito-borne bunyavirus infection occurring in many parts of sub-saharan africa. it infects primarily sheep, cattle, and goats, and is maintained in nature by transovarial transmission in floodwater aedes mosquitoes. it has been shown that infected eggs remain dormant in the dambos (i.e., depressions) of east africa and hatch after heavy rains and initiate mosquito-livestock-mosquito transmission giving rise to large epizootics. remote sensing via satellite can predict the likelihood of rvf transmission by detecting both the ecological changes associated with heavy rainfall and the depressions from which the floodwater mosquitoes emerge. transmission to humans is also possible from direct and aerosol exposure to blood and amniotic fluids of livestock. most human infections manifest themselves as uncomplicated febrile illness, but severe hemorrhagic disease, encephalitis, or retinal vasculitis is possible. in , rvf has been transported, probably by infected camels to egypt, where it caused major epidemics with several hundred thousand infections of humans. it has been suggested that introduction of rvf may be a risk to other potentially receptive areas such as parts of asia and the americas. floods occurring during the el niño phenomenon of in east africa subsequently gave rise to large epidemics and further spread to the arabian peninsula. most recent epidemics occurred in and following heavy rainfalls in kenya, somalia, and sudan, causing several hundred deaths. besides mosquito control, epidemics are best prevented by vaccination of livestock. leishmaniasis, a protozoal transmitted by sandflies, has shown a sharp increase in the number of recorded cases and spread to new endemic regions over the last decade. presently, countries are affected with an estimated million cases worldwide. there are about . million new cases of cutaneous and mucocutaneous leishmaniasis, a nonfatal but debilitating disease with % of cases occurring in afghanistan, brazil, bolivia, iran, peru, saudi arabia, and syria. the incidence of visceral leishmaniasis (vl), a disease with a high fatality rate when untreated, is estimated at around , per year. the situation is further aggravated by emerging drug resistance (table . ) and the deadly synergy of vl/hiv coinfection. epidemics usually affect the poorest part of the population and have occurred recently in bangladesh, brazil, india, nepal, and sudan. for many years, the public health impact of the leishmaniases has been grossly underestimated. they seriously hamper socioeconomic progress and epidemics have significantly delayed the implementation of numerous development programs. the spread of leishmaniasis is associated with factors favoring the vector such as deforestation, building of dams, new irrigation schemes, and climate changes, but also with urbanization, migration of nonimmune people to endemic areas, poverty, malnutrition, and the breakdown of public health. antimicrobial resistance of epidemiological relevance has emerged as a major problem in the treatment of many infectious diseases (table . ). resistance is no longer a problem that predominantly affects the chemotherapy of bacterial infections. it became increasingly important in parasitic and fungal diseases, and despite the short history of antiviral chemotherapy, it already plays a prominent role in the treatment of hiv infection and other viral diseases. resistance is also a problem in some of the emerging infections and will further complicate their treatment and control. resistance of bacterial pathogens has become a common feature in nosocomial infections, especially in the icu and in surgical wards. currently, the number one problem in most hospitals is s. aureus resistant to methicillin (mrsa, see chapter ). however, common problems of resistance also extend to other major bacterial pathogens such as enterococci, various gram-negative enteric bacilli, and pseudomonas species. resistance has developed not only to standard antibiotics (e.g., penicillins, cephalosporins, aminoglycosides, macrolides, or quinolones) but also to second-line antibiotics including carbapenems, glycopeptides, and newer quinolones. however, there is considerable geographic variation. in , the european antimicrobial resistance surveillance system (earss), a network of national surveillance systems, reported vancomycin-resistant rates among enterococci ranging from none in iceland, norway, romania, bulgaria, denmark, and hungary to % of enterococcus faecium strains in greece (earss ) . a surveillance study conducted in the united states hospitals from to showed that % of nosocomial bloodstream infections were caused by enterococci and that % of e. faecalis isolates and % of e. faecium isolates were vancomycin resistant (wisplinghof et al. ) . rates and spectrum of antibacterial resistance of e. coli and other gram-negative enteric bacilli may differ considerably from one hospital to the other. in some important pathogens of hospital-related infections such as klebsiella, enterobacter, and pseudomonas species, resistance to almost all available antimicrobials has been observed. this may complicate the choice of an effective initial chemotherapy considerably. therefore, each hospital has to monitor the epidemiological situation of resistance regularly, at least for the most important bacteria causing nosocomial infections, such as staphylococci, enterococci, gram-negative enteric bacilli, and pseudomonas. even in community-acquired infections, there has been a considerable increase in resistance problems. at present, approximately % of pneumococcal isolates in the united states are resistant to penicillin, and % exhibit intermediate resistance. the rate of resistance is lower in countries that, by tradition, are conservative in their antibiotic use (e.g., netherlands, germany) and higher in countries where use is more liberal (e.g., france). in hong kong and korea, resistance rates approach %. in addition, about one-quarter of all pneumococcal isolates in the united states are resistant to macrolides. this rate is even higher in strains highly resistant to penicillin, and increasingly there is multiresistance against other antibiotics such as cephalosporins. the prevalence of meningococci with reduced susceptibility to penicillin has been increasing, and high-level resistance has been reported in some countries (e.g., spain, united kingdom). although high-dose penicillin is effective in infections with strains of intermediate resistance, most national and international guidelines recommend broad-spectrum cephalosporins such as ceftriaxone as first-line drugs. however, in most developing countries, penicillin and chloramphenicol are the only affordable drugs. in recent years, certain strains of community-acquired s. aureus with resistance to methicillin (cmrsa) have been observed which produce a toxin (panton-valentine leukocidin) that is cytolytic to pmns, macrophages, and monocytes, and which are an emerging cause of community-acquired cases and outbreaks of necrotic lesions involving the skin or the mucosa, and in some patients also of necrotic hemorrhagic pneumonia with a high case fatality (vandenesch et al. ) . development of resistance is mainly determined by two factors: -the genetic potential of a certain pathogen, i.e., mobile elements such as plasmids, transposons, or bacteriophages, genes coding for resistance, and mutation rate. -the selection pressure caused by the therapeutic or the para-therapeutic application of antimicrobial drugs. in the hospital these factors are supported by -microbial strains that are highly adapted to this environment (e.g., rapid colonization of patients, resistance to disinfectants), -an increasing percentage of patients who are highly susceptible to infections due to old age, multimorbidity, immunosuppression, extended surgery, and invasive procedures, and -the frequent use of broad-spectrum antibiotics or combinations of antimicrobial drugs. another source of resistant bacteria has been identified in mass animal production and the use of antimicrobials as growth promoters (e.g., the glycopeptide avoparcin, the streptogramin virginiamycin) or as mass treatment in the therapy or the prevention of infections. the inadequate use of antimicrobial drugs is also an important factor responsible for the development of resistance in community-acquired infections. this is especially true in developing countries where only a limited spectrum of antibiotics is available, where shortage of drugs often leads to treatment that is underdosed or too short, and where uncontrolled sale and use of antibiotics is commonplace. as a consequence, resistance of gonococci is extremely frequent in southeast asia, and resistance of salmonella typhi, shigella, and campylobacter to standard antibiotics is common. some of the still effective second-line antibiotics have to be given parenterally or are not available because they are too costly. a typical example of the consequences of insufficient chemotherapy due to lack of compliance and/or unavailability of drugs is the alarming increase in multiresistance and extreme resistance in tb (see chapter ). resistance is also a problem in parasitic diseases such as malaria (see chapter ), leishmaniasis, or african trypanosomiasis. plasmodium falciparum developed resistance against all major antimalarial drugs as soon as they were used on a broad scale. resistance had contributed significantly to the increase in malaria-associated morbidity and mortality observed in many endemic areas (wongsichranalai et al. ) . a recent report on failures of the new artemisinin combination treatment for p. falciparum malaria at the thai-cambodian border supports fears of the development of resistance to this most promising class of drug at present (dondrop et al. ). resistance against antiviral drugs has developed almost from the beginning of antiviral chemotherapy (table . ). in the treatment of hiv infection, the risk of development of resistance has been drastically reduced by the combination of several drugs with different mechanisms of action (see chapter ). however, drug resistance remains the achilles' heel of the highly active antiretroviral therapy (haart) and may be at a considerable risk of expanding haart to the developing world. today, we have to realize that as we develop antimicrobial drugs, microbes will develop strategies of counterattack. antimicrobial resistance occurs at an alarming rate among all classes of pathogens. even in rich countries it causes real clinical problems in managing infections that were easily treatable just a few years ago. in life-threatening infections such as sepsis, nosocomial infections, or falciparum malaria, there is a substantial risk that the initial chemotherapy might not be effective. in addition, the delay caused by inadequate treatment might favor transmission to other people and support the spread of resistant pathogens (e.g., multiresistant tb). last but not the least, surveillance and control and the necessity to use expensive second-line drugs or combinations of antimicrobials are enormous cost factors. for developing countries this is a major limitation in the treatment and control of infections caused by resistant agents. so, in many ways, emerging resistance contributes to the emergence of infectious diseases. despite the availability of effective strategies for treatment and prevention, infectious diseases have remained a major cause of morbidity and mortality worldwide. however, the problems associated with infections are due to considerable changes. in industrialized countries the mortality caused by infectious diseases has decreased tremendously during more than years. however, during recent years, both mortality and morbidity associated with infections are increasing again. ironically, this is closely associated with the advances in medicine which have contributed to profound changes in the spectrum of both patients and their infections. advanced age, underlying conditions, and an altered immune response are common features in the seriously infected hospital patient today. immunosuppressive therapy is frequently used to treat neoplastic and inflammatory diseases or to prevent the rejection of transplants. some infections, most notably hiv/aids, cause immunosuppression by itself. in the compromised patient, infections are generally more severe or may be caused by opportunistic pathogens that will not harm the immunocompetent host. antimicrobial treatment is often less effective in these patients and tends to be further complicated by antimicrobial resistance which may manifest itself or develop at a higher frequency in the immunocompromised patient. an increasing percentage of infections are hospital acquired or otherwise health care associated. it is estimated that nosocomial infections affect . million patients and contribute to approximately , deaths in us hospitals annually (klevens et al. ). considering the rising number of elderly and immunocompromised patients, a further increase in severe infections can be predicted. in developing countries, the significance of infectious diseases has remained high for ages and despite the advances in medicine. until now, infections are by far the leading cause of both disability-adjusted life years and life years lost. the reasons are obvious and mostly related to poverty and lack of development causing poor and unhealthy living conditions, inadequate health systems, and lack of resources for prevention and treatment. this is, of course, just an integral part of the general socioeconomic problems of developing countries. however, poor health conditions per se are an important obstacle to development, and infections such as hiv/aids in sub-saharan africa can be a major cause of lack of development, increasing poverty, and political instability. generally, the situation of many developing countries has not improved during the last two decades, and the gap between the first and the third world has increased. however, most of the mortality and morbidity associated with infectious diseases is avoidable. as laid down in the millennium goals, a major task of the world community will be to counteract the imbalance between the industrialized and the developing countries and to find strategies to ensure participation in the progress of modern medicine for all. developing countries also carry the main burden of diseases caused by newly emerging and re-emerging infections (table . and . ) . however, the consequences of economical and political crises on emerging infectious diseases are obvious in industrialized countries also-such as the return of diphtheria or the increase in tb and multiresistant tb after the breakdown of the former soviet union. today, all countries worldwide are affected by emerging infections as well as by emerging antimicrobial resistance. in the age of globalization, travel and transport of people, animals, and goods of all kinds have increased tremendously. as a consequence, infectious agents may travel over long distances and at high speed. this is clearly evident with influenza pandemics or outbreaks such as the sars epidemic or with imported cases of viral hemorrhagic fever transmissible from person to person. the spread of antimicrobial resistance or the re-emergence of tb seems to be less spectacular, but the consequences may be at least as important in the long run. management and control of emerging and re-emerging infectious diseases can be very different from disease to disease and has to allow for all relevant factors of the populations at risk and of the specific disease including the ecology of the agent, its vectors, and reservoirs. however, some basic principles apply to all situations: -surveillance -information and communication -preemptive planning and preparedness -provision and implementation of • adequate treatment • adequate control and prevention -international cooperation active and passive surveillance systems with rapid reporting and analysis of data are essential for the early detection of outbreaks, changes in epidemiology, and other events of public health concern (see chapters and ). however, many resourcepoor countries do not have functional surveillance systems. in addition, reporting of infectious diseases may be neglected or delayed because of fears of stigma, international sanctions including trade and travel restrictions, or interference with tourism. classical examples are plague and cholera, but also recent examples such as the bse/vcjd crisis in the united kingdom or sars originating from china showed undue delays between first occurrence of cases and information to the public. although, in outbreaks of new and unknown diseases it may be difficult, or even impossible, to predict or assess the magnitude of the problem and the potential consequences, timely and adequate information and communication is not only obligatory, according to international regulations, but also the best strategy to avoid rumors, misbeliefs, panic, or disregard. in recent years, many countries have installed national plans of action for important epidemiological scenarios and outbreaks such as pandemic influenza, bioterrorism, import of viral hemorrhagic fevers transmissible from person to person, sars, and comparable diseases or outbreaks. all member states of the world health assembly that have so far not been able to install functional surveillance and/or pre-emptive planning are obliged to do so within a maximum of years after their ratification of the new international health regulations (who ) . preparedness not only means surveillance and planning but also has to include the provision of facilities to adequately treat and, if necessary, to isolate patients with infectious diseases of public health importance and relevant epidemic potential and/or at risk of transmission to other persons including health-care workers. task forces and high containment facilities for both laboratory diagnostic services and treatment of patients using barrier nursing have been set up in several countries. however, all health facilities of a certain level such as general hospitals should be prepared by their organization and structure to treat patients with infections of public health relevance such as multiresistant tb under appropriate isolation and barrier nursing conditions. this also applies to hospitals in resource-poor countries. adequate training of health-care workers and strict management have been effective to control outbreaks of highly contagious infections within rural african hospitals lacking sophisticated technical equipments (cdc ) . strategies for control and prevention may be quite different for various emerging infections. effective vaccinations are available only for some infections and are usually lacking for newly emerging infections (table . ). for the majority of emerging infections, control and prevention have to rely on information, education and exposure prophylaxis, interruption of transmission by vector control and control of reservoir hosts (e.g., rodents), and case finding with early diagnosis and treatment. for diseases and outbreaks caused by infections of public health relevance that are transmissible from person to person, containment procedures including isolation and treatment of patients under condition of barrier nursing as well as tracking and surveillance of contacts are warranted by national and international health regulations. here, international cooperation is essential to successfully contain outbreaks and epidemics such as the sars epidemic in . despite dramatic progress in their treatment and prevention, infectious diseases are still of enormous global significance with tremendous economic and political implications. emerging and re-emerging infectious diseases as well as emerging antimicrobial resistance are major challenges to all countries worldwide. for the management of current and future problems, it will be most important to counteract the imbalance between the industrialized world, new economies, and developing countries, and to adequately and timely react to new threats on a global scale. a new type of papillomavirus dna, its presence in genital cancer and in cell lines derived from genital cancer world health organization: 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hantavirus-erkrankungen erreichte in deutschland einen neuen höchststand prevalence and determinants of helicobacter pylori infection in preschool children: a population-based study from germany hantaviruses: a global disease problem safety and efficacy of a recombinant hepatitis e vaccine tick-borne diseases in the united states the national creutzfeld-jakob disease surveillance unit (ncjdsu) marburg virus infection detected in a common african bat community-acquired methicillin-resistant staphylococcus aureus carrying panton-valentine leukocidin genes: worldwide emergence multiple exposures during a norovirus outbreak on a river-cruise sailing through europe toxin production by an emerging strain of clostridium difficile associated with outbreaks of severe disease in north america and europe prevalence of borrelia burgdorferi antibodies in hamburg blood donors nipah virus outbreaks in bangladesh revision of the international health regulations nosocomial bloodstream infections in us hospitals: analysis of cases from a prospective nationwide surveillance study large outbreak of norovirus: the baker who should have known better epidemiology of drugresistant malaria nipah virus infection in bats (order chiroptera) in peninsular malaysia key: cord- -ujflw b authors: newcomer, benjamin w.; cebra, chris; chamorro, manuel f.; reppert, emily; cebra, margaret; edmondson, misty a. title: diseases of the hematologic, immunologic, and lymphatic systems (multisystem diseases) [image: see text] date: - - journal: sheep, goat, and cervid medicine doi: . /b - - - - . - sha: doc_id: cord_uid: ujflw b nan in this chapter, multisystemic diseases are discussed in small ruminants (sheep, goats, and cervids). these include diseases of the hematologic, immunologic, and lymphatic systems. in general, species will be discussed together, but when pertinent data are available, each species will be considered separately. the terms "cervid" and "deer" have been used interchangeably in parts of this chapter by the authors. an adequate volume of blood for hematologic and biochemical analysis is best obtained from the jugular vein. a docile animal may be restrained in a standing position or tipped up (sheep only) with the head turned away from the jugular vein to be used. wilder ones, such as some cervids, may require restraint devices or chemical sedation. ideally, the animal should be restrained by someone other than the blood collector, although the same person may be able to both restrain a sheep and collect blood if the animal is tipped up or a halter is used (see chapter ) . the animal should be at rest, with minimal excitement. the collector parts or clips the wool or hair to visualize the jugular vein and then uses the hand not holding the needle to apply digital pressure proximally just above the thoracic inlet to block blood movement through the vein. the vessel may take a second or more to distend after pressure is applied. the collector may then use the needlebearing hand to "strum" the vessel and cause the blood to oscillate. if in doubt about whether the distended vessel is the jugular vein, the collector can release the hand placing pressure on the vessel and observe whether the distended vessel disappears; if it does, the distended vessel was probably the jugular vein. the collector should avoid vessels that pulsate because these are likely to be the carotid arteries. the area should be cleaned with alcohol or other disinfectant, water, or a clean, dry gauze sponge. an -or -gauge, -to . -inch needle is usually adequate to collect blood from an adult, whereas a -gauge needle may be used in a neonate. the skin of adults or males may be thicker and more difficult to penetrate with the needle. a syringe or evacuated tube attached to a vacutainer (becton dickinson inc., rutherford, nj) can be used to collect blood. the needle should be plunged through the skin into the vein at an approximate -degree angle. the blood should not come out of the vessel in pulsatile waves; this is suggestive of an arterial stick. after aseptically obtaining an adequate volume of blood, the collector removes the needle and releases the pressure on the vessel near the thoracic inlet. pressure should be applied to the site of puncture for a minute or more to prevent extravascular leakage of blood and hematoma formation. the blood should be carefully transferred to a vial containing the appropriate anticoagulant to prevent red blood cell (rbc) rupture. goat erythrocytes are small and particularly prone to hemolysis. to minimize this problem, goat blood should be collected with a needle and syringe, not a vacutainer. white blood cell (wbc) differential distribution, individual blood cell staining characteristics, and morphology may be assessed by microscopic examination of a stained blood film. the differential distribution provides more information than total wbc count because inflammatory conditions in artiodactyls often result in a shift in neutrophil populations toward more degenerate, toxic, or immature forms without changing the overall wbc count. the preferred anticoagulant for a complete blood count (cbc) is ethylenediaminetetraacetate (edta), and tubes should be filled to ensure the proper blood-to-anticoagulant ratio. blood samples should be processed as soon as possible after collection. if a delay is anticipated, the blood sample should be refrigerated ( ° c) and an air-dried blood smear should be made because prolonged contact of blood with edta causes changes in wbc morphology and the separation of some rbc parasites. blood can be refrigerated for hours and still yield an accurate cbc. a reference range for hematologic data for sheep and goats is provided in table . (see appendix , tables and ) . goats tend to have a low mean corpuscular volume (mcv) because of their small erythrocytes. sheep and goats younger than months old tend to have lower hematocrit, rbc count, hemoglobin, and plasma protein concentrations, as well as a higher total wbc count. neonates often have a high hematocrit at birth that decreases with colostral ingestion. lactating animals may have decreased hematocrits, rbc counts, and hemoglobin concentrations. animals grazing at high altitude (mountain goats and bighorn sheep) tend to have increased rbc counts, hematocrits, and hemoglobin concentrations. interpreting hematologic changes in cervids is more complex. restraint method affects a variety of parameters in non-acclimated individuals. physical restraint yields red cell counts and hematocrit and hemoglobin concentrations that are to % higher than animals immobilized chemically. , neutrophil, lymphocyte, monocyte, and total white cell counts are also to % higher in physically restrained cervids (see appendix , tables and ) . adult deer also have seasonal variations in their hemogram. red cell numbers and related values are highest during midsummer and late winter. white cells, especially neutrophils, are also highest in midsummer, and platelet counts are highest in spring and fall. these changes may relate to diet or to seasonal activities, such as antler growth and rutting conflicts, which increase the chance of trauma. red cell stickling has also been reported in a variety of deer species. this appears to relate to a mutation in hemoglobin's b-globin component, similar to the disorder in people, but no pathologic role has been described. bone marrow aspirates and core biopsy samples taken from sites of active erythropoiesis can be useful to evaluate erythrocyte production and determine the cause of anemia and other hemogram abnormalities. the sites of biopsy include the sternebrae, femur, and ileum. the procedure should be done under chemical sedation or anesthesia (see chapter ) . the area over the biopsy site is clipped and surgically prepared; the sampler should wear sterile gloves to maintain asepsis. aspirates can be obtained by inserting a sterile needle attached to a -or -cc syringe containing one or two drops of edta through the bone and into the bone marrow. drawing back on the syringe plunger several times may aid in the procurement of an acceptable sample; such a sample may consist of as little as . ml of bone marrow. if the sample is going to be processed immediately, no anticoagulant is required. core biopsies are obtained using a jamshidi or westerman-jensen biopsy needle. the skin is incised with a scalpel and the biopsy needle is inserted into the bone and turned several times to obtain a core sample. more than one site may be used. the sampler then closes the skin with sutures or staples. biopsy samples are preserved by placing them in % neutral buffered formalin solution. impression smears can be made from these samples by gently rolling them on a clean glass slide before placing them in the formalin solution. information obtained from bone marrow samples includes subjective data regarding cell density, megakaryocyte numbers, abnormal cells, maturation patterns of rbcs and wbcs, and the ratio of erythroid to myeloid cells. prussian blue stain can be used on bone marrow to demonstrate iron stores. bone marrow aspirates and biopsies are painful and invasive procedures. therefore, animals should be placed on antibiotics and antiinflammatory drugs prophylactically. blood cultures can be useful in diagnosing bacteremia in an intermittently or persistently febrile animal or one with numerous sites of organ infection. ideally, the clinician should obtain the sample before instituting antimicrobial therapy. however, if this is impossible, antimicrobial therapy should be discontinued to hours before sampling. samples should be taken before and during febrile episodes. the jugular vein is most commonly used to attain a blood culture. as described previously, the skin over the jugular vein should be clipped and surgically prepared. the person collecting the blood sample should wear sterile gloves and use a sterile needle and syringe. blood samples should be placed immediately in a blood culture flask. the chances of attaining a positive culture from bacteremic animals increase with the size of the sample up to about ml, but adding more than the recommended amount to any single culture vial may overwhelm the capacity of the specialized antibiotic-absorbing resins within the flasks. the clinician should change the needle on the sample syringe after collecting the blood and before putting the sample in the culture medium. samples should be refrigerated until they can be sent to a diagnostic laboratory, where aerobic and sometimes anaerobic cultures are made. as an alternative to hematologic testing, comparing conjunctival color to swatches on a standardized famacha chart has been used as a rapid and inexpensive assessment of anemia in whole flocks, primarily to assess the impact of haemonchus contortus and other blood-sucking parasites. , results from a number of trials have yielded fair to good sensitivity to packed cell volume and h. contortus load in both sheep and goats. similar to body condition scoring systems, it is essential to calibrate assessors to ensure consistency when using this system. also, some breeds hematocrit (%) - - hemoglobin (g/dl) - . [ ] [ ] [ ] [ ] [ ] red blood cell count ( /ml) - . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] mean corpuscular volume (fl) - - mean corpuscular hemoglobin concentration (g/dl) - [ ] [ ] [ ] [ ] [ ] [ ] [ ] platelet count ( /ml) . - . . - . total white blood cell count (/ml) - , - , segmented neutrophils (/ml) - - band neutrophils (/ml) lymphocytes (/ml) - - monocytes (/ml) - - eosinophils (/ml) - - basophils (/ml) - - total plasma protein (g/dl) . - . . - . fibrinogen (mg/dl) - read differently on the cards, and use of an electronic color analyzer, while more expensive and less field-friendly, may detect anemia earlier (see chapter , figure . a, b, and chapter ) . easy use of this technique in deer is limited by their intractability and has not been reported. the most common and significant abnormality of the hemogram is anemia. anemia occurs most commonly after blood loss, hemolysis, or chronic disease. blood loss is usually covert and commonly caused by gastrointestinal or external parasites. overt blood loss is usually caused by major trauma such as that caused by dog bites, severe lacerations, male rivalry fighting, or complications of castration or dehorning. cbc values appear normal immediately after acute blood loss. however, after a few hours of fluid redistribution, anemia and hypoproteinemia are evident. evidence of red cell regeneration (macrocytosis, reticulocytosis, and nucleated red cells) should appear within a day or two of the blood loss. hemolysis occurs most commonly after ingestion of toxic plants, rbc parasitism, intravenous (iv) injection of hypotonic or hypertonic agents, contact with bacterial toxins, water intoxication, or immune-mediated destruction of opsonized erythrocytes. ingested toxins include sulfur compounds from onions and brassica plants (kale and canola), [ ] [ ] [ ] [ ] nitrates, nitrites, and copper. [ ] [ ] [ ] [ ] except for that caused by copper, hemolysis usually occurs within a day or two after ingestion. copper toxicosis can occur after acute overingestion but more commonly is seen in animals that are chronically overfed copper and suffer some stressful event. goats are more tolerant of excess copper than sheep are, and certain breeds of sheep, particularly the suffolk, are highly sensitive to copper toxicosis (see chapters and ) . hemolytic bacterial toxins include those from clostridium perfringens type a, clostridium haemolyticum, and leptospira interrogans. , intraerythrocytic parasites include anaplasma species, mycoplasma (eperythrozoon) species, and babesia species. [ ] [ ] [ ] [ ] [ ] immune-mediated rbc destruction is very uncommon except with parasitemia, the administration of certain drugs (penicillin), or bovine colostrum to small ruminant neonates. rapid reduction of plasma osmolality can lead to osmotic lysis of erythrocytes. this can occur locally as a sequela to rapid iv injection of hypotonic substances or after ingestion of a large quantity of water following a period of water deprivation and dehydration (water intoxication). selenium and copper deficiency have also been associated with heinz body anemia. parasite infestation, opsonization, and ingestion of toxic plants typically cause extravascular hemolysis. in these cases, damaged erythrocytes are removed by cells of the reticuloendothelial system, resulting in anemia, pallor, weakness, depression, icterus, and dark urine. bacterial toxins, changes in plasma osmolality, and copper toxicosis cause intravascular hemolysis, resulting in the additional signs of hemoglobinemia and hemoglobinuria. other signs such as fever, neurologic symptoms, and sudden death may be seen with specific diseases. signs of regeneration should be seen on the hemogram to days after the onset of hemolysis. anemia that is not related to the loss or destruction of erythrocytes usually results from a lack of production and thus are nonregenerative. although mild forms may exist in pregnant sheep and goats and those deficient in vital minerals (e.g., iron, selenium, copper, and zinc), the most common cause of nonregenerative anemia is chronic disease. under these conditions, iron is sequestered in an unusable form in the bone marrow; staining a marrow sample with prussian blue stain reveals large iron stores, differentiating this disease from iron-deficiency anemia. the causes of anemia of chronic disease are numerous and include infectious conditions (e.g., pneumonia, foot rot, and caseous lymphadenitis), malnutrition, and environmental stressors. most anemia does not require treatment. unless loss of rbc mass is rapid and severe, the animal is usually able to compensate to the decreased oxygen-carrying capacity by decreasing activity. it is important to remember in this regard that anemia often first becomes apparent to the manager of a flock or herd when animals appear overly stressed or die during movement or handling. if possible, the cause of the anemia should be addressed. this can involve trying to control internal and external parasites, changing the diet, and treating infectious diseases. maintaining adequate hydration is essential in animals with intravascular hemolysis to avoid hemoglobin-induced renal tubular damage. specialty compounds such as molybdenum salts, such as ammonium molybdate, and sulfur or penicillamine for copper toxicosis and methylene blue ( mg/kg in a % solution in % dextrose or normal saline intravenously) for nitrate toxicity are usually too expensive or difficult to be used on a flock-wide basis but may be useful in valuable individual animals. veterinarians should be aware that methylene blue is no longer approved for use in food-producing animals. animals with severe acute blood loss or hemolysis may benefit from a whole blood transfusion. because transfusion reactions are rare and strong erythrocyte antigens have not been identified in small ruminants (including cervids), almost any donor of the same species is acceptable for a first transfusion. cross-matching can be done to ensure compatibility, which becomes more important if the animal receives more than one transfusion. blood should be withdrawn aseptically from the donor and collected by a bleeding trocar into an open flask or by a catheter into a special collection bag. blood should be mixed at a . : ratio with acid-citrate dextrose, or : with % sodium citrate, or another suitable anticoagulant and administered through a filtered blood administration set. if the jugular vein is not accessible, blood may be infused into the peritoneal cavity, but the slower absorption from that site makes it less effective for treating acute blood loss. the first to minutes of administration should be slow. if no reaction is seen (fever, tenesmus, tachypnea, tachycardia, and shaking), the rate may be increased. transfused erythrocytes may only survive a few days, and therefore, the original cause of the anemia must be addressed. peripheral wbcs include granulocytes (neutrophils, eosinophils, and basophils) and mononuclear cells (lymphocytes and monocytes). immature forms of neutrophils and lymphocytes may be seen during severe inflammatory diseases. abnormalities of the neutrophil line are usually the best cellular evidence of inflammation in small ruminants, and inflammation is almost always a sequela of infection. an increase in neutrophil numbers and their proportional contribution to the total wbc count is usually seen in mild gram positive, subacute, or chronic bacterial infections. animals with more severe disease may exhibit high or normal counts, but a greater proportion of the neutrophils will have toxic changes or be immature forms (band cells, metamyelocytes, or myelocytes). in severe, acute inflammation and many diseases caused by gram negative bacteria, a temporary reduction in neutrophil numbers is observed, often with a concurrent shift toward more toxic or immature forms. if the animal survives the peracute disease, neutropenia should resolve over to days, first through an increase in immature cells, and later through a mature neutrophilic response. another important cause of increased total and relative neutrophil counts is stress (or glucocorticoid administration), which inhibits neutrophil margination and extravasation and thereby increases the number of these cells in the midstream blood. increases in eosinophil counts are usually related to exposure to eukaryotic parasites. decreases are rarely of clinical significance and may be part of the stress response. idiopathic allergic-type reactions also are indicators of pathology but are very rare. increases in basophils are rarely clinically significant. increases in lymphocyte counts often reflect chronic inflammatory disease such as that seen with internal abscesses. in rare cases, lymphocytosis may consist of abnormal, blast-type cells and indicate a lymphoproliferative neoplasm. lymphopenia is an important part of the stress response; nevertheless, the clinician must keep in mind that many diseases stimulate a stress response. therefore, lymphopenia and neutrophilia may represent either stress or inflammation, and an examination of neutrophil morphology and plasma fibrinogen concentrations may be useful in distinguishing the two situations. a high fibrinogen concentration, toxic changes, and high counts of immature neutrophils indicate inflammation under those circumstances. blood monocyte counts also may indicate stress or chronic inflammation. the difficulties in interpreting individual cell count abnormalities highlight the importance of obtaining a differential wbc count and description of cellular morphology in assessing sick sheep and goats. leukogram abnormalities are rarely given specific treatment. it is far more common and useful to use the information from the leukogram to develop a plan to treat the disease responsible for the abnormality. palpation of external lymph nodes is part of the thorough physical examination. lymph nodes that can be found in normal sheep and goats include the submandibular, prescapular, and prefemoral nodes. none of these should be prominent or painful on palpation. additional nodes that may be palpated occasionally in normal animals include the parotid, retropharyngeal, supramammary, perirectal, and popliteal nodes. internal lymph nodes that may be identified during specialized diagnostic procedures include the mediastinal, mesenteric, and other abdominal nodes. enlargement of lymph nodes may be focal, multifocal, or generalized. identification of a single enlarged superficial node does not always rule out a multifocal or generalized disorder because the status of the internal nodes often cannot be determined. enlargement generally indicates either inflammation or neoplasia. inflammatory enlargement is generally related to an associated disease with an infectious component. small ruminants are particularly sensitive to lymph node-based infections (e.g., caseous lymphadenitis), so the search often does not extend beyond aspirating or draining the lymph node itself. neoplastic enlargement almost always results from lymphosarcoma. lymphosarcoma pathogenesis. neoplastic transformation of a member of the lymphocyte cell line leads to unregulated clonal expansion of that cell. the cause of transformation is usually unknown; in rare cases, especially in flock outbreaks in sheep, it can be linked to exposure to the bovine leukemia virus, which has occurred experimentally and as a result of the administration of whole blood anaplasma vaccines. whether the bovine leukemia virus can induce lymphosarcoma in goats and cervids is still unclear. multicentric lymphosarcoma has been reported sporadically in white-tailed deer (odocoileus virginiatus) and other deer, but bovine leukemia virus infection has not been diagnosed in cervids. in one study of neoplastic diseases affecting goats from to , lymphoma was identified as the most common neoplasm, accounting for . % of the assessed tumors. in contrast to other species such as cattle, sheep, and horses, lymphomas in goats are predominantly t-cell lymphomas affecting the mediastinum. a recent study attempted to classify the type of lymphoma affecting goats. using immunohistochemistry (ihc), it was determined that % (n ) of affected goats had t-cell lymphoma and only % (n ) had b-cell lymphoma. proliferation of t or b lymphocytes leads to mass lesions and infiltration of viscera. these changes cause physical obstruction (to breathing, blood flow, urination, defecation, etc.), ulceration of mucosal surfaces (blood loss, bacterial invasion), immune system dysfunction, organ failure, and generalized malaise and cachexia. tissue masses may be internal or visible on external examination. clinical signs. clinical signs in affected animals vary according to the type of lymphoma (t-or b-cell) and the location of the masses. t-cell lymphomas in goats are usually localized in the thoracic cavity and/or neck, suggesting thymic origin or homing. in contrast, b-cell lymphomas tend to have a multicentric distribution. lymphoma in small ruminants usually presents with non-specific signs that can mimic other respiratory or gastrointestinal conditions. slowly progressive weight loss is the most common finding. in some cases, generalized peripheral lymphadenopathy and expansile masses are noted ; at first, they usually are presumed to be caseous lymphadenitis abscesses. progressive chemosis and exophthalmos have been reported in a sheep and a goat with multicentric b-cell lymphoma. , most masses form at the sites of internal or external lymph nodes. in sheep, masses in the brain, skin, joint, and lymphoid tissue have been reported. leukemia is rare. the most common abnormalities are those of chronic disease and cachexia and include nonregenerative anemia and hypoalbuminemia. bone marrow examination may reveal clonal expansion of lymphoid precursor cells. in cervids, lymphadenopathy and multifocal masses affecting the heart, blood vessels, kidney, urinary bladder, and peritoneum have been reported. a more recent report described a subcutaneous maxillary mass in a -year-old captive-born, female whitetailed deer. the mass was diagnosed as focal lymphosarcoma with local metastasis. diagnosis. history and clinical signs are important in the diagnosis of lymphoma in small ruminants. age of affected animals ranges from to years and no gender or breed predisposition has been reported. final diagnosis of affected animals is achieved through necropsy, histopathology, and ihc. lesions seen at necropsy include homogeneous white to tan masses that bulge on the cut surface. they may be small or large. less commonly, diffuse paleness of the reticuloendothelial organs is noted. microscopic examination of these tissues reveals infiltrates of abnormal cells of the lymphocyte line. prevention. avoiding exposure to the bovine leukemia virus and restricting the use of instruments to one animal between cleaning procedures may help prevent the spread of lymphosarcoma. in most animals, however, this neoplasm appears to develop spontaneously. pathogenesis. lambs, kids, and fawns are born with functional lymphocytes that can produce endogenous immunoglobulin. these cells develop the ability to respond to foreign antigens in the fetus during mid to late gestation. because of a lack of in utero exposure, however, basal concentrations of immunoglobulin are very low at birth. these cells therefore are naïve to foreign antigens and unable to develop protective immunity through specific cellmediated and immunoglobulin production. additionally, as with other ruminants, no transplacental passage of maternal immunoglobulin to fetal sheep, goats, and fawns occurs. lambs, kids, and fawns depend exclusively on intestinal absorption of maternally derived colostral antibodies, immune cells (t-lymphocytes), and other immune factors to provide a ready supply of specific immunity and allow opsonization of pathogens for the first months of life. adequate passive transfer requires delivery of a sufficient quantity of good-quality colostrum (immunoglobulin g [igg] concentration in mg/ml) into the gastrointestinal tract, as well as adequate absorption of antibodies (timely) from the colostrum into the blood. however, the amount of maternal colostrum produced by the dam, and its composition, as well as the ability of the newborn to stand and nurse in a timely manner, can be affected by several factors. colostrum igg concentration and volume of production can be influenced by breed, age, nutrition, body condition score (bcs) at parturition, and vaccination status of the dam. the igg concentration in colostrum samples from ewes of different breeds can vary between and mg/ml. one study demonstrated that primiparous ewes with low bcs (, . ) at lambing produced less colostrum compared with multiparous ewes with similar bcs. additionally, ewes with higher bcs (. . ) tended to produce higher volumes of colostrum compared with ewes with lower bcs. another study suggested that undernutrition of ewes during late gestation can affect colostrum quality and immune development and function in newborn lambs. it has been suggested that at least g of total igg should be fed to newborn lambs and kids during the first hours of life to reach adequate transfer of passive immunity. adequate transfer of passive immunity in small ruminant neonates has been suggested as serum igg levels at hours of life of  mg/ml. one study indicated that lambs that nurse low-quality colostrum (igg , mg/ml) had lower serum igg concentrations compared with lambs that that nurse colostrum of higher quality (igg . mg/ml), indicating that the concentration of igg in colostrum is a determining factor for the presentation of failure in the transfer of passive immunity. other factors such as pregnancy toxemia, gastrointestinal parasitism, excess of iodine intake during pregnancy, and inadequate vaccination of the dam can result in poor colostrum synthesis and quality. timely consumption of maternal colostrum during the first hours of life is essential to achieve adequate transfer of passive immunity. in small ruminants, cells of the small intestine are able to internalize and transfer igg into the blood during the first hours of life; however, the absorption efficiency of igg is higher during the first to hours of life. , factors associated with the neonate, such as weakness, inability to stand, and congenital abnormalities, will prevent timely nursing of maternal colostrum and lead to failure of passive transfer (fpt). litter size and body weight (bw) of the kid(s) have also been correlated with inadequate absorption of igg from colostrum. one study demonstrated that litter sizes of three light goat kids (, . kg bw) or more had significantly lower mean serum igg levels at hours of life when compared with litter sizes of one or two heavier kids ( . versus . mg/ml, respectively). this suggests that special attention and monitoring should be paid to multiple fetus gestation as the risk of fpt under these circumstances at kidding is higher; however, the quality of colostrum, amount ingested, and adequacy of absorption are rarely monitored by small ruminant producers in natural or artificial rearing systems. the use of monitoring tools to evaluate colostrum quality and igg absorption is common in modern dairy cattle operations, and these tools are readily available for small ruminant production systems. recent reports have presented the use of %brix in maternal colostrum and neonate serum and its positive correlation with serum total proteins (stps) at hours as effective monitoring tools of fpt in lambs and goat kids. [ ] [ ] [ ] the use of stp has also been used to monitor colostrum deficiency intake in mule deer fawns ; however, adequate values of serum igg for cervid neonates have not been established yet. inadequate colostrum intake and low serum igg at to hours of life have been consistently associated with higher morbidity and mortality rates in lambs, goat kids, and fawns. one study reported that % of lamb mortality between hours and weeks of age can be attributed to fpt. another study suggested that colostrum deficiency and low serum igg in goat kids resulted in higher mortality rates at weeks and of life due to chronic infections with pasteurella multocida and escherichia coli. other reports demonstrated that % of lambs with a serum igg of , mg/ml at hours died before weeks of age compared with only % of the lambs with a serum igg of . mg/ml at hours. in a previous report, mule deer (odocoileus hemionus) fawns with a stp of # g/dl between days and of age developed diarrhea and died before days of age compared with fawns with stp . g/dl. in a more recent report, a -day-old formosan sambar deer (rusa unicolor swinhoei) with a history of colostrum deprivation died due to severe suppurative meningitis caused by e. coli infection. in addition to immunoglobulins, colostrum also contains large quantities of fat-soluble vitamins that do not cross the placenta. the most important of these are vitamins a, d, and e, which are important in bone development and the immune or inflammatory response. neonates that have not ingested enough colostrum are likely to be deficient in these vitamins. diagnosis. history of dam dystocia, inadequate colostrum nursing, complete colostrum deprivation, and signs of undernourishment or sepsis in the first few days after birth are usually a presumptive indication of failure in the transfer of passive immunity. a high prevalence of diarrhea and respiratory disease in neonates should prompt investigation and evaluation of passive transfer of immunity in affected herds or flocks. owners occasionally evaluate lambs or kids for adequate intake by picking up the animal and holding it at ear level, while carefully cradling the head and neck, and then shaking the abdomen to hear milk in the abomasum; however, this is not a reliable indication of adequate transfer of passive immunity. a definitive diagnosis of fpt can be made by direct laboratory measurement (single radial immunodiffusion [srid]) of igg in serum at hours of life. although some practitioners use the value of igg used in dairy calves ( mg/ml), others have suggested an igg value , mg/ml to establish the presence of fpt in small ruminants. numerous semiquantitative methods of estimating igg are available and are easy to use in sheep, goats, and cervids. the most common is the measurement of serum total solids or stp values at hours of life through an optical refractometer. the stp at hours of life in a well-hydrated animal has demonstrated correlation with serum igg in calves, lambs, and goat kids. studies in goat kids indicated that an stp between . and . g/dl was associated with adequate transfer of passive immunity. , another study demonstrated fpt in lambs with stp values , . g/dl at hours of life. a study in mule deer suggested that fawns with an stp # g/dl had inadequate colostrum intake and fpt. recently, the measurement of %brix in maternal colostrum and serum with a digital brix refractometer has become an alternative method to evaluate colostrum quality and fpt in dairy operations. colostrum %brix . % and serum %brix . . % have been associated with adequate transfer of igg in calves and goat kids. other qualitative methods to assess the transfer of passive immunity in large animals include various agglutination (glutaraldehyde), precipitate assays (sodium sulfate), and measurement of g-glutamyl transferase (ggt) in serum. these methods may be relied on to give an overall flock assessment of adequacy of passive transfer, but they are rarely accurate enough to provide definitive information on individual animals. treatment. fpt is not in itself pathologic, but it greatly increases the neonate's susceptibility to infectious diseases. the amount of colostrum absorbed across the gut decreases with time, especially in animals that have been ingesting other proteins (e.g., the casein in milk); it also decreases with illnesses that decrease gastrointestinal function. neonatal small ruminants should receive at least g of igg/kg of bw or ideally g of total mass of igg from a good-quality colostrum source (. mg/ml of igg) during the first hours of life. other authors recommend an intake of to ml of colostrum/kg during the first hours of life. in artificial rearing systems or lamb feedlots, feeding of colostrum every hours until hours of life is recommended. when same species' maternal colostrum is unavailable, goat colostrum or bovine colostrum/colostrum replacers or are a good alternative; however, hemolysis has been reported in lambs receiving cattle colostrum. one study demonstrated that there was no difference in serum igg levels of lambs that received the same volume of sheep or goat colostrum at birth. another study demonstrated that lambs that received ml of a bovine colostrum replacer at birth in addition to ml of stored sheep colostrum at hours of life had higher serum %brix values at hours and had less incidence of disease during the preweaning period compared with lambs that received the same volume of stored sheep colostrum at birth and at hours of life. since igg absorption cannot be extended more than hours after birth, administration of an oral colostrum source is the best treatment in the immediate postpartum period in still-healthy neonates. after the window for immunoglobulin absorption has closed, plasma, serum, or whole blood administered by the iv or intra-peritoneal route is the best way to raise the neonate's blood immunoglobulin concentrations. adult donor plasma contains approximately . to . g of immunoglobulin/dl, so administration of a volume equivalent to % of bw or a dose of to ml/kg has been recommended for the treatment of large animal neonates. if plasma is used instead of colostrum, administration of vitamins a, d, and e also may be beneficial. if colostrum and plasma are unavailable or cost-prohibitive, "closing" the gut as quickly as possible with milk, maintaining high standards of hygiene, and possibly administering prophylactic antibiotics offer the greatest prospects for preventing infectious disease. vaccination of the neonate or the administration of antitoxin hyperimmune serum should not be considered protective but may be of value. prevention. prevention of fpt should be based on the establishment of an adequate colostrum program managing the previously mentioned factors that affect production, quality, and absorption of maternal colostrum components in lambs, goat kids, and fawns. ensuring colostral quality is best done through good nutrition, health care, and vaccination of dam (see chapters and ) . administration of vaccines weeks before parturition, followed in weeks with a booster, provides the highest quantity of protective immunoglobulin in the colostrum. antepartum leakage is rarely the problem in small ruminants that it is in horses and cattle. however, in a flock or herd environment, still-pregnant dams may steal babies from other sheep or goats. to prevent such theft and the resultant loss of colostrum by the "adopted" neonate, owners may choose to keep pregnant animals separate from those that have already delivered. if complete separation is not possible, the dam and her offspring should be allowed to bond with each other in a private pen ("jug" or "crate") for at least hours before being placed back with the flock. clipping excessive wool or mohair from around the perineal area and udder before lambing or kidding, expressing the teats to ensure they are not plugged, and having extra colostrum available when pregnant females are placed in jugs or crates are other good preventive measures. etiology and pathogenesis. uncomplicated diarrhea in lambs, goat kids, and fawns may be caused by infectious agents such as viruses, bacteria, and protozoa. in goat kids and elk calves, metabolic causes of diarrhea have been described. , group b and a rotavirus, enterotoxigenic e. coli k , cryptosporidium parvum, and other cryptosporidium spp. have been commonly identified as causal agents of diarrhea in small ruminant neonates. [ ] [ ] [ ] [ ] with recent advances in diagnostics and metagenomics of the enteric environment of large animals, novel viruses have been identified as potential causal agents of diarrhea in lambs and goat kids. adenovirus, astrovirus, calicivirus, coronavirus, and picornavirus have been identified in feces of diarrheic lambs and goat kids ; however, their role in the pathogenesis of neonatal diarrhea is still uncertain. these organisms differ from the agents of complicated diarrhea in that they do not invade beyond the gut wall or result in systemic toxemia (see chapter ) . additional causes of diarrhea reported in goat kids and elk include lactose intolerance and hypernatremia, respectively. , less frequently, bacteria such as c. perfringens, clostridium difficile, and attaching and effacing e. coli have been associated with complicated diarrhea in small ruminant neonates. , the net result of such an infection is that a large volume of water and electrolytes are lost into the bowel due to malabsorptive, hypersecretory, or hyperosmolar processes. if enough fluid and electrolytes are lost, dehydration and metabolic acidosis arise, inducing systemic clinical signs of depression and weakness in association with diarrhea. in goats, this clinical entity is one component of the floppy kid syndrome. clinical signs. profuse, watery, yellowish-green to brown diarrhea without fever is the hallmark clinical sign. with severe dehydration and acidosis, affected lambs, kids, and fawns become weak and dull and lack appetite. [ ] [ ] [ ] excessive salivation and loss of suckle reflex have also been reported in affected lambs and kids. , mucous membranes become tacky, and skin tenting times are prolonged. shock signs may develop. physical assessment often must take the place of clinicopathologic analysis in affected neonates. mild, nonclinically complicated diarrhea is characterized by profuse diarrhea with minimal systemic signs. the affected animal is bright and alert, with minimal skin tenting, and can stand and eat readily, with a strong suckle reflex. it is less than % dehydrated, with a blood ph of . to . , and bicarbonate deficit is minimal. moderate uncomplicated diarrhea is characterized by profuse diarrhea in a dull but responsive animal. skin tenting is prolonged, but eye luster is normal. the affected animal is able to stand and eat but eats slowly and has a weak suckle reflex. the head typically is held down. it is to % dehydrated, with a blood ph of . to . and a bicarbonate deficit of to meq/l. severe uncomplicated diarrhea is characterized by profuse diarrhea. the affected animal is dull and minimally responsive, with a very long skin tent time and dull, sunken eyes. it can stand only with assistance and prefers to stay in sternal recumbency with its head up. the animal eats very slowly, if at all, and has a minimal suckle reflex. it is to % dehydrated, with a blood ph of . to . and a bicarbonate deficit of meq/l. very severe uncomplicated diarrhea is characterized by profuse diarrhea and profound weakness. the animal's skin remains tented for more than minute, and its eyes are very sunken and dull. it is nonresponsive with no suckle response. it is unable to maintain sternal recumbency, lying on its side instead. the animal is to % dehydrated, with a blood ph of . to . and a bicarbonate deficiency of to meq/l. epidemiology. morbidity and mortality of uncomplicated diarrhea in small ruminants and fawns vary depending on the cause. reports of rotaviral diarrhea in newborn lambs indicate morbidity rates between % and % and mortality rates between and % , ; however, one study reported a % case fatality rate in lambs affected with types b and a rotavirus diarrhea. another study reported mortality rates between % and % in lambs and kids affected with c. parvum diarrhea. most of infectious agents associated with uncomplicated neonatal diarrhea in small ruminants are shed by adult animals and older lambs/kids around stressful events such as lambing/kidding and extreme weather conditions. one study reported that pregnant does shed to times more oocysts during the weeks around kidding compared with other time periods. additionally, poor husbandry/hygiene of lambing/kidding sheds, fecal soiling, flock size (. animals), lambing/kidding season (winter/spring), and the presence of c. perfringens type a in feces have been suggested as potential risk factors for uncomplicated diarrhea in small ruminant neonates. [ ] [ ] [ ] clinical pathology. the leukogram should be normal or show abnormalities compatible with stress. serum biochemical or blood gas analysis may reveal evidence of intestinal malabsorption, electrolyte loss, metabolic acidosis (hypoglycemia, hyponatremia, hypochloremia, hyperkalemia, low bicarbonate, and increased anion gap), and dehydration (hyperalbuminemia and increased blood urea nitrogen [bun] and creatinine). in contrast with the common leukogram and biochemical abnormalities found in calves, lambs, and goat kids with uncomplicated diarrhea, elk calves with diarrhea develop leukocytosis, hyperchloremia, and hypernatremia (serum na . meq/l). additionally, increased anion gap, bun, creatinine, and albumin concentrations have been reported in affected elk calves. a presumptive diagnosis may be based on the characteristic history and clinical signs. response to conservative treatment also is supportive of this diagnosis. identification of the specific causative agent is less important than proper treatment of affected animals; however, feces or intestinal contents from affected animals can be submitted for electron microscopy, reverse-transcription polymerase chain reaction (pcr), and cell culture immunofluorescent assays to identify viruses. [ ] [ ] [ ] additionally, intestinal tissue can be submitted for ihc for rotavirus and c. parvum. , feces of affected animals can also be submitted for enzyme-linked immunosorbent assay (elisa), ziehl-neelsen staining technique, light or fluorescence microscopy, sugar flotation, and auramine or fluorescent antibody staining for the diagnosis of c. parvum infection. fecal culture to determine a bacterial cause is recommended. treatment. the immediate goals of treatment are rehydration, replacement of lost electrolytes, and restoration of acid-base balance as these are usually the leading causes of death in affected neonates. less immediate goals are provision of nutrition and replacement of ongoing losses. the aggressiveness of treatment is dictated by the severity of the condition, as well as economic considerations. . rehydration: calculate the percent dehydration and use to calculate fluid requirements for a -hour period. example: % dehydration in a -kg lamb: dehydration: . kg kg/l . l or ml. maintenance: ml/kg/day . l or ml. total fluids to replace in hours . l or ml fluid loss due to dehydration ( ml in this case) should be replaced during the first hours and the rest can be replaced in the next hours. . replace lost electrolytes: sodium, chloride, and bicarbonate are lost roughly in proportion to extracellular fluid (ecf) in the acute phase of diarrhea ( - days) in untreated animals. potassium tends to be increased in this phase due to the presence of metabolic acidosis and care should be taken when selecting fluids containing potassium to treat affected animals at this time. in chronic cases of diarrhea, and especially in cases where the owner/producer has given oral milk replacer or electrolyte supplements/replacements to affected animals before veterinary evaluation, the serum concentration of sodium, potassium, and bicarbonate might be variable or increased. special care should be taken in these cases when selecting fluids to treat affected animals as the risk of causing hypernatremia is higher. in cases of diarrhea in elk calves, hypernatremia is common, and fluids should be selected accordingly. in the majority of cases, initial replacement of sodium, chloride, and bicarbonate with fluids containing proper composition is recommended. example: assessment suggests a bicarbonate deficit of meq bicarbonate in a -kg, comatose lamb with prolonged skin tenting ( . is the multiplier for ecf in a neonate): . ( meq) kg meq bicarbonate. commercial iv . % sodium bicarbonate solutions contain meq of bicarbonate per milliliter and could be added directly to iv fluids in severely dehydrated and acidotic animals. therefore, the immediate goal is to provide ml of fluid and meq of bicarbonate to this lamb in a formulation that resembles normal ecf. fluids can be given by various routes. selection of route of administration of fluids depends on degree of dehydration, presence or not of a strong suckle reflex, and degree of depression. neonates with advanced degrees of dehydration, depression, and absence of suckle reflex will benefit from iv fluid therapy. in contrast, neonates with mild dehydration and active suckle reflex can be effectively treated with oral electrolytes ; however, if oral fluids have not produced an improvement within to hours, iv treatment should be strongly considered. other routes such as subcutaneous, intra-peritoneal, and intra-osseous can also be used for fluid administration to neonates. • advantages: oral fluids are inexpensive (nonsterile) and easy to give. they are less likely to cause fatal arrhythmias or neurologic disease than iv fluids. • disadvantages: an animal receives a maximum of its gastric volume ( % of bw), and good gastric motility is required. oral fluids may not be well absorbed by a damaged gut. absorption also is slow. intravenous • advantage: this method allows rapid correction of all deficits, even in moribund animals. • disadvantages: it is expensive (sterile), requires venous access, and can rapidly lead to overcorrection. subcutaneous • advantages: this method does not require venous access or good gut motility. • disadvantages: it is expensive (sterile), and the fluids may not be well absorbed in very dehydrated animals. absorption is not as quick as by iv administration. animals should be given only hypotonic or isotonic fluids. intra-peritoneal • advantages: this method does not require venous access or gut motility. fluids are absorbed quickly by this route. • disadvantages: it is expensive (sterile) and can cause peritonitis. isotonic fluids are best used in this route. only a limited volume can be given. many commercial oral electrolyte solutions for neonatal ruminants are available; however, not all of them fulfill the requirements to adequately replace fluids and electrolytes in neonatal ruminants with diarrhea. oral electrolyte solutions must contain enough sodium , provide agents that increase absorption of water (glycine, glucose, and acetate), provide an alkalinizing agent (bicarbonate, propionate, acetate, and citrate; acetate has demonstrated best results), and an energy source (glucose). the amount of carbohydrates might vary and is usually higher in "high-energy" solutions specifically used for severely affected neonates that are not eating and develop negative energy balance. less carbohydrate is needed in less severely affected animals because they are usually eating some and are less likely to have severe negative energy balance. fluids to be avoided include medicated milk replacers and unbuffered saline solutions. iv treatment should be provided with a sterile commercial product. such preparations typically contain to meq/l of base. additional sodium bicarbonate solution or sterile powder can be added to fluid therapy based on the bicarbonate deficit ( meq/ml of . % solution and meq of bicarbonate/g of powder, respectively). the bicarbonate deficit should be over the first hours. after deficits are replaced, the following continued treatments and adjuncts may be considered: . continued administration of fluids (oral rather than iv, if possible) to replace ongoing losses: • oral electrolytes at a volume equal to % of the bw per feeding can be given; the number of feedings can be increased from two (normal) to three to six per day. • iv fluids can be continued at twice the maintenance fluid rate until appetite is restored. • more bicarbonate may be necessary. . consideration of addition of milk to the treatment regimen: • milk or milk replacers should be added to the therapy of neonates with diarrhea. they provide nutrition to the affected neonate, preventing negative energy balance and promoting intestinal healing. • care should be taken to not mix oral electrolyte solutions with milk or milk replacers in the same container as the concentration of sodium and overall osmolarity of the solution can dramatically increase, leading to hypernatremia or other metabolic abnormalities. • milk or milk replacers should be given in small volumes (, % of total requirements) but at a higher frequency (every - hours) to avoid overloading the abomasum and intestine of affected animals. lambs fed milk lose less weight with scours. • free water helps prevent hypernatremia. • milk is a good potassium source (see chapter ). elk deer calves. elk deer calves commonly develop diarrhea with hypernatremia (serum na . meq/l) compared with other large animal neonates, where hyponatremia is more common. therefore, administration of oral electrolyte solutions designed for other ruminants (calves, lambs, and kids) should be avoided in these animals. a dilution ( : or : ) of commercially available bovine calf electrolyte solutions to reduce sodium content is recommended for the treatment of elk calf diarrhea. the use of lactated ringer's solution, which has a low sodium concentration in addition to a very low reduction rate of serum sodium (, . meq/l/hour) has been advocated in the fluid therapy of hypernatremic elk calves with diarrhea. additional therapy. dextrose ( . - %) solutions can be added to the fluid therapy of hypoglycemic animals. the use of nonsteroidal antiinflammatory drugs (nsaids) in neonatal ruminants with diarrhea is controversial due to the risk of renal damage and abomasal ulceration; however, in cases of diarrhea complicated by septicemia or endotoxemia, nsaids should be used to reduce the effects of systemic inflammation. flunixin meglumine at a dose of . to . mg/kg is the only nsaid approved for food animal use. similarly, the use of oral or systemic antibiotics in cases of uncomplicated diarrhea is controversial due to its potential effect on the intestinal microbiota and development of bacterial resistance; however, their use is warranted in the presence of septicemia or endotoxemia in addition to diarrhea. in these cases, b-lactams such as oral amoxicillin or systemic ceftiofur are usually good choices. the effect of mucosal protectants and probiotics in cases of diarrhea is unknown in small ruminant neonates, and their use is left to practitioners based on their own experiences (see appendix ) . prevention. prevention of uncomplicated diarrhea in small ruminant neonates is based primarily on the timely feeding of adequate amounts of good quality maternal colostrum or colostrum replacer (see "failure of passive transfer" section). vaccination of dams with antigens of common infectious agents associated with uncomplicated neonatal diarrhea before parturition has demonstrated to be effective increasing colostrum immunity and prevention of diarrhea in lambs. maintenance of adequate husbandry and hygiene conditions in lambing/kidding sheds or barns is necessary to reduce neonatal exposure to infectious agents normally shed in feces of dams during parturition such as rotavirus and c. parvum. ruling out infectious causes of depression and weakness is difficult, and clinicians often do well to assume that an infectious disease is contributing to clinical signs when making treatment decisions. however, several noninfectious systemic disturbances also can depress neurologic and muscular function. successful treatment often requires identification and correction of each of these disturbances. among the more common abnormalities leading to depression in neonates are hypoxemia, metabolic or respiratory acidosis, hypothermia, hyperthermia, hypoglycemia, dehydration, azotemia, and some electrolyte imbalances. hypothermia and hyperthermia can easily be diagnosed by measuring body temperature with a rectal thermometer. hypothermia is far more common and can result from weakness, shock, and environmental stress. cold, windy weather or tube feeding with cold milk replacer or fluids can lead to a rapid drop in core body temperature, especially in neonates that are small or weak or have been inadequately licked off or were rejected by their dams. strong, vigorous neonates usually are protected by heat produced during muscular activity and are able to seek food and shelter. clinical signs appear when the rectal temperature drops to ° f ( . ° c) or below. protection from wind and cold such as with an individual ewe jug or pen, heat lamps (positioned far enough away so as not to burn the neonate), hot water bottles, blankets, and administration of warm fluids is helpful in treating and preventing hypothermia. shearing the ewe before lambing is of value because it forces the ewe to seek shelter. if this management technique is used, care should be taken to avoid inducing severe hypothermia in the dam. environmental hyperthermia is much less common than fever in neonates. therefore, treatment for infectious diseases in young animals with high temperatures usually is warranted. providing cool shelter with good ventilation, minimizing stressful events, ensuring adequate fluid intake, and shearing the adults are the best defenses against environmental heat stress. hypoglycemia also is easy to diagnose with the aid of an inexpensive, portable glucose meter. lambs and kids typically develop hypoglycemia under the same circumstances as those leading to hypothermia. administering ml/kg of dextrose (approximately . fl oz/lb, or % of bw) in warm milk replacer or ml/kg of % dextrose, by either the iv or oral route (diluted to % dextrose), should provide ample energy to correct hypoglycemia. iv administration may be necessary if gut motility is absent. follow-up treatment may be necessary if the neonate does not regain its appetite. except during severe conditions, normal lambs and kids should be able to maintain normal body core temperature. they should therefore be examined for an underlying disorder if they exhibit signs of hypothermia or hyperthermia. clinicians and owners should not assume that warming and feeding a cold, weak neonate will always correct the problem. hypoxemia is much more difficult to diagnose. portable blood gas meters for arterial analysis and radiography units for thoracic imaging are available but are still not in common use in small ruminant practice. for those reasons, hypoxemia usually is underdiagnosed. hypoxemia can result from prematurity or dysmaturity, infection, depression or weakness (decreased ventilation), meconium aspiration, bullous emphysema, hernias, and other thoracic fluid or tissue masses. it is likely to be a contributing factor in illness and death in most weak neonates younger than days of age. such animals benefit from the provision of supplemental oxygen, either through a nasal insufflation tube or by oxygen tent. in addition to its direct effect on general wellbeing and behavior/ attitude, hypoxemia at birth leads to poor gut function and subsequent poor colostral absorption. many animals that exhibit fpt and subsequent sepsis had a previous bout of hypoxemia. azotemia, metabolic acidosis, and electrolyte imbalances are difficult to diagnose without clinicopathologic analysis. therefore, these problems are best treated in animals showing signs of dehydration with the administration of a balanced, physiologic electrolyte solution. metabolic acidosis usually is accompanied by either obvious evidence of bicarbonate loss (diarrhea) or severe dehydration. however, neither of these conditions is present with floppy kid syndrome. this descriptive title is applied to muscle weakness, anorexia, and depression in kids observed in the first weeks of life. by its strictest definition, floppy kid syndrome refers to metabolic acidosis with a high anion gap without dehydration or any known cause in young kids that were normal at birth. a variety of disorders and conditions have been proposed as the cause of metabolic acidosis without dehydration, including intestinal fermentation of milk in well-fed kids with subsequent absorption of volatile fatty acids, transient neonatal renal tubular acidosis, and lactic acidosis secondary to toxic impairment of cardiovascular function. overgrowth of c. perfringens type a often is suggested as a source of the toxin. with a high anion gap, a pathologic condition that leads to overproduction of an organic acid is more likely than one that leads to bicarbonate loss. the disease can occur in individual animals or in outbreaks; although parity of the dam and number of offspring have not been associated with this metabolic disturbance, aggressively feeding kids are more likely to suffer from milk fermentation or clostridial overgrowth. an infectious etiology appears to be more likely in herds displaying an increased incidence of this metabolic disturbances as the kidding season progresses. the disease also is reported to be more common in meat goats than in dairy goats. the prevalence can vary tremendously from year to year in a single flock or region. a similar disease has been reported in calves and llama crias, and lambs are likely to be susceptible under the right conditions. because blood gas analysis and exclusion of other diseases often are impractical, the term floppy kid syndrome frequently is used by owners to refer to any kid that is weak and does not have an overt, organ-specific sign (e.g., diarrhea). different pathologic processes are grouped together by their common clinical endpoint (as with "thin ewe syndrome"), and the veterinarian is charged with determining the etiology in a specific flock. most possible causes are found in the previous list of conditions that cause weakness and depression in neonates. among these entities, sepsis and hypoxemia are the most important items and therefore must also be considered possible causes of floppy kid syndrome. treatment and prevention of floppy kid syndrome currently follow the same lines as for treatment and prevention of neonatal sepsis or enteritis. spontaneous recovery of animals with floppy kid syndrome may occur. however, in valuable kids, quick assessment of blood chemistry and base deficits will allow requisite correction of electrolyte and blood ph abnormalities with . % sodium bicarbonate. tissue-invading clostridia are large, straight, gram positive rods that are to mm in length. c. perfringens and c. haemolyticum are smaller bacteria, and clostridium novyi, clostridium chauvoei, and clostridium septicum are larger. the bacteria grow best under anaerobic conditions and produce waste gases. clostridia bear spores, which may be the only viable form in the environment (soil and decomposed organic matter). identification of these spores within bacteria on microscopic examination is useful to identify clostridia, but it is not diagnostic of disease. spores in c. perfringens are central and do not affect the shape, whereas most other species have the spore toward one end and appear slightly club shaped. clostridia cause infectious, noncontagious disease. the bacteria inhabit the intestinal tract and are present in the feces of ruminants. small numbers of organisms in their dormant spore form also may reside in tissues such as liver and skeletal muscle. they can be isolated from soil, where most are thought to have short life spans. soil concentrations are highest in locations recently contaminated with ruminant feces, especially crowded, overused facilities such as feedlots and lambing sheds. environmental contaminations are associated with cool, damp times of the year such as late winter and spring. the concentration of organisms and their toxins found in the feces, gut contents, and internal organs of most adult ruminants usually is small. competition and peristalsis prevent overgrowth in the gut, and aerobic conditions prevent overgrowth in other tissues in live animals. however, rapid overgrowth and tissue invasion ensue after death, making rapid postmortem examination essential to ascertain whether clostridial organisms are responsible for the death. pathogenic clostridial organisms all produce heat-labile protein exotoxins. most make a variety of toxins, and the relative contribution of each toxin to the disease state is not known. c. perfringens is a normal commensal of the intestinal tract of clinically healthy large animals, including cervids; however, the number of bacteria and their toxin production within the intestine usually remain low due to peristalsis and normal homeostasis. c. perfringens is classified into five biotypes (a, b, c, d, and e) based on the production of four major exotoxins, namely alpha (cpa), beta (cpb), epsilon (etx), and iota (itx); however, the production of more than different exotoxins in various combinations has been associated with these bacteria, including perfringolysin o (pfo), enterotoxin (cpe), and beta toxin (cpb ). the different biotypes of c. perfringens cause different diseases in relation with the exotoxins they produce. the major effect of the phospholipase/ sphingomyelinase cpa, produced by all c. perfringens biotypes, is cell lysis and hemolysis, and its role on intestinal disease of large animals is not well understood. however, this toxin has been associated with hemolytic disease and hemorrhagic enteritis in large animals; cpb, produced by c. perfringens types b and c, is a trypsinlabile toxin associated with necrotizing enteritis and enterotoxemia in large animal neonates; etx, produced by c. perfringens types d and b, is a trypsin-activated necrotizing toxin associated to vasculitis, edema, and necrosis of the cns and enterotoxemia; and itx, another trypsin-activated necrotizing toxin produced by c. perfringens type e, has also been associated to intestinal disease in small ruminants. , c. perfringens types c and d are considered the most important types in veterinary medicine as they can cause disease in most farm animals. severe clinical disease due to bacteria sporulation and massive toxin production only occurs when the normal intestinal environment and microbial balance are disrupted in affected individuals. decreased peristalsis and poor ruminal and abomasal function have also been proposed as factors that contribute to disease presentation. weather and handling stresses, feed changes, and an overabundance of high-energy feeds such as milk, bakery products, and cereal grains might promote bacteria overgrowth and exotoxin synthesis and release. additionally, other enteric infections that disrupt the mucosal border may increase systemic absorption of toxins and promote severe disease. c. perfringens type a is a normal inhabitant of the intestinal tract of large animals and is ubiquitous in the environment (soil). one study reported c. perfringens type a as the most common isolate among other clostridia from healthy young lambs. c. perfringens type a has been associated with a fatal hemolytic syndrome in younger lambs and cattle but not goats ("yellow lamb disease"), , acute hemorrhagic enteritis and hemolytic enterotoxemia in cattle (hemorrhagic bowel/jejunal syndrome) and goats, , , and intestinal hemorrhage and splenomegaly in farmed deer. , risk factors for infection have not been established; however, high soluble carbohydrate diets and high bcss have been associated with clinical disease. , , this disease occurs most commonly in lambs to months old. under favorable conditions, the organisms proliferate and cause a corresponding increase in alpha toxin production. the alpha toxin (cpa), in synergy with the beta toxin (cpb ), is responsible for hemolytic crisis, vasculitis, and gastrointestinal lesions. the clinical course usually is less than hours. clinical signs. in most cases, sudden death or history of found dead is common. clinical signs observed usually include weakness, depression, fever or hypothermia, icterus, anemia, hemoglobinuria, tachypnea, colic, hemorrhagic diarrhea or absence of feces, and terminal recumbency. , , [ ] [ ] [ ] adult animals also are susceptible to hemolytic disease and vasculitis caused by c. perfringens type a infection. fatal abomasitis and rumenitis in neonates and juveniles also have been blamed on c. perfringens type a, but the rapid postmortem proliferation of the organism makes substantiation of this claim difficult. morbidity in a flock is lower than for many of the other enteric clostridial diseases, but the mortality rate is very high. diagnosis. the most characteristic clinicopathologic change is neutrophilic leukocytosis with a left shift. other evidence of systemic toxemia (metabolic acidosis, azotemia, and increases in liver and muscle enzymes) also may be seen. laboratory evaluation reveals evidence of intravascular hemolysis. necropsy in sheep, goats, and cervids usually reveals evidence of hemolysis, pallor, jaundice, hemoglobinuria, hyperemic and edematous intestines, splenomegaly, gastrointestinal serosal and mucosal hemorrhage, and multifocal internal petechial hemorrhages. , , [ ] [ ] [ ] the isolation of c. perfringens type a from necropsied animals is not itself diagnostic. definitive diagnosis can be made based on identification of the alpha toxin and the absence of other toxins by elisas or older, live animal assays. more recently, multiplex pcr techniques are replacing immunodiffusion assays for the identification of a specific toxin-producing gene isolate, typing of bacteria, and demonstration of toxins or toxin genes. gut content and intestinal samples collected from freshly dead animals make the most meaningful samples for diagnosis. treatment. administration of high doses (. , iu/kg bid) of penicillin and clostridium antitoxin ( - ml subcutaneously [sc] or orally [po] ) is the mainstay of treatment, although animals may die acutely before therapies can be instituted. prevention. a conditionally licensed toxoid against the clostridial alpha toxin is available for cattle in the united states. a recent report demonstrated that a new vaccine including recombinant cpa, cpb, and etx was effective at inducing protective antibodies to c. perfringens biotypes in cattle, sheep, and goats. this could be an alternative for the prevention of morbidity and mortality caused by c. perfringens type a. prevention efforts should focus on environmental hygiene and avoiding gut conditions favorable for proliferation of the organism (high content of soluble carbohydrates in the diet). because this type appears to survive better in soil than other types, preventing ingestion of soil may be important in preventing disease. c. perfringens types b and c occur in the soil and the animals' housing environment and can be shed by asymptomatic individuals. the reported geographic range of both diseases is limited (type b to the united kingdom and south africa and type c to the united kingdom, australia, and north america), even though infection with c. perfringens type c appears to occur worldwide. these organisms cause very similar diseases called lamb dysentery and hemorrhagic enterotoxemia, respectively. very young lambs and kids ( - days to - weeks of age) are usually affected due to the presence of trypsin inhibitors in colostrum. older animals may become susceptible as a result of overwhelming infection or trypsin inhibition by some soy and sweet potato products or temporary suppression of pancreatic trypsin production (struck in adult sheep). with both diseases, the beta toxin (cpb) is a required pathophysiologic factor, and inactivation of this toxin after maturation of pancreatic trypsinogen secretion is what commonly limits the susceptible population to neonatal animals. the cytolytic and necrotizing effects of the beta toxin (cpb), in synergy with the beta toxin (cpb ), cause necrosis and ulceration of the intestinal mucosa and are translocated into circulation, causing severe toxemia and death. the diseases initially affect lambs and kids younger than days of age, with illness occasionally occurring in older lambs. the incidence of disease in lambs and kids can be around to %, with a case fatality rate of %. high stocking density in lambing areas, cold weather, single-born lambs, and high milk production of dams have been suggested as potential risk factors for type b and c enterotoxemia. because of management practices in young animals and age-related vulnerability, fecal contamination of teats, hands, and equipment that enter the mouths of the neonates (orogastric tubes and nipples) is a major cause of infection. clinical signs. severely affected animals or those at the beginning of an outbreak usually are found dead. less acutely affected animals expel initially yellow, fluid feces that progressively become brownish and/or hemorrhagic. feces may also contain flecks of blood and show splinting of the abdomen, especially when handled, along with signs of colic and feed refusal. the clinical course usually is short, and the disease is almost always fatal. one study reported acute abdominal pain, hemorrhagic diarrhea, and death within hours of experimental oral inoculation of three goat kids with a field strain of c. perfringens type c. dehydration, anemia, and severe weakness are also common clinical signs in affected animals. terminal convulsions and coma occasionally are noted, especially in outbreaks in the united states. c. perfringens type c in older sheep causes the disease known as "struck." affected animals usually are found dead or with signs of toxemia. specific antemortem signs of gastrointestinal disease are rare. specific antemortem signs of gastrointestinal disease are rare. clinical pathology changes observed in these animals include neutrophilic leukocytosis with a left shift. additional evidence of systemic toxemia (metabolic acidosis, azotemia, and increases in liver and muscle enzymes) also may be seen. necropsy findings. postmortem examination reveals focal hemorrhagic ulcers (up to . cm in diameter) in the small intestine (mostly in the ileum) with type b infection and diffuse reddening with hemorrhage and necrosis of the abomasum and the entire segments of the intestine with type c infection. type c infections in ruminants can also present with generalized peritonitis, subendocardial and subepicardial hemorrhages, and hemorrhagic lymph nodes. animals that die very rapidly may exhibit minimal or no gross abnormalities of the intestine. a similar syndrome of type c enterotoxemia has been previously reported in a sika deer (cervus nippon). sudden death, severe hemorrhagic gastritis including forestomach and abomasum, and catarrhal enteritis was observed in the affected animal. diagnosis. diagnosis of these diseases is made by identification of characteristic history, clinical signs, postmortem lesions, and positive toxin assays. because the beta toxin is very labile, negative toxin assays are less significant than negative assays for presence of other tissue-invading clostridia. the isolation of c. perfringens type b or c from necropsied animals is not itself diagnostic. immunodiffusion assays or multiplex pcr of intestinal contents for specific isolate and beta toxin (cpb) identification are recommended to obtain final diagnosis (see "diagnosis" in "c. perfringens type a" section). treatment. if the infection is identified early in the disease course, high doses of oral and parenteral penicillin and c. perfringens c and d antitoxin may be of benefit. iv fluids and antiinflammatory agents may be indicated as well. usually, the condition is not recognized early enough, and animals are found dead or dying. prevention. a beta toxoid is available in the united states and other countries. it usually is packaged with an epsilon toxoid. the best protection is achieved by vaccinating pregnant dams twice, with the second dose administered approximately to weeks before lambing or kidding and annual booster. deer does should receive double the dose of sheep as low antibody responses to clostridia have been reported in these animals. , vaccination of pregnant dams is directed to increase specific colostrum antibodies to protect neonates. juveniles also should be vaccinated twice or three times at months, months, and months. adults, including males, should receive an annual booster. in the face of an outbreak, the lambing area should be moved to a different place. additionally, vaccination of dams and newborns with a beta toxoid and administration of c. perfringens c and d antitoxin can be carried out in the face of an outbreak to reduce morbidity and mortality. c. perfringens type d produces epsilon toxin (etx), which is responsible for causing type d enterotoxemia in sheep, goats, calves, and deer. , other common names for the disease include "overeating disease" or "pulpy kidney disease." the disease has a worldwide distribution and occurs primarily in suckling lambs of to weeks of age, although it has also been reported in weaned lambs up to months of age and adult sheep. the disease is also common in grazing goats and deer. the prevalence of disease has been reported from . to . %, with a % case fatality rate in feedlot lambs. one study on proportional distribution of goatherd mortality in the province of quebec, canada, reported a . % mortality of goats to c. perfringens type d enterotoxemia. the disease is more common in feedlot lambs after they enter the lot. tail docking, castration, and other management interventions are thought to decrease the incidence of this disease by temporarily decreasing appetite. the disease also affects unvaccinated adult sheep, even without any history of stressors or feed changes. sudden changes in the diet are the main predisposing factor in goats. the disease can occur in vaccinated goats, as vaccination has not demonstrated to be completely protective in this species. , c. perfringens type d is normally found in the gastrointestinal tract of healthy ruminants, but the acid environment of the abomasum and continuous peristalsis help to keep numbers of bacteria and levels of toxin production low. however, under specific conditions such as overingestion of high-energy feeds (milk, grain, and lush pasture), excess of fermentable starches in the intestine, and intestinal stasis, the organism proliferates rapidly, producing lethal quantities of epsilon toxin. these conditions are usually triggered in well-conditioned, fast-growing animals that are on a highly nutritious diet. the epsilon toxin, once produced, acts locally, causing increasing gut permeability and widespread tissue damage. epsilon toxin and other exotoxins are then absorbed through the intestinal tract into systemic circulation and transported to the brain, lungs, and kidneys, causing increased endothelial permeability, perivascular edema, and generalized necrosis. , the characteristic increased vascular permeability and perivascular edema in the kidney and brain are responsible for the name of "pulpy kidney disease" and "focal symmetric encephalomalacia." clinical signs. the course of the disease is usually very short ( . - hours), so sudden or spontaneous death is a common clinical sign across affected small ruminant species. , - natural disease caused by c. perfringens type d differs between sheep and goats, possibly because of a difference in relative local and systemic actions of the epsilon toxin, although experimental models have demonstrated that both species develop similar lesions. , , in sheep, systemic actions of the toxin leads to mostly neurological signs such as dullness, depression, ataxia, trembling, stiff limbs, opisthotonus, convulsions, frothy mouth, and rapid death. in goats, actions of the toxin appear to be more localized to the intestinal tract, causing enterocolitis, colic, diarrhea, dehydration, and occasional neurological signs. , necropsy findings. postmortem findings in sheep are characterized by edema of the brain, lungs, and heart in addition to hydropericardium. edema of the kidneys (pulpy kidney lesion) is inconsistent. sheep usually demonstrated minor and inconsistent intestinal changes. other lesions reported in cattle and deer include hemorrhages on the epicardium, thymus, and diaphragm and petechial hemorrhages in the jejunal mucosa. , necropsy lesions reported in goats include pseudomembranous enterocolitis with mucosal ulceration, as well as fibrin, blood clots, and watery contents in the bowel lumen. evidence of systemic toxemia, including multifocal petechial and ecchymotic hemorrhage, proteinaceous exudates in body cavities, pulmonary edema, hydropericardium, and cerebral malacia with perivascular cuffing, have also been reported in goats and affected deer. , , , , clinical pathology. characteristic clinicopathological changes include pronounced hyperglycemia and glucosuria, which are considered a hallmark of c. perfringens d enterotoxemia. additionally, neutrophilic leukocytosis with a left shift and evidence of systemic toxemia (metabolic acidosis, azotemia, and increases in liver and muscle enzymes) also may be seen. treatment. in general, the course of disease is too acute for the establishment of any treatment. however, as with infections with types b and c, if the disease is identified early in the disease course, high doses of oral and parenteral penicillin in addition to clostridium c and d antitoxin may be of benefit. iv fluids and antiinflammatory agents may be indicated as well. prevention. vaccination of pregnant ewes with two doses of toxoid, with the second dose given to weeks before lambing, and adequate ingestion of colostrum are the best methods of protecting newborn lambs. vaccination of older lambs should occur before exposure to diets rich in carbohydrates (grain-feedlot settings) or lush pastures. in these cases, lambs should be vaccinated twice or three times around , , and months of age. males and adult females that are not part of the breeding program may be vaccinated annually. vaccination has been shown to protect goats from experimental disease, but clinical evidence suggests that well-vaccinated goats are still susceptible to developing clostridial enteritis. the toxoids may not protect against local action of the toxins in the goat, which appears to play a greater role in their disease than it does in the sheep. , , more frequent vaccination (every months) in goats is suggested to increase protection. the adjuvant present in some multivalent clostridial vaccines may cause subcutaneous reactions that may lead to abscess formation. in the face of an outbreak, immediate mass administration of c and d antitoxin ( iu/kg) in addition to vaccination is recommended. nonenteric clostridial infections c. novyi, c. septicum, c. chauvoei, and c. sordelli have been identified as causal agents of severe muscle, liver, and abomasal necrosis in small ruminants and cervid species. , [ ] [ ] [ ] these organisms are usually present in the soil and environment and in the gastrointestinal tract and liver of healthy ruminants. pathogenesis is usually facilitated by trauma of affected tissues, local multiplication of the organism, local and systemic damage by exotoxin production, and ultimately death. , four types of c. novyi have been described, a, b, c, and d. c. novyi type c is considered nontoxigenic and therefore is not associated with disease. c. novyi type a produces alpha toxin and is associated with wound infections and myonecrosis in cases of "bighead" and "malignant edema." c. novyi type b produces alpha and beta toxins and is associated with infectious necrotic hepatitis or "black disease." , the temporal and geographic distributions of black disease resemble those of fascioliasis, with the highest incidence of disease in milder, moister months in many countries. black disease is less common in sheep than in cattle and is rare in goats. , c. novyi type d (c. haemolyticum) produces beta toxin and is associated with bacillary hemoglobinuria (red water disease). c. septicum produces alpha toxin and is associated with malignant edema and necrotic abomasitis (braxy). c. chauvoei produces alpha and beta toxins and is associated with severe myonecrosis observed in blackleg and c. sordelli produces a hemolytic toxin associated with myonecrosis in cases of malignant edema and blackleg. , pathogenesis. spores of the organism shed in feces of carrier animals contaminate the environment and are ingested with feed/ grass and stored within kupffer cells. , liver damage caused by migrating liver fluke larvae (fasciola hepatica, fasciola gigantica, and cysticercus tenuicollis) create perfect ischemic conditions that induce germination of c. novyi type b spores and toxin synthesis and production. , , the alpha toxin is necrotoxic and causes liver necrosis and diffuse damage of the vascular system. the beta toxin is produced in smaller amounts and contributes to vascular damage and systemic toxemia. infective organisms also may be brought into the liver by the flukes. clinical signs. the course of disease from first illness to death is short and never lasts more than a few hours in sheep. therefore, peracute or sudden death is not uncommon in this species. wellnourished adult sheep between and years are more commonly affected. the disease course is a little longer ( - days) in cattle and deer. , affected sheep are debilitated, fail to keep up with the flock, and exhibit generalized weakness, sternal recumbency, separation, and anorexia. tachypnea and tachycardia may be seen; high fever ( - ° f) occurs early in the disease. clinical signs observed in cattle, goats, and deer are similar and may include severe depression, anorexia, abdominal distention, colic, ruminal stasis, and lateral recumbency. , , , , , a report of black disease in a forest reindeer (rangifer tarandus fennicus) described serosanguinous discharge from mucocutaneous orifices (nostrils and anus), periorbital edema, and nystagmus in addition to other clinical signs. necropsy findings. necropsy might be difficult due to rapid autolysis of tissues in affected animals. severe venous congestion usually darkens the underside of the skin of affected animals, giving this disease its common name of "black disease." fluid in the pericardial sac, pleural space, and peritoneal cavity is usually present. endocardial and epicardial hemorrhages are a common finding. the liver is swollen and congested and on its diaphragmatic surface presents pale foci of coagulation necrosis; however, solid organs such as liver and kidneys could be in an advanced state of autolysis. characteristic lesions of black disease in the liver are single or multiple yellow to white areas ( - cm in diameter) of necrosis surrounded by a bright hyperemic zone. a recent report of black disease in a reindeer described moderate amounts of dark red thoracic and pericardial fluid, edema of the lungs and upper respiratory tract, swollen spleen, and several well-circumscribed areas of black discoloration in the liver. diagnosis. the most characteristic clinicopathological change is neutrophilic leukocytosis with a left shift. additional evidence of systemic toxemia (metabolic acidosis, azotemia, and increases in liver and muscle enzymes) also may be seen; however, diagnosis of black disease is based on characteristic history (endemic liver fluke areas), clinical signs, and postmortem findings and testing. an impression smear of the margins of the liver might reveal large numbers of gram positive rods, but this is not definitively diagnostic. anaerobic culture of c. novyi from typical liver lesions, in addition to demonstration of the alpha/beta toxins from peritoneal fluid or liver (fresh-refrigerated), through elisa or pcr is required to establish final diagnosis. , the use of fluorescent antibody and ihc for the identification of c. novyi on liver impression smear samples or other liver (formalin-fixed) samples have also been described. , treatment and prevention. treatment is rarely possible because of the fulminant clinical course of the disease; however, if treatment is attempted, high doses of penicillin g sodium ( , - , iu/kg) iv every hours or oxytetracycline mg/kg iv every hours should be initiated. supportive care, including iv fluids, nutritional support, and stress reduction, may be beneficial. in the face of an outbreak, vaccination of the whole herd/flock should be initiated immediately. efforts to control fluke infestation constitute the most effective approach to prevention of this disease. administration of multivalent clostridial vaccines containing c. novyi is highly effective. animals should be vaccinated every months starting around to months of age and before parturition as protective immunity is short lived. in flocks at high risk for developing this disorder, a booster vaccine given month before expected fluke exposure may provide additional protection. , deer should be vaccinated in the same fashion as sheep but double the vaccine dose for sheep should be used for these animals as they do not develop a strong antibody response to commercially available multivalent vaccines. , efforts to eliminate the organism from soil and environment are usually unrewarding but carcasses of animals dying from the disease should be burned, deeply buried, or removed from the premises. pathogenesis. c. novyi type d (c. haemolyticum) is the etiologic agent associated with red water disease. c. haemolyticum is similar to other clostridial species in its life cycle and appears to thrive on alkaline soils and pastures with standing water. the disease tends to be seasonal occurring at times of high larval fluke migration. similar to c. novyi b, c. haemolyticum colonizes the livers of healthy animals and proliferates after liver damage, including damage caused by migrating flukes (f. hepatica, fascioloides magna, dicrocoelium dendriticum, and c. tenuicollis), liver abscessation (fusobacterium necrophorum or trueperella pyogenes), or damage incurred during liver biopsy. , under ischemic conditions of the liver, spores of c. haemolyticum germinate and produce high amounts of beta toxin. the beta toxin causes localized hepatic necrosis and after reaching circulation induces severe intravascular hemolysis and damage of the capillary endothelium. intravascular hemolysis leads to rapid anemia and death due to anoxia. the disease is seen worldwide and is more commonly reported in sheep than in goats. bacillary hemoglobinuria has been reported in a free-ranging elk calf (cervus elaphus roosevelti) found dead in the southwest of the state of washington, united states. clinical signs. bacillary hemoglobinuria usually affects wellnourished animals older than year of age. , in most cases, the disease is per-acute and sudden dead or found dead is the only sign. in cases where signs are recognized antemortem, affected animals appear weak, depressed, and febrile ( - ° f); blood or blood-tinged froth may be present in the nostrils; rectal bleeding and bloody feces may be present; and severe hemoglobinuria (dark red, port wine-colored urine) is usually observed. , blood appears thin and watery and mucous membranes are pale and icteric. heart and respiratory rates are high and become much higher with any sort of effort or stress. other terminal signs include bloat and the presence of blood in the nostrils, mouth, vagina, and rectum. death occurs within hours to a few days after onset of clinical signs. necropsy findings. gross lesions include jaundice of mucous membranes and tissues and subcutaneous petechial/ecchymotic hemorrhages, edema, and emphysema. marked autolysis of internal organs might prevent identification of typical lesions. dark red urine is present in the bladder. lymph nodes and spleen are congested and hemorrhagic. hemorrhagic abomasitis and enteritis might occur, as well as the presence of hemoglobin-stained transudate in pleural and peritoneal cavities and pericardial sac. pulmonary edema is common. the pathognomonic lesion is the ischemic hepatic infarcts ranging from to cm in diameter with a hyperemic interface with healthy liver tissue. , diagnosis. clinicopathological abnormalities usually include anemia, leukocytosis with mature neutrophilia, and degenerative left shift (immature forms of neutrophils and toxic changes) often is present. , serum biochemical evaluation may reveal increased levels of liver enzymes such as sorbitol dehydrogenase, ggt, aspartate aminotransferase, and increased indirect total serum bilirubin. [ ] [ ] [ ] presumptive diagnosis can be made on history, clinical sigs, clinicopathological abnormalities, and postmortem findings; however, similar to black disease, final diagnosis should be based on anaerobic culture of c. novyi from typical liver lesions in addition to demonstration of the beta toxins from peritoneal fluid or liver (fresh-refrigerated) through elisa or pcr techniques. , , , the use of fluorescent antibody and ihc for the identification of c. novyi on liver impression smears or other liver (formalin-fixed) samples has also been described. , more recently, a pcr assay for the detection of c. novyi type d in cattle has been reported. treatment and prevention. treatment is rarely possible because of the fulminant clinical course of the disease; however, if treatment is attempted, high doses of penicillin g sodium ( , - , iu/kg) iv every hours or oxytetracycline mg/kg iv every hours should be initiated. supportive therapy should include the administration of iv fluids, blood transfusions, and antiinflammatory agents. efforts to control liver flukes and prevent other causes of liver damage are most important. administration of multivalent clostridial vaccines containing c. novyi is highly effective. animals should be vaccinated every months starting around to months of age and before parturition as protective immunity is short lived. in flocks at high risk for developing this disorder, a booster vaccine given month before expected fluke exposure may provide additional protection. deer should be vaccinated in the same fashion as sheep, but double the vaccine dose for sheep should be used as these animals as they do not develop a strong antibody response to commercially available multivalent vaccines. , efforts to eliminate the organism from soil and environment are usually unrewarding but carcasses of animals dying from the disease should be burned, deeply buried, or removed from the premises. pathogenesis and clinical signs. fecal and soil contamination of wounds received during fighting (head-butting) or dehorning (disbudding) leads to proliferation of c. novyi type a in damaged head and neck tissues. accumulation of secreted toxins leads to swelling, edema, serohemorrhagic exudates, and local tissue necrosis. wounds appear and smell gangrenous. systemic toxemia may affect internal organs, leading to the death of the animal. c. sordelli causes identical disease. diagnosis. laboratory analysis may reveal an increase in enzymes of muscle or liver origin as well as neutrophilic leukocytosis with many immature and toxic neutrophils. postmortem findings include local necrosis around the injury site. diagnosis usually is made by characteristic clinical signs and lesions. treatment. wound management (disinfection, debridement) and administration of high doses of penicillin g sodium ( , - , iu/kg) iv every hours are important treatment considerations. prevention. ram management may aid in the prevention of head-butting wounds. vaccination with multivalent clostridial toxoids starting around weaning time ( - months of age) and with annual boosters also may be helpful. in flocks with a high prevalence of this disorder, a booster vaccine given to rams month before the breeding season and to ewes/does before parturition may provide additional protection. pathogenesis. c. septicum is the most important agent in the pathogenesis of malignant edema and braxy. in the case of malignant edema, other tissue-invasive clostridia (c. chauvoei, c. sordelli, and c. perfringens a) have also been associated with this disease, and mixed infections are common. the pathogenesis of infection is often similar to that seen with bighead and blackleg: soil or fecal clostridial invasion of a contaminated wound. in sheep and goats, this disease has been reported following lambing/kidding, after shearing of tail docking. c. septicum can also invade the abomasal lining of lambs, causing severe hemorrhagic, necrotic abomasitis known as braxy. activation of dormant bacteria in previously damaged tissue (myositis/abomasitis) similar to that seen in clostridial necrotic hepatitis also occurs. in both cases (malignant edema and braxy), bacterial toxins precipitate local tissue necrosis and systemic toxemia. the alpha, beta, gamma, and delta toxins produced by c. septicum are lecithinase, deoxyribonuclease, hyaluronidase, and hemolysin, respectively. commonly affected sites of malignant edema include castration, dehorning, and injection sites; the umbilicus; and the postpartum uterus. factors that promote braxy have not been identified, although it usually affects weaned and yearling lambs in the winter after ingestion of frozen feedstuffs implicated as initial causes of abomasitis. , both forms of the disease have worldwide distribution and are described more in sheep than in goats. , clinical signs. malignant edema is characterized by local lesion (wound) or regional pain characterized by swelling and edema that progressively becomes tense and dark (skin). high fever, signs of shock/toxemia, and frothy exudation of the wound are usually present. evidence of subcutaneous gas production is less common in this infection than in blackleg. uterine infection may cause a fetid vaginal discharge. death occurs within hours to a few days after onset of clinical signs. braxy usually causes death before any abnormalities are noted. on rare occasions, signs of sudden onset of illness with high fever, abdominal distention, depression, colic, and recumbency may be seen before death. diagnosis. characteristic clinicopathologic changes include neutrophilic leukocytosis with a left shift. a decrease in wbc and rbc counts also is possible because of the leukocidal and hemolytic effects of the toxins. additional evidence of systemic toxemia (metabolic acidosis, azotemia, and increases in liver and muscle enzymes) also may be seen. examination of a gram-stained smear from the edematous swelling(s) or wound swabs could give an early diagnosis. one study reported the successful use of a pcr assay for the identification of bacteria associated with malignant edema in cattle, sheep, and other ruminants. postmortem changes with malignant edema include dark red, swollen muscle filled with hemorrhagic, proteinaceous exudate and little or no gas. with braxy, the abomasal wall is hemorrhagic and necrotic. both diseases are associated with rapid postmortem decomposition of the carcass. treatment and prevention. wound management and the rapid administration of high doses of penicillin (penicillin g sodium at , - , iu/kg iv every hours) are important in treating malignant edema. local treatment consists of surgical incision of the affected area to provide drainage and irrigation with peroxide. injection of penicillin directly into or in the periphery of the lesions may help. ancillary treatments such as iv fluids, antiinflammatory agents (e.g., flunixin meglumine, mg/kg iv), and nutritional support may be necessary. maintenance of good hygiene during procedures such as lambing, tail docking, shearing, castration, obstetric manipulation, and administering injections is helpful in preventing malignant edema. multivalent clostridial toxoids may provide some protection and should be given annually to animals at risk for the disorder. pathogenesis. several species of clostridial organisms can cause myonecrosis in small ruminants. , , the disease is acute to per-acute, has a short course of duration, and is usually fatal. c. chauvoei, c. septicum, and c. sordelli are commonly involved with clostridial myonecrosis in ruminants. [ ] [ ] [ ] blackleg can be enzootic in some areas or farms because of increased bacterial contamination and occurs more commonly in the warm months of the year. [ ] [ ] [ ] animals between months and years of age can be affected. , c. chauvoei is the most important cause of blackleg. c. sordelli tends to be involved in the myonecrosis of older feedlot animals. these organisms are found in the soil and can gain access to muscles after translocation from the gastrointestinal tract and liver into systemic circulation. additionally, direct inoculation of the organisms by penetrating wounds or intramuscular injections has been suggested. local tissue trauma, wounds, unsanitary procedures (i.e., shearing, tail docking, and castration), umbilical infection (neonates), or vaginal trauma from lambing can create perfect conditions for the germination of clostridial spores inducing rapid toxin synthesis and production. in some cases, bacterial proliferation appears to occur in a site distant from the original wound (i.e., fetal infections after shearing of a ewe and myocardial necrosis in cattle and sheep). bacterial toxins cause severe local tissue necrosis, systemic toxemia, and ultimately death. as with braxy, several other strains of tissue-invasive clostridia can cause this disease and mixed infections are common. clinical signs. clostridial myonecrosis usually progresses rapidly and sudden death or history of found dead is not uncommon. [ ] [ ] [ ] clinical signs in animals who are still alive include local to regional painful, edematous swelling most commonly in the limbs or trunk muscles. skin of the affected area can become discolored and crepitus; however, in affected sheep, subcutaneous edema and gaseous crepitation are uncommon and cannot be felt before death. other signs might include stiff gait, lameness, fever, and signs of shock. in cases where the infection occurred through a wound, there is extensive local damage and malodorous serosanguinous fluid discharge. c. chauvoei also causes uterine infection and severe gangrenous mastitis in postparturient ewes. , in these cases, uterine and mammary infections may cause fetid vaginal and mammary discharge, respectively. death often occurs within to hours after onset of clinical signs. necropsy findings. rapid tissue autolysis is not uncommon in animals that succumb to clostridial myonecrosis. bloodstained fluid and froth can be observed discharging from nostrils and anus. in small ruminants and especially sheep, affected muscle areas are more localized and deeper, brown to black discoloration is present, the subcutaneous edema is not as severe, and, although there is gas present, is not in such large amounts as in cattle. in cases of infection from skin wounds, the area demonstrates subcutaneous edema, swelling, and underlying muscle discoloration. in cases of infection through the urogenital tract, typical lesions are found in the perineal area, vagina, uterus, and fetus. lung congestion, fibrinohemorrhagic pleuritis, pericarditis, myocardial damage, and bloat are also common findings. , diagnosis. it is rarely possible to obtain samples for clinicopathological analysis due to the per-acute course of the disease. if samples can be obtained, common findings include neutrophilic leukocytosis with a left shift. a decrease in wbc and rbc counts also is possible because of the leukocidal and hemolytic effects of the toxins. additional evidence of systemic toxemia-metabolic acidosis, azotemia, and increases in liver and muscle enzymesalso may be seen. presumptive diagnosis can be made from history, characteristic clinical signs, and gross pathology findings; however, aspirates or tissue specimens from affected muscles for direct smear examination, fluorescent antibody testing, or anaerobic culture are required for definitive diagnosis. , a multiplex pcr is available for identification of pathogenic clostridia on fluid and tissue samples. treatment and prevention. aggressive antibiotic therapy (e.g., penicillin g sodium or potassium penicillin at , - , iu/kg iv every hours), in combination with surgical debridement of affected tissues (fasciotomy), and supportive care (nutritional support, iv fluids, and antiinflammatory agents) are important within the treatment plan for clostridial myositis. prognosis for treatment of all types of clostridial myositis cases is usually guarded to poor and depends on the duration and extension of the lesions. maintaining excellent hygiene during invasive procedures such as castration, obstetric manipulation, shearing, tail docking, and administering injections is helpful in preventing blackleg. multivalent clostridial toxoids may provide some protection and should be given to all animals starting at weaning time, before parturition, and annually. , both tetanus and botulism are important diseases in small ruminant medicine. these two diseases are covered elsewhere in this book (see chapters , , , , and ) . older animals are generally more resistant to sepsis than neonates because they have larger amounts of circulating antibodies. however, this resistance can be overwhelmed by aggressive bacteria, or loss of immune function can allow invasion by opportunistic bacteria. malnutrition, parasitism, transport, overcrowding, other diseases, extreme weather conditions, and other stressors are the major causes of immune suppression. sepsis may produce peracute, acute, or chronic disease signs. peracute signs include fever, injected mucous membranes (including the sclera), tachycardia, tachypnea, dyspnea, swollen joints, lameness, splinting of the abdomen, weakness, depression, anorexia, recumbency, seizures, coma, and sudden death. acute signs are similar, except that they persist for a longer period and therefore are more likely to be noticed. chronic signs usually result from the partial clearance of infection after an acute episode, which may be clinical or inapparent. pathogenesis. gram negative bacteria and their toxins gain access to the blood from a site of proliferation or destruction. the most important toxin is endotoxin, a group of lipopolysaccharide molecules that reside within the wall of the bacteria. bacteria or endotoxins incite a systemic inflammatory response, chiefly through activation of host macrophages and stimulation of host cytokine release. these cytokines cause inflammation, produce leukocyte recruitment, increase capillary permeability, induce fever through stimulation of the hypothalamus, and have regional or diffuse vasomotor effects. because the ruminant gut has a plentiful population of gram negative bacteria, it is implicated as the source of most cases of gram negative sepsis. grain overload causes a die-off of the normal gram negative ruminal flora, ulcerative enteric disease allows invasion of bacteria or absorption of their toxins, and ingestion of pathogens provides a suitable place for proliferation and route for invasion of the body. gram negative sepsis caused by opportunistic organisms is best recognized in immunocompromised neonates but also can be seen in stressed or immunocompromised animals of all ages. e. coli is commonly found in fecal material, klebsiella pneumoniae is found in feces and wood products, f. necrophorum lives in the gastrointestinal tract and in soil and invades through compromised gastric mucosa or foot-rot lesions, and pseudomonas aeruginosa is commonly found in water and wash solutions. primary pathogens are most common in adults. although some coliform bacteria may fit into this category, by far, the most important genus is salmonella. sources of salmonella infection are numerous and include carrier animals of the same species, cattle, rodents, birds, other animals, environmental contamination, and possibly feedstuffs. only one serotype of salmonella is specifically adapted to sheep (salmonella abortus ovis), and it is not found in north america. no strain is known to be host-adapted to goats or cervids. therefore, all infections in sheep, goats, and cervids have the potential to spread to and from other species, including humans. serotypes of salmonella that have caused important infections in sheep or goats include salmonella typhimurium, salmonella dublin, and salmonella montevideo. most of these infections lead to bacteremia with mild systemic signs, followed by abortion. s. dublin and s. typhimurium tend to cause more illness in adults because of fibrinonecrotic enteritis. clinical signs. affected animals can exhibit anything, from mild depression with a low-grade fever to shock. common signs include fever, tachycardia, tachypnea, depression with slow or absent eating and drinking, weakness or recumbency, and injection or cyanosis of mucous membranes. organ-specific signs may betray the source or at least the primary location of the infection. fetid discharge may be seen with metritis or abortion; dyspnea and abnormal lung sounds may be seen with pulmonary infection; and bloat, ruminal atony, abdominal distention, and diarrhea may be seen with gastrointestinal infections. diagnosis. the most common abnormality identified on a cbc with peracute gram negative sepsis is panleukopenia. over the course of several days, this condition may resolve, first through an increase in immature neutrophils and later through an increase in mature neutrophils and restoration of lymphocyte counts. very immature cells, severe toxic changes, and persistence of neutropenia suggest a poor prognosis. serum biochemical changes often reflect the severity of the condition. the greater the evidence of shock or tissue damage, the worse the prognosis. metabolic acidosis with a large anion gap and azotemia suggest advanced disease. necropsy findings include diffuse evidence of inflammation, including pulmonary congestion, and polyserositis with body cavity exudates. hemorrhagic pneumonia or fibrinonecrotic enteritis may be seen and reflect the source of bacterial invasion. in all cases, diagnosis is best confirmed by bacteriologic culture of body tissues or fluids. in the live animal, culture of blood, feces, or tracheal fluid yields the best results. when several animals are infected, environmental samples (including feed, water, and bedding) should be tested for the presence of the bacteria. bacteriologic culture of aborted fetuses or placentas frequently yields heavy growth of the organism. prevention. maintaining overall good health and hygiene is the best means of preventing gram negative sepsis. antiendotoxin bacterins are available for cattle in the united states, but their use in small ruminants has been too limited to assess their efficacy. during a flock outbreak, the use of autogenous bacterin may help prevent the spread of disease on a farm. actinobacillus seminis is a gram negative bacillus or coccobacillus that affects primarily the male and female reproductive tracts. infection causes posthitis, epididymitis, and orchitis in rams and metritis and abortion in ewes. other sites of infection, including rare occurrences of chronic sepsis, also are possible. serologic tests are much more useful for identifying infected flocks than infected individuals within flocks. definitive diagnosis depends on bacteriologic culture of the organism and differentiation of it from brucella ovis. the bacillus is common in sheep in some parts of the world but is uncommon in north american sheep and goats. t. pyogenes is best known as an abscess-forming bacterium because of the thick pus formed in response to infection by it and the fibrinous response it elicits. it occasionally also causes sepsis. its association with chronic sepsis lends credence to the belief that trueperella is often a secondary invader that colonizes tissues damaged by another bacterium (see chapter ) . bacillus anthracis is a large, gram positive, anaerobic bacillus that causes anthrax. it forms spores under aerobic conditions (such as on culture plates) but rarely does so when oxygen tensions are low, as in carcasses. the organism affects most mammals, with herbivores being most susceptible. it is usually carried from one area to another by shedding or dying animals and also can multiply in alkaline, nitrogenous soils. periods of heat and intermittent flooding promote overgrowth of the organism. b. anthracis spores may be inhaled or ingested; in rare cases, the bacillus itself may be spread by biting flies. after local replication, the organism gains access to the blood, where it multiples readily. large numbers of the organisms colonize the spleen. b. anthracis secretes a holotoxin made of edema factor), protective antigen, and lethal factor. this toxin impairs phagocytosis, increases capillary permeability, and inhibits clotting. splenic engorgement, generalized edema, circulatory shock, and bleeding diathesis are the most common lesions and signs of anthrax. generalized infection should be considered uniformly fatal. death may occur before or within hours of initial recognition that the animal is sick. prophylactic antibiotic treatment of healthy animals (oxytetracycline mg/kg iv sid) may decrease spread and mortality during outbreaks. the disease is reportable in many areas. local forms of anthrax also occur, most commonly after transmission through a skin wound or fly bite. local heat, pain, swelling, and necrosis are seen first, and the generalized syndrome often follows. bacterial organisms are rarely identified before important treatment decisions must be made. therefore, treatment should follow general principles and have a wide spectrum of efficacy. antimicrobial drugs are the cornerstone of treatment. in meat-or milkproducing animals, the veterinarian must be careful to use drugs within label directions or have a rational plan for extra-label drug use. the issue of extra-label drug use is especially important in small ruminants and cervids because very few pharmaceutical products have been licensed for them in north america. unless a specific organism is suspected (clostridiosis or anaplasmosis), a single antibiotic or combination of antimicrobial drugs to provide a broad spectrum of coverage should be selected. penicillins, macrolides, tetracyclines, and cephalosporins all provide effective coverage against gram positive pathogens. the newer third-generation cephalosporins are effective against many systemic and enteric gram negative pathogens. the gram negative pathogens of the respiratory tract are often sensitive to other classes of antibiotics. macrolides and tetracyclines also are effective against mycoplasma species and rickettsial organisms. nsaids are almost always beneficial in severe infectious conditions because of their antiinflammatory, antipyretic, and antiendotoxic effects. they are likely to be more effective than corticosteroids because they provide benefits without suppressing the immune response. all such drug use should be considered extralabel and administered accordingly with appropriate withdrawal times established. specific antisera are available for some of the clostridial diseases and may be beneficial if given before widespread tissue necrosis has occurred. severely compromised animals should be treated with fluids for shock (see chapter ). the most common zoonotic disease risk posed by exposure to small ruminants is orf, also known as contagious ecthyma in animals (see chapter ) . the disease is caused by an epitheliotropic poxvirus and is transmitted to humans by direct contact with infected animals. skin trauma is a significant risk factor for transmission in both humans and animals. in humans, erythematous macules or papules appear at the site of infection to days following exposure. the infection is generally self-limiting in immunocompetent individuals with complete healing occurring within weeks. brucella melitensis. apart from contagious ecthyma, the greatest risk of zoonotic disease from small ruminants is due to pathogens typically found in the reproductive tract that are transmitted to humans through contact with aborted fetuses, the placenta, or birthing fluids or through the consumption of raw or improperly pasteurized dairy products. b. melitensis is more common in goats than sheep (see chapter ) . swine, cattle, and other ruminants are common hosts. infection in animals usually causes inapparent mammary infection and abortions; infection in humans is characterized by undulant fever, myalgia, and fatigue. coxiella burnetii. c. burnetii is a rickettsial organism that is an important cause of abortion in sheep and goats (see chapter ) . wildlife and farm-raised deer may serve as reservoir hosts for infection in other ruminants and humans. infection is a documented cause of reproductive failure in farmed deer and prolonged shedding of the organism is an important source of environmental contamination. in addition to abortion, newly infected sheep and goats occasionally have mild, transient fevers. c. burnetii is far more important as the cause of q fever in humans, who become infected after inhaling particles, handling contaminated animals, or coming into contact with contaminated body fluids (uterine fluid, milk) from infected animals. infection in humans may be asymptomatic, present with flu-like symptoms, or, in the chronic form, present as granulomatous hepatitis, osteomyelitis, or bacterial endocarditis. chlamydophila spp. chlamydophila abortus (previously chlamydia psittaci) is an obligate intracellular parasite and the cause of enzootic abortion of small ruminants (see chapter ) . chlamydophila pecorum may cause polyarthritis and keratoconjunctivitis (see chapter ) in sheep and goats. transmission between animals and to humans most commonly occurs through direct contact with infected tissues or materials. infection in humans results in an acute febrile syndrome or respiratory symptoms. chlamydial diseases are more commonly reported in sheep than in goats. chlamydial diseases are suspected to cause disease in other species, including deer. recent serologic evaluation of wild ungulates identified multiple species of deer with antibodies against several chlamydial species. the clinical significance of serological infection in these species remains undetermined. francisella tularensis. f. tularensis is more common in sheep than goats. the organism has many hosts, of which the most important are wild rabbits and rodents. it can contaminate water sources. transmission to sheep is usually through biting arthropods that have previously fed on an infected wild mammal. acute or chronic sepsis may be seen, with more widespread and severe disease occurring in sheep with poor immune function. at necropsy, the disease is characterized by military foci of necrosis in the liver, and less commonly in the lymph nodes, spleen, and lungs. most cases in humans result in acute onset of flu-like symptoms a few days after exposure. l. interrogans. pathogenesis. leptospira spp. are spirochete bacteria that live in moist environments. their survival time outside of hosts is usually short, so their most important reservoirs are the kidneys of infected animals, especially rodents. infected animals shed the organisms through urine and most other body fluids. organisms enter new hosts through mucous membranes and skin breaks and cause bacteremia. signs of sepsis range from inapparent to severe, with more severe signs predominating in neonates. intravascular hemolysis may result. in animals that survive the acute stage, infection may localize in sites such as the kidneys, eyes, and fetoplacental unit. abortion may occur a month or more after acute signs first become evident while renal shedding may occur for several months. leptospirosis is zoonotic. in most cases, infections in humans are asymptomatic and selflimiting. however, in approximately % of cases, severe, and potentially fatal, systemic disease may develop, including jaundice, renal failure, and pulmonary hemorrhage. clinical signs acute leptospirosis causes signs of sepsis, including fever, depression, dyspnea, exercise intolerance, weakness, and death (see chapter ) . additionally, many affected animals show signs of intravascular hemolysis such as anemia, icterus, and hemoglobinuria. diagnosis evidence of intravascular hemolysis such as anemia, hyperbilirubinemia, hemoglobinuria, and hemoglobinemia is suggestive of this disease. in chronic infection, non-specific inflammatory changes and azotemia may be seen. animals dying in the acute hemolytic stage are likely to have dark, discolored urine, bladder, and kidneys. spirochetes can be identified on dark-field microscopy of fresh urine or plasma from infected animals and may be cultured with special techniques. in animals with less severe infection, a rise in antibody titers can be used to support a diagnosis of leptospirosis. prevention numerous vaccines are available for sheep. because protection is serotype specific, it is important to vaccinate against common serotypes in the area. leptospira pomona is the most consistent isolate from sheep and goats; leptospira hardjobovis is the predominate serovar in deer. vaccination immunity is thought to be short lived; boosters should be given at least twice a year in endemic areas. vaccination of deer against serovars hardjobovis and pomona has been associated with decreased urine shedding and increased growth rate in young animals. pathogenesis. l. monocytogenes causes disease with similar frequency in sheep and goats (see chapter ) . the organism is a common soil and fecal contaminant. it also proliferates in silage that is not properly acidified and in rotting, woody debris. risk of exposure depends on the feed and environment of the animals. environmental and fecal contamination is a more common source than silage in small ruminants overall because most sheep and goats throughout the world are not fed silage. infection in humans almost always results from ingestion of contaminated food products or unpasteurized milk. clinical signs. nervous system dysfunction and abortion are the most common manifestations of the disease. animals with the brainstem form of the disease display signs reflective of cranial nerve dysfunction, including drooped ears or eyelids, decreased facial sensation, and deviated nasal septum. a head tilt and circling may be present; in advanced cases of the disease, the animal is recumbent. clinical signs are mainly unilateral, occasionally bilateral, according to the nerve nuclei affected. diagnosis. antemortem diagnosis of listeriosis is difficult. a presumptive diagnosis is made based on history, clinical signs, and potential response to treatment. histopathologic identification of microabscesses in the brainstem and culture of the organism from affected tissues can be used to confirm the diagnosis. pathogenesis. p. multocida is a small, gram negative, bipolar, ovoid rod that inhabits the pharynx of healthy ruminants. it can survive in soil and water for varying amounts of time after contamination with ruminant nasal secretions. healthy ruminants shed p. multocida much more frequently than mannheimia haemolytica. disease occurs when bacteria colonize the lower respiratory tract or enter the blood. risk factors for pulmonary and systemic infection include viral or mycoplasmal respiratory diseases, temperature extremes, respiratory tract irritants, transport, overcrowding, changes to higher-energy feeds, and handling stress. these factors are thought to both increase bacterial replication in the airway and suppress mechanisms to clear the infection. pasteurellosis is a major problem in feedlot sheep but less common in small breeding or hobby flocks. pasteurellosis also is a significant disease in certain wild small ruminants such as bighorn sheep. direct spread of the organism between animals occurs with nasal contact, and indirect spread occurs after contact with infected nasal secretions. the organism persists in the environment for longer periods during warm, moist weather. p. multocida produces a polysaccharide capsule that inhibits phagocytosis and an endotoxin that contributes to clinical signs. the major disease caused by p. multocida is pneumonia (see chapter ). however, pasteurella spp. also are capable of entering the blood to cause septicemia in young lambs and hemorrhagic septicemia in adults. occasionally, focal infections such as septic arthritis and mastitis are found. clinical signs. clinical signs of pneumonic and septicemic pasteurellosis include severe depression, bilateral purulent nasal discharge, coughing, diarrhea, anorexia, high fever, and edema of the head, neck, and brisket. the disease course can be short with septicemic pasteurellosis and is usually more insidious with p. multocida pneumonia. pasteurella mastitis is characterized by the bluebag condition or gangrene of the udder. diagnosis. inflammatory changes in the leukogram and hyperfibrinogenemia are the most frequent abnormalities. with severe disease and in the septicemic form, immature neutrophils may predominate over mature cells. inflammation of the intestine and abomasum also may be seen. hemorrhage and fibrin are usually absent or less prominent than in pneumonia caused by m. haemolytica. samples for bacteriologic culture are usually obtained postmortem. blood or tracheal fluid may be obtained before death if the value of the animal warrants it. m. haemolytica is a gram negative rod that is a common commensal inhabitant of the tonsils of young animals. disease is much more frequently described in sheep than in goats and occurs when the organism gains access to the lower respiratory tract. clinical signs and diagnosis. the most common syndrome is enzootic pneumonia, which is seen in young lambs and their dams (see chapter ) . hemorrhagic bronchopneumonia is the major lesion and respiratory signs predominate. gangrenous mastitis (bluebag) is seen in some of the dams, presumably after they have been nursed by infected offspring. factors that promote respiratory disease, including viral infections, airborne irritants, high stocking density, and stress, are thought to promote invasion of the lower airway by these bacteria. b. trehalosi is a gram negative rod that is a commensal inhabitant of the upper respiratory tract (see chapter ) . disease is much more frequently described in sheep than in goats and occurs when the organism gains access to the lung or blood. replication occurs in the lung and systemic toxemia or bacteremia resulting in septicemic pasteurellosis. septicemic pasteurellosis is a significant cause of mortality in young lambs and in some farms is the leading cause of death in the age group. clinical signs. septicemic pasteurellosis occurs most commonly in weaned lambs, often following some form of stress such as transport, marketing, or weaning itself. the course of the disease is relatively rapid, and animals may be found dead within hours without showing premonitory clinical signs. when observed, clinical signs include depression, recumbency, and signs of toxemia. diagnosis. septicemic pasteurellosis should be suspected when presented with a dead, recently weaned, sheep with a recent history of stress. diagnosis is best confirmed by typical lesions at necropsy and culture of the organism from bodily tissues. demonstration of b. trehalosi in nasal swabs is of limited value due to the high prevalence of upper respiratory tract colonization in healthy lambs. at necropsy, there may be no evidence of pneumonia, but blood-stained foam can be found in the upper respiratory tract. ulceration of the pharynx and esophagus is commonly present as is subcutaneous hemorrhage of the neck and thorax. prevention. treatment is difficult due to the rapid course of disease. efforts should be made to minimize stressors, particularly during and following weaning, and to manage management factors that may contribute to the disease. vaccination with pasteurella bacterins is rarely effective at controlling natural outbreaks of disease. pathophysiology. abscess-forming bacteria are usually able to survive phagocytosis and thereby avoid destruction by cells of the immune system. alternatively, they invoke such an inflammatory response that the host body "walls off" the entire region with fibrous tissue. abscesses may occur locally, frequently after a wound infection, or at numerous or distant sites from the point of infection. for abscesses to occur at the latter sites, the organism must travel either by way of the blood or within leukocytes. disease characterized by multifocal or internal abscesses usually results from a low-grade, transient event of bacteremia. the best known and most important abscess-forming bacterium in small ruminants is corynebacterium pseudotuberculosis, the gram positive, facultative anaerobic coccobacillus that causes caseous lymphadenitis. infection is usually maintained in a flock by infected animals that spread the organism to others through purulent material draining from open abscesses. the organism is very hardy, so infection can occur through direct contact or indirect contact with contaminated common instruments and facilities. infection is usually introduced into a flock through acquisition of an infected animal, although it also can occur when a naive flock is moved into a contaminated area. horses, cattle, and humans also are minor hosts. infection is thought to occur after ingestion, inhalation, or wound contamination. except for lower respiratory tract invasion, a surface break is thought to be necessary. contaminated shears, tail-docking knives, and emasculators readily spread the organisms through a flock. abscesses can form at the site of invasion or more commonly at the site of the local lymph node. clinical signs. clinical signs of external abscesses include surface swellings and draining lesions. drainage may be intermittent and usually consists of thick, yellow-white purulent material. internal abscesses are more difficult to diagnose. thoracic masses may cause inspiratory dyspnea or occlude venous return to the heart. abdominal lesions may cause tenesmus, stranguria, and occasionally colic. the most common sign of internal abscesses is weight loss with or without intermittent fever. common external sites include the submandibular or retromandibular space and the preinguinal, prefemoral, and supramammary lymph nodes. head and neck lesions are more common in goats, whereas sheep have a more even distribution of cranial and caudal lesions, presumably as a result of shearing wounds. external infections rarely cause clinical illness beyond the draining abscess, although some degree of cachexia may be present. diagnosis. diagnosis is often made by the characteristic lesions with their thick, nonmalodorous pus. bacteriologic culture provides a definitive diagnosis, which may be important for flock management. serologic tests have been developed to identify carrier animals and may be useful if the manager wishes to eliminate infection from the flock. treatment. treatment is often unrewarding: antibiotic sensitivity profiles do not reflect the degree of protection afforded the organisms within the abscesses. long-term treatment with antibiotics and drainage of any compromising masses may lead to some degree of resolution, but internal abscesses are likely to persist. prevention. prevention through the use of vaccines has been attempted. vaccines appear to reduce the severity of the disease but do not completely prevent infection. moreover, live attenuated bacterins lead to de facto infection of all vaccinated animals and therefore should not be used in naïve flocks. other abscess-forming bacteria are most important as differential diagnoses for caseous lymphadenitis. t. pyogenes is another wound contaminant that affects focal areas or regional external lymph nodes. it also commonly colonizes damaged internal tissues such as postpneumonic lungs, postacidotic livers, and damaged feet and heart valves. it is thought to be ubiquitous and poorly invasive in ruminants and therefore does not have the same flock significance as c. pseudotuberculosis. flocks with outbreaks of this infection often have suboptimal management. f. necrophorum causes similar disease and often coinfects with t. pyogenes. it is generally more necrotizing and leads to greater systemic signs of acute illness, including death. f. necrophorum also produces fetid pus, whereas t. pyogenes usually does not. rhodococcus equi is a rare cause of pulmonary abscesses in sheep. numerous small, coalescent, nodular skin abscesses may result from pseudomonas pseudomallei infection (melioidosis). infection usually occurs after the sheep or goat is bitten by an insect that previously fed on an infected rodent. this organism is found in many subtropical regions, including the caribbean, but is not reported in north america. f. necrophorum causes or is associated with a variety of diseases in sheep and is likely to cause many similar diseases in goats. it is best known as a cause of foot rot and hepatic abscesses and appears to be important in lip-leg ulceration. it is an enteric gram negative anaerobe and as such can cause gram negative sepsis after entrance of the bacteria or its toxins into the circulation. f. necrophorum has a poor ability to invade healthy tissue. however, it readily colonizes regions damaged by trauma, persistent moisture, and infection. in addition to endotoxin, the bacterium produces leukocidal and cytolytic toxins that form zones of necrosis around bacterial colonies. this tissue necrosis and the foul-smelling waste gases produced by the bacteria are characteristic of necrobacillosis, or f. necrophorum infection. clinical signs include necrotic, fetid lesions, usually of the mouth or feet, that can cause ingestion or lameness problems. efforts to maintain good hygiene are helpful in preventing fecal contamination. additionally, preventing trauma to foot and mouth tissues through good surface choices and proper pasture drainage is important. pathogenesis. yersinia spp. are gram negative bacteria. yersinia enterocolitica and yersinia pseudotuberculosis both have many mammalian and avian hosts, including humans, and cause clostridial enteritis-like disease in goats. rodent and bird hosts may be important reservoir populations for infections in domestic animals. kids younger than months develop enteritis, bacteremia, and diarrhea that is watery but not bloody. severe toxemia and sudden death can occur. older kids and flocks with chronic exposure tend to have less severe acute disease. instead, chronic diarrhea and weight loss are seen, usually in association with gut wall and abdominal abscesses. sheep, deer, and wild ungulates are rarely affected. clinical signs. signs of enteritis or sepsis predominate in acute disease, whereas signs of wasting are more common in chronic disease. diagnosis. evidence of acute or chronic inflammation is provided by blood work. characteristic necropsy lesions include numerous microabscesses in the gut wall and mesenteric lymph nodes, as well as other evidence of enteritis or sepsis. culture of lesions and demonstration of a rising antibody titer are diagnostic. prevention. avoiding exposure to sources and maintaining overall flock health are helpful in preventing losses due to yersiniosis. pathogenesis. mycobacteria are small, aerobic, straight or curved pleomorphic rods with thick lipid cell walls. they can be stained with acid-fast stains and are usually gram positive. the bacteria live within infected animals of many mammalian species and survive for several years in warm, moist environments. infection occurs after ingestion or inhalation. an identifying characteristic of the mechanism of infection by mycobacteria is the bacteria's ability to survive within macrophages by preventing fusion of phagosomes and lysosomes. the organisms are carried to local lymphatic vessels or lymph nodes, where they form granulomas. as they enlarge, granulomas may develop necrotic or mineralized centers surrounded by macrophages and giant cells. disease can be local, regional, or generalized, depending on the distance the organism is carried from the original site of infection. granulomatous pneumonia, enterocolitis, and lymphadenitis are the most common local and regional forms of the disease. organisms from ruptured granulomas may be spread in contaminated respiratory secretions and feces. mycobacterial infections of all types are uncommon in north american sheep, goats, and cervids, and these species are considered to be relatively resistant to infection. mycobacterium bovis is the most common organism associated with ovine tuberculosis in other countries (see chapter ), but mycobacterium avium is more common in the united states. the most common mycobacterial infection is johne's disease (paratuberculosis) caused by the etiologic agent m. avium subsp. paratuberculosis (see chapter ) . mycobacterium tuberculosis is rare in the united states. mycobacterial infections are reportable in most parts of the united states. some debate is ongoing about human susceptibility to m. avium subsp. paratuberculosis; the other organisms are known to be pathogenic in people. clinical signs. the most common clinical sign is emaciation. diarrhea may be seen terminally in both tuberculosis and paratuberculosis. the disease is insidious, with signs becoming more apparent over several weeks to months. respiratory signs may be seen, especially with infection by m. bovis or m. avium subsp. diagnosis. reports of clinicopathologic abnormalities are rare. hypoalbuminemia and hypoproteinemia are likely to be common with chronic enterocolitis caused by either tuberculosis or paratuberculosis. the most common necropsy lesions seen in tuberculosis are nodular lesions of the lung, liver, lymph nodes, spleen, and intestines. histologic evaluation reveals the nodules to be granulomas with giant cells and acid-fast organisms. frequently, the center of the lesion is necrotic and mineralized. intestinal lesions appear to be more common than pulmonary lesions in goats. the lesions of paratuberculosis are centered around the ileocecocolic junction and the adjacent mesentery. the regions may appear normal or be notably thickened. thickening of bowel or nodular infiltrates of lung or liver may be detected antemortem using imaging modalities, such as ultrasonography or computed tomography. postmortem diagnosis is made by identifying characteristic lesions and culturing the organisms. antemortem diagnosis of tuberculosis is best achieved by observing the reaction to intradermal injection of tuberculin with or without comparative injection of purified protein derivatives of m. bovis and m. avium subsp. paratuberculosis. all tuberculosis testing should be done in accordance with local regulations. antemortem diagnosis of johne's disease can be achieved by fecal culture of the organism, but this test takes several weeks to months to complete and is far less reliable in sheep or goats than cattle, with a sensitivity as low as . . serologic tests (e.g., elisa) appear to be sensitive and specific for johne's disease in animals demonstrating clinical disease rather than preclinical infection. serologic detection of clinical johne's disease in cervids has been shown to be highly sensitive and specific while the sensitivity of fecal culture is low in both sheep and goats. the recommended organism detection method in both species is fecal pcr. fecal or milk pcr can be used on pooled samples for flock identification and to type the organism. prevention. tuberculosis should not be endemic in flocks in the united states because positive animals are quarantined or destroyed. preventing exposure to wild ruminants and other possible sources is crucial. except in goat flocks raised for the production of milk that is to be sold unpasteurized, testing is uncommon, so animals are usually not identified until they develop overt disease. paratuberculosis is much more common and may be maintained in flocks by carrier animals. no effective treatment is available for either disease, nor should any be encouraged because efforts should be concentrated on eliminating infection from the flock or herd. vaccination of sheep is used extensively in australia to control paratuberculosis. prolonged vaccination has been shown to decrease fecal shedding in infected animals over time. pathogenesis. mycoplasma spp. are very small, simple bacteria that parasitize cells of higher species. they are common inhabitants of mucous membranes and can have either a commensal or pathogenic relationship with the host. transmission between animals is most likely through direct or indirect contact with body fluids from infected animals, inhalation of respiratory droplets, and arthropod vectors. common sites for superficial infection include the ocular membranes, lung, mammary gland, and female reproductive tract. the organisms can also enter the blood and cause septicemia, abortion, pleuritis, and polyarthritis. flare-ups often occur during times of crowding and during parturition, when neonates can spread the organisms from the mother's mouth to her udder and in turn become infected by ingesting contaminated milk. the most important mycoplasma species in the united states are mycoplasma conjunctivae, mycoplasma capricolum, and the less pathogenic mycoplasma ovipneumoniae. they are most commonly associated with keratoconjunctivitis, acute or chronic sepsis, and pneumonia, respectively. m. conjunctivae and c. abortus are the most common causes of pinkeye in north american small ruminants. mycoplasma spp. are thought to inhibit tracheal ciliary function and thus may have a role similar to viruses in "shipping fever pneumonia" in facilitating lower respiratory tract invasion by primary bacterial pathogens. many of the major pathogenic serotypes found in other countries (some of which cause severe pleuropneumonia without the participation of another bacteria), including mycoplasma mycoides subsp. mycoides, mycoplasma mycoides subsp. capri, mycoplasma agalactiae, and strain f , are not found in or have been eradicated from north america clinical signs. keratoconjunctivitis, mastitis, exudative vulvovaginitis, fever, cough, dyspnea, exercise intolerance, abortion, lameness, swollen joints, neonatal death, and depression may all be seen with mycoplasma infections. diagnosis. no specific clinical pathologic findings occur with these diseases. mycoplasma infection should be suspected in sheep and goats with severe exudative pleuropneumonia in some parts of the world. mycoplasma can be identified by bacteriologic culture or staining of exudates. examiners must take care in interpreting positive cultures from body surfaces because nonpathogenic mycoplasma are common. prevention. vaccines against mycoplasmal infections are available in some parts of the world, but not in the united states. providing fly control, preventing stress and overcrowding, and isolating sick animals from healthy ones may help prevent the spread of disease. anaplasma ovis, mycoplasma ovis, and babesia spp. a. ovis and m. ovis are small bacteria that lack cells walls and parasitize erythrocytes. these and similar organisms have undergone recent reclassification following molecular analysis. other species of hemotropic mycoplasmas may affect sheep and cervids. the organisms are spread from animal to animal by insect or mechanical vectors. known arthropod vectors for a. ovis include ticks and horseflies; other biting flies may be more important with m. ovis infection. hypodermic needles and equipment used for tail-docking, castrating, or disbudding animals may be important in iatrogenic transmission. after being introduced into a naive host, the organisms proliferate, and the number of red cells infected increases rapidly until an effective immune response begins to weeks later. a similar proliferation of organisms may occur in chronically infected animals after temporary immune suppression. the humoral and cellular immune responses against a. ovis lead to opsonization of parasitized erythrocytes and their removal by cells of the reticuloendothelial system; m. ovis infection is thought to cause more intravascular hemolysis. the result in both cases is hemolytic anemia. the protozoon parasites babesia ovis and babesia motasi have similar life cycles and cause similar diseases, but they have been eradicated and are reportable in the united states. babesia spp. affecting small ruminants are generally less pathogenic than are their bovine counterparts. animals surviving acute hemolytic crisis reduce the parasites to low numbers but rarely clear the infection completely; they serve as sources of infection for other animals. sheep and goats are susceptible to infection by either organism; goats generally appear to be more resistant to the development of severe parasitemia and clinical signs. clinical signs. signs present during hemolytic crises include fever, weakness, pale mucous membranes, and pigmenturia. urine discoloration results from increased amounts of bilirubin in most cases, although hemoglobinuria may be seen in some sheep with m. ovis infection. icterus is usually present only after the acute hemolytic crisis. clinical signs are exacerbated during times of stress, and infection is often first noted when the animals are moved or handled. chronically infected animals may appear clinically normal, may have recrudescence of infection after stress, or may display signs of ill-thrift such as poor body condition and fleece. babesiosis occasionally causes concurrent central neurologic signs. diagnosis. the major clinical laboratory finding is regenerative anemia with detection of the intraerythrocytic bodies. chronically infected sheep often have high counts of nucleated erythrocytes. because m. ovis consumes glucose, hypoglycemia and metabolic acidosis may be detected, especially in blood samples that are not processed immediately. diagnosis is by identification of the organisms on blood smears. special stains are available to make the organisms more visible. postmortem lesions include pallor or icterus of membranes and splenomegaly. some evidence of vasculitis, including edema or exudates in body tissues or cavities, may be seen with m. ovis infection. treatment. mycoplasma spp. and anaplasma spp. are sensitive to tetracycline antibiotics. babesiosis is more difficult to treat. effective drugs include diminazene, pentamidine, and imidocarb dipropionate. supportive care for all blood parasite infections includes whole blood transfusions, nutritional support, and administration of fluids. prevention. prevention in most cases involves maintaining low levels of parasites rather than eliminating them entirely. this method ensures continual stimulation of the immune response, whereas eradication often leaves the animal susceptible to another bout of acute infection. vector control can also be important in management of the disease. pathogenesis. two organisms belonging to the anaplasmataceae family, ehrlichia ovis and anaplasma phagocytophilum, infect ovine wbcs, causing fever, immune suppression, and some organ damage. a. phagocytophilum is the causative agent of tick borne fever in sheep and granulocytic anaplasmosis in horses, dogs, and humans. the organism is transmitted by ticks (ixodes spp.) and maintained in the environment by asymptomatic carrier animals. the distribution and incidence of disease is seasonal with the life cycle of the tick. the organism infects cells of the granulocytic lineage, leading to severe persistent neutropenia and acute lymphopenia. fever occurs to weeks after infection, lasts as long as weeks, and occasionally relapses. chronic infection is common. spleen, lung, liver, and kidney tissue may show some damage because of immune destruction of infected cells, but organ-specific signs are usually the result of secondary infection. secondary bacterial joint infections in lambs infected with a. phagocytophilum develop debilitating lameness known as tick pyemia. e. ovis causes fever (benign ehrlichiosis) to weeks after infection. because of this organism's predilection for mononuclear cells, the degree of immunosuppression and subsequent importance of this disease are much less than for a. phagocytophilum infection. diagnosis. specific diagnosis is best made by identifying darkly stained bodies at the periphery of granulocytic cells, as well as occasional large bodies deep within the cytoplasm of some cells. stained bodies also can be seen on the periphery of mononuclear cells from a blood smear during the acute febrile stage or in tissues during chronic infection. serologic tests are available for detection of anaplasmosis. the available celisa is incapable of distinguishing species of anaplasma and serologic results must be interpreted appropriately, and the species confirmed by pcr. both infections affect sheep and goats (a. phagocytophilum also affects many other ruminants, including white-tailed deer), but neither has been reported in north america. a recent study demonstrated that sheep are capable of being experimentally infected with a human isolate a. phagocytophilum. interestingly, the sheep did not develop clinical disease. such findings suggest that sheep could serve as asymptomatic carriers and potential reservoirs for humans. a. phagocytophilum is widespread in northwestern europe, including the united kingdom, scandinavia, and india, and e. ovis is found mainly in countries bordering the indian ocean. in spite of documented seropositive status of animals, there have been no reports of sheep or goats naturally infected with a. phagocytophilum in the united states developing clinical disease. treatment and prevention. treatment and prevention efforts should focus on reducing vectors and bacterial counts during vector season. both organisms are susceptible to treatment with tetracycline. people and animals can become infected with trypanosome protozoa. the trypanosomes can complete their developmental cycle only in tsetse flies (glossina species). trypanosomes multiply in blood, tissues, and body fluids of their vertebrate hosts and are transmitted between vertebrate hosts in the saliva of blood-sucking flies as they feed. the trypanosome species that are known to infect goats and sheep include trypanosoma congolense, trypanosoma vivax, trypanosoma brucei subsp. brucei, trypanosoma evansi, and trypanosoma simiae. pathogenesis. after entering through the skin, trypanosomes reach the bloodstream by way of the lymphatic system. the parasites multiply, and the prepatent period lasts for to days after infection. the infection is characterized by periods of parasitemia, followed by the absence of parasites. this pattern of infection occurs because of antigenic variation: trypanosomes vary the antigenic nature of their glycoprotein surface coat to evade the host's immune system. this immune system-evasive maneuver prolongs infection and is responsible for chronic disease. some trypanosomes tend to invade extravascular spaces, such as the ocular aqueous humor and cerebrospinal fluid. the pathogenicity of trypanosomes varies with the different host species. trypanosomes may produce a hemolysin early in the course of the disease that causes anemia in the host. later, increased phagocytic activity results in massive erythrocyte destruction. clinical signs. the clinical signs are variable and non-specific and depend on the speed of onset of anemia and the degree of organ impairment. entire herds may be affected. all aspects of production are impaired-fertility, birth weight, lactation, weaning weight, growth, and survival. trypanosomiasis may predispose the animal to the development of other diseases that mask the underlying trypanosome infection. trypanosomiasis may be acute, subacute, or chronic, with chronic infection occurring most commonly. acute disease often causes abortion. dairy goats may show a sudden drop in milk production. depression, anorexia, and a stiff gait may be present. physical examination reveals tachycardia, tachypnea, and a slight fever. hyperemic mucous membranes and excessive lacrimation may be noted. affected animals often become recumbent and anorexic and die within to weeks of onset of clinical signs. if the animal survives, progression to the subacute phase, characterized by listlessness, weight loss, enlargement of superficial lymph nodes, and a dull, dry hair coat, may occur. in such cases, auscultation findings are similar to those in other forms of acute cardiac disease, as well as pale mucous membranes and a pronounced jugular pulse. the animal may linger for several weeks or months, or the chronic form of the disease may develop. affected animals show ill-thrift: dull and dry hair coat, inelastic skin, lethargy, emaciation, peripheral lymphadenopathy, pale mucous membranes, and exercise and stress intolerance. death may occur many months or even years after infection and usually results from congestive heart failure. subclinical trypanosomiasis causes acute episodes when animals are stressed by inadequate nutrition, increased production demands, or concurrent disease. diagnosis. diagnosis is difficult because the parasitemia is intermittent, clinical signs are non-specific, and infection is not always synonymous with disease. a pcr assay is gaining acceptance as the most sensitive diagnostic modality, but not all infected animals exhibit clinical disease. although a tentative diagnosis of pathologic trypanosomiasis can be made on the basis of history, clinical signs, and the presence of appropriate vectors, a definitive diagnosis requires identification of trypanosomes on a fresh blood smear, a giemsa-stained blood smear, or less commonly, a lymph smear. examination of the buffy coat of centrifuged blood with darkfield phase-contrast spore illumination is the most sensitive direct microscopic method and is useful when parasite numbers are low. pathogenic trypanosomes must be distinguished from more ubiquitous, nonpathogenic species particularly common in cattle, such as trypanosoma theileri. repeated blood sampling in individual animals often is necessary, because as noted, parasitemia is intermittent. the diagnosis is supported by evidence of anemia on a cbc. indirect diagnostic methods include an indirect fluorescent antibody test and the elisa. these tests are less helpful for diagnosis of a single clinical case but are useful in assessment for herd infection. both t. congolense and t. brucei readily infect rats and mice, and detection of these pathogens can be used to diagnose the infection indirectly. treatment. treatment consists of the use of trypanocidal agents and supportive care. animals with acute, subacute, and subclinical disease respond better to treatment than those with chronic disease because of the irreversible damage to hematopoiesis associated with chronic infection. with most trypanocides, the therapeutic index is low and varies with the host species. trypanocide efficacy also varies with the species of trypanosome present; resistance to agents is common. some trypanocides are irritating to the skin and may cause severe inflammation at the injection site. in sheep and goats with t. brucei infection, the trypanocide of choice is diminazene aceturate, which should be used at a higher dosage rate ( mg/kg given intramuscularly [im] or sc) than that recommended for cattle. protection after trypanocide use usually lasts to months, depending on the season. animals must be rested before and after treatment. supportive care consists of providing fluids, an environment conducive to rest, good nutrition, and possibly blood transfusions. prevention. vector control, stress and nutrition management, and selection of trypanosome-tolerant breeds of sheep and goats all help control or prevent trypanosomiasis. no vaccine is available. animals can be treated with insecticides (pyrethroids) to prevent bites by tsetse flies and other flies. control is accomplished by strategic use of trypanocides during the peak season. continued parasitologic and clinical surveillance is essential to determine the efficacy of control measures. pathogenesis. sarcocystis spp. are protozoon parasites that have a two-host life cycle. sexual reproduction occurs in the bowel of a carnivore (mainly dogs and wild canids) after the carnivore ingests cysts in the muscles of sheep, goats, and cervids. sporocysts are passed in the carnivore's feces and later ingested by a sheep, goat or cervid. the sporocysts hatch in the ruminant gut and invade the vascular endothelium during three phases of asexual reproduction. after the third phase (approximately to weeks after ingestion), merozoites enter the ruminant's muscle tissue and encyst. clinical signs are uncommon but can occur during the stages of reproduction and muscle invasion of the host. n. caninum has a similar life cycle and causes similar disease, except that it appears more likely to cause abortion and affect the central nervous system. clinical signs. most infections are asymptomatic. however, if a large number of sporocysts are ingested, tissue damage may occur during the intestinal, vascular, and muscle stages of the sarcocystis life cycle. fever, lameness or a stiff gait, reluctance to move, and diarrhea may be seen. central neurologic signs (blindness, changes in mentation, and seizures) may occur if the organisms invade the brain or interrupt blood flow to it. abortion can occur as early as weeks after ingestion. with severe chronic infections, emaciation and anorexia are seen. diagnosis. the most characteristic abnormality is an increase in muscle enzyme activity in the blood. anemia is common and may result from extravascular hemolysis. cerebrospinal fluid may show mild mononuclear pleocytosis or may appear normal. on necropsy, muscles may display pale streaks or macroscopic cysts throughout. other evidence of vasculitis includes hemorrhagic serosal surfaces, body cavity fluids, and lymphadenopathy. microscopic or ultrastructural examination of affected tissues should reveal the presence of organisms. specific antibody tests are available and do not cross-react with t. gondii antibodies. blood antibody titers often peak around the onset of clinical signs and should be markedly higher than baseline values. antibody preparations also are available for identification of organisms in tissue preparations. treatment. sheep infected with sarcocystis species can be treated with salinomycin ( ppm in complete feed), monensin ( . - mg/kg po), or amprolium ( - mg/kg po). drugs such as sulfadiazine or trimethoprim ( - mg/kg im sid), pyrimethamine ( . - mg/kg po sid), and clindamycin have shown some success in treating neospora infections. these treatments are off-label and thus are governed by regulations regarding extra-label drug use. prevention. preventing contamination of feedstuffs with the feces of infected carnivores and preventing ingestion of raw meat by carnivores are most important, but these measures may not be possible in flocks handled with dogs or those living on range land. anticoccidial drugs appear to decrease the chance of clinical disease. pathogenesis. t. gondii is a protozoon parasite with a life cycle very similar to sarcocystis, except that the definitive host is the cat and that a wider range of mammalian and avian species, including humans, appear to be capable of acting as intermediate hosts. sporocysts are infective a few days after passage in cat feces, and most ruminants are infected by eating feed contaminated with cat feces. people can become infected by ingesting raw meat or milk from infected animals. abortion, stillbirth, and neonatal death are the most common forms of clinical disease in sheep and goats, and toxoplasma should be considered one of the most common causes of perinatal losses in small ruminants (see chapter ) . abortion usually occurs during the final month of pregnancy. fever, vasculitis-induced disease, and neurologic disease are less common manifestations. clinical signs. beyond abortion, clinical disease is rare in adults and resembles systemic sarcocystosis. clinical signs include fever, dyspnea, depression, and anorexia. neurologic signs are more common than with sarcocystis infection, especially in lambs and kids infected in utero. diagnosis. no specific laboratory abnormalities are associated with toxoplasmosis. nodular lesions similar to sarcocysts may be seen in various tissues, including the brain. aborted or stillborn fetuses may appear normal except for histologic lesions in the brain, liver, or lung, but more commonly fetuses are macerated. the placenta is usually abnormal, with gross and microscopic evidence of necrosis of the cotyledons. microscopic identification of the organism in body tissues is the most common means of diagnosis. serologic tests also are available. treatment and prevention. drugs similar to those used to treat neospora may be effective against toxoplasma. preventing contamination of feeds with cat feces and preventing ingestion of dead animals by cats are the most important ways of stemming the spread of this organism. both methods are likely to be difficult in most flocks. direct spread from one animal to another is rare. clinical signs. bluetongue disease has two different manifestations-reproductive problems (see chapter ) and acute vasculitis of several organ systems. with vasculitis, a spiked fever often precedes depression, anorexia, and rapid weight loss. leukopenia is present. affected animals may develop edema of the lips, tongue, throat, ears, and brisket. other signs include excessive salivation and hyperemia or cyanosis of the oral mucosa, including the tongue (hence the name bluetongue). affected sheep often produce profuse serous nasal discharge that soon becomes mucopurulent and produces crusts and excoriations around the nose and muzzle. oral lesions progress to petechial hemorrhages, erosions, and ulcers. pulmonary edema is often severe, and pneumonia may develop. skin lesions can progress to localized dermatitis. affected sheep may exhibit stiffness or lameness because of muscular changes and laminitis. cyanosis or hemorrhagic changes of the skin of the coronet can extend into the horny tissue. after recovery, a definite ridge in the horn of the hoof may be present for many months. in severe cases, the hoof sloughs. mortality varies widely. in africa, the virus is much more virulent than in the united states, and mortality ranges from to %. the reproductive or teratogenic form of the disease varies greatly with strain, host, and environmental factors. teratogenic effects include abortions, stillbirths, and weak, live "dummy lambs." congenital defects may include hydranencephaly. diagnosis. in parts of the world where the disease is common, the diagnosis is usually based on clinical signs alone. the virus can be isolated from blood, semen, or tissues (spleen and brain from aborted fetuses). viral isolation from blood obtained during the viremic state is the most definitive means of diagnosis. serologic evaluation involves two types of viral antigen groups called p and p . the former is found in all bluetongue viruses, and the latter determines the serotype. sera are commonly tested with complement fixation, agar gel immunodiffusion (agid), or one of several elisa tests. a competitive elisa is considered the best serologic test for detecting group antibodies to bluetongue virus. a direct fluorescent antibody test is available. molecular tests (e.g., pcr) for bluetongue have recently become available and are extremely sensitive and specific. they can be useful for distinguishing serotypes. other clinicopathologic signs that aid in diagnosis include leukopenia during the early febrile stage of the disease and an increase in serum ck corresponding to the latter phase of muscle stiffness and lameness. treatment. treatment is non-specific and consists of nursing care. because of the reluctance of animals to eat, they should be fed a gruel of alfalfa pellets by stomach tube or encouraged to eat soft feeds and green grass. broad-spectrum antimicrobials are often used to treat secondary pneumonia and dermatitis. animals should be kept on soft bedding with good footing. water and shade should be readily available. nsaids are commonly used. prevention. the culicoides vector is difficult to eliminate, so animals should be kept indoors during periods of peak gnat activity (dusk and early evening). owners should attempt to eliminate gnat breeding grounds such as overflowing watering troughs and shallow septic systems and should limit exposure of sheep to gnats with the use of repellent sprays. modified live vaccines based on local strains and serotypes are available in some parts of the world. some cross-protection among serotypes does occur. the vaccine should be administered at least weeks before breeding season to prevent teratogenic effects. vaccinated breeding rams may have a slight risk of decreased fertility. lambs can be vaccinated in the face of an outbreak. pregnant animals cannot be vaccinated with modified live vaccines. sheep that have recovered from an attack of bluetongue are solidly resistant for months to infection by the same viral strain and to some other viral types. active immunity in sheep requires both humoral and cellular immunity. etiology. epizootic hemorrhagic disease virus (ehdv) is an orbivirus belonging to the family reoviridae. the virus is structurally related to bluetongue virus, and the pathogenesis and clinical signs of disease resulting from these two viral infections are very similar. at least seven distinct serotypes of ehdv are recognized, although formal classification of serotypes has yet to be finalized. only two serotypes (ehdv and ehdv ) have historically circulated throughout north america, and those serotypes are largely considered to be endemic in almost all areas of the united states, with the exception of the northeast and arid areas of the southwest. however, in , ehdv was isolated from surveillance efforts in dead white-tailed deer. since then, ehdv has been increasingly identified from both surveillance samples and clinical cases and is also believed to be endemic in several regions. pathogenesis. epizootic hemorrhagic disease (ehd) is a noncontagious disease that is transmitted by the culicoides biting midges. culicoides sonorensis is the primary vector of ehdv in the united states, although other species are also suspected to transmit the disease based on the geographic distribution of clinical cases, although this has yet to be formally shown. due to the vector-borne route of transmission, peak incidence of the disease is closely associated with peak vector population, namely, in the late summer and fall of the year. although capable of infecting a wide range of wild and domestic ruminants, ehdv is largely a pathogen of wild cervids, particularly white-tailed deer. episodes of clinical disease are less common in mule deer, pronghorn antelope, and bighorn sheep and have lower morbidity and mortality. sheep are only rarely infected with the virus and goats appear to be resistant to the virus. cattle are commonly infected based on seroprevalence surveys, but overt clinical disease is uncommon. as a rule, infection in livestock is usually asymptomatic except for periodic epidemics. the last major ehd epidemic in the united states occurred in and affected a variety of captive and wild ruminant species. in endemic areas, seroprevalence in cervids and other ruminants is high, but clinical disease is not commonly seen. conversely, where seroprevalence is low, introduction of the virus results in widespread infection, where morbidity and mortality can reach % and %, respectively. following transmission of the virus by biting midges, ehdv replicates in the endothelial cells of the lymphatics surrounding the site of the bite. a primary viremia allows for systemic spread of the virus and secondary replication in lymph nodes throughout the body and the spleen. viremia is important for disease propagation and generally lasts no more than weeks following infection, although the virus can occasionally be isolated from deer infected days previously. antibodies to ehdv are first detected to days following infection but are not always capable of completely neutralizing the infection. thus, it is possible to find both neutralizing antibodies and live virus in the same animal. passive antibodies in fawns can be found up to approximately months of age. as in adults, antibodies in fawns may not protect from infection but generally protect from severe clinical signs. clinical signs. clinical disease in white-tailed deer can be peracute, acute, or chronic. the course of the peracute syndrome of diseaseis relatively short, with death often occurring within hours of infection, with or without the presence of clinical signs. when present, clinical signs include severe edema of the head and neck, swelling of the tongue and conjunctiva, anorexia, fever, weakness, and respiratory distress. hemorrhagic diatheses are not present antemortem but may occur after death. in contrast, in the acute form of the disease, the clinical signs of the peracute form are accompanied with bleeding throughout body tissues (figure . a, b) . ulcers may be evident in the oral cavity and throughout the upper gastrointestinal tract, forestomachs, and abomasum. case fatality rates are high for both the peracute and acute forms. deer that recover after several weeks of illness are said to suffer from the chronic form of the disease. signs of previous illness may include breaks or rings in the hoof horn due to interrupted growth and synthesis leading to lameness, sometimes severe. ulceration and scarring of the rumen and gastrointestinal tract may result in loss of body condition despite a seemingly normal appetite and ample nutrition. widespread evidence of vasculitis may be observed histopathologically. diagnosis. the gold standard for ehdv diagnosis is virus isolation. demonstration of neutralizing antibodies to ehdv reference strains is evidence of previous infection but may be of limited value in endemic areas where seroprevalence levels are expected to be high. also, all potentially suspected serotypes must be used when testing the sample, thereby increasing the time and cost involved with the test. continued research and refinement of molecular techniques, including pcr, are ongoing and are attractive due to the short turnaround times and the potential for high throughput of samples. however, it is important to remember that a positive result using molecular techniques does not equate to the presence of infectious virus, and thus, interpretation of results must be done with caution. control. control of ehd is difficult and relies on a combination of disease surveillance, vector control, and potentially, vaccination. eradication of vector-borne diseases from endemic areas is difficult and time-consuming, and thus, disease control is likely more attainable than strict eradication. vector control is more important in the late fall and summer, when populations are at peak levels and viral transmission is more likely. midge-proofed housing and the treatment of animals with pyrethroid insecticides have been attempted but may be logistically challenging and have yet to have been demonstrated efficacious. vaccine availability in north america is limited, but inactivated autogenous vaccines have been developed from isolates obtained from ill or recently diseased animals. autogenous vaccines are tested for purity but not necessarily for efficacy. vaccine usage must be approved by the u.s. department of agriculture prior to administration. etiology. peste des petits ruminants (ppr) is an acute or peracute, febrile, often fatal disease of ruminants caused by a virus in the family paramyxoviridae and genus morbillivirus. sheep are less susceptible than goats and white-tailed deer. cattle are only subclinically infected, and some wild ungulates, as well as camels, appear to suffer the occasional epizootic. the virus (pprv) is serologically related to the virus that causes rinderpest. geographically, the virus is found throughout northern africa, the middle east, and adjacent regions of asia, with possible movement into southern africa and europe noted. pathogenesis. the main route of infection is respiratory, and ppr is spread by airborne droplets. all secretions and excretions of infected animals are contagious throughout the course of the disease, but no carrier state exists. the virus targets lymphoid tissue. lymphocytes are destroyed in germinal centers in lymph nodes, peyer's patches, tonsils, splenic corpuscles, and cecal lymphoid tissue. immunosuppression results from lymphoid destruction. lymphocytes are partially replaced by plasma cells, macrophages, an eosinophilic acellular matrix, and occasionally neutrophils. the epithelial lining of the mouth and digestive tract is highly vulnerable to the pprv. with the loss of the alimentary tract mucosa, weight loss and diarrhea become severe. the incubation period is usually to days, with up to days possible. clinical signs. the clinical disease produced by pprv in sheep and goats closely resembles that of rinderpest, but the course is much more rapid. with the acute form, sheep and goats typically display an abrupt rise in temperature to ° to ° f ( °- ° c). within a few days, infected animals develop nasal and lacrimal discharge, depression, thirst, anorexia, and leukopenia. congestion of the conjunctival and other mucous membranes occurs, followed by serous and mucopurulent exudates. sheep and goats develop oral erosions with necrotic foci, which results in excessive salivation. diarrhea that may be profuse but rarely hemorrhagic develops within to days and is accompanied by abdominal pain, tachypnea, emaciation, and severe dehydration. bronchopneumonia, particularly that caused by pasteurella spp., may be a terminal • fig. . a. the lungs of the adult pen-raised, white-tailed deer, have been retracted to reveal to ecchymoses on the ventral surface of the "ribcage." petechiae and ecchymoses can occur anywhere within the carcass in cases of epizootic hemorrhagic disease (ehd), but common locations are on the epicardium, on the pleural surface the ribs, subcutaneously, and on the surface of the spleen. b. ecchymoses over the surface of the reticulum (bottom right of photo) and the surface of the rumen (left side of photo). in addition to ehd, this deer also had bronchopneumonia (fibrin overlying consolidated lung can be seen in the far right of photo). (courtesy dr. kelley steury, auburn, al.) a b sequela. death usually occurs to days after the onset of fever. pregnant sheep or goats with ppr may abort. diagnosis. a presumptive diagnosis of ppr can be made on the basis of clinical, pathologic, and epizootiologic findings. the diagnosis can be confirmed by isolating the virus from blood or tissues, including lymph nodes, tonsils, spleen, and lung. immunocapture elisa or pcr may be used to detect infection several days before the development of clinical disease. most serologic tests (complement fixation or agid) cannot differentiate between ppr and rinderpest. characteristic postmortem findings include necrotic stomatitis that is generally confined to the inside of the lower lip and adjacent gum, the cheeks near the commissures, and the ventral surface of the free portion of the tongue. abomasal erosions are often present. in the small intestine, peyer's patches are markedly affected, particularly in the first portion of the duodenum and terminal ileum. the large intestine may be severely affected. lesions occurring near the ileocecal valve, at the cecocolic junction, and in the rectum are often described as zebra stripes that indicate areas of congestion along the folds of the mucosa. treatment and prevention. infection with pprv has no specific treatment. mortality can be reduced by supportive care, including the administration of antimicrobial and antiinflammatory agents, as well as nutritional support. in the united states, state and federal veterinarians should be notified if pprv is suspected. methods used to eradicate rinderpest are useful in the eradication and control of ppr. all sick sheep and goats and those exposed should be slaughtered and disposed of by burning, burying, or rendering. the premises should be decontaminated, and the area quarantined. sheep and goats can be protected against ppr by immunization with rinderpest vaccines or by the simultaneous administration of ppr hyperimmune bovine serum and virulent pprv. pathogenesis. louping ill is a tickborne disease caused by a flavivirus. it affects mainly lambs but occasionally also affects other livestock species and infrequently affects deer, camelids, and humans. transmission is most common during tick season, and ixodes ricinus is thought to be the most important infective host. many sheep clear the infection after a few days of fever and viremia, but others develop severe, fatal viral encephalitis. the virus is shed in many secretions, including milk, which is an important source of infection for other animals (and humans). the severity of the disease depends on herd immunity because previous exposure gives long-lasting immunity. colostrum from immune females is protective for the neonate. high antibody titers also appear to shorten the duration and level of viremia and thereby prevent invasion of the central nervous system. naïve flocks may have fatality rates as high as %. clinical signs. high biphasic fever, anorexia, and depression are seen in most infected sheep. lambs may die quickly before illness is noted. some sheep also develop central neurologic signs, including hyperexcitability, muscle tremors, and rigidity. abnormal coordination and muscle activity may cause sheep to move with a bounding gait (hence the name louping ill). diagnosis. the condition has no characteristic gross lesions. microscopic examination of animals with neurologic signs reveals evidence of viral meningoencephalitis. diagnosis is made by history (based on location, signs, and time of year), the identification of characteristic lesions, virus isolation, or fluorescent antibody staining of fresh brain tissue. a demonstrated increase in specific antibody titers in survivors strongly suggests the presence of this infection. prevention. vaccines are available in endemic areas to control infection. vector control during tick season also is important. lambing season should also be timed so that lambs have high colostral antibody protection at the time of exposure to ticks. pathogenesis. foot-and-mouth disease is caused by a highly contagious picornavirus and has been eradicated from the united states. vesicular stomatitis is caused by a rhabdovirus and is intermittently eradicated from the united states. both diseases are highly contagious, nearly indistinguishable from each other clinically, and reportable. foot-and-mouth disease has a broad host range that includes most hoof stock (including pigs but not horses) and several other mammalian species. vesicular stomatitis also affects many species of hoof stock, including both pigs and horses. sheep and goats are relatively less susceptible than cattle, particularly to vesicular stomatitis. the viruses are spread by aerosol and mechanical vectors and primarily colonize skin or mucous membranes. milking machines, flies, birds, and humans all may be important mechanical vectors. vesicular stomatitis tends to remain at the site of infection, and colonization is facilitated by damage to the skin. oral mucous membranes, coronary bands and interdigital skin, and teat-end skin are common sites of lesions. vesicular stomatitis outbreaks in the united states tend to occur in the summer or fall and end with the first killing frost. viremia plays more of a role with foot-and-mouth disease. the virus is present in most body tissues and fluids in infected animals and can be transmitted through milk, meat, bone, and hide products; semen; equipment that pierces the skin; and biting arthropods. it also tends to spread through the circulation from the site of infection to other susceptible tissues, including the sites of vesicular stomatitis, as well as to the nasal cavity, mammary glandular epithelium, and ruminal pillars. the basic lesion for both diseases are the vesicles that form in the oral cavity and on the teats and coronary band. the vesicles quickly rupture and may not be visualized before forming erosions. ruptured vesicles leave deep erosions on the skin or mucous membranes and appear to cause pain. tissue damage and inflammation are often compounded by secondary bacterial infection, which can cause greater morbidity and mortality than the original viral infection. morbidity is related to feed refusal, increased recumbency, and secondary infections of the mouth, udder, and feet. clinical signs. sheep and goats usually develop minor lesions, if any, and are more important in many outbreaks as transport or multiplying hosts than as primary clinical cases. however, identification of lesions should raise suspicion of this disorder. in the worst cases, vesicles, erosions, and ulcers are seen at target sites. they may appear mildly inflamed and erythematous; if they are infected, they may appear severely inflamed with hemorrhage and necrosis. other signs vary according to the location and severity of the lesions. lingual and buccal lesions cause salivation, dysphagia, and feed refusal. foot lesions, which are the most common clinical manifestation in small ruminants, cause lameness and recumbency. teat lesions cause reluctance to be milked or nursed and a decrease in production. fever also may be seen early in the disease, when vesicles are most apparent. the fever then usually abates, and vesicles are replaced by erosions or ulcers. abortion may occur, especially with foot-and-mouth disease, and is probably related to the fever rather than to fetal infection. the disease is usually self-limiting; most animals recover within to weeks. shedding of the virus causing vesicular stomatitis is thought to subside soon after healing of lesions. foot-and-mouth disease virus may be shed for as long as months, and all body secretions and tissues should be considered contagious, including milk, semen, meat, and offal. both viruses have zoonotic potential and cause a disease in humans that resembles mild influenza. the diseases are self-limiting, but people can shed the viruses in sufficient quantities to infect other animals. diagnosis. no characteristic clinicopathologic changes are reported for either virus. gross lesions resemble those seen before death and include vesicular, erosive, and ulcerative lesions of the mouth, feet, and teat ends; foot-and-mouth disease also causes lesions of the mammary gland and ruminal epithelium. microscopic findings include hydropic degeneration of cells of the stratum spinosum of the epidermis without inclusion bodies. secondary bacterial infection may lead to deeper ulcers and complicate identification of the viral etiology of these lesions. myocarditis lesions may be seen with some forms of foot-and-mouth disease. a presumptive diagnosis may be made by identifying characteristic lesions during a season and in an area at risk for one of these infections. in north america, bluetongue should be considered as an important differential diagnosis for ulcerative oral lesions in sheep. a confirmed diagnosis of foot-and-mouth disease is achieved by a combination of virus isolation (from vesicles), ihc, and serology by regulatory officials. identifying the source of infection also is very important. diagnosis of vesicular stomatitis is achieved by complement fixation or fluorescent antibody staining of virus in vesicular fluid or detection of a rise in antibody titers. flocks with either of these diseases in the united states are subject to quarantine and possible destruction (especially for foot-and-mouth disease). prevention. meticulous personal hygiene and avoidance of contact with new animals are important during outbreaks to prevent spread between flocks. vaccines against foot-and-mouth disease are available in many parts of the world, but not in the united states. most nations slaughter or quarantine affected animals. vaccines against vesicular stomatitis are available and are most commonly used if the risk of outbreak is high, but vaccination does not prevent infection or shedding. good hoof and teat care and soft feeds may help prevent spread of the virus by providing a healthy, intact barrier against invasion. pathogenesis. sheep and goat pox are caused by two closely related poxviruses. some strains are infective to both sheep and goats; most are species specific. they are maintained in populations by infected animals, and transmission occurs by aerosol or direct or indirect contact. flies may play an important role as mechanical vectors in some flocks. viruses remain infective in the environment for as long as months. after infection, viremia and inflammation of the oral, nasal, and ocular mucous membranes occur. erythematous papular pox lesions appear a few days later. severity varies according to strain pathogenicity, breed susceptibility, and immune status. mild infections are characterized by lesions concentrated in the non-wooled or hairless regions of the skin. severe infections produce lesions throughout the oral cavity, respiratory tract, and peritoneal cavity. secondary infection is common with the severe form and mortality is high. if the animal survives, lesions heal in to weeks. both diseases have been eradicated from the united states and are reportable. people can develop mild disease on exposure to these viruses. clinical signs. fever, inappetence, conjunctivitis, and upper respiratory signs are seen in the initial stages. pox lesions are visible shortly thereafter. secondary infection can lead to a variety of more serious signs indicative of respiratory disease, sepsis, and shock. diagnosis. characteristic pox lesions are highly suggestive of this disease. microscopic analysis reveals eosinophilic intracytoplasmic inclusion bodies, acantholysis, and pustule formation within the epidermis and occasionally the dermis. viral particles may be seen on ultrastructural examination. gross and microscopic lesions are characteristic with the severe form, but mild disease may produce mild lesions that are difficult to differentiate from other viral diseases that cause oral proliferative or ulcerative lesions. virus can be isolated from blood or tissues (mainly skin) during the acute viremic stage and identified by antibody staining of more chronic lesions. serologic tests are available to detect rising titers in convalescent animals. treatment and prevention. no specific treatment is available for sheep or goat pox. antibacterial drugs may be useful to treat secondary infection. judicious use of insecticides and confinement of affected animals may prevent spread. vaccines are available in some countries, but not in the united states. infected flocks are placed under quarantine or destroyed in regions where the diseases are not endemic. these viruses are difficult to eradicate from flocks because of their environmental persistence and the constant supply of susceptible hosts. caprine arthritis-encephalitis virus (caev) is an enveloped, singlestranded retrovirus in the lentivirus genus. like other retroviruses, caev integrates into the host chromosomal dna before replicating. the virus is able to remain latent or undergo sporadic bouts of productive viral replication. caev is closely related to ovine lentiviruses. clinical signs. clinical disease may be evident in only % of goats from a caev-infected herd at any given time. as many as % of seropositive goats may be clinically normal. caev produces four clinical syndromes: encephalomyelitis, arthritis, interstitial pneumonia, and indurative mastitis. the pattern of disease usually varies with age. arthritis is generally seen in sexually mature goats, whereas encephalomyelitis is generally seen in kids to months old. interstitial pneumonia and indurative mastitis are more common in adult goats. some goats suffer from a wasting disorder characterized by poor body condition and rough hair coat. diagnosis. a presumptive diagnosis of caev can be made on the basis of history and clinical signs suggestive of one or more of the syndromes. in general, elisa tests are better for detecting disease in an individual animal because the sensitivity of the test is higher than that of the agid, whereas the agid is better for herd screening that requires high specificity. with the agid test, false negatives may occur in goats that have not yet seroconverted to recent infection. individual goats may take months or years to seroconvert or may never do so. parturition or advanced stages of disease also may contribute to a false-negative result. false positives may occur in goats younger than days old that have colostral antibodies. for this reason, it is often suggested that kids be at least months old before they are tested. pcr testing has high specificity and sensitivity and can detect infection within a day of exposure. other less commonly used tests include a western blot to detect antibodies and a northern blot to look for mitochondrial rna. because of the limitations in interpreting serologic results, caev-induced disease can only be definitively diagnosed by identification of characteristic lesions from examination of biopsy specimens or postmortem viral isolation. treatment. no specific treatments are available for any of the syndromes associated with caev. young goats suffering from encephalomyelitis may benefit from physical therapy if they are recumbent, and bottle feeding may help maintain hydration and caloric intake. antibiotics may be beneficial to goats affected with interstitial pneumonia or mastitis if secondary bacterial infection is present. generally, the prognosis is poor for the encephalitic form and guarded for the other forms. prevention. prevention of caev is crucial because infection is lifelong. infected colostrum and milk are the most important sources of infection. newborn kids should be prevented from ingesting colostrum from infected does and should instead be fed pasteurized goat's milk or milk from caev-negative goats. all goats in a herd should undergo serologic testing twice yearly; seropositive goats should be segregated or culled to prevent direct contact between infected and uninfected animals. ovine progressive pneumonia (opp) is an ultimately fatal retroviral disease that causes chronic, progressive, debilitating inflammatory conditions of the lungs (united states) and central nervous system (other parts of the world). it also is called maedi-(maeði is icelandic for "shortness of breath") visna (meaning "wasting"). the virus is a member of the lentivirus genus of retroviruses and is closely related to caev. recombination between opp and cae viruses has been observed. the virus primarily affects sheep and rarely goats and has been identified worldwide, except in australia and new zealand. the disease has a long incubation period and protracted clinical course. pathogenesis. only sheep older than years of age are affected by opp virus (oppv). the virus is spread by direct contact, probably in respiratory and salivary secretions, and by excretion in the milk and colostrum. transplacental transfer is of minor importance. virus is excreted by animals that exhibit clinical signs and asymptomatic animals. infection is established in the monocyte and macrophage cell line and spread by these cells to the lungs, lymph nodes, choroid plexus, spleen, bone marrow, mammary gland, and kidneys. like caev, oppv evades the cellular and humoral immune system of the host by incorporation of its provirus in host dna, low-grade replication of virus only when monocytes differentiate into macrophages (restricted replication), and production of antigenic variants that are not neutralized by existing antibodies. continual antigenic stimulation of the host by low-grade replication of oppv results in chronic inflammation and resultant lymphoid proliferation in various target tissues. the virus may prevent b lymphocytes from differentiating into plasma cells in lymph nodes and may thereby impair immunoregulation. seroconversion occurs within to weeks after infection. clinical signs. in the united states, serologic surveys reveal infection rates of between and % but rarely is more than % of a flock lost to oppv. icelandic, texel, border leicester, and finnish landrace appear to be susceptible sheep breeds. more resistant sheep breeds include rambouillet, suffolk, and columbia. various clinical syndromes are associated with oppv and include wasting (thin ewe syndrome), dyspnea occasionally with a dry cough, pneumonia, mastitis ("hard bag"), posterior paresis, arthritis, and vasculitis. in north america, pneumonia and indurative aseptic mastitis are common sequelae of infection. coinfection with the jaagsiekte virus (the cause of pulmonary adenomatosis) worsens respiratory signs. visna, the neurologic form, is more common in goats. over the course of up to a year, subtle signs such as a head tilt or hindlimb weakness progress to gross incoordination, whole body tremors, and rarely more profound cranial nerve signs. diagnosis. a presumptive diagnosis can be made on the basis of clinical signs, poor response to treatment, characteristic postmortem findings, and serologic testing. definitive diagnosis requires pcr or isolation of the virus from wbcs (buffy coat of whole blood sample) or tissues. less expensive and faster serologic tests include agid, elisa, and an indirect immunofluorescence test. the agid test is frequently used as a flock screening test, but the elisa is more sensitive on an individual basis and can detect antibodies earlier in the course of the disease. as with caev, false negatives and false positives are possible. characteristic postmortem lesions include generalized wasting and firm, noncollapsing lung or firm, mottled mammary glands, both with regional lymphadenopathy. microscopic evaluation of those tissues reveals interstitial non-septic, mononuclear cell infiltrates, although these may be complicated by secondary infections. histopathology of nervous tissue reveals meningoleukoencephalitis. treatment. no effective treatment is available for oppv. supportive therapy that includes appropriate husbandry and control of secondary infection with antibiotics may prolong life for a few weeks or months but, ultimately, the disease is fatal. because of the poor prognosis and risk of exposure of naive animals to clinical disease, long-term treatment is not recommended. prevention. the only known method of preventing oppv infection in a flock is to prevent exposure to the virus. management practices that help decrease the incidence of horizontal transmission include disinfection of milking equipment, dehorning instruments, and tail docking and castration tools before use and between animals. contaminated feed and water also are potential routes of infection and should not be shared among infected and uninfected animals. serologic testing and separation or culling of seropositive animals may help reduce infection. although oppv can readily be isolated from ewe colostrum, colostral transmission of oppv has not been definitively established. however, many prevention guidelines recommend that offspring from infected dams be separated from the dam before they nurse and then be fed cow colostrum and artificially reared. quarantine and serologic testing of flock additions before placing them with the current flock and purchase of sheep only from oppv-free flocks are important to prevent the introduction of new infections. because of the potential cross-species spread, all precautions taken for sheep also apply to contact goats. serologic testing should be performed at least annually in a flock until two consecutive negative test results are obtained. border disease virus (bdv) is in the genus pestivirus and family flaviviridae, which also includes the two genotypes of bovine viral diarrhea virus (bvdv) and classical swine fever virus. it rarely causes disease in adults and is most important as a cause of in utero infection of lambs and kids. the condition gets its name from the fact that it was first reported in sheep along the welsh border of the united kingdom. other names such as "hairy shakers" and "fuzzy lamb disease" refer to some of the clinical signs seen in affected newborns. it is important to recognize that although bdv is genetically distinct from the two types of bvdv, sheep and goats also are susceptible to some strains of bvd. pathogenesis. horizontal transmission of bdv occurs through contact with secretions and excretions of body fluids and tissues from infected animals. the virus crosses intact mucous membranes and can spread rapidly through a flock. the major reservoir is the persistently infected sheep or goat. these reservoirs are usually asymptomatic, congenitally infected, and often seronegative animals that shed large quantities of virus. these may be residents of a flock with an ongoing problem or bought in as replacement animals to a naïve flock. some cross-infection from other species is possible, particularly from cattle. adult, immunocompetent sheep rarely show any signs of acute infection. however, if a pregnant ewe or doe is infected, the virus may be transmitted vertically to the embryo or fetus. depending on the stage of gestation, embryonic or fetal infection may have different outcomes ranging from embryonic reabsorption to normal birth. these infections are the most important aspect of border disease. the major organ system targeted by bdv is the fetal central nervous system. the hallmark lesion is hypomyelination, or degeneration of oligodendroglial cells. three factors contribute to this lesion. the first is direct viral damage. the second is viral-induced inhibition of the thyroid gland that causes decreased secretion of thyroid hormones. in the absence of these hormones, a resultant lowered concentration of a specific nucleotide in the central nervous system also contributes to the hypomyelination. the third factor is altered immune function. the virus causes the host to produce a virus-specific delayed hypersensitivity reaction that causes inflammation in the central nervous system. it also causes immunosuppression. death often results from opportunistic conditions such as parasitism, diarrhea, and bronchopneumonia. clinical signs. clinical signs depend on the time during gestation when the fetus or embryo is exposed to the virus. clinical signs also may vary in severity from animal to animal because different fetuses develop competent immune systems at different times. if the fetus or embryo is exposed to the virus within days of conception, it dies and is resorbed or aborted. these losses are not usually noticed by the flock manager. the principal manifestation in the flock is a large number of open ewes and a small lamb crop. infection of the fetus between days and of gestation causes damage to rapidly growing systems such as the skin and nervous, lymphoid, thyroid, and skeletal systems. congenital malformations are seen at birth. lambs have abnormal fleece characteristics (hairy rather than woolly in consistency), small stature, domed heads, shortened legs, and dark pigmentation of the skin, particularly on the dorsal aspect of the neck. the lamb may exhibit tonic-clonic tremors ("hairy shakers") when awake, which may prevent standing or suckling. most of these lambs die within a few days of birth. if they survive, the hair changes disappear in to weeks and the central nervous system signs resolve by weeks. goats infected at this time have similar symptoms except that they rarely exhibit hair coat changes. if kids are infected before day of gestation and are still viable, they may become persistently infected and immunologically compromised. they are small at birth and generally weak. typical outbreaks of border disease cause abortions and birth of weak lambs in the first year as the virus rapidly spreads throughout a susceptible flock and then insignificant losses in the succeeding years as adult sheep develop immunity. however, if new naïve ewes are introduced in the flock, substantial losses may occur in perpetuity. diagnosis. border disease viral antigens can be demonstrated in abomasum, pancreas, kidney, thyroid, skin, and testicle tissues from aborted fetuses and persistently infected animals using fluorescent antibody tests. however, ihc on ear notch samples is not considered as reliable for detecting persistently infected small ruminants as it is for cattle. the virus can be isolated, or viral antigen detected by elisa, from serum, heparinized whole blood, and tissue taken from brain, spinal cord, spleen, and bone marrow from affected lambs. whole blood is better than serum if colostral antibodies are likely to be high; serum is an adequate sample in neonates and juveniles that have not suckled. antibodies to the virus may be quantified by serum neutralization, agid, and complement fixation with hyperimmune bvd antiserum. serologic tests are useful to detect exposure in lategestation (after day ) neonates and unvaccinated animals but may be confounded by colostral antibodies in suckling neonates, previous exposure, and vaccination in older animals. any titer in a presuckling neonate indicates in utero exposure, whereas a serum neutralization titer of : to : suggests infection in adults. the presence of specific antibodies in the cerebral spinal fluid suggests bdv infection. negative presuckling serologic tests do not rule out exposure because persistently infected lambs tend to be immunotolerant to the bdv and therefore are born without an antibody titer. these animals may subsequently develop a titer that is indistinguishable from that of a normal animal. although persistently infected animals do not respond immunologically to the strain of the virus they carry, they may respond to other strains of the virus, including vaccine strains. as with bvd, pcr assays are gaining popularity for the detection of bdv in fluids and tissue samples. these assays appear to be superior to other techniques, except in autolyzed tissues. realtime pcr may also be used to differentiate bdv from bvd and to type isolates. gross postmortem findings include hydranencephaly, porencephaly, microcephaly, cerebellar hypoplasia, abnormal rib curvature, brachygnathia, doming of the frontal bones of the skull, narrowing of the distance between the orbits, shortening the crown-to-rump length, shortening of the diaphyseal length, retention of secondary hair fibers, and abnormal skin pigmentation. the major histopathologic changes include hypomyelination and hypercellularity of the white matter. glial cells appear normal. treatment. no treatment is available for border disease infection. supportive care may include assistance in nursing and standing for affected lambs, provision of good bedding and solid footing, and treatment of secondary opportunistic infection. prevention. control is primarily achieved by eliminating persistently infected carrier animals from the flock and preventing the addition of new carrier animals. this is easiest in a closed flock but especially difficult in small ruminant flocks because of the frequent desire to import new genetics. to identify carriers, virus isolation must be performed on every animal in the flock; carrier animals must be culled. additionally, all unborn animals must be considered potential carriers and should be tested at birth. an alternative solution in hobby flocks is to arrest breeding activity until all animals have been shown to be free of infection. new animals should be quarantined and tested before admission to the flock. herd screening with the ear skin biopsy test using fluorescent antibody staining to detect virus is less expensive and more convenient than the whole blood virus isolation test. the role of vaccination in preventing infection is still unclear. no vaccine against bdv is available, but some reports suggest that bvdv vaccines for cattle may be helpful for sheep at risk. however, these vaccines have proven to be more effective at preventing clinical disease in vaccinated animals than in preventing in utero infection because they do not prevent transient viremia. vaccination decreases viremia and fetal infection but does not eliminate them. therefore, vaccines play a role in decreasing economic loss but do not replace culling of carrier animals as the major method of control. another member of the slow infection group of diseases of small ruminants is scrapie. it is an afebrile, chronic, progressive degenerative disorder of the central nervous system of sheep and occasionally of goats (see chapter ) . scrapie is caused by a prion and, as such, is one of the transmissible spongiform encephalopathies. sheep (and goats and mouflon to a lesser degree) are the natural hosts for scrapie. clinical signs often do not usually appear until animals are years old, and animals as old as years may exhibit clinical disease. both vertical and horizontal transmission have been demonstrated experimentally in sheep and goats. abnormal scrapie protein has been identified in milk, urine, and seminal plasma of sheep up to months prior to the development of clinical signs. also, new evidence from deer with chronic wasting disease, a similar disorder, suggests that infective prions are excreted in the saliva and feces well before the development of clinical signs. these new revelations may help explain horizontal transmission of infection. clinical signs. the onset of scrapie is insidious. initially, sheep show subtle changes in behavior such as mild apprehension, staring or fixed gaze, failure to respond to herding dogs, and boldness around humans. several months later, the animals become intolerant of exercise and develop a clumsy, unsteady gait and floppy ears. later, the sheep develop itchy skin that causes them to rub themselves excessively against firm, immobile objects (origin of the name scrapie). this leads to excoriations and wool damage. there is a general decline in body condition and coordination. diagnosis. histologically, the only consistent lesions are degenerative changes in the central nervous system consisting of bilaterally symmetric vacuolation of the neurons in the brainstem and spinal cord with accompanying spongy degeneration. as a preclinical test, ihc may be performed in lymphoid tissue from the tonsils, third eyelid, or rectoanal mucosa, but none of these methods is foolproof. cwd is discussed in chapters , , and . testing for clinical anaemia caused by haemonchus spp. in goats farmed under resource-poor conditions in south africa using an eye colour chart developed for sheep validation of the fama-cha eye color chart for detecting clinical anemia in sheep and goats on farms in the southern united states validation of the famacha © eye colour chart using sensitivity/ specificity analysis on two south african sheep farms is the famacha chart suitable for every breed? correlations between famacha scores and different traits of mucosa colour in naturally parasite infected sheep breeds rumen bacteria are involved in the onset of onion-induced hemolytic anemia in sheep the role of free radicals in brassicainduced anaemia of sheep: an esr spin trapping study kale poisoning: the brassica anaemia factor hemolytic anemia in sheep fed wild onion (allium validum) copper toxicosis in sheep: a case report chronic copper poisoning in sheep. i. the relationship of methaemoglobinemia to heinz body formation and haemolysis during the terminal crisis chronic copper toxicity of ruminants copper poisoning in a flock of sheep. copper excretion patterns after treatment with molybdenum and sulfur or penicillamine evaluation of mechanisms of leptospiral hemolytic anemia fatal hemolytic anemia attributed to leptospirosis in lambs studies on eperythrozoon ovis-infection in sheep eperythrozoon ovis-a blood parasite of sheep experimental eperythrozoon ovis infection of sheep mycoplasma ovis comb. nov. (formerly eperythrozoon ovis), an epierythrocytic agent of haemolytic anaemia in sheep and goats molecular characterization of two different strains of haemotropic mycoplasmas from a sheep flock with fatal haemolytic anaemia and concomitant anaplasma ovis infection bovine colostrum as a cause of hemolytic anemia in a lamb heinz body anaemia in lambs with deficiencies of copper or selenium maxillary lymphosarcoma in a white-tailed deer (odocoileus virginianus) large animal internal medicine effect of physical restraint and xylazine sedation on haematological values in red deer (cervus elaphus) seasonal variations in red deer (cervus elaphus) hematology related to antler growth and biometrics measurements the genetic basis and evolution of red blood cell sickling in deer one hundred two tumors in goats lymphoma classification in goats exophthalmos due to multicentric b-cell lymphoma in a goat ocular involvement of multicentric malignant b-cell lymphoma in a ewe. a case report diseases and parasites of white-tailed deer, miscellaneous publication no. . tall timbers research station colostrum composition of santa inês sheep and passive transfer of immunity to lambs effects of maternal undernutrition during late gestation and/or lactation on colostrum synthesis and immunological parameters in the offspring failure in passive transfer of immunoglobulin g to lambs: measurement of immunoglobulin g in ewe colostrums iodine supplementation of the pregnant dam alters intestinal gene expression and immunoglobulin uptake in the newborn lamb short communication: apoptosis regulates passive immune transfer in newborn kids effects of newborn characteristics and length of colostrum feeding period on passive immune transfer in goat kids a field trial evaluating the health and performance of lambs fed a bovine colostrum replacement use of a digital brix refractometer to estimate serum immunoglobulin in goat kids field methods for estimating serum immunoglobulin concentrations in newborn kids colostrum deficiency in mule deer fawns: identification, treatment and influence on neonatal mortality passive transfer of colostral immunoglobulins from ewe to lamb and its influence on neonatal lamb mortality transfer of maternal passive immunity to kids in goat herd suppurative meningitis in a -day-old formosan sambar deer (cervus unicolor swinhoei) caused by escherichia coli factors affecting igg concentration in day-old lambs effects of maternal nutrition on udder development during late pregnancy and on colostrum production in scottish blackface ewes with twin lambs the effect of colostrum source (goat vs. sheep) and timing of the first colostrum feeding ( h vs. h after birth) on body weight and immune status of artificially reared newborn lambs bovine neonatal pancytopenia and anaemia in lambs caused by feeding cow colostrum secondary lactose intolerance in a neonatal goat hypernatremia in neonatal elk calves: cases ( - ) group b rotavirus associated with an outbreak of neonatal lamb diarrhea rotaviruses associated with neonatal lamb diarrhea in two wyoming shed-lambing operations novel group a rotavirus g p[ ] as primary cause of an ovine diarrheic syndrome outbreak in weaned lambs role of enteric pathogens in the aetiology of neonatal diarrhoea in lambs and goat kids in spain enteric viral infections in lambs or kids suspected clostridium difficile-associated hemorrhagic diarrhea in a -week-old elk calf observations and immunohistochemical detection of coronavirus, cryptosporidium parvum and giardia intestinalis in neonatal diarrhoea in lambs and kids giardia duodenalis and cryptosporidium parvum infections in adult goats and their implications for neonatal kids case control study of diarrhoea and faecal soiling in two-to six-month-old lambs comparison of two techniques for diagnosis of cryptosporidiosis in diarrhoeic goat kids and lambs in cyprus fluid therapy in calves passive immunisation of neonatal lambs against infection with enteropathogenic escherichia coli via colostrum of ewes immunised with crude and purified k pili floppy kid syndrome (metabolic acidosis without dehydration in kids clostridium perfringens toxins involved in mammalian veterinary diseases first isolation of clostridium perfringens type e from a goat with diarrhea clostridial enteric diseases of domestic animals isolation and molecular characterization of clostridium perfringens from healthy merino lambs in patagonia region lamb losses associated with clostridium perfringens type a hemorrhagic bowel syndrome in dairy cattle: cases clostridium perfringens type a and beta toxin associated with enterotoxemia in a -week-old goat investigation of a syndrome of sudden death, splenomegaly, and small intestinal hemorrhage in farmed deer gastric mucormycosis in a sika deer (cervus nippon) associated with proliferation of clostridium perfringens the relationship between the presence of helicobacter pylori, clostridium perfringens type a, campylobacter spp, or fungi and fatal abomasal ulcers in unweaned beef calves multiplex pcr method for genotyping clostridium perfringens the effect of clostridium perfringens type c strain cn and its isogenic beta toxin null mutant in goats beta toxin is essential for the intestinal virulence of clostridium perfringens type c disease isolate cn in a rabbit ileal loop model clostridial diseases vaccines for control, prevention and eradication of disease in farmed deer development and application of an oral challenge mouse model for studying clostridium perfringens type d infection enterotoxaemia caused by clostridium perfringens type d in farmed fallow deer rates of diseases and their associated costs in two colorado sheep feedlots ( - ) proportional mortality: a study of goats submitted for necropsy from goat herds in quebec, with a special focus on caseous lymphadenitis the pathology of experimental clostridium perfringens type d enterotoxemia in sheep enterotoxaemia in goats: a review diagnosis of clostridium perfringens intestinal infections in sheep and goats clinico-pathological findings of clostridium perfringens type d enterotoxaemia in goats and its hemolytic activity in different erythrocytes experimental clostridium perfringens type d enterotoxemia in goats clinical signs, treatments, and postmortem lesions in dairy goats with enterotoxemia: cases epsilon toxin is essential for the virulence of clostridium perfringens type d infection in sheep, goats, and mice clinicopathologic features of experimental clostridium perfringens type d enterotoxemia in cattle ulcerative enterocolitis in two goats associated with enterotoxin-and beta toxin-positive clostridium perfringens type d the passive protection of lambs against clostridium perfringens type d with semi-purified hyperimmune serum blackleg in deer bacterial diseases of farmed deer and bison black disease in a forest reindeer bovine vaccines and herd vaccination programs toxigenic clostridia characterization of the catalytic domain of clostridium novyi alpha-toxin first report of infectious necrotic hepatitis (black disease) among nubian goats in sudan clostridium novyi (myonecrosis, black disease, and bacillary hemoglobinuria) and clostridium septicum (braxy) infections first report of infectious necrotic hepatitis (black disease) among nubian goats in sudan liver and biliary system bacillary hemoglobinuria: induction by liver biopsy in naturally and experimentally infected animals bacillary hemoglobinuria in a free-ranging elk calf bacillary hemoglobinuria in dairy cows an outbreak of bacillary haemoglobinuria in sheep in india successful treatment of bacillary hemoglobinuria in japanese black cows acute abomasitis due to clostridium septicum infection in experimental sheep rapid identification and differentiation of pathogenic clostridia in gas gangrene by polymerase chain reaction based on the s- s rdna spacer region suppurative abomasitis associated with clostridium septicum infection clostridial myocarditis in lambs outbreak of clostridial myocarditis in calves clostridial myositis in cattle: bacteriology and gross pathology clostridial vaccination efficacy on stimulating and maintaining an immune response in beef cows and calves failure of clostridium chauvoei vaccines to protect against blackleg prevalence of coxiella burnetti infection in wild and farmed ungulates coxiella burnetii shedding by farmed red deer (cervus elaphus) high prevalence of antibodies against chlamydiaceae and chlamydophila abortus in wild ungulates using two regional seroprevalence of leptospirosis on deer farms in new zealand growth response and shedding of leptospira spp. in urine following vaccination for leptospirosis in young farmed deer corynebacterium pseudotuberculosis paratuberculosis (johne's disease) in cattle and other susceptible species efficacy of a killed vaccine for the control of paratuberculosis in australian sheep flocks detection of a novel reassortant epizootic hemorrhagic disease virus (ehdv) in the usa containing rna segments derived from both exotic (ehdv- ) and endemic (ehdv- ) serotypes the first years ( - ) of epizootic hemorrhagic disease virus serotype in the usa review of the epizootic hemorrhagic disease outbreak in domestic ruminants in the united states peste des petits ruminants demonstration of coinfection with and recombination by caprine arthritis-encephalitis virus and maedi-visna virus in naturally infected goats key: cord- -pk ealu authors: hu, yi title: a farewell to the “sick man of east asia”: the irony, deconstruction, and reshaping of the metaphor date: - - journal: rural health care delivery doi: . / - - - - _ sha: doc_id: cord_uid: pk ealu susan sontag revealed how a disease could be turned into a metaphor in social evolution, from merely a disease of the body to moral judgment or even political oppression. in her article “aids and its metaphors” written in , she offers a plan to do away with the metaphor: “with this illness, one that elicits so much guilt and shame, the effort to detach it from these meanings, these metaphors, seems particularly liberating, even consoling. but the metaphors cannot be distanced just by abstaining from them. they have to be exposed, criticized, belabored, used up” (songtag ). in sontag’s terms, “metaphor” mainly refers to the symbolic social oppression of the diseases. for example, cancer is a metaphor for the defect of the sick person in personality. while diseases were a biological phenomenon, the “metaphor” was a social one. what i would like to demonstrate here was none other than the related “political metaphor” started by the “anti-germ warfare.” united states had the intention to involve china in the war after crushing the democratic people's republic of korea in one movement. from the very beginning of the war, the chinese people and the chinese government maintained to resort to peaceful methods when solving the korea problem and that warnings be given to the united states about withdrawing the armed forces from taiwan, stopping the aggression against north korea, and solving the problem of korea and the far east peacefully. however, the united states ignored these warnings. in the early winter of , the american aggressors crossed the th parallel and attacked the areas around yalu river and tumen river as well as the airspace of northeast china. many a chinese were killed in bomb attacks and property was ruined. as the national security was seriously threatened, the chinese people's volunteer army entered korea on october , , and began the great war of "aiding korea and defending the homeland." this was a war between two parties with disparity of strength in many aspects. economy: while half of the world's population was involved in world war ii, causing million deaths or injuries, the united states somewhat benefi tted from the war. it quickly grew into the largest industrial power in the world. at that time, the us industrial output value accounted for more than half of the total capitalist world industrial output value. us steel production reached . million tons in ; wheat production accounted for more than % of production of the capitalist countries; the industrial and agricultural output value reached . billion us dollars. in , the us gold reserves were valued at more than . billion usd, accounting for % of the total gold reserves of the entire capitalist world. in the aggression against korea, the direct expenses of the war of the united states reached more than billion usd. war material destined for north korea totaled million tons (peng dehuai ) . in comparison, the nascent prc from the ruins of wars did not even completely liberate all its territory. successive wars not only crippled china's modern industry but also damaged its primitive agriculture. in , new china's industrial and agricultural output value was only . billion yuan, less than a fractional amount of that of the united states if converted into us dollars. armed forces: one third of the us army, one fi fth of its air force, and most of its navy were assembled in the war in korea, in addition to the troops of the vassal countries (peng dehuai ) . by contrast, the people's liberation army was still trying to eradicate the remnant kuomintang forces in the southwest and northwest of china. only those , border guards in northeast china could be mobilized, but some of the forces must be reserved to protect the northeast industrial base. military equipment: the united states boasted atomic bombs and other weapons of mass destruction, the world's greatest number of advanced combat aircrafts, and the world's largest battle fl eet. eighteen aircraft carriers were under construction at the end of world war ii, and the number and the gross tonnage of them accounted for % of the world's total. every infantry division was equipped with more than tanks and seventy-mm-diameter canons; the fi repower of the us army was also at the top of the world. almost all the most advanced weapons (except atomic bombs) were employed in the korean war. the us superiority in navy and air force was maintained all the time. in contrast, china did not have any tanks or air force of its own. air defense weapons were very few. on the other hand, the whole volunteer army were only equipped with seventy-mm-diameter guns. basically, this army was still the so-called millet plus rifl es -even the rifl es were composed of those of different periods and different types. thanks to the support from the soviet union, and from all the chinese people in their donation campaign, an air force was created and fi repower was strengthened. the enemy's superior state was not fundamentally changed, nevertheless. command: the us commander in chief changed three times during the war: douglas macarthur (dismissed because of his defeats in the battles), matthew bunker ridgway (notorious for launching the germ warfare), and mark clark (who signed the armistice agreement). actually, they had all been prominent commanders who withstood the test of world war ii and gained unrivalled fi rsthand experience. the united nations forces under their command in the korean war had employed a variety of tactics, such as the blitzkrieg, taking advantage of the weaknesses (in operation chromite), "strangling battle" that paralyzed china's transportation line, and the inhumane germ warfare. the united states and people all over the world were dumbfounded with the result of the war between the "sick men of east asia" and the world police: after signing the armistice agreement, the united states had to admit that the korean war was "the wrong war, at the wrong place, at the wrong time, and with the wrong enemy." former us secretary of defense marshall once said, "the myth has been punctured. the united states is not such a great power as it has been imagined" (peng dehuai ) . indeed, the myth had been exploded; seemingly powerful countries are sometimes like a "paper tiger," a phrase used once by mao zedong meaning someone or something outwardly powerful or dangerous but inwardly weak or ineffectual. then, how about the "sick men of east asia"? were they still sick beyond cure and doomed to a hopeless fate? peng dehuai said, "long gone are the days when the western invaders could occupy a country if only they could shoot a couple of cannons on the oriental sea" (peng dehuai ) . historical evidence convincingly suggested that the sick men were not always sick. when the awakened sick men were organized and had a stronger will, they would become strong enough to defeat a powerful enemy and to rewrite the history of the "sick man of east asia." the confession confi rmed that "the master plan of the germ warfare in korea was ordered by the meeting of the u.s. joint chiefs of staff in october ." this plan was sent to the far east commander in chief (general ridgway) to "start the germ warfare in korea." "various kinds of military weapons, carriers, and various kinds of aircrafts" were to be experimented "in every area possible or a combination of areas" and "under extremely hot or cold weather." "depending on the results and the situation in korea, the fi eld trials might be extended to be a part of formal war operation." the plan was transferred from ridgway to the us fifth air force via the us far east air force commander lieutenant general wiranto and was implemented on a large scale on a trial basis in november . the first air force alliance participated in this experimental mission and in the formal operational task of "building a trans-korean contaminated zone" in may . meanwhile, the chinese people's committee for world peace held "exhibitions of crimes committed in the germ warfare of the u.s. government" in beijing, vienna, berlin, etc. evidence collected by various parties of the us germ warfare in fl agrant defi ance of the geneva convention (note: in , the geneva protocol or the "protocol for the prohibition of the use in war of asphyxiating, poisonous or other gases, and of bacteriological methods of warfare" was signed by various countries in geneva) was publicly displayed (fang shishan ). on february , , mark clark, the general commander in the invasion of korea, published a declaration, in which it was admitted that schwable and bligh were the us air force personnel, that they made the confessions, but it was supposed that the confessions were "fake," extorted by the china side through "torture" (li siguang ). any facts of the "germ warfare" were emphatically denied. subsequently, those air force prisoners of war were forced to make an affi davit to the united nations general assembly, and the so-called proposal relating to china's "atrocity" (li siguang ) was brought forward to the united nations, together with countries such as the uk, france, australia, and turkey, the intention being to deny crimes committed in the germ warfare categorically. in this regard, the chinese government refuted that there were other captured prisoners of war, other than schwable and bligh, who had confessed: a lieutenant inuk and a lieutenant quinn of the third bomber team of the us air force and a lieutenant o'neal and a lieutenant knits of the eighteenth fighter-bomber brigade. from the confessions made by the six men from the us air force, one could clearly see every step of the germ warfare from planning to implementation. on the other hand, north korea and china's lenient policies for prisoners could be detected from the confessions made by the prisoners of war of the us air force, from talks of those prisoners of war who had been repatriated, from the reports made by the british and american journalists, or even from us army minister stevens and the british army minister. it could be safely concluded that those confessions were none other than "blame of consciousness" rather than a result of "torture." just as schwable exclaimed, "morally, it is an irreparable crime"; "from the standpoint of dignity and loyalty, it is shameful." the united states crimes committed in waging germ warfare could be confi rmed by evidence from many other aspects. after investigating in northeast china and north korea, scientists of the international scientifi c commission collected a body of evidence (physical specimens including insects, bacteria, and other clinical evidence) for the investigation of the pacts concerning bacterial warfare in korea and china. a conclusion had been drawn that the united states had organized a large-scale, disguised germ warfare. dr. joseph needham, who was a member of the royal society of biologists and the international scientifi c commission, published an open letter saying that the truth of the germ warfare "was by no means determined by what the air force personnel confessed, nor was it determined by what they had denied in the new and different circumstances" (li siguang ). dr. samuel b. pessoa (brazil), also a member of the international scientifi c commission and who participated in the investigation, wrote after his visit to "exhibitions of crimes committed in the germ warfare of the u.s. government": "although it appeals to the broad mass of the population, the exposure process of all the facts is highly scientifi c; it is in no way exaggerated; it is with the aim to explain the truth, or to explain the real situation. what i lament on is that such good techniques of the exhibition should be used to expose such dirty evil deeds." the bloody crimes of the united states committed in the germ warfare, as well as other crimes such as the ill-treatment of the prisoners of war and the massacre of civilians, were also exposed after the investigation by some impartial bodies such as investigation group of crimes of the germ warfare made by the imperialist united states, investigation group of the international association of democratic lawyers, and the international democratic women's federation. overshadowed by the long-term hegemonic discourse of colonialism, the backward countries had not only become the exploited and the plundered but also been oppressed by various political metaphors such as the "sick man of east asia." in the metaphorical politics, the colonial countries and the developing countries were often accused of, and blamed for, being the sources of a variety of diseases, communicable diseases particularly, thus falling into both a moral and political dilemma. as revealed by guenter b. risse, the socially marginalized groups, minorities, and the poor are often accused of being the culprit during outbreaks of diseases. in europe, jews were regarded as the creators of the black death. in new york, irish people there were considered responsible for the outbreak of cholera. in brooklyn, the italians were seen as a source of poliomyelitis. in such cases, the colonial countries would assume the role of a guardian to prevent the spread of the diseases and play the role of the "benevolent" and even the "savior" through dispatching missionary doctors. the irrefutable evidence of germ warfare launched by the united states reveals another perspective of history: the controller of communicable diseases can also be the initiator of communicable diseases. the historical process confi rmed this perspective: the major diseases popular in the modern world (smallpox, syphilis, pulmonary diseases encompassing tuberculosis, pneumonia, and sars) originated in europe. it was with the footsteps of the colonizers, and sometimes as the earliest forms of chemical and biological weapons, that these diseases were spread to the colonial areas. it was from the diseases brought by european settlers that the great majority of indians in north and south america died (diamond ) . a return to the humane world was said to have begun since the renaissance and the enlightenment in western societies. the rise of rationalism directly contributed to the development of modern science and led to powerful scientism, as well as something closely related to it -the technological revolution and the industrial revolution. in line with rationalism, humanism triggered cultural reform and institutional reform, with the western democracy being one of the solid achievements. when guns and fl eets of the western countries easily forced open the door to the colonies, conquer in thought also began, forming the distinct dichotomy between the traditional and the modern, the advanced and the backward, the civilized and the barbarian. an image of the "civilized world" began to take shape and strengthened in the long colonization process. this positive image was, however, tarnished by the launching of the germ warfare of the united states and by its sophistry. after investigation, the international women's federation published "a report of the international women's investigation group on the atrocities made by the u.s. and the rhee armies." in the report, brute facts were established, such as the us army cold-bloodedly killed korean residents. in areas that had temporarily been occupied by the us army and syngman rhee's army, hundreds of thousands of civilian inhabitants, young and old alike, were tortured, burned, killed, or buried alive. the atrociousness had exceeded what the nazis and adolf hitler had made when they occupied europe (li siguang ). a canterbury dean johnson, invited to china, said after he learned the news that the united states had launched germ warfare, "a country, under the name of christianity, is shameful, connected with this matter." a representative from el salvador, dias, wrote after a visit to the exhibition, "this exhibition exposed, most conclusively, the way of the u.s. armed forces in launching germ warfare. the u.s. government, high command of the army, and scientists have committed heinous crimes against humanity and no punishment of any kind is suffi cient to ease the anger caused by such crimes." a costa rican deputy, sanz, wrote at the peace conference of asian and the pacifi c regions, "what i saw here was evidence and documents demonstrating the employment of bacteriological weapons by a self-styled civilized country. we must stop it, and expose it in every possible way." a stark historical fact was gradually ascertained in these accusations and angry words: the construction process of the "civilized world" was built in a very "uncivilized" manner. examples were many: the enclosure movement in britain where "sheep eat people," "reign of terror" of the french jacobins, the genocide waged against the native americans in the westward movement, etc. in his communist manifesto , karl marx seemed to have pointed out a more desirable attitude as to the complex interweaving of the "civilized" and the "uncivilized": he affi rmed that the development of capitalism had created unprecedented social productive forces, the results of which even exceeded the sum of any previous era. on the other hand, the actual process of capitalism was ruthlessly criticized: "sweating blood and fi lth with every pore from head to toe." that the weak and the sick men could actually defeat the strong world police, that the controller of communicable diseases should become the real source of the communicable diseases, and that the self-proclaimed civilized world was really permeated with fi lthy, uncivilized behavior were so astonishing that when history unveiled to its real image and shatter illusions surrounding it, an irony took the place of the metaphor of the "sick men of east asia" constructed on the basis of hygiene. in this dramatically ironic process, the deconstructive process of the metaphor of "the sick men" also began. in foucault's thorough analysis of the modern medical system, the complex underlying mechanism of the construction of metaphors such as the "sick man of east asia" was presented. far from being merely a process of "medical progress," the modern system of western medicine was also a social process in which the technology for social organization and social control continuously improved and intensifi ed. the medical system virtually became the origin of the "modern political system." in defi ning what is "healthy" and what is "unhealthy," what is hygienic and what is unhygienic, modern medicine also implies political or moral judgments of being "sinful" or "decadent." more importantly, foucault believed that the modern medical system, which originated from state behavior, such as controlling the spread of epidemics, was also an "aggressive system" full of "war mentality." in etiology, all diseases come from the infection of bacteria (microorganisms), to practice medicine is to fi ght with microbes, and to be a doctor is to be a warrior. diseases cannot be wiped out without a social system of well-organized, combative doctorpolice. that is why the practice of the western colonial countries or imperialistic countries was discovered to have a close connection with modern hygiene when they were rebuilding the world order. apartheid was necessary because the colonized people were thought to be the sources of communicable diseases in addition to being cheap labor resources. the metaphor of the "sick man of east asia" implied physical and moral denigration to the oppressed state and its people; in addition, the world police system is to prevent, control, and eradicate what was, in their eyes, the physical diseases as well as the social "diseases" -resistance, revolts, rebels, etc. the creation and proposal of the metaphor of the "sick man of east asia" alone did not mean, in reality, that they could be turned into a dominant and oppressive force. only when the target of the discourse had accepted and internalized the metaphor as it was found to be supported by social facts could the realistic force of the metaphor be brought out into full play. during this process, violence plays a vital role. violence had become the premise and the basic properties in the rise of the nation-states. through the writings of famous thinkers and theorists in modern times, we can discover that almost without exception, they would emphasize this feature of the state: hobbes described the state directly as a potentially violent "leviathan"; karl marx argued that the state is nothing but a machine for the oppression of one class at the hands of another; max weber articulated his celebrated defi nition of the state as a human community that "successfully claims the monopoly of the legitimate use of force within a given territory." giddens even considers "military industrialization" the defi ning moment from the traditional country to the modern nation-state. organized violence of the state not only became a space construction instrument dividing the borders and establishing boundaries but also played a crucial role in the process of colonization when the original pattern of world trade drastically changed, a new world order and market order were created, and the advantageous position of the western counties was assured. the premodern agrarian countries were defenseless when confronted with such organized, monopolized, and industrialized state violence. the fi asco of combating the western countries undermined the sense of superiority and confidence these agricultural countries originally enjoyed. more often than not, they felt hopeless and shameful in being forced to cede their territory and pay indemnities. the frequent attacks of feelings of hopelessness and shamefulness would suppress their original resistance awareness and let them accept the status quo. thus, they internalized the metaphor of the "sick man of east asia." in chinese people's refl ections upon a weak and declining china, and in their futile actions, the implications of the metaphor of the "sick man of east asia" were further broadened and more widely accepted. the repeated defeat and failure, and the growing sense of the nation experiencing a crisis especially, forced the chinese people to exert themselves to fi nd ways to save the country. "westernization movement," the "reform movement of ," the "new deal of autonomy," and "new culture movement" were all evidence of a continuous self-denial process focusing fi rst on some particular objects, then on the institutions, and then on culture. in this series of self-denial, "to resort to the other places" or "to resort to novel ideas in a foreign land" became the fi nal or the most practical choice. however, the choice was fi rst and foremost based on the premise of self-negation. the "sick men" was turned from a metaphor to a self-portrait of and a realistic oppressive discourse to the chinese people of the time. of course, it also meant space and possibility for resistance to the "oppression." the social fact of sickliness reinforced the shaping of the metaphor of the "sick man of east asia." since the han dynasty, the civil and the military had been separated and the civilians and the offi cers did not have anything to do with each other. this situation was aggravated in the song dynasty. "when it is established that the emphasis is on the civil side, the military side has faded, and the atmosphere is sort of soft. two millenniums of corruption are deep in the brain of the civilians" (liang qichao ) . opium importation, the fl ooding of opium after the opium war, especially, consumed not only china's fi nancial resources but also the nationals themselves. in addition, in the frenzied plunder and exploitation of the western countries, coupled with the infl ux of western industrial products, the country's economy rapidly slumped and the people's living standards were dramatically lowered, and the infi rmity due to malnutrition had become chronic. different from the traditional relatively static agrarian society, there tended to be more interactions among people who were involved in modern industry and commerce, which was conducive to the spread of diseases. thus, scenery of a "sick country" consisting of "sick people" emerged. the successful attempt to "clean" the country by banning prostitution and drugs after the founding of new china not only highlighted the characteristics of the nascent state as being "clean" but also brought about multiple perspectives: if the social ills and crimes that had lasted for thousands of years could be extirpated in a relatively short time in the resolute attempts of a new regime and the "patients" that had long been victimized could "turn from a ghost to a human" with the care and reconstructive attempts of the state, then what gave rise to so many sick persons in the fi rst place? why hadn't they stepped onto the highroad to health earlier? who should be responsible for the overall "sickness" of the state? besides internal inspection, the external reasons were also uncovered and questioned. the new state attributed the internal and the historical reasons to the "old exploitative system," which was entirely consistent with william mcneill's theory of the "microparasite" and "macroparasite." in mcneil's mind, the relationship between the ruler and the ruled in human history is macroparasitic, while the relationship between the human body and the pathogenic microorganisms is microparasitic (mcneill ) . the existence of the "parasites" not only produces such social ills as prostitution or drugs but also weakens the effective unity of the grassroots society during the national crisis. the bottomless pit of double "parasites" made the grassroots society miserable. perhaps this could be cited as a reason why mao zedong felt so exhilarated that he spent a sleepless night when learning the news that schistosomiasis was eradicated in yujiang. the outbreak of the war in north korea, the launching of the germ warfare in particular, revealed a more complex parasitic mode. macroparasitically, the western countries had been the occupier in the colonial world order by virtue of its military power in modern times. meanwhile, china had suffered continual defeats and the loss of sovereignty and dignity. reduced to a semicolonial country, china was in an even more miserable situation than that of a colonial country. the exploitative means of the parasite countries included, among other things, the ceding of territory, fi nancial exploitation, priorities the western countries claimed, and unfair market competition in the coastal areas and in the inland areas alike. the multiple parasites and long-time extortion made the oncerich-and-beautiful exploited countries become ugly, weak, and sick. the state and its people were both sick. after the sick men awakened and began an organized resistance, however, the western powers turned to violence (the war in north korea) as a new parasitic means. microparasitically, the natural properties of pathogenic microorganisms were separated and more social, political, and even cultural signifi cances were added. metaphors such as the "sick man of east asia," the "yellow peril," and others were used to denigrate the chinese people politically, morally, and in many other ways. next, diseases caused by microparasites, communicable diseases especially, were used as a means to extend the rights or benefi ts of the macroparasites (the plague in northeast china in part i can be referred to in this regard). in addition, advanced medicine was imported to strengthen its advantageous and civilized position so that the sentiments of resistance or rebelling of the colonial people could be broken down in a secret and artful way. furthermore, when the macroparasites went through a crisis in their survival, microparasite could be turned to as the last resort; "germ warfare" was invoked as a means to debilitate the combating force in the colonial area and to incur social panic. in reality, standing in strong contrast to the irony, and with the disintegration of the sick man metaphor, the metaphor began to be effectively dissolved and a turnaround occurred when resistance by means of armed forces turned to ideological condemnation by means of exposure of the crimes committed by the united states in bacterial warfare. while the western society used modern hygiene to construct the metaphor of the "sick men" and to establish the colonial order, those "sick men," who now had means of criticism at their hands, also used the knowledge framework for modern hygiene to create a basic narrative model and correspondent discourse system of the "virus or pathogens versus colonizers or aggressors." in a time when a variety of discourses and thoughts of "modern," "modernity," "postmodern," and even "post-postmodern" emerge, "farewell" seems to have become a popular and fashionable word in contemporary china: "a farewell to the tradition," "a farewell to revolution," "a farewell to ideology," and "a farewell to the state." however, can one so easily bid farewell? the olden times of the "sick men" are fading, but history is still unraveling itself. at this moment, when we indulge in vivid imagination and visions of modernization or modernity, we seem to have forgotten the past, which is not very far-gone. however, if we could bid farewell to the sick man metaphor because of "weapons of the weak," then how about modernization? when the modernization complex that has clung to the minds of chinese people since the modern times, when sometimes it even becomes an oppressive discourse, in what way is its basic approach different from the construction of the metaphor of the "sick men"? when the irony in between (e.g., growth without development) presents itself continuously, do we possess the basic consciousness and ability to deconstruct it? have we found the "weapons of the weak"? maybe what follows will be useful and offer some food for meditation. guns, germs, and steel: the fates of human societies suppression of u.s. germ warfare crimes. people's daily, . li siguang on new people -on the emphasis on military affairs plagues and peoples (yang yulin i think this turn is more than an "imagination"; it also evolved into realistic social action and achieved many instantaneous or far-reaching these forms need almost no prior coordination or planning. with their tacit understanding and informal networks, the peasants could help themselves without directly or symbolically fi ghting against the authority report on chinese people's voluntary army in the war to resist u.s. aggression and aid korea epidemics and history: ecological perspectives and social responses weapons of the weak: everyday forms of peasant resistance illness as metaphor social history of diseases in modern china key: cord- -c chbfa authors: reynolds, chris title: global health security and weapons of mass destruction chapter date: - - journal: global health security doi: . / - - - - _ sha: doc_id: cord_uid: c chbfa the global proliferation of weapons of mass destruction (wmd) presents a clear and present danger to global health security. unlike conventional weapons that confine themselves to a defined and targeted area, wmd’s cross international boundaries and borders. moreover, the release of wmds can be achieved using a low technology approach resulting in a transformation and redefinition of the mission of global health providers. this chapter will focus on the ease of access to wmds, the impact biological weapons and bioterrorism plays on global health security, united states global policies on public health, and the role actors and non-state actors play in the global health landscape. in addition, this chapter will focus on global wmd proliferation prevention to include international efforts, treaties, and conventions. the chapter will conclude with a discussion of ongoing research initiatives, identification of emerging threats, and additional recommended readings. union and other failed nation states. wmd includes chemical, biological, radiological, nuclear weapons and explosives. in addition, there is great concern regarding the spread of scientific knowledge among terror groups who can produce chemical and biological weapons with little technical expertise. both the proliferation of wmd and spread of scientific knowledge to terrorists preset a global wmd threat. dennis blair [ ] states in an dni threat assessment, "most terrorist groups that have shown some interest, intent or capability to conduct cbrn attacks have pursued only limited, technically simple approaches that have not yet caused large numbers of casualties. in particular, we assess the terrorist use of biological agents represents a growing threat as the barriers to obtaining many suitable started cultures are eroding and open source technical literature and basic laboratory equipment can facilitate production" [ ] . in his opening statement before the senate committee on homeland security and governmental affairs, senator joseph lieberman, summarized his concerns surrounding global proliferation of legitimate biotechnology research and expertise. as senator liberman noted, ". . .while so much of a benefit in so many ways, also creates this problem because that work can be used to create weapons of mass bioterror" [ ] . attacks using wmd the fall of the soviet union and warsaw pact nations resulted in the rise of concern that wmd weapons held by these nations would find themselves on the black market and perhaps, made available to terrorists. this added dimension to proliferation makes it even more difficult to mitigate. the potential for non-state actors, which includes both domestic and international terrorists, successfully obtaining access to wmd's is a very real threat to the safety and security of all people [ ] . one should realize that a nexus exists between wmd and terrorism. the driving motivation for terrorism is to inflict fear and create destruction to achieve their goals. the prospect of a terrorist faction successfully obtaining wmd poses one of the gravest risks to civilization. a successful wmd terror attack could potentially kill thousands and result in many more thousand casualties. likewise, the social, political, and economical impacts of such an attack would threaten the civilized world. the interconnected nature of people, economies, and international infrastructure around the world can infuse seemingly isolated or remote events with global consequences [ ]. significant efforts have been made in the united states and other countries to eliminate the threat of the spread of wmd. in , president george bush signed the proliferation security initiative (psi), which was designed to stop the global trafficking of wmd. on may , president bush unveiled the proliferation security initiative (psi) in krakow, poland, which outlined a new interdiction cooperative agreement outside of treaties and multilateral export control regimes [ ] . psi is not a program housed in only one agency, but instead is a set of activities with participation by multiple u.s. agencies and other countries [ ] . in its december national strategy to combat weapons of mass destruction (wmd) proliferation, the bush administration articulated the importance of countering proliferation once it has occurred and managing the consequences of wmd use. in particular, interdiction of wmd-related goods gained more prominence. u.s. policy sought to "enhance the capabilities of our military, intelligence, technical, and law enforcement communities to prevent the movement of wmd materials, technology, and expertise to hostile states and terrorist organizations [ ] . president bush's efforts follow a long line of previous efforts to curb the proliferation of wmd (illustration ). in , beginning with the signing of the biological weapons convention, which prohibited the development, production, stockpiling, acquisition, retention or transfer of biological weapons, was the first multilateral disarmament treaty illustration organization for the prohibition of chemical weapons [ ] banning an entire category of wmd. while this was a valiant attempt, the agreement fell short as there was no built-in verification mechanism [ ] . in , the landmark chemical weapons convention was held in paris that resulted in countries agreeing on the elimination of chemical weapons [ ] . it also established the organization for the prohibition of chemical weapons (opcw), whose mission is to assure the objectives outlined in the cwc are carried out and for ensuring the implementation the cwc provisions. this includes the verification of compliance of cwc directives ( , ) . the year marked the tenth anniversary of the cwc, which boasted -member states. in the preceding years between and , approximately , metric tons of chemical weapons were destroyed, with over international inspections conducted. even with the successes of the opcw, the world witnessed syria launch a chemical wmd attack on civilians, which we will discuss later in the chapter. according to the worldwide threat assessment of the us intelligence community, the mideast nations of iraq and syria have already demonstrated their use of wmd on civilians. in his statement for the record, united states director of national intelligence, daniel r. coats [ ] outlined the following situation status: russia has developed a ground-launched cruise missile (glcm) that the united states has declared is in violation of the intermediate-range nuclear forces (inf) treaty. despite russia's ongoing development of other treaty-compliant missiles with intermediate ranges, moscow probably believes that the new glcm provides sufficient military advantages to make it worth risking the political repercussions of violating the inf treaty. in , a senior russian administration official stated publicly that the world had changed since the inf treaty was signed in . other russian officials have made statements complaining that the treaty prohibits russia, but not some of its neighbors, from developing and possessing ground-launched missiles with ranges between and km. the chinese people's liberation army (pla) continues to modernize its nuclear missile force by adding more survivable road-mobile systems and enhancing its silobased systems. this new generation of missiles is intended to ensure the viability of china's strategic deterrent by providing a second-strike capability. china also has tested a hypersonic glide vehicle. in addition, the pla navy continues to develop the jl- submarine-launched ballistic missile (slbm) and might produce additional jin-class nuclear-powered ballistic missile submarines. the jin-class submarinesarmed with jl- slbms-give the pla navy its first long-range, sea-based nuclear capability. the chinese have also publicized their intent to form a triad by developing a nuclear-capable nextgeneration bomber. tehran's public statements suggest that it wants to preserve the joint comprehensive plan of action because it views the jcpoa as a means to remove sanctions while preserving some nuclear capabilities. iran recognizes that the us administration has concerns about the deal but expects the other participants-china, the eu, france, germany, russia, and the united kingdom-to honor their commitments. iran's implementation of the jcpoa has extended the amount of time iran would need to produce enough fissile material for a nuclear weapon from a few months to about year, provided iran continues to adhere to the deal's major provisions. the jcpoa has also enhanced the transparency of iran's nuclear activities, mainly by fostering improved access to iranian nuclear facilities for the iaea and its investigative authorities under the additional protocol to its comprehensive safeguards agreement. iran's ballistic missile programs give it the potential to hold targets at risk across the region, and tehran already has the largest inventory of ballistic missiles in the middle east. tehran's desire to deter the united states might drive it to field an icbm. progress on iran's space program, such as the launch of the simorgh slv in july , could shorten a pathway to an icbm because space launch vehicles use similar technologies. north korea's history of exporting ballistic missile technology to several countries, including iran and syria, and its assistance during syria's construction of a nuclear reactor-destroyed in -illustrate its willingness to proliferate dangerous technologies. in north korea, for the second straight year, conducted a large number of ballistic missile tests, including its first icbm tests. pyongyang is committed to developing a long-range, nuclear-armed missile that is capable of posing a direct threat to the united states. it also conducted its sixth and highest yield nuclear test to date. the assessment is that north korea has a longstanding bw capability and biotechnology infrastructure that could support a bw program. we also assess that north korea has a cw program and probably could employ these agents by modifying conventional munitions or with unconventional, targeted methods. pakistan continues to produce nuclear weapons and develop new types of nuclear weapons, including short-range tactical weapons, sea-based cruise missiles, air-launched cruise missiles, and longer-range ballistic missiles. these new types of nuclear weapons will introduce new risks for escalation dynamics and security in the region. the syrian regime used the nerve agent sarin in an attack against the opposition in khan shaykhun on april , in what is probably the largest chemical weapons attack since august . we continue to assess that syria has not declared all the elements of its chemical weapons program to the chemical weapons convention (cwc) and that it has the capability to conduct further attacks. despite the creation of a specialized team and years of work by the organization for the prohibition of chemical weapons (opcw) to address gaps and inconsistencies in syria's declaration, numerous issues remain unresolved. the opcw-un joint investigative mechanism (jim) has attributed the april sarin attack and three chlorine attacks in and to the syrian regime. even after the attack on khan shaykhun, we have continued to observe allegations that the regime has used chemicals against the opposition [ ] . the danger from hostile state and non-state actors who are trying to acquire nuclear, chemical, radiological, and biological weapons is increasing. the syrian regime's use of chemical weapons against its own citizens undermines international norms against these henious weapons, which may encourage more actors to pursue and use them. isis has used chemical weapons in iraq and syria. terrorist groups continue to pursue wmd-related materials [ ] . with respect to proliferation, it is important to remember the line between countries and terrorist groups is not always distinct. it is clear that some terrorist groups are supported by nation-states and vice versa. and it is evident that some terrorist groups act as proxies for nation-states. in addition, leading scientists working within a country might not be under the control of national authorities, as was the case in the history of nuclear weapons proliferation (www.fas.org/sgp/crs/nuke/rl .pdf). in , the united nations security council passed resolution , with the intent of keeping wmd out of the hands of non-state actors, which included nuclear, biological, and chemical weapons, their means of delivery, and related materials. resolution included the following three core directives: [ ] . . all states are prohibited from providing any form of support to non-state actors seeking to acquire weapons of mass destruction, related materials, or their means of delivery. . all states must adopt and enforce laws criminalizing the possession and acquisition of such items by non-state actors, as well as efforts to assist or finance their acquisition. . all states must adopt and enforce domestic controls over nuclear, chemical, and biological weapons, their means of delivery, and related materials, in order to prevent their proliferation. biological weapons are perhaps, the most insidious form of wmd's. these are weapons that contain viruses and/or bacterial pathogens or poisonous substances that have been engineered to cause severe illness or death in human beings, animals and vegetation. in their natural state, these pathogens or substances are not normally fatal to living beings and must be amplified or weaponized to become a threat. in addition, biological weapons also require a delivery mechanism. the centers for disease control (cdc) categorizes biological threats into three distinct categories based on lethality, with each category containing specific biological agents. category a contains the most lethal agents that pose the greatest threat, as they are easily disseminated and have the highest mortality rates [ ] . category a agents include anthrax-bacillus anthracis, botulism-clostridium botulinum, plague-yersinia pestis, smallpox-variola virus, tularemia-francisella tularensis, and viral hemorrhagic fever viruses (which includes the ebola virus) [ ] . category b agents have a low to moderate morbidity and are less threatening to the general public. category b agents include bacterial, rickettsial, and protozoal agents (brucellosis, glanders, melioidosis, q fever, psittacosis, typhus fever, cholera, and cryptosporidiosi); toxins (staphylococcus enterotoxin b, c. perfringens epsilon toxin, and ricin toxin); and, viral agents (viral encephalitides, including venezuelan, western, and eastern equine encephalitis) [ , ] . the final category is category c, which are those pathogens that can be engineered for mass dissemination because they are readily available, have a general ease of production, and their potential for high mortality rates [ ] . these include emerging viral pathogens, including nipah virus, hantavirus, which also includes hantavirus pulmonary syndrome and hantavirus hemorrhagic fever syndrome. these pathogens have a higher mortality than cat b agents [ ] . one only need look at history to see the impact of biological weapons. the greeks contaminated the water wells of their enemies in b.c. later, in the french and indian war, the british army distributed smallpox infected blankets to the indians. british general sir jeffrey amherst proposed presenting local indian tribes with the smallpox-laden blankets, which would allow colonist an easier path to colonization [ ] . at a peace conference, the blankets were presented as gifts to the unsuspecting indians. what the tribes did not realize, was that the blankets came from a smallpox-infected soldiers that were located in the area. the resulting impact was an outbreak of smallpox in the indian tribes of the area which was estimated to have a case fatality rate of almost % [ ] . in the second world war, the most notorious was conducted by the japanese army under the leadership of lt. gen. shiro ishii. ishii commanded the infamous unit and employed over scientists [ ] . unit operated in over six different cities with more than researchers who all focused on the development of deadly biological agents [ ] . among the biological toxins researched included anthrax, plague, and typhus. their test subjects included prisoners and innocent populations. it is estimated that over , people endured this horrible experimentation and later died as a result [ ] . one of unit 's most notorious attacks occurred in with the air distribution of plague infected wheat and mosquitos over the town of chang the, china. within a week, residents of the town began dying of plague. the final death toll estimate was people [ ] . in the s, the united states navy sprayed a low pathogenic bacterium over san francisco bay by boat to assess the vulnerability of a large american coastal town to a biological attack [ ] . in the s, the ussr maintained a clandestine biological weapons research lab that was known as chief directorate for biological preparation (biopreparat) that produced plague, tularemia, anthrax, glanders, smallpox and venezuelan equine encephalomyelitis [ ] . shortly after the september th, attacks on the world trade center and pentagon, several us government leaders received "anthrax letters", which caused panic in washington, dc. although this was a relative small-scale attack, it still elicited fear from throughout the united states. one of the key goals of a terrorist is to disrupt normal day-to-day life. the anthrax letters did just that-they cause very little damage and no one was infected, but they caused widespread panic. attacks do not have to be successful in creating casualties to be successful. indeed, the psychological damage done by launching a biological attack will have a tremendous impact on the government and population. any response to an incident involving biological substances brings about a higher level of concern and will challenge a community's emergency response infrastructure. new or engineered pathogens can spread quickly throughout the world. in his book, "hot zone", author richard preston writes a fictional account of the spread of the ebola virus. readers learned just how dangerous this pathogen was. although this was a fictional account, an actual ebola outbreak nearly occurred in ranson, virginia in at a cdc primate lab when monkeys became infected with a hemorrhagic fever outbreak. although the incident was contained, it required the ethnicization of primates by the united states army medical research institute of infectious diseases (usamriid). fortunately for the primate lab scientists, their strain of ebola was not harmful to humans. this outbreak gave birth to the new ebola-reston strain, which is only one of five ebola strains not harmful to humans [ ] . the world's attention was again focused on the ebola virus when in , a dallas hospital nurse became infected with ebola after treating an ebola patient. as the world learned of the ebola incident, citizens and concerned scientists concerns over laboratory safety began to be heard. the pandemic potential of accidental release of insufficient biosafety presents a danger [ ] . ebola is just one example of a biological threat-there are many others. it is important to note that each pathogen is unique and requires differing forms of response and treatment. as noted in the department of homeland security's (dhs) biological incident annex, individual pathogens present a real threat to public health and local plans should be written to deal with the aftermath of such threats [ ] . given the difficulty of weaponizing and distributing biological agents in enough quantity to create a mass casualty incident, it is unlikely that terror groups have this capability. in the senate committee on homeland security and governmental affairs report, the commission concluded that the united states should be less concerned that terrorists will become biologists and far more concerned that biologists will become terrorists [ ] . the cornerstone of international efforts to prevent biological weapons proliferation and terrorism is the biological weapons convention (bwc). this treaty bans the development, production, and acquisition of biological and toxin weapons and the delivery systems specifically designed for their dispersal. the bwc forbids member states (now numbering more than ) from assisting other governments, non-state entities, or individuals in obtaining biological weapons [ ] . the future threat of biological weapons is also significant. advances in bioengineering and biotechnologies that synthesize dna has created a new biohazard known as "synthetic genomics." this capability allows scientists to synthesize any virus whose dna has been decoded. imagine the impact of synthesizing the smallpox virus. although smallpox was eradicated in , samples remain frozen in cryogenic containers [ ] . attention to global health security that includes efforts to help prepare for and address pandemic and epidemic diseases has grown significantly over the past few decades, driven by the ongoing threat posed by emerging infectious diseases (eids), including hiv, sars, h n , ebola, and zika [ ] . the threat that weapons of mass destruction places on communities worldwide cannot be overstated. chemical weapons present unique challenges to emergency responders and healthcare practitioners requiring specialized decontamination procedures and treatment. chemical weapon use anywhere in the world poses a grave threat to the safety and security of all worldwide. the presence and usage of chemical weapons also pose a continuing threat and risk to global security and instability. a chemical attack is the spreading of toxic chemicals with the intent to do harm. a wide variety of chemicals could be made, stolen, or otherwise acquired for use in an attack. industrial chemical plants or the vehicles used to transport chemicals could also be sabotaged [ ] . both the concentration and toxicity of a chemical impacts the severity of an attack. similarly, whether the agent is released in a closed space or in the open air will impact the persistence of chemical agents. it is important to note that chemical weapons are banned under customary international law, the geneva protocol and the chemical weapons convention (cwc) [ ] . the organization for the prohibition of chemical weapons (opcw) is the implementing body for the chemical weapons convention, which entered into force on april . the opcw, with its member states, oversees the global endeavor to permanently and verifiably eliminate chemical weapons [ ] . the opcw divides chemicals into three distinct schedules with each category listing chemicals by the threat they pose. schedule chemicals are those that present the highest risk, as they include those chemicals that are prohibited by the chemical weapons convention. these chemicals have little or no use for peaceful purposes in commercial or industrial activities. among them are chemicals that have actually been produced, stockpiled or used as weapons, such as vx, sarin, mustard and two biological toxins-ricin and saxitoxin (opcw ). schedule chemicals are those that present a significant risk because of their lethal, incapacitating or other properties that could enable them to be used as a chemical weapon. examples include amiton, bz, thiodiglycol, and pinacolyl alcohol (opcw ). schedule chemicals are similar to schedule chemicals in that many have been stockpiled or used as weapons, but different in that they generally are produced in large commercial quantities for purposes not prohibited by the convention. they may represent a risk to the object of the cwc due to their toxicity or to their importance in producing any of the chemicals listed in schedule or precursors listed in schedule . examples of schedule chemicals include phosgene, hydrogen cyanide, triethanolamine, and phosphorus trichloride (opcw ). the history of chemical weapons can be traced back to world war i, where the germans used chlorine and phosgene weapons that resulted in hundreds of thousands of chemical casualties. in , in ypres, belgium, the germans opened the valves on more than steel cylinders, releasing tons of chlorine gas on the unsuspecting french trenches killing more than french and algerian soldiers and wounding more than soldiers [ ] . again in , the germans introduced a new chemical agent-mustard gas-which was referred to as the "king of the battle gasses." unlike chlorine or phosgene, mustard gas is a vesicant, also referred to as a "blister agent", whose symptoms may not be realized until - h after initial exposure [ ] . mustard gas produces large blisters on the skin and if inhaled, can cause blistering in the lungs. mustard gas produced more chemical casualties than all the other agents combined, including chlorine, phosgene, and cyanogen chloride [ ] . in , iraqi leader saddam hussein attacked the city of halabja, iraq with mustard gas and nerve agents, killing , civilians and injuring another , [ ] . in , an obscure japanese religious cult, aum shinrikyo, launched a sarin gas attack on the japanese subway system killing and injuring more that other subway passengers (rand ). in , the despot leader of syria, president bashar al-assad attacked his own population in khan al asal near aleppo killing civilians and injuring more than others. again, in , he released another chemical attack in douma, outside of damascus, syria that captured world attention after the bodies of children were broadcast worldwide. in this attack, innocent civilians were killed, including women and children [ ] . this attack prompted united states president donald trump to launch punitive strikes on syrian targets that were associated with the syrian regime's chemical-weapons programs [ ] . numerous treaties and agreements have attempted to thwart the development and deployment of chemical weapons. regulation attempts of chemical weapons dates back to when "the first international agreement limiting the use of chemical weapons was signed between france and germany, prohibiting the use of poison bullets." [ ] in the brussels convention on the law and customs of war was signed, which prohibited the employment of poison or poisoned weapons, and the use of arms, projectiles or material to cause unnecessary suffering [ ] . in , an agreement was signed that was a part of the hague peace conference in which countries agreed to abstain from the use of projectiles, the sole object of which is the diffusion of asphyxiating or deleterious gases [ ] . as we have read, the first half of the twentieth century witnessed nations putting great resources into the development of chemical weapons. from the cold war years , the united states and the soviet union were the two major superpowers still producing and maintaining chemical weapons stockpiles. in , the world's first multilateral disarmament agreement witnessed signatory nations agree to specifically at eliminating chemical weapons stockpiles, which was known as the chemical weapons convention (cwc) [ ] . their success was such that the opcw was awarded the nobel peace prize in . illustration depicts the efforts of disarmament and non-proliferation in cbrn weapons. the danger that chemical weapons pose to the world's population is significant, as they have the ability to incapacitate, injure, and kill without discrimination. their exposure presents dire consequences to any population or person who comes into contact with them. as we have read in this chapter, the sad history of chemical weapons use has resulted in nations attempting to stop the production and use of these agents. the public health impact cannot be overstated-from exposure, clean up, and contamination to decontamination and displacement of those impacted populations, it is critical that all public health personnel become familiar with the threat these weapons pose. radiological agents occur naturally and are used in everyday life, from medical x-rays to industrial applications. it is important to note that a radiological device is not a nuclear weapon. the threat radiological devices pose is through low-order detonation of explosives that spread the radiological agent in the atmosphere, ground and water. topical exposure or inhalation of radiologically-contaminated substances is where the threat lays. as we have scene with biological and chemical substances, terrorists are always seeking the materials to construct radiological dispersal devices (rdds). radiological events include the potential for terrorists to obtain these materials in an attempt to create the nonnuclear release of radioactive materials [ ] . as we will read about under the nuclear section of this chapter, the fall of the former soviet union and lapse of security in former nuclear sites potentially allowed for the sale of these materials on the black market. there are sites all around the world that radiological materials exist and many of these locations have virtually no security. rdds are likely to be the radiological weapon of choice because of their relative simplicity and widespread availability of rdd-adaptable radioactive materials in medicine, scientific research, and industries, such as civil engineering, petroleum engineering, aeronautics, and radio-thermal energy generation [ ] . as stated previously, an rdd is not a nuclear weapon and its main purpose is spreading radioactive materials in a low-order explosive. although far less catastrophic than a nuclear detonation, an rdd attack would likely result in few immediate casualties, but would certainly have longer term impacts on public health. the ancillary impacts of an rdd include the potential of widespread panic, economic loss, and costly cleanup [ ] . according to the congressional research service report, "dirty bombs": technical background, attack prevention and response, issues for congress," the author states that governments and organizations have taken steps to prevent an rdd attack [ ] . within the united states, the nuclear regulatory commission (nrc) has issued regulations to secure radioactive source, which has assisted both united states and other countries to secure and prepare for rdd attacks. internationally, the international atomic energy agency (iaea) has led efforts to secure radioactive sources. other nations and nongovernmental organizations have acted to secure sources as well. key points include: [ ] • nuclear regulatory commission actions have done much to instill a security culture for u.s. licensees of radioactive sources post- / . • many programs have sought to improve the security of radioactive sources overseas, but some incidents raise questions about security. even though tougher regulatory measures have been put into place, additional steps are needed to help reduce the rdd threat. it is truly a nightmare scenario if a terrorist detonates an rdd and spreads radioactive material across dozens of square miles, causing panic in the target area and beyond, costing tens of billions of dollars to remediate, costing further sums in lost wages and business, compelling the demolition and rebuilding of contaminated buildings, forcing difficult decisions on how to dispose of contaminated rubble and decontamination chemicals, and requiring people to relocate from areas with elevated levels of radiation [ ] . in a scenario involving an rdd detonation in washington, dc., the sandia national laboratories projected the impact of such an attack. their scenario included the detonation of a rdd that included curies of cesium- chloride (about grams). their model includes exposure from radioactive material both deposited on the surface and resuspended into the air and inhaled. the following map is based on an atmospheric dispersion model, depicting where individuals would be projected to have an increased risk of developing cancers due to radiation exposure over a year or more [ ] . one can see the increase in the cancer risk over time. depending where they are at the time of the exposure, this type of attack would increase the lifetime incidence of cancer by people, and lifetime deaths from cancer by . the figure assumes no relocation, sheltering, or decontamination. all these actions would occur in the real world, significantly reducing cancer incidence and deaths caused by the attack [ ] . nuclear weapons and the materials that make them up presents a true danger to civilization. the cold war years between and witnessed a dramatic rise in both the united states and soviet union's nuclear stockpiles. the conventional wisdom of stockpiling these weapons was the concept of "mutually assured destruction," which simply meant both the united states and soviet union would completely destroy one another in a nuclear war. towards the end of the cold war, other nations began acquiring nuclear weapons. these nations included china, pakistan, north korea, and india. the addition of these nations added to the complex calculus of mutual assured destruction. twenty years ago, russia and other newly-independent states emerged from the breakup of the soviet union, which put into question the status of their , nuclear weapons spread out at thousands of sites across a vast eurasian landmass that stretched across time zones (graham ). the concern the world faces is what happens when a terrorist group obtains a nuclear weapon. one thing is for certain, we are in an age where terrorism is almost common place, with terrorists always seeking different ways to achieve mass casualties. while it is unlikely that a terrorist group could obtain an in-tact nuclear weapon, they could construct a crude device. indeed, it is potentially within the capabilities of a technically sophisticated terrorist group, as numerous government studies have confirmed [ ] . in , a report written by harvard university's project on managing the atom concluded that "a capable and well-organized terrorist group plausibly could make, deliver, and detonate at least a crude nuclear bomb capable of incinerating the heart of any major city in the world." [ ] the consequences of detonation of even a crude terrorist nuclear bomb would be severe, turning the heart of modern city into a smoldering radioactive ruin and sending reverberating economic and political aftershocks around the world [ ] . without argument, a nuclear detonation would be catastrophic and cause death and destruction the likes of which we have never seen. a more likely scenario for a terror group would be in the form of a "dirty bomb", or radiological dispersal device (rdd). this is a device that is a mix of explosives, such as dynamite, and radioactive powder or pellets. it is important to note a dirty bomb cannot create an atomic blast. when the bomb explodes, the blast carries radioactive material into the surrounding area where it can cause widespread radiation exposure and sickness. people nearby could be injured by pieces of radioactive material from the bomb. only people who are very close to the blast site would be exposed to enough radiation to cause immediate serious illness. however, the radioactive dust and smoke can spread farther away and could be dangerous to health if people breathe in the dust, eat contaminated food, or drink contaminated water. people injured by radioactive pieces or contaminated with radioactive dust will need medical attention [ ]. triaging, treating and transporting victims of radiation, chemical, or biological exposure require swift and effective decontamination procedures. the risk of spreading contaminates to healthcare workers is significant, which also includes workers, bystanders, or others who may be in the contamination area or downwind. contaminated victims will require a special assessment for decontamination needs, which may include rapid decontamination on the scene of the incident and/or the hospital [ ] . the risk of secondary contamination is a significant concern that needs to be addressed in emergency response plans. triage is the process of determining the priority of a victim's treatments based on the severity of their condition. before treatment can begin, however, a mechanism must be in place to determine whether victims must also be decontaminated. it is equally important, however, to identify patients or victims who will not require decontamination and can be quickly evacuated from the incident site. the process of triage will determine the order of decontamination of victims. quick observance of victim signs and symptoms will help determine whether decontamination is necessary. the three most important reasons for decontaminating exposed victims are: [ ] . to remove the contaminant from the victim's skin and clothing, thus reducing further agent exposure and physical effects. . protecting emergency responders, medical personnel, family members, or others from secondary transfer exposures. . preventing victims from spreading contamination over additional areas of their body. the decision to decontaminate victims must occur through the medical branch of the incident command system, with the approval of the incident commander. the decision points the medical branch utilizes to make this decision is based on the follow outside indicators: [ ] • the victim's signs and symptoms to include airway, breathing, and circulation. • visual proof of contaminants on the skin or victim's clothing. • whether the victim was in the contamination zone. • positive contamination results from the use of chemical detection paper/tape, chemical agent monitor, geiger counter, or other technology. • proof of potential chemical exposure after reviewing the material safety data sheets (msds). the ultimate goal of decontamination is to be expedient and thorough. one must also remember that the longer it takes for victims to undergo decontamination, the longer it will take for them to be transported and treated at a hospital. decontamination can be divided into tiers, which allows for flexibility and adaptability based on the incident type. additionally, each of the tiers can be conducted on the scene of the incident or at a medical treatment facility [ ] . decontamination activities conducted for a large number of potentially contaminated patients, which may exceed the typical response capacity of an organization, may require additional resources or personnel, and require that patients be prioritized for the decontamination process. the number of patients that constitutes mass decontamination is dependent on the jurisdiction, responding agency, and capacity. mass decontamination may occur within any of the decontamination tiers. actions that a patient can perform for him/herself, including distancing him/herself from the site of release, removing clothing, and wiping visible contamination from skin and clothing in order to reduce his/her own contamination level immediately, without waiting for a formal decontamination process to be set up. actions likely to be performed by or with the assistance of first responders or first receivers in order to achieve a gross or hasty reduction in contamination, significantly reducing contamination on skin or clothing, as soon as possible after contamination has occurred. planned and systematic actions, likely to be performed under the guidance of or with the assistance of first responders or first receivers, to achieve contamination reduction to a level that is as low as possible. weapons of mass destruction presents a threat to civilization by both hostile states and non-state actors, including terrorists. numerous legislative efforts have attempted to halt the proliferation of wmd which works for nations who intend on following the law. the danger exists with non-state actors, rogue nations and terrorists, anyone of whom wouldn't think twice on using them. it is important for nations and international law enforcement agencies to keep tabs on these rogue nations and terrorists. the threat is too great and the cost is just too high if these weapons fall into the wrong hands. global proliferation of weapons of mass destruction (wmd) presents a clear and present danger to global health security and unlike conventional weapons that confine themselves to a defined and targeted area, wmd's cross international boundaries and borders. from the sarin attacks in and in japan and anthrax attacks to the syrian chemical attack on innocent civilians and vx nerve agent assignation in malaysia, weapons of mass destruction are a sad reality in today's society. as we have learned in this chapter, the driving motivation of terrorism is to strike fear and kill or injure innocent civilians to achieve their twisted goals. wmd's pose a much larger threat than conventional weapons and could potentially kill thousands and result in many more thousand casualties. wmd's include chemical agents, biological pathogens, radiological agents, and nuclear weapons, each of which require special protective measures for responders and decontamination for victims. chemical agents include lung damaging agents (chlorine (cl) and phosgene (cg)), blood agents (cyanogens), blister agents (mustard (h), lewisite (l), and phosgene oxime (cx)), and nerve agents (tabun (ga), sarin (gb), soman (gd), and vx). biological agents are those that contain viruses and/or bacterial pathogens or poisonous substances that have been engineered to cause severe illness or death in human beings, animals and vegetation. in their natural state, these pathogens or substances are not normally fatal to living beings and must be amplified or weaponized to become a threat. in addition, biological weapons also require a delivery mechanism. the centers for disease control (cdc) categorizes biological threats into three distinct categories based on lethality, with each category containing specific biological agents. category a contains the most lethal agents that pose the greatest threat, as they are easily disseminated and have the highest mortality rates [ ] . category a agents include anthrax-bacillus anthracis, botulism-clostridium botulinum, plague-yersinia pestis, smallpox-variola virus, tularemia-francisella tularensis, and viral hemorrhagic fever viruses (which includes the ebola virus) [ ] . category b agents have a low to moderate morbidity and are less threatening to the general public. category b agents include bacterial, rickettsial, and protozoal agents (brucellosis, glanders, melioidosis, q fever, psittacosis, typhus fever, cholera, and cryptosporidiosi); toxins (staphylococcus enterotoxin b, c. perfringens epsilon toxin, and ricin toxin); and, viral agents (viral encephalitides, including venezuelan, western, and eastern equine encephalitis) [ , ] . the final category is category c, which are those pathogens that can be engineered for mass dissemination because they are readily available, have a general ease of production, and their potential for high mortality rates [ ] . these include emerging viral pathogens, including nipah virus, hantavirus, which also includes hantavirus pulmonary syndrome and hantavirus hemorrhagic fever syndrome. these pathogens have a higher mortality than cat b agents. the radiological threat are those posed by the spread of radioactive materials in the atmosphere. radiological dispersal devices (rdds) may be explosive-driven-a dirty bomb-or use nonexplosive means like a crop duster airplane. radioactive material may be dispersed indoors to contaminate a building, though the scenario most commonly discussed involves detonation of a dirty bomb outdoors. the nuclear threat is the greatest of all threats the concern the world faces is what happens when a terrorist group obtains a nuclear weapon. one thing is for certain, we are in an age where terrorism is almost common place, with terrorists always seeking different ways to achieve mass casualties. the united states and united nations have worked hard to eliminate the threat of the spread of wmd, but even with the best intentions, it is difficult to maintain enforcement with rogue states and terrorists. it is critically important that all public health providers maintain vigilance and become aware of the wmd threat. testimony before the subcommittee on emergency preparedness, response, and communications, committee on homeland security, house of representatives. dhs's chemical, biological, radiological annual threat assessment of the us intelligence community for the senate select committee on intelligence hearing before the committee on homeland security and governmental affairs ensuring effective interagency interoperability and coordinated communication in case of chemical and/or biological attacks. new york . department of homeland security the bush administration's nonproliferation policy: successes and future challenges united states government accountability office (gao) ( ) proliferation security initiative: agencies have adopted policies and procedures but steps needed to meet reporting requirement and to measure results national strategy to combat weapons of mass destruction (wmd) organization for the prohibition of chemical weapons (opcw) ( ) origins of the chemical weapons convention and the opcw united nations office for disarmament affairs (unoda) ( ) the contribution of the biological weapons convention to global biosecurity statement for the record: worldwide threat assessment of the us intelligence community national security strategy of the united states. the white house terrorism and weapons of mass destruction: united nations security council resolution . chatham house, london overview of category a bioterrorism agents biological warfare and bioterrorism: a historical review bioweapons and bioterrorism: a review of history and biological agents biological warfare. a historical perspective general ishii shiro: his legacy is that of genius and madman. electronic theses and dissertations nuclear blindness: an overview of the biological weapons programs of the former soviet union and iraq ebola reston: a look back at the monkey house. inside nova, woodbridge . inglesby t, relman da ( ) how likely is it that biological agents will be used deliberately to cause widespread harm? biological incident annex to the response and recovery federal interagency operational plans the u.s. government and global health security. the henry j. kaiser family foundation, menlo park . department of homeland security ( ) chemical weapons fact sheet from the national academies the use of chemical weapons in syria: implications and consequences. one hundred years of chemical warfare: research, deployment, consequences about the opcw. retrieved on the poisonous cloud: chemical warfare in the first world war united states centers for disease control (cdc) ( ) toxic syndrome descriptions the tragedy of halabja (a pathological review on social-legal aspects of the case from historical and international points of view) how will this attack on syria be any different? the atlantic reducing nuclear and radiological terrorism threats understanding radiologic and nuclear terrorism as public health threats: preparedness and response perspectives dirty bombs": technical background, attack prevention and response, issues for congress preventing nuclear terrorism continuous improvement or dangerous decline? securing the bomb: an agenda for action, project on managing the atom united states department of health and human services (hhs) ( ) patient decontamination in a mass chemical exposure incident: national planning guidance for communities guidelines for mass casualty decontamination during a hazmat/weapon of mass destruction incident, vol i and ii what happened to the soviet superpower's nuclear arsenal? clues for the nuclear security summit aum shinrikyo, al qaeda, and the kinshasa reactor. rand corporation, santa monica . organization for the prohibition of chemical weapons (opcw) ( a) the structure of the opcw organization for the prohibition of chemical weapons (opcw) ( b) monitoring chemicals with possible chemical weapons applications key: cord- - lop pk authors: artenstein, andrew w. title: biological attack date: - - journal: ciottone's disaster medicine doi: . /b - - - - . - sha: doc_id: cord_uid: lop pk nan biological attack bioterrorism can be broadly defined as the deliberate use of microbial agents or their toxins as weapons. the broad scope and mounting boldness of worldwide terrorism exemplified by the massive attacks on new york city and washington, dc, on september , , coupled with the apparent willingness of terrorist organizations to acquire and deploy biological weapons, constitute ample evidence that the specter of bioterrorism will continue to pose a global threat. as in other aspects of daily life and the practice of medicine, in particular, the concept of "risk" is germane to considerations regarding an attack using biological agents. risk, broadly defined as the probability that exposure to a hazard will lead to a negative consequence, can be accurately calculated for a variety of conditions of public health importance (table - ) . however, the quantification of risk as it pertains to bioterrorism is imprecise because accurate assessment of exposure depends on the whims of terrorists, by nature, an unpredictable variable. although the probability of exposure to a biological attack is statistically low, it is not zero. because the negative consequences of an attack are potentially catastrophic, an understanding of biological threat agents and a cogent biodefense strategy are important components of disaster medicine. biological weapons have been used against both military and civilian targets throughout history, perhaps as early as bc. in the fourteenth century, tatars attempted to use epidemic disease against the defenders of kaffa, by catapulting plague-infected corpses into the city. british forces gave native americans blankets from a smallpox hospital in an attempt to affect the balance of power in the ohio river valley in the eighteenth century. in addition to their well-described use of chemical weapons, axis forces purportedly infected livestock with anthrax and glanders to weaken allied supply initiatives during world war i. perhaps the most egregious example of biological warfare involved the japanese program in occupied manchuria from to . based on survivor accounts and confessions of japanese participants, thousands of prisoners were murdered in experiments using a variety of virulent pathogens at unit , the code name for a notorious japanese biological weapons facility. the united states maintained an active program for the development and testing of offensive biological weapons from the early s until , when the program was terminated by executive order of then president nixon. current efforts continue as countermeasures against biological weapons. the convention on the prohibition of the development, production, and stockpiling of biological and toxin weapons and on their destruction (bwc) was ratified in , formally banning the development or use of biological weapons, and assigning enforcement responsibility to the united nations. unfortunately, the bwc has not been effective in its stated goals; multiple signatories have violated the terms and spirit of the agreement. the accidental release of aerosolized anthrax spores from a biological weapons plant in the soviet union in , with at least human deaths from inhalational anthrax reported downwind, was proven years later to have occurred in the context of offensive weapons production. events within the past years have established bioterrorism as a credible and ubiquitous threat: for example, the incident in the dalles, oregon, involving the intentional contamination of restaurant salad bars with salmonella, by a religious cult attempting to influence a local election. public fears were additionally heightened by the international events following the japanese aum shinrikyo cult's sarin attack in tokyo in , especially after investigations revealed that the group had been experimenting with aerosolized anthrax release from rooftops for several months prior. more recently, un weaponsinspector findings of significant quantities of weaponized biological compounds in iraq during the gulf war and the subsequent aftermath has served as sentinel warnings of a shift in terrorism trends. this trend culminated with the october anthrax attacks in the united states, which elevated bioterrorism to the forefront of international dialogue and heightened public concerns regarding systemic health care preparation against the threat of biological attacks. biological agents are considered weapons of mass destruction (wmds) because, as with certain conventional, chemical, and nuclear weapons, their use may result in large-scale morbidity and mortality. a world health organization (who) model based on the hypothetical effects of the intentional release of kg of aerosolized anthrax spores upwind from a population center of , (analogous to that of metropolitan providence, ri) estimated that the agent would disseminate in excess of km downwind and that nearly , people would be killed or injured by the event. biological weapons possess unique properties among wmds. by definition, biological agents are associated with a clinical latency period of days to weeks, in most cases, during which time early detection is quite difficult with currently available technology. yet, early detection is critical because specific antimicrobial therapy and vaccines are available for the treatment and prevention of illness caused by certain biological weapons. casualties from other forms of wmds can generally only be treated by decontamination (with antidotes available for only some types), trauma mitigation, and supportive care. additionally, the possibility of a biological attack provokes fear and anxiety-"terror"-disproportionate to that seen with other threats, given their often invisible nature. the goals of bioterrorism are those of terrorism in general: morbidity and mortality among civilian populations, disruption of the societal fabric, and exhaustion or diversion of resources. a successful outcome from a terrorist standpoint may be achieved without furthering all of these aims but instead disrupting daily life. the anthrax attacks in the united states in evoked significant anxiety and diverted resources from other critical public health activities despite the limited number of casualties. in many cases, the surge capacity of our public health system has been inadequate to deal with the emergency needs, resulting in reform and additional planning after the event. to be used in large-scale bioterrorism, biological agents must undergo complex processes of production, cultivation, chemical modification, and weaponization. for these reasons, state sponsorship or direct support from governments or organizations with significant resources, contacts, and infrastructure would predictably be required in large-scale events. however, revelations have suggested that some agents may be available on the worldwide black market and in other illicit settings, thus obviating the need for the extensive production process. although traditionally thought to require an efficient delivery mode, recent events, including the united states anthrax attacks, demonstrated the devastating results that can be achieved with relatively primitive delivery methods (e.g., high-speed mail-sorting equipment and mailed letters). numerous attributes contribute to the selection of a pathogen as a biological weapon: availability or ease of large-scale production, ease of dissemination (usually by the aerosol route), stability of the product in storage, cost, and clinical virulence. the last of these refers to the reliability with which the pathogen causes high mortality, morbidity, or social disruption. the centers for disease control and prevention (cdc) has prioritized biological-agent threats based on the aforementioned characteristics, and this has influenced current preparation strategies (table - ). category a agents, considered the highest priority, are associated with high mortality and the greatest potential for major effects on the public health. category b agents are considered "incapacitating" because of their potential for moderate morbidity but relatively low mortality. most of the category a and b agents have been experimentally weaponized in the past and thus have proven feasibility. category c agents include emerging threats and pathogens that may be available for development and weaponization. another factor that must be addressed in assessing future bioterrorism risk is the historical record of experimentation with specific pathogens, informed by the corroborated claims of various high-level soviet defectors and data released from the former offensive weapons programs of the united states and united kingdom. , , information from these sources, combined with the burgeoning fields of molecular biology and genomics, demonstrates that future risk scenarios will likely have to contend with genetically altered and "designer" pathogens intended to bypass current known medical countermeasures or defenses. to this end, a miscellaneous grouping of potential threat agents is added to the extant cdc categories in table bioterrorist attacks are often insidious. absent of advance warning or specific intelligence information, clinical illness will likely manifest before the circumstances of a release event are known. for this reason, health care providers are likely to be the first responders and reporting agents of this form of terrorism. this is in contrast to the more familiar scenarios in which police, firefighters, paramedics, and other emergency services personnel are deployed to the scene of an attack with conventional weaponry or a natural disaster. physicians and other health care workers must therefore maintain a high index of suspicion of bioterrorism, and recognize suggestive epidemiologic clues and clinical features to enhance early recognition and guide initial management of casualties. early recognition and rapid deployment of specific therapy remains the most effective way to minimize the deleterious effects of bioterrorism on both exposed individuals and public health. unfortunately, early recognition is hampered for multiple reasons. as previously discussed, it is likely that the circumstances of any event will only be known in retrospect. therefore responders may be unable to discern the extent of exposure immediately. also, terrorists have a nearly unlimited number of targets in most open democratic societies, and it is unrealistic to expect any governing body without detailed intelligence of an impending attack to secure an entire population at all times. certain sites, such as government institutions, historic landmarks, or large public gatherings, may be predictable targets; however, other facilities may fall victim to bioterrorism. in fact, government data support that businesses and other economic concerns were the main targets of global terrorism during the period from to . metropolitan areas are traditionally considered especially vulnerable given the dense populations and already existing public gathering areas such as subways and office buildings. because of the expansion of suburbs and the commuter lifestyle, as well as the clinical latency period between exposure and symptoms, casualties of bioterrorism are likely to present for medical attention in diverse locations and at varying times after a common exposure. an event in new york city on a wednesday morning may result in clinically ill persons presenting over the ensuing weekend to a variety of emergency departments within a -mile radius. finally, current modes of transportation ensure that there will be affected persons thousands of miles away, at both national and international locations, related to a single common exposure. this adds layers of complexity to an already complicated management strategy and illustrates the critical importance of surveillance and real-time communication in the response to suspected bioterrorism. further hindering the early recognition of bioterrorism is that initial symptoms of a biological weapon may be nonspecific and nondiagnostic. in the absence of a known exposure, many symptomatic persons may not seek medical attention early, or if they do, they may be misdiagnosed as having a viral or flu-like illness. if allowed to progress beyond the early stages, many of these illnesses deteriorate quite rapidly, and treatment may be significantly more difficult. most of the diseases caused by agents of bioterrorism are rarely, if ever, seen in modern first-world clinical practice. physicians are likely to be inexperienced with their clinical presentation and be less aware of alarming symptomatic constellations. additionally, these agents by definition will have been manipulated in a laboratory and may not present with the classic clinical features of naturally occurring infection. this was dramatically illustrated by some of the inhalational anthrax cases in the united states in october . early recognition of bioterrorism is facilitated by the recognition of epidemiologic and clinical clues. clustering of patients with common signs and symptoms-especially if regionally unusual or otherwise characteristic of bioterrorism agents-is suggestive of an intentional exposure and should prompt expeditious notification of local public health authorities. this approach will also lead to the recognition of outbreaks of naturally occurring disease or emerging pathogens. the recognition of a single case of a rare or nonendemic infection, in the absence of a travel history or other potential natural exposure, should raise the suspicion of bioterrorism. finally, unusual patterns of disease, such as concurrent illness in human and animal populations should raise suspicions of bioterrorism or another form of emerging infection. an effective response to bioterrorism requires coordination of the medical system at all levels, from the community physician to the tertiary care center, with rapid activation of public health, emergency management, and law enforcement infrastructures. this section provides a broad overview of the biological threat agents thought to be of major current concern-largely, the cdc category a agents. extensive coverage of specific pathogens can be found in related chapters in this text and in other sources. these agents can possess rapid person-to-person transmission or the potential for rapid dissemination if weaponized, with high-mortality potential, small infective doses, and significant environmental stability. , data concerning clinical incubation periods, transmission characteristics, and infection-control procedures for agents of bioterrorism are provided in table - . syndromic differential diagnoses for select clinical presentations are detailed in table - . anthrax results from infection with bacillus anthracis, a gram-positive, spore-forming, rod-shaped organism that exists in its host as a vegetative bacillus and in the environment as a spore. details of the microbiology and pathogenesis of anthrax are found in chapter . in nature, anthrax is a zoonotic disease of herbivores that is prevalent in many geographic regions; sporadic human disease results from environmental or occupational contact with endospore-contaminated animal products. the cutaneous form of anthrax is the most common presentation; gastrointestinal and inhalational forms are exceedingly rare in naturally acquired disease. an additional form, injectional anthrax, represents a potentially lethal, deep soft-tissue infection that has been well described in injection heroin users in several western european countries. a cutaneous anthrax occurred regularly in the first half of the twentieth century in association with contaminated hides and wools used in the garment industry, but it is uncommonly seen in current-day industrialized countries because of importation restrictions. the last-known fatal case of naturally occurring inhalational anthrax in the united states occurred in , when an individual was exposed to imported wool from pakistan. case reports of naturally occurring anthrax do occur within the united states, although they are rare. it has been previously hypothesized that large-scale bioterrorism with anthrax would involve aerosolized endospores with resultant inhalational disease, but the attacks in the united states illustrate the difficulties in predicting modes and outcomes in bioterrorism. these attacks were on a relatively small scale, and nearly % of the confirmed cases were of the cutaneous variety. the serious morbidity and mortality of anthrax is instead related to inhalational disease, as was the case in the sverdlovsk outbreak in . as a result, planning for larger-scale events with aerosolized agent is warranted given the high-mortality cost of an exposure to this more weaponized form of anthrax. the clinical presentations and differential diagnoses of cutaneous and inhalational anthrax are described in table of cutaneous anthrax may be similar in appearance to other lesions, including cutaneous forms of other agents of bioterrorism; however, it may be distinguished by epidemiologic, as well as certain clinical, features. anthrax is traditionally a painless lesion, unless secondarily infected, and is associated with significant local edema. the bite of loxosceles reclusa, the brown recluse spider, shares many of the local and systemic features of anthrax but is typically painful from the outset and lacks such significant edema. cutaneous anthrax is associated with systemic disease, and it carries an associated mortality in up to % of untreated cases, although with appropriate antimicrobial therapy mortality is less than %. once the inhaled endospores reach the terminal alveoli of the lungs-generally requiring particle sizes of to μm-they are phagocytosed by macrophages and transported to regional lymph nodes. here the endospores germinate into vegetative bacteria and subsequently disseminate hematogenously. spores may remain latent for extended periods in the host, up to days in experimental animal exposures. this translates to prolonged clinical incubation periods after respiratory exposure to endospores. cases of inhalational anthrax occurred up to days after exposure in the sverdlovsk accident, although the average incubation period is thought to be to days, perhaps influenced by exposure dose. , before the u.s. anthrax attacks in october , most of the clinical data concerning inhalational anthrax derived from sverdlovsk, the largest outbreak recorded. although there is much overlap between the clinical manifestations noted previously and those observed during the recent outbreak, data that are more detailed are available from the recent u.s. experience. there were confirmed persons with inhalational anthrax, ( %) of whom died. this contrasts with a casefatality rate of greater than % reported from sverdlovsk with an estimated deaths. the reliability of reported data from this outbreak is questionable, given soviet documentation, but a majority of victims were located downwind of the ill-fated weapons plant. , patients almost on average present of . days after symptom onset with fevers, chills, malaise, myalgias, nonproductive cough, chest discomfort, dyspnea, nausea or vomiting, tachycardia, peripheral neutrophilia, and liver enzyme elevations. , , many of these findings are nondiagnostic, and they overlap considerably with those of influenza and other common viral respiratory tract infections. recently compiled data suggest that shortness of breath, nausea, and vomiting are significantly more common in anthrax, whereas rhinorrhea is uncommonly seen in anthrax but noted in the majority of viral respiratory infections, an important clinical distinction. other common clinical manifestations of inhalational anthrax include abdominal pain, headache, mental status abnormalities, and hypoxemia. abnormalities on chest radiography appear to be universally present, although these may only be identified retrospectively in some cases. pleural effusions are the most common abnormality, although radiographs may demonstrate patchy infiltrates, consolidation, and/or mediastinal adenopathy. the latter is thought to be an early indicator of disease, but computed tomography appears to provide greater sensitivity compared with chest radiographs for this finding. the clinical manifestations of inhalational anthrax generally evolve to a fulminant presentation with progressive respiratory failure and shock. b. anthracis is routinely isolated in blood cultures if obtained before the initiation of antimicrobials. pleural fluid is typically hemorrhagic; the bacteria can either be isolated in culture or documented by antigen-specific immunohistochemical stains of this material in the majority of patients. in the five fatalities in the u.s. series, the average time from hospitalization until death was days (range, to days), which is consistent with other reports of the clinical virulence of this infection. autopsy data typically reveal hemorrhagic mediastinal lymphadenitis and disseminated, metastatic infection. pathology data from the sverdlovsk outbreak confirm meningeal involvement, typically hemorrhagic meningitis, in % of disseminated cases. the diagnosis of inhalational anthrax should be entertained in the setting of a consistent clinical presentation in the context of a known exposure, a possible exposure, or epidemiologic factors suggesting bioterrorism (e.g., clustered cases of a rapidly progressive illness). the diagnosis should also be considered in a single individual with a clinical illness consistent with anthrax exposure in the absence of another etiology. the early recognition and prompt treatment of inhalational anthrax is likely associated with a survival advantage. therefore the emergency physician should promptly initiate empiric antimicrobial therapy if infection is clinically suspected. combination parenteral therapy is appropriate in the ill person for a number of reasons: to cover the possibility of antimicrobial resistance, to target specific bacterial functions (e.g., the theoretical effect of clindamycin on toxin production), to ensure adequate drug penetration into the central nervous system, and perhaps to favorably affect survival. drainage of pleural effusions is indicated to reduce toxin burden. detailed therapeutic and post-exposure prophylaxis recommendations have been recently reviewed elsewhere. a a monoclonal antibody targeted at the protective antigen component of anthrax toxin, raxibacumab, is available for the adjunctive treatment of systemic anthrax. a in the future, it is likely that novel therapies such as toxin inhibitors or cell-specific receptor antagonists will be available to treat anthrax post exposure. detailed therapeutic and postexposure prophylaxis recommendations for adults, children, and special groups have been recently reviewed elsewhere. with regard to postexposure prophylaxis, the anthrax vaccine adsorbed is effective for prevention of cutaneous anthrax in human clinical trials, as well as preventing inhalational disease after aerosol challenge in nonhuman primates. current studies are investigating the efficacy of this vaccine when paired with antibiotics in the postexposure period. for preexposure prophylaxis, the vaccine is generally very safe, but it requires five doses over months, with the need for annual boosting for ongoing preventative immunity. preexposure use of the vaccine is currently limited to individuals at high risk for anthrax exposure, such as military personnel and specific laboratory workers. although not currently available, additional research into second-generation anthrax vaccines is aimed to generate a more easily distributed means of mass prophylaxis following an anthrax exposure. the last-known naturally acquired case of smallpox occurred in somalia in . in one of the greatest triumphs of modern medicine, smallpox was officially certified as having been eradicated in , the culmination of a -year intensive campaign undertaken by the who. however, because of concerns that variola-virus stocks may have either been removed from or sequestered outside of their officially designated repositories, smallpox is considered a potential and certainly dangerous agent of bioterrorism. multiple features make smallpox an attractive biological weapon and ensure that any reintroduction into human populations would be a global public health catastrophe: it is stable in aerosol form, has a low infective dose, is associated with up to a % case-fatality rate, and has a large vulnerable target population because civilian vaccination was terminated in . smallpox is also especially dangerous because secondary attack rates among unvaccinated close contacts are estimated at % to % and are only further amplified by the lack of vaccine-induced immunity and a lack of naturally circulating virus to induce low-level booster exposures. because of the successful eradication, preexposure vaccination is currently limited to specific military and laboratory professionals. there are currently no antiviral therapies of proven effectiveness against this pathogen. after an incubation period of to days (average to days), patients will develop a prodrome of fever, rigors, headache, and backache that may last to days. this is followed by a centrifugally distributed eruption that generalizes as it evolves through macular, papular, vesicular, and pustular stages in synchronous fashion over approximately days, with umbilication in the latter stages. enanthem in the oropharynx typically precedes the exanthem by to hours. the rash typically involves the palms and soles early in the course of the disease. the pustules begin crusting during the second week of the eruption; separation of scabs is usually complete by the end of the third week. the differential diagnosis of smallpox is delineated in table - . historically, varicella and drug reactions have posed the greatest diagnostic dilemmas; this would likely be further complicated by the absence of this clinical disease and therefore experience in its diagnosis for the past years. smallpox is transmitted person to person by respiratory droplet nuclei and (although less commonly) by contact with lesions or contaminated fomites. airborne transmission by fine-particle aerosols has also been documented under certain conditions. the virus is communicable from the onset of the enanthem until all of the scabs have separated, although patients are thought to be most contagious during the first week of the rash because of high titers of replicating virus in the oropharynx. household members, other face-to-face contacts, and health care workers have traditionally been at highest risk for secondary transmission, given their proximity to infected individuals during the highly infectious period. as a result, patients with signs and symptoms concerning for smallpox should be placed in negative-pressure rooms with contact and airborne precautions to minimize this risk. those not requiring hospital-level care should remain isolated at home to avoid infecting others in public places. the suspicion of a single smallpox case should prompt immediate notification of local public health authorities and the hospital epidemiologist. containment of smallpox is predicated on the "ring vaccination" strategy, which was successfully deployed in the who global eradication campaign. this strategy mandates the identification and immunization of all directly exposed persons, including close contacts, health care workers, and laboratory personnel. vaccination, if deployed within days of infection during the early incubation period, can significantly attenuate or prevent disease and may favorably affect secondary transmission. because the occurrence of even a single case of smallpox would be tantamount to bioterrorism, an immediate epidemiologic investigation is necessary to establish a biological perimeter and trace initially exposed individuals for ring vaccination purposes. botulism is an acute neurologic disease caused by clostridium botulinum, which occurs both sporadically and in focal outbreaks throughout the world related to wound contamination by the bacterium or the ingestion of the foodborne toxin. a detailed discussion of botulism is found in chapter . aerosolized forms of the toxin are fortunately a rare mode of acquisition in nature, but they have been weaponized for use in bioterrorism. botulinum toxin is considered the most toxic molecule known; it is lethal to humans in very minute quantities. it is estimated that a single gram of concentrated clostridium botulinum neurotoxin could kill up to million otherwise healthy individuals. the toxin functions by blocking the release of the neurotransmitter acetylcholine from presynaptic vesicles, thereby inhibiting muscle contraction. botulism presents as an acute, afebrile, symmetric, descending, and flaccid paralysis. the disease manifests initially in the bulbar musculature and is unassociated with mental status or sensory changes. fatigue, dizziness, dysphagia, dysarthria, diplopia, dry mouth, dyspnea, ptosis, ophthalmoplegia, tongue weakness, and facial muscle paresis are early findings seen in more than % of cases. progressive muscular involvement leading to respiratory failure ensues. the clinical presentations of foodborne and inhalational botulism are indistinguishable in experimental animals. fortunately, outside of the toxin itself being utilized for bioterrorism, botulism is not spread directly from person to person. typically, these patients will recover with supportive care in weeks to months. the diagnosis of botulism is largely based on epidemiologic and clinical features and the exclusion of other possibilities (table - ) . clinicians should recognize that any single case of botulism could be the result of bioterrorism or could herald a larger-scale "natural" outbreak. a large number of epidemiologically unrelated, multifocal cases should be clues to an intentional release of the agent, either in food sources, water supplies, or as an aerosol. the mortality from foodborne botulism has declined from % to % over the last four decades, likely because of improvements in supportive care and mechanical ventilation. because the need for the latter may be prolonged, limited resources (e.g., mechanical ventilators) would likely be exceeded in the event of a large-scale bioterrorism event. treatment with an equine antitoxin, available in limited supply from the cdc, may ameliorate disease if given early. there is no currently available vaccine. plague, a disease responsible for multiple epidemics throughout human history, is caused by the gram-negative pathogen yersinia pestis. this pathogen is found in a variety of forms in the natural world. it is extensively covered in chapter . plague is endemic in parts of southeast asia, africa, and the western united states. aerosolized preparations of the agent, the expected vehicle in bioterrorism, would be predicted to result in cases of primary pneumonic plague outside of endemic areas. additional forms of the disease, such as bubonic and septicemic plague, are also concerning from a bioterrorism perspective. primary pneumonic plague classically presents as an acute, febrile, pneumonic illness with prominent respiratory and systemic symptoms. patients will often endorse gastrointestinal symptoms and purulent sputum production, with variable levels of reported hemoptysis. chest x-rays will typically show patchy, bilateral, multilobar infiltrates or consolidations. unlike other forms of community-acquired pneumonia, in the absence of appropriate treatment, there may be rapid progression to respiratory failure, vascular collapse, purpuric skin lesions, necrotic digits, and death. the differential diagnosis for these symptoms including rapidly progressive pneumonia is very broad as noted in table - . plague is suggested by the characteristic small gramnegative coccobacillary forms found in stained sputum specimens with the bipolar uptake ("safety pin") of giemsa or wright stain. culture confirmation is necessary to establish the diagnosis; the microbiology laboratory should be notified in advance if plague is suspected because special techniques and precautions must be employed. of note, initial gram staining of samples can often be negative despite positive culture in y. pestis detection. serologic testing is also possible if the aforementioned studies are persistently negative. treatment recommendations for plague have been reviewed elsewhere. pneumonic plague can be transmitted from person to person by respiratory droplet nuclei, thus placing close contacts, other patients, and health care workers at risk for secondary infection. prompt recognition and treatment of this disease, appropriate deployment of postexposure prophylaxis, and early institution of droplet precautions will help to interrupt secondary transmission. both live and attenuated plague vaccines exist; however, these are not currently approved for commercial use in the united states. high-risk populations, including laboratory and military personnel, may receive a formaldehyde-killed version of the vaccine as prophylaxis in certain situations. fortunately, new recombinant vaccines are currently in development, although some parts of the world continue to use live versions of the vaccine. tularemia francisella tularensis, the causative agent of tularemia, is another small gram-negative coccobacillus with potential to cause a primary pneumonic presentation if delivered as an aerosol agent of bioterrorism. this bacterium is commonly found in smaller mammals, most classically hares and rabbits. humans serve as an accidental host; typically, natural infections occur via insect bites, consuming infected animal products, or direct contact with infected domesticated animals. the causative bacteria can be transmitted between humans by close contact via mucous membrane contact, cutaneous inoculation, and inhalation if patients are exposed to aerosolized forms of the bacteria. pulmonary tularemia presents with the abrupt onset of a febrile, systemic illness with prominent upper-respiratory symptoms of a highly variable nature. patients may exhibit inconsistent development of pneumonia, hilar adenopathy, hemoptysis, pulse-temperature dissociation, malaise, and progression toward respiratory failure and death in excess of % of those who do not receive appropriate therapy. the diagnosis is generally based on clinical features after other agents are ruled out, but again it requires a high level of clinical suspicion. confirmatory serology using various immunologic assays is currently available. laboratory personnel should be notified in advance if tularemia is suspected because the organism can be very infectious under culture conditions. this agent is discussed in depth in chapter . moreover, treatment typically consists of antibiotic therapy with streptomycin or gentamicin, with an estimated overall mortality after treatment of only %. a live attenuated vaccine against tularemia exists; however, it is not currently available for human use in the united states. tularemia remains a significant concern, given the lack of current vaccine, especially when coupled with the high infectivity and mortality of pulmonary tularemia. the agents of viral hemorrhagic fevers are members of four distinct families of ribonucleic acid viruses that cause clinical syndromes with overlapping features: fever, malaise, headache, myalgias, prostration, mucosal hemorrhage, and other signs of increased vascular permeability with circulatory dysregulation. unfortunately, they are all capable of leading to shock and multiorgan system failure in advanced cases. specific agents are also associated with specific target organ effects, although each has a propensity to damage vascular endothelium. these pathogens, discussed in detail in chapters to , include ebola, marburg, lassa fever, rift valley fever, and congo-crimean hemorrhagic fever. hemorrhagic fever viruses have been viewed as being emerging infections because of their sporadic occurrence in focal outbreaks throughout the world; the ongoing epidemic of ebola hemorrhagic fever in west africa has resulted in more than , cases and , deaths since . a often in novel outbreak situations, these severe effects of these viruses on humankind are thought to be the results of human intrusion into a viral ecologic niche. they are concerning potential weapons of bioterrorism because they are highly infectious in aerosol form, are transmissible in health care settings, cause high morbidity and mortality, and are purported to have been successfully weaponized. blood and other bodily fluids from infected patients are extremely infectious, and person-to-person airborne transmission may occur, as well. as a result, strict contact and airborne precautions should be instituted if viral hemorrhagic fevers are implicated in a terrorism event. the diagnosis of viral hemorrhagic fevers is complicated, especially in a potential bioterrorist attack, which would lack a known exposure, or following recent travel to africa. microbiology studies and immunological testing are difficult to perform routinely, and often require evaluation by cdc laboratories. treatment is largely supportive, and it includes the early use of vasopressors as needed. ribavirin is effective against some forms of viral hemorrhagic fevers but not those caused by ebola and marburg viruses. for a majority of these diseases, the treatment is largely supportive therapy. nonetheless, ribavirin should be initiated empirically in patients presenting with a syndrome consistent with viral hemorrhagic fever until the exact etiology is confirmed. even though there are vaccines available for similar diseases, such as yellow fever and argentine hemorrhagic fever, there are no current options for preexposure vaccination for viral hemorrhagic fevers. this paired with the highly infectious nature and significant mortality rates make this category of viruses worrisome potential agents of bioterrorism. the approach to the management of diseases of bioterrorism must be broadened to include children, pregnant women, and immunocompromised persons. specific recommendations for treatment and prophylaxis of these special patient groups for selected bioterrorism agents have been recently reviewed. , , a general approach requires an assessment of the risk of certain drugs or products in select populations versus the potential risk of the infection in question, accounting for extent of exposure and the agent involved. the issue extends to immunization because certain vaccines, such as smallpox, pose higher risk to these special groups than to others. this will affect mass vaccination strategies and will likely warrant case-by-case decisions. of note, the prevalence of antivaccine sentiments has implications with regard to global biosecurity. a decline in herd immunity against a vaccine-preventable communicable disease could leave even a medically prepared society vulnerable to a terrorist-introduced agent previously well controlled with prophylactic vaccinations. this will be yet another special population to consider in the event of a mass casualty bioterrorist attack. an often overlooked but vitally important issue in bioterrorism is that of psychosocial sequelae. these may take the form of acute anxiety reactions and exacerbations of chronic psychiatric illness during the stress of the event, or posttraumatic stress disorder (ptsd) in its aftermath. nearly half of the emergency department visits during the gulf war missile attacks in israel in were related to acute psychological illness or exacerbations of underlying problems. data from recent acts of terrorism in the united states suggest that ptsd may develop in as many as % of those affected by the events. in the early period after the / attacks in new york, ptsd and depression were nearly twice as prevalent as in historical control subjects. although close proximity to the events and personal loss were directly correlated with ptsd and depression, respectively, there was a substantial burden of morbidity among those indirectly involved. among individuals working on capitol hill following the anthrax scare, % were diagnosed with ptsd, with up to % diagnosed with any variety of psychiatric disorder. moreover, a majority of these patients were not adherent with antibiotics prescribed, perhaps because of a newfound lack of trust in the health care system. although not always clinically apparent, the psychological effect of a bioterrorism event is certainly a significant and important consideration for ongoing public health management strategies following any biological threat or terrorist attack. the response to bioterrorism is unique among wmds because it necessitates consequence management that is common to all disasters, as well as the application of basic infectious diseases principles. disease surveillance, diagnosis, infection control, antimicrobial therapy, postexposure prophylaxis, and mass preventative vaccinations are all important considerations when managing a bioterrorism event. for these reasons, physicians are likely first responders to bioterrorism and will be expected to be reliable sources of information for their patients, colleagues, and public health authorities. a remaining number of potential pitfalls regarding disasters involving a biological attack must be identified and managed to optimize the public health response. as alluded to above, the clinical latency period between exposure to an agent and the manifestation of signs and symptoms is approximately days to weeks with most of the cdc category a, b, or c agents. thus, early diagnoses of the first cases are likely to prove problematic and require heightened clinical vigilance, a difficult task considering a majority of these agents are rarely observed in the developed world. even after initial victims have been diagnosed, communications among hospitals and other health care institutions on a local, regional, national, and international level will be essential to help define the epidemiology and identify possible exposure sources. given the extent and ease of rapid individual movement within our globalized world, clinical presentations from a point-source biological attack could occur in widely disparate geographic locations. additionally it is possible that a terrorist attack would be multifocal in any case, with components of wmds paired with biological weapons for maximum effect. a fundamental and consistent epidemiologic approach using case definitions, case identification, surveillance, and real-time communications is necessary, whether the event is a malicious attack, emergent from nature, or of unknown etiology. other potential bioterrorism management pitfalls reside in the arena of diagnostic techniques, treatment, and prevention of disease related to biological agents. although an active area of research, the development of field-ready and highly predictive rapid screening tests for many agents of bioterrorism has not yet progressed to the point at which such assays are approved by the u.s. food and drug administration and available in a "point-of-care" format. treatment and prevention issues such as the absence of effective therapies for many forms of viral hemorrhagic fevers, shortages in the availability of multivalent antitoxin for botulism, projected shortages in the availability of mechanical ventilators to manage a large-scale botulism attack, lack of human data regarding the use of antiviral agents in smallpox, and the unfavorable toxicity profiles of some currently available smallpox vaccines remain unresolved but active areas of research. emerging molecular biology techniques capable of producing genetically altered pathogens with "designer" phenotypes including antimicrobial or vaccine resistance add additional layers of complexity to an already multifaceted problem. as was vividly illustrated in the severe acute respiratory syndrome epidemic and previously well recognized when smallpox occurred with regularity, transmission of infection of potential bioterrorism agents within hospitals is common and difficult to control. , health care workers, our first line of defense against an attack using biological agents, remain at significant occupational risk. research in the field of bioterrorism recognition has demonstrated a perceived weakness among clinicians in recognition of category-a infectious agents. as pathogens of bioterrorism are not frequently encountered in daily practice, they often fall low on the differential without clinician knowledge of an insidious local mass casualty event. clearly, awareness of a recent local event heightens clinical suspicion, but it is imperative for the front-line clinician to recognize, report, and initiate treatment of affected patients. this will only serve to facilitate the initial containment and facilitate rapid disaster-protocol activation. early recognition and initiation of a prompt, unified response will remain the primary challenge for all health care providers in the current era of bioterrorism. biological warfare and bioterrorism: a historical review biological warfare: a historical perspective factories of death: japanese biological warfare, - , and the american cover-up a large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars world health organization. health aspects of chemical and biological weapons: report of a who group of consultants. geneva: world health organization germs: biological weapons and america's secret war biological and chemical terrorism: strategic plan for preparedness and response united states department of state. patterns of global terrorism bioterrorism-related inhalational anthrax: the first cases reported in the united states medical aspects of chemical and biological warfare. textbook of military medicine series. part i, warfare, weaponry and the casualty medical aspects of bio-terrorism biowarfare and bioterrorism novel approaches to the treatment of systemic anthrax anthrax as a biological weapon: medical and public health management investigation of inhalation anthrax case, united states anthrax as a biological weapon, : updated recommendations for management cutaneous anthrax associated with microangiopathic hemolytic anemia and coagulopathy in a -monthold infant fatal inhalational anthrax in a -year-old connecticut woman considerations for distinguishing influenza-like illness from inhalational anthrax anthrax vaccine: evidence for safety and efficacy against inhalational anthrax tackling anthrax centers for disease control and prevention expert panel meetings on prevention and treatment of anthrax in adults pathology of inhalational anthrax in cases from the sverdlovsk outbreak of use of anthrax vaccine in the united states: recommendations of the advisory committee on immunization practices (acip) phase trial evaluating the immunogenicity and safety of a three-dose biothrax( ® ) regimen for postexposure prophylaxis in healthy adults smallpox and its eradication. geneva: world health organization diagnosis and management of smallpox smallpox response plan and guidelines (version . ) botulinum toxin: bioweapon & magic drug botulinum toxin as a biological weapon: medical and public health management occupational plague plague as a biological weapon: medical and public health management prophylaxis and therapy of plague tularemia: the disease and the weapon tularemia as a biological weapon: medical and public health management immunotherapy for tularemia ebola outbreak in west africa-case counts hemorrhagic fever viruses as biological weapons: medical and public health management polio outbreak leads to calls for a "vaccination ceasefire" in syria medical aspects of the iraqi missile attacks on israel post-traumatic stress disorder psychological sequelae of the september terrorist attacks in new york city exposure to bioterrorism and mental health response among staff on capitol hill bioterrorism and physicians infectious diseases bioterrorism and physicians public health measures to control the spread of the severe acute respiratory syndrome during the outbreak in toronto critical challenges ahead in bioterrorism preparedness training for clinicians recognition of community-acquired anthrax: has anything changed since key: cord- - aj hz authors: macpherson, douglas w.; gushulak, brian d. title: health screening in immigrants, refugees, and international adoptees date: - - journal: the travel and tropical medicine manual doi: . /b - - - - . - sha: doc_id: cord_uid: aj hz nan health screening in immigrants, refugees, and international adoptees douglas w. macpherson and brian d. gushulak it is much more important to know which sort of a patient has a disease than to know what sort of disease a patient has. in an increasingly globalized world, migration and population mobility are important factors in the demographic makeup of national populations. in the united states, for example, recent estimates indicate that the foreign-born cohort comprises some million people, or % of the total population. many foreign-born individuals arrive as immigrants, refugees, or children adopted abroad. as such, and depending on their status, health screening may be a required or recommended component of their migratory process. migration-associated health screening is undertaken for two major purposes. first, screening may help identify medical conditions that have implications in terms of personal and community health. second, foreign nationals seeking residence through organized immigration and refugee programs undergo screening due to legislative, regulatory, or administrative directives and mandates. similar epidemiologic principles govern the science and application of both screening processes. however, the rationale underlying these two screening approaches differs in terms of historical basis, operational characteristics, and ultimate goals. • screening for medical conditions of personal health significance is intended to improve health parameters or outcomes for the migrant and may not be legally required or mandated. • mandatory medical screening for immigration purposes is undertaken for regulatory reasons, such as the determination of admissibility on medical grounds under immigration legislation. reflecting the duality of screening related to migrants, this chapter on screening is presented in two parts. the routine examination of travelers and migrants is one of the oldest recorded activities directed at civic administration and protecting the health of the public. the development of european quarantine practices in the mid- th century was associated with the routine inspection of new arrivals, commercial goods, and conveyances in an attempt to prevent the introduction of epidemic infectious diseases. those deemed to be at risk following inspection were contained, excluded, or expelled. these early public health activities accompanied the european settlement of the americas. shortly after achieving nationhood, early legislative tools were introduced creating the us public health service, whose initial role was to provide medical care to seafarers and to control the importation of serious diseases epidemic at the time, such as cholera and plague. a linkage to immigration later followed, with the screening of immigrants to exclude those with unwanted medical conditions such as certain loathsome diseases, individuals of suspected low moral behavior, and people with mental deficiencies who were likely to become wards of the state. in the united states, this process began in the late s when the control of immigration was legally recognized as a congressional responsibility. subsequently, the us immigration act of made specific reference to controlling the admission of immigrants on medical grounds. the routine medical inspection of immigrants was legislatively mandated in the united states in . public health programs and policies designed to manage the major medical challenges of the day became linked to the routine medical inspection of immigrants on arrival. by the s, the immigration medical inspection was extended to the european points of origin for the majority of migrants, creating a system of pre-departure immigration medical screening that continues to this day. the legal basis governing inadmissibility to the united states because of health-related conditions and authorization to undertake medical examination to determine that admissibility is found in the immigration and nationality act (ina) (title us code). under these provisions foreign aliens residing outside of the united states can be denied visas and rendered ineligible to enter the country. these provisions also extend to foreigners already residing in the united states who apply to become permanent residents. the immigration medical examination provides the opportunity to determine whether the foreign national (known as an "alien" in the legislation) is ineligible for permission to enter the united states (known as class a conditions) or has an illness or disorder that may interfere with independent self-care, education, or employment or may require future extensive medical treatment or institutional support (known as class b conditions). health-related reasons that exclude admission (class a conditions) to the united states include: . a communicable disease of public health significance . a physical or mental disorder or behavior posing a threat to property, safety, or welfare (either currently present or likely to recur) . drug abuse or addiction . failure to present documentation demonstrating having received recommended vaccinations. the department of health and human services provides specific regulations (medical examination of aliens cfr, part ) to define and implement the health aspects of the ina. these regulations identify those who require medical examination, outline the process, define where and by whom the examinations are performed, and list the specific conditions associated with inadmissibility. the regulations also define conditions or disorders that, while not serious enough for exclusion, are significant enough (class b conditions) that they must be brought to the attention of consular authorities. the division of global migration and quarantine at the centers for disease control and prevention (cdc) administers the regulations. currently, the regulations list the following as communicable diseases of public health significance: • for example, smallpox, poliomyelitis due to wild-type poliovirus, cholera, or viral hemorrhagic fevers (including ebola) currently a medical examination is required for all refugees entering the united states and all those applying for an immigrant visa from outside the united states. foreign residents in the united states applying to become permanent residents also require mandated medical examinations. panel physicians, designated by consular officers of the us department of state, perform medical examinations abroad, and civil surgeons, designated by the us citizenship and immigration services, perform medical examinations for aliens who are already present in the united states. both groups of physicians receive technical instruction and guidance from the cdc's division of global migration and quarantine. detailed medical history and physical examination are required for all individuals (see summary in table . ). in addition, applicants who are ≥ years undergo routine chest radiography and serologic testing for hiv and syphilis. those between and years of age who reside in a country where tuberculosis incidence rates (based on who data) are ≥ per , have either a tuberculin skin test (tst) or an interferon gamma release assay (igra). if either the tst or igra are positive, the individual undergoes chest radiography. depending on the clinical history, tst, igra, and radiological findings, supplementary screening requirements for tuberculosis include smears of respiratory secretions for acid-fast bacilli and cultures for tuberculosis. any positive cultures undergo drug susceptibility testing. those rated class a for tuberculosis (smear-positive infectious) generally must be treated until their sputum smears are negative before they are allowed to transit for immigration. those rated class b for tuberculosis are cleared for travel within certain time limits. failure to journey to the united states within those time limits will require the individual to undergo rescreening. since , individuals applying for immigrant visas to entry into the united states have had to demonstrate proof of vaccination for several vaccine-preventable diseases. initially, these were general, routine vaccinations as recommended by the advisory committee for immunization practices (acip) for the domestic us population. in , however, specific criteria for those requiring an immigration medical exam were adopted by the cdc. those criteria are: . the vaccine must be age appropriate (as recommended by the acip). and . at least of these two conditions must be met: a) the vaccine must offer protection against a disease with the potential to cause an outbreak. b) the vaccine must protect against a disease that has been eliminated or is being eliminated in the united states. at the time of the preparation of this chapter, required vaccines were: pre-admission vaccination requirements do not apply for refugees or non-immigrant visa applicants. however, those individuals are required to meet the vaccination standards when they adjust their status in the united states after admission. as a procedural consequence, the immunization status of refugees is recorded during immigration process. in the case of children adopted abroad, the vaccination requirements do not apply to those years of age or younger. however, the adoptive parents must sign documentation stating that they are aware of us vaccination requirements and will ensure that all required vaccinations will be received within days of the child's arrival in the united states. the importance and cost-effectiveness of preventative medical interventions in the overseas environment, before transit to the united states, is receiving greater attention as a potential part of the immigration medical process. currently, some refugee populations being resettled in the united states who are determined to be at increased risk for specific infections receive population-based treatment for malaria and intestinal parasites in addition to the routine immigration medical screening. additionally, outbreaks of communicable diseases in refugee camps or transit facilities can trigger additional interventions or treatment prior to arrival. in terms of harmful behavior, immigration medical screening is intended to identify those with neurologic or behavioral conditions associated with the risk of "ever causing serious injury to others, major property damage or having trouble with the law because of a medical condition, mental condition, or influence of alcohol or drugs" or "ever taken actions to end your [the applicant's] life." high-risk conditions in this group may be determined to be class a (inadmissible) or class b (admissible) conditions by panel physicians, depending on clinical findings, history, and situation. drug abuse or addiction (dependence) presents a class a (inadmissible) situation. those barred from admission are those who: • use a controlled substance (defined by the controlled substances act) and • meet the diagnostic and statistical manual of mental disorders criteria for a mild, moderate, or severe substance use disorder. it is sometimes possible for those individuals subject to medical examination who are determined to have a communicable disease of public health significance to still enter the united states. the legislation provides for a waiver process by which those determined to be inadmissible may request entry subject to conditions. documents providing further operational descriptions on the immigration medical screening process for both applicants abroad and those applying within the united states, including details on applicants seeking a change in immigration status, the use of panel physicians and civil surgeons, and reporting requirements, are available at http://www .cdc.gov/immigrantrefugeehealth/. mandatory medical screening to determine medical inadmissibility for immigration purposes is an important administrative process for applicants for permanent residency in the united states and may also be applied to certain temporary resident applicants. although the immigration medical examination does screen for some important medical conditions, it has clinical limitations. it is not designed to be a tool for identifying personal health risks, and it is procedurally limited to specific disorders and conditions of regulated public health concern. as a consequence, pre-existing medical conditions that do not fall under the immigration medical screening profile and other medical conditions of personal health significance may not be detected or reported during mandatory immigration screening. those conditions, while not relevant for immigration purposes, can be significant for new arrivals, and their identification and clinical management in the united states is important in some migrant populations. in addition to an absolute increase in immigration, there has been a shift in source countries, with immigrants from latin american nations other than mexico, as well as africa, asia, and oceania, increasingly contributing to the immigrant pool. the growing number and increasing diversity of foreign-born residents of the united states is important in numerous areas of clinical practice. local health environments at their place of origin and relative disparity in health and disease indicators mean that some migrants may have disease exposure and acquisition patterns different from those at their new home. in some communities, migrants represent rapidly increasing components of the population, and their specific health concerns may be different from those of the receiving community. international adoptions, for example, are now a major component of the adoption process in the united states. of the approximately . million adopted children less than years of age in the united states, % were foreign born, representing more than , individuals. appropriately targeted and applied screening can assist in meeting the differential health challenges of these diverse foreign-born populations. increasing cultural and linguistic diversity can pose challenges to health systems and for physician and institutional healthcare service delivery. health screening of immigrants and refugees can be done as part of primary care assessment in which routine immunizations should be documented and brought up-to-date if necessary; maternal-child health issues can be addressed; and specific health assessments for other defined populations (e.g., children, adolescents, women, and the elderly) can be performed. in addition to language, some migrant groups experience difficulty accessing and utilizing healthcare services for other reasons. cultural issues, including fear of interacting with official bureaucracies and concerns about affordability, may limit migrants' use of health prevention and promotional services. services designed for the general populations often include health counseling and screening programs that may be unfamiliar to or underused by migrant populations. medical and health conditions of importance in new arrivals in the united states fall into two groups: those conditions for which existing screening programs are available for the local population that also occur in migrants, and those conditions not common or endemic in the united states affecting particular populations of migrants for which no routine screening programs exist in the united states. migrants may need special attention in terms of screening for: • risk behaviors, such as smoking, alcohol, and other substance abuse • health implications of diet and exercise • risks of sexual health practices • early recognition of mental and psychosocial health • impact of environmental risks presented by toxic substances, including lead in drinking vessels or paint • occupational exposures related to safe labor practices. in addition, there are many targeted health promotion activities for specific groups, such as maternal-child care, which may not have been commonly available for many migrants in their home countries. programs such as prenatal blood pressure monitoring, screening for gestational diabetes, and thyroid function may be unfamiliar to many migrants. antenatal screening for infections such as rubella, syphilis, hepatitis b, and hiv can be important in migrant populations who originate from regions of the world where these diseases are more prevalent than they are in the united states and where screening practices are not uniformly available or are unfamiliar to women. there are other important targeted screening programs of relevance to migrants. they may not have had access to genetic screening for inborn errors of metabolism or physical conditions such as congenital hip dysplasia and cataracts. additionally, there are several diseases that may be more prevalent at the migrants' place of origin, such as malaria, thalassemia, and micronutrient deficiencies, for which screening may be indicated. finally, it is important to note that many migrants may be unfamiliar with the basis and rationale underlying health-screening programs. common examples include screening programs for malignant disease such as uterine cervical dysplasia (pap smear) and skin, bowel, breast, and prostate examinations. depending on their location and status, many other migrants may have never been screened for common illnesses such as diabetes and hypertension. this is particularly true for vulnerable and disadvantaged migrant groups, such as refugees, asylum seekers, and migrants displaced by conflict. healthcare disparities affecting access due to language and culture can occur, but also in some health jurisdictions in the united states there are legislative initiatives that may create barriers to available healthcare services on "right of access" based on citizenship or "willingness to pay" (self-pay or medicare entitlement). migrants' use of unregulated medical service providers may be an important component in the subsequent health assessment of this population. migrant populations may also be using traditional, herbal, alternative, or complementary medicines, some of which will be imported from abroad. unregulated therapies and agents that do not meet standards of pharmacologic care in united states may not be revealed to attending healthcare professionals unless diligently sought. these alternate therapies may have the potential to complicate clinical presentations and in some cases may themselves be a source of illness. many migrants from diverse backgrounds also have significant disparities in health determinants (e.g., socioeconomics, behavior, genetics and biology, environment) directly related to the migration process. the pre-departure component of health determination is carried through the migration process and is affected by the transit conditions, particularly for irregular arrivals, the post-arrival period, and any return travel undertaken by migrants or their offspring. for the healthcare professional providing services to migrants, this requires an in-depth knowledge of the geographic components of health determination and disease expression that will be carried over to low prevalence or non-endemic countries, such as the united states. the historical focus of immigration and international public health has tended to be on contagious diseases of epidemic potential such as trachoma, syphilis, tuberculosis, and, recently, hiv/acquired immune deficiency syndrome (aids). however, there has been a recent shift in attention to the personal health risks associated with immigration and other infectious and non-infectious diseases. table . presents some of the clinical screening issues for healthcare providers working with defined migrant populations. with globalization of economies and trade, rapidity of interregional transportation, and increasing international population mobility for temporary and permanent relocation, healthcare professionals will increasingly need both to recognize imported clinical syndromes and to be sensitive to quiescent conditions of both personal and public health significance when dealing with migrants. screening can be targeted at asymptomatic individuals or can be mass community screening of previously defined at-risk populations; both of these are based on demographic and biometric profiles representing disparity in frequency or severity of outcome. increasingly in high-health service regions with low prevalence of any poor health indicators and excellent local public health programs, migrants and other mobile populations are becoming the continued "at risk" populations. many of the factors impacting on adverse health outcomes in migrants are amenable to screening, and there are effective interventions for health promotion or disease prevention. high-risk populations of migrants, including refugees, workers, adopted children, victims of torture, and trafficked individuals, may require specialized medical care as well as specifically designed screening based on medical and sociological assessment of their needs. professional healthcare providers, health educational, training, and professional societies, and governments and nongovernmental agencies will be challenged to develop policies and programs to respond to this emerging and dynamic challenge to address the health needs of internationally mobile populations. advisory committee on immunization practices infectious disease issues in adoption of young children centers for disease control and prevention. technical instructions for panel physicians and civil surgeons detailed background and instructions related to us immigration medical screening practices disparities in preventive health behaviors among non-hispanic white men: heterogeneity among foreign-born arab and european americans article describing the differential knowledge and practice of preventive health measures by foreign-born and native-born populations strategies in infectious disease prevention and management among us-bound refugee children recent overview of infectious disease challenges in pediatric refugee populations destined to the united states the foreign-born population in the united states data on the demography of the scope and diversity of the us foreign-born cohort population mobility and infectious diseases: the diminishing impact of classical infectious diseases and new approaches for the st century review article outlining the importance of communicable diseases in migrant populations that are not usually subject to routine immigration medical screening globalization of infectious diseases: the impact of migration article describing and outlining the influence of population mobility on global disease epidemiology disease surveillance among newly arriving refugees and immigrants-electronic disease notification system, united states recent review of the scope and status of systems in the united states to identify and notify state health departments of diseases in migrants new approaches in a globalizing world review article that outlines how modern migration challenges traditional disease-control practices unauthorized immigrant totals rise in states, fall in : decline in those from mexico fuels most state decreases. pew research center's hispanic trends project statistics and demographic analysis of the unauthorized/irregular foreign-born population in the united states population-based comparison of biomarker concentrations for chemicals of concern among latino-american and non-hispanic white children an example of disparities in environmental health risks present in foreign-born populations screening of international immigrants, refugees, and adoptees albendazole therapy and enteric parasites in united states-bound refugees article that describes enhanced pre-departure screening and treatment for high-risk migrant populations in certain circumstances office of minority health. minority population profiles immigrant medicine. elsevier, philadelphia. reference text on the health aspects of migration key: cord- -daz vokz authors: devereux, graham; matsui, elizabeth c.; burney, peter g.j. title: epidemiology of asthma and allergic airway diseases date: - - journal: middleton's allergy doi: . /b - - - - . - sha: doc_id: cord_uid: daz vokz nan epidemiology is the study of the distribution of disease in populations. it is essential for assessing the spread and burden of disease. it is the appropriate method for understanding the cause and pathogenesis of disease. research into allergy has had a long history with many changes in direction, and the language that has been developed to describe what has been found has changed over time. this can lead to confusion. in this chapter, we use the term sensitization to indicate the production of immunoglobulin e (ige) antibodies in response to allergens. we use the term allergy to refer to the presence of one or more diseases associated with ige sensitization, the most common of which are asthma, eczema, and rhinitis. the term atopy was originally introduced to account for the observation that the main allergic diseases occurred in the same families and appeared to have a common origin. however, it is often used synonymously with the term allergy. test standards. good tests should possess reliability and validity. a test is reliable if it always gives the same answer when applied under similar circumstances. validity implies that the result of the test coincides well with the true condition of the person being tested. validity has two components: sensitivity, which is the ability of the test to identify an existing condition, and specificity, which is the ability to identify as normal people who are free of the condition. measuring the validity of a test for a condition that is poorly defined, such as asthma, is a problem because it presupposes a gold standard test with which the proposed test can be compared. although validity in an absolute sense may always be contested, what is as important in epidemiologic studies is standardization, meaning that the test is identical wherever and by whomever it is administered. validity is essential to the measurement of absolute prevalence, but in many epidemiologic studies, we are as interested in relative prevalence, such as relative prevalence between age groups, countries, or districts, or differences between people exposed to various environmental or genetic risks. standardization is essential for this, and considerable effort has been made to provide standardized measures, particularly for international studies. tests of sensitization. sensitization can be assessed directly by determining the presence of specific ige to allergens in serum. in many places, mites, grass, and cat allergens are among the most common allergens, and most sensitized individuals can be identified by testing for relatively few allergens. , some test kits can identify a mixture of several allergens. in the past, they have been used to test for the occurrence of sensitization, and this may be cost-effective, but it leaves unclear which allergens are » epidemiology is the study of the distribution of disease and, by extension, its causes and consequences, mostly in general populations. » the rates of allergic sensitization and allergic diseases have been increasing, although the increase in prevalence of allergic diseases has slowed among children. » allergic disease is less common in rural parts of low-income countries, although allergic sensitization can be common in these areas. » there has been very little success in explaining the increased prevalence of allergic disease, although it has been linked to urbanization. the great changes observed in prevalence and distribution strongly suggest a major role for the environment. » factors that initiate allergy and allergic diseases should be differentiated from factors that exacerbate them after they have been established. » allergies are affected by environmental factors, including diet; exposure to a normal, diverse microflora; infections; exposure to air pollutants; and occupational exposures. » allergy is not associated with higher mortality rates or loss of lung function, but asthma is associated with both. » outcomes for asthma can be considerably improved by good management. test of whether someone had asthma. what had been provided was, in his view, no more than a description. second, he pointed out that most diseases were concepts rather than "things" and that their definitions were therefore bound to be contested. since then, there have been many attempts to define asthma (table - ) , although most have paid little attention to the issues raised by this led to more complicated descriptions but not to any greater clarity. some have introduced additional assumptions about mechanisms and causes. despite these strictures, asthma has been an enduring and trusted concept clinically, but a separate question remains about how the condition can be identified in epidemiologic studies. there are effectively three broad methods of identifying asthma in surveys: questionnaires asking about diagnosed asthma, questions about the symptoms of asthma, and physiologic tests of airway responsiveness. questions asking whether someone has asthma, often qualified by asking whether a doctor has ever confirmed the diagnosis, are common. they are regarded as highly specific, meaning that there are few people who answer this question in the affirmative but do not have asthma, but there are many people who may be defined as asthmatic who deny that they have the condition. the worst characteristic of these questions is the lack of standardization. the answers to the questions depend on local medical practice and the terms used by health professionals when talking to patients. variations in the use of the term asthma likely have influenced estimates of time trends and observed differences in mortality between countries. over the past years, the prevalence of people with asthma has increased markedly, and there has been much debate about whether this can be explained by differences in the way the term has been used. this possibility is supported by the encouragement given to pediatricians, particularly from the s onward, to diagnose all wheezy children as asthmatic because this would encourage the use of medication and was shown to enhance the quality of life of children regardless of the exact diagnosis. in the s, kelson and heller sent scenarios of patients who had died to a representative group of physicians signing death certificates in several european countries. one scenario (box - ) described a person who had some symptoms of asthma but many of the features of chronic obstructive lung disease. figure - shows the relationship between the proportion of the physicians in each country ascribing this death to asthma and the national mortality rate for asthma. there is a strong suggestion that the way doctors in each country view such marginal cases may be influencing the national mortality data. whether this is still the case is uncertain. since then, there has been a major increase in international consensus documents. asking about symptoms rather than diagnosed disease avoids some of these problems, and efforts have been made to find suitable questionnaires and to standardize them across countries. the most commonly used questionnaire for children is that developed for the international study of asthma and allergies in childhood (isaac). for adults, the questionnaire developed for the international union against tuberculosis and lung disease (iuatld) , was subsequently adapted for use in the european community respiratory health survey (ecrhs) and was further adapted for the world health survey. responsible for symptoms. microchip technology and the development of recombinant and purified allergens have enabled testing for several allergens simultaneously and allowed more precise identification of the relevant allergens. the technology remains expensive and is not widely used in epidemiologic studies. an alternative method of identifying sensitized individuals is to undertake skin-prick tests. they do not require a laboratory and do not involve taking blood. the technique involves introducing a small amount of allergen under the outer layers of the skin using a needle or lancet and reading the size of the wheal that appears in the minutes after the test is applied. this is compared with the wheal produced by a control solution (usually the diluent in which the allergens have been dissolved) and with a positive (usually histamine) control that tests whether the skin is able to respond to the release of mediators that the allergen induces. skin tests have more operatordependent variation than serologic tests, because they are influenced in part by the technique of the technician, but they typically are cheap and provide an immediate answer, which can be more satisfactory for the patient or participant. the criterion for a positive test result varies according to the purpose of testing. using any test greater than the diluent control is more repeatable and less prone to observational error and reflects well the presence of allergen-specific ige. however, in a clinical context, small wheals are rarely associated with allergic disease that can be ascribed to that allergen, and in a clinical context, wheals less than mm in diameter usually are discounted as irrelevant. defining the prevalence of sensitization in a population depends to some extent on which allergens are tested. in western europe and the united states, there is little change in overall prevalence after five or six allergens have been included in the panel. , although less is known about other countries, mite allergens appear to be widespread in tropical and subtropical areas. for the most part, skin tests and serologic tests for sensitization give similar results when technical failures and differences between allergens are taken into account. however, they are not equivalent. skin tests also depend on the ability of mast cells to degranulate and for the skin to respond to histamine. when skin test results are negative, clinical allergy is unlikely even in the presence of specific ige. modern attempts to define asthma start with the ciba guest symposium of on the terminology, definitions, and classification of chronic pulmonary emphysema and related conditions. the symposium defined asthma as "the condition of subjects with widespread narrowing of the bronchial airways, which changes its severity over time spontaneously or under treatment, and is not due to cardiovascular disease". it further identified the clinical characteristics as "abnormal breathlessness, which may be paroxysmal or persistent, wheezing, and in most cases, relief by bronchodilator drugs (including corticosteroids)." soon after the publication of this report, scadding, one of the contributors to the symposium, made two important points. first, what had been described as a definition in the report was not a true definition in that it did not provide a clear year definition ciba foundation condition of subjects with widespread narrowing of the bronchial airways, which changes its severity over short periods spontaneously or during treatment american thoracic society disease characterized by increased responsiveness of the trachea and bronchi to various stimuli and manifested by widespread narrowing of the airways that changes in severity spontaneously or as a result of therapy world health organization (who) chronic condition characterized by recurrent bronchospasm resulting from a tendency to develop reversible narrowing of the airway lumina in response to stimuli of a level or intensity not inducing such narrowing in most individuals american thoracic society clinical syndrome is characterized by increased responsiveness of the tracheobronchial tree to a variety of stimuli. major symptoms are paroxysms of dyspnea, wheezing, and cough, which may vary from mild and almost undetectable to severe and unremitting (i.e., status asthmaticus). primary physiologic manifestation of this hyperresponsiveness is variable airway obstruction, occurring in the form of fluctuations in the severity of obstruction after bronchodilator or corticosteroid use, or increased obstruction caused by drugs or other stimuli, as well as evidence of mucosal edema of bronchi, infiltration of bronchial mucosa or submucosa with inflammatory cells (especially eosinophils), shedding of epithelium, and obstruction of peripheral airways with mucus. nhlbi/nih lung disease with the following characteristics: ( ) airway obstruction that is reversible (but not completely in some patients) spontaneously or with treatment, ( ) airway inflammation, and ( ) increased airway responsiveness to a variety of stimuli. nhlbi/nih , chronic inflammatory disorder of the airways in which many cells play a role, particularly mast cells, eosinophils, and t lymphocytes. in susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough in early morning. symptoms are usually associated with widespread but variable airflow limitation that is at least partly reversible spontaneously or with treatment. inflammation also causes an increase in airway responsiveness that is associated with a variety of stimuli. nih/nhlbi chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. the chronic inflammation causes an increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. these episodes are usually associated with widespread but variable airflow obstruction that is often reversible spontaneously or with treatment. nhlbi/nih, national heart, lung, and blood institute/national institutes of health. symptom questionnaires do not have the disadvantages of reported diagnoses, but they have problems of their own. first, used alone, symptoms are rarely diagnostic of a condition. this may not be a serious problem when there is no need for an accurate diagnosis in every case, but some symptoms are highly nonspecific. there may be considerable crossover of symptoms between different airway diseases such as asthma and bronchitis. second, the interpretation of similar symptoms may vary among different people. this may become a serious problem when making comparisons in the settings of different cultures and languages. in translating asthma questionnaires, there may be particular problems in translating terms such as wheeze when there may not be an equivalent word, and even people who speak the same language may interpret wheeze differently. given the lack of a gold standard to test these questionnaires against, their validity cannot be fully assessed, because it depends in part on whether they are seen as plausible indicators of the presence of asthma and standardization against a plausible alternative indicator. in the iuatld questionnaire, this indicator was the airway response to histamine, which usually increases tests. they have some of the same limitations as reversibility testing. more promising has been the use of bronchial challenge tests, most of which use a direct bronchoconstrictor such as histamine or methacholine. lung function is assessed before and after inhaling increasing doses of the agent. the decline in lung function (usually the forced expiratory volume in second [fev ]) is regarded as a marker of asthma. , this may be expressed as the dose or concentration of agent that produces a given (often %) fall in lung function, in which case the result usually is dichotomized as those falling by at least that amount (i.e., hyperresponsive) and those that do not (i.e., normal). alternatively, the slope of the dose-response curve has been used as a continuous measure of airway reactivity, a method that uses epidemiologic information more efficiently but may be clinically less intuitive. development of these tests for use in surveys has provided a tool for assessing a physiologic measure associated with asthma. there is little difference between the use of histamine and methacholine, but methacholine is more widely used because it has fewer side effects. one disadvantage of nonspecific challenge tests is that they produce positive results for those with asthma and also with chronic obstructive pulmonary disease (copd). , this has led to the use of alternative agents that act indirectly by releasing mediators from mast cells in the airway. challenge agents include adenosine, hypertonic solutions (e.g., saline, mannitol), exercise, and cold, dry air. these alternatives have not been used as widely as methacholine. exercise testing usually has been confined to studies of children. its effects depend on weather conditions (e.g., cold, dry conditions produce a greater stimulus than warm, moist conditions), and it requires well-motivated groups of participants. equipment to provide cold, dry air has not been widely available. use of saline and mannitol has promise, but they have not been widely used in surveys. the theoretical advantage of using these methods is that they are less likely to provoke airway constriction in those with copd. allergic rhinitis has been investigated much less frequently than asthma using epidemiologic approaches. population-based studies are made difficult by misclassification arising from reliance on questionnaires to establish the presence of allergic rhinitis. typically, the questionnaires used by epidemiologists ascertain self-reports of responders having something they call allergic rhinitis or hay fever. nonetheless, studies show that allergic rhinitis is among the most common chronic diseases. symptoms of individuals with rhinitis include sneezing, nasal irritation, rhinorrhea, and nasal blockage. these symptoms can also involve the eyes, ears, and throat, including postnasal drainage. allergic rhinitis is most commonly classified as seasonal, perennial, or occupational, but a recent guidelines statement advocated classifying allergic rhinitis as intermittent or persistent. the symptoms of allergic rhinitis are associated with exposure to allergen sources such as pollens, pets, and house-dust mites (hdms). symptoms result from inflammation induced by a specific ige-mediated immune response to the allergens. criteria for diagnosing chronic rhinosinusitis have been published. , a questionnaire based on the symptomatic part of this definition has been devised and tested for epidemiologic surveys. in patients with asthma. although it is not diagnostic of asthma, it is reassuring to find that answers to the questionnaires can predict the results of the alternative test and that they can do this in approximately the same way in different countries and different translations. for the isaac questionnaires, a video was developed that demonstrated the symptoms of asthma, and it was used to help standardize comprehension of the questionnaire in different settings. although fully validated questionnaires for diagnosing asthma are not available, the current questionnaires do allow comparison of symptoms that plausibly represent conditions close to asthma in a standardized way. although cautious interpretation is always advisable, they have enabled substantial advances in our knowledge of the relative distribution of the condition. an objective test for asthma that did not depend on interpretation of questionnaires would be ideal, and several tests have been proposed. the lack of a gold standard for diagnosing asthma and the similarity of asthma to other conditions make a perfectly validated test unattainable, but tests do provide additional tools to check the findings of surveys that use questionnaires only. the physiologic tests for asthma have been based on the definition of asthma as a condition of the airways that changes its severity over time spontaneously or after treatment (box - ). reversibility of airway obstruction after use of a bronchodilator (i.e., reversibility testing) has been used in clinical studies to distinguish between asthma and fixed airway obstruction, and some have used it as a test in surveys to identify asthma. the difficulty lies in interpreting the results. a positive test result indicates the likely presence of asthma, but a negative test result is uninformative. because a patient with asthma who is receiving good treatment or in remission for some other reason does not respond to a bronchodilator, this approach has not found much use in surveys of the general population. spontaneous changes in airway caliber can be assessed using peak flow diaries, a clinical technique that has been commonly used in primary care in the united kingdom. although they can be difficult to use in large-scale studies, they do provide data comparable to that using more invasive bronchial challenge kingdom, and the netherlands. low prevalence rates were found in spain, iceland, and italy. the second phase of the isaac study estimated the prevalence of positive skin-prick test responses to at least one of six allergens in children between the ages of and years living in sites, mostly in western europe. , estimated prevalence ranged from . % in tallin, estonia, and . % in mumbai, india, to . % in rome, italy, and . % in almeira, spain. unlike in western countries, the prevalence of sensitization in africa heavily depends on the methods used to assess sensitization. in rural areas, the prevalence of positive skin-prick test results is very low, whereas the prevalence of allergen-specific ige is high. the high prevalence of allergen-specific ige in poor rural areas was first shown in zimbabwe (formerly called southern rhodesia) by merrett and associates, but the dissociation in these environments between specific ige levels and skin test results also has been shown in kenya and south africa. where skin test results are negative, even in the presence of specific ige to aeroallergens, clinical allergy is rare. asthma is a global problem. it is estimated that approximately million people worldwide have asthma. prevalence rates for children and adults are substantially different in countries around the world. the first phase of the isaac study provides the most extensive information on variation in childhood asthma prevalence. in , the isaac steering committee reported findings for , -to -year-old children ( centers in countries) and , -to -yearold children ( centers in countries). for the younger and older children, the prevalence of asthma symptoms was based on a positive response to this question: have you had wheezing or whistling in the chest in the past months? across countries, there was an approximately twentyfold range of prevalence, with the highest rates usually found in more developed countries (figs. - and - ) . the countries with the highest prevalence rates (> %) were the isle of man, the united kingdom, new zealand, ireland, australia, peru, panama, costa rica, the united states, and brazil. the ecrhs assessed geographic variation in asthma among , adults from countries. a sixfold variation in the prevalence of current asthma was found among the countries. a high (> %) prevalence of asthma was found in australia, new zealand, the united states, ireland, and the united kingdom. asthma prevalence of less than % was found in iceland, parts of spain, germany, italy, algeria, and india. current asthma was defined in the ecrhs as "having an attack of asthma in the past months or currently taking medicine for asthma." the ecrhs did not examine many sites outside the developed market economies, but the world health survey interviewed adults older than years of age in six continents using questions derived from the ecrhs on wheezing and diagnosed asthma. the prevalence of diagnosed asthma ranged from . % in vietnam to . % in australia (fig. - ) . a very wide variation in the prevalence of diagnosed asthma (and wheezing) was found in all countries, regardless of gross national income per capita adjusted for purchasing power parity. in countries eczema similar to allergic rhinitis, the epidemiology of eczema is less well understood than the epidemiology of asthma. eczema, also known as atopic dermatitis, is a pruritic rash characterized by chronic, recurrent papular lesions typically affecting skin at the flexor surfaces, buttocks, and back of the neck. infants frequently have involvement of the face. in its acute and subacute forms, eczema is characterized primarily by erythema and a papular eruption, but in its chronic form, it is characterized by lichenification of affected areas. allergic sensitization plays an important role in provoking eczema flares, particularly in pediatric patients. some studies have relied on physician diagnosis to define eczema, but standardized questions have been developed for identifying eczema cases with or without additional information from standardized examination. these questions are included in the isaac questionnaire, and they focus on the chronic and recurrent nature of the rash, its location, and the presence of pruritus. during the past years, food allergy has received increased attention, and there is a growing body of literature available regarding its epidemiology. food allergy is an immune-mediated reaction to a food. it can produce a wide spectrum of clinical manifestations, including acute ige-mediated reactions, mixed ige-mediated and non-ige-mediated reactions that are often characterized by insidious gastrointestinal symptoms, and non-ige-mediated syndromes such as allergic colitis and food protein-induced enterocolitis syndrome. even among patients with acute ige-mediated types of food-allergic reactions, symptoms can vary and include one or many of the following: urticaria, angioedema, pruritus, cough, wheezing, hoarseness, vomiting, diarrhea, oral pruritus, hypotension, and rhinorrhea. because the diagnosis is based on the clinical history and diagnostic test results, with the gold standard being a double-blind, placebo-controlled food challenge, conducting large epidemiologic surveys can be difficult because of reliance on questionnairebased tools for identification of food allergy and evidence of ige sensitization. because there is no validated questionnaire for food allergy and many reported food allergies are not confirmed when a full diagnostic evaluation is completed, estimates obtained from questionnaires are likely to be inflated. the prevalence of sensitization depends on the selection of allergens. for this reason, the relative prevalence of responses to a standardized panel of allergens is more informative than an absolute prevalence. the ecrhs estimated the prevalence of specific ige (≥ . ku/l) to mites (dermatophagoides pteronyssinus), cats, grass (timothy grass), or cladosporium among young adults between the ages of and years in centers, mostly in western europe. the prevalence of a positive response to any of the four common allergens ranged from . % to . % ,with a median prevalence of . %. high prevalence rates were found in australia, new zealand, the united states, the united rates for different questionnaire-based indicators of asthma: physician report, current disease, and the symptom of wheezing used in the national health and nutrition survey of the united states from through . questions that ask about asthma or wheeze provide estimates that are almost twice those of questions asking about either alone, and this difference varies with age. for those between the ages of and years, with the lowest incomes (<us$ ), none of sites had a prevalence of diagnosed asthma of more than %; among countries with intermediate incomes, ( %) of countries had a prevalence higher than %; and among counties with the highest incomes (<us$ ), ( %) of countries had a prevalence above %. the national health interview survey (nhis) and the national health and nutrition examination survey (nhanes) include random samples of the whole u.s. population. both also provide periodic prevalence estimates. standardization of the methods of prevalence surveys is essential because the wording of questions on asthma or other aspects of data collection may affect estimates based on the questionnaires. for example, table - provides prevalence country wheeze is much more likely to be associated with a diagnosis of asthma. state-specific asthma prevalence data for adults are available from the behavioral risk factor surveillance system (brfss), a state-based, random-digit-dialed survey of noninstitutionalized u.s. adults age years or older. it was conducted by the centers for disease control and prevention (cdc) and the state or territorial departments of health. information was gathered from all states, puerto rico, the virgin islands, and the district of columbia. the definition for current asthma was based on providing positive answers to two questions: have you ever been told by a doctor, nurse, or other health professional that you had asthma? do you still have asthma? the overall current asthma prevalence rate was . %, ranging on the mainland from % in tennesee to . % in vermont ( fig. - ) . asthma prevalence rates in the united states vary with demographic and social conditions. figure - gives prevalence rates from the nhis for through . children have more reported asthma than adults, women have more than men, those in poverty have more asthma than those not in poverty, asian respondents reported less asthma than any other group, and all other racial groups have more asthma than white respondents. estimating incidence and prevalence of allergic rhinitis is as challenging as for asthma. the diagnosis is symptom based, and there is no consensus for measurement. some attempts have been made to estimate the incidence of allergic rhinitis using cohort or longitudinal data. in a birth cohort study from germany that followed children for years, % of them developed seasonal allergies, defined as a combination of exposure-related symptoms and sensitization. a % cumulative incidence rate was determined in a -year longitudinal study of college students. the researchers also observed that regression of hay fever symptoms was inversely related to age of onset. almost % of those with hay fever onset before years of age had improvement of their symptoms. the isaac researchers collected data on -month prevalence of allergic rhinoconjunctivitis for children to years old from countries. allergic rhinoconjucntivitis was defined as having a problem with sneezing or a runny or a blocked nose without a cold or flu and accompanied by itchy, watery eyes. there was a thirtyfold variation in the prevalence rate among the sites, from . % to . %. estimates for adults obtained in the ecrhs ranged from . % in algeria to . % in australia. the median prevalence of nasal allergies in the ecrhs was about %. countries with significantly high prevalence rates were the netherlands, belgium, switzerland, france, the united kingdom, new zealand, australia, and the united states. chronic rhinosinusitis is an inflammation of the nose and paranasal sinuses lasting over weeks. another multicenter european study estimated the prevalence of chronic rhinosinusitis using a questionnaire based on the european position paper on rhinosinusitis and nasal polyps (ep os) on symptom criteria to be about % among adults, ranging from % in helsinki, finland, to % in coimbra, portugal. the condition was more common in women, in younger participants, and in smokers. the worldwide prevalence of eczema was best documented in isaac phase three, in which the prevalence for -to -year-old children ranged from . % in india to . % in ecuador. , the worldwide prevalence of eczema in children to years of age has increased in most regions of the world and has remained stable only in western, northern, and eastern europe. for this younger age group, the prevalence in isaac phase three was . %, an increase from the prevalence in phase one of . %. the overall prevalence among -to -year-old adolescents declined to . % in isaac phase three from . % in phase one. the regions with the most striking increases in eczema prevalence were asia and latin america. a growing number of population-based studies have estimated food allergy prevalence and incidence. the prevalence of food allergy and the foods that are most commonly implicated in food allergy vary widely across the world. for example, a metaanalysis found that the self-reported prevalence of food allergy ranged from % to %. although some of the heterogeneity observed is attributable to study methodology, other studies that have focused on specific geographic regions and populations support the notion that there is marked worldwide heterogeneity in food allergy prevalence. for example, in the united states, the estimated prevalence of food allergy is % to % among children, , and in australia, a prevalence of more than % among -year-old children has been reported. in contrast, findings from a population-based birth cohort from the united kingdom indicate that between . % and . % of infants have food allergy in the first year of life, and in other u.k. studies, the estimated prevalence of food allergy among -year-old children is . % to . %, and among adolescents, it is . %. an international study that used allergen-specific ige data for young adults confirmed the heterogeneity of food allergy prevalence observed in the questionnaire-based studies. in this study, prevalence of sensitization to any of foods ranged from . % in iceland to . % in the united states. however, sensitization to the major foods, such as fish, egg, and milk, was uncommon (< %). the incidence and prevalence of allergy to specific foods have been studied. a random telephone survey administered in to estimate the prevalence of seafood allergy in the united states found that . % of the general population reported allergy to fish or shellfish. another telephone survey was conducted in and repeated in and to estimate the prevalence and incidence of peanut and tree nut allergies. , the prevalence rate of peanut or tree nut allergy was stable at . % among adults, but it increased from . % to . % to . % among children during this period. in contrast, data from u.k. general practices were used to estimate a prevalence rate of peanut allergy of . %, and a school-based survey in singapore and the philippines estimated a prevalence rate of peanut and tree nut allergy of less than %. in australia, the prevalence of peanut allergy may be higher than that observed in the united states or united kingdom, because the prevalence of peanut allergy among -year-old children was estimated to be %. there is limited information about the epidemiology of allergic gastrointestinal diseases. however, the incidence and prevalence of eosinophilic esophagitis appear to have increased over the past decade. a range of gastrointestinal symptoms and mucosal eosinophilia characterizes eosinophilic esophagitis. approximately one half of cases demonstrate ige sensitivity to foods. what was once thought to be a rare disease was found people born later in the century having a higher prevalence of disease throughout their lives. in cross-sectional surveys, this pattern of disease is indistinguishable from a decline in disease with age. in the ecrhs, there was almost no net change in the prevalence of sensitization over the years between the surveys within any birth cohort, but succeeding birth cohorts had increasingly high prevalence rates. a subsequent analysis of some british data showed that this phenomenon was apparent in successive birth cohorts since at least the s. to evaluate changes in prevalence, repeated surveys are required for the same populations and using the same instruments for assessment. in the s and s, smith in birmingham, england, first observed that the prevalence of asthma was rising among schoolchildren undergoing school medical examinations. since then, many studies have assessed changes in prevalence. these studies are summarized in figure - , which by one study based in switzerland to have increased in incidence from . to . per , adults from to . , in another study in hamilton county, ohio, the incidence in children younger than years old has increased from . to . % per year, and the prevalence has increased from . % to . % from to . a few studies have made serial assessments of the levels of ige specific to common allergens in the same populations over many years. these studies have shown a fairly consistent increase in the prevalence of sensitization over time. analysis of the data from the tucson and the first and second ecrhs surveys found that the apparent decline in the prevalence of sensitization with age was more easily explained as a birth cohort effect. the apparent effect of age results from . year of survey germany in two surveys made very close together in time and seem unlikely to represent a long-term trend. the isaac reassessed prevalence of asthma and other allergic diseases by questionnaire for -to -year-old children in centers in countries and for -to -year-old children in centers in countries. the results for asthma prevalence are given in figure - . among the younger children, rates were more commonly rising than declining, whereas among the older children, the rising and declining rates were more evenly balanced. among the older children in centers with a high prevalence, the rates were more likely to be declining. in the united states, the nhis, a population-based interview survey of u.s. households, is a key source of information on trends in the prevalence of asthma. before , prevalence estimates were based on a positive response to one question: during the past months, did you have asthma? in , the nchs redesigned the nhis questionnaire. consequently, answers to the nhis questionnaire after cannot be compared with those in previous surveys because the new questions assess asthma morbidity differently. lifetime incidence is measured by this question: have you ever been told by a doctor or other health professional that you had asthma? the prevalence of asthma attacks is obtained by a positive response to another question: during the past months, have you had an episode of asthma or asthma attack? the asthma attack prevalence in was . % for all age groups. in , nchs added a question (do you still have asthma?) after the lifetime incidence question to provide estimates of current asthma prevalence (table - ). the estimates indicate that . % of u.s. residents currently have asthma that has been diagnosed by a doctor or other health professional. table - provides the estimates for asthma prevalence before and after the revisions of the nhis questionnaire. figures - and - show data from the nhis with different estimates of prevalence of asthma over time for children and adults and by race or ethnic group. for children and adults, the -month and lifetime prevalence rates increased over time. current and attack prevalence rates have not shown a marked trend since the use of these outcomes began. prevalence rates also vary among racial and ethnic groups; this variation likely reflects differences in genetic, environmental, social, shows the changes in prevalence over time plotted on a logarithmic scale. most of the studies surveyed children, although a few looked at military conscripts in countries with compulsory military service. the very large variations in the absolute prevalence estimates reflect differences in the definitions used and the populations examined. from the late s to the mid- s, the values rose uniformly at a rate that represented a doubling of prevalence approximately every years, and this occurred regardless of the definition used and the starting prevalence. only in the mid- s did reports begin to suggest that this increase had slowed down. a much smaller number of studies have assessed changes in the prevalence of airway responsiveness ( fig. - ). during the s, a small number of studies showed increases in prevalence over time. [ ] [ ] [ ] [ ] the study of dubois, which showed a yearly increase in prevalence among belgian conscripts over years, is particularly persuasive given the difficulties of standardizing the tests. since the s, most studies have shown a flattening of or a decline in prevalence, [ ] [ ] [ ] although increases were seen in a study from ghana, and a large increase was observed in year prevalence (%) asthma period prevalence current asthma prevalence asthma attack prevalence and cultural influences among population groups. between and , the prevalence of asthma had increased from . % to . % among whites and from . % to . % among blacks, representing cumulative increases of approximately % per annum. between and , rates of current asthma had increased from . % to . % among whites, a cumulative increase of approximately . % per annum, and from . % to . % among blacks, a further increase of approximately % per annum (see fig. - ). many of the studies that reported changes in the prevalence of asthma and wheeze also found increased reporting of other allergic diseases, most notably allergic rhinitis and eczema in children. as for asthma, almost all studies reporting before the mid- s found increases in other atopic conditions with time. since then, results have been more mixed, and the isaac has provided a more representative spread of data than is possible from individual studies. (fig. - ) for the -to -yearold children, most sites showed an increase in prevalence of allergic rhinoconjunctivitis and eczema in the years after the baseline surveys of isaac phase one. for the -to -year-old children, the changes were more evenly distributed between increases and decreases, and the size of the annual percentage change (positive and negative) appeared to be proportional to the initial value. a follow-up of the ecrhs sample approximately years later estimated an incidence rate of rhinitis of . cases per thousand people per year. males had a greater risk in childhood and a lower risk in adulthood of incident rhinitis compared with females. atopic subjects had the highest incidence of rhinitis, at more than cases per thousand people per year. were compared for fathers ( . %) and sons ( . %) and for mothers ( . %) and daughters ( %). later findings from a u.k. study suggested that the prevalence of hay fever had been stable in the latter half of the s. the worldwide prevalence of eczema among -to -year-old children has increased in most regions of the world and has remained stable only in western, northern, and eastern europe. for this younger age group, the prevalence found in the isaac phase three was . %, an increase from the prevalence in phase one of . %. the overall prevalence among -to -year-old children declined to . % in the isaac phase three from . % in the isaac phase one. the regions with the most striking increases in eczema prevalence were asia and latin america. two cross-sectional chinese studies from chongqing showed a statistically significant increase in food allergy prevalence, from . % in to . % in , among young children between the ages of and months. these studies also showed that sensitization to food allergens assessed by positive skin-prick test results had almost doubled, rising from . % to % during the same -year period. other than these studies, there is little evidence on time trends using food challenge tests in general populations, although there is more circumstantial evidence for an increase over time. the prevalence of allergic rhinitis has increased over time in the united states. the nhis estimated a seasonal allergic rhinitis prevalence of %, , an increase of % from the prevalence estimate of . % based on the nhis. the nhis estimated that about . million americans, . million of them younger than age years, have allergic rhinitis. , the survey also showed geographic variation in the prevalence of seasonal allergic rhinitis, with the highest estimated prevalence for the western united states ( . %), followed by the northeast ( . %), south ( . %), and midwest ( . %). studies in other countries have also documented an increase in the prevalence of allergic rhinitis over time. von mutius and colleagues observed a significant increase in hay fever prevalence among schoolchildren from leipzig, germany. the hay fever prevalence rate in the - survey was . %; in the - survey, the prevalence had increased to . %. an italian retrospective study compared data on allergic rhinitis prevalence among italian recruits observed in and from to . the investigators found a significant increase in allergic rhinitis prevalence, from . % in to . % in the - period. results from surveys conducted in and of an adult danish population showed a significant increase of % in the prevalence of allergic rhinitis after adjustment by age and gender. a scottish study observed a threefold increase in the age-adjusted prevalence rate of hay fever between and and in middle-age adults. the hay fever prevalence rates change per year (%) mean prevalence (%) eczema d some genotypes were specifically associated with childhoodonset asthma. gender data from epidemiologic studies consistently reveal male gender to be a risk factor for asthma among young children, whereas studies of adolescents and adults show females to be at greater risk. a review of prospective studies showed that male children were at greater risk for incident asthma or wheeze, and studies of adolescents or adults showed females to be at greater risk. , one hypothesis explaining the excess of asthma seen in boys during childhood is the different airway geometry in boys and girls. boys have smaller airways for a given lung size than girls. lower flow rates were found for boys to years of age, and they have higher airway resistance compared with girls of the same age. this difference in airway anatomy predisposes boys to more wheezing, and they have a higher incidence of lower respiratory tract infections. , martinez and coworkers suggested that reduced lung function was a key determinant of wheezing in boys and girls. in the tucson study, lung function was measured within weeks of birth in healthy infants. the subsequent incidence of wheezing illness over the first years of life was increased in boys with high respiratory resistance and in girls with low functional residual capacity. one hypothesis for females being at higher risk of developing asthma or wheeze during adolescence or adulthood is the smaller relative airway caliber in women compared with men after puberty. epidemiologic studies consistently show an association between atopy and asthma, although the strength of the association varies with the index used and the study population. part of the problem lies in the ambivalent nature of the term asthma.the symptoms of asthma in older adults also can indicate copd, and the differential diagnosis may be difficult even in a clinic. a distinction used to be made between asthma and other wheezy syndromes in children. however, the management is very similar, the distinction has fallen largely into disuse, and use of the term nonatopic asthma has become common for children, whereas it was prviously reserved for a condition associated with eosinophilic inflammation but negative skin test results that predominantly presented in middle age, often among women, and had a relatively poor prognosis. the idea that atopic and airway components of asthma are distinct , has been confirmed by genetic studies thatidentified gene polymorphisms associated with asthma but not obviously related to the regulation of ige or associated immunologic responses. isaac found little variation in the prevalence of nonatopic asthma that could be explained by the local gross income, but prevalence of asthma associated with sensitization became less common in low-income settings. , the distinction is important, because atopic asthma in children apears to have a less benign course than nonatopic disease. burrows and colleagues assessed this association in a random sample selected from tucson, arizona, using skin tests with local antigens as an index of atopic status. in children to years old, atopy was strongly associated with attacks of wheezing and dyspnea, regardless of whether asthma had been diagnosed. later analyses of the tucson population indicated that the total serum ige level was more strongly associated with the prevalence of asthma, an association that was also found in an nhanes analysis (discussed later). another study using self-reported during the -year period from to , hospital admissions for food allergy showed continuing increases of to cases per million people overall and to cases per million children, particularly in the -year-old age group. hospital admissions attributed to "dermatitis due to food" increased in england and wales from cases per million people in to cases per million people in , an increase of almost % per annum. , apart from true changes in the epidemiology of food allergy, alternative explanations for this dramatic increase in health care use for presumed food allergy include changes in the coding behavior of doctors, changes in the awareness and behavior of patients, and changes in the health care system. in the united states, the nhis recorded much smaller increases in parent-reported food allergy, although such reports are usually regarded as unreliable. increasing reports of more specific complaints of peanut allergy have been made for children in the united states and the united kingdom. a genetic component of asthma has long been recognized, based initially on the observation that asthma tends to cluster in families. familial aggregation, twin, genetic linkage, and association studies subsequently provided evidence to support this hypothesis. detailed descriptions of the molecular genetics of asthma and atopic disease are provided in chapter . family aggregation studies compare disease occurrences between family members. disease aggregation between siblings and between parents and children supports a hereditary component, whereas increased aggregation between spouses suggests that environment is more important. however, aggregation among related individuals may represent shared genes or a common household environment. evidence of a hereditary component of asthma has been demonstrated in numerous family-based studies. [ ] [ ] [ ] [ ] population-based studies also have shown an increased prevalence of asthma among first-degree relatives of index cases. [ ] [ ] [ ] [ ] [ ] twin studies compared disease frequency in monozygotic (mz) twins, who share % of their genes, with dizygotic (dz) twins, who share on average % of their genes. this is another method to determine the relative contribution of genetic and environmental factors. a greater occurrence of disease in mz than in dz twins is evidence for a genetic component to the disease because both types of twins are assumed to share environmental factors similarly. significantly higher concordance rates for mz twins have been observed in some small studies. larger studies of twin registries also suggest a significant genetic contribution to asthma. in twin pairs from the swedish twin registry, edfors-lubs found the prevalence of asthma to be . %. the higher concordance of asthma in mz ( . %) over dz ( . %) pairs suggests that genetic factors contribute to asthma. similarly, duffy and associates observed a % concordance in mz twins and % in dz twins in a total of australian pairs. whole-genome association studies have identified specific loci associated with clinical asthma. the genes associated with total ige levels were not strongly associated with asthma, and many related methodologic issues complicate the study of diet and disease. obtaining unbiased exposure estimates is difficult because of recall problems, difficulties in measuring intake, and limited range of variation in the western diet. diet is fundamental to existence and is closely associated with many lifestyle, social, cultural, and environmental factors that may influence the development of disease. although many studies adjust for potential confounders, it has been argued that this is insufficient and that many or all of the reported associations between diet and disease are likely to be confounded by social and behavioral factors acting across the life course. , several reviews on the topic of diet and asthma and allergic disease are available. [ ] [ ] [ ] [ ] [ ] [ ] [ ] observational and randomized studies have directly correlated dietary sodium levels with increased bronchial responsiveness to histamine challenge. [ ] [ ] [ ] one study showed this response occurred in males but not in females. ecologic data from england and wales support these experimental findings; the purchases of table salt correlated with the regions of increased asthma mortality for men and children. other population-based studies, however, have not shown a relationship between urinary sodium levels and methacholine airway responsiveness, [ ] [ ] [ ] although two did show an association with higher levels of potassium excretion. , britton and associates found that increased magnesium intake was associated with a reduced risk of bronchial hyperresponsiveness and wheeze. because of the relationships among sodium, potassium, and magnesium, these investigators suggest the possibility that low levels of dietary magnesium may confound the association of sodium and potassium with bronchial hyperresponsiveness or asthma. a systematic review of the clinical trials of dietary sodium reduction in persons with asthma concluded that dietary sodium reduction does not significantly improve asthma control. dietary sodium reduction was associated with some improvement in lung function in people with exercise-induced asthma, but because extremely large reductions in sodium intake were required, the clinical utility, as distinct from the potential public health relevance of this finding, is likely to be small. a systematic review of the studies correlating asthma and allergic disease in children with dietary intake or status of vitamin a, vitamin c, vitamin e, selenium, zinc, copper, iron, fruits, vegetables, and components of the mediterranean diet identified eligible reports. there were no randomized, controlled trials, and all studies were judged to be at moderate to substantial risk of bias. meta-analyses demonstrated that serum vitamin a was lower in children with asthma compared with controls (odds ratio [or] = . ; % confidence interval [ci], . to . ). the meta-analyses also showed that high maternal dietary vitamin e intake during pregnancy was protective against development of childhood wheezing (or = . ; % ci, . to . ) and that maternal adherence to a mediterranean diet during pregnancy was protective against persistent wheeze (or = . ; % ci, . to . ) and atopy (or = . ; % ci, . to . ) in children. seventeen of fruit and vegetable studies reported beneficial associations with asthma and allergic outcomes. although weak, the available epidemiologic evidence supports dietary intake of vitamin a, vitamin d, vitamin e, zinc, fruits, vegetables, and a mediterranean diet for the prevention of asthma. the fatty acid composition of the diet, particularly the relative amounts of n- (ω- ) and n- (ω- ) polyunsaturated fatty diagnosis of hay fever in a population sample from western pennsylvania showed atopy to be more common in asthmatic than nonasthmatic children. two other studies demonstrated parental atopy and asthma as risk factors for asthma in their children. , the results also demonstrated a complex interaction between these factors and the gender of the child. a study of new zealand children assessed the relationship of total serum ige levels at the age years and asthma, and investigators found that the prevalence of diagnosed asthma was strongly related to the serum ige level (p trend < . ). , asthma was not reported for children with ige levels of less than iu/ ml, whereas % of children with ige levels of iu/ml or higher had asthma. asthma and atopy are closely linked, and the causal nature of the factors seems to be complex and require more investigation. nonetheless, atopy in parents and children does increase the risk of asthma and can be used as an empiric predictor. diet diet, including breastfeeding, food intolerance and sensitivity, and intake levels of specific micronutrients, has been investigated as a potential risk factor for asthma for over decades. in , burney was among the first to propose diet as a potential explanation for the rising frequency of asthma, suggesting the possibility that increasing salt intake might have a role. the rationale for investigating diet as a possible risk factor for asthma and allergic disease is that diet has changed in recent decades and biologically plausible mechanisms exist. many dietary constituents have been investigated for potential involvement in the pathogenesis of asthma and allergic disease, including antioxidants (e.g., vitamin e, vitamin c, carotenoids, flavonoids), polyunsaturated fatty acids, vitamin d, folate, , foods (e.g., fruits, vegetables), metals or trace minerals (e.g., sodium, magnesium, selenium, zinc, copper), and components of the mediterranean diet ( increased ige levels, eosinophilia, methacholine responsiveness, asthma-related hospitalization, exacerbations, use of antiinflammatory medication, and use of oral corticosteroids and with reduced asthma control scores. analogous findings have been reported for adults with asthma. similarly, for children with atopic dermatitis, lower serum -oh-d concentrations have been associated with increased severity of atopic dermatitis. longitudinal cohort studies quantifying vitamin d status before the development of disease are not subject to many of the limitations of cross-sectional studies, such as reverse causation, whereby the vitamin d status of an individual is influenced by the presence of disease (e.g., children with asthma may spend more time indoors). a systematic review and metaanalysis of the longitudinal studies relating maternal vitamin d status during pregnancy to childhood outcomes concluded that high maternal dietary vitamin d intake is associated with a reduced risk of children wheezing up to the age of years (or = . ; % ci, . to . ). however, maternal dietary vitamin d intake during pregnancy is not indicative of total body vitamin d status, because % of vitamin d is derived from cutaneous exposure to ultraviolet light. in contrast to maternal dietary vitamin d intake, high (> nmol/l) maternal serum -oh-d levels in late pregnancy have been associated with an increased likelihood of childhood eczema at age months and asthma at age years. during infancy, increased vitamin d intake has been associated with an increased risk of atopic dermatitis at age years and an increased likelihood of allergic rhinitis and atopic sensitization at the age of years. , in later childhood, an increased serum -oh-d concentration at years of age has been associated with a reduced likelihood of asthma at years of age, and an increased serum -oh-d concentration at years of age has been associated with a reduced likelihood of asthma, rhinoconjunctivitis, and atopic sensitization at years of age. the epidemiologic data support the hypotheses that vitamin d may have beneficial and adverse influences on the development of asthma and allergic disease. ongoing clinical trials are clarifying the potential clinical role of vitamin d in modifying the risk of developing asthma and as an adjunct to asthma and atopic dermatitis therapy. although breastfeeding of infants is recommended because of well-documented benefits for mother and child, the effects of breastfeeding on the subsequent development of atopic dermatitis, wheezing disease, and asthma are not clear. , conceptually, the advantageous consequences of breastfeeding for the infant include acquisition of maternal antibodies and immune-competent cells such as macrophages and leukocytes and protection against early occurrence of lower respiratory tract infections. however, breastfeeding may also be a route of exposure to a variety of immunologically active substances from the mother, such as tobacco smoke, cow's milk, eggs, wheat, maternal ige, and sensitized lymphocytes. many studies have investigated the association between breastfeeding, asthma, wheezing illness, and atopic disease, and they have been subject to several systematic reviews, most of which highlight the limitations and difficulties in conducting and interpreting such studies (e.g., confounding, recruitment bias, reporting bias, reverse causation, variation in breastfeeding patterns, inability to randomize and blind). the systematic reviews have themselves been reviewed in consensus documents, which conclude that the exclusive breastfeeding for to months of acids (pufas) found in fish and vegetable oils, respectively, affects cell functioning. fatty acids appear to have specific roles in inflammatory and immune responses, and changes in fatty acid consumption are a postulated cause of the rising incidence of asthma and other allergic diseases. , conflicting observational data relating n- and n- pufa intake or status during pregnancy, childhood, and adulthood to asthma and allergic disease have been surpassed by intervention trials. a systematic review with meta-analysis evaluated the interventional studies of n- and n- pufa supplementation in the context of primary prevention of asthma and allergic disease. ten reports from six double-blind, randomized, controlled trials were identified. four studies compared n- pufa supplements with placebo, and two studies compared n- pufa supplements with placebo. the meta-analyses failed to identify any consistent or clear benefits associated with n- pufa supplementation during pregnancy or infancy for atopic dermatitis two subsequent trials reported the consequences of n- pufa supplementation during pregnancy. in the first, highdose n- pufa supplementation of pregnant women from weeks' gestation and during breastfeeding reduced the incidence of food allergy and ige-associated atopic dermatitis in children in the first year of life compared with placebo ( % versus % [p < . ] and % versus % [p < . ], respectively). in the second, larger study of pregnant women, high-dose n- pufa supplementation from weeks' gestation until delivery did not reduce the incidence of ige-associated disease or atopic dermatitis during the first year of life compared with placebo (rr = . [ % ci, . to . ] and rr = . [ % ci, . to . ], respectively). there is insufficient evidence to recommend pufa supplementation in any period of life as a means of reducing the burden of asthma and allergic disease. the role of vitamin d in the cause asthma and allergic disease remains unclear. the increase in asthma and allergic disease in developed countries has been attributed to early-life vitamin d supplementation as rickets prophylaxis, and widespread vitamin d deficiency is thought to be a consequence of more time being spent indoors and the active promotion of sun avoidance. cross-sectional, observational studies have reported vitamin d status to be no different or increased in adults with asthma but decreased in children with asthma. , blood levels of -hydroxyvitamin d ( -oh-d) concentrations were found to be lower in adults with atopic dermatitis and allergic rhinitis. , in two studies using nhanes data, blood levels of -oh-d have been no different in adults with evidence of atopic sensitization; however, atopic sensitization was associated with reduced blood -oh-d levels in children and adolescents in one study but not in adolescents in the other. the effect of blood -oh-d levels on current wheeze depended on age and atopic status in another study using nhanes data, with nonatopic individuals and adults years of age or older having a greater risk of wheeze if they had lower -oh-d levels. in children with asthma, lower blood levels of -oh-d have been associated with increased asthma severity, including have reported associations between the prevalence of asthma and obesity, it is not possible to exclude reverse causation, whereby asthma may contribute to obesity through inactivity and use of oral corticosteroids. the most relevant data come from prospective cohort studies that have assessed risk for incident asthma in relation to initial weight or bmi. beuther and sutherland systematically reviewed prospective studies evaluating the association between bmi and incident asthma among adults. meta-analysis of the data from , subjects participating in the seven identified studies demonstrated that being overweight or obese (bmi ≥ ) was associated with an increase in the rate of -year incident asthma (or = . ; % ci, . to . ), with evidence of a dose effect for being overweight (or = . ; % ci, . to . ) or obese (or = . ; % ci, . to . ). there was no difference between sexes. a systematic review of similar literature for children and adolescents concluded that obesity precedes and is associated with the persistence and intensity of asthma symptoms. in observational designs, a potential methodologic concern is that nonspecific respiratory symptoms resulting from cardiorespiratory loading and deconditioning may be misclassified as asthma. careful studies of children and adults suggest that asthma is not inappropriately overdiagnosed in the obese. , observational studies have also reported adverse associations for bmi, obesity and overweight, and atopic dermatitis and atopic sensitization in children and adults. [ ] [ ] [ ] [ ] a retrospective case-control study of children with a mean age of . years confirmed an association between obesity and atopic dermatitis and reported that early-life and prolonged obesity was associated with atopic dermatitis. atopic dermatitis was more prevalent among children who were obese before years of age (or = . ; % ci, . to ) and between and years of age (or = . ; % ci, . to . ). obesity after the age of years was not associated with atopic dermatitis. children who were obese for . to . years (or = . ; % ci, . to . ) and for more than years (or = . ; % ci, . to . ) were more likely to be diagnosed with atopic dermatitis. infants at high risk for atopic disease reduces the likelihood of atopic dermatitis and that breastfeeding beyond to months appears to confer no additional benefit. , the available evidence also suggests that the breastfeeding of infants at low risk for atopic disease does not reduce the incidence of atopic dermatitis. the evidence for a protective effect of breastfeeding against respiratory disease is controversial. although breastfeeding appears to reduce the incidence of virus-associated wheezing episodes in young children (< years), the evidence of an effect on breastfeeding on the development of asthma is inconsistent. systematic reviews suggest that exclusive breastfeeding for to months is associated with a reduced risk of asthma in children to years old, but this beneficial effect is limited to infants at high risk for atopic disease. some systematic reviews have revisited the literature relating breastfeeding to childhood atopic dermatitis, asthma, and wheezing. a systematic review examining the association between exclusive breastfeeding for months or longer and the development of childhood atopic dermatitis identified reports from study populations and concluded that there was no strong evidence that exclusive breastfeeding confers a beneficial effect on the development of childhood atopic dermatitis (summary or = . ; % ci, . to . ), even in children at high familial risk (or = . ; % ci, . to . ). another systematic review clarified the association between breastfeeding and childhood asthma and wheezing after years of age. it examined publications and concluded that breastfeeding for months or longer did not confer any beneficial effect on the incidence of asthma and wheezing illness after the age of years. the summary odds ratio for any breastfeeding and wheezing was . ( % ci, . to . ), and for exclusive breastfeeding and wheezing, it was . ( % ci, . to . ). the prevalence of obesity increased dramatically in many countries, particularly western and other developed countries in the latter decades of the twentieth century. in the united states, for example, the prevalence of overweight and obesity among adults rose sharply across the s, such that most adults are now overweight. the prevalence of childhood overweight is also rising rapidly. the rise in obesity parallels the rise of asthma, and a hypothesis has been advanced that obesity could be a risk factor for asthma. several mechanisms have been postulated for the association, including the mechanical effects of obesity, a higher frequency of gastric esophageal reflux, upregulation of immunologic and inflammatory correlates of obesity, and a shared genetic basis for both conditions. , the association of obesity with asthma has been investigated in children and adults. camargo and colleagues offered one of the first reports in their paper based on the nurses' health study ii. the body mass index (bmi) in was positively and strongly associated with asthma risk over the next few years (fig. - ) . similar studies have addressed obesity and asthma in children. in a cross-sectional study using nhanes iii data, von mutius and colleagues found a positive association between bmi and asthma risk (or = . ; % ci, . to . ) by comparing the highest and lowest quartiles of bmi. in the tucson study, girls becoming overweight or obese between the ages of and years had a sevenfold increased risk for asthma. although many cross-sectional observational studies ≥ . at years. because most children are not hospitalized for lower respiratory tract disease, these results apply only to the more severe infections. a population-based study of children in east boston, massachusetts, however, found that a history of bronchiolitis or croup was a predictor of increased airway responsiveness. in another boston area study, children from a birth cohort with lower respiratory tract infection (i.e., croup, bronchitis, bronchiolitis, or pneumonia) in the first year of life were twice as likely to report two or more episodes of wheeze than children with no lower respiratory tract infection. the tucson children's respiratory study provides relevant data on follow-up from birth to age years. , results from this longitudinal study show that rsv infection was associated with an increased risk of infrequent and frequent wheeze by age years. the relative risk for wheeze after years of age for children with rsv infection compared with children with no rsv infection decreased over time. the relative risk decreased with age from . and . at age years to no risk at age years for infrequent wheeze and frequent wheeze, respectively. support for the idea that severe rsv-associated respiratory disease probably does not contribute to the development of asthma has been provided by a large ( pairs) danish twin registry study that applied genetic variance and direction of causation models to data on rsv-associated hospitalization and the development of asthma. a model in which asthma caused rsv-related hospitalization fit the data significantly better than a model in which rsv-related hospitalization caused asthma, suggesting that rsv infection does not cause asthma but reflects an underlying predisposition to asthma. the role of viruses in the natural history of asthma has been highlighted by several longitudinal cohort studies. the wisconsin childhood origins of asthma (coast) study prospectively evaluated the timing, frequency, severity, and cause of symptomatic viral infection in the first years of life in relation to later wheezing illness in a cohort of neonates at high familial risk for asthma. by using molecular technologies to identify viral infections in nasal lavage samples collected routinely and when symptomatic, this study highlighted the prognostic importance of hrv. having one or more hrvassociated wheezing episodes during the first years of life was more strongly associated with wheezing in the third year (or = . ; % ci, . to . ) than having one or more rsv-associated wheezing episodes during the first years of life (or = . ; % ci, . to . ). first-year wheezing associated with hrv was the strongest predictor for third-year wheeze (or = . ). the pattern of viral respiratory tract infection in the first years was different for children with or without asthma at the age of years (fig. - ) . asthma at years of age was strongly associated with hrv-associated wheeze in the first years of life (or = . ; % ci, . to . ). the frequency of hrv-induced wheezing episodes increased in the first years of life for children diagnosed with asthma by age , whereas for children without asthma, hrv-associated wheezing episodes declined in the first years (see fig. - ) . almost % of children with hrv-associated wheezing episodes in year had been diagnosed with asthma by the age of years, and hrv-associated wheeze was a more robust predictor for subsequent asthma than atopic sensitization to aeroallergens. asthma at years of age was also associated with rsv-associated wheezing episodes in the first years (or = . ; % ci, . to . ). the likelihood of asthma by age years being associated with rsv-induced wheeze in the first years of life was increased these findings are provocative and indicate another potential risk factor for asthma and allergic disease, one that is increasingly prevalent and amenable to intervention. a better understanding of the mechanisms and potential role of intervention in the primary and secondary prevention of disease is needed. respiratory infections are common in the first years of life, and they provoke wheezing in children with or without asthma. less certain is whether viral or other respiratory infections have a direct role in the pathogenesis of asthma or they merely reveal that a child is predisposed to asthma. investigation of the association of viral infection and asthma has been limited by available technology, with culture, serology, and antigen detection having % to % detection rates. the newer molecular technologies have improved the rates of viral detection up to about % and have revealed the importance of previously unknown viruses, such as human rhinovirus c (hrv-c). lower respiratory tract infections in children, which are caused by hrvs, respiratory syncytial virus (rsv), parainfluenza viruses, and other pathogens, are universal in childhood. a community-based study in tecumseh, michigan, estimated that children experience, on average, . lower respiratory tract infections in the first year of life and . such infections between and years of age. another cohort study of respiratory illnesses from birth through months in albuquerque, new mexico, adapted a surveillance system similar to the one used in tecumseh and found comparable incidence rates from through . the incidence of severe episodes of viral respiratory infections was captured in another study using surveillance through a pediatric group practice. this study showed that % of children were affected in the first year of life, that % had annual occurrences by age years, and that % of children to years old experienced annual episodes of infection. follow-up studies of children with a history of hospitalization for respiratory infections suggest that these illnesses may predispose to the development of asthma. in several studies, children with past hospitalizations tended to have abnormal lung function that was indicative of airflow obstruction, including hyperinflation, increased respiratory resistance, and reduced spirometric flow rates. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in children with past hospitalizations, increased airway reactivity occurred after assessment by exercise, cold air inhalation, methacholine, or histamine inhalation challenge. [ ] [ ] [ ] infants hospitalized with rsv-associated bronchiolitis are more likely to wheeze and develop asthma later in childhood. a study of swedish children found that those who were hospitalized with rsv bronchiolitis in infancy were almost nine times more likely to have physician-diagnosed asthma at age years than those without infection. being hospitalized with rsv bronchiolitis in infancy was an independent risk factor for current asthma and recurring wheezing (or = . ; % ci, . to . ). henderson and colleagues described the relationship of hospitalization for rsv bronchiolitis in infancy and asthma in a population-based birth cohort study of more than children from the united kingdom. hospitalization for rsv bronchiolitis was associated with physician-diagnosed asthma at age years (or = . ; % ci, . to . ) only among nonatopic children. no association was observed for children with atopy type (hrv- ) replicates more readily in the airway epithelial cells of people with asthma, and the airway epithelial cells are more likely to lyse and have greatly impaired interferon-λ (ifn-λ) and ifn-β responses. van der zalm and coworkers reported that increased neonatal airway resistance was related to an increased likelihood of hrv-associated wheeze in the first year of life (or = . ; % ci, . to . ). hrv was originally classified as serotypes hrv-a and hrv-b, but in , a novel hrv designated hrv-c was identified using reverse transcription-polymerase chain reaction (rt-pcr). hrv-c has been implicated in the natural history of wheezing disease and asthma, and it appears to have prognostic importance. in a prospective, population-based study of children younger than years of age who were hospitalized in two u.s. counties with acute respiratory illness or fever, hrv was detected in %, and hrv-c was isolated slightly more than % of them. children from whom hrv-c was isolated were significantly more likely than those with hrv-a or hrv-b to have underlying high-risk conditions such as asthma (or = . ; % ci, . to . ). in australia, hrv serotypes were isolated from % of children to years old who presented to the hospital with acute asthma. hrv-c was isolated from % of the children, and these children had higher asthma severity scores than those infected with hrv-a or hrv-b. in a study of children hospitalized in hong kong, hrvs were isolated from % of children admitted because of acute asthma and from % of control, nonatopic children hospitalized with nonasthma respiratory conditions. hrv-c was isolated from % of the children with acute asthma and % of the controls, and children with hrv-c were more likely to require supplemental oxygen. these studies implicate hrv-c in most episodes of acute asthma requiring hospital attention. hrv-c appears to be more virulent than other hrv serotypes, particularly in children with atopic sensitization. although the major focus has been on viral respiratory tract infection, asymptomatic early-life bacterial airway colonization has also been associated with childhood wheeze and asthma. in the copenhagen prospective study of asthma in childhood, neonates at high familial risk for asthma had their hypopharyngeal regions sampled at month of age, and the children were then followed up to years of age. neonatal colonization of the hypopharyngeal region by streptococcus pneumoniae, haemophilus influenzae, and moraxella catarrhalis (but not staphylococcus aureus) in isolation or in combination was associated with increased likelihood of subsequent wheeze, hospitalization with wheeze, and asthma. hypopharyngeal colonization at year of age was not associated with neonatal colonization or the development of wheeze or asthma. although has been postulated that early-life bacterial colonization induced neutrophilic airway inflammation with consequent wheeze and asthma, it also has been suggested that neonatal airway colonization by these bacteria reflects defective early-life innate immune responses that predispose to asthma. asthma-like symptoms, especially in young children, often are treated with antibiotics, and an association has been observed between the use of these drugs and the risk of asthma. the simultaneously increased use of antibiotics in children and the increasing prevalence of asthma in developed countries has led to the hypothesis (consistent with the hygiene hypothesis) that antibiotic use may contribute to asthma by altering the normal colonization of gut flora in infants and increasing the only for children who had also had hrv-associated wheezing episodes. measurement of lung function in the coast cohort at age years demonstrated that hrv-associated wheezing episodes in the first years of life were associated with reduced lung function: fev of % of predicted for those with hrvassociated wheeze versus % for no hrv-associated wheeze (p < . ). similar differences were found for absolute fev , forced expiratory volume in . second (fev . ), and forced expiratory flow determined over the middle % of a patient's expired volume (fef ). lung function at age was not associated with the frequency of hrv-associated wheeze nor with rsv-associated wheeze. although studies such as coast demonstrate that hrv respiratory infection is prognostically more important than rsv infection for subsequent asthma, whether virus-associated wheezing episodes (particularly hrv) contribute to the pathogenesis of asthma or are merely manifestations of infection in children predisposed to asthma remains an unanswered question. there is evidence supporting the concept that children predisposed to asthma have lung function and airway epithelial abnormalities from very early in life that increase the likelihood of virus-associated wheezing episodes. [ ] [ ] [ ] human rhinovirus cross-sectional studies. in one of the earliest reports, northway and coworkers considered the first possibility-that asthma is a long-term consequence of bronchopulmonary dysplasia (bpd). bpd is a syndrome of chronic lung disease in premature infants who are mechanically ventilated for at least week as a treatment for rds. the clinical diagnosis requires the symptoms of persistent respiratory distress during infancy, dependence on supplemental oxygen, and abnormal chest radiographs. northway and colleagues then studied adolescents and young adults born between and who had bpd in infancy and compared their long-term pulmonary outcomes with those of two control groups. they found that most subjects with a history of bpd in infancy had pulmonary dysfunction. moreover, the increase in airway reactivity was not associated with a more frequent family history of asthma in this sample or with an increased prevalence of atopy. these findings suggest that lung injury resulting from mechanical ventilation of premature infants has a role in the pathogenesis of persistent pulmonary dysfunction that is similar to asthma. bertrand and associates investigated the role of rds in prematurity in the pathogenesis of airway hyperresponsiveness (ahr) in subjects who did not have bpd as infants. the group with a history of rds had evidence of more hyperinflation and airway obstruction compared with controls. however, results from the histamine challenge to determine ahr and familial aggregation of ahr were inconclusive. the incidence of airway reactivity was elevated among cases and controls and among the mothers and siblings of cases and controls. the investigators suggest that the elevated incidence of ahr among mothers of both groups supports the hypothesis that there may be an association between the onset of premature labor and airway reactivity. because no comparison group was established for mothers of term children, however, this assertion cannot be affirmed from the study. some researchers have investigated the effect of very low birth weight (vlbw < g) and bpd on asthma development in birth cohorts. [ ] [ ] [ ] [ ] [ ] [ ] [ ] children with vlbw were followed for years as part of the newborn lung project conducted in wisconsin and iowa. , results at age years did not show a consistent association between asthma and bpd. children with diagnosed bpd and children with radiographically identified bpd had about a threefold and twofold increase, respectively, in the risk of bronchodilator use up to age years, adjusted for birth weight, gestational age, gender, race, and neonatal center. among children with bpd, the prevalence of ever having asthma at age years did not show a difference by the period of birth. however, the prevalence of wheezing in the last year at years of age decreased from % to % over time. as the researchers observed, this finding could have resulted from the introduction of surfactant therapy as a bpd treatment. prematurity as a risk factor for asthma has been explored in cross-sectional studies. [ ] [ ] [ ] [ ] [ ] [ ] a significant association between current asthma prevalence and premature girls was observed in a study of schoolchildren. significantly more premature children had a family history of asthma than did term children, and this association was stronger among children who required mechanical ventilation as premature infants. another german study of schoolchildren did not show an association between former or current asthma and low birth weight (lbw < g) among premature children. however, bronchial hyperresponsiveness was significantly increased in children born at atopic, helper t cell type (th ) immune responses. , in support of this hypothesis, humans exposed to stable and farm environments, which are rich in microbes, show significantly reduced levels of asthma and atopic disease compared with those in other rural or nonrural environments. other studies have shown that the different proportion of aerobic and anaerobic gut flora in children from sweden compared with estonia parallels the difference in atopy incidence between these populations. , animal studies also support the hypothesis. mice given oral antibiotics had altered intestinal flora and impaired helper t cell type (th ) immune responses. epidemiologic studies of asthma and allergic disease in relation to antibiotic use are beset by biases, including reverse causality (i.e., asthma leads to more common prescription of antibiotics) and confounding by indication (i.e. respiratory infections leading to antibiotic use may be implicated in the development of asthma). to illustrate this problem, in a carefully conducted tucson birth cohort study, information on illness, antibiotic use, and physician visits was ascertained on seven occasions in the first months of life and correlated with the development of asthma and allergic disease up to the age of years. a significant association between the number of early-life courses of antibiotics and asthma was reported. the number of physician visits was associated with the number of antibiotic courses and with asthma. however, after adjustment for the number of physician visits, antibiotic use was not associated with asthma, and it was concluded that any association between early-life antibiotic use and asthma was an artifact of the number of physician visits for illness, which was strongly associated with antibiotic use and risk of asthma. two systematic reviews have provided insight into the possible causative association between early-life antibiotic use and asthma and allergic disease. a systematic review of studies that have related antibiotic exposure during pregnancy or in the first year of life with risk of childhood asthma identified relevant studies. antibiotic use in the first year of life was associated with an increased likelihood of childhood asthma (or = . ; % ci, . to . ). stratified analysis indicated that retrospective studies reported the strongest associations (or = . ; % ci, . to . ) compared with database and prospective studies (or = . ; % ci, . to . ) . studies that addressed potential biases by adjusting for respiratory infections reported the weakest associations (or = . ; % ci, . to . ). a second systematic review focusing on longitudinal studies identified studies, and a meta-analysis indicated that antibiotic use was associated with subsequent wheeze or asthma (or = . ; % ci, . to . ). however, after eliminating nine studies with a high risk of bias, the magnitude of the association was reduced (or = . ; % ci, . to . ). both systematic reviews concluded that there might be a weak link between antibiotic use and subsequent asthma and that biases had exaggerated the strength of any association that might exist. premature birth has been associated with the development of symptoms consistent with asthma and other long-term pulmonary sequelae in a number of studies. the cause of the sequelae is uncertain. the pulmonary injury may be acquired during mechanical ventilation of preterm infants with respiratory distress syndrome (rds), from the rds itself, or from some other facet of prematurity. prematurity has been examined as a risk factor for asthma in cohort studies of affected children and in plants (e.g., grain dust, flour, latex, castor bean, green coffee bean), enzymes (e.g., subtilisin from bacillus subtilis, papain, fungal amylase), wood dust or barks (e.g., western red cedar, oak, reactive dyes), drugs (e.g., penicillin, methyldopa), metals (e.g., halogenated platinum salts, cobalt), and others such as oil mists. they have been classified according to possible pathogenetic mechanisms: high-molecular-weight agents that induce specific ige antibodies; low-molecular-weight substances, such as isocyanates, for which underlying mechanisms are largely unknown; and irritant gases, fumes, and chemicals that induce occupational asthma by nonimmunologic mechanisms. more extensive coverage of these agents and the topic is available elsewhere. , other causes of occupational asthma have been identified through clinical reports, epidemiologic investigations, and population studies. jaakkola and colleagues conducted a casecontrol study in finland. risk for asthma was found to be increased for several occupational groups, including some for which occupational asthma had not been previously reported, such as being a male or female waiter. le moual and coworkers explored associations for occupation and occupational exposures with asthma in , participants in a french survey conducted in . several jobs were associated with an increased risk of asthma of about %. a similar analysis was reported for the united states based on the nhanes iii. several studies provide estimates of the overall importance of occupational asthma. kogevinas and colleagues analyzed data from more than , young adults participating in the ecrhs. an estimated . % of asthma was attributed to occupation, with asthma defined by asthma symptoms or use of medication and assessed by questionnaire. when asthma was defined by questionnaire responses and bronchial hyperresponsiveness, the attributable risk estimated for occupation increased to . %. among members of a u.s. health maintenance organization, one third of persons identified as having new or recurrent asthma were classified as having a potential association with work as the basis for asthma. blanc and toren conducted a meta-analysis of studies on occupational asthma from to mid- . the median attributable risk estimate for occupational asthma was % for all studies identified. when the study quality was taken into account and analyses were limited to those of higher quality, the estimate was %. these estimates included new-onset asthma and reactivation of preexisting asthma. outdoor air pollutants can be classified by origin as natural or manmade. among the naturally occurring air pollutants are particulate matter (including bioaerosols), volatile organic compounds, and ozone. for asthma, the key manmade pollutants result from combustion of fossil fuels in cars, power plants, heating devices, and industrial point sources and from emissions of chemicals from manufacturing facilities, storage tanks, and accidental releases. in the united states, air pollutants have been categorized on the basis of their regulation under the clean air act as criteria pollutants (e.g., lead, nitrogen dioxide [no ], sulfur dioxide [so ], particulate matter [pm], ozone [o ], carbon monoxide [co]) and as air toxics, a specified listing of chemicals that includes some irritants relevant to asthma. these pollutants are a concern throughout the world's polluted cities and regions. many cities and smaller towns and term with lbw compared with children born with normal birth weight, with values adjusted for height, gender, and age. a study conducted as part of the ecrhs examined birth characteristics and asthma symptoms in young adults from norway. the researchers observed a significant decrease in asthma symptoms per -g increase in birth weight, adjusted for gestational age, length at birth, parity, maternal age, gender, adult height, hay fever, and current smoking habits. race and socioeconomic status may be determinants of prematurity and asthma. to test the hypothesis that prematurity was a risk factor for asthma independent of race or socioeconomic status, oliveti and colleagues performed a case-control study using a population restricted to african-american children from impoverished inner-city census tracts in cleveland, ohio. their findings confirmed previous findings with regard to prematurity and lbw. asthmatic children had significantly lower birth weights and gestational ages than nonasthmatic children and were more likely to have required positive-pressure ventilation (ppv) after birth. the risk of asthma was increased more than three times for children receiving ppv after birth. however, the increased risk of asthma due to lbw and prematurity was not significant when maternal history of asthma, bronchiolitis, lack of prenatal care, low maternal weight gain, and ppv were considered simultaneously. this suggests that lung injury and perhaps mechanical ventilation lead to an asthma-like syndrome, rather than lbw and prematurity directly. researchers have examined the lung function of preterm children over time. koumbourlis and associates followed preterm children with chronic lung disease, including bpd, from to years of age. the investigators observed improvements in the lung volumes of these patients throughout childhood and into adolescence, and these improvements were experienced by all children, regardless of the severity of the neonatal chronic lung disease. if patients had airway obstruction, it was primarily localized to the smaller airways, associated with ahr, and relatively fixed over time. two systematic reviews have investigated the association between prematurity and childhood asthma and wheezing outcomes. patelarou and colleagues identified nine studies that had reported on the association between adverse birth outcomes (e.g., premature, lbw, vlbw, fetal growth retardation) and early ( to years) childhood wheeze. they concluded that adverse birth outcomes were associated with wheezing in early life. similarly, a systematic review that identified studies reported that preterm (< weeks' gestation) was associated with an increased likelihood of childhood asthma (or = . ; % ci, . to . ). these results suggest that premature infants with or without neonatal respiratory disease may be at higher risk for asthma or a syndrome similar to asthma than term infants. however, the mechanistic pathways involved and the potential interactions with other asthma risk factors, such as viral respiratory infections and susceptibility genes, remain uncertain. occupational asthma is defined as variable airflow limitation or bronchial hyperresponsiveness due to exposure to a specific agent or conditions in a particular occupational setting but not to stimuli encountered outside the workplace. several hundred agents have been identified as causes of occupational asthma. , they include animal allergens (e.g., urine, dander), for children from east germany, where pollution originated from burning brown coal and industrial emissions. however, living in west germany was not an independent risk factor for asthma after adjustment for sensitivity to pollen, hdms, and cat allergens. another german study conducted from through obtained similar results. current asthma prevalence for children from munich was . %, compared with the prevalence for their counterparts from dresden of . %. significant differences in physician-diagnosed asthma prevalence were observed by comparing children in munich ( . %) and those in dresden, former east germany ( . %). a study enrolling children to years of age who were living in hong kong compared physician-diagnosed asthma prevalence in a high-pollution district and a low-pollution district. the researchers found that asthma prevalence was almost doubled in the high-pollution area compared with the low-pollution area. some studies have investigated the possible role of specific air pollutants in the development of asthma. in a cross-sectional study that was conducted as part of the isaac phase two and enrolled the same german children from dresden, an increase in estimated traffic-related exposure to benzene was associated with an increased prevalence in physician-diagnosed asthma after adjusting for potential confounders. however, this association reached statistical significance only when the home and school addresses used as the exposure indicators were combined. the prevalence of asthma was not associated with concentrations of so , no , and co. an increase in the exposure to air pollutants (except ozone) was associated with an increased prevalence of physician-diagnosed asthma in nonatopic children ( to years and to years old). this relationship was not observed in atopic children. another cross-sectional study evaluating the effects of general air pollution was conducted among , high school students in taiwan as part of the isaac. the researchers investigated the role of long-term exposure (i.e., annual average concentration) to air pollution and the prevalence of asthma. long-term exposure to total suspended particles, no , co, ozone, and airborne dust was associated with increased prevalence of asthma after adjusting for exercise, smoking, alcohol consumption, incense use, and environmental tobacco exposure. a similar study of , middle school students living in counties and cities in taiwan found a positive association between physician-diagnosed asthma prevalence and exposure to co and nitrogen oxides (no x ) when adjusted for age, history of atopic eczema, and parental education. baldi and coworkers reanalyzed data from a survey of children and , adults from seven french towns between and . they estimated a significant increase (or = . ; % ci, . to . ) in asthma prevalence per µg/m in the so -year-period annual mean after adjusting for age, education, and smoking status. the association remained significant when they restricted the analysis to adults reporting their first attack after moving to the study areas. they did not observe this relationship for children. these cross-sectional studies address the prevalence of asthma, which reflects the incidence and duration of the disease. if air pollution increases the duration of asthma, the prevalence would be increased, even without an effect on incidence. the clearest evidence of a causal association between outdoor air pollution and childhood asthma comes from cohort studies. villages in the developing world have the problem of smoke from biomass fuel use for indoor cooking and heating that is emitted outdoors. although it is accepted that exposure to outdoor air pollution can exacerbate existing asthma, - the role of outdoor air pollution in the development of childhood asthma is less well established. however, there is increasing evidence, especially from studies with a focus on exposure related to traffic within urban areas, that implicates outdoor air pollution in the development of childhood asthma [ ] [ ] [ ] and lung function. the outbreaks of acute asthma in barcelona illustrate the consequences of exposure to an airborne contaminant and the need to investigate asthma epidemics. during the s, a remarkable series of epidemics of asthma occurred in barcelona, a port city. careful analysis of one outbreak showed spatial clustering near the harbor, and an epidemiologic investigation showed a very strong association between unloading of soybeans at the harbor and occurrence of the epidemics. an antigen was identified in the soybeans that proved to be responsible for the outbreaks. the outbreaks were traced to releases of dust at a particular silo, and control measures were enacted. subsequently, a review of the historical record showed that there had been similar outbreaks of soybean asthma in new orleans. a large body of experimental and observational evidence links outdoor air pollution to exacerbation of asthma. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] compilations of the evidence can be found in the criteria documents prepared by the u.s. environmental protection agency (epa) for particulate matter and ozone. , human experimental studies have provided some insights, showing for example, that the oxidant pollutants nitrogen dioxide and ozone may enhance the effects of allergens, possibly by increasing the permeability of airways. , epidemiologic data, primarily coming from studies of panels of persons with asthma or of medical morbidity, have shown that the adverse effects of air pollution on asthma are relevant clinically and are significant from a public health perspective. there is uncertainty about the relative effects of specific pollutants compared with the overall toxicity of the air pollution mixture. gent and colleagues investigated the effect of exposure to ozone and particulate matter of . µm in diameter (pm . ) in a u.s. cohort study of asthmatic children. among children using maintenance medication, the level of ozone, but not pm . , was significantly associated with worsening of respiratory symptoms and an increase in rescue medication use. significant associations were not found for children not using maintenance medication. these findings suggest that children with asthma using maintenance medication are especially vulnerable to ozone, even after adjusting for exposure to pm . and at air pollution levels below the epa air quality standards. various lines of epidemiologic evidence continue to indicate a potential role of air pollution in the cause of asthma. crosssectional studies have investigated asthma prevalence and air pollution. after the unification of east and west germany, studies were conducted to compare respiratory diseases among children who had a relatively homogenous genetic background but had experienced exposures to air pollution at very different concentrations. [ ] [ ] [ ] [ ] in a study conducted between and , children to years old from munich (west) had a higher prevalence of physician-diagnosed asthma than those from leipzig and halle (east). current asthma prevalence among children living in west germany, an area with a greater amount of heavy road traffic, was . %, compared with . % also raised. the disparity between cross-sectional and prospective studies suggests that although the incidence of asthma among those living close to traffic is increased, it is not evident at a population level because of the small effect size and the lack of variation in the distance between home and traffic. cohort studies published since the comeap are consistent with its findings, but they also highlight a possible early-life effect and the importance of exposure while at school. the dutch prevention and incidence of asthma and mite allergy (piama) birth cohort study related symptom data prospectively collected annually from children up to the age of years to land-use regression estimates of individual no , pm . , and soot exposures at their birth addresses. pm . was associated with an increased annual incidence of asthma (or . ; % ci, . to . ), prevalence of asthma (or = . ; % ci, . to . ), and asthma symptoms (or = . ; % ci, . to . ). the associations between outcomes and no and soot exposures were similar, but there was a high correlation (r > . ) for pm . , no , and soot exposures. only % of the cohort were still living at the birth address at age years, and the associations between pollutants and outcomes were evident only in those who had not moved house; for the children who had moved from the birth addresses, the only significant association was between pm . and the prevalence of wheezing symptoms (or = . ; % ci, . to . ). the southern californian health study evaluated symptom-free children recruited in kindergarten or the first grade (≤ years old) from communities, each with continuous ambient ozone, no , pm . , and pm measurement. the incidence of asthma in the subsequent years was determined by annual questionnaires and correlated with individualized estimates of traffic-related pollution at home and at school. the incidence of asthma was increased by nonfreeway traffic-related pollution at home (hazard ratio [hr] = . ; % ci, . to . ) and at school (hr = . ; % ci, . to . ) . although the balance of evidence suggests an association between outdoor air pollution and the development of asthma in some individuals who live near busy roads, there does not appear to be an association between air pollution and the development of asthma at the population level. moreover, the welldocumented increase in asthma prevalence in the latter decades of the twentieth century cannot be readily explained by changes in levels of the major combustion pollutants. the emerging association between traffic-related emissions and asthma requires further investigation. in the home and other indoor environments, children and adults inhale diverse pollutants that may be associated with the risk for asthma. , they include combustion-source emissions from cooking stoves and ovens, space heaters fueled by gas or kerosene, wood-burning stoves or fireplaces, and tobacco smoking; volatile and semivolatile organic compounds released from household products, furnishings, and other sources; and allergens from insects, molds, mites, rodents, and pets. , many of these pollutants can be present in higher concentrations indoors than outdoors, providing a rationale for studies that have examined indoor pollutants as factors that may cause or exacerbate asthma. for example, in a prospective cohort study of inner-city u.s. children with asthma, indoor no and pm were associated with asthma symptoms. the associations were independent of each other and of outdoor the traffic-related air pollution and childhood asthma (trapca) study is a birth cohort study of children from the netherlands, germany, and sweden that is funded by the european union. preliminary results from the german children followed for their first years of life showed a % ( % ci, . to . ) increase in the risk of asthmatic, spastic, or obstructive bronchitis for those living close to major roads (< m) compared with children farther away. a cohort study of almost children between the ages of and years, who lived in nine communities surveyed in the california children's health study and four other communities, was started in to evaluate characteristics that might increase children's susceptibilities to the effects of traffic-related pollution. preliminary results showed that living within m of a major road was associated with an increased risk of physician-diagnosed asthma (or . ; % ci, . to . ), prevalent asthma (or = . ; % ci, . to . ), and wheeze (or = . ; % ci, . to . ). among long-term residents (i.e., living in the same home since the child was years old or younger) with no parental history of asthma, an increased risk of physician-diagnosed asthma (or = . ; % ci, . to . ), prevalent asthma (or = . ; % ci, . to . ), and wheeze (or = . ; % ci, . to . ) was associated with living within m of a major road. increased risk was not associated with the exposure for children with a parental history of asthma and for short-term residents. the adventist health study on smog (ahsmog) is a prospective cohort study that enrolled more than nonsmoking adults ( to years old) living in california in . in the first years of follow-up, abbey and colleagues examined incident asthma cases in relation to pm and found a % increased risk of asthma for a hr/yr exposure to concentrations of pm that exceeded µg/m . a later report on the ahsmog participants used the - -hour mean ozone concentration as the exposure and found that the risk of developing asthma doubled per parts per billion increase for males but not in females after adjusting for age, education, respiratory infection before age years, and smoking status. a systematic review commissioned by the u.k. committee on the medical effects of air pollution (comeap) was established to investigate whether outdoor air pollution causes asthma. this review identified cross-sectional studies relating asthma prevalence in more than four cities to quantitative pollution measures; the number of cities ranged from to and covered europe, north america, and asia. a metaanalysis revealed no significant associations between no , pm , or so and period prevalence of wheeze and lifetime prevalence of asthma. the review also identified studies of birth cohorts and studies of cohorts recruited during child or adulthood. in these studies, exposures were individualized by modeling, usually to the individual's home address. in contrast to the cross-sectional studies, meta-analysis revealed associations between no and the incidence of asthma (or = . ; % ci, . to . ; studies) and between pm . and the incidence of asthma (or = . ; % ci, . to . ; studies). the comeap systematic review concluded that the evidence from the cohort studies is consistent with a significant increase in the incidence of asthma associated with no and pm from traffic sources. the possibilities of air pollution aggravating existing subclinical asthma and residual confounding by factors associated with asthma and residential proximity to traffic were assessed early indoor allergen exposure and physician-diagnosed asthma or wheeze and did not find an association. they concluded that their results did not support the hypothesis that allergen exposure causes asthma. prospective cohort studies have studied the relationship between exposure to mold and the risk of asthma. a study of finnish children to years old used parents' reports of mold and dampness as a surrogate for exposure to aeroallergens in the home. after years of follow-up, exposure to mold was found to be an independent risk factor for asthma among finnish children. the incidence of physician-diagnosed asthma was double for children in homes with reported mold odor compared with those that did not. jaakkola and jaakkola reviewed the literature on indoor molds and asthma, and they concluded that exposure to molds at home increases the risk of asthma among adults and that exposure to molds at work increases the risk of wheezing. they observed that exposure to indoor molds increases the severity of asthma and that removing the source relieves or eliminates symptoms and signs of asthma. sensitization to mold has been linked to the presence, persistence, and severity of asthma. , a review of housing interventions designed to improve outcomes concluded that asthma symptoms could be reduced by removing moldy items and eliminating leaks and other moisture sources in homes. intervention studies with avoidance of aeroallergens and food allergens have not consistently found a reduction of asthma risk among children. the canadian childhood asthma primary prevention study included high-risk children who were randomized to intervention (i.e., avoidance of hdm by use of mattress covers and acaricides, pets, and passive smoking and encouragement of breastfeeding with delayed introduction of solid foods) or to control groups before birth. for children at years of age, the prevalence of physician-diagnosed asthma was significantly lower for the intervention group ( %) than for the control group ( %). another intervention study of a birth cohort of high-risk children living on the isle of wight assessed asthma (i.e., wheeze and bronchial hyperresponsiveness) prevalence at age years and found that the asthma risk was ninefold higher for the control group than the intervention group. intervention included breastfeeding by a mother on a low-allergen diet or giving a hydrolyzed formula and reducing hdm exposure with an acaricide and mattress covers. however, the australian childhood asthma prevention study, which included highrisk children randomized to an hdm avoidance intervention group or control group, did not find a significant reduction in the prevalence of current asthma at age years for the intervention group compared with the control group. a systematic review and meta-analysis of prospective birth cohort studies evaluating the effects of allergen (i.e., hdm or dietary) avoidance during pregnancy concluded that early-life allergen avoidance in isolation does not reduce the likelihood of asthma in children at age years (or = . ; % ci, . to . ). however, multifaceted antenatal intervention that combines breastfeeding with allergen avoidance and maternal smoking cessation does reduce the likelihood of asthma in children at age years (or = . ; % ci, . to . ). exposure to tobacco smoke has serious adverse effects on the respiratory tract. perhaps because of the sensitivity of the concentrations of the pollutant. a full examination of this literature is beyond the scope of this chapter, but reviews of indoor air pollution are available. whether these exposures by themselves, in the absence of underlying genetic susceptibility, can cause asthma is uncertain. however, mounting evidence indicates that maternal smoking is associated with an increased risk for asthma in offspring and later exacerbations of asthma (see "involuntary or passive smoking") and that levels of allergen exposure are associated with the incidence of asthma and wheezing. however, there have been only limited investigations of indoor air pollution and the incidence of asthma linked to risk factors other than passive exposure to tobacco smoke. an institute of medicine committee reviewed the evidence on indoor air pollution and childhood asthma and derived conclusions regarding causation and exacerbation. this topic also has been reviewed elsewhere. , several investigations have addressed the prevalence of asthma and exposure to nitrogen oxides from cooking stoves. homes with natural gas-fueled or propane-fueled cooking stoves tend to have no levels substantially above those of homes with electric stoves. some investigations indicate a general increased risk of respiratory symptoms, including wheezing, in households with gas stoves, but the data are inconsistent and not indicative of increased asthma incidence caused by nitrogen oxides. , the myriad exposures to volatile and semivolatile organic compounds that can occur in homes and other locales have been investigated as risk factors for childhood asthma. although many cross-sectional studies report an association between volatile organic compound exposure and asthma in children , and adults, , these studies cannot establish causality and are beset by the problem of reverse causality, whereby parents modify their houses (e.g., laminate flooring) as a consequence of their children developing asthma. cohort studies suggest that maternal volatile organic compound exposure during pregnancy can influence the development of childhood allergic disease. this is an area of ongoing research because of the potential for intervention by behavioral modification and low volatile organic compound technology. studies of indoor allergens have largely focused on the status of children with asthma in relation to levels of allergen rather than considering the levels of allergens as predictors of asthma. a prospective cohort study conducted in the united kingdom found levels of hdms in the home to predict later development of asthma, and children with higher levels of hdm antigen in their homes tended to wheeze at a younger age. the german multicentre allergy study followed children from birth to years of age and found that sensitization to perennial allergens such as hdms, cat hair, and dog hair that developed before years of age was associated with a loss of lung function at school age. a u.s. study of children indicated that exposure to two or more dogs or cats in the first year of life might reduce subsequent allergic sensitization risk to multiple allergens during childhood. not all studies support the conclusion that allergen exposure causes asthma. a british cohort study did not find a significant association between levels of hdm exposure and sensitization or wheeze. results from a german birth cohort of children followed until age years showed a strong association between sensitivity to hdm allergens or cat allergens and wheezing from years of age. however, the investigators also during pregnancy has also been associated with increased in vitro cord blood mononuclear cell proliferative and cytokine responses after stimulation with allergens. , there is extensive literature on the relationship between passive smoking and childhood wheeze and asthma. a systematic review identified relevant prospective cohort studies. exposure to maternal (prenatal and postnatal), paternal, and household sources of cigarette smoke was associated with an increased likelihood of children wheezing up to the age of years. the strongest associations for childhood wheeze were for postnatal exposure to maternal cigarette smoking: wheeze at years or younger (or = . ; % ci, . to . ), to years (or = . ; % ci, . to . ), and to years (or = . ; % ci, . to . ). the associations between exposure to maternal, paternal and household cigarette smoke and childhood asthma were not as strong as for wheeze, but they were most noticeable for maternal smoking during pregnancy: childhood asthma at years or younger (or = . ; % ci, . to . ) and to years (or = . ; % ci, . to . ). paternal smoking was associated with an increase in childhood asthma between and years, and household smoking was associated with an increase in childhood asthma after the age of years. the children's health study based in california reported a transgenerational association, suggesting that exposure to cigarette smoke in utero may have epigenetic effects. in a nested case-control study of children at years of age ( with asthma and controls), the likelihood of childhood asthma was increased if the mother (or = . ; % ci, . to . ) or the maternal grandmother (or = . ; % ci, . to . ) smoked during pregnancy. if the mother and grandmother smoked during pregnancy, the likelihood of childhood asthma was increased further (or = . ; % ci, . to . ). although allergic rhinitis is common, few epidemiologic studies have focused on this disease. the most frequently cited risk factors include increasing age, atopy, and high socioeconomic status. parental history is positively associated with the development of allergic rhinitis in offspring. in the tucson birth cohort study, a maternal history of physician-diagnosed allergy was significantly associated with a diagnosis of rhinitis by age years (or = . ; % ci, . to . ). perinatal and infant risk factors have been examined. for example, younger gestational age at birth has been associated with a decreased risk of allergic rhinitis. , some researchers have postulated that early-life exposures to microbes may modulate risk of allergic rhinitis, and this hypothesis has been supported by the observations that birth by cesarean section is a risk factor for allergic rhinitis, as is reduced diversity of the intestinal microbiota in infancy. other risk factors under investigation include genetics, early-life exposure to infections, acetaminophen use, oral contraceptive use, and indoor and outdoor air pollution exposure. risk factors for eczema include gender, race or ethnicity, family history, early-life antibiotic use, environmental exposures, and dietary factors, including breastfeeding, timing of the introduction of solids, and inclusion of probiotics. family history of asthmatic lung to cigarette smoke, young smokers tend to have somewhat greater lung function and less underlying airway responsiveness than nonsmokers-a phenomenon sometimes referred to as the healthy smoker effect. nonetheless, substantial data show that active smoking increases nonspecific responsiveness of the airways, perhaps by inducing inflammation or by narrowing baseline airway caliber in older people. smokers also tend to report wheezing more frequently than nonsmokers, and wheezing tends to decline after cessation of smoking. increased airway responsiveness in active smokers also tends to abate after smoking cessation. , a systematic review of studies exploring the temporal association between active smoking and asthma reported that most studies indicated that people who smoked were at increased risk for asthma. these studies evaluated diverse sample populations and used different methods, and the review highlighted the potential for residual confounding by health behaviors (e.g., physical exercise). the review concluded that although active smoking might be a risk factor for asthma, the evidence was insufficient to conclusively state whether smoking was a causal or proxy risk factor for asthma. the nonsmoking child is exposed to second-hand smoke, a name given to the mixture of sidestream smoke released by a burning cigarette and the mainstream smoke exhaled into the air by the smoker. this mixture has also been called environmental tobacco smoke. smoking adds respirable particles and irritant gases to indoor air, and it represents one of the major sources of fine particles in the air of u.s. homes. exposure of children to particles and gases in tobacco smoke has been documented by measuring personal exposures and using biomarkers that indicate the levels of tobacco smoke components absorbed into the body. cotinine, a major metabolite of nicotine, has been extensively investigated in children in relation to parental smoking. compared with children living in households in which there is no smoking, children living with smokers tend to have substantially higher cotinine levels. , in the past, exposure to second-hand smoke was widespread. almost all participants, including nonsmokers, in the - nhanes iii had detectable serum cotinine levels. ten years later, nhanes iv showed a dramatic reduction in cotinine levels, a trend that has continued. exposure to second-hand smoke contributes to both the causation and the exacerbation of asthma. first, passive smoking may increase the risk of more severe lower respiratory tract infections during the early years of life. second, the direct toxic effects of second-hand smoke may induce and maintain the heightened nonspecific responsiveness of airways found in asthmatic children. third, many children have secondhand smoke exposure during gestation and after birth. substantial evidence suggests that in utero exposure to tobacco smoke components affects fetal airway and immune system development. young and associates assessed nonspecific airway responsiveness using a histamine challenge for normal infants at a mean age of . weeks. even at this young age, parental smoking and a family history of asthma were associated with an increased level of airway responsiveness. in a similar prospective investigation, hanrahan and colleagues found that children whose mothers smoked during pregnancy had a lower level of airway function soon after birth. maternal smoking later epidemiologic studies provided a deeper understanding of the physiologic consequences of having childhood asthma and indicated that the lungs of these children might already have heightened airway responsiveness at birth. birth cohort studies that include indices of ventilatory function and airway responsiveness during the first weeks of life indicate that infants at risk for asthma because of a parental history of asthma and atopy already have heightened responsiveness to a challenge. the tucson study clarified the early natural history of wheezing. , martinez and colleagues described the natural history of wheezing beginning before years of age and found that some children had only transient early wheezing. children who continued to wheeze up to years of age were more likely to have mothers with a history of asthma and to have an elevated serum ige levels, suggesting that the early wheezing represented asthma. children whose wheezing did not persist had diminished airway function in early life but did not tend to have mothers with asthma or elevated ige levels. the pattern of persistence of wheezing during childhood and into adulthood was similar in a smaller cohort study of children in england, who were followed from birth to age years. in this highrisk cohort, early wheezing was not likely to persist, but wheezing at years of age did tend to persist. the results of these studies imply that clinicians should be cautious in labeling all early childhood illnesses with wheezing as asthma, because some children are predisposed to wheeze with respiratory infections because of reduced airway function. population-based groups of children have been followed over time in prospective cohort studies (table - ) . because most of these studies have drawn participants from defined populations, there is less potential for bias by the selection process, and the children with asthma are more likely to be representative. information collected from childhood to early adulthood is available from several investigations, including two particularly large studies involving lengthy follow-up: the cohort study in australia and the birth cohort study in the united kingdom. , findings of a number of smaller studies have been similar (see table - ). one of the first studies using a birth cohort design was conducted in australia, initially by williams and mcnicol. , [ ] [ ] [ ] on enrollment in , the children were years of age, and after years of follow-up, they were years old. [ ] [ ] [ ] wheezing tended to track over time, but % were no longer wheezing at years of age, and only % had wheezing at least weekly. those with more severe wheezing at age years tended to have a lower level of lung function tested by spirometry and to have a higher degree of airway responsiveness to a methacholine challenge. over time, some improved, but an approximately equal proportion worsened. at age years, % of the group with wheezy bronchitis at baseline was free of wheeze, and only % of this group had persistent asthma. symptoms continued in % of the original asthma group and in % of the severe asthma group. almost one half of the severe asthma group continued to have persistent asthma at age years. those with severe asthma had suffered a loss in lung function by years of age, but this loss did not progress in adulthood. children with milder symptoms did not have a significant loss of lung function. in another large, long-term study, members of the birth cohort in the united kingdom were followed up to age years. , , parents were interviewed when the participants eczema has been identified as a risk factor for eczema in several studies, pointing to genetic determinants of eczema. loss-offunction mutations in the filaggrin gene (flg), which encodes a protein critical to skin barrier function, have been directly linked to eczema, and approximately % of people heterozygous for these mutations develop eczema. black and asian race or ethnicity is a risk factor, along with male gender, , although isaac phase three found that worldwide, boys were less likely to have eczema than girls. earlylife exposure to endotoxin appears to protect against the development of eczema, as reported in several studies. , dietary factors, including breastfeeding, infant formulas, timing of solid food introduction, and supplementation with probiotics, have been studied. neither breastfeeding nor timing of solid food introduction has been associated with protection against eczema. [ ] [ ] [ ] [ ] [ ] [ ] evidence suggests that hydrolyzed infant formulas and supplementation with probiotics may afford some protection against eczema, , but study results are mixed, and infection by the probiotic organism has been reported in infants receiving probiotic supplementation. established risk factors for food allergy include male gender for children, eczema, and an atopic family history. [ ] [ ] [ ] other possible risk factors are diet and feeding practices during early childhood. controversy exists about whether early allergen introduction or allergen avoidance may predispose to the development of food allergy. the natural history of asthma is a concern for affected children, their parents, the clinicians providing care, and researchers. parents ask whether the child will outgrow asthma, and clinicians should be able to answer this question. researchers have studied the natural history of asthma and searched for factors that determine prognosis. during adulthood, the former asthmatic child may be exposed to environmental agents, including cigarette smoke, which may adversely affect respiratory health. childhood asthma has been postulated to increase the likely adverse effects of these exposures and other long-term consequences, such as persistent physiologic impairment from airway remodeling. , initial information on the natural history of childhood asthma largely came from cohort studies of children attending general practices or clinics. , these studies, some dating to the s, were a principal source of data on the natural history of asthma until population-based investigations were implemented beginning in the s. these early studies provided evidence of waning of clinical symptoms over time in a substantial proportion of children with asthma. however, most children tended to remain symptomatic. interpretation of these data is constrained by differences between past and current therapeutic approaches, possible lack of representativeness of children receiving care at a particular clinical facility, and by diversity of the research methods. these studies drew the participants from general practices and clinics, and presumably, more severe asthma was represented. nevertheless, they provide evidence that the prognosis is favorable for some children with asthma, even in an era antedating contemporary therapeutic approaches. bronchial challenge testing, and allergy testing. of the participants with complete data for the follow-up period, . % had persistent wheezing into adulthood, and only . % never reported wheezing. the remainder had various patterns of intermittent wheezing. predictors of persistent wheezing included sensitization to hdms, female sex, and smoking at age years. pulmonary function was reduced in those with persistent wheezing. evaluation of the natural history of asthma in adults is complicated by the occurrence of copd and the potential difficulty of separating copd from asthma. in adults, asthma includes disease originating in childhood and following its natural course into adulthood and asthma developing during the adult years. these natural histories have not been carefully delineated, although the lengthier studies of childhood asthma can provide information on its course into adulthood. there is less information on asthma in adulthood that is comparable to that on childhood asthma, such as the longitudinal picture of symptoms and clinical status. however, the effect of having asthma on the decline of lung function has been assessed, and there is limited information on the development of irreversible airflow obstruction in persons with asthma (table - ). the evidence on asthma and change in lung function over time is inconsistent with some studies showing were , , and years of age, and the participants themselves were interviewed at age and years. asthma tended to remit over time; of the children with a report of asthma or wheezy bronchitis before years of age, only % had wheezing in the last year at age years, although this figure increased to % at age years. lung function was evaluated in a sample of of the participants with a history of asthma or wheezy bronchitis and controls. for those not reporting wheezing at age years, lung function was only slightly reduced compared with controls. for those with wheezing, fev was reduced by approximately % compared with controls. similar results were found in a follow-up study of dutch individuals. subjects were extensively tested as children years earlier and reexamined as adults. the data revealed that % of persons were no longer considered asthmatic, % had an fev greater than % of predicted, % were no longer bronchial hyperresponsive, and % did not report asthmatic symptoms. results of these studies support the hypothesis that early intervention in mild asthma may lead to improved outcomes. in a longitudinal, population-based, cohort study carried out in dunedin, new zealand, children were enrolled, and a substantial proportion was followed to age years with repeated assessment by questionnaires, lung function testing, in the copd group and a -ml loss in the intermediate group. the balance of the evidence indicates that a diagnosis of asthma is associated with an increased rate of fev decline (see table - ). perhaps reflecting this excess decline, many elderly persons with asthma have fixed airflow obstruction. there are few studies on the clinical course of asthma in adults (table - ) , and as airway obstruction becomes fixed with advancing age, separating asthma from copd becomes increasingly difficult. in the study by schachter and coworkers, of the male participants age years or older with asthma, % improved and only % worsened during follow-up. among female participants, % improved and none worsened during follow-up. bronniman and burrows followed asthmatics, who were drawn from the general population sample in tucson, arizona, of persons, over a -year period. participants were classified as in remission if they had active disease at baseline and on follow-up denied medication use, asthma attacks, and frequent attacks of shortness of breath with wheezing during the preceding year. after years of follow-up, % were in remission, with the highest rate found among those between and years of age at enrollment ( %) and the lowest rate found for those between and years of age ( %). remission was more common in those with less frequent wheezing, less frequent asthma attacks, and less frequent attacks of shortness of breath with wheezing. remission was significantly less likely increased decline in persons with asthma compared with controls and others showing no difference between asthmatics and controls. peat and woolcock followed persons with asthma, who were to years old on enrollment, and control participants from busselton, australia. the asthmatic individuals had lower lung function values at enrollment and the fev declined at ml/yr more in the persons with asthma compared with the controls. schachter and colleagues followed the lung function of persons with asthma and with wheezing. over a -year interval, there was a similar excess loss of fev in the persons with asthma. ulrik and lange followed subjects over a -year period and found that asthmatic subjects had lower baseline lung function values and an excess annual decline in fev compared with nonasthmatics; the excess annual decline was ml in asthmatic men and ml in asthmatic women. some individuals with asthma appear to eventually develop irreversible airflow obstruction, which has been related to duration and severity of asthma. , a continuing effect of asthma was found when follow-up was extended to years. other studies have not shown increased loss of function associated with having a diagnosis of asthma. burrows and colleagues examined the course of asthma over years in asthmatics from the general population and compared them with two other groups: copd subjects and subjects who did not fit clearly into either group. the asthmatic subjects had a ml/yr decline in fev , compared with a -ml decline years. this was a highly selected group with many comorbidities, which probably influenced the eventual outcome. unfortunately, little is known about the outcome of elderly asthmatics that are not as ill. panhuysen and colleagues followed persons with asthma over years. the participants had been comprehensively evaluated in an asthma clinic in the netherlands between and at the ages of to years (mean, years). on retesting, % no longer showed bronchial hyperresponsiveness on histamine challenge, and based on a lack of bronchial hyperresponsiveness, symptoms, and lung function level, % were considered to no longer have asthma. settipane and colleagues followed a group of college students over years. half of those with asthma on follow-up reported the disease as inactive, although about % of the new cases occurred during follow-up. in those with chronic productive cough or a coexisting diagnosis of chronic bronchitis or emphysema. a normal level of percent predicted fev at baseline was the most powerful predictor of remission. persons to years old with active symptoms had only a % remission rate over years. broder and colleagues reported similar findings, with a remission rate of . % for patients between and years of age and % in those years of age or older. 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symptoms by sex, age and smoking in a community study early life risk factors for current wheeze, asthma, and bronchial hyperresponsiveness at years of age a -year follow up of a birth cohort study prognosis of asthma in childhood incidence and remission of asthma: a retrospective study on the natural history of asthma in italy comparison of a beta -agonist, terbutaline, with an inhaled steroid, budesonide, in newly detected asthma tenor study group. gender differences in igemediated allergic asthma in the epidemiology and natural history of asthma: outcomes and treatment regimens (tenor) study a comparison of bronchodilator therapy with or without inhaled corticosteroid therapy in obstructive airways natural history of asthma in childhood-a birth cohort study physician-diagnosed asthma and allergic rhinitis in manitoba: - food allergy as a risk factor for lifethreatening asthma in childhood: a casecontrolled study outcome of wheeze in childhood. symptoms and pulmonary function years later a sevenyear follow-up study of adults with bronchial asthma respiratory symptoms in young adults should not be overlooked lung function in young adults who had asthma in childhood childhood asthma and lung function in mid-adult life association between allergy and asthma from childhood to middle adulthood in an australian cohort study preschool wheezing and prognosis at wheezy bronchitis in childhood: a distinct clinical entity with lifelong significance? the state of childhood asthma in young adulthood decline in lung function in the busselton health study: the effects of asthma and cigarette smoking the characteristics of bronchial asthma among a young adult population mortality and decline in lung function in adults with bronchial asthma: a ten year follow up key: cord- - oti zg authors: panlilio, adelisa l; gerberding, julie louise title: occupational infectious diseases date: - - journal: textbook of clinical occupational and environmental medicine doi: . /b - - - - . - sha: doc_id: cord_uid: oti zg nan infections acquired in the work setting represent an eclectic group that is seldom, if ever, considered together as a single category. occupational infections involve several organ systems, respiratory, enteric, and skin infections being particularly common. transmission involves not only casual person-to-person contact, but also a variety of other routes in special work environments. it is thus important to consider what unique features characterize the infectious diseases that can be considered occupational. perhaps one useful way of thinking about these diseases is that, as a group, they tend to be transmitted during work schedules or practices that are systematized. therefore, they can be anticipated, and to the extent that unsafe infectionprone practices can be identified and modified, they can be systematically prevented. another common feature is that many of the occupational infectious diseases can be regarded as behavioral. to the extent that unsafe practices have been defined, and practice policies modified to reduce infection risk, continued transmission often represents failure to follow accepted standards. although certain occupational infections can be prevented by vaccines (e.g., hepatitis b), prevention often depends on simple behavioral changes, such as hand hygiene, use of gloves, and not working while ill. finally, the anthrax cases during the fall of in the united states demonstrate the possibility of intentional (and criminal) exposure to infectious agents in the workplace, in this instance among those handling mail. these intentional exposures, fortunately, are rare events, but should be considered in assessing sources of exposure for unexpected illnesses. prevention depends primarily on defining risky occupational practices or environments, clearly articulating policies for preventing communicable disease acquisition; removing structural barriers to compliance with policies (e.g., providing soap, hand cleansers, and gloves; allowing time away from work during periods of illness); and promoting healthy practices through behavioral change. because infectious diseases may represent the most common cause of time lost from work, it is important for the clinician concerned with occupational medicine to understand the relationship of specific infections to specific work environments and practices, and to give at least as much attention to prevention as to diagnosis and treatment. occupationally acquired infections have historically been associated with animal exposures and unsanitary work environments. modernization of agrarian techniques and improvement in sanitation have markedly decreased the incidence of these infections in the developed world, though they remain problematic in developing countries. while nearly all infectious diseases could conceivably be transmitted in the workplace, the emphasis here is on those that can be transmitted by casual contact or by specific workrelated exposures, with emphasis on diseases that are most common, most serious, or most readily prevented. healthcare settings pose a unique challenge because of the proximity of infectious patients, susceptible patients, and healthcare personnel. infections transmitted from personnel may have devastating effects on certain groups of patients, particularly the immunosuppressed. likewise, certain infections transmitted to personnel, such as multidrug-resistant tuberculosis, may have serious or even fatal, consequences. table . summarizes the microbial etiology, sources, routes of infection, categories of workers at risk, and clinical manifestations of selected infectious diseases that have occupational predilections. a detailed discussion of waterborne microbial diseases is also provided in chapter . because the treatment of occupationally acquired infections does not differ from that of infections acquired non-occupationally, the emphasis of this chapter is on the recognition and prevention of these infections. etiologic category, as well as the potential for recurrences, account for the high incidence of the common cold, even among healthy adults. colds are more common in the fall, winter, and early spring, perhaps because of increased crowding among children during the colder seasons. workers are most apt to acquire colds from exposure to young children in the home. secondary cases among coworkers may then develop. adults experience two to four colds each year, although the incidence among adult women exceeds that of men by a small margin, and smokers have a substantially increased risk. the modes of transmission of cold viruses are not entirely elucidated. for rhinoviruses, transmission among experimental subjects occurs most readily by direct handto-hand contact, with a case followed by autoinoculation of the mucous membranes of the eye or nose. such finger-tomucous membrane contact is ubiquitous and unavoidable. other viruses are transmissible by aerosolized droplets. the importance of fomites (such as drinking glasses, telephone receivers, and shared office equipment) as vectors of transmission has not been determined. clinical manifestations typical cold symptoms include nasal congestion, coryza, non-productive cough, sneezing, pharyngitis, and laryngeal irritation. fever is often low grade, or may be absent. viral upper respiratory infections usually resolve within - days, but longer durations are not uncommon. treatment, prevention, and control treatment for uncomplicated infections is symptomatic. decongestants are more useful in relieving symptoms than are antihistamines. expectorants, saline gargles, and other nonprescription remedies are useful in some cases. antibiotics should not be prescribed for the treatment of colds. colds are difficult to prevent. a policy of work restriction until symptoms improve may prevent the spread of colds but is likely to be impractical (table . ). the cost-benefit analysis of such an approach could be useful, especially in childcare and healthcare settings. hand washing after contact with nasal secretions may be helpful. care should be taken to use tissues when coughing or sneezing and to dispose of soiled tissues after use. epidemiology influenza is a self-limited respiratory illness caused by types a and b influenza virus. epidemics of influenza occur annually in the winter months. adults remain susceptible to the illness despite prior episodes of infection because the antigenic structure of influenza viruses changes frequently, leading to new epidemics. influenza is spread from person to person, primarily by the coughing and sneezing of infected persons or sometimes by direct contact, either with infected persons or a contaminated surface. the disease is easily transmitted, and a single index case may transmit to a large number of susceptible persons in a short period of time. adults and children typically are infectious from - days before through - days after the onset of symptoms. clinical syndromes an attack of influenza starts abruptly with fever, malaise, myalgia, and headache. respiratory symptoms mimicking those of the common cold and lower respiratory symptoms including dry cough also are frequent. fever resolves in uncomplicated cases in - hours, but other symptoms may persist for days to weeks. influenza pneumonia, associated with hypoxemia, cough, and interstitial infiltrates, is not common in healthy adults. elderly patients and those with underlying immunodeficiencies and chronic pulmonary diseases are at high risk for secondary bacterial pneumonias, often caused by streptococcus pneumoniae and less often by haemophilus influenzae and staphylococcus aureus. the diagnosis of influenza frequently is made on the basis of clinical symptoms and signs. however, influenza is very difficult to differentiate from respiratory illnesses caused by other pathogens on the basis of clinical symptoms alone. other pathogens that can cause similar symptoms include, but are not limited to, mycoplasma pneumoniae, adenovirus, respiratory syncytial virus (rsv), rhinovirus, parainfluenza viruses, and legionella species. many pathogens, including influenza, rsv, and parainfluenza, cause outbreaks in a seasonal pattern. laboratory confirmatory tests can be performed to differentiate influenza from other illnesses. appropriate patient samples to collect for laboratory testing can include a nasopharyngeal or throat swab from adults, or nasal wash or nasal aspirates, depending on which rapid test is used. samples should be collected within the first days of illness. rapid influenza tests provide results within hours; viral culture provides results in - days. most of the rapid tests are more than % sensitive for detecting influenza and more than % specific. because as many as % of samples that would be positive for influenza by viral culture may give a negative rapid test result, negative rapid tests should be followed by viral culture in a sample of the swabs collected. viral culture can also identify other causes of influenza-like illness when influenza is not the cause. serum samples can be tested for influenza antibody to diagnose acute infections. two samples should be collected per person: one sample within the first week of illness and a second sample - weeks later. if antibody levels increase from the first to the second sample, influenza infection likely occurred. because of the length of time needed for a diagnosis of influenza by serologic testing, other diagnostic testing should be used for rapid detection of possible outbreaks. during community outbreaks, specific virologic or serologic diagnosis is not necessary once the type(s) of influenza virus causing the outbreak have been identified. treatment, prevention, and control persons at high risk for serious morbidity (persons aged and older, persons with chronic underlying diseases) should receive influenza vaccine annually. immunization also is recommended for healthcare personnel and others at risk for transmitting influenza to high-risk patients ( had been associated with reduced work absenteeism and fewer deaths among nursing home patients. , most employers do not provide influenza prevention programs for workers outside the healthcare field. amantadine and rimantadine can reduce the duration of uncomplicated influenza a illness when administered within days of onset of illness in otherwise healthy adults. zanamavir and oseltamivir can reduce the duration of uncomplicated influenza a and b illness by approximately day compared with placebo. none of these antiviral agents has been shown to be effective in preventing serious influenza-related complications. to reduce the emergence of antiviral drug-resistant viruses, the duration of therapy should typically be no longer than days. both amantadine and rimantadine are indicated as prophylaxis for influenza a, but not for influenza b infection. oseltamivir has been approved as prophylaxis for influenza a and b. zanamivir has not been approved for prophylaxis, but has been shown to be as effective as oseltamivir in preventing febrile, laboratory-confirmed influenza illness. they are approximately - % effective in preventing illness from influenza a. chemoprophylaxis can be a component of influenza outbreak control programs. epidemiology the incidence of measles (rubeola) has steadily declined in the united states during the last decade and is no longer considered endemic. measles is a major cause of morbidity and mortality worldwide. the majority of cases in the united states in recent years have been imported or secondary cases epidemiologically linked to imported cases. infected persons are highly contagious by the air-borne route during the viral prodrome, and when cough and coryza are prominent, until about days after the rash appears. infection confers lifelong immunity. although most adults born prior to experienced childhood infection and are no longer susceptible, up to % may lack natural immunity. in recent epidemics, cases occurred among unimmunized children, as well as children and young adults who had received a single vaccination with live virus, and among older adults. clinical syndromes measles progresses in several phases. initial virus replication occurs in the respiratory tract and leads to a primary viremic phase, which usually is asymptomatic. release of virus from infected reticuloendothelial cells produces secondary viremia and infection of the entire respiratory system, accompanied by symptoms of coryza, cough, and in some, bronchiolitis or pneumonia. koplik's spots, a bluish-gray enanthem most prominent on the buccal mucosa, precede development of the rash. in a typical case of measles, the rash begins on the face, then progresses to the trunk and distal extremities, and disappears in the same sequence after - days. treatment, prevention, and control live-attenuated vaccine for prevention of measles became available in the early s. all healthy children should receive the vaccine at age months. because % do not respond to a single dose of vaccine, a second dose is now recommended to improve vaccine efficacy. all healthy adults born after who have not received two doses of live virus vaccine or have not experienced measles also are advised to receive vaccine (table . ). persons who received killed vaccine have a risk of developing atypical measles, and require re-immunization with live virus vaccine. live virus vaccine is contraindicated in infants, pregnant women, and immunosuppressed persons. passive immunization with γ globulin is available for unimmunized persons exposed to infected individuals, but is not routinely recommended for adults. measles rarely can exacerbate tuberculosis and cause a temporary inhibition of delayed hypersensitivity. vaccine administration should be delayed for month after tuberculin testing, and until treatment is under way in persons with active tuberculosis. epidemiology mumps is a viral illness transmitted by the oral or respiratory route during contact with contaminated fomites or aerosolized droplet secretions. mumps is less contagious than measles or rubella but produces significant morbidity, especially among adults. the incubation period ranges from to weeks. virus is detectable for days prior to and days after the appearance of symptoms. most adults are immune to mumps, but - % of unimmunized adults have no serologic evidence of prior infection and are considered susceptible. mumps incidence is now very low in all areas of the united states. the substantial reduction in mumps incidence during the past few years likely reflects the change in the recommendations for use of measles mumps rubella (mmr*) vaccine. clinical syndromes parotitis typically is bilateral, but unilateral disease and involvement of other salivary glands occurs in some persons. localized parotid tenderness and swelling, fever, and painful swallowing suggest the diagnosis. aseptic meningitis is common but benign. encephalitis is a rare but serious manifestation. about % of affected postpubescent men develop orchitis, epididymitis, or both, which is bilateral in % of cases and may be the sole manifestation of mumps infection. about % of cases of mumps orchitis result in testicular atrophy, but neither sterility nor impotence are common sequelae. oophoritis occurs in about % of women with mumps. vaccine separated by at least month (i.e., a minimum of days), and administered on or after the first birthday, are recommended for all children and for certain highrisk groups of adolescents and adults. adult men and healthcare personnel with no history of mumps or mumps immunization should be screened for immunity and vaccinated if they are susceptible. immunization is contraindicated in persons with immunosuppression and in pregnant women (table . ). passive immunization with mumps immune globulin decreases the incidence of orchitis and is recommended for mumps in adult men with a single testis. individuals with active mumps should be excluded from work until days after the onset of parotitis to avoid transmission to others in the workplace (table . ). epidemiology fifth disease, also called erythema infectiosum or 'slapped cheek disease', is an infection caused by parvovirus b . it is a common rash illness that is usually acquired in childhood, but can be an occupational risk for school and childcare personnel. it has been transmitted to personnel in healthcare settings. clinical syndromes symptoms begin with mild fever and symptoms of fatigue. after a few days, the cheeks take on a flushed 'slapped' appearance. there may also be a lacy rash on the trunk, arms, and legs. not all infected persons develop a rash. the child is usually not very ill, and the rash resolves in - days. most persons who get fifth disease are not very ill and recover without any serious consequences. an adult who is not immune can be infected with parvovirus b and either have no symptoms or develop the typical rash of fifth disease, joint pain or swelling, or both. usually, joints on both sides of the body are affected. the joints most frequently affected are the hands, wrists, and knees. the joint pain and swelling usually resolve in a week or two, but they may last several months. about % of adults, however, have been previously infected with parvovirus b , have developed immunity to the virus, and cannot get fifth disease. fifth disease is believed to be spread through direct contact, fomites, or large droplets. the period of infectivity is before the onset of the rash. once the rash appears, a person is no longer contagious. the incubation period is - days but may be as long as days. treatment, prevention, and control symptomatic treatment for fever, pain, or itching is usually all that is needed for fifth disease. adults with joint pain and swelling may need to rest, restrict their activities, and take anti-inflammatory medications to relieve symptoms. transmission can be prevented by careful attention to hygiene, especially hand washing. no special precautions are necessary. excluding persons with fifth disease from work, childcare centers, or schools is not likely to prevent the spread of the virus, since people are contagious before they develop the rash. epidemiology pertussis, or whooping cough, is an acute infectious disease caused by the bacterium bordetella pertussis. pertussis continues to be an important cause of mortality in the united states. a dramatic decline in the incidence followed the widespread use of whole-cell pertussis vaccines in the mid- s. however, since the early s, the reported pertussis incidence has increased cyclically with peaks occurring every - years. , contributing to this increase in incidence is the waning of immunity over time following vaccination, particularly in older age groups. transmission most commonly occurs by contact with respiratory secretions or large aerosol droplets from the respiratory tracts of infected persons and less frequently by contact with freshly contaminated articles of an infected person. analysis of national surveillance data for pertussis during - indicates that pertussis incidence continues to increase in infants too young to receive three doses of pertussis-containing vaccine and in adolescents and adults. clinical syndromes the incubation period of pertussis is commonly - days. pertussis begins insidiously with non-specific upper respiratory symptoms including coryza, sneezing, low-grade fever, and a mild, occasional cough, similar to the common cold. the cough gradually becomes more severe, and after - weeks, the second, or paroxysmal stage, begins. characteristically, the patient has paroxysms of numerous, rapid coughs generally with a characteristic high-pitched whoop, commonly followed by vomiting and exhaustion. the patient usually appears normal between attacks. older persons (i.e., adolescents and adults), and those partially protected by the vaccine may become infected with b. pertussis, but usually have milder atypical disease. pertussis in these persons may present as a more persistent cough of greater than days duration, and may be indistinguishable from other upper respiratory infections. inspiratory whoop is uncommon. b. pertussis is estimated to account for up to % of cough illnesses per year in older persons. even though the disease may be milder in older persons, these infected persons may transmit the disease to other susceptible persons, including unimmunized or underimmunized infants. the medical management of pertussis cases is primarily supportive, although antibiotics are of some value, with erythromycin being the drug of choice. this therapy eradicates the organism from secretions, thereby decreasing communicability and, if initiated early, may modify the course of the illness. there is no pertussis-containing vaccine (including dtap) currently licensed for persons years of age or older, and vaccination with dtap currently is not recommended after the th birthday. vaccine reactions are thought to be more frequent in older age groups, and pertussis-associated morbidity and mortality decrease with increasing age. studies are currently under way to determine if a booster dose of acellular pertussis vaccine administered to older children or adults may reduce the risk of infection with b. pertussis. this may in turn reduce the risk of transmission of b. pertussis to infants and young children who may be incompletely vaccinated. studies among older children, adolescents, and adults examining pertussis disease burden and transmission of disease to infants might guide future policy decisions on the use of acellular pertussis vaccines among persons more than seven years of age. currently, vaccination of children more than years of age, adolescents, and adults is not recommended either routinely or as an outbreak control measure. in the future, licensure of pertussis vaccines for adolescents or adults may lead to new recommendations for the use of vaccines in outbreaks. epidemiology most epidemics of bacterial pneumonia in the workforce are due to community-acquired infections. however, legionellosis is one type of pneumonia which can be transmitted in the workplace. legionella pneumophila is an important cause of both epidemic and endemic adult pneumonia, and it can be associated with outbreaks in the workplace. this organism colonizes aquatic ecosystems and potable water, and it is transmitted to humans by the air-borne route. contaminated air conditioners, humidifiers, and shower heads have been implicated in outbreaks among workers and hospital patients. outbreaks of legionellosis have occurred after persons have breathed mists that come from a water source (e.g., air conditioning cooling towers, whirlpool spas, showers) contaminated with legionella bacteria. persons may be exposed to these mists in homes, workplaces, hospitals, or public places. legionellosis is not passed from person to person. a careful occupational history should be obtained from all adults who present with pneumonia, because occupational exposures cause many otherwise rare pneumonias. public health authorities should be notified if an occupational source is suspected so that an epidemiologic investigation to identify transmission routes and other susceptible individuals may commence. clinical pneumonia syndromes community-acquired bacterial pneumonia usually is exhibited acutely, with fever, chills, productive cough, and often, pleurisy. chest examination demonstrates signs of consolidation that may be confirmed radiologically. sputum examination may aid implementation of empiric therapy by suggesting the etiologic pathogen. blood cultures should be obtained when invasive disease is suspected, and lumbar puncture to evaluate meningeal fluid is indicated when symptoms or signs of meningitis are present. patients with legionnaire's disease usually have fever, chills, and a cough, which may be dry or productive. some patients also have muscle aches, headache, tiredness, loss of appetite, and, occasionally, diarrhea. chest x-rays often show pneumonia but are not pathognomonic. it is difficult to distinguish legionnaire's disease from other types of pneumonia by symptoms alone; other tests are required for diagnosis. the definitive test is culture isolation of the organism in sputum, bronchoalveolar fluid, or pleural fluid. other useful diagnostic tests detect the bacteria in sputum by specialized stains, identify legionella antigens in urine samples, or compare antibody levels to legionella in two blood samples obtained - weeks apart. the time between the patient's exposure to the bacterium and the onset of illness for legionnaire's disease is - days. treatment, prevention, and control empiric ambulatory therapy of acute community-acquired bacterial pneumonia, not requiring hospitalization, should include coverage for pneumococcus and h. influenzae, if the patient has a history of chronic obstructive lung disease. amoxicillin, trimethoprim-sulfamethoxazole and cefixime are reasonable choices, unless atypical pneumonia caused by m. pneumoniae or c. pneumoniae is suspected, in which case erythromycin is preferred. erythromycin is the antibiotic currently recommended for treating persons with legionnaire's disease. in severe cases, a second drug, rifampin, may be added. preventing bacterial pneumonia is a difficult challenge. workers at risk for pneumococcal and haemophilus infections should be immunized, although the efficacy of this approach among patients at highest risk is debated (table . ). influenza immunization could eliminate a major risk factor for both primary and secondary bacterial pneumonias. occupational exposures to potential pathogens should be minimized with proper ventilation. prevention of legionellosis is achieved by maintaining an environment that is not conducive to survival or multiplication of legionella. the necessary preventive measures may involve water treatment or modification of air conditioning and ventilation systems. these preventive steps, which may be costly, should be directed at healthcare facilities, and occupational settings where cases have been identified. epidemiology rubella (german measles) virus is transmitted person to person by mucosal exposure to infected droplets of respiratory secretions. since , children in the united states have been routinely immunized against rubella at age months, so that the majority of recognized cases today occur in adults and unimmunized children. since , reported indigenous rubella has continued to occur at a low but relatively constant endemic level with an annual average of less than rubella cases. recent data indicate that the rate of rubella susceptibility and risk for rubella infection are highest among young adults. no large epidemics have occurred since the vaccine was licensed for use in . however, outbreaks continue to occur among groups of susceptible persons who congregate in locations that increase their exposure, and among persons with religious and philosophic beliefs against vaccination. several recent outbreaks have occurred in workplaces where most employees are foreign born, particularly from latin america. reinfection can occur following natural or acquired immunity, but it is usually asymptomatic and only rarely accompanied by viremia. rubella virus is shed from the respiratory tract of infected persons beginning days before the development of rash and for several days after the rash appears. the onset of the rash coincides with the period of maximal contagiousness, and infected persons are not considered infectious for more than days after the rash appears. infected infants shed virus for several months despite the presence of antibody. clinical syndromes adult rubella is often asymptomatic. symptoms occur - days after exposure. following a prodrome of fever and malaise, adults exhibit a maculopapular rash that begins on the face and extends downward, persists for - days, and often is accompanied by regional lymphadenopathy of the head and neck, which persists for days to weeks. one-third of adult women may develop arthritis in the fingers, knees, and wrists during the exanthematous phase of illness. children develop hemorrhagic complications more often than adults. in contrast, encephalitis, albeit rare, is more common in adults and is fatal in - % of cases. maternal rubella infection acquired in the first weeks of gestation frequently results in congenital rubella. the earlier in pregnancy rubella occurs, the more severe the fetal consequences. infection in the first trimester results in deafness, congenital heart disease, cataracts or glaucoma, endocrine abnormalities, and mental retardation in up to % of newborns. spontaneous abortion also occurs commonly. treatment, prevention, and control immunization of children and susceptible adults with live attenuated rubella virus effectively prevents rubella and accounts for the dramatic decline in the incidence of this disease in the united states. however, many adult women of childbearing age remain susceptible to rubella and require immunization prior to conception to prevent congenital rubella. the hemagglutination-inhibition serologic assay detects natural or acquired immunity. the advisory committee on immunization practices (acip) recommends screening of healthcare personnel who have not been vaccinated, and immunization of susceptible individuals. complications of rubella vaccine occur among adults and include lowgrade fever, symmetric polyarthralgias, distal paresthesias, lymphadenopathy, and rash. vaccine is contraindicated in immunosuppressed persons and pregnant women. pregnancy should be avoided for months after vaccination (table . ). susceptible household contacts of infected adults and children pose a transmission risk in the workplace during the period of virus shedding, beginning about days before the development of rash (about week after exposure) until days after rash appears. therefore, susceptible individuals should not report to work during this time interval (table . ). epidemiology tuberculosis (tb) is caused by mycobacterium tuberculosis and, rarely today, by m. bovis. the incidence of tuberculosis (tb) in the united states declined steadily until the mid- s, but then sharply increased, especially in urban areas. the resurgence of tb in the united states in the late s and early s was associated with the emergence of multidrug-resistant tb (mdr-tb) and the hiv/aids epidemic. with this resurgence of tb in the united states came several high-profile nosocomial outbreaks associated with lapses in infection control practices and delays in diagnosis and treatment of persons with infectious tb, as well as the appearance and transmission of mdr-tb strains. since , the declines in the overall number of reported tb cases, including the level of mdr-tb, appear to reflect successful efforts to strengthen tb control following the resurgence of tb and the emergence of mdr-tb. activities emphasizing the first priority of tb control (i.e., promptly identifying persons with tb, initiating appropriate therapy, and ensuring completion of therapy) have been the most important factors in achieving this improvement. such activities reduced community transmission of m. tuberculosis, particularly in areas with a high incidence of aids. improvements in implementation of infection control measures in healthcare settings, concurrent with mobilization of the nation's tb control programs, succeeded in reversing the upsurge in reported cases of tb, and case rates have declined to their lowest levels to date. the threat of mdr-tb is decreasing, and the transmission of tb in healthcare facilities continues to abate due to implementation of infection controls and reductions in community rates of tb. nevertheless, some healthcare personnel are at risk for acquiring tb. pulmonary tb is most commonly transmitted in healthcare settings by inhalation of aerosolized droplet nuclei derived from the respiratory secretions of patients with active respiratory tb. close contact usually is required. most other categories of workers generally are not at risk without close and sustained workplace contact with a person who has active untreated disease. ingestion of unpasteurized milk from cows infected with m. bovis is no longer an important source of tb in most industrialized countries. clinical syndromes primary infection usually is asymptomatic in adults. teenagers and young adults are at higher risk for rapid progression to active disease, usually characterized by apical cavitary disease, than are older adults. primary infection in the elderly usually is exhibited as lower lobe consolidation with hilar adenopathy. primary tuberculosis in persons with advanced hiv infection is commonly symptomatic and progressive. once infection occurs, the organism may disseminate from the lungs to other sites, including the gastrointestinal and genitourinary tracts, and bone. normally, the infection is contained by the host's immune response at this stage. the risk for reactivation is highest in the first year after exposure and declines thereafter. however, aging and stressors such as immunosuppression, intercurrent illness, and chronic malnutrition may increase the risk for reactivation or dissemination of the disease later in life. clinically, reactivation tuberculosis usually is exhibited as upper lobe pulmonary cavitary disease, but virtually any organ system may be involved. treatment, prevention, and control tuberculin skin testing allows determination of prior exposure to tb in immunologically healthy adults, by assessing delayed hypersensitivity to tuberculin antigens using purified protein derivative. the tuberculin skin test (tst) is the only proven method for identifying infection with m. tuberculosis in persons who do not have tb disease. although the available tst antigens are neither % sensitive nor specific for detection of infection with m. tuberculosis, no better diagnostic methods have yet been devised. the preferred skin test for diagnosing m. tuberculosis infection is the mantoux test. it is administered by injecting . ml of tuberculin units (tu) ppd intradermally into the dorsal or volar surface of the forearm. tests should be read - h after test administration, and the transverse diameter of induration should be recorded in millimeters. there are three cut-off levels recommended for interpretation of the tst results. in hiv-infected persons, any reaction resulting in an induration larger than mm is read as positive. among others, the presence of mm or more of induration always indicates a positive test, - mm indicates a positive result in persons at risk for tb, and less than mm is negative. a positive tst means an individual has been exposed to tb in the past and is at risk for reactivation. a baseline chest radiogram should be performed on all persons with newly diagnosed tst positivity. if the x-ray study suggests active disease, sputum samples should be obtained, stained for acid-fast bacilli, and cultured for mycobacteria. treatment should be implemented immediately if the index of suspicion is high. public health officials should be notified to institute case management and evaluation of contacts in the home and work environment. if the x-ray study is negative, treatment with isoniazid to suppress or eradicate latent organisms may be recommended, especially in persons younger than age and for those who have recently converted to positive tsts. although bcg vaccine is the most widely administered of all vaccines in the world, and has the highest coverage of any vaccine in the who expanded programme on immunization, it appears to have had little epidemiologic impact on tb. despite its shortcomings, and because of its beneficial effect in children and against leprosy, bcg vaccine likely will remain a component of childhood vaccination strategies in developing countries. however, because of questions about the vaccine's efficacy, and because it induces dermal hypersensitivity to purified protein derivative (ppd) tuberculin in most recipients, bcg has never been recommended for programmatic use in the united states. healthcare providers should follow appropriate infection control procedures, including use of isolation rooms and respiratory protection, when caring for patients with active tuberculosis. , varicella/zoster epidemiology varicella virus, the causative agent of chickenpox and zoster, is a highly contagious herpes virus spread by the respiratory route from person to person. the incubation period is about days, and the period of infectivity begins a few days prior to the onset of the rash to about days after the first crop of vesicles appears. immunosuppression usually prolongs the period of infectivity, especially if varicella zoster immune globulin (vzig) has been administered. zoster represents reactivation of varicella virus that is latent in sensory nerve ganglia, and it is not a manifestation of primary infection except in newborns infected in utero. the incidence of zoster increases with age and immunosuppression. susceptible persons in direct contact with zoster lesions risk developing primary varicella. in the prevaccine era, varicella was endemic in the united states, and virtually all persons acquired varicella by adulthood. as a result, the number of cases occurring annually was estimated to approximate the birth cohort, or approximately million per year. this incidence has likely decreased since licensure of the vaccine in . varicella is not a nationally notifiable disease, and surveillance data are limited. clinical syndromes varicella in otherwise healthy children usually is a benign, self-limited disease characterized by low-grade fever and vesicular rash, often preceded by a viral prodrome. varicella vesicles of primary infection appear first on the scalp and trunk and disseminate in crops showing various stages of development over the next - days. healing results in crusting accompanied by intense pruritus. manifestations of varicella are more severe in adults than in children. about % of adults with varicella show radiographic evidence of pulmonary involvement, but this is rarely clinically significant. however, cough, tachypnea, and impaired gas exchange can occur and persist for months after infection. varicella during pregnancy can produce congenital varicella. in its most severe form, this infection can result in mental retardation, blindness, growth retardation, deafness, chorioretinitis, and a peculiar dermatomal lesion of the upper or lower extremity associated with limb atrophy. zoster, the most common manifestation of varicella infection among adults, characteristically produces unilateral vesicular eruptions preceded by pain in one to three dermatomes. disseminated zoster, which is more likely in immunosuppressed patients, probably poses the same risk of infection transmission as primary varicella infection. the major complication of zoster is postherpetic neuralgia, which is especially common in the elderly and may be extremely debilitating. zoster frequently produces cerebrospinal fluid pleocytosis and occasionally encephalitis. immunologically healthy persons may experience recurrences of zoster, usually in the same dermatome as the initial outbreak. zoster is a marker of deteriorating cellmediated immunity among hiv-infected patients, and it may disseminate. treatment, prevention, and control passive immunization with vzig is recommended for immunosuppressed susceptible persons, children with leukemia and other malignancies, and neonates exposed in utero within days before delivery. several antiviral drugs are active against varicella zoster virus, including acyclovir, valacyclovir, famciclovir, and foscarnet. famciclovir and valacyclovir are approved for use only in adults. clinical studies indicate that these drugs may be beneficial if given within hours of onset of rash, resulting in a reduction in the number of days new lesions appeared, in the duration of fever, and in the severity of cutaneous and systemic signs and symptoms. antiviral drugs have not been shown to decrease transmission of varicella, reduce the duration of absence from school, or reduce complications. oral acyclovir can be considered in otherwise healthy adolescents and adults or secondary cases in the household, because of the increased risk of severe illness in these groups. antiviral therapy may also be considered for persons with chronic cutaneous or pulmonary disorders, persons receiving long-term salicylate therapy, and for children receiving short, intermittent or aerosolized courses of corticosteroids. antiviral drugs are not recommended for routine postexposure prophylaxis. systemic steroids in older adults (more than years old) may reduce the incidence and severity of postherpetic neuropathy if started early (within days of skin manifestations). varicella has been difficult to prevent because of the high degree of contagion in households, schools, and healthcare settings. live attenuated virus vaccines have demonstrated efficacy in preventing primary infection, and one was licensed for use in the united states in . routine immunization is now recommended for children less than months of age. varicella vaccination should be given to susceptible adolescents and adults who are at high risk of exposure to varicella. this group includes persons who live or work in environments in which there is a high likelihood of transmission of varicella, such as teachers of young children, residents and staff in institutional settings, and military personnel. varicella vaccination is also recommended for susceptible adolescents and adults who will have close contact with persons at high risk for serious complications of acquired varicella, including healthcare personnel and susceptible family contacts of immunocompromised individuals. the acip recommends that all healthcare personnel be immune to varicella, either from a reliable history of prior varicella infection or vaccination, to reduce the risk of infection and its complications, and to decrease the possibility of transmission of varicella zoster virus to patients (table . ). susceptible adults exposed to children with varicella or with disseminated zoster pose a risk of transmitting varicella to non-immune coworkers, and they should not work until the incubation period is over or, if they become ill, until all lesions are crusted (table . ). dermatomal zoster is not spread efficiently by the air-borne route and otherwise healthy adults afflicted with this illness may be allowed to work if they can avoid touching the lesions and contaminating the work environment. the role of vaccine in the postexposure management of susceptible employees needs to be elucidated. data from the united states and japan in a variety of settings indicate that varicella vaccine is effective in preventing illness or modifying the severity of illness if used within days, and possibly up to days, of exposure. acip recommends vaccine be used in susceptible persons following exposure to varicella. personnel should be excluded from work who have onset of varicella until all lesions have dried and crusted (table . ). following exposure to varicella, personnel who are not known to be immune to varicella (by history or serology) should be excluded from duty beginning on the th day after the first exposure until the st day after the last exposure ( th day if vzig was given). epidemiology acute gastrointestinal infection follows upper respiratory illness as the next leading category of infectious diseases causing absenteeism among adult workers. a wide array of pathogens, including viruses, bacteria, and protozoa, can result in acute infections of the stomach, small bowel, or colon. a comprehensive discussion of enteric pathogens is provided in chapter (waterborne microbial diseases). most of the etiologic agents are acquired by the fecal-oral route; produce mild, self-limited diseases; and resolve without specific therapy. agents of dysentery (e.g., shigella spp.) often are highly transmissible through low-inoculum exposures. occupational transmission of food-borne or water-borne illnesses occurs; person-to-person transmission has propagated outbreaks of many of these illnesses in healthcare settings, daycare and nursery schools, and institutions where sanitation is poor. instances of such transmission have generally involved food handlers, who are often poorly trained and short-term employees, serving as sources of transmission to others. occupations requiring travel to countries with poor sanitation present a major risk for gastrointestinal infections. poultry workers are frequently exposed to salmonella infections. avoidance of oral contact with sources of fecal contamination is the most important strategy for preventing transmission of pathogens associated with intestinal infections. maintaining good personal hygiene, including careful hand hygiene after using restrooms and before food preparation; proper cooking and storage of foods; and avoidance of contaminated foods and water when traveling are essential prevention strategies. food handlers with diarrheal illnesses should not work until symptoms have resolved, and cure of bacterial infections should be documented by obtaining negative stool cultures more than hours after antimicrobial therapy is completed (table . ). the only vaccines for any of the etiologic agents for acute enteric infections are for typhoid and hepatitis a, which are recommended for personnel in laboratories who frequently work with salmonella typhi or hepatitis a virus (table . ). epidemiology cytomegalovirus (cmv) is a ubiquitous herpes virus transmitted by direct inoculation with infected body fluids (including blood, blood products, respiratory secretions, saliva, and urine) and through sexual contact with infected partners. at least % of healthy adults have serologic evidence of prior cmv infection. infection can be acquired perinatally, in utero during maternal primary infection, during birth by passage through infected vaginal secretions, or through ingestion of infected breast milk. cmv is known to be highly transmissible in daycare centers and nursery schools. sexually active adults and recipients of blood products are also at high risk for infection. infants and young children excrete cmv in their urine, saliva, and respiratory secretions for several months after infection. virus is much less readily detected in healthy adults, but intermittent shedding has been documented. like all herpes viruses, cmv remains latent in the host after initial infection. previously infected persons may be reinfected with new strains of cmv. occupational transmission of cmv has been documented in childcare settings, where person-to-person spread through exposure to infected secretions and urine is believed to provide an efficient mode of transmission. up to % of seronegative workers in preschool daycare centers have acquired cmv infection in some studies, indicating a potentially serious risk to women of child-bearing age, because of the adverse effects of primary maternal cmv infection on the fetus. at one time, employment in healthcare settings also was believed to pose a high risk for cmv acquisition. however, epidemiologic investigations suggest that most infections in healthcare personnel are acquired sexually, or from exposure to young children in the home, and not from work-related contact. is asymptomatic in healthy persons. a self-limited mononucleosis-like illness occurs in a minority, which may be complicated by hepatitis, pneumonitis, hematologic abnormalities, and myocarditis. immunosuppressed children and adults with primary cmv infection, reactivation, or reinfection may develop severe sequelae. organ transplant recipients, hiv-infected patients, and persons with malignancies have a risk of developing cmv viremia, pneumonia, hepatitis, pancreatitis, enteritis, and retinitis. primary cmv infection at any stage of pregnancy carries a greater risk to the fetus than does recurrent cmv infection during pregnancy. symptoms of congenital cmv infection may be present at birth, and are due to the consequences of active virus replication and resultant end-organ damage. congenital cytomegalic inclusion disease, the most severe form of this entity, includes central nervous system disease, respiratory distress, hepatitis, hepatosplenomegaly, rash, and multi-system failure. infection acquired from exposure to cervical cmv during birth usually is asymptomatic and detected by the onset of virus shedding - weeks postpartum. with ganciclovir or foscarnet for cmv infection is reserved for immunosuppressed persons at high risk for severe complications. the safety and effectiveness of these agents in preventing congenital cmv have not been established. avoidance of mucosal contact with infected body fluids is the best strategy for preventing cmv transmission. hand washing after contact with secretions and fomites is essential, especially in nurseries and daycare settings. the presence of persons at risk for cmv shedding in the workplace does not pose a hazard to other employees unless direct contact with infected secretions is anticipated. isolation of infected neonates or children is not essential if hand washing is performed after contact with secretions, blood, and urine. pregnant healthcare providers compliant with hand washing protocols can generally safely care for patients with cmv infection. [ ] [ ] [ ] no work restriction is necessary for individuals with cmv infection (table . ). direct exposure to blood and other infected body fluids. children born to infected mothers are at high risk for hbv infection. persons parenterally exposed to blood, including multi-transfused patients, hemophiliacs, dialysis patients, and injection drug users, also are at significant risk. sexual contact with infected partners is another efficient mode of hbv spread. in most industrialized countries, adult infections usually are acquired sexually or by injection drug use. hbv is a relatively hardy virus capable of surviving on environmental surfaces and fomites. transmission in households is well documented and may, in part, be attributable to mucosal contact with fomites contaminated with secretions or blood from infected persons. healthcare personnel and others at risk for occupational blood exposure through percutaneous, mucosal, or dermal routes can acquire hbv infection. the risk associated with accidental needle-stick inoculation of infected blood to susceptible healthcare personnel varies between % to %, depending on the hepatitis b e antigen (hbeag) status, and hence the viral titer of the source. in up to % of occupational infections, a discrete exposure cannot be identified. hepatitis b has an incubation period of - days. the period of infectivity precedes the development of jaundice by - weeks and correlates with the presence of hepatitis b surface antigen (hbsag) in the serum; - % of persons with acute (but often clinically silent) infection develop chronic antigenemia. in the united states, up to % of adults are carriers of hbv, and provide a reservoir for maintenance of the disease in the population. apparent hepatitis in about one-third of acutely infected adults. clinical hepatitis may be preceded by a prodrome of fever, malaise, urticarial or maculopapular rash, and arthralgias for several days. fever usually resolves before the onset of jaundice. jaundice, dark urine, and scleral icterus usually are present by the time patients seek medical attention. right upper quadrant tenderness, mild hepatic enlargement, and occasionally, splenomegaly are signs that should suggest the diagnosis. the most striking laboratory abnormality is the finding of extreme elevations in the aminotransferase enzymes. alanine aminotransferase (alt) and aspartate aminotransferase (ast) may be elevated to more than times the normal levels, whereas the bilirubin and alkaline phosphatase levels are increased to a much lesser extent. fulminant liver involvement occurs in about % of adults and may be complicated by more serious abnormalities, including hypoglycemia, coagulopathy, and hypoalbuminemia. hepatic encephalopathy, hepatorenal syndrome, and bleeding diatheses are life-threatening complications seen in these patients. about % of adults with clinically apparent acute hbv infection proceed to chronic hbs-antigenemia, and are at risk for chronic hepatitis, postnecrotic cirrhosis, and primary hepatocellular carcinoma. patients with asymptomatic primary hbv infection are at higher risk for chronic infection than those with symptomatic infection. while chronic persistent hepatitis, a benign illness of little clinical consequence except for the potential for hbv transmission to susceptible individuals, may occur, the major health concern is chronic active hepatitis, which eventually may produce cirrhosis, liver failure, and hepatoma. hepatitis b is differentiated from other causes of hepatitis by serologic assays. a positive hepatitis b surface antigen (hbsag) test identifies patients with current infection and correlates with infectivity during acute and chronic infection. titers of hbsag in the chronic phase of illness may wax and wane and occasionally fall below the limits of laboratory detection, so sequential testing should be performed if chronic hbv is suspected. the presence of hbeag correlates with active virus replication and is a marker of high infectivity and high titer of hbv in the liver and blood. antibody to hepatitis b surface antigen (hbsab) appears when hbsag is cleared and is positive in individuals with immunity after recent or prior infection or immunization. persons with hbsab are not susceptible to acute infection or chronic hepatitis b, except in the very rare case in which reinfection occurs with a strain of hepatitis b against which the normal antibody response does not provide cross-protection. hepatitis b core antibody (hbcab) appears before hbsab and just after hbsag is cleared from the serum, and this is a useful test for diagnosing acute hepatitis b in the window period before hbsab appears. high titers of hbcab persist in chronically infected persons and obviously do not predict immunity from further liver disease. there currently is no treatment for acute hepatitis b. alpha interferon and lamivudine have been licensed for the treatment of persons with chronic hepatitis b. these drugs are effective in up to % of cases. hbv infection is largely preventable. inoculation with recombinant vaccines containing hbsag components is safe and highly immunogenic, and appears to confer protection from infection for at least years (table . ). postvaccination testing should be done - months after completion of the three-dose series to document an appropriate response (i.e., > miu/ml). more than % of persons immunized with three properly timed doses (e.g., , , and months) of vaccine administered intramuscularly in the deltoid region develop protective hbsab levels. factors associated with a lack of response include improper vaccination (improperly stored vaccine, gluteal inoculation, subcutaneous injection), obesity, older age, and smoking. persons who do not respond to the primary vaccine series should receive a second three-dose series or be evaluated for hbsag positivity. since , substantial progress has been made toward eliminating hbv transmission in children and reducing the risk for hbv infection in adults. recommendations of acip have evolved from universal childhood vaccination, to prevention of perinatal hbv transmission, vaccination of adolescents and adults in high-risk groups, and catch-up vaccinations for susceptible children in high-risk populations. , the acip vaccination strategies for children and adolescents have been implemented successfully in the united states, and routine immunization of all children is now recommended. the occupational safety and health administration's (osha's) blood-borne pathogen standard mandates provision of vaccine at no cost to all healthcare employees and others at occupational risk for blood exposure. substantial declines in the incidence of acute hepatitis b have occurred among highly vaccinated populations, such as young children and healthcare personnel. vaccine should also be provided to susceptible individuals before sexual maturity, particularly to teenagers in those settings (e.g., inner cities, concentration of poverty) where hbv is highly prevalent, and to all adults at risk for sexual or occupational exposure. preimmunization screening for evidence of prior or persistent infection usually is not cost effective. however, postimmunization testing for antibody response is recommended - months after the rd dose to detect nonresponders among persons at high risk for exposure. titers of hbsab fall over time and may be undetectable after - years. the duration of vaccine protection is under investigation. most data suggest that protection persists even when hbsab titers fall below the level of detection, and routine screening and boosting are not recommended. the need for prophylaxis for persons sustaining accidental percutaneous or mucosal exposures to blood should be based on several factors, including the hbsag status of the source, and the hepatitis b vaccination and vaccineresponse status of the exposed person. such exposures usually involve persons for whom hepatitis b vaccination is recommended. any blood or body fluid exposure to an unvaccinated person should lead to initiation of the hepatitis b vaccine series. a summary of prophylaxis recommendations for percutaneous or mucosal exposure to blood according to the hbsag status of the exposure source and the vaccination and vaccine-response status of the exposed person is shown in table . . when hepatitis b immune globulin (hbig) is indicated, it should be administered as soon as possible after exposure (preferably within hours). the effectiveness of hbig when administered more than days after exposure is unknown. when hepatitis b vaccine is indicated, it § hepatitis b immune globulin; dose is . ml/kg intramuscularly. ¶ a responder is a person with adequate levels of serum antibody to hbsag (i.e., anti-hbs ≥ miu/ml). ** a non-responder is a person with inadequate response to vaccination (i.e., serum anti-hbs < miu/ml). † † the option of giving one dose of hbig and reinitiating the vaccine series is preferred for non-responders who have not completed a second three-dose vaccine series. for persons who previously completed a second vaccine series but failed to respond, two doses of hbig are preferred. § § antibody to hbsag. should also be administered as soon as possible (preferably within hours) and can be administered simultaneously with hbig at a separate site (vaccine should always be administered in the deltoid muscle). for exposed persons who are in the process of being vaccinated but have not completed the vaccination series, vaccination should be completed as scheduled, and hbig should be added as indicated (table . ). persons exposed to hbsag-positive blood or body fluids who are known not to have responded to a primary vaccine series should receive a single dose of hbig and reinitiate the hepatitis b vaccine series with the first dose of the hepatitis b vaccine as soon as possible after exposure. alternatively, they can receive two doses of hbig, one dose as soon as possible after exposure, and the second dose month later. the option of administering one dose of hbig and reinitiating the vaccine series is preferred for non-responders who did not complete a second three-dose vaccine series. for persons who previously completed a second vaccine series but failed to respond, two doses of hbig are preferred. states. it is estimated that . % of americans have been infected with hcv. hcv-associated end-stage liver disease is the most frequent indication for liver transplantation among us adults. the incubation period for acute hcv infection ranges from to weeks (averaging - weeks). hcv transmission occurs primarily through exposure to infected blood, such as through injection drug use, blood transfusion, solid organ transplantation from infected donors, unsafe medical practices, occupational exposure to infected blood, and birth to an infected mother (i.e., vertical transmission). hcv may also be acquired through sexual contact, but the importance of this mode of transmission in the united states is not well characterized. hcv is not transmitted efficiently through occupational exposures to blood. healthcare personnel who are parenterally exposed to infected blood through needlestick injuries may acquire hcv infection, but the magnitude of risk (approximately in hcv needlesticks) is less than that associated with hbv exposure. one epidemiologic study indicated that transmission occurred only from hollow-bore needles compared with other sharps. transmission rarely occurs from mucous membrane exposures to blood, and no transmission in hcv has been documented from skin exposures to blood. data are limited on survival of hcv in the environment. in contrast to hbv, the epidemiologic data for hcv suggest that environmental contamination with blood containing hcv is not a significant risk for transmission in the healthcare setting, with the possible exception of the hemodialysis setting where hcv transmission related to environmental contamination and poor infection control practices have been implicated. the risk for transmission from exposure to fluids or tissues other than hcv-infected blood also has not been quantified but is expected to be low. hcv is not known to be transmissible through the airborne route, through casual contact in the workplace, or by fomites. clinical syndromes hepatitis c virus infection produces a spectrum of clinical illness similar to hbv and is indistinguishable from other forms of viral hepatitis based on clinical symptoms alone. serologic tests are necessary to establish a specific diagnosis of hepatitis c. most adults acutely infected with hcv are asymptomatic. after acute infection, - % of persons appear to resolve their infection without sequelae as defined by sustained absence of hcv rna in serum and normalization of alt levels. chronic hcv infection develops in most persons ( - %), with persistent or fluctuating alt elevations indicating active liver disease developing in - % of chronically infected persons. no clinical or epidemiologic features among patients with acute infection have been found to be predictive of either persistent infection or chronic liver disease. moreover, various alt patterns have been observed in these patients during follow-up, and patients might have prolonged periods (greater than or equal to months) of normal alt activity even though they have histologically confirmed chronic hepatitis. thus, a single alt determination cannot be used to exclude ongoing hepatic injury, and long-term follow-up of patients with hcv infection is required to determine their clinical status and prognosis. the course of chronic liver disease is usually insidious, and progresses slowly without symptoms or physical signs in the majority of patients during the first two or more decades after infection. chronic hepatitis c frequently is not recognized until asymptomatic persons are identified as hcv positive during blood donor screening, or elevated alt levels are detected during routine physical examinations. most studies have reported that cirrhosis develops in - % of persons with chronic hepatitis c over a period of - years, and hcc in - %, with striking geographic variations in rates of this disease. however, when cirrhosis is established, the rate of development of hcc might be as high as - % per year. longer follow-up studies are needed to assess lifetime consequences of chronic hepatitis c, particularly among those who acquired infection at young ages. although factors predicting severity of liver disease have not been well defined, recent data indicate that increased alcohol intake, being aged greater than years at infection, and being male are associated with more severe liver disease. in particular, among persons with alcoholic liver disease and hcv infection, liver disease progresses more rapidly; among those with cirrhosis, a higher risk for development of hcc exists. in addition, persons who have chronic liver disease are at increased risk for fulminant hepatitis a. screening enzyme immunoassay (eia) and supplemental confirmatory immunoblot tests are licensed and commercially available to detect antibodies to hcv (anti-hcv). anti-hcv may be detected within - weeks after the onset of infection but a single anti-hcv test cannot distinguish between acute, chronic, or past infection. hcv rna can be detected within - weeks of exposure to the virus and several weeks before elevations of alt and detection of anti-hcv. testing for anti-hcv by eia is recommended - months after an exposure to detect infection; testing for hcv rna may be performed - weeks after exposure if earlier detection of infection is desired. treatment, prevention, and control hcv-positive patients should be evaluated for the presence and severity of chronic liver disease. initial evaluation for presence of disease should include multiple measurements of alt at regular intervals, because alt activity fluctuates in persons with chronic hepatitis c. patients with chronic hepatitis c should be evaluated for severity of their liver disease and for possible treatment. alpha interferon (with or without ribavirin) treatment of hcv appears to prevent hcv replication, decrease hepatic inflammation, and improve symptoms among chronically infected persons. persons with chronic hcv have undergone successful liver transplantation, although recurrences have been documented in this setting. antiviral therapy is recommended for patients with chronic hepatitis c who are at greatest risk for progression to cirrhosis. these persons include anti-hcv-positive patients with persistently elevated alt levels, detectable hcv rna, and a liver biopsy that indicates either portal or bridging fibrosis or at least moderate degrees of inflammation and necrosis. therapy for hepatitis c is a rapidly changing area of clinical practice and consultation with a knowledge specialist (e.g., hepatologist) is recommended. no clinical trials have been conducted to assess postexposure use of antiviral agents (e.g., interferon with or without ribavirin) to prevent hcv infection, and antivirals are not fda approved for this indication. available data suggest that an established infection might need to be present before interferon can be an effective treatment. , because there is currently no postexposure prophylaxis (pep) for hcv, the intent of recommendations for postexposure management is to achieve early identification of infection and, if present, referral for evaluation of treatment options. in addition, no guidelines exist for administration of therapy during the acute phase of hcv infection. however, limited data indicate that antiviral therapy might be beneficial when started early in the course of hcv infection. when hcv infection is identified early, the person should be referred for medical management to a specialist knowledgeable in this area. at present, avoidance of parenteral exposure to blood is the only available strategy for preventing hcv infection. epidemiology it is estimated that more than million persons worldwide had been infected by hiv and that million were living with hiv/aids by the end of the year . in the united states, almost million persons are living with hiv. most individuals with hiv infection are active adults employed in the workforce. the primary means of acquiring infection among adults is either through behaviors such as unprotected homosexual or heterosexual intercourse with an infected partner, involving the exchange of body fluids, or injecting drug use involving shared needles and syringes. the virus also is perinatally transmitted to approximately - % of children born to infected mothers, (e.g., vertical transmission). breastfeeding is a bidirectional mode of transmission, to nursing infants of infected mothers and, rarely, to mothers of nursing infants when nipple maceration and biting occur. since , all donated blood in the united states has been screened for hiv infection. the risk of hiv infection due to transfusion of blood products screened by current methods is estimated to be in , , units transfused. screening does not completely eliminate the potential for a seronegative but infected unit from a recently infected donor to escape detection. hiv is not transmitted by the air-borne route, by household or workplace contact with infected persons, by exposure to contaminated environmental surfaces, or by insect vectors. the virus is easily inactivated by most common disinfectants, including household bleach (diluted : ). commercial sex workers are at the greatest risk of acquiring hiv infection occupationally. the other group of workers at risk for acquiring hiv infection occupationally is healthcare personnel. healthcare providers and other workers in contact with blood or other body fluids who sustain accidental percutaneous or mucosal inoculations with virus-infected material are at risk for infection. the magnitude of risk depends on the severity of exposure, but on the average, about in hiv needlesticks results in infection. the risk for infection following mucosal exposures is estimated to be lower at approximately . %. in the absence of direct exposure, healthcare providers are not at occupational risk for hiv infection. in the united states, through december , there have been cases of occupationally acquired hiv infection reported with an additional possible cases. clinical syndromes the clinical course of hiv infection is variable and changing with the advent of antiretroviral therapy, as well as treatment and prophylaxis for infectious complications. early after infection, within a few weeks to months, an acute febrile illness characterized by malaise, pharyngitis, lymphadenopathy, maculopapular rash, and headache may occur. the frequency of this mononucleosis-like illness has varied widely in reports of seroconverting individuals. at initial presentation of such patients, hiv antibody screening tests (enzyme immunoassay (eia)) may be negative, but viral antigen (p antigen) and serologic reactivity to one or more viral components (western blot test) allows the diagnosis to be established at this stage. hiv infection should be suspected in any person with a mononucleosis syndrome lacking a positive heterophil antibody response (monospot test). following initial infection, most persons have generalized asymptomatic lymphadenopathy and appear well. however, laboratory tests document a gradual decline in the number of circulating t-helper lymphocytes (cd cells), beginning soon after infection and continuing over the next several years. t-helper cells are essential components of the immune system and mediate aspects of both cellular and humoral immunity. symptoms, signs, and illness suggestive of mild to moderate immunodeficiency appear after about years, when cd cells decrease by about %, to less than cells/dl. intermittent fever, oral thrush, bacterial pneumonia, enteric infections, and reactivated tb are typically diagnosed at this time. signs suggestive of more rapid deterioration include oral hairy leukoplakia (a wart-like white growth in the oral cavity), shrinking lymphadenopathy, fever, weight loss, and elevated erythrocyte sedimentation rate. when cd cell counts fall below , serious opportunistic infections can be anticipated. pneumocystis pneumonia (pcp) was the most common index diagnosis in the first years of the epidemic, but the advent of effective pcp prophylaxis has altered the picture. other opportunistic infections and malignancies, including kaposi's sarcoma, lymphoma, disseminated tb, toxoplasmosis, and cryptococcal meningitis, now account for the majority of index hiv diagnoses. with the exception of tb, the infectious complications of hiv infection generally are not transmissible to healthy individuals and pose no risk in the workplace. indeed, the causative organisms are ubiquitous and most adults have already been exposed. opportunistic infections in hivinfected patients usually represent reactivation of dormant organisms when the immune system can no longer keep them inactive. be offered to all patients with symptoms ascribed to hiv infection. recommendations for offering antiretroviral therapy in asymptomatic patients require analysis of many real and potential risks and benefits. information regarding treatment of acute hiv infection from clinical trials is very limited. ongoing clinical trials are addressing the question of the long-term clinical benefit of potent treatment regimens for primary infection. in general, treatment should be offered to individuals with fewer than cd t cells/mm or plasma hiv rna levels exceeding , copies/rnl (by rt-pcr or bdna assay). once the decision has been made to initiate antiretroviral therapy, the goals should be maximal and durable suppression of viral load, restoration and/or preservation of immunologic function, improvement of quality of life, and reduction of hivrelated morbidity and mortality. hiv-infected individuals found to have latent tb infection should be treated with antituberculous therapy to prevent activation of disease. persons at risk for direct contact with blood and other potentially infected materials should receive specific instruction in universal/standard precautions for infection control, as recommended by the centers for disease control and prevention , and mandated by the occupational safety and health administration. for most environments outside healthcare settings, common sense and attention to personal hygiene are adequate to protect workers. gloves should be worn to clean up visible sites of blood contamination. environmental surfaces can then be decontaminated with disinfectant solutions or household bleach (diluted : ). , individuals sustaining accidental parenteral exposures to hiv should be counseled to undergo baseline and followup testing for months after exposure (e.g., weeks, months, and months) to diagnose occupational infection. postexposure chemoprophylaxis with antiretroviral agents has been recommended by the us public health service since after certain exposures to hiv-infected sources which pose a risk of infection transmission, such as needlesticks, mucous membrane, and non-intact skin exposures (tables . and . ). data from animal models of prophylaxis with these agents suggest that antiviral activity is diminished when treatment is delayed for more than hours. for this reason, immediate reporting and access to chemoprophylaxis is recommended. occupational exposure is a frightening experience. consultation with clinicians knowledgeable about hiv transmission risks who can provide supportive counseling to the worker is essential during the follow-up interval. cdc recommends that occupationally exposed workers refrain from unsafe sexual practices, pregnancy, and blood and organ donation for months after exposure to minimize the risk of transmission. zoonoses are infections that are maintained in nature by transmission between vertebrate animals, and they can be transmitted from other vertebrates to humans or from humans to other vertebrates. zoonotic pathogens can be divided into two major groups: ( ) those transmitted primarily among wild animals (e.g., yersinia pestis, rabies), and ( ) those transmitted primarily among domestic animals (e.g., sporothrix schenkii, non-typhoid salmonella spp.). other infections not properly classified as zoonoses can result from working directly with animals (e.g., infected wounds resulting from animal bites) or with animal products (e.g., anthrax in carpet weavers). many zoonotic infections present occupational risks, not only to those who work with live or dead vertebrate animals or animal products but also to workers exposed to certain environments contaminated by animals or animal products. thus, workers in veterinary medicine, animal husbandry, and animal research are at risk for acquiring a host of zoonotic infections specific to the type of live animal exposure, just as those involved in healthcare work with humans are at risk for infections acquired from humans. examples of such zoonotic infections include q fever in veterinarians, psittacosis (caused by chlamydia psittaci) in duck farmers, orf (contagious ecthyma) in shepherds, lymphocytic choriomeningitis (e.g., leptospirosis) in laboratory workers who handle rodents, fatal herpes virus simiae infection in primate handlers, and more recently, monkeypox in veterinarians and pet store owners. , influenza a (h nl) (avian flu) infection was shown to have been transmitted from ducks and chickens to poultry workers in hong kong and has become an important source of epidemic infection in various international settings; lyssavirus (related to rabies virus) infections have been transmitted from bats to humans in australia, and a large outbreak of febrile encephalitic and respiratory illnesses among workers who had exposure to pigs was shown to be due to infection with a previously unrecognized paramyxovirus (formerly known as hendra-like virus, now called nipah virus). brucellosis is an example of a zoonotic infection in abattoir workers exposed to live or dead animals or animal products. examples of zoonotic infections acquired by workers exposed to environments harboring or contaminated by contagious animals include leptospirosis in rice field workers, and argentine hemorrhagic fever typically acquired by adult males harvesting corn in cornfields inhabited by rodents, which serve as the reservoir for junin or machupo virus. it is beyond the scope of this chapter to review the large number of zoonoses (about have been described) that could pose a risk to workers in unique jobs that involve contact with various animals or environments. for each type of occupation that involves regular animal contact, it is important to recognize the types of infectious disease risks involved, consider baseline studies and storage of serum for future serologic tests if risks are high, plan preventive measures when possible, and prepare for early diagnosis and treatment of such infections when illness occurs. some of the zoonoses, the occupational groups they affect, and their clinical presentations are included in table . . infectious diseases continue to emerge, posing threats to the health of workers in numerous settings. a prime example of such a threat is severe acute respiratory syndrome or sars, first identified in early and responsible for illness and death primarily among exposed healthcare personnel. emerging infectious issues which may prove to be challenges for occupational health include those posed by bioterrorism, biotechnology, and emerging and reemerging infections. these emerging infections emphasize the need for continued vigilance and for careful history taking about occupational exposures when evaluating individuals for illnesses that could possibly be occupationally acquired. timeliness in identification and reporting of cases assists in the accurate estimation of the magnitude of the infectious disease problem and in the development of additional preventive and therapeutic measures. screening of employees for infection with or susceptibility to infectious diseases is an important part of healthcare maintenance, especially when the occupational setting poses a significant risk of transmitting or acquiring infections. screening also is warranted if specific interventions are available to prevent disease transmission among workers. assessment of behaviors, such as smoking, that increase the risk of acquiring infections also is valuable so that employees can be provided educational and other interventions to modify risks. preventing infectious diseases in workers can decrease absenteeism and financial costs associated with disability, sick leave, and health insurance, even if the primary source of infection is non-occupational. attending to these issues at the time of employment obviates the need for ongoing surveillance of many infections and simplifies outbreak investigations by documenting the pre-exposure immune status of contacts. tst screening for active disease identifies those persons who would benefit from prophylaxis (tables . and . ). tb vaccination with bacillus of calmette-guerin (bcg) vaccine, a live attenuated strain of m. bovis, is provided for children and some workers in most european countries, but it is not recommended in the united states because of its unproven efficacy when used in adults and because it induces dermal hypersensitivity to purified protein derivative (ppd) tuberculin in most recipients, impeding the usefulness of tst as a screening tool. persons age years and older, persons with chronic diseases or pulmonary disorders, and healthcare personnel should be offered pneumococcal vaccine and annual influenza vaccine (table . ). rubella immune status should be ascertained and men and women immunized in settings where women of childbearing age are employed (table . ). even though rubella is not often transmitted in the workplace, outbreaks can occur among susceptible individuals and vaccination is an important public health intervention. medical personnel should demonstrate proof of rubella immunity or vaccination prior to patient contact. measles vaccine should be provided to all workers born after with no documented history of measles who have not received two injections of live virus vaccine (table . ). screening for immunity to varicella and mumps is not routinely recommended, except for healthcare providers and adults with no history of infection with these agents who are exposed to young children. all adults require tetanus immunization. tetanus diphtheria toxoid (td) boosters should be administered every years to adults who have completed primary immunization (table . ). employees with no prior history of tetanus diphtheria immunization or with uncertain histories should receive a series of three primary vaccine injections. similarly, adults with no history of polio immunization should undergo primary immunization with inactivated polio vaccine, especially if they are employed in healthcare settings or when travel to endemic areas is anticipated. persons employed in occupations that pose a risk for parenteral contact with blood and other body fluids should be offered hepatitis b immunization (table . ). healthcare personnel, laboratory workers, animal handlers, first responders, and personal service workers such as barbers, tattooists, and cosmetologists are included in this category. adults with multiple sexual partners also should be encouraged to undergo immunization. serum banking to allow documentation of baseline serostatus is useful for laboratory and healthcare personnel at risk for other bloodborne infections such as hiv or more exotic infections. laboratory workers and animal handlers may be at risk for unusual infectious diseases. q fever, a rickettsial disease transmitted by the air-borne route, is a special risk encountered by handlers of sheep and similar animals. serologic testing for q fever titers prior to occupational exposure is important to document baseline status and to detect seroconversion at follow-up testing. although smallpox vaccine is no longer recommended routinely, genetically engineered vaccines prepared from vaccinia may pose a risk to researchers and clinicians treating patients enrolled in vaccine trials. laboratory workers who handle vaccinia or recombinant vaccinia preparations in culture or in animals should receive vaccinia vaccine. healthcare personnel caring for patients immunized with vaccinia or other orthopoxviruses or tissues and specimens from patients with these infections also should be immunized. a program for smallpox vaccination for selected individuals who may be in the frontline for responding to a bioterrorist attack has recently been initiated in the united states. consultation should be obtained to determine the need for screening, immunization, and testing for other exotic infections. some animal handlers are at risk of acquiring rabies through bites or exposure to infected secretions and tissues. immunization with human diploid cell vaccine (three -ml intradermal doses on day , , and or ) should be provided to workers at risk for rabies and for persons traveling for more than month to areas where rabies is endemic (table . ). booster injections should be provided every years for those with continuing exposure. surveillance of infectious diseases is conducted to detect increased occurrence of disease so that preventive interventions can be initiated. surveillance can be passive (based on employee health consultations or reports from contractual providers or supervisors) or active (actual monitoring of disease occurrence). active surveillance for infectious diseases is not required in most occupational settings. in work environments where exposure to m. tuberculosis may occur -such as healthcare settings, residential care facilities, shelters, and correctional facilities -active tst surveillance among susceptible individuals is indicated. periodic tsts are especially important in the wake of several recent outbreaks associated with drug-resistant strains of m. tuberculosis in hospitals, adult care settings, and home healthcare settings. skin testing should be performed at least annually in these settings, and perhaps as often as every months, for personnel at high risk for exposure to active tb. surveillance of teachers, travelers to endemic areas, and employees in other institutional settings where close contact with infected individuals is possible also may be warranted, depending on the local prevalence of tb. surveillance for infections among laboratory workers and animal handlers exposed to specific pathogens should be individualized in accordance with standard guidelines for biosafety in microbiologic and biomedical laboratories. maintaining standardized records of reportable infectious diseases is an important component of passive surveillance in the workplace. centralized collection and assessment of these records at regular intervals may allow early detection of outbreaks of occupational infections amenable to specific control interventions. geographic or temporal clusters of cases or clustering among persons with similar attributes or occupational tasks suggest a common source of exposure and infection and warrant investigation. local public health officials and regulatory agencies should be consulted promptly when an outbreak is initially suspected. reporting of occupationally acquired infections permits public health agencies to identify clusters of old and emerging illnesses and ultimately prevent them. these events should be reported as mandated by state and local regulations. , return-to-work criteria employees diagnosed with communicable infectious diseases should not return to work until the period of infectivity is past. specific guidelines should be consistent with local public health regulations. some workers, for example food handlers with certain diarrheal illnesses, cannot resume their duties until culture evidence of cure is obtained. employees should be advised of the return-towork policies at the time of employment and when illness is diagnosed. a table for length of work restriction for healthcare personnel can be used to guide return-to-work policies for the workplace (table . ). common sense dictates attention to personal hygiene among all workers. hand washing after using the bathroom and before handling food is essential. the mouth should be covered while sneezing or coughing, and soiled tissues and dressings should be disposed of in trash containers. employers have a responsibility to minimize crowding in the work setting. facilities for hand washing should be available in bathrooms and food preparation areas. proper ventilation also is important. trash should be emptied at regular intervals, and work areas should be clean and free of pests. smoking should be prohibited in common work areas. spills of blood, body fluids, and other potentially infectious substances should be removed with disposable paper towels or other suitable procedures. contaminated areas should then be disinfected with commercial products or with a solution of household bleach (diluted : ). , infection control in healthcare settings infection control programs in healthcare settings are necessary to prevent transmission of healthcare-related infections to patients and healthcare personnel. the cdc has established a two-tiered system of infection control precautions. the first tier consists of 'standard precautions' which are precautions recommended for delivery of care to all patients regardless of diagnosis or presumed infection status. they are designed to limit exposure to blood or other body substances and include elements such as hand hygiene and use of appropriate protective barriers, e.g., masks, eye protection, and gloves, as needed to prevent direct contact. the second tier of precautions recommended by cdc are 'transmission-based precautions', designed for the management of patients known or suspected to be infected with pathogens whose transmission can be limited by the adoption of additional measures beyond those which are part of standard precautions. they apply to pathogens transmitted by the air-borne or aerosol routes, droplets, and by direct and indirect contact. respiratory precautions are employed for patients with infections communicable by the air-borne route. such patients are housed in private rooms with special ventilation and should wear surgical masks when leaving their rooms. respiratory protection (i.e., n- respirators) also are advised for providers in close contact with patients on respiratory precautions. however, the re-emergence of epidemic and mdr-tb has led to a re-emphasis of other fundamentals for prevention of transmission of tuberculosis in healthcare and other settings. early identification of tb allows early indication for therapy, and requires alertness in considering tb in high-risk patients with pulmonary symptoms, especially those with hiv infection. special ventilation measures and respiratory protection are especially important for cough-inducing procedures, such as sputum induction and aerosolized pentamidine administration. healthcare personnel who have the potential for being exposed to m. tuberculosis should be screened on employment and at least annually thereafter by ppd skin testing, comparing previous test results to current results to identify those who have converted to skin test positivity. procedures for disposal of infectious wastes have been developed by the cdc. needles and other sharp objects should be sterilized prior to disposal. liquid and laboratory wastes may be dumped into sewage systems. materials heavily contaminated with bacteria or blood should be placed in special bags that are specifically labeled for infectious waste and should be disposed of according to community standards for such materials. employers have a responsibility to educate employees about infection control. barriers to prevent exposure, including masks, gowns, eye protection, and gloves, should be readily available to workers at risk. hand washing facilities and hand hygiene supplies are essential. where access to sinks or running water is not feasible, alcohol hand rubs or packaged towels containing disinfectants should be provided. impervious containers for the disposal of needles and other sharp objects are essential. such containers should be made available on ambulances and provided to home health aides and other visiting healthcare personnel. personal service workers who use needles, razors, and other sharp objects also should have access to safe disposal units. persons receiving care at home who require injections or other procedures that demand the use of needles also should be provided with impervious disposal containers and instructed in proper disposal methods to protect sanitation workers and others in contact with waste. despite improvements in engineering controls, work practices, and personal protective equipment, laboratory personnel are nevertheless at risk for occupationally acquired infections. laboratory personnel may acquire infection by aerosolization of specimens, mouth pipetting, or percutaneous injury or mucocutaneous contact. methods of infection control applicable to laboratory settings are described in the cdc document entitled 'biosafety in microbiological and biomedical laboratories'. by , it was estimated that . million children were attending out-of-home daycare in a variety of settings including licensed child daycare centers, regulated daycare homes, and unregulated family daycare homes. many serious infections occur as endemic or microepidemic problems in the daycare setting. these include h. influenzae type b, hepatitis a, cytomegalovirus, parvovirus b , and enteric infections (shigella, giardia, rotavirus, clostridium difficile, campylobacter, cryptosporidium, calcivirus, salmonella, enteric adenovirus, astrovirus, and several types of e. coli infections). in addition, the high rate of acute respiratory infections leads to early onset of otitis media, frequent antibiotic use, and emergence of multidrug-resistant enteric pathogens. thus, workers in close contact with children risk exposure to a wide variety of communicable pathogens contained in secretions, urine, and stool. all such personnel, as well as all children in schools and daycare centers, should be screened for immunity to common childhood infections and vaccinated if immunity is not present (table . ). regulation of childcare facilities is essential to reduce risks to children and workers. national standards for infection control in childcare facilities were promulgated in . hand washing facilities and policies are the most important component of disease prevention in school and daycare settings. hands should be washed after contact with mucous membranes and potentially infected body fluids. older children should be instructed in personal hygiene. children with fever or diagnosed infections should be excluded from attending daycare or school until transmission risk is no longer present, and policies for such exclusion should be in place. prompt reporting of disease outbreaks and prompt involvement of public health authorities are essential. employees should be instructed in common-sense first aid procedures for handling wounds, bites, and other situations in which exposure to infected blood or tissues is possible. barrier protection is rarely required in schools, but gloves should generally be available for emergencies requiring first aid. infection with a variety of agents during pregnancy has the potential to cause fetal damage, especially when primary infection occurs. while a number of these infections can be community acquired, the likelihood of exposure to certain of these pathogens can be greater in healthcare settings. infections with as rubella, cmv, and parvovirus are among the infectious agents which may be of special concern to pregnant healthcare personnel. in general, adherence to standard precautions as well as preexposure immunizations when available and appropriate are the best way of preventing the devastating effects of such infections (table . ). , immunodeficient workers are at increased risk of devastating infections, particularly with opportunistic agents. the greatest risk for such workers is likely in the healthcare setting where there can be ample opportunity for exposure to these agents. many immunocompromising illnesses would be viewed by the us legal system as disabilities and therefore, individuals with those conditions would be covered under the provisions of the americans with disabilities act of (see chapter . ). such persons should be informed about their risks and furthermore, their employers should make reasonable accommodations to allow their employees to continue to perform their jobs, taking into consideration the provisions of applicable federal, state, and local regulations. occupational infectious diseases encompass a large variety of infections which can involve many organ systems. they include some common infections, such as influenza, that pose a special problem in the workplace because of close interpersonal contact and crowding, and that taken together account for a large proportion of time lost from work. many of these infections are preventable by policies that promote hygiene and provide exclusion from work during periods of contagion. in addition, a variety of less common, but sometimes serious, infections are particularly associated with specific occupations. recognition of the types of infection risk associated with specific occupations can, in most cases, lead to effective, often simple steps for primary prevention, as well as opportunities for early diagnosis and treatment. bioterrorismrelated inhalational anthrax: the first cases reported in the united states principles and practice of infectious diseases centers for disease control and prevention. prevention and control of influenza: recommendations of the advisory committee on immunization practices (acip) influenza vaccination in long-term-care hospitals reduces the mortality of elderly patients measles, mumps, and rubella -vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the advisory committee on immunization practices (acip) changing epidemiology of pertussis in the united states: increasing reported incidence among adolescents and adults guidelines for the control of pertussis outbreaks ashrae guideline - : minimizing the risk of legionellosis associated with building water systems guideline for prevention of nosocomial pneumonia. the hospital infection control practices advisory committee progressing toward tuberculosis elimination in low-incidence areas of the united states: recommendations of the advisory council for the elimination of tuberculosis centers for disease control and prevention. targeted tuberculin testing and treatment of latent tuberculosis infection the role of bcg vaccine in the prevention and control of tuberculosis in the united states: a joint statement by the advisory council for the elimination of tuberculosis and the advisory committee on immunization practices guidelines for preventing the transmission of tuberculosis in health-care facilities guideline for isolation precautions in hospitals. the hospital infection control practices advisory committee prevention of varicella: update recommendations of the advisory committee on immunization practices (acip) epidemiology and prevention of vaccine-preventable diseases guideline for infection control in healthcare personnel guideline for hand hygiene in health-care settings: recommendations of the healthcare infection control practices advisory committee and the hicpac/shea/apic/idsa hand hygiene task force infection control precautions for the pregnant healthcare worker. bailliere's risk and management of bloodborne infections in healthcare workers updated us public health service guidelines for the management of occupational exposures to hbv, hcv, and hiv and recommendations for postexposure prophylaxis achievements in public health: hepatitis b vaccination -united states hepatitis b virus: a comprehensive strategy for eliminating transmission in the united states through universal childhood vaccination: recommendation of the immunization practices advisory committee (acip) protection against viral hepatitis: recommendations of the immunization practices advisory committee (acip) occupational safety and health administration, department of labor. cfr part . , occupational exposure to bloodborne pathogens; final rule recommendations for prevention and control of hepatitis c virus (hcv) infection and hcv-related chronic disease national institutes of health consensus development conference panel statement. management of hepatitis c an unequal epidemic in an unequal world the risk of transfusion-transmitted viral infections surveillance of healthcare personnel with hiv/aids, as of panel on clinical practices for the treatment of hiv infection. guidelines for the use of antiretroviral agents in hiv-infected adults and adolescents. us department of health and human services recommendations for prevention of hiv transmission in healthcare settings update: universal precautions for prevention of transmission of human immunodeficiency virus, hepatitis b virus, and other bloodborne pathogens in health-care settings guideline for environmental control in healthcare facilities centers for disease control and prevention. multistate outbreak of monkeypox -illinois risk of influenza a (h n ) infection among poultry workers, hong kong, - emerging viral diseases: an australian perspective outbreak of hendra-like virus -malaysia and singapore, - risks and prevention of nosocomial transmission of rare zoonotic diseases sars -looking back over the first days occupational standards for the protection of employees in biotechnology centers for disease control and prevention. general recommendations on immunization: recommendations of the advisory committee on immunization practices (acip) and the american academy of family physicians (aafp) recommendations for using smallpox vaccine in a pre-event vaccination program: supplemental recommendations of the advisory committee on immunization practices (acip) and the healthcare infection control practices advisory committee (hicpac) us department of health and human services centers for disease control. case definitions for public health surveillance mandatory reporting of infectious diseases by clinicians. mandatory reporting of occupational diseases by clinicians selecting, evaluating, and using sharps disposal containers. dhhs (niosh) publication no. - child care arrangements for preschoolers by family characteristics: fall national standards for infection control in out-ofhome child care americans with disabilities act of , stat. , u.s.c. sec. et seq immunization of health-care workers: recommendations of the advisory committee on immunization practices (acip) and the hospital infections control practices advisory committee (hicpac) known responder ¶ known non-responder** antibody response unknown hbig § × and initiate hepatitis b vaccine series no treatment hbig x and initiate revaccination or hbig × † † test exposed person for anti-hbs: § § if drug resistance is a concern, obtain expert consultation. initiation of postexposure prophylaxis (pep) should not be delayed pending expert consultation, and, because expert consultation alone cannot substitute for face-to-face counseling, resources should be available to provide immediate evaluation and follow-up care for all exposures. § source of unknown hiv status (e.g., deceased source person with no samples available for hiv testing). ¶ unknown source (e.g., splash from inappropriately disposed blood). ** small volume (i.e., a few drops). † † the designation 'consider pep' indicates that pep is optional and should be based on an individualized decision between the exposed person and the treating clinician. § § if pep is offered and taken, and the source is later determined to be hiv negative, pep should be discontinued. ¶ ¶ large volume (i.e., major blood splash). key: cord- -xpyldrw authors: zelicoff, alan p. title: laboratory biosecurity in the united states: evolution and regulation date: - - journal: ensuring national biosecurity doi: . /b - - - - . - sha: doc_id: cord_uid: xpyldrw in light of terrorist events in the united states and in recognition of the potential for diversion of highly pathogenic organisms for illicit purposes, the us congress has in the past years enacted a series of laws designed to enhance laboratory biosecurity. the office of the president has also issued orders intended to implement and augment these new statutes imposing additional procedural and technical requirements on laboratories working with select agents and toxins. researchers and laboratory managers can substantially influence the implementation of new mandates with a thorough understanding of the regulatory process, reviewed in this chapter from a historical perspective with an emphasis on the practical aspects of rule-making procedures carried out by the departments of agriculture and health and human services. the term "biosecurity" is used in a wide variety of contexts and carries with it an equally diverse set of meanings. for example, veterinarians traditionally view biosecurity as the set of management practices to protect animals -livestock or others of economic value -against microbial threat, some of which may be inadvertently introduced by humans. preventing influenza in pig farming and tuberculosis (mycobacterium tuberculosis) among elephants in zoological parks are two illustrations [ ] . "biosecurity" takes on an entirely different meaning in international political agreements such as the biological and toxin weapons convention of , where it refers to measures to prevent the research and development of microorganisms or their products for hostile purposes [ ] . and it is not too far a reach to think of biosecurity as the prevention of infectious disease -and specifically communicable infectious disease -in humans [ ] . for the purposes of this chapter and those that comprise the balance of this text we will employ the definition promulgated by the us department of health and human services [ ] : [t] he term biosecurity refers to the protection, control of, and accountability for high-consequence biological agents and toxins and critical relevant biological materials and information within laboratories to prevent unauthorized possession, loss, theft, misuse, diversion, or intentional release. biosecurity is achieved through an aggregate of practices including the education and training of laboratory personnel, security risk assessments, biological select agent and toxin (bsat) access controls, physical security (facility) safeguards, and the regulated transport of bsat. achieving effective comprehensive biosecurity for bsat is a shared responsibility between the federal government and facilities/individuals that possess, use or transfer bsat. complementary to, but distinct from, biosecurity is biosafety based on principles of containment and risk assessment in the laboratory. containment includes: "the microbiological practices, safety equipment, and facility safeguards that protect laboratory workers, the environment and the public from exposure to infectious microorganisms that are handled and stored in the laboratory," whereas risk assessment is "the process that enables the appropriate selection of microbiological practices, safety equipment, and facility safeguards that can prevent laboratory-associated infections" [ ] . a helpful means of distinguishing "biosecurity" and "biosafety" is to note that they commonly differ on intent, that is, biosecurity is implemented to obviate the intentional diversion or release of biological materials, whereas biosafety measures limit their unintentional dissemination in order to protect laboratory workers and the surrounding community and environment from accidental exposure to pathogens [ , ] . the functional components of biosecurity architecture will be described below. the purpose of this chapter is to review the evolution of biosecurity and modern tenets of its implementation as it applies to high-containment laboratories or those working with "select agents" as defined by statute. many (if not most) laboratorians are unaware of the historical origins of biosecurity. perhaps of greater importance is that laboratory officials and researchers working with dangerous pathogens may be naïve to the origins in the law of the now lengthy list of operational biosecurity requirements, obviously of practical relevance in the day-to-day functions of research facilities. the key pieces of legislation that have mandated these requirements were responses to events such as bioterrorism threats in the late s and the downing of the world trade center buildings in as we shall see in more detail shortly. biosecurity laws passed by the congress vest considerable authority in government departments such as health and human services (hhs) and agriculture (usda) to formulate and then implement regulations (frequently referred to by officials as "rules") with which laboratory workers, researchers, staff and security personnel must comply. these rules are revised at intervals, sometimes on a regular basis and also when new laws are passed. we will summarize the processes by which agencies with hhs and usda -typically the centers for disease control and prevention (cdc) and the animal and plant health inspection service (aphis) -interpret the will of congress (via laws that have been proposed, debated and passed), formulate proposed regulations, solicit comments from individuals and entities likely to be affected, and then disseminate final rules. beyond the legislation itself, the president may issue directives: these include executive orders or "eo"s, which have the full force of the law and must be published in the federal register (fr); and administrative orders such as memorandums, determinations, notices, which have the same legal effect but do not have a publication requirement in the fr and may therefore be "born classified." all of these may prompt executive agencies (such as hhs and usda) to craft new rules as well. several biosecurity-relevant eos will also be reviewed. but neither congress nor the executive office of the president act without also taking into account the advice -sometimes directly solicited, sometimes not -of subject matter experts in academia and professional practice. thus, over the past few decades there have also been several key reports from professional organizations, ad hoc groups and government-sponsored panels that have had a dramatic influence on biosecurity practice. their importance goes beyond mere operational standards for laboratories. rather, documents such as those produced at the ground-breaking asilomar conference in [ ] through the recent publications of national science advisory board for biosecurity (nsabb) and the federal experts security advisory panel have set in motion an inclusive process for scientists in and outside of government to recommend revision of biosecurity requirements that reflect research priorities involving naturally occurring organisms and (regrettably) those which might be used in bioterrorism. because of their importance to laboratorians these reports will also be summarized. in the end, the detailed regulations now extant in laboratories where certain pathogens and toxins -those dangerous to humans, animals or plants if released either inadvertently or intentionally -are kept for research purposes came about as a result of the complex interaction of public apprehension expressed in congressional legislation and eos, technical analysis from scientists and expert groups, and practical concerns from researchers who seek to carry out noble work in disease prevention and treatment. the now famous "select agent and toxin list" (satl) is perhaps the most visible result of the regulatory framework that applies to many biological laboratories and we will show its development over the past decade-and-a-half in detail. in so doing, we hope to foster involvement of thoughtful scientists in formulating policy. after all, bench scientists often have far more familiarity with cutting-edge research and experience with laboratory practices than most officials in the executive branch of government tasked with enacting far-reaching legislation. finally, since the turn of the century there have been a few high-profile "near misses" where the breakdown of biosecurity in containment laboratories could have resulted in infections among personnel or the public. investigations directed at root-cause analysis often result in additional regulatory restrictions with both direct and indirect costs. we will attempt to weigh their benefits against perceived and real costs. in the mid-nineteenth century a series of "international sanitary conferences" were held in paris, vienna, constantinople, washington, rome and dresden with the goal of interrupting recurring epidemics of three diseases recently arrived or reappearing in europe and north america: cholera, plague and yellow fever (each disease entity had a clinical pedigree and its epidemiologic characteristics roughly described, though all were without known cause). over the course of meetings starting in and ending in , participants from the medical and diplomatic communities debated the origins of these diseases and the preventive actions that could be taken to "protect [people] and control" biological agents. this was the naissance of biosecurity in its most straightforward sense, and in retrospect is surprising given that the germ theory of disease was, at that moment in history, barely being formulated and understood. absent that theory, early on in the sanity conferences, physicians and diplomats representing about a dozen countries from the united states to russia argued over the effectiveness of quarantine and the very nature of what is now recognized as infectious disease. anthony perrier of great britain declared at the first gathering that cholera was not "communicable" and that "contagion is not a fact, but a hypothesis invented to explain a number of facts that without this hypothesis would be inexplicable" [ ] . offering no better explanation himself, perrier went on to note that his colleagues "persisted in the routine path of practices that are outmoded, useless and ruinous to commerce and harmful to public health in that instead of enlightening the peoples on the true means of guaranteeing themselves against epidemics, they inspire on the contrary a false sense of security that prevents them from taking the only sanitary precautions that can offer real guarantees." perrier did not at this juncture specify what might constitute those "guarantees." this is perhaps the first association of the words "security" and "public health" in the setting of (then unknown) infectious diseases. remarkably enough, less than years after perrier's confusing admonitions, the origin and routes of transmission for all three diseases had been identified and effective preventive practices put into routine use -"biosecurity" by any other name. as the sanitary conferences continued to meet, in december representatives decided to formalize the forum into the "office international d'hygiène publique" (oihp), ultimately subsumed into the league of nations at the end of world war i. it became known as the league's "health organization" and produced an astonishing body of work including outbreak control and mitigation (with locales that ranged from europe to ports in the far east), nutrition (across the age spectrum from infants to adults), standards for medications, vitamins, antitoxins and vaccines, epidemiology of cancer (of a variety of organs) and even building construction guidelines to name but a small portion of their work [ ] . the oihp continued to operate until when the nascent world health organization (who), today's premier international health security institution, subsumed its functions [ ] . though more than seven decades would pass from the inception of the ohip, in the who published the laboratory biosafety manual establishing standards for worker safety and laboratory practices. by the time of the third edition in the manual evolved to include succinct definitions of biosafety and biosecurity. "'laboratory biosafety' is the term used to describe the containment principles, technologies, and practices that are implemented to prevent unintentional exposure to pathogens and toxins or their accidental release. 'laboratory biosecurity' refers to institutional and personal security measures designed to prevent the loss, theft, misuse, diversion or intentional release of pathogens and toxins" [ ] . the who manual further describes biocontainment (including biocontainment levels) and risk assessment as the foundations of biosecurity, which in turn have informed us biosecurity strategies in legislation and laboratory practice. in its common application and also as enshrined in various us laws, biosecurity is generally taken to be comprised of five or six main components (depending somewhat on definitions), all designed to limit access to pathogens and toxins to prevent their loss, theft or misuse [ , ] : • risk assessment that is a detailed listing of the hazardous characteristics of an organism or toxin, the probable consequences of unwanted exposure and associated occupational health plans. • access control equipment and barriers, perhaps including perimeter and internal monitoring. • personnel reliability, which may include background investigations, medical screening and assessment of expertise and experience. • control and accountability of materials (with associated documentation of archived materials). • training and emergency planning. • program management and supervision. as noted earlier, none of these constituents is completely unique to biosecurity. successful biosafety programs also depend to one extent or another on the same processes and physical constructs. while most laboratory managers and scientists working with pathogens and toxins are aware of the numerous regulations that govern access to and use of those materials, fewer understand the legal processes by which these come into effect. it is useful to understand the source of legislative action that lead directly to many of the current laboratory biosecurity/biosafety rules and procedures because scientists have the opportunity to influence the rule-making process even (and some would say "especially") after us congress passes new laws. we begin with a brief review of the legislative process starting with its inception in congress through the rule-making procedures that actually implement the law. with this knowledge in mind, we can then put into context the origin of the satl, now familiar even to those infectious disease researchers who do not necessarily work with these organisms and toxins. the constitution of the united states vests "all legislative powers" in "a congress of the united states". any member of congress may introduce legislation, and such proposals are usually referred to as "bills." bills originating in the house are designated as "house resolutions," and carry the abbreviation "hr" before the unique number assigned to it. similarly in the senate one finds "s," that is "senate" (with "resolution" omitted) for bills proposed by one or more its members. thus, when tracking the course of a bill through congress, it is convenient to specify the "hr" or "s" number. both hr and s require approval by the other body and the signature of the president to become law. after a bill is introduced, congressional committees almost always hold formal hearings designed to gather information about the impact of the bill on already existing laws and any new requirements it imposes, and costs (if money has to be appropriated to fund the bill). committee chairmen invite both private and government experts to testify (especially from departments or agencies that will help write the regulations that implement the bill if it passes), and in the process the bill is typically changed (or "marked up") before the committee takes a vote to either move the bill forward or not. it is not unusual for a full committee to refer a bill for discussion to a subcommittee. should a bill be "reported out of committee" -meaning it is referred to the full body of the house or senate -it is then debated "on the floor" where any member can request time to speak. generally, after debate has completed, amendments can be offered, and then the bill is voted upon. a similar version of the bill goes through the same process in the other body, and if passed by a majority of both houses in the same form, is then sent to the president for signature. there are, of course, complications that frequently derail the more-or-less straightforward description above, often deriving from the complex committee structure in the congress. there are currently committees in the house and in the senate. with rare exception, each committee has several subcommittees (as of this writing a total of subcommittees in the house and about in the senate), and subcommittees often have overlapping jurisdiction, so several may hold hearings on a given bill simultaneously. thus, only a minority (around %) of introduced bills are reported out of committee for vote on the floor of house and senate, and few bills escape the committee process without substantial rewriting of the original proposed text based on the decisions of committee members after listening to witnesses at hearings, or taking into account the views of their constituents. and even after surviving this process, the senior leadership of the house and senate each decide whether or not they will, in fact, allow a bill to come up for floor debate at all. should a bill pass both houses in something other than identical form -as often occurs when one house makes amendments to a bill originating in the other body -a "conference committee" must reconcile the differences. if (as is not unusual) a dozen or more subcommittees from each house have been involved in discussing the bill, more than a hundred members may appear at the conference committee (or "conference" for short) meetings. after the conference negotiates the differences in house and senate versions of the bill, it is sent back to both bodies for a final vote; usually the bill is passed after all effort described above is completed. before printing of the bill, it receives a numerical designation of the session of congress and the number of the bill for that session. for example, the "antiterrorism and effective death penalty act of " (the "popular name" of the original bill) was originally introduced in the senate of the th congress and (in session from to ) as s , and was the nd piece of legislation considered, so when passed it received the numerical indicator - , in addition to its popular name, which is then abbreviated as "public law - " or "pl - ". the president may sign the bill or choose to veto it, and congress may override that veto with a two-thirds vote in both houses. upon the president's signature, or in the case of a veto followed by a congressional override, a "bill" becomes a "law" and the various provisions of the law "statutes." the vast majority of laws are denoted as "public laws" which means that they apply to individuals and their relationship with government or society. (there are also "private laws" applying to the relationships between individuals, such as contracts). laws are, in essence, codes of conduct, and public laws (also called "acts") often impose new rules for behavior of individuals, companies or institutions. public laws almost always also make modifications to existing laws that comprise the united states code (formally abbreviated as "usc"), currently arranged in "titles," really sections of law covering familiar aspects of life such as commerce and trade, crimes and criminal procedure, copyrights, food and drugs, taxes, foreign relations, alcohol and firearms, banks and transportation to name but a few. of particular interest in biosecurity law is title -"the public health and welfare" also denoted as " usc" -that is comprised of many hundreds of sections. so, perhaps unsurprisingly pl - made more than a dozen changes to title since laboratory safety and security naturally impact the public's health. but it also made changes to usc ("crimes and criminal procedure"). new public laws routinely mandate actions to be taken by cabinet departments in the executive branch of government, such as hhs. it is then the responsibility of the cabinet secretary to implement those actions. as we will see shortly, with recent biosecurity-related legislation, the secretaries of both hhs and usda are now required to formulate and update a list of organisms and toxins that may be of particular importance to public health if inadvertently released or misused (for example in a biological weapon). how does this implementation happen in practice? in order to execute new laws, the secretary (one or more are always specified in the law) designates an agency within her department to publish an initial proposal indicating the intent of the executive branch to carry out the will of congress, and it appears in the fr as a "notice of proposed rule-making" (nprm), often within days of the president's signature on the original act. it is worth noting that the secretary is granted latitude in interpreting congressional intent, and as we shall see exercises considerable judgment in publishing the nprm. the fr is closely read by administrators in business, government, law, and law enforcement, along with individuals who may be affected by the new pl. via the announcement in the fr, any interested party may submit comments or critiques of the agency's proposed means of implementing the law. comment periods typically last - days (and may even be supplemented by public meetings if the new regulations that result from the rule-making procedure are sweeping enough), after which the agency assembles the suggestions and testimonies. a "final rule" is published in the fr as soon as the agency adjudicates the (frequently disparate) collection of views, which then becomes new regulation. the agency and cabinet secretary are under no obligation to accept any particular individual or individual entity's views, and by no means is the decision on the structure and requirements of the new regulation a matter of simply tallying the net opinion of commenters. rather, the agency uses its own experts -including attorneys who interpret the oft-subtle intention of the congress -in formulating the regulation. it may take many months for the cabinet department to publish the final rule. shortly after the final rule appears in the fr, the new regulation is enshrined in the code of federal regulations (the cfr, not to be confused with the united states code) where it remains in force until a review is ordered by congress, or if a new legislation includes provisions for updating the regulation; agencies may also publish proposed updates in the fr and solicit additional comments from individuals or organizations likely to be affected. the cfr is, like the usc, organized by "title" whose names mostly parallel the titles in the us code (unfortunately, this is not always the case). in summary, after a bill is introduced into congress, debated and then enacted into law by signature of the president, executive agencies (e.g. hhs or department of agriculture) are then mandated to implement the detailed requirements by a "rulemaking" process that is initiated with a nprm published in the fr. individuals, organizations, businesses or other entities are invited to comment on the agency's initial plans. these comments are considered by the agency tasked with crafting the new rule, and then published as a "final rule" that is, in practice, the set of regulations that carry out the will of congress which are then recorded in the cfr. on april , the alfred p. murrah federal building in oklahoma city was destroyed by a truck bomb planted by timothy mcveigh, a former solider and militia movement sympathizer. this event, which resulted in deaths and hundreds of injuries and property damage in excess of a half-billion dollars, stood as the deadliest terrorist attack on us soil until the downing of the world trade center years later. with the memory of yet another terrorist attack -the world trade center bombing -still fresh, president bill clinton had already introduced antiterrorism legislation in early (called "the omnibus counterterrorism act"), but within days of the oklahoma city event senate majority leader robert dole was motivated to propose a similar but more sweeping bill, "the comprehensive terrorism prevention act," s [ ] . when initially introduced, the most prominent component of the act was a limitation on habeas corpus actions brought to federal court by prisoners suspected of an act of terror. when finally passed by the congress as the antiterrorism and effective death penalty act (atedpa) of exactly year to the day after the oklahoma tragedy, the new law (pl - ) included requirements for the secretary of hss to: • "establish and maintain a list of each biological agent that has the potential to pose a severe threat to public health and safety," based on specific criteria including effect on human health, degree of contagiousness, availability and effectiveness of immunization and treatments for illness caused by the agent, and "any other criteria that the secretary considers appropriate in consultation with scientific experts." • regulate transfers of listed biological agents including establishing and enforcing safety procedures, safeguards to prevent access to listed agents for use in terrorism or other criminal purposes while maintaining "appropriate availability of biological agents for research, education, and other legitimate purposes" [ ] . the act was signed into law by president clinton on april , . on june th of the same year, the cdc, acting on behalf of the secretary of hhs published in the fr a "nprm" soliciting comment on implementing the new requirements of pl - to ensure public safety, strengthen public-private sector accountability and collect information concerning the location of potentially hazardous infectious agents while tracking the acquisition of those agents. the satl was born. the cdc also by there were at least two other factors motivating the congress. in may of that year larry wayne harris a member of aryan nation and a self-styled biological weapons expert purchased several vials of yesinia pestis, the causative organism of plague from the american type tissue collection a microbiologic supply house in maryland. harris was arrested but at the time there was no us law prohibiting individuals from purchasing disease-causing organisms so officials charged him with mail fraud because he misrepresented himself as the operator of a legitimate medical laboratory. also a few weeks before mr harris' arrest on march , members of aum shinrikyo, an apocalyptic cult in japan, released an unknown quantity of sarin gas in the tokyo subway system. thirteen people were killed and more than individuals with varying symptoms (some of which were surely related to panic alone) were seen in hospital emergency rooms [ ] . http://www.gpo.gov/fdsys/pkg/fr- - - /pdf/ - .pdf proposed procedures for alerting law enforcement of unauthorized attempts to acquire select agents. the final rule took into account over written comments and was published in the fr on october , . the satl (changed from "select infectious agents list") was comprised of viruses or virus groups, seven bacteria species, three rickettsiae species, coccidioides immitis as the sole fungal species and toxins. at the same time, the cdc also informed entities owning select agents that it would provide application forms for facility registration with the possibility of facility inspection depending on documentation provided and agent transfer forms. the federal bureau of investigations (fbi) (and perhaps other federal agencies) would have access to records and databases for law enforcement purposes. the final rule took effect on april , and was placed in the cfr title part (later moved to part , see below). thus, the history of creating the initial satl and its associated reporting and implementation requirements was: • introduction of "the comprehensive terrorism prevention act" to congress as a result of terrorist attacks on us soil. passage of a markedly revised bill renamed as "the antiterrorism and death penalty act" of and signed into law as pl - by president clinton. • changes are made to the us code and in particular title of the us code, "public health and welfare". • because the secretary of hhs was required by pl - to regulate transfer of certain dangerous pathogens and toxins, the cdc, an agency within hhs and acting on its behalf, publishes a proposed rule making for implementation in the fr. the cdc accepts comments from any interested party, since the proposed rule was only that -a proposal -written by technical experts in the department. • after comments were received the cdc made decisions for implementation of the pl (it did not have to accept any particular suggestion, nor did it accept most) and published a final rule. the "final rule" included the date when the new regulations will go into effect. http://www.gpo.gov/fdsys/pkg/fr- - - /pdf/ - .pdf as a starting point, the cdc adopted the list of organisms and toxin on the "australia list", a pre-existing export control regulation limiting the shipment of potentially dangerous biological materials to only selected states (initially comprised of countries). see http://www.australiagroup.net/en/origins.html http://www.gpo.gov/fdsys/pkg/fr- - - /pdf/ - .pdf the entire code of federal regulations is available electronically at: http://www.ecfr.gov/. the most recent version of the select agents list may be seen at: http://www.ecfr.gov/cgi-bin/text-idx?sid= c fb f fc e a &node= : . . . . &rgn=div http://www.law.cornell.edu/uscode/text/ • the rule was added to us cfr. in this case title of the cfr part (abbreviated in legal parlance as " cfr " now entitled as the "select agents and toxins" section of the cfr) specifically part . . a very similar series of legislative and regulatory events took place after the terror attacks of september , . less than months after that horrific day, the congress passed the uniting and strengthening america by providing appropriate tools required to intercept and obstruct terrorism [ ] (abbreviated as the usa patriot act in a rather tortured acronym). while not directly impacting laboratory biosecurity, the act defines possessing a biological weapon as a crime and also defined a "restricted person" as one who may not ship or transport any biological agent or toxin that is listed as a select agent (adding to title of the us code "crimes and criminal procedures" an entirely new section in "biological weapons" chapter called "possession by restricted persons"). but / led to yet another milestone in biosecurity law in the following year. the public health security and bioterrorism preparedness and response act of (phsbra) [ ] was passed in congress and signed by the president in june. from the standpoint of biological laboratory management and work the act required the following: • the secretaries of both hhs and usda must undertake a biennial review of select agents and are instructed to consider agents that should be added or removed from the satl. the purpose of including the department of agriculture was so that biological materials dangerous to animals or plants could be included in the satl. this would thus enlist the expertise of specialists in the usda not necessarily available at cdc. • required all facilities in possession of select agents to designate an ro who "will need to inventory its facility and consult with others (e.g. principal investigators) as necessary to obtain the information required for this application". the scope of pl - was enormous and several iterations of proposed rules for implementing the law were published in the fr. briefly the official publications (date and fr volume and page) bringing the terms of the law into effect were: throughout the ½-year period -which also included a public meeting in late -about written comments were received by officials at the cdc and many more at aphis (the agency within and designated by usda to implement the requirements of the legislation). although most of the suggestions submitted by commenters were rejected by the agencies, some clarifications and changes were made to the proposed rules as a result. an additional outcome was a re-organization of cfr to make its structure similar to analogous rules promulgated by the usda that appeared in cfr . thus, there are three legislative milestones that have largely defined biosecurity as practiced in laboratories in the united states: the anti-terrorism and effective death penalty act of establishing the first satl and reporting and archiving requirements for transfer of those agents (later put into effect by the cdc acting on behalf of the secretary of hhs); the us patriot act of , defining possession of a biological weapon as a crime, and also "restricted persons" who may not possess or transfer any biological agent -that is, not merely "select agents" that can cause disease; and phsbra that required a biennial review of the satl by both the secretary of hhs and the secretary of agriculture, and also mandated security requirements for access to listed agents, including background checks (a "security risk assessment") of laboratory researchers and designated ro, performed by the fbi and ultimately approved by the attorney general. presidents may issue eos in order to "take care that the laws [of the united states] be faithfully executed" even though there is no explicit provision for these declarations in the us constitution. since the time of george washington through the administration of barack obama more than , eos of various types -some proclamations, others directives for implementing laws or establishing policy -have been issued. it is solely at the discretion of the president to determine whether a policy matter or resolution of ambiguities in the administration of laws warrant an eo. so it has been with biosecurity. shortly before the end of his term in office on january , , president george w. bush issued eo entitled "strengthening the biosecurity of the united states" establishing a formal working group of the same name comprised of cabinet secretaries, the attorney general, the director of in addition, cfr contains the rules promulgated by usda for the select agent list for organisms that can damage important food crops. as should now be unsurprising, title of the code of federal regulations is "animals and animal products", with part addressing "possession, use and transfer of select agents". title of the code is "agriculture" with part also referring to select agents. us constitution article ii section . http://www.presidency.ucsb.edu/data/orders.php national intelligence and the director of the national science foundation [ ] . three tasks were assigned to the working group: . review and evaluate the efficiency and effectiveness of existing laws, regulations, guidance and practices relating to select agents and toxins, physical, facility, and personnel security and assurance at federal and non-federal facilities that function as described above. . obtain information or advice from heads of executive departments and agencies, elements of foreign governments and international organizations with responsibility for biological matters. . prepare a written report to the president, including recommendations for new legislation, regulations, guidance, or practices in laboratories including new oversight mechanisms [ ] . in its report in may the working group recommended: • with respect to select agents and toxins, that the us government perform a risk assessment for each listed item and develop a "stratification scheme that includes biodefense and biosecurity criteria as well as risk to public health." • with regard to personnel security enhancements to the "security risk assessment … to allow for improved vetting of us citizens and foreign nationals" with access to select agents and toxins. • to improve physical security, the development of a "a set of minimum prescriptive security standards." • a review of existing risk assessment of transportation of select agents and toxins. professional societies were quick to respond to the working group's recommendations. for example, the american biological safety association (absa) commented that: "select agent regulations are [already] sufficiently rigorous" and "should not be made more prescriptive;" that the "federal government absolutely should not develop prescriptive physical security requirements;" and that inspections of laboratories with select agents would benefit from "careful selection and training of inspectors," probably reflecting frustration on the part of laboratory managers with questionable results of inspections. there were also concerns that "additional restrictions on shipping will inhibit important research" citing the example of h n samples from mexico that had to be shipped to canada because of restricting us import and transfer regulations. the absa also objected to components of enhanced personnel security requirements that would include the "two person rule" in all circumstances and recommended instead that federal funds "be used to develop or enhance existing biosafety and biosecurity training programs." finally absa objected to licensure of individual researchers as "unnecessary and undesirable." notwithstanding the criticism of the working group's recommendations, eo was followed about months later by eo in july . this directive required the secretaries of hhs and agriculture to review the satl in order to: • designate a subset of the list called "tier agents" that present "the greatest risk of deliberate misuse with most significant potential for mass casualties" or other severely adverse effects on the economy or public confidence, • identify options for graded protection of these tier agents with "tailored risk management practices" and • consider reducing the number of agents on the satl. thus, since the attacks of september , us presidents have shown increasing interest in biosecurity reflected in two key eos, the most recent of which directed subject matter experts at cdc and usda/aphis to review the satl, to further stratify the agents based on risk (for greatest potential harm if released), and to make changes in security arrangements at facilities to minimize those risks. we will see shortly how these eos melded with existing law to generate the most recent modifications to the satl and other security and procedural requirements in laboratories. in addition to the report of the working group summarized above, several other reports from biological scientists stand out as key documents providing guidance to the congress and the executive branch on measures that might be taken to enhance biosecurity in the united states. the national research council in released "biotechnology research in an age of terrorism" [ ] . this document focused mainly on dual use research of concern, but also recommended the creation of a national science advisory board for biodefense (nsabb) that, inter alia would periodically review existing federal government legislation to "provide protection of biological materials and supervision of personnel working with these materials." in addition the council opined "it is crucial to avoid well-meaning but counter-productive regulations on pathogens. rules for containment and registration of potentially dangerous materials must be based on scientific risk assessment and informed by a realistic appraisal of scientific implications." the council suggested that the nsabb could "provide advice … about revising regulations in response to new developments" and that "rules governing transfer of materials between laboratories… might also be regularly reviewed by nsabb" in light of new threats. shortly thereafter, the nsabb was chartered by the secretary of hhs [ ] . in , the commission on the prevention of weapons of mass destruction, proliferation, and terrorism (c-wmd) tasked by the congress in pl - (implementing recommendations of the / commission act of ) produced a comprehensive report entitled "world at risk" [ ] . the commission regarded as "likely" that there would be a terrorist attack somewhere on the globe utilizing a weapon of mass destruction (wmd) within years, and further believed that terrorists were more likely to use a biological than a nuclear weapon. the commission's prediction has fortunately not come to pass. nonetheless, few would regard the risk of wmd use as receding. among the recommendations of the commission of importance to biological scientists were that the united states should: "conduct a comprehensive review of the domestic program to secure dangerous pathogens, … tighten government oversight of high-containment laboratories, … [and] promote a culture of security awareness in the life sciences community." these measures closely align with the biosecurity principles of access control to disease-causing organisms and toxins, accounting of those agents and personnel reliability programs. the last of the commission's recommendations was explored in detail by the nsabb in . in a report entitled "enhancing personnel reliability among individuals with access to select agents" [ ] , board members recognized that research programs involving nuclear materials often involved sensitive national security issues and might serve as a model for addressing the "insider threat" problem in biological laboratories, but at the same time realized that there are significant differences between pathogens and nuclear materials (including nuclear materials that might be part of weapons systems). noting that local institutions were already successfully screening individuals who might work with select agents (and based on the very few applications rejected by the department of justice in the security risk assessment program), the board counseled against a "formal, national personnel reliability program" as it might have "unintended and detrimental consequences" for scientific research. instead the board suggested that individual institutions should work to enhance a "culture of responsibility and accountability" in combination with education on biosecurity issues within professional societies. the board also recommended reducing the list of select agents or stratifying them further by risk, which was in fact taken up by eo in . thus, we can see the careful considerations of the c-wmd and nsabb finding their way into us government policy. at about the same time and in response to a request from the homeland security council at the white house, the national academies of sciences released its study "responsible research with biological select agents and toxins" that listed a series of recommendations similar to those from the nsabb and also suggested stratifying the list of select agents by risk [ ] . the academy group further advised that some baseline level of physical security be established for facilities holding select agents. also in , a us government interagency "working group on strengthening the biosecurity of the united states" created under eo reviewed procedures at facilities possessing select agents and toxins, specifically: • evaluating the efficiency and effectiveness of existing laws, regulations … and practices relating to physical, facility and personnel security and assurance at facilities. obtaining advice from heads of us government executive agencies and departments and elements of foreign governments and international organizations that have similar responsibilities. like the c-wmd, the working group recommended a reduction or stratification of select agents so that security measures might be tailored to the level of risk; require at the local level that facility managers review the behavior and practices of individuals with access to select agents; and development of a set of minimum security standards with enhancements based on risk associated with select agents [ ] . all of these reports ultimately contributed to the content of the eo , "optimizing the security of biological select agents and toxins in the united states," which as noted earlier called for a special designation for the highest-risk agents as "tier agents," and graded protection of the items on the satl. the timing of eo , early july of , coincided with the second biennial review of the satl and an "advanced nprm and request for comments" appeared in the fr on / / ( fr ) that included the new "tiering" as directed by the president. as a result of eo and acting on authorization already enshrined in law as a result of the phsbpra of , over the next years the cdc (acting on behalf of the secretary of hss) and the aphis (acting on behalf of the secretary of agriculture) produced a final rule on october , that established "tier " agents as follows finally, three viruses were added to the satl with the publication of the new rule: sars-cov (the organism causing the severe acute respiratory syndrome first identified in ), lujo virus (a hemorrhagic fever virus closely related to old world arenaviruses) and chapare virus (a new world arenavirus also causing hemorrhagic fever in humans). for tier agents, new requirements emerged from the cdc and aphis as follows (with their location in the cfr noted for ease of reference): • clinical laboratories must immediately report by telephone, facsimile or e-mail the identification of any of the hhs or overlap tier agents ( cfr . and . ). • security plans for select agents must also include for tier agents ( cfr . ): • a description of pre-access suitability assessment of persons who will have access to tier agents. • procedures for how an ro will coordinate their efforts with the entity's safety and security professionals. • procedures for ongoing assessment of the suitability of personnel with access to tier agents. • additional security enhancements must be put in place to ( cfr . ): • limit access to tier i agents only those individuals who are approved by the hhs secretary after fbi security risk assessment. • outside of normal laboratory hours, ro approval access to agents. • a minimum of three security barriers where each barrier adds to the delay in reaching secured areas where agents are stored. • facility biosafety plans must include an occupational health program for individuals with access to tier agents ( cfr . ). • facility incidence response plans must describe an entity's response in the case of failure to detect intrusion and procedures for notifying appropriate officials and law enforcement ( cfr . ). hence, four related but distinct forces have resulted in current laboratory biosecurity practices and procedures: statutes, landmark studies from practicing professionals, eos from the president, and recommendations from practitioners via professional organizations, academia and individual comment (see figure . ). it is important to note that via the rule-making process subject matter experts in laboratory practices and management had the opportunity to influence the formulation of the satl and some of the physical security and accounting practices now in force at facilities holding those potentially dangerous materials. the formation of the satl and its associated security measures is a good template for gaining insight into federal agency rule making after a new law is enacted. since the comments received by an agency can be quite extensive, they may overwhelm the ability of individuals reviewing them to do so within the -or -day comment period. in addition, some comments may point to new information that was either overlooked or not available at the time of the original fr publication. thus, the rulemaking period may be extended; notification of such is made via the fr. the evolution of the satl -the centerpiece of much of the biosecurity apparatus in the hundreds of facilities across the united states that hold the agents -is summarized in the timeline from through when the "tiering" of select agents came into force as a result of eo (see figure . ). it appears clear that biosecurity rule-making has, in the recent timeframe, become very complex and may extend over several years, involving as it does a wide variety of congressional mandates and the need to solicit comments from researchers in academia and industry working with dangerous pathogens. whether or not the plethora of regulations will result in actually strengthening biosecurity remains to be seen. professionals in the field are not always successful in changing the initial draft of an agency's proposed rules. in this particular episode of rule-making, comments were received "from researchers, scientific organizations, laboratories and universities" (see fr , dated october , , accessible at: http://www.gpo.gov/fdsys/pkg/fr- - - /pdf/ - .pdf). most of the recommendations for changes in the proposed rule were rejected by, in this case, the department of agriculture, but the rationale for each rejection was specifically addressed. in other cases, recommendations from comments are more frequently incorporated into the final rule. advice and guidance to the cdc director and … director of laboratory safety" [ ] . it remains to be seen whether the advisory group's recommendations will lead to further revision of cfr and cfr biosecurity regulations. many researchers have noted that well-intentioned regulations designed to protect public safety and limit the illicit use of select agents result in unintended consequences including significant costs to bring facilities into compliance with technical requirements [ ] and decreased productivity as measured by publication count and even abandonment of research involving live agents [ ] . current-day biosecurity procedures and regulations are, in large measure, a result of several near-calamitous terrorist events in the united states, raising public awareness of the threat posed by a particular infectious agents and toxins that, if released by intent or accident, could have devastating effects on human or animal health, and even that of important food plants. congress has responded by passing legislation that imposes formidable requirements on laboratories possessing "select agents and toxins," and the executive branch of government has, as compelled by the constitution, implemented those mandates with the assistance of technical experts inside and outside of government. substantial but hard-to-quantify costs accrue to facilities that in turn may decrease research productivity. it is probably impossible to know whether existing biosecurity legislation passed starting in actually reduces the chances of illicit use of biological materials or even accidents in their transfer or handling. recent security breeches will likely result in additional congressional action and eos, some of which may prove costly. laboratorians have opportunities to influence the process of rule-making by which laws are brought into effect, but only with a keen awareness of the process and review of proposed regulations in order to provide key federal agency administrators with critiques and suggestions to reduce the prospect of new biosecurity requirements that are either ineffective or onerous. while there is no guarantee that intervention from professionals will stem the tide of regulations, laboratory managers, biosafety officers and institutional oversight committee members must make an effort to remain current with proposed rules and to vigorously comment to regulatory agencies. overview of biosecurity convention of the prohibition of the development, production and stockpiling of bacteriological (biological) and toxin weapons and on their destruction staff immunisation: policy and practice in child care office of the assistant secretary for preparedness and response biosafety in microbiological and biomedical laboratories microbial threat lists: obstacles in the quest for biosecurity? biosecurity challenges of the global expansion of high-containment biological laboratories summary statement of the asilomar conference on recombinant dna molecules the scientific background of the internatioal sanitary conferences league of nations bulletin of the hygiene organization of the league of nations eyes on the prize: lessons from the cholera wars for modern scientists, physicians, and public health officials world health organization. laboratory biosafety manual implementation of biosurety systems in a department of defense medical research laboratory are we only burning witches? the antiterrorism and effective death penalty act of 's answer to terrorism aum shinrikyo: insights into how terrorists develop biological and chemical weapons the antiterrorism and effective death penalty act uniting and strengthening america by providing appropriate tools required to intercept and obstruct terrorism public health security and bioterrorism preparedness and response act of executive order : strengthening laboratory biosecurity in the united states biotechnology research in an age of terrorism. committee of research standards and practices to prevent the destructive application of biotechnology oversight of dual-use biological research: the national science advisory board for biosecurity world at risk. the report of the commission on the prevention of weapons of mass destruction proliferation and terrorism enhancing personnel reliability among individuals with access to select agents responsible research with biological select agents and toxins cdc lab determines possible anthrax exposures: staff provided antibiotics/monitoring infectious diseases: smallpox watch report on the inadvertent cross-contamination and shipment of a laboratory specimen with influenza virus h n cdc announces the formation of an external laboratory safety workgroup select-agent status could slow development of anti-sars therapies effects of the usa patriot act and the bioterrorism preparedness act on select agent research in the united states what might the future bring?as of the time of this writing, there have been two recent events that are likely to result in yet more oversight of biosecurity practices in the united states.on june , , cdc researchers working in the bioterrorism rapid response and advanced technology (brrat) laboratory transferred samples of b. anthracis (ames strain) from a biosafety level (bsl- ) suite to a bsl- lab on the belief that neither viable vegetative cells nor spores were in the samples as they had been subjected to an inactivation process before being moved. however, at least some of the samples were not sterile, potentially risking infection in cdc personnel, although subsequent investigation revealed this possibility to be "highly unlikely" [ ] . this breech of biosafety practice was announced on july , [ ] .further, on july , the cdc reported that several vials labeled "variola" (variola virus is the causative agent of smallpox) had been found at a cold storage facility operated by the food and drug administration on the campus of the national institutes of health (nih) in bethesda, maryland [ ] . subsequent testing performed at the cdc confirmed the presence of viable virus in two of six vials. by international agreement, all variola virus is to be kept in secure storage at two laboratories: at the cdc in atlanta and at the state research center for virologic research in koltsovo, russia, and is technically "owned" by the who, which must approve all experiments involving its use. while such news was not wholly surprising -variola had turned up in at least two european laboratories since the who required destruction of the virus or transfer to the official who repositories -it did raise the question of accountability for extraordinarily dangerous pathogens in the united states.also, in january at the cdc's influenza division laboratory in atlanta, a sample of low-pathogenic avian influenza type a (subtype h n ) was contaminated with a highly pathogenic avian influenza type a (subtype h n ) with "subsequent shipment of the contaminated culture to an external high-containment laboratory." although there were no apparent adverse effects, the episode clearly posed a risk to individuals in the receiving laboratory (and perhaps others who handled the material before it was shipped). many new review procedures and oversight processes were put into place (presumably at substantial cost) at the cdc [ ] .these episodes were more than an embarrassment for the nih and cdc. since the cdc provides the staff to carry out inspections at facilities registered to hold select agents and toxins, most researchers would probably assert that the cdc has a special responsibility to uphold all biosafety and biosecurity regulations. the head of the brrat resigned. perhaps even worse, the united states was in violation of a critical international agreement intended to prevent the reintroduction of variola into the human population.at the end of july, cdc director frieden announced the formation of an external advisory group comprised of leading researchers and biosecurity experts to "provide key: cord- - mexup n authors: jain, lucky title: racial disparities in perinatal outcomes are a blight on our progress date: - - journal: clin perinatol doi: . /j.clp. . . sha: doc_id: cord_uid: mexup n nan the year will remain etched in our memories like none other in recent times. multiple disruptions have created unprecedented challenges, which have engulfed the entire globe. first, it was the sars-cov- virus, and the pandemic it caused, that paralyzed every nation, big and small, and brought life as we know it to a standstill. then came the economic downturn, lost jobs, and businesses turned upside down and their many downstream consequences. and then, particularly for those of us in the united states, unrest related to racial injustice spread like a wildfire. it highlighted the disproportionately high toll covid- has taken on minorities as well as the health disparities that are so pervasive in our environment. indeed, births to non-hispanic black women are associated with a significantly higher risk of prematurity and other adverse outcomes when compared with non-hispanic white women. a systematic review and metaanalysis by and colleagues showed that black women had a twofold higher risk of preterm birth compared with whites. similar data can be seen in annual vital statistics year after year and across all preterm gestations (fig. ). a better understanding of these differences could help shape interventions, but little progress has been made in this regard. decades ago, david and colleagues showed that black women born in the united states were at greater risk for delivering low-birth-weight babies than women with similar ancestry who had immigrated to the united states from africa. studies such as these questioned previously held beliefs about racial differences in birth outcomes resulting from genetic differences and laid bare the consequences of life in the united states as a person of color. the interplay of social and environmental factors contributing to poorer perinatal outcomes in black women has been the subject of much investigation. glimmers of hope come from "pockets of progress" in certain counties where racial differences in outcomes have all but disappeared (fig. ) . positive experiences from these areas could and should set the stage for larger public health interventions to remove health disparities once and for all. that will require political will and a societal call for action. needless to say, there is more to improving perinatal outcomes than just eliminating racial and health disparities. in this issue of the clinics in perinatology, drs gyamfi-bannerman and miller have brought together experts in perinatology to cover topics of great importance in neonatal-perinatal medicine. the authors cover a wide array of topics, including prematurity, infections, maternal conditions, and racial disparities, to name just a few. as always, i am grateful to the publishing staff at elsevier, including racial and ethnic differences in preterm birth: a complex, multifactorial problem ethnic and racial disparities in the risk of preterm birth: a systematic review and meta-analysis differing birth weight among infants of us born blacks, african-born blacks, and us-born whites pockets of progress amidst persistent racial disparities in low birthweight rates key: cord- -fctcfoak authors: romano, john l. title: politics of prevention: reflections from the covid- pandemic date: - - journal: nan doi: . / sha: doc_id: cord_uid: fctcfoak the covid- pandemic from a prevention science perspective, including research topics, is discussed. political considerations that influence prevention activities, with examples from the pandemic and from more typical prevention initiatives in schools and communities, are presented. the definitions of prevention science and prevention interventions are delineated, and a brief summary of prevention history is given. the relationship between health disparities and covid- is discussed. two theoretical perspectives that may help to inform effectiveness of covid- prevention measures, health belief model and theory of reasoned action and planned behavior, are summarized. the article emphasizes the importance of adapting prevention applications to the intended recipients, especially ethnic and cultural groups. the need to strengthen prevention training in graduate education and strategies to reform the education to meet accreditation and licensing standards are suggested. daily news reports, social media messages, press conferences, and other sources provide information and opinions about the coronavirus pandemic that has swept across the world like a major natural disaster. however, unlike natural disasters, the virus, also called covid- , the disease caused by the novel virus, knows no boundaries, and at this writing, neither a vaccine nor therapy has been developed to control the virus. furthermore, despite months of study by expert specialists across the global scientific landscape, much is unknown about the virus; although, hopefully, more will be understood by the time this article is published. thus, as of now, prevention is the cornerstone and main strategy to control and mitigate the spread of the virus. although covid- research has been initiated among social scientists, the research projects this author has seen focus on the important psychosocial effects of the virus, such as managing anxiety and stress, and providing psychological support. this author, appreciating that his sources are limited, has yet to see a social science research project that studies the effectiveness of recommended prevention interventions or other virus prevention initiatives from a psychosocial perspective. the national institute of mental health ( ) recently published its strategic plan for research with prevention and cure as one of its major goals. it is timely to mount interdisciplinary research projects that address the psycho-social-behavioral aspects of covid- prevention recommendations and other initiatives. therefore, it is appropriate that the inaugural issue of the journal of prevention and health promotion (jphp) includes a paper that speaks to this historic global pandemic, which relies primarily on prevention science and prevention interventions to reduce illness and death caused by prevention is an interdisciplinary science, with contributions from many specialties. however, my primary area of training and specialization is prevention psychology. therefore, i am writing this article from a prevention psychology perspective and recognize that other specialists may offer differing and complementary perspectives. the article is organized in five sections. initially, distinctions between prevention science and prevention interventions are reviewed, along with a brief history of prevention. this discussion is followed by the influence of political considerations on prevention interventions, whether smaller scale interventions or major global interventions recommended to contain covid- . in the health disparities, prevention, and covid- section, u.s. population health and economic disparities exposed by the pandemic and their influence on covid- prevention recommendations are highlighted. the section prevention applications: understanding the audience provides guidance for the development of prevention applications. in this section, two theories are summarized: health belief model (hbm; hochbaum, ; rosenstock, ) and theory of reasoned action and planned behavior (trapb; ajzen, ; fishbein, ) . they are presented as examples of theories with long histories studying prevention interventions and relevant within a covid- prevention context. the future directions: implementing a prevention agenda for applied psychology section of the article offers suggestions for prevention research related to the pandemic, and recommendations for training in prevention science including multidisciplinary education in applied psychology. throughout the article, examples as they apply to covid- prevention interventions are discussed, as well as prevention projects that might be implemented within local institutions and communities. prevention science is an interdisciplinary specialization that draws expertise from multiple disciplines, including psychology, social work, medicine, public health, economics, and public policy. the society for prevention research states that the major goal of prevention science "is to improve public health by identifying malleable risk and protective factors, assessing the efficacy and effectiveness of preventive interventions and identifying optimal means for dissemination and diffusion" (society for prevention research, , p. ) . this goal encompasses a broad range of human ecology across the life span and, within various environments, whether they be schools, communities, or nations, to maximize health and well-being. prevention science is the foundation for the development of prevention interventions. early on, caplan ( ) developed a now classic framework to categorize prevention interventions. caplan called prevention interventions (a) primary (to prevent a disease or illness and suitable for everyone, such as mass media vaccination messages), (b) secondary (delivered to those at risk, such as teen sex education programs), and (c) tertiary (to reduce the impact of an existing problem, e.g., rehabilitation programs for stroke victims). caplan's framework was initially designed for public health or medical preventive interventions, such as childhood vaccinations, although the framework has been regularly applied to social, emotional, and behavioral interventions. however, in the context of behavioral health, primary prevention may not be a goal as preferred behaviors may change at different periods of a person's life. for example, a school-based prevention intervention goal might be to reduce teen pregnancy or delay alcohol use through psychoeducational interventions, but these will change as the adolescent matures into adulthood. as a follow-up to caplan ( ) , gordon ( ) presented a continuum of prevention interventions that he labeled (a) universal, (b) selective, (c) indicated. universal interventions, like primary prevention, are for everyone within a population or targeted group. selective and indicated interventions (like secondary prevention) are designed for those at lesser or greater levels of risk in relation to the problem or disorder. gordon did not believe that tertiary interventions belonged within a prevention intervention classification scheme because the problem had already occurred. gordon's intervention classification was adopted by the institute of medicine's committee on prevention of mental disorders (mrazek & haggerty, ) . more than years ago, romano and hage ( ) expanded on earlier categories of prevention interventions presented by caplan ( ) and gordon ( ) to include the promotion of individual protective attitudes, behaviors and skills (protective factors), and systemic and advocacy interventions to promote health and well-being. others have also expanded prevention interventions to include promotion of protective factors (conyne, ; cowen, ; national research council and institute of medicine, ) and advocacy for systemic interventions that promote community health (pieterse et al., ; prilleltensky, ) . in terms of individuals and communities, promotion of protective interventions might include, for example, strengthening family-based services, offering affordable and quality child care services, providing community parent education programs, conducting workshops on job-seeking strategies, and promoting increased community adolescent recreational opportunities. numerous examples have been implemented in schools for many years, including social-emotional learning programs designed to foster healthy peer relationships, self-awareness, and enhance self-esteem. since mid-march , u.s. public health professionals have strongly recommended practices to protect citizens from covid- . very quickly, most citizens know about the potentially lifesaving behaviors, for example, stay at home and maintain social distance when outside the home, frequent handwashing, and masks in public. these behaviors of lifestyle rapidly became very common for most people across the globe. it is ironic that given the tremendous advances in medicine and other fields during the last years, as of now, these protective preventive interventions are the best tools to contain the spread of the virus. studies of covid- preventive interventions offer rich potential to prevention scientists, researching topics such as effectiveness of recommended behaviors, compliance across different demographic groups, and effectiveness of varying media messages. systemic prevention interventions that enhance personal, social, and physical well-being across institutions, communities, and larger entities, such as cities, states, or countries, have been advocated across many different problem areas (american psychological association [apa], ). for example, tobacco use and secondhand exposure is a major health hazard. as a result, amid much controversy, many communities across the united states and beyond prohibit the use of tobacco products in bars, restaurants, and other public places, such as outdoor recreational areas. to reduce addiction risk among teenagers and young adults, communities have also enacted preventive legislation by increasing to years the legal age to purchase tobacco products. another systemic intervention example is the restrictions on the marketing and purchasing of vaping products and e-cigarettes as communities have moved quickly to control advertising and purchases. the centers for disease control and prevention (cdc, n.d-b) has put forth strong recommendations against their use, considering them unsafe for youth, young adults, pregnant women, and adults who are not using tobacco products. furthermore, although they may have some benefits to help tobacco users stop using tobacco, the health risks are unknown as is their ability to assist in smoking cessation. as such, e-cigarettes and vaping have been heavily regulated or banned in many countries and in several u.s. states (cdc, ; global center for good governance in tobacco control, ). several years ago, south korea initiated a country-wide initiative to prevent internet addiction (cho, ) . the systemic intervention includes several components delivered across the population, including addiction prevention education in schools, training internet addiction counselors, and comprehensive social media campaigns. in the united states, an ongoing and contentious battle on gun control and gun availability has been waged over many years (spitzer, ) , and the american public health association calls gun violence an epidemic (benjamin, ) . many scholars and prevention specialists argue that stricter gun-control measures save lives, whereas opponent objections are based on the second amendment of the u.s. constitution (right to bear arms) and restriction of individual freedoms. in the united states, and other countries, many systemic prevention strategies are recommended and, in some cases, required, in attempts to mitigate the spread of covid- . several states instituted "stay at home" policies and other recommendations. however, these measures have resulted in a severe economic depression across the country. the economic consequences have created a vigorous debate about the necessity for the prevention recommendations in parts of the united states. although legislation has provided some financial compensation for businesses, and unemployment benefits for employees, the effects of the economic decline are devastating for many in the united states. the debate is a reminder that political considerations are very important to address when designing prevention interventions. political considerations can influence the level of support for preventive actions. therefore, it is important that prevention specialists consider the political dynamics that may surround a prevention intervention proposal, whether on a small scale as in one school, or a large school district or community. although prevention specialists will be excited about an intervention they wish to implement, they must be cognizant of the political dynamics that surround an intervention. therefore, it is necessary for prevention specialists to carefully assess sources of support for and resistance to an intervention. an intervention that is well supported in one locale or group may lack support in another group or setting. careful attention to communicating with key stakeholders at the earliest stages of a prevention project is critical. as the covid- pandemic has unfolded, preventive recommendations to reduce the virus spread have exposed major differences among stakeholders, regions, and political beliefs. the differences include social distancing and face mask use recommendations and timelines to open businesses, gatherings for religious purposes, and recreational areas. the core of the controversies centers around economic issues, citizen health and well-being, and individual freedom versus the common good. specialists from fields such as medicine and public health, and government officials debate the urgency and actions needed. the differences have become more disparate as the pandemic has evolved. some become impatient with prevention recommendations as they impinge on personal freedoms and reduce sources of financial and social support and pleasure. of course, political disagreements surrounding the prevention of the covid- virus are much greater and immediate threats to health and well-being compared with more typical prevention applications that specialists offer in schools, communities, and workplaces. however, knowing about and considering differences among stakeholders are critically important for the success and sustainability of a prevention project. as an example, instructive for this discussion with relevance to prevention and psychology, is the process to gain apa approval of the guidelines for prevention in psychology (apa, ). the guidelines were approved by apa council after about years of development by a guidelines task force of apa members. although there were obstacles during the journey to approval, one is especially important in the context of this article. guidelines drafts were reviewed by apa committees and boards as well as stakeholders within the public domain (e.g., state boards of psychology). one of the major concerns of apa governance bodies during the review process was the inclusion of phrases and terms such as "social action" and "advocacy." according to apa governance at the time, guidelines are not designed to promote a social agenda. thus, to proceed with the approval process, the task force made concessions to remove these terms from the title and body of the article. interestingly, apa has a very active advocacy initiative within its structure, reporting regularly to the membership about its work with policy makers on topics such as promoting social justice and human rights, reducing health disparities, addressing violence prevention, and encouraging members to do likewise. perhaps apa only objected to the inclusion of the terms in guideline development at the time of approval, and the policy has now changed. however, at the time, the guidelines task force was surprised by the apa position, because much prevention activity is focused on advocacy and social justice kenny & hage, ; romano, ) . although the guidelines were eventually approved, apa concerns about terminology and language were unexpected and caused significant delays in eventual approval. just about everyone agrees that "prevention is better than cure." however, prevention specialists, especially those newer to the field, would be wise to consider differences among recipients and stakeholders. the implementation of prevention projects will often be supported or resisted in ways that mirror the larger population in which the prevention project is implemented. furthermore, as seen with covid- prevention recommendations, recipients and stakeholders may lose patience with prevention interventions as outcome evaluations do not yield immediate results. although other types of evaluations (e.g., formative) are useful, stakeholders (e.g., community leaders, political figures) may expect an intervention to correct a problem rapidly. however, as seen with the hurried attention to develop a covid- vaccine, infectious disease scientists remind us that development will take considerable time, require collaboration across the scientific community, and incur considerable costs before its effectiveness and safety can be established (corey et al., ) . of course, developing a vaccine for a worldwide pandemic does not compare with local psychosocial prevention interventions, but the development, effectiveness, and sustainability of an intervention is, nevertheless, demanding and time consuming. in an apa convention presentation (romano, ) , i discussed three issues, not mutually exclusive, that are likely to lend controversy to prevention interventions, even though, at the outset, all might agree that the prevention idea is good. the issues are (a) values, (b) morality, and (c) economics. first, understanding individual and community values related to potential prevention interventions is important. a value-related issue is differences between the needs of the individual and needs of the community. what is good for the community may not be supported by individuals. in highly individualistic cultures such as much of the united states, collectivistic beliefs will create controversy. in the covid- pandemic, recommendations to practice social distance, stay-at-home, and face masks, as measures to protect community health, have been resisted and angrily protested in u.s. cities. the issue is complex due to differing values between individuals, communities, and regions of the united states. furthermore, due to work requirements and socioeconomic levels, some do not have the luxury of staying at home (e.g., health care providers, grocery store employees). brown ( ) comments that stay-at-home and social distance recommendations are choices available to wealthier members of society, less so for members of lower socioeconomic groups. in collectivistic societies, with values and behaviors associated with community benefits, rather than individuals, citizens are more accepting of country-wide policies that have the potential to reduce community spread of covid- . drawing comparisons between countries is difficult, due to factors such as enforcement of preventive regulations, availability of virus testing, methods of reporting, and population density. however, a few examples are illustrative. as of may , , the united states had , covid- cases and deaths per million population, whereas south korea had covid- cases and five deaths per million population, singapore had , covid- cases and four deaths per million population, and malaysia had covid- cases and deaths per million population (worldometer, ) . all three asian countries, with a tradition of collectivism, have much lower death rates compared with the united states. although singapore's incidence rate is like the united states, the other two countries have much lower incidence rates compared with the united states. values are also related to the use of contact tracing, a prevention strategy used by public health professionals to mitigate spread of community disease. contact tracing is a process of contacting individuals who have been in close contact with someone who tested positive for the virus to recommend selfquarantine. contact tracing is used in different countries and the united states. however, the strategy offers disadvantages, including training of public health personnel who are not familiar with contact tracing, costs, reluctance of people to accept information when notified that they have been exposed to the virus, and resistance of citizens to submit to government surveillance (temple, ) . the last disadvantage will be especially prominent if widespread surveillance is conducted via cell phone apps. citizens in more individualistic countries are more likely to resist what they perceive as threats to freedom and privacy, and governmental interference. singapore has been using contact tracing via cell phone apps since march , perhaps one reason for the country's low covid- death rate. the united kingdom is developing a similar cell phone plan as a strategy to more quickly reduce virus spread and open the country to increased freedom of movement (chowdbury et al., ) . values influencing prevention interventions were also revealed in the debate about cigarette smoking. in some locales, tobacco use is prohibited in closed spaces, and some cities also prohibit tobacco use in outdoor areas. tobacco use regulations vary across u.s. communities. similarly, in the context of schools, differing values among educators about the amount of time children are excused from academic classes to participate in social-emotional learning activities requires discussion. prevention specialists need to work with educators and parents to balance academic instruction with proposed psychosocial prevention activities to reduce resistance to the intervention. methods to resolve differences will be different based on school subjects, student grade level, school administrators, and parental preferences. the second issue to consider in prevention intervention planning is morality. an example from the covid- pandemic is the issue of attendance at religious ceremonies and events when stay-at-home and social distancing orders are in place. some argue that during this time of distress and need for community, it is especially important that people congregate with members of their faith community. others contend that following the stay-at-home recommendation is the more moral position to stay healthy and minimize the virus spread. in a school-based example, some parents will accept and deem important prevention programs that teach sex education to develop healthy sexual behavior, reduce teen pregnancy, and promote respect and acceptance of different sexual identities. other parents will disagree, stating that this type of education is best left to parents and the family. also, bully prevention programs in schools generally receive strong support. a component of such programs to indirectly reduce bullying behaviors might include promotion of social groups and increased mental health support of students who are more likely to be bullied (e.g., lesbian, gay, bisexual, transgender, and queer [lgbtq] students, special needs students). the need for such interventions is best explained to parents and stakeholders who may not be fully aware of the importance of the intervention in a comprehensive bully prevention program. the third issue that merits discussion is the economics of prevention. finances may be a more acceptable form of resistance and used to camouflage other reasons for resisting, "this is a good idea, but we just can't afford it." this argument has been used in the covid- pandemic as local and national leaders debate the importance of relaxing stay-at-home recommendations to support local businesses and community economies. similarly, communities in the united states have outlawed the sale of electronic vaping devices to anyone below years. cities have instituted such laws based on the potential harmful effects of vaping and danger of nicotine addiction, especially in brain development of adolescents. however, stores that sell these products may lose business, similarly, to bans on selling tobacco products to adolescents and young adults. another economic issue relates to the mental health of youth and young adults. specifically, the need for mental health services for children, adolescents, and postsecondary students is growing rapidly, and resources to serve students in educational institutions are inadequate (hunt & eisenberg, ; kaffenberger & o'rouke-trigiani, ; oswalt et al., ) . the units that house school counselors, school social workers, college and university counselors, and psychologists are often understaffed in educational institutions. mental health professionals are heavily engaged in crisis-intervention work, which leaves less time for prevention activity. data showing school counselor shortages have been presented for many years by the american school counselor association (asca). asca recommends a ratio of one school counselor to students, whereas the mean ratio across the united states is students to each counselor, with a range across the states from a low of to to a high of to (bray, ) . different reasons across the states can account for such large discrepancies, but insufficient funding to support mental health professionals in schools and higher education usually resolves around limited public education funding and differing educational priorities mitchell et al., ) . recent advocacy for increased student mental health support occurred in the st. paul, minnesota, school district when teachers went on strike in march . this was the first district strike in years. one of the main grievances of the educators was lack of student mental health support personnel. the strike ended just before the schools closed due to the pandemic, but not before the district agreed to increased funding for student mental health personnel. funding decisions and values are intertwined, as values dictate spending, whether in personal finances, or within a large unit or system. funds are dispersed based on values, and funding will dictate the strength and scope of prevention initiatives. a disadvantage of many prevention interventions is that immediate results are not usually realized. therefore, prevention leaders must keep stakeholders engaged in the project through regular reporting of progress and evaluation processes. a final example that relates to values and funding is the suspension in fall of of the national registry of evidence-based programs and practices (nrebpp) by the u.s. government. in january , nrebpp was no longer funded by the u.s. government. nrebpp was a substance abuse mental health services administration (samhsa) program that had evaluated prevention programs across topics and age groups since . despite objections to the closure of nrebpp from different sectors of the country, federal health officials stated that nrebpp had a flawed system of evaluating programs, and a new system would replace it. the new system, also sponsored by samhsa, is called evidence-based practices (ebp) resource center. however, green-hennessy ( ) stated that nrebpp had a long history, and the system had been strengthened over the years, and rather than replace nrebpp, the money could have been better spent to eliminate weaknesses or flaws in nrebpp. perhaps there were other motivations for replacing nrebpp, but its demise was shocking to prevention specialists as nrebpp was an important resource. hopefully, the ebp resource center is sufficiently improved compared with nrebpp to justify the funds to create it. as the covid- panic spreads across the united states, vast differences in incidence and death rates within population groups are observed. although the data are incomplete as most jurisdictions have not reported data by race and ethnicity at this writing, what has been reported is alarming and distressing. for example, news outlets report that african americans in some of the largest cities account for many more virus incidences and deaths disproportionate to their numbers in the population. data from chicago show although blacks make up % of the city's population, blacks account for % of the city's covid- fatalities, and % of the virus cases. similar data were found in milwaukee, where blacks make up % of the city's population, but account for % of deaths. michigan and louisiana show similar disproportionate data (cineas, ; johnson & buford, ) . similarly, the cdc (n.d-a) reports new york city data showing virus death rates substantially higher for blacks/african americans and hispanic/latinx persons compared with whites and asians. as of mid-april , data show the death rate for black persons at . / , , hispanic/latinx persons at . / , , white persons at . / . , and asian persons at . / , . the devastating impact of the virus on the navajo nation populations was reported by silverman et al. ( ) , showing that the navajo nation had the highest per capita cases of covid- in the united states at , / , surpassing new york city at , / , . multiple reasons account for these disparities including u.s. history of racism among ethnic minorities that leads to discrimination, low social economic status, inadequate or lack of health care, limited english language proficiency, immigration status, housing in confined spaces, and homelessness. furthermore, the pandemic's universal prevention recommendations are difficult or impractical to follow for many. frontline (e.g., health care personnel, factory workers, grocery store employees) employee work responsibilities cannot be conducted from a distance, and they are often lower paid. thus, they do not have the luxury of following stay-at-home recommendations (brown, ) . the covid- pandemic has shed a bright light on health care inequities and disparities in the united states. health disparities have been a focus of scholars and u.s. officials for some time. the u.s. office of disease prevention and health promotion (n.d.) notes that groups within the united states experience health disparities that contribute to poor health and ability to achieve maximum health. groups include those based on race and ethnicity, sex, sexual identity, age, disability, socioeconomic status, and geographic location. research from different scholarly perspectives has examined health disparities, including differences between rural and urban areas (james et al., ) , impact of racial oppression on health outcomes (gale et al., ) , public policy solutions to address disparities (assari, ) , health care experiences of transgender binary and nonbinary university students (goldberg et al., ) , and access to integrated health care (buki & selem, ; tucker et al., ) . in addition to spotlighting health inequities, covid- has also exposed extreme xenophobia, racial harassment, and discrimination primarily against asian populations. a few u.s. leaders may have fueled this behavior by referring to the virus as the "chinese virus," which some may interpret as people of chinese ancestry spreading the virus, although leaders have denied the accusation. although face masks have become more regularly used as the virus has spread across the country, some asians feel stigmatized by using them, and thus, putting their health at risk (zhou et al., ) . the social, emotional, psychological, and behavioral components of preventing covid- illness and deaths are important areas of study for prevention scientists. however, regardless of whether prevention interventions are large or small, to maximize positive outcomes, the interventions must be culturally relevant and prevention specialists culturally competent, partnering with population groups receiving the prevention intervention (reese &vera, ) . the next section will further expand on this topic. the above discussion provides examples on how differing values, morality, funding, and ethnic and socioeconomic disparities can influence prevention initiatives, whether they be worldwide and very dangerous pandemics such as covid- or local prevention applications. this section will summarize suggestions to assist prevention personnel as they develop prevention projects, and present them to stakeholders, including policy makers, community groups, and project recipients. it is understood that each stakeholder group may have different opinions about a prevention project, and they are likely influenced by their values, questions of morality, and funding considerations. therefore, the prevention specialist must be willing to dialogue with members from each of the stakeholder groups prior to initiating an intervention. some of the dialogue may be informal or in formal group meetings. prevention activities that seem quite important and necessary to the prevention specialist may not be so for others who will have control over the implementation process, ongoing activities, evaluation, and sustainability of the intervention. the setting for a prevention intervention can vary from a relatively small institution (e.g., schools) to larger community settings, or, as with the pandemic, a global initiative. in the united states, pandemic media coverage is primarily focused on the united states, but there are implications for other nations in terms of working together to prevent virus spread. for example, nations are restricting air and sea travel across borders, and nations are collaborating on sharing medical supplies and working to develop a therapy and vaccine. however, some of the issues have been contentious and opinions vary on the importance of collaboration across nations and among political leaders. the united states and other nations are operating in unchartered waters with respect to covid- decision making, as the last global pandemic occurred in , when population size, health industries, communication systems, and world dynamics were very different. countries determine to what extent they will collaborate, either through global organizations, such as world health organization, or within regions. decisions will be driven by values, beliefs, trust, and importance attached to collaborate versus going it alone. within the united states, several adjoining states have formed collaborations to share knowledge and strengthen the impact of their prevention measures. similarly, prevention initiatives on the local level are likely to be successful and sustainable if local leaders, recipients, and beneficiaries of the prevention initiative are consulted from the very beginning of the project. one way to begin the dialogue is the formation of an advisory group. this group is best composed of members who have technical expertise about the project, represent the cultural and demographic characteristics of the community (or school), and are political stakeholders in the community. it is important that one or two coleaders of the group are invested in the success of the project but who have not initiated the project. the advisory group can then begin to discuss the project in relation to community needs and how best to meet the need. in developing prevention activities, it is recommended to consider not only behavior that needs to be prevented (e.g., school bullying) but also behaviors that are promoted to serve as protections for individuals and the larger community (e.g., respectful and inclusive school environment). comprehensive prevention projects are best designed to stop or decrease problem behaviors by reducing risk factors, promoting protective factors, and addressing community (school) wide interventions that reduce risks and support protections. thus, a robust prevention project will emphasize activities that are individual or small group oriented, as well as systemic interventions designed to reduce risks and promote protections across the system whether a school, school district, city, or other entity. major covid- prevention recommendations to prevent spread of the disease include stay-at-home, frequent handwashing, maintain social distance, and wear face masks to reduce risk and increase protection for self and others. the guidelines are followed and enforced in varying degrees of consistency within the united states and globally. citizens decide the best behavior for themselves and the community, not unlike other prevention recommendations (e.g., seasonal flu shot, refrain from tobacco use). although it took many years for some jurisdictions to approve legislation to restrict cigarette smoking in public places, for example, the highly contagious coronavirus does not allow the luxury of time, and citizens are dependent on public health and political leaders to offer prevention recommendations for the good of society. however, as with other types of prevention recommendations, individuals have freedom of choice to follow them in most countries. most prevention specialists will have more modest and less immediate goals compared with stopping a global pandemic. there is a long history of prevention and promotion interventions across institutions and communities such as preventing sexual harassment and abuse on college campuses, reducing gun violence in communities, promoting social-emotional learning in children and youth, ending illegal drug use and inappropriate use of legal drugs across the life cycle, and preventing suicide (vera, ) . these problem behaviors are traumatic and potentially deadly. fortunately, there are examples of prevention programs to reduce or eliminate problems within a given context. samsha's ebp resource center, cited above, is one resource to search for prevention initiatives that have been reviewed and evaluated. however, it is recommended that prevention activities be adjusted or adapted to a location and population, as one set of activities and evaluation tools successful in one locale may not be effective in another context (romano & israelashvili, ) . this recommendation was observed in prevention projects that were developed in different countries, but prevention scientists and specialists adapted the previously developed prevention activities to meet the needs and requirements of their own region or country (israelashvili & romano, ) . prevention is an interdisciplinary science, but it is not atheoretical. prevention activities are best grounded in a theoretical framework that will support the intervention activities and the evaluation process. some of the more commonly taught theories of psychotherapy for clinical use have formed a theoretical basis for prevention interventions (e.g., cognitivebehavioral; christensen et al., ; montgomery et al., ) . motivational interviewing, with person-centered theory as foundational, has also been used in a variety of prevention interventions (e.g., strait et al., ) . transtheoretical model of behavior change has a long history of use within a prevention framework, especially interventions that address behavioral changes to improve health outcomes (e.g., prochaska et al., ). in the following sections, two theoretical perspectives (i.e., health belief model [hbm] and theory of reasoned action and planned behavior [trapb]) will be summarized. these were chosen because of their long history within prevention science, and readers may not be familiar with them. hbm was developed within the u.s. public health service in the s to help understand reasons for people not participating in tuberculous screenings to prevent the illness and promote early disease detection (hochbaum, ; rosenstock, ) . the prevention goals of covid- are similar in terms of prevention and disease identification. the hbm researchers found that a person's beliefs about a disease and need for screening helped to differentiate those who participated in the screening and those who did not. hbm can be applied to covid- and people's willingness to use prevention measures. according to hbm, four personal health beliefs are predictive of whether a person is likely to adhere to prevention recommendations and participate in screenings. they are (a) perceived susceptibility to the disease, (b) perceived severity of contacting the disease, (c) perceived benefits of participating in the prevention measures, and (d) perceived barriers and disadvantages to participating in prevention activities (romano, ) . much research has been conducted to validate hbm variables in diverse populations in the united states and other countries. examples of the research projects include willingness of low-income african american women to participate in cancer screenings and promoting behaviors that reduce sexual risks (champion & sugg skinner, ) . as applied to preventing covid- , hbm offers explanations for behaviors. for example, young adults on southern beaches likely perceive themselves as less susceptible to the virus, compared with older adults. however, as knowledge about the virus has increased, young and middle-aged adults have also been victims of the disease, although not as severely as older persons. those who understand and accept the benefits of pandemic prevention recommendations compared with disadvantages will more likely use them. according to the hbm framework, delivering targeted pandemic prevention information to subgroups of citizens based on the four hbm beliefs promises to yield more favorable compliance outcomes. hbm has value as a theoretical framework for more typical prevention projects, especially related to preventing behaviors that impair health. for example, hbm can be helpful to understand behaviors that place adolescents at risk of sexually transmitted infections, pregnancy, and drug and alcohol use. the four components of hbm can give prevention personnel a framework to better understand resistance to following prevention messages and participating in prevention activities. however, it is important to assess the health beliefs of the group receiving the intervention prior to developing prevention messages and activities. theory of reasoned action (tra) has a long history, dating back to fishbein ( ) who developed the theoretical framework to better understand the relationship between personal beliefs, attitudes, and behavior. several years later, ajzen ( ) added planned behavior (pb) as an extension of tra to address the amount of control that individuals believe they have over one or more behaviors. trapb is more complex than hbm, as trapb addresses several variables that can influence participation in a health promotion or prevention campaign. trapb posits that intentions to carry out a desired behavior will be more likely followed if the individual's attitudes, social norms of those important to the person, and perceived personal control support the desired behavior. the relationships of these variables can be presented symbolically as: behavior ~ intentions ~ (attitudes + norms + control; montaño & kasprzyk, ; romano, ) . a major component of the theory is a process called elicitation research. the process involves conducting group interviews of a similar but different sample of future intervention participants to ascertain personal beliefs, attitudes, behavioral intentions, social norms, and perceived control over the desired behavior. once elicitation data are collected, they will inform intervention activities and messages. the theory is widely used. according to a review of theories used in designing and evaluating interventions to change health-related behaviors informed by social scientists, trapb was the second most frequently used theory behind the transtheoretical model of behavior change (davis et al., ) . according to fishbein ( , as cited in montaño & kasprzyk, , the theoretical constructs of the theory have been studied in more than high-and low-income countries. with respect to the covid- prevention recommendations, trapb can help explain people's willingness to follow recommendations. for example, does a person's attitude about a prevention recommendation lead to increased use? do others important to the person follow the prevention guidelines and does the person believe they have control over the behavior? with respect to preventing virus spread, most people have personal control over the cdc prevention recommendations, unless employment requirements reduce their assessment of personal control. also, their intention to follow recommendations is a function of their attitudes toward the behavior and the level of perceived social support to follow the recommendations. for example, in the united states, some leaders are less likely to follow some of the recommendations, resulting in poor modeling and weakening social support for them. romano and netland ( ) describe a hypothetical example of trapb. in their example, the authors show how trapb and elicitation research are used to reduce physical aggression among sixth-grade boys. through elicitation research, prevention personnel learn about differences between subgroups of all sixth-grade boys in the school, as it cannot be assumed that all sixth-grade boys (or any group) will have similar beliefs, social support, and perceived personal control to carry out intended behaviors. without collecting subgroup information about these variables beforehand, differences between subgroups are unknown. elicitation research provides a process to adjust or better align prevention activities with trapb variables important to subgroups, leading to better outcomes. of course, other theoretical frameworks to guide prevention projects can be considered by prevention specialists. for example, conyne ( ) has summarized several prevention strategies, including self-competency facilitation, community organizing and systems intervention, and redesign of the physical environment. if a project is based on a theoretical model, project goals, design, activities, and evaluation methods will help to explain outcomes, and hopefully lead to sustainability as future changes to improve the intervention are made based on the theoretical model. prevention scientists and applied prevention specialists are experiencing a global epidemic of historic proportions. prevention is the main strategy to prevent the spread of covid- . however, despite overwhelming news coverage and mass media reports, little, if any, coverage is presented on the role of behavioral science expertise in helping to control the pandemic. there are many behavioral science specialists devoted to assisting others in this time of crisis. this activity is highly valued and understandable given the emotional impact of the pandemic. in addition, remediation and crisis-intervention education is prominent within the helping professions. furthermore, the public's perception of applied psychology and other helping professions is to fix problems, rather than prevent them. however, prevention science can be instrumental in assisting in multiple ways during this epidemic. for example, prevention specialists from across disciplines and in research teams are well positioned to study prevention-based research questions. hopefully, some of the research has begun, and the national institute of mental health (nimh) prevention research agenda cited above will encourage development of future research projects. a few research questions to consider are as follows: (a) do the major media messages of social distancing, handwashing, and mask wearing serve all segments of the u.s. population equally? (b) how might these messages be perceived within different ethnic, cultural, and socioeconomic groups? (c) what types of media are most effective to reach diverse population groups? (d) how might the health beliefs of different groups influence their adherence to preventive actions? (e) how do attitudes, beliefs, and sense of personal control influence adherence to prevention recommendations? (f) what social influences are most effective to promote the use of prevention recommendations within groups, whether they be family, government officials, or others within personal networks? (f) how does compliance with prevention recommendations compare across nations? these are a few of the questions that can be examined utilizing the expertise of prevention social scientists. it is critically important that professionals from diverse specialties such as psychology, public health, medicine, social work, public policy, and economics work in collaboration in efforts to contain the spread of covid- through preventive measures. as with other specialties, applied psychology must continue to emphasize and encourage the role of prevention within the profession. for example, in counseling psychology, much has been accomplished, including the publication of this inaugural journal issue. however, much more needs to be accomplished during the next decade, and, hopefully, a more robust recognition of the importance of prevention psychology in the public domain and policy decisions will occur. the advancement and prominence of prevention psychology, along with prevention science in other social science disciplines, will require adjustments in training strategies to meet accreditation and licensing requirements. unfortunately, prevention education is seriously lacking in much of applied psychology, although some progress has been made in the last decade (see hage et al., ; romano, ) . as conyne et al. ( ) discuss, there are multiple ways to provide prevention training within graduate education and postgraduate training. one key component to prevention education is encouraging student coursework outside the major area of study. applied psychology programs are encouraged to make it more possible for students to enroll in courses in fields such as public health, medicine, social work, public policy, and economics. furthermore, field work, practicum, and internship experiences could also give attention to training experiences in prevention science. this model of multidisciplinary education can also be more widely applied in other disciplines. however, graduate programs in applied psychology are already packed with courses to meet accreditation and licensing requirements, but the apa accreditation process may offer some enlightenment. apa is reviewing accreditation standards for the newly developed master's program in health services psychology (mphsp; grus, ) . my cursory review of the proposed accreditation standards for mphsp found them lacking in prevention content. accreditation standards for this program, like doctoral programs, are categorized into broad psychological content areas, and graduate programs usually offer specific courses to meet the standards. because prevention science education is relevant to multiple content areas (e.g., social, affective, cognitive, behavioral), prevention education can be infused across multiple courses instead of one or more stand-alone courses. this strategy would reduce expansion of the curriculum. if graduate programs show that specific courses or multiple courses that include prevention content meet accreditation and licensing board standards, infusion of prevention education is possible. however, such changes require faculty with interest, expertise, and commitment to prevention science, and students who desire such education. the covid- pandemic has highlighted the importance of prevention to reduce disease and death. although it is hoped that covid- is a once-ina-lifetime pandemic, there will be other epidemics that risk health, hopefully on a smaller scale, and the expertise of prevention scientists from the behavioral sciences will be sought. however, apart from health-related epidemics, prevention science must continue to provide guidance and expertise related to major social problems (e.g., bullying and social violence, poor school achievement, drug and alcohol addiction, racial stereotyping, and sexual harassment). this article highlighted the role of prevention science in covid- while providing examples and applications across schools and communities. as a final comment, counseling psychology is commended and congratulated for producing this inaugural jphp, only the second journal sponsored by the society of counseling psychology (apa division ) in its -year history. the journal is an important outlet to disseminate prevention research and scholarship by scientists and practitioners from different disciplines and specialties. it took several years to launch jphp, and now the inaugural issue is published during a massive and deadly global pandemic in which prevention is central to containment of the virus. appropriately, jphp is being launched at a momentous time in the history of the world. the author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. the author received no financial support for the research, authorship, and/or publication of this article. guidelines for prevention in psychology health disparities due to diminished return among black americans: public policy solutions gun violence is an epidemic. it is time for a public health response. the guardian one school counselor per students: nationwide average improves. counseling today social distancing is a class privilege. the new york times health disparities: issues and opportunities for counseling psychologists principles of 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doc_id: cord_uid: nzcch ji the emergence and transfer of wealth promote the evolution of civilizations. through the pursuit of the form of wealth valued by the members of society, the self-assertiveness demands of a society can be met and thus stimulate creativity. as means of overdrawing the future, sovereign currency and bonds have gradually become modern forms of wealth and have strongly promoted scientific and technological progress and social development. however, due to the unequal distribution of wealth, the sustainability of sovereign currency and bonds is not certain. the world has been changing rapidly since the outbreak of covid- , and new forms of wealth need to be constructed as an extension of the self of the masses, among which digital currency may be an effective carrier of value. china is on an upward trajectory, and the complex and volatile global environment can provide an opportunity for china to focus on developing aspects of its science and technology, optimize its system of governance and strengthen its internal driving force. monetary theory is an important and controversial field. the united states has begun to give cash to every citizen. in just a few months, the federal reserve's liabilities have increased from more than $ trillion to more than $ trillion. in the past two years, china has begun to deploy new infrastructures intensively. by the middle of april , thirteen provinces, autonomous regions and municipalities had released related investment plans for key projects, and eight of them had announced a total planned investment of . trillion rmb. these plans can also be seen as the extension and innovation of mmt policy. we have proposed elsewhere the additional implementation of a people-centered monetary system and the establishment of individual social security accounts transferred directly from the central bank such that the pressure of rmb appreciation can be turned into dividends to be distributed equally to citizens across the country. that property is also an aspect of mmt. in addition to the risks posed by the global practice of modern monetary theory, china also has to deal with external pressure. some worry that a us-led monetary union is deliberately seeking to exclude china and that the fed's massive quantitative easing is akin to fleecing the flock. in such a tense global situation, china's position and future development require a more sober and rational analysis. we propose examining the current situation in china in terms of the relationship between the rise and fall of civilizations, the transfer of wealth and the transfer of scientific and technological centers and to respond to the pressure of mmt and decoupling. in most cases, people tend to evaluate themselves as above average within their own cognitive range, and they believe that they deserve a greater share of total wealth than they receive. this tendency is called self-assertiveness demand. bloch's ( ) experimental data showed that % of the subjects evaluated themselves to be better than they actually were along various measures compared with their colleagues. myers' ( ) survey showed that % of business managers thought their performance was better than other managers, and % thought they were more ethical than their colleagues. svenson's research shows that more than % of people believe that they drive better than others. self-assertiveness demand is rigid demand and is never weaker than material needs. on one hand, people tend to affirm themselves and will drive the progress of society, but on the other hand, due to people's tendency to evaluate themselves as above average, the overall self-assertiveness demands will be greater than the social aggregate supply at current production levels. the resulting gap is a severe challenge for any administrator. therefore, to maintain the harmony and stability of a society, the administrator must provide additional supplies to fill the gap. from the perspective of the state, there are four primary means of resource supply or wealth creation that can be utilized to fill the gap and meet the self-assertiveness demands within a society. the first way is through learning and innovation, especially in application to institutional systems and technology levels. the innovation of systems occurs with the introduction of alternatives to existing social system, while innovation to technology is triggered by new technology and new scientific discovery. institutional innovation enables the old relations of production to be replaced by new and more advanced ones. learning from the outside is less resource-intensive and more explosive than independent innovation; therefore, there are many examples of latecomers taking the lead. the second way is external acquisition, including trade with external societies to gain comparative advantages, natural territorial expansion, ancient nomadic looting, and imperialist carving up and plundering of the world. trade is the most permanent and practical form of external acquisition. mercantilist countries attempt to export more than they import such that the harmonious development within the country can be realized by the supplement of external wealth. the third way is to overdraw the future using future wealth to fill the present gap. by printing money, borrowing, and selling bonds, stocks, and other financial derivatives, we can use future resources in advance. in principle, the future is endless; therefore, the overdraft can be notably large. however, this kind of overdraft behavior is also highly variational. when the economy is stronger, people are also more optimistic, and confidence in the future is higher, meaning that the overdraft will be greater. when the economy is bad and people are pessimistic, they focus more on safeguarding their current wealth to ensure future security, and the overdraft will therefore be less. this fluctuation in confidence in the future may lead to financial market instability and financial crisis. the last option is to start again after the crash. the transfer of wealth centers in the west in the past five hundred years has a quasi-cyclical pattern similar to the dynastic change in chinese history. the essence of the collapse of empires or dynasties lies in the fact that the old distribution structure of wealth cannot efficiently meet the self-assertiveness demands of the whole society, and a new starting point gives people new hope. the invasion and annexation of developed countries by backward countries in recent centuries was also a feature of the change of dynasties. both the east and the west have quasi-cyclical patterns of development. the development history of the west is reflected in the transfer of wealth centers between different countries, as shown in figure . earlier, portugal and spain co-ruled the world. spain was responsible for the governance of the western hemisphere, while portugal was responsible for the eastern hemisphere. later came the period of dutch rule followed by the rapid development and rule of the united kingdom, and then the united states took the leading role in the development of the world. the transfer of science and technology centers is also shown in figure . the yuasa phenomenon shows that the transfer of science and technology centers is usually not synchronized with the transfer of fortune centers in time and space but slightly lags behind, indicating that the accumulation of wealth is the first step before the emergence of innovation and creation. the center of science and technology moved from italy to the united kingdom, concurrent with the scientific revolution, and then to france, and then to germany, which became famous for its chemical industry, and then to the united states. technology centers have also tended to be unable to maintain their status as such for a long time, as the rise of a competing technology center usually had the support of sufficient accumulated wealth and could appropriate and build on the technological advances of the existing technology center. according to self-assertiveness demands, innovators in the existing technology center believed that they maintained superiority over others; therefore, the innovators spared themselves the effort of pursuing technological catch-up and innovation, making it easier for rising competitors to come to the fore. however, in cases where the center of science and technology developed in the second and third generation, scientists began to divide into factions. in the scientific research system, obeying the rules of one's own faction will be promoted, scientific research becomes profitable, the motivations of science cease to be pure, and the nation becomes less innovative as a consequence. with the emergence of new resources, on the other hand, researchers will have purer motivations for conducting scientific research and innovation; they will find research interesting, focus on technological breakthroughs, and possibly help to form the next technology center. today, the united states is both the wealth center and the technology center, its total industrial output value (quasi-gdp) having already surpassed that of the united kingdom in , and the nation having accumulated a large amount of wealth. the technology center was later transferred to the united states after . technology, of course, has further cemented america's wealth with fortunes in the form of electricity, steel, cars and oil and other commodities. though the united states is the center of both wealth and technology, it is still not secure. the net asset appreciation rate of large american companies is approximately %, and the net asset growth rate of some emerging industry companies can even be as high as %. even if calculated at %, according to einstein's law, the assets of these companies double about every years, and after years of accumulation, the assets will increase by approximately , times ( ). america's gdp grows by approximately % a year, or approximately times in years. in other words, years from now, the increase in financial assets will be , times the increase in gdp, with this large gap being mainly due to the inflation of future expectations and the overdraft of the future through sovereign money and bonds. the united states has issued a large amount of national debt during its transformation to a strong country. the outside world's expectation of its development is constantly changing. if other countries believe that the future development in the u.s. will continue to be robust, these countries will continue to pay for it. however, the united states' rolling accumulation of debt cannot last forever. rather, it will inevitably stop growing as history progresses, possibly as a result of accidental causes. one unexpected factor is natural disasters, and another factor is external changes. for example, as long as people still believe that the united states will remain the strongest, then they will go on buying u.s. treasuries, but if there suddenly appeared an economic entity with a more promising future, then people will tend to buy the new entity's treasuries, and the united states will be fundamentally affected. this situation places the u.s. into irreconcilable conflict with emerging economies. national debt and bonds, as means of overdrawing the future, have gradually become new forms of wealth in some countries and regions. a bond can be an asset for one group and thus a liability for another group, and these properties are largely balanced. piketty believes that the core contradiction of capitalism is that the rate of return on capital is greater than the rate of economic growth (r >g), and the gap between the two must be filled by extra resources. bonds can temporarily satisfy the annual growth demand of the middle layer (namely, interest groups) of more than %, which actually consume the interests of the top layer (such as the u.s. federal government) and the resources of the common people at the bottom. many american citizens are already in a state of negative equity. when issuing bonds, state sovereignty is highly important. some latin american countries' tragic situations lie in their pursuit of short-term interests, selling out stateowned assets to foreign capital, such as power plants and water plants, which are directly related to the people's livelihood. when the financial crisis took place, these governments did not have useful resources to depend on and had to print money, leading to serious currency devaluation. affected by the outbreak of covid- , the interest rate of u.s. treasury bonds continues to fall, and the u.s. has started to print money, as well. at present, since most members of the middle class are willing to continue to hold bonds as assets, there is no obvious inflation of the u.s. dollar, even as these bonds are overissued. in contrast, the u.s. dollar has recently been appreciating. however, this way of printing money still cannot solve the problem. in the longer term, the wealthiest layer will receive more of these dollars, and the ordinary people who are struggling at the bottom receive only chicken feed; as a result, the gap between the rich and the poor widens. as the challenge of sustainability will be more severe, the federal government will become more heavily indebted, the bottom will be further squeezed, and the middle layer will become dissatisfied, being unable to maintain % growth. the demand of the selfassertiveness of each of these parties cannot be met, which will eventually lead to social decline or even collapse. it is all the more necessary to construct new forms of wealth as carriers of value such that people will be willing to pay, use and preserve them, and they therefore can serve as an extension of the self of the public. are against libra, as is the u.s. president donald trump, on the grounds that fiat money is on shaky ground. although libra maintains that it will not compete with sovereign currencies and only acts as a means of payment and a stable currency with collateral, it is bound to become a de facto competitor to fiat currencies in the context of financial instability. libra has adjusted its plan and is no longer linked to a basket of currencies but instead to a single currency (the u.s. dollar). this property may initially strengthen america's international position, but it will strongly threaten the u.s. dollar in the future. the u.s. dollar is endorsed by the government through future taxes, but as the world's hegemon, the u.s. has accumulated considerable debts. america's national debt exceeds $ trillion, but its liabilities to the future are a considerably more formidable number by comparison. such liabilities are expressed as personal assets, as well as debts owed by the state, which need to be paid continuously in the future. these liabilities are discounted to the present value of about $ trillion. if libra were allowed to issue digital currency, it would be nimbler than the debt-laden dollar. with facebook having more than . billion monthly users, more than the population of any country in the world, this situation could subject the u.s. dollar to fierce competition with sovereign currencies in the near future. a sustainable monetary system usually has a healthy ecology. however, if the gap between the rich and the poor is too large, the hierarchical structure becomes unreasonable, and the self-assertiveness demands of each layer are not satisfied for a long time, then the monetary system tends to become fragile and cannot withstand external shocks. this situation represents an unhealthy ecology. is the ecology of the u.s. dollar system healthy and resilient to outside shocks? libra is more similar to a special commodity than a credit currency if it is tied solely to the dollar and only used as a payment instrument, such as only allowing spending when having the assets without introducing credit. in a normal society or a healthy ecology, credit must be used for expansion and overdrawing the future, not only paid out of the assets themselves. many people believe that the fully collateral asset is the best solution, but we see that this situation is not the case. if everyone uses existing assets (such as gold and silver) to serve as collateral for the full specified amount, we will find that even if all social wealth were taken as collateral, it would still not be enough to fill the gap because self-assertiveness demands function unceasingly to make the requirements of the people to exceed actual social output, thereby causing challenges to sustainability, which is also the major problem with libra lacking a credit mechanism. therefore, credit currency is inevitable, since everyone has the motivation of pursuing wealth, and for the sake of social sustainability, the credit currency is bound to come into being. digital currency may be an effective carrier of value as an extension of the human self and even as the token of the future world. technologies such as ai and blockchain may challenge traditional businesses but could also provide an important basis for future forms of wealth. with the power of technology, people can have better understandings of credit characteristics; thus, the money or token of the future will be more inclined to credit, rather than actually owned assets, for collateral. under the recent historical trend of rapid development of technology, the essential law is still that of self-assertiveness demands such that everyone will overestimate their contribution and importance and hope to obtain more returns; this situation will still lead to credit expansion, and the over-expansion will still lead to collapse. almost always, people's expectations will keep growing, but real wealth will not grow fast enough to catch up the expectations, and the bubble will therefore burst sooner or later. that law leads to the first feature of the future currency, which is that it must have some inflation. for example, wage illusion is needed in companies. it is easy to increase one's salary, but it is difficult to reduce it, and this reduction will hurt the person whose salary is reduced considerably. therefore, many companies maintain wage illusion to make the employees feel that their salaries keep rising to meet their self-assertiveness demands, but in fact, the inflation rate may offset much of the increase. the second feature of future currency is the mechanism causing wealth to flow to the bottom. because of self-assertiveness demands, people will seek advantages and avoid disadvantages. wealth naturally flows to a small number of people at the top. the monetary authorities need to provide a mechanism for wealth to return to the bottom; otherwise, it will flow upward too quickly and crash more easily. individual bankruptcy filings and food coupons in the west and secondary distribution or transfer payments in china, for example, are all ways of providing for the flow of wealth to the bottom. a good institutional system should restrain the impulse of capital as much as possible and let the social impetus be released in a slow and orderly manner. the third characteristic of the currency of the future should be multicurrencies and should exist in an era of inexpensive money. the situation now is that japan has retained low interest rates and negative interest rates for a long time, europe has negative interest rates already, and the united states is moving in the same direction. why do we emphasize multiple currencies? if all the people go up in the same value system, it is more difficult to satisfy their self-assertiveness demands. when society provides various value systems, each person may choose the most suitable value system, in which there is enough room for one's improvement. for example, many people are investing in shoe speculation, which may not be rational, but it reflects the value of collecting and hobbies, which means more than a string of numbers in the bank account and can better meet these investors' self-assertiveness demands. people have different cognitive levels, and as ai technology advances, the differences become clearer. in the future, we will need distinguished currencies to reflect various value systems. at present, we can see such new currencies in, for example, the united states, where you can use food coupons to buy food or groceries, but you cannot use them to invest or buy luxuries. in another example, china has currently made targeted cuts in the reserve requirement ratio and industrial policies that can be implemented in different currencies in the future. in the modern financial system, tokens or digital certificates can be positioned as a tool for quickly reaching consensus in a limited domain. sovereign currency is the consensus of the whole country, representing a broad consensus that one can buy anything in the country with the fiat currency. in some countries, the government issues fiat currency, but people fail to reach a consensus, and fiat currencies can depreciate quickly. at present, many blockchain digital currencies are down to zero: that is, although the digital currency has been issued, its users are still unable to form a consensus. digital credentials or tokens should first reach an effective consensus in a small scale and then gradually form a consensus in a larger scale. the insurance salesman is responsible for the specific work of educating customers and upgrading their cognition according to the specific situation of each user. the insurance company can issue sales-incentive tokens according to the performance of the salesman. the salesman's income not only comes from the commission of the insurance sales but also from increases with the accumulation of the contribution of all the salesmen to the company. with the expansion of the company's scale, the value of the company will also be reflected in the growth of the whole company; therefore, the salesmen with the tokens can also share the benefits brought by the growth of the company. that measure seems simple, but it can greatly improve the sales process and generate positive incentives for employees. compared with companies without such a mechanism, the insurance company providing tokens will surely attract more excellent employees and thus continue to stimulate the growth of the company. in addition, token incentives can also be introduced in the design of insurance products. the design reward token and the sales reward token have different time attributes, which is more accurate and reasonable than the traditional stock and option incentives. using tokens in limited domain can lead to a consensus quickly, the whole process is clearly visible to all users, and the tamper-proof traceable data provide a credible witness basis. therefore, such a mechanism of openness is beneficial to the company or industry in attracting more talent, absorbing greater external resources, and achieving greater value. if the tokens are all placed on exchanges (that is, if the price relationship between different tokens is established), the effect is the formation of a broader consensus, which is exactly what is needed in the future. the reason why we use the work of design and sales as an example is that the completion of such work depends on subjective ability of a very high degree, as well as on excellent sales personnel, such as li jiaqi and viya, whose sales can exceed those of others hundreds or even thousands of times. unfortunately, these advantages in the process are difficult to quantify at the beginning; therefore, we must place them in a competitive market and let everyone compete and then reach consensus. our understanding of the many relevant factors is still in its early stages, and the fluctuations of their corresponding effects token price may be severe. in particular, highly creative cognition is still inadequate at present, tokens are needed to be issued in a limited domain to reach a consensus, and future economic behavior is actually pricing those tokens or consensus, which makes it relatively accurate. blockchain technology gives us a new way to reach consensus. at the beginning, it was primarily intended to reach a consensus about technology, but at present, it is gradually reflected in the community consensus, which is an inevitable direction in the future. the goal of community is ideally not to be very large, but for it to be easy to reach consensus on small issues, which will bring about changes in values. this kind of transfer of values should be encouraged. in the community, a group of people who truly believe in the value of the tokens can be gathered, and they can be allowed to find their own ways to extend themselves within the value system and meet their selfassertiveness demands. even if digital currencies pose a challenge to fiat currencies, we should actively respond, rather than exclude all tokens. one of the significant innovations that could be brought about in the future is to conduct initial token offerings (ito) that can be used for such purposes as governing communities and implementing blockchain reforms. sponsors providing resources in reserve and issuing tokens with reserve can accordingly attract talents to participate in the research and development of key products or technologies and attract investors to support the project, thereby helping the organization to enhance innovation capabilities and providing new financing channels. companies can invest in key technologies for other organizations to quickly achieve a multidimensional strategic layout, as well. the pricing method of ito is a composite method that combines call auctioning with the commanding price. the sponsor plays a significant role in transactions. on the one hand, the sponsor needs to hold the collateral assets as a reserve according to the number and price of issued tokens to determine the token's initial reserve rate. on the other hand, the sponsor is responsible for fulfilling users' transaction needs. in normal cases, the latest price is determined by call auctioning among all nodes involved in circulation, and then the closing price of each transaction is solved backwards. under certain conditions, the sponsor is authorized to establish a commanding price, and the commanding price will serve as the starting price in the next round of call auctioning. the range or rule of the commanding price can be specified in the smart contract in advance. finally, each transaction can be confirmed according to a tamper-proof, validated order record. most people underestimate china's role in the world in modern times and are likely to continue to underestimate its future role. in the process of china's rapid development and self-confidence building, strong public opinions and excessive behaviors are all possible. powerful countries have all experienced similar processes. the key is to build confidence for the younger generation, reach consensus, prepare for the future, develop technology and strengthen internal motivation to embrace and lead the future. it will be easier for china to lead in the future because the west will bask in the glory it has already experienced and underestimate the changes that lie ahead. it is not appropriate to evaluate the development potential of a country in terms of the number of patents, the number of nobel prizes and military prowess. japan, for example, is awarded one nobel prize per year on average, far exceeding china, but the prize is a lagging indicator that is largely awarded to the baby boomers of the post-world war ii era. young people born in the united states are not as active. for example, many of present technological elite are first-generation immigrants, many of the heads of big businesses are of indian origin, and the most prominent figures in american politics are elderly, while young people are rarely observed in the political arena. large military expenditure is also not the sign of strength. for example, rich countries often lose money in wars, because the cost to rich countries is much higher than for poor countries. if rich countries win, they will spend money like water, but if they lose, they will lose both money and status. at present, china's gdp has reached two-thirds that of the united states, and if calculated according to the rules of purchasing power parity, china has already surpassed the united states. however, there is still room for china to grow until china's per capita gdp surpasses that of the united states. the largest advantage of china is its rising national trend. first, china is in the stage of starting again after the collapse, and there are abundant resources to be allocated. second, china shares the advantage of a trade surplus, which is also a way of making external acquisitions. third, china has people to learn from and excellent learning ability. even though china is characterized critically as copying others' advanced technology, it can still quickly learn and form its own technologies in many fields. gathering these advantages will ensure that china's development will not be crushed by setbacks. it is reasonable to believe that there will not be decoupling from china or encirclement of china by the west, because china has the most comprehensive industrial system and the largest market in the world. while china will not voluntarily decouple, we do not need to worry too much even if decoupled passively. the united states had an early monroe doctrine, and the united kingdom had an early splendid isolation, taking care only of its immediate interests and not much else. china needs to learn from those experiences, but the western route of expansion is not necessarily suitable for china. the production slowdown caused by covid- may provide an opportunity for china to optimize industrial layout. for example, the inland provinces and cities can undertake coastal manufacturing industry in accordance with the principles of industrial agglomeration and supply chain optimization, thereby unleashing the vitality of technological innovation in the coastal areas. the credit theory of money staatliche theorie des geldes (the state theory of money) modern money theory : a reply to critics the quantity theory of money: a restatement predictive testing for huntington's disease: ii. demographic characteristics, life-style patterns, attitudes, and psychosocial assessments of the first fifty-one test candidates the pursuit of happiness reorient: global economy in the asian age coined: the rich life of money and how its history has shaped us capital in the twenty-first century credit and capital: a development finance research before the rise of machines: the beginning of the consciousness and the human intelligence the creation of people-oriented monetary institutions setting up universal social insurance accounts --redistribution of rmb appreciation dividends self-assertiveness demands surplus: a new interpretation of the u. s. financial crisis a blockchain system with integrated human and computer intelligence the chinese version《论数字货币与世界财富、科技中心的转移》was firstly published in frontiers《人民论坛·学术前沿》 key: cord- -evh b o authors: brokopp, charles; resultan, eric; holmes, harvey; wagner, michael m. title: laboratories date: - - journal: handbook of biosurveillance doi: . /b - - / - sha: doc_id: cord_uid: evh b o nan results from laboratory testing are an important source of information for biosurveillance systems. clinical laboratory tests are vital for the correct diagnosis and treatment of individuals. clinical laboratories analyze blood, urine, mucus, saliva, respiratory secretions, cerebrospinal fluid, semen, vaginal secretions, sweat, feces, fluid aspirated from joints, and tissues from humans and animals. the tests performed include cell counts; analytical chemistries, including drug and toxin tests; and examinations to detect and identify microbes and markers of current and past infection. environmental testing is critical to the detection of outbreaks, the prevention of disease, and the monitoring of the environment. environmental laboratories analyze samples of water, food, air, soil, plant material, and unknown powders, as well as samples taken from surfaces for evidence of bacterial, viral, toxin, or chemical contamination. data produced by laboratories are important for biosurveillance of virtually every disease caused by biological agents, chemicals, or toxins. data collected during the preanalytical, analytical, and postanalytical phases of testing can be captured and incorporated directly into biosurveillance systems. preanalytical data, such as the type of test ordered and the reason for a test, can provide an early clue to the existence of an outbreak. similarly, analytic results, such as the initial gram stain of a cerebrospinal fluid specimen, can potentially confirm a diagnosis when combined with other clinical information, as it did in the first case of inhalational anthrax in the postal attack. the actual results of tests are obviously foundational to biosurveillance. the range of tests offered by an individual laboratory varies significantly among laboratories in the united states. many small laboratories perform a limited number of tests that are needed on an urgent basis or for screening purposes. larger laboratories provide more complex confirmatory analyses. the majority of clinical laboratories in the united states are small laboratories located in physician offices; however, the larger laboratories account for a high volume of all tests performed. table . describes the clinical laboratory tests that contribute to the diagnosis of inhalational anthrax. anthrax, as well as many other infectious diseases, is diagnosed after the performance of presumptive and confirmatory tests in combination with the clinical presentation. clinical specimens, such as blood, cerebrospinal fluid, urine, sputum, throat swabs, and skin scrapings, are used to isolate a causative agent that is later subjected to further testing with confirmatory procedures to make the final identification. preliminary tests results are sometimes released before the confirmatory tests results become available. when preliminary results are reported, the report often contains a statement about when final results will be available. laboratories that produce the types of data most useful for biosurveillance include clinical laboratories operated by the human or animal health systems, commercial laboratories, and governmental laboratories. laboratories typically specialize in either human or animal testing. commercial laboratories are free-standing laboratories that are not associated with hospitals or healthcare facilities and that often provide a broad range of services over a wide geographical area. governmental laboratories exist at the federal, state, and local level and often provide testing that is not readily available from other laboratories. we describe each of these types of laboratories in this chapter. laboratories that test for biologic agents are classified as biosafety level , , , or , with biosafety level providing the highest degree of protection to personnel and the environment. most clinical laboratory work is performed at level . these biosafety levels combine the use of laboratory safety practices, safety equipment, and laboratory facilities to provide greater levels of safety for the more dangerous organisms. each level is specifically appropriate for handling various biologic agents (cdc, ) . there are more than , clinical laboratories in the united states in which clinical laboratory scientists, pathologists, the centers for medicare and medicaid services (cms) registers all clinical laboratories in the united states that examine materials derived from the human body for diagnosis, prevention, or treatment. cms administers the program for the secretary of health and humans services in conjunction with the centers for disease control and prevention (cdc) and the food and drug administration (fda). cms regulates laboratories and establishes criteria for other organizations, such as state health departments, that also regulate laboratories to ensure compliance with the federal clinical laboratory improvement act (clia). clia was first enacted by congress in and set guidelines for large independent laboratories. in , congress amended clia to expand the type of laboratories that must comply; clia further established quality standards for laboratories to ensure accuracy, reliability, and timeliness of test results. in august, , , laboratories were registered with the cms (centers for medicare and medicaid services, ) . table . shows the distribution of these laboratories by type. more than % of these laboratories are located in physician offices. skilled nursing facilities ( . %), hospitals ( . %) ,and home health agencies ( . %) accounted for an additional % of laboratories. the remaining clinical laboratories are found in community health clinics, health maintenance organizations, blood banks, industrial facilities, medical technologists, and laboratory technicians perform billion or more diagnostic tests annually (centers for medicare and medicaid services, ) . the american society for clinical pathology (ascp) currently certifies more than , laboratory professionals who primarily work in clinical diagnostic and research laboratories. clinical laboratory services in the united states are delivered either by commercial clinical laboratories or by "in-house" laboratories at healthcare facilities (hospitals, clinics, physician offices), departments of health, veterinary hospitals, and clinics. individual veterinarians and physicians and the staff within their offices also conduct laboratory testing and produce results that are important for biosurveillance. professional laboratorians provide services that include simple, rapid screening tests; more advanced diagnostic tests; and complex confirmatory analyses. clinicians use the information provided by laboratories to establish diagnoses and to make treatment decisions on virtually every patient. the demand for testing is increasing as the population ages and requires more health care, including analytical services. new tests are frequently introduced that improve diagnosis and care. the emergence of new diseases, the threat of bioterrorism, and the need for better biosurveillance systems have increased the demand for qualified laboratory professional in all fields, especially infectious disease testing. although the demand for more laboratory professionals is increasing, the number of established laboratory professional training programs is decreasing. test kits determined by the fda to be sufficiently simple to perform that there is little risk of operator error. laboratories that perform waived tests must enroll in the clia program, pay certification fees, and follow the manufacturers' test instructions. however, laboratories that perform only waived tests do not undergo inspections or need to comply with other clia requirements for larger laboratories. laboratories that perform tests that use a microscope to examine specimens that are not easily transportable during the course of a patient visit are required to enroll in a clia program, pay applicable fees, and maintain certain quality and administrative requirements. these laboratories, known as provider-performed microscopy providers (ppmps), represent % of the registered laboratories and are not subject to routine inspections. the remaining clinical laboratories must either be accredited by of approved clinical laboratory accrediting organizations (american association of blood banks, american osteopathic association, american society of histocompatibility and immunogenetics, college of american pathologists; commission on office laboratory accreditation, joint commission on accreditation of healthcare organizations) or obtain a compliance certificate directly from cms. in august , these six organizations had accredited , ( . %) laboratories, and cms had certified , ( . %) laboratories. the balance of the clinical laboratories ( , ) were either waived test providers or ppmps (centers for medicare and medicaid services, ) . accreditation of clinical laboratories helps ensure that laboratories meet or exceed clinical standards established by governmental and nongovernmental associations. cms, insurance companies, and healthcare plans require laboratories to be certified or accredited by these organizations for reimbursement of laboratory services. table . shows the annual test volume of the , clinical laboratories that were certified by cms in august . over % of these laboratories perform fewer than , tests per year. only of these laboratories performed , or more tests per year. these laboratories represent only . % of all laboratories, yet they perform approximately % of all tests. two state health departments have developed and currently administer state clinical laboratory improvement programs that cms deems equivalent to the cms program. laboratories in washington and new york must meet the standards of these state programs. approximately additional states have laboratory licensure programs. they receive funding from cms to implement the federal clia program. in states that do not have clinical laboratory regulatory programs, the laboratories must choose between accreditation through one of the six approved organizations or submitting to inspection and certification by cms. environmental testing laboratories perform physical, chemical, and microbiological analysis of specimens collected in the environment. for example, a water sample may undergo physical testing (temperature, turbidity, odor, color), chemical testing (nitrates, sulfates, pesticides, metals), and microbiological testing (total plate counts, coliforms, giardia, cryptosporium). environmental testing laboratories provide a wide range of testing that is in many ways similar to the testing performed in clinical laboratories. sanitarians or water quality technicians often perform basic tests (e.g., for temperature, ph, volatility, and physical appearance) at the site where samples are collected. they transmit the results of these simple tests to the laboratory along with the samples, where chemists and microbiologists perform additional presumptive and confirmatory testing. results from the simple tests may suggest the need for more definitive testing, using instruments such as atomic adsorption spectrophotometers, gas chromatographs, and mass spectrometers. laboratories perform much of the routine environmental testing in batches of to samples on semiautomated or fully automated instruments. the raw analytical data are captured, processed, and reported by using software that interfaces directly with the instrument and the laboratory's data management system. environmental laboratories are certified by accreditation authorities recognized by the environmental protection agency (epa) as part of the national environmental laboratory accreditation program (nelap). at least states currently are recognized by the epa as environmental laboratory accrediting authorities. these state programs apply nationally recognized standards to the laboratories that they accredit so that there is some consistency in the quality of tests performed by accredited laboratories. commercial laboratories are an important component of the medical delivery system in the united states. a commercial laboratory is a laboratory that is free-standing; that is, it is not associated with a hospital or other healthcare organization. commercial laboratories may specialize in clinical specimens, environmental specimens, or both. commercial laboratories can be important partners for organizations that wish to develop biosurveillance systems because of size of the laboratories and their use of information technology. commercial laboratories have grown significantly in size during the past decade as a result of mergers and consolidations, and they may offer tests that are not readily available. many of these laboratories began as specialized reference laboratories, offering tests that could not be economically provided by smaller laboratories. small laboratories merged with larger laboratories that were, in turn, purchased by large laboratory corporations. regional consolidation of clinical laboratories that provided services to healthcare organizations led to the formation of large commercial laboratories. these commercial laboratories, such as lab corp, arur and quest, have developed service systems that allow them to provide clinical testing at their headquarters and at distributed sites around the country. large commercial laboratories have established elaborate courier systems that collect samples locally for overnight distribution to the appropriate laboratory in their network. although a sample may be transported to a distant laboratory, the results, nevertheless, frequently become available overnight. the commercial laboratories use information systems referred to as laboratory information management systems (limss) to track tests and results. these systems monitor test requests, capture test results, and electronically report the results, often within hours of the sample being received. as discussed in chapter , clinical laboratories are required to report notifiable diseases to local health departments. the large, multistate commercial laboratories face challenges in complying with notifiable disease reporting requirements that vary by state. further, reporting requirements frequently change as new diseases of public health interest are identified and many states have expanded laboratory reporting requirements to include suspected cases of notifiable diseases. commercial laboratories are increasingly using electronic laboratory reporting to satisfy these complex and changing requirements. commercial laboratories may specialize in environmental testing. these commercial environmental laboratories provide testing on a variety of samples, such as water, air, hazardous materials, dust, and soil. these laboratories often contract with governmental agencies, such as epa, department of defense (dod), and u.s. department of agriculture (usda) at the federal level and with environmental and regulatory agencies at the state and local level. federal, state, and local government agencies, such as health departments, operate laboratories or contract with commercial laboratories for testing related to diagnosis, regulatory compliance, investigations, and environmental monitoring. since the early s, governmental laboratories have performed testing that led to the identification of outbreaks of diphtheria, cholera, smallpox, and typhoid fever. during the th century, these laboratories, in conjunction with academic laboratories, helped develop vaccines and contributed to the detection of polio, rubella, measles, and whooping cough. the response to west nile fever in the united states and the release of viable bacillus anthracis in required these laboratories to develop procedures quickly for diagnosis and identification of agents that they had not previously encountered. governmental laboratories are key to the recognition of new and emerging infectious diseases and are vital to surveillance efforts. the department of health and human services (dhhs), usda, department of energy (doe), dod, and departments of commerce and justice, and the epa operate or fund clinical, environmental, forensic, and research laboratories. federal laboratories provide reference testing and are often involved with the development of new technologies, as well as the transfer of these technologies to other laboratories. many federal laboratories collaborate with international partners and serve as reference centers for specialized testing. federal laboratories often provide training, confirmatory testing, and reference materials for other governmental laboratories. the dhhs laboratories that are associated with disease detection, control, and surveillance activities are found at the national institutes of health (nih), cdc, and fda. the nih, headquartered in bethesda, maryland, conducts research on acute and chronic diseases, develops new therapies and immunizations, and develops new laboratory and diagnostic technologies for many infectious and noninfectious diseases and health conditions. much of the nih work is done through extramural grants and contracts with universities, private companies, and other governmental organizations. the cdc's laboratories focus on infectious diseases, occupational diseases, and environmental causes of diseases. the cdc specialized laboratories are in colorado, ohio, west virginia, and puerto rico, in addition to its headquarters in atlanta, georgia. the cdc has led the development of rapid national laboratory reporting systems that have been successfully used to identify multistate outbreaks of diseases ( bean et al., ; hutwagner et al., ) . cdc-based scientists have developed and used new technologies to identify outbreaks of disease in cooperation with state and local public health laboratories. one such example of the successful application of a new technology is known as pulsenet (discussed in chapters and ; http:// www.cdc.gov/pulsenet/). pulsenet is a national network of public health laboratories that perform dna "fingerprinting" of foodborne pathogens and clinical isolates to allow matching of isolates. this epidemiological typing method is the basis for detecting clusters of disease that are geographically diffuse, and for linking bacteria found in a specific food to bacteria found in one or more persons with a particular disease. pulsenet permits recognition of outbreaks that previously went undetected. a multistate outbreak of listeriosis in was identified only after the isolates of listeria monocytogenes were tested by using pulsed-field gel electrophoresis and determined to all have a common pulsenet pattern (cdc, ) . fda laboratories focus primarily on monitoring the food supply and ensuring the purity and potency of drugs and other pharmaceuticals. these regulatory laboratories frequently become involved in the investigation of food contamination (including ground beef, poultry) and the adulteration of drugs. fda maintains regional laboratories in washington, new york, colorado, michigan, kansas, california, georgia, and arkansas, as well as specialized laboratories in ohio, pennsylvania, puerto rico, and massachusetts. the fda laboratories provide testing to support investigation and compliance activities. fda's electronic laboratory exchange network (elexnet) is a web-based system for real-time sharing of laboratory data derived from foods. this system allows public health officials to compare laboratory findings and to identify outbreaks earlier. the usda operates laboratories that support many of their regulatory, monitoring, and investigative programs. usda laboratories conduct research on animal and plant diseases and provide testing of animals and agricultural products. the usda's national veterinary services laboratories (nvsl) located in ames, iowa, tests for domestic and foreign animal diseases, and function as the primary animal disease reference laboratory. the nvsl provides diagnostic support for disease control and eradication programs, import and export testing of animals, and laboratory certification for selected animal diseases. diseases, such as anthrax, rabies, brucellosis, and bovine spongiform encephalopathy (mad cow disease), may impact both animals and humans and, therefore, constitute priorities at this laboratory. a former usda laboratory, the foreign animal disease diagnostic laboratory (faddl), which is located on plum island off long island, new york, was recently transferred to the department of homeland security after supporting years of research on some of the most dangerous animal pathogens. the doe oversees the operation of doe national laboratories, many of which were established to support the production, use, and response to nuclear materials. after the end of the cold war, the focus of some of the doe laboratories shifted to other projects, including the human genome project and the development of technologies and assays to support homeland security initiatives. the doe national laboratories develop new technologies for countering biologic and chemical threats, including systems for the detection, modeling, and response to terrorist attacks (see www-ed.fnal.gov/doe/ doc_labs.html). the dod has established laboratories worldwide in locations such as peru, indonesia, egypt, thailand, and kenya. dod laboratories serve the needs of the armed forces and function as screening or sentinel laboratories for infectious diseases. the u.s. army medical research institute of infectious diseases (usamriid) has the capability to detect unusual biological agents that often require advanced testing techniques. this laboratory, located in maryland, is a member of the laboratory response network (lrn; discussed later) and one of a few laboratories worldwide that can isolate and identify the most dangerous human agents, such as ebola, smallpox and marburg viruses. the epa operates regional environmental testing laboratories across the united states. these laboratories have a research and environmental monitoring mission: they analyze air, drinking water, ground water, surface water, soil, sediment, and hazardous materials for biological, chemical, and radiological materials that are toxic to the environment. epa develops standard methods for the analysis of environmental samples. epa maintains large databases of environmental monitoring data produced by its own laboratories and others. its office of research and development (ord) directs laboratory activities at locations, including the national center for environmental assessment in research triangle park, north carolina. although the capability and capacity of the federal laboratories described above is large, this capacity was challenged by the volume of environmental and clinical samples generated during the anthrax postal attack. the distribution of anthrax spores in mail during october led to an unprecedented demand for quality testing throughout the united states owing to discovery of real and suspected contaminations. although few of the more than , environmental samples tested contained b. anthracis, the existing network of public and commercial laboratories was barely able to meet the demands for testing, and there were significant delays caused by the sheer volume of samples. the concept of a high-throughput laboratory capable of testing thousands of biologic, chemical, or radiological samples would require the laboratory to be equipped with the latest automated instrumentation and supported with an efficient lims (layne and beugelsdijk, ) . the establishment of high-throughput laboratories to support the nation's homeland security needs is a reasonable concept, especially if the major federal partners were to colocate resources on a national interagency homeland security laboratory campus. approximately of the more than , laboratories in the united states are classified as state public health laboratories. included in this number are about regional or branch laboratories that are administered as part of the state public health laboratory. more than , laboratory professionals are employed by state public health laboratories. each state and five territories operate a state public health laboratory. one major function of theses laboratories is to provide diagnostic and analytical services for surveillance of infectious, communicable, genetic, and chronic diseases. state (and local) public health laboratories provide testing to support many public health programs (tuberculosis, sexually transmitted diseases, hiv, immunizations, and newborn screening). areas of analysis include clinical and environmental chemistry, immunology, pathogenic microbiology, virology, and parasitology. state laboratories serve as reference laboratories, and they provide confirmatory testing of specimens submitted from other laboratories. the state public health laboratories frequently measure toxicants in human samples to document exposures to chemicals found in the diet or environment. this specialized testing requires expensive equipment (mass spectrometers, chromatographs) and well-trained chemists. the capabilities, responsibilities, and practices of the state public health laboratories vary. during recent years, many of these laboratories have received substantial federal funding to increase staff, equipment, and capabilities to respond to biologic and chemical threats, as part of the dhhs' cooperative agreement on public health preparedness and response for bioterrorism. a large percentage of the state public health laboratories have used some of the federal funding to build, remodel, and upgrade facilities. funding for state laboratories is generally a mix of state and federal funds. many states rely on fees, reimbursements, and service contracts to carry out their mission. some states have regional or district laboratories to provide the necessary services throughout an entire state. state public health laboratories partner with public health laboratories operated by counties or cities to meet the needs of their communities. state public health laboratories are generally better prepared to respond to an incident requiring biologic testing as opposed to an incident requiring chemical testing. although research is not the primary mission of public health laboratories, several state public health laboratories have developed close ties with academic institutions. the opportunity to work on surveillance projects with faculty and students from schools of public health and academic training programs for laboratory professionals has been beneficial to these laboratories. arrangements with academic centers afford opportunities to improve laboratory services and surveillance systems. flexible funding and other resources, such as grants, faculty, and students, help support special research projects and training opportunities within public health laboratories. state laboratories provide services to health departments; healthcare organizations; local, state, and federal law enforcement; local hazardous materials (hazmat) teams; civil support teams; and other private and governmental laboratories. state laboratories analyze thousands of water and air samples daily. state laboratories involved in the analysis of drinking water and other environmental samples are accredited by the nelar certified by epa office of drinking water programs, or accredited by state-specific accreditation programs. state public health laboratories are the backbone of the laboratory response network (lrn), which we discuss below. the lrn also includes laboratories under the jurisdiction of federal agencies discussed in this chapter. at the time of publication, state and local public health laboratories make up the laboratories that are members of the lrn. of these, state, territorial, and metropolitan public health laboratories are part of the lrn's chemical testing network. more than , local public health laboratories provide support for city and county public health programs. these laboratories offer onsite testing for child health screening, tuberculosis, refugee screening, food safety, sexually transmitted diseases, and lead poisoning prevention, as well as epidemiologic investigations and environmental monitoring. local public health laboratories often forward specimens to their state laboratories for tests that are not available locally. approximately % of the local public health laboratories only perform waived tests. another % perform moderate complexity testing, and % perform highly complex testing (association of public health laboratories, ) . many state and locally operated laboratories in addition to clinical and public health laboratories produce test results that may be useful for surveillance. forensic laboratories and toxicology laboratories are frequently associated with departments of public safety or with state or local medical examiners. these forensic laboratories may be positioned at the federal, state, or local level, depending on the jurisdiction. medical examiners contribute to biosurveillance by elucidating unusual causes of death (see chapter ). medical examiners and forensic pathologists frequently rely on laboratories to establish the exact cause of death. readers may understand laboratories as only providing test results after the analysis of samples that are submitted. this view of laboratories only focuses on one of their products and overlooks services provided by the professionals who work in the laboratories. laboratory professionals provide consultation on the selection of the most useful tests for screening, diagnosis, and verification of disease. they provide information on the proper handling and transportation of samples. development of new technologies, evaluation of technologies, and the application of technologies are other important services provided by laboratory professionals. laboratories evaluate test kits for ease of use, storage conditions, and performance characteristics. laboratories train individuals to perform testing and educate and inform users of laboratory services. laboratories may also operate laboratory-based surveillance systems for respiratory and enteric diseases. laboratories employ many analytic technologies to provide testing for diagnosis and surveillance. these tests range from simple screening tests to presumptive diagnostic tests and confirmatory tests. simple laboratory tests are used to screen biologic samples for the presence of biological agents or other substances that might indicate a disease, an infection with a biologic agent, or a contamination with a toxin or other chemical. the classical approach to identification of biologic agents involves direct examination of stained materials by microscopic examination for the presence of agents (dhhs/cdc, n.d.; york, ) . microscopic examination relies on staining characteristics and the size and shape of the organisms found. with few exceptions, it is rarely possible to identify an agent based only on microscopic characteristics. direct stains may help eliminate organisms from further consideration, but they are usually not sufficient without further testing to identify a pathogen. wet mounts are used for the direct microscopic examination of clinical materials for fungi and parasitic agents. additional simple assays take advantage of the ability of an organism to metabolize chemicals or produce chemical reactions that result in color changes of a substrate. recently, many assay kits have been developed for waived tests. these waived test kits can produce reliable results in most cases; however, one must understand the limitations of these kits and the need for confirmatory testing. field test kits, often referred to as handheld assays, have become popular with first responders who have a need to know if an unknown material contains a biologic agent or toxic chemical. simple immunologic reactions, coupled with a colorimetric indicator, form the detection systems for many handheld assays. validating the performance of handheld assays in comparative studies is a task generally reserved for governmental agencies or contract laboratories (emanuel et al., ) . the major advantage of the simple assays is that they are quick, as a result may be available in to minutes. the short turnaround time makes these tests ideal for use by surveillance systems provided one understands the limitations of the tests and that a method for confirmatory testing is available. presumptive diagnostic tests are procedures that, when properly performed, may indicate the presence of a particular agent or closely related agents. presumptive diagnostic tests for biologic and chemical agents are more complex and require more time to perform than do the simple tests described above. most bacterial and viral agents can readily be grown in culture media or cell culture if the appropriate conditions are met. these conditions include the appropriate temperature, ph, and a source of energy (e.g., glucose). inhibitory substances, such as antibiotics, are often placed into the growth media to prevent the growth of unwanted organisms. growth of organisms in cell culture or artificial media takes hours to or more days, depending on the organism. once organisms are detected on or in growth media, various techniques are used to determine the genus and species of the organism. for bacteria, the differential growth on select media, metabolism of various carbohydrates and other chemicals, and the presence of selected enzymes are often used for identification. special stains that incorporate florescent dyes coupled with antibodies to selected organisms are used for identification of bacteria and viruses. laboratories use immunologic assays to identify many biologic agents and for the subspecies typing that is needed for epidemiological purposes. immunologic assays generally involve the use of a specific antibody that can attach to or react with the outer-surface structures of an agent. other immunologic assays are used to detect antibodies in biological materials after infection with biological agents. after the isolation and identification of many organisms, drug-susceptibility testing determines the organism's susceptibility to drugs that are used to treat infections with the organism. a definitive or confirmatory test is a test that will identify with a very high degree of certainty the true identity of an agent. these tests have a very low likelihood of providing a falsepositive result. many of the definitive and confirmatory assays used today are molecular assays, which detect genetic material that is specific to a bacterium, virus, protozoa, or other organism. nucleic-acid-based assays rely on the unique differences found in the structure of single strands of dna and rna. the unique pattern of bases is specific for a single organism or closely related organisms. the nucleic-acid-based assays involve the use of probes, which are strands of dna or rna that match distinctive dna or rna patterns of the organism being tested and will bind with that dna or rna if it is in the clinical specimen. once the binding occurs, the binding can be detected by using electrochemical, colorimetric, and optical systems (committee on research and development needs for improving civilian medical response to chemical and biological terrorism incidents, ) . this binding provides extreme selectivity between the known probes and the material found in clinical specimens. the use of a technique known as polymerase chain reaction (pcr) makes it is possible to amplify trace quantities of dna or rna in a clinical specimen to enable the detection of as few as , bacteria or viruses. the high specificity and sensitivity of molecular assays makes them especially suited for detecting minute quantities of biologic agents and toxins. the use of genetic fingerprints has become a valuable tool for microbial forensics (murch, ) . by identifying distinct features of genes using sequencing techniques, it is possible to identify individual strains of organisms and to use this information as epidemiological markers. molecular techniques allow investigators to link strains from various sources and to form associations that often unravel the mystery of disease outbreaks. libraries of genetic patterns, or fingerprints, make it possible to trace the origin of many outbreaks. not only does sequencing identify dna or rna patterns unique to a particular organism, but, in many cases, these probe technologies are simpler, faster, and less technology-dependent than are other traditional assays. many biotechnology companies are pursuing production of microarray systems that will test for to , or more different dna fragments simultaneously. the technology embeds the probes on a single glass or nylon substrate called a microchip. by using these arrays and various detection systems onto which the clinical specimen is applied, the individual components of the microchip will react with dna fragments in the specimen and be detected. as this technology develops, it will become more common to use the microarray systems for screening and detection of diseases. simultaneous pcr assays for multiple respiratory viruses now have sufficient sensitivity and specificity to be a valuable tool for diagnosis of respiratory viral infections (hindiyeh et al., ) . in the future, pcr assays will be able to screen a single specimen for a multitude of biologic agents. a lims is a computer system that a laboratory uses to track specimens and manage analytical data. the function of a lims can perhaps best be explained by tracing a single test-a white blood count--from the time that a clinician orders the test until the time the clinician receives the result of the test. a clinician requests (orders) that a laboratory perform a white blood count on a blood sample from a patient in one of several ways. the clinician writes the order on paper, gives a verbal order to a nurse, or enters the order directly into a computer system. a lims may receive this order in one of several ways: directly, if the lims provides an order-entry component that either the clinician uses directly or the nurse or ward clerk uses on her behalf; indirectly, if a paper order form accompanies the specimen; or electronically, from an order-entry system embedded in another information system (such a point-of-care system as discussed in chapter ). we will trace the most automated path in which the lims receives the order electronically. the received order sets up a specimen-tracking process that is a central lims function. the lims (or a point-of-care system) controls a printer, which is often located in the clinical area from which the order originated. the printer generates a bar-coded label. a phlebotomist attaches the label to a "purple top" vial (containing magnesium citrate or ethylenediaminetetraacetic acid [edta] to prevent the blood from coagulating). the phlebotomist draws the blood after checking carefully that the identification on the labeled tube matches the patient, and sends the sample to the laboratory. oftentimes, the labeled specimen is transported by pneumatic chute from clinical areas, such as the emergency department, or by express overnight delivery to the laboratory. a technician in the laboratory scans the barcode of the specimen with an optical scanner, which is connected to the lims. if the laboratory has an automated analyzer for blood counts, the technician simply places the vial into the specimen carousel of the analyzer. the analyzer recognizes the bar code, communicates with the lims over an internal laboratory network to determine which tests were ordered for the spedmen, runs the tests, and transmits the results to the lims. other types of specimens may require preparation, such as centrifugation, before being placed into the carousel of an automatic analyzer, but the information processing and communication between the analyzer and the lims are otherwise identical. for tests that are done by hand, the lims provides user-interfaces into which medical technologists register specimens and enter intermediate and final results of tests. depending on the laboratory and the needs of its clinical customers, the lims may deliver the results as paper reports, via web-browser interfaces, or by e-mail. a lims typically offers all of these options. a lims invariably has an outbound computerto-computer interface that can transmit results to other clinical information and public health information systems. although our example is of a clinical test, the process is identical for environmental tests ordered by sanitarians, water quality technicians, or outbreak investigators. the vast majority of laboratory work in the united states is highly automated in the fashion just described. with the exception of tests done in the field or in office practices, limss track and manage the analytic results of most laboratory tests performed in the united states. limss are designed to make test results available to clinicians and other information systems soon after they are performed. limss are highly reliable and operate in real time. limss are developed within the laboratory by information technology staff, purchased from commercial vendors, or a combination of both. because of the importance of laboratory tests in biosurveillance, biosurveillance organizations are attempting to establish connections between limss and their own biosurveillance computers. at present, however, there are significant technical barriers to connecting a lims located in a laboratory with a computer located in a biosurveillance organization. the most difficult technical barrier is data incompatibility. most laboratories do not use standard coding systems to identify the names and results of laboratory tests. data standards exist, but few laboratories use them. most laboratories have evolved their own naming or coding systems for the tests that they perform and the results of those tests. they use these proprietary codes (or free text) to identify the laboratory test, specimen type, organism, or other results of a test. as a result, each lims-tobiosurveillance-computer interface requires significant effort to understand the data and to create means to translate the data into a standard format so that it can be integrated with data coming from other lims. we discuss standard data formats in detail in chapter . outbound communication standards, such as hl , also exist and we discuss them in chapter . although most lims support these standards, the specific implementations vary. even if both the biosurveillance computer and the lims use the hl standard, they will not be able to communicate without significant effort to understand the specifics of the messages and to create a means for extracting the data from the messages. importantly, a new version of hl (version . ) will solve this problem; but its penetration in the lims market is low at present. because of the customization required to connect even a single lims to a biosurveillance organization, there are only a few regions that have integrated data from most of the limss that serve their region into biosurveillance. ultimately, these barriers will be addressed by standardization, but as we discuss in chapter , it takes many years to achieve widespread standardization of any component in a biosurveillance system. the organization of laboratories into collaborative networks has been ongoing for more than a decade. the concept of laboratory networks arose from the need to ensure that critical laboratory services were available throughout the country (gilchrist, ) . the cdc, fda, usda, and state governmental laboratories formed many of the original partnerships that grew into the laboratory networks that exist today. early networks included the national laboratory system (nls) of clinical, public health and federal laboratories (mcdade and hughes, ) , and the public health laboratory information system (phlis). phlis was an early dos-based system that involved voluntary reporting of selected laboratory tests directly to the cdc by state and local public health laboratories and numerous military laboratories (see chapter ). phlis was one of the earliest laboratory-based surveillance systems that became an effective tool for the identification of outbreaks of salmonellosis (bean et al., ; hutwagner et al., ) . the cdc's lrn was established in in compliance with a presidential directive that outlined federal agencies' counterterrorism goals and responsibilities. the mission of the lrn is "to maintain an integrated national and international network of laboratories that can respond quickly to acts of chemical or biological terrorism, emerging infectious diseases and other public health threats and emergencies." the lrn was first tasked to address state and local public health laboratory preparedness and response for bioterrorism. since its inception, its mission has expanded to include chemical terrorism. the scope of laboratories in the lrn has expanded beyond state and local public health laboratories in order to meet national security needs (http://www.bt. cdc.gov/lrn/). the lrn and its partners maintain a network of laboratories that can respond quickly to acts of chemical or biological terrorism, emerging infectious diseases, or other public health threats and emergencies. the network included federal, state, and local public health; military; and international laboratories as of august , . figure . shows the distribution of lrn laboratories by type as of march , . the lrn employs tests that can detect biological threat agents in clinical specimens, environmental samples, food, animals, and water. the association of public health laboratories was a partner in the early development of the lrn and has played an important role in ensuring that the lrn provides the training, standardized methods, and equipment necessary for detecting biologic agents of terrorism and other threats to public health. the federal bureau of investigation (fbi) was also a key partner in establishing the network. the fbi brought its forensic expertise and evidence-gathering requirements to the program. public health and law enforcement have overlapping approaches to their investigations that required collaboration between cdc and law enforcement to both enhance and protect the integrity of their investigations. three levels of laboratories are recognized within the lrn for bioterrorism agent detection. lrn laboratories responsible for bioterrorism agent detection are designated as national, reference, or sentinel laboratories (figure . ). the national laboratories include laboratories at the cdc, usamriid, and the naval medical research center. they have unique resources to safely identify highly infectious agents (biological safety level agents) and the ability to provide definitive characterization of biologic agents. the national laboratories have developed standard tests and protocols, trained laboratory analysts, and established secure communications for the rapid sharing of laboratory results from reference laboratories. reference laboratories in the lrn perform tests to detect and confirm the presence of biological threat agents, such as those that cause anthrax, plague, tularemia, smallpox, or botulism. these laboratories ensure that state and local laboratories can have a timely response in the event of a bioterrorism incident or an emerging disease. rather than having to rely on confirmation testing from national laboratories, reference laboratories are capable of producing conclusive results needed by local authorities for rapidly responding to emergencies. specimens received by reference laboratories that contain threat agents are usually submitted to a national laboratory for definitive characterizations of the agent. state and local public health laboratories comprise most of the reference laboratories within the lrn. although sentinel laboratories are not counted among the lrn laboratories, they represent the thousands of clinical (human and veterinary) and environmental laboratories identified by the state lrn reference laboratory to serve as the front line of defense in detecting agents of terrorism. qualification of the sentinel laboratory is based on the experience and competency of the laboratory staff, appropriateness of facilities, and completion of training provided by the lrn. sentinel laboratories can often rule out potential bioterrorism agents based on a battery of simple tests. in a covert terrorist attack, a sentinel laboratory could be the first facility to identify a suspicious agent or an unusual cluster f i g u r e . laboratory response network (lrn) structure for bioterrorism response laboratories. of diseases. a sentinel laboratory's responsibility is to rule out other diseases and refer a suspicious sample to an appropriate reference laboratory. the lrn uses an array of presumptive and confirmatory assays to detect biological threat agents or chemical agents. presumptive assays generally include traditional microbiological assays, such as growth on special media, use of special stains, and the use of rapid molecular diagnostic assays, such as real-time pcr. confirmatory methods used by the national laboratories are considered the gold standard for detecting the target agent. methods, such as time-resolved fluorescence (trf) and molecular characterization, have replaced many of the more traditional confirmatory methods that were based on the growth and biochemical properties of the agent. reference laboratories have access to lrn protocols through a secure web site and are supplied standardized reagents needed to perform the necessary tests. uniform procedures for use by sentinel laboratories have also been developed and are used for training of sentinel laboratory staff. all laboratories that are part of the lrn must provide a safe and secure environment for performing tests and must participate in a recognized proficiency testing program. the chemical component of the lrn employs a more centralized structure, with only a few laboratories currently prepared to provide definitive analysis of specimens for chemical agents or their metabolites. lrn laboratories responsible for chemical agent detection are designated as level , , or laboratories. five laboratories located in california, michigan, new mexico, new york, and virginia participate in level activities. at this level, personnel are trained to detect exposure to an expanded number of chemicals in human blood or urine, including all level laboratory analyses, plus analyses for mustard agents, nerve agents, and other toxic chemicals. fortyone laboratories participate in the chemical lrn by providing level activities. at this level, laboratory personnel are trained to detect exposure to a limited number of toxic chemical agents in human blood or urine. analysis of cyanide and toxic metals in human samples are examples of level laboratory activities. each of the chemical network members participates in level activities. level laboratories are responsible for the following: working with hospitals in their jurisdiction knowing how to properly collect and ship clinical specimens ensuring that specimens used as evidence in a criminal investigation are handled properly and chain-of-custody procedures are followed being familiar with chemical agents and their health effects training on anticipated clinical sample flow and shipping regulations working to develop a coordinated response plan for their respective state and jurisdiction initial testing in a suspected chemical event will occur at cdc or i of level i chemical laboratories that have been established by cdc. by use of mass spectrometry, cdc laboratories perform tests on the first or more clinical specimens to measure human exposure. results of these tests would be reported to affected states, and if needed, appropriate lrn members may be asked to test additional samples. this approach is necessary because the analytical expertise and technology resources required to respond to a chemical event is expected to be high. the lrn supports secure communications on emerging and emergency issues, a secure mechanism for ordering reagents and testing protocols, and a system for electronically reporting test results. the lrn provided valuable testing after the release of anthrax spores in , the identification of monkey pox in , and the response to severe acute respiratory syndrome (sars) in . in , canada created a laboratory network, known as the canadian public health laboratory network (cphln), to strengthen the linkages between federal and provincial public health laboratories. this canadian network is modeled after the lrn in the united states. the cphln has been providing responses to naturally occurring infections and deliberate releases of biologic agents and toxins. the cphln coordinates pathogen detection and infectious disease prevention activities, as well as conducts laboratory-based surveillance and early warning systems for emerging pathogens and bioterrorism threats. the national animal health laboratory network (nahln) is part of a national strategy in the united states to coordinate the nation's federal, state, and academic animal health laboratories. the usda has taken the lead in the development of this network, which includes agriculture and animal health laboratories operated by state agricultural agencies and those associated with veterinary teaching facilities. the facilities and professional expertise of nahln members allows authorities to better respond to animal health emergencies that might include a bioterrorist event, the emergence of a new domestic animal disease, or the appearance of a foreign animal disease that could threaten the nation's food supply and public health. because many of the biologic agents that cause the greatest concern as terrorist agents infect both humans and animals, the role of veterinarians in the early detection of disease is very important. the nahln currently consists of laboratories in states. an effort is underway to deploy standardized testing methods in member laboratories and to improve the information technology system used by member laboratories to track test requests and report results. the u.s. animal health association (usaha) and the american association of veterinary laboratory diagnosticians (aavld) have members who participate in the nahlh and contribute expertise to protect animals and public health. the national plant diagnostic network (npdn) is an agricultural laboratory network that provides detection, identification, and reporting of pests and pathogens that have been deliberately or accidentally introduced into agricultural systems. the primary concern of this network is food security and the economic threats to the nation's food supplies. the npdn includes five regional centers located at cornell university, michigan state, kansas state, university of florida at gainesville, and the university of california at davis. the npdn recently implemented a new database that helps with required reporting to state and national agencies. a web-based plant diagnostic system using digital photography allows laboratories to share images with specialists in remote locations. the food emergency response network (fern) is a network of state and federal laboratories that are committed to analyzing food samples in the event of a biological, chemical, or radiological terrorist attack in the united states. the federal partners in the fern include the fda, usda, cdc, and epa. as of may , there are laboratories in fern, representing states and puerto rico. twenty-six federal laboratories, state laboratories, and five local laboratories are enrolled in fern. the mission of fern is to integrate the nation's food testing laboratories for the detection of threat agents in food while using standardized diagnostic protocols and procedures. of the laboratories in fern, there are that perform chemical tests on food, that perform biological tests on food, and that perform radiological tests on food. these laboratories strengthen preparedness and provide surge capacity. the fda and usda jointly share the leadership within fern and have been working to obtain federal funds that can be made available to support further development of the network. the data capture and information exchange system for fern is the elexnet, is an integrated, secure system designed for use by multiple governmental agencies involved in food safety activities. laboratories report test results and public health officials assess risks and analyze trends in foodborne diseases, elexnet has gis reporting functions and uses hl data exchanges between laboratories. similar to those in lrn, participants in fern receive training on the latest equipment and are required to participate in proficiency testing programs, elexnet provides the necessary infrastructure for an early warning system that can identify potentially hazardous foods and share laboratory reports in a timely manner. as of january , federal, state, and local laboratories in all states have joined the elexnet system. about laboratories actively exchange data by using elexnet. the radiological emergency analytical laboratory network (realnet) is a national network of radiological laboratories that are capable of responding to the needs for radiological testing after a terrorist attack. academic, commercial, military, federal, state, and local laboratories participate in realnet. these laboratories serve as a science and technology asset for the department of homeland security. realnet is modeled after the lrn and fern and includes a web-based database containing information on the capabilities, capacity, and competence of member laboratories. information on accreditation, certification, and performance testing is also maintained. standards, guidelines, and laboratory procedures are developed and distributed by realnet. gaps in the standards are being addressed by appropriate standards development organizations. internet-based tools, such as bulletin boards and list servers, are used to promote the exchange of information. the system provides links to other resources that would be useful during an emergency caused by the release of a radioactive material. the expansion of laboratory networks designed to produce test results in response to an act of terrorism or other public health emergency has led to increased sharing of laboratory results. coordination and integration of the various networks has not always been a priority. duplicate systems and overlapping missions suggest that an integrated consortium of laboratory networks could provide timely results for early detection and response to acts of terrorism. the networks need to agree on standardized tests and policies that would promote a timely response no matter which network is reporting results. an overall system to ensure that laboratory capacity will be available to test clinical (human and animal) specimens and environmental samples, including food and water, does not exist. laboratories that can perform screening, monitoring, and definitive testing are needed for each class of specimen. although laboratory information systems have been developed for capturing and sharing data, the diverse systems are not fully compatible with each other. failure to standardize nomenclatures and use recognized data transmission protocols make sharing of large quantities of data for surveillance purposes problematic. in an effort to improve coordination among laboratory networks, the department of homeland security is working to integrate these networks through the creation of the integrated consortium of laboratory networks (icln). the icln employs the lrn model for coordinating laboratory assets for terrorism among federal, state, local, and scientific partners. a memorandum of agreement was signed in by the usda, dod, doe, dhhs, epa, and the departments of homeland security, state, justice, and interior to form the icln. these federal agencies will collaborate to ensure that laboratory resources available within each agency can be used to respond to terrorist events and other national emergencies. clinical, commercial, and governmental laboratories are an important source of data for biosurveillance systems. test results obtained from the analysis of human and animal specimens may be early indicators of disease within the population. before the establishment of a definitive diagnosis, a sudden rise in the number of tests being requested by clinicians might be the first indication of an outbreak. the combination of laboratory data from environmental laboratories and the occurrence of illness in humans or animals might signal onset of an infectious disease or poisoning. the establishment of a lims that can rapidly capture and report laboratory data electronically will greatly contribute to the use of laboratory data in biosurveillance. challenges still exist for integrating , laboratories into a real-time network to support biosurveillance. the multitude of laboratory networks that are being formed will enhance the analytical capabilities of laboratories as well as the ability of laboratories to distribute peak loads during emergencies and quickly and efficiently share data electronically. enormous potential exists for the use of data that that is locked up in systems by the lack of standardization. although much recent emphasis has been focused on building laboratory networks in preparation for a biological, chemical, or nuclear attack, many of the enhanced laboratory capabilities will assist with the response to other public health emergencies. association of public health laboratories national plant diagnostic network (npdn) informatics for the clinical laboratory: a practical guide laboratory information management systems: development, and implementation for a quality assurance laboratory phlis: an electronic system for reporting public health data from remote sites detection and measurement of biological agents. in chemical and biological terrorism--research and development to improve civilian medical response validating the performance of biological detection equipment: the role of the federal government a national laboratory network for bioterrorism: evolution from a prototype network of laboratories performing routine surveillance evaluation of the prodesse hexaplex multiplex pcr assay for direct detection of seven respiratory viruses in clinical specimens using laboratory-based surveillance data for prevention: an algorithm for detecting salmonella outbreaks c gi ? cmd---r etriev e &db=pub med &dop t=citation high-throughput laboratories for homeland and national security the u.s. needs a national laboratory system microbial forensics: building a national capacity to investigate bioterrorism sentinel bioterrorism responders: are hospital labs ready key: cord- -zrnczve authors: craighead, geoff title: security and fire life safety threats date: - - journal: high-rise security and fire life safety doi: . /b - - - - . - sha: doc_id: cord_uid: zrnczve nan l vandalism. "such willful or malicious acts intended to damage or destroy property." included among these acts is the use of graffiti, whereby often a sharp instrument (such as a key or a pocket knife) is used to scratch initials or symbols; whereby the graffiti is written using color markers, crayons, lipstick, pencils, correction fluid, or spray paint; or whereby the graffiti is etched into glass using acid (all such instances being commonly known as "tagging"). in buildings, graffiti can be found in restrooms and toilets, on walls of elevator lobbies and on walls and doors of elevator cars (particularly those of service or freight elevators), on walls adjacent to public telephones, and on exterior glass windows. vandalism may also involve tampering with equipment (for example, standpipes on upper floors to cause flooding inside a building). although it may not be technically "willful" damage, the use of bicycles, scooters, skateboards, roller skates, and similar devices can lead to the destruction of property in building exterior areas and parking structures. "skateboarders regularly wear down concrete surfaces, scuff up painted exteriors, and damage planters, handrails, [park benches,] and fountains." also, inadvertently, bicyclists, skateboarders, and roller skaters may collide with other people or seriously injure themselves. in addition, there may be the disruption of building utilities such as water; electrical power; natural gas; sewer; heating, ventilation, and air-conditioning (hvac); telecommunication; security; and life safety systems. this interference may involve a cyberattack, whereby unauthorized access is gained to networks that control these systems. such an attack is becoming increasingly possible as many building systems are placed on networks, and the ability of persons to attack such networks is becoming progressively more sophisticated. some security threats may involve terrorism. "terrorism is considered an unlawful act of force and violence against persons or property to intimidate or coerce a government, the civilian population, or any segment thereof, in furtherance of political or social objectives." a person is guilty of a terroristic threat "if he [or she] threatens to commit any crime of violence with purpose to terrorize another or to cause evacuation of a building, place of assembly, or facility of public transportation, or otherwise to cause serious public inconvenience, or in reckless disregard of the risk of causing such terror or inconvenience." cyberterrorism is [t]he convergence of terrorism and cyberspace. it is generally understood to mean unlawful attacks and threats of attack against computers, networks, and the information stored therein when done to intimidate or coerce a government or its people to further political or social objectives. moreover, to qualify as cyberterrorism, an attack should result in violence against persons or property, or at least cause enough harm to generate fear. attacks that lead to death april , , milan, italy-at : p.m ., a small aircraft piloted by an elderly businessman crashed into the th floor of -story pirelli tower, the tallest building in milan, killing a cleaning woman, a government lawyer and the pilot. at least people were injured. the pilot reported mechanical trouble shortly before impact. the cause of the accident has not been finally determined, although suicide of the pilot has been widely suggested. october , , new york-mid-afternoon , a small single-engine plane, with new york yankees pitcher cory lidle and his flight instructor, tyler stanger, aboard crashed into the th and st floors of a -story apartment building. both occupants were killed in the crash, and flaming debris, including parts of the aircraft, rained down on sidewalks. in each incident, the structural damage to the building was localized to the point of impact of the plane. on the morning of september , , within a -minute time frame, four commercial airliners fully loaded with fuel for transcontinental flights departed from boston, newark, and washington, dc, airports. within minutes of takeoff, four-to five-man teams on board hijacked these planes. two of these aircraft, each with a fuel-carrying capacity of , u.s. gallons ( , liters) of aviation fuel and a maximum takeoff weight of , pounds ( , kg), rammed into the twin towers of the world trade center in new york city ( . "it is estimated that, at the time of impact, each aircraft had approximately , gallons of unused fuel on board (compiled from government sources)." the resulting fire soon led to the total collapse of both these -story buildings. one other plane smashed into the pentagon in washington, dc. the fourth, reportedly bound for the white house, crashed in an open field in pennsylvania after several of its passengers fought against the hijackers. "the events in new york city (nyc) on september , , were among the worst building disasters and loss of life from any single building event in the united states." shockwaves from these acts reverberated throughout the united states and the world. within minutes of the second plane hitting the world trade center, all u.s. domestic flights were grounded. within hours, owners and managers of major u.s. high-rises, including the sears tower in chicago, advised occupants to leave their buildings. the los angeles times reported that even in europe, authorities evacuated high-rise buildings as a safety measure. u.s. markets closed and foreign stock markets plummeted. u.s. president george w. bush declared the attacks in new york and washington "acts of war." in october , a u.s.-led coalition began bombing afghanistan, the country harboring the al qaeda terrorist organization and its infamous leader, osama bin ladin, r who had been identified as the instigator of the espn.com news services. lidle dies after plane crashes into nyc high-rise. http://sports.espn.go.com/ mlb/news/story?id ; october , . osama bin laden, with some spelling variations, is the name used in english to refer to usamah bin muhammad bin `awad bin ladin (arabic: ) (wikipedia. october , . http://en.wikipedia.org/wiki/osama_bin_laden; october , ) . attacks. the terrorist-supporting taliban regime was ousted from power and a new government established. the events that occurred in a fateful hour, minutes, and seconds, were as follows: : : a.m.-american airlines flight , a boeing airliner, with passengers and crew on board a scheduled flight from boston to los angeles, crashed into the north face of the north tower (wtc ) of the world trade center. the north tower was struck r between the rd and th floors. "evidence suggests that all three rr of the building's stairwells became impassable from the nd floor up. hundreds of civilians were killed instantly by the impact. hundreds more remained alive but trapped." : : a.m. -united airlines flight , a boeing airliner, with passengers and nine crew on board, also on a scheduled flight from boston to los angeles, crashed into the south face of the south tower (wtc ) of the world trade center and struck between the th and th floors. "the plane banked as it hit the building, leaving portions of the building undamaged on impact floors. as a consequence-and in contrast to the situation in the north tower-one of the stairwells (a) [of the three] initially remained passable from at least the st floor down, and likely from top to bottom." figure - depicts the approximate flight paths of the two aircraft. "each plane banked steeply as it was flown into the building, causing damage across multiple floors. according to government sources, the speed of impact into the north tower was estimated to be knots, or miles per hour (mph) [ kilometers per hour], and the speed of impact into the south tower was estimated to be knots, or mph [ kilometers per hour]. as the two aircraft impacted the buildings, fireballs erupted. ibid., p. . information about the events, including exact times (eastern daylight time) of the impact of the planes, was obtained from the national institute of standards and technology final report on the collapse of the world trade center towers (nist ncstar , ) . some information was also obtained from the / commission report, . r columbia university scientists using a seismograph determined that the plane that hit the north tower "registered magnitude- . on the seismograph, equal to a small earthquake" ("for many on september , survival was no accident" [usa today. december , : ] , authored by dennis cauchon with contributors barbara hansen, anthony debarros, and paul overberg. article reprinted in the nfpa "emergency response planning workshop participant workbook, appendix v" conducted in san francisco by mark schofield and douglas p. forsman [march , : ] ). rr "the world trade center had an excellent stair system, much better than required by building codesboth when it was built years ago and now. each tower had three stairwells. new york city building codes require two. stairways a and c, on opposite sides of the building's core, were inches wide. in the center, stairway b was inches wide. the bigger the stairway, the faster an evacuation can proceed. in -inch stairways, a person must turn sideways to let another pass-for example, a rescuer heading up. in a -inch stairway, two people can pass comfortably" ("for many on september , survival was no accident" [usa today. december , : ] , authored by dennis cauchon with contributors barbara hansen, anthony debarros, and paul overberg. article reprinted in the nfpa "emergency response planning workshop participant workbook, appendix v" conducted in san francisco by mark schofield and douglas p. forsman [march , : ] ). the / commission report, final report of the national commission on terrorist attacks upon the united states, investigation of "facts and circumstances relating to the terrorist attacks of september , " by the national commission on terrorist attacks upon the united states (also known as the / commission) (w. w. norton & company: new york & london. www. - commission.gov/report/index. htm; july : ). the term fireball is used to describe deflagration, or ignition, of a fuel vapor cloud." "part of this fuel immediately burned off in the large fireballs that erupted at the impact floors. remaining fuel flowed across the floors and down elevator and utility shafts, igniting intense fires throughout upper portions of the buildings. as these - . fires spread, they further weakened the steel-framed structures, eventually leading to total collapse." shows the areas where aircraft debris landed outside of the towers. : : a.m.- minutes after it was hit, the top floors of the south tower collapsed, causing the entire building to fall down. : : a.m.- hour and minutes (or hour, minutes, and seconds to be precise) after it was struck, the north tower collapsed. according to the federal emergency management association report, fema : the world trade center building performance study: data collection, preliminary observations, and recommendations, the following then occurred: as the towers collapsed, massive debris clouds consisting of crushed and broken building components fell onto and blew into surrounding structures, causing extensive collateral damage and, in some cases, igniting fires and causing additional collapses. most of the fires went unattended as efforts were devoted to rescuing those trapped in the collapsed towers. the -story marriott world trade center hotel (wtc ) was hit by a substantial amount of debris during both tower collapses. portions of wtc were severely damaged by debris from each tower collapse, but progressive collapse r of the building did not occur. however, little of wtc remained standing after the collapse of wtc . wtc , , and had floor contents and furnishings burn completely and suffered significant partial collapses ibid., p. . ibid. ibid., pp. - . r according to the national institute of standards and technology (nist) best practices for reducing the potential for progressive collapse in buildings, "the term 'progressive collapse' has been used to describe the spread of an initial local failure in a manner analogous to a chain reaction that leads to partial or total collapse of a building. the underlying characteristic of progressive collapse is that the final state of failure is disproportionately greater than the failure that initiated the collapse. asce standard - defines progressive collapse as 'the spread of an initial local failure from element to element resulting, eventually, in the collapse of an entire structure or a disproportionately large part of it' (asce ) .… based on the above description, it is proposed that the professional community adopt the following definition, which is based largely on asce - : progressive collapse-the spread of local damage, from an initiating event, from element to element resulting, eventually, in the collapse of an entire structure or a disproportionately large part of it; also known as disproportionate collapse" (nistir best practices for reducing the potential for progressive collapse in buildings. washington, dc: national institute of standards and technology, u.s. department of commerce; february : ). "the concept of progressive collapse can be illustrated by the famous collapse of the ronan point apartment building. the structure was a -story precast concrete-bearing wall building. a gas explosion in a corner kitchen on the th floor blew out the exterior wall panel and failure of the corner bay of the building propagated upward to the roof and downward almost to the ground level. thus, although the entire building did not collapse, the extent of failure was disproportionate to the initial damage" (nistir best practices for reducing the potential for progressive collapse in buildings; february : ) . also, the collapse of wtc on september , , has been defined as progressive collapse by the national institute of standards and technology (nist) investigation of the collapse of world trade center building (nist ncstar a federal building and fire safety investigation of the world trade center disaster. final report on the collapse of world trade center building . executive report. washington, dc: national institute of standards and technology; august :xxxii). from debris impacts and from fire damage to their structural frames. wtc , a -story building that was part of the wtc complex, burned unattended for hours before collapsing at : p.m. in total, major buildings experienced partial or total collapse and approximately million square feet of commercial office space was removed from service, of which million belonged to the wtc complex. since september , there was much discussion r about the design and performance of high-rise buildings. two major studies rr have been designed to evaluate ibid., p. . r for example, the question has been asked as to whether tall buildings should continue to be built in the future and whether they should be designed to resist all hazards, including explosions (the issue of designing buildings to resist explosions was also raised after the world trade center and the oklahoma city bombings). also, there have been suggestions to change future high-rise building design to include lower heights, more stairwells, lower occupancies, upgraded refuge areas, and safe elevators that could be used during emergencies such as fire (fahy r, proulx g. a comparison of the and evacuations of the world trade center. presentation to the nfpa world safety congress & exhibition. minneapolis, mn: may , ) . even the threat from the air led to a policy change in chicago-approved by the federal aviation administration (faa)-expanding "the 'no-fly zone' over the city to an area significantly larger than that mandated by the faa immediately after september . this expansion was temporary, and the area has since been reduced" (archibald r, medby jj, rosen b, schachter j. security and safety in los angeles high-rise buildings after / . rand documented briefing. santa monica, ca; april : ) . rr in addition, soon after september , the council on tall buildings and urban habitat and the national science foundation announced the following studies: ( ) the council on tall buildings and urban habitat (ctbuh) formed a task force to explore options "to further increase the level of safety in tall buildings including the establishment of guidelines to better educate its report, called the world trade center building performance study: data collection, preliminary observations and recommendations, "fulfilling its goal 'to determine probable failure mechanisms and to identify areas of future investigation that could lead to practical measures for improving the damage resistance of buildings against such unforeseen events. '" observations and findings the following observations and findings are from the world trade center building performance study: the structural damage sustained by each of the two buildings [wtc and wtc ] as a result of the terrorist attacks was massive. the fact that the structures were able to sustain this level of damage and remain standing for an extended period of time is remarkable and is the reason that most building occupants were able to evacuate safely. events of this type, resulting in such substantial damage, are generally not considered in building design, and the ability of these structures to successfully withstand such damage is noteworthy. preliminary analyses of the damaged structures, together with the fact the structures remained standing for an extended period of time, suggest that, absent other severe loading events such as a windstorm or earthquake, the buildings could have remained standing in their damaged states until subjected to some significant additional load. however, the structures were subjected to a second, simultaneous severe loading event in the form of the fires caused by the aircraft impacts. the large quantity of jet fuel carried by each aircraft ignited upon impact into each building. a significant portion of this fuel was consumed immediately in the ensuing fireballs. the remaining fuel is believed either to have flowed down through the buildings or to have burned off within a few minutes of the aircraft impact. the heat produced by this burning jet fuel does not by itself appear to have been sufficient to initiate the structural collapses. however, as the burning jet fuel spread across several floors of the buildings, it ignited much of the buildings' contents, causing simultaneous fires across several floors of both buildings. the heat output from these fires is estimated to have been comparable to the power produced by a large commercial power generating station. over a period of many minutes, this heat induced additional stresses into the damaged structural frames while simultaneously softening and weakening these frames. this additional loading and the resulting damage were sufficient to induce the collapse of both structures. the ability of the two towers to withstand aircraft impacts without immediate collapse was a direct function of their design and construction characteristics, as was the vulnerability of the two towers to collapse a - . result of the combined effects of the impacts and ensuing fires. many buildings with other design and construction characteristics would have been more vulnerable to collapse in these events than the two towers, and few may have been less vulnerable. it was not the purpose of this study to assess the codeconformance of the building design and construction, or to judge the adequacy of these features. however, during the course of this study, the structural and fire protection features of the buildings were examined. the study did not reveal any specific structural features that would be regarded as substandard, and, in fact, many structural and fire protection features of the design and construction were found to be superior to the minimum code requirements. several building design features have been identified as key to the buildings' ability to remain standing as long as they did and to allow the evacuation of most building occupants. these included the following: robustness and redundancy of the steel framing system adequate egress stairways that were well marked and lighted conscientious implementation of emergency exiting training programs for building tenants similarly, several design features have been identified that may have played a role in allowing the buildings to collapse in the manner that they did and in the inability of victims at and above the impact floors to safely exit. these features should not be regarded either as design deficiencies or as features that should be prohibited in future building codes. rather, these are features that should be subjected to more detailed evaluation, in order to understand their contribution to the performance of these buildings and how they may perform in other buildings. these include the following: the type of steel floor truss system present in these buildings and their structural robustness and redundancy when compared to other structural systems use of impact-resistant enclosures around egress paths resistance of passive fire protection to blasts and impacts in buildings designed to provide resistance to such hazards grouping emergency egress stairways in the central building core, as opposed to dispersing them throughout the structure…. wtc , wtc , west street, the bankers trust building, the verizon building, and world financial center were impacted by large debris from the collapsing towers and suffered structural damage, but arrested collapse to localized areas. the performance of these buildings demonstrates the inherent ability of redundant steel-framed structures to withstand extensive damage from earthquakes, blasts, and other extreme events without progressive collapse. the ensuing years will reveal the total impact of this disaster on society and the world of skyscrapers. some changes will be determined by the findings of the world trade center building performance study and later studies. the following comments are from the world trade center building performance study: during the course of this study, the question of whether building codes should be changed in some way to make future buildings more resistant to such attacks was frequently explored. depending on the size of the aircraft, it may not be technically feasible to develop design provisions that would enable all structures to be designed and constructed to resist the effects of impacts by rapidly moving aircraft, and the ensuing fires, without collapse. in addition, the cost of constructing such structures might be so large as to make this type of design intent practically infeasible. although the attacks on the world trade center are a reason to question design philosophies, the bps team believes there are insufficient data to determine whether there is a reasonable threat of attacks on specific buildings to recommend inclusion of such requirements in building codes. some believe the likelihood of such attacks on any specific building is deemed sufficiently low to not be considered at all. however, individual building developers may wish to consider design provisions for improving redundancy and robustness for such unforeseen events, particularly for structures that, by nature of their design or occupancy, may be especially susceptible to such incidents. although some conceptual changes to the building codes that could make buildings more resistant to fire or impact damage or more conducive to occupant egress were identified in the course of this study, the bps team felt that extensive technical, policy, and economic study of these concepts should be performed before any specific code change recommendations are developed. this report specifically recommends such additional studies. future building code revisions may be considered after the technical details of the collapses and other building responses to damage are better understood. the debris from the collapses of the wtc towers also initiated fires in surrounding buildings, including wtc , , , and ; west street; and cedar street. many of the buildings suffered severe fire damage but remained standing. however, two steel-framed structures experienced fire-induced collapse. wtc collapsed completely after burning unchecked for approximately hours, and a partial collapse occurred in an interior section of wtc . studies of wtc indicate that the collapse began in the lower stories, either through failure of major load transfer members located above an electrical substation structure or in columns in the stories above the transfer structure. the collapse of wtc caused damage to the verizon building and west broadway. the partial collapse of wtc was not initiated by debris and is possibly a result of fire-induced connection failures. the collapse of these structures is particularly significant in that, prior to these events, no protected steel-frame structure, the most common form of large commercial construction in the united states, had ever experienced a fire-induced collapse. thus, these events may highlight new building vulnerabilities, not previously believed to exist. possible considerations for improved egress in damaged structures, the public understanding of typical building design capacities, issues related to the study process and future activities, and issues for communities to consider when they are developing emergency response plans that include engineering response…. [regarding one of these aspects,] building evacuation, the following topics were not explicitly examined during this study, but are recognized as important aspects of designing buildings for impact and fire events. recommendations for further study are to: perform an analysis of occupant behavior during evacuation of the buildings at wtc to improve the design of fire alarm and egress systems r in highrise buildings. perform an analysis of the design basis of evacuation systems in high-rise buildings to assess the adequacy of the current design practice, which relies on phased evacuation. evaluate the use of elevators rr as part of the means of egress for mobilityimpaired people as well as the general building population for the evacuation of high-rise buildings. in addition, the use of elevators for access by emergency personnel rrr needs to be evaluated…. [regarding another of these aspects,] education of stakeholders (e.g., owners, operators, tenants, authorities, designers) , [they] should be further educated about building codes, the minimum design loads typically addressed for building design, and the extreme events that are not addressed by building codes. should stakeholders desire to address events not included in the building codes, they should understand the process of developing and implementing strategies to mitigate damage from extreme events. r for example, to facilitate counterflow by occupants moving downward and emergency responders (such as firefighters) moving upward, nfpa life safety code requires that each stairwell that must accommodate a total cumulative occupant load of fewer than , persons have a stair width of inches ( . meters), and those that must accommodate more than or equal to , persons have a stair width of inches ( . meters) (cote r, harrington g. nfpa life safety code handbook. quincy, ma: national fire protection association; : , ) . rr for some years this issue has been a major concern of fire protection individuals. commenting on this subject, charles jennings, ms, mrp, john jay college, stated that "the latest and most advanced thought is now devoted to developing pressurization requirements for elevator shafts and lobbies. the objective of these current efforts is to make elevators a useful component of the building evacuation system during a fire" (jennings c. high-rise office building evacuation planning: human factors versus 'cutting edge' technologies. [j appl fire sci. - ; ( ): - , baywood publishing co., inc.; : ] ). since / there has been much discussion as to the feasibility of using elevators to evacuate occupants under emergency conditions. see chapter for additional information. rrr "because of tragic / stories of doomed firefighters overburdened with gear and out of radio contact, chicago and other cities are reviewing emergency communications and requiring or recommending that skyscrapers install lockers or closets with hoses, axes and oxygen tanks on upper floors so firefighters don't have to carry them" ("high-rises remain vulnerable after / ." o'driscoll p. the investigators examined the design of the buildings, the behavior of the people, and the evacuation process in detail to ascertain the factors that figured prominently in the time needed for evacuation. in analyzing these factors, nist recognized that there were inherent uncertainties in constructing a valid portrayal of human behavior on that day. these included limitations in the recollections of the people, the need to derive findings from a statistical sampling r of the building population, the lack of information from the decedents on the factors that prevented their escape, and the limited knowledge of the damage to the interior of the towers. the port authority estimated that the population of the wtc complex on september , , was , people, including those r "to document the egress from the two towers as completely as possible, nist:  contracted with the national fire protection association and the national research council of canada to index a collection of over previously published interviews with wtc survivors.  listened to and analyzed - - emergency phone calls made during the morning of september .  analyzed transcripts of emergency communication among building personnel and emergency responders.  examined complaints filed with the occupational safety and health administration by surviving occupants and families of victims regarding emergency preparedness and evacuation system performance. in addition nist, in conjunction with nustats, partners, llp as a nist contractor, conducted an extensive set of interviews with survivors of the disaster and family members of occupants of the buildings. first, telephone interviews were conducted with survivors, randomly selected from the list of approximately , people who had badges to enter the towers on that morning. the results enabled a scientific projection of the population and distribution of occupants in wtc and wtc , as well as exploration of factors that affected evacuation. second, face-to-face interviews, averaging hours each, gathered detailed, first-hand accounts and observations of the activities and events inside the buildings on the morning of september . these people included occupants near the floors of impact, witnesses to fireballs, mobility-impaired occupants, floor wardens, building personnel with emergency response responsibilities, family members who spoke to an occupant after : a.m., and occupants from regions of the building not addressed by other groups. third, six complementary focus groups, a total of people, were convened" (nist ncstar : of the estimated , people in the towers, people perished and thousands were injured. an undetermined number of people died entrapped in building elevators rr (there were elevators in each tower). table - provides the likely locations of wtc decedents. of the deceased, six were security managers, were private security officers who worked at the wtc complex, and one was a security officer at a nearby building (their names are provided in the dedication [p. v.] of this book). in wtc , rrr of the fatalities were people trapped on or above the nd floor (due to the fact that all three of the building stairwells were severely damaged and could not be used as a means of escape). "of the roughly , building occupants who started that morning below the nd floor, all but escaped the building. those left r "on any given workday, up to , office workers occupied the towers, and , people passed through the complex" (the / commission report; : ) . the lower than usual population on september was attributed to the fact that some people were voting in new york city's mayoral primary election; some were taking their children for the first day of school; due to asia's financial recession, many asian investment firms had released employees or closed offices in the wtc; the th floor south tower observation deck was not scheduled to open until : a.m.; most retail stores under the complex were not yet open; and being : a.m., a lot of workers were yet to arrive ("for many on september , survival was no accident" [usa today. december , : ] , authored by dennis cauchon with contributors barbara hansen, anthony debarros, and paul overberg. article reprinted in the nfpa "emergency response planning workshop participant workbook, appendix v" conducted in san francisco by mark schofield and douglas p. forsman [march , : ] ). "nist estimated that if the towers had been fully occupied with , occupants each, it would have taken just over hours to evacuate the buildings and about , people might have perished because the stairwell capacity would not have been sufficient to evacuate that many people in the available time" (nist ncstar ; :xxxix rr "eighty-three [elevator] mechanics from ace elevator of palisades park, n.j., left the buildings when the second jet hit. dozens of people were trapped inside elevators at the time, according to the port authority. an elevator mechanic from another company rushed to the buildings from down the street and died trying to rescue people" ("for many on september , survival was no accident" [usa today. december , : ] , authored by dennis cauchon with contributors barbara hansen, anthony debarros, and paul overberg. article reprinted in the nfpa "emergency response planning workshop participant workbook, appendix v" conducted in san francisco by mark schofield and douglas p. forsman [march , : ] ). rrr these people "soon realized that they were unable to go downward to get away from the smoke and heat that [was] building up around them.… some of the people went toward the roof. however, there was no hope behind were trapped by debris, awaiting assistance, helping others, or were just too late in starting their egress. for the most part, the evacuation was steady and orderly." where possible, nist used eyewitness accounts to place individuals. where no specific accounts existed, nist used employer and floor information to place individuals. these individuals were typically security guards and fire safety staff who were observed performing activities below the floors of impact after the aircrafts struck. these individuals were largely performing maintenance, janitorial, delivery, safety, or security functions. emergency responders were defined to be people who arrived at the site from another location. in wtc , of the fatalities were people trapped on or above the th floor due to the fact that of the three building stairwells only "one stairway r remained open above the crash, but few used it to escape. stairway a, one of the three, was unobstructed from top to bottom…. others went up these stairs in search of a helicopter rescue that wasn't possible because of heavy smoke on the rooftop." rr "of the roughly , people who started the morning below the th floor, all but evacuated the building, indicating sufficiently efficient movement within the three stairwells in the time available." therefore, in both towers, a total of occupants below the floors of impact perished. "among the decedents below the aircraft impact floors, investigators identified seven who were mobility impaired, rrr but were unable to determine the mobility capability of the remaining ." "approximately percent of the estimated , occupants of the towers, and percent of those located below the impact floors, evacuated successfully." r "an elevator machine room on the st floor, where the jet's nose hit, helped protect one stairway in the south tower. … the elevator equipment room covered more than half the width of the st floor. its size forced the tower's designers to route stairway a around the machines. the detour moved stairway a from the center of the building … (on most floors, the stairways were about feet [ . meters] apart in the core) … toward the northwest corner-away from the path the hijacked jet would take" (cauchon d, moore mt. machinery saved people in wtc: row of elevator hoists sheltered stairwell when jet hit tower. usa today. may , : - there were a number of evacuees with disabilities that included two blind men with guide dogs, two deaf people and several wheelchair users. all indications are that the occupants who were able to evacuate did so in an orderly and competent manner. the world trade center had a comprehensive, wellexecuted fire life safety program and emergency plan that helped emergency staff and occupants to react appropriately to the catastrophic events that unfolded. of one clear message that applies to all high-rise buildings, whether they are evaluated to be at risk to a terrorist event or not, is that all occupants should be well trained in evacuation procedures. their offices? after the first plane hit the north tower, for surviving occupants in the south tower, "building announcements were cited by many as a constraint to their evacuation, principally due to the : a.m. announcement instructing occupants to return to their work spaces. "as a result of the announcement, many civilians remained on their floors. others reversed their evacuation and went back up." r "similar advice was given in person by security officials in both the ground floor lobby [of the south tower]-where a group of that had descended by the elevators was personally instructed to go back upstairs-and in the upper sky lobby, where many waited for express elevators to take them down. security officials who gave this advice were not part of the fire safety staff." "nineteen of them returned upstairs, where died; the th was told by her supervisor, who was in the group, to leave rather than return upstairs. the supervisor also survived." "several south tower occupants called the port authority police desk in wtc. some were advised to standby for further instructions; others were strongly advised to leave." "it is not known whether the order by the fdny to evacuate the south tower was received by the deputy fire safety director making announcements there. however, at approximately : -less than a minute before the building was hit-an instruction ibid., p. . the / commission report, final report of the national commission on terrorist attacks upon the united states, investigation of "facts and circumstances relating to the terrorist attacks of september , " by the national commission on terrorist attacks upon the united states (also known as the / commission) (w. w. norton & company: new york & london. www. - commission.gov/report/index .htm; july : ). r a note (no. ) in the / commission report to this reference was "when a notable event occurred, it was standard procedure for the on-duty deputy fire safety director to make an 'advisory' announcement to tenants who were affected by or might be aware of the incident, in order to acknowledge the incident and to direct tenants to stand by for further instruction. the purpose of advisory announcements, as opposed to 'emergency' announcements (such as to evacuate), was to reduce panic" (the / commission report, chapter , note , citing various civilian and fdny interviews, and port authority of new york and new jersey interviews and statements, , p. ). the over the south tower's public-address system advised civilians, generally, that they could begin an orderly evacuation if conditions warranted. like the earlier advice to remain in place, it did not correspond to any prewritten emergency instruction." it must be realized that at the time the first plane hit the north tower, no one explicitly knew that this was a terrorist act or that another aircraft was only minutes and seconds away from slamming into the south tower. after the first collision there were large amounts of material falling from the crash site to the ground outside of the north and south towers as well as a number of occupants who had started jumping from upper floors. the first priority of the wtc emergency personnel would have been to address the life safety of occupants in the north tower. based on the information known at the time, it would not have been considered prudent to evacuate occupants from the south tower, since this may have involved placing those persons in danger from falling objects. it was only after the second plane hit that an indication of the diabolical nature of the disaster was revealed. the tragic consequences of the september , , attacks were directly attributable to the fact that terrorists flew large jet-fuel laden commercial airliners into the wtc towers. buildings for use by the general population are not designed to withstand attacks of such severity; building regulations do not require building designs to consider aircraft impact. in our cities, there has been no experience with a disaster of such magnitude, nor has there been any in which the total collapse of a high-rise building occurred so rapidly and with little warning. while there were unique aspects to the design of the wtc towers and the terrorist attacks of september , , nist has compiled a list of recommendations to improve the safety of tall buildings, occupants, and emergency responders based on its investigation of the procedures and practices that were used for the wtc towers; these procedures and practices are commonly used in the design, construction, operation, and maintenance of buildings under normal conditions. public officials and building owners will need to determine appropriate performance requirements for those tall buildings, and selected other buildings, that are at higher risk due to their iconic status, critical function, or design. the eight major groups of recommendations are listed as follows in an order that does not reflect any priority: performance-based design "applies a procedure to predict and estimate damage or behavior anticipated of a structure's design to design events, compared against preselected objectives. the design is revised until the predictive methodology indicates that acceptable performance can be obtained" (manley be. fundamentals of structurally safe building design. in: fire protection handbook. th ed. quincy, ma: national fire protection association; : - ). the prescriptive design approach "includes extensive detailed criteria for the design of systems that have been developed over many years of experience" (cholin jm. fire protection handbook. th ed. woodworking facilities and processes. quincy, ma: national fire protection association; : - ). the recommendations call for action by specific entities regarding standards, codes, and regulations, their adoption and enforcement, professional practices, education, and training; and research and development. only when each of the entities carries out its role will the implementation of a recommendation be effective. the recommendations do not prescribe specific systems, materials, or technologies. instead, nist encourages competition among alternatives that can meet performance requirements. the recommendations also do not prescribe specific threshold levels; nist believes that this responsibility properly falls within the purview of the public policy setting process, in which the standards and codes development process plays a key role. nist believes the recommendations are realistic and achievable within a reasonable period of time. only a few of the recommendations call for new requirements in standards and codes. most of the recommendations deal with improving an existing standard or code requirement, establishing a standard for an existing practice without one, establishing the technical basis for an existing requirement, making a current requirement risk-consistent, adopting or enforcing a current requirement, or establishing a performance-based alternative to a current prescriptive requirement. nist strongly urges that immediate and serious consideration be given to these recommendations by the building and fire safety communities in order to achieve appropriate improvements in the way buildings are designed, constructed, maintained, and used in evacuation and emergency response procedures-with the goal of making buildings, occupants, and first responders safer in future emergencies. nist also strongly urges building owners and public officials to ( ) evaluate the safety implications of these recommendations to their existing inventory of buildings and ( ) take the steps necessary to mitigate any unwarranted risks without waiting for changes to occur in codes, standards, and practices. nist further urges state and local agencies to rigorously enforce building codes and standards since such enforcement is critical to ensure the expected level of safety. unless they are complied with, the best codes and standards cannot protect occupants, emergency responders, or buildings. the building code experts represent a broad spectrum of specific organizations (e.g., nfpa, icc, asce, boma, and u.s. accessibility board) and areas of expertise (e.g., architecture, engineering, risk assessment, law enforcement, social science/egress, [security,] and insurance) that can address all of the recommendations. this core expertise will be augmented with the participation of other experts representing organizations and technical areas required to address one or more specific recommendations. the timeline for this effort is governed by the established development cycle for the model codes. the nist wtc recommendations impact about specific national standards, codes, and practice guidelines or regulations. in carrying out this r for example, nfpa international formed a high-rise building safety advisory committee (hrb-sac) to initially review the nist recommendations and forward each recommendation to the appropriate nfpa technical committee for consideration for its code establishment cycle. rr these acronyms are explained in the acronym section at the back of this book. work, nist recognizes that not all of the recommendations will have an impact on model building codes. many will impact standards that are referenced in model codes. others will impact stand alone standards used in practice but not referenced in model codes. a few will impact practices, including education and training, that don't have any impact on codes and standards. r a list of the recommendations and their implementation status can be viewed online at the nist website. bombs and bomb threats are very real possibilities in today's world, and in some countries, a frequent occurrence. they may be acts of terrorism used by a person or a group of persons attempting to control others through coercive intimidation or by those who want the changes, adopted at icc's hearings held september - , , in minneapolis, minnesota, will be incorporated into the edition of the i-codes (specifically the international building code, or ibc, and the international fire code, or ifc), a state-of-the-art model code used as the basis for building and fire regulations promulgated and enforced by u.s. state and local jurisdictions. those jurisdictions have the option of incorporating some or all of the code's provisions but generally adopt most provisions. the new codes address areas such as increasing structural resistance to building collapse from fire and other incidents; requiring a third exit stairway for tall buildings; increasing the width of all stairways by percent in new high-rises; strengthening criteria for the bonding, proper installation, and inspection of sprayed fire-resistive materials (commonly known as 'fireproofing'); improving the reliability of active fire protection systems (such as automatic sprinklers); requiring a new class of robust elevators for access by emergency responders in lieu of an additional stairway; making exit path markings more prevalent and more visible; and ensuring effective coverage throughout a building for emergency responder radio communications. (new international building code address fire safety and evacuation issues for tall structures. sciencedaily. october , . www.sciencedaily.com/releases/ december , ) . also, in response to nist's request for "timely, expedited recommendations," the nfpa , life safety committee, has responded by "introducing several changes to the edition of the life safety code related to high-rise safety and evacuation…[in addition to] the and editions of nfpa [which] also addressed several provisions before the release of the nist study" (" code changes" by alisa wolf [nfpa journal. may/june ; ]). one particular change relates to elevator use in emergencies, "a new adoptable annex, annex b, offers criteria for keeping smoke from reaching elevator lobby smoke detectors and water from reaching the hoistway to extend the safe use of an elevator early in a fire. if smoke can be kept away from the detectors, high-rise building occupants may be able to continue to use elevators, as long as communications systems are also provided to let them know, in real time, the operating status of the elevators. these guidelines would also require an exit stair enclosure adjacent to the elevator lobby to provide egress for occupants waiting in the lobby once the elevator has been called out of service" (" to promote their views by claiming direct responsibility or causing other targeted groups to be blamed for an incident. terrorism may also include kidnappings, taking hostages, and other criminal acts such as bombings (although the september , , destruction of the new york world trade center involved hijacked aircraft that were in effect turned into bombs, the incident was treated in the previous section "aircraft collisions"). bombs involve either explosives or incendiary devices. webster's college dictionary defines the former as "devices designed to explode or expand with force and noise through rapid chemical change or decomposition"; the latter are "devices used or adapted for setting property on fire" and can be activated by mechanical, electrical, or chemical means. explosives may also be delivered in the form of a missile, such as a shoulder-launched, rocket-propelled grenade (rpg), or a mortar. conventional explosives may also be encased in radioactive waste material. known as radiological or "dirty bombs," if detonated these devices disperse radioactive material over an area determined by the size of the explosion, the kind and amount of material, weather conditions, and the types of facilities in the vicinity. after the detonation of a dirty bomb in a major urban area, as the level of radioactivity increased it could "spark panic, r overburdening the health-care system and perhaps forcing abandonment of many square blocks for decades." "bombs can be constructed to look like almost anything and can be placed or delivered in any number of ways. rr the probability of finding a bomb that looks like a stereotypical bomb is almost nonexistent. the only common denominator that exists among bombs is that they are designed to explode." most bombs are improvised (hence the terms an improvised explosive device, rrr an ied, and a vehicle-borne ied or a vbied rrrr ). walk-in suicide bombers with explosives attached to their bodies or contained in a suitcase are extremely difficult to detect and can strike anywhere at any time. in the united states, the highly publicized "unabomber" incidents involved mail bombs. this serial bomber was so named by the federal bureau of investigation (fbi) because the targets of these letter and package bombs sent since had previously been academics and executives at universities and airlines. in april , after bomb attacks, with three dead and injured, the unabomber, ted kaczynyski, was arrested, convicted, and later sentenced to life imprisonment without the possibility of parole. bomb threats and physical security planning. bureau of alcohol, tobacco and firearms, atf p . ; . rrr an ied is a "device placed or fabricated in an improvised manner incorporating destructive, lethal, noxious, pyrotechnic, or incendiary chemicals and designed to destroy, incapacitate, harass, or distract. it may incorporate military stores, but is normally devised from nonmilitary components" (definition from dod, nato as stated on answers.com website. . www.answers.com/topic/improvised-explosive-device; september , ). rrrr a vbied is a "military term for a car bomb or truck bomb. these are typically employed by suicide bombers and can carry a relatively large payload. they can also be detonated from a remote location. vbieds can create additional shrapnel through the destruction of the vehicle itself, as well as using vehicle fuel as an incendiary weapon" (wikipedia. http://en.wikipedia.org/wiki/ied; september , ). reason for the concern, as the israeli government has learned, is that no amount of preparedness can stop such bombers-not swarms of police patrols, stepped-up border enforcement or increased intelligence-gathering missions. in most cases, one person armed with less than a handful of plastic explosives can walk into a public gathering, flick a detonation switch and kill dozens of people." bombs delivered by a vehicle (a car, a van, or a truck) are a grave reality. "a car bomb is an effective weapon because it is a[n] easy way to transport a large amount of explosives and flammable material to the site where the explosion should take place. a car bomb also produces a large amount of shrapnel, or flying debris, that causes secondary damage to bystanders and buildings." car bombs and detonators function in a diverse manner of ways, and there are numerous variables in the operation and placement of the bomb within the vehicle. earlier and less advanced car bombs were often wired to the car's ignition system, but this practice is now considered more laborious and less effective than other more recent methods, as it required a greater amount of work for a system that could often be quite easily defused. while it is more common nowadays for car bombs to be fixed magnetically to the underside of the car, the underneath of passenger/driver's seat, or inside of the mudguard, detonators triggered by the opening of the vehicle door or by pressure applied to the brakes or accelerating pedals are also used. bombs may also be detonated when a victim approaches the vehicle, when the vehicle is in motion, or when the vehicle passes by another vehicle that contains the explosives. "in recent years, car bombs have become widely used by suicide bombers who seek to ram the car into a building and simultaneously detonate it." the destructive power of such a bomb depends on factors such as the type and amount of explosives, the location of the bomb in relation to a building, and the structural strength of the facility to withstand the explosion. r table r to obtain sources of information about vehicle bomb explosion hazards and evacuation distances, one can approach a structural engineer, a blast design consultant or expert, or the appropriate agencies. rr dates and some details of incidents involving al qaeda versus united states and allies, - , were obtained from "the chicago. project on suicide terrorism," robert pape, professor of political science, the university of chicago. http://jtac.uchicago.edu/conferences/ /resources/pape_formatted% for% dtra. pdf. others were obtained from various agencies and news sources, many of which are identified in the ensuing summaries of the incidents. at times, reports of casualties were conflicting. therefore, the number of persons killed and injured could not always be definitively determined. is addressed in the previous section). although not all incidents involve high-rise buildings, they underline the seriousness of the threat that western civilization faces today. the highly publicized international terrorist bombing of the new york world trade center twin towers, at the time the world's second tallest buildings and a symbol of urea nitrate fertilizer, located in a parked van, detonated and tore a "five-story subgrade crater that measured to meters ( to feet) across on some levels" in the subterranean parking garage of the -story new york world trade center (wtc) located in lower manhattan ( figure - ). of the estimated , -plus occupants and visitors of this seven-high-rise building complex, the explosion left six dead and , injured (most suffered from smoke inhalation). it severely damaged many of the complex's fire protection systems. for example, the fire alarm communication system for the twin towers of the trade center was incapacitated, and there was an interruption of primary and emergency power systems. the bomb also resulted in a fire that rapidly disbursed thick, dark clouds of smoke to upper levels of the twin towers through horizontal openings-stairwell doors propped open while occupants were waiting to enter stairwells-and vertical openingsstairwells and elevator shafts. during this emergency, thousands of building occupants walked down darkened and smoke-filled stairwells to evacuate the building without the assistance of emergency lighting or of advisory emergency instructions delivered over the public address (pa) system. (generators supplying emergency power to these systems started up, but after minutes they overheated and shut down because of damage from the explosion.) "many persons were needlessly exposed to smoke inhalation and stress in premature evacuation from a structure in which upper floors were safer and more hospitable than the escape routes." according to the bureau of alcohol, tobacco and firearms (atf), a vehicle identification number from the van, which had been rented but reported stolen the day prior to the explosion, was uncovered after the explosion. the ensuing investigation ultimately led to the identification and indictment of seven suspects, four of whom were convicted on conspiracy, assault, and various explosives charges. the evidence linked the defendants to the purchase of chemicals and hydrogen tanks used to manufacture the bomb, to the rental of the shed to warehouse the chemicals and later the bomb, and to the rental of the van that contained the bomb. each of the four muslim extremists directly responsible for this incident was sentenced to life in prison. considerable information relating to this bombing was obtained from the atf and the nfpa. after the incident, two atf national response teams assisted the new york city police department and the federal bureau of investigation (fbi) in their inquiry. a thorough fire investigation report on the world trade center explosion and fire can be obtained from the nfpa. according to the world trade center bombing: report and analysis, "it is estimated that approximately , people were evacuated from the wtc complex, including nearly , from each of the two towers. fire alarm dispatchers received more than , phone calls, most reporting victims trapped on the upper floors of the towers. search and evacuation of the towers were completed some hours after the incident began." according to an evacuation study conducted by the nfpa and the nrcc (national research council of canada) with funding provided by the national institute of standards and technology (nist), the evacuation of occupants from the twin towers ranged from minutes to hours, and less than percent of the evacuees had previously participated in evacuation drills. the wtc bombing vividly demonstrated that sometimes a building emergency may be of such magnitude that security personnel are unprepared to handle both the emergency itself and the heightened security demands created by the incident. r after the explosion, wtc security staff were involved in caring for the injured, assisting firefighters (at that time, the several hundred of which constituted the greatest single response to a fire in new york city fire department's history) and other emergency services in occupant evacuation, and helping other agencies-the port authority police and the new york transit police among others-to control access to the complex. because of the enormity of the incident, the thousands of people affected, and the disastrous effects the explosion had on the towers' fire life safety systems, building security personnel were as can also be the case with serious fires (particularly if multiple ones simultaneously occur), explosions, workplace violence, civil disturbances, and some natural disasters. inundated with demands for their services and were strained to the breaking point. of course, the incident placed an almost indescribable burden on all involved, including those who lost their lives while helping others. in , a state appeals court unanimously upheld a jury's verdict that the port authority (pa) of new york and new jersey, which owned the wtc complex, because it was percent liable for the bombing and the terrorists percent liable, was liable for percent of the recoverable damages caused by the bombing. the ruling found "that the agency had not properly protected its underground public parking garage.… the appeals court noted the port authority did not argue that the bombing was unforeseeable, since the bombing method was not only foreseen but was brought to pa executives' attention by the agency's own internal study group. the group's report said the trade center was vulnerable to terrorist attack through its parking garage. it detailed 'with exact prescience' how that vulnerability could be exploited, the appeals court said." "in , peter goldmark, then the port authority's executive director, recognizing the trade center's 'iconic' stature, asked scotland yard to assess the security of the complex and reported back to his colleagues that british officials were 'appalled' that there was public parking underneath the towers. in july , an outside engineering consultant, charles schnabolk, issued a report saying that it was not only possible but 'probable' that there would be an attempt to bomb the trade center, and that it was 'highly vulnerable through the parking lot.'" according to doug karpiloff, the late security and life safety director for the world trade center, "prior to the bombing, the wtc was an open building during the day, but closed at night. after the bombing, the center was relegated to a closed facility, in which public parking was completely eliminated." as reported by security, security upgrades against the risk of vehicle bombs included the following measures: after the wtc bombing, some high-rise office buildings installed cctv systems at the entrance and exit points of under-building or subterranean parking garages. these cameras facilitated recording closeup images of the driver and license plate of every vehicle entering and the license plate of all vehicles exiting these areas. if there were an incident, this would help to identify vehicles that may have been involved. the bishopsgate bombing occurred on april , when the provisional irish republican army (ira) detonated a truck bomb in london's financial district in bishopsgate, city of london, england. one person was killed in the explosion and injured, causing £ million in damage. as a result of the bombing, the ring of steel r was introduced to protect the city, and many firms introduced disaster recovery plans in case of further attacks. the ring of steel is the popular name for the security and surveillance cordon surrounding the city of london, installed to deter the ira and other threats" ('ring of steel' widened. bbc news online, - - . http://en.wikipedia.org/wiki/city_of_london's_ring_of_steel retrieved on - - ). "roads entering the city are narrowed and have small chicanes to force drivers to slow down and be recorded by cctv cameras. these roads typically have a concrete median with a sentry box where police can stand guard and monitor traffic" ('ring of steel' widened. bbc news online, - - . http://en.wikipedia.org/wiki/ city_of_london's_ring_of_steel retrieved on - - ). a chicane is "a sequence of tight serpentine curves (usually an s-shape curve …) in a roadway, used in motor racing and on city streets to slow cars. on modern raceways, chicanes are usually located after long straightaways, making them a prime location for overtaking" (wikipedia. http://en.wikipedia.org/wiki/chicane; may , ). april , , oklahoma city-at : a.m., when parents were dropping off their youngsters at the alfred p. murrah federal office building's day-care center, a homemade bomb containing an "estimated , kg ( , lb) of ammonium nitrate [fertilizer] and fuel oil (anfo)" placed in a large rented truck parked in a no-parking, no-standing zone circular driveway outside the building detonated and blew away the facade and nearly half of this nine-story reinforced concrete frame building located in downtown oklahoma city (figure - ) . windows were shattered, numerous nearby buildings suffered structural damage, and vehicles were damaged throughout the downtown business section. of the estimated -plus occupants and visitors of this structure, the explosion left dead, including children in the demolished day-care center. in addition, there were four fatalities at an adjacent building, one outside and one in a parked vehicle, while a nurse running to the scene was killed by a falling piece of concrete. people were injured. the building was demolished as a result of the incident. immediately following the explosion, the general services administration (gsa) placed over federal buildings throughout the united states on a security alert with building exterior patrols, inspection of packages, briefcases and vehicles, and heightened surveillance for persons and objects, including vehicles, which were suspicious or looked out of place. parking was restricted around some buildings and some erected concrete barriers in front of the structures to protect against this type of threat. timothy mcveigh was later executed for this incident, up until september , , the worst terrorist attack in u.s. history. before this incident, there were no government-wide standards for security at federal facilities in the united states. after it, a study titled vulnerability assessment of federal facilities was conducted by the standards committee consisting of security specialists and representatives of the u.s. department of justice, including the federal bureau of investigation (fbi), and of the u.s. secret service, general services administration (gsa), state department, social security administration, and department of defense. this committee developed "a set of [ ] minimum security standards that can be applied to federal facilities. the standards cover the subjects of perimeter, entry, and interior security, and security planning" and embodied "new parking restrictions within buildings and in adjacent areas, use of x-rays and metal detectors at entrances for visitors and packages, erection of physical barriers, deployment of roving patrols outside the buildings, closed-circuit television monitoring, installation of shatterproof glass on lower floors, better alarm systems, locating new buildings farther from streets, grouping agencies with similar security needs, and tougher standards for visitor and employee identification." "the standards committee divided federal holdings into five security levels to determine which security standards are appropriate for which security levels. these categories are based on such factors as size, number of employees, use, and required access to the public. site security design guide, r which "establishes the principles, explores the various elements, and lays out the process that security professionals, designers, and project and facility managers should follow in designing site security at any federal project, be it large or small, at an existing facility or one not yet built. although this incident did not reportedly involve explosives, it is mentioned here as it bears some similarties to the taj mahal palace and tower hotel and oberoi hotel incidents in mumbai, india (see later description of these incidents), which also targeted westerners. citizenship of the bombers and the lack of strong ties between them and an international terrorist group illustrate the potential threat of "homegrown" terrorists as perpetrators of future attacks. "on july , four attempted bomb attacks disrupted part of london's public transport system two weeks after the july london bombings. the explosions occurred around midday at shepherd's bush, warren street and oval stations on london underground, and on a bus in shoreditch. a fifth bomber dumped his device without attempting to set it off." four men were found guilty for the attacks. "the failed bombers targeted three tube trains and a bus-as happened on / -but the devices ["only the detonators exploded" ] failed to explode. "it is thought the second car was found parked illegally in the west end by traffic wardens in the early hours of this morning. it was then towed to the pound-located in the car park-but left outside in the public area when staff reported that it smelt of fuel". "the cars and their devices were recovered intact for forensic examination and both were found to contain petrol cans, gas canisters and a quantity of nails, with a mobile phone-based trigger." june , , glasgow international airport "a jeep cherokee trailing a cascade of flames rammed into glasgow airport on saturday, shattering glass doors just yards from passengers at the check-in counters. police said they believed the attack was linked to two car bombs found in london the day before." both of the car's occupants were arrested. "police identified the two men as bilal abdullah, a british-born, muslim doctor of iraqi descent working at the royal alexandra hospital, and kafeel ahmed, also known as khalid ahmed, the driver, who was treated for severe burns at the same hospital." ahmed later died. "a jury found the doctor, bilal abdulla, a passenger in the jeep cherokee, guilty of two charges of conspiracy to commit murder and conspiracy to cause explosions in three bungled car bombing attempts in glasgow and london over hours…. the day before that attack, dr. abdulla and mr. ahmed drove to london's west end theater district in two mercedes-benz sedans, primed with bombs similarly constructed from gasoline canisters and propane cylinders, along with , nails for shrapnel. outside a nightclub and beside a busy bus stop. the two attackers waited nearby with mobile phones linked to other phones wired to the bombs used as triggers. but evidence at the trial showed that the two vehicles had failed to explode despite repeated signals from the mobile phones because of faulty assembly of the so-called fuel air bombs involved." september , , at approximately : p.m., a dump truck containing an estimated , pounds ( kilograms) of military-grade explosives rammed a metal barrier and came to a halt about feet ( meters) from the marriott hotel, which is surrounded by government buildings and is located in pakistan's capital. detonated by the driver, the resulting explosion killed people, injured more than people, severely damaged the hotel, and left a crater feet ( meters) wide and feet ( . meters) deep in front of the main building. " "the government released surveillance camera footage showing the attack. a suicide bomber at the wheel of a dump truck opened fire at marriott security guards who refused to let him into the parking lot. he then detonated himself and started a small fire. the guards spent four minutes trying to extinguish the blaze when another, much bigger explosion went off." "the massive blast ripped through the marriott hotel's walls, blew out ceilings, scorched trees, reduced nearby cars to charred husks of twisted metal and shattered windows hundreds of yards away. flames began shooting out of the windows of many of the hotel's rooms." the explosion was during the muslim holy month of ramadan and so the hotel's restaurants would have contained many muslims breaking their daily fast. "no group immediately claimed responsibility for the blast, though suspicion fell on al-qaeda and the pakistani taliban. analysts said the attack served as a warning from islamic militants to pakistan's new civilian leadership to stop cooperating with the u.s.-led war on terror." on november , , "hooded gunmen, firing automatic weapons and throwing hand grenades, attacked at least two luxury hotels, the city's largest train station, a jewish center, a movie theater, even a hospital…. even by the standards of terrorism in india, which has suffered a rising number of attacks this year, the assaults were particularly brazen in scale, coordination and execution. "the death toll from the series of coordinated attacks was at [later estimated at ], including at least six foreigners, by thursday afternoon authorities said. the italian foreign ministry confirmed one of its citizens had been killed. the nationalities of the others was still being checked. another people were wounded in the attacks, including seven british and two australian citizens. in addition, at least nine gunmen were killed in fighting with police. also among the dead was hemant karkare, the chief of the mumbai police's anti-terror squad, and as many as police officers." "ashok pawar, a local police constable who arrived at the taj mahal palace & hotel [ figure - ] shortly after the gunmen lay siege to it, said he could see their carefully scripted tableau in the closed-circuit tv cameras in the hotel's second floor security room. in two teams of two, the gunmen kicked down hotel room doors, forced guests to come out into the hallway, tied the men's hands behind their backs, usually with a bedsheet, and herded their captives into one room…. the gunmen soon realized they were being watched, and so they smashed the cameras, lobbed a grenade and started firing at mr. pawar and his colleagues in the security room." "the leader of a commando unit involved in a gun battle thursday morning inside the taj said during a news conference on friday that he had seen a dozen dead bodies in one of the rooms. his team also discovered a gunman's backpack, which contained dried fruit, rounds of ak- ammunition, four grenades, indian and american money, and seven credit cards from some of the world's leading banks. they pack also had a national identity card from the island of mauritius, off africa's southeastern coast. the attackers were 'very, very familiar with the layout of the hotel,' said the commander." "it is possible the mumbai attackers chose the taj and oberoi because security at the two facilities was not as prominent or visible as in other hotels. in any case, that the mumbai attackers pre-positioned explosives and other weapons for their use inside the hotel indicates they conducted extensive preoperational surveillance of the targets and likely understood the security countermeasures present in each location." "india has accused a senior leader of the pakistani militant group lashkare-taiba of orchestrating last week's terror attacks that killed at least people here, and demanded the pakistani government turn him over and take action against the group. just two days before hitting the city, the group of terrorists who ravaged india's financial capital communicated with yusuf muzammil and four other lashkar leaders via a satellite phone that they left behind on a fishing trawler they hijacked to get to mumbai, a senior mumbai police official told the wall street journal. the entire group also underwent rigorous training in a lashkar-e-taiba camp in pakistanicontrolled kashmir, the official said." subsequently, two senior leaders of lashkare-taiba and other alleged militants were arrested by pakistan and the death toll was amended to . commenting on the incident, "what happened in mumbai on november will always remain etched in the minds of every indian. the terrorists' attack on iconic buildings and elsewhere has definitely raised the issue of security of high-rise buildings, both commercial and residential, in our country." "while the taj and oberoi hotels probably were attacked in part because of their status as mumbai landmarks, the direct targeting of foreigners indicates the hotels also were chosen in a bid to strike westerners…. the mumbai attacks showed that attacking locations where westerners are known to congregate, rather than attacks against marketplaces or cinemas that will primary kill indian nationals, could well be a more efficient and effective way for militants to use their limited resources. and as hotels and other traditional soft targets harden their facilities and implement new security countermeasures to prevent further mumbai-style attacks, militants will seek less-secure venues that will achieve the same result. such targets could include apartment complexes or neighborhoods that primarily house westerners-similar to the attacks on the saudi arabian oil co. residential facilities in al khobar, saudi arabia-or other soft targets such as western-style marketplaces or restaurants. bomb threats are delivered in a variety of ways. sometimes a threat is communicated in writing, via e-mail, or by an audio recording. there is more than one reason for making or reporting a bomb threat. for instance, a caller who has definite knowledge or believes an explosive or incendiary device has been or will be placed may want to minimize personal injury or property damage. this caller could be the person who placed the device or someone who has become aware of such information. on the other hand, a caller may simply want to create an atmosphere of anxiety and panic, which will, in turn, disrupt the normal stratfor website (www.stratfor.com) december , . from the new york landmarks plot to the mumbai attack. fred burton and ben west. www.stratfor.com/weekly/ _new_york_landmarks_ plot_mumbai_attack; december , . according to its website, "stratfor is the world's leading online publisher of geopolitical intelligence. our global team of intelligence professionals provides our members with insights into political, economic, and military developments to reduce risks, to identify opportunities, and to stay aware of happenings around the globe.… stratfor provides published intelligence and customized intelligence service for private individuals, global corporations, and divisions of the us and foreign governments around the world" (about stratfor. www.stratfor.com/about_stratfor; december , ). activities at the facility where the device is purportedly located. whatever the reason for the report, there will certainly be a reaction to it. through proper planning, the wide variety of potentially uncontrollable reactions can be greatly reduced. the height of high-rise buildings may attract people who want to gain notoriety, publicize a cause, or quickly end their own life. in the s, the newly constructed twin towers of the new york world trade center were the scenes of three daring acts by a tightrope walker, a parachutist, and a climber. that he designed to fit the window-washing equipment tracks, in three and a half hours climbed the outside of one of the twin towers. the spectacle was watched by thousands of onlookers on the ground and millions of viewers on television. when he safely reached the roof he was greeted by two police officers. later, the city of new york sued him for a quarter of a million dollars to cover the costs of police overtime and the police helicopters that were dispatched to the scene to stop news helicopters from flying too close to the towers. the lawsuit was later dropped and willig paid a $ . fine, which equated to a penny a floor. an essential element in preventing the first two types of these acts is controlling access to building roofs. in the last type, it is important for a building's perimeter to be controlled using security personnel, video surveillance, or a combination of both. base is an acronym for building, antenna, span (bridges), and earth (cliffs). base jumping is a practice by which parachutists leap off high fixed objects. sometimes, high-rise building owners permit these jumps, particularly where a special film permit or sporting competition is being staged. for example, the los angeles times reported that petronas towers, at the time the world's tallest two buildings, was the site of the malaysia international extreme skydiving championships in kuala lumpur. however, in many jurisdictions these jumps violate trespassing and reckless endangerment laws. "in private, some veterans tell of concocting elaborate ruses involving forged employee passes, paying off security guards and removing air-conditioning grates, all to pull off a stealth building jump. in , base jumpers were arrested or cited for parachuting off buildings in cities including minneapolis, new york and paris." "in a bid for credibility-and more legal jump sites-veteran jumpers are offering training sessions and camps that stress safety, and selling gear made especially for their sport." according to jean potvin, a skydiver and physics professor, "the new basespecific gear is reliable, and the sport can be practiced safely by experienced jumpers if all goes well. but the ante is upped for those who want to jump off buildings, he said. odd winds that swirl around high-rises could slam a parachutist into a window. vision becomes tricky on a nighttime jump from a high-rise, when the backdrop is darkness and not sky blue. jumpers must be able to steer their chutes away from power lines, telephone poles and other obstacles. all in a matter of seconds." strictly controlling access to the roof is the way to stop base jumpers. protestors have attempted to drape large banners promoting their raison d'être over the front of a building, and daredevils have used high-rises as their own personal stages to perform outlandish feats to gain attention, achieve notoriety, or simply to prove that they can do it. suicides numerous people have gone to a building's roof and, tragically, committed suicide by jumping over the side. some have scaled an upper floor wall facing a building atrium; climbed over an office, apartment, or hotel guestroom balcony wall or wrought-iron railing; climbed out of windows that can be opened; and even broken out a window on a floor and subsequently jumped to their deaths. undoubtedly, in older high-rise buildings equipped with exterior fire escapes, some have used this means of escape as a means of death. daredevils, protestors, and suicides can also be a serious problem when a building is being constructed. strict access control to the construction site is the key to preventing such incidents. since the late s, elevators have been developed with fully integrated, state-of-the-art microcomputer-based systems that analyze calls, set priorities, and dispatch cars on demand, enabling operators to control every aspect of elevator function. however, not all elevator systems located in high-rise buildings are this modern and sophisticated. sometimes, despite rigid continuing-maintenance schedules, they may malfunction or break down. common elevator malfunctions r include elevator cars that do not correctly align with the floor when they arrive there, elevator doors that do not close, and elevator cars that "slip" while in motion (possibly caused by stretching of the elevator cables used in traction elevators) or stall between floors, thereby entrapping occupants. if any of these conditions occurs, it must be reported promptly to management, engineering, or security staff, who in turn will notify the elevator company responsible for maintaining the equipment. the first three problems may result in temporary shutdown of the elevator for maintenance. passenger entrapment, however, is a problem that requires immediate attention. an elevator may momentarily stop and then immediately self-release the occupants, or it may stop completely and require an elevator technician to release the occupants (or, if a medical emergency occurs with a trapped occupant(s), the situation may necessitate calling the fire department or emergency services to deal with the situation). attempts by a passenger to self-exit stalled elevators can have tragic consequences. sometimes crimes against persons-such as an assault (including that of a sexual nature) or a robbery-can occur within an elevator car, where, unless viewed by a video camera inside the car, often no one (apart from the victim of the assault or robbery) is present to witness the incident (because the perpetrator will usually not commit such a crime if anyone other than the intended victim is present). a word of caution here is that with today's telecommunications capabilities, one must be particularly careful when granting access to elevator programming functions. the following incident of using an elevator to commit theft illustrates this point: was always the same. the computers would disappear from locked tenant spaces after normal business hours. there were never any visible signs of unauthorized entry. every conceivable pathway, the thief might have taken to remove the items from the building was examined. it was determined that the only possible means for removal of the items was using the single service/freight elevator. however, after normal business hours this elevator was always programmed to be "on security." it was finally ascertained that the elevator was being taken "off security" for a time period that coincided with the thefts. further investigation revealed that a building engineer had accessed the elevator system remotely from his home computer and changed the elevator's security status. the engineer then had gone to the building and to the tenant floor using the freight elevator. the thefts were carried out using a building master key to gain access to the tenant suite. the stolen items were then loaded into the elevator car and transported down to the loading dock, where there were no cctv cameras to view the incident. later the elevator was then remotely placed back "on security." also, acts of vandalism can occur inside elevator cars. a possible solution is to install vandal-resistant interiors. ("in general all lift [elevator] surfaces should be robust and resistant to damage from cleaning materials and body fluids. there should be no visible fixings [,] and gaps between moving parts should be restricted to avoid attack. stainless steel is often specified in [a] hostile environment." ) another mitigating measure is the use of elevator cars with transparent sidewalls in a transparent elevator shaft. r however, the problem of elevator vandalism may be related to the operation of the elevator itself. as noted, "clearly, installing vandal-resistant interiors and control panels in the elevator cabs will reduce the number of incidents and costs to repair damage. but if you are having repeated incidents, look beyond the surface. is the elevator system control system working properly? long wait times and long travel times will increase frustration. and more frustration is going to spur more elevator vandalism." despite the fact that elevators are a very safe form of transportation in modern high-rise buildings, elevator technicians and workers may sustain injuries or death while sustaining towers website. "lifts." april , . www.sustainingtowers.or/liftsa.htm; december , . r "a unique enhancement to building design observation elevators add[s] beauty and elegance to buildings while offering passengers a pleasantly novel experience. they can usually be found in hotels, shopping malls, sightseeing towers and the like, but recently they can even be seen in office buildings, [and parking garages] where they contribute to a more comfortable and stimulating atmosphere" ("observation elevators." international elevator & equipment, inc. . www.iee.com.ph/observe.html; august , ). such transparent "views are desired, for example, for safety reasons so that a potential elevator user can immediately recognize whether other persons, who may be disagreeable to him or her, in a given case also dogs, are in the elevator car. on the other hand, undesired views into the elevator car, for example from below, can be avoided. the transparency of the glass areas at the shaft doors and at the car doors can in that case be so controlled that these are transparent only at times of low usage, thus, for example, at night or-in office buildings-on non-work days" (freepatentsonline. "wall plate with glass part of an elevator installation, and elevator installation with such a wall part." - . www working on or near elevator systems. also, the passengers who use them are potentially at risk. r escalator riders can be the victims of petty theft by pickpockets and more serious crimes such as physical assaults. escalators can also be the scene of injuries and deaths caused by loose shoelaces, heels of women's shoes, unsuitable shoes, and loose clothing being caught in the moving stairs or handrails; riders (particularly young children and possibly older persons) slipping and falling, particularly when exiting the escalator; and escalator installers and repair persons being injured or killed while working on an escalator. rr also accidents can occur when people try to travel in the opposite direction of the (cpwr: center for construction research and training, silver spring, md, www.cpwr.com, published on electronic library of construction occupational safety and health website. www.cdc.gov/elcosh/docs/d / d /d .html#appendix ; december , ). during this same period [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] ( ), washington ( ) , and wisconsin ( ) . the eight "caught in/between" deaths usually resulted after clothing became trapped at the bottom or top of an escalator or between a stair and escalator sidewall; seven of the fall deaths were from head injury. four of the fall deaths occurred due to falling off the escalator while riding the escalator siderails. in , the consumer product safety commission [cpsc] estimated that there were , escalator and , elevator injuries requiring hospitalization (cpsc. . escalator safety. cpsc document # . ,www.cpsc.gov/cpscpub/pubs/ .html.; cooper david. barcelona, spain. ,www.elevator-expert.com/escalato.htm.) . the data were based on a nationwide survey of hospitals. based on the number of elevators and escalators in the united states, the cpsc estimated that there were . accidents per escalator and . accidents per elevator annually. the cpsc estimated that % of the escalator injuries resulted from falls, % from entrapment at the bottom or top of an escalator or between a moving stair and escalator sidewall, and % "other." the "caught-in" incidents generally resulted in more serious injuries than did falls. of particular concern is the fact that half of the approximately moving walkway (sometimes this happens when a person who has just boarded an escalator changes his or her mind and turns degrees in the opposite direction and tries to walk back to the point where he or she boarded the escalator), when riders kneel or sit on the escalator steps, or when people do not hold onto the handrails. r as long as buildings have existed, the risk of fire occurring in them has been of special concern. "in terms of reported [high-rise building] fires, there are actually four property classes that dominate the statistics. office buildings and hotels and motels are among them, but so are apartment buildings and hospitals (and other facilities that care for the sick)." the threat of fire is always present in high-rise buildings. high-rise fires can be particularly dangerous to building occupants. "the most critical threats in high-rise structures include fire, explosion, and contamination of life-support systems such as air and potable water supplies. these threats can be actuated accidentally or intentionally, and because they propagate rapidly, they can quickly develop to catastrophic levels." before proceeding, it is helpful to understand the makeup of fire and the behavior of building occupants when it occurs. fire is the combustion of fuels (whether solids, liquids, or gases) in which heat and light are produced. combustion is a chemical reaction between a substance and oxygen that needs three factors to occur-fuel, oxygen, and heat-to occur. removal of any one of these factors usually results in the fire being extinguished. within a high-rise building, there is an abundance of fuel, much equipment and furnishings being made from highly combustible synthetic materials. the centralized heating, ventilation, and air-conditioning (hvac) systems ensure that there is a plentiful supply of oxygen within interior spaces. an accidental or deliberate application of heat to this scenario may have dire consequences to the life safety of occupants. when combustion occurs, heat can travel by moving from areas of high temperature to areas of lower temperature. this transfer is accomplished by means of conduction, convection, radiation, or direct contact with a flame (figure - ) . conduction is the movement of heat by direct contact of one piece of matter (whether solid, liquid, or gas, but most often a solid) with another. this heat transfer is crucial to the spread of a fire in a high-rise. for example, in a steel-framed building, when heat is conducted from one end along a steel beam that passes through a fireproof barrier, its other end can ignite materials. convection involves the movement of heat when a liquid or gas is heated, expands, becomes less dense, rises, and is displaced by lower temperature and, hence, denser liquid or gas. this denser liquid or gas is then heated and the process continues. the danger r some of this information was obtained from the escalator safety guide. www.safetyinfo.ca/pdf/ttc_ escalator_safety_brochure.pdf; december , . more escalator safety information can be obtained from the escalator, elevator safety foundation (www.eesf.org, www.safetrider.org, www.asaferide.orgwww.eesf. org, www.safetrider.org, www.asaferide.org). of heat transfer by circulating air is heightened in high-rise buildings because when a fire occurs, convection currents can carry hot gases produced by combustion upward through floor-to-floor air-conditioning systems, elevator shafts, open stairshafts, dumbwaiters, mail chutes, laundry and linen chutes, unsealed poke-throughs, r and, in some high-rises, the exterior skin of a building-thereby spreading the fire to upper floors. this phenomenon is known as stack effect (figure - ). stack effect, as described by quiter, "results from the temperature differences between two areas, usually the inside and outside temperatures, which create a pressure difference that results in natural air movements within a building. in a high-rise building, this effect is increased due to the height of the building. many high-rise buildings have a significant stack effect, capable of moving large volumes of heat and smoke through the building." radiation is the movement of heat across a space or through a material as waves. direct contact is self-explanatory. smoke is usually the principal threat to building occupants' life safety, and is the "total airborne effluent from heating or burning a material." it may spread not only vertically between floors but also horizontally through a floor's corridors, open spaces, conduits and ducts, and hvac systems. smoke may also spread rapidly through the concealed space that extends throughout the entire floor area of many steel-framed high-rises, especially if this space is used as a return plenum for the hvac systems. gann and nelson stated, along with heat, the burning of every combustible material or product r produces smoke-gases and aerosols that, in sufficiently high concentration, present hazards to people in the vicinity. products near those already burning may also contribute to the smoke as they decompose from exposure to the benedetti rp. fire hazards of materials. fire protection handbook. th ed. quincy, ma: national fire protection association; : - . r "product refers to a finished commercial item, and material refers to a single substance. thus, for example, a chair (the product) is composed of several materials (e.g., a wooden frame, polyurethane padding, cotton batting, an aramid fire barrier, and a polyester/cotton cover fabric)" (gann rg, bryner np. combustion products and their effects on life safety. in: fire protection handbook. th ed. quincy, ma: national fire protection association; : - ). although not a major event, the following incident highlights the fact that many times a fire is the result of one apparently innocuous but unsafe action. as reported in " injured in explosion at westwood high-rise," ibid. no other information was found regarding this incident. ibid. no other information was found regarding this incident. ibid. no other information was found regarding this incident. by louis sahagun, on december , , a fire and explosion occurred on the rd floor of a westwood, california, residential high-rise and burned five workman. "some workers had been spraying lacquer in an elevator vestibule that had been screened off with clear plastic drapes, humphrey [los angeles fire department spokesman brian humphrey] said. 'someone, either entering or leaving the area, had pulled back the curtain, allowing the volatile vapor to come into contact with a halogen work lamp,' he said. there was a flash fire, and then an explosion powerful enough to blow out a large window and shake the entire building" asch building triangle shirtwaist company fire because locked exits contributed to its high number of fatalities and underscored the need to move occupants to a safe area during fire incidents. some of these incidents are addressed in more detail as follows. according to the nfpa centennial edition, (figure - ) . the -story building had only one exterior fire escape and just two staircases when it should have had three. in addition, one of its two freight elevators was out of service. to prevent what some supervisors thought was an increase in pilferage, they'd further reduced the odds of escape by locking many of the exit doors. as the fire spread unchecked, workers grabbed the standpipe hose line and tried to extinguish it, but they quickly found that the hose had rotted and the valves were frozen shut. in a panic, the workers surged towards the most familiar exits, where they were met with a wall of flame racing up the stairs. those who could scrambled to another exit and discovered that the door was locked. when they tried to force it open, they found that the door swung inward, and the press of people jammed it shut. faced with a horrible death by fire, many of the workers, most of whom were young women, leapt to their deaths from the windows. the fire, which killed people, marked a turning point in the way u.s. fire protection codes address such occupancies. r incendio a video produced by the national fire protection association indicated that when the airconditioning unit was installed, an electrical circuit breaker for it was not available. it had been installed in a manner that bypassed the floor's electrical control panel (nfpa media productions, technical advisor, john sharry, ) . the video was based on information from a joint investigation of the national fire protection association and the national bureau of standards, u.s. department of commerce. mgm grand hotel, las vegas, nevada november , the mgm grand hotel fire resulted in the death of persons, r injury to about , and more than $ million in property damage. the fire started at approximately : a.m. in a restaurant in the main casino and resulted in considerable smoke spread throughout the -story hotel building. there were approximately , registered hotel guests. of the body locations identified, were in the high-rise tower and on the casino level. the most probable cause of the fire was heat caused by an electrical fault in the restaurant. according to the nfpa's investigation study, the major contributing factors in this fire, and significant additional findings included the following: rapid fire and smoke development on the casino level due to available fuels, building arrangement, and the lack of adequate fire barriers…. lack of fire extinguishment in the incipient stage of the fire…. unprotected vertical openings contributed to smoke spread to the highrise tower…. substandard enclosure of interior stairs, smokeproof towers and exit passageways contributed to heat and smoke spread and impaired the means of egress from the high-rise tower…. smoke spread through elevator hoistways r to the high-rise tower…. the performance of automatic sprinkler protection in protected areas on the casino level was excellent and halted the spread of fire into those areas. this performance is contrasted with extensive fire development and spread in non-sprinklered areas…. there was no evidence of the execution of a fire emergency plan, and there was some delay in notifying occupants and the fire department…. , : - . rr according to hall and cote, led by strong industry associations and fire safety-conscious professionals at the major chains, the industry began to respond. in , the year of the mgm grand hotel fire, sprinklers were reported present in only one of nine hotel or motel fires reported to u.s. fire departments. detectors were reported present in just over one-fourth of reported hotel or motel fires. an industry-sponsored study of sprinkler usage in found sprinklers present in roughly half of all properties, suggesting the percentage today is much higher still. the latest data show smoke detectors in more than percent of hotel and motel fires and automatic sprinklers in percent of hotel and motel fires and more than three-fourths of high-rise hotels. it is reasonable to assume that the new level of built-in fire protection had much to do with the dramatic drop in the number of hotel and motel fires since . nfpa statistics from through indicated that sprinklers cut the chances of dying in a given fire by percent and also reduced the average property loss per fire by percent. in terms of the deadliest fires, beginning in , only two hotel or motel fires have killed or more people, and each of them was on the outer fringes of the industry that formed on the exterior of the building exposed each elevator lobby on the floors above primarily by radiation. the fire progressed vertically from floor to floor to the top of the building via the building 's exterior. occupants who were trapped or who remained in their rooms and telephoned the hotel operators were told to put wet towels and sheets around the doors and wait for the fire department. most of the smoke inhalation injuries occurred when guests opened their room doors or tried to evacuate the building. four victims were found in guest rooms.… all the rooms had open doors to the corridor or evidence that corridor doors had been opened…. there were no fatalities in rooms in which occupants kept the doors closed and waited out the fire or waited for rescue. according to the nfpa's fire investigation, [t]he most significant factors that contributed to the fire spread and subsequent fatalities, injuries and damage in the fire incident were: failure to extinguish the fire in its incipient stage and the presence of highly combustible carpeting on the walls and ceilings of the involved elevator lobbies contributing to the exterior fire spread. the resulting fire spread exposed a large number of the building's occupants on multiple floors. "the person who initially called in the fire alarm to the security dispatcher was arrested, charged, and indicted for eight counts of homicide and arson. the individual was a hotel room service bus boy, and had been employed there only a few weeks. " dupont plaza hotel & casino, puerto rico december , , san juan, puerto rico-the dupont plaza hotel and casino fire [ figure - ] resulted in the death of persons and over injuries. the mid-afternoon fire resulted in smoke that spread to the -level hotel tower guest room floors. eighty four of the fatalities were located in the casino.… five fatalities occurred in the lobby area, three were found in a passenger elevator stopped between the basement and the first floor level, one fatality was in a guest room on the west side of the fourth floor, and two victims were found on the exterior of the building at the poolside bar … like the five occupants trapped in the lobby, the victims in the casino were caught by the violent extension of the fire through the casino/lobby level. local authorities and the bureau of alcohol, tobacco and firearms (atf) even though significant amounts of smoke, heat, and toxic gases penetrated the high-rise tower, especially on its lower levels, there was only one fatality in the tower. it is felt that exterior balconies provided occupants trapped for hours with a safe refuge area until the fire could be suppressed or they could be assisted by rescuers. first interstate bank building, los angeles, california may , , los angeles, california-the first interstate bank building fire ( figure - ), at wilshire boulevard, resulted in the tragic death of a building engineer trapped in a service elevator that he used to travel to the initial fire floor to investigate the source of automatic fire alarms, smoke inhalation suffered by many of the people located inside the office building at the time of the fire, and a loss estimated by the national fire protection association fire analysis and research division at $ million. r "severe fires in occupied office buildings during business hours are very rare, in large part due to the awareness of people in the building to unusual conditions. occupants of high-rise office buildings are mobile, awake, and alert, and they are effective early detectors if they are adequately trained to summon help. when such alerting occurs, fires usually are in their initial phase of growth, when they can be controlled more easily. this illustrates the importance of occupant training that includes emergency fire notification procedures" (klem tj. may , , as flames shoot from the windows of the -story building. fire officials described the ½-hour blaze as the worst high-rise fire in the history of los angeles. used with permission of ap images. the death of the building engineer investigating the fire alarms was attributed to the fact that he took an elevator that directly penetrated the fire floor. to do so, he bypassed the building's fire life safety system and rode a service elevator to the fire floor. on arrival at the th floor, the engineer began to open the metal elevator car doors, but they buckled because of the intense heat of a fire that had intruded into the elevator vestibule. as a result, the doors could not be closed and he died crying out for help on his portable radio. taking an elevator that can directly access the floor where a fire or fire alarm is occurring is extremely dangerous, particularly by nonfire department personnel who lack firefighter training, are not wearing protective clothing, and are not equipped with the breathing apparatus and forcible entry tools that firefighters have when they respond to fire incidents. june , , atlanta, georgia-the peachtree th building fire resulted in the death of five occupants, including an electrician who apparently caused the fire, the injury of building occupants and six firefighters, and direct property damage estimated at over $ million. the fire began on the sixth floor of this -story office building at : a.m. on a friday. "caused by improper repairs to an electrical distribution system, this fire was an extreme, sudden, and intense fire." the atlanta city fire department extinguished the fire only after it had caused heavy damage to the sixth floor and to electrical rooms on the fourth and fifth floors. according to the nfpa's investigation of the fire, factors contributing to the loss of life and severity of the fire included the following: other natural cracks and voids such as small openings between the top of interior partitions and the suspended ceiling assemblies. second, the ceiling collapsed outside the room of fire origin, and pressurized smoke quickly filled the plenum space that extended all over the office areas. this smoke then entered the offices through the ceiling vents used to collect return air and seeped through cracks and crevices in the ceiling assembly." one meridian plaza, philadelphia, pennsylvania february , , philadelphia, pennsylvania- the one meridian plaza fire resulted in the tragic death of three firefighters because of smoke inhalation and destroyed eight floors of this -story high-rise office building. the fire started on the nd floor at : p.m. it was caused by "spontaneous ignition of improperly stored linseed-soaked rags that were being used to restore and clean." eighteen and one-half hours later, the philadelphia city fire department declared it under control on the th floor (the first floor above the fire floor that had an automatic sprinkler system). according to the nfpa, the following significant factors affected the outcome of the fire: the lack of automatic sprinklers on the floor of fire origin; the effectiveness of automatic sprinklers on the th floor which, supplied by fire department pumpers, halted the fire's vertical spread; the lack of early detection of the incipient fire by automatic means; inadequate pressures for fire hoses because settings of pressure-reducing valves were too low for the specific application in this building; the improper storage and handling of hazardous materials, producing both the initial ignition and rapid early fire growth; and the early loss of the building's main electrical service and emergency power. in this fire, when the first automatic fire alarm was received from the nd floor, a maintenance worker almost lost his life when he took an elevator to investigate the source of the alarm, leaving a security guard at the first-floor desk. "when he reached that floor and the elevator doors opened, he encountered heat and dense smoke. the man dropped to the floor, notified the security guard of the fire by portable radio, and told the guard that he could not close the elevator doors. however, he was able to tell the guard how to override the elevator controls so the guard could return the elevator to the first floor. the guard gained control of the elevator, and the maintenance man returned safely to the ground level." ibid, p. . residential building, north york, ontario, canada january , , north york, ontario, canada-at approximately : a.m., a fire in a residential high-rise building led to the deaths of six residents. "all were found on upper stories in exit stairways. the fire appeared to have been ignited by the improper disposal of smoking materials and initially involved a couch in a fifth-floor apartment. the fire caused severe damage to the apartment and to an exit access corridor." "after unsuccessfully attempting to extinguish the fire, the occupant in the apartment of fire origin left without closing the dwelling unit door to the corridor. fire and smoke passed through the open door into the exit access corridor and made that corridor untenable for many fifth-floor residents. the residents who did not escape early in the incident stayed in their apartments until they were rescued by firefighters. the combination of closed doors and noncombustible walls prevented untenable conditions and deaths from occurring in other fifth-floor apartments…. in many instances, the people who remained in their apartments or moved to the balconies were exposed to less risk to their safety than those who attempted to escape." based on the nfpa's investigation of this fire, staff members smelled what they thought was gas emanating from the buffet area of the coffee shop. investigating its source, a staff member noticed that gas was leaking from the valve assembly of a -kilogram ( -pound) liquid propane gas cylinder.... the man tried to shut down the cylinder's main control valve. however, he inadvertently turned the valve the wrong way and, instead of shutting off the flow of gas, actually increased it. the vapor, expanding as it was released, quickly ignited.... a combination of combustible wood-and-vinyl-covered furnishings in the area of fire origin, the combustible decor of the coffee shop, the wooden decor of the complex, and the lack of any active fire suppression systems allowed the fire to develop rapidly.... combustible interiors, the westerly breeze, and the lack of fire separation, compartmentation, and active suppression systems allowed the fire to spread rapidly through the lower levels of the complex. as the fire grew, the lack of pressurization in the stairwell, the lack of selfclosers on many of the upper-level doors, and the lack of firestopping in the service shafts allowed smoke to penetrate the upper levels, causing the hotel to fill with smoke.... according to the local police officers responsible for the initial investigation, the sister of one of the hotel's senior managers had fled the area of the fire before she realized that no one had begun to evacuate the resort's guests. when she re-entered the complex to do so, she was overcome by the fire. this incident is addressed earlier in this chapter as an aircraft collision. chicago fire department (cfd) logged in a call to by a security officer at : : p.m. and arrived at the building at : : p.m. the fire was reported as "knocked down" at : : p.m. according to the report of the cook county commission investigating the west washington building fire of october , , victims were found in the southeast stairwell of the -story office building after that stairwell filled with smoke. all of the fatalities were attributed to smoke inhalation. the southeast stairwell filled with smoke at approximately : p.m. to : p.m. after members of the chicago fire department opened the stairwell door on the th floor, which was the floor where the fire was located. the opening of the door irretrievably compromised the stairwell as a safe escape route. approximately minutes after opening the door, the fire department searched the stairwell above the th floor for the first time. the fire department discovered the victims within a few minutes after beginning that search. based on its investigation, the commission has concluded that the six deaths and the serious injuries that occurred in the fire would not have "therefore, the fatalities (and much of the damage) could have been avoided by the presence of sprinklers. what was learned from this fire? perhaps only that the knowledge that is already known should be applied. sprinklers greatly increase the safety of buildings, and locked stairwells, even from the stair side, create a hazard." according to the nfpa fire journal, sometime before midnight on october , , a fire began on the th floor of the east tower of the parque central, a -story government [reinforced concrete] office building in caracas, venezuela, and south america's tallest high-rise. fortunately, the building was unoccupied at the time, except for a handful of security personnel who evacuated safely. despite the fact that a sprinkler system had been installed in the parque central the fire did more than u.s. $ million in damage, burning the structure's contents from the th floor to the th. why? because, as previous inspections revealed, the sprinkler system had not been properly tested or maintained, thus it wasn't in a working condition; the building designers said local fire alarm panels weren't connected to a building-wide panel; and the standpipe system was inoperable at the time of the fire…. past history and performance shows that this fire could probably have been controlled quickly by a standard wet-pipe sprinkler system and that the fire department's chances of controlling the fire at, or a few floors above, the floor of fire origin would have increased if the standpipe system had been working. this fire highlights the importance of periodic inspection, testing, and maintenance of fire protection systems, as well as the importance of strictly following manufacturers ' installation instructions. windsor building, madrid, spain "on the night of february , , a fire started in the windsor building [edificio windsor] in madrid, spain, a -story tower framed in steel-reinforced concrete. at its peak, the fire, which burned for almost a day, completely engulfed the upper ten stories of the building. more than firefighters battled to prevent the uncontrollable blaze from spreading to other buildings." ibid., p. . the report contains detailed conclusions and recommendations, "for more information on this report or to received the full version of the report and supporting documentation, contact the fire commission attorney" (cook county info center. www.co.cook.il.us/fire_reportreport.htm; march , "the fire apparently caused the collapse of the top floor spans surrounding the still-standing core structure of the ten uppermost floors." according to arup, r the long delay rr between detection and fire brigade rrr intervention played an important role in allowing the unsprinklered fire to grow out of control. in addition the rapid spread of the fire above the st floor appears to be due to failure of the compartmentation measures between the facade detail and the floor which is intended to prevent vertical fire spread. fire safety design in many countries relies heavily on sprinkler protection to prevent fire growth and thereby limit possibilities for fire spread via the facade. the lack of sprinklers, along with the failure of compartmentation, appears to be an important factor in this case. although there is a requirement to fire stop rrrr the gap between the slab edge and the inside of the curtain wall, most codes do not address the tie-back connection of the curtain wall to the structure. therefore a light facade structural element can heat up quickly and the resulting expansion can produce an outward bulging away from the slab edge, which can create internal flues if it happens before the facade glazing breaks. in other words by not considering the thermo-mechanical response of the system, there are no provisions to prevent such damage in building codes worldwide. an added complication in the case of edificio windsor was that the curtain wall facade had recently been replaced and it appears that a new support structure had been fixed onto the outside of the original mullion and transom arrangement. this means that there would have been a double-layered gap that needed to be fire stopped, complicating this detail still further…. lessons to be learned procedures to ensure early call out to the fire brigade provisions for speedy access to the fire floor via protected fire fighting lifts and use of wet risers the windsor building fire. http:// research.wtc .net/wtc/analysis/compare/windsor.html; october , . r as stated on its website arup is "a global firm of designers, engineers, planners and business consultants." the article by arup states that "the following is an arup view based upon what is known about the fire event in conjunction with our structural fire design and analysis experience. it has been prepared based upon information in the public domain only and will be updated as further information becomes available" (madrid windsor fire: the arup view. www.arup.com/fire/feature.cfm?pageid ; october , ). programme, especially in an occupied building structural fire full frame analysis, rather than single element small-scale fire tests, as a basis for design. fire alarms are significant events in high-rise buildings. a fire alarm is "a signal initiated by a fire alarm-initiating device such as a manual fire alarm box, automatic fire detector, waterflow switch, or other device in which activation is indicative of the presence of a fire or fire signature." as bryan explained, "the primary purpose of a fire detection system is to respond to a fire, and to transform this response into a visual-audible signal which should alert the building's occupants and the fire department that a fire has been initiated. the fire detection system is intended to respond to the initial signs, signals, or stimuli which indicates that a fire has begun." (see the section titled "manual fire alarm stations" in chapter for the sequence of events caused by fire alarms in modern high-rise buildings.) whenever a fire or a fire alarm occurs, all building occupants need to be alerted to the existence (or possible existence) of fire and to initiate emergency procedures. all occupants should be evacuated in a prompt, safe, and orderly fashion according to procedures established in the building emergency management plan. "some of the life-safety requirements [for a high-rise structure] actually pose unique security difficulties. the code provision which insists upon unimpeded exit during a building emergency means that if such an emergency can be faked, egress may be possible under little or no surveillance. even if the emergency is genuine, it may occur at a time when the security forces are unprepared for the joint demands of emergency response and heightened security attention." for example, in a high-rise office building, an individual could set off a fire alarm by activating a manual fire alarm station. this should result in the evacuation of occupants from that floor, and floors above and below the incident (the actual number of floors will depend on the emergency plan for the building concerned). after all occupants have left, the person could then quickly roam unchallenged through offices and steal items (including possibly from handbags and billfolds in coats left behind in the hurry to evacuate). the thief could then enter a stairwell, descend to the ground level, and freely walk out of the building. two individuals could similarly stage such an event to gain unauthorized entry to a floor that is normally secured (i.e., the elevators only proceed to the floor if authorized access cards are used). one person could activate a manual fire alarm station on one floor, thereby causing the stairwell doors to unlock automatically (if this feature is provided) throughout the building. an accomplice waiting in a stairwell on the targeted floor could then proceed into the tenant space (sometimes stairwells lead directly into tenant areas rather than into common corridors) and gain access to commit a crime. afterward, the thief could then board a passenger elevator-because during fire alarm situations in many modern high-rise buildings, the elevators remain in service unless a smoke detector in the elevator lobby, elevator shaft, or elevator machine room has been activated r or the elevators have been manually recalled from the fire command center-or reenter the stairwell and proceed down to the ground level to exit the building. some buildings require security staff to manually recall all elevators serving floors in alarm to prevent occupants from using them during fire and fire alarm situations. this practice has the added advantage of securing the floor from unauthorized access using elevators. the following measures can be considered to maintain security during a fire or fire alarm: . if stairwells lead directly into tenant areas, consider redesigning the space to remove this security hazard. . train building occupants to always take personal valuables with them during evacuation and, if such actions do not place them in danger, to quickly secure other valuable assets. . position video cameras with alarm-activated recording capability in tenant highrisk areas (particularly where valuables such as cash and high-value assets are located) and in building stairwells close to the ground-level exits to at least obtain a record of an incident. a hazardous material is "a substance (solid, liquid, or gas) capable of creating harm to people, property, and the environment." such a substance may be corrosive, explosive, flammable, irritating, oxidizing, poisonous, radioactive, or toxic in effect. hazardous materials may be chemical, biological, or nuclear in nature. in the high-rise setting, hazardous materials may be in a building for legitimate operational purposes or be maliciously introduced into the building in order to harm people. hazardous materials in a high-rise building may include a variety of substances that will vary according to the type of occupancy. such materials may include diesel fuel for the building's emergency generator, cleaning materials for use by janitorial staff, construction materials, and chemicals such as chlorine for swimming pools and hot tubs. the types of hazardous materials outside a high-rise building may include pcbs (as already mentioned), radioactive substances in a nearby nuclear facility, potentially dangerous materials transported along an adjacent or under-building railway line or roadway, or flammable and potentially harmful chemicals contained in a nearby chemical manufacturing plant or oil refinery. as previously stated, "the most critical threats in high-rise structures include fire, explosion, and contamination of life-support systems such as air and potable water supplies. these threats can be actuated accidentally or intentionally, and because they propagate rapidly, they can quickly develop to catastrophic le els." therefore, to minimize or eliminate the hazards to people, property or the environment, every hazardous material incident should be handled by building emergency staff according to standard operating procedures (described later in the sample building emergency procedures manual in chapter ). the threat of chemical and biological weapons (cbw) has existed for some time in the modern world. however, since the mid- s, the potential for the use of cbw against civilians has dramatically increased. "as early as , european intelligence officials learned that chemical and biological warfare instructions disseminated from al qaeda sources in pakistan and afghanistan were circulating among islamic terrorist cells. that year, belgium police seized what turned out to be an , -page guerilla manual for jihad. r one chapter, titled 'how to kill,' described how to prepare 'toxins, toxic gas and toxic drugs. '" according to the u.s. centers for disease control and prevention, r "the literal meaning of jihad is struggle or effort, and it means much more than holy war. muslims use the word jihad to describe three different kinds of struggle:  a believer's internal struggle to live out the muslim faith as well as possible  the struggle to build a good muslim society  holy war: the struggle to defend islam, with force if necessary many modern writers claim that the main meaning of jihad is the internal spiritual struggle, and this is accepted by many muslims. however there are so many references to jihad as a military struggle in islamic writings that it is incorrect to claim that the interpretation of jihad as holy war is wrong" (bbc religion and ethics-islam. october , . www.bbc.co.uk the potential for deliberate contamination of buildings with toxic chemical substances, such as sarin gas or hydrogen cyanide, and dangerous biological material, such as anthrax (bacillus anthracis) and ricin, is a concern, particularly due to several highprofile incidents involving sarin gas and anthrax. march , tokyo, japan-a japanese cult terrorist group deliberately released sarin gas on a tokyo subway. it killed people and caused , more to seek medical attention. "first responders had difficulty in identifying the odorless, colorless chemical and in knowing how to simultaneously protect themselves, handle mass casualties and stop the toxin from spreading in the subway system. some of the deaths included subway maintenance workers who rushed to the scene and unknowingly touched, breathed in and further agitated the lethal nerve agent." september , east coast united states-five anthrax-contaminated letters were mailed to two democratic senators and news media (cbs, nbc, and the new york post). these letters were received soon after the september , , terrorist attacks on the new york world trade center and the pentagon and led to the deaths of five people and others being infected. according to barbara rosenberg, a molecular biologist, "the anthrax discovered in the letters mailed to the two u.s. senators was so refined that it contained trillion spores per gram, characteristic of the 'weaponized' anthrax made by u.s. defense labs." on july , , the suspected perpetrator of these attacks, u.s. government microbiologist bruce ivins, died of an apparent suicide while under investigation for these crimes. the difference between a chemical and biological attack is that "a biological [and radiological] agent will almost never cause immediate symptoms; a chemical agent almost always will." "nuclear terrorism denotes the use, or threat of the use, of nuclear or radiological weapons in acts of terrorism, including attacks against facilities where radioactive materials are present. in legal terms, nuclear terrorism is an offense committed if a person unlawfully and intentionally 'uses in any way radioactive material … with the intent to cause death or serious bodily injury,' according to international conventions." the institute of real estate management states, the immediate effects of a nuclear attack are unmistakable: a flash of intense light followed by a blast of heat and radiation. likewise, the secondary effect is [well] known … radioactive fallout. the degree of immediate and secondary effects will depend on the size and type of weapon, the terrain (hilly versus flat), the height of the explosion (e.g., near or far from the ground), the distance from the explosion, and weather conditions. people near the explosion most likely would be killed or seriously injured by the initial blast, heat, or radiation. those several miles away from the explosion would be endangered by the initial blast, heat, and subsequent fires. others probably would survive but would be affected by radioactive fallout. it is for these people that an emergency plan must be provided. the only precaution that a property manager can take to prevent loss due to a nuclear attack is to provide an emergency shelter for occupants, employees, and others at the property at the time of such an attack. such a shelter could be a special building, underground bunker, or any space with walls and roof thick enough to absorb radioactive waves given off by fallout. "there is also growing concern about so-called dirty bombs, [or a radiological dispersal device (rdd) ] laced with radioactive material from a hospital, nuclear plant or manufacturing facility, for instance, that can contaminate the environment." a dirty bomb uses conventional explosives to spread radioactive material. depending on the type and quantity of radioactive material used in a device and variables such as weather conditions and the size of particles released, the impact of an rdd attack could vary greatly. however, experts generally agree that an rdd is most appropriately characterized as a weapon of mass disruption, rather than mass destruction. a typical attack would result in few, if any, immediate casualties from radiation exposure, but the ensuing contamination would likely prompt widespread panic, causing significant economic and psychosocial damage. long-term economic consequences, moreover, could be very significant if affected areas included major commercial or industrial sites and could not be readily restored to public use. such a weapon could be hand-carried into a building concealed in a suitcase. kidnapping is "the forcible abduction or stealing and carrying away of a person…. a person is guilty of kidnapping if he unlawfully removes another from his place of residence or business, or a substantial distance from the vicinity where he is found, or if he unlawfully confines another for a substantial period in a place of isolation, with any of the following purposes: (a) to hold for ransom or reward, or as a shield or hostage; or (b) to facilitate commission of any felony or flight thereafter; or (c) to inflict bodily injury on or to terrorize the victim or another; or (d) to interfere with the performance of any governmental or political function." high-rise buildings may be the site of kidnappings of business executives, wealthy citizens, children involved in custody battles, political hostages, diplomats, politicians, and other individuals. a hostage is "an innocent person held captive by one who threatens to kill or harm him if his demands are not met." high-rise buildings have been the site of hostage-taking situations, examples of which follow: , first interstate bank building, los angeles, california-a man entered this story high-rise office building, accosted the building's chief engineer in the main lobby, and demanded to be taken to the roof. on reaching it, he then tried to obtain publicity for a cause he was promoting-in this case, that smoking is bad for your health. building management immediately called the police department, and after a tense standoff, the individual eventually surrendered without anyone being injured. the gunman held as many as people hostage in the building's main lobby, and more than people were trapped in their offices. after seven hours, the gunman shot himself. all hostages were freed unharmed. reportedly, the gunman was protesting the advertising practices of a major electronics firm that was previously headquartered in the high-rise. december , , citigroup center, chicago, illinois-"joe jackson forced a security guard at gunpoint to take him up to the th floor offices of wood, phillips, katz, clark & mortimer, which specialized in intellectual property and patents. he carried a revolver, knife and hammer in a large manila envelope and chained the office doors behind him, the police said. "jackson, , told the police before he was shot that he had been cheated over a toilet he had invented for use in trucks, superintendent phil cline of the police department said saturday…. the gunman who fatally shot three people in a law firm's high-rise office before he was killed by police felt cheated over an invention." "the building was locked down during the seige. occupants of the other offices were instructed to lock themselves into their offices and not to venture out into the halls. the lockdown took place for minutes. all metra train services [a train station is located at the building] were shut down until : pm, while the crime scene was considered active." events such as labor disputes, demonstrations, and civil disorder can have a significant impact on the day-to-day operation of a high-rise building. their effects will be influenced by the nature of the incident, the number of persons participating in it, the conduct of the participants, the response of building management and involved outside agencies, and the location of the incident in relation to the building. labor disputes may be peaceful affairs where orderly groups of persons assemble outside the building; quietly display placards, signs, and banners to passing motorists; pass out leaflets explaining their cause; and present petitions to the parties involved. they can, however, be violent events, where large groups of angry persons protesting a labor issue pertaining to the building, or one of its tenants, throw rocks and various other objects in an attempt to forcibly enter the building or surround the building to prevent occupants and visitors from entering or leaving. a demonstration is a gathering of people for the purposes of publicly displaying their attitude toward a particular cause, issue, or other matter. such an activity, if carried out the associated press. dutchman in product dispute takes hostages, kills himself. los angeles times. march , :a . the associated press. police: ill. gunman felt cheated over an invention. december , . www. msnbc.msn.com/id/ /#storycontinued; may , . peacefully on public property, is permissible. however, the activity must not obstruct, block, or in any way interfere with the ingress to and egress from private property such as a high-rise building. as with a labor dispute, a demonstration may vary from a peaceful affair to a violent one. civil disorder is "any public disturbance involving acts of violence by assemblages of three or more persons, which causes an immediate danger of or results in damage or injury to the property or person of any other individual." sometimes civil disorder is known as a civil disturbance. a riot is "a form of civil disorder characterized by disorganized groups lashing out in a sudden and intense rash of violence, vandalism or other crime. while individuals may attempt to lead or control a riot, riots are typically chaotic and exhibit herd behavior.... riots typically involve vandalism and the destruction of private and public property. the specific property to be targeted varies depending on the cause of the riot and the inclinations of those involved. targets can include shops, cars, restaurants, state-owned institutions, and religious buildings." medical emergencies that can occur in high-rise buildings range from people choking to drug overdoses, from respiratory emergencies to seizures, from food poisoning to dental emergencies, and from serious injury to suicide. because building populations are made up of people often working under pressure and stress, there is always the possibility of heart attacks or strokes. natural disasters may be earthquakes, tsunamis, volcanoes, heat waves, storms (non cyclone, tornadoes, and tropical cyclones [cyclones, hurricanes, and typhoons]), and floods and landslides. the foundations of the earth shake. the earth is broken asunder, the earth is split through, the earth is shaken violently. earthquake is "a term used to describe both sudden slip on a fault, and the resulting ground shaking and radiated seismic energy caused by the slip, or by volcanic or magmatic publisher's editorial staff. black's law dictionary. th ed. (nolan jr, nolan-haley jm, co-authors). st. paul, mn: west publishing; : . activity, or other sudden stress changes in the earth." earthquakes range from an almost indiscernible tremble of the ground to the violent shaking of a major quake. this shaking is sometimes side-to-side and other times up-and-down; it can last for a few seconds or for several minutes. when earthquakes occur, the strength and duration of the shaking largely determines the potential for damage. some earthquakes are preceded by smaller quakes called foreshocks, some occur suddenly with no forewarning, some occur in groups of approximately the same magnitude (called swarms or clusters), and some are followed by smaller quakes called aftershocks. according august , . bull seismol soc am. ( ) : - . in , there were about stations operating in the world; today, there are more that , stations and the data now comes in rapidly from these stations by telex, computer and satellite. this increase in the number of stations and the more timely receipt of data has allowed us and other seismological centers to locate many small earthquakes which were undetected in earlier years, and we are able to locate earthquakes more rapidly. the neic now locates about , to , earthquakes each year or approximately per day. also, because of the improvements in communications and the increased interest in natural disasters, the public now learns about more earthquakes. according to long-term records (since about ) , we expect about major earthquakes ( . - . ) and one great earthquake ( . or above) in any given year. however, let's take a look at what has happened in the past years, from years, from through years, from , so far. our records show that years, from , and years, from - were the only years that we have reached or exceeded the long-term average number of major earthquakes since . in and in a temporal increase in earthquake activity does not mean that a large earthquake is about to happen. similarly, quiescence, or the lack of seismicity, does not mean a large earthquake is going to happen. a temporary increase or decrease in the seismicity rate is usually just part of the natural variation in the seismicity. there is no way for us to know whether or not this time it will lead to a larger earthquake. swarms of small events, especially in geothermal areas, are common, and moderate-large magnitude earthquakes will typically have an aftershock sequence that follows. all that is normal and expected earthquake activity. in many parts of the world, modern high-rise buildings in areas subject to earthquake activity are constructed in accordance with strict building codes. older buildings erected before seismic design considerations may need structural retrofits to bring them up to code. the effect of earthquakes on a high-rise building depends on factors such as the building's location in relation to the quake's epicenter, type of soil or rock beneath the structure, magnitude of the quake, duration of the shaking, type of motion the structure is subjected to, and the building's design and construction. the shaking of an earthquake may cause no structural damage, or it may cause damage so severe that the building collapses. modern high-rise buildings can be seismically designed to withstand certain magnitude earthquakes. "the idea of earthquake-proof construction is unrealistic, unless exceptionally expensive measures are taken. any building will collapse if the ground under it shakes hard enough or becomes permanently deformed. but structures can be designed and constructed to incorporate a high degree of earthquake resistance." as dames and moore/urs corporation explained, "to resist seismic forces, steel buildings are either constructed with braced frames (such as x-bracing) or moment frames (rigid beam-column assembly r )." many structures, particularly seismically designed steel-framed buildings, have been constructed to flex and move without breaking. lower floors may shake more rapidly, but movement of the building from side to side is greatest on uppermost floors. "to dissipate the force of the ground shaking through a tall structure, the building is designed to sway rr as a unit in a side-to-side motion." case study: , northridge earthquake january , . a.m. an earthquake of magnitude . rocked the heavily populated san fernando valley. it severely impaired the public transportation network and residential community; people were killed and , people were treated for earthquake-related injuries. steel moment frames "consist of beams and columns joined by a combination of welding and bolting" (property risk. "what are steel moment frames?" www.propertyrisk.com/refcentr/steel-side.htm; november , ). dames & moore/ urs corporation, "how buildings fared," the northridge earthquake, january , (dames and moore: los angeles; : ) . rr most high-rise buildings are designed to sway in a gentle wind but not so much that occupants on upper floors experience motion sickness. the object is to "make [the building] stiff enough that people wouldn't get sick, but not so rigid that it could snap if it got too big a load…. often big buildings are designed to be stiff enough that the period to go one way and back the other way is to seconds, or even seconds. that keeps people from getting sick." (eagar, dr., thomas, commenting on the world trade center collapse in "why the towers fell." april , [nova online. www.pbs.org/wgbh/nova/wtc/collapse.html; , ; january , ] were attributed to heart attacks." thousands were left homeless in the wake of this disaster that had an insured loss of $ , , , . the january , , northridge earthquake raised some serious safety concerns about the degree of earthquake resistance that high-rise buildings, in particular steel moment frame structures, afford. unlike braced frames, these moment frames feature larger beams and columns, with additional welding or bolting of the connections. before this earthquake, this structural system was thought to be among the safest seismically. as john hall, an associate professor of civil engineering at the california institute of technology, pointed out, during the northridge earthquake, many modern steel buildings suffered unexpected fractures in welded beam-to-column connections. although none of these buildings collapsed, fractured connections are a serious matter since they reduce the lateral strength of the structure, and, thereby, increase the risk of collapse. the problem is apparently widespread and, at this point, one must assume that any welded steel moment-frame is susceptible to this type of connection failure. the following comments regarding this situation were written shortly after the quake in the northridge earthquake, january , after this disaster, the city of los angeles by ordinance required that owners of steel moment frame buildings inspect for damage, and the federal emergency management agency (fema) subsequently prepared guidelines to address this potential hazard. even though issues about weld cracks in steel-framed construction were the most startling results of the quake, the failures of concrete-framed parking structures were among the most dramatic (figure - ) . as the engineering news record reported, "in response to such collapses, federal officials anticipate a new treatment of parking structures in the national earthquake hazard reduction program's provisions, to serve as a basis for model codes." during a severe earthquake, occupants and building contents will be shaken. items not properly secured may fall; desks and furniture may slide; filing cabinets and bookcases may topple; ceiling tiles may be dislodged; windows may crack or shatter; sprinkler heads may shear off and result in water discharge; seismic devices may cause building elevators to go to the nearest floor in the direction of travel, stop, automatically open elevator car doors, and then cease operation; automatic fire detection and reporting equipment may produce multiple false alarms; electrical power may be disrupted; lights may go off; the telephone system may be damaged or, shortly after the shaking has stopped, be deluged with calls. falling objects will often cause injuries. soil liquefaction, landslides, and fires are common results of major earthquakes. liquefaction occurs in areas where loose soils with a high water table are present. "as the earthquake causes water to percolate up through the loose soil, it creates quicksand. heavy objects such as buildings and other structures may sink or tilt into the liquefied soil." fires can result from fuel spillage, rupturing of gas lines, and the many ignition engineering news record. new york: mcgraw-hill, inc.; january , : - . sources available in urban areas. if the earthquake is a major one, public fire fighting capabilities will be severely strained because of extraordinary demands for service, difficulties in transporting equipment along damaged or blocked roadways and freeways, and possible disruption of the public water supply. a tsunami is "a large wave caused by earthquakes, submarine landslides, and, infrequently, by eruptions of island volcanoes. during a major earthquake, an enormous amount of water can be set in motion as the seafloor moves up and down. the result is a series of potentially destructive waves that can move at more than miles [ kilometers] per hour." "tsunamis travel at high speed through deep water ( [ kilometers] to miles [ kilometers] per hour) with modest wave heights (inches or feet) that have wavelengths that are hundreds of kilometers long. these open ocean tsunamis are imperceptible to humans, but can be detected by water pressure sensors on the ocean floor. when it reaches shallower coastal waters, the tsunami slows down, causing its wave height to build rapidly. tsunamis are common in the pacific ocean and less frequent in the indian and atlantic oceans." (see table - for a listing of major tsunamis that have occurred in the world.) japan has a history of tsunamis following major earthquakes; its government has developed a tsunami early warning system similar to the u.s. emergency broadcast system, which broadcasts warnings over television and radio networks. "the tsunami warning system (tws) in the pacific, comprised of participating international member states, has the functions of monitoring seismological and tidal stations throughout the pacific basin to evaluate potentially tsunamigenic earthquakes and disseminating tsunami warning information. the pacific tsunami warning center (ptwc) is the operational center of the pacific tws. located near honolulu, hawaii, ptwc provides tsunami warning information to national authorities in the pacific basin." according to cbc news online, a volcano is a geological formation, usually a conical mountain, that forms when molten rock, called magma, flows up from the interior of the earth to the surface. magma finds its way upwards along fissures or cracks in the planet's crust and bursts out onto the surface, resulting in a volcano. the earth's crust is composed of plates that float on the molten layer beneath them. most volcanoes line the boundaries of these plates. one of these boundaries is referred to as "the circle of fire" and extends from the west coast of the americas to the east coast of asia. seventy-five per cent of the world's active volcanoes are found along this "circle of fire." a volcano erupts in one of two ways: either the magma is forced up to the surface or the rising magma heats water trapped within the surface, causing an explosion of steam. in either case, the eruption can eject rocks, volcanic ash, cinders and hot gases into the air. the rapidly cooling lava can form volcanic glass. see table - for a listing of the world's deadliest volcanoes. "the best warning of a volcanic eruption is one that specifies when and where an eruption is most likely to occur and what type and size eruption should be expected. such accurate predictions are sometimes possible but still rare in volcanology. the most accurate warnings are those in which scientists indicate an eruption is probably only hours to days away based on significant changes in a volcano's earthquake activity, ground deformation, and gas emissions. experience from around the world has shown that most eruptions are preceded by such changes over a period of days to weeks." a heat wave is "a period of abnormally and uncomfortably hot and usually humid weather. to be a heat wave such a period should last at least one day, but conventionally it lasts from several days to several weeks." deadly heat waves have struck areas such as europe in r and india in india in , india in , and shanghai in and chicago in ; japan in ; and athens in . "in australia during the th century, heatwaves caused if a building is not air conditioned, a heat wave can be a threat to the life safety of its occupants. in a widespread heat wave impacting a city or region, there will greater pressure on public utilities to meet increased demands for electrical power to operate cooling fans and air conditioners. as a result, electrical power outages may occur at buildings, and as a consequence hvac systems will shut down. a storm is "any disturbed state of the atmosphere, especially as affecting the earth's surface, implying inclement and possibly destructive weather…. storms range in scale from tornadoes and thunderstorms, through tropical cyclones, to widespread extratropical cyclones … rainstorms, windstorms, hailstorms, snowstorms, etc. notable special cases are blizzards, ice storms, sandstorms, and duststorms." noncylone noncyclone storms may include torrential rains, windstorms, hailstorms, snowstorms, blizzards, ice storms, sandstorms, and dust storms. a tornado is defined by the glossary of meteorology as "a violently rotating column of air, in contact with the ground, either pendant from a cumuliform cloud or underneath a cumuliform cloud, and often (but not always) visible as a funnel cloud." r "tornadoes are generally spawned by thunderstorms, though they have been known to occur without the presence of lightning. the stronger tornadoes attain an awe-inspiring intensity, with wind speeds that exceed mph [ kilometers per hour] and in extreme cases may approach mph [ kilometers per hour]…. tornadoes can come one at a time, or in clusters, and they can vary greatly in length, width, direction of travel, and speed. they can leave a path yards [ meters] wide or over a mile [ . kilometers] "tornadoes occur on all continents r but are most common in the united states, where the average number of reported tornadoes is roughly per year, with the majority of them on the central plains and in the southeastern states (see tornado alley rr ). they can occur throughout the year at any time of the day. in the central plains of the united states they are most frequent in spring during the late afternoon." in the united states, if a threat of tornadoes is reported, tornado watch or tornado warning advisories may be issued by the national weather service (nws). a tornado watch means that tornadoes are possible; a tornado warning means that tornadoes actually have been sighted in the area. a tropical cyclone is "the general term for a cyclone that originates over the tropical oceans. this term encompasses tropical depressions, tropical storms, hurricanes, and typhoons." "a tropical cyclone is a storm system characterized by a low pressure center and numerous thunderstorms that produce strong winds and flooding rain." a cyclone is "an atmospheric cyclonic circulation, a closed circulation. a cyclone's direction of rotation (counterclockwise in the northern hemisphere) is opposite to that of an anticyclone. while modern meteorology restricts the use of the term cyclone to the so-called cyclonic-scale circulations, it is popularly still applied to the more or less violent, small-scale circulations such as tornadoes, waterspouts, dust devils, etc. (which may in fact exhibit anticyclonic rotation), and even, very loosely, to any strong wind." "hurricanes rrr and typhoons are large and sometimes intensely violent storm systems. in meteorological terms, they are tropical cyclones that have maximum sustained r perkins stated that one exception is antarctica. perkins, sid ( - - winds of at least km/h ( mph). atlantic and eastern pacific storms are called hurricanes, from the west indian huracan ("big wind"), whereas western pacific storms are called typhoons, from the chinese taifun, "great wind." in addition to high winds, heavy rains characterize tropical cyclones. although the winds can cause serious damage, including broken building windows, the majority of damage is a result of flooding during and after the tropical cyclone. torrential rain, melting snow, a tsunami, or a hurricane may produce too much water for land, rivers, and flood control channels to handle and therefore results in serious flooding that will impact an entire area, including high-rise buildings. floods also can occur as a result of a public water main pipe break or a reservoir failing. subterranean parking garages located beneath high-rise buildings can become flooded with water. this can result in damage to vehicles and substantial damage to elevator systems because of water cascading into elevator shafts. building operations can be paralyzed for days as a result of the cleanup of impacted areas and repair of damaged equipment. also, a severe landslide could result in the collapse of a building. r a disease is "an abnormal condition of an organism that impairs bodily functions and can be deadly." an infectious disease-also called a contractible or a communicable diseaseis caused by pathogenic microbial agents. "transmission of an infectious disease may occur through one or more of diverse pathways including physical contact with infected individuals. these infecting agents may also be transmitted through liquids, food, body fluids, contaminated objects, airborne inhalation, or through vector-borne r spread." some diseases such as influenza, severe acute respiratory syndrome (sars), and tuberculosis are infectious and contractible. these diseases are an ever-increasing threat to the public as outbreaks result in public health emergencies. "influenza (the flu) is a contagious respiratory infection caused by influenza viruses. it can cause mild to severe illness, and at times can lead to death." "an influenza pandemic rr is an epidemic of an influenza virus that spreads on a worldwide scale and infects a large proportion of the human population." "influenza pandemics occur when a new strain of the influenza virus is transmitted to humans from another animal species. species that are thought to be important in the emergence of new human strains are pigs, chickens and ducks. these novel strains are unaffected by any immunity people may have to older strains of human influenza and can therefore spread extremely rapidly and infect very large numbers of people." three influenza viruses within the th century have produced major outbreaks: "pandemics become possible when the population has had no opportunity to build up immunity and no vaccine is available. in the case of the so-called bird flu or avian flu-the h n flu virus-there is no evidence at this point that the strain has mutated to be easily transmitted from human to human. most of the people who have died from r a vector-borne disease is "one in which the pathogenic microorganism is transmitted from an infected individual to another individual by an arthropod or other agent, sometimes with other animals serving as intermediary hosts" (changes in the incidence of vector-borne diseases attributable to climate change. www.ciesin.columbia.edu/tg/hh/veclev .html; november , ). h n in asia have had very close contact with birds carrying it. however, the cdc r claims that h n is a rapidly mutating virus, and if it were to begin passing from human to human, a pandemic could ensue." because of the extended period needed to develop a vaccine for an influenza pandemic the number of deaths can be extremely high. "severe acute respiratory syndrome (sars) is a respiratory disease in humans which is caused by the sars corona virus (sars-cov)." in november , sars originated in southern china and then spread to hong kong. visitors in a hong kong hotel were then infected and traveled to canada, singapore, taiwan, and vietnam. the disease then spread to those countries. between november and july , there were , known cases and deaths worldwide. "symptoms of sars can be similar to those of other viral infections. the first symptoms begin - days after exposure and may include the following: fever (temperature of more than . °f), headache, fatigue (tiredness), muscle aches and pain, malaise (a feeling of general discomfort), decreased appetite, and diarrhea. respiratory symptoms develop or more days after exposure. respiratory symptoms include the following: dry cough, shortness of breath, runny nose and sore throat (uncommon). by day - of the illness, almost all patients with laboratory evidence of sars infection had pneumonia that could be detected on x-ray films." diagnosis can be through a combination of observation, blood tests, and chest x-rays. tuberculosis, or "consumption" as it was previously known, is an infectious disease that causes lumplike lesions to form in the lungs. inside the lesions there are degenerating macrophages and tuberculosis bacteria, which when ruptured can infect the lung and the entire body. "tuberculosis usually attacks the lungs (as pulmonary tb) but can also affect the central nervous system, the lymphatic system, the circulatory system, the genitourinary system, the gastrointestinal system, bones, joints, and even the skin…. the typical symptoms of tuberculosis are a chronic cough with blood-tinged sputum, fever, night sweats and weight loss…. tuberculosis is spread through the air, when people who have the disease sneeze, cough, or spit." some people infected with tuberculosis may not be aware of it because they do not feel any symptoms or experience any discomfort. this is called latent r the cdc is the u.s. department of health and human services' centers for disease control. lang rf. pandemic flu issues and your response. security technology & design. january : . tb disease. "transmission [of tb] can only occur from people with active-not latent-tb." "treatment for tb uses antibiotics to kill the bacteria." "a rising number of people in the developed world are contracting tuberculosis because their immune systems are compromised by immunosuppressive drugs, substance abuse, or aids." the problem with contractible diseases such as pandemic influenza, severe acute respiratory syndrome (sars), and tuberculosis is that any building user, including visitors, could be infected, and before symptoms develop they could infect many other building occupants with the disease. failure of electrical power to a building has a serious impact on its operations, including computer memory loss and equipment damage, particularly if the failure occurs when the building is fully occupied. a power failure may be a brownout (a partial reduction in service) or a total blackout. power failure can be caused by man-made or natural events. man-made causes may include vehicle drivers who collide with utility poles or power transformers, human error in operating equipment within the building or outside of it (such as at the utility company supplying the power), or malicious tampering. natural events include storms, floods, and earthquakes. because of the large numbers of tenants and visitors using high-rise buildings, slip-and-falls (whether a trip only, a slip only, a fall only, a trip-and-fall, a slip-and-fall, or a slip-tripand-fall) do occur. it is most important that these incidents are properly handled according to established procedures, particularly as these types of events frequently lead to claims for compensation from the building owner, and they sometimes lead to litigation. stalking although the legal definition of stalking varies from country to country and from state to state, a general definition is a pattern of repeated, unwanted attention, harassment, and contact. it is a course of conduct that can include the following: "stalking is a distinctive form of criminal activity composed of a series of actions that taken individually might constitute legal behavior. for example, sending flowers, writing love notes, and waiting for someone outside her place of work are actions that, on their own, are not criminal. when these actions are coupled with intent to instill fear or injury, however, they may constitute a pattern of behavior that is illegal. though antistalking laws are gender neutral, most stalkers are men and most victims are women." a study of the incidence of stalking behaviors conducted among , men and women in the australian state of victoria revealed the following: the majority of those reporting stalking were female ( %). some % were aged between - when the behaviour commenced, though all age groups were vulnerable to pursuit. perpetrators of stalking behaviours were overwhelmingly male ( %). in % of cases stalking victims were pursued by a person of the same gender, with males significantly more likely to experience such harassment than females ( % versus %). the majority of those reporting stalking were pursued by someone previously known to them ( %)…. in % the perpetrator was a stranger to the victim, or someone whose identity, though suspected, was yet to be revealed. since the instigation and passage of antistalking legislation in the us, stalking has generated in most english-speaking nations a growing discourse in legal, scientific and popular domains. this study confirms that such attention and concern is not misplaced. workplace violence is "any physical assault, threatening behavior, or verbal abuse occurring in the work setting. a workplace may be any location either permanent or temporary where an employee performs any work-related duty. this includes, but is not limited to, the buildings, and surrounding perimeters, including the parking lots, field locations, clients' homes and traveling to and from work assignments." it is "any incident in which a person is abused, threatened or assaulted in circumstances relating to their work. this can include verbal abuse or threats as well as physical attacks." howard developed categories for describing workplace violence by defining the relationship between the victim and the perpetrator. table - interprets these findings. the following statements indicate that workplace violence is affecting workers in many parts of the world: richardson and windau, about three-quarters of workplace homicides result from injuries inflicted with guns. the seriousness of homicide has made it the focus of the concern about workplace violence. the rate of workplace homicide has declined gradually since the s and fell somewhat more rapidly than the rate for all homicides in the s. the building occupancies discussed in this book-office, hotel, residential and apartment, and mixed-use buildings-could be the setting for someone to commit workplace violence. for office buildings, hotels, and residential buildings, the workplace violence may be as simple as the verbal abuse that security staffs, particularly security officers, doormen, and concierge/receptionists sometimes receive. although it is difficult to make generalizations about the types of perpetrators of workplace violence, the following observations have been made about them: frustrated employees, who in many instances are simply shuffled between jobs requiring only menial tasks with very little advancement opportunity open to them. professionals who are experiencing personal frustration and cannot handle emotional deflations such as workforce cutbacks or layoffs. individuals who are simply bitter, dissatisfied people and are unable to "shake" their negativity toward everything. people unable to accept personal blame for their own problems. individuals with uncontrollable pent-up rage who operate on a "short fuse" when it comes to getting upset or mad over anything. persons who have little or no support systems such as family, friends, neighbors, and who are unable to vent their rage by either confiding in someone or having some other avenue of relief in which they can "blow off steam." people who are prone to use firearms and have access to weaponry of any kind. in dealing with employees, the ideal solution would be for employers to screen out, during the initial hiring process, those applicants who have an inclination for violence. this could include inquiring about an applicant's prior criminal convictions and conducting a thorough background check with previous employers. despite some ethical questions and a degree of uncertainty about their predictive powers, psychological tests are also used to screen prospective employees-and still it is difficult to recognize potentially problematic employees. the following are indicators of potential workplace violence: sound personnel practices, such as preemployment screening and meaningful job performance evaluations, may help identify and screen out potential problem employees. employers may take the following preventive measures, some of which have been adapted from the cal/osha guidelines for workplace security, to address the workplace violence problem: according to the asis international foundation research council crisp report by dana loomis, "enforcing a no-weapons policy for employees as allowed by law is a fundamental component of establishing effective countermeasures. weapons policies should be written, made known to all employees, and consistently enforced." this report also cautions that "not enough rigorous research has been conducted to gauge the effectiveness of mandatory or voluntary measures for preventing workplace violence. to date, most research has focused on the use of crime prevention through environmental design (cpted r ) concepts used to prevent robbery-related, or type i [see table - ], violence, in retail businesses. , " a number of preventive measures can be accomplished without great expense to the employer. for example, if workforce reductions are anticipated, they should be thoroughly planned with dignity and respect afforded to the affected employees. workers who will be laid off need as much advance notice as possible. giving severance benefits and offering placement counseling and assistance will help outgoing employees cope with their situation r "the cpted [pronounced sep-ted] concept, coined by dr. c. ray jeffery in his book by the same title, expands upon the assumption that the proper design and effective use of the built environment can lead to a reduction in the fear of crime and the incidence of crime, and to an improvement in the quality of life" (crowe td. crime prevention through environmental design. nd ed. woburn, ma: butterworth-heinemann; : ). and nurture a supportive work environment for the remaining employees. it has the added potential of lowering insurance premiums, because it may avoid triggering an incident of violence in the workplace and the expensive litigation that can result. motor vehicles such as cars, buses, vans, and trucks commonly enter the parking areas of high-rise buildings. as on public thoroughfares, traffic accidents sometimes occur. although the incident may have occurred on private property, depending on its seriousness, immediate medical aid or public law enforcement assistance may need to be summoned. a water leak in a high-rise building-particularly those on upper floors of a high-risecan result in considerable damage to the structure and its contents. water may drain down through multiple floors via stairwells, elevator shafts, and poke-throughs. this can lead to water in concealed ceiling spaces, soaked acoustical ceiling tiles that may fall from their own weight, water-soaked walls, and malfunction and possible failure of electrical systems if water comes in contact with them. leaks may be caused by a broken water pipe, a severed fire system sprinkler head, seepage through subterranean walls, overflow of a toilet receptacle, a backed-up sewer line, a blocked drain, failure of a sump pump, or a malfunctioning fountain. someone deliberately leaving a water tap running in an area such as a public restroom may also cause a leak. there are many potential security and fire life safety threats to the people who use high-rise buildings and to the assets contained within them. l sometimes threats can become events that quickly develop into emergencies. these include aircraft collisions; bombs and bomb threats; daredevils, protestors, and suicides; elevator and escalator incidents; fires and fire alarms; hazardous materials, chemical and biological weapons, and nuclear attack; kidnappings and hostage situations; labor disputes, demonstrations, and civil disorder; medical emergencies; natural disasters; contractible diseases; power failures; slip-and-falls; stalking and workplace violence; traffic accidents; and water leaks. present; or (c) creates a hazardous or physically offensive condition." depending on the nature of the offense can be considered a threat to people or property. earthquake. "a term used to describe both sudden slip on a fault, and the resulting ground shaking and radiated seismic energy caused by the slip, or by volcanic or magmatic activity, or other sudden stress changes in the earth." emergency. "an event, actual or imminent, which endangers or threatens to endanger life, property or the environment, and which requires a significant and coordinated response." espionage. "the crime of 'gathering, transmitting or losing' information respecting the national defense with intent or reason to believe that the information is to be used to the injury of the [country], or to the advantage of any foreign nation." this could also be perpetrated by a business competitor engaging in industrial espionage. explosives. "devices designed to explode or expand with force and noise through rapid chemical change or decomposition." also known as bombs. fire alarm. "a signal initiated by a fire alarm-initiating device such as a manual fire alarm box, automatic fire detector, waterflow switch, or other device in which activation is indicative of the presence of a fire or fire signature." fire stop. "material or member that seals open construction to inhibit spread of fire." floor plan. "architectural drawings showing the floor layout of a building and including precise room sizes and their relationships. the arrangement of the rooms on a single floor of a building, including walls, windows, and doors." heat wave. "a period of abnormally and uncomfortably hot and usually humid weather. to be a heat wave such a period should last at least one day, but conventionally it lasts from several days to several weeks." hoistway. "the structural component in which the elevators move in a building." hostage. " an innocent person held captive by one who threatens to kill or harm him if his demands are not met." murder. "the unlawful killing of a human being by another with malice aforethought, either express or implied." panic. "a sudden terror often inspired by a trifling cause or a misapprehension of danger and accompanied by unreasoning or frantic efforts to secure safety." partial or zoned evacuation. this strategy "provides for immediate, general evacuation of the areas of the building nearest the fire incident. a partial evacuation may be appropriate when the building fire protection features assure that occupants away from the evacuation zone will be protected from the effects of the fire for a reasonable time. however, evacuation of additional zones may be necessary." sometimes known as staged evacuation. performance-based codes. "detail the goals and objectives to be met and establish criteria for determining if the objective has been reached.… thus, the designer and builder gain added freedoms to select construction methods and materials that may be viewed as nontraditional as long as it can be shown that the performance criteria can be met." performance-based design. "applies a procedure to predict and estimate damage or behavior anticipated of a structure's design to design events, compared against preselected objectives. the design is revised until the predictive methodology indicates that acceptable performance can be obtained." physical security. "that part of security concerned with physical measures designed to safeguard people, to prevent unauthorized access to equipment, facilities, material and documents, and to safeguard them against espionage, sabotage, damage, theft and loss." poke-throughs. holes cut through floors to allow the passage of conduits or ducts, primarily for the passage of electrical wiring, plumbing, heating, air-conditioning, communications wiring, or other utilities. problems arise when the space between the conduit or the duct and the surrounding floor is not completely sealed with fire-resistant material, thereby negating the fire-resistance rating of the floor and potentially providing a passageway for deadly fire gases. prescriptive-based codes. "spell out in detail what materials can be used, the building geometry (heights and areas), and how the various components should be assembled." also known as specification-based codes. prescriptive design approach. "includes extensive detailed criteria for the design of systems that have been developed over many years of experience." of a building, place of assembly, or facility of public transportation, or otherwise to cause serious public inconvenience, or in reckless disregard of the risk of causing such terror or inconvenience." theft. "a popular name for larceny. the act of stealing. the taking of property without the owner's consent.… it is also said that theft is a wider term than larceny and that it includes swindling and embezzlement and that generally, one who obtains possession of property by lawful means and thereafter appropriates the property to the taker's own use is guilty of a 'theft.'" larceny-theft includes offenses such as shoplifting, pickpocketing, auto theft, and other types of stealing where no violence occurs. see also larceny. threat. "any indication, circumstance, or event with the potential to cause loss of, or damage to an asset." tornado. "a violently rotating column of air, in contact with the ground, either pendant from a cumuliform cloud or underneath a cumuliform cloud, and often (but not always) visible as a funnel cloud." trespass. "any unauthorized intrusion or invasion of private premises or land of another…. criminal trespass is entering or remaining upon or in any land, structure, vehicle, aircraft or watercraft by one who knows he [or she] is not authorized or privileged to do so." this includes remaining on property after permission to do so has been revoked. tropical cyclone. "general term for a cyclone that originates over the tropical oceans. this term encompasses tropical depressions, tropical stroms, hurricanes, and typhoons." see also cyclone. tsunami. "a large wave caused by earthquakes, submarine landslides, and, infrequently, by eruptions of island volcanoes. during a major earthquake, an enormous amount of water can be set in motion as the seafloor moves up and down. the result is a series of potentially destructive waves that can move at more than miles [ kilometers] per hour." tuberculosis. a contagious disease that "usually attacks the lungs (as pulmonary tb) but can also affect the central nervous system, the lymphatic system, the circulatory system, the genitourinary system, the gastrointestinal system, bones, joints, and even the skin." typhoon. "hurricanes and typhoons are large and sometimes intensely violent storm systems. in meteorological terms, they are tropical cyclones that have maximum sustained institute of real estate management term "radiological dispersal device (rdd)" stated in the four faces of nuclear terrorism references cited: cameron c. the great kanto earthquake and fire kanamori h. importance of historical seismograms for geophysical research some remarks on historical seismograms and the microfilming project update and english translation of noviy katalog sil'nykh zemletryaseniy na territoriy sssr s drevneyshikh vremyen do g contribution to the seismotectonics of iran (part ii), geological survey of iran catalogue of strong italian earthquakes from b.c. to , istituto nazionale di geofisica, rome and storia geofisica ambiente catalog of significant earthquakes, b.c- a.d. including quantitative casualties and damage, noaa national geophysical data center kanamori h. importance of historical seismograms for geophysical research some remarks on historical seismograms and the microfilming project lobash m. hertz group: coming to grips with storm's devastation cruden ( ) as quoted in samah fa. paper : landslides in the hillside development in the hulu kland, klang valley; . http:// eprints.utm.my/ / /landslides_in_the_hillside_development___in_the_hulu_klang,_ klang_valley.pdf -story apartment building, located below po shan road, in the hong kong island mid-levels district, was destroyed by a hillside collapse and resultant landslide, following heavy rains, causing deaths (www.csb.gov.hk/hkgcsb/doclib/showcasing_ced_e.pdf as reported on edward cy yiu's (assistant professor department. of real estate and construction -story apartment building, highland towers, selangor, malaysia, collapsed due to a landslide after days of continuous rainfall, resulting in deaths (wikipedia infectious disease. mcgraw-hill encyclopedia of science and technology. the mcgraw-hill companies, inc.; , as referenced in disease rr according to the world health organization, "a pandemic can start when three conditions have been met: ( ) a new disease emerges among the population; ( ) the agent infects humans, causing serious illness, and ( might be) pandemic flu issues and your response. security technology & design caister academic press; as referenced in wikipedia. severe acute respiratory syndrome it's time to plan. security management summary of probable sars cases with onset of illness from november severe acute respiratory syndrome (sars): sars symptoms. emedicinehealth. www. emedicinehealth.com/severe_acute_respiratory_syndrome_sars/page _em.htm essentials of anatomy & physiology. new york: mcgraw hill workplace violence prevention united kingdom, health and safety executive. www.hse.gov.uk/violence/ as stated in preventing gun violence in the workplace by dana loomis [crisp report connecting research in security to practice an international expert on stress and workplace violence, and duncan chappell, past president of the new south wales mental health review, australia, and the commonwealth arbitral tribunal census of fatal occupational injuries (cfoi): current and revised data trends in workplace homicides in the u.s., - : a decade of decline diversity of trends in occupational injury mortality in the united states census of fatal occupational injuries (cfoi)-current and revised data fatal and nonfatal assaults in the workplace trends in workplace homicides in the preventing gun violence in the workplace (crisp report connecting research in security to practice effectiveness of crime prevention through environmental design (cpted) in reducing robberies preventing workplace violence through environmental and administrative controls asis online glossary of terms fema : reference manual to mitigate potential terrorist attacks against buildings. fema risk management series : ). the original definition was u.s. centric and has been modified to be applicable to any threatened country publisher's editorial staff. black's law dictionary publisher's editorial staff. black's law dictionary www.asisonline.org/library/glossary/index.xml; asis international emergency management australia canberra, as quoted in the srm lexicon, srmbok security risk management body of knowledge, julian talbot and dr. miles jakeman (risk management institution of australasia limited edition (from webster's college dictionary by random house, inc. copyright , , by random house, inc. reprinted by permission of random house publisher's editorial staff. black's law dictionary nfpa glossary of terms. national fire code. quincy, ma: national fire protection association national association of realtors the construction info exchange. www.constructioninfoexchange.com/constructiondictionary.aspx ?dictionarysearchkeyf emergency evacuation elevator systems guideline. council on tall buildings and urban habitat department of the interior publisher's editorial staff. black's law dictionary hurricanes and typhoons are large and sometimes intensely violent storm systems. in meteorological terms, they are tropical cyclones that have maximum sustained winds of at least km/h ( mph) a device placed or fabricated in an improvised manner incorporating destructive, lethal, noxious, pyrotechnic, or incendiary chemicals and designed to destroy, incapacitate, harass, or distract the forcible abduction or stealing and carrying away of a person…. a person is guilty of kidnapping if he unlawfully removes another from his place of residence or business … or if he unlawfully confines another for a substantial period in a place of isolation the unlawful taking and carrying away of property of another with intent to appropriate it to use inconsistent with the latter's rights the unjustifiable, inexcusable, and intentional killing of a human being without deliberation, premeditation and malice a type of injury which permanently render[s] the victim less able to fight offensively or defensively; it might be accomplished either by the removal of (dismemberment), or by the disablement of, some bodily member useful in fighting. today, by statute, permanent disfigurement has been added people with physical disabilities rely on a variety of artificial means for mobility. such devices range from canes and walkers to motorized wheelchairs fire administration. www.usfa.fema.gov edition (from webster's college dictionary by random house, inc. copyright , , by random house, inc. reprinted by permission of random house definition from dod, nato as stated on answers.com website. . www.answers.com/topic/ improvised-explosive-device publisher's editorial staff. black's law dictionary hurricane and typhoon. grolier online. www.scholastic.com/browse/article.jsp?id  publisher's editorial staff. black's law dictionary webster's third new international dictionary strategies for occupant evacuation during emergencies. fire protection handbook building and fire codes and standards ma: national fire protection association fundamentals of structurally safe building design ma: national fire protection association asis online glossary of terms. www.asisonline.org/library/glossary/index.xml brannigan's building construction for the fire service building and fire codes and standards. fire protection handbook national fire protection association the spread of local damage, from an initiating event, from element to element, eventually resulting in the collapse of an entire structure or a disproportionately large part of it a form of civil disorder characterized by disorganized groups lashing out in a sudden and intense rash of violence, vandalism, or other crime. while individuals may attempt to lead or control a riot, riots are typically chaotic and exhibit herd behavior riots typically involve vandalism and the destruction of private and public property felonious taking of money, personal property, or any other article of value, in the possession of another, from his [or her] person or immediate presence, and against his wil[l]ful and malicious destruction of employer's property during a labor dispute or interference with his normal operations a respiratory disease in human which is caused by the sars corona virus (sars-cov) a type of employment discrimination, includes sexual advances, requests for sexual favors, and other verbal or physical conduct of a sexual nature prohibited by … law consist of beams and columns joined by a combination of welding and bolting terrorism is considered an unlawful act of force and violence against persons or property to intimidate or coerce a government, the civilian population, or any segment thereof, in furtherance of political or social objectives a person is guilty of a terroristic threat "if he [or she] threatens to commit any crime of violence with purpose to terrorize another or to cause evacuation what is stalking? the national center for victims of crime. www.ncvc.org/ncvc/main.aspx?dbname documentviewer&documentid  fema : risk assessment: a how-to guide to mitigate potential terrorist attacks against buildings asce - (nist ncstar a federal building and fire safety investigation of the world trade center disaster. final report on the collapse of world trade center building publisher's editorial staff. black's law dictionary publisher's editorial staff. black's law dictionary publisher's editorial staff. black's law dictionary publisher's editorial staff. black's law dictionary fema : risk assessment: a how-to guide to mitigate potential terrorist attacks against buildings publisher's editorial staff. black's law dictionary glossary of meteorology big wind'), whereas western pacific storms are called typhoons, from the chinese taifun a military term for a car bomb or truck bomb. these are typically employed by suicide bombers, and can carry a relatively large payload. they can also be detonated from a remote location. vbieds can create additional shrapnel through the destruction of the vehicle itself, as well as using vehicle fuel as an incendiary weapon a geological formation, usually a conical mountain, that forms when molten rock, called magma, flows up from the interior of the earth to the surface. magma finds its way upwards along fissures or cracks in the planet's crust and bursts out onto the surface, resulting in a volcano any physical assault, threatening behavior, or verbal abuse occurring in the work setting. a workplace may be any location either permanent or temporary where an employee performs any work-related duty. this includes, but is not limited to, the buildings, and surrounding perimeters, including the parking lots, field locations, clients' homes and traveling to and from work assignments norton information resources center building performance study: data collection, preliminary observations, and recommendations, federal emergency management agency lessons learned from the oklahoma city bombing defensive design nist ncstar : federal building and fire safety investigation of the world trade center disaster: final report on the collapse of the world trade center towers structural fire fighting. quincy, ma: national fire protection association publisher's editorial staff. black's law dictionary workplace violence prevention hurricane and typhoon. grolier online. www .scholastic.com/browse/article.jsp?id  all hazardous materials should be identified, their characteristics documented, and instructions provided for their safe handling. r the presence of hazardous materials in a building can cause serious problems, particularly when an explosion occurs. the following example illustrates this point.april , , new york, new york-a late-morning explosion caused by volatile chemicals severely damaged the façade, hailing sheets of glass and debris onto the street, of a -story manhattan commercial building. the blast that originated in the basement was possibly linked to shipments of -gallon drums of acetone used by a sign company. "the explosion, which rocked the busy commercial neighborhood, triggered mass evacuations of surrounding buildings and caused widespread alarm in the area, witnesses said." as unlikely as a nuclear attack may be, the events of september , , have brought the widespread realization that certain individuals in this world will stop at nothing to achieve their objectives. therefore, a nuclear attack needs to be addressed as a possible threat to high-rise buildings situated in major urban centers. assault. "any willful attempt or threat to inflict injury upon the person of another, when coupled with an apparent present ability so to do, and any intentional display of force such as would give the victim reason to fear or expect immediate bodily harm, constitutes an assault. an assault may be committed without actually touching, or striking, or doing bodily harm, to the person of another." assault and battery. "any unlawful touching of another which is without justification or excuse." asset. "any real or personal property, tangible or intangible, that a company or individual owns, that can be given or assigned a monetary value. intangible property includes things such as goodwill, proprietary information, and related property." "a resource of value requiring protection. an asset can be tangible (e.g., people, buildings, facilities, equipment, activities, operations, and information) or intangible (e.g., processes or a company's information and reputation is licensed or privileged to enter." chicane. "a sequence of tight serpentine curves (usually an s-shape curve …) in a roadway, used in motor racing and on city streets to slow cars. on modern raceways, chicanes are usually located after long straightaways, making them a prime location for overtaking." civil disorder. "any public disturbance involving acts of violence by assemblages of three or more persons, which causes an immediate danger of or results in damage or injury to the property or person of any other individual." sometimes known as a civil disturbance. crime. "an act or omission which is in violation of a law forbidding or commanding it for which the possible penalties for an adult upon conviction include incarceration, for which a corporation can be penalized by a fine or forfeit, or for which a juvenile can be adjudged delinquent or transferred to criminal court for prosecution. the basic legal definition of crime is all punishable acts, whatever the nature of the penalty." ibid., p. . ibid., p. . crime prevention through environmental design (cpted-pronounced sep-ted) . "the cpted concept, coined by dr. c. ray jeffery in his book by the same title, expands upon the assumption that the proper design and effective use of the built environment can lead to a reduction in the fear of crime and the incidence of crime, and to an improvement in the quality of life." cyberattack. "an assault against a computer system or network." cyberterrorism. "the convergence of terrorism and cyberspace. it is generally understood to mean unlawful attacks and threats of attack against computers, networks, and the information stored therein when done to intimidate or coerce a government or its people to further political or social objectives. moreover, to qualify as cyberterrorism, an attack should result in violence against persons or property, or at least cause enough harm to generate fear. attacks that lead to death or bodily injury, explosions, plane crashes, water and food contamination, or severe economic loss are examples. serious attacks against critical infrastructures can be acts of cyberterrorism depending on their impact. attacks that disrupt nonessential services or that are mainly a costly nuisance are not." cyclone. "an atmospheric cyclonic circulation, a closed circulation. a cyclone's direction of rotation (counterclockwise in the northern hemisphere) is opposite to that of an anticyclone. while modern meteorology restricts the use of the term cyclone to the so-called cyclonic-scale circulations, it is popularly still applied to the more or less violent, small-scale circulations such as tornadoes, waterspouts, dust devils, etc.(which may in fact exhibit anticyclonic rotation), and even, very loosely, to any strong wind." demonstration. a gathering of people for the purposes of publicly displaying their attitude toward a particular cause, issue, or other matter. dirty bomb. a radiological dispersal device (rdd) that uses conventional explosives to spread radioactive material. disaster. "a serious disruption of the functioning of a community or a society causing widespread human, material, economic or environmental losses which exceed the ability of the affected community or society to cope using its own resources." disorderly conduct. "if, with purpose to cause public inconvenience, annoyance or alarm, or recklessly creating a risk thereof, he (a) engages in fighting or threatening, or in violent or tumultuous behavior; or (b) makes unreasonable noise or offensively coarse utterance, gesture or display, or addresses abusive language to any person key: cord- -ncia h m authors: luker, gary d.; boettcher, adeline n. title: transitioning to a new normal after covid- : preparing to get back on track for cancer imaging date: - - journal: radiol imaging cancer doi: . /rycan. sha: doc_id: cord_uid: ncia h m nan i n p r e s s needed to ensure the safety of their patients, and thus many imaging practices went on a temporary shutdown or scale-down as the pandemic continued to emerge within the united states. the current responses now reflect the rapid changes that were implemented in radiology clinics during the severe acute respiratory syndrome pandemic ( ) . as of this writing, , people have been diagnosed with covid- in the united states alone ( ) with an expected peak of cases being projected for mid-april to may ( ) . given the lack of widespread testing, this number almost certainly underestimates the extent of infection with sars-cov- . to reduce the burden on any single hospital facility, many cities in the united states are assembling temporary hospitals and care facilities or deploying hospital ships to care for covid- and non-covid- patients. officials in selected states, like illinois and california, have recruited retired doctors and nurses to come back to clinical service to help with the covid- response. in addition, medical schools are moving up graduation for fourth-year students and credentialing early as medical doctors. the covid- pandemic presents institutions and radiologists with two formidable challenges: ) trying to maintain clinical and research operations in the face of social distancing and stay-at-home-orders; and ) plotting a course to transition from the immediate threat of the sars-cov- virus to an uncertain future that certainly will not resemble conditions we previously regarded as normal. while recognizing that covid- has disrupted essentially all aspects of life, this commentary focuses on the immediate and projected future impact on clinical care and research in cancer imaging and image-guided therapy. we asked leaders in cancer imaging from a variety of institutions to respond to a series of questions about temporary shutdowns and resultant impact on clinical imaging and research in cancer moving forward. we summarized i n p r e s s responses to each question listed as subheadings in this commentary. responses come from a variety of clinics and universities from the united states, as well as from the united kingdom and china. our intent is to inform the cancer imaging community of ongoing practices and policies implemented in response to covid- rather than presenting a rigorous scientific analysis. what processes were used by institutions to determine which cancer imaging or image-guided therapy studies would need to be canceled? as the outbreak of covid- emerged in the united states, there were two main priorities that clinics had with regard to decision-making on cancer imaging appointments: keeping people healthy and preserving personal protective equipment resources. practicing social distancing and preserving personal protective equipment during an imaging appointment would be difficult, forcing institutions to prioritize appointments. many institutions categorized appointments into three general groups: nonurgent, semi-urgent, and urgent. imaging appointments that fell under the nonurgent category were general elective screening appointments (mostly lung and breast screenings) and those in which the outcome would not change a specific therapy or treatment plan. in many cases, nonurgent imaging appointments were planned to be rescheduled in the time period of may-june depending on geographic location (while adjusting for ongoing changes of the outbreak). triage procedures for prioritizing appointments also caused postponement of non-urgent treatments, including interventional radiology procedures and radionuclide therapy. semi-urgent cases were assessed on a case-by-case basis. appointments that were deemed urgent were scheduled as planned in many cases. urgent appointments were those in which patients were planning to come in for follow-up imaging for previous high-risk cancers (lung-i n p r e s s to see all symptomatic cancer patients and honored appointments if patients came. tumor boards at some clinics still held meetings over web-based platforms. clinics have been conscious of the language used to describe the postponement of appointments, and some have not used the word "canceled" but rather emphasized to patients that imaging appointments were "delayed" and planned to be "rescheduled". some institutions have provided two to three different alternative dates for appointments, with flexibility to changing stay-at-home orders. some patients have requested to keep imaging appointments due to concerns of losing their job or health insurance during the course of the outbreak. as of this writing, the projected peak of cases in the united states is mid-april to may ( ) . "bending of the curve" in many states will extend this curve into the months of may and june, with a reduced rate of new covid- cases. institutions are monitoring the progression of infection in their respective states. current estimates from different u.s. institutions suggest that appointments could start to be tentatively rescheduled sometime starting may to june , . social distancing, lay-offs, and a reduced number of patients with health insurance may result in prolonged amount of time to get back to normalcy with some physicians estimating that this process could take - months. while some facilities may be closed, telehealth appointments are being made for surgery consultations during this time. telehealth appointments offer a means to encourage patients to reengage in cancer imaging studies, although patients clearly will need to come to a central or mobile facility for actual imaging studies. in china, hospitals are requiring a chest ct scan and a nucleic acid test for patients who are hospitalized to exclude i n p r e s s covid- . as of early april , some hospitals in china have already resumed normal cancer screening appointments. similar testing practices may need to be taken as the pandemic progresses in other areas of the world. do institutions think there will be a "surge"? how will institutions manage a "surge" in cancer imaging patients after the shutdown ends?' some institutions expect that there will be a high demand for scheduling appointments once stay-at-home orders are relaxed. personnel are beginning to make plans for re-opening after the shutdown is over. to help adjust for a surge of patients, institutions are planning extended operating hours to appointments on evening and weekends. in some cases, imaging protocols may be shortened to help increase throughput of patients. even with proposed modifications to availability of scanners and examination time, most institutions already operate imaging equipment at near capacity with appointment slots during evenings and weekends. trying to reschedule several months of imaging appointments likely will result in prolonged (weeks to months) wait times, which may deter many patients. one important factor that will need to be considered as the stay-at-home orders are relaxed is the high likelihood that social distancing practices will remain in force until mid- ( ) . social distancing practices will need to be implemented as patients come in for their appointments to protect both patients and clinical personnel. throughput of patients likely will be delayed due to continued enforcement of more extensive cleaning procedures for imaging rooms and equipment. to what extent could this break in screening and cancer imaging impact future imaging studies to patients? there were a variety of opinions on this topic that mainly fell within two general categories: patient mentality and availability of health insurance. it may be likely that patient mentality about screenings will not change, and patients will continue to come in for screenings once clinics open back up again. due to the potentially extended time period of the outbreak, some patients may opt out of screening for this year but return for next year's screening examination. reminder emails may need to be sent out to help patients get back on track for their imaging. another factor that will need to be considered is potential fear of going back out into public places after the initial outbreak spike is over (predicted to be june ); some models suggest that this pandemic will last - months ( ) . patients undergoing chemotherapy are at an increased risk of severe covid- infection, and it is likely that these individuals will not opt to immediately go back out into society when the initial outbreak has ended. there are concerns that patients in remission may decide not to schedule appointments for follow-up imaging. in this regard, it will be important that clinics emphasize that they will take every precaution necessary to keep these patients safe and protected during their appointments. facilities are considering dedicated entrances and traffic patterns for immunocompromised patients, including patients undergoing chemotherapy, who return to hospitals and treatment centers for clinic appointments and imaging studies. instances of patients missing appointments, not seeking medical treatment, and becoming worse due to fear of covid- have been reported in china. one of the dramatic effects that we have witnessed in the united states during the month of march was the rapid increase in unemployment. within the second half of march, there were as many as . million unemployment claims that had already been submitted throughout the i n p r e s s united states ( ). as of this writing (april , ), unemployment claims exceeded million. this number is likely to rise even more as stay-at-home orders are being extended to the end of april and even until the beginning of june in some areas. since most persons in the united states receive health insurance coverage through work, unemployed individuals and their families may not have sufficient resources to pay out-of-pocket costs for nonurgent or even semi-urgent imaging studies. these financial obstacles will make it difficult for patients to come in for their normal screening or other imaging appointments. similar to the implementation of postponement of imaging appointments, most research restrictions occurred between march - , in the united states. these closures undoubtedly led to the loss of valuable data because "ramping down" typically occurred over the course of a few days. research labs were instructed to only continue research if terminating the project would harm the project, be prohibitively costly, or time consuming. any noncritical research activities were shut down. labs that were in these situations were told to designate one to two key personnel to work on these projects, while larger projects were permitted three to four people. additionally, as there are many labs that use animal models for research, key personnel were assigned for the care of these animals for the duration of the outbreak. labs were asked to reduce or terminate breeding of any new animals during the shutdown and not start any new experiments with animals. many investigators euthanized mice to minimize costs of housing animals during a shutdown, and some institutions required researchers to prioritize only a small subset of mice to save in case of severe shortages of veterinary personnel. one exception to this rule was to continue any ongoing research directly related to covid- or other essential human subject research. projects related to covid- had to be submitted to the institutional review boards for prioritization so that these projects could be initiated in an expedited manner. institutions differed in policies for continuing cancer therapy trials that rely on imaging studies to monitor response to treatment. at some institutions, almost all imaging studies for cancer trials continued with minimal interruptions. conversely, other facilities suspended all but essential human subject research studies in which the absence of imaging would impact the health of a patient with a clinically significant standard of care component (such as keeping a patient on a drug). researchers and investigators are taking advantage of the stay-at-home orders to finish writing manuscripts and grant proposals. some individuals have remote virtual private network access into their systems, so some may even be able to start retrospective studies during this time. additionally, students are also being encouraged to take new courses and write manuscripts. it may be possible that there will be many retrospective studies that are submitted and published once the lock down is over. to accommodate demands of a remote workforce, institutions have been forced to rapidly expand hardware and support for information technology. from an administrative point of view, it will be necessary for programs to make sure that appropriate extensions are permitted for students and faculty. for example, faculty working on acquiring tenure may need an extension due to lost time to generate new data. universities and i n p r e s s institutions will need to assess the availability of contingency funding to help labs get back on track once the shutdown is over. additionally, many phd or medical school interviews, as well as school selections may have been disrupted during this time period, and schools should be flexible with decisions that are being made by these prospective students. there are multiple concerns about the future of cancer imaging research. prospective, longitudinal studies that were ongoing during this period of time may have lost valuable datapoints. however, depending on the cancer growth rate, imaging of slow-growing tumors potentially will not change much in data analysis. it may take some time for researchers to collect additional data for prospective studies to make up for lost time. the forced hiatus in imaging studies may provide some insight on to what extent delayed imaging directly impacts clinical care and potentially allow opportunities for optimizing the timing of imaging in the future. as institutional review boards may be prioritizing covid- related projects, there may be a delay in new cancer imaging studies that can be approved and initiated. institutional review boards also will need to implement policies for protocol deviations caused by research shutdowns. even after institutions reverse shutdowns or ramp downs of research, we anticipate that social distancing policies will remain in place for several months to prevent a second wave of infections. maintaining social distancing poses great challenges to studies involving clinical research, which typically relies heavily on interpersonal interactions among researchers, technicians, and patients. imaging research involving wet-lab and animal experiments also will face ongoing challenges. laboratory work areas and small animal imaging suites typically do not have sufficient space to prevent close interactions among people, and multiple users commonly i n p r e s s share lab instruments and imaging scanners. laboratories may be required to enact staggered work schedules to allow persons access while avoiding interactions. there is some uncertainty of where priorities will lie during the next round of funding for some agencies. it is probable that priorities will shift to research on infectious diseases, virology, immunology, and general pandemic responses, similar to requests for proposals related to bioterrorism research after the / attacks in the united states. substantial concerns exist about a reduction in basic and clinical research funding and activity due to the economic crisis caused by covid- . for example, the cancer prevention and research institute of texas (cprit) will delay funding for grants in and suspended the first cycle of funding in due to budget constraints. internal funding at universities and clinics may be required to help maintain research activities in cancer imaging and other fields. however, institutions have incurred unexpected expenditures and losses of revenue during the pandemic, which will limit internal funds to support research in cancer imaging and other areas. economic effects of covid- also have and will continue to impact faculty and research positions at institutions. many universities enacted hiring freezes and canceled searches for new faculty positions during the current period of social distancing. at least one institution imposed hiring freezes for all new faculty and staff through the next months with exceptions requiring approval at the highest levels of administration. such policies remove opportunities for junior faculty wanting to begin careers in cancer imaging research. moreover, salary support for many researchers at all levels, from faculty to trainees, comes predominantly if not exclusively from grants. inevitable losses of productivity during periods of shutdown or slow down, delays i n p r e s s associated with ramping research back up, and a more challenging economic climate place jobs and careers of many cancer imaging scientists at tremendous risk. disruptions in life caused by covid- clearly have extended to cancer imaging for patients and research. within the next few months, clinics will need to continue to act aggressively in their responses, deliberate unique ways to address the potentially ongoing spread of covid- , and compensate for lost imaging appointments during this time. after weeks or months of persons hearing messages to stay at home and remain away from people, convincing persons to enter a hospital environment will require concerted messaging efforts and precautionary measures. while a majority of what has occurred in this pandemic is negative, this period has been exemplary of how radiologists, physicians, and research staff worked together to respond rapidly and diligently to this situation. the blueprint of responses and action plans for the current pandemic will serve as a model if ever needed again in the future. ms-sichuan academy of medical science and sichuan provincial peoples hospital md-cincinnati children's hospital, us first case of novel coronavirus in the united states an interactive web-based dashboard to track covid- in real time déjà vu or jamais vu? how the severe acute respiratory syndrome experience influenced a singapore radiology department's response to the coronavirus disease (covid- ) epidemic forecasting covid- impact on hospital bed-days, icu-days, ventilatordays and deaths by us state in the next months impact of non-pharmaceutical interventions (npis) to reduce covid mortality and healthcare demand key: cord- -rcv pl d authors: o’ryan, miguel l.; nataro, james p.; cleary, thomas g. title: microorganisms responsible for neonatal diarrhea date: - - journal: infectious diseases of the fetus and newborn infant doi: . /b - - - / - sha: doc_id: cord_uid: rcv pl d nan at the beginning of the st century, diari..eal disease continues to be a significant cause of morbidity and mortality worldwide. during the period of to , an estimated . billion children younger than years suffered an episode of acute diarrhea every year in developing countries; among these, . million required outpatient medical care, and million required hospitalization. approximately million diarrhea-associated deaths occurred in this age group annually, primarily in the most impoverished areas of the world.' these estimates are somewhat lower than the more than million annual deaths from diarrhea reported in the prior years? indicating progress in prevention and treatment of acute diarrhea. in the united states, approximately childhood deaths per year were reported during the late ~,~*~ although the actual number may be higher: accurate incidence rates for acute diarrhea in neonates from different populations are not readily available. the relative sparing of the newborn probably results from low exposure to enteropathogens and protection associated with brea~t-feeding.~-' after the first few months of life, increasing interaction with other individuals and the environment, including introduction of artificial feeding, increases the risk of exposure to enteropathogens. for most pathogens, the incidence of acute diarrhea peaks in children between months and years old? neonatal diarrhea is more common in underdeveloped areas, where low educational levels, crowding, and poor standards of medical care, environmental sanitation, and personal hygiene favor early contact with enteropathogens. as the incidence of neonatal gastroenteritis rises, there is a proportional increase in neonatal deaths because medical care for the poor often is inadequate.' *" for very low birth weight infants (< g), the death rate from diarrhea is -fold greater than for higher-birth-weight infants. this chapter discusses the pathogenesis, diagnosis, treatment, and prevention of gastroenteritis based on the available knowledge about pathogens that can cause neonatal diarrhea. pathogens that rarely or never cause acute diarrhea in neonates are not discussed. after an overview of host defense mechanisms and protective factors in human milk, the remainder of the chapter is devoted to specific pathogens that cause inflammatory or noninflammatory diarrhea. the neonate is a host that is uniquely susceptible to enteric infections. neonates have not had the opportunity to develop local or systemic immune responses, and in the first few days of life, they have not acquired the highly important enteric flora that protects the normal adult gastrointestinal tract.i -" still less is known about the barrier effect of the neonate's gastric acidity," intestinal mucus,z or each of which provides protection against gastrointestinal tract infections in older infants, children, and adults. the gastric acid barrier appears to be least effective during the first months of life. the average gastric ph level of the newborn is high (ph to ; mean, ). , although the ph falls to low levels by the end of the first day of life (ph to ), it subsequently rises again; by to days of life, the hydrochloric acid output of the neonatal stomach is far less than that of older infants and ~hildren.~~.'~ the buffering action of frequent milk feedings and the short gastric emptying interpose additional factors in the neonate that would be expected to permit viable ingested organisms to reach the small intestine. the intestinal epithelium serves as a nutrient absorptive machine, barrier to pathogen entry, and regulator of inflammation. intestinal epithelial cells have receptors for bacterial products and produce chemokines (e.g., interleukm [ il]- , monocyte chemotactic protein type [ mcp- , granulocyte macrophage-cell stimulating factor [ gm-csf] ) and proinflammatory cytokines (e.g., il- , tumor necrosis factor-a [tnf-a], il- ) in response to invasion by enteropathogens." the gut epithelium orchestrates the immune response. however, in the newborn, phagocytic, chemotactic, and complement functions are immature. b and t lymphocyte functions are impaired, resulting in a preferential igm production in response to antigenic stimulation. igg is actively transferred from mother to infant across the placenta at about weeks' gestation and peaks by about weeks; premature neonates, especially those born before weeks' gestation, are deficient in these maternally derived serum antib~dies.~' h e - the importance of breast-feeding infants for the prevention of diarrheal disease has long been e m p h a s i~e d .~~~~* -~~ published studies reporting the association between breastfeeding and diarrhea are extensive and suggest that infants who are breast-fed suffer fewer episodes of diarrhea than those who are not. this protection is greatest during a child's first months of life and declines with increasing age, during the period of weaning, partial breast-feeding confers protection that is intermediate between that gained by infants who are exclusively breast-fed and that by those who are exclusively bottle-fed. a striking demonstration of the protection afforded by breast-feeding of newborns has been provided by mata and urrutiai in their studies of a population of infants born in a rural guatemalan village. despite extremely poor sanitation and the demonstration of fecal organisms in the colostrum and milk of almost one third of diarrheal disease did not occur in any newborns. the incidence of diarrhea rose significantly only after these infants reached to months old, at which time solids and other fluids were used to supplement the human milk feedings. at that time, escherichia coli and gram-negative anaerobes (e.g., bacteroides) were found to colonize the intestinal tract.i in contrast, urban infants of a similar ethnic background who were partly or totally artificially fed frequently acquired diarrheal disease caused by enteropathogenic e. coli (epec) . multiple mechanisms by which breast-feeding protects against diarrhea have been postulated. breast-feeding confers protection by active components in milk and by decreased exposure to organisms present on or in contaminated bottles, food, or water. many protective components have been identified in human milk and generally are classified as belonging to the major categories of cells, antibody, antiinflammatory factors, and glycoconjugates and other nonantibody f a~t o r s .~~-~' examples of milk antibodies are summarized in table - . for any given pathogen, multiple milk factors may help protect the infant. human milk typically targets a major pathogenic mechanism using multiple, redundant strategies. redundancy of milk protective factors and targeting of complex virulence machinery have created a formidable barrier to enteropathogens. despite the fact that pathogens can rapidly divide and mutate, milk continues to protect infants. for example, human milk has secretory antibodies to shigellu virulence antigens and lipopoly-saccharide^,^^.^^ neutral glycolipid gb to bind shiga and lactoferrin to disrupt and degrade the surface-expressed virulence antigen^.^^-^^ in a similar way, milk contains antibodies directed toward the surface expressed virulence antigens of epec, ' oligosaccharides that block cell attachment? and lactoferrin that disrupts and degrades the surface expressed epec antigens ' human milk can initiate and maintain the growth of bifidobacterium and low ph in the feces of newborn infants, creating an environment antagonistic to the growth of e. ~o l i . ' the protective effect of human milk antibodies against enteropathogen-specific disease has been described for vibrio cholerae, campylobacter j e j~n i , ~~ epec, enterotoxigenic e. coli (etec), shigella, ' and giardia lamblia , and for bovine milk concentrate against etec, rota~irus,~' and shigella. in , the nonlactose carbohydrate fraction of human milk was found to consist mainly of oligosa~charides.~~ in , montreuil and mullet determined that up to . % of colostrum and up to . % of mature milk are oligosaccharides. human milk contains a larger quantity of the oligosaccharides than does milk from other mammals, and its composition is singularly complex. the metabolic fate of the oligosaccharides is of interest. only water, lactose, and lipids are present in greater amounts than the oligosaccharides. despite the fact that substantial energy must be expended by the mother to synthesize the many hundreds of different milk oligosaccharides, the infant does not use them as food. most of the oligosaccharides pass through the gut undigested. it is thought that they are present primarily to serve as receptor analogues that misdirect enteropathogen attachment factors away from gut epithelial carbohydrate receptors. likewise, enteropathogens use the oligosaccharide portion of glycolipids and glycoproteins as targets for attachment of whole bacteria and toxins. evidence is emerging that these glycoconjugates may have an important role in protection of the breast-fed infant from disease. human milk protects suckling mice from the heat-stable enterotoxin (st) of e. coli; on the basis of its chemical stability and physical properties, the protective factor has been deduced to be a neutral fucosyloligosaccharide. ~ experiments have shown that epec attachment to hep- cells can be inhibited by purified oligosaccharide fractions from human milk. oligosaccharides also may be relevant to protection from norwalk virus and other caliciviruses, because these viruses attach to human abo, lewis, and secretor blood group antigens. ' human milk contains large amounts of these carbohydrates. the ganglioside fraction in human milk has been shown to inhibit the action of heat-labile toxin (lt) and cholera toxin on ileal loops more effectively than secretory iga. s lactadherin in human milk has been shown to bind rotavirus and to inhibit viral replication in vitro and in v~v o . ~~ a study of infants in mexico showed that lactadherin in human milk protected infants from symptoms of rotavirus infection. e. coli organisms promptly colonize the lower intestinal tracts of healthy infants in their first few days of life - and constitute the predominant aerobic coliform fecal flora throughout life in humans and in many animals. the concept that this species might cause enteric disease was first suggested in the late th and early th centuries, when several veterinary workers described the association of diarrhea (i.e., in , m r '~ observed that bacterium (now escherichia) coli was found more often in the small intestines of children with diarrhea than in children without diarrhea. adam * confirmed these findings and noted the similarity with asiatic cholera and calf scours. he further extended these observations by suggesting that e. coli strains from patients with diarrhea could be distinguished from normal coliform flora by certain sugar fermentation patterns. although he called these disease-producing organisms dyspepsicoli and introduced the important concept that e. coli could cause enteric disease, biochemical reactions have not proved to be a reliable means of distinguishing nonpathogenic from pathogenic e. coli strains. there are now at least six recognized enteric pathotypes of e. ~oli.'~ the pathotypes can be distinguished clinically, epidemiologically, and pathogenetically (table - ) . - etec organisms are defined by their ability to secrete the lt or the st enterotoxin, or both. lt is closely related to cholera toxin and similarly acts by means of intestinal adenylate c y c l a~e , '~~~'~~ prostaglandin s y n t h e~i s , '~~~'~~ and possibly platelet activating f a c t~r . '~~' '~~ st (particularly the variant sta) causes secretion by specifically activating intestinal mucosal guanylate cyclase.' "-' l the stb toxin causes noncyclic, nucleotide-mediated bicarbonate secretion and appears to be important only in animals. ' -" enteroinvasive e. coli (eiec) has the capacity to invade the intestinal mucosa, thereby causing an inflammatory enteritis much like shigellosi~.'~~~''~ epec elicits diarrhea by a signal transduction m e~h a n i s m~~~'~~~~~'~'~~ which is accompanied by a characteristic attaching-and-effacing histopathologic lesion in the small intestine. ' enterohemorrhagic e. coli (ehec) also induces an attaching-and-effacing lesion, but in the colon?' ehec also secretes shiga toxin, which gives rise to the sequela of hemolytic-uremic syndrome (hus). diffusely adherent e. coli executes a signal transduction effect, which is accompanied by the induction of long cellular processes. enteroaggregative e. coli (eaec) adheres to the intestinal mucosa and elaborates enterotoxins and a major problem in the recognition of etec, eiec, epec, and ehec strains of e. coli is that they are indistinguishable from normal coliform flora of the intestinal tract by the usual bacteriologic methods. serotyping is of value in recognizing epec serotypes' and eiec, because these organisms tend to fall into a limited number of specific serogroups (see table - ).' ' eiec invasiveness is confirmed by inoculating fresh isolates into guinea pig conjunctivae, as described by sereny. ' the ability of organisms to produce enterotoxins (lt or st) is encoded by a transmissible plasmid that can be lost by one strain of e. coli or transferred to a previously unrecognized although the enterotoxin plasmids appear to prefer certain serogroups (different from epec or invasive serogro~ps),'~~ etec is not expected to be strictly limited to a particular set of serogroups. instead, these strains can be recognized only by examining for the enterotoxin. this is done in ligated animal or by enzyme-linked immunosorbent assay (elisa)' for lt or in suckling mice for st. , specific dna probes also are available for lt and st. whether there are other mechanisms involved in the ability of the versatile e. coli species to cause enteric disease, such as by producing other types of enterotoxins"' or by fimbriate adherence traits a l~n e , '~~. '~' remains to be elucidated. cytoto~ns. ~ , in tissue although early work on the recognition of e. coli as a potential enteric pathogen focused on biochemical or serologic distinctions, there followed a shift in emphasis to the enterotoxins produced by previously recognized and entirely "new" strains of e. coli. beginning in the mid- s with work by de and colleague^'^^^'^^ in calcutta, e. coli strains from patients with diarrhea were found to cause a fluid secretory response in ligated rabbit ileal loops analogous to that seen with v; cholerue. work by taylor and associate^'^"^^ showed that the viable e. coli strains were not required to produce this secretory response and that this enterotoxin production correlated poorly with classically recognized epec serotypes. in sho paulo, trabulsi'& made similar observations with e. coli isolated from children with diarrhea, and several veterinary workers demonstrated that etec was associated with diarrhea in piglets and cal~es.'~~-'~o a similar pattern was described in with acute undifferentiated diarrhea in adults in bengal from whom e. coli could be isolated from the upper small bowel only during acute i l l n e~s . '~' "~~ these strains of e. coli produced a nondialyzable, lt, ammonium sulfate-precipitable enterotoxin.' analogous to the usually short-lived diarrheal illnesses of e. coli reported by several workers, a short-lived course of the secretory response to e. coli culture filtrates compared with the secretory response of cholera toxin was de~cribed."~ however, like responses to cholera toxin, secretory responses to e. coli were associated with activation of intestinal mucosal adenylate cyclase that paralleled the fluid secretory r e~p o n s e . '~~. '~~ the two types of enterotoxins produced by e. have been found to be plasmid-encoded traits that are potentially separable from each other and from the equally important plasmid-encoded adherence traits for patho-st causes an immediate and reversible secretory whereas the effects of lt (e.g., cholera toxin) follow a lag period necessitated by its intracellular site of a~t i o n . '~~' '~' '~~ only lt appears to cause fluid secretion by activating adenylate cyclase, which is accomplished by toxininduced adp-ribosylation of the gsa signaling p r~t e i n .~' "~~ the activation of adenylate cyclase by lt and by cholera toxin is highly promiscuous, occurring in many cell types and resulting in development of nonintestinal tissue culture assay systems such as the chinese hamster ovary (cho) cell assay' and y adrenal cell assay.' the antigenic similarity of lt and cholera toxin and their apparent binding to the monosialoganglioside gm, have enabled development of elisas for detection of lt and cholera t~x i n . '~~, '~' -'~~ st is a much smaller molecule and is distinct antigenically from lt and cholera t~x i n . '~~, '~'~'~' al though it fails to alter camp levels, st increases intracellular intestinal mucosal cyclic guanosine monophosphate (cgmp) concentrations and specifically activates plasma membrane-associated intestinal guanylate cy~lase."'-"~ like camp analogues, cgmp analogues cause intestinal secretion that mimics the response to st."' the receptor for sta responds to an endogenous ligand called guunylin, of which sta is a structural homologue.'" because the capacity to produce an enterotoxin may be transmissible between different organisms by a plasmid or even a bacteri~phage,''~-'~' interstrain gene transfer genesis. [ ] [ ] [ ] may be expected to be responsible for occasional toxigenic non-e. coli. enterotoxigenic klebsiella and citrobacter strains have been associated with diarrhea in a few reports, often in the same patients with etec.' ,' likewise, certain strains of salmonella appear to produce an lt, cho cellpositive toxin that may play a similar role in the pathogenesis of the watery, noninflammatory diarrhea sometimes seen with salmonella enteritidis i n f e c t i~n . '~~"~ at least equally important as enterotoxigenicity for e. coli to cause disease is the ability of these organisms to colonize the upper small bowel, where the enterotoxin produced has its greatest effect. a separable, plasmid-encoded colonization trait was first recognized in porcine e. coli. veterinary workers demonstrated that the fimbriate k- surface antigen was necessary for etec to cause disease in piglets. ' an autosomal dominant allele appears to be responsible for the specific intestinal receptor in piglets. in elegant studies by gibbons and c o -~o r k e r s , '~~ the homozygous recessive piglets lacked the receptor for k- and were resistant to scours caused by etec. at least analogous colonization factors have been described for human e. coli isolate^^^"^'"^^ against which local iga antibody may be produced. these antigens potentially may be useful in vaccine development. data on the epidemiology and transmission of etec remain scanty for the neonatal period. in the past decades, these strains have been recognized among adults with endemic, cholera-like diarrhea in calcutta, india, and in dacca, banglade~h,''~*'~' and among travelers to areas such as mexico and central a f r i~a . '~~-'~~ the isolation of etec is uncommon in sporadic diarrheal illnesses in temperate climates where sanitation facilities are good and where winter viral patterns of diarrhea predominate. etec is commonly isolated from infants and children with acute watery summer diarrhea in areas where sanitary facilities are less than optimal. - *' -' these include areas such as afria, ~~~il, , , , , gentir~a,'~~ bengal,' '' mexico,' o and native american reservations in the southwestern united state^."^"'^ in a multicenter study of acute diarrhea in infants and children in china, india, mexico, myanmar, and pakistan, % of cases (versus % of controls) had etec.le a case-control study from northwestern spain showed a highly significant association of etec with . % of neonatal diarrhea, often acquired in the ho~pital.''~ although all types of etec (lt and/or st producers) are associated with cholera-like, non inflammatory, watery diarrhea in adults in these areas, they probably constitute the major cause (along with rotaviruses) of dehydrating diarrhea in infants and young children in these areas. in this setting, peaks of illnesses tend to occur in the summer or rainy season, and dehydrating illnesses may be life threatening, especially in infants and young ~h i l d r e n . ~~'~'~'~ humans are probably the major reservoirs for the human strains of etec, and contaminated food and water probably constitute the principal vector^.''^"^^ although antitoxic immunity to lt and asymptomatic infection with ltproducing e. coli tends to increase with age, st is poorly immunogenic, and st-producing e. coli continues to be associated with symptomatic illnesses into adulthood in endemic area~.l'~>l'~ the association of etec with outbreaks of diarrhea in newborn nurseries is well documented. ryder and colleagues'g isolated an st-producing e. coli from % of infants with diarrhea, from the environment, and in one instance, from an infant's formula during a -month period in a prolonged outbreak in .a special care nursery in texas. another st-producing e. coli outbreak was reported in by gross and a~sociates'~~ from a maternity hospital in scotland. etec and epec were significantly associated with diarrhea among infants younger than year in bang ade~h.l~ ' an outbreak of diarrhea in a newborn special care nursery that was associated with enterotoxigenic organisms that were not limited to the same serotype or even the same species has been reported.lg the short-lived etec, klebsiella, and citrobacter species in this outbreak raised the possibility that each infant's indigenous bowel flora might become transiently toxigenic, possibly by receiving the lt genome from a plasmid or even a bacteriophage. the clinical manifestations of etec diarrhea tend to be mild and self-limited, except in small or undernourished infants, in whom dehydration may constitute a major threat to life. in many parts of the developing world, acute diarrheal illnesses are the leading recognized causes of death. there is some suggestion that the diarrheal illnesses associated with st-producing etec may be particularly severe.' most probably the best definition of the clinical manifestations of etec infection comes from volunteer studies with adults. ingestion of ' to '' human etec isolates that produce lt and st or st alone resulted in a % to % attack rate of mild to moderate diarrheal illnesses within to hours that lasted to days.' these illnesses, typical for traveler's diarrhea, were manifested by malaise, anorexia, abdominal cramps, and sometimes explosive diarrhea. nausea and vomiting occur relatively infrequently, and up to one third of patients may have a low-grade fever. although illnesses usually resolve spontaneously within to days, they occasionally may persist for week or longer. the diarrhea is noninflammatory, without fecal leukocytes or blood. in outbreaks in infants and neonates, the duration has been in the same range ( to days), with a mean of approximately days. as in cholera, the pathologic changes associated with etec infection are minimal. from animal experiments in which thiry-vella loops were infected with these organisms and at a time when the secretory and adenylate cyclase responses were present, there was only a mild discharge of mucus from goblet cells and otherwise no significant pathologic change in the intestinal tract.lo unless terminal complications of severe hypotension ensue, etec organisms rarely disseminate beyond the intestinal tract. like cholera, etec diarrhea is typically limited to being an intraluminal infection. the preliminary diagnosis of etec diarrhea can be suspected by the epidemiologic setting and the noninflammatory nature of stool specimens, which reveal few or no leukocytes. although the ability of e. coli to produce enterotoxins may be lost or transmitted to other strains, there is a tendency for the enterotoxin plasmids to occur among certain predominant serotypes, as shown in table - ."' these serotypes differ from epec or invasive serotypes, but their demonstration does not prove that they are enterotoxigenic. the only definitive way to identify etec is to demonstrate the enterotoxin itself by a specific gene probe for the toxin codon, by a bioassay such as tissue culture or ileal loop assays for lt or the suckling mouse assay for st, or in the case of lt, by immunoassay such as elisa. however, even these sensitive bioassays are limited by the unavailability of any selective media for detecting etec by culture. even though substantial improvements have been made in enterotoxin assay (particularly for lt), the necessary random selection of e. coli from a relatively nonselective stool culture plate resulted in a sensitivity of only % of epidemiologically incriminated cases in an outbreak when to isolates were randomly picked and tested for enter~toxigenicity."~ by also examining paired serum samples for antibody against lt, only % demonstrated significant serum antibody titer rises, for a total sensitivity of etec isolation or serum antibody titer rises of only %. some have suggested that isolates may be pooled for lt or st assay. the capacity to prove with radiolabeled or enzyme-tagged oligonucleotide gene sequences for the enterotoxins (lt or st) further facilitates the identification of enterotoxigenic organisms.' s a novel method of combining immunomagnetic separation (using antibodycoated magnetic beads) followed by dna or polymerase chain reaction (pcr) probing may enhance the sensitivity of screenin fecal or food specimens for etec or other the mainstay of treatment of any diarrheal illness is rehydration."' this principle especially pertains to etec diarrhea, which is an intraluminal infection. the glucose absorptive mechanism remains intact in e. coli enterotoxininduced secretion, much as it does in cholera, a concept that has resulted in the major advance of oral glucose-electrolyte therapy. this regimen can usually provide fully adequate rehydration in infants and children able to tolerate oral fluids, replacing the need for parented rehydration in most cases . , its use is particularly critical in rural areas and developing nations, where early application before dehydration becomes severe may be lifesaving. the standard world health organization solution contains . g nacl, . g nahco,, . g kcl, and g glucose per liter of clean or boiled drinking water.i ' this corresponds to the following concentrations: mmoyl of sodium, mmovl of potassium, mmoyl of bicarbonate, mmol/l of chloride, and mmol/l of glucose. a variety of recipes for homemade preparations have been described?" but unless the cost is prohibitive, the premade standard solution is preferred. each ounces of this solution should be followed by ounces of plain water. if there is concern about hypertonicity, especially in small infants in whom a high intake and constant direct supervision of feeding cannot be ensured, the concentration of salt can be reduced.' a reduced osmolality solution with mmol/l of sodium and mmoyl of glucose and a total osmolality of (instead of ) mosm/kg has been found to reduce stool output by % and illness duration by % in a multicenter trial involving children in four countries. commercially available rehydration solutions are increasingly available ~orldwide.'~' pathogens. lf , the role of antimicrobial agents in the treatment or prevention of etec is controversial. this infection usually resolves within to days in the absence of antibacterial therapy. moreover, there is concern about the potential for coexistence of enterotoxigenicity and antibiotic resistance on the same plasmid, and co-transfer of multiple antibiotic resistance and enterotoxigenicity has been well d~cumented."~ widespread use of prophylactic antibiotics in areas where antimicrobial resistance is common has the potential for selecting for rather than against enterotoxigenic organisms. the prevention and control of etec infections would be similar to those discussed under epec serotypes. the use of breast-feeding should be encouraged. eiec causes diarrhea by means of shigella-like intestinal epithelial invasion (discussed later). s ' the somatic antigens of these invasive strains have been identified and seem to fall into of recognized groups (see table - ). most, if not all, of these bacteria share cell wall antigens with one or another of the various shigelza serotypes and produce positive reactions with antisera against the cross-reacting antigen."* however, not all strains of e. coli belonging to the serogroups associated with dysentery-lke illness are pathogenic, because a large ( mda) invasive plasmid is also required. additional biologic tests, including the guinea pig conjunctivitis (sereny) test or a gene probe for the plasmid, are used to confirm the property of inva~iveness."~ although an outbreak of foodborne eiec diarrhea has been well documented among adults who ate an imported cheese,"' little is known about the epidemiology and transmission of this organism, especially in newborns and infants. whether the infectious dose may be as low as it is for shigella is unknown; however, studies of adult volunteers suggest that attack rates may be somewhat lower after ingestion of even large numbers of eiec than would be expected with shigella. the outbreak of eiec diarrhea resulted in a dysentery-like syndrome with an inflammatory exudate in stool and invasion and disruption of colonic mucosa."' descriptions of extensive and severe ileocolitis in infants dying with e. coli diarrhea indicate that neonatal disease also can be caused by invasive strains capable of mimicking the pathologic features of shigellosis. the immunofluorescent demonstration of e. coli together with an acute inflammatory infiltrate " in the intestinal tissue of infants tends to support this impression, although it has been suggested that the organisms may have invaded the bowel wall in the postmortem ~e r i d . l '~ there is still little direct evidence concerning the role of invasive strains of e. coli in the cause of neonatal diarrhea. the infrequency with which newborns manifest a dysentery-like syndrome makes it unlikely that this pathogen is responsible for a very large proportion of the diarrheal disease that occurs during the first month of life. the diagnosis should be suspected in infants who have an inflammatory diarrhea as evidenced by fecal polymorphonuclear neutrophils or even bloody dysenteric syndromes from whom no other invasive pathogens, such as campylobacter, shigella, salmonella, vibrio, or yersinia, can be isolated. in this instance, it may be appropriate to have the fecal e. coli isolated and serotyped or tested for invasiveness in the sereny test. plasmid pattern analysis and chromosomal restriction endonuclease digestion pattern analysis by pulsed-field gel electrophoresis have been used to evaluate strains involved in outbreaks. the management and prevention of eiec diarrhea should be similar to those for acute shigella or other e. coli enteric infections. the serologic distinction of e. coli strains associated with epidemic and sporadic infantile diarrhea was first suggested by goldschmidt in and confirmed by dulaney and michelson in . these researchers found that certain strains of e. coli associated with institutional outbreaks of diarrhea would agglutinate with antisera on slides. in , bra?" isolated a serologically homogeneous strain of e. coli (subsequently identified as serogroup ) from % of infants with summer diarrhea in england. he subsequently summarized a larger experience with this organism isolated from only % of asymptomatic controls but from % of infants with diarrhea, one half of which was hospital this strain (initially called e. coli-gomez by varela in ) also was associated with infantile diarrhea in a second type of e. coli (called beta by giles in and subsequently identified as ) was associated with an outbreak of infantile diarrhea in aberdeen, s~o t l a n d .~'~*~'~ from this early work primarily with epidemic diarrhea in infants has developed an elaborate serotyping system for certain e. coli strains that were clearly associated with infantile these strains first were called enteropathogenic e. coli by neter and colleagues in , and the association with particular serotypes can still be observed. as shown in table - , these organisms are distinct from the enterotoxigenic or enteroinvasive organisms or those that inhabit the normal gastrointestinal tract. they exhibit localized adherence to hep- cells, a phenotype that has been suggested to be useful for diagnosis and pathogenesis research. 'i epec is an important cause of diarrhea in infants in developing or transitional c~u n t r i e s .~"~~' -~~~ outbreaks have become rare in the united states and other industrialized countries, but they still ccur. ~~ some have attributed the rarity of this recognition of illness in part to the declining severity of diarrheal disease caused by epec within the past years, resulting in fewer cultures being obtained from infants with relatively mild symptom^.^^^^^^ however, several other variables influence the apparent incidence of this disease in the community. a problem arises with false-positive epec on the basis of the nonspecific cross-reactions seen with improper shortening of the serotyping p r o c e d~r e .~~~,~~~ because of their complexity and relatively low yield, neither slide agglutination nor hep- cell adherence or dna probe tests are provided as part of the routine identification of enteric pathogens by most clinical bacteriology laboratories. failure to recognize the presence of epec in fecal specimens is the inevitable consequence. the apparent incidence of epec gastroenteritis also varies with the epidemiologic circumstances under which stool cultures are obtained. the prevalence of enteropathogenic strains is higher among infants from whom cultures are obtained during a community epidemic compared with those obtained during sporadic diarrheal disease. neither reflects the incidence of epec infection among infants involved in a nursery outbreak or hospital epidemic. epec gastroenteritis is a worldwide problem, and socioeconomic conditions play a significant role in determining the incidence of this disease in different populations. s for instance, it is unusual for newborn infants born in a rural environment to manifest diarrheal disease caused by epec; most infections of the gastrointestinal tract in these infants occur after the first months of conversely, among infants born in large cities, the attack rate of epec is high during the first months of life. this age distribution reflects in large part the frequency with which epec causes crossinfection outbreaks among nursery populations' '~ ~ ; however, a predominance of epec in infants in the first months of life also has been described in community epidemic^^^'-^^^ and among sporadic cases of diarrhea acquired outside the h~s p i t a l . '~' -~~~ the disparity in the incidence of neonatal epec infection between rural and urban populations has been ascribed to two factors: the trend away from breast-feeding among mothers in industrialized societies and the crowding together of susceptible newborns in nurseries in countries in which hospital deliveries predominate over home d e l i~e r i e s . '~~~'~~ although the predominant serogroup can vary from year to year, , , ,z . ~ the same strains have been prevalent during the past years in great britain? puerto r~c o ?~~ guatemala: panama, newfoundland, indonesia, thailand, and south when living conditions are poor and overcrowding of susceptible infants exists, there is a rise in the incidence of neonatal diarrhea in general and epec gastroenteritis in p a r t i c~l a r .~'~~~~~~~~~ a h igher incidence of asymptomatic family carriers is found in such situations. b newborn infants can acquire epec during the first days of life by one of several routes: ( ) organisms from the mother ingested at the time of birth; ( ) bacteria from other infants or toddlers with diarrheal disease or from asymptomatic adults colonized with the organism, commonly transmitted on the hands of nursery personnel or parents; ( ) airborne or droplet infection; ( ) fomites; or ( ) organisms present in formulas or solid food supplements. only the first two routes have been shown conclusively to be of any real significance in the transmission of disease or the propagation of epidemics. most neonates acquire epec at the time of delivery through ingestion of organisms residing in the maternal birth canal or rectum. stool cultures taken from women before, during, or shortly after delivery have shown that % to % carry epec at some time during this period. ~s ~ ~ ~ ' use of fluorescent antibody techniquesz ' or cultures during a community outbreak of epec gastroenteritis" revealed twice this number of persons excreting the organism. virtually none of the women carrying pathogenic strains of e. coli had symptoms referable to the gastrointestinal tract. many of the mothers whose stools contain epec transmit these organisms to their infant~, ~*~' resulting in an asymptomatic infection rate of % to % among newborns cultured at random in nursery surveys. ~ ~ '~ these results must be considered conservative and are probably an artifact of the sampling technique. one study using antisera to identify as many e. coli as possible in fecal cultures showed a correlation between the coliform flora in % of motherinfant pairs? of particular interest was the observation that the groups of e. coli isolated from the infants' mucus immediately after delivery correlated with those subsequently recovered from their stools, supporting the contention that these organisms were acquired orally at the time of birth. in mothers whose stools contained the same group as their offspring, the mean time from rupture of membranes to delivery was about hours longer than in those whose infants did not acquire the same serogroups, suggesting that ascending colonization before birth also can play a role in determining the newborn's fecal flora. the contours of the epidemiologic curves in nurse$ - and communi@ - outbreaks are in keeping with a contact mode of spread. transmission of organisms from infant to infant takes place by way of the fecal-oral route in almost all cases, most likely on the hands of persons attending to their care. * , , ill infants represent the greatest risk to those around them because of the large numbers of organisms found in their stools - and crossinfection also has been initiated by infants who were healthy at the time of their admission to the nursery. , - a newborn exposed to epec is likely to acquire enteric infection if contact with a person excreting the organism is intimate and prolonged, as in a hospital or family setting. stool culture surveys taken during outbreaks have shown that between % and % of term neonates residing in the nursery carry epec in their intestinal tracts.' , , 'm despite descriptions of nursery outbreaks in which virtually every neonate or low-birth-weight infant became infected, there is ample evidence that exposure to pathogenic strains of e. coli does not necessarily result in greater likelihood of illness for premature infants than for term infants. , * , any increased prevalence of cross-infections that may exist among premature infants can be explained more readily by the prolonged hospital stays, their increased handling, and the clustering of infants born in different institutions than by a particular susceptibility to epec based on immature defense mechanisms. the most extensive studies on the epidemiology of gastroenteritis related to e. coli have dealt with events that took place during outbreaks in newborn nurseries. unfortunately, investigations of this sort frequently regard the epidemic as an isolated phenomenon and ignore the strong interdependence that exists between community-and hospital-acquired ~~~~~~ , , n ot surprisingly, the direction of spread is most often from the reservoir of disease within the community to the hospital. when the original source of a nursery outbreak can be established, frequently it is an infant born of a carrier mother who recently acquired her epec infection from a toddler living in the home. cross-infection epidemics also can be initiated by infected newborns who have been admitted directly into a clean nursery unit from the surrounding d i s t r i~t~~~~~~~*~~~ or have been transferred from a nearby hospital. after a nursery epidemic has begun, it generally follows one of two major patterns. some are explosive, with rapid involvement of all susceptible infants and a duration that seldom exceeds or months. * , * the case-fatality rate in these epidemics may be very high. other nursery outbreaks have an insidious onset with a few mild, unrecognized cases; the patients may not even develop illness until after discharge from the hospital. during the next few days to weeks, neonates with an increased number of loose stools are reported by the nurses; shortly thereafter, the appearance of the first severely ill infants makes it apparent that an epidemic has begun. unless oral antimicrobial therapy is instituted (see "therapy"), nursery outbreaks like these may continue for months - or with cycles of illness followed by periods of relative quiescence. this pattern can be caused by multiple strains (of different phage or antibiogram types) sequentially introduced into the nursery? * . the nursery can be a source of infection for the community. the release of infants who are in the incubation stages of their illness or are convalescent carriers about to relapse may lead to secondary cases of diarrheal disease among young siblings living in widely scattered areas. , , these children further disseminate infection to neighboring households, involving playmates of their own age, young infants, and mothers. as the sickest of these contact cases are admitted to different hospitals, they contaminate new susceptible persons, completing the cycle and compounding the outbreak. this feedback mechanism has proved to be a means of spreading infantile gastroenteritis through entire ~o~n t i e s , ~~~~~~,~~~ and even provinces. one major epidemic of diarrhea related to epec :b that occurred in the metropolitan chicago and northwestern indiana region during the winter of involved more than children and community hospitals during a period of months. , almost all of the patients were younger than years old, and % were younger than month, producing an age-specific attack rate of nearly % of neonates in the community. the importance of the hospital as a source of cross-infection in this epidemic was demonstrated through interviews with patients' families, indicating that a minimum of % of infants had direct or indirect contact with a hospital shortly before the onset of their illness. it has been suggested, but not proved, that asymptomatic carriers of epec in close contact with a newborn infant, such as nursery personnel or family members, might play an important role in its t r a n s m i~s i o n .~~~'~"~~~ stool culture surveys have shown that at any one time about % of and % to % of young who are free of illness harbor epec strains. higher percentages have been recorded during community epidemics? * s be cause this intestinal carriage is transitory: the number of individuals who excrete epec at one time or another during the year is far higher than the % figure recorded for single specimens. nursery personnel feed, bathe, and diaper a constantly changing population of newborns, about % to % of whom excrete epec. * despite this constant exposure, intestinal carriage among nursery workers is surprisingly low. even during outbreaks of diarrheal illness, when dissemination of organisms is most intense, less than % of the hospital personnel in direct contact with infected neonates are themselves excreting pathogenic strains of e. coli. ', , although adult asymptomatic carriers generally excrete fewer organisms than patients with acute illness large numbers of pathogenic bacteria may nevertheless exist in their stools? s however, no nursery outbreak and few family cases o have been traced to a symptomless carrier. instead, passive transfer of bacteria from infant to infant by the hands of personnel appears to be of primary importance in these outbreaks. cities, . , epec can be recovered from the throat or nose of % to % of infants with diarrheal illness p and from about % of asymptomatic the throat and nasal mucosa may represent a portal of entry or a source of transmission for epec. environmental studies have shown that epec is distributed readily and widely in the vicinity of an infant with active diarrheal disease, often within day of admission to the ~a r d . '~' , '~~ massive numbers of organisms are shed in the diarrheal stool or vomitus of infected e. coli organisms may survive to weeks in dust . and can be found in the nursery air when the bedding or diapers of infected infants are disturbed during routine nursing procedure^^^^^^^ or on floors, walls, cupboards, and nursery equipment such as scales, hand towels, bassinets, incubators, and oxygen tents of other infant^?^,'^^,'^^ documentation of the presence of epec in nursery air and dust does not establish the importance of this route as a source of cross-infection. one study presented evidence of the respiratory transmission of epec; however, even in the cases described, the investigators pointed out that fecal-oral transmission could not be completely ruled additional clinical and experimental data are required to clarify the significance of droplet and environmental infection. coliform organisms have also been isolated in significant numbers from human mi k, ~ ~ prebottled infant f rmulas, ~~ and formulas prepared in the home. epec in particular has been found in stool cultures obtained from donors of human milk and workers in a nursery formula room. o in one instance, epec :b was isolated from a donor, and subsequently, the same serogroup was recovered in massive amounts in almost pure culture from her milk. pathogenic strains of e. coli have also been isolated from raw cow's milk '' and from drinking ~a t e r .~" likewise, epec has been isolated from flies during an epidemic, but this fact has not been shown to be of epidemiologic significance. ' infection of the newborn infant with epec takes place exclusively by the oral route. attempts to induce disease in adult volunteers by rectal instillation of infected material have been unsuc~essful.~~ there are no reports of disease occurring after transplacental invasion of the fetal bloodstream by enteropathogenic or nonenteropathogenic strains of e. coli. ascending intrauterine infection after prolonged rupture of the membranes has been reported only once; the neonate in this case suffered only from mild diarrhea. bacterial cultures of the meconium and feces of newborns indicate that enteropathogenic strains of e. coli can colonize effectively the intestinal tract in the first days of although e. coli may disappear completely from stools of breast-fed children during the ensuing weeks, this disappearance is believed to be related to factors present in the human milk rather than the gastric secretions. ~ ~ the use of breast-feeding or expressed human milk has even been effective in terminating nursery epidemics caused by epec :b , probably by reducing the incidence of crossinfections among infants. although dose-effect studies have not been performed among newborns, severe diarrhea has occurred after ingestion of ' epec organisms by very young the high incidence of cross-infection outbreaks in newborn nurseries suggests that a far lower inoculum can often effect spread in this setting. the role of circulating immunity in the prevention of gastrointestinal tract disease related to epec has not been clearly established. virtually % of maternal sera have been found to contain hemaggl~tinating, '~~~''~~'~ or bacteriostatic ' ~ ' antibodies against epec. the passive transfer of these antibodies across the placenta is extremely inefficient. titers in blood of newborn infants are, on average, to times lower than those in the corresponding maternal sera. group-specific hemagglutinating antibodies against the antigen of epec are present in % to % of cord blood samp es, ~ ~ whereas b a~t e r i c i d a l~'~~~~~ or bacterio-static " activity against these organisms can be found much more frequently. tests for bacterial agglutination, which are relatively insensitive, are positive in only a small percentage of neonate^.'^^'^" the importance of circulating antibodies in the susceptibility of infants to epec infection is unknown. experiments with suckling mice have failed to demonstrate any effect of humoral immunity on the establishment or course of duration of intestinal colonization with e. coli in mothers or their infants. similar observations have been made in epidemiologic studies among premature human infants using enteropathogenic ( :b ) and nonenteropathogenic ( :h ) strains of e. coli as the indicator organisms. in a cohort of mothers and their infants followed from birth to months old, cooper and associate^'^ were able to show a far higher incidence of clinical epec disease in infants of epec-negative mothers than in infants born of mothers with epec isolated from stool cultures. this finding suggested to the investigators the possibility that mothers harboring epec in their gastrointestinal tracts transfer specific antibodies to their infants that confer some protection during the first weeks of life. protection against enteric infections in humans often correlates more closely with levels of local secretory than serum antibodies. although it is known that colonization of newborns with e. coli leads to the production of coproantibodies against the ingested the clinical significance of this intestinal immunity is uncertain. the previously mentioned experiment with mice showed no effect of active intestinal immunity on enteric col~nization.~'~ in human infants, the frequency of bacteriologic and clinical relapse related to epec of the same and the capacity of one strain of epec to superinfect a patient already harboring a different train^^^,^^^,^^^ also cast some doubt on the ability of mucosal antibodies to inhibit or alter the course of intestinal infection. studies of the protective effects of orally administered epec vaccines could help to resolve these question^.'^' the mechanism by which epec causes diarrhea involves a complex array of plasmid and chromosomally encoded traits. epec serotypes usually do not make one of the recognized enterotoxins (lt or st) as usually measured in tissue culture or animal r n~d e l s ,~'~~~'~ nor do these serotypes cause a typical invasive colitis or produce a positive sereny test only uncommonly do epec strains invade the bloodstream or disseminate. nevertheless, epec strains that test negative in these tests are capable of causing diarrhea; inocula of '' e. coli or organisms caused diarrhea in of adult volunteers. some epec strains may secrete weak enterot~xins,~~''~'~ but the consensus opinion is that the attaching and effacing lesion constitutes the critical secretory virulence pheno-clinical pathologic reports reveal the characteristic attachin and effacing lesion in the small intestine of infected infants? the lesion is manifested by intimate (about nm) apposition of the epec to the enterocytes plasma membrane, with dissolution of the normal brush border and rearrangement of the cyto~keleton.'''~~~~ in some instances, the bacteria are observed to rise up on pedestal-like structures, which are diagnostic of the infection.i ' villus blunting, crypt hypertrophy, histiocytic infiltration in the lamina propria, and a reduction in the brush border enzymes may also be ~bserved.~'~'~'~ two major epec virulence factors have been described; strains with both factors are designated as typical epec. * * ' one such factor is the locus of enterocyte effacement (lee), a type secretion system encoded by the lee chromosomal pathogenicity i~land.~'~-~'* the lee secretion apparatus injects proteins directly from the cytoplasm of the infecting bacterium into the cytoplasm of the target enter~cytes.~'~ the injected proteins constitute cytoskeletal toxins, which together elicit the close apposition of the bacterium to the cell, cause the effacement of microvilli, and most likely give rise to the net secretory one critical secreted protein, called towinterleukin- receptor (tir),"' inserts into the plasma membrane of the epithelial cell, where it serves as the receptor for a lee-encoded epec outer membrane protein called intimin.'" animals infected with attaching and effacin pathogens mount antibody responses to intimin and t i r ! and both are considered potential immunogens. the lack of protection from epec reinfection suggests that natural antibody responses to tir and intimin are not protective. the second major virulence factor of typical epec is the bundle-forming pilus (bfp), which is encoded on a partially conserved mda virulence plasmid called epec adherence factor bfp, a member of the type iv pilus family, mediates aggregation of the bacteria to each other and probably to enterocytes themselves, thereby facilitating mucosal colonization. a bfp mutant was shown to be attenuated in adult volunteers. the principal pathologic lesion with epec is the focal destructive adherence of the organism, effacing the microvillous brush border with villus blunting, crypt hypertrophy, histiocytic infiltration of the lamina propria, and reduced brush border enzymes. rothbaum and colleagues described similar findings with dissolution of the glycocalyx and flattened microvilli with the nontoxigenic epec strain :b . there has been a wide range of pathologic findings reported in infants dying of epec gastroenteritis. most newborns dying with diarrheal disease caused by epec show no morphologic changes of the gastrointestinal tract by gross or microscopic examination of tiss~es.~'~'~'' bra?" described such "meager" changes in the intestinal tract that "the impression received was that the term gastroenteritis is incorrect." at the other extreme, extensive and severe involvement of the intestinal tract, although distinctly unusual among neonates with epec diarrhea, has been discussed in several reviews of the pathologic anatomy of this disease. v , changes virtually identical to those found in infants dying with necrotizing enterocolitis have been reported. drucker and c o -~o r k e r s~'~ found that among infants who were dying of epec diarrhea, "intestinal gangrene, and/or perforation, andlor peritonitis were present in five, and intestinal pneumatosis in five." the reasons for such wide discrepancies in epec disease pathology are not clear. the severity of intestinal lesions at the time of death does not correlate with the birth weight of the patient, the age of onset of illness, the serogroup of the infecting strain, or the prior administration of oral or systemic antimicrobial agents. the suggestion that the intensity of inflammatory changes may depend on the duration of the diarrhea '' cannot be corroborated in autopsy s t~d i e s~'~*~"~~~ or small intestinal it is difficult to reconcile such a thesis with the observation that a wide range of intestinal findings can be seen at autopsy among newborns infected by a single serotype of epec during an epidemic. the nonspecific pathologic picture described by some researchers includes capillary congestion and edema of the bowel wall and an increase in the number of eosinophils, plasma cells, macrophages, and mononuclear cells in the mucosa and submucosa. , , villous patterns are generally well preserved, although some flattening and broadening of the villi are seen in the more severe cases. almost complete absence of villi and failure of regeneration of small bowel mucosa have been reported in an extreme case. edema in and around the myenteric plexuses of auerbach, a common associated finding, has been suggested as a cause of the gastrointestinal tract dilatation often seen at autopsy in infants with epec infection^.^^^'^^^'^^^ in general, the distal small intestine shows the most marked alterations; however, the reported pathologic findings may be found at all levels of the intestinal tract. several complications of epec infection have been reported. candidal esophagitis accounted for significant morbidity in two series collected before'" and the antibiotic era. oral thrush has been seen in % of epecinfected infants treated with oral or systemic antib i o t i c~. '~~,~~"~~ some degree of fatty metamorphosis of the liver has been reported by several investigators" i ' ; however, these changes are nonspecific and probably result from the poor caloric intake associated with persistent diarrhea or vomiting. some degree of bronchopneumonia, probably a terminal event in most cases, exists in a large proportion of newborns dying of epec i n f e~t i o n .~" " '~'~~~ in one reported series of infant cases, epec was demonstrated by immunofluorescent staining in the bronchi, alveoli, and interalveolar septa. mesenteric lymph nodes are often swollen and congested with reactive germinal centers in the lymphoid f o l l i~l e s . '~~~~, '~~ severe lymphoid depletion, unrelated to the duration or severity of the antecedent illness, also has been de~cribed.'~~ the kidneys frequently show tubular epithelial toxic changes. various degrees of tubular degeneration and cloudy swelling of convoluted tubules are common finding^.^'^,'^^,^^^ renal vein thrombosis or cortical necrosis may be observed in infants with disseminated intravascular coagulation in the terminal phases of the illness. the heart is grossly normal in most instances but may show minimal vacuolar changes of nonspecific toxic myocarditis on microscopic examinati n. ~~'~~' candidal abscesses of the heart and kidneys' , , have been described. with the exception of mild congestion of the pia arachnoid vessels and some edema of the meninges, examination of the central nervous system reveals few changes? despite the observation of braf l that "inflammation of the middle ear [is] exceptional," strains of epec have been isolated from a significant number of specimens of the middle ear in case series in which dissection of the temporal bone has been performed. exposure of newborns to epec may be followed by one of several possible consequences: no infection, infection without illness, illness with gastroenteritis of variable severity and duration, and rarely, septicemia with or without metastatic foci of infection accompanying gastroenteritis. when infants are exposed to epec, a significant number become colonized as temporary st , or pharyngeal carriers with no signs of clinical disease. although l a~r e l l~~' showed that the percentage of asymptomatic infections rises steadily as age increases, this observation has not been confirmed by other investigator^.^'^.^^^ similarly, the suggestion that prematurity per se is associated with a low incidence of inapparent epec infection has been documented in several clinical but refuted in others. , most neonates who acquire infection with epec eventually show some clinical evidence of gastroenteritis. the incubation period is quite variable. its duration has been calculated mostly from evidence in outbreaks in newborn nurseries, where the time of first exposure can be clearly defined in terms of birth or admission dates. in these circumstances, almost all infants show signs of illness between and days after exposure, and most cases show signs within the first days. , , in some naturally and experi-menta infections with heavy exposure, the incubation period may be as short as hours; the stated upper limit is days. the first positive stool culture and the earliest recognizable clinical signs of disease occur simultaneously in most although colonization may precede symptoms by to days. , th e gastroenteritis associated with epec infection in the newborn is notable for its marked variation in clinical pattern. clinical manifestations vary from mild illness manifest only by transient anorexia and failure to gain weight to a sudden explosive fulminating diarrhea causing death within hours of onset. prematurity, underlying disease, and congenital anomalies often are associated with the more severe forms of illness. , , , experienced clinicians have observed that the severity of epec gastroenteritis has declined markedly during the past decades. the onset of illness usually is insidious, with vague signs of reluctance to feed, lethargy, spitting up of formula, mild abdominal distention, or even weight loss that may occur for or days before the first loose stool is passed. diarrhea usually begins abruptly. it may be continuous and violent, or in milder infections, it may run an intermittent course with or more days of normal stools followed by or more days of diarrhea. emesis sometimes is a prominent and persistent early finding. stools are loose and bright yellow initially, later becoming watery, mucoid, and green. flecks or streaks of blood, which are commonly seen with enterocolitis caused by salmonella, campylobacter, or shigella, are rarely a feature of epec diarrheal disease. a characteristic seminal smell may pervade the environment of infants infected with epec :b , , , and an odor variously described as "pungent," "musty," or "fetid" often surrounds patients excreting other strains in their stool^.^^','^^ because the buttocks are repeatedly covered with liquid stools, excoriation of the perianal skin can be an early and persistent problem. fever is an inconstant feature, and when it occurs, the patient's temperature rarely rises above " c. convulsions occur infrequently; their occurrence should alert the clinician to the possible presence of electrolyte disturbances, particularly hypernatremia. prolonged hematochezia, distention, edema, and jaundice are ominous signs and suggest an unfavorable p r o g n o~i s .~'~,~~~*~*~ m ost infants receiving antimicrobial agents orally show a cessation of diarrhea, tolerate oral feedings, and resume weight gain within to days after therapy has been those with mild illness who receive no treatment can continue to have intermittent loose stools for to weeks. in one outbreak related to epec :k , more than one third of the untreated or inappropriately treated infants had diarrhea for more than days in the absence of a recognized enteric pathogen on repeated culturing. recurrence of diarrhea and vomiting after a period of initial improvement is characteristic of epec e n t e r i t i~. '~'~~~~~~~ though seen most often in newborns who have been treated inadequately or not treated at all, clinical relapses also occur after appropriate therapy. occasionally, the signs of illness during a relapse can be more severe than those accompanying the initial attack of illness. , , not all clinical relapses result from persistent infection. a significant number of relapses, particularly those that consistently follow attempts at reinstitution of formula fee ding^?^^.^^^ are caused by disaccharide intolerance rather than bacterial proliferation. intestinal superinfections, caused by another serotype of epecz or by completely different enteric pathogens, such as salmonella or shigella, also can delay the resolution of symptoms. rarely, infants suffer a "relapse" caused by an organism from the same group as the original strain but differing in its h antigen. unless complete serotyping is performed on all epec isolates, such an event easily could be dismissed as being a recurrence rather than a superinfection with a new ~r g a n i s m . '~~*~~~ antimicrobial agents to which the infecting organisms are susceptible often may not eradicate epec: , , which may persist for weeks , , or months after the acute illness has subsided. although reinfection cannot always be excluded, a significant number of infants are discharged from the hospital with positive rectal dehydration is the most common and serious complication of gastroenteritis caused by epec or a toxin-producing e. coli. virtually all deaths directly attributable to the intestinal infection are caused by disturbances in fluids and electrolytes. when stools are frequent in number, large in volume, and violent in release, as they often are in severe infections with abrupt onset, a neonate can lose up to % of body weight in a few h o~r s .~~~,~~~ rarely, fluid excretion into the lumen of the bowel proceeds so rapidly that reduction of circulating blood volume and shock may intervene before passage of even a single loose before the discovery of the etiologic agent, epidemic diarrhea of the newborn was also known by the term cholera infantum. mild disease, particularly when aggravated by poor fluid intake, can lead to a subtle but serious deterioration of an infant's metabolic status. sometimes, a week or more of illness elapses before it becomes apparent that an infant with borderline acidosis and dehydration who seemed to be responding to oral fluids alone requires parenteral therapy for impr~vement?~~ it is incumbent on the clinician caring for small infants with gastroenteritis to follow them closely, with particular attention to serial weights, until full recovery can be confirmed. there are few other complications, with the possible exception of aspiration pneumonia, directly related to epec gastroenteritis. protracted diarrhea and nutritional failure may occur as a consequence of functional damage to the small intestinal mucosa, with secondary intolerance to dietary necrotizing enterocolitis, which occasionally results in perforation of the bowel and peritonitis, has not been causally related to infection with epec. , , a review of most of the large clinical series describing epec disease in infants who ranged in age from neonates to children aged years revealed only three proven instances of ba~teremia:~~**~~ one possible urinary tract infection: and one documented case of meningitis in an infant of unspecified age. focal infections among neonates were limited to several cases of otitis and a subcutaneous abscess from which epec was isolated. additional complications include interstitial pneumonia, gastrointestinal bleeding with or without disseminated intravascular coagulatio , ~.~~~ and methemoglobinemia caused by a mutant of epec :b that was capable of generating large quantities of nitrite from proteins present in the gastrointestinal tract. the gold standard of epec diagnostics is identification in the stool of e. coli carrying genes for bfp and lee. identification of these genes can be accomplished by molecular methods (discussed later), but lack of access to these methods has led many labs to rely on surrogate markers, such as serotyping." classic epec has been recovered from the vomitus, stool, or bowel contents of infected newborns. isolation from bile and the upper respiratory t r a~t~~~~~~*~~~ ha s been described in those instances in which a specific search has been made. less commonly, epec is isolated from ascetic fluid'" or purulent exudates * * , occasionally, the organism has been recovered from blood c u l t~r e s ?~~,~~~ urine: and cerebrospinal fluid. stool cultures generally are more reliable than rectal swabs in detecting the presence of enteric pathogens, although a properly obtained swab should be adequate to demonstrate epec in most cases. ' , * specimens should be obtained as early in the course of the illness as possible because organisms are present in virtually pure culture during the acute phase of the enteritis but diminish in numbers during convalescence. because of the preponderance of epec in diarrheal stools, two cultures are adequate for isolation of these pathogens in almost all cases of active disease. studies using fluorescent antibody methods for identification of epec in stool specimens have demonstrated that during the incubation period of the illness, during convalescence, and among asymptomatic carriers of epec, organisms can be excreted in such small numbers that they escape detection by standard bacteriologic methods in a significant proportion of as many as to specimens may be required to detect epec using methods that identify individual epec isolates in the ~t . ~~~ after a stool specimen is received, it should be plated as quickly as possible onto noninhibiting media or placed in a preservative medium if it is to be held for longer periods. deep freezing of specimens preserves viable epec when a prolonged delay in isolation is necessary?" no selective media, biochemical reactions, or colonial variations permit differentiation of pathogenic and nonpathogenic strains. certain features may aid in the recognition of two important serogroups. cultures of serogroups :b and :b , unlike many other coliforms, are sticky or stringy when picked with a wire loop and are rarely hemolytic on blood whereas :b colonies emit a distinctive evanescent odor commonly described as "~e m i n a l . ' '~~~,~~~ this unusual odor first led b r a y to suspect that specific strains of e. coli might be responsible for infantile gastroenteritis. because serotyping is simpler than molecular detection and because epec have long been known to belong to certain highly characteristic serotypes, serotyping can be used to identify likely epec strains, especially in outbreaks? e. coli, like other enterobacteriaceae members, possesses cell wall somatic antigens (o), envelope or capsular antigens (k), and if motile, flagellar antigens (h). many of the groups may be further divided into two or more subgroups (a, b, c), and the k antigens are divisible into at least three varieties (b, l, a) on the basis of their physical behavior. organisms that do not possess flagellar antigens are nonmotile (designated nm). the epec b capsular surface antigen prevents agglutination by antibodies directed against the underlying antigen. heating at °c for hour inactivates the agglutinability and antigenicity of the b antigen. slide agglutination tests with polyvalent or ob antiserum may be performed on suspensions of colonies typical of e. coli that have been isolated from infants with diarrhea, especially in nursery outbreaks. however, because of numerous false-positive "cross-reactions:' the and k (or b) type must be confirmed by titration with the specific a n t i~e r a .~~~ the presence of epec does not prove that epec is the cause of diarrhea in an individual patient. mixed cultures with two or three serotypes of epec have been demonstrated in % to % of patients. * * this need not mean that two or three serotypes are causative agents. secondary infection with hospital-acquired strains can occur during convalesand some infants may have been asymptomatic carriers of one serotype at the time that another produced diarrheal disease. a similar explanation may pertain to mixed infections with epec and salmonella or shigella. * nelson reported the presence of these pathogens in combination with epec in % of infants who were cultured as part of an antibiotic therapy trial. salmonella and shigella that had not been identified on cultures obtained at admission were isolated only after institution of oral therapy with neomycin. the investigator postulated that the alteration in bowel flora brought about by the neomycin facilitated the growth of these organisms, which had previously been suppressed and obscured by coliform over- the importance of seeking all enteric pathogens in primary and follow-up cultures of infantile diarrhea is apparent, particularly when the specimen originates from a patient in a newborn nursery or infants' ward. although epec gastroenteritis was once considered to be synonymous with "summer diarrhea," community outbreaks have occurred as frequently, if not more frequently, in the colder seasons. , * it has been suggested that the increased incidence at that time of year might be related to the heightened chance of contact between infants and toddlers cence,l , , , that is bound to occur when children remain indoors in close contact.z nursery epidemics, which depend on the chance introduction and dissemination of epec within a relatively homogeneous population and stable environment, demonstrate no seasonal prevalence. average relative humidity, temperature, and hours of daylight have no significant effect in determining whether an outbreak will follow the introduction of enteropathogenic strains of e. coli into a ward of infants. there are no clinical studies of the variations in peripheral leukocyte count, urine, or cerebrospinal fluid in neonatal enteritis caused by epec. microscopic examination of stools of infants with acute diarrheal illness caused by these organisms usually has revealed an absence of fecal polymorphonuclear l e~k o c y t e s~'~~~~~~~~~*~~~ although data on fecal lactoferrin in human volunteers suggest that an inflammatory process may be important in epec diarrhea. , stool ph can be neutral, acid, or alkaline. serologic methods have not proved to be useful in attempting to establish a retrospective diagnosis of epec infection in neonates. rising or significantly elevated agglutinin titers rarely could be demonstrated in early investigation^^'^"'^^^'; hemagglutinating antibodies showed a significant response in no more than % to % of cases. , fluorescent antibody techniques have shown promise for preliminary identification of epec in acute infantile diarrhea. this method is specific, with few false-positive results, and it is more sensitive than conventional plating and isolation t e c h n i q~e s .~~~,~~' .~~~ the rapidity with which determinations can be performed makes them ideally suited for screening ill infants and possible carriers in determining the extent and progression of a n~r s e r f '~,~~~ or om mu nit$^^^^'' outbreak. because immunofluorescence does not depend on the viability of organisms and is not affected by antibiotics that suppress growth on culture plates, it can be used to advantage in following bacteriologic responses and relapses in patients receiving oral the rap^.^","^ the use of fluorescent antibody techniques offers many advantages in the surveillance and epidemiologic control of epec gastroenteritis. immunofluorescent methods should supplement but not replace standard bacteriologic and serologic methods for identification of enteric pathogens. specific gene probes and pcr primers for the bfp adhesin, the intimin-encoding gene (eue) and for a cryptic plasmid locus (eaf) are a~ailable.~~ detection of bfp or eaf are superior to detection of eue, because many non-epec, including nonpathogens, carry the eae gene. b pcr and gene probe analysis can be performed directly on the stools of suspect infants. however, confirmation of infection by the identification of the organism in pure culture should be pursued. before widespread use of molecular methods, the hep- cell adherence assay was proposed for epec diagnosis."' the presence of a focal or localized adherence (la) pattern on the surface of hep- or hela cells after -hour coincubation is a highly sensitive and specific test for detection of epec. the requirement for cell culture and expertise in reading this assay limits its utility to the research setting. an elisa for the bfp has been described but is not readily available? the capacity of la + epec to polymerize f-actin can be detected in tissue culture cells stained with rhodamine-labeled phall~idin.~~' this fluorescence-actin staining (fas) test is cumbersome and impractical for routine clinical use. the mortality rate recorded previously in epidemics of epec gastroenteritis is impressive for its variability. during the s and s, when organisms later recognized as classic enteropathogenic serotypes were infecting infants, the case-fatality ratio among neonates was about %. during the s and s, many nursery epidemics still claimed about one of every four infected infants, but several outbreaks involving the same serotypes under similar epidemiologic circumstances had fatality rates of less than h. in th e s, reports appeared in the literature of a nursery epidemic with a % neonatal mortality rate and of an extensive outbreak in a nursery for premature infants with % fatalities ; another report stated that among " consecutive infants admitted to the hospital for epec diarrheal disease, none died of diarrheal disease per se." a significant proportion of the infants who died during or shortly after an episode of gastroenteritis already were compromised by preexisting disease , , or by congenital m a l f~r m a t i o n s~'~,~~'~~~~ at the time they acquired their illness. these underlying pathologic conditions appear to exert a strongly unfavorable influence, probably by reducing the infant's ability to respond to the added stresses imposed by the gastrointestinal tract infection. although prematurity is often mentioned as a factor predisposing to a fatal outcome, the overall mortality rate among premature infants with epec gastroenteritis has not differed significantly over the years from that recorded for term the management of epec gastroenteritis should be directed primarily toward prevention or correction of problems caused by loss of fluids and electr ytes.i~~ most neonates have a relatively mild illness that can be treated with oral rehydration. infants who appear toxic, those with voluminous diarrhea and persistent vomiting, and those with increasing weight loss should be hospitalized for observation and treatment with parenteral fluids and careful maintenance of fluid and electrolyte balance and possibly with antimicrobial therapy. clinical studies suggest that slow nasogastric infusion of an elemental diet can be valuable in treating infants who have intractable diarrhea that is unresponsive to standard modes of therapy. there is no evidence that the use of proprietary formulas containing kaolin or pectin is effective in reducing the number of diarrheal stools in neonates with gastroenteritis. attempts to suppress the growth of enteric pathogens by feeding lactobacillus to the infant in the form of yogurt, powder, or granules have not been shown to be of value. a trial of cholestyramine in newborns with epec gastroenteritis had no effect on the duration or severity of the diarrhea. the use of atropine-like drugs, paregoric, or loperamide to reduce intestinal motility or cramping should be avoided. inhibition of peristalsis interferes with an efficient protective mechanism designed to rid the body of intestinal pathogens and may lead to fluid retention in the lumen of the bowel that may be sufficient to mask depletion of extracellular fluid and electrolytes. the value of antimicrobial therapy in management of neonatal epec gastroenteritis, if any, is uncertain. there are no adequately controlled studies defining the benefits of any antibiotic in eliminating epec from the gastrointestinal tract, reducing the risk of cross-infection in community or nursery outbreaks, or modifymg the severity of the illness. proponents of the use of antimicrobial agents have based their claims for efficacy on anecdotal observations or comparative studies. nonetheless, several clinical investigations have provided sufficient information to guide the physician faced with the dilemma of deciding whether to treat an individual infant or an entire nursery population suffering from epec diarrheal disease. it should be emphasized, however, that these guidelines must be considered tentative until rigidly controlled, double-blind studies have established the efficacy of antibiotics on a more rational and scientific basis. oral therapy with n e o m y~i n ,~'~'~~' ~olistin,'~~or chloram-phenic ~~~ appears to be effective in rapidly reducing the number of susceptible epec organisms in the stool of infected infants. studies comparing the responses of infants treated orally with ne~mycin?~' gentamicin: p~l p y x i n :~~ or kanamy~in'~' with the responses of infants receiving supportive therapy alone have shown that complete eradication of epec occurs more rapidly in those receiving an antimicrobial agent. in most cases, stool cultures are free of epec to days after the start of therapy. bacteriologic failure, defined as continued isolation of organisms during or after a course of an antimicrobial agent, can be expected to occur in % to % of patients? s such relapses generally are not associated with a recurrence of ~y m p t~m~.~~i *~~~*~~~ the effectiveness of oral antimicrobial therapy in reducing the duration of epec excretion serves to diminish environmental contamination and the spread of pathogenic organisms from one infant to another. breaking the chain of fecal-oral transmission by administering antimicrobial agents simultaneously to all carriers of epec and their immediate contacts in the nursery has appeared to be valuable in terminating outbreaks that have failed to respond to more conservative m e a s~r e s .~'~,~~,~~~ the apparent reduction in morbidity and mortality associated with oral administration of neomycin, . , colistin, . . p o l y m y x i r~,~~~ or gentamicin & during nursery epidemics has led to the impression that these drugs also exert a beneficial clinical effect in severely or moderately ill infants. reports describing bacteriologic: or histopathol~gic~'~ evidence of tissue invasion by epec have persuaded some investigators to suggest the use of parenteral rather than oral drug therapy in debilitated or malnourished infants. on the basis of these data, there appears to be sufficient evidence to recommend oral administration of nonabsorbable antibiotics in the treatment of severely or moderately ill newborns with epec gastroenteritis. the drug most frequently used for initial therapy is neomycin sulfate in a dosage of mg/kg/day administered orally every hours in three divided doses. s in communities in which neomycin-resistant epec has been prevalent, treatment with colistin sulfate or polymyxin b in a dosage of to mglkglday orally and divided into three equal doses may be appropriate. however, it is rarely necessary to use this approach. treatment should be continued only until stool cultures become negative for epec. because of the unavoidable delay before cultures can be reported, most infants receive therapy for to days. if fluorescent antibody testing of rectal swab specimens is available, therapy can be discontinued as soon as epec no longer is identified in smears; this takes no more than hours in more than % of cases. after diarrhea and vomiting have stopped and the infant tolerates formula feedings, shows a steady weight gain, and appears clinically well, discharge with outpatient follow-up is indicated. bacteriologic relapses do not require therapy unless they are associated with illness or high epidemiologic risks to other young infants in the household. because the infecting organisms in these recurrences generally continue to show in vitro susceptibility to the original drug, it should be reinstituted pending bacteriologic re~ults. ~~ when clinical judgment suggests that a neonate may be suffering from bacterial sepsis and epec diarrheal disease, parenteral antimicrobial therapy is indicated after appropriate cultures have been obtained. the routine use of systemic therapy in severe cases of epec enteritis is not appropriate on the basis of current clinical experience. antimicrobial susceptibility patterns of epec are an important determinant of the success of therapy in infections with these organism^.^^',^^'^^^ these patterns are unpredictable, depending on the ecologic pressures exerted by local antibiotic and on the incidence of transmissible resistance factors in the enteric flora of the particular population served by an i n s t i t~t i o n .~~~"~~ for these reasons, variations in susceptibility patterns are apparent in different n~r s e r i e s~~~, '~~ and even from time to time within the same institution. , , sudden changes in clinical response may even occur during the course of a single epidemic as drugsusceptible strains of epec are replaced by strains with multidrug r e~i s t a n c e .~~~'~~' ,~~' because differences can exist in the susceptibilities of different epec serogroups to various antimicrobial agents, regional susceptibility patterns should be reported on the basis of ob group or serotype rather than for epec as a whole. knowledge of the resistance pattern in one's area may help in the initial choice of antimicrobial therapy. the prevention of hospital outbreaks of epec gastroenteritis is best accomplished by careful attention to infection control policies for a nursery. all infants hospitalized with diarrhea should have a bacteriologic evaluation. if the laboratory is equipped and staffed to perform fluorescent antibody testing, infants transferred from another institution to a newborn, premature, or intensive care nursery and all infants with gastroenteritis on admission during an outbreak of epec diarrhea or in a highly endemic area can be held in an observation area for or hours until the results of the fluorescent antibody test or pcr are received. because of the difficulty in diagnosing epec infection, reference laboratories, such as those at the centers for disease control and prevention (cdc), should be notified when an outbreak is suspected. infants suspected to be excreting epec, even if healthy in appearance, then can be separated from others and given oral therapy until the test results are negative. some experts have suggested that when the rapid results obtainable with fluorescent antibody procedures are not available, all infants admitted with diarrhea in a setting where epec is common may be treated as if they were excreting epec or some other enteric pathogen until contrary proof is obtained. stool cultures should be obtained at admission, and contact precautions should be enforced among all who come into contact with the infant. additional epidemiologic studies are needed to establish the advantages of careful isolation and nursing techniques, particularly in smaller community hospitals in which the number of infants in a "gastroenteritis ward may be small. the use of prophylactic antibiotics has been shown to be of no value and can select for increased r e~i s t a n c e .~~~"~~ unfortunately, it can be difficult to keep a nursery continuously free of epec. specific procedures have been suggested for handling a suspected outbreak of bacterial enteritis in a newborn nursery or infant care ~n i t .~~~l~~~*~~~ evidence indicating that a significant proportion of e. coli enteritis may be caused by nontypeable strains has required some modification of these earlier recommendations. the following infection control measures may be appropriate: . the unit is closed, when possible, to all new admissions. . cultures for enteric pathogens are obtained from nursing personnel assigned to the unit at the time of the outbreak. . stool specimens obtained from all infants in the nursery can be screened by the fluorescent antibody or another technique and cultured. identification of a classic enteropathogenic serotype provides a useful epidemiologic marker; however, failure to isolate one of these strains does not eliminate the possibility of illness caused by a nontypeable epec. . antimicrobial therapy with oral neomycin or colistin can be considered for all infants with a positive fluorescent antibody test or culture result. the initial drug of choice depends on local patterns of susceptibility. depending on the results of susceptibility tests, subsequent therapy may require modification. . if an identifiable epec strain is isolated, second and third stool specimens from all infants in the unit are reexamined by the fluorescent antibody technique or culture at -hour intervals. if this is not practical, exposed infants should be carefully followed. . early discharge for healthy, mature, uninfected infants is advocated. . an epidemiologic investigation should be performed to seek the factor or factors responsible for the outbreak. a surveillance system may be established for all those in contact with the nursery, including physicians and other health care personnel, housekeeping personnel, and postpartum mothers with evidence of enteric disease. a telephone, mail, or home survey may be conducted on all infants who were residing in the involved unit during the weeks before the outbreak. . when all patients and contacts are discharged and control of the outbreak is achieved, a thorough terminal disinfection of the involved nursery is mandatory. above all, personnel and parents should pay scrupulous attention to hand hygiene when handling infants. ' since a multistate outbreak of enterohemorrhagic colitis was associated with e. coli :h , shiga toxin-producing e. coli (stec) have been recognized as emerging gastrointestinal pathogens in most of the industrialized world. a particularly virulent subset of stec, ehec, causes frequent and severe outbreaks of gastrointestinal the most virulent ehec belong to serotype :h . ehec has a bovine reservoir and is transmitted by undercooked meat, unpasteurized milk, and contaminated vegetables such as lettuce, alfalfa sprouts, and radish sprouts (as occurred in more than schoolchildren in japan). it also spreads directly from person to the clinical syndrome is that of bloody, noninflammatory (sometimes voluminous) diarrhea that is distinct from febrile dysentery with fecal leukocytes seen in shigellosis or eiec infection^.^^ most cases of ehec infections have been recognized in outbreaks of bloody diarrhea or hus in daycare centers, schools, nursing homes, and c o m m~n i t i e s .~~~-~~~ although ehec infections often involve infants and young children, the frequency of this infection in neonates remains unclear; animal studies suggest that receptors for the shiga toxin may be developmentally regulated and that susceptibility to disease may be age related. the capacity of ehec to cause disease is related to the phage-encoded capacity of the organism to produce a vero cell cytotoxin, subsequently shown to be one of the shiga toxins. - shiga toxin is neutralized by antiserum against shiga toxin, whereas shiga toxin , although biologically similar, is not neutralized by anti-shiga toxin. , like shiga toxin made by shigella dysenteriae, both e. coli shiga toxins act by inhibiting protein synthesis by cleaving an adenosine residue from position in the s ribosomal rna (rrna) to prevent elongation factor- -dependent aminoacyl transfer rna (trna) from binding to the s rrna. the virulence of ehec also may be determined in part by a -mda plasmid that encodes for a fimbrial adhesin in and . , this phenotype is mediated by the lee pathogenicity island, which is highly homologous to the island present in epec strains. ehec and other stec infections should be suspected in neonates who have bloody diarrhea or who may have been exposed in the course of an outbreak among older individuals. because most cases are caused by ingestion of contaminated food, neonates have a degree of epidemiologic protection from the illness. diagnosis of stec diarrhea is made by isolation and identification of the pathogen in the feces. e. coli :h does not ferment sorbitol, and this biochemical trait is commonly used in the detection of this s e r~t y p e .~~. '~~ because some nonpathogenic e. coli share this characteristic, confirmation of the serotype by slide agglutination is required. these techniques can be performed in most clinical laboratories. however, detection of non- serotypes is problematic and relies on detection of the shiga toxin; available methods include shiga toxin elisa, latex agglutination, and molecular method^.^^,^^^ these should be performed by a reference laboratory. hus in infants is not necessarily caused by stec infection. even in older patients, however, the stool is typically negative for stec at the time the that hus develops. ' serum and fecal detection of cytotoxin has been performed in such patients, but no diagnostic modality is definitive once hus has s~pervened!~~,~~~ antimicrobial therapy should not be administered to patients who may have stec infection, although their role in inducing hus remains c o n t r o~e r s i a l .~~~'~~~ management of the diarrhea and possible sequelae is supportive, with proper emphasis on fluid and electrolyte replacement. aggressive rehydration is helpful in minimizing the frequency of serious sequelae. the hep- adherence assay is useful for the detection of epec, which exhibit a classic la pattern."' two other adherence patterns can be discerned in this assay: aggregative (aa) and diffuse (da). these two patterns have been suggested to define additional pathotypes of diarrheogenic e. coli." strains exhibiting the aa pattern (i.e., eaec) are common pathogens of infants.lz eaec cause diarrhea by colonization of the intestinal mucosa and elaboration of enterotoxins and c y t o t o~i n s .~~~~~ many strains can be shown to elicit secretion of inflammatory cytokines in vitro, which may contribute to growth retardation associated with prolonged otherwise asymptomatic colonization.io several virulence factors in eaec are under the control of the virulence gene activator aggr. presence of the aggr regulator or its effector genes has been proposed as a means of detecting truly virulent eaec strains (called typical eaec), , and an empirical gene probe long used for eaec detection has been shown to correspond to one gene under aggr the mode of transmission of eaec has not been well established. in adult volunteer studies, the infectious dose is high (> lo colony-forming units [ cfu] ), suggesting that in adults at least, person-to-person transmission is unlikely. .m several outbreaks have been linked to consumption of contaminated f~o d . "~~,~'~ the largest of these outbreaks involved almost schoolchildren in japan "; a contaminated school lunch was the implicated source of the outbreak. some studies have demonstrated contamination of condiments or milk, which could represent vehicles of foodborne transmission. several nursery outbreaks of eaec have been bserved, ~'~~'~ although in no case has the mechanism of transmission been established. the fist reported nursery outbreak involved infants in nis, serbia, in . because these infants did not ingest milk from a common source, it is presumed that horizontal transmission by environmental contamination or hands of health care personnel was possible. most of the infants were full term and previously well, and they were housed in two separate nursery rooms. the earliest epidemiologic studies of eaec implicated this organism as a cause of endemic diarrhea in developing c o~n t r i e s .~'~-~'~ in this setting, eaec as defined by the m pattern of adherence to hep- cells can be found in upward of % of the population at any one time>l newer molecular diagnostic modalities have revised this figure downward, although the organism remains highly prevalent in many areas. several studies from the indian subcontinent implicated eaec among the most frequent enteric pathogen^.^'^.^'^.^^^ other sites reproducibly reporting high incidence rates include and bra~il."~'*~~' there is evidence that eaec may be emerging in incidence. a study from spo paulo, brazil, implicated eaec as the prevalent e. coli pathotypes in infants i ; epec had previously been shown to be the most common pathogen in this community. many other sites in developing countries of africa:" asia, ° ~ and south america " have described high endemic rates. several studies have suggested that eaec is also a common cause of infant diarrhea in industrialized c~u n t r i e s . "~~~~~~ using molecular diagnostic methods, a large prospective study in the united kingdom implicated eaec as the second most common enteric bacterial pathogen after cumpylob~cter.~~~ a similar study from switzerland found eaec to be the most common bacterial enter~pathogen.~'~ studies from the united states also have demonstrated a high rate of eaec diarrhea in infants; using molecular diagnostic methods, eaec was implicated in % and % of outpatient and inpatient diarrhea cohorts, respectively, compared with less than % of asymptomatic control infants (p < . ). although epidemiologic studies have shown that eaec can cause diarrhea in all age groups, several studies suggest that the infection is particularly common in infants younger than months d. * descriptions from outbreaks and volunteer studies suggest that eaec diarrhea is watery in character with mucus but without blood or frank pus. o o patients typically are afebrile. several epidemiologic studies have suggested that many infants may have bloody diarrhea, i but fecal leukocytes are uncommon. the earliest reports of eaec infection suggested that this pathogen may be particularly associated with persistent diarrhea (> days). - however, later studies suggest that persistent diarrhea may occur in only a subset of infected infants!" in the serbian outbreak of infected infants, the mean duration of diarrhea was . days ''; diarrhea persisted more than days in only three patients. infants in this outbreak had frequent, green, odorless stools. in three cases, the stools had mucus, but none had visible blood. eleven babies developed temperatures in excess of oc; only one had vomiting. despite a lack of clinical evidence suggesting inflammatory enteritis, several clinical studies have suggested that eaec is associated with subclinical inflammation, including the shedding of fecal cytokines and la~toferrin.'~~.~'~ studies in fortaleza, brazil, suggest that children asymptomatically excreting eaec may exhibit growth shortfalls compared with uninfected peers.lo a study from germany reported an association between eaec isolation and infant colic in infants without diarrhea. z this observation has not been repeated. eaec should be considered in the differential diagnosis of persistent diarrhea and failure to thrive in infants. diagnosis of eaec requires identification of the organism in the patient's feces. the hep- adherence assay can be used for this purpose"'; some reports suggest that the adherence phenotype can be observed using formalin-fixed cell^^^'^^^' thereby obviating the need to cultivate eukaryotic cells for each assay. pcr and gene probe for typical eaec are available. successful antibiotic therapy has been reported using fluoroquinolones in adult although preliminary studies suggest that a~ithrornycin~~~ or r i f a~i m i n~~~ also may be effective. therapy in infected infants should be guided by the results of susceptibility testing, as eaec frequently is antibiotic re~istant.~" additional e. coli pathotypes have been described, including diffusely adherent e. coli (daec), and cytodetaching e. c i .~~~ daec has been specifically associated with diarrhea outside of infancy, as infants may have some degree of inherent resistance to infection. cytodetaching e. coli represent organisms that secrete the e. coli hem~lysin.~~' it is not clear whether these latter organisms are true enteric pathogens. there are differences in invasiveness of salmonella strains related to serotype. s. typhi, s. choleraesuis, salmonella heidelberg, p and salmonella dub inm are particularly invasive, with bacteremia and extraintestinal focal infections occurring frequently. salmonella species possess genes closely related to those for the shigella invasion plasmid anti ensthese genes are probably essential to intestinal infection. virulence plasmids, which increase invasiveness in some serotypes, have been recognized, although the precise mechanisms of virulence remain to be elucidated; resistance to complement-mediated bacteriolysis by inhibition of insertion of the terminal c b- membrane attack complex into the outer membrane may be laboratory studies have demonstrated dramatic strain-related difference in the ability of s. typhimurium t o evoke fluid secretion, to invade intestinal mucosa, and to disseminate beyond the production of an enterotoxin immunologically related to cholera toxin by about two thirds of salmonella strains may be related to the watery diarrhea often seen. part because of the properties of their lipopolysaccharide~~~~~~~~ persistence of the organism within phagolysosomes of phagocytic cells may occur with any species of salmonella. it is not completely clear how the organisms have adapted to survive in the harsh intracellular environment, but their survival has major clinical significance. it accounts for relapses after therapy. it explains the inadequacy of some antimicrobial agents that do not penetrate phagolysosomes. it perhaps is the reason for prolonged febrile courses that occur even in the face of appropriate therapy. although humoral immunity and cell-mediated immunity are stimulated during salmonella infections, it is believed that cell-mediated immunity plays a greater role in eradication of the ba~teria. '~ t cell activation of macrophages appears to be important in killing intracellular salmonella. defective interferon-y production by monocytes of newborns in response to s. typhimurium lipopolysaccharide may explain in part the unusual susceptibility of infants to salmonella infection. studies in mice suggest that helper t cell (th ) responses in peyer's patches and mesenteric lymph nodes may be central to protection of the intestinal m~c o s a .~~~ humans who lack the il- receptor and therefore have impaired th responses and interferon-y production are at increased risk for salmonella infe~tion.~~' in typhoid fever, presence of an envelope antigen, vi, is known to enhance virulence. patients who develop classic enteric fever have positive stool cultures in the first few days after ingestion of the organism and again late in the course after a period of bacteremia. this course reflects early colonization of the gut, penetration of gut epithelium with infection of mesenteric lymph nodes, and reseeding of the gut during a subsequent bacteremic pha~e. ~' studies of s. typhimurium in monkeys suggest similar initial steps in pathogenesis (e.g., colonization of gut, penetration of gut epithelium, infection of mesenteric lymph nodes) but failure of the organism to cause a detectable level of ba~teremia. ~~ although both salmonella and shigella invade intestinal mucosa, the resultant pathologic changes are different. shigella multiplies within and kills enterocytes with production of ulcerations and a brisk inflammatory response, whereas salmonella passes through the mucosa and multiplies within the lamina propria, where the organisms are ingested by phagocytes; consequently, ulcer formation is less striking, although villus tip cells are sometimes sloughed. acute crypt abscesses can be seen in the stomach and small intestine, but the most dramatic changes occur in the colon, where acute diffuse inflammation with mucosal edema and crypt abscesses are the most consistent findings. v with s. typhi there also is hyperplasia of peyer's patches in the ileum, with ulceration of overlying tissues. salmonella strains, with the exception of s. typhi, are well adapted to a variety of animal hosts; human infection often can be traced to infected meat, contaminated milk, or contact with a specific animal. half of commercial poultry samples are contaminated with salmonella. definition of the serotype causing infection can sometimes suggest the likely source. for example, s. dublin is closely associated with cattle; human cases occur with a higher-than-predicted frequency in people who drink raw milk.@' for s. typhimurium, which is the most common serotype and accounts for more than one third of all reported human cases, a single source has not been established, although there is an association with cattle. despite the ban by the u.s. food and drug administration (fda) on interstate commercial distribution of small turtles, these animals continue to be associated with infection, as illustrated by a series of cases in puerto ~i~~.~~~ various pet reptiles are an important source of a variety of unusual salmonella serotypes such as salmonella marina, salmonella chameleon, salmonella arizonae, salmonella java, salmonella stanley, salmonella poona, salmonella jangwain, salmonella tilene, salmonella pomona, salmonella miami, salmonella manhattan, salmonella litchfield, salmonella rubislaw, and salmonella w a~s e n a a r .~~-~~ salmonella organisms are hardy and capable of prolonged survival; organisms have been documented to survive in flour for nearly a year? salmonella tennessee has been shown to remain viable for many hours on non-nutritive surfaces (i.e., glass, hours; stainless steel, hours; enameled surface, hours; rubber mattress, hours; linen, hours; and rubber tabletop, infection with salmonella is, like most enteric infections, more common in young children than in adults. the frequency of infection is far greater in the first years of life; roughly equal numbers of cases are reported during each decade beyond years of age. although the peak incidence occurs in the second through sixth months of life, infection in the neonate is relatively common. researchers at the cdc have estimated the incidence of salmonella infection in the first month of life at nearly cases per , infants? adult volunteer studies suggest that large numbers of salmonella ( lo to lo ) need to be ingested to cause di~ease. ~' however, it is likely that lower doses cause illness in infants. the occurrence of nursery ~u t b r e a k s~"~~~~~ and intrafamilial spread suggests that organisms are easily spread from person to person; this pattern is typical of low-inoculum diseases transmitted by the fecal-oral route. the neonate with salmonella infection infrequently acquires the organism from his or her mother during delivery. although the index case in an outbreak can often be traced to a mother, - , subsequent cases result from contaminated objects in the nursery e n~i r o n m e n t~~"~~~ serving as a reservoir coming in contact with hands of attending p e r~o n n e l .~~.~'~ the mother of an index case may be symptomatic ~ i ~ or asymptomatic with preclinical infecti n, '~ convalescent infedon, , , or chronic carriage. the risk of the newborn becoming infected once salmonella is introduced into a nursery has been reported to be as high as % to %, , but the frequency of infection may be lower because isolated cases without a subsequent epidemic are unlikely to be reported. gastric acidity is an important barrier to salmonella infection. patients with anatomic or functional achlorhydria are at increased risk of developing salmonellosis. ~ the hyp~chlorhydria'~ and rapid gastric emptying typical of early lifez may in part explain the susceptibility of infants to salmonella. premature and low-birth-weight infants appear to be at higher risk of acquiring salmonella infection than term whether this reflects increased exposure because of prolonged hospital stays or increased susceptibility on the basis of intestinal or immune function is unclear. contaminated food or water is often the source of salmonella infection in older patients; the limited diet of the infant makes contaminated food a less likely source of infection. although human milk? - raw milk? powdered milk, - formula: and cereal i have been implicated in transmission to infants, more often fomites, such as delivery room resu~citators, ~' rectal thermometer~, '~>~'~ oropharyngeal suction device^,^^^'^^' water baths for heating formula? soap dispenser^,^" " clean" medicine airconditioning mattresses, radiant and serve as reservoirs. one unusual outbreak involving premature and term infants was traced to faulty plumbing, which caused massive contamination of environment and personnel. after salmonella enters a nursery, it is difficult to eradicate. epidemics lasting to week^,'@^,^^' weeks,& months, b year:' " and to months b have been reported. spread to nearby pediatric wards has the incubation period in nursery outbreaks has varied widely in several studies where careful attention has been paid to this variable. in one outbreak of salmonella oranienburg involving newborns, % of cases occurred within days of in an outbreak of s. typhimurium, each of the ill infants presented within days of birth. these incubation periods are similar to those reported for salmonella newport in older children and adults, % of whom have been reported to be ill within days of e~p o s u r e .~'~'~~' conversely, one outbreak of salmonella nienstedten involving newborns was characterized by incubation periods of to days. the usual incubation period associated with fecal-oral nursery transmission is not found with congenital typhoid. during pregnancy, typhoid fever is associated with bacteremic infection of the fetus. the congenitally infected infants are symptomatic at birth. they are usually born during the second to fourth week of untreated maternal illness. usually, the mother is a carrier; fecal-oral transmission of s. typhi can occur with delayed illness in the newborn. several major clinical syndromes occur with nontyphoidal salmonella infection in young infants. colonization without illness may be the most common outcome of ingestion of salmonella by the neonate. such colonization usually is detected when an outbreak is under investigation. most infected infants who become ill have abrupt onset of loose, green, mucus-containing stools, or they have bloody diarrhea; an elevated temperature is also a common finding in salmonella gastroenteritis in the first months of life. o grossly bloody stools are found in the minority of patients, although grossly bloody stools can occur in the first hours of life. hematochezia is more typically associated with noninfectious causes (e.g., swallowed maternal blood, intestinal ischemia, hemorrhagic diseases, anorectal fissures) at this early age. there appear to be major differences in presentation related to the serotype of s. enteritidis causing infection. for example, in one epidemic of s. oranienb~rg~'~ involving newborns, % had grossly bloody stools, % were febrile, % had mucus in their stools, and only % were healthy. in a series of s. newport infections involving premature infants; % of infants with gastroenteritis had blood in their stools, % had fever, % had mucus in their stools, and % were asymptomatic. in an outbreak of s. typhim~rium~~' involving ill and healthy infants, none had bloody stools; all of the symptomatic infants were febrile and usually had loose, green stools. of infants infected by salmonella virchow, % were asymptomatic; the rest had mild diarrhea! seals and colleagues described infants with s. nienstedten, all of whom had watery diarrhea and low-grade fever; none had bloody stools. in a large outbreak in zimbabwe of s. heidelberg infection reported by bannerman, % of infants were asymptomatic, % had diarrhea, % had fever, % had pneumonia, and % developed meningitis. an outbreak of salmonella worthington was characterized primarily by diarrhea, fever, and jaundice, although of infants developed meningitis and % died. in dramatic contrast to these series, none of infants with positive stool cultures for s. tennessee had an illness in a nursery found to be contaminated with that organism. a few infants with salmonella gastroenteritis have developed necrotizing e n t e r o c o l i t i~, ~~~~~~ but it is not clear whether salmonella was the cause. although gastroenteritis is usually self-limited, chronic diarrhea has sometimes been attributed to s a l r n~n e l l a .~~~~~~~ whether chronic diarrhea is caused by salmonella is uncertain. although some infants develop carbohydrate intolerance after a bout of salmonella and salmonella is typically listed as one of the causes of postinfectious protracted diarrhea, it is difficult to be sure that the relationship is causal. the prolonged excretion of salmonella after a bout of gastroenteritis may sometimes cause non-specific chronic diarrhea to be erroneously attributed to salmonella. major extraintestinal complications of salmonella infection may develop in the neonate who becomes bacteremic. extraintestinal spread may develop in infants who initially present with diarrhea and in some who have no gastrointestinal tract signs. bacteremia appears to be more common in the neonate than in the older a study of more than children with salmonella infection showed that extraintestinal infection occurred significantly more often ( . % versus . %) in the first months of life. several retrospective studies suggest that infants in the first month of life may have a risk of bacteremia as high as % to %. one retrospective suggests that the risk is not increased in infancy and estimates that the risk of bacteremia in childhood salmonella gastroenteritis is between . % and . %. prospective studies of infants in the first year of life suggest that the risk of bacteremia is . % to . %. * although selection biases in these studies limit the reliability of these estimates, the risk is substantial. the salmonella species isolated from infants include some serotypes that appear to be more invasive in the first months of life than in older children or healthy adults (s. newport, s. agona, s. blockley, s. derby, s. enteritidis, s. heidelberg, s. infantis, s. javiana, s. saint-paul, and s. typhimurium) and serotypes that are aggressive in every age group (s. choleraesuis and s. dublin). other serotypes appear more likely to cause bacteremia in adults (s. typhi, s. paratyphi a, and s. paratyphi b). virtually any salmonella serotype can cause bacteremic disease in neonates. a few infants with salmonella gastroenteritis have died with e. coli or pseudomonas aeruginosa sepsis; but the role of salmonella in these cases is unclear. unlike the situation in older children in whom bacteremic salmonellosis often is associated with underlying medical conditions, bacteremia may occur in infants who have no immunocompromising conditions. salmonella bacteremia is often not suspected clinically because the syndrome is not usually d i s t i n~t i v e . ~~~~~ even afebrile, well-appearing children with salmonella gastroenteritis have been documented to have bacteremia that persists for several days. although infants with bacteremia may have spontaneous resolution without therapy: a sufficient number develop complications to warrant empirical antimicrobial therapy when bacteremia is suspected. the frequency of complications is highest in the first month of life. meningitis is the most feared complication of bacteremic salmonella disease. between % and % of all cases of nontyphoidal salmonella meningitis occur in the first months of life. the serotypes associated with neonatal meningitis (s. typhimurium, s. heidelberg, s. enteritidis, s. saint-paul, s. newport, and s. panama) are serotypes frequently associated with bacteremia. meningitis has a high mortality rate, in part because of the high relapse rates. relapse has been reported in up to % of ca~es. ~' in some studies, more than % of patients with meningitis have died, although more typically, % to % of infants die. * the survivors suffer the expected complications of gram-negative neonatal meningitis, including hydrocephalus, seizures, ventriculitis, abscess formation, subdural empyema, and permanent neurologic impairment. neurologic sequelae have included retardation, hemiparesis, epilepsy, visual impairment, and a t h e t o~i s .~~~ in large nursery outbreaks, it is common to find infants whose course is complicated by pneum~nia?'~ osteo-myeliti~, ">~~~ or septic arthriti~. '~,~'~ othe r rare complications of salmonellosis include p e r i~a r d i t i s ,~~ p y e l i t i~,~~ peritonitis: otitis media: mas ti ti^,^^^ chole~ystitis,~~' endophthalmiti~,~~~ cutaneous abscesses, and infected cephal~hematoma?~' other focal infections seen in older children and adults, such as endocarditis and infected aortic aneurysms, rarely or never have been reported in neonates. , altho ugh the mortality rate in two reviews of nursery outbreaks was . % to . %," in some series, it reached %. enteric fever, most often related to s. typhi but also occurring with s. paratyphi a, s. paratyphi b, s. paratyphi c, and other salmonella species, is reported much less commonly in infants than in older patients. infected infants develop typical findings of neonatal sepsis and meningitis. current data suggest that mortality is about y .~~' in utero infection with s. typhi has been described. typhoid f e~e r~" *~~' and nontyphoidal salmonella infections during pregnancy put women at risk of aborting the fetus. premature labor usually occurs during the second to the fourth week of maternal typhoid if the woman is untreated. in a survey of typhoid fever in pregnancy during the preantibiotic era, of women with well-documented cases delivered prematurely, with resultant fetal death; the rest delivered at term, although only infants survived. the outlook for carrying the pregnancy to term and delivering a healthy infant appears to have improved dramatically during the antibiotic era. however, one of seven women with typhoid in a series still delivered a dead fetus with extensive liver necrosis. in the preantibiotic era, about % of pregnant women with typhoid fever died. with appropriate antimicrobial therapy, pregnancy does not appear to put the woman at increased risk of death. despite these welldescribed cases, typhoid fever is rare early in life. of cases of typhoid fever that osler and m~c r a e~~~ reported, only were in the first year of life. in areas where typhoid fever is still endemic, systematic search for infants with enteric fever has failed to find many cases. the few infections with s. typhi documented in children in the first year of life often present as a brief nondescript "viral syndrome" or as p n e~r n o n i t i s ?~~*~~' fever, diarrhea, cough, vomiting, rash, and splenomegaly may occur; the fever may be high, and the duration of illness may be many weeks. the current practice of early discharge of newborn infants, although potentially decreasing the risk of exposure, can make recognition of a nursery outbreak difficult. diagnosis of neonatal salmonellosis should trigger an investigation for other cases. other than diarrhea, signs of neonatal salmonella infection are similar to the nonspecific findings seen in most neonatal infections. lethargy, poor feeding, pallor, jaundice, apnea, respiratory distress, weight loss, and fever are common. enlarged liver and spleen are common in those neonates with positive blood cultures. laboratory studies are required to establish the diagnosis because the clinical picture is not distinct. the fecal leukocyte examination reveals polymorphonuclear leukocytes in % to % . of persons with salmonella infection, but it has not been evaluated in neonates. obviously, the presence of fecal leukocytes is consistent with colitis of any cause and therefore is a nonspecific finding. routine stool cultures usually detect salmonella if two or three different enteric media (i.e., macconkey's, eosin-methylene blue, salmonella-shigella, tergitol , xylose-lysine-deoxycholate, brilliant green, or bismuth sulfite agar) are used. stool, rather than rectal swab material, is preferable for culture, particularly if the aim of culture is to detect carriers. on the infrequent occasions when proctoscopy is performed, mucosal edema, hyperemia, friability, and hemorrhages may be seen.*' infants who are bacteremic often do not appear sufficiently toxic to raise the suspicion of b a~t e r e m i a .~~~ blood cultures should be obtained as a routine part of evaluation of neonates with suspected or documented salmonella infection. ill neonates with salmonella infection should have a cerebrospinal fluid examination performed. bone marrow cultures also may be indicated when enteric fever is suspected. there are no consistent abnormalities in the white blood cell count. serologic studies are not helpful in establishing the diagnosis, although antibodies to and flagellar antigens develop in many infected newborns. if an outbreak of salmonellosis is suspected, further characterization of the organism is imperative? determination of somatic and flagellar antigens to characterize the specific serotype may be critical to investigation of an outbreak. when the serotype found during investigation of an outbreak is a common one (e.g., s. typhimurium), antimicrobial resistance testing , and use of molecular techniques such as plasmid chara~terization~~~ can be helpful in determining whether a single-strain, common-source outbreak is in progress. and ampicillin or amoxicillin versus placebo. in contrast to these studies, data suggest that there may be a role for quinolone antibiotics in adults and ~h i l d r e n ,~~~,~~~ but these drugs are not approved for use in neonates, and resistance has been en~ountered.~'~ because these studies have few data as to the risk-benefit ratio of therapy in the neonate, it is uncertain whether they should influence treatment decisions in neonates. studies that have included a small number of neonates suggest little benefit from antimicrobial therapy. * * however, because bacteremia is common in neonates, antimicrobial therapy for infants younger than months who have salmonella gastroenteritis often is recommended, v v especially if the infant appears toxic. premature infants and those who have other significant debilitating conditions also should probably be treated. the duration of therapy is debatable but should probably be no more than to days if the infant is not seriously ill and if blood cultures are sterile. if toxicity, clinical deterioration, or documented bacteremia complicates gastroenteritis, prolonged treatment is indicated. even with antimicrobial therapy, some infants develop complications. the relatively low risk of extraintestinal dissemination must be balanced against the well-documented risk of prolonging the carrier state. for infants who develop chronic diarrhea and malnutrition, hyperalimentation may be required; the role of antimicrobial agents in this setting is unclear. the infant with typhoid fever should be treated with an antimicrobial agent; relapses sometimes occur after therapy. colonized healthy infants discovered by stool cultures during evaluation of an outbreak ought to be isolated but probably should not receive antimicrobial therapy. such infants should be discharged from the nursery as early as possible and followed carefully as outpatients. antimicrobial treatment of neonates who have documented extraintestinal dissemination must be prolonged. bacteremia without localization is generally treated with at least a -day course of therapy. therapy for salmonella meningitis must be given for at least weeks to lessen the risk of relapse. about three fourths of patients who have relapses have been treated for three weeks or less? similar to meningitis, treatment for osteomyelitis must be prolonged to be adequate. although cures have been reported with weeks of therapy, to weeks of therapy is recommended. in vitro susceptibility data for salmonella isolates must be interpreted with caution. the aminoglycosides show good in vitro activity but poor clinical efficacy, perhaps because of the low ph of the phagolysosome. aminoglycosides have poor activity in an acid environment. the stability of some drugs in this acid environment also may explain in vitro and in vivo disparities. the intracellular localization and survival of salmonella within phagocytic cells also presumably explains the relapses encountered with virtually every regimen. resistance to antibiotics has long been a problem with salmonella i n f e c t i~n .~~,~~~,~~' there has been a steady increase in resistance to salmonella in the united states over the last years. with the emergence of typhimurium type dt , resistance to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline has increased from . % in and to % in . resistance plasmids have been selected and transmitted, partly because therapy has been given for mild illness that should not have been treated and partly because of use of antibiotics in animal feeds. resistance to chloramphenicol and ampicillin has made trimethoprim-sulfamethoxazole increasingly important for the treatment of salmonella infection in those patients who require therapy. however, with increasing resistance to all three of these agents in asia? the middle e~r o p e ,~~~,~'~ ar gentina, and north america, , the third-generation cephalosporins and quinolones represent drugs of choice for invasive salmonellosis. the quinolones currently are not approved for persons younger than years. cefotaxime, ceftriaxone, and cefoperazone represent acceptable alternative drugs for typhoidal and nontyphoidal salmonellosis when resistance is e n c o~n t e r e d .~~"~~~ because the second-generation cephalosporins, such as cefuroxime, are less active in vitro than the third-generation cephalosporins and are not consistently clinically effective, they should not be data suggest that cefoperazone may sterilize blood and cause patients with typhoid fever to become afebrile more rapidly than with chl~ramphenicol,~~~ perhaps because cefoperazone is excreted into bile in high concent r a t i o n~.~~~ the third-generation cephalosporins may have higher cure and lower relapse rates than ampicillin or chloramphenicol in children with salmonella meningitis. the doses of ampicillin, chloramphenicol, or cefotaxime used in infants with gastroenteritis pending results of blood cultures are the same as those used in treatment of sepsis. because of the risk of gray baby syndrome, chloramphenicol should not be used in neonates unless other effective agents are not available. trimethoprim-sulfamethoxazole, although useful in older children and adults, is not used in neonates because of the risk of kernicterus. nosocomial infection with strains of salmonella resistant to multiple antibiotics, including third-generation cephalosporins, has emerged as a problem in south america. nonantibiotic interventions are important in the control of salmonella infections. limited data suggest that intravenous immune globulin (igiv) ( mg/kg on days , , , and of therapy) along with antibiotic therapy may decrease the risk of bacteremia and death in preterm infants with salmonella ga~troenteritis.~~~ early recognition and intervention in nursery outbreaks of salmonella are crucial to control. when a neonate develops salmonellosis, a search for other infants who have been in the same nursery should be undertaken. when two or more cases are recognized, environmental cultures, cultures of all infants, cohorting and contact isolation of infected infants, rigorous enforcement of hand hygiene, early discharge of infected infants, and thorough cleaning of all possible fomites in the nursery and delivery rooms are important elements of control. if cases continue to occur, the nursery should be closed to further admissions. cultures of nursery personnel are likely to be helpful in the unusual situation of an s. typhi outbreak in which a chronic carrier may be among the caretakers. culture of health care personnel during outbreaks of salmonellosis caused by other salmonella species is debatable, although often recommended. data suggest that nurses infected with salmonella rarely infect patients in the hospital setting. the fact that nursing personnel are sometimes found to be colonized during nursery outmay be a result rather than a cause of those epidemics. the potential role of vaccines in control of neonatal disease is minimal. for the vast number of non-s. ryphi serotypes, there is no prospect for an immunization strategy. multiple doses of the commercially available oral live attenuated vaccine (ty la; vivotif, berna), has been shown in chilean schoolchildren to reduce typhoid fever cases by more than %. , however, the vaccine is not recommended for persons younger than years, in part because immunogenicity of ty la is age dependent; children younger than months fail to respond with development of immunity!" vi capsular polysaccharide vaccine is available for children older than years and is effective in a single dose. whether some degree of protection of infants could the virulence of shigellae has been studied extensively since their recognition as major pathogens at the beginning of the th century. the major determinants of virulence are encoded by a -to -mda p l a~m i d .~~~.~~~ this plasmid, which is found in all virulent shigellae, encodes the synthesis of proteins that are required for invasion of mammalian cells and for the vigorous inflammatory response that is characteristic of the d i s e a~e .~~*~~ shigellae that have lost this plasmid, have deletions of genetic material from the region involved in synthesis of these proteins, or have the plasmid inserted into the chromosome lose the ability to invade eukaryotic cells and become aviru ent o ; maintenance of the plasmid can be detected in the clinical microbiology lab by ability to bind congo red. the ability to invade cells is the basic pathogenic property shared by all ~h i g e l l a e~~'~~~~ and by the shigella-like invasive e. coli, which also possesses the shigella virulence plasmid. ~ ~ ~ ~ in the laboratory, shigella invasiveness is studied in tissue culture (hela cell invasion), in animal intestine, or in rabbit or guinea pig eye, where instillation of the organism causes keratoconjunctivitis (sereny test)."' animal model studies have shown that bacteria penetrate and kill colonic mucosal cells and then elicit a brisk inflammatory response. in addition to the virulence plasmid, several chromosomal loci enhance virulence. v this has been best studied in s. flexneri in which multiple virulence-enhancing regions of the chromosome have been defined. s - the specific gene products of some of the chromosomal loci are not known; one chromosomal virulence segment encodes for synthesis of the repeat units of lipopolysaccharide. intact lipopolysaccharide is necessary but not sufficient to cause virulence. at least two cell-damaging cytotoxins that also are chromosomally encoded are produced by shigellae. one of these toxins (shiga toxin) is made in large quantities by s. dysenteriae serotype (the shiga bacillus) and is made infrequently by other shigellae. shiga toxin is a major virulence factor in s. dysenteriae, enhancing virulence at the colonic mucosa and also giving rise to sequelae similar to those caused by stec (discussed earlier). this toxin kills cells by interfering with peptide elongation during protein ~y n t h e s i s .~'~-~'~ additional toxins may also be secreted by shigellae, although their roles in virulence are not established. although much of the epidemiology of shigellosis is predictable based on its infectious dose, certain elements are unexplained. shigellae, like other organisms transmitted by the fecal-oral route, are commonly spread by food and water, but the low infecting inoculum allows person-to-person spread. because of this low inoculum, shigella is one of the few enteric pathogens that can infect swimmers. the dose required to cause illness in adult volunteers is as low as organisms for s. dysenteriae serotype , " about organisms for s. f l e~n e r i ,~~~ and organisms for s. ~o n n e i .~'~ personto-person transmission of infection probably explains the continuing occurrence of shigella in the developed world. enteropathogens that require large inocula and hence are best spread by food or drinking water are less common in industrialized societies because of sewage disposal facilities, water treatment, and food-handling practices. in the united states, daycare centers currently serve as a major focus for acquisition of shigell~sis.~'~ numerous outbreaks of shigellosis related to crowding, poor sanitation, and the low dose required for diseases have occurred in this setting. given the ease of transmission, it is not surprising that the peak incidence of disease is in the first years of life. it is, however, paradoxical that symptomatic infection is uncommon in the first year of life. - the best data on the age-related incidence of shigellosis come from mata'~~'~ prospective studies of guatemalan infants. in these studies, stool cultures were performed weekly on a group of children followed from birth to years old. the rate of infection was more than -fold lower in the first months of life than (fig. - ) . the same age-related incidence has been described in the united states and in a rural egyptian village. this anomaly has been explained by the salutary effects of brea~t-feeding.~~'-~~' however, it is likely that breast-feeding alone does not explain the resistance of infants to shigellosis. a review of three large case series - suggests that about . % ( of ) of shigellosis cases occur in infants in the neonatal period. the largest series of neonatal ~higellosis~~~ suggests that the course, complications, and etiologic serogroups are different in neonates than in older children. although newborns are routinely contaminated by maternal feces, neonatal shigellosis is rare. other aspects of the epidemiology of shigellosis elude simple explanation. the seasonality (summer-fall peak in the united states, rainy season peak in the tropics) is not well explained. the geographic variation in species causing infection likewise is not well understood. in the united states, most shigella infections are caused by s. sonnei or, less commonly, s. flexneri. in most of the developing world, the relative importance of these two species is reversed, and other shigella serotypes, especially s. dysenteriae serotype , are identified more frequently. as hygiene improves, the proportion of s. sonnei increases and that of s. flexneri decreases. data from bangladesh suggest that s. dysenteriae is less common in neonates, but s. sonnei and s. boydii are more c mmon. ~~ there appear to be some important differences in the relative frequencies of various complications of shigella infection related to age. some of these differences and estimates are based on data that are undoubtedly compromised by reporting biases. s. dysenteriae serotype characteristically causes a more severe illness than other shigellae with more complications, including pseudomembranous colitis, hemolysis, and hus. however, illnesses caused by various shigella serotypes usually are indistinguishable from each other and conventionally are discussed together. the incubation period of shigellosis is related to the number of organisms ingested, but in general, it is between and hours. volunteer studies have shown that after ingestion, illness may be delayed for a week or more. neonatal shigellosis seems to have a similar incubation period. more than one half of the neonatal cases occur within days of birth, consistent with fecal-oral transmission during parturition. mothers of infected neonates are sometimes carriers, although more typically they are symptomatic during the perinatal period. intrauterine infection is rare. in the older child, the initial signs are usually high fever, abdominal pain, vomiting, toxicity, and large-volume watery stools; diarrhea may be bloody or may become bloody. painful defecation and severe, crampy abdominal pain associated with frequent passage of small-volume stools with gross blood and mucus are characteristic findings in older children or adults who develop severe colitis. many children, however, never develop bloody diarrhea. adult volunteer studies have demonstrated that variations in presentation and course are not related to the dose ingested because some patients develop colitis with dysentery but others develop only watery diarrhea after ingestion of the same i n o c u l~m .~~~ the neonate with shigellosis may have a mild diarrheal syndrome or a severe ~o l i t i s .~~~~~~~-~~ fever in neonates is usually low grade (< " f) if the course is uncomplicated. the neonate has less bloody diarrhea, more dehydration, more bacteremia, and a greater likelihood of death than the older ~h i l d . ~~ physical examination of the neonate may show signs of toxicity and dehydration, although fever, abdominal tenderness, and rectal findings are less striking than in the older complications of shigellosis are common. although the illness is self-limited in the normal host, resolution may be delayed for a week or more. in neonates and malnourished children, chronic diarrhea may follow a bout of shigello~is. ~',~~ between % and % of hospitalized children with shigella have convulsions before or during the course of usually, the seizures are brief, generalized, and associated with high fever. seizures are uncommon in the first months of life, although neonates have been described with seizures. the cerebrospinal fluid generally reveals normal values in these children, but a few have mild cerebrospinal fluid pleocytosis. the neurologic outcome generally is good even with focal or prolonged seizures, but fatalities do occasionally occur, often associated with toxic encephalpa thy.^^' although the seizures had been postulated to result from the neurotoxicity of shiga toxin, this explanation was proved to be incorrect because most shigellae make little or no shiga toxin and the strains isolated from children with neurologic symptoms do not produce shiga t~x i n .~'~,~~' hemolysis with or without development of uremia is a complication primarily of s. dysenteriae serotype infection. sepsis during the course of shigellosis may be caused by the shigella itself or by other gut flora that gain access to the bloodstream through damaged mucosa. ' * the risk of sepsis is higher in the first year of life, particularly in neo-nates, . - , , in malnourished children, and in those with s. dysenteriae serotype infection. sepsis occurs in up to % of neonates with given the infrequency of neonatal shigellosis, it is striking that % of reported cases of shigella sepsis have involved infants in the first month of life. one of the infants with ba~teremia~~' reportedly had no discernible illness. disseminated intravascular coagulation may develop in those patients whose course is complicated by sepsis. meningitis has been described in a septic neonate. colonic perforation has occurred in n e o n a t e~, ~"~~~ older children,@' and adults. although this complication of toxic megacolon is rare, it appears to be more common in neonates than in older individuals. bronchopneumonia may complicate the course of shigellosis, but shigellae are rarely isolated from lungs or tracheal secretions." the syndrome of sudden death in the setting of extreme toxicity with hyperpyrexia and convulsions but without dehydration or sepsis (i.e., ekiri ~yndrome)~~'"~ is rare in neonates. in the nonbacteremic child, other extraintestinal foci of infection, including ~a g i n a~~~. "~ and eye,"' rarely occur. reiter's syndrome, which rarely complicates the illness in children, has not been reported in neonates. although infection is less common in infants than in toddlers, case fatality rates are highest in infant^.^^'^^' the mortality rate in newborns appears to be about twice that of older children. in industrialized societies, less than % of children with shigellosis die, whereas in developing countries, up to % die. these differences in mortality rates are related to n~t r i t i o n . ~~ availability of medical care, antibiotic resistance of many shigellae, the frequency of sepsis, and the higher frequency of s examination of stool for leukocytes as an indication of colitis is useful in support of the clinical suspicion of shigellosis. the white blood cell count and differential count also are used as supporting evidence for the diagnosis. leukemoid reactions (white blood cells > , /mm ) occur in almost % of children with s. dysenteriae serotype but in less than % of children with other ~h i g e l l a e .~~~ leukemoid reactions are more frequent in infants than in older ~hildren. ~' even when the total white blood cell count is not dramatically elevated, there may be a striking left shift. almost % of children with shigellosis have greater than % bands on the differential cell few reports address the white blood cell count in newborns, but those that do suggest that normal or low rather than elevated counts are more common. although serum and fecal antibodies develop to lipopolysaccharides and the virulence plasmid-associated polypeptide~, ~~ serologic studies are not useful in the diagnosis of shigellosis. pcr can identify shigella and eiec in feces. colonoscopy typically shows inflammatory changes that are most severe in the distal segments of therapy because dehydration is particularly common in neonatal shigellosis, attention to correction of fluid and electrolyte disturbances is always the first concern when the illness is suspected. although debate continues over the indications for antimicrobial therapy in the patient with shigellosis, the benefits of therapy generally appear to outweigh the risks. the chief disadvantages of antimicrobial therapy include cost, drug toxicity, and emergence of antibiotic-resistant shigellae. because of the self-limited nature of shigellosis, it has been argued that less severe illness should not be treated. however, children can feel quite ill during the typical bout of shigellosis, and appropriate antimicrobial therapy shortens the duration of illness and eliminates shigellae from stool, decreasing secondary spread. complications are probably decreased by antibiotics. given the high mortality rates of neonatal shigellosis, therapy should not be withheld. the empirical choice of an antimicrobial agent is dictated by susceptibility data for strains circulating in the community at the time the patient's infection occurs. multiresistant shigellae complicate the choice of empirical therapy before availability of susceptibility data for the patient's isolate. plasmid-encoded resistance (r factors) for multiple antibiotics has been observed frequently in s. dysenteriae serotype outbreaks and with other ~higellae.~'~.~'~ antimicrobial resistance patterns fluctuate from year to year in a given locale. however, despite the guesswork involved, early preemptive therapy is indicated when an illness is strongly suggestive of shigellosis. in vitro susceptibility does not always adequately predict therapeutic responses. cefa~lor, ~~ furazolidone, ~ephalexin, '~ amo~icillin, ~' kanam~cin, ~' and ~e f a m a n d o l e~~~ all are relatively ineffective agents. the optimal duration of therapy is debatable. studies in children older than years and in adults suggest that singledose regimens may be as effective in relieving symptoms as courses given for days. the single-dose regimens generally are not as effective in eliminating shigellae from the feces as are the longer courses. a third-generation cephalosporin, such as ceftriaxone, may be the best empirical choice. optimal doses for newborns with shigellosis have not been established. trimethoprim at a dose of lomg/kg/day (maximum, mg/day) and sulfamethoxazole at a dose of mg/kg/day (maximum, mg/day) in two divided doses for a total of days are recommended for the older child if the organism is s~s c e p t i b l e . ~~-~~~ if the condition of the infant does not permit orally administration, the drug usually is divided into three doses given intravenously over ampicillin at a dose of mg/kg/day in four divided doses taken orally for days may be used if the strain is susceptible. for the rare newborn who acquires shigellosis, appropriate therapy often is delayed until susceptibility data are available. this occurs because shigellosis is so rare in newborns that it is almost never the presumptive diagnosis of the child with watery or bloody diarrhea. although a sulfonamide is as efficacious as ampicillin when the infecting strain is sus~eptible, ~~ sulfonamides are avoided in neonates because of concern about the potential risk of kernicterus. the risk of empirical ampicillin therapy is that shigellae are frequently resistant to the drug; % of shigellae currently circulating in the united states are ampicillin resistant. for the neonate infected with ampicillin-resistant shigella, there are few data on which to base a recommendation. ceftriaxone is generally active against shigellae, but in the neonate, this drug can displace bilirubin-binding sites and elicit clinically significant cholestasis. data on children and adults suggest that clinical improvement occurs with c e f t r i a x~n e .~~~*~~~ quinolones, such as ciprofloxacin and ofloxacin, have been shown to be effective agents for treating s h i g e l l o s i~~~~~~~~ in adults, but they are not approved for use in children younger than years. other drugs sometimes used to treat diarrhea pose special risks to the infant with shigellosis. the antimotility agents, in addition to their intoxication risk, may pose a special danger in dysentery. in adults, diphenoxylate hydrochloride with atropine has been shown to prolong fever and excretion of the ~rganism.~" the response to appropriate antibiotic therapy is generally gratifying. improvement is often obvious in less than hours. complete resolution of diarrhea may not occur until a week or more after the start of treatment. in those who have severe colitis or those infected by s. dysenteriae serotype , the response to treatment is somewhat delayed. for most of the developing world, the best strategy for prevention of shigellosis during infancy is prolonged breastfeeding. specific antibodies in milk appear to prevent symptomatic shigellosis ' ; nonspecific modification of gut flora and the lack of bacterial contamination of human milk also may be important. breast-feeding, even when other foods are consumed, decreases the risk of shigellosis; children who continue to consume human milk into the third year of life are still partially protected from in the united states, the best means of preventing infection in the infant is good hand hygiene when an older sibling or parent develops diarrhea. even in unsanitary environments, secondary spread of shigellae can be dramatically decreased by hand hygiene after defecation and before meals. spread of shigellae in the hospital nursery can presumably be prevented by the use of contact isolation for infants with diarrhea and attention to thorough hand hygiene. although nursery personnel have acquired shigellosis from infected newborns, further transmission to other infants in the nursery, although is rare. in contrast to salmonella, large outbreaks of nosocomial shigellosis in neonates are rare. unfortunately, good hygiene is a particularly difficult problem in daycare centers. the gathering of susceptible children, breakdown in hand hygiene, failure to use different personnel for food preparation and diaper changing, and difficulty controlling the behavior of toddlers all contribute to daycare-focused outbreaks of shigellosis. immunization strategies have been studied since the turn of the th century, but no satisfactory immunization has been developed. even if immunizations are improved, a role in managing neonates seems unlikely. campylobacter was first recognized in an aborted sheep fetus in the early o s o and was named vibrio fetus by smith and taylor in . this organism subsequently was identified as a major venereally transmitted cause of abortion and sterility and as a cause of scours in cattle, sheep, and goats. s it was not until , when it was isolated from the blood culture of a pregnant woman who subsequently aborted at months' gestation, that the significance of campylobacter as a relatively rare cause of bacteremia and perinatal infections in humans was a~preciated.~l'-~'~ during the s, campylobacter was recognized to be an opportunistic pathogen in debilitated in , v fetus and related organisms were separated from the vibrios (such as v cholerae and v parahaemolyticus) and placed in a new genus, campylobacter (greek word for "curved rod"). since , several campylobacter species have been recognized as a common cause of e n t e r i t i~~l~.~~~ and, in some cases, extraintestinal infections. the genus campylobacter contains species, most of which are recognized as animal and human pathogens. the most commonly considered causes of human disease are campylobacter fetus, campylobacter jejuni, campylobacter coli, campylobacter lari, and campylobacter upsaliensis (table - ),' - although campylobacter mucosalis has been isolated from stool of children with diarrhea. dna hybridization studies have shown that these species are distinct, sharing less than % dna homology under stringent hybridization ~o n d i t i o n s .~~~,~~~ helicobacter pylori was originally named campylobacter pylori, but because of differences in dna, it was reclassified and is no longer considered in the campylobacter genus. strains of c. fetus are divided into two subspecies: c. fetus subsp. fetus and c. fetus subsp. venerealis. the first subspecies causes sporadic abortion in cattle and sheep ; in by far the most common syndrome caused by a campylobacter species is enteritis. c. jejuni and c. coli cause gastroenteritis and generally are referred to collectively as c. jejuni, although dna hybridization studies show them to be different. in the laboratory, c. jejuni can be differentiated from c. coli because it is capable of hydrolyzing hippurate, whereas c. coli is not. most isolates that are associated with diarrhea ( % to %) are identified as c. jejuni, - and in some cases, individuals have been shown to be simultaneously infected with c. jejuni and c. ~o l i . ~~~ because of the fastidious nature of c. jejuni, which is difficult to isolate from fecal flora, its widespread occurrence was not recognized until . - previously called related vibrios by this organism had been associated with bloody diarrhea and colitis in infants and adults only when it had been associated with a recognized b a~t e r e m i a .~~~-~~~ in the late s, development of selective fecal culture methods for c. jejuni enabled its recognition worldwide as one of the most common causes of enteritis in persons of all ages. it is an uncommon infection in neonates who generally develop gastroenteritis when i n f e~t e d .~'~-~~~-~~' bacteremia with c. jejuni enteritis also is uncommon. ~ , l* * - maternal symptoms considered to be related to c. jejuni infection generally are mild and include fever ( %) and diarrhea ( %). in contrast to the serious disease in newborns that is caused by c. fetus, neonatal infections with although meningitis occurs in rare third trimester infection related to c. fetus or c. jejuni may results in abortion or stillbirth. pathogenesis c. fetus does not produce recognized enterotoxins or cytotoxins and does not appear to be locally invasive by the sereny instead, these infections may be associated with penetration of the organism through a relatively intact intestinal mucosa to the reticuloendothelial system and blo~dstream.~'~ whether this reflects a capacity to resist serum factors or to multiply intracellularly remains to be determined. c. jejuni is capable of producing illness by several mechanisms. these organisms have been shown to produce an lt enterotoxin and a c y t o t o x i r~.~~~~~~~ this enterotoxin is known to be a heat-labile protein with a molecular mass of to mda. it shares functional and immunologic properties with cholera toxin and e. coli lt. c. jejuni and c. coli also elaborate a cytotoxin that is toxic for a number of mammalian cells. - the toxin is heat labile, trypsin sensitive, and not neutralized by immune sera to shiga toxin or the cytotoxin of clostridium dificile. the role of these toxins as virulence factors in diarrheal disease remains unpr~ved.'~~,~~ several animal models have been tested for use in the study of this pathogen. potential models for the study of c. jejuni enteritis include dogs, which may acquire symptomatic infection ; -to -day old ~h i c k s~~' -~~; chicken embryo cells, which are readily invaded by c. jejuni "; rhesus monkeys ; and rabbits by means of the removable intestinal tie adult rabbit technique. an established small mammal model that mimics human disease in the absence of previous treatment or surgical procedure has not been successful in adult mice. an infant mouse mode , and a hamster of diarrhea appear promising. c. jejuni is negative in the sereny test for invasivenes~,~~~ and most investigators report no fluid accumulation in ligated rabbit ileal loops. the pathologic findings of c. fetus infection in the perinatal period include placental necrosis '' and, in the neonate, widespread endothelial proliferation, intravascular fibrin deposition, perivascular inflammation, and hemorrhagic necrosis in the brain. the tendency for intravascular location and hepatosplenomegaly in adults infcctcd with c. fetus has been the pathologic findings in infants and children infected with c. fetus can include an acute inflammatory process in the colon or rectum, as evidenced by the tendency for patients to have bloody diarrhea with numerous fecal leukocytes. there also can be crypt abscess formation and an ulcerative colitis or pseudomembranous colitis-like or a hemorrhagic jejunitis or ileitis. b , , mesenteric lymphadenitis, ileocolitis and acute appendicitis also have been described. infection with campylobacter species occurs after ingestion of contaminated food, including unpasteurized milk, poultry, and contaminated water.' , - m any farm animals and pets, such as chickens, dogs, s and cats (especially young animals), are potential sources. the intrafamilial spread of infection in h o~s e h o l d s ,~~~,~~~ the occurrence of outbreaks in and the apparent laboratory acquisition of c. jejuni all suggest that c. jejuni infection may occur after person-to-person transmission of the organism. outbreaks of c. jejuni in the child daycare setting are not common. volunteer studies i have shown a variable range in the infecting dose, with many volunteers developing no illness. the report of illness after ingestion of lo organisms in a glass of milk and production of illness in a single volunteer by organisms i substantiate the variation in individual susceptibility. the potential for low-inoculum disease has significant implications for the importance of strict enteric precautions when infected persons are hospitalized, particularly in maternity and nursery areas. when diarrhea in neonates caused by c. jejuni has been r e p~r t e d ,~~~-~~' maternal-infant transmission during labor has generally been documented. ~ * ~ p ~ the lior serotyping system, restriction length polymorphism, and pulse-field gel electrophoresis have been used to confirm the identity of the infant and maternal isolates. most mothers gave no history of diarrhea during pregnancy. * , outbreaks have occurred in neonatal intensive care units because of person-to-person spread. z the frequency of asymptomatic carriage of c. jejuni ranges from % to . % ' , to as high as % to %. , , , - in a cohort study in mexico, % of all infections related to c. jejuni were asymptomatic. infected children, if untreated, can be expected to excrete the organisms for or weeks; however, more than % are culture negative after ~e e k s .~~~,~~~a~ ymptomatic excreters pose a significant risk in the neonatal period, in which acquisition from an infected mother can be clinically important. , s , c. jejuni has increasingly been recognized as a cause of watery and inflammatory diarrhea in temperate and tropical climates throughout the world. it has been isolated from % to % of all fecal cultures from patients with diarrheal illnesses in various parts of the world. - , * - there is a tendency for c. jejuni enteritis to occur in the summer in countries with temperate climates. the reservoir of campylobacter is the gastrointestinal tract of domestic and wild birds and animals. it infects sheep, cattle, goats, antelope, swine, chickens, domestic turkeys, and pet dogs. c. fetus often is carried asymptomatically in the intestinal or biliary tracts of sheep and cattle. during the course of a bacteremic illness in pregnant animals, c. fetus organisms, which have a high affinity for placental tissue, invade the uterus and multiply in the immunologically immature fetus. the infected fetuses generally are aborted. whether this organism is acquired by humans from animals or is carried asymptomatically for long periods in humans, who may then transmit the organism through sexual contact as appears to occur in animals, is unclear. it is believed that this subspecies rarely is found in the human intestine and that it is not a cause of human enteriti~?'~ c. fetus infections predominantly occur in older men with a history of farm or animal exposure and in pregnant women in their third trimester. ~ , , symptomatically or asymptomatically infected women may have recurrent abortions or premature deliveries and are the source of organisms associated with life-threatening perinatal infections of the fetus or newborn infant. , - in several instances of neonatal sepsis and meningitis, c. fetus was isolated from culture of maternal cervix or vagina. , s a n osocomial nursery outbreak has been associated with carriage in some healthy infants. ' other outbreaks have been associated with meningitis , cervical cultures have remained positive in women who have had recurrent abortions and whose husbands have antibody titer elevations. the most commonly incriminated reservoir of c. jejuni is poultry. ,s , , m ost chickens in several different geographic locations had a large number (mean, x /g) of c. jejuni in the lower intestinal tract or feces. this occurred in some instances despite the use of tetracycline, to which the campylobacter was susceptible in vitro, in the chicken feed. the internal cavities of chickens remain positive for carnpylobacter even after they have been cleaned, packaged, and fr zen. ~~ however, unlike salmonella, c. jejuni organisms that survive usually do not multiply to high concen-tration~?~' domestic puppies or kittens w i t h c. jejuni diarrhea also can provide a source for spread, especially to infants or c. jejuni enteritis also has been associated in a number of outbreaks with consumption of unpasteurized in retrospect, the first reported human cases of c. jejuni enteritis were probably in a milk-borne outbreak reported in . because campylobacter infections of the udder are not seen, milk is probably contaminated from fecal shedding of the organism. these organisms are killed by adequate heating. fecally contaminated water is a potential vehicle for c. jejuni infections. several phenotypic and genotypic methods have been used for distinguishing c. jejuni strains from animals and humans involved in epidemics. clinical manifestations of infection caused by campylobacter depend on the species involved (see table - ). human infections with c. fetus are rare and generally are limited to bacteremia in patients with predisposing condition^^^^.^^^ or to bacteremia or uterine infections with prolonged fever and pneumonitis that lasts for several weeks in women during the third trimester of pregnancy. unless appropriately treated, symptoms usually resolve only after abortion or delivery of an infected infant? j , - * these infected neonates, who are often premature, develop signs suggesting sepsis, including fever, cough, respiratory distress, vomiting, diarrhea, cyanosis, convulsions, and jaundice. the condition typically progresses to meningitis, which may be rapidly fatal or may result in serious neurologic ~equelae.~" additional systemic manifestations include pericarditis, pneumonia, peritonitis, salpingitis, septic arthritis, and abscesses. c. jejuni infection typically involves the gastrointestinal tract, producing watery diarrhea or a dysentery-like illness with fever and abdominal pain and stools that contain blood and ~u c u s .~~~~~~'~~' " ' older infants and children generally are affected, but neonates with diarrhea have been reported. infection in neonates generally is not clinically apparent or is mild. stools can contain blood, mucus, and pus p * * ; fever often is ab~ent. ~~"~' the illness usually responds to appropriate antimicrobial which shortens the period of fecal shedding. extraintestinal infections related to c. jejuni other than bacteremia are rare but include cholecystitis, urinary tract and meningitis. bacteremia is a complication of gastrointestinal infe~tion, ~' especially in malnourished children. meningitis that appears to occur secondary to intestinal infection also has been reported in premature infants who have had intraventricular needle aspirations for neonatal hydrocephalus.'i complications in older children and adults that have been associated with c. jejuni enteritis include reiter's syndrome, guillain-barre ~y n d r o m e , ~~~~~* and reactive persistent c. jejuni infections have been described in patients infected with human immunodeficiency extraintestinal manifestations generally occur in patients who are immunosuppressed or at the extremes of age.' campybbacter zari has caused chronic diarrhea and bacteremia in a neonate!% most important in the diagnosis of campylobacter infection is a high index of suspicion based on clinical grounds. c. fetus and c. jejuni are fastidious and may be overlooked on routine fecal cultures. isolation of campylobacter from blood or other sterile body sites does not represent the same problem as isolation from stool. growth occurs with standard blood culture media, but it may be slow. in the case of c. fetus infecting the bloodstream or central nervous system, blood culture flasks should be blindly subcultured and held for at least days or the organism may not be detected because of slow or inapparent the diagnosis of c. fetus infection should be considered when there is an unexplained febrile illness in the third trimester of pregnancy or in the event of recurrent abortion, prematurity, or neonatal sepsis with or without meningitis. a high index of suspicion and prompt, appropriate antimicrobial therapy may prevent the potentially serious neonatal complications that may follow maternal c. fetus infection. campylobacter is distinguished from the vibrio organisms by its characteristics of carbohydrate nonfermentation and by its different nucleotide base omp position.^^^^^^^-^^^*^^^ campylobacter is . to . fm wide and . to . long. it is a fastidious, microaerophilic, curved, motile gram-negative bacillus that has a single polar flagellum and is oxidase and catalase positive, except for c. upsaliensis, which is generally catalase negative or weakly positive. c. jejuni and c. fetus are separated by growth temperature (c. fetus grows best at ' c but can be cultured at ' c; c. jejuni grows best at ' c) and by nalidixic acid and cephalosporin susceptibilities, because c. jejuni is susceptible to nalidixic acid and resistant to cephalosporins. c. jejuni grows best in a microaerobic environment of % oxygen and % carbon dioxide at ' c. it grows on a variety of media, including brucella and mueller-hinton agars, but optimal isolation requires the addition of selective and nutritional supplements. growth at ' c in the presence of cephalosporins is used to culture selectively for c. jejuni from fecal specimens. in a study of six media, charcoal-based selective media and a modified charcoal cefoperazone deoxycholate agar were the most selective for identification of campylobacter species. extending the incubation time from to hours led to an increase in the isolation rate regardless of the medium its typical darting motility may provide a clue to identification, even in fresh fecal specimens, when viewed by phase-contrast microscopy. when the organism has been cultured, it is presumptively identified by motility and by its curved, sometimes sea gulllike appearance on carbolfuchsin stain. polymorphonuclear leukocytes are usually found in stools when bloody diarrhea occurs and indicate the occurrence of ~o l i t i s .~~~*~~* to avoid potentially serious c. jejuni infection in the newborn infant, careful histories of any diarrheal illnesses in the family should be obtained, and pregnant women with any enteric illness should have cultures for this and other enteric pathogens. detection of c. jejuni and c. coli by pcr has been reported and in the future may be useful for the rapid and reliable identification of this organism. the differential diagnosis of c, fetus infections include the numerous agents that cause neonatal sepsis or meningitis, especially gram-negative bacilli. diagnostic considerations for inflammatory or bloody enteritis include necrotizing enterocolitis, allergic proctitis, and salmonella; rarely shigellu, and other infectious agents occur. agglutination, complement fixation, bactericidal, immunofluorescence, and elisa tests have been used for serologic diagnosis of c. jejuni infection and to study the immune response, but these assays are of limited value in establishing the diagnosis during an acute infection. the prognosis is grave in newborn infants with sepsis or meningitis caused by c. fetus. in infants with c. jejuni gastroenteritis, limited data suggest that appropriate, early antimicrobial therapy results in improvement and rapid clearance of the organism from stool. campylobacter species are often resistant to p-lactams, including ampicillin and cephalosporins. v mo st strains are susceptible to erythromycin, gentamicin, tetracycline, chloramphenicol, and the newer quinolones, although resistance to these agents has been r e p~r t e d .~~' ,~~~ it appears that a parenteral aminoglycoside is the drug of choice for c. fetus infections, pending in vitro susceptibility studies. in the case of central nervous system involvement, cefotaxime and chloramphenicol are potential alternative drugs. depending on in vitro susceptibilities, which vary somewhat with locale, erythromycin is the drug of choice for treating c. jejuni e n t e r i t i~.~~~~~"~~' ' if erythromycin therapy is initiated within the first days of illness, a reduction in excretion of the organism and resolution of symptoms occur. although data regarding treatment of asymptomatic or convalescent carriers are not available, it seems appropriate to treat colonized pregnant women in the third trimester of pregnancy when there is a risk of perinatal or neonatal infection. the failure of prophylactic parenteral gentamicin in a premature infant has been documented, followed by successful resolution of symptoms and fecal shedding with erythromycin. because there appears to be an increased risk of toxicity with erythromycin estolate during pregnancy and other forms of erythromycin should probably be used in these settings. azithromycin appears to be effective if the organism is susceptible. strains that are erythromycin resistant often are resistant to azithromycin. cumpylobucter tends to have higher minimal inhibitory concentrations for clarithromycin than for a~ithromycin.~~~ furazolidone has been used in children and ciprofloxacin in nonpregnant patients older than years. contact precautions should be employed during any acute diarrheal illness and until the diarrhea has subsided. hand hygiene after handling raw poultry and washing cutting boards and utensils with soap and water after contact with raw poultry may decrease risk of infection. pasteurization of milk and chlorination of water are critically important. infected food handlers and hospital employees who are asymptomatic pose no known hazard for disease transmission if proper personal hygiene measures are maintained. ingestion of human milk that contains anti<. jejuni antibodies has been shown to protect infants from diarrhea due to c. j e j~n i .~~,~~~ c. dificile is a spore-forming, gram-positive, anaerobic bacillus that produces two toxins. in the presence of antibiotic pressure, c. dificile colonic overgrowth and toxin production occur. the virulence properties of c. dificile are related to production of an enterotoxin that causes fluid secretion (toxin a) and a cytotoxin detectable by its cytopathic effects in tissue culture (toxin b). * both the usual manifestations of c. dificile disease in older children and adults include watery d&rhea, abdominal pain and tenderness, nausea, vomiting, and low-grade fever. grossly bloody diarrhea is unusual, although occult fecal blood is common. leukocytosis is present during severe illness. diarrhea usually begins to days into a course of antimicrobial therapy but may be delayed until several weeks after completion of the therapeutic course. usually, the illness is mild and self-limited if the offending drug is discontinued. severe colitis with pseudomembranes is less common now than in previous years because the risk of diarrhea developing during antimicrobial therapy is recognized and the antimicrobial agent typically is stopped. it is unclear whether this organism causes disease in newborns. one study from a newborn intensive care unit suggests that toxin a in stools is associated with an increased frequency of abnormal stools. endoscopic findings of pseudomembranes and hyperemic, friable rectal mucosa suggest the diagnosis of pseudomembranous colitis. pseudomembranes are not always present in c. dificile colitis; mild cases are often described as nonspecific colitis. several noninvasive techniques are used to establish the diagnosis, including enzyme immunoassay (eia) for toxin detection and pcr. - isolation of c. dificile from stool does not distinguish between toxigenic and nontoxigenic isolates. if c. dificile is isolated, testing for toxin by cell culture or eia should be performed to confirm the presence of a toxigenic strain. there are multiple commercially available eias that detect either toxin a or both toxins a and b. - these assays are sensitive and easy to perform. other assays are available for epidemiologic investigation of outbreaks of disease due to c. d i f i~i l e .~~~ in older children and adults, the diagnosis is confirmed by culture of c. dificile and demonstration of toxin in feces. in neonates, these data are inadequate to prove that an illness is related to c. dificile. when the clinical picture is consistent, the stool studies are positive for c. dificile and no other cause for illness is found, a diagnosis of "possible" c. dificile is made. a favorable response to eradication of c. dificile is supportive evidence that the diagnosis is c rrect. ~~ because of the uncertainty implicit in the ambiguity of neonatal diagnostic criteria, other diagnoses must be considered. when the decision is made that a neonate's illness might be related to c. difjcile, the initial approach should include fluid and electrolyte therapy and discontinuation of the offending antimicrobial agent. if the illness persists or worsens or if the patient has severe diarrhea, specific therapy with r n e t r o n i d a z~l e~~~*~~~ should be instituted. metronidazole is considered to be the treatment of choice for most patients with c. difjcile ~olitis. ~' rarely is there a need to consider orally administered vancomycin or bacitracin in after initiation of therapy, signs of illness generally resolve within several days, titers decrease, and fecal toxins disappear eventually. recurrence of colitis after discontinuation of metronidazole or vancomycin has been documented in % to % of adults.g relapses are treated with a second course of metronidazole or vancomycin. drugs that decrease intestinal motility should not be administered. neutralizing antibody against c. dificile otoxin has been demonstrated in human colostrum.' secretory component of siga binds to toxin a to inhibit its binding to receptors data show that there are nonantibody factors present in milk that interfere with the action of toxin b in addition to secretory iga directed at toxin a. breast-feeding appears to decrease the frequency of colonization by c. d i f j~i l e .~'~ in addition to standard precautions, contact precautions are recommended for the duration of illness. meticulous hand hygiene techniques, proper handling of contaminated waste and fomites, and limiting the use of antimicrobial agents are the best available methods for control of c. dificile infection. b! cholerue is a gram-negative, curved bacillus with a polar flagellum. of the many serotypes, only enterotoxin-producing organisms of serotype and cause epidemics. b! cholerue is divided into two serotypes, inaba and ogawa, and two biotypes, classic and el tor; the latter is the predominant biotype. nontoxigenic strains and non- strains of v cholerae can cause diarrhea and sepsis but do not cause outbreaks? ~ a pathogenesis b! cholerue group is the classic example of an enteropathogen whose virulence is caused by enterotoxin production. cholera toxin is an -mda protein whose five b subunits cause toxin binding to the enterocyte membrane ganglioside gm, and whose a subunit causes adenosine diphosphate ribosylation of a guanosine triphosphate-binding regulatory subunit of adenylate cy~lase."~~~'~ the elevated camp levels that result from stimulation of enterocytes by cholera toxin cause secretion of salt and water with concomitant inhibition of absorption. two other toxins are also encoded within the virulence cassette that encodes cholera toxin. these toxins, zona occludens toxin (zot) and accessory cholera toxin (ace), are consistently found in illness-causing strains of and but not usually in v; cholerae organisms that are less virulent. since , v cholerae , biotype el tor, has spread from india and southeast asia to africa, the middle east, southern europe, and the southern, western, and central pacific islands in the aquatic environment. the usual reported vehicles of transmission have included contaminated water or ice; contaminated food, particularly raw or undercooked shellfish; moist grains held at ambient temperature; and raw or partially dried fish. the usual mode of infection is ingestion of contaminated food or water. boiling water or treating it with chlorine or iodine and adequate cooking of food kill the organism. asymptomatic infection of family contacts is common but direct person-to-person transmission of disease has not been documented. persons with low gastric acidity are at increased risk for cholera infection. cholera acquired during pregnancy, particularly in the third trimester, is associated with a high incidence of fetal miscarriage can be attributed to a fetal acidosis and hypoxemia resulting from the marked metabolic and circulatory changes that this disease induces in the mother. it is not surprising that the likelihood of delivering a stillborn child is closely correlated with the severity of the maternal illness. the inability to culture v; cholerue from stillborn infants of infected mothers, together with the usual absence of bacteremia in cholera, suggests that transplacental fetal infection is not a cause of intrauterine death. neonatal cholera is a rare disease. this generalization also applies to the new strains, although mild '* and severe forms of illness have rarely been described in newborns. among neonates admitted to a cholera research hospital in dacca, bangladesh, there were infants ill with ~holera.~" even infants born to mothers with active diarrheal disease may escape infection, despite evidence that rice-water stools, almost certain to be ingested during the birth process, may contain as many as lo organism~/ml.~~~ the reason for this apparently low attack rate among newborns is not certain; however, it probably can be attributed in large part to the protection conferred by breast-feedingg ' human milk contains antibodies and receptor-like glycoprotein that inhibit adherence of v choleraeu and gangliosides that bind cholera toxin. the role of transplacentally acquired vibriocidal maternal antibodies has not been determined. because v cholerae causes neither bacteremia nor intestinal invasion, protection against illness is more likely to be a function of mucosal rather than serum additional factors that may reduce the incidence of neonatal cholera include the large inoculum required for infection and the limited exposure of the newborn to the contaminated food and water. clinicians should request that appropriate cultures be performed for stool specimens from persons suspected of having cholera. the specimen is plated on thiosulfate citrate bile salts sucrose agar directly or after enrichment in alkaline peptone water. isolates of v cholerae should be confirmed at a state health department and then sent to the cdc for testing for production of cholera toxin. a fourfold rise in vibriocidal antibody titers between acute and convalescent serum samples or a fourfold decline in titers between early and late (> months) convalescent serum specimens can confirm the diagnosis. probes have been developed to test for cholera toxin. * the most important modality of therapy is administration of oral or parented rehydration therapy to correct dehydration and electrolyte imbalance and maintain h y d r a t i~n .~~ antimicrobial therapy can eradicate vibrios, reduce the duration of diarrhea, and reduce requirements for fluid replacement. one cholera vaccine, which is administered parenterally, is licensed in the united states but is of very limited value. several experimental oral vaccines are being t e~t e d ? *~-~~' i.: enterocolitica is a major cause of enteritis in much of the industrialized enteritis due to this organism primarily occurs in infants and young children, and infections in the united states are reported to be more common in the north than in the s o~t h .~~~-~~~ h i m als, especially swine, have been shown to serve as the reservoir for y. enterocolitica. a history of recent exposure to chitterlings (i.e., pig intestine) is common. transmission has also occurred after ingestion of contaminated milk and infusion of contaminated blood p r o d~c t s .~~~,~~~ virulence of y. enterocolitica is related primarily to a virulence plasmid, which is closely related to the virulence plasmids of yersinia pseudotuberculosis and yersinia p e s t i~.~~'~~~~ an st enterotoxin, which is closely related to the st of etec, may also be important. infection with y. enterocolitica is recognized as one of the causes of bacterial gastroenteritis in young children, but knowledge of neonatal infection with this organism is fragmentary. even in large series, isolation of yersinia from newborns is rare? , the youngest infants whose clinical course has been described in detail were days to several months old at the onset of their illness. , - there were no features of the gastroenteritis to distinguish it from that caused by other invasive enteric pathogens such as shigella or salmonella. infants presented with watery diarrhea or with stools containing mucus with streaks of blood. sepsis was common in these infants particularly in the first months of life when % of enteritis was complicated by sepsis. , , , fever is not a consistent finding in children with bacteremia, and meningitis is rare. in older children, fever and right lower quadrant pain mimicking appendicitis are often found. diagnosis y enterocolitica can be recovered from throat swabs, mesenteric lymph nodes, peritoneal fluid, blood, and stool. because laboratory identification of organisms from stool requires special techniques, laboratory personnel should be notified when yersinia is suspected. because avirulent environmental isolates occur, biotyping and serotyping are useful in assessing the clinical relevance of isolates. pcr has been used to detect pathogenic strain^.^^^'^^^ the effect of antimicrobial therapy on the outcome of gastrointestinal infection is uncertain. it has been recommended that antibiotics be reserved for sepsis or prolonged and severe gastroenteritisg '; however, there are no prospective studies comparing the efficacy of various antimicrobial agents with each other or with supportive therapy alone. most strains of y. enterocolitica are susceptible to trimethoprimsulfamethoxazole, the aminoglycosides, piperacillin, imipenem, third-generation cephalosporins, amoxicillin-clavulanate potassium, and chloramphenicol, and resistant to amoxicillin, ampicillin, carbenicillin, ticarcillin, and m a c r o l i d e~.~~~-~~~ therapy in individual cases should be guided by in vitro susceptibility testing, although cefotaxime has been successfully used in bacteremic infants? aerornonas hydrophila is widely distributed in animals and the environment. although wound infection, pneumonia, and sepsis (especially in immunocompromised hosts) represent typical aeromonas infections, gastroenteritis increasingly is being recognized. the organism is a gramnegative, oxidase-positive, facultatively anaerobic bacillus belonging to the family vibrionaceae. like other members of this family, it produces an enter~toxin~~' that causes fluid secretion in rabbit ileal loops.%' some strains cause fluid accumulation in the suckling mouse model,"' whereas other strains are i n~a s i v e~~~ or cytotoxic. the enterotoxin is not immunologically related to cholera toxin or the heat lt of although volunteer studies and studies with monkeys have failed to provide supportive evidence for enteropathog e n i~i t y ?~~,~~ there is good reason to believe that a. hydrophila does cause diarrhea in children. the earliest description of aeromonas causing diarrhea was an outbreak that occurred in a neonatal unit. although several studies have failed to show an association with diarrhea,% - most studies have found more aeromonas isolates among children with gastroenteritis than among ~o n t r o l s ?~~-~~~ part of the controversy may be caused by strain differences; some strains possess virulence traits related to production of gastroenteritis, whereas others do not. , the diarrhea described in children is a disease of summer, primarily affecting children in the first years of life. in one study, ( %) of cases of aeromonas detected during a -month period occurred in infants younger than month. typically, watery diarrhea with no fever has been described; although there are descriptions of watery diarrhea with fever? however, in %, a dysentery-like illness occurred. dysentery-like illness has been described in the neonate. in one third of children, diarrhea has been reported to last for more than ~eeks. ~' there may be species-related differences in clinical features of aeromonas-associated gastroenteritis in children. organisms that were formerly classified as a. hydrophila are now sometimes labeled as aeromonas sobria or aeromonas ~a v i a e .~~'~~~' fever and abdominal pain appear to be particularly common with a. sobria. one series of a. hydrophila isolates from newborns in dallas showed more blood cultures than stool cultures positive for a e r o m o n a~.~~~ diagnosis of enteric infection associated with aeromonas often is not made because this organism is not routinely sought in stool cultures. when the organism is suspected, the laboratory should be notified so that oxidase testing can be performed. the organism is usually susceptible to aztreonam, imipenem, meropenem, third-generation cephalosporins, trimethoprim-sulfamethoxazole, and chloramphenicol.q ~ plesiomonas shigelloides is a gram-negative, facultative anaerobic bacillus that, like aeromonas, is a member of the vibrionaceae family. it is widely disseminated in the environment; outbreaks of disease are usually related to ingestion of contaminated water or seafood. although it has been associated with outbreaks of diarrheal disease and has been found more commonly in ill than well controls, the role of i? shigelloides in diarrheal disease has remained contro~ersial.~~~ if it is a true enteropathogen, the mechanism by which it causes disease is ~n c l e a r . ~~'~~' the role of this organism in neonatal diarrhea has not been extensively investigated. infections of neonates have been r e p~r t e d ?~' .~~~ but most cases of enteric disease currently reported in the united states are in adults. typical illness consists of watery diarrhea and cramps; sometimes, fever, bloody stools, and emesis occur and last for to days. diagnosis is not usually made by clinical microbiology laboratory testing because, as with aeromonas, coliforms can be confused with l ? shigelloides unless an oxidase test is performed. the true frequency of infection is unknown. the organism has antibiotic susceptibilities similar to those of a e r~m o n a s .~~~'~~~ proving that an organism causes diarrhea is difficult, particularly when it may be present in large numbers in stools of healthy persons. bacteria that have been associated with acute gastroenteritis may be considered causative when the following criteria are met: . a single specific strain of the organism should be found as the predominant organism in most affected infants by different investigators in outbreaks of enteric disease in different communities. . this strain should be isolated in a significantly lower percentage and in smaller numbers from stool specimens of healthy infants. . available methods must be used to exclude other recognized enteropathogens, including viruses and parasites, enterotoxigenic agents, and fastidious organisms such as ca mpylobacter. . demonstration of effective specific antimicrobial therapy and specific antibody responses and, ultimately, production of experimental disease in volunteers are helpful in establishing the identity of a microorganism as a pathogen. optimally, the putative pathogen should have virulence traits that can be demonstrated in model systems. most bacteria that have been suggested as occasional causes of gastroenteritis in neonates fail to fulfill one or more of these criteria. their role in the cause of diarrheal disease is questionable. this is particularly true of microorganisms described in early reports in which the possibility of infection with more recently recognized agents could not be excluded. much of the clinical, bacteriologic, and epidemiologic data collected earlier linking unusual enteropathogens to infantile diarrhea must be reevaluated in light of current knowledge and methodology. several reports of acute gastroenteritis believed to have been caused by klebsiella suggest that, rather than playing an etiologic role, these organisms had probably proliferated within an already inflamed b~w e l .~~~-' '~' the recovery of klebsiella-enterobacter in pure culture from diarrheal stools has led several investigators to suggest that these bacteria may occasionally play a causative role in infantile gastroenteritis and enterocoliti~.'~~~~'"~ ingestion of infant formula contaminated with enterobacter sakazakii has been associated with development of bloody diarrhea and sepsis.'oo however, klebsiella species also may be isolated in pure culture from stools of newborns with no enteric s y m p t o m~. '~~~~'~' ' in one study, certain capsular types of klebsiella were more often isolated from infants with diarrheal disease than from normal infants.ioo later work has shown that klebsiella pneumoniae, enterobacter cloacae, and citrobacter species are capable of isolation of citrobacter species, such as those of klebsiella species, describe associations with enteric illnesses in up to % of cases. - there is inadequate evidence to define the roles of klebsiella, enterobacter, and citrobacter species as etiologic agents of enteric illnesses. listeria monocytogenes, one of the classic causes of neonatal sepsis and meningitis (see chapter ), has been linked to outbreaks of febrile diarrheal disease in immunocompetent adults and ~h i l d r e n . '~'~~'~~' seventy-two percent of ill individuals have had fever.ioz outbreaks have been related to ingestion of contaminated foods. listeria has rarely been described as a cause of neonatal gastroenteriti~.'~~~-~~~~ infection with enterotoxin-producing bacteroides fragilis has been associated with mild watery diarrhea.' these infections have a peak incidence in -to -year-old infants. these toxin-producing organisms cannot be detected in routine hospital laboratories. a variety of organisms has been isolated from infant stools during episodes of diarrhea. most of these reports have failed to associate illness with specific organisms in a way that has stood the test of time. for example, i? aeruginosa - and have been associated with diarrhea, but proteus , [ ] [ ] [ ] [ ] [ ] [ ] [ ] there are few convincing data suggesting that either is a true enteropathogen. these organisms generally are recovered as frequently from healthy infants as from infants with diarrheal disease, suggesting that their presence in stool cultures is significant. , - an association between providencia and neonatal enteritis has been substantiated largely by anecdotal reports of nursery outbreaks. . ~ @' these bacteria are rarely isolated from infants with sporadic or community-acquired diarrheal disease.' ~' m" b~ candida albicans usually is acquired during passage through the birth canal and is considered a normal, although minor, component of the fecal flora of the neonate (see chapter ).' ' intestinal overgrowth of these organisms frequently accompanies infantile gastroenteriti~, "~~~~~'~~~*'~~~ particularly after antimicrobial therapy. , ,' - the upper small gut may become colonized with candida in malnourished children with diarrhea ; whether the presence of the organism is cause or effect is unclear. stool cultures obtained from infants with diarrheal disease are therefore inconclusive, and although candida enteritis has been reported in adults,' the importance of this organism as a primary cause of neonatal gastroenteritis has been difficult to prove. clinical descriptions of nursery epidemics of candidal enteritis are poorly documented, generally preceding the recognition of epec and rotaviruses as a cause of neonatal diarrhea. even well studied cases of intestinal involvement add little in the way of substantive proof because secondary invasion of candida has been shown to be a complication of coliform enteritis. , producing e n~e r o~o~n s~ ~~~~ ~ ~ ' " ~ reports of although diarrhea has sometimes been described as a finding in neonatal disseminated candidiasis, more typically, gastrointestinal tract involvement with disseminated candida is associated with abdominal distention and bloody stools mimicking necrotizing enterocoliti~.~~~"~~~-~~~~ typically, affected infants are premature and have courses complicated by antibiotic administration, intravascular catheter use, and surgical procedures during the first several weeks of life. a trial of oral anticandidal therapy may be helpful in neonates suffering from diarrhea in the presence of oral or cutaneous candidiasis. if the therapy is appropriate, a response should be forthcoming within to days. diarrhea sometimes occurs as a manifestation of systemic infection. patients with staphylococcal toxic shock syndrome, for example, often have diarrhea. loose stools sometimes occur in sepsis, but it is unclear whether the diarrhea is a cause or an effect. the organisms isolated from blood cultures in a group of bangladeshi infants and children with diarrhea included staphylococcus aureus, haemophilus inpuenzae, streptococcus pneumoniae, r aeruginosa, and various gramnegative enteric bacilli.' it is unknown whether the bacteriology of sepsis associated with diarrhea is similar in the well-nourished infants seen in industrialized countries. acute diarrhea associated with intestinal parasites is infrequent during the neonatal period. in areas with high endemicity, infection of the newborn is likely to be associated with inadequate maternal and delivery care, insufficient environmental sanitation, and poor personal hygiene standards. the occurrence of symptomatic intestinal parasitic infection during the first month of life requires acquisition of the parasite during the first days or weeks; the incubation period for e. histolytica and g. larnblia is to weeks, and for cryptosporidium parvum, it is to days. the newborn can be infected during delivery by contact with maternal feces, o in the hospital through contact with the mother or personnel, or in the household through contact with infected individuals in close contact with the child. contaminated water can be an important source of infection for g. lamblia and c. parvum. organisms formerly identified as e. histolytica have been reclassified into two species that are morphologically identical but genetically distinct: e. histolytica and e. dispar. the former can cause acute nonbloody and bloody diarrhea, necrotizing enterocolitis, ameboma, and liver abscess, and the latter is a noninvasive parasite that does not cause disease. early acquisition of disease tends to be more severe in young infants; rarely, amebic liver abscess and rapidly fatal colitis have been reported in infant^."^^-'^^^ for example, a -dayold child from india who presented with to episodes of watery and mucous diarrhea, lethargy, jaundice, and mildly elevated liver enzymes has been described; the child recovered completely after days of intravenous o m i d a~o l e . '~~~ however, asymptomatic colonization of neonates with various species of ameba is common in areas of high endemi~ity."~~ diagnosis can be established by stool examination for cysts and trophozoites and by serologic studies.' through the use of pcr, isoenzyme analysis, and antigen detection assays, e. histolytica and e. dispar can be differentiated. ' serum antibody assays may be helpful in establishing the diagnosis of amebic dysentery and extraintestinal amebiasis with liver involvement. the efficacy of treatment with metronidazole for colitis or liver abscess has not been established for the newborn period, although this therapy has been used with success. o patients with colitis or liver abscess caused by e. histolytica are treated also with iodoquinol, as are asymptomatic carriers. g. lamblia is a binucleate, flagellated protozoan parasite with trophozoite and cyst stages. it is spread by the fecal-oral route through ingestion of cysts. child-care center outbreaks reflecting person-to-person spread have demonstrated high i n f e~t i v i t y . "~~~'~~~ foodborne transmission and waterborne transmission also occur. infection is often asymptomatic or mildly symptomatic; cases of severe symptomatic infection during the immediate newborn period have not been reported. symptoms in giardiasis are related to the age of the patient, with diarrhea, vomiting, anorexia, and failure to thrive typical in the youngest children. seroprevalence studies have demonstrated evidence of past or current infection in % of peruvian children by the age of months.io ' in a study of lactating bangladeshi mothers and their infants, % of women and % of infants excreted giardia once during the study; in some infants, this occurred before they were months old.'o of these infected infants, % had diarrhea, suggesting that the early exposure to the parasite resulted in disease. in a prospective study of diarrhea conducted in mexico, infants frequently were infected with giardia from birth to months, with a crude incidence rate of first giardia infection of . infections per child-year in this age group. the symptom status of these children was not reported but this study strongly suggests that g. lamblia may be more common than currently recognized among newborns living in developing areas. the diagnosis of giardiasis can be made on the basis of demonstration of antigen by eia or by microscopy of feces, duodenal fluid or, less frequently, duodenal b i~p~y . ' '~~~' '~' breast-feeding is believed to protect against symptomatic g i a r d i a~i s .~-~~* '~~~ this protection may be mediated by cellular and humoral i nrnunity ~~"~~*"~~ and nonspecifically by the antigiardial effects of unsaturated fatty acids.iob giardia infections causing severe diarrhea may respond to metronidazole or furazolidone.' c. parvum is a coccidian protozoon related to toxoplasma gondii, lsospora belli, and plasmodium species. s' the life cycle involves ingestion of thick-walled oocysts; release of sporozoites, which penetrate intestinal epithelium; and development of merozoites. there is asexual and sexual reproduction, with the latter resulting in formation of new oocysts that can be passed in stools. cryptosporidium species are ubiquitous. infection often occurs in persons traveling to endemic areas.'o because cryptosporidium infects a wide variety of animal species, there is often a history of animal contact among infected individ~als."~' person-to-person spread, particularly in household c~n t a c t s '~~'~' '~~ and daycare center^,"^^"'^^ is well documented and suggests that the organism is highly infectious. waterborne outbreaks of cryptosporidiosis occur and can be of massive proportion^."^^ the clinical manifestations of illness in immunocompetent persons resemble those of giardia infection but are somewhat shorter in d~ration'"~; asymptomatic carriage is rare. symptoms and signs include watery diarrhea, abdominal pain, myalgia, fever, and weight loss. * ~ ~' " ~' infection in the first month of life has been described.""~"" because symptoms resolve before excretion of oocysts ceases, a newborn whose mother has been ill with cryptosporidiosis in the month before delivery might be at risk even if the mother is asymptomatic at the time of the child's birth."'* with the increasing frequency of human immunodeficiency virus infection, it is likely that women with symptomatic cryptosporidiosis occasionally will deliver an infant who will become infected. infants infected early in life may develop chronic diarrhea and maln~trition."'~ the diagnosis of cryptosporidiosis is most typically made by examination of fecal smears using the giemsa stain, ziehl-neelsen stain, auramine-rhodamine stain, sheather's sugar flotation, an immunofluorescence procedure, a modified concentration-sugar flotation method, or an eia.' io , lo nitazoxanide is effective therapy of immunocompetent adults and children ill with cryptosporidiosis.'io because illness is usually self-limited in the normal host, attention to fluid, electrolyte, and nutritional status usually suffices. enteric isolation of hospitalized infants with this illness is appropriate because of the high infectivity. several studies suggest that the risk of infection early in life may be decreased by breast-feeding. ' '"j viruses that infect the intestinal mucosa and cause primarily gastroenteritis are referred to as enteric viruses; they should not be confused with enteroviruses, members of picornaviridae family that are associated primarily with systemic illnesses. enteric viruses include rotaviruses, enteric adenoviruses, human caliciviruses, and astroviruses. other viruses such as coronaviruses, breda viruses, pestiviruses, parvoviruses, toroviruses, and picobirnaviruses have been sporadically associated with acute diarrhea but are currently considered of uncertain relevance. extensive reviews on the role of enteric viruses in childhood diarrhea can be found elsewhere." -"" all four enteric viruses could conceivably infect the newborn, but the extent of exposure and clinical manifestations are largely unknown for astrovirus, enteric adenovirus, and human caliciviruses. rotavirus is the most extensively studied enteric virus. neonatal rotavirus infections have similar virologic and clinical characteristics to infection in older children, although some differences exist. rotavirus is a -nm, nonenveloped virus composed of three concentric protein shells: a segmented genome ( segments), an rna-dependent polymerase, and enzymes required for messenger rna synthesis are located within the inner core. each segment codes for at least one viral protein (vp). the vp can be part of the structure of the virus, or it may be a nonstructural protein (nsp) required for replication, viral assembly, budding, determination of host range, or viral pathogenesis."" six distinct rotavirus groups (a through f) have been identified serologically based on common group of which three (a, b, and c) have been identified in humans.'io because group a rotaviruses represent more than % of isolated strains in humans worldwide, further discussion focuses on this group. group a rotaviruses are subclassified into serotypes based on neutralization epitopes located on the outer capsid. both rotavirus surface proteins, vp and vp , can induce production of neutralizing antibodies. at least vp types (g serotypes: gi to g , g to g , and g ) and nine vp types (p serotypes: pia, plb, p a, p , p b, p , p , p , and p ) have been detected among human r o t a v i r u~e s .~~~~-~~~~ by sequencing the vp -coding gene, eight genomic p types (genotypes) have been identified that correspond to one or more of the described p antigenic types (genotype to antigenic type pla, to plb, to p a, to p , to p b, to p , to p , and to p )."" combining g antigenic with p antigenic and genetic typing, a specific rotavirus strain can be identified p antigenic type (p genetic type), g type. as an example, the human neonatal m strain is described as p a[ ], gi. from newborn nurseries, some of which seem to be endemic to the newborn units with high rates of asymptomatic infe~tion,"~~-"~' and less commonly, outbreaks of symptomatic infection.iiz these findings suggest that specific conditions of the newborn environment (e.g., child, nursery, personnel) may increase the possibility of reassortments between human strains; such strains may persist in these settings possibly through constant transmission involving asymptomatic newborns, adults, and contaminated surfaces. rotavirus primarily infects mature enterocytes located in the mid and upper villous e p i t h e l i~m .~~~~-"~~ lactase, which is present only on the brush border of the differentiated epithelial cells at these sites, may act as a combined receptor and uncoating enzyme for the virus, permitting transfer of the particles into the cell. perhaps for this reason, infection is limited to the mature columnar enterocytes; crypt cells and crypt-derived cuboidal cells, which lack a brush border, appear to be resistant to rotaviral i n f e~t i o n . "~~' "~~ this concept also may explain why rotavirus infection is less common in infants younger than weeks' gestational age than in more mature infants ; between and weeks' gestational age, lactase activity is approximately % of that found in term infants. the upper small intestine is most commonly involved, although lesions may extend to the distal ileum and rarely to the ~ l n .~~~~ ~~~~ interaction between intestinal cell and rotavirus structural and nonstructural proteins occurs, resulting in death of infected villous enter~cytes."~~ once infected, the villous enterocyte is sloughed, resulting in an altered mucosal architecture that becomes stunted and flattened. the gross appearance of the bowel is usually normal; however, under the dissecting microscope, scattered focal lesions of the mucosal surface are apparent in most cases. light microscopy also shows patchy changes in villous morphology, compatible with a process of infection, inflammation, and accelerated mucosal renewal. the villi take on a shortened and blunt appearance as tall columnar cells are shed and replaced by less mature cuboidal entero-ischemia may also play a role in the loss and stunting of villi" and activation of the enteric nervous system; active secretion of fluid and electrolytes may be another pathogenic mechanism. during the recovery phase, the enteroblastic cells mature and reconstruct the villous structure. because of the loss of mature enterocytes on the tips of the villi, the surface area of the intestine is reduced. diarrhea that occurs may be a result of this decrease in surface area, disruption in epithelial integrity, transient disaccharidase deficiency, or altered countercurrent mechanisms and net secretion of water and electrolytes. ' ~ ~ ~ ~ ~ nsp has been found to induce age-dependent diarrhea in cd mice by triggering calcium-dependent chloride and water secretion. the potential role of this "viral enterotoxin" in human disease is not yet clear. , infants with asymptomatic rotavirus infections in the nursery are less likely than uninfected nursery mates to experience severe rotavirus infection later in life - ; this finding suggested protective immunity and supported vaccine development. most studies have indicated that serum and intestinal antirotavirus antibody levels are correlated with protection against i n f e~t i o n "~~-"~~ although this correlation has not been ~n i v e r s a l .~~~~-~~~~ breast-feeding protects against rotavirus disease during the first year of life, probably including newborns. the high prevalence of antirotaviral antibodies in colostrum and human milk has been demonstrated by numerous investigators in widely diverse geographic areas. maternal rotavirus infection or immunization is accompanied by the appearance of specific antibodies in milk, probably through stimulation of the enteromammary immune between % and % of women examined in london, bangladesh, guatemala, costa rica, and the united states had antirotaviral iga antibodies in their milk for up to years of rotavirus-specific igg antibodies have been found during the first few postpartum days in about one third of human milk samples a~s a y e d ,~~@~"~~ whereas i@ antibodies were detectable in about one half. glycoproteins in human milk have been shown to prevent rotavirus infection in vitro and in an animal model." the concentration of one milk glycoprotein, lactadherin, was found to be significantly higher in human milk ingested by cytes.l , , infants who developed asymptomatic rotavirus infection than in milk ingested by infants who developed symptomatic infe~tion. ~ rotaviruses probably infect neonates more commonly than previously recognized, although most infections seem to be asymptomatic or mildly symptomatic. " ~ - in a prospective study, the prevalence of rotavirus infection among neonatal intensive care unit patients was . %. rotavirus has a mean incubation period of days, with a range of to days in children and in experimentally infected adults. fecal excretion of virus often begins a day or so before illness and maximal excretion usually occurs during the third and fourth days, and generally diminishes by the end of the first week, although low concentrations of virus have been detected in neonates for up to weeks. , [ ] [ ] [ ] [ ] rotavirus infections are markedly seasonal (autumn and winter) in many areas of the world, although in some countries seasonality is less striking; the reason for this is u n~l e a r .~~~" '~~ in nurseries in which persisting endemic infection has permitted long-term surveillance of large numbers of neonates, rotavirus excretion can follow the seasonal pattern of the community but can also show no seasonal it is not clear how units in which infection remains endemic for months or years differ from those with a low incidence of rotavirus. some nurseries are free of rotavirus infection' or minimally a f f e~t e d~~"~" whereas others have rotavirus diarrheal disease throughout the year or in outbreaks that involve % to % of low birth weight does not seem to be an important factor in determining the attack rate among infants at risk but may be important in rn rta ity.i~~~ infants in premature or special-care nurseries, despite their prolonged stays and the increased handling necessary for their care, do not demonstrate a higher susceptibility to infection; data regarding shedding of the virus are inconsi~tent!~*~~~~ after infection is introduced into a nursery, rotavirus probably will spread steadily and remain endemic until the nursery is closed to new admissions or nursing practices permit interruption of the cycle. exactly how the virus is introduced and transmitted is uncertain, although limited observations and experience with other types of enteric disease in maternity units suggest several possibilities. the early appearance of virus in stools of some neonates indicates that infection probably was acquired at delivery. virus particles can be detected on the first v s or second" day of life in a significant number of infected infants. by day or , most infected infants who will shed virus, with or without signs of illness, are doing so. , the large numbers of virus particles e x~r e t e d "~~,~~~~ suggest a fairly large and early oral inoculum. it is unlikely that contamination from any source other than maternal feces could provide an inoculum large enough to cause infection by the second day. transfer of particles from infant to infant on the hands of nursing and medical staff is probably the most important means of viral spread. with ' to " viral particles usually present in g of stool, the hands of personnel easily could become contaminated after infection is introduced into a nursery. there are numerous reports of nosocomial and daycare center rotavirus gastroenteritis outbreaks that attest to the ease with which this agent spreads through a hospital or institutional setting.'io admission of a symptomatic child usually is the initiating event, although transfer of a neonate with inapparent infection from one ward to another also has been incriminated. the most important factors influencing the incidence of rotavirus diarrhea in a nursery are the proximity to other newborns and the frequency of handling. during a -month study, infants cared for by nursing staff and kept in communal nurseries experienced three epidemics of diarrhea with attack rates between % and %. during the same period, only % of infants rooming in with their mothers became ill, even though they had frequent contact with adult relatives and siblings. there is no clear evidence of airborne or droplet infection originating in the upper respiratory tract or spread by aerosolization of diarrheal fluid while diapers are changed. indirect evidence of airborne transmission includes the high infection rate in closed settings, the isolation of the virus from respiratory secretions,izo and the experimental observation of transmission by aerosol droplets in mice.' however, the respiratory isolation achieved by placin an evidence indicates that transplacental or ascending intrauterine infection occurs. transmission of virus through contaminated fomites, formula, or food is possible but has not been documented in newborns. rotavirus particles have not been found in human milk or c o l o~t r u m .~~~~~~~~ exposure of a newborn to rotavirus can result in asymptomatic infection or cause mild or severe gastro-outbreaks with high attack rates as measured by rotavirus excretion have been described but the extent of symptomatic infection severe rotavirus infection is seldom reported during the newborn period but the extent of underreporting of severe disease, especially in the less developed areas of the world, has not been evaluated. it has been hypothesized that asymptomatic infections during the newborn period are the result of naturally attenuated strains circulating in this environment. rna electrophoretic patterns of rotaviruses found in certain nurseries have shown uniform and it has been suggested that these strains may be attenuated. the presence of unusual antigenic types such as the p a[ ] type within nurseries also suggests "less virulent strains." at least rotavirus strains were documented to co-circulate in a tertiary care center during a -month period " and in a different setting the same rotavirus strains by electropherotype produced asymptomatic infection in neonates and symptomatic infection in older infants. newborns within a nursery exposed to a given rotavirus strain can develop symptomatic or asymptomatic infection. ~ ~ i because newborns routinely have frequent relatively loose stools, it is possible that mild diarrhea episodes caused by rotavirus are being wrongly labeled as asymptomatic episodes. no clinical feature is pathognomonic of rotaviral gastroenteritis. early signs of illness, such as lethargy, irritability, vomiting, and poor feeding, usually are followed in a few hours by the passage of watery yellow or green stools free of blood but sometimes containing mucus. , - diarrhea usually decreases by the second day of illness and is much infant in a closed incubator is not fully protective. s no enteritisel . . . , ,l , , varies. . . . , improved by the third or fourth day. occasionally, intestinal fluid loss and poor weight gain may continue for or weeks, particularly in low-birth-weight infants. although reducing substances frequently are present in early fecal ~a m p l e s "~~~'~~~' ~ this finding is not necessarily abnormal in neonates, particularly those who are breast-fed. nevertheless, infants with prolonged diarrhea should be investigated for monosaccharide or disaccharide malabsorption or intolerance to cow's milk protein or in a prospective % of newborns with gastrointestinal symptoms in a neonatal intensive care unit had rotavirus detected in their stools. frequent stooling (present in %), bloody mucoid stool ( %), and watery stools ( %) were risk factors for a rotavirus infection. bloody mucoid stools, intestinal dilatation, and abdominal distention were significantly more common in preterm infants, but severe outcomes such as necrotizing enterocolitis and death did not differ among infected term and preterm infants. longitudinal studies in newborn nurseries and investigations of outbreaks among neonates rarely describe a severe adverse outcome or death. , , because these infants are under constant observation, early detection of excessive fluid losses and the availability of immediate medical care are probably major factors in determining outcome. rotavirus gastroenteritis causes almost , deaths of infants every year,i i concentrated largely in the poorest regions of the world. it is likely that in places where hospital-based care is uncommon, rotavirus causes neonatal deaths secondary to dehydration. group a rotavirus has been associated with a wide array of diseases in infants and children; reye syndromes, encephalitis-aseptic meningitis, sudden infant death syndrome, inflammatory bowel disease, and kawasaki syndrome have been described but not systematically studied. case reports and small case series have associated neonatal rotavirus infection with necrotizing e n t e r o c~l i t i s .~~'~"~~~ rotavirus infection may play a role in a small proportion of cases of necrotizing enterocolitis, although it probably represents one of many potential triggering factors. a significant association between neonatal rotavirus infection and bradycardia-apnea episodes was detected in one prospective study. the possible association between natural rotavirus infection and i n t u s s u~c e p t i o n~~~~~~~~~ gained support after the association was made between the human-simian reassortant vaccine and intussusception in infants older than months (attributable risk = : , ). intussusception is extremely uncommon in the newborn; it is highly unlikely that rotavirus triggers this disease in neonates. there are many methods used for detection of rotavirus in stool specimens, including electron microscopy, immune electron microscopy, elisa, latex agglutination, gel electrophoresis, culture of the virus, and reverse transcriptasepolymerase chain reaction. elisa and latex agglutination currently are the most widely used diagnostic techniques for detection of rotavirus in clinical samples. many commercial kits are available that differ in specificity and ~e n s i t i v i t y . '~~~-'~~~ in general, latex agglutination assays are more rapid than elisas but are less sensitive. the sensitivity and specificity of the commercially available elisas surpass %. checking of the elisa by another method such as gel electrophoresis or pcr amplification may be desirable if there is concern about false-positive results. fecal material for detection of rotavirus infection should be obtained during the acute phase of illness. whole-stool samples are preferred, although suspensions of rectal swab specimens have been adequate for detection of rotavirus by rotavirus are relatively resistant to environmental temperatures, even tropical temperatures, although °c is desirable for short-term storage and - °c for prolonged storage.'io excretion of viral particles may precede signs of illness by several days' ; maximal excretion by older infants and children usually occurs to days after onset of symptoms. neonates can shed virus for to weeks after onset of symptoms. the primary goal of therapy is restoration and maintenance of fluid and electrolyte balance. despite the documented defect in carbohydrate digestion with rotavirus diarrhea, rehydration often can be accomplished with glucoseelectrolyte or sucrose-electrolyte solutions given orally . , - intravenous fluids may be needed in neonates who are severely dehydrated, who have ileus, or who refuse to feed. persistent or recurrent diarrhea after introduction of milkbased formulas or human milk warrants investigation for secondary carbohydrate or milk protein i n t~l e r a n c e . '~~~~~~" disaccharidase levels and xylose absorption return to normal within a few days to weeks after infe~tion."~~ intractable diarrhea related to severe morphologic and enzymatic changes of the bowel mucosa is possible although rare in the newborn; it may require an elemental diet or parenteral nutrition. efficacy of anti-rotavirus antibodies (e.g., hyperimmune colostrum, antibody-supplemented formula, human serum immunoglobulin) and of probiotics has been p~s t u l a t e d , '~~~~'~~' although not convincingly shown ; the widespread clinical use of these measures seems remote. one study suggests that use of lactobacillus during the diarrheal episode may decrease the duration of rotavirus-associated hospital stays, especially when used early in the course of the disease, although more studies are needed before recommending widespread use. hand hygiene before and after contact with each infant remains the single most important means of preventing the spread of infection. because rotavirus is often excreted several days before illness is recognized, isolation of an infant with diarrhea may be too late to prevent cross-infection unless all nursing personnel and medical staff have adhered to this fundamental precaution. infants who develop gastroenteritis should be moved out of the nursery area if adequate facilities are available and the infant's condition permits transfer. the use of an incubator is of value in reducing transmission of disease only by serving as a reminder that proper hand-hygiene and glove techniques are required, but is of little value as a physical barrier to the spread of encouraging rooming-in of infants with their mothers has been shown to be helpful in preventing or containing nursery epidemics.' temporary closure of the nursery may be required for clinically significant outbreaks that cannot be controlled with other measures. development of rotavirus vaccines began in the early s. candidate vaccines included bovine and rhesus monkey elisa. , attenuated strains, human attenuated strains, and bovinehuman and rhesus-human reassortant strains."" in august , the first licensed rotavirus vaccine, rotashield, an oral formulation of a simian-human quadrivalent reassortant vaccine, was recommended for use in children when they were , , and months old. after approximately , children were vaccinated with more than million doses, a significantly increased risk of intussusception was observed among vaccinated children, with an overall odds ratio of . .iz use of this vaccine was terminated. two new vaccine candidates are undergoing phase i clinical trials: a "pentavalent" bovine-human reassortant vaccine including g types gl-g and p type pla[ ] and a monovalent human attenuated pla[ ]g vaccine. the epidemiology of rotavirus infection will change significantly if one or both candidates become widely available in the future. the impact on neonatal infection will depend on the effect of herd immunity in decreasing circulation of rotavirus strains. stools from breast-fed neonates are typically watery and yellow, green, or brown. the frequency of stooling can vary from one every other day to eight evacuations per day. in an active, healthy infant who is feeding well, has no vomiting, and has a soft abdomen, these varied patterns of stooling are not a cause for concern. physicians need to consider the child's previous frequency and consistency of stools and establish a diagnosis of acute diarrhea on an individual basis. close follow-up of weight increase in infants with nonformed stools can help confirm the clinical impression. a normal weight gain should direct medical action away from stool exams or treatment. diarrhea during the neonatal period is a clinical manifestation of a wide variety of disorders (table - ). the most common initiating factor is a primary infection of the gastrointestinal tract that is mild to moderate in severity, chapter self-limited, and responsive to supportive measures. acute diarrhea can also be an initial manifestation of a systemic infection, including bacterial and viral neonatal sepsis. infants with moderate to severe diarrhea require close monitoring until the etiologic diagnosis and the clinical evolution are clarified. there are noninfectious diseases leading to chronic intractable diarrhea that may result in severe nutritional disturbances or even death unless the specific underlying condition is identified and treated appropriately. the differential diagnosis of a diarrheal illness requires a careful clinical examination to determine whether the child has a localized or a systemic process. lethargy, abnormalities in body temperature, hypothermia or hyperthermia, decreased feeding, abdominal distention, vomiting, pallor, respiratory distress, apnea, cyanosis, hernodynamic instability, hypotension, hepatomegaly or splenomegaly, coagulation or bleeding disorders, petechiae, and exanthemas should lead to an intense laboratory investigation directed at systemic viral or bacterial infection. if the process is deemed a localized intestinal infection, initial evaluation can be focused on differentiating an inflammatory-invasive pathogen from those that cause a noninflammatory process. for this, stool examination for fecal leukocytes, red blood cells, and lactoferrin can be a helpful indicator of the former. inflammatory diarrhea can be caused by shigella, salmonella, carnpylobacter, v parahaemolyticus, k: enterocolitica, eiec, eaec, c. difjcile, necrotizing enterocolitis, antibioticassociated colitis, and allergic colitis (i.e., milk or soy intolerance). noninflammatory causes of diarrhea include etec, epec, rotaviruses, enteric adenoviruses, calicivirus, astrovirus, g. larnblia and cryptosporidium. although supportive fluid therapy is mandatory for all types of diarrhea, the brief examination for fecal leukocytes and red blood cells can direct the diagnostic and therapeutic approach. pathogens such as shigella, salmonella, and ehec can 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infection-associated persistent diarrhea key: cord- -scbteel authors: richards, timothy j.; rickard, bradley title: covid‐ impact on fruit and vegetable markets date: - - journal: nan doi: . /cjag. sha: doc_id: cord_uid: scbteel canadian fruit and vegetable markets were significantly impacted by the spread of the novel coronavirus sars‐cov‐ (and covid‐ disease), beginning in march . due to the closure of restaurants, bars, and schools, produce growers and distributors were forced to shift supplies almost entirely from the foodservice to the retail channel. shippers reported labor and logistical constraints in making the change, but the fresh produce supply chain remained robust. in the long term, we expect lasting changes in consumers’ online food‐purchasing habits, heightened constraints on immigrant labor markets, and tighter concentration in fresh produce distribution and perhaps retailing. the spread of novel coronavirus, sars-cov- , and the covid- disease it causes has had unprecedented impacts on all food markets, including the market for fruits and vegetables. throughout the value chain, grower-shippers accustomed to just-in-time inventory management systems and retailers able to stock every product with minimal interruption faced shocks in both supply and demand. in this article, we review the nature of these changes due to the spread of covid- in canada and elsewhere and document some of the industry's response, from consumers and retailers through to produce suppliers. we divide our analysis into short-term, or immediate, impacts on the fruit and vegetable supply chain, and then consider longer term impacts that are likely to persist for the entire duration of the pandemic, and perhaps longer. our primary interest is on the implications to canadian markets; however, given the degree of integration between horticultural supply chains in mexico, the united states, and canada, we will provide a north american perspective and focus on the key overlapping issues across the three countries. the various issues affecting their day-to-day operations, taking time for "contingency planning" represented the most substantial change to their daily routines. finding workers, scheduling workers, and ensuring their safety are the most important operational concerns. these operational issues, however, are only the tip of the spear as the industry undergoes fundamental changes and dislocations in an otherwise well-operating value chain. in the short term, closing restaurants and schools-the near-complete loss of an entire distribution channel-has had the most dramatic impact. in , foodservice (both restaurant and institutional) sales in canada totaled $ . billion, while sales in the retail channel were $ . billion (usda, ) . it is reasonable to assume that total food consumption does not change, as the volumes lost to the foodservice channel are likely being picked up by retail. in response, suppliers are setting up packing lines and converting existing lines to move from foodservice to retail buyers. using us data as evidence, by march , , as quarantine measures began in only the most affected of the states in the united states, retail food sales were already up some . % in total, and . % in fresh produce (nickle, b) . we expected this shift to accelerate as the virus spreads, and it has. by march , volumes of fresh produce in the retail channel were up . % over the previous year (s. lutz, personal communication, march , ) . unit prices in the foodservice sector tend to be higher than retail (usda, a), but expenditure in each channel is roughly the same, so this means a roughly % shift in volume across supply chains that differ in fundamental ways. that is, the set of wholesale distributors for the foodservice sector is not always the same as the set that services retail accounts, and many retail accounts are served directly by grower-shippers. although foodservice distributors will clearly see an almost complete loss of demand, retail distributors need to be able to pack more frequently, have trucks in place more quickly, and anticipate moving greater volumes in the next few months. this will demand unprecedented flexibility in terms of shifting lines and suppliers as needs change. farm products destined for the retail and foodservice channels are largely fungible. that is, a head of lettuce contracted to a foodservice distributor is largely the same as one that would be sold to retail. however, that is where the similarity ends, as fresh produce in the retail channel is far more likely to be purchased on contract than it was years ago and more likely to be sold under contract than produce in the foodservice channel. contracting for fresh produce helps buyers ensure a consistent supply of high-quality produce from trusted suppliers, with lower transaction costs than purchasing from a spot, or terminal, market. however, these dedicated relationships break down when end-markets disappear. contracts in the retail fresh produce market are subject to a wide range of force majeure clauses that render them unenforceable in the event of an "act of god," which, we suspect, includes pandemic spread. from a business perspective, sellers servicing foodservice buyers will need to find alternative buyers in the retail channel and vice versa-retail buyers will need to quickly locate suppliers that have been selling to foodservice buyers. all of this search activity also needs to be completed before the current crop, which is highly perishable in most cases, becomes unsellable through any channel. in fact, perishability separates the fresh produce industry from most other agricultural sectors, particularly in terms of the most visible impact of covid- on the retail market. hoarding in both the united states and canada is rampant. however, consumers are only stockpiling nonperishable items as they, perhaps expecting to be completely excluded from food stores, are forward buying in the anticipation of not being able to purchase any of their basic needs. however, retailers have managed to keep relatively complete assortments of fresh fruits and vegetables at reasonable prices. suppliers of nonperishables will feel their armageddon in july or august when the current demand spike has run its course and consumers take months to work through their stockpiles of items. producers of perishable items are experiencing little of the same forward purchasing. there are reports of sporadic stockouts in some of the more storable produce items-table potatoes, onions, and sweet potatoes, for example-but most items in the fresh produce aisle appear to be readily available. some of the trends discussed above for the fresh produce sector are less prevalent for processed (frozen and canned) fruits and vegetables, which is a nontrivial market in canada. in fact, the value of processed fruit and vegetable production in canada is approximately $ billion (statscan, b). anecdotal evidence suggests that, like several nonperishable products, consumers have been stockpiling frozen fruits and vegetables, which has the potential to dampen current and future sales of fresh produce. furthermore, depending on consumers' experiences with processed fruits and vegetables, any short-term changes in the mix of fresh and processed fruits and vegetables have the capacity to alter shopping patterns in the future. this may prove to be an important time for the marketers of both fresh and processed fruit and vegetable firms to maintain, attract, and expand their consumer base (kapsak, ) . there are many reasons why fresh produce shelves remain relatively well stocked while nonperishables disappear quickly, reflecting differences in both supply and demand. first, decisions to grow most vegetables (and seasonal berries) are made from to months in advance of retail shipments, depending on the item in question. therefore, the onset of a crisis that occurred as rapidly as covid- does not necessarily interrupt the biological process of planting and harvesting. although the crops may be available in the field, harvesting crops that are currently in the field may face some difficulties as growers in the southern us (the main source of imports to canada) are reporting some problems obtaining h- a workers (the usual source of seasonal harvesting laborers). rising unemployment among domestic workers in the coming months may provide a ready supply of substitute workers, but attracting workers to the fields will require higher wages and production costs. as the pandemic began to move through the united states, suppliers reported little difficulty in moving their usual volume of fresh fruits and vegetables to retail stores. second, on the demand side, the fact that consumers are stocking up on nonperishable items means that they are likely substituting across-categories within the store at a rate that we have not seen before. retailers are, by now, very sophisticated in terms of their use of inventory and demand-management data in order to optimize prices and assortments in real time. the fact that shelves are empty for some categories (e.g., toilet paper and pasta) and not others (e.g., apples, tomatoes, and strawberries) is a testament to the knife's edge upon which retailers operate. even a small change in demand leads to category-reallocations within the store that result in perceptions of scarcity, even though retail supply chains remain relatively robust. there is evidence that category-substitution, even in normal times, is relatively strong. empirically, we know that consumers exhibit substitution patterns between different foods and food categories. okrent and alston ( ) examine the own-and crossprice elasticities of demand for six food-at-home categories (including fruits and vegetables), two beverage categories, and a food-away-from-home category. their results show that the fruit and vegetable category has important substitution patterns with the cereal and bakery category, meats, and nonalcoholic beverages (which includes fruit juices). so, in addition to any future switching patterns we see between individual fruits and vegetables and between fresh and processed fruits and vegetables, okrent and alston ( ) suggest that consumers will also substitute across food categories. with this shock-driven demand reallocation, budget constraints are likely to have substantially stronger effects, so past estimates may understate the true state of affairs. even items that were complements, such as meat and potatoes, may become substitutes as stockpiling in one leaves less money for the other. intuitively, if the budget share of toilet paper is typically %, the demand for toilet paper is almost meaningless to apple purchases, but when it becomes %, toilet paper purchases drive apple demand down through the budget constraint. although there are no reports of retailers price gouging hoarded-item categories, it is conceivable that higher retail prices for these items could, in turn, generate higher demand for fresh produce as the spread of the virus worsens. category substitution and the eventual run-down of household inventories of nonperishable items may have important implications for future purchases of fresh fruits and vegetables and dietary quality. if households substitute between nonperishable (or frozen) products that were stockpiled and stored during late-winter and the spring of , this could have nontrivial effects in fruit and vegetable markets and lead to a range of market responses in mid-to late . we know that consumers substitute readily between fresh and frozen fruits and vegetables (blumberg thompson, ) , so this effect is likely to be strong. first, the consumption of stockpiled items could begin to occur at the same time that harvest seasons begin for many canadian-produced fruits and vegetables, and this would place downward pressure on prices of fresh produce markets. this scenario would be particularly difficult for small-and medium-sized fruit and vegetable producers who rely more heavily on local and regional markets for their products. second, and perhaps more importantly, different food categories provide different micro and macronutrients to consumers, and the stockpiling and the potential large substitution patterns between food categories could have implications for dietary quality in canada. fruits and vegetables, in particular, are important sources of dietary fiber and many vitamins and minerals. any substitution patterns stemming from the eventual management of stockpiled items (mostly cereals) may inadvertently discourage consumers from eating the recommended amount of fruits and vegetables (canada food guide, ). of course, much of the produce sold in canada is imported. in fact, in , total retail sales of fresh fruits and vegetables produced domestically averaged about $ million (cdn) per month (statscan, a), while imports averaged approximately seven times that amount (statista, ) . consequently, most of the impact of changing consumption patterns will be felt by importers, including wholesalers, distributors, and retailers, and any impact on availability will be determined by conditions in the us fresh fruit and vegetable supply chain. among domestic stakeholders in the fresh value chain, importers, including distributors, wholesalers, and retailers will be the most directly impacted. in fact, retailers may experience changes that last well beyond the duration of the pandemic. borders remained open to commercial traffic well into the crisis. however, further restrictions on cross-border movement will dramatically affect trade-dependent firms, like those in the fruit and vegetable industries. losing access to us imports will clearly limit canadian retail sales this summer to items grown primarily in canada, reducing the variety of fresh items that canadian consumers have become accustomed to. reflecting consumers' fears of being in proximity to others, online food sales surged as the pandemic spread. prior to the spread of covid- , only . % of groceries were sold online in canada, a number that had grown to over . % by the third week of march (charlebois, ) . in fact, grocery chains were reporting surges in online orders of up to % (o'malley, ), and some were limiting physical access to stores. although much of this online ordering activity was surely for nonperishable and household items, the fact that many supermarkets charge fixed online delivery fees means that shoppers have an incentive to order their entire shopping list online and avoid the risk of shopping in physical stores. once consumers learn how to shop online and experience the benefits in terms of convenience and speed, many will remain online shoppers at least occasionally. for fresh produce retailers, many believe this experience could represent the tipping point that moves fresh food delivery beyond tech-savvy, regular online purchasers to the center of mass of the food-buying public. direct channels, such as farmers' markets and farm stands, have become an important source for fresh fruits and vegetables. although small in volume in canada (statscan, a), farmers' markets often represent the face of the industry as they attract the most engaged segment of the fresh produce market. although social distancing likely means the end of most face-to-face markets for fresh produce in the short term, it also provides an opportunity for community-supported agriculture organizations to seize a market opportunity by expanding local delivery services. shifting fruit and vegetable consumption from restaurants to home-based meals has potentially important implications for food waste. there are three mechanisms at work; leaving the net effect uncertain. first, gooch, felfel, and marenick ( ) estimate that some % of food waste in canada occurs in the home, while the foodservice sector is responsible for %-much different from the proportions of food volume consumed at home and away from home. therefore, shifting consumption from foodservice to households may, in fact, increase the amount of fresh produce that is wasted. second, overpurchasing is one of the key drivers of household food waste. if anxiety over the viability of the fresh produce supply chain leads to hoarding, or at least overbuying, then more fresh produce will be wasted as a result. on the other hand, perceptions of scarcity are likely to lead households to become more efficient, both in their use of food on hand and in planning food purchases. determining which effect dominates would be a fruitful question for future research. there are other effects that are more likely to persist or that reflect long-term developments in fresh produce supply chains. we identify three of the most significant in this context as an access to labor issues in the fresh produce growing industries of the united states and canada, consolidation, and the move to online food purchasing. canada obtains most of its fresh produce from the united states (statista, ) . reliance on imports, mainly from the united states, means that anything that interrupts production and distribution schedules in the united states may have dramatic effects on canadian availability. in that regard, a shortage of farm workers in produce-growing regions of the united states-not just for harvest, but for a wide range of production jobs-has, for many years, been perhaps the most important issue facing fresh produce growers, well before the spread of covid- (hertz & zahniser, ; richards, ; richards & patterson, ) . because this issue is structural, endemic to the us labor market, and defies an easy political solution, there has been a patchwork of policy remedies suggested and enacted over the past years. the us immigration and nationality act of established the h- guestworker visa program, which was later divided into the h- b program for seasonal workers in nonagricultural industries (and subject to strict limits) and the h- a program (not subject to limits on the number of workers). due to its bureaucratic and heavily regulated nature, workers hired under the h- a program represented only a small share of all agricultural workers each year, some , workers out of a total workforce of over . million. in the recent years, however, heightened enforcement of immigration laws in the united states, reduced out-migration from mexico, aging of the workforce in the united states, and the reluctance of domestic workers to do farm labor meant that the share of h- a workers rose from . % of the entire workforce in to some . % in (see figure , usda, b). as covid- spread in early , restrictions on cross-border movement between the united states and mexico meant that growers could no longer rely on a ready supply of h- a workers. although the spread of covid- began before the harvest season for most fruits and vegetables, growers could not conduct early-season planning for the coming harvest. somewhat perversely, perhaps, unemployment caused by the shock to the us economy more generally has provided an immediate pool of available workers. however, during the previous period of relatively high unemployment during the financial crisis of - , growers could not attract domestic workers, even by promising higher wages. as counterintuitive as it may seem, us workers' reluctance to do farm jobs may mean that crops go unharvested, despite a real demand for the final good and plenty of workers able to do the job. domestic production in canada faces many of the same issues. canada admits some , guestworkers annually, many of whom are employed in the fresh fruit and vegetable industry. although workers are still allowed into the country, difficulties in obtaining approval in mexico and traveling to canada may mean that far fewer than are needed will make the trip this growing season. moreover, canadians-even newly unemployed canadians-are not likely to take these jobs and risk losing unemployment support. if growers are forced to raise wages to attract domestic workers, the price of domestically grown produce may rise substantially. second, we expect the rate of consolidation to increase throughout the fresh produce supply chain. similar to the rest of the economy, much of the growth of small business in the produce sector during the - recovery and boom period was fueled by debt. although the consequences of debt-funded growth and declining cash flow are more obvious in the shale-oil industry, bankruptcies and consolidation will also rise in the fresh produce industry. in periods of financial instability, only large, stable firms with the ability to service interest payments and sustain business relationships through cash shortages survive. further, there is little reason to believe that per-capita consumption of fresh produce will change as we emerge from the pandemic, so the same amount of business will essentially be spread among fewer businesses. among empirical industrial-organization economists, the linkage between concentration and market power is far from settled. but, it is undeniable that the potential for margin expansion by large retailers on the consumer side, powerful packers and distributors on the wholesale-buying side, and exporters selling into the canadian market will be much greater in the absence of a strong, competitive fringe of small firms. another potential long-term trend that may emerge from the covid- pandemic is the way consumers purchase food and how they buy fruits and vegetables. the move to online grocery shopping has been particularly notable given the share of online purchases made by retirees and households that have not traditionally purchased groceries from home (charlebois, ) . this has important implications for produce as there is evidence that some consumers are more likely to make healthier purchases when groceries are ordered online, or at least less impulsive, as consumers tend to use automated shopping lists online (pozzi, ) . in predicting how this short-term response to covid- will affect longer term fruit and vegetable sales (both fresh and processed), the outlook will depend greatly on customers' satisfaction with their initial online shopping experiences in march and april . online grocery sales are expected to reach % of total grocery sales by (albrecht, ) ; some are now predicting that our experience with covid- will be a defining moment in north america's embrace of online grocery shopping. any further movement online will only accentuate the consolidation effect described above. after amazon's purchase of whole foods in , the movement online and increased concentration of retail grocery sales came to be viewed as essentially two manifestations of the same underlying dynamic. supermarket retailing is notoriously capital intensive, and endogenizing fixed costs is an important tool for strategic competition among grocery retailers (ellickson, ) . online grocery may appear to consumers to be "just an app," but to do it in a way that competes with amazon requires building distribution centers, establishing a delivery network, integrating with physical stores, and expanding geographic reach. small, independent, neighborhood stores may not be able to compete in a world in which consumers demand online grocery options. we believe that the greatest impact of the covid- pandemic in the short term will be felt through the realignment of fresh produce supply chains due to the closure of nearly all foodservice outlets. as consumers move to buying food almost completely through the retail channel, distribution infrastructure specific to retail will remain strained throughout the spread of the disease and will test supply-chain relationships for some time after. over the longer term, the potential impacts will be felt through input markets, most notably labor, and through structural changes in the industry, which may undergo fundamental and largely irreversible shocks, such as consolidation and a move toward online shopping. the fact that canada imports much of its fresh produce requirements does not insulate it from these shocks. rather, the price of imported produce will rise with the cost of production in the united states and with any changes in the structure of the exporting industry. these changes, while being rational responses to short-term incentives, may change fresh fruit and vegetable distribution forever. https://orcid.org/ - - - study: online sales to hit $ billion by . the spoon heterogeneity in the demand for fruits and vegetables: how much can price and quantity reveal? working paper eat vegetables and fruits why covid- will change canadian grocery industry forever: expert. retail insider food waste in canada. value chain management centre is there a farm labor shortage now is the time to promote produce. produce business how the coronavirus is affecting the produce industry. the packer retail produce sales rising amid coronavirus concerns. the packer coronavirus: many large grocery chains experiencing online order delays. globalnews demand for food in the united states: a review of the literature, evaluation of previous estimates and presentation of new estimates of demand shopping cost and brand exploration in online grocery immigration reform and farm labor markets hysteresis and the shortage of agricultural labor monthly import value of fruit, nuts and vegetables in canada from table: - - - channels of distribution for horticulture product sales and resales naics for fruit and vegetable preserving and specialty food manufacturing food dollar series farm labor key: cord- -s hdhh authors: zeimet, anthony; mcbride, david r.; basilan, richard; roland, william e.; mccrary, david; hoonmo, koo title: infectious diseases date: - - journal: textbook of family medicine doi: . /b - - - - . - sha: doc_id: cord_uid: s hdhh nan infections of the upper respiratory tract accounted for more than million ambulatory medical visits in , according to the national ambulatory medical care survey (cherry et al., ) . although a large percentage of these infections are viral in origin, antibiotics are still prescribed for more than % of patients with acute respiratory tract infection (arti). acute bronchitis, in the arti category, is defined as a respiratory infection in which cough is the predominant symptom and there is no evidence of pneumonia. antibiotics are often prescribed despite limited evidence that they shorten the duration of acute bronchitis. with increasing incidence of antibiotic resistance, bronchitis allows physicians to practice "prescriptive restraint" and to provide supportive therapy. consider using the phrase "chest cold" to help patients understand the viral and benign nature of this infection. chronic bronchitis is one of the manifestations of chronic obstructive pulmonary disease (copd) and is defined clinically as cough and sputum production on most days for months annually for years. chronic bronchitis is thought to be primarily inflammatory in origin, although infection may be associated with acute exacerbations; with increased sputum production and worsening dyspnea, antibiotics have proved effective in acute episodes. however, systemic corticosteroids are the mainstay of copd exacerbation management. the patient with acute bronchitis presents with cough, often productive. patients may report clear or colored mucus in association with the presumed diagnosis of acute bronchitis. despite what many patients believe, the color of sputum, even purulent sputum, is not predictive of bacterial infection. the cough of bronchitis can last up to weeks, sometimes even longer. typically, acute bronchitis is associated with other manifestations of infection, such as malaise and fever. respiratory viruses are thought to cause the majority of cases of acute bronchitis. influenza a and b, parainfluenza, respiratory syncytial virus (rsv), coronavirus, adenovirus, and rhinovirus are common pathogens in the viral category. clues to a specific virus may be found in the patient history; for example, rsv might be considered when there is household exposure to infected children. influenza typically presents with sudden onset of symptoms, including fever, myalgias, cough, and sore throat. neuraminidase inhibitors are modestly effective in shortening the duration of influenza in ambulatory and healthy patients (by about day), if initiated in the first hours of illness. the resistance patterns of influenza a and b have shifted in the last several years and may vary based on yearly viral strains. influenza b has remained, as of , sensitive to zanamivir (relenza) and oseltamivir (tamiflu). currently circulating strains of influenza a, both h n and h n , and influenza b have generally remained sensitive to both oseltamivir and zanamivir (fiore et al., ) . family physicians are advised to consider restraint in the prescribing of these agents, since resistance is of great concern. yearly influenza immunization and cough etiquette and hygiene are likely the most useful techniques for influenza management. studies have identified other pathogens, such as mycoplasma pneumoniae and chlamydophila pneumoniae, in a small minority of cases of clinical acute upper respiratory illness with cough as the predominant symptom. no significant benefit has been found in treating these infections with antibiotics. an exception in the treatment of acute bronchitis-like illness with antibiotics is when confirmed or probable bordetella pertussis is present. early treatment with a macrolide antibiotic and patient isolation will likely decrease coughing paroxysms and limit spread of disease (braman, ) . although common upper respiratory bacterial pathogens, such as moraxella (branhamella) catarrhalis, streptococcus pneumoniae, and haemophilus influenzae, may be isolated from patients with acute bronchitis, their relevance is questionable because these bacteria can be present in the respiratory tract of healthy individuals. obtaining sputum for culture when bronchitis is the diagnosis generally is not useful. antibiotics may offer a modest benefit in the treatment of acute bronchitis, with many studies showing no statistical significance in the outcome of treated versus not-treated groups. measures of function, such as duration of illness, loss of work, and limitation of activity, have not shown clinically significant improvement in those with acute bronchitis taking antibiotics. coupled with cost and the potential for side effects, the use of antibiotics for acute bronchitis is not recommended. if a provider decides to use an antibiotic in a specific patient situation, narrow-spectrum respiratory agents are preferred, such as a first-generation macrolide or doxycycline. treating the symptom of cough in acute bronchitis is an important concern for patients. in adults with acute bronchitis with signs of airway obstruction, evidenced by wheezing on examination or decreased peak expiratory flow rate, beta- agonists may be helpful in alleviating cough. these agents are not helpful for children with acute cough or adults with cough and no evidence of airway obstruction. side effects of tremor and an anxious feeling must be weighed against this benefit. patients often are primarily interested in alleviating symptoms caused by respiratory illness. unfortunately, there is mixed evidence for the use of over-the-counter (otc) and prescription cough medications. dextromethorphan and codeine may be somewhat effective, although they have not been evaluated in randomized, double-blinded, placebo-controlled trials for acute bronchitis. combination first-generation antihistamine-decongestant products may be effective for the cough associated with colds. naproxen showed efficacy against cough in one upper respiratory model study (sperber et al., ) . guaifenesin acts as an expectorant and may have some effect on cough by its mucus-thinning properties. community-acquired pneumonia (cap) is defined as an acute infection of the pulmonary parenchyma and, along with influenza, is the seventh leading cause of death in the united states. fever, cough, sputum production, pleuritic chest pain, and dyspnea are common symptoms of cap. nausea, vomiting, and diarrhea also may occur, and in elderly patients, cap may present with mental status changes. although its absence usually makes pneumonia less likely, fever can be absent in the elderly patient. other physical examination findings include an elevated respiratory rate, conversational dyspnea, tachycardia, and rales. egophony and dullness to percussion may be noted with focal consolidation. typical laboratory findings include leukocytosis. the diagnosis of pneumonia is based on the presence of symptoms and the presence of an infiltrate on chest radiograph. if infiltrate is not present, consider obtaining a chest tomography scan (which has higher sensitivity) to rule in or rule out cap. if negative, other diagnoses should be considered. the most common microbiologic agent of pneumonia is often not isolated (table - ). furthermore, studies have shown that bacteriologic causes of pneumonia cannot be determined by radiographic appearance (i.e., "typical" vs. "atypical"). in the proper clinical setting, certain clinical microbes should be considered because they can affect treatment considerations and epidemiologic studies. these include legionella spp., influenza a and b, and communityacquired methicillin-resistant staphylococcus aureus (mrsa). certain diagnostic tests are performed based on clinical setting. blood cultures are not routinely done in the outpatient setting but should always be done if the patient is being admitted to the hospital, ideally before antibiotics are given. the use of gram stain and sputum culture remains controversial but can provide more evidence of a bacterial cause (e.g., many pmns). if sputum cultures are being obtained, it is recommended that the physician have the patient expectorate directly into a specimen cup and have it sent immediately for processing. this can increase the yield of isolating streptococcus pneumoniae among antibiotics for the treatment of bronchitis is not recommended because of the cost, potential for side effects, and lack of clinical benefit (braman, ; smith et al., ) (sor: a). in the treatment of bordetella pertussis, early administration of a macrolide antibiotic and patient isolation will likely decrease coughing paroxysms and limit spread of disease (braman, ) (sor: a). in adults with acute bronchitis with signs of airway obstruction, as evidenced by wheezing on examination or decreased peak expiratory flow rate, beta- agonists may be helpful in alleviating cough (braman, ) (sor: b). for acute exacerbation of copd associated with purulent sputum and increased shortness of breath, treatment with antibiotics decreases mortality by % and treatment failure by % (ram et al., ) (sor: a). other respiratory pathogens. other tests include urine antigen tests for s. pneumoniae, legionella pneumophila serogroup , and nasal swab for influenza a and b. in young children, rsv, adenovirus, and parainfluenza in addition to influenza are common causes. nasal swab for rsv and influenza can be rapidly done, but the other causes can be determined with viral cultures, serology, enzyme-linked immunosorbent assay (elisa), and polymerase chain reaction (pcr), although results usually are received after resolution of the acute symptoms. perhaps the most important decision for clinicians is to determine the location of treatment. the american thoracic society (ats) and the infectious diseases society of america (idsa) recommend use of the pneumonia severity index (psi), which uses variables to risk-stratify the patient into five mortality classes, or the curb- , which measures five clinical variables in this decision making. the curb- may be the easiest and most convenient to use at the site of decision making. a score of or indicates treatment as an outpatient; a score of requires hospital admission to the general medical ward; and a score of or more indicates admission to an intensive care unit (icu) (box - ). treatment of cap should be targeted toward the most likely etiology (table - ). outpatient therapy for patients who have no comorbidities and have not received antibiotics within the last months includes doxycycline or a macrolide antibiotic. use of a fluoroquinolone antibiotic (levofloxacin or moxifloxacin) should be reserved for patients with more complicated pneumonia and those requiring hospitalization. patients who have comorbid conditions or recent antibiotic exposure, or who will be hospitalized, should receive a respiratory fluoroquinolone or combination therapy with a betalactam drug plus a macrolide, for to hours after fever abates (usually - days' total therapy). if an organism is isolated, therapy may be narrowed to cover the causative agent. the clinician should consider longer therapy and appropriate antibiotics to cover for infection by less common organisms such as staphylococcus aureus or pseudomonas aeruginosa. if the patient has no more than one abnormal value (temperature < . ° c, heart rate < , respiratory rate < , sbp > , o saturation > %, po > on room air) and the patient is able to maintain oral intake and has a normal mental status, the clinician can safely switch to oral therapy and discharge the patient from the hospital. unless the etiology of the pneumonia is known, the physician should switch to oral antibiotics in the same class as the intravenous antibiotics used. the u.s. preventive services task force (uspstf) along with idsa and ats recommend annual influenza vaccinations to those over years of age, those who are (or who reside with those who are) at high risk for influenza complications, and all health care workers. furthermore, the pneumococcal vaccine should be given to all those over age . smoking cessation is also important and should be discussed at each clinic visit. • concerns about development of resistant seasonal and h n swine-derived influenza virus should be considered in the decision to administer antiviral medications to healthy patients with these infections. • the abrupt onset of fever with chills, headache, malaise, myalgias, arthralgias, and rigors during "flu season" is sufficient to diagnose influenza. • prevention of influenza is generally with vaccination. influenza deserves special mention because it is an important cause of pneumonitis and can precede a bacterial pneumonia. influenza viruses are medium-sized enveloped ribonucleic acid (rna) viruses that consist of a lipid bilayer with matrix proteins with spiked surface projections of glycoproteins (hemagglutinins, neuraminidase) on the outer surface ( figure - ) . both influenza a and influenza b have eight segmented pieces of single-stranded rna. the only difference between influenza a and b is that b does not have an m ion channel. hemagglutinins, three types of which typically infect humans (h , h , h ), bind to respiratory epithelial cells and allow fusion with the host cell. neuraminidase, consisting of two types (n , n ), allows release of virus from the infected cells. a unique aspect of influenza is that antigenic variation occurs annually. antigenic shift is caused by a genetic reassortment between animal and human influenza strains, producing a novel virus that generally causes the worldwide pandemics. influenza viruses circulate mostly among humans, birds, and swine. sometimes; a human strain and an animal strain can intermingle and create a new, unique virus. this is what happened during spring , heralding the most recent pandemic and creating "novel h n influenza" (swine influenza). genotype analysis • score or : outpatient treatment • score : inpatient treatment on a general medical floor • score > : inpatient treatment in an intensive care unit bun, blood urea nitrogen. locally adapted guidelines should be implemented to improve the processing of care variables and relevant clinical outcomes in pneumonia (mandell et al., ) (sor: b) . objective criteria or scores should always be supplemented with physician determination of subjective factors, including the patient's ability to take oral medication safely and reliably and the availability of outpatient support resources (sor: b). for patients with curb- score of or higher, more intensive treatment (i.e., hospitalization or, where appropriate and available, intensive in-home health care services) is usually warranted (sor: c). of this strain determined that components came from an influenza virus circulating among swine herds in north america that combined with a virus circulating among ill swine in eurasia, creating a new influenza strain capable of causing disease in humans. because this virus had not previously infected humans, it had the potential to cause widespread morbidity and mortality worldwide. during pandemics, the u.s. centers for disease control and prevention (cdc) estimates an additional , to , deaths caused by influenza. although higher than in nonpandemic years, mortality was significantly less than initially predicted in . no recent antibiotic therapy a respiratory fluoroquinolone alone or an advanced macrolide plus a β-lactam † † an advanced macrolide plus a β-lactam, or a respiratory fluoroquinolone alone (regimen selected will depend on nature of recent antibiotic therapy) intensive care unit (icu) a β-lactam † † plus either an advanced macrolide or a respiratory fluoroquinolone pseudomonas infection is not an issue but patient has a β-lactam allergy a respiratory fluoroquinolone, with or without clindamycin pseudomonas infection is an issue ‡ ‡ (cystic fibrosis, impaired host defenses) either ( ) copd, chronic obstructive pulmonary disease; mrsa, methicillin-resistant staphylococcus aureus. * azithromycin or clarithromycin. † that is, the patient was given a course of antibiotic(s) for treatment of any infection within the past months, excluding the current episode of infection. such treatment is a risk factor for drug-resistant streptococcus pneumoniae and possibly for infection with gram-negative bacilli. depending on the class of antibiotics recently given, one or another of the suggested options may be selected. recent use of a fluoroquinolone should dictate selection of a nonfluoroquinolone regimen, and vice versa. ‡moxifloxacin, levofloxacin, or gemifloxacin. § dosage: g orally (po) three times daily (tid). ¶ dosage: g po twice daily (bid). ** high-dose amoxicillin ( g tid), high-dose amoxicillin-clavulanate ( g bid), cefpodoxime, cefprozil, or cefuroxime. † † cefotaxime, ceftriaxone, ampicillin-sulbactam, or ertapenem. ‡ ‡the antipseudomonal agents chosen reflect this concern. risk factors for pseudomonas infection include severe structural lung disease (e.g., bronchiectasis) and recent antibiotic therapy, health care-associated exposures or stay in hospital (especially in the icu). for patients with cap in the icu, coverage for s. pneumoniae and legionella species must always be considered. piperacillin-tazobactam, imipenem, meropenem, and cefepime are excellent β-lactams and are adequate for most s. pneumoniae and h. influenzae infections. they may be preferred when there is concern for relatively unusual cap pathogens, such as p. aeruginosa, klebsiella spp., and other gram-negative bacteria. § § piperacillin, piperacillin-tazobactam, imipenem, meropenem, or cefepime. ## data suggest that older adults receiving aminoglycosides have worse outcomes. ¶ ¶ dosage for hospitalized patients, mg/day. the abrupt onset of fever, along with chills, headache, malaise, myalgias, arthralgias, and rigors during "flu season," is sufficient to diagnose influenza. as the fever resolves, a dry cough and nasal discharge predominate. a rapid nasal swab or viral cultures can be used to confirm the diagnosis of influenza but is rarely needed. in fact, the sensitivity of these rapid tests can range from % to %, so a negative test does not rule out influenza. the primary care physician needs to determine if the patient has influenza or the common cold, because symptoms of both illnesses generally overlap (table - ) . treatment of influenza is generally not necessary because it is usually a self-limiting condition. treatment should be reserved for those with comorbidities who present within hours of symptom onset. neuraminidase inhibitors (zanamivir and oseltamivir) prevent the release of virus from the respiratory epithelium and are approved for both influenza a and influenza b. the m inhibitors (amantadine and rimantadine) are approved by the u.s. food and drug administration (fda) for the treatment of influenza a because these drugs block the m ion protein channel, preventing fusion of the virus to host cell membrane (influenza b has no m ion channel). the use of m inhibitors is limited because of increasing resistance among influenza a viruses, as well as causing central nervous system (cns) problems that are usually exacerbated in elderly persons, who are more likely to seek treatment for influenza (table - ). the major complication of influenza is a secondary bacterial pneumonia or exacerbation of underlying copd. initial improvement in clinical symptoms followed by deterioration usually suggests a secondary bacterial pneumonia, which can usually be confirmed with a chest radiograph showing an infiltrate. other, less common complications of influenza include myositis, myocarditis, pericarditis, transverse myelitis, encephalitis, and guillain-barré syndrome. prevention of influenza is generally with vaccination. box - outlines patients at risk for influenza complications who should be vaccinated yearly. although anyone wanting an influenza vaccine should be vaccinated, during periods of vaccine shortage, high-risk groups have priority. a well-matched vaccine can prevent influenza among % to % of adults and decrease work absenteeism. conversely, a poorly matched vaccine only prevents influenza in % of healthy adults. proper hand hygiene and covering one's cough are two additional important components in preventing the spread of influenza virus. • population-based vaccination programs have been highly effective in decreasing the incidence of many viral infections. • acyclovir can be used in adults and children with varicella to decrease symptoms if given in the first hours after rash onset, but its benefit must be weighed against its cost and the possibility of development of viral resistance. • antiviral medications should be considered to decrease the incidence of postherpetic neuralgia, particularly in older patients. early treatment (within hours of onset of symptoms) with oseltamivir or zanamivir is recommended for influenza a (jefferson et al., ) (sor: a). use of oseltamivir and zanamivir is not recommended for patients with uncomplicated influenza with symptoms for more than hours (kaiser and hayden, ) (sor: a). oseltamivir and zanamivir may be used to reduce viral shedding in hospitalized patients or to treat influenza pneumonia (sor: c). (from treanor jj: influenza viruses, including avian influenza and swine influenza. in mandell gl, bennett je, dolin rd (eds) . mandell, douglas, and bennett's principles and practices of infectious diseases, th ed. philadelphia, churchill livingstone, , p .) • measles has had a resurgence in recent years and should be suspected when a patient presents with cough, coryza, conjunctivitis, and head-to-toe rash. • epstein-barr virus and cytomegalovirus infections are generally not clinically distinguishable, and their treatment is primarily supportive. vaccinations have dramatically decreased the incidence of a number of historically common viral infections; smallpox has been eradicated through widespread vaccination. however, recent outbreaks of measles and mumps on college campuses underscore the need to remain vigilant in administering vaccines at the population level, even though no vaccine is available for many common viruses. varicella is one of the classic viral exanthems of childhood. before routine vaccination, having chickenpox was one of childhood's "rites of passage." the virus, a herpesvirus (human herpesvirus ), is effectively transmitted, causing outbreaks in schools and households. patients with primary varicella present with fever, headache, and sore throat. generally within to days of onset of symptoms, a papulovesicular rash erupts diffusely. the classic description of the chickenpox lesion is "a dewdrop on a rose petal," suggesting a central vesicle on an erythematous base. lesions continue to appear for to days. all lesions going from papule to vesicle to crusted lesion takes about weeks. patients are considered to be infectious, primarily through respiratory secretions, during the days before symptoms appear and until all lesions are crusted. treatment of varicella is generally supportive. control of spread may be a concern in group-living environments such as schools or residence halls. isolation of the infected patient away from those susceptible to varicella infection is standard practice. acyclovir can be started within the first hours after rash eruption to achieve an attenuation of the infectious course. in children, this means a decrease in the duration of fever by about day and a decrease in the number of lesions (swingler, ) . in adults, acyclovir decreases rash duration and the number of lesions, although the results are less significant than for children. adult dosing of acyclovir for varicella is mg five times daily. the marginal benefit must be weighed against the possible development of resistance at a population level and the cost of the medication. complications of varicella can include secondary infection of skin lesions, pneumonitis, encephalitis, and dehydration from vomiting and diarrhea. varicella is prevented primarily through administration of vaccine. the vaccine is highly effective in children, with recommended dosing at to months with a second dose at to years. varicella is now included in a measles-mumpsrubella (mmr) vaccine, which can be given between months and years of age. the varicella vaccine is a live, attenuated virus and should not be given to certain immunocompromised patients. the vaccine can also be administered to exposed immunocompetent contacts, although the benefit is clearer for children than adults. severely immunocompromised patients exposed to varicella (particularly those with advanced hiv disease) may be given high-dose acyclovir to prevent development of disease. herpes zoster is a reactivation of the neurotropic varicella virus, typically in a dermatomal distribution. this is more common in elderly or immunocompromised patients but can occur in healthy people as well. patients with zoster may note generalized malaise, hyperesthesia, numbness, tingling, and pain in the skin before development of a rash. the appearance of the rash is the same as for chickenpox, although most often isolated to a unilateral dermatome. the diagnosis of herpes zoster is clinical based on the history and the classic appearance of the rash. in immunocompromised patients, however, the rash may not be dermatomally isolated. when the diagnosis is unclear, viral culture can be obtained from the base of a lesion. antiviral medications are likely to decrease the incidence of postherpetic neuralgia and are recommended, particularly in elderly patients (wareham, ) . valacyclovir ( g three times daily) or famciclovir ( mg every hours) for days is likely more effective than acyclovir in achieving this result. either drug should be started as soon after the diagnosis as possible, preferably within to hours of rash onset. when patients have established postherpetic neuralgia, gabapentin and tricyclic antidepressants are helpful in alleviating the pain. the rash of zoster is infectious to the touch. patients should be advised to keep the rash covered until all the lesions have crusted. zoster of the trigeminal nerve can extend to the eye and warrants immediate ophthalmologic intervention. a vaccine to prevent herpes zoster in adults was released in . the zoster vaccine differs from the varicella vaccine in that the amount of attenuated virus is times higher in the zoster vaccine. the vaccine decreases the incidence of zoster by %. it is recommended for administration by the american academy of family physicians (aafp) to adults over age , regardless of prior varicella or zoster history. although generally well tolerated, the vaccine is somewhat costly. in , more measles cases were reported than in any other year since (cdc, ) . measles is the "first disease" of childhood from the history of medicine. in adults, measles infection may be acquired in the face of waning immunity from remote immunization. a booster dose of mmr vaccine is recommended before college entry. clinically, measles presents with cough, coryza (nasal irritation and congestion), and conjunctivitis. fever is common several days before the onset of the rash. the rash of measles typically spreads from head to toe and has an erythematous, papular appearance with a "sandpaper" feeling. koplik's spots are erythematous papules with a bluish center on the oral mucosa and appear early in measles. measles is highly contagious through droplets. lymphopenia and neutropenia are common laboratory findings with measles infection. complications of measles include primary infections such as pneumonia, gastroenteritis, encephalitis, and the rare subacute sclerosing panencephalitis. secondary infections such as otitis media, pneumonia, and adenitis may also occur. treatment is supportive, and the implications of measles infection are primarily in the public health realm. patients with measles should be isolated for at least days after the appearance of the rash. it is important to recognize that patients are contagious for days before the development of symptoms. careful verification of immunization status for close contacts is essential. clinical infectious mononucleosis is a common infection in adolescents and early adults. the clinical syndrome is most often caused by epstein-barr virus (ebv), although cytomegalovirus (cmv) may also be the source in this clinical syndrome, which includes fever, exudative tonsillitis, adenopathy (often including posterior cervical or occipital nodes), and fatigue. ebv is transmitted in oral secretions and may be transmitted sexually as well. b cells are infected with ebv either directly or after contact with epithelial cells, resulting in diffuse lymphoid enlargement. the diagnosis of infectious mononucleosis is made by recognizing the clinical symptoms of fever, pharyngitis, and adenopathy along with the laboratory findings of greater than % lymphocytes with % or more atypical lymphocytes (hoagland, ) . also, a positive serologic test for heterophile antibody assists the family physician in the diagnosis. to differentiate ebv from cmv mononucleosis, serology (igg and igm) may be obtained. results of these tests are generally not available in time to have a significant benefit clinically. splenic enlargement as part of this lymphoid hypertrophy can lead to splenic rupture ( . % risk) (dommerby et al., ) . athletes with infectious mononucleosis must be managed carefully to avoid their participation in sports that could result in abdominal trauma. other risks associated with infectious mononucleosis include upper airway obstruction, asymptomatic transaminase elevation, thrombocytopenia, and rash after the administration of ampicillin or amoxicillin. routinely obtaining transaminase levels in patients without clinical hepatitis is of little value and can increase the overall cost of management. treatment of infectious mononucleosis is largely supportive. patients should be instructed to treat fever with antipyretics, rest, and expect symptom duration of to weeks, although symptoms can last for several months. the use of steroids, such as prednisone, has shown limited benefit. data suggest an initial benefit hours after steroid administration, although this is lost within several days (candy and hotopf, ) . combination of steroid and an antiviral (valacyclovir) may have some positive effect on fatigue. • the most common presentation of tuberculosis is pulmonary disease. • tuberculosis is diagnosed by acid-fast bacilli smears and cultures. • standard first-line agents to treat tb are isoniazid, rifampin, pyrazinamide, and ethambutol. • high-risk patients with a positive purified protein derivative skin test or quantiferon-tb gold test should be treated for latent tb infection. • the current recommendation for first-line treatment for latent tb is months of oral isoniazid. tuberculosis skin testing should be interpreted without regard to bacille calmette-guérin (bcg) history, because bcg is administered in areas where tb is endemic and bcg does not provide complete protection from tb infection. tuberculosis (tb) is a disease that has plagued humans since antiquity, with evidence of spinal tb in neolithic and early egyptian remains. at present, tb affects approximately one third of the world's population. tb is the world's second most common cause of death from infectious disease after human immunodeficiency virus or acquired immunodeficiency syndrome (hiv/aids). tuberculosis is caused by mycobacterium tuberculosis, an acid-fast bacillus. tb is acquired by inhalation of respiratory droplets. these respiratory droplets are spread by coughing. brief contact carries little risk for acquiring tb, and infection generally does not occur in open air; open-air sanatoriums were the cornerstone of tb treatment before antimicrobial therapy. in the united states, tb incidence rates have been on the decline since , coinciding with the control of hivinduced aids by antiretroviral therapy. however, tb remains prevalent in certain high-risk groups (i.e. immigrants, iv drug use, homeless persons). most cases of tb are in people age to years. tb in elderly persons is generally caused by a reactivation of latent infection acquired in the remote past, whereas tb in young children indicates ongoing active transmission in the community. infection in children is more likely to progress to active tb and disseminated disease. persons with hiv infection have a disproportionately higher risk for acquiring tb than the general population. tuberculosis is most frequently manifested clinically as pulmonary disease, but it can involve any organ. extrapulmonary tb accounts for about % of disease in hiv-seronegative persons but is more common in hiv-seropositive persons. pulmonary tb typically manifest with fever, night sweats, chronic cough, sputum production, hemoptysis, anorexia, and weight loss. chest radiographs in patients with pulmonary tb typically reveal upper-lobe cavitary lesions and can reveal infiltrates or nodular lesions, as well as lymphadenopathy ( figure - ). tb in the setting of advanced hiv co-infection does not generally manifest in the typical manner (table - ) . acyclovir started within the first hours after varicella rash eruption can attenuate the infectious course, decreasing duration of fever by day and reducing the number of lesions (sor: a). administration of varicella vaccine to a susceptible child within days of exposure will likely modify or prevent disease (macartney and mcintyre, ) the diagnosis of pulmonary tb is made by the demonstration of acid-fast bacilli (afb) in sputum and the growth of m. tuberculosis in culture. these patients typically have an abnormal chest radiograph, as previously described. m. tuberculosis is a slow-growing bacterium, and cultures can take up to weeks to grow. a pcr assay developed for m. tuberculosis can be run on afb smear-positive sputum to hasten the diagnosis of pulmonary tb. a positive pcr on afb-positive sputum is diagnostic of pulmonary tb, but a negative test does not rule out the diagnosis. patients with afb positive smears from sputum samples should be started on anti-tb therapy while awaiting results of pcr and cultures. the treatment of tb always uses multiple agents with anti-tb activity. single agents should never be used. the standard first-line agents are isoniazid (inh), rifampin (rif), pyrazinamide (pza), and ethambutol (emb) (figure - and table - ). if administered, inh should be given with pyridoxine (vitamin b ; - mg orally daily) to prevent neuropathy. treatment of active pulmonary tb is generally for months regardless of hiv status, but treatment may need to be extended in certain situations. directly observed therapy (dot) is the preferred mechanism of administration to ensure compliance. many local county and state health departments have systems for dot. treatment of hiv-seropositive patients with tb who are receiving an antiretroviral (arv) regimen that contains a protease inhibitor is complicated by the latter's interaction with rifamycins (particularly rifampin). management of such patients should be coordinated with an infectious diseases specialist, who also should manage drug-resistant tb treatment. in the united states, latent tuberculosis infection (ltbi) is the most prevalent form of tuberculosis. ltbi is the term given to patients with a positive purified protein derivative (ppd) skin test without evidence of active tb. ppd has been used for more than years and relies on delayed-type hypersensitivity (dth) to m. tuberculosis cellular proteins. early late figure - treatment algorithm for tuberculosis. patients in whom tb is proved or strongly suspected should have treatment initiated with isoniazid, rifampin, pyrazinamide, and ethambutol for the initial months. a repeat smear and culture should be performed when months of treatment has been completed. if cavities were seen on the initial chest radiograph or the acid-fast smear is positive at completion of months of treatment, the continuation phase of treatment should consist of isoniazid and rifampin daily or twice weekly for months to complete a total of months of treatment. if cavitation was present on the initial chest radiograph and the culture at completion of months' therapy is positive, the continuation phase should be lengthened to months (total of months of treatment). if the patient has hiv infection and the cd + cell count is less than /mm , the continuation phase should consist of daily or three-times-weekly isoniazid and rifampin. in hiv-uninfected patients having no cavitation on chest radiograph and negative acid-fast smears at completion of months of treatment, the continuation phase may consist of either once-weekly isoniazid and rifapentine, or daily or twice-weekly isoniazid and rifampin, to complete a total of months (bottom). patients receiving isoniazid and rifapentine, and whose -month cultures are positive, should have treatment extended by an additional months (total of months). *emb may be discontinued when results of drug susceptibility testing indicate no drug resistance. †pza may be discontinued after it has been taken for months ( doses). ‡rpt should not be used in hiv-infected patients with tb or in patients with extrapulmonary tb. therapy should be extended to months if -month culture is positive. afb, acid-fast bacilli; cxr, chest radiograph (x-ray); emb, ethambutol; inh, isoniazid; pza, pyrazinamide; rif, rifampin; rpt, rifapentine. because ppd relies on dth, any factor that reduces the dth affects the host response to ppd. the most common clinical example is use of corticosteroids, which blunt the dth response and can complicate ppd interpretation. therefore, ppd testing should not be performed while a patient is taking corticosteroids. also, tb testing should be targeted to those with higher risk of infection and should not routinely be done in those with low risk (ats/cdc, ) . the ppd can also give false-positive results in patients with previous bacille calmette-guérin (bcg) vaccination or with infection by other mycobacterial infections. in the united states, this may cause difficulties in testing immigrants from countries who routinely use bcg vaccination programs. however, previous bcg vaccination should not change the interpretation of the ppd or willingness to treat such individuals accordingly. ‡when dot is used, drugs may be given days per week and the necessary number of doses adjusted accordingly. although there are no studies that compare five with seven daily doses, extensive experience indicates this would be an effective practice. § patients with cavitation on initial chest radiograph and positive cultures on completion of months of therapy should receive a -month ( weeks, either doses [daily] or doses [twice weekly]) continuation phase. ¶ five-days-a-week administration is always given by dot. rating for day per week regimens is aiii. ¶ ¶ not recommended for hiv-infected patients with cd + cell counts < cells/μl. ** options c and b should be used only in hiv-negative patients who have negative sputum smears at completion of months of therapy and who do not have cavitation on initial chest radiograph. for patients started on this regimen and found to have a positive culture from the -month specimen, treatment should be extended an extra months. the dth response can wane over time. to overcome this problem, nonreacting patients may undergo repeat ppd week after their initial ppd. the diagnosis of ltbi is made by interpretation of a ppd and by ascertaining the patient's risk factors for progression to active tb if left untreated . interpretation of the ppd should be based on the area of induration and not the area of surrounding erythema. persons whose ppds have converted from negative to positive within years are presumed to have been infected recently. the decision to use ppd means treating the patient for ltbi if the ppd test is positive. patients at increased risk for progression to active tb include those who have been recently infected (recent ppd converters); patients who are hiv seropositive; patients who have silicosis, diabetes, or chronic renal failure (including those receiving hemodialysis); solid-organ transplant recipients; patients with gastrectomy or jejunoileal bypass or head and neck cancer; injection drug users; patients with chest radiograph evidence of prior tb; and patients who weigh at least % less than ideal body weight. patients taking chronic corticosteroid therapy and those who are to receive tumor necrosis factor alpha (tnf-α) blockers (e.g., infliximab) are also at risk. patients taking corticosteroids also have higher risk of progression to active tb with larger doses and longer courses of corticosteroids. standard therapy for ltbi is inh, mg orally daily for months, regardless of hiv status. again, inh should always be administered with pyridoxine to prevent neuropathy. to overcome the false-positive results and confusion of ppd testing in certain populations, newer interferon-gamma (ifn-γ) release assays such as the quantiferon-tb gold (qft-g) test have been developed to detect latent m. tuberculosis. qft-g quantifies the release of ifn-γ from lymphocytes of the host's blood in response to three m. tuberculosis target antigens that are absent from bcg and most other nontuberculous mycobacterium spp. the advantages of using qft-g include one-time blood testing without the need for followup visit, no triggering of amnestic responses, and possibly more specific response to m. tuberculosis. however, qtf-g use in immunocompromised or anergic patients is limited, with indeterminate results. some studies also show discordant results in individuals tested with both ppd and qtf-g. in general, qtf-g may be used in all circumstances in which the ppd is used. however, whether the qtf-g is truly more specific or sensitive than the ppd in latent or active tb is yet to be determined. • the u.s. preventive services task force recommends "highintensity" behavioral counseling to at-risk adults and adolescents to prevent sexually transmitted infections. • be specific in addressing patients' sexual practices so as to provide appropriate prevention advice. hiv-positive persons recent contacts of tuberculosis patients fibrotic changes on chest radiography consistent with prior tuberculosis patients with organ transplants and other immunosuppressed patients (receiving equivalent of ≥ mg/day of prednisone for at least month) development in the primary prevention of stis is immunization against human papillomavirus (hpv). the vaccine can prevent infection with certain strains of hpv that cause cervical cancer and genital warts. trials are ongoing to determine the effectiveness of daily arv therapy in preventing transmission of hiv. vaccination investigation is ongoing for herpes simplex, chlamydia trachomatis, and hiv. this breadth of research effort holds promise for the future in the prevention of stis. the uspstf recommends "high-intensity" behavioral counseling to at-risk adults and adolescents to prevent stis. highintensity counseling involves multiple sessions and often is delivered to groups of patients. unfortunately, this type of intervention has limitations in its practicality for population-based delivery. no risk of harm was discovered in the delivery of counseling for sti prevention. vaccination is the most important form of primary prevention of common infectious diseases. two vaccines are currently on the market for hpv prevention-one that protects against four viral subtypes ( , , , ) and is licensed for use in males and females to years of age, and the other against two subtypes ( , ), licensed for females to years of age. hepatitis b is a sexually transmitted infection, and immunization is recommended for adolescents who have not been previously inoculated. this is a requirement in many states for school entry. hepatitis a can be transmitted by oro-anal sexual contact, and vaccination should be offered to patients who are contemplating engaging in this sexual practice. recommendations surrounding the use of barrier methods for sti prevention should be tailored to the sex practices of the client. for example, a percentage of women use anal sex as a method of birth control but may not consider the need for condom use with this practice. the question, "do you regularly use condoms?" has little relevance to infection control for many sexual practices. evidence supports the advice to use barrier methods of latex or other approved material in a manner that prevents the exchange of blood and body fluids in decreasing stis. condoms confer a % risk reduction for herpes simplex and up to an % risk reduction for hiv, when used correctly (weller and davis-beaty, ; martin et al., ) . the secondary prevention of stis is achieved through direct and nonjudgmental patient assessment and screening and avoiding assumptions about patient sexual practices. screening is a tool to prevent the inadvertent spread of infection as well as the sequelae of undetected disease. infectious genital ulcers are associated with herpes simplex virus (hsv), syphilis, chancroid, lymphogranuloma venereum, and granuloma inguinale. hsv is by far the most common, affecting million people in the united states. hsv- and hsv- are chronic, neurotropic viral infections that enter through epithelium and come to rest in the dorsal root ganglia. therefore, infection leads to lifetime presence of the virus, but the clinical manifestation of this condition is variable. a small percentage of those with serologic evidence of hsv- ( %- %) have had symptoms of clinical herpes infection. in addition, patients with hsv infection can shed the virus in the absence of symptoms, creating a prime opportunity for spread. herpes simplex outbreak may be followed by a prodrome of malaise, fever, and regional lymphadenopathy before the appearance of grouped vesicles on an erythematous base. the vesicles are typically quickly broken and become ulcerated in appearance, with each vesicle usually less than several millimeters in size. true first-time infections tend to present more severely than secondary presentations of previously infected individuals, with a prodrome present in % of cases. the lesions can be in any location around the genitals or rectum, on the proximal thighs and buttocks, inside the vagina, and in and around the mouth. the lesions are most who to screen? often painful, particularly when on mucosal surfaces, or itchy. in women, herpes simplex can present with cervicitislike symptoms with bleeding and discharge and cervical ulcerations on examination, or simply mucopurulent cervicitis. herpetic lesions around the urethra tend to be extremely painful and can make urination difficult. rectal hsv can be confused with irritation, perianal fissure, and even candidiasis because of its often beefy-red appearance and itching. vesicles typically appear days after infection and can last up to weeks in an initial infection. subsequent outbreaks tend to have a shorter duration and to be less uncomfortable for patients. confirmation of infection is helpful, but the diagnosis can be made primarily on the clinical appearance of the exanthema. vigorous sample collection from an ulcer (which the patient may not appreciate) to be sent for pcr identification and typing is the most readily available method of laboratory diagnosis. serum antibody testing is not useful in the initial hsv diagnosis because antibody levels will not be appreciable early in infection. the appearance of convalescent immunoglobulin g (igg) and igm levels several weeks after a suspected outbreak might help to support the diagnosis of hsv infection. the value of screening for hsv immunity is debatable and should generally not be recommended for asymptomatic individuals. in addition, the uspstf recommends against screening asymptomatic pregnant women for hsv to prevent transmission to the newborn. given that many patients with hsv infection never manifest symptoms, the value of knowing that one is hsv seropositive is questionable. in addition, hsv- and hsv- , although classically oral and genital, respectively, can "mix and match" based on sexual practices. it is often confusing for asymptomatic individuals to know that they have hsv antibody (do i have cold sores? do i have genital herpes? how should this change the way i live my life?). in monogamous couples with one partner known to be hsv positive and the other with unknown status, testing of the latter may indicate suppressive therapy in the seropositive partner if the other is found to be negative. regular barrier method use decreases transmission of herpes in both men and women, with patients using condoms % of the time having a % reduction in hsv acquisition from those who never use condoms (martin et al., ) . serodiscordant couples may also decrease transmission through antiviral suppressive therapy to the hsv-positive partner (table - ) . syphilis is a spirochetal infection that has resurged since , the nadir year since . syphilis infection rates are highest in men who have sex with men. syphilis is much less common than the other stis, with an infection rate of . per , population in the united states (vs. per , for chlamydia). syphilis presents in several stages. the primary phase of syphilis is a painless ulcer called a chancre (figure - ) . the chancre may be visible on the genitals, although it can also be inside the vagina, mouth, or rectum, making it difficult to find. this lesion will appear within weeks of transmission and will last for several weeks untreated. the secondary phase of infection is disseminated and involves a diffuse macular rash, typically with palm and sole lesions, generalized lymphadenopathy, fever, and condyloma latum (smooth, moist lesions on genitals without cauliflower appearance of condyloma acuminatum). tertiary syphilis is often asymptomatic but affects the heart, eyes, and auditory system and can be associated with gumma formation. gummas are soft, granulomatous growths in organs that can cause mechanical obstruction and weakening of blood vessel walls. latent infection often involves the cns. diagnosis of primary syphilis is challenging. the test of choice is darkfield microscopy, which is not readily available. direct fluorescent (monoclonal) antibody (dfa) testing may be available. antibody tests for syphilis, such as the rapid plasma reagin (rpr) and the less frequently used venereal disease research laboratories (vdrl), are often not positive early in infection and thus cannot be used to rule out primary syphilis based on a single reading. treponemal antigen testing (eia) may be available in some laboratories. the fluorescent treponemal antibody absorption (fta-abs) test may also be negative in the early infection. direct pcr for primary syphilis lesions has been tested but is not yet fda approved. a physician may choose to treat presumptively if a painless chancre and risk factors are present and may then do a convalescent rpr test in to weeks to confirm the infection by the appearance of a positive reaction. one would expect a fourfold change in titer of either test to indicate the presence of disease. primary and secondary syphilis are treated with a single injection of penicillin g, . million units. other regimens do not have proven effectiveness but can be used in the penicillin-allergic patient, including doxycycline, mg twice daily for days; ceftriaxone, mg to g intramuscularly (im) daily for to days; or azithromycin, g as a single oral dose, although resistance to azithromycin has been observed. patients treated for primary syphilis should have periodic clinical follow-up and serologic testing to determine a fourfold decrease in rpr reactivity within months. latent syphilis can be either early, meaning infection within the last year, or late, meaning infection beyond a year. early latent syphilis is treated with a single injection of penicillin g, . million units. syphilis of late latency or unknown duration is treated with three injections of penicillin g, . million units, in consecutive weeks. for penicillin-allergic patients, doxycycline, mg twice daily for days, is required. those with latent syphilis should have ophthalmic examination as well as evaluation for vascular gumma formation. suspected neurologic involvement of latent syphilis must be evaluated with cerebrospinal fluid (csf) examination and treatment with aqueous penicillin g, - million units intravenously (iv) every hours for to days. partners of patients with newly diagnosed syphilis are at risk for infection. partners within days of a diagnosis of primary syphilis should be tested, but treated presumptively even if serologic testing is negative. for partners prior to days before diagnosis, serology is generally reliable in detecting presence of infection and may guide treatment. patients with secondary syphilis should inform partners within months before diagnosis, or months for those diagnosed with tertiary syphilis (table - ). chancroid may occur in regional outbreaks and presents with a painful genital ulcer and suppurative regional adenopathy. herpes and syphilis should both be ruled out in the patient suspected of having chancroid infection. chancroid is caused by haemophilus ducreyi and there is currently no fda approved test to directly detect this organism. treatment with azithromycin ( g as single dose), ceftriaxone ( mg im as a single dose), ciprofloxacin ( mg twice daily for days), or erythromycin ( mg three times daily for days) are all alternatives (table - ). it may be necessary to perform incision and drainage on fluctuant inguinal nodes. patients should be reexamined in to weeks to ensure healing of the primary ulcer(s) and resolution of the adenopathy. partners who had contact with the infected patient starting days before development of the patient's symptoms should be treated, regardless of the presence of symptoms. less common ulcerating stis include lymphogranuloma venereum (lgv) and granuloma inguinale ( figure - ). lgv causes regional adenopathy and often an ulcer at the point of entry. rectal lgv may cause a proctocolitis with anal pain, discharge, bleeding, and diarrhea. lgv is caused by chlamydia trachomatis serotypes and can be detected by testing swabbed material from open lesions or aspirates from lymph nodes with culture, dfa, or nucleic acid detection. treatment is noted above (table - ) . granuloma inguinale, caused by klebsiella granulomatis, is rare in the united states and causes progressive ulcerative disease of the genitals. a second sti category includes those causing the clinical presentation of vaginal discharge, pelvic pain, dyspareunia, and dysuria in women and penile discharge and dysuria in men, as well as possible rectal pain and discharge in men and women. of this group, chlamydia trachomatis is the most common, causing . million infections in the united states in (cdc, ). in fact, chlamydia is the most frequently reported reportable infection. the majority of women with chlamydia infection are without symptoms. many men are asymptomatic as well. regular screening for chlamydia, as recommended by the uspstf, can significantly reduce the incidence of pelvic inflammatory disease (pid), one of the most serious sequelae of untreated infection. in women with untreated chlamydia infection, in addition to pid, tubo-ovarian abscess, tubal scarring and ectopic pregnancy, and infertility can all result. as previously mentioned, regular screening is currently recommended for all sexually active women under age , all pregnant women under , and at-risk pregnant and nonpregnant women over . chlamydia testing can be performed on several liquid-based papanicolaou (pap) tests. endocervical swabs for nucleic acid amplification are acceptable when a conventional pap smear is being used. given the recent liberalization of recommendations about pap testing for women under years of age, urine nucleic acid amplification is a readily available alternative for chlamydia testing. this can easily be done at a contraceptive counseling clinic. urine testing is also an acceptable method of testing for men, in addition to a urethral swab. rectal chlamydia infection can occur in individuals who practice receptive anal intercourse. an fda-approved method of testing should be used for screening and diagnosis of this infection. asymptomatic chlamydia infection is treated with either a single dose of azithromycin, g orally, the drug of choice, or doxycycline, mg twice daily, for days (table - ) . patient-delivered partner therapy (pdpt), the practice of dispensing treatment to diagnosed patients to treat their partner(s), has proved effective in reducing reinfection rates and further spread of infection. ept is legally allowable in states and potentially allowable in another . chlamydia infection may present symptomatically in men or women with symptoms of dysuria and with discharge and with pelvic pain and dyspareunia in women. the discharge of c. trachomatis, versus that of neisseria gonorrhoeae, is said to be more mucoid than purulent, although this characteristic is not specific enough to provide diagnostic accuracy. symptomatic chlamydia, without evidence of pid, is treated the same as asymptomatic infection. many practitioners will treat presumptively for chlamydia and gonorrhea in patients who present with the symptoms previously mentioned while they wait for confirmatory testing. neisseria gonorrhoeae infection may be asymptomatic in both men and women. the current uspstf recommendation is for screening women at risk. men with penile gonorrhea typically present with purulent penile discharge and dysuria with n. gonorrhoeae infection. mucopurulent discharge, dysuria, pelvic pain, and dyspareunia are typical symptoms in women. in patients who engage in anal intercourse, anal discharge, rectal pain, and bleeding can be presenting symptoms. gonococcal pharyngitis is within the differential of exudative pharyngitis in sexually active patients. when symptomatic, throat pain, tonsillar exudates, and anterior cervical adenopathy may be present. testing for gonorrhea can be done using liquid-based pap technologies, cervical or urethral swabs, or urine for nucleic acid amplification. in men with visible discharge, a gram stain with white blood cells (wbcs) and gram-positive intracellular diplococci has a high degree of sensitivity. culture testing may be preferred for suspected pharyngeal and rectal specimens pending fda approval of other methods. again, physicians may opt to treat patients with mucopurulent cervicitis or urethritis presumptively for gonorrhea and chlamydia while waiting for confirmatory testing. fluoroquinolone therapy is no longer recommended because of widespread resistance (table - ) . because reinfection with gonorrhea is common for several months after treatment, it may be advisable to retest patients with confirmed gonorrhea in the months after treatment. similarly, stis may be an indicator of risk behavior, and a complete risk history and testing for other stis is advisable if not completed at the initial visit. in male patients with symptomatic urethritis, a causative agent may not be identified, a situation often referred to as nongonococcal urethritis (ngu). technically, chlamydia is included in this category. organisms such as ureaplasma urealyticum and mycoplasma genitalium may be the cause and may be difficult to detect. treatment for these infections is the same as for symptomatic chlamydia, with azithromycin or doxycycline (table - ). it is recommended that partners of patients with ngu should be evaluated and treated. in some cases, testing of partners may detect a specific organism as the cause of infection (e.g., chlamydia). trichomonas vaginalis causes vaginitis in women, who may have a stereotypic frothy, green, and foul-smelling discharge. many women are asymptomatic with trichomoniasis. in addition to causing asymptomatic infection in men, t. vaginalis may cause urethritis. this organism may be suspected in men when patients have repeated treatment failures and no other explanation for symptoms. microscopic examination of vaginal discharge is % to % sensitive in women. a first voided urine specimen or urethral swab for microscopic exam may be helpful in identifying the protozoa. culture for trichomonas, which requires a special medium, may be necessary to identify this infection accurately in men. trichomonas is effectively treated with a single -g dose of metronidazole (table - ) . for non-sti causes of vaginal discharge, see the online discussion at www.expertconsult.com. pelvic inflammatory disease can be caused by a number of organisms, including chlamydia, and presents with pelvic pain and discharge. findings that contribute to the diagnosis of pid include fever greater than ° f, cervical or vaginal mucopurulent discharge, abundant wbcs on saline preparation of vaginal discharge, elevated erythrocyte sedimentation rate (esr), elevated c-reactive protein (crp), and evidence of n. gonorrhoeae or c. trachomatis infection. hospitalization with parenteral antibiotics may be necessary in pregnant patients, patients in whom surgical emergency cannot be ruled out, those who do not respond to oral treatment, those who cannot tolerate oral treatment, and patients who have severe illness or tubo-ovarian abscess. when treating pid parenterally, improvement of symptoms for hours may prompt a change to oral therapy (table - ) . conversely, if oral therapy is not producing significant improvement within to days, admission for parenteral therapy may be necessary. patient awareness of human papillomavirus infection has greatly increased in recent years, in large part related to the patient-directed advertising of the hpv vaccine. hpv is likely the most common sti. thirty types of hpv can infect the genital area, some causing genital warts, some causing malignancies of the genital organs, and most being asymptomatic. the gross categories most often used are "high risk" (most often types and ) and "low risk" (types and ) hpv infection, the former more often associated with genital cancer. prevention of hpv infection and cervical cancer was revolutionized with the release of the hpv vaccine, which is effective in reducing the incidence of hpv-associated disease. currently, two vaccines are licensed in the united states. gardasil (merck), released in , includes protection against viral types , , , and . it is approved for the prevention of vulvar and vaginal cancer and for the prevention of cervical cancer, cervical dysplasia, and genital warts in females age to . the vaccine was recently approved for males of the same age range for the prevention of genital warts. more recently, cervarix (glaxosmithkline) was approved for the prevention of cervical cancer and cervical dysplasia from hpv types and in women age to . ideally, the vaccine should be administered before initiation of sexual activity to prevent initial acquisition of these hpv types. patients who are already sexually active may also receive the vaccine. the transmission of hpv to men decreases with consistent condom use, from . % in men who never use condoms to . % in men who "always" use them. unfortunately, hpv can infect skin that is not covered by the use of traditional barrier methods (nielson et al., ) . male circumcision may decrease the transmission of hpv. patients have many questions about hpv, in particular about screening for asymptomatic infection. hpv infection occurs with high frequency in the sexually active population; up to % or more of sexually active individuals have hpv at some point in their life. in addition, hpv is effectively transmitted, even if contact does not involve genital-togenital touching (i.e., manual stimulation can transmit the virus). again, most hpv infections are without symptoms and resolve spontaneously through eradication by the intact immune system. for all these reasons, screening for the mere presence of hpv infection has minimal utility. there is no treatment for asymptomatic hpv infection. the most common presentation of hpv infection is in the context of an abnormal pap smear. hpv is directly linked to cervical dysplasia. for women over age and under , hpv testing with high-risk viral detection is common. the presence of high-risk hpv informs further management of the pap result. it is currently recommended that women over be automatically tested for high-risk hpv infection at the pap smear. patients may present with visible warts, or these may be detected at routine or sti screening. genital warts are often cosmetically unacceptable to patients, even though they are infrequently functionally problematic. in some circumstances, wart burden can be high enough to cause physical discomfort or relative obstruction of the vagina or rectum. vulvovaginal candidiasis and bacterial vaginosis are generally not thought to be sexually transmitted, although they are often in the differential diagnosis of sexually transmitted infection (sti). both these infections likely are related to changes in the vaginal ph and the normal flora distribution. it is not always clear which of these factors is primary and which is secondary, because at diagnosis, both ph and normal vaginal flora will often be abnormal. vulvovaginal candidiasis is a common infection causing typically white, curdlike discharge, itching, and sometimes dysuria. the causative organism is usually candida albicans but can be other candida spp. antibiotics can alter normal vaginal flora, so the recent use of antibiotics may predispose women to candidiasis. physical examination may reveal erythematous external genitalia as well as external and internal white, clumping discharge. usually, no distinctive odor is associated with vaginal yeast. wet preparation of vaginal specimen or treatment with potassium hydroxide (koh) may reveal branching pseudohyphae and yeast. when ph is performed, it should be directly on the vaginal discharge and not on the saline-diluted specimen because the saline will alter the ph of the specimen. typically, the ph of yeast discharge is less than . (normal vaginal ph, . - . ). bacterial vaginosis (bv) is the most common cause of infectious vaginal discharge (spence and melville, ) . many different organisms are associated with the diagnosis of bv, including gardnerella vaginalis and mycoplasma hominis. women with bv may report discharge, vaginal irritation, vaginal odor, and at times, dysuria. findings of bv are often detected during a normal screening pap smear or pelvic examination. physical findings may reveal signs of vaginal irritation. the discharge is usually thin and gray. an amine (fishy) odor may be produced with the application of koh. the finding of clue cells, or epithelial cells with adherent bacteria, under saline preparation microscopy and a decrease in normal lactobacilli are common findings. the amsel criteria are useful in bv diagnosis; other scoring systems (e.g., nugent criteria) have been used but require gram staining. the specific amsel criteria are ( ) milky, homogeneous, adherent discharge; ( ) discharge ph greater than . ; ( ) positive whiff test (fishy smell with addition of koh); and ( ) at least % clue cells on microscopic examination. if three of the four criteria are present, the likelihood of bv is %. in routine vaginal examination and bimanual examination for patients with vaginal discharge, signs and symptoms of vaginitis are poor predictors of the microbiologic cause of infection (schaaf et al., ) . the clinical examination and office testing, in fact, are fair predictors of the true cause of infection (lowe et al., ). many patients with vaginal discharge will use over-the-counter preparations before consulting a physician, which can delay correct diagnosis of the etiology of symptoms. patient-collected, low vaginal swabs may be as useful as provider-collected specimen in making a diagnosis for the patient with vaginal discharge. the purpose of bimanual examination is to evaluate for signs of pelvic inflammatory disease and is not necessary in the low-risk patient with vaginal discharge. treatment of asymptomatic bv or vaginal yeast is not necessary in the nonpregnant patient or usually is not needed to test or treat partners of patients with isolated yeast or bv. when infection is recurrent, particularly when a woman's male partner is uncircumcised, treatment of the male partner for carriage of either infection may be warranted. options for treatment of recurrent infections are presented in etable - . the treatment of warts is destructive and may serve to stimulate an immune response to the hpv-infected cells, which are typically "above" the surveillance mechanisms of the immune system in the epidermis. office methods of treatment include cryotherapy and trichloroacetic acid or podophyllin resin application. patients may apply podofilox . % solution or gel or imiquimod % cream (table - ) . for more extensive cases of warts or intra-anal or intravaginal infections that are difficult to treat using the previous methods, surgical techniques may be necessary to achieve resolution. untreated, warts may resolve spontaneously, remain the same, or worsen. patients with pediculosis pubis, or pubic lice, most often present with pruritus or with visible nits. pubic lice are visible on inspection of the pubic area, as are nits, which are adherent to the hair shaft. partners of patients with pubic lice should also be treated to prevent reinfection. linens and clothing should be laundered or dry-cleaned or kept in a closed plastic container or bag for hours. scabies diagnosis can be challenging. again, patients present with itching that can be anywhere on the body, although often in the genital area or on the buttocks when infection is sexual in origin. the pruritus associated with sarcoptes scabiei is a result of sensitization to the mite droppings underneath the skin as the mite burrows. the classic "burrow" or linear papular eruption is not always present. scraping of lesions with microscopic examination may be performed to identify the mite. as with pediculosis, close contacts should be treated. linens and clothing should be laundered or dry-cleaned or isolated in plastic containers for hours. the pruritus-associated with scabies can take several weeks to resolve after treatment. patients living in group settings (dormitories or apartments) may reinfect one another as a result of inadequate primary treatment of all contacts ( cryotherapy trichloroacetic acid (tca): small amount applied until wart whitens podophyllin resin, % to % all these may be repeated every to weeks until warts are resolved. podofilox . % solution or gel applied twice daily for days, followed by days of no therapy. imiquimod % cream applied once daily at bedtime three times a week for up to weeks; washed off to hours after application. urinary tract infection (uti) is defined as significant bacteriuria in the presence of symptoms. uti accounts for a significant number of emergency department visits; an estimated % of women experience a uti in their lifetime. the urinary tract is normally sterile. uncomplicated uti involves the urinary bladder in a host without underlying renal or neurologic disease. the bladder mucosa is invaded, most often by enteric coliform bacteria (e.g., e. coli) that ascend into the bladder via the urethra. sexual intercourse can promote this migration, and cystitis is common in otherwise healthy young women. frequent and complete voiding has been associated with a reduction in the incidence of uti. complicated uti occurs in the setting of underlying structural, medical, or neurologic disease. signs and symptoms of a uti include dysuria, frequency, urgency, nocturia, enuresis, incontinence, urethral pain, suprapubic pain, low back pain, and hematuria. fever is unusual. up to % of patients with symptoms of cystitis have a smoldering pyelonephritis, especially when symptoms have been present for more than week. a patient with pyelonephritis usually appears ill, with fever, sweating, and prostration, along with costovertebral angle (flank) tenderness in most cases. the differential diagnosis of uncomplicated uti includes use of diuretics or caffeine, interstitial cystitis, vaginitis, pregnancy, pelvic mass, pid, and benign prostatic hypertrophy (bph). if a uti is suspected, the initial test of choice is urinalysis, although with classic signs and symptoms of infection in women, this test is not always necessary. pyuria, as indicated by a positive result on the leukocyte esterase dip test, is found in the majority of patients with uti. the presence of urinary nitrites is fairly specific for uti. the combination of positive leukocyte esterase and nitrites improves sensitivity. on urine microscopy, levels of pyuria as low as two to five leukocytes per high-power field ( - wbcs/hpf) in a centrifuged specimen are significant in the female patient with appropriate symptoms, as is the presence of bacteriuria. urine culture and sensitivity are not needed in simple utis. cultures should be done in patients with recurrent utis, patients with pyelonephritis, and pregnant patients. antibiotic therapy can be given in a -day regimen for young, sexually active women. a -to -day course of antibiotics should be used in pregnant patients and patients with complicated utis. all the drugs listed in table - can be used in a -day or -to -day course. clinical practice guidelines that include telephone assessment and treatment have shown a decrease in unnecessary laboratory utilization while maintaining quality of care (saint et al., ) . trimethoprim-sulfamethoxazole (tmp-smx) has been a mainstay of uti therapy, but in some localities, resistance of e. coli to tmp-smx is % (mehnert-kay, ) . if a urine culture is done and the organism is resistant to the drug prescribed, a change in antibiotics is indicated only if the patient is still symptomatic. for symptomatic treatment, a bladder anesthetic can be used, such as phenazopyridine (pyridium), mg three times daily for days. patients should be warned that this produces an orange tinge in tears and urine. patients should also be instructed to increase fluid intake. pyelonephritis is suggested by a failure of a short course of antibiotics. signs and symptoms of pyelonephritis include shaking chills and fever higher than . ° c ( . ° f), flank pain, malaise, urinary frequency and burning, and costover-tebral angle tenderness. the infection can produce septic shock. a patient who is unable to tolerate oral intake should be hospitalized and given empiric iv antibiotics aimed at broad-spectrum gram-negative coverage, such as third-generation cephalosporins, fluoroquinolones, or aminoglycosides, while awaiting results of blood and urine cultures. a -day course of antibiotic therapy (iv or po) is recommended. although the most common bacterial infection during pregnancy, the incidence of uti in pregnancy is similar to that reported in sexually active nonpregnant women of childbearing age. up to % of pregnant women with tmp-smx, / mg q h trimethoprim, mg q h fluoroquinolones ‡ ciprofloxacin, - mg q h ciprofloxacin xr, mg qd gatifloxacin, mg qd levofloxacin, mg qd nitrofurantoin monohydrate/macrocrystals, mg q h nitrofurantoin macrocrystals, - mg qid amoxicillin, mg q h or mg q h cephalexin, mg q h, or other cephalosporin consider -day regimen. amoxicillin, mg q h or mg q h nitrofurantoin monohydrate/macrocrystals, mg q h nitrofurantoin macrocrystals, - mg qid cephalexin, mg q h, or other cephalosporin tmp-smx, / mg q h male gender, diabetes, symptoms for days, recent antimicrobial use, age > tmp-smx, § / mg q h fluoroquinolones, as per -day regimens cephalexin, mg q h, or other cephalosporin consider -day regimen. from hooton tm, stamm we. diagnosis and treatment of uncomplicated urinary tract infection. infect dis north am ; : . tmp-smx, trimethoprim-sulfamethoxazole; qd, every day; q h, every hours; q h, every hours; q h, every hours; qid; four times daily. * treatments listed to be prescribed before etiologic agent is known (gram stain may help); therapy can be modified when cause is identified. † characteristic pathogens are escherichia coli ( %- %) and staphylococcus saprophyticus ( %- %); other organisms account for less than % of cases and include proteus mirabilis, klebsiella pneumoniae, and enterococcus spp. ‡fluoroquinolones should not be used in pregnancy. § although classified as pregnancy category c, tmp-smx is widely used; however, avoid its use in the first and second trimesters. untreated bacteriuria in the first trimester develop acute pyelonephritis later in pregnancy. premature births and perinatal mortality are increased in pregnancies complicated by uti. therefore, in pregnant women, asymptomatic bacteriuria should be actively sought and aggressively treated with at least one urinalysis, preferably toward the end of the first trimester. nitrofurantoin, ampicillin, and the cephalosporins have been used most extensively in pregnancy and are the regimens of choice for treating asymptomatic or minimally symptomatic uti. tmp-smx should be avoided in the first trimester because of possible teratogenic effects and should be avoided near term because of a possible role in the development of kernicterus. fluoroquinolones are avoided because of possible adverse effects on fetal cartilage development. for pregnant women with overt pyelonephritis, admission to the hospital for parenteral therapy should be the standard of care; beta-lactam agents with or without aminoglycosides are the cornerstone of therapy. prevention of uti, including pyelonephritis, can be accomplished during pregnancy with nitrofurantoin or cephalexin taken prophylactically after coitus or at bedtime without relation to coitus. such prophylaxis should be considered for patients who have had acute pyelonephritis during pregnancy, patients with bacteriuria during pregnancy who have had a recurrence after a course of treatment, and patients who had recurrent uti before pregnancy that required prophylaxis. catheter-associated utis are associated with increased mortality and costs. risk factors for catheter-associated utis include the duration of catheterization, lack of systemic antibiotic therapy, female gender, age older than years, and azotemia. to help prevent infection, urinary catheters should be avoided when possible and used only as long as needed. the catheter should be inserted with strict aseptic technique by trained persons, and a closed system should be used at all times. treatment of catheter-associated uti depends on the clinical circumstances. symptomatic patients (e.g., those with fever, chills, dyspnea, and hypotension) require immediate antibiotic therapy along with removal and replacement of the urinary catheter if it has been in place for a week or longer. in an asymptomatic patient, therapy should be postponed until the catheter can be removed. patients with long-term indwelling catheters seldom become symptomatic unless the catheter is obstructed or is eroding through the bladder mucosa. in patients who do become symptomatic, appropriate antibiotics should be administered and the catheter changed. therapy for asymptomatic catheterized patients leads to the selection of increasingly antibiotic-resistant bacteria. recurrence of uncomplicated cystitis in reproductive-age women is common, and some form of preventive strategy is indicated if three or more symptomatic episodes occur in year. however, risk factors specific to women with recurrent cystitis have received little study (sen, ) . several antimicrobial strategies are available, but before initiating therapy, the patient should try such simple interventions as voiding immediately after sexual intercourse and using a contraceptive method other than a diaphragm and spermicide. ingestion of cranberry juice has been shown to be effective in decreasing bacteriuria with pyuria, but not bacteriuria alone or symptomatic uti, in an elderly population. cranberry juice may be effective for preventing uti in young, otherwise healthy women. if simple nondrug measures are ineffective, continuous or postcoital-if the infections are temporally related to intercourse-low-dose antimicrobial prophylaxis with tmp-smx, a fluoroquinolone, or nitrofurantoin should be considered. typically, a prophylactic regimen is initially prescribed for months and then discontinued. if the infections recur, the prophylactic program can be instituted for a longer period. an alternative approach to antimicrobial prophylaxis for women with less frequent recurrences (< a year) is to supply tmp-smx or a fluoroquinolone and allow the patient to self-medicate with short-course therapy at the first symptoms of infection. a minority of patients have relapsing uti, as evidenced by finding the same bacterial strain within weeks after completion of antimicrobial therapy. two factors can contribute to the pathogenesis of relapsing infection in women: ( ) deep tissue infection of the kidney that is suppressed but not eradicated by a -day course of antibiotics and ( ) structural abnormality of the urinary tract, particularly calculi. patients with true relapsing utis should undergo renal ultrasound, intravenous pyelogram (ivp), or voiding cystourethrogram, and longer-term therapy should be considered. urinary tract infection is one of the most common infections of childhood. factors predisposing to uti include taking broad-spectrum antibiotics (e.g., amoxicillin, cephalexin), which are likely to alter gastrointestinal and periurethral flora; incomplete bladder emptying or infrequent voiding; voiding dysfunction; and constipation. uti in young children serves as a marker for abnormalities of the urinary tract. imaging of the urinary tract is recommended in every febrile infant or young child with a first uti to identify children with abnormalities that predispose to renal damage. imaging should consist of urinary tract ultrasonography to detect dilation of the renal parenchyma. voiding cystourethrography is often ordered but does not appear to improve clinical outcomes in uncomplicated utis (alper and curry, ) . a common complication of uti in men is prostatitis. bacterial prostatitis is usually caused by the same gram-negative bacilli that cause uti in female patients; % or more of such infections are caused by escherichia coli. the pathogenesis of this condition is poorly understood. antibacterial substances in prostatic secretions probably protect against such infections. a national institutes of health (nih) expert consensus panel has recommended classifying prostatitis into three syndromes: acute bacterial prostatitis, chronic bacterial prostatitis, and chronic pelvic pain syndrome (cpps). acute bacterial prostatitis is a febrile illness characterized by chills, dysuria, urinary frequency and urgency, and pain in the perineum, back, or pelvis. the bladder outlet can be obstructed. on physical examination, the prostate is found to be enlarged, tender, and indurated. pyuria is present, and urine cultures generally grow e. coli or another typical uropathogen. chronic bacterial prostatitis is a clinically more occult disease and may be manifested only as recurrent bacteriuria or variable low-grade fever with back or pelvic discomfort. urinary symptoms usually relate to the reintroduction of infection into the bladder, with both pyuria and bacteriuria. a chronic prostatic focus is the most common cause of recurrent uti in men. cpps is the diagnosis for the large group of men who present with minimal signs on physical examination but have a variety of irritative or obstructive voiding symptoms; perineal, pelvic, or back pain; and sexual dysfunction. these men can be divided into those with and those without inflammation (defined as > wbcs/hpf in expressed prostatic secretions). the etiology and appropriate management in these patients, regardless of inflammatory status, is unknown. • laboratory findings in acute tick-borne infection often include a normal or low wbc count, thrombocytopenia, hyponatremia, and elevated liver enzymes. • doxycycline is the drug of choice for patients with rmsf. • appropriate antibiotic treatment should be initiated immediately with strong suspicion of ehrlichiosis. • if left untreated, lyme disease can progress to cognitive disorders, sleep disturbance, fatigue, and personality changes. in the united states, more vector-borne diseases are transmitted by ticks than by any other agent. tick-borne diseases can result from infection with pathogens that include bacteria, rickettsiae, viruses, and protozoa. most tick-borne diseases are transmitted during the spring and summer months when ticks are active. a knowledge of which species of tick is endemic in an area can help narrow the diagnosis (table - ) . rocky mountain spotted fever (rmsf) is the most severe and most often reported rickettsial illness in the united states. it is caused by rickettsia rickettsii, a species of bacteria that is spread to humans by ixodid (hard) ticks (figure - ) . initial signs and symptoms include sudden onset of fever, headache, and muscle pain, followed by development of rash. the disease can be difficult to diagnose in the early stage. rmsf is most common among males and children. risk factors are frequent exposure to dogs and living near wooded areas or areas with high grass. the presentation of rsmf is nonspecific, following an incubation of about to days after a tick bite. initial symptoms can include fever, nausea, vomiting, severe headache, muscle pain, and lack of appetite. later signs and symptoms include rash, abdominal pain, joint pain, and diarrhea. the rash first appears to days after the onset of fever. most often it begins as small, flat, pink, nonitchy spots on the wrists, forearms, and ankles. the characteristic red spotted rash of rmsf is usually not seen until the sixth day or later after onset of symptoms. as many as % to % of patients never develop a rash (figure - ) . no widely available laboratory assay provides rapid confirmation of early rmsf, although commercial pcr testing is available. therefore, treatment decisions should be based on epidemiologic and clinical clues. treatment should never be delayed while waiting for confirmation by laboratory results. routine clinical laboratory findings suggestive of rmsf include normal wbc count, thrombocytopenia, hyponatremia, and elevated liver enzyme levels. serologic assays are the most often used methods for confirming cases of rmsf. doxycycline is the drug of choice for patients with rmsf. therapy is continued for at least days after fever subsides and until there is unequivocal evidence of clinical improvement, generally for a minimum total course of to days. tetracyclines are usually not the preferred drug for use in pregnant women. whereas chloramphenicol is typically the preferred treatment for rmsf during pregnancy, care must be used when administering chloramphenicol late during the third trimester of pregnancy because of risks associated with gray baby syndrome. three species of ehrlichia in the united states are known to cause disease in humans. ehrlichia chaffeensis, the cause of human monocytic ehrlichiosis, occurs primarily in southeastern and south-central regions and is primarily transmitted by the lone star tick, amblyomma americanum ( figure - ) . human granulocytic ehrlichiosis is caused by anaplasma phagocytophila or anaplasma equi and is transmitted by ixodes ticks. ehrlichia ewingii is the most recently recognized human pathogen, with cases reported in immunocompromised patients in missouri, oklahoma, and tennessee. after an incubation period of about to days following the tick bite, initial symptoms generally include fever, pregnant women should be screened for asymptomatic bacteriuria in the first trimester of pregnancy (wadland and plante, ) (sor: a). pregnant women who have asymptomatic bacteriuria should be treated with antimicrobial therapy for to days (nicolle et al., ) (sor: b) . pyuria accompanying asymptomatic bacteriuria should not be treated with antimicrobial therapy (nicolle, ) (sor: c ). a -day course of tmp-smx (bactrim, septra) is recommended as empiric therapy of uncomplicated utis in women, in regions where the rate of resistant e. coli is less than % (warren et al., ) (sor: c). fluoroquinolones are not recommended as first-line treatment of uncomplicated utis, to preserve their effectiveness for complicated utis (warren et al., ) (sor: c). a randomized, placebo-controlled trial of women over months found that cranberry juice and cranberry extract tablets significantly decreased the number of patients having at least one symptomatic uti per year (stothers, ) appropriate antibiotic treatment should be initiated immediately when there is a strong suspicion of ehrlichiosis on the basis of clinical and epidemiologic findings. the treatment recommendations are the same as for rocky mountain spotted fever. rifampin has been used successfully in a limited number of pregnant women with documented ehrlichiosis. babesiosis is caused by hemoprotozoan parasites of the genus babesia. the white-footed deer mouse is the main reservoir in the united states, and the vector is ixodes ticks. most infections are probably asymptomatic. manifestations of disease include fever, chills, sweating, myalgias, fatigue, hepatosplenomegaly, and hemolytic anemia. symptoms typically occur after an incubation period of to weeks and can last several weeks. the disease is more severe in immunosuppressed, splenectomized, or elderly patients. diagnosis can be made by microscopic examination of thick and thin blood smears stained with giemsa, looking for the parasite in red blood cells (rbcs). options for treatment include clindamycin plus quinine or atovaquone plus azithromycin. lyme disease is caused by the spirochetal bacterium borrelia burgdorferi. ixodes ticks are responsible for transmitting lyme disease bacteria to humans. in the united states, lyme disease is mostly localized to states in the northeastern, mid-atlantic, and upper north-central regions, as well as northwestern california. lyme disease most often manifests with a characteristic bull's-eye rash (erythema migrans) accompanied by nonspecific symptoms such as fever, malaise, fatigue, headache, muscle aches, and joint aches (figure - ) . lyme disease spirochetes disseminate from the site of the tick bite, causing multiple (secondary) erythema migrans lesions. other manifestations of dissemination include lymphocytic meningitis, cranial neuropathy (especially facial nerve palsy), radiculoneuritis, migratory joint and muscle pains, myocarditis, and transient atrioventricular blocks of varying degree. if left untreated, the disease can progress to intermittent swelling and pain of one or a few joints (usually large weight-bearing joints such as the knee), cognitive disorders, sleep disturbance, fatigue, and personality changes. the diagnosis is based primarily on clinical findings, and it is often appropriate to treat patients with early disease solely on the basis of objective signs and a known exposure. serologic testing may provide valuable supportive diagnostic information in patients with endemic exposure and objective clinical findings that suggest later-stage disseminated lyme disease. treatment for to weeks with doxycycline or amoxicillin is generally effective in early disease. cefuroxime axetil or erythromycin can be used for persons allergic to penicillin or who cannot take tetracyclines. later disease, particularly with objective neurologic manifestations, can require treatment with intravenous ceftriaxone or penicillin for weeks or more, depending on disease severity. tularemia is caused by francisella tularensis, one of the most infectious pathogenic bacteria known. most cases in the united states occur in south-central and western states. humans can become infected through diverse environmental exposures, including bites by infected arthropods; handling infectious animal tissues or fluids; direct contact with or ingestion of contaminated food, water, or soil; and inhalation of infective aerosols. inhaled f. tularensis causes pleuropneumonitis. some exposures contaminate the eye, resulting in ocular tularemia; penetrate broken skin, result- ing in ulceroglandular or glandular disease; or cause oropharyngeal disease with cervical lymphadenitis. untreated, bacilli inoculated into skin or mucous membranes multiply, spread to regional lymph nodes, multiply further, and then can disseminate to organs throughout the body. the onset of tularemia is usually abrupt, with fever, headache, chills and rigors, generalized body aches, coryza, and sore throat. a dry or slightly productive cough and substernal pain or tightness often occur with or without objective signs of pneumonia. nausea, vomiting, and diarrhea can occur. sweats, fever, chills, progressive weakness, malaise, anorexia, and weight loss characterize continuing illness. rapid diagnostic testing for tularemia is not widely available. respiratory secretions and blood for culture should be collected in suspected patients and the laboratory alerted to the need for special diagnostic and safety procedures. streptomycin ( g im bid for days) is the drug of choice, and gentamicin is an acceptable alternative. tetracyclines and chloramphenicol can also be used. colorado tick fever is an acute viral infection transmitted by the bite of the dermacentor andersoni tick (figure - ) . the disease is limited to the western united states and is most prevalent from march to september. symptoms start about to days after the tick bite. fever continues for days, stops, and then recurs to days later for another few days. other symptoms include excessive sweating, muscle aches, joint stiffness, headache, photophobia, nausea, vomiting, weakness, and an occasional faint rash. routine blood tests might show a low wbc count, mildly elevated liver function, and mildly elevated creatine phosphokinase (cpk). diagnosis is confirmed by testing blood for complement fixation immunofluorescent antibody staining to colorado tick virus. treatment is removal of the tick and treatment of symptoms. physicians should advise patients who walk or hike in tickinfested areas to tuck long pants into socks to protect the legs and wear shoes and long-sleeved shirts. ticks show up on white or light colors better than dark colors, making them easier to remove from clothing. if attached, ticks should be removed immediately by using a tweezers, pulling carefully and steadily. insect repellents such as deet, alone or in combination with permethrin, may be helpful. • most cases of cellulitis are caused by staphylococci or streptococci, but other causes should be considered by clinical situation. • physicians must rule out more ominous causes of skin inflammation, such as necrotizing fasciitis and pyomyositis, when considering cellulitis. • edema-associated cellulitis is best treated by mobilizing edema fluid. cellulitis is an acute, spreading inflammation of the derma and subcutaneous issue. patients complain of tenderness, warmth, swelling, and spreading erythema. in contrast to erysipelas, cellulitis usually lacks sharp demarcation at the border. factors that predispose to cellulitis include trauma, an underlying skin lesion (furuncle, ulcer), or a complication arising from a wound, ulcer, or dermatosis. occasionally, cellulitis results from a blood-borne infection that metastasizes to the skin. pain and erythema usually develop within several days and are often associated with malaise, fever, and chills. the area involved is often extensive, red, hot, and swollen. patchy involvement with skip lesions can be seen. regional lymphadenopathy is common, and bacteremia can occur. several clinical entities resemble cellulitis, including pyoderma gangrenosum, gout, and insect bites. necrotizing fasciitis and gas gangrene are surgical emergencies. given that the predominant organism involved in most cases of cellulitis is a grampositive coccus, clinical history and morphology on physical examination usually suffice in the diagnosis and treatment of cellulitis. a history of freshwater exposure may implicate aeromonas hydrophila as the causative organism; saltwater appropriate antibiotic therapy should be initiated immediately when there is suspicion of rocky mountain spotted fever, ehrlichiosis, or relapsing fever rather than waiting for laboratory confirmation (bratton and corey, ; spach et al., ) (sor: c). treatment with doxycycline (vibramycin) or tetracycline is recommended for rmsf, lyme disease, ehrlichiosis, and relapsing fever (bratton and corey, ; spach et al., ) (sor: c). recommended actions to prevent tick-borne disease include avoidance of tick-infested areas; wearing long pants and tucking the pant legs into socks; applying diethyltoluamide (deet) insect repellents; using bed nets when camping; and carefully inspecting oneself frequently while in an at-risk area (bratton and corey, ; spach et al., ) (sor: c). antibiotic prophylaxis is not routinely recommended for a tick bite to prevent lyme disease, unless the risk of infection is high (wormser et al., ) (sor: b). recommended treatment for suspected tularemia is streptomycin or gentamicin given empirically before evidence of laboratory confirmation (bratton and corey, ; spach et al., ) (sor: c). exposure suggests vibrio spp. cellulitis in a patient with liver disease and shellfish ingestion moves vibrio vulnificans to the top of the differential. patients with soft tissue infection should have blood drawn for laboratory testing if signs and symptoms of systemic toxicity are present (e.g., fever or hypothermia, tachycardia, hypotension). laboratory testing should include blood culture and drug susceptibility tests; wbc count with differential; and measurement of creatinine, bicarbonate, cpk, and crp levels. hospitalization should be considered for patients with hypotension or an elevated creatinine level, low serum bicarbonate level, elevated cpk level (i.e., - times upper limit of normal), marked left shift, or crp level greater than mg/l ( . nmol/l). gram stain with culture and culture of needle aspiration or punch biopsy specimens should be performed to determine a definitive etiology, and a surgical consult should be considered for inspection, exploration, and drainage. findings that may signal potentially severe, deep, soft tissue infection and that may require emergent surgical evaluation include cutaneous hemorrhage, gas in the tissue, pain disproportionate to physical findings, rapid progression, skin anesthesia, skin sloughing, and violaceous bullae. radiologic studies may be helpful if abscess or osteomyelitis is a possibility. ultrasonography is helpful in detecting a subcutaneous collection of fluid. magnetic resonance imaging (mri) is also useful in differentiating cellulitis from necrotizing fasciitis. the diagnosis of necrotizing cellulitis is by direct surgical examination or by frozen pathology sections. empiric antibiotics for immunocompetent patients with cellulitis should be targeted toward gram-positive cocci (table - ) . broader coverage should be initiated for diabetic patients to include gram-positive aerobes, gram-negative aerobes, and anaerobes. patients who present with severe infection or whose infection is progressing despite empiric antibiotic therapy should be treated more aggressively; the treatment strategy should be based on results of appropriate gram stain, culture, and drug susceptibility analysis. in the case of staphylococcus aureus, the physician should assume that the organism is resistant, and agents effective against mrsa, such as vancomycin, linezolid (zyvox), or daptomycin (cubicin), should be used. the antibiotic may be switched from an intravenous drug to an oral drug when fever has subsided and the skin lesion begins to resolve, usually in to days. the total duration of therapy should be to days. longer duration may be required if the response is slow or is associated with abscess, tissue necrosis, or underlying skin processes (infected ulcers or wounds). treatment of cellulitis should include elevation and immobilization to decrease swelling. patients with interdigital dermatophytic infections should be treated with a concomitant topical antifungal applied once or twice daily. topical antifungals can also help reduce the risk of recurrence of the cellulitis. support stockings, good skin hygiene, and prompt treatment of tinea pedis helps with prevention of cellulitis in patients with peripheral edema, who are predisposed to recurrence. in patients who continue to have frequent episodes of cellulitis or erysipelas, prophylactic treatment with penicillin v, mg or mg orally twice daily, or erythromycin, mg once or twice daily (for penicillin-allergic patients), may be indicated. • the majority of furuncles and carbuncles are caused by staphylococcus spp., increasingly, community-acquired methicillin-resistant s. aureus. • drainage of pus is of primary importance in treating skin and soft tissue infections. • culture of sstis is important in guiding antibiotic treatment when initial measures of drainage are not effective. • for recurrent boils, consider referral to infectious disease specialist, possibly to eradicate carriage state. furuncles, or boils, are infections of the skin and soft tissue usually associated with a hair follicle. carbuncles are an extension of this skin and soft tissue infection continuum and involve more of the surrounding and subcutaneous tissue. the broad category skin and soft tissue infections (sstis) is used to describe this continuum that includes furuncles and carbuncles. sstis are common in both healthy and immunocompromised patients and likely initiate with some breach of the skin integrity, such as irritation of hair follicles from friction or microscopic trauma to the skin. up to % of furuncles and carbuncles are caused by community-acquired methicillin-resistant staphylococcus aureus (ca-mrsa) (cdc, ). other potential causative organisms include nonresistant staphylococcus spp. and streptococcus spp. it has become increasingly important to obtain culture of a lesion to direct antibiotic coverage given the increase in ca-mrsa. there is no reliable historical or examination element that will distinguish a ca-mrsa from a methicillin-sensitive staphylococcal skin lesion. stereotypically, patients report ca-mrsa lesions starting like a spider bite. furuncles and carbuncles can occur anywhere on the body, although the axillae, groin, and buttocks are particularly common sites. in addition, practices that cause skin trauma (e.g., shaving, waxing) are often noted in patients with these sstis. fever and malaise are uncommon with milder lesions but become more frequent with the increasing scope of localized infection. of primary importance in the management of carbuncles and furuncles is facilitation of drainage of any purulent material. with smaller lesions, this may be accomplished by heat application by the patient at home. as lesions increase in size and fluctuance, surgical drainage is essential to facilitate resolution of an ssti. it is important to consider culture penicillin, given parenterally or orally depending on clinical severity, is the treatment of choice for erysipelas (sor: a). for cellulitis, a penicillinase-resistant semisynthetic penicillin (amoxicillin/clavulanate) or a first-generation cephalosporin should be selected, unless streptococci or staphylococci resistant to these agents are common in the community (sor: a). for suspected mrsa skin infections, oral treatment options include trimethoprim-sulfamethoxazole, clindamycin, and doxycycline of purulent material when performing incision and drainage in the event that the patient fails to improve and antibiotic coverage becomes necessary. cure rates of lesions with drainage alone exceed %. careful follow-up after drainage is essential to ensure clinical improvement; daily dressing changes in the office after surgical drainage is effective. the addition of postdrainage antibiotics has not shown much added benefit. to prevent the spread of infection to others who come into contact with the patient recovering from an ssti, an occlusive dressing to prevent leakage of lesion fluid and careful hygiene are indicated. there is no evidence that extensive cleaning of common spaces (e.g., locker rooms) prevents the spread of ssti-causing bacteria more than routine cleaning measures. towels and soiled clothing should be laundered in hot water, and any common equipment should be cleaned per manufacturer recommendations. when lesions do not respond to heat, or when lesions are larger yet not amenable to drainage, antibiotics may be used. reasonable first-line antibiotic coverage for nonfluctuant lesions may include dicloxacillin, first-or secondgeneration cephalosporins, macrolides, or clindamycin. in patients with suspected ca-mrsa, better choices include tmp-smx, tetracycline, or clindamycin. it is important to note that up to % of ca-mrsa species will be resistant to clindamycin, particularly if the patient has been treated with other antibiotics in the previous weeks to months . oral administration of these antibiotics is acceptable in the nontoxic patient. patient signs and symptoms that would warrant hospital admission include fever or hypothermia, tachycardia, or hypotension as signs of sepsis and lesions greater than cm in size (table - ) . for patients with recurrent sstis, evaluation for the presence of nasal carriage with a nasal culture is indicated. the value of eradication of bacterial carriage is unclear. referral for infectious disease specialist evaluation may be indicated to guide decision making in the patient with recurrent furuncles and carbuncles. • the existence, severity, and extent of infection, as well as vascular status, neuropathy, and glycemic control, should be assessed in patients with a diabetic foot infection. • visible bone and palpable bone on probing suggest underlying osteomyelitis in patients with a diabetic foot infection. • before an infected wound of a diabetic foot infection is cultured, any overlying necrotic debris should be removed to eliminate surface contamination and to provide more accurate results. patients with diabetes are prone to skin ulcers caused by neuropathy, vascular insufficiency, and diminished neutrophil function. minor wounds can be secondarily infected, leading to ulcer formation. these ulcers often have extensive undermining with necrotic tissues and are often close to the anus, thus promoting an environment suitable for multiple species of microorganisms, including anaerobes. diabetic foot infections range in severity from superficial paronychia to deep infection involving bone. non-limb-threatening infections involve superficial ulcers with minimal cellulitis (< cm from portal of entry), no signs of systemic toxicity, and no significant ischemia in the limb. cure rates of fluctuant skin lesions with drainage alone is over %. postdrainage antibiotics do not significantly improve outcomes rajendran et al., ) (sor: a). trimethoprim-sulfamethoxazole (tmp-smx), clindamycin, and tetracycline are first-choice antibiotics when ca-mrsa is suspected. up to % of ca-mrsa species will be resistant to clindamycin, particularly in the patient previously treated with other antibiotics (sor: c). subcutaneous tissues, and prominent ischemia. infection in patients who have recently received antibiotics or who have deep, limb-threatening infection or chronic wounds are usually caused by a mixture of aerobic gram-positive, aerobic gram-negative (e.g., escherichia coli, proteus spp., klebsiella spp.), and anaerobic organisms (e.g., bacteroides, clostridium, peptococcus, and peptostreptococcus spp.) . surgery is necessary to unroof encrusted areas, and the wounds need to be examined and probed to determine the extent of the infection and check for bone involvement (dinh et al., ) . debridement or drainage should be promptly performed. deep wound cultures should be obtained if possible. if deep culture is not feasible, gram stain and culture from the curettage of the base of the ulcer or from purulent exudates may be needed to guide antibiotic therapy (figure - ) . plain radiography of the foot is indicated for detection of osteomyelitis, foreign bodies, and soft tissue gas. when plain radiography is negative but osteomyelitis is clinically suspected, radionuclide scan or mri should be performed. mri provides more accurate information regarding the extent of the infectious process. the presence of peripheral artery disease and neuropathy should be assessed. the antibiotic regimen should be based on meaningful bacteriologic data. however, the initial regimen for a previously untreated patient with non-limb-threatening infection should focus on s. aureus and streptococci. mild infections may be treated with dicloxacillin or cephalexin for weeks. amoxicillin/clavulanate may be used if polymicrobial infection is suspected. if msra is suspected, oral treatment options include tmp-smx or doxycycline. for limb-threatening infections, broad-spectrum antibiotics are recommended for coverage of group b streptococci, other streptococci, enterobacteriaceae, anaerobic gram-positive cocci, and bacteroides spp. treatment regimens include ampicillin-sulbactam or ertapenem (invanz), clindamycin plus a third-generation cephalosporin, and clindamycin plus ciprofloxacin. intravenous vancomycin should be added if mrsa infection is suspected. ciprofloxacin as a single agent is not recommended. in addition to antibiotic treatment, good glycemic control should be obtained and open wounds gently packed with sterile gauze moistened with ¼-strength povidone-iodine (betadine) solution. edema should be reduced by bed rest, elevation, and diuretic therapy as indicated. for prevention of diabetic foot ulcers, all patients with diabetes should have an annual foot examination that includes assessment for anatomic deformities, skin breaks, nail disorders, loss of protection sensation, diminished arterial supply, and inappropriate footwear. • the use of prophylactic antibiotics may be necessary in the initial management of bite wounds, particularly if the bite is on the hand or face or from a cat. • first-generation cephalosporins (e.g., cephalexin) are not effective as monotherapy for bite wounds because of resistance issues. • avoid primary wound closure in the management of bite wounds. it is estimated that bites account for , medical visits annually in the united states, making up % of emergency department visits. bite wounds consist of lacerations, evulsions, punctures, and scratches. the microbiology of bite wounds is generally polymicrobial, with an array of potential bacteria from the environment, the victim's skin flora, and the biter's oral flora. dog bites account for approximately % of all animal bites requiring medical attention, in which % are provoked attacks. most dog bites occur on the distal extremities, but children tend to sustain facial bites. patients who present for medical attention are often concerned about the care of disfiguring wounds or the need for appropriate vaccination (i.e., tetanus, rabies). however, up to % of medically treated wounds may become infected. these wounds are often contaminated with multiple strains of aerobic and anaerobic bacteria. local signs of infection with erythema, edema, pain, and purulent drainage are common with animal bite wounds. although the most frequently isolated pathogen related to dog and cat bite wounds is pasteurella multocida, the array of potential organisms is much greater. anaerobes such as bacteroides tectum, prevotella spp., fusobacteria, and peptostreptococci can be isolated from animal bite wounds % of the time, mostly from wounds with abscess formation. capnocytophaga canimorsus has also been associated with fatal infection from fulminant sepsis in asplenic patients. wounds inflicted by cats are often scratches or tiny punctures located on the extremity and are likely to become infected and lead to abscess formation. in the united states, venomous snakes bite approximately people yearly. envenomation in such snakebites account for the majority of morbidity and mortality associated with such bites. however, infection of soft tissue structures may also occur as a result of oral flora from the snake, which tends to be fecal in nature because live prey usually defecate in the snake's mouth with their ingestion. human bites are not uncommon, especially in children. human bites have a higher complication and infection rate than do animal bites. human bite wounds most often affect the hand and fingers and in some cases may present as "love routine wound swabs and cultures of material from sinus tracts are unreliable and strongly discouraged in the management of diabetic foot infection (pellizzer et al., ; senneville et al., ) nips" to the breast and genital areas. self-inflicted bites often include wounds of the lip and tissues surrounding the nail, such as paronychia. also included in this are clenched-fist injuries or "fight bites," which result in small lacerations to the knuckles when striking a person in the mouth. normal human oral flora, rather than skin flora, is the source of most bacteria isolated from human bite wound cultures (viridans streptococci, eikenella corrodens). management of bite wounds is the same as for any other wound: good wound care in the form of adequate irrigation and debridement of nonviable tissue as needed (table - ) . bite wounds in general do not require primary closure, but after adequate irrigation and debridement, wounds may be approximated and closed by delayed primary or secondary intention. an exception to this rule may include bite wounds to the face. general wound management measures such as tetanus toxoid administration should also be employed. bite wounds involving the hands should be evaluated by a hand surgeon, given the risk of adjacent tendon sheath, bone, or joint involvement and the dire consequences if such structures are involved. the transmission of rabies through the bites of domestic pets in the united states and developed countries is rare. in fact, the dog strain of rabies is considered eliminated in the u.s. dog population, and cat bites are often managed through observation of the animal, without the immediate need for rabies postexposure treatment (pet). however, wild mammal exposure, especially bat, skunk, or raccoon, often warrants pet, which involves thorough cleaning of the bite wound, ideally with povidone-iodine solution, along with rabies immune globulin given at the wound site and rabies vaccine given on days , , , and . bite wounds should be considered contaminated wounds from presentation, given the oral microbial flora of humans and animals, and most patients should probably receive antibiotics early. empiric antibiotics are used to eradicate oral flora inoculated from the mouth of the biter, whether human or animal, into the wound. all moderate to severe animal bite wounds, or wounds that have an associated crush injury or that are close to a bone or joint, should be considered contaminated with potential pathogens, and these patients should receive to days of "prophylactic" antimicrobial therapy. gram stains with culture of bite wounds are specific but not sensitive indicators of bacterial growth. nonetheless, gram stain can be used to help guide initial empiric antibiotic therapy. amoxicillin-clavulanic acid (amoxicillin-clavulanate; augmentin) or penicillin plus a penicillinase-resistant penicillin are normally first-line agents for empiric therapy directed at bite wounds. first-generation cephalosporins (e.g., cephalexin) are not effective as monotherapy because of resistance of some anaerobic bacteria and e. corrodens. a -to -day course of antibiotics is usually adequate for infections limited to the soft tissue, and a minimum of weeks of therapy is required for infections involving joints or bones. close follow-up is required in all bites to ensure adequate healing. of special consideration in human bite wounds is the potential for spread of viral pathogens, most notably hepatitis b virus (hbv) and hiv, if the source person is positive. hbv exposure in this setting should be handled in the same manner as other exposures, with administration of hbig and hbv vaccination. with regard to hiv, cdc guidelines for managing nonoccupational hiv exposure recommend handling each case individually in consultation with an infectious diseases specialist. • the diagnosis of osteomyelitis is based on radiographic findings (plain radiograph or mri) showing bony destruction along with histologic analysis and culture results. • chronic osteomyelitis is not an emergency, and antibiotics can be safely withheld until an etiologic diagnosis is established. • diabetic foot infections require a careful evaluation to assess perfusion and vascular supply, and corrective measures should be undertaken to reestablish adequate perfusion if necessary. • in diabetic foot ulcers, if one can probe to bone, the patient most likely has osteomyelitis. • orthopedic hardware infections are best managed in conjunction with an infectious diseases specialist and orthopedic surgeon. osteomyelitis is defined as progressive, inflammation leading to destruction of the bone, usually secondary to an infectious agent. bacteria can enter bone through hematogenous seeding or a contiguous focus after trauma, implantation of a foreign device, or a local soft tissue infection. acute osteomyelitis is defined as infection that evolves over a few weeks. chronic osteomyelitis implies persistent infection of several weeks to months. hematogenous osteomyelitis occurs primarily in children within the metaphyses of long bones (tibia and femur) and vertebrae in adults. in addition to local signs of inflammation and infection, patients generally have various systemic signs, including fever, irritability, and lethargy. physical findings include tenderness over involved area and decreased range of motion in adjacent joints. chronic osteomyelitis usually occurs in adults, caused by an open injury to bone and surrounding soft tissue. erythema, drainage around area, and bone pain are usually present on physical examination. systemic symptoms occur less frequently. the diagnosis of osteomyelitis is based on the clinical picture and supporting laboratory and radiologic findings. leukocytosis and elevations in crp and esr may use of antibiotic prophylactic after bites of the hand reduces the incidence of infection (medeiros and saconato, ) (sor: b) . antibiotic prophylaxis after bites by humans reduces incidence of infection (sor: c). animal bite: ascertain the type of animal, whether the bite was provoked or unprovoked, and the situation/environment in which the bite occurred. if the species can be rabid, locate the animal for days' observation or sacrifice. patient: obtain information on antimicrobial allergies, current medications, splenectomy, mastectomy, liver disease, and immunosuppression. record a diagram of the wound with the location, type, and depth of injury; range of motion; possibility of joint penetration; presence of edema or crush injury; nerve and tendon function; signs of infection; and odor of exudate. infected wounds should be cultured and a gram stain performed. anaerobic cultures should be obtained in the presence of abscesses, sepsis, serious cellulitis, devitalized tissue, or foul odor of the exudate. small tears and infected punctures should be cultured with a minitipped (nasopharyngeal) swab. copious amounts of normal saline should be used for irrigation. puncture wounds should be irrigated with a "high-pressure jet" from a -ml syringe and an -gauge needle or catheter tip. devitalized or necrotic tissue should be cautiously debrided. debris and foreign bodies should be removed. radiographs should be obtained if fracture or bone penetration is possible to provide a baseline for future osteomyelitis. wound closure may be necessary for selected, fresh, uninfected wounds, especially facial wounds, but primary wound closure is not usually indicated. wound edges should be approximated with adhesive strips in selected cases. prophylaxis: consider prophylaxis ( ) for moderate to severe injury less than hours old, especially if edema or crush injury is present; ( ) if bone or joint penetration is possible; ( ) for hand wounds; ( ) for immunocompromised patients (including those with mastectomy, liver disease, or steroid therapy); ( ) if the wound is adjacent to prosthetic joint; and ( ) if the wound is in the genital area. coverage should include pasteurella multocida, staphylococcus aureus, and anaerobes. treatment: cover p. multocida, s. aureus, and anaerobes. use oral medication if the patient is seen early after a bite and only mild to moderate signs of infection are present. the following can be considered for cat or dog bites in adults: • first choice: amoxicillin/clavulanic acid, / mg bid or / mg tid with food. • penicillin allergy: no alternative treatment for animal bites has been established for penicillin-allergic patients. the following regimens can be considered for adults: . clindamycin ( mg po qid) plus either levofloxacin ( mg po daily) or trimethoprim-sulfamethoxazole ( double-strength tablets po bid). . doxycycline, mg po bid. . moxifloxacin, mg po daily. . in the highly penicillin-allergic pregnant patient, macrolides have been used, but the wounds must be watched carefully. on emergency department discharge, a single starting dose of parenteral antibiotic, such as ertapenem ( g), may be useful in selected cases. if hospitalization or closely monitored outpatient follow-up is required, intravenous agents should be used. current choices include ampicillin/sulbactam and cefoxitin. the rising incidence of community-acquired s. aureus isolates that are methicillin resistant and therefore resistant to the drugs recommended here emphasizes the importance of susceptibility-testing any s. aureus isolates. indications include fever, sepsis, spread of cellulitis, significant edema or crush injury, loss of function, a compromised host, and patient noncompliance. give tetanus booster (td; tetanus and diphtheria toxoids for adults) if original three-dose series has been given but none in the past years. adults who have not received acellular pertussis vaccine (tdap), should be given this instead of td. give a primary series and tetanus immune globulin if the patient was never immunized. rabies vaccine (on days , , , , and ) with hyperimmune globulin may be required, depending on the type of animal, ability to observe the animal, and locality. elevation may be required if any edema is present. lack of elevation is a common cause of therapeutic failure. be seen but can also be normal. blood cultures may be positive in up to half of children with acute osteomyelitis. if plain radiographs show bone destruction and inflammation; the diagnosis of osteomyelitis is confirmed. typical findings on plain-radiographs will include osteolysis, periosteal reaction, and sequestra (segments of necrotic bone separated from living bone by granulation tissue). findings seen on plain radiographs usually denote a process that has been ongoing for at least weeks. bone scintigraphy (bone scan) is often performed on patients with suspected osteomyelitis; however, sensitivity is quite low, and a negative result can offer false reassurance to the physician, so its routine use is not recommended. if the plain-radiographs are negative but the suspicion for osteomyelitis is still high, an mri scan should be considered. once the diagnosis of osteomyelitis has been made, the next step is to obtain an etiologic diagnosis. histopathologic and microbiologic examination of bone is the "gold standard." cultures of sinus tracts are not reliable for identifying the causative organism. common causative bacteriologic organisms in neonates include staphylococcus aureus, group b streptococci, and escherichia coli. later in life, s. aureus is most common, and in elderly persons, gram-negative organisms such as pseudomonas aeruginosa and serratia spp. have increased incidence. empiric antibiotics are rarely required for chronic disease but are often necessary for acute osteomyelitis. ideally, surgical debridement of all necrotic tissue and inflammatory debris (pus) should be undertaken and multiple surgical cultures with bone histology samples obtained. antimicrobial therapy will be dictated by test results. generally, treatment is for to weeks. with the exception of the fluoroquinolone class of antibiotics, which achieve high serum levels with oral administration, bone antibiotic levels cannot exceed the minimum inhibitory concentration (mic) for the infecting organism; therefore, antibiotics must be given intravenously. this underscores the importance in obtaining a bacterial diagnosis so that the appropriate antibiotic can be used for the duration of treatment. acute osteomyelitis is usually readily curable; however, chronic osteomyelitis is generally more refractory to therapy and requires repeat debridement and antibiotic courses. patients with uncontrolled diabetes are at increased risk for development of osteomyelitis, especially in the presence of neuropathy or venous or arterial insufficiency. s. aureus and beta-hemolytic streptococci are the predominant organisms, although other gram-positive or gram-negative aerobic or anaerobic bacteria may also be seen. plain radiographs should be the initial test to evaluate for the presence of osteomyelitis, followed by mri if negative. if there is a draining sinus, the "probe to bone" test should be performed with a sterile probe; if bone is palpated, the diagnosis of osteomyelitis is highly likely. further evaluation of the diabetic patient should be to assess for vascular insufficiency with the use of ankle-brachial indices and transcutaneous oximetry. if significant compromise is found, arteriography followed by revascularization should be undertaken. surgical debridement is again the cornerstone of treatment, along with antibiotics directed toward the causative microorganism. infections secondary to orthopedic hardware devices have become common problems with the increasing incidence of hip, knee, and shoulder replacement surgeries. also, patients with traumatic injury resulting in a fracture often have hardware implanted to stabilize the bone. these patients present in one of the three following ways: . early: symptoms develop less than months after surgery and have an acute presentation with pain, erythema, and warmth, usually caused by s. aureus and gram-negative bacilli. . delayed: symptoms develop to months after surgery, generally with subtle signs of infection, including implant loosening and persistent pain, and usually caused by less virulent organisms such as coagulasenegative staphylococci and propionibacterium acnes. . late: symptoms develop months after surgery and are usually caused by hematogenous seeding from skin, dental, respiratory, and urinary infections. treatment requires debridement of the surrounding tissue and hardware removal, although this cannot always be done in patients with bone instability. it is recommended that treatment follow-up should occur at hours and perhaps hours for outpatients. reporting the incident to a local health department may be required. from goldstein ejc. bites. in mandell gl, bennett je, dolin rd (eds). mandell, douglas, and bennett's principles and practice of infectious diseases, th ed. philadelphia, churchill livingstone--elsevier, . po, orally; bid, twice daily; tid, three times daily; qid, four times daily. of these infections be done in conjunction with an infectious diseases specialist working with the orthopedic surgeon. septic arthritis is defined as infection within the joint space of two bones. the major causative organisms include s. aureus and in the sexually promiscuous individual, neisseria gonorrhoeae. intravenous drug users are likely to develop septic arthritis within unusual joints (e.g., sternoclavicular, sacroiliac). rheumatoid arthritis, presence of joint prostheses, and steroid use are predisposing factors for development of septic arthritis. diagnosis is usually based on clinical presentation of a warm, swollen joint with limitation in range of motion. a joint aspiration should be completed and the synovial fluid sent for gram stain with culture, wbc count with differential, and crystal analysis to rule out gout and pseudogout. blood cultures should also be drawn before initiation of antibiotics. gonococcal arthritis usually presents as an acute arthritis involving one or more joints in a sexually active individual. two thirds of patients have dermatitis with one or multiple, usually asymptomatic, lesions that progress from macular to papular and finally vesicular or pustular. joint fluid, urethral, and rectal cultures should also be obtained. treatment is generally with a third-generation cephalosporin intravenously until improvement, followed by oral therapy to complete a -week course of therapy. treatment of nongonococcal arthritis requires proper draining of the infected joint. this is often done surgically, although repeat needle drainage may also be successful if the joint is easily accessible. treatment generally depends on the gram stain and includes a third-generation cephalosporin, with the addition of vancomycin if gram-positive cocci in clusters are seen. duration of therapy is to weeks. • a comprehensive history and physical examination with laboratory and radiologic evaluation are important in the workup for fever of unknown origin (fuo). • if routine information is unrevealing, more specific testing for fuo is undertaken based on the patient's age, travel history, and disease process to develop a differential diagnosis. • the serum ferritin level (often elevated with malignancy) and naproxen test (reduces fever with malignancy) may be helpful in determining an underlying malignant process. • initiation of empiric antibiotics should be done only in specific fuo situations to prevent skewing culture results, thus maximizing isolation of the causative organism. patients who have a persistent fever despite workup are generally classified as having a "fever of unknown origin" (fuo). in , petersdorf and beeson described patients with persistent fever, otherwise known as fever of unknown origin. they introduced the standard, classic definition of fuo: fever higher than . ° c ( ° f) on several occasions, persisting without diagnosis for at least weeks, with week of investigational study in the hospital setting. with advancing technology, this definition has been revised to allow for more than two outpatient visits, or days if investigation is in the hospital setting. most patients with fuo have chronic or subacute symptoms and can be safely evaluated in the outpatient setting, with a median time to diagnosis of days. the differential diagnosis of fuo is quite broad and extensive. determining an etiologic diagnosis of an fuo depends on generating a differential diagnosis compatible with the patient's history and physical examination. the principal disease categories for fuo include infection ( % overall), neoplasms ( %), collagen vascular diseases ( %), and miscellaneous ( %) (box - ). because of this broad differential, a newer classification system divides fuo into four groups: classic, nosocomial, neutropenic, and hiv associated, which helps narrow the differential diagnosis. furthermore, classic fuo can be broken down into three subgroups: infants and children, elderly, and travelers. despite an extensive workup, the etiologic diagnosis usually remains elusive in % to % of patients (box - ) . the diagnostic workup of fuo should begin with a thorough history and physical examination, including documentation of the fever. the patient may provide a diary noting the date and time of fever. routine noninvasive investigations are recommended in all patients before diagnosing fuo (box - ). acute febrile illness is never called an fuo. the patient's medication profile is reviewed because numerous drugs can be the cause. if unrevealing, a workup is initiated based on the differential diagnosis for the patient's age, travel history, geographic location, and disease process. dukes criteria for infective endocarditis have % specificity in patients with fuo. when the initial investigations are not helpful in identifying a cause, imaging should be considered, such as computed tomography (ct) scans of the chest, abdomen, and pelvis; ct may reveal an abscess or suggest an underlying malignancy. an elevated serum ferritin level can suggest a neoplasm or myeloproliferative disorder and, if normal, greatly decreases the chance that the patient has an underlying malignancy. lower-extremity doppler ultrasound should be considered in the sedentary or obese patient to rule out deep venous thrombosis. a temporal artery biopsy should be considered in the elderly patient to rule out temporal arteritis. liver biopsy has a high diagnostic yield with minimal toxicity, whereas bone marrow cultures usually have a low yield and should be considered only in special situations. empiric therapy with antibiotics is rarely appropriate for the patient with fuo. a diagnosis is essential to guide treatment of osteomyelitis requires surgical debridement followed by a -to -week course of intravenous antibiotic therapy (sor: c). septic arthritis is usually caused by a gonococcus in a sexually active adult, and use of a third-generation cephalosporin is the mainstay of therapy (sor: a). nongonococcal arthritis should be treated with surgical debridement or repeated needle aspirations, with a third-generation cephalosporin and vancomycin if gram-positive cocci are seen (goldenberg, ) (sor: b). treatment, and use of antibiotics may delay determining a causative infectious agent. the naproxen test (naprosyn; mg po every hours for days) is helpful in determining if the fever is secondary to infection or malignancy. a dramatic decrease in the patient's temperature during the test generally indicates a malignant focus, whereas minimal or no response indicates an infectious etiology. the prognosis of fuo depends on the etiologic category. undiagnosed fuo has a very favorable outcome. patients in whom diagnostic investigations fail to identify an etiology should be followed clinically with serial history reviews and physical examinations until the fever resolves or new diagnostic clues are found. connective tissue diseases are more prominent. infections: malaria, hepatitis, pneumonia/bronchitis, uti/pyelonephritis, dysentery, dengue fever, enteric fever, tb, rickettsial infection, acute human immunodeficiency virus (hiv) infection, amebic liver abscess. postoperative urinary and respiratory tract instrumentation; use of intravascular devices; drug therapy; immobilization. septic thrombophlebitis, pulmonary embolus, clostridium difficile colitis, drug fever. fungal: % susceptible to empiric antifungals, % will be resistant to empiric therapy. bacterial: % not responding to empiric antimicrobial therapy and usually with cryptic focus. unusual pathogens: % will be toxoplasmosis (toxoplasma gondii) reactivation, atypical mycobacterial, tb, fastidious pathogens (legionella, mycoplasma, chlamydophila). viral: % of causes (hsv, cmv, ebv, hhv- , vzv, rsv, influenza, parainfluenza). other: % will be transplant related (e.g., gvhd) following stem cell transplant, % will be undefined. infections: mycobacterium avium complex (mac), pneumocystis carinii pneumonia (pcp), cytomegalovirus (cmv), histoplasmosis, viral (hcv, hbv, adenovirus, hsv esophagitis, vzv encephalitis), tb, other fungi, cerebral toxoplasmosis, disseminated cryptosporidiosis. neoplasms: lymphoma, kaposi's sarcoma. other: drug fever, castleman's disease. hsv, herpes simplex virus; ebv, epstein-barr virus; hhv, human herpesvirus; vzv, varicella-zoster virus; rsv, respiratory syncytial virus; gvhd, graft-versus-host disease; hcv, hepatitis c virus; hbv, hepatitis b virus. abscesses: hepatic, subhepatic, gallbladder, subphrenic, splenic, periappendiceal, perinephric, pelvic, and other sites. granulomatous: extrapulmonary and miliary tuberculosis, atypical mycobacterial infection, fungal infection. intravascular: catheter-related endocarditis, meningococcemia, gonococcemia, listeria, brucella, rat-bite fever, relapsing fever. viral, rickettsial, and chlamydial: infectious mononucleosis, cytomegalovirus, human immunodeficiency virus, hepatitis, q fever, psittacosis. parasitic: extraintestinal amebiasis, malaria, toxoplasmosis. collagen vascular diseases: rheumatic fever, systemic lupus erythematosus, rheumatoid arthritis (particularly still's disease), vasculitis (all types). granulomatous: sarcoidosis, granulomatous hepatitis, crohn's disease. tissue injury: pulmonary emboli, sickle cell disease, hemolytic anemia. familial mediterranean fever fabry's disease cyclic neutropenia intra-abdominal infections may either be uncomplicated (limited to the gut lumen, such as gastroenteritis or colitis) or complicated (extending through to the peritoneum) . the clinical presentation of complicated intra-abdominal infections can range from mild symptoms such as nausea, mild abdominal pain, and cramping to lifethreatening septic shock. clinical findings result from local or diffuse inflammation with or without abscess formation. fever and abdominal pain are typically present, with additional symptoms depending on the organ involved. elderly and immunocompromised patients present with atypical, usually milder symptoms. imaging studies form an important adjunct to diagnosis. management involves empiric antibiotic coverage for bowel flora-mainly streptococci, enterococci, enteric gram-negative rods, and anaerobes-as well as controlling the source of infection, usually through surgery. • spontaneous bacterial peritonitis usually occurs in the setting of ascites and chronic liver disease. • spontaneous bacterial peritonitis is a diagnosis of exclusion. • ascitic fluid culture yield improves with inoculation into blood culture bottles at bedside. spontaneous bacterial peritonitis (sbp) is a form of infectious peritonitis without a surgically correctable cause and is therefore a diagnosis of exclusion. the route of infection in sbp is usually not apparent and is often presumed to be hematogenous, lymphogenous, by transmural migration through an intact gut wall from the intestinal lumen, or in women, from the vagina via the fallopian tubes (levison and bush, ) . sbp occurs in the setting of ascites in most cases, and it is particularly common in patients with cirrhosis. in pediatric populations, those with postnecrotic cirrhosis or nephrotic syndrome are more often affected. in adults, almost % of patients who develop sbp have child-pugh class c liver disease, and % to % of hospitalized patients with cirrhosis and ascites have sbp (mowat and stanley, ) . sbp is almost always caused by a single organism, typically enteric gram-negative rods, most often e. coli, followed by klebsiella pneumoniae. gram-positive cocci account for about % of episodes of sbp, and streptococci are isolated most often. sbp caused by anaerobes is rare. growth of more than one organism should raise the suspicion of secondary peritonitis. signs and symptoms of sbp are subtle and require a high index of suspicion. fever greater than ° f ( ° c) is the most common presenting sign, occurring in % to % of cases. abdominal pain, nausea, vomiting, and diarrhea are usually present. peritoneal signs (abdominal tenderness or rebound tenderness) are common but may be absent in patients with ascites. in adults, mental status changes may also occur. sbp is often confused with acute appendicitis in children. in adults, sbp should be suspected in any patient with previously stable chronic liver disease who undergoes acute decompensation in clinical status. spontaneous bacterial peritonitis is diagnosed by analysis of ascitic fluid obtained by abdominal paracentesis. infection has been typically defined as an ascitic fluid wbc count higher than cells/mm , which is considered diagnostic even when the culture of the ascitic fluid is negative. in cases where bloody fluid is obtained ("traumatic paracentesis"), the wbc count should be corrected by wbc per rbcs/mm . the use of bedside dipstick for leukocyte esterase has a high false-negative rate and is not recommended (nguyen-khac et al., ) . ascitic fluid culture yield can be increased by inoculating blood culture bottles with ml of ascitic fluid at the bedside. blood cultures should also be obtained as part of the workup. after the diagnosis of peritonitis is established, secondary peritonitis should be ruled out. ct of the abdomen with oral and intravenous contrast can help direct the surgeon to a particular source of infection, as opposed to doing a full exploratory laparotomy. a high ascitic fluid total protein (> g/dl) or amylase level is suggestive of secondary peritonitis. the treatment of choice is generally a third-generation cephalosporin such as cefotaxime ( g iv every - hours) or ceftriaxone ( g iv once daily). patients who have an ascitic fluid wbc count higher than cells/mm should be given empiric intravenous antibiotics without delay. oral amoxicillin-clavulanic acid can be used for mild, uncomplicated cases (navasa et al., ) . duration of treatment varies diagnosis of fuo may be assisted by the dukes criteria for endocarditis, ct scan of the abdomen, nuclear scanning with a technetiumbased isotope, and liver biopsy (mourad et al., ) (sor: b) . routine bone marrow cultures are not recommended in the fuo workup (mourad et al., ) (sor: b) . empiric antibiotics should be initiated only in specific situations, to avoid skewing culture results and thus maximizing potential isolation of the causative organism (mourad et al., ) (sor: b). from to days depending on clinical response. patients usually respond to appropriate antibiotic therapy within to hours; otherwise, a repeat paracentesis should be performed. if the ascitic fluid wbc count does not decrease by more than %, alternative diagnoses should be considered. prophylaxis with a fluoroquinolone or trimethoprim-sulfamethoxazole should be considered, particularly in high-risk patients (garcia-tsao and lim, • bacterial meningitis is life threatening and requires urgent medical attention and treatment. • viral encephalitis should be treated with acyclovir until herpes simplex virus is ruled out. • most brain abscesses are caused by streptococci and staphylococcus aureus. • the cns infections most likely to be encountered in clinical practice include meningitis, encephalitis, and abscess. • all cns infections can be difficult to diagnose, and a high index of suspicion by the health care provider is sometimes indicated to ensure patient survival. • mri is the most sensitive neuroimaging test for encephalitis. • acyclovir should be started immediately and continued until hsv pcr testing is obtained. meningitis can be acute, subacute, or chronic. in otherwise healthy children, the three most common organisms causing acute bacterial meningitis are streptococcus pneumoniae, neisseria meningitidis, and haemophilus influenzae type b (hib). isolation of an organism other than these three organisms from the csf of a child older than months always requires an explanation or evaluation for unusual host susceptibility. children with cochlear implants, asplenia, hiv infection, or csf leak from basilar skull or cribriform fracture are at greater risk for pneumococcal meningitis. deficiencies in terminal components of complement lead to greater risk for meningococcal infection (saez-llorens and mccracken, ) . in adults, the common etiologic agents of acute meningitis include s. pneumoniae, n. meningitidis, and listeria monocytogenes. patients with acute meningitis most often present with fever, headache, meningismus, and altered mental status. infants can present with nonspecific symptoms such as inconsolable crying, irritability, nausea, vomiting, and diarrhea. lethargy, anorexia, and grunting respirations indicate a critically ill infant. older children may complain of headache, vomiting, back pain, myalgia, and photophobia; may be confused or disoriented; and may verbalize specifically that the neck is stiff or sore. seizures are noted in up to % to % of children before hospital admission or early in the course of the illness. in contrast, patients with subacute or chronic meningitis may have the same symptoms with a much more gradual onset, lower fever, and associated lethargy and disability. mycobacterium tuberculosis, treponema pallidum (syphilis), borrelia burgdorferi (lyme disease), and fungi (e.g., cryptococcus neoformans, coccidioides spp.) are the most common agents (tunkel et al., ) . physical examination should look for papilledema, middle ear and sinus infections, petechiae (common with n. meningitidis), nuchal rigidity, and in infants, a bulging fontanel. blood cultures should be taken. a lumbar puncture (lp) for csf analysis should be done as soon as possible. a brain ct scan before lp is not necessary if the patient has no evidence of immunocompromise, cns disease, new seizure, papilledema, altered consciousness, or focal neurologic deficit, and if a subarachnoid hemorrhage is not suspected. if neuroimaging is necessary, blood cultures should be taken and antibiotics given before the study; a delay in administration of antibiotics leads to a worse outcome. csf should be sent for cell count, wbc differential, glucose, protein, and gram stain with culture. acid-fast bacilli stain and cryptococcal antigen may be obtained when indicated. empiric antibiotics for the initial treatment of bacterial meningitis are listed in table - , but these should be tailored to the isolated organisms whenever possible. adjunctive dexamethasone is recommended for children and infants with hib meningitis, but not if they have already received antibiotics. in adults, adjunctive dexamethasone is recommended for pneumococcal meningitis (tunkel et al., ) . close contacts of patients with n. meningitidis should receive rifampin, mg/kg (not to exceed mg) twice daily for days, or ciprofloxacin, mg as a single dose, or ceftriaxone, mg im as a single dose. unimmunized persons exposed to h. influenzae meningitis should receive rifampin (turkel et al., ) . pregnant women should not receive rifampin or doxycycline. a repeat lp should be done if no clinical response is seen after hours of appropriate antibiotic therapy, particularly for patients with resistant pneumococcal disease and those who received dexamethasone. neonates with gram-negative bacilli and patients with ventriculoperitoneal (vp) shunts require documentation of csf sterility. the duration of antimicrobial therapy is days for patients with n. meningitidis or hib, to days for pneumococcal meningitis, and to days for streptococcus agalactiae. spontaneous bacterial peritonitis is treated with third-generation cephalosporins (cefotaxime or ceftriaxone), with ampicillin-sulbactam, fluoroquinolones, or carbapenems as alternative agents (solomkin et al., ) (sor: b) . patients with diffuse peritonitis should undergo an emergency surgical procedure as soon as possible, even if ongoing measures to restore physiologic stability need to be continued during the procedure (sor: b). viral meningitis viral meningitis manifests similar to bacterial meningitis, although its course is rarely aggressive. the diagnostic process and examination are similar to those for bacterial meningitis. viral meningitis is usually caused by enteroviruses, hsv, mumps virus, and hiv. along with the signs of meningitis, signs that suggest a viral etiology include genital lesions (hsv- ), diarrhea, or a maculopapular rash (enteroviruses). diagnosis is made by the history, examination, and csf results. early in the course, the csf might show predominantly neutrophils that can resemble bacterial meningitis. treatment is symptomatic. suppressive therapy should be offered to patients with recurrent hsv meningitis. although encephalitis can also be caused by bacteria and fungi, the great majority of cases are caused by viruses. herpes simplex accounts for % of cases. patients present with fever, acute decreased level of consciousness, and occasionally, seizures and language, memory, or behavior disturbances. mri is the most sensitive neuroimaging test for encephalitis and might show temporal lobe inflammation in early hsv encephalitis. csf studies and electroencephalography (eeg) are also recommended for all patients with encephalitis. herpes simplex pcr should be done, and acyclovir should be given immediately until hsv encephalitis is ruled out. during late summer and early fall, doxycycline should be considered to cover for tick-borne illnesses, and testing should include the mosquito-borne encephalitides such as west nile, st. louis, eastern equine, and western equine. treatment depends on the suspected etiologic agent but is generally supportive (tunkel et al., ) . a brain abscess is a focal, intracerebral infection that develops into a collection of pus surrounded by a well-vascularized capsule. although fungi and protozoa (particularly toxoplasma) can also cause brain abscesses, bacterial causes are much more common. streptococci are found in % of bacterial abscesses and are usually from oropharyngeal infection or infective endocarditis, whereas staphylococcus aureus accounts for % to % of isolates and is more often found after trauma. community-associated mrsa strains have been increasing. enteric gram-negative bacilli (e.g., e. coli; proteus, klebsiella, and pseudomonas spp.) are isolated in % to % of patients, often in patients with ear infection, septicemia, or immunocompromise and those who have had neurosurgical procedures. most clinical symptoms are caused by the size and location of the abscess rather than the systemic signs of an infection. headache is the most common complaint and may be accompanied by fever, mental status changes, evidence of increased intracranial pressure (nausea, vomiting, papilledema), or focal neurologic deficits. diagnosis is usually made by ct scan with iv contrast showing the characteristic hypodense center with a peripheral uniform ring enhancement, with or without a surrounding area of brain edema. mri is becoming the preferred imaging modality because of increased sensitivity, particularly for detecting satellite lesions. additional testing depends on risk factors and the likely underlying source of infection and may include blood cultures, chest imaging, testing for hiv and antibodies to toxoplasma, and transesophageal echogram. empiric therapy typically involves vancomycin, ceftriaxone, and metronidazole. optimal management also includes surgical drainage for most abscesses, both to find an etiologic microorganism and to improve chances of cure (turkel, ) . • most acute diarrheal illness is viral and can be managed symptomatically and with appropriate attention to hydration. • travelers' diarrhea is usually caused by diarrheogenic escherichia coli. • the infection in travelers' diarrhea is usually self-limited. • antibiotics may shorten the duration of diarrhea by to days. • the most common cause of antibiotic-associated diarrhea is clostridium difficile. • treatment of antibiotic-associated diarrhea involves discontinuing the offending agent, if possible. adjunctive dexamethasone is recommended for children and infants with h. influenzae type b meningitis, but not if they have already received antibiotics (tunkel et al., ) (sor: a). in adults, adjunctive dexamethasone is recommended for pneumococcal meningitis (tunkel et al., ) (sor: b). diarrhea is a common presenting complaint in the primary care physician's office. not all causes of diarrhea are infectious, and not all infectious causes of diarrhea require specific antibiotic therapy. diarrhea remains a major cause of morbidity and mortality, particularly for children in the developing world. diarrhea is an alteration of normal bowel function, characterized by an increase in the water content, volume, or frequency of stools. acute diarrhea is typically defined as present less than days, and diarrhea is considered chronic when symptoms persist longer than days (figure - ). infectious diarrhea seen in the primary care physician's office is most frequently caused by viruses. a number of viral agents can cause diarrheal illness (box - ). rotaviruses are the principal enteric pathogens in children less than years of age and the most important cause of hospitalization and infant mortality related to diarrheal illnesses. noroviruses evaluate severity and duration obtain history and physical examination [ ] [ ] [ ] [ ] [ ] treat dehydration report suspected outbreaks check all that apply: are the most common cause of food-borne disease worldwide. viral gastroenteritis is usually an acute self-limited illness, referred to as the "stomach flu." enteric viruses are easily spread by fecal-oral transmission, through contamination of food and water, fomites, and person-to-person spread. secondary attack rates can be high. nausea and vomiting are the most prominent symptoms of viral gastroenteritis. diarrhea, fever, headache, and constitutional symptoms may also be experienced. these viral infections can occur at any time during the year, but tend to occur more often in the winter. there is no specific therapy. treatment is supportive, with particular emphasis on adequate replacement of fluids and electrolytes. if rehydration can be accomplished enterally, it is preferred. both the pentavalent bovine-human reassortment (rv ) and the oral, live-attenuated monovalent (rv ) rotavirus vaccines are effective for prevention of severe gastroenteritis. the rv vaccine series is recommended for children at ages , , and months, whereas the rv vaccine should be administered to children and months of age. approximately % of travelers to developing regions of the world will develop diarrhea. bacteria are responsible for approximately % of diarrhea acquired by travelers. other important causes include viruses and parasites. the onset of the majority of cases of travelers' diarrhea is usually within to days after arrival. the presentation is typically a noninflammatory, nonbloody diarrhea associated with abdominal discomfort, fever, nausea, or vomiting. the duration is usually to days. enterotoxigenic e. coli is responsible for approximately % of travelers' diarrhea. enteroaggregative e. coli is the second most common bacterial agent and causes % of cases. salmonella, shigella, and campylobacter spp. are less often detected but are important causes of dysentery, particularly in asia and africa. dysentery is severe inflammatory diarrhea manifested by fever and bloody stools. most cases of travelers' diarrhea are self-limited, but chronic postinfectious irritable bowel syndrome may occur in up to % of those who experience diarrhea. prevention of travelers' diarrhea is an important component of pretravel counseling for high-risk countries. food should be boiled, cooked, or peeled and water boiled to avoid consumption of fecal contamination. if a person develops travelers' diarrhea, a short course of antibiotics with rifaximin, ciprofloxacin, or azithromycin can shorten the duration of illness by to days. antibiotic therapy is recommended for persons with bloody diarrhea or fever. rifaximin, a nonabsorbed antibiotic, is not effective against invasive pathogens and should not be administered for dysentery. ciprofloxacin or azithromycin should be used for dysenteric symptoms based on local antimicrobial susceptibilities. antibiotics are frequently prescribed in the primary care physician's office for a variety of infections. unfortunately, antibiotics can alter the normal host microflora that can be protective against other infections. antibiotic effects on the normal gastrointestinal tract microbiome can lead to antibiotic-associated diarrhea, which causes significant morbidity and mortality. administration of antibiotics usually precedes symptoms of antibiotic-associated diarrhea by about week but can be as distant as or months. strong associations with clindamycin (cleocin), cephalosporins, penicillins, and fluoroquinolones have been demonstrated, but any antibiotic can lead to antibiotic-associated diarrhea. the most important cause of antibiotic-associated diarrhea is clostridium difficile, an anaerobic, gram-positive, spore-forming rod. c. difficile is implicated as the cause in up to % of antibiotic-associated diarrhea cases, in % to % of antibiotic-associated colitis cases, and in more than % of antibiotic-associated pseudomembranous colitis cases. risk factors for c. difficile diarrhea include antibiotics, health care exposure (recent stay in hospitals or long-term care facilities), older age (> ), and comorbid conditions. the clinical presentation of c. difficile colitis is usually diarrhea, abdominal pain or cramping, and fever in a patient who recently received antibiotics. leukocytosis is common and may be profound; levels can be consistent with leukemoid reaction. a rare but potentially fatal complication is toxic megacolon. toxic megacolon manifests as acute colonic dilation to a diameter greater than cm, associated with systemic toxicity and the absence of mechanical obstruction. with its high associated mortality, any patient who develops toxic megacolon requires immediate surgical evaluation for possible colectomy. diagnosis of c. difficile diarrhea is achieved by demonstration of c. difficile toxin a or b in the stool by enzyme immunoassay (eia) or cell culture cytotoxicity assay in a symptomatic patient with a previous history of antibiotic use. asymptomatic patients should not be tested. with the improved sensitivities of these diagnostic assays, one stool sample is usually sufficient to test for c. difficile, unless symptoms recur. test of cure after therapy with repeat stool for c. difficile toxin is not recommended because stools may remain positive for c. difficile toxin despite clinical resolution. endoscopy can demonstrate pseudomembranes in the colon. pseudomembranes are diagnostic of c. difficile infection, but are often not present. endoscopy may only reveal the presence of nonspecific colitis. clostridium difficile colitis is treated by discontinuing the offending agent(s) if possible and initiating antibiotic therapy (box - ). antimotility agents should be avoided. oral metronidazole (flagyl), mg three times daily for to days, is recommended for mild-moderate c. difficile diarrhea. severe diarrhea should be treated with oral vancomycin. oral vancomycin is currently not recommended for all patients with c. difficile diarrhea because of concerns for the promotion of vancomycin-resistant enterococci (vre) and its expense. about % to % of patients experience relapse in travelers' diarrhea, in which enterotoxigenic e. coli or other bacterial pathogens are likely causes, prompt treatment with a fluoroquinolone, azithromycin, or rifaximin or, in children, azithromycin mg/kg/day once daily can reduce the duration of an illness from to days to to days (dupont, ) (sor: a). after therapy. for relapse, a repeat course of the original c. difficile treatment should be administered. patients who have mild to moderate cases without volume depletion or systemic toxicity can be treated as outpatients. discussions of the following infections can be found online at www.expertconsult.com: • infectious viral hepatitis • endocarditis treat mild-moderate c. difficile diarrhea with metronidazole (zar et al., ) evidence-based reviews of the diagnosis and treatment of many common clinical problems. www.mdcalc.com/curb- -severity-score-community-acquired-pneumonia curb- score calculator to determine the severity of communityacquired pneumonia and need for hospitalization. the complete reference list is available online at www.expertconsult.com. anthony zeimet hepatitis is defined as inflammation of the liver that is commonly induced by viruses that include the hepatitis viruses a through e, which will be the focus of this discussion. other viruses that can induce hepatitis include epstein-barr virus (ebv), cytomegalovirus (cmv), herpes simplex virus (hsv), varicella zoster virus (vzv), adenovirus, and coxsackievirus. various medications and alcohol abuse are two important nonviral causes. most infectious causes of hepatitis are self-limiting; however, hepatitis b and c viruses can cause a chronic infection that may lead to cirrhosis and eventual liver failure, as well as hepatocellular carcinoma. hepatitis a virus (hav) and hepatitis e virus (hev) are spread by the fecal-oral route and only cause an acute infection. hepatitis b, c, and d viruses (hbv, hcv, hdv) are spread through the blood and have an acute form of disease that sometimes can become chronic. the clinical presentation of hepatitis is clinically indistinguishable. asymptomatic infections are more common than symptomatic infection. symptoms generally include right upper quadrant (ruq) abdominal pain, anorexia, nausea, vomiting, diarrhea, dark-colored urine, pale stools, and generalized malaise; patients may notice a yellow hue to their skin or eyes. pruritus is common, caused by deposition of bilirubin in the skin. the physical examination generally reveals jaundice and sclera icterus in addition to ruq pain. hepatomegaly is seen in % and splenomegaly in % of patients with hepatitis. liver function tests reveal elevated levels of aspartate transaminase (ast), alanine transaminase (alt), and bilirubin, and to a lesser extent, alkaline phosphatase (alp). hepatitis a virus is the most common cause of viral hepatitis worldwide. poor hygiene practices in both the industrial and the developing world account for its prevalence. in the united states, hav is common among lower socioeconomic groups, daycare attendants and workers, men who have sex with men (msm), and illicit drug users. hepatitis a is often acquired by travelers to endemic areas. the incubation period is to days (mean, days). hav is highly contagious, and peak fecal shedding generally occurs at the onset of illness in most infected patients. viremia averages to days. hav infection manifests as an acute, self-limited illness, with the prodromal symptoms lasting about a week before the onset of jaundice. jaundice generally resolves after weeks, and most patients recover. fulminant hepatic failure is possible but extremely rare. diagnosis of acute hav infection is made by demonstration of anti-hav immunoglobulin m (igm) in the patient's serum. this may be negative if the patient presents early, and repeat testing may be necessary if hav is strongly suspected. anti-hav igg in the serum indicates remote infection or immunization (efig - ). treatment is primarily supportive, except in patients with fulminant liver failure, who may require a liver transplant. vaccination should be administered to all patients who are seronegative and to persons at increased risk for acquiring hav, including those about to travel to endemic areas, patients with chronic liver disease or receiving clotting factor concentrates, msm, hiv-positive patients, and illicit drug users. certain areas of the united states now require mandatory vaccination of children as well as those who work in the restaurant industry. the vaccine is safe and highly efficacious and is given as a two-dose series at and at to months. passive immunization with immune globulin is recommended for those exposed to the virus by a known contact, including household and sexual contacts, and those who are traveling to an endemic area for less than weeks but never vaccinated. any person who receives immune globulin should also start the vaccination series. hepatitis b virus infection can be acute or chronic. about , people die from acute hbv infection annually, and , die of cirrhosis and hepatocellular carcinoma caused by chronic infection. about million people worldwide are living with chronic hbv infection. in the united states, an estimated . million residents have chronic hbv infection, with to deaths each year. significant burdens of disease are seen in asia, pacific islands, sub-saharan africa, amazon basin, and eastern europe. most adults with acute hbv will clear the virus, with less than % progressing to chronic infection. chronic infection will develop in almost all children infected perinatally and in % of those who become infected at to years of age. hbv is transmitted through exchange of body fluids, sexually and perinatally. in the united states, most hbv cases are acquired during adolescence and early adulthood with onset of sexual activity, experimentation with drug use, and sometimes occupational exposure. fever, polyarthralgia, rash, and a serum sickness-like illness are features of hbv infection in addition to jaundice and may be seen in association with polyarteritis nodosa. clinicians have the most difficulty in interpreting the various serologic tests for diagnosis of hepatitis b (etable - ) . the mean incubation period is to days, with a range of of days after infection. diagnosis of acute infection can be detected by obtaining hbv surface antigen (hbsag), which can appear as early as week after exposure but generally by day . in a patient strongly suspected to have hbv infection, the clinician can consider checking the hbv dna viral load; which can be detected as early as week after exposure. eventually the patient will develop an anti-hbv surface antibody, which indicates recovery from the illness. the other viral serologies for hbv are rarely obtained in acute illness. in chronic hbv infection, there are three major phases of infection: . immune tolerant. active viral replication in the liver with high levels of hbv dna levels but essentially normal or minimal elevation of ast and alt. most patients eventually progress to the next stage. . immune active. more robust liver inflammation with alt elevation, and liver biopsy shows inflammation with or without fibrosis. hbv early antigen (hbeag) is detected along with hbsag. . inactive carrier state. as patients enter this phase, they clear the hbeag and develop anti-hbe antibody and have undetectable or low levels of hbv dna, with normalization of alt and liver inflammation. if patients become hbsag negative, they then develop anti-hbs and have resolved their infection; otherwise, they are considered a chronic carrier. treatment of acute hbv is primarily supportive. in the last decade, however, there have been significant advances in the treatment of chronic hbv infection. the use of interferon has long been the mainstay of treatment and has a defined, limited course but is generally poorly tolerated. with the advent of the hiv/aids epidemic and research into treatment of hiv disease, antiviral medications are now starting to replace interferon as the preferred treatment option for hbv patients. nucleoside/nucleotide analogs such as lamivudine, adefovir, entecavir, tenofovir, and telbivudine are generally given for long-term, indefinite therapy to prevent progression of liver disease and development of hepatocellular carcinoma. any patient with chronic hbv infection should be referred to an infectious diseases specialist or a hepatologist to determine the appropriate treatment course. universal vaccination of newborns and infants is routine in the united states since , and the incidence of hbv infection has declined. during primary care visits, the vaccination status of any adult or adolescent born before should be reviewed and the vaccine offered. the vaccine requires three doses given at , , and months. an unvaccinated person or neonate who is exposed to the body fluids of a hbv-infected individual should start the vaccination series in addition to receiving the hepatitis b immune globulin (hbig). hepatitis c virus infection is the most common cause of chronic viral hepatitis in the united states. hcv does have an acute form of infection but is usually subclinical and rarely diagnosed. the cdc estimates that there are more than . million people with hcv infection. hcv is generally transmitted parenterally, as in injection drug users who share needles. before , those who received a blood transfusion may have contracted hcv. sexual transmission acute hbv has been reported in monogamous couples, with one partner who has hcv infection and the other without infection who eventually acquires the virus. this occurs in % to % of couples and represents a rare mode of transmission. because the most common mode of acquisition is sharing needles, any patient who is hcv positive should be screened for hiv because these two infections often occur together (ebox - ). the diagnosis of acute hcv infection can be made by obtaining a hcv rna viral load; although this is rarely done because the initial infection is subclinical. chronic disease is generally discovered by a positive anti-hcv antibody along with an elevated hcv rna viral load. hcv genotype should also be obtained in any positive individual, because this has important prognostic factors with regard to therapy, with genotype a and b the predominant type in the united states and unfortunately having a poor response to therapy. as with hbv, chronic hcv infection can lead to cirrhosis and the development of hepatocellular carcinoma. treatment consists of to weeks of interferon and ribavirin therapy. any patient being considered for therapy should be referred to an infectious diseases specialist or hepatologist. a liver biopsy is often needed to determine appropriate treatment candidates. also known as the hepatitis delta antigen virus, hdv is a defective virus that requires the presence of hbv to be infectious. hdv should be suspected in any patient with chronic hbv who develops acute hepatitis. hepatitis d is endemic in the mediterranean, balkans, africa, middle east, and amazon basin. diagnosis is made through an anti-hdv antibody in the presence of someone with positive hbsag or anti-hb core antibody igm or igg. treatment is supportive. any person vaccinated against hbv cannot become infected with hdv. similar to hav infection, hev is spread by the fecal-oral route. hev only has an acute form and does not progress to chronic infection. most reported epidemics have been related to consumption of contaminated drinking water. hev is endemic to southeast and central asia, north africa, middle east, mexico, brazil, venezuela, and cuba. hepatitis e can be considered a cause of infectious hepatitis in the united states in the traveler returning from an endemic area. the incubation period is days. infection is of major concern during pregnancy, which can cause death in late pregnancy. diagnosis is made by demonstration of anti-hev antibody in serum. treatment is supportive. • endocarditis prophylaxis is now recommended solely for patients at high risk of a complicated course with a more narrow range of cardiac conditions. • routine prophylaxis for gi and gu procedures is no longer recommended. • the duke criteria represent a reliable scoring system for diagnosing endocarditis. • echocardiography is indicated to confirm suspected endocarditis. bacterial endocarditis is one of the most feared infections; although uncommon, it carries high morbidity and mortality. increase in antibiotic resistance among bacteria causing this infection has created challenges for effective treatment. the fundamental view of the american heart association (aha) in preventing infective endocarditis has shifted in recent years. views on pathophysiology have not changed substantially, but it is now recognized ebox - persons for whom hepatitis c virus (hcv) screening is recommended persons who have injected illicit drugs in the recent and remote past, including those who injected only once and do not consider themselves to be drug users. persons with conditions associated with a high prevalence of hcv infection, including: persons with human immunodeficiency virus (hiv) infection persons with hemophilia who received clotting factor concentrates before persons who have ever received hemodialysis persons with unexplained abnormal transaminase (aminotransferase) levels prior recipients of transfusions or organ transplants before july , including: persons who were notified that they had received blood from a donor who later tested positive for hcv infection persons who received a transfusion of blood or blood products persons who received an organ transplant children born to hcv-infected mothers health care, emergency medical, and public safety workers after a needle stick injury or mucosal exposure to hcv-positive blood current sexual partners of hcv-infected persons * modified from centers for disease control and prevention. recommendations for prevention and control of hepatitis c virus (hcv) infection and hcv-related chronic disease. mmwr ; (rr): - . *although the prevalence of infection is low, a negative test in the partner provides reassurance, making testing of sexual partners of benefit in clinical practice. • universal vaccination of infants with hepatitis b vaccine reduces the risk of acute hepatitis, chronic carrier state, and complications of chronic infection and may be more effective than selective vaccination of high-risk individuals (lee et al., ) (sor: a). • as part of a comprehensive health evaluation, all persons should be screened for behaviors that place them at high risk for hepatitis c infection (ghany et al., ) (sor: b). • liver biopsy may be considered in patients with chronic hcv infection to determine fibrosis stage for prognostic purposes or to make a treatment decision (ghany et al., ) (sor: b). that cumulative daily episodes of bacteremia likely carry more risk than the transient bacteremia caused by dental procedures. infective endocarditis likely begins with turbulent flow and damaged endothelium around heart valves, which allow platelet aggregation and thrombus formation, causing a "nonbacterial thrombotic endocarditis" (wilson et al., ) . the presence of bacteremia then allows this vegetation to become seeded with infection. bacterial "adhesins" are present to a greater degree in some species and allow for more effective attachment to the injured area of endothelium. with high concentrations of bacteria in the mouth, vagina, gi tract, and perhaps gu system, antibiotic prophylaxis was initiated when these anatomic locations were manipulated. recommendations for infective endocarditis prevention changed in - , with aha recognizing more likely benefit from providing adequate population-based dental care and good oral hygiene, and thus less significant ongoing bacteremia at home in brushing, flossing, and "toothpicking," than in providing antibiotic prophylaxis to patients undergoing a dental procedure. no prospective rct has shown that dental prophylaxis prevents infective endocarditis. with recognition of the risk associated with administration of antibiotics (gi upset, diarrhea, rash, anaphylaxis) and the risk of contributing to increasing antibiotic resistance, versus the likely negligible benefit, aha has substantially changed its advice on this long-held practice. a preexisting cardiac condition produces a predisposition to the development of infective endocarditis (ebox - ). for example, those who have valve replacement for infection of an infected native valve carry a lifetime risk of per , patient-years. the risk in the general population without known heart disease is per , patient-years. more concerning, however, is the risk to a given patient of poor outcome if the patient develops endocarditis, which drives current aha recommendations. those with an infected mechanical valve have a mortality rate of about %, versus % or less for patients with an infected native valve (wilson et al., ) . a summary of current recommendations for endocarditis prophylaxis is provided in etable - . of note, gi and gu procedures have been removed from those for which antibiotics are recommended, unless those systems are actively infected at the time of the procedure. the same is true for skin and soft tissue procedures, in that only infected tissue would warrant antibiotics to prevent infective endocarditis. it is still recommended to provide prophylaxis for respiratory tract procedures, if the respiratory wall will be invaded through biopsy or the procedure. in addition, respiratory procedures to treat infections (e.g., empyema) should be combined with antibiotic administration (nishimura et al., ) . antibiotic regimens for prophylaxis for dental procedures are still based primarily on synthetic penicillins as their cornerstone. this is with recognition that streptococcus viridans is both a mouth floral inhabitant and a common agent causing infective endocarditis. with other procedures, antibiotics should be targeted to bacterial pathogens causing any active infection in the system being manipulated. ebox - cardiac conditions associated with the highest risk of adverse outcome from endocarditis for which prophylaxis with dental procedures is reasonable prosthetic cardiac valve or prosthetic material used for cardiac valve repair previous ie congenital heart disease (chd) * unrepaired cyanotic chd, including palliative shunts and conduits completely repaired congenital heart defect with prosthetic material or device, whether placed by surgery or by catheter intervention, during the first months of the procedure † repaired congenital heart defect with residual defects at the site or adjacent to the site of a prosthetic patch or prosthetic device (which inhibit endothelialization) cardiac transplantation recipients who develop cardiac valvulopathy *except for the conditions listed above, antibiotic prophylaxis is no longer recommended for any other form of chd. †prophylaxis is reasonable because endothelialization of prosthetic material occurs within months after the procedure oral antibiotic william osler discussed "malignant endocarditis" in and its great diagnostic challenge. in the modified duke criteria remains a reliable tool for assessing patients with endocarditis. endocarditis is suspected in febrile patients without an obvious source, in those with recent bacteremia (including iv drug use), in those with underlying cardiac predisposition, and perhaps in patients with the clinical finding of a new cardiac murmur. in establishing a diagnosis of infective endocarditis, a patient is considered to have definite disease if two major or one major and three minor or five minor criteria are present. possible disease is defined as one major and one minor or three minor criteria (ebox - ). pathologic specimens showing changes consistent with endocarditis would make a definitive diagnosis. echocardiography is indicated in making the diagnosis of infective endocarditis. transthoracic echocardiography (tte) is helpful if vegetations are seen, although size of the patient and other disease (e.g., copd) may limit the ability of tte to view the cardiac valves adequately. if tte is negative and suspicion remains, transesophageal echocardiography (tee) is indicated. tte may be more widely available, depending on regional and institutional variation, and should be used rather than delaying this diagnostic test. bacteria present within valvular vegetations are often less metabolically active, which partly explains the requirement for longer courses of antibiotics for this type of infection. clearly, therapy for endocarditis should be targeted at the organism identified on blood culture, if any. the counting of antibiotic days should begin when the blood culture becomes negative and not at the start of the particular agent. recommendations for antibiotic use in infectious endocarditis are highly variable and based on the presence or absence of synthetic valvular material and the infectious agent (etable - ). generally speaking, a minimum of weeks of iv antibiotics is indicated. in cases of resistant organisms, up to weeks may be required. in either case, synergistic use of agents such as gentamicin may be indicated for the first several weeks of treatment, which then can be discontinued. the ability of a given patient to complete this course at home versus in a health care facility is dependent on the dosing frequency of the antibiotic, availability of inhome nursing services, and the type of intravenous access through which the antibiotic will be delivered. at the completion of endocarditis therapy, echocardiography should be repeated to re-assess the function of the valve(s) in question. valvular dysfunction at the completion of therapy is a good indication that the patient will need valve replacement in the future. there are circumstances, like the development of congestive heart failure in the face of endocarditis, in which primary surgery is indicated. typical microorganisms consistent with ie from separate blood cultures: viridans streptococci, streptococcus bovis, hacek group, staphylococcus aureus; or community-acquired enterococci in the absence of a primary focus; or microorganisms consistent with ie from persistently positive blood cultures, defined as follows: at least positive cultures of blood samples drawn > hours apart; or all of or a majority of ≥ separate cultures of blood (with first and last sample drawn at least hour apart). single positive blood culture for coxiella burnetii or anti-phase igg antibody titer > : echocardiogram positive for ie (tee recommended for patients with prosthetic valves, rated at least "possible ie" by clinical criteria, or complicated ie [paravalvular abscess]; tte as first test in other patients) defined as follows: oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation; or abscess; or new partial dehiscence of prosthetic valve; new valvular regurgitation (worsening or changing or preexisting murmur not sufficient) predisposition, predisposing heart condition, or idu fever, temperature > ° c vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and janeway's lesions immunologic phenomena: glomerulonephritis, osler's nodes, roth's spots, and rheumatoid factor microbiologic evidence: positive blood culture but does not meet a major criterion as noted above * or serological evidence of active infection with organism consistent with ie echocardiographic minor criteria eliminated echocardiography should be performed in all patients with suspected infective endocarditis (baddour et al., ) there is no evidence that antibiotic prophylaxis is effective or ineffective for preventing infectious endocarditis after dental procedures in patients at risk (chung, ) (sor: c). regimen dosage * and route duration (wk) chronic cough due to acute bronchitis: accp evidencebased clinical practice guidelines interim recommendations for the use of influenza antiviral medications in the setting of oseltamivir resistance among circulating influenza a (h n ) viruses, - influenza season national ambulatory medical care survey: summary short-course antibiotic treatment in acute exacerbations of chronic bronchitis and copd: meta-analysis of doubleblind studies antibiotics for exacerbations of chronic obstructive pulmonary disease antibiotics for acute bronchitis effects of naproxen on experimental rhinovirus colds: a randomized, double-blind, controlled trial infectious diseases society-american thoracic society consensus guidelines on management of community-acquired pneumonia in adults emergence of a novel swineorigin influenza a (h n ) virus in humans acute pneumonia influenza. in: schlossberg d, ed. clinical infectious disease seasonal influenza in adults and children: diagnosis, treatment, chemoprophylaxis, and institutional outbreak management. clinical practice guidelines of the infectious diseases society of america antivirals for influenza in healthy adults: systematic review hospitalizing influenza in adults infectious diseases society-american thoracic society consensus guidelines on management of community-acquired pneumonia in adults influenza viruses, including avian influenza and swine influenza steroids for symptom control in infectious mononucleosis hepatosplenomegaly in infectious mononucleosis, assessed by ultrasonic scanning infectious mononucleosis vaccines for post-exposure prophylaxis against varicella (chickenpox) in children and adults centers for disease control and prevention (ats/cdc). targeted tuberculin testing and treatment of latent tuberculosis infection centers for disease control and prevention. extensively drug-resistant tuber culosis-united states short-course therapy with rifampin plus isoniazid, compared with standard therapy with isoniazid, for latent tuberculosis infection: a meta-analysis genital warts expedited partner therapy in the management of sexually transmitted diseases. atlanta: us department of health and human services center for disease control and prevention. sexually transmitted disease surveillance. division of std prevention accuracy of the clinical diagnosis of vaginitis compared with a dna probe laboratory standard a pooled analysis of the effect of condoms in preventing hsv- acquisition consistent condom use is associated with lower prevalence of human papillomavirus infection in men the limited value of signs and symptoms in the diagnosis of vaginal infections cervical cancer condom effectiveness in reducing heterosexual hiv transmission sexually transmitted diseases treatment guidelines genitourinary infections urinary tract infection in children diagnosis and management of uncomplicated urinary tract infections american geriatric society. guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults asymptomatic bacteriuria: when to screen and when to treat the effectiveness of a clinical practice guideline for the management of presumed uncomplicated urinary tract infection in women recurrent cystitis in non-pregnant women a randomized trial to evaluate effectiveness and cost effectiveness of naturopathic cranberry products as prophylaxis against urinary tract infection in women screening for asymptomatic bacteriuria in pregnancy: a decision and cost analysis guidelines for antimicrobial treatment of uncomplicated acute bacterial cystitis and acute pyelonephritis in women tick-borne infections tick-borne diseases tick-borne diseases in the united states the clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis practice guidelines for the diagnosis and management of skin and soft tissue infections furuncles and carbuncles centers for disease control and prevention. health-care-associated methicillin-resistant staphylococcus aureus (mrsa) double-blind, placebo-controlled trial of cephalexin for treatment of uncomplicated skin abscesses in a population at risk for community-acquired methicillin-resistant staphylococcus aureus infection practice guidelines for the diagnosis and management of skin and soft-tissue infections bacteriological study of diabetic foot infections diabetic foot infection diagnostic accuracy of the physical examination and imaging tests for osteomyelitis underlying diabetic foot ulcers: meta-analysis diagnosis and treatment of diabetic foot infections deep tissue biopsy vs. superficial swab culture monitoring in the microbiological assessment of limb-threatening diabetic foot infection culture of percutaneous bone biopsy specimens for diagnosis of diabetic foot osteomyelitis: concordance with ulcer swab cultures bite infections antibiotic prophylaxis for mammalian bites (cochrane review) sexually transmitted diseases treatment guidelines fever of unknown origin a comprehensive evidence-based approach to fever of unknown origin fever of unexplained origin: report on cases complicated intra-abdominal infections; spontaneous bacterial peritonitis; and secondary bacterial peritonitis and intra-abdominal abscesses members of veterans affairs hepatitis c resource center program. management and treatment of patients with cirrhosis and portal hypertension: recommendations from the department of veterans affairs hepatitis c resource center program and the national hepatitis c program mandell, douglas, and b ennett's principles and practices of infectious diseases spontaneous bacterial peritonitis: diagnosis, treatment and prevention review article: the utility of reagent strips in the diagnosis of infected ascites in cirrhotic patients randomized, comparative study of oral ofloxacin versus intravenous cefotaxime in spontaneous bacterial peritonitis diagnosis and management of complicated intra-abdominal infection in adults and children. guidelines by the surgical infection society and the infectious diseases society of america acute bacterial meningitis beyond the neonatal period brain abscess practice guidelines for the management of bacterial meningitis the management of encephalitis: clinical practice guidelines of the infectious disease society of america acute meningitis guidelines on acute infectious diarrhea in adults. the practice parameters committee of the american college of gastroenterology a comparison of vancomycin and metronidazole for the treatment of clostridium difficileassociated diarrhea, stratified by disease severity acute cholecystitis nett's principles and practices of infectious diseases diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the surgical infection society and the infectious diseases society of america infectious viral hepatitis national institutes of health consensus development conference statement: management of hepatitis b acute viral hepatitis hepatitis b virus infection chronic viral hepatitis chronic hepatitis diagnosis, management and treatment of hepatitis c: an update acute viral hepatitis hepatitis c virus infection effect of hepatitis b immunisation in newborn infants of mothers positive for hepatitis b surface antigen: systematic review and meta-analysis chronic hepatitis b: update infective endocarditis: diagnosis, antimicrobial therapy, and complications prescription of antibiotics for prophylaxis to prevent bacterial endocarditis experience with a oncedaily aminoglycoside program administered to adult patients acc/aha guideline update on valvular heart disease: focused update on infective endocarditis prevention of infective endocarditis: guidelines from the american health association. circulation key: cord- -rrverrsj authors: delano, margaret l.; mischler, scott a.; underwood, wendy j. title: biology and diseases of ruminants: sheep, goats, and cattle date: - - journal: laboratory animal medicine doi: . /b - - / -x sha: doc_id: cord_uid: rrverrsj nan since the first edition of this book, the use of ruminants as research subjects has changed dramatically. formerly, large animals were primarily used for agricultural research or as models of human diseases. over the past decade, ruminants have continued in their traditional agricultural research role but are now extensively used for studies in molecular biology, genetic engi-british stock with egyptian and indian goats. this breed is relatively heat tolerant and produces milk with the highest butterfat (about - %). fiber breeds include the angora and the cashmere. the angora, the source of mohair, originated in turkey. the cashmere breed is found primarily in mountainous areas of central asia. the la mancha, a newer breed of dairy goat first registered in the united states in , has rudimentary ears that are a genetically dominant distinguishing characteristic of the breed. the meat breeds include the boer, sapel, ma tou, kambling, and pygmy. the pygmy goat is small and is sometimes used for both meat and milk. the mubend of uganda and the red sokoto of west africa produce quality skins for fine leather (smith and sherman, ) . most breeds of cattle are classified as "dairy" or "beef"; a few breeds are considered "dual-purpose." common dairy breeds in the united states include holstein-friesian, brown swiss, jersey, ayrshire, guernsey, and milking shorthorn. holsteins have the largest body size, whereas jerseys have the smallest. of breeds in temperate regions, jerseys have been considered to be the most heat tolerant, but holsteins have been found to adapt to warmer climates. there are many beef breeds. the more common in the united states include angus (also called aberdeen-angus), hereford (both polled and horned), and simmental (briggs and briggs, ; schmidt et al., ) . breeds indigenous to other continents, such as the cape buffalo, have been found to have unique innate immune characteristics that protect them from endemic trypanosomiasis (muranjan et al., ) . more detailed information regarding these and other ruminant breeds is available in briggs and briggs ( ) . "rare" or "minor" breeds of sheep, goats, and cattle are studied for their genetic and production characteristics. discussions of these and efforts at conservation are described in detail elsewhere (national research council, ) . several terms are unique to ruminants. in relation to sheep, a ewe is the female, and a ram is the adult intact male. a lamb is the young animal, and ram lamb and ewe lamb are commonly used terms. a wether is a castrated male. the birthing process is referred to as lambing. with respect to goats, a doe or nanny is the female. a buck or billy is the adult intact male. a kid or goatling is a young goat. a young male may be referred to as a buckling, and a young female may be referred to as a doeling. a castrated male in this species is also called a wether. the birthing process is called kidding. with respect to cattle, an adult female is a cow, and an adult male is a bull. a calf is a young animal. a heifer is a female who has not had her first calf. a steer is a castrated male. calving refers to the act of giving birth. ruminants have been used as research models since the inception of the land grant college system, first in production agriculture and now also in basic and applied studies for the anatomic and physiologic sciences and in biomedical research for a variety of purposes. healthy, normal young ruminants serve as models of cardiac transplantation and as preclinical models for evaluation of cardiac assist or prosthetic devices, such as vascular stents and cardiac valves (salerno et al., ) . for many years, ruminants have been useful research subjects for reproductive research, such as research on embryo transfer, artificial insemination, and control of the reproductive cycle (wall et al., ) . several important milestones in gene transfer, cloning, nuclear transfer, and genetic engineering techniques have been developed or demonstrated using these species (ebert et al., ; schnieke, ; cibelli et al., a,b) (see fig. ). one of many proposed uses of genetically engineered ruminants is the production of proteins that will be secreted in the milk and later isolated (ebert et al, ; memon and ebert, ) . healthy sheep and goats are also often used for antibody production (hanly et al., ) . genome mapping developed rapidly during the s; extensive information is available and is increasing for sheep and cattle (broad et al., ; womack, ) . sheep are often selected for studying areas such as ruminant physiology and nutrition. these animals provide obvious bene-fits over the use of cattle in research from the standpoint of size, ease of handling, cost of maintenance, and docile behavior. sheep are also widely used models for basic and applied fetal and reproductive research (buttar, ; rees et al., ; ross and nijland, ) . the species is used for investigating circadian rhythms related to day length (lehman et al., ) , and the interaction between olfactory cues and behavior (kendrick et al., ) . the number and diversity of natural-and induceddisease research models in sheep are great and increasing. natural models include congenital hyperbilirubinemia/hepatic organic anion excretory defect (dubin-johnson syndrome) in the corriedale breed, congenital hyperbilirubinemia/hepatic organic anion uptake defect (gilbert syndrome) in the southdown breed, glucose- -phosphate dehydrogenase deficiency in the dorset breed, gm~ gangliosidosis in the suffolk breed, and pulmonary adenomatosis (jaagsiekte) in many breeds (hegreberg, l a) . induced models include arteriosclerosis, hemorrhagic shock, copper poisoning (wilson's disease), and metabolic toxocosis (hegreberg, lb) . goats are used in a wide variety of agricultural and biomedical disciplines such as immunology, mastitis, nutrition, and parasitology research. vascular researchers select the goat because of the large, readily accessible jugular veins. goats with inherited caprine myotonia congenita ("fainting goats") have been used as a model for human myotonia congenita (thomsen's disease) (kuhn, ) . a line of inbred nubians serves as models for the genetic disease [ -mannosidosis and prenatal therapeutic cell transplantation strategies (lovell et al., ) . (these disorders are discussed in more detail in section iii,b, .) goats are used as a model for osteoporosis research (welch et al., ) . cattle are often used as a source of ruminal fluid for research, teaching, or treatment of other cattle, by placing a permanent fistula in the left abdominal wall to allow sampling of ruminal fluid (dougherty, ) . cattle also serve as models of many infectious diseases, including zoonoses, and several inherited metabolic diseases. this species is useful for the basic and comparative research on the pathogenesis and immunology of inherited and infectious diseases. bovine trichomoniasis, caused by tritrichomonas (trichomonas)fetus, has been identified as a useful model for the human infection by trichomonas vaginalis (corbeil, ) . inherited cardiomyopathies have been found in the holstein-friesian, simmental-red holstein, black spotted friesian, and polled hereford with woolly coat (weil et al., ) . lipofuscinosis has been identified in ayrshires and friesians, and glycogenesis in shorthorns and brahmans. metabolic diseases such as hereditary orotic aciduria and hereditary zinc deficiency have been characterized in holstein-friesian or friesian cattle. holstein cattle also serve as a model for leukocyte adhesion deficiency syndrome (afip, ) . common breeds of normal, healthy ruminants are usually readily available, although seasonality may play a role, as noted below. agricultural sources and reputable farms may be located through land-grant universities or agricultural schools, cooperative extension and -h networks, regional ruminant breeders' associations, and farm bureaus. commercial sources of purposebred animals are found in technical publications and annual listings of research animal vendors. breeds carrying genetic traits of interest, either as animal models or as valuable production characteristics, may be located through literature or internet searches, animal science societies, breed or livestock conservation associations, and information resources such as the armed forces institute of pathology. organizations such as the institute for laboratory animal research (ilar), national center for research resources (ncrr), or the animal welfare information center (awic) may also serve as information sources about the animals needed. purpose-bred research sheep and goats are available from commercial vendors and are usually maintained in registered facilities under federal standards that are also acceptable to research animal accrediting agencies. these commercial animals are frequently described as specific pathogen-free (spf) and housed as biosecure or closed flocks. animal health programs are in place, and health reports or other quality assurance reports are usually available on request. agricultural sources of either small ruminant may be acceptable, but specific research needs may not have been addressed or may not be understood. lambs, kids, and milking goats may be difficult to locate in fall and winter months because most breeds of sheep and goats are seasonal breeders. management practices exist, however, to extend the breeding and milking seasons. most cattle used as animal models in research in the united states are from one of the dairy breeds, usually holstein, because this breed is now the most common. purpose-bred, specific pathogen-free research cattle are not typically available. because of selection and the management of dairy production units, calves and young stock are available year-round. availability of young beef cattle is more seasonal, according to production cycles typically followed by that industry. auction barns or sales are not appropriate sources for research ruminants. many of these animals are culls and will be poor-quality research subjects. they may be in poor body condition and stressed, may be sources of disease, and may contaminate other healthy animals, as well as the research facility. selection of the suppliers should be made only after research needs have been carefully considered. consistently working with and buying directly from as few sources as possible are best. certain types of research (i.e., agricultural nutrition studies) may better be served by selecting animals from local agricultural suppliers rather than commercial vendors located in a different geographical area. the selection of sources for research ruminants includes scrutiny of flock or herd record keeping; health monitoring, vaccination, and preventive medicine programs (including hoof care); production standards and management practices consistent with the industry; management of the breeding flock or herd; sanitation and waste handling programs; vermin and insect control measures (especially for flies and other flying insects); rearing programs for and condition of young stock; the location, health, and condition of the other animals on the premises; intensity of housing; and animal housing facilities. preliminary and periodic visits to the source farms should be conducted. it is important to establish a good relationship with the local attending large-animal veterinarians, who will be valuable resources for current approved therapies and practices. they may need to be oriented on the specific requirements of animal research. creative ways can be used to initiate and foster a good working relationship between the agricultural supplier and the research facility. supplying the vaccines or dewormers required for flock health programs, providing services such as quarterly serological testing or fecal examinations for the herd or flock, and paying a premium (rather than market price) for animals that meet the quality criteria established for the research animals are often helpful. a set of testing standards can be developed based on one high-quality supplier, and then flocks or herds can be "qualified" based on those standards. qualifying entails evaluations utilizing the facility and management aspects mentioned above and testing either a percentage of the herd or flock or the entire herd or flock for a number of infectious agents. the testing regimen itself should be carefully developed and evaluated. once qualified, each source farm should be reevaluated periodically to maintain its status. slaughter checks may be appropriate; otherwise necropsy of sentinel animals may be required. selected animals undergoing screening tests should be quarantined from the rest of flock or herd while awaiting test results. vaccination and deworming regimens can be instituted during these quarantine periods. a second quarantine should occur when animals arrive at the research facility. the animal screening process also depends on the origin of the animal (state, country) and the scientific program. federal and state regulations must be followed. socialization of the animals at the source facility should also be considered in terms of ease of handling and safety for personnel in the confinement of the research lab, barn, or farm. for example, frequently handled calves will be easier to manage, and adult dairy goats that have been acclimated to human contact are preferable. several texts provide information on industry standards for flock and herd management and preventive medicine strategies that can provide helpful orientation to those unfamiliar with these aspects. these references also provide information regarding vaccination products licensed for use in ruminants and typical herd and flock vaccination parasite control schedules ("current veterinary therapy," , "council report," ; "large animal internal medicine," ; smith and sherman, ) when designing a vaccination program during qualification of a source or at the research facility, it is important to evaluate the local disease incidence and the potential for exposure. vaccination programs should be conducted with an awareness of duration of passive immunity and stresses in ruminants' lives (e.g., weaning, grouping, management changes, and shipping) that may impair immunity or increase susceptibility to infectious diseases. it is also prudent to evaluate the cost-effectiveness of vaccination; labor and vaccine expenses may be much higher than the potential animal morbidity or mortality for diseases in a particular locality. not all of the vaccines mentioned subsequently will be necessary in all herds or flocks. vaccination needs for research animals will also depend on the local disease history, intent of the research, the age of the animals needed for research, and the length of time the animals will be housed. typical health screening programs for sheep include q fever (coxiella burnetii); contagious ecthyma; caseous lymphadenitis (corynebacterium pseudotuberculosis); johne's disease (mycobacterium paratuberculosis); ovine progressive pneumonia; internal parasitism such as nasal bots, lungworms, and intes-tinal worms; and external parasitism such as sheep keds. each supplier should be queried about vaccination programs for bluetongue, brucella ovis, campylobacter spp., chlamydia (enzootic abortion of ewes), clostridial diseases, pneumonia complex (parainfluenza , pasteurella haemolytica, and p. multocida), ovine ecthyma, rabies, dichelobacter (bacteroides) nodosus, arcanobacterium pseudotuberculosis, bacillus anthracis, and fusobacterium necrophorum. because of the limited number of biologics approved for small ruminants, products licensed for cattle have been used with success in sheep, and some licensed for sheep are used in goats ("council report," javma, ) . in some cases, approved feed additives, such as coccidiostats, are fed to sheep. the basic screening profile for goats should include q fever (coxiella burnettii), caprine arthritis encephalitis (cae), brucellosis, tuberculosis, and johne's disease (mycobacterium paratuberculosis) . goats may also be tested for caseous lymphadenitis, contagious ecthyma, or mycoplasma as needed. herd vaccination programs may include immunizations against tetanus and other clostridial diseases, chlamydia, campylobacter, contagious ecthyma, caseous lymphadenitis, corynebacterium pseudotuberculosis, and escherichia coli. cattle herds should be screened for johne's disease, brucellosis, tuberculosis, respiratory diseases, internal and external parasitism, and foot conditions such as hairy heel warts and foot rot. determination of the status of the herd with respect to bovine leukemia virus (blv) may be worthwhile. herd programs may include essential or highly recommended vaccines against bovine viral diarrhea virus (bvdv), infectious bovine rhinotracheitis virus (ibrv), bovine respiratory syncytial virus (brsv), parainfluenza (pi- ), leptospira pomona, tritrichomonas fetus, rotavirus, coronavirus, campylobacter (vibrio) , pasteurella haemolytica and p. multocida, and brucella abortus. other vaccination programs, dependent on herd status, endemic diseases, or geographic location, may include immunizations against the clostridial diseases, moraxella bovis (pinkeye), fusobacterium necrophorum (foot rot), staphylococcus aureus (mastitis), haemophilus somnus, rabies, tetanus, bacillus anthracis, enterotoxigenic e. coll anaplasma, and other leptospira species. some products considered to have limited efficacy include vaccines against salmonella dublin and s. typhimurium. some autogenous vaccines may be more effective than the commercially available products--for example, the bovine papillomavirus (warts) vaccines. rearing programs for dairy calves differ from those for the smaller ruminants, including the withdrawal of calves from their dams immediately or by hours after birth. in the cattle industry, antibiotics, ionophores (antibiotics that control selected populations of ruminal organisms), coccidiostats, probiotics, and other approved additives may be part of the milk replacers, grain and concentrate formulations, and/or creep feeding regimens. use varies by the segment of the industry, and regulations vary by country. subcutaneous hormonal implants (such as estradiol benzoate and progesterone combined, zeranol, or [~-estradiol) are administered, especially to beef calves destined for market rather than breeding, to promote growth. transportation of the animals from the source to the research facility must be carefully planned, and all applicable livestock travel regulations followed. it is best to have the animals transported in vehicles regularly utilized by the source farm. if commercial haulers are used, then disinfecting trucks, trailers, and associated equipment, such as ramps and chutes, beforehand is particularly important. the loading, footing, and distribution of the animals in the trailers and trucks, as well as environmental conditions during shipping, are important to consider to minimize stress and injury to the animals. sufficient time for acclimation to the facility, pens, handlers, feed, and water must be allowed once at the destination ("livestock handling and transport," ). recent publications address many general considerations as well as specifics about the facilities, husbandry, space requirements, and standard practices for research and production ruminants. institutions, private entities, researchers, and facility staff must also be aware of the recent adoption by the u.s. department of agriculture (usda) of specific guidelines for regulation of farm animals, such as ruminants, that are used in biomedical and other nonagricultural research. the usda animal care policy notes that the "guide for the care and use of agricultural animals in agricultural research and teaching" and the "guide for the care and use of laboratory animals" provide additional information to supplement the existing animal welfare act regulations (cfr, ; fass, ; hays et al., ; nrc, a; usda, ) . in all cases, stress should be considered and minimized in the husbandry and handling of ruminants. animals need to be provided adequate time to adapt to new surroundings. stress decreases feed intake, and the resulting energy, vitamin, and mineral deficiencies will affect the growth and development in younger animals. reproductive soundness and rumen function are affected by transport and similar stresses. standard practices such as weaning, castration, dehorning, vaccinations, deworming and treatments for external parasites, shipping and the associated feed and water deprivation, introduction to a new housing environment and new personnel, and intercurrent disease are all stressors (houpt, ) . animals should be acclimated to the use of halters and leads, temporary restraint devices, and other handling equipment associated with the research program. personnel in the research facility who are unfamiliar with ruminants should be trained in appropriate handling techniques. ap-preciation for ruminant behaviors has grown in recent years, and refined ruminant handling techniques have been published (houpt, ; grandin, ) . when ruminants are confinement-housed, care should be taken to provide adequate but draft-free ventilation. ammonia buildup and other waste gases may induce respiratory problems. in cold weather, if the ceiling, walls, or water pipes condense water, then the ventilation should be increased even at the expense of lower temperatures. even adult goats and younger cattle are quite comfortable in cold, even subfreezing temperatures, if provided with adequate amounts of dry dust-free bedding and draft protection. sheep, because of their wool, are remarkably tolerant to both hot and cold extremes. newborn lambs and recently shorn adults are susceptible to hypothermia, hyperthermia, and sunburn. therefore, in outside housing areas, sheep should be provided with shelters to minimize exposure to sun and inclement weather. animals housed under intensive confinement should be kept clean, and excreta should be removed from the pens or enclosures daily. feed and water equipment should be maintained in sound, clean condition and should be constructed to prevent fecal contamination. waterers should not create a muddy environment in paddocks or pens. there should be sufficient continuous-access waterers placed around the area to prevent competition or fighting. feeders should be constructed to conform to species size and feeding characteristics and to prevent entrapment of head and limbs. pens, other enclosures, passageways, chutes, and floors must be very sturdy to withstand such factors as the frequent cleaning; the strength, weight, and curiosity of all ages of animals; and the investigative and climbing behaviors of goats. chain-link fences are dangerous because goats (as well as some breeds and ages of sheep) are curious and tend to stand on their hind legs against fencing or walls. forelimbs may be caught easily in the mesh. floors in any areas where animals will be housed, led, or herded must ensure secure footing at all times to prevent slipping injuries. all ruminants are social and herding animals. therefore, they should be housed in groups or at least within eyesight and hearing of other animals. singly housed animals should have regular human contact. environmental enrichment should be governed by the experimental protocol or standard operating procedures, and durable play objects should be supplied to those animals that are housed in confinement. calves, in particular, that must be singly housed or that have been recently weaned, need play objects (morrow-tesch, ) . because sheep and goats are sensitive to changes in light cycle (especially reproductive parameters), photoperiod must be taken into account. normally, sheep and goats should be maintained on a cycle comparable to natural conditions. light intensity should be maintained at about lux (ilar, ; fass, ) . light cycles can be manipulated for experimental reasons. the development of the digestive system and the unique function of the rumen are among the most notable comparative anatomic and physiologic characteristics of ruminants. there is a three-compartment forestomach (rumen, reticulum, and omasum) and a true stomach (abomasum). the mature rumen functions as an anaerobic fermentation chamber in which the enzymes, such as cellulase, of the resident bacteria allow the animals to prosper as herbivores. digestion is also aided by other microorganisms, such as protozoa ( - /ml) and bacteria ( - ~ that contribute to rumen fermentation. the result is the production of volatile fatty acids (acetic, propionic, and butyric) . unlike in the monogastrics, fermentative digestion and volatile fatty acid absorption also occur in the large intestines. the main sources of energy for ruminants are volatile fatty acids (vfas) rather than glucose. glucose is formed from propionic acid (or from amino acids) for metabolism in the central nervous system (cns), uterus, and mammary glands. plasma glucose in ruminants is much lower than and is regulated differently from that in nonruminants. the rumen microorganisms also synthesize vitamins, such as b and k, and provide protein that is used by the animals' systems. large amounts of fermentation gases such as co and methane, and small amounts of nitrogen, are naturally eructed (hecker, ; schimdt et al., ) . intestinal immunoglobulin absorption by pinocytosis in the neonates is crucial to the success of passive transfer. this transfer mechanism is functional for approximately the first hr after birth. neonatal ruminants are immunocompetent, however, and this condition is used to advantage for vaccinations against some common diseases of the neonatal and later juvenile periods, such as infectious bovine rhinotracheitis (ibr) vaccine (using modified live virus vaccines) to calves when their dams' colostrum is lacking antibody against this virus. unlike hepatic lipogenesis in humans, lipogenesis in sheep primarily occurs in adipose tissue and the mamrnary gland (hecker, ) . in addition to normal lymph node chains, and as in other ruminants, sheep have small red "nodes" associated with blood vessels. inadvertently named hemal "lymph nodes," they contain numerous red blood cells. sheep have a relatively large pituitary gland, and accessory adrenal medullary tissue may be interspersed throughout the abdominal cavity. three major ovine histocompatability classes have been identified and designated as ovar (ovis aries) classes i, ii, and iii (franz-werner et al., ) . bovines are recognized as having several unique aspects involving their immune systems. the bovine lymphocyte antigen (bola) system ranks after the hu-man (hla) and murine (h- ) systems in terms of depth of knowledge (lewin, ) . cattle are considered free of autoimmune diseases (schook and lamont, ) . the complexity of the immunobiology of the bovine mammary gland is being studied extensively because mastitis is the most prevalent disease in the dairy industry. several innate immune mechanisms and cellular defenses, and their variation throughout lactation, have been described (sordillo et al., ) . hematology and clinical reference texts are available for the ruminant species and include overviews of normal values for age, sex, and breed-specific ranges, as well as discussions regarding the influences on the hemogram of many management, nutritional, geographic, metabolic, physiologic (including lactation), medication, and iatrogenic variables (duncan and prasse, ; jain, ; kaneko et al., ) . these references should be consulted when preparing to include blood collection data in research protocols and when reviewing hematologic findings. in addition, most veterinary diagnostic laboratories have also developed databases for normal ranges for hematologic and clinical chemistry values based on subjects from their service areas, and these may be useful as local and breed references. appropriate control groups must be incorporated into each research plan, however, to establish the normal values (see table i ) for the particular locale, diagnostic facilities, breed, age, sex, and research circumstances. normal hematologic and clinical biochemistry data are presented in tables ii and iii. some general statements apply to most ruminants. most ruminants have fewer neutrophils than lymphocytes. the blood urea nitrogen (bun) values cannot be used as an indicator of renal function because of the metabolism of urea nitrogen by rumen microflora. because of the large volume of rumen water, ruminants can generally go several days without drinking before significant dehydration occurs. erythrocytes may become more fragile during rehydration, resulting in some degree of hemolysis and hemoglobinuria. severe dehydration can occur quickly, however, in animals that are ill. urine ph is generally alkaline in adult ruminants. ruminant erythrocytes are smaller than those in other mammals, and hematocrits tend to be overestimated unless blood samples are centrifuged for longer amounts of time for packing of the cell pellet. increased red-cell fragility is also associated with the smaller erythrocyte. rouleau formation does not occur in cattle but does to a limited extent in sheep and goats. in addition to fetal hemoglobin, sheep are reported to have at least six different hemoglobins (hecker, ) . blood coagulation in sheep is similar to that in humans. (di / , dc / , dp / ) = (di / , dc / , dp / ) = (di / , dc / , dp / ) = permanent dental formula ( / , c / , m / ) = ( / , c / , m / ) = ( / , c / , m / ) = avital sign data for goats are from "large animal internal medicine" ( ) . sheep weight data represent weights of feeder lamb and adult dry ewe (federation of animal science societies [fass], ) . goat weight data are for a large-breed male goat. cattle weight data represent weights of female holstein or guernsey dairy cattle (fass, ) . life span data for sheep and cattle are from brooks et al. ( ) . erythrocytes in pygmy and toggenburg goats tend to be more fragile than erythrocytes from other goat breeds. normal caprine erythrocytes lack central pallor because they are fiat and lack biconcavity. normal caprine erythrocytes may exhibit poikilocytosis. at least five blood groups have been reported in goats: b, c, m, r-o, and x. because transfusion reaction rates may be as high as - %, cross-matching is advisable although not always practical (smith and sherman, ) . blood loss of up to % of the red cell mass at a single time point can be tolerated by healthy goats. blood may safely be obtained in volumes of ml/kg body weight and given in volumes of - ml/kg. in general, aspartate aminotransferase (ast) and lactate dehydrogenase (ldh) are not liverspecific in goats, and alanine aminotransferase (alt; formally serum glutamic-pyruvic transaminase, or sgpt) cannot be used to evaluate hepatic disease in goats. ~,-glutamyltransferase (ggt) and alkaline phosphatase (ap) are associated with biliary stasis, and elevations in ggt are generally associated with hepatic damage. the nutritional needs of ruminants vary considerably according to the species, breed type, different phases of development, the use of the animals, location, and different stresses in their lives. for example, mineral requirements and other nutritional requirements vary even among breeds of cattle. several references are available that describe the varying requirements and are useful for determining the requirements of ruminants consistent with the parameters noted above and the type of feeds available (jurgens, ; "large animal clinical nutrition," ; nrc, nrc, , nrc, , nrc, , b "large animal internal medicine," ) . preformulated commercial feeds, concentrates, and supplements are available specifically for the different species of ruminants. some of these provide complete energy and protein requirements or may be used as supplements for what cannot be provided entirely by pasture, forage, hay, or silage. concentrate mixtures contain salt, minerals, and other elements. concentrates should contain a protein source such as soybean meal, cottonseed meal, or linseed meal. computer programs are also readily available for those who may need to formulate and balance rations. the palatability of feeds should be taken into account. mineral deficiencies and supplementation have been shown to influence several physiologic parameters such as immune function. introduction of young stock should include continuation of the feeding program of the source or gradual transition to appropriate feed for the animals available in the region of the research facility (nrc, ) . good-quality pasture can support ruminants under certain circumstances. lush spring pastures, especially pastures containing alfalfa, can induce bloat, diarrhea, grass tetany, or nitrate poisoning. ruminants not acclimated to lush pasture should be fed good-quality hay and slowly introduced to pasture environments. when ruminants have access to pasture, it is important to be aware of different eating habits. sheep and cattle are grazers. goats are browsers and will readily eat grasses, as well as seeds, nuts, fruit, and woody-stemmed plants. goats, however, can also be selective eaters and will only eat the leafy, more nutritious parts of the plant. therefore, goats have a tendency to "waste" hay. other eating habits should also be considered. finely ground concentrates are not tolerated well by goats; pelleted concentrates are preferred because the goat will pick out large particles in mixes. generally, goats do not prefer "sweet" feeds that contain molasses and do not need supplemental concentrates if a good-quality pasture or hay is fed. when given access to a salt block, goats generally are self-regulating. grass-fed goats and lactating goats may need supplementation with calcium and phosphorus, whereas alfalfa-fed goats do not (bretzlaff et al., ) . horse and sheep feeds may be fed to goats provided that the feed does not contain much molasses (bretzlaff et al., ) . the copper content of horse feed is not excessive for goats, as it is for sheep. pelleted horse feeds with - % fiber and - % protein are good goat rations. goats will consume - % of body weight in dry-matter intake (whereas cattle will usually consume only % of body weight). goats enjoy human contact, and small alfalfa cubes make tasty treats for the goat. rations that have excessive calcium-phosphorus ratios or elevated magnesium levels may induce urinary calculi in male ruminants. these may also occur when forage grasses are high in silicates and oxalates. to increase ovulation rate in does, some producers "flush" females by feeding . - lb concentrate per head per day for several weeks before and after the initiation of the breeding season. thin pregnant dairy goats should be fed lb concentrate per ) . - . ( . ) . - . potassium (k; mmol/l) hp . - . ( . ) . - . ( . ___ . ) . - . ( . adata presented as ranges with mean and standard deviation in parentheses, s, serum; p, plasma; hp, heparinized plasma. clinical biochemistry data from kaneko et al. ( ) . day, with the amount increasing to . lb per head per day during the last weeks of gestation. forage should be fed ad libitum during this time. all newborn ruminants must receive passive immunity from colostrum, the first postpartum milk of a dam that contains concentrated protective maternal antibodies (most as igg ), functional leukocytes, cytokines, vitamins, minerals, and protein. colostrum also has laxative properties. trypsin inhibitors in the colostrum allow the passage of intact antibody molecules, by pinocytosis, through the neonate's gut wall and into the bloodstream during the first few days after birth. the quality of the colostrum is directly related to herd or flock management, vaccination programs, and the dam's overall condition and nutrition throughout gestation and at the time of parturition. ensuring effective colostrum transfer is also dependent on the timing and amount taken by the neonate. most neonatal ruminants can suckle well within hr of birth. those that do so have been shown to have significantly less diarrhea (naylor, ) . neonates weakened by dystocia or hypothermia, for example, should be hand-fed or tube-fed colostrum. if necessary, the dam should be hand-milked and the newborn fed colostrum (for example, - ml for kids) every - hr for the first - days. in typical management situations, dairy calves either are separated from their dams immediately after birth and bottle-fed colostrum, or they remain with their dams for only about hr and suckle fresh colostrum during this time. dairy producers then refrigerate and/or freeze the colostrum that cannot be consumed by the calf during that time and then feed this diluted : with warm water times a day to the calves during the next - days. extra frozen colostrum for emergencies may be obtained from dairy farmers; it is advantageous to obtain colostrum from well-managed herds and from the multiparous cows in the herd (not heifers) in the same geographic locale. holstein calves, for example, should receive a minimum of - liters within hr of birth and then be fed about - % of body weight in colostrum by hr of age. after days, calves are then placed on milk replacers. although young ruminants generally do well receiving their dams' milk, commercially available milk replacers are available and should generally be prepared and fed according to the manufacturer's recommendations. containers used to prepare and feed these replacers should be sanitized daily. the fat content of both calf and lamb milk replacers is excessive; however, calf milk replacers can be used for kids if care is taken not to overfeed. young ruminants can be offered good-quality hay (such as second cutting) to nibble on by week of age. calves may be provided with calf starter, a commercially available concentrate with appropriate levels of energy and protein, fed according to the manufacturer's recommendations at - weeks of age. they can be weaned off milk replacer by - weeks of age. young ruminants ( - months of age) need good-quality forage as well as grain and concentrate supplementation to promote development of the rumen. in farm management situations, forage can be silage, pasture, and hay. in a confinement situation like a research unit, good-quality hay, such as second cutting, is desirable. animals should not be overfed and should be offered a mineral mix free-choice. in contrast to dairy calves, beef calves remain with their mother cows until weaning at months of age. calves tend to suckle many times per day. as they mature, calves are creepfed, with the energy and protein content of the ration determined by the milk production of the dams and by the available forage, such as pasture. several useful references addressing ruminant reproduction in detail are available ("current veterinary therapy: food animal practice," practice," , practice," , "large animal internal medicine," ; "current therapy in large animal theriogenology," ; hafez, ) . sheep are seasonally polyestrous; most breeds will express estrus in the fall (northern hemisphere) and subsequently lamb in the spring. some breeds of sheep may cycle in both the fall and the spring. between seasonal periods of receptivity, the females undergo a long period of sexual quiescence called anestrus. in a research environment, ewes can be artificially stimulated to progress from anestrous to estrous cyclicity by maintaining the females in hr of light and hr of dark for - weeks. puberty is reached at about - months (or earlier) in both rams and ewes; rams will typically reach puberty before their female counterparts. ewes will display signs of estrus for about - hr and will ovulate spontaneously at the end of estrus. the estrous cycle length is - days, with an average of about days. following breeding, the average length of gestation is - days. slightly longer gestations are observed in animals carrying single lambs (singlets), in animals carrying rams, and in certain breeds such as those derived from merinos. prolificacy, or the number of lambs produced per gestation, tends to be dependent on the maturity of the dam (older dams tend to have multiple lambs) and on breed characteristics (some fine-wool breeds have fewer multiple births). the finn and dorset breeds are especially prolific. lambs vary in size at birth from about - lb up to lb. factors that affect birthweight include parental size, number of lambs in the litter (fewer lambs or singlets tend to be larger), age of the ewe (younger ewes have smaller lambs), lamb gender (males tend to be heavier), nutrition, and season or temperature (spring lambs tend to be larger than fall lambs). goats are seasonally polyestrous in temperate regions, so that young are born in favorable times of the year. they are shortday breeders, in that estrus (heat) is brought about by the decreasing light of shorter days. in temperate climates of the northern hemisphere, goats are normally anestrous during the summer and begin cycling in the fall. the actual length of the sexual cycle depends on day length, breed, and nutrition. most dairy goats cycle between august and february or march. nubians often have extended breeding cycles, and the sexual season of some breeds, including the alpine, can be extended by artificial means. the caprine gestation length averages days with a variation of - days. does bear singletons, twins, and triplets, with slightly shorter gestation when the doe is carrying triplets. cows are polyestrous. domestication of cattle has included selection against seasonality of the breeding season, particularly in dairy breeds but to some extent also in the beef breeds. in spite of this, cattle have been found to be still sensitive, in varying manifestations, to photoperiodicity. reproductive physiology in cattle is influenced by many factors. the reproductive programs in source herds and at well-managed facilities will be production-related. extensive coverage of both physiologic basics and specific industry-related criteriamfor retention of a cow as a breeder, for examplenare addressed in detail in texts and references oriented toward herd and production management ("current veterinary therapy," ). gestation in cattle is approximately days, with a range of - days. the length of gestation in cattle is influenced by fetal sex; fetal numbers; age and parity of the cow; breed; genotype of cow, bull, or fetus; nutrition; and local environmental factors. as noted, these factors are also important in sheep and goats. cows usually bear single calves, although twin births do occur. when twins are combinations of male and female calves, the female should be evaluated for freemartinism. ovine estrus detection is usually accomplished by the ram. nonetheless, because artificial insemination is achievable in ewes, clinical signs of estrus are important. typically, ewes in heat will show a mild enlargement of the vulva, with slight increases of mucus secretion. ewes may isolate from the flock and appear anxious. it is often better and clearly more reliable to employ the help of a sterile ram to mark females when they are in standing heat. two mating systems commonly employed include hand mating and group mating. with hand mating, ewes are placed either singly or in small groups with the ram of choice. ewes are removed as serviced. group mating involves placement of a mature ram with approximately - ewes for the entire -week breeding season. in either mating system, it is best to attach a marking harness to the male so that individual ewes can be identified as serviced. this is important so that parturition dates can be calculated. an easy, natural way to estimate pregnancy is by placing sterile teaser rams with the ewes at the end of the breeding season. any animal marked by the ram probably has not conceived. ultrasound scanners are also used for pregnancy detection. the ultrasound transducer is placed against the right abdomen; presence of a fetus is indicated on the machine. claims of % accuracy at weeks postbreeding have been made, although accuracy is generally best beyond days of gestation. interrectal doppler ultrasound probes detect fetal pulses. fetal heart rate is in the range of - beats per minute, whereas maternal heart rates tend to be - beats per minute. accuracy is best beyond days of pregnancy. rectal-abdominal palpation is an inexpensive alternative. a plastic probe is introduced intrarectally into the ewe, which is restrained on her back in a cradle. the plastic probe is then manipulated toward the abdomen while palpating for the fetus with the opposite hand. the age of the doe when she first expresses heat varies with breed. some does will express signs of heat between and months old. however, does should be - months old or at least - lb in weight before being bred. the caprine estrous cycle lasts - days. the duration of estrus is - hr but averages about hr. the estrous cycle can be more erratic in the beginning than in the end of the breeding season (smith, season (with winter delaying), and the level of nutrition (with higher levels hastening puberty). in some cases, the presence of mature cycling cows influences heifer puberty. with adequate nutrition, dairy breeds will reach puberty at - months and beef breeds at - months, and estrous cycles will occur regularly after the pubertal (first) estrus, maturing heifers will often have one or more ovulations before showing overt signs of estrus. only one follicle usually ovulates per estrous cycle (hafez, ) estrus, or standing heat, in cattle averages - hr in length, with a range of - hr ("large animal internal medicine," ) . detection of standing heat is important because it is closely related to the time of ovulation. ovulation occurs approximately - hr after estrus. detection of estrus is usually accomplished by visual observation of vaginal mucous discharge, mounting behavior by other females (i.e., the cow standing to be mounted is the individual in estrus), and receptivity to a bull (willingness to stand). successful visual detection of standing heat is dependent on observation skills of handlers, knowledge of the herd, stresses (e.g., detection decreased in bos taurus during heat stress), barn and yard surfaces (estrus detected better on dirt than on concrete), and maintaining a consistent observation schedule. teaser animals outfitted with marking devices are also used. other methods of detecting estrus include monitoring progesterone levels; glass slide and other evaluations of cervical mucus; change in vaginal ph; and body temperature changes (hafez, ) . estrous cycles are usually days in length, with a range of - days. it is recommended that a heifer deliver her first calf by years of age. after successful conception, progesterone levels in the cow remain elevated for most of the pregnancy, as the result of the ). "standing heat" is usually - hr but can be as short corpus luteum of pregnancy, and they decline only during the as a few hours. signs of estrus in goats include uneasiness, tail switching or "flagging," redness and swelling of the vulva, clear vaginal discharge that becomes white by the end of estrus, vocalization such as continuous bleating, and occasionally riding and standing with other does. a doe that is not in heat will not stand to back pressure or for attempts to hold her tail. does can be induced to show signs of heat by buck exposure and will ovulate within - days after introduction of the buck. goats ovulate during the later part of the estrous cycle, most between - hr after the onset of estrus. nevertheless, goats should be mated once signs of estrus are recognized and every hr until the end of estrus. most goats kid only once a year, although some goats near the equator may kid twice. once bred successfully, a goat will only rarely show signs of heat again. in fact, the first sign of pregnancy is usually a failure to return to heat, so animals should be carefully watched. pregnancy can be affirmed by a variety of means. goats will generally decrease milk production with pregnancy and should have at least a -to -week dry period for the udder to fully involute and prepare for the next milking period. in cattle, age of first estrus is dependent on the breed, the final month. conceptus implantation occurs beginning at about day . if the pregnancy fails before this time, the cow will begin to cycle again between days - , but if the pregnancy ends after day , there may be a delayed return to estrus. realtime ultrasonography can be used to determine pregnancy as early as days after insemination, with embyros seen by days - . fetal gender can also be determined by experienced personnel by this method by about day . detection of pregnancy can be successful by - days after conception by observation of failure to return to estrus or by palpation per rectum (detecting fetal membrane slip by days - and/or amniotic vesicle by days - ). palpation of the fetus is possible by day and placentomes by approximately days - . palpation later in presumed pregnancy will provide information based on differences in size of the two uterine horns, changes in the uterine wall, and fremitus in the miduterine artery. pregnancy can also be determined with reasonable success rates by determining if progesterone levels are elevated at days - after insemination. levels of bovine pregnancy-specific protein b may also be measured; this is produced by trophoblastic cells and is detectable by days - and elevated throughout pregnancy. placentation in sheep, goats, and cattle is epitheliochorial and ft. evaluation of a cow's udder prior to breeding and especotyledonary, in contrast to the diffuse or microcotyledonary cially as parturition approaches is important in order to assure placentas of horses and pigs. the placentomes, the infolded adequate nutrition and success of passive transfer by the functional units of the placenta, are formed as the result of fu-neonate. if the udder is edematous or if mastitis is present, for sion of the villi of the fetal cotyledons projecting into the crypts example, an alternate source of colostrum (such as frozen reof the maternal caruncles (specialized projections of uterine " serves) must made be available. poor udder conformation may mucosa). caruncles of sheep and goats are concave in shape, whereas those of cows are convex. the placentomes are distributed between the pregnant and nonpregant horns of the uterus in sheep, and there are - . in cattle, although the placentomes initially develop around the fetus, they will eventually be distributed to the limit of the chorioallantoic membrane even in the nongravid horn. the placentomes in the nongravid horn will be smaller than in the gravid horn. the total number will be - . the best birthing preparation for all dams is to ensure a proper plane of nutrition (not overnutrition) and adequate exercise. if possible, the dam should be confined to a birthing pasture or sanitized maternity pen a few days prior to parturition. the birthing environment will be very important in the overall health of the dam and offspring; stress minimization and a clean environment will benefit the immune health of both in the short and long term. outdoor parturition in a small birthing pasture has advantages. there is less stress and less intensity of pathogens. indoor maternity pens should be clean, dry, warm, well bedded, well ventilated but draft-free, and well lighted. adequate space per pen minimizes losses of neonates from being stepped and sat on by the dam. management of these pens, especially if concentrated in an area, is important to minimize pathogens to which dam and young are exposed. water troughs or buckets should be elevated or placed outside the pen, because lambs and kids have a tendency to fall or be pushed into them. soiled bedding should be removed from the birthing pen between dams, the area sanitized and allowed to dry, and fresh bedding installed for the next occupant. moving the female immediately before or during parturition may delay the birthing process. in goats, furthermore, in utero death may occur if parturition is unduly delayed. dams should be monitored closely during parturition for dystocias; these may result in loss of young or in young severely weakened from the prolonged birthing process. prior to parturition, ewes should be sheared or crutched. crutching refers to removing wool around the perineal and mammary areas; this minimizes fetal contamination during the birth process. foot trimming can be done at this time as well. the tail and perineal area of the doe should be clipped and cleaned to improve postbirth sanitation. in general, the pregnant doe needs a ft ( . m x . m) area for the birthing process, and area needs to be increased after birthing to allow spacing for kids. each cow should have a minimum pen area of ft x also be problematic; contingency plans should be made to ensure adequate support for the young if they cannot suckle from those udders. inexperienced heifers may react indifferently or aggressively to their offspring and should be monitored more closely than older, multiparous cows with uneventful calving histories. ewes approaching parturition generally isolate themselves from the flock, become restless, stamp their feet, blat, and periodically turn and look at their abdomen. the pelvic region will appear relaxed, and milk will be present in the udder. once hard labor contractions begin, lambs will usually be born quickly. animals that do not appear to be progressing correctly should be examined for dystocia. most cases of fetal malpresentation or malpositioning can be corrected via vagino-uterine manipulation. occasionally cesarean sections will be necessary. sanitation, cleanliness, and adequate lubrication are of utmost importance when performing obstetrical procedures. for about a week before parturition, rectal temperature of the doe will be above normal, or about ~ depending on environmental temperatures. approximately hr prior to birth, rectal temperature will fall to slightly below normal. many large dairy-goat facilities attempt to control the onset of parturition in order to assist birthing. the drug of choice to induce parturition in the goat is prostaglandin f ~ (pgf ~) (ott, ) . on day of gestation, goats given pgf ~ ( . - mg) will deliver kids within - hr. most goats prefer to kid alone and do so unaided. human interaction can actually interfere with normal birthing, especially in young or nervous does. some does may reject kids if extensive human interference occurs. does nearing parturition have an obviously swollen udder and a red, swollen vulva. pelvic ligaments at the base of tail relax. the doe may circle to make a bed, get up and down, look at her tail or sides, push other goats away, and bleat softly. signs of impending parturition include restlessness; vocalization (bleating softly); uneasiness, including getting up and down, pawing, and bedding; and a mucous discharge, leading to a moist tail. eight to hr prior to parturition, the cervix will dilate and the cervical mucous plug will be evident as a tan, smeared substance on the tail and perineum of the dam. kids should present within - hr in either anterior or posterior position. a posterior presentation can be recognized by the presence of upward-pointing feet. most does will rest between fetuses and are best left alone. however, if labor is prolonged more than hr, a vaginal exam is indicated. if the pregnant goat is housed with other goats, then herdmates will express great interest in the dam. unless moved prior to parturition, it is best to leave the dam with the group until after parturition, because removal may delay parturition. goats are not prone to retained placenta. normal kids will be quite active and will quickly attempt to stand and nurse. weak kids should be towel-dried, warmed (via heat lamp, heat pad, or warm water bottle), and assisted to nurse or fed colostrum. the goat is one of the few ungulate species that will exhibit "false pregnancy," or pseudopregnancy. this is a fairly common condition. does may have characteristically distended abdomens and may develop hydrometra and "deliver" large volumes of cloudy fluid at expected due dates. subsequent pregnancies can be normal. goats should be tested for pregnancy by days of age. veterinary use of prostaglandins has been successful in treating this condition. as in other species, parturition in cattle results from a combination of hormonal changes associated with the maturity of the fetus, notably acth (adrenocorticotropic hormone) and subsequent increases in fetal corticosteriods within days of birth. administration of acth to a fetus, or administration to the dam, results in premature birth. pregnancy is extended if fetal pituitary or adrenal glands are removed surgically. the fetal cortisol probably affects placental steroid production, accounting for sharp increases in the estrogens and estrogen precursors. coincident with this, maternal progesterone levels fall. the rising levels of estrogen cause release of maternal pgf ~ and induction of oxytocin receptors. most cows will separate themselves from the rest of the herd. a cow will lift her tail and arch her back when she is within a few hours of delivering the calf, and most cows are recumbent when delivering the calf. typically, the whole birthing process takes about min. the length of labor of cows carrying larger calves also will be longer. nervous heifers will take longer to deliver, and if they are disturbed, their labor may cease. all postparturient animals should be monitored for successful passage of these fetal membranes within hr of birth. veterinary intervention is required if not. cows occasionally eat placentas, which may subsequently obstruct rumen outflow and require surgical correction. for cattle, it is now recommended practice to remove membranes that have passed, in order to prevent ingestion. following lambing, it is critical that the newborns be "processed" so that they will have greatest survival chances. in a well-managed flock, many lambs and ewes will not need much assistance. when assistance is given, the newborn lamb's nose and mouth should be wiped free of secretions; gently swinging the lambs, head down, aids in removal of these fluids. the lamb should be dried off and stimulated through rubbing to aid its breathing. the lamb's navel should be dipped in an iodine solution to prevent subsequent navel infections. and the lamb should be identified by the application of an ear tag or ear notch. it is extremely important that the lamb be supplied with highquality colostrum within the first hr of birth. lambs that are not nursing on their own should be tube-fed with colostrum that has been collected and saved previously (i.e., frozen in ice cube trays) or collected from the mother after parturition. passive transfer can be assessed by measuring serum y-glutamyltransferase (ggt) levels (tessman et al., ) . after the first few days, colostrum changes over to milk. nursing lambs will ingest increasing amounts of milk as they grow. if the ewe cannot produce sufficient milk, the lamb should be "grafted" onto another ewe or fed artificially with a baby bottle. powdered milk replacers are commercially available; the content of ewe milk is much different from that of cow's milk; thus lamb milk replacer should specifically be used. one report notes that - % of lamb deaths occur during the first week of life and up to % occur within the first month. good management of ewes during gestation, care of the lamb at parturition, application of an appropriate vaccination program, and observation and intervention within the first several weeks of a lamb's life will minimize losses (ross, ) . immediately after birth, the placenta and any birthing materials should be removed from the doe's pen. kids do not usually need assistance. if kids are to be raised by the dam, they can be left alone; otherwise, kids should be towel-dried and removed from the dam. kids are cold-sensitive and may require a heat lamp or other source of added warmth in cold weather. navel cords should be dipped in tincture of iodine, and kids should be dehorned and castrated within the first several days of life. to control caprine arthritis encephalitis (cae), kids should be immediately removed from the dam and hand-fed heattreated colostrum. colostrum should be heat-treated for hr at ~ e the first feeding can be up to ml of colostrum. kids should receive a total of ml colostrum within the first - hr of birth. after day , kids can be placed on milk replacer. milk replacers should contain - % fat and - % milkbased protein. by days of age, kids should be consuming approximately . - . liters of milk per day. kids should be introduced to forages as soon as possible and may be weaned by - weeks or - lb body weight. milk that is fed can be reduced by weeks of age by decreasing either the volume fed or the number of feedings. as with other dams, a cow is usually very attentive to her newborn calf, cleaning and softly vocalizing to the neonate. calves typically are standing by hr after birth and are suckling within hr. as noted previously, dairy calves may be removed from the cow even before suckling, and the colostrum milked from the dam and given to the calf. assistance may be required for nervous heifers, after dystocias and in extreme circumstances such as severe cold. cleaning the newborn's nose and mouth, rubbing down the neonate, assuring that the calf does not get chilled, and assuring that it receives adequate colostrum are all important under any of these circumstances. a stressed calf's umbilical may be treated with an iodine or chlorhexidine solution, although some authors note no benefit of navel treatment, specifying that successful transfer of passive immunity and sound sanitary management of birthing area are the most crucial factors in preventing omphalitis (navel ill) (house, ; kersting, ; kasari and roussel, ) . because newborn calves can be deficient in vitamin a and iron, these may be injected to improve disease resistance (wikse and baker, ) . in cases in which the dams' colostrum is known to be deficient in antibodies against common diseases, vaccinations may be administered at day old and followed with boosters at regular intervals. dehorning is performed when horn buds appear. castration is performed between and weeks of age or later. sexing the young in any of the ruminant species is straightforward. the vulva of the female young is located just ventral to the anus. the genitalia of the male include a penis, located along the ventral midline, and a scrotum, located in the inguinal region. the phenomenon of the freemartin, a genetic female born as a twin to a male, is the result of anastomoses between placental circulations of the twin fetuses; the mixing of bloodforming cells and germ cells results in the xx/xy chimeras. this occurs in - % of phenotypic bovine females born as co-twins with males. the female will often have abnormal vulva and clitoris, and the vagina will be a blind end because of the lack of a cervix. sometimes singleton freemartins are born if the male fetus is lost after days' gestation. multiple births are selected for and are common in sheep; the freemartin phenomenon is regarded as rare. twinning is common in goats, and freemartinism occurs in about % of male-female pairs of twins. intersexes are seen in some goat breeds and when polled goats are mated. proof is usually based on evidence of abnormal genital development and reports of abnormal sexual behavior. prior to weaning, it must be established that lambs can nutritionally survive without mother's milk. thus, grain, and later roughage, should be offered to lambs well in advance of the day of weaning so that they can adjust to the feedstuff. to prevent the ewes from ingesting the lamb ration, a "creep" should be set up by building an area adjacent to the ewe-lamb pen and devising a slatted entry for the lambs to enter but not the ewes. therefore, the lambs will be accustomed to the new ration through this creep-feeding process. if lambs and ewes will be pastured later in the spring, it is still beneficial to creep-feed lambs until pasture growth is adequate enough to fulfill the requirements of the growing lambs. lambs that are consuming . - lb of creep feed per day may be weaned. depending on the individual program, lambs may be weaned as early as weeks of age, although - weeks of age is more common. if ewes are of a breed that will cycle twice a year, and if it is expected that they will be rebred, then the lambs must be weaned as early as possible so that lactational anestrus will resolve and ewes will recycle. another factor is the cost of lactation rations for the ewes; if lamb grain is more economical than ewe grain, then lambs should be weaned. about - days prior to weaning, feeding of the lactation ration to the ewes should be discontinued, and only roughage fed. at weaning, the lambs should be removed in the creep, and the ewes removed to an area that is not within sight (and preferably sound) of the lambs. the ewes should be monitored for postweaning mastitis and treated as necessary. ewes that have physical or disease problems or that have not been productive at lambing or feeding their lambs should be culled. the lambs should be monitored to assure that they continue to gain weight and are eating the new ration. kids should be introduced to forages within the first week of life because the natural curiosity of these animals will cause them to investigate sources of feed. kids can be weaned by - weeks or - lb. hand-fed milk should be reduced by weeks of age by reducing the volume fed or by decreasing the number of feedings. dairy calves are now usually removed from their dams immediately after birth. it is less common now to allow the calves to remain with their dams for about hr and suckle fresh colostrum during this time, because their intake will be inadequate. dairy producers refrigerate and/or freeze the colostrum produced during the first hr and feed this, diluted : with warm water, twice a day to the calves during the next - days. holstein calves, for example, should receive a minimum of - liters within hr of birth and then be fed about - % of body weight in colostrum by hr of age. after days, calves are then placed on milk replacers, preformulated powders reconstituted with water that provide complete nutrition. milk replacers are commercially available and should be fed according to manufacturer's recommendations vaccination programs for calves vary with the preventive medicine program for the overall herd. passive immunity provided by colostrum from cows on sound management programs will last until a calf is about - months old; normally vaccinations are not necessary and are contraindicated during those first months. the duration of passive immunity varies considerably among calves, however; some producers choose to begin vaccinating calves at - months of age and continue with monthly booster immunizations until the animals are months old, when passive immunity is no longer a possibility. artificial insemination (ai) in sheep is more difficult than in cattle because sheep are smaller and cannot be reproductively manipulated via the rectum and because the cervix of sheep is more difficult to traverse with the insemination pipette. breeding animals artificially with fresh semen produces pregnancy rates averaging % (not unlike that of cattle); artificial insemination with frozen semen is less successful. several artificial insemination techniques have been used. laparoscopic ai involves the surgical instillation of semen into the uterus through a small abdominal opening. the procedure is successful but is technically involved and costly. cervical ai involves the transvaginal introduction of semen into the cervix. a modification of this technique (transcervical ai) allows for penetration through the cervix into the uterus. this method (called the guelph system for transcervical ai) leads to successful penetration into the uterus in up to % of ewes when performed by an experienced inseminator. artificial insemination is now an integral part of dairy herding; natural insemination as a management practice is relatively rare. technicians performing the ai technique are available through commercial enterprises. dairy production employees are also trained. information regarding the management of the donors and recipients, the storage and handling of the semen, and the skills and record keeping required is covered extensively elsewhere (nebel, ) . because sheep are hormonally similar to other ruminants, estrous synchronization techniques are comparable. progesterone suppresses follicle-stimulating hormone (fsh) secretion, preventing animals from developing follicles and exhibiting estrus. artificial or natural progesterone can be administered in the feed, through parenteral injection, subcuticular implants, and vaginal pessaries. the progesterone is withdrawn in about - days, after which the fsh secretion will initiate the process of follicle development (trower, ) . estrus usually will occur in - hr (average is hr). a natural method of synchronization, often applied to promote flock breeding within a short period of time (and thus parturition will be within a narrow window as well), is the introduction of sterile rams with the ewes before the beginning of the normal fall mating period. pheromones released from males naturally stimulate the females to cycle and to synchronize their heats. it should be noted that introduction of a male during late anestrus will often stimulate ovulation in about days; however, this cycle will generally be without clinical signs of estrus (silent heat). vasectomy of rams is one method of producing sterile "teaser rams." introduction of the buck to a group of does will induce ovulation and may even synchronize does. does that are kept separate from the buck will show signs of estrus, will ovulate within - days, and will have normal pregnancies when introduced to a buck. bucks with horns and intact scent glands are better able to induce ovulation than dehorned bucks, whose scent glands often been removed. control of breeding in the goat has been studied mostly in dairy breeds in order to produce milk throughout the year and to reduce kidding labor. goats in the luteal phase of the estrous cycle, days - , are sensitive to pgf ~ ( . - mg im) and will show estrus in - hr postinjection (bretzlaff, ) . dosing cycling animals twice days apart will synchronize goats, and artificial insemination using this method has resulted in - % conception rates (bretzlaff, ; greyling and van niekerk, ) . programs for timed breeding have been described and involve administering progestogens (bretzlaff, ) . vaginal pessaries of fluorogestone acetate left in place for days in the doe followed by an injection of pregnant mare serum gonadotropin (pmsg) at the time of pessary removal have proven successful. also, when primed by pgf ~, an day regimen of fluorogestone acetate with pmsg given on day has been successful. synchronization of cattle estrous cycles and superovulation are used as management techniques in certain commercial cattle and dairy production settings where estrus synchronization or embryo transfer is advantageous to production and management. the methodology is also used in the research setting for coordinating donors and recipients of embryos or other genetically manipulated tissues for implantation. the options and dosing regimens are described in detail in veterinary clinical texts (wenzel, ; vanderboom et al., ) . in synchronization, the principle is lysis of the existing corpus luteum. the more common practices involve the use of products approved for use in cattle such as pgf ~, one of its analogs, or products containing estradiol valerate. progestogens are also used in conjunction with estradiol valerate. other approaches, involving management techniques combined with pharmacologic interventions, are considered less successful. superovulation regimens involve injections of fsh either alone or with pgf ~ at timed internals. estrus is expected hr after the final injection, and two inseminations are performed at hr intervals after estrus detection. preparation of recipients involves injection of pgf ~ or progestogens with gonadotropins such as pmsg. for greatest success as management tools, these must be combined with a consistent program that provides appropriate nutrition for all cattle involved. synchronization of animals is also influenced by several other factors, however, such as time in the cycle when hormones are administered, response by each individual animal, whether the cow is a dairy or beef animal, parity and maturity of the cows, success of heat detection after the luteolysis, and accurate record keeping. embryo transfer involves the removal of multiple embryos from a superovulated embryo donor and transferring them to synchronized recipients. this method maximizes the genetic potential of the donor animal. the donor animal is hormonally superovulated and inseminated. in sheep, about week after breeding, the embryos are surgically removed from the donor's uterus. in cattle, the procedure is nonsurgical. about % of expected embryos (determined by counting corpora lutea) can be recovered; successful recovery is affected by factors such as age of the donor, reproductive health, and experience of the surgeon or technician. furthermore, not all collected embryos are of transferable quality. recipients are hormonally synchronized with the donor animals. on the day of embryo collection, transferable embryos are implanted into the uterus of the recipient; laparoscopy has been used in the past and is now being replaced by nonsurgical methods. pregnancy rates average about %. if recipients are not available, embryos, like sperm, can be frozen and kept for later transfer. embryo transfer is commonly practiced in cattle as a herd improvement technique and as a research technique for engineered embyros. disease screening programs for all animals involved are important because several pathogens can be transmitted directly or indirectly, such as bovine viral diarrhea virus, bluetongue virus, infectious bovine rhinotracheitis virus, and mycoplasmal species. in sheep flocks and goat herds, as noted, male young are usually castrated by month of age. the elastrator method is the more popular for animals less than week of age. other methods include the emasculatome (crushing) and surgical removal ("knife method"). the distress associated with castration and tail docking in lambs is the subject of debate and has been researched recently (kent et al., ) . as noted, male calves are usually castrated as early as possible and no later than month of age. in some production situations, however, where maximum hormone responsive muscle development and grouping animals together for procedures dictate scheduling, the procedure may be performed on older males. open and closed techniques are used, depending on the age of animals and on veterinary or farm practice. breeding and vasectomized rams and bucks are usually maintained by medium to large production farms. smaller farms often borrow breeding males. breeding males are typically selected by production record, pedigree, and/or breed. vasectomized males are often retired breeders and should be tattooed or identified clearly to avoid any wasted breeding time. the vasectomy technique for both species is comparable (smith and sherman, ) . rams may be housed together for most of the year, whereas bucks are penned separately. because ewes will exhibit only a limited number of estrous cycles before becoming reproductively quiescent, it is critical that the male be capable of successfully breeding the female in an expeditious manner. any defects in the external genitalia, reproductive diseases, or musculoskeletal abnormalities may prevent successful copulatory behaviors. furthermore, it is impor-tant to know the semen quality of the ram as one indicator of fertility. semen can be collected via electroejaculation or by use of a teaser mount. once semen is collected, it should be handled carefully and kept warm to prevent sperm death, leading to improper conclusions about the male. typically, the characteristics usually evaluated as a determinate of sperm quality are volume (normal between . and . ml); motility (% of sperm moving in a forward wave; high quality is associated with motility of approximately %); concentration (sperm count per unit of volume as measured by a hemocytometer; high-quality semen should contain . x sperm per ml); morphology (live versus dead cells, as determined by special stains and the percentage of abnormal-appearing sperm; neither the abnormalities nor the dead sperm should exceed % in high-quality semen). the extensive use of artificial insemination in the dairy cattle industry has minimized the use of bulls on many farms, although a farm may maintain a few bulls for heat detection and for "cleanup" breeding. breeding bulls are maintained in beef production establishments. breeding bulls must be part of the herd vaccination program, with special attention to appropriate timing of immunizations for the commonly transmitted venereal diseases campylobacteriosis and trichomoniasis. tail docking is a relatively recent development in dairy herd management and is practiced in the belief that it will minimize bacterial contamination of the udder and therefore the milk. tails are typically docked to about inches in length. the practice is more popular in certain regions in the united states. to date, there is no published study indicating that this technique provides any distinctive advantage over keeping the tail switch hair clipped short. healthy ruminants have good appetites, chew cud, are alert and curious, have healthy intact coats, move without hindrance, and have clear, bright, clean eyes and cool dry noses. even adult animals, when provided sufficient space, will play. sheep and goats have tidy "pelleted" dark green feces. cattle have pasty, moist, dark green-brown feces. ruminants normally vocalize, and handlers will learn to recognize normal communication among the group or directed at caregivers in contrast to that when animals are stressed. excessive, strained vocalizations are often a sign of stress in cattle. "bruxism," or grinding of the teeth by a ruminant, is usually associated with discomfort or pain. other signs of discomfort, stress, or illness include decreased time spent eating and cud chewing, restlessness, prolonged recumbency with outstretched neck and head, and hunched back when standing. unhealthy ruminants may be thin, may arch their backs or favor a limb, or may have external lumps or swollen joints, an unusual abdominal profile, or rough or dull coats. all ruminants are herd animals to some extent and social individuals; therefore, every effort should be made to allow contact among animals, in terms either of direct contact or of sound, smell, or sight. human contact and handling should be initiated promptly and maintained regularly and consistently throughout the animal's stay in the research facilities. animals should be provided sufficient time to acclimate to handlers and research staff. cattle and sheep can hear at higher frequencies than humans can and may react to sounds not perceived by handlers. knowledge of the peculiarities of sheep behavior will increase the ease of handling and decrease stress-related effects in research. generally, fine-wooled breeds, such as rambouillet, are the most gregarious and are best handled in groups. the meat, or "downs," breeds tend to be less gregarious, and the long-wooled breeds tend to be solitary (ross, ; asia, ) . nonetheless, movement of animals is simplified by proper facility design. sheep have a wide-angle visual field and are easily scared by activities that are taking place behind them. sheep should be moved slowly and gently. to capture individuals within a flock, it is best to confine the flock to a smaller space and use a shepherd's crook or to gently catch the animal in front of the neck/thorax. grabbing the wool can injure the animals, as well as damage the wool and the underlying tissues. sheep move best in chutes that have solid walls, and individual animals will generally follow a lead animal. any escape route will be challenged and, if successfully breached, will disrupt the entire flock movement. sheep movement is also disrupted by contrasts such as light and shadows that impinge on a chute or corral. finally, like most animals, sheep have a flight zone (minimum zone of comfort), the penetration of which will result in sheep scattering. this minimal flight distance can be modified by increasing handling of the animals and working at the edge of the zone, but it should always be considered when working with animals in chutes, pens, or other confined areas. goats exhibit behavioral characteristics that make them quite distinct from other ruminants. their browsing activity makes them quite orally investigative. goats will readily nibble or chew just about anything they come in contact with, so researchers should keep all paperwork and equipment out of reach. a herd of goats will readily chew through wood gates and fencing, especially when confined in areas without alternatives for chewing behavior. goats are also inquisitive, restless, agile jumpers and climbers, and quite mischievous. if maintained in paddocks, strong high fences are essential, as are adequate spaces for exercise or boulders or rock piles for hoof maintenance and recreational climbing. goats are more tolerant of isolation and are more easily acclimated to human contact than sheep are, but goats will confront unfamiliar intruders and make sneezing noises. goats with horns will use them to advantage, and horns may also become entangled in fencing. although less strongly affected by flock behavior, goats are social animals. most goats raised in close human contact are personable and cooperative and can easily be taught to stand for various procedures, including blood collection. an understanding of breed behaviors, sources of stress in cattle, play behaviors, calf behaviors, and dominance determinants will contribute to prevention of injuries to handlers and better health and welfare of the animals. ruminants of all ages, especially cattle of all ages, should be handled with an appreciation of the serious injury to human handlers that may result (houpt, ) . cattle have a wide visual field, as sheep do, and a flight zone that varies in size, according to previous handling experiences (gentle handling and animal tameness make the flight zone smaller) and the circumstances of the moment (grandin, ) . groups of cattle are moved effectively around a facility by utilizing chute systems, with sequences of gates, that minimize chances of animals turning around. dairy cattle have been bred and selected over centuries for their docile, tractable characters and production characteristics. in contrast, beef breeds have not been selected for docility and are generally more difficult to handle and restrain. beef breeds, such as angus, are known for their independent natures and protective maternal instincts. all cattle respond well to feed as a reward for desired behavior. healthy cattle typically are very curious and watchful and are alert to sounds and smells. when not grazing or eating, they hold their heads up. when sleeping, the head and neck may be tucked back. because of ruminant digestive and metabolic needs, much of the day is spent eating or cud chewing. occasionally, adult cows sit upright like dogs. cattle maintained inside tend to be more docile. in addition to forced isolation from other cattle, sources of stress include rough attitudes of handlers and unfamiliar visual patterns, routines, or environments. these stressors may exacerbate signs of systemic illnesses. calves are known for non-nutritive suckling, bar licking, and tongue rolling. non-nutritive suckling behavior is greater in hungry calves and also right after a milk meal. it is best to provide nipples and other clean noninjurious materials for the animals to suck. non-nutritive suckling can be detrimental in group-housed calves because it can result in disease transmission and hair ball formation. environmental enrichment devices have been developed to cope with this behavior. the behavior diminishes as the animals are weaned onto solid food (morrow-tesch, ) . play activity and vocalizations of calves mimic adult dominance behaviors. play activity by young adult cattle is more common in males, can be quite rough, and is often triggered by a change in the environment. dominance behaviors are dependent on direct physical contact among the cattle, and dominance hierarchies are established within a herd. horns, age, and weight have been reported to be the most important determi-nants. aggressive behaviors in cattle may be triggered by newly introduced animals or unfamiliar visual patterns and by feeding when animals are very hungry. aggression is more common among intact adult males. this section focuses primarily on the more common diseases affecting sheep, goats, and cattle in the united states and elsewhere in north america and those that are reportable. for detailed information not included in this limited overview and for diseases of importance internationally, the authors recommend several excellent comprehensive and focused veterinary clinical texts and periodicals that address ruminant diseases, preventive medicine, and individual and flock or herd management. these are listed under "major references" in the reference list at the end of this chapter. recommendations for current drug therapies, both approved and off-label use in ruminants, including withholding prior to slaughter, formularies, and related information can be found in the references noted above and in formularies (hawk and leary, ; plumb, ) . in addition, the food animal residue avoidance databank (farad), accessible on the internet <http://www.farad.org>, should be used as a resource. farad is a food safety project of the u.s. department of agriculture and is an information resource to prevent drug and pesticide residues in food animals and animal products. food; may be anorexic, weak, unthrifty and depressed; and may salivate excessively. diagnosis is made based on clinical signs and is confirmed by culture. epizootiology and transmission. the organism penetrates wounds of the skin, mouth, nose, gastrointestinal tract, testicles, and mammary gland. rough feed material and foreign bodies may play a role in causing abrasions. actino bacillus lignieresii then enters into deeper tissues, where it causes chronic inflammation and abscess formation. lymphatic spread may occur, leading to abscessation of lymph nodes or infection of other organs. necropsy findings. purulent discharges of white-green exudate drain from the tracts that often extend from the area of colonization to the skin surface. exudates will also contain characteristic small white-gray (sulfurlike) granules. the pus is usually nonodorous. differential diagnosis. contagious ecthyma and caseous lymphadenitis are the primary differentials. diseases or injuries causing oral pain and discomfort, such as dental infections, foreign bodies, and trauma, should be considered. treatment. animals should be fed softer feeds. antibiotics such as sulfonamides, tetracyclines, and ampicillin are effective, although high doses and long durations of therapy are required. penicillin is not effective. weekly systemic administration of sodium iodide for several weeks is not as effective as antibiotic therapy. surgical excision and drainage are not recommended. etiology. actinobacillus lignieresii is an aerobic, nonmotile, non-spore-forming, gram-negative rod that is widespread in soil and manure and is found as normal flora of the respiratory, gastrointestinal, and reproductive tracts of ruminants. in sheep and cattle, a. lignieresii causes sporadic, noncontagious, and potentially chronic disease characterized by diffuse abscess and granuloma formation in tissues of the head and occasionally other body organs. this disease, called wooden tongue, has not been documented in goats. clinical signs. skin lesions are common. tongue lesions are more common in cattle than in sheep. lip lesions are more common in sheep. soft-tissue or lymph node swelling accompanied by draining tracts is observed in the head and neck regions, as well as other areas. animals may have difficulty prehending prevention and control. because the organism enters through tissue wounds, especially those associated with oral trauma, feedstuffs should be closely monitored for coarse material and foreign bodies. b. arcanobacterium infection (formerly actinomycosis, or "lumpy jaw") etiology. arcanobacterium (formerly known as actinomyces or corynebacterium) pyogenes and a. bovis are anaerobic, nonmotile, non-spore-forming, gram-positive, pleomorphic rods to coccobacilli. arcanobacterium bovis is a normal part of the ruminant oral microflora and is the organism associated with "lumpy jaw" in cattle; this syndrome is rarely seen in sheep and goats. this organism has also been associated with pharyngitis and mastitis in cattle. clinical signs and diagnosis. arcanobacterium bovis causes mandibular lesions primarily. the mass will be firm, nonpainful, and immovable. draining tracts may develop over time. if teeth roots become involved, painful eating and weight loss are evident. radiographic studies are helpful for determining fistulas. diagnosis is based on clinical signs, and culture is required to confirm arcanobacterium. the prognosis is poor for lumpy jaw. epizootiology and transmission. these organisms are normal flora of the gastrointestinal tracts of ruminants and gain entrance into the tissues through abrasions and penetrating wounds. necropsy. draining lesions with sulfurlike granules (as with actinobacillosis) are frequently observed. ious degrees of depression and anorexia, and purulent discharges may be seen draining from the umbilicus. involvement of the urachus is usually followed by cystitis and associated signs of dysuria, stranguria, hematuria, and so on. severe sequelae may include septicemia, peritonitis, septic arthritis (joint ill), meningitis, osteomyelitis, and endocarditis. research complications. young stock affected by omphalophlebitis may be inappropriate subjects because of growth setbacks and physiologic stresses from the infection. affected adult animals will not thrive and, even with therapy, may not be appropriate research subjects. pathogenesis. arcanobacterium pyogenes is known to produce an exotoxin, which may be involved in the pathogenesis. differential diagnosis. actinobacillus lignieresii and caseous lymphadenitis are important differentials for draining tracts. a major differential for omphalophlebitis is an umbilical hernia, which will typically not be painful or infected. there are many differentials for septic joints and polyarthritis: chlamydia spp., mycoplasma spp., streptococci, coliforms, erysipelothrix rhusiopathiae, fusobacterium necrophorum, and salmonella spp. tumors, trauma to the affected area, such as the mandible, and dental disease or oral foreign body should also be considered. prevention and control. arcanobacterium bovis lesions can be prevented or minimized by feeds without coarse or sharp materials. treatment. penicillin or derivatives such as ampicillin or amoxicillin are treatments of choice. sodium iodides (intravenous) and potassium iodides (orally) have been utilized also. extended antibiotic therapy may be necessary. surgical excision is an option. in addition to medications noted above, isoniazid is somewhat effective for a. bovis infections in nonpregnant cattle. research complications. the possibility of long-term infection and long therapy are factors that will diminish the value of affected research animals. omphalophlebitis, omphaloarteritis, omphalitis, and navel ill are terms referring to infection of the umbilicus in young animals. arcanobacterium pyogenes is the most common organism causing omphalophlebitis, an acute localized inflammation and infection of the external umbilicus. most cases occur within the first months of age, and animals are presented with a painful enlargement of the umbilicus. animals may exhibit var- etiology. bacillus anthracis is a nonmotile, capsulated, sporeforming, aerobic, gram-positive bacillus that is found in alkaline soil, contaminated feeds (such as bonemeal), and water. common names for the disease anthrax include woolsorters' disease, splenic fever, charbon, and milzbrand. clinical signs and diagnosis. anthrax is a sporadic but very serious infectious disease of cattle, sheep, and goats characterized by septicemia, hyperthermia, anorexia, depression, listlessness, depression, and tremors. subacute and chronic cases may occur also and are characterized by swelling around the shoulders, ventral neck, and thorax. the incubation period is day to weeks. bloody secretions such as hematuria and bloody diarrhea often occur. abortion and blood-tinged milk may also be noted. the disease is usually fatal, especially in sheep and goats, after - days. death is the result of shock, renal failure, and anoxia. diagnosis is based on the clinical signs of peracute deaths and hemorrhage. stained blood smears may show short, single to chained bacilli. blood may be collected from a superficial vein and submitted for culture. epizootiology and transmission. cattle and sheep tend to be affected more commonly than goats, because of grazing habits. older animals are more vulnerable than younger, and bulls are more vulnerable than cows. although the disease occurs worldwide, and even in cold climates, most cases in the united states occur in the central and western states, and outbreaks usually occur as the result of spore release after abrupt climatic changes such as heavy rainfall after droughts or during warmer, dryer months. spores survive very well in the environment. the anthrax organisms (primarily spores) are generally ingested, sporulate, and replicate in the local tissues. abrasive forages may play a role in infection. transmission via insect bites or through skin abrasions rarely occurs. necropsy. necropsies should not be done around animal pens or pastures, and definitive diagnoses may be made without opening the animals. incomplete rigor mortis, rapid putrefaction, and dark, uncoagulated blood exuding from all body orifices are common findings. blood collected carefully and promptly from peripheral veins of freshly dead animals can be used diagnostically. splenomegaly, cyanosis, epicardial and subcutaneous hemorrhages, and lymphadenopathy are characterisitic of the disease. pathogenesis. the rapidly multiplying organisms enter the lymphatics and bloodstream and result in a severe septicemia and neurotoxicosis. encapsulation protects the organisms from phagocytosis. liberated toxins cause local edema. differential diagnosis. although anthrax should always be considered when an animal healthy the previous day dies acutely, other causes of acute death in ruminants should be considered, e.g., bloat, poisoning, enterotoxemia, malignant edema, blackleg, and black disease. prevention and control. outbreaks must bereported to state officials. anthrax is of particular concern as a bioterrorism agent. any vaccination programs should also be reviewed with regulatory personnel. herds in endemic areas and along waterways are usually vaccinated routinely with the sterne-strain spore vaccine (virulent, nonencapsulated, live). careful hygiene and quarantine practices are crucial during outbreaks. dead animals and contaminated materials should be incinerated or buried deeply. biting insects should be controlled. the disease is zoonotic and a serious public health risk. treatment. treatment of animals in early stages with penicillin and anthrax antitoxin (hyperimmune serum, if available) may be helpful. amoxicillin, erythromycin, oxytetracycline, gentamicin, and fluoroquinolones are also good therapeutic agents. during epidemics, animals should be vaccinated with the sterne vaccine. research complications. natural and experimental anthrax infections are a risk to research personnel; the pathogen may be present in many body fluids and can penetrate intact skin. the organism sporulates when exposed to air, and spores may be inhaled during postmortem examinations. etiology. brucella is a nonmotile, non-spore-forming, nonencapsulated, gram-negative coccobacillus. brucella abortus is one of several brucella species that infects domestic animals but cross-species infections occur rarely. brucella abortus or b. melitensis may cause brucellosis in sheep, cattle, and goats. brucella melitensis (biovar , , or ) is the primary cause of sheep disease (garin-bastuji et al., ) . brucella ovis is more commonly associated with ovine epididymitis or orchitis than abortion. in the united states, clusters of brucellosis are still found in western areas contiguous to yellowstone national park. bang's disease is the common name given to the disease in ruminants. clinical signs and diagnosis. brucella melitensis in the adult ewe is generally asymptomatic and self-limiting within about months. however, because the organism may enter and cause necrosis of the chorionic villi and fetal organs, abortion or stillbirths may occur. abortion usually occurs in the third trimester, after which the ewe will appear to recover. it has been reported that up to % of infected ewes may abort more than once. rams will also be infected and may develop orchitis or pneumonia. the disease caused by b. ovis is manifested by clinical or subclinical infection of the epididymis, leading to epididymal enlargement and testicular atrophy. brucella ovis causes decreased fertility. brucella melitensis is the more common cause of brucellosis in goats. brucella abortus has been shown to infect goats in natural and experimental infections, and b. ovis has also been shown to infect goats experimentally. does infected with b. melitensis will also abort during the third trimester. infections with b. abortus in cattle produce few clinical signs. there may be a brief septicemia during which organisms are phagocytosed by neutrophils and fixed macrophages in lymph nodes. in cows, the organism localizes in supramammary lymph nodes and udders and in the endometrium and placenta of pregnant cows. infection may cause abortions after the fifth month, with resulting retained placentas. permanent infection of the udder is common and results in shedding of organisms in milk. in bulls, the organism may cause unilateral orchitis and epidydimitis and involvement of the secondary sex organs. organisms may be in the semen. in infected herds, lameness may also be a clinical sign. diagnosis of brucellosis can be made by bacterial isolation of the brucella organism from necropsy samples (especially the fetal stomach contents), as well as by supportive serological evidence. many serological tests are available, such as the tube and plate agglutination tests, the card or rose bengal test, the rivanol precipitation test, complement fixation, enzyme-linked immunosorbent assay (elisa), polymerase chain reaction (pcr), and others. test selection is often dependent on state requirements in the united states. epizootiology and transmission. the primary route of transmission of b. abortus is ingestion of the organism from infected tissues and fluids (milk, vaginal and uterine discharges) during and for a few weeks after abortion or parturition; contaminated semen is considered to be a minor source of infection. exposure to the organism may occur via the gastrointestinal tract (contaminated feed or water), the respiratory tract (droplet infection), or the reproductive tract (contaminated semen) and through other mucous membranes such as the conjunctiva. brucella ovis is transmitted in the semen, as well as orally or nasally through contaminated feed and bedding. necropsy findings. a sheep fetus aborted due to brucella will exhibit generalized edema. the liver and spleen will be swollen, and serosal surfaces will be covered with petecchial hemorrhages. peritoneal and pleural cavities often contain serofibrinous exudates. the placenta will be leathery. pathogenesis. ruminants are considered especially susceptible to brucella infection, because of higher levels of erythritol (a sugar alcohol), which is a growth stimulant for the organism. brucella utilizes erythritol preferentially over glucose as an energy source. placentas and male genitalia also contain high levels of erythritol. brucella organisms also evade lysis when phagocytosed by macrophages and neutrophils and survive intracellularly in phagosomes. abortion is the result of placentitis, typically during the third trimester of gestation. brucella ovis enters the host through the mucous membranes, then passes into the lymphatics, causes hyperplasia of reticuloendothelial cells, and is spread to various organs via the blood. the organism localizes in the epididymides, the seminal vesicles, the bulbourethral glands, and the ampullae. orchitis may be a sequelae of the disease. epididymitis can be diagnosed by identifying gross lesions by palpation of the epididymides, by serological evidence of antibodies to b. ovis, and by semen cultures. differential diagnosis. differential diagnoses include all other abortion-causing diseases. many other agents, such as actinobacillus spp., arcanobacterium (actinomyces) pyogenes, eschericia coli, pseudomonas spp., proteus mirabilis, chlamydia, mycoplasma, and others may be associated with ovine epididymitis and orchitis. a clinically and pathologically similar agent, actinobacillus seminis, has been isolated from virgin rams. this organism has morphological and staining characteristics similar to those of b. ovis and complicates the diagnosis (genetzky, ) . prevention and control. the rev vaccine has been recommended for vaccination of ewe lambs in endemic areas, but this vaccine is not used in the united states. separating young rams from potentially infected older males, sanitizing facilities, and vaccinating them with b. ovis bacterin can prevent the disease. over the past years, aggressive federal and state regulatory and cattle herd health programs in the united states have provided control and prevention mechanisms for this pathogen through a combination of serological monitoring of herds, slaughter of diseased animals, herd management, vaccination programs, and monitoring of transported animals. most states are considered brucellosis-free in the cattle populations; thus, procurement of ruminants that have been exposed to this infectious agent will be unlikely. cattle vaccination programs can be very successful when conducted on a herd basis to reduce likelihood of exposure. strain and the recently validated attentuated strain rb are live vaccines and can be used in healthy heifer calves - months old. vaccination for older animals may be done under certain circumstances. vaccination of bull calves is not recommended, because of low likelihood of spread through semen and possibility of vaccination-induced orchitis. the strain vaccine induces long-term cell-mediated immunity, protects a herd from abortions, and protects the majority of a herd from reactors during a screening and culling program. the vaccine will not, however, protect the animals from becoming infected with b. abortus. strain vaccine induces an antibody response in cattle. the rb vaccine does not result in antibody titers and therefore is advantageous because infection with brucella can be determined serologically. the rb vaccine has been designated as the official calfhood bovine brucellosis vaccine in the united states by the u.s. department of agriculture's animal and plant health inspection service (aphis) (stevens et al., ) . brucella vaccine should be administered to unstressed, healthy cattle, with attention to particular side effects of the vaccination material and to prevention of compounding stresses associated with weaning, regrouping, other management changes, and shipping. the rb is regarded as less pathogenic and abortigenic in cattle. clinical signs and diagnosis. ovine vibriosis is a contagious disease that causes abortion, stillbirths, and weak lambs. the organism inhabits the intestines and gallbladder in subclinical carriers. abortion generally occurs in the last trimester, and abortion storms may occur as more susceptible animals, such as maiden ewes, become exposed to the infectious tissues. it is reported that - % of the flock may become infected and up to % of the ewes will die (jensen and swift, ) . some lambs may be born alive but will be weak, and dams will not be able to produce milk. diagnosis is achieved by microscopic identification or isolation of the organism from placenta, fetal abomasal contents, and maternal vaginal discharges. tentative identification of the organism can be made by observing curved ("gull-wing") rods in giemsa-stained or ziehl-neelsen-stained smears from fetal stomach contents, placentomes, or maternal uterine fluids. epizootiology and transmission. campylobacteriosis occurs worldwide. campylobacter spp., such as c. jejuni, normally inhabit ovine gastrointestinal tracts. transmission of the disease occurs through the gastrointestinal tract, followed by shedding, especially associated with aborted tissues and fluids. in abortion storms, considerable contamination of the environment will occur due to placenta, fetuses, and uterine fluids. ewes may have active campylobacter organisms in uterine discharges for several months after abortion. the bacteria will also be shed in feces, and feed and water contamination serve as another source. there is no venereal transmission in the ovine. necropsy. aborted fetuses will be edematous, with accumulation of serosanguinous fluids within the subcutis and muscle tissue fascia. the liver may contain - cm pale foci. placental tissues will be thickened and edematous and will contain serous fluids similar to those of the fetus. the placental cotyledons may appear gray. pathogenesis. the organism enters the bloodstream and causes a short-term bacteremia ( - weeks) prior to the localizing of the bacteria in the chorionic epithelial cells and finally passing into the fetus. should be considered in late gestation ovine abortions. a bacterin is available to prevent the disease. carrier states have been cleared by treating with a combination of antibiotics, including penicillin and oral chlortetra-cycline. aborting ewes should be isolated immediately from the rest of the flock. after an outbreak, ewes will develop immunity lasting - years. treatment. infected animals should be isolated and provided with supportive therapy. prompt decontamination of the area and disposal of the aborted tissues and discharges are important. research complications. losses from abortion may be considerable. campylobacter ssp. are zoonotic agents, and c. fetus subsp, intestinalis may be the cause of "shepherd's scours." ii. clinical signs and diagnosis. preliminary signs of a problem in the herd will be a high percentage of cows returning to estrus after breeding and temporary infertility. this will be particularly apparent in virgin heifers that may return to estrus by days after breeding. long interestrous intervals also serve an indication of a problem. spontaneous abortions will occur in some cases, typically during the fourth to eighth months of gestation. severe endometritis may lead to salpingitis and permanent infertility. demonstration or isolation of the organism, a curved rod with corkscrew motility, is the basis for diagnosis. the vaginal mucous agglutination test is used to survey herds for campylobacteriosis. serology will not be worthwhile, because the infection does not trigger a sufficient antibody response. culture from breeding animals may be difficult because campylobacter will be overgrown by faster-growing species also present in the specimens. epizootiology and transmission. the bacteria is an obligate, ubiquitous organism of the genital tract. transmission is from infected bulls to heifers. older cows develop effective immunity. necropsy findings. necrotizing placentitis, dehydration, and fibrinous serositis will be found grossly. in addition, bronchopneumonia and hepatitis will be seen histologically. pathogenesis. campylobacter organisms grow readily in the genital tract, and infection is established within days of exposure. the resulting endometritis prevents conception or causes embyronic death. differential diagnosis. the primary differential diagnosis for campylobacteriosis is trichomoniasis. other venereal diseases should be considered when infertility problems are noted in a herd. these include brucellosis, mycoplasmosis, ureaplasmosis, infectious bovine rhinotracheitis-infectious pustular vulvovaginitis (ibr-ipv), and bovine virus diarrhea (bvd). leptospirosis should also be considered. in addition, management factors such as nutrition and age of heifers at introduction to the herd should be considered. prevention and control. killed bacterin vaccines are available, either as oil adjuvant or as aluminum hydroxide adsorbed. the former is preferred because of duration of immunity but causes granulomas. that vaccine also has specific recommendations regarding administration several months before the breeding season. the latter product is administered closer to the breeding season, and the duration of immunity is not as prolonged. in both cases, boosters should be given after the initial immunization and as part of the regular prebreeding regimen. only one bacterin product is approved for use in bulls. many combination vaccine products contain only the aluminum hydroxide adsorbed product. artificial insemination (ai) is particularly useful at controlling the disease, but bulls used for ai must be part of a screening program for this and other venereal diseases such as trichomoniasis. treatment. cows will usually recover from the infection, and treatment with antibiotics such as penicillin, administered as an intrauterine infusion, improve the chances of returning to breeding condition. etiology. the most common caprine bacterial skin infection is caused by staphylococcus intermedius or s. aureus and is known as staphylococcal dermatitis (smith and sherman, ) . the staphylococcus organisms are cocci and are categorized as primary pathogens or ubiquitous skin commensals of humans and animals. staphylococcus aureus and s. intermedius are classified as primary pathogens and produce coagulase, a virulence factor. clinical signs and diagnosis. small pustular lesions, caused by bacterial infection and inflammation of the hair follicle, occur around the teats and perineum. occasionally, the infection may involve the flanks, underbelly, axilla, inner thigh, and neck. staphylococcal dermatitis may occur secondary to other skin lesions. diagnosis is based on lesions. culture will distinguish s. aureus. pathogenesis. simple boredom may cause rubbing, followed by staphylococcal infection of damaged epidermis. differential diagnosis. the presence of scabs makes contagious ecthyma a differential diagnosis, along with fungal skin infections and nutritional causes of skin disease. treatment. severe infections should be treated with antibiotics based on culture and sensitivity. severe lesions and lesions localized to the underbelly, thighs, and udder benefit by periodic cleaning with an iodophor shampoo and spraying with an antibiotic and an astringent (smith and sherman, ) . h. clostridial diseases i. clostridium perfringens type c infection (enterotoxemia and struck) etiology. clostridium perfringens is an anaerobic, grampositive, nonmotile, spore-forming bacterium that lives in the soil, in contaminated feed, and in gastrointestinal tracts of ruminants. the bacteria is categorized by toxin production. toxins include alpha (hemolytic), beta (necrotizing), delta (cytotoxic and hemoltyic), epsilon, and iota. types of c. perfingens are a, b, c, d, and e. this is a common and economically significant disease of sheep, goats, and cattle. clinical signs and diagnosis. the beta toxin associated with overgrowth of this bacterium results in a fatal hemorrhagic enterocolitis within the first hr of a young ruminant's life. many animals may be found dead, with no clinical presentation. affected animals are acutely anemic, dehydrated, anorexic, restless, and depressed and may display tremors or convulsions as well as abdominal pain. feces may range from loose gray-brown to dark red and malodorous. morbidity and mortality may be nearly %. a similar noncontagious but acutely fatal form of enterotoxemia in adult sheep, called struck, occurs in yearlings and adults. struck is rare in the united states. the disease is also caused by the beta toxin of c. perfringens type c and is often associated with rapid dietary changes or shearing stresses in sheep. although affected animals are usually found dead, clinical signs include uneasiness, depression, and convulsions. mortality is usually less than %. diagnosis is usually based on necropsy findings, although confirmation can be made by culture of the organism. identification of the beta toxin in intestinal contents may be difficult because of instability of the toxin. necropsy findings. necropsy findings include a milk-filled abomasum, and hemorrhage in the distal small intestine and throughout the large intestine. petechial hemorrhages of the serosal surfaces of many organs, especially the thymus, heart, and gastrointestinal tract, will be visible. hydropericardium, hydroperitoneum, and hemorrhagic mesenteric lymph nodes will also be present. pulmonary and brain edema may also be seen. histologically, the gram-positive c. perfringens organisms may be visible in excess numbers along the mucosal surface of the swollen, congested, necrotic intestines. in cases of struck, necropsy findings include congestion and erosions of the mucosa of the gastrointestinal tract, serosal hemorrhages, and serous peritoneal and pericardial fluids. in late stages of the disease and especially if prompt necropsy is not performed, the organism will infiltrate the muscle fascial layers and produce serohemorrhagic and gaseous infiltration of perimysial and epimysial spaces. pathogenesis. hemorrhagic enterotoxemia is an acute, sporadic disease caused by the beta toxin of clostridium perfringens type c. neonates ingest the organism, which then proliferates and attaches to the gastrointestinal microvilli and elaborates primarily the beta toxins. the trypsin inhibitors present in colostrum prevent inactivation of the beta toxin. the toxins injure intestinal epithelial cells and then enter the blood, leading to acute toxemia. the intestinal injury may result in diarrhea, with small amounts of hemorrhage. associated electrolyte and water loss result in dehydration, acidosis, and shock. differential diagnosis. differential diagnoses include other clostridial diseases such as blackleg and black disease, as well as coccidiosis, salmonellosis, anthrax, and acute poisoning. clinical signs in chronic cases in older animals, such as adult goats, include soft stools, weight loss, anorexia, depression, and severe diarrhea, sometimes with mucus and blood. mature affected sheep may be blind and anorectic and may head-press. necropsyfindings. necropsy findings are similar to those seen with c. perfringens type c. additionally, extremely necrotic, soft kidneys ("pulpy kidneys") are usually observed immediately following death. (this phenomenon is in contrast to what is normally associated with later stages of postmortem autolysis.) focal encephalomalacia, and petechial hemorrhages on serosal surfaces of the brain, diaphragm, gastrointestinal tract, and heart are common findings. diagnosis can be made from the typical clinical signs and necropsy findings as well as the observation of glucose in the urine at necropsy. shock, probably through vascular damage. the noncontagious, peracute form of enterotoxemia occurs in suckling, fast-growing animals, either nursing from their dams or on high-protein, high-energy concentrates. the largest, fastest-growing animals generally are predisposed to this condition; for example, lambs, fat ewe lambs, and usually singleton lambs tend to be most susceptible. the hyperglycemia and glucosuria seen in acute cases are due to epsilon toxin effects on liver glycogen metabolism. should be administered to the pregnant animals prior to parturition. an alternative includes administration of an antitoxin to the newborn lambs. the disease may become endemic once it is on the premises. treatment. treatment is difficult and usually unsuccessful. antitoxin may be useful in milder cases, and the antitoxin and toxoid can also be administered during an outbreak. differential diagnosis. tetanus, enterotoxigenic e. coli, botulism, polioencephalomalacia, grain overload, and listeriosis are differentials. prevention and control. vaccination prevents the disease. maternal antibodies last approximately weeks postpartum; thus young animals should be vaccinated at about this time. feeding regimens to young, fast-growing animals and feeding of concentrates to adults should be evaluated carefully. research complications. this disease can be costly in losses of neonates and younger animals. treatment. treatment consists of support (fluids, warmth), antitoxin administration, oral antibiotics, and diet adjustment. toxin that is proteolytically activated by trypsin. this disease caused by c. perfringens tends to be associated with sheep and is of less importance in goats and cattle. clinical signs. the peracute condition in younger animals is characterized by sudden deaths, which are occasionally preceded by neurological signs such as incoordination, opisthotonus, and convulsions. because the disease progresses so rapidly to death (within - hr), clinical signs are rarely observed. hypersalivation, rapid respirations, hyperthermia, convulsions, and opisthotonus have been noted. in acute cases, hyperglycemia and glucosuria are considered almost pathognomonic. etiology. clostridium tetani is a strictly anaerobic, motile, spore-forming, gram-positive rod that persists in soils and manure and within the gastrointestinal tract. at least serotypes of c. tetani exist. clinical signs. infection by c. tetani is characterized by a sporadic, acute, and fatal neuropathy. after an incubation period of days to weeks, the animal exhibits bloat; muscular spasticity; prolapse of the third eyelid; rigidity and extension of the limbs, leading to a stiff gate; an inability to chew; and hyperthermia. erect or drooped ears, retracted lips, drooling, hypersensitivity to external stimuli, and a "sawhorse" stance are frequent signs. the animal may convulse. death occurs within - days, and mortality is nearly %, primarily from respiratory failure. diagnosis is based on clinical signs. musclerelated serum enzymes such as aspartate aminotransferase (ast), creatinine kinase (ck), and lactate dehydrogenase (ldh) might be elevated. (jensen and swift, ) . serum cortisol may also be elevated, and stress hyperglycemia may be evident. permanent lameness may result in survivors. contaminant and is often found as part of the gut microflora of herbivores. the organisms sporulate and persist in the environment. all species of livestock are susceptible, but sheep and goats are more susceptible than cattle. individual cases may occur, or herd outbreaks may follow castration, tail docking, ear tagging, or dehorning. mouth wounds may also be sites of entry. pathogenesis. tetanus, or lockjaw, is caused by the toxins of c. tetani. all serovars produce the same exotoxin, which is a multiunit protein composed of tetanospasmin, which is neurotoxic, and tetanolysin, which is hemolytic. a nonspasmogenic toxin is also produced. contamination of wounds results in anaerobic proliferation of the bacterium and liberation of the tetanospasmin, which diffuses through motor neurons in a retrograde direction to the spinal cord. the toxin inhibits the release of glycine and y-aminobutyric acid from renshaw cells; this resuits in hypertonia and muscular spasms. proliferation of c. tetani in the gut of affected animals may also serve as a source and may produce clinical signs. the uterus is the most common site of infection in postparturient dairy cattle with retained placentas. differential diagnoses. early in the course of the infection, differential diagnoses include bloat, rabies, hypomagnesemic tetany, polioencephalomalacia, white muscle disease, enterotoxemia in lambs, and lead poisoning. polyarthritis of cattle is a differential for the gait changes in that species. necropsy findings. findings are nonspecific except for the inflammatory reaction associated with the wound. because of the low number of organisms necessary to cause neurotoxicosis, isolation of c. tetani from the wound may be difficult. administering tetanus antitoxin (e.g., at least iu in an adult sheep or goat); vaccinating with tetanus toxoid; administering of antibiotics (penicillin, both parenterally [potassium penicillin intravenously and procaine penicillin intramuscularly] and flushed into the cleaned wound), a sedative or tranquilizer (e.g., acepromazine or chlorpromazine) and a muscle relaxant; and keeping the animal in a dark, quiet environment. supportive fluids and glucose must be administered until the animal is capable of feeding. if the animal survives, revaccination should be done days after the previous dose. prevention and control like other ubiquitous clostridial diseases, tetanus is impossible to eradicate. the disease can be controlled and prevented by following good sanitation measures, aseptic surgical procedures, and vaccination programs. tetanus toxoid vaccine is available and very effective for stimulating long-term immunity. tetanus antitoxin can be administered ( iu in lambs) as a preventive or in the face of disease as an adjunct to therapy. both the toxoid and the antitoxin can be administered to an animal at the same time, but they should not be mixed in the syringe, and each should be administered at different sites, with a second toxoid dose administered weeks later. animals should be vaccinated or times during the first year of life. does and ewes should receive booster vaccinations within months of parturition to ensure colostral antibodies. research complications. unprotected, younger ruminants may be affected following routine flock or herd management procedures. contaminated or inadequately managed open wounds or lesions in older animals may provide anaerobic incubation sites. etiology. clostridium novyi, an anaerobic, motile, sporeforming, gram-positive bacteria, is the agent of bighead and black disease. clostridium novyi type d (c. hemolyticum) is the cause of bacillary hemoglobinuria, or "red water." clostridium chauvoei is the causative agent of blackleg. clinical signs. bighead is a disease of rams characterized by edema of the head and neck. the edema may migrate to ventral regions such as the throat. additional clinical signs include swelling of the eyelids and nostrils. most animals will die within - hours. black disease, or infectious necrotic hepatitis, is a peracute, fatal disease associated with c. novyi. it is more common in cattle and sheep but may be seen in goats. the clinical course is - days in cattle and slightly shorter in sheep. otherwise healthy-appearing adult animals are often affected. clinical signs are rarely seen, because of the peracute nature of the disease. occasionally, hyperthermia, tachypnea, inability to keep up with other animals, and recumbency are observed prior to death. bacillary hemoglobinuria is an acute disease seen primarily in cattle and characterized by fever and anorexia, in addition to the hemoglobinemia and hemoglobinuria indicated by the name. animals that survive a few days will develop icterus. mortality may be high. blackleg, a disease similar to bighead, causes necrosis and emphysema of muscle masses, serohemorrhagic fluid accumulation around the infected area, and edema (jackson et al., ) . blackleg is more common in cattle than in sheep. the incubation period is - days and is followed by hyperthermia, muscular stiffness and pain, anorexia, and gangrenous myositis. the clinical course is short, - hr, and untreated animals invariably die. blackleg in cattle can be associated with subcutaneous edema or crepitation; these do not usually occur in sheep. most lesions are associated with muscles of the face, neck, perineum, thigh, and back. epizootiology and transmission. bighead is caused by the toxins of c. novyi, which enters through wounds often associated with horn injuries during fighting. the c. novyi type b organisms produce alpha and beta toxins, and the alpha toxins are mostly responsible for toxemia, tissue necrosis, and subsequent death. clostridium novyi type d is endemic in the western united states. it is hypothesized that the c. chauvoei organisms enter through the gastrointestinal tract. black disease and bacillary hemoglobinuria are associated with concurrent liver disease, often associated with fasciola infections (liver flukes); it is sometimes seen as a sequela to liver biopsies. the diseases are more common in summer months, and fecal contamination of pastures, flooding, and infected carcasses are sources of the organism. birds and wild animals may be vectors of the pathogen. ingested spores are believed to develop in hepatic tissue damaged and anoxic from the fluke migrations. necropsy. diagnosis of black disease is usually based on postmortem lesions. subcutaneous vessels will be engorged with blood, resulting in dried skin with a dark appearance. carcasses putrefy quickly. in addition, hepatomegaly and endocardial hemorrhages are common, and hepatic damage from flukes may be so severe that diagnosis is difficult. blood coagulates slowly in affected animals. pathogenesis. the propagation of the clostridial organisms is self-promoted by the damage caused by the toxins and the increased local anaerobic environment created. clostridium novyi proliferates in the soft tissues of the head and neck, and the resultant clostridial toxin causes increased capillary permeability and the liberation of serous fluids into the tissues. mixed infections with related clostridial organisms may lead to increasing hemorrhage and necrosis in the affected tissues. diagnosis is based on clinical signs. in black disease and bacillary hemoglobinuria disease, the ingested clostridial spores are absorbed, enter the liver, and cause hepatic necrosis. associated toxemia causes subcutaneous vascular dilatation; increased pericardial, pleural, and peritoneal fluid; and endocardial hemorrhages. the toxins produced by c. novyi, identified as beta, eta, and theta, and each having enzymatic or lytic properties or both, also contribute to the hemolytic disease. clostridium chauvoei spores proliferate in traumatized muscle areas damaged by transportation, rough handling, or injury. differential diagnosis. differential diagnoses include other clostridial diseases as well as photosensitization. hemolytic diseases such as babesiosis, leptospirosis, and hemobartonellosis should be included as differentials. treatment. for c. chauvoei infection (blackleg), early treatment with penicillin or tetracycline may be helpful. treatment for black disease is not rewarding even if the animal is found before death. carcasses from bacillary hemoglobinuria losses should be burned, buried deeply, or removed from the premises. prevention and control. vaccinating animals with multivalent clostridial vaccines can prevent these diseases. subcutaneous administration of vaccine material is recommended over intramuscular. vaccinations may be useful in an outbreak. careful handling of ruminants during shipping and transfers will contribute to fewer muscular injuries. for bighead, mature rams penned together should be monitored for lesions, especially during breeding season. control of fascioliasis is very important in prevention and control of black disease and in the optimal timing of vaccinations. etiology. clostridium septicum is the species usually associated with malignant edema, but mixed infections involving other clostridial species such as c. chauvoei, c. novyi, c. sordellii, and c. perfringens may occur. clostridium spp. are motile (c. chauvoei, c. septicum) or nonmotile, anaerobic, spore-forming, gram-positive rods. clinicial signs. malignant edema, or gas gangrene, is an acute and often fatal bacterial disease caused by clostridium spp. the incubation period is approximately - days. the affected area will be warm and will contain gaseous accumulations that can be palpated as crepitation of the subcutaneous tissue around the infected area. regional lymphadenopathy and fever may occur. the animal becomes anorexic, severely depressed, and possibly hyperthermic. edema and crepitation may be noted around the wound; death occurs within hr to days. epizootiology and transmission. the organisms are ubiquitous in the environment and may survive in the soil for years. the disease is especially prevalent in animals that have had recent wounds such as those that have undergone castration, docking, ear notching, shearing, or dystocia. necropsy findings. the tissue necrosis and hemorrhagic serous fluid accumulations resemble those of other clostridial diseases. pathogenesis. in most cases, the clostridial organisms cause a spreading infection through the fascial planes around the area of the injury; vegetative organisms then produce potent exotoxins, which result in necrosis (alpha toxin) and/or hemolysis (beta toxin). furthermore, the toxins enter the bloodstream and central nervous system, resulting in systemic collapse and high mortality. necropsy. spreading, crepitant lesions around wounds are suggestive of malignant edema. affected tissues are inflamed and necrotic. gas and serosanguineous fluids with foul odors infiltrate the tissue planes. large rod-shaped bacteria may be observed on histopathology; confirmation is made through culture and identification. intramuscular inoculation of guinea pigs causes a necrotizing myositis and death. organisms can be cultured from guinea pig tissues. treatment. infected animals can be treated with large doses of penicillin and fenestration of the wound is recommended. prevention and control. proper preparation of surgical sites, correct sanitation of instruments and the housing environment, and attention to postoperative wounds will help prevent this disease. multivalent clostridial vaccines are available. research complications. morbidity or loss of animals from lack of or unsuccessful vaccination and from contaminated surgical sites or wounds may be consequences of this disease. etiology. escherichia coli is a motile, aerobic, gram-negative, non-spore-forming coccobacillus commonly found in the environment and gastrointestinal tracts of ruminants. escherichia coli organisms have three areas of surface antigenic complexes (o, somatic; k, envelope or pili; and h, flagellar), which are used to "group" or classify the serotypes. colibacillosis is the common term for infections in younger animals caused by this bacteria. clinical signs. presentation of e. coli infections vary with the animal's age and the type of e. coli involved. enterotoxigenic e. coli infection causes gastroenteritis and/or septicemia in lambs and calves. colibacillosis generally develops within the first hr of life when newborn animals are exposed to the organism. the enteric infection causes a semifluid, yellow to gray diarrhea. occasionally blood streaking of the feces may be observed. the animal may demonstrate abdominal pain, evidenced by arching of the back and extension of the tail, classically described as "tucked up." hyperthermia is rare. severe acidosis, depression, and recumbancy ensue, and mortality may be as high as %. the septicemic form generally occurs between and weeks of age. animals display an elevated body temperature and show signs suggestive of nervous system involvement such as incoordination, head pressing, circling, and the appearance of blindness. opisthotonos, depression, and death follow. occasionally, swollen, painful joints may be observed with septicemic colibacillosis. blood cultures may be helpful in identifying the septicemic form. in ruminants, e. coli is is a less common cause of cystitis and pyelonephritis. the cystitis is characterized by dysuria and pollakiuria; gross hematuria and pyuria may be present. the infection may or may not be restricted to the bladder; in the later presentation, and in cases of pyelonephritis, a cow will be acutely depressed, have a fever and ruminal stasis, and be anorexic. in chronic cases, animals will be polyuric and undergo weight loss. escherichia coli may also cause in utero disease in cattle, resulting in abortion or weakened offspring. epizootiology and transmission. escherichia coli is one of the most common gram-negative pathogens isolated from ruminant neonates. zeman et al. ( ) classify e. coli infections into four groups: enterotoxigenic, enterohemorrhagic, enteropathogenic, and enteroinvasive. enterotoxigenic e. coli (etec) attach to the enterocytes via pili, produce enterotoxins, and are the primary cause of colibacillosis in animals and humans. fimbrial (pili) antigens associated with ovine disease include k and f . enterohemorrhagic e. coli (ehec) attach and efface the microviuus, produce verotoxins, and occasionally cause disease in humans and animals. enteropathogenic e. coli (epec) colonize and efface the microvillus but do not produce verotoxins. epec are associated with disease in humans and rabbits and cause a secretory diarrhea. enteroinvasive e. coli (eiec) invade the enterocytes of humans and cause a shigella-like disease. overcrowding and poor sanitation contribute significantly to the development of this disease in young animals. the organism will be endemic in a contaminated environment and present on dams' udders. the bacteria rapidly proliferate in the neonates' small intestines. the bacteria and associated toxins cause a secretory diarrhea, resulting in the loss of water and electrolytes. if the bacteria infiltrate the intestinal barrier and enter the blood, septicemia results. diagnosis of the enteric form can be made by observation of clinical signs, including diarrhea and staining of the tail and wool. necropsy findings. swollen, yellow to gray, fluid-filled small and large intestines, swollen and hemorrhagic mesenteric lymph nodes, and generalized tissue dehydration are common. septicemic lambs may have serofibrinous fluid in the peritoneal, thoracic, and pericardial cavities; enlarged joints containing fibrinopurulent exudates; and congested and inflamed meninges. isolation and serotyping of e. coli confirm the diagnosis. elisa and latex agglutination tests are available diagnostic tools. differential diagnosis. differential diagnoses include the enterotoxemias caused by c. perfringens type a, b, or c; campylobacter jejuni; coccidia, rotavirus, coronavirus, salmonella, and cryptosporidia. other contributing causes of abomasal tympany in young ruminants, such as dietary changes, copper deficiency, excessive intervals between feedings of milk replacer, or feeding large volumes should be considered. prevention and control. the best preventive measures are maintenance of proper housing conditions, limiting overcrowding, and frequently sanitizing lambing areas. attention to colostrum feeding techniques and colostral quality are important means of preventing disease. treatment must include intravenous fluid hydration and reestablishment of acid-base and electrolyte abnormalities. treatment. antibiotics such as trimethoprim-sulfadiazine, enrofloxacin, cephalothin, amikacin, and apramycin may be helpful; oral antibiotics are not recommended. vaccines are available for prevention of colibacillosis in cattle. etiology. corynebacterium pseudotuberculosis (previously c. ovis) are nonmotile, non-spore-forming, aerobic, short and curved, gram-positive coccobacilli. caseous lymphadenitis (cla) is such a common, chronic contagious disease of sheep and goats that any presentation of abscessing and draining lymph nodes should be presumed to be this disease until proven otherwise. the disease has been reported occasionally in cattle. clinical signs and diagnosis. abscessation of superficial lymph nodes, such as the superficial cervical, retropharyngeal, subiliacs (prefemoral), mammary, superficial inguinals, and popliteal nodes, and of deep nodes, such as mediastinal and mesenteric lymph nodes, is typical. radiographs may be helpful in identifying affected central nodes. peripheral lymph nodes may erode and drain caseous, "cheesy," yellow-green-tan secretions. the incubation period may be weeks to months. over time, an infected animal may become exercise-intolerant, anorexic, and debilitated. fever, increased respiratory rates, and pneumonia may also be common signs. exotoxin-induced hemolytic crises may occur occasionally. morbidity up to % is common, and morbid animals will often eventually succumb to the disease. diagnosis is based on clinical lesions; elisa serological testing is also available. smears of the exudate or lymph nodes aspirates can be gram-stained. lymph node aspirates may also be sent for culturing. epizootiology and transmission. the organism can survive for months or more in the environment and enters via skin wounds, shearing, fighting, castration, and docking. ingestion and aerosolization (leading to pulmonary abscesses) have been reported as alternative routes of entry. necropsy findings. disseminated superficial abscesses as well as lesions of the mediastinal and mesenteric lymph nodes will be identified. cut surfaces of the affected lymph nodes may appear lamellated. lungs, liver, spleen, and kidneys may also be affected. cranioventral lung consolidation with hemorrhage, fibrin, and edema are seen histologically. pathogenesis. corynebacterium pseudotuberculosis produces an exotoxin (phospholipase d) that damages endothelial and blood cell membranes. this process enhances the organisms' ability to withstand phagocytosis. the infection spreads through the lymphatics to local lymph nodes. the necrotic lymph nodes seed local capillaries and hematogenously and lymphatically spread the organisms to other areas, especially the lungs. differential diagnosis. differentials include pathogens causing lymphadenopathy and abscessation. treatment. antibiotic therapy is not usually helpful. abscesses can be surgically lanced and flushed with iodinecontaining and/or hydrogen peroxide solutions. abscessing lymph nodes can be removed entirely from valuable animals. during warmer months, an insect repellent should be applied to and around healing lesions. all materials used to treat animals should be disposed of properly. because of the contagious nature of the disease, animals with draining and lanced lesions should be isolated from cla-negative animals at least until healed. commercial vaccines are available (piontkowski and shivvers, ) . minimizing contamination of the environment, using proper sanitation methods for facilities and instruments, segregating affected animals, and taking precautions to prevent injuries are all important. research complications. this pathogen is a risk for animals undergoing routine management procedures or invasive research procedures, because of its persistence in the environment, its long clinical incubation period, and its poor response to antibiotics. etiology. corynebacterium renale, c. cystitidis, and c. pilosum are sometimes referred to as the c. renale group. these are piliated and nonmotile gram-positive rods and are distinguished biochemically. corynebacterium renale causes pyelonephritis in cattle, and c. pilosum and c. cystitidis cause posthitis, also known as pizzle rot or sheath rot, in sheep and goats. in many references, all these clinical presentations are attributed to c. renale. clinical signs and diagnosis. acute pyelonephritis is characterized by fever, anorexia, polyuria, hematuria, pyuria, and arched back posture. untreated infections usually become chronic, with weight loss, anorexia, and loss of production in dairy animals. relapses are common, and some infections are severe and fatal. diagnosis of pyelonephritis is based on urinalysis (proteinuria and hematuria) and rectal or vaginal palpation (assessing ureteral enlargement). urine culturing may not be productive. in chronic cases, e. coli and other gram-negatives may be present. posthitis and vulvovaginitis are characteriazed by ulcers, crusting, swelling and pain. the area may have a distinct malodor. necrosis and scarring may be sequelae of more severe infections. fly-strike may also be a complication. diagnosis is based on clinical signs and on investigation of feeding regimens. epizootiology and transmission. ascending urinary tract infections with cystitis, ureteritis, and pyelonephritis are widespread problems, but incidence is relatively low. the vaginitis and posthitis contribute to the venereal transmission, but indirect transmission is possible because the organisms are stable in the environment and present on the wool or scabs shed from affected animals. posthitis occurs in intact and castrated sheep and goats. necropsy findings. pyelonephritis, multifocal kidney abscessation, dilated and thickened ureters, cystitis, and purulent exudate in many sections of the urinary tract are common finding at gross necropsy. of bovine genitourinary tracts. the pilus mediates colonization. conditions such as trauma, urinary tract obstruction, and anatomic anomalies may predispose to infection. in addition, more basic ph urine levels may block some immune defenses. infections ascend through the urinary tract. the bacteria are urease-positive when tested in vitro, and the ammonia produced in vivo during an infection damages mucosal linings, with subsequent inflammation. corynebacterium cystitidis and c. pilosum are normally found around the prepuce of sheep and goats. high-protein diets, resulting in higher urea excretion and more basic urine, are contributing factors. posthitis and vulvovaginitis may develop within a week of change to the more concentrated or richer diet, such as pasture or the addition of high-protein forage. the ammonia produced irritates the preputial and vulvar skin, increasing the vulnerability to infection. differential diagnosis. urolithiasis is a primary consideration for these diseases. contagious ecthyma should be considered for the crusting that is seen with posthitis and vulvovaginitis, although the lesions of contagious ecthyma are more likely to develop around the mouth. ovine viral ulcerative dermatosis is also a differential for the lesions of posthitis and vulvovaginitis. prevention and treatment. because high-protein feed is often associated with posthitis and vulvovaginitis, feeding prac-tices must be reconsidered. clipping long wool and hair also is helpful. treatment. long-term ( weeks) penicillin treatment is effective for pyelonephritis. reduction of dietary protein, clipping and cleaning skin lesions, treating for or preventing fly-strike, and topical antibacterial treatments are effective for posthitis and vulvovaginitis; systemic therapy may be necessary for severe cases. surgical debridement or correction of scarring may also be indicated in severe cases. etiology. erysipelothrix rhusiopathiae is a nonmotile, nonspore-forming, gram-positive rod that resides in alkaline soils. clinical signs. erysipelothrix causes sporadic but chronic polyarthritis in lambs less than months of age. in older goats, erysipelas has been associated with joint infections. epizootiology and transmission. the disease may follow wound inoculation associated with castration, docking, or improper disinfection of the umbilicus. following wound contamination and a -to -day incubation period, the lamb exhibits a fever and stiffness and lameness in one or more limbs. joints, especially the stifle, hock, elbow, and carpus, are tender but not greatly enlarged. necropsy findings. thickened articular capsules, mild increases in normal-appearing joint fluid and erosions of the articular cartilage are usually found. the joint capsule is infiltrated with mononuclear cells, but bacteria are difficult to find. diagnosis is based on clinical signs of polyarthritis, and confirmation is made by culturing the organism from the joints. differential diagnosis. differential diagnoses include polyarthritis caused by chlamydia or other bacteria and stiffness caused by white muscle disease. other bacteria causing septic joints include areanobacterium pyogenes and fusobacterium necrophorum. caprine arthritis encephalitis (cae) should also be considered. prevention and control. proper sanitation and prevention of wound contamination are important in preventing the infection in lambs. screening of goat herds for cae is recommended. therapy. erysipelas is sensitive to penicillin antibiotic m. etiology. dermatophilus congolensis is an aerobic, grampositive, filamentous bacterium with branching hyphae. dermatophilosis is a chronic bacterial skin disease characterized by crustiness and exudates accumulating at the base of the hair or wool fibers (scanlan et al., ) . clinical signs. animals will be painful but will not be pruritic. two forms of the disease exist in sheep: mycotic dermatitis (also known as lumpy wool) and strawberry foot rot. mycotic dermatitis is characterized by crusts and wool matting, with exudates over the back and sides of adult animals and about the face of lambs. strawberry foot rot is rare in the united states but is characterized by crusts and inflammation between the carpi and/or tarsi and the coronary bands. animals will be lame. in goats and cattle, similar clinical signs of crusty, suppurative dermatitis are seen; the disease is often referred to as cutaneous streptothricosis in these species. lesions in younger goats are seen along the tips of the ears and under the tail. diagnosis is based on clinical signs as well as the typical microscopic appearance on stained skin scrapings, cultures, and serology. epizootiology and transmission. the disease occurs worldwide, and the dermatophilus organism is believed to be a saprophyte. transmission occurs by direct or indirect contact and is aggravated by prolonged wet wool or hair associated with inclement weather. biting insects may aid in transmission. necropsy findings. lymphadenopathy as well as liver and splenic changes may be observed. histopathologically, superficial epidermal layers are necrotic and crusted with serum, white blood cells, and wool or hair. dermal layers are hyperemic and edematous and may be infiltrated with mononuclear cells. pathogenesis. lesions typically begin around the muzzle and hooves and the dorsal midline. prevention and control. potash alum and aluminum sulfate have been used as wool dusts in sheep to prevent dermatophilosis. minimizing moist conditions is helpful in controlling and preventing the disease. in addition, controlling external parasites or other factors that cause skin lesions is important. lesions will resolve during dry periods. treatment. animals can be treated with antibiotics such as penicillin and oxytetracycline. treating the animals with povidone-iodine shampoos or chlorhexidine solutions is also useful in clearing the disease. n. etiology. two bacteria, dichelobacter (bacteroides) nodosus and fusobacterium necrophorum, work synergistically in caus-ing contagious foot rot in sheep and goats. other organisms may be involved as secondary invaders. both dichelobacter and fusobacterium are nonmotile, non-spore-forming, anaerobic, gram-negative bacilli. foot rot is a contagious, acute or chronic dermatitis involving the hoof and underlying tissues (bulgin, ) . it is the leading cause of lameness in sheep. at least serotypes of dichelobacter are known. arcanobacterium pyogenes may also contribute to the pathogenicity or to foot abscesses in goats. foot scald, an interdigital dermatitis, is caused primarily by d. nodosus alone. clinical signs. varying degrees of lameness are observed in all ages of animals within - weeks of exposure to the organisms. severely infected animals will show generalized signs of weight loss, decreased productivity, and anorexia associated with an inability to move. the interdigital skin and hooves will be moist, with a distinct necrotic odor. morbidity may reach % in susceptible animals. diagnosis is based on clinical signs. smears and cultures confirm the definitive agents. clinical signs of the milder disease, foot scald, include mild lameness, redness and swelling, and little to no odor. epizootiology and transmission. fusobacterium necrophorum is ubiquitous in soil and manure, in the gastrointestinal tract, and on the skin and hooves of domestic animals. in contrast, dichelobacter contaminates the soil and manure but rarely remains in the environment for more than about weeks. some animals may be chronic carriers. overcrowded, warm, and moist environments are key elements in transmission. outbreaks are likely in the spring season. shipping trailers and contaminated pens or yards should be considered also as likely sources of the bacteria. pathogenesis. both organisms are transmitted to the susceptible animal by direct or indirect contact. the organisms enter the hoof through injuries or through sites where strongyloides papillosus larvae have penetrated. fusobacterium necrophorum initiates the colonization and is followed by d. nodosus. the latter attaches and releases proteases; these cause necrosis of the epidermal layers and separation of the hoof from the underlying dermis. the pathogenicity of the serotypes of d. nodosus is correlated with the production of these proteases and numbers of pili. additionally, f. necrophorum causes a severe, damaging inflammatory reaction. differential diagnosis. foot abscesses, tetanus, selenium/ vitamin e deficiencies, copper deficiency, strawberry foot rot, bluetongue virus infection (manifested with myopathy and coronitis), and trauma are among the many differentials that must be considered. treatment. affected animals are best treated by manually trimming the necrotic debris from the hooves, followed by application of local antibiotics and foot wraps. systemic antibiotics such as penicillin, oxytetracycline, and erythromycin may be used. goats have improved dramatically when given a single dose of penicillin ( , u/kg) (smith and sherman, ) . footbaths containing % zinc sulfate, % copper sulfate, or % formalin (not legal in all states) can be used for treatment as well as for prevention of the disease. affected animals should be separated from the flock. vaccination has been shown to be effective as part of the treatment regimen. some breeds of sheep and some breeds and lines of goats are resistant to infection. individual sheep may recover without treatment or are resistant to infection. epizootiology and transmission. cases may be sporadic, or epizootics may occur. bos taurus dairy breeds and animals with wide interdigital spaces are more commonly affected. the factors here are comparable to those present in foot rot of smaller ruminants. necropsy findings. findings at necropsy include dermatitis and necrosis of the skin and subcutaneous tissues. although necropsy would rarely be performed, secondary osteomyelitis may be noted in severe cases by sectioning limbs. prevention and control. prevention and control programs involve scrutiny of herd and flock management; quarantine of incoming animals; vaccination; segregation of affected animals; careful and regular hoof trimming; discarding trimmings from known or suspected infected hooves; maintaining animals in good body condition; avoiding muddy pens and holding areas; and culling individuals with chronic and nonresponsive infections. dichelobacter nodosus bacterins are commercially available; cross protection between serotypes varies. biannual vaccinination in wet areas may be essential. some breeds may develop vaccination site lumps. footbaths of % zinc sulfate, % formalin (where allowed by state regulations), or % copper sulfate are also considered very effective preventive measures. goats are less sensitive than sheep to the copper in the footbaths. treating and controlling foot rot is costly in terms of time, initial handling and treatments and their follow-up, housing space, and medications. etiology. interdigital necrobacillosis of cattle is caused by the synergistic infection of traumatized interdigital tissues by fusobacterium necrophorum and bacteroides melaninogenicus. like f. necrophorum, b. melaninogenicus is a nonmotile, anaerobic, gram-negative bacterium. dichelobacter nodosus, the agent of interdigital dermatitis, may be present in some cases. this is a common cause of lameness in cattle. clinical signs. clinical signs include mild to moderate lameness of sudden onset. hindlimbs are more commonly affected, and cattle will often flex the pastern and bear weight only on the toe. the interdigital space will be swollen, as will be the coronet and bulb areas. characteristic malodors will be noted, but there will be little purulent discharge. in more severe cases, animals will have elevated body temperature and loss of appetite. the les~ons progress to fissures with necrosis until healing occurs. the diagnosis is by the odor and appearance. anaerobic culturing confirms the organisms involved. pathogenesis. the bacteria enter through the skin of the interdigital area after trauma to the interdigital skin, from hardened mud, or from softening of the skin due to, for example, constant wet conditions in pens. colonization leads to cellulitis. in addition, f. necrophorum releases a leukocidal exotoxin that reduces phagocytosis and causes the necrosis, whereas the tissues and tendons are damaged by the proteases and collagenases produced by b. melaninogenicus. zinc deficiency may play a role in the pathogenesis in some situations. differential diagnoses. the most common differentials for sudden lameness include hairy heel warts and subsolar abcesses. bluetongue virus should also be considered. grain engorgement and secondary infection from cracks caused by selenium toxicosis should also be considered. the exotic footand-mouth disease virus would be considered in areas where that pathogen is found. prevention and control. as with foot rot in smaller ruminants, management of the area and herd are important. paddocks and pens should be kept dry, well drained, and free of material that will damage feet. footbaths and chlortetracycline in the feed have been shown to control incidence. affected animals should be segregated during treatment. chronically affected or severely lame animals should be culled. new cattle should be quarantined and evaluated. ing within a week include cleaning the feet and trimming necrotic tissue; parenteral antimicrobials, such as oxytetracycline or procaine penicillin, or sulfonomethazine in the drinking water or tetracyclines in feed; and footbaths (such as % zinc sulfate, . % formalin, or % copper sulfate) twice a day. in severe cases, more aggressive therapy such as bandaging the feet or wiring the digits together may be needed. animals can recover without treatment but will be lame for several weeks. acquired immunity is reported to be poor. research complications are comparable to those noted for foot rot in smaller ruminants. fusobacterium necrophorum is also associated with foot abscesses, the infection of the deeper structures of the foot, in sheep and goats. only one claw of the affected hoof may be involved. the animals will be three-legged lame, and the affected hoof will be hot. pockets of purulent material may be in the heel or toe. etiology. bacteria such as fusobacterium spp., bacteroides spp., and dichelobacter nodosus have been isolated from bovine heel lesions. spirochete-like organisms have also been shown in the lesions of cows with papillomatous digital dermatitis (pdd), in the united states and europe; these have culturing requirements similar to those of treponema species. treatment. antibiotic and antiseptic regimens have been used successfully for this problem. antibiotics include parenteral cephalosporins and pencillins, as well as topical tetracyclines with bandaging. antiseptic or antibiotic solutions in footbaths include tetracyclines, zinc sulfate, lincomycin, spectinomycin, copper sulfate, and formalin. the footbaths must be well maintained, minimizing contamination by feces and other materials. tandem arrangements, such as the cleaning footbaths and then the medicated footbaths, and preventing dilution from precipitation are useful. other treatments such as surgical debridement, cryotherapy, and caustic topical solutions have been successful. research complications. infectious, contagious ppd is one of the major causes of lameness among heifers and dairy cattle and is a costly problem to treat. the outbreaks are generally worse in younger animals in chronically infected herds. the immune response is not well understood, and it may be temporary in older animals. clinical signs. all lesions occur on the haired, digital skin. one or all feet may be affected. most lesions occur on the plantar surface of the hindfoot (near the heel bulbs and/or extending from the interdigital space), but the palmar and dorsal aspect of the interdigital spaces may also be involved. progression of lesions, typically over - weeks, includes erect hairs, loss of hair, and thickening skin. moist plaques begin as red and remain red or turn gray or black. exudate or blood may be present on the plaque. plaques enlarge and "hairs" protrude from the roughened surface. lesioned areas are painful when touched. the lesions may or may not be malodorous. epizootiology and transmission. facility conditions and herd management are considered contributing factors. the following have been examined as contributing factors: nutrition, particularly zinc deficiency; poorly drained, low-oxygen, organic material underfoot; poor ventilation; rough flooring; damp and dirty bedding areas; and overcrowding. these interdigital lesions occur commonly in young stock and in dairy facilities throughout the world. the disease is seen only in cattle. pathogenesis. the organisms noted above, combined with poor facility and herd management, are critical in the pathogenesis. differential diagnosis. differentials for lameness will include sole abscesses, laminitis, and trauma. prevention and control. each facility and management condition noted above should be addressed in conjunction with appropriate antibiotic and/or antiseptic treatment regimens. all equipment used for hoof trimming must be cleaned and disinfected after every use. trucks and trailers should also be sanitized between groups of animals. etiology. haemophilus somnus is a pleomorphic, nonencapsulated, gram-negative bacterium. diseases caused by this organism include thromboembolic meningoencephalitis (teme), septicemia, arthritis, and reproductive failures due to genital tract infections in males and females. haemophilus somnus is a also major contributor to the bovine respiratory disease complex. haemophilus spp. have been associated with respiratory disease in sheep and goats. clinical signs. the neurologic presentation may be preceded by - weeks of dry, harsh coughing. neurologic signs include depression, ataxia, falling, conscious proprioceptive deficits; signs such as head tilt from otitis interna or otitis media, opisthotonus, and convulsions may be seen as the brain stem is affected. high fever, extreme morbidity, and death within hr may occur. respiratory tract infections are usually part of the complex with infectious bovine rhinotracheitis virus, bovine respiratory syncytial virus, bovine viral diarrhea virus, parainfluenza , mycoplasma, and pasteurella, and the synergism among these contributes to the signs of bovine respiratory disease complex (brdc). in acute neurologic as well as chronic pneumonic infections, polyarthritis may develop. abortion, vulvitis, vaginitis, endometritis, placentitis, and failure to conceive are manifestations of reproductive tract disease. in all cases, asymptomatic infections may also occur. diagnosis based on culture findings is difficult because h. somnus is part of the normal nasopharyngeal flora. paired serum samples are recommended; single titers in some animals seem to be high because of passive immunity, previous vaccination, or previous exposure. in cases of abortion, other causes should be eliminated from consideration. because the organism is considered part of the normal flora of cattle and can be isolated from numerous tissues, the distinction between the normal flora and the status of chronic carrier is not clear. outbreaks are associated with younger cattle in feedlots in western united states, but stresses of travel and coinfection with other respiratory pathogens are involved in some cases. adult cattle have also been affected. vaccination for viral respiratory pathogens may increase susceptibility. transmission is by respiratory and genital tract secretions. the organism does not persist in the environment. times of stress to the cattle is worthwhile. killed whole-cell bacterins are commercially available; these have been shown to be effective in controlling the respiratory disease presentation. control of other clinical aspects of the h. somnus disease by these bacterins has not been well described. treatment. rapid treatment at the first signs of neurologic disease is important in an outbreak. haemophilus somnus is susceptible to several antibiotics, such as oxytetracycline and penicillin, and these are often used in sequence until the cattle are recovered. necropsy findings. pathognomonic central nervous system lesions include multifocal red-brown foci of necrosis and inflammation on and within the brain and the meninges. many thrombi with bacterial colonies will be seen in these affected areas. ocular lesions may also be seen, including conjunctivitis, retinal hemorrhages, and edema. usually animals with neurological disease will not have respiratory tract lesions. the respiratory tract lesions include bronchopneumonia and suppurative pleuritis. when combined with pasteurella infection, the pathology becomes more severe. aborted fetuses will not show lesions, but necrotizing placentitis will be evident histologically. pathogenesis. inhalation of contaminated respiratory secretions from carrier animals is the primary means of transmission. the anatomical location of bacterial residence within the carriers has not been identified. after gaining access by way of the respiratory tract, the bacteria proliferate, and a bacteremia develops. the bacteria are phagocytosed by neutrophils but are not killed. the thrombosis formation is due to the adherence by the nonphagocytosed organisms to vascular endothelial cells, degeneration and desquamation of these cells, and exposure of subendothelial collagen, with subsequent initiation of the intrinsic coagulation pathway. antigen-antibody complex formation, resulting in vasculitis, is also correlated with high levels of agglutinating antibodies. other pathogens associated with neurological disease and respiratory disease such as pasteurella hemolytica, p. multocida, and p. aeruginosa. in smaller ruminants, corynebacterium pseudotuberculosis should be considered. prevention and control. stressed animals or those exposed to known carriers can be treated prophylactically with tetracycline administered parenterally or orally (in the feed or water). the late-stage polyarthritis is resistant to antibiotic therapy, because of failure of the antibiotic to reach the site of infection. planning vaccination programs carefully will decrease chances of outbreaks. for example, avoiding vaccinating animals for infectious bovine rhinotrachetitis and bovine viral diarrhea during clinical signs. leptospirosis is a contagious but uncommon disease in sheep and goats. the disease may cause abortion, anemia, hemoglobinuria, and icterus and is often associated with a concurrent fever. after a -to -day incubation period, the organism enters the bloodstream and causes bacteremia, fever, and red-cell hemolysis. leptospiremia may last up to days. immune stimulation is apparently rapid, and antibodies are detectable at the end of the first week of infection; crossserovar protection does not occur. during active bacteremia, hemolysis may result in hemoglobin levels of % below normal. hyperthermia, hemoglobinuria, icterus, and anemia may be observed during this phase, and ewes in late gestation may abort. abortion usually occurs only once. mortality rates of above % have been reported in infected ewes and lambs (jensen and swift, ) . subclinical infection is more common in nonpregnant and nonlactating animals. sheep infected with leptospirosis may display a hemolytic crisis associated with igm acting as a cold-reacting hemagglutinin. acute and chronic infections in cattle are more common than infections in sheep and goats. acute forms in cattle display signs similar to those in sheep. acute infection in calves may progress to meningitis and death. lactating cows will have severe drops in production. chronic cases may lead to abortion, with retained placenta, and weakened calves or animals that carry the infection. infertility may also be a sequela. epizootiology and transmission. leptospires are a large genus, and leptospirosis is a complicated disease to prevent, treat, and control. the organism survives well in the environment, especially in moist, warm, stagnant water. cattle, swine, and other domestic and wild animals are potential carriers of serovars common to particular regions. wild animals often serve as maintenance hosts, but domestic livestock may be reservoirs also. organisms are shed in urine, in uterine discharges, and through milk. animals become carriers when they are infected with a host-adapted serovar; sporadic clinical disease is more commonly associated with exposure to a non-hostadapted serovar (heath and johnson, ) . infection may occur via oral ingestion of contaminated feed and water, via placental fluids, or through the mucous membranes of the susceptible animal. placental or venereal transmission may occur. as the organisms are cleared from the bloodstream, they chronically infect the renal convoluted tubules and the reproductive tract (and occasionally the cerebrospinal fluid or vitreous humor). chronically infected animals may shed the organism in the urine for days or longer. necropsy. diagnosis is confirmed by identification of leptospires in fetal tissues. the leptospires are visible in silver-or fluorescent antibody-stained sections of liver or kidney. leptospires may also be seen under dark-field or phase-contrast microscopy of fetal stomach contents. fetal and maternal serology, and diagnostic tests such as the microscopic agglutination test, are useful; interpretation is complicated because of cross reaction of antibodies to many serovars. differential diagnosis. more than one serovar may cause infection in one animal, and each serovar should be considered as a separate pathogen. because of the associated anemia, differential diagnoses should include copper toxicity and parasites, in addition to other abortifacient diseases. prevention and control. polyvalent vaccines, tailored to common serovars regionally, are available and effective for preventing leptospirosis in cattle. immunity is serovar specific. because serological titers tend to diminish rapidly ( - days in sheep [jensen and swift, ] ), frequent vaccination may be necessary. other prevention measures such as species-specific housing, control of wild rodents, and proper sanitation should be instituted. treatment. antibiotic treatment is aimed at treating ill animals and trying to clear the carrier state. treatment methods for acute leptospirosis include oxytetracycline for - days. addition of oxytetracycline or chlortetracycline to the feed for week may be helpful. these antibiotics are considered best for removal of the carrier state of some serovars. vaccination and antibiotic therapy can be combined in an outbreak. research complications. leptospirosis is zoonotic and may be associated with flulike symptoms, meningitis, or hepatorenal failure in humans. etiology. listeria monocytogenes is a pleomorphic, motile, non-spore-forming, [ -hemolytic, gram-positive bacillus that inhabits the soil for long periods of time and has been often found in fermented feedstuffs such as spoiled silage. of the known serovars, several produce clinical signs in ruminants. listeria ivanovii (associated with abortions in sheep) is serovar . clinical signs. listeriosis is an acute, sporadic, noncontagious disease associated with neurological signs or abortions in sheep and other ruminants. the overall case rate is low. the disease may present as an isolated case or with multiple animals affected. three forms of disease are described: encephalitis, placentitis with abortion, and septicemia with hepatitis and pneumonia. the encephalitic form is most common in sheep; septicemic forms may occur in neonatal lambs (scarratt, ) . clinically, the encephalitic form begins with depression, anorexia, and mild hyperthermia after an incubation period of - weeks. as the disease progresses, animals exhibit nasal discharges and conjunctivitis and begin to walk in circles, as if disoriented. facial paralytic lesions, including drooping of an ear or eyelid, dilation of a nostril, or strabismus occur unilaterally on the affected side as the result of dysfunction of some or all the cranial nerves v-xii. the neck will by flexed away from the affected side. facial muscle twitching, protrusion of the tongue, dysphagia, hypersalivation, and nasal discharges may be noted. the hypersalivation may lead to metabolic acidosis in advanced cases in cattle. anorexia, prostration, coma, and death follow. the placental form usually results in last-trimester abortions in ewes and does, which typically survive this form of the disease. the affected females may be asymptomatic or may show severe clinical signs such as fever and depression, with subsequent retained placenta or endometritis. abortion usually occurs within weeks of listeria infection. in cattle, abortion occurs during the last months of gestation and has been induced experimentally - days after exposure. cows present with the range of clinical signs seen in smaller-ruminant dams. there is no long-term effect on the fertility of affected dams. epizootiology and transmission. the organism is transmitted by oral ingestion of contaminated feeds and water or possibly by inhalation. by the oral route, the organism enters through breaks in the oral cavity and ascends to the brain stem by way of nerves. when severe outbreaks occur, feedstuffs should be assessed for spoilage. listeria organisms can be shed by asymptomatic carriers, especially at the end of pregnancy and at lambing. diagnosis and necropsy findings. diagnosis is usually made from clinical signs. culture confirms the diagnosis (cold enrichment at ~ is preferable but not essential for isolation). impression smears will show the pleomorphic gram-positive characterisitics of the pathogen. tissue fluorescent antibody techniques may also be utilized. gross lesions are not observed with the encephalitic form. microscopic lesions include thrombosis, neutrophilic or mononuclear foci in areas of inflammation, and neuritis. the pons, medulla, and anterior spinal cord are primarily affected in the encephalitic form. microabscesses of the midbrain are characteristic of listeria encephalitis in sheep. aborted fetuses that are intact may show fibrinous polyserositis, with excessive serous fluids; small, necrotic foci of the liver; and small abomasal erosions. necrotic lesions of the fetal spleen and lungs may also be seen. in goats, listeria-induced neurological lesions occur only in the brain stem. placentitis, focal bronchopneumonia, hepatitis, splenitis, and nephritis may be seen with other forms. pathogenesis. with the encephalitic form, the organism penetrates mucosal abrasions and enters the trigeminal or hypoglossal nerves. the listeria organisms then migrate along the nerves and associated lymphatics to the brain stem (medulla and pons). in the septicemic form, the organism penetrates tissues of the gastrointestinal tract and enters the bloodstream, to be distributed to the liver, spleen, lungs, kidneys, and placenta. after infection, organisms are shed in all body secretions (infected milk is an important risk factor for zoonosis). a toxin produced by listeria monocytogenes is correlated with pathogenicity, but the mechanism of the pathogenesis of this molecule has not been elucidated. differential diagnoses. rabies, bacterial meningitis, brain abscess, lead toxicity, and otitis media must be considered as differentials. in sheep, the differentials include organisms that cause abortion, and neurological signs, such as enterotoxemia due to clostridium perfringens type d. in goats, the major differentials include caprine arthritis encephalitis viral infection and chlamydial and mycoplasmal infections. in both species, scrapie is a differential. in cattle, aberrant parasite migration or hemophilus somnus infection must also be considered. prevention and control. affected dams should be segregated and treated. other animals in the group may be treated with oxytetracycline as needed. aborted tissues should be removed immediately. proper storage of fermented feeds minimizes this source of contamination. when silage spoils, the ph increases, producing a suitable growth environment for the organism. commercial vaccines are not available in the united states. treatment. affected animals can be treated aggressively with penicillin, ampicillin, oxytetracycline, or erythromycin. exceptionally high levels of penicillin are required for treating affected cattle. severely affected animals should receive appropriate fluid support and other nursing care. treatment is less successful, and mortality is especially high in sheep. recovered animals tend to resist reinfection. research complications. in addition to the loss of fetal animals, stress to the dams, and risks to other animals, any aborted tissue by a ruminant should be regarded as a potential zoonotic risk. listeria can cause mild to severe flulike symptoms in humans and may be a particular risk for pregnant women and for older or immune-compromised individuals. listeriosis in humans is a reportable disease. etiology. lyme disease is caused by the spirochete borrelia burgdorferi. clinical signs and diagnosis. reports in ruminants indicate seroconversion to b. burgdorferi, but there are few definitive correlations to the arthritis that is present. diagnosis requires culturing from the affected joints and diagnostic elimination of other causes of lameness and arthritis. epizootiology and transmission. the organism is present throughout much of the northern hemisphere and has been reported in many mammals and also in birds. ticks of the ixodes ricinus complex are the major vectors of the spirochete and must be attached for hr for successful transmission. pathogenesis. the ixodes ticks have three life stages: larval, nymphal, and adult. feeding occurs once during each stage, and wild animals are the source of blood meals. the larval stages feed from rodents, such as the white-footed deer mouse, peromyscus leucopus, from which they acquire the spirochete. the nymphal stage is that which usually infects other animals. the adult ticks are usually found on deer. differential diagnosis. seroconversion to b. burgdorferi does not necessarily confirm the cause of arthritis. other causes of arthritis and lameness in ruminants include trauma, caprine arthritis encephalitis virus, mycoplasma spp., chlamydia psittaci, erysipelothrix spp., arcanobacterium pyogenes, brucella spp., and rickets. prevention and control. control of the tick vector is the most important factor in preventing the possibility of exposure or disease. treatment. antibiotic therapy, with tetracycline, penicillin, amoxicillin, and cephalosporins, is used for diagnosed or suspected lyme arthritis. research complications. lyme disease is zoonotic, and the lxodes ticks transmit the disease to humans. v. mastitis i. ovine mastitis mastitis in ewes may be acute, subclinical, or chronic. acute mastitis often results in anorexia, fever, abnormal milk, and swelling of the mammary gland. pasteurella haemolytica is the most common cause of acute mastitis. additional isolates may include, in order of prevalence, staphylococcus aureus, actinomyces (corynebacterium) spp., and histophilus ovis. escherichia coli and pseudomonas aeruginosa have also been found to cause acute mastitis. as many as six serotypes of pasteurella haemolytica have been isolated from the mammary glands of mastitic ewes. furthermore, intramammary inoculation of these organisms isolated from ovine and bovine pulmonary lesions has resulted in clinical mastitis in ewes (watkins.and jones, ) . subclinical mastitis is detected only indirectly, by counting somatic cells. the most common isolate from ewes with subclinical mastitis is coagulase-negative staphylococci. other isolates include actinomyces bovis, streptococcus uberis, s. dysgalactiae, micrococcus spp., bacillus spp., and fecal streptococci. most of these organisms are commonly found in the environment. diffuse chronic mastitis, or hardbag, results from interstitial accumulations of lymphocytes in the udder. both glands are usually affected, but no inflammation is present. serological evidence suggests that diffuse chronic mastitis is caused by the retrovirus that causes ovine progressive pneumonia (opp or maedi/visna virus). other bacterial agents or mycoplasma have not usually been isolated from udders with this type of mastitis. acute mastitis occurs in approximately % of lactating ewes annually, and it usually occurs either soon after lambing or when lambs are - months old (lasgard and vaabenoe, ) . subclinical mastitis occurs in - % of lactating ewes (kirk and glenn, ) . subclinical mastitis is more common in ewes from high-milk-producing breeds. skin or teat lesions and dermatitis increase the prevalence of disease. acute mastitis can be diagnosed in ewes with associated systemic signs of disease by physical examination of the udder and inspection of the milk. subclinical mastitis is often suggested by somatic cell counts elevated above x cells/ml. when high somatic cell counts are identified, subclinical mastitis can be diagnosed by milk culture. the california mastitis test may also be helpful as an indicator of mastitis. manual palpation of a hard, indurated udder as well as serological testing for the maedi/visna virus is helpful in confirming the diagnosis of diffuse chronic mastitis. treatment for acute bacterial mastitis should include aggressive application of broad-spectrum antibiotics (intramammary and systemic) and supportive therapy such as fluids and anti-inflammatory drugs. it is may be helpful to milk out the infected ud-der frequently; oxytocin injections preceding milking will improve gland evacuation. because somatic cell counting is often not routinely performed, treatment of subclinical mastitis is seldom done. there is currently no treatment available for diffuse chronic mastitis. ii. caprine mastitis lactating goats are subject to inflammation of mammary gland, or mastitis. the primary causative organisms are staphylococcus epidermidis and other coagulasenegative staphylococcus spp. clinical signs of mastitis include abnormal coloration or composition of milk, mammary gland redness, heat and pain, enlargement of the mammary gland, discoloration of the mammary gland, and systemic signs of septicemia. large abscesses may be present in the affected gland. staphylococcus aureus is also associated with caprine mastitis, and toxemia may be part of the clinical picture. this organism produces a necrotizing alpha toxin that can result in gangrenous mastitis. caprine mastitis may be clinical or subclinical, and the first indication of mastitis may be weak, depressed, or thin kids. diagnosis is based on careful culture of mastitic milk. treatment includes frequent stripping, intramammary antibiotics, and nonsteroidal anti-inflammatory drugs. oxytocin ( - u) may help milk letdown for frequent strippings. bovine mastitis products can be used in the goat; however, care should be taken not to insert the mastitis tube tip fully, because damage to the protective keratin layer lining the teat canal may occur. in severe acute systemic cases, steroids, fluids, and systemic antibiotics may be necessary. other less common causes of mastitis in goats include streptococcus spp. (s. agalactiae, s. dysgalactiae, s. uberis, and zooepidemicus). gram-negative causes of caprine mastitis include escherichia coli, klebsiella pneumoniae, pasteurella spp., pseudomonas, and proteus mirabilis. corynebacterium pseudotuberculosis can cause mammary gland abscessation, whereas mycoplasma mycoides may cause agalactia and systemic disease. "hard udder" can be caused by caprine arthritis encephalitis virus (caev). brucellosis and listeriosis can cause a subclinical interstitial mastitis (smith and sherman, ) . iii. bovine mastitis mastitis is the disease of greatest economic importance for the dairy cattle industry. the majority of the impact will be on the production and overall health of the cows, but low-incidence herds also diminish the risk of calves' ingesting or being exposed to pathogens. the most common bovine mastitis pathogens include staphylococcus aureus and streptococcus agalactiae, s. dysgalactiae, and s. uberis; coliform agents such as escherichia coli, enterobacter aerogenes, serratia marcescens, and klebsiella pneumoniae; mycoplasmal species such as mycoplasma bovis, m. bovigenitalium, m. californicum, m. canadensis, and m. alkalescens; and salmonella spp. such as s. typhimurium, s. newport, s. enteritidis, s. dublin, and s. muenster. many of these agents such as staphylococcus spp., salmonella spp., and the coliforms can cause both acute and chronic mastitis, as well as severe systemic disease, including fever and anorexia. these must be regarded as herd and environmental pathogens in terms of treatment and prevention. the pathogenesis of staphylococcal infections is comparable to that in goats. staphylococcus agalactiae can be cleared from udders because it does not invade other tissues, is an obligate resident of the glands, and is susceptible to penicillin. in contrast, s. uberis and s. dysgalactiae are environmental organisms and can be highly resistant to pencillin. mycoplasma bovis is the more common of the mycoplasmal pathogens and can cause severe infections. transmission of the mycoplasmas is not well defined but may be related to their presence in other organ systems. treatments for mycoplasmal mastitis are not successful; culling is recommended. there are many interrelated factors associated with prevention and control of mastitis in a herd, including herd health and dry cow management, order of animals milked, milking procedures, milking equipment, condition of the teats, and the condition of the environment. management of the overall herd includes aspects such as vaccination programs, nutrition, isolation of incoming animals, and quarantine and treatment of or culling diseased individuals. culturing or testing newly freshened cows and monitoring the bulk milk tank serve as indicators of subclinical mastitis. herd management will diminish teat lesions. bacterin vaccines are available for preventing and controlling coliform mastitis and s. aureus mastitis. at the time of dry-off, all cows must be treated by intramammary route. some infections can be successfully cleared during this time. younger, disease-free animals should be milked first; any animals with diagnosed problems should be milked after the rest of the herd and/or segregated during treatment. milkers' hands easily serve as a means of pathogen transmission, and wearing rubber gloves is recommended. teat and udder cleaning practices include washing and drying with single-service paper or cloth towels or pre-and postmilking dipping. milking equipment must be maintained to provide proper vacuum levels and pumping rates, and liners should be the appropriate size. facilities that provide clean and dry areas for the animals to rest, feed, and move will diminish teat injuries and reduce exposures to mastitis pathogens. in that regard, inorganic bedding such as clean sand harbors few pathogens in contrast to shavings and sawdust. w. etiology. moraxella bovis, a gram-negative coccobacillus, is the most common cause of infectious bovine keratoconjunctivitis (ibk) in cattle. this organism is not a cause of keratoconjunctivitis in sheep and goats. the disease includes conjunctivitis and ulcerative keratitis. the pathogenic m. bovis strain is piliated, and at least seven serotypes exist. clinical signs. lacrimation, photophobia, and blepharospasm are seen initially. conjunctival injection and chemosis develop within a day of exposure, and then keratitis with corneal edema and ulcers. anterior uveitis may be a sequela within a few days, and thicker mucopurulent ocular discharge may be seen. corneal vascularization begins by days after onset. reepithelialization of the corneal ulcers occurs by - weeks after onset. diagnosis is usually based on clinical signs, but culturing is helpful and fluoroscein staining is useful for demonstrating corneal ulceration. epizootiology and transmission. the disease is more severe in younger cattle. the clinical signs of ibk tend to be more severe in cattle that are also infected with infectious bovine rhinotracheitis (ibr) virus or those that have been vaccinated recently with modified live ibr vaccine. the bacteria are shed in nasal secretions and cattle with no clinical symptoms may be carriers. transmission is by fomites, flies, aerosols, and direct contact. incidence in winter months is very low. nonhemolytic strains are associated with the winter epidemics, and hemolytic strains are associated with summer epidemics. necropsy findings. necropsy is not typically performed on these cases. corneal edema, ulceration, hypopyon, and uveitis would be noted, depending on the stage of infection. pathogenesis. the pili ofm. bovis bind to receptors of corneal epithelium. the virulent strains of the bacteria then release the enzymes that damage the corneal epithelial cells. other factors contributing to infection include ultraviolet light and trauma from dust and plant materials. differential diagnoses. infectious bovine rhinotrachetitis virus causes conjunctivitis, but the central corneal ulceration that is characteristic of ibk is not seen with m. bovis infections. mycoplasma, listeria, branhamella (neisseria) , and adenovirus may be cultured from affected bovine eyes but none has been shown to produce the corneal lesions when inoculated into susceptible animals. prevention and control. cattle should not be immunized intranasally with modified live infectious bovine rhinotracheitis vaccine during ibk outbreaks; this will likely exacerbate the infection. new animals should be quarantined and treated prophylactically before introduction to herds. the available vaccines, containing. m. bovis pili or killed m. bovis, help decrease incidence and severity of disease; these preparations are not completely effective, because the m. bovis strain may not be homologous to that used for the vaccine preparation. other preventive measures include % permethrin-impregnated bilateral ear tags, pour-on avermectins, or dust bags or face rubbers containing insecticide (such as % coumaphos) to control flies throughout the season and premises; mowing of high pasture grass to minimize ocular trauma; provision of shade; control of dust and sources of other mechanical trauma; and segregation of animals by age. treatment. cattle can recover without treatment, but younger animals should be treated as soon as the infection is detected. antibiotic treatments include topical, subconjunctival administration and intramuscular dosing. several standard topical antibiotics have been shown to be effective, including oxytetracycline, gentamicin, and triple antibiotic combinations. these should be administered twice per day. subconjunctival injections of antibiotics, such as penicillin g, provide higher corneal levels of drug; these are typically administered only once or twice in severe cases. intramuscular doses of long-acting oxytetracycline, given on alternate days, are effective in larger herds, and doses hr apart eliminate carriers. third-eyelid flaps, temporary tarsorrhaphy, or eye patches may be useful in certain cases. epizootiology and transmission. although m. bovis can be killed by sunlight, it otherwise survives a long time in the environment and in cattle feces. animals acquire the infection from the environment or from other animals via aerosols, from contaminated feed and water, and from secretions such as milk, semen, genital discharges, urine, and feces. clinically normal animals may serve as carriers. the bacilli stimulate an initial neutrophilic tissue response. neutrophils become necrotic and are phagocytosed by macrophages, forming giant epithelioid cells called langhans' giant cells. an outer lymphocytic zone is formed, and fibrotic encapsulation creates the classical caseous nodules. vascular erosion and hematogenous migration of the organisms may lead to lesions throughout the body. necropsy findings. yellow primary tubercles (granulomas) with central areas of caseous necrosis and calcification are present in the lungs. caseous nodules are also associated with gastrointestinal organs and mesenteric lymph nodes. research complications. this pathogen does present a complication due to the carrier status of some animals, the likelihood of herd outbreaks, the severity of disease in younger animals, and the morbidity, possible progression to uveitis, and time and treatment costs associated with infections. the overall condition of the cattle will be affected for several weeks, and permanent visual impairment or loss, as well as ocular disfigurement, may occur. mycobacterium bovis infection (tuberculosis) etiology. mycobacteria are aerobic, nonmotile, non-sporeforming, acid-fast pleomorphic bacteria. most cases of tuberculosis in sheep are related to mycobacterium bovis or m. avium. cases in goats have been attributed to m. bovis, m. avium, or m. tuberculosis. mycobacterium bovis, or the bovine tubercle bacillus, is the cause in cattle but has been isolated from many domestic and wild mammals. other agents of mammalian tuberculosis include m. microti and m. africanum. clinical signs. tuberculosis is a sporadic, chronic, contagious disease of ruminants and is zoonotic. the infection is often asymptomatic later in the illness, and it may be diagnosed only at necropsy. the respiratory system (m. bovis) or the digestive system (m. avium) is the primary site of infection; other tissues such as mammary tissue and reproductive tract may be infrequently involved. locations of the characteristic tubercles will determine whether clinical signs are seen. respiratory signs may include dyspnea, coughing, and pneumonia. digestive tract signs include diarrhea, bloat, or constipation; diarrhea is most common. lymphadenopathy occurs in advanced cases. fever and generalized disease may be seen after calving. infected goats lose weight and develop a persistent cough. prevention and control. significant progress has been made in eradication programs in the united states during the past several decades, but during the s, infected animals continued to be found in domestic cattle herds and particularly in captive deer herds in hunting preserves. the intradermal tuberculin test, using purified protein derivative (ppd), is usually used as a diagnostic indicator in live animals. this test should be performed annually on bovine and caprine dairy herds (and bison herds); the official tests are the caudal fold, comparative cervical, and single cervical tests. notification to state officials is required following identification of intradermal-positive animals. great care must be exercised in any handling of tissue or necropsies of reactors, and state animal health officials should be consulted regarding disposal of materials and cleaning of premises following depopulation of positive animals. no treatment is recommended, and treatment is usually not allowed, because of the zoonotic potential, chronicity of the disease, and the treatment costs. slaughter is preferred, to prevent potential transmission to humans. paratuberculosis, or johne 's disease (mycobacterium paratube rculo sis) etiology. mycobacterium paratuberculosis, the causative agent of johne's disease, is a fastidious, non-spore-forming, acid-fast, gram-positive rod. the organism is actually a subspecies of m. avium, but m. paratuberculosis does not produce the siderophore mycobactin (an iron-binding molecule) of m. avium. clinical signs and diagnosis. johne's disease is a chronic, contagious, granulomatous disease of adult ruminants and is characterized by unthriftiness, weight loss, and intermittent diarrhea. in sheep and goats, chronic wasting is usually seen, occasionally with pasty feces or diarrhea. in cattle, chronic diarrhea and rapid weight loss are the most common clinical signs of the disease. usually older adult animals are infected, but over time in an infected herd, younger animals will become infected when sufficient doses of organisms are ingested. although clinical signs are nonspecific, johne's disease should be considered if the affected diarrheic animals have a good appetite and are on a good anthelmintic program. the disease is diagnosed based on clinical signs and laboratory analyses, although none of the tests is more than % sensitive. in addition, the sensitivity of the serological tests differs between species. the standard is the fecal culture that takes - weeks. theenzyme-linked immunosorbent assay (elisa) is now considered the most reliable serological test, but false negatives do occur. other serological tests such as agar gel immunodiffusion (agid) and complement fixation are useful. herd screening may be done using the agid or elisa serological tests. identification of the organism on culture, or the presence of acid-fast organisms on mucosal or mesenteric lymph node smears or from rectal biopsies, helps confirm the diagnosis. some animals serologically negative for johne's disease, however, have been found to be positive on fecal culture. commercial agid tests approved for use in cattle may be useful in diagnosing johne's disease in sheep (dubash et al., ) . serological tests cross-react with other species of mycobacterium, especially m. avium. epizootiology and transmission. the organism is prevalent in the environment and is transmitted to young animals by direct or indirect contact. although vertical transmission has been reported, the organism more commonly enters the gastrointestinal tract and penetrates the mucosa of the distal small intestine, primarily the ileum. chronic carriers may intermittently shed the organisms. parasite that grows only in macrophages of infected animals. nursing infected dams are a primary source of infection of neonates. if the organism is not cleared, it proliferates slowly in the tissue, leading to inflammatory reactions that progress through neutrophilic to mononuclear stages. the organism may penetrate the lymphatics and proliferate in mesenteric lymph nodes. after an incubation period of a year or more, some of the carriers will progress to clinical disease manifested by fibrotic and hyperplastic changes in the ileum, leading to the classic thickening in the region. gut changes result in intermittent diarrhea, with subsequent dehydration, electrolyte imbalances, and malnutrition, although this clinical sign is more common in cattle than in sheep or goats. necropsy and diagnosis. the ileum from infected cattle is grossly thickened; this is not seen in sheep and goats. ileal and ileocecal lymph nodes provide the best samples for histology and acid-fast staining. differential diagnosis. diseases causing chronic wasting and poor coat and body condition of all ruminants should be considered. these include chronic salmonellosis, peritonitis, severe parasitism, winter dysentery, and pyelonephritis. deer can be infected, and the lesions can be confused with those of tuberculosis. prevention and control. prevention is the most effective method to manage this pathogen. efforts should be focused on eliminating the disease through test and slaughter. neonates should not be reared by infected dams. some states have johne's disease eradication programs. facilities and pastures where animals testing positive for johne' disease were maintained should be thoroughly cleaned and kept vacant for a year after culling. other considerations. mycobacterium paratuberculosis is being investigated as a factor in the development of crohn's disease in humans. etiology. the most common organism causing infection of the umbilicus is arcanobacterium (formerly actinomyces, corynebacterium) pyogenes; other bacteria may be present. arcanobacterium spp. are anaerobic, nonmotile, non-sporeforming, gram-positive, pleomorphic rods to coccobacilli. other environmental contaminants are also associated with this disease, such as escherichia coli, enterococcus spp., proteus, streptococcus spp., and staplylococcus spp. clinical signs and diagnosis. navel ill is an acute localized inflammation and infection of the external umbilicus. animals present with fever and painful enlargement of the umbilicus. animals may exhibit various degrees of depression and anorexia, and purulent discharges may be seen draining from the umbilicus. involvement of the urachus is usually followed by cystitis and associated signs of dysuria, stranguria, and hematuria. other common severe sequelae include septicemia, pneumonia, peritonitis, septic arthritis (joint ill), meningitis, osteomyelitis, uveitis, endocarditis, and diarrhea. neonates, and most cases occur within the first months of age. cleanliness of the birthing and housing environment and successful transfer of passive immunity are important factors in the occurrence of the disease. dystocia resulting in weak neonates can be a factor predisposing to the development of the disease. navel ill is diagnosed by typical clinical signs. the presence of microabscesses and palpation of the umbilical area for firm intra-abdominal structures extending from the umbilicus are abnormal. assessment of colostral immunoglobulin transfer may contribute to determination of the prognosis. navel ill should always be considered for young ruminants with fever of unknown origin during the first week of life and for slightly older lambs, kids, or calves that are not thriving. arthrocentesis of affected joints and culture of the fluid for identification of the pathogen are also diagnostic options and essential for effective antimicrobial selection. differential diagnosis. the major differential is an umbilical hernia, which will typically not be painful or infected and can often be reduced. mycoplasmal arthritis is a differential in kids. in the past, erysipelothrix rhusopathiae was a common navel ill pathogen in sheep. treatment. omphalitis can be treated with a to day course of broad-spectrum antibiotics such as ampicillin, amoxicillin, penicillin, ceftiofur, florfenicol, and erythromycin. if an isolated abscess is palpable, it should be surgically opened and repeatedly flushed with iodine solutions. surgical reduction of the infected umbilicus is indicated if intra-abdominal structures are involved. the prognosis for recovery is good if systemic involvement has not occurred. prevention and control. the disease is best prevented and controlled by providing clean birthing environments, ensuring adequate colostral immunity, thoroughly dipping the umbilicus of newborns in tincture of iodine or strong iodine solution (lugol's), monitoring for dystocias, and maintaining young growing animals in noncontaminated environments. may invade the bloodstream, causing disseminated septicemia. clinically, the lambs may exhibit nasal discharge of mucopurulent to hemorrhagic exudate, hyperthermia, coughing, dyspnea, anorexia, and depression. with the respiratory form, auscultation of the thorax suggests dullness and consolidation of anteroventral lobes; this will be confirmed by radiographs. the disease is diagnosed by clinical signs, blood cultures from septicemic animals, blood smears showing bipolar organisms, and history of predisposing stressors. in cultures, p. hemolytica is distinguished from p. multocida by hemolysis on blood agar; only p. multocida produces indole. epizootiology and transmission. the organism is ubiquitous in the environment and in the respiratory tracts of these animals. younger ruminants, between and months of age, are especially prone to infection during times of stress, such as weaning, transportation, dietary changes, weather changes, and overcrowding. the pneumonic form appears as a complex associated with concurrent infections such as parainfluenza , adenovirus type , respiratory syncytial virus, mycoplasmas, chlamydia, pasteurella multocida and bordetella parapertussis (martin, ; brogden et al., ) . the organism is transmitted between animals by direct and indirect contact, through inhalation or ingestion. necropsy findings. necropsy lesions include areas of necrosis and hemorrhage in the small intestines and multifocal mm lesions distributed on the surfaces of the lungs and liver. with the pneumonic form, serofibrinous exudates fill the alveoli; ventral lung lobes are consolidated and are congested and purple-gray in color. fibrinous pleuritis, pericarditis, and hematogenously induced arthritis also may be evident.. the disease can be costly to treat, and the toll taken on young animals due to the consequences of systemic infection may detract from their research value. etiology. pasteurella hemolytica and p. multocida are aerobic, nonmotile, non-spore-forming, bipolar, gram-negative rods. biotype a serotypes are associated with pneumonia and septicemia in all ruminants (ellis, ) . serotype of p. hemolytica is considered a major cause of pulmonary lesions of bovine bronchopneumonia and fibrinous bronchopneumonia. clinical signs. pasteurellosis is an acute bacterial disease characterized by bronchopneumonia, septicemia, and sudden death. the organism invades the mucosa of the gastrointestinal tract or respiratory tract and causes localized areas of necrosis, hemorrhage, and thrombosis. the lungs and liver are frequent areas of formation of microabscesses. acute rhinitis or pharyngitis often precedes the respiratory form. the organism also pathogenesis. a leukotoxin is considered to be a key factor in the pathogenesis of the p. hemolytica infection. macrophages and neutrophils are lysed by the toxin as they arrive at the lung, and the enzymes released by the neutrophils cause additional damage to the tissue. treatment. treatment may include the use of antibiotics such as penicillin, ampicillin, tylosin, sulfonamides, or oxytetracycline. newer antibiotics, such as ceftiofur, tilmicosin, spectinomycin, and florfenicol, are very effective and approved for use in cattle. in outbreaks, cultures from fresh necropsies are helpful for determining sensitivities useful for the remaining group. prevention and control. the incidence of disease can be decreased by minimizing the degree of stress; by improving management, such as nutrition and control of parasitism; and, in cattle and sheep, by vaccinating for viral respiratory infections such as parainfluenza. early pasteurella hemolytica bacterin vaccines for use in cattle are not considered effective, but newer products based on immunizing against the leukotoxin and some bacterial capsule surface antigens are effective. pasteurella multocida bacterins and live streptomycin-dependent mutant vaccines are available. in young animals, passive immunity is protective. preventive measures also include maintaining good ventilation in enclosures and barns. new animals to the flock or herds should be quarantined for at least weeks before introduction. etiology. salmonella typhimurium is a motile, aerobic to facultatively anaerobic, non-spore-forming, gram-negative bacillus and is the organism associated with enteric disease and some abortions in ruminants. it is a common inhabitant of the gastrointestinal tract of ruminants. current nomenclature categorizes s. typhimurium as a serovar within the species s. enteritidis (the other two species are s. typhi and s. choleraesuis). salmonella typhimurium, s. dublin, and s. newport are the common species seen in bovine cases. salmonella typhimurium, s. dublin, s. anatum, and s. montevideo are seen in ovine and caprine cases, although a host-adapted species has not been identified in the goat. ovine abortions due to various salmonella species are not reported in the united states but are enzootic in other countries. salmonella serotypes have been associated with aborted fetuses in all ruminant species. clinical signs and diagnosis. salmonellosis causes acute gastroenteritis, dysentery, and septicemia (anderson and blanchard, ) . clinically, the animals become anorexic and hyperthermic. diarrhea or dysentery develops; feces may contain mucus and/or blood and have a putrid odor. animals become severely depressed and weak, losing a high percentage of their body weight. animals may die in - days because of dehydration associated with dysenteric fluid loss, septicemia, shock, and acidosis. morbidity may be %, and mortality may be high. septicemia may result in subsequent meningitis, polyarthritis, and pneumonia. chronically infected animals may have intermittent diarrhea. in goats, salmonellosis may be recognized as diarrhea and septicemia in neonates, as enteritis in preweaned kids and mature goats, and, rarely, as abortion. adult cases may be sporadic, with intermittent bouts of diarrhea, subacute or even chronic. morbidity and mortality will be highest in neonates, and some may simply be found dead. the older animals generally tend to fare better during the disease. abdominal distension with profuse yellow feces is common. kids become severely depressed, anorexic, febrile (with temperatures as high as ~ dehydrated, acidotic, recumbent, and comatose. salmonella abortions may occur throughout gestation. there may not be any other clinical signs, or abortion may be seen with diarrhea, fever, and vulvar discharges. hemorrhage, placental necrosis, and edema will be present. metritis and placental retention may occur. some mortality of dams may occur. diagnosis is based on clinical signs and can be confirmed by culturing fresh feces or at necropsy. because of intermittent shedding of organisms, culture may be difficult; repeated cultures are recommended. leukopenia and a degenerative shift to the left are not uncommon hematological findings. epizootiology and transmission. stresses associated with recent shipping, overcrowding, and inclement weather may predispose the animal to enteric infection. birds and rodents may be natural reservoirs of salmonella in external housing environments. transmission is fecal-oral. after ingestion, the organisms may proliferate throughout the gastrointestinal tract and may penetrate the mucosa of the intestines, invade the peyer's patches and lymphatics, and migrate to the spleen, liver, and other organs. animals that survive may become chronic carriers and shedders of the organisms, and this has been demonstrated experimentally (arora, ) . fecal-oral transmission is also associated with salmonella abortion; veneral transmission has not been reported. necropsy findings and diagnosis. animals will have noticeable perineal staining. intestines (particularly the ileum, cecum, and colon) may contain mucoid feces with or without hemorrhages. petechial hemorrhages and areas of necrosis may be noticed on the surface of the liver, heart, and mesenteric lymph nodes. the wall of the intestines, gallbladder, and mesenteric lymph nodes will be edematous, and a pseudodiphtheritic membrane lining the distal small intestines and colon may be observed. this membrane is not normally seen in the goat (smith and sherman, ) . splenomegaly may be present. aborted fetuses will often be autolysed. placentitis, placental necrosis, and hemorrhage are commonly seen. serologic evidence of recent infection can be demonstrated in the dam. salmonella can be isolated from the aborted tissues. pathogenesis. after ingestion, the organism proliferates in the intestine. damage to the intestines and the resulting diarrhea are due to the bacterial production of cytoxin and endotoxin. although the salmonella organisms will be taken up by phagocytic cells involved in the inflammatory response, they survive and multiply further. septicemia is a common sequela, with the bacteria localizing throughout the body. in latently infected animals, it is often shed from the gallbladder and mesenteric lymph nodes. younger animals may be susceptible because of immature immunity and intestinal flora and higher intestinal ph. carriers may develop clinical disease when stressed. differential diagnoses. in young animals, differentials include other enteropathogens: escherichia coli, rotavirus and coronavirus, clostridia, cryptosporidia, and other coccidial forms. these pathogens may also be present in the affected animals. differentials in adults include bovine viral diarrheas and winter dysentery in cattle and parasitemia and enterotoxemia in all ruminants. prevention and control. affected animals should be isolated during herd outbreaks. samples for culture should include herdmates, water and feed sources, recently arrived livestock (other species), and area wildlife, including birds and rodents. repeated cultures, culling of animals, intensive cleaning, and disinfection of facilities are all important during outbreaks. the bacteria survive for about a week in moist cow manure. vaccination using the commercially available killed bacterin or autologous bacterins may be useful in outbreaks involving pregnant cattle, although the j- bacterin is now considered better. treatment. nursing care includes rehydration and correction of acid-base abnormalities. antibiotic therapy may be useful in cases with septicemia, but it is controversial because it may induce carrier animals. gentamicin, trimethoprim-sulfadiazine, ampicillin, enrofloxacin, and amikacin antibiotics may be successful. negative, rod-shaped bacterium. type a is more virulent than type b. clinical signs. although tularemia is a disease of livestock, pets, and wild animals, sheep are most commonly affected. the disease is characterized by hyperthermia, muscular stiffness, and lymphadenopathy. infected animals move stiffly, are depressed, and are hyperthermic. anemia and diarrhea may develop, and infected lymph nodes enlarge and may ulcerate. mortality may reach %. animals that recover will have immunity of long duration. epizootiology and transmission. the disease is most commonly transmitted by ticks or biting flies. the wood tick, dermacentor andersoni, is an important vector in transmitting the disease in the western united states, and, as natural hosts, wild rodents and rabbits tend to be reservoirs of the pathogen. research complications. salmonellosis is zoonotic, and some serotypes of the organism have caused fatalities even in immunocompetent humans. attempts should be made to identify and cull carrier animals. pathogenesis. the organisms, entering the tick bite wound, move via lymphatics to lymph nodes and subsequently to the bloodstream, where they cause septicemia. the organisms can also be transmitted orally through contaminated water. etiology. spirochete-like organisms are associated with this disease; it is now recognized that the agent is not a chlamydial organism. the disease has been reported only in the foothills bordering the central valley of california. necropsy findings. ticks may also be present on the carcasses. suppurative, necrotic lymph nodes are typical. lungs will be congested and edematous. diagnosis is confirmed by prompt culturing of the organism from lymph nodes, spleen, or liver where granulomatous lesions form; p. tularensis does not survive for long periods in carcasses. serological findings may also be helpful. clinical signs. cows that become infected with the causative agent before months of gestation abort or give birth to weak calves without any clinical sign of infection. cows infected after months of gestation give birth to normal calves. affected cows rarely abort in subsequent pregnancies. the tick vector is ornitho- necropsy. fetuses show several pathological changes, including enlargement of the cervical lymph nodes, spleen, and liver. the calf's thymus will be small, and histologically there will be losses of thymic cortical lymphocytes. histologic changes in lymph nodes and spleen include vasculitis, necrosis, and histiocytosis. treatment. chlortetracycline treatment has been effective in controlling this disease. etiology. tularemia is caused by pasteurella (francisella) tularensis a nonmotile, non-spore-forming, aerobic, gram-control and prevention. eliminating the tick vectors can prevent tularemia. animals should be provided with fresh water frequently. the organism can survive in freezing conditions and in water and mud for long periods of time. caretakers, veterinarians, and researchers should take special precautions before handling the tissues of infected sheep, because this is a method of zoonotic spread. research complications. the disease is zoonotic, and transmission to people may result from tick bites or from handling contaminated tissues. although not a major disease of concern in sheep, researchers using potentially infected animals from western range states of the united states should be aware of it. the organism is antigenically related to brucella spp. etiology. yersiniosis is caused by infections with yersinia enterocolitica, a gram-negative, aerobic, and facultative anaerobe of the family enterobacteriaceae. there are serotypes reported for y. enterocolitica. yersinia pseudotuberculosis infections have also been seen in ruminants. enteric infections predominate in the diseases caused by these bacteria. clinical signs and diagnosis. clinical disease may be seen rarely in many groups of ruminants. goats of - months old suffer from the enteric form of the disease, which is characterized by sudden death or the acute onset of watery diarrhea lasting or more days. spontaneous abortions and weak neonates are also clinical manifestations of infection. lactating does may have mastitis that becomes chronically hemorrhagic. bacteremia results in internal abscesses, abortion, and acute deaths. yersinia pseudotuberculosis has been associated with laboratory goat epizootics (obwolo, ) . diarrhea in pastured sheep, stressed by other factors, has also been reported. diagnosis is based on culture and serology. epizootiology and transmission. the bacteria are carried by wild birds and rodents, and transmission is by ingestion of contaminated feed and water. research complications. yersinia is zoonotic. prevention and control. control measure are not well defined, because the epidemiology of the disease is poorly understood (smith and sherman, ) . tissues from affected goats must be handled and disposed of properly. areas housing affected goats must be thoroughly sanitized. treatment. in case of an abortion storm, treatment of goats with tetracycline has been useful. other broad-spectrum antibiotics may also be useful. clinical signs. contagious caprine pleuropneumonia is characterized by severe dyspnea, nasal discharge, cough, and fever (mcmartin et al., ) . infections with other mycoplasma species also have similar clinical signs. septicemia without respiratory involvement may also be a presentation. epizootiology and transmission. this disease is highly contagious, with high morbidity and mortality. transmission is by aerosols. mycoplasma mycoides subsp, mycoides has become a serious cause of morbidity and mortality of goat kids in the united states. necropsy. large amounts of pale straw-colored fluid and fibrinous pneumonia and pleurisy are typical. some lung consolidation may be present. meningitis, fibrinous pericarditis, and fibrinopurulent arthritis may also be found. diagnosis is usually made at necropsy by culture of the organism from lungs and other internal organs. differential dagnosis. in the united states, the principal differential for m. mycoides subsp, mycoides is caprine arthritis encephalitis. treatment. tylosin and oxytetracycline are effective. some infections are slow to resolve. prevention and control. vaccines are available in some areas. infected herds are quarantined. new goats should be quarantined before introduction to the herd. research complications. the worldwide distribution of the f biotype, as well as the aerosol transmission and high mor-bidity and mortality characteristics of mycoplasmal infectious, make these infections economically important diseases. considerable attention is presently given to this genus as a source of morbidity and mortality in goats. iv. mycoplasma conjunctivae (mycoplasmal keratoconjunctivitis) etiology. mycoplasma conjunctivae causes infectious conjunctivitis, or pinkeye, in sheep and goats with associated hyperemia, edema, lacrimation, and corneal lesions. mycoplasma mycoides subsp, mycoides, m. agalactiae, m. arginini, and acholeplasma oculusi have also been associated with keratoconjunctivitis in these species. respiratory disease and other infections, such as mastitis, may also be observed. clinical signs and diagnosis. all ages of animals may be affected. initially, lacrimation, conjunctival vessel injection, and then keratitis and neovascularization are seen. sometimes uveitis is evident. although the presentation is usually unilateral, bilateral involvement is possible. recurring infections are common. culturing provides the better diagnostic information, and cultures will be positive even after clinical signs have diminished. ily between animals by direct contact. animals can become reinfected, and carrier animals may be a factor in outbreaks. necropsy. it is unlikely that animals would die or be euthanized and undergo necropsy for this problem. conjunctival scrapings would include neutrophils during earlier stages and lymphocytes during later stages. epithelial cell cytoplasm should be examined for organisms. differential diagnosis. the primary differential in sheep and goats is chlamydia, as well as branhamella, rickettsia (colesiota) conjunctivae, and infectious bovine rhinotracheitis in goats only. it is important to consider these differentials if arthritis, pneumonia, or mastitis is present in the group or the individual. treatment. animals do recover spontaneously within about weeks. tetracycline ointments and powders are also used. third-eyelid flaps may be necessary if corneal ulceration develops. prevention and control. new animals should be quarantined and, if necessary treated, before introduction to the flock or herd. etiology. eperythrozoonosis is a rare, sporadic, noncontagious, blood-borne disease in ruminants worldwide caused by the rickettsial agent eperythrozoon. host-specific species of importance are e. ovis, the causative species in sheep and goats, and e. wenyoni, e. tegnodes, and e. tuomii, the causative agents in cattle. although the disease is of minor importance, it can cause severe anemia and debilitation in affected animals. haemobartonella bovis is also rare, and is usually found only in association with other rickettsial diseases. clinical signs and diagnosis. the disease is more severe in sheep. following an incubation period of - weeks, infected animals exhibit episodic hyperthermia, weakness, and anemia. losses may be greater in younger lambs. cattle are usually latently infected but may have swollen and tender teats and legs. fever, anemia, and depression will be present if the cattle are stressed by another systemic disease. diagnosis is based on clinical evidence of anemia and is confirmed by observing the rickettsiae on the surface of red blood cells in a blood smear. epizootiology and transmission. the rickettsial organisms are transmitted typically to young sheep by biting insects, ticks, contaminated needles or blood-contaminated surgical instruments. necropsyfindings. necropsy findings include splenic enlargement and tissue icterus. has resulted in transient hyperthermia, mild respiratory disease, and mastitis. abortions, stillbirths, and births of weak lambs are also seen. epizootiology and transmission. coxiella burnetii is extremely resistant to environmental changes as well as to disinfectants; persistence in the environment for a year or longer is possible. the organism is associated with either a free-living or an arthropod-borne cycle. coxiella burnetii is found in a variety of tick species, such as ixodid or argasid, where it replicates and is excreted in the feces. once introduced into a mammal, coxiella may be maintained without a tick intermediate. the organism is especially concentrated in placental tissues, replicates in trophoblasts, and will be in reproductive fluids. additionally, the organism is shed in milk, urine, feces, and oronasal secretions. necropsy findings. no specific lesion will be seen in aborted or stillborn fetuses, but necrotizing placentitis will be a finding in cases of abortion. the placenta will contain white chalky plaques and a red-brown exudate. the disease can be diagnosed by identifying the rickettsial organisms in smears of placental secretions. the organism has been found in the placentas of clinically normal animals. the organism stains red with modified ziehl-neelsen and macchiavello stains and purple with giemsa stain. pathogenesis. the organism invades and destroys red blood cells. it is believed that intravascular hemolysis and erythrophagocytosis contribute to the macrocytic anemia. as with other red blood cell parasites, splenectomy aggravates the disease. differential diagnosis. because of the organisms' similarity to chlamydia, confirmation must be made by culture techniques, immunofluorescent procedures, elisa, and complement fixation tests. differential diagnosis. clontridium novyi type d, babesiosis, and leptospirosis are the primary differentials. prevention and control. following strict sanitation practices for surgical procedures and controlling external parasites prevent the disease. treatment. treatment is not usually recommended, but oxytetracycline has been used. sheep will develop immunity if supported nutritionally during the disease. research complications. splenectomized animals are the experimental models used to study these diseases. ii. q fever, or query fever (coxiella burnetii) etiology. coxiella burnetii is a small, gram-negative, obligate intracellular rickettsial organism that causes query fever and is regarded as a major cause of late abortion in sheep. clinical signs. infection of ruminants with c. burnetii is usually asymptomatic. experimental inoculation in other mammals treatment. coxiella can be treated with oxytetracyclines. a vaccine is not commercially available. prevention and control. any aborting animals should be segregated from other animals, and other pregnant animals should be treated prophylactically with tetracycline. serologic screening of ruminant sources should be performed routinely. barrier housing, a review of ventilation exhaust, and defined handling procedures are often required. all placentas and all aborted tissues should be handled and disposed of carefully. q fever has been reported in many mammalian species, including cats. research complications. coxiella burnetii-free animals are particularly important in studies involving fetuses and placentation. because of its zoonotic potential, c. burnetii presents a unique problem in the animal research facility environment. a single organism has been shown to cause disease. some of the greatest concerns are the risk to immunocompromised individuals, pregnant women, and other animals, and the presence of carrier animals or those that may shed the organism in placentas, for example. etiology. the ruminant adenoviruses are dna viruses that cause respiratory and reproductive tract diseases. nine antigenic types of the bovine adenovirus have been identified, with type associated with respiratory disease. two of the ovine and two of the caprine antigenic types have been identified. clinical signs. signs of infection range from subclinical to severe, including pneumonia, enteritis, conjunctivitis, keratoconjunctivitis, weak calf syndrome, and abortion. respiratory tract and intestinal tract diseases may be concurrent. infections caused by this virus are often found associated with other viral and bacterial infections. epizootiology and transmission. the virus is believed to be widespread, but prevalence and characteristics of infection have not been characterized. transmission of adenoviruses in other species (e.g., canine) is by aerosols or fecal-oral routes. necropsy findings. lesions found after experimental infections include atelectasis, edema, and consolidation of the lungs. etiology. the bluetongue virus is an rna virus in the orbivirus genus and reoviridae family. five serotypes ( , , , , and ) have been identified in the united states, where it is seen mostly in western states. bluetongue is an acute arthropodborne viral disease of ruminants, characterized by stomatitis, depression, coronary band lesions, and congenital abnormalities (bulgin, ) . clinical signs and diagnosis. sheep are the most likely to show clinical signs. clinical disease is less common in goats and cattle. early in the infection, animals will spike a fever and will develop hyperemia and congestion of tissues of the mouth, lips, and ears. the virus name, bluetongue, is associated with the typical cyanotic membranes. the fever may subside, but tissue lesions erode, causing ulcers. increased salivary discharges and anorexia are often related to ulcers of the dental pad, lips, gums, and tongue, although salivation and lacrimation may precede apparent ulceration. chorioretinitis and conjunctivitis are also common signs in cattle and sheep. lameness may be observed associated with coronitis and is evident in the rear legs. skin lesions such as drying and cracking of the nose, alopecia, and mammary glands are also observed. secondary bacterial pneumonia may also occur. animals may also develop severe diarrhea and become recumbent. sudden deaths due to cardiomyopathy may occur at any time during the disease. hematologically, animals will be leukopenic. the course of the disease is about weeks, and mortality may reach %. if animals are pregnant, the virus crosses the placenta and causes central nervous system lesions. abortions may occur at any stage of gestation in cattle. prolonged gestation may result from cerebellar hypoplasia and lack of normal sequence to induce parturition. cerebellar hypoplasia will also be present in young born of the infected dams, as well as hydrocephalus, cataracts, gingival hyperplasia, or arthrogryposis. diagnosis is suspected with the characteristic clinical signs and exposure to viral vectors. virus isolation is the best diagnostic approach if blood is collected during the febrile stage of the disease or brains from aborted fetuses. fluorescent antibody tests, elisa, virus neutralization tests, pcr, and agar gel immunodiffusion (agid) tests are also used to confirm the diagnosis. necropsy findings. at necropsy, erosive lesions may be observed around the mouth, tongue, palate, esophagus, and pillars of the rumen. ulceration or hyperemia of the coronary bands may also be seen. many of the internal organs will contain petechial and ecchymotic hemorrhages of the surfaces, and hemorrhage may be seen at the base of the pulmonary artery. pathogenesis. the virus multiplies in the hemocoel and salivary glands of the fly and is excreted in transmissible form in the insect's saliva. after entering the host, the virus causes prolonged viremia. the incubation period is - days. the virus migrates to and attacks the vascular endothelium. the resulting vasculitis accounts for the lesions of the skin, mouth, tongue, esophagus, and rumen and the edema often found in many tissues. ballooning degeneration of affected tissues, followed by necrosis and ulceration, occurs. the effects on fetuses appear to be due to generalized infections of developing organs. differential diagnosis. differentials include other infectious vesicular diseases such as foot-and-mouth disease, contagious ecthyma, bovine viral diarrhea virus-mucosal disease, infectious bovine rhinotracheitis, bovine papular stomatitis, and malignant catarrhal fever. rinderpest is a differential in countries where it is endemic. photosensitization should be considered. foot rot is a differential for the lameness and coronitis. differentials for the manifestations such as arthrogryposis include border disease virus and genetic predispositions of some breeds such as charolais cattle and merino sheep. prevention and control. cellular and humoral immunity are necessary for protection from infection. the bluetongue virus is insidious because the genome is capable of reassortment, and some vaccines will not have the antigenic components represented in the local infection. in addition, there is little to no cross protection between strains. modified live vaccines are available in some parts of the united states but should not be used in pregnant animals. vaccinating lambs and rams in an outbreak is worthwhile, for example, but vaccinating lategestation ewes may cause birth defects or abortions. congenital defects are more common from vaccine use than from naturally occurring infection. minimizing exposure to the vector in endemic areas will decrease the incidence of the disease. treatment. supportive care and nursing care are helpful, including gruels or softer feeds, easily accessed water, and shaded resting places. nonsteroidal anti-inflammatory drugs are often administered. for the cases of secondary bacterial pneumonia and some cases of bluetongue conjunctivitis, antibiotics may be administered. research complications. this is a reportable disease because clinical signs resemble foot-and-mouth disease and other exotic vesicular diseases. etiology. bovine lymphosarcoma refers to lymphoproliferative diseases in young cattle that are not associated with bovine leukemia virus (blv) infection, and those in older cattle that are associated with b lv. b lv is a b lymphocyte-associated retrovirus (johnson and kaneene, a,b,c) . clinical signs. forms of bovine lymphosarcoma that are not associated with blv infection are calf, or juvenile; thymic, or adolescent (animals months to years old); and cutaneous (any age). the calf form is rare and characterized by generalized lymphadenopathy. onset may be sudden, and the disease is usually fatal within a few weeks. signs include lymphadenopathy, anemia, weight loss, and weakness. some animals may be paralyzed because of spinal cord compression from subperiosteal infiltration of neoplastic cells. the adolescent form is also rare, the course rapid, and the prognosis poor. the disease is seen most often in beef breeds such as hereford cattle and is characterized by space-occupying masses in the neck or thorax. these masses are also often present in the brisket. secondary effects of the masses are loss of condition, dysphagia, rumen tympany, and fatal bloat. the cutaneous presentation has a longer course and may wax and wane. the masses are found at the anus, vulva, escutcheon, shoulder, and flank; they are painful when palpated, raised, and often ulcerated. the animals are anemic, and neoplastic involvement may affect cardiac function. generalized or limited lymphadenopathy may be apparent. only the adult, or enzootic, form of bovine lymphosarcoma is associated with blv infection. many animals do not develop any malignancies or clinical signs of infection and simply remain permanently infected. some cows manifest disease only during the periparturient period. malignant lymphoma is the more common, whereas leukosis, due to b-lymphocyte proliferation, is rare. clinical signs are loss of condition and a drop in production of dairy cattle, anorexia, diarrhea, ataxia, paresis, and other signs dependent on the location of the neoplastic tissue. tumors are associated with lymphoid tissues. common sites also include the abomasum, spinal canal, and uterus. cardiac tumors develop at the right atrial or left ventricular myocardium, and associated beat and rate abnormalities may be auscultated. the common ocular manifestation of the disease is exophthalmos due to retrobulbar masses. many internal organs may be involved, and tumors may be palpable per rectum. secondary infections will be due to immunosuppression and the weakened state of the animal. sheep have acquired blv infection naturally and have been used as experimental models; in both situations, this species is susceptible to tumor and leukemia development. goats seroconvert but do not develop the clinical syndromes. diagnosis is based on the animal's age, clinical signs, serology, hematology findings according to the form, aspirates or biopsies of masses, and necropsy findings. kits are available for running agid, for which the blv antigens gp- and gp- are used; antibodies may be detected within weeks after exposure and may also help in predicting disease in clinically normal cattle. elisa and pcr diagnostic aids will also be helpful. worldwide. it is estimated that at least % of the cattle in the united states are infected with blv. as few as % of these animals develop lymphosarcoma, but the adult form of the disease described here is the most common bovine neoplastic disease in the united states. larger herds tend to have higher rates. genetic predisposition may be involved; in addition to the presence of blv, the type of bovine lymphocyte antigen (bola) may be correlated to resistance or susceptibility and to the course of the disease. transmission is believed to be by inhalation of blv in secretions; in colostrum; horizontally by contaminated equipment not sanitized between cattle; and by rectum (e.g., mucosal irritation during per-rectum exams or procedures). natural-service bulls may transmit the infection to cows. cows infected with blv may transmit the infection to their calves in utero. tabanid and other flies also serve as vectors, but these represent a minor means of transmission. necropsy findings. neoplastic infiltration of many organs and tissues are found in the calf form and the cutaneous forms. tumors may be local or widely distributed in the enzootic form. definitive diagnosis of neoplastic tissue specimens is by histology. pathogenesis. as with other retroviruses, the blv integrates viral dna into host target cell dna by means of the reverse transcriptase enzyme, creating a provirus. epizootiology and transmission. the virus is reported to be widespread. occurrence is often seasonal, and biting insects may be vectors. transmission with successful infection requires deep penetration of the skin. transmission may be by contaminated milkers' hands, contaminated equipment, and other fomites. differential diagnosis. differential diagnoses include other diseases that cause lesions on teats such as pseudocowpox, papillomatosis, and vesicular stomatitis. other vesicular diseases may be considered, but other more severe clinical signs might be associated with those. there is no vaccine for this disease. development and maintenance of a blv-free herd, or controlling infection within a herd, requires financial and programmatic commitments: blv-positive and blv-negative animals maintained separately; serologic testing (such as at least every months) and separating positive animals; and washing and then disinfecting instruments, needles (or using sterile singleuse products), and equipment for ear tagging and dehorning and other such equipment between animals. a fresh rectal exam sleeve and lubricant should be used for each animal examined. otherwise serologically positive cows may have undetectable antibodies during the periparturient period. embryo transfer recipients should be negative, and the virus will not be transferred by the embryonic stage. calves should be fed colostrum from serologically negative cows. treatment. treatment regimens of corticosteroids and cancer chemotherapeutic agents provide only short-term improvement. in cases where ova, embryos, or semen need to be collected, supportive care for the affected animals is essential. research complications. the united states and several countries, some in europe, have official programs for eradication of enzootic bovine leukosis. prevention and control. established milking hygiene practices are important control measures: having milkers wash their hands with germicidal solutions or wear gloves, cleaning equipment between animals, and separating affected animals. treatment. there is no treatment, and affected animals should be separated from the herd and milked last. lesions can be cleaned and treated with topical antibacterials. etiology. the bovine viral diarrhea virus (bvdv) is a pestivirus of the flaviviridae family. the flaviviridae include hog cholera virus and border disease virus of sheep. the virus contains a single strand of positive-sense rna. a broad range of disease and immune effects is produced by b vdv only in cattle. in addition, this virus is important in the etiology of bovine pneumonias. bovine viral diarrhea/mucosal disease (bvd/md) is one of the most important viral diseases and one of the most complex diseases of cattle. strains of bvdv are characterized as cytopathic (cp) and noncytopathic (ncp), based on cell-culture growth characteristics. the virus has also been categorized as type and type isolates. heterologous strains exist that may confound even sound vaccination programs. etiology. bovine herpesvirus causes bovine herpes mammillitis, a widespread disease characterized by teat and udder lesions, as well as oral and skin lesions. clinical signs and diagnosis. lesions begin suddenly with teat swelling; the tissue will be edematous and tender when touched. the udder lesions may extend to the perineum. the lesions progress to vesicles, then to ulcers; these may take weeks to heal. lesions rarely may also develop focally around the mouth and generally on the skin of the udder. secondary mastitis may occur, because of bacteria associated with the scabs. diagnosis is by clinical signs and serologically. clinical signs and diagnosis. signs of bvdv infections may be subclinical but also include abortions, congenital abnormalities, reduced fertility, persistent infection (pi) with gradual debilitation, and acute and fatal disease. the presence of antibodies, whether from passive transfer or immunizations, does not necessarily guarantee protection from the various forms of the disease. an acute form of the disease, caused by type bvdv, occurs in cattle without sufficient immunity. after an incubation period of - days, clinical signs include fever, anorexia, oculonasal discharge, oral erosions (including on the hard palate), diarrhea, and decreased milk production. the disease course may be shorter with hemorrhagic syndrome and death within days. clinical signs of b vdv in calves also include severe enteritis and pneumonia. when susceptible cows are infected in utero from gestational be found extending throughout the gastrointestinal tract to the days - , or gestational cows are vaccinated with a modi-cecum. the respiratory tract lesions will often be complicated fled live vaccine, abortion or stillbirth result. congenital defects caused by bvdv during gestational days - include impaired immunity (thymic atrophy), cerebellar hypoplasia, ocular defects, alopecia or hypotrichosis, dysmyelinogenesis, hydranencephaly, hydrocephalus, and intrauterine growth retardation. typical signs of cerebellar dysfunction will be evident in calves, such as wide-based stance, weakness, opisthotonus, hyperflexion, hypermetria, nystagmus, or strabismus. some severely affected calves will not be able to stand. ophthalmic effects include retinal degeneration and microphthalmia. fetuses can also be infected in utero, normal at birth, immunotolerant to the virus, and persistently infected (pi). the term mucosal disease is commonly associated with this form of the infection. many pi animals do not survive to maturity, however, and many have weakened immune systems. the pi animals are important because they shed virus and will probably show the clinical signs of mucosal disease (md) caused by a cp b vdv strain derived from an ncp b vdv strain. these md clinical signs include fever, anorexia, and profuse diarrhea that may include blood and fibrin casts, and oral and pharyngeal erosions, as well as erosion at the interdigital spaces and on the teats and vulva. many other associated clinical signs include anemia, bloat, lameness, or corneal opacities and discharges. secondary effects of hemorrhage and dehydration also contribute to the morbidity and mortality. animals that do not succumb to the disease will be chronically unthrifty, debilitated, and infection-prone. diagnosis in affected calves is based on herd health history, clinical signs, and antibodies to b vdv in precolostral serum. viral culturing from blood may be useful. in older animals, oral lesions, serology, detection of viral antigen, and virus isolation contribute to the diagnosis. leukopenia, and especially lymphopenia, are seen. serology must be interpreted with the awareness of the possibility of pi immunotolerant animals. vaccination against the disease carries its own set of side effects and potential problems, especially when using modified live vaccines, whether against cp or ncp strains. the condition of the animals is also a variable. epizootiology and transmission. bvdv is present throughout the world. transmission occurs easily by direct contact between cattle, from feed contaminated with secretions or feces, and by aborted fetuses and placentas. pi females transmit the virus to their fetuses. semen also is a source of virus. necropsy findings. in affected calves, histopathologic findings include necrosis of external germinal cells, focal hemorrhages, and folial edema. later in the disease, large cavities develop in the cerebellum, and atrophy of the cerebellar folia and thin neuropil are evident. older calves may have areas of intestinal necrosis. in cases where oral erosions occur, erosions will by secondary bacterial pneumonia. when the hemorrhagic syndrome develops, petechiation and mucosal bleeding will be present. pathogenesis. the cp and ncp strains are thought to be related mutations of the bvdv; the cp short-lived isolates are believed to arise from the ncp strains. the ncp strains are those present in the pi animals, and the strains are maintained in cattle populations. cp and ncp isolates vary in virulence, and classification of these types is based on viral surface proteins. considerable antigenic variation also exists between strains and types. other viral infections, such as bovine respiratory syncytial virus and infectious bovine rhinotracheitis, may also be present in the same animals. the pathology caused by b vdv is due to its ability to infect epithelial cells and impair the functioning of immune cell populations through out the bovine system. in type bvdv hemorrhagic syndrome, death results from viral-induced thrombocytopenia. in fetuses, the virus infects developing germinal cells of the cerebellum. the purkinje's cells in the granular layer are killed, and necrosis and inflammation follow. the immune effects are the result of the virus's interfering with neutrophil and macrophage functions and of lymphocyte blastogenesis. all of these predispose the affected animals to bacterial infections with pasteurella haemolytica. b vdv damages dividing cells in fetal organ systems, resulting in abortions and congenital effects. differential diagnosis. many differentials must be considered for the clinical manifestations of b vdv infections. differentials for enteritis of calves include viral infections, cryptosporidia, escherichia coli, salmonella, and coccidia. salmonella, winter dysentery, johne's disease, intestinal parasites, malignant catarrhal fever (mcf), and copper deficiency are differentials for the diarrhea seen in the disease in adult animals. respiratory tract pathogens such as bovine respiratory syncytial virus, pasteurella, haemophilus, and mycoplasma must be considered for the respiratory tract manifestations. oral lesions are also produced by mcf, vesicular stomatitis, bluetongue, and papular stomatitis. infectious bovine herpesvirus , leptospirosis, brucellosis, trichomoniasis, and mycosis should be considered in cases of abortion. prevention and control. combined with sound management in a typical cattle herd, vaccination is the best way to prevent b vdv and should be integrated into the herd health program, timed appropriately preceding breeding, gestation, or stressful events. vaccine preparations for b vdv are modified live virus (mlv) or killed virus. each has advantages and disadvantages. the former induces rapid immunity (within week) after a single dose, provides longer duration of immunity against sev-eral strains, and induces serum neutralizing antibodies. mlv vaccines are not recommended for use in pregnant cattle, may induce mucosal disease, and may be immunosuppressive at the time of vaccination. the immunosuppression is detrimental if cattle are concurrently exposed to field-strain virus because it will facilitate infection and possible clinical disease. the mlv strains may cross the placenta, resulting in fetal infections. the killed vaccines are safer in pregnant animals but require booster doses after the initial immunization, may need to be given - times per year, and do not induce cell-mediated immunity. passive immunity may protect most calves for up to - months of age. subsequent vaccination with mlv may provide lifelong immunity, but this is not guaranteed. annual boosters are recommended to protect against vaccine breaks. the virus persists in the environment for weeks and is susceptible to the disfectants chlorhexidine, hypochlorite, iodophors, and aldehydes. maintenance of a closed herd to prevent any possibility of the introduction of the virus is difficult. isolation of new animals, avoidance of the purchase of pregnant cows, scrutiny of records from source farms, use of semen tested bulls, minimization of stress, testing of embryo-recipient cows, and maintainenance of populations of ruminants (smaller or wild species) separately on the premises will minimize viral exposure. other management strategies may require a program for testing and culling pi cattle. this can be expensive but may be a worthwhile investment to remove the virus shedders from a herd. no specific treatment is available. supportive care and treatment with antibiotics to prevent secondary infection are recommended. animals that survive the infection should be evaluated a month after recovery to determine their status as pi or virus-free. etiology. cache valley virus (cvv), of the arbovirus genus of the bunyaviridae family, is a cause of congenital defects in lambs. cvv infection in fetal and newborn lambs include arthrogryposis, microencephaly, hydranencephaly, porencephaly, cerebellar hypoplasia, and micromyelia. stillbirths and mummified fetuses are seen. lambs will be born weak and will act abnormally. diagnosis is by evidence of seroconversion in precolostral blood samples or fetal fluids, as the result of in utero infection. western united states, although it has been isolated in a few midwestern states. although considered a disease of sheep, virus has been isolated from cattle and from wild ruminants and antibodies found in white-tailed deer. transmission is by arthropods during the first trimester of pregnancy. etiology. caprine arthritis encephalitis virus (caev) occurs worldwide, with a high prevalence in the united states. caprine arthritis encephalitis (cae) is considered the most important viral disease of goats. the caev is in the lentivirus genus of the retroviridae family. it causes chronic arthritis in adults and encephalitis in young. caev is in the same viral genus as the ovine progressive pneumonia virus (oppv). clinical signs and diagnosis. the most common presentation in goats is an insidious, progressive arthritis in animals months of age and older. animals become stiff, have difficulty getting up, and may be clinically lame in one or both forelimbs. carpal joints are so swollen and painful that the animal prefers to eat, drink, and walk on its "knees." in dairy goats, milk production decreases, and udders may become firmer. this retrovirus also causes neurological clinical signs in young kids - months old. kids may be bright and alert, afebrile, and able to eat normally even when recumbent. some kids may initially show unilateral weakness in a rear limb, which progresses to hemiplegia or tetraplegia. mild to severe lower motor neuron deficits may be noted, but spinal reflexes are intact. clinical signs may also include head tilt, blindness, ataxia, and facial nerve paralysis. older animals in the group may experience interstitial pneumonia or chronic arthritis. the pneumonia is similar to the pneumonia in sheep caused by oppv; the course is gradual but progressive, and animals will eventually lose weight and have respiratory distress. some animals in a herd may not develop any clinical signs. diagnosis is based on clinical signs, postmortem lesions, and positive serology for viral antibodies to caev. an agar gel immunodiffusion (agid) test identifies antibodies to the virus and is used for diagnosis. kids acquire an anti-caev antibody in colostrum, and this passive immunity may be interpreted as indicative of infection with the virus. the antibody does not prevent viral transmission. ep&ootiology and transmission. the virus is prevalent in most industrialized countries. the common means of transmission, from adults to kids, is in the colostrum and milk in spite of the presence of anti-caev antibody in the colostrum. transmission may occur among adult goats by contact. intrauterine transmission is believed to be rare. transmission to sheep has occurred only experimentally; there is no documented case of natural transmission. necropsy findings. necropsy and histopathology reveal a striking synovial hyperplasia of the joints with infiltrates of lymphocytes, macrophages, and plasma cells. other histologic lesions include demyelination in the brain and spinal cord, with multifocal invasion of lymphocytes, macrophages, and plasma cells. in severe cases of mastitis, the udder may appear to be composed of lymphoid tissue. tem, resulting in the formation of non-neutralizing antibody to viral core proteins and envelope proteins. immune complex formation in synovial, mammary gland, and neurological tissue is thought to result in the clinical changes observed. most commonly, the carpal joint is affected, followed by the stifle, hock, and hip. the infection is lifelong. differential diagnosis. the differential diagnosis for the neurologic form of caev should include copper deficiency, enzootic pneumonia, white muscle disease, listeriosis, and spinal cord disease or injury. the differential diagnosis for caev arthritis should include chlamydia and mycoplasma. prevention and control. herds can be screened for cae by testing serologically, using an agid or an enzyme-linked immunosorbent assay (elisa) test. the elisa is purported to be more sensitive, whereas the agid is more specific. individual animals show great variation in development of antibody. because cae is highly prevalent in the united states, and because seronegative animals can shed organisms in the milk, retesting herds at least annually may be necessary. recently, an immunoprecipitation test for cae has been developed that has high sensitivity and specificity. control measures include management practices such as test and cull, prevention of milk transmission, and isolation of affected animals. parturition must be monitored, and kids must be removed immediately and fed heat-treated colostrum ( ~ for hr). caev-negative goats should be separated from caevpositive goats. treatment. there is no treatment for caev. is also referred to as bovine herpesvirus (bhv- ) and is an alphaherpesvirus. ibrv causes or contributes to several bovine syndromes, including respiratory and reproductive tract diseases. it is one of the primary pathogens in the bovine respiratory disease complex. strains include bhv-i. (associated with respiratory disease), bhv . (associated with respiratory and genital diseases), and bhv . (associated with neurological diseases), which has been reclassified as bovine herpesvirus . clude conjunctivitis, rhinotracheitis, pustular vulvovaginitis, balanoposthitis, abortion, encephalomyelitis, and mastitis. the respiratory form is known as infectious bovine rhinotracheitis, and clinical signs may range from mild to severe, the latter particularly when there are additional respiratory viral infections or secondary bacterial infections. the mortality rate in more mature cattle is low, however, unless there is secondary bacterial pneumonia. fever, anorexia, restlessness, hyperemia of the muzzle, gray pustules on the muzzle (that later form plaques), nasal discharge (that may progress from serous to mucopurulent), hyperpnea, coughing, salivation, conjunctivitis with excessive epiphora, and decreased production in dairy animals are typical signs. open-mouth breathing may be seen if the larynx or nasopharygneal areas are blocked by mucopurulent discharges. neonatal calves may develop respiratory as well as general systemic disease. in these cases, in addition to the symptoms already noted, the soft palate may become necrotic, and gastrointestinal tract ulceration occurs. young calves are most susceptible to the encephalitic form; signs include dull attitude, head pressing, vocalizations, nystagmus, head tilt, blindness, convulsions, and coma, as well as some signs, such as discharges, seen with respiratory tract presentations. this form is usually fatal within days. abortion may occur simultaneously with the conjunctival or respiratory tract diseases, when the respiratory infection appears to be mild, or may be delayed by as much as months after the respiratory tract disease signs. infectious pustular vulvovaginitis is most commonly seen in dairy cows, and clinical signs may be mild and not noticed. otherwise, signs are fever, depression, anorexia, swelling of the vulvar labia, vulvar discharge, and vestibular mucosa reddened by pustules. the cow will often carry her tail elevated away from these lesions. these soon coalesce, and a fibrous membrane covers the ulcerated area. if uncomplicated, the infection lasts about - days, and lesions heal in weeks. younger infected bulls may develop balanoposthitis with edema, swelling, and pain such that the animals will not service cows. epizootiology and transmission. ibrv is widely distributed throughout the world, and adult animals are the reservoirs of infection. the disease is more common in intensive calf-rearing situations and in grouped or stressed cattle. transmission is primarily by secretions, such as nasal, during and after clinical signs of disease. modified live vaccines are capable of causing latent infections. necropsy findings. fibrinonecrotic rhinotracheitis is considered pathognomic for ibrv respiratory tract infections. there will be adherent necrotic lesions in the respiratory, ocular, and reproductive mucosa. when there are secondary bacterial infections, such as pasteurella bronchopneumonia, findings will include congested tracheal mucosa and petechial and ecchymotic hemorrhages in that tissue. lesions from the encephalitic form include lymphocytic meningoencephalitis and will be found throughout the gray matter (neuronal degeneration, perivascular cuffing) and white matter (myelitis, demyelination). intranuclear inclusion bodies are not a common finding with this herpesvirus. pathogenesis. in the encephalitic form, the virus first grows in nasal mucosa and produces plaques. these resolve within days, and the encephalitis develops after the virus spreads centripetally to the brain stem by the trigeminal nerve dendrites. latent infections are also established in neural tissue. differential diagnosis. the severe oral erosions seen with bvdv infections are rare with infectious bovine rhinotracheitis-infectious pustular vulvovaginitis (ibr-ipv). the conjunctivitis of ibr may initially be mistaken for that of a moraxella bovis (pinkeye) infection; the ibr will be peripheral, and there will not be corneal ulceration. bovine viral diarrhea virus and ibrv are the most common viral causes of bovine abortion. differentials for balanoposthitis include trauma from service. vated, attenuated, modified live, and genetically altered preparations. some are in combination with parainfluenza (pi- ) virus. the mlv preparations are administered intranasally; these are advantageous in calves for inducing mucosal immunity even when serologic passive immunity is already present and adequate. some newer vaccines, with gene deletion, allow for serologic differentiation between antibody responses from infection or immunization. bulls with the venereal form of the infection will transmit the virus in semen; intranasal vaccine may be used to provide some immunity. treatment. uncomplicated mild infections will resolve over a few weeks; palliative treatments, such as cleaning ocular discharges and supplying softened food, are helpful in recovery. antibiotics are usually administered because of the high likelihood of secondary bacterial pneumonia. the encephalitic animals may need to be treated with anticonvulsants. etiology. parainfluenza , an rna virus of the family paramyxoviridae, causes mild respiratory disease of ruminants when it is the sole pathogen. the viral infection often predisposes the respiratory system to severe disease associated with concurrent viral or bacterial pathogens. viral strains are reported to vary in virulence. serotypes seen in the smaller ruminants are distinct from those isolated from cattle. clinical signs and diagnosis. infections ranging from asymptomatic to mild signs of upper respiratory tract disease are associated with this virus by itself; infections are almost never fatal. clinical signs include ocular and nasal discharges, cough, fever, and increased respiratory rate and breath sounds. in pregnant animals, exposure to pi- can result in abortions. clinical signs become apparent or more severe when additional viral pathogens are present, such as bovine viral diarrhea virus, or a secondary bacterial infection, such as pasteurella haemolytica infection, is involved. greater morbidity and mortality will be sequelae of the bacterial infections. viral isolation or direct immunofluorescence antibody (ifa) from nasal swabs can be used for definitive diagnosis. presently it is assumed that the virus is widespread in goats, but firm evidence is lacking. for an infection of pi- only, findings will be negligible. some congestion of respiratory mucosa, swelling of respiratory tract-associated lymph nodes, and mild pneumonitis may be noted grossly and histologically. intranuclear and intracytoplasmic inclusion bodies may be present in the mucosal epithelial cells. findings will be similar but not as severe as those caused by bovine respiratory syncytial virus. immunohistochemistry may also be used. pathogenesis. pi- infects the epithelial mucosa of the respiratory tract; however, the disease is often asymptomatic when uncomplicated. differential diagnosis. differentials, particularly in cattle, include infections with other respiratory tract viruses of ruminants: ibrv, bvdv, bovine respiratory syncytial virus, and type bovine adenovirus. prevention and control. immunization, management, and nutrition are important for this respiratory pathogen, as for others. in cattle, modified live vaccines for intramuscular (im), subcutaneous (sc), or intranasal (in) administration are available. the im and sc routes provide immune protection within week after administration but will not provide protection in the presence of passively acquired antibodies. it is contraindicated for pregnant animals because it will cause abortion. the in route immunizes in the presence of passively acquired antibodies, provides immunity within days of administration, and stimulates the production of interferon. other vaccine formulations, about which less information is reported, include inactivated or chemically altered live-virus preparations; both are administered im, and followup immunizations are needed within weeks. booster vaccinations are recommended for all preparations within - months after the initial immunization. all presently marketed vaccine products come in combination with other bovine respiratory viruses as multivaccine products. the humoral immunity protects against pi- abortions. there is no approved pi- vaccine for sheep and goats. the use of the cattle formulation in these smaller ruminants is not recommended. sound management of housing, sanitation, nutrition, and preventive medicine programs are all equally important components in prevention and control. treatment. uncomplicated disease is not treated. etiology. the respiratory syncytial viruses are pneumoviruses of the paramyxoviridae family and are common causes of severe disease in ruminants, especially calves and yearling cattle. two serotypes of the bovine respiratory syncytial virus (brsv) have been described for cattle; these may be similar or identical to the virus seen in sheep and goats. clinicalfindings and diagnosis. infections may be subclinical or develop into severe illness. clinical signs include fever, hyperpnea, spontaneous or easily induced cough, nasal discharge, and conjunctivitis. interstitial pneumonia usually develops, and harsh respiratory sounds are evident on auscultation. development of emphysema indicates a poor prognosis, and death may occur in the severe cases of the viral infection. secondary bacterial pneumonia, especially with pasteurella haemolytica, with morbidity and mortality, is also a common sequela. abortions have been assciated with brsv outbreaks. diagnosis is based on virus isolation and serology (acute and convalescent). nasal swabs for virus isolation should be taken when animals have fever and before onset of respiratory disease. prevention and control. vaccination should be part of the standard health program, and all animals should be vaccinated regularly. vaccinations should be administered within - months of stressful events, such as weaning, shipping, and introduction to new surroundings. currently available vaccines include an inactivated preparation and a modified live virus preparation administered intramuscularly or subcutaneously; immunity develops well in yearling animals, and colostral antibodies develop when cows are vaccinated during late gestation. passive immunity from colostrum provides at least partial protection to calves in herds where disease is prevalent. but this immunity suppresses the mucosal iga response and serum antibody responses. the basis for successful immune protection is the mucosal memory iga, but this is difficult to achieve with present vaccine formulations. the virus is easily inactivated in the environment. preventive measures in preweaning animals should include preconditioning to minimize weaning stress. treatment. recovery can be spontaneous; however, antibiotics and supportive therapy are useful to prevent or control secondary bacterial pneumonia. in severe cases, antihistamines and corticosteriods may also be necessary. use of vaccine during natural infection is not productive and may result in severe disease. etiology. ulcerative dermatosis is a contagious disease of sheep only. it is caused by a poxvirus similar to but distinct from the causative agent of contagious ecthyma ("current veterinary therapy," ). epizootiology and transmission. these viruses are considered ubiquitous in domestic cattle and are transmitted by aerosols. teroventral lung lobes. edema and emphysema are present. as the name indicates, syncytia, which may have inclusions, form in areas of the lungs infected with the virus. necrotizing bronchiolitis, bronchiolitis obliterans, and hyaline membrane formation will be evident microscopically. crusts associated with the skin and mucous membranes of the genitalia, face, and feet (bulgin, ) . genital lesions are much more common than the facial or coronal lesions. discomfort may be associated with the lesions. paraphimosis occasionally occurs. these lesions are painful; during breeding season, animals will avoid coitus. morbidity is low to moderate, and mortality negligible if the flock is otherwise healthy. diagnosis is based on clinical signs. pathogenesis. the severe form of the disease, which often follows a mild preliminary infection, is thought to be caused by immune-mediated factors during the process of infection in the lung. virulence may vary greatly among viral strains. united states, ulcerative dermatosis is transmitted through direct contact with abraded skin of the prepuce, vulva, face, and feet. necropsy findings. necropsy would rarely be necessary to diagnose an outbreak in a healthy flock. findings will be similar to those described for contagious ecthyma. when no contact with cattle has occurred. persistently infected animals, such as lambs, are shedding reservoirs of the virus in urine, feces, and saliva throughout their lives. pathogenesis. following an incubation period of - days, the virus replicates in the epidermal cells and leads to necrosis and pustule formation. pustules rapidly break, forming weeping ulcers. the ulcers scab over and eventually form a fibrotic scar. the disease usually resolves in - weeks. rarely, the disease will persist for many months to more than a year. differential diagnosis. the main differential is contagious ecthyma, which is grossly and histopathologically associated with epithelial hyperplasia. this is also a feature of ulcerative dermatosis. imals, especially males, should not be used for breeding. treatment. affected animals should be separated from the rest of the flock. treatment is supportive, including antiseptic ointments and astringents. research complications. breeding and maintenance of the flocks' condition, because of the pain associated with eating, will be compromised during an outbreak. etiology. border disease, also known as hairy shaker disease (or "fuzzies" in the southwestern united states), is a disease of sheep caused by a virus closely related to the bovine viral diarrhea virus (bvdv), a pestivirus of the togaviridae family. goats are also affected. the virus causes few pathogenic effects in cattle. clinical signs and diagnosis. border disease in ewes causes early embryonic death, abortion of macerated or mummified fetuses, or birth of lambs with developmental abnormalities. lambs infected in utero that survive until parturition may be born weak and often exhibit a number of congenital defects such as tremor, hirsutism (sometimes darkly pigmented over the shoulders and head), hypothyroidism, central nervous system defects, and joint abnormalities, including arthrogryposis. later, survivors may be more susceptible to diseases and may develop persistent, sometimes fatal, diarrhea. the virus infection produces similar clinical manifestations in goats, except that the hair changes are not seen. diagnosis includes the typical signs described above, as well as serological evidence of viral infection. virus isolation confirms the diagnosis. wide, and reports of disease are sporadic. disease has occurred necropsy findings. lesions include placentitis, and characteristic joint and hair-coat changes in the fetus. histologically, axonal swelling, neuronal vacuolation, dysmyelination, and focal microgliosis are observed in central nervous system structures. pathogenesis. the virus entering the ewe via the gastrointestinal or respiratory tracts penetrates the mucous membranes and causes maternal and fetal viremia. infection during the first days of gestation causes embryonic death. in lambs infected between and days, the virus activates follicular development, diminishes the myelination of neurons, and causes dysfunction of the thyroid gland. infection after days of gestation results in lambs that are born persistently infected. infected lambs have high perinatal mortality; survivors have diminished signs over time but, as noted, continue to shed the virus. prevention and control. border disease can be prevented by vaccinating breeding ewes with killed-bvdv vaccine. congenitally affected lambs should be maintained separately and disposed of as soon as humanely possible. new animals to the flock should be screened serologically. if cattle are housed nearby, vaccination programs for bvdv should be maintained. treatment. there is no treatment other than supportive care for affected animals. etiology. contagious ecthyma, also known as contagious pustular dermatitis, sore mouth, or off, is an acute dermatitis of sheep and goats caused by a parapoxvirus. this disease occurs worldwide and is zoonotic. naturally occurring disease has also been reported in other species such as musk ox and reindeer. other parapoxviruses infect the mucous membranes and skin of cattle, causing the diseases bovine pustular dermatitis and pseudocowpox. clinical signs and diagnosis. the disease is characterized by the presence of papules, vesicles, or pustules and subsequently scabs of the skin of the face, genitals of both sexes, and coronary bands of the feet. lesions develop most frequently at mucocutaneous junctions and are found most commonly at the commissures of the mouth. off is usually found in young animals less than year of age. younger lambs and kids will have difficulty nursing and become weak. lesions may also develop on udders of nursing dams, which may resist suckling by offspring to nurse, leading to secondary mastitis. the scabs may appear nodular and raised above the surface of the surrounding skin. morbidity in a susceptible group of animals may exceed %. mortality is low, but the course of the disease may last up to weeks. diagnosis is based on characteristic lesions. biopsies may reveal eosinophilic cytoplasmic inclusions and proliferative lesions under the skin. electron microscopy will reveal the virus itself. disease is confirmed by virus isolation. epizootiology and transmission. all ages of sheep and goats are susceptible. seasonal occurrences immediately after lambing and after entry into a feedlot are common; stress likely plays a role in susceptibility to this viral disease. older animals develop immunity that usually prevents reinfection for at least or more years. resistant animals may be present in some flocks or herds. the virus is very resistant to environmental conditions and may contaminate small-ruminant facilities, pens, feedlots, and the like for many years as the result of scabs that have been shed from infected animals. transmission occurs through superficial lesions such as punctures from grass awns, scrapes, shearing, and other common injuries. necropsy findings. necropsy findings include ballooning degeneration of epidermal and dermal layers, edema, granulomatous inflammation, vesiculation, and cellular hyperplasia. secondary bacterial infection may also be evident. pathogenesis. the virus is typical of the poxviridae, resembling sheep poxvirus (not found in the united states) and vaccinia virus and replicating in the cytoplasm of epithelial cells. following an incubation period of - days, papules and vesicles develop around the margins of the lips, nostrils, eyelids, gums, tongue, or teats; skin of the genitalia; or coronary band of the feet. the vesicles form pustules that rupture and finally scab over. virus should be considered in both sheep and goats. an important differential in goats is staphylococcal dermatitis. prevention and control. individuals handling infected animals should be advised of precautions beforehand, should wear gloves, and should separate work clothing and other personal protective equipment. clippers, ear tagging devices, and other similar equipment should always be cleaned and disinfected after each use. colostral antibodies may not be protective. vaccinating lambs and kids with commercial vaccine best prevents the disease. dried scabs from previous outbreaks may also be used by rubbing the material into scarified skin on the inner thigh or axilla. animals newly introduced to infected premises should be vaccinated upon arrival. precautions must be taken when vaccinating animals, because the vaccine may induce orf in the animal handlers; it is not recommended to vaccinate animals in flocks already free of the disease. affected dairy goats should be milked last, using disposable towels for cleaning teat ends. treatment. affected animals should be isolated and provided supportive care, especially tube feeding for young animals whose mouths are too sore to nurse. treatment should also address secondary bacterial infections of the orf lesions, including systemic antibiotics for more severe infections. treatment for myiasis may also be necessary. the viral infection is self-limiting, with recovery in about weeks. research complications. carrier animals may be a factor in flock or herd outbreaks. contagious ecthyma is a zoonotic disease, and human-to-human transmission can also occur. the virus typically enters through abrasions on the hands and results in a large (several centimeters) nodule that is described as being extremely painful and lasting for as many as weeks. lesions heal without scarring. etiology. foot-and-mouth disease (fmd) is caused by the foot-and-mouth disease virus, a picornavirus in the aphthovirus genus. the disease is also referred to as aftosa or aphthous fever. seven immunologically distinct types of the virus have been identified, with subtypes within those . epidemics of the disease have occurred worldwide. north and central america have been free of the virus since the mid- s. this is a reportable disease in the united states; clinical signs are very similar to other vesicular diseases. cattle (and swine) are primarily affected, but disease can occur in sheep and is usually subclinical in goats. clinical signs and diagnosis. in addition to vesicle formation around and in the mouth, hooves, and teats, fever, anorexia, weakness, and salivation occur. vesicles may be as large as cm, rupture after days, and subsequently erode. secondary bacterial infections often occur at the erosions. anorexia is likely due to the pain associated with the oral lesions. high morbidity and low mortality, except for the high mortality in young cattle, are typical. diagnosis must be based on elisa, virus neutralization, fluorescent antibody tests, and complement fixation. epizootiology and transmission. domestic and wild ruminants and several other species, such as swine, rats, bears, and llamas are hosts. asymptomatic goats can serve as virus reservoirs for more susceptible cohoused species such as cattle. greater mortality occurs in younger animals. the united states, great britain, canada, japan, new zealand, and australia are fmd-free, whereas the disease is endemic in most of south america, parts of europe, and throughout asia and africa. the virus is very contagious and is spread primarily by the inhalation of aerosols, which can be carried over long distances. transmission may also occur by fomites, such as shoes, clothing, and equipment. human hands, soiled bedding, and animal products such as frozen or partially cooked meat and meat products, hides, semen, and pasteurized milk also serve as sources of virus. necropsy findings. vesicles, erosions, and ulcers are present in the oral cavity as well as on the rumen pillars and mammary alveolar epithelium. myocardial and skeletal muscle degeneration (zenker's) is most common (and accounts for the greater mortality) in younger animals. histological findings include lack of inclusion bodies. vesicular lesions include intracellular and extracellular edema, cellular degeneration, and separation of the basal epithelium. replicates in the pharynx and digestive tract in the cells of the stratum spinosum, and viremia and spread of virus to many tissues occur before clinical signs develop. virus shedding begins about hr before clinical signs are apparent. vesicles result from the separation of the superficial epithelium from the basal epithelium. fluid fills the basal epithelium, and erosions develop when the epithelium sloughs. persistent infection also occurs, and virus can be found for months or years in the pharnyx; the mechanisms for the persistence are not known. differential diagnosis. vesicular stomatitis is the principal differential. other differentials include contagious ecthyma (orf), rinderpest, bluetongue, malignant catarrhal fever, bovine papular stomatitis, bovine herpes mammillitis, and infectious bovine rhinotracheitis virus infection. products from endemic areas is regulated. quarantine and slaughter are practiced in outbreaks in endemic areas. quarantine and vaccination are also used in endemic areas, but vaccines must be type-specific and repeated or times per year to be effective and will provide only partial protection. autogenous vaccines are best in an outbreak. passive immunity protects calves for up to months after birth. the virus is inactivated by extremes of ph, sunlight, high temperatures, sodium hydroxide, sodium carbonate, and acetic acid. treatment. nursing care and antibiotic therapy to minimize secondary reactions help with recovery. humoral immunity is considered the more important immune mechanism, with cellmediated immunity of less importance. research complications. rare cases in humans have been reported. importation into the united states of animal products from endemic areas is prohibited. etiology. malignant catarrhal fever (mcf) is a severe disease primarily of cattle. the agents of mcf are viruses of the gammaherpesvirinae subfamily. alcelaphine herpesvirus and and ovine herpesvirus are known strains. the alcelaphine strains are seen in africa. the ovine strain is seen in north america. the alcelaphine and ovine strains differ in incubation times and duration of illness. disease may occur sporadically or as outbreaks. clinical signs and diagnosis. signs range from subclinical to recrudescing latent infections to the lethal disease seen in susceptible species, such as cattle. sudden death may also occur in cattle. presentations of the disease may be categorized as alimentary, encephalitis, or skin forms; all three may occur in an animal. corneal edema starting at the limbus and progressing centripetally is a nearly pathognomonic sign; photophobia, severe keratoconjunctivitis, and ocular involvement may follow. other signs include prolonged fever, oral mucosal erosions, salivation, lacrimation, purulent nasal discharge, encephalitis, and pronounced lymphadenopathy. as the disease progresses, cattle may shed horns and hooves. in north america, cattle will also have severe diarrhea. the course of the disease may extend to week. recovery is usually prolonged, and some permanent debilitation may occur. the disease is fatal in severely affected individuals. history of exposure, as well as the clinical signs and lesions, contributes to the diagnosis. serology, pcr-based assays, viral isolation, and cell-culture assays, such as cytopathic effects on thyroid cell cultures, are also used. because of the susceptibility of rabbits, inoculation of this species may be used. in less severe outbreaks or individual animal disease, definitive diagnosis may never be made. necropsy. gross findings at necropsy include necrotic and ulcerated nasal and oral mucosa; thickened, edematous, ulcerated, and hemorrhagic areas of the intestinal tract; swollen, friable, and hemorrhagic lymph nodes and other lymphatic tissues; and erosion of affected mucosal surfaces. lymph nodes should be submitted for histological examination. histological findings include nonsuppurative vasculitis and encephalitis; large numbers of lymphocytes and lymphoblasts will be present without evidence of virus. pathogenesis. the incubation period may be up to months. vascular endothelium and all epithelial surfaces will be affected. the virus is believed to cause proliferation of cytotoxic t lymphocytes with natural killer cell activities, and the resulting lesions are due to an autoimmune type of phenomenon. differential diagnoses. the differentials for this disease are bovine viral diarrhea/mucosal disease, bovine respiratory disease complex, infectious bovine rhinotracheitis, bluetongue, vesicular stomatitis, and foot-and-mouth disease. causes of encephalitis, such as bovine spongiform encephalopathy and rabies, should be considered. in africa, rinderpest is also a differential. other differentials are arsenic toxicity and chlorinated naphthalene toxicity. in north america, sheep, as well as cattle that have been either exposed or that have survived the disease, are reservoirs for outbreaks in other cattle. if there is concern regarding presence of the virus, animals should be screened serologically; once an animal has been infected, it remains infected indefinitely. lambs can be free of the infection if removed from the flock at weaning. the virus is very fragile outside of host's cells and will not survive in the environment for more than a few hours. lobes; and hematological findings indicate anemia and leukocytosis. the rare neurological signs include flexion of fetlock and pastern joints, tremors of facial muscles, progressive paresis and paralysis, depression, and prostration. death occurs in weeks to months. the disease can be serologically diagnosed with agar gel immunodiffusion (agid) tests, virus isolation, serum neutralization, complement fixation, and enzyme-linked immunosorbent assay (elisa) tests. sixty-eight percent of sheep in some states have been infected with the virus (radostits et al., ) . it is transmitted horizontally via inhalation of aerosolized virus particles and vertically between the infected dam and fetus. in addition, transmission through the milk or colostrum is considered common (knowles, ) . necropsy findings. lesions are observed in lungs, mammary glands, joints, and the brain. pulmonary adhesions, ventral lung lobe consolidation, bronchial lymph node enlargement, mastitis, and degenerative arthritis are visualized grossly. meningeal edema, thickening of the choroid plexus, and foci of leukoencephalomalacia are seen in the central nervous system (cns). histologically, interalveolar septal thickening, lymphoid hyperplasia, histiocyte and fibrocyte proliferation, and squamous epithelial changes are seen in the lungs. meningitis, lymphoid hyperplasia, demyelination, and glial fibrosis are seen in the cns. affected and any exposed animals should be isolated from healthy animals. there is no specific treatment for mcf; supportive treatment may improve recovery rates. corticosteroids may be useful. etiology. an rna virus in the lentivirus group of the retroviridae family causes ovine progressive pneumonia (opp), or maedi/visna. maedi refers to the progressive pneumonia presentation of the disease; visna refers to the central nervous system disease, which is reported predominantly in iceland. visna has been reported in goats but may have been due to caprine arthritis encephalitis infection. clinical signs and diagnosis. opp is a viral disease of adult sheep characterized by weakness, unthriftiness, weight loss, and pneumonia (pepin et al., ; de la concha bermejillo, ) . clinically, animals exhibit signs of progressive pulmonary disease after an extremely long incubation period of up to years. respiratory rate and dyspnea gradually increase as the disease progresses. the animal continues to eat throughout the disease; however, animals progressively lose weight and become weak. additionally, mastitis is a common clinical feature. thoracic auscultation reveals consolidation of ventral lung pathogenesis. the virus has a predilection for the lungs, mediastinal lymph nodes, udder, spleen, joints, and rarely the brain. after initial infection, the virus integrates into the dna of mature monocytes and persists as a provirus. later in the animal's life, infected monocytes mature as lung (and other tissue) macrophages and establish active infection. the virus induces lymphoproliferative disease, histiocyte and fibrocyte proliferation in the alveolar septa, and squamous metaplasia. pulmonary alveolar and vascular changes impinge on oxygen and carbon dioxide exchange and lead to serious hypoxia and pulmonary hypertension. secondary bacterial pneumonia may contribute to the animal's death. pulmonary adenomatosis is the differ-prevention and control. isolating or removing infected animals can prevent the disease. facilities and equipment should also be disinfected. ii. proliferative stomatitis (bovine papular stomatitis) etiology. a parapoxvirus is the causative agent of bovine papular stomatitis. this virus is considered to be closely related to the parapoxvirus that causes contagious ecthyma and pseudocowpox. it is also a zoonotic disease. the disease is not considered of major consequence, but high morbidity and mortality may be seen in severe outbreaks. in addition, lesions are comparable in appearance to those seen with vesicular stomatitis, bovine viral diarrhea virus, and foot-and-mouth disease. the disease occurs worldwide. clinical signs and diagnosis. raised red papules or erosions or shallow ulcers on the muzzle, nose, oral mucosa (including the hard palate), esophagus, and rumen of younger cattle are the most common findings. in some outbreaks, the papules will be associated with ulcerative esophagitis, salivation, diarrhea, and subsequent weight loss. lesions persist or may come and go over a span of several months. morbidity among herds may be %. mortalities are rare. bovine papular stomatitis is associated with "rat tail" in feedlot cattle. animals continue to eat and usually do not show a fever. no lesion is seen on the feet. the infection may also be asymptomatic. diagnosis is based on clinical signs, histological findings, and viral isolation. epizootiology and transmission. cattle less than year of age are most commonly affected, and disease is rare in older cattle. transmission is by animal-to-animal contact. necropsy findings. raised papules may be found around the muzzle and mouth and involve the mucosa of the esophagus and rumen. histologically, epithelial cells will show hydropic degeneration and hyperplasia of the lamina propria. eosinophilic inclusions will be in the cytoplasm of infected epithelial cells. pathogenesis. following exposure to the virus, erythematous macules most commonly appear on the nares, followed by the mouth. these become raised papules within a day, regressing after days to weeks; the lesions that remain will be persistent yellow, red, or brown spots. some infections may recur or persist, with animals showing lesions intermittently or continuously over several months. differential diagnosis. pseudocowpox, vesicular stomatitis, foot-and-mouth disease, and bovine viral diarrhea virus infection are the differentials for this disease. the differential for the "rat tail" clinical sign is sarcocystis infection. there is no vaccine available for bovine papular stomatitis. because of the similarity of this virus to the parapoxvirus of contagious ecthyma, it is important to be aware of the persistence in the environment and susceptibility of younger cattle. vaccination using the local strain, and the skin scarification technique for off, have been protective. handlers should wear gloves and protective clothing. treatment. cattle usually will not require extensive nursing care, but lesions with secondary bacterial infections should be treated with antibiotics. their hands at sites of contact with lesions of cattle. iii. pseudocowpox etiology. pseudocowpox is a worldwide cattle disease caused by a parapoxvirus related to the causative agents of contagious ecthyma and bovine papular stomatitis (see sections iii,a, ,m and iii,a, ,q,ii). lesions are confined to the teats. this is also a zoonotic disease. clinical signs and diagnosis. minor lesions are usually confined to the teats. these are distinctive because of the ring-or horseshoe-shaped scab that develops after days. additional lesions sometimes develop on the udder, the medial aspect of the thighs, and the scrotum. the teat lesions may predispose to mastitis. etiology. pulmonary adenomatosis is a rare but progressive wasting disease of sheep, with worldwide distribution. pulmonary adenomatosis is caused by a type d retrovirus antigenically related to the mason-pfizer monkey virus. jaagsiekte was the designation when the disease was described originally in south africa. progressive respiratory signs such as dyspnea, rapid respiration, and wasting. the disease is diagnosed by these chronic clinical signs and histology. epizootiology and transmission. the disease is transmitted by aerosols. body fluids of viremic animals, such as milk, blood, saliva, tears, semen, and bronchial secretions, will contain the virus or cells carrying the virus. necropsy. the adenomas and adenocarcinomas will be small firm lesions distributed throughout the lungs. the adenocarcinomas metastasize to regional lymph nodes. pathogenesis. as with ovine progressive pneumonia (opp), the incubation period is up to years long. adenocarcinomatous lesions arising from type ii alveolar epithelial cells may be discrete or confluent and involve all lung lobes. with or is a differential diagnosis for opp. etiology. cutaneous papillomatosis is a very common disease in cattle and is much less common among sheep and goats. the disease is a viral-induced proliferation of the epithelium of the neck, face, back, and legs. these tumors are caused by a papillomavirus (dna virus) of the papovaviridae family, and the viruses are host-specific and often body site-specific. most are benign, although some forms in cattle and one form in goats can become malignant. in cattle, the site specificity of the papillomavirus strains are particularly well recognized. designations of the currently recognized bovine papillomavirus (bpv) types are bpv- through bpv- . clinical signs and diagnosis. the papillomas may last up to months and are seen more frequently in younger animals. lesions have typical wart appearances and may be single or multiple, small ( mm) or very large ( mm). the infections will generally be benign, but pain will be evident when warts develop on occlusal surfaces or within the gastrointestinal tract. in addition, when infections are severe, weight loss may occur. when warts occur on teats, secondary mastitis may develop. in cattle, bpv- and bpv- cause fibropapillomas on teats and penises or on head, neck, and dewlap, respectively. bpv- causes flat warts that occur in all body locations, b pv- causes warts in the gastrointestinal tract, and b pv- causes small white warts (called rice-grain warts) on teats. warts caused by bpv- and bpv- do not regress spontaneously. prognosis in cattle is poor only when papillomatosis involves more than % of the body surface. in sheep, warts are the verrucous type. the disease is of little consequence unless the warts develop in an area that causes dis-comfort or incapacitation such as between the digits, on the lips, or over the joints. in adult sheep, warts may transform to squamous cell carcinoma. in goats, the disease is rare, and the warts are also of the verrucous type and occasionally may develop into squamous cell carcinoma. warts on goat udders tend to be persistent. diagnosis is made by observing the typical proliferative lesions. epizootiology and transmission. older animals are less sensitive to papillomatosis than young animals, although immunosupressed animals of any age may develop warts as the result of harbored latent infections. the virus is transmitted by direct and indirect (fomite) contact, entering through surface wounds and sites such as tattoos. pathogenesis. the incubation period ranges from to months. the virus induces epidermal and fibrous tissue proliferation, often described as cauliflower-like skin tumors. the disease is generally self-limiting. differential diagnosis. in sheep and goats, differentials include contagious ecthyma, ulcerative dermatosis, strawberry foot rot, and sheep and goat pox. for cattle) or autogenous vaccines must be used with a recognition that papovavirus strains are host-specific and that immunity from infection or vaccination is viral-type-specific. autogenous vaccines are generally considered more effective. some vaccine preparations are effective at prevention but not treatment of outbreaks. viricidal products are recommended for disinfection of contaminated environments. minimizing cutaneous injuries and sanitizing equipment (tattoo devices, dehorners, ear taggers, etc.) in a virucidal solution between uses are also recommended preventive and control measures. halters, brushes, and other items may also be sources of virus. treatment. warts will often spontaneously resolve as immunity develops. in severe cases or with flockwide or herdwide problems, affected animals should be isolated from nonaffected animals, and premises disinfected. warts can be surgically excised and autogenous vaccines can be made and administered to help prevent disease spread. cryosurgery with liquid nitrogen or dry ice has also proven to be successful for wart removal. topical agents such as podophyllin (various formulations) and dimethyl sulfoxide may be applied to individual lesions once daily until regression. etiology. pseudorabies is an acute encephalitic disease caused by a neurotropic alphaherpesvirus, the porcine herpesvirus . one serotype is recognized, but strain differences exist. the disease has worldwide distribution. it is a primarily a clinical dis-ease of cattle, with less frequent reports (but no less severe clinical manifestations) in sheep and goats. during the rapid course of this usually fatal disease. at the site of virus inoculation or in other locations, abrasions, swelling, intense pruritus, and alopecia are seen. pruritus will not be asymmetric. animals will also become hyperthermic and will vocalize frantically. other neurological signs range from hoof stamping, kicking at the pruritic area, salivation, tongue chewing, head pressing and circling, to paresthesia or hyperesthesia, ataxia, and conscious proprioceptive deficits. nystagmus and strabismus are also seen. animals will be fearful or depressed, and aggression is sometimes seen. recumbency and coma precede death. diagnostic evidence includes clinical findings; virus isolation from nasal or pharyngeal secretions or postmortem tissues; and histological findings at necropsy. serology of affected animals is not productive, because of the rapid course. if swine are housed nearby, or if swine were transported in the same vehicles as affected animals, serological evaluations are worthwhile from those animals. epizootiology and transmission. swine are the primary hosts for pseudorabies virus, but they are usually asymptomatic and serve as reservoirs for the virus. the infection can remain latent in the trigeminal ganglion of pigs and recrudesce during stressful conditions. other animals are dead-end hosts. the unprotected virus will survive only a few weeks in the environment but may remain viable in meat (including carcasses) or saliva and will survive outside the host, in favorable conditions, in the summer for several weeks and the winter for several months. transmission is by oral, intranasal, intradermal, or subcutaneous introduction of the virus. when the virus is inhaled, the clinical signs of pruritus are less likely to be seen. transmission can also be by inadvertent exposure (e.g., contaminated syringes) of ruminants to the modified live vaccines developed for use in swine. spread between infected ruminants is a less likely means of transmission, because of the relatively short period of virus shedding. transport vehicles used for swine may also be sources of the virus. raccoons are believed to be vectors of the virus. horses are resistant to infection. there is no pathognomonic gross lesion. definitive histologic findings include severe, focal, nonsuppurative encephalitis and myelitis. eosinophilic intranuclear inclusion bodies (cowdry type a) may be present in some affected neurons. methods such as immunofluorescence and immunoperoxidase staining can be used to show presence of the porcine herpesvirus . pathogenesis. the incubation period is - hr and duration of the illness is - hr. the longest duration is seen in animals with pruritus around the head. differential diagnoses. differentials for the neurologic signs of pseudorabies infection include rabies, polioencephalomalacia, salt poisoning, meningitis, lead poisoning, hypomagnesemia, and enterotoxemia. those for the intense pruritus include psoroptic mange and scrapie in sheep, sarcoptic mange, and pediculosis. prevention and control. pseudorabies is a reportable disease in the united states, where a nationwide eradication program exists; states are rated regarding status. effective disinfectants include sodium hypochlorite ( % solution), formalin, peracetic acid, tamed iodines, and quaternary ammonium compounds. five minutes of contact time is required, and then surfaces must be rinsed. other disinfectant methods for viral killing include hr of formaldehyde fumigation, or min of ultraviolet light. transport vehicles should be cleaned and disinfected between species. serological screening for pseudorabies of swine housed near ruminants is essential. there is no treatment, and most affected ani-research complications. swine housed close to research ruminants should be serologically screened prior to purchase, and all transport vehicles should be cleaned and disinfected between loads of large animals. humans have been reported to seroconvert. the porcine herpesvirus shares antigens with the infectious bovine rhinotracheitis virus. etiology. rabies is a sporadic but fatal, acute viral disease affecting the central nervous system. the rabies virus is a neurotropic rna virus of the lyssavirus genus and the rhabdoviridae family. sheep, goats, and cattle are susceptible. the zoonotic potential of this virus must be kept in mind at all times when handling moribund animals with neurological signs characteristic of the disease. rabies is endemic in many areas of the world and within areas of the unites states. this is a reportable disease in north america. clinical findings and diagnosis. animals generally progress through three phases: prodromal, excitatory, and paralytic. many signs in the different species during these stages are nonspecific, and forms of the disease are also referred to as dumb or furious. during the short prodromal phase, animals are hyperthermic and apprehensive. animals progress to the excitatory phase, during which they refuse to eat or drink and are active and aggressive. repeated vocalizations, tenesmus, sexual excitement, and salivation occur during this phase. the final paralytic stage, with recumbency and death, occurs over several hours to days. this paralytic stage is common in cattle, and animals may simply be found dead. the clinical course is usually - days. diagnosis is based on clinical signs, with a progressive and fatal course. confirmation presently is made with the fluorescent antibody technique on brain tissue. epizootiology and transmission. the rabies virus is transmitted via a bite wound inflicted by a rabid animal. cats, dogs, raccoons, skunks, foxes, wild canids, and bats are the common disease vectors in north america. virus is also transmitted in milk and aerosols. necropsy findings. few lesions are seen at necropsy. many secondary lesions from manic behaviors during the course of disease may be evident. histological findings will include nonsuppurative encephalitis. negri bodies in the cytoplasm of neurons of the hippocampus and in purkinje's cells are pathognomonic histologic findings. pathogenesis. after exposure, the incubation period is variable, from weeks to several months, depending on the distance that the virus has to travel to reach the central nervous system. the rabies virus proliferates locally, gains access to neurons by attaching to acetylcholine receptors, via a viral surface glycoprotein, migrates along sensory nerves to the spinal cord and brain, and then descends via cranial nerves (trigeminal, facial, olfactory, glossopharyngeal) to oral and nasal cavity structures (i.e., salivary glands). the fatal outcome is currently believed to be multifactorial, related to anorexia, respiratory paralysis, and effects on the pituitary. differential diagnosis. rabies should be included on the differential list when clinical signs of neurologic disease are evident. other differentials for ruminants include herpesvirus encephalitis, thromboemobolic meningoencephalitis, nervous ketosis, grass tetany, and nervous cocciodiosis. prevention and control. vaccines approved for use cattle and sheep are commercially available and contain inactivated virus; there is not one available in the united states for goats. ruminants in endemic areas, such as the east coast of the united states, should be routinely vaccinated. any animals housed outside that may be exposed to rabid animals should be vaccinated. vaccination programs generally begin at months of age, with a booster at year of age and then annual or triennial boosters. awareness of the current rabies case reports for the region and wildlife reservoirs, however, is important. monitoring for and exclusion of wildlife from large-animal facilities are worthwhile preventive measures. the virus is fragile and unstable outside of a host animal. research complications. aerosolized virus is infective. personal protective equipment, including gloves, face mask, and eye shields, must be worn by individuals handling animals that are manifesting neurological disease signs. bovine spongiform encephalopathy, a transmissible spongiform encephalopathy (tse), is not known to occur in the united states, where since it has been listed as a reportable disease. the profound impact of this disease on the cattle industry in great britain during the past two decades is well known. the disease may be caused by a scrapielike (prion) agent. it is believed that the source of infection for cattle was feedstuff derived from sheep meat and bonemeal that had been inadequately treated during processing. the incubation period of years, the lack of detectable host immune response, the debilitating and progressive neurological illness, and the pathology localized to the central nervous system are characteristics of the disease, and are is comparable to the characteristics of other tse diseases such as scrapie, which affects sheep and goats. in addition, the infectious agent is extremely resistant to dessication and disinfectants. confirmation of disease is by histological examination of brain tissue collected at necropsy; the vacuolation that occurs during the disease will be symmetrical and in the gray matter of the brain stem. molecular biology techniques, such as western blots and immunohistochemistry, may also be used to identify the presence of the prion protein. differentials include many infectious or toxic agents that affect the bovine nervous and musculoskeletal systems, such as rabies, listeriosis, and lead poisoning. metabolic disorders such as ketosis, milk fever, and grass tetany are also differentials. there is no vaccine or treatment. prevention focuses on import regulations and not feeding ruminant protein to ruminants; recent usda regulations prohibit feeding any mammalian proteins to ruminants. etiology. scrapie is a sporadic, slow, neurodegenerative disease caused by a prion. scrapie is a reportable disease. it is much more common in sheep than in goats. the disease is similar to transmissible mink encephalopathy, kuru, creutzfeldt-jakob disease, and bovine spongiform encephalopathy (mad cow disease). prions are nonantigenic, replicating protein agents. clinical signs and diagnosis. during early clinical stages, animals are excitable and hard to control. tremors of head and neck muscles, as well as uncoordinated movements and unusual "bunny-hopping" gaits are observed. in advanced stages of the disease, animals experience severe pruritus and will self-mutilate while rubbing on fences, trees, and other objects. blindness and abortion may also be seen. morbidity may reach % within a flock. most animals invariably die within - weeks; some animals may survive months. in goats, the disease is also fatal. pruritus is generally less severe but may be localized. a wide range of clinical signs have also been noted in goats, including listlessness, stiffness or restlessness, or behavioral changes such as irritability, hunched posture, twitching, and erect tail and ears. as with sheep, the disease gradually progresses to anorexia and debilitation. diagnosis can be made by clinical signs and histopathological lesions. a newer diagnostic test in live animals is based on sampling from the third eyelid. tests for genetic resistance or susceptibility require a tube of edta blood and are reasonably priced. epizootiology and transmission. the suffolk breed of sheep tends to be especially susceptible. scrapie has also been reported in several other breeds, including cheviot, dorset, hampshire, corriedale, shropshire, merino, and rambouillet. it is believed that there is hereditary susceptibility in these breeds. targhees tend to be resistant. genomic research indicates there are two chromosomsal sites governing this trait; these sites are referred to codons (q, r, or h genes can be present) and (a or v genes can be present). of the five genes, r genes appear to confer immunity to clinical scrapie in suffolks in the united states. affected suffolks in the united states that have been tested have been aa qq. the disease is also enzootic is many other countries. the disease tends to affect newborns and young animals; however, because the incubation period tends to range from to years, adult animals display signs of the disease. scrapie is transmitted horizontally by direct or indirect contact; nasal secretions or placentas serve as sources of the infectious agent. vertical transmission is questioned, and transplacental transmission is considered unlikely. necropsy findings. at necropsy, no gross lesion is observed. histopathologically, neuronal vacuolization, astrogliosis, and spongiform degeneration are visualized in the brain stem, the spinal cord, and especially the thalamus. inflammatory lesions are not seen. pathogenesis. replication of the prions probably occurs first in lymphoid tissues throughout the host's body and then progresses to neural tissue. differential diagnosis. in sheep and goats, depending on the speed of onset, differentials for the pruritus include ectoparasites, pseudorabies, and photosensitization. prevention and control. if the disease diagnosed in a flock, quarantine and slaughter, followed by strict sanitation, are usually required. the u.s. department of agriculture has approved the use of % sodium hydroxide as the only disinfectant for sanitation of scrapie-infected premises. prions are highly resistant to physicochemical means of disinfection. artificial insemination or embryo transfer has been shown to decrease the spread of scrapie (linnabary et al., ) . research complications. as noted, this is a reportable disease. stringent regulations exist in the united states regarding importation of small ruminants from scrapie-infected countries. etiology. vesicular stomatitis (vs) is caused by the vesicular stomatitis virus (vsv), a member of the rhabdoviridae. three serotypes are recognized: new jersey, indiana, and isfahan. the new jersey and indiana strains cause sporadic disease in cattle in the united states. the disease is rare in sheep. clinical signs and diagnosis. adult cattle are most likely to develop vs. fever and development of vesicles on the oral mucous membranes are the initial clinical signs. lesions on the teats and interdigital spaces also develop. the vesicles progress quickly to ulcers and erosions. the animal's tongue may be severely involved. anorexia and salivation are common. weight loss and decreased milk production are noticeable. morbidity will be high in an outbreak, but mortality will be low to nonexistent. diagnostic work should be initiated as soon as possible to distinguish this from foot-and-mouth disease. diagnosis is based on analysis of fluid, serum, or membranes associated with the vesicles. virus isolation, enzyme-linked immunosorbent assay (elisa), competitive elisa (celisa), complement fixation, and serum neutralization are used for diagnosis. epizootiology and transmission. this disease occurs in several other mammalian species, including swine, horses, and wild ruminants. vsv is an enveloped virus and survives well in different environmental conditions, including in soil, extremes of ph, and low temperatures. outbreaks of vs occur sporadically in the united states, but it is not understood how or in what species the virus survives between these outbreaks. incidence of disease decreases during colder seasons. equipment, such as milking machines, contaminated by secretions is a mechanical vector, as are human hands. transmission may also be from contaminated water and feed. transmission is also believed to occur by insects (blackflies, sand flies, and culicoides) that may simply be mechanical vectors. it is believed that carrier animals do not occur in this disease. necropsy. it is rare for animals to be necropsied as the result of this disease. typical vesicular lesion histology is seen, with ballooning degeneration and edema. there is no inclusion body formation. pathogenesis. lesions often begin within hr after exposure. the virus invades oral epithelium. injuries or trauma in any area typically affected, such as mouth, teats, or interdigital areas, will increase the likelihood of lesions developing there. animals will develop a long-term immunity; this immunity can be overwhelmed, however, by a large dose of the virus. differential diagnosis. foot-and-mouth disease lesions are identical to vs lesions. other differentials in cattle include bovine viral diarrhea, malignant catarrhal fever, contagious ecthyma, photosensitization, trauma, and caustic agents. prevention and control. quarantine and restrictions on shipping infected animals or animals from the premises housing affected animals are required in an outbreak. vaccines are available for use in outbreaks and have decreased the severity of lesions. phenolics, quaternaries, and halogens are effective for inactivating and disinfecting equipment and facilities. treatment. affected animals should be segregated from the rest of the herd and provided with separate water and softened feed. these animals should be cared for after unaffected animals. any feed or water contaminated by these animals should not be used for other animals; contaminated equipment should be disinfected. topical or systemic antibiotics control secondary bacterial infections. cases of mastitis secondary to teat lesions must be treated as necessary. any abrasive materials that could cause further trauma to the animals should be removed. research complications. animals developing vesicular lesions must be reported promptly to eliminate the possibility of an outbreak of foot-and-mouth disease. personal protective equipment, especially gloves, should be worn when handling any animals with vesicular lesions. vsv causes a flulike illness in humans. x. viral diarrhea diseases i. ovine. rotavirus, of the family reoviridae, induces an acute, transient diarrhea in lambs within the first few weeks of life. four antigenic groups (a-d) have been identified by differences in capsid antigens vp and vp . primarily group a, but also groups b and c, have been isolated from sheep. the disease is characterized by yellow, semifluid to watery diarrhea occurring - days after infection. the disease can progress to dehydration, anorexia and weight loss, acidosis, depression, and occasionally death. the virus is ingested with contaminated feed and water and selectively infects and destroys the enterocytes at the tips of the small intestinal villi. the villi are replaced with immature cells that lack sufficient digestive enzymes; osmotic diarrhea results. virus may remain in the environment for several months. the disease is diagnosed by virus isolation, electron microscopy of feces, fecal fluorescent antibody, fecal elisa tests (marketed tests generally detect group a rotavirus), and fecal latex agglutination tests. rotavirus diarrhea is treated by supportive therapy, including maintaining hydration, electrolyte, and acid-base balance. a rotavirus vaccine is available for cattle; because of cross-species immunity, oral administration of high-quality bovine colostrum from vaccinated cows to infected sheep may be helpful ("current veterinary therapy," ). coronavirus, of the family coronaviridae, produces a more severe, long-lasting disease when compared with rotavirus. clinical signs are similar to above, although the incubation period tends to be shorter ( - hr), and animals exhibit less anorexia than those with rotavirus. additionally, mild respiratory disease may be noted (janke, ) . like rotavirus, coronavirus also destroys enterocytes of the villus tips. the virus can be visualized with electron microscopy. treatment is supportive; close consideration of hydration and acid-base status is essential. bovine vaccines are available. ii. caprine. rotavirus, coronavirus, and adenoviruses affect neonatal goats; however, little has been documented on the pathology and significance of these agents in this age group. it appears that bacteria play a more important role in neonatal kid diarrheal diseases then in neonatal calf diarrheas. iii. bovine. rotaviruses, coronaviruses, parvoviruses, and bovine viral diarrhea virus (bvdv) are associated with diarrheal disease in calves. each pathogen multiplies within and destroys the intestinal epithelial cells, resulting in villous atrophy and clinical signs of diarrhea (soft to watery feces), dehydration, and abdominal pain. these viral infections may be complicated by parasitic infections (e.g., cryptosporidium, eimeria) or bacterial infections (e.g., escherichia coli, salmonella, campylobacter). treatment is aimed at correcting dehydration, electrolyte imbalances, and acidosis; cessation of milk replacers and administration of fluid therapy intravenously and by stomach tube may be necessary, depending on the presence of suckle reflex and the condition of the animals. diagnosis is by immunoassays available for some viruses, viral culture, exclusion or identification of presence of other pathogens (by culture or fecal exams), and microscopic examination of necropsy specimens. prevention focuses on calves suckling good-quality colostrum; other recommendations for calf care are in section ii,b, . combination vaccine products are available for immunizing dams against rotavirus, coronavirus, and enterotoxigenic e. coli. additional supportive care for calves includes providing calves with sufficient energy and vitamins until milk intake can resume. rotaviruses of serogroup a are the most common type in neonatal calves; -to -day old calves are typically affected, but younger and older animals may also be affected. the small intestine is the site of infection. antirotavirus antibody is present in colostrum, and onset of rotavirus diarrhea coincides with the decline of this local protection. transmission is likely from other affected calves and asymptomatic adult carriers. the diarrhea is typically a distinctive yellow. colitis with tenesmus, mucus, and blood may be seen. this virus may be zoonotic. coronaviruses are commonly associated with disease in calves during the first month of life, and they infect small-and large-intestinal epithelial cells. the virus infection may extend to mild pneumonia. transmission is by infected calves and also by asymptomatic adult cattle, including dams excreting virus at the time of parturition. calves that appear to have recovered continue to shed virus for several weeks. parvovirus infections are usually associated with neonatal calves. b vdv infections also are seen in neonates and also affect many systems and produce other clinical signs and syndromes that are described in section iii,a, ,e. iv. winter dysentery. winter dysentery is an acute, winterseasonal, epizootic diarrheal disease of adult cattle, although it has been reported in -month-old calves. the etiology has not yet been defined, but a viral pathogen is suspected. coronavirus-like viral particles have been isolated from cattle feces, either the same as or similar to the coronavirus of calf diarrhea. outbreaks typically last a few weeks, and first-lactation or younger cattle are affected first, with waves of illness moving through a herd. individual cows are ill for only a few days. the incubation period is estimated at - days. the outbreaks of disease are often seen in herds throughout the local area. clinical signs include explosive diarrhea, anorexia, depression, and decreased production. the diarrhea has a distinctive musty, sweet odor and is light brown and bubbly, but some blood streaks or clots may be mixed in with the feces. animals will become dehydrated quickly but are thirsty. respiratory symptoms such as nasolacrimal discharges and coughing may develop. recovery is generally spontaneous. mortalities are rare. diagnosis is based on characteristic patterns of clinical signs, and elimination of diarrheas caused by parasites such as coccidia, bacterial organisms such as salmonella or mycobacterium paratuberculosis, and viruses such as b vdv. pathology is present in the colonic mucosa, and necrosis is present in the crypts. etiology. chlamydia psittaci is a nonmotile, obligate, intracytoplasmic, gram-negative bacterium. clinical signs. enzootic abortion in sheep and goats is a contagious disease characterized by hyperthermia and late abortion or by birth of stillborn or weak lambs or kids (rodolakis et al., ) . the only presenting clinical sign may be serosanguineous vulvar discharges. other animals may present with arthritis or pneumonia. infection of animals prior to about days of gestation results in abortion, stillbirths, or birth of weak lambs. infection after days results in potentially normal births, but the dams or offspring may be latently infected. latently infected animals that were infected during their dry period may abort during the next pregnancy. ewes or does generally only abort once, and thus recovered animals will be immune to future infections. and specific antigens associated with the cell surface. the group antigen is common among all chlamydia; the specific antigen is common to related subgroups. two subgroups are recognized, one that causes eae and one that causes polyarthritis and conjunctivitis. the disease is transmitted by direct contact with infectious secretions such as placental, fetal, and uterine fluids or by indirect contact with contaminated feed and water. necropsy. placental lesions include intercotyledonary plaques and necrosis and cotyledonary hemorrhages. histopathological evidence of leukocytic infiltration, edema, and necrosis is found throughout the placentome. fetal lesions include giant-cell accumulation in mesenteric lymph nodes and lymphohistiocytic proliferations around the blood vessels within the liver. diagnosis is based on clinical signs and laboratory (serological or histopathological) identification of the organism. impression smears in placental tissues stained with giemsa, gimenez, or modified ziehl-neelsen can provide preliminary indications of the causative agent. immunofluorescence, enzyme-linked immunosorbent assay (elisa), and polymerase chain reaction (pcr) methods also aid in diagnosis. differential diagnosis. q fever will be the major differential for late-term abortion and necrotizing placentitis. campylobacter and toxoplasma should also be considered for late-term abortion. treatment. animals may respond to treatment with oxytetracycline. abortions are prevented through administration of a commercial vaccine, but the vaccine will not eliminate infections. this is a sheep vaccine and should be administered before breeding and annually to at least the young females entering the breeding herd or flock. research complications. in addition to losses or compromise of research animals, pregnant women should not handle aborted tissues. etiology. chlamydia psittaci is a nonmotile, obligate intracellular, gram-negative bacterium. chlamydial polyarthritis is an acute, contagious disease characterized by fever, lameness (bulgin, ) , and conjunctivitis (see section iii,a, ,c) in growing and nursing lambs. clinical signs. clinically, animals will appear lame on one or all legs and in major joints, including the scapulohumeral, humeroradioulnar, coxofemoral, femorotibial, and tibiotarsal joints. lambs may be anorexic and febrile. animals frequently also exhibit concurrent conjunctivitis. the disease usually resolves in approximately weeks. joint inflammation usually resolves without causing chronic articular changes. epizootiology and transmission. the disease is transmitted to susceptible animals by direct contact as well as by contaminated feed and water. the organism penetrates the gastrointestinal tract and migrates to joints and synovial membranes as well as to the conjunctiva. the organism causes acute inflammation and associated fibrinopurulent exudates. necropsy findings. lesions are found in joints, tendon sheaths, conjunctiva, and lungs. pathological sites will be edematous and hyperemic, with fibrinous exudates but without articular changes. lesions will be infiltrated with mononuclear cells. lung lesions include atelectasis and alveolar inspissation. diagnosis is based on clinical signs. synovial taps and subsequent smears may allow the identification of chlamydial inclusion bodies. treatment. animals respond to treatment with parenteral oxytetracycline. etiology. chlamydia psittaci, a nonmotile, obligate intracellular, gram-negative bacterium, is the most common cause of infectious keratoconjunctivitis in sheep. chlamydia and mycoplasma are considered to be the most common causes of this disease in goats. chlamydial conjunctivitis is not a disease of cattle. clinical signs. infectious keratoconjunctivitis is an acute, contagious disease characterized in earlier stages by conjunctival hyperemia, epiphora, and edema and in later stages by, corneal edema, ulceration, and opacity. perforation may result from the ulceration. animals will be photophobic. in less severe cases, corneal healing associated with fibrosis and neovascularization occurs in - days. lymphoid tissues associated with the conjunctiva and nictitating membrane may enlarge and prolapse the eyelids. morbidity may reach - %. bilateral and symmetrical infections characterize most outbreaks. relapses may occur. other concurrent systemic infections may be seen, such as polyarthritis or abortion in sheep and polyarthritis, mastitis, and uterine infections in goats. epizootiology and transmission. direct contact, and mechanical vectors such as flies easily spread the organism. necropsy. if the chlamydial or mycoplasmal agents are suspected, diagnostic laboratories should be contacted for recommendations regarding sampling. conjunctival smears are also useful. pathogenesis. the pathogen penetrates the conjunctival epithelium and replicates in the cytoplasm by forming initial and elementary bodies. the infection moves from cell to cell and causes an acute inflammation and resultant purulent exudate. the chlamydial organism may penetrate the bloodstream and migrate to the opposite eye or joints, leading to arthritis. diagnosis is suggested by the clinical signs. cytoplasmic inclusions observed on conjunctival scrapings and immunofluorescent techniques help confirm the diagnosis. differential diagnosis. nonchlamydial keratoconjunctivitis also occurs in sheep and goats. the primary agents involved include mycoplasma conjunctiva, m. agalactiae in goats, and branhamella (neisseria) ovis. a less common differential for sheep and cattle is listeria monocytogenes. other differentials include eye worms, trauma, and foreign bodies such as windblown materials (pollen, dust) and poor-quality hay; these latter irritants and stress may predispose the animals' eyes to the infectious agents. should be minimized whenever possible. quarantine of new animals and treatment, if necessary, before introduction into the flock or herd are important measures. shade should be provided for all animals. treatment. the infections can be self-limiting in - weeks without treatment. treatment consists of topical application of tetracycline ophthalmic ointments. systemic or oral oxytetracycline treatments have been used with the topical treatment. atropine may be added to the treatment regimen when uveitis is present. shade should be provided. a. protozoa i. anaplasmosis etiology. anaplasmosis is an infectious, hemolytic, noncontagious, transmissible disease of cattle caused by the protozoan anaplasma marginale. anaplasma is a member of the anaplasmatacae family within the order rickettsiales. in sheep and goats, the disease is caused by a. ovis and is an uncommon cause of hemolytic disease. anaplasmosis has not been reported in goats in the united states. some controversy exists regarding the classification. most recently it is classified as a protozoal disease because of similarities to babesiosis. it has also been classified as a rickettsial pathogen. this summary addresses the disease in cattle with limited reference to a. ovis infections, but there are many similarities to the disease in cattle. clinical signs and diagnosis. acute anemia is the predominant sign in anaplasmosis, and fever coincides with parasitemia. weakness, pallor, lethargy, dehydration, and anorexia are the result of the anemia. four disease stagesnincubation, developmental, convalescent, and carriermare recognized. the incubation stage may be long, - weeks, and is characterized by a rise in body temperature as the infection moves to the next stage. most clinical signs occur during the -to -day developmental stage, with hemolytic anemia being common. death is most likely to occur at this stage or at the beginning of the convalescent stage. death may also occur from anoxia, because of the animal's inability to handle any exertion or stress, especially if treatment is initiated when severe anemia exists. reticulocytosis characterizes the convalescent stage, which may continue for many weeks. morbidity is high, and mortality is low. the carrier stage is defined as the time in the convalescent stage when the animal host becomes a reservoir of the disease, and anaplasma organisms and any parasitemia are not discernible. common serologic tests are the complement fixation test and the rapid card test. these become positive after the incubation phase and do not distinguish between the later three stages of disease. definitive diagnosis is made by clinical and necropsy findings. staining of thin blood smears with wright's or giemsa stain allows detection of basophilic, spherical a. marginale bodies near the red blood cell peripheries. evidence will most likely be found before a hemolytic episode. a negative finding should not eliminate the pathogen from consideration. epizootiology and transmission. the disease is common in cattle in the southern and western united states. anaplasma organisms are spread biologically or mechanically. mechanical transmission occurs when infected red blood cells are passed from one host to another on the mouthparts of seasonal biting flies. sometimes mosquitoes or instruments such as dehorners or hypodermic needles may facilitate transfer of infected red cells from one animal to another. biological transmission occurs when the tick stage of the organism is passed by dermacentor andersoni and d. occidentalis ticks. the carrier stage covers the time when discernible anaplasma organisms can be found on host blood smears. recovered animals serve as immune carriers and disease reservoirs. necropsy. pale tissues and watery, thin blood are typical findings. splenomegaly, hepatomegaly, and gallbladder distension are common findings. pathogenesis. the parasites infect the host's red blood cells, and acute hemolysis occurs during the parasites' developmental stage. the four stages of the parasite's life cycle are described above because these are closely linked to the clinical stages. differential diagnosis. the clinical disease closely resembles the protozoal disease babesiosis. whole organism) programs are not entirely effective, and vaccine should not be administered to pregnant cows. neonatal isoerythrolysis may occur because of the antierythrocyte antibodies stimulated by one vaccine product. vaccinated animals can still become infected and become carriers. the cattle vaccine has shown no efficacy in smaller ruminants, and there is no a. ovis vaccine. identifying carriers serologically and treating with tetracycline during and/or after vector seasons may be an option. removing carriers to a separate herd is also an approach. interstate movement of infected animals is regulated. treatment. oxytetracycline, administered once, helps reduce the severity of the infection during the developmental stage. other tetracycline treatment programs have been described to help control carriers. ii. babesiosis (red water, texas cattle fever, cattle tick fever) etiology. babesia bovis and ba. bigemina are protozoa that cause subclinical infections or disease in cattle. these are intraerythrocytic parasites. babesia bovis is regarded as the more virulent of the two organisms. this disease is not seen in the smaller ruminants in the united states. clinical signs and diagnosis. the more common presentation is liver and kidney failure due to hemolysis with icterus, hemoglobinuria, and fever. hemoglobinuria indicates a poor prognosis. acute encephalitis is a less common presentation and begins acutely with fever, ataxia, depression, deficits in conscious proprioception, mania, convulsions, and coma. the encephalitic form generally also has a poor prognosis. sudden death may occur. thin blood smears stained with giemsa will show babesia trophozoites at some stages of the disease, but lack of these cannot be interpreted as a negative. the trophozoites occur in a variety of shapes, such as piriform, round, or rod. complement fixation, immunofluorescent antibody, and enzyme immunoassay are the most favored of the available serologic tests. babesiosis is present on several continents, including the americas. in addition to domestic cattle, some wild ruminants, such as white-tailed deer and american buffalo, are also susceptible. bos indicus breeds have resistance to the disease and the tick vectors. innate resistance factors have been found in all calves. if infected, these animals will not show many signs of disease during the first year of life and will become carriers. stress can cause disease development. prevention and control. offspring of immune carriers resist infection up to months of age because of passive immunity. vector control and attention to hygiene are essential, such as between-animal rinsing in disinfectant of mechanical vectors such as dehorners. there is no entirely effective means, however, to prevent and control the disease. vaccination (killed necropsy findings. signs of acute hemolytic crisis are the most common findings, including hepatomegaly, splenomegaly, dark and distended gallbladder, pale tissues, thin blood, scattered hemorrhages, and petechiation. animals dying after a longer course of disease will be emaciated and icteric, with thin blood, pale kidneys, and enlarged liver. pathogenesis. the protozoon is transmitted by the cattle fever ticks boophilus annulatus, b. microplus, and b. decoloratus; these one-host ticks acquire the protozoon from infected animals. it is passed transovarially, and both nymph and adult ticks may transmit to other cattle. only b. ovis is transmitted by the larval stage. clinical signs develop about weeks after tick infestations or mechanical transmission but may develop sooner with the mechanical transmission. hemolysis is due to intracellular reproduction of the parasites and occurs intra-and extravascularly. in addition to the release of merozoites, proteolytic enzymes are also released, and these contribute to the clinical metabolic acidosis and anoxia. the development of the encephalitis form is believed to be the result of direct invasion of the central nervous system, disseminated intravascular coagulation, capillary thrombosis by the parasites and infarction, and/or tissue anoxia. differential diagnosis. in addition to anaplasmosis, other differentials for the hemolytic form of the disease are leptospirosis, chronic copper toxicity, and bacillary hemoglobinuria. several differentials in the united states for the encephalitic presentation include rabies, nervous system coccidiosis, polioencephalomalacia, lead poisoning, infectious bovine rhinotracheitis, salt poisoning, and chlorinated hydrocarbon toxicity. prevention and control. control or eradication of ticks and cleaning of equipment to prevent mechanical transmission, as noted in section iii,a, ,a,i, are important preventive measures. some vaccination approaches have been effective, but a commercial product is not available. treatment. supportive care is indicated, including blood transfusions, fluids, and antibiotics. medications such as diminazene diaceturate, phenamidine diisethionate, imidocarb diprionate, or amicarbalide diisethionate are most commonly used. treatment outcomes will be either elimination of the parasite or development of a chronic carrier state immune to further disease. research complications. this is a reportable disease in the united states. iii. coccidiosis etiology. coccidiosis is an important acute and chronic protozoal disease of ruminants. in young ruminants, it is characterized primarily by hemorrhagic diarrhea. adult ruminants may carry and shed the protozoa, but they rarely display clinical signs. intensive rearing and housing conditions and stress increase the severity of the disease in all age groups. coccidia are protozoal organisms of the phylum apicomplexa, members of which are obligatory intracellular parasites. there are at least reported species of coccidia in sheep, of which several are considered pathogenic: eimeria ashata, e. crandallis, and e. ovinoidalis (schillhorn van veen, ). at least species of eimeria have been recognized in the goat (foreyt, ) . eimeria ninakohlyakimovae, e. arloingi, and e. christenseni are regarded as the most pathogenic. eimeria bovis and e. zuernii (highly pathogenic), and e. auburnensis and e. alabamensis (moderately pathogenic), are among the species known to infect cattle. eimeria zuernii is more commonly seen in older cattle and is the agent of "winter coccidiosis." clinical signs and diagnosis. hemorrhagic diarrhea develops days to weeks after infection. fecal staining of the tail and perineum will be present. animals will frequently display tenesmus; rectal prolapses may also develop. anorexia, weight loss, dehydration, anemia, fever (infrequently), depression, and weakness may also be seen in all ruminants. the diarrhea is watery and malodorous and will contain variable amounts of blood and fibrinous, necrotic tissues. the intestinal hemorrhage may subsequently lead to anemia and hypoproteinemia. depending on the predilection of the coccidial species for small and/or large intestines, malabsorption of nutrients or water may occur, and electrolyte imbalances may be severe. concurrent disease with other enteropathogens may also be part of the clinical picture. in sheep, secondary bacterial infection with organisms such as fusobacterium necrophorum may ensue. young goats may die peracutely or suffer severe anemia from blood loss into the bowel. older goats may lose the pelleted form of feces. cattle may have explosive diarrhea and develop anal paralysis. the disease is usually diagnosed by history and clinical signs. numerous oocysts will frequently be observed in fresh fecal flotation (salt or sugar solution) samples as the diarrhea begins. laboratory results are usually reported as number of oocysts per gram of feces. coccidia seen on routine fecal evaluations reflect shedding, possibly of nonpathogenic species, without necessarily being indicative of impending or resolving mild disease. epkzootiology and transmission. as noted, coccidiosis is a common disease in young ruminants. in goats, young animals aged weeks to months are primarily affected, but isolated outbreaks in adults may occur after stressful conditions such as transportation or diet changes. coccidia are host-specific and also host cell-specific. the disease is transmitted via ingestion of sporulated oocysts. coccidial oocysts remain viable for long periods of time when in moist, shady conditions. necropsy. necropsies provide information on specific locations and severity of lesions that correlate with the species involved. ileitis, typhlitis, and colitis with associated necrosis and hemorrhage will be observed. mucosal scrapings will frequently yield oocysts. various coccidial stages associated with schizogony or gametogony may be observed in histopathological sections of the intestines. fibrin and cellular infiltrates will be found in the lamina propria. pathogenesis. this parasite has a complex life cycle in which sexual and asexual reproduction occurs in gastrointestinal enterocytes (speer, ) . the severity of the disease is correlated primarily with the number of ingested oocysts. specifics of life cycles vary with the species, and those characteristics contribute to the pathogenicity. in most cases, the disease is well established by the time clinical signs are seen. oocysts must undergo sporulation over a -to -day period in the environment. after ingestion of the sporulated oocysts, sporozoites are released and penetrate the intestinal mucosa and form schizonts. schizonts initially undergo replication by fission to form merozoites and eventually undergo sexual reproduction, forming new oocysts. the organisms cause edema and hyperemia; penetration into the lamina propria may lead to necrosis of capillaries and hemorrhage. differential diagnosis. differential diagnoses include the many enteropathogens associated with acute diarrhea in young ruminants: cryptosporidia, colibacilli, salmonella, enterotoxins, yersinia, viruses, and other intestinal parasites such as helminths. in cattle, for example, bovine viral diarrhea virus and helminthiasis caused by ostergia must be considered. management factors, such as dietary-induced diarrheas, are also differentials. in older animals, differentials in addition to stress are malnutrition, grain engorgement, and other intestinal parasitisms. prevention and control. good management practices will help prevent the disease. oocysts are resistant to disinfectants but are susceptible to dry or freezing conditions. proper sanitation of animal housing and minimizing overcrowding are essential. coccidiostats added to the feed and water are helpful in preventing the disease in areas of high exposure. treatment. affected animals should be isolated. on an individual basis, treatment should also include provision of a dry, warm environment, fluids, electrolytes (orally or intravenously), antibiotics (to prevent bacterial invasion and septicemia), and administration of coccidiostats. coccidiostats are preferred to coccidiocidals because the former allow immunity to develop. although many coccidial infections tend to be self-limiting, sulfonamides and amprolium may be used to aid in the treatment of disease. other anticoccidial drugs include decoquinate, lasalocid, and monensin; labels should be checked for specific approval in a species or specific indications. animals treated with amprolium should be monitored for development of secondary polioencephalomalacia. pen mates of affected animals should be considered exposed and should be treated to control early stages of infection. mechanisms of immunity have not been well defined but appear to be correlated with the particular coccidial species and their characteristics (for example, the extent of intracellular penetration). immunity may result when low numbers are ingested and there is only mild disease. immunity also may develop after more severe infections. iv. cryptosporidiosis etiology. cryptosporidium organisms are a very common cause of diarrhea in young ruminants. four cryptosporidium species have been described in vertebrates: c. baileyi and c. meleagridis in birds and c. parvum and c. muris in mammals. cryptosporidium parvum is the species affecting sheep (rings and rings, ) . debate continues regarding whether there are definite host-specific variants. clinical signs and diagnosis. cryptosporidiosis is characterized by protracted, watery diarrhea and debilitation. the diarrhea may last only - days or may be persistent and fatal. the diarrhea is watery and yellow, and blood, mucus, bile, and undigested milk may also be present. infected animals will display tenesmus, anorexia and weight loss, dehydration, and depression. in relapsing cases, animals become cachectic. overall, morbidity will be high, and mortality variable. mucosal scrapings or fixed stained tissue sections may be useful in diagnosis. the disease is also diagnosed by detecting the oocysts in iodine-stained feces or in tissues stained with periodic acid-schiff stain or methenamine silver. cryptosporidium also stains red on acid-fast stains such as kinyoun or ziehl-neelsen. fecal flotations should be performed without sugar solutions or with sugar solutions at specific gravity of . (foryet, ) . fecal immunofluorescent antibody (ifa) techniques have also been described. epizootiology and transmission. younger ruminants are commonly affected: lambs, kids (especially kids between the ages of and days old), and calves less than days old. like other coccidians, cryptosporidium is transmitted via the fecal-oral route. in addition to local contamination, water supplies have also been sources of the infecting oocysts. the oocysts are extremely resistant to desiccation in the environment and may survive in the soil and manure for many months. necropsy findings. the lesions caused by cryptosporidium are nonspecific. animals will be emaciated. moderate enteritis and hyperplasia of the crypt epithelial cells with villous atrophy as well as villous fusion, primarily in the lower small intestines, will be present. cecal and colonic mucosae may sometimes be involved. gastrointestinal smears may be made at necropsy and stained as described above. pathogenesis. although cryptosporidium infections are clinically similar to eimeria infections (moore, ) , cryptosporidium, in contrast to eimeria, invades just under the surface but does not invade the cytoplasm of enterocytes. there is no intermediate host. the oocysts are half the size of eimeria oocysts and are shed sporulated; they are, therefore, immediately infective. within - days of exposure, diarrhea and oocyst shedding occur. the diarrhea is the result of malabsorption and, in younger animals, intraluminal milk fermentation. autoinfection within the lumen of the intestines may also occur and result in persistent infections. in addition, several other pathogens may be involved, such as concurrent coronavirus and rotavirus infections in calves. environmental stressors such as cold weather increase mortality. intensive housing arrangements increase morbidity and mortality. differential diagnosis. other causes of diarrhea in younger ruminants include rotavirus, coronavirus, and other enteric viral infections; enterotoxigenic escherichia coli; clostridium; other coccidial pathogens; and dietary causes (inappropriate use of milk replacers). in addition, these other agents may also be causing illness in the affected animals and may complicate the diagnosis and the treatment picture. eimeria is more likely to cause diarrhea in calves and lambs at - weeks of age. giardia organisms may be seen in fecal preparations from young ruminants but are not considered to play a significant role in enteric disease. blood. animals exhibit fever, dehydration, and depression. chronic cases may result in a "poor doer" syndrome with weight loss and unthriftiness. giardia can be diagnosed by identifying the motile piriform trophozoites in fresh fecal mounts. oval cysts can be floated with zinc sulfate solution ( %). standard solutions tend to be too hyperosmotic and to distort the cysts. newer enzyme-linked immunosorbent assay (elisa) and ifa tests are sensitive and specific. epizootiology and transmission. giardia infection may occur at any age, but young animals are predisposed. chronic oocyst shedding is common. transmission of the cyst stage is fecaloral. wild animals may serve as reservoirs. necropsy findings. gross lesions may not be evident. villous atrophy and cuboidal enterocytes may be evident histologically. prevention and control. precautions should be taken when handling infected animals. affected animals must be removed and isolated as soon as possible. animal housing areas should be disinfected with undiluted commercial bleach or % ammonia. formalin ( %) fumigation has proven successful (foryet, ) . after being cleaned, areas should be allowed to dry thoroughly and should remain unpopulated for a period of time. because enteric disease often is multifactorial, other pathogens should also be considered, and management and husbandry should be examined. no known drug treatment is available. the disease is generally self-limiting, so symptomatic, supportive therapy aimed at rehydrating, correcting electrolyte and acid-base balance, and providing energy is often effective. supplementation with vitamin a may be helpful. age resistance begins to develop when the animals are about month old. research complications. cryptosporidiosis is a zoonotic disease. it is easily spread from calves to humans, for example, even as the result of simply handling clothing soiled by calf diarrhea. adult immunocompetent humans are reported to experience watery diarrhea, cramping, flatulence, and headache. the disease can be life-threatening in immunocompromised individuals. v. giardiasis etiology. giardia lamblia (also called g. intestinalis and g. duodenalis) is a flagellate protozoon. giardiasis is a worldwide protozoal-induced diarrheal disease of mammals and some birds (kirkpatrick, ), but it not considered to be a significant pathogen in ruminants. clinical signs and diagnosis. diarrhea may be continuous or intermittent, is pasty to watery, is yellow, and may contain pathogenesis. following ingestion, each giardia cyst releases four trophozoites, which attach to the enterocytes of the duodenum and proximal jejunum and subsequently divide by binary fission or encyst. the organism causes little intestinal pathology, and the cause of diarrhea is unknown but is thought to be related to disruption of digestive enzyme function, leading to malabsorption. disturbances in intestinal motility may also occur (rings and rings, ) . prevention and control. intensive housing and warm environments should be minimized. cysts can survive in the environment for long periods of time but are susceptible to desiccation. effective disinfectants include quaternary ammonium compounds, bleach-water solution ( : or : ), steam, or boiling water. after cleaning, areas should be left empty and allowed to dry completely. treatment. giardia has been successfully treated with oral metronidazole. benzimidazole anthelmintics are also effective, but these are not approved for use in animals for this purpose. should be taken when handling infected animals. etiology. neosporosis is a common, worldwide cause of bovine abortion caused by the protozoal species neospora caninum. abortions have also been reported in sheep and goats. neonatal disease is seen in lambs, kids, and calves. until , these infections were misdiagnosed as caused by toxoplasma gondii. some similarities exist between the life cycles and pathogeneses of both organisms. clinical signs and diagnosis. abortion is the only clinical sign seen in adult cattle and occurs sporadically, endemically, or as abortion storms. bovine abortions occur between the third and seventh month of gestation; fetal age at abortion correlates with the parity of the dam as well as with pattern of abortion in the herd. although cows that abort tend to be culled after the first or second abortion, repeated n. caninum-caused abortions will occur progressively later in gestation (up to about months) and within a shorter time frame in the same cow (thurmond and hietala, ) . although infections in adults are asymptomatic other than the abortions, decreased milk production has been noted in congenitally infected cows. many neospora-infected calves will be born asymptomatic. weakness will be evident in some infected calves, but this resolves. rare clinical signs include exophthalmos or asymmetric eyes, weight loss, ataxia, hyperflexion or hyperextension of all limbs, decreased patellar reflexes, and loss of conscious proprioception. some fetal deaths will occur, and resorption, mummification, autolysis, or stillbirth will follow. immunohistochemistry and histopathology of fetal tissue are the most efficient and reliable means of establishing a postmortem diagnosis. serology (ifa and elisa) is useful, including precolostral levels in weak neonates, but this indicates only exposure. titers of dams will not be elevated at the time of abortion; fetal serology is influenced by the stage of gestation and course of infection. earlier and rapid infections are less likely to yield antibodies against neospora. none of the currently available tests is predictive of disease. epizootiology and transmission. the parasite is now acknowledged to be widespread in dairy and cattle herds. the life cycle of n. caninum is complex, and many aspects remain to be clarified. the definitive host is the dog (mcallister et al., ) . placental or aborted tissues are the most likely sources of infection for the definitive host and play a minor role in transmission to the intermediate hosts. the many intermediate hosts include ruminants, deer, and horses. transplacental transmission is the major mode of transmission in dairy cattle and is the means by which a herd's infection is perpetuated. a less significant mode of transmission is by ingestion of oocysts, which sporulate in the environment or in the intermediate host's body. reactivation in a chronically infected animal's body is the result of rupture of tissue cysts in neural tissue. seropositive immunity does not protect a cow from future abortions. many seropositive cows and calves will never abort or show clinical signs, respectively. some immunological cross-reactivity may exist among neospora, cryptosporidia, and coccidium. necropsy findings. aborted fetuses will usually be autolysed. in those from which tissue can be recovered, tissue cysts are most commonly found in the brain. spinal cord is also useful. histological lesions include mild to moderate gliosis, nonsuppurative encephalitis, and perivascular infiltration by mixed mononuclear cells. pathogenesis. as with toxoplasma, cell death is the result of intracellular multiplication of neospora tachyzoites. neospora undergoes sexual replication in the dog's intestinal tract, and oocysts are shed in the feces. the intermediate hosts develop nonclinical systemic infections, with tachyzoites in several organs, and parasites then localize and become encysted in particular tissues, especially the brain. infections of this type are latent and lifelong. except when immunocompromised, most cattle do not usually develop clinical signs and do not have fetal loss. fetuses become infected, leading to fetal death, mid-gestation abortions, or live calves with latent infections or congenital brain disease. it usually takes - weeks for a fetus to die and to be expelled. many aspects of the role of the maternal immune response and pregnancy-associated immunodeficiency in the patterns of neospora abortions remain to be elucidated. differential diagnosis. even when there is a herd history of confirmed neospora abortions, leptospirosis, bovine viral diarrhea virus (bvdv), infectious bovine rhinotracheitis virus (ibrv), salmonellosis, and campylobacteriosis should be considered. bvdv in particular should be considered for abortion storms. differentials for weak calves are b vdv, perinatal hypoxia following dystocia (immediate postpartum time), bluetongue virus, toxoplasma, exposure to teratogens, or congenital defects. prevention and control. the primary preventive measure is preventing contact with contaminated feces. oocysts will not survive dry environments or extremes of temperature. dog populations should be controlled, and dogs and other canids should not have access to placentas or aborted fetuses. dogs should also be restricted from feed bunks and other feed storage areas. preventive culling is not economically practical for most producers. a vaccine recently became available. if embryo transfer is practiced, recipients should be screened serologically before use. laxis. there is no known treatment or immunoprophy- clinical signs and diagnosis. clinical signs of sarcocystosis infection are seen in cattle during the stage when the parasite encysts in soft tissues. often the infections are asymptomatic. fever, anemia, ataxia, symmetric lameness, tremors, tail-switch hair loss, excessive salivation, diarrhea, and weight loss are clinical signs. abortions in cattle occur during the second trimester and in smaller ruminants days after ingestion of the sporulated oocysts. definitive diagnosis is based on finding merozoites and meronts in neural tissue lesions. clinical hematology results include decreased hematocrit, decreased serum protein, and prolonged prothrombin times. sarcocystis-specific igg will increase dramatically by - weeks after infection. there is no cross-reaction between sarcocystis and toxoplasma. epizootiology and transmission. infection rates among cattle in the united states are estimated to be very high. transmission is by ingestion of feed and water contaminated by feces of the definitive hosts. dogs are the definitive hosts for the species that infect the smaller ruminants. cats, dogs, and primates (including humans when s. hominis is involved) are the definitive hosts for the species that infect cattle. necropsy. aborted fetuses may be autolysed. lesions in neural tissues, including meningoencephalomyelitis, focal malacia, perivascular cuffing, neuronal degeneration, and gliosis, are most marked in the cerebellum and midbrain. lesions may be found in other tissues, such as lymphadenopathy, and hemorrhages may be found in muscles and on serous surfaces. cysts in cardiac and skeletal muscles are common incidental findings during necropsies. pathogenesis. ingestion of muscle flesh from an infected ruminant results in sarcocystis cysts' being broken down in the carnivore's digestive system, release of bradyzoites, infection of intestinal mucosal cells by the bradyzoites, differentiation into sexual stages, fusion of the male and female gametes to form oocysts, and shedding as sporocysts by the definitive hosts. the sporocysts are eaten by the ruminant and penetrate the bowel walls; several stages of development occur in endothelial cells of arteries. merozoites are the form that enters soft tissues, such as muscle, and subsequently encysts. prevention and control. feed supplies of ruminants must be protected from fecal contamination by domestic and wild carnivores. these animals should be controlled and must also not have access to carcasses. in larger production situations, monensin may be fed as a prophylactic measure. treatment. monensin fed during incubation is prophylactic, but the efficacy in clinically affected cattle is not known. etiology. toxoplasmosis is caused by the obligate intracellular protozoon toxoplasma gondii, a coccidial parasite of the family eimeridae. cats are the only definitive hosts, and several warm-blooded animals, including ruminants, have been shown to be intermediate hosts. the disease is a major cause of abortion in sheep and goats and less common in cattle. clinical signs and diagnosis. clinical signs depend on the organ or tissue parasitized. toxoplasmosis is typically associated with placentitis, abortion, stillbirths, or birth of weak young (underwood and rook, ; buxton, ) . it has also been shown to cause pneumonia and nonsuppurative encephalitis. the enteritis at the early stage of infection may be fatal in some hosts. hydrocephalus does not occur in animals as it does in human fetal toxoplasma infections. rare clinical presentations in ruminants include retinitis and chorioretinitis; these are usually asymptomatic. infection of the ewe during the first trimester usually leads to fetal resorption, during the second trimester leads to abortion, and during the third trimester leads to birth of weak to normal lambs with subsequent high perinatal mortality. congenitally infected lambs may display encephalitic signs of circling, incoordination, muscular paresis, and prostration. in sheep, weak young will develop normally if they survive the first week after birth. infected adult sheep show no systemic illness. infected adult goats, however, may die. diagnosis may be difficult, and biological, serological, and histological methods are helpful. serological tests are the most readily available. complement fixation and the sabin-feldman antibody test may assist in diagnosis. antibodies found in fetuses are indicative of congenital infection and are typically detectable days after infection; fetal thoracic fluid is especially useful in demonstrating serological evidence of exposure. biological methods, such as tissue culture or inoculation of mice with maternal body fluids, or with postmortem or necropsy tissues, are more time-consuming and expensive. epizootiology and transmission. this protozoon is considered ubiquitous. fifty percent ( %) of adult western sheep and % of feedlot lambs have positive hemagglutination titers ( : or higher) (jensen and swift, ) . transmission among the definitive host is by ingestion of tissue cysts. necropsy findings. at necropsy, placental cotyledons contain multiple small white areas that are sites of necrosis, edema, and calcification. fetal brains may show nonspecific lesions such as coagulative necrosis, nonsuppurative encephalomyelitis, pneumonia, myocarditis, and hepatitis. histologically, granulomas with toxoplasma organisms may be seen in the retina, myocardium, liver, kidney, brain, and other tissues. impression smears of these tissues, stained appropriately (e.g., with giemsa), provide a rapid means of diagnosis. identification of the organism in tissue sections (especially of the heart and the brain) also confirms the findings. toxoplasma gondii is crescent-shaped, with a clearly visible nuclei, and will be found within macrophages. pathogenesis. the protozoon has three infectious stages: the tachyzoite, the bradyzoite, and the sporozoite within the oocyst. the definitive hosts, felids, become infected by ingesting cyst stages in mammalian tissues, by ingesting oocysts in feces, and by transplacental transfer. ingested zoites invade epithelial cells and eventually undergo sexual reproduction, resulting in new oocysts, which the cats will shed in the feces. cats rarely show clinical signs of infection. one cat can shed millions of oocysts in gm of feces, but the asymptomatic shedding takes place for only a few weeks in its life. oocysts sporulate in cat feces after day. ruminants are intermediate hosts of toxoplasmosis and become infected by ingesting sporulated oocyst-contaminated water or feed. as in the definitive host, the ingested sporozoite invades epithelial cells within the intestine but also further invades the bloodstream and is transported throughout the host. the organism migrates to tissues such as the brain, liver, muscles, and placenta. placental infection develops about days after ingestion of the oocysts. the damage caused by an infection is due to multiplication within cells. toxoplasma does not produce any toxin. campylobacter, chlamydia, and q fever. prevention and control. feline populations on source farms should be controlled. eliminating contamination of feed and water with cat feces is the best preventive measure. sporulated oocysts can survive in soil and other places for long periods of time and are resistant to desiccation and freezing. vaccines for abortion prevention in sheep are available in new zealand and europe. treatment. toxoplasmosis treatment is ineffective, although feeding monensin during pregnancy may be helpful (underwood and rook, ) . (monensin is not approved for this use in the unites states.) weak lambs that survive the first week after birth will mature normally and will not deliver toxoplasmainfected young. research complications. because toxoplasmosis is zoonotic, precautions must be taken when handling tissues from any abortions or neurological cases. infections in immunocompromised humans have been fatal. etiology. trichomoniasis is an insidious venereal disease of cattle caused by tritrichomonas (also referred to as trichomonas) fetus, a large, pear-shaped, flagellated protozoon. the organism is an obligate parasite of the reproductive tract, and it requires a microaerophilic environment to establish chronic infections. in the united states, it is now primarily a disease seen in western beef herds. there are many similarities between trichomoniasis and campylobacteriosis; both diseases cause herd infertility problems. clinical signs and diagnosis. clinical signs include infertility manifested by high nonpregnancy rates as well as periodic py-ometras and abortions during the first half of gestation. often the problem is not recognized until herd pregnancy checks indicate many "open," delayed-estrus, late-bred cows, or cows with postcoital pyometras. the abortion rate varies from % to %, and placentas will be expelled or retained. tritrichomonas fetus also causes mild salpingitis but this does not result in permanent damage. other than these manifestations, infection with t. fetus causes no systemic signs. diagnosis is based on patterns of infertility and pyometras. for example, pyometras in postcoital heifers or cows are suggestive of this pathogen. diagnostic methods include identifying or culturing the trichomonads from preputial smegma, cervicovaginal mucus, uterine exudates, placental fluids, or abomasal contents of aborted fetuses. other nonpathogenic protozoa from fecal contamination may be present in the sample. the trichomonad has three anterior flagellae, one posterior flagella, and an undulating membrane; it travels in fluids with a characteristic jerky movement. culturing must be done on specific media, such as diamond's or modified pastridge. real exposure from breeding bulls or cows or, in some cases, contaminated breeding equipment. necropsy findings. nonspecific lesions, such as pyogranulomatous bronchopneumonia of fetuses and placentitis, may be seen in aborted material; some cases will have no gross lesions. histologically, trichomonads may be visible in the fetal lung lesions and the placenta; those tissues are also the most useful for culturing. pathogenesis. tritrichomonas fetus colonizes the female reproductive tract, and subsequent clinical manifestations may be related to the size of the initial infecting dose. tritrichomonas fetus does not interfere with conception. embryonic death occurs within the first months of infection. affected cows will clear the infection over a span of months and maintain immunity for about months. infections in younger bulls are transient; apparently organisms are cleared by the bulls' immune systems and are dependent on exposure to infected females. older bulls become chronic carriers, probably because of the ability of t. fetus to colonize deeper epithelial crypts of the prepuce and penis. differential diagnosis. campylobacteriosis is the other primary differential for reduced reproductive efficiency of a herd. other venereal diseases should be considered when infertility problems are noted in a herd: brucellosis, mycoplasmosis, ureaplasmosis, and infectious pustular vulvovaginitis. in addition, management factors such as nutrition and age of heifers at introduction to the herd should be considered. heifers, cows, and breeding bulls are vaccinated subcutaneously twice at to week intervals, with the booster dose administered weeks before breeding season starts. similar timing is recommended for administration of the annual booster; a long, anamnestic response does not occur. bulls used for artificial insemination (ai) are screened routinely for t. fetus (and campylobacter) . ai reduces but does not eliminate the disease. the use of younger, vaccinated bulls is recommcmded in all circumstances. new animals should be tested before introduction to the herd. control measures also include culling affected cows or else removing them from the breeding herd for months to rest and clear the infection. culling chronically infected bulls is strongly recommended. treatment. imidazole compounds have been effective, but the use of these is not permitted in food animals in the united states. therapeutic immunizations are worthwhile when a positive diagnosis has been made. these will not curtail fetal losses but will shorten the convalescence of the affected cows and improve immunity of breeding bulls. research complications. trichomoniasis should be considered whenever natural service is used and fertility problems are encountered. nematodes are important ruminant pathogens that cause acute, chronic, subclinical, and clinical disease in adults and adolescents. the major helminths may cause gastroenteritis associated with intestinal hemorrhage and malnutrition. nematodiasis is associated with grazing exposure to infective larvae; animals procured for research may have had exposure to these helminths. mixed infections of these parasites are common. generally, older animals develop resistance to some of the species; thus, animals between about months and years of age are most susceptible to infection. because of the parasites' effects on the animals' physiology, infection in these younger animals is a major contributor to a cycle of poor nutrition and digestion, compromised immune responses, and impaired growth and development. diagnosis is primarily based on fecal flotation techniques; however, because many of these nematodes have similar-appearing ova, hatching the ova and identifying the larvae are often required (baermann technique). a number of anthelmintics can be used to interrupt nematode life cycles. see zajac and moore ( ) and pugh et al. ( ) for comprehensive reviews of treatment and control of nematodiasis. i. haemonchus contortus, h. placei (barber's pole worm, large stomach worm) . haemonchus contortus is the most important internal parasite of sheep and goats, and the brief description here focuses on the disease in the smaller ruminants. haemonchus contortus and h. placei infections do occur in younger cattle and are similar to the disease in sheep. haemonchus is extremely pathogenic, and the adults feed by sucking blood from the mucosa of the abomasum. severe anemia may lead to death. weight loss, decreased milk production, poor wool growth, and intermandibular and cervical edema due to hypoproteinemia ("bottle jaw") are also common clinical signs. diarrhea is not seen in all cases but may sometimes be severe or chronic. the life cycle is direct. under optimal conditions, a complete life cycle, from ingestion of larvae to eggs passed in the feces, occurs in weeks. embryonated eggs may develop into infective larvae within a week. hypobiotic (arrested) larvae may exist for several months in animal tissues, serving as a reservoir for future pasture contamination. periparturient increases in egg shedding by ewes contribute to large numbers of eggs spread on spring pastures ("spring rise"). resistance to common anthelmintics has developed; currently ivermectin or benzimidazole products are used, with a minimum of dosings given - weeks apart. levamisole is also used. in severe cases, animals may benefit from blood transfusions and iron supplementation. because animals may easily acquire infective larvae from ingestion of contaminated feed and from contaminated pastures, general facility sanitation and pasture management and rotation are important preventive and control measures. haemonchus contortus is susceptible to destruction by freezing temperatures and dry conditions. ii. ostertagia (teladorsagia) circumcincta (medium stomach worm). ostertagia circumcincta is also highly pathogenic for sheep and goats and, like haemonchus, attaches to the abomasal mucosa and ingests blood. the life cycle is comparable to that of haemonchus, including the phenomenon of hypobiosis. larvae are especially resistant to cool temperatures, however, and will overwinter on pastures. larvae-induced hyperplasia of abomasal epithelial glands results in a change of gastric ph from about . to near . , leading to decreased digestive enzyme activity and malnutrition. clinical syndromes are categorized as type or type . the former type is associated with infections acquired in fall or spring and is seen in younger animals. the latter type is associated with emergence of the arrested larvae during spring or fall. clinical signs include anemia, weight loss, decreased milk production, and unthriftiness. diarrhea is usually seen in type only; the symptoms of type are comparable to those of haemonchus infections. anthelmintic drug therapy is comparable to that for haemonchus, and drug resistance is also a problem with ostertagia. iii. ostertagia ostertagi (cattle stomach worm). ostertagia ostertagi is the most pathogenic and most costly of the cattle nematodes. ostertagia leptospicularis and o. bisonis also cause disease. the life cycle is direct, and egg shedding by the cattle may occur within - weeks of ingestion of infective larvae. hypobiosis is also a characteristic of o. ostertagi. in the initial steps of infection, the normal processes of the abomasum are profoundly disrupted and cells are destroyed as the larvae develop within and emerge from the glands. moroccan leather appearance is the term to describe the result of cellular hyperplasia and loss of cell differentiation. cycles of infection and morbidity depend on geographic location, climate, and production cycles. type cattle ostertagiasis is associated with ingestion of large numbers of infective larvae, occurs in animals less than years old, and causes diarrhea and anorexia. type ostertagiasis occurs in cattle - years old and older adults, is the result of the emergence and development of hypobiotic larvae, and in addition to signs seen with type , hypoproteinemia with development of submandibular edema, fever, and anemia is a clinical sign. treatment options include ivermectin, fenbendazole, and levamisole; all are effective against the arrested larvae. ostertagia is susceptible to desiccation but is resistant to freezing. iv. trichostrongylus vitrinus, t. axei, t. colubriformis (hair worms) . trichostrongylus species favor cooler conditions, and some larvae may overwinter. although the different species may affect different segments of the gastrointestinal tract, the nematode attaches to the mucosa and affects secretion and/or absorption. trichostrongylus vitrinus and t. colubriformis infect the small intestine of sheep and goats. trichostrongylus axei infects the abomasum of cattle, sheep, and goats and causes increases in abomasal ph similar to those seen with ostertagia. mucosal hyperplasia is not seen. the prepatent period is about weeks. affected animals display unthriftiness, anorexia, decreased milk production, weight loss, diarrhea, and dehydration. these worms show intermediate resistance to freezing temperatures and dry conditions. v. nematodirus spathiger, n. battus (thread-necked worms vii. strongyloides papillosus. strongyloides papillosus is a small-intestinal parasite of sheep and cattle. strongyloides has a different life cycle from that of many nematodes. the eggs, expelled in the feces, are larvated, and when they hatch, they form both free-living males and females or parasitic females only. the parasitic females may enter the gastrointestinal tract through oral ingestion, such as in milk during nursing, or through direct penetration of the skin. penetrating larvae enter the bloodstream and are transported to the lungs, where they penetrate the alveoli, are coughed up, and then swallowed to ultimately enter the gastrointestinal tract. adult females may reproduce in the small intestines by parthenogenesis. clinical signs associated with strongyloides include weight loss, diarrhea, unthriftiness, and dermatitis in cases where large numbers migrate through the skin. the current broad-spectrum anthelmintics are effective against strongyloides. strongyloides, bunostomum infection may involve oral ingestion or direct penetration of the skin (followed by tracheal migration and swallowing). the larvae mature in the small intestines and suck blood. larvae are susceptible to desiccation and freezing. heavy infection with bunostomum may result in anemia, diarrhea, intestinal hemorrhage, edema, and weight loss. ix. oesophagostomum columbianum, o. venulosum (nodule worms) . oesophagostomum spp. primarily infect the large intestine and occasionally the distal small intestine, causing nodule worm disease, or simply gut. oesophagostomum columbianum and o. venulosum infect sheep and cattle. these nematodes may affect sheep from months to years of age, and the prepatent period is about weeks. larvae are highly sensitive to freezing and desiccation and rarely overwinter. larvae penetrate the large-intestinal mucosa but occasionally move into the deeper areas of the intestinal wall near the serosa. the resultant inflammatory reaction may lead to the formation of a caseous nodule that may mineralize over time. intestinal lesions may accelerate peristalsis, leading to diarrhea, or may inhibit peristalsis (later stages), resulting in constipation. clinical signs include weakness, unthriftiness, alternating episodes of diarrhea and constipation, and severe weight loss. nodular lesions are typical at necropsy. x. chabertia ovis (large-mouth bowel worm). chabertia ovis is a minor colon parasite of sheep, goats, and cattle and is seen primarily in sheep. signs of infection are not usually seen in cattle. prepatent periods are up to days. heavy infection, which may result from as few as worms located at the proximal end of the colon, may lead to hemorrhagic mucoid diarrhea, weight loss, weakness, colitis, and mild anemia. xi. trichuris (whipworms). trichuris spp. are mildly pathogenic nematodes and are usually attached to the cecal mucosa. trichuris has a rather long prepatent period, extending from to months. the oval eggs are double-operculated and survive well in pasture environmental extremes. the adult worms also have a characterisitic morphology, with one thicker end appearing as a whip handle. the nematodes cause a minor cecitis and will feed on blood. clinical infection is rare and results in diarrhea with mucus and blood. treatment and prevention methods are similar to those for other nematodes. xii. dictyocaulus (lungworms). dictyocaulus spp., or lungworms, are nematodes that cause varying clinical signs in ruminants. in sheep, dictyocaulus filaria, protostrongylus rufescens, and muellerius capillaris cause disease; dictyocaulus is the most pathogenic. goats are infected by the same species as sheep, but infections are uncommon. dictyocaulus viviparus is the only lungworm found in cattle, causing "fog fever." infections with these parasites in the united states tend to be associated with cooler, moister climates. lungworms induce a severe parasitic bronchitis (known as husk, or verminous pneumonia) in sheep between approximately and months of age. sheep infected with any of the lungworm species may display coughing, dyspnea, nasal discharge, weight loss, unthriftiness, and occasionally fever. coughing and dyspnea are symptoms in goats. diagnosis is suggested by persistent coughing and nasal discharge and is confirmed by identifying larvae in the feces or adults in pathological samples. the baermann technique, involving prompt examination of room-temperature feces, is usually used; zinc sulfate flotation is also used. dictyocaulus has a direct life cycle. the adult worms reside in the large bronchi. dictyocaulus produces embryonated eggs that are coughed up and swallowed; the eggs then hatch in the intestines, and larvae are expelled in the feces. the expelled larvae are infectious in about - days and, after ingestion, penetrate the intestinal mucosa and move through the lymphatics and blood into the lungs, where they develop into adults in about weeks. dictyocaulus filaria causes an especially severe bronchitis in sheep. protostrongylus inhabits smaller bronchioles. muellerius is of minor pathogenicity. protostrongylus and muellerius require the snail or slug as an intermediate host. infection occurs through ingestion of infected snails; infections are less likely than those caused by the direct ingestion of dictyocaulus larvae. immunity wanes over a year. viral and bacterial respiratory tract infections may be associated with the parasitic infection. more severe illness is seen after infections with cooperia and ostertagia, because of a synergism between the nematodes even if the cattle are not currently infected with those parasites. hypobiosis (arrested development of immature worms in lung tissue) is associated with dictyocaulus infections; cattle will be silent carriers, showing no clinical signs and serving as a means for the infection to survive over winter or a dry season. pastures can be heavily contaminated during the next grazing season. necropsy lesions include bronchiolitis and bronchitis, atelectasis, and hyperplasia of peribronchiolar lymphoid tissue. nematodes frequently reside in the bronchi of the diaphragmatic lung lobes and are frequently enmeshed with frothy exudate. prevention and control of the disease involve appropriate pasture management. elimination of intermediate hosts is important in sheep and goat pastures. in a laboratory setting, animals may be procured that are already harboring the disease. infected animals can be treated with anthelmintics such as ivermectin or levamisole. muellerius tends to be resistant to levamisole. there is no anthelmintic currently approved for goats, but fenbendazole, administered weeks apart, has been effective for all three tapeworms are rarely of clinical or economic importance. in younger animals, heavy infections result in potbellies, constipation or mild diarrhea, poor growth, rough coat, and anemia. moniezia expansa, and less commonly moniezia benedini, inhabit the small intestines of grazing ruminants. moniezia expansa has the widest distribution of the tapeworm species in north america. soil mites (galumna spp. and oribatula spp.) contribute to the life cycle as intermediate hosts, a period that lasts up to weeks. cysticercoids released from the mites are grazed, pass into the small intestines, and mature. no clinical or pathological sign is usually observed with moniezia infection; diagnosis is made by observing the characteristic triangularshaped eggs in fecal flotation examinations. infection is treated with cestocides. thysanosoma actinoides, or the fringed tapeworm, is a cestode that resides in the duodenum, bile duct, and pancreatic duct of sheep and cattle raised primarily west of the mississippi river in the united states. thysanosoma is of the family anoplocephalidae. the life cycle is indirect, and the intermediate host is the psocid louse. larval forms, or cysticercoids, are ingested by grazing animals, and the prepatent period is several months. typically, no clinical signs are observed with thysanosoma infection; nonetheless, liver damage, resulting in liver condemnation at slaughter, occurs. necropsy lesions include bile and/or ductal hyperplasia and fibrosis. thysanosoma is diagnosed premortem by identifying the gravid segments in the feces. ii. abdominal or visceral cysticercosis. abdominal or visceral cysticercosis is an occasional finding at slaughter. the socalled bladder worms typically affect the liver or peritoneal cavity and are the larval form of taenia hydatigena, the common tapeworm of the dog family. taenia hydatigena resides in the small intestines of canids, and its gravid segments, oncospheres, contaminate feed and water sources. after ingestion, the larvae penetrate the intestinal mucosa, are transported via the bloodstream to the liver, and cause migration tracts throughout the liver parenchyma. the larvae may leave the liver and migrate into the peritoneal cavity, where they attach and develop over the next - months into small fluid-filled bladders. the life cycle is completed only after these bladders are ingested by a carnivore, thus completing the maturation of the adult tapeworms. although larval migration may cause nonspecific signs such as anorexia, hyperthermia, and weight loss, affected animals are usually asymptomatic. at necropsy, the bladder worms will be observed attached to the peritoneal or organ surfaces. migration tracts may result in fibrosis and inflammation. diagnosis is usually made at necropsy. because of the migration through the liver, fasciola hepatica is a differential diagnosis. minimizing exposure to canine feces-contaminated feeds and water effectively interrupts the life cycle. research animals may have been exposed prior to purchase. echinococcosis, like cysticercosis, is an occasional finding at slaughter or necropsy. the hydatid cyst is the larval intermediate of the adult tapeworm echinococcus granulosus, which resides in the small intestines of dogs and wild canids. embryonated ova are expelled in the feces of the primary host and are ingested by herbivores, swine, and potentially humans. the eggs hatch in the gastrointestinal tract, and the oncospheres penetrate the mucosal lining, enter the bloodstream, and are transported to various organs such as the liver and lungs. the cystic structure develops and potentially ruptures, forming new cystic structures. clinically, echinococcosis presents minimal clinical signs; unthriftiness or pneumonic lesions may be associated with infected organs. cysts are typically observed at necropsy. prevention should be aimed at decreasing fecal contamination of feed and water by canids. additionally, tapeworm-infected dogs can be treated with standard tapeworm therapies. treatment of infected ruminants is uncommon. iv. gid. coenuris cerebralis, the larval form of the canid tapeworm taenia (multiceps) multiceps, is the causative agent of the rare condition called gid. the disease occurs in ruminants as well as many other mammalian species. the larval parasite, ingested from fecal-contaminated food and water, invades the brain and spinal cord and develops as a bladder worm that causes pressure necrosis of the nervous tissues. the resultant signs of hyperesthesia, meningitis, paresis, paralysis, ataxia, and convulsions are observed. diagnosis is usually made at necropsy. eliminating transfer from the canid hosts prevents the disease. the cercariae leave the intermediate host, swim to grassy vegetation, lose their tail, and become a cystlike metacercaria. the metacercariae may remain in a dormant stage on the grass for months or longer until ingested by a ruminant. the ingested metacercariae penetrate the small-intestinal wall and migrate through the abdominal cavity to the liver. there they locate in a bile duct, mature, and remain for up to years. acute liver fluke disease is related to the damage caused by the migration of immature flukes. migratory flukes may lead to liver inflammation, hemorrhage, necrosis, and fibrosis. fascioloides magna infections in sheep and goats can be fatal as the result of just one fluke tunneling through hepatic tissue. in cattle, infections are often asymptomatic because of the host's encapsulation of the parasite. liver fluke damage may predispose to invasion by anaerobic clostridium species such as c. novyi that could lead to fatal black disease or bacillary hemoglobinuria. chronic disease may result from fluke-induced physical damage to the bile ducts and cholangiohepatitis. blood loss into the bile may lead to anemia and hypoproteinemia. liver damage also is evidenced by increases in liver enzymes such as y-glutamyl transpeptidase (ggt). persistent eosinophilia is also seen with liver fluke disease. other clinical signs of liver fluke disease include anorexia, weight loss, unthriftiness, edema, and ascites. at necropsy, livers will be pale and friable and may have distinct migration tunnels along the serosal surfaces. bile ducts will be enlarged, and areas of fibrosis will be evident. diagnosis can be made from clinical signs and postmortem mites cause a chronic dermatitis. the principal symptom of these infections is intense pruritus. in addition, papules, crusts, alopecia, and secondary dermatitis are seen. anemia, disruption of reproductive cycles, and increased susceptibility to other diseases may also occur. mites are rare in ruminants in the united states, but infections of sarcoptes and psorergates mange must be reported to animal health officials. ruminants in poorly managed facilities are generally the most susceptible to infection, and infections are more frequent during winter months. diagnosis is based on signs, examination of skin scrapings, and response to therapy. no effective treatment for demodectic mange in large animals has been found. the differential for mite infestations is pediculosis. several genera of mites may affect sheep. these have been eradicated from flocks in the united states or are very rare and include psoroptes ovis (common scabies), sarcoptes scabiei (head scabies, barn itch), psorergates ovis (sheep itch mite), chorioptes ovis (foot scabies, tail mange), and demodex ovis (follicular mange). goats can also be infected by sarcoptic, chorioptic, and psoroptic mange. the scabies mite sarcoptes rupicaprae invades epidermal tissue and causes focal pruritic areas around the head and neck. the chorioptic mite, either chorioptes bovis or c. caprae, does not invade epidermal tissue but rather feeds on dead skin tissue. the chorioptic mite prefers distal limbs, the udder, and the scrotum and can be a significant cause of pruri-tus. the psoroptic mite psoroptes cuniculi commonly occurs in the ear canal and causes head shaking and scratching. repeated treatments of lime sulfur, amitraz, or ivermectin may be effective (smith and sherman, ) . goats are also susceptible to demodectic mange caused by demodex caprae. adult mites invade hair follicles and sebaceous glands. pustules may develop with secondary bacterial infection. psoroptes bovis continues to be present in cattle in the united states, although it has been eradicated from sheep. chorioptes bovis typically infects lower hindlimbs, perineum, tail, and scrotum but can become generalized. the sarcoptic mange mite s. scabei can survive off the host, so fomite transmission is a factor. the mange usually begins around the head but then spreads. this parasite can be transmitted to humans. demodex bovis infects cattle; nodules on the face and neck are typical. demodex bovis infections may resolve without treatment. lindane, coumaphos, malathion, and lime sulfur are used to treat psoroptes and psorergates. ivermectin is effective against sarcoptes and is approved for use in cattle. lice that infect ruminants are of the orders mallophaga, biting or chewing lice, and anoplura, sucking lice. these are wingless insects. members of the mallophaga are colored yellow to red; members of the anoplura are blue gray. lice produce a seasonal (winter-to-spring), chronic dermatitis. in sheep, biting lice include damalinia (bovicola) ovis (sheep body louse). sucking lice that infect sheep include linognathus ovillus (blue body louse) and l. pedalis (sheep foot louse). in goats, biting lice infection are caused by d. caprae (goat biting louse), d. limbatus (angora goat biting louse), and d. crassipes. suckir/g louse infections in goats are caused by l. stenopis and l. africanus. damalinia bovis is the cattle biting louse. sucking lice include l. vituli, solenopotes capillatus, haematopinus eurysternus, and h. quadripertusus. pruritus is the most common sign and often results in alopecia and excoriation. the host's rubbing and grooming may not correlate with the extent of infestation. hairballs can result from overgrooming in cattle. in severe cases, the organisms can lead to anemia, weight loss, and damaged wool in sheep and damaged pelts in other ruminants. young animals with severe infestations of sucking lice may become anemic or even die. pregnant animals with heavy infestations may abort. in sheep infected with the foot louse, lameness may result. lice are generally species-specific. those infecting ruminants are usually smaller than mm. goats may serve as a source of infection for sheep by harboring damalinia ovis. transmission is primarily by direct contact between animals. transmission can also occur by attachment to flies or by fomites. some animals are identified as carriers and seem to be particularly susceptible to infestations. biting or chewing lice inhabit the host's face, lower legs, and flanks and feed on epidermal debris and sebaceous secretions. sucking lice inhabit the host's neck, back, and body region and feed on blood. lice eggs or nits are attached to hairs near the skin. three nymphal stages, or instars, occur between egg and adult, and the growth cycle takes about month for all species. lice cannot survive for more than a few days off the host. all ruminant mite infestations are differentials for the clinical signs seen with pediculosis. animals that are carriers should be culled, because these individuals may perpetuate the infection in the group. lice are effectively treated with a variety of insecticides, including coumaphos, dichlorvos, crotoxyphos, avermectin, and pyrethroids. label directions should be read and adhered to, including withdrawal times. products should not be used on female dairy animals. treatments must be repeated at least twice at intervals appropriate for nit hatches (about every days) because nits will not be killed. fall treatments are useful in managing the infections. systemic treatments in cattle are contraindicated when there may be concurrent larvae of cattle grubs (hypoderma lineatum and h. bovis). back rubbers with insecticides, capitalizing on self-treatment, are useful for cattle. sustained-release insecticide-containing ear tags are approved for use in cattle. etiology. ruminants are susceptible to many species of ixodidae (hard-shell ticks) and argasidae (softshell ticks). many diseases, including anaplasmosis, babesiosis, and q fever are transmitted by ticks. clinical signs and diagnosis. tick infestations are associated with decreased productivity, loss of blood and blood proteins, transmission of diseases, debilitation, and even death. feeding sites on the host vary with the tick species. ticks are associated with an acute paralytic syndrome called tick paralysis. this disease is characterized by ascending paralysis and may lead to death if the tick is not removed before the paralysis reaches the respiratory muscles. diagnosis is based on identification of the species. epizootiology and transmission. ticks are not as host-specific as lice. ticks are classified as one-host, two-host, or three-host; this refers to whether they drop off the host between larval and nymphal stages to molt. pathogenesis of tick infestations. patterns of feeding on the host differ between argasidae and ixodidae. the former feed repeatedly, whereas the latter feed once during each life stage. pathogenesis of tick paralysis. following a tick-feeding period of - days, the tick salivary toxin travels hematogenously to the myoneural junctions and spinal cord and inhibits nerve transmission. removal of the ticks reverses the syndrome unless paralysis has migrated anteriorly to the respiratory centers of the medulla. in these cases, death due to respiratory failure occurs. insecticides. ticks can be treated using systemic or topical h. other parasites i. nasal bots (nasal myiasis, head grubs). nasal myiasis causes a chronic rhinitis and sinusitis. the disease is caused by the larval forms of the botfly oestrus ovis. the botfly deposits eggs around the nostrils of sheep. the ova hatch, and the larvae migrate throughout the nasal cavity and sinuses, feeding on mucus and debris. in - months, the larvae complete their growing phase, migrate back to the nasal cavity, and are sneezed out. the mature larvae penetrate the soil and pupate for - . months and emerge as botflies. clinically, early in the disease course, animals display unique behaviors such as stamping, snorting, sneezing, and rubbing their noses against each other or objects. hypersensitivity to the larvae occurs (dorchies et al., ) . later, mucopurulent nasal discharges associated with the larval-induced inflammation of mucosal linings will be observed. at necropsy, larvae will be observed in the nasal cavity or sinuses. mild inflammatory reactions, mucosal thickening, and exudates will accompany the larvae. the disease is diagnosed by observing the behaviors or identifying organisms at necropsy. up to % of a flock will potentially be infected; treatment should be employed on the rest of the flock. ivermectins and other insecticides will eliminate the larvae; but treatment should be done in the early fall, when larvae are small. fly repellents may be helpful at preventing additional infections. ii. screwworm flies. cochliomyia hominivorax (callitroga americana) is the the screwworm that causes occasional disease in the southwestern united states along the mexico border. eradication programs have been pursued, and the disease is reportable. large greenish flies lay large numbers of white eggs as shinglelike layers at the edges of open wounds (including docking and castration sites), soiled skin, or abrasions. eggs hatch within hr. larvae are obligate parasites of living tissue, and the cycle is perpetuated because the increasingly large wound continues to be attractive to the next generation of flies. larvae eventually drop off, pupate best in hot climates, and hatch in weeks. large cavities in parasitized tissue are formed, and lesions are characterized by malodor, large volumes of brown exudate, and necrosis. single animals or entire herds may be affected. treatment is intensive, with dressings and larvicidal applications. if there is no intervention, the host succumbs to secondary infections and fluid loss. effective current control regimens include subcutaneous injection of ivermectin and programs that release sterile male flies. iii. sheep keds ("sheep ticks"). in sheep and goats, sheep keds produce a chronic irritation and dermatitis with associated pruritus. the disease is caused by melophagus ovinus, which is a fiat, brown, blood-sucking, wingless fly; the term sheep tick is incorrectly used. the adult fly lives entirely on the skin of sheep. females mate and produce - larvae following a gestation of about - days. the larvae attach to the wool or hair and then pupate for about weeks. the adult female feeds on blood and lives for - months; the life cycle is completed in about - weeks. infection is highest in fall and winter. pruritus develops around the neck, sides, abdomen, and rump. in severe cases, anemia may occur. keds can transmit bluetongue virus. keds are diagnosed by gross or microscopic identification. ivermectin or other insecticides are useful treatment agents. portant, other immune mechanisms are not well understood. immunity may not be of long duration. recovery is enhanced by correcting nutritional deficiencies and improving housing and ventilation problems. a number of topical treatments, such as - % lime-sulfur solution, % captan, iodophors, thiabendazole, and . % sodium hypochlorite, can be used. in severe cases, systemic therapy with griseofulvin may be successful. prevention and control. the animals' environment and overall physical condition should be reassessed with particular attention to ventilation, crowding, sanitation, and nutrition. pens should be thoroughly cleaned and disinfected. research complications. ringworm is a zoonotic disease. etiology. dermatophytosis, or infection of the keratinized layers of skin, is caused mostly by species of the genera trichophyton and microsporum. the primary causes in sheep are t. mentagrophytes and t. verrucosum. in goats, the agents are t. mentagrophytes, m. canis, m. gypseum, t. verrucosum, t. schoenleinii, and epidermophyton floccosum. in cattle, t. verrucosum is the primary causative agent. dermatophytosis is a common fungal infection of the epidermis of cattle and is less common in sheep and goats. clinical signs and diagnosis. multiple, gray, crusty, circumscribed, hyperkeratotic lesions are characteristic of infection. lesions will vary in size. in all ruminants, lesions will be around the head, neck, and ears. in goats and cattle, lesions will extend down the neck, and in cattle, lesions develop particularly around the eyes and on the thorax. cattle lesions are unique in the marked crustiness, which progressively appears wartlike. hair shafts become brittle and break off. intense pruritus is often associated with the alopecic lesions. the disease can be diagnosed by microscopic identification of hyphae and conidia on the hairs following skin scraping and % potassium hydroxide digestion. dermatophyte test media (dtm) cultures are the most reliable means to diagnose the fungus. broken hairs from the periphery of the lesion are the best sources of the fungus. epizootiology and transmission. younger animals are more susceptible, and factors such as crowding, indoor housing, warm and humid conditions, and poor nutrition are also important. transmission is by direct contact or by contact with contaminated fomites, such as equipment, fencing, or feed bunks. pathogenesis. incubation can be as long as weeks. the organisms invade and multiply in hair shafts. treatment. spontaneous recovery occurs in all species in - months. although cell-mediated immunity is considered im- inverted eyelids are a common inherited disorder of lambs and kids of most breeds. generally, the lower eyelid is affected and turns inward, causing various degrees of trauma to the conjunctiva and cornea. young animals will display tearing, blepharospasm, and photophobia initially. if the disorder is left uncorrected, corneal ulcers, perforating ulcers, uveitis, and blindness may occur. placing a suture or a surgical staple in the lower eyelid and the cheek, effectively anchoring the lid in an everted position, successfully treats the condition. the procedure likely results in the formation of some degree of scar tissue within the lower lid, because when the suture eventually is removed, the condition rarely returns. other treatments include the injection of a "bleb" of penicillin in the lid, regular manual correction over a -day period early in the animal's life, and application of ophthalmic ointments, powders, and solutions. boric acid or % argyrol solutions have been used as treatments. because of the genetic predisposition, prevention of the condition requires removal of maternal or paternal carriers. [ -mannosidosis is an autosomal recessive lysosomal storage disease of goats. the disease affects kids of the nubian breed and is identified by intention tremors and difficulty or inability of newborns to stand. cells of affected animals are vacuolated because of a lack of lysosomal hydroxylase, which results in accumulation of oligosaccharides. newborn kids are unable to rise, and they have characteristic flexion of the carpal joint and hyperextension of the pastern joint. kids are born deaf and with musculoskeletal deformities such as domed skull, small narrow muzzle, small palpebral fissures, enophthalmos, and depressed nasal bridge (smith and sherman, ) . carrier adults can be identified by plasma measurements of [ -mannosidase activity. caprine congenital myotonia is an inherited autosomal dominant disease that affects voluntary striated skeletal muscles. goats with this disease are commonly known as fainting goats. "fainting" is actually transient spasms of skeletal musculature brought about by visual, tactile, or auditory stimuli (smith and sherman, ) . muscle fiber membranes appear to have fewer chloride channels than normal, resulting in decreased chloride conduction across the membrane, with subsequent increased membrane excitability and repetitive firing (smith and sherman, ) . contractions of skeletal muscle are sustained for up to min. kids exhibit the condition by weeks of age, and males appear to exhibit more severe clinical signs than females (smith and sherman, ) . electromyographic studies produce an audible "dive-bomber" sound characteristic of hyperexcitable cell membranes (smith and sherman, ) . i. congenital erythropoietic porphyria. congenital erythropoietic porphyria (cep) is an autosomal recessive disease of cattle seen primarily in holsteins, herefords, and shorthorns. the disease also occurs in limousin cattle, humans, and some other species. in the homozygous recessive animal, symptoms of the disease may vary from mild to severe and occur at different times of the year and in different ages of animals. a reddish brown discoloration of teeth and bones is a characteristic of the disease, as is discolored urine, general weakness and failure to thrive, photosensitization, and photophobia. bones are more fragile compared with bones of normal animals. a regenerative anemia occurs as the result of the shortened life span of erythrocytes, due to accumulations of porphyrins. the genetic defect is associated with low activity of an essential enzyme, uroporphyrinogen iii synthase, in the porphyrin-heme synthesis pathway in erythrocytic tissue. the ranges in the presentation of the disease are believed to be related to varying cycles of porphyrin synthesis. porphyrins are excreted in varying amounts in the urine and the discoloration fluoresces under a wood's lamp. diagnosis is based on these clinical and visible signs of porphyria; skin biopsy provides definitive diagnosis. heterozygotes may have milder symptoms. many other genetic defects, in all major organ systems, have been described in numerous breeds of cattle and are described in detail elsewhere ("large animal internal medicine," ) . in many cases, the genetic basis has been clarified, and associated defects also noted. many defects are reported in particular breeds, but as crossbreeding increases and new breeds are developed, these traits are appearing in these animals. the bovine genome continues to be further characterized, and more linkage maps and gene locations are forthcoming (womack, ) . some bovine genetic defects are also regarded as models of genetic disease, such as leukocyte adhesion deficiency of holstein cattle. some of the more commonly reported defects include syndactyly in holsteins and other breeds and polydactyly in simmentals; lysosomal storage diseases such as a-mannosidosis in some beef breeds; enzyme deficiencies such as citrullinemia in holsteins; and progressive degenerative myeloencephalopathy ("weaver") in brown swiss. ii. goiter of sheep. a defect in the synthesis of thyroid hormone has been identified in merino sheep (radostits et al., ) . lambs born with the defect have enlargement of the thyroid gland, a silky appearance to the wool, and a high degree of mortality. edema, bowing of the legs, and facial abnormalities have also been noted in animals with this disorder. immaturity of the lungs at birth causes neonatal respiratory distress and resuits in dyspnea and respiratory failure. spider lamb syndrome is an inherited, often lethal, musculoskeletal disorder primarily occurring in suffolk and hampshire breeds. severely affected lambs die shortly after birth. animals that survive the perinatal period develop angular limb deformities, scoliosis, and facial deformities. with time, affected animals become debilitated, exhibit joint pain, and develop neurological problems associated with the spinal abnormalities. radiologically, secondary ossification centers--especially the physis, subchondral areas, and cuboidal bonesmare affected. abnormal endochondral ossification leads to excess cartilage formation, notably apparent in the elbows. lambs will typically display abnormally long limbs, medial deviation of the carpus and tarsus, flattening of the sternum, scoliosis/kyphosis of the vertebrae, and a rounded nose. muscle atrophy is common. diagnosis can be based on typical clinical signs, which are similar to those seen with marfan syndrome in humans (rook et al., ) . long-term survival is rare; treatment is unsuccessful. i. abomasal and duodenal ulcers. abomasal and duodenal ulcers occur more frequently in calves and adult cattle than in sheep and goats. like rumenitis, abomasal and duodenal ulcers may be associated with lactic acidosis. concurrent disease, such as salmonellosis, bluetongue, or overuse of anti-inflammatory drugs, or recent shipping or environmental stresses may also lead to ulcer formation. copper deficiency, dietary changes, mycotic infections, clostridium perfringens abomasitis, and abomasal bezoars are associated with this disease in calves. in older adult cattle, abomasal lymphosarcoma may be the underlying condition. gastric acid hypersecretion in conjunction with insufficient gastric mucous secretion will physically destroy the gastric epithelium. deep ulceration may cause serious hemorrhage and/or perforation with peritonitis. chronic hemorrhage may lead to anemia. although ulcers are often asymptomatic in calves, perforation with peritonitis is more common than hemorrhage. dark feces or melena and abdominal pain may be observed. arched back, restlessness, kicking at the abdomen, bruxism, and anorexia are common signs of abdominal pain. fecal occult blood is as an easy diagnostic test. treatment includes gastrointestinal protectants and histamine antagonists. anemia may be symptomatically treated with parenteral iron injections and anabolic steroids. preventive measures in cattle herds include ensuring optimal passive immunity for calves, minimizing stress to calves, and striving for a herd free of bovine leukosis virus. ii. abomasal emptying defect. abomasal emptying defect of sheep is a sporadic syndrome associated with abomasal distension and weight loss. suffolks tend to be especially predisposed, although the disease has been diagnosed in hampshires, columbias, and corriedales. the mechanism of the disease is unknown. affected animals will exhibit a gradual weight loss with a history of normal appetites. feces will continue to be normal. ventral abdominal distension associated with abomasal accumulation of feedstuffs will be apparent in many of the animals. diagnosis is primarily based on history and clinical signs. elevations in rumen chloride concentrations (> meq/liter) are commonly found. radiography or ultrasonography may be helpful at identifying the distended abomasum. abomasal emptying defect is usually eventually fatal. medical treatment with metoclopramide and mineral oil may be helpful in early disease. iii. abomasal displacement. displaced abomasum (da) is a sporadic disorder usually associated with multiparous -to year-old dairy cows in early lactation, but the condition can occur even in young calves. displacement to the right (rda) may be further complicated by torsion (rta), a surgical emergency. left displacement (lda) is more common than rda. clinical signs include anorexia, lack of cud chewing, decreased frequency of ruminal contractions, shallow respirations, increased heart rate, treading, and decreased milk production. diagnosis is based on characteristic areas of tympanic resonance during auscultation-percussion of the lateral to lateral-ventral abdomen ("pings"), ruminal displacement palpated per rectum, and clinical signs. cow-side clinical chemistry findings include hypoglycemia and ketonuria; more extensive evaluations will often indicate moderate to severe electrolyte and acid-base abnormalities. da occurs because of gas accumulation within the viscus, and the abomasum "floats" up from its normal ventral location to the lateral abdominal wall. no exact cause of da has been identified, but it is commonly associated with stress; high levels of concentrate in the diet, leading to forestomach atony; and many disorders, including lack of regular exercise, mastitis, hypocalcemia, retained placenta, metritis, or twins. factors such as body size and conformation indicate the possibility of genetic predisposition. treatments include surgical and nonsurgical techniques for lda; the former has a better chance of per-manent correction. emergency surgery is necessary for rta; the disorder is fatal within hr. recurrence is rare after surgical correction. electrolyte and acid-base imbalances are likely in severe cases and especially with rta. prevention includes reducing stress, taking greater care in the introduction and feeding of concentrates, and reducing incidence of predisposing diseases noted above (rohrbach et al., ) . fat cow syndrome is seen in peri-or postparturient overconditioned or obese multiparous dairy cows. factors in the development of the condition include negative energy balance related to the normal decreased dry matter intake as parturition approaches; hormonal changes associated with parturition; and concurrent diseases of parturition that decrease feed intake and increase energy needs. the possible concurrent diseases include metritis, retained fetal membranes, mastitis, parturient paresis, and displaced abomasum. signs are nonspecific and include depression, anorexia, and weakness. prognosis is usually guarded. diagnosis is based on herd management, the animal's condition, ketonuria, and clinical signs. in prepartum cattle and in lactating cows, blood levels of nonesterified fatty acids (nefa) greater than ~teq/liter and - ~teq/liter, respectively, are abnormal (gerloff and herdt, ) . triglyceride analysis of liver biposy specimens are useful. in affected cows, body fat is mobilized, in the form of nefa in response to the energy demands. hepatic lipidosis occurs rapidly as the nefa are converted into hepatic triglycerides. the ability of the liver to extract the albumin-bound nefa from the blood is better than that of other tissues that need and can also use nefa as an energy source. treatment for any concurrent diseases must be pursued aggressively, as well as measures to increase and stabilize blood glucose, decrease nefa production, and increase forestomach digestion to improve production of normally metabolized volatile fatty acids. therapeutic measures include intravenous glucose drips, insulin (nph or lente) injections every hr, and transfaunation of ruminal fluid from a normal cow. prevention includes minimizing stress to lategestation cows. dry and lactating cows should be maintained separately; their energy, protein, and dry matter requirements are very different. cows with prolonged lactation or delayed breeding should be managed to prevent weight gain. i. bloat. bloat or tympanites refers to an excessive accumulation of gas in the rumen. the condition most frequently occurs in animals that have been recently fed abundant quantities of succulent forages or grains. bloat is classified into two broad categories: frothy bloat and free-gas bloat. frothy bloat is associated with ingestion of feeds that produce a stable froth that is not easily expelled from the rumen. fermentation gases such as co , ch , and minor gases such as n , , h , and h s incorporate into the froth, overdistend the rumen, and eventu-ally compromise respiration by limiting diaphragm movement. the froth is often derived from a combination of salivary mucoproteins, protozoal or bacterial proteins, and proteins, pectins, saponins, or hemicellulose associated with ingested leaves or grain. typical foodstuffs that cause frothy bloat include green legumes, leguminous hay (alfalfa, clover), or grain (especially barley, corn, and soybean meal). free-gas bloat is less related to feeds ingested; rather, it is caused by rumen atony or by physical or pathological problems that prevent normal gas eructation. some examples of causes of free-gas bloat are esophageal obstructions (foreign bodies, tumors, abscesses, and enlarged cervical or thoracic lymph nodes), vagal nerve paralysis or injury, and central nervous system conditions that affect eructation reflexes. clinically, the animal will exhibit rumen distension, and tympany will be observed in the left paralumbar fossa. additional signs may include colic-like pain of the abdomen and dyspnea. passage of a stomach tube helps to differentiate between free-gas bloat and frothy bloat; and with free-gas bloat, expulsion of gas through the stomach tube aids in treatment of the disorder. once rumen distension is alleviated with free-gas bloat, the underlying cause must be investigated to prevent recurrence. frothy bloat is more difficult to treat, because the foam blocks the stomach tube. addition of mineral oil, household detergents, or antifermentative compounds via the tube may help break down the surface tension, allowing the gas to be expelled. in acute, life-threatening cases of bloat, treatment should be aimed at alleviating rumen distension by placing a trocar or surgical rumenotomy into the rumen via the paralumbar fossa. limiting the consumption of feedstuffs prone to induce bloat can prevent the disease. additionally, poloxalene or monensin will decrease the incidence of frothy bloat. ii. lactic acidosis. lactic acidosis, or rumen acidosis, is an acute metabolic disease caused by engorgement of grains or other highly fermentable carbohydrate sources. the disease is most frequently related to a rapid change in diet from one containing high roughage to one containing excessive carbohydrates. diet components that predispose to acidosis include common feed grains; feedstuffs such as sugar beets, molasses, and potatoes; by-products such as brewer's grains; and bakery products. biochemically, ingestion of large amounts of the carbohydrate-rich diet causes the normally gram-negative rumen bacterial populations to shift to gram-positive streptococcus and lactobacillus species. the gram-positive organisms efficiently convert the starches to lactic acid. the lactic acid acidifies the rumen contents, leading to rumen mucosal inflammation, and increases the osmolality of rumen fluids, leading to sequestration of fluids and osmotic attraction of plasma and tissue fluid to the rumen. lactic acid-induced rumenitis predisposes the animal to ulcers, to liver abscesses from "absorbed" bacterial pathogens, to laminitis from absorbed toxins, and to polioencephalomalacia from the inability of the new rumen bacterial populations to produce sufficient thiamine needed to maintain normal nervous system function. clinically, animals will become anorexic, depressed, and weak within - days after the initial insult. incoordination, ataxia, dehydration, hemoconcentration, rapid pulse and respiration, diarrhea, abdominal pain, and lameness will also be noted rumen distension and an acetone-like odor to the breath, milk, or urine may also be observed. diagnosis is based on history and clinical signs. blood, urine, or milk ketones can be detected (moore and ishler, ) . additionally, rumen ph, which is normally above . , will drop to less than . and in severe cases may achieve levels as low as . . similarly, urine ph will become acidic, blood ph will drop below . , and hematocrit will appear to increase due to the relative hemoconcentration. necropsy findings will be determined by secondary conditions. the primary lactic acidosis will cause swelling and necrosis of rumen papillae and abomasal hemorrhages and ulcers. treatment must be applied early in the syndrome. in early hours of severe carbohydrate engorgement, rumenotomy and evacuation of the contents are appropriate. the t patient should be given mineral oil and antlfermentatlves to prevent the continued conversion of starches to acids and the absorption of metabolic products. bicarbonate or other antacids like magnesium carbonate or magnesium hydroxide introduced into the rumen will aid in adjusting rumen ph. furthermore, animals can be given oral tetracycline or penicillin, which will decrease the gram-positive bacterial population. iii. rumen parakeratosis. parakeratosis is a degenerative condition of the rumen mucosa that leads to keratinization of the papillary epithelium excessive and continuous feeding of diets low in roughage causes the mucosal changes generally, this condition is seen in feedlot lambs and steers that are fed an all-grain diet. clinically, animals may exhibit only poor rates of gain, due to changes in the absorptive capacity of the injured mucosa. at necropsy, papillae will be thickened and rough. they will frequently be dark in color, and multiple papillae will clump together. abscessation may be observed. histopathologically, papilla surfaces will have hyperkeratinization of the squamous epithelium. chronic laminitis may be observed. however, diagnosis of parakeratosis is generally made at necropsy. feeding adequate roughage, such as stemmy hay, will prevent the disease. antibiotics may be administered to prevent secondary liver abscess formation. iv. rumenitis. rumenitis is an acute or chronic inflammation of the rumen, which occurs most commonly as a sequela to lactic acidosis in addition to concentrate feeding, inadequate roughage in the diet is also associated with this disorder rumenitis may occur with contagious ecthyma infection or following ingestion of poisons or other irritants. because rumenitis is often associated with lactic acidosis, it tends to occur in feedlot animals. the inflamed ruminal epithelium becomes necrotic and sloughs, creating ulcers. endogenous rumen bacteria such as fusobacterium necrophorum may invade the ulcers, penetrate the circulatory system, and induce abscesses of the liver. clinically, the animals will appear depressed and anorexic. rumen motility will be decreased, and animals will lose weight. the disease may resolve in a week to days; mortality may reach %. necropsy lesions include rumen inflammation and ulcers in the anteroventral sac. granulation tissue and scarring may be observed following healing. rumenitis is not typically diagnosed clinically; thus, specific treatment is not commonly done. the disease can be prevented by minimizing the incidence of lactic acidosis. etiology. traumatic reticulitis-reticuloperitonitis is a disease of cattle related to their exploratory tendencies and ingestion of many different, nonvegetative materials. the disease is rarely seen in smaller ruminants. clinical signs. clinical signs range from asymptomatic to severe, depending on the penetration and damage by the foreign object after settling in the animal's forestomach. many signs during the early, acute stages will be nonspecific, ranging from arched back, listlessness, anorexia, fever, decrease in production, ketosis, regurgitation, decrease or cessation of ruminal contractions, bloat, tachypnea, tachycardia, and grunts when urinating, defecating, or being forced to move. the prognosis is poor when peritonitis becomes diffuse. sudden death can occur if the heart, coronary vessels, or other large vessels are punctured by the migrating object. epizootiology and transmission. this is a noncontagious disease. the occurrence is directly related to sharp or metallic indigestible items in the feed or environment that the cattle mouth and swallow. necropsy findings. in severe cases, necropsy findings include extensive inflammation throughout the cranial abdomen, malodorous peritoneal fluid accumulations, and lesions at the reticular sites of migration of the foreign objects. cardiac puncture will be present in those animals succumbing to sudden death. pathogenesis. consumed objects initially settle in the rumen but are dumped into the reticulum during the digestive process, and normal contraction may eventually lead to puncture of the reticular wall. this sets off a localized inflammation or a localized or more generalized peritonitis. the inflammation may also temporarily or permanently affect innervation of local tissues and organs. further damage may result from migration and penetration of the diaphragm, pericardium, and heart. diagnosis is based on clinical signs, knowledge of herd management techniques in terms of placement of forestomach magnets, and reflection of acute or chronic infection on the hemogram. radiographs and abdominocentesis may be useful. differential diagnosis. differentials include abomasal ulcers, hepatic ulcers, neoplasia (such as lymphosarcoma, usually in older animals, or intestinal carcinoma), laminitis, and cor pulmonale. infectious diseases that are differentials include systemic leptospirosis and internal parasitism. diseases causing sudden death may need to be considered. prevention and control. this problem can be prevented entirely by elimination of sharp objects in cattle feed and in the housing and pasture environments. adequately sized magnets placed in feed handling equipment and forestomach magnets (placed per os with a bailing gun in young stock at - months of age) are also significant prevention measures. treatment. provision of a forestomach magnet, confinement, and nursing care, including antibiotics, are the initial treatments. in severe cases, rumenotomy may be considered. etiology. pregnancy toxemia is a primary metabolic disease of ewes and does in advanced pregnancy. beef heifers are susceptible to protein energy malnutrition (pem) syndrome, which is also referred to as pregnancy toxemia. clinical signs. in sheep, this disease is characterized by hypoglycemia, ketonemia, ketonuria, weakness, and blindness. hypoglycemic and ketotic ewes begin to wander aimlessly and to move away from the flock. they become anorexic and act uncoordinated, frequently leaning against objects. advanced signs may include blindness, muscle tremors, teeth grinding, convulsions, and coma. body temperature, heart rate, respiratory rate, and rumen motility continue normally. up to % of infected ewes may die from the disease. the course of the disease may last up to a week. in goats, the disease usually occurs in the last weeks of gestation, especially in does carrying triplets. pregnancy toxemia should be considered with any goat showing signs of illness in late gestation. the doe may separate herself from the herd, stagger, or circle and may appear blind. appetite is poor, and tremors may be evident. a rapid metabolic acidosis results in subsequent recumbency. urinalysis will readily reveal ketonuria. if fetal death occurs, acute toxemia and death of the doe may result. in beef heifers, weight loss and thin body condition, weakness and inability to stand, and depression are clinical signs. some cows develop diarrhea. because the catabolic state is often so advanced, most affected heifers die even if treated. pregnancy toxemia is diagnosed by evidence of typical clinical signs. sodium nitroprusside tablets or ketosis dipsticks may be used to identify ketones in the urine or plasma of ewes and does. blood glucose levels found to be below mg/dl and ketonuria are good diagnostic indicators. in cattle, ketonuria is not a typical finding; hypocalcemia and anemia may be present. that are obese or bearing twins or triplets. the disease develops during the last weeks of pregnancy. pem most frequently occurs in heifers during the final trimester of pregnancy. necropsy findings. at necropsy, affected ewes will often have multiple fetuses, which may have died and decomposed. the liver will be enlarged, yellow, and friable, with fatty degeneration. the adrenal gland may also be enlarged. in cattle, heifers will be very thin, and in addition to a fatty liver, signs of concurrent diseases may be present. pathogenesis. rapid fetal growth, a decline in maternal nutrition, and a voluntary decrease in food intake in overfat ewes result in an inadequate supply of glucose needed for both maternal and fetal tissues. the ewe develops a severe hypoglycemia in early stages of the disease. the ruminant absorbs little dietary glucose; rather, it produces and absorbs volatile fatty acids (acetic, propionic, and butyric acids) from consumed feedstuffs. propionic acid is absorbed and selectively converted to glucose through gluconeogenesis. when the animal is in a state of negative energy balance, it hydrolyzes fats to glycerol and fatty acids. glycerol is converted to glucose while the fatty acids are metabolized for energy. the oxidation of fatty acids in the face of declining oxaloacetate levels (required for normal krebs cycle function) results in the formation of ketone bodies (acetone, acetoacetic acid, and [ -hydroxybutyric acid), thus causing the condition ketoacidosis. heifer cattle have high energy requirements for completing normal body growth and supporting a pregnancy. additional energy requirements are needed during pregnancy for winter conditions and during concurrent diseases. marginal diets and poor-quality forage will place the cows in a negative energy balance. differential diagnosis. hypocalcemia is a common differential diagnosis. in cattle, differentials include chronic or untreated diseases such as johne's disease, lymphosarcoma, parasitism, and chronic respiratory diseases. prevention and control. pregnancy toxemia can be prevented by providing adequate nutrition during late gestation and by maintaining animals in appropriate nonfat condition during pregnancy. in late pregnancy, the dietary energy and protein should be increased . - times the maintenance level. pem can be prevented by maintaining appropriate body condition earlier in pregnancy and supplying good-quality forage for the last trimester. treatment. in sheep, because the morbidity may be as high as %, treatment should be directed at the flock rather than the in-dividual. treating the individual is usually unsuccessful. oral administration of ml of propylene glycol or % glucose twice a day, anabolic steroids, and high doses of adrenocorticosteroids may be helpful. if ewes are still responsive and not severely acidotic or in renal failure, cesarean section may be successful by rapidly removing the fetus, which is the dietary drain for the ewe. in goats, pregnancy toxemia is best treated by removal of the fetuses either by cesarean section or induction of parturition. parturition can be induced in does by either dexamethasone ( mg) or pgf a ( ~tg). in addition, goats may be treated with % dextrose ( to ml iv) or propylene glycol ( ml per os or times a day). adjunctive therapy includes normalizing acid base and hydration status, administration of vitamin b and transfaunation. heifers may be force-fed alfalfa gruels, given propylene glycol per os, placed on iv % glucose drips, and treated for concurrent disease. research complications. in research requiring pregnant ewes in late stages of gestation, for example, this disease should be considered if the animals are likely to bear twins and will be transported or stressed in other ways during that time. f hypocalcemia (parturient paresis, milk fever) etiology. hypocalcemia is an acute metabolic disease of ruminants that requires emergency treatment; the presentation is slightly different in ewes, does, and cows. clinical signs and diagnosis. in sheep, the disease is seen in ewes during the last weeks of pregnancy and is characterized by muscle tetany, incoordination, paralysis, and finally coma. as calcium levels drop, ewes begin to show early signs such as stiffness and incoordination of movements, especially in the hindlimbs. later, muscular tremors, muscular weakness, and recumbency will ensue. animals will frequently be found breathing rapidly despite a normal body temperature. morbidity may approach %, and mortality may reach as high as % in untreated animals. affected does become bloated, weak, unsteady, and eventually recumbent. cows are affected within - hr before or after parturition. cows initially are weak and show evidence of muscle tremors, then deteriorate to sternal recumbency, with the head usually tucked to the abdomen, and an inability to stand. tachycardia, dilated pupils, anorexia, hypothermia, depression, ruminal stasis, bloat, uterine inertia, and loss of anal tone are also seen at this stage. the terminal stage of disease is a rapid progression from coma to death. heart rates will be high, but pulse may not be detectable. hypocalcemia is diagnosed based on the pregnancy stage of the female and on clinical signs. it is later confirmed by laboratory findings of low serum calcium. with hypocalcemia in ewes, the plasma concentrations of calcium drop from normal values of - mg/dl to values of - mg/dl. in cattle, plasma levels below . mg/dl are hypocalcemic; at the terminal stages levels may be mg/dl. ewes during the last weeks of pregnancy or during the first few weeks of lactation. the disease is not as common in the dairy goat as in the dairy cow. high-producing, older, multiparous dairy cows are the most susceptible, and the jersey breed is considered susceptible. cows that have survived one episode are prone to recurrence. in addition, dry cows must be managed carefully regarding limiting dietary calcium. the disease is not common in beef cattle unless there is an overall poor nutrition program. ing at necropsy. there is no pathognomonic or typical find-pathogenesis. during the periparturient period, calcium requirements for fetal skeletal growth exceed calcium absorbed from the diet and from bone metabolism. additionally, dietary calcium intake is thought to be compromised because, in advanced pregnancy, animals may not be able to eat enough to sustain adequate nutrient levels, and intestinal absorption capabilities do not respond as quickly as needed. after parturition, calcium needs increase dramatically because of calcium levels in colostrum and milk. recent information suggests that legume and grass forages, high in potassium and low in magnesium, create a slight physiological alkalosis (at least in cattle), which antagonizes normal calcium regulation (rings et al., ) . thus, bone resorption, renal resorption, and gastrointestinal absorption of calcium are less than maximal. prevention and control. maintaining appropriate nutrition during the last trimester is helpful in preventing the disease. in cows and does, for example, limiting calcium intake by removing alfalfa from the diet is helpful. treatment. hypocalcemia must be treated quickly based on clinical signs; pretreatment blood samples can be saved for later confirmation. twenty percent calcium borogluconate solution should be administered by slow intravenous infusion. response will often be rapid, with the resolution of the animal's dull mentation. less severely affected animals will often try to stand in a short time. relapses are common, however, in sheep and cattle. hypermagnesemia and hypophosphatemia often coincide with hypocalcemia. these imbalances should be considered when animals appear to be unresponsive to treatment. hypocalcemia in the goat can be treated with - ml of calcium borogluconate. heart rate should be monitored closely throughout calcium administration. if an irregular or rapid heart rate is detected, then calcium treatment should be slowed or discontinued. calcium gels and boluses are also available for treatment (rings et al, ) . prognosis is generally good if the animal is treated early in the disease, but the prognosis will often be poor when treatment is initiated in later stages of the disease. etiology. urolithiasis is a metabolic disease of intact and castrated male sheep, goats, and cattle that is characterized by the formation of bladder and urethral crystals, urethral blockage, and anuria (murray, ) . the disease occurs rarely in female ruminants. clinical signs and diagnosis. affected animals will vocalize and begin to show signs of uneasiness, such as treading, straining postures, arched backs, raised tails, and squatting while attempting to urinate. these postures may be mistaken for tenesmus. male cattle may develop swelling along the ventral perineal area. affected animals will not stay with the herd or flock. small amounts of urine may be discharged, and crystal deposits may be visible attached to the preputial hairs. additionally, in smaller ruminants, the filiform urethral appendage (pizzle) often becomes dark purple to black in color. the pulsing pelvic urethra may be detected by manual or digital rectal palpation, and bladder distention may be noticeable in cattle by the same means. as the disease progresses to complete urethral blockage, the animal will become anorexic and show signs of abdominal pain, such as kicking at the belly. the abdomen will swell as the bladder enlarges, and rupture can occur within hr after development of clinical signs. bladder or urethral rupture may cause a short-lived period of apparent pain relief; subsequent development of uremia will eventually lead to death. the disease may progress over a period of - weeks, and the mortality is high unless the blockages are reversed. diagnosis is made by the typical clinical signs. abdominal taps may yield urine. calculi are usually composed of calcium phosphate or ammonium phosphate matrices. clinical disease is usually seen in growing intact or castrated males. the disease may be sporadic or there may be clusters of cases in the flock or herd. necropsy findings. necropsy findings include urine in the abdomen with or without bladder or urethral rupture. renal hydronephrosis may be evident. calculi or struvite crystal sediment will be observed in the bladder and urethra. histologically, trauma to the urethra and ureters will be present. etary, anatomical, hormonal, and environmental factors. male sheep and goats have a urethral process that predisposes them to entrapment of calculi. in cattle, the urethra narrows at the sigmoid flexure, and calculi lodge there most frequently. additionally, the removal of testosterone by early castration is thought to result in hypoplasia of the urethra and penis. this physical reduction in the size of the excretory tube may predispose to the precipitation of and blockage by the struvite minerals. grains fed to growing animals tend to be high in phosphorus and magnesium content. these calculogenic diets lead to the formation of struvite (magnesium ammonium phosphate) crystals. other minerals associated with urolithiasis include silica (range grasses), carbonates (some grasses and clover pastures), calcium (exclusively alfalfa hay), and oxalates (fescue grasses). differential diagnosis. grain engorgement colic, gastrointestinal blockage, and causes of tenemus, such as enteritis or trauma, are differentials. trauma to the urethral process should be considered. urinary tract infections are uncommon in ruminants. prevention and control. one case often is indicative of a potential problem in the group. urolithiasis can be minimized by monitoring the calcium:phosphorus ratio in the diet. the normal ratio should be : . additionally, increasing the amount of dietary roughage will help balance the mineral intake. increasing the amount of salt (sodium chloride, - %) in the diet to increase water consumption, or adding ammonium chloride to the diet, at gm/head/day or % of the ration, to acidify the urine, will aid in the prevention of this disease. palatability of and accessibility to water should be assessed as well as functioning of automatic watering equipment. treatment. treatment is primarily surgical (van metre et al. ) . initially, amputation of the filiform urethral appendage may alleviate the disease since urethral blockage often begins here. as the disease progresses, urethral blockage in the sigmoid flexure as well as throughout the urethra may occur. in more advanced stages, perineal urethrostomy may yield good results. the prognosis is poor when the condition becomes chronic, reoccurs, or surgery is required. research complications. young castrated and intact male ruminants used in the laboratory setting will be the susceptible age group for this disorder. rickets is a disease of young, growing animals but rarely occurs in goats. it is a metabolic disease characterized by a failure of bone matrix mineralization at the epiphysis of long bones due to lack of phosphorus. the condition can occur as an absolute deficiency in vitamin d , an inadequate dietary supply of phosphorus, or a long-term dietary imbalance of calcium and phosphorus. the syndrome must be differentiated from epiphisitis (unequal growth of the epiphyses of long bones in young, rapidly growing kids fed diets with excess calcium). clinical signs include poor growth, enlarged costochondral junctions, narrow chests, painful joints, and reluctance to move. spontaneous fractures of long bones may occur. animals will recover when dietary phosphorus is provided and if joint damage is not severe. a. copper deficiency (enzootic ataxia, swayback) etiology. chronic copper deficiency in pregnant ewes and does may produce a metabolic disorder in their lambs and kids called enzootic ataxia. in goats, this deficiency also causes swayback in the fetuses. clinical signs and diagnosis. this disease results in a progressive hindlimb ataxia and apparent blindness in lambs up to about months of age. additionally, because copper is essential for osteogenesis, hematopoiesis, myelination, and pigmentation of wool and hair, ewes may appear unthrifty, may be anemic, and may have poor, depigmented wool with a decrease in wool crimp. affected kids are born weak, tremble, and have a characteristic concavity to the spinal cord, leading to the name swayback. when the deficiency occurs later during gestation, demyelination is limited to the spinal cord and brain stem. kids are born normally but develop a progressive ataxia, leading to paralysis, muscle atrophy, and depressed spinal reflexes with lower motor neuron signs. diagnosis is based on low copper levels found in feedstuffs and tissues at necropsy. diagnosis is based on clinical signs, feed analysis, and pathological findings. epizootiology and transmission. enzootic ataxia is rarely seen in western states; most north american diets have sufficient copper levels to prevent this disease. copper antagonists in the feed or forage at sufficient levels, such as molybdenum, sulfate, and cadmium, however, may predispose to copper deficiencies. pathogenesis. the maternal copper deficiency leads to a disturbance early in the embryonic development of myelination in the central nervous system and the spinal cord. copper is part of the cytochrome oxidase system and other enzyme complexes and is important in myelination, osteogenesis, hematopoiesis (iron absorption and hemoglobin formation), immune system development, and maintenance and normal growth (smith and sherman, ) . differential diagnosis. the differential diagnosis for newborns includes [ -mannosidosis, hypoglycemia, and hypothermia. for older animals the differential should include caprine arthritis encephalitis (goats), enzootic muscular dystrophy, listeriosis, spinal trauma or abscessation, and cerebrospinal nematodiasis. prevention and control. copper deficiency can be prevented by providing balanced nutrition for pregnant animals. necropsy findings. gross encephalomalacia has been noted. histopathologically, white matter of the brain and spinal cord displays gelatinization and cavitation. extensive nerve demyelination and necrosis are evident. postmortem lesions include extensive demyelination and neuronal degeneration. treatment. because the condition is developmental, supplemental copper may improve clinical signs but not eliminate them. necropsy findings. common findings at necropsy include icterus; a soft, dark, friable, enlarged spleen; an enlarged, yellow-brown friable liver; and "gun-barrel" black kidneys. hemoglobin-stained urine will be visible in the bladder. copper accumulations in the liver reaching - ppm are toxic. pathogenesis. hemolysis occurs when sufficient amounts of copper are ingested or released suddenly from the liver and is believed to be due direct interaction of the copper with red-cell surface molecules. stresses such as transportation, lactation, and poor nutrition or exercise may precipitate the hemolysis. etiology: acute or chronic copper ingestion or liver injury often causes a severe, acute hemolytic anemia in weanling to adult sheep and in calves and adult dairy cattle. growing lambs may be the most susceptible. copper toxicosis is rare in goats. differential diagnosis. other causes of hemolytic disease include babesiosis, trypanosomiasis, and plant poisonings such as kale. arsenic ingestion, organophosphate toxicity, and cyanide or nitrate poisoning should also be considered as the source of poisoning. urethral obstruction and gastrointestinal emergencies should be considered for the abdominal pain. clinical signs and diagnosis. the clinical course in sheep can be as short as - days, and mortality may reach %. hemolysis, anemia, hemoglobinuria, and icterus characterize the acute hemolytic crisis, associated with copper released from the overloaded liver. some clinical signs are related to direct irritation to the gastrointestinal tract mucosa. weakness, vomiting, abdominal pain, bruxism, diarrhea, respiratory difficulty, and circulatory collapse are followed by recumbency and death. hepatic biopsy is currently considered the best diagnostic approach; serum or plasma levels of copper and hepatic enzymes such as aspartate aminotransferase (ast) and y-glutamyltransferase (ggt) may provide some information, but it is generally believed that these will not accurately reflect total copper load or hepatic damage. and goats is the range of - mg/kg, and for cattle it is - mg/kg. chronic poisoning in sheep may occur when . mg/kg is ingested. copper-containing pesticides, soil additives, therapeutics, and improperly formulated feeds may potentially lead to copper toxicity. phytogenous sources include certain pastures such as subterranean clover. feed low in molybdenum, zinc, or calcium may lead to increased uptake of copper from properly balanced rations. a common cause of the disease in sheep is feeding concentrates balanced for cattle; cattle feeds and mineral blocks contain much higher quantities of copper than are required for sheep. chronic ingestion of these feedstuffs leads to copper accumulation and toxicity. copper toxicosis has been reported in calves given regular oral or parenteral copper supplements, and in adult dairy cattle given copper supplements to compensate for copper-deficient pasture. pregnant dairy cattle may be more susceptible to copper toxicity. rare sources of copper ingestion may include copper sulfate footbaths. control and prevention. the disease is prevented by carefully monitoring copper access in sheep and copper supplementation in cattle. sheep and goats should not be fed feedstuffs formulated for cattle, and dairy calf milk replacer should not be used for lambs and kids. molybdenum may be administered to animals considered at high risk. molybdenum-deficient pastures may be treated with molybdenum superphosphate. herd copper supplementation should be undertaken with the knowledge of existing hepatic copper levels, and existing copper and molybdenum levels, in the feedstuffs. treatment. oral treatment for sheep consists of ammonium or sodium molybdenate ( - mg/day), and sodium thiosulfate ( . - . mg/day) for weeks aids in excretion of copper. oral d-penicillamine daily for days ( mg/kg) has also been shown to increase copper excretion in sheep. ammonium molybdenate has been administered intravenously to goats at . mg/kg for treatments on alternate days. cattle have been treated orally with sodium molybdenate ( gm/day) or sodium thiosulfate ( gm/day). treatment for anemia and nephrosis may be necessary in severe cases. merino crosses and the british breeds, may be more susceptible to copper toxicosis caused by phytogenous sources. (nutritional muscular dystrophy, nutritional myodegeneration, white muscle disease, stiff lamb disease) etiology. white muscle disease, also known as stiff lamb disease, is a nutritional muscular dystrophy caused by a deficiency of selenium or vitamin e. clinical signs and diagnosis. clinically two forms of the disease have been identified: cardiac and skeletal. the cardiac form occurs most commonly in neonates. in these, respiratory difficulty will be a manifestation of damage to cardiac, diaphragmatic, and intercostal muscles. young will be able to nurse when assisted. in slightly older animals, the disease is characterized by locomotor disturbances and/or circulatory failure. clinically, animals may display paresis, stiffness or inability to stand, rapid but weak pulse, and acute death. mortality may reach % (jensen and swift, ) . paresis and sudden death in neonates with associated pathological signs are frequently diagnostic. with the skeletal form, affected animals are stiff and reluctant to move, and muscles of affected animals are painful. young will be reluctant to get up but will readily nurse when assisted. peracute to acute myocardial degeneration may occur in the cardiac form, and animals may simply be found dead. serum selenium levels are usually below ppb (normal is - ppb) (nelson, ) . diagnosis may also include determination of antemortem whole blood levels of selenium and plasma levels of vitamin e. glutathione peroxidase levels in red blood cells can be measured as an indirect test. clinical biochemistry findings of significant elevations of aspartate aminotransferase (ast) in creatinine kinase (ck) are also supportive of the diagnosis. epizootiology and transmission. selenium deficiency has been associated with formulated diets deficient in selenium, forages grown on selenium-deficient soils in certain geographic regions, and forages such as alfalfa and clover that have an inability to efficiently extract available selenium from the soils. rumen bacterial reduction of selenium compounds to unavailable elemental selenium may also contribute to the disease. necropsy findings. necropsy lesions include petechial hemorrhages and muscle edema. hallmarks are pale white streaking of affected skeletal and cardiac muscle. these are due to coagulation necrosis. pale striated muscles of the limb, diaphragm, and tongue are also seen. antioxidants that protect lipid membranes from oxidative destruction. selenium is a cofactor for glutathione peroxidase, which converts hydrogen peroxide to water and other nontoxic compounds. lack of one or both results in loss of membrane integrity. differential diagnosis. in neonatal ruminants presenting with respiratory and cardiac dysfunction, differentials include congenital cardiac anomalies. differentials generally for weak neonates or sudden or peracute neonatal deaths should include septicemia, pneumonia, toxicity, diarrhea, and dehydration. prevention and control. awareness of regional selenium deficiencies is important. control involves providing good-quality roughage, vitamin e and selenium supplementation, and parenteral injections prior to parturition and weaning. treatment. affected animals may be treated by administering vitamin e or selenium injections. administering vitamin e or selenium to ewes in late pregnancy can prevent white muscle disease (kott et al., ) . the label dose for selenium is . - mg/ kg of body weight. combination products are available and can be used in goats at the sheep dose (smith and sherman, ) . proper mineral balance in the diet is critical. selenium toxicity occurs most frequently as the result of excessive dosing to prevent or correct selenium deficiency or as the result of ingestion of selenium-converting plants. the main preventive measure for the former is the use of the appropriate product for the species. secondarily, the concentration of the available product should be double-checked. in the united states, ruminants in the midwest and western areas may be subject to selenium toxicity when pastured in areas containing selenium-converting plants. signs of overdosing include weakness, dyspnea, bloating, and diarrhea. shock, paresis, and death may occur. initial clinical signs of excessive selenium intake from plants are observed in the distal limb, with cracked hoof walls and subsequent infection and irregular hoof growth. etiology. polioencephalomalacia (pem) is a noninfectious, noncontagious disease characterized by neurological signs. growing and adult ruminants on high-concentrate diets are typically affected. animals exposed to toxic plants or moldy feed containing thiaminases, feed high in sulfates, or unusually high doses of some medications are also at risk. clinical signs and diagnosis. an early sign may be mild diarrhea. acute clinical signs include bruxism, hyperesthesia, involuntary muscle contractions, depression, partial or complete opisthotonus, nystagmus, dorsomedial strabismus, seizures, and death. in subacute cases of the disease, animals may appear to walk aimlessly as if blind or may display head-pressing postures. hypersalivation may be present, but body temperatures and ocular reflexes are normal. morbidity and mortality may be high, especially in younger animals. diagnosis is suggestive from clinical signs and from response to intensive parental thiamine hydrochloride. epizootiology and transmission. pem is caused by a thiamin deficiency. the disease tends to be seen more frequently in cattle and sheep feedlots where the concentrates fed are high in fermentable carbohydrates. pastured animals are also vulnerable if grain is feed. thiaminase-containing plants, such as bracken fern, are often unpalatable so will less likely be a contributing factor. recent studies have also indicated that high levels of sulfate in the diet, such as in the fermentable, low-fiber concentrates, may play an important role. medications such as as amprolium, levamisole, and thiabendazole have thiaminantagonizing activity when given in excessive doses. sherman, ) . vitamin a deficiencies associated with hyperkeratosis have been reported, as well as vitamin e-responsive and selenium-responsive dermatitis. necropsy signs. cerebral lesions characterized by softening and discoloration are grossly observed in the gray matter. microscopically, neurons will exhibit edema, chromatolysis, and shrinkage. gliosis and cerebral capillary proliferation may be observed. a lack of thiamin results in inappropriate carbohydrate metabolism and accumulation of pyruvate and other intermediaries that lead to cerebral edema and neuronal degeneration. differential diagnosis. several important differentials include acute lead poisoning, nitrofuran toxicity, hypomagnesemia, vitamin a deficiency, listeriosis, pregnancy toxemia, infectious thromboembolic meningoencephalitis, and type d clostridial enterotoxemia. prevention and control. the disease can be prevented by monitoring the diet and by providing adequate roughage necessary to prevent overgrowth of thiaminase-producing ruminal flora and to maximize ruminal production of b vitamins. if excess sulfur is the primary factor, immediate removal of the source is critical. neonatal ruminants are born without immunoglobulins and must receive colostrum by hr after birth. the morbidity and mortality associated with failure of or inadequate passive transfer, such as enteric and respiratory illnesses, can be severe. measures to assure passive immunity for neonatal ruminants are covered in section ii,b, , and clinical signs of illness associated with lack of immunity are addressed in the discussions of bacterial diseases (e.g., escherichia coli infections) and, of viral diseases (e.g., diarrheas) in section iii,a, and iii,a, . generally, transfer of less than mg/dl of immunoglobulins in the serum is classified as failure of transfer, - mg/dl is partial, and above mg/dl is complete transfer. methods to determine success of transfer should be performed within a week of birth and include single radial immunodiffusion (quantitates immunogloblin classes); zinc sulfate turbidity (semiquantitative); sodium sulfite precipitation (semiquantitative); glutaraldehyde coagulation (coagulates above specific level); and, y-glutamyltransferase (assays enzyme in high concentration in colostrum and absorbed simultaneously with colostrum). treatment. early aggressive treatment is essential to save animals. the disease is treated by frequent parenteral administration of thiamine hydrochloride, the first dose being administered intravenously. dexamethasone, b vitamins, and diazepam may also be required. treatment is less successful when sulfur plays a prominent role in the etiology. research complications. this disease is preventable. although the disease is less likely to occur in smaller groups of confined ruminants, the risks of feeding concentrates or moldy feed, for example, with minimal good-quality roughage, should be kept in mind. vitamin d toxicity can result either from iatrogenic overadministration or ingestion of the plant trisetum flavescens. serum calcium levels may be high enough that blood in edta tubes will clot. laminitis is common in ruminants and can be caused by sudden changes in diet, excess dietary energy, and grain overload (or overeating). laminitis is also associated with mastitis and metritis. facility conditions, such as concrete flooring, poor manure management, and inadequate resting areas may also contribute to the pathogenesis of the disease. the complete pathogenesis of laminitis is poorly understood; however, it is thought that changes in the diet cause changes in rumen microbial populations, resulting in acidosis and endotoxemia. dramatic changes in the vascular endothelium result in chronic inflammation of the sensitive laminae of the hoof, separation of corium and hoof wall, and rotation of the third phalanx. affected animals may be reluctant to get up or walk, will shift their weight frequently, and will grind teeth or walk on carpi. chronically, the hoof wall takes on a "slipper" appearance. treatment consists of identifying the underlying cause, administering antiinflammatories (phenylbutazone, flunixin meglumin), feeding good-quality forages only, and regular foot trimming. in goats, nutritional deficiencies often manifest as a generalized poor coat that is dry, scaly, thin, and erectile. zincresponsive dermatitis has been reported in goats (smith and otherwise normal, well-managed lambs, kids, and calves can develop loose, pasty feces due to a nutritional imbalance caused by overfeeding and/or improper mixing of milk replacers. only milk replacer formulated for the particular species should be used. once nutritional imbalances are corrected, the feces readily return to normal. sudden changes in diet can also result in loose feces. photosensitization is an acute dermatitis associated with an interaction between photosensitive chemicals and sunlight. the photosensitive chemicals are usually ingested, but in some cases exposure may be by contact. animals with a lack of pigment are more susceptible to the disease. three types of photosensitization occur: primary; secondary, or hepatogenous; and aberrant. primary photosensitization is related to uncommon plant pigments or to drugs such as phenothiazine, sulfonamides, or tetracyclines. secondary photosensitization is more common in large animals and is specifically related to the plant pigment phylloerythrin. phylloerythrin, a porphyrin compound, is a degradation product of chlorophyll released by rumen microbial digestion. liver disease or injury, which prevents normal conjugation of phylloerythrin and excretion through the biliary system, predisposes to photosensitization. the only example of aberrant photosensitization is congenital porphyria of cattle (see section iii,b, ). pathologically, the photosensitive chemical is deposited in the skin and is activated by absorbed sunlight. the activated pigments transfer their energy to local proteins and amino acids, which, in the presence of oxygen, are converted to vasoactive substances. the vasoactive substances increase the permeability of capillaries, leading to fluid and plasma protein losses and eventually to local tissue necrosis. photosensitization can occur within hours to days after sun exposure and produces lesions of the face, vulva, and coronary bands; lesions are most likely to occur on white-haired areas. initially, edema of the lips, corneas, eyelids, nasal planum, face, vulva, or coronary bands occurs. the facial edema, nostril constriction, and swollen lips potentially lead to difficulty in breathing. with secondary photosensitization, icterus is also common. necrosis and gangrene may occur. diagnosis is based on clinical lesions and exposure to the photosensitive chemi-cals and sunlight. treatment is symptomatic. the prognosis for hepatogenous type may be guarded if hepatic disease is severe. from excessive straining associated with dysuria from the pressure of the fetuses and/or abdominal contents on the bladder. if the prolapse obstructs subsequent urination, rupture of the bladder may occur. the vaginal prolapse can be reduced and repaired if discovered early, and techniques in small and large ruminants are comparable. the animal should be restrained, and the prolapsed tissue should be cleansed with disinfectants. best done under epidural anesthesia, the vagina is replaced into the pelvic canal and the vulvar or vestibular opening is sutured closed (buhner suture). alternatively, a commercial device called a bearing retainer (or truss) can be placed into the reduced vagina and tied to the wool, thereby holding the vagina in proper orientation without interfering with subsequent lambing. vaginal prolapses may have a hereditary basis in ewes and cows and may prolapse the following year. these animals should be culled. vaginal prolapses may occur in nonpregnant animals that graze estrogenic plants or as a sequela to docking the tail too close to the body (ross, ) . uterine prolapses occur sporadically in postpartum ewes and cattle. the gravid horn invaginates after delivery and protrudes from the vulva. the cause is unknown, but excessive traction utilized to correct dystocia or retained placenta, uterine atony, hypocalcemia, and overconditioning or lack of exercise have been implicated. in cattle, the uterine prolapses usually develop within week of calving, are more common in dairy cows than in beef cows, and are often associated with dystocia or hypocalcemia. cows may also have concurrent parturient paresis. initially, the tissue will appear normal, but edema and environmental contamination or injuries of the tissue develop quickly. clinical signs will include increased pulse and respiratory rates, straining, restlessness, and anorexia. if identified early, the uterus can be replaced as for vaginal prolapses. electrolyte imbalances should be corrected if present. additional supportive therapy, including the use of antibiotics should always be considered. tetanus prophylaxis should be included. oxytocin should be administered to induce uterine reduction. vaginal closures are less successful at retaining uterine prolapses. preventive and control measures include regular exercise for breeding animals, and management of prepartum nutrition and body condition. vaginal and uterine prolapses occur in ewes, does, and cows. the conditions are not common in does. vaginal prolapses usually occur during late gestation and may be related to relaxation of the pelvic ligaments in response to hormone levels. in sheep, these are most common in overconditioned ewes that are also carrying twins or triplets. overconsumption of roughages, which distends the rumen, and lack of exercise leading to intraabdominal fat may predispose an animal to vaginal prolapse by increasing intra-abdominal pressure. the condition may result f rectal prolapse rectal prolapse is common in growing, weaned lambs and in cattle from months to years old. the physical eversion of the rectum through the anal sphincter is usually secondary to other diseases or management-related circumstances. rectal prolapses may occur secondary to gastrointestinal infection or inflammation, especially when the colon is involved. diseases that cause tenesmus, such as coccidiosis, salmonellosis, and intestinal worms, may result in prolapse. urolithiasis may result in prolapses as the animal strains to urinate. any form of cystitis or urethritis, vaginal irritation, or vaginal prolapse and some forms of hepatic disease may lead to rectal prolapse. abdominal enlargement related to advanced stages of pregnancy, excessive rumen filling or bloat, and overconditioning may cause prolapse. finally, excessive coughing during respiratory tract infections, improper tail docking (too short), growth implants, prolonged recumbency, or overcrowded housing with animal piling may lead to prolapses. diagnosis is based on clinical signs. early prolapses may be corrected by holding the animal with the head down, while a colleague places a pursestring suture around the anus. the mucosa and underlying tissue of prolapses that have been present for longer periods of time will often become necrotic, dry, friable, and devitalized and will require surgical amputation or the placement of prolapse rings to remove the tissue. rectal prolapse may also be accompanied by intestinal intussusceptions that will further complicate the treatment and increase mortality. occasionally, acute rectal prolapse with evisceration will result in shock and prompt death of the animal. prognosis depends on the cause and extent of the prolapse as well as the timeliness of intervention. in all cases of treatment, determination and elimination of the underlying cause are essential. gastrointestinal accumulations or obstructions of hair (and/ or sometimes very coarse roughage, forming bezoars) occur in cattle and sheep. cattle that are maintained on a low-roughage diet, that lick their coats frequently, that have long hair coats from outdoor housing, or that have heavy lice or mite infestations and associated pruritus will often develop bezoars. in addition, younger calves with abomasal ulcers have been found to be more likely to have abomasal tric. hobezoars as well. clinical signs may be mild or severe according to size, number, and location. ruminal trichobezoars rarely result in clinical signs. obstruction will be accompanied by signs of pain, development of bloat, and decreased fecal production. serum profiles will show hypochloridemia; other imbalances depend on the duration of the problem. diagnosis is also based on abdominal auscultation, rectal palpation, and ultrasound (useful in calves and smaller ruminants). treatment is surgical, such as paracostal laparotomy (for abomasal), paralumbar celiotomy with manual breakdown, or enterotomy. supportive care should be administered as necessary to correct electrolyte imbalances and to prevent inflammation and sepsis. prognosis is generally good if the condition is diagnosed and treated before dehydration and imbalances become severe and peritonitis develops. prevention includes providing good-quality roughage and treating lice and mange infestations. wounds may be sustained from poorly constructed pens or fences, or from skirmishes among animals. predators will usu-ally be sources of bite wounds. standard veterinary wound assessment and care are essential for wounds or bites. tetanus antitoxin may be indicated. use of approved antibiotics may be appropriate. the lesion should be cleaned with disinfectants and repaired with primary closure if it is clean and uncontaminated. thorough cleaning, regular monitoring, and healing by second intention are recommended for older wounds. abscesses may also occur in the soft tissues of the hooves (sole abscesses; see section iii,c, ) because of entrapped foreign bodies or hoof cracks that fill with dirt. preventive measures include improvement of housing facilities, pens, and pastures; monitoring hierarchies among animals penned together; and implementing predator control measures, such as sound fencing, flock guard dogs, or donkeys, in pasture situations. acute anaphylatic reactions in sheep, goats, and cattle are often clinically referable to the respiratory system. anaphylactic vaccine reactions cause acute lung edema; lungs are the primary site of lesions if collapse and death are sequelae. the animals will also be anxious and shivering and will become hyperthermic. salivation, diarrhea, and bloat also occur. immediate therapy must include epinephrine by intravenous infusion at ( ml of : per kg of body weight for goats and : , ( . mg/ml) or . mg/kg (about ml) for adult cows.) furosemide ( mg/kg) may be beneficial to reduce edema. prognosis is usually guarded. recovery can occur within hr. in a research environment, catheter sites or experimental surgeries may be sources of iatrogenic infection. traumatic injuries to peripheral nerves can cause acute lameness. improper administration of therapeutics can easily cause this type of lameness. injections given in gluteals or between the semimembranosus and semitendinosus can cause irritation to the sciatic nerve and subsequent lameness. contraction of the quadriceps results in the limb being pulled forward. injections in the caudal thigh can damage the peroneal nerve and cause knuckling at the fetlock. traumatic injury to the radial nerve can result in a "dropped elbow" (nelson, ) . husbandry procedures such as tail docking, castration, dehorning, dosing with a bailing gun, and shearing may result in superficial lesions, dermal infections, or cases of tetanus. bailing-gun injuries to the pharynx may lead to cellulitis with coughing, decreased appetite, and sensitivity to palpation. standard veterinary assessment and care are essential for these cases. local and systemic antibiotics with supportive care may be indicated. swelling around peripheral nerves caused by inoculations may be reduced by diuretics and anti-inflammato-ries. mild cases of peripheral nerve damage may recover in - days. personnel training, including review of relevant anatomy, preprocedure preparation, appropriate technique, careful surgical site preparation, rigorous instrument sanitation, and sterile technique will minimize the incidence of potential complications from surgical procedures. albumin values and foaming urine. the proteinuria also distinguishes amyloidosis (and glomerulonephritis) from other causes of weight loss and diarrhea in cattle such as johne's disease, parasitism, copper deficiency, salmonellosis, and bovine viral diarrhea virus infection. prognosis is poor, and no treatment is reported. neoplasia and tumors are relatively rare in ruminants. lymphosarcoma/leukemia in sheep has been shown to result from infection by a virus related (or identical) to the bovine leukemia virus. pulmonary carcinoma (pulmonary adenomatosis) and hepatic tumors are found in sheep. virus-induced papillomatosis (warts), discussed in section iii,a, ,s, and squamous cell carcinomas have also been reported in sheep. in goats, thymoma is one of the two most common neoplasias reported, although no distinct clinical syndrome has been described. cutaneous papillomas are the most common skin and udder tumor of goats, and although outbreaks involve multiple animals, no wart virus has been identified. persistent udder papillomas may progress to squamous cell carcinoma. lymphosarcoma is reported rarely in goats. although adrenocortical adenomas have been reported frequently and almost exclusively in older wethers, no clinical condition has been described. lymphosarcoma of various organ systems and "cancer eye" (bovine ocular squamous cell carcinoma, or oscc) are the most commonly reported cancers in cattle. lymphosarcoma is described in section iii,a, ,c. lack of periocular pigmentation and the amount and intensity of exposure to solar ultraviolet light are considered important factors in oscc. genetic factors may also play a role. many cases occur in herefords. this is a disease of older cattle; no case has been reported in animals less than years of age. the cancer metastasizes through the lymph system to major organs. treatment in either lymphosarcoma or oscc is recommended only as a palliative measure. the extent of ocular neoplastic involvement is a significant criterion for carcass condemnation. papillomatosis (warts) are common in cattle (see section iii,a, ,s). dental wear is seen most commonly in sheep. as sheep age, excessive dental wear may lead to an inability to properly masticate feed, manifesting as weight loss and unthriftiness. several factors predisposing to dental wear should be considered. the diet should be properly balanced for minerals, especially calcium and phosphorus, because primary or secondary calcium deficiency during teeth development results in softening of the enamel and dentin. dietary contamination with silica (i.e., hays and grains harvested in sandy regions) will lead to mechanical wear on the teeth. likewise, animals grazing or being fed in sandy environments will have excessive tooth wear. sheep older than about years of age are especially prone to tooth wear and should be checked frequently, especially if signs of weight loss or malnutrition are evident. managing the content and consistency of the diets can best prevent the disease. of the ruminants, cows are the most frequently affected by subsolar absesses. dirt becomes packed into cracks in the horny layer of the sole of the hoof, and contamination eventually extends into the sensitive areas of the hoof, with lameness and infection resulting. animals maintained in very soiled or muddy conditions, combined with poor hoof care, are more likely affected. fusobacterium necrophorum is often the pathogen involved. separation of the animal, supportive care, surgical drainage, and antibiotic treatment are indicated. amyloidosis amyloidosis in adult cattle is due to accumulations of amyloid protein in the kidney, liver, adrenal glands, and gastrointestinal tract. the disease has been classified as aa type, or associated with chronic inflammatory disease, although other unknown factors are believed to be involved in some cases. clinical signs include chronic diarrhea, weight loss, decreased production, nonpainful renomegaly, and generalized edema. the loss of protein in the urine contributes to abnormal plasma advances in sheep and goat medicine animals and animal products, subchapter a, animal welfare formulary for laboratory animals domestic animal behavior for veterinarians and animal scientists schlam's veterinary hematology diseases of sheep animal feeding and nutrition guide for the care and use of laboratory animals veterinary drug handbook veterinary medicine: a textbook of the diseases of cattle, sheep, pigs, goats, and horses sheep production and management animal and plant health inspection service (aphis), policy # , farm animals used for nonagricultural purposes goats the clinical syndromes caused by salmonella infection armed forces institute of pathology (afip) ( ) the effect of stress on the carrier state of salmonella typhimurium in goats bibliography of naturally occurring models of human disease clinical signs, treatment, and postmortem lesions in dairy goats with enterotoxemia: cases control of the estrous cycle the goat industry: feeding for optimal production neurologic disease in sheep and goats modern breeds of livestock the sheep gene map pasteurella haemolytica complicated respiratory infections in sheep and goats ungulates as laboratory animals diagnosis of lameness in sheep an overview of the influence of ace inhibitors on fetalplacental circulation and perinatal development protozoan infections (toxoplasma gondii, neospora caninum, and sarcocystis spp.) in sheep and goats: recent advances cloned transgenic calves produced from nonquiescent fibroblasts transgenic bovine chimeric offspring produced from somatic cell-derived stem-like cells use of an animal model of trichomoniasis as a basis for understanding this disease in women council report: vaccination guidelines for small ruminants (sheep, goats, llamas, domestic deer, and wapiti) ( ) maedi-visna and ovine progressive pneumonia pathophysiology of oestrus ovis infection in sheep and goats: a review experimental surgery in farm animals evaluation of an agar gel immunodiffusion test kit for detection of antibodies to mycobacterium paratuberculosis in sheep veterinary laboratory medicine induction of human tissue plasminogen activator in the mammary gland of transgenic goats pasteurella haemolytica infections in sheep coccidiosis and cryptosporidiosis in sheep and goats the major histocompatibility complex region of domestic animal species brucella melitensis infection in sheep: present and future hemoglobin switching epididymitis in rams current veterinary therapy: food animal practice livestock handling guide: management practices that reduce livestock bruises and injuries, and improve handling efficiency. livestock conservation institute synchronization of oestrus in the boer goat doe: dose effect of prostaglandin in the double injection scheme. south afr guide to the dissection of domestic ruminants reproduction in farm animals review of polyclonal antibody production procedures in mammal and poultry considerations in the design and construction of facilities for farm species clinical update: leptospirosis the sheep as an experimental animal bibliography oflnduced animal models of human disease bibliography of naturally occurring models of human disease postpartum assessment and care of the newborn ruminant animal genetics guide for the care and use of laboratory animals blackleg: a new perspective on an old disease protecting calves from viral diarrhea bovine leukemia virus. part : descriptive epidemiology, clinical manifestations, and diagnostic tests bovine leukemia virus. part : risk factors of transmission bovine leukemia virus. part : zoonotic potential, molecular epidemiology, and an animal model. in "infectious disease in food animal practice bovine leukemia virus. part : economic impact and control measures brucella abortus strain rb vaccine: its advantages and risks current veterinary therapy: food animal practice neural control of maternal behavior and olfactory recognition of offspring comparison of the burdizzo and rubber ring methods for castrating and tail docking lambs postpartum care of the cow and calf advances in the control of foot rot in sheep mastitis in ewes giardiasis in large animals laboratory diagnostic tests for retrovirus infections of small ruminants effects of dietary vitamin e supplementation during late pregnancy on lamb mortality and ewe productivity myotonia congenita (thomsen) and recessive myotonia genetic and environmental causes of variation in mastitis in sheep the gnrh system of seasonal breeders: anatomy and plasticity genetic organization, polymorphism, and function of the bovine major histocampaticulity complex scrapie in sheep biochemical and morphological expression of early prenatal caprine beta-mannosidosis respiratory infections of sheep dogs are the definitive hosts of neospora caninum a century of classical contagious caprine pleuropneumonia from original description to aetiology sheep and goat practice gene manipulation in goats through biotechnology minimizing morbidity and mortality from cryptosporidiosis managing dairy cows during the transition period: focus on ketosis environmental enrichment for dairy calves and pigs the trypanocidal cape buffalo serum protein is xanthine oxidase oral rehydration therapy for diarrheic calves neonatal ruminant diarrhea techniques for artificial insemination of cattle with frozenthawed semen noninfectious causes of lameness neosporosis: its prevalence and economic impact a review of yersinosis (yersinia pseudotuberculosis infection) dairy goat reproduction maedivisna virus in sheep: a review evaluation of a commercially available vaccine against corynebacterium pseudotuberculosis for use in sheep ruminant production management: control programs for gastrointestinal nematodes in sheep and goats fetal brain injury following prolonged hypoxemia and placental insufficiency: a review managing cryptosporidium and giardia infections in domestic ruminants milk fever: seeking new solutions to an old problem recent advances on ovine chlamydial abortion risk factors for abomasal displacement in dairy cows the spider syndrome: a report on one purebred flock development of ingestive behavior current state of in vivo preclinical heart valve evaluation dermatophilus congolensis infections in cattle and sheep ovine listeric encephalitis coccidiosis in ruminants principles of dairy science human factor ix transgenic sheep produced by transfer of nuclei from transfected fetal fibroblasts the major histocompatibility complex region of domestic animal species clinical reproductive anatomy and physiology of the doe immunobiology of the mammary gland coccidiosis brucella abortus strain rb : a new brucellosis vaccine for cattle use of age and serum gamma-glutamyltransferase activity to assess passive transfer status in lambs effect of congenitally acquired neospora caninum infection on risk of abortion and subsequent abortions in dairy cattle artificial control of breeding in ewes toxoplasmosis infection in sheep bovine reproductive biotechnology transgenic dairy cattle. genetic engineering on a large scale the effect of intra-mammary inoculation of lactating ewes with pasteurella haemolytica isolates from different sources bovine surgery and lameness reduction of myocardial myoglobin in bovine dilated cardiomyopathy intraosseous infusion of prostaglandin e prevents disuse-induced bone loss in the tibia estrous cycle synchronization the bronchopneumonias (respiratory disease complex of cattle, sheep, and goats) the cattle gene map treatment and control of gastrointestinal nematodes in sheep diagnosis, treatment, and management of enteric colibacillosis key: cord- -haf y authors: offit, paul a.; destefano, frank title: vaccine safety date: - - journal: vaccines doi: . /b - - - - . - sha: doc_id: cord_uid: haf y nan during the past years, pharmaceutical companies have made vaccines against pertussis, polio, measles, rubella, and haemophilus influenzae type b (hib), among others ( table - ) . as a consequence, the number of children in the united states killed by pertussis decreased from , each year in the early th century to fewer than ; the number paralyzed by polio from , to ; the number killed by measles from , to ; the number with severe birth defects caused by rubella from , to ; and the number with meningitis and bloodstream infections caused by hib from , to fewer than . vaccines have been among the most powerful forces in determining how long we live. but the landscape of vaccines is also littered with tragedy: in the late s, starting with louis pasteur, scientists made rabies vaccines using cells from nervous tissue (such as animal brains and spinal cords); the vaccine prevented a uniformly fatal infection, but the rabies vaccine also caused seizures, paralysis, and coma in as many as of every people who used it. [ ] [ ] [ ] [ ] in , the military injected hundreds of thousands of american servicemen with a yellow fever vaccine. to stabilize the vaccine virus, scientists added human serum. unfortunately, some of the serum came from people unknowingly infected with hepatitis b virus. as a consequence, , soldiers were infected, severe hepatitis developed in , , and died. [ ] [ ] [ ] [ ] in , five companies made jonas salk's new formaldehydeinactivated polio vaccine. however, one company, cutter laboratories of berkeley, california, failed to completely inactivate poliovirus with formaldehyde. because of this problem, , children were inadvertently injected with live, dangerous poliovirus; in , , mild polio developed, were permanently paralyzed, and were killed. it was one of the worst biological disasters in american history. vaccines have also caused uncommon but severe adverse events not associated with production errors. for example, acute encephalopathy after whole-cell pertussis vaccine, , acute arthropathy following rubella vaccine, - thrombocytopenia following measles-containing vaccine, , guillain-barré syndrome (gbs) after swine flu vaccine, paralytic polio following live attenuated oral polio vaccine, anaphylaxis following receipt of vaccines containing egg proteins (ie, influenza and yellow fever vaccines), , severe or fatal viscerotropic disease following yellow fever vaccine, possible narcolepsy following a squalene-adjuvanted influenza vaccine, and severe allergic reactions associated with gelatin contained in the measles-mumps-rubella vaccine are problems associated with the use of vaccines, albeit rarely. as vaccine use increases and the incidence of vaccine-preventable diseases is reduced, vaccine-related adverse events become more prominent in vaccination decisions ( figure - ) . even unfounded safety concerns can lead to decreased vaccine acceptance and resurgence of vaccine-preventable diseases, as occurred in the s and s as a public reaction to allegations that the wholecell pertussis vaccine caused encephalopathy and brain damage ( figure - ). recent outbreaks of measles, mumps, and pertussis in the united states are important reminders of how immunization delays and refusals can result in resurgences of vaccine-preventable diseases. - because vaccines are given to healthy children and adults, a higher standard of safety is generally expected of immunizations compared with other medical interventions. tolerance of adverse reactions to pharmaceutical products (eg, vaccines, contraceptives) given to healthy people-especially healthy infants and toddlers-to prevent certain conditions is substantially lower than to products (eg, antibiotics, insulin) used to treat people who are sick. this lower tolerance for risks from vaccines translates into a need to investigate the possible causes of much rarer adverse events after vaccinations than would be acceptable for other pharmaceutical products. for example, side effects are essentially universal for cancer chemotherapy, and % to % of people receiving high-dose aspirin therapy experience gastrointestinal symptoms. safety monitoring can be done before and after vaccine licensure, with slightly different goals based on the methodological strengths and weaknesses of each step. - although the general principles are similar irrespective of country, the specific approaches may differ because of factors such as how immunization services are organized and the level of resources available. vaccines, similar to other pharmaceutical products, undergo extensive safety and efficacy evaluations in the laboratory, in animals, and in phased human clinical trials before licensure. , phase trials usually include fewer than participants and can detect only extremely common adverse events. phase trials generally enroll to several hundred people. when carefully coordinated, as in the comparative infant diphtheria and tetanus toxoids and acellular pertussis (dtap) vaccine trials, important insight into the relationship between concentration of antigen, number of vaccine components, formulation, effect of successive doses, and profile of common reactions can be drawn and can affect the choice of the candidate vaccines for phase trials. , sample sizes for phase vaccine trials are based principally on efficacy considerations, with safety inferences drawn to the extent possible based on the sample size (approximately to ) and the duration of observation (often < days). typically only observations of common local and systemic reactions (eg, injection site swelling, fever, fussiness) have been feasible. the experimental design of most phase to clinical trials includes a control group (a placebo or an alternative vaccine) and detection of adverse events by researchers in a consistent manner "blinded" to which vaccine the patient received. this allows relatively straightforward inferences on the causal relationship between most adverse events and vaccination. several ways of enhancing prelicensure safety assessment of vaccines have been developed. one of these ways includes the brighton collaboration ( www.brightoncollaboration.org ), established to develop and implement globally accepted standard case definitions for assessing adverse events following immunizations in prelicensure and postlicensure settings. without such standards, it was difficult if not impossible to compare and collate safety data across trials in a valid manner. for example, in the large multisite phase infant dtap trials, definitions of high fever across trials varied by temperature ( . °c vs . °c), measurement (oral vs rectal), and time (measured at vs hours). this was unfortunate because standardized case definitions had been developed in these trials for efficacy but not for safety, even though the safety concerns provided the original impetus for the development of dtap. , the brighton case definitions for each adverse event are further arrayed by the level of evidence provided (insufficient, low, intermediate, and highest); therefore, they also can be used in settings with fewer resources (eg, studies in less developed settings or postlicensure surveillance). another of the recent advances to prelicensure safety assessments of vaccines has stemmed from the recognition of the need for much larger safety and efficacy trials before licensure. because of pragmatic limits on the sample sizes of prelicensure studies, there are inherent limitations to the extent to which they can detect very rare, yet real, adverse events related to vaccination. even if no adverse event has been observed in a trial of , vaccinees, one can only be reasonably certain that the real incidence of the adverse event is no higher than in , vaccinees. thus, to be able to detect an attributable risk of per , vaccinees (eg, such as the approximate risk found for intussusception in the postlicensure evaluation of rotashield vaccine), a prelicensure trial of at least , vaccinees and , control subjects is needed. both second-generation rotavirus vaccines (rotateq and rotarix) were subjected to phase trials that included at least , infants. , while these trials were adequately powered to detect the problem with intussusception found following rotashield, in general, the cost of such large trials might limit the number of vaccine candidates that go through this process in the future. because rare reactions, reactions with delayed onset, or reactions in subpopulations may not be detected before vaccines are licensed, postlicensure evaluation of vaccine safety is critical. historically, this evaluation has relied on passive surveillance and ad hoc epidemiologic studies, but, more recently, phase trials and preestablished large linked databases have improved the methodological capabilities to study rare risks of specific immunizations. such systems may detect variation in rates of adverse events by manufacturer , or specific lot. more recently, clinical centers for the study of immunization safety have emerged as another useful infrastructure to advance our knowledge about safety. in contrast with the methodological strengths of prelicensure randomized trials, however, postlicensure observational studies of vaccine safety pose a formidable set of methodological difficulties. confounding by contraindication is especially problematic for nonexperimental designs. specifically, persons who do not receive vaccine (eg, because of a chronic or transient medical contraindication or low socioeconomic group) may have a different risk for an adverse event than vaccinated persons (eg, background rates of seizures or sudden infant death syndrome (sids) may be higher in unvaccinated people). therefore, direct comparisons of vaccinated and unvaccinated children are often inherently confounded, and teasing this issue out requires understanding of the complex interactions of multiple, poorly quantified factors. informal or formal passive surveillance or spontaneous reporting systems (srss) have been the cornerstone of most postlicensure safety monitoring systems because of their relative low cost of operations. - the national reporting of adverse events following immunizations can be done through the same reporting channels as those used for other adverse drug reactions, as is the practice in france, vaccine manufacturers also maintain srss for their products, which are usually forwarded subsequently to appropriate national regulatory authorities. , in the united states, the national childhood vaccine injury act of mandated that health care providers report certain adverse events after immunizations. the vaccine adverse events reporting system (vaers) was implemented jointly by the centers for disease control and prevention (cdc) and the us food and drug administration (fda) in to provide a unified national focus for collection of all reports of clinically significant adverse events, including, but not limited to, those mandated for reporting. the vaers form permits narrative descriptions of adverse events. patients and their parents-not just health care professionals-are permitted to report to vaers, and there is no restriction on the interval between vaccination and symptoms that can be reported. report forms, assistance in completing the form, and answers to other questions about vaers are available on the vaers web site (vaers.hhs.gov). web-based reporting and simple data analyses are also available. a contractor, under cdc and fda supervision, distributes, collects, codes (currently using the medical dictionary for regulatory activities (www.meddramsso.com/index.asp), and enters vaers reports in a database. reporters of selected serious events are contacted by trained clinical staff on report receipt and are sent letters at year after report receipt to provide additional information about the vaers report, including the patient's recovery. approximately , vaers reports are now received annually, and these data (without personal identifiers) are also available to the public (at vaers.hhs.gov and at wonder.cdc.gov/vaers.html). several other countries also have substantial experience with passive surveillance for immunization safety. in , canada developed the vaccine associated adverse event (vaae) reporting system, , which is supplemented by an active, pediatric hospital-based surveillance system that searches all admissions for possible relationships to immunizations (immunization monitoring program-active, or impact). serious vaae reports are reviewed by the advisory committee on causality assessment consisting of a panel of experts. the netherlands also convenes an annual panel to categorize reports, which are then published. the united kingdom and most members of the former commonwealth use the yellow card system, whereby a reporting form is attached to officially issued prescription pads. , data on adverse drug (including vaccine) events from several countries are compiled by the world health organization (who) collaborating center for international drug monitoring in uppsala. with so many different passive surveillance systems that collect information on various medical events following vaccination, standardized definitions of vaccine-related adverse events are necessary. in the past, different definitions were developed in brazil, canada, india, and the netherlands. however, implementation of similar standards across national boundaries has been advanced by the international conference on harmonization and the brighton collaboration. vaers often first identifies potential new vaccine safety problems because of clusters of cases in time or space, often with unusual clinical features. for example, in , passive reports to vaers of intussusception among children vaccinated with rotashield was the first postlicensure signal of a problem, leading to epidemiologic studies that verified these findings. , similarly, initial reports to vaers of a previously unrecognized serious yellow fever vaccine-associated neurotropic disease and viscerotropic disease , have since been confirmed elsewhere. because of the success in detecting these signals, there have been various attempts to automate screening for signals using srss reports. new tools developed for pattern recognition in extremely large databases are beginning to be applied. these include empirical bayesian data mining to identify unexpectedly frequent vaccine-event combinations. vaers has provided some of the first safety data after the introduction of a number of vaccines. - vaers has also successfully served as a source of cases for further investigation of idiopathic thrombocytopenic purpura after measles-mumpsrubella (mmr) vaccine, encephalopathy after mmr, , and syncope after immunization. when denominator data on vaccine doses distributed or administered are available from other sources, vaers can be used to evaluate changes in reporting rates over time or when new vaccines replace old vaccines. for example, vaers showed that after millions of doses had been distributed, reporting rates for serious events such as hospitalization and seizures after dtap in toddlers were one third of those after diphtheria and tetanus toxoids and whole-cell pertussis (dtp). because vaers is the only surveillance system covering the entire us population with data available on a relatively timely basis, it is the major means available currently to detect possible new, unusual, or extremely rare adverse events. despite the aforementioned uses, srss for drug and vaccine safety have a number of major methodological weaknesses. underreporting, biased reporting, and incomplete reporting are inherent to all such systems, and potential safety concerns may be missed. - aseptic meningitis associated with the urabe mumps vaccine strain, for example, was not detected by srss in most countries. , some increases in adverse events detected by vaers may not be true increases, but instead may be due to increases in reporting efficiency or vaccine coverage. for example, an increase in gbs reports after influenza vaccination during the to season was found to be largely due to improvements in vaccine coverage and increases in gbs independent of vaccination. an increased reporting rate of an adverse event after one hepatitis b vaccine compared with a second brand was likely due to differential distribution of brands in the public vs private sectors, which have differential vaers reporting rates (higher in the public sector). finally, pending litigation resulted in the filing of a large number of vaers reports claiming that vaccines caused autism. perhaps the most important methodological weakness of vaers, however, is that it does not contain the information necessary for formal epidemiologic analyses. such analyses require calculation of the rate of the adverse event after vaccination and a comparison rate among unvaccinated persons. the vaers database, however, provides data only for the number of persons who may have experienced an adverse event following immunization and, even then, only in a biased and underreported manner. vaers lacks data on the denominator of total number of people vaccinated and the corresponding data on number of cases and denominator population of unvaccinated people. sometimes reporting rates can be calculated by using vaers case reports for the numerator and, if available, doses of vaccines administered (or, if unavailable, data on vaccine doses distributed or vaccine coverage survey data) for the denominator. these rates can then be compared with the background rate of the same adverse event in the absence of vaccination, if available. because of underreporting, however, vaers reporting rates will usually be lower than the actual rates of adverse events following immunization. a higher proportion of serious events, such as seizures, that follow vaccinations are likely to be reported to vaers than milder events, such as rash, or delayed events requiring laboratory assessment, such as thrombocytopenic purpura after mmr vaccination. the reporting efficiency or sensitivity of srss can sometimes be estimated if an independent source of cases of specific adverse events following immunization is available to conduct capture-recapture analyses. such an analysis was conducted to estimate that vaers reporting completeness for intussusception following rotashield vaccine was %. formal evaluation has been limited by the quality of diagnostic information on vaers reports, especially the probability that a serious event reported to vaers has been diagnosed accurately. of cases reported to vaers in which gbs developed after influenza vaccination during the to season, and for which hospital charts were reviewed by an independent panel of neurologists blinded to immunization status, the diagnosis of gbs was confirmed in ( %). intussusception was verified in % of vaers reports filed after rotashield vaccination. clinical reviews of vaers reports submitted following h n influenza vaccine were able to verify % of possible gbs reports and % of reports of possible anaphylaxis. clinical review verification rates were similar for vaers reports following human papillomavirus vaccination: % for gbs and % for anaphylaxis. these studies highlight the often crude nature of signals generated by vaers and the difficulty in ascertaining which potential vaccine safety concerns warrant further investigation. the problems with reporting efficiency and potentially biased reporting and the inherent lack of an adequate control group limit the certainty with which conclusions can be drawn. recognition of these limitations in large part has helped stimulate the creation of more population-based methods of assessing vaccine safety. vaccines may undergo clinical trials after licensure to assess the effects of changes in vaccine formulation, vaccine strain, age at vaccination, number and timing of vaccine doses, simultaneous administration, and interchangeability of vaccines from different manufacturers on vaccine safety and immunogenicity. unanticipated differential mortality among recipients of high-and regular-titered measles vaccine in developing countries (albeit lower than among unvaccinated children) led to a change in recommendations by the who for the use of such vaccines. to improve the ability to detect adverse events that are not detected during prelicensure trials, some recently licensed vaccines in developed countries have undergone formal phase surveillance studies on populations with sample sizes that have included as many as , people. these studies usually have used cohorts in managed care organizations (mcos) supplemented by diary or phone interviews. these methods were first used extensively after the licensure of polysaccharide and conjugated hib vaccines. - large postlicensure studies on safety and efficacy have also been conducted for several other vaccines, including those for dtap, varicella, and herpes zoster. , requirements for phase evaluation have even been extended to less frequently used vaccines, such as japanese encephalitis vaccine. historically, ad hoc epidemiologic studies have been used to assess signals of potential adverse events detected by srss, the medical literature, or other mechanisms. some examples of such studies include the investigations of poliomyelitis after inactivated , and oral polio vaccines, sids after dtp vaccination, - encephalopathy after dtp vaccination, , meningoencephalitis after mumps vaccination, injection site abscesses after vaccination, and gbs after influenza vaccination. , , the institute of medicine (iom) has compiled and reviewed many of these studies. , unfortunately, such ad hoc studies are often costly, timeconsuming, and limited to assessment of a single event or a few events or outcomes. given these drawbacks and the methodological limitations of passive surveillance systems (such as described for vaers), pharmacoepidemiologists began to turn to large databases linking computerized pharmacy prescription (and later immunization records) and medical outcome records. these databases derive from defined populations such as members of mcos, single-provider health care systems, and medicaid programs. such databases cover enrollee populations numbering from thousands to millions, and, because the data are generated from the routine administration of the full range of medical care, underreporting and recall bias are reduced. with denominator data on doses administered and the ready availability of appropriate comparison (ie, unvaccinated) groups, these large databases provide an economical and rapid means of conducting postlicensure studies of safety of drugs and vaccines. , [ ] [ ] [ ] [ ] the cdc initiated the vaccine safety datalink (vsd) project in to conduct postmarketing evaluations of vaccine safety and to establish an infrastructure allowing for highquality research and surveillance. selection of staff-model prepaid health plans minimized potential biases for more severe outcomes resulting from data generated from fee-for-service claims. currently, eight mcos in the united states participate in the vsd. the eight participating mcos comprise a population of more than million members. each mco prepares computerized data files using a standardized data dictionary containing demographic and medical information on their members, such as age and sex, health plan enrollment, vaccinations, hospitalizations, outpatient clinic visits, emergency department visits, urgent care visits, and mortality data, as well as additional birth information (eg, birth weight) when available. other information sources, such as medical chart review; member surveys; and pharmacy, laboratory and radiology data are often used in vsd studies to validate outcomes and vaccination data. there is rigorous attention to the maintenance of patient confidentiality, and each study undergoes institutional review board review. the vsd project's main priorities include evaluating new vaccine safety concerns that may arise from the medical literature, , from vaers, , from changes in immunization schedules, or from introduction of new vaccines. , the creation of near real-time data files has enabled the development of near real-time postmarketing surveillance for newly licensed vaccines and changes in vaccine recommendations. the size of the vsd population also permits separation of the risks associated with individual vaccines from those associated with vaccine combinations, whether given in the same syringe or simultaneously at different body sites. for example, vsd safety monitoring found that the combined mmrv vaccine carried an increased risk of febrile seizures compared with giving mmr and varicella vaccines simultaneously as separate injections. such studies are especially valuable in view of combined pediatric vaccines. more than studies have been or are being performed within the vsd project, including general screening studies of the safety of inactivated influenza vaccines among children and of thimerosal-containing vaccines. disease-or syndrome-specific investigations have been or are being performed, including studies investigating autism, multiple sclerosis, thyroid disease, acute ataxia, alopecia, rheumatoid arthritis, asthma, diabetes, and idiopathic thrombocytopenic purpura following vaccination. amid these promises, a few caveats are appropriate. although diverse, the population in the mcos currently in the vsd project is not wholly representative of the united states in terms of geography or socioeconomic status. more important, because of the high coverage attained in the mcos for most vaccines, few nonvaccinated control subjects are available. therefore, vsd studies often rely on risk-interval analyses (eg, to study the question of whether outcome "x" is more common in period "y" following vaccination compared with other periods) (table - ). this approach, although powerful for evaluating acute adverse events, has limited ability to assess associations between vaccination and adverse events with delayed or insidious onset (eg, autism). the vsd project also cannot easily assess mild adverse events (such as fever) that do not always come to medical attention. finally, because vac-cines are not delivered in the context of randomized, controlled trials, the vsd project may not be able to successfully control for confounding and bias in each analysis, and inferences on causality may be limited. despite these potential shortcomings, the vsd project provides an essential, powerful, and cost-effective complement to ongoing evaluations of vaccine safety in the united states. , in view of the methodological and logistic advantages offered by large linked databases, the united kingdom and canada also have developed systems linking immunization registries with medical files. , because of the relatively limited number of vaccines used worldwide and the costs associated with establishing and operating these large databases, it is unlikely that all countries will be able to or need to establish their own. these countries should be able to draw on the scientific base established by the existing large linked databases for vaccine safety and, if the need arises, conduct ad hoc epidemiologic studies. more recently, there has been an increasing awareness that the usefulness of srss as potential disease registries and the immunization safety infrastructure can be usefully augmented by tertiary clinical centers. well-organized, well-identified clinical infrastructures for the study of rare vaccine safety outcomes were first developed in certain regions in italy and australia. , in the united states, the cdc established the clinical immunization safety assessment (cisa) network in with the following primary goals: ( ) to develop research protocols for clinical evaluation, diagnosis, and management of adverse events following immunization (aefi); ( ) to improve the understanding of aefi at the individual level, including determining possible genetic and other risk factors for predisposed persons and high-risk subpopulations; ( ) to develop evidence-based algorithms for vaccination of persons at risk of serious adverse events following immunization; and ( ) to provide a resource of subject matter experts for clinical vaccine safety inquiries. the cisa investigators bring in-depth clinical, pathophysiologic, and epidemiologic expertise to assessing causal relationships between vaccines and adverse events and to understanding the pathogenesis of adverse . define biologically plausible risk interval for adverse event after vaccination (eg, days after each dose). . partition observation time for each child in the study into periods within and outside of risk intervals, and sum respectively (eg, for a child observed for days during which three doses of vaccine were received, total risk interval time = × person-days = persondays; total nonrisk interval time = − = person-days). birth dose dose dose days . add (a) total risk interval and nonrisk interval observation times for each child in the study (person-time observed; for mathematical convenience, the following example uses and , person-months of observation) and (b) adverse events occurring in each period to complete a × table (for illustration, the example uses and cases): events following vaccinations. the cisa investigators have published a standardized algorithm for evaluating and managing persons who have suspected or definite immediate hypersensitivity reactions such as urticaria, angioedema, and anaphylaxis following vaccines. some of the studies undertaken by cisa include an assessment of extensive limb swelling after dtap, a study of the usefulness of irritant skin test reactions for managing hypersensitivity to vaccines, the clinical evaluation of patients with serious adverse events following yellow fever vaccine administration, and evaluation of vaccine safety among children with inborn errors of metabolism. new understanding of the human genome, pharmacogenomics, and immunology hold promise for future cisa studies and may make it possible to elucidate the biological mechanisms of vaccine adverse reactions, which in turn could lead to the development of safer vaccines and safer vaccination practices, including revaccination when indicated. in mass immunization campaigns during which many people are vaccinated in a short time, it is critical to have a vaccine safety monitoring system in place that can detect potential safety problems early so that corrective actions can be taken as soon as possible. mass immunization campaigns pose specific safety challenges precisely because large populations are vaccinated during a short time and often they are conducted outside the usual health care setting. mass immunization campaigns are often conducted in developing countries, which poses a particular challenge of ensuring injection safety. in any setting in which large numbers of immunizations are being administered, more adverse events will coincidentally occur following immunization. thus, it is important to have background rates available of expected adverse events to allow rapid evaluation of whether reported adverse events are occurring at a rate following immunization that is higher than would be expected by chance alone. the resources devoted to mass vaccination campaigns also provide opportunities to enhance existing immunization safety monitoring systems or to establish a system if none exists, and these may lead to long-term improvements in immunization safety monitoring beyond the specific mass immunization campaign. the response to the h n influenza pandemic involved probably the largest and most intense immunization safety monitoring effort ever undertaken in the united states and internationally. the emergence of a novel influenza a (h n ) virus prompted the development of influenza a (h n ) monovalent vaccines. the fda licensed the first -h n vaccines in september . with potentially hundreds of millions of people expected to be vaccinated, adverse events were anticipated to occur in some recently vaccinated people. to address the question of whether the vaccine could be causing the adverse events, background rates for several adverse events were developed. to rapidly detect any unforeseen safety problems, the federal government implemented enhanced postlicensure -h n vaccine safety monitoring. first, vaers undertook special outreach efforts to encourage providers to report, and daily reviews and followup of submitted reports were conducted by medical personnel to rapidly evaluate the reports and obtain any needed additional clinical or other information. second, a new web-based active surveillance system was implemented to prospectively follow tens of thousands of vaccinees for medically attended adverse events. third, large population-based systems that link computerized vaccination data with health care encounter codes were used to conduct rapid ongoing analyses to evaluate possible associations of h n vaccination with selected adverse events, including potential associations suggested by vaers or other sources. such systems included the existing vsd project; a new collaboration involving additional large health plans covering several million people that also performed rapid ongoing analyses similar to vsd; and the databases of the department of defense, medicare, and the veterans administration. fourth, active case finding for gbs was conducted in areas of the united states with a combined population of about million. the findings from the various safety monitoring activities were regularly reviewed by government and other scientists and an independent vaccine safety review panel convened by the department of health and human services. initial safety data were provided by vaers, which found that the adverse event profile after -h n vaccine in vaers ( > , reports) was consistent with that of seasonal influenza vaccines, although the reporting rate was higher after -h n than seasonal influenza vaccines, which may be, at least in part, a reflection of stimulated reporting; death, gbs, and anaphylaxis reports after -h n vaccination were rare (each < per million doses administered). , preliminary results from the large special study of gbs found . excess cases of gbs per million vaccinations, which is similar to the increased risk found with some seasonal influenza vaccines. similar efforts to intensely monitor the safety of influenza a (h n ) vaccines occurred in other countries, primarily in north america, europe, and australia, but also included the development of new immunization safety monitoring systems in countries such as taiwan. these countries collaborated in their activities and routinely shared information among themselves and with other countries that have limited vaccine safety monitoring capabilities. these extensive international safety monitoring activities and collaborations represented an unprecedented commitment to ensuring the safety of influenza a (h n ) vaccines, as well as a model for how we might improve tracking of safety for all vaccines going forward. unfortunately, vaccine safety issues have increasingly taken on a life of their own outside of the scientific arena-arguably to society's overall detriment. liability concerns, for example, have severely limited development of maternal immunizations to protect their newborn infants against diseases such as from group b streptococcus . more worrisome, however, are various chronic diseases (and their advocates) in search of a simple cause, for which immunizations-as a relatively universal exposuremake all too convenient a hypothesized link. case studies of some of these fears are discussed in the following sections. in , kulenkampff and coworkers reported a series of cases of children with mental retardation and epilepsy following receipt of the whole-cell pertussis vaccine. during the next several years, fear of the pertussis vaccine generated by media coverage of this report caused a decrease in pertussis immunization rates in british children from % to % and resulted in more than , cases and deaths due to pertussis. media coverage of the kulenkampff report also caused decreased immunization rates and increased pertussis deaths in japan, sweden, and wales. however, many subsequent excellent well-controlled studies found that the incidence of mental retardation and epilepsy following whole-cell pertussis vaccine was similar in vaccinated children compared with children who did not receive the vaccine and that many of these children actually suffered from dravet's syndrome (a neuronal sodium channel transport defect caused by an scn a mutation). - , a in the mid- s, the antivaccine group called dissatisfied parents together raised the notion that the whole-cell pertussis vaccine could cause sids. subsequent study of children who did or did not receive dtp vaccine showed that the incidence of sids was not greater in the vaccinated group. in the early s, when the hepatitis b vaccine was recommended for routine use in newborns, a program on abc's / raised the question of whether vaccines could cause sids. again, studies failed to find any association between hepatitis b vaccine and sids. , , two recent reviews have confirmed the notion that vaccines do not cause sids. , vaccines cause mad-cow disease by july , at least people in the united kingdom developed a progressive neurological disease termed variant creutzfeldt-jakob disease that likely resulted from eating meat prepared from cows with "mad-cow" disease, a disease caused by proteinaceous infectious particles (prions). some vaccines were made with serum or gelatin obtained from cows in england or from countries at risk for mad-cow disease. two products obtained from cows may be present in vaccines: trace quantities of fetal bovine serum used to provide growth factors for cell culture and gelatin used to stabilize vaccines. however, the bovine-derived products used in vaccines are not likely to contain prions for several reasons. first, fetal bovine serum and gelatin are obtained from blood and connective tissue respectively; neither are sources that have been found to contain prions. second, fetal bovine serum is highly diluted and eventually removed from cells during the growth of vaccine viruses. third, prions are not propagated in cell cultures used to make vaccines. fourth, transmission of prions occurs from eating meat contaminated with nervous tissue obtained from infected animals or, in experimental studies, from directly inoculating preparations of brains from infected animals into the brains of experimental animals. transmission of prions has not been documented after inoculation into the muscles or under the skin (routes used to vaccinate). taken together, the chance that currently licensed vaccines contain prions is essentially zero. the notion that the origin of aids could be traced to poliovirus vaccines that were administered in the belgian congo between and was the subject of a popular magazine article and book. the logic behind this assertion was as follows: ( ) the polio vaccine used in the belgian congo was grown in chimpanzee kidney cells. ( ) the chimpanzee kidney cells used at that time contained simian immunodeficiency virus (siv). ( ) siv is very closely related to human immunodeficiency virus (hiv). ( ) people were inadvertently inoculated with siv that then mutated to hiv and caused the aids epidemic. this reasoning is problematic and based on several false assumptions. - first, siv most closely related to hiv has been demonstrated in chimps in the cameroon, far from the chimps near stanleyville that were used to make the vaccine. second, siv and hiv are not very close genetically; mutation to hiv from siv would likely require decades, not years. third, polymerase chain reaction (pcr) analysis showed that the cell substrate used to make the vaccine was monkey, not chimp. fourth, siv and hiv are enveloped viruses that are easily disrupted by extremes in ph. if given by mouth (in a manner similar to the oral polio vaccine), both of these viruses would likely be destroyed in the acid environment of the stomach. last, and most important, original lots of the polio vaccine (including those used in africa for the polio vaccine trials) did not contain hiv or siv genomes as determined by the very sensitive reverse-transcription pcr assay. unfortunately, the notion that live attenuated polio vaccine could cause aids remains an obstacle to eliminating polio in some countries in africa. simian virus (sv ) was present in monkey kidney cells used to make the inactivated polio vaccine, live attenuated polio vaccine, and inactivated adenovirus vaccines in the late s and early s. recently, investigators found sv dna in biopsy specimens obtained from patients with certain unusual cancers (ie, mesothelioma, osteosarcoma, and non-hodgkin lymphoma), leading some to hypothesize a link between vaccination and the subsequent development of cancer. however, genetic remnants of sv were present in cancers of people who had or had not received contaminated polio vaccines; people with cancers who never received sv -contaminated vaccines were found to have evidence for sv in their cancerous cells; and epidemiologic studies did not show an increased risk of cancers in people who received polio vaccine between and and people who did not receive these vaccines. taken together, these findings do not support the hypothesis that the sv contained in polio vaccines administered before caused cancers. one hundred years ago, children received one vaccinesmallpox. today, young children receive vaccines routinely. although some vaccines are given in combination, infants and young children could receive more than shots and three oral doses by years of age, including as many as five shots at one time. the increase in the number of vaccines, and the consequent decline in vaccine-preventable illnesses, has focused attention by parents and health care professionals on vaccine safety. specific concerns include whether vaccines weaken, overwhelm, , or in some way alter the normal balance of the immune system, paving the way for chronic diseases such as diabetes, asthma, multiple sclerosis, and allergies. although we have witnessed a dramatic increase in the number of vaccines routinely recommended for infants and young children, the number of immunogenic proteins and polysaccharides contained in vaccines has declined (table - ). the decrease in the number of immunogenic proteins and polysaccharides contained in vaccines is attributable to discontinuation of the smallpox vaccine and advances in the field of protein purification that allowed for a switch from whole-cell to acellular pertussis vaccine. a practical way to determine the capacity of the immune system to respond to vaccines would be to consider the number of b and t cells required to generate adequate levels of binding antibodies per milliliter of blood. calculations are based on the following assumptions: -approximately ng/ml is likely to be an effective concentration of antibody directed against a specific epitope. -approximately b cells/ml are required to generate ng of antibody/ml. -given a doubling time of about . days for b cells, it would take about days to generate b cells/ml from a single b-cell clone. -because vaccine-specific humoral immune responses are first detected about days after immunization, those responses could initially be generated from a single b-cell clone per milliliter. -one vaccine contains about immunogenic proteins or polysaccharides ( table - ). -each immunogenic protein or polysaccharide contains about epitopes (ie, epitopes per vaccine). -approximately b cells are present per milliliter of blood. given these assumptions, the number of vaccines to which a person could respond would be determined by dividing the number of circulating b cells (approximately /ml) by the average number of epitopes per vaccine ( ). therefore, a person could theoretically respond to about vaccines at one time. the analysis used to determine the theoretical capacity of a person to respond to as many as vaccines at one time, although consistent with the biology and kinetics of vaccine-specific immune responses, is limited by lack of consideration of several factors. first, only vaccine-specific b-cell responses are considered. however, protection against disease by vaccines may also be mediated by vaccine-specific cytotoxic t lymphocytes (ctls). for example, virus-specific ctls are important in the regulation and control of varicella infections. second, in part because of differences in the capacity of various class i or class ii glycoproteins (encoded by the mhc) to present viral or bacterial peptides to the immune system, some people are not capable of responding to certain virus-specific proteins (eg, hepatitis b surface antigen). third, some proteins are more likely to evoke an immune response than others (ie, immunodominance). fourth, although most circulating b cells in a neonate are naïve, the child very quickly develops memory b cells that are not available for response to new antigens and, therefore, should not be considered as part of the circulating naïve b-cell pool. fifth, the immune system is not static. a study of t-cell population dynamics in hiv-infected persons found that adults have the capacity to generate about × new t lymphocytes each day. although the quantity of new b and t cells generated each day in healthy people is unknown, studies of hiv-infected persons demonstrate the enormous capacity of the immune system to generate lymphocytes when needed. primarily because of this fifth reason, the assessment that people can respond to at least vaccines at one time might be low. within hours of birth, cells of the innate and adaptive immune systems are actively engaged in responding to challenges in the environment (eg, colonizing bacterial flora). , similarly, newborn and young infants are quite capable of generating protective immune responses to single and multiple vaccines. for example, children born to mothers infected with hepatitis b virus are protected against infection after inoculation with hepatitis b vaccine (given at birth and month of age). [ ] [ ] [ ] similarly, newborns inoculated with bacille calmette-guérin (bcg) vaccine are protected against severe forms of tuberculosis presumably by activation of bacteria-specific t cells. [ ] [ ] [ ] in addition, about % to % of infants inoculated in the first months of life with multiple vaccines, including diphtheria-tetanus-pertussis, pneumococcus, hib, hepatitis b and polio, develop protective, vaccine-specific immune responses. conjugation of bacterial polysaccharides (such as streptococcus pneumoniae and hib) to carrier molecules that elicit helper t cells circumvents the poor immunogenicity of unconjugated polysaccharide vaccines in infants and young children. , vaccines weaken the immune system infection with wild-type viruses can cause a suppression of specific immunologic functions. for example, infection with wild-type measles virus causes a reduction in the number of circulating b and t cells during the viremic phase of infection and a delay in the development of cell-mediated immunity. , downregulation of cell-mediated immunity by wild-type measles virus probably results from downregulation of the production of interleukin- by measles-infected macrophages and dendritic cells. taken together, the immunosuppressive effects of wild-type measles virus account, in part, for the increase in morbidity and mortality from measles infection. similarly, the immunosuppressive effects of infections with wild-type varicella virus or wild-type influenza virus cause an increase in the incidence of severe invasive bacterial infections. live viral vaccines replicate (albeit far less efficiently than wild-type viruses) in the host and, therefore, can weakly mimic events that occur after natural infection. for example, measles, mumps, or rubella vaccines can significantly depress reactivity to the tuberculin skin test, can cause a decrease in protective immune responses to varicella vaccine, and high-titered measles vaccine (edmonston-zagreb strain) can cause an excess of cases of invasive bacterial infections in developing countries. all of these phenomena are explained by the likely immunosuppressive effects of measles vaccine viruses. however, current vaccines (including the highly attenuated moraten strain of measles vaccine) do not seem to cause clinically relevant immunosuppression in healthy children. studies have found that the incidence of invasive bacterial infections following immunization with diphtheria, pertussis, tetanus, bcg, measles, mumps, rubella, or live attenuated poliovirus vaccines was not greater than that found in unimmunized children. [ ] [ ] [ ] [ ] [ ] vaccines cause autoimmunity mechanisms are present at birth to prevent the development of immune responses directed against self-antigens (autoimmunity). t-and b-cell receptors of the fetus and newborn develop with a random repertoire of specificities. in the thymus, t cells that bind strongly to self-peptide-mhc complexes die, while those that bind with a lesser affinity survive to populate the body. this central selection process eliminates strongly selfreactive t cells, while selecting for t cells that recognize antigens in the context of self-mhc. in the fetal liver, and later in the bone marrow, b-cell receptors (ie, immunoglobulins) that bind self-antigens strongly are also eliminated. therefore, the thymus and bone marrow, by expressing antigens from many tissues of the body, enable the removal of the majority of potentially dangerous autoreactive t and b cells before they maturea process termed central tolerance. however, it is not simply the presence of autoreactive t and b cells that result in autoimmune disease. autoreactive t and b cells are present in all people because it is not possible for every antigen from every tissue of the body to participate in the elimination of all potentially autoreactive cells. a process termed peripheral tolerance further limits the activation of autoreactive cells. , mechanisms of peripheral tolerance include the following: ( ) antigen sequestration (antigens of the central nervous system, eyes, and testes are not regularly exposed to the immune system unless injury or infection occurs.); ( ) anergy (lymphocytes partially triggered by antigen but without costimulatory signals are unable to respond to subsequent antigen exposure.); ( ) activation-induced cell death (a self-limiting mechanism involved in terminating immune responses after antigen is cleared); and ( ) inhibition of immune responses by specific regulatory cells. [ ] [ ] [ ] [ ] therefore, the immune system anticipates that self-reactive t cells will be present and has mechanisms to control them. any theory of vaccine causation of autoimmune diseases must take into account how these controls are circumvented. as discussed subsequently, epidemiologic studies have not supported the hypothesis that vaccines cause autoimmune diseases. this is consistent with the fact that no mechanisms have been advanced to explain how vaccines could account for all of the prerequisites that would be required for the development of autoimmune disease. at least four key conditions must be met for development of autoimmune disease. first, self-antigen-specific t cells or selfantigen-specific b cells must be present. second, self-antigens must be presented in sufficient amounts to trigger autoreactive cells. third, costimulatory signals, cytokines, and other activation signals produced by antigen-presenting cells (such as dendritic cells) must be present during activation of self-reactive t cells. fourth, peripheral tolerance mechanisms must fail to control destructive autoimmune responses. if all of these conditions are not met, the activation of self-reactive lymphocytes and progression to autoimmune disease are not likely. evidence that vaccines do not cause autoimmunity rigorous epidemiologic studies of infant vaccines and type diabetes found that measles vaccine was not associated with an increased risk for diabetes; other investigations found no association between bcg, smallpox, tetanus, pertussis, rubella, or mumps vaccine and diabetes. a study in canada found no increase in risk for diabetes as a result of receipt of bcg vaccine. in a large year follow-up study among finnish children enrolled in an hib vaccination trial, no differences in risk for diabetes were found among children vaccinated at months of age (followed later with a booster vaccine) and children vaccinated at years only or with children born before the vaccine trial. the weight of currently available epidemiologic evidence does not support a causal association between currently recommended vaccines and type diabetes in humans. [ ] [ ] [ ] the hypothesis that vaccines might cause multiple sclerosis was fueled by anecdotal reports of multiple sclerosis following hepatitis b immunization and two case-control studies showing a small increase in the incidence of multiple sclerosis in vaccinated persons that was not statistically significant. - however, the capacity of vaccines to cause or exacerbate multiple sclerosis has been evaluated in several excellent epidemiologic studies. - two large case-control studies showed no association between hepatitis b vaccine and multiple sclerosis and found no evidence that hepatitis b, tetanus, or influenza vaccines exacerbated symptoms of multiple sclerosis. other well-controlled studies also found that influenza vaccine did not exacerbate symptoms of multiple sclerosis. - indeed, in a retrospective study of patients with relapsing multiple sclerosis, infection with influenza virus was more likely than immunization with influenza vaccine to cause an exacerbation of symptoms. a recent review also showed that the novel h n vaccine had an attributable risk for guillain-barré syndrome of - cases per million doses administered, not higher than that found following the - seasonal influenza vaccine. allergic symptoms are caused by soluble factors (eg, ige) that mediate immediate-type hypersensitivity; production of ige by b cells is dependent on release of cytokines such as interleukin- by th cells. two theories have been advanced to explain how vaccines could enhance ige-mediated, th -dependent allergic responses. first, vaccines could shift immune responses to potential allergens from th -like to th -like. second, by preventing common prevalent infections (the "hygiene hypothesis"), vaccines could prolong the length or increase the frequency of th -type responses. , although all factors that cause changes in the balance of th and th responses are not fully known, it is clear that dendritic cells have a critical role. for example, adjuvants (eg, aluminum hydroxide or aluminum phosphate ["alum"] contained in some vaccines) promote dendritic cells to stimulate th type responses. , adjuvants could cause allergies or asthma by stimulating bystander, allergen-specific th cells. however, vaccine surveillance data show no evidence for environmental allergen priming by vaccination. furthermore, local inoculation of adjuvant does not cause a global shift of immune responses to th or th type. , the other hypothesis advanced to explain how vaccines could promote allergies is that by preventing several childhood infections (the hygiene hypothesis), stimuli that evolution has relied on to cause a shift from the neonatal th -type immune response to the balanced th -th response patterns of adults have been eliminated. , however, the diseases that are prevented by vaccines constitute only a small fraction of the total number of illnesses to which a child is exposed, and it is unlikely that the immune system would rely on only a few infections for the development of a normal balance between th and th responses. for example, a study of , illnesses performed in cleveland, ohio, in the s found that children experienced six to eight infections per year in the first years of life; most of these infections were caused by viruses such as coronaviruses, rhinoviruses, paramyxoviruses, and myxovirusesdiseases for which children are not routinely immunized. also at variance with the hygiene hypothesis is the fact that children in developing countries have lower rates of allergies and asthma than children in developed countries despite the fact that they are commonly infected with helminths and worms-organisms that induce strong th -type responses. finally, the incidence of diseases that are mediated by th -type responses, such as multiple sclerosis and type diabetes, have increased in the same populations as those that experienced an increase in allergies and asthma. although some relatively small early observational studies supported the association between whole-cell pertussis vaccine and development of asthma, more recent studies have suggested otherwise. a large clinical trial performed in sweden found no increased risk, and a very large longitudinal study in the united kingdom found no association between pertussis vaccination and early-or late-onset wheezing or recurrent or intermittent wheezing. two studies from the vsd project have also lent data to this controversy. in one study of , infants with wheezing during infancy, vaccination with dtp and other vaccines was not related to the risk of wheezing in full-term infants, and, in another study of more than , children, childhood vaccinations were not associated with an increased risk for developing asthma. finally, a study from finland also suggested that children with a history of natural measles were at increased risk for atopic illness. such findings would run contrary to the hypothesis that the increase in atopic illnesses seen in several countries is due to the reduction in wild measles resulting from immunizations. another separate concern is whether inactivated influenza vaccination may induce asthma exacerbations in children with preexisting asthma. results of studies examining the potential associations between administration of inactivated influenza vaccine and various surrogate measures of asthma exacerbation, including decreased peak expiratory flow rate, increased use of bronchodilating drugs, and increase in asthma symptoms, have yielded mixed results. most studies, however, have not supported such an association. in fact, after controlling for asthma severity, acute asthma exacerbations were less common after inactivated influenza vaccination than before, and inactivated influenza vaccination seems to be associated with a decreased risk for asthma exacerbations throughout influenza seasons. several more recent studies have also shown a lack of correlation between receipt of vaccines and the development of asthma. - autism is a chronic developmental disorder characterized by problems in social interaction, communication, and responsiveness and by repetitive interests and activities. although the causes of autism are largely unknown, family and twin studies suggest that genetics has a fundamental role. in addition, overexpression of neuropeptides and neurotrophins has been found in the immediate perinatal period among children later diagnosed with autism, suggesting that prenatal or perinatal influences or both have a more important role than postnatal insults. however, because autistic symptoms generally first become apparent in the second year of life, some scientists and parents have focused on the role of mmr vaccine because it is first administered around this time. concern about the role of mmr vaccine was heightened in when a study based on children proposed an association between the vaccine and the development of ileonodular hyperplasia, nonspecific colitis, and regressive developmental disorders (later termed by some as "autistic enterocolitis"). among the proposed mechanisms was that mmr vaccine caused bowel problems, leading to the malabsorption of essential vitamins and other nutrients and eventually to autism or other developmental disorders. concern about this issue led to a decline in measles vaccine coverage in the united kingdom and elsewhere. significant concerns about the validity of the study included the lack of an adequate control or comparison group, inconsistent timing to support causality (several of the children had autistic symptoms preceding bowel symptoms), and the lack of an accepted definition of the syndrome. subsequently, population-based studies of autistic children in the united kingdom found no association between receipt of mmr vaccine and autism onset or developmental regression. , a study in the united states in the vsd project investigated whether measlescontaining vaccine was associated with inflammatory bowel disease and found no relationship between receiving mmr vaccine and inflammatory bowel disease or between the timing of the vaccine and risk for disease. soon after the lancet published the article that ignited the controversy, two ecologic analyses found no evidence that mmr vaccination was the cause of apparent increased trends in autism over time, , while two other studies found no evidence of a new variant form of autism associated with bowel disorders secondary to vaccination. , several more recent studies have also refuted the notion that mmr vaccine caused autism. [ ] [ ] [ ] [ ] [ ] [ ] in february , the lancet retracted the original article claiming an association. because of the level of concern surrounding this issue, the cdc and the national institutes of health requested an independent review by the iom. the immunization safety review committee appointed by the iom to review this issue was unable to find evidence supporting a causal relationship at the population level between autistic spectrum disorders and mmr vaccination, nor did the committee find any good evidence of biological mechanisms that would support or explain such a link. the fda modernization act of called for the fda to review and assess the risk of all mercury-containing food and drugs. this led to an examination of mercury content in vaccines. public health officials found that infants up to months old could receive as much as . µ g of ethylmercury (thimerosal) from vaccines, a level that exceeded recommended safety guidelines for methylmercury from the environmental protection agency, but not levels recommended by the fda or the agency for toxic substance disease registry. consequently, the routine neonatal dose of hepatitis b vaccine in infants born to hepatitis b surface antigen-negative mothers was suspended in the united states until preservative-free vaccines became available, and transitioning to a vaccine schedule free of thimerosal began as a precautionary measure. currently, some multidose influenza vaccines contain preservative quantities (ie, µ g per dose) of thimerosal although thimerosal-free vaccines are available. mercury is a naturally occurring element found in the earth's crust, air, soil, and water. since the earth's formation, volcanic eruptions, weathering of rocks, and burning of coal have caused mercury to be released into the environment. once released, certain types of bacteria in the environment can change inorganic mercury to organic (methylmercury). methylmercury makes its way through the food chain in fish, animals, and humans. at high levels, it can be neurotoxic. thimerosal contains ethylmercury, not methylmercury. studies comparing ethylmercury and methylmercury suggest that they are processed differently; ethylmercury is broken down and excreted much more rapidly than methylmercury. therefore, ethylmercury is much less likely than methylmercury to accumulate in the body and cause harm. a several pieces of biological and epidemiologic evidence support the notion that thimerosal does not cause autism. first, in iraq imported grain that had been fumigated with methylmercury. farmers ate bread made from this grain. the result was one of the worst, single-source, mercury poisonings in history. methylmercury in the grain caused the hospitalization of , iraqis and killed . pregnant women also ate the bread and delivered infants with epilepsy and mental retardation. however, there was no evidence that these infants had an increased incidence of autism. second, several large studies have now compared the risk of autism in children who received vaccines containing thimerosal with children who received vaccines without thimerosal or vaccines with lesser quantities of thimerosal; the incidence of autism was similar in all groups. - the iom has reviewed these studies and concluded that evidence favored rejection of a causal association between vaccines and autism and that autism research should shift away from vaccines. denmark, a country that abandoned thimerosal as a preservative in , actually saw an increase in the disease beginning several years later. third, studies of the head size, speech patterns, vision, coordination, and sensation of children poisoned by mercury show that the symptoms of mercury poisoning are distinguishable from the symptoms of autism. fourth, methylmercury is found in low levels in water, infant formula, and breast milk. although it is clear that large quantities of mercury can damage the nervous system, there is no evidence that the small quantities contained in water, infant formula, and breast milk do. an infant who is exclusively breastfed for months will ingest more than twice the quantity of mercury that was ever contained in vaccines and times the quantity of mercury contained in the influenza vaccine. one known and unfortunate sequela from the uncertainty surrounding the safety of thimerosal was confusion surrounding administration of the birth dose of hepatitis b vaccine. following the suspension of the routine use of hepatitis b vaccine for low-risk newborns in , there was a marked increase in the number of hospitals that no longer routinely vaccinated all infants at high risk of hepatitis b. as a result, there have been cases of neonatal hepatitis b that could have been prevented but were not because of many hospitals suspending their routine neonatal hepatitis b vaccination program. the hypothesis for why vaccines might cause autism has continued to shift. in , the concern was that the mmr vaccine caused autism. the following year, the concern shifted to include the fear that thimerosal in vaccines caused autism. as data continued to be generated showing that both of these concerns were ill founded, the hypothesis shifted again-this time to include the fear that too many vaccines given too soon caused autism. to address this concern, michael smith and charles woods mined data from a previous study that had been performed by cdc researchers to determine whether thimerosal in vaccines was associated with an increased risk of autism or neurodevelopmental delays. smith and woods compared children who had received vaccines according to the cdc/american academy of pediatrics schedule with children for whom a decision was made to delay, withhold, separate, or space out vaccines, noting no difference between the two groups in neurodevelopmental outcomes. aluminum salts have safely been used to adjuvant vaccines since the s. however, by the mid- s, parents became concerned that aluminum in vaccines might be harmful. indeed, high levels of aluminum can cause local inflammatory reactions, osteomalacia, anemia, or encephalopathy, typically in preterm infants or infants with absent or severely compromised renal function who are also receiving high doses of aluminum from other sources (eg, antacids). studies have shown that children who receive aluminum-containing vaccines have serum levels of aluminum that are well below the toxic range. [ ] [ ] [ ] formaldehyde in vaccines is harmful formaldehyde has been used in vaccines to detoxify bacterial toxins (ie, diphtheria toxin, tetanus toxin, pertussis toxins) and to inactivate viruses (ie, poliovirus). because formaldehyde at high concentrations can cause mutational changes in cellular dna in vitro, some parents have become concerned that formaldehyde in vaccines might be dangerous. however, because formaldehyde is a product of single-carbon metabolism, everyone has formaldehyde detectable in serum. indeed, the level of formaldehyde in the circulation is about -fold more than would be contained in any vaccine. also, people exposed to high levels of formaldehyde in the workplace (eg, morticians) are not at greater risk of cancer than people who are not exposed to formaldehyde. finally, the quantity of formaldehyde present in vaccines is at least -fold lower than that necessary to induce toxicity in experimental animals. two cell lines, mrc- and wi- , both derived from elective abortions performed in europe in the early s, have been used as cell substrates in vaccine manufacture. four vaccines continue to require the use of these cell lines: varicella, rubella, hepatitis a, and one of the rabies vaccines. human fetal cells were valuable in vaccine research because they support the growth of many human viruses and are sterile; they were first used at around the time that researchers found that primary monkey kidney cells were contaminated with sv virus. some religious groups have become concerned about the use of cells originally obtained from elective abortions. however, the pontifical academy of life of the catholic church has deemed vaccines made using these cells worthy of continued use, despite their origins. disease prevention, especially if it requires continuous nearuniversal compliance, is a formidable task. in the preimmunization era, vaccine-preventable diseases such as measles and pertussis were so prevalent that the risks and benefits of disease vs vaccination were readily evident. as immunization programs successfully reduced the incidence of vaccine-preventable diseases, however, an increasing proportion of health care providers and parents have little or no personal experience with vaccine-preventable diseases. for their risk-benefit analysis, they are forced to rely on historical and other more distant descriptions of vaccine-preventable diseases in textbooks or educational brochures. in contrast, some degree of personal discomfort, pain, and worry is generally associated with each immunization. in addition, parents searching for information about vaccines on the world wide web are likely to encounter web sites that encourage vaccine refusal or emphasize the dangers of vaccines. , similarly, the media may sensationalize vaccine safety issues or, in an effort to present "both sides" of an argument, fail to provide perspective. , for reasons discussed earlier, there may be uncertainty if vaccines are associated with rare or delayed adverse reactions if only because the scientific method does not allow for acceptance of the null hypothesis. therefore, one cannot prove that a vaccine never causes a particular adverse event, only that an adverse event is unlikely to occur by a certain statistical probability. the combination of these factors may have an impact on parental beliefs about immunizations. a national survey found that although the majority of parents support immunizations, % to % have misconceptions that could erode their confidence in vaccines. within this context, the art of addressing vaccine safety concerns through effective risk communication has emerged as an increasingly important skill for managers of mature immunization programs and health care providers who administer vaccines. the science of risk perceptions and risk communications, developed initially for technology and environmental arenas, has only recently been formally applied to immunizations. for scientists and other experts, risk tends to be synonymous with the objective probability of morbidity and mortality resulting from exposure to a particular hazard. in contrast, research has shown that laypersons may have subjective, multidimensional, and value-laden conceptualizations of risk. among the key principles and lessons learned about public perceptions of risk are the following: -individual people differ in their perceptions of risk depending on their personality, education, life experience, and personal values; , educational materials tiered for different needs are therefore likely to be more effective than a single tier. -perceptions of risk may differ dramatically among various stakeholders, such as members of government agencies, industry, or activist groups. the level of trust between stakeholders has an impact on all other aspects of risk communication. trust is generally reinforced by open communication about what is known and unknown about risks and by providing candid accounts of the evidence and how it was used in the decisionmaking process. -certain hazard characteristics, including involuntariness, uncertainty, lack of control, high level of dread, and low level of equity, lead to higher perceived risk; only risks with similar characteristics should be compared in risk communication efforts. -for quantitatively equivalent risk that is due to action (eg, vaccination reaction) vs inaction (eg, vaccinepreventable disease caused by nonvaccination), many people prefer the consequences of inaction to action. -when there is uncertainty about risks, patients frequently rely on the advice of their physician or other health care professionals; continuing education of health care professionals on vaccine risk issues is key. -finally, different ways of presenting, or framing, the same risk information (eg, using survival rates vs mortality rates) can lead to different risk perceptions, decisions, and behaviors. , risk communication can be used for the purposes of advocacy, public education, or decision-making partnership. people care not only about the magnitude of risks, but also how risks are managed and whether they participate in the risk-management process, especially in a democratic society. in medical decision making, this has resulted in a transition from more paternalistic models to increasing degrees of informed consent. some have argued that a similar transition to informed consent also should occur with immunizations. however, immunization is unlike most other medical procedures (eg, surgery) in that the consequences of the decision affect not only the individual person, but also others in the society. because of this important distinction, many countries have enacted public health (eg, immunization) laws that severely limit an individual person's right to infect others. without such mandates, persons may attempt to avoid the risks of vaccination while being protected by the herd immunity resulting from others being vaccinated. unfortunately, the protection provided by herd immunity may disappear if too many people avoid vaccination, resulting in outbreaks of vaccine-preventable diseases. , debates in the united states have focused on whether philosophical (in addition to medical and religious) exemptions to mandatory immunizations should be allowed more universally and, if so, what standards for claim of exemption are needed. , , thus, vaccine risk communications should not only describe the risks and benefits of vaccines for individual people, but also should include discussion of the impact of individual immunization decisions on the larger community. empathy, patience, scientific curiosity, and substantial resources are needed to address concerns about vaccine safety. although each evaluation of a vaccine safety concern is in some ways unique, some general principles may apply to most cases. as with all investigations, the first step is objective and comprehensive data gathering. it is also important to gather and weigh evidence for causes other than vaccination. for individual cases or clusters of cases, a field investigation to gather data firsthand may be necessary. , advice and review from a panel of independent experts also may be needed. , , causality assessment at the individual level is difficult at best; further evaluation via epidemiologic or laboratory studies may be required. even if the investigation is inconclusive, such studies can often help to maintain public trust in immunization programs. scientific investigations are only the beginning of addressing vaccine safety concerns. in many countries, people who believe they or their children have been injured by vaccines have organized and produced information highlighting the risks of and alternatives to immunizations. from the consumer activist perspective, even if vaccine risks are rare, this low risk does not reassure the person who experiences the reaction. such groups have been increasingly successful in airing their views in electronic and print media, frequently with poignant individual stories. , because the media frequently raise controversies without resolution and choose "balance" over perspective, one challenge is to establish credibility and trust with the audience. , factors that aid in enhancing credibility include demonstrating scientific expertise, establishing relationships with members of the media, expressing empathy, and distilling scientific facts and figures down to simple lay concepts. however, statistics and facts compete poorly with dramatic pictures and stories of disabled children. emotional reactions to messages are often dominant, influencing subsequent cognitive processing. therefore, equally compelling firsthand accounts of people with vaccine-preventable diseases may be needed to communicate the risks associated with not vaccinating. clarifying the distinction between perceived and real risk for the concerned public is critical. if further research is needed, the degree of uncertainty (eg, whether such rare vaccine reactions exist at all) should be acknowledged, but what is certain also should be noted (eg, millions of people have received vaccine x and have not developed syndrome y; even if the vaccine causes y, it is likely to be of magnitude z, compared with the magnitude of known risks associated with vaccine-preventable diseases). in the united states, written information about the risks and benefits of immunizations developed by the cdc has been required to be provided to all people vaccinated in the public sector since . the national childhood vaccine injury act requires every health care provider, public or private, who administers a vaccine that is covered by the act to provide a copy of the most current cdc vaccine information statement (vis) to the adult vaccinee or, in the case of a minor, to the parent or legal representative each time a dose of vaccine is administered. health care providers must note in each patient's permanent medical record the date printed on the vis and the date the vis was given to the vaccine recipient or his or her legal representative. viss are the cornerstone of provider-patient vaccine risk-benefit communication. each vis contains information on the disease(s) that the vaccine prevents, who should receive the vaccine and when, contraindications, vaccine risks, what to do if a side effect occurs, and where to go for more information. current viss can be obtained from the cdc's national center for immunization and respiratory diseases at www.cdc.gov/vaccines and are available in more than languages from the immunization action coalition at www.immunize.org. an increasing number of resources that address vaccine safety misconceptions and allegations also have become available, including web sites, brochures, resource kits, and videos (table - ) . some studies have been conducted to assess the use and effectiveness of such materials; - however, more research in this area is needed. immunization programs and health care providers should anticipate that some members of the public may have deep concerns about the need for and safety of vaccines. a few may refuse certain vaccines or even reject all vaccinations. an understanding of vaccine risk perceptions and effective vaccine risk communication are essential in responding to misinformation and concerns. toward this end, cdc's vaccine safety website (http://www.cdc. gov/vaccinesafety/index.html) provides basic information on the safety of routinely administered vaccines, as well as responses to frequently asked questions. the website also provides more detailed information on how vaccines are tested and monitored for safety; cdc's specific projects for monitoring, evaluation, and research on vaccine safety (vaers, vsd, and cisa); detailed sections addressing common concerns (eg, autism, thimerosal); and a resource library with articles, fact sheets, and other related materials on immunization safety. parental vaccine acceptance in a new era: the role of health care providers and public health professionals one consequence of the success of vaccines is that an increasing number of parents and clinicians have little or no personal experience with or knowledge of many of the diseases that vaccines prevent. thus, vaccine-preventable diseases often are not perceived as a real threat by parents. , moreover, increasingly parents want to be fully informed about their children's medical care, thus merely recommending vaccination may not be sufficient. also in this new era, stories in the media highlighting adverse events (real or perceived) may cause some parents to question the safety of vaccines. apart from the media attention on vaccine safety issues, a confluence of factors has an influence on parents' vaccine attitudes in the present environment of a low incidence of vaccinepreventable diseases. these factors would be relatively unimportant in an environment where diseases such as polio and measles were common and people lived in fear of their children contracting disease; however, they have become predominant in the current climate for some parents. some of these factors are: ( ) lack of appropriately tailored information about the benefits of vaccines and contrary information from alternative health practitioners, ( ) mistrust of the source of the information, ( ) perceived serious side effects, ( ) not perceiving the risks of vaccines accurately, and ( ) insufficient biomedical literacy. addressing these issues is a challenge for medical and public health professionals because the typical arrangement for providing medical care does not allow full reimbursement of health care providers for educating patients and parents. nevertheless, it is important for us to try to meet the challenge because an understanding of the aforementioned factors and a proactive approach to vaccine education may prevent future concerns from escalating into widespread refusal of vaccines, with a consequent increased incidence of vaccine-preventable diseases. most people today want to be thoroughly informed about their health care. the desire for more information also applies to parents with regard to medical issues for their children. parents want to be part of the decision-making process when it comes to immunizations for their children. providing the appropriate information at the appropriate time is especially important now with the increased questioning of vaccines and with states allowing philosophical exemptions in . there is an association between information and vaccine acceptance. a recent study found that while % of parents agreed that they had access to enough information to make a good decision about immunizing their children, % of parents disagreed or were neutral. parents who disagreed they had enough vaccine information had negative attitudes about immunizations, health care providers, immunization requirements and exemptions, and trust in people responsible for immunization policy. moreover, a larger percentage of parents who reported they did not have access to enough information about vaccines also had several specific vaccine concerns compared with parents who were neutral or agreed they had access to enough information. it may be that when there is a void of accurate, trusted information, doubts about vaccines arise and misinformation is more readily accepted. other studies have demonstrated the effect of providing information on the well-being of patients. for example, information is one factor that has been shown to positively influence a sense of control in patients with rheumatoid arthritis, and perceived lack of information among mothers was one reason contributing to nonimmunization of children in india. by using the principle of audience segmentation (partitioning a population into segments with shared characteristics), a survey study identified five parent groups that varied on health and immunization attitudes and beliefs. the two audience segments identified as most concerned about immunizations ("worrieds" and "fencesitters") were chosen as the focus of a follow-up study to obtain the input of mothers in these segments in the development of evidence-based, tailored educational materials. the purpose of these materials would be to assist health care providers in busy office settings to address questions from these two groups of parents. presentation of these tailored brochures by children's health care providers to parents in an empathetic and respectful manner could aid in improving the health care provider-parent relationship, increasing vaccine acceptance, and ultimately preventing vaccine-preventable diseases. the viss are typically given to parents the day the child is scheduled for immunization. , , this often places the parent in a conflict situation of attending to the vis or attending to a frightened or upset child. not surprisingly, studies have shown that parents would rather receive the information in advance of the first vaccination visit. , [ ] [ ] [ ] suggested earlier times for vaccine education include prenatal clinic visits and just after delivery in a hospital. a national survey indicated that % of providers said that a preimmunization booklet for parents would be useful for communicating risks and benefits to parents. the use of complementary and alternative medicine (cam) has been increasing during the past years in the united states. part of this increase is due to mcos providing coverage for some cam therapies. chiropractic care is among the top most commonly used cam therapies. it is of note that some chiropractic colleges teach a negative view of immunizations. in one study, one third of chiropractors agreed that there is no scientific proof that immunizations prevent disease. the basis for the negative views of vaccine effectiveness may lie in the chiropractic doctrine that disease is the result of spinal nerve dysfunction caused by subluxation coupled with the rejection of the germ theory of disease. , it may be that some chiropractors who adhere to this belief influence parents against immunizing their children. in one study, parents who requested immunization exemptions for their children were more likely to report cam use in their families than parents who did not request these exemptions. this emphasizes the importance of a trusting physician-patient relationship and providing parents with tailored information in advance of their child's immunizations; in this manner their questions are answered and they are prepared with the facts when they encounter contrary information from other sources. reaching out to chiropractic organizations to foster a better understanding of the benefits of immunizations may be advantageous to medical and public health professionals. parental concern about immunizations has been associated with a lack of trust. for example, one of the factors influencing parents who choose not to vaccinate their children for pertussis is doubt about the reliability of the vaccine information. in another study, compared with parents of vaccinated children, parents of children with an immunization exemption were more likely to express a low level of trust in the government, in addition to other factors such as low perceived susceptibility to and severity of vaccine-preventable diseases and low perceived efficacy and safety. these parents were less likely to believe that medical and public health professionals are good or excellent sources of immunization information. the majority of parents ( %), however, report receiving immunization information from a physician. thus, having a physician who engenders trust providing immunization information and who is available to listen and answer questions is the optimal situation from the public health perspective. if trust in a child's physician is low, parents may be drawn to other, less credible sources of information. when a child experiences an adverse event following receipt of a vaccine, it often raises the question "was this vaccine necessary"? to the parent, it may seem that the risks of the vaccine are greater than the risks of not getting the vaccine. parents who sought medical attention for any of their children owing to an apparent adverse event following immunizations ( . %) not only expressed more concern about immunizations, but also were more likely to have a child who lacked one or more doses of three high profile vaccines compared with parents who reported that none of their children had experienced an adverse event following immunization. two scenarios were seen as plausible. it may be that parents who were already concerned about vaccines before their child began the vaccination schedule were more reactive and thus sought medical attention for minor side effects (eg, fever) or nonrelated problems. it is also possible that an apparent adverse event following immunization that resulted in parents seeking medical attention for their child caused the parents' perception of vaccines to become more negative. both possibilities may result in parents declining future vaccines for their children. negative attitudes could be addressed by improving communication between clinician and parent. benefit-cost analysis research has shown that physician advice can produce benefits for health issues (eg, problem drinking). moreover, positive communication behaviors such as humor and soliciting questions are associated with lowered physician's risk of a malpractice suit. it may be that in this era of low vaccine-preventable disease incidence and increased public questioning of immunizations, improved provider communication can produce a positive net benefit for parents (reduced anxiety), a cost benefit to the health care system (reduced calls and medical visits for nonserious adverse events following immunization), and an improved physician-patient relationship (more trust and fewer malpractice suits). individual people can vary in their perception of the magnitude of vaccine risks. studies have shown that various factors such as sex, race, political worldviews, emotional affect, and trust are associated with risk perception. in addition, risk perception factors such as involuntariness, uncertainty, lack of control, and high level of dread can lead to a heightened perception of risks. all of these can be seen as associated with childhood immunizations. moreover, these factors have been referred to as "outrage" factors in the risk communication literature. outrage can lead to a person responding emotionally and can increase further the level of perceived risk. it can be difficult to communicate the risk of many vaccinepreventable diseases given their low prevalence in the united states and difficult to communicate the risks of serious vaccine adverse events because they affect such a small proportion of vaccine recipients. , several factors have been studied that might help people to better understand risk; the first are comparisons. comparisons that are similar (apples to apples) are reported to be better accepted, and, thus, comparisons for vaccines should focus on things that generally prevent harm in children but could pose a small risk (such as bicycle helmets, car seats). the second are visual presentations that help people understand numerical risk, including risk ladders, stick figures, line graphs, dots, pie charts, and histograms. unfortunately, there has been little research done in either of these areas. trust in the source of the risk information is an important factor in its ability to influence people and, as discussed, is developed through listening and ongoing communications. in , american adults had an average score of . on an index of biomedical literacy designed to measure understanding of biomedical terms and constructs. people with scores less than would likely find it difficult to understand medical stories about why antibiotics are not effective in combating the common cold and the relationship between certain genes and health. the main factors associated with biomedical literacy are the following: ( ) level of formal education, ( ) number of college-level science courses, and ( ) age. some characteristics of scientific literacy include the following abilities: ( ) distinguishing experts from the uninformed; ( ) recognizing gaps, risks, limits, and probabilities in making decisions involving a knowledge of science or technology; ( ) recognizing when a cause-and-effect relationship cannot be drawn; and ( ) distinguishing evidence from propaganda, fact from fiction, sense from nonsense, and knowledge from opinion. unfortunately, parental characteristics of those least motivated to obtain timely immunizations for their children are often characterized by low educational level of either parent. there is a wide gap in the level of biomedical understanding across the us population, and this gap emphasizes the need for tailored information. the need for tailored information applies to all areas of health, including childhood immunizations. immunization educational materials aimed at a middle level or a "one size fits all" are not likely to satisfy all parents' needs. the importance of educating parents concerned about vaccines why should we care about a small number of parents who are worried about vaccines for their children? we should care because it is not only ethically the right thing to do, it is also the right thing to do from a practical viewpoint. vaccine acceptability refers to the factors that go into parents' decisions to have their children immunized. it is important not to assume that just because most parents are having their children immunized that they will continue to do so. while the host of factors contributing to parents' decisions to have their children immunized (eg, need for information, experience with adverse events) might remain stable for some time, it is possible that one or more of the factors may change so that some parents perceive the risks of vaccines to be greater than the risk of disease. this would then push the parents above a theoretical "unacceptability threshold" in which they would choose not to have their children immunized with one or more vaccines. this is especially possible as more vaccines are added to the immunization schedule. an increasing number of parents have a choice, through religious or philosophical immunization exemption laws or schooling their children at home. averting the future possibility of outbreaks of vaccine-preventable diseases will take a concerted effort by health care and public health professionals to educate and better communicate with parents concerned about immunizations. in guidance for clinicians, the american academy of pediatrics suggests that pediatricians should listen carefully and respectfully to parents' immunization concerns, factually communicate the risks and benefits of vaccines, and work with parents who may be concerned about a specific vaccine or having their child receive multiple vaccines in one visit. providers can make a huge impact on vaccine acceptance, resulting in a cascading effect in which providing information can increase trust and increasing trust can lead to greater acceptance of and confidence in vaccines. for health care providers to be able to optimally fill this important role, however, two related issues should be addressed. the first is the need for quality communication courses and training in medical schools and residencies and training programs for medical and public health professionals. , the second is for mcos and medical insurance companies to adequately reimburse physicians for health education. lack of reimbursement to physicians has been noted as a barrier to implementation of behavioral treatments for health issues such as heart disease and smoking. it is important to note that studies have shown education programs can be a cost savings to health care systems. , we live in a world already benefiting from vaccines that exist, and there is the promise of more vaccines to come. the challenge we have now is to make sure that the promise is not lost because we did not present the benefits and risks of vaccines in a meaningful way acceptable to the public. an optimal immunization safety system requires rigorous attention to safety during prelicensure research and development; active monitoring for potential safety problems after licensure; and clinical research and risk management activities, including risk communication, focused on minimizing potential vaccine adverse reactions. prelicensure activities form the foundation of vaccine safety. rapid advances in biotechnology are leading to the development of new vaccines, and novel delivery technologies, such as dna vaccines and new adjuvants, are being developed to permit more antigens to be combined, reducing the number of injections. , new technologies can also be expected to be used to detect potential safety problems throughout the research and development process (eg, adventitial agents). a challenge will be determining the proper role and interpretation of new technologies. for example, a recent study used powerful new metagenomics and panmicrobial microarray technologies to screen for adventitious viral nucleic acid sequences in a number of vaccines. the study identified the presence of dna from porcine circovirus type (pcv ) in rotarix. this finding led to a temporary suspension of the use of the vaccine while the fda evaluated the study and its implications. ultimately, it was determined that the presence of the pcv nucleic acid sequences did not represent a health concern, and use of the vaccine was allowed to resume. in the prelicensure evaluation of new vaccines, the trend is likely to continue to conduct larger phase trials enrolling tens of thousands of participants. while such larger trials are helpful in identifying more rare adverse events, even these larger trials may not be large enough to detect increased risks of rare events. for example, the rotarix preclinical trial identified no increased risk of intussusception in a study that enrolled more than , infants. the manufacturer nevertheless committed to conduct a large postlicensure safety monitoring study. a preliminary analysis of postlicensure monitoring data from mexico identified a statistically significant increased risk within days of vaccination with an attributable risk of approximately per , . the attributable risk was much less than that found for rotashield (approximately per , ), and no changes were made to the vaccine recommendations. although technological advances and more thorough evaluation of safety before vaccines are licensed should lead to the development of safer vaccines, there will continue to be a need for comprehensive postlicensure safety monitoring systems. combined with the difficulties associated with identifying rare, delayed, or insidious vaccine safety problems in prelicensure studies, the well-organized consumer activist organizations, internet information of questionable accuracy, , media eagerness for controversy, , and relatively rare individual encounters with vaccine-preventable diseases virtually ensure that vaccine safety concerns are unlikely to go away. the existence of a robust vaccine safety monitoring system is essential for providing assurance of the safety of currently marketed vaccines and for rapidly identifying and responding to potential safety problems. currently, srss, such as vaers, serve as the frontline systems for the early identification of vaccine safety problems. such systems could be improved if reporting were more complete. application of web-based and text messaging technologies could make reporting easier and more accurate and also enable more active follow-up of vaccinated persons. alerts built into electronic medical record systems could also improve reporting to vaers, as could linkages with immunization registries. some of these advances will be particularly important to enable monitoring vaccine safety in mass vaccination campaigns during which vaccinations may be administered primarily outside of the traditional health care system. an optimal vaccine safety monitoring system must also include a mechanism or infrastructure to rapidly conduct formal epidemiologic evaluations of potential safety problems identified from srss or other sources. in the united states, this function is primarily served by the vsd project. the diffusion of electronic health records and the capability to link records across data systems (such as large health insurance claims databases and immunization registries) may allow the expansion of the population that could be included in postlicensure epidemiologic evaluations of vaccine safety. for example, the fda sentinel initiative has a goal to develop a national electronic system covering million people for monitoring the postmarket safety of drugs and other medical products, including vaccines. for adverse reactions that are established to be caused by vaccines, clinical and laboratory research is essential for determining the biological mechanisms of the adverse reaction, which in turn could lead to the development of safer vaccines. clinical research is also essential for the development of protocols for safer vaccination, including revaccination of persons who have previously experienced an adverse reaction. advances in genomics and immunology hold particular promise for elucidating biological mechanisms of vaccine adverse reactions and the development of possible screening strategies for persons who may be at high risk for an adverse reaction. a challenge for such research will be identifying sufficient numbers of people who may have rare vaccine adverse reactions and enrolling them into studies in which appropriate biological samples can be collected, stored, and analyzed under a standardized protocol. scientific data are essential in the monitoring and evaluation of vaccine safety, but scientific evidence alone often is not sufficient for providing reassurance about the safety of a vaccine. although immunization levels of us children are high, a sizable fraction of parents do not have their children fully immunized, and concern about vaccine safety is the leading reason for underimmunization. these concerns persist despite the scientific evidence that vaccines do not cause autism or a host of other conditions that have been alleged to be caused by vaccines, such as asthma, diabetes, and autoimmune diseases. thus, it is critically important that public health agencies, medical organizations, and other influential authorities continue to focus on the safety of vaccines and assure public confidence by providing clear, consistent messages on vaccine safety concerns; supporting effective and transparent vaccine safety monitoring systems and research activities; providing review and recommendations by respected independent expert groups on vaccine safety controversies; and engaging advocacy groups in constructive and open dialogue about their vaccine safety concerns. although the efforts of government, medical, and other authorities are important, it is health care providers who have the greatest influence in determining the acceptance of vaccines by individual people. even among parents who believe that vaccines may not be safe, most will have their children vaccinated if they have a trusting relationship with an influential health care provider. thus, development of tools and strategies that can assist health care providers in effectively communicating with their patients on the risks and benefits of vaccines will continue to be important. vaccine safety has also become an important concern in developing countries. the high-titer measles vaccine mortality experience highlighted the importance of improving the quality control and evaluating the safety of vaccines used in developing countries. plans to eliminate neonatal tetanus and measles via national immunization days, during which millions of people receive parenteral immunizations over a period of days, pose substantial challenges to ensuring injection safety, especially given concerns about inadequate sterilization of reusable syringes and needles, recycling of disposable syringes and needles, and cross-contamination resulting from the current generation of jet injectors. the who has promoted the use of safer auto-disposable syringes and disposal boxes. these and other new, safer administration technologies are urgently needed. in addition, there is a need to establish minimal vaccine safety monitoring capabilities, such as srss, and the capability to rapidly investigate vaccine safety problems and effectively communicate the findings of the investigations. vaccines are among the most successful and cost-effective public health tools for preventing disease and death. vaccines, however, are not completely without risk of side effects or other adverse outcomes. a timely, credible, and effective monitoring system, coupled with prompt action in response to identified safety problems, is essential to preventing adverse effects of vaccination and to maintaining public confidence in immunizations. since immunizations are typically administered to healthy people and are often recommended or mandated to provide societal and individual protection, vaccines must be held to a very high standard of safety. vaccine safety monitoring and research should optimally be able to detect potentially very small levels of increased risk, especially for adverse events that can result in death or permanent disability from vaccines that are universally recommended or mandated. the ultimate goal of such research, including the application of new developments in biotechnology, is to develop safer vaccines and vaccination practices. access the complete reference deadly choices: how the anti-vaccine movement threatens us all ensuring the optimal safety of licensed vaccines: a prospective of the vaccine research, development, and manufacturing companies active surveillance for adverse events: the experience of the vaccine safety datalink project understanding the role of human variation in vaccine adverse events: the clinical immunization safety assessment network addressing parents' concerns: do multiple vaccines overwhelm or weaken the infant's immune system? addressing parents' concerns: do vaccines cause allergic or autoimmune diseases? measles-mumps-rubella vaccine and autism thimerosal in vaccines: a joint statement of the american academy of pediatrics and the public health service autism's false prophets: bad science, risky medicine, and the search for a cure addressing parents' concerns: do vaccines contain harmful preservatives, adjuvants, or residuals we are grateful to robert davis, deborah gust, robert chen, and charles hackett who contributed sections of this chapter in previous editions of this book and for the excellent assistance on this chapter rendered by the following persons: dan salmon, john iskander, susan scheinman, christine korhonen, allison kennedy, michele russell, tamara murphy, penina haber, and gina mootrey. key: cord- -gxv y authors: alkhamis, moh a.; li, chong; torremorell, montserrat title: animal disease surveillance in the st century: applications and robustness of phylodynamic methods in recent u.s. human-like h swine influenza outbreaks date: - - journal: front vet sci doi: . /fvets. . sha: doc_id: cord_uid: gxv y emerging and endemic animal viral diseases continue to impose substantial impacts on animal and human health. most current and past molecular surveillance studies of animal diseases investigated spatio-temporal and evolutionary dynamics of the viruses in a disjointed analytical framework, ignoring many uncertainties and made joint conclusions from both analytical approaches. phylodynamic methods offer a uniquely integrated platform capable of inferring complex epidemiological and evolutionary processes from the phylogeny of viruses in populations using a single bayesian statistical framework. in this study, we reviewed and outlined basic concepts and aspects of phylodynamic methods and attempted to summarize essential components of the methodology in one analytical pipeline to facilitate the proper use of the methods by animal health researchers. also, we challenged the robustness of the posterior evolutionary parameters, inferred by the commonly used phylodynamic models, using hemagglutinin (ha) and polymerase basic (pb ) segments of the currently circulating human-like h swine influenza (si) viruses isolated in the united states and multiple priors. subsequently, we compared similarities and differences between the posterior parameters inferred from sequence data using multiple phylodynamic models. our suggested phylodynamic approach attempts to reduce the impact of its inherent limitations to offer less biased and biologically plausible inferences about the pathogen evolutionary characteristics to properly guide intervention activities. we also pinpointed requirements and challenges for integrating phylodynamic methods in routine animal disease surveillance activities. in the past few decades, genetic analysis of rapidly evolving pathogens has become an integral part of animal disease surveillance systems worldwide ( ) ( ) ( ) ( ) . most current and past molecular surveillance studies of animal disease pathogens of both public health and economical importance such as influenza ( ) ( ) ( ) , foot-and-mouth disease (fmd) ( ) ( ) ( ) , and porcine reproductive and respiratory syndrome (prrs) ( ) ( ) ( ) viruses are dependent on classical epidemiological and phylogenetic methods. these studies or surveillance systems used classical phylogenetic methods, including parsimony, neighbor-joining, or maximum likelihood (ml) approaches to either genotype novel emerging strains, classify viral lineages, or assess tree topologies to distinguish between novel and emerging strains ( , , ) . in addition, classical phylogenetic approaches were used to assess correlations between the similarities of nucleotide sequences and related epidemiological characteristics, while ignoring uncertainties associated with estimates of phylogenetic relationships, host, temporal, and spatial factors ( , , , ) . furthermore, they investigated spatio-temporal and evolutionary dynamics of the virus isolates in a disjointed analytical framework and made joint conclusions from both analytical approaches ( , , , ) . therefore, many of the past and current molecular surveillance studies of animal diseases have ignored that epidemiological and evolutionary dynamics of rapidly evolving viruses occur on approximately the same time-scale ( ) . thus, studying them in a unified analytical framework will refine their interpretations and limit biased conclusions to subsequently improving the related molecular surveillance activities. classical phylogenetic approaches are not capable of accounting for the uncertainties in evolutionary processes of rapidly evolving pathogens or integrating related epidemiological features into their phylogeny, which is an important advantage of bayesian phylodynamic methods. the bayesian phylodynamic methods were borrowed from the field of evolutionary biology and have become a powerful tool for exploring the evolutionary epidemiology of infectious pathogens ( ) ( ) ( ) ( ) . during the last two decades, the rapid growth of pathogens' genetic data and computational resources increased the applications of phylodynamic methods in animal and human disease surveillance ( ) . these methods are capable of accounting for uncertainties, and uniquely integrate complex epidemiological and evolutionary processes in populations using a single bayesian statistical framework ( , ) . this framework handles the parameters of the phylodynamic model as random variables, in which each parameter is set by a specified prior probability distribution (and a parallel inferred posterior probability distribution). therefore, this innovative quantitative integration improved disease investigation by answering novel epidemiological questions about the evolutionary history, spatiotemporal origins, within and between-host transmission, and environmental risk factors for rapidly evolving pathogens ( ) . in fact, during the last decade, phylodynamic models have become well-established tools for studying the evolution of animal viral diseases specially influenza ( ) , fmd ( ) , and prrs ( ) . besides, several studies advocated for the integration of phylodynamic methods in the routinely molecular surveillance pipelines of animal diseases with the objectives of reclassifying viral genotypes, distinguishing between emerging and endemic viral strains, and selecting proper vaccine strains ( , ( ) ( ) ( ) . these approaches will provide a robust platform for guiding the allocation of resources within a surveillance system, for example, targeting emerging strains with higher evolutionary rates or hosts at high risk of generating new strains, which subsequently will reduce the economic costs of sampling, control, and prevention activities. phylodynamic methods are implemented in many open-source statistical software packages, while the most popular user-friendly software package is formally known as bayesian evolutionary analysis by sampling tree (beast) ( ) . while past studies illustrated the great potential of phylodynamic tools, the methods are sensitive to the density and coverage of sequence sampling, selection of genetic regions, quality and quantity of the associated surveillance data, and prior selection for the evolutionary parameters ( , , ) . these limitations may result in biased posterior inferences, which subsequently lead to inaccurate or biological implausible conclusions about the evolutionary epidemiology of the pathogen under study (e.g., false divergence time or geographical origins). that said, most phylogenetic studies suffer from these inherent limitations. however, setting a thorough phylodynamic analytical pipeline, while acknowledging these limitations, can reduce their impact on the resulting posterior inferences and their related conclusions. unfortunately, many published phylodynamic studies ignored such limitations, particularly in their analytical approach, in which they used simple naïve priors for their evolutionary parameters while ignoring the underlying assumptions for these priors ( ) ( ) ( ) ( ) ( ) . for example, prior selection should adhere to the assumption that different pathogens have unique evolutionary characteristics ( ) , and therefore, using the same simple prior on different pathogens will likely lead to the conclusion that such pathogens behaved similarly during their evolutionary history. also, these studies ignored the impact of selecting different prior models on their posterior evolutionary inferences of the pathogen under study ( , ) . for example, the use of different prior models often leads to different conclusions about the geographical origins of the pathogen under study, and hence, bayesian model selection is a critical step in phylodynamic analysis pipelines ( , ) . there are many studies in the published literature comparing the results of phylodynamic models inferred from different gene segments or evolutionary parameters' priors ( ) ( ) ( ) . however, few studies raised concerns about the sensitivity of the results to the choice of different evolutionary models ( , ) as well as suggested a focused phylodynamic analytical pipeline for animal disease molecular surveillance ( ) . here, we demonstrate the basic principles for building a phylodynamic analytical pipeline, illustrate examples on the impact of gene segment and prior selection on the posterior evolutionary inferences, and highlight the prospects of the methods in improving animal disease surveillance. we selected a publicly available dataset compromising of full genome sequences for human-like h swine si collected as part of the united states department of agriculture influenza surveillance system between and as a working example. we provided a detailed description of a classical phylodynamic analytical pipeline encompassing both demographic and discrete phylogeographic reconstruction of the human-like h virus using beast. our phylodynamic analyses included comparisons between commonly inferred evolutionary posterior parameters (e.g., substitution rate/site/year, divergence times, phylogeographic root state posterior probabilities, significant dispersal route between states) under different combinations of node-age and branch rate prior models. furthermore, we extended this analytical pipeline into comparing posterior parameters inferred from ha and pb gene segments. interpretation of the resulting posterior inferences under different scenarios, described above, has been discussed in detail, and we highlighted examples of their misuse in past phylodynamic studies. our results identified the prospects and limitations of the presented phylodynamic pipeline in the context of animal disease surveillance on regional and global scales. furthermore, our results provide researchers and stakeholders of the swine industry in the united states valuable insights on decisions related to the sampling and sequencing of the influenza virus genome when conducting future phylodynamic studies and improving the design of currently implemented surveillance systems. the summary flow chart of our phylodynamic analytical pipeline is presented in figure . this bayesian statistical framework is popular and well-established for studying rapidly evolving pathogens as described elsewhere ( ) ( ) ( ) . the pipeline is divided into five steps (figure ) , in which two steps are dedicated to sequence preparation and curation of relevant viral lineages, while the following three steps are dedicated for phylodynamic analyses of the subsequently selected lineages. a critical step for a sound phylodynamic analysis is sequence preparation. this step can take two directions, depending on the study design and the objectives of the analysis. the first direction involves primary data analyses of novel sequences, in which they are either part of a designed study to identify the evolutionary characteristics of newly emerging viral strains ( , , ) or part of an ongoing active surveillance program ( ) . this direction usually includes the collection and sequencing of novel viral isolates from ongoing outbreaks. the second direction involves secondary data analyses of sequence collections published in publicly available genomic databases such as the genbank, to mainly explore the evolutionary history of specific pathogens either on regional or global scales ( , , ) . secondary frontiers in veterinary science | www.frontiersin.org sequence analysis can either target all available viral isolates or specific well-defined lineages (i.e., monophyletic clades) ( , , ) . to reduce the impact of sampling bias on the results of a phylodynamic analyses, it is essential to ensure the representativeness of the viral isolates under study to the available sequences data on both temporal and spatial scales. this step is most important for primary sequence analyses, in which the dataset under study needs to cover all close relatives of novel viral isolates published elsewhere. retrieving and combining relatives of novel viral isolates in a single dataset will warrant a proper inference of representative phylogenetic relationships of a tree topology based on all available related sequences. as on many occasions, novel sequences might belong to different distinct viral lineages published elsewhere ( , ) . the basic local alignment search tool (blast; https://blast.ncbi.nlm.nih.gov/blast.cgi) is the most popular tool for retrieving relatives of novel sequences (figure ) . finally, the retrieval process should include complete and near-complete sequences to avoid distorting the phylogenetic relationships between the novel and the related isolates. the integration of a pathogen's epidemiological characteristics into its inferred phylogeny is the ultimate justification for the preference of the phylodynamic approach over the classical phylogenetic methods. therefore, the thorough preparation of sequence metadata, which includes retrieval of information related to the isolate under study, is another critical step for a sound subsequent phylodynamic analysis. sequence metadata can be retrieved either from public genomic databases such as the genbank or from the related published literature. because phylodynamic methods largely depend on time-stamped data, this step starts with retrieving the data of collection for the viral isolates under study. thus, viral isolates with no temporal data are typically excluded from the analyses pipeline. next, the date of collection is converted into beast readable format known as fractional years to estimate divergence times. for example, a virus collected on april , , is converted into " . " as a fractional year, where " " is the year of collection, and " . " is the number of days from the beginning of that year till the day for sequence collection divided by the total number of days within a typical year. additionally, dates can be imported to beauti by a separate text file that include the complete date of sequence collection with explicit separators (e.g., -or /). however, in many instances, the complete date of collection is not available, in which it misses either the exact date or month of collection. therefore, we can either specify the age of the isolate as the mid-point of the corresponding month or year, respectively. other epidemiological characteristics such spatial or host information can be prepared in a separate text delaminated format with unique identifiers that link them to the isolates in the sequence dataset. isolates missing a none-temporal information should be kept in the analyses and are usually labeled with a question mark "?" to represent a missing information. in the context of the phylodynamic field, epidemiological characteristics such as country or host of origin are defined as a discrete trait and are described in more detail in the running and selecting phylodynamic models section. however, careful selection of these characteristics is recommended to be considered at the beginning of the analyses pipeline as a critical part of the data preparation for the subsequent analyses. geographical discrete traits can be defined as the country of origin where the pathogen was isolated or can be redefined on smaller or larger spatial scales such as administrative regions within a country ( ) or continental scale ( ) , respectively, depending on the study's hypothesis. besides the host of origin, other non-spatial discrete traits such as host and environmental attributes can also be defined as discrete traits ( ) . multisequence alignment (msa) is another primary key step in the data preparation stage of the pathogen's genetic data (figure ) . it is worth noting that alignment uncertainty, for example, in terms of the choice of alignment algorithm can affect the subsequent phylogenetic inferences, such as tree topology ( ) . however, the impacts of alignment uncertainties have not been reported with simple pathogens like viruses, mainly when dealing with small gene segments. therefore, this issue might be considered when dealing with whole genomes or with more complex pathogens like bacteria and fungi, which can be resolved by multiple sequence alignment averaging using different alignment algorithms ( ) . common alignment algorithms include clustal ( ) , t-coffee ( ) , and muscle ( ), while aliview is a user-friendly graphical interface that can deal with large sequence datasets and integrate multiple alignment algorithms ( ) . performing the multisequence alignment using an algorithm, and manually deleting the gaps within the translated alignment, are the most common steps for most phylogenetic studies ( ) . also, confirming the reading frame of each gene segment (excluding the ′ utr) by examining the amino acid translation is another step within the msa procedure. this step is commonly done, for example, for influenza virus ha and pb gene segments, and potentially for segments and , to account for the frameshifted m and ns genes. however, it is worth noting that this step is only important for partitioned nucleotide models, described below. phylodynamic analyses require both time and computational resources, and therefore, conducting exploratory phylogenetic analyses using classical methods is an essential step that will ensure the proper setup of the subsequent phylodynamic models' priors. classical methods for inferring basic phylogenetic trees (i.e., non-time-stamped trees) include the maximum likelihood (ml) ( ), maximum parsimony (mp) ( ) , and neighborjoining ( ) algorithms. inferring the basic phylogenetic tree of a sequence dataset will help in the preliminary assessment of the tree's topology in terms of the magnitude of structure across branches, degree of topological (in)congruence between different gene segments, and selection of lineages (in large datasets) for the subsequent phylodynamic analyses. classical phylogenetic algorithms are implemented in many open-source software packages such as mega ( ) and raxml ( ) . the rapid spread and transmission of viral diseases during epidemics provide plenty of time for the pathogen to accumulate informative mutations in their genomes ( ) . therefore, % identical sequences within a dataset dilute such information. also, retrieved sequence datasets suffer from inherent redundancy due to sampling bias and issues related to the sequencing procedure ( ) . hence, removing % identical sequences from the dataset under study, will reduce the impact of such redundancies, strengthen the tree structure, and shorten the computational time. furthermore, if the proportion of % identical sequences was substantially large, it will typically lead to weaker evolutionary signals and subsequently poorer phylodynamic model convergence. recombination is a natural biological phenomenon of rapidly evolving viruses like influenza and occurs when viral genomes co-infect the same host cell and exchange fragments of their gene segments resulting in new viral strains ( ) . ignoring recombination events in a sequence dataset may advisedly bias the inferred posterior phylogenetic relationships and, therefore, must be excluded ( ) . recombination events can be detected using the recombination detection program ( ) . however, recombination events are more often detected in whole genomes than in single-gene segments. therefore, conducting phylodynamic analyses on whole-genome sequences only will lead to the exclusion of many isolates resulting in a substantially smaller dataset and subsequently biased inferences. nevertheless, the occurrence of recombination events at the beginning of a novel viral outbreak might be limited. assessing the magnitude of temporal structure in the phylogeny of the sequences data collected at different points of time is the final recommended step within the preliminary phylogenetic analyses stage ( ) . here, the term "temporal structure" is defined as the measurable difference in terms of nucleotide or amino acid substitution between two genetic sequences sampled at two distinct points of time ( ) . therefore, if the sequence data lacks sufficient temporal structure, then proceeding to the phylodynamic analysis may lead to biased posterior estimates and misleading conclusions ( ) . an interactive regression-based approach is implemented in the tempest software package ( ) to assess the strength of the association between sequences' sampling dates and genetic divergence through time. r values closer to than estimated from a time-stamped ml tree using the root-to-tip genetic distance linear regression indicate a strong temporal structure ( ) . finally, tempest can identify incongruent sequences that are defined as outlier isolates that caused substantially more or less genetic divergence from the tip to the root than one would expect given their sampling date ( ) . incongruent sequences usually result from low sequencing quality, alignment errors, laboratory adopted and vaccine strains, as well as natural biological processes such as recombination. once the sequence dataset and their metadata are curated (by the past two steps, described above), we provide a variety of choices for selecting and running phylodynamic models depending on the objectives of the study. steps involving prior specification, simulations, and summarizing posterior inferences are all implemented in the beast software package ( ) . large evolutionary distances (i.e., substitution per site) between pairs of sequences caused by multiple substitution events through time can be underestimated when using simple distance measures (e.g., hamming distance) ( ) . hence, the distance correction technique provided by the substitution models can compensate for the underestimation of such large evolutionary distances ( ) . phylogenetic tree algorithms such as the ml approach incorporates substitution models that employs continuoustime markov chain (ctmc) models ( ) . ctmc models are stochastic methods that take values from a discrete state evolutionary space at random times, which is analogous to a nucleotide or amino acid substitution process, allowing for glimpsing the complete state history over the entire phylogeny where statistical inferences are drawn ( , , ) . out of many available substitution models, the hasegawa, kishino, and yano (hky) ( ) and the general time-reversable (gtr) ( , ) are the most common models used to infer the phylogeny of rapidly evolving pathogens. briefly, both substitution models assume a constant rate of evolution and have two major parameters, including a rate matrix (q) and an equilibrium vector of base frequencies. however, the hky model rate matrix has two exchangeability parameters, including one transition rate and one transversion rate parameters ( ) , while the gtr model has a symmetrical substitution rate matrix where all the exchangeability parameters are free ( ) . accommodating the rate variation across sites can be achieved by combining substitution models with site models such as the discrete gamma (Ŵ) model ( ) . however, when assuming that the evolution rate is equal to zero, the invariant site (i) model is combined with the corresponding substitution model ( ) . selection pressure in protein-coding genes of rapidly evolving pathogens, in terms of synonymous to nonsynonymous substitutions, usually occurs at high rates ( ) . this evolutionary phenomenon can affect estimates of divergence time and, therefore, need to be accounted for when selecting a substitution model ( ) . partitioning the gene segment into unique codon positions and assigning different substitution and site model combinations can accommodate the differences in the evolutionary dynamics within gene segments of the pathogen under study ( , ) . different substitution, sites, and codon partitioning models are implemented in many ml software packages as well as in beast. however, selecting the most realistic substitution/site model and partitioning scheme for the sequence data can be statistically achieved using either bayesian information criterion (bic) ( ), akaike information criterion (aic), or the corrected akaike information criterion (aicc) ( , ) . these ml-based statistical methods are wellimplemented in both partitionfinder ( ) and jmodeltest ( ) . yet, a more robust bayesian method for selecting a site model and an associated substitution model is implemented as an add-on package in beast .x ( ) . time-calibrated trees are modeled with the genetic differences between sequences through the molecular clock models, which is defined as the clock that occurs after a stochastic waiting time in the context of substitution rate ( ) . when assuming that the substitution rate across the branches is uniform over the entire tree, then the molecular clock model is defined as strict. however, changes in the rate of evolution of rapidly evolving pathogens usually differ between the subtrees of its inferred phylogeny, and therefore, relaxed branch-rate models account for the variation in the rate of molecular evolution from clade to clade across the branches of the tree ( ) . substitution rates across branches are assumed to be either autocorrelated ( ) (i.e., substitution rates are dependent) or uncorrelated ( ) (i.e., substitution rates are independent). the uncorrelated branch-rate prior commonly used for rapidly evolving viruses, in which the branch rates are drawn either from exponential or log-normal parent distribution ( ) . another alternative to the strict clock model is local molecular clocks, which can estimate different rates for different predefined branch groups within a tree ( ) . however, for large datasets, the manual task of assigning branches to different groups is impractical ( ) , and therefore, bayesian random local clocks can nest a series of local clocks with each extending over a group of branches within the full phylogeny ( ) . phylogenetic trees are inferred from individually sampled sequences to estimate the statistical properties of the population where the sequences were collected ( ). kingman's n-coalescent theory (i.e., node-age model) is the first stochastic model framework aimed at estimating the size of the sequences' population ( ) . the theory describes the distribution of coalescent times in the phylogeny as a function of the size of the population from which the sequences were drawn ( ) . hence, in the past few decades, the coalescent theory is the core of phylodynamic methods and has shown to be the most useful for inferring essential parameters that shapes the evolution and population dynamics of evolving populations including their effective size ( ), rate of growth ( ), structure ( ), recombination, and reticulate ancestry ( ) . expanding the temporal frame of sampling times is the ultimate approach for increasing the statistical power and precision of the coalescent model in estimating substitution rates and population demographics of rapidly evolving viruses ( ) . an essential evolutionary parameter estimated from the coalescent model is effective population size (n e ) at a specific time (t) and interpreted as the natural population that represents sample genealogies that have statistical features of an idealized population size through time n e (t) ( ) . however, such interpretation is only suitable for a non-recombinant single population, whereas complex populations with more frequent recombination events require the use of structured tree models ( ) described in the following section. estimating the posterior phylogeny of a well-mixed population with changing population size can be attained using either parametric or non-parametric node-age models ( ) . parametric node-age models accommodate standard continuous population functions, the simplest and most naïve, namely, the constant population growth (cp), which assumes that the population growth rate is zero ( ) . the other three parametric models include the logistic (lg) growth (assumes the population growth rate is decreasing over time), exponential (ex) growth (assumes the population growth rate is fixed over time), and the expansion (egx) growth (assumes the population growth rate is increasing over time) ( ) . one would expect, in the event of an epidemic caused by a rapidly evolving virus like influenza and in the absence of new vaccination, the population growth rate of the virus would realistically fit either an exponential or an expansion growth rate model ( , ) . unlike parametric node-age models, non-parametric models can be used to visually infer the history of population size through time (i.e., genetic diversity) from the sequence data in terms of inclines and declines ( ) . these models treat each coalescent interval as a separate segment to represent a parameter for population size in a given time, in which the number of segments can be specified by the investigator to generate a sky plot ( ) . the piece-wise constant bayesian skyline (bs) is the simplest non-parametric model, which assumes that the effective population size is experiencing an episodic stepwise changes through time ( ) . however, the bs model is shown to be very sensitive to the total number of change points (i.e., coalescent intervals) when specified as a prior as well as to the number of sequences sampled at each point of time ( ) . hence, a gaussian markov random fields bayesian skyride (gmrf) was proposed as an alternative model to bs ( ) . the gmrf model is less sensitive to the prior number of change points because it implements a temporal smoothing approach to recover accurate population size trajectories ( ) . however, an improved version of the gmrf is the skygrid (sg), which takes into account mutation parameters of multi-locus sequences ( ) . the sg provides a more realistic estimate of demographic history in terms of population size and divergence times, as well as flexibility in terms of the ability to specify cut-points to the time trajectories ( ) . furthermore, the sg model is the least sensitive to the temporal distribution of sequences ( ) . a notable example of sky plots utility in prrs virus molecular surveillance in the united states was demonstrated by alkhamis et al. ( ) and alkhamis et al. ( ) . their sky plot inferred a distinctly high genetic diversity through time for the emerging - - rflp-type prrv virus ( ), while inferred consistent seasonal increases and decreases in the relative genetic diversity through time for endemic strains isolated between and ( ) . mugration models are substitution models used to infer the migration processes of evolving organisms ( ) . the most notable implementation of a migration model was developed by lemey et al. ( ) using a ctmp to infer h n avian influenza virus's global origins and movements between countries. they used countries from which the sequences have been sampled as discrete traits to estimate migration rates between pairs of predefined sets of geographical locations, and therefore, the method is named discrete phylogeography ( ) . also, the method is known as discrete trait analysis (dta) because it has the flexibility to use any other discrete trait such as host or farm characteristics from which the sequences have been isolated to model migration rates between infected hosts and farms ( , ) . besides, the method can infer ancestral origins (i.e., from the assigned discrete traits) for the internal nodes of the phylogeny through their estimated root state posterior probabilities (rspp) ( ) . however, the most notable feature of discrete phylogeographic models is the integration of a bayesian stochastic search variable selection (bssvs) procedure to identify significant viral dispersal routes between geographical regions or host species ( ) . bssvs can also infer the significance of the directionality in the migration process between pairs of discrete traits through integrated symmetric and asymmetric substitution models. the symmetric (sym) model assumes that the transition rate from state "a" to "b" is the same as the transition rate from state "b" to "a" (i.e., directional spread between traits is insignificant), while the asymmetric (asym) model assumes that the transition rate from state "a" to "b" is different from the transition rate from state "b" to "a" (i.e., directional spread between traits is significant) ( ) . however, the lack of a sufficient number of sequences closer to the root of the phylogeny can impact accurate estimation of ancestral traits (i.e., ancestral geographical location or host) by the dta method ( ) . therefore, dta robustness can be improved by increasing the geographical density and temporal depth of sampling ( ) . dta is also limited by the type and number of variables that can be used to estimate ancestral states. therefore, the bssvs framework has been extended to accommodate a transitional rate matrix between discrete traits as a generalized linear model (glm) ( , ) . the method improves biological plausibility of the inferred rspp for the ancestral traitsby simultaneously estimating the inclusion probabilities of geographic, demographic, and environmental predictors ( ) . however, the method is shown to be more sensitive to sampling bias than the standard bssvs approach ( ) . hence, comparative sensitivity analyses to sampling bias between the approaches are recommended to avoid severely biased inferred rspps. in some settings, geographical boundaries cannot be defined by discrete spatial traits such as the distribution of wildlife hosts or disease vectors and, therefore, viral evolution and spread better modeled by continuous spatial diffusion models ( ) . when precise geographical information is available (i.e., longitude and latitude), continuous phylogeographic can reconstruct the viral spatio-temporal evolutionary history using relaxed random walk models ( ) . these models can additionally estimate viral dispersal rate in km /year and can distinguish whether the spatial diffusion process was homogenous (e.g., dispersal by air) or heterogeneous (dispersal by movements) ( , ) . in many instances, sequence samples tend to cluster within a geographical region leading to incomplete mixing and formation of structure in the population. this might bias the posterior inferences that estimated the coalescent phylogeographic models mentioned above. hence, the recently developed structured coalescent tree models for inferring phylogeography can simultaneously model the migration process between regions while allowing for those regions to have their unique coalescent rates ( , ) . unlike beast .x, beast .x has recently implemented several structured coalescent models for inferring geographic and between-host transmission histories, including bayesian structured coalescent approximation (basta) ( ) , structured coalescent transmission tree inference (scotti) ( ) , and marginal approximation of the structured coalescent (mascot) ( ) . the complexity of infectious disease transmission dynamics pushed the capacity of phylodynamic models beyond demographic and phylogeographic reconstructions into investigating traditional and new epidemiological problems. one notable example was demonstrated by volz et al. by developing a structured coalescent susceptible-infected-recovered (sir) model to infer reproductive numbers from viral sequences data ( ) . similar, but more complex, implementations of mathematical epidemiology in the phylodynamic models were described elsewhere ( , ) . prior phylodynamic models described above can be readily selected and set using a graphical user interface (gui) implemented within the beast software package, namely, the bayesian evolutionary analysis utility (beauti) ( , ) . after selecting and setting the models, the software generates a standard xml format structured text file allowing for flexible modifications for more sophisticated evolutionary models. however, the generated xml files are very complex in their structure, and therefore, manual modifications should be made by relevant experts to avoid the introduction of significant error into the model ( ) . additional tutorials on selecting and setting evolutionary models using beast .x are available elsewhere ( ) ( ) ( ) . phylodynamic model selection is a critical component of the analysis pipeline described in figure , simply because different pathogens or gene segments have different evolutionary processes. therefore, using a single phylodynamic model with similar priors to infer the evolution of multiple pathogens may be biologically implausible, leading to biased inferences. exploring the fit of the sequence data to different phylodynamic model combinations, in terms of substitution, branch rate, and node age to infer divergence times, time to the most recent common ancestor (tmrcas), evolutionary rates is the best strategy for ensuring accurate estimation of posterior inferences. for inferring viral demographic history, our suggested pipeline (figure ) leads to the generation of eight phylodynamic model combinations for a single gene segment, including the selected substitution model (by partitionfinder), two branch rate priors (uced and ucln), and four node-age priors (cp, ex, exg, and sg). however, when inferring phylogeographic history using dta, we suggest exploring both sym and asym bssvs models (figure ) , which will lead to the generation of models. our rigorous analytical pipeline is indeed timely and computationally demanding, but on the other hand, it will lead to the selection of the most realistic model that fits the sequence data with confidence. however, this suggested pipeline is not a strict set of procedures that will ensure appropriate inferences, and therefore, researchers may explore other model or analytical pipelines relevant to their evolutionary hypotheses. it is worth noting that the computational efficiency has been substantially improved in beast version . and the accompanied software library broadplatform evolutionary analysis general likelihood evaluator (beagle; permits flexible parallel computing) when compared to earlier versions. the fit of the sequence data to the most realistic phylodynamic model can be assessed through simultaneous estimating the marginal likelihood (mll) using the path sampling (ps) ( ) and stepping-stone sampling (ss) ( ) implemented in beauti using the standard settings (i.e., simulating across samples for million cycle from the posterior to the prior with a prior reflection point of beta [ . , . ]). the joint posterior probability density of the models' parameters is estimated by the mcmc algorithms. setting the appropriate length of the mcmc chains (i.e., number of cycles) to ensure model convergence is dependent on the number of sequences in the dataset. one recommended approach is to quadratically increase the chain length relative to the number of sequences (e.g., million states per sequence) ( ) . finally, creating duplicate runs from each generated model can aid in assessing the performance stability of the mcmc simulations and their mll estimates. mcmc log-files generated by beast can be thoroughly evaluated using a friendly gui software known as tracer ( ) . the software provides a simultaneous platform for summarizing and visualizing posterior estimates. appropriate model convergence can be evaluated by examining the mcmc mixing (based on acceptance ratios) using trace plots, after discarding the % of the sample (the "burn-in"). besides, assessing the estimates of the effective sample sizes (ess) for each parameter, in which ess values > , indicates good model convergence ( ) . on some occasions, good model convergence does not ensure consistent parameter estimation due to the use of non-informative priors implemented in beauti. therefore, it is critical to compare posterior parameter estimates (e.g., evolutionary rates, population growth rates, ps, and ss mll estimates) between independent runs for each model to warrant that each parameter is closely identical to its duplicate run. in case of improper model convergence and inconsistent parameter estimation, it is recommended to either increase the length of the mcmc chain or the use of informative priors from previous mcmc runs for the same gene segment or pathogen. model selection is achieved by comparing the bayes factor (bf) of the resulting mll estimates (from the ps and ss methods) of their corresponding candidate models ( ) . briefly, the bf value of the candidate models is summarized using a matrix and computed using the following equation: where y is the sequence data, m i is the candidate model "i, " m j is the competing candidate model "j, " and lnp (y|m) is the mll estimate by either ss or ps simulators. bf values estimated by the ss method are summarized on the upper off-diagonal of the matrix, while bf values estimated by the ps method are summarized on the lower off-diagonal of the matrix. a model with horizontal (i.e., row side of the maxtrix) bf values greater than other candidate models is selected. additional applied examples on model selection using beast .x are available elsewhere ( ) ( ) ( ) . the ultimate goal of the model selection procedure is to find the best fitting model that generated the data, while combining simplicity with biological realism, to appropriately represent the evolutionary characteristics of the pathogen under study ( , ) . inferred relative genetic diversity through time (or other reconstructed demographic trajectories) and its highest posterior density (hpd) interval can be summarized using sky plots (e.g., skygrid plot) generated by tracer. similarly, estimates of divergence time, tmrcas, and substitution rate/site/year with their hpd intervals can be summarized in tracer using either box or violin plots ( ) . also, tracer provides a flexible platform for simultaneous comparison of evolutionary estimates inferred by multiple phylodynamic models. next, the resulting marginal posterior probability density of the selected model is summarized as a maximum clade credible (mcc) tree using treeanotator ( ) to generate a tree file. mcc tree (from the tree file) can be then visualized and annotated with either posterior support values or rssps of the discrete traits at the internal nodes using figtree ( ) . in addition, figtree provides many customizable tree visualization options as well as it allows the users to upload additional information using a text file to annotate flexibly descriptions on the nodes and branches of the trees. spread is an interactive java-based parsing and rendering tool that can summarize and visualize phylodynamic reconstructions to infer spatio-temporal and trait evolutionary history ( ) . also, spread integrates javascript d libraries to provide a web-based visualization platform for phylogeographic trees and their related inferences by combining information from the mcc tree and geojson-based geographic map files ( ) . spread can generate a time-lapse that superimposes the mcc tree annotated with either discrete or continuous spatial traits on a map, which can be visualized using either gis-klm virtual globe software (e.g., google earth) or modern web-browsers (e.g., safari or chrome). this time-lapse demonstrates the epidemic reconstruction of pathogen evolutionary history through space and time, which can quantify the diffusion processes within and between geographical regions. furthermore, spread can identify and plot well-supported rates between pairs of discrete traits using bfs estimated from the symmetric or the asymmetric bssvs models. statistically significant rates with large bf values can be used to demonstrate critical viral dispersal routes between geographical regions or transmission cycles between host species. the spillover of h si virus from humans to swine in the early s in the united states resulted in a novel emerging virulent strain, which was antigenically distinct from endemic swine strains, and therefore was named "human-like" h virus ( ) . swine-related anthropological activities such as pig movement and vaccination are the most likely factors for the continuous emergence of si novel strains ( ) . therefore, integrating phylodynamic methods with influenza surveillance systems may reduce the continuous evolutionary implications of si viruses on both public and animal health in the united states and worldwide. here, we chose dta models for our comparative phylodynamic analyses example, due to their popularity, ease of use, interpretation, and computational efficiency when compared to more complex similar models. hence, we retrieved ha and pb nucleotide sequences of human-like h si from the influenza research database ( ) to explore their evolutionary history using our suggested phylodynamic pipeline, described above (figure ) . the data comprised sequences with complete date and geographical information for each gene segment and was collected from u.s. states (arkansas, illinois, indiana, iowa, kentucky, maryland, michigan, minnesota, missouri, north carolina, ohio, oklahoma, oregon, pennsylvania, south dakota, west virginia, wisconsin) between january , and june , . the sequence data were collected from the swine production systems and exhibition swine agricultural state fairs as part of the united states department of agriculture (usda) swine influenza surveillance program ( ) and was partially analyzed by walia et al. using classical phylogenetic methods ( ) . we aligned the sequences for both gene segments and assessed the topological (in)congruence of their phylogeny by performing an ml analysis for the individual segments using the gtr + Ŵ substitution model, which entailed through bootstrap searches with ml replicates in each run (supplementary figure ) . for the subsequent phylodynamic analyses, we removed recombinant and % identical sequences, which reduced the dataset to sequences for each gene segment (supplementary table ). we then evaluated the fit of the sequences to the most realistic substitution model and partitioning scheme using the bic approach. finally, we evaluated the temporal signal in the sequence data and found that both segments were suitable for the subsequent molecular clock analyses (r = . and . for ha and pb , respectively) (supplementary figure ) . we assessed the sensitivity of the inferred posterior evolutionary of human-like h si sequence data to the choice of different gene segments (i.e., ha vs. pb ) and phylodynamic priors, including substitution, discrete spatial trait, branch rate, and node-age models on the (figure ) . for each gene segment, we generated phylodynamic models (a total of runs for both segments) using the default none-informative priors' combinations implemented in beauti (figure ) . these prior models included: ( ) the gtr + Ŵ vs. the hky + Ŵ for the site models; ( ) the symmetric vs. asymmetric for discrete spatial models; ( ) the ucln vs. uced for the clock models; and ( ) the cp vs. the eg vs. the egx vs. the sg for the coalescent tree models (figure ) . we excluded spatial traits (i.e., u.s. states) with only one sequence (supplementary table ) leading to the inclusion of states in the subsequent dta. also, we evaluated the fit of the phylodynamic models to the ha and pb sequences using the bf comparisons of their mll estimated by the ps and ss simulator in order to select the most realistic model and correctly interpret its posterior inferences. we then used two replicate mcmc simulations for million cycles and sampled every , th state for each candidate model. after assessing for proper model convergence, we compared the inferred evolutionary demographics of each candidate model by summarizing their inferred divergence times, substitution rates, and tmrcas. besides, we then generated the sg plots to compare relative genetic diversity for ha and pb gene segments inferred from the two different sites and discrete spatial models. similarly, we compared the phylogeographic inferences of each model by generating mcc trees, summarizing the rspps of the states, and plotting them at the internal nodes of their corresponding trees. finally, we selected and plotted the statistically significant dispersal routes between states under each candidate model using a cutoff bssvs-bf ≥ . the bic values, described above, indicated that the hky + Ŵ is the best fitting substitution model for the ha gene segment (bic = , ), while the gtr + Ŵ is the best fitting substitution model for the pb gene segment (bic = , ). in addition, results of the bf values (≥ ) indicates that the best fitting branch-rate and node-age models to the sequence data were the sg + ucln for ha and sg + uced for pb segments (supplementary tables - ) . however, there were no significant changes in the posterior demographic inferences when choosing the opposite substitution model for both gene segments. similarly, our results indicate that the choice of discrete spatial and node-age models does not substantially change the estimated divergence times and substitution rates/site/year (figure ) for each gene segment alone. additionally, these estimates were also not sensitive to the choice of branch-rate models (i.e., uced and ucln). however, when comparing divergence times between segments, our results indicate substantial differences in a magnitude of ∼ years, in which the divergence time for the ha segment was around (figure a) , while for the pb segment, it was around (figure c) . no differences were observed in the substitution rates/site/year between the two gene segments, which were ranging between . × − ( % hpd; from . × − to . × − ) and . × − ( % hpd; from . × − to . × − ) for ha and pb segments, respectively (figures b,d) . similarly, posterior estimates of tmrcas were not sensitive to the choice of phylodynamic priors but were different between the two gene segments (figure ) . hence, based on the ha segment, our results hint that the oldest humanlike h strains emerged from the state of minnesota in mid- (figures a,b) , but with a notable overlap in the % hpd of the tmrcas inferred for other states (excluding maryland). however, results distinctly suggest that the youngest strains emerged from the state of maryland in early . results of the pb segment were inconclusive in terms of determining the oldest strains, but identical to the ha gene in identifying maryland as the state of the youngest viral strains (figures c,d) . also, the choice of spatial trait model did not affect our estimates of genetic diversity for both ha and pb segments (figure ) . our sg plots inferred seasonal variations in terms of increases and decreases, in the genetic diversity through time for ha segments (figures a,b) , while the genetic diversity of the pb segment gene slightly declined after (figures c,d) . our inferred phylogeographic posteriors did not show sensitivity to the selection of substitution or molecular clock priors. however, substantial differences were inferred when selecting different node-age and discrete spatial trait priors. inferences from both the cp and the ex node age with the asymmetric models implicated missouri as the most likely ancestral state for the human-like h virus currently circulating in the united states when using the ha gene segment (figures a,b) . however, the egx and the sg with the asymmetric models illinois and minnesota as the most likely ancestral states, respectively (figures c,d) . yet, when using the ha segment, the symmetric model with the cp, eg, and egx priors consistently implicated minnesota with approximately similar estimates of rspps (figures e-g) . in contrast, the use of the symmetric model with the sg prior implicated iowa as the ancestral location for the currently circulating human-like h strains (rspp = . ) (figure h) . interestingly, the ha sequence data uniquely favored this prior combination when using the bf comparisons for the best fitting phylodynamic model (supplementary tables , ) . our bf values suggested that the pb sequence data favored the asymmetric model with the sg prior, but with a very slight edge over the symmetric model with the same coalescent prior (supplementary tables , ). rspps inferred from the pb segment were almost equal for all states and, hence, were inconclusive, when using the asymmetric model with the four coalescent priors (figures a-d) . similarly, using the symmetric model with the four coalescent priors was inconclusive in terms of identifying the ancestral location for the currently circulating viral strains (figures e-h) . more specifically, the magnitude of differences between minnesota and missouri and in the inferred rspps, across different coalescent priors, was substantially small (figures e-h) . for example, when using the sg prior, the inferred rspps were . and . for missouri and minnesota, respectively ( figure h) . our bf-bssvs analyses, using the asymmetric model with the cp and the ex coalescent priors for the ha gene segment, suggest that the top three most significant unidirectional routes of viral dispersal (bf > ) were between minnesota, iowa, illinois, and missouri (figures a,b) . the inferred routes maintained their unidirectionality from the origin to the destination geographical locations, using cp and ex priors (figures a,b) . similarly, the order of statistical significance suggests that the route from iowa to minnesota is the most important for viral dispersal between states (figures a,b) . in contrast, the exg with the asymmetric model suggests that the route from ohia to indiana is substantially the most significant dispersal route (bssvs-bf = , ) ( figure c) . nevertheless, the sg prior agrees with the results of the cp and ex priors in inferring the route from iowa to minnesota as the most significant (bssvs-bf = ) (figure d) , while inferences from the symmetric model and the four coalescent priors consistently agreed that the top most significant bidirectional route of viral dispersal (bf ≥ ) was between indiana and ohio (figures e-h) . however, disagreements were inferred on the second and the third most significant routes when using the cp and ex on one side and exg and sg on the other (figure h) . dispersal routes inferred for pb (including the order of significance) were also sensitive to the selected discrete spatial model and slightly to the coalescent priors (figure ) . thus, when using the asymmetric model, the top two unidirectional routes included ( ) iowa → minnesota; ( ) indiana → kentucky (figures a-d) . while the cp, ex, and exg inferred the route from illinois to missouri as the third most significant route ( figures a-c) , the sg prior inferred the route from ohio to indiana as the third most significant route ( figure d) . finally, our inferred top three significant dispersal routes were from the symmetric model between ( ) indiana and ohio; ( ) minnesota and iowa; ( ) indiana and kentucky (figures e-h) . in the past decade, our phylodynamic pipeline became wellestablished and demonstrated powerful potentials to trace the evolutionary history of both animal and human pathogens making it an ideal tool for designing new molecular surveillance systems. in this study, we revisited essential concepts and definitions within the field of phylodynamic methods. also, we challenged the robustness of the posterior evolutionary parameters, inferred by the commonly used phylodynamic models, using two gene segments, of the currently circulating human-like h si viruses isolated in the united states, and multiple priors. subsequently, we compared similarities and differences between the posterior parameters inferred from ha and pb sequence data using multiple phylodynamic models. hence, we explored the robust and sensitive aspects of si phylodynamic models and highlighted the importance of model selection within their analytical framework. however, unlike classical phylogenetic methods currently implemented within the si surveillance system in the united states, we were able to reveal higher resolution insights into the evolutionary epidemiology of human-like h viruses by quantifying their demographic and phylogeographic history. therefore, animal health researchers and stakeholders need to be aware of the method's features, strengths, and limitations for generating reliable inference to guide future disease intervention activities properly. epidemiology of swine influenza in the u.s. based on the results of the best fitting phylodynamic models for both ha and pb segments, evolutionary rates of currently circulating human-like h viruses in the united states remain high with no apparent signs of substantial declines (figures b,d) and were similar to what was inferred elsewhere ( ). furthermore, inferred relative genetic diversity through time did not decline for the ha segment and showed evidence of seasonal variation between and (figures a,b) , while a slight decline in the genetic diversity was inferred for the pb segment between and (figures c,d) . these findings suggest that currently circulating human-like h viruses will continue evolutionary activity leading to the generation of novel strains, which is attributed to the frequent and continuous exchange of viruses between commercial and exhibition swine operations in the united states with the later as the epicenter of that exchange ( ) . our estimates of the tmrcas for ha segment slightly agree on the notion that the oldest h viruses diverged from earlier outbreaks in the state of minnesota, which is a central region for the swine industry in the united states (figure ) . however, the notable overlap in the inferred % hpds of the tmrcas between most states ( figure b ) suggest that the currently circulating strains are shifting their evolutionary dynamics in terms of re-emergence and dispersal when compared to earlier strains. additionally, both gene segments agree on the assumption that h outbreaks were recently introduced into the state of maryland (figure ) . the state of minnesota was inferred to be the ancestral location of human-like h viruses isolated from outbreaks observed between and ( ) , which agrees with our tmrcas inferred from ha segment (figure ) . however, results of the sg + ucln symmetric model, selected as the best fitting model for ha sequence data (supplementary table ) , implicates the state of iowa as the ancestral region (after ) for currently circulating human-like h viruses, followed by the state of minnesota as a secondary ancestral location ( figure h ). this is not surprising since iowa and minnesota share the most prominent swine production system in the united states with the highest swine density, unrestricted and intense movement of animals between states. although iowa and minnesota are the original hotspots of h viruses, our bssvs bf results showed a markedly significant viral dispersal route between indiana and ohio (bf = ) ( figure h ). this suggests that the h viral gene flow between ohio and indiana, inferred for - viruses remains a vital migration route since, particularly within exhibition swine populations ( ) . even though illinois and indiana formulate one swine production system, there was no significant viral dispersal route inferred between the states. despite the continuous nature of animal movement within the production system of minnesota and iowa, no significant dispersal route was inferred between the two states using the ha segment ( figure h) . nevertheless, using the pb segment, a highly significant dispersal route was inferred from iowa to minnesota, suggesting that iowa might be the new epicenter for virus dispersal of the currently circulating h lineages ( figure d ). this result is further supported by the significant migration route between iowa on one side and illinois and ohio on the other when using the ha segment ( figure h) . also, the inferred dispersal route between iowa and illinois ( figure h ) may reflect interstate movements of exhibition pigs ( ) . hence, the movements of exhibition pigs across the united states possibly led to expanding the spatial spread of h viruses to states with limited swine production systems ( ) . unlike the ha segment, rspps inferred from the most realistic phylodynamic model for pb sequences (i.e., asymmetric + sg + uced) (supplementary table ) did not yield conclusive results about the ancestral geographical origin of human-like h in the united states ( figure d) . instead, this result demonstrates a homogenous spatio-temporal diffusion process of the pb gene between states (figure d) , suggesting that the virus has maintained an endemic status across the united states after . also, results of the sg plot for pb , described above, showed an overall stationarity in its genetic diversity through time (despite the slight early incline and later decline) (figure c) , when compared to the ha gene (figures a,b) , supporting the notion of endemic status. however, using the pb segment, we inferred a notably significant dispersal route originating from iowa to minnesota (bssvs = ) (figure d) , reflecting a well-established swine transportation route within a production system, as described above. however, this route was not inferred as significant when using the best fitting model for the ha segment ( figure h) . these results may be attributed to the fact that pb evolutionary dynamics are moderately slower than the ha segment (figure ) in terms of strength of the temporal signal (supplementary figure ) , substitution rate (figure ) , and age of the segment (figure ) . therefore, the pb segment maintained similar evolutionary dynamics to earlier strains that emerged in minnesota and dispersed into iowa ( ) . yet, both ha and pb segment agree on the importance of iowa as a geographical region for dispersal of currently circulating h lineages (figures h, d) . additionally, we inferred two significant viral dispersal routes originating from kentucky to indiana and from ohio to indiana (figure d) , which further supports the role of exhibition of swine movements between states in maintaining the spread of h viruses. both dispersal routes are mainly maintained by the annual agricultural fairs where exhibition susceptible swine and humans from these states are frequently exposed to direct and indirect contacts from the same infected hosts ( ) . it is worth noting that the route from kentucky to indiana was hypothesized to be important for h gene flow between states, but past evolutionary analyses did not observe it due to the lack of sufficient samples ( ) . the uneven sampling of sequences in terms of temporal depth and frequency of associated discrete traits is an inherent limitation of most phylodynamic studies. for example, the inclusion of many recent sequences from a single geographical location may lead to a biased bottleneck effect in the shape of inferred population size through time when using a coalescent model from the skyline family ( ) . this issue can be resolved by designing studies with uniform probability sampling with respect to space and time ( ) . further, setting dta is user friendly and computationally more efficient when compared to more complex coalescent models, but it underlays a few assumptions, such as that the sequence sample size is proportional to the size of the selected discrete state ( ) . thus, including sequences from severely undersampled discrete traits will tend to produce unreliable posterior inferences, where for example, inferred rspps will be skewed toward oversampled areas. nevertheless, undersampling is a common problem, especially in passive surveillance data, and therefore, the use of structural coalescent models (e.g., basta) might be more appropriate ( ) . despite this inherited sensitivity of phylodynamic methods to uneven sampling, our posterior inference from the best fitting models showed remarkable robustness toward such limitation. although the largest number of collected sequences was in ( ) (supplementary table ) , estimates of relative genetic diversity through time did not show any striking jumps in that year for both ha and pb segments (figures b, d) . additionally, for the ha gene, iowa (with sequences) rather than ohio ( sequences) was inferred as the ancestral location ( figure h, supplementary table ) . however, seven out of the u.s. states were excluded from the dta due to the lack of sufficient sequences, and therefore, their role was unquantified in shaping the spatio-temporal evolution of si. yet, these states had substantially fewer swine-related activities as well as si outbreaks than analyzed states. further, we showed how the posterior estimates of demographic reconstruction were almost insensitive to the choice of different phylodynamic priors for each gene segment (figures - ) . however, inferred evolutionary estimates from different gene regions may differ ( ) or coincide ( ) due to the natural variation in their mutation rate over time. this raises the question of whether using longer gene segments or whole genomes provides deeper resolution into the evolutionary history of rapidly evolving pathogens. past influenza a studies ( , , ) , including the present study, showed that ha and na segments typically exhibit higher evolutionary rates than more conserved segments like pb and pb . subsequently, segments with higher evolutionary rate will also display stronger evolutionary signals, as described above. in our analyses, the width of the % hpds (i.e., length of the time scale) for the median age and tmrcas of pb were remarkably wider than the ha segment (figures , ) . this sizeable width of the posterior intervals reflects the magnitude of uncertainty surrounding inferences from the pb segment, as well as suggests that inferences from the ha segment were more precise (or robust) than the pb segment. also, we demonstrated how the pb segment failed to identify the ancestral geographical location of currently circulating h viruses ( figure d) . while, using the symmetric model, we inferred four candidate ancestral locations with inconclusive rspps (figure h) . further, nelson et al. ( ) were not able to infer a significant migration route between indiana and ohio using the pb segment. yet, we were able to infer this particular route as significant using both the ha and the pb segments (figures h, d) . additionally, scotch et al. ( ) confirmed agreements in the phylogeographic inferences between ha and na gene segments. this highlights another decisive question about the suitability and efficiency of using single, multiple, or whole genome when using phylodynamic methods for molecular surveillance of viral diseases. most researchers advocate for whole-genome analysis by either analyzing each segment alone or as concinnated segments. however, in the presence of a large number of sequences, these strategies are ill timed and require massive computational resources, making them inefficient for targeted and near-realtime surveillance systems. it is worth noting that substitution rate and divergence time inferred by alkhamis et al. ( ) using the fmd sat vp segment were similar to the evolutionary estimates inferred by lasecka-dykes et al. ( ) using wholegenome sequences, confirming the robustness of phylodynamic methods. nevertheless, the presence of recombination events can severely impact the robustness of phylodynamic methods leading to inferring biased evolutionary histories ( ) . hence, targeting the most rapidly evolving gene segment at the beginning of an epidemic may suffice molecular surveillance activities. that said, the choice between gene segments or the whole genome should depend on the evolutionary properties of the pathogen, frequency of recombination events, availability of resources, and objectives of the molecular surveillance system. as described above, phylodynamic inferences tend to be biased toward the available subsets of sequences data. hence, when analyzing novel sequence datasets, it is critical to combine them with genetically related lineages published in the scientific literature or publicly available databases to reduce the impact of sampling bias as well as improve the reliability and accuracy of posterior evolutionary inferences. unfortunately, several examples published in the scientific literature used phylodynamic methods on novel sequence datasets while ignoring their published relatives ( ) ( ) ( ) . this led to inferring mcc trees with unaccounted phylogenetic relationships such as nodes, branches, and roots. our worked example opens considerations for future work involving the use of more complex phylodynamic models, described above, to shed deeper insights into the evolutionary epidemiology of si. for example, when the exact geographical locations of the sequences are available, the use of continuous phylogeographic models will enable us to include all states in the analyses, including states with few sequences. besides, we can estimate the spatiotemporal dispersal speed of the virus as well as identify dispersal patterns (i.e., homogeneous vs. heterogeneous) across different geographical regions. also, the use of glm geographical models can directly quantify the importance of different environmental (e.g., climate) and demographical (e.g., pig density) factors in shaping the evolutionary history of si in the united states. finally, exploring the potentials of structured coalescent models in improving the reliability of inferences derived from basic dtas should be considered as well. the current surveillance programs rely heavily on collecting and analyzing spatial, temporal, and genomic aspects of an outbreak using classical statistical methods in a disjointed analytical framework. this disjointed framework suffers from many biases and is not capable of answering more profound epidemiological questions about the outbreak of current dynamics. using our suggested phylodynamic analytical pipeline, we were able to fulfill critical epidemiological questions about the emergence and evolution of currently circulating humanlike h si viruses in the united states, with the primary goal of guiding risk-based surveillance resources. for example, using inferences from the ha segment, we were able to identify the dates of epidemic introduction to each state. also, we were able to identify the geographic origins of the current outbreaks and observed their genomic-spatio-temporal diffusion process through time between states. also, we identified highrisk viral dispersal routes between states, rank-ordered their significance, and defined their directions. all of these are integral components of an effective risk-based molecular surveillance program, and the ability to achieve in real time is the future molecular surveillance of animal diseases. nevertheless, the availability of computational resources for designing an ongoing phylodynamic-based molecular surveillance system will always remain a challenge, especially for developing countries. that said, a few open-source software developed recently can perform basic phylodynamic analysis (e.g., estimate molecular clocks and infer evolutionary models) using an ml statistical framework, including timetree ( ), treedater r package ( ) , and least square dating ( ) . while the algorithms implemented in these software trades off the advantages of the bayesian framework, in the presence of large sequence datasets, they can produce evolutionary estimates similar to those estimated by beast using substantially less computational resources ( , , ) . nextstrain (https://nextstrain.org), which implements treetime is a futuristic working example of a web-based real-time molecular surveillance system for important human pathogens such as influenza, ebola, dengue, and the newly emerging corona viruses. this surveillance system has an on-going phylodynamic analytical engine that traces, in real-time genetic diversity, divergence times, geographical origins, and dispersal on global scales. the system updates the results of the mcc tree once new sequences are deposited in other web-based publicly available genomic databases. however, this project is achieved through rigorous and consistent global collaboration and data sharing. in the united states, resources for developing a similar system for tracing animal diseases are readily available. nevertheless, the chain of collaboration between researchers, government, and producers in the animal sector is hard to maintain due to logistic, economic, and educational (i.e., lack of awareness and skill in phylodynamic methods) reasons. nevertheless, recent scientific literature on the use of phylodynamic methods for animal disease surveillance is notably growing, which reflects the increased awareness between veterinarians about the capacities of such methods and the goodwill of the industry leaders to voluntarily share their data ( , ) . therefore, we anticipate a new era of animal disease prevention and control in the united states. in contrast, veterinary infrastructure in developing countries is severely lacking, in terms of reporting and data sharing, when compared to their human health sectors. consequently, the question related to the future of implementing phylodynamic methods in global animal surveillance remains unanswered. our selected phylodynamic analytical pipeline offers an integrated approach to not only answering more profound epidemiological questions about emerging and endemic animal diseases but also attempts to reduce the impact of its inherent limitations to offer less biased and biologically plausible inferences about the pathogen evolutionary characteristics to properly guide intervention activities. this study has highlighted the value of phylodynamic methods in improving current and future molecular surveillance efforts against animal diseases using human-like h si virus as a working example. we reviewed and outlined basic concepts and aspects of phylodynamic methods and attempted to summarize essential components of the methodology in one analytical pipeline to facilitate the proper use of the methods by animal health researchers. we also pinpointed 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over years phylodynamics of h n avian influenza virus in indonesia dynamics and evolution of highly pathogenic porcine reproductive and respiratory syndrome virus following its introduction into a herd concurrently infected with both types and treetime: maximum-likelihood phylodynamic analysis scalable relaxed clock phylogenetic dating phylodynamic applications in (st) century global infectious disease research. glob health res policy the study was designed by ma and mt. the data were collected and organized by cl. all statistical analyses were conducted by ma. ma, cl, and mt wrote the first draft of the manuscript. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/ . /fvets. . /full#supplementary-material conflict of interest: the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © alkhamis, li and torremorell. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- -o mh wz authors: olano, juan p.; peters, c.j.; walker, david h. title: distinguishing tropical infectious diseases from bioterrorism date: - - journal: tropical infectious diseases doi: . /b - - - - . - sha: doc_id: cord_uid: o mh wz nan bioterrorism can be defined as the intentional use of infectious agents or microbial toxins with the purpose of causing illness and death leading to fear in human populations. the dissemination of infectious agents with the purpose of attacking livestock and agricultural resources has similar motives. many of the agents that could potentially be used in bioterror (bt) attacks are also responsible for naturally occurring infectious diseases in the tropics. as such, naturally occurring outbreaks must be differentiated from bt attacks for public health, forensic, and security reasons. if a bt attack occurs in tropical underdeveloped countries, owing to their weak public health infrastructure, the public health implications would be even more dramatic than in developed countries. an outbreak of smallpox due to a bt attack would probably require vaccination and mandatory quarantine of millions of people in order to control the outbreak and quell global public unrest. this chapter will concentrate on selected infectious agents that have the potential to be used as bioterror agents in human populations. the first step in managing the damage from a covert biological dissemination is recognition of the attack and the organism(s). as in most emerging infections, we predict that in bioterrorist attacks the etiological diagnosis will be made by a clinician or pathologist and the recognition of a bioterrorist event will be through geographical and epidemiological anomalies. we have very limited environmental detection capability at this time, and there are no comprehensive pointof-care diagnostics for most of the high-impact bt agents. some diseases such as inhalational anthrax or smallpox may be relatively readily recognized by an alert clinician because of their very distinctive presentation in many cases. however, the leading edge of a bt epidemic may arrive on a pathologist' s doorstep without prior suspicion. for example, individual cases of pneumonic plague as the earliest harbingers of an attack will presumably present as community-acquired pneumonia and probably die without clinical diagnosis. given the short window available for successful treatment, the recognition of these earliest cases is paramount. sartwell has demonstrated empirically that incubation periods follow a log-normal distribution, which results in "front-loading" of cases ( fig. - ). delay in recognizing the epidemic through reliance on syndromic surveillance or other surrogates will likely result in most of the cases of diseases such as plague and tularemia being well into their disease course and perhaps unsalvageable. bioterrorist events will enlarge our knowledge of tropical diseases. for example, inhalational anthrax and several viral hemorrhagic fevers (vhf) thought to be transmitted mainly by aerosol are under-represented in naturally occurring case series, and a bt attack would provide an opportunity to answer questions about the underlying host factors and pathogenesis. indeed, the extension of the risk population to include children, the elderly, and the immunosuppressed is likely to provide considerable insight into these oftenunderstudied groups. it is also likely that our lack of information about them will challenge our current diagnostic algorithms. in october , anthrax spores were distributed covertly in the u.s. postal service, leading to cases of human anthrax and billions of dollars spent on controlling the potentially devastating effects of a small inhalational anthrax epidemic. , this attack was by no means the first intentional attempt to use infectious agents as weapons of terror. ever since the times of the ancient greeks and romans, humans have tried to inflict damage by the use of contagion on other populations. , less than % of the people or groups responsible for terrorist attacks on human populations take responsibility for their actions. therefore, the use of biological weapons is ideal to conduct covert attacks. in addition, it has been estimated that to kill the same number of human beings with biological weapons as compared to chemical or nuclear weapons, the cost is far less with biological weapons ($ /human casualty) compared with chemical ($ / human casualty) and nuclear ($ , , /human casualty) weapons. hypothetical bt attacks would range from an overt attack of a large city with a bomb containing several kilograms of an agent (weaponized bacteria, viruses, or toxins) to discrete or covert intentional release of the infectious agent through a delivery system, such as spray devices, postal service, ventilation ducts, water supplies, and food supply. based on transmissibility, severity of morbidity and mortality, and likelihood of use (availability, stability, weaponization), potential bt agents are divided into three categories (table - ) . this chapter will concentrate on selected agents from categories a and b and on the diagnostic challenges posed by illnesses caused by such agents. table - are capable of producing illness under natural circumstances. therefore, the first challenge is to identify the infectious agent responsible for a certain disease correctly, followed by a thorough epidemiologic and microbiologic analysis of the epidemic or outbreak. in some circumstances, the identification of a bt attack would be obvious. a case of smallpox in any human population is an international emergency that would trigger a massive response of the public health systems around the world. sophisticated epidemiological investigations would follow in order to characterize the outbreak, identify the source, and possibly label it "intentional." in other cases, the identification of the outbreak as secondary to intentional dissemination of an infectious agent will require the use of sophisticated epidemiological and molecular tools, especially for diseases endemic to the area where the outbreak occurs. the need to use genetic sequences as markers has spawned a new discipline referred to as microbial forensics, sister to phylogenetics and "molecular epidemiology." differentiation between natural infections and a biological warfare attack rests firstly on disease patterns given by several epidemiological clues. they include presence of disease outbreaks of the same illness in noncontiguous areas, disease outbreaks with zoonotic impact, different attack rates in different environments (indoor versus outdoor), presence of large epidemics in small populations, increased number of unexplained deaths, unusually high severity of a disease for a particular pathogen, unusual clinical manifestations owing to route of transmission for a given pathogen, presence of a disease (vector-borne or not) in an area not endemic for that particular disease, multiple epidemics with different diseases in the same population, a case of a disease by an uncommon agent (smallpox, viral hemorrhagic fevers, inhalational anthrax), unusual strains of microorganisms when compared to conventional strains circulating in the same affected areas, and genetically homogenous organisms isolated from different locations. , these are a few guidelines that could prove helpful when investigating an outbreak, but it has to be kept in mind that the deduction will not be based on any single finding but rather the pattern seen in its totality. first and foremost, the possibility of an attack must be ever in mind, or differentiation of a covert bt attack and a natural outbreak of an infectious disease may not be made. in fact, the outbreak of salmonellosis in oregon in was due to a covert attack planned by the rajneeshee leadership and accompanied by distinctive epidemiological clues. it was not labeled as intentional until somebody came forward with the information leading to the responsible group; as in most of medicine, the unsuspected diagnosis is the easiest to miss. an increasing number of public health departments are now acquiring the technology necessary to perform syndromic surveillance. this new method of surveillance is based on syndromic disease rates such as respiratory, gastrointestinal, and neurological syndromes or analysis of other health-related activities such as laboratory test requests and results, purchasing rates for certain pharmaceutical agents, unexplained death rates, and veterinary surveillance. , , the purpose of syndromic surveillance is to detect a bt attack as early as possible by analyzing the previously mentioned variables by extracting and analyzing data through computer networks. the rationale behind syndromic surveillance is the nonspecific nature of early signs and symptoms of many of the illnesses caused by bt agents. examples of proposed syndromes are as follows: gastroenteritis of any apparent infectious etiology, pneumonia with the sudden death of a previously healthy adult, widened mediastinum in a febrile patient, acute neurologic illness with fever, and advancing cranial nerve impairment with weakness. a key component factors affecting syndromic surveillance include selection of data sources, definition of syndrome categories, selection of statistical detection thresholds, availability of resources for follow-up, recent experiences with false alarms, and criteria for initiating investigations. it must be emphasized that these systems are experimental and not yet of proven value in managing bt attacks. they are expensive, require follow-up confirmation, have unproven sensitivity and specificity, and ultimately depend on the clinician. they may prove to be more useful in managing an event than in expeditiously detecting one. conventional epidemiological investigations are by no means obsolete with the availability of more sophisticated methods to study possible bt attacks. they include the confirmation of an outbreak once it is suspected. confirmation is based in many cases on laboratory analysis of patients' samples or autopsy material. a case definition is constructed to increase objectivity of the data analyzed and to enable determination of the attack rate. other variables are included in the analysis, such as time and place, and an epidemiological curve can be constructed. epidemiological curves are an important tool to analyze epidemics and suggest the mode of transmission and propagation. a point source epidemic curve is classically log-normal in distribution and would suggest a common exposure of a population to an infectious agent. of course, there can be variations depending on the presence of susceptible subpopulations (e.g., children, immunosuppressed, aged) and on varying doses of the agent. propagative curves are more characteristic of highly communicable agents such as smallpox. a short description of selected category a and b agents follows. all these pathogens are addressed as naturally occurring disease agents in other chapters of this book. bacillus anthracis (anthrax) b. anthracis (see chapter ) is without a doubt the microorganism that has received the most attention as a bt agent due to its high lethality (inhalational form), ease of propagation, and high environmental stability. fortunately, the disease is not transmitted from person to person. however, the first three characteristics make it one of the ideal bioweapons. anthrax presents in humans as four different clinical syndromes, depending on the portal of entry: cutaneous (the most common form of the disease resulting from contact with infectious animal products), gastrointestinal and oral/oropharyngeal (both secondary to ingestion of contaminated meat), and inhalational (woolsorter' s disease), secondary to inhalation of spores from the environment. in the event of a bioterror attack, either overt or covert, the clinical presentation of the patients affected by the attack would be that of inhalational anthrax. this form of anthrax is so rare that a single case of inhalational anthrax should raise immediate suspicion, as dramatically demonstrated during the bt attacks in the fall of . [ ] [ ] [ ] during those attacks, % of cases were cutaneous anthrax thought to be secondary to handling of anthraxlaced mail envelopes or environmental surface contamination in the presence of minor cutaneous lesions, providing a portal of entry for the spores. an outbreak of inhalational anthrax also took place in sverdlovsk (former soviet union) as a result of an accidental release into the air of b. anthracis spores from a facility producing anthrax for the bioweapons program in the ussr. , [ ] [ ] [ ] inhalational anthrax should be suspected clinically in any individual presenting with fever and a widened mediastinum on chest radiograph (due to hemorrhagic mediastinitis). , the incubation period is normally to days, but in some cases it can be as short as days and as long as days depending on inoculum and the time of germination of the spore. based on research performed on rhesus monkeys, the ld is estimated to be to , spores. [ ] [ ] [ ] however, as few as to spores may be capable of producing a fatal outcome in approximately % of those exposed to these quantities. the initial symptoms are nonspecific and consist of fever, malaise, anorexia, fatigue, and dry cough. these symptoms are followed in to days by an abrupt onset of respiratory insufficiency, stridor, diaphoresis, and cyanosis. the subsequent clinical course is rapid, and patients usually die within to hours after clinical deterioration. mortality is % without antibiotic therapy. , [ ] [ ] [ ] early diagnosis, aggressive treatment with antimicrobial agents to which the bacteria are susceptible, and aggressive supportive therapy decreased the mortality to % in the attacks. pathologic studies performed on the sverdlovsk victims confirmed some of the findings in animal models of inhalational anthrax, such as hemorrhagic lymphadenitis and mediastinitis. however, many patients also developed hematogenous hemorrhagic pneumonia. pleural effusions were usually large and frequently led to severe lung atelectasis. in about half of cases, hemorrhagic meningitis developed, leading rapidly to central nervous system (cns) manifestations terminating in coma and death. , , yersinia pestis (plague) y. pestis (see chapter ) is a gram-negative, aerobic, nonsporulating coccobacillus, member of the enterobacteriaceae with a wide host range, including rodents, felines, and humans. the most important reservoirs are urban rats, and its main vector is the rat flea. in rural epizootics, reservoirs include prairie dogs and squirrels in the united states. y. pestis has been responsible for some of the most devastating pandemics in human history in the preantibiotic era ( th, th, and th centuries). public health measures have made this disease a rarity in the united states (around cases/year) and around the world, although approximately cases are reported to the world health organization (who) every year (countries reporting plague include madagascar, tanzania, and peru, among others). clinical presentation in naturally acquired infections takes five forms, namely bubonic, septicemic, pneumonic, cutaneous, and meningeal. the pneumonic form is the most likely presentation in a case of plague due to a bt attack. it is worth mentioning that plague has already been used as a bt agent when japan dropped thousands of y. pestis-infected fleas over china leading to small outbreaks of bubonic plague in continental china during world war ii. , the incubation period for pneumonic plague is short, ranging from to days. it is the rarest form in natural infections ( % or less) but has the highest mortality, reaching % in untreated patients. the initial presentation is nonspecific and consists of cough, fever, and dyspnea. cough may be productive (bloody, purulent, or watery in the initial phases). this is followed by a rapid clinical course leading to respiratory failure and the patient' s demise if not treated with antibiotics early in the course of the disease. , , the factors that led to the severe manchurian pneumonic plague outbreaks in the early th century are unknown, but weather, hygiene, and crowding were important factors. more recent outbreaks worldwide and particularly in the united states have been much smaller and readily controlled. pneumonic cases are common in the united states, but secondary transmission has been rare in the last years. modeling of pneumonic transmission using eight small outbreaks to derive the parameters find average of secondary cases per primary case (ro) to be approximately . prior to any control measures. this is one of the most scientifically neglected microorganisms with bt potential. tularemia is a zoonotic infection caused by a strictly aerobic, gram-negative, nonsporulating small coccobacillus. two subspecies are recognized, namely f. tularensis subspecies holarctica (jellison type b) and f. tularensis subspecies tularensis (jellison type a). type a is by far the more virulent and is present only in north america. of the bacteria with potential as bt agents, f. tularensis has by far the widest host range, including wild and domestic animals, humans, fish, reptiles, and birds. vectors are also numerous and include ticks, fleas, mosquitoes, and biting flies. , this is an impressive range for any human pathogen. in contrast to other diseases described in this chapter, tularemia does not have the remarkable history that some of the other pathogens have. in europe, tularemia was first described in ; in the united states, it was first described in in california in the aftermath of the san francisco earthquake. in natural infections, the most common source of infection is a tick bite and manipulation of infected animals such as wild rabbits. six different clinical syndromes have been described as follows: ulceroglandular, glandular, oculoglandular, pharyngeal, pneumonic, and typhoidal. marked overlap exists among all these forms, and for practical purposes two syndromes (ulceroglandular and typhoidal) have been proposed. [ ] [ ] [ ] as a bt agent, f. tularensis will most likely cause a disease with a primary pulmonary component with secondary dissemination (typhoidal/systemic). in natural infections, both ulceroglandular and typhoidal forms can have a hematogenous pulmonary component, although it is more common in typhoidal forms. pulmonary features include cough, pleural effusions, and multifocal bronchopneumonic infiltrates. if not treated promptly, patients usually develop adult respiratory distress syndrome leading to respiratory insufficiency and the patient' s demise. case-fatality rate approaches % if not treated with appropriate antibiotics. smallpox eradication remains the single most important victory in the war against infectious diseases. smallpox (see chapter ) is the only disease so far eradicated from the face of the earth due to human intervention. the who declared smallpox eradicated in after the last case of natural disease was diagnosed in somalia in , and vaccination ceased around the world, rendering humankind vulnerable to reintroduction of the virus. [ ] [ ] [ ] a laboratory accident was responsible for two more cases in in england. this accident prompted the who to restrict the frozen virus to two places in the world: the cdc in atlanta, georgia, and the institute for polyomyelitis and viral encephalitides in moscow, later moved to npo vector, novosibirisk, russia. however, it is suspected that secret military repositories exist after the fragmentation of the soviet union and the subsequent exodus of scientists involved in its bioweapons program (biopreparat). , the agent responsible for this disease is an orthopox virus with no known animal reservoir, but high aerosol infectivity, stability, and mortality. although not a category a agent, monkeypox is responsible for outbreaks in africa and is the only other member of the orthopox genus capable of producing systemic disease in humans. the clinical disease is potentially indistinguishable from smallpox, where mortality rates in tropical africa are around % to %. in may and june , an outbreak of monkeypox occurred in the united states. thirty-seven infections were laboratory-documented and involved humans exposed to infected prairie dogs that had become infected because of contact with infected gambian rats and dormice, two animal species shipped from africa earlier that year. infected humans included veterinarians, exotic pet dealers, and pet owners. the clinical spectrum in this outbreak ranged from asymptomatic seroconversions to febrile illness with papulovesicular rash. no deaths were associated with this outbreak. however, phylogenetic analysis of the virus placed it in the west africa clade as opposed to the central africa clade which carries the previously mentioned case-fatality rate of % to %. a single case of smallpox would trigger a massive public health response in order to contain the outbreak. an outbreak in germany in resulted in cases with , people vaccinated to contain the infection. in , yugoslavia underwent an epidemic with a total of cases ( deaths) and a vaccination program that included million people in order to contain the outbreak and obtain international confidence. vaccination with the vaccinia virus (a related orthopox virus) is the most effective way to prevent the disease and can be administered up to days after contact with ill patients. strict quarantine with respiratory isolation for days is also mandatory. the newer generation of antivirals that have been developed after the disease was eradicated has never been tested in human populations, but in vitro data and experiments in animal models of poxvirus disease suggest some antiviral activity for the acyclic nucleoside phosphonates such as cidofovir. the only vaccine available in the united states is dryvax, and sufficient doses have been manufactured to cover the entire u.s. population. however, newer vaccines that may have fewer side effects are being developed. the clinical presentation is characteristic. the incubation period ranges from to days. the initial phase is nonspecific, common to other viral syndromes, and is characterized by abrupt onset of fever, fatigue, malaise, and headaches. during this prodromal phase in % of patients with fair complexion, a discrete erythematous rash appears on the face, forearms, and hands. the typical smallpox rash has a centrifugal distribution (that is, more abundant on the face and extremities than on the trunk and abdomen). an enanthem also develops with presence of oral ulcerations by the time the exanthem appears. systemic manisfestations begin to subside once the rash appears and can reappear with superinfection of skin lesions or superimposed bacterial bronchopneumonia. progression of the lesions is synchronous (maculopapules, vesicles, pustules). after pustules rupture, scabs form and detach in to weeks, leaving depigmented, scarred areas. this form of the disease, called variola major, is fatal in up to % of unvaccinated patients and % of vaccinated individuals. various hemorrhagic forms exist. in some cases, the rash progresses very slowly and hemorrhage develops into the base of the lesions, which remain flat and soft instead of tense, carrying a bad prognosis. in some other cases, the disease is hemorrhagic from the beginning, leading to death to days after the initial symptoms appear (case-fatality rate: %). finally, in some cases, a severe and overwhelming illness is followed by dusky skin lesions; these patients have a large quantity of virus and are extremely dangerous epidemiologically. previously vaccinated individuals usually develop a milder disease that consists of a mild pre-eruptive phase followed by few skin lesions that appear more superficial, evolve more rapidly, and are not as synchronous as the classical type. viral hemorrhagic fever (vhf; see chapter ) is caused by a heterogenous group of rna viruses that belong to several different families. the cdc identified filoviruses (ebola and marburg viruses), arenaviruses (lassa, junin, machupo, guanarito, and sabia), and bunyaviruses (crimean-congo hemorrhagic fever [cchf] and rift valley fever [rvf]). [ ] [ ] [ ] the common denominator in these infections is the increased vascular permeability in the microcirculation leading to hemorrhagic diathesis and systemic manifestations such as pulmonary edema and cerebral edema related to leaky capillaries. these viruses usually have a very narrow geographic range determined by their natural reservoirs and vectors. humans are accidental hosts. these diseases have caught great public attention due to their high mortality. this, combined with their aerosol infectivity, has led to the use of biosafety level laboratories in their study. clinical presentation is usually nonspecific and consists of fever and malaise, followed by signs of increased vascular permeability and circulatory compromise. vhf usually terminates in shock, generalized mucocutaneous hemorrhages, and multiorgan failure. differences exist among the clinical details and pathogenesis of the different viruses (see chapter for an overview and the individual chapters for details). for example, vhf due to filoviruses usually have prominent hemorrhagic manifestations and disseminated intravascular coagulation (dic) as a terminal event. rvf virus leads to liver damage, dic, and hemorrhagic manifestations in approximately % of patients with severe disease. cchf also behaves like the filoviral infections with prominent hemorrhagic manifestations. lassa fever has few neurologic or hemorrhagic manifestations. the south american arenaviral hemorrhagic fevers usually have hemorrhagic and neurologic components. toxins in the context of bt agents are substances of biologic origin that are capable of producing human illness. toxins are usually proteins synthesized by living bacteria, fungi, or plants. toxins are generally less dangerous than infectious agents. the most potent biological toxin is that from clostridium botulinum and it is -fold or more less lethal than anthrax on a weight basis. other toxins such as ricin are more than a -fold less toxic than botulinum toxin and sarin is -fold less toxic than ricin. there are seven similar toxins produced by seven different serotypes of c. botulinum (a to g), all leading to the same clinical manifestations and with the same lethality. the toxins have a molecular weight of approximately kda and block neurotransmission at the presynaptic level in cholinergic neurons including the neuromuscular junction, leading to progressive palsies of cranial nerves and skeletal muscle. botulinal toxins are among the most lethal substances known to mankind with ld of . μg/g of body weight when administered parenterally. , , the aerosol route decreases its lethality to times. both aerosol attacks and contamination of food supplies are potential bt scenarios. clinical manifestations consist of progressive bulbar and skeletal paralysis in the absence of fever, including diplopia, dysphagia, blurred vision, ptosis, dysarthria, dysphonia, mydriasis, dry mucosae, and descending paralysis. , the cause of death in lethal cases is respiratory insufficiency due to paralysis of respiratory muscles. onset of symptoms is variable and depends on the inoculum, ranging from hours to several days after exposure. most cases of naturally occurring intoxication are related to consumption of improperly sterilized canned food or ingestion of preserved fish. rare cases of inhalational botulism were documented in germany in the early s due to accidental laboratory exposure. the rapid absorption through the respiratory tract may offer a different pathogenesis and it is not known if antitoxin is useful in therapy, although animal models show efficacy in prophylaxis. all the agents in category a are generally recognized as serious threats for causing extensive casualties. categories b and c are much more heterogeneous. they were considered to provide significant threat potential but there are continuing reassessments. these conditions are caused by the genus alphavirus, family togaviridae (eastern, western, and venezuelan equine encephalitis [vee] viruses; see chapter ). natural infections are usually transmitted by mosquitoes, but aerosol transmission is the notorious cause of numerous laboratory infections and is the basis of its historic weaponization. , most of these viruses cause systemic illness characterized by fever, myalgias, and prostration. clinically apparent involvement of the central nervous system is present in some cases and varies among the different viruses. eastern equine encephalitis (eee) is by far the most virulent, leading to case-fatality rates of % to %, and survivors usually have severe neurologic sequelae. , vee, in contrast, leads to cns manifestations in no more than % of cases and almost all vee infections are symptomatic even in the absence of cns involvement. [ ] [ ] [ ] rickettsia prowazekii (epidemic typhus) and r. rickettsii (rocky mountain spotted fever) typhus (see chapter ) is another disease that has played a historic role in human populations. [ ] [ ] [ ] [ ] millions of people perished in world war i and world war ii due to epidemic, louse-borne typhus. large outbreaks of the disease still occur in tropical regions around the world in areas stricken by war, famine, and poverty. rocky mountain spotted fever (rmsf), on the other hand, is transmitted by tick bites and occurs endemically in south and central america as well as north america. rickettsiae target the microvascular endothelium leading to leaky capillaries systemically. the main causes of morbidity and mortality are noncardiogenic pulmonary edema and cerebral edema leading to diffuse alveolar damage and meningoencephalitis. clinical manifestations are nonspecific and include fever, malaise, headache, myalgias/arthralgias, cough, nausea, vomiting, confusion, stupor, and coma in severe cases. skin rash ranges from maculopapular to petechial, depending on the severity, and is observed in around % of patients with rmsf and % to % of cases of epidemic typhus, depending on the darkness of cutaneous pigmentation. rickettsiae are remarkably underestimated biothreats as they are highly infectious by low-dose aerosol exposure, possess a stable extracellular form, and are resistant to most empirically administered antibiotics, including β-lactams, aminoglycosides, and macrolides, and are exacerbated by sulfonamides. case-fatality rates can be as high as % to % without antibiotic therapy and % to % with adequate antibiotic coverage. lethal cases are usually due to delayed diagnosis. , , these rickettsiae are highly infectious by aerosol and are potent bt agents. they are often discounted because of their susceptibility to tetracycline and chloramphenicol. however, the severity of the illness, the exhaustion of antibiotics in the face of a mass attack, and the existence of antibiotic-resistant organisms suggest they are still formidable players. this gram-negative, obligately intracellular bacterium has a high degree of infectivity (one organism is capable of causing infection by inhalation) and low lethality. [ ] [ ] [ ] [ ] the distribution of q fever is worldwide and results from exposure to animals such as sheep, cattle, goats, cats, rabbits, and others. c. burnetii has spore-like characteristics that can withstand harsh environmental conditions and be transported by wind to other places. in natural infections, % of cases are asymptomatic and are diagnosed by seroconversion. in symptomatic cases, the presentation is nonspecific and includes malaise, fever, myalgias, cough, chills, headaches, anorexia, weight loss, and in some cases pleuritic chest pain. hepatomegaly and splenomegaly are sometimes observed, although not frequently. transmission occurs by exposure to infected animal products (meat, milk). less common routes of infection are inhalational and cutaneous. the clinical presentation of brucellosis is highly variable, even after inhalational exposure. the clinical spectrum ranges from asymptomatic seroconversion to severe acute systemic disease. intermediate forms include undulant fever or chronic disease, characterized by presence of brucella in virtually any organ. acute systemic disease is highly incapacitating with high fever, headache, nausea, vomiting, chills, severe sweating, and, in very severe cases, delirium, coma, and death. undulant fever is characterized by relapses of fever, weakness, generalized aching, and headache. chronic infections may have manifestations related to several organ systems such as the gastrointestinal and genitourinary tracts, cns, joints, and bones. [ ] [ ] [ ] developing countries with insufficient water treatment and food security are more vulnerable to enteric bt attack. these agents include shigella dysenteriae, salmonella spp., enterohemorrhagic e. coli, vibrio cholerae, and cryptosporidium parvum. shigella and salmonella have in fact already been used as agents of biorevenge or biopolitics in small-scale attacks: one (shigella) in an office setting by a disgruntled employee and one in oregon by a religious sect that led to nearly cases of salmonella-related gastroenteritis. , these agents are indeed ideal for small-scale attacks since large-scale attacks would require contamination of large water supplies which, because of enormous dilution factors and susceptibility of all these agents (except for c. parvum) to standard chlorinating procedures, would decrease the number of bacteria to below that required to infect large numbers of people. occasional outbreaks of nontyphoidal salmonella and shigella infections occur in the united states. shigella is a highly infectious organism that requires very low numbers ( - organisms) to provoke clinical disease. the illness caused by shigella and enterohemorrhagic e. coli is explosive and starts with fever, vomiting, severe abdominal cramping, bloody diarrhea, and systemic manifestations such as hypotension, and circulatory collapse if not treated rapidly. both microorganisms produce an exotoxin responsible for most of the systemic manifestations associated. a distinct complication, hemolytic uremic syndrome, occurs in a small percentage of cases, being more common in children younger than years of age, leading to renal failure and hemolysis. salmonella is less infectious and less explosive than shigella, and leads to fever, vomiting, diarrhea, abdominal cramping, and in some cases to typhoidal manifestations. imported cases of v. cholerae have been diagnosed in the united states in the past. however, the disease occurs in southern asia and latin america as large outbreaks. the clinical illness is characterized by explosive watery diarrhea that leads to rapid dehydration and circulatory collapse. c. parvum infections are characterized by watery diarrhea and abdominal cramping for to weeks. the disease is self-limited except in patients with acquired immunodeficiency syndrome (aids) or other conditions of compromise, in whom illness can last for months or years if immune function is not restored. c. parvum is resistant to standard chlorine concentrations in water supplies. the largest outbreak in this country occurred in milwaukee in the early s and was responsible for thousands of cases and increased mortality among those with aids. , , this section addresses other toxins considered of potential bt use, such as staphylococcal enterotoxin b (seb) and ricin toxin (derived from castor beans, which in turn are the fruit of the ricinus communis plant). the ricin toxin is composed of two glycoproteins of approximately , kda. the toxin inhibits protein synthesis by blocking elongation factor (ef ) at the ribosomal level. ricin toxin is not a weapon of mass destruction since its lethal dose in humans is much higher than previously believed. however, the use of the toxin in small bt attacks is possible in the tropics because of its ready availability and relatively easy extraction from the beans. clinical presentation depends on the route of administration as does the ld . in cases where large amounts of the toxin are ingested, the manifestations include nausea, vomiting, severe abdominal cramping, rectal hemorrhage, and diarrhea. as the clinical course progresses, anuria, mydriasis, severe headaches, and shock supervene leading to the patient' s demise in to days. clinical manifestations usually appear within hours after ingestion of the toxin. inhalational exposure leads to prominent pulmonary manifestations to hours after exposure and fever, dyspnea, progressive cough, cyanosis, and death. histologically, there is widespread necrosis of pulmonary parenchyma and pulmonary edema. a single case of parenteral intoxication was documented. a defector from bulgaria was injected with a pellet containing ricin from a weapon disguised in an umbrella, resulting in local necrosis, regional lymphadenopathy, gastrointestinal hemorrhage, liver necrosis, nephritis, and dic. staphylococcus aureus enterotoxin b (seb) is a -kda, heatstable exotoxin produced by certain strains of s. aureus and is responsible for food poisoning after ingestion of the preformed exotoxin in improperly handled food. in bt scenarios, exposure can occur either by inhalation or ingestion leading to seb food poisoning or seb respiratory syndrome. the toxin is highly incapacitating and not very lethal. the dose that causes symptoms in half of exposed persons and ld differ by a magnitude of log scales for inhalational exposure. thus, it is thought of as an incapacitating agent. incubation time after ingestion is short ( - hours) followed by explosive vomiting that persists for several hours. weaponization of the toxin as an aerosol is possible due to its high stability. manifestations after inhalation of the seb are related to the respiratory system and consist of fever, cough, chills, myalgias, chest pain, and pulmonary insufficiency due to alveolar edema. general symptoms and signs are universal and consist of multiorgan failure secondary to a cytokine storm. these toxins are superantigens due to their ability to bind to major histocompatibility complex (mhc) class ii molecules on large numbers of lymphocytes and macrophages, leading to a hyperactivation of the immune system and massive cytokine release including interferon-gamma (ifn-γ), tumor necrosis factor-alpha (tnf-α), interleukin (il- ), and other mediators such as leukotrienes and histamine. the role of the clinical laboratory in the diagnosis of possible cases related to a bt attack is of utmost importance. , on the one hand, standard clinical microbiology laboratories will be receiving specimens for diagnostic purposes, and communication with clinicians regarding their suspicions is critical. certain isolates in the laboratory are not pursued further (bacillus spp. is a classic example) unless specifically requested due to the frequent isolation of contaminants with similar characteristics. in addition, handling of certain specimens will require added biosafety level requirements due to their infectivity (table - ) . certain samples will have to be shipped to highly specialized laboratories for initial or further work-up. environmental testing is challenging due to the complexity of the samples to be analyzed. , this type of testing takes place in highly specialized laboratories and is not undertaken by the standard clinical microbiology laboratory. the bacterial diseases caused by the bt agents outlined in this chapter, with the exception of c. burnetii and rickettsia spp., can be diagnosed by standard isolation techniques in clinical microbiology laboratories. isolation of rickettsiae and the bt viruses requires specialized laboratories with bsl- or bsl- biocontainment. serological assays are available for detection of antibodies against all bt agents. however, for many organisms serological assays require the presence of rising antibody titers, and therefore the serologic diagnosis is usually retrospective in nature. for some viral diseases, a reliable diagnosis can be established based on elevation of immunoglobulin m (igm) titers in the acute phase of the disease. with the advent of molecular techniques, rapid and sensitive diagnostic tests are becoming available for bt agents during the acute phase of the disease. [ ] [ ] [ ] this is of utmost importance in a bt event since identification of the first cases would be critical for a rapid and effective public health response. in addition, treatment and prophylactic measures can also be initiated as quickly as possible. molecular diagnostic techniques can be applied to potential bt agents in an additional setting: as part of the epidemiological and forensic investigations that a bt attack would immediately trigger. postmortem diagnosis is also possible by analysis of frozen or paraffin-embedded tissues by immunohistology or nucleic acid-based amplification techniques. rapid diagnosis of the initial case (cases) in a bt event requires a high degree of clinical suspicion from the physicians having contact with such patients in the emergency room or outpatient setting. the clinical laboratories would then play a critical role in detecting the suspected agent and/or referring the appropriate specimens to higher level laboratories for specialized testing (table - ) . , , several of the agents discussed in this chapter are zoonotic diseases. therefore, diagnosis of certain zoonotic diseases in animals may be important in identifying some bt attacks. in such situations, animals could be seen as either direct victims of the attack or as sentinel events in a human outbreak. there are currently efforts to establish a network of laboratories dedicated to diagnosis of veterinary agents. bsl- suitable for work involving well-characterized agents not known to cause disease in healthy bacillus subtilis adult humans and of minimal potential hazard to laboratory personnel and the environment. naegleria gruberi canine hepatitis virus bsl- suitable for work involving agents of moderate potential hazard to personnel and the measles virus environment. laboratory personnel have specific training in handling pathogenic agents salmonella spp. and are directed by competent scientists; access to the laboratory is limited when work toxoplasma spp. is being conducted; extreme precautions are taken with contaminated sharp items; and hepatitis b virus certain procedures in which infectious aerosols or splashes may be created are conducted in biological safety cabinets or other physical containment equipment. bsl- suitable for work with infectious agents which may cause serious or potentially lethal coxiella burnetii disease as a result of exposure by the inhalation route. in addition to the requirements rickettsia spp. described for work in bsl- environment, all procedures are conducted within biological m. tuberculosis safety cabinets, or other physical containment devices, and by personnel wearing alphaviruses appropriate personal protective clothing and equipment. laboratory should be located in a separate building or an isolated zone within a building. laboratories are equipped with double door entry, directional inward flow, and single-pass air. bsl- required for work with dangerous and exotic agents that pose a high individual risk of filoviruses aerosol-transmitted laboratory infections and life-threatening disease. members of the arenaviruses laboratory staff have specific and thorough training in handling extremely hazardous infectious agents. they are supervised by competent scientists who are trained and experienced in working with these agents. access to the laboratory is strictly controlled by the laboratory director. the facility is either in a separate building or in a controlled area within a building, which is completely isolated from all other areas of the building. all activities are confined to class iii biological safety cabinets, or class ii biological safety cabinets used with one-piece positive pressure personnel suits ventilated by a life support system. the biosafety level laboratory has special engineering and design features to prevent microorganisms from being disseminated into the environment. the diagnosis of inhalational anthrax is based on isolation and identification of b. anthracis from a clinical specimen collected from an ill patient. in cases of inhalational anthrax, samples of sputum, blood, or cerebrospinal fluid (csf) may yield growth of the agent. demonstration of b. anthracis from nasal swabs has more epidemiological and prophylactic implications than clinical importance. standard diagnostic techniques are based on visualization and isolation in the clinical microbiology laboratory and serological demonstration of antibodies against b. anthracis. [ ] [ ] [ ] [ ] [ ] visualization of b. anthracis from clinical specimens (blood cultures, csf, and cutaneous lesions) by gram stains is not difficult. b. anthracis appears as large gram-positive, spore-forming rods with a bamboo appearance. isolation is achieved by inoculating standard sheep blood agar plates, and colonies appear as small, gray-white, nonhemolytic colonies. a selective medium (polymyxin-lysozyme-edta-thallous acetate agar) is available mostly for environmental samples and inhibits the growth of other bacillus spp., such as b. cereus. growth is rapid ( - hours) . confirmatory tests include γ-phage lysis, detection of specific cell wall and capsular antigens, and polymerase chain reaction (pcr) amplification of dna followed by sequencing. serological tests available for clinical diagnosis are based on detection of antibodies directed against protective antigen (pa). cross-reactive antibodies decrease the specificity of this test. assays based on toxin detection are available in specialized centers and are based on capture of anthrax toxins by using antibodies. antibody-coated immunomagnetic beads are then analyzed by electrochemiluminescence technology. the analytical sensitivity of this technique for detection of anthrax toxin is at the picogram to femtogram level ( − to − ). , immunoliposomal technology combined with real-time pcr (for a dna reporter sequence) is also in the early stages of development for several toxins (ricin, cholera, and botulinum) and appears promising with analytical sensitivity in the attomolar to zeptomolar ( − to − ) range for cholera toxin. the specificity of this assay is given by the toxin-capturing antibody. nucleic acid amplification techniques (pcr) are also available both in standard format and real-time format. extraction of dna from spores is challenging and requires modification of dna extraction protocols in order to facilitate release of dna from spores or induction of germination prior to dna extraction. real-time pcr tests have been developed by applied biosystems (taqman ' nuclease assay) and roche applied science (lightcycler). [ ] [ ] [ ] the analytical sensitivity of both techniques is extremely high, and testing times have been decreased to to hours. portable pcr instruments are being developed for rapid deployment to the field. examples include the rugged advanced pathogen identification device (rapid), the smartcycler (cepheid, ca), and the miniature analytical thermal cycler instrument (matci) developed by the department of energy' s lawrence livermore national laboratory. this instrument later evolved into the advanced nucleic acid analyzer (anaa) and handheld advanced nucleic acid analyzer (hanaa). molecular subtyping of b. anthracis is also possible by using the s ribosomal rna (rrna) subunit gene, multiplelocus vari-able number tandem repeat analysis of eight genetic loci, and amplified fragment length polymorphism (aflp) techniques. , environmental testing also plays a role in the investigation of a bt event. in this setting, detection of b. anthracis relies heavily on molecular techniques for confirmation of potentially contaminated samples (e.g., surfaces, air). , postmortem diagnosis is also possible by using gram stains on paraffin-based tissues or immunohistochemical procedures using polyclonal or monoclonal antibodies against various anthrax antigens. diagnosis of y. pestis is based on demonstration of the bacillus in blood or sputa from patients. standard diagnostic techniques in the laboratory include visualization of gramnegative coccobacilli, which by giemsa, wright, or wayson stains reveal a "safety pin" appearance. isolation is performed in blood and mcconkey agar plates on which colonies appear as nonlactose fermentors. the organisms are identified preliminarily by direct immunofluorescent assay with y. pestisspecific antibodies, with final identification based on biochemical profiles in clinical microbiology laboratories. molecular diagnostic techniques based on real-time pcr have become available in recent years and involve detection of y. pestis genes such as plasminogen activator (pla), genes coding for the yop proteins and the capsular f antigen, and the s rrna gene, which allows distinction from other yersinia spp. [ ] [ ] [ ] assays have been developed to detect resistance to particular antibiotics. the importance of these diagnostic techniques in a disease such as plague is evident. the log-normal epidemic curve with a narrow dispersion of the incubation periods (see fig. - ) and the short interval for successful antibiotic therapy mandate recognition of the earliest cases if the bulk of the exposed are to be saved. molecular subtyping of y. pestis is also possible by analyzing polymorphic sites in order to identify the origin of strains in the event of a bt attack. diagnosis is made in the clinical laboratory by demonstration of the microorganisms in secretions (sputa, exudates) by direct immunofluorescence or immunohistochemically in biopsy specimens. isolation in the clinical laboratory may be achieved by using regular blood agar plates, posing a risk to laboratory personnel not employing bsl- facilities and procedures. the procedure for isolation of f. tularensis in the laboratory is very similar to that described for y. pestis. final identification in the clinical laboratory is based on the biochemical profile. molecular diagnostic techniques are based on pcr detection of f. tularensis by using primers for different genes such as outer membrane protein (fop) or tul and real-time detection systems. , , smallpox virus diagnosis of variola major is suggested by its clinical presentation and the visualization of guarnieri bodies in skin biopsy samples. preliminary confirmation requires visualization of the typical brick-shaped orthopox virus by electron microscopy, followed by isolation from clinical specimens and accurate molecular identification to differentiate it from the morphologically (and sometimes clinically) similar monkeypox virus. confirmation of this diagnosis is performed only under bsl- containment facilities at the cdc. molecular techniques are based on pcr amplification using real-time or standard technology followed by sequencing or use of restriction fragment length polymorphism (rflp) for accurate identification. technologies so far developed for smallpox molecular testing include taqmanand lightcycler-based assays with primers designed for the hemagglutinin gene and a-type inclusion body proteins. [ ] [ ] [ ] [ ] sequencing of the smallpox genome has been completed for some asian strains of variola major and one of variola minor. other strains are being sequenced and will provide more information for probe design and treatment targets. diagnosis of these diseases is performed in highly specialized centers in the united states because special isolation procedures and highly contained laboratories are required. initial diagnosis of these diseases is suspected on clinical and epidemiologic grounds. laboratory diagnosis involves isolation, electron microscopy, and serological assays. immunohistochemical detection of hemorrhagic fever viral antigens in paraffin-embedded tissues is also performed in highly specialized centers such as the cdc. [ ] [ ] [ ] [ ] [ ] molecular diagnostic techniques have also improved dramatically during the last few years. serum or blood is the most common specimen used for reverse transcriptase-pcr amplification of viral nucleic acids. both standard and realtime techniques are available. design of primers for this heterogenous group of rna viruses that are highly variable is one of the limitations. therefore, multiplex pcr techniques are required to detect as many targets as possible in a single assay. , real-time pcr based on detection of the target sequence using fluorescent probes therefore limits the number of targets that can be identified because of the limited wavelength range for fluorescent applications (usually only four different wavelengths can be detected at the same time). [ ] [ ] [ ] the use of microchips containing several thousands of oligonucleotides from all viruses known to be pathogenic to humans is an encouraging development. in fact, the rapid identification and characterization of the novel human coronavirus responsible for the sars outbreak in is an excellent example of the power of hybridization-based microchips. the creation of an automated and easily deployable instrument capable of detecting all possible potential bt agents based on highly sensitive techniques such as electrochemoluminescence (ecl) or pcr would be ideal. the nonspecific nature of presenting symptoms is a major problem with several of the agents. the rapid recruitment of cases into the infected cohort requires that an early diagnosis of the epidemic be established, particularly for organisms such as y. pestis in which there is only a short window for successful treatment. in fact, such projects are already in the making. an example of this system is the automated biological agent testing system (abats) that combines the techniques mentioned previously. the system is the result of integrating several commercially available technologies into a single automated and robotized instrument for detection of viruses, bacteria, and parasites considered potential bt agents. the technologies incorporated into this "super system" include automated specimen preparation (both nucleic acid-based and protein-based such as immunodiagnostics), thermocyclers for pcr detection, chemiluminescent detectors for immunobased assays, sequencers, and software programs for sequence analysis. rickettsia prowazekii (epidemic typhus) and r. rickettsii (rocky mountain spotted fever) diagnosis of these infections in the clinical microbiology laboratory currently rests on the identification of antibodies in serum during the acute and convalescent period in order to demonstrate seroconversion or rising titers. the diagnosis is therefore retrospective. , detection of rickettsial dna from blood or skin samples during the acute phase of the disease is possible via pcr assays. however, these assays are not standardized and are not commercially available. primers have been designed for amplification of several rickettsial genes including citrate synthase, -kda protein gene, ompa, and ompb. [ ] [ ] [ ] [ ] [ ] the clinical sensitivity and specificity of standard or real-time pcr techniques have not been determined. most likely real-time pcr is superior due to the higher analytical sensitivity of this technique and low risk of sample contamination with dna amplicons when compared to standard pcr amplification methods. isolation of rickettsiae from clinical specimens is performed in very few specialized laboratories in the nation and requires the use of cell monolayers, embryonated eggs, or animals. detection of rickettsial antigens or whole bacteria in blood specimens is theoretically possible by using ultrasensitive methods, but such assays are currently only in the early phases of development. immunohistochemical detection of rickettsiae in paraffin-embedded tissue has also been applied to tissue samples obtained pre-or postmortem. [ ] [ ] [ ] salmonella spp., shigella dysenteriae, vibrio cholerae, and cryptosporidium parvum (acute enteric syndromes) diagnosis of salmonella, shigella, and vibrio infections is based on isolation of the offending agent on standard microbiological media in the clinical laboratory, followed by specialized confirmatory tests to identify the specific serotype involved. diagnosis of c. parvum is based on visual identification of the protozoan in fecal specimens by using modified trichrome stain. the diagnosis rests on serological demonstration of antibodies by immunofluorescent assay (ifa) or enzyme-linked immunosorbent assay (elisa). antibodies remain elevated for years after the acute infection, and therefore a fourfold rise in titers is the gold standard for diagnosis. pcr detection of c. burnetii dna from blood or tissues also yields a diagnosis of q fever. brucella spp. diagnosis of brucellosis requires a high degree of clinical suspicion due to the protean manifestations related to this disease. laboratory diagnosis is based on isolation of the microorganism from blood, bone marrow, or other tissue samples. isolation is not easy due to the slow-growth of brucella spp. colonies usually appear after to weeks, and therefore communication with the clinical laboratory is important so that appropriate media will be used and the cultures will be held long enough for colonies to be detected. serologic assays for demonstration of rising antibody titers are available, although the diagnosis is retrospective. pcr detection is promising, but it is not standardized. [ ] [ ] [ ] alphaviruses (encephalitic syndromes: venezuelan, eastern, and western equine encephalomyelitis) diagnosis is based on isolation of the virus from serum or brain (postmortem specimens) in a bsl- environment. pcr detection of viral sequences is also possible. serologic diagnosis is based on demonstration of antibodies in acute and convalescent sera. [ ] [ ] [ ] botulinum toxins the diagnosis of botulism relies heavily on clinical parameters. an afebrile patient with signs and symptoms of progressive bulbar palsies and descending neuromuscular paralysis is highly suspected of having botulism. demonstration of the toxin in cases of botulism due to ingestion of contaminated food is made from gastric samples, feces, blood, and urine. however, detection of minute amounts of toxin (and contacts with samples from cases may prove fatal due to the toxin' s potency) would be difficult by current immunoassay systems such as elisa platforms. detection techniques based on electrochemiluminescence and immunoliposomes are currently under development. , pcr assays can be performed in cases of ingestion of contaminated food in order to detect the genetic material present in c. botulinum. if weaponized toxin is used in the absence of c. botulinum organisms, detection of the genetic material would be difficult and would rely on the presence of residual dna after toxin purification procedures. if inhalational botulism is suspected, respiratory secretions and nasal swabs should be obtained as early as possible. postmortem samples of liver and spleen can be used for detection of botulinum toxins. diagnosis is also based on clinical presentation and requires a high index of suspicion due to the nonspecific nature of the signs and symptoms. laboratory diagnosis rests on detection of the toxin in body fluids by immunoassays (capture elisa and igg elisa). a new generation of tests using more sensitive detection methods is under development (see preceding discussion). diagnosis is also suspected on clinical grounds and confirmed by demonstration of the toxin in nasal swabs early in the disease process, feces, and, in fatal cases, from kidney and lung tissue. serum can be analyzed by elisa, and pcr can be performed for detection of toxin genes of s. aureus if present. the distribution and incubation periods of infectious diseases 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of active infection of both human and bovine brucellosis genus-specific detection of alphaviruses by a semi-nested reverse transcription-polymerase chain reaction standardization of immunoglobulin m capture enzyme-linked immunosorbent assays for routine diagnosis of arboviral infections toxins as weapons of mass destruction: a comparison and contrast with biological warfare and chemical warfare agents sensitive detection of biotoxoids and bacterial spores using an immunomagnetic electrochemiluminescence sensor key: cord- - fptiwmy authors: walters, anne title: inequities in access to education: lessons from the covid‐ pandemic date: - - journal: nan doi: . /cbl. sha: doc_id: cord_uid: fptiwmy the covid‐ pandemic has brought attention to the stark inequities in public education worldwide, with the united nations sharing these statistics: schools closed in countries, affecting . billion students and million primary and secondary school teachers. half of students did not have access to a computer, and % did not have internet access. a total of million children live in areas that are not served by mobile networks — for example, in sub‐saharan africa. in the united states, about million school‐aged children are in homes without home internet service. t he covid- pandemic has brought attention to the stark inequities in public education worldwide, with the united nations sharing these statistics: schools closed in countries, affecting . billion students and million primary and secondary school teachers. half of students did not have access to a computer, and % did not have internet access. a total of million children live in areas that are not served by mobile networks -for example, in sub-saharan africa. in the united states, about million school-aged children are in homes without home internet service. on may , the boston globe noted that % of boston public school students have not logged into their virtual learning programs since may (tonnes, ) . this may not be a fully accurate picture because of difficulties in tracking this information, but it is nonetheless startling. two of the primary impediments noted are lack of internet connection and difficulty gaining access to district chromebooks. english-language learners seem to be particularly affected. solutions have been to set up an information hotline, employ school-based problem-solving teams, and/or send a school social worker out to the child's home to assist with connecting. clearly, this has required creative thinking among the school teams and will necessitate further work on alternatives such as community radio or tv broadcasts, both in the united states and internationally. schools were caught by surprise by the speed of closures, and those that already had robust online learning platforms certainly fared better. in addition, lower-resourced districts with as many of % of their students relying on school breakfast and lunch programs focused initially on food security, and thus were slower to address access to learning. funding initiatives from a variety of sources provided internet access and technology support for some. the pandemic has also brought attention to the inequities in the abilities of parents to take on virtual learning. for children in two-parent families, often higher-resourced to begin with, the transition to online learning has been easier. for single-parent families, large families living in small spaces, families where one or both parents are without advanced education, and the % of the homeless who are children, this task is herculean (schneider, ) . our local experiences in a behavioral health setting with children engaged in online learning have been varied. one common feature, though, is the extreme stress it creates for families of children with mental health needs who are often already struggling with basic compliance and day-to-day life at home prior to the pandemic. adding teaching to the mix has been the final straw for many and has led to increased demand for services, which are also virtual and at times insufficient to keep families out of crisis. more of our treatment has been focused on establishing schedules and routines for families who are not accustomed to having to structure their child's entire day without access to social, community opportunities or school. anecdotally, length of stay in higher-level services at present is longer. yet we are all too aware that there are populations that we do not have access to -some of which may be coping well and some of whom are not. it has been notable to see variability in the involvement of schools with these children as well. for the most part, personnel have been eager to collaborate, and most parents have had numbers and email addresses to make this contact possible. some teams have set up weekly meetings for children and their families with school counselors and social workers to assist vulnerable students with their adjustment, and the academic teams have also been willing to check in with specific students as needed. many parents have been appreciative of finding more support than they had anticipated. at the same time, this is not the experience of all. in many ways, this is not new information; we have been talking about educational inequality and the achievement gap for a generation now. most researchers on public education are noting the pressing need for a focus on access to the internet and investing in the technology needed to close the digital divide in online learning for all students. others have noted that this is not just an educational issue, but points to broader inequalities, a viewpoint that would be supported by the health disparities that have been highlighted among communities during this pandemic. all suggestions seem to point to a need to expand resources for schools serving low-income children -not just with access to online learning, but with other interventions designed to address the achievement gap. these include reduced class sizes, summer programming, early childhood education -all interventions that we know will reduce the inequalities that have been highlighted during this challenging time. perspective: how covid- laid bare the vast inequities in u.s. public education one in five boston public school children may be virtual dropouts key: cord- -i hfj ca authors: hufbauer, gary clyde; jung, euijin title: what's new in economic sanctions? date: - - journal: eur econ rev doi: . /j.euroecorev. . sha: doc_id: cord_uid: i hfj ca nan exceptions and monetary rewards. also, cyber warfare and private litigation are illustrated as unconventional measures. the emergence of new weapons and the growing preference of sender countries to use them creates fresh concerns, which are discussed at the end of this section. financial tools. very early in the post second world war era, the united states and its european allies used the international monetary fund, the world bank, and regional development banksinstitutions they controlled --as on-off spigots to block or limit funding to target countries. this was supplemented by outright denial or slow-walking bilateral grants and loans (military and economic) to persuade recalcitrant foreign leaders. the soviet union did much the same to coerce wayward satellites during these decades. prior to south african sanctions in the late s and early s, private banks headquartered in western countries were rarely instructed or even cautioned by their home governments to restrict loans or financial services to target countries (such services as correspondent relations or floating sovereign debt). partly this reflected the operations of private banks in that era: they did relatively little business in countries that were prime candidates for economic sanctions. but also, it reflected hesitation by western governments to "meddle" in the affairs of private banks. all this changed with the presidency of barack obama, and the wide-ranging sanctions against middle east targets. private banks based in the west were instructed not to do business with iraq or iran, and heavy fines were imposed on european banks (such as société générale and hsbc) that sought to evade the strictures. equally important, when sanctions against iran gathered force in , most iranian banks were cut off from the world's financial centers. this was achieved both by proscriptions against doing business with iranian banks and by denial of their wire transfers through swift or fedwire. these novel techniques threw sand into the creaky domain of iranian finance, hobbling an economy that was already suffering from severe mismanagement. why was president obama so eager to enlist financial institutions in the conflict with iran? saddled with flagging military ventures in iraq and afghanistan, obama wanted to avoid, at all costs, a third military front with iran. like multiple leaders before him, obama searched for "silver bullet" sanctions that would force iran to the bargaining table. finance seemed to fit the bill, and indeed financial pressure was a critical element in creating the joint comprehensive program of action (jcpoa) which seemed to end the conflict over nuclear weapons in . not so quick. president trump dismissed the jcpoa as ineffective. yet he resurrected and reinforced the financial techniques applied by his predecessors, though european cooperation became more reluctant than during the obama years. many european foreign ministers believe that the jcpoa was as good a deal as iran would ever sign and, unlike trump, hesitated to blow it up. however, iran's threat, publicized on june , , to enrich more uranium than permitted in the jcpoa agreement unless european sanctions are lifted, could eventually alter european views. offers hard to refuse. prior to the st century, alliances of willing sender country were formed under un auspices, often with blessings from the security council, the organization of american states, or ad hoc groups. in earlier decades, the united states enacted statutes (e.g., the helms-burton law in ) and issued regulations designed to force foreign subsidiaries of us firms, and even foreign firms, not to do business with targets such as cuba and china. these laws and regulations sparked nationalist backlashes in canada, france and other us allies because us measures were perceived to intrude on sovereign powers abroad. in recent decades, the united states has devised a more direct technique --offer banks and industrial firms in europe, japan, korea and elsewhere a choice: do business in the target country, or do business in the united states, but not both. this was obama's way of implementing broad sanctions against iran, and trump is doing the same. this new approach of making offers bank-by-bank, and firm-by-firm achieves results with far less backlash. moreover, the surveillance techniques of the national security agency (nsa) and central intelligence agency (cia) provide powerful deterrence against "cheating". very likely the offer technique will be applied widely in the future. as beijing flexes its economic muscle, china may well adopt the same technique. as a harbinger, china has extended belt-and-road loans to nearly every country in latin america except paraguaywhich committed the offense of granting diplomatic recognition to taiwan. humanitarian exceptions. seldom acknowledged but hard to deny, broad economic sanctions are akin to area bombing, also known as carpet bombing, a technique favored by sir arthur "bomber" harris during the second world war and embraced by winston churchill. carpet bombing inevitably kills innocent children and other civilians; broad sanctions inevitably inflict privation and disease on the poorer strata of society, often the young and old. one answer to the moral dilemma is to make exceptions for exports of food, medicines and other arguably humanitarian products. this answer, intended to pacify critical western journalists as well as help the vulnerable, came into vogue in the s and is now a regular component of nearly every episode. even president trump's renewed sanctions against cuba and north korea have humanitarian exceptions. critics of trump's sanctions against venezuelacutting off us oil purchases and diverting citgo earningshave been quick to cite the humanitarian harm to ordinary venezuelans. nevertheless, the overwhelming trend in the past two decades is away from comprehensive sanctions to "smart" or "targeted" sanctions. in the scores of cases unknown to the general public, limited sanctions are the preferred toolsanctions aimed at specific individuals, companies or transactions, without causing humanitarian harm to the public. however, in high profile casesthe ones average readers remember, such as iran, cuba, north korea and venezuelathe flavor is comprehensive sanctions. so, humanitarian exceptions remain as key component of sanctions policy. diplomatic exceptions. in pre- st century episodes, sender countries were nominally "all in" the sanctions regime. however, cheating was widespread among senders, even for declared adherents to a un security council resolution. less than faithful observance was an informal means of avoiding burdens. as well, token compensation was sometimes extended to states neighboring the target, to mitigate their hardship from diminished trade. the serbian and iraq episodes are examples. to recruit countries into the "sheriff's posse", tailored exceptions were woven into the iranian sanction regime spearheaded by president obama. countries heavily dependent on iranian oil could maintain traditional, or modestly scaled back, import levels. such exceptions enlisted turkey, india, china and a few others into the regime. president trump's renewed sanctions against iran contained similar exceptions, but with flexible time limits that eventually ran out. the new approach anticipates the reality of unenthusiastic posse members by negotiating diplomatic exceptions in the launch plan. whether diplomatic exceptions and humanitarian carve outs make a difference in assembling a "coalition of the willing", or the ultimate success of sanctions, remains to be explored. weaponized tariffs. president trump has inaugurated an almost novel technique to the realm of economic sanctionsnot an easy feat after more than two centuries of practice since the napoleonic wars. trump has weaponized the us tariff regime, raising selective rates well above maximum ("bound") levels committed both in the wto and regional and bilateral free trade agreements. during the great depression of the s, many countries raised their tariffs as a retaliatory tool in response to the smoot-hawley act. but in that era international commitments did not bind national tariff levels. trump's justification for weaponization is simple: "when a country [usa] is losing many billions of dollars on trade with virtually every country it does business with, trade wars are good, and easy to win." once trump settled in the white house, his campaign promises were put in action through tariffs on merchandise imports from china and mexico. contending that chinese practices of forcing technology transfers and stealing intellectual property are threats to the us economy and national security, trump imposed percent and percent tariffs on $ billion imports from china. in response, china retaliated by imposing tariffs on some $ billion imports from the united states, and lowering tariffs to imports from other countries. trump threatened to impose tariffs on the rest of chinese imports (about $ billion), but the threat was shelved at the g summit held in osaka, japan on june - , . in september , however, trump raised us tariffs on some imports and more tariffs were threatened. but in january , the us and china negotiated a "phase one" deal committing china to step up its purchases of us goods and services (a huge increase over two years of $ billion compared with ), and the additional tariffs were put on ice. if the us is dissatisfied with chinese performance on any of the phase one commitments, the tariffs can be reinstated. that could well happen in the runup to the us presidential election in november , as one means for trump to advertise that he is tougher on china than his rival, former vice president joe biden. a much smaller version of the same strategy was applied to mexico, to resolve the issue of central american refugees passing through mexico to the united states. trump announced that a percent tariff would be imposed on all products imported from mexico, starting june , , unless mexico reduced the flow of illegal migrants. moreover, he threatened to increase the tariff in percent stages, up to percent, to be reached on october , . mexico caved, and agreed to deploy up to , national guard troops to its southern border and take additional measures to slow the refugee flow. in turn, trump suspended the imposition of tariffs. in , the percentage of us trade affected by sanctions was under percent. several conflicts later, but before trump entered the white house, still only percent of us trade was similarly affected. just adding trump's tariffs on $ billion imports from china and chinese retaliation against $ billions of us exports, that percentage has now reached percent, a magnitude of macroeconomic significance. one unintended result is to erode business confidence worldwide and diminish cross-border investment. with his weaponized approach, trump has significantly eroded the distinction between routine commercial tactics in search of markets abroad, on the one hand, and economic sanctions in pursuit of foreign policy goals, on the other. the erosion is particularly evident with respect to china, where trump's trade war presages a new cold war (explored later, and likely to be pursued, with fresh vigor, if a democrat captures the white house in ). since the founding of the general agreement on tariffs and trade (the gatt) in , the united states and other members have imposed penalty duties on top of bound tariffs in retaliation against specific foreign practicesnotably countervailing duties against subsidized imports and anti-dumping duties against imports sold below average cost or prevailing prices abroad. but these and other penalty duties are targeted on narrow product categories in response to individual offenses. trump's tariffs are aimed at a wide range of products (all autos, all steel, everything chinese) in pursuit of broad goals that mix commerce and foreign policy (e.g., slash bilateral trade deficits, restore us preeminence as a manufacturing power, or limit technology exports that could strengthen china's military). in kindred spirit, the trump administration is pushing a bill titled the "reciprocal trade act" that would enhance presidential powers to raise us tariffs against specific imports from countries that impose higher tariffs than existing us rates. it is hard to classify the draft bill as commercial policy or sanctions policy, since it conflates the two. moreover, trump's tariff agenda is buttressed by fresh limitations on foreign investment in the united states, via regulations issued under the new foreign investment risk review modernization act (firrma). the regulations create a pilot program that will reviewin a secret star chamber process under the auspices of the committee on foreign investment in the united states (cfius) --virtually every foreign acquisition, even of minority interests, in any us company with a technology flavor. again, the distinction is blurred almost beyond recognition between commercial objectives and foreign policy goals. likewise, new regulations issued under the export control reform act of (ecra) subject a broad range of technology exports to government oversight, another conflation of commercial and foreign policy. new databases have yet to catch up with the weaponization of import tariffs, investment policy, and export controls. for the moment, case-by-case studies will be needed to appraise the success of trump's approach. the imposition of steel and aluminum tariffs, and the threat of auto tariffs, on canada and mexico appear to have wrested concessions from the two neighbors in the renegotiation of the north american free trade agreement (nafta)negotiations that led to the us-mexico-canada agreement (usmca). further, mexico clamped down on central american refugees bound for the united states, in response to trump's threat of escalating tariffs. in january , the phase one agreement promised a massive increase in chinese purchases of us exports, along with many market-opening measures. whether beijing can or will carry out these promises remains to be seen, especially in the wake of the coronavirus epidemic and heightened technology tensions with washington. whatever the outcome of these episodes, the conflation of commercial policy with sanctions policy has dramatically and adversely changed the face of world trade and finance. since the second world war, the united states has espoused market principles for trade and financea world economy where government sets the rules, but private firms determine purchases and prices. the new flavor, in the trump era, is managed trade and financegovernment both sets rules and determines outcomes. as other countries emulate trump, it's hard to believe the us will benefit. the research task for scholars is to evaluate not only the outcome of individual episodes, but also how the new flavor affects the global system. if the conflation becomes a customary staple of sanctions and commercial policy, past the trump administration, our prognosis is gloomy. monetary rewards. every sanctions episode contains the seeds of relief, simply from the potential removal of barriers to trade, investment and finance. ever since the marshall plan was launched to thwart soviet expansion, the united states has conditioned military or economic aid on the behavior of recipient countries. in the th century, south korea, pakistan, chile, egypt and others have been targets of such positive measures. the new twist, in the realm of positive measures, is the twinning of negative threats with positive incentives. this was done by europe to slow the arrival of syrian and other refugees via turkey. the negative threat was to harden the border between turkey and its european neighbors; the positive measure was money. eu promised to pay about $ . billion to turkey to contain refugees at the eu-turkish border in . in a similar spirit, president trump has tabled vague offers of loans and grants, coupled with the threat of stiffer sanctions, to entice north korea and iran to curtail and even eliminate their nuclear arsenals. following the celebrated meeting of presidents trump and kim jung un at the end of june , more positive measures seemed to be on the negotiating table, but a subsequent chill seems to have ended the nascent détente. far more massive, china launched its "belt and road" initiative, offering huge loans, possibly with a grant element, for infrastructure projects in adjacent and distant friendly countries. how much will be expended to improve sea, rail and road ties with china remains to be determined, but the amounts are likely to run into hundreds of billions if not trillions of dollars. indeed, a new study suggests the belt and road initiative could eventually invest as much as $ trillion in infrastructure projects. anything approaching this magnitude will give china enormous leverage to influence recipient countries, both by offering finance and by withdrawing finance. the realm of "positive sanctions", as they have been called, is potentially broad and ambiguous. we prefer to confine the term to situations where the promise of monetary rewards is twinned with the imposition or threat of negative sanctions in a quid pro quo fashion. for example, beltand-road loans are clearly conditioned on the target country not recognizing taiwan and establishing friendly trade and investment relations with china. us offers to north korea and iran hinge on their abandonment of nuclear weapons. cyber warfare. cyber-attacks clearly rate as a st century innovation. through nsa wizardry, the united states has possessed the capability, for at least a quarter century, to descend chaos on the banking, telecommunications, and power systems of adversaries. other countries, not only china and russia, but also north korea and india, and allies like germany, france, britain and israel possess similar if not quite equal capabilities. moreover, the united states is highly vulnerable, still struggling to create a cyber command capable of mounting defensive measures. during obama's tenure, the pentagon and the national security advisor eschewed offensive use of cyber capabilities, arguing that cyber warfare was akin to kinetic warfare. in a classified executive order, president trump has reversed that policy, opening the possibility of offensive cyber-attacks in future economic sanctions episodes. media reports indicate that cyber measures have already been deployed against russia (its electrical grid) and iran (its financial system). russia made its mark with extensive disinformation and hacking activities during the us presidential election. but influencing foreign elections is nothing new in the sanctions world; the united states often deployed media campaigns during the cold war to shift election results in europe and latin america. what's new is posting fake opinions and news on social media and hacking private email accounts. future episodes seem all but certain, starting with the november us presidential election. private litigation. in a bygone era, sovereign states were shielded from foreign private litigation by the doctrine of sovereign immunity. while the doctrine has been gradually eroded, we define private litigation, when launched in the courts of a hostile country, as a new weapon in the sanctions armory. thus, in april , the trump administration withdrew the executive order, issued by its predecessors, which barred private litigation against cuban and foreign entities for "trafficking" in cuban property expropriated from american firms and citizens. such suits were authorized by the helms-burton law of but suspended by the clinton administration to settle a case brought against the united states in the wto by the european union. the trump administration's action could unleash multiple private cases, with claims aggregating billions of dollars. once the cases are filed, it will be beyond the administration's powers to shut them down. hence, they will not be useful as bargaining chips with the cuban government, but they will inflict punishment on cuban and foreign firms (principally european and canadian corporations). blocking statutes and bruised relations between washington and its allies seem likely. as another example, using the amended foreign sovereign immunities act (fsia) that allows us victims of terrorism to sue designated state sponsors of terrorism for their terrorist acts, the us federal courts over the last two decades issued some judgments finding iran liable for terrorist action that claimed american victims, resulting in over $ billion in damages against iranian government entities and officials. for example, us courts found iran --acting through hezbollah --liable for americans killed in the bombing of the us marine corps barracks in beirut and other attacks. recently the us supreme court ruled that $ billion in frozen iranian assets can be turned over to the survivors of the bombing. trump's policies with respect to cuba may set a precedent for other sanctions cases. private litigation could become more common if the congress amends the foreign sovereign immunities act of to broaden existing exceptions to the immunities doctrine to include "trafficking" and other offenses that sanctioned countries and their commercial partners are likely to commit (for example, canceling contracts or imposing tariffs on us exports). from the standpoint of us foreign policy, private litigation may serve as deterrent and retribution, but not as a tool of international negotiation. use. an overriding reason for the us preference is the record of murky outcomes and outright failures in military actions against somalia, iraq and afghanistanall reminiscent of vietnam. economic sanctions rarely lead to american deaths, unlike military operations. whether sanctions succeed in achieving their goals seems far less important to the public than the outcome of military conflicts. moreover, when it comes to challenging russia or china, sanctions are the only tool: us military measures would threaten nuclear war. parallel concerns can be found in the preference of other great powers for economic weapons. the chinese market, like its us counterpart, is big enough that shutting access commands the attention of an adversary. south korea is the exemplary case, with implications for vietnam, malaysia and thailand. china cannot threaten military strikes against south korea, taiwan or japan without triggering a us military response, but china can easily close its market to exports from offending neighbors. russia faces the same dilemma with respect to nato members, but it has enjoyed a relatively free military hand in georgia, ukraine and syriacorrectly calculating that the united states would not respond in those theaters. for other theaters, social media and cyber campaigns are far cheaper than overt or covert russian military actions. the european union lacks a joint military force and has no prospect of acquiring one. apart from moral suasion, economic sanctions are the eu's sole enforcement tool with bearable economic and political cost. in sum, the growing use of economic sanctions carries adverse implications for the stability and survival of nato and wto. for nato, frictions between the united states and its security allies weaken the effectiveness of sanctions on iran and other targets and foster dissent between senior officials. the misalignment in iran sanction policy became worse when the european union blocked the us attempt to reimpose un sanctions on iran. meanwhile, trump's cuban policy irritates business firms abroad and seems pointless to canadian and european military leaders. trump's broad national security justification for section tariffs under the trade act, and his tariff reprisals under section of the trade act, directly threaten the rules-based multilateral trading system overseen by the wto. on their face, us trade measures conflict with wto rules, but since collateral us actions have dismantled the wto's appellate body, aggrieved foreign countries have no meaningful forum for settling disputes. accordingly, they have resorted to retaliatory measures which are equally inconsistent with wto rules. underlying the largest frictions is the new cold war and it's not at all clear that the wto system can house both the united states and china. given the global trade and investment reach of both antagonists, a split of the wto into two domains will inflict substantial costs on the other member countries. in practice, if not in name, the world trade organization may not survive. through the turn of century, the united states was the dominant sender country, participating in about percent of cases, often with a posse of allies, followed by the erstwhile soviet union, the united kingdom and the european union. after the end of the cold war in , the united states sometimes secured un security council resolutions that enlisted nominally committed sender countries. during that era, us targets dotted the globe, while russian targets were concentrated in neighboring countries, and uk and eu targets were concentrated in africa (but the uk often joined far-flung us-led episodes). in recent years, new actors and new targets are changing the traditional landscape of sanctions, reflecting technological advances and the rise of social media. to this day, the united states remains the dominant sender, but starting in the late s and early s the european union became much more active, allied with the united nations, regional partners or the united states. eu targets were concentrated in africa, usually countries ridden with strife, ruled by despots, or victims of military coups. the european union sometimes achieved a modest degree of success in stabilizing these countries or displacing their political leaders. for example, the european union introduced restrictive measures against zimbabwe in in relation to the escalating domestic repression against political opponents, and the violation of human rights including freedom of speech. the eu sanctions included arms embargo, travel restrictions and asset freeze. after the constitutional referendum in zimbabwe was held, most sanctions have been suspended, but several congolese individuals are still subject to asset freeze and travel bans. entering the s, the european union built a policy framework for more effective use of targeted sanctions. to this end, the eu updated its guidelines for member states, calling for timely implementation and evaluation. eu sanctions aim to deter terrorism (e.g. iran), delay nuclear proliferation (e.g. iran and north korea), reduce human rights violations (e.g., nicaragua), reverse annexation of foreign territory (e.g. russia), and destabilize foreign leaders (e.g., ivory coast). between and , the european union introduced more than different sanctions against states. for example, in , eu members agreed to impose travel bans and asset freezes on nicaraguan individuals and entities responsible for human rights violations. all designated individuals and entities are listed in the official eu sanctions database. one eu concern is coping with us "extraterritorial" sanctions. when trump revoked us participation in the iranian nuclear agreement and imposed secondary sanctions against firms doing business with iran (mainly energy deals), third countries became subject to us sanctions. some argued that european foreign policy autonomy was at risk because the eu could be seen as coerced into following us foreign policy. to bypass this perception, france, germany and britain created the "instrument for supporting trade exchanges" (instex) as a special vehicle to help eu firms do business with iran and facilitate non-us dollar transactions. despite trump's criticism of instex, the eu successfully made its first transaction with iran using this financial mechanism in march . however, this divergence weakened the overall impact of sanctions and lessened the already small likelihood that iran would abandon its nuclear goals. when trump re-imposed nuclear sanctions, iran became less compliant with the jcpoa. in iran has exceeded a threshold on uranium enrichment agreed to in the deal, but continues to work with iaea inspectors in verification and monitoring of sites related to the deal with limiting their access to certain sites. russia. shorn of direct control over its erstwhile satellites, russia turned to active diplomacy towards the "near abroad". economic sanctions accompanied the diplomatic mix, leading to episodes aimed at discouraging ties with the west, seizing disputed territory, or protecting russian-speaking minorities. for instance, russia imposed economic sanctions on estonia and latvia in response to alleged discrimination against russian minorities ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . restrictions on oil and gas exports and access to russian markets are customary tools. entering the s, russia often imposed sanctions as a retaliatory instrument to counteract western measures against russia's own provocative actions, such as the invasion of ukraine, the nerve agent attack on a former russian spy, and the cyberattack on us elections. responding to us and eu sanctions for the invasion of ukraine in , russia imposed travel bans and food embargos on the two senders. following annual renewals, these will remain in effect until the end of . counter sanctions also apply to ukraine in response to ukraine's decision to expand its own list of prohibited imports from russia. trade in energy and food products between russia and ukraine has essentially stopped. xi jinping, apparently leader for life, has changed the music. ten sanction cases can be identified between and , which is triple the number of cases between and . china's growing economic power and its integration with the world markets enables china to influence the foreign policies of neighboring countries and even distant nations. president xi's belt-and-road initiative is by far the largest "positive sanction" since the marshall plan. as they embrace belt-and-road projects, many countries in asia and latin america adopt a friendly approach to china in the united nations and other international fora. alongside, china deploys negative measures such as trade and investment restrictions, popular boycotts, limits on chinese tourism, and informal pressure on business entities. unilateral sanctions are typically imposed when china perceives specific threats to its national security and sovereignty. for example, china cut off diplomatic and trade talks, and curtailed imports of norwegian salmon, when norway awarded the nobel peace prize to chinese dissident liu xiaobo. in a similar vein, after south korea installed its defensive missile system of us design in - , china restricted tourism and imports of cultural products and used regulatory measures to close almost south korean owned retail stores in china. these sanctions did not reverse norwegian or south korean policies, but they did send diplomatic signals to other countries that might consider crossing chinese "red lines" (harrell et al, ) . all three countries have different reasons for employing sanctions-related policies. the european union prioritizes its own liberal principles, even as it disagrees with us positions on iran and other targets. russia's approach to dominate its neighbors hasn't changed much, but in addition russia has frequently imposed retaliatory sanctions when russia itself became a target country. as a newcomer to the offensive use of sanctions, china has specialized in coercive measures that boldly announce the "red lines" in its relations with foreign powers. non-state actors. in the united states and europe, civil society has actively pushed government to impose sanctions for bad behavior abroad, particularly in the realm of human rights. the first big campaign took place in the late s when ad hoc groups persuaded us states and private firms to sever ties with south africa. more recently, the kimberly process, aimed at limiting the global market for "conflict diamonds", was embraced by de beers and other dominant firms. the magnitsky act --retaliation against human rights abuses and death suffered by the russian lawyer magnitskystemmed from the lobbying efforts of his erstwhile employer to blacklist the responsible russian officials. finally, a group of ngos impelled us sanctions against senior burmese military leaders responsible for severe violations of human rights during episodes of killing rohingya people. gathering steam today are efforts to punish china for its harsh treatment of the uighur population and hong kong protestors andover a longer time framenew sanctions against purveyors of coal and other fossil fuels. civil society has increased its influence on sanction process as its network spreads to the globe via social networks and helps raise public awareness of concerning issues. "specially designated" targets. fairly recent is the imposition of sanctions against "specially designated" persons or firms. terrorists, drug dealers and money launderers were early targets, but an innovation is black-listing political and business leaders and select firms. thanks to advanced technology in communication and data processing, national intelligence agencies such as nsa and cia can identify assets, travel patterns, families and commercial contacts of designated firms and individuals. since january , significant sanctions were launched against designated entities. the european union imposed its first sanctions in response to a chemical attack, targeting four russian military intelligence agents for poisoning a former russian double agent living in britain. meanwhile, the us sanctioned a state-owned oil company, petroleos de venezuela, s.a. (pdvsa), restricting us firms from buying venezuelan crude. the us complaint against pdvsa was its financial support of the maduro regime. in august , the trump administration imposed financial sanctions on individuals who implemented china's national security law in hong kong, including chief executive carry lam. in turn, china retaliated with similar measures against us politicians who were prominent critics. deterrence. while certainly not a new goal, deterrence has played a large role in recent cases. no analyst could expect sanctions to diminish putin's support of pro-russian forces in eastern ukraine, much less dislodge russian occupation of crimea. but intelligence officers and foreign ministers could reasonably expect that stiff sanctions in response to russian adventures would deter further russian military expansioninto moldova, the baltics, or central asia. at this writing, putin has not followed hitler's playbook, beyond the takeover of crimea in march and the subsequent support of pro-russian forces in eastern ukraine. perhaps deterrence worked. turning to another theater, us and allied sanctions against iran, even with renewed force starting in , were unlikely to force the supreme leader to abandon his nuclear weapons project, then in its th year. but alongside the threat of a military strike, the sanctions apparently deterred iran from either testing its bombs or miniaturizing them to fit on missiles. in turn, restraint helped pave the way for the joint comprehensive plan of action (jcpoa). less appreciated is the impact of us and allied sanctions, plus unpublicized on-again, off-again support from china, in limiting north korea's nuclear ambitions. kim jong un almost certainly could have conducted additional long-distance missile tests and detonated more powerful bombs. but the coupling of us-led and chinese sanctions, along with the high-profile june and june meetings with president trump in singapore and the dmz respectively, may have stayed kim's hand. again, perhaps a win for deterrence, though well short of a win for nuclear disarmament. most recently, reciprocal us and chinese sanctions over beijing's absorption of hong kong into the mainland legal regime stand no chance of swaying chinese policy nor of curtailing us criticism. moreover, it's not obvious that these sanctions will deter further episodes in the new cold war. but to determine whether deterrence was achieved in these and other cases requires persuasive counterfactual scenarios, not easy to construct. retribution. again, retribution is not new, but it features prominently in post- cases. thanks to digital technology, nsa and cia sleuths, along with their european counterparts, can identify "bad guy" individuals and firms. in turn, the "bad guys" can be singled out for "special designation" status that hits their wallets and persona. for example, in the wake of the jared khashoggi's murder in istanbul, the us revoked visas of saudis connected to the assassination squad. this will inconvenience the designated individuals, even though the chief instigators, likely including crown prince mohammed bin salman, will not be brought to justice. on a much larger scale, in response to russia's annexation of crimea and intervention in ukraine, dozens of well-connected firms and elite russians were subject to financial, trade and travel sanctions. careful research by ahn and ludema ( ) plus fresh analysis presented at the workshop, shows that russian firms were severely affected, on average losing a quarter of their sales. but their pain will not persuade putin to vacate crimea or withdraw support from dissidents in eastern ukraine. indeed, as new research by ahn and ludema ( ) shows, putin shielded some "strategic firms" from the brunt of sanctions, at a cost calculated at nearly a half of the total pain imposed on russian firms by the targeted measures. as a rule, retribution against individuals and firmsa common response --does not achieve lofty foreign policy goals but it may deter future misdeeds. in fact, severe sanctions against major powers (russia and china) and against small countries with entrenched autocrats (north korea and cuba) rarely achieve advertised goals, but they do punish the targets. and this is important. in democracies, influential constituentsgiven voice in parliament and congressinsist on punishing foreign countries for their misdeeds. retribution is its own goal, and punishment gives satisfaction. justice is served. whether sanctions stand a chance of altering policies abroad is a secondary matter. rehabilitation. "mission impossible" aptly describes the role of rehabilitation in major episodes of the st century. russia will not abandon imperial aspirations, nor will cuba and north korea transition to democratic states. but by far the most ambitious goals of st century sanctions are to arrest china's military, economic, and technological rise. if anything, us trade, investment and technology sanctions will spur china's efforts, commercially divorced from the united states, to deepen cooperation with russia and a few western countries, and to rely on its own ample resources. former german chancellor helmut schmidt was scornful of sanctions on russia, calling them 'nonsense'. travel bans and asset freezes, he claimed, are symbolic and "affect the west as much as the russians". if chancellor schmidt were still alive, he would probably have still more scathing words for the current us economic campaign against china. at the workshop scholars presented new theoretical models designed to generate hypotheses worthy of testing against the findings recorded in new databases. the models have two common features: they are mathematically demanding, and they build on costs or benefits incurred by senders and targets. the models often distinguish between threats and imposition, drawing on insights from thomas schelling's famous canoe trip. in this section, new databases and new analyses by various scholars from the workshop are summarized to bring attention to their contributions. quoted by gerald schneider at the workshop. original source is at derek scally, "schmidt attacks western sanctions on russia as 'nonsense '," irish times, may , . thomas schelling ( ) . new and more comprehensive datasets have been constructed since research in the s and s. the main databases now used for empirical research include: • hufbauer, schott, elliott and oegg ( ) lord rutherford, the distinguished british scientist at the turn of the th century, declared, "all science is either physics or stamp collecting". rutherford might have classified the databases mentioned above as "stamp collecting". however, a priori hypotheses as to the impact of sanctions, often held with great conviction by leading statesmen, can only be tested with the benefit of these collections. first, ahn and ludema ( ) add to their own pioneering work that analyzed the cost to russian firms of us and eu sanctions in the wake of the crimean annexation and ukrainian occupation. collecting firm/individual data from the bureau van dijk (bvd) orbis and lexisnexis worldcompliance databases, the authors developed a model to assess the impact of sanctions at the firm level that features domestic government shielding of "strategic" firms from foreign measures. their results showed that strategic firms systemically outperformed non-strategic firms under sanctions, implying a cost to the regime that adds to the total cost of sanctions. besedes, goldbach and nitsch ( ) fresh research by grauvogel and attia ( ) revealed an additional and unexpected positive outcome from the termination of sanctions. political stability in the target country improved, if the country had resisted strong demands from the sender. resistance evidently enhanced the ability of political leaders to ward off internal rivals. in an innovative piece of workshop research, weber and schneider ( ) found that unilateral threats are more persuasive, but multilateral imposition stands a higher chance of success. the reasoning is that a unilateral sender, typically the united states, shows more resolve than a heterogenous group of senders, each with a different agenda. but when threats fail to convince the target, multilateral action brings greater heft to the bargaining table. meanwhile, joshi and mahmud ( ) presented a model that demonstrate how the frequency of sanctions and the frequency of violations of international norms depends on unilateral or multilateral actions using network structure theory. miromanova ( ) investigated whether sanctions on products identified at the -digit level of the harmonized system exerted a greater impact on the number of importing firms in the target country (the extensive margin) or on the import flow per affected firm (the intensive margin). she found that the extensive margin is the more important channel. portela and sanguinetti (forthcoming) found that single-party regimes are resistant to sanctionsand single party regimes are common across the globe. however, in countries where two or more parties compete for power there is less resistance, but no significant difference whether the government of the day is a military or personal regime, or a democracy. morgan (forthcoming) observed that the cost of sanctions might be better thought of as the enforcement cost (on the part of senders) and adjustment costs (on the part of targets) rather than more traditional metrics such as the volume of trade curtailed. he emphasized that threats are a bargaining tool, but that actual imposition means that diplomacyin other words, bargaining between two sovereignsfailed. president trump, with bipartisan support, has now proclaimed a second cold war, this time with china, letting the press use the term and not denying its essential accuracy. chinese provocations, according to trump, are the theft and appropriation of us technology, and commercial malfeasance by running an annual bilateral trade surplus of several hundred billion dollars. in the second cold war, unlike the first, trump is leading with economic sanctions, but a military buildup is likely to follow, whether trump or a democrat wins the presidential election. trump's sanctions take the form of high tariffs, both imposed and threatened, that could eventually cover nearly all us imports from china; a star chamber screening process, under cfius auspices, that will deny chinese investment in any us firm with a technology flavor; and criminal charges against the world's leading telecom company, huawei, and its chief financial officer, meng wanzhou, for stealing trade secrets and evading economic sanctions on iran; and the forced sale of tiktok assets in the united states. beyond these immediate measures, many americans are gripped with fear that china will dominate st century technologyquantum computing, g telecommunications, artificial intelligence, robotics, and much more. the response is to "decouple" (meaning divorce) us high-technology firms, as well as individual scientists and engineers, from their chinese counterparts. the us effort to constrict huawei's leadership in g technologyby denying components and marketsis only the first installment of a broad campaign. in addition, trump amplified such efforts by issuing executive orders that prevent the use of two chinese mobile apps, wechat and tiktok. broad restrictions on us technology exports to china, the access to chinese mobile products, and scientific cooperation with chinese institutions, are in the works. by far, this makes china the largest target of sanctions in the st century. as well, the nature of sanctions between the four great powersthe united states, china, russia and the european unionis changing. when one of the great powers targets a smaller countrysay mexico, south korea, georgia or equatorial guineait can use the traditional range of trade and financial measures. when the great powers target each other, more ingenuity is required. history has shown that great powers are relatively impervious to sanctions: they are not immune to economic damage, but they are highly resistant to changing course. military conflict between the great powers runs the risk of nuclear escalation, to be avoided at all costs. hence themes raised in this essay play an important role when great powers are at odds. of special note are financial restrictions, cyber assaults against leading firms and through social media, offers hard to refuse directed at private firms, weaponized tariffs and kindred investment and technology restrictions, and measures against specially designated leaders. conclusions st century sanctions practice has the flavor of evolution more than revolution. new weapons reflect, in part, new technologies (finance and cyber), and in part new statecraft (offers hard to refuse, weaponized tariffs and positive measures). as the geopolitical world shifted from a single hegemon to a system of great powers, players besides the united states became significant actors, with new target choices. pinpoint sanctions aimed at "bad guys" are popular, partly because they avoid moral qualms, partly because digital technology makes them effective. the new cold war was largely responsible for conflating commercial policy and sanctions policy. evaluated against traditional standards of "success"in other words, was the foreign goal achieved and did sanctions materially contribute to the outcome? - st century innovations have not made sanctions more effective. indeed, weber and schneider ( ) conclude that the effectiveness of eu, us and un sanctions for concluded episodes did not change much during the years between and . these finding echoes analysis done by huebauer, schott, elliott and oegg ( ). to be sure, measured by traditional standards, sanctions often promote regime change and humanitarian objectives in small or chaotic countries. but in big cases, goals appear to be evolving, leading practitioners to stress different metrics. deterrence, whether actual or imagined, looms large. as does punishment for its own sake. rehabilitation, often remote, has diminished as a measure of success. after this essay was written, covid- swept the world, creating the biggest economic downturn since the great depression of the s. it remains to be seen whether economic sanctions are more less numerous, and more or less effective, in dramatically different circumstances. china and economic sanctions: where does washington have leverage china's response to u.s.-south korean missile defense system deployment and its implications the magnitsky act, explained why iran will never give up on nuclear weapons trump and kim arrive in singapore for historic summit meeting us to revoke visas of saudis implicated in killing of writer crozet and hinz ( ) and haidar ( ); for capital flows iron curtain" speech transcript, the history place edges toward new cold-war era with china us trade balance in goods and services with china was $ huawei and top executive face criminal charges in the u.s the sword and the shield: the economics of targeted sanctions department of state the office of the chief economist (oce) working paper series cheap talk? financial sanctions and non-financial activity you're banned! the effect of sanctions on german cross-border financial flows collateral damage: the impact of russia sanctions on sanctioning countries' exports on target? the incidence of sanctions across listed firms in iran on the effects of sanctions on trade and welfare: new evidence based on structural gravity and a new database how do international sanctions end? towards a processoriented, relational, and signalling perspective sanctions and export deflection: evidence from iran. economic policy china's use of coercive economic measures the rd edition of economic sanctions reconsidered examining the debt implications of the belt and road initiative from a policy perspective sanctions in networks: the most unkindest cut of all the effects of embargoes on international trade: evidence from russia the new deterrent: international sanctions against russia over the ukraine crisis mds bury their mistakes, we don't have to: learning from empirical findings that suggest your theory is wrong the threat and imposition of economic sanctions - : updating the ties dataset arms and influence the response of russian security prices to economic sanctions: policy effectiveness and transmission aid sanctions and autocratic rule: does regime type matter helms-burton and canadian-american relations at the crossroads: the need for an effective, bilateral cuban policy making the world safe for liberalism? evaluating the western sanctions regime with a new dataset key: cord- -gqekw si authors: samanta, indranil; joardar, siddhartha n.; das, pradip k. title: chapter biosecurity strategies for backyard poultry: a controlled way for safe food production date: - - journal: food control and biosecurity doi: . /b - - - - . - sha: doc_id: cord_uid: gqekw si abstract the people of rural and periurban india depend on backyard farming system for poultry meat and eggs. it is used by weaker sections of society, such as marginal farmers as insurance against crop failure, for ready cash and to ensure basic economic returns and the empowerment of women and children. however, backyard farming does not appear to be a promising strategy to achieve the poverty reduction until the production level is increased. the major constraint in increasing the production in backyard birds is microbial infection due to lack of biosecurity knowledge among the farmers. the mitigation of the microbial infection depends on the detection of the infection route and its prevention. the source of microbial infection (salmonella, escherichia coli) and their dissemination through the eggs in backyard flocks kept in different agroclimatic zones of west bengal, a major egg producing state in india, was identified. the pattern of virulence gene specially associated with urinary tract infection and antibiotic resistance genes, such as extended spectrum β lactamase (esbl) genes of the isolates was studied. the chapter will elaborate the backyard farming including breeds reared, housing, feeding with special emphasis on suggested biosecurity strategies and consequence of the adapted strategy. the food and agricultural organization of the united nations (fao) classified poultry production system into four sectors based on the level of biosecurity and marketing of birds and their products (fao, ) . apart from commercial poultry maintained in integrated farming systems with moderate to high levels of biosecurity (sector - ), there is a "backyard" or "village level" poultry sector with minimal biosecurity (sector ). in this backyard sector, native birds or locally available breeds are maintained, and the birds or their products are mostly consumed locally. the concept of backyard farming is as old as civilization. many families in the villages of the rural world keep a small chicken flock of various ages. the majority of these birds are kept in free-range systems, in which the birds scavenge around the house or in the backyard during daytime. the term backyard farming is originated from it. a primitive type of poultry house is offered to the birds during night. the feed consists of household wastes or kitchen scraps like raw vegetables, cooked rice, insects, larvae, seeds, and so on (samanta et al., ) . the world organisation for animal health (oie) considered the backyard system as the most familiar system of poultry rearing throughout the world because the system is highly adaptable to local climate, and it requires less capital and other inputs to establish (fao, a) . in the economy of developing countries this kind of poultry plays a major role by means of income generation and household food security. it is an important component of small farmers' livelihoods and a tool for poverty alleviation (sambo et al., ) . it can provide meat and eggs throughout the year and ready cash in times of hardship or emergency, which may make the difference between life and death. the ready cash is also used for school expenditure, daily household need, buying of other domestic animals, etc. (fao, a) . the supply of eggs and meat can be maintained by backyard farming to meet the rising demand. sometimes the products are consumed by the owners or used as gifts to the friends and relatives during festival and as sacrificial offer to traditional deity (hamilton-west et al., ) . in bhutan, backyard products also act as a source of protein for the female members of the household during pregnancy and postparturition period (tashi and dorji, ) . backyard chicken eggs are popular among urban and educated consumers due to their higher nutritional quality. these eggs contain higher concentration of vitamins, omega- fatty acids, and β-carotene (long and alterman, ) . the backyard farming reduces environmental pollution by the conversion of kitchen scraps into proteins (meat and eggs), and the use of chicken manure as garden fertilizer. moreover, production of meats and eggs locally reduces the transport of the items from distant places and thus reduces carbon emission (fukumoto, ). besides rural backyard farming, in the urban area of developed countries, also, there is a growing trend for keeping chickens in backyards. this rearing system is known as "hobby/ peridomestic/fancy poultry" or "urban backyard farming." in urban backyard farming, the birds are primarily kept for a homemade source of food, for fun, or as a hobby or companion pet to improve psychological health of the owners. this last purpose is usually a family tradition, exposing children to the food production process and general affection for birds, and functioning as insect control (usda, ) . this kind of farming is not associated with economical benefit because their rearing costs are often higher than the production (pollock et al., ) . in urban united states, keeping backyard poultry flocks have been steadily increasing in popularity. the study in the united states detected that . % of urban and . % of suburban residents prefer to keep backyard poultry (elkhorabi et al., ) . even a number of cities in the united states, such as columbia, missouri, ann arbor, michigan, denver, colorado, and auburn, alabama have passed regulations allowing chickens to be kept at residences (bartling, ) . the trend of keeping urban backyard poultry is also detected in the greater london area in the united kingdom (karabozhilova et al., ) , canada (burns et al., ) , and new zealand (lockhart et al., ) . in british columbia (canada), an authorized person may keep up to egg-producing hens and may produce up to kg of chicken meat per year (british columbia farm review board, ). backyard poultry farming is considered as an integral part of livelihood for many rural families throughout the world. in ethiopia (africa), chicken constitutes the largest share among the farm animal species (mammo et al., ) and % of the chicken population is maintained under a scavenging system (yemane et al., ) . similarly, in asian countries, such as in vietnam, thailand, and bangladesh, % of rural households rear poultry in their backyard and it makes a contribution to the monthly income of rural families and to the national economy (chakma, ; chantong and kaneene, ; edmunds et al., ) . in india, the majority of families ( %- %) in west bengal, tripura, and assam practiced backyard poultry production (nsso, ) . in pakistan, after textiles, the poultry industry is the biggest commercial sector in the country and it contributes considerably to the national economy. pakistan also maintains a large backyard poultry sector and it is observed that every rural family and every fifth urban family breed poultry at home (sadiq, ) . in developing countries, this kind of farming system also offers women empowerment, because women directly control the farming and the income generated from the sale of chickens and chicken products. studies in ethiopia and other african countries showed that this is the only source of independent income for women due to scarcity of resources (wilson, ) . in rural bangladesh, poultry rearing is an occupation of % of women (sultana et al., a) . no literature is currently available regarding the economic importance of this means women empowerment through backyard farming. in developed country, such as in chile, %- % of the studied farms were maintained by men alone or jointly with women (hamilton-west et al., ) . in bangladesh, % of the total egg production is contributed by backyard sector with an annual egg production of . billion from this sector itself (dolberg, ) . in india, this rural poultry sector contributes % of the total national egg production (ngullie and sharma, ) and the income per bird per annum ranges between us$ . - . (indian rupees - per bird/month) (ahuja et al., ) . this contribution is considerably low for a rural livelihood, but it can be increased by expanding the egg production level. the major constraint in increasing the egg production in backyard birds is microbial infection due to lack of biosecurity practices followed by the farmers (conan et al., ) . similarly, in developed countries, such as chile, the farmers mostly sell their products to their neighbors during any occasion or to the tourists who occasionally visit the farms (hamilton-west et al., ) . thus, the income is not sustainable and considerably low. chicken (gallus sp.) is the most common species kept in backyard farming throughout the world. for example, the majority of the backyard farmers in chile, new zealand (north island) and egypt prefer to rear domestic chicken (abdelwhab and hafez, ; hamilton-west et al., ; zheng et al., ) . in ethiopia, however, cattle are the most common species reared by backyard farmers, which is followed by chickens (sambo et al., ) . other species of birds, such as turkeys (meleagris gallopavo), geese (aseranser), ducks (anas sp.), muscovy ducks (cairina sp.), quail (coturnix sp.), pigeons (columbidae sp.), and guinea fowl (numididae sp.) are also reared in some countries and sometimes housed together. ducks are the second predominant species after chicken kept by backyard farming in southeast asian countries (e.g., thailand). in thailand, ducks are raised on rice fields after the harvest to feed on leftover rice grains. the ducks are moved by truck or other vehicle from one rice field to another during the postharvest season ( - months out of the year) (gilbert et al., ) . the ducks are also reared on ponds or channels with or without fish/ pig farming on the same site. rearing pigs in an enclosure within the backyard farm was also observed in new zealand (zheng et al., ) . in some countries (e.g., india), fighting cocks are reared for income generation in places where cock fighting is a traditional recreation among villagers. cockerels (male chickens less than year of age) are reared for cultural and religious purposes in some places (fao, a) . a small number of people (e.g., % of studied population in chile and some people of thailand) prefer to keep wild birds, such as austral thrush (turdus falcklandii), shiny cowbird (molothrus bonariensis), austral blackbird (curaeus curaeus) and common diuca finch (diuca diuca), and ostrich (struthio camelus) as backyard pets (gilbert et al., ; hamilton-west et al., ) . selection of livestock or poultry breeds is an age-old practice that depends on the folk traditions, needs, agroclimatic zone of the country, and availability of the breeds (banerjee et al., ) . among the domestic chicken breeds, indigenous or native or nondescript breeds are preferred for backyard farming due to easy availability, higher adaptability to the local environment, resistance to some diseases, good egg and meat flavor, hard eggshell, high fertility and hatchability, and high dressing percentage (abdelqader et al., ) . in west bengal (india), common indigenous breeds that are maintained in backyard farming are native feathered chickens (desi), naked neck chickens (galakata murgi), frizzled fowls (sojaru murgi), muffed/bearded fowl (dariwala murgi), creeper chickens (bete murgi), crested fowls (khopa murgi), rumpless fowl (bocha murgi), and feathered shank fowl (aseel, haringhata black/black haringhata) (figs. . and . ) (banerjee, ; samanta et al., ) . similarly in bangladesh, indigenous or nondescript breeds of chickens are the preferable choice for rearing. sometimes, the farmers keep fayoumiand sonali (cross-breed of rhode island red and fayoumi) chickens in a semiscavenging system (biswas et al., ) . in bhutan, native breeds, such as seim (sm), phulom (pl), yuebjha narp (yn), and khuilay (kl) are ideal breeds for backyard farming (tashi and dorji, ) . the most common backyard chicken breeds in thailand are native and mixed breed chickens (e.g., three-bloodbreed). three types of duck breeds are reared in thailand-namely, egg-laying ducks (khaki campbell), crossbreed of khaki campbell and native laying ducks, and a small number of meat type ducks (pekin, white cherry valley) (gilbert et al., ) . in sudan and ethiopia (africa), large beladi (lb), bare neck (bn), betwil (bt) dwarf, naked neck, and gasgie and gugut breeds of chickens are kept in backyard farms (getu et al., ; wani et al., ) . some temperate/artificial breeds of poultry were introduced in tropical countries, such as in india and ethiopia for better production and up gradation of native breeds, which altered the traditional husbandry systems. in india and ethiopia, the rhode island red (rir) breed was introduced through government-sponsored developmental schemes, such as rastriyo krishi vikas yojana (rkvy), a self-help group developmental program in india and poultry extension package in ethiopia (dinka et al., ; samanta et al., ) . the better egg production ( eggs per bird/annum) of rir chicken than the native breeds ( - eggs/bird/annum) was observed in west bengal (india) when the birds were provided with supplemented feed along with scavenging . in ethiopia, rir breeds of chicken showed poor tolerance to the local climate. moreover, supply of rir hen's eggs, pullets, and cocks in the localities reduced the brooding capacity of the native breeds and their adaptation to the local feeding system (dinka et al., ) . moreover, a synthetic breed (kuroiler) developed by a private organization was introduced in india for backyard rearing. kuroiler is a dual type bird having higher production capacity than the indigenous (desi) chickens with some features of native birds, such as feather color and alertness ( fig. . ) (ahuja et al., ) . in urban backyard farming, chickens are the most preferred species in the united states. layer breeds of chickens producing colored eggs, such as rir, plymouth rock, ameraucana, orpington, and wyandotte are preferred (elkhorabi et al., ) , although in minnesota (usa), meat-type chickens are also reared (yendell et al., ) . other birds, such as turkeys, ducks, pigeons, doves, game birds, and guinea fowl are also reared (beam et al., ) . in some countries, raptors (hunting birds) are reared in the backyard (fao, b) . the management practices for keeping backyard birds vary between the countries throughout the world. in chile, the birds are kept in three types of systems-namely, permanent confinement, free-range, and a mixed confinement. in mixed confinement, the birds scavenge freely in the courtyard of the farmer's house during daytime, and at night they are kept in an indigenous pen. among these three systems, the mixed confinement is the most common one (hamilton-west et al., ) . the indigenous pens are mostly made of bamboo with or without an asbestos shade in asian countries (samanta et al., ) . in thailand and sudan, at night the birds are kept under a bamboo basket also (chantong and kaneene, ; wani et al., ) . on the north island of new zealand, most of the farms ( %) allow free movement of chickens and ducks in nearby pastures, including access to waterways, such as ponds, streams, rivers, and drains (zheng et al., ) . in bangladesh, most of the farmers ( %) keep the birds within their houses, and others keep them in a coop in the front yard. the coop is made of soil or wood and it has a tin shade (alam et al., ; sultana et al., a) . the majority of the farmers prefer to keep the birds on a wooden perch constructed inside their own houses in ethiopia (yemane et al., ) . resting of the birds on treetops at night was observed in south pacific island countries (ajuyah, ) . development of brick houses for the poultry is rarely observed ( %) in india (west bengal) (banerjee, ) . during crisis periods, such as flooding the farmers keep the chickens in a cage and hang the cage inside the room as observed in bangladesh (sultana et al., a) . the average flock size of the birds in rural backyard farming is variable. in ethiopia and sudan, the average flock size per household was . and . , respectively (wani et al., ; yemane et al., ) . in another study in ethiopia, a lower average flock size ( . ) was detected (sambo et al., ) . in other countries, such as in bangladesh and belgium, the mean flock size of small holdings of poultry was observed to be less than (alam et al., ; van steenwinkel et al., ) . in a study in some districts of west bengal (india), such as jalpaiguri, dinajpur, west medinipur, howrah, and south parganas, the average flock size was observed as - (samanta et al., b) . scavenging in yards, animal sheds, bushes, neighbouring houses and the nearest grain field is the major source of feed for the backyard birds. mostly small worms, insects, snails, rice, fallen cereal brans, kitchen wastes, household vegetables, and green grasses are taken by the birds during the scavenging period and are considered as scavenging feed resource base (sfrb). in asian countries, such as in india, bangladesh, and thailand, women also offer the supplementary feed and drinking water from local ponds to the birds once or twice in a day (chantong and kaneene, ; sultana et al., a; samanta et al., ) . in developed countries, such as in new zealand (north island), however, the birds were mostly provided with drinking water collected from bore ( %), rivers, and streams ( %). only a few people ( %) use ponds or dams as a source of drinking water for their birds (zheng et al., ) . the birds are mostly bred within the flock to increase the flock size. the breeding activity of the birds is conducted by the women of the family, as observed in ethiopia and chile (aklilu et al., ; hamilton-west et al., ) . in new zealand, chickens were usually homebred ( %) (zheng et al., ) . in bangladesh, the women of the family select a space within their bedroom or on the windowsill for the chickens to lay and brood eggs. however, ducks prefer to lay the eggs where they stay at night (sultana et al., a) . the farmers utilize other sources of birds to introduce new birds in the existing flocks. examples of other sources include neighbors, local markets, commercial farms, breeders, shows/auctions, and government supported developmental schemes. in chile, % of the studied population used the other sources to purchase new birds (hamilton-west et al., ) . in new zealand, % of the owners obtained the chickens privately, and a few people ( %) bought the chicken from local commercial dealers (zheng et al., ) . in ethiopia, an average of . chickens were added to a flock annually (yemane et al., ) . during the introduction of new birds, no quarantine or other preventive measures to reduce the transmission of infections are followed. urban backyard farming is a little different than the rural farming. most of the persons keeping the birds have high income, higher education, and in the united states only % people were associated with agriculture. the flock size is almost the same as it is in rural backyard farming. in the united states, most of the people rear - birds (elkhorabi et al., ) . in new zealand too, small flock size (median, ; range, - ) was detected (lockhart et al., ) . however, higher flock size ( - ) was detected in minnesota (usa) (yendell et al., ) . the age range of chickens in the flocks surveyed in the united states was - years with predominantly female chickens. among the studied flocks, % of flocks had no rooster, % had , and % more than rooster in a flock (elkhorabi et al., ) . most of the bird keepers in the united states prefer to keep the birds indoor in a shed/coop. some of them ( %) provided enclosed run space along with the coop, % of them provided free-range during daytime and a small proportion of keepers ( %) preferred both of them (elkhorabi et al., ; yendell et al., ) . very few bird keepers used portable housing or cages for rearing the birds. in a us-based study, perches ( %) and nest boxes ( %) were mostly used as roosting and egg-laying space, respectively (elkhorabi et al., ) . similarly, in new zealand, the majority of the bird keepers rear the birds by free-range within the boundaries of the property during daytime (lockhart et al., ) . the women even with high educational background mostly take care of the birds like rural backyard farming. in the united states, the birds ( %) mostly receive a mixed ration of feed (purchased and kitchen scraps). although a small fraction of keepers ( . %) did not offer any supplementary feed to the birds in expectation that the birds will collect their feeds from free range. similarly, majority of the keepers ( %) provide fresh water to the birds and only . % of the keepers allowed the birds to obtain the drinking water from natural sources. the bird keepers ( %) also used supplemental grit and calcium for their birds, especially for the laying hens (elkhorabi et al., ) . in new zealand, the majority of the keepers use purchased feeds (lockhart et al., ) . in the european union, countries feeding kitchen scraps (except raw vegetables from the garden) to the food-producing animals, including chickens kept as pets, is banned since to prevent the transmission of zoonotic infections. access of poultry to the compost mass containing kitchen waste is also restricted (whitehead and roberts, ) . in developing countries, the backyard poultry sector mostly suffers from two infectious diseases, such as avian influenza (ai) and newcastle disease (nd) due to lack of biosecurity and proper vaccination (alexander, ) . surveillance of infectious diseases (such as ai) in backyard and free-grazing poultry is challenging due to the reluctance of the farmers to report outbreaks (kanamori and jimba, ) . avian influenza virus (aiv) infection is reported from poultry and wild birds in asia, africa, and europe (oie, ). the transmission of zoonotic aiv has so far (january ) generated human cases with deaths (who, .). among different subtypes of aiv, h and h are considered as pathogenic and are frequently isolated from chicken, turkeys, quails, and pheasants (suarez et al., ) . ducks and shorebirds mostly carry h , h , h , h , h , and h sybtypes of aiv (suarez and schultz-cherry, ) . genetic reassortment between avian and swine influenza can occur and generate a new subtype. h n is an example of a reassorted subtype that was detected in backyard birds and swine in ohio (killian, among the african countries, egypt is considered as endemic for aiv in spite of several attempts to eradicate the virus. in , backyard flocks accounted for % of the ai outbreaks in poultry. the infection was further confirmed in human patients having exposure to the backyard flocks (kandeel et al., ) . moreover, higher infection rates of aiv (h and h ) were observed in backyard birds and birds from local bird markets in comparison to birds from commercial farms in egypt (osman et al., ) . furthermore, a higher prevalence of aiv was reported in backyard flocks that had mixed populations of chickens and waterfowls together (el-zoghby et al., ) . two clades of hpai-h n are circulating in egypt, known as classic . . and variant . . strains (hafez et al., ) . the classic strain originated from ducks (saad et al., ) and currently is maintained in backyard birds. the variant strain has been circulating in commercial poultry since late (hafez et al., ) . the phylogenetic analysis of hpai strains from egypt revealed close relationship with the h n viruses circulating in gaza and israel, suggesting a common virus progenitor (el bakrey et al., ) . similarly in libya, hpai-h n belonged to . . lineage having similarities with egyptian isolates. it was detected in backyard flocks (kammon et al., ) . (chaka et al., ) . furthermore, in central africa (cameroon, central african republic, congo-brazzaville, gabon), evidence of aiv was detected in chickens, ducks, songbirds, and kingfishers (fuller et al., ) . in mali (west africa), ai seroprevalence was significantly higher in backyard birds than the commercial farms (molia et al., ) . severe h n outbreaks were detected in all kinds of poultry in thailand (asia) during - , which was later controlled, and in , toie declared thailand as free of h n infection (oie, ) . the study with the scenario of the tree modeling approach in backyard flocks in thailand also revealed the high probability to be free from h n infection (goutarda et al., ) . however, the backyard flocks in other asian countries possess the aiv. evidence of h n aiv was observed in a village backyard flock in kandal province in cambodia (theary et al., ) . in pakistan, two highly pathogenic subtypes (h n and h n ) caused a sporadic ai outbreak in poultry in . vaccination was done in poultry against h , h , and h subtypes to control the infection. as a consequence of reassortment with vaccine strains a more virulent subtype (h n ) of the virus appeared, which crossed the species barrier and further infected human. this reassorted subtype (h n ) possessed a nonstructural gene segment of h n , which increased the capacity of the virus to adapt to new hosts (due to ifn-β inhibitory activity) and environments (munir et al., ) . currently the existence of h n subtype is also detected in apparently healthy backyard flocks in pakistan. so, the backyard flocks in pakistan act as asymptomatic carrier of h n with increased possibility of human transmission (munir et al., ) . the h n virus circulating in pakistan belonged to the g lineage of virus (qa/hk/g / ), which was also common in hong kong (iqbal et al., ) . h n originated in turkeys in (homme and easterday, ) . since then it has been considered as a low pathogenic strain (lpai) and is panzootic in multiple avian species in asia, middle east, africa, and europe (capua and alexander, ) . the property of cross species transmission to human was first detected in in hong kong and china, which also originated from poultry (peiris et al., ; butt et al., ) . in bangladesh (asia), h n subtype of lpai is frequently detected in commercial poultry and backyard flocks that are phylogenetically related to south asian and middle east isolates (parvin et al., ) . moreover, h n isolates of bangladesh also possessed the evidence of reassortment between h n and h n subtypes like their counterparts in pakistan (parvin et al., ) . a low proportion ( %) of backyard birds in bangladesh die every day due to hpai infection. clinical study showed that cyanotic comb and wattle are frequently observed in both commercially farmed and backyard poultry (p = . ), but edema of the head and face, drowsiness, and huddling were more common in backyard farms (p = . ; p = . ) (biswas et al., a,b) . furthermore, full genome analysis of hpai viruses (h n ) isolated from poultry including backyard flocks in bangladesh revealed the evidence of reassortment between two circulating clades of viruses ( . . . and . . . ) and also between hpai (h n ) and lpai (h n ) strains (gerloff et al., ) . the virus clade . . . was introduced in bangladesh after and the strain spread into different places and species (chickens, crows) in the country (islam et al., ) . the aiv belonged to similar lineage with bangladeshi isolates were also detected in nepal suggesting the transboundary transmission either through trade or wild birds (nagarajan et al., ) . similarly in india (neighbouring country of bangladesh) the existence of hpai-h n clade . . . was observed in poultry since (nagarajan et al., ) . until , the clade . dominated in indian poultry (chakrabarti et al., ; pattnaik et al., ) . in europe, ai virus belonging to clade . was most prevalent among poultry and wild birds (brown, ). however, in romania, hpai h n virus of clade . . was detected in backyard flocks (reid et al., ) . in italy, eight hpai outbreaks in backyard poultry flocks infected with h n virus were reported in - (alexander, ) , while chickens raised for recreational purposes in the urban localities in the netherlands acted as major risk factors for a hpai outbreak in (slingenbergh et al., ) . in maryland (united states), low seroprevalence ( . %) of aiv was detected in backyard birds. no evidence of subtypes h , h , and h was observed. the seroprevalence was positively correlated (not statistically significant) with exposure to waterfowl, pest control, and location (madsen et al., ) . in new zealand also, low seroprevalence ( . %) of hpai was detected in backyard chickens and no influenza a virus was detected by molecular technique (zheng et al., ) . newcastle disease virus (ndv) belonged to the genus avulavirus and family paramyxoviridae (niewiesk and oglesbee, ) . all the ndvs come under a single serotype but based on phylogenetic analysis it is divided into two classes: class i and class ii. class i strains are mostly apathogenic for chicken except one isolated from waterfowl and shore birds. all the pathogenic strains belonged to class ii, and this class is further divided into genotypes (i-xi). among them, i, ii, iii, iv, and ix genotypes are considered as "early/old" (appeared between and ) and the genotypes appeared after are considered as late/recent (v, vi, vii, viii, x, xi) (kim et al., ) . backyard flocks throughout the world, especially in asian and african countries suffer or carry the ndv infection (permin and pedersen, ) . pakistan (asia) is considered as endemic for ndv infection in poultry. both commercial and backyard flocks can carry the infection, and all the virus isolates from both of the sectors belonged to genotype vii. the backyard flocks, however, do not show any syndrome of nd, but the virus isolated from the backyard flocks possessed a typical motif in f-protein associated with virulence. frequent contact with commercial poultry might be responsible for the transmission of virulent ndv into the backyard flocks and the virus was later adapted in the backyard flocks (munir et al., ) . however, in nepal, nd was detected to be responsible for % mortality in backyard flocks during (alexander, ) . in iran (bushehr province), % seroprevalence of ndv antibody was detected in unvaccinated backyard chickens (saadat et al., ) . in africa, studies revealed an average nd serological prevalence of . [ % (ci) . - . ] in poultry, which is more prevalent in the area with low altitudes, high humidity, and high human and poultry population densities. these predisposing factors are also favorable for persistence of ndv in backyard flocks because high humidity enhances virus survival and further transmission through the oral route. comparison of the ndv transmission rate within the flocks revealed more rapid transmission in the commercial sector than in the backyard flocks (miguel et al., ) . in a study in ethiopia, overall seroprevalence of the ndv antibody in backyard flocks was detected as . %- % in different seasons, which is higher than the average ndv seroprevalence ( . %) in africa . the backyard farmers also identified nd as the most prevalent infection among the birds in ethiopia (sambo et al., ) . moreover, in mali, among unvaccinated backyard birds, nd seroprevalence was . %, and the seropositivity was more associated with adult, female chickens than the ducks (molia et al., ) . in the middle-east countries, ndv has been circulating in poultry populations since the last century. in oman, high seroprevalence ( %) of ndv was detected in backyard flocks with mild or no symptoms. the management practices, such as introduction of new birds into existing flocks, direct contact with neighboring poultry and feeding of uncooked poultry waste were correlated with this high seroprevalence (al . the seroprevalence data of ndv in backyard flocks in other countries is variable. in new zealand, . %- % of the studied backyard chickens were seropositive for ndv antibody. all the chickens reared with ducks were found seropostive (dunowska et al., ) . in the periurban area of madagascar, a study showed that ndv was responsible for % of annual mortality in local backyard chickens (maminiaina et al., ) . in brazil, higher seroprevalence of ndv was detected in backyard flocks in which the farmers introduced their own poultry to restock the flock. this replacement caused the continuous presence of virus in the flock. further, proximity to water bodies (estuary) provided direct contact with other infected birds and favored the transmission of ndv (marks et al., ) . the ectoparasites were the most commonly reported health problem in backyard flocks in developed countries, such as in united states and canada (garber et al., ; burns et al., ) . in a study in california (united states), % of the backyard premises were observed to be infested with ectoparasites. the permanent ectoparasites detected in the study were six species of chicken louse, such as menacanthus stramineus ( %), goniocotes gallinae ( %), lipeurus caponis ( %), menopon gallinae ( %), menacanthus cornutus ( %), and cuclotoasterheterographus ( %). among the chicken mites, three species were most prevalent [ornithonyssus sylviarum ( %), knemidocoptes mutans ( %), dermanyssus gallinae ( %)]. it is noteworthy to mention that these parasites were exclusively detected in backyard flocks, not in commercial layers in california (murillo and mullens, ) . backyard flocks kept in and around the mississippi river delta suffered from black fly (simulium spp.) infestations. the external signs, such as cutaneous hemorrhagic lesions and a huge numbers of black flies within the digestive tract of the birds (after post mortem) were found. black flies can also transmit some blood protozoa (leucocytozoon spp., haemoproteus spp.), which cause further infection in the affected poultry. moderate occurrence ( %) of leucocytozoon spp. was detected in black fly infested backyard flocks (jones et al., ) . in the united states, toxoplasma was detected in %- % of backyard chickens although clinical cases of toxoplasmosis are rarely reported in poultry (dubey and jones, ) . in tropical countries, humid climatic conditions favor the growth of helminths, which reduce the egg and meat production of backyard poultry. in a study in india (jammu and kashmir), % of the backyard flocks were determined infested with gastrointestinal helminths. in the studied state of india, ascaridia galli was the most prevalent helminth ( . %) among the flocks. other helminths, such as heterakis gallinarum, raillietina cesticillus, and raillietina echinobothrida were also detected. the backyard chickens of the studied area take various insects as feed present in the soil, which may act as intermediate hosts for helminths ( fig. . ) (katoch et al., ) . similarly, in other tropical countries, such as in ethiopia (africa), % of the backyard flocks were infected with several cestode and nematodes (hussen et al., ) . low occurrence ( %) of histomonas meleagridis, a blood protozoon, was detected in backyard flocks in vietnam (nguyen et al., ) . triatoma dimidiata, a vector of trypanosoma cruzi causing chagas disease in humans was identified in the chicken coops in mexico (koyoc-cardeña et al., ) . in australia, the study showed that % of the backyard flocks suffer from coccidiosis (eimeria). the weather of australia, such as ambient temperatures around °c and high humidity (> %), favors the growth of eimeria and three species, such as e. mitis, otu-y, and e. acervulina were most prevalent (godwin and morgan, ) . meat and poultry products are recognized as the major sources for transmission of salmonella spp.(a gram-negative zoonotic bacterium) to human with % of the clinical cases attributed to the consumption of egg and poultry products (sanchez et al., ) . nontyphoidal salmonella spp. is reported to cause . million sufferings, including , people admitted to hospitals and deaths in a year in the united states (scallan et al., ) . sometimes, poultry birds, although infected with salmonella spp. and appearing healthy, can shed the bacteria through the faeces (behravesh et al., ) . human outbreaks of salmonellosis, especially between the caretaker and children associated with backyard poultry, are a global concern nowadays (cdc, ). moreover, many serovars of salmonella spp. can produce serious diseases and deaths in chickens too, especially at a young age (samanta, ) . the seroprevalence rate of salmonella in backyard chicken was moderate ( %) in argentina (xavier et al., ) . however, a lower isolation rate was reported by (jafari et al., , namata et al., and leotta et al., who found . , , and . % as salmonella prevalence in backyard chicken flock in iran, belgium, and paraguay, respectively. in a study in backyard birds (rir breed) in india (west bengal), the isolation rate of salmonella was %. salmonella isolates were also obtained from feed ( %), drinking water ( %), and eggs ( %) of the studied backyard flocks. no salmonella was detected from utensil swabs, litter, swab from the wall of the poultry house, dried manure under the house, and soil collected from all the studied agroclimatic zones. salmonella isolation rate was significantly correlated (p < . ) with a higher-age group of the backyard birds ( - weeks) as compared to the middle-or lower-age group. further, none of the salmonella isolates possessed extended spectrum β lactamase (esbl) genes probably due to a lack of antibiotic exposure (samanta et al., a) . transmission of antimicrobial-resistance genes into the commensal flora may take place in the intestinal tract of animals, including birds (gustafson and bowen, ) . specifically, the esbl enzymes are increasingly expressed by many strains of bacteria with a potential for dissemination. these esbls diminish the activity of wide-spectrum antibiotics, creating major therapeutic difficulties in treatment of the patients (samanta et al., a) . e. coli are present as commensal microflora of the intestinal tract of mammals including poultry and their environment. among several pathotypes, avian pathogenic e. coli (apec) are able to cause colibacillosis due to possession of specific virulence factors (samanta, ) . in california, e. coli were the most commonly diagnosed infectious diseases among backyard birds (mete et al., ) . e. coli are also classified under several phylogenetic groups. the phylogenetic group b strains are commonly found in mammals and are often associated with extraintestinal infection in humans, pets, and avian species. the group b strains are more commonly associated with ectotherms, birds, and environment (blyton et al., ) . sometimes, e. coli present in avian (apec) and humans (uropathogenic e. coli, upec) share common virulence factors, such as iucc, tsh, papc (rodriguez-siek et al., ) . in india, e. coli isolated from backyard flocks (rir breed) did not possess the virulence genes (iucc, tsh, papc) associated with upec (samanta et al., b) . similarly, virulence gene (papc) was not detected in any of the e. coli isolates from free-range healthy layers in australia (obeng et al., ) . further, none of the e. coli isolates from backyard flocks in india (west bengal) was found to possess extended-spectrum β-lactamases (bla tem , bla shv , bla ctx-m ) or quinolone resistance gene (qnra) due to a lack of antibiotic exposure (samanta et al., b) . thus, the studied backyard birds in india can be considered as safe food in relation to virulent and antibiotic resistant commensal bacteria. similarly, no esbl-producing e. coli were detected in backyard flocks in finland (pohjola et al., ; miranda et al., ) , which also reported lower levels of antibiotic resistance in e. coli isolates from organic poultry meat. in contrast, tetracycline resistance was most common in e. coli isolates from backyard poultry ( %) than in-care birds ( %) and wild birds ( %) in australia due to the use of tetracycline for treatment of the birds (blyton et al., ) . fowlpox virus belongs to the genus avipoxvirus and family poxviridae. it can infect the poultry throughout the world. most of the infections in backyard birds are reported from asia. in a study in india (west bengal), fowlpox virus was detected in a backyard flock with pock lesions in comb, eyelid, beak, and wattle. sequence analysis revealed the presence of nearly full-length reticuloendotheliosis provirus within the genome of fowlpox virus (biswas et al., a,b) . a number of fowlpox outbreaks without reticuloendotheliosis virus have also been reported from backyard poultry at different regions of india and iran (dana et al., ; das et al., ; gholami-ahangaran et al., ; roy et al., ; saha, ) . further study detected immunodominant b-cell and t-cell antigens in the fowlpox virus isolates from backyard birds, which will be useful for vaccine production (roy et al., ) . . it seems that backyard poultry and free-ranging birds act as a center for ibv transmission currently (promkuntod, ) . in canterbury, new zealand, revealed the presence of campylobacter spp. in % of the studied backyard chicken flocks (anderson et al., ) . campylobacter jejuni alone, campylobacter coli alone and both c. jejuni and c. coli were detected in ( %), ( %), and ( %) of the flocks, respectively. pfge analysis and comparison of the genotypes with the pulsenetaotearoa campylobacter database showed the similarity of the isolates with the isolates from human and commercial chickens indicating the possibility of crosstransmission. in finland, backyard chickens were also detected as a reservoir of c. jejuni strains (pohjola et al., ) . clinical listeriosis is rare in birds. however, recently an outbreak of listeria monocytogenes was observed in backyard flocks in seattle (united states). depression, lack of appetite, labored breathing, and increased mortality were noted in several affected birds. the pathologic changes in the internal organs of infected birds included severe myocarditis, pericarditis, pneumonia, hepatitis, and splenitis. no lesions were noted in the brain (crespo et al., ) . in finland too, backyard chickens were observed to possess l. monocytogenes, although their role as a primary reservoir is questionable (pohjola et al., ) . in europe, seroprevalence studies in backyard and fancy-breed poultry flocks revealed the presence of mycoplasma gallisepticum, ornithobacterium rhinotracheale, and avian metapneumovirus antibodies (haesendonck et al., ) . in another study in oman, backyard flocks were positive for avian metapneumovirus subtype b (al- . pasteurella multocida causing fowl cholera was detected in . % backyard birds in egypt. most of the p. multocida isolates belonged to a: serotype (mohamed et al., ) . among noninfectious conditions, fatty liver hemorrhagic syndrome (flhs) and reproductive tract adenocarcinoma were the leading causes of mortality in backyard flocks in california (mete et al., ) . necropsy findings in flhs include abundant coelomic fat and an enlarged, tan to yellow, friable liver with hemorrhages. another study revealed absence of hepatocellular lipidosis in % of the flhs cases and mild hepatocellular lipidosis in % of the flhs cases in the backyard birds (trott et al., ) . lead toxicosis was detected in backyard flocks in california and the flaking paint from a wooden structure in the chicken coop was identified as the source of toxicosis. no clinical signs in the birds were detected. however, the birds were excreting the lead through the eggs. the edible portion of the eggs contained lead levels as high as . µg/g (bautista et al., ) . in urban backyard flocks in the united states, ectoparasites, diarrhea, injuries, prolapsed vent, sour crop, and vices (feather pecking, cannibalism, piling, aggression) are most common menaces. mortality due to diseases or vices is uncommon. the predation is the major cause of mortality in urban backyard flocks both in the united states and the united kingdom (elkhorabi et al., ; karabozhilova et al., ) . in minnesota, lameness was the most commonly observed symptom followed by nasal or eye discharge, coughing, sneezing, and swollen sinuses in urban backyard flocks (yendell et al., ) . vaccinations are an important tool for disease prevention in all poultry flocks throughout the world. the vaccines against ndv infection are available for decades, but in most of the countries they are sold in large vials of more than doses, which are expensive for small-scale backyard farmers. the reconstituted vaccine should be used within a short period of time to avoid the loss of potency (merck animal health, ) . further, in remote villages, accessibility of the vaccines, proper diluents, cold chain, and, moreover, qualified paraveterinarians are limited. in some countries, such as in ethiopia, the vaccines are produced locally, which also creates challenges, such as irregular supply of specific pathogen-free (spf) eggs, required for sustainable vaccine production (sambo et al., ) . consequently, production and supply of vaccine is often hampered. because of all these factors, conventional vaccination is not usually performed in most of the backyard flocks each year to prevent the outbreaks. in the literature, very few examples are present regarding successful vaccination in backyard flocks. in java (indonesia), a large-scale mass vaccination was carried out to control outbreaks of hpai in backyard flocks, and positive titer to h was detected in %- % of poultry sampled in the mass vaccination area. in the hpai-nd combined vaccination group, %- % of the population had positive nd titers, compared to %- % in the areas without nd vaccination . in another study in indonesia, the results suggested that the hpai-nd combined vaccination significantly reduced the incidence of hpai in backyard poultry (bett et al., ) . several types of inactivated h n and h n vaccines were also used in egypt to control hpai outbreaks (abdelwhab and hafez, ) . however, use of live vaccine against hpai is a controversial issue, and it is presumed that such vaccination against hpai in china helped in the evolution of more virulent virus strain (smith et al., ) . in pakistan, too, it is speculated that import of live poultry and extensive use of live vaccines can pose a huge risk for the emergence of new ndv strain (munir et al., ) . in most of the endemic countries, such as in india, vaccination is not practiced to control the hpai infection in poultry. culling or stamping out birds in a - km declared infected area is the official policy to control the outbreak in india (dadf, ). the metapopulation dynamic study of a poultry population in the united states demonstrated the effectiveness of culling in reducing the number of outbreaks in large poultry populations (hosseini et al., ) . besides conventional vaccines, a novel approach in the form of fast-dissolving tablets (fdt) against nd virus was also produced. the virus (lasota strain) was freeze-dried into tablets containing a small number of doses, which is economically feasible for backyard farmers. the vaccine tablet can be diluted in water and administered either in drinking water of birds or by intraocular and/or intranasal route. the compact packaging of the fdts will also provide cost savings in storing and distributing the vaccine in the cold chain (lal et al., ) . treatment of diseases in backyard flocks is also limited. the backyard poultry farmers in india (west bengal) are reluctant to call for the assistance of local veterinarians or paraveterinarians due to lack of awareness, time, and motivation. in addition, doorstep services are also unavailable, especially in the remote villages (debnath et al., ) . the landless or marginal farmers also could not afford the treatment or vaccine costs (indian rupees or us$ . per bird/year) (sapplpp, ) . this is the probable reason the backyard birds reared in this part of india are not exposed to the antimicrobials and thus the commensal (e. coli, salmonella spp.) present in the birds do not possess major antibiotic resistance genes (samanta et al., b) . in bangladesh, sometimes the farmers prefer to collect the medicines and suggestions from the local medicine shops. the farmers also avoid the government animal health centers due to lack of proper diagnosis and availability of poultry medicines (sultana et al., b) . the reluctance of owners to seek veterinary attention was also noted even in developed countries, such as the united states ( . % farmers use veterinary service), the united kingdom, and chile (garber et al., ; hamilton-west et al., ; karabozhilova et al., ) . the urban backyard farmers in the united states mostly use dewormers (coccidiostats) and antibiotics in larger flocks (< ) of birds (elkhorabi et al., ) . in chile, the backyard birds were sometimes treated with the drugs approved for human use, which could be responsible for presence of drug residues in the poultry products (greenlees, ) . the animals and animal products (examination for residues and maximum residue limits) regulations, , control residues of medicines in food animals, including poultry, in european union countries. these regulations divide medicinal substances into three categories: allowed, prohibited, and unlisted. use of prohibited/unlisted medicines in poultry (commercial and backyard) is illegal (table . ) (whitehead and roberts, ) . occasionally, elderly farmers offered ethnoveterinary medicines, such as sour fruits, chili, and warm water to their backyard flocks (sultana et al., a) . similarly, in ethiopia, tobacco leaf, "melia" plant, pepper, garlic, lemon juice, and table oil is administrated with drinking water to the sick birds (sambo et al., ; yemane et al., ) . in brazil, ash is applied on the body of backyard birds to prevent parasite infestation. in nigeria, the ashes after burning of nicotiana rustica, n. tabacum, or carica papaya leaves are used. this is rubbed into the plumage to protect against parasitic infestation. shea butter is used as a curative method against bird scabies. palm oil is used especially against fleas and mites. tobacco leaves (nicotiana tabacum) provide protection for approximately month against sarcoptes, psoroptes, and demodex (salifou et al., ) . in bangladesh, indonesia and china, the sick birds are slaughtered and consumed when the treatment fails (padmawatia and nichterb, ; sultana et al., b; zhang and pan, ) . addition of an indigenous homemade probiotic (axone/akhuni) in diet (at % w/w) significantly improved the growth rate, egg production, and egg weight of backyard poultry in india (vanraja variety). microbiological analysis of the probiotic (axone) revealed the presence of bacillus coagulans, a well-known beneficial bacterium (singh and singh, ) . the zoonotic pathogens, such as hpai are transmitted to humans from the backyard birds through direct or indirect contact. the direct contact takes place while walking through the flocks and handling sick poultry and while slaughtering poultry personally without appropriate protection (burns et al., ; liao et al., ). at the time of slaughter, the most commonly identified risk factors were direct contact with infected blood or other body fluids (van kerkhove et al., ) . associated risk factors related to environmental exposure include cleaning poultry areas, removal of feces, using poultry waste as fertilizer, inhalation, ingestion, and intranasal inoculation of contaminated water (van kerkhove et al., ) . indirect contact is more frequent and takes place when backyard farmers are exposed to apparently healthy poultry without any precautions (rabinowitz et al., ) and when the farmers meet with each other (burns et al., ) . backyard poultry acted as greater source of hpai transmission than the commercial birds due to the absence of biosecurity measures. it is also estimated that average daily contact rate of humans was higher with the backyard flocks than with commercial poultry ( . or contacts per year) (patyka et al., ) . rural people are at higher risk of hpai transmission than their urban counterparts due to greater amount rearing of these backyard birds. besides from being an essential component of rural livelihood, poultry rearing is also an important sector of the agricultural ecosystems. the droppings of chickens are used to feed aquatic animals and as soil fertilizers, which facilitates pathogen transmission (liao et al., ) . moreover, asian rural people prefer to take freshly slaughtered poultry than the packaged and processed meat. in a study in southeast asia, it was observed that almost all vietnamese and more than half of the thai people slaughtered the birds by themselves at home. this kind of practice also increases the possibility of disease transmission (liao et al., ) . cock fighting (a traditional recreation in rural asia) with backyard birds may also play a role in disease transmission. the owners transport their birds long distances to participate in bouts and sometimes they lick the wounds on their fighting cocks (edmunds et al., ) . more hazardous practices, such as keeping birds inside the bedroom, scavenging of birds around the places where food is cooked, using the same water source where villagers bath or wash their utensils for the birds' drinking were observed in bangladesh (sultana et al., b) . the hpai virus belonged to clade . . and was prevalent in backyard and commercial poultry in india and bangladesh before (who, ) . during that period ( ), an hpai outbreak in humans was detected, which was also followed by two subsequent human cases. in all these cases, the etiological virus belonged to clade . . with other similar genetic characteristics indicating the cross-transmission from the poultry (brooks et al., ) . in vietnam, most of the human exposure ( %) to hpai occurred from the backyard poultry (fielding et al., ) . in thailand, during - , confirmed h n cases in humans were detected of which persons died (who, ) . the history of direct contact to the backyard chickens and free-grazing ducks appeared to be related to h n infections in humans in thailand (chantong and kaneene, ) . in china, a total of h n infections were identified in the zhejiang province in humans during . all the live poultry markets were closed and backyard poultry were slaughtered to control the outbreak in the locality (gong et al., ) . in beijing (china), farmers who reared ducks in their backyards possessed antibody against avian influenza, but they never vaccinated, indicating the means for possible transmission . using logistic regression, it was shown that backyard poultry could act as a source of campylobacter jejuni infection to children (el-tras et al., ) . lpai is also transmitted from poultry to humans causing influenza-like syndrome (cdc, ) . antibodies against h and h avian influenza virus were detected in a small locality in lebanon among the backyard farmers (kayali et al., ) . there is serologic evidence that waterfowl hunters, wildlife professionals, and veterinarians are at higher risk of infection with lpai (gill et al., ; myers et al., ) . urban backyard flocks also pose a major risk for transmission of zoonotic pathogens, such as salmonella spp. in young and elderly persons handling the birds (pollock et al., ) . centres for disease control and prevention (cdc) had warned about handling of poultry by people below years of age (cdc, ) . other than transmission of zoonotic pathogens, eggs of the backyard birds are also detected to be contaminated with dioxins (lin et al., ) . during scavenging, the birds get access to the source of dioxins, such as soil, feeds, plants, insects, building materials containing fly ashes, debris, etc. (solorzano-ochoa et al., ) . dioxins enter the body through ingestion and mostly accumulate in the liver, ovarian follicles, and the adipose tissue (piskorska-pliszczynska et al., ) . the vicious cycle of hpai virus transmission from the reservoir ducks into the backyard flocks was detected. in south asia, domestic ducks were the major risk factor for hpai persistence and transmission into the backyard poultry (gilbert and pfeiffer, ) . in madagascar, the high density of ducks (palmipeds) and prevalent rice paddies were associated with ai infection in backyard birds (andriamanivo et al., ) . the water bodies and their banks or rice paddies are contaminated with the virus excreted by the reservoir ducks. the virus survives in the lower temperature of the water. the backyard flocks are exposed to the contaminated water and the virus is transmitted through oral route. so the presence of water bodies adjacent to the backyard farm is considered a major risk factor for the transmission of pathogens. other than ducks, wild birds found around the water bodies, such as teals (anas chlorotis), swans (cygnus atratus), shags (phalocrocorax carbo), seagull (larus novaehollandiae scopulinus), pheasant (phasianus colchicus), turkeys (meleagris gallopavo), and hawks (circus approximans) also play an important role in transmission of hpai in backyard flocks (zheng et al., ) . sparrows (passer domesticus) and starlings (sturnus vulgaris) most commonly visit the place where the backyard flocks are kept. both sparrows and starlings are susceptible to experimental hpai infection (boon et al. ) and thus may act as a source of infection for the backyard birds. moreover, in a metapopulation dynamics study, it was observed that movement of ai virus between commercial and backyard poultry may contribute to the maintenance of outbreaks in an area, but direction of the viral transmission cannot be predicted (farnsworth et al., ) . in bangladesh, the poultry purchased from the market are slaughtered at home and the remnants are offered to their backyard flocks. this malpractice is considered as the strongest risk factor for transmission of hpai in backyard flocks in bangladesh (biswas et al., ) . in egypt, significant correlation exists between disposal of poultry carcass and feces in the environment and hpai infection in poultry (f = . , p < . ) (sheta et al., ) . in ethiopia, scavenging behavior of backyard chickens and chicken dealers were considered a major risk factor for infecting the backyard flocks. a number of farmers identified dogs bringing infected carcasses home to be an additional risk factor for transmission of infection (sambo et al., ) . female backyard birds were found to be more susceptible to ndv infection than male chickens due to extensive roaming throughout the village with a greater possibility of exposure to infected birds (molia et al., ) . biosecurityis in practical terms a mindset or philosophythat must be developed by the producers to prevent the entry of disease into the flock. it is an approach with a focus on maintaining or improving the health status of the birds and preventing the introduction of new pathogens by assessing all the possible risks (permin and detmer, ) . in rural backyard farming specially in developing countries, biosecurity measures are not practiced due to a lack of awareness and high cost of the measures (samanta et al., c) . for example, the cost of a hen house in cambodia (southeast asia) is us$ , whereas, the average monthly income of a cambodian family is us$ (conan et al., ) . a study conducted in a broiler farm in finland detected . euro cents (us$ . ) per bird as an average biosecurity cost (siekkinen et al., ) . in bangladesh, although government circulated -point biosecurity measures to prevent aiv transmission, the backyard farmers ignored these recommendations because they were unable to identify the infection and measure the transmission risk. most of the farmers considered the disease as fate or god's will or due to exposure to evil gas and air (sultana et al., b) . after confirmation of human h n infections in anhui province (china), the provincial government decreed that all backyard poultry must be kept in cages but the authority failed to implement the law (kaufman, ) . similarly, poultry farmers of indonesia (java) and china (haining) ignored the biosecurity practices due to lack of knowledge regarding zoonotic potentiality of avian influenza (padmawatia and nichterb, ; zhang and pan, ) . in literatures, there are very few examples of the biosecurity practices being followed in the rural backyard farms in the developing countries. in ethiopia, removal of manure and bedding from the chicken coops was occasionally performed to sell the objects directly as fertilizer. the materials used to build the chicken sheds, such as mud and cow dung made it difficult for sufficient cleaning with chemical disinfectants (sambo et al., ) . in ghana, general biosecurity practices, such as hand washing after handling poultry, was low in the farmers (odoom et al., ) . in bangladesh, the farmers who kept the birds in the sheds, cleaned the sheds every - days. the dried poultry feces and other debris were collected in a basket and directly used as fertilizer. the sick birds were mostly slaughtered for consumption. hand washing with soap after slaughter, cleaning up the slaughter place in the yard with detergent was rarely practiced. the offals and visceras after slaughter were thrown into the nearest water bodies and bushes (sultana et al., b) . similarly in india (west bengal), a low level of biosecurity awareness was observed among the backyard farmers, such as preparation of feed with boiled water (only % of the cohort), cleaning of feeding utensils and the drinking trough once in a month ( %), frequency of change of drinking water in the trough in days interval ( %), frequency of change of litter in days ( %), and storage of eggs at room temperature ( %). majority of the farmers ( %) did not wash their hands before providing feed to the birds and before entry or exit of the poultry houses (table . ) (samanta et al., c) . in developed countries, a moderate level of biosecurity awareness among the backyard farmers was observed probably due to higher education and socioeconomic conditions. in chile, dead or sick backyard birds were neither consumed nor sold (hamilton-west et al., ) . in european union countries, consumption of birds kept for the purpose samanta, i., joardar, s.n., ganguli, d., das, p.k., sarkar, u., b . evaluation of egg production after adoption of biosecurity strategies by backyard poultry farmers in west bengal. vet. world , [ ] [ ] [ ] [ ] [ ] [ ] of showing or as pets is prohibited (whitehead and roberts, ) . in new zealand, poultry waste was composted prior to use as fertilizer on pastures or gardens to reduce the possibility of disease transmission (zheng et al., ) . in canada (british columbia), the biosecurity measures, such as limiting human visitors to the flock, isolation of new and sick birds, use of footbaths during entry or exit of the shed, changing clothes when returning home, designing pens to decrease risk of wild bird contact, and not sharing equipments were observed (burns et al., ; yendell et al., ) . in the united states, the keepers of the backyard flocks followed similar kind of biosecurity measures, especially hand washing after handling the birds (beam et al., ) . however, majority of them did not use separate clothes to enter the coops and allowed visitors in the coop area. feed and water of their birds were accessible to wild birds and rodents. the keepers were mostly unaware about the disease transmission possibility associated with the presence of wild birds or rodents (elkhorabi et al., ) . lack of knowledge regarding the sources of infection and transmission pathways is still deficient among bird keepers, even in developed countries (beam et al., ; burns et al., ; garber et al., ; karabozhilova et al., ; lockhart et al., ) . cdc played a major role by publishing educational documents on the risk of zoonotic pathogens from contact with live poultry, especially for inexperienced flock owners (cdc, ) . the guideline is also framed for urban backyard poultry owners to reduce the risk of pathogen transmission. the guideline stressed limited flock size, composting of manure before using as fertilizer, prohibition of slaughter, required veterinary care to sick birds, and appropriate disposal of dead birds (tobin et al., ) . the fao had issued several guidelines for the farmers on how to increase biosecurity in backyard flocks, but a significant proportion of villagers continue their at-risk practices as observed in several countries (fao, (fao, , . this discrepancy was explained by the fact that measures were often costly and may not be correlated with the economic benefits of the farmers (aini, ) . in bangladesh, the biosecurity recommendation issued by the government to decrease the transmission of ai was not followed by the farmers because change in practices caused financial losses (sultana et al., b) . in india (west bengal), a cost-effective, agroclimatic zone-specific biosecurity strategy was developed for backyard farmers. the strategy stressed daily cleaning of the utensils with ash, offering potable drinking water to the birds, preparation of feed with boiled water, daily change of drinking water in the trough, sprinkling of detergent water left after washing of clothes in the scavenging area, disposal of carcasses by garden burial, washing of the eggs, storage of the eggs in cold temperature maintained by indigenous structures, and so forth. the strategy was moderately well adopted among the farmers due to its cost-effective nature and the ease of administration. adoption of such strategies caused change in practices (table . ) and as a consequence, the egg production level in the studied village increased (samanta et al., c) . the chapter elaborated the backyard farming including breeds reared, housing, feeding, with special emphasis on suggested biosecurity strategies and consequence of the adapted strategy. other than chicken as the primary species, turkeys, geese, ducks, muscovy ducks, quail, pigeons, and guinea fowl are reared by backyard farming throughout the world. the birds are kept by permanent confinement, free-range, and mixed confinement. in developing countries, the backyard poultry sector mostly suffers from two infectious diseases, such as ai and nd due to lack of 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legislation, zoonoses, and disease prevention cumulative number of confirmed human cases of avian influenza a(h n ) reported to who. who continued evolution of highly pathogenic avian influenza a (h n ): updated nomenclature cumulative number of confirmed human cases of avian influenza a(h n ) reported to who. who poultry production and performance in the federal democratic republic of ethiopia seroprevalence of salmonella and mycoplasma infection in backyard chickens in the state of entre ríos in argentina characterization of village chicken production performance under scavenging system in halaba district of southern ethiopia antibody prevalence of lowpathogenicity avian influenza and evaluation of management practices in minnesota backyard poultry flocks surviving the crisis: adaptive wisdom, coping mechanisms and local responses to avian influenza threats in haining, china a cross-sectional survey of influenza a infection, and management practices in small rural backyard poultry flocks in two regions of new zealand influence of different rearing systems on natural immune parameters in broiler turkeys a cross-sectional survey of influenza a infection, and management practices in small rural backyard poultry flocks in two regions of new zealand estimates of enteric illness attributable to contact with animals and their environments in the united states avian fatty liver hemorrhagic syndrome: a comparative review avian and pandemic human influenza policy in south-east asia: the interface between economic and public health imperatives university of hawaii at manoa, college of tropical agriculture and human resources key: cord- - yt fzo authors: mcloud, theresa c.; boiselle, phillip m. title: pulmonary infections in the normal host date: - - journal: thoracic radiology doi: . /b - - - - . - sha: doc_id: cord_uid: yt fzo nan the computed tomography (ct) features of lobar pneumonia are similar to those seen on standard radiography ( fig. - ). there is usually evidence of confluent opacification with air bronchograms. the air bronchograms are often more easily visualized with ct examination. table - summarizes the radiographic clues to the cause of pneumonia. bronchopneumonia (i.e., lobular pneumonia) results when organisms are deposited in the epithelium of peripheral airways (i.e., distal bronchi or bronchioles), resulting in epithelial ulcerations and formation of a peribronchiolar exudate. the inflammatory process spreads through the airway to involve the peribronchiolar alveoli, which become filled with edema and pus. lobules may be affected in a patchy pattern initially, and further spread results in involvement of contiguous pulmonary lobules. eventually, a confluent bronchopneumonia may resemble lobar pneumonia. offending organisms that produce this type of pathologic response include s. aureus, gram-negative organisms, anaerobic bacteria, and l. pneumophila. the radiographic appearance of bronchopneumonia pneumonia is most frequently that of multiple, ill-defined nodular opacities that are patchy but that may eventually become confluent and produce consolidation with airspace opacification (fig. - ) . the opacification may be multifocal and involve several lobes, or it may be diffuse. as the disease progresses, segmental and lobar opacification develops, similar to the pattern of a lobar pneumonia. early necrosis and cavitation can occur. the nodular opaci- ties of bronchopneumonia can be identified with facility on ct scans. the small nodules, usually less than cm in diameter, represent peribronchiolar areas of consolidation or ground-glass opacity. they are called acinar or airspace nodules, but these nodules histologically are found in a peribronchiolar location. they are ill-defined and may be of homogenous soft tissue opacity and obscuring vessels, or they may be hazy and less dense so that adjacent vessels are clearly seen (i.e., ground-glass opacity). these nodules usually have a centrilobular location because of their proximity to small bronchioles. this type of pneumonia is usually produced by viral organisms, which result in edema and mononuclear cell infiltration around the bronchi and bronchiolar walls and extend into the interstitium of the alveolar walls. bronchopneumonia or an acute interstitial pneumonia may be seen with viral infections . the early radiographic appearance is that of thickening of end-on bronchi and tram lines. however, this often evolves into a reticular pattern that may be seen extending outward from the hila. hematogenous spread to the lungs from bacterial infection may occur, although this is unusual. one of the most frequent manifestations is septic infarcts. they usually originate from right-sided tricuspid endocarditis or infected thrombi within major systemic veins. this phenomenon is seen in intravenous drug abusers and patients with longstanding indwelling central catheters. septic infarcts tend to be multiple and peripheral and to abut the pleural surface. they occur more frequently in the lower lobes. these nodules or wedge-shaped opacities may show evidence of cavitation ( fig. - ) . ct often demonstrates a vessel connected to the area of infarction. on ct, the septic infarcts appear as wedge-shaped, peripheral opacities abutting the pleura. they may contain air bronchograms or rounded lucencies of air, sometimes referred to as pseudocavitation. true cavitation is common. occasionally, septic bacterial infection may result in diffuse massive seeding of the lungs with a miliary pattern (i.e., very small nodular pattern), although this is much more common with hematogenous dissemination of granulomatous infections. box - outlines the complications of pneumonia. necrosis of lung parenchyma with cavitation ( fig. - ) may occur in pneumonia, particularly that produced by virulent bacteria, including s. aureus, streptococci, gram-negative bacilli, and anaerobic bacteria. if the inflammatory process is localized, a lung abscess will form. it is usually rounded and focal, and it appears to be a mass ( fig. - ) . with liquefaction of the central inflammatory process, a communication may develop with the bronchus; air enters the abscess, forming a cavity, which often contains an air-fluid level. the walls of the cavity may be smooth, but more often, they are thick and irregular. multiple, small cavities or microabscesses may develop in necrotizing pneumonia ( fig. - ). they are recognized as multiple areas of lucency within a consolidated lobe or segment. a similar appearance may be produced by consolidation superimposed on areas of preexisting emphysema. if the necrosis is extensive, arteritis and vascular thrombosis may occur in an area of intense inflammation, causing ischemic necrosis and death of a portion of lung. this is a particular complication of klebsiella pneumonia and other pneumonias producing lobar enlargement. the radiographic features include multiple areas of cavitation, often with air-fluid levels. portions of dead lung may slough and form intracavitary masses. coned-down view of the right lung demonstrates a fine reticulonodular pattern, which is more prominent centrally. pneumatoceles are usually associated with pneumonia caused by virulent organisms; the classic offender is s. aureus (fig. - ) . they usually form subpleural collections of air, which result from alveolar rupture. radiographically, they appear as single or multiple, cystic lesions with thin and smooth walls. they may show rapid change in size and location on serial radiographs. intrathoracic lymphadenopathy that can be recognized on standard radiographs is uncommon in most bacterial and viral infections; some notable exceptions include mycobacterium tuberculosis, pasteurella tularensis, and yersinia pestis. adenopathy may be associated with fungal infections or bacterial infections that are long-standing or virulent, as in lung abscesses. ct may show slightly enlarged nodes (> cm) in patients with common bacterial infections that are not visible on standard radiography. pleural effusion is a common complication of pneumonia, occurring in about % of cases ( fig. - ). most effusions are parapneumonic, but infection of the pleural space with empyema requiring drainage is an important but uncommon complication of some pneumonias. empyemas can be recognized by the presence of gross pus within the pleural space, by a white blood cell count in the pleural fluid of greater than , cells/mm , by the presence of bacteria within the pleural fluid, or by a ph less than . . chapter provides more detail on the pleural complications of pneumonia. parenchymal necrosis in an underlying pneumonia may produce a fistula between the bronchus and the pleural space (i.e., bronchopleural fistula), and this results in an empyema with an air-fluid level. further discussion of these entities can be found in chapter . rapidly progressive and fulminant bacterial or viral pneumonia may result in the acute respiratory distress syndrome (ards). in the preantibiotic era, bronchiectasis was an extremely common complication of bacterial pneumonia, but the incidence of bronchiectasis has declined with the advent of antibiotics. most pneumonias clear within or weeks, but in elderly patients, resolution may take to months. necrotizing pneumonias also tend to resolve slowly. recurrent pneumonias are frequently found in patients with predisposing factors such as chronic obstructive lung disease, bronchiectasis, alcoholism, and diabetes. although recurrent or persistent pneumonia in the same location raises the possibility of an obstructing endobronchial lesion due to lung carcinoma, cancer accounts for less than % of such cases. the most common gram-positive bacteria causing pneumonia include s. pneumoniae (pneumococcus), s. aureus, and streptococcus pyogenes. s. pneumoniae (box - ) is responsible for one third to one half of community-acquired pneumonias in adults. these infections occur more frequently in the winter and early spring. pneumococcal pneumonia occurs in healthy people, but it is much more common in alcoholic, debilitated, and other immunocompromised individuals. the radiographic features include consolidation that is usually unilateral, although it may be bilateral, and it typically affects the lower lobes (see fig. - ) . although it is a lobar pneumonia, it is uncommon for the lobe to be completely consolidated. cavitation is rare, and large pleural effusions are uncommon. when present, they suggest the development of empyema. sometimes, especially in children, the pneumonia may have a rounded, masslike appearance ( fig. - ) . this is called a round pneumonia; it results from centrifugal spread of the rapidly replicating bacteria by way of the pores of kohn and canals of lambert from a single primary focus in the lung. s. aureus (box - ) is a gram-positive coccus, and the spherical organisms occur in pairs and clusters. this pneumonia rarely develops in healthy adults, but it is sometimes a complication of viral infections and is much more common in infants and children. in infants, unilateral or bilat-eral consolidation involving the lower lungs is the most frequent radiographic presentation. pneumatoceles, thinwalled cysts filled with air or partially filled with fluid, may develop and occasionally rupture into the pleural space, resulting in pneumothorax. in adults, the disease is usually bilateral and is preceded by an atypical pneumonia such as influenza. cavitation is a common feature, and the cavities may be multiple, thick walled, and irregular ( fig. - ). there is a high incidence of large pleural effusions, and empyema resulting from bronchopleural fistula is a common complication. methicillin resistant staphylococcus aureus (mrsa) pneumonia usually occurs as a nosocomial infection in health care centers particularly in older, immunocompromised or intensive care unit patients. staphylococcal infection in the lungs may occur by way of the hematogenous route. this is usually the result of septic emboli, which arise in the central veins or as vegetations on cardiac valves, particularly in intravenous drug abusers and patients with indwelling intravenous catheters. the radiographic appearance is that of multiple nodular masses with or without cavitation, as previously described. streptococci (box - ) are gram-positive cocci that occur in pairs and chains. the pneumonia occasionally occurs in epidemic proportions. this form of pneumonia is much less common than that caused by staphylococcus or s. pneumoniae (pneumococcus). the radiographic features include lower lobe consolidation, often occurring with a segmental distribution. pleural effusions occur frequently, but localized empyema is unusual. pneumonias caused by gram-negative organisms usually are nosocomial pneumonias that affect hospitalized patients. these pneumonias tend to occur in patients maintained on artificial ventilators or in those who have intravenous catheters or a variety of other ancillary support systems. the incidence of gram-negative pneumonia acquired in the community is increasing, which may be related to the a b c klebsiella pneumonia (box - ) usually occurs in middle-aged or elderly patients, in those with underlying chronic lung disease, and in alcoholic individuals. radiographic features consist of an upper lobe consolidation. cavitation is common, and the lobar consolidation may lead to an expanded lobe with bulging interlobar fissures (see fig. - ). if necrosis is extensive, pulmonary gangrene may develop. e. coli pneumonia (box - ) may be caused by direct extension from the gastrointestinal or genitourinary tract across the diaphragm or result from bacteremia. as is true of most of the gram-negative pneumonias, it is frequently characterized by the development of necrosis and multiple cavities. the lower lobes are more frequently involved. p. aeruginosa pneumonia (box - ) usually occurs in hospitalized patients, particularly those with debilitating disease (see fig. - ). organisms that affect the lungs often result from contamination of suction and tracheostomy devices. radiographic features include a lower lobe predilection. however, the consolidation may spread rapidly to affect both lungs. pleural effusions are uncommon. multiple, irregular nodules may develop and are usually associated with bacteremia. these nodules may cavitate. h. influenzae pneumonia (box - ) usually develops in patients with copd. the appearance is typically that of a bronchopneumonia with homogeneous segmental opacities, usually in the lower lobes. cavitation and pleural effusions are rare. chemical pneumonitis and acute lung injury diffuse consolidation resembling pulmonary edema aspiration of particulate matter or foreign bodies may produce different clinical syndromes, depending on the size of the aspirated material and the level of airway obstruction. large food particles or foreign bodies may be aspirated into the larynx and upper trachea, resulting in the so-called café coronary syndrome, which is caused by acute upper airway obstruction. these patients exhibit respiratory distress and aphonia. results of chest radiographs are usually normal for patients who have aspirated foreign bodies. if the foreign body is opaque, it may be visible in the airways. air trapping may occur if the foreign body causes airway obstruction of one of the major bronchi. this can be demonstrated by inspiratory and expiratory radiographs, decubitus views, or chest fluoroscopy. occasionally, complete obstruction of the bronchus results in atelectasis and, if the foreign body is unrecognized, in the development of distal pneumonitis or bronchiectasis. ninety percent of aspiration pneumonias and lung abscesses are caused by anaerobic organisms. the pathogens include prevotella, bacteroides, fusobacterium, and peptostreptococcus. because of the presence of oxygen in the lung, the progression of anaerobic infection is slow, beginning in the dependent lung zones. if the patient is in a supine position when the aspiration occurs, the superior segments of the lower lobes are most commonly affected, with the right side affected more frequently than the left (fig. - ) . aspiration can also affect the posterior segments of both upper lobes. chronic or recurrent aspiration, particularly in patients who are in the upright position, usually results in consolidation involving the basilar segments of the lower lobes. the middle lobe and lingula are uncommon sites for aspiration pneumonia. aspiration is the most common cause of a primary lung abscess (see fig. - ) . a primary lung abscess refers to a focal, walled-off area of anaerobic pneumonia with central liquefaction necrosis. it is most commonly identified in the superior segments of either lower lobe. lung abscesses have a fairly thick wall and may or may not have an air-fluid level. a rounded, masslike lesion may precede the development of cavitation. occasionally, aspiration of nontoxic material that contains insufficient bacteria to produce an infection or insufficient volume to produce atelectasis may occur. the radiographic appearance usually consists of basilar patchy opacities resembling atelectasis, and these areas clear within several days. mendelson's syndrome is a specific form of aspiration that results from the aspiration of gastric acid. this event produces a chemical pneumonitis and acute lung injury. the radiographic manifestations of gastric aspiration are similar to those of noncardiogenic pulmonary edema. the distribution is usually diffuse. atypical pneumonia syndrome (box - ) describes pneumonias that do not respond to usual empiric antimicrobial therapy or do not have clinical features distinctive from the usual bacterial pathogens responsible for communityacquired pneumonias. originally, these atypical pneumonias were thought to be caused by viruses. however, other treatable organisms have emerged as important causes of atypical pneumonia, including m. pneumoniae, l. pneumophila, and chlamydia. these nonviral, atypical pneumonias are for the most part readily treatable with antibiotics. most patients with atypical pneumonia present with a nonspecific syndrome consisting of fever, usually without shaking chills, and nonproductive cough, headache, myalgias, and some degree of dyspnea. this contrasts with the classic presentation of bacterial pneumonia, which is characterized by abrupt onset with fever, shaking chills, and purulent sputum, often with chest pain. patients with the latter signs and symptoms usually have a bacterial pneumonia attributable to pneumococci, group a streptococci, klebsiella, s. aureus, or h. influenzae. many of the atypical pneumonias are associated with extrapulmonary manifestations. for example, diarrhea is a prominent part of legionella and mycoplasma infection. m. pneumoniae (box - ) accounts for approximately % of all cases of pneumonia. it usually occurs during the winter months in enclosed populations, such as students in college dormitories. the incubation period is to weeks, and the onset is often insidious, with low-grade fever and nonproductive cough. extrapulmonary manifestations may include otitis, nonexudative pharyngitis, and diarrhea. the radiographic features are usually those of a fairly diffuse, interstitial, fine reticulonodular pattern. this may evolve to patchy airspace consolidation, particularly in the lower lobes ( fig. - ). hilar adenopathy is seen in approximately % to % of patients. the radiographic appearance is very similar to that of many viral infections. the diagnosis is made by serologic evaluation. the first outbreak of legionnaires' disease was recognized in philadelphia at a legionnaires' convention (box - ). clinical features include acute febrile illness without pneumonia; systemic disease with primarily pulmonary manifestations; a peak incidence in patients older than years; a predisposition in smokers and those with alcoholic liver disease; high fever, shaking chills, and cough with small amounts of mucoid sputum; pleuritic chest pain; watery diarrhea in about one half of patients; and headache. the organism is spread by airborne transmission, usually through moist air exhaust or cooling towers. the radiographic features of legionnaires' disease often consist of segmental opacification and consolidation, particularly of an upper lobe. rapid development of coalescence with complete consolidation of an involved lobe and rapid extension to adjacent lobes are common features ( fig. - ). parenchymal changes are extensive, but pleural effusions are uncommon. the diagnosis of legionnaires' disease is usually made by serology using indirect fluorescent antibody. direct identification of the organism may be confirmed by direct fluorescent antibody (dfa) techniques using properly collected specimens. chlamydia, a long recognized cause of pneumonia in neonates, is an increasingly frequent cause of communityacquired atypical pneumonia in adult patients (box - ). it is caused by the twar agent (chlamydia pneumoniae). chlamydia pneumonia may occur in compromised and noncompromised adults as an atypical pneumonia. the disease is characterized by fever and nonproductive cough. it is often preceded by pharyngitis. radiographic features may be similar to those of mycoplasma pneumonia. however, more commonly there is a localized area of consolidation in the middle or lower lobes, which may be patchy or homogeneous ( fig. - ). atypical nonviral pneumonias are rare. they include psittacosis; q fever, a rickettsial disease; and tularemia. chlamydia psittaci is the etiologic agent of psittacosis, which may be transmitted by any avian species, and it is contracted by inhalation of infected aerosol material. the clue to the diagnosis is the history, which should include information about any contact with birds. psittacosis usually mimics a standard bacterial pneumonia on chest radiography. coxiella burnetii is the etiologic agent of q fever, which is a rickettsial disease. it is most common in the western and southwestern parts of the united states, and it can be transmitted by infected dust from animals. the radiographic features vary, but the most specific pattern simulates mycoplasma or viral pneumonia and usually consists of bilateral, diffuse reticulonodular opacities. tularemia, another animal-associated, atypical pneumo nia, is transmitted by ticks in summer and rabbits in winter. there is an ulceroglandular form, which produces a skin papule that eventually ulcerates at the port of entry. regional lymph nodes may become enlarged and eventually drain and ulcerate. in the typhoidal form, no portal of entry is apparent, but patients are characteristically extremely ill with gastrointestinal symptoms. pneumonia may occur in patients with either of these presentations. the most common radiographic feature is that of a localized and homogenous opacity, but lobar consolidation has also been reported. occasionally, multiple lobes are involved. bilateral hilar adenopathy may occur. primary respiratory viruses (box - ) include the parainfluenza and influenza group of viruses, respiratory syncytial virus (rsv), adenovirus, and picornavirus. the incidence of these infections varies with the age of the patient. for example, in children, rsv is responsible for up to % of epidemic lower respiratory tract infections and up to % of all pneumonias; in adults, the influenza and parainfluenza groups are responsible for most of the epidemic viral pneumonias. they usually occur during late winter. adenovirus and picornavirus cause nonepidemic respiratory infections. other viruses (e.g., cytomegalovirus) produce pneumonia as part of a systemic infection. in all cases, the infection usually begins in the larger central airways. at this stage, the chest radiograph frequently appears normal. the radiologic correlates of severe inflammation and edema of the bronchial walls include coarse reticular opacities in the form of rings and parallel lines (i.e., tram tracks) due to bronchial wall thickening in the central perihilar lung zones. when the small airways are involved, bronchiolitis develops. involvement of terminal bronchioles may lead to airway obstruction. this is more likely to occur in infants and young children because the cross-sectional area of the airways is small. diffuse overinflation and air trapping can be visualized. when the infection spreads to the alveoli, the disease is usually limited to the parenchyma around the terminal airways. the radiographic features in children and adults usually consist of a diffuse reticulonodular pattern, often with focal and patchy areas of consolidation (see fig. - ). multiple lobes are usually involved. ct may reveal the anatomic localization of the disease. the bronchiolitis and surrounding inflammation produces nodular opacities, which are located in the center of the lobules. branching centrilobular opacities represent impaction of small airways, and their appearance has been referred to as the treein-bud pattern ( fig. - ). other common ct findings of viral pneumonia include ground-glass attenuation with a lobular distribution and foci of segmental and subsegmental consolidation. influenza is one of the most frequently reported contagious diseases. symptoms include fever, nonproductive cough, weakness, and myalgias. most patients who develop severe pneumonia have underlying disease or superinfection with bacterial organisms. radiographic features may reflect the complicating bacterial pneumonia. however, a diffuse reticulonodular pattern may be seen in infants and children with the disease. adenovirus may occur in epidemic or pandemic proportions. when pneumonia develops, there may be destructive changes involving the peripheral airways, leading to chronic bronchitis, bronchiectasis, and bronchiolitis obliterans. symptoms tend to persist after resolution of pneumonia. radiographic features are very similar to pneumococcal pneumonia in pattern and distribution. rsv, rarely reported in adults, is the most prevalent respiratory viral pathogen in the first months of life. it usually produces focal and diffuse bronchiolitis. if radiographs are abnormal, they usually show increased lung volumes and air trapping, and linear interstitial opacities occasionally may be identified. varicella-herpes zoster (i.e., chickenpox) infection may be responsible for severe pneumonia in adults. the radiographic features are fairly characteristic. they consist of nodules ranging from to mm in diameter, with illdefined margins diffusely distributed throughout both lungs (fig. - ) . radiographic resolution usually occurs over many weeks. one of the interesting sequelae of chickenpox pneumonia is the development of diffuse, discrete pulmonary calcifications that can be identified on routine radiographs obtained after the infection (fig. - ) . histoplasmosis should be considered in the differential diagnosis of this radiologic appearance. cytomegalovirus infection is discussed in chapter . the epstein-barr virus is the presumed etiologic agent for infectious mononucleosis. although upper respiratory symptoms predominate, patients may develop a nonproductive cough. the chest radiograph is usually normal, but occasionally, pronounced hilar lymph node enlargement with an ill-defined, diffuse reticular pattern in the lungs may be seen. mycobacteria are aerobic, nonmotile, non-spore-forming rods that have in common the characteristics of staining bright red with carbol fuchsin and resistance to discoloration by strong acid solutions. the organisms are therefore referred to as acid-fast bacilli (afb). there are several mycobacterial species, but the most important include mycobacterium leprae, the cause of leprosy; m. tuberculosis and mycobacterium bovis, responsible for tuberculosis; and the nontuberculous mycobacteria that are important etiologic agents in the development of pulmonary disease. in the latter part of the th century, tuberculosis (box - ) was a leading cause of death in the united states. the advent of drug therapy and improved public health measures led to a steady decline in the incidence of tuberculosis after world war ii until . for the next years, a slow but steady increase in the incidence of tuberculosis was observed. this rise was primarily attributed to a large number of cases associated with acquired immunodeficiency syndrome (aids). immigration into the united states of individuals from third world countries also might have contributed to the increased prevalence of tuberculosis. since , the rate of tuberculosis has declined considerably. in , the rate of tuberculosis in the united states was the lowest since the beginning of national record keeping in . the tuberculosis rate is continuing to decline, but the rate of decline has recently slowed. respiratory or systemic symptoms patients older than years diarrhea common airborne spread through moist air exhaust or cooling towers diagnosis by serology with indirect fluorescent antibody affects upper lobes rapid spread to other lobes from to , there was also a decrease in the percentage of multidrug-resistant tuberculosis cases among persons with no prior history of tuberculosis, with a reduction from . % to . %. since , the rate has remained steady at approximately %. in the united states, tuberculosis case rates vary considerably among different racial and ethnic populations and are lowest among whites. for example, compared with whites, the case rates are nearly times higher for asians and times higher for blacks and hispanics. the rate of tuberculosis among foreign-born persons in the united states is nearly times higher than that of persons born in the united states. other susceptible populations include the aged and the immunocompromised, particularly patients with aids. infection with tuberculosis occurs as the result of inhalation of airborne droplets containing the tubercle bacilli. the initial infection, referred to as primary tuberculosis, is most common in the lower lobes. the bacteria are ingested by macrophages and initially spread to local lymph nodes at this stage, and they then may disseminate throughout the body. the infection is usually contained if the host is immunocompetent. however, walled-off tubercle bacilli representing a dormant focus of tuberculosis may activate under appropriate conditions. this may occur in the second type of tuberculosis, referred to as reactivation or postprimary tuberculosis. reactivation or post primary tuberculosis can occur any time after the primary infection, but the highest rate of reactivation occurs during the first and second years after the initial infection. reactivation tuberculosis usually involves the lung apex, but a dormant focus of tuberculosis may become active in other organs, such as the bones, kidney, or brain. clinically active disease may develop at the time of primary tuberculous infection (i.e., primary progressive tuberculosis) or when dissemination occurs (i.e., miliary tuberculosis). clinical reactivation disease results when there is an ineffective t-cell immune reaction. the typical pathologic feature of tuberculosis is the caseating granuloma. chlamydia pneumoniae (twar agent) nonproductive cough preceding pharyngitis localized consolidation in lower lobes patchy or homogeneous pattern patients with primary tuberculosis are usually asymptomatic but occasionally may have a symptomatic pneumonia. patients with acute or chronic reactivation tuberculosis usually present with a chronic cough, weight loss, and occasionally with hemoptysis and dyspnea. the symptoms are often insidious. ninety-five percent of patients with active tuberculosis have a positive tuberculin skin test result. the diagnosis must be made on the basis of culture of the organism, although the presence of afb on the smear from the sputum is strong presumptive evidence of tuberculosis. classification of tuberculosis into primary or reactivation phases is based on the radiographic appearance. in third world countries and in the united states during th and early th centuries, primary tuberculosis was a disease of children, and reactivation tuberculosis was typically a disease of young adults. however, a significant change in the pattern of adult tuberculosis has occurred in the past several decades. because of diminished exposure of children to tuberculosis, the disease often occurs in the primary form in adults. this has resulted in atypical radiographic manifestations of tuberculosis in adults, attributable to primary infection rather than reactivation of the disease. the radiographic features of primary tuberculosis are summarized in box - . primary tuberculous pneumonia can occur in any lobe of the lung but is more common at the lung bases (fig. - ) . in more than one half of cases, the disease occurs in the lower lobes. any chronic consolidation, particularly in the bases of the lungs, may suggest tuberculosis. cavitation, although rare in primary tuberculosis, is more frequently reported in adults than in children with the primary form of disease. mediastinal and hilar adenopathy is another feature of primary tuberculosis (fig. - ) . it may occur alone or in association with consolidation in the lung. it tends to be particularly predominant in children. ct may be helpful in identifying and localizing adenopathy. on ct scans, tuberculous adenopathy has a predilection for the right paratracheal, right tracheobronchial, and subcarinal regions. occasionally, atelectasis may result from extrinsic obstruction of a bronchus by enlarged lymph nodes. on ct scans obtained with intravenously administered contrast material, these nodes often demonstrate low-attenuation necrotic centers. pleural effusion due to tuberculous pleurisy, also a feature of primary infection, develops when subpleural foci of tuberculosis rupture into the pleural space. patients present to months after the initial exposure. organisms are rarely found in the fluid, and the diagnosis must be confirmed with a pleural biopsy. the ghon lesion (fig. - ) is a manifestation of primary tuberculosis, which usually occurs in childhood and is selflimited. the host defense mechanisms handle the initial infection, and the area of consolidation in the lung slowly regresses to a well-circumscribed nodule. this nodule then shrinks and may disappear completely or remain as a solitary, calcified granuloma. the adenopathy regresses and may also exhibit calcification (i.e., rhanke complex). reactivation tuberculosis usually occurs in the apical and posterior segments of the upper lobes and in the superior segment of the lower lobes. it is characterized by chronic, patchy areas of consolidation (fig. - ) . cavitation is a hallmark of reactivation tuberculosis (fig. - ) . cavities result when areas of caseation necrosis erode into the bronchial tree, expelling liquefied debris. ct is more sensitive than plain radiography in the detection of small cavities (fig. - ) . they may have thick or thin walls, which can be smooth or irregular. bronchogenic spread of tuberculosis occurs when a cavity erodes into an adjacent airway and organisms spread endobronchially to other parts of the lung. the typical radiographic features (fig. - ) consist of ill-defined nodules that usually are to mm in diameter. they are numerous and often bilateral. on ct, the pattern of bronchogenic spread can easily be recognized by a tree-in-bud pattern. this consists of centrilobular, branching, linear opacities with or without the presence of centrilobular nodules within to mm of the pleural surface or interlobular septa. this pattern is best appreciated on high-resolution ct (hrct). it is not specific for bronchogenic spread of tuberculosis and may occur in other inflammatory diseases involving the peripheral airways. the chronic lesion of reactivation tuberculosis usually consists of fibronodular opacities in the upper lobes, often with the presence of calcification (fig. - ) . it is usually associated with volume loss and retraction of the hila. another feature of chronic reactivation tuberculosis is bronchiectasis. tuberculosis should be considered in the differential diagnosis of upper lobe bronchiectasis. the activity of tuberculous disease cannot be determined by radiographs; it is confirmed only by positive cultures. however, tuberculosis is considered radiographically stable if there has been no change over months. unusual patterns of tuberculosis (box - ) may occur in the patient who has altered host resistance to the primary infection. miliary tuberculosis is a term used to describe diffuse hematogenous dissemination of tuberculosis that has progressed when the host defense system is overwhelmed by massive hematogenous dissemination of organisms. it may occur at any time after the primary infection. the radiographic appearance (fig. - ) is that of multiple, tiny nodules in the interstitium of the lung that are approximately to mm in diameter. ct may allow earlier detection than standard radiography (fig. - ) . miliary disease takes up to weeks to become apparent on plain radiographs. pneumothorax occasionally results from tuberculosis. tuberculosis may also cause ulceration of the bronchi, and advanced endobronchial tuberculosis may produce lobar atelectasis and strongly simulate a primary carcinoma of the lung. a localized nodular focus of tuberculosis, referred to as a tuberculoma (fig. - ) , occurs in any portion of the lung and may result from primary or reactivation tuberculosis. it is usually solitary, spherical, and smooth. it may contain a central calcification, but tuberculomas occasionally may be multiple and simulate metastatic disease. tuberculous empyema and bronchopleural fistula may result from a tuberculous pleural effusion. such effusions can become loculated and remain dormant for years. radiographic patterns of tuberculous disease in patients with acquired immune deficiency syndrome (aids) may vary. they are described in chapter . nodule communicating with the right upper lobe posterior segment bronchus (single arrow), with associated centrilobular nodular opacities in the superior segment of the right lower lobe (three arrows). b, ct of another patient shows a typical tree-in-bud pattern. centrilobular nodules and branching opacities can be identified close to the pleural surface (arrows). characteristics some nontuberculous mycobacteria (box - ) are pathogenic in humans. the most important of these organisms are mycobacterium avium-intracellulare, often referred to as the mac complex, and mycobacterium kansasii. these organisms often exhibit common features. they are usually found in the soil and water. bronchopulmonary disease is caused by inhalation of the organisms, but no human-tohuman transmission occurs. unlike tuberculosis, nontuberculous mycobacterial infections do not manifest separate patterns of primary or reactivation disease. certain geographic areas have a preponderance of these forms of nontuberculous mycobacterial disease. for example, m. kansasii is more prevalent in the western and southern united states, and mac is found more often in the southeastern united states. the three major clinical presentations depend to some degree on the immune status of the host (chapter describes mac disease in aids patients). in human immunodeficiency virus (hiv)-negative hosts, mac typically affects male patients who are heavy smokers with underlying copd. similar infections may occur in patients with silicosis or bronchiectasis. the radiographic features of m. kansasii and mac in this group of patients are indistinguishable from tuberculosis. however, mac lung disease may develop in older women who are considered immunologically competent and who do not have a background of thickening and multiple, calcified nodular and irregular opacities can be seen in the left upper lobe (arrows). volume loss is not a prominent feature in this case. although such an appearance suggests inactive disease, serial radiographs are necessary to determine stability. viable organisms may be present, and the development of clinically active disease may rarely occur. hematogenous dissemination diffuse, -to -mm nodules pneumothorax endobronchial tuberculosis lobar or segmental atelectasis tuberculoma single or multiple nodules larger than cm tuberculous empyema bronchopleural fistula copd. this disease is usually noncavitary. many women with this form of nontuberculous mycobacterial infection share similar clinical characteristics and bodily features, including scoliosis and pectus excavatum. it is uncertain whether these skeletal features predispose patients to infection due to poor tracheobronchial secretion drainage and ineffective mucociliary clearance or they are associated with markers for specific genotypes that affect body morphotype and susceptibility to infection. because nontuberculous mycobacteria are common contaminants, the identification of invasive disease caused by these infections should be made only when defined clinical, radiographic, and microbiologic criteria have been met as defined by the american thoracic society (ats) and infectious disease society of america (idsa) guidelines. radiologic criteria include the presence of nodular or cavitary opacities on the chest radiograph or an hrct scan that shows multifocal bronchiectasis with multiple small nodules. establishing a diagnosis of nontuberculous mycobacteria does not necessitate the need for treatment in all cases: rather, the decision to institute multidrug therapy should be based on an assessment of the relative risks and benefits of therapy on an individual patient basis. the classic form of atypical mycobacterial infection produces features almost identical to those of reactivation tuberculosis (fig. - ) . involvement occurs in the apical and posterior segments of the upper lobes and superior segment of the lower lobes. cavitation is common, and multiple cavities may be observed. the disease tends to be slowly progressive. mac lung disease occurring in older women who are usually nonsmokers without evidence of copd is noncavitary and is associated with bronchiectasis. the classic radiographic features are best appreciated on ct ( fig. - ) . the findings are those of cylindrical bronchiectasis associated with multiple, small, focal lung nodules that are approximately mm in diameter. any lobe may be involved, but disease in the lingula and middle lobe has the highest prevalence. occasionally, airspace disease may be delineated. evidence indicates that patients with these findings are truly infected and not colonized with mac and that the mac infection causes the bronchiectasis rather than colonizing preexisting disease. the wide variety of fungi that may produce lung disease can be divided into two groups. some are truly pathogenic and can produce pulmonary infection in normal hosts. they include histoplasma, coccidioides, blastomyces, and cryptococcus. a second group of fungi are secondary invaders or opportunistic organisms, which produce disease in immunosuppressed patients. this group includes aspergillus, candida, cryptococcus, and mucor. the latter group is discussed in chapter . histoplasma capsulatum (box - ) is a dimorphous fungus that gains entry to the lung by inhalation. distribution is worldwide, and in the united states, it occurs along river valleys, particularly the ohio, mississippi, and st. lawrence. the organism exists in the soil, particularly when it is contaminated by the excrement of birds (e.g., pigeons) or bats. many epidemics may occur when there is heavy exposure due to demolition or construction in areas containing these droppings, such as bat caves, chicken houses, or attics of old buildings. in endemic areas, up to % of the population may be infected, but most individuals are asymptomatic. inhalation of spores results in a localized infection of the lung, which then migrates to mediastinal and hilar lymph nodes and eventually migrates to the spleen and liver. the organisms usually are destroyed, and there is no residual of the initial infection, although a scar or calcification may occur. if individual foci of infection and necrosis persist, they may enlarge, resulting in a chronic cavitary lesion indistinguishable from that of tuberculosis. pathologically, well-defined granulomas may be found during the acute phase of disease in the lung, in the mediastinum, and in the various organs to which the organism disseminates. when healed, these granulomas are small and densely calcified. outbreaks of histoplasmosis are usually associated with constitutional symptoms and nonproductive cough. many cases never come to medical attention. the radiographic manifestations of histoplasmosis vary. the acute phase of the disease is characterized by single or multiple areas of consolidation, which are usually segmental or sublobar in distribution. these areas may be accompanied by ipsilateral hilar or mediastinal adenopathy, and occasionally, adenopathy alone may be the only finding. in the epidemic form of the disease, multiple, discrete nodules may be seen throughout both lungs; nodules may occur alone or be associated with hilar adenopathy (fig. - ) . they are usually to mm in diameter, discrete, and poorly marginated. with healing, the nodules may remain visible as multiple, discrete, calcified lesions less than cm in diameter with or without calcified hilar lymph nodes (fig. - ) . a third radiographic pattern consists of a solitary granuloma or histoplasmoma, which is usually well defined and can range in size from several millimeters to cm. it typically contains a central or target type of calcification. these lesions usually occur in the lower lobes, and they may have associated smaller, calcified satellite nodules. additional radiographic features may be identified in patients with histoplasma infection. they include calcifications in the spleen, which often are best detected on ct. mediastinal lymphadenopathy is common as a sole manifestation of histoplasmosis or accompanying pulmonary consolidation or nodules. nodes frequently calcify as healing occurs. calcified lymph nodes may lead to two complications: broncholiths and fibrosing mediastinitis. calcified lymph nodes may over time erode into a bronchus, producing broncholithiasis and its resulting symptom complex. patients may have unexplained chronic cough and hemoptysis. ct can best identify the intrabronchial calcification that may be associated with distal atelectasis of a segment or lobe (fig. - ) a rare chronic form of histoplasmosis can simulate tuberculosis. it usually consists of thin-or thick-walled cavities with patchy areas of consolidation, particularly involving the upper lobes with fibrosis and retraction. disseminated histoplasmosis, which may occur in normal individuals, is much more common in immunosuppressed patients. radiographically, the appearance is identical to that of miliary tuberculosis. coccidioides immitis infection (box - ) follows inhalation of infected spores in endemic areas such as desert areas of the southwestern united states and central and south america. clinical manifestations vary. most individuals are asymptomatic, or they may experience a mild flulike illness of the lower respiratory system. acute, severe disease may be associated with fever, cough, and pleuritic chest pain. with the initial inhalation of the spores, a local response or pneumonitis occurs. the immune system eventually destroys the organism, with resolution of the pneumonia. about % of individuals may have a chronic, often asymptomatic pulmonary lesion, such as a pulmonary nodule or cavity. similar to tuberculosis, reactivation of the initial focus can occur. dissemination of the organism to hilar and mediastinal nodes is common, and diffuse dissemination is rare but almost universally fatal. the initial pneumonic form of the disease is characterized by an area of consolidation anywhere in the lung but most commonly in the lower lobes. it is usually sublobar, segmental, or patchy. it may be bilateral. hilar and mediastinal lymph node involvement occurs in about % of cases, and rarely, it can be seen in the absence of the parenchymal consolidation. most of these lesions resolve spontaneously without therapy. the radiographic features of chronic coccidioidomycosis include solitary or multiple nodules. these tend to cavitate rapidly, and the cavities typically have very thin walls ( fig. - ) . the thin-walled cavity is the classic lesion of coccidioidomycosis, but it occurs in only % to % of cases. disseminated coccidioidomycosis is rare and is characterized radiographically by nodules ranging from mm to cm in diameter. a classic miliary pattern can also be observed. (box - ) is a dimorphic fungus that grows in a mycelial form in the soil. infection can occur by inoculation of the skin or by inhalation of organisms into the lungs. the organism is endemic in north america, occurring mostly in the same areas where histoplasmosis occurs but also in the southeastern united states. blastomycosis is an infection associated with hunters because the organisms are prevalent in wooded areas. the organism is usually inhaled from the soil, and if the initial port of entry is the lung, a focal pneumonic process will occur. the disease can be self-limited, or a disseminated form can occur. the radiographic findings are nonspecific but consist of areas of inhomogeneous consolidation in a segmental or nonsegmental distribution in any area of the lung. the next most common manifestation is that of solitary and multiple pulmonary nodules. the solitary nodules may simulate lung carcinoma. these nodules are to mm in diameter. a third pattern results from disseminated disease and consists of a diffuse nodular or micronodular pattern. cryptococcus neoformans (box - ) is an encapsulated, yeastlike fungus that exists in the soil and in the yeast form in humans. the soil may be contaminated by pigeon or chicken excreta. seventy percent of individuals who have clinical disease are immunocompromised (see chapter ). the central nervous system is the most frequently affected site. in the normal host, the most common finding is that of single or multiple pulmonary nodules that are approximately to cm in diameter and that usually occur in the lower lobes (fig. - ) . cavitation, lymph node enlargement, and pleural effusion are uncommon. adenopathy is rarely identified. characteristically, the single or multiple nodules tend to abut the pleura. characteristics candidiasis (box - ) may be caused by a group of various organisms in the candida genus, of which candida albicans is the most important species. c. albicans lives in human and animal sources and may be a normal inhabitant of the spores in soil contaminated with pigeon and chicken excreta of patients with clinical disease, % are immunocompromised central nervous system involvement single or multiple nodules larger than cm affects lower lobes oral pharynx. as a result, short of an open lung biopsy, the true invasiveness or pathogenicity of this organism when recovered from the sputum is difficult to determine. it is an unusual infection found in immunocompromised individuals. the most common sites of infection are the mucous membranes and skin. pulmonary candidiasis is unusual but may occur as a primary infection of the lungs, presumably resulting from aspiration of the organisms from the oral cavity. in most immunocompromised patients, pulmonary infection accompanies a diffuse, widespread fungemia. the radiographic findings are usually nonspecific. although most fungal diseases, particularly in immunocompromised hosts, are characterized by multiple nodules with cavitation, candida pneumonia is more likely to produce areas of consolidation that are multiple and patchy and involve both lungs. cavitation and hilar adenopathy are rare, and pleural effusion occurs in approximately % of cases. characteristics actinomyces (box - ) is a rod-shaped bacterium rather than a fungus, but it is often considered a fungus because of its clinical presentation and radiographic findings. the organism is found in the mouth, and pulmonary infection usually occurs in people with extensive dental caries and poor oral hygiene. involvement results from aspiration of these organisms. there are three forms of actinomycosis: cervicofacial, gastrointestinal, and thoracic. the hallmark of the pulmonary disease is a focal abscess with extension to the chest wall, with secondary complications such as osteomyelitis, bronchopleural fistula, and pericarditis. the organism is an anaerobe, and anaerobic cultures must be obtained to confirm the diagnosis. typical sulfur granules may be identified on pathologic specimens. the radiographic features initially consist of an area of consolidation in the lung. this area may become rounded and suggest an abscess. classic signs include extension of the disease process into the chest wall with bone destruction and osteomyelitis (fig. - ) . chest wall invasion is best appreciated on ct. pleural effusions are moderately common. invasion of the ribs or vertebral bodies characteristically causes bone destruction and fairly extensive reactive periostitis. notice the erosion of the cortex of the overlying rib (arrows). characteristics nocardia (box - ) is a gram-positive organism, and although it is classified as a bacterium, it shares many features with fungal disease. it is weakly acid fast and can be confused with mycobacteria or legionella. it is similar to actinomyces, but the disease usually occurs in immunocompromised patients rather than in normal hosts (see chapter ). focal consolidation is the most common finding, although the disease can appear as single or multiple nodules with cavitation. unlike aspergillosis, progression of disease usually is rather slow. chest wall involvement may occur but is rare. aspergillus (table - ) is a dimorphic fungus. the most common of the many species is aspergillus fumigatus. aspergillus grows widely in soil and water, in decaying vegetation, and in animal material. aspergillosis occurs in several different forms in the lung, including noninvasive (mycetoma) and semi-invasive aspergillosis, invasive aspergillosis, and allergic bronchopul-monary aspergillosis. the type of involvement depends on the immune status of the host. infection is initiated by the inhalation route, and aspergillus spores may exist in the mouth and airways of normal hosts. immunocompetent or mildly immunosuppressed patients may acquire mycetomas or semi-invasive aspergillosis, whereas those who are severely immunosuppressed develop invasive aspergillosis. allergic bronchopulmonary aspergillosis usually occurs in asthmatic patients. the most common radiographic form of aspergillosis is the mycetoma or fungus ball. the fungus ball consists of aspergillus hyphae, mucus, and cellular debris developing within a preexisting cyst, cavity, bulla, or area of bronchiectasis. it grows as a saprophytic organism and usually is noninvasive. a high prevalence of mycetoma has been found among patients with sarcoidosis or cystic fibrosis. symptoms usually include hemoptysis, which may be life threatening. the radiographic appearance of a fungus ball or mycetoma can be quite characteristic (fig. - ) . typically, there is a solid, round opacity within a cavity or thin-walled cyst. air may dissect into the solid mass, creating the appearance of an air crescent. in most cases, the fungus ball is mobile, and changes in position occur with changes in body posture. extensive pleural thickening at the apex of the thorax frequently accompanies the development of a mycetoma. in making the differential diagnosis, necrotizing squamous cell carcinoma and an intrapulmonary abscess should be considered. no treatment is necessary for asymptomatic individuals, but for those who develop severe hemoptysis, there gram-positive, acid-fast bacilli immunocompromised hosts single or multiple nodules with or without cavitation slow progression focal consolidation are several therapeutic options. one is an interventional radiologic technique that consists of embolization of bronchial arteries that supply the cavity. direct installation of amphotericin b in the form of a paste inserted through a percutaneous catheter into the cavity has been successful in some cases. semi-invasive aspergillosis occurs in mildly immunosuppressed patients, such as those with alcoholism, chronic debilitating illness, or advanced malignancy. the lesion usually begins as a focal consolidation in the apex of one or both lungs that progresses over a period of months to become cavitary. it may form a crescent of air (i.e., air crescent sign) similar to that seen in a mycetoma. a thick-walled cavity, which later becomes thin walled and contains a fungus ball, is then formed. the appearance may be identical to that of a mycetoma. it consists of a cavity with or without a fungus ball and air crescent, or it may be a localized area of consolidation. extensive pleural thickening can be identified. the features of invasive aspergillosis are described in chapter , which discusses pulmonary infections in the immunocompromised patient. characteristics allergic bronchopulmonary aspergillosis (see chapter ) occurs almost exclusively in asthmatic individuals. aspergillus spores contained within mucous plugs in the tracheobronchial tree incite an allergic reaction. the syndrome consists of blood eosinophilia with positive precipitins and marked elevation of ige antibodies. large masses of mucus and aspergillus hyphae can become trapped in the airways, producing mucoid impaction of the bronchi. the most characteristic pattern is that of mucoid impaction of the bronchus. central branching opacities, which sometimes are referred to as a finger-in-glove or v pattern, are identified. a more extensive description is provided in chapter . atelectasis distal to the areas of mucoid impaction usually does not occur because of collateral air drift. air trapping may be identified, and lobar consolidation may be present. as the mucous plugs are expectorated, areas of central bronchiectasis can be identified, particularly on ct scans. patients usually respond to steroids, but in the chronic form of the disease, scarring and upper lobe bronchiectasis are prominent features. mucormycosis, almost exclusively a disease in immunocompromised patients, is discussed in chapter . pneumocystis jiroveci (formerly called pneumocystis carinii) is discussed in chapter . in the united states, parasitic infection of the lung is rare. pneumonia is caused by a hypersensitivity reaction to the organisms, or it results from systemic invasion of the lungs and pleura. toxoplasma gondii pulmonary involvement usually develops as part of a more generalized disease. the congenital variety is the most common, and it results from transmission of the organism from mother to fetus. it is associated with a consolidative and hemorrhagic pneumonia in neonates. in adults, toxoplasmosis, like pneumocystosis, occurs in patients who are immunocompromised. the radiographic appearance is that of fairly diffuse reticulonodular opacities. echinococcus granulosus (box - ), the cause of most cases of human hydatid disease, occurs in two forms: pastoral and sylvatic, which differ in definitive and intermediate hosts and in geographic distribution. the pastoral variety is more common and occurs in sheep, cows, or pigs as the intermediate hosts, and in dogs as the definitive host. it is particularly common in sheep-raising areas. the sylvatic variety has as the definitive host the dog, wolf, or arctic fox. approximately % to % of echinococcus cysts occur in the liver, and % to % occur in the lungs. the hydatid cyst is composed of two layers, an exocyst and an endocyst. daughter cysts may be formed within the endocyst. cysts may rupture in the lung parenchyma, with resulting intense inflammation. rupture into the bronchus may result in severe hypotensive shock. echinococcal cysts are usually well-circumscribed, spherical or oval masses that may be single or multiple (fig. - ) . they are usually located in the lower lobes. if communication develops between the cysts and the bronchial tree, air may enter between the pericyst and exocyst, producing the appearance of a thin crescent of air around the periphery of the cyst, sometimes called the meniscus or crescent sign. bronchial communication occurs directly into the endocyst. occasionally, an air crescent sign and air-fluid level can be identified. the membrane of the cyst, which has ruptured into the bronchial tree, may float on the fluid within the cyst, giving rise to the classic water lily sign. ct can differentiate cystic from solid lesions and may identify the pathognomonic features in ruptured or complicated hydatid cysts, such as the presence of daughter cysts and endocyst membranes. calcification of a pulmonary hydatid cyst is rare. pulmonary amebiasis is rare and is usually a sequela of hepatic or gastrointestinal involvement. amebiasis is caused by the protozoan entamoeba histolytica. this organism causes dysentery and has a worldwide distribution. pleuropulmonary complications usually occur when the liver is involved. patients present with right upper quadrant and right-sided pleuritic chest pain. the common radiographic features are right-sided pleural effusion with basal consolidation. involvement of the lung may result from rupture of an amebic abscess in the liver. occasionally, areas of consolidation in the right lower lobe may progress to abscess formation with cavitation. schistosomiasis is a common disease in many areas of the world, including central and south america, the middle east, and the far east. the intermediate host of this parasite is the snail. humans contact the parasites in water. the parasites penetrate the skin, reach the circulation, and eventually grow in the mesenteric or pelvic venous plexus, where they mature into adult worms and lay eggs. pulmonary symptoms may occur during the larval migration phase in the lungs due to a hypersensitivity reaction. a progressive diffuse endarteritis and thrombosis may result from impaction of ova in the pulmonary circulation, with the eventual development of pulmonary arterial hypertension. pathologic changes in the lungs result from deposition of eggs or ova, which are released directly into the systemic venous blood or occasionally into the portal system, where eggs can reach the lungs through anastomotic channels as the liver becomes cirrhotic. the embolized ova become impacted in pulmonary arterioles and then extruded into the surrounding tissue. this causes an obliterative arteriolitis, which can result in increased pulmonary artery pressure. the ova may mature into adult worms in the lungs and can cause lung damage. pulmonary arterial hypertension is the most common finding in patients with pulmonary schistosomiasis (fig. - ) . the appearance consists of dilation of the central pulmonary arteries with rapid tapering. the passage of larva through the pulmonary capillaries can cause a transitory eosinophilic pneumonia, simulating loeffler's syndrome. this is characterized by the presence of peripheral areas of consolidation. the lungs may be infected by a number of worms, causing ascariasis, strongyloidiasis, trichinosis, ancylostomiasis (i.e., hookworm disease), and filariasis (i.e., tropical eosinophilia). most of these organisms produce hypersensitivity reactions in the lungs, similar to loeffler's syndrome (see chapter ). outbreaks of several newly recognized viral infections, including avian influenza, severe acute respiratory syndrome-associated coronavirus, and hantavirus, have been associated with high mortality rates. these infections have presented challenges to clinicians, radiologists, scientists, and public health officials. avian influenza is caused by the h n subtype of the influenza a virus. human transmission occurs through close contact with infected birds, usually from ingestion of infected poultry. the first documented case occurred in in hong kong. in , the virus resurfaced in vietnam. approximately people throughout southeast asia have been infected, with a nearly % mortality rate. affected patients present with a rapidly progressive pneumonia that may lead to respiratory failure and ards. chest radiographs usually show abnormalities at the time of presentation. the most common finding is multifocal consolidation (fig - ) , which is bilateral in % of cases. consolidation may infrequently be complicated by areas of cavitation. bilateral pleural effusions occur in about one third of cases. severe acute respiratory syndrome (sars) is caused by the sars-associated coronavirus. it results in a systemic infection that is manifested clinically as a progressive pneumonia. the first reported case in humans occurred in china in . in , sars spread to hong kong and subsequently to canada, singapore, and vietnam. before the infection could be contained by vigorous public health measures, more than persons were infected, with a nearly % fatality rate. no additional human infections have been reported since . after an initial incubation period of to days (mean, days), affected patients typically present with headache, malaise, fever, and nonproductive cough. chest radiographs show abnormalities at the time of clinical presentation in about % of cases. the most common radiographic finding is poorly defined airspace consolidation. although about one half of cases appear to have a focal distribution at the time of presentation, progression to multifocal involvement is common. areas of consolidation have a predilection for the lower lobes and lung periphery. ct shows abnormalities at the time of clinical presentation, even when chest radiographs do not. the most common ct finding is ground-glass opacification (fig - ) , which is often accompanied by small foci of consolidation and interlobular and intralobular thickening. severe sars may progress to diffuse alveolar damage. overall, % of patients with sars require mechanical ventilation, and % of patients do not survive the infection. survivors often have residual abnormalities seen on ct, reflecting interstitial fibrosis and small airways disease. hantaviruses are carried by rodent vectors. human infection occurs after inhalation of aerosolized rodent feces or urine. the sin nombre hantavirus (translated as "the nameless virus") was initially discovered in the southwestern united states in as a cause of pulmonary edema and respiratory failure accompanied by hematologic abnormalities. this clinical entity is referred to as the hantavirus pulmonary syndrome (hps). hps is caused by endothelial damage to the lung. the initial interstitial edema manifests radiographically as kerley lines, bronchial wall thickening, and subpleural edema. although some patients recover fully from the initial stage of infection, many progress to diffuse alveolar edema, which is manifested by symmetric perihilar and basilar airspace consolidation (fig - ). this phase of illness requires mechanical ventilation and is associated with a high mortality rate. as the disease progresses, it may be accompanied by myocardial depression, which worsens tissue hypoxia and contributes to the high mortality rate associated with this syndrome. the centers for disease control and prevention (cdc) lists several infectious agents as a category a threats, denoting the highest potential for public health impact. these agents include inhalational anthrax (bacillus anthracis), plague (y. pestis), smallpox (variola major), botulism (clostridium, botulinum), tularemia (francisella tularensis), and hemorrhagic fever (ebola and marburg filoviruses). among these infections, anthrax has the unique distinction that imaging studies may allow prompt diagnosis and institution of life-saving therapy before organ damage is irreversible. for this reason, the discussion focuses on anthrax. anthrax has been used as a biologic weapon since world war ii. the most recent episode occurred in , when highly refined anthrax spores were placed in envelopes and mailed through the united states postal system. this act of bioterrorism resulted in diagnosed cases of anthrax, which were evenly split between inhalational and cutaneous forms. almost one half of those with the inhalational form died. b. anthracis is a sporulating, gram-positive bacterium that may result in cutaneous, gastrointestinal, or pulmonary infection. the latter, which is also referred to as inhalational anthrax, is the deadliest form. the spores are to μm, an ideal size for deposition in the distal respiratory tract after inhalation. once inhaled, the spores are ingested by macrophages. surviving spores are transported to mediastinal lymph nodes, where they germinate for to days (mean, week). radiologic findings have not been identified before germination. after germination, the organisms synthesize a toxin, resulting in the prodromal phase of the disease. this is manifested by flulike symptoms of fever, chills, fatigue, and cough. the prodromal phase lasts about days and is rapidly followed by the second phase of the illness, which is characterized by stridor, respiratory failure, and shock. in many cases, death occurs despite antibiotic therapy. imaging findings for anthrax reflect hemorrhagic lymphadenitis and mediastinitis caused by the release of anthrax toxin within the mediastinum. in the prodromal phase of the illness, the chest radiograph typically demonstrates mediastinal widening and unilateral or bilateral hilar enlargement. these findings are frequently accompanied by pleural effusions. although limited peribronchovascular airspace opacities may be present, extensive consolidation is uncommon. imaging findings of mediastinal widening and pleural effusions are helpful for differentiating inhalational anthrax from a community-acquired respiratory infection. ct may provide convincing evidence of inhalational anthrax before confirmatory laboratory tests have returned (fig - ). unenhanced ct may show high-attenuation ( to hounsfield units) mediastinal and hilar lymph nodes, which may rapidly enlarge over a period of days. these findings reflect the presence of hemorrhage and edema within lymph nodes. because of this characteristic appearance, unenhanced ct is considered the imaging modality of choice for the diagnosis of inhalational anthrax. after contrast administration, rim enhancement and central low attenuation of lymph nodes may be seen. rapidly enlarging pleural effusions are commonly identified by ct, and they may contain dependently layering, highattenuation fluid, reflecting serosanguineous exudates. peribronchovascular thickening correlates with the presence of edema, hemorrhage, and necrosis of the airways and adjacent lymphatics. the constellation of these ct findings is almost pathognomonic for inhalational anthrax, but a variety of other causes of mediastinitis may produce similar findings in the appropriate clinical setting. inhalational anthrax is treated with an antibiotic regimen that includes ciprofloxacin or doxycycline combined with two other agents, usually rifampin and clindamycin. early recognition of anthrax and prompt administration of antibiotics before the onset of fulminant illness can dramatically improve patient survival. tree-in-bud pattern: frequency and significance on thin section ct aspiration and inhalation pneumonias pulmonary coccidioidomycosis reported tuberculosis in the united states. department of health and human services, cdc pulmonary manifestations of mycobacterium intracellulare epidemiology of tuberculosis chlamydia pneumoniae pneumonia in hospitalized patients an overview of pulmonary fungal infections mycobacterium tuberculosis coccidioidal pneumonia legionella pneumonias gram-negative bacillary pneumonias tuberculous pleural effusions the chest radiograph in legionnaires' disease: further observations aspiration pneumonia, lung abscess, and empyema the roentgen manifestations of thoracic actinomycosis fraser and pare's diagnosis of diseases of the chest inhalational anthrax semi-invasive pulmonary aspergillosis: a new look at the spectrum of aspergillus infections of the lung the spectrum of pulmonary aspergillosis the acute bacterial pneumonias histoplasma capsulatum the varied roentgen manifestations of primary coccidioidomycosis an official ats/ idsa statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases pulmonary blastomycosis: radiologic manifestations mycobacterium aviumintracellulare complex: evaluation with ct mycoplasmal, viral, and rickettsial pneumonias viral pneumonia radiology of severe acute respiratory syndrome (sars): the emerging pathologic-radiologic correlates of an emerging disease radiology of bacterial weapons-old and the new? hantavirus pulmonary syndrome: radiologic findings in patients thoracic cryptococcosis: immunologic competence and radiologic appearance viral pneumonia in adults: radiologic and pathologic findings clinicoradiographic correlation with the extent of legionnaire disease ct features of thoracic mycobacterial disease pulmonary septic emboli: changes with ct anaerobic pleural and pulmonary infections pneumonia caused by mycoplasma pneumoniae infection ct features of pulmonary mycobacterium avium complex infection studies in chronic allergic bronchopulmonary aspergillosis. i. clinical and physiological findings thoracic manifestations of tropical parasitic infections: a pictorial review pneumatocele formation in adult pneumonia tuberculosis: frequency of unusual radiographic findings pulmonary infections granulomatous infections of the lung tuberculosis in the normal host: radiological findings spectrum of pulmonary non-tuberculous mycobacterial infection atypical mycobacterial infection in the lung: ct appearance pulmonary aspiration complexes in adults guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention pneumococcal pneumonia in hospitalized patients' clinical and radiological presentations pulmonary cryptococcosis adult respiratory distress syndrome infectious pneumonias-including aspiration states the radiologic manifestations of h n avian influenza hilar and mediastinal adenopathy caused by bacterial abscess of the lung viral pneumonitis thoracic histoplasmosis other mycobacterium species tuberculosis among elderly persons: an outbreak in a nursing home imaging of bacterial pulmonary infection in the immunocompetent patient severe acute respiratory syndrome: radiographic appearance and pattern of progression in patients pulmonary aspiration of gastric contents update: the radiographic features of pulmonary tuberculosis pulmonary bacterial and viral infections key: cord- -s zxu vo authors: lowe, james; gauger, phillip; harmon, karen; zhang, jianqiang; connor, joseph; yeske, paul; loula, timothy; levis, ian; dufresne, luc; main, rodger title: role of transportation in spread of porcine epidemic diarrhea virus infection, united states date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: s zxu vo after porcine epidemic diarrhea virus (pedv) was detected in the united states in , we tested environmental samples from trailers in which pigs had been transported. pedv was found in . % of trailers not contaminated at arrival, , suggesting that the transport process is a source of transmission if adequate hygiene measures are not implemented. after porcine epidemic diarrhea virus (pedv) was detected in the united states in , we tested environmental samples from trailers in which pigs had been transported. pedv was found in . % of trailers not contaminated at arrival, , suggesting that the transport process is a source of transmission if adequate hygiene measures are not implemented. p orcine epidemic diarrhea virus (pedv) was detected in herds of pigs in the united states during april ( ) . pedv is a member of the cornaviridae family that produces a malabsorptive diarrhea secondary to atrophy of the small intestinal villi ( ) . initial clinical cases were detected in herds in indiana and iowa during may . the virus spread rapidly across large geographic regions; cases of infection were identified in states during the first weeks of the outbreak ( ) . subsequent testing of historical samples collected during the week of april , identified the index herd in ohio ( ) . veterinarians became concerned about the role that facilities where pigs are harvested for processing into food and the transportation equipment used to move pigs from farms to those facilities were playing in the spread of pedv. these concerns were based on evidence that equipment used to transport live pigs transmits another enteric coronavirus, transmissible gastroenteritis virus, between sites in the united states (j.f. lowe, unpub. data). pigs are commonly transported to harvest facilities in vehicles that have not been cleaned and disinfected between loads. implementation of "all in-all out" sites, which are sites in which pigs are grown and all pigs in a group are removed before arrival of the next group, limits the spread of disease introduced by transport vehicles. in many cases, the risks and associated costs of disease introduced late in the growing period are thought to be less than the cost of cleaning and disinfecting vehicles. transport vehicles are often shared by different pig owners, enabling the spread of disease across large regions. the objective of this study was to assess the risks that harvest facilities and transport vehicles engendered in promoting the initial outbreak of a novel disease organism by estimating the incidence of trailer contamination with pedv during the unloading process at harvest facilities. environmental samples were collected from livestock trailers before and after pigs were unloaded into holding pens, or lairages, at harvest facilities ( - trailers per facility) located in the central united states. samples were collected during a period of - days at each facility during june - , . for each trailer, the following information was collected: transport company and trailer identification, time of unloading, dock used, whether the truck driver stepped on the dock, and whether facility personnel entered the trailer. sample collection consisted of rubbing a phosphate-buffered saline-moistened pad (swiffer, procter & gamble, cincinnati, oh, usa) over an ≈ cm area of the trailer floor, cm from the rear door. the pad was placed in a sterile bag (whirl-pac, nasco, fort atkinson, wi, usa) and the liquid was collected by applying manual pressure. the liquid was transferred to a sterile tube ( ml falcon tube, fisher scientific, chicago, il, usa), immediately placed on ice, and maintained at °c during transport to the iowa state university veterinary diagnostic laboratory. new latex gloves were worn for each sample collection to minimize the risk for cross-contamination. rna extraction was performed with ml of each environmental sample by using the magmax viral rna isolation kit (life technologies, carlsbad, ca, usa) and a kingfisher instrument (thermo scientific, waltham, ma, usa) and kingfisher program am_ _ dw_hv_v provided by the manufacturer of the viral extraction kits. viral rna was eluted into μl of buffer. real-time reverse transcription pcr (rrt-pcr) was performed on nucleic acid extracts by using the path-id multiplex one-step rt-pcr kit (life technologies) according to the manufacturer's recommendations. primers and probe targeting conserved regions of the pedv nucleocapsid protein gene were as described ( ) with modifications specific to the sequence isolated in north america deposited in genbank (accession no. kf ). the forward primer sequence was ′-cgcaaagact-gaacccactaacct- ′, the reverse primer sequence was ′-ttgcctctgttgttacttggagat- ′, and the probe sequence was ′-tgttgccattaccac-gactcctgc- ′. sequences were labeled by using the fam/zen/ ′ iowa black detector (integrated dna technologies, coralville, ia, usa). all rrt-pcr reactions were conducted on an abi fast (applied biosystems, foster city, ca, usa) and results analyzed by system software. samples were tested separately from routine diagnostic samples in the laboratory to minimize risks for cross-contamination. before unloading, ( . %) of the trailers were contaminated with pedv. the proportion of contaminated trailers ranged from % to . % among the harvest facilities; the facility level median was . %. of the remaining , ( . %) that were not contaminated at arrival were contaminated in the unloading process (table) . of the trailers that were contaminated on arrival, environmental samples from ( . %) were negative for pedv after unloading. environmental samples from these trailers tended to have higher cycle threshold values than those from the trailers that were positive before and after unloading: . versus . , respectively. this result suggests that the pigs transported to the harvest facility on the trailers may not have been shedding pedv, but instead, the trailers had been contaminated by previous loads of pigs, so viral quantities in the trailer were low or at the limit of detection. contamination during unloading occurred at a higher rate if harvest facility staff entered the trailer (or . , % ci . - . ) or if unloading occurred immediately after unloading another trailer that was found to be contaminated (or . , % ci . - . ). facilities in which more pedv was identified in truck trailers on arrival had a higher overall incidence of contamination. this was measured by multiplying the prevalence of contamination at arrival by the inverse of the cycle threshold value from trailers contaminated at arrival (r = . , p = . ). all drivers stepped into the harvest facility at least once, leading to a high rate of contact between drivers, the trailers, and the harvest facility. harvest facilities serve as a source of contact between many swine farms with different health statuses. this study suggests that collection points, such as harvest facilities and livestock auction markets, can be an efficient source of contamination of transport vehicles that return to pig farms and likely played a role in rapidly disseminating pedv across vast geographic regions shortly after pedv was first identified in the united states. these data also suggest that the contamination of transport vehicles leaving the harvest facilities increased as the prevalence of pedvpositive transport vehicles and virus load coming into the facility increased. the results of this study suggest that proactive disease control measures should include improved sanitation, hygiene, and segregation practices at collection points to limit the spread of the agent early in the outbreak. current data suggest that novel agents, such as pedv, may be present in a country but remain undetected for an extended period. thus, control measures may be implemented too late to limit the spread of the disease through fomites that are identified, such as, in this instance, contaminated vehicles returning from swine collection points. simple measures such as limiting contact between drivers and the collection point and requiring drivers to remain on trucks and out of the collection point during the unloading process may have a dramatic effect on limiting the transmission of novel agents. these biosecurity measures are simple but require a coordinated effort between producers, transporters, harvest facility owners, and regulators to achieve effective implementation. this study of pedv transmission by fomites should serve as an example of the risks that a modern, highly technical animal protein industry may encounter during a novel disease introduction. pedv's introduction and subsequent spread in the united states should spur action to minimize these risks before a disease that can affect international trade or food safety is introduced. emergence of porcine epidemic diarrhea virus in the united states: clinical signs, lesions, and viral genomic sequences diseases of swine animal and plant health inspection service, national veterinary services laboratories. porcine epidemic diarrhea virus (pedv) testing data from nahln laboratories multiplex real-time rt-pcr for the simultaneous detection and quantification of transmissible gastroenteritis virus and porcine epidemic diarrhea virus key: cord- - g n e authors: steele, james harlan title: veterinary public health: past success, new opportunities date: - - journal: preventive veterinary medicine doi: . /j.prevetmed. . . sha: doc_id: cord_uid: g n e abstract animal diseases are known to be the origin of many human diseases, and there are many examples from ancient civilizations of plagues that arose from animals, domesticated and wild. records of attempts to control zoonoses are almost as old. the early focus on food-borne illness evolved into veterinary medicine's support of public health efforts. key historical events, disease outbreaks, and individuals responsible for their control are reviewed and serve as a foundation for understanding the current and future efforts in veterinary public health. animal medicine and veterinary public health have been intertwined since humans first began ministrations to their families and animals. in the united states, the veterinary medical profession has effectively eliminated those major problems of animal health that had serious public health ramifications. these lessons and experiences can serve as a model for other countries. our past must also be a reminder that the battle for human and animal health is ongoing. new agents emerge to threaten human and animal populations. with knowledge of the past, coupled with new technologies and techniques, we must be vigilant and carry on. farmer keeping animals in his midst. the people who domesticated the animals were thus the first to be victims. those early humans then developed resistance to some zoonotic diseases that had emerged (diamond, ) . the relation of animal diseases to human disease was observed in the ancient civilizations of babylon, the nile valley, and china and noted by leviticus in the old testament, and later by hippocrates in greece, and virgil and galen in rome. millions of people across europe during the middle ages suffered from plague carried by rat fleas. the invasion of europe by rinderpest in the th century disrupted commerce and government so much that the papal authority created a medical commission to advise the vatican on what measures should be taken to control the animal plague/rinderpest . the movement of animal diseases into the americas is believed to have been in the support of the settlements founded by columbus in santo domingo in . these livestock were the foundation animals for spanish colonies in the americas. in the next century, de soto, the spanish explorer of florida and the southeast, brought cattle, horses, and swine, as well as dogs that thrived. farther north, the virginia colonists brought animals to roanoke island, but none survived, neither humans nor animals. later the jamestown colonists imported domestic animals that survived and became valuable foundation stock, but no zoonotic diseases are recorded in any of these earliest settlements. not until was rabies the first zoonosis recorded in the us colonies, and later as an epizootic in both the colonies and the federation of states in the late th century (smithcors, a,b) . in , the newly founded medical repository editors were the first to inquire about emerging diseases in the united states and territories. they asked for information on human diseases, diseases among domestic animals, accounts of insects, the condition of the vegetation, and even the state of the atmosphere. they hoped to put the facts together as an annual report on the status of health in the united states. surgeon general luther terry ( ) of the us public health service (usphs) in his address at the american veterinary medical association (avma) centennial called this report the first reference to veterinary medicine in support of public health. a few years after this report, benjamin rush called for the establishment of veterinary medical education at the university of pennsylvania. the united states sanitary commission, organized during the civil war by public-spirited women, was concerned largely with sanitary conditions, including food hygiene. they were the first to call attention to the putrid meat and later embalmed beef sent to the army. the commission was to be a forerunner of public health in the years following the civil war (furman, ) . by the s, there was interest in developing a national health service. yellow fever epidemics were frightening as they spread up the mississippi river from new orleans. the possibility that yellow fever involved animals brought professor john gamgee, a famous veterinarian, from england to investigate the epidemic. he recognized the seasonal occurrencethat cold weather stopped the epidemic -and even suggested river traffic be limited to the colder months. however, he failed to associate the effect of cold weather with the decline of the numbers of mosquito populations, the vector of yellow fever (furman, ) . the us board of health came into being largely because of the yellow fever epidemic and the morbidity and mortality that it caused. by the time of the board's inception in , malaria was widespread in the south, and tuberculosis was a recognized disease. typhoid fever and enteric diseases were also common. in addition, animal diseases were present, especially the spread of glanders and anthrax following the civil war (furman, ) . in the president of the us board of health, dr. j.l. cabell, asked james law, professor of veterinary medicine at cornell university, to advise the board on how they should supervise the diseases and movements of domestic animals. law's report ( ) was the first comprehensive recognition of the effects of zoonotic diseases upon public health published in the united states (steele, ) . the organization of public health in the post civil war period has been reviewed by miles ( ) , former historian of the national institutes of health (nih). his report discusses the struggle between public health and agricultural interests in the decade leading up to the inauguration of the bureau of animal industry in . the interest of the bureau was to protect animal health, and later to provide a meat inspection service for public health, international trade, and subsequently interstate commerce. the relation of animal diseases to the public health and their prevention by frank s. billings ( ) was the first book to review the problems and the state of bacteriology as well as parasitology in the s. although the book is limited to trichinosis, hog-cholera, tuberculosis, anthrax, texas fever, rabies, and glanders, his knowledge of these diseases is remarkable for the time. billings gained this knowledge through education in berlin, where he learned about the history of animal diseases in the greco-roman period and the latin origin of ''veterinarians,'' which he says first appeared in the th century writings of vegetii. he also traveled extensively in europe, where he observed veterinary activities. billings makes a strong plea for the development of veterinary public health to control the animal diseases that affect man. he stated that this could be accomplished only by having trained veterinarians who were scientifically educated. he was one of the veterinarians who was active in the early years of the american public health association (apha), during which discussions of trichinosis, tuberculosis and other animal diseases took place at the early annual meetings. a true visionary of veterinary public health, billings pointed out that milk from diseased cows is dangerous. he appealed to the government to set up laboratories to use the new science of bacteriology to find the cause of illness of milk origin. food hygiene came into being only with the new science of bacteriology (billings, ) . the frightful toll of milk borne disease is reviewed by stenn ( ) . in his report, he cites the shocking figure of deaths per births in new york city in . spoiled milk accounted for the deaths of thousands of children in the early s, and in many other cities. the records of , cited by stenn, list many milk borne outbreaks of typhoid fever and diphtheria. he goes on to state that % of the milk cans sampled contained tubercle bacilli, and in cities, % of the milk had tubercle bacilli. in a milk borne typhoid epidemic occurred in washington, dc, that caused president theodore roosevelt to order the usphs to investigate the local supply. surgeon general walter wyman ordered his staff to examine not only the washington milk problem but to examine the national milk problem. the report milk and its relation to public health by milton rosenau, issued by the usphs, brought reform to the dairy industry and support for the bureau of animal industry program to control bovine tuberculosis (myers and steele, ) . pasteur took milk safety even further, changing science and veterinary medicine by creating a new concept of the origin of disease. no longer would the myth of spontaneous origin of disease guide society, although there were as many objections to scientific advances then as now. the centennial celebration of the rabies vaccine revealed in pasteur a man of many accomplishments. he was a chemist who discovered the cause of fermentation and applied it to the beer and wine industries, a process that led to milk pasteurization. he was an artist who was known to the impressionists of the th century as the man who prepared better paint colors. he was also a genius who gave public health the science and vaccines to combat th century diseases and prepare for the th century's emerging problems (koprowski and plotkin, ) . although the concept of pasteurization of beer and wine brought fame to pasteur, the application to milk was less known, and it was accepted no more readily than the concept of evolution. it was asserted that all kinds of illness and changes in well being would ensue from pasteurization. the eradication of bovine tuberculosis and brucellosis (bang's disease) insured a safe milk supply and protected the health of farmers, dairymen, veterinarians and the handlers of milk and milk products. the case for pasteurized milk and milk products is conclusive. in the late th century, a new array of milk borne zoonoses is of concern to public health and veterinarians. some date back to the th century, such as salmonella. the salmonella were identified in by one of the most distinguished public servants of the veterinary profession, dr. daniel salmon. as the first chief of the bureau of animal industry (bai) from to , he assembled and trained a great staff. this included theobald smith, v.a. moore and e.c. schroeder, who solved the epidemiology of texas fever caused by babesia bigemina, which is carried by the tick boophilus annulatus. salmon was the leading proponent of veterinary public health in the s. he asked for, and received from congress, authority for a federal meat inspection service in to meet the demands of foreign commerce. however, his national program was circumvented by local interests citing states' rights; therefore, the meat inspection act of was ineffective nationally. salmon sought support from the apha and the american medical association for these early veterinary efforts to protect public health. unfortunately, these agencies did not support him (schwabe, a) . the federal meat inspection service act of came about only after sinclair ( ) exposed the filthy conditions of the chicago stockyards. salmon was blamed for the local hygiene failure over which he had no authority and was removed from office. however, he is remembered today by the usda's salmon award for leadership. in , the bai initiated tuberculin testing of dairy cattle in the district of columbia, a demonstration that revealed an infection rate of almost %. this was the beginning of a successful tuberculosis control campaign that led to its eradication under john r. mohler, bai director from to . the late jay arthur myers memorialized the near eradication of bovine tuberculosis in his book, entitled ''man's greatest victory over tuberculosis'' (myers, ) . at the start of the th century, pathologists were greatly interested in comparative medicine. they were led by karl f. meyer, a swiss veterinarian who was to become one of the leaders and outstanding scientists of the th century. he was among the early public health scientists to delve into virology as professor of pathology at the university of pennsylvania (penn), and in he may have been among the first to recover a virus causing equine encephalitis. as director of the pennsylvania livestock sanitary board laboratory, he published on glanders, anthrax, anaplasmosis, sporotrichosis, paratuberculosis, septicemia, and many other diseases of animals. in he left the university of pennsylvania to accept a position at the university of california's newly established tropical medical center. the following year, he accepted an appointment to the george williams hooper foundation for medical research at the university of california medical center. he remained there the rest of his life and become a legend. his lectures introduced medical students to the biologically active world, including the zoonoses, plant life, the atmosphere and all that is called the environment today. at the hooper foundation, meyer researched a wide spectrum of animal diseases of public health importance. after being active in the investigation of human influenza in - , he went to the field to define the epidemiology of malaria, dysentery, and even dental diseases. his study of the bacterial causes of abortion in animals resulted in bringing together brucella abortus, brucella melitensis, and brucella suis in a new genus honoring david bruce. another important event was his report on clostridium botulinum in nature. botulism became a national concern in the s when california canned fruit and vegetables were found to contain botulinum toxin. the industry asked meyer to resolve the problems and underwrote a laboratory to maintain surveillance. thereafter, meyer was active in food safety, but he was also concerned with humane animal care in which he maintained an interest all his life. in , meyer and his long time lab associate bernice eddie began their series of psittacosis reports in birds. these reports eventually led to control years later with tetracycline-impregnated seed. the same antibiotic is now used to prevent ornithosis in domestic fowl (meyer, ) . one of meyer's most memorable lectures was in when he called attention to the importance of the animal kingdom as a reservoir of diseases that endanger the health and welfare of people throughout the world (meyer, ) . in , he first reviewed the state of the animal reservoir of diseases, by then referred to as zoonotic diseases, before the world health organization (who) general assembly. he repeated the same theme before the who expert committees for the zoonoses, plague, food hygiene and for the pan american health organization (paho) until his th year. meyer's work on plague was reported in the special supplement of the journal of infectious diseases to commemorate his th birthday. this was underwritten by max stern, president of hartz mountain, which supported the psittacosis control investigations at the hooper foundation (steele, ) . meyer died in san francisco on may , , less than a month before his th birthday. larry altman ( ) , the medical editor of the new york times, wrote a lengthy obituary from which the following excerpt is taken. it also appears on the fore page of the journal of infectious diseases (supplement), may : ''dr. karl fredrich meyer was regarded as the most versatile microbe hunter since louis pasteur and a giant in public health [. . .] . public health leaders yesterday called his contributions to medicine 'monumental.' his scientific work had such broad implications that it touched on virtually all fields of medicine.'' the obituary was placed in the congressional record that same month. in , albert sabin ( ) wrote a biographical memoir of meyer for the national academy of science, of which meyer was a member from l to . sabin explains that as a youth in basel, switzerland, pictures of the black death so fascinated meyer that he became an outdoor scientist instead of following in the aristocratic business world in which he grew up. he told friends that in choosing to become a veterinarian he could ''be a universal man and study all diseases in all species.'' the s were memorable for public health growth and scientific advances. the viral etiology of influenza was uncovered by richard shope and thomas francis at the rockefeller institute. the use of egg embryos was a new method of growing viruses that would lead to the chick-embryo rabies vaccine and other viral vaccines. the development of the strain brucella vaccine and the stern anthrax vaccine in south africa were important to the control of brucellosis and anthrax worldwide. earlier investigation of toxoids by gaston ramon, a french military veterinarian, led to the discovery of tetanus toxoid for both horses and humans. discovery of the sulfa drugs and penicillin gave the clinician medication he had not dreamt of, a prelude to great advances in medicine. to be a veterinary student in the late s was both exciting and slightly dangerous. the brucellosis epidemic among veterinarians -both students and clinicians -raised epidemiological questions as to how brucellosis was spread. in michigan state college experienced an epidemic among veterinary students and others in the bacteriology building (holland, ) . up to then the disease was thought to be caused by direct exposure or ingestion of milk borne brucella, and airborne brucella was not given much consideration. the episode at michigan state college would change that oversight. as a student in the brucellosis testing laboratory, i heard discussion of the means of spread being water borne and back siphonage. professor i.f. huddleson, whose research laboratory was the focus of this investigation, disagreed with the state investigators, who were public health scientists and engineers focusing on the water borne theory. these investigators suggested contaminated glassware was not being autoclaved properly, and in turn, viable brucella was getting into the water system (newitt et al., ) . the discussion of the epidemic, which affected most of the people in the building, along with other public health interests of dean ward giltner, professor h.j. stafseth, professor i.f. huddleson and dr. w.t.s. thorp of the michigan state university college of veterinary medicine, led me to think about a career in public health. dr. stafseth encouraged many students to consider public health as a career (stalheim and steele, ) . when he learned of my interest, he and dean giltner worked out a program to make me eligible for a usphs fellowship. i was excused from senior clinics to pursue the fellowship. my assignment was an internship at the michigan health department. there i observed and learned from health department veterinarians, pathologists and bacteriologists how to remove and examine an animal brain for rabies and to inoculate mice to further confirm the diagnosis. vaccinia were grown on the belly of a calf that had been shaved, scrubbed and disinfected. after harvesting the scabs, the vaccinia would be tested for contaminants. it was a lengthy procedure. the same high standards were maintained for the pertussis/whooping cough vaccine, equine antiserum for tetanus and rabbit pneumococcal antiserum. it was a learning period that would serve me well. dean giltner and c.c. young, the director of the michigan public health laboratories, put together my fellowship application to the usphs and harvard school of public health. approval came the week before graduation, and my bride-to-be aina oberg and i were elated. we were married the evening after graduation, with many of the faculty and classmates in attendance two days later i took the michigan examination to practice veterinary medicine. the summer of was spent as an intern at the petoskey animal hospital. there i learned about swimmer's itch-a common affliction of man and pets caused by an avian schistosome. i was exposed to the parasite while swimming in inland lakes. at harvard it became my thesis subject. later it was the first subject i reported on at the avma convention in chicago ( ) with dean giltner in the audience. at harvard, there was talk of war. president conant addressed the incoming class with the admonition there would be important world changes during their student years. the school of public health's dean cecil drinker, the faculty, and the students were stimulating. i was the only veterinarian, which attracted some attention, and the medical school librarian was delighted to know there was a veterinarian around. she showed me a remote section of the library that contained many old books on veterinary medicine-harvard had a veterinary faculty from to . we students were delighted with our newly found classmates, and many of us would remain lifetime friends. to me, the academic work was not demanding except for statistics, which took much time. after all, in those days, we used hand-cranked machines for tabulations. my wife, aina, first worked at the harvard co-op and then with the british american ambulance volunteers. she enjoyed the students and compliments and being invited to fundraisers for the volunteers. then tragedy struck. a sudden collapse with fever hospitalized her. the diagnosis was advanced tracheal-bronchial tuberculosis that would confine her to sanitariums and hospitals for the next years, from january to april . after innumerable surgeries, the newly discovered streptomycin saved her life after months of treatment. eventually, we established a home and family with two sons, jay and david, in atlanta, georgia, for years. there aina died from the complications of arrested pulmonary tuberculosis in . the new year ( ) brought unforeseen problems, mainly medical bills, even though student health expenses were covered to a lesser extent. i sought work at the angel memorial animal hospital, where i knew some of the staff. when dean drinker heard of my after-school work plans, he called me into his office and told me to concern myself with school and taking care of my wife. a check signed by dean drinker awaited me in his secretary's office, a practice that continued until graduation. the drinker society still honors his contributions at the harvard school of public health, which we support. as graduation neared, many of us knew we were going into uniformed service job opportunities. i was deferred by the lansing michigan draft board, but i volunteered for the army veterinary corps and the navy special services, an epidemiology unit. both declined my services, and in the meantime, i found no positions of interest. i wanted to do epidemiology of the animal diseases affecting human health, but all the positions i was interested in required a medical degree. finally i brought my dilemma to dean drinker's attention. shortly thereafter, he asked me to his office to talk over my future. i was upset that it seemed i must have a medical degree to be an epidemiologist. should i get an md? dr. drinker and his wife, also a physician, heard me out. their reply was to list my attributes: good student, industrious, good appearance, good speaker, and creative ambitions. that said, they followed with memorable advice: ''jim, fly under one flag.'' before leaving harvard, i met kf meyer who was lecturing at the school of public health. some days later, i learned he had asked about me because he anticipated some research contracts with the us army epidemiology board and would need staff. i was elated when he offered me a position, and aina and i left boston with high expectations. some days later we arrived in chicago, only to find out a week later that meyer had not received the contract and had no funds to support the research position. i was depressed: no job and a sick wife. a few days later i visited the usphs chicago regional offices to seek their help in finding work. i appeared unannounced and asked a secretary to see the director. while waiting, a medical officer appeared and asked if he could help. i explained that i was a usphs fellow they had supported in getting an mph, and my objective was to find a position where i could investigate the epidemiology of animal diseases that affect the public health. dr. henry holle, the medical officer, listened and replied he never heard about such a situation. so he took me to see the medical director, mark ziegler, a tall, soft-spoken, southern gentleman. the availability of a young mph graduate led them to call washington. a week later after a review of my qualifications and evidence of my education, i was offered an internship as a civilian sanitarian in the ohio department of health. there i would spend the next year, july -october . the challenges were milk sanitation problems, food borne diseases, diarrhea, typhoid, rabies and the ohio river flood, a great learning experience. in september , the us army offered me a commission as a veterinary officer which i planned to tentatively accept. within days, medical director frank meriwether told me since the usphs had given me a fellowship, they should have a first call to commission me. i received a commission as a sanitarian on november , . afterward, i spent a short tour of duty in the midwest region with senior sanitarian william h. haskell, an authority on pasteurization methods and practice. he was one of the civil service veterinarians brought in by the usph milk specialists early in . in , other newly recruited veterinarians raymond helvig, ray fagan, and ted price were also commissioned as sanitarians. they were the only veterinarians in the usphs except for a veterinarian who was an animal control officer in world war i in and two parasitologists willard wright and maurice hall at the nih in the s. from chicago, i was ordered to report to washington, dc, for orientation. there i learned of my assignment to puerto rico and the virgin islands where i was to be responsible for coordinating milk and food sanitation and evaluating any zoonotic diseases in areas that had been isolated by the war. brucellosis and bovine tuberculosis were widespread. the diagnosis of venezuelan equine encephalitis and bat rabies in trinidad caused some concern in the islands but did not spread beyond trinidad. rabies was indigenous in the dominican republic and cuba in the s. in march , the pan american sanitary bureau asked the usphs san juan, puerto rico, office to do an assessment of the post-war veterinary public health problems in the dominican republic and haiti, neither of which had a functional veterinary service. i was directed to make a report on their problems. in the dominican republic, there were no reported diseases, but bovine tuberculosis, brucellosis and mastitis were known. no veterinary laboratory support existed, and the abattoirs kept no records. rabies had been reported in dogs, and possibly in horses, and some years later there was an epizootic of equine encephalitis. president trujillo kept some racing horses near ciudad trujillo (santo domingo), and i was asked to examine them. these old horses were brought to the dominican republic before the war in - . all were broken down and hardly fit to run. regardless, the dominican republic officials thought i could repair their ailments. when i told them i could not, they complained that i was not cooperative to the u.s. embassy, who then told me to be cooperative. later i visited the trainer, who told me, ''we will do what we can.'' thereafter, i was anxious to leave and went to haiti within a few days. port-au-prince was a rundown but hospitable capital. the country had been ravaged by tropical fevers for decades; malaria and filariasis were widespread. animal diseases were mainly fever and parasites, but an epizootic of anthrax in the early s was still present in : the disease was sporadic in the countryside. to my amazement, the dead animals were salvaged regardless of what they died from. there were no veterinarians in the government or in practice. still, the abattoir in port-au-prince was an elegant open iron structure. the cattle were immobilized by pithing, in which a small blade severs the spinal cord after which they are bled and eviscerated. the procedure was done rapidly, usually late at night, and the meat was distributed early the next day. however, a serious shortage of animal products existed, and few shops had any meat for sale. all in all, my stay at port-au-prince and the rural areas was a distressing experience. some weeks later i was in washington for further assignment as the war wound down. while there, i visited the pan american sanitary bureau to discuss my report with surgeon general hugh s. cumming who served the pan american sanitary bureau for a decade, after retiring from the usphs. at our meeting, i emphasized the need for a veterinary public health program to help in updating the animal health, preventing zoonotic diseases, and enhancing food safety. dr. cumming suggested i discuss the need for a veterinary public health program with his medical staff, where the proposal was enthusiastically accepted. the veterinary public health program was initiated with dr. aurelio malaga alba, a peruvian military veterinarian, as a consultant. dr. fred soper, the post-war director of the reorganized paho appointed dr. ben blood to organize a veterinary public health program in june . he carried on until and was followed by the outstanding public health veterinarian dr. pedro acha. the temporary duty in dc left my future uncertain. i was to be assigned to kansas city to prepare for the problems that might evolve with the invasion of japan. i took leave to spend some weeks with my hospitalized wife whose health was failing. the end of the war in europe and the pacific shortly thereafter changed my reassignment. i returned to dc to meet with assistant surgeon general joe mountin, whom i met earlier in puerto rico. dr. joe dean, his deputy, had arranged the interview. after a few inquiries about my wife's health, dr. mountin came to the point: ''what are you veterinarians going to do for the public health now that the war is over?'' the follow-up to that interview is in the appendix of ''the th anniversary of the veterinary medical corps officers of the u.s. public health service.'' after the approval of a veterinary public health section in the states relation division in december , i spent some months at the national institutes of health. i also worked to establish liaisons with the usda, bai, federal agencies, congressional interests, state relations, the avma and apha. in september after surgeon general parran's approval of the veterinary medical officer cadre, dr. mountin felt my washington activities were successful. he told me i was to be assigned to the newly created communicable diseases center, formerly the malaria control in war areas. there the veterinary public health program was established as a division, but it was a challenge to integrate. the new director of the centers for disease control (cdc) was dr. r.a. vonderlehr, previously chief of the puerto rico regional office, who i served under. he gave excellent support as did his deputy, dr. justin andrews, who succeeded dr. vonderlehr a year later. rabies was a national problem after the war. there was a great movement of people as war industries and encampments closed, and as a result, pets were lost or abandoned. the incidence of human rabies was the highest ever recorded, and unfortunately, human vaccine therapy was not always effective. canine rabies vaccine protection was short, with the vaccines being given every months. therefore, rabies became the lead program of the veterinary public health division. to head the activity, dr. ernest tierkel, a university of pennsylvania graduate who had completed his mph at columbia school of public health in , was recruited. he, dr. robert kissling and martha eidson along with a staff of animal handlers became the nucleus of the national rabies program at the rockefeller rabies investigation center in montgomery alabama (steele and tierkel, ) . the center was transferred to the cdc for $ . . they successfully demonstrated the effectiveness of a new chicken embryo rabies vaccine in the laboratory (tierkel et al., ) and in epidemic situations in memphis, tennessee (tierkel et al., ) . dr. mountin had learned from the public health authorities of indiana, michigan and others that brucellosis in man was of concern. they went so far as to say that as the sanitariums lost tuberculosis patients, brucellosis patients would take their place. the indiana health department was to be a brucellosis project site under dr. sam damen, the director of laboratories. the goal was to determine what action the health agencies should take. the federal bovine brucellosis control program was active in all states, so it became apparent that if the health authorities gave their support, the federal state brucella control program could eliminate the animal source of the human disease. late we brought the problem to the attention of dr. herman bunderson, chicago's dynamic health officer who remembered the struggle to eradicate bovine tuberculosis in the chicago milk shed, which included dairy herds in six midwestern states. in , he had required all milk coming into chicago to be from tb-free herds regardless of whether the milk was to be pasteurized. he recognized the brucella problem and shortly thereafter instituted the same standards for the elimination of bovine brucellosis in the s. the brucella eradication program was supported by the usphs milk code, which required that all grade a milk be from disease-free herds (us public health service, ) . the chicago brucella control program was soon adopted by big city health authorities, which gave impetus to the joint state federal brucella programs. as a result of these efforts, human brucellosis declined rapidly in the midwest from a high of thousands of human infections to hundreds in less than a decade. thereafter most of the human cases were of occupational origin, in travelers or in people using raw milk in rural areas. in the s there was a scare of brucellosis at dugway proving grounds, a military research center in western utah. dr. herbert stoenner investigated the alleged contaminated area and found the problem to be a rodent disease caused by brucella neotoma. this organism does not cause disease in man or domestic animals, but will cause antibody formation in cattle (stoenner and lackman, ) . after world war ii, there was great interest in the application of atomic energy for civilian use. professor s.f. gould ( ) at wayne state medical school initiated studies on the use of irradiation to destroy trichinella. he persuaded the american medical association to host a trichinosis symposium in in which the cdc participated. the evidence was conclusive that gamma radiation was effective at low doses (gould et al., ) . this was the beginning of my interest in promoting food irradiation, but it was not until that irradiation for commercial use was approved by federal agencies. the zimmerman human tissue survey - revealed the lowest rate of trichinosis ever (zimmerman et al., ) . modern pig raising, the prohibition of garbage feeding of swine, and consumer education are all contributing factors in the decline of the disease in pigs and humans (steele, ) . trichinosis has continued to decline in the states except in wild animals especially bears. other veterinary public health studies of parasitic diseases involved creeping eruption, also known as cutaneous larva migrans. this condition is due to the common dog hookworm larva ancylostoma caninum entering the skin and causing intense itching. this disease was common in the southeast states among persons exposed to damp, sandy soil; children playing in sandboxes; bathers at the beach, and utility men (cypess, b) . toxocariasis or visceral larva migrans is another parasite due to the dog, and sometimes the cat, roundworm larva migrating in the body of a foreign host, human beings (cypess, a) . dr. peter schantz confirmed these findings as a world health problem. toxoplasmosis was recognized as a human infection, and the domestic cat is recognized as a common source of human infection. infection is more likely to be caused by consumption of raw or undercooked meat. irradiation is effective in destroying this oocyst in meat (gould et al., ) . in the early s, a large equine encephalitis epizootic in central california required the assignment of all cdc veterinary officers. later another equine encephalitis epizootic occurred in new jersey in . since then there have been only occasional epizootics of the equine encephalitides. although the principal reservoir is birds, there is also survival of the virus in mosquito eggs that over winter. the cdc-fort collins laboratory has been at the forefront of these investigations. the most recent mosquito born disease is the introduction of west nile virus into north america in . wild birds and common city birds are the reservoirs, and the culex mosquito is involved in the transmission. horses may show clinical signs. control of the vector mosquito breaks the transmission cycle. plague, primarily a disease of rodents, is sporadic in the united states. the appearance of plague in domestic and feral cats and squirrels has brought the ancient scourge to households in the western states (poland and barnes, ) . however, dogs were never identified as carriers of the disease to man. an unusual epidemic of anthrax caused alarm in animal and human public health circles in the s. the anthrax was introduced by contaminated bone meal used in animal feed to improve lactation in sows. a radio announcer in cincinnati raised the question if cows' milk could be a vehicle for anthrax to be carried to humans. a search of literature found that milk was never a vehicle or cause of human or animal anthrax disease because the high fever of the disease stops lactation (steele and helvig, ) . salmonellosis was a recognized public health problem early in the s as well as during world war ii and afterwards among the civilian populations (galton et al., ) . after the war, investigators demonstrated it was widely disseminated. dr. phil edwards led the way at the university of kentucky and later at the cdc. mildred galton, chief of the veterinary public health laboratory contributed with her unusual ability to find evidence that others had overlooked. she demonstrated salmonella in many animals. her studies of transported pigs revealed how stress caused latently infected pigs to become shedders. the same reaction was found in other species. her work on raw eggs and meats led to the pasteurization of egg slurry used in baked or cooked products. she was among the first to find salmonella in raw milk years ago, and her work on the frequent presence of salmonella in poultry led to the federal poultry inspection program in the late s (steele and galton, ) . thirty years before weil described leptospirosis in humans in , animal leptospirosis was identified as its own problem. a record of an canine epidemic in stuttgart, germany, exists, but the etiologic agents were not determined. years after the canine epidemic, it was discovered that microorganisms morphologically identical caused the disease in both dogs and humans. leptospirosis proved confusing to all health professionals partly because ''isolated serovars were given names denoting the clinical signs observed in the patients from whom they were isolated'' (torten, ) . therefore, it was thought that serovar grippotyphosa would cause signs similar to catarrhal fever, and serovar icterohemorrhagia would cause hemorrhagic jaundice. it was not recognized that both serotypes are capable of causing both signs (torten, ) . in the us, there were numerous outbreaks among animal handlers, veterinarians and swimmers as well as people whose occupation exposed them to contaminated waste water in the - period. leptospirosis is now recognized as a problem associated with disasters such as flooding and earthquakes. there is wide agreement that vaccination of cattle and dogs has reduced environmental contamination (stoenner et al., ) . galton ( ) edited the ''leptospiral serotype distribution list '' through , and sulzer ( ) carried it up to . they were truly dedicated in keeping these records. listeriosis was first recorded in in sheep, and the first reported human case was in denmark in (bomer et al., ) . prevention of listeriosis is still not possible with the knowledge available, as there are no immunizing agents of proven worth. killed bacterins have been disappointing, and living attenuated vaccines have not been evaluated properly nor have they shown promise in limited experiments. good physical hygiene is essential to prevention (bomer et al., ) . groups at high risk of infection are pregnant women, neonates, diabetics, alcohol dependents, persons with neoplastic disease, or those being treated with corticosteroids or antimetabolites. among animals, ewes are at the highest risk late in the first pregnancy. sheep in late pregnancy should not be fed ensilage of doubtful quality nor be exposed to severe cold or inclement weather and crowding (bomer et al., ) . improved measures for preventing and controlling human listeriosis depend on increasing awareness of its diverse clinical manifestations and an increasing index of suspicion. because l. monocytogenes, the causative agent of listeriosis, is sensitive to most antibiotics, their early administration, once the diagnosis has been established, significantly decreases mortality. cortisone and its derivatives may, however, cause asymptomatic listeria infections to become overt (bomer et al., ) . after the end of the war in europe, the breakdown of food hygiene there allowed salvaged food to spread zoonotic diseases. at the same time there were numerous cases of listeriosis reported in france that caused abortion, stillbirths and reproductive tract disease (seeliger, ) . the disease remains prevalent in western europe to the extent that all midwives and obstetricians alert their patients to report symptoms. since there has been a steady decline of reported cases. food borne listeriosis elsewhere was virtually forgotten until when an outbreak occurred in the maritime provinces of canada and was associated with consumption of contaminated coleslaw (schleck et al., ) . then years later, a major outbreak in massachusetts between june and august of was epidemiologically linked to consumption of a particular brand of pasteurized whole and % milk (fleming et al., ) . although questions have been raised about the adequacy of the epidemiologic study (ryser and marth, ) , no other food has emerged as the vehicle that transmitted l. monocytogenes in this outbreak. in mexican-style cheese made in a factory near los angeles was definitively linked to a large outbreak listeriosis (linnan et al., ) . this was followed in by the linking of consumption of vacherin mont d'or, a variety of cheese, to an outbreak of listeriosis in the canton of vaud in switzerland (bille et al., ) . in recent years, food borne outbreaks continue to be reported in north america and europe. during the s, many more human cases and deaths were reported in the united states. the vehicles reported as contaminated were cold cuts, canned meats and frankfurter sausages. worldwide, listeriosis is a problem mostly in the temperate zones. another emerging zoonotic food borne disease is escherichia coli o :h , the enterohemorrhagic strains as well as those characterized by cytotoxins. these e. coli and others of human origin are major causes of the human enteric disease. however, they are less causative in food producing animals that may be infected but show few or no clinical signs. pasteurization of milk is effective in the control of e. coli spread. irradiation has proven effective for pasteurization of food of animal origin for the protection of the public health. recently improved inspection and hygiene have reduced reported human diseases, even though toxic e. coli is wide spread among cattle. the same can be said for newly identified emerging food borne zoonotic diseases. cryptosporidia parvum is a coccidian protozoa found worldwide. giardia are found in numerous animals, and during the late th century, the flagellate protozoan was identified worldwide as a water borne disease of humans and animals. old problems new to the states are taenia saginata and t. solium, largely found in immigrant workers. the tapeworm cysts found in meat, beef and pork are easily destroyed by irradiation, a technology that slowly is being accepted in the southern countries where tapeworm disease is recognized as both an economic as well as a public health problem. the acceptance of veterinary public health internationally by the paho has been previously discussed. the inauguration of veterinary public health as a national program in the usphs in stimulated interest worldwide, especially in the newly created international agencies. the united nations health office organizing committee chaired by surgeon general tom parran met in new york in june to further public health worldwide. the public health service officers and personnel were asked by the surgeon general's chief of staff, g.l. dunnahoo, to suggest topics. veterinary public health was new, but a few weeks before the organizing group was to meet, i was directed to make a veterinary public health presentation and answer questions at the surgeon general's staff meeting. after the meeting, i asked dr. dunnahoo if he would be interested in a recommendation for a veterinary public health program for the who organizing committee. he urged me to give him a memo recommending a veterinary public health activity. that may , , i wrote a memo paraphrased as follows: ''regarding our conversation and your encouragement, i propose that in the organization of the united nation's health office there be a veterinary public health (vph) program. the vph program would be concerned with animal diseases transmissible to man. the vph would carry on liaisons with veterinary activities in the agriculture agencies and collect information on animal health.'' some months later i asked how the vph recommendation was received. dr. dunnahoo said there were no objections or discussion: the vph item was accepted and placed in the records. years later i learned an american veterinarian, martin m. kaplan, was recruited by an english physician with whom kaplan worked with in the united nations relief and rehabilitation administration (unrra) in greece. in kaplan came to the newly established who in geneva, switzerland. he developed a vph program in the communicable disease division that is a model for a public health program in the developing world. during the next years, he organized the expert committee meetings and technical reports. the first was in l (who, ) to review tuberculosis, which was a major disease problem in humans and animals at the end of world war ii. an american tuberculosis authority, dr. franklin top, a us army consultant, had reported that % of the human cases in occupied germany were caused by mycobacteria tuberculosis bovis. the problem was referred to the who expert zoonoses committee by the who expert tuberculosis committee. there was no consensus on what recommendation to make. the danish veterinarian dr. plum spoke for the classical tuberculin test and identification. the french urged the use of bacille calmette-guérin (bcg) vaccinations. the success of bovine tuberculosis eradication in the united states was recommended as the ideal method. eventually the committee recommended test and removal, with the caveat for developing countries to try other methods, including the bcg vaccination, which had no success in field trials. a number of other diseases were reviewed with the recommendation for control. there was a consensus on the following: q fever, anthrax, psittacosis, and hydatidosis. another issue was to settle on a definition of veterinary public health. a current definition of public health is summarized as diseases that are naturally transmitted between animals and man. the following year, , who called together a panel of rabies experts, including e.s. tierkel of the cdc (who, ). tierkel and others who followed from the cdc, namely george baer, keith sikes, jerry winkler and currently charles rupprecht, contributed to rabies control and prevention. the first of the who expert committees on the zoonoses was followed by zoonoses study groups in , which meyer chaired in stockholm (who, ) . he was most effective in leading the committee, and in his closing remarks he passed the leadership to james steele. at the next meeting of the who zoonoses expert committee in geneva in , i was the chairman (who, ) . the next meeting in was chaired by calvin schwabe (who, ) , professor of epidemiology at the university of california school of veterinary medicine and the school of human medicine. schwabe ( b) summarizes the who veterinary public health in his monumental third edition of veterinary medicine and human health: ''the final objective of veterinary medicine does not lie in the animal species that the veterinarian commonly treats. it lies very definitely in man, and above all in humanity.' ' we in veterinary public health recognize the contributions of acha and szyfres ( ) for their invaluable book, zoonoses and communicable diseases common to man and animals in spanish and english. it has been the foundation of veterinary public health epidemiology and surveillance in the spanish speaking countries of the americas. at this time, dr. george beran is to be recognized as one of the consultants to paho and who, and for his work in the philippines. he has carried on in admirable style for more than years in teaching, research, health promotion and consulting, and as author and editor. he has updated the chemical rubber company (crc) handbook of zoonoses series (beran, ) and the paho zoonoses reports, and hopefully will continue to do so. he is a historian of veterinary public health. in closing we pay tribute to the american veterinarians who demonstrated and promoted veterinary public health in the united states. most of these early pioneers years ago were recruited by the cdc and assigned to states that had zoonotic disease problems, mainly rabies. among the early cdc recruits assigned to a state was ernest wine. he was sent to pennsylvania, where he remained for years, rising to the position of state epidemiologist. oscar sussman went to arizona, and later the new jersey health department recruited him, where he built an outstanding program. martin baum served colorado for many years after leaving the cdc. john mason served in new mexico. art wolff did excellent service in michigan before returning to washington, where he became a leader at the usphs in environmental health as a radiation authority and assistant surgeon general. herbert stoenner went to utah and raymond fagan to indiana as described earlier. monroe holmes followed stoenner to utah, and john scrugs went to indiana when fagan went to the harvard school of public health. john winn, francis abimanti, don mason, and lauri luoto were among the early investigators of q fever in california. stoenner, in addition to his investigation of brucellosis and leptospirosis, was also a leader in q fever studies. don mason, john richardson, and paul arnstein worked on the control of psittacosis in k.f. meyer's laboratory at ucsf. dick parke, joe held and robert huffaker kept the cdc office responsive to many inquires and provided service to the states. james glosser closed his career at the cdc in . his work coordinating the venezuelan equine encephalitis epizootic and epidemic with the u.s. department of agriculture veterinary services earned him the united states department of agriculture's outstanding service award. the veterinarians service to public health in the th century resulted in better health in all humans and animals. what are the st century challenges? animal medicine and veterinary public health have been intertwined since humans first began ministrations to their families and animals. dr. william foege, former director of the communicable disease center and professor at emory school of public health and now consultant to the bill gates foundation center, expressed this more forcefully in saying that we cannot have good public health unless we have good animal health. we can invert that and say we cannot have good animal health unless we have good public health. in the united states, the veterinary medical profession has carried on effectively in eliminating those major problems of animal health that had serious public health ramifications, namely bovine tuberculosis and brucellosis. in recent years the advances in rabies immunization have eliminated the disease from our pets, and humans have benefitted. the new human cases that occur are mainly the result of bat exposure. looking beyond that, we can see there is a sizable list of parasitic diseases, namely trichinosis and tapeworms, that have been brought under control in the united states. however, tapeworms are now being introduced by the recruitment of workers from mexico, central america and south america. these problems affect society in the united states, but it is apparent that we have an obligation to share our knowledge with our neighbors of the americas as well as africa and asia. all of these countries face the same problems the united states, solved in the past century. now as we move into the st century, the technology for controlling these diseases is available. these proven effective procedures in the united states can be used worldwide. some challenges exist, however, for methods that control bovine tuberculosis. there is a continuous demand for vaccines to prevent tuberculosis in animals, but there is little evidence there is any value in routine vaccination. these procedures are quite costly, and the best examples are in europe in the past years. after world war ii, tuberculosis was a major problem in central europe especially in germany, eastern europe, what is now russia, and western europe. there has been an uncalled-for degree of confidence in the tuberculosis vaccine, bcg, but with constant pressure from the world health organization, the world animal health organization (oie), the food and agricultural organization and united states agencies and consultants, the use of vaccines has been put aside. the old test and removal strategies have proven to be the most successful. to introduce that method into mexico, central america, south america and asia is difficult at this time because they are hopeful that a good vaccine will be developed. unfortunately we have lived with that hope for years. the major problem that remains is to compensate farmers for diseased animals that are removed. the neighboring countries of mexico, central america and south america have the opportunity to further their own disease control by employing the proven techniques used in the united states, canada and europe. the control of brucellosis in the developing world is a much bigger problem than tuberculosis. in veterinary epidemiologist george baer described the human disease in mexico and said that most rural people who had reached the age of had evidence of past infection with brucellosis. the same can be said for the countries of latin america where goats have a high rate of b. melitensis infections. to control b. melitensis is a difficult task and is a matter of the governments facing up to the issue. a new vaccine developed in the united states, the rb rough strain, had been researched for years or more before the united states department of agriculture veterinarians were able to find a solution to producing an effective vaccine for cattle. the vaccines have not proven valuable for goats and sheep. the control of widespread brucellosis in north africa and the middle east across asia has been given little attention. the who, through their consultancies and expert committees on rabies, has spread the knowledge of dog vaccination throughout the world. we can say with some degree of pride that the technology developed by veterinarians at the communicable disease center and carried to other parts of the world by authorities such as the late ernie tierkel and others who worked with him and george baer have made a great contribution to the world scene. we do see the light at the end of the tunnel for worldwide control of canine rabies. other efficient rabies vaccines have been developed in south america and europe. looking at the parasitic infections of the world, there is certainly a great deal of interest in control of trichinosis, which has been fostered through scientific congresses every few years. the world wide results are favorable today with a drastic reduction in north america and europe. unfortunately new problems have arisen in connection with the disease in wild animals, especially those found in the arctic zones of the world. taenia saginata and t. solium are receiving more attention as we face worldwide problems with the measurements of disease. in the americas the problem has been carried from one country to another by human carriers and then spread to animals. new foci have been established in north america, where there have been meetings to plan for initiating a worldwide control program. in my own way of thinking, the control of t. saginata is a measurement of good hygiene and good waste control in any country where it is present. dr. peter schantz has advocated world control of tapeworm and hydatid disease with the goal of eradication. many other new problems arising in zoonotic and parasitic diseases are constantly coming to our attention. the continuous migration of workers seeking better opportunities in industrialized countries also carries the risk of infections being brought with them. the surgeon general has spoken for the globalization of public health. the veterinary public health program of the cdc has been active in globalization of veterinary public health, namely in the control of rabies, parasitic diseases and food borne diseases. many of the veterinary officers have served on who expert zoonosis committees have carried out detailed missions for who. the cdc program has been supportive of paho veterinary activities with assignments of veterinary officers to mexico, panama, peru, argentina, and most recently david ashford and hugh mainzer to brazil for foot and mouth disease control and other problems. the number of emerging diseases increased in the latter part of the th century. infectious disease scientists have found that acquired immune deficiency syndrome (aids) is a disease that makes people more susceptible to zoonotic diseases, including bovine tuberculosis and related mycobacterial infections, toxoplasmosis, cryptosporidiosis, food borne salmonella and enteric infections including campylobacter, listeria and yersinia. it is possible that other zoonotic diseases that are dormant or infrequent may emerge in individuals with aids, human immunodeficiency virus infection, or other immune-compromised conditions. related latent or nonpathogenic viral diseases have been described in tropical cats of africa including lions as well as domesticated cats. in australia and malaysia new diseases which also affect humans have been reported in horses and swine. these diseases are caused by the morbilliviruses, a measles-like virus that causes canine distemper and rinderpest. another virus that killed the wild felids in the cairo zoo has not been identified. could this be another form of distemper? some of the emerging viral diseases that have a rodent or unknown animal host have caused fatal, devastating diseases in humans in africa and south america, namely lassa fever and south american hemorrhagic diseases in argentina and bolivia. in africa, ebola virus hemorrhagic fever and marburg hemorrhagic fever virus infection, linked to monkey disease, caused disease in medical personnel, handlers and people who had only casual exposure. an incident that surprised us many years ago was the deaths of workers in middle east abattoirs caused by crimean hemorrhagic fever carried by ectoparasites. one example of developing, emerging, or relatively unknown diseases is severe acute respiratory syndrome (sars), a disease that erupted a few years ago in china and was carried to many parts of the world. recently information has suggested that bats are a natural reservoir of a sars like coronavirus. even though sars may have been an occasional emerging disease that disappeared as rapidly as it appeared, there may have been other infections from bats that have been around the world for millenia. naturally, an infection that has been given much attention now is where we stand with the influenza virus. are wild birds the true reservoir? apparently, birds are the reservoir based on the information we have gathered showing that wild birds transmitted the virus to avian domestic flocks. all this new information is challenging. the emerging diseases of the world are reasonably covered in the table of the last chapter of merck veterinary manual's ninth edition zoonosis section, . in addition to infectious diseases, we have a new class of diseases that are caused by prionsproteinaceous infectious parties that transfer diseases without any dna or rna. transmissible diseases are not the same as infectious diseases which are characterized by replication of dna or rna. this is certainly a bewildering situation especially when we read that saliva may be a means of transfer. immediately veterinarians think of rabies which is transmitted by saliva. is it possible the prion of the diseased brain can be secreted through nerve fibers that innervate the salivary gland? the prions are of great and continuing concern as a cause of concern as new types of diseases. our associates in chemistry, physics, and physiology may offer clues to other neurological diseases. one last subject i want to mention is humaneness. it is important that we abide by sensible, humane policies, but humaneness can be carried to such an extreme that it destroys values that we hold so high for protecting our pets, farm animals, and the wild animals around us. periodically we all read about overpopulations in different areas. society calls for conservative measures for population control that applies to all pets, wild animals and domestic animals. in a broader sense, it has applications to the human race. we are aware of the collapse of earlier civilizations that have overpopulated their given area or were destroyed by natural events such as starvation. so i say all veterinarians, especially those in public health, have a responsibility in developing humane regulations for animal population control and public guidance. in the united states, - % of veterinarians treat our animal associates or pets for various diseases. it is important that veterinarians have a broad, basic knowledge of public health issues and are alert for new public health issues that can be resolved with tender loving care, new antibiotics, and new procedures. the , or more veterinarians in the avma in the united states are key to the control of zoonotic diseases by public health agencies. the health of our animal population is tied to the emotional and mental well being of those humans who are close to animals in their lives. animals are vital companions to those homebound, and animal health becomes a family concern. an area i have stressed is the need for basic veterinary science. we see in current publications that most research is based on support from nih. at the avma meeting in july , the speaker us senator hatch of utah spoke highly of the public health activities of veterinary medicine. he went on to say that there may be a nih veterinary institute in the future. it behooves us all that the agricultural interest in public health be recognized as an important issue to the american public. i think highly of the importance of animal health in providing good public health. public health should not be guided by economic interest but by the welfare of all society. i go back to my earlier statement that animal health and public health are of great importance to all, and we must have good animal health to have good public health. good public health provides a means for good animal health. as we look to the future, we have to have open minds and think in terms that anything can occur in biology. i would like to quote my dean from michigan state, ward giltner, who said the only thing about biology we can accept that remains a firm truth is there always is new information that provides exceptions. looking at it broadly, all infectious things in nature, and prions which may cause disease are always looking for a new host. i like to say they are seeking social security, as most of the world is. carry on in the st century. i wish i could continue to be a part of it, but it seems time has a way of saying, ''you have been here. you have enjoyed it.'' i especially enjoy the recognition of years of public health service, i am elated. to the audience, especially to the teachers of public health science, thank you. carry on. dr. steele does not have a financial or personal relationship with other people or organisations that could inappropriately influence or bias the paper entitled ''veterinary public health: past success, new opportunities.'' zoonoses and communicable diseases common to man and animals. pan american health organization viral scientist dies-public health giant handbook of zoonoses section a: bacterial, rickettsial, chlamydial and mycotic. section b: viral, second ed epidemic food-borne listeriosis in western switzerland. ii. epidemio ogy the relation of animal diseases to the public health and their prevention listeriosis visceral larva migrans cutaneous larva migrans guns, germs, and steel: the fates of human societies pasteurized milk as a vehicle of infection in an outbreak of listeriosis a profile of the us public health service - . pub. no. nih- - . us department of health, education and welfare. us government printing office leptospiral serotype distribution lists (through ). veterinary public health laboratory. us department of health, education, and welfare public health service the world problem of salmonellosis prevention of trichinosis by gamma irradiation of pork as a public health measure control of trichinosis by gamma irradiation of pork undulant fever outbreak at michigan state college. mich world's debt to pasteur report on diseases of domestic animals epidemic listeriosis associated with mexican-style cheese the animal kingdom-a reservoir of disease history of medical research and public health: an oral interview history of the bureau of animal industry, appendix man's greatest victory over tuberculosis. c.c. thomas attempts to control tuberculosis among cattle water borne outbreak of brucella melitensis infection plague milk and its relation to public health karl friedrich meyer - : a biographical memoir epidemic listeriosis: evidence for transmission by food food safety veterinary medicine and human health listeriosis the jungle. double, page & company the veterinarian in america - the socioeconomic responsibilities of veterinary medicine biographical notes on the occasion of karl f. meyer's th birthday trichinosis zoonoses - : an update of james law's report on diseases of animals epidemiology of food borne salmonellosis present status of anthrax rabies: problems and control. a nationwide program nurture turned to poison a new species of brucella isolated from the desert wood rat neotoma lepida (thomas) the epizootiology of bovine leptospirosis in washington leptospiral serotype distribution lists ( to ). veterinary public health laboratory. us department of health, education, and welfare public health service a century's progress in public health effective control of an outbreak of rabies in memphis and shelby county a brief survey and progress report of controlled comparative experiments in canine rabies immunization leptospirosis milk ordinance and code. public health bulletin no. . department of the treasury joint who/fao expert group on rabies. who technical report series no. . who joint who/fao expert group on zoonoses: bovine tuberculosis, q fever, anthrax who, . joint who/fao expert committee on zoonoses, report on the nd session. who technical report series no. . who, geneva. who, . joint who/fao expert committee on zoonoses trichiniasis in the u.s. population, - . prevalence and epidemiologic factors the symposium at which this paper was presented was sponsored by bayer animal health. the author also wishes to acknowledge and thank dr. cynthia hoobler for assistance with the preparation of this paper. key: cord- -cqol zf authors: goodman, larry; segreti, john title: infectious diarrhea date: - - journal: disease-a-month doi: . /s - ( ) - sha: doc_id: cord_uid: cqol zf abstract infectious diarrhea is an extremely common illness that affects millions of americans annually. for most patients, the illness is a self-limited one. its major risk is dehydration. however, for some patients, diarrhea can lead to severe dehydration or be associated with bacteremia and metastatic infection. patients with these conditions require prompt treatment. a large number of organisms have been associated with diarrhea in humans, and most laboratories routinely screen for salmonella, shigella, and campylobacter. other bacteria, parasites, and viruses account for a significant percentage of diarrhea cases and frequently go undetected. this article summarizes many of these pathogens and describes the settings in which they can be acquired. food distribution networks have made the delivery of previously rare foods to remote areas a commonplace occurrence; this has also led to new challenges in the diagnosis and prevention of food-borne illnesses. outbreaks of diarrhea now frequently extend across many states. the identification of a rare strain of a bacterial pathogen or changes in the isolation rate of common pathogens may be early clues to the cause of such an ongoing outbreak. most enteric pathogens cause disease by either stimulating the secretion of fluids at the level of the small bowel or by irritating and invading the colon. organisms that cause disease by the latter mechanism have the potential to invade the blood stream and spread to other parts of the body, including the bones and the central nervous system. several organisms have been associated with specific postinfectious syndromes that are responsible for additional morbidity and mortality. the antibiotic resistance of bacterial pathogens has been increasing, and this has a limiting effect on the empiric treatment choices available for suspected bacterial diarrhea. careful attention to local sensitivity patterns and appropriate testing of the patient's isolate are among the important factors that lead to successful treatment decisions. abstract-infectious diarrhea is an extremely common ihess that affects millions of americans annually. for most patients, the ilhress is a self-lhnited one. its major risk is dehydration. however, for some patients, diarrhea can lead to severe dehydration or be associated with bacteremia and metastatic infection. patients with these conditions requhe prompt treatment, a large number of organisms have been associated with diarrhea in humans, and most laboratories routinely screen for salmonella, shigelea, and campylobacter. other bacteria, parasites, and viruses account for a signihcant percentage of diarrhea cases and frequently go undetected. this article summarizes many of these pathogens and describes the settings in which they can be acquired. food distribution networks have made the delivery of previously rare foods to remote areas a commonplace occurrence; this has also led to new challenges in the diag no& and prevention of food-borne ilhiesses. outbreaks of diarrhea now frequently extend across many states. the identiilcation of a rare strain of a bacterial pathogen or changes in the isolation rate of common pathogens may be early clues to the cause of such an ongoing outbreak. most enteric pathogens cause disease by either stimulating the secretion of fluids at the level of the small bowel or by irritating and invading the colon. organisms that cause disease by the latter mechanism have the potential to invade the blood stream and spread to other parts of the body, including the bones and the central nervous system. several organisms have been associated with specilic posth&ctious syndromes that are responsible for additional morbidity and mortality. the antibiotic resistance of bacterial pathogens has been hwmuhg, aud this has a limithrg effect on the empiric treatment choices available for suspe&d bacterial diarrhea. careful attention to local sensitivity patterns and appropriate testhtg of the patient's isolate are among the important f'actors that lead to sud tteatment decisions. it is estimated that there are approximately . episodes of diarrhea per person per year in the united states. in developing nations, the incidence of diarrhea is much higher, and in many countries, diarrhea is the leading cause of potential years of life lost. worldwide, children are the most affected by this condition, which causes more than million child deaths annually. however, in the united states, more than half of the deaths attributed to diarrhea occur in the elderly population. diarrhea is acquired by ingesting a causal pathogen or toxin, and several foods are particularly common vehicles for the ones that cause diarrhea. water is a common source of giardia lamblia, cryptosporidium, cyanobacterium, and norwalk virus. milk is a common vehicle for salmonella, campylobactel: and yersinia. outbreaks of salmonella and campylobacter have been traced to contaminated chicken, and eggs have been the source of several large outbreaks of sahonella. fish have been the source of infections caused by ebrio, norwalk virus, and several toxins. there are several key host defenses that decrease a person's chances of developing diarrhea after ingestion of a pathogen. the main ones are gastric acidity, small bowel motility, local antibody formation, and the colonic microflora. of these, gastric acidity is the most important. a fasting ph of less than eradicates most pathogens that are ingested, but this barrier is overcome if either a very large inoculum is ingested or if other foods are ingested first, which can buffer gastric acidity. organisms cause diarrhea by the production of a toxin (enterotoxin, neurotoxin, or cytotoxin), by adherence to the mucosa, or by invasion of the tissue and blood stream. many of these pathogenic properties can be transmitted to other organisms. fever, incubation period, and the presence of white blood cells in the stool are all useful clues when categorizing a diarrheal illness. incubation periods shorter than hours suggest an enterotoxin-producing organism; fever and white blood cells in the stool are generally associated with an invasive pathogen. the microbiology laboratory provides the definitive tests for diagnosis. cultures and toxin assays are the gold standard diagnostic tests. when specific pathogens (such as vibrio) are suspected, the laboratory must be informed so that appropriate testing can be performed. more than half of the patients who develop bacterial gastroenteritis improve within days. although antibiotic therapy may further reduce this period, the real benefits of therapy are to treat patients who are particularly ill and possibly experiencing bacteremia and to eradicate the organism from the stool, thereby decreasing secondary transmission. enteric pathogens have become increasingly resistant to many common antibiotics, making treatment decisions more complex. the widespread use of antibiotics in animal feed and the overuse of antibiotics in humans have contributed to this serious problem. infectious diarrhea diarrhea diseases are among the most common illnesses of the patients that come to a general practitioner. diarrhea is also a common problem for travelers, and it is often seen in hospitalized patients. in each of these settings, there are key differences among the initial work-ups and treatments of the patients. an understanding of the basic pathophysiology of diarrhea and its common infectious and noninfectious causes greatly limits the differential diagnosis and, therefore, the cost of the work-up. estimates of the number of cases of diarrhea in the united states have ranged from million annually to . episodes per person per year.' although usually a self-limited condition, the impact of diarrhea, as measured by lost days of work, physician or hospital visits, or lost vacation days, is significant. diarrhea has among the broadest differential of infectious causes of any common syndrome; bacteria, toxins, viruses, and parasites are all common causes, and sometimes fungi and mycobacteria may be the cause. routine laboratory tests do not distinguish all of these agents, and toxins and viruses in particular frequently are not detected. today, with modem food processing, refrigeration, and distribution systems, food-borne outbreaks frequently encompass wide geographic areas. the association of diarrhea infections with subsequent syndromes that are not gastrointestinal (eg, escherichiu coli : h with hemolytic uremic syndrome) demonstrates the impact that epidemiologic studies have had on our understanding of these infections and their sequelae. finally, although this review will mainly cover the infectious causes of diarrhea, there are numerous noninfectious causes of diarrhea that also must be considered for the differential diagnosis. frequently a patient's history will be helpful in determining these other causes. noninfectious causes should particularly be considered when dealing with a patient with persistent or recurrent diarrhea. on a global scale, diarrhea accounts for approximately , ,ooo child deaths annually, making it the leading cause of potential years of life lost in many parts of the world.* in many developing nations, diarrhea can occur at the rate of to episodes per person per year. children are at a particular risk of developing diarrhea just after they are weaned from breast-feeding. in developed nations with adequate sewage and refriger-ation systems, a frequency of to episodes of diarrhea per person per year is more typical. debilitated patients and patients at the extremes of age have a higher risk of dying from severe diarrhea, usually because of dehydration or the effects of the malabsorption of necessary medications. in the united states, a recent increase in mortality caused by diarrhea has been seen in the elderly. a review of all deaths associated with diarrhea from to found just over , cases in which diarrhea was listed as the primary cause of death. of these deaths, % were of patients in the hospital who were more than years old. the age-specific annual mortality was higher for the elderly than for children to months old ( . deaths per , person years vs . deaths per , person years). a more recently published study in cuba disclosed similar findings. between and , cubans died from diarrhea. sixtytwo percent of the patients that died were retired people, and mortality was highest in males more than years old. the most common health problem facing the more than million people that travel internationally each year is travelers' diarrhea. the risk to the traveler varies and depends on the destination and the eating habits of the traveler. relatively low-risk destinations include canada, australia, and northern europe. southern europe and several of the caribbean islands have a higher risk, and the areas with the highest risk for travelers are latin america, africa, parts of asia, and the middle east. studies of people who have traveled to these highest-risk destinations have demonstrated an incidence of diarrhea of up to % to %. $ although most cases of travelers' diarrhea are self-limited, the loss of business or vacation days is significant and prompts many travelers to ask their physicians questions about prevention and treatment. diarrhea is a common condition of patients in the hospital. although many of these cases have noninfectious causes, clostridium dificile is recognized as the most common infectious cause; in several studies it accounted for about % of all cases. j the incidence of diarrhea among some hospitalized patient populations may rival the incidence seen in travelers. this makes clear the need for special prevention and treatment strategies. also, unlike cases of diarrhea seen in other settings, the fact that a single pathogen accounts for such a high percentage of all nosocomial cases changes the diagnostic and therapeutic approach. several underlying illnesses greatly increase a patient's risk of infectious diarrhea. for example, hemolytic diseases such as sickle cell anemia are associated with a higher incidence of sulmonelzu, and children with common variable immune deficiency and x-linked agammaglobulinemia are more susceptible to giurdiu. of all underlying illnesses, patients with acquired immunodeficiency syndrome (aids) have the highest incidence of diarrhea. gastrointestinal symptoms are reported in % to % of patients with aids in developed countries and in nearly % of patients with aids who are in developing nations. t diarrhea is one of the most common infectious syndromes in the world. appropriate management requires knowledge of the setting in which the patient became ill, the underlying disease state, and the physical findings and laboratory results at the time the patient presented with the condition. diarrhea is a common final expression of infection with a myriad of pathogens. optimal evaluation and treatment of each of these infections (as well as of cases caused by noninfectious organisms) can limit the duration of illness, the morbidity rate, the cost of work-up, and the spread of secondary infection. nearly all cases of infectious diarrhea are acquired from the ingestion of contaminated foods or beverages. respiratory droplet (sneezing, coughing) and penetrating injury-common routes for other infectionsare not modes of the spread of gastrointestinal pathogens. infection caused by person-to-person contact does occur and, similarly, inanimate objects may also play a role in the spread of disease. in each of these scenarios, the contact facilitates fecal-oral spread. also, when dealing with patients for whom c dijkile is the cause, alteration of the bacterial flora of the gut with antibiotics or other medications appears to be critical. meticulous attention to the food and beverage one consumes can decrease the risk of infectious diarrhea, but only somewhat. contaminated food often smells and tastes normal. practical steps one can take include drinking only chemically treated or filtered water and avoiding milk products that are not pasteurized. when consuming food that is served warm, eating it at piping hot (steaming) temperatures is an added precaution. certain foods and beverages have been particularly associated with specific organisms. and norwalk virus. in the united states, giurdiu is the pathogen most commonly associated with waterborne outbreaks." the surface water of lakes and streams frequently becomes contaminated with giurdiu cysts from either human or animal sources. these cysts survive well at cold temperatures. outbreaks, particularly in the rocky mountain areas, have occurred because of inadequate treatment of this surface water before it is consumed. chlorination alone is adequate to eradicate giardia cysts. however, flocculation, sedimentation, and filtration of public water supplies are also recommended for added safety. appropriate precautions for wilderness campers and travelers to areas without adequate treatment facilities include boiling water for at least minutes (longer at higher altitudes), chemical treatment (chlorine or iodine), or filtration with pore sizes of pm or less. campers should be reminded that careful treatment of drinking water is not enough. the water used to wash fruits and vegetables and that used for tooth brushing should be similarly treated to avoid infection. ice made of contaminated water remains a risk. ice has been a documented source of infection with escherichia coli, norwalk virus, and vibrio cholera.' t travelers frequently make the mistake of drinking bottled water with ice that is locally available and made from inadequately treated water. even when water meets all current treatment requirements, it may still contain pathogens. to test the hypothesis that further treatment would decrease the incidence of diarrhea, payment et all added water filters to households and compared the incidence of diarrhea to households drinking regular tap water. people from the households with the added filter had less diarrhea (p < .ol). it was estimated that, even in this setting, % of all diarrhea was water-related. poultry products are also associated with a high rate of contamination with organisms that cause infectious diarrhea. in particular, chicken has frequently been identified as the vehicle for infection with salmonella and campylobacter. evans et all recently reported an outbreak that illustrated several points. the authors found that in cardiff, wales, cumpylobacter was isolated from people who were among customers that visited a restaurant with a hawaiian theme. twelve of these patrons became ill with gastroenteritis. food-specific attack rates implicated chicken as the vehicle (relative risk . , % confidence interval), and all campylobacter isolates were of the same serotype (hs phage type ). as is the case with most food-borne outbreaks, all individuals who ate the contaminated food did not become ill. sometimes this is because the contaminated food was eaten at different times, and those that ate the food later ingested a larger dose of organisms because of the organisms' continued growth on the food. alternatively, differences among individuals make some more prone to infection than others (see pathophysiology below). the authors postulated that the food implicated in this outbreak might have been inadequately cooked because large pieces of chicken were being stir-fried. also reported in that study is that there were additional campylobacter isolates of the same serotype identified in cardiff during the months immediately preceding the outbreak, suggesting that this occurrence may have not been an isolated event. serotyping of outbreak isolates can be a valuable tool that may help explain the occurrence of disease beyond the outbreak investigation. because poultry is so frequently a vehicle for cumpyzobacter, the method and timing of the contamination of poultry flocks with cumpylobacter is important because it may lead to improved prevention strategies. wallace et all have shown that turkey chicks are born without the organism but that colonization begins by day and is % by day . campylobacter was found throughout the length of the bird's gastrointestinal tract, with the highest concentration found furthest from the beak. flocks of laying hens and uncooked chickens from grocery stores are also frequently colonized with salmonella. this has led to several strategies for preventing the spread of the organism, ranging from the use of antibiotics in the animals to the irradiation of the food products that come from them. thorough cooking of poultry is a more effective and cost-efficient approach. however, it should be noted that even with thorough cooking, any surface (such as a cutting board) where the raw birds are prepared might be a source for the cross-contamination of other food. given the high rate of the contamination of flocks of laying hens with salmonella and campylobacter, it should not be surprising that eggs are frequently contaminated with these organisms. in , the new england area experienced an increase in cases of salmonella enteritides. however, it wasn't until an outbreak in that involved people across states that salmonella in flocks of laying hens was clearly linked to subsequent sporadic and outbreak cases. y by the number of s enteritidis cases was markedly increased in the entire mid-atlantic area and, by , this increased incidence had spread along the length of the country to the pacific coast. o infected eggs will not necessarily have visible cracks or be of inferior quality in any measurable way. an outbreak in tennessee demonstrated that chickens that are colonized with the bacteria can transmit infection to humans even when their eggs are inspected as grade a and are completely intact. today, s enteritidis accounts for approximately % of all sazmonezza infections. the consumption of raw eggs in cake batter, caesar salad dressing, mousse, and sunny-side up or soft-boiled eggs is clearly a risk. the use of pasteurized egg products is recommended for institutions as a means of decreasing this risk. milk was the vehicle of the largest outbreak of sazmonezza in the united states. in in chicago, approximately , cases of salmonella typhimurium were traced to contaminated m&. although the milk had been pasteurized, it was postulated that the pasteurized milk became contaminated with unpasteurized milk later in the process. unpasteurized milk has also been the source of infections with campylobacter, other salmonella species, and yersinia. another dairy product, cheese, has been linked to infection with listeria monocytogenes. fish has been associated with a wide variety of infections. the consumption of shellfish includes the risk of the acquisition of vibrio species, neurotoxic shellfish poisoning, paralytic shellfish poisoning, and norwalk virus, and thorough cooking of the shellfish may not significantly reduce the risk. during an outbreak of oyster-associated gastroenteritis in florida in , mcdonnell et a interviewed oyster eaters. those who said that they ate only thoroughly cooked oysters (grilled, stewed, or fried) were as likely to have developed diarrhea as those who ate raw oysters (relative risk . , % confidence interval). the oysters had presumably become contaminated as a result of the users of small boats, including fishing boats, dumping human waste in the water over the oyster beds. in a recent review of food-borne diseases,*o recent key changes in the types of food-borne outbreaks now seen in the united states were described. for example, an increasing number of outbreaks have involved fresh fruits and vegetables as the vehicle of transmission. because of large distribution areas, outbreaks may begin as a multistate or even a nationwide problem. at times an outbreak may only be detected above background baseline levels of infection because of the predominance of an unusual serotype or susceptibility pattern. new pathogens are being identified as important causes of human diseases. an optimal response to these pathogens requires a coordinated approach that involves both local and national public health officials and industry. although final inspection of products and goods was the main quality strategy of the past, hazard analysis and the determination of critical control points is now preferred. this approach attempts to identify and correct potential contamination points throughout the journey of food from farm to table. future strategies will include reductions in the contamination of food and water given to animals and the soil and water used to grow and transport produce. once a diarrhea-causing organism is ingested, it must successfully avoid a number of host defenses to reach the site of action in the small bowel or colon. the main host defenses against the acquisition of enteric disease are ( ) gastric acidity; ( ) small bowel motility; ( ) local antibody formation; and ( ) the colonic microflora. the normal fasting gastric ph of less than is a very effective barrier to infection with ingested organisms. at this ph level there is a greater than % eradication of most diarrhea-causing bacteria within minutes. many viruses and parasites are similarly affected. neutralization of this ph barrier with antacids or gastric resection or neutralization that is caused by achlorhydria greatly decreases the number of organisms necessary to cause disease. this also explains why many people may eat the same contaminated meal and only some become ill. even if all individuals ate the specific item that was contaminated, they may have significant differences in their gastric ph at the time of ingestion. for example, if gravy on meat was contaminated and this was eaten first, that individual would have maximum stomach acidity to combat this infection. however, if several rolls were eaten before the contaminated gravy, stomach acidity would be buffered, which would allow for a greater susceptibility to infection by a smaller number of organisms. the small bowel is in constant motion. this motion makes it difficult for organisms that act by attachment and invasion to attach themselves. patients with decreased peristalsis caused by diabetes or antimotility medications have a resultant increase in the contact time of the organism and the mucosa in the small bowel. this facilitates attachment and increases the chance that diarrhea symptoms will develop. in a study of patients with shigezza infections, therapy with the antimotility drug diphenoxylate hydrochloride with atropine (lomotil; g. d. searle & co, chicago, ill) was associated with a more prolonged period of fever and positive cultures. impaired motility also increases the concentration of anaerobic bacteria in the proximal gastrointestinal tract, which can cause malabsorption. local antibodies appear to provide some protection against the acquisition of diarrhea pathogens, although their role is relatively minor. the main secretory antibody class is immunoglobulin a. patients with immunoglobulin a deficiency may have an increased incidence of giardiasis, and patients with hypogammaglobulinemia may also have an increased risk of malabsorptive diarrhea. the normal microflora of the colon is a significant host defense. of the approximately " organisms per gram of feces, over % are anaerobes. these organisms protect the host by competing with invading pathogens for nutrients and attachment sites. they also produce chemicals, such as short chain fatty acids, that may be toxic for some organisms. gastrointestinal pathogens cause disease by means of a number of different mechanisms. the most common virulence factor is the production of a toxin by the organism. diarrhea pathogens produce several types of toxins. enterotoxins may be produced on the food before it is ingested and act at the level of the small bowel. there the enterotoxin increases local cyclic adenosine monophosphate and, through a series of chemical reactions, leads to changes in sodium and potassium absorption and a net movement of fluid into the gut lumen. this secretory diarrhea can produce voluminous fluid loss, many liters per day. enterotoxin production is the main mechanism of diarrhea produced by cholera, enterotoxigenic e coli, clostridium perji-ingens, and bacillus cereus. neurotoxins contribute to the symptoms of gastroenteritis with the use of a different mechanism. they act on the autonomic nervous system and cause hyperperistalsis, and they may also act centrally as a stimulant to emesis. staphylococcus food-poisoning toxin and one of the toxins associated with b cereus act in this manner. these toxins also are frequently formed on the contaminated food before it is ingested. cytotoxins represent a third type of toxin that is associated with gastrointestinal pathogens. unlike enterotoxins and neurotoxins, cytotoxins cause direct mucosal damage. these toxins are usually formed inside the body by the ingested organism and act at the level of the colon. toxins within these classes have more similarities than just mechanism of action. for example, the heat-labile toxin of enterotoxigenic e cozi has great antigenic and molecular similarity to the enterotoxin of v cholera. other heat-labile toxins found in some klebsiella, salmonella, and citrobacter organisms also have similar antigenic structures. another example is the similarity seen between the cytotoxin of enterohemorrhagic e coli and shiga's toxin, a cytotoxin produced by shigella. here the likeness is so close that the toxin found in e colt is considered to be a "shiga-like toxin." many of these toxins are found on plasmids, which are bits of extrachromosomal dna. these plasmids, with the genetic codes for toxin production, may be transferred among organisms. other microbial virulence factors include their motility, chemotaxis, invasiveness, and their ability to attach and adhere to mucosa. these organisms have multiple properties and, sometimes, more than type of toxin. this explains why infection with a single pathogen may begin as a watery diarrhea and progress to fever and to an invasive syndrome. because some toxins are preformed and act at the level of the small bowel and others are formed in the body after ingestion and act at the level of the colon, the timing of the effects of the various toxins on the host is staggered. table summarizes the various host and organism factors. the evaluation of a patient with an acute diarrhea illness should focus on the aspects of that patient's history, physical examination, and laboratory findings that are most likely to lead to a diagnosis. important questions in the history include the duration of the illness, previous occurrence of similar symptoms, the presence or absence of fever or sweats, whether blood or pus has been visible in the stool, and whether the patient has any symptoms that suggest of dehydration. symptoms consistent with dehydration include dizziness when standing, rapid heart rate, and feelings of weakness. the incubation period is an important clue to the organism causing the symptoms, but it is often very difficult to ascertain this information from most patients because the incriminating meal has not been identified. patients will often link the illness to a food that "tasted funny" or to the only meal that they ate away from their family because no other family members are ill. however, it is important to remember that contaminated food often smells and tastes normal and that not all people who eat con- taminated food will become ill. these conjectures by the patient typically do not help determine the incubation period or the responsible food vehicle. the one instance in which the history alone can fix the incubation period is when multiple persons become ill after eating a common meal. if they have had no other meals together, this strongly implicates the meal they had in common and identifies the incubation period as the time from the meal to the onset of the symptoms. the physical examination should include focused attention to the findings that might narrow the differential diagnosis or dictate immediate therapy needs. careful evaluation of the patient's fluid status is paramount because dehydration is the major cause of morbidity and mortality. orthostatic blood pressure and pulse should be measured. skin tenting and the observed finding of "sunken eyeballs" are less accurate findings. the presence of fever suggests an invasive pathogen. fever is not usually associated with organisms that act solely by means of enterotoxin production, so this finding is helpful for narrowing down the number of organisms under consideration. hypoactive bowel sounds and severe abdominal pain are ominous findings and may precede the more classic findings of a surgical abdomen. when dealing with a case of diarrhea, a patient's progression to hypoactive bowel sounds and distension should raise the consideration of toxic megacolon. an x-ray of the abdomen is helpful in the diagnosis of this condition, and it usually shows dilation of the transverse colon that is cm or more. toxic megacolon may be seen as a complication of any of the invasive pathogens. noninfectious causes include inflammatory bowel disease, volvulus, and ischemic colitis. about a third of the cases of toxic megacolon that complicate ulcerative colitis occur during the patient's first episode. jaundice is not usually associated with gastrointestinal pathogens and should suggest the possibility of a different primary process. when jaundice is seen in a traveler, malaria should be considered, because a significant percentage of patients with malaria present with diarrhea and other abdominal symptoms in addition to the jaundice more commonly associated with that illness. the presence of a rash is also not typical of most primary gastrointestinal infections and should suggest a primary process outside the gut lumen. some types of viral gastroenteritis may be associated with a nonspecific erythematous rash, and about a third of suzmonelzu typhi infections are associated with a pink maculopapular rash (rose spots) on the trunk. hemorrhagic bullae are associated with infection with vibrio vulnljkus. although most patients have diarrhea as part of this syndrome, it is usually an illness characterized by bacteremia and septic shock. most patients have a preexisting liver disease, such as cirrhosis. despite these examples, the presence of a rash should direct the clinician to other considerations such as toxic shock syndrome, meningococcal disease, rocky mountain spotted fever, viral exanthem, or a drug reaction. each of these processes can have diarrhea as part of the constellation of presenting symptoms and findings. this underscores the need to broadly evaluate the patient before focusing on the gastrointestinal tract as the main site of infection. of the laboratory tests currently available, the microscopic examination of the stool for cells is the most useful. the appearance of white and red blood cells suggests the presence of an invasive pathogen such as salmonella, shigellu, cumpylobucter, yersiniu, c dificile, or entumoebu histolyticu. on the basis of the above information, one can categorize organisms that cause acute diarrhea as having main types of presentations. type i is a watery diarrhea without fever. examination of the stool of these patients reveals no white or red blood cells, and the patients have a low risk of bacteremia. the organisms that cause this syndrome usually act by amplifying an enterotoxin or neurotoxin. because the toxin is often already formed on the food and the site of action is the small bowel, the incubation period is short, usually to hours. because the organism may not even be present in large numbers at the time of toxin ingestion and because the organism does not have invasive properties, there is rarely a local inflammatory reaction (white blood cells in the stool) or a systemic inflammatory reaction (fever). for these same reasons, bacteremia is rare. type i organisms include staphylococcus uureus, cperfringens, enterotoxigenic e coli, enteroaggregative e coli, diffusely adherent e coli, cryptosporidium, and giurdiu lumbliu. type ii is a diarrhea characterized by fever and by the finding of cells when the stool is microscopically examined. the organisms that cause this type of diarrhea act at the level of the colon and, once there, attach to and invade tissue. this explains their longer incubation of to days. type ii organisms frequently augment a cytotoxin or have other invasive properties that lead to a local and inflammatory host reaction (eg, blood cells in the stool, fever). organisms in this group include shigezzu, salmonella, campylobacter, yersinia, enteroinvasive e coli, and e histolytica. the differences between type i and type ii diarrhea syndromes are summarized in table . it should be noted that, for the parasitic organisms in each group, the incubation period is longer than for the other group members. it is important to realize that many diarrhea illnesses progress from one type of presentation to the other. for example, some salmonella and shigella strains may also contain an enterotoxin. they may begin with an afebrile watery diarrhea syndrome and then progress to fever and bacteremia. as long as the clinician modifies the differential diagnosis to reflect the evolving clinical picture, appropriate diagnostic and treatment strategies should follow. escherichiu coli. e coli is one of the most commonly identified members of the bowel flora. this facultative bacterium, although frequently living in symbiosis with the human host, is also among the most common causes of infectious diarrhea worldwide. e coli organisms that cause diarrhea are indistinguishable morphologically from nonpathogenic organisms, and this presents a real challenge to the microbiology laboratory. there are main types of e coli organisms that have been associated with diarrhea. these include ( ) enterotoxigenic e coli (etec); ( ) enteropathogenic e coli (epec); ( ) enteroinvasive e cozi; and ( ) enterohemorrhagic e coli (ehec). two additional types of e coli organisms have also been associated with diarrhea. enteroaggregative e coli is named for its tendency to adhere and aggregate to specific cells in culture, and diffusely adherent e coli also adheres to these cells in culture. although these types of e coli have been associated with diarrhea in children in developing countries, the pathogenic potential for these organisms has not been fully established. etec was first recognized as a cause of diarrhea in the s. it has since been identified as the cause of nearly % of travelers' diarrhea, and it has also been found to be a common cause of diarrhea in infants. etec organisms cause diarrhea by the amplification of or more enterotoxins, and these enterotoxins have been characterized as a heatstable toxin and a heat-labile toxin. genes that have been found on transferable plasmids code for these toxins. an e coli organism may have one, both, or neither of these toxins. the heat-labile toxin has antigenic similarity to the cholera enterotoxin. g as with other enterotoxin-mediated infectious diarrhea, the main syndrome that develops is a watery afebrile diarrhea that is usually self-limited and lasts to days. etec is not usually considered to be a cause of diarrhea that is acquired in the united states. because most microbiology laboratories do not routinely screen for this organism, the incidence of this disease is difficult to estimate. a recent report about a food-borne outbreak demonstrated that etec was also a cause of diarrhea in patients who had not been traveling. etec organisms were isolated from people who had attended a labor union banquet in milwaukee with attendees from throughout the united states. an estimated % of the attendees met the case definition of or more loose stools within a -hour period, with the first occurring within days of the event. because attendees had dispersed back to their home states only a small number were available for testing, but the isolation of etec from of the attendees and the fact that no other pathogen was identified confirmed it as the cause. as newer methods of identifying these toxin-producing pathogens are developed, it is likely that part of the relatively large percentage of diarrhea illnesses that are "culture negative" will be diagnosed. epec causes diarrhea by means of a different method. these organisms adhere to the brush border of the small intestine and efface the surface. there is no enterotoxin or cytotoxin production, but a watery diarrhea is produced. a similar pattern of focal adherence can be demonstrated in cell culture. both plasmid-mediated and chromosomal-derived genes code for this pathogenic mechanism. epec causes diarrhea mainly in children in developing countries. although the diarrhea is usually self-limited, a prolonged diarrhea caused by epec has also been described. epec had been associated with outbreaks of diarrhea in nurseries in the past, but with improvements in sanitation, this is rare today. enteroinvasive e coli produces a dysentery syndrome that is indistinguishable from that produced by shigda. these organisms act at the level of the large bowel, where they invade and cause cell death. both the genes that code for this invasive property and the genes that code for invasion in shigda are located on a large plasmid. e coli harboring this plasmid have other similarities to shigezza. they are less motile and do not ferment lactose. the clinical syndrome produced is a febrile diarrhea with severe abdominal cramping. fecal leukocytes and occasional gross blood and pus are seen in the stool. ehec produce an unusual syndrome of gross blood per rectum and only about a third of patients experiencing fever. fecal leukocyte examination is typically negative. inflammatory bowel disease and ischemic colitis are considered as diagnostic possibilities because of the severity of onset. stool examinations of patients with this clinical picture often revealed e coli :h . this serotype accounts for the majority of diagnosed cases of enterohemorrhagic colitis, but serotypes such as :hll and :h can also cause this disease. the cause of this syndrome is a cytotoxin. the organism has been associated with several different cytotoxins, each of which can cause the same syndrome. the toxins are so similar to the shiga-toxin of shigezza dysenteria they are called "shiga-like toxins." a review by the centers for disease control and the washington state department of social and health services demonstrated that this organism was also associated with a nonbloody diarrhea and asymptomatic carriage. ehec organisms are associated with hemolytic uremic syndrome (ibis). this syndrome includes the triad of thrombocytopenia, acute renal failure, and hemolytic anemia. hus is also seen in children with severe shigezza infection and therefore may be related to some effect of the shiga-like toxin. unlike shigezza, hus caused by ehec is not confined to children but may be seen in patients of all ages. thrombotic thrombocytopenic purpura is also associated with preceding ehec infection. about half of the patients diagnosed with hus will require dialysis, and most will need transfusions. there is no evidence that antibiotic treatment during the diarrhea infection will decrease the incidence of subsequent hus or thrombotic thrombocytopenic purpura. in fact, some investigators have suggested that antibiotic therapy could increase the risk of these conditions by altering protective gut flora and increasing toxin production. outbreaks of ehec have been associated with eating undercooked hamburger meat, drinking apple cider, and swimming water contaminated with feces. l recent hamburger ingestion is also a risk factor for sporadic cases. because handling raw beef is a risk, careful handwashing and cleaning of preparation surfaces are important prevention strategies. table summarizes the characteristics of the various e coli diarrhea pathogens. campylobacter jejuni. c jejuni is the most common bacteria isolated from patients with diarrhea. this organism is a curved gram-negative rod that can occasionally be identified during careful microscopic examination of the stool because the normal flora does not contain curved rods. the other curved gram-negative rods that cause diarrhea belong to the kbrio species. however, the epidemiology and clinical picture of wbrio infections are different (see vibrio cholera below). c jejuni grows best at °c in an atmosphere of % to % oxygen. this microaerophilic atmosphere has to be created in the laboratory with the use of special gas tanks, chemical packs, or a candle jar. these special growth requirements explain why campylobacter has only recently been recognized as such a common pathogen. campylobacter is acquired from animals. the organisms are commonly found in the gastrointestinal tracts of cattle, fowl, dogs, cats, sheep, and rodents. undercooked chicken, unpasteurized milk, and domestic pets are common sources of infection. person-to-person spread also occurs. campylobacter is an invasive organism that acts at the level of the colon. the incubation period is usually to days, and the clinical syndrome is one of fever, abdominal pain, and diarrhea. microscopic examination of the stool usually discloses fecal leukocytes and red blood cells. other campylobacter and related organisms associated with diarrhea include campylobacter coli, campylobacter upsaliensis, helicobatter cinaedi, and helicobacter fennelliae. the last organisms have mainly been isolated from homosexual men with diarrhea. shigella. shigella species are divided into main groups: shigella dysenteriae, shigella sonnei, shigella flexneri, and shigella boydii. the shigezza organism is a small gram-negative rod that has been a known cause of diarrhea for approximately the last century. shigella infections have played a major part in times of war, with a greater number of casualties attributed to this infection than to bullets and explosives. shigezza causes an invasive syndrome in the colon, and it includes fever. in a study of experimental infection with shigella sonnei, the height of the fever correlated with the severity of the illness. o shigezza bacteremia is relatively rare but does occur. risk factors are an age of less than year and protein malnutrition. shigezza may also cause chronic vulvovaginitis in children. the recognition of this diagnosis is important because it may otherwise be wrongly diagnosed as a sexually transmitted disease. finally, as noted previously, shigezza has been associated with the subsequent development of hus in children. yersiniu enterocolitim. in many parts of the world, y enterucolitica rivals salmonella in the frequency of the number of times it is isolated from the stool of patients with diarrhea. the scandinavian countries, belgium, canada, and japan have the highest rates of isolation of this organism. in these countries, serotype : and : are the most common isolates. in the united states, serotype : predominates. yersinia grows at room temperature, body temperature, and °c (refrigeration temperature). this ability to grow at cold temperatures has proved useful in the microbiology laboratory for the selective growth of yersinia from a specimen; it also may be a factor in the food-borne outbreaks where small amounts of contamination may become more significant even when the food has been adequately refrigerated. yersinia has been isolated from animals, lake and stream water, and a variety of foods, and person-toperson spread does occur. pigs are a particularly important reservoir. yersinia has been isolated from pig tonsils and intestines, and an outbreak in atlanta in was traced to the household preparation of chitterlings (pig intestines). transfusion-associated yersinia has also been reported. in , the centers for disease control reported that cases of transfusion-associated y enterocolitica occurred between and . these cases were reported from different states, and of these patients died from the infection. the transfusions they had received were packed red blood cells that had been stored at °c for a mean of days. patients developed fever and hypotension within minutes of transfusion. half of the donors reported a diarrheal illness that had occurred within the days before they had donated blood. the clinical presentation of y enterocolitica diarrhea is similar to shigezza or enteroinvasive e cd. an associated pharyngitis may be present. the incubation period is about to days, and ulceration of the mucosa at the level of the terminal ileum may be seen. this syndrome may mimic regional enteritis (crohn's disease) or appendicitis. yersinia infections have also been associated with the subsequent development of a reactive polyarthritis in human leukocyte antigen-b positive patients. this has also been reported in patients after they have been infected with salmonella or campylobacter. yersinia pseudotuberculosis can also cause diarrhea, particularly in children. it is a rare isolate and, like y enterocolitica, it is acquired from animals. salmonella salmonella are gram-negative motile rods that do not form spores. as is the case with many other enteric pathogens, animals are important sources of infection. poultry, beef, milk, and eggs have all been documented vehicles in outbreaks and in cases of person-to-person spread. there are over serotypes of salmonella, many of which are named for the animal from which the organism was first isolated or for the city in which it was first identified. not all of these serotypes are pathogenic for humans. s typhimutium, s enteritidis, and salmonella heidelberg are common isolates in the united states. enterotoxins and cytotoxins have been isolated from salmonella species, but the main mechanism of diarrhea appears to be a combination of the penetration of the mucosa and of an inflammatory/immune response. salmonella can survive inside phagocytes, which provide a protected intracellular site for survival and for the avoidance of other host defense measures. bacteremia is a more common complication of salmonella infection than other enteric infections, and patients with defects in cell-mediated immunity (eg, aids, high-dose steroid therapy, lymphoma) and those with hemolytic illnesses (eg, sickle cell disease) are at increased risk. persistent bacteremia, often with few gastrointestinal symptoms, has also been reported, and this syndrome is often caused by salmonella choleraesuis. there is a marked increased risk of infection of endovascular surfaces for patients infected with these organisms, particularly for elderly patients with atherosclerotic disease or vascular g~&s.~* infection of an aortic aneurysm, occasionally with fistula formation to the duodenum, is a well-reported complication. typhoid fever is caused by s typhi, an organism that is only found in humans. abdominal pain, fever, and bacteremia characterize this infection. approximately % of patients are bacteremic during the first week of illness, and bone marrow cultures can be positive in up to % of cases. the bacteria's ability to penetrate the mucosa and survive in peyer's patches in the ileum is associated with a % to % risk of intestinal perforation. this complication usually occurs during the second or third week of illness and carries a % mortality rate. the enteric fever syndrome (typhoidal syndrome) can also be seen with infection caused by salmonella paratyphi. patients who have excreted the organism in the stool or urine for year or more are identified as chronic carriers. most chronic carriers are asymptomatic, but they may dm, july need treatment if they have an occupation, such as a job in food preparation, that poses a risk for transmission to others. vibrio cholera. vibrio organisms are curved gram-negative rods that are morphologically similar to cumpylobacter. vibrio organisms are commonly found in surface water, and inadequate sanitation and water purification methods are the main contributors to proliferation of the bacteria. v cholera is the classic enterotoxin-mediated watery diarrhea pathogen. the volume of fluid loss is so significant that a previously healthy person may die within hours of the onset of this type of diarrhea unless appropriate fluid replacement therapy is provided. the world health organization's oral rehydration fluid therapy, which contains sodium chloride, sodium bicarbonate, potassium chloride, and glucose, can be life-saving even for severely ill patients. infection with vibrio species usually follows exposure to salt water or shellfish. raw or undercooked clams and oysters in particular are associated with the acquisition of vibrio species. several vibrio organisms cause disease. vibrio paruhaemolyticus is a major cause of diarrhea in japan. this organism produces an enterotoxin, and it also causes an inflammatory reaction in the bowel, so both syndromes may be seen. vibrio mimicus is a less-commonly isolated diarrhea pathogen. vibrio alginolyticus is a cause of wound infections after exposure to salt water, and v vulnificus is a cause of bacteremia and sepsis. for v vulnificus, risk factors for acquisition of infection include preexisting liver disease and the ingestion of raw oysters or clams. clos*m d@ide. c diflcile is the most common cause of nosocomial infectious diarrhea. up to % of diarrhea acquired in the hospital is caused by this pathogen. ~ the most important risk factor for the development of this infection is treatment with antibiotics. the organism is a spore-forming gram-positive anaerobic rod. it is found in the stool of about % of healthy persons and in a much higher percentage of newborns. c dificile produces an enterotoxin (toxin a) and a cytotoxin (toxin b). although the organism itself does not invade the mucosa and bacteremia is rare, mucosal ulceration secondary to cytotoxin activity is commonly seen. in severe disease, pseudomembranes can form (pseudomembranous colitis). the incidence of this disease is highest among the elderly. recently, tube feedings, especially postpyloric feedings, were found to be an additional risk. numerous strategies to decrease the incidence of this disease have been tried and have including barrier precautions, promotion of handwashing, and training about the use of antibiotics. nearly every antimicrobial agent has been associated with the subsequent development of this infection, although clindamycin (cleocin; upjohn co, kalamazoo, mich) has been linked most closely. a recent study from the veteran's administration hospital at the medical college of virginia and virginia commonwealth university demonstrated that the formulary restriction of clindamycin is an effective way of reducing cases in a setting where clindamycin use is identified as risk before intervention. listeriu monocytogenes. l monocytogenes has, until recently, been thought of primarily as a cause of bacteremia and meningitis in immunocompromised patients. however, several recent studies have demonstrated that in many cases the organism can be acquired through the consumption of contaminated food. soft cheeses and foods such as cold cuts from a deli counter have been shown to be the most common vehicles. inadequately pasteurized milk has also been associated with foodborne outbreaks. diarrhea from these sources may affect all hosts, but invasive disease with bacteremia is much more common in the immunocompromised host. risk factors include pregnancy, extremes of age, and defects in cell-mediated immunity. it is estimated that viral pathogens account for % to % of diarrhea disease in the united states. the main viruses that cause diarrhea in the immunocompetent patient are rotavirus, norwalk virus (and other calciviruses), enteric adenovirus, astrovirus, and enteric coronavirus. clinical viral gastroenteritis is similar to an enterotoxin-mediated diarrhea with the sudden onset of watery diarrhea that does not include fecal cells. however, unlike bacterial enterotoxin illnesses, viral gastroenteritis is more commonly associated with fever. rotavirus is usually a wintertime illness that is worse in young children; it accounts for about half of hospital admissions for diarrhea in children. the incubation period is to days, and the illness may last a week or more. norwalk virus has a shorter incubation period (< hours) and involves all age groups, and community outbreaks account for a significant percentage of the cases of the illness. commercially available enzyme-linked immunosorbent assays have now made the diagnosis of viral gastroenteritis possible in hospital laboratories. caused by parasites a number of protozoal parasites are important infectious causes of diarrhea. these organisms are larger than viruses or bacteria and, therefore, are usually diagnosed by staining a stool specimen and observing it under a microscope. in the united states, the most commonly isolated of the parasites is g zumbliu. the exact mechanism of diarrhea in giardiasis is not known. giardia does not produce an enterotoxin or cytotoxin, and it is not invasive. deconjugation of bile salts by an associated bacterial overgrowth may play a role. the syndrome is a noninflammatory malabsorptive diarrhea. after an incubation period of to weeks, patients develop bloating, steatorrhea, and nausea. patients are afebrile, and examination of the stool for blood cells is negative. if left untreated, symptoms may wax and wane, but they often persist for weeks or months. the cyst is the infectious form of the organism, and the ingestion of only a small number of cysts can cause disease. e histolyticu is the causative agent of amebiasis. unlike giardiasis, amebiasis is an invasive illness, and it affects the large bowel. patients experience a gradual onset of illness, but once it has fully developed, the clinical picture is similar to that of s dysenteriae or enteroinvasive e coli. fever and gross blood and pus in the stool are common. extraintestinal disease may complicate amebic colitis. the most common sites of infection include the liver (liver abscess), the peritoneal cavity, the brain, and the pericardial sac. cryptosporidium purvum, a cause of persistent diarrhea in patients with aids, can also cause of self-limited diarrhea in immunocompetent patients. , watery diarrhea associated with nausea and low-grade fever are included in the most typical presentation. a recent -year longitudinal study in peru showed that infection early in life (first months) led to a decreased rate of growth and that children who had been infected did not catch up with their peers. outbreaks have been associated with contaminated drinking water and swimming in a contaminated pool. cyclosporu cuyetunensis is a protozoan that has been recently recognized as a cause of diarrhea. this organism, like cryptosporidium, can be detected by an acid-fast stain of the stool. cyczosporu causes a watery and malabsorptive diarrhea that may last to weeks. in a study of cases that occurred in , food histories strongly suggested raspberries as the vehicle for the majority of these illnesses. cyclosporu can be treated with trimethoprim-sulfamethoxazole. unfortunately, the clinical presentation of a person with diarrhea usually does not suggest a specific causal agent. there is significant overlap, and one organism can cause several different syndromes. o the laboratory work-up of a patient with diarrhea may therefore be necessary. in general, a complete blood count and a metabolic profile may be required if the patient appears to be septic or dehydrated. in addition, if the patient appears septic, blood cultures drawn at different sites may be useful. the question of whether to obtain stool cultures for a patient with diarrhea is not always a simple one. in general most people with diarrhea do not have a bacterial pathogen, and even when they do, stool cultures are often negative. nevertheless it may be important from a public health standpoint, as well as for the treatment of the individual patient, to determine if that patient has a bacterial pathogen. an approach used to distinguish those patients who are more likely to have a pathogen from those not likely to have a pathogen has been to look for white blood cells in the stool. microscopic examination of stool samples that have demonstrated the presence of fecal leukocytes suggests that the diarrhea has an inflammatory cause and that it is caused specifically by organisms such as shigella, salmonella, campylobacter, or c dificile. ~ however, the use of fecal leukocyte detection has several limitations. - first of all, the smear must be performed on a fresh specimen; a delay in processing the sample results in lysis of the fecal leukocytes. even if fresh specimens are examined, accurate microscopy is very dependent on the skill and expertise of the microscopist. some have questioned whether the presence of white blood cells in the stool has proved to be of any clinical use."- choi et al@' have developed a fecal lactoferrin latex agglutination assay to help determine if fecal leukocytes are indeed present in the stool. this, in general, appears to be much more sensitive than fecal leukocyte microscopy, and it may help to determine which people should have fecal cultures obtained. although stool cultures are considered to be the gold standard for the diagnosis of bacterial causes of gastroenteritis, their clinical use is limited to organisms that are routinely cultured. most laboratories only attempt to culture for salmonella, shigella, and campylobacter. common organisms that can cause diarrhea, such as enteroinvasive e coli and enterotoxigenic e coli, are not routinely looked for. unusual organisms such as yersinia species and vibrio species, which may be important in certain locations, are not routinely tested for. therefore it is important to obtain information from the patient about recent travel and to know the local epidemiology of diarrhea-producing pathogens. for example, if a person has recently traveled to the states along the gulf of mexico and eaten oysters, examining the stool for vibrio may be important. if a person presents with gross blood in the stool, then enterohemorrhagic e coli may be a possible cause. the laboratory must be informed of these concerns so that appropriate testing can be performed. routine culture for these organisms is otherwise not indicated. stool examination for ova and parasites should be performed if a patient has recently traveled outside of the united states and also if a patient is potentially immunosuppressed; these tests should also be performed for male homosexuals with acute diarrhea. otherwise stool examination for ova and parasites should not be routinely obtained unless the diarrhea persists despite negative bacterial cultures. stool examination for c d@cize should only be performed in hospitalized patients and only for patients who have been on antibiotics during the preceding day@; it is not cost-effective to check stool for c dijficile in any other patient population. as a corollary, it is not cost-effective to routinely test for stool pathogens or for ova and parasites in a patient in the hospital or in a patient who has been on antibiotics during the preceding days. y diarrhea in these situations is almost always related to c dificile. stool examination for ova and parasites and for enteric pathogens should be limited to patients who are otherwise immunosuppressed, to those who have a negative result despite continued symptoms, and to times of a known outbreak of a bacterial pathogen in the hospital or the community. unfortunately, a study that proves the optimal method for diagnosing diarrhea caused by c dificile has not yet been performed. the use of fecal leukocytes or stool lactoferrin in the screening for c difficile diarrhea has not been great enough for these studies to serve as good screening tools ; neither a positive nor a negative result of a fecal leukocyte test will replace specific testing for c dificile or c difjicize toxin. currently the cell cytotoxin assay is the most specific test, and the stool culture is the most sensitive test. however, neither one of these studies has a rapid turnaround, and both are associated with excessive cost and time commitments. more rapid assays such as the enzyme immunoassay for detecting toxin a and b are specific, but they are much less sensitive than the cell cytotoxin assay. a latex agglutination assay does not distinguish toxigenic from nontoxigenic c dificile; it is neither sensitive nor specific, and it should not be routinely used. testing the stool of asymptomatic patients for c di&ize to test a cure is not recommended except for epidemiologic or research purposes. effective treatment of bacterial gastroenteritis is important on an individual basis, and it also has potential public health implications. because most of these organisms are spread by person-to-person contact, it is important to eliminate reservoirs of these bacteria whenever possible. unfortunately there are few data that support the routine use of antiinfective antibiotics for most patients with bacterial gastroenteritis. more than half of the patients who develop bacterial gastroenteritis improve within days even without specific therapy. it has also been shown that antibiotics do not reduce the duration of diarrhea or fever in patients with salmonella gastroenteritis, and they may increase the risk for bacterial relapse. the typical goal of the treatment of gastroenteritis is supportive therapy with hydration; this usually involves oral rehydration methods, although intravenous rehydration may be necessary in certain situations. nonspecific treatment to decrease bowel motility and improve symptoms is another option. in the past, drugs that decrease bowel motility have been discouraged because of the possibility that they might worsen symptoms or decrease the clearance of the bacteria. the use of loperamide in the setting of travelers' diarrhea that is primarily caused by enterotoxigenic e coli has shown that use of loperamide with ciprofloxacin was the most effective treatment. however, similar studies are not available for infections caused by an invasive organism such as salmonella, shigella, or campylobacter or for c d@cileassociated diarrhea. until more data are available, the routine use of loperamide should be avoided for patients who potentially have invasive pathogens causing their diarrhea. as noted above, most patients with diarrhea do not require antimicrobial therapy. however, antimicrobial therapy may be beneficial independent of culture or fecal leukocyte test results. goodman et ala compared the use of ciprofloxacin with the use of trimethoprimsulfamethoxazole and placebo in a randomized, double-blind study. a causal organism was isolated in only % of patients, and only % of patients with a positive culture had a positive fecal leukocyte smear. the smear was positive in % of patients with negative cultures. these data suggest that neither culture nor fecal leukocyte testing may be very useful for most patients with community-acquired diarrhea. however, antibiotic treatment-especially with ciprofloxacin, as compared with placebo-resulted in a reduction in the duration of symptoms of approximately day. another study by dryden et a about the empiric treatment of severe community-acquired gastroenteritis with ciprofloxacin had similar conclusions. nonetheless, routine antibiotic therapy for all patients with diarrhea may be a problem in the future. a major potential problem is the increasing incidence of antimicrobial resistance in organisms such as salmonella, shigella, and campylobacter. ~ campylobacter are routinely resistant to most antibiotics, with the exceptions of macrolides and quinolones, and an increasing incidence of quinolone resistance has been noted in several countries, which has been attributed to the use of dm, july quinolones in animal feed. [ ] [ ] [ ] in addition, salmonella that produce extended-spectrum beta-lactamases have been reported. these organisms are also often quinolone-resistant, and quinolone-resistant shigella have recently been described. many of these organisms were also resistant to unrelated classes of antibiotics such as tetracychnes, cephalosporins, chloramphenicol, and trimethoprim-sulfamethoxazole. because of all of this information, the routine empiric use of antibiotics-including quinolones-for the treatment of bacterial gastroenteritis needs to be reevaluated. unlike those with community-acquired gastroenteritis, most patients with c difjicize-associated diarrhea will require specific therapy. metronidazole and vancomycin are effective agents that are currently available in the united states. metronidazole is currently considered the drug of choice because its clinical efficacy is comparable with that of vancomycin ; it is also much less expensive than oral vancomycin, and there is some concern about the development of glycopeptide resistance in enterococci with the use and overuse of oral vancomycin. metronidazole in doses of mg times day or in doses of mg times a day can be useful. an alternative choice is a mg dose of vancomycin times a day. there is no need to obtain a stool sample from patients with c dilgicile-associated diarrhea at the end of treatment unless symptoms recur. approximately % to % of patients will develop recurrent symptoms, regardless of initial therapy. these patients usually respond to the same drug that was used to treat them initially. a very small percentage of patients will have multiple relapses of c d@cizeassociated diarrhea. the optimal management of such patients is not known at this time. some physicians recommend the combination of vancomycin and rifampin for days, but there are no comparative data currently available. making a diagnosis of cause in cases of bacterial gastroenteritis remains a difficult prospect. the treatment of most cases of bacterial enteritis is usually supportive, but the use and overuse of antibiotics may result in an increased incidence of resistance, which could continue to be problematic in the future. closing the gap. health policy task force on infectious diseases who reports decry neglect of world health problems diarrheal deaths in the united states, through . a special problem for the elderly epidemiology of travelers' diarrhea: current perspectives epidemiologic studies of travelers' diarrhea, severe gastrointestinal infections, and cholera nosocomial infection with c. di#icize diarrhea: a neglected nosocomial hazard? gastrointestinal infections in aids evaluation of diarrhea in hiv-infected patients craun ge waterborne giardiasis in the united states cholera in africa: lessons on transmission and control for latin america a multistate outbreak of norwalk virus gastroenteritis associated with consumption of commercial ice a randomized trial to evaluate the risk of gastrointestinal disease due to consumption of drinking water meeting current microbiological standards a campylobucter outbreak associated with stir-fried food the colonization of turkeys by thermophilic campylobacters a restaurant associated cumpylobacter outbreak the emergence of grade a eggs as a major source of salmonella enteritidis infections. new implications for the control of sahnonellosis outbreaks of salmonella serotype enteritidis infection associated with consumption of raw shell eggs-united states, - emerging foodbome diseases: an evolving public health challenge salmonella enteritidis gastroenteritis transmitted by intact chicken eggs massive outbreak of antimicrobial-resistant salmonellosis traced to pasteurized milk failure of cooking to prevent shellfish-associated viral gastroenteritis adverse effect of lomotil therapy in shigellosis toxic megacolon waterborne typhoid fever in dade county, florida. clinical and therapeutic evaluation of bacteremic patients syndromes of vibrio vulnificus infections. clinical and epidemiologic features in florida cases travellers' diarrhea molecular evolution of pathogenic escherichia coli clinical features of infections due to escherichia coli producing heat-stable toxin during an outbreak in wisconsin: a rarely suspected cause of diarrhea in the united states patterns of adherence of diarrheagenic escherichia coli to hep- cells a clinicopathologic study of enterocyte-adherent escherichia coli: a cause of protracted diarrhea in infants illnesses associated with escherichia coli :h infections. a broad clinical spectrum the increasing incidence of the hemolytic-uremic syndrome in king county, washington: lack of evidence for ascertainment bias escherichia coli :h : clinical, diagnostic, and epidemiological aspects of human infection escherichia coli :h infection in humans an outbreak of diarrhea and hemolytic uremic syndrome from escherichia co i :h in fresh-pressed apple cider risk factors for sporadic infection with escherichia coli :h infections with campylobacter jejuni and campylobacter-like organisms in homosexual men an analysis of the quantitative relationship between oral temperature and severity of illness in experimental shigellosis shigella septicemia: prevalence, presentation, risk factors, and outcome chronic vulvovaginitis in children due to shigella flexneri hemolytic-uremic syndrome after shigellosis. relation to endotoxemia and circulating immune complexes yersiniu enterocolitica infection and pork: the missing link yersinia enterocolitica : infections in infants and children, associated with the household preparation of chitterlings salmonella infections in patients with the acquired immunodeficiency syndrome the risk of endothelial infection in adults with salmonella bacteremia intestinal perforation in typhoid fever: a historical and state-ofthe-art review antibiotic-associated diarrhea risk factors for clostridium dzjicile carriage and c. dz#zcize-associated diarrhea in a cohort of hospitalized patients acquisition of clostridium di$icize and clostridium dificile-associated diarrhea in hospitalized patients receiving tube feedings hospital-wide restriction of clindamycin: effect on the incidence of clostridium dificile-associated diarrhea and cost role of foods in sporadic listeriosis. ii. microbiologic and epidemiologic investigation. the listeria study group combination drug therapy for cryptosporidiosis in aids an outbreak of cryptosporidiosis associated with a swimming pool effects of cryptosporidium parvum infection in peruvian children: growth faltering and subsequent catch-up growth inflammatory enteritides empiric antimicrobial therapy of domestically acquired acute diarrhea in urban adults fecal leukocytes in diarrheal illness role of stool screening tests in diagnosis of inflammatory bacterial enteritis and in selection of specimens likely to yield invasive enteric pathogens application of rejection criteria for stool ovum and parasite examinations application of rejection criteria for stool cultures for bacterial enteric pathogens fecal leukocytes in stool specimens submitted for clostridium dificile toxin assay to culture or not to culture: fecal lactoferrin screening for inflammatory bacterial diarrhea screening for escherichia coli :h in illinois clostridium d@cile-associated diarrhea treatment of travelers' diarrhea: ciprofloxacin plus loperamide compared with ciprofloxacin alone. a placebo-controlled, randomized trial empirical treatment of severe acute communityacquired gastroenteritis with ciprofloxacin trends in antibiotic resistance among diarrheai pathogens isolated in thailand over years high-level quinolone resistance in clinical isolates of campylobacter jejuni emergence of fluoroquinolone resistance in campylobacter jejuni and campylobacter coli in subjects from finland an outbreak of extended-spectrum, beta-lactamase-producing salmonella senfenberg in a bums ward shigella and the fluorinated quinolones key: cord- -m i q ww authors: christian, michael d.; devereaux, asha v.; dichter, jeffrey r.; geiling, james a.; rubinson, lewis title: definitive care for the critically ill during a disaster: current capabilities and limitations from a task force for mass critical care summit meeting, january – , , chicago, il date: - - journal: chest doi: . /chest. - sha: doc_id: cord_uid: m i q ww in the twentieth century, rarely have mass casualty events yielded hundreds or thousands of critically ill patients requiring definitive critical care. however, future catastrophic natural disasters, epidemics or pandemics, nuclear device detonations, or large chemical exposures may change usual disaster epidemiology and require a large critical care response. this article reviews the existing state of emergency preparedness for mass critical illness and presents an analysis of limitations to support the suggestions of the task force on mass casualty critical care, which are presented in subsequent articles. baseline shortages of specialized resources such as critical care staff, medical supplies, and treatment spaces are likely to limit the number of critically ill victims who can receive life-sustaining interventions. the deficiency in critical care surge capacity is exacerbated by lack of a sufficient framework to integrate critical care within the overall institutional response and coordination of critical care across local institutions and broader geographic areas. m ass casualty events occur frequently worldwide ; fortunately, the majority of these do not generate overwhelming numbers of critically ill or injured victims requiring definitive critical care. mass critical care events, though, have garnered increasing attention and stimulated new interest in critical care disaster preparedness. [ ] [ ] [ ] [ ] [ ] [ ] [ ] in , an analysis of us critical care disaster response identified major limitations to respond to serious epidemics. in light of the increasing consternation about a potential influenza pandemic, , an updated review of critical care response capabilities is warranted. authorities continue to call for development of comprehensive guidance for managing mass casualty events. a number of efforts are underway to meet this need, but detailed guidance regarding how to provide critical care for large volumes of patients remains underdeveloped. , to this end, the task force for mass casualty critical care (hereafter called the task force) was convened. the task force steering committee members (listed in the appendix) were fairly certain that current critical care surge capacity for disasters had a number of limitations. however, the specific strengths and weaknesses of critical care response capabilities must be delineated to best inform development of novel strategies to augment critical care. this manuscript summarizes the current us and canadian critical care disaster response capabilities, and provides the rationale and context for the guidance of the task force for critical care surge capacity and allocation of scarce life-sustaining interventions. disaster medical management has focused primarily on the response to trauma victims. , victims who suffer critical injuries frequently die immediately or before rescue, so the vast majority of those who survive to receive hospital-based treatment have non-life-threatening injuries. - disaster plans have assumed that critical care resources will be available when needed, and generally this assumption has been correct. however, with the anticipation of large volumes of critically ill patients in future disasters, some believe that hospital capacity, and in particular critical care capability, will be a major limiting factor for survival. , numerous authorities have forecast scenarios that will result in large numbers of critically ill and injured casualties. table summarizes scenarios developed by the us department of homeland security. eleven of the scenarios predict numbers of critically ill patients ranging from hundreds to tens of thousands in a metropolitan area. if such events occur, the demand on critical care resources will be multiple orders of magnitude greater than previous emergencies experienced in the past half century in north america. the experience with the severe acute respiratory syndrome in toronto, although not a mass casualty event, stands as example where critical care can prevent deaths even for a disease lacking specific treatment. in the absence of critical care, the case fatality rate in toronto would have been more than triple ( %) the observed rate of . %. this lesson may have profound import were a serious influenza pandemic to occur. further, the effectiveness of community mitigation as well as the utility and availability of antivirals to forestall serious illness remain uncertain. , many people, particularly high-risk groups, may have critical illness and without critical care will assuredly die. if critical illness directly or indirectly resulting from influenza is not uniformly fatal with essential critical care services, then availability of life-sustaining interventions may have a profound impact on community survival. the need to augment critical care is not unique to an influenza pandemic. illness developing after exposures to chemicals, infection with serious pathogens, and exposure to radiologic materials are all likely to result in life-threatening clinical conditions, such as severe sepsis or ards. natural catastrophes, such as earthquakes - and tsunamis, can also generate many victims with severe organ dysfunction. in the united states and canada, severe sepsis and acute respiratory failure, including ards, are commonly treated in icus - ; and importantly, at least half of patients survive with aggressive icu care. [ ] [ ] [ ] [ ] [ ] [ ] unlike the duration of surge demands on emergency departments (eds) in mass casualty incidents, which are often measured in units of minutes or hours, the critical care response may need to be sustained for days to weeks. several recent examples highlight this issue. following the rhode island nightclub fire, the emergency department (ed) response lasted only hours, yet critically ill patients admitted to a single hospital resulted in icu patient days with an average icu length of stay of days. similarly, following the london bombings, the major incident lasted in the ed lasted h and min, yet the average length of stay for the critically injured was . days (range, to days). , complications seen in the critically ill or injured, such as ards, prolong recovery times in icu , [ ] [ ] [ ] and should be anticipated in planning for future mass critical care events. within an effective command and control system to coordinate regional response, surge capacity in critical care depends on three crucial elements: ( ) "stuff," medical equipment and supplies; ( ) "staff," appropriately trained health professionals to competently care for critically ill and injured patients; and ( ) "space," the physical location suitable for safe provision of critical care. although a rather simplistic conceptual approach, one can confidently state that a system that fails to meet any one of these requirements will not be able to cope with a large surge. medical response to disasters, including the critical care response, is dependent on a number of nonclinical medical institution services (eg, logistics and procurement, environmental services, food services) and external services (eg, transportation, consistent functional utilities, commerce infrastructure). for expediency, this article will focus on critical carespecific capabilities. mechanical ventilators are unique to the critical care environment, and they are essential equipment for the management of respiratory failure. there are no realistic substitutes for ventilators. proposals to train hundreds of volunteers to provide manual ventilation to patients during a pandemic are naïve and fraught with serious logistical and scientific shortfalls, such as the lack of staff or volunteers during bioevents as well as the risk of secondary transmission to the caregivers who must remain at the bedside and the adverse consequences of prolonged manual ventilation. estimates of the total number of full-feature icu ventilators available in the united states vary widely. one study reported , ventilators ( ventilators per , population); other published studies and unpublished data place the estimate between , and , ( to per , population). these devices are distributed among the , to , non-federal icu beds in the united states. in los angeles found that % of hospitals in the los angeles area had fewer than six ventilators available for immediate use at any time. if several local hospitals require additional ventilators, rental supplies may be insufficient to meet need, as it is common for vendors to contract to provide the same finite pool of ventilators to several institutions. data from the national healthcare safety network show that the majority of icus have, on average, Ͻ % of their occupied beds filled with patients receiving invasive mechanical ventilation. based on these data, at least , full-feature ventilators are likely available across the united states at any time for use during a disaster. this predicted available national mechanical ventilator quantity may at first seem reassuring, but it also has potential to mislead. numerous logistic hurdles will hamper immediate distribution to areas of need during a disaster. thousands of ventilators may be available at hospitals nationwide, yet an affected community requiring just hundreds of additional devices may not be able to get them in a timely manner. also, published and unpublished models of varying sophistication portend there will still be a large gap between the total number of ventilators required during the peak of a serious influenza pandemic and available devices. , - in all models, the predicted need will far exceed even the tens of thousands of available ventilators. hence, strategies for rational augmentation of positive pressure ventilation capacity are necessary. in the united states and canada, stockpiles of ventilators are available from government sources. , currently the strategic national stockpile in the united states has approximately , ventilators, and there is a stated intention to purchase additional ventilators. furthermore, some local institutions, municipalities, and states are also developing stockpiles. for some events, these devices, together with staff augmentation strategies, may allow for many additional patients to survive (see "definitive care for the critically ill during a disaster: a framework for optimizing critical care surge capacity" and "definitive care for the critically ill during a disaster: medical resources for surge capacity"). for more catastrophic events, these additional ventilators may be beneficial but still insufficient to serve all in need; in such cases, scarce mechanical ventilators will need to be allocated to those patients who are prioritized (see "definitive care for the critically ill during a disaster: a framework for allocation of scarce resources in mass critical care"). the "just-in-time" supply chain management systems used by many hospitals creates a significant threat to successful disaster response as many hospitals maintain only a minimal store of medical supplies on site. of the typically "consumable" medical supplies required for the provision of critical care some may have the potential for limited disinfection and reuse in a disaster when no alternative exists. there are a variety of inotropes and vassopressors that are interchangeable again increasing availability. however, oxygen remains a critical consumable resource which has a limited supply and distribution network. most hospitals rely on large storage tanks of liquid oxygen. if this source runs low, oxygen must be trucked in from a supplier. the number of suppliers of medical grade oxygen in north america is limited as are the number of tanker trucks available to transport oxygen. portable oxygen supplies for use during an infrastructure failure or in s off-site critical care facilities are very limited, inefficient and not included in the strategic national stockpile. staff like many areas of health care, critical care units face shortages of various team members required for critical care delivery. , , [ ] [ ] [ ] [ ] [ ] data from ontario show that % of critical care units had nursing vacancies and % had physician vacancies. icus facing staffing shortages are routinely forced to cancel surgeries and divert ed admissions to other hospitals. the need to resort to such actions even in non-surge periods bespeaks the limited surge capacity in the critical care system. in the past, staff shortages have not typically been a major problem during disasters. however, a report revealed that staffing can be a problem, with staff absenteeism during a disaster ranging from to %. the authors described disasters that were prolonged, were of a type rare for the community, or impacted the personal lives of employees (ie, school closures, day-care closures, or elder-care issues) were associated with higher rates of absenteeism. estimated absenteeism for future bioevents is predicted to be even higher. , in bioevents, staff may fail to report for duty for a variety of reasons, including fear of infection or infecting their families. [ ] [ ] [ ] [ ] although volunteers often converge on disaster-stricken communities, , rarely do these volunteers possess the skills necessary to provide critical care; and even if they do, rapidly verifying credentials during a disaster can be logistically challenging. it is important that the staff available to respond have adequate preparation to do so. critical care physicians in general are poorly prepared to respond to mass casualty disasters. , , a study of other physician groups report that preparedness for bioterrorism or public health emergencies are particular areas of weakness, and deficiencies in training to respond to mass casualty events are not limited to physicians. hospital administrators, who are often called on to lead the response in a health-care facility, also lack appropriate training. critical care requires specific functionalities, including electricity, oxygen, suction, medical gas, monitoring equipment, and physical space for equipment and patient management. as a result, there are limited areas in which critical care can be provided on a routine basis outside of current critical care areas (icu, postanesthesia care unit, ed). as with staffing, some hospitals face shortages of critical care spaces, , - although occupancy varies across the united states. in ontario in , there were , critical care beds, , of which were capable of accommodating mechanical ventilation. the occupancy rate for these beds approaches %. demands on critical care resources are expected to increase in both the united states and canada as the populations age. on a day-to-day basis, additional capacity can be created in the critical care system by expanding critical care to areas of the hospital such as the postanesthesia care unit. however, this expansion is still limited by the issues of stuff and staff discussed earlier. therefore, even though the bed spaces may be available to use for critical care, if the hospital rents its ventilators and has no more on site, the ability to expand critical care remains limited unless specific advanced planning and preparation are undertaken. finally, although it is possible to convert off-site locations , (ie, hotels, gymnasiums, sports fields) into medical treatment facilities, the ability to convert such areas to critical care facilities on a large scale is curtailed because of the functional requirements and logistical challenges, such as large-volume portable oxygen supplies. while unlimited stockpiles of medical equipment could mitigate the shortfall of critical care resources during a disaster, this is not a realistic solution in part because of the costs of stockpiling. extrapolating from even an incomplete list of equipment required to care for critically ill patients results in an estimated cost of $ , , to manage critically ill patients for days. this cost does not take into account the cost of the financing to purchase the stockpile or the potential returns from alternative investments those funds could be used for. this considerable expense also does not include the cost of maintaining and storing equipment. furthermore, the period of treatment being considered is very short and not representative of the typical length of icu stay. thus the cost is substantial, imposing significant fiscal limitations on the ability to stockpile. therefore, a balance must be struck between service provision today and preparation for potential events of the future. finally, stockpiling does not resolve the staffing issue. one option most health-care facilities consider when they are overwhelmed is to seek help from outside, either by transferring patients out or having help sent in. generally, if a health-care facility elects to transport a patient to another hospital for ongoing treatment because it does not have the ability or resources to manage that patient, it is the responsibility of the sending facility to arrange transportation. however, this is often difficult to do during a disaster when ambulances are occupied with the ongoing prehospital response. moreover, most areas will not have a sufficient number of dedicated critical care transport teams to evacuate large numbers of critically ill; thus, regular critical care staff would be required. this would take critical care staff away from the hospital during transport and would be an inefficient use of valuable staff (ie, : or : registered nurse/respiratory technician/ medical doctor-to-patient ratio). if local resources are insufficient for patient evacuation, the us department of health and human services maintains contracts with a private ambulance service for ground transport coordination, and the department of defense is responsible for evacuation within the national disaster medical system (ndms). although the department of defense is capable of transporting critically ill patients, , its ability to do so is has been estimated at patients in h. civilian ground, aeromedical rotor-wing, and fixed-wing assets may assist, if not dedicated to the on-scene major incident response, but the total number of aircraft in the united states is limited (eg, civilian rotor-wing aircraft), and all are designed for the transport of one to two critically ill patients at a time. this limited capacity certainly is not sufficient to move large surges of critically ill patients; nor is it likely that these transport assets from outside regions will be available during the first to h of a mass casualty event. thus, a hospital cannot rely on immediately evacuating critically ill patients as a response to a mass casualty event. if patients cannot go to help, then it is logical for help to come to the patient. depending on the situation, assistance can come from the local, regional/ state, or national levels. local assistance is usually facilitated by the sharing of staff in an emergency through a prearranged mutual aid agreement. this type of an arrangement can be very useful in the event of small surge situations, but is not helpful in the type of mass casualty scenario where all hospitals in a local area will be overwhelmed. the us federal health response includes the ndms to address medical and mental health needs during a disaster. the ndms was created to address civilian disasters and military contingencies in which there might be a large number of casualties that cannot be accommodated by the departments of defense or veterans affairs. the ndms is a private/public partnership that includes a number of specialized teams comprising some , to , volunteers and a network of , hospitals with a total of approximately , beds. similar teams are being developed elsewhere in north america. the ndms has been a valuable resource in many prior disasters. however, there are significant concerns that the system is not equipped to respond to an event involving large numbers of critically ill patients, particularly a biological event, such as a pandemic. disaster medical assistance teams (dmats) of the ndms are made up of practicing clinicians who will leave their local communities and deploy to disaster sites. while it may be possible to piece together a team or two of available volunteers from a distant unaffected area to respond to a geographically isolated event, it will be a significant challenge to find enough available dmat members to meet the needs of many communities during a widespread event, such as an influenza pandemic or simultaneous terrorist attacks in major cities across the nation. for disasters in which dmats are available, another limitation is their critical care capability. the teams are staffed primarily by members who are not trained in critical care, and the teams are not equipped to provide critical care beyond initial resuscitation. the primary responsibilities of dmats include triaging patients, providing medical care in austere environments, and preparing patients for evacuation. finally, assuming that dmats are able to be staffed and equipped to provide critical care on a large scale, they still face the issue of time, something many critically ill patients do not have. because of logistic issues, deployment typically may take hours to days. , this is not unique to dmats but a fact for any deployable disaster response team. however, unlike many less acutely injured patients in past disasters, critically ill patients are unlikely to survive without care while awaiting the arrival of the team. although great strides have been made to prepare the health-care system to respond to disaster, these plans fall short for mass casualty events with a large number of critically ill. most countries have insufficient critical care staff, medical equipment, and icu space to provide timely, usual critical care to a surge of critically ill and injured victims. were a mass casualty critical care event to occur tomorrow, many people with clinical conditions that are survivable under usual health-care system conditions might have to forgo 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of disasters date: - - journal: nursing management of pediatric disaster doi: . / - - - - _ sha: doc_id: cord_uid: yfuuirnw disasters are increasing around the world. children are greatly impacted by both natural disasters (forces of nature) and man-made (intentional, accidental) disasters. their unique anatomical, physiological, behavioral, developmental, and psychological vulnerabilities must be considered when planning and preparing for disasters. the nurse or health care provider (hcp) must be able to rapidly identify acutely ill children during a disaster. whether it is during a natural or man-made event, the nurse or hcp must intervene effectively to improve survival and outcomes. it is extremely vital to understand the medical management of these children during disasters, especially the use of appropriate medical countermeasures such as medications, antidotes, supplies, and equipment. skeleton as a result of incomplete calcification and active bone growth centers. protected organs, such as the lungs and heart, may be injured due to overlying fractures. cervical spine injuries can also be pronounced, as in patients with head trauma. in fact, spinal cord injury may be present without any radiographic abnormalities of the spine. finally, vital signs will vary based on the pediatric patient's age. this may be a pitfall during rapid evaluation by any nurse or hcp not accustomed to the care of children. younger pediatric patients have higher metabolic rates and, therefore, higher respiratory rates and heart rates. this can be a distinct disadvantage versus older pediatric patients when encountering similar diseases. an example is inhaled toxins (e.g., nerve agents and lung-damaging agents). infants and children will suffer greater toxicity since they inhale at a faster rate due to higher metabolic demands and thus, distribute the toxin more rapidly to various end-organs. understanding respiratory differences is essential to the management of the acutely ill pediatric patient. the most common etiology for cardiorespiratory arrest in children is respiratory pathology, typically of the upper airway. most of the airway resistance in children occurs in the upper airway. nasal obstruction can lead to severe respiratory distress due to infants being obligate nose breathers. their relatively large tongue and small mouth can lead to airway obstruction quickly, especially when the neuromuscular tone is abnormal such as during sedation or encephalopathy. in infants, physiologic (i.e., copious secretions) and pathologic (i.e., edema, vomitus, blood, and foreign body) factors will exaggerate this obstruction. securing the airway in such events can be quite challenging. typically, the glottis is located more anterior and cephalad. appropriate visualization during laryngoscopy can be further hampered by the prominent occiput that causes neck flexion and, therefore, reduces the alignment of visual axes. the omega or horseshoeshaped epiglottis in young infants and children is quite susceptible to inflammation and swelling. as in epiglottitis, the glottis becomes strangulated in a circumferential manner leading to dangerous supraglottic obstruction. children also have a natural tendency to laryngospasm and bronchospasm. finally, due to weaker cartilage in infants, dynamic airway collapse can occur especially in states of increased resistance and high expiratory flow. along with altered pulmonary compensation and compliance, a child may rapidly progress to respiratory failure and possibly arrest. cardiovascular differences are critical in the pediatric patient. typical physiological responses tend to allow compensation with seemingly normal homeostasis. with tachycardia and elevated systemic vascular resistance, younger pediatric patients can maintain normal blood pressure despite decreased cardiac output and poor perfusion (compensated shock). since children have less blood and volume reserve, they progress to this state quickly. in pediatric patients with multiorgan injury or severe gastrointestinal losses, these compensatory mechanisms are pushed to their limits. the unaccustomed hcp may be lulled into complacency since the blood pressure is normal. all the while, the pediatric patient's organs are being poorly perfused. once these compensatory mechanisms are exhausted, the patient rapidly progresses to hypotension and, therefore, hypotensive shock. if not reversed expeditiously, this may lead to irreversible shock, ischemia, multiorgan dysfunction, and death. pediatric patients with altered mental status pose significant problems. the differential diagnosis will be very broad in the comatose patient based on development alone. for example, younger pediatric patients can present with nonconvulsive status epilepticus (ncse) instead of generalized convulsive status epilepticus (gcse). in fact, ncse is more common among younger pediatric patients than gcse, especially in those from to months of age. furthermore, many of them are previously well without preexisting diseases such as epilepsy. other disease states may include poisoning, inborn errors of metabolism, meningitis, and other etiologies of encephalopathy. using the modified pediatric glasgow coma scale (gcs) is the cornerstone when evaluating the young pediatric patient when they are preverbal. pupillary response, external ocular movements, and gross motor response may be challenging to evaluate in a developmentally young or delayed pediatric patient. pediatric traumatic brain injury is extremely devastating. whether considered accidental (motor vehicle crash) or nonaccidental (abusive head trauma), evaluation of the neurological status of the acutely injured pediatric patient can be problematic, especially the gcs. some prefer to use the avpu system (alert, responds to verbal, responds to pain, and unresponsive). due to the disproportionately larger head and weaker neck muscles, there is more risk of acceleration-deceleration injuries (fall from a significant height, vehicular ejection, and abusive head trauma). furthermore, the softer skull, dural structural differences, and vessel supply will place the pediatric patient at risk for brain injury and intracranial hemorrhage. finally, due to pediatric brain composition, the risk of diffuse axonal injury and cerebral edema is much higher. although spinal cord injury is rare in young pediatric patients, morbidity and mortality are significant. in pediatric patients less than years of age, the most commonly seen injuries are in the atlas, axis, and upper cervical vertebrae. in young pediatric patients, spinal injuries tend to be anatomically higher (cervical) versus adolescents (thoracolumbar). furthermore, congenital abnormalities, such as atlantoaxial abnormalities (trisomy ), may exaggerate the process. the clinical presentation of spinal cord injury varies in young pediatric patients due to ongoing development. laxity of ligaments, wedge-shaped vertebrae, and incomplete ossification centers contribute to specific patterns of injuries. finally, spinal cord injury without radiographic abnormality (sciwora) may result. because of the disproportionately larger head, weaker neck muscles, and elasticity of the spine, significant distraction and flexion injury of the spinal cord may occur without apparent ligament or bony disruption (hilmas et al. ; jacobson and severin ; severin ). motor skills develop from birth. gross and fine motor milestones are achieved in a predictable manner and must be assessed during each hcp encounter. cognitive development will follow a similar pattern of maturation. the development of these skills can often predict injuries and their extent. for example, consider a house fire. a young infant, preschooler, and adolescent are sleeping upstairs in house when a fire breaks out in the middle of the night. the smoke detectors begin to alarm. each child is awoken by the ensuing noise and chaos. based on the development, the adolescent will most likely make it out of the house alive. he will comprehend the threat, run down the stairs, and exit the house without delay. smoke inhalation may be minimal. if it is a middle adolescent, an attempt may be made to jump out of the window leading to multiple blunt trauma with or without traumatic brain injury. the preschooler most likely will be too scared and not understand how to escape. tragically, he may hide under a bed or in a closet. when the firefighters arrive and search the house, the preschooler may remain silent because of fear, especially of strangers in the house. he will most likely succumb to thermal injuries along with the effects of carbon monoxide and die. as far as the infant, he cannot walk, climb, crawl, or run. furthermore, he cannot scream for help or know how to escape. as the smoke engulfs the room, he will most likely suffer severe smoke inhalation injury including extensive carbon monoxide toxicity along with thermal injuries and die. this example also points out another important difference in pediatric patients: their dependence on caregivers. when considering neonates, for example, their entire existence depends on the caregiver, including feeding, changing of diapers, nurturing, and environmental safety. these dynamics are essential to the pediatric patient's health and survival, especially during a disaster. another aspect of development is the attainment of language skills. this, too, develops over time in a predictable fashion. one of the biggest challenges in pediatrics is the lack of the patient's ability to verbally convey complaints. as described above, verbal milestones vary among the different age ranges of the pediatric patient. hcps are often faced with a caregiver's subjective assessment of the problem. although it can be revealing and informative, this may not be available in an acute crisis situation. it will take the astute hcp to determine, for example, if an inconsolably crying infant is in pain from a corneal abrasion or something more life-threatening such as meningitis. this can also be a challenging task in a teenager, especially during middle adolescence. an hcp will have to determine, for example, if the seemingly lethargic middle adolescent is intoxicated with illicit drugs or has diabetic ketoacidosis. finally, the hcp will have to address developmental variances among their pediatric patients and any comorbid features. young pediatric patients can regress developmentally during any illness or injury. this is especially seen in patients with chronic medical conditions (cancer) or during prolonged hospitalization with rehabilitation (multisystem trauma). furthermore, those pediatric patients with developmental and intellectual disabilities, for example, will be difficult to evaluate based on the effects of their underlying pathology. these pediatric patients typically have unique variances in their physical exams (jacobson and severin ; severin ) . please refer to chap. for more detailed information on pediatric development. pediatric patients will often reflect the emotional state of their caregiver. they take verbal and physical cues from their caregiver. at times, this may also occur in the presence of a nurse or hcp. the psychological impact of illness will vary greatly with the child's development and experience. children tend to have a greater vulnerability to post-traumatic stress disorder especially with disaster events. furthermore, they are highly prone to becoming psychiatric casualties despite the absence of physical injury to themselves. and as any pediatric hcp can tell you, the younger pediatric patients tend to also have greater levels of anxiety, especially while preparing for invasive procedures such as phlebotomy and intravenous line placement (hilmas et al. ; jacobson and severin ; severin ) . please refer to chap. for more detailed content on mental health. the world health organization and the pan american health organization define a disaster as "an event that occurs in most cases suddenly and unexpectedly, causing severe disturbances to people or objects affected by it, resulting in the loss of life and harm to the health of the population, the destruction or loss of community property, and/or severe damage to the environment. such a situation leads to disruption in the normal pattern of life, resulting in misfortune, helplessness, and suffering, with adverse effects on the socioeconomic structure of a region or a country and/or modifications of the environment to such an extent that there is a need for assistance and immediate outside intervention" (lynch and berman ). types of disasters usually fall into two broad categories: natural and man-made. natural disasters are generally associated with weather and geological events, including extremes of temperature, floods, hurricanes, earthquakes, tsunamis, volcanic eruptions, landslides, and drought. naturally occurring epidemics, such as the h n , ebola, and novel coronavirus outbreaks, are often included in this category. man-made disasters are usually associated with a criminal attack such as an active shooter incident, or a terrorist attack using weapons such as explosive, biological, or chemical agents. however, man-made disasters can also refer to human-based technological incidents, such as a building or bridge collapse, or events related to the manufacture, transportation, storage, and use of hazardous materials, such as the chernobyl radiation leak and the bhopal toxic gas leak. even though disasters can be primarily placed into any of these two categories, they can often impact each other and compound the magnitude of any disaster incident (united states department of homeland security, office of inspector general ). a prime example is the march tohoku earthquake leading to a tsunami (natural) that triggered the fukushima daiichi nuclear disaster (man-made). disasters can also be characterized by the location of such an event. internal disasters are those incidents that occur within the health care facility or system. employees, physical plant, workflow and operations of the clinic, hospital, or system can be disrupted. external disasters are those incidents that occur outside of the health care facility or system. this impacts the community surrounding the facility, proximally or distally, but does not directly threaten the facility or its employees. as with natural and man-made disasters, internal and external disasters can impact each other. for example, an overflow of patients during a high census period may lead to the shutdown of the hospital to any new patients (internal disaster). this will place the hospital on bypass and possibly stress other hospitals in the community beyond their means (external disaster). a terrorist event, such as the release of sarin in a subway system during a busy morning commute, can lead to massive disruption in the community (external disaster). all the victims of the attack will seek medical care at nearby hospitals, possibly overwhelming the health care staff and depleting critical resources (internal disaster). characterization of disasters by geography (local, state, national, and international) can also be used. again, no matter the site of the incident, a disaster in one area could easily create a disaster in another geographical region. for example, a factory and its community could be ravaged by a hurricane (local disaster). if this is the only factory in the world to produce a certain medication, this could lead to critical shortages to hospitals all around the world (international disaster). the term "disaster preparedness" has been used over the years as a way to describe efforts to manage any disaster event. however, preparedness is only one aspect of the process. the use of the term disaster planning is more appropriate. it considers all aspects needed for an effective effort and is dependent on additional phases, not just preparedness. national preparedness efforts, including planning, are now informed by the presidential policy directive (ppd) that was signed by the president in march and describes the nation's approach to preparedness (united states department of education, office of elementary and secondary education, office of safe and healthy students ; united states department of homeland security b). a recommended method for disaster preparedness efforts is the utilization of an "all-hazards" model of emergency management (adini et al. ; waugh ) . the four overlapping phases of the model include mitigation, preparedness, response, and recovery. the mitigation phase involves "activities designed to prevent or reduce losses from a disaster" (waugh ) . examples include land use planning in flood plains, structural integrity measures in earthquake zones, and deployment of security cameras. the preparedness phase includes the "planning of how to respond in an emergency or a disaster, and developing capabilities for more effective response" (waugh ) . examples include training programs for emergency responders, drills and exercises, early warning systems, contingency planning, and development of equipment and supply caches. up to this point, all planning efforts are proactive and not reactive. often times, a hazard analysis is conducted to delineate areas of strengths and identify potential risks. it helps in "the identification of hazards, assessment of the probability of a disaster, and the probable intensity and location; assessment of its potential impact on a community; the property, persons, and geographic areas that may be at risk; and the determination of agency priorities based on the probability level of a disaster and the potential losses" (waugh ) . after a disaster or emergency incident occurs, the response phase, or "immediate reaction to a disaster", (waugh ) begins. examples include mass evacuations, sandbagging buildings and other structures, providing emergency medical services, firefighting, and restoration of public order. in some situations, the response period may be a short (e.g., house fire), intermediate (e.g., bomb detonation), or extended (e.g., pandemic influenza) duration. after a period of time, the recovery phase follows. these are "activities that continue beyond the emergency period to restore lifelines" (waugh ) . examples include the provision of temporary shelter, restoration of utilities such as power, critical stress debriefing for responders, and victims, job assistance and small business loans, and debris clearance. recovery always seems to be the most unpredictable; it may take days to months to years. as demonstrated with recent hurricanes harvey, irma, and maria in , the most affected regions are still in the phase of recovery and may be along a prolonged track as hurricane katrina in . as mentioned, the early phases of planning (mitigation and preparedness) truly hinge upon the environment or community surrounding the health care site (e.g., clinic, hospital, or long-term care facility). identification of potential hazards and risks is a key step in disaster planning. using a hazard vulnerability assessment (hva) or a threat and hazard identification and risk assessment (thira) can provide a basis for mitigation and prevention tasks. an hva/thira emphasizes which types of natural or man-made disasters are likely to occur in a community (e.g., tornado, flood, chemical release, or terrorist event). they further highlight the impact those disasters may have on the community and any capabilities that are in place that may lessen the effects of the disaster (illinois emergency medical services for children ). a basic principle of the hva methodology is to determine the risk of such an event or attack occurring at a given hospital or hospital system. simply, the risk is a product of the probability of an event and the severity of such an event if it occurs (risk = probability × severity). however, there are many complexities in quantifying terrorism risk (waugh ; woo ) . it is important to note that in some circumstances, exposure may need to be included in the equation (risk = probability × severity × exposure), but usually for operational risk management applications (mitchell and decker ) . at any rate, issues to consider for the probability of an event occurring include, but are not limited to, geographic location and topography, proximity to hazards, degree of accessibility, known risks, historical data, and statistics of various manufacturer/vendor products. severity, on the other hand, is dependent on the gap between the magnitude of an event and mitigation for the given event (severity = magnitude -mitigation). magnitude varies upon the impact of the event to humans, property, and/or business. mitigation varies upon the development of internal and external readiness before a disaster strikes. as one can surmise, if the magnitude of the event outstrips the mitigation, the event is considered a threatening hazard. once the hva is completed, the health care site should immediately prioritize planning efforts for the top - hazards and develop plans accordingly. all other identified hazards must also be addressed to ensure a broad and robust disaster plan. it is important to realize that local and regional entities also perform comprehensive hvas. a concerted analysis among a hospital and key community stakeholders is optimal for a coordinated plan. an hva/thira contains both quantitative and qualitative components. specific tools have been developed through private and public organizations (e.g, fema) that can help in the analysis (united states department of homeland security, federal emergency management agency ). using these tools as a guide, the entity can determine what types of hazards have a high, medium, or low probability of occurring within specific geographic boundaries. typically, these tools do not have components specific to children or other at-risk populations. however, the tools can be adapted either directly by adding children to specific hazards or ensuring considerations specific to children are incorporated into the hva/thira calculations. the hva/thira should be reviewed and updated minimally on an annual basis to identify changing or external circumstances. this includes conducting a pediatric-specific disaster risk assessment to identify where children congregate and their risks (e.g., schools, popular field trip designations, summer camps, houses of worship, and juvenile justice facilities) (illinois emergency medical services for children ). of note, hva techniques have been utilized for pediatric-specific disaster plans. having a separate pediatric hva (phva) is crucial to a well-rounded and robust health care disaster plan. first, it demonstrates the extent of the pediatric population in the community. it is estimated that % of the population fits within the age range of pediatric patients. in some situations, it may be more. during the performance of a phva, it was demonstrated that % of the community was less than years of age (jacobson and severin ) . second, a phva increases the situational awareness of those tasked to plan for disasters that involve children and adolescents. often times, children and adolescents are excluded from local and regional disaster plans. the unique vulnerabilities of pediatric patients will demand appropriate drills, exercises, equipment, medications, and expertise. thirdly, identifying pediatric risks in a community will help prioritize efforts of planning, especially in those hospitals not accustomed to caring for pediatric patients. finally, a phva helps to develop a framework for global pediatric disaster planning. this can extend beyond a local community and actually advance city, state, regional, and national disaster planning efforts. there has been a development of web-based tools to simplify and enhance the phva process (jacobson and severin ) . after an hva/thira has been completed, the results should be used to help direct and plan drills/exercises based on high impact and high probability threats. it is advised to conduct an hva/thira on an annual basis to assess specific threats unique to your organization's physical structure as well as the surrounding geographic environment. it will also provide insight into whether there is an improvement in previous planning efforts. completion of a population assessment that provides a demographic overview of the community with a breakdown of the childhood population is strongly recommended in conjunction with the hva/ thira. collaborating with other community partners, such as local health departments and emergency management agencies, can assist an organization with the conduction of a comprehensive hva/thira (illinois emergency medical services for children ). please see chap. for further information on hospital planning. pediatric supplies, equipment, and medications will be scarce during a disaster. it will become more of an issue if the health care facility is not accustomed to caring for acutely ill pediatric patients. this will be further exacerbated by a massive surge of acutely ill pediatric patients, a widespread or prolonged disaster, and supply line disruptions. to protect the health security of children and families during a public health emergency, the assistant secretary for preparedness and response (aspr) manages and maintains the strategic national stockpile (sns), a cache of medical countermeasures for rapid deployment and use in response to a public health emergency or disaster (fagbuyi et al. ) . various pediatric-specific supplies and countermeasures are included in the sns. maintaining a supply of medications and medical supplies for specific health threats allows the stockpile to respond with the right product when a specific disease or agent is known. if a community experiences a large-scale public health incident in which the disease or agent is unknown, the first line of support from the stockpile is to send a broad-range of pharmaceuticals and medical supplies. place and martin ) . the emergency equipment and supply lists can easily be adapted for any pediatric disaster emergency (place and martin ) or incident requiring pediatric mass critical care (desmond et al. ) . ageappropriate nutrition, hygiene, bedding, and toys/distraction devices should also be available (illinois emergency medical services for children ) (tables . and . ). endotracheal tubes • uncuffed: . and . mm • cuffed or uncuffed: . , . , . , . , and . mm • cuffed: . , . , . , . , and . mm feeding tubes ( f and f) laryngoscope blades curved: and ; straight: , , , and laryngoscope handle magill forceps (pediatric and adult) nasopharyngeal airways (infant, child, and adult) oropharyngeal airways (sizes - ) stylets for endotracheal tubes (pediatric and adult) suction catheters (infant, child, and adult) tracheostomy tubes (sizes . , . , . , . , . , . , and . mm) yankauer suction tip bag-mask device (manual resuscitator), self-inflating (infant size: ml; adult size: ml) clear oxygen masks (standard and nonrebreathing) for an infant, child, and adult masks to fit bag-mask device adaptor (neonatal, infant, child, and adult sizes) nasal cannulas (infant, child, and adult) nasogastric tubes (sump tubes): infant ( f), child ( f), and adult ( f- f) laryngeal mask airway a vascular access arm boards (infant, child, and adult sizes) catheter over-the-needle device ( - gauge) intraosseous needles or device (pediatric and adult sizes) intravenous catheter-administration sets with calibrated chambers and extension tubing and/or infusion devices with ability to regulate rate and volume of infusate umbilical vein catheters ( . f and . f) b central venous catheters ( . f- . f) intravenous solutions to include normal saline, dextrose % in normal saline, and dextrose % in water fracturemanagement devices extremity splints, including femur splints (pediatric and adult sizes) spine-stabilization method/devices appropriate for children of all ages c (continued) laryngeal mask airways could be shared with anesthesia but must be immediately accessible to the ed b feeding tubes (size f) may be used as umbilical venous catheters but are not ideal. a method for securing the umbilical catheter, such as an umbilical tie, should also be available c a spinal stabilization device is one that can stabilize the neck of an infant, child, or adolescent in a neutral position when a pediatric disaster victim presents acutely ill to the hospital, various emergency interventions will be needed to stabilize the patient. evaluation of the pediatric patient should include a primary survey (abcde), secondary survey (focused sample history and focused physical examination), and diagnostic assessments (laboratory, radiological, and other advanced tests). this will guide further therapeutic interventions. particular attention should be given to the identification of respiratory and/or circulatory derangements of the child, including airway obstruction, respiratory failure, shock, and cardiopulmonary failure. interventions will be based on physiologic derangements of the pediatric patient and determined by the scope of practice and protocols, such as standard resuscitation algorithms for neonatal (american academy of pediatrics and american heart association et al. ) and pediatric (american heart association ) victims. the hcp must be knowledgeable of various emergency medications (table . ) used for children, the appropriate dosages and their mechanism of action, any potential side effects, and drug/drug interactions. other medications, such as antibiotics, antidotes, or countermeasures, may be needed as well. pharmacologic therapy should be initiated immediately based on clinical suspicion and not delayed due to pending laboratory tests (e.g., antibiotics for presumed infection/sepsis or antidotes for suspected nerve agents). dosages should be based on the patient's weight or a length-based weight system. (montello et al. ) or hard copy countermeasure manuals may be more practical, especially during a disaster incident when computer service or internet access may be unreliable. in , the centre for research on the epidemiology of disasters (cred) launched the emergency events database (em-dat). em-dat was created with the initial support of the world health organization (who) and the belgian government. the main objective of the database is to serve the purposes of humanitarian action at national and international levels. the initiative aims to rationalize decision-making for disaster preparedness as well as provide an objective base for vulnerability assessment and priority setting. em-dat contains essential core data on the occurrence and effects of over , mass disasters in the world from to the present day. the database is compiled from various sources, including united nation agencies, nongovernmental organizations (ngos), insurance companies, research institutes, and press agencies (cred ). as described in the cred report entitled natural disasters : lower mortality, higher cost, a disaster is entered into the database if at least one of the following criteria is fulfilled: or more people reported killed; or more people reported affected; declaration of a state of emergency; and/or call for international assistance (cred ). in economic losses, poverty and disasters - : cred/unisdr report, the cred defines a disaster as "a situation or event which overwhelms local capacity, necessitating a request at national or international level for external assistance; an unforeseen and often sudden event that causes great damage, destruction and human suffering" (cred ). the cred em-dat classifies disasters according to the type of hazard that triggers them. the two main disaster groups are natural and technological disasters. there are six natural disaster subgroups. geophysical disasters originate from the solid earth and include earthquake (ground movement and tsunami), dry mass movement (rock fall and landslides), and volcanic activity (ash fall, lahar, pyroclastic flow, and lava flow). lahar is a hot or cold mixture of earthen material flowing on the slope of a volcano either during or between volcanic eruptions. meteorological disasters are caused by short-lived, micro-to meso-scale extreme weather and atmospheric conditions that last from minutes to days and include extreme temperatures (cold wave, heat wave, and severe winter conditions such as snow/ice or frost/ freeze), fog, and storms. storms can be extra-tropical, tropical, or convective. convective storms include derecho, hail, lightning/thunderstorm, rain, tornado, sand/dust storm, winter storm/blizzard, storm/surge, and wind. derecho is a widespread and usually fast-moving windstorm associated with convection/convective storm and includes downburst and straight-line winds. hydrological disasters are caused by the occurrence, movement, and distribution of surface/subsurface freshwater and saltwater and include floods, landslides (an avalanche of snow, debris, mudflow, and rockfall), and wave action (rogue wave and seiche). flood types can be coastal, riverine, flash, or ice jam. climatological disasters are caused by longlived, meso-to macro-scale atmospheric processes ranging from intraseasonal to multidecadal climate variability and include drought, glacial lake outburst, and wildfire (forest fire, land fire: brush, bush, or pasture). biological disasters are caused by the exposure to living organisms and their toxic substances or vectorborne diseases that they may carry and include epidemics (viral, bacterial, parasitic, fungal, and prion), insect infestation (grasshopper and locust), and animal accidents. extraterrestrial disasters are caused by asteroids, meteoroids, and comets as they pass near-earth, enter earth's atmosphere, and/or strike the earth, and by changes in the interplanetary conditions that affect the earth's magnetosphere, ionosphere, and thermosphere. types include impact (airbursts) and space weather (energetic particles, geomagnetic storm, and shockwave) events (cred ). there are three technological disaster subgroups. industrial accidents include chemical spills, collapse, explosion, fire, gas leak, poisoning, radiation, and oil spills. a chemical spill is an accidental release occurring during the production, transportation, or handling of hazardous chemical substances. transport accidents include disasters in the air (airplanes, helicopters, airships, and balloons), on the road (moving vehicles on roads or tracks), on the rail system (train), and on the water (sailing boats, ferries, cruise ships, and other boats). miscellaneous accidents vary from collapse to explosions to fires. collapse is an accident involving the collapse of a building or structure and can either involve industrial structures or domestic/nonindustrial structures (cred ). technological disasters are considered man-made, but as suggested by their subgroup, they are accidental and not intentional. the united nations office for disaster risk reduction (unisdr) and cred report, economic losses, poverty, and disasters - , reviews global natural disasters during that time period, their economic impact, and the relationship with poverty. between and , climate-related and geophysical disasters killed . million people and left a further . billion injured, homeless, displaced, or in need of emergency assistance. although the majority of fatalities were due to geophysical events, mostly earthquakes and tsunamis, % of all disasters was caused by floods, storms, droughts, heatwaves, and other extreme weather events. the financial impact was staggering. in - , disaster-hit countries reported direct economic losses valued at us$ billion, of which climate-related disasters caused us$ billion or % of the total. this was up from % (us$ billion) of losses (us$ billion) reported between and . overall, reported losses from extreme weather events rose by % between these two -year periods. in absolute monetary terms, over the last -years, the usa recorded the biggest losses (us$ billion), reflecting high asset values as well as frequent events. china, by comparison, suffered a significantly higher number of disasters than the usa ( vs. ) but lower total losses (us$ billion) (cred ) (figs. . , . , . , . , . , . , . , . and . in , climate-related and geophysical incidents in the world were estimated with , deaths and over million people impacted. indonesia recorded approximately half of the deaths with india accounting for half of those impacted by disasters. notable features of were intense seismic activity in indonesia, a series of disasters in japan, floods in india, and an eventful year for both volcanic activity and wildfires. however, an ongoing trend of lower death tolls from previous years continued into (centre for research on the epidemiology of disasters (cred) and united nations office for disaster risk reduction (unisdr) ) (tables . , . , . , . , . , . and . there are no specific deviations when medically managing children after a natural disaster. according to sirbaugh and dirocco ( ) "small-scale mass casualty incidents occur daily in the united states. few present unusual challenges to the local medical systems other than in the number of patients that must be treated at one time. except in earthquakes, explosions, building collapses, and some types of terrorist attacks, the same holds true for large-scale disasters. sudden violent disaster mechanisms can produce major trauma cases, including patients needing field amputations or management of crush syndrome. for the most part, medicine after a disaster is much the same as it was before the disaster, with more minor injuries, more people with exacerbations of their chronic illnesses, and number of patients seeking what is ordinarily considered primary care. this is true for children and adults." it should be noted, however, that children have a predisposition to illness and injury after natural disasters. the hcp must be able to identify any health problems and treat the child effectively and efficiently while utilizing standard resuscitation protocols as indicated. traumatic injuries may be seen after any natural disaster. the injuries can range from minor scrapes and bruises to major blunt trauma or traumatic brain injury. children are at increased risk for injury since adults are distracted by recovery efforts and may not be able to supervise them closely. the environment may not be safe due to environmental hazards, such as collapsed buildings, sinkholes, and high water levels. dangerous equipment used during relief efforts may be present, such as heavy earth moving equipment, chainsaws, and power generators. hazardous chemicals, such as gasoline and other volatile hydrocarbons, may be readily accessible or taint the environment. without suitable shelter, children are also exposed to weather, animals, and insects (sirbaugh and dirocco ) . infectious diseases may also pose a problem to children after a natural disaster. infectious patterns will persist during a disaster based on the season and time of year. there may be outbreaks or epidemics of highly contagious infections (e.g., influenza, respiratory syncytial virus, streptococcus pyogenes) due to mass sheltering of children and families. poor nutrition or decreased availability of food may lower their resistance against infections. various water-borne or food-borne diseases may cause illnesses in children. poor hygiene and mass shelter environments may exacerbate these illnesses. immunized children should be protected against common preventable diseases after a natural disaster but still could be a problem in mass groups that are not completely or appropriately immunized. after the haiti earthquake, there were increased cases of diarrhea, cholera, measles, and tetanus in children months after the earthquake despite some level of vaccination (sirbaugh and dirocco ) . children are at risk for various environmental emergencies. austere environments will impact children greatly. heat exposure coupled with minimal access to drinkable water may lead to severe dehydration. exposure to the cold may lead to frostbite or hypothermia. children are at risk for carbon monoxide toxicity due to generator use or natural gas poisoning due to disrupted gas lines. there is always a risk for thermal injury due to the use of candles and other flame sources. exposure to animals (snakes) and insects (spiders) may increase the risk of envenomation. submersion injury and drowning incidents may escalate. this will be due to lack of supervision of children around storm drains, newly formed bodies of water, or rushing waters of storm diversion systems (sirbaugh and dirocco ) . mental health issues are often seen in children after natural disasters. even though a child may not be injured, they may become "psychiatric casualties" due to the horrific sights they have seen during or after the disaster. children and adolescents with behavioral or psychiatric problems may experience worsening symptoms and signs due to stress, trauma, disruption of routines, or availability of medications. this is often exacerbated if the parent, guardian, caregiver, or hcp is also having difficulty coping with the stress of the disaster. in general, the most common mental health problem in children is a post-traumatic stress disorder. however, separation anxiety, obsessive-compulsive symptoms, and severe stranger anxiety can also be seen in children after a traumatic event (sirbaugh and dirocco ) . see chap. for more detailed information. terrorism impacts children and families all around the world (tables . and . ). after the events of / , much attention has been given to the possibility of another mass casualty act of terrorism, especially with weapons of mass destruction, that include chemical, biological, nuclear, radiological, and explosive devices (cbnre), or other forms of violence such as active shooter incidents and mass shootings (jacobson and severin ) . since then, other incidents, both foreign and domestic, have involved children and complicates the concept of and the response to terrorism. johnston ( ) said it best in his review of terrorist and criminal attacks targeting children: "one of the more accepted defining characteristics of terrorism is that it targets noncombatants including men, women, and children. however, terrorist attacks specifically targeting children over other noncombatants are uncommon. this is for the same reason that most terrorists have historically avoided mass casualty terrorism: the shock value is so great that such attacks erode support for the terrorists' political objectives. the / attacks represent an increasing trend in mass casualty terrorism. at the same time, policymakers are examining this evolving threat, they must increasingly consider the threat of terrorist attacks targeting children." based on historical events, it is clear infants, toddlers, children, and adolescents have been victims of terrorism. this global trend of terrorists targeting children seems to be escalating (johnston ) . therefore, it is imperative to understand terrorism and ways it impacts the children and families served by the health care community. combs ( ) defines terrorism as "an act of violence perpetrated on innocent civilian noncombatants in order to evoke fear in an audience". however, she goes on to argue that to become an operational definition, there must also be the addition of a "political purpose" of the violent act. therefore, "terrorism, then, is an act composed of at least four crucial elements: ) it is an act of violence, ) it has a political motive or goal, ) it is perpetrated against civilian noncombatants, and ) it is staged to be played before an audience whose reaction of fear and terror is the desired result." (combs ) . there are different typologies of terrorism. at least five types of terror violence have been suggested by feliks gross: "mass terror is terror by a state, where the regime coerces the opposition in the population, whether organized or unorganized, sometimes in an institutionalized manner. dynastic assassination is an attack on a head of state or a ruling elite. random terror involves the placing of explosives where people gather (such as post offices, railroads, and cafes) to destroy whoever happens to be there. focused random terror restricts the placing of explosives, for example to where significant agents of oppression are likely to gather. finally, tactical terror is directed solely against the ruling government as a part of a 'broad revolutionary strategic plan'" (combs ). an additional typology offered is "lone wolf terror which involves someone who commits violent acts in support of some group, movement, or ideology, but who does stand alone, outside of any command structure and without material assistance from any group" (combs ) . martin ( ) reviews eight different terrorism typologies in the ever shifting, multifaceted world of modern terrorism. the new terrorism "is characterized by the threat of mass casualty attacks from dissident terrorist organizations, new and creative configurations, transnational religious solidarity, and redefined moral justifications for political violence" (martin ) . state terrorism is "committed by governments against perceived enemies and can be directed externally against adversaries in the international domain or internally against domestic enemies" (martin ) . dissident terrorism is "committed by nonstate movements and groups against governments, ethno-national groups, religious groups, and other perceived enemies" (martin ) . religious terrorism is "motivated by an absolute belief that an otherworldly power has sanctioned and commanded the application of terrorist violence for the greater glory of the faith…[it] is usually conducted in defense of what believers consider to be the one true faith" (martin ) . ideological terrorism is "motivated by political systems of belief (ideologies), which champion the self-perceived inherent rights of a particular group or interest in opposition to another group or interest. the system of belief incorporates theoretical and philosophical justifications for violently asserting the rights of the championed group or interest" (martin ) . international terrorism "spills over onto the world's stage. targets are selected because of their value as symbols of international interests, either within the home country or across state boundaries" (martin ) . criminal dissident terrorism "is solely profit-driven, and can be some combination of profit and politics. for instance, traditional organized criminals accrue profits to fund their criminal activity and for personal interests, while criminalpolitical enterprises acquire profits to sustain their movement" (martin ) . gender-selective terrorism "is directed against an enemy population's men or women because of their gender. systematic violence is directed against men because of the perceived threat posed by males as potential soldiers or sources of opposition. systematic violence is directed against women to destroy an enemy group's cultural identity or terrorize the group into submission" (martin ) . the all-hazards national planning scenarios are an integral component of dhs's capabilities-based approach to implementing homeland security presidential directive : national preparedness (hspd- ). the national planning scenarios are planning tools and are representative of the range of potential terrorist and natural disasters and the related impacts that face the nation. the federal interagency community has developed all-hazards planning scenarios for use in national, federal, state, and local homeland security preparedness activities. the objective was to develop a minimum number of credible scenarios to establish the range of response requirements to facilitate disaster planning (dhs ) (table . ). twelve of the scenarios represent terrorist attacks while three represent natural disasters or naturally occurring epidemics. this ratio reflects the fact that the nation has recurring experience with natural disasters but faces newfound dangers, including the increasing potential for use of weapons of mass destruction by terrorists. the scenarios form the basis for coordinated federal planning, training, exercises, and grant investments needed to prepare for all hazards. dhs employed the scenarios as the basis for a rigorous task analysis of prevention, protection, response, and recovery missions and identification of key tasks that supported the development of essential all-hazards capabilities (united states department of homeland security, federal emergency management agency ) (table . ). each of the scenarios follows the same outline to include a detailed scenario description, planning considerations, and implications. for each of the terrorismrelated scenarios, fema national preparedness directorate (npd) partnered with dhs office of intelligence and analysis (i&a) and other intelligence community and law enforcement experts to develop and validate prevention prequels. the prequels provide an understanding of terrorists' motivation, capability, intent, tactics, techniques and procedures, and technical weapons data. the prequels also provide a credible adversary based on known threats to test the homeland security community's ability to understand and respond to indications and warnings of possible terrorist attacks (united states department of homeland security, federal emergency management agency ). a chemical agent of terrorism is defined as any chemical substance intended for use in military operations to kill, seriously injure, or incapacitate humans (or animals) through its toxicological effects. chemicals excluded from this list are riot-control agents, chemical herbicides, and smoke/flame materials. chemical agents are classified as toxic agents (producing injury or death) or incapacitating agents (producing temporary effects). toxic agents are further described as nerve agents (anticholinesterases), blood agents (cyanogens), blister agents (vesicants), and lung-damaging agents (choking agents). incapacitating agents include stimulants, depressants, psychedelics, and deliriants (banks ; departments of the army, the navy, and the air force, and commandant, marine corps ). nerve agents are organophosphate anticholinesterase compounds. they are used in various insecticide, industrial, and military applications. military-grade agents include tabun (ga), sarin (gb), soman (gd), cyclosarin (gf), venom x (vx), and the novichok series. these are all major military threats. the only known battlefield use of nerve agents was the iraq-iran war. however, other nerve agent incidents, such as the tokyo subway attack (sarin), the chemical attacks in syria (chlorine, sarin, mustard), and the attempted assassination of sergei skripal in salisbury, uk (novichok), support that civilian threats also exist. nerve agents are volatile chemicals and can be released in liquid or vapor form. however, the liquid form can become vapor depending upon its level of volatility (e.g, g-agents are more volatile than vx). the level of toxicity depends on the agent, concentration of the agent, physical form, route and length of exposure, and environmental factors (temperature and wind) (tables . and . ). nerve agents exert their effects by the inhibition of esterase enzymes. acetylcholinesterase inhibition prevents the hydrolysis of acetylcholine. the clinical result is a cholinergic crisis and subsequent overstimulation of muscarinic and nicotinic receptors throughout the body including the central nervous system. clinical muscarinic responses include sludge (salivation, lacrimation, urination, defecation, gastrointestinal distress, and emesis) and dumbels (diarrhea, urinary incontinence, miosis/muscle fasciculation, bronchorrhea/bronchospasm/bradycardia, emesis, lacrimation, and salivation). nicotinic responses vary by site. preganglionic sympathetic nerve stimulation produces mydriasis, tachycardia, hypertension, and pallor. however, stimulation at the neuromuscular junction leads to muscular fasciculation and cramping, weakness, paralysis, and diaphragmatic weakness. central nervous system presentations range from anxiety and restlessness to seizures, coma, and death (banks ; rotenberg and newmark ; rotenberg b ). pediatric manifestations (table . ) may vary from the classic clinical responses due to their unique vulnerabilities (hilmas et al. ): • children may manifest symptoms earliest and possibly more severe presentations. • could be hospitalized for similarly related illnesses and diseases. • smaller mass. • lower baseline cholinesterase activity. • tendency to bronchospasm. • pediatric airway and respiratory differences. • altered pulmonary compensation. • lower reserves of cardiovascular system and fluids. • isolated central nervous system signs (stupor, coma). • less miosis. • vulnerability to seizures and neurotransmitter imbalances (excitability). • immature metabolic systems. differential diagnoses include upper or lower airway obstruction, bronchiolitis, status asthmaticus, cardiogenic shock, acute gastroenteritis, seizures, and poisonings (carbon monoxide, organophosphates, and cyanide). diagnostic tests include acetylcholinesterase levels, red blood cell cholinesterase levels, and an arterial blood gas. treatment (tables . and . ) includes decontamination (reactive skin decontamination lotion ® [potassium , -butanedione monoximate], soap and water, and . % hypochlorite solution), supportive care, and administration of nerve agent antidotes (atropine, pralidoxime chloride, and diazepam). atropine is a competitive antagonist of acetylcholine muscarinic receptors and reverses peripheral muscarinic symptoms. it does not restore function at the neuromuscular junction nicotinic receptors. it does, however, treat early phases of convulsions. pralidoxime chloride separates the nerve agent from acetylcholinesterase and restores enzymatic function. it also binds free nerve agent. the major goal is to prevent "aging" of the enzyme (e.g., gd). diazepam provides treatment of nerve agent-induced seizures and prevents secondary neurologic injury. typically, associated seizures are refractory to other antiepileptic drugs. the antiseizure effect of diazepam is enhanced by atropine (banks ; cieslak and henretig ; messele et al. ) . potential medical countermeasures include trimedoxime (tmb ), hi- (an h-series oxime), obidoxime, "bioscavengers" (butyrylcholinesterase, carboxylesterase, organophosphorus acid anhydride hydrolase, and human serum paraoxonase), novel anticonvulsant drugs, n-methyl-d-aspartate (nmda) receptor antagonists (ketamine, dexanabinol), and common immunosuppressants such as cyclosporine a (jokanovic ; merrill et al. ; national institutes of health ; united states department of health and human services ). all patients should be observed closely for electroencephalographic changes and neuropsychiatric pathologies. polyneuropathy, reported after organophosphate insecticide poisoning, has not been reported in humans exposed to nerve agents and has been produced in animals only at unsurvivable doses. the intermediate syndrome has not been reported in humans after nerve agent exposure, nor has it been produced in animals. muscular necrosis has occurred in animals after high-dose nerve agent exposure but reversed within weeks; it has not been reported in humans (banks ). on march , , sergei skripal, a former russian double agent, and his daughter, yulia skripal, were found unresponsive on a park bench in salisbury, uk. they were brought to a nearby hospital and treated for signs consistent with a cholinergic crisis due to a nerve agent exposure. analysis of the skripals found the presence of a secret nerve agent called novichok. further testing found high concentrations of the agent on the front-door handle of his home. one of the investigating police officers, detective sergeant nick bailey, unknowingly touched the door-handle and also became ill. all three survived due to rapid recognition of the nerve agent exposure by hospital personnel. four months later, two other people, dawn sturgess and charlie rowley, became ill with identical symptoms in the town of amesbury, miles from salisbury. they were later confirmed to have high concentrations of novichok on their hands from a perfume bottle found in a recycling bin. both were immediately treated, but dawn sturgess later died. charlie rowley survived. it was believed the discarded perfume bottle contained novichok and was discarded by the assailants after the attempt on sergei skripal. on september , , the uk government revealed that their investigation uncovered two suspects from closed circuit television (cctv) footage near the skripal's home. the suspects entered the uk on russian passports using the names alexander petrov and ruslan boshirov, stayed in a london hotel for days, visited salisbury briefly, and then returned to moscow. minute traces of novichok were also found in the london hotel where they had stayed. the uk prime minister, teresa may, said that the suspects are thought to be officers from russia's military intelligence service the glavnoye razvedyvatel'noye upravleniye (gru), and that this showed that the poisoning was "not a rogue operation" and was "almost certainly" approved at a senior level of the russian state. the two suspects later appeared on russian tv denying the accusations and saying they were just "tourists" who had traveled all the way from moscow to salisbury just to see the "famous cathedral". however, cctv of the cathedral area found no evidence of the two men visiting the cathedral, although they were captured on cctv near the skripal's home. in a development in september , one of the men was revealed as actually being a russian intelligence officer named colonel anatoliy chepiga and was a decorated veteran of russian campaigns in chechnya and ukraine. and later in october, the second man was named as dr. alexander mishkin, a naval medical doctor allegedly recruited by the gru (chai et al. ; may ) . novichok (Новичоќ: russian for "newcomer") is a highly potent nerve agent developed from the russian classified nerve agent program known as foliant. almost everything known about these agents is due to a russian defector, vil mirzayanov ( ) who was an analytical chemist at the russian state research institute of organic chemistry and technology (gosniiokht). he has described the details of the novichok program in his book "state secrets: an insider's chronicle of the russian chemical weapons program". the first three nerve agents of the novichok series developed in the program were substance- , a- , and a- (table . ). they were synthesized as unitary agents, like vx, tabun, soman, and sarin. unitary means that the chemical structure was produced at its maximum potency. however, the novichok agents were developed as binary agents: maximum potency when two inert substances are combined together prior to deployment to create the active nerve agent (cieslak and henretig ) . very little is known about the chemistry of these weaponized organophosphate agents. however, they appear to be more potent than current nerve agents. for example, the ld of novichok agents is reported . μg/kg similar to -(dimethylamino)ethyl n,n-dimethylphosphoramidofluoridate (vg), a novel fourth generation nerve agent. furthermore, novichok- is × more effective than vx and novichock- is × more effective than soman (cieslak and henretig ; hoenig ) . clinically, they behave like other organophosphates by binding to acetylcholinesterase preventing the breakdown of acetylcholine thereby leading to a cholinergic crisis. there appears to be a similar "aging" process as seen with other nerve agents. in addition, the novichok agents binding to peripheral sensory nerves distinguishes this class of organophosphates. prolonged or high-dose exposure results in debilitating peripheral neuropathy. exposure to these agents is fatal unless aggressively managed (cieslak and henretig ) . decontamination is essential to prevent ongoing exposure to the patient and medical personnel. clothing should be removed and quickly placed in a sealed bag (prevents ongoing exposure to the emission of vapors) followed by thorough washing with soap and water. application of dry bleach powder should be avoided as it may hydrolyze nerve agents into toxic metabolites that can produce ongoing cholinergic effects. supportive care is essential. antidote therapy should be given as usual for nerve agents, including atropine, diazepam, and pralidoxime chloride (united states department of health and human services, office of the assistant secretary for preparedness and response, national library of medicine ; united states department of health and human services, chemical hazards emergency medical management (chemm) ). of note, the toxicity of the novichok agents may not rely on anticholinesterase inhibition. some have suggested that reactive oximes like potassium , -butanedione monoximate are preferred oximes for antidotal therapy (cieslak and henretig ) . cyanide is a naturally occurring chemical. it can be found in plants and seeds. it is also used in many industrial applications and is a common product of combustion of synthetic materials. typical cyanogens include hydrogen cyanide (ac) and cyanogen chloride (ck). low levels of cyanide are detoxified by a natural reaction in the human body using the rhodanese system. there is reversible metabolism with vitamin b a to vitamin b (cyanocobalamin). an irreversible reaction occurs with sulfanes to produce thiocyanates and sulfates. the former is excreted via the urinary tract. when cyanide overwhelms this natural process, cyanide binds to ( ) a vx = venom x (cieslak and henretig ) cytochrome oxidase within the mitochondria and disrupts cellular respiration. cyanide has an affinity for fe+ in the cytochrome a complex and oxidative phosphorylation is interrupted. cells can no longer use oxygen to produce atp and lactic acidosis ensues from resultant anaerobic metabolism. when inhaled, cyanide produces rapid onset of clinical signs. findings include transient tachypnea and kussmaul breathing (from hypoxia of carotid and aortic bodies), hypertension and tachycardia (from hypoxia of aortic body), and neurologic findings such as seizures, muscle rigidity (trismus), opisthotonus, and decerebrate posturing. other findings include cherry red flush, acute respiratory failure/ arrest, bradycardia, dissociative shock, and cardiac arrest. venous blood samples exhibit a bright red color. arterial blood gas may demonstrate a metabolic acidosis with an increased anion gap due to lactic acid (banks ; cieslak and henretig ; rotenberg a) . pediatric manifestations (table . ) may vary from the classic clinical responses due to their unique vulnerabilities (hilmas et al. ): • thinner integument leading to shorter time from exposure to symptom development. • higher vapor density (ck) and concentration accumulation in living zone of children, • higher minute ventilation and metabolism. • abdominal pain, nausea, restlessness, and giddiness are common early findings. • cyanosis mostly noted other than classic cherry red flushing of the skin. • resilient with recovery even when just using supportive measures alone. differential diagnoses include meningitis, encephalitis, gastroenteritis, ischemic stroke, methemoglobinemia, and poisonings (nerve agents, organophosphates, methanol, hydrogen sulfide, and carbon monoxide). diagnostic tests include arterial blood gas, lactic acid, and thiocyanate levels. treatment (tables . and . ) includes decontamination, supportive care, and administration of cyanide antidote kit (nitrites and thiosulfate). the nitrites facilitate the production of methemoglobinemia (fe+ ) which attracts cyanide molecules forming cyanmethemoglobin. amyl nitrite pearls are crushed into gauze and placed over the mouth/nose or in a mask used for bag/mask ventilation. sodium nitrite is given parenterally and dosed according to the patient's estimated hemoglobin so as to prevent severe methemoglobinemia. since the formation of cyanmethemoglobin is a reversible reaction, and sodium thiosulfate is given to extract the cyanide. dosing is also dependent upon estimated hemoglobin. along with the naturally occurring rhodanese enzymatic system, the irreversible reaction forms thiocyanate. thiocyanate is water soluble and is excreted harmlessly via the kidneys (banks ; cieslak and henretig ). potential medical countermeasures (national institutes of health ; united states army medical research institute of infectious diseases (usamriid) ) include hydroxocobalamin, cobinamide (a cobalamin precursor), dicobalt edetate, cyanohydrin-forming compounds (alpha-ketoglutarate and pyruvate), s-substituted crystallized rhodanese, sulfur-containing drugs (n-acetylcysteine), and methemoglobin inducers ( -dimethylaminophenol and others). blistering agents, or vesicants, promote the production of blisters. typical examples include sulfur mustard (hd), nitrogen mustard (hn), and lewisite (l). these agents, especially sulfur mustard, are considered capable chemical weapons since illness may not occur until hours or days later. vesicants are alkylating agents that affect rapidly reproducing and poorly differentiated cells in the body. however, they can also produce cellular oxidative stress, deplete glutathione stores, and promote immature cognitive function unable to flee emergency immature coping mechanisms inability to discern threat, follow directions, and protect self high risk for developing ptsd bbb blood-brain barrier, bsa body surface area, cns central nervous system, ptsd post-traumatic stress disorder (hilmas et al. ) intense inflammatory responses. clinical findings are initially cutaneous (erythema, pruritus, yellow blisters, ulcers, and sloughing), respiratory (hoarseness, cough, voice changes, pneumonia, respiratory failure, acute lung injury, and acute respiratory distress syndrome), and ophthalmologic (pain, irritation, blepharospasm, photophobia, conjunctivitis, corneal ulceration, and globe perforation) in nature. after exposure through these primary portals of entry, other sites are affected, including the gastrointestinal tract (nausea, vomiting, and mucosal injury), the hematopoietic system (bone marrow suppression), the cardiovascular system (l), reproductive system (hd, hn) , and the central nervous system (lethargy, headache, malaise, and depression) (banks ; yu et al. ) . pediatric manifestations (table . ) may vary from the classic clinical responses due to their unique vulnerabilities (hilmas et al. ): • thinner integument leading to shorter time from exposure to symptom development. • higher vapor density and concentration accumulation in the living zone. • higher minute ventilation and metabolism. • greater pulmonary injury. • ocular findings more frequent (less self-protection and more hand/eye contact). • gastrointestinal manifestations more prominent. • unable to escape and decontaminate. • unable to verbalize complaints (i.e., pain). treatment (tables . and . ) includes decontamination and supportive care. currently, there are no antidotes for mustard toxicity (cieslak and henretig ) . agents under investigation include antioxidants (vitamin e), anti-inflammatory drugs (corticosteroids), mustard scavengers (glutathione, n-acetylcysteine), and nitric oxide synthase inhibitors (l-nitroarginine methyl ester). other therapeutics under investigation include the use of british anti-lewisite (bal), reactive skin protectants, and ocular therapies (national institutes of health ; usamriid ). lung-damaging agents are toxic inhalants and potentially can affect the entire respiratory tract. typical examples include chlorine (cl ), phosgene (carbonyl chloride), oxides of nitrogen, organofluoride polymers, hydrogen fluoride, and zinc oxide. since many of these chemicals are readily available and have multiple industrial applications, they are considered terrorist weapons of opportunity. toxicity is dependent upon agent particle size, solubility, and method of release. large particles produce injury in the nasopharynx (sneezing, pain, and erythema). midsize particles affect the central airways (painful swelling, cough, stridor, wheezing, and rhonchi). small particles cause injury at the level of the alveoli (dyspnea, chest tightness, and rales). highly soluble agents, such as chlorine, dissolve with mucosal moisture and immediately produce strong upper airway reactions. less soluble agents, such as phosgene, travel to the lower airway before dissolving and subsequently causing toxicity. it is important, however, to realize that very few lungdamaging agents affect only the upper or lower airway (e.g., cl ). if the agent is aerosolized, solid or liquid droplets suspend in the air and distribute by size. if it is a gas or vapor release, there is uniform distribution throughout the lungs and toxicity will be based on solubility and reactivity of the agent (banks ; burklow et al. ; cieslak and henretig ) . pediatric manifestations (table . ) may vary from the classic clinical responses due to their unique vulnerabilities (hilmas et al. ): • pediatric airway and respiratory tract issues (obligate nose breathers, relatively small mouth/large tongue, copious secretions, anterior/cephalad vocal cords, omega or horseshoe-shaped epiglottis, tendency of laryngospasm and bronchospasm, and anatomically small, "floppy" airways). • high vapor density and concentration accumulation in the living zone. • unable to verbalize or localize physical complaints. • rapid dehydration and shock secondary to pulmonary edema. • increased minute ventilation and metabolism. differential diagnoses include smoke inhalation injury, cardiogenic shock, heart failure, traumatic injury, asthma, bronchiolitis, and poisoning (cyanide). treatment (tables . and . ) includes decontamination and supportive care. currently, there are no antidotes for lung-damaging agent toxicity (cieslak and henretig ) . potential countermeasures include novel positive-pressure devices, drugs to prevent lung inflammation, and treatments for chemically induced pulmonary edema (beta agonists, dopamine, insulin, allopurinol, and ibuprofen). in addition, drugs are being investigated that act at complex molecular pathways of the lung the centers for disease control and prevention (cdc) has delineated bioterrorism agents and diseases into three categories based on priority. category a agents include organisms with the highest risk because the ease of dissemination or transmission from person-to-person, result in high mortality rates, have the potential for major public health impact, promote public panic and social disruption, and require special action of public health preparedness. these agents/diseases include smallpox (variola major), anthrax (bacillus anthracis), plague (yersinia pestis), viral hemorrhagic fevers (filoviruses [ebola, marburg] and arenaviruses [lassa, macupo]), botulinum toxin (from clostridium botulinum), and tularemia (francisella tularensis). category b agents, the second highest priority, include those that are moderately easy to disseminate, result in moderate morbidity and low mortality rates, and require specific enhancements of diagnostic capacity and enhanced disease surveillance. these agents/diseases include ricin toxin (ricinus communis), brucellosis (brucella species), epsilon toxin of clostridium perfringens, food safety threats (salmonella species, escherichia coli o :h , shigella), glanders (burkholderia mallei), meliodosis (burkholderia pseudomallei), psitticosis (chlamydia psittaci), typhus fever (rickettsia prowazekii), q fever (coxiella burnetii), staphylococcal enterotoxin b, trichothecenes mycotoxin, viral encephalitis (alphaviruses, such as eastern equine encephalitis, venezuelan equine encephalitis, and western equine encephalitis), and water safety threats (vibrio cholera, cryptosporidium parvum). category c agents have the next priority and include emerging pathogens that could be engineered for mass dissemination because of availability, ease of production and dissemination, and have the potential for high morbidity and mortality rates and major health impact. recognition of a biologic attack is essential. there are various epidemiologic clues to consider when determining whether the outbreak is natural or man-made (markenson et al. ; cieslak ; usamriid ) : • the appearance of a large outbreak of cases of a similar disease or syndrome, or especially in a discrete population. • many cases of unexplained diseases or deaths. • more severe disease than is usually expected for a specific pathogen or failure to respond to standard therapy. • unusual routes of exposure for a pathogen, such as the inhalational route for disease that normally occur through other exposures. • a disease case or cases that are unusual for a given geographic area or transmission season. • disease normally transmitted by a vector that is not present in the local area. • multiple simultaneous or serial epidemics of different diseases in the same population. • a single case of disease by an uncommon agent (smallpox, some viral hemorrhagic fevers, inhalational anthrax, pneumonic plague). • a disease that is unusual for an age group. • unusual strains or variants of organisms or antimicrobial resistance patterns different from those known to be circulating. • a similar or identical genetic type among agents isolated from distinct sources at different times and/or locations. • higher attack rates among those exposed in certain areas, such as inside a building if released indoors, or lower rates in those inside a sealed building if released outside. • outbreaks of the same disease occurring in noncontiguous areas. • zoonotic disease outbreaks. • intelligence of a potential attack, claims by a terrorist or aggressor of a release, and discovery of munitions, tampering, or other potential vehicle of spread (spray device, contaminated letter). one should know the cellular, physiological, and clinical manifestations of each biologic agent. furthermore, knowledge of distinct presentation patterns of children will be helpful to diagnosis. in any event, the ten steps in the management of biologic attack victims, pediatric, or otherwise, should be applied (cieslak and henretig ; cieslak ; usamriid smallpox is caused by the orthopoxvirus variola and was declared globally eradicated in . the disease is highly communicable from person-to-person and remains a threat due to its potential for weaponization. the only stockpiles are at the cdc and at the russian state centre for research on virology and biotechnology. however, clandestine stockpiles in other parts of the world are unknown. since the cessation of smallpox vaccination, the general population has little or no immunity. the three clinical forms of smallpox include ordinary, flat, and hemorrhagic. another form, modified type, occurred in those previously vaccinated who were no longer protected. the asymptomatic incubation period is from to days (average days) after exposure. a prodrome follows that lasts for - days and is marked by fever, malaise, and myalgia. lesions start on the buccal and pharyngeal mucosa. the rash then spreads in a centrifugal fashion, and the lesions are synchronous. initially, there are macules followed by papules, pustules, and scabs in - weeks. other clinical features include extensive fluid loss and hypovolemic shock, nausea, vomiting, diarrhea, bacterial superinfections, viral bronchitis and pneumonitis, corneal ulceration with or without keratitis, and encephalitis. death, if it occurs, is typically during the second week of clinical disease. variola minor caused a mortality of % in unvaccinated individuals. however, the variola major type caused death in % and % in those vaccinated and unvaccinated, respectively. flat (mostly children) and hemorrhagic (pregnant women and immunocompromised) types caused severe mortality in those populations infected. the differential diagnoses for smallpox include chickenpox (varicella), herpes, erythema multiforme with bullae, or allergic contact dermatitis. varicella typically has a longer incubation period ( - days) and minimal or no prodrome. furthermore, the rash distributes in a centripetal fashion and the progression is asynchronous (images . and . ). diagnosis of smallpox is mostly clinical (centers for disease control and prevention a). if considered, contact public health immediately. laboratory confirmation (cdc or who) can be done by dna sequencing, polymerase chain reaction (pcr), restriction fragment-length polymorphism (rflp), real-time pcr, and microarrays. these are more sensitive and specific than the conventional virological and immunological approaches (goff et al. ) . generally, treatment is largely supportive (table . ). fluid losses and hypovolemic shock must be addressed. also, due to electrolyte and protein loss, replacement therapy will be required. bacterial superinfections must be aggressively treated with appropriate antibiotics. biologic countermeasures and antivirals against smallpox are under investigation, including cidofovir, brincidovir (cmx- ), and tecovirimat (st- ). these agents have shown efficacy in orthopoxvirus animal models and have been used to treat disseminated vaccinia infection under emergency use. cidofovir has activity against poxviruses in animal studies (in vitro and in vivo) and some humans (eczema vaccinatum and molluscum contagiosum). brincidovir is an oral formulation of cidofovir with less nephrotoxicity and has recently been announced as an addition to the strategic national stockpile (sns) for patients with smallpox. tecovirimat is a potent and specific inhibitor of orthopoxvirus replication. a recent study found that treatment with tecovirimat resulted in % survival of cynomolgus macaques challenged with intravenous variola virus. the disease was milder in tecovirimat-treated survivors and viral shedding was reduced compared to placebo-treated survivors. prophylaxis comes in the form of the smallpox vaccine (vaccinia virus), acam ® , which replaced wyeth dryvax™ in . safety profile of the two vaccines appears to be similar. side effects of vaccination range from low-grade fever and axillary lymphadenopathy to inadvertent inoculation of the virus to other body sites to generalized vaccinia and cardiac events (myopericarditis). rare, but typically fatal complications include progressive vaccinia, eczema vaccinatum, postvaccination encephalomyelitis, and fetal vaccinia. modified vaccinia ankara (mva) smallpox vaccine (bavarian nordic's imvamune ® ) is a live, highly attenuated, viral vaccine that is under development as a future nonreplicating smallpox vaccine (greenberg et al. ; kennedy and greenberg ). passive immunoprophylaxis exists in the form of vaccinia immune globulin (vig) and is used for primarily treating complications from smallpox vaccine. limited information suggests that vig may be of use in postexposure prophylaxis of smallpox if given the first week after exposure and with vaccination. monoclonal antibodies may represent another form of immunoprophylaxis. postexposure administration of human monoclonal antibodies has protected rabbits from a lethal dose of an orthopoxvirus. as mentioned, smallpox is highly communicable person-to-person (table . ). contact precautions with full personal protective equipment (ppe) are required. airborne isolation with the use of an n- mask is needed for baseline protection. an n- mask or powered airpurifying respirator (papr) is recommended for protection during high risk procedures (beigel and sandrock ; goff et al. ; rotz et al. ; pittman et al. ; usamriid ). anthrax is caused by the aerobic, spore-forming, nonmotile, encapsulated gram-positive rod bacillus anthracis. it is a naturally occurring disease in herbivores. humans contract the illness by handling contaminated portions of infected animals, especially hides and wool. infection is introduced by scratches or abrasions on the skin. there is concern for potential aerosol dispersal leading to intentional infection through inhalation: it is fairly easy to obtain, capable of large quantity production, stable in aerosol form, and highly lethal. anthrax spores enter the body via skin, ingestion, or inhalation. the spores germinate inside macrophages and become vegetative bacteria. the vegetative form is released, replicates in the lymphatic system, and produces intense bacteremia. the production of virulence factors leads to overwhelming sepsis. the main virulence factors are encoded on two plasmids. one produces an antiphagocytic polypeptide capsule. the other contains genes for the synthesis of three proteins it secretes: protective antigen, edema factor, and lethal factor. the combination of protective antigen with lethal factor or edema factor forms binary cytotoxins, lethal toxin, and edema toxin. the anthrax capsule, lethal toxin, and edema toxin act in concert to drive the disease. three clinical syndromes occur with anthrax: cutaneous, gastrointestinal, and inhalational. cutaneous anthrax is the most common naturally occurring form. after an individual is exposed to infected material or the agent itself, there is a - day (average days) incubation period. a painless or pruritic papule forms at the site of exposure. the papule enlarges and forms a central vesicle, which is followed by erosion into a coal-black but painless eschar. edema surrounds the area and regional lymphadenopathy may occur. gastrointestinal anthrax is rare. typically, it develops after ingestion of viable vegetative organisms found in undercooked meats of infected animals. the two forms of gastrointestinal anthrax, oropharyngeal and intestinal, have incubation periods of - days. the oropharyngeal form is marked by fever and severe pharyngitis followed by ulcers and pseudomembrane formation. other findings include dysphagia, regional lymphadenopathy, unilateral neck swelling, airway compromise, and sepsis. the intestinal form begins with fever, nausea, vomiting, and abdominal pain. bowel edema develops which leads to mesenteric lymphadenitis with necrosis, shock, and death. endemic inhalational anthrax (woolsorters' disease) is also extremely rare and is due to inhaling spores. therefore, any case of inhalational anthrax should be assumed to be due to intentional exposure until proven otherwise. the incubation period is - days but can be up to days. there is a prodrome of - days consisting of fever, malaise, and cough. within h, the disease rapidly progresses to respiratory failure, hemorrhagic mediastinitis (wide mediastinum), septic shock, multiorgan failure, and death. patients with inhalational anthrax may also have hemorrhagic meningitis. mortality is greater than % in - h despite aggressive treatment of inhalational anthrax. the differential diagnoses of ulceroglandular lesions include antiphospholipid antibody syndrome, brown recluse spider bite, coumadin/heparin necrosis, cutaneous leishmaniasis, cutaneous tuberculosis, ecthyma gangrenosum, glanders, leprosy, mucormycosis, orf, plague, rat bite fever, rickettsial pox, staphylococcal/ streptococcal ecthyma, tropical ulcer, tularemia, and typhus. the differential diagnoses of ulceroglandular syndromes include cat scratch fever, chancroid, glanders, herpes, lymphogranuloma venereum, melioidosis, plague, staphylococcal and streptococcal adenitis, tuberculosis, and tularemia. the differential diagnoses for inhalational anthrax include influenza and influenza-like illnesses from other causes. the differential diagnoses of mediastinal widening include normal variant, aneurysm, histoplasmosis, sarcoidosis, tuberculosis, and lymphoma. the diagnosis of anthrax is by culture and gram stain of the blood, sputum, pleural fluid, cerebrospinal fluid, or skin. specimens must be handled carefully, especially by lab personnel and those performing autopsies. elisa and pcr are available at some reference laboratories. the chest radiograph of inhalational anthrax shows the classic widening of the mediastinum. additional findings include hemorrhagic pleural effusions, air bronchograms, and/or consolidation (purcell et al. ). supportive treatment is indicated, including mechanical ventilation, pleural effusion drainage, fluid and electrolyte support, and vasopressor administration. for inhalational anthrax, antibiotic treatment is unlikely to be effective unless started before respiratory symptoms develop. treatment (table . ) includes ciprofloxacin (or levofloxacin or doxycycline), clindamycin, and penicillin g. raxibacumab, a monoclonal antibody, was approved by the fda in for the treatment of inhalational anthrax in combination with recommended antibiotic regimens and prophylaxis for inhalational anthrax when other therapies are unavailable or inappropriate. it works by inhibiting anthrax antigen binding to cells and, therefore, prevents toxins from entering cells (kummerfeldt ) . the adult dose is mg/kg given iv over h and min. the dose for children is weight based; ≤ kg: mg/kg; > - kg: mg/kg; > kg: mg/kg. premedication with diphenhydramine iv or po is recommended h before the infusion. it can also be used as postexposure prophylaxis in high risk spore exposure cases (cieslak and henretig ; migone et al. ; the medical letter ). obiltoxaximab (anthim) is a recently approved monoclonal antibody treatment for inhalational anthrax in combination with recommended antibiotic regimens and prophylaxis for inhalational anthrax when other therapies are unavailable or inappropriate. adults and children > kg should receive a single obiltoxaximab dose of mg/kg. the recommended dose is mg/kg for children > - kg and mg/kg for those weighing ≤ kg. premedication with diphenhydramine is recommended to reduce risk of hypersensitivity reactions (the medical letter ). in patients with inhalational anthrax, intravenous anthrax immune globulin (anthrasil) should be considered in addition to appropriate antibiotic therapy (mytle et al. ; the medical letter ; usamriid ). postexposure prophylaxis includes ciprofloxacin (or levofloxacin or doxycycline) for days plus administration of vaccine; since spores can persist in human in addition to appropriate antibiotic regimen, monoclonal antibody therapy (see text for dosing) and intravenous anthrax immune globulin should be administered for inhalational anthrax c levofloxacin or ofloxacin may be an acceptable alternative to ciprofloxacin d rifampin or clarithromycin may be acceptable alternatives to clindamycin as a drug that targets bacterial protein synthesis. if ciprofloxacin or another quinolone is employed, doxycycline may be used as a second agent because it also targets protein synthesis e ampicillin, imipenem, meropenem, or chloramphenicol may be acceptable alternatives to penicillin as drugs with good cns penetration f assuming the organism is sensitive, children may be switched to oral amoxicillin ( - mg/kg/d divided q h) to complete a -day course. the first days of therapy of postexposure prophylaxis, however, should include ciprofloxacin or levofloxacin and/or doxycycline regardless of age. vaccination should also be provided; if not, antibiotic course will need to be longer g according to most experts, ciprofloxacin is the preferred agent for oral prophylaxis h ten days of therapy may be adequate for endemic cutaneous disease. a full -day course is recommended in the setting of terrorism, however, because of the possibility of concomitant inhalational exposure tissues for a long time, antibiotics must be given for a longer period if vaccine is not also given. the anthrax vaccine adsorbed (ava biothrax™) is derived from sterile culture fluid supernatant taken from an attenuated strain of bacillus anthracis and does not contain any live or dead organisms. the vaccine is given . ml intramuscularly at and weeks then at , , and months followed by yearly boosters (pittman et al. ; usamriid ) . consult with cdc for current pediatric recommendations. anthrax is not contagious in the vegetative form during clinical illness (table . ). contact with infected animals increases likelihood of spread. therefore, contact should be limited and the use of appropriate ppe in endemic areas is indicated (beigel and sandrock ; purcell et al. ; usamriid ) . plague is caused by yersinia pestis, a nonmotile, nonsporulating gram-negative bacterium. it is a zoonotic disease of rodents. it is typically found worldwide and is endemic in western and southwestern states. humans develop the disease after contact with infected rodents, or being bitten by their fleas. after a rodent population dies off, the fleas search for other sources of blood, namely humans. this is when large outbreaks of human plague occur. pneumonic plague is a very rare disease and when it is present in a patient, it may be highly suspicious for intentional dispersal of this deadly agent. three clinical syndromes occur with plague: bubonic plague ( %), septicemic plague ( %), and primary pneumonic plague ( - %). bubonic plague occurs after an infected flea bites a human. after an incubation period of - days, there is onset of high fever, severe malaise, headache, myalgias, and nausea with vomiting. almost % have abdominal pain. around the same time, a characteristic bubo forms which is tender, erythematous, and edematous without fluctuation. buboes typically form in the femoral or inguinal lymph nodes, but other areas can be involved as well (axillary, intraabdominal). the spleen and liver can be tender and palpable. the disease disseminates without therapy. severe complications can ensue, including pneumonia, meningitis, sepsis, and multiorgan failure. pneumonia is particularly concerning since these patients are extremely contagious. mortality of untreated bubonic plague is %, but % with efficient and effective treatment. septicemic plague is characterized by acute fever followed by sepsis without bubo formation. the clinical syndrome is very similar to other forms of gram-negative sepsis: chills, malaise, tachycardia, tachypnea, hypotension, nausea, vomiting, and diarrhea. in addition to sepsis, disseminated intravascular coagulation can ensue leading to thrombosis, necrosis, gangrene, and the formation of black appendages. multiorgan failure can quickly follow. untreated septicemic plague is almost % fatal versus - % in those treated. pneumonic plague is very rare and should be considered due to an intentional aerosol release until proven otherwise. the incubation period is relatively short at - days. sudden fever, cough, and respiratory failure quickly follow. this form produces a fulminant pneumonia with watery sputum that usually progresses to bloody. within a short period of time, septic shock and disseminated intravascular coagulation develop. ards and death may occur. mortality rate of pneumonic plague is very high but may respond to early treatment. plague meningitis is a rare complication of plague. it can occur in % of patients with septicemia and pneumonic forms and is more common in children. usually occurring a few weeks into the illness, it affects those receiving subtherapeutic doses of antibiotics or bacteriostatic antibiotics that do not cross the blood-brain barrier (tetracyclines). fever, meningismus, and other meningeal signs occur. plague meningitis is virtually indistinguishable from meningococcemia. the differential diagnoses of bubonic plague include tularemia, cat scratch fever, lymphogranuloma venereum, chancroid, scrub typhus, and other staphylococcal and streptococcal infections. the differential diagnoses of septicemic plague should include meningococcemia, other forms of gram-negative sepsis, and rickettsial diseases. the differential diagnosis of pneumonic plague is very broad. however, sudden appearance of previously healthy individuals with rapidly progressive gram-negative pneumonia with hemoptysis should strongly suggest pneumonic plague due to intentional release. diagnosis can be made clinically as previously described. demonstration of yersinia pestis in blood or sputum is paramount. methylene blue or wright's stain of exudates may reveal the classic safety-pin appearance of yersinia pestis. culture on sheep blood or macconkey agar demonstrates beaten-copper colonies ( h) followed by fried-egg colonies ( h). detection of yersinia pestis f -antigen by specific immunoassay is available, but the result is available retrospectively. chest radiograph of patients will demonstrate patchy infiltrates (centers for disease control and prevention a; worsham et al. ) . treatment includes mechanical ventilation strategies for ards, hemodynamic support (fluid and vasopressor administration), and antimicrobial agents (table . ). gentamicin or streptomycin is the preferred antimicrobial treatment. alternatives include doxycycline or ciprofloxacin or levofloxacin or chloramphenicol. in cases of meningitis, chloramphenicol is recommended due to its ability to effectively cross the blood-brain barrier. streptomycin is in limited supply and is available for compassionate use. it should be avoided in pregnant women. postexposure prophylaxis includes doxycycline or ciprofloxacin. no licensed plague vaccine is currently in production. a previous licensed vaccine was used in the past. it only offered protection against bubonic plague but not aerosolized yersinia pestis. the plague bacterium secretes several virulence factors (fraction (f ) and v (virulence) proteins) that as subunit proteins are immunogenic and possess protective properties. recently, an f -v antigen (fusion protein) vaccine developed by usamriid provided % protection in monkeys against high-dose aerosol challenge. there is no passive immunoprophylaxis (i.e., immune globulin) available for pre-or postexposure of plague (usamriid ). use of standard precautions for patients with bubonic and septicemic plague is indicated. suspected pneumonic plague will require strict isolation with respiratory droplet precautions for at least h after initiation of effective antimicrobial therapy, or until sputum cultures are negative in confirmed cases. an n- respirator should be used for baseline protection (table . ). it is also recommended to use an n- respirator or papr for high risk procedures (beigel and sandrock ; ; centers for disease control and prevention ; centers for disease control and prevention b; pittman et al. ; usamriid ) . in a mass casualty setting, parenteral therapy might not be possible. in such cases, oral therapy (with analogous agents) may need to be used b ofloxacin (and possibly other quinolones) may be acceptable alternatives to ciprofloxacin or levofloxacin; however, they are not approved for use in children c concentration should be maintained between and μg/ml. some experts have recommended that chloramphenicol be used to treat patients with plague meningitis, because chloramphenicol penetrates the blood-brain barrier. use in children younger than may be associated with adverse reactions but might be warranted for serious infections d ribavirin is recommended for arenavirus or bunyavirus infections and may be indicated for a viral hemorrhagic fever of an unknown etiology although not fda approved for these indications. for intravenous therapy use a loading dose: kg iv once (max dose, g), then mg/kg iv q h for days (max dose, g), and then mg/kg iv q h for days (max dose, mg). in a mass casualty setting, it may be necessary to use oral therapy. for oral therapy, use a loading dose of mg/kg po once, then mg/kg/day po in divided doses for days viral hemorrhagic fever has a variety of causative agents. however, the syndromes they produce are characterized by fever and bleeding diathesis. the etiologies include rna viruses from four distinct families: arenaviridae, bunyaviridae, filoviridae, and flaviviridae. the filoviridae (includes ebola and marburg) and arenaviridae (includes lassa fever and new world viruses) are category a agents. based on multiple identified characteristics, there is strong concern for the weaponization potential of the viral hemorrhagic fevers. specifically, there has been demonstration of high contagiousness in aerosolized primate models. there are five identified ebola species, but only four are known to cause disease in humans. the natural reservoir host of ebola virus remains unknown. however, on the basis of evidence and the nature of similar viruses, researchers believe that the virus is animal-borne and that bats are the most likely reservoir. four of the five virus strains occur in an animal host native to africa. marburg virus has a single species. geographic distribution of ebola and marburg is africa (fitzgerald et al. ). both diseases are very similar clinically. incubation period is typically - days with a range of - days. symptoms may include fever, chills, headache, myalgia, nausea, and vomiting. there is rapid progression to prostration, stupor, and hypotension. the onset of a maculopapular rash on the arms and trunk is classic. disseminated intravascular coagulation and thrombocytopenia develops with conjunctival injection, petechiae, hemorrhage, and soft tissue bleeding. there is a possible central nervous system and hepatic involvement. bleeding, uncompensated shock, and multiorgan failure are seen. high viral load early in course is associated with poor prognosis. death usually occurs during the second week of illness. mortality rate of marburg is - % and for ebola - %. in a retrospective cohort study of children during the / ebola outbreak in liberia and sierra leone (all less than years with a median age of years with one-third less than years of age), the most common features upon presentation were fever, weakness, anorexia, and diarrhea. about % were initially afebrile. bleeding was rare upon initial presentation. the overall case fatality rate was %. factors associated with death included children less than years of age, bleeding at any time during hospitalization, and high viral load (smit et al. ) . in another retrospective cohort study of children at two ebola centers in sierra leone in (all less than years of age), presenting symptoms included weakness, fever, anorexia, diarrhea, and cough. about % were afebrile on presentation. the case fatality rate was higher in children less than years ( %) versus - years of age ( %) and times more likely to die if child had a higher viral load. signs associated with death included fever, emesis, and diarrhea. interestingly, hiccups, bleeding, and confusion were only observed in children who died (shah et al. ) . lassa virus and new world viruses (junin, machupo, sabia, and guanarito) are transmitted from person-to-person. the vector in nature is the rodent. the incubation period is from to days. the geographical distribution is west africa and south america, respectively. the south american hemorrhagic fevers are quite similar but differ from lassa fever. the onset of the south american viruses is insidious and results in high fever and constitutional symptoms. petechiae or vesicular enanthem with conjunctival injection is common. these fevers are associated with neurologic disease (hyporeflexia, gait abnormalities, and cerebellar dysfunction). seizures portend a poor prognosis. mortality ranges from % to over %. on the contrary, lassa viruses are mild. less than % of infections result in severe disease. signs include chest pain, sore throat, and proteinuria. hemorrhagic disease is uncommon. other features include neurologic disease such as encephalitis, meningitis, cerebellar disease, and cranial nerve viii deafness (common feature). mortality can be as high as %. differential diagnoses include malaria, meningococcemia, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and typhoid fever. diagnosis is through detection of the viral antigen testing by elisa or viral isolation by culture at the cdc. no specific therapy is present and generally involves supportive care, especially mechanical ventilation strategies for ards, hemodynamic support, and renal replacement therapy. for the arenaviridae and bunyaviridae groups, ribavirin may be indicated ( (pittman et al. ) . there is no current vaccine for ebola that is licensed by the fda. an experimental vaccine called rvsv-zebov was found to be highly protective against ebola virus in a trial conducted by the world health organization (who) and other international partners in guinea in . fda licensure for the vaccine is expected in . until then, , doses have been committed for an emergency use stockpile under the appropriate regulatory mechanism in the event and an outbreak occurs before fda approval is received (centers for disease control and prevention b; henao-restrepo et al. ) . another ebola vaccine candidate, the recombinant adenovirus type- ebola vaccine, was evaluated in a phase trial in sierra leone in . an immune response was stimulated by this vaccine within days of vaccination and strict contact precautions (hand hygiene, double gloves, gowns, shoe and leg coverings, and face shield or goggles) and droplet precautions (private room or cohorting, surgical mask within ft) are mandatory for viral hemorrhagic fevers. airborne precautions (negative-pressure isolation room with - air exchanges per h) should also be instituted to the maximum extent possible and especially for procedures that induce aerosols (e.g., bronchoscopy). at a minimum, a fit-tested, hepa filter-equipped respirator (e.g., an n- mask) should be used, but a battery-powered papr or a positive pressure-supplied air respirator should be considered for personnel sharing an enclosed space with, or coming within ft of, the patient. multiple patients should be cohorted in a separate ward or building with a dedicated airhandling system when feasible (table . ). environmental decontamination is accomplished with hypochlorite or phenolic disinfectants (beigel and sandrock ; radoshitzky et al. ; usamriid ; won and carbone ) . francisella tularensis, a small aerobic, nonmotile gram-negative coccobacillus, causes tularemia (rabbit fever). clinical disease is caused by two isolates, biovars jellison type a and b. this organism can be stabilized for weaponization and delivered in a wet or dry form. the incubation period is usually - days (range - days). initial symptoms are nonspecific and mimic the flu-like symptoms or other upper respiratory tract infections. there is acute onset of fever with chills, myalgias, cough, fatigue, and sore throat. the two clinical forms of tularemia are typhoidal and ulceroglandular diseases. typhoidal tularemia ( - %) occurs after inhalational exposure and sometimes intradermal or gastrointestinal exposures. there is abrupt onset of fever, headache, malaise, myalgias, and prostration. it presents without lymphadenopathy. nausea, vomiting, and abdominal pain are sometimes present. untreated, there is a % mortality rate in naturally acquired cases (vs. - % in those treated). it is higher if pneumonia is present. this form would be most likely seen during an aerosol release of the agent. ulceroglandular tularemia ( - %) occurs through skin or mucus membrane inoculation. there is abrupt onset of fever, chills, headache, cough, and myalgias along with a painful papule at the site of exposure. the papule becomes a painful ulcer with tender regional lymph nodes. skin ulcers have heaped up edges. in - %, there is focal lymphadenopathy without an apparent ulcer. lymph nodes may become fluctuant and drain when receiving antibiotics. without treatment, they may persist for months or even years. in some cases ( - %), the primary entry port is the eye leading to oculoglandular tularemia. patients have unilateral, painful, and purulent conjunctivitis with local lymphadenopathy. chemosis, periorbital edema, and small nodular granulomatous lesions or ulceration may be found. oropharyngeal tularemia with pharyngitis may occur in % of patients. findings include exudative pharyngitis/tonsillitis, ulceration, and painful cervical lymphadenopathy. the differential diagnosis is antibiotic unresponsive pharyngitis, infectious mononucleosis, and viral pharyngitis. pulmonary involvement ( - %) is seen in naturally occurring disease. it ranges from mild to fulminant. various processes include pneumonia, bronchiolitis, cavitary lesions, bronchopleural fistulas, and chronic granulomatous diseases. left untreated, % will die. differential diagnoses include those for typhoidal (typhoid fever, rickettsia, and malaria) or pneumonic (plague, mycoplasma, influenza, q-fever, and staphylococcal enterotoxin b) tularemia. diagnosis should be considered when there is a cluster of nonspecific, febrile, systemically ill patients who rapidly progress to fulminant pneumonitis. tularemia can be diagnosed by recovering the organism from sputum (pcr or dfa) or serology at a state health laboratory. chest radiograph is nonspecific with possible hilar adenopathy. treatment is streptomycin or gentamicin (table . ). alternatives include doxycycline, ciprofloxacin, or chloramphenicol. a live-attenuated vaccine (ndbr ) exists and typically used for laboratory personnel working with francisella tularensis. there is no passive immunoprophylaxis. ciprofloxacin or doxycycline can be given as pre-and postexposure prophylaxis (beigel and sandrock ; hepburn et al. ; pittman et al. ; usamriid ) . botulinum neurotoxins (bont) are produced from the spore-forming, gram-positive, obligate anaerobe clostridium botulinum. it is the most potent toxin known to man. a lethal dose is ng per kilogram. it is , times more toxic than sarin (gb). there are seven serotypes of botulinum toxin (a through g). a new serotype (h) has been tentatively identified in a case of infant botulism but has not been fully investigated. most common are serotypes a, b, and e. the toxin acts on the presynaptic nerve terminal of the neuromuscular junction and cholinergic autonomic synapses. this disrupts neurotransmission and leads to clinical findings. there are three forms of botulism: foodborne, wound, and intestinal (infant or adult intestinal). botulinum toxin can also be released as an act of bioterrorism via ingestion or aerosol forms. incubation can be from h after exposure to several days later. clinical findings of botulism include cranial nerve palsies such as ptosis, diplopia, and dysphagia. this is followed by symmetric descending flaccid paralysis. however, the victim remains afebrile, alert, and oriented. death is typically due to respiratory failure. prolonged respiratory support is often required ( - months). differential diagnoses include guillain-barre syndrome, myasthenia gravis, tick paralysis, stroke, other intoxications (nerve gas, organophosphates), inflammatory myopathy, congenital and hereditary myopathies, and hypothyroidism. diagnosis is mostly clinical. laboratory confirmation can be obtained by bioassay of patient's serum. other assays include immunoassays for bacterial antigen, pcr for bacterial dna, and reverse transcriptase-pcr for mrna to detect active synthesis of toxin. cerebrospinal fluid demonstrates normal protein (unlike guillain-barre syndrome). emg reveals augmentation of muscle action potential with repetitive nerve stimulation at - hz. treatment (table . ) is mainly supportive including intubation and ventilator support. tracheostomy may be required due to prolonged respiratory weakness and failure. antibiotics do not play a role in treatment. botulism antitoxin heptavalent [a, b, c, d, e, f, g]-equine (bat) was approved by the fda in . bat was developed at usamriid as one of two equine-derived heptavalent bont antitoxins. bat is approved to treat individuals with symptoms of botulism following a known or suspected exposure. it has the potential to cause hypersensitivity reactions in those sensitive to equine proteins. the safety of bat in pregnant and lactating women is unknown. evidence regarding safety and efficacy in the pediatric population is limited. in , the fda approved botulinum immune globulin intravenous (babybig), a human botulism immune globulin derived from pooled plasma of adults immunized with pentavalent botulinum toxoid. it is indicated for the treatment of infants with botulism from toxin serotypes a and b. immediately after clinical diagnosis of botulism, adults (including pregnant women) and children should receive a single intravenous infusion of antitoxin (bat or, for infants with botulism from serotypes a or b, babybig) to prevent further disease progression. the administration of antitoxin should not be delayed for laboratory testing to confirm the diagnosis. the pentavalent toxoid vaccine (previously for protection against a, b, c, d, and e; but not f or g) is no longer available as of . no replacement vaccine is currently available. standard isolation precautions (table . ) should be followed (beigel and sandrock ; dembek et al. ; pittman et al. ; timmons and carbone ; usamriid ). ricin is a potent cytotoxin derived from the castor bean plant ricinus communis. it is related in structure and function to shiga toxins and shiga-like toxin of shigella dysenteriae and escherichia coli, respectively. it consists of two glycoprotein subunits, a and b, connected by a disulfide bond. the b-chain allows the toxin to bind to cell receptors and gain entrance into the cell. once ricin enters the cell, the disulfide chemical linkage is broken. the free a chain then acts as an enzyme and inactivates ribosomes thereby disrupting normal cell function. cells are incapable of survival and soon die. ricin has a high terrorist potential due to it characteristics: readily available, ease of extraction, and notoriety (maman and yehezkelli ) . three modes of exposure exist: oral, inhalation, and injection. four to eight hours after inhalation exposure, the victim develops fever, chest tightness, cough, dyspnea, nausea, and arthralgias. airway necrosis and pulmonary capillary leak ensues within - h. this is followed quickly by severe respiratory distress, ards, and death due to hypoxemia within - h. injection may cause minimal pulmonary vascular leak. pain at the site and local lymphadenopathy may occur. however, it may be followed by nausea, vomiting, and gastrointestinal hemorrhage. ingestion leads to necrosis of the gastrointestinal mucosa, hemorrhage, and organ necrosis (spleen, liver, and kidney). diagnosis is suspected when multiple cases of acute lung injury occur in a geographic cluster. serum and respiratory secretions can be checked for antigen using elisa. pulmonary intoxication is managed by mechanical ventilation. gastrointestinal toxicity is managed by gastric lavage and use of cathartics. activated charcoal has little value due to the size of ricin molecules. supportive care is indicated for injection exposure. in general, treatment is largely supportive, especially for pulmonary edema that can result from the capillary leak. there is no vaccine available or prophylactic antitoxin for human use. however, there are two ricin vaccines in the development that focus on the ricin toxin a (rta) chain subunit. a mutant recombinant rta chain vaccine, rivax, has been shown to be safe and immunogenic in humans. the other vaccine is another recombinant rta chain vaccine, rvec . it has shown effectiveness in animal models by producing protective immunity against aerosol challenge with ricin in animal models. standard precautions are advised for health care workers (pittman et al. ; roxas-duncan et al. ; traub ; usamriid ). recent events which include the nuclear reactor meltdown at fukushima and international tension between nuclear powers, spark concern over potential devastation from nuclear catastrophes. there are numerous examples of radiation disasters in history. sixty-six thousand people were killed in hiroshima and thirty-nine thousand people were killed in nagasaki from nuclear bombs detonated over these cities in (avalon project-documents in law, history and diplomacy n.d.). many other people suffered from long-term consequences of radiation poisoning. in , , square kilometers of land in russia, ukraine, and belarus were contaminated with radiation from a meltdown at a nuclear power plant in chernobyl, ukraine. one hundred and thirty-five thousand people were permanently evacuated from their homes (likhtarev et al. ) . long-term health consequences included many children who developed thyroid cancer several years later. many of these children died. a tsunami pummeled the east coast of japan in march of . the power outage that ensued at the fukushima power plant led to a failure of the cooling system of the fuel rods, leading to a meltdown of four of the reactors at the plant. a massive quantity of radiation was released into the atmosphere, forcing people to evacuate their homes indefinitely. creative thinking and heroic actions by the tokyo fire department prevented entire populations of cities from being poisoned with radiation. terrorism experts are concerned that terrorist organizations will produce and detonate a radiological dispersion device (rdd), sometimes referred to as a dirty bomb. this is a conventional explosive, loaded with radioactive material which would be dispersed upon detonation. this would likely involve only one radioisotope. fewer people would be exposed and a smaller area would be contaminated than what would transpire with the detonation of a nuclear weapon. spreading fear and panic would be the primary purpose of such a device (mettler jr and voelz ) . radiation is the emission and propagation of energy through space or through a medium in the form of waves. radiation can be ionizing or nonionizing depending on the amount of energy released. most radiation that people encounter is low energy and, therefore, nonionizing with no biological effects. ionizing radiation emits enough energy to strip electrons from an atom, which provokes cellular changes and thereby, results in biological effects. radiation emitted from nuclear decay is always ionizing (radiation emergency assistance center/training site (react/s-cdc) ). atomic nuclei are held together by a very powerful binding energy despite positively charged protons repelling each other. this energy is released from unstable nuclei in the form of electromagnetic waves or particles. when ionizing radiation reaches biological tissue, chemical bonds are disrupted, free radicals are produced, and dna is broken. electromagnetic waves are of two types, x-rays and gamma rays. x-rays are relatively low energy and less penetrating. gamma rays have a shorter wavelength and contain relatively higher energy, making them more penetrating of biological tissue. ionizing radiation in the form of particles consists of alpha particles, beta particles, and neutrons. alpha particles are the largest of the forms of particulate radiation. they are composed of two neutrons and two protons. they do not easily penetrate solid surfaces, including clothes and skin. however, they can cause severe damage to an organism if internalized. in , in the united kingdom, alexander litvienko, an ex kgb agent was poisoned with a radioactive element called polonium (mcphee and leikin ). a small amount of polonium was sprinkled into his food. polonium releases alpha particles when it decays. it was relatively safe for the assassin to carry this element with him because of the relatively poor ability of alpha particles to penetrate clothing and skin. once it is ingested, however, alpha particles have profound biological effects. mr. litvienko became very ill, and ultimately died. beta particles are high energy electrons discharged from the nucleus and are highly penetrating. neutrons emitted from a nucleus are also highly penetrating. in general, neutrons are only released by the detonation of a nuclear weapon. ionizing radiation of any form cannot be detected by our senses. it is not smelled, felt by touch, tasted, or seen. it is possible to be exposed to a lethal dose of radiation without realizing it. in goiania, brazil, in , children found a canister of radioactive cesium ( cs) that had been looted from a medical center and left in the street. the children liked the appearance of the substance but were not able to sense any abnormalities or danger with it. they began to rub it on their bodies because they liked the way it made them glow in the dark. the children all became ill. ultimately, people were exposed to this radioisotope. it took days before physicians recognized that the people had radiation poisoning. four people died of acute radiation syndrome. four factors determine the severity of exposure to ionizing radiation: time, distance, dose, and shielding. time is the time of exposure to the radiation source. distance is the distance from the radiation source. based on the inverse square law, exposure is reduced exponentially with increasing distance from the radiation source. dose is measured by the amount of energy released by the source and is numerically described by how many disintegrations per second occur, in curies (ci) or becquerels (bq). shielding is the efficacy of the barrier to the radioactive source. lead is well-known to be a very effective shield to x-rays. in a radiation exposure, injury to skin from trauma or burns may cause a greater degree of contamination because of loss of the shielding of the skin. there are four important principles for the nurse or hcp to understand with regard to exposure to ionizing radiation: external exposure, external contamination, internal contamination, and incorporation. external contamination occurs when radioactive material is carried on a person after exposure. this person can then contaminate others. removing contaminated clothing eliminates % of the toxin. others are then less vulnerable to exposure. internal contamination is when a radioactive substance enters the body through inhalation, ingestion, or translocation through open skin. incorporation is internalization of the toxin into body organs. incorporation is dependent on the chemical and not the radiological properties of the radioactive toxin. radioactive iodine, i, is taken up by the thyroid gland because iodine enters the gland as part of normal physiology (advanced hazmat life support (ahls) ). ionizing radiation can damage chromosomes directly and indirectly, causing ravaging biological effects. indirect damage comes from the production of h + and oh − . free radical formation upsets biochemical processes and causes inflammation. these effects can take anywhere from seconds to hours to be expressed. clinical changes can take from hours to years to be realized (zajtchuk et al. ). immediately after a major radiation exposure, the clinical matters of most concern are those related to trauma from blast and thermal injuries. these injuries may be life-threatening and must be addressed first. after thermal and traumatic injuries are addressed, attention should be paid to the severity of radiation exposure. severe exposure can cause acute radiation syndrome. "the acute radiation syndrome is a broad term used to describe a range of signs and symptoms that reflect severe damage to specific organ systems and that can lead to death within hours or up to several months after exposure" (national council on radiation protection (ncrp) and measurements ; national council on radiation protection (ncrp) and measurements ). the mechanism of cell death from toxic radiation exposure is related to the inhibition of mitosis. organs with the most rapidly dividing cells are the most susceptible. the gastrointestinal and the hematopoietic are the organ systems most notably affected. the organs of pediatric patient have a higher mitotic index, in general, to those of adults and are more vulnerable to injury from radiation poisoning. the time of onset and the severity of acute radiation syndrome are controlled by the total radiation dose, the dose rate, percent of total body exposed, and associated thermal and traumatic injuries. there is a % death rate (ld ) within days for people exposed to a dose of radiation of . - . gy. the ld is lower for the pediatric population. the acute radiation syndrome is composed of four phases: prodromal, latent, manifest illness, and death or recovery. inflammatory mediator release during the prodromal phase causes damage to cell membranes. this phase occurs during the first h after exposure to radiation. nausea and vomiting and fever can occur during this time. if these symptoms occur during the first h after exposure, there is a poor prognosis. the onset of the latent phase is usually in the first days post exposure but can ensue anytime during the first days thereafter. all cell lines of the hematopoietic system are affected. lymphocytes and platelets, the most rapidly dividing cells of the bone marrow, are most severely affected. the illness phase manifests after days since radiation exposure. infection, impaired wound healing, anemia, and bleeding occur during this time of illness. the hematopoietic, gastrointestinal, central nervous, and integumentary are the organ systems affected. there is a marked reduction of cells from all cell lines of the bone marrow. there is a direct correlation with the drop in absolute lymphocyte count with the dose of radiation received. the absolute lymphocyte count is commonly used to estimate the dose of radiation received. the gastrointestinal (gi) epithelial lining, one of the most rapidly dividing cell lines of the body is the second most vulnerable to radiation poisoning. the radiation dose required to affect the gi system is gy. vomiting, diarrhea, and a capillary leak syndrome for gi tract are common manifestations. hypovolemia and electrolyte instability ensue. translocation of bacteria into the bloodstream, combined with the diminished immunity caused by the decimation of the hematopoietic system, place victims at high risk for septic shock. another organ system affected by the acute radiation syndrome is the central nervous system. this requires a large dose of at least gy. manifestations include cerebral edema, disorientation, hyperthermia, seizures, and coma. acute radiation syndrome that involves the central nervous system is always fatal. the integumentary system is frequently affected by the acute radiation syndrome, especially if the skin is in direct contact with a radioisotope. epilation, erythema, dry desquamation, wet desquamation, and necrosis occur respectively with increasing severity associated with increasing doses of radiation. radiation burns can be distinguished from thermal or chemical burns by their delayed onset. it can take days to weeks for radiation burns to affect victims. thermal and chemical burns cause signs and symptoms more acutely. hospitals that anticipate victims of radiation should prepare areas of triage with decontamination supplies and techniques ready to be deployed. an emergency department (ed) should be divided into "clean" and "dirty" areas. the dirty area is created for the purpose of decontamination to prevent the spread of radioisotopes. all health care personnel should wear ppe including surgical scrubs and gowns, face shields, shoe covers, caps, and two pairs of gloves. the inner pair of gloves is taped to the sleeves of the gown. each health care worker should be monitored for the exposure of the radiation and its dose with a dosimeter worn underneath the gown. the radiation safety officer of the hospital should take a leadership role in health care worker protection and decontamination procedures. consultation from the radiation emergency, assistance center (react/ts) is imperative. react/ts is a subsidiary of the u.s. department of energy. its contact information is as follows: phone number during business hours is - - . the phone number is - - after business hours. the react/ts website is http://orise.orau. gov/reac/ts/. as victims arrive, triage protocols of mass casualty scenarios should be implemented. it should be noted that radiation exposure is not "immediately" lifethreatening. initial clinical management should focus on the abcde (airway, breathing, circulation, disability, and exposure) of basic trauma protocol. the "d" in the above acronym can also be a symbol for decontamination. after airway, breathing, and circulation are addressed, initial phase of decontamination entails careful removal of potentially contaminated clothing. caution should be exercised to remove the clothing gently, while rolling garments outward to prevent the release of dust of radioactive material that could contaminate people in the treatment area. further decontamination procedures take place after initial stabilization. skin decontamination procedures are identical to those of toxic chemical exposure with the following exceptions: • ppe are slightly different as described above. • gentle skin rubbing is done to prevent provocation of an inflammatory response and further absorption of the radioactive toxin. • only soap and water are used. rubbing alcohol and bleach should be avoided. it is advisable to shampoo the hair first, because it is usually the site of the highest level of contamination of the body, and runoff onto the body can then be cleansed during skin decontamination (radiation event medical management (remm) of the u.s. dept. of health and human services n.d.). it should be noted that health care workers are not at risk for contamination if they wear proper ppe during the resuscitation and decontamination process. the lack of knowledge of this point may lead to reluctance to treat patients and increase morbidity and mortality for victims. "no hcp has ever received a significant dose of radiation from handling, treating, and managing patients with radiation injuries and/or contamination."(react/s-cdc ). when initial resuscitation and decontamination have been completed, attention should be paid to ongoing support of ventilation, oxygenation, the management of fluid and electrolytes, and treatment of traumatic and burn injuries. infection control procedures are important due to the impending immunocompromised state of the victims. it is important to ascertain the details of the catastrophic event. data on the nature and size of the exposure and the types of radioactive agents involved are vital for ongoing management and decontamination. after the details of the nature of the exposure are uncovered, diagnostic tests should be done, including serial cbc and cytogenetic analysis of lymphocytes, otherwise known as cytogenic dosimetry (react/s-cdc ). measurements of change in lymphocyte counts and cytogenetic dosimetry are sensitive markers for the dose of radiation received by a victim. measurements of internal decontamination are done by the sampling and analysis of nasal and throat swabs, stool, and h urine. wound samples and irrigation fluid should also be sampled. after initial stabilization, external decontamination, and diagnostic testing, internal decontamination is performed. external decontamination involves removal of clothes and cleaning the skin and hair. internal decontamination removes radioisotopes that are internalized via inhalation, ingestion, and entry into open wounds. because ionizing radiation is being released inside the body, internal decontamination must be performed promptly after initial resuscitation. since radioisotopes behave identically to their nonradioactive counterparts, antidotes are chosen based on the chemical, and not the radiological properties of the element. basic strategies of internal decontamination include chelation, competitive inhibition, enhanced gastrointestinal elimination, and enhanced renal elimination. specific agents are used for chelation of different radioisotopes. dtpa (diethyenetriaminepentaacetic acid) is administered for the elimination of heavy metals such as americium, californium, curium, and plutonium. dtpa comes in two forms, calcium dtpa (ca-dtpa) and zinc-dtpa (zn-dtpa). ca-dtpa is ten times more effective than zn-dtpa. for adults and adolescents, administration is as follows: • g of ca-dtpa iv initially in the first h, followed by g zn-dtpa iv daily for maintenance. • for children less than years of age administer: • fourteen mg/kg ca-dtpa iv initially, followed by fourteen mg/kg of zn-dtpa iv daily thereafter (national council on radiation protection (ncrp) and measurements ). • the initial dose of dtpa may be administered via inhalation to adolescents and adults if the contamination occurred via inhalation. this method of administration is not approved for pediatric use. chelation with dimercaprol (bal) is used to eliminate polonium. bal is a highly toxic drug and should be administered with caution. the dose is . mg per kg im four times a day for days, then twice a day on the third day and once a day for - days, thereafter (national council on radiation protection (ncrp) and measurements ). alkalinization of the urine is renal protective during administration. a less toxic alternative to bal, dimercaptosuccinic acid (dmsa), otherwise known as chemet ® is also available. the dose of dmsa is ten mg per kg po every h for days. the same dose is given every h for days, thereafter (national council on radiation protection (ncrp) and measurements ). another mechanism for internal decontamination is competitive inhibition. the radioisotope, i, is released during a meltdown of a reactor at a nuclear power plant. potassium iodide (ki) is widely recognized as a competitive inhibitor to its radioactive counterpart, i, from being incorporated into the thyroid gland. ki blocks % of i uptake into the thyroid gland if ki is given within the first hour of exposure. it will block % of incorporation if given within h of exposure. its protective effect lasts for h. with administration of this drug, thyroid function should be monitored closely. dosing guidelines (table . ) are included in the table below (u.s. food and drug administration n.d.). gastrointestinal elimination is another mechanism of internal decontamination (table . ). an ion exchanger, prussian blue, (ferric ferrocyanide), binds elements that circulate through the enterohepatic cycle. since it is not absorbed through the gastrointestinal tract, prussian blue carries the toxins into the stool. it is highly effective in the elimination of cs or thallium and was used during the cs incident in goiania, brazil. the dosing of prussian blue is as follows: • infants: . - . mg per kg po three times a day (not fda approved). • children - years of age: g po three times a day. • children ≥ years of age: g po three times a day. • prussian blue is administered for at least days, and can be adjusted based on the degree of poisoning (national council on radiation protection (ncrp) and measurements ). urinary elimination is another useful method of internal decontamination. tritium can be eliminated with excess fluid administration. uranium is eliminated by alkalinizing the urine to a ph of - . sodium bicarbonate is given at a dose of meq/kg iv every - h and is titrated to effect. if renal injury occurs, dialysis may be required. the basic approach to treating acute radiation syndrome is supportive therapy. gi losses from gastrointestinal difficulties are treated with iv fluids and electrolyte replacement. -ht antagonists can be used to suppress vomiting and benzodiazepines for anxiety. a patient suffering from acute radiation syndrome may be severely immunocompromised and requires a room with positive pressure isolation. colony stimulating agents for granulocytes and erythrocytes can be used for bone anemia and leukopenia. bone marrow transplant may be required for severe cases. a patient with skin contamination with radiation should be decontaminated with soap and water. a geiger counter can be helpful to identify areas of contamination. scrubbing is performed in a concentric matter, beginning at the outer layers of contamination and moving into the center since the area of greatest contamination is in the center. in this way, the area of contamination remains contained. attention should be paid to good nutrition and pain control. burn and plastic surgery service should also be consulted. more details on decontamination can be found in chap. . the psychological impact of a radiation catastrophe on the pediatric victims is likely to be devastating (american academy of pediatrics (aap) ). sleep disturbances, social withdrawal, altered play, chronic fear and anxiety, and developmental regression can occur. a correlation between the parent's psychological response and that of the child would occur as with other types of disaster. mental health professionals should be consulted in the event of this type of situation. please refer to chap. for more information. a lot of concern has been expressed over the possibility of terrorist attacks involving explosive devices in recent years (depalma et al. ) . explosive devices are relatively simple to manufacture and easy to detonate. they can injure and kill many people and spread fear over large populations. victims of bomb blasts sustain more body regions injured, have more body injury severity scores, and require more surgeries than victims of nonexplosive trauma incidents. victims of explosives also have a higher mortality (kluger et al. ) . these observations are also true of pediatric victims (daniel-aharonson et al. ) . many factors influence the number of people injured and the severity of the injuries in an explosion. the magnitude of the explosion and its proximity to people and the number of people in the area affect the severity and number of injuries. other factors include the collapse of building or structure from the blast, promptness of the rescue operation, and the caliber and proximity of medical resources in the vicinity. victims who experience explosions in closed spaces are especially vulnerable to more severe injuries. twenty-nine case reports of injuries from terrorist bombings were reviewed (arnold et al. a) . the investigators compared the injury severity of victims of explosions who sustained injuries from structural collapse, closed space explosions without structural collapse, and open space explosions. the mortality rate for these victims was %, %, and %, respectively. hospitalization rates were %, %, and %, respectively. ed visits were %, %, and %, respectively. victims of closed space explosions without structural collapse experienced greater hospitalizations rates than those involved in a structural collapse, because many of the victims involved in the structural collapse experienced immediate death. an explosion is defined as a rapid chemical conversion of a liquid or solid into a gas with energy release. substances that are chemically predisposed to explosion, called explosives, are characterized as low or high order, depending on the speed and magnitude of energy release. low-order explosives release energy at a relatively slow pace and explosions from these substances tend not to produce large air pressure changes or a "blast." the energy release is caused by combustion, producing heat. the involved material "goes up in flames." gunpowder, liquid fuel, and molotov cocktails are examples of low-order explosives (centers for disease control and prevention ). explosions from high-order materials cause a blast with a pressure wave in addition to causing the release of heat and light. the blast pressure wave causes compression of the surrounding medium which is physically transformed in all directions from the exact point of explosion. when an explosion occurs on land, air is the surrounding medium compressed. in bodies of water, the surrounding medium is water. the degree of medium compression and the distance that the energy wave travels is determined by the magnitude of the explosion. the power of the blast is measured in pounds per square inch (psi). the pressure blast wave has distinctive characteristics. the amplitude of the wave reaches its highest point immediately after the blast. the blast wave then rapidly decays as it travels through space. as the blast wave propagates, and compresses the surrounding medium, it leaves a vacuum because of displaced molecules in the surrounding medium and a negative phase of the wave ensues. in a land explosion, air molecules are displaced by the initial positive pressure, after which a negative pressure occurs in the vacated space. a wave that propagates through a confined space rebounds off of the wall and reverberates. it may interact with victims in the confined space many times, causing more severe injuries (stuhmiller et al. ) (fig. . ). four kinds of injury occur in high energy explosions. primary blast injuries occur directly from the pressure wave of the blast. secondary injuries occur from being struck by flying objects from the blast. these injuries can be blunt or penetrating. tertiary injuries occur when victims are displaced from a location and strike other objects or surfaces. all other injuries related to the blast are called quarternary. they include burns, inhalational injuries, toxic exposures, and traumatic injuries from structural collapse. primary injuries from blast waves affect bodily tissues with a tissue gas interface. when a pressure wave enters the body, tissue of gas filled organs compress slower than the air inside the tissue, causing stress in the tissue, possibly damaging it. this baseline positive phase originally described by friedlander, a blast wave consists of a short, high-amplitude overpressure peak followed by a longer depression phase. injury potential depends on the wave's amplitude as well as the slopes of its increase and decrease in pressure. x-axis refers to time and y-axis refers to pressure. (jacobson and severin ) also known as the "spalling effect." as the negative pressure phase of the blast wave propagates through, it causes more stress on the tissue and further damage. in addition to damaging tissues with an air tissue interface, pressure blasts can cause injury to the brain and can lead to limb detachments. despite the fact that primary blast injuries can be ravaging, they are less common than other types of injury from blasts. the tympanic membranes, lungs, and gastrointestinal tract are the most common organs sustaining injury from pressure waves. the tympanic membrane is the most vulnerable of these three organ systems (depalma et al. ; garth ) . five psi, which is considered a weak blast, will rupture % of tympanic membranes. to put this in perspective, c , a commonly used explosive generates a pressure of four million psi. otoscopy can reveal ruptured tympanic membranes. neuropraxia, deafness, tinnitus, and vertigo are symptoms that can be experienced. severe blast injuries of the ear can result in damage to the organ of corti, resulting in permanent hearing loss. the second most common organ injured from a blast wave is the lung. fifteen psi are required to cause injury to this organ. lung injuries are more likely to occur from a blast within a closed space, or when victims sustain burns (burns commonly cause acute lung injury from release of inflammatory mediators). direct alveolar damage, blood vessel with bleeding, and inflammation are the three different manifestations of lung injury from blasts. alveolar damage can cause pneumothorax and pulmonary interstitial emphysema. when air dissects along the bronchovascular sheath, pneumomediastinum, pneumopericardium, and subcutaneous emphysema can occur. air that enters the pulmonary venous system can result in a systemic arterial air embolism, and possibly, a stroke. inflammation of the lungs from direct pressure damage to the tissue, cause acute lung injury and possibly, disseminated intravascular coagulation. clinical signs of lung injury include tachypnea, chest pain, hypoxia, rales, and dyspnea. if there is vascular disruption, hemoptysis can occur. air leaks from alveolar injury can result in diminished breath sounds, subcutaneous crepitance, increased resonance, and tracheal deviation. hemodynamic compromise will occur with tracheal deviation. alveolar damage, leading to air in the pulmonary venous system, can lead to a systemic arterial air embolism. air in the coronary arteries can lead to coronary ischemia with st and/or t waves changes on ecg. air embolism to cerebral arteries leads to cerebral vascular accidents (strokes) with focal neurological deficits. other manifestations of systemic air embolism include mottling of the skin, demarcated tongue blanching, and/or air in the retinal vessels (the most common sign of arterial air embolus). rapid death after initial survival is most often caused by arterial air embolus. initiation of positive pressure ventilation may trigger this event (ho and ling ) . a lung injury from a blast can also precipitate a vagal reflex resulting in bradycardia and hypotension. it is postulated that this occurs from the stimulation of c fibers in the lungs (guy et al. ). the gastrointestinal system is the third most common organ system affected by primary blast injury. physical stress and/or mesenteric infarct leads to weakening of the bowel wall with possible rupture. hemorrhage can also occur (paran et al. ; sharpnack et al. ) . the most common site of injury is the colon. injury to the bowel can be delayed and occur up to several days after the inciting incident. solid organs are spared because of their homogeneity and lack of air tissue interface. brain injury is becoming increasingly recognized as a result of primary blast. shearing injuries of the brain occur as a result of wave reverberation in the skull. hippocampal injury causing cognitive impairment has been shown in animal studies (cernak ; cernak et al. ; singer et al. ) . observations in humans have revealed electroencephalographic abnormalities and attention deficit disorder (born ) . human autopsies have revealed punctate hemorrhages and disintegration of nissl substance in victims who sustained blast injury without direct head trauma (guy et al. ) . research involving yucatan minipigs revealed that the brain sustains neuronal loss in the hippocampus after being subjected to primary blast injury. brain injury also occurred from the inflammation that ensued post blast (goodrich et al. ) . novel therapeutic approaches may be on the horizon for treatment of traumatic brain injury, including that caused by primary blast. intranasal insulin administered to rats subjected to traumatic brain injury resulted in enhanced neuronal glucose uptake and utilization, and subsequently improved motor function and memory. decreased neuroinflammation and preservation of the hippocampus were also noted (brabazon et al. ) . in a different investigation, a neuroprotective nucleotide, guanosine, was administered to rats subjected to traumatic brain injury. the treatment group of rats had better locomotor and cognitive outcomes than did the placebo group. programmed cell death and inflammation were also attenuated in the treatment group (gerbatin et al. ) . the leading cause of death from blast is from flying objects striking victims (secondary blast injury). eyes are particularly vulnerable. injuries resulting from displacement of the victims who strike objects are known as tertiary injuries. lighter weight children are particularly susceptible to this type of injury. burns, toxic exposures, and crush injuries constitute quaternary injuries. crush injuries commonly occur in explosions with structural collapse. the "crush syndrome" can occur when a trapped limb sustains prolonged compromise to the circulation, leading to rhabdomyolysis. tissue destruction and inflammatory response then occur. lifethreatening electrolyte abnormalities including hyperkalemia, renal failure, hyperuricemia, metabolic acidosis, acute respiratory distress syndrome, disseminated intravascular coagulation, and shock can result from crush syndrome (gonzalez ) . the crush syndrome is commonly seen in natural disasters that result in a lot of structural collapse. structural collapse and fires can cause the release of toxic materials such as carbon monoxide and cyanide. knowledge of the details of a blast can greatly enhance the ability of nurses and hcps to care for victims of a blast in a hospital setting. knowledge of whether a blast occurred in a closed or open space, whether structural collapse occurred, or if a victim was rescued from a collapsed area are details that can alert nurses and hcps as to what kind of injuries that they may anticipate. if toxic substances are released with a blast, nurses and hcps can prepare for decontamination techniques and antidote therapies. it would be advantageous for a hospital to be aware of the number of victims that are arriving for care. a mass casualty incident will stress the resources of the institution. hospital personnel should take stock of the resources that are available. the number of available ventilators and o-blood are examples of finite resources that should be considered. advanced trauma life support (atls) principles should be applied to all blast injury victims. abcd of initial resuscitation is applied. the "d" stands for disability as well as decontamination. decontamination techniques should be deployed if there is uncertainty about toxic exposure as described elsewhere in this chapter. on completion of abcd of initial resuscitation a secondary survey is performed, as described by atls protocol. attention should be paid to potential injuries that occur with blast injuries. ruptured tympanic membranes should alert the nurse or hcp of problems from primary blast injury. impaled objects should remain in place and removed in the operating room by surgical staff so that bleeding may be controlled. a thoracoscopy tube should be placed with an open three point seal over a wound on the side of the chest with an open pneumothorax. a hemothorax is also treated with a thoracoscopy tube. an autotransfusion setup can be applied to recirculate the blood from the pleural cavity of a hemothorax (wightman and gladish ) that would help preserve donor blood for other victims. for severe respiratory distress and/or impending respiratory failure, endotracheal intubation should be performed and positive pressure ventilation should be instituted. because lung tissue could be weakened from primary blast injury, caution should be exercised because of a high risk of pneumothorax, hemorrhage, or arterial air embolus. gentle application of positive pressure ventilation should be applied to avoid these complications. if only one lung is injured unilateral lung ventilation can be considered for larger children and adults. this technique is not suitable for babies and small children. supplemental oxygen with an fio of % should be administered to patients suspected of having an arterial air embolus. hyperbaric oxygen therapy could even be considered to help accelerate the removal of air from the arteries. placement of the patient in the left lateral recumbent position may reduce the likelihood of the air lodging in the coronary arteries. victims of blast injuries should be treated identically to those of other types of trauma after initial resuscitation is completed. if primary blast injury occurred, frequent chest and abdominal x-rays should be performed in consideration of the possibility of lung or gastrointestinal injuries. limbs with open fractures should be immobilized and covered with sterile dressings. systemic, broad spectrum antibiotics should be administered to patients with open limb injuries. eyes that sustained chemical injury should be irrigated with water for an hour. all injured eyes should be covered. most ruptured tympanic membranes will heal spontaneously. victims with tympanic membrane injury should be advised to avoid swimming for some time. topical antibiotics are prescribed if dirt or debris is seen in the ear canal. oral prednisone is prescribed for hearing loss. victims with crush injuries should be treated with large volumes of iv fluids to treat inflammatory shock and possibly rhabdomyolysis. electrolytes should be monitored carefully as these patients are at risk for hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and acidosis. smoke inhalation, burns, and toxic exposures should be treated according to guidelines of burn, trauma, and toxicology protocols. mass casualty incidents (i.e. mass shootings, active shooter events, bombings, and other multifatality crimes) often attract extensive media coverage as well as the attention of policy makers. many agencies and organizations record and publish data on these incidents. the measurement and reporting does vary based on the absence of a common definition. however, it is clearly evident that mass casualty incidents (mcis) continue to increase in both number and scope (federal bureau of investigation ; office for victims of crime, office of justice programs, u.s. department of justice ). in the u.s., mass shootings are the most common and most closely tracked. the congressional research service (crs) defines mass shootings as events where more than four people are killed with a firearm "within one event, and in one or more locations in close proximity." congress uses the term mass killings and describes these events as "three or more killings in a single incident." the federal bureau of investigation (fbi) uses the term active shooter, which it defines as "an individual actively engaged in killing or attempting to kill people in a populated area." it is important to realize that nongovernmental ( ranking third of all locations for and , seven of the incidents occurred in educational environments resulting in five killed and wounded. two incidents occurred in elementary schools, resulting in two killed (including a firstgrade student) and eight wounded (one teacher shot, three students shot, and four wounded from shrapnel). one incident occurred in a junior/senior high school, resulting in none killed and four wounded (two from shrapnel, all students). four incidents occurred at high schools (one outside a school during prom), resulting in three killed (all students) and seven wounded (all students). fortunately, no incident occurred at institutions of higher learning during or (advanced law enforcement rapid response training (alerrt) center, texas state university and federal bureau of investigation, u.s. department of justice ). notably, two of the incidents occurred in houses of worship, resulting in killed and wounded. one of these incidents occurred at the first baptist church in sutherland springs, texas, and had the third highest number of casualties ( killed and wounded) in . the dead included women, men, children ( girls and boy), and an unborn child (goldman et al. ) . a summary report has also been developed for all active shooter incidents from to , including incidents per year (fig. . ), casualties per year (fig. . ) , and location ( fig. . ) categories (federal bureau of investigation ; federal bureau of investigation ). overall, there was an increase in number of active shooter incidents and casualties per year. location categories with number of incidents and statistics of their contribution were provided: areas of educational environments account for a large portion of locations for active shooter incidents, ranking only second to commercial areas. of the incidents ( . %) occurring at schools, one took place at a nursery (pre-k) school and one incident occurred during a school board meeting that was being hosted on school property but no students were involved (neither perpetrator or victim). the remainder ( incidents) were perpetrated by or against students, faculty, and/or staff at k- schools (federal bureau of investigation ). finally, active shooter incidents ( %) did occur at institutions of higher learning. as a reminder, no incident occurred at institutions of higher learning during or . table . provides a detailed summary of educational environment incidents from to . since the beginning of , other tragic active shooter attacks have occurred in the u.s. and greatly impacted children and adolescents. two of these such events have occurred in educational environments (united states secret service national threat assessment center ). on february , , a gunman opened fire at marjory stoneman douglas high school. fourteen students and three staff members were killed while fourteen others were injured (follman et al. ) . twelve victims died inside the building, three died just outside the building on school premises, and two died in the hospital. the shooter was a former student of the school. another active shooter event occurred on may , at santa fe high school in santa fe, texas. the shooter killed ten individuals including eight students and two teachers while injuring others. the shooter was an enrolled student at the school (follman et al. ) . based on the statistics of active shooter incidents, casualties, and locations, it is vital to prepare schools and plan for such events. national preparedness efforts, including planning, are now informed by the presidential policy directive (ppd) that was signed by the president in march and describes the nation's approach to preparedness. this directive represents an evolution in our collective understanding of national preparedness based on the lessons learned from terrorist attacks, hurricanes, school incidents, and other experiences. ppd- defines preparedness around five mission areas and can be applied to school active shooter incidents. on march , , at : p.m., jeffery james weise, , armed with a shotgun and two handguns, began shooting at red lake high school in red lake, minnesota. before the incident at the school, the shooter fatally shot his grandfather, who was a police officer, and another individual at their home. he then took his grandfather's police equipment, including guns and body armor, to the school. a total of nine people were killed, including an unarmed security guard, a teacher, and five students; six students were wounded. the shooter committed suicide during an exchange of gunfire with police campbell county comprehensive high school (education) on november , , at : p.m., kenneth s. bartley, , armed with a handgun, began shooting in campbell county comprehensive high school in jacksboro, tennessee. before the shooting, he had been called to the office when administrators received a report that he had a gun. when confronted, he shot and killed an assistant principal and wounded the principal and another assistant principal. the shooter was restrained by students and administrators until police arrived and took him into custody pine middle school (education) on march , , at : a.m., james scott newman, , armed with a handgun, began shooting outside the cafeteria at pine middle school in reno, nevada. no one was killed; two were wounded. the shooter was restrained by a teacher until police arrived and took him into custody essex elementary school and two residences (education) on august , , at : p.m., christopher williams, , armed with a handgun, shot at various locations in essex, vermont. he began by fatally shooting his ex-girlfriend's mother at her home and then drove to essex elementary school, where his ex-girlfriend was a teacher. he did not find her, but as he searched, he killed one teacher and wounded another. he then fled to a friend's home, where he wounded one person. a total of two people were killed; two were wounded. the shooter also shot himself twice but survived and was apprehended when police arrived at the scene orange high school and residence (education) on august , , at : p.m., alvaro castillo, , armed with two pipe bombs, two rifles, a shotgun, and a smoke grenade, began shooting a rifle from his vehicle at his former high school, orange high school in hillsborough, north carolina. he had fatally shot his father in his home that morning. one person was killed; two were wounded. the shooter was apprehended by police weston high school (education) on september , , at : a.m., eric jordan hainstock, , armed with a handgun and a rifle, began shooting in weston high school in cazenovia, wisconsin. one person was killed; no one was wounded. the shooter was restrained by school employees until police arrived and took him into custody west nickel mines school (education) on october , , at : a.m., charles carl roberts, iv, , armed with a rifle, a shotgun, and a handgun, began shooting at the west nickel mines school in bart township, pennsylvania. after the shooter entered the building, he ordered all males and adults out of the room. after a -min standoff, he began firing. the shooter committed suicide as the police began to breach the school through a window. five people were killed; five were wounded on april , , at : a.m., su nam ko, aka one l. goh, , armed with a handgun, began shooting inside oikos university in oakland, california. he then killed a woman to steal her car. seven people were killed; three were wounded. the shooter was arrested by police later that day on august , , at : a.m., robert wayne gladden jr., , armed with a shotgun, shot a classmate in the cafeteria of perry hall high school in baltimore, maryland. the shooter had an altercation with another student before the shooting began. he left the cafeteria and returned with a gun. no one was killed; one person was wounded. the shooter was restrained by a guidance counselor before being taken into custody by the school's resource officer sandy hook elementary school and residence (education) on december , , at : a.m., adam lanza, , armed with two handguns and a rifle, shot through the secured front door to enter sandy hook elementary school in newtown, connecticut. he killed students and six adults, and wounded two adults inside the school. prior to the shooting, the shooter killed his mother at their home. in total, people were killed; two were wounded. the shooter committed suicide after police arrived taft union high school (education) on january , , at : a.m., bryan oliver, , armed with a shotgun, allegedly began shooting in a science class at taft union high school in taft, california. no one was killed; two people were wounded. an administrator persuaded the shooter to put the gun down before police arrived and took him into custody new river community college, satellite campus (education) on april , , at : p.m., neil allen macinnis, , armed with a shotgun, began shooting in the new river community college satellite campus in the new river valley mall in christiansburg, virginia. no one was killed; two were wounded. the shooter was apprehended by police after being detained by an off-duty mall security officer as he attempted to flee santa monica college and residence (education) on june , , at : a.m., john zawahri, , armed with a handgun, fatally shot his father and brother in their home in santa monica, california. he then carjacked a vehicle and forced the driver to take him to the santa monica college campus. he allowed the driver to leave her vehicle unharmed but continued shooting until he was killed in an exchange of gunfire with police. five people were killed; four were wounded sparks middle school (education) on october , , at : a.m., jose reyes, , armed with a handgun, began shooting outside sparks middle school in sparks, nevada. a teacher was killed when he confronted the shooter; two people were wounded. the shooter committed suicide before police arrived arapahoe high school (education) on december , , at : p.m., karl halverson pierson, , armed with a shotgun, machete, and three molotov cocktails, began shooting in the hallways of arapahoe high school in centennial, colorado. as he moved through the school and into the library, he fired one additional round and lit a molotov cocktail, throwing it into a bookcase and causing minor damage. one person was killed; no one was wounded. the shooter committed suicide as a school resource officer approached him berrendo middle school (education) on january , , at : a.m., mason andrew campbell, , armed with a shotgun, began shooting in berrendo middle school in roswell, new mexico. a teacher at the school confronted and ordered him to place his gun on the ground. the shooter complied. no one was killed; were wounded: students and an unarmed security guard. the shooter was taken into custody (continued) on june , , at : p.m., aaron rey ybarra, , armed with a shotgun, allegedly began shooting in otto miller hall at seattle pacific university in seattle, washington. he was confronted and pepper sprayed by a student as he was reloading. one person was killed; were wounded. students restrained the shooter until law enforcement arrived reynolds high school (education) on june , , at : a.m., jared michael padgett, , armed with a handgun and a rifle, began shooting inside the boy's locker room at reynolds high school in portland, oregon. one student was killed; teacher was wounded. the shooter committed suicide in a bathroom stall after law enforcement arrived marysville-pilchuck high school (education) on october , , at : a.m., jaylen ray fryberg, , armed with a handgun, began shooting in the cafeteria of marysville-pilchuck high school in marysville, washington. four students were killed, including the shooter's cousin; students were wounded, including one who injured himself while fleeing the scene. the shooter, when confronted by a teacher, committed suicide before law enforcement arrived florida state university (education) on november , , at : a.m., myron may, , armed with a handgun, began shooting in strozier library at florida state university in tallahassee, florida. he was an alumnus of the university. no one was killed; were wounded. the shooter was killed during an exchange of gunfire with campus law enforcement. umpqua community college (education) on october , , at : a.m., christopher sean harper-mercer, , armed with several handguns and a rifle, began shooting classmates in a classroom on the campus of umpqua community college in roseburg, oregon. nine people were killed; were wounded. the shooter committed suicide after being wounded during an exchange of gunfire with law enforcement. madison junior/ senior high school (education) on february , , at : a.m., james austin hancock, , armed with a handgun, allegedly began shooting in the cafeteria of madison junior/senior high school in middletown, ohio. he shot two students before fleeing the building. no one was killed; four students were wounded (two from shrapnel). the shooter was apprehended near the school by law enforcement officers antigo high school (education) on april , , at : p.m., jakob edward wagner, , armed with a rifle, began shooting outside a prom being held at his former school, antigo high school in antigo, wisconsin. two law enforcement officers, who were on the premises, heard the shots and responded immediately. no one was killed; two students were wounded. the shooter was wounded in an exchange of gunfire with law enforcement officers and later died at the hospital townville elementary school (education) on september , , at : p.m., jesse dewitt osborne, , armed with a handgun, allegedly began shooting at the townville elementary school playground in townville, south carolina. prior to the shooting, the shooter, a former student, killed his father at their home. two people were killed, including one student; three were wounded, one teacher and two students. a volunteer firefighter, who possessed a valid firearms permit, restrained the shooter until law enforcement officers arrived and apprehended him on january , , at : a.m., ely ray serna, , armed with a shotgun, allegedly began shooting inside west liberty salem high school, in west liberty, ohio, where he was a student. after assembling the weapon in a bathroom, the shooter shot a student who entered, then shot at a teacher who heard the commotion. the shooter shot classroom door windows before returning to the bathroom and surrendering to school administrators. no one was killed; two students were wounded. school staff members subdued the shooter until law enforcement arrived and took the shooter into custody freeman high school (education) on september , , at : a.m., caleb sharpe, , armed with a rifle and a pistol, allegedly began shooting at freeman high school in rockford, washington, where he was a student. one student was killed; three students were wounded. a school employee confronted the shooter, ordered him to the ground, and held him there until law enforcement arrived and took him into custody rancho tehama elementary school and multiple locations in tehama county, california (education) on november , , at : a.m., kevin janson neal, , armed with a rifle and two handguns, began shooting at his neighbors, the first in a series of shootings occurring in rancho tehama reserve, tehama county, california. after killing three neighbors, he stole a car and began firing randomly at vehicles and pedestrians as he drove around the community. after deliberately bumping into another car, the shooter fired into the car and wounded the driver and three passengers. the shooter then drove into the gate of a nearby elementary school. he was prevented from entering the school due to a lockdown, so he fired at the windows and doors of the building, wounding five children. upon fleeing the school, the shooter continued to shoot at people as he drove around rancho tehama reserve. law enforcement pursued the shooter; they rammed his vehicle, forced him off the road, and exchanged gunfire. the shooter's wife's body was later discovered at the shooter's home; the shooter apparently had shot and killed her the previous day. in total, five people were killed; were wounded, eight from gunshot injuries (including one student) and six from shrapnel injuries (including four students). the shooter committed suicide after being shot and wounded by law enforcement during the pursuit aztec high school (education) on december , , at approximately : a.m., william edward atchison, , armed with a handgun, began shooting inside aztec high school in aztec, new mexico. the shooter was a former student. two students were killed; no one was wounded. the shooter committed suicide at the scene, before police arrived a in a study of active shooter incidents in the united states between and , the fbi identified locations where the public was most at risk during an incident. these location categories include commercial areas (divided into business open to pedestrian traffic, businesses closed to pedestrian traffic, and malls), education environments (divided into schools [prekindergarten through th grade] and institutions of higher learning), open spaces, government properties (divided into military and other government properties), residences, houses of worship, and health care facilities. in , the fbi added a new location category, other location, to capture incidents that occurred in venues not included in the previously identified locations (federal bureau of investigation ). this table only includes educational environments. an entire list of all incidents from to at all locations can be found at https://www.fbi.gov/file-repository/activeshooter-incidents- .pdf/view (federal bureau of investigation prevention means the capabilities necessary to avoid, deter, or stop an imminent crime or threatened/actual mass casualty incident. prevention is the action schools take to prevent a threatened or actual incident from occurring. protection means the capabilities to secure schools against acts of violence and man-made or natural disasters. protection focuses on ongoing actions that protect students, teachers, staff, visitors, districts, networks, and property from a threat or hazard. mitigation means the capabilities necessary to eliminate or reduce the loss of life and property damage by lessening the impact of an event or emergency at the school. it also means reducing the likelihood that threats and hazards will happen. response means the school's or school district's capabilities necessary to stabilize an emergency once it has already happened or is certain to happen in an unpreventable way, establish a safe and secure environment, save lives and property, and facilitate the transition to recovery. recovery means the capabilities necessary to assist schools affected by an event or emergency in restoring the learning environment. it also means teaming with community partners to restore educational programming, the physical environment, business operations, and social, emotional, and behavioral health. the majority of prevention, protection, and mitigation activities generally occur before an incident, although these three mission areas do have ongoing activities that can occur throughout an active shooter incident. response activities occur during an incident, and recovery activities can begin during an incident and occur after an incident (united states department of education, office of elementary and secondary education, office of safe and healthy students ; united states department of homeland security b; united states department of homeland security ). in the k- school security guide, the u.s. department of homeland security (dhs) focuses on prevention and protection since the activities and measures associated with them occur prior to an incident ( ). effective preventative and protective actions decrease the probability that schools (or other facilities) will encounter incidents of gun violence or should an incident occur, it reduces the impact of that incident. the guide emphasizes that the level of security at a facility will be based on hazards relevant to the facility, people, or groups associated with it. it also warns that as new or different threats become apparent, the perception of the relative security changes and insecurity should drive change to reflect the level of confidence of the people of groups associated with the facility. the dhs utilizes a hometown security approach that emphasizes the process of connect, plan, train, and report (cptr) with the objective to realize effective, collaborative outcomes (united states department of homeland security b). the initial phase is connect and occurs by a school or district reaching out and developing relationships in the community, including local law enforcement. having these relationships before an incident or event can help speed up the response when something happens. each school must begin with identification or development of a security team, group, or organization. this phase also emphasizes outreach, collaboration, and building of a coalition. there should be coalition members from within a school and may include district/school administrators, teachers, aides, facility operations personnel, human resources, administrative, counseling, and student groups. external groups directly related to the school might include boards of education, parent organizations, mental health groups/agencies, and teacher and bus driver unions. external groups indirectly related to the school include all responder organizations such as police and fire departments, sheriff's office, emergency medical services, emergency management, and the local dhs protective security advisor (psa). other tangential groups such as volunteer organizations, utility providers, and facilities in close geographic proximity should also be considered. core and advisory members of the coalition are established. a coalition champion is also identified and is the person who owns the majority of the responsibility for achieving a school's security goals. the champion organizes the coalition as it grows and matures (united states department of homeland security b). the next phase is plan. this will bring the coalition together. the guide for developing high quality school emergency operations plans (united states department of education, office of elementary and secondary education, office of safe and healthy students ) is an excellent resource for the coalition. a school security survey for gun violence can be completed and the coalition or user can quickly and effectively determine a facility's security proficiency (united states department of homeland security. ). specific portions of or topics within a school plan should be assigned to individuals, committees, or working groups most qualified to address them. the planning process must be sustainable. the amount of time spent in the planning phase should be commensurate with the amount of effort expended on the other phases (united states department of homeland security b). the next phase of the process is to train on the plan developed by the coalition. determining who is responsible for what and how it should be done is the basic function of planning. in fact, telling various members of the team what is expected of them and when to do that activity is the function of training. it is vital to utilize the curricula development expertise possessed by the k- community. school administrators should take advantage of this skill set and find creative ways to address difficult topics, such as gun violence. it should be carried out in an effective and nontraumatic way. presenting the training in pieces or steps allows for a more comprehensive learning experience. it is important to validate training through exercises and drills, all of which should include the students. the training event should be followed by the completion and implementation of an after-action improvement plan with adjustment of the cptr as indicated (united states department of homeland security b). the final phase in the process is report. the reporting phase is arguably the most important of all the phases. reporting principles underlie the other three phases and have profound prevention and protection impacts by driving forward information. dhs models the reporting phase using the "if you see something, say something ® " campaign (u.s. dhs, ) and the nationwide suspicious activity reporting (sar) initiative (nationwide suspicious activity reporting initiative (nsi) ). "if you see something, say something ® " focuses on empowering anyone who sees suspicious activity to do something about it by contacting local law enforcement, or if an emergency to call - - (united states department of homeland security a). this is a compelling capability when well organized and managed. a good plan for reporting, especially for a k- school, involves training staff and students on what is considered suspicious. there are many methods in which schools can employ to facilitate this, such as dedicated telephone numbers, websites for anonymous reporting, email or text messaging, and mobile phone applications. conducting simple drills for reporters and receivers keeps skills sharp and reinforces the importance of the effort with the goal to save lives. if the plan includes sharing all suspicious activity calls with the local fusion center then the probability of higher fidelity reporting increases (united states department of homeland security b). when making changes to a school's plans, procedures, and protective measures, it is imperative the needs of individuals with special health care needs be addressed throughout the process. planning, training, and execution should always consider accessible alert systems for those who are deaf or hard of hearing; students, faculty, and staff who have visual impairments or are blind; individuals with limited mobility; alternative notification measures; people with temporary disabilities; visitors; people with limited english proficiency; sign cards with text-and picture-based emergency messages/symbols; and involving people with disabilities in all planning (united states department of homeland security, interagency security committee ). it is important to understand that no "profile" exists for an active shooter (united states department of education, office of elementary and secondary education, office of safe and healthy students ). however, research indicates there may be signs or indicators. o'toole ( ) presents an in depth, systematic procedure for school shooter threat assessment and intervention. the model was designed to be used by educators, mental health professionals, and law enforcement agencies. its fundamental building blocks are the threat assessment standards, which provide a framework for evaluating a spoken, written, and symbolic threat, and the fourpronged assessment approach which provides a logical, methodical process to examine the threatener and assess the risk that the threat will be carried out. schools should learn the signs of a potentially volatile situation that may develop into an active shooter situation and proactively seek ways to prevent an incident with internal resources, or additional external assistance (united states department of education, office of elementary and secondary education, office of safe and healthy students ). potential warning signs of a school shooter may include increasingly erratic, unsafe, or aggressive behaviors; hostile feelings of injustice or perceived wrongdoing; drug and alcohol abuse; marginalization or distancing from friends and colleagues; changes in performance at work or school; sudden and dramatic changes in home life or in personality; pending civil or criminal litigation; and observable grievances with threats and plans of retribution (united states department of homeland security b). at a minimum, schools should establish and enforce policies that prohibit, limit, or determine unacceptable behaviors and consequences of weapons possession/use, drug possession/use, alcohol/tobacco possession/use, bullying/harassment, hazing, cyber-bullying/harassment/stalking, sexual assault/misconduct/harassment, bias crimes, social media abuse, and any criminal acts (united states department of homeland security b). in addition to policies and positive school climates, school districts and administrators should establish dedicated teams to evaluate threats, such as a threat assessment team (tat). the team should include mental health professionals (e.g., forensic psychologist, clinical psychologist, and school psychologist) to contribute to the threat assessment process (united states department of homeland security b). it is the responsibility of the tat to investigate and analyze communications and behaviors to make a determination on whether or not an individual poses a threat to him/herself or others (united states department of education, office of elementary and secondary education, office of safe and healthy students ). as well as tats, some schools have even opted to establish social media monitoring teams which look for keywords that may indicate bullying or other concerning statements. if a school opts to create such a team, it should work very closely with the tat to ensure that applicable privacy, civil rights and civil liberties, other federal, state and local laws, and information sharing protocols are followed. please refer to chap. for further information. after an active shooter incident, field triage (e.g., jumpstart) must commence and the patient must be evaluated by an experienced emergency medicine or trauma surgeon, preferably by a pediatric specialist in those disciplines. if an active shooter incident is coupled with detonation of an explosive device, the child must be screened and decontaminated for radiation exposure ("dirty bomb"). triage tags are extremely helpful when multiple victims present in a short period of time. medical response to an active shooter event will focus on control of external hemorrhage along with circulatory stabilization. operative emergencies will be common and receive the highest priority. severe extremity injuries may be controlled with tourniquet application or other forms of hemorrhage control. re-evaluation is paramount to prevent ischemia to distal regions. however, thoracic or abdominal (truncal) injuries will need immediate surgical exploration and intervention. penetrating trauma will cause more vascular injuries than blunt trauma, and vascular surgical trays may be in short supply at a hospital. major procedure or surgical trays may become short in supply based on the increased operative demand. resuscitative blood transfusion therapy may utilize a massive blood transfusion protocol. since whole blood may be short in supply, some will simply use the : : rule (administer one unit of packed cells: one unit of fresh frozen plasma: one unit of platelets). a unit for children may be substituted as an aliquot based on size of the patient (e.g., administer ml/kg of packed cells: ml/kg of fresh frozen plasma: ml/kg of platelets). calcium must also be replaced when there is a large volume transfusion. due to extensive blood product utilization, there may be a heavy impact on institutional or regional blood supplies. plans should be in place to address these problems, including the implementation of allocation of scarce resources. mental health support and staff debriefs are essential and 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-okbxllit authors: grabau, john c.; hughes, stephen e.; rodriguez, edwin m.; sommer, jamie n.; troy, eleanor t. title: investigation of sudden death from mycobacterium tuberculosis in a foreign-born worker at a resort hotel() date: - - journal: heart lung doi: . /j.hrtlng. . . sha: doc_id: cord_uid: okbxllit a year-old man born in central america died suddenly in the hallway of his residence on the grounds of a resort hotel where he worked as a dishwasher. the dishwashing station was in a large, poorly ventilated area where a substantial number of food service workers (cooks, wait staff, bus persons, dishwashers, supervisors, etc.) shared air space with the index patient. several social contacts of the patient reported that he had been coughing for many months before his death. the county department of health conducted a contact investigation, which identified individuals in need of follow-up. thirty-six percent of those tested in the first round were tuberculin skin test-positive; a second round of testing yielded a % ( of ) conversion rate. in the late th century, tuberculosis (tb) killed of every people living in the united states and europe. today, tb kills approximately million people worldwide annually, and without further intervention during the period through , approximately billion people will be newly infected, million people will become ill, and million people will die of tb. the annual incidence of tb has decreased substantially during the past century in the united states. the increased morbidity that occurred during the late s and early s has decreased, and cases reported nationally reached a record low number of , in . the annual number of deaths caused by tb has also decreased in recent years; between and , national tb deaths decreased from , to . while under treatment for tb, a proportion of individuals die from the disease. in india, % of patients age to years old died in a directly observed therapy program. death rates were independently associated with weight Ͻ kg and history of previous treatment. a study in mexico found that the risk of death from pulmonary tb was associated with delays in treatment after the onset of disease and to poor adherence by patients to the treatment regimen. in ghana, patients who died were likely to be human immunodeficiency virus (hiv)-positive, to be older, live in a rural area, have sputum smear-negative disease, and prolonged duration of symptoms before diagnosis. a united kingdom study indicated that delay in diagnosis was the main contributing factor leading to death from tb. delayed diagnosis of active pulmonary tb among hospitalized patients (which leads to greater morbidity, mortality, and transmission of infection) in canada was associated with atypical clinical and demographic characteristics. an investigation conducted among inner city residents in a large united states city identified predictors of death to be underlying illnesses such as diabetes mellitus, renal failure, chronic obstructive pulmonary disease, and hiv infection. cases of tb can go undetected until discovered after death. among , tb cases in san francisco, california, % were identified at death. factors associated with these cases were age Ն years, male sex, white race, birth in the united states, and injecting drug use. death from tb may sometimes have a rapid onset and progression. tbrelated sudden death has been related to bronchopneumonia in percent (n ϭ ) of reported patients, of which % had hemoptysis (n ϭ ). in new york state, exclusive of new york city, deaths from tb appear to be relatively rare events. in , of the tb cases reported, were identified at death. there are a number of reasons why tb cases are "missed" and are identified and reported at death. individuals may have had a concurrent condition masking tb disease; they may have been treated for tb disease or infection in the past and suffered an unidentified reactivation; or they may have encountered economic or sociocultural barriers to accessing health care. a tb-related sudden death, where tb disease was not suspected or detected until autopsy, led to a large contact investigation and prompted the new york state department of health to look into other tb deaths in an effort to identify patterns where tb disease may have gone undetected and to identify opportunities for intervention to prevent transmission of infection and subsequent development of disease. some of the results of this investigation were previously reported as an abstract. at a large resort hotel ( employees providing service to guest rooms and a food service capacity of , guests/sitting), the security officer was on routine patrol when she was notified by radio of an individual lying on the hallway floor of one of the buildings where resort employees reside. on arrival, the officer found a man lying on his back, not breathing and without a pulse. one officer observed blood on the walls and floor of the hallway. there were no obvious signs of violence. the local rescue unit and the state police were summoned. the officer started cardiopulmonary resuscitation (cpr), and the others cordoned off the area. the patient was transported by ambulance to the hospital, and the officers secured the area as a crime scene until notified by the hospital, hours later, that the man had died from natural causes. the officers cleaned the area with bleach and a biohazard clean-up kit, and the man's room was padlocked. because the death was unattended, the hospital conducted an autopsy. the cause of death was de-termined to be cardiorespiratory failure caused by or as a consequence of tb, and the county health department was immediately notified. the case had never received medical attention for tb and was unknown to the county staff. the postmortem examination of lung tissue identified mycobacterium tb complex, which was susceptible to all first-line drugs, e.g., rifampin, isoniazid, pyrazinamide, ethambutol, and streptomycin. a contact investigation was launched immediately. county staff contacted the manager of the resort to report a tb death in one of the resort staff and explained both the need to conduct, and the logistics of, a contact investigation. the resort management worked closely with the county nurses to be sure that complete and accurate information was available for the investigation. the resort is located in a sparsely populated area north of new york city. service worker staff for resorts of this type frequently have ties to new york city and travel to area resorts for seasonal jobs. these employees often live in housing available right on the resort grounds and include a high proportion of foreign-born individuals who often are not fluent in english. foreignborn staff in this investigation came from countries outside the united states, many of which were central or south america; however, other countries of origin included china, former soviet union, and indonesia. language barriers were addressed through existing staff at the local health unit and the use of commercially available telephone-based translating services. management of the resort recognized the importance of the contact investigation and provided all necessary work schedules and assignments to facilitate identification of staff who may have been exposed to the patient. transportation to the county clinic proved to be a barrier to attendance despite the provision of shuttles by the resort, so additional clinic sessions were held on the grounds of the resort at a location not accessible to the guests. the initial investigation focused on individuals one would consider to be close contacts, i.e., those sharing living quarters, individuals working in close proximity with the patient, and friends with whom the patient spent time in social settings. the local newspaper ran several stories about the death at the resort, which generated substantial interest in being tested among resort employees who had little or no contact with the patient. the county elected to test all individuals who requested the test; however, for purposes of the contact investigation, data were segregated into categories of "close" and "not close." the index case was a -year-old black hispanic man born in central america. his date of entry into the united states and immigration status is unknown. in may , he started work at the hotel as a dishwasher. his residence was on the grounds of the resort. the building contained single-room units, each approximately feet ϫ feet and containing a sink. there was a common hall and shared bathroom for the residents. the patient's medical history was incomplete. there was no known history of tb. a few weeks before his death he had been seen by a local physician and treated for an upper respiratory infection. symptomatology indicative of tb could not reliably be documented; however, his associates reported a history of frequent coughing. the autopsy identified ⁄ -inch cavitary necrotic lesions in the upper lobe of each lung containing purulent yellowish-green material. multiple well-circumscribed, soft, yellowish-white nodules were present ranging in diameter up to ⁄ inch, and the tracheobronchial and arterial tree was unremarkable. microscopically, the sections taken from each lung showed extensive caseating granulomatous inflammation, and scattered acid-fast bacilli were identified. a direct acid-fast bacilli smear was graded ϩ and identified as mycobacterium tb complex. all food service activities took place in large, poorly ventilated area; food was cooked, wait staff picked up plates to be served, bus staff returned soiled plates, and dishes were washed and stacked. the dishwashing station was at the end of the room where a large floor standing fan was positioned to ventilate the area by pushing air back into the center of the room. the patient worked long hours, often worked overtime, and had worked at his dishwashing job the day before he died. the contact investigation included individuals, of whom were determined to be close contacts, and the remaining were determined not to be close contacts. given the attention raised by the local media around the case, the county health department agreed to test the not-close contacts, but their primary attention was focused on those contacts determined to be close. close and notclose contacts differed remarkably by place of birth: % of the close contacts were born outside of the united states compared with % of the not-close contacts. not-close contacts were also notably younger than close contacts. the large number of close contacts included food service staff from sev-eral shifts and friends working at the resort. firstround testing of close contacts looked at individuals, ( %) of whom were known by the local health department to be tb skin test (tst)-positive. they were not tested but were interviewed for signs and symptoms and told to return if indications of tb developed. of the close contacts not known to be positive, ( %) were tested in the first round. positive ppd (purified protein derivative of mycobacterium tb) results (Ն mm) were seen in ( %) of those tested (of the , were foreign-born), ( %) were negative, and failed to return for the reading. second-round testing included of the first-round negative individuals. positive reactions were identified in ( %), bringing the total number of tst-positive individuals to ( %) those identified as close contacts (figure ). among the notclose contacts, were tested; ( %) were positive, and ( %) were tst-negative on first-round testing. only of those people presented for secondround testing, and of these tested positively. all ppd-positive individuals were interviewed by a public health nurse, evaluated by a physician, had an aspartate aminotransferase study if Ͼ years or reported a history of liver problems, had chest xrays taken, and were offered hiv testing. chest x-ray results did not identify any current cases of tb, and of individuals accepting hiv testing, no positive results were identified. individuals with latent tb infection were prescribed months of isoniazid treatment (the recommended regimen at the time). fifty-four individuals were recommended for treatment, and accepted and started the medication. twenty contacts ( %) completed at least months of isoniazid treatment for latent infection; individuals stopped therapy because of increased enzymes or severe symptoms; and the remaining individuals were lost to follow-up. during , foreign-born individuals accounted for % of the reported tb morbidity in new york state exclusive of new york city. in the investigation described here, the index patient was identified at death as having extensive tb disease and likely infected a substantial number of coworkers and social contacts. individuals born outside of the united states in countries where there is a high prevalence of tb are at risk for developing active tb after immigrating to this country. follow-up of these individuals can be challenging because of their fear of interaction with government agencies, lack of access to health care, cultural beliefs and practices, and language barriers, etc. this rather large contact investigation yielded individuals not previously known to be ppd positive. interpretation of this number is complicated by factors. among the close contacts there was a high proportion of foreign-born individuals ( %). many of those people were from high-prevalence countries in central and south america. the second complicating factor is that the index patient had advanced tb. given the advanced stage of disease and his history of frequent coughing, the patient may have been capable of transmitting infection for quite some time. therefore, although some of the first-round tst-positive individuals may have been infected before coming into contact with the patient, others may have been infected by the patient months earlier and had already converted their skin test at the time of first-round testing. in the second round of testing, individuals were documented to have converted their skin test. exposure to the index patient as the cause of their conversion is a viable hypothesis. although the index patient in this investigation had a rather dramatic presentation that led to the diagnosis of tb, this incident does raise questions about missed opportunities to identify tb and the public and personal health implications for "missing" these patients earlier in their disease course. the death of the resort employee from tb prompted a review of the state tuberculosis registry (exclusive of new york city) to identify any other individuals in whom tb was detected at death. eight other tb cases were identified at death in .the other cases accounted for contacts investigated and reported occurrence of latent tb infection. the other cases were remarkable in that they were all born in the united states (compared with case load Ͼ percent foreign-born), were male, were white, none were hispanic, and the median age was years (range of to ). one patient was known to be resistant to isoniazid and rifampin. despite the fact that tb has reached record low case counts in the united states, people are still dying of and with tb disease. the combination of public health programs and careful clinical management during the past years have significantly decreased the number of newly reported tb cases. tuberculosis has not gone away. some people still die of tb and completely bypass detection until a postmortem examination. other tb patients are identified but still die from the disease alone or in conjunction with comorbid conditions. as national attention is drawn to anthrax, smallpox, and severe acute respiratory syndrome, tb cannot be ignored because it is still an important personal and public concern. the epidemiology of tb may have changed with shifting immigration patterns and the impact of hiv-related diseases. however, older, nonminority individuals are still dying from tb, and although fatalities may be comparatively rare events, tb should be considered in a differential diagnosis of patients with the characteristics previously described. tuberculosis: fact sheet no centers for disease control and prevention. trends in tuberculosis morbidity-united states reported tuberculosis in the united states united states department of health and human services risk factors associated with default, failure and death among tuberculosis patients treated in a dots programme in tiruvallur district predictors of death from pulmonary tuberculosis: the case of vera cruz, mexico pulmonary tuberculosis in adults: factors associated with mortality at a ghanaian teaching hospital. w african tuberculosis mortality in notified cases from - in birmingham delay in diagnosis among hospitalized patients with active tuberculosis-predictors and outcomes survival of patients with pulmonary tuberculosis: clinical and molecular epidemiologic factors the epidemiology of tuberculosis diagnosed after death in san francisco, - tuberculosis and sudden death: a case report and review a large contact investigation following a fatal case of tb at a resort hotel global tuberculosis control: surveillance, planning, financing. world health organization key: cord- -oz eziy authors: munyikwa, michelle title: my covid‐ diary date: - - journal: anthropol today doi: . / - . sha: doc_id: cord_uid: oz eziy written in weekly instalments, michelle munyikwa's covid‐ diary reflects upon the experience of an unfolding pandemic from her dual role as a medical trainee and anthropologist living in the united states. her observations centre on everyday encounters with scenes or objects that reflect the growing crisis, from the absence of masks outside patient rooms to emergent forms of care through telemedicine. the diary follows the author as she experiences grief, ambivalence and disorientation in the first weeks of the pandemic. in this narrative, michelle munyikwa, an anthropologist and medical doctor-in-training, reflects on developments in the covid- pandemic in the form of a diary from philadelphia. how do you know when you are living through a crisis? crisis requires recognition -the point when a dawning awareness settles into an uneasy certainty. it may be the moment when you enter a store and find that the toilet paper or water you had intended to buy has gone -the empty shelf a signifier not only of what is to come, but of what has already happened. for me, that moment came when i could no longer easily don a mask to see patients. simultaneously reacting to and anticipating public panic, the hospital where i am a medical student had sequestered them in order to prevent theft and regulate use. in order to obtain one, you had to declare your intention to the unit secretary, who would look up the patient you were seeing and hand a mask to you only when she or he had verified you had a use for it. in an instant, the absent mask conveyed the impending change. over the last two weeks, the united states has undergone a transformation in its appreciation of the threat of covid- , the disease caused by the novel coronavirus sars-cov- . we have collectively struggled to make sense of the epidemic. scrolling social media feeds, one is inundated by reports from other countries, graphs and tables attempting to predict the future, and calls to understand the past of previous epidemics such that we might not repeat our errors. one is also bombarded by assertions that this is merely the flu, a media hoax or an example of the mass hysteria that the -hour news cycle can fuel. we live, and make choices, in an affectively saturated, information-rich (and often, truth-poor) environment. this uniquely st-century crisis is an object lesson in what it feels like to live through an emerging epidemic during what has often been described as an age of anxiety. how do we navigate unfolding uncertainty in a context where truth is wobbly and misinformation pervasive? i am a doctor-in-training and an anthropologist, currently completing clinical rotations, which means that i work in a different specialty every month. over my last few days in the hospital, i have watched the crisis unfold. hospitals are stripping down their staff to essential personnel, planning for the worst. teams that would normally see patients in large groups are paring down in the hopes of saving personal protective equipment (ppe), like masks and gowns, which are already in short supply. already, we have suspected cases in philadelphia, which was all but an eventuality, given the cases in new york. the question on everyone's mind is just how worried we should be. should we stock up for a doomsday scenario? or is this merely the flu, coupled with a politically inflected overreaction? i had been tracking the outbreak since its emergence in december. in january, i happened to be on a rotation in infectious diseases. my colleagues regarded the unfolding panic with an air of bemusement, more concerned about quotidian but deadly matters like the flu. still, i found myself sitting in on meetings where we discussed strategy with a growing sense of dread: how would we ensure that doctors out in the community felt adequately prepared? how many cases could we reasonably handle in our hospitals? could faster, more local tests be developed? this was before the virus reached other nations, let alone the united states, in significant numbers. throughout january and february, concern about an american covid- epidemic seemed tepid. most of my social networks were not talking about it, and i was only able to find communities talking about the virus in the hospital and online. this shifted around tuesday of last week, as more nations started to report cases and the case number went up substantially. soon, friends were contacting me about the virus, expressing their concern. the world health organization (who) recently announced that the worldwide death rate is . per cent, but all epidemiological evidence suggests that deaths are not evenly distributed. we also know that there is a high rate of nosocomial infection, with large quantities of healthcare workers getting infected. here in philadelphia, i am concerned by how our public health infrastructure and significant economic inequality will shape who is affected by the disease and who will die. philadelphia is often described as the poorest big city in the united states; . per cent of our resi-dents live below the federal poverty line, the highest rate among the nation's largest cities. while in a period of celebrated growth, the city is still recovering from the decline of manufacturing and its attendant public divestment and suburban flight, and the current landscape of the city is shaped by racialized class inequality and the assaults to public health that these dynamics produce. we also have a serious problem with hospitals; while there are many elite hospitals in philadelphia, that also means that we have a high concentration of complex, chronically ill patients, precisely those who will be at significant risk were covid- to become a significant public health problem here. like many american cities, we also lack a public hospital, and few ways to access care without concern for the massive, crushing bills that our specialized care foists upon patients. we will need to worry about the chronically ill and the fact that many american hospitals cannot handle a surge in patients at this time of year. in the best of times, patients can languish in the emergency department for hours while they wait for beds in increasingly crowded hospitals. in this first week, it feels as though there is nothing to do but wait, track the epidemic in other countries and hope the government pulls together a response. scepticism, anticipation, anxiety and disgust. other anthropologists have written extensively about the problems this epidemic lays bare, most notably the illumination of cleavages in our social fabric and the truly deadly implications of such divisions across the lines of race, class and national origin. this work has drawn attention to this pandemic's disregard for borders and the xenophobic and racist responses public domaina that contagion engenders. it highlights the ongoing negotiations around scientific expertise and practice and the dizzying array of projections and models that shape the daily response to the pandemic, particularly the infamous study from imperial college london. the situated labour of anthropologists has also drawn attention to the differential unfolding of this pandemic across different spaces and in local communities. as the sense of crisis transforms from a speculative possibility into a reality, i have also been struck by how overwhelming this is, in part because of a deluge of media that urges us to perform an affective reorientation to the present. affect theory offers us a language for examining the structures of feeling (williams [ ] ) that shape our response to the world. it helps us to understand the sense that we are living through history, situating our experience of the unfolding present (ahmed ; berlant ) . the lens of affect also helps us to understand how efforts to change the course of things necessarily entail attempts to manipulate such structures of feeling. as public opinion about covid- has oscillated between disgust, scepticism and anticipation, so too have the discursive strategies to combat each of these entrenched positions. as we navigate affectively shaped worlds, experts and laypeople alike engage in affective mitigation that tugs on the contours of the affective in order to transform individual sentiments and understanding. in other words, we attempt to transform one another's orientation to the epidemic in order to inform action that mitigates the crisis. scoffing on fox news, for example, politicians tug on concerns about immigrant invasions and the peril inherent in progressive politics to simultaneously maximize fear of the other and stoke confusion about the pandemic. affective mitigation also shapes our use of history, alternately stoking or taming a response through historical analogy: the flu, for example, or the sars (severe acute respiratory syndrome) and mers (middle east respiratory syndrome) events that never came to pass (arnett ). our response is characterized by a wild oscillation between scepticism and anticipation. scepticism has been attributed to members of the political right, whose news sources have projected the message that this epidemic is a fabrication of a panicked, over-anxious media. anticipation: the left, those plugged into the latest epidemiological models and projections. in the contemporary american moment, we can see that modes of preparation and prevention have failed to produce the desired effects. we find ourselves amidst a crisis that has been not only weeks, but decades in the making, with the sense that normative modes of prediction and anticipation have failed. we are daily negotiating emerging relations to expertise, authority and truth, which have always been at stake in the declaration and management of public health crises. this week, the picture is bleak. friends working in hospitals across america tell me of critical shortages of masks, sickened col-leagues and stolen equipment. due to concern about the possibility that medical students, perceived as young and healthy, could serve as asymptomatic vectors, schools around the country cancelled clinical rotations. i amalong with my classmates -at home, watching the pandemic from afar, as friends working in hospitals around the country supply me with a stream of updates. being away from the hospital, experiencing the pandemic through mediated resources, has shifted my sense of the crisis, making it at once more deeply felt and more distantly understood. doctors and advocates are organizing to halt detention, protect prisoners, feed and house the homeless and struggle to put together a social safety net hardy enough to withstand social distancing. we have seen beautiful acts of social solidarity, mutual aid and altruism. these acts balance the misery with hope, though they force us to question why they are necessary in the first place. so what does one do in the meantime? what are the stories one tells in dark times? how can a narrative of defeat enable a place for the living or envision an alternative future? (hartman ) we tell ourselves stories in order to live. (didion ) if i'm being honest, i suspect that there are no words that are adequate to the task of describing the slow-moving disaster we are living through. we often characterize this sensation as the ambiguous pleasure-paincuriosity of watching an accident unfold. i am reminded of a time when i was driving down the highway; as i approached, i saw an enormous plume of black smoke. whizzing by, it took a moment after i passed to realize that the smoke was emerging from an enormous fire in the engine of a car, which had been parked, strangely, in the opposite lane. only much later did i think to ask: what is a burning car doing on the highway? how did it come to be there? is everyone okay? there are harbingers of disaster around us: empty streets devoid of their usual traffic; a space on the shelf where your favourite bread normally dwells; cars piled full, mysteriously, with toilet paper; realizing just how often you have come to rely on small conveniences; a bizarre longing for hugs from strangers or quotidian, banal interactions. things are different. over the last week, nations around the world have locked down. the borders of the united states have closed; expatriates around the world have been encouraged to return home. here in philadelphia, we have continued to prepare for the worst. medical students, disconnected from clinical rotations, have organized to coordinate food deliveries and babysitting services for frontline providers. others have started collecting ppe, which is scarce, while still more gather to support local businesses that are suffering in the absence of foot traffic. there are efforts to aid the many people who are without housing and food, and campaigns to transform empty hotels into housing gain traction. letters circulate, some with thousands of signatures, imploring the ice (us immigration and customs enforcement) to decrease enforcement and the state to release prisoners. in moments like this, we turn to history (jones ). many of the articles circulated across my social media feeds encourage us to understand the past to orient our present response. we go clawing into the archive for lessons we wish we had already learned, and attempt to learn them too quickly, all at once. i may have read more about the - influenza pandemic in the last week than ever before in my life, and i am a student of medicine, history and anthropology. and yet, every day, another journalist uncovers these lessons with their moral: take this seriously. never forget. we, too, are vulnerable. perhaps one reason we tell ourselves these stories is because they convince us that we will, in fact, survive this. we hope that this means we might surmount the growing threat, for if others have lived to tell the tale of our devastating past, then perhaps there is hope for our future. but there is nothing to say that we are permanent presences on this earth, no reason to believe that we, unlike all other species, are not susceptible to extinction. that is not to say that the end of humanity is likely (however closely environmental collapse hovers, threatening to complete the job). it is, however, to suggest that the world that we have known up to this moment, no longer exists. returning to that normal ceased to be one of the possibilities many steps ago in this unfolding chain. its possibility was stifled most proximally by failures of government, but perhaps even more by the choices we made, entrenching rapacious capitalism, greed and immoral incompetence. we might have seen the proverbial smoke from a distance when we elected generations of leaders more invested in enriching the elite than strengthening the poor. when i am thinking about history, politics and its use, i often return to the poetic prose of saidiya hartman, whose historical imagination seeks to uncover but not redeem the past. she knows, as we all do, that we change nothing simply by noticing what has happened. after all, 'we all know better. it is much too late for the accounts of death to prevent other deaths; and it is much too early for such scenes of death to halt other crimes' (hartman ) . saidiya hartman was speaking, of course, of the not-quite-past of slavery and her repeated visits to the archive of that atrocity, saturated as it is with the tales of the dead whose loss we will never recuperate. as this pandemic visits devastation unevenly upon poor communities, people of colour and immigrants, the body count of racial capitalism mounts and we are left to account for it. if it is the case that we are always hanging in the balance between presence and absence when recounting the injustices of history, then what do we hope for with respect to telling these tales in the present? i want to believe that revisiting the lives that were unnecessarily lost years ago during the flu pandemic will spur us to do differently. i want to believe that being haunted by the archive of bodies piled in the streets might shift our perspective, such that we will successfully avoid what is to come. i want to think that knowing that this is all wrong may keep us from continuing to do it. i also wonder if by the time it occurs to us to marshal the evidence of the past, it is already too late. i fear that we are like i was: blinking into realization the image of a burning car on the road, long after i could have done anything about it. an image of destruction seared into my consciousness, for nought. when is it time to dream of another country or to embrace other strangers as allies or to make an opening, an overture, where there is none? when is it clear that the old life is over, a new one has begun, and there is no looking back? (hartman ) we're over , cases here in the united states, as many states have placed shelter in place orders and the economy has come to a grinding halt. hundreds of thousands have lost their jobs and the threat of economic disaster looms. politicians and citizens alike worry that our response is an overreaction. donald trump, concerned about stock prices, has been at the centre of a push to reopen the economy and loosen restrictions on those communities where disease prevalence is lower or allow lower-risk citizens to work. rallying around the cry that 'the cure cannot be worse than the disease', people desperate for economic relief suggest that we go back to the way things were, allowing the epidemic to run its course. perhaps, they suggest, we can merely isolate the 'at risk', allowing the rest of the country to go to work. this, despite the increasingly dire situation in new york and other cities around the country. this week has also seen the spread of covid- throughout africa, with a reported , + cases across the continent, likely an underestimate. i am now worried about the spread in these countries, which include my home nation of zimbabwe, where rumours surrounding our first death suggest that we are woefully underprepared for the task of fighting this pandemic. i worry about my extended family, who remain there, and what they will do if one of them becomes sick. while the conditions in countries with fewer resources will be dire, an abundance of wealth does not seem likely to prevent horrible outcomes in the united states, where we are quickly developing the worst epidemic in the industrialized world. in new york, massachusetts and michigan, medical students are being graduated early to help with the crisis. philadelphia-area doctors warn of an impending ventilator shortage, and the institution prepares guidance for the worst: rationing and the reality of preventable death. we are not there yet in philadelphia, but the anticipation permeates the entire health system. every day, hospital leadership sends new projections, attempting to calculate the impact of this pandemic -do we have enough beds? enough clinicians? enough gloves? -each time assuring us that we are ready. however, some projections are more terrifying than others, suggesting a flow of hundreds of patients a day into a hospital with just barely enough space for those patients we anticipate. my best friend, an emergency doctor, texts me news every day. 'intubated a -year-old woman today'; ' intubations in one shift, there's normally only one'; 'we're down to the donated ppe'. the hospital is a ghost town, with elective surgeries cancelled and other patients avoiding care for fear of contracting the virus. we are nowhere near the peak yet, so the hospital is the emptiest it has been in years. this feels like the calm before the storm. stories of young healthcare workers dying of respiratory failure circulate in my medical social circles. my mother, also a doctor, worries about the impending shortage at her hospital. it becomes clear that healthcare providers will be among those who bear the brunt of this, to say nothing of the poorly paid essential workers across many industries. hospitals around the country begin trialling hydroxychloroquine as prophylaxis, and as donald trump and scientists alike promote the possibility of the drug, we hope they are right. the debate around the drug reveals deep uncertainty about the proper course of treatment, bringing up important concerns about ethics, patient harm and medical responsibility. march- april: time compression, pandemic fatigue and the new normal as i am editing this, the united states has nearly , cases and over , deaths. the disease is now the largest cause of death in the country. my experience of the pandemic has transformed from a frenzy into a slow unfolding, each day simultaneously more terrible and mundane than the last. as we round out one month of sheltering in place, my experience of each day becomes more and more rapid, as i blink and days have passed. at the same time, it feels as if this pandemic has lasted a thousand lifetimes. this is in part because the nature of my work has changed so much, from intense labour in the hospital to digitally mediated interactions on video chatting platforms. i spend most of my day in front of a screen, like many of my peers, completing both school and volunteer work digitally. across the healthcare system, students and providers alike have been repurposed. psychiatrists and gynaecologists act as frontline providers in areas of the hospital where they usually do not work, while others pivot to telemedicine. as medical students, we have been forbidden from interacting with patients, but we continue to volunteer. some students participate in grocery delivery programmes, picking up an extra bag of food on their weekly trips and dropping them off for patients in need. others staff our tele-icu (intensive care unit), watching over intubated patients with a camera from a safe distance a mile away from the hospital and adjusting vent settings from afar -more a scene from science fiction than real life. i have signed up to a project attempting to address the social needs of patients in our massive healthcare system. a team of medical students and social workers has assembled to intervene in the social fallout from this disease, from unstable housing to domestic violence, health insurance woes to food insecurity. based on a referral from a doctor, the team calls to perform a screening: do you feel safe at home? do you have enough to eat? are you worried about paying your rent? my first call was to a woman who had lost her job and her insurance due to covid- related layoffs, just in time to contract the disease. or it should have been; i called her all morning, but her phone had already been disconnected. other patients, covid-positive and acting as caregivers for family members who were now at risk, needed help with food, making money, surviving. who will get my groceries if i can't leave my house and everyone who lives with me might also be contagious? can someone come to take care of my elderly grandmother who has dementia? can i go back to work? these conversations force athens airport, february : the covid- virus hell in italy is just beginning. i arrived in greece in early february before the chaos started; today, i am heading to kavála, the field base for my comparative project on the protest movements against the trans adriatic pipeline in greece and southern italy. out of habit, twice, perhaps three times, i say 'grazie' as i navigate airport procedures. it's enough to elicit worried looks and whispered comments among the bystanders. a sudden and uncomfortable feeling grips me. the next day, greece records its first covid- case, 'imported' from italy. ever since that announcement, an invisible wall has arisen between me and my greek neighbours. soon, it also affects my fieldwork. 'i don't speak to italians' i overhear while sitting in the car of one of my informants, as he calls a fellow activist and introduces me. next day, immediately after he posts a picture of us on facebook, the warnings fly: 'be careful! you're not even wearing masks!' though followed by smiley emojis, such 'joking' remarks are anything but. then there's the street vendor's inquisitive and concerned look when he places my accent, my neighbour's 'teasing' gesture of shielding himself from me by forming an x with his arms, and the pharmacist who suddenly steps back and denies me the much-requested disinfectant hand gel as it is destined 'only for local customers' -while grunting. in response, i speak as little as possible to avoid making mistakes in greek and to 'hide' my nationality. this hits me particularly hard as i'm usually warmly received in greece. i'm a southern italian who grew up in salento (puglia), where a variety of greek -'griko' -is still spoken. on this shore of the shared sea, griko tends to elicit admiration and self-celebratory comments about the durability of hellenism. suddenly i'm no longer called i ellinìda tis kato italias ('the greek from southern italy'). the distinction between purity and danger fills into symbolic -and physical -boundary maintenance, as mary douglas observed in her book purity and danger. abruptly, i'm simply italian and italian means 'polluted and polluting' -the enemy. meanwhile, gallows humour circulates via memes: 'not finding a seat on the bus? no problem. cough, say buongiorno a tutti -"good morning everyone [in italian]" -and sit wherever you want!' (facebook, february) . then again, irony can be a weapon as much as self-irony can be a defence: 'i'd say that if we keep coughing, we'll end up re-conquering the roman empire' (facebook, march) . however, as things in italy take a catastrophic turn, and as infections climb in greece, public expressions of concern and closeness towards italians follow. when the covid- nightmare started in matryx / pixabay.com questions of reciprocity, solidarity and obligation. every patient chart, every documented encounter, is an unflattering look into our devastatingly leaky social safety net. the virus continues to unmask the consequences of our late capitalist social order, which differentially exposes communities to death (taylor ) . in philadelphia, these are apparent in statistics collected by our public health officials, which reveal that it is easiest to get tested in our affluent neighbourhoods, despite a larger number of cases in poorer communities. to get a test outside of a hospital, you must wait in a drive-through line, leaving those without cars to scramble for other means of testing. meanwhile, my peers are still collecting ppe. my partner and i, not generally prone to crafting, pull out a long-neglected set of sewing machines to produce masks for ourselves and friends as the recommendations shift and community use of masks is encouraged. we draw on his expertise as an engineer to design and fabricate alternatives to n surgical masks, anticipating a day when our doctor and nurse friends will go to work to find protection absent. i'm reminded of a message my mother sent me early in the pandemic, as critical shortages of ppe became apparent and her daily work in the hospital revealed an overwhelming lack of preparedness. the message said simply: 'no gloves. no eyewear. no ppe. who's [this] s**thole country now?' it has become increasingly difficult to gain the distance from this pandemic that would allow me to make sense of it. at the same time, there has been a veritable boom in social theory since the pandemic began. every day, advertisements for webinars and digital lectures fill my inbox. calls for papers have already pivoted around this latest crisis, and i expect to see dozens of covid- -related panels at the next big conference. a prominent social theorist has already penned a book about the pandemic. i feel self-conscious about my dulled capacity to distance, to theorize, to make sense of something which is overwhelming and surreal. it is true that as anthropologists, we are precisely in the business of making sense of what is going on around us. perhaps it is a need for control, the will to know, that impels us to attempt to tame what ultimately can't be tamed. or it is worth noting that the federal poverty line is only one of the many ways of characterizing widespread precarity in the city of philadelphia, though it is most often cited. . here, i am thinking especially of some of the compelling contributions to somatosphere's covid- forum, particularly adia benton's elaboration of the racialized geography of blame also see: macgregor it is worth noting that it is not always the case that medical students are healthy and that this elides those who are living with chronic illness or are otherwise at risk. . i heard rumours before i started to see formal reporting, like nyoka ( ). also, a later account describes the family's perspective it is worth noting that the use of invasive ventilation for covid- is contested terrain, with considerable disagreement about when to intubate, the ethics of early intubation and the potential harm to patients of overly aggressive care affective economies years ago, another epidemic terrorized the city. the boston globe border promiscuity, illicit intimacies, and origin stories: or what contagion's bookends tell us about new infectious diseases and a racialized geography of blame. somatosphere (blog) cruel optimism the white album: essays venus in two acts history in a crisis -lessons for covid- novelty and uncertainty: social science contributions to a response to covid- covid- -struck family speaks of ordeal. the standard (blog) coronavirus: zimbabwean broadcaster zororo makamba died 'alone and scared'. bbc news counting coronavirus: delivering diagnostic certainty in a global emergency reality has endorsed bernie sanders. the new yorker the pew charitable trusts . philadelphia : state of the city keywords: a vocabulary of culture and society mona lisa protecting her environment from infection by covid- key: cord- - na gndu authors: benito, daniel a.; pasick, luke; mulcahy, collin f.; rajasekaran, karthik; todd-hesham, hosai; joshi, arjun s.; goodman, joseph f.; thakkar, punam title: local spikes in covid- cases: recommendations for maintaining otolaryngology clinic operations date: - - journal: am j otolaryngol doi: . /j.amjoto. . sha: doc_id: cord_uid: na gndu the coronavirus disease- (covid- ) pandemic has created an unprecedented economic and public health crisis in the united states. following efforts to mitigate disease spread, with a significant decline in some regions, many states began reopening their economies. as social distancing guidelines were relaxed and businesses opened, local outbreaks of covid- continue to place person on healthcare systems. among medical specialties, otolaryngologists and their staff are among the highest at risk for becoming exposed to covid- . as otolaryngologists prepare to weather the storm of impending local surges in covid- infections there are several practical measures that can be taken to mitigate the risk to ourselves and our staff. the first confirmed case of covid- in the united states was reported in northern washington on january , [ ] and by march , , the world health organization declared covid- a pandemic. [ ] covid- has since created an unprecedented economic and public health crisis in the united states. as healthcare system strain became imminent, the centers for medicare and medicaid services (cms) , the surgeon general, and the american college of surgeons (acs) [ ] recommended postponing elective procedures in efforts to mitigate the spread of disease and preserve personal protective equipment (ppe). along these lines, the american academy of otolaryngology put forth recommendations for urgent and nonurgent patient care on march , . these recommendations included delaying all elective procedures, rescheduling elective and non-urgent visits, rescheduling elective and non-urgent admissions, delaying inpatient and outpatient surgical and procedural cases, and postponing routine dental and eyecare visits. [ ] further, due to the high risk nature of the examination of the ear, nose, and throat [ ] , otolaryngology outpatient visits have been drastically reduced throughout the country. such measures have restructured otolaryngology practices with telemedicine playing a crucial role in the continuing care. cms continues to encourage telehealth modalities, however, the acs released guidance for the resumption of elective procedures on april , . [ ] while aspects of these guidelines are relevant for the outpatient setting, they do not address all outpatient clinic workflow issues. further, given that otolaryngologists and clinic staff are at unique risk due to close contact with mucous membranes of the upper respiratory tract [ ] , there is a need for specialty specific recommendations for the resumption of otolaryngology clinics. a recent report from a group in northern italy (an area severely affected by covid- ) provides guidance on reorganizing outpatient otolaryngology services in light of the current pandemic. [ ] many states began reopening businesses and healthcare centers within the context of these guidelines, however regionally there have been significant differences in implementation of masking and social distance mandates, leading to a reimplementation of restrictions. our goal is to provide recommendations focused on outpatient otolaryngology clinics in the united states. it is important to note that these recommendations should not supplant evolving united states centers for disease control (cdc), and relevant federal, state and local public health guidelines. the increased emphasis placed on telemedicine presents specific challenges for the otolaryngologist, given the wide scope of practice that entails both procedural and medical management of ailments. while some chief complaints require in-person office evaluation, many patient consultations can be conducted and reimbursed via telemedicine.[ . ] increasingly, however, otolaryngology practices have been opening for in person office visits in accordance with published guidelines. although universal covid- screening has not been widely adopted, strategies such as universal masking and staggered approach to appointments to reduce waiting room occupancy have been effective. accordingly, it is imperative that patients are j o u r n a l p r e -p r o o f journal pre-proof triaged by administrative or nursing staff prior to clinic arrival. further, it is important to know if the patient or an accompanying family member is at high risk for severe covid- illness, as defined by the cdc. [ ] when the decision is made for an in-person evaluation, patients should be screened for covid- symptoms prior to their arrival. [ ] in addition, patients who may require office-based procedures should be screened and should be strongly considered to undergo covid- testing prior to arrival, if possible ( table ). in-person examinations pose obvious risks of sars-cov (novel coronavirus) transmission among patients, family and friends of patients, and clinical staff. as such, implementing strategies to mitigate this transmission is critically important. overall, we have implemented strategic reorganization of patient flow (scheduling, waiting room interactions, check-in process, and physical barrier placement) and adaptations within the examination room to protect both patients and clinical staff alike ( table ) . considerations for endoscopic examination are also presented in table , should clear indications such as difficult airway management or malignancy be present. adjunct use of transcutaneous laryngeal ultrasound may be a rapid noninvasive method well suited for evaluation of vocal fold motion [ ] , however an aerosol-generating procedure was performed. [ ] [ ] [ ] [ ] [ ] [ ] [ ] these recommendations should be used in conjunction with current guidelines for patient care and public safety [ ] [ ] [ ] [ ] and are adaptable to meet the needs of specific practice environments. as operations in the otolaryngology clinic have resumed, considerations for workforce availability, staffing ratios, sanitation protocols, and hcw screening must be maintained to ensure a safe working environment for both patients and staff. strategies can be focused on maintaining the lowest staffing ratio available in order to efficiently check-in patients, triage calls, escort patients and record vitals, and assist in any planned procedures ( table ). this may require day-to-day alterations in ratios. moreover, staff should be advised to follow cdc recommendations for social distancing from other staff and patients in order to avoid "close contact." large viral droplets (greater than µm) can remain in the air for only a short time and travel distances generally less than meter. [ ] [ ] [ ] virus-laden small (less than µm) aerosolized droplets can remain in the air and travel distances greater than meter. [ ] this is defined as greater than feet distance between oneself and a covid- case. as the highest degree of viral shedding from the nasopharynx is thought to occur up to - hours prior to symptom onset [ ] , patients should be assumed to be asymptomatic carriers until testing capacity is sufficient to perform point-of-care testing prior to the patient visit should use of laryngoscopy be needed. many institutions have moved to testing patients between - hours prior to elective surgery or laryngoscopy [ , ] . temperature screening of all patients and staff through a non-contact temperature check at the entrance should be instituted, however should not be relied upon to rule out covid- . use of barrier glass, such as glass or plastic windows at the front desk are recommended for protection against droplet infection. [ , ] as j o u r n a l p r e -p r o o f journal pre-proof state re-opening and restrictions evolve, it will become increasingly important for the otolaryngologist and team to monitor the covid- incidence rate in their area, and develop a threshold for re-entering the mitigation phase when a resurge is evident. [ ] self-protective measures for both the otolaryngologist and staff begins with preparation prior to the work-day, continues with prudent use of ppe in the clinic, and ends with a practical hygiene routine upon returning home (table ). [ ] with a growing body of evidence, the transmission of sars-cov- is becoming better understood. face masks or face coverings should be worn by everyone in an otolaryngology clinic and clinicians in direct contact with patients should wear full droplet precaution ppe. airborne precaution should be donned for aerosol-generating procedures (table ) . while n respirators are the minimum level of respiratory protection recommended for airborne precautions, higher level respirators (n , n , elastomeric respirator, papr, capr) may offer greater protection from virus transmission. [ , ] in practice, however, use of an n mask with a face shield has become standard for all procedures where there is a potential exposure to respiratory droplets and the provider is in close proximity to the patient. in our experience, patients who were asymptomatic at the time of visit but developed symptoms and a positive covid test within days of the office procedure, did not transmit the virus to staff or other patients using these precautions.  uv-c light should be utilized for minutes following a standard visit [ , , ] patient visit with aerosol generating procedure  delay entering examination room to disinfect and remove soiled instruments j o u r n a l p r e -p r o o f j o u r n a l p r e -p r o o f first case of novel coronavirus in the united states world health organization. who director-general's remarks at the media briefing on cms adult elective surgery and procedures recommendations: limit all non-essential planned surgeries and procedures, including dental, until further notice american college of surgeons. local resumption of elective surgery guidance new recommendations regarding urgent and nonurgent patient care covid- and the otolaryngologist: preliminary evidence-based review how to reorganize an ear, nose, and throat outpatient service during the covid- outbreak: report from northern italy mitigation of head and neck cancer service disruption during covid- in hong kong through telehealth and multi-institutional collaboration embracing telemedicine into your otolaryngology practice amid the covid- crisis: an invited commentary covid- : people who are at higher risk for severe illness covid- ): phone advice line tool for possible covid- patients laryngeal evaluation during the covid- pandemic: transcervical laryngeal ultrasonography. otolaryngol neck surg is office laryngoscopy an aerosol-generating procedure? evaluation of an ultraviolet c (uvc) light-emitting device for disinfection of high touch surfaces in hospital critical areas perioperative covid- defense effectiveness of ultraviolet-c light and a high-level disinfection cabinet for decontamination of n respirators evaluation of a pulsed xenon ultraviolet disinfection system for reduction of healthcare-associated pathogens in hospital rooms high-risk aerosol generating procedures in covid- : respiratory protective equipment considerations. otolaryngol -head neck surg safety recommendations for evaluation and surgery of the head and neck during the covid- pandemic. jama otolaryngol -head neck sick/social-distancing.html precautions for operating room team members during the covid- pandemic covid- outbreak associated with air conditioning in restaurant environmental factors affecting the transmission of respiratory viruses transmission routes of respiratory viruses among humans aerobiology and its role in the transmission of infectious diseases temporal dynamics in viral shedding and transmissibility of covid- developing perioperative covid- testing protocols to restore surgical services. nejm catal innov care deliv overview of covid- testing and implications for otolaryngologists protecting patients and healthcare personnel from covid- : considerations for practice and outpatient care in cardiology centers for disease control and prevention. summary for healthcare facilities: strategies for optimizing the supply of n respirators during the covid- response how to train health personnel to protect themselves from sars-cov- (novel coronavirus) infection when caring for a patient or suspected case letter: precautions for endoscopic transnasal skull base surgery during the covid- pandemic infection control measures for operative procedures in severe acute respiratory syndrome-related patients in reply: precautions for endoscopic transnasal skull base surgery during the covid- pandemic reply: precautions for endoscopic transnasal skull base surgery during the covid- pandemic illness in intensive care staff after brief exposure to severe acute respiratory syndrome possible sars coronavirus transmission during cardiopulmonary resuscitation novel coronavirus disease (covid- ): the importance of recognising possible early ocular manifestation and using protective eyewear symptom screening at illness onset of health care personnel with sars-cov- infection in king county guidance for risk assessment and public health management of healthcare personnel with united states environmental protection agency. disinfectants for use against sars-cov- cost-effectiveness of transfacial glandpreserving removal of parotid sialoliths centers for disease control and prevention. evaluating and testing persons for coronavirus disease airborne transmission route of covid- : why meters/ feet of inter-personal distance could not be enough criteria for return to work for healthcare personnel with suspected or confirmed covid- information overload: a method to share updates among frontline staff during the covid- pandemic. otolaryngol neck surg key: cord- - q jbcl authors: coppola, damon p. title: participants – multilateral organizations and international financial institutions date: - - journal: introduction to international disaster management doi: . /b - - - - . - sha: doc_id: cord_uid: q jbcl multilateral organizations are composed of sovereign governments. they may be regional, organized around a common issue or function, or global. international financial institutions (ifis) are international banks composed of sovereign member states that use public money from the member states to provide technical and financial support for developing countries. the united nations is the organization most involved in the mitigation of, preparedness for, response to, and recovery from disasters around the world. it is considered the best equipped to do so because of its strong relationships with most countries, especially the developing countries where assistance is most needed. when disasters strike, the un is one of the first organizations to mobilize, and it remains in the affected countries during the recovery period for many years after. the consolidated appeal process is one way the un garners international support for relief and reconstruction. in many regions, governments have formed smaller international organizations, many of which address risk, as well. the ifis provide nations with low capital reserves funding in the aftermath of disasters recovery reconstruction. the world bank is regarded as one of the largest sources of development assistance. a multilateral organization is an organization composed of the central governments of sovereign nations. multilateral organizations are also called intergovernmental organizations and international organizations. member states come together under a charter of rules and responsibilities they have drawn up and agreed on. multilateral organizations may be regionally based (e.g., the european union [eu] , the association of south east asian nations [asean]), organized around a common issue or function (e.g., the north atlantic treaty organization [nato] , the organization of the petroleum exporting countries [opec]), or globally based (e.g., the united nations [un] ). like sovereign states, they are recognized as having an established legal status under international law. the un is the most well-known and largest of all of the multilateral organizations because its membership draws from nearly every nation, and because it covers a wide range of issues. the first international organization to address the topic of disaster management was the international relief union (iru), which was founded in italy in and later integrated into the league of single vote, with key issues decided by two-thirds majority. (less significant matters are decided by simple majority.) as mentioned earlier, the general assembly cannot force its decisions on a sovereign state, although they generally receive wide support. the assembly holds regular sessions from september to december, and special/emergency sessions may be called at any time. when not in session, the assembly's work is carried out by its six main committees, other subsidiary bodies, and the secretariat. the un security council's primary responsibility is maintaining international peace and security in accordance with the un charter. this council, which convenes at will, consists of members, five of which are permanent members (china, france, the russian federation, the united kingdom, and the united states). all un member states are obligated to carry out the council's decisions. decisions require nine affirmative votes, including all five votes of the permanent members. when the council source: un, a. considers threats to international peace, it first explores peaceful settlement options. if fighting is under way, the council attempts to secure a cease-fire, and it may send a peacekeeping mission to help the parties maintain the truce and keep opposing forces apart. the council can take measures to enforce its decisions, such as imposing economic sanctions or arms embargoes. on rare occasions, the council has authorized member states to use "all necessary means," including collective military action, to see that its decisions are carried out. these are referred to as "peacemaking operations." the economic and social council is the central mechanism by which international economic and social issues are addressed and by which policy recommendations are created. it also consults with non-governmental organizations (ngos) to create and maintain working partnerships between the un and civil society. the council has members, elected by the general assembly for three-year terms. it meets throughout the year, but its main session is held in july, during which major economic, social, and humanitarian issues are discussed. the council has several subsidiary bodies that regularly meet to address issues such as human rights, social development, the status of women, crime prevention, narcotic drugs, and environmental protection. the trusteeship council originally provided international supervision for trust territories administered by seven member states and ensured that adequate steps were taken to prepare the territories for self-government or independence. by , all trust territories had attained self-government or independence. its work completed, the trusteeship council now consists of the five permanent members of the security council. it has amended its rules of procedure to allow it to meet as and when the occasion may require. the international court of justice, also known as the world court, is the un's main judicial organ. the world court consists of judges elected jointly by the general assembly and the security council. it serves to settle disputes between countries. participation is voluntary, but when a state agrees to participate, it must comply with the court's decision. the court also provides advisory opinions to the general assembly and the security council on request. the secretariat carries out the day-to-day work of the un as directed by the general assembly, the security council, and the other organs. at its head is the secretary general, who provides overall administrative guidance. the secretariat is made up of various departments and offices and maintains a total staff of about , people throughout the world. duty stations include the un headquarters in new york and offices in geneva, vienna, and nairobi, as well as other locations. the secretariat's functions are diverse, ranging from "administering peacekeeping operations to mediating international disputes, from surveying economic and social trends and problems to preparing studies on human rights and sustainable development" . the secretariat staffs also work to publicize the un's work through the world media and to organize conferences on issues of global concern. secretariat staffs are considered international civil servants and answer only to the un for their activities. disaster-response-oriented projects to disaster mitigation, the un adopted the international strategy for disaster reduction to promote disaster reduction and risk mitigation as part of its central mission. this initiative continues to evolve in its pursuit of disaster risk reduction, promoting global resilience to the effects of natural hazards, and reducing human, economic, and social losses by: • increasing public awareness of the hazard risks faced and the options to address them • obtaining commitment from public authorities to mainstream risk reduction into their work • stimulating interdisciplinary and intersectoral partnership and expanding risk-reduction networking at all levels • enhancing scientific research on the causes of natural disasters and the effects of natural hazards and related technological and environmental disasters on societies these strategies are integrated into the work carried out by each un country office and promoted to the national and local governments in each member country where the un works. hazard mitigation and disaster preparedness strategies are communicated to members of all levels of society via public awareness campaigns, and promoted by obtaining commitment from public authorities, facilitating cooperation and communication between various government and non-governmental sectors, and enabling the provision or transfer of technical knowledge. because the un is such a complex organization, it can be difficult to illustrate the myriad ways in which it addresses disaster management other than to describe the role of each organization and agency in this area. the un general assembly does not partake in any operational disaster management activities. however, as the main deliberative organ of the un, it is responsible for launching many influential and effective disaster management programs that are ultimately carried out by the various un offices and by the un member state governments. examples include the endorsement of the undp capacity for disaster reduction initiative (cadri) and the launching of the international decade for natural disaster reduction and its subsequent international strategy for disaster reduction. the general assembly is also responsible for organizing and reorganizing the un system to maximize its disaster management capabilities, as in under the un program for reform ( ) , which created the office for the coordination of humanitarian affairs (ocha) and the un office for disaster risk reduction (unisdr). the un secretariat is the international working staff of un employees located at duty stations throughout the world. the un secretariat employees carry out the diverse day-to-day work of the various un offices. it services the principal un organs and administers the programs and policies laid down by them. at its head is the secretary-general, who is appointed by the general assembly on the recommendation of the security council for five-year renewable terms. the secretariat has approximately , employees. as international civil servants, staff members and the secretary-general answer only to the un and take an oath not to seek or receive instructions from any government or outside authority. under the charter, each member state agrees to respect the appointed valerie amos of guyana to replace mr. john holmes of the united kingdom as under-secretary-general for humanitarian affairs/un emergency relief coordinator. ocha regional offices monitor the onset of natural and technological disasters. staff are trained in disaster assessment and post-disaster evaluation methods before disasters strike. once an impending or actual disaster event is identified, ocha initiates response and generates a situation report to provide the international response community with detailed information, including damage assessment, actions taken, needs assessment, and current assistance provided. if necessary, ocha may then deploy a un disaster assessment and coordination (undac) team to assist relief activity coordination and assess damages and needs. if a disaster appears inevitable or is already unfolding, the erc in consultation with iasc may designate a humanitarian coordinator (hc), who becomes the most senior un humanitarian official on the ground for the emergency. the hc is directly accountable to the erc, increasing the likelihood that the humanitarian assistance provided is quick, effective, and well-coordinated. the hc appointment generally signals that the event merits a long-term humanitarian presence. the criteria used by the erc to determine whether to appoint an hc center on the need for intensive and extensive political ocha organizational chart source: ocha, a. management, mediation, and coordination to enable the delivery of humanitarian response, including negotiated access to affected populations; massive humanitarian assistance requiring action by a range of participants beyond a single national authority; and a high degree of external political support, often from the un security council. an on-site operations coordination center (osocc) may be set up in the field to assist local firstresponse teams to coordinate the often overwhelming number of responding agencies. the osocc has three primary objectives: ( ) to be a link between international responders and the government of the affected country; ( ) to provide a system for coordinating and facilitating the activities of international relief efforts at a disaster site; and ( ) to provide a platform for cooperation, coordination, and information management among international humanitarian agencies. finally, ocha can set up communications capabilities if they have been damaged or do not exist at an adequate level, as required by the un responding agencies. ocha generally concludes its responsibilities when the operation moves from response to recovery. overall, ocha coordination is performed to maximize the response and recovery capabilities that converge on the disaster scene, and to minimize duplications and inefficiencies. the structures and policies that have been established to support this function include (adapted from ocha ): • developing common strategies. humanitarian assistance is most effective when common priorities and goals exist among stakeholders and responders agree on tactics and jointly monitor progress. ocha works with its partners to develop a common humanitarian action plan and to establish clear divisions of responsibility. • assessing situations and needs. ocha staff assume responsible for assessing damages and identifying needs, developing a plan of action to meeting those needs, and monitoring progress. responses are adjusted, if necessary, using ongoing analysis of political, social, economic, and military environments and by assessing humanitarian needs to help the responding agencies better understand the situation. • convening coordination forums. in its role as coordinator, ocha holds a wide range of meetings to bring together the various disaster management players for planning and information exchange. these meetings help the participants to more accurately analyze the overall status of humanitarian relief efforts as well as network and share lessons learned and best practices. • mobilizing resources. through the cap, ocha leads the drive to get governments to commit funding and resources necessary to address the identified needs. allocation of funds has been found to be more efficient within this centralized system. • addressing common problems. every crisis is unique, and both new and old problems arise. as coordinator, ocha analyzes and addresses problems common to humanitarian actors, such as negotiating with warring parties to gain access to civilians in need, or working with un security officials to support preparedness and response measures in changing security situations. • administering coordination mechanisms and tools. ocha, and the un in general, have several tools with which they can better address the humanitarian needs of disaster victims. these include the iasc; rapid-response tools, such as the un disaster assessment and coordination teams and the international search and rescue advisory group; and smaller forums such as the geographic information support team. ocha also assists with civil-military cooperation, ensuring a more efficient use of military and civil defense assets in humanitarian operations. the field coordination support unit in geneva manages ocha's human, technical, and logistical resources. these resources are primarily provided by the danish and norwegian refugee councils, the danish emergency management agency, the swedish rescue services agency, and the emergency logistics management team of the united kingdom overseas development administration. the under-secretary-general for humanitarian affairs/emergency relief coordinator advises the un secretary-general on disaster-related issues, chairs the executive committee on humanitarian affairs (echa), and leads the iasc. the coordinator is assisted by a deputy, who holds the position of deputy emergency relief coordinator (derc) and is responsible for key coordination, policy, and management issues. the inter-agency standing committee (iasc) was established in under un resolution / . it serves as a platform within which the broad range of un and non-un humanitarian partners (including un humanitarian agencies, the international organization for migration, three consortia of major international ngos, and the red cross movement) may come together to address the humanitarian needs resulting from a disaster. the iasc's primary role is to formulate humanitarian policy that ensures a coordinated and effective response to all kinds of disaster and emergency situations. the primary objectives of the iasc are to: • develop and agree on system-wide humanitarian policies • allocate responsibilities among agencies in humanitarian programs • develop and agree on a common ethical framework for all humanitarian activities • advocate common humanitarian principles to parties outside the iasc • identify areas where gaps in mandates or lack of operational capacity exist • resolve disputes or disagreement about and between humanitarian agencies on system-wide humanitarian issues (ocha ) iasc members (both full members and standing invitees) include: • the ocha donor relations section (drs), separated from the cap in , is the focal point for all relations with donors, particularly for funding-related issues. drs advises the senior management team on policy issues related to interaction with donors and resource mobilization. in addition, it plays a key role in facilitating the interaction of all ocha entities with donors, both at headquarters and in the field level. the coordination and response division (crd) was created in by joining the former new yorkbased humanitarian emergency branch and the geneva-based response coordination branch. crd is responsible for providing disaster-related direction, guidance, and support to the erc, the un resident/humanitarian coordinators, and ocha's field offices (including the deployment of extra personnel as necessary, or providing emergency cash grants). based in geneva, the ocha emergency services board (esb) was created to expedite the provision of international humanitarian assistance. esb develops, mobilizes, and coordinates the deployment of ocha's international rapid response "toolkit"-the expertise, systems, and services that aim to improve humanitarian assistance in support of disaster-afflicted countries. esb's humanitarian response activities include the coordination of disaster response and assessment (undac; see in the following section), the setting of international urban search and rescue standards (insarag; see in the following section), and the establishment of osoccs. esb supports ocha field offices through the following: • surge capacity and standby partnerships • military and civil liaison and mobilization of military and civil defense assets • dispatch of relief supplies and specialized assistance in environmental emergencies • dissemination of disaster-related information by means of reliefweb, the central register of disaster management capacities, and the virtual onsite operations coordination center. within the esb are seven separate sections, established to manage particular aspects of disaster response: . civil-military coordination section . emergency preparedness section . environmental emergencies unit . emergency relief coordination centre . field coordination support section . logistics support unit . surge capacity section established by the iasc in , the civil military coordination section (cmcs), previously named military and civil defense unit (mcdu), is the focal point for the efficient mobilization of military and civil defense assets for use in humanitarian emergencies and for liaison with governments, international organizations, regional organizations, and military-civil defense establishments deploying these assets. it also coordinates un agency participation and participates in major military exercises comprising significant humanitarian scenarios. this section is responsible for the overall management of the ocha central register of disaster management capacities, with specific maintenance of the mcda directory of military and civil defense assets and expertise. cmcs acts as a facilitator and secretariat to the development of documents involving the broad international humanitarian community and is custodian of the "oslo" and "mcda" guidelines detailing the use of mcda in support of un humanitarian operations in natural, technological, and environmental disasters and complex emergencies, respectively. the emergency preparedness section (eps) helps to maintain ocha's operational readiness and to reinforce disaster preparedness work. eps works with stakeholders at the national government level in un member countries in order to help build disaster response and recovery capacity in advance of disasters. much of the work performed by this unit is guided by the hyogo framework for action, which recommends the strengthening of disaster preparedness for effective response at all levels. the environmental emergencies unit, or the joint un environmental programme (unep)/ocha environment unit, serves as the integrated un emergency response mechanism that provides international assistance to countries experiencing environmental disasters and emergencies. this joint unit can rapidly mobilize and coordinate emergency assistance and response resources to countries facing environmental emergencies and natural disasters with significant environmental impacts. the unit performs several key functions geared toward facilitating rapid and coordinated disaster response: • monitoring. the unit performs continuous monitoring and ongoing communication with an international network of contacts and permanent monitoring of news services and websites for early notification of environmental occurrences. • notification. when disasters strike, the unit alerts the international community and issues "information and situation" reports to a comprehensive list of worldwide contacts. • brokerage. the unit is able to quickly establish contact between the affected country and donor governments ready and willing to assist and provide needed response resources. • information clearinghouse. the unit serves as an effective focal point to ensure information on chemicals, maps, and satellite images from donor sources and institutions are channeled to relevant authorities in the affected country. • mobilization of assistance. the unit mobilizes assistance from the international donor community when requested by affected countries. • assessment. the unit can dispatch international experts to assess an emergency's impacts and to make impartial and independent recommendations about response, cleanup, remediation, and rehabilitation. • financial assistance. in certain circumstances, the unit can release ocha emergency cash grants of up to $ , to meet immediate emergency response needs. the emergency relief coordination center (ercc) is the physical facility where ocha centralized coordination activities are focused. the facility enables closer collaboration between internal and external humanitarian stakeholders and has the capacity to serve as an ocha situation centre, providing updates on humanitarian relief activities worldwide. the centre consists of a main task force room, a small conference room that can also be used for a second task force, and a technical room to control all facility capabilities. the ercc allows ocha to coordinate two response teams simultaneously. the field coordination support section (fcss) was established within esb in to support national governments and the un resident coordinators in developing, preparing, and maintaining "standby capacity" for rapid deployment to sudden-onset emergencies to conduct rapid needs assessments and coordination. fcss manages several programs and offices to improve international disaster coordination and cooperation, including: • the united nations disaster assessment and coordination (undac) team. the undac team is made up of disaster management specialists selected and funded by the governments of un member states, ocha, undp, and operational humanitarian un agencies (such as wfp, unicef, and who). it provides rapid needs assessments and supports national authorities and the un resident coordinator in organizing international relief. undac teams are on permanent standby status so that they can deploy within hours. • the international search and rescue advisory group (insarag) . insarag is an intergovernmental network within the un that manages urban search and rescue (usar) and related disasterresponse issues. it promotes information exchange, defines international usar standards, and develops methodologies for international cooperation and coordination in earthquake response. • the virtual on-site operations coordination centre (virtual osocc). the internet has made it possible for humanitarian relief agencies to share and exchange disaster information continuously and simultaneously, and between any locations where internet access can be obtained. the virtual osocc is a central repository of information maintained by ocha that facilitates this exchange of information with ngos and responding governments. the information is stored on an interactive web-based database, where users can comment on existing information and discuss issues of concern with other stakeholders. the logistics support unit (lsu) manages stocks of basic relief items that can be dispatched immediately to disaster-or emergency-stricken areas. the stockpile, which is located at the un humanitarian response depot in brindisi, italy, includes nonfood, nonmedical relief items (such as shelter, water purification and distribution systems, and household items) donated by un member governments. the lsu is also involved in other logistical challenges, such as designing contingency plans for the rapid deployment of emergency relief flights and providing interface on logistical matters with other humanitarian agencies (such as wfp, who, unhcr, ifrc, and icrc). the lsu participates in the operation of a un joint logistics center (see exhibit . ) and has co-sponsored an effort to adopt a un-wide system for tracking the un joint logistics center (unjlc) is an interagency facility reporting to the humanitarian coordinator [within a che], and overall to the iasc. its mandate is to coordinate and optimize the logistics capabilities of humanitarian organizations in large-scale emergencies. unjlc operates under the direction of the world food programme (wfp), who is responsible for the administrative and financial management of the centre. the unjlc is funded from voluntary contributions channeled through wfp. the requirement to establish [the unjlc] was born out of the humanitarian response to the eastern zaire crisis, which demanded intensified coordination and pooling of logistics assets among unhcr, wfp, and unicef. the interagency logistics coordination model was applied on subsequent unjlc interventions in somalia, kosovo, east timor, mozambique, india, and afghanistan. in march , unjlc concept was institutionalized as a un humanitarian response mechanism, under the aegis of wfp, by the inter-agency standing committee working group (iasc-wg). the unjlc core unit was subsequently established in rome. in case of major disaster with substantial humanitarian multi-sector involvement during the immediate relief phase, the un agencies involved may consider that the establishment of a joint logistics centre would contribute to the rapid response, better coordination, and improved efficiency of the humanitarian operation at hand. . . . a standby capacity will be developed for facilitating, if required, the timely activation and deployment in the field of a united nations joint logistics centre-unjlc. the unjlc will support the united nations agencies and possibly other humanitarian organisations that operate in the same crisis area. the capacity includes the option to establish satellite joint logistic centres (jlc) dispersed at critical locations in the [affected area] and offering logistics support on a reduced scale. . . . upon [unjlc] activation, agencies will establish a deployment requirements assessment (dra) team to carry out a quick evaluation of the logistics situation and determine the requirements to deploy the unjlc in the crisis area. this dra team will work in close coordination with the humanitarian authorities and, if deployed, with the united nations disaster assessment and coordination (undac) team. it will take all necessary measures for installing the unjlc and draft ad hoc terms of reference (tor) for endorsement by the relevant humanitarian authorities. in case of peacekeeping operations or in a complex environment, the unjlc activation will be coordinated with the department of peacekeeping operations (dpko) or the relevant military entities. • the role of the unjlc will be to optimise and complement the logistics capabilities of cooperating agencies within a well-defined crisis area for the benefit of the ongoing humanitarian operation. • the unjlc will provide logistics support at operational planning, coordination, and monitoring levels. unless specified otherwise, the un agencies and other humanitarian bodies, which are established in the area, will continue (continued) relief supplies and common procedures for air operations. finally, the lsu contributes information related to stockpiles and customs facilitation agreements (which helps speed up the delivery of relief items). the surge capacity section (scs) works to ensure ocha always has the means and resources to rapidly mobilize and deploy staff and materials to address the needs of countries affected by suddenonset emergencies. scs operates using a number of distinct surge capacity resources, which include: • the emergency response roster (err). err, which became active in june , aims to rapidly deploy ocha staff to sudden-onset emergencies to conduct assessments and establish initial coordination mechanisms. the staff included in the err are deployable within hours of a request for their services through a deployment methodology based on the undac model. staff serve on the roster for about six months. • the stand-by partnerships programme (sbpp). sbpp is structured on legal agreements with partner organizations that provide short-term staffing to field operations free of charge when gaps arise. partners maintain their own rosters of trained and experienced humanitarian professionals, many of whom have ocha or other un humanitarian experience. sbpp staff can usually be deployed within four weeks of the formal request, and an average deployment lasts five to six months. • associates surge pool (asp). asp, which was created in late , helps to bridge the gap between the immediate response surge and the arrival of regular staff. asp comprises external disaster management staff who can be deployed for up to six months upon the issuance of a temporary appointment. contracting and deployment preparations take an average of three to four to exercise their normal responsibilities. as a result, the unjlc will not be involved in policy and establishment of humanitarian needs and priorities. • responsibilities will be defined as per the requirements on a case-by-case basis but will, in principle, be limited to logistic activities between the points of entry and distribution in the crisis area. detailed responsibilities . . . would be: • collecting, analysing, and disseminating logistics information relevant to the ongoing humanitarian operation; • scheduling the movement of humanitarian cargo and relief workers within the crisis area, using commonly available transport assets; • managing the import, receipt, dispatch, and tracking of non-assigned food and nonfood relief commodities; • upon specific request, making detailed assessments of roads, bridges, airports, ports, and other logistics infrastructure and recommending actions for repair and reconstruction. • the scope of the unjlc activities may vary with the type of emergency, the scale of involvement of the cooperating partners, and the humanitarian needs. the reso and roso positions were created following a need to have senior surge staff available to deploy to new and escalating emergencies for up to three months to provide leadership and stability to ocha operations. they spend percent of their time in the field and percent at headquarters. when not in the field, resos and rosos work with the surge staff development team to develop and deliver trainings and support lesson learning and other exercises to improve ocha emergency response during non-deployment periods. although ocha's efforts primarily focus on coordinating the response to major disasters, the agency also performs various tasks related to disaster risk reduction. for instance, ocha representatives work with disaster management agencies to develop common policies aimed at improving how the wider stakeholder community of responders prepare for and respond to disasters. it also works to promote preparedness and mitigation efforts in member states to decrease vulnerability. crd and esb work closely with the un development programme, other un programs as necessary, and outside organizations on various projects and activities to increase working relationships with national governments and apply lessons learned from completed disaster responses. ocha's geneva offices are continually monitoring geologic and meteorological conditions, as well as major news services, for early recognition or notification of emerging disasters. working with un resident coordinators, country teams, and regional disaster response advisers, ocha maintains close contact with disaster-prone countries in advance of and during disaster events. ocha's regional disaster response advisers work with national governments to provide technical, strategic, and training assistance. they also provide this assistance to other un agencies and regional organizations to improve international disaster management capacity. • it facilitates the negotiations of member states in many intergovernmental bodies on joint courses of action to address ongoing or emerging global challenges. • it advises national governments on translating un-developed policy frameworks into countrylevel programs and, through technical assistance, helps build national capacities. this final area is where desa addresses disaster management activities within its division for sustainable development. as part of this effort, desa launched a plan of action during the world summit on sustainable development in johannesburg, south africa, that included commitments to disaster and vulnerability reduction. see exhibit . for more information on this plan of action. the un center for regional development (uncrd) is another component of desa that addresses disaster management issues. through its headquarters in nagoya, japan, and its regional offices in nairobi, kenya, and bogotá, colombia, uncrd supports training and research on regional an integrated, multi-hazard, inclusive approach to address vulnerability, risk assessment, and disaster management, including prevention, mitigation, preparedness, response, and recovery, is an essential element of a safer world in the twenty-first century. actions are required at all levels to: . strengthen the role of the international strategy for disaster reduction and encourage the international community to provide the necessary financial resources to its trust fund; . support the establishment of effective regional, subregional, and national strategies and scientific and technical institutional support for disaster management; . strengthen the institutional capacities of countries and promote international joint observation and research, through improved surface-based monitoring and increased use of satellite data, dissemination of technical and scientific knowledge, and the provision of assistance to vulnerable countries; . reduce the risks of flooding and drought in vulnerable countries by, [among other things], promoting wetland and watershed protection and restoration, improved land-use planning, improving and applying more widely techniques and methodologies for assessing the potential adverse effects of climate change on wetlands and, as appropriate, assisting countries that are particularly vulnerable to those effects; . improve techniques and methodologies for assessing the effects of climate change, and encourage the continuing assessment of those adverse effects by the intergovernmental panel on climate change; . encourage the dissemination and use of traditional and indigenous knowledge to mitigate the impact of disasters and promote community-based disaster management planning by local authorities, including through training activities and raising public awareness; . support the ongoing voluntary contribution of, as appropriate, ngos, the scientific community, and other partners in the management of natural disasters according to agreed, relevant guidelines; . develop and strengthen early warning systems and information networks in disaster management, consistent with the international strategy for disaster reduction; . develop and strengthen capacity at all levels to collect and disseminate scientific and technical information, including the improvement of early warning systems for predicting extreme weather events, especially el niño/la niña, through the provision of assistance to institutions devoted to addressing such events, including the international center for the study of the el niño phenomenon; . promote cooperation for the prevention and mitigation of, preparedness for, response to, and recovery from major technological and other disasters with an adverse impact on the environment in order to enhance the capabilities of affected countries to cope with such situations. development issues and facilitates information dissemination and exchange. uncrd maintains a disaster management planning office in hyogo, japan, that researches and develops communitybased, sustainable projects for disaster management planning and capacity-building in developing countries. the hyogo office also runs the global earthquake safety initiative, designed to improve risk recognition and reduction in cities around the world. five regional economic commissions are within the economic and social council. the secretariats of these regional commissions are part of the un secretariat and perform many of the same functions (including the disaster management functions listed earlier). the five commissions promote greater economic cooperation in the world and augment economic and social development. as part of their mission, they initiate and manage projects that focus on disaster management. while their projects primarily deal with disaster preparedness and mitigation, they also work in regions that have been affected by a disaster to ensure that economic and social recovery involves adequate consideration of risk reduction measures. the five regional commissions are: • in response periods of disasters, the united nations development programme (undp) sees that development does not cease during emergencies. if relief efforts are to contribute to lasting solutions, sustainable human development must continue to be vigorously supported, complementing emergency action with new curative initiatives that can help prevent a lapse into crisis. (un, ) the undp was established in during the un decade of development to conduct investigations into private investment in developing countries, to explore the natural resources of those countries, and to train the local population in development activities such as mining and manufacturing. as the concept and practice of development expanded, the undp assumed much greater responsibilities in host countries and in the un as a whole. the undp was not originally considered an agency on the forefront of international disaster management and humanitarian emergencies because, while it addressed national capacities, it did not focus specifically on the emergency response systems (previously considered to be the focal point of disaster management). however, as mitigation and preparedness received their due merit, undp gained increased recognition for its vital risk reduction role. capacity building has always been central to the undp's mission in terms of empowering host countries to be better able to address issues of national importance, eventually without foreign assistance. international disaster management gained greater attention as more disasters affected larger populations and caused greater financial impacts. developing nations, where the undp worked, faced the greatest inability to prepare for and/or respond to these disasters, largely as a result of the development trends described in chapter . undp's projects have shifted toward activities that indirectly fulfill mitigation and preparedness roles. for instance, projects seeking to strengthen government institutions also improve those institutions' capacities to respond with appropriate and effective policy, power, and leadership in the wake of a disaster. undp fully recognizes that disaster management must be viewed as integral to their mission in the developing world as well as to civil conflict and che scenarios. there are implicit similarities between undp ideals and those of agencies whose goals specifically aim to mitigate and manage humanitarian emergencies. undp work links disaster vulnerability to a lack of or a weak infrastructure, poor environmental policy, land misuse, and growing populations in disaster-prone areas. when disasters occur, a country's national development, which the undp serves to promote, can be set back years, if not decades. even small-to medium-size disasters in the least developed countries can "have a cumulative impact on already fragile household economies and can be as significant in total losses as the major and internationally recognized disasters" (undp ) . it is the undp's objective to "achieve a sustainable reduction in disaster risks and the protection of development gains, reduce the loss of life and livelihoods due to disasters, and ensure that disaster recovery serves to consolidate sustainable human development" (un ) . in , as part of the un's changing approach to humanitarian relief, the emergency response division (erd) was created within the undp, augmenting the organization's role in disaster response. additionally, percent of undp budgeted resources were allocated for quick response actions in special development situations by erd teams, thus drastically reducing bureaucratic delays. the erd was designed to create a collaborative framework among the national government, un agencies, donors, and ngos that immediately respond to disasters, provide communication and travel to disaster management staff, and distribute relief supplies and equipment. it also deploys to disaster-affected countries for days to create a detailed response plan on which the undp response is based. in , under the un programme for reform, the mitigation and preparedness responsibilities of the ocha emergency relief coordinator were formally transferred to the undp. in response, the undp created the disaster reduction and recovery programme (drrp) within the erd. soon after, the undp again reorganized, creating the bureau of crisis prevention and recovery (bcpr) with an overarching mission of addressing a range of non-response-related issues: • disaster risk reduction and climate change management • conflict prevention • rule of law, justice, and security in countries affected by crises • women in conflict prevention, peacebuilding, and recovery • immediate crisis response • livelihoods and economic recovery • crisis governance bcpr helps undp country offices prepare to activate and provide faster and more effective disaster response and recovery. it also works to ensure that undp plays an active role in the transition between relief and development. undp's disaster management activities focus primarily on the development-related aspects of risk and vulnerability and on capacity-building technical assistance in all four phases of emergency management. it emphasizes: • incorporating long-term risk reduction and preparedness measures in normal development planning and programs, including support for specific mitigation measures where required; • assisting in the planning and implementation of post-disaster rehabilitation and reconstruction, including defining new development strategies that incorporate risk-reduction measures relevant to the affected area; • reviewing the impact of large settlements of refugees or displaced persons on development, and seeking ways to incorporate the refugees and displaced persons in development strategies; • providing technical assistance to the authorities managing major emergency assistance operations of extended duration (especially in relation to displaced persons and the possibilities for achieving durable solutions in such cases). undp spends between $ and $ million each year on disaster risk reduction projects. the focus of these projects has included the establishment or strengthening of early warning systems, the conduct of risk assessments and drafting of hazard maps, and the establishment of national disaster management agencies. through their projects, undp staff help to strengthen national and regional capacities by ensuring that new development projects consider known hazard risks, that disaster impacts are mitigated and development gains are protected, and that risk reduction is factored into disaster recovery. following conflict, crises, and disasters, countries must transition from response to recovery. many countries are unable to manage the difficult and widespread needs of recovery on their own, as they may have experienced widespread loss of infrastructure and services. displaced persons and refugees may have little to return to, and economies may be damaged or destroyed. bcpr operates during the period when the response or relief phase of the disaster has ended but recovery has not fully commenced (sometimes referred to as the "early recovery period"). sustainable risk reduction is central to the undp recovery mission. the bureau recognizes that local expertise in risk management and reduction may not be available, and that the technical assistance they provide may be the only option these communities have to increase their resilience to future disasters. this program has proved effective in many countries' recovery operations, including cambodia after three decades of civil war, afghanistan after the conflict, and gujarat, india, after the earthquake. the top recipients of undp crisis prevention and recovery funding include: to meet these recovery priorities, five support services have been developed to assist the undp country offices and other undp/un agencies to identify areas where bcpr can provide assistance. these support services include: • early assessment of recovery needs and the design of integrated recovery frameworks. this includes assessing development losses caused by conflict or natural disaster, the need for socioeconomic and institutional recovery, identification of local partners, and the need for capacity building and technical assistance. • planning and assistance in area-based development and local governance programs. area-based development and local governance programs play key roles in recovery from conflict because they tailor emergency, recovery, and development issues across a country area by area, based on differing needs and opportunities. area-based development helps bring together different actors at the operational level, promoting enhanced coordination, coherence, and impact at field level. areabased development is often seen as the core mechanism that most benefits reintegration. • developing comprehensive reintegration programs for idps, returning refugees, and ex-combatants. internal displacement, returning refugees, and demobilized former combatants create a huge need for in-country capacity building on different levels. protection and security become serious issues, and efforts to sustainably reintegrate these populations into their host communities are critical. bcpr provides expertise on reintegration of idps, returnees, and ex-combatants, including capacity building benefiting both the returnees and the formerly displaced, as well as their host communities, through activities such as income generation, vocational training, and other revitalization activities. • supporting economic recovery and revitalization. one main characteristic of disasters and conflict is their devastating impact on the local and national economies. livelihoods are destroyed through insecurity, unpredictability, market collapse, loss of assets, and rampant inflation. for recovery to be successful, these issues need to be well understood from the outset and addressed accordingly. • supporting capacity building, coordination, resource mobilization, and partnerships. protracted conflict and extreme disasters tend to create political stressors that temporarily exceed the capacities of un country offices and other ngo partners. however, many recovery needs must be addressed right away to ensure that recovery sets out on a sustainable course. bcpr offers several services to accommodate the needs of this intense phase through the provision of surge capacity and short-to medium-term staff, assistance in resource mobilization within specific fundraising and coordination frameworks (such as the cap), and partnership building. when required to assist in recovery operations, bcpr may deploy a special transition recovery team (trt) to supplement undp operations in the affected country. the focus for these teams varies according to specific needs. for instance, when neighboring countries have interlinked problems (such as cross-border reintegration of ex-combatants and displaced persons), the trt may support a subregional approach to recovery. it is important to note that the undp has no primary role in the middle of a che peacekeeping response, only a supportive one in helping to harmonize development with relief. during recovery and reconstruction, together with others, they take the lead. in addition to the previously mentioned roles and responsibilities, the undp leads several interagency working groups. one such group (which consists of representatives from the wfp, who, the food and agriculture organization [fao] , the un populations fund, and unicef) develops principles and guidelines to incorporate disaster risk into the common country assessment and the un development assistance framework. the international strategy for disaster reduction working group on risk, vulnerability, and disaster impact assessment sets guidelines for social impact assessments. undp also coordinates a disaster management training programme in central america, runs the conference "the use of microfinance and micro-credit for the poor in recovery and disaster reduction," and has created a program to elaborate financial instruments to enable the poor to manage disaster risks. the undp has several reasons for its success in fulfilling its roles in the mitigation, preparedness, and recovery for natural and man-made disasters. first, as a permanent in-country office with close ties to most government agencies, activities related to coordination and planning, monitoring, and training are simply an extension of ongoing relationships. the undp works in the country before, during, and long after the crisis. it is able to harness vast first-hand knowledge about the situations leading up to a crisis and the capacity of the government and civil institutions to handle a crisis, and can analyze what weaknesses must be addressed by the responding aid agencies. in addition, its neutrality dispels fears of political bias. second, the undp functions as a coordinating body of the un agencies concerned with development, so when crisis situations appear, there is an established, stable platform from which it may lead. from this leadership vantage, it can (theoretically) assist in stabilizing incoming relief programs of other responding un bodies, such as the wfp, unicef, the department of humanitarian affairs, and the unhcr. once the emergency phase of the disaster has ended and ocha prepares to leave, undp is in a prime position to facilitate the transition from response efforts to long-term recovery. and third, the undp has experience dealing with donors from foreign governments and development banks, and can therefore handle the outpouring of aid that usually results during the relief and recovery period of a disaster. this contributes greatly to reducing levels of corruption and increasing the cost-effectiveness of generated funds. in several recent events, the undp has established formalized funds to handle large donor contributions, which have been used for long-term post-disaster reconstruction efforts. (see exhibits . and . ). when a major disaster operation requires extended efforts, the undp may accept and administer special extra-budgetary contributions to provide the national government with both technical and material assistance, in coordination with ocha and other agencies involved in the un disaster management team (dmt). an example of such assistance includes the establishment and administration of a un dmt emergency information and coordination (eic) support unit. special grants of up to $ . million also may be provided, allocated from the special programme resources funds for technical assistance to post-disaster recovery efforts following natural disasters. see exhibit . for information about the undp capacity for disaster reduction initiative (cadri). like most major un agencies, unicef (formerly known as the united nations international children's emergency fund) was established in the aftermath of world war ii. its original mandate was to aid children suffering in postwar europe, but this mission has been expanded to address the needs of women and children throughout the world. unicef is mandated by the general assembly to advocate for children's rights, to ensure that each child receives at least the minimum requirements for survival, and to increase children's opportunities for a successful future. under the convention on the rights of on may , , the government of sri lanka declared military victory over the rebel liberation tigers of tamil eelam, formally ending a decades-long armed conflict. in the wake of the war, undp demonstrated that developing and building on strong partnerships is key to ensuring a fast and well-targeted response. an estimated , idps gathered in camps during the first half of . many of them lacked basic documentation, making it difficult to access basic services and prove claims to land and assets. undp assisted the registrar general to establish a temporary office inside one of the largest camps with capacity to process birth and marriage certificates per day, complemented by additional staffing capacity in colombo to handle the increased number of document requests. between july and december the camp office processed close to , requests, prioritizing those from children who needed identification to sit for national school exams. undp also supported mine action coordination and management. survey and clearance activities advanced rapidly, and by the end of a total of square kilometers of land had been released for resettlement. this allowed the pace of returns and resettlements to increase exponentially in the fourth quarter of , with over , idps returning or resettling. in the eastern province, fao, ilo, wfp, unhcr, and undp continued to champion the "delivering as one" approach to support community-based recovery and contribute to the stability of returnees in selected divisions of the east. as the funding conduit, undp was in charge of the overall coordination of project implementation while also directly implementing small-scale infrastructure construction such as roads, wells, and community centers (which provided a space for cooperatives and trading groups to come together). the selection of target communities was informed through village profile maps and data generated by unhcr, while wfp provided six months' worth of food supply rations, until the foundations for agricultural self-reliance and food security for resettled families were laid. undp also launched a new initiative in to foster partnerships between sri lanka's manufacturers and resettled communities. undp, with its presence in the field, played a catalytic role, identifying the resettled communities, facilitating meetings with the large consumer companies, securing fair and long-term contracts, and supporting training as well as supply of equipment to improve production. through this project, farming and fishing families in the north and the east have secured income for the next two to three years. on may , , cyclone aila hit southern bangladesh, resulting in widespread tidal flooding and the destruction of large parts of the region's protective embankment network. economic losses were estimated at $ million and more than , families were affected in satkhira, the district that had also suffered the most from cyclone sidr in . many of the affected were still recovering from the impact of the earlier disaster. the government of bangladesh provided emergency relief and planned for the reconstruction of the damaged embankment network, but many of the most vulnerable families have been unable to return to their homes, which remain submerged. with funding from the undp bureau of crisis prevention and recovery (bcpr), an early recovery program focused on livelihoods was developed, covering all villages in the worst-affected part of satkhira. the program included a cash-forwork component that built on self-recovery efforts of affected families. this resulted in the creation of an estimated , work days devoted to road repair and ground elevation. the program also included support for the restoration of essential community infrastructure; support to local small enterprises through working capital grants for carpentry tools, sewing machines, and tea stall equipment; and assistance for home-based income-generating activities, such as vegetable cultivation, crab fattening, handicrafts, poultry rearing, and fish drying. this effort benefited more than , families. the child (crc), a treaty adopted by countries, the unhcr holds broad-reaching legal authority to carry out its mission. as of late , unicef maintains country offices in more than different nations. this is probably its greatest asset in terms of the agency's disaster management capacity. preparedness and mitigation for disasters among its target groups is a priority, with programs able to address both local-level action and national-level capacity building. in keeping with the recommendations laid out by the yokohama strategy and plan of action for a safer world, unicef incorporates disaster reduction into its national development plans. it also considers natural hazard vulnerability and capacity assessments when determining overall development needs to be addressed by un country teams. through public education campaigns, unicef works to increase public hazard awareness and knowledge and participation in disaster management activities. unicef country offices include activities that address these pre-disaster needs in their regular projects. for example, they develop education materials required for both children and adults, and then design websites so educators and program directors can access or download these materials for use in their communities. in situations of disaster or armed conflict, unicef is well poised to serve as an immediate aid provider to its specific target groups. its rapid-response capacity is important because vulnerable groups are often the most marginalized in terms of aid received. unicef works to ensure that children have access to education, health care, safety, and protected child rights. in the response and recovery periods of humanitarian emergencies, these roles expand according to victims' needs. (in countries where uni-cef has not yet established a permanent presence, the form of aid is virtually the same; however, the timing and delivery are affected, and reconstruction is not nearly as comprehensive.) the unicef office of emergency programmes (emops), which has offices in new york and geneva, maintains overall responsibility for coordinating unicef's emergency management activities. cadri was created in as a joint program of the undp bureau for crisis prevention and recovery (undp/bcpr), the united nations office for the coordination of humanitarian affairs (ocha), and the secretariat of the international strategy for disaster reduction (isdr). recognizing that capacity development is a cross-cutting activity for disaster risk reduction as stipulated in the hyogo framework (hf), cadri's creation is designed to support all five priorities of the hf. cadri was formally launched by the three organizations at the global platform for disaster risk reduction meeting, june , geneva. cadri succeeds the un disaster management training programme (dmtp), a global learning initiative, which trained united nations, government, and civil society professionals between and . dmtp is widely known for its pioneering work in developing high-quality resource materials on a wide range of disaster management and training topics. more than trainers' guides and modules were developed and translated. cadri's design builds on the success and lessons learned from the dmtp and reflects the significant evolution in the training and learning field since the start of the dmtp, particularly regarding advances in technology for networking and learning purposes. cadri's design also reflects the critical role that the un system plays at the national level in supporting governments' efforts to advance disaster risk reduction. in the context of the un's increasingly important role, cadri provides capacity enhancement services to the un system at the country level as well as to governments. these include learning and training services and capacity development services to support governments to establish the foundation for advancing risk reduction. emops works closely with the unicef programme division, managing the unicef emergency programme fund (epf; see the following section) and ensuring close interagency coordination with other participating humanitarian organizations. in this role, unicef is also in the position to act as coordinator in specific areas in which it is viewed as the sector leader. for instance, unicef was tasked with leading the international humanitarian response in the areas of water and sanitation, child protection, and education for the asia tsunami and earthquake response. (in aceh province alone, more than agencies addressed water and sanitation issues.) unicef maintains that humanitarian assistance should include programs aimed specifically at child victims. its relief projects generally provide immunizations, water and sanitation, nutrition, education, and health resources. women are recipients of this aid as well, because unicef considers women to be vital in the care of children. (see exhibit . .) to facilitate an immediate response to an emergency situation, unicef is authorized to divert either $ , or $ , from country program resources (depending on whether the country program's annual budget is above or below $ million, respectively) to address immediate needs. if the disaster is so great it affects existing unicef programs operating in the country, the unicef representative can shift these programs' resources once permission is received from the national government and unicef headquarters. unicef also maintains a $ million global epf, which provides funding for initial emergency response activities. by the end of the three weeks of fighting in early in gaza, children had been killed and , injured, and much of gaza's infrastructure, including schools, health facilities, and vital infrastructure for water and sanitation, had been damaged. unicef was on hand to provide humanitarian support. it led the collective efforts of un agencies on the ground to restore education, provide emergency water supplies and sanitation, maintain nutritional standards, and protect children from further harm. from the early days, unicef made sure that first aid and emergency medical kits, essential drugs, and water purification tablets flowed into gaza. emergency education supplies such as classroom tents and school-in-a-box kits maintained some sense of continuity and normalcy for children. unicef and its partners were able to reach more than , school-age children. unicef raised global awareness of the harm being done to children through extensive media coverage and advocacy. attention was also raised by the visits of the special representative of the secretary-general for children and armed conflict, radhika coomaraswamy-who called for the protection of children-and unicef executive director ann m. veneman, as well as goodwill ambassadors mia farrow and mahmoud kabil. unicef also extended psychosocial services, including in-depth counselling and structured recreational activities, across gaza. training reinforced the capacities of psychosocial workers to protect children and help them heal. radio programmes and , leaflets designed for children warned of the risks of mines and unexploded ordnance left behind. unicef water tankers ensured a steady supply of clean drinking water to schools with , students, while desalination units were installed to rid water of dangerous concentrations of chlorides and nitrates. to thwart the risk of acute malnutrition, unicef worked through health clinics for mothers and children to offer supplements of micronutrients and fortified food. the quality and supply of teaching materials were improved through unicef's provision of math and science teaching kits. programmes for vulnerable adolescents concentrated on supporting remedial learning, relieving stress, and providing life skills-based education and opportunities to engage in civic activities. through unicef's systematic advocacy with partner organizations, almost half the attendees were girls. the world food programme (wfp) is the un agency tasked with addressing hunger-related emergencies. it was created in by a resolution adopted by the un general assembly and the un fao. today, the program operates in countries and maintains eight regional offices. in the year alone, the wfp provided . million metric tons of food aid to . million people in countries through its relief programs. over the course of its existence, the wfp has provided more than million metric tons of food to countries worldwide. wfp was an early member of the former inter-agency task force for disaster reduction (see below) and maintains disaster risk reduction as one of its priority areas, focusing on reducing the impact of natural hazards on food security, especially for the vulnerable. the wfp policy on disaster risk reduction and management, approved in , highlights this role as being central to the organization's work. wfp drr programs seek to build resilience and reduce risk through such activities as soil and water conservation, rehabilitating infrastructure, and training community members in disaster risk management and livelihood protection. the meret project in ethiopia is one example. this program targets food-insecure communities in degraded fragile ecosystems prone to drought-related food crises. other programs maintained by wfp include: • r resilience initiative: the rural resilience initiative (r ) is a partnership between wfp and oxfam america, with support from global reinsurance company swiss re, to test a new, comprehensive disaster risk reduction and climate change adaptation approach. the program allows cash-poor farmers and rural households to pay for index insurance with their own labor, so they can both manage and take risks to build resilient livelihoods. • livelihoods early assessment and protection (leap): wfp has been assisting the government of ethiopia to develop an integrated risk management system through the livelihoods early assessment and protection (leap) project. leap provides early warning data on food security that allows a rapid scale-up of the "national productive safety net programme" by activating contingency plans. when a serious drought or flood is detected, resources from a us$ million contingency fund are made immediately available to ensure early and more effective emergency response, thereby protecting livelihoods and saving lives. • the joint wfp/ifad weather risk management facility (wrmf): wrmf supports the development of innovative weather and climate risk management tools, such as weather index insurance (wii). the goal of these programs is to improve quality-of-life issues and to reduce the incidence of food shortages. this program was launched in through funding from the bill and melinda gates foundation. it has been piloted in china and ethiopia. wfp has established a steering committee for disaster mitigation to help its offices integrate these activities into regular development programs. examples of mitigation projects that focus on food security include water harvesting in sudan (to address drought), the creation of grain stores and access roads in tanzania, and the creation of early warning and vulnerability mapping worldwide. because food is a necessity for human survival and is considered a vital component of development, a lack of food is, in and of itself, an emergency situation. the wfp works throughout the world to assist the poor who do not have sufficient food so they can survive "to break the cycle of hunger and poverty." hunger crises are rampant-more than billion people across the globe receive less than the minimum standard requirement of food for healthy survival. hunger may exist on its own, or it may be a secondary effect of other hazards such as drought, famine, and displacement. the wfp constantly monitors the world's food security situation through its international food aid information system (fais). using this system, wfp tracks the flow of food aid around the world (including emergency food aid) and provides the humanitarian community with an accurate inventory and assessment of emergency food-stock quantities and locations. this database also includes relevant information that would be needed in times of emergency, such as anticipated delivery schedules and the condition and capabilities of international ports. in rapid-onset events such as natural disasters, the wfp is a major player in the response to the immediate nutritional needs of the victims. food is transported to the affected location and delivered to storage and distribution centers. (see figure . .) the distribution is carried out according to preestablished needs assessments performed by ocha and the undp. the wfp distributes food through contracted ngos that have the vast experience and technical skills to plan and implement transportation, storage, and distribution. the principal partners in planning and implementation are the host rice donated by japan is loaded by the world food programme onto wfp trucks to feed survivors of the asia tsunami and earthquake events sources: skullard, ; wfp, . governments, who must request the wfp aid, unless the situation is a che without an established government, in which case the un secretary-general makes the request. the wfp works closely with all responding un agencies to coordinate an effective and broad-reaching response, because food requirements are so closely linked to every other vital need of disaster victims. during the reconstruction phase of a disaster, the wfp often must continue food distribution. rehabilitation projects are implemented to foster increased local development, including the provision of food aid to families, who, as a result, will have extra money to use in rebuilding their lives; and food-for-work programs, which break the chains of reliance on aid as well as provide an incentive to rebuild communities. wfp administers the international emergency food reserve (iefr), which was originally designed to store a minimum of , tons of cereals. this program has not enjoyed the full support of donors as agreed in its creation, however, and as such, annual funding levels have fluctuated significantly. if supported, iefr would manage separate resources provided by donors to address long-term operations such as ches, and would dedicate $ million from its general resources for emergency assistance in addition to $ million for long-term emergency assistance. the program's immediate response account is a cash account maintained for rapid purchase and delivery of food in emergency situations. resources would be purchased from local markets (whenever possible), thereby ensuring food arrives sooner than other aid, which must move through regular channels. wfp response begins at the request of the affected country's government. . in the early days of an emergency, while the first food supplies are being delivered, emergency assessment teams are sent in to quantify exactly how much food assistance is needed for how many beneficiaries and for how long. they must also work out how food can best be delivered to the hungry. . equipped with the answers, wfp draws up an emergency operation (emop), including a plan of action and a budget. [the emop] lists who will receive food assistance, what rations are required, the type of transport wfp will use, and which humanitarian corridors lead to the crisis zone. . next, wfp launches an appeal to the international community for funds and food aid. the agency relies entirely on voluntary contributions to finance its operations, with donations made in cash, food, or services. governments are the biggest single source of funding. [more than governments support wfp's worldwide operations.] . as funds and food start to flow, wfp's logistics team works to bridge the gap between the donors and the hungry. [in , the agency delivered . million metric tons of food aid by air, land, and sea.] (wfp ) ships carry the largest wfp cargo, their holds filled to the brim with , tons or more of grain, cans of cooking oil, and canned food; the agency has ships on the high seas every day, frequently rerouting vessels to get food quickly to crisis zones. in extreme environments, wfp also uses the skies to reach the hungry, airlifting or airdropping food directly into disaster zones. before the aid can reach its country of destination, logistics experts often need to upgrade ports and secure warehouses. trucks usually make the final link in wfp's food chain, transporting food aid along the rough roads that lead to the hungry. where roads are impassable or nonexistent, wfp relies on less conventional forms of transport: donkeys in the andes, speedboats in the mozambique floods, camels in sudan, and elephants in nepal. at this stage, local community leaders work closely with wfp to ensure rations reach the people who need it most: pregnant mothers, children, and the elderly. the world health organization (who) was proposed during the original meetings to establish the un system in san francisco in . in , at the united health conference in new york, the who constitution was approved, and it was signed on april , (world health day). who proved its value by responding to a cholera epidemic in egypt months before the epidemic was officially recognized. who serves as the central authority on sanitation and health issues throughout the world. it works with national governments to develop medical and health care capabilities and assist in the suppression of epidemics. who supports research on disease eradication and provides expertise when requested. it provides training and technical support and develops standards for medical care. who was an early member of the former interagency task force for disaster reduction (see below), and continues to assist local and national governments as well as regional government associations with health-related disaster mitigation and preparedness issues. it does this primarily by providing education and technical assistance to government public health officials about early detection, containment, and treatment of disease and the creation of public health contingency plans. who activities address primary hazards, such as epidemics (e.g., avian influenza, malaria, dengue fever, sars, swine flu, and mers/cov), and the secondary health hazards that accompany most major disasters. through their website and collaboration with various academic institutions, who has also worked to advance public health disaster mitigation and preparedness research and information exchange. the who director-general is a member of the iasc and the iasc working group. in those capacities, the who recommends policy options to resolve the more technical and strategic challenges of day-to-day emergency operations in the field. to incorporate public health considerations in un interagency contingency planning and preparedness activities, the who also participates in the iasc task force on preparedness and contingency planning. the who emergency risk management and humanitarian response department was created to enable who to work closely with member states, international partners, and local institutions in order to help communities prepare for, respond to, and recover from emergencies, disasters, and crises. the emergency response framework (erf) was developed in to clarify the who role and their responsibilities in emergency situations (who ). in the event of a disaster, who responds in several ways to address victims' health and safety. most important, it provides ongoing monitoring of diseases traditionally observed within the unsanitary conditions of disaster aftermath. who also provides technical assistance to responding agencies and host governments establishing disaster medical capabilities and serves as a source of expertise. it assesses the needs of public health supplies and expertise and appeals for this assistance from its partners and donor governments. per the erf, who is obligated to respond to emergencies under several conventions and agreements, including the international health regulations and the interagency steering committee. the key functions of hac in times of crises are: • measure health-related problems and promptly assess health needs of populations affected by crises, identifying priority causes of disease and death; • support member states in coordinating action for health; • ensure that critical gaps in health response are rapidly identified and filled; and • revitalize and build capacity of health systems for preparedness and response. when other government agencies, private medical facilities, or ngos cannot meet the public health needs of the affected population, who's country-level emergency response team and international emergency support teams bring together expertise in epidemics, logistics, security coordination, and management, collaborating with un agencies participating in response and recovery. who has several bilateral agreements with other un agencies and ngos (including the red cross and red crescent movement) and coordinates the interagency medical/health task force (imtf), an informal forum that provides guidance on technical and operational health challenges in humanitarian crises. the who global emergency management team (gemt) was created in to lead the planning, management, implementation, monitoring, and evaluation of who's emergency work (including national preparedness, institutional readiness, and emergency response for disasters that exhibit public health consequences.) the gemt is made up of staff from both who headquarters and regional office directors responsible for disaster risk management issues (e.g., preparedness, surveillance, alert, and response). as needed, other relevant staff are invited to join gemt efforts. gemt focuses on all-hazards emergency risk management, notably that of leadership on the health cluster. when technical expertise beyond that held by the team's members is needed, the global emergency network (gen), comprising directors (or delegates) of departments and programs that have various emergency management functions, is consulted. the gemt continuously tracks global health events and the organization-wide use of internal and external resources in all emergencies, and reports on all major emergencies. during an actual emergency or disaster, a subset of the gemt, known as the gemt-response (gemt-r), is mobilized to grade and manage the response to a specific emergency. for larger-scale emergencies, the gemt-r is responsible for making recommendations to executive management on the best use of who resources given the event's scale, scope, duration, and complexity (given other existing requirements in ongoing events). since its inception, six regional offices have been established. these offices focus on the health issues in each region: • regional office for africa • pan american health organization • regional office for south-east asia • regional office for europe • regional office for eastern mediterranean • regional office for the western pacific the food and agriculture organization (fao) was established as a un agency in in quebec city, canada. the organization's mandate is to "raise levels of nutrition, improve agricultural productivity, better the lives of rural populations and contribute to the growth of the world economy" (fao ) . it provides capacity-building assistance to communities that need to increase food production. in , fao pledged to help current and future generations achieve food security by . in spite of their work, more than million people worldwide continue to suffer the effects of food shortages, including more than million children under five years of age who show signs of malnutrition-based growth stunting. fao is headquartered in rome, italy. the organization also maintains five regional, five subregional, and country offices, each of which works with un member countries and other partners to coordinate various activities, including disaster management. it has member nations, two associate member nations, and one member organization (the european union). fao was an early member of the interagency task force on disaster reduction prior to its becoming the global platform for disaster risk reduction. the world food summit mandated fao to assist un member countries in developing national food security, vulnerability information, and specialized mapping systems to cut worldwide malnutrition. a key component of this strategy is strengthening the capacity of communities and local institutions to prepare for natural hazards and respond to food emergencies during disasters and crises. this objective focuses on: • strengthening disaster preparedness and mitigation against the impact of emergencies that affect food security and the productive capacities of rural populations; • forecasting and providing early warning of adverse conditions in the food and agricultural sectors and of impending food emergencies; • strengthening programs for agricultural relief and rehabilitation and facilitating the transition from emergency relief to reconstruction and development in food and agriculture; and • strengthening local capacities and coping mechanisms by guiding the choice of agricultural practices, technologies, and support services to reduce vulnerability and enhance resilience. in , fao released strategic objective i, which guided the organization in conducting "preparedness for, and effective response to, food and agricultural threats and emergencies." this strategy laid out three specific results that were sought, including: . countries' vulnerabilities to crises, threats, and emergencies is reduced through better preparedness and integration of risk prevention and mitigation into policies, programs, and interventions; . countries and partners respond more effectively to crises and emergencies with food-and agriculture-related interventions; and . countries and partners have improved transition and linkages between emergency, rehabilitation, and development. within fao, the emergency coordination group is the organizational mechanism for the overall coordination of emergency and disaster reduction issues. this group strengthens fao's capacity to perform food-based disaster management activities in support of member countries and partners in a more integrated way. ecg is chaired by the director of the office for coordination of normative, operational and decentralized activities and has a secretariat provided by the office of the special advisers to the director-general. key units of this group include: the investment centre division prepares investment programs and projects for funding by major multilateral development banks during the rehabilitation and reconstruction and the recovery phases. fao field offices are in developing countries. regional and subregional offices are also maintained. at any time, fao is involved in some , agricultural projects in the developing world. experts working on these projects in affected countries are frequently called upon to help with emergency needs assessments and field operations. in a disaster, fao representatives in developing countries respond by coordinating with the government and other partners. in countries with ches, fao coordinates actions that address emergency agricultural needs and assists in the development and implementation of strategies for creating conditions conducive to recovery and sustained development. fao's approach is to set up coordination units that: • provide technical assistance to help the impacted government and its citizens to manage agricultural relief; • monitor the ongoing crisis relative to food; • advise ngos and other organizations involved in food and agriculture; • help build the necessary national capacity to transition from response to recovery; and • establish information collection and database management systems. examples of countries where fao emergency coordination units have been set up include bosnia, tajikistan, rwanda, burundi, liberia, sierra leone, somalia, iraq, and angola. fao also maintains a website of disaster reduction information through its world agricultural information center (waicent). this online portal provides access to the global information and early warning system, information on crop prospects, and other relevant documents and data. fao also works to help countries adopt sustainable agricultural and other land-use practices. its land and water division has helped to reverse land loss, thus increasing disaster resilience, by promoting the development of disaster-resistant agro-ecosystems and the sound use of land and water resources. in times of disaster, the emergency operations and rehabilitation division helps communities recover. while other agencies, such as wfp, address immediate food needs by providing the actual food aid to victims, fao provides assistance to restore local food production and reduce dependency on food aid. the fao's first action following disasters, in partnership with wfp, is to send missions to the affected areas to assess crops and food supply status. the emergency operations service of the emergency operations and rehabilitation division leads these missions, sending fao experts to consult with farmers, herders, fisheries, and local authorities to gather disaster and recovery data. using their assessment, fao designs an emergency agricultural relief and rehabilitation program and mobilizes the funds necessary for its implementation. the emergency operations and rehabilitation division distributes material assets such as seeds, fertilizer, fishing equipment, livestock, and farm tools. in a che, fao helps affected communities bolster overall resources and restore and strengthen agricultural assets to make them less vulnerable to future shocks. for example, fao has been working in regions outside government authority in the sudan to conduct community-based training of animal health workers aimed at keeping their livestock-a vital part of local livelihoods-from dying. when a disaster occurs, the emergency operations and rehabilitation division of fao establishes an emergency agriculture coordination unit consisting of a team of technical experts from a wide range of fields (including crop and livestock specialists). this field-level team provides information and advice to other humanitarian organizations and government agencies involved in emergency agricultural assistance in the affected area. fao coordination units also facilitate operational information exchange, reducing duplications of and eliminating gaps in assistance. fao's primary beneficiaries include: • subsistence farmers • pastoralists and livestock producers • artisan "fisherfolk" • refugees and internally displaced people • ex-combatants • households headed by women or children and/or afflicted by hiv/aids the special emergency programmes service (tces), also within the emergency operations and rehabilitation division, is responsible for the effective implementation of specially designed emergency programs. these programs require particular attention because of the political and security context surrounding their interventions and the complexity of the institutional setup. tces was responsible for fao's intervention in the framework of the oil for food program in iraq and fao's emergency and early rehabilitation activities in the west bank and gaza strip. the rehabilitation and humanitarian policies unit (tcer) is the final component of the emergency operations and rehabilitation division. tcer is responsible for making recommendations regarding disaster preparedness, post-emergency, and rehabilitation initiatives. the unit coordinates fao's position on humanitarian policies and ensures that fao addresses the gap between emergency assistance and development. tcer also liaises with other un entities dealing with humanitarian matters. the fao's disaster-and emergency-related projects are funded by contributions from governmental agencies, ngos, other un agencies, and by the fao technical cooperation programme (tcp). each year, approximately percent of fao emergency funds are raised through the cap. fao expenditure on emergency efforts has grown significantly during the past few years, indicative of the greater role the organization has assumed in disaster management. current emergency-related projects include: • improved food security for hiv/aids-affected households in africa's great lakes region • rehabilitation of destroyed greenhouses in the west bank and gaza strip • land-tenure management in angola • emergency agricultural assistance to food-insecure female-headed households in tajikistan • consolidation of peace through the restoration of productive capacities of returnee and host communities in conflict-affected areas in sudan • rehabilitation of irrigation systems in afghanistan • rehabilitation of farm-to-market roads in the democratic republic of the congo the position of united nations commissioner for refugees (unhcr) was created by the general assembly in to provide protection and assistance to refugees. the agency was given a three-year mandate to resettle . million european world war ii refugees. today, unhcr is one of the world's principal humanitarian agencies, operating through the efforts of more than , personnel and addressing the needs of . million people in more than countries. unhcr promotes international refugee agreements and monitors government compliance with international refugee law. unhcr programs begin primarily in response to an actual or impending humanitarian emergency. in complex humanitarian disasters and in natural and other disasters that occur in areas of conflict, there is a great likelihood that refugees and idps will ultimately result. the organization's staffs work in the field to provide protection to refugees and displaced persons and minimize the threat of violence many refugees are subject to, even in countries of asylum. the organization seeks sustainable solutions to refugee and idp issues by helping victims repatriate to their homeland (if conditions warrant), integrate in countries of asylum, or resettle in third countries. unhcr also assists people who have been granted protection on a group basis or on purely humanitarian grounds, but who have not been formally recognized as refugees. unhcr works to avert crises by anticipating and preventing huge population movements from recognized global areas of concern ("trouble spots"). one method is to establish an international monitoring presence to confront problems before conflict breaks out. for example, unhcr mobilized a "preventive deployment" to five former soviet republics in central asia experiencing serious internal tensions following independence. unhcr also promotes regional initiatives and provides general technical assistance to governments and ngos addressing refugee issues. in times of emergency, unhcr offers victims legal protection and material help. the organization ensures that basic needs are met, such as food, water, shelter, sanitation, and medical care. it coordinates the provision and delivery of items to refugee and idp populations, designating specific projects for women, children, and the elderly, who comprise percent of a "normal" refugee population. the blue plastic sheeting unhcr uses to construct tents and roofing has become a common and recognizable sight in international news. unhcr maintains an emergency preparedness and response section (eprs), which has five emergency preparedness and response officers (epro) who remain on call to lead emergency response teams into affected areas. the epros may be supported by a range of other unhcr human resources, including: • emergency administrative officers and emergency administrative assistants, for quickly establishing field offices • the members of the emergency roster, which includes staff with diverse expertise and experience, are posted throughout the world and are available for rapid emergency deployment • staff (by existing arrangement) from the danish refugee council, the norwegian refugee council, and un volunteers, to provide specialized officials on short notice as needed (more than people are available at any given time) • individuals registered on a roster of "external consultant technicians," who are specialized in various fields often required during refugee and idp emergencies (including health, water, sanitation, logistics, and shelter) • select ngos that have been identified as capable of rapid deployment to implement assistance in sectors of need (e.g., health, sanitation, logistics, and social services) unhcr has the capacity to respond to a new emergency impacting up to , people. the agency can also mobilize more than trained personnel within hours. these experts come from its emergency response team (ert) roster. unhcr has also developed mechanisms for the immediate mobilization of financial resources to help meet the response to an emergency without delay. unhcr staff may be supported under an agreement with the swedish rescue services agency, which is prepared to establish a base camp and office in affected areas within hours' notice. other supplies and resources, such as vehicles, communications equipment, computers, personal field kits, and prepackaged office kits are maintained for rapid deployment to support field staff. unhcr maintains stockpiles of relief aid, including prefabricated warehouses, blankets, kitchen sets, water storage and purification equipment, and plastic sheeting. these are stored in regional warehouses or may be obtained on short notice from established vendors that guarantee rapid delivery. unhcr also maintains agreements with stockpiles outside the un system from which they may access items, such as the swedish rescue board and various ngos. unhcr developed a quick impact project (qip) initiative. qips are designed to bridge the gap between emergency assistance provided to refugees and people returning home and longer-term development aid undertaken by other agencies. these small-scale programs are geared toward rebuilding schools and clinics, repairing roads, and constructing bridges and wells. unhcr is funded almost entirely by voluntary contributions from governments, intergovernmental organizations, the private sector, and individuals. it receives a limited subsidy of less than percent of the un budget for administrative costs and accepts "in-kind" contributions, including tents, medicines, trucks, and air transportation. as the number of people protected or of concern by unhcr has reached record highs, its annual budget has likewise jumped several fold in just a few years. in , the unhcr budget was a record $ . billion, yet by that number rose to over $ . billion-a rate that has been maintained ever since. (see figure . .) in , unhcr established a new global emergency stockpile in dubai, united arab emirates. the new stockpile is the largest of several unhcr global stockpiles. it is used to store relief items such as tents, blankets, plastic sheeting, mosquito nets, kitchen sets, and jerry cans, among other items, for up to , people. prefabricated warehouses and other safety and security equipment for staff and office support are also available. in , items from the stockpile were sent to countries, including syria, jordan, lebanon, turkey, and others in africa and asia. the items shipped included , , blankets, , buckets, , jerry cans, , kitchen sets, , sleeping mats, , mosquito nets, , plastic tarpaulins, and , family tents (unhcr ). although unhcr does not often become involved in natural disaster response, rather focusing on areas of conflict, its expertise and assistance were required in the aftermath of the october earthquake that severely impacted south asia. during the response phase of this disaster, unhcr provided flights loaded with supplies from its global and regional stockpiles and contributed , family tents, , blankets, , plastic sheets, and thousands of jerry cans, kitchen sets, stoves, and lanterns. the aid items were drawn from its existing warehouses in pakistan and afghanistan, as well as other locations throughout the world. because of the earthquake, roads used to access , afghan refugees affected by the earthquake were severely damaged, but unhcr was able to quickly assess damages and needs and meet those needs through their existing networks (unhcr ) . in the event of a large-scale disaster, the un may form a disaster management team (dmt) in the affected country. if the disaster clearly falls within the competence and mandate of a specific un agency, that organization will normally take the lead, with the un dmt serving as the forum for discussing how other agencies will work to support that lead agency. the un dmt is convened and chaired by the un resident coordinator and comprises country-level representatives of fao, undp, ocha, unicef, wfp, who, and, where present, unhcr. specific disaster conditions may merit participation by other un agencies. the leader of the undac team, assigned by ocha, automatically becomes a member of the un dmt. a undp official called the disaster focal point officer often serves as the un dmt secretary, but the team is free to choose another person, if necessary. undp is also responsible for providing a venue for the team and any basic administrative support needs. the un dmt's primary purpose is to ensure that in the event of a disaster, the un is able to mobilize and carry out a prompt, effective, and concerted response at the country level. the team is tasked with coordinating all disaster-related activities, technical advice, and material assistance provided by un agencies, as well as taking steps to avoid wasteful duplication or competition for resources by un agencies. the un dmt interfaces with the receiving government's national emergency management team, from which a representative may, where practical, be included in the un dmt. the central emergency response fund (cerf) was created in through un general assembly resolution / to allow for faster operational action by un agencies. the fund, which was originally called the central emergency revolving fund but renamed in under resolution / , is administered on behalf of the un secretary-general by the emergency relief coordinator. during times of disaster, cerf provides agencies involved in the humanitarian response with a constant source of funding to cover their activities. its purpose is to shorten the amount of time between the recognition of needs and the disbursement of funding. agencies that have received pledges from donors but have not yet received actual funds, or agencies that expect to receive funds from other sources in the near future, can borrow equivalent amounts of cash, interest free, through cerf. voluntary contributions from donor nations and private-sector donors have raised billions since the inception of cerf, of which more than $ billion has been allocated in the form of grants to almost countries. the program's goal is to have $ million replenished annually. (see table . for a full list of donors.) at the outset, cerf was designed only for ches, but in the general assembly voted . the lending agency submits a request for an advance to the erc, which includes a descriptive justification on the project or activities to be funded. if a future pledge for funding has been promised by a donor or if the agency has other means for repaying the loan, this information is included in the request. . an ocha officer reviews the request. if it is accepted (statistics show that the majority are accepted), the erc informs the agency and sets out the loan use and repayment terms. . disbursement usually occurs within hours. payment is made through an internal un "voucher." . loans must be repaid within six months. this entire process is conducted at ocha's new york office. figure . illustrates patterns of use by the various un agencies. the consolidated appeals process (cap), which began in , allows humanitarian aid organizations to plan, implement, and monitor their activities. these organizations can work together to produce a common humanitarian action plan (chap; see the following section) and an appeal for a specific disaster or crisis, which they present to the international community and donors. the cap fosters closer cooperation between governments, donors, aid agencies, and many other types of humanitarian organizations. it allows agencies to demand greater protection and better access to vulnerable populations, and to work more effectively with governments and other actors. the cap is initiated in three types of situations: . when there is an acute humanitarian need caused by a conflict or a natural disaster . when the government is either unable or unwilling to address the humanitarian need . when a single agency cannot cover all the needs on november , , typhoon haiyan (yolanda) hit the philippines. the humanitarian situation in the areas devastated by the typhoon was catastrophic. an estimated million people were affected, including million children. close to million people were displaced and in dire need of humanitarian assistance. in response, the united nations emergency relief coordinator, valerie amos, released us$ million to seven united nations agencies and the international organization for migration (iom) on november. • the united nations children's fund (unicef) received $ , , to ensure water, sanitation, and hygiene facilities. unicef also provided child protection, including protective learning environments, and reduced the risk of outbreaks of vaccine-preventable diseases among children aged to months. finally, unicef provided nutrition interventions to children aged to months as well as to pregnant and lactating women. • with an allocation of $ , , the food and agriculture organization (fao) provided emergency food assistance. • the united nations population fund (fpa) received $ , to ensure access to reproductive health services and to prevent gender-based violence. • to support the internally displaced persons (idps), the united nations high commissioner for refugees (unhcr) provided emergency shelter assistance through an allocation of $ , , . • the world food programme (wfp) received $ , , to provide emergency food assistance. wfp also coordinated the humanitarian operations in the areas affected. • the world health organization (who) provided health services through an allocation of $ , , . • the united nations development programme (undp) received $ , , to manage time-critical debris disposal. • through an allocation of $ , , , iom supported evacuation centers and idp sites by procuring and distributing emergency shelter kits and essential non-food items. the cerf allocations were expected to ultimately benefit more than . million people. the cap is led by the hc, who triggers the interagency appeal and collaborates with the iasc country team at the local level and the erc at headquarters. participants in the process include: • iasc. although all team members are encouraged to participate in chap development, some members may make appeals for funding outside of the un and its cap (as is often the case with the red cross). • donors. donors participate in chap development by committing to "good humanitarian donorship principles." • host government(s). the cap is best prepared in consultation with the host government, particularly the ministries the un operational agencies are working with on a day-to-day basis. • affected population(s). whenever possible, it is always advantageous to include the affected populations' perspective into relief and recovery planning. a consolidated appeal (ca) is a fundraising document prepared by several agencies working to outline annual financing requirements for implementing a chap. although governments cannot request funding through the ca, ngos can make a request as long as their proposed project goals are in line with chap priorities. the ca is usually prepared by the hcs in september or october, and then launched globally by the un secretary-general at the donor's conference held each november. the ca lasts as long as is necessary for funding purposes, usually a year or more. the sectors that may be considered by the ca include: • agriculture • coordination and support services the process for filing a ca is as follows: . at the onset of the emergency, a situation report is issued (can cover from day to week ). . in the meantime, a flash appeal may be prepared and launched (covers week to month ). . finally, a ca may be issued. if the situation and needs in the field change, a revision to any part of an appeal can be issued at any time. additionally, projects can be added, removed, or modified within the appeal at any time. approximately percent of cap and flash appeal funding comes from a small group of wealthy nations, including canada, the european community humanitarian office (echo) and the european commission, germany, japan, the netherlands, norway, sweden, the united kingdom, and the united states. in high-profile events, private donors may constitute a large percentage of donations, such as occurred in the case of the tsunami disaster in asia. the chap is a strategic plan developed by agencies working together at the field level that assesses needs in an emergency and coordinates response. it acts as the foundation for a ca, and includes the following information: . common analysis of the context for humanitarian assistance . needs assessment . best, worst, and most likely scenarios . identification of roles and responsibilities (who does what and where) . clear statement of long-term objectives and goals . framework for monitoring strategy and revising as necessary a flash appeal is a special kind of ca, designed for structuring a coordinated humanitarian response for the first three to six months of an emergency. whenever a crisis or natural disaster occurs, the un hc may issue a flash appeal in consultation with all stakeholders involved in the humanitarian response (including the affected government). it is normally issued between the second and fourth weeks of the response and provides a concise overview of urgent lifesaving needs. it may also include early recovery projects if they can be implemented within the appeal's time frame. in , as a part of the inter-agency standing committee (iasc) transformative agenda, the united nations changed the way that the cap was issued. the appeal, which addresses the emergencies, was the largest appeal to date, calling for $ . billion (more than $ . billion greater than the appeal) to support million people in countries. the increase was primarily due to a $ . billion request for the complex humanitarian emergency in syria, as well as another che in the central african republic and typhoon haiyan in the philippines. the changes begin with the document's name, which is now called the "overview of global humanitarian response" rather than the former "overview of consolidated appeals process." the overall goal of the change is to ensure that the cap process is needs-based and funds are adequately monitored. the change is explained in the appeals document as follows: "now, instead of one overweight cap document trying to present all elements of the program cycle, for the key elements appear in a series of documents produced in sequence: humanitarian needs overview; strategic response plan (comprising the country strategy plus cluster plans); and periodic monitoring bulletins reporting on basic delivery and outputs compared to targets. discussions are ongoing about the possible production of end-of-year reports on achievements versus objectives" (un b). (see exhibit . ). since , more than consolidated and flash appeals have been launched, collectively raising more than $ billion for ngos, the international organization for migration (iom), and un agencies. in addition to the un agencies discussed previously, which tend to be the primary agencies involved in all forms of disaster management, a handful of organizations provide more focused assistance as deemed necessary in most disasters that require international participation. as illustrated in figure . , which details un assistance to the various countries affected by the december asian tsunami and earthquake events, a different mix of un assistance is needed in each country, even within the same international disaster scenario. several of these organizations are detailed in the following list. • international labour organization (ilo). the ilo works with the affected population to address issues related to employment, including job creation, skills training, employment services, small business assistance, and other functions. (see exhibit . .) • international organization for migration (iom) . the iom provides rapid humanitarian aid to displaced populations by supplying emergency shelter, transporting relief materials, and assisting in medical evacuations. the organization stabilizes populations through the provision of short-term community and microenterprise development programs. iom also actively supports governments in the reconstruction and rehabilitation of affected communities by being the lead service provider of : haiti cannot afford to become a forgotten crisis. important progress has been made in recent years, but the country is still one of the most exposed to risk from disaster and climate change. multiple disasters combined with high unemployment, increased inequality, and poor access to basic social services have prolonged the vulnerability of an estimated three million haitians to displacement, food insecurity, and fragile living conditions. haiti suffers the world's largest cholera epidemic, which has affected over , people and killed , . although the humanitarian situation in south sudan has stabilized on several fronts, needs remain high-driven primarily by violence and displacement, persistent food insecurity, and chronic poverty. national capacity to deliver basic services is low, with aid agencies the main providers of health care, clean water, livelihoods support, and other services in many parts of the country. while needs are expected to remain high in - , in some areas such as food insecurity, there are opportunities for innovative and more targeted approaches to break recurring cycles of hardship. the strategy for - has three objectives: responding to immediate needs, enhancing communities' resilience against shocks and stresses, and building national capacity to deliver basic services. alongside core programmes to save lives and ease suffering, partners are increasingly integrating actions to reduce the risk of natural disasters, strengthen and diversify livelihoods, and address the long-term needs of vulnerable groups, including refugees and children. the strategy also emphasizes the importance of delivering aid in partnership with line ministries and national ngos to ensure humanitarian relief has a long-term positive impact. the strategy spans three years, to better address deep-rooted challenges and measure the impact of relief actions. requirements: $ . billion funding received against requirements: % people in need: . million people to receive help: . million in yemen, more than half the population needs some form of humanitarian aid. the collapse of basic services in - , endemic food insecurity, destroyed or damaged livelihoods and under-development, along with displacement resulting from conflict, have combined to plunge the country into a humanitarian emergency which may persist into . inflows of refugees and migrants from the horn of africa and returning yemeni migrants count among the vulnerable. ten and a half million people are food-insecure or severely food-insecure, and , , children under five suffer from acute or severe malnutrition. about half the population has no access to adequate water sources or sanitation facilities, and a further . million have insufficient access to health services. an estimated , returnees need assistance to rebuild their lives, while , refugees, mostly from somalia, and tens of thousands of mainly ethiopian migrants are stranded in the country. it is expected that the number of returning yemeni migrants, estimated to be , people, will double in . the weakness of rule-of-law institutions has been identified as a serious protection risk. according to the latest ilo estimates, . million out of the . million workers who have either temporarily or permanently lost their livelihoods were working in the service sector. over one third, or . million, were in agriculture and around per cent in the industry sector. "service sector includes people working in shops, public markets, restaurants, vendors, tricycle and jeepney drivers, mechanics, clerks, teachers, . . . who, like farmers and fisherfolks, have seen their source of income wiped away," said ilo philippine office director lawrence jeff johnson. "at least . million affected workers were already in a vulnerable situation before the typhoon struck, often living at or near the poverty line, doing whatever work they could find to survive and provide for their families. these people have lost the little they had to begin with. they have no home, no income, no savings and no one to turn to for help," said director johnson. "as the reconstruction efforts gather pace, the number one priority is to ensure that these workers have access to decent jobs, which include at least minimum wage, social protection, and safe working conditions," johnson said. the department of labor and employment (dole) and the department of social welfare and development (dswd) are rolling out emergency employment programmes to respond to the enormous reconstruction and livelihoods needs. the ilo is working closely with them as well as with local governments, business' and workers' organizations, and international partners. "these programmes comply with philippine regulation and international labour standards, ensuring that people are not exploited while they help to rebuild their communities and local economies," johnson explains. workers under the emergency employment programmes receive the minimum wage prevailing in the area and are employed for a minimum of days. they also have access to social protection benefits. "this is a very first step to jump start the economy and quickly put the affected communities back in the driver's seat in rebuilding their lives. ensuring minimum wage and social protection will help stimulate economic growth and speed the recovery process." johnson said. source: ilo, . unaids works with victims to protect them from the kinds of violence and activity that spreads hiv. in , the un general assembly held a special session on hiv/aids and declared that through unaids: [the un would] develop and begin to implement national strategies that incorporate hiv/aids awareness, prevention, care, and treatment elements into programs or actions that respond to emergency situations, recognizing that populations destabilized by armed conflict, humanitarian emergencies, and natural disasters, including refugees, internally displaced persons, and in particular, women and children, are at increased risk of exposure to hiv infection; and, where appropriate, factor hiv/ aids components into international assistance programs. (un ) • united nations population fund (unfpa). unfpa works to promote basic human rights throughout the world, and to increase the possibilities of women and young people to lead healthy and productive lives. their work focuses specifically on reproductive health and safe pregnancies and deliveries. during humanitarian crises, there is often a demand for reproductive health services even though distribution and health care systems have broken down. unfpa works closely with its humanitarian relief partners to support early and effective action to meet the reproductive health needs of refugees, idps, and others caught in crisis situations. supply shortages compound health risks in already dangerous situations and are a major obstacle to reproductive health in emergencies. existing supplies may fall far short of demand when large numbers of people move into a safer location. supplies, equipment, and medicine are organized and stored by unfpa for immediate distribution when an earthquake, flood, violent conflict, or other crisis arises. a rapid-response fund enables unfpa to mount a quick response to emergencies, especially in the initial stages. supplies are packaged in different emergency reproductive health kits, including a "clean birthing kit." once an emergency situation stabilizes, the procurement of reproductive health materials becomes a regular part of a more comprehensive healthcare program. • united nations human settlement programme (un-habitat) . un-habitat is mandated by the un general assembly to "promote socially and environmentally sustainable towns and cities with the goal of providing adequate shelter for all" (un ). un-habitat is mandated through the habitat agenda (a global settlement plan adopted in june by the international community) to take the lead in mitigation, response, and post-disaster rehabilitation capabilities in human settlements. the habitat agenda clearly outlines the link between human settlement development and vulnerability to disasters. in addition, it emphasizes the need for coordination and close partnerships with national and local governments, as well as civil society. finally, the habitat agenda recognizes the strong impact disasters have on women, and affirms the need for women's active involvement in disaster management. these steering principles underpin all normative and operational activities of the un-habitat disaster management programme (dmp). dmp operates under the disaster, post-conflict and safety section (dpcss), urban development branch. it was created to marshal the resources of un-habitat and other international agencies to provide local government, civil society, and the private sector with practical strategies for mitigating and recovering from conflicts and natural disasters in the context of human settlements. specific areas of attention include: • protecting and rehabilitating housing, infrastructure, and public facilities • providing technical and policy support to humanitarian agencies before and after crisis in the context of human settlements • building partnerships and providing complementary expertise in resettlement of displaced persons and refugees • restoring local social structures through settlement development • rehabilitating local government structures and empowering civil society • land and settlements planning and management for disaster prevention un-habitat launched the city resilience profiling programme (crpp) to support local government efforts to build capacity to reduce disaster risk. through their guidance, governments are assisted in the development of comprehensive and integrated urban planning and implementation of a resilient management approach. the city resilience profile is a baseline assessment of a city-system's ability to withstand and recover from potential hazards. examples of cities that have participated in the program include balangoda, sri lanka; barcelona, spain; beirut, lebanon; dagupan, philippines; dar es salaam, tanzania; lokoja, nigeria; portmore, jamaica; talcahuano/concepcion, chile; tehran, iran; and wellington, new zealand. un-habitat plays an important role in disaster recovery, given the impact on housing so many disasters have. the organization has lead agency status within the united nations system for coordinating activities related to human settlement. it is mandated in this role through the habitat agenda. the organization's responsibilities in this regard are to support national governments, local authorities, and civil society in ensuring that risk is not retained in the reconstruction housing that follows the event. housing reconstruction often begins soon after the disaster has occurred, and un-habitat seeks to deploy quickly to ensure that resilient building practices are incorporated into the recovery planning process. • united nations environmental program (unep). unep is the un agency focused on the protection of the environment and wise use of natural spaces. unep has several divisions that address global emergency and disaster management needs. • unep's disasters and conflicts sub-program was created to assess and address the environmental impacts of disasters and conflicts, especially as they relate to human health, livelihoods, and security. since , this program has responded to crises in more than countries. their assistance is provided to other un agencies responding as well as directly to the host country government. the disasters and conflicts sub-program has four overarching objectives: • perform post-crisis environmental assessments; • support post-crisis environmental recovery; • foster environmental cooperation for peacebuilding; and • promote disaster risk reduction. as the focal point for environment within the un crisis response system, unep also works to integrate environmental considerations within humanitarian and peacekeeping operations. coordinated by unep's post-conflict and disaster management branch, the disasters and conflicts sub-program is delivered through several key actors and partners, including the joint unep/ocha environment unit, the environment and security (envsec) initiative, and the apell (awareness and preparedness from emergencies on a local level) programme. apell, which is based out of the unep industry and environment office in paris, supports disaster risk reduction and disaster preparedness. it seeks to minimize the occurrence and harmful effects of technological accidents and emergencies resulting from human activity or as the consequence of natural disasters, particularly in developing countries. understandably, unep plays a major role in climate change activities, including climate change adaptation. the organization supports developing countries in their efforts to identify and address risk specifically related to changing temperature and precipitation that are associated with global climate change patterns, including sea level rise. one of the primary functions of this office is to help governments to integrate climate change adaptation policy throughout all sectors of government, such that it becomes a major policy goal rather than a distinct, stove-piped component of government. finally, unep promotes sustainable land-use management and helps countries identify opportunities to reduce carbon emissions, which are often blamed for the bulk of climate variability. • united nations educational, scientific, and cultural organization (unesco). unesco's goal is to contribute to the peace and security of the world through education, science, and culture. unesco has been involved in disaster management for decades. this organization advocates for the need for a shift in emphasis from relief and emergency response to prevention and increased preparedness and education of potentially affected populations. it strongly supports the design and dissemination of mitigation measures, as well as public education and awareness. unesco works to increase the role of academic and research sectors in creating risk and vulnerability reduction measures, and supports existing and new institutions through financial and material support. unesco proclaims that their function regarding disaster management is: to promote a better understanding of the distribution in time and space of natural hazards and of their intensity, to set up reliable early warning systems, to devise rational land-use plans, to secure the adoption of suitable building design, to protect educational buildings and cultural monuments, to strengthen environmental protection for the prevention of natural disasters, to enhance preparedness and public awareness through education and training communication and information, to foster post-disaster investigation, recovery and rehabilitation, to promote studies on the social perception of risks. (unesco ) • in , the un general assembly created un women, which merged four existing un organizations that focused exclusively on gender equality and women's issues. these included the united nations development fund for women (unifem), the international research and training institute for the advancement of women (instraw), the office of the special adviser on gender issues and advancement of women (osagi), and the division for the advancement of women (daw). un women works to ensure that the needs of women are considered in disaster planning and preparedness efforts, as well as in the aftermath of disasters and in the recovery from them, when women face extraordinary vulnerabilities. un women provides financial and technical assistance to innovative programs and strategies to foster women's empowerment and gender equality. (see exhibit . .) • united nations institute for training and research (unitar). unitar was created to provide training and research within the un system with the goal of increasing the effectiveness of all un programs. in recent years, more of these efforts have focused on the four phases of disaster management, addressing many related topics such as climate change, hazardous materials and pollution, land use, and biodiversity. the global platform for disaster reduction was established in as a forum for information exchange. the platform meets every two years and allows participants to discuss innovations and developments in drr as well as to share existing knowledge and build partnerships among the various stakeholders. the goal in creating the program was to improve drr implementation by fostering better communication and coordination among stakeholders, to serve as a way for un members to voice their concerns and needs, and to share their best practices and lessons learned. the global platform replaces the former interagency task force for disaster reduction (iatf/ dr), which was led by the un under-secretary-general for humanitarian affairs and composed of representatives from un agencies, international organizations, ngos, and other civil society for millions of people in rural viet nam, the impacts of climate change are mounting and sometimes deadly. as weather patterns change, many of viet nam's women in particular are paying a high price. "the weather becomes more extreme and erratic. storms, heavy rains, and floods destroy fields and houses, kill animals and people every year," said ranh nguyen, , a farmer and the head of the women's union group in an dung commune, in binh dinh province, central viet nam. there, ranh and her neighbours have joined the viet nam women's union and are working with un women to strengthen the role of women in disaster risk-reduction and disaster-reduction management. some kilometers from the city of binh dinh, an dung commune is always at high risk of flooding, as it only has one road connecting it to other communes,and landslides often occur during the storm season. almost every year, the commune suffers at least one severe flood that damages crops and houses heavily. and women are often the most affected. however, things are starting to change. "thanks to good preparation and detailed mapping that we developed in the meetings before each storm, nobody in the village was killed or injured severely in the last year storm season. crops, fowl, and cattle were saved," explains ranh, now an official member of the committee for flood and storm control in her commune. prior to the project, there were few women on the committees for flood and storm control (cfsc) in the village. through the training of women in disaster management, as well as national lobbying-supported by un women, undp and other stakeholders-the contribution of women has been recognized. a government decree issued in september now provides an official space for the women's union in decision-making boards of the cfsc at all levels. "after being involved in the project, i am more aware of the situation of climate change and its impacts on us. last year, we participated in the training and exchanged experiences with other women. we prepared better for our families and our village before the storm came," ranh said. she said that she talked to the other members of the communal committee for flood and storm control. as a result, before the flooding began, they had plans ready to evacuate people living in lowland areas and near the river. "the mapping we did together in the training was really helpful. we discussed how to encourage people to harvest earlier, before the storm season started." in the end, she said, no lives were lost. last year, a four-year-old boy was saved from drowning because his mother performed cpr on him. she and another women and girls learned this technique from the rescue and first aid training provided by the project. "i could not swim before and used to be frightened by the flooded river. but now i am no longer afraid of water thanks to the swimming classes. i will teach my children how to swim and tell other people to learn how to swim too," ranh said. this project continues to be implemented in four new provinces including thua thien hue, quang binh, ca mau and dong thap, all of which face a high risk of flooding. this project is financed through core funding to un women and from the government of luxemburg. stakeholders. the global platform is organized by the un office for disaster risk reduction (unisdr; see below). the global platform for disaster risk reduction is considered the most significant gathering of disaster risk reduction and disaster management stakeholders worldwide. every ten years, the world conference on disaster reduction is held. the first was held in . the second world conference, held in in kobe, japan, led to the launching of the hyogo framework for action (hfa). the world conference is to be held in sendai, japan, which was significantly impacted by the great east japan earthquake and tsunami in . the focus of the conference is on the follow-up to the hyogo framework for action, termed the post- framework for disaster risk reduction in the lead-up to the conference. the united nations office for disaster risk reduction (unisdr) is the secretariat of the international strategy of disaster reduction and the global hub of the disaster risk reduction community, which includes national governments, ngos, intergovernmental organizations, financial institutions, technical bodies, and others. unisdr serves as the focal point for the implementation of the hyogo framework for action (hfa), the ten-year plan to address global disaster risk that commenced in and is set to expire in . unisdr was created in , at the end of the international decade for natural disaster reduction. the organization functions as a clearinghouse for disaster reduction information; campaigns to raise hazard awareness; and produces articles, journals, and other publications and promotional materials related to disaster reduction. unisdr maintains an organizational vision that is guided by the three strategic goals of the hfa for which it is tasked to oversee. these include: integrating disaster risk reduction into sustainable development policies and planning; . developing and strengthening institutions, mechanisms and capacities to build resilience to hazards; and . incorporating risk reduction approaches into emergency preparedness, response, and recovery programs. the organization describes the four key functions that guide its efforts as follows: • we coordinate international efforts in disaster risk reduction and guide, monitor as well as report regularly on progress of the implementation of the hyogo framework for action. we organize a biennial global platform on disaster risk reduction with leaders and decision makers to advance risk reduction policies and support the establishment of regional, national and thematic platforms. • we campaign and advocate to create global awareness of disaster risk reduction benefits and empower people to reduce their vulnerability to hazards. our current campaigns focus on safer schools and hospitals as well as resilient cities. • we encourage for greater investments in risk reduction actions to protect people's lives and assets including climate change adaptation, more education on drr, and increased participation of men and women in the decision making process. • we inform and connect people by providing practical services and tools such as the risk reduction website preventionweb, publications on good practices, country profiles and the global assessment report on disaster risk reduction, which is an authoritative analysis of global disaster risks and trends. (unisdr ) unisdr is led by the un special representative of the secretary-general for disaster risk reduction. margareta wahlstrom currently holds this post. the position was created in to lead and oversee all drr activities mandated by the un general assembly (ga), the economic and social council (ecosoc), and the hyogo framework for action (hfa), as well as policy directions by the secretary-general. other responsibilities include the ongoing and arduous process of facilitating the development of the post- framework for drr that will follow the hfa, overseeing the management of the trust fund for the international strategy for disaster reduction, and carrying out highlevel advocacy and resource mobilization activities for risk reduction and implementation of the hfa. one of the most significant functions of unisdr is monitoring the progress achieved by nations and global regions per the hyogo framework for action. monitoring is an almost ongoing process, with reports on progress produced every two years (as well as interim reports on off years, in some instances). the hfa monitor is an online reporting system that nations and regional organizations use to assess their capabilities and progress according to the indicators outlined in the hfa. the hfa monitor template, found on the hfa monitor website, defines the areas of assessment. the result of this process is a national or regional hfa progress report. not all countries produce the reports, and for those that do, reports are not necessarily submitted for each reporting period. critics note that it is a self-reporting and ranking system, but in the absence of any other system on the scale of the hfa monitor, the information it provides is highly informative and very useful in estimating capacity. the information is also used to produce papers and reports on various thematic issues, such as gender in disaster management, integration of drr and climate change adaptation, early warning, and others. the world bank and unisdr work closely together on a number of key disaster risk reduction issues, notably those related to development and disaster reconstruction, through a unisdr/world bank global facility for disaster reduction and recovery (wb/gfdrr) partnership. other similar drr-and disaster risk management-focused partnerships have been formed with various regional international organizations, including the association of southeast asian nations (asean), organization of the islamic conference (oic), pan american health organization (paho), applied geoscience and technology division of the secretariat of the pacific community (sopac), economic community of west african states (ecowas), and african union (au). unisdr is headquartered in geneva and has representation at the un headquarters in new york city. the organization also has regional offices in africa (nairobi), the americas (panama and brazil), asia/pacific (bangkok, japan, and korea), the pacific (sub-regional office in suva), the arab states (cairo), europe (brussels and bonn), and central asia (sub-regional office in almaty). (see figure . .) unisdr also works with and advises a number of key thematic platforms on disaster risk reduction issues, including: response (un-spider) the un is the only global international organization of its kind. it is not, however, the only governing organization made up of several national governments. many of the world's regions have pooled their collective resources and services to create large, influential organizations. like the un, these organizations address issues of regional and global importance, many of which focus on or peripherally address disaster management. in times of disaster, both within and outside of their regions of concern, they bring much of the same financial, technical, and equipment resources discussed throughout this book. this section identifies and briefly describes the largest of these organizations. the north atlantic treaty organization (nato) is an alliance of countries from north america and europe formed by a treaty signed on april , . its fundamental goal is safeguarding its members' freedom and security using political and military means. over the years, nato has taken on an increasing role in international disaster management and peacekeeping missions. nato maintains a military force made up of member countries' troops. although they work in concert, troops always remain under the control of their home nation's government. nato has helped to end violent conflicts in bosnia, kosovo, and the former yugoslav republic of macedonia. nato's disaster and crisis management activities, which extend beyond its typical military operations, are geared toward protecting populations. as part of the worldwide civil protection drive described in chapter , nato began developing measures to protect member nation citizens from nuclear attack as early as the s. as elsewhere, nato member countries soon realized that these capabilities could be used effectively during disasters induced by floods, earthquakes, and technological incidents and during humanitarian disasters. nato's first involvement in disaster operations came in , following devastating floods in northern europe. in , it established detailed procedures for the coordination of assistance between nato member countries in case of disasters. these procedures remained in place and provided the basis for nato's civil emergency planning in subsequent years. in , nato established the euro-atlantic disaster response coordination center to coordinate aid provided by member and partner countries to a disaster-stricken area in a member or partner country. it also established a euro-atlantic disaster response unit, which is a non-standing, multinational mix of national civil and military elements volunteered by member or partner countries for deployment to disaster areas. civil emergency planning has become a key facet of nato involvement in crisis management. in recent years, nato has assisted flood-devastated albania, czech republic, hungary, romania, and ukraine, supported the unhcr in kosovo, sent aid to earthquake-stricken turkey, helped to fight fires in the former yugoslav republic of macedonia and in portugal, supported flood response in pakistan, and supported ukraine and moldova after extreme weather conditions destroyed power transmission capabilities. nato has taken an active role in the response to the south asia earthquake, as described in exhibit . . nato also regularly conducts civil emergency planning exercises. the european union (eu) originated in may of , when six european countries (belgium, germany, france, italy, luxembourg, and the netherlands) joined together to address common issues related to the coal and steel industries. since that time, the scope of their work has expanded significantly, as has their membership. the eu is now a major regional international organization representing member states and is in the process of admitting several other eastern and southern european countries in a push toward greater inclusion. the eu considers itself a "family of european countries, committed to working together for peace and prosperity" (bbc ). like the un, it is not a government, nor does it have any authority over its members; it is an organization established for increased regional cooperation. regional international organizations the devastating october earthquake in pakistan is estimated to have killed , people and left up to three million without food or shelter just before the onset of the harsh himalayan winter. on october , , in response to a request from pakistan, nato launched an operation to assist in the urgent relief effort. nato airlifted supplies donated by nato member and partner countries as well as the unhcr via two air bridges from germany and turkey; flights delivered almost , tons of relief supplies. the supplies provided included thousands of tents, stoves, and blankets necessary to protect the survivors from the cold. in addition, nato deployed engineers and medical units from the nato response force to assist in the relief effort. the first teams arrived on october , . in just three months of operations, nato achieved the following: • nato's air bridges flew almost tons of aid to pakistan with flights. these flights carried in nearly , tents, , blankets, nearly , stoves/heaters, more than , mattresses, , sleeping bags, tons of medical supplies, and more. • nato's field hospital treated approximately , patients and conducted major surgeries. mobile medical units treated approximately , patients in the remote mountain villages; they also contributed significantly to the who immunization program that has helped to prevent the outbreak of disease. • in the cities of arja and bagh, nato engineers repaired nearly kilometers of roads and removed over , cubic meters of debris, enabling the flow of aid, commerce, and humanitarian assistance to the inhabitants of the valley. nine school and health structures were completed and tent schools erected. the engineers distributed cubic meters of drinking water and upgraded a permanent spring water distribution and storage system to serve up to , persons per day. • nato engineers also supported the pakistani army in operation winter race, by constructing multipurpose shelters for the population living in the mountains. • nato helicopters transported more than , tons of relief goods to remote mountain villages and evacuated over , disaster victims. • nato set up an aviation fuel farm in abbottabad, which carried out some , refueling missions for civilian and military helicopters. during the mission some , engineers and supporting staff, as well as medical personnel, worked in pakistan. nato was part of a very large effort aimed at providing disaster relief in pakistan. the pakistani army provided the bulk of the response, with the support of nato, the un, and other international organizations and several individual countries. on october , nato received from pakistan a request for assistance in dealing with the aftermath of the october earthquake. the next day, the north atlantic council approved a major air operation to bring supplies from nato and partner countries to pakistan. the airlift began on october and the first tons of supplies arrived in pakistan on october. on october, nato opened a second air bridge from incirlik, turkey, to deliver large quantities of tents, blankets, and stoves donated by the unhcr. on october, in response to a further request from pakistan, nato agreed to deploy engineers and medical personnel from the nato response force to pakistan to further assist in the relief effort. a nato headquarters was deployed to pakistan on october to liaise with pakistani authorities and pave the way for the incoming troops. the first troops, the advance elements of the medical team, began arriving on october, and immediately began treating hundreds of people a day. engineering teams followed and began working in the area around bagh in support of pakistani efforts to repair roads and build shelters and medical facilities. nato engineers also supported the pakistani army in operation winter race, by constructing multipurpose shelters for the population living in the mountains. on november, nato opened a sophisticated -bed field hospital, which provided a wide range of care including complex surgical procedures. on the same day, heavy-lift transport helicopters assigned to nato for the operation began flying and delivering supplies to remote mountain villages and evacuating victims. nato also set up an aviation fuel farm in abbottabad, which carried out refueling for civilian and military helicopters, which were essential to the relief effort. on october, additional foreign secretary of pakistan tariq osman hyder addressed a meeting of the euro-atlantic partnership council at nato headquarters in brussels, asking for further assistance. he said that nato could provide continued airlift, funds, logistic and airspace management, mobile fuel tanks, spare parts for helicopters and tactical aircraft, command and control, and winterized tents and sleeping bags. that same day, nato's euro-atlantic disaster response coordination center (eadrcc) received an urgent request from the unhcr for the transport of additional shelter and relief items stored in turkey to pakistan before the winter sets in. nato's relief mission came to an end, on schedule, on february . nato's short-term relief mission was based on the following five elements: . coordination of donations from nato and partner countries through the eadrcc in brussels; . the air bridge from turkey and germany for the transport of relief goods to pakistan; . five helicopters operating in the earthquake-affected area for the transport of supplies to remote mountain villages and evacuation of victims; . medical support with a field hospital and mobile medical teams in the area of bagh; . engineer support operating in the area around bagh in support of pakistani efforts for the repair of roads and building of shelters, schools, and medical facilities. humanitarian assistance has been a part of the eu mission since , and since that time the organization's work in that area has grown such that today it is the world's most significant humanitarian aid donor. taken together, its members represent a sizeable piece of the global economy, thus enabling them the ability to provide more than percent of all humanitarian aid worldwide. the eu has also structured itself to be an active stakeholder in international disaster management. their work in this regard is not limited to europe and in fact has a global presence. since taking on disaster management responsibilities, the eu has responded through one or more of its various departments to disasters in more than countries. in , the eu restructured its global hazard risk and disaster management capacities. these changes resulted in the merging of two former divisions: one that handled humanitarian assistance and another that centered on civil protection. together these units formed the combined directorate general for humanitarian aid and civil protection (echo). the acronym is a carryover from a former component of the eu's response mechanism called the european community humanitarian office. the move effectively integrated these two functions, which, over time, saw duplicative missions. exhibit . is drawn from an eu factsheet describing how the eu responded to typhoon haiyan in the philippines in using this combined function. through its humanitarian aid and civil protection department (echo), the european commission made available us$ . million to help the survivors of the typhoon with food assistance, shelter, water and sanitation, health and nutrition, short-term livelihood support, reconstruction of schools, emergency logistics, and coordination of relief efforts. within hours after the disaster struck, the european commission's experts had been deployed to identify priority needs. the commission implemented its assistance primarily through the following partner organizations: assistance supported by echo reached approximately . victims in the areas affected by the typhoon. the eu civil protection mechanism was activated to ensure coordination of european relief efforts. participating member states supplied personnel and material to support the operation. the eu civil protection mechanism, coordinated by the commission's emergency response and coordination centre (ercc), also supported the transport of civil protection assets to the region with around us$ . million. in addition to humanitarian funds, the european commission has released $ . million from the eu's development funds to help rebuild people's lives by assisting in recovery and rehabilitation. examples of eu-funded humanitarian projects are described in the following section. • to address food insecurity among the affected population who had little to eat and little to no access to markets, the eu funded the efforts of the world food programme (wfp). wfp provided general distribution of food, including highenergy biscuits during the emergency phase, and then provided supplementary feeding for children and pregnant and lactating women. "food-for-work" and "cash-for-work" initiatives were established. • the eu provided funds to the international committee of the red cross (icrc) and national red cross societies to provide thousands of families with shelter repair kits and to support the livelihoods recovery and wash clusters. the national red cross societies projects supported the delivery of non-food items, including blankets and water storage containers. many families were provided with unconditional cash grants, and communities were given assistance in improving sanitation facilities, restoring primary healthcare services (including medicines), disease prevention, and hygiene awareness. • the eu supported a consortium that includes plan international and oxfam. funding helped to provide relief for the most significantly affected households by enabling livelihoods recovery, distribution of cash-for-work vouchers, and rehabilitation of public service infrastructure, including child-friendly spaces, classrooms, day care centers, and health stations. • to help the approximately million people left homeless by the typhoon, the eu funded the international organization for migration (iom) efforts to improve the well-being and living conditions of those who were displaced, who have returned, or who are planning to go back to their places of origin. special attention was given to persons with disabilities and other special needs. the project provided shelter repair kits to the affected populations and ensured quality management of displacement sites and timely information on communities' return and relocation processes. finally, vulnerable groups targeted by the initiative received health services, psychosocial support, and non-food items such as blankets. based on: ec, . echo enables the eu to respond to most major crises regardless of where they are in the world. at the time of this publication, the eu was involved in the response to ches in syria, south sudan, and the central african republic and was working in several other countries that were no longer entrenched in conflict but nonetheless faced humanitarian needs (e.g., côte d'ivoire). in recent years, the eu annual budget allocation for humanitarian operations has remained at around us$ . billion, or about us$ per person from the combined population of the eu member countries. through this funding, the organization has reached on average about million people each year. echo maintains a staff of more than at its brussels headquarters and more than dispersed throughout field offices in countries worldwide. when a disaster strikes, and presumably upon request, echo staff deploy in order to conduct a needs assessment. if it is determined that assistance is warranted, staff will remain and monitor the situation as it progresses and oversee the implementation of the humanitarian aid projects that echo supports. echo has established relationships with more than other disaster management stakeholders, including un agencies and ngos. echo humanitarian assistance can come in several forms, including food aid; clothing; healthcare supplies; and materials for shelter, water, and sanitation. echo also supports relief work, such as infrastructure repair, removal of mines, psychological support, and education, among many others. echo has a special program, called the "forgotten crisis assessment," that focuses on less salient events. through this program, echo tries to raise the profile of serious incidents it finds are receiving too little attention among the humanitarian community, for the purpose of increasing the funds available to impacted victims. in , echo distributed humanitarian aid worth us$ . billion (which amounts to less than percent of the eu budget, yet is, in gross terms, a significant amount in total funding when compared to most other donors). this funding assisted million people in more than countries outside the european union. echo also oversees the eu civil protection mechanism, which comprised states ( eu member states, plus former yugoslav republic of macedonia, iceland, liechtenstein, and norway). this mechanism enables these nations to coordinate and cooperate in the event of a disaster in one or more eu countries or elsewhere in the world. civil protection agencies from member countries provide inkind assistance, equipment, and teams, or experts that perform damage and needs assessments. echo civil protection relies on the resources of member governments and, if assistance is required in non-eu countries, it typically works in parallel with the humanitarian aid component of echo. for european countries, the coordination and cooperation provided under echo is, in essence, a highly formalized mutual assistance compact that increases the capacity of all nations involved. nations pool their resources and maximize their collective efforts. the key instrument for european civil protection is the civil protection mechanism (cpm), which was established in . the operational heart of cpm is the european commission's monitoring and information centre (mic), which will soon become the european emergency response centre (erc). any country inside or outside eu affected by a disaster and overwhelmed by its magnitude can make an appeal for assistance through the mic/erc. to provide formalized mitigation and preparedness assistance, echo launched its disaster preparedness program, disaster preparedness echo (dipecho), in . dipecho attempts to reduce population vulnerability in disaster-prone regions. between and , dipecho provided more than $ million for hundreds of projects worldwide. dipecho-funded projects are implemented by aid agencies working in the region of concern, and support training, capacity building, awareness raising, and early warning projects, as well the organization of relief services. echo disaster preparedness efforts, however, extend beyond dipecho. many of echo's major humanitarian financing decisions, for example, include disaster preparedness or prevention as an objective. even post-disaster emergency responses can seek to reduce future risk. examples of echo risk-reduction activities include livestock shelters built after extreme cold snaps to protect against further herd depletion (peru), training and equipping of community-based fire brigades in forest fire risk zones (indonesia), cholera preparedness and health information (malawi), and antirust measures to prevent water pollution and protect pipes from the effects of volcanic ash (ecuador). the organization of american states (oas) was established in by nations located in north, central, and south america and the caribbean that wished to strengthen cooperation and advance their common interests in the western hemisphere. through the oas charter these nations committed to a set of common goals. respect for each other's sovereignty has always played a central role in oas affairs. today, all independent nations in the region have ratified the oas charter and serve as members of the organization (though the cuban government was excluded from participation in oas from to , and has yet to rejoin since the lifting of its ban). the oas is heavily involved in disaster risk reduction and preparedness efforts in the region. the vast majority of such projects are facilitated by the oas office for sustainable development and environment (osde), which supports activities in both individual countries and those that involve multiple countries. the more prominent of these activities focus on the following goals: • supporting the management of trans-boundary water resources • improving information for decision making in biological diversity • establishing land-tenure reform and property rights • supporting the exchange of best practices and technical information in environmental law and enforcement, renewable energy, water management, and biodiversity • improving management systems to reduce the impacts of natural disasters • understanding climate-related vulnerabilities affecting small island states the following is a list of projects that illustrates the range of disaster risk reduction and preparedness activities carried out by oas: mitigation capacity building program. the three-year program assisted countries in the caribbean region to develop comprehensive, national hazard vulnerability reduction policies and associated implementation programs, and develop and implement safer-building training and certificate programs. improvement program with assistance from oas to offer hurricane-resistant home improvement options to low-income families. this program trains local builders in safer construction, offers small loans to families wishing to upgrade their homes, and provides the services of a trained building inspector who approves materials to be purchased and checks minimum standards. in addition to the osde, oas supports disaster risk reduction through its inter-american committee for natural disaster reduction (iacndr). iacndr is the organization's main forum for integrating disaster risk reduction into sustainable development practices. the oas general assembly established the iacndr to strengthen its role in natural disaster reduction and emergency preparedness. the southern african development community (sadc) began in , when a loose alliance of nine southern african states formed (then known as the southern african development coordination conference, or sadcc). the organization's aim was to coordinate development projects to decrease economic dependence on south africa. in , it shifted from a "coordination conference" to a development community known as the sadc. sadc member states are angola, botswana, the democratic republic of congo, lesotho, madagascar, malawi, mauritius, mozambique, namibia, seychelles, south africa, swaziland, united republic of tanzania, zambia, and zimbabwe. sadc's primary mission is to help define regional priorities, facilitate integration, assist in mobilizing resources, and maximize regional development. it approaches problems and national priorities through regional cooperation and action. several sadc programs address the region's safety and security, primarily through risk-reduction mechanisms that include disaster preparedness and mitigation. the following are some examples of sadc disaster-related programs: • food, agriculture, and natural resources directorate • regional early warning unit • regional remote sensing unit the coordination center for natural disaster prevention in central america (cepredenac) was established in as a coordination center to strengthen the central american region's ability to reduce their population's vulnerability to natural disasters. in may , cepredenac became an official organization to foster regional cooperation among the governments of costa rica, el salvador, guatemala, honduras, nicaragua, and panama. the organization's headquarters are in guatemala city, guatemala. since its founding, the organization has been instrumental in securing region-wide commitment to disaster risk reduction through the passing of several resolutions and the creation of several plans and strategies signed by participating countries. the organization's agenda parallels and coordinates with other specialized regional entities in areas including hydrological resources, agriculture, nutrition, and food security. the cepredenac regional disaster reduction plan (prrd) was created to foster disaster reduction as an integral part of the sustainability of central american societies. its strategic objectives are: • promoting the incorporation of disaster risk reduction in legislation, policies • enhancing and developing greater resilience of the population to disaster risk • promoting the incorporation of disaster risk analysis in the design and implementation of prevention, mitigation, response, recovery, and reconstruction in the countries of the region a participating state may request disaster response assistance once its capabilities have been overwhelmed. cdema solicits and coordinates the assistance offered by other governments, organizations, and individuals, both within and outside the region. this is cdema's primary function. other functions include: • securing, collating, and channeling disaster information to interested governmental organizations and ngos as needed • mitigating disaster consequences affecting participating states • establishing and maintaining sustainable disaster response capabilities among participating states • mobilizing and coordinating disaster relief from governmental organizations and ngos for affected participating states the cdema participating states are structured into four subregions, each of which is headed by an operation unit known as a sub-regional focal point. the functions of each focal point relevant to the recovery effort are to: • acquire and maintain comprehensive emergency management capacity information • test and maintain communications with the coordinating unit and with national disaster management agencies • ensure subregion continuity of operations membership in cdema requires the participating state to establish or maintain a national disaster organization (ndo) or a national relief organization capable of responding swiftly, effectively, and in a coordinated manner to disasters in participating states (typically the government body tasked with domestic emergency management). ndos are headed by the national disaster coordinator (ndc), who is a government official responsible for the day-to-day management of the organization; ndos are the national focal points for cdera's activities in the participating state. the participating states are, in addition, required to: • establish planning groups and define national policies and priorities to address disasters • provide national relief organizations with adequate support, including named emergency coordinators, liaison officers with key ministries, emergency services, utilities, etc. • define the disaster role and functions of government agencies • establish and equip a suitable emergency operations center (eoc) • develop and maintain an appropriate emergency telecommunications system • perform disaster operations planning and associated drills and exercises • review and rationalize disaster-related statutory authorities • develop an emergency shelter policy program involving local participation • develop and implement a comprehensive disaster public awareness program • develop and implement appropriate training programs for disaster management staff in , twenty-four countries in eastern and southern africa established a drought monitoring centre, with its headquarters in nairobi (the dmcn) and a sub-center in harare (dmch), in response to a series of devastating weather-related disasters. in october , the heads of state and governments of the intergovernmental authority on development (igad) held their th summit in kampala, uganda, where dmcn was adopted as a specialized igad institution. the name of the institution was changed to igad climate prediction and applications centre (icpac) in order to better reflect its expanded mandates, mission, and objectives within the igad system. a protocol was signed in april , integrating the institution fully into igad. icpac is responsible for seven member countries (djibouti, eritrea, ethiopia, kenya, somalia, sudan, and uganda) and three other countries (burundi, rwanda, and tanzania). the centre's vision is "to become a viable regional centre of excellence in climate prediction and applications for climate risk management, environmental management, and sustainable development," while its mission is "provision of timely climate early warning information and support specific sector applications to enable the region to cope with various risks associated with extreme climate variability and change for poverty alleviation, environment management and sustainable development of the member countries" the objectives of the centre are: . to provide timely climate early warning information and support specific sector applications for the mitigation of the impacts of climate variability and change for poverty alleviation, management of environment, and sustainable development; . to improve the technical capacity of producers and users of climatic information, in order to enhance the use of climate monitoring and forecasting products in climate risk management and environment management; . to develop an improved, proactive, timely, broad-based system of information/product dissemination and feedback, at both sub-regional and national scales through national partners; . to expand climate knowledge base and applications within the sub-region in order to facilitate informed decision making on climate risk related issues; and . to maintain quality controlled databases and information systems required for risk/vulnerability assessment, mapping and general support to the national/ regional climate risk reduction strategies. (icpac n.d.) the centre has several functions relative to these objectives, which are: • acquisition of climate and remotely sensed data; • develop and archive national and regional climate databanks including calibration of remote sensing records; • process data and develop basic climatological statistics required for baseline risk scenarios and other applications; • monitor, predict, and provide early warning information of the space-time evolutions of weather and climate extremes over the sub-region; • hazards and climate risk mapping of the extreme climate events thresholds; • networking with wmo, the national meteorological and hydrological institutions as well as regional and international centers for data and information exchange; • capacity building in the generation and applications of climate information and products; • applications of climate tools for specific climate sensitive sector risk reduction, environment management , and sustainable development, including integration of indigenous knowledge; • monitor, assess, detect and attribute climate change and associated impacts, vulnerability, adaptation and mitigation options; • develop relevant tools required to address the regional climate challenges through research and applications in all climate sensitive socio-economic sectors including addressing linkages with other natural and man-made disasters; and • networking and exchange of information regarding disasters in the sub-region. (icpac n.d.) the centre offers a number of informational products, including periodic climate and weather bulletins, updates on climate and el niño, and annual climate summaries. to date, the centre has been instrumental in increasing drr in the sub-region through the provision of capacity enhancement, informational products, networking assistance, and more. the league of arab states (las) is a regional igo based in cairo, egypt and encompassing north africa and southwest asia. las was formed in following the adoption of the alexandria protocol, with a stated goal to "draw closer the relations between member states and co-ordinate collaboration between them, to safeguard their independence and sovereignty, and to consider in a general way the affairs and interests of the arab countries." member states include algeria, bahrain, comoros, djibouti, egypt, iraq, jordan, kuwait, lebanon, libya, mauritania, morocco, oman, state of palestine, qatar, saudi arabia, somalia, sudan, syria, tunisia, united arab emirates, and yemen. in response, and as a follow-up to the first arab summit on socio-economic development, the council of arab ministers responsible for the environment adopted specific actions relating to disaster risk reduction through a decision in may of to develop an arab strategy for disaster risk reduction. this strategy, entitled the arab strategy for disaster risk reduction , adopted in december of , has a two-fold purpose: . to outline a vision, strategic priorities, and core areas of implementation for disaster risk reduction in the arab region, and . to enhance institutional and coordination mechanisms and monitoring arrangements to support the implementation of the strategy at the regional, national, and local level through preparation of a programme of action. the arab strategy for disaster risk reduction is designed to complement existing and ongoing efforts in disaster risk reduction by national institutions and regional technical organizations in the las region. implementing partners of the strategy are to focus on multi-sectorial approaches with the purpose of reducing emerging risks across the arab region by , in line with the global priorities outlined by the hyogo framework for action (hfa) and the millennium development goals. the five priorities of the las strategy directly mirror those of the hfa, including the desire to increase nations' capacity to incorporate drr into disaster recovery. specific commitments detailed under these priorities, which pertain to recovery planning actions in the region, include: • ensuring that disaster risk reduction measures are integrated into post-disaster recovery and rehabilitation processes • establishing disaster preparedness plans, contingency plans, and recovery and reconstruction plans at all administrative levels with the participation of women, the aged, children, idps, and people with special needs • ensuring that national/ local financial reserves and contingency mechanisms are in place and well understood by all stakeholders to ensure effective response and recovery when required • addressing national trans-boundary cooperation on disaster response, preparedness and recovery among arab states in the arab region, funding remains the main challenge faced by national and local authorities, civil society organizations, and humanitarian workers implementing disaster risk reduction measures targeting communities at risk. las encourages its members to dedicate at least percent of national development funding and development assistance toward disaster risk reduction measures. specifically, it was recommended that member states assess the possibility of utilizing existing regional funds and mechanisms (including, among other mechanisms, socio-economic development funds and national disaster relief and response budgets) by allocating a dedicated budget for disaster risk reduction and recovery activities at the subregional, national, or local level. the las regional centre for disaster risk reduction (rcdrr) was established in by a partnership between the kingdom of saudi arabia, the united nations international strategy for disaster reduction (unisdr), and the arab academy for science, technology and maritime transport (aas-tmt), as an intergovernmental organization of the league of arab states targeting the achievement of sustainable development in the arab region. the centre seeks to address risk through knowledge, research, and training of scientific and technical cadres in various disciplines on drr. the main objectives of rcdrr, as per the rcdrr statutes, are: • integration of drr into regional and national sustainable development policies, strategies, and plans • enhancing regional and national capacities in the field of drr research, education, and training • contributing to the development and harmonization of regional drr methodologies and tools, including database and guidelines • promoting partnership building with a multi-stakeholder approach to accelerate the implementation of the hyogo framework of action the south asian association of regional cooperation (saarc) was officially established in . the objectives of the organization are to: • promote the welfare of the people of south asia and to improve their quality of life • accelerate economic growth, social progress, and cultural development in the region and to provide all individuals the opportunity to live in dignity and to realize their full potential • promote and strengthen selective self-reliance among the countries of south asia • contribute to mutual trust, understanding, and appreciation of one another's problems • promote active collaboration and mutual assistance in the economic, social, cultural, technical, and scientific fields • strengthen cooperation with other developing countries • strengthen cooperation among themselves in international forums on matters of common interest • cooperate with international and regional organizations with similar aims and purposes. the saarc member countries include afghanistan, bangladesh, bhutan, india, maldives, nepal, pakistan, and sri lanka. after • establish and strengthen the regional disaster management system to reduce risks and to improve response and recovery management at all levels • identify and elaborate country and regional priorities for action • share best practices and lessons learnt from disaster risk reduction efforts at national levels • establish a regional system to develop and implement regional programs and projects for early warning • establish a regional system of exchanging information on prevention, preparedness, and management of natural disasters • create a regional response mechanism dedicated to disaster preparedness, emergency relief, and rehabilitation to ensure immediate response • create a regional mechanism to facilitate monitoring and evaluation of achievements toward goals and strategies. the saarc disaster management centre (sdmc) was established in october of at the facilities of the national institute of disaster management in new delhi to serve as a center of excellence for knowledge, research, and capacity building in disaster management. the centre has the mandate to serve the saarc member countries by providing policy advice and facilitating capacity building services, including strategic learning, research, training, system development, and exchange of information for effective disaster risk reduction and management in south asia. sdmc conducts studies and research, organizes workshops and training programs, publishes its reports and documents, and provides various policy advisory services to the member countries. the secretariat of the pacific community (spc) was founded in australia in under the canberra agreement to restore order in the region following world war ii. in , the spc applied geoscience and technology division (sopac) was created as a undp regional project, and in it became an independent igo. in , sopac became a new division under spc, dedicated to promoting sustainable development in its member countries, and its work is carried out through its secretariat based in suva, fiji. sopac members include australia, cook islands, fiji islands, guam, federated states of micronesia, kiribati, marshall islands, new zealand, papua new guinea, samoa, solomon islands, tonga, tuvalu and vanuatu, niue, nauru, and palau. associate members (local administrations of nonself-governing territories) include american samoa, french polynesia, new caledonia, and tokelau. the purpose of sopac is to ensure the earth sciences (inclusive of geology, geophysics, oceanography, and hydrology) are utilized fully in the fulfillment of the spc mission. to fulfill this purpose, the division has three technical work programs: • ocean and islands • water and sanitation • disaster reduction these three programs share common technical support services: the sopac disaster reduction programme (drp) provides technical and policy advice and support to strengthen disaster risk management practices in pacific island countries and territories. the program carries out this responsibility in coordination and collaboration with other technical program areas within sopac and also with a range of regional and international development partners and donors. the overarching policy guidance for drp is the hfa-linked pacific disaster risk reduction and disaster management framework for action - (pacific drr and dm framework for action), which supports and advocates for the building of safer and more resilient communities. the other significant regional policy instruments that help to guide the efforts of the drp are the pacific plan and the pacific islands framework for action on climate change - . the sopac disaster risk management policy and planning team (ppt) is responsible for the drm mainstreaming initiative, which sopac spearheads on behalf of the pacific disaster risk management partnership network. in fulfilling this responsibility, the ppt provides the following services to pacific island countries and territories (picts): • leads and coordinates high level advocacy at cabinet/political level to garner support for drm mainstreaming in national, sectorial, local, and community planning and budgetary processes • leads and coordinates the development and implementation of drm national action plans with the support of other members of the pacific drm partnership network • supports the integration of drm and climate change adaptation initiatives at the national level within picts • analyzes budgeted drm investment in annual appropriations of picts • analyzes the economic impact of disaster events • analyzes the cost-benefit of drm measures a major focus of the ppt is to build member country resilience by facilitating the creation of disaster risk management national action plans (naps). the partnership network continued to provide strong support in terms of the realization of drm initiatives linked to nap exercises and also for other risk reduction and disaster management-related activities. in the past several years, this support has shifted to development of joint national action plans (jnaps) that integrate policy on disaster risk reduction and climate change adaptation. several of the countries in the region have established jnaps at the national level. the region is also moving toward a regional-level integrated joint strategy for disaster risk reduction and climate change. at present, regional-level disaster risk reduction and climate change adaptation policies remain separate. sopac led the development of the pacific disaster risk reduction and disaster management framework for action (rfa), signed in , and the secretariat of the pacific community environmental programme (sprep) led the development of the pacific islands framework for action on climate change (pifacc), also signed in . however, these organizations initiated an effort in to establish a more integrated solution to coincide with the year expiration of both frameworks. an ongoing process named "the roadmap" is marked by wide stakeholder involvement via a steering committee and broad technical support provided by a technical working group (which includes spc/sopac, sprep, and unisdr). the roadmap process has to date resulted in a draft-integrated strategy entitled the strategy for disaster and climate resilient development in the pacific (srdp). the draft strategy is designed to promote action that is harmonized with existing member state institutional arrangements for climate change adaptation and disaster risk reduction "[to] ensure that efforts are nested within the context of countries' national development strategies and reflected in their budgets, encourage the participation of multiple stakeholder groups, strengthen countries' capacities for risk governance and support the development of well-coordinated innovative funding mechanisms" (spc ). drp supports the strengthening of disaster management governance, which has included the development of institutional, policy, and decision-making processes such as disaster management legislative and planning frameworks, and national focal points (ndmos) and guidelines or models of good practice for national application. the emergency management preparedness, response, and coordination capabilities within countries will be critically assessed to determine the level of resources and capacity that is available to protect vulnerable communities. a priority will be to ensure that effective emergency response, communication, and coordination processes are established, and that existing resources are utilized in the most effective way. the drp disaster management team provides the following services to picts: • technical advice and support to review and update national drm governance arrangements and legislation, operational plans and procedures • support for the design and conduct of operational and table-top exercises to test emergency response plans and procedures • support for the conduct of disaster risk management training in collaboration with the pacific drm program of the asia foundation/office of us foreign disaster assistance • design and development of professional training courses in collaboration with taf/ofda and the fiji national university in , sopac established the pacific disaster risk management partnership network to provide a collaborative and cooperative mechanism to support disaster risk management capacity building in the region and help pacific island countries and territories adapt and implement the pacific drr and dm framework for action. the partnership is an "open-ended, voluntary" membership of international, regional, and national government and non-government organizations, with comparative advantages and interests in supporting pacific countries toward mainstreaming drm through addressing their disaster risk reduction and disaster management priorities. the members of the partnership network agree that: • disaster risk reduction and disaster management are sustainable development issues within the broader context of economic growth and good governance; • national governments have a critical role in developing disaster risk reduction and disaster management national programs and plans that reflect the needs of all stakeholders in a whole-ofcountry approach; • a regional effort must be responsive to and support and complement national programs and plans to strengthen resilience to disasters; • as regional partners, we commit to coordinating our activities and to work cooperatively and collaboratively under the guidance of the pacific plan and regional framework for action - ; and • we can build safer and more resilient nations and communities to disasters if we work in unison and accept this disaster risk management charter as a basis for future action. international financial institutions (ifis) provide loans for development and financial cooperation throughout the world. they exist to ensure financial and market stability and to increase political balance. these institutions are made up of member states arranged on a global or regional basis that work together to provide financial services to national governments through direct loans or projects. in a disaster's aftermath, nations with low capital reserves often request increased or additional emergency loans to fund the expensive task of reconstruction and rehabilitation. without ifis, most developing nations would not have the means to recover. several of the largest ifis are detailed in the following section, including the world bank; one of its subsidiaries, the international monetary fund (imf); the asian development bank; and the inter-american development bank. the world bank was created in to rebuild europe after world war ii. in , france received the first world bank loan of $ million for post-war reconstruction. financial reconstruction assistance has been provided regularly since that time in response to countless natural disasters and humanitarian emergencies. today, the world bank is one of the largest sources of development assistance. in the fiscal year, it provided more than $ . billion in loans, breaking all previous lending records for the organization. in fiscal year , the amount of loans had fallen to $ . billion, but the bank remains one of the largest development lenders. the world bank is owned collectively by countries and is based in washington, dc. it comprises several institutions referred to as the world bank group (wbg): • international bank for reconstruction and development • international development association the world bank's overall goal is to reduce poverty, specifically to "individually help each developing country onto a path of stable, sustainable, and equitable growth, [focusing on] helping the poorest people and the poorest countries" (wagstaff ) . as disasters and ches take a greater and greater toll on the economic stability of many financially struggling countries, the world bank is taking on a more central role in mitigation and reconstruction. developing nations, which are more likely to have weak disaster mitigation or preparedness capacity and therefore little or no affordable access to disaster insurance, often sustain a total financial loss. in the period of rehabilitation that follows the disaster, loans are essential to the success of programs and vital to any level of sustainability or increased disaster resistance. the world bank lends assistance at several points along this cycle. for regular financial assistance, the world bank ensures that borrowed funds are applied to projects that give mitigation a central role during the planning phase. it utilizes its privilege as financial advisor to guide planners, who otherwise might forego mitigation measures in an effort to stretch the loaned capital as far as possible. ensuring that mitigation is addressed increases systems of prediction and risk analysis in projects funded by the world bank. once a disaster occurs, the world bank may be called on for help. because it is not a relief agency, it will not take on any role in the initial response; however, it works to restore damaged and destroyed infrastructure and restart production capabilities. (see exhibit . .) a world bank team may assist with initial impact assessments that estimate financial losses resulting from the disaster and estimated costs of reconstruction, including raised mitigation standards. the world bank also could restructure the country's existing loan portfolio to allow for expanded recovery projects. in addition, world bank projects that have not yet been approved but are in the application process can be redesigned to account for changes caused by the disaster. finally, an emergency recovery loan (erl) can be granted to specifically address recovery and reconstruction issues. erls restore affected economic and social institutions and reconstruct physical assets such as essential infrastructure. it is important to note that erls are not designed for relief activities. they are most appropriate for disasters that adversely impact an economy, are infrequent (recurrent disasters are accommodated by regular lending programs), and create urgent needs. erls are expected to eventually produce economic benefits to the borrowing government; they are usually implemented within three years and are flexible to accommodate the specific needs of each unique scenario. construction performed with erls must use disaster-resistant standards and include appropriate mitigation measures, thus providing overall preparedness for the country affected. once an erl has been granted, the world bank coordinates with the imf, the undp, ngos, and several other international and local agencies to create a strategy that best utilizes these funds within the overall reconstruction effort. the two lending arms of the world bank are the international bank for reconstruction and development and the international development association. international bank for reconstruction and development (ibrd) . established in , the ibrd reduces poverty in middle-income and creditworthy poorer countries. the ibrd attempts to promote sustainable development activities through its loans. it also provides guarantees and other analytical and advisory services. following disasters, countries with strong enough credit can borrow or refinance their existing loans from the ibrd to pay the often staggering costs of reconstruction. international development association (ida). the ida lends to the world's poorest countries, classified as those with a income of less than $ , per person. sixty-four countries currently are eligible to borrow from the ida. it provides interest-free loans and grants for programs aimed at boosting economic growth and improving living conditions. this need is almost always present in the aftermath of disasters, including those caused by violent conflict. in , the global facility for disaster risk reduction, or gfdrr, was created, with the world bank designated as facility manager on behalf of the countries and eight international organizations that make up its membership. gfdrr has a secretariat, based in the washington dc world bank headquarters, which carries out its day-to-day operations. the purpose of gfdrr is to help developing countries address disaster vulnerability and vulnerability to the effects of climate change. its work is primarily driven by the hyogo framework for action, and its programs focus on mainstreaming exhibit . world bank disaster assistance to bosnia and herzegovina washington, june , - the world bank group's board of executive directors today approved a us$ million credit for the floods emergency recovery project for bosnia and herzegovina (bih), to meet critical needs and restore the functionality of infrastructure essential for public services and economic recovery in affected areas in the aftermath of the worst flooding to hit the country in documented history. the project was prepared in record time in view of the dire situation in the country and will be financed from the international development association's (ida) crisis response window resources. this project will target areas that were hit hardest by the devastating floods. preliminary evidence shows that the largest impact from this disaster was on livelihoods, housing, transport, agriculture, and energy. given the magnitude of the damage caused by flooding and subsequent landslides, the project is designed to support efforts by local and entity governments to quickly re-establish public services to pre-flood levels. the project will also support the government's on-going economic recovery initiatives, in particular in the agriculture sector. in addition to this project, the world bank is working on several other fronts to ensure the provision of a comprehensive package of support for bih as it recovers and rebuilds from the physical and economic devastation. notably, the bank is participating in a systematic recovery needs assessment, led by the bosnia and herzegovina (bih) authorities and supported also by the european union and the united nations. the assessment will provide a basis for developing effective rehabilitation measures for infrastructure and services in the affected areas. the world bank is also considering the restructuring of existing projects in its bih portfolio to meet reconstruction needs. while immediate recovery needs are the top priority of this project, the world bank also stands ready to work with the bih authorities to scale-up flood protection and implement early warning systems. the recently approved drina flood protection project is a good example of the type of work that could be scaled-up, as it addresses the need to prevent future flooding. as emphasized by laura tuck, world bank vice president for europe and central asia, "the floods emergency recovery project will finance critical goods, such as fuel and electricity imports, as well as the reconstruction of local infrastructure. this immediate response, combined with the drina river flood protection project, will support economic recovery in the affected areas, and will help restore bosnia and herzegovina to a growth path following the floods." the world bank portfolio of active projects in bih now includes operations totaling approximately us$ . million. areas of support include agriculture, environment, energy efficiency, health, social safety and employment, local infrastructure, and private sector development. release, . disaster risk reduction and climate change adaptation throughout all government sectors in member countries. gfdrr organizes its efforts according to three "business lines," which include: • track i: global and regional partnerships -track i supports unisdr in helping countries to leverage resources to perform pre-disaster investments and activities related to prevention, disaster risk reduction, and disaster preparedness. the key objectives of track i are to: ) enhance global and regional advocacy, strategic partnerships, and knowledge management for mainstreaming disaster risk reduction; and ) promote the standardization and harmonization of hazard risk management tools, methodologies, and practices. • track ii: mainstreaming disaster risk reduction in development -track ii provides pre-disaster assistance to developing countries to mainstream and expand disaster risk reduction and climate change adaptation activities. work in this track is performed in conjunction with world bank regional teams, un agencies, and national governments, and is aimed at integrating disaster risk reduction into poverty reduction and development efforts. there are also several sub-programs that include risk assessment, risk reduction, risk financing, and climate change adaptation. • track iii: sustainable recovery -track iii is aimed at early post-disaster recovery in low-income countries through its standby recovery financing facility (srff). track iii is less programmatic than track i and track ii because it is deployed for post-disaster situations, but it does work to build national capacity and facilitate knowledge management with the long term in mind. srff support includes two financing windows: ) the technical assistance (ta) fund, which supports damage, loss, and needs assessments and develops national capacity for recovery planning and implementation; and ) the callable fund for accelerated recovery, which provides speedy access to financial resources for disaster recovery and reconstruction. the international monetary fund (imf) was established in to "promote international monetary cooperation, exchange stability and orderly exchange arrangements; to foster economic growth and high levels of employment; and to provide temporary financial assistance to countries to help ease balance of payments adjustment." it carries out these functions through loans, monitoring, and technical assistance. since , the imf has provided emergency assistance to its member countries after they were struck by natural disasters, and, in a great many cases, when affected by complex emergencies. the assistance provided by the imf is designed to meet the country's immediate foreign-exchange financing needs, which often arise because earnings from exports fall while the need for imports increases (among other causes). imf assistance also helps the affected countries avoid serious depletion of their external reserves. in , the imf began to provide this type of emergency assistance to countries facing post-conflict scenarios in order to enable them to reestablish macroeconomic stability and to provide a foundation for recovery, namely in the form of long-term sustainable growth. this type of assistance is particularly important when a country must cover costs associated with an "urgent balance of payments need, but is unable to develop and implement a comprehensive economic program because its capacity has been damaged by a conflict, but where sufficient capacity for planning and policy implementation nevertheless exists" (imf ) . the imf maintains that their support must be part of a comprehensive international effort to address the aftermath of a conflict in order to be effective. its emergency financing is provided to assist the affected country and to gather support from other sources. it is not uncommon for a country to severely exhaust its monetary reserves in response to an emergency situation. in the event of a natural disaster, funding is directed toward local recovery efforts and any needed economic adjustments. the imf lends assistance only if a stable governing body is in place that has the capacity for planning and policy implementation and can ensure the safety of imf resources. after stability has been sufficiently restored, increased financial assistance is offered, which is used to develop the country in its post-emergency status. when a country requests emergency assistance, it must submit a detailed plan for economic reconstruction that will not create trade restrictions or "intensify exchange." if the country is already working under an imf loan, assistance may be in the form of a reorganization of the existing arrangement. it can also request emergency assistance under the rapid financing instrument (rfi). the rapid financing instrument (rfi) is the vehicle that the imf uses to meet disaster-impacted countries' financing needs. the rfi provides funding quickly and with few requirements in instances where it is determined that a disaster or emergency situation has resulted in urgent balance-of-payments needs. emergencies need not be related to a natural or technological hazard-they can also be the result of rapid increases in the price of certain commodities or because of an economic crisis. unlike other imf assistance, there does not need to be a full-fledged financing program in place. prior to the creation of the rfi, the imf used a number of separate programs to address emergency needs, including the emergency natural disaster assistance (enda) program and the emergency post-conflict assistance (epca) program. the creation of the rfi program combines all emergency needs. rfi financial assistance is provided in the form of outright purchases without the need for a full-fledged program or reviews. however, when a country does request assistance under rfi, they must cooperate with the imf to make every effort to solve their balance-of-payment problems, and must explain the economic policies it proposes to follow to do so. the imf makes the rfi program available to all of its members, though oftentimes very poor countries are more likely to seek assistance under a different program called the rapid credit facility (rcf), which provides similar assistance but has economic-based requirements that many wealthier countries cannot meet. funds access under the rfi program is limited to percent of a nation's quota per year and percent of quota on a cumulative basis. under the rcf program, the access limits are percent of a nation's quota per year and percent of quota on a cumulative basis. the level of access in each case depends on the country's balance-of-payments need. financial assistance provided under the rfi is subject to many of the same financing terms that nations would see in other imf programs, and the funds borrowed are ideally paid back within to months (imf ). in certain cases, as decided by the imf and according to specific criteria, recipients of emergency funding may benefit from the imf poverty reduction and growth facility (prgf). the prgf is the imf's low-interest lending facility for low-income countries. prgf-supported programs are underpinned by comprehensive country-owned poverty reduction strategies. under this program, the interest rate on loans is subsidized to . percent per year, with the interest subsidies financed by grant contributions from bilateral donors. this program has been available for post-conflict emergencies since , but in january , following the south asia tsunami events, the imf executive board agreed to provide a similar subsidization of emergency assistance for natural disasters upon request. the government of a country devastated by disaster often requires technical assistance or policy advice because it has no experience or expertise in this situation. this is especially common in post-conflict situations, where a newly elected or appointed government has been established and officials are rebuilding from the ground up. the imf offers technical assistance in these cases to aid these countries in building their capacity to implement macroeconomic policy. this can include tax and government expenditure capacity; the reorganization of fiscal, monetary, and exchange institutions; and guidance in the use of aid resources. the asian development bank (adb) is a multilateral development financial institution whose primary mission is reducing poverty in asia and the pacific. adb was established in by countries from both within and outside the region, and has grown to include members as of . forty-eight are from the region and are from other regions. its clients are the member governments, who are also the adb's shareholders. the adb provides emergency rehabilitation loans to its member countries following disasters. adb determined that its assistance in this critical phase of recovery would allow an affected developing country to maintain its development momentum. bank analysts found that, without such assistance, the affected country may reallocate its scarce budgetary resources away from development issues to cover disaster-related expenses, sidetracking development progress. additionally, they found that the production of goods and services would quickly suffer or fail completely if the country could not perform adequate rehabilitation following a disaster. adb assistance in emergencies began in , but was initially extended only to smaller developing countries (e.g., the maldives, papua new guinea, and the smaller pacific island states). loans were limited to $ , (increased to $ million in ), with funded projects to be completed within months of disbursement. the funding was designed to address only simple repair and rehabilitation activities as needed in the immediate aftermath of a disaster, with more comprehensive repair being covered by regular bank lending programs. lending was designed to be provided within six weeks of being requested. in , emergency lending was extended to all developing member countries regardless of their size. this change included a fundamental shift in what the emergency loans would cover, from simple repairs to more comprehensive, informed rehabilitation activities. most important, adb wanted to ensure that projects funded by its loans reduced overall risk to the affected nation and its population. other major changes in adb emergency lending policy are included in the following list: • introducing a typology of the causes and effects of disasters • more clearly defining the adb's response during various phases of post-disaster situations • identifying the nature, focus, and coverage of rehabilitation projects • introducing detailed, yet simplified, guidelines for processing rehabilitation projects • targeting rehabilitation loans toward restoring infrastructure and production activities, including capacity building and modernization • mandating that risk analysis and disaster prevention measures be included in all adb projects in disaster-prone developing member countries • closely coordinating disaster responses at all levels (local, national, and international) with those of other external funding agencies, ngos, and community groups • specifying that disaster prevention and mitigation activities were to be promoted along with regional cooperation • including non-natural disasters, for example, wars, civil strife, and environmental degradation (adb ) between and , adb provided $ . billion to disaster-affected countries in the form of loans at a rate of approximately one loan per month. the vast majority of the adb emergency loan services during this period were provided in response to natural disaster events, with the remaining dedicated to post-conflict situations. these loans rarely averaged more than percent of the total annual lending by adb and were concentrated primarily in south asia. the project comprises two components: (i) reconstruction and upgrading of damaged roads and bridges in sichuan and shaanxi provinces, and (ii) reconstruction and improvements of damaged schools in shaanxi province. the project will rehabilitate and reconstruct high-priority earthquake-damaged roads in the worst affected counties of sichuan province and subprojects in the four worst affected counties of shaanxi province. the project will rehabilitate and reconstruct highpriority earthquake-damaged education facilities in the three worst affected counties in shaanxi province. these components are designed to be mutually supporting in achieving the overall objective of restoring the affected communities' access to infrastructure to pre-earthquake levels, and ensuring restored infrastructure is in strict compliance with the latest seismic code. based on the government's damage and needs assessment and the request of the prc government, the project identifies specific sectors that require emergency assistance in two of the worst earthquake-affected provinces (i.e., sichuan and shaanxi). the project seeks to (i) build on the immediate relief provided by the government in the earthquake-affected provinces; (ii) contribute to coordinated rehabilitation and reconstruction by different development partners and the government; and (iii) specifically address sustainable recovery priorities by providing indirect livelihood support through public infrastructure rehabilitation and reconstruction, which generates public employment and underpins the restoration of livelihood activities by rehabilitating roads, bridges, and schools. the project design draws on the adb experience in delivering emergency assistance acquired in different developing member countries over the past two decades, and complements relief and other rehabilitation and reconstruction assistance provided by the government, united nations agencies, ngos, bilateral development partners, and the world bank. by meeting the earthquake reconstruction needs of the next three years, the project is consistent with adb's disaster and emergency assistance policy ( ) . the project supports the state overall plan for post-wenchuan earthquake restoration and reconstruction approved by the government on september . the impact of the project is accelerated restoration of education and transport infrastructure in earthquake-affected areas of sichuan and shaanxi provinces. the project will support the government's efforts to (i) restore the livelihoods and economic activities of the affected population; (ii) accelerate poverty alleviation in the earthquake-affected counties, many of which have a high incidence of poverty; and (iii) rehabilitate and reconstruct public and community-based infrastructure that is vulnerable to natural disasters. the outcome of the project is restoration of people's access to transport and education infrastructure to preearthquake levels in counties of sichuan and four counties of shaanxi provinces. the total project cost is estimated at $ . million equivalent. a loan of $ million from adb's ordinary capital resources will be provided under adb's london interbank offered rate (libor)-based lending facility. the loan will have a grace period of years with a maturity period of years, an interest rate determined in accordance with adb's libor-based lending facility, a commitment charge of . % per annum, and such other terms and conditions set forth in the draft loan and project agreements. until june , . adb also provides mitigation-related project loans and regional technical assistance (reta) aimed at reducing member countries' overall disaster vulnerability. between august and december , adb approved $ . billion for more than disaster risk management-related projects (in addition to the $ . billion provided in disaster-related financing). mitigation and preparedness projects are not considered "emergency" in nature and are therefore funded through the bank's regular lending activities. because mitigation and preparedness activities are most often included as components within larger development projects, adb does not maintain records of its total financial risk reduction-based lending. projects may include resilience-increasing activities such as reforestation, watershed management, coastal protection, agricultural diversification, slope stabilization, and land-use planning, although the project's overall goal is more development oriented. reta and single-country technical assistance activities have included hazard management and disaster preparedness software programs and infrastructure protection assistance. adb has december , . as the project is for emergency assistance, implementation will start immediately after approval and be completed within months. sichuan provincial communications department in sichuan province; and hanzhong city government and baoji city government in shaanxi province implementing agencies sichuan highway administration bureau in sichuan province; and county-level highway administration bureaus for roads and bridges, and county-level education bureaus for schools in shaanxi province. the project will bring benefits to the project area by (i) reconstructing and improving road conditions and accessibility in townships and in villages in the sichuan and shaanxi provinces, (ii) reconstructing and improving schools in shaanxi province, and (iii) creating local employment opportunities from project construction and related activities. the project will provide equal benefits to females and males. the economic benefits of the rural roads and bridges include (i) savings in vehicle operating costs as a result of improved traffic and road conditions, (ii) time-savings for rural road users, (iii) savings in road accident costs as a result of fewer accidents, and (iv) economic benefits from generated traffic. the reconstruction and upgrading of rural roads in sichuan and shaanxi provinces will benefit about . million people, three-quarters of whom are rural and one-third of whom are poor. as reliable transport to markets becomes more readily available, cash crop farming in remote or isolated areas will be stimulated and access to off-farm employment opportunities will be broadened. the project will focus on reconstruction of and improvements to model schools to appropriate design standards, including six junior secondary and six primary schools. this will bring immediate benefits to the schools' , students (including more than female students), and long-term benefits to future students drawn from the , residents of the areas serviced by the schools, about % of whom are from rural areas of remote counties. the project will contribute to the government's efforts to rebuild the economy, rehabilitate public infrastructure and utilities, reinstate seismic code compliance, and generate employment. the rehabilitation and reconstruction of damaged schools will enable education services to be restored and will offer long-term benefits for affected persons by supporting opportunities for employment and participation in economic activities. finally, adb assists countries in restarting rehabilitation and overall development in the aftermath of armed conflict. in the past, adb post-conflict intervention focused almost exclusively on infrastructure rehabilitation, an area in which the adb has extensive experience. its focus in this area began to shift in the s to preventing conflicts and helping post-conflict countries move along a solid path of economic and social development. adb is now committed to assisting affected member countries develop mechanisms to effectively manage conflict, including addressing the problems of poor governance and corruption. in , adb established the asia pacific disaster response fund (apdrf) to provide quick funding in the aftermath of a disaster to help governments meet urgent life-saving disaster-response needs. between and , grants were approved under the fund. apdrf assistance is provided as a grant that may be no larger than us$ million per event. the size of the grant is determined by: . the geographical extent of the disaster's damage; . initial estimates of fatalities, injuries, and displaced persons; . the country's disaster response capacity; and . the date and magnitude of the last disaster to have impacted the country (thereby taking into account the cumulative effect of disasters on the country's ability to respond) (adb ). in , adb approved a pilot asian development fund disaster response facility for countries eligible for low-interest loans in the event of a disaster. the pilot program, which runs from to , is being conducted to strengthen adb's ability to respond to disaster-impacted member countries in a manner that is less ad hoc. the drf will require countries that are eligible to borrow from the asian development fund (adf countries) to contribute a small fraction of their allocations for the benefit of accessing the drf in case of a disaster. the drf will be available to these countries in the case of natural disasters, and will support relief, response, recovery, and reconstruction needs. per the pilot program, the size of the drf will be percent of the total performance-based allocation (pba) received. in case of a disaster, an adf country can get up to percent of its annual pba, or us$ million per disaster, whichever is higher, from the drf. a blend country, which is a country eligible for both the adf and adb ordinary capital resources, can receive up to percent of its annual pba from the drf if affected by a disaster. established in december , the inter-american development bank (iadb) is the oldest and largest regional multilateral development institution. it was first created to help accelerate economic and social development in latin america and the caribbean. the iadb has been a pioneer in supporting social programs; developing economic, social, educational, and health institutions; promoting regional integration; and providing direct support to the private sector, including microenterprises. the iadb addresses disaster and risk management through its sustainable development department. through the efforts and actions of this department and its disaster risk management policy, the iadb addresses the root causes of the region's high vulnerability to disasters. building on its mandate to promote sustainable development in latin america and the caribbean, the iadb works with countries to integrate risk reduction into their development practice, planning, and investment, and to increase their capacity to manage risk reduction. it also provides funding that directly or indirectly supports disaster mitigation and preparedness. in their "plan of action: facing the challenge of natural disasters in latin america and the caribbean," the iadb outline their six strategic areas of assistance: . national systems for disaster prevention and response: building national legal and regulatory frameworks and programs that bring together the planning agencies, local governments, and civil society organizations; developing national strategies for risk reduction; and assessing intersectoral priorities, backed by separate budgets. . a culture of prevention: developing and disseminating risk information and empowering citizens and other stakeholders to take risk-reduction measures. . reducing the vulnerability of the poor: supporting poor households and communities in reducing their vulnerability to natural hazards and recovering from disasters through reconstruction assistance. . involving the private sector: creating conditions for the development of insurance markets, encouraging the use of other risk-spreading financial instruments where appropriate, and designing economic and regulatory incentives for risk reduction behavior. . risk information for decision-making: evaluating existing risk assessment methodologies; developing indicators of vulnerability, and stimulating the production and wide dissemination of risk information. . fostering leadership and cooperation in the region: stimulate coordinated actions and to mobilize regional resources for investments in risk mitigation. (iadb ) the iadb created two mechanisms to allow for rapid loan disbursement in times of disaster: the disaster prevention sector facility and the facility for the immediate response to natural and unexpected disasters (formerly the immediate response facility). in the iadb established the natural disaster network, represented by each of its borrowing member countries. network members meet annually to discuss topics related to disaster management, such as "national systems for risk management" ( ) the iadb revised its disaster risk management policy in . the new policy is designed to improve the iadb's ability to assist member countries in reaching their development goals by supporting their disaster risk management efforts. (see appendix . for the full text of the iadb disaster risk management policy guidelines.) . iadb supports disaster risk reduction through the disaster prevention sector facility, which provides up to $ million to assist countries in taking an integrated approach to reducing and managing their risk. the iadb also provides loans to help countries cope with financial or economic crises and natural or other disasters through its emergency lending program. in the case of a financial or economic crisis, the iadb requires that the emergency loan fits within an imf-approved and monitored macroeconomic stabilization program. emergency loan disbursement periods are much shorter than other non-disaster loans, ranging up to months in duration. they may be used to support national, provincial, state, and municipal governments and autonomous public institutions. they have a five-year term and a three-year grace period. in the case of natural or other disasters, the emergency lending program is known as the emergency projects, in order to improve project viability. whenever significant risks due to natural hazards are identified in project preparation, appropriate measures will be taken to secure the viability of the project, including the protection of populations and investments affected by bank-financed activities. the bank has nonreimbursable resources that may be used to cover the transaction costs incurred with the implementation of these guidelines. . . these guidelines will also recommend ways to evaluate the benefits and opportunity costs of loan reformulations and give guidance on how to ensure adequate transparency and effective monitoring, auditing, and reporting on the use of redirected funds. in addition, the guidelines describe precautions to be taken to avoid rebuilding or increasing vulnerability during rehabilitation and reconstruction. . . the guidelines are designed to be flexible in their application to the various situations that borrowing member countries and the bank may experience, in the face of natural hazards and disasters affecting their development prospects and performance. . . the present guidelines apply to all natural hazards, including the hydrometeorological hazards-windstorms, floods, and droughts-that are associated with both the existing climate variability and the expected change in long-term climate conditions. of note for risk assessments, climate change is expected to change some countries' disaster risk (their probable losses) by changing the characteristics of the hydrometeorological hazards. . although uncertainty persists, recent advances in downsizing climate models are allowing disaster managers to better calibrate their risk assessments to understand potential impacts due to climate change at the subnational level. tools for identifying such climate risk at the country and project levels, and measures for mitigating these increased risks to bank investments (climate change adaptation) will be developed under pillar of the bank's sustainable energy and climate change initiative (secci) action plan. purpose and scope . . the purpose of this section is to provide guidance to bank teams on the implementation of directive a- of the disaster risk management policy, particularly for countries classified as having high disaster risk, as well as for those sectors that are associated with a high vulnerability to natural disasters and in which the bank has identified opportunities for financing. in accordance with this policy, the bank will encourage countries to include proactive drm in programming activities in those countries, as indicated in directive a- of the policy: . . a- . programming dialog with borrowing member countries. the bank will seek to include the discussion on proactive disaster risk management in the dialog agenda with borrowing member countries. the bank will give due consideration to vulnerability associated with natural hazards and risk management in relation to the priority areas of intervention discussed and agreed with the borrowers for the development of country and regional strategies, and operational programs. the bank will identify countries according to their level of exposure to natural hazards based on existing indicators and bank experience. for countries that are highly exposed to natural hazards, the bank will identify their potential vulnerability as a major development challenge and propose a country level disaster risk assessment. when the assessments identify that potentially important disruptions in the country's social and economic development could be caused by disasters resulting from natural hazards, the bank will encourage the inclusion of disaster risk management activities in the country strategy and operational program agreed with the borrower. these may include policy reforms, specific institutional strengthening and land-use planning activities, measures of financial protection such as through risk transfer, and investment projects conducive to reducing vulnerability at the national, regional, and municipal levels. where the natural hazards may affect more than one country, the bank will encourage a regional approach within the existing programming framework. the bank will promote the use of the disaster prevention sector facility and the disaster prevention fund, described in section v of this policy, and other means it offers to finance the recommended actions resulting from the assessment process. to meet the requirement of the drm policy to identify countries according to their level of risk exposure, a provisional country classification has been developed. the provisional classification will be subject to change, based on expert knowledge, and eventually on the complete data set of risk information derived from the implementation of the bank's indicators for disaster risk and risk management program in its borrowing member countries. the indicators program has been completed in countries to date. as indicated in directive a- , countries that have been identified as being highly exposed to natural hazards will be encouraged by the bank to include drm as a priority area for bank assistance. in those cases, the bank will propose that a country disaster risk assessment be carried out. the assessment would give an overview of the risks facing a country; identify the sectors and geographical areas that should receive priority attention; and provide initial policy orientation, reviews of relevant institutional capacities, and assistance needs. these assessments may already exist, or may be put together from country and secondary sources. . . the evaluation of the macroeconomic impacts as part of the country disaster risk assessment may allow for the identification of risk reduction needs and the quantification of possible resource gaps between available resources and funding needed for disaster response and recovery. recommendations will be prepared concerning opportunities for the bank to contribute to financial protection against disasters, as appropriate, such as direct funding for risk identification and support for risk transfer in financial markets in order to improve the effectiveness of the country's development efforts in the areas and sectors of bank involvement. . . identification of opportunities for bank financing. in line with the new country development risk framework, a more detailed disaster risk assessment will be recommended when disaster risks faced by certain areas/sectors of bank involvement could significantly jeopardize the achievement of a country's development objectives. these sector-specific or areaspecific assessments would analyze how these risks could affect specific areas/sectors and make recommendations on how best to address the risks identified. for this purpose, loans, technical cooperations, and nonfinancial bank products for proactive drm may be proposed within the country programming activities. . implementation of the country strategy: programming dialogue and portfolio management . . when deemed necessary by the bank and if the borrower agrees, drm activities will be included as in the implementation of the country strategy. the bank will give due consideration to the following: in the programming and portfolio reviews, the bank and the borrower may seek to implement risk reduction investments in the priority sectors and geographical areas through disaster prevention and mitigation measures. these investments may be financed with free-standing loans or as part of larger investment programs, policy based loans (pbl), or private sector operations. technical assistance may be considered for carrying out area-or sector-specific risk evaluations, strengthening risk management through policy reforms, organizational design, land-use planning activities, the preparation of new prevention loan programs, and supporting the implementation of financial protection schemes such as through insurance to cover disaster losses. loan portfolio modifications will likely be necessary due to the occurrence of major disasters during the regular programming cycle. borrowers may request new emergency or reconstruction financing and will have access to either new resources, for instance, through the immediate response facility for emergencies caused by disasters (gn- - and gn- - ), or "existing" resources, through loan reformulations (see directive b- ). . . the results of the drm implementation in-country programming will be evaluated using the monitoring system defined in the country strategy document. the bank may recommend activities of a regional nature whenever it is known that a particular disaster could affect several borrowing member countries simultaneously. examples of this situation are the enso (el niño southern oscillation) phenomenon, and the hurricanes and tropical storms in the caribbean and central america. . . the regional activities that possibly involve bank financing will be agreed beforehand with the affected borrowing member countries and may involve coordination with other international entities. the resulting operations to be included in the regional portfolio of the regional strategy document could be funded through bank instruments, such as technical cooperation of the regional public goods program or disaster prevention fund, or loans prepared in parallel, in close cooperation with the countries interested in a regional program. . . the purpose of this section is to provide guidance to project teams on the implementation of the bank's disaster risk management policy directive a- : risk and project viability. this directive is designed to promote the incorporation of drm in a systematic manner during project preparation and execution. the objective is to reduce risk to levels that are acceptable to the bank and the borrower, as indicated in directive a- of the policy: . . identification and reduction of project risk. bank-financed public and private sector projects will include the necessary measures to reduce disaster risk to acceptable levels as determined by the bank on the basis of generally accepted standards and practices. the bank will not finance projects that, according to its analysis, would increase the threat of loss of human life, significant human injuries, severe economic disruption, or significant property damage related to natural hazards. during the project preparation process project teams will identify if the projects have high exposure to natural hazards or show high potential to exacerbate risk. the findings will be reported to the bank through the social and environmental project screening and classification process. project teams should consider the risk of exposure to natural hazards by taking into account the projected distribution in frequency, duration, and intensity of hazard events in the geographic area affecting the project. project teams will carry out a natural hazard risk assessment for projects that are found to be highly exposed to natural hazards or to have a high potential to exacerbate risk. special care should be taken to assess risk for projects that are located in areas that are highly prone to disasters as well as sectors such as housing, energy, water and sanitation, infrastructure, industrial and agricultural development, and critical health and education installations, as applicable. in the analysis of risk and project viability, consideration should be given to both structural and nonstructural mitigation measures. this includes specific attention to the capacity of the relevant national institutions to enforce proper design and construction standards and of the financial provisions for proper maintenance of physical assets commensurate with the foreseen risk. when significant risks due to natural hazard are identified at any time throughout the project preparation process, appropriate measures should be taken to establish the viability of the project, including the protection of populations and investments affected by bank-financed activities. alternative prevention and mitigation measures that decrease vulnerability must be analyzed and included in project design and implementation as applicable. these measures should include safety and contingency planning to protect human health and economic assets. expert opinion and adherence to international standards should be sought, where reasonably necessary. in the case of physical assets, the bank will require that, at the time of project preparation, the borrower establish protocols to carry out periodic safety evaluations (during construction as well as during the operating life of the project) and appropriate maintenance of the project equipment and works, in accordance with generally accepted industry norms under the circumstances. the bank's social and environmental project screening and classification process will evaluate the steps taken by project teams to identify and reduce natural hazard risk. . . under the bank's new risk management development effectiveness framework, a common approach to the management of project risks is proposed. disaster risk is one of several project risks. these guidelines are an input to the bank's approach on project risk management. they apply to bank-financed investment loans and technical cooperation projects in the public and private sector as well as to operations supported by the multilateral investment fund. . . during the assessment, management, and monitoring of disaster risk at the project level, the disaster risk is reviewed at various stages of project preparation and implementation. on this basis, appropriate actions are taken to protect project benefits and outcomes. . . directive a- requires that the bank's social and environmental project screening and classification process provide for project teams to identify and reduce disaster risk. the recommended drm steps are as follows: project screening and classification outcome: identifies those projects where the drm policy is applicable and classifies as high, moderate or low risk. document: report of the social and environmental safeguards policy filter (spf) and social and environmental safeguards screening form. document: disaster risk profile in the environment and social strategy. disaster risk assessment (dra), including disaster risk management plan outcome: provides a detailed evaluation of the impacts of the significant natural hazards identified during project classification on project components; and outlines appropriate risk management and mitigation measures. document: dra report, prepared by the borrower (this may be a stand-alone report or it may be incorporated into the environmental impact assessment report). disaster risk management summary outcome: provides information on the specific disaster risks associated with the project and the risk management measures proposed by the borrower. document: drm summary, for inclusion in the environmental and social management report (esmr), prepared by project teams. project implementation, monitoring and evaluation outcome: identifies the approaches which the executing agency applies during project implementation; and which project teams apply during project monitoring and evaluation. . . the bank's social and environmental screening and classification system of projects will be used to filter and classify those projects for which disaster risk is likely to be an issue for project viability and effectiveness. . . there are two possible types of disaster risk scenarios: type : the project is likely to be exposed to natural hazards due to its geographic location. type : the project itself has a potential to exacerbate hazard risk to human life, property, the environment or the project itself. . . the purpose of this step is to establish, early in the project preparation process, whether natural hazards are likely to pose a threat to the project area during the execution (construction) period and/or the operational life of the project, due to type and type risk scenarios. project classification . . type risk scenario: the level of disaster risk associated with a given project is dependent on the characteristics of the natural hazards as well as on the vulnerability of the sector and project area. the project is classified on the basis of an estimate of the impacts/losses due to the significant hazards associated with type risk scenario. project teams classify their projects in terms of high, moderate, or low disaster risk on the basis of the (i) projected frequency of occurrence and magnitude or intensity of the hazard and (ii) estimated severity of the impacts associated with the hazard, i.e., the magnitude and extent of the likely social, economic, and environmental consequences of the hazard on the various project components and on the general zone of influence of the project. the classification process also provides project teams with a preliminary indication of the hazards likely to be of greatest significance, as well as their likely impacts on project components. and reported as part of the disaster risk profile presented in the environment and social strategy document. the project team will report its findings to the bank unit responsible for social and environmental screening and classification of projects, as part of the bankwide safeguards and risk management procedure. high-risk projects . . the project will typically be classified as high-risk if one or more of the significant natural hazards may occur several times during the execution (construction) period and/ or the operational life of the project and/or the likely severity of social, economic, and/or environmental impacts in the short to medium term are major or extreme. these impacts are of sufficient magnitude to affect project viability and may affect an area broader than the project site. as such hazards may affect project viability, a more detailed investigation of disaster risk, in the form of a dra, is required. moderate-risk projects . . the project will typically be classified as moderate risk if one or more of the prevalent natural hazards are likely to occur at least once during the execution (construction) period and/or the operational life of the project and/or the likely severity of impact in the short to medium term is average. these impacts are typically confined to the project site and can be mitigated at reasonable costs. projects associated with a moderate disaster risk do not typically require a dra. however, a more limited dra may be required, depending on the complexity of the project and where the anticipated vulnerability of a specific project component may compromise the achievement of project outcomes. low-risk projects . . the project will typically be classified as low risk if natural hazards are not likely to occur during construction and/or the operational life of the project and/or associated with a low severity of impact in the short to medium term. those impacts that occur do not lead to a disruption in the normal functioning of the operation and can be corrected as part of project maintenance. the occurrence of the hazard event does not impact on the achievement of project outcomes. a dra is not required. . . type risk scenario: the impacts associated with type risk scenario are addressed under directive b- of the bank's environment and safeguards compliance policy (op- ). such impacts are thus considered and included in the categorization of environmental impacts. . . the unit responsible for environmental and social risk mitigation reviews the classification of all operations and may recommend a new classification based on the review of the disaster risk profile presented in the environment and social strategy. the unit and line divisions will need to agree on the final classification of the operations, the level of disaster risk assessment required, and a proposed strategy to address and manage the anticipated impacts. for projects that are identified as high-risk, a dra is required and is prepared by the borrower. the objective of the assessment is to evaluate in greater detail the impacts of the significant natural hazards identified during project classification on project components. the results of the risk assessment will guide the selection of appropriate risk management and mitigation measures. evaluates the frequency, intensity, and severity of previous hazard events that have affected the project area, as well as those predicted to affect the site over the project's operational life. identifies the vulnerability and probable losses of project components, i.e., the nature and magnitude of the probable social, economic, and environmental impacts due to each hazard; this includes both direct and indirect impacts. provides a disaster risk management plan, including proposals for the design of disaster prevention and mitigation measures, including safety and contingency plans to protect human health and economic assets, and their estimated costs; an implementation plan; a monitoring program and indicators for progress; and an evaluation plan. the implementation plan includes protocols to undertake periodic safety evaluations from project implementation up to project completion and maintenance of project equipment and works. project teams include a summary of the dra report in the environmental and social management report, which is reviewed by both the bank unit responsible for environmental and social risk mitigation screening and the sector divisions chiefs will sign off on the esmr and safeguard compliance plan, including the drm activities. the drm summary provides information on the specific disaster risks associated with the project and the risk management measures proposed by the borrower. . . the project's proposed management and mitigation measures should comply with international standards of good practice and relevant national laws and regulations, such as national planning policies, laws and regulations, as well as national building codes and standards. . . project teams will analyze the impact of the disaster risk prevention and mitigation elements in their assessment of project viability, verifying that identified hazard impacts on project components are reduced to acceptable levels. . . the executing agency is responsible for ensuring that all drm activities ( including prevention and mitigation measures) associated with the project are implemented in accordance with the provisions of the loan agreement. this includes periodic safety evaluations and appropriate maintenance during project implementation and through project completion. project teams will monitor implementation to verify that the drm actions in the project risk management plan are carried out effectively; they shall use standard monitoring (project performance monitoring report; ppmr) procedures. purpose and scope . . the loan reformulation addressed by these guidelines provides financing for postdisaster response to the impacts of natural hazard events and physical damage (such as structural collapse and explosions) caused by technological accidents or other types of disasters resulting from human activity. loan reformulation includes the diversion of existing loan resources to specific analysis needs to determine performance indicators, based on the possible revisions and reformulations being considered. analysis of loans used as a source of funding . . the impact of redirecting loan resources from existing loans will be estimated taking into account the intended uses and project objectives of the loan or loans to be used as a source relative to the new proposed use of the funds, thereby creating the conditions for more informed decisions. resource transfers could be done between cost categories within a project (in which case more streamlined approval procedures will apply), or between separate loans as stipulated by bank procedures. . . for choosing existing projects as origin of resources, following factors (in order of priority) would be considered: a. public sector projects. only public sector loans would be considered. loans to the private sector should not be included in the package of loans for possible reformulation as a result of disasters. b. development impact in the reformulated operations. the loans that are having a relatively low economic/financial impact in the country should be considered first as a source for redirecting resources from existing loans toward emergency funding. redirecting resources that are within a loan generally have a smaller effect than those involving several operations. the original development objectives may not be achieved due to the new social or economic situation created by the disaster or it could be considered too expensive to reorient the resources within the old operation. recommendations regarding the redirection of resources will be based on project performance indicators used by the bank. c. level of execution. operations with a low level of physical execution or disbursements and commitments could be chosen for redirection, except for those loans with a very high development impact. the selection should not only be based on a low disbursement rate of the existing loans alone, but also on an analysis of the underlying causes of the poor performance and any remaining opportunities for attaining project goals. d. loans in affected sectors. resource transfers within an affected sector will be preferred due to the greater similarity of their respective objectives compared with those of loans in different sectors. e. loans in affected region(s). in general, existing projects in the disaster area will not be used to provide resources to be transferred to other programs in the same area. however, when damage is so severe that the attainment of the original development objectives is in jeopardy, or the continuation of a certain component of the project as a whole is unjustifiable on account of excessive costs, parts or all of the undisbursed balances may be re-channeled toward emergency or rehabilitation and reconstruction projects in the same area. factors to be considered in projects receiving funding . . the following are the recommended actions to be considered by project teams, while preparing the funding analysis: . i. technical analysis. for emergencies, the technical analysis will be aimed at re-establishing basic services and critical infrastructure in a time efficient manner. the attainment of fully functioning facilities and productive capacity through rehabilitation and reconstruction will be measured through a detailed technical analysis with the objective of reaching disaster resistance, and fulfilling technical standards across the board and performance criteria required by the bank. . ii. socioeconomic analysis. for emergency response, the socioeconomic analysis will be limited to the evaluation of the cost-effectiveness of restoring the basic services and critical infrastructure. if information is scarce, the analysis may be done based on comparable data from similar operations elsewhere. any delays in the analysis and processing of the emergency financing may limit the bank to have a meaningful contribution to resolve critical needs that are affecting the population, urgent re-establishment of basic services and critical activities. the analysis for rehabilitation and reconstruction investments will follow standard bank practices. if future project benefits cannot be estimated, cost-effectiveness analysis will be carried out. . iii. evaluation of institutional capacity and coordination. in order to gain sustainability, existing agencies are preferred to the establishment of new, ad hoc entities. a rapid analysis will be carried out of the institutional capacity, procurement management capability, and financial track record of the existing agencies. based on its results, it will be determined if the resources will be disbursed on an ex post or on a concurrent basis. the administrative and technical responsibilities of all the participating institutions in different sectors and means of coordination need to be clearly defined to facilitate successful execution in a limited time frame. planned strategies and activities need to be coordinated with other international agencies participating in the post-disaster financing. . i. procurement procedures. the applicable bank policy and rules will be followed for the procurement of goods and services. as an exception, for emergency situations, specific procurement procedures are available, in view of the special nature of these operations and the urgency involved. . ii. transparency in financing. the financial management and evaluation of procurements, expenses, and the utilization of goods and services to be funded with bank resources for emergency situations will be audited on a concurrent basis, following current bank practices. for rehabilitation and reconstruction investments the review may be on a concurrent or ex post basis depending on risk of lack of transparency estimated by the project teams. loan resources can be used to contract the services of independent public accountants to audit the operation's financial statements as required by the bank. . iii. monitoring and evaluation. bank resources will be subject to review on a concurrent basis for emergency investments. for rehabilitation and reconstruction, an audit will be required on a concurrent or ex post basis, depending on the risk of lack of transparency as estimated by the project team. data collection will be planned for monitoring and evaluation. only direct project impacts will need to be evaluated. . . vulnerability should not be replicated when designing disaster response financing. in the preparation of reformulations for rehabilitation and reconstruction, a proportion of the resources of the operation should be allocated to prevention and mitigation activities. the percentage of the total cost that will be dedicated to prevention and mitigation should be defined and the viability of these investments assessed by the project team. the project team should also justify any potential deviations from international practices in these allocations for disaster prevention and mitigation. purpose and scope . . the purpose of this section is to provide assistance to project teams on the implementation of directive b- : reconstruction. specifically guidance is provided on the precautions that country programming process and project teams should take to promote revitalization of development efforts in the aftermath of disasters, while ensuring that rehabilitation and reconstruction projects do not lead to a rebuilding of or an increase in vulnerability. as indicated in directive b- of the policy: . . avoiding rebuilding vulnerability. operations that finance rehabilitation and reconstruction after a disaster require special precautions to avoid rebuilding or increasing vulnerability. these include the precautions mentioned in a- , as well as correcting deficiencies in risk management policies and institutional capacity as reflected in a- . a significant share of the new investment will be earmarked to reduce vulnerability to future disasters and improve the country's capacity for comprehensive disaster risk management. particular attention must be given to lessons learned from recent hazard events. the bank will not assume that pre-disaster conditions persist in whole or in part in the affected area. disaster risk assessment of the reconstruction project should be carried out taking into account the specifics of the area, the sector, and the infrastructure concerned, as well as the current environmental, social, and economic situation and any changes in the affected area as a result of the disaster. . . reconstruction may follow as a response to the impacts of natural hazard events, and physical damage (such as structural collapse and explosions) resulting from technological accidents or other types of disasters resulting from human activity. . . the guidelines for directive a- : risk and project viability, as described in section of these guidelines, also apply to rehabilitation and reconstruction projects. for projects identified as high risk, the disaster risk assessment, and design and implementation of risk reduction measures, will incorporate the lessons learned from the disaster event, including the performance of the physical works, the relevant sectors, institutions, and other project components. risk reduction measures will include enhancements in national, regional, and sectoral risk management policies and strengthening of institutional capacity. . . in order to avoid the rebuilding of or an increase in vulnerability, a proportion of the resources of the operation will be allocated to prevention, mitigation, and risk transfer. the percentage of the total cost is at the discretion of the project team, but will be guided by international practices. used with permission from iadb, . reconstruction facility or immediate response facility for emergencies caused by natural and unexpected disasters. the emergency reconstruction facility can use up to $ million of the iadb's ordinary capital or up to $ million of the fund for special operations to assist an impacted country the ifis described in this chapter bstdb) • caribbean development bank (cdb) • council of europe development bank (coeb) • development bank of southern africa (dbsa) • european bank for reconstruction and development (ebrd) • islamic development bank (idb) • north american development bank (nadb) proposed loan: peoples republic of china emergency assistance for wenchuan earthquake reconstruction project european commission fao's mandate. fao website facing the challenge of natural disasters in latin america and the caribbean service sector severely affected by typhoon haiyan nato (north atlantic treaty organization), . pakistan earthquake relief operation ocha- fm c/$file/ocha_ar _hi% res.pdf?openelement japan diverts rice to tsunami survivors. world food programme (wfp) roadmap towards a strategy for disaster and climate resilient development in the pacific (srdp) by : executive summary un-habitat. secretary-general's envoy for youth overview of global humanitarian response johannesburg plan of implementation. united nations website disaster profiles: third un conference on least developed countries united nations educational, scientific, and cultural organization) unhcr in dubai: first line responder in emergencies. unhcr supply office, dubai. unicef (united nations children's fund) about the unjlc. unjlc website connect and convince to reduce disaster impacts lives saved in viet nam by involving women in disaster planning. press release economics, health, and development: some ethical dilemmas facing the world bank and the international community fast food: wfp's emergency response food aid information system: quantity reporting emergency response framework world bank group to support flood recovery in bosnia and herzegovina through their efforts to mitigate, prepare for, respond to, and recover from natural disasters, multilateral organizations have a major role in international disaster management. all nations are at risk from disasters and, likewise, all nations face the prospect of one day finding themselves requiring help from one or more of these organizations. multilateral organizations direct the collective experience and tools of their member states to benefit all nations in need of assistance-even the wealthiest ones. the progress witnessed by the international disaster management community in recent years can be traced directly to the work of these multilateral organizations, especially focused initiatives such as the international strategy for disaster reduction. provide effective and efficient support to borrowing members in reducing disaster risks and (ii) to facilitate rapid and appropriate assistance by the bank to its borrowers after a disaster. the guidelines are part of the bank's framework for the management of development risk at the country and project levels. there are four possible strategies to manage risks: (i) acceptance, when risks remain below levels deemed tolerable by the parties involved; (ii) prevention and mitigation; (iii) sharing, when risks can be effectively transferred to a third party, for example through insurance; and (iv) rejection ("avoidance"), when the level of risk exceeds the risk level deemed acceptable but cannot be lowered at a reasonable cost. . . the policy directives outline the actions that are to be used both by the iadb staff and by teams of the borrowers, who are responsible for a. country programming-policy directive a- b. preparation and execution of new projects-directive a- c. loan reformulations for financing disaster response-directive b- d. preparation and execution of reconstruction projects-directive b- . . the guidelines will contribute to the mainstreaming of disaster risk management (drm) into the bank's programming exercises with the borrowers, particularly in high-risk countries.to determine which of the idb's borrowing member countries will require a country risk assessment, a provisional classification of all countries has been prepared. . . the guidelines will be used for the design and implementation of lending programs, technical cooperations, small projects, cofinancing, and preinvestment activities consistent with the identified risk level. they will address ways to manage risk in public and private sector activities within the same project or to another existing project, in order to finance unplanned disaster response. reformulations may thus involve just a single loan or several operations. . . loan reformulation allows for the reallocation of resources from existing loans to other projects under certain circumstances, in the aftermath of disasters, as stipulated in directive b- of the policy: . . the bank may approve the reformulation of existing loans in execution in response to disasters if: (i) a state of emergency or disaster has been officially declared by the government; (ii) the impact of the loan reformulation has been estimated taking into account the intended uses and project objectives of the loan or loans to be reformulated relative to the new proposed use of the funds, thereby creating the conditions for more informed decisions on the part of the approving authorities; (iii) adequate transparency and sufficient mechanisms for monitoring, auditing, and reporting the use of the redirected funds are in place, while taking into account the need of a timely response given the nature of the situation; and (iv) a significant share of the redirected funds will be earmarked to reduce the borrower's vulnerability to future disasters and improve the country's capacity for comprehensive disaster risk management. in order to be considered for loan reformulation funding in response to a disaster, the government must have declared a state of emergency or its equivalent, for a region or the country as a whole, according to the laws and regulations of the country. . . the country office should prepare an originating document after the formal declaration of state of emergency by the government, recommending the decisions that should be taken in relation to the projects/programs potentially affected by the disaster. . . the bank may offer technical support to the government in preparing an official request for financing through loan reformulation, on the basis of the originating report. . . once a financing request is received, a project team is appointed, and the approval process of the reformulation operation(s) will follow the established bank procedures on delegation of authority, according to regular bank procedures. once the bank has received an official request from the borrowing country for financing disaster response, the possibility of using fresh idb resources, such as through the immediate response facility (gn- - and gn- - ), is analyzed. if their use is not considered feasible, the impact of the loan reformulation will be estimated by vpc, with support from vps, taking into account the intended uses and project objectives of the loan(s) to be reformulated either: (i) as a provider of funding or (ii) as a recipient of resources. the analysis for operations receiving funding in response to a natural hazard or physical damage from technological activities or other types of disasters resulting from human activity will reflect the nature of the projects, available information, and use of the reallocated resources for an emergency, rehabilitation, and reconstruction. . . the revision of the portfolio in emergency situations should be done jointly with the borrower. those projects whose development objective is unlikely to be achieved should be considered first as candidates for reformulation. the team responsible for the portfolio key: cord- -zjwlmzj authors: liu, shinan; schmitt, paul; bronzino, francesco; feamster, nick title: characterizing service provider response to the covid- pandemic in the united states date: - - journal: nan doi: nan sha: doc_id: cord_uid: zjwlmzj the covid- pandemic has resulted in dramatic changes to the daily habits of billions of people. users increasingly have to rely on home broadband internet access for work, education, and other activities. these changes have resulted in corresponding changes to internet traffic patterns. this paper aims to characterize the effects of these changes with respect to internet service providers in the united states. we study three questions: ( )how did traffic demands change in the united states as a result of the covid- pandemic?; ( )what effects have these changes had on internet performance?; ( )how did service providers respond to these changes? we study these questions using data from a diverse collection of sources. our analysis of interconnection data for two large isps in the united states shows a - % increase in peak traffic rates in the first quarter of . in particular, we observe traffic downstream peak volumes for a major isp increase of - % while upstream peaks increased by more than %. further, we observe significant variation in performance across isps in conjunction with the traffic volume shifts, with evident latency increases after stay-at-home orders were issued, followed by a stabilization of traffic after april. finally, we observe that in response to changes in usage, isps have aggressively augmented capacity at interconnects, at more than twice the rate of normal capacity augmentation. similarly, video conferencing applications have increased their network footprint, more than doubling their advertised ip address space. the covid- pandemic has resulted in dramatic shifts in the behavioral patterns of billions of people. these shifts have resulted in corresponding changes in how people use the internet. notably, people are increasingly reliant on home broadband internet access for work, education, and other activities. the changes in usage patterns have resulted in corresponding changes in network traffic demands observed by internet service providers. many reports have noted some of the effects of these changes from service provider networks [ , ] , application providers [ , ] , and internet exchange points [ ] . generally, previous findings and conventional wisdom suggest that while overall traffic demands increased, the internet responded well in response to these changing demands. previous work has shed light on the nature of the resulting changes in traffic patterns. in europe, internet exchange points saw a - % increase in overall traffic volumes [ ] , in some cases resulting in peaks in round trip latency in some countries (e.g., italy) that were approximately % higher than normal [ ] . because users were less mobile, downlink traffic volume decreased by up to % for cellular networks in the uk [ ] . while some of the characteristics of shifting traffic demands are known, and certain aspects of the internet's resilience in the face of the traffic shifts are undoubtedly a result of robust design of the network and protocols, some aspects of the internet's resilience are a direct result of providers' swift responses to these changing traffic patterns. this paper explores these traffic effects from a longitudinal perspective-exploring traffic characteristics during the first half of to previous years-and also explores how service providers responded to the changes in traffic patterns. service providers and regulatory agencies implemented various responses to the traffic shifts resulting from covid- . at&t and comcast have made public announcements about capacity increases in response to increases in network load [ , ] . the federal communications commission (fcc) also announced the "keep americans connected" initiative to grant providers (such as at&t, sprint, t-mobile, u.s. cellular, verizon, and others) additional spectrum to support increased broadband usage [ ] . web conferencing applications zoom and webex were also granted temporary relief from regulatory actions [ ] . these public documents provide some perspectives on responses, but to date, there are few independent reports and studies of provider responses. this paper provides an initial view into how some providers responded in the united states. we study the effects of the shifts in internet traffic resulting from the covid- pandemic response on internet infrastructure. we study three questions: • how did traffic patterns change as a result of covid- ? traffic volumes and network utilization are changing as a reaction to changes in user behaviors. it is critical to measure the exact alterations in a long time span. • what were the resulting effects on performance? considering an expected surge around the dates when states issued stayat-home orders or declared states of emergency, we seek to observe possible changes in the latency and throughput of network traffic across locations. further, different isps also have different capacity and provisioning strategies, which provides us a finer granularity based on these differences. • how did isps and service providers respond? finally, to deal with the usage boosts and performance degradations during the covid- response, operations and reactions of isps and service providers were taken which may explain the changes in network performance. the answer to this question informs us of the networks robustness and their effective disaster provisioning strategies. these questions have become increasingly critical during the covid- pandemic, as large fractions of the population have come to depend on reliable internet access that performs well for a variety of applications, from video conferencing to remote learning and healthcare. to answer these questions, we study a diverse collection of datasets about network traffic load, through granular measurements, proprietary data sharing agreements, and user experiences, as well as extensive baseline data spanning over two years. summary of findings. first, we study the traffic pattern changes in the united states ( § ) and find that, similar to the changes previously explored for european networks, our analysis reveals a - % increase in peak traffic volumes. in the comcast network in particular, we find that downstream peak traffic volume increased - %, while upstream peak traffic volume increases by more than %. certain interconnect peers exhibit significant changes in the magnitude of traffic during the lockdown. second, we observe a temporary, statistically significant increase in latency lasting approximately two months ( § ). we observe a temporary increase of about % in average latency around the time that stay-at-home orders were issued. typical latency values returned to normal a few months after these orders were put in place. we also find heterogeneity between different isps. finally, we explore how service providers responded to this increase in traffic demands by adding capacity ( § ). isps aggressively added capacity at interconnects, more than x the usual rates. on a similar note, application service providers (e.g., video conferencing apps) increased the advertised ip address space by . - x to cope with the corresponding - x increase in traffic demand. the pandemic response has modified people's habits, causing them to rely heavily on the internet for remote work, e-learning, video streaming, etc. in this section, we present some previous efforts in measuring the effects of covid- and past disaster responses on networks and applications. network measurements during covid- . previous work has largely focused on aggregate traffic statistics surrounding the initial covid- lockdowns. traffic surged about % in europe for broadband networks [ ] . in the united states, a blog post [ ] reveals that the national downstream peak traffic has recently stabilized, but in the early weeks of the pandemic, it showed a growth of . %. for wireless networks in the us, volume increases of up to . % for voice and . % for data by the top four providers were shown in an industry report [ ] . mobile networks in the uk reported roughly % drops in downlink data traffic volume [ ] . industry operators have self-reported on their network responses largely through blog posts [ , , , ] . for traffic performance changes, different patterns appear in different regions. facebook shows that less-developed regions exhibited larger performance degradations through their analysis of edge networks [ ] . network latencies were approximately % higher during the lockdown in italy [ ] . according to an ncta report, networks in the united states saw less congestion [ ] . due to decreased user mobility, cellular network patterns have shifted [ ] : the authors found a decrease in the average user throughput as well as decreased handoffs. feldmann et al. [ ] observed that the fixed-line internet infrastructure was able to sustain the - % increase in traffic that happened rapidly during a short window of one week. our work differs from and builds on these previous studies in several ways: first, this study extends over a longer time frame, and it also uses longitudinal data to compare traffic patterns during the past six months to traffic patterns in previous years. due to the nascent and evolving nature of covid- and corresponding isp responses, previous studies have been limited to relatively short time frames, and have mainly focused on europe. second, this work explores the isp response to the shifting demands and traffic patterns; to our knowledge, this work is the first to begin to explore isp and service provider responses. application measurements during covid- . previous work has also studied application usage and performance, such as increases in web conferencing traffic, vpn, gaming, and messaging [ ] . favale et al. studied ingress and egress traffic from the perspective of a university network and found that the internet proved capable of coping with the sudden spike in demand in italy [ ] . another paper used network traffic to determine campus occupancy at the effect of covid- related policies on three campus populations across singapore and the united states [ ] . the cybercrime market was also statistically modeled during the covid- era to characterize its economic and social changes [ ] . network measurements of other disasters. while covid- responses are ongoing and evolving, making measurement efforts incomplete, network responses under other disastrous events can be informative. in , the japan earthquake of magnitude . caused circuit failures and subsequent repairs within a major isp. nationwide, traffic fell by roughly % immediately after the earthquake. however, surprisingly little disruption was observed from outside [ ] . in , hurricane sandy hit the eastern seaboard of the united states and caused regional outages and variances over the network [ ] . for human-caused disasters such as the september th attacks, routing, and protocol data were analyzed to demonstrate the resilience of the internet under stress. their findings showed that although unexpected blackouts did happen, they only had a local effect [ ] . oppressive regimes have also caused internet outages, such as a complete internet shutdown due to censorship actions during the egypt and libya revolts [ ] , where packet drops and bgp route withdrawals were triggered intentionally. although there have been several preliminary measurements of the effects of the covid- response, none have holistically studied traffic data, performance analysis, routing data, and isp capacity information together, as we do in this paper. it is crucial to collect and correlate such information to better understand the nature of both traffic demands, the effects of these changes on performance, and the corresponding responses. this paper does so, illuminating the collaborative view of responses of service providers in the united states. we leverage multiple network traffic datasets to facilitate our study: traffic demands and interconnect capacity: internet connection measurement project. we leverage a dataset that includes network interconnection statistics for links between anonymized access isps and their neighboring partner networks in the united states. the dataset consists of ipfix-based statistics over five-minute intervals, including: timestamp, region (as access isps may connect to a partner network in multiple geographic regions), anonymized partner network, access isp, ingress bytes, egress bytes, and link capacity. the dataset contains roughly % of links from all participating isps. all of the links represented in the dataset are private (i.e., they do not involve public ixp switch fabrics). each five-minute interval includes the sum of the utilization of traffic flows that were active during that interval. we also calculate secondary statistics from the dataset, including: timestamp for the peak ingress and egress hour for each day on each link in terms of usage, ingress/egress peak hour bytes, and daily th and th percentile usage. performance data: federal communications commission measuring broadband america (mba). we analyze the fcc's ongoing nationwide performance measurement of broadband service in the united states [ ] . the raw data is collected from a collection of distributed measurement devices (named whiteboxes) placed in volunteer's homes and operated by samknows. measurements are conducted on an hourly basis. the dataset includes raw measurements of several performance metrics, such as timestamp, unit id, target server, round trip time, traffic volume, etc. each whitebox also includes information pertaining to its isp, technology, and state where it is located. we also define dates related to the status of the pandemic response (e.g., stay-at-home orders, state of emergency declaration, etc.). based on these, we can compute more statistics for specified groups (e.g., break into isps): average and standard deviation among whiteboxes, daily th and th percentile latency/throughput. to keep the network capacity consistent and to record eventual changes solely based on utilization factors, we pre-process the mba dataset with several filters. first, we filter the non-continuous data within the dates of interest (dec. st, to june, th , and the previous year) to capture successive shifts. then, we eliminate the whiteboxes which do not aggregate a statistically significant amount of data, such as some states, isps, and technologies with limited data (e.g., satellite). finally, we choose the measurements from whiteboxes to the top most targeted servers across the united states to represent the overall us performance. these servers are sparsely located in major cities of the us and they have the most whiteboxes (over for each isp) connecting with them. ip prefix advertisements: routeviews. to gain insight into changes in ip address space, we parse internet-wide bgp information globally from several locations and backbones via routeviews. raw ribs (routing information bases) files were obtained from route-views [ ] data on a weekly basis. the average of each tuesday is computed to represent that week. the ribs are then parsed to obtain ipv prefix-to-autonomous system (as) relationships, including mappings of ip prefix, prefix length, paths of as numbers. in section . , we compute the total advertised ipv spaces for as numbers associated with two popular video conferencing applications: zoom and cisco webex [ ] . because most previous studies [ , , ] focus on europe, we begin our explorations by validating whether similar traffic changes are observed in the united states. we consider peak hour link utilization from the interconnect measurement project as a measure of traffic demand. we pre-process the interconnect dataset and remove anomalous data points that are caused by failures in the measurement system. in particular, we do not analyze dates that are greater than two standard deviations outside of a -day rolling mean for each link. figure shows both the absolute utilization and the utilization normalized against the link capacity for two anonymized isps. for each isp, we plot the value corresponding to the th percentile link utilization for a given day. we observe from figure a that isp a saw a dramatic increase in raw utilization at roughly the same time as the initial covid- lockdowns (early march ), with values tapering off slightly over the summer of . isp b, on the other hand, saw a smaller raw increase in utilization for its th percentile links. to better understand whether isp b's smaller increase is a byproduct of different operating behaviors, we explore possible trends in the normalized data (figure b) . here we see that both isps experienced significant increases in utilization in march and april . we also investigated how traffic patterns changed between isp a and each of its peers, in both the upstream and downstream directions. for this analysis, we focused on the dates around the utilization peaks shown in figure . we compared the peak hour download and upload rates on all of isp a's interconnects on ( ) january , , and ( ) april , ( figure ). in general, we see that traffic patterns to peers do not vary greatly between the two dates. we do see, however, that traffic volumes to (and from) some peers change significantly-some by several orders of magnitude. the identities of the peers are anonymous in the dataset, but some patterns are nonetheless clear: for example, some peers show an increase of upstream utilization by two or three orders of magnitude. such drastic changes may be attributable to users working from home and connecting to services that would cause more traffic to traverse the peer link in the upstream direction. we confirmed these results with the operators at isp a and report that they observed that streaming video traffic decreased from to % of the total traffic, but video conferencing increased from % to % as a percentage of overall traffic. the surge in interconnect utilization poses a challenge for service providers, as high utilization of interconnects can potentially introduce high delays for interactive traffic, packet loss, or both. these effects can ultimately be observed through changes in latency (and, potentially, short-term throughput). to examine whether we can observe these effects, we look into the latency and throughput reported by the measuring broadband america (mba) dataset [ ] . we explore these effects over the course of several years to understand whether (and how) performance anomalies that we observe during covid- lockdown differ significantly from performance anomalies observed during other time periods. to better understand how performance changed as a result of changing traffic patterns during the covid- lockdown in the united states, we explored how latency evolved over the course of . to establish a basis for comparison, we show the time period from late through mid- . the appendix also contains a similar analysis for the - time period. we compute the average latency per-whitebox per-day, and subsequently explore distributions across whiteboxes for each isp. (as discussed in section , we consider only whiteboxes in fixed-line isps for which there are an adequate number of whiteboxes and samples.) we use march th , the average declaration of emergency date [ ] , to mark the beginning of the covid- pandmic phase (red shaded for figures). note that this is also the launch date of call of duty warzone peer peak download rate on jan figure shows a seven-day moving average of average round-trip latencies between all whiteboxes in this study. we observe an increase in average round-trip latency by as much as %, this increase in mean latency is significant, corresponding to x standard deviation among all whiteboxes. at the end of april, latencies return to early levels. it is worth noting that, although this increase in average latency is both sizable and significant, similar deviations and increases in latency have been observed before (see the appendix for comparable data from - ). thus, although some performance effects are visible during the covid- lockdown, the event and its effect on network performance are not significantly different from other performance aberrations. part of the reason for this, we believe, may be the providers' rapid response to adding capacity during the first quarter of , which we explore in more detail in section . in addition to the overall changes in performance, we also explored per-isp latency and throughput effects before and during the covid- lockdown period. figures and show these effects, showing (respectively) the th and th percentiles of average round-trip latency across the whiteboxes. these results show that, overall th percentile latency across most isps remained stable; th percentile latency, on the other hand, did show some deviations from normal levels during lockdown for certain isps. notably, however, in many cases the same isps experienced deviations in latency during other periods of time, as well (e.g., during the december holidays). high latencies can sometimes be reflected in achieved throughput, given the inverse relationship between tcp throughput and roundtrip latency. to explore whether latency aberrations ultimately result in throughput effects, as well as how those effects manifest at different times of day, we explored the distribution of latencies before covid- emergency declarations (ed), after the ed but before the stay-at-home order (so). our hypothesis was that we might see higher latencies (and lower throughputs) during "peak hours" of the day from broadband access networks, with the peak hours effectively expanded to the weekday working hours, in accordance with previous descriptions of these effects [ ] . we explored these metrics for a baseline period predating covid- , the time between state declaration of emergency and stay at home ordered [ ] , after stay-at-home declarations were ordered, and two months after stay-at-home ordered. because these dates differed across states, we used known dates for each state [ ] and matched the corresponding dates for each state against the known location of the whiteboxes. figure shows the distribution throughput and latency distributions across all whiteboxes for four time intervals, plotted in four-hour intervals. from figure a , it is clear that the quantiles, median, and maximum latencies all exhibit effects that correlate with these time periods. the period between ed and so corresponds to abrupt routing changes, and the latency data thus reflects a corresponding degradation during this time interval, perhaps at least partially due to the fact that providers cannot immediately respond after the initial emergency declaration (we discuss the timeframes during which capacity was added to the networks in section ). as the transition continues, so appears to be a point in time where latency stabilizes. figure b shows that distributions of throughput measurements are more robust, although the upper end of the distribution is clearly affected, with maximum achieved throughputs lower. the median and minimum have negligible changes during time periods in late april suggesting (and corresponding to) aggressive capacity augmentation, which we discuss in more detail in section . how did service providers respond? in this section, we study how service providers responded to the changes in traffic demands. we focus on the capacity changes during lockdown by inspecting two data sources: ( ) to understand how isps responded by adding capacity to interconnects, we study the interconnect capacity of two large isps in the united states; and ( ) to understand how video service providers expanded their network footprints in response to increasing demand, we analyze ipv address space from two major video conference providers-webex and zoom-and find that both providers substantially increased advertised ip address space. we begin by exploring how isps responded to changing traffic demands by adding network capacity at interconnect links. to do so, we use the interconnect measurement project dataset. we calculate the total interconnect capacity for each isp by summing the capacities for all of the links associated with the isp. to enable comparison between isps that may have more or less infrastructure overall, we normalize the capacity values for each using min-max normalization. we again filter out date values that are beyond two standard deviations from a rolling -day window mean. to show aggregate infrastructure changes over time, we take all of the data points in each fiscal quarter and perform a least-squares linear regression using scikit learn. this regression yields a slope for each quarter that illustrates the best-fit rate of capacity increases over that quarter. we scale the slope value to show what the increase would be if the pace was maintained for days (i.e., a slope of would result in a doubling of capacity over the course of a year). figure shows the resulting capacity plots. the overall trend shows how these two isps in the united states aggressively added capacity at interconnects-at more than twice the rate at which they were adding capacity over a comparable time period in the previous year. second, both isps significantly added capacity in the first quarter of -at a far greater rate than they were adding capacity in the first quarter of . recall from the usage patterns shown in figure , isp a tends to operate their links at nearly full capacity, in contrast to isp b, where aggregate utilization is well below %. both isps witnessed a jump in usage around the lockdown; the response of aggressively adding capacity appears to have mitigated possible adverse effects of high utilization rates. the increase in capacity was necessary to cope with the increased volume: although network performance and utilization ratios returned to pre-covid- levels, the absolute traffic volumes remain high. to cope with abrupt changes caused by covid- , application service providers also took action to expand their infrastructure. previous work has observed shifted traffic in communication applications (such as video conferencing apps, email, and messaging) after lockdown [ ] . it has been reported informally that many application providers expanded serving infrastructure, changed the routes of certain application traffic flows, and even altered the bitrates of services to cope with increased utilization. while not all of these purported responses are directly observable in public datasets; however, routeviews makes available global routing information, which can provide some hints about routes and infrastructure, and how various characteristics of the internet routing infrastructure change over time. this data can provide some indication of expanding infrastructure, such as the amount of ipv address space that a particular autonomous system (as) is advertising. in the case of video conference providers, where some of the services may be hosted on cloud service providers or where the video service is a part of a larger as that offers other services (e.g., google meet), such a metric is clearly imperfect, but it can offer some indication of response. to understand how service providers announced additional ipv address space, we parsed bgp routing tables from routeviews [ ] . for each route that originates from ases of certain application providers, we aggregate ip prefixes and translate the resulting prefixes into a single count of overall ipv address space. we focus on two popular video conferencing applications, zoom and webex, since they are two of the largest web conference providers in the united states-as also recognized by the fcc in their recent order for regulatory relief [ ] . we track the evolution of the advertised ip address space from the beginning of through october . figure demonstrates how each provider added advertised ipv address space from before the pandemic through october . after the beginning of the covid- pandemic, both zoom and webex rapidly begin to advertise additional ipv address space. table enumerates the absolute values of advertised ip address space: zoom and webex increased advertised ip address space by about x and . x respectively, roughly corresponding to the - x increase in video conferencing traffic. this paper has explored how traffic demands changed as a result of the abrupt daily patterns caused by the covid- lockdown, how these changing traffic patterns affected the performance of isps in the united states, both in aggregate and for specific isps, and how service providers responded to these shifts in demand. we observed a - % increase in peak traffic rates for two major isps in the us corresponding with significant increases in latency in early weeks of lockdown, followed by a return to pre-lockdown levels, corresponding with aggressive capacity augmentation at isp interconnects and the addition of ipv address space from video conferencing providers. although this paper presented the first known study of interconnect utilization and service provider responses to changes in patterns resulting from the covid- pandemic, this study still offers a somewhat limited viewpoint into these effects and characteristics. future work could potentially confirm or extend these findings by exploring these trends for other isps, over the continued lockdown period, and for other service providers. this section provides a basis for performance comparison in section . following the same analysis, we choose the exact same time period in the previous year (i.e., late to mid- ) in the united states. we compute the average latency per-whitebox per-day, and subsequently explore distributions across whiteboxes for each isp. longitudinal evolution of aggregate, average round-trip latency. figure shows the aggregate average latency per-whitebox per-day. the previous year has an overall latency of about ms lower than . we observe that the latency keeps stable until the end of april, where a deviation of about ms is shown. the rate of increase is of about %, echoing similar effects around lockdown. longitudinal evolution of per-isp latencies. we further break the aggregate results into the granularity of isps. we report both th and th percentile latencies here. note that in the th percentile plot, we show the groups differently, mainly because of major differences of latency for mediacom and at&t. from figure , we find that the majority of isps performed stably, while mediacom has a large variance in the average rtt. they both have a tail that contributes to what we observed in . figure is grouped the same as figure , which shows that for certain isps, they experience similar deviations during similar periods of different years. we put a supplementary figure referred to in section in this appendix. it shows the distributional changes in latency and throughput on a -hour basis. detailed explanations are in the main text. : changes in latency and throughput before and after the lockdown. ed means "emergency is declared" so means "stay-at-home ordered". a- covid- : our response how the internet reacted to covid- -a perspective from facebook's edge network impact of the covid- pandemic on the internet latency: a large-scale study the japan earthquake: the impact on traffic and routing observed by a local isp covid- network update the wireless industry responds to covid- : network performance analysis of country-wide internet outages caused by censorship campus traffic and e-learning during covid- pandemic keep americans connected measuring broadband raw data releases the lockdown effect: implications of the covid- pandemic on internet traffic wikimedia foundation. accessed october, . u.s. state and local government responses to the covid- pandemic keeping our network infrastructure strong amid covid- a preliminary analysis of network outages during hurricane sandy a characterization of the covid- pandemic impact on a mobile network operator traffic parts of a whole: effect of covid- on us internet traffic covid- : how cable's internet networks are performing: metrics, trends & observations network traffic insights in the time of covid- keeping the internet up and running in times of crisis the internet under crisis conditions: learning from university of oregon route views project turning up the dial: the evolution of a cybercrime market through set-up, stable, and covid- eras prashant shenoy, and rajesh balan. . analyzing the impact of covid- control policies on campus occupancy and mobility via passive wifi sensing key: cord- -ron oqrn authors: afshordi, niayesh; holder, benjamin; bahrami, mohammad; lichtblau, daniel title: diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states date: - - journal: nan doi: nan sha: doc_id: cord_uid: ron oqrn the sars-cov- pandemic has caused significant mortality and morbidity worldwide, sparing almost no community. as the disease will likely remain a threat for years to come, an understanding of the precise influences of human demographics and settlement, as well as the dynamic factors of climate, susceptible depletion, and intervention, on the spread of localized epidemics will be vital for mounting an effective response. we consider the entire set of local epidemics in the united states; a broad selection of demographic, population density, and climate factors; and local mobility data, tracking social distancing interventions, to determine the key factors driving the spread and containment of the virus. assuming first a linear model for the rate of exponential growth (or decay) in cases/mortality, we find that population-weighted density, humidity, and median age dominate the dynamics of growth and decline, once interventions are accounted for. a focus on distinct metropolitan areas suggests that some locales benefited from the timing of a nearly simultaneous nationwide shutdown, and/or the regional climate conditions in mid-march; while others suffered significant outbreaks prior to intervention. using a first-principles model of the infection spread, we then develop predictions for the impact of the relaxation of social distancing and local climate conditions. a few regions, where a significant fraction of the population was infected, show evidence that the epidemic has partially resolved via depletion of the susceptible population (i.e.,"herd immunity"), while most regions in the united states remain overwhelmingly susceptible. these results will be important for optimal management of intervention strategies, which can be facilitated using our online dashboard. the new human coronavirus sars-cov- emerged in wuhan province, china in december (chen et al., ; li et al., ) , reaching , confirmed cases and deaths due to the disease (known as by the end of january this year. although travel from china was halted by late-january, dozens of known introductions of the virus to north america occurred prior to that (holshue et al., ; kucharski et al., ) , and dozens more known cases were imported to the us and canada during february from europe, the middle east, and elsewhere. community transmission of unknown origin was first detected in california on february , followed quickly by washington state (chu et al., b) , illinois and florida, but only on march in new york city. retrospective genomic analyses have demonstrated that case-tracing and self-quarantine efforts were effective in preventing most known imported cases from propagating (ladner et al., ; gonzalez-reiche et al., ; worobey et al., ) , but that the eventual outbreaks on the west coast (worobey et al., ; chu et al., b; deng et al., ) and new york (gonzalez-reiche et al., ) were likely seeded by unknown imports in mid-february. by early march, cross-country spread was primarily due to interstate travel rather than international imports (fauver et al., ) . in mid-march , nearly every region of the country saw a period of uniform exponential growth in daily confirmed cases -signifying robust community transmission -followed by a plateau in late march, likely due to social mobility reduction. the same qualitative dynamics were seen in covid- mortality counts, delayed by approximately one week. although the qualitative picture was similar across locales, the quantitative aspects of localized epidemics -including initial rate of growth, infections/deaths per capita, duration of plateau, and rapidity of resolution -were quite diverse across the country. understanding the origins of this diversity will be key to predicting how the relaxation of social distancing, annual changes in weather, and static local demographic/population characteristics will affect the resolution of the first wave of cases, and will drive coming waves, prior to the availability of a vaccine. the exponential growth rate of a spreading epidemic is dependent on the biological features of the virus-host ecosystem -including the incubation time, susceptibility of target cells to infection, and persistence of the virus particle outside of the host -but, through its de-pendence on the transmission rate between hosts, it is also a function of external factors such as population density, air humidity, and the fraction of hosts that are susceptible. initial studies have shown that sars-cov- has a larger rate of exponential growth (or, alternatively, a lower doubling time of cases ) than many other circulating human viruses (park et al., ) . for comparison, the pandemic influenza of , which also met a largely immunologically-naive population, had a doubling time of - d (yu et al., ; storms et al., ) , while that of sars-cov- has been estimated at - d (sanche et al., ; oliveiros et al., ) (growth rates of ∼ . d − vs. ∼ . d − ). it is not yet understood which factors contribute to this high level of infectiousness. while the dynamics of an epidemic (e.g., cases over time) must be described by numerical solutions to nonlinear models, the exponential growth rate, λ, usually has a simpler dependence on external factors. unlike case or mortality incidence numbers, the growth rate does not scale with population size. it is a directly measurable quantity from the available incidence data, unlike, e.g., the reproduction number, which requires knowledge of the serial interval distribution (wallinga and lipsitch, ; roberts and heesterbeek, ; dushoff and park, ) , something that is difficult to determine empirically (champredon and dushoff, ; nishiura, ). yet, the growth rate contains the same threshold as the reproduction number (λ = vs. r = ), between a spreading epidemic (or an unstable uninfected equilibrium) and a contracting one (or an equilibrium that is resistant to flare-ups). thus, the growth rate is an informative direct measure on that space of underlying parameters. in this work, we leverage the enormous data set of epidemics across the united states to evaluate the impact of demographics, population density and structure, weather, and non-pharmaceutical interventions (i.e., mobility restrictions) on the exponential rate of growth of covid- . following a brief analysis of the initial spread in metropolitan regions, we expand the meaning of the exponential rate to encompass all aspects of a local epidemic -including growth, plateau and decline -and use it as a tracer of the dynamics, where its time dependence and geographic variation are dictated solely by these external variables and per capita cumulative mortality. finally, we use the results of that linear analysis to calibrate a new nonlinear model -a renewal equation that utilizes the excursion probability of a random walk to determine the incubation period -from which we develop local predictions about the impact of social mobility relaxation, the level of herd immunity, and the potential of rebound epidemics in the summer and fall. diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states initial growth of cases in metropolitan regions is exponential with rate depending on mobility, population, demographics, and humidity as an initial look at covid- 's arrival in the united states, we considered the ∼ most populous metropolitan regions -using maps of population density to select compact sets of counties representing each region (see supplementary material) -and estimated the initial exponential growth rate of cases in each region. we performed a linear regression to a large set of demographic (sex, age, race) and population variables, along with weather and social mobility (fitzpatrick and karen, ) preceding the period of growth ( figure ). in the best fit model (r = . , bic = − ), the baseline value of the initial growth rate was λ = . d − (doubling time of . d), with average mobility two weeks prior to growth being the most significant factor ( figure b ). of all variables considered, only four others were significant: population density (including both populationweighted density (pwd) -also called the "lived population density" because it estimates the density for the average individual (craig, ) -and population sparsity, γ, a measure of the difference between pwd and standard population density, see methods), p < . and p = . ; specific humidity two weeks prior to growth, p = . ; and median age, p = . . while mobility reduction certainly caused the "flattening" of case incidence in every region by late-march, our results show ( figure c ) that it likely played a key role in reducing the rate of growth in boston, washington, dc, and los angeles, but was too late, with respect to the sudden appearance of the epidemic, to have such an effect in, e.g., detroit and cleveland. in the most extreme example, grand rapids, mi, seems to have benefited from a late arriving epidemic, such that its growth (with a long doubling time of d) occurred almost entirely post-lockdown. specific humidity, a measure of absolute humidity, has been previously shown to be inversely correlated with respiratory virus transmission (lowen et al., ; shaman and kohn, ; shaman, goldstein, and lipsitch, ; kudo et al., ) . here, we found it to be a significant factor, but weaker than population density and mobility ( figure c ). it could be argued that dallas, los angeles, and atlanta saw a small benefit from higher humidity at the time of the epidemic's arrival, while the dry latewinter conditions in the midwest and northeast were more favorable to rapid transmission of sars-cov- . in the remainder of this report, we consider the exponential rate of growth (or decay) in local confirmed deaths due to covid- . the statistics of mortality is poorer compared to reported cases, but it is much less dependent on unknown factors such as the criteria for testing, local policies, test kit availability, and asymptomatic individuals (pearce et al., ) . although there is clear evidence that a large fraction of covid- mortality is missed in the official counts (e.g., leon et al., ; modi et al., ) , mortality is likely less susceptible to rapid changes in reporting, and, as long as the number of reported deaths is a monotonic function of the actual number of deaths (e.g., a constant fraction, say %), the sign of the exponential growth rate will be unchanged, which is the crucial measure of the success in pandemic management. to minimize the impact of weekly changes, such as weekend reporting lulls, data dumps, and mobility changes from working days to weekends, we calculate the regression of ln [mortality] over a -day interval, and assign this value, λ (t), and its standard error to the last day of the interval. since only the data for distinct -week periods are independent, we multiply the regression errors by √ to account for correlations between the daily estimates. together with a "rolling average" of the mortality, this time-dependent measure of the exponential growth rate provides, at any day, the most up-to-date information on the progression of the epidemic (figure ). in the following section, we consider a linear fit to λ , to determine the statistically-significant external (non-biological) factors influencing the dynamics of local exponential growth and decline of the epidemic. we then develop a first-principles model for λ that allows for extrapolation of these dependencies to predict the impact of future changes in social mobility and climate. epidemic mortality data explained by mobility, population, demographics, depletion of susceptible population and weather, throughout the first wave of covid- we considered a spatio-temporal dataset containing estimates of the exponential growth measure, λ , covering the three month period of march - june in the us counties for which information on covid- mortality and all potential driving factors, below, were available (the main barrier was social mobility information, which limited us to a set of counties that included % of us mortality). a joint, simultaneous, diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states linear fit of these data to potential driving factors (table ) revealed only factors with independent statistical significance. re-fitting only to these variables returned the optimal fit for the considered factors (bic = − ; r = . ). we found, not surprisingly, that higher population density, median age, and social mobility correlated with positive exponential growth, while population sparsity, specific humidity, and susceptible depletion correlated with exponentially declining mortality. notably the coefficients for each of these quantities was in the % confidence intervals of those found in the analysis of metropolitan regions (and vice versa). possibly the most surprising dependency was the negative correlation, at − . σ between λ and the total number of annual deaths in the county. in fact, this correlation was marginally more significant than a correlation with log(population), which was − . σ. one possible interpretation of this negative correlation is that the number of annual death is a proxy for the number of potential outbreak clusters. the larger the number of clusters, the longer it might take for the epidemic to spread across their network, which would (at least initially) slow down the onset of the epidemic. to obtain more predictive results, we developed a mechanistic nonlinear model for infection (see supplementary material for details). we followed the standard analogy to chemical reaction kinetics (infection rate is proportional to the product of susceptible and infectious densities), but defined the generation interval (approximately the incubation period) through the excursion probability in a d random walk, modulated by an exponential rate of exit from the infected class. this approach resulted in a renewal equation (heesterbeek and dietz, ; champredon and dushoff, ; champredon, dushoff, and earn, ) , with a distribution of generation intervals that is more realistic than that of standard sir/seir models, and which could be solved formally (in terms of the lambert w function) for the growth rate in terms of the infection parameters: the model has four key dependencies, which we describe here, along with our assumptions about their own dependence on population, demographic, and climate variables. as mortality (on which our estimate of growth rate is based) lags infection (on which the renewal equation is based), we imposed a fixed time shift of ∆t for timedependent variables: . we assumed that the susceptible population, which feeds new infections and drives the growth, is actually a sub-population of the community, consisting of highly-mobile and frequently interacting individuals, and that most deaths occurred in separate subpopulation of largely immobile non-interacting individuals. under these assumptions, we found (see supp. mat.) that the susceptible density, s(t), could be estimated from the cumulative per capita death fraction, f d , as: where d tot is the cumulative mortality count, n is the initial population, and the initial density is s( ) = k pwd. . we assumed that the logarithm of the "rate constant" for infection, β, depended linearly on social mobility, m, specific humidity, h, population sparsity, γ, and total annual death, a d , as: where a barred variable represents the (populationweighted) average value over all us counties, and where the mobility and humidity factors were timeshifted with respect to the growth rate estimation window: m = m (t − ∆t) and h = h (t − ∆t). . the characteristic time scale to infectiousness, τ , is intrinsic to the biology and therefore we assumed it would depend only on the median age of the population, a. we assumed a power law dependence: where we fixed the pivot age, a , to minimize the error in τ . . the exponential rate of exit from the infected class, d, was assumed constant, since we found no significant dependence for it on other factors in our analysis of us mortality. from the properties of the lambert w function, when the infection rate or susceptibility density approach zero -through mobility restrictions or susceptible depletion -the growth rate will tend to λ ≈ −d, its minimum value. with these parameterizations, we performed a nonlinear regression to λ (t) using the entire set of us county mortality incidence time series (table ). compared to the linear model of the previous section (table b) diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states individual's probability of becoming infectious, and the distributions of incubation period and generation interval, all as a function of the median age of the population (see supplementary material). the model was very well fit to the mortality growth rate measurements for counties with a high mortality ( figure ). more quantitatively, the scatter of measured growth rates around the best-fit model predictions was (on average) only % larger than the measurement errors, independent of the population of the county . importantly, when the model was calibrated on only a subset of the data -e.g., all but the final month for which mobility data is available -its % confidence prediction for the remaining data was accurate (figure ) given the known mobility and weather data for that final month. this suggests that the model, once calibrated on the first wave of covid- infections, can make reliable predictions about the ongoing epidemic, and future waves, in the united states. possibly the most pressing question for the management of covid- in a particular community is the combination of circumstances at which the virus fails to propagate, i.e., at which the growth rate, estimated here by λ , becomes negative (or, equivalently, the reproduction number r t falls below one). in the absence of mobility restrictions this is informally called the threshold for "herd immunity," which is usually achieved by mass vaccination (e.g., john and samuel, ; fine, eames, and heymann, ) . without a vaccine, however, ongoing infections and death will deplete the susceptible population and thus decrease transmission. varying the parameters of the nonlinear model individually about their spring population-weighted mean values ( figure ) suggests that this threshold will be very much dependent on the specific demographics, geography, and weather in the community, but it also shows that reductions in social mobility can significantly reduce transmission prior the onset of herd immunity. to determine the threshold for herd immunity in the absence or presence of social mobility restrictions, we considered the "average us county" (i.e., a region with population-weighted average characteristics), and examined the dependence of the growth rate on the cumulative mortality. we found that in the absence of social distancing, a covid- mortality rate of . % (or per million population) would bring the growth rate to zero. however, changing the population density of this average county shows that the threshold can vary widely ( figure ). examination of specific counties showed that the mortality level corresponding to herd immunity varies from to per million people (figure ). at the current levels of reported covid- mortality, we found that, as of june nd, , only ± out of counties (inhabiting . ± . % of us population) have surpassed this threshold at % confidence level ( figure ). notably, new york city, with the highest reported per capita mortality ( per million) has achieved mobility-independent herd immunity at the σ confidence level, according to the model ( figure ). a few other large-population counties in new england, new jersey, michigan, louisiana, georgia and mississippi that have been hard hit by the pandemic also appear to be at or close to the herd immunity threshold. this is not the case for most of the united states, however ( figure ). nationwide, we predict that covid- herd immunity would only occur after a death toll of , ± , , or ± per million of population. we found that the approach to the herd immunity threshold is not direct, and that social mobility restrictions and other non-pharmaceutical interventions must be applied carefully to avoid excess mortality beyond the threshold. in the absence of social distancing interventions, a typical epidemic will "overshoot" the herd immunity limit (e.g., handel, longini jr, and antia, ; fung, antia, and handel, ) by up to %, due to ongoing infections ( figure ). at the other extreme, a very strict "shelter in place" order would simply delay the onset of the epidemic; but if lifted (see figures and ), the epidemic would again overshoot the herd immunity threshold. a modest level of social distancing, however -e.g., a % mobility reduction for the average us county -could lead to fatalities "only" at the level of herd immunity. naturally, communities with higher population density or other risk factors (see figure ), would require more extreme measures to achieve the same. avoiding the level of mortality required for herd immunity will require long-lasting and effective nonpharmaceutical options, until a vaccine is available. the universal use of face masks has been suggested for reducing the transmission of sars-cov- , with a recent meta-analysis (chu et al., a) suggesting that masks can suppress the rate of infection by a factor of . - . ( % ci), or equivalently ∆ ln(transmission) = − . ± . (at σ). using our model's dependence of the infection rate constant on mobility, this would correspond to an equivalent social mobility reduction of ∆m mask − % ± %. warmer, more humid weather has also considered a factor that could slow the epidemic (e.g., wang et al., a; notari, ; xu et al., a). annual changes in specific humidity are ∆h g/kg ( figure b in supplementary material), which can be translated in our model to an effective mobility decrease of ∆m summer − % ± %. combining these two effects could, in this simple analysis, yield a modestly effective defense for the summer months: ∆m mask+summer − % ± %. therefore, this could be a reasonable strategy for most communities to manage the covid- epidemic at the aforementioned - % level of mobility needed to arrive at herd immunity with the least excess death. more stringent measures would be required to keep mortality below that level. of course, this general prescription would need to be fine-tuned for the specific conditions of each community. by simultaneously considering the time series of mortality incidence in every us county, and controlling for the time-varying effects of local social distancing interventions, we demonstrated for the first time a dependence of the epidemic growth of covid- on population density, as well as other climate, demographic, and population factors. we further constructed a realistic, but simple, first-principles model of infection transmission that allowed us to extend our heuristic linear model of the dataset into a predictive nonlinear model, which provided a better fit to the data (with the same number of parameters), and which also accurately predicted latetime data after training on only an earlier portion of the data set. this suggests that the model is well-calibrated to predict future incidence of covid- , given realistic predictions/assumptions of future intervention and climate factors. we summarized some of these predictions in the final section of results, notably that only a small fraction of us counties (with less than ten percent of the population) seem to have reached the level of herd immunity, and that relaxation of mobility restrictions without counter-measures (e.g., universal mask usage) will likely lead to increased daily mortality rates, beyond that seen in the spring of . in any epidemiological model, the infection rate of a disease is assumed proportional to population density (jong, diekmann, and heesterbeek, ) , but, to our knowledge, its explicit effect in a real-world respiratory virus epidemic has not been demonstrated. the universal reach of the covid- pandemic, and the diversity of communities affected have provided an opportunity to verify this dependence. indeed, as we show here, it must be accounted for to see the effects of weaker drivers, such as weather and demographics. a recent study of covid- in the united states, working with a similar dataset, saw no significant effect due to pop- ulation density (hamidi, sabouri, and ewing, ), but our analysis differs in a number of important ways. first, we have taken a dynamic approach, evaluating the time-dependence of the growth rate of mortality incidence, rather than a single static measure for each county, which allowed us to account for the changing effects of weather, mobility, and the density of susceptible individuals. second, we have included an explicit and real-time measurement of social mobility, i.e., cell phone mobility data provided by google (fitzpatrick and karen, ), allowing us to control for the dominant effect of intervention. finally, and perhaps most importantly, we calculate for each county an estimate of the "lived" population density, called the population-weighted population density (pwd) (craig, ) , which is more meaningful than the standard population per political area. as with any population-scale measure, this serves as a proxy -here, for estimating the average rate of encounters between infectious and susceptible people -but we believe that pwd is a better proxy than standard population density, and it is becoming more prevalent, e.g., in census work (dorling and atkins, ; wilson, ) . we also found a significant dependence of the mortality growth rate on specific humidity (although since temperature and humidity were highly correlated, a replacement with temperature was approximately equivalent), indicating that the disease spread more rapidly in drier (cooler) regions. there is a large body of research on the effects of temperature and humidity on the transmission of other respiratory viruses (moriyama, hugentobler, and iwasaki, ; kudo et al., ) , specifically influenza (barreca and shimshack, ). influenza was found to transmit more efficiently between guinea pigs in low relative-humidity and temperature conditions (lowen et al., ) , although re-analysis of this work pointed to absolute humidity (e.g., specific humidity) as the ultimate controller of transmission (shaman and kohn, ) . although the mechanistic origin of humidity's role has not been completely clarified, theory and experiments have suggested a snowballing effect on small respiratory droplets that cause them to drop more quickly in high-humidity conditions (tellier, ; noti et al., ; marr et al., ) , along with a role for evaporation and the environmental stability of virus particles (morawska, ; marr et al., ) . it has also been shown that the onset of the influenza season (shaman et al., ; shaman, goldstein, and lipsitch, ) -which generally occurs between late-fall and early-spring, but is usually quite sharply peaked for a given strain (h n , h n , or influenza b) -and its mortality (barreca and shimshack, ) are linked to drops in absolute humidity. it is thought that humidity or temperature could be the annual periodic driver in the resonance effect causing these acute seasonal outbreaks of influenza (dushoff et al., ; tamerius et al., ) , although other influences, such as school diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states (moriyama, hugentobler, and iwasaki, ; neher et al., ) , and there have been some preliminary reports of a dependence on weather factors (xu et al., b; schell et al., ) . we believe that our results represent the most definitive evidence yet for the role of weather, but emphasize that it is a weak, secondary driver, especially in the early stages of this pandemic where the susceptible fraction of the population remains large (baker et al., ) . indeed, the current early-summer rebound of covid- in the relatively dry and hot regions of the southwest suggests that the disease spread will not soon be controlled by seasonality. we developed a new model of infection in the framework of a renewal equation (see, e.g., champredon, dushoff, and earn, and references therein), which we could formally solve for the exponential growth rate. the incubation period in the model was determined by a random walk through the stages of infection, yielding a non-exponential distribution of the generation interval, thus imposing more realistic delays to infectiousness than, e.g., the standard seir model. in this formulation, we did not make the standard compartmental model assumption that the infection of an individual induces an autonomous, sequential passage from exposure, to infectiousness, to recovery or death; indeed, the model does not explicitly account for recovered or dead individuals. this freedom allows for, e.g., a back passage from infectious to noninfectious (via the underlying random walk) and a variable rate of recovery or death. we assumed only that the exponential growth in mortality incidence matched (with delay) that of the infected incidence -the primary dynamical quantity in the renewal approachand we let the cumulative dead count predict susceptible density -the second dynamical variable in the renewal approach -under the assumption that deaths arise from a distinct subset of the population, with lower mobility behavior than those that drive infection (see supplementary material) . therefore, we fitted the model to the (rolling two-week estimates of the) covid- mortality incidence growth rate values, λ , for all counties and all times, and used the per capita mortality averaged over that period, f d , to determine susceptible density. regression to this nonlinear model was much improved over linear regression, and, once calibrated on an early portion of the county mortality incidence time series, the model accurately predicted the remaining incidence. because we accounted for the precise effects of social mobility in fitting our model to the actual epidemic growth and decline, we were then able to, on a county-bycounty basis, "turn off" mobility restrictions and estimate the level of cumulative mortality at which sars-cov- would fail to spread even without social distancing measures, i.e., we estimated the threshold for "herd immunity." meeting this threshold prior to the distribution of a vaccine should not be a goal of any community, because it implies substantial mortality, but the threshold is a useful benchmark to evaluate the potential for local outbreaks following the first wave of covid- in spring . we found that a few counties in the united states have indeed reached herd immunity in this estimation -i.e., their predicted mortality growth rate, assuming baseline mobility, was negative -including counties in the immediate vicinity of new york city, detroit, new orleans, and albany, georgia. a number of other counties were found to be at or close to the threshold, including much of the greater new york city and boston areas, and the four corners, navajo nation, region in the southwest. all other regions were found to be far from the threshold for herd immunity, and therefore are susceptible to ongoing or restarted outbreaks. these determinations should be taken with caution, however. in this analysis, we estimated that the remaining fraction of susceptible individuals in the counties at or near the herd immunity threshold was in the range of . % to % (see supplementary materials) . this is in strong tension with initial seroprevalence studies (rosenberg et al., ; havers et al., a) which placed the fraction of immune individuals in new york city at % in late march and % in late april, implying that perhaps % of that population remains susceptible today. we hypothesize that the pool of susceptible individuals driving the epidemic in our model is a subset of the total population -likely those with the highest mobility and geographic reachwhile a different subset, with very low baseline mobility, contributes most of the mortality (see supplementary ma-diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states terial). thus, the near total depletion of the susceptible pool we see associated with herd immunity corresponds to the highly-mobile subset, while the low-mobility subset could remain largely susceptible. one could explicitly consider such factors of population heterogeneity in a model -e.g., implementing a saturation of infectivity as a proxy for a clustering effect (capasso and serio, ; mollison, ; de boer, ; farrell et al., )but we found (in results not shown) that the introduction of additional of parameters left portions of the model unidentifiable. despite these cautions, it is interesting to note that the epidemic curves (mortality incidence over time) for those counties that we have predicted an approach to herd immunity are qualitatively different than those we have not. specifically, the exponential rise in these counties is followed by a peak and a sharp decline -rather than the flattening seen in most regions -which is a typical feature of epidemic resolution by susceptible depletion. at the time of this writing, in early summer , confirmed cases are again rising sharply in many locations across the united states -particularly in areas of the south and west that were spared significant mortality in the spring wave. the horizon for an effective and fully-deployed vaccine still appears to be at least a year away. initial studies of neutralizing antibodies in recovered covid- patients, however, suggest a waning immune response after only - months, with % of those that were asymptomatic becoming seronegative in that time period (long et al., ) . although the antiviral remdesivir (beigel et al., ; grein et al., ; wang et al., b) and the steroid dexamethasone (horby et al., ) have shown some promise in treating covid- patients, the action of remdesivir is quite weak, and high-dose steroids can only be utilized for the most critical cases. therefore, the management of this pandemic will likely require non-pharmaceutical intervention -including universal social distancing and mask-wearing, along with targeted closures of businesses and community gathering places -for years in the future. the analysis and prescriptive guidance we have presented here should help to target these approaches to local communities, based on their particular demographic, geographic, and climate characteristics, and can be facilitated through our online simulator dashboard. finally, although we have focused our analysis on the united states, due to the convenience of a diverse and voluminous data set, the method and results should be applicable to any community worldwide, and we intend to extend our analysis in forthcoming work. baker, rachel e et al. ( ) . "susceptible supply limits the role of climate in the early sars-cov- pandemic". in: science. barreca, alan i. and jay p. shimshack ( ) john d et al. ( ) . "high humidity leads to loss of infectious influenza virus from simulated coughs". in: plos one . , e . oliveiros, barbara et al. ( ) . "role of temperature and humidity in the modulation of the doubling time of covid- cases". in: medrxiv. park, sang woo et al. ( ) . "reconciling earlyoutbreak estimates of the basic reproductive number and its uncertainty: framework and applications to the novel coronavirus (sars-cov- ) outbreak". in: medrxiv. pearce, n et al. ( ) . "accurate statistics on are essential for policy guidance and decisions." in: american journal of public health, e . roberts, mg and jap heesterbeek ( ) . "modelconsistent estimation of the basic reproduction number from the incidence of an emerging infection". in: journal of mathematical biology . (figure was obtained from the noao global surface summary of the day (gsod) database (national oceanic and atmospheric observatory, ). the nearest wban station with daily dew point and pressure values (for calculation of specific humidity), and daily average temperature was chosen for each county or metropolitan region. weather data was averaged over a two-week period for λ , and over a window equal to the growth period for metropolitan regions. google's covid- community mobility reports dataset (fitzpatrick and karen, ), specifically "workplace mobility," was used to estimate the human social mobility in each county ( figure ). population-weighted population density (or, population weighted density, pwd) (craig, ; wilson, ; dorling and atkins, ) , was calculated using the global human settlement population raster dataset (european commission joint research centre, ), which contains m-resolution population values worldwide, taken from census data. the value of pwd for a countyor for a set of counties, in the metropolitan region analysis -was calculated as the population-weighted average of density over all ( m) -area pixels contained within the region, i.e., where p j is the value (i.e., the population) of the jth pixel, a j = . km is the area of each pixel (the ghs-pop image uses the equal-area molleweide projection), and i p i is the total population of the region. this measure has also been called the lived population density because it is the population density experienced by the average person. in high density counties, the population weighted density pwd is close to the mean density of the county d = pop/area, suggesting a uniform distribution of population (see figure ). however, in lower density counties, the mean density is much lower than the population weighted density, due to heterogeneous dense pockets of population amidst vast empty spaces outlined diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states by political boundaries. to represent the degree to which the population density changes across the region (county or metropolitan region) we define the population sparsity index, γ. assuming that the population-weighted population density declines approximately as a power law with "pixel" area, pwd √ area ∼ area −γ , we define: in other words we estimate the assumed power-law decline using two data points. the distribution of γ and its correlation with county population and population density are shown in figure ( ) . we can see that γ ranges from . (i.e., very uniform) for the most populous/dense counties to . (i.e. very sparse) for least populated/dense counties. for reference, the value of γ for new york city is . . for each of the top metropolitan regions (united states census, b), a logarithmic-scale population heat map, windowed from the full ghs-pop raster image, was used to select a minimal connected set of us counties enclosing the region of population enhancement. in this process, overlap and merger reduced the total number of metropolitan regions under consideration to . as is discussed in the main text, nearly every metropolitan region saw, in mid-march , an exponential increase of daily confirmed cases, followed by a flat/plateau period of nearly constant daily confirmed cases. in a few cases, the second phase -primarily caused by the country-wide lockdown -lasted only days or weeks (possibly signaling a depletion of the susceptible population, see discussion in main text), but for most metropolitan regions the plateau persisted for months (indeed, persists or is again increasing at the time of this writing). thus, the initial value of the exponential growth rate, λ, of daily confirmed cases could be reliably and automatically estimated by fitting the case numbers to a logistic function where t represents the transition time from exponential growth to a constant, f max is the plateau value in case numbers, and f logistic (t) ∝ exp[λt] for t t . fits were performed on the logarithm of the case numbers, yielding the maximum likelihood estimation of parameters under the assumption lognormally-distributed errors (an analysis of the fit residuals, not shown, confirmed this assumption: case number fluctuations exhibit a variance far in excess of poisson noise, but are well modeled by a log-normal probability density function with constant width), and associated estimates of the variance in each parameter. to avoid polluting the exponential growth phase with singular early cases, a "detection limit" of was imposed, and all daily case values less than or equal to that limit were ignored in fitting. the only manual intervention required for this fit was the specification of the upper limit of its range, i.e., the end of the plateau region, for each data set. to analyze the effect of demographic, population, mobility, and weather variables on this initial growth rate, we perform a weighted linear regression to the lambda values (and their standard errors) of the metropolitan regions. to choose representative cities for the visual examples in figures a and c , we performed an additional logistic fit to the mortality incidence data of each region and retained for figure c only those that had ( ) less than % error in both growth rates, and ( ) |λ case − λ death | < . d − . this was done in an effort to specifically comment on or highlight only those cities for which the growth rate was accurately determined, and was well correlated with the more reliable measure, mortality growth, that we used for the remainder of the analysis. a standard weighted least squares analysis was performed on the measured exponential growth rate, λ , as a function of demographic, mobility, population and weather variables, with weights equal to inverse root of the estimated variance. we construct a model where, in the standard analogy to chemical reaction kinetics, the incidence of infections per unit area at time, i(t), is proportional to the product of the density of susceptible individuals, s(t), and the density of infected individuals, i(t). but, we allow for the rate constant for infection in the encounter, β, to depend on the infected individual's "stage" of infection, c, with c = immediately following infection. the incidence then has the form: where i(c, t) is the density of infected per stage at time t, and the first equality expresses that we neglect changes in a physical picture of collisions, the rate constant of infection is β(c) = σv eff (c), i.e., the scattering cross section of an encounter between a susceptible individual and an infectious individual in stage c, σ, multiplied by their relative velocity, v. to the susceptible population by all means other than infection. the density of infected individuals is found by integration over the stages of infection, if the rate constant were taken to be independent of stage, i.e., β(c) =β, we would obtain the familiar expressioṅ s(t) = −βs(t)i(t). we will assume spatial homogeneity and that the total density of individuals is constant and equal to s( ) for a particular region, but, that the density could vary when comparing different regions. we assume that an infected individual's evolution through the stages of infection, c, follows a gaussian random walk in time, but modulated by an exponential rate, d, of death or recovery. therefore we have where a is the "age" of an infection (time since infection), and the probability density function for the stage at a given age is given by where τ is the characteristic time scale of the random walk . integrating the expression for i(c, t) over all stages and taking the derivative with respect to time yields the familiar expressionİ(t) = i(t) − di(t), showing that the model reduces to the sir model if a stageindependent rate constant,β, is assumed. as we show here, using the random walk to specify the dependence of infection stage on time allows for both a non-exponential distribution of delays to infectiousness (which is more realistic than that of the simplest model with incubation, the seir model) and a formal solution for the exponential growth rate. inserting the expression for i(t, c) into the incidence equation yields which is in the form of a renewal equation (heesterbeek and dietz, ; champredon and dushoff, ; champredon, dushoff, and earn, ) , with the bracketed expression being the expected infectivity of an individual with infection age a. to obtain the simplest nontrivial incubation period, we assume that β(c) =β Θ(c − )where Θ(x) is the heaviside step function -meaning diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states that an infected individual is only infectious once they reach stage c = , and the infection rate constant is otherwise unchanging. this implies that the incidence is where is the probability that an individual infected a time units ago is infectious. if we now assume that the density of susceptibles is constant s(t) =s over some interval of time, and that the incidence grows (or decays) exponentially in that interval, i(t) = ae λt , we find which, assuming λ + d > (i.e., the exponential growth rate cannot go below −d), can be integrated to obtain this expression for (λ + d) has a formal solution in terms of the lambert w-function, with simple asymptotic forms: for the early stages of the epidemic, when we can assume that the population of susceptibles is approximately constant and large, we see that the growth rate depends approximately linearly on the square of the logarithm of the density. in later stages, when either the base contact rate declines due to social distancing interventions, or the population of susceptibles decreases, we see that the exponential rate takes the value λ ≈ −d. in practice, we utilize the exact lambert w-function expression as our "nonlinear model" for fitting λ , where we parameterize β and τ by the demographic, population, and weather variables (see main text). to estimate the susceptible density,s, in this procedure we must use the reported mortality statistics. thus far we have not specified the dynamics of death. we now make the assumption that the probability of death increases proportionally to the number of exposures an individual experiences. as we prove in a separate section, below, this implies that the susceptible density is related to the fraction of dead in the community, f d = d tot /n (where d tot is the cumulative mortality and n is the total population), by the basic reproduction number, r , and the distribution of generation intervals, g(t g ), are defined (champredon and dushoff, ; nishiura, ) through the function f(a): ( ) the generation interval (or, generation time), t g , is the time between infections of an infector-infectee pair, and is often estimated from clinical data by the serial interval, which is the time between the start of symptoms (britton and scalia tomba, ), and the basic reproduction number is the average number of infectees produced by a single infected individual, assuming a completely susceptible population. these quantities can be calculated exactly for our model, as and where the expected value and variance of the generation interval are then: relation between the remaining susceptible density, s(t) and the death fraction, f d (t) in epidemic models the infection of susceptible individuals is typically determined bẏ where i * is the density of infectious (contagious) individuals, and for our model, βsi * is the right-hand side of eqn. . this can be solved, formally, as: alternatively, the susceptible density can be expressed in terms of the cumulative number of infected individuals, i tot , i.e., diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states where f i (t) = i tot /n , with n the total population. when fitting the exponential growth rate of mortality, λ (t) to our nonlinear model, eqn. ( ) (see main text), we must estimate the value of the susceptible density driving growth at that time. without any reliable information about the true infected or infectious populations, we must do so using the mortality statistics. we show here how the previous two equations can be used, along with reasonable assumptions about distinct sub-populations driving infection and death, to determine a relationship between the reported cumulative mortality (per capita) and the remaining susceptible density. our basic assumption is that there are two different categories of susceptible individuals underlying the dynamics of the epidemic: (a) highly mobile individuals with a large geographic reach that frequently interact with other individuals (in particular, infectious individuals) and thus drive the dynamics of infection (these could be termed "super-spreaders" (liu, eggo, and kucharski, ) ); and (b) essentially non-mobile individuals that have quite rare contacts with infectious individuals, but have a much higher probability of death once infected, and therefore make up the majority of the mortality burden. the dynamics of each susceptible population is governed by an equation of the form in eqn. ( ), with a common density of infectious individuals, i * , but with different rate constants, β a β b . from eqn. ( ), we see that the susceptible densities of the two populations are then related, at any time, by: expressing the non-mobile population in terms of the cumulative fraction infected, we have and, assuming that the infection fatality rate (ifr) is a constant factor, f d (t) = ifr × f i (t − ∆t), where ∆t is the delay from infection to death, we can write: finally, having assumed that the ratio of infection rates is large, we can approximate this as: the "a" category of individuals, as defined above, are exactly those individuals driving the infection in our model (and, presumably, in the real world), and, therefore, the susceptible density s a is exactly that which must be estimated for eqn. ( ). on the other side, with people aged and over accounting for ∼ % of covid- deaths, and with approximately ∼ % of deaths linked to nursing homes, the mortality statistics are clearly tracing individuals similar to category "b." therefore, we use this relationship, to estimate the susceptible density in terms of the reported per capita mortality, where we assume s( ) is proportional to the population weighted density (pwd). we also considered the standard approach, in which the population is a single homogeneous group. in that case, the susceptible density could be estimated as ( ) in testing both models, we found that the two-component population scenario was preferred by the data at the ∼ σ confidence level, with the homogeneous population model failing to capture the observed dependence of the growth rate on the per capita mortality (figure ). the broader implications of our assumption of two populations is that the required proportion of individuals with immunity for "herd immunity" to take effect, is lower than population with homogeneous mobility characteristics, i.e., the epidemic will slow as a significant proportion of the "super-spreader" category have been infected (category a, above), regardless of the level of infection and immunity in the rest of the population. indeed, the effect of population heterogeneity on lowering the "herd immunity" threshold for covid- was recently noted (britton, ball, and trapman, ), and will be important in interpreting the results of randomized serology tests across the entire population (havers et al., b) . the nonlinear epidemic model described above posits that the incubation of sars-cov virus within an infected individual can be modelled by a stochastic random walk starting at zero, with excursions beyond ± corresponding to episode(s) of infectiousness. this makes our model distinct from the standard se m i n r compartmental models (see, e.g., (champredon, dushoff, and earn, ) ), where the progress of the disease is only in one direction -e → e → . . . → i → i → . . . -while in our model (figure ) , the individual can jump back and forth between different stages (with the obvious exception of death), with a constant exit rate of d for quarantine, recovery, or death. this can be described using a (leaky) diffusion equation: based on this picture, and the best-fit parameters to the us county mortality data (table ) , we can infer the probabilities associated with the different stages of the disease. for example, by looking at the steady-state solutions of equation ( ), we can compute the probability that an exposed individual (who starts at c = ) will ever become infectious (i.e., make it beyond c = c inf = ): this is plotted as a function of the median age of the community in figure ( a) . for example, for the median age of all us counties, a = . -yr, we get: p inf ( . years) = . + . − . ( % c.l.), i.e., less than % of exposed individuals will ever be able to infect others, although this fraction increases in older communities. next, we can compute the distribution of times for the onset of infectiousness, i.e., the incubation period. this can be done by using a first crossing probability of a random walk, which we did by solving equation diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states ( ) using a discrete fourier series in the ( , + ) interval. the resulting probability density is shown in figure ( b), again showing a shorter incubation period in older communities. finally, we can compute the probability density function for the generation interval, g(t g ), defined in equation ( ) (figure c ). this shows a similar qualitative dependence on age as the incubation period, but the median incubation period is, as expected, shorter than the generation interval for each age group. using eqn. ( ) and our parameterization of τ , we find a mean generation interval of e[t g ]( . years) = ± d . this estimate is much longer than those found by tracking the serial interval (time from between the start of symptoms for an infector-infectee pair) in covid- patients (ganyani et al., ; nishiura, linton, and akhmetzhanov, ) , which are on the order of - d. it is possible that the long tail of these distributions, generated by the slow asymptotic exponential decay at rate d ≈ . d − , raises the mean generation interval, while a clinical study, is necessarily biased toward shorter serial intervals. one of the most pressing questions in any exercise in physical modelling is whether we have a good understanding of the uncertainty in the predictions of the model. while we have an estimate of the measurement uncertainties for the mortality growth rates, λ , which we discussed in the main text, we also should characterize whether the deviation of the best-fit model from the measurements are consistent with statistical errors. to evaluate this, we can look at the average of the ratio of the variance of the model residuals to that of the measurement errors, otherwise known as reduced χ , or χ red . this is shown in figure ( ) , demonstrating that we see no systematic error in model that is significantly bigger than statistical errors, across counties with different populations. as another consistency check, table ( ) examines whether the parameters of the model change significantly from urban counties with large, uniform populations, to rural counties with a small and more sparse population (figures - ). from counties with enough covid mortality data, roughly those with population inhabit half of the total population, which we chose as our threshold, separating large from small counties. we notice no statistically significant difference, and table ( ) even suggests that fisher errors quoted here might be overestimating the true errors. this comparison brings further confidence in the universality of the nonlinear model across geography and demography. on average, we find that (either county-weighted or population-weighted) χ diverse local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of table ( ), we use temperature rather than specific humidity (ct rather than ch), as the latter was not available for some small counties. nevertheless, the parameters remain also statistically consistent with table ( ). local epidemics reveal the distinct effects of population density, demographics, climate, depletion of susceptibles, and intervention in the first wave of covid- in the united states heesterbeek first case of novel coronavirus in the united states effect of dexamethasone in hospitalized patients with covid- : preliminary report". in: medrxiv herd immunity and herd effect: new insights and definitions covid- data repository by the center for systems science and engineering (csse) at johns hopkins university how does transmission of infection depend on population size? early dynamics of transmission and control of covid- : a mathematical modelling study low ambient humidity impairs barrier function and innate resistance against influenza infection defining the pandemic at the state level: sequence-based epidemiology of the sars-cov- virus by the arizona covid- genomics union (acgu) covid- : a need for real-time monitoring of weekly excess deaths early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia clinical and immunological assessment of asymptomatic sars-cov- infections influenza virus transmission is dependent on relative humidity and temperature mechanistic insights into the effect of humidity on airborne influenza virus survival, transmission and incidence how deadly is covid- ? a rigorous analysis of excess mortality and agedependent fatality rates in italy sensitivity analysis of simple endemic models droplet fate in indoor environments, or can we prevent the spread of infection? seasonality of respiratory viral infections global surface summary of the day (gsod). ftp.ncdc. noaa.gov potential impact of seasonal forcing on a sars-cov- pandemic time variations in the generation time of an infectious disease: implications for sampling to appropriately quantify transmission potential serial interval of novel coronavirus (covid- ) infections". in: international journal of infectious diseases temperature dependence of covid- transmission we are indebted to helpful comments and discussions by our colleagues, in particular bruce bassett, ghazal geshnizjani, david spergel, and lee smolin. na is partially supported by perimeter institute for theoretical physics. research at perimeter institute is supported in part by the government of canada through the department of innovation, science and economic development canada and by the province of ontario through the ministry of colleges and universities. red . , suggesting that the model errors are only % bigger than statistical errors.we further compare the model-prediction vs measured mortality growth rate in figure ( ) for all our available data. we find that the -σ error in the model prediction (in excess measurement errors) is on average ±σ = ± . , i.e. . % error in the daily mortality growth rate. this is shown in figure ( ) as the red region, which compares the model prediction with the observed mortality growth rates. we can also see that there appears to be no significant systematic deviation from the predictions, at least for λ < . /day.given an understanding of the physical model and its uncertainties, we can provide realistic simulations to forecast the future of mortality in any community, similar to those provided in the main text (figure ) , which can be made on-demand using our online dashboard: https://wolfr.am/covid dash.in order to perform these simulations, we follow these simple steps. to predict the daily mortality on day t + , d(t + ), we use the prior days of d(t), as well as the total mortality up to that point: ( ), plugging in prior total mortality, county information, weather, mobility and parameters in table to find λ . every simulation uses a random realization of model parameters (from their posterior fits), which remain fixed through that simulation. . add the random model uncertainty to λ using: where g t s are random independent numbers drawn from a unit-variance normal distribution. this captures the model uncertainty mentioned above, while ensuring that it remains correlated across the days that are used to define λ . . having fixed the logarithmic slope for daily mortality λ , find the best-fit intercept and its standard error for ln[d(t ) + / ] for the preceding days, i.e. t − ≤ t ≤ t, which can then be used to find a random realization for ln[d(t + ) + / ] . advance to next day and return to step . key: cord- -ev h b authors: kapil, sanjay; yeary, teresa j. title: canine distemper spillover in domestic dogs from urban wildlife date: - - journal: veterinary clinics of north america: small animal practice doi: . /j.cvsm. . . sha: doc_id: cord_uid: ev h b canine distemper virus (cdv) causes a major disease of domestic dogs that develops as a serious systemic infection in unvaccinated or improperly vaccinated dogs. domesticated dogs are the main reservoir of cdv, a multihost pathogen. this virus of the genus morbillivirus in the family paramyxoviridae occurs in other carnivorous species including all members of the canidae and mustelidae families and in some members of the procyonidae, hyaenidae, ursidae, and viverridae families. canine distemper also has been reported in the felidae family and marine mammals. the spread and incidences of cdv epidemics in dogs and wildlife here and worldwide are increasing. attachment factor, protein h, controls the host specificity and cell tropism and induces the majority of cvd-neutralizing antibodies. [ ] [ ] [ ] humoral immunity due to the presence of neutralizing antibodies to cdv, elicited by either immunization or natural infection, is detectable within to days, providing protection against infection or reinfection. viral infection of a susceptible host cell begins when the h protein of cdv binds to the signaling lymphocyte activation molecule (slam; cd ) receptor site of the cell. a conformational change of the h protein occurs on binding, which signals the f protein-mediated fusion of the cdv envelope with the host cell membrane. binding between slam and the h protein is a high-affinity, host-virus specific interaction. , the h and f glycoproteins may mediate fusion activity between neighboring cells leading to syncytium formation and, ultimately, to cell lysis. host cell surface sites cd and a heparin-like receptor have been suggested as putative h protein receptors in slam-negative cells, but strong supporting evidence is lacking at this time. , disease distemper is a highly contagious disease that poses a threat mainly to concentrated populations of previously unexposed or unvaccinated, susceptible species. in these populations, distemper is almost always fatal. the disease is complex in that it presents varying clinical symptoms and may run varying clinical courses. outcomes of cdv infection range from complete recovery to persistent disease to death depending on the age and immune status of the animal infected. robustness of the humoral immune response correlates with the disease outcome. canine distemper virus replicates initially in the lymphoid tissues of the upper respiratory tract followed by immune-mediated progression of the disease over a period of to weeks. a diphasic fever is a characteristic feature of the disease, occurring or days after infection, that drops rapidly and again climbs by day or . clinical signs of distemper are often unapparent or initially mild during this time, and disease is characterized by mucopurulent oculonasal discharges, conjunctivitis, respiratory distress, anorexia, vomiting, diarrhea and dehydration, and cutaneous rash. anti-cdv antibody titers that develop to days postinfection contribute to viral elimination and recovery when a vigorous humoral response occurs characterized by highly specific anti-h protein antibodies. cell-mediated immunity also plays a role in recovery from cdv infection, and a strong t-cell-mediated cdv-specific immune response causes viral elimination in convalescing dogs. weak humoral and cell-mediated responses lead to systemic intracellular spread of virus to the epithelial cells of the gastrointestinal and urinary tracts, skin, and the endocrine and central nervous systems causing direct virus-mediated damage. additional clinical signs that may occur are localized twitching, ascending paresis/ paralysis, and/or convulsions. hyperkeratosis of the foot pads and nose may be seen. the infection may either prove fatal or persist resulting in subacute or chronic central nervous system (cns) signs. delayed lymphocytolysis correlates with persistence of cdv in the cns. within to weeks after recovery from gastrointestinal and respiratory signs, depression and neurologic signs indicating cns involvement are often evident, although sometimes neurologic impairment does not occur until months later, even without a history of systemic signs. dogs that recover from acute disease with persistent infection may shed virus in urine and through the skin on the foot pads. these animals should be isolated from contact with unvaccinated animals, especially puppies. canine distemper infection can be challenging to diagnose because many diseases can cause symptoms resembling canine distemper. the respiratory symptoms of canine distemper may be mistaken as canine respiratory disease complex. canine parvovirus, coronavirus, bacterial, and internal parasite infections should be ruled out as causes of vomiting and diarrhea. often, cdv-infected animals that exhibit neurologic signs are mistaken as having rabies. neurologic symptoms must be differentiated from other infections, trauma, and ingestion of toxins. vaccination history of the affected animal, clinical symptoms, and laboratory testing support a probable diagnosis of cdv infection. state and commercial veterinary diagnostic laboratories offer testing for canine distemper and advice practitioners on appropriate specimens to submit, tests to order and the limitations of test results given the circumstances of each individual case submitted. the following diagnostic methods are commonly offered: use of monoclonal antibodies to differentiate recent field isolates from older field isolates and vaccine strains of cdv has met with limited success and the reagents developed are not widely available. , currently, in-clinic serologic test kits are licensed for sale in the united states, the titerchek cdv/cpv elisa-based assay (synbiotics, san diego, ca, usa) and the immunocomb canine vaccicheck (modern veterinary products, coral gables, fl, usa). both kits evaluate an immune response to cdv from vaccination or infection but neither differentiates between titers to the vaccine or infection with wild-type cdv strains. licensed rt-pcr kits for detection of cdv are not available in the united states. among the commercial and state veterinary diagnostic laboratories that perform rt-pcr testing of their own design to detect cdv, one of the challenges is differentiating between vaccine strains and wild-type isolates that may be present concurrently in samples. the rt-pcr assays are typically designed to amplify a portion of the h, f, m, or n gene to verify the presence of cdv rna in specimens. absolute identification of strains and differentiation between vaccine and wild-type cdv may be performed by sequence analysis of the cloned rt-pcr amplified h gene region. rapid methods have been designed to differentiate cdv strains as either wild-type or vaccine derived without the need to perform time-consuming gene sequencing. two popular methods are based on rt-pcr of a specific cdv structural protein genes followed either by a restriction fragment length polymorphism (rflp) analysis of the amplified nucleic acid or by a second round of nested pcr with analyses by electrophoresis. , [ ] [ ] [ ] other unique approaches that have been developed are multiplex rt-nested pcr (rt-npcr) of the m protein and amplification refractory mutation system (arms)-pcr of the cdv m-f intergenic and untranslated, prepeptide regions of the f gene followed by rflp. , most cdv vaccines in the united states, canada, and europe are of the american- (onderstepoort) lineage with the exception of the vanguard vaccine (pfizer animal health, madison, nj, usa), which is of the america- genotype. , the major vaccine strains were isolated in the s and it is not known if they continue to circulate in nature as they have not been detected for many years. , although cdv vaccine strains have not changed in the past years, there is potential for newer antigenic variants of cdv to emerge around the world. however, the current vaccines have largely provided adequate protection against clinical disease when properly administered to healthy domesticated dogs in this country. core vaccination guidelines, including canine distemper mlv and recombinant canarypox vectored canine distemper virus (rcdv) vaccines, recommended by the american animal hospital association canine vaccine guidelines, were revised in . recommendations for administering the rcdv and mlv vaccines are similar. advantages of the rcdv vaccine is that it does not contain live virus that replicates and spreads from vaccinees and it is more likely to produce immunity in puppies that have passively acquired maternal antibodies. vaccination failures can occur when mlv vaccines are used to immunize puppies that have not cleared maternal antibodies. maternal antibodies are adsorbed in the intestine from colostrum during the first days of life and are cleared to weeks later. it is recommended that puppies receive a series of vaccinations beginning at to weeks of age to achieve complete immunity to cdv followed by a booster at year of age. canine distemper virus vaccines impart long-term immunity in dogs. duration of immunity of years has been reported for both mlv and rcdv vaccines. , in animal shelters and high-risk environments, one dose of mlv or rcdv vaccine has been reported to be protective in puppies already exposed to cdv. ferrets are also highly susceptible to cdv and the disease is virtually % fatal. the american ferret association recommends vaccinating ferrets with purevax ferret distemper vaccine (merial inc, athens, ga, usa), the only usda-licensed vaccine product labeled for use in ferrets, following the product label for kits or adults. reasons that a vaccine may fail, in addition to the presence of maternal antibodies in puppies, are incomplete immunity due to failure to complete the puppy booster vaccination series, stressors in the physical environment, the animal's immune competence and specific responsiveness to cdv antigen or intercurrent exposure to other virulent viruses such as canine parvovirus or coronavirus or even parasites, and improper storage and handling of vaccine. , [ ] [ ] [ ] a concern voiced by scientists is that new genetic cdv variants may be associated with pathogenesis changes or immune evasion in dogs vaccinated with current vaccines. in infected dogs with a history of recent vaccination with mlv vaccine, exposure to wild-type cdv prior to vaccination is usually assumed to be the source of the cdv infection. however, cdv infections reported in previously vaccinated dogs in japan, mexico, and the united states were caused by novel cdv lineages distantly related to the america- vaccine group. , , - variation of key amino acid residues and the addition or loss of n-glycosylation sites on the h and f proteins may alter interaction between the h and f proteins during binding and fusion with susceptible cells, leading to changes in antigenicity, virulence, and tissues targeted by cdv variants. , continued surveillance, study of genetic and antigenic drift in circulating cdv strains, and molecular analysis of emerging cdv variants are warranted to ensure that vaccines for prevention of distemper continue to be potent and efficacious in preventing infection in domestic dogs. in addition to immunization of domestic dog populations, hygienic measures are necessary. unvaccinated puppies should be isolated from dogs other than their bitches. strict isolation of dogs infected with cdv is the most important step in controlling the disease. virus is shed in all body secretions and excretions during the acute systemic disease. direct dog-to-dog contact and indirect aerosol transmission are the main routes of viral spread, but cdv can be transmitted from fomites at room temperature or lower for several hours. disinfection of cdv in the environment, particularly in shelters and kennels, is important. inactivation of canine distemper virus with benzalkonium chloride ( . %), a quaternary ammonium compound, occurs in minutes at room temperature. similarly, % ethanol is effective against cdv. nucleic acid sequence analysis of the h gene is the gold standard for phylogenetic analysis, classification, and genotyping of cdv because it has the greatest heterogeneity (about % amino acid variation) of the structural proteins of cdv. studies of complete h gene sequences have identified distinct geographically separated clusters of cdv genotypes: american- (including most vaccine strains), american- (north america), arctic (arctic region and europe), asia- , asia- , asia- , europe, european wildlife, south africa, argentina, rockborn-like, and a new genotype of primarily mexican strains. , , [ ] [ ] [ ] serengeti isolates are distinctive from cdv isolates from other parts of the world. in the united states, genotypes that have been identified in dogs and wildlife in addition to the american- and america- strains are the european wildlife, edomex, and arctic strains in domestic dogs. , , amino acid sequence variation between the genotypes is greater than % and strains within each genotype have less than % amino acid variation. characterization of cdv strains from south america may be of special interest. scientific archivists point to documentation of distemper-like epizootics occurring in peruvian dogs in the mid- s that may have spread to europe circa with the importation of diseased dogs by spanish colonials. sequence analysis of cdv strains from different geographical locations and animal species indicates that the h protein gene undergoes genetic drift. viral recombination in cdv has been documented in an isolate recovered from a giant panda. recently, a cdv genotype designated "wildlife europe - (we/ - )" found exclusively in wild carnivores was described that evolved and spread over a wide geographical area in northern italy in months following its initial detection in . bavarian wildlife isolates collected during the distemper outbreak in the southern alps were . % to % similar to the italian isolates. the evolutionary origin of the group was estimated to have diverged from its most recent ancestor months prior to identification of the first virus cdv. the mean nucleic acid substitution rate in the new cdv genotype was estimated to be . ϫ - subs per site per year, which was within the range typically observed for cdv. phylogenetic analysis of cdv h gene and h protein sequences from dog and non-dog hosts indicated that amino acid residues and are under positive selection, and these residues are located in the regions of the h protein that are important in binding to the host cell slam receptor and triggering activation of the f protein cellular entry. , , this provides compelling evidence that repeated evolution at known functional sites of emerging strains of cdv is associated with multiple independent occurrences of disease emergence in a range of novel host species. facilitation of large-scale diagnostic and molecular epidemiologic studies of cdv requires rapid molecular-based methods that accurately differentiate among the genotypes and between vaccine and wild-type strains of cvd without the need to perform either full-length or partial sequencing of the h gene for each isolate. a hemi-nested pcr system was developed that can genotype of the cdv lineages (america- , europe, asia- , asia- , and arctic) using specific primers targeted to the h gene. the arms-pcr method followed by rflp also differentiates a broad variety of lineages. further development of rapid protocols for distinguishing among all cdv genotypes is needed to advance epidemiologic studies of this important pathogen. genotyping is important for tracing the relatedness of cdv isolates and cross-transmission between and within species of carnivores. distemper outbreaks in rhesus monkeys (macaca culatta) have occurred since at the largest monkey breeding farm in mainland china that supplies breeding stock for biomedical research facilities and zoos. over , monkeys contracted the disease and more than , died at the farm and at the facilities it serves. the entire genome of the isolated virus was sequenced. phylogenetic analysis of the h gene places it within the larger clade of asian genotypes yet it is unique in the number of amino acid changes to its structural proteins. although monkeys and monkey-derived cell cultures have been experimentally infected with cdv, only one other natural cdv outbreak of monkeys (macaca fuscata) occurring in japan was reported in . canine distemper is not a clinically recognized entity in domestic cats; however, large felids are susceptible to infection with cdv. most of the large cats are threatened or endangered species; thus surveillance of pathogens that have the potential to cause their extinctions is critical. where cdv has caused widespread distemper outbreaks in nondomestic cats, domestic dogs, raccoons, or wild canids have been implicated as reservoirs of the disease. cdv outbreaks with multiple mortalities were reported in lions, tigers, jaguars, and leopards in zoos and wildlife safari parks in the s. raccoons living in the area surrounding one suburban zoo had increased numbers of fatal distemper cases and may have transmitted the disease to the large cats. cdv isolated from large felids in the zoo was of the america- genotype circulating in the local feral raccoons. a retrospective immunohistochemistry study of paraffin tissues from necropsy cases of lions and tigers from swiss zoo and circus cats collected from through indicated that were cdv positive. of asiatic lions from captive breeding centers in western india tested in for antibodies against cdv, % were positive. in addition to domestic dogs, urban wildlife in the united states such as raccoons, foxes, and skunks may play a role in direct transmission of distemper to large felids and other carnivores in zoos, wildlife parks, circuses, and captive breeding facilities. many studies of canine distemper in free-ranging large felids have been reported. - african lions of the serengeti are the most intensively studied of the large felids with regard to the prevalence of cdv. in , a cdv epidemic in serengeti lions caused fatalities in % of the population with only an estimated , lions remaining in . prior to , disease-related mortality due to cdv infection of lions had not been documented, although retrospective serology tests indicated that % of lions that were living in the area from to had titers to cdv. a single cdv genotype was common among the susceptible animal species living in the serengeti during the cdv outbreak that included lions, hyenas, bat-eared foxes, domestic dogs, and jackals. unowned, feral domestic dogs living in or near the serengeti are not vaccinated, experience periodic distemper outbreaks, and likely serve as a primary reservoir of cdv. jackals and hyenas may be amplifying species that spread cdv throughout the park to lions and other felids. , , a brazilian study was performed in state parks with the goal of determining the prevalence of cdv titers in wild felid populations (jaguars, pumas, and ocelots) and correlating it with the prevalence of cdv titers in, and density of, domestic dogs in the areas adjacent the parks. dog owners in small rural settlements surrounding the parks were questioned about the cdv vaccination status of their dogs. unvaccinated dogs were tested for cdv titers. jaguars ( %) and pumas ( %) from one park had titers to cdv and % of the dogs living adjacent to the park were seropositive for cdv. none of the large felids tested at the second park had cdv titers and only % of the local unvaccinated dog population was seropositive for cdv. the occurrence of cdv in wild felids appears to be related with home range and close association with unvaccinated, infected domestic dogs living nearby. vaccine coverage of % of domesticated dogs is needed to control canine distemper in these pets. currently the best means for breaking the circulation of cdv between susceptible wildlife populations and domestic dogs is through regular vaccination of pet dogs and preventing them from roaming freely and interacting with unvaccinated dogs and wildlife that may harbor the virus. free roaming wildlife are not vaccinated in the united states unless federal and state authorities determine that an endangered species may benefit from vaccination in captive breeding programs designed to stabilize and increase existing populations for release back into the wild. one study reported the vaccination of wild raccoons with mlv canine distemper vaccine prior to in a forest preserve near a chicago area zoo. in the s through the s, primarily killed vaccines (kv) were used to vaccinate endangered wildlife and zoo animals against cdv. , virus-neutralizing titers developed postvaccination to the kv were generally quite low, and several exotic species that had been vaccinated died from outbreaks of cdv infection. use of mlv cdv vaccines is often fatal to many wildlife and zoo animals; thus they have only been used in rare situations in the united states to control disease in endangered species and display animals in zoologic parks. , - after the univalent canarypox vectored recombinant distemper vaccine, purevax ferret (merial inc), was licensed and marketed in , many north american zoological institutions began using the rcdv vaccine to vaccinate numerous at-risk species. currently, the american association of zoo veterinarians' distemper vaccine subcommittee recommends the extralabel use of the rcdv purevax ferret distemper vaccine (merial, inc) in all susceptible zoological display animals where cdv is endemic in local wildlife. vaccination of endangered species that are susceptible to cdv has been an important in the success of recovery programs. initially, commercial kv and mlv cdv vaccines were used to vaccinate the endangered black-footed ferret but these products proved to be nonprotective or fatal. , , in , an experimental canarypox vectored rcdv vaccine (merial inc) used to vaccinate ferrets in the captive breeding program successfully prevented distemper, one of several diseases that had threatened the species with extinction. all wild-born black-footed ferrets are trapped and vaccinated. after the cdv outbreak on santa catalina island, california, the native island fox population plummeted from , to less than individuals. infected domesticated dogs or stowaway raccoons from boats anchoring on the island mingling with the foxes may have caused the outbreak. the federally endangered island fox was vaccinated with the rcdv vaccine to reestablish the population beginning in with permission from the california department of fish and game. , wildlife rescue and research organizations also vaccinate cdvsusceptible animals in areas where distemper is endemic. the rcdv vaccine, purevax, is used prevent disease in captive southern sea otters at california institutions. free-ranging sea otters are susceptible to cdv. immune-stimulating complexes (iscoms), a novel form of adjuvant that, combined with antigens, generally induces strong activation of both the cell-mediated and humoral immunity. african wild dogs (lycaon pictus), which are on the international union for conservation of nature red list of threatened species, cannot be vaccinated with mlv cdv vaccines, which are always fatal. one study reported the use of iscoms incorporating the f and h proteins to vaccinate african wild dogs. the dogs initially vaccinated at the beginning of the captive breeding program in developed protective immunity. however, in , when the of dogs in the colony succumbed to distemper, neutralizing anti-cdv antibodies were not measurable despite a recent vaccination. although the use of iscoms appeared to be promising for control of cdv in a variety of wildlife, the successes have been limited. oral bait vaccines to control zoonotic diseases like rabies and plague in wildlife are currently in use. oral vaccines to control wildlife distemper are not yet available. two major issues in developing an efficacious oral bait vaccine for distemper are achieving an adequate mucosal immune response in the gut and overcoming interference from maternal antibodies in infant animals. attempts at inducing mucosal immunity using vaccinia and canarypox vectored cdv vaccines have been reported using ferrets as model animals. , [ ] [ ] [ ] highly attenuated vaccinia and canarypox virus strains expressing the h and f proteins of cdv were administered by parenteral, intranasal, and intradoudenal routes. juvenile ferrets receiving either vaccine intramuscularly or intranasally had % survival rates, but intradoudenal vaccination protected only %. in studies of infant ferrets with and without maternal antibody, the vaccinia and canarypox vectored vaccines were administered parenterally or intranasally. all infant ferrets vaccinated parenterally with either vaccine in the absence of maternal antibody survived challenge. parenteral vaccination with either vaccine in the presence of maternal antibody did not protect against death from cdv challenge. intranasal vaccination with either vaccine, in ferrets with or without maternal antibody, was not protective against cdv. other studies have shown low efficiency in producing a protective immune response with the nonparenteral delivery of cdv canarypox vectored vaccines. , as with the raboral v-rg (merial, inc), the cdv vaccinia vectored vaccines stimulate a stronger protective mucosal immune response. if an efficacious cdv oral bait vaccine can be developed for wildlife, vigorous domestic dog vaccination programs here and abroad will continue to be the primary means to control the disease. in the united states, several federal agencies are tasked with surveillance of animal diseases of wildlife. the u.s. department of agriculture-aphis wildlife services' administers the national wildlife disease program (nwdp), which participates in wildlife disease monitoring and surveillance in all regions of the united states. additionally, nwdp assists state, federal, tribal and international agencies, and nongovernment organizations, with development of local wildlife disease monitoring programs and nationally coordinated wildlife surveillance systems. canine distemper is among diseases of interest to the surveillance program, although minor. over the past years, the nwdp has assisted in distemper surveillance monitoring and research activities with state agencies and veterinary colleges. , , the usda national wildlife research center is currently assisting the zambian wildlife authority and the african wild dog conservation trust in the development of conservation management plans for several critically endangered species including african wild dogs, african lions, bat-eared foxes, and leopards. it has been postulated that diseased village dogs are the reservoirs of distemper, rabies, parvovirus, and a number of parasites that are infecting african wildlife. , three programs within the u.s. department of the interior also monitor threats to wildlife and wildlife health in the united states: the fish and wildlife service (fws), national park service (nps), and u.s. geological survey (usgs). the fws administers health monitoring programs for endangered and threatened terrestrial and freshwater species under the endangered species act of . in , in association with state and private organizations, the fws began a captive breeding and vaccination program of black-footed ferrets, which were nearly extinct due to outbreaks of canine distemper and sylvatic plague. , the fws was involved in the captive breeding and vaccination program and continuing surveillance of the santa catalina island fox population after the canine distemper outbreak. by the end of , the fox population rebounded from foxes to , individuals. , , grey wolves reintroduced by the fws to yellowstone national park are monitored for canine distemper, which caused population declines in , , and . the nps biological resource management division performs surveillance and disease management of wildlife health within the federal park system. the usgs national wildlife health center, which provides wildlife health and disease investigative, research, and training support to federal, state, local, and international conservation agencies, was designated as an oie collaborating centre for research and diagnosis of emerging and existing pathogens of wildlife, by the world organization for animal health (oie) in july of . the epidemiology and transmission of cdv are complicated by the wide host range of animals susceptible to distemper. canine distemper virus is present on all continents wherever there are carnivores. domestic dogs are considered to be the primary reservoir of cdv, which disseminates between free-ranging, unvaccinated or incompletely vaccinated dogs (pets and feral) and urban or rural wildlife. raccoons, foxes, and skunks have adapted well to urban environments and, in the united states, raccoons, a secondary reservoir of cdv, are among the most common wildlife species found in cities and towns. cyclical outbreaks of distemper commonly occur in north america among raccoons associated with an increase in their populations. the periodic increase in distemper outbreaks in raccoons leads to spillback to domestic and feral dogs and spillover to other wildlife (skunks, foxes, badgers, coyotes, wolves, etc.). over the past decade, many outbreaks of canine distemper in urban wildlife have been reported in the united states and canada, prompting health officials to issue advisories to the public to avoid feeding or otherwise attracting wildlife to their property, keep dogs current on cdv vaccinations, and confine their pets in fenced enclosures or on a leash. , infection with cdv also is an important conservation threat to many carnivore species in their natural habitats, especially for small, endangered populations that already face environmental insults. , distemper has contributed to population declines in black-footed ferrets, catalina island foxes, native florida mink, gray wolves, coyotes, sea otters, pumas, and ocelots in the united states and many other wild carnivores worldwide. often, multiple competent hosts for cdv exist within a region, allowing localized persistence of disease. susceptible captive animals that are held in high densities are especially vulnerable to infection; thus quarantine, vaccinations, and meticulous hygiene are important measures to take, as is reducing the potential for contact with free roaming wildlife that serve as reservoirs of disease. , - transmission of cdv between animals is via aerosol or respiratory secretions (coughing, sneezing, barking, licking) and bodily excretions (urine and feces) or through direct contact with shared, virus-contaminated food and water bowls, garbage, compost piles, and other organic materials. other disease-causing contacts include chasing, mating, fights, simultaneous and sequential feeding events at carcasses, and grooming. wild animals with distemper have similar symptoms as infected dogs. they are often mistaken as rabid because they display unusual behavior, disorientation, aimless wandering, and/or aggression and walk with an unusual gait due to cns involvement. the majority of cases in wildlife are most often observed in spring and summer since juveniles are more susceptible to infection, but cases occur year round. studies of threatened, endangered, or reintroduced carnivore species in the greater yellowstone ecosystem and in the serengeti national park, tanzania, have supplied a wealth of information on the epidemiology of cdv in these expansive natural habitats over many decades. , , , , , however, little is known of the overall health status and disease problems in free-ranging wildlife populations that have direct and regular contact with domestic dogs. the domestic dog is the most numerous of carnivores in the world with an estimated population of over million worldwide. domestic dogs have been sources of many zoonotic viruses, bacteria, helminths, arthropods, protozoa, and fungi and have served as a link for exchange of pathogens among livestock, wildlife, and humans. [ ] [ ] [ ] an international expert meeting on dog population management was held in banna, italy, in march as a joint effort between the food and agricultural organization of the united nations and the world society for the protection of animals with technical support from the world health organization, to address the challenges of domestic and stray dog population management throughout the world. regular domestic animal health care is not universally available in developing nations or even in remote areas of developed countries. this hinders development of effective disease detection and preventative veterinary medicine programs. lack of vaccination to achieve herd immunity, uncontrolled reproduction of domestic dogs, and free-roaming dogs, they are whether owned, abandoned, or feral, are major roadblocks to preventing further spread of cdv to all susceptible species. , , , studying the demographic characteristics of dog populations in urban and rural areas is critical for understanding the epidemiology of canine infectious diseases and to make decisions in planning and implementing dog population management schemes to control zoonotic diseases and diseases that are of conservation interest such as cdv. , , three recent prospective studies of large felids in brazil, iberian lynx in andalusia, spain, and wolves in the remote north coastal mainland and islands of british columbia, canada, suggest that unvaccinated dogs in towns and small settlements do pose a significant risk; seroprevalence for cdv exposure in these animals is high. , , additional prospective studies of disease in threatened and endangered species and dog populations that reside in transecting areas of urban populations, towns or settlements, and wilderness areas are needed to provide baseline health and serologic information. the heterogeneity of cdv genotypes that have been isolated in restricted geographical areas within the united states, europe, and elsewhere are postulated as being the result of intense, legal, or uncontrolled trade and travel of domestic dogs and uncontrolled movement receptive wild species. , , recent reports of european wildlife and edomex genotypes isolated from north american dogs that have not traveled outside the united states underscore the need to gather additional sequence information to elucidate the epidemiologic patterns of cdv on a local and global scale. characterization of circulating cvd genotypes in domestic dogs and wildlife within a discrete territory over a protracted timeline would also further our understanding of how the virus spreads and evolves within and between species. reliable information about transmission of cdv among domestic and wild carnivores should enable more effective management of the disease. canine distemper is a highly contagious disease of domestic dogs that also infects multiple wildlife hosts, some that serve as secondary or amplifying reservoirs of the virus. transmission of cdv among dogs and other susceptible hosts continues to present many challenges in the united states and worldwide. control of distemper in dog populations requires a strong commitment by many constituencies. cdv is the most significant viral threat to the extinction of endangered carnivores, eclipsing rabies. effective vaccines for distemper are available to control cdv in domestic dogs, although the vaccine strains that are used in commercial vaccines have not changed in the past years. client education about the serious consequences of cdv to both their pet dogs and to wildlife is the critical first step to curtail the spread of cdv, followed by reducing reproduction rates of dogs and abandonment of pets. it is important for veterinarians, dog owners, animal control officers, wildlife wardens, and quarantine officers to understand that canine distemper can cross continents during the transportation of dogs. a major challenge in diagnostic testing is differentiating infection due to attenuated vaccine virus from infection caused by wild-type virus so that recently cdv-vaccinated dogs are not unnecessarily euthanized where outbreaks of distemper occur, particularly in animal shelters. because canine distemper is an rna virus, a potential for emergence of antigenic variants exists, particularly in situations where wildlife that are infected with a strain of cdv that has adapted to that host spills back to domestic dogs. introduction of novel canine distemper viruses in improperly vaccinated dog populations with insufficient immunity can cause new outbreaks of cdv. increased surveillance of cdv in dog and wildlife populations to identify new genotypes and trace movement of strains within and between species will broaden our epidemiologic knowledge base and advise the veterinary profession and biologics industry as to the need for changes to vaccine strains to protect domestic dogs. canine vaccination-providing broader benefits for disease control canine distemper in terrestrial carnivores: a 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mammals dogs as sources and sentinels of parasites in humans and wildlife, northern canada world society for the protection of animals. wspa and the fao call for global dog population body demography of domestic dogs in rural and urban areas of the coquimbo region of chile and implications for disease transmission urban domestic dog populations as a source of canine distemper virus for wild carnivores in the coquimbo region of chile exposure to infectious agents in dogs in remote coastal british columbia: possible sentinels of diseases in wildlife and humans canine distemper: still a major concern in central europe. lucrari stiintifice universitatea de stiinte agricole a banatului timisoara key: cord- - fcw ol authors: tetro, jason a. title: from hidden outbreaks to epidemic emergencies: the threat associated with neglecting emerging pathogens date: - - journal: microbes infect doi: . /j.micinf. . . sha: doc_id: cord_uid: fcw ol not all infectious disease outbreaks undergo full epidemiological investigations. in certain situations, the resultant lack of knowledge has led to the development of epidemics and public health emergencies. this review will examine six emerging pathogens including their history, present status, and potential to expand to epidemics. recommendations to improve our understanding of these hidden outbreaks and others also will be provided in the context of health systems policy. infectious disease outbreaks are common worldwide. while every occurrence deserves a proper epidemiological investigation, several constraints such as limited resources, political considerations, and an assumed familiarity with the pathogen may hinder the process [ , ] . this may result in what are known as "hidden outbreaks" in which spread is known to transpire in a localized environment (such as an endemic pathogen) but inquiries are not considered to be worthwhile in the larger context of global human health. this practice may be considered sound, however there is the potential an outbreak may expand to become an epidemic such that both caseload and costs are significantly increased [ , ] . the hidden outbreak begins no differently than isolated outbreaks with a single point-source such as a household, hospital, or restaurant. while several to dozens of people may be infected, the overall impact on society is considered to be low. yet, as seen in several instances over the last decade, certain pathogens have become international juggernauts (fig. ) . public health authorities are caught off guard, calls for alarm are made by the scientific and medical communities, and the media must find a balance between objective reporting and the inevitable contagion of fear [ ] . the quintessential example of such expansion is the ebola virus epidemic in [ ] . a small outbreak occurred in the small village of meliandou in guinea at the end of the previous year and eventually turned into a crisis in three west african nations and led to domestic cases in europe and the united states. the spread was so troubling, the world health organization declared a public health emergency of international concern (pheic) [ ] . the event eventually was controlled yet the virus was considered to be too volatile to ignore any further. any sign of ebola in the human population regardless of population size was deemed serious enough to be met with a significant response [ ] to control spread. in addition to understanding the biological nature of a pathogen as the etiology of an outbreak, an examination of the anthropogenic effects facilitating amplification to epidemic status is needed. these factors have been reviewed elsewhere [ ] and include the grouping of susceptibles in both the healthcare environment as well as the community, changes in human consumption of natural habitats, territories, and food sources, increased amount and ease of international travel, globalized trade, and political strife. in the context of expanding hidden outbreaks, two factors are considered the most important, travel and trade [ , ] . one of the best known examples of travel-related spread of a hidden outbreak into an epidemic is the sars coronavirus [ ] . the outbreak began in the small village of foshan in china and expanded to various areas of the country as well as hong kong, singapore, vietnam, and canada. although a lack of proper containment of the virus at the source may have facilitated the spread of the virus into the community [ ] , travel was deemed as the most influential anthropogenic factor in the development of this epidemic [ ] . another travel-related expansion began in the same year as sars in the province of quebec, canada. known as the toxinotype iii, north american pfge type , and pcr-ribotype (nap / ) strain of clostridium difficile [ ] , the bacterium was found to produce up to times the amount of toxin of other known subtypes and led to over , deaths [ ] . this should have sounded alarms, yet the emergency was considered to be localized with no other regions reporting such activity [ ] . eventually, the outbreak was found to be part of a larger, unrecognized community-based spread of the pathogen. by , nap / was found to be prevalent worldwide [ ] . travel of animals through trade has also proven to be a contributing factor. escherichia coli o :h was originally identified as a human pathogen in [ ] but for many years thought to be a sporadic illness [ e ] . however, the strain spread throughout canada and the united states and over time into other parts of the world due in part to travel as well as livestock movement through commercial routes [ , ] . trade in general also can lead to inadvertent spread of a pathogen via arthropod vectors such as mosquitoes. this route has been seen as the means for the expansion of the zika virus [ , ] , which was originally found in uganda in . due to international trade [ ] , the virus found its way to the pacific and eventually the americas leading to the now infamous epidemic in brazil. while the exact vehicle has not identified, a possible route may have involved the importation of mosquitoes in high enough numbers to meet the minimum requirements for establishment in the new environment [ ] . due to lessons learned, increased surveillance for these infectious agents and other well-known species, such as avian influenzaviruses [ ] , polioviruses [ ] , and measles [ ] are now in place. yet, several pathogens given little attention have begun to show signs of expansion from hidden outbreaks into large scale epidemics. although none currently poses a significant global threat, increased vigilance is needed to ensure history does not repeat itself. this review will examine six hidden outbreaks that have for the most part eluded widespread attention and will explore their potential to form epidemics. these analyses will include a list of questions that require answering to gain a better understanding of the potential of each pathogen to expand into significant pathogens of concern. . current hidden outbreaks in , satoh et al. [ ] discovered a strain of yeast in the ear canal of a japanese individual. genetic analysis revealed the isolate was a new species which was named c. auris. the species was closely associated with c. ruelliae and c. haemulonii, the latter of which had been known to cause fungemia [ ] . c. auris was later isolated in other south korean patients with otitis media [ ] . the discovery was concerning yet assessing the significance in terms of risk for an epidemic was difficult at best. two years later, the first cases of c. auris fungemia in south korea [ ] were detected, including one from an isolate taken years earlier in . the findings suggested the species already could possibly be endemic in the country. moreover, an increased tolerance to fluconazole was identified suggesting future cases could be more difficult to control. over the next three years, antimicrobial resistant strains of c. auris healthcare-acquired infections were observed in kuwait [ ] india [ ] , and south africa [ ] . in , the yeast was discovered in the united kingdom [ ] , south america [ ] , europe [ ] and canada [ ] . genetic rdna analysis of isolates in the uk demonstrated several geographic origins [ ] highlighting the importance of human travel in the spread of the species. to date, c. auris remains for the most part a health-care associated infection affecting immunocompromised individuals. while there is increasing attention in the healthcare field to the risk of this pathogen [ ] , the international surveillance program sentry has demonstrated the contribution of c. auris to the overall burden of candida species remains small and limited to healthcare facilities. however, the nearly simultaneous emergence of the species across several continents suggests the yeast is ubiquitous in the environment and may pose a threat to an increasingly immunocompromised population [ ] . additionally, the increase in antimicrobial resistance seen in numerous isolates confers significant hurdles to combat fungemia [ ] . guidelines to deal with c. auris are either in place [ ] or in development [ ] but as seen in the case of c. difficile, this may only have a limited effect in controlling its spread in the community and through travel. public surveillance is necessary to determine the as of yet unknown prevalence of the yeast in the community and potential routes of transmission should also be examined to determine whether preventative strategies such as hygiene measures in the community may help to reduce the burden. coccidioidomycosis has been a recognized disease since [ ] although it is better known as valley fever [ ] due to the geographic location of the first american cases, the san joaquin valley in california. the disease is caused by the fungal pathogen coccidioides immitis [ ] and is marked by skin lesions and the potentially fatal formation of granulomas in numerous organs. at first, the pathogen was considered to be limited to arid desert regions in the united states and argentina [ ] , however, wider surveillance has detected the fungus in other geographic regions of the united states including arkansas [ ] , utah [ ] , arizona [ ] , texas [ ] as well as in canada [ , ] , central and south america [ ] . in addition, a retrospective analysis of coccidioidomycosis in china revealed cases involving no history or travel to endemic areas [ ] suggesting the fungus already may be spreading globally with no defined routes identified. although the mortality of this pathogen is quite low at less than one case per million person-years [ ] , its expansion over the last half century highlights the potential for an increase in prevalence not only in the americas but also asia. should the species become endemic in china, there is a greater potential for a rapid increase in outbreaks, and possible epidemics as evidenced by sars. moreover, the ability of the fungus to infect animals, such as dogs, cats, bats, rodents, and armadillos [ ] , potentiates even greater spread via domesticated and possibly feral reservoirs. combined with a noted increase in planetary temperature and resultant increases in desertification [ ] , there is a need to increase surveillance and explore the modes of transmission including environmental dissemination of dust through wind currents [ ] . human t-lymphotrophic virus was first isolated in [ ] from skin cancer and was considered an atypical oncovirus. other diseases were eventually associated with this virus including adult t-cell leukemia, htlv- associated myelopathy, tropical spastic paraparesis, uveitis, dermatitis, psychological disorders, and general immunosuppression [ ] . though the virus was detected worldwide, until recently, it was considered sporadic. that view has changed due to epidemics in several regions including brazil, spain, sub-saharan west africa, the middle east, the caribbean, japan, and australia [ ] . due to the bloodborne nature of the virus, which can only be transmitted efficiently through unprotected sexual contact [ e ], the virus typically remains endemic to a region without significant geographic spread. however, historical analyses of htlv- reveal the virus can be introduced into another area through large scale population movements from endemic regions [ , ] . for example, trevino et al. [ ] examined htlv in spain and discovered htlv- has entered the country as a result of migration. while the virus has yet to become endemic in the spanish population, the authors suggest this will occur in time. due to the continued effect of mass migrations from endemic areas into naïve ones, the risk for an increase in the prevalence of htlv- exists. surveillance for this virus needs to be recognized as a priority in countries receiving these individuals. while halting the spread of the virus requires a focus on safe sexual practices, there is a need to identify possible warning signs such as those in spain prior to expansion of the virus. discovered in as an atypical mycobacterium species, m. ulcerans has been widely seen as a rare infectious agent in comparison to other species such as m. tuberculosis and m. leprae. according to k€ aser et al. [ ] , two different lineages of the bacterium exist with one being far more virulent than the other. the virulent strain is known to cause painful skin lesions known as buruli ulcers, named after the ugandan region where this infection was first described [ ] . the bacterium and associated disease has subsequently been found in several other areas of africa including angola [ ] , benin [ ] , the democratic republic of the congo [ ] , côte d'ivoire [ ] , ghana [ ] , nigeria [ ] , and togo [ ] . the infection also has been identified in australia [ ] , and most recently jordan [ ] . while the association between the bacterium and the symptoms are well established, the mode of transmission has yet to be elucidated. the infection is self-limiting and several reports suggest the highest risk is associated with living in a riverine region [ e ]. as to the potential route for inoculation, several theories have been suggested such as bites from water bugs [ , ] and the potential for colonization with the bacterium through contact with soil [ ] and watersheds [ , ] . without knowing the exact route of transmission, determining the risk of spread from one environment to another is difficult at best. in a genetic analysis of the spread of the pathogenic branch in africa, vandelannoote et al. [ ] suggested the bacterium spread at the same time as populations were divided by european colonial rule. infected individuals contaminated pristine water sources allowing for the growth and dissemination of the species. in this regard, the potential for spread of the bacterium relies on migration of those who are infected. while the morbidity associated with this disease should prevent such movements by those infected, political and socioeconomic strife may lead to forced travel during infection. surveillance for ulcers should be conducted in healthcare facilities to identify new cases in non-endemic regions. in the event a case is discovered, efforts to minimize the potential spread to watersheds need to be in place to prevent the development of endemicity. s. pyogenes has been a significant pathogen for centuries in the form of scarlet fever [ ] . however, the bacterium has the ability to invade systemically causing bacteremia, endocarditis, toxic shock syndrome, necrotizing fasciitis and endometritis [ , ] . several contributing factors are associated with these complications [ , ] including fibronectin binding proteins to facilitate invasion, cysteine proteases to escape immune attack, and superantigens that trigger a massive immune response leading to the potential for tissue damage and organ failure. for the last two decades, a significant increase in the number of invasive infections has been seen in certain regions of north america and europe. gheradi et al. [ ] have shown several serotypes have increased their circulation in these areas. while between and % have been associated with one particular serotype, emm , the risk of complications associated with the other serotypes, including known invasive members such as emm , emm and emm [ ] as well as emm [ ] and emm [ ] . the inability to identify a single serogroup to explain the rise in cases suggests the risk factors associated with the rise of this infection lies in the nature of the susceptible population. nelson et al. [ ] examined cases of invasive group a streptococcus infection and found several human factors associated with invasion and mortality including early childhood, advanced age, underlying chronic illness, and immunosuppression. given the population-based obstacles regarding prevention of invasive infection, emphasis needs to be placed on surveillance of all s. pyogenes infections. while this does occur in many regions of the developed world, more needs to be done to prepare for the inevitable introduction of an invasive serotype into a community. although this likely will not prevent illnesses and small outbreaks, public health authorities will have sufficient information to warn the public of a new invader and emphasize hygiene guidelines aimed at prevention of spread. yellow fever has been known for over four centuries as a serious illness with the potential to cause death [ ] . the virus is present in both africa and south america although limited to a few regions on these continents. however, due to the ubiquity of its mosquito vectors, aedes and haemagogus species, there is potential for escape from these regions. shearer et al. [ ] performed a modeling analysis of this virus and determined numerous areas of the world including southeast asia, and central america may be receptive to the virus. in addition, the virus may be transported to non-traditional regions such as the southern regions of china and the united states. in another example, ibañez-justicia et al. [ ] reported on the introduction of aedes aegypti into a netherlands airport. while only six insects were identified, as saarman et al. [ ] point out, the number of mosquitoes required to develop a potentially endemic population may be as little as . moreover, yellow fever can develop an urban transmission cycle in an unvaccinated population [ ] . historically, yellow fever has not caused significant widespread concern due to the usually remote nature of endemicity both in africa and south america [ ] and the availability of a vaccine. however, a recent outbreak in brazil has raised the concerns for those traveling to the region [ , ] . hamer et al. [ ] describe cases of yellow fever in travelers of whom died. none were vaccinated. moreover, due to the precedent of zika virus [ ] , concerns have been raised regarding the potential of the virus to move north into central and north america where populations are not vaccinated against the virus. the resultant scare has led to a concern for vaccine supply [ ] as there is not enough to cover the entire american population living within zones where aedes may thrive. the most important tool in determining the risk of yellow fever expansion is surveillance. the identification of mosquitoes in amsterdam [ ] is one example of how proper environmental screening of packages from endemic areas may serve to prevent the introduction and eventual reception of a pathogen. in addition, promotion of vaccination will help to reduce the likelihood of infection in travelers. while human to human transmission has not been demonstrated for this virus, the virus may be brought into a region where competent mosquitoes thrive allowing for the initiation of the sylvatic and/or urban transmission cycles. the abundance of infectious disease outbreaks worldwide outnumbers the resources available to perform extensive investigations, mitigate morbidity, and determine prevention strategies. decisions are not easy to make in light of the potential for misjudging a potential epidemic-causing strain as an isolated or sporadic case. though these occurrences are rare, as demonstrated by previous epidemic of worldwide concern, the consequences may be drastic. moving forward, each outbreak associated with these six pathogens needs to be seen as a potential epidemic and algorithms for management need to be in place. developing these decisionbased policies require the use of advanced methods to improve confidence in results. the use of advanced molecular analysis techniques such as whole genome sequencing may provide a wider perspective on the nature of the outbreak and whether it truly is isolated or is a part of a larger problem. molecular and syndromic surveillance in at-risk areas can provide real time assessments and provide predictive information. the latter may be aided through the use of social media, which is currently being examined for its power in identifying and predicting outbreaks [ e ]. mathematical modeling of anthropogenic effects apart from travel and trade, such as climate change, urbanization, and food supply and demand can enhance the fidelity and accuracy of these calculations. finally, the appreciation of social and cultural practices can offer valuable insight into how healthcare workers and the community may react in the event of pathogen detection. this information also can offer best practices for collaborative efforts to reduce the chances for amplification and spread to wider areas. in the case of the six pathogens listed in this review, there has yet to be an expansion of cases to epidemic status. however, this situation quickly can change and lead to an expansion into a larger public space. while we may be able to vaguely predict how such escapes may occur, they are only guesses with little contributory value to policy and health systems development. for this to occur, appropriate algorithms need to be put in place and used to assess each outbreak as it happens. this may require valuable resources and could be met with resistance from numerous levels of government and the public in general. however, in light of the economic burden already seen with what amount to preventable epidemics, the cost may be fully justified. diseaseinduced resource constraints can trigger explosive epidemics is this an outbreak? a retrospective evaluation of syndromic surveillance for emerging infectious disease quantifying reporting timeliness to improve outbreak control epidemic and economic impacts of delayed detection of foot-and-mouth disease: a case study of a simulated outbreak in california mass media and the contagion of fear: the 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detection and prediction through social networking sites social media and outbreaks of emerging infectious diseases: a systematic review of literature. pii: s e ( ) - using social media for actionable disease surveillance and outbreak management: a systematic literature review combining search, social media, and traditional data sources to improve influenza surveillance none. key: cord- -f j bb authors: sabater gonzález, mikel; calvo carrasco, daniel title: emergencies and critical care of commonly kept fowl date: - - journal: vet clin north am exot anim pract doi: . /j.cvex. . . sha: doc_id: cord_uid: f j bb fowl are birds belonging to one of the biological orders, the game fowl or land fowl (galliformes) and the waterfowl (anseriformes). studies of anatomic and molecular similarities suggest these two groups are close evolutionary relatives. multiple fowl species have a long history of domestication. fowl are considered food-producing animals in most countries and clinicians should follow legislation regarding reportable diseases and antibiotic use, even if they are pets. this article reviews aspects of emergency care for most commonly kept fowl, including triage, patient assessment, diagnostic procedures, supportive care, short-term hospitalization, and common emergency presentations. refill time (crt). normally, when the finger is removed from the vein, refilling cannot be witnessed visually. if it can be witnessed visually the bird is considered approximately % dehydrated, and if second can be counted, then the bird is about % dehydrated or in shock. in chickens, the comb should be firm and red. a crt can be assessed on the comb. it should refill within seconds. mucous membrane color can be assessed by everting the vent or the eyelid. respiratory monitoring includes auscultation of the upper and lower respiratory tracts, assessing breathing frequency and quality, as well as detection of signs of dyspnea (eg, orthopneic gait or tail bobbing). the levels of brightness, alertness, and response should be evaluated as part of a first neurologic examination. birds showing depression or severe weakness should be placed immediately in a prewarmed incubator with % to % humidified oxygen and complete physical examination or diagnostic procedures may be delayed until the bird is stable enough to tolerate them. secondary survey includes obtaining a complete medical history, a full physical examination, assessment of the response to initial therapy, and more diagnostic procedures, which may provide a comprehensive diagnostic and therapeutic plan as well as orientate the owner about the potential economic costs and prognosis. a complete anamnesis should include, but is not restricted to, species; breed; age; gender; presenting complaint; source of the bird; diet; number of birds in the household; open or closed flock; acquisition date; date of the last addition to the flock; number and species of animals affected; potential exposure to toxins; length of illness; changes in behavior; history of previous diseases, treatments, and outcomes; reproductive history; and clinical signs, including their duration and progression. physical examination in fowl is similar to that of other avian species. careful observation of the bird before handling is mandatory in order to determine the length and depth of the physical examination and further diagnostics that the patient is likely to tolerate. all equipment and supplies are readied before removing the bird from the holding container or the intensive care unit. if the patient is debilitated, examination can be performed in a stepwise fashion with small breaks given to the bird between handling, examination, diagnostics, and treatments. in general, fowl species may be handled without chemical restraint. precautions should be taken in order to avoid physical injuries to the bird or the handler (bites, scratches [eg, from tarsal spurs], or blows from the wings [larger species]). fowl should be grasped across the back with or without a towel to avoid wing flapping. then, the legs should be firmly grasped placing finger between them to prevent pressure damage. the bird should then be restrained close to the handler's body or against a hard, nonmovable surface. fractious birds may benefit from having their heads covered with a cloth. smaller species of waterfowl may be held singlehandedly by restraining the animal with the wings folded or with fingers of one hand under each wing supporting the proximal humerus and the other hand supporting the bird's abdomen. larger species, such as geese and swans, are typically restrained keeping the wings folded and facing backward under the arm of the handler. large, calm species may also be straddled on the floor (fig. ) . the position of the bird during physical examination, diagnostic procedures, and therapeutic procedures may affect its cardiorespiratory function. dorsal recumbency in conscious chickens decreases tidal volume by % to % and increases breathing frequency by % to %. birds showing signs of respiratory distress should be held upright. respiratory compromise may be worsened in fowl by the inertial resistance of the large pectoral muscle mass to respiratory excursions of the keel. enlarged viscera, excessive intracoelomic fat, or fluid within the coelom may compress the air sacs, reducing their effective volume and potentially leading to hypercapnia, respiratory acidemia, and death. cloacal or body core temperature can be measured. cloacal temperature depends on body temperature and cloacal activity over time. normal range for body temperature in waterfowl is c to c. to read body core temperature, the probe of a thermistor thermometer should be inserted along the esophagus until it passes the thoracic inlet. normal range for core body temperature in chickens is . c to . c. the body condition should be assessed and an accurate weight obtained on a gram or appropriately sized scale in order to correctly calculate potential drug dosages or to compare with previous or future weights (fig. ) . the patient's needs must be prioritized. despite preferring that samples for hematologic and biochemical analysis be obtained before treatment for the best diagnostic ability, fowl in shock must be stabilized before extensive diagnostic sampling. a conservative minimum database includes determination of packed cell volume, total solids, and estimated white blood cell count. there is intraspecies variation in blood volume ( ae ml/kg for common pheasants and ae ml/kg for redhead and canvasback ducks). in healthy patients, the amount of blood that can be removed without deleterious effects is % of body weight in ducks, % in chickens, and % in pheasants. in compromised patients, this should be reduced to . % of body weight. reference values for multiple avian species can be found in the literature. intravenous or intraosseous fluid administration is essential when treating critical patients. catheters can be placed under general anesthesia if necessary. sites for intravenous catheterization include the medial metatarsal vein, the ulnar vein, and the jugular vein (fig. ) . intraosseous catheters can be placed in the distal ulna or proximal tibiotarsus. pneumatic bones, such as the femur or humerus, should be avoided. most birds benefit from intravenous or intraosseous administration of warmed crystalloids at ml/ g body weight. because fluid resuscitation in critically ill birds is difficult, administration of bolus of crystalloids with oxyglobin to hypovolemic birds may be beneficial. different types of colloids may be used as an alternative to oxyglobin. capnography, direct and indirect blood pressure, electrocardiography, and blood gas analysis are additional monitoring techniques that may be useful in assessing unstable patients. deciding the instrumentation to use depends on practicality and procedure length. capnography measures end-tidal carbon dioxide concentrations in expired air and is a useful indicator of arterial carbon dioxide concentrations. the use of capnographs with sidestream sensors is recommended for small avian patients. pulse oximetry has not yet been validated for birds. the characteristics of oxygenated and deoxygenated avian and human hemoglobin are different, resulting in underestimation of hemoglobin saturation. an ultrasonic doppler flow detector is most commonly used for cardiac monitoring but can also be used for indirect blood pressure measurement. indirect blood pressure measurement techniques used in fowl include doppler, photoplethysmographic/photoacoustic probes with a sphygmomanometer, and oscillometric monitors. systolic blood pressure determination via ultrasonic doppler flow detection correlates well with direct blood pressure measurements in ducks (a platyrhynchos). diastolic, and therefore mean, blood pressure cannot be obtained with this method. direct arterial pressure measurement is ideal but not commonly used because of the need for specific technical skill, the invasive nature of the procedure, and the cost of equipment. for medium to large birds (> g), the deep radial artery is the preferred site for arterial catheter placement, whereas for smaller birds (< g) the superficial ulnar artery is preferred. for waterbirds or long-legged birds, the cranial tibial or dorsal metatarsal arteries are acceptable sites for catheterization. catheterization of the external carotid artery usually requires a cut-down for proper visualization. a study performed on anesthetized galliformes comparing glomerular filtration rate and blood pressure found that galliformes were able to maintain their glomerular filtration rate when mean arterial pressure (map) ranged between and mm hg. when map decreased to less than mm hg, chickens were unable to sustain glomerular filtration and urine output ceased. unlike chickens that have normal systolic, mean, and diastolic arterial blood pressures of ae , ae , and ae mm hg, respectively, values for normotension are higher in other galliformes (eg, turkeys). , if the definition of hypotension in humans (reduction of % from the baseline of conscious maps) is extrapolated to birds, the level of blood pressure at which birds are considered hypotensive would have a tendency to be higher than that recorded in mammals, with the exception of some galliformes and anseriformes species. hypovolemia is treated with intraosseous or intravenous bolus administration of crystalloids ( - ml/kg) or colloids ( ml/kg) until systolic pressures are restored. , reference blood pressure values have been determined for different species of fowl. , electrocardiography can be used to monitor cardiac rate and rhythm. electrocardiographic parameters can be highly variable between fowl species, as shown by electrocardiographic studies published for several species including the chicken, turkey, quail, duck, swans, muscovy ducks, guinea fowl, and rock and chukar partridges. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] arterial blood gasometry is the gold standard for assessing the acid-base status, ventilation, and tissue perfusion. it provides essential physiologic information for patients with critical illness or respiratory disease and is vital in the correction of any metabolic respiratory disorders. detailed information about blood gases in birds has been published. sedation or anesthesia may minimize stress to fractious or painful patients. it also may aid in minimizing risk of capture myopathy in canada geese or turkeys. , midazolam is increasingly used in birds to produce sedation, hypnosis, anxiolysis, anterograde amnesia, centrally mediated muscle relaxation, and anticonvulsion activity. the pharmacokinetics of midazolam hydrochloride following intravenous administration at mg/kg were determined in broiler chickens, turkeys, ring-necked pheasants, and bobwhite quail. several articles regarding fowl anesthesia and analgesia have been published. , , inhalation anesthesia with isoflurane or sevoflurane is the most common in-hospital method for anesthetizing fowl. oxygen flow rates of to l/min allow rapid changes in anesthetic concentration if vaporizer setting is altered. induction is typically via a face mask. the apnea and bradycardia that occur when an induction mask is placed over the beak and face are consequences of a stress response caused by stimulation of trigeminal nerve receptors. [ ] [ ] [ ] preoxygenation with % oxygen for several minutes reduced this response in dabbling but not diving ducks. the isoflurane vaporizer is set to % to % for induction. intubation with a noncuffed endotracheal tube is recommended for anesthetic procedures lasting more than minutes. waterfowl females may require an endotracheal tube . to full size larger than males of the same species. if intubation is not feasible because of the nature of the procedure to be performed or anatomic structures preventing intubation (eg, presence of crista ventralis), ventilation can be achieved via air sac perfusion. airway patency should be regularly checked during waterfowl anesthesia because the thickening of mucus in the trachea or glottis may completely obstruct the endotracheal tube, leading to death of the patient. anticholinergic drugs reduce pharyngeal and tracheal secretions but also increase their viscosity, and so are only recommended for treatment of bradycardia. in chickens and ducks, isoflurane has a minimum anesthetic concentration (mac) of . % and . %, respectively. , isoflurane produces dose-dependent cardiopulmonary depression in birds and in pekin ducks induces tachycardia and hypotension. in geese, an average paco of mm hg was necessary for spontaneous respiration to occur, and no respiration occurred with a paco less than or equal to mm hg. intermittent positive pressure ventilation may be used in anesthetized birds, even if some spontaneous breathing is present, to ensure adequate oxygenation of the blood. ventilation is assisted manually using the reservoir bag on the breathing system or a mechanical ventilator. a spontaneously breathing bird is given greater than or equal to assisted beats per minute. if an anesthetized bird is apneic, the assisted ventilation rate is greater than or equal to to beats per minute depending on size (large birds require fewer breaths than small birds). analysis of blood gases showed that effective gas exchange is achieved using mechanical ventilation. in chickens, sevoflurane mac is . %. at mac, heart rate did not change significantly and cardiac arrhythmias were not observed at less than or equal to times mac. in another study in chickens, hypotension was observed during both spontaneous and controlled ventilation. however, this effect was only dose dependent during critical care of commonly kept fowl controlled ventilation. tachycardia occurred during spontaneous ventilation, whereas heart rate remained unchanged during controlled ventilation. analgesia species variability occurs because of differences in pain sensitivity, the conscious response to pain, and the physiologic response to analgesic therapy. dosages and effects of opioids and nonsteroidal antiinflammatory drugs in fowl have been reviewed. , , hospitalization many birds benefit from symptomatic treatment such as oxygen supplementation, nebulization, fluid therapy, broad-spectrum antibiotics, antifungals, and/or nutritional support and observation for to hours in a warmed incubator before diagnostic tests are performed. separate equipment and housing should be used for birds with suspected contagious diseases and all equipment and cages should be thoroughly disinfected after use to minimize the risk of disease transmission. the optimum temperatures for ill birds are . c to . c. administration of oral or subcutaneous fluids is reserved for stable fowl that are less than % dehydrated. oral fluid administration requires a patient that can maintain an upright body position and has a functional gastrointestinal tract to avoid regurgitation and aspiration of fluids. subcutaneous fluids may be administered in the inguinal web, interscapular area, axillary region, lateral flank, or midback. replacement fluid therapy is critical before nutritional support is instituted. diets for stable hospitalized fowl should ideally be selected according to the natural diet of the species. commercially available feeding formulas, such as a formulated critical care diet lafeber's critical care diet (lafeber company, cornell, il) or hill's a/d diet (a/d canine/feline; hill's pet nutrition, topeka, ks) can be used on a short-term basis. the use of emeraid exotic carnivore diet improves postsurgical recovery and survival of long-tailed ducks (fig. ) . the most common causes of blood loss in birds include traumatic injury and hemorrhagic lesions of internal organs. the ld (lethal dose, %) for acute blood loss in mallard ducks was % of total blood volume. after chronic blood loss, the ld of mallard ducks was reached when % of blood volume was removed, compared with an ld in pheasants and chickens of % to % loss of total blood volume. recommendations for fluid resuscitation after severe blood loss in birds have included the administration of crystalloids, colloids, and whole blood. although no statistical difference in mortality was appreciated among the fluid resuscitation groups (crystalloids, hetastarch, or a hemoglobin-based oxygen-carrying solution [hbocs]) in the acute blood loss study, a trend of decreased mortality was observed in the hbocs group. an early regenerative response was apparent following acute blood loss. trauma traumatic injuries occur fairly frequently in fowl kept outdoors, either as a result of predator attack, gunshot, electrocution, or as a result of inappropriate housing. a thorough physical examination is essential to determine the extent of trauma and the best approach for treatment. prioritize therapy (oxygen therapy, fluid therapy, and analgesia), control active hemorrhage, cleanse wounds, and stabilize fractures initially until patient stabilization allows a more specific treatment. any animal that has a bite wound should be provided with antibiotics after a sample has been taken for microbiological culture and sensitivity. clinical signs of head trauma may include, but are not restricted to: anisocoria, head tilt, depression, or other neurologic signs, skull fractures, retinal detachment, or hemorrhage from the nares, oral cavity, ears, and/or anterior chamber of the eye. mentation, pupil symmetry and size, and pupillary light reflex should be constantly monitored. changes in pupil size to dilated and loss of pupillary light reflex along with mentation progression to stupors or coma indicate neurologic deterioration. soft tissue injuries in the head and neck are commonly seen, and may require surgical repair. posttraumatic exposed epibranchial bones, part of the hyoid apparatus, can be surgically excised without significant postsurgical impairment, allowing easier surgical repair of wounds in the crown. fractures of the skull bones (eg, mandible, quadrate, jugal arches, palatine, pterygoid, and maxilla) can also occur. if the animal is able to groom and feed, healing by second intention can create a false joint allowing normal function. surgical repair of the beak and the use of prostheses have been reported. , anseriformes are prone to foreign body injuries. ingestion of fishing hooks and lines is common in swans (fig. ) . lesions can be observed in the rhamphotheca, tongue, skin of the neck, and gastrointestinal tract. management varies depending on the severity of the injuries. endoscopy can be attempted, but sometimes surgery is required. management of a neck injury caused by a nail shot from a pneumatic nail gun in a young muscovy duck (cairina moschata) has been reported. ocular injuries can also be seen after head trauma. if the eye is not visual and is severely damaged, enucleation may be considered. injuries over the coelomic cavity should always be assessed to make sure no penetrating injuries are present. in such cases the prognosis is poor. skin and muscle injuries can be surgically repaired when indicated, or managed medically to allow healing by second intention. fracture repair follows the same principles as in other avian species. in laying hens, pathologic fractures caused by hypocalcemia and metabolic bone disease might occur, and calcium status should be assessed and deficiencies corrected before surgical repair. vitamin c deficiency can also cause secondary fractures. emergency care for bone fractures should align the fracture as fully as possible so further damage of the surrounding tissues and pain are minimized, and weight bearing can occur as soon as possible, avoiding excess stress and load on the unaffected limb. luxations should be reduced as soon as possible to provide the best chance for joint mobility. bandaging includes soft bandage material and splints applied for temporary support or permanent fixation of fractures. bandaging techniques commonly used in other avian species (tape splint, football-type bandage, plastic spica bandage, modified robert jones bandage, schroeder-thomas splint, ehmer-type bandage, and figure-of-eight bandage) can be also used in fowl (figs. and ) . damage to the cervical air sac can cause emphysema because of the leakage of air into the subcutaneous space. this condition is often self-limiting. a cauterized skin defect can also be created over the swelling to allow the air to escape. the cauterized hole takes longer to heal than the air sac lesion, preventing recurrence. older hens quickly run for shelter when the weather conditions are not desirable. however, juvenile animals may stand on the wet ground, becoming hypothermic rapidly, especially those with thin skulls and crest, such as polands and those with wooly feathering, such as silkies. nevertheless, adequate shelter must be always provided. hypothermic patients may be warmed externally and via infusion of warmed fluids. poultry experience heat distress when high temperatures accompanied by high humidity increase beyond their comfort zone. when the environmental temperatures are between c and c, birds use nonevaporative cooling in ways: ( ) increasing the surface area by relaxing the wings and hanging them loosely at their sides, and ( ) increasing the peripheral blood flow. as the environmental temperature approaches the body temperature of the bird ( c), the rate of respiration increases and the bird open-mouth breathes in order to increase evaporative cooling or water evaporation. if panting fails to prevent body temperature from increasing, birds become listless, comatose, and finally die of respiratory, circulatory, or electrolyte imbalances. respiratory disease is a common presentation in avian practice. clinical signs are often unspecific, and hardly ever pathognomonic. respiratory signs are not only seen with primary respiratory disease but also with any organomegaly or distended coelom as a result of the pressure to the air sacs, or secondary to other disorders, such as cardiovascular disease. sinusitis is a common presentation in chickens and waterfowl, and often presents because of swelling of the periocular sinuses. different agents could cause sinusitis, such as mycobacterium spp, pasteurella spp, escherichia coli, pseudomonas spp, and some viral agents, such as avian influenza and newcastle disease (both reportable diseases in the united kingdom, european union [eu], and united states (us); fig. ). however, newcastle disease, avian influenza, and infectious laryngotracheitis are all rare in backyard poultry, and the most common causative agent of sinusitis in fowl in the us is mycoplasma. [ ] [ ] [ ] different agents are often isolated from the nasal cavity, aggravating the clinical presentation. in such cases, the authors recommend performing an initial sinus flush with sterile saline, in order to obtain samples for culture and polymerase chain reaction (pcr) identification. sinus flush should be performed under general anesthesia with an uncuffed endotracheal tube placed, to avoid fluid going into the respiratory tract. once samples have been obtained, f , enrofloxacin (not to be used in the usa and only to be used on label in egg laying chickens and turkeys in europe), amikacin or gentamicin flush could be performed, and repeat it as necessary. if purulent material is present in the sinus, the author recommends surgical access to remove as much purulent material as possible, because antibiosis alone is unlikely to resolve it. mycoplasmosis is the most common respiratory condition seen in backyard poultry. , poultry is mainly affected by species of mycoplasma: mycoplasma gallisepticum, mycoplasma synoviae, mycoplasma meleagridis, and mycoplasma iowae. m gallisepticum is often the pathogen causing respiratory signs, although m synoviae can also cause respiratory signs (sneezing, foamy nasal and ocular discharge, conjunctivitis, sinusitis, and/or purulent aural discharge). mycoplasma spp can be latent within the flock and often causes disease when there is immunosuppression, stressful factors, and concomitant infections. tylosin is the recommended treatment because it is licensed (at least in the united kingdom/eu and united states). antibiotic therapy does not eliminate mycoplasma, but it can resolve clinical signs; equally important is to assess and treat any other stressful factors (ammonia and dust sabater gonzá lez & calvo carrasco levels, densities, overall hygiene, food and water quality). however, if symptoms persist despite treatment, euthanasia should be considered for the well-being of the flock. anseriformes are an important reservoir for avian influenza, often being asymptomatic carriers even from some of the high-pathogenic strains. avian influenza or fowl plague is a rare disease in wild waterfowl, with few records in the wild. despite being uncommon, in particular in mixed flocks or flocks exposed to wild waterfowl, avian influenza should be considered and investigated in cases with compatible clinical signs, such as mucopurulent or caseous sinusitis. important management factors to control this disease, such as hygiene and density levels, should be assessed in captive waterfowl showing clinical signs. newcastle disease or avian paramyxovirus can also present with signs of upper respiratory disease, such as conjunctivitis or tracheitis, and it can also cause central nervous system and gastrointestinal signs. , zoonosis can also occur, although this only causes mild conjunctivitis in humans. it is a relevant disease given the high economic losses it can produce in the commercial poultry industry, because there is no effective treatment. vaccinations are available to reduce the likelihood of outbreaks. vaccination against newcastle disease is not currently allowed in the uk, but seems to be standard practice in the us. infectious laryngotracheitis (ilt) is caused by a herpesvirus, as well as marek disease. ilt can affects chickens (mainly meat breeds) as well as pheasants, and is similar in presentation to other respiratory diseases. it is characterized by the formation of a diphtheritic membrane in the trachea that can cause obstruction; animals can present gasping. vaccination can be attempted in an outbreak to reduce morbidity and mortality. early vaccination prevents clinical manifestation, but not latent infection. modified live vaccines are available in the uk, eu, and us. aspergillosis is a common condition affecting waterfowl, although it can also affect gallinaceous birds, such as chickens. as in other avian species, aspergillus fumigatus is the main isolated pathogen, although others species of the genus aspergillus can also cause disease. , in chickens, despite most healthy birds coping with a moderate exposure to the aspergillus conidia, infection may occur in immunocompromised birds or when exposed to an overwhelming quantity of spores. common sources of aspergillus are contaminated food and moldy substrates. clinical signs might include dyspnea, but it can present as lethargy, anorexia, and significant weight loss. diagnosis and treatment present similar challenges to those faced in other avian species. treatment is based in antifungal therapy, often an azole drug, together with supportive care. infectious bronchitis is caused by a highly infectious coronavirus and is characterized by having main presentations depending on the age of the infected animals; in young chicks, respiratory disease is the predominant manifestation, whereas salpingitis and the subsequent decrease in egg production is most commonly seen in older laying hens. soft, irregular, or rough-shelled eggs are often seen. in certain animals the lesions caused might impair normal laying for the rest of the animal's life, or even cause secondary problems, such as egg coelomitis. c psittaci is a well-known pathogen among avian practitioners worldwide, not only relevant for its high prevalence but also for its zoonotic potential. more than a species have been shown to be infected, including galliformes. because of its very wide infection range, many different species can act as a reservoir, such as pigeons and waterfowl. a recent study in pigeons showed a prevalence of % in adult animals, which was twice as high in juvenile birds. outbreaks in fowl occur only occasionally. in poultry, infection is often systemic, and occasionally fatal. clinical signs, incubation periods, morbidity, and mortality vary widely depending on the virulence of the strain infecting the flock. common clinical signs observed with chlamydiosis are sinusitis, rhinitis, diarrhea, and weakness. postmortem findings in affected birds include splenomegaly, hepatomegaly, airsacculitis, pericarditis, and peritonitis. , in turkeys, the disease pattern differs from other species and tends to present as an explosive outbreak. clinical signs can be aggravated by concurrent infections, such as salmonella or pasteurella. ideally, a combination of serology and pcr identification is used to diagnosis chlamydia. however, after adequate therapy, there is no currently available test to ascertain whether affected birds are no longer carriers; therefore, treatment should be carefully considered, because of its zoonotic risk, especially in collections open to the public. chlortetracycline ( ppm; ie, . g/kg food daily for days) has been recommended in turkeys, although doxycycline ( mg/kg po twice a day or ppm in food daily for days; or - mg/kg im weekly on occasions) is also used in outbreaks to reduce mortality in turkeys as well as in other species. , avian tuberculosis can present as a respiratory emergency when lesions are localized in the pharynx or trachea. certain parasites can also cause respiratory disease in fowl, such as syngamus trachea (commonly known as gapeworm), duck leeches (theromyzon tessulatum), streptocariasis, (streptocara spp), and air sac mites (cytodites nudus). [ ] [ ] [ ] if upper airways are affected, animals present gasping for air or open-mouth breathing, coughing, or retching. diagnosis is based on identification of the parasites (adult forms, ova, or larvae). riemerella anatipestifer can cause a peracute infection in ducklings, which might present with upper respiratory clinical signs, such as dyspnea, or nasal or ocular discharge. this condition evolves quickly and can cause sudden death. samples should be obtained for culture and sensitivity, to allow adequate antibiotic therapy. neurologic disease is common in fowl. clinicians must be vigilant and aware of the reportable diseases that can present with neurologic signs, such as newcastle disease, avian influenza, and chlamydiosis. marek disease is common in unvaccinated chickens, and heavy metal poisoning should always be considered in waterfowl. other possible causes are trauma, nutritional deficiencies, central nervous system ischemia, vascular insult, and other intoxications (fig. ) . marek disease is caused by gallid herpesvirus , and has recently been described as the most common disease diagnosed in backyard poultry. the disease is characterized by the presence of t-cell lymphoma as well as mononuclear infiltration of nerves, organs, reproductive tract, internal viscera, iris, muscle, and skin. the mononuclear infiltration of peripheral nerves, in particular the sciatic nerve, causes paralysis. however, there is no treatment of affected birds and euthanasia should be considered in unvaccinated suspicious cases. early vaccination (within the first days of hatching) does not stop infection (the virus is considered ubiquitous worldwide) but achieves more than % protection under commercial conditions. lead poisoning is thought to be one of the most significant causes of neurologic disease in waterfowl. a recent report estimated between , and , (approximately . %- . % of the wintering population) wildfowl deaths each winter are caused by lead poisoning. that number represents a quarter of all recorded deaths regarding migratory swans. not only waterfowl are affected by this, because other terrestrial game birds and fowl may ingest lead pellets that they mistake for grit or food; lead pellets may be buried in mud, in areas where fishing or hunting has previously taken place. animals can experience chronic intoxication when ingesting small numbers of lead pellets intermittently, but can also present acutely and in the form of an outbreak when reduced water levels or other circumstances expose lead that was previously unavailable. in the united kingdom, the sale and use by fishermen of lead leger weights and split shot weighing less than g has been banned since . since then, the incidence of lead poisoning has reduced significantly. however, the environmental contamination will still have an effect for many years. characteristic clinical signs of lead toxicity include weight loss, weakness, and green faces; weakness of the neck muscles causes a typical posture with the head resting on the bird's dorsum. whole-body radiographs might reveal the presence of metallic objects in recent cases; however, the grinding action and ph of the ventriculus dissolves the lead pellets within a few days. other common findings in chronic cases on radiographs are dilatation and impaction of the proventriculus. a blood sample should always be tested for lead levels to achieve a definitive diagnosis (normal, < . ppm; diagnostic, . - . ppm; severe, > . ppm). moderate anemia ( %- % hematocrit) can be observed. delta amino levulinic acid dehydrase activity has been suggested as a more sensitive diagnostic indicator for lead intoxication. early treatment of lead toxicosis should include stopping any further lead absorption; lead particles within the gastrointestinal tract can be removed by lavage under general anesthesia with warm fluid via a gastric tube. some investigators recommend repeating gastric lavage within to hours if lead particles are still present in postlavage radiographs, because fragments of lead can be trapped in crevices in the koilin. those particles precipitate when muscle activity has restarted. chelation therapy should be started in all affected animals. sodium calcium edetate ( - mg/kg intramuscularly every hours for days, with a -day break at day ) is the recommended treatment of lead and zinc toxicosis. penicillamine can be used as an alternative if sodium calcium edetate (nacaedta) is not available, or at the same time in severe cases. zinc toxicosis is less common in animals housed outdoors, and is similar in diagnosis and treatment to lead intoxication. botulism occurs when animals are kept in water with anaerobic conditions, particularly in warm, dry periods. clostridium botulinum overgrows and produces toxin type c, causing flaccid paralysis. other clinical signs are similar to other heavy metal poisoning, such as weakness. a good anamnesis and water analysis allows a presumptive diagnosis. other intoxications are common in fowl, such as coccidiostats in waterfowl (found in chicken-formulated commercial diets) or pesticides (dimetridazole and organophosphorus pesticides). , diarrhea diarrhea can have many different causes; after physical examination, clinicians should perform a direct observation, flotation, and diff-quik examination of a fresh fecal sample. samples should also be taken for viral identification. duck plague or duck viral enteritis is caused by a herpesvirus, and can cause significant losses in waterfowl collections. presentation can be peracute, including sudden death without previous obvious signs. other described clinical signs are cloacal lethargy, diarrhea, hemorrhage, prolapse of the penis, photophobia, ataxia, and tremors. , outbreaks are often seasonal (may to june in the united kingdom). it can cause morbidities between % and % in unvaccinated collections. in affected animals, the prognosis is very poor with no effective treatment. annual vaccination is recommended in endemic areas. avian or fowl cholera, caused by pasteurella multocida, is the most common pasteurellosis in poultry. chickens, duck, geese, and turkeys can be affected. outbreaks in turkeys can cause up to % mortality. clinical signs include oral and nasal discharge, dyspnea, diarrhea, and sudden death. this condition seems to be less frequent in the united kingdom than in north america, where annual outbreaks can cause significant mortalities. impaction of the crop, proventriculus, or gizzard has occasionally been reported in poultry and waterfowl. affected birds commonly present showing lethargy, emaciation, and esophageal or crop distension. despite the crop/esophagus, proventriculus, and/or gizzard being full of a solid mass of interwoven fibrous material, the intestines of birds with this condition are frequently empty. poultry have been known to ingest poorly digestible items (eg, grass, newspaper, sawdust shavings/ wood chips, and feathers) out of curiosity or as a response to stress, causing crop impaction. crop impaction is most frequently seen in spring, when chickens ingest long stems of grass that get impacted in the crop. captive waterfowl, especially geese, suddenly exposed to new environments may ingest nondigestible items like newspaper or plant products, like grasses. ingestion of grains that have low moisture content with concurrent exposure to water can lead to grain swelling and result in impaction of the esophagus. gizzard impaction can cause high mortality during the first weeks of life in turkey flocks. although rehydration of the impaction, gentle massage or flushing (only for crop or esophageal impactions), and liquid paraffin may help to resolve the impaction in early cases, surgical intervention might be necessary (fig. ) . these conditions occur sporadically in domestic fowl. intussusception occurs most frequently in the intestine, but it has also been reported in the proventriculus. in young birds volvulus of the small intestine may be caused by twisting around the yolk sac. intussusception and volvulus have been reported in chickens secondary to enteritis or abnormal peristalsis caused by nematode or coccidial infection. intestinal torsion has also been associated with pedunculated neoplastic stalks. clinical signs are anorexia and progressive weight loss, which may lead to death within a few days. diagnosis may be achieved by ultrasonography, radiography, or endoscopy. if an early diagnosis is made, resection of the affected intestine can be performed. coelomitis is an occasional cause of morbidity and mortality in waterfowl and a common condition in chickens, particularly seen in laying or ex-battery hens. infection of the coelom can become established following infection of the respiratory system, penetrating injuries, neoplasia, heavy parasitism, or reproductive diseases. in chickens, e coli is often responsible of the oviduct infections. salmonella pullorum or infectious bronchitis can also cause lesions in the reproductive tract. diagnosis may be achieved by aspiration of coelomic fluid (ultrasonographically guided if possible). powerful antibiotic therapy is recommended (fig. ) . egg coelomitis may occur because of an ectopic ovulation, when the follicle or yolk misses the infundibulum, or when the follicle in the oviduct moves back in a retroperistaltic manner. this condition can be caused by an underlying disorder or can occur fig. . ultrasonography in a chicken with distended coelom. critical care of commonly kept fowl after a stressful event while the egg was forming within the oviduct. in both situations the yolk reaches the coelomic cavity causing a coelomitis. secondary bacterial colonization can occur. often this occurs because of pathologic changes in the oviduct, with either infectious or neoplastic causes, or because of oviductal damage in battery hens. a recent study performed in backyard poultry in the united states revealed that the most common condition diagnosed was marek disease. in that study, the most common finding observed in gross postmortem was the presence of tumors affecting internal organs or carcinomatosis, which can affect the ovaries. equally, non-viralinduced reproductive neoplasia, despite having significantly different findings in the different institutions involved in the study, is also considered common. salpingitis was one of the most common presentations in of the institutions, with . % of the presented cases. initial treatment can include coelomoentesis when dyspnea is observed; this technique, although not free of risk, also helps in achieving a diagnosis by analyzing the fluid drained. fluid therapy, antibiosis, analgesia, and assisted feeding are required at initial stabilization. salpingohysterectomy is likely to be required for long-term treatment because this condition is likely to reoccur. stress, age, obesity, and poor nutrition can contribute to the presentation of this condition, and good layers seem to have a higher predisposition. this condition can be seen in animals with egg binding. often animals had experienced trauma of exposed tissue from the other animals in the flock. medical management is often unsuccessful and salpingohysterectomy is the preferred treatment option according to the investigators. alternatively, a gonadotrophin-releasing hormone agonist implant (deslorelin acetate) can be used, once the prolapsed tissue has been repositioned and infection and inflammation controlled. repeated applications are required longterm, and in certain animals the duration of the implant seems to decrease after repeated applications. this condition may result from inflammation of the oviduct, partial paralysis of the muscles of the oviduct, or production of an egg so large that it is physically impossible for it to be laid. young pullets laying an unusually large egg are most prone to the problem. as in other avian species, this condition is often linked to calcium imbalance, caused by a combination of dietary deficiencies, stress, and other husbandry-related problems. treatment includes fluid therapy, calcium, and oxytocin administration. if initial medical management is unsuccessful, ovocentesis (either directly into the egg shell or via the coelomic wall) should be the next step. the egg should not be manually broken or pulled, because iatrogenic damage to the oviduct may occur. if the shell of the egg is not eliminated within hours, salpingohysterectomy is indicated because the remnants of the shell might adhere to the oviduct, inevitably causing further complications in future oviposition. phallus prolapse is occasionally seen in anseriformes associated with mechanical damage, infection (ie, cryptosporidum spp., mycoplasma spp, neisseria spp.), hypersexsuality or immunosuppression. frostbite and bacterial infection may occur as a sequela of phallus prolapse. treatment may include analgesics, local and/or systemic antibiotherapy, and decongestive and lubrifying local therapies which allow reposition of prolapsed healthy tissues. severe cases may require amputation of the phallus. euthanasia might be required in cases with a poor prognosis and when certain infectious diseases have been confirmed. euthanasia should always be performed in a humane manner. the authors' preferred method is intravenous administration of barbiturates, but other methods can be used. fowl are stoic patients that commonly mask signs of illness in the early stages of disease and are not commonly presented as emergencies until the acute or chronic condition is severe. an understanding of intraspecific and interspecific anatomic and physiologic variations is crucial to the successful management of critically ill fowl. stabilization of the patient should be prioritized over diagnostic procedures. clinicians treating fowl should be aware of infectious and noninfectious conditions causing emergencies in fowl. a classification of the living birds of the world base 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application. lake worth (fl): wingers publishing bsava manual of farm pets. gloucester (united kingdom): british small animal veterinary association bsava manual of raptors, pigeons, and waterfowl. cheltenham (united kingdom): british small animal veterinary association aspergillus infections in birds: a review outbreak of psittacosis in a group of women exposed to chlamydia psittaci-infected chickens avian chlamydophilosis (chlamydiosis/psittacosis/ornithosis) chlamydia psittaci in ducks: a hidden health risk for poultry workers epidemiological investigations on the possible risk of distribution of zoonotic bacteria through apparently healthy homing pigeons experimental ornithosis in turkeys respiratory and pericardial lesions in turkeys infected with avian or mammalian strains of chlamydia psittaci chlamydiosis (psittacosis, ornithosis) use of ovotransferrin as an antimicrobial in turkeys naturally infected with chlamydia psittaci, avian metapneumovirus and ornithobacterium 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expressed proteins related to organophosphorus-induced delayed neuropathy in the brains of hens duck, geese, swans, and screamers: infectious diseases the comprehensive diagnosis and prevention of duck plague in northwest shandong province of china fowl cholera in turkeys persistence of pasteurella multocida in wetlands following avian cholera outbreaks backyard poultry medicine and surgery. a veterinary guide for veterinary practitioners bsava manual of raptors, pigeons, and waterfowl. cheltenham (united kingdom): british small animal veterinary association key: cord- -n w psr authors: halperin, daniel t. title: coping with covid- : learning from past pandemics to avoid pitfalls and panic date: - - journal: glob health sci pract doi: . /ghsp-d- - sha: doc_id: cord_uid: n w psr it is imperative to concur on the main transmission routes of covid- to explain risk and determine the most effective means to reduce illness and mortality. we must avoid generating irrational fear and maintain a broader perspective in the pandemic response, including assessing the possibility for substantial unintended consequences. as we wrestle with how best to mitigate covid- , it is imperative to concur on the likely main drivers of transmission (notably, infection clusters resulting from prolonged indoor respiratory exposure) in order to clearly explain risk and to determine the most effective, realistic behavioral and other means to reduce illness and mortality. n at the same time, we must avoid generating irrational fear and maintain a broader perspective, including assessing the possibility for substantial unintended consequences from the response to the pandemic. i n june , when the first cases were reported of what became known as aids, i was living in the san francisco bay area. as the waves of death mounted, i volunteered at a hospice in oakland, california, and later conducted epidemiological research at the university of california. there are major differences between hiv and severe acute respiratory syndrome coronavirus (sars-cov- ) and their resulting pandemics (aids and coronavirus disease ([covid - ] ). however, i'm having déjà vu: from the devastating number of deaths and the pervasive atmosphere of confusion, fear, and often panic. tragically, political leaders from ronald reagan to nelson mandela were slow to respond to the aids epidemic. all sides engaged in acrimonious ideological warfare that often ignored the epidemiological evidence. in hindsight, health authorities also made some decisions-especially under the pressure of needing to act immediately-that led to suboptimal and ultimately costly outcomes. , policies often became hardwired over time and difficult to walk back, even after new evidence appeared. well-meaning but overly simplistic messages such as, "always use a condom with anyone or die" inadvertently created other problems. , , earlier openness to innovative approaches, such as male circumcision and addressing sexual networks, could have saved many lives, particularly in sub-saharan africa. , , in subsequent years, as greater funding for research and treatment eventually poured in, a kind of "aids exceptionalism" also became imbedded. during the first years of the aids response, much was unknown regarding the causes and main modes of transmission. yet, even after hiv was identified in and the basic science became clearer, a great deal of uncertainty, persecution of marginalized groups, and terror persisted. rumors proliferated that anything from mosquitoes to using contaminated condoms to sharing toothbrushes were spreading the virus. in the s, after earvin "magic" johnson tested positive for hiv, counseling centers became overrun by the "worried well." , heterosexual college students flooded centers to get tested, petrified from having engaged in deep kissing or intimate touching "without protection," thereby diverting attention from those who were actually at significant risk of infection. with covid- , much remains unclear, but some basic facts are known and more emerge daily. yet, a palpable climate of confusion and anxiety pervades. (one mindboggling indication is that the johns hopkins university coronavirus resource center website is recording some billion hits a day! ) although under such circumstances fear-even when it becomes irrational-is understandable and can help motivate behavior change, , panic often leads to poor decision making and other unintended consequences. , moreover, there are troubling signs that we have failed to learn other important lessons from the previous pandemic, including the danger of polarized infighting. for example, politicians and the media as well as some medical experts are presenting us with a false dichotomy: having to choose between recklessly abandoning mitigation efforts to reopen the economy versus rigidly continuing present lockdown measures. the u.s. territory of puerto rico where i reside implemented a nearly complete shutdown in mid-march after the first death here (of an italian cruise ship passenger). since then, many people, convinced the virus is "everywhere" and infection is nearly unavoidable, won't leave their homes even to pick up groceries. when delivery services became overwhelmed, elderly and sick persons sometimes have not been able to obtain essential supplies. most of those who do drive or go outdoors use masks (needlessly) even when far away from other people. wearing masks in the hot, humid climate can be uncomfortable and has created issues, including elderly persons fainting while waiting in the sun for a long time to enter stores (which often only allow a handful of customers to enter at once). until recently, joggers and others were stopped and occasionally fined by police for venturing outside or for violating the pm curfew, which remains in effect after nearly months. (even in most of the world's hardest-hit countries, such as spain and italy, people are now allowed outdoors to exercise.) numerous restaurants, especially asian-owned ones, have closed after losing takeout customers. some stores require customers to wear gloves, despite evidence suggesting limited utility or that their use may actually increase risk of infection. in puerto rico, as in other parts of the world, many people (even many youth) with asthma are terrified of experiencing severe outcomes if they become infected with the virus, prompting shortages of inhalers and other critical supplies. the u.s. centers for disease and prevention (cdc) website lists people with asthma near the top of those at risk of severe covid- outcomes, even though only clinical study has investigated whether a relationship exists and has found no link. although other emerging data strongly appear to confirm the lack of an association, it is unclear whether the cdc will correct its public information. what is clear, based on evidence from several countries (and despite media attention to statistically anomalous cases of healthy and younger victims), is that severe outcomes and deaths from covid- are overwhelmingly associated with preexisting (and especially multiple) serious illnesses such as diabetes and heart disease, [ ] [ ] [ ] more so in men and particularly when exacerbated by obesity and smoking. , indeed, it may be that advanced age alone, in the absence of such predisposing conditions, is less of an independent risk factor than has been assumed. firstly, the elderly are more likely to have chronic illnesses, which confounds the association between outcomes and age. moreover, the fact that between % (in the united states ) and more than % (in italy ) of covid- -related deaths, at any age, have occurred in persons with preexisting conditions could suggest that even very old but otherwise healthy people may not be at greatly elevated risk of dying from the disease. further research and analysis, including assessing whether the important angiotensin-converting enzyme protein (ace- ) is more prevalent in the elderly could help explain the often higher infection (not only higher mortality) rates in older populations. in any case, such data underscore the ongoing need in general to prioritize preventing chronic diseases, which kill more than million people annually (over % in lower-and middleincome countries), and to address underlying conditions such as obesity and smoking. , regarding covid- prevention, it is imperative for experts to agree on what are the likely main transmission routes and to carefully determine which are, accordingly, the most effective (and realistically achievable) behavioral and other ways to reduce morbidity and mortality. it is probable that, as with other respiratory illnesses such as influenza, most covid- infections occur from close exposure to coughing, sneezing, shouting, singing, or other direct and relatively prolonged contact with someone who is symptomatic or presymptomatic. (there is evidence that some asymptomatic carriers are contagious, but from existing studies they appear not to represent a very substantial proportion of total covid- transmission.) in february, a team of world health organization (who) researchers led by david heymann investigated the outbreak in wuhan, china, and concluded that the large majority of transmission events occurred within indoor clusters between family members (accounting for %- % of estimated infections) and coworkers, with no identified cases of child-to-adult transmission identified. in addition, some data suggest that severity of outcomes is associated with initial exposure it may be that advanced age alone, in the absence of preexisting conditions, is less of an independent risk factor than has been assumed. it is probable that most infections occur from close exposure to coughing, sneezing, shouting, singing, or other direct and prolonged contact with an infected person. coping with covid- : learning from past pandemics to avoid pitfalls www.ghspjournal.org viral-load levels. [ ] [ ] [ ] moreover, it increasingly appears that infection risk from contaminated surfaces has been at least somewhat overstated, as the cdc recently acknowledged. indeed, it is conceivable that future science historians may conclude that many current covid- prevention strategies had little if any impact, particularly because they targeted drivers of spread accounting for no more than a small proportion of total infections. as some experts eventually did with hiv, , they could also help the public distinguish between those behaviors and situations posing the highest risk for covid- infection, those of likely lower risk (such as the virus lingering on hard surfaces for extended periods), and those of highly unlikely or no risk (such as being outdoors with no one else around). although the cdc has posted some basic guidance on its website (in the frequently asked questions section) regarding how covid- is mainly transmitted, the public would benefit from a more clearly communicated and much more robust public information campaign (e.g., including the virtual equivalent of placing a leaflet under every u.s. resident's door). this would help reduce time and attention spent addressing lowrisk concerns, such as when healthy people avoid leaving home for necessary activities even if carefully taking precautions. there is a crucial distinction between risk of indoor transmission-where physical distancing (whether mandated or voluntary) and perhaps other measures , are critical-versus risk of outdoor transmission, which is far lower (possibly by an order of magnitude) for various reasons, including dissipation of droplets in the air , and the deactivating effects of ultraviolet radiation and heat. [ ] [ ] [ ] a contact tracing study from china found that % of infections involved household members and % involved mass transit (multiple potential transmission routes were considered), whereas only a single infection event of the , cases investigated was linked to casual outdoor transmission. , , although politicians and the media have been obsessed with the danger of frolicking on beaches (or of participating in protest gatherings), a vastly greater risk is the common (public health) admonition for sick persons to remain home as long as possible before seeking hospital care, without providing access to alternative, clinically-provisioned quarantine residences, as several asian countries and iceland have successfully instituted. [ ] [ ] [ ] delays in seeking care not only diminish survival chances but also expose household members to significant infection risk. , , , is feet distancing strictly necessary? one example of inconsistent public health messaging is that european and asian authorities and the who recommended physical distancing based on data that droplets containing the virus had been identified almost a meter away from coughing individuals. in the united states, for some reason meter was initially translated into feet and subsequently became "over feet." although perhaps arguably not the highest priority, it would be useful for the cdc and other experts to determine whether such abundance-of-caution guidance is worth maintaining or perhaps is not scientifically warranted, and may inadvertently feed excessive concern. (in fact, the entire concept of physical or "social" distancing is not specifically relevant to transmission risk, primarily related to respiratory droplets: the pertinent issue is not the distance per se between people's bodies but rather between their faces, particularly if unmasked. for example, if people are positioned back-to-back, then obviously the distance can safely be much less.) this issue of distancing is particularly relevant as weather improves and outdoor exercise becomes more common, as many health departments , , encourage people to do (even though a hypothetical model based on untested assumptions sparked alarm by suggesting that joggers or cyclists could spread the virus over greater distances ). and critically, as the economy begins to reopen, it would be especially challenging for some businesses (and eventually schools) to adhere strictly to a -foot rule. this could be particularly excessive for outdoor activities, including construction, farming, recreation, and outdoor dining. it is certainly more practical to maintain a distance of about feet than feet in many situations, such as grocery shopping (where interactions are typically brief) or while strolling with a companion. indeed, it is likely that more "surgical"-more carefully targeted and realistic, evidence-based approaches , - -could be similarly efficacious as more extreme isolation strategies that have been there is a crucial distinction between risk of indoor transmission, where physical distancing is critical, versus the risk of outdoor transmission, which is far lower. future historians may conclude that many current prevention strategies had little impact because they targeted unlikely drivers of infection. the pertinent factor is not the physical distance between people's bodies, but rather the distance between their faces. coping with covid- : learning from past pandemics to avoid pitfalls www.ghspjournal.org global health: science and practice | volume | number widely implemented. for example, singapore had initially achieved a notably effective response without shutting schools. (however, subsequently there was a surge in cases due to an outbreak in crowded migrant-worker dormitories.) taiwan, which never closed its schools, has continued to report very few cases. similar to the first severe acute respiratory syndrome (sars) epidemic in - , , the vast majority of children infected with sars-cov- escape severe outcomes. there has been much media attention to multisystem inflammatory syndrome in children (mis-c), which has features similar to kawasaki disease. however, of the more than million covid- infections reported worldwide to date, only a few hundred cases of mis-c have been identified so far. , (although the usual kawasaki disease is more common in east asia, in the united states about , cases occur annually. ) of more than , covid- deaths reported worldwide, some children are known to have died, about half of them in the united states and the rest in europe. by comparison, more than children died last year from the flu in the united states alone, along with some , others from various childhood diseases. further contextualizing the mis-c and other childhood deaths from covid- , in the united states, per-capita mortality in persons aged years and older is , times higher than in children aged years and younger. (an intriguing question posed by some researchers is whether mis-c is definitely or always caused by covid- , considering that in some cases up to one-third of afflicted children have tested negative for covid- , both on polymerase chain reaction and antibody tests. ) although the emerging mis-c must be closely monitored, as with kawasaki disease most cases appear to recover fairly rapidly, especially if detected and treated early. [ ] [ ] [ ] because young people typically come in contact with many other children and adults, they are often efficient spreaders of respiratory pathogens. however, growing evidence suggests that, as with the earlier sars, , children are less likely to become infected with sars-cov- . [ ] [ ] [ ] [ ] [ ] [ ] [ ] according to the cdc, only about . % of u.s. cases of covid- have been reported in persons aged years or younger. researchers theorize that previous exposure to other coronaviruses (e.g., those producing many of the common colds frequently acquired by children) may confer some partial resistance to sars-cov- . , , interestingly, when blood samples collected before fall (i.e., before people began getting infected) were analyzed, about half the people studied appeared to already have some protective t-cell immunity to the new virus, resulting from past exposure to other coronaviruses. importantly, young people also produce smaller amount of the aforementioned ace- protein, a critical nasal cell entry point for both sars viruses. , , moreover, the evidence suggests that even when children do become infected, they are probably considerably less contagious than adults. , - , a recent german study found viral loads in infected children at levels comparable to adults. however, the number of children studied was very small and other methodological concerns have been raised. more importantly, although for some pathogens (such as hiv) viral load is highly associated with infectivity, the implications of viral load for covid- clinical progression and contagiousness remain unclear. , , because the many asymptomatic youth infected with covid- are not coughing or sneezing, they emit far fewer infectious droplets. and remarkably, contact tracing studies conducted in china, iceland, netherlands, and united kingdom have failed to identify a single case of child-toadult infection of thousands of transmission events analyzed. , , - a review of household transmission studies from several asian countries concluded that less than % of household clusters involved a child index case, and a analysis of different covid- interventions in the united states found no evidence for the impact of school closures. it should be noted that some of these data probably underestimate children's actual contagiousness, as they were collected after lockdowns and other mitigation measures had been implemented. however, the striking findings from the contact tracing studies in particular, as well as the evidently significant biological differences between covid- and other respiratory pathogens, suggest that children are not major sources of infection, especially as compared to the common cold strains of coronaviruses, for example. even without the substantial amount of data that emerged subsequently (which presumably would have reduced the predicted impact of school closures), in march , modelers from the imperial college of london estimated that closing schools might prevent only %- % of premature deaths in the united kingdom (i.e., predominantly of older adults with predisposing conditions such as chronic diseases, obesity, and smoking, who could become directly or indirectly infected from schoolchildren.) in contrast, the modelers estimated that %- % of total deaths can be prevented from self-quarantining at home. in denmark, norway, and new zealand, where schools reopened in april , the numbers of new covid- cases have continued to fall, similar to trends in finland, france, germany, netherlands, and vietnam, where schools all reopened in mid-may or earlier (though cases have increased in madagascar, but perhaps not mainly due to reopening schools). it will, of course, be vitally important to implement adequate testing and safety measures for teachers and other school employees , and to closely monitor the data as schools also begin reopening in australia, israel, japan, and elsewhere (even as some u.s. school districts and colleges have announced that fall instruction will be conducted strictly online). (in switzerland, health authorities also announced permission for grandparents to hug their young grandchildren. ) certainly, as decisions are made regarding the reopening of schools, it must be taken into account that school closures have been depriving over a billion students worldwide of essential classroom learning, vital social connections, and physical activity. in addition, socioeconomic disparities are increasingly exacerbated, as some families have the technological, parental academic assistance, and other resources to enhance online learning, while less privileged children fall further behind. , , , other huge consequences of school closures include documented surges in child abuse; hunger from missed subsidized meals; and greater anxiety, depression and isolation, which often are most acutely experienced by students with autism, down syndrome, attentiondeficit/hyperactivity disorder and other special needs challenges. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] one alternative to lockdown: moving toward herd immunity? although many experts continue to believe that stayin-place measures are needed to flatten the curve, others have proposed a phase alternative-instead of attempting to prevent any new infections-of essentially allowing younger and healthier people to gradually return to work and school, based on a herd-immunity strategy. , , , although many of them could eventually become infected, most individuals would be expected to experience relatively mild to moderate symptoms and, ideally after self-quarantining, would effectively be "naturally vaccinated" (i.e., they would presumably no longer be contagious, for perhaps a year or more). such an approach assumes, of course, that reinfection is uncommon, which-although most experts believe is quite probably the case-remains unconfirmed. , note that if previous infection does not confer immunity, it may prove very difficult to develop a vaccine that does so. this sort of herd-immunity approach could be strongly enhanced by large-scale antibody testing to identify previous infection, as china, germany, spain, united kingdom, and some u.s. locales have begun to implement. , crucially, we must determine how best to isolate or otherwise protect the most vulnerable populations from infection-certainly no easy task. if it were to be the case, as previously discussed, that elderly but otherwise healthy people are not actually at considerably greater risk of severe illness or death, then clearly this would make the challenge somewhat less daunting. however, the evidence is not yet sufficient to base policy on this still-hypothetical possibility. although obviously far from ideal, something akin to such an alternative approach may emerge (including perhaps in some lower-income regions) as one of the least terrible, more realistic longer-term alternatives, until a vaccine is available. interest in such strategies is intensified by the potential for a resurgence of infections once containment measures are eased, including a possible second wave in late and early . outcomes will need to be rigorously assessed in places like sweden, where despite most businesses and schools having stayed open, covid- deaths have been declining, though not as sharply as in most other european countries. ongoing attention has focused on sweden's percapita death rate being much higher than in other scandinavian countries. however, a crucial difference is that in sweden most reported cases (not only deaths) have occurred heavily among the elderly, particularly those residing in long-term care homes-similarly to the situation in belgium, france, italy, netherlands, spain, and the united kingdom. , , those countries (and, for example, the new york/new jersey area) all have higher reported death rates than sweden, despite tightly locking down since at least late march . that sweden's covid- mortality is lower than in those european countries becomes even more evident if comparing via excess mortality (current deaths compared to typical levels in preceding , , whereas in denmark and norway, similar to the situation in germany, japan, and south korea, a much larger proportion of infections has for some reason occurred in relatively younger people, consequently resulting in considerably lower covid- death rates. apparently also very salient, if rarely mentioned, is that recent immigrants in sweden have suffered disproportionally far greater infection and mortality rates, reportedly due in part to insufficiently targeted prevention campaigns. , by one estimate, perhaps % of all covid- deaths in the capital city, stockholm, have been solely among somali refugees (who comprise a minority of foreign-born immigrants in the city, after iraqis, syrians, and afghans, in that order). non-european residents also comprise-differently than the case elsewhere in scandinavia-the majority of the country's nursing home employees. although certainly understandable, the possible fear by the swedish government of a xenophobic or islamophobic backlash may, however, have resulted in grave public health consequences, reminiscent of prevention campaigns during the earlier aids years that shifted attention, also understandably but similarly deleteriously, away from those at highest risk to avoid homophobia and discrimination against marginalized groups. , it also appears noteworthy that in the u.s. states that never imposed stricter isolation measures, observable increases in new cases have not occurred, as compared to demographically and otherwise similar neighboring rural states that implemented tight lockdowns. this observation is consistent with the fact that modeling predictions in late april of a sharp uptick of death across the united states, as many (largely rural) states began reopening, turned out to be considerably overdrawn. , a key implication of the experience from the non-lockdown u.s. states and sweden is not that death rates in those places have been lower than elsewhere, but if outcomes generally have not been worse, this suggests that similar results may be achieved at a less drastic economic and societal cost. (in the case of sweden, a fairer comparison would be to more epidemiologically similar european countries, rather than utilizing the "ecological fallacy" of comparing its experience only to the other scandinavian nations.) in any case, the urge to apply an either/or, one-size-fitsall approach, which also hampered the response to aids and some other past health crises, , , , should be questioned, including in lower-and middle-income world regions. , - it is crucial that an evidence-based and transparent debate underpin decisions, obviously taking into consideration the unprecedented consequences of financial collapse and lost income resulting from a prolonged economic shutdown, , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] as most painfully experienced among socioeconomically disadvantaged populations. such disruptions are being felt most dangerously in the lowest-income regions of sub-saharan africa and south asia, where the prospect looms for unintended consequences of harrowing proportions. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] , these include potentially vast increases in deaths from malaria, tuberculosis, measles, polio, diarrheal and other diseases, and malnutrition, as vaccination, maternal and child health, family planning, and other basic services are suspended due to lockdowns or are deprioritized while health efforts increasingly focus on covid- . , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] considering that young children are likely to be particularly impacted, this would represent an even greater magnitude of devastation if measured in terms of years-of-life-lost, and not only via crude mortality numbers. the catastrophic number of deaths directly resulting from covid- -which eventually may eclipse the estimated million from the "hong kong" flu in - , (when the world's population was less than half of today's)-along with the many who could suffer long-term sequelae, , must be considered alongside the increased mortality and compromised outcomes for it is noteworthy that in the u.s. states that never imposed stricter isolation measures, observable increases in new cases have not occurred. the urge to apply an either/or, onesize-fits-all approach should be resisted. coping with covid- : learning from past pandemics to avoid pitfalls www.ghspjournal.org global health: science and practice | volume | number the numerous persons suffering from non-covid- -related cardiac arrest, stroke, appendicitis, and other urgent conditions who have been denied medical attention or have delayed treatment for fear of seeking hospital care. , [ ] [ ] [ ] moreover, job losses and mass school closures from the lockdowns are intensifying socioeconomic disparities, including potentially dooming hundreds of millions of children to long-term educational, psychosocial, and vocational disadvantages. , , , , , , , policy makers, such as the who, foreign donors, and local governments, appear to be making enormously consequential decisions without fully taking into account some key demographic as well as potentially significant climate [ ] [ ] [ ] and childhood vaccinerelated , differences between lower-income regions (characterized typically by more rural populations and an age pyramid dominated by young people) and europe and north america (more urban, older, and often more obese populations, thus probably much more vulnerable to covid- mortality). [ ] [ ] [ ] [ ] , furthermore, it is critical to consider the consequences of remaining inside (often cramped) living quarters for extended durations, including reported increases in domestic violence [ ] [ ] [ ] and child abuse, [ ] [ ] [ ] as well as other physical and mental health issues related to chronic diseases ; obesity ; social isolation ; anxiety, depression, and suicide , , , [ ] [ ] [ ] [ ] ; obsessivecompulsive disorder ; poisoning from overuse of toxic cleaning products ; and autism, attentiondeficit/hyperactivity disorder, and other developmental challenges. as has occasionally occurred with other health crises such as hiv/aids, , we must not lose sight of the bigger picture. it is sadly possible, especially in the lowest-income regions, that the remedy could be worse-perhaps tragically even far worse-than the disease itself. how the west sparked the aids epidemic and how the world can finally overcome it the invisible cure: why we are losing the fight against aids in africa last night in paradise: sex and morals at the century's end quarantine fatigue is real. the atlantic public health. reassessing hiv prevention putting a plague in perspective death counts become the rhythm of the pandemic in the absence of national mourning a meta-analysis of fear appeals: implications for effective public health campaigns it's dangerous to be ruled by fear five ways to conquer your covid- fears coronavirus: can latex gloves protect you from catching deadly virus? the independent clinical characteristics of patients infected with sars-cov- in wuhan asthma is absent among top covid- risk factors, early data shows % of those who died from virus had other illness, italy says report of the who-china joint mission on coronavirus disease (covid- ) hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease -covid-net, states coronavirus: obesity doubles risk of needing hospital treatment, study suggests. the independent smoking is associated with covid- progression: a meta-analysis number of coronavirus cases by age group (for various countries) chronic illnesses: un stands up to stop million avoidable deaths per year. un news annual medical spending attributable to obesity: payer-and service-specific estimates puerto rico's man-made disasters will kill more people than natural catastrophes. miami herald reducing risks from coronavirus transmission in the home-the role of viral load how long you are exposed to coronavirus can determine if you get sick, experts say. miami herald why are some people so much more infectious than others? new york times virus 'does not spread easily' from contaminated surfaces or animals, revised cdc website state erin bromage: covid- musings blog review of "covid- outbreak associated with air conditioning in restaurant stop shaming people for going outside. the risks are generally low, and the benefits are endless. business insider uv light influences covid- activity through big data: trade-offs between northern subtropical, tropical, and southern subtropical countries will coronavirus pandemic diminish by summer? massachusetts institute of technology effects of temperature and humidity on the daily new cases and new deaths of covid- in countries indoor transmission of sars-cov- the successful asian coronavirus-fighting strategy america refuses to embrace how iceland beat the coronavirus multi-risk sir model with optimally targeted lockdown the characteristics of household transmission of covid- don't cancel the outdoors; 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hayre, christopher m. title: a survey exploring personalized medicine among of radiography academics within the united kingdom date: - - journal: j med imaging radiat sci doi: . /j.jmir. . . sha: doc_id: cord_uid: vfdoelk introduction: this article explores the application of personalized medicine (pm) within the academic environment in the united kingdom. there is a growing acceptance of the utility of pm in health care and the role medical imaging can play. in response, this article explored the views and opinions of diagnostic and therapeutic academics and the utilization of pm in education. methods: this study primarily adopted a quantitative approach using an online survey. however, participants were also encouraged to provide qualitative comments in response to open-ended questions. the survey was distributed to radiography and radiotherapy academic departments, which received a response rate of %. results: the findings identify some important considerations. on the one hand some participants reported teaching pm on their programmes ( %, n = ), whereas % (n = ) did not. importantly, the remaining academics ( %) were either unsure or did not know what pm was. this finding, coincided with qualitative commentary, highlights some discrepancies linked to knowledge and understanding of pm within higher education and highlights areas where academics may need additional support. conclusion: this article concludes by recognizing the challenges of delivering pm by some academics. it is noted that although the findings cannot be fully generalized, it does highlight fragmented understanding of pm among academic staff. this is important to reflect upon following the increasing requirements for radiography to become “more personalized.” r esultats : les r esultats ont permis d'arriver a des consid erations importantes. d'un côt e, certains r epondants indiquent que la mp est enseigne dans leurs programmes ( %, n ¼ ), tandis que % (n ¼ ) ne le font pas. chose importante, les autres universitaires ( %) dise ne pas savoir ou ne pas savoir avec certitude ce qu'est la mp. ce constat co€ ıncide avec les commentaires qualitatifs qui soulignent des ecarts dans la connaissance et la compr ehension de la mp au sein de l'enseignement universitaire et met en lumi ere des domaines dans lesquels les universitaires pourraient avoir besoin de plus de soutien. conclusion : l'article conclut en reconnaissant les d efis de l'enseignement de la mp pour certains universitaires. il est not e que si les conclusions ne peuvent pasêtre enti erement g en eralis ees, elles contributors: all authors contributed to the conception or design of the work, the acquisition, analysis, or interpretation of the data. all authors were involved in drafting and commenting on the paper and have approved the final version. funding: this study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. competing interests: all authors declare no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. ethical approval: ethical approval was sought and approved by the university of suffolk's research ethics committee. on its th birthday, the national health service (nhs) launched a new era in genomic health, whereby people in england will have access to genetic tests. this is a step towards personalized medicine (pm) [ ] . health education england defines pm as ''the treatment and care of patients with a particular condition, which uses new approaches to better manage patients' health and target therapies to achieve the best outcomes in the management of a patient's disease or predisposition to disease'' [ ] . today's conception of pm aims to use a wide range of data, such as molecular imaging, lifestyle, diet, and other medical information, to holistically look after the health of people [ , ] . a white paper by the research committee of the european society of radiology stated that for pm to be successful, medical imaging must play an integral part [ ] . the white paper called for the radiology workforce to be prepared for this paradigm shift in health care and reflect on what it would mean for education, research, and practice. this has been echoed in a recent paper by the authors exploring the opportunities and challenges of pm in medical imaging in the contemporary space [ ] . similarly, sloane and miller [ ] recently explored radiology service managers' views on the radiography curriculum and points to the need for a curriculum that is responsive to the rapidly changing technological, organizational, and social contexts of modern society and health care. pm in medical imaging ranges from the adjustment and use of alternative imaging modalities and exposure parameters to suit patient characteristics and the use of positron emission tomography (pet) imaging to determine tumour response radiotherapy treatment [ , ] . pm use in medical imaging also has potential in the emergence of ''companion diagnostics.'' to target therapies to an individual's unique characteristics, patients are tested for biomarkers. a biomarker can be prognostic (a characteristic that has the potential to affect the course or outcome of the disease) or predictive (patient characteristics that can predict a patient's likelihood of benefiting from a treatment or intervention) [ ] . here, genetic and other tests (including medical imaging) are coupled with targeted therapies. this constitutes a good fit for medical imaging through potential expertise in functional and molecular imaging [ ] . there is a general consensus that radiology will be greatly impacted by pm [ ] . the need for increased knowledge and expertise in this area has been mentioned. notable among these was the lecture by professor audrey paterson at the united kingdom radiology conference in , title: ''can radiography survive the next decade?'' [ ] . this has been echoed by dr richard fowler, in his radiology / presentation [ ] . these seminal perspectives call for an update in the curriculum to reflect the inevitable change likely to occur in the profession because of pm. in response to the aforementioned, the aim of this study was to investigate the extent to which pm was being taught or incorporated in contemporary radiographic curriculums in higher education institutions (heis) offering programmes of study leading to a bsc in diagnostic radiography or bsc in radiotherapy and oncology in the united kingdom. this study primarily adopted a quantitative approach by using an online survey; yet, the survey also offered participants an opportunity to provide qualitative comments, which are used as part of the results to uncover some feelings and beliefs toward pm in practice. a short questionnaire was designed using surveymonkey consisting of questions. because of the limited radiographic literature discussing pm, it was decided that the study would be exploratory and keep questions short by exploring how much/or little radiography academics knew about pm and uncover how it was incorporated within the radiography curriculum. ethical approval was sought and approved by the university of suffolk's research ethics committee. in addition to ethical clearance, it is important to highlight other ethical strategies used by the authors to ensure that ( ) no harm was done to any survey respondent and ( ) no survey respondent was unduly pressured or made to feel obligated to participate. first, participants were fully informed of the intentions of the survey. for instance, potential respondents were informed of the purpose and what would be expected from them, coincided with the expected length of time to complete the survey. second, it was imperative to acknowledge that all responses would be kept confidential; thus, individual demographics, such as name, email address, and location of workplace were omitted from the data collection process to elicit better responses. key participants were contacted initially and asked to disseminate the survey among their peers to enhance the response rate. key participants were identified by the authors. this was achieved through the examination of diagnostic radiography/radiotherapy staff profiles via publicly available heis websites. on identifying the course leader, he/she remained our primary contact for this study and an aid for dissemination to academic peers. this method of sampling is commonly referred to as ''snowball sampling'' whereby study subjects recruit future subjects from among their professional acquaintances. the advantage of this includes the ability for a study to take place if/when participants remain unknown to the researchers. the questions posed to academics began by asking, ''what programme (diagnostic radiography and/or radiotherapy and oncology) they taught on?'' follow-up questions then asked participants about their job role, whether they teach pm on their academic programmes and how the subject of pm is delivered. participants were then asked for the rationale of not teaching pm (if applicable) on their undergraduate degree programme(s), supported with a question exploring where training could be available to obtain competencies to deliver pm in higher education. knapp et al [ ] recently evaluated the academic workforce in the united kingdom. their study offers insight into the number of diagnostic and therapeutic academics currently practicing in heis (n ¼ ). although the study acknowledges that only of institutions responded in the united kingdom, the value provides an approximation of the total number of potential participants who could have taken part in this survey. in response, then, of a potential participants, the initial response rate was low (n ¼ ) when first distributed to colleagues via email; yet, on a follow-up request to colleagues, a significant increase in responses was received (n ¼ ). the authors felt this sample offered an insight into the concept of pm among radiography academics. however, it is important to recognize that the findings presented here should not be generalized, as the approximate sample of % remained too low for inferential statistics. descriptive statistics have been used to provide some insight into the application of pm in heis in the united kingdom. as identified earlier, the maximum sample of academics in the united kingdom was limited. thus, of an approximate respondents, participants ( %) responded to this survey. these consisted of academics in roles identified as course leader/programme director, module leader, module contributor, academic team manager, and admissions tutor. in total, % (n ¼ ) were diagnostic radiography academics, whereas % (n ¼ ) were academics delivering therapeutic radiography. this is consistent with the approximated academic workforce identified previously [ ] . figure shows the number of respondents who reported teaching pm on their undergraduate programmes ( %, n ¼ ), whereas % (n ¼ ) reported not teaching pm. the remaining academics ( %, n ¼ ) were either unsure or did not know what pm was. it is important to highlight that a relatively large number of academics, % (n ¼ ) of respondents, did not know what pm was. there is also a clear distinction in the level of teaching of pm, whereby a larger proportion of therapeutic lecturers taught pm when compared with their diagnostic radiography counterparts. although this finding is relevant, it is not surprising, as radiotherapy and oncology, in general, has arguably been more overtly ''personalized based'' depending on patient tumours and personal characteristics [ ] [ ] [ ] . the format in which pm was delivered varied considerably among academics, demostrated in figure . some cover the topic ''as part of imaging modality/technology module'' ( %, n ¼ ) or ''as part of emerging modalities/technologies module'' ( %, n ¼ ). furthermore, this question indicated that pm was not necessarily taught overtly as a discrete concept, but rather incorporated in a variety of ways within the curriculum. this was captured qualitatively by a number of the participants who answered ''other (please specify)'' ( %, n ¼ ): ''i direct students to current literature and we discuss this rather than me actually teaching about it. the survey identified the rationale for not teaching pm in the radiographic curriculum ( figure ). for example, academics felt they had a ''lack of knowledge'' regarding pm ( %, n ¼ ) followed by a ''lack of expertise'' ( %, n ¼ ). in addition, % (n ¼ ) said that although they were interested in the subject, they felt they did not have the appropriate qualifications nor competencies to teach it as a concept. although respondents chose not answer this question, for those who did, qualitative comments highlight its use for those selecting ''other (please specify)'' ( %, n ¼ ): ''i think we touch upon the topic in various modules but it is not embedded fully. we would need to improve our knowledge on the topic in order to introduce it more fully into the programme. together, % (n ¼ ) of respondents thought pm was not relevant to clinical practice or to the curriculum. furthermore, % (n ¼ ) of respondents were unaware of training opportunities to gain the necessary competencies to teach pm. although this seemed an impossible question (as stated by one respondent), the aim of the question was to gauge how successfully messages about a course filters into the academic world within a radiography/radiology context, because attitudes emanating from knowledge are a good predictor of future behaviour [ ] . figure depicts the rationale for not using pm within undergraduate radiography programmes. some participants in this study expressed their wishes to learn more about pm in order for them to enhance their academic work, whereas others fully understood its value in the delivery of contemporary education: ''i think it is critical that we embrace personalised medicine in the curriculum. personalised medicine has the potential to completely revolutionise patient care. it is imperative, therefore, that we become much better informed ourselves so that we might support students' learning and prepare them for a brave new world!'' [therapeutic academic] ''just to reiterate that in relation to teaching personalized medicine on a therapeutic radiography programme i think we would have to learn more about its emerging use in cancer specific pathways and how it links or will link to therapeutic radiography. a study day for lecturers and for clinical educators would be very useful.'' [therapeutic academic] ''i think this is an incredibly important area to be considered within oncology generally and within radiotherapy. as advances are made and technologies improve so will our practice. therefore we need to provide our students with the most up to date information as they will be the future workforce.'' [therapeutic academic] the narratives above suggest a clear drive for pm by some academics. they importantly recognize its value in shaping curriculum whereby advances in technology and genomics will continue. in short, it remains imperative that the radiographic community reflects on nuanced areas that will impact on both students and health care practitioners in future years. genomics england was established in by the department of health to deliver the , genomes project and sequence , genomes of nhs patients with rare diseases and also patients with common cancers [ ] . the aim of this project was to lay the foundations for the united kingdom to be a world leader in making such technologies mainstream while also ensuring that health care remains personalized. to support this project, the genomics education programme was created to ensure that the nhs had the knowledge, skills, and experience to ensure that the nhs remains a world leader in genomic and precision medicine [ ] . this £ million education programme involves heis and will fund at least master's in genomic medicine programmes and numerous other courses in genomics and bioinformatics, including doctoral-level programmes. online and selfdirected study resources have also been made available for health care staff and thus important that health care staff are made aware of such opportunities [ ] . the findings in this study are consistent with published literature, especially in radiotherapy and oncology, where it is argued that the interplay between a patients' environment, behaviour, and genetics have, for a long time, been factored into diagnoses, treatment planning, risk stratification, and estimation of drug response [ ] . the question that arises, here, is whether the concept of pm would benefit from being figure . delivery of personalized medicine within the academic curriculum. addressed more overtly to facilitate pedagogical and andragogical approaches in undergraduate radiography teaching? the survey highlighted that the term ''pm'' may not be widely recognized among some radiography academics in heis in the united kingdom. this is important to recognize as a discipline if there is to be collegial approach to delivering pm within a learning and teaching context to undergraduate radiography students. this stated lack of awareness of pm and allied fields of genomics is not unique to radiography academics. there is a general lack of awareness and understanding of such concepts in the public sphere and a clear link between awareness and levels of engagement with it [ ] [ ] [ ] . as identified earlier, there are funded opportunities for health care practitioners to undertake further study in the united kingdom within this growing field, which may help build the knowledge base of radiography academics. in medical imaging, a person's clinical and personal characteristics are used to ensure that the correct imaging procedure and modality is undertaken for the right patient and to keep potential detrimental effects of ionizing radiation to the minimum. contemporary examples include the use of low-dose computed tomography (ct) protocols for the detection of urinary calculi [ ] , calculating the weight of a patient in determining the quantity of contrast media [ ] , weightbased isotope injections in radionuclide imaging, and the adjustment of exposure parameters based on patient build. in addition, cross-sectional imaging modalities such as magnetic resonance imaging (mri) and ct are being combined effectively with quantitative metabolic modalities such as pet and single-photon-emission ct imaging to better visualize cancers [ , ] , whereas pet/ct is being used to accurately predict tumour recurrence in breast cancer [ ] . these modalities will continue to be essential imaging practices in the delivery of sound image acquisition and diagnosis, yet only a small number of study participants acknowledged this as pm, as part of an emerging technology module. as outlined, a vast majority of the respondents felt that although pm was ''touched upon,'' it was not specifically discussed in any academic depth. the rationale among those who responded in this survey for not incorporating was linked to a lack of knowledge and uncertainty around its application within the radiography curriculum. pm has been driven by developments in genomic technologies and has led to enhanced optimism among the scientific community in that it holds promise for the future of health care. the mapping of the human genome coincided with subsequent initiatives such as the , genome project (in the united kingdom) has led to a heightened awareness that specific genetic/molecular variations underlie certain diseases and that they can, in turn, be managed based on these variations [ ] [ ] [ ] . pm is taking various forms, including the identification of cancer risk and targeted therapy resulting from the identification of biomarkers, prediction of drug response (pharmacogenetics/genomics), and the prediction of the chances of disease recurrence through the analysis of cancerous tissue [ ] . as a contemporary illustration, a recent finding from the coronavirus outbreak is the variation in susceptibility, presentation, and response to the disease [ , ] . one of the possible reasons being investigated at the wellcome genome campus in cambridge (united kingdom) is the link with underlying individual genetics and possible mutation of the virus in individuals [ ] . this could probably have implications for variations in coronavirus disease -related imaging. although the virtues of pm are identified, there were a range of reasons for not incorporating it at an undergraduate level. although the most common answers were linked to knowledge, understanding, competency, and expertise among academics, there was also the suggestion that pm was not relevant at an undergraduate level for students. it is important, however, to recognize that some respondents welcomed the introduction of pm in the overarching curriculum, as it would help teaching staff understand the concept more. the variation in attitudes towards pm is not surprising because it has been argued that health care has always considered the individual circumstances of patients [ ] and that there is the need to reduce the hype of the promise of pm [ ] . the contemporary conception of pm, by proponents, highlights the potential role of the increased power of digital technologies that have enabled the aggregation and use of patient information from a wide range of sources [ ] [ ] [ ] . in short, it could be argued that the concept of pm may not be widely understood among radiography academics in the united kingdom. this may also resonate with other academic staff transnationally. the small but relevant findings of this article presents an opportunity to discuss the application of pm within an academic context and how pm should be considered as part of an overarching radiography curriculum in future years. this study sought to gauge the extent to which pm is being incorporated in the curricula of programmes offering courses in diagnostic and therapeutic radiography in the united kingdom. a larger proportion of those who taught and understood the concept of pm were those registered as therapeutic radiographers. the survey also found that the foremost reason for not teaching pm was a lack of awareness and understanding from academics. the qualitative commentary highlights that although some recognize the value of pm in both contemporary and future curriculum development, it was evident that more awareness is needed for integration. pm is here and should remain a topic discussion for academics worldwide to better inform the education of students. the response rate of % constitutes the most significant limitation of this survey. because of the snowballing sampling strategy, there was a great reliance on radiography course leaders to disseminate the survey to their colleagues. a common disadvantaged of this sampling method is the difficulty of determining the sampling error and/or whether to make inferences about a population based on this sample. survey-monkey collects the internet protocol (ip) addresses of workstations completing the survey; thus, duplication of ip addresses would have been identified by the researchers if respondents undertook the survey twice, for example. the authors also acknowledge that there is always the possibility that course leaders may not have distributed the survey appropriately or could have (themselves) repeated the survey, but it was felt that because of their own professional obligations and codes of ethical practice, this would have been highly unlikely. a more direct and personal approach returned a better response, yet on reflection, this could have been improved. the absence of direct academic contact information remained a major constraint for the authors. however, the information received in both quantitative and qualitative data constituted a valuable source of foundational information for larger scaled studies. finally, although attempts were made at the beginning of the survey to explain the concept of pm, it is acknowledged that perhaps a definition and a more detailed explanation of the concept would have assisted in the responses. in light of the small, but relevant findings, the following recommendations are offered: there is an opportunity for continued professional development, reflection, and debate among radiography academics whereby better understanding of pm may encourage the application of pm within course/subject areas. diagnostic radiographers may need further support and guidance when incorporating pm into their daily academic practices when compared with their therapeutic counterparts. greater understanding of pm remains central to ensure its delivery is sound and impactful within heis. a more in-depth quantitative and qualitative approach is needed with 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available at: http://societyandethicsresearch. wellcomegenomecampus.org/catalogue/socialising-the-genome-makinggenomics-resonate attitudes of publics who are unwilling to donate dna data for research current status of low dose multi-detector ct in the urinary tract optimizing contrast medium injection protocol individually with body weight for high-pitch prospective ecg-triggering coronary ct angiography improvements in cancer staging with pet/ct: literature-based evidence as of current role of fdg pet/ct in lymphoma volumebased parameters of f-fluorodeoxyglucose positron emission tomography/computed tomography improve disease recurrence prediction in postmastectomy breast cancer patients with to positive axillary lymph nodes personalized medicine: a comprehensive approach in oncology initial impact of the sequencing of the human genome a map of human genome variation from population-scale sequencing personalized medicine in oncology: ethical implications for the delivery of healthcare covid- and african americans failure to publish data on bame deaths could put more lives at risk, mps warn | world news | the guardian. the guardian new partnership to sequence human genomes in the fight against coronavirus | genomics england. department of health and social care doctors' stories: the narrative structure of medical knowledge the promise and the hype of 'personalised medicine' biomarkers and their consequences for the biomedical profession: a social science perspective nih videocast -all of us research program stakeholder briefing personalized medicine: empowered patients in the st century? key: cord- -xhem l authors: tulchinsky, theodore h. title: bismarck and the long road to universal health coverage date: - - journal: case studies in public health doi: . /b - - - - . - sha: doc_id: cord_uid: xhem l the sustainable development goals (sdgs) state that all united nations member states have agreed to try to achieve universal health coverage by . this includes financial risk protection, access to quality essential health care services and access to safe, effective, quality and affordable essential medicines and vaccines for all. universal health coverage (uhc) means inclusion and empowerment for all people to access medical care, including treatment and prevention services. uhc exists in all the industrial nations except the us, which has a mixed public-private system and struggles with closing the gap between the insured and the uninsured population. middle- and low-income countries face many challenges for uhc achievement, including low levels of funding, lack of personnel, weak health management, and issues of availability of services favoring middle- and upper-class communities. community health services for preventive and curative health services for needs in populations at risk for poor health in low-income countries must be addressed with proactive health promotion initiatives for the double burden of infectious and noncommunicable diseases. each nation will develop its own unique approach to national health systems, but there are models used by a number of countries based on principles of national responsibility for health, social solidarity for providing funding, and for effective ways of providing care with comprehensiveness, efficiency, quality, and cost containment. universal access does not eliminate social inequalities in health by itself, including a wide context of reducing social inequities. understanding national health systems requires examining representative models of different systems. health reform is necessarily a continuing process as all countries must adapt to face challenges of cost constraints, inequalities in access to care, aging populations, emergence of new disease conditions and advancing technology including the growing capacity of medicine, public health and health promotion. the growing stress of increasing obesity, diabetes, and other chronic diseases, requires nations to modify their health care systems. learning from the systems developed in different countries helps to learn from the processes of change in other countries. the world health organization (who) defines a health system as: "the people, institutions and resources, arranged together in accordance with established policies, to improve the health of the population they serve, while responding to people's legitimate expectations and protecting them against the cost of ill-health through a variety of activities whose primary intent is to improve health. it is a set of elements and their relationship in a complex whole, designed to serve the health needs of the population. health systems fulfill three main functions: health care delivery, fair treatment to all, and meeting health expectations of the population." who's world health reports ( , , ) focused on health systems financing and management in the search for universal health coverage. under the globally endorsed sdgs, universal health coverage (uhc) is designated goal (health and wellbeing), target . : "achieve universal health coverage (uhc), including financial risk protection, access to quality essential health care services, and access to safe, effective, quality, and affordable essential medicines and vaccines for all". box . outlines who building blocks for uhc. universal access is a means of assuring that the economic barrier to health care is mostly if not completely removed for the total population and may lead to increased access to medical and hospital services for those previously excluded. while uhc increases access to medical care and health indices, it does not, of itself, guarantee achievement of many important health targets. allocation of resources is an even more fundamental problem to address the needs of those with the highest risk of early disability or avoidable premature death. a system of national health must be able to allocate resources to meet those needs and must not simply be a payment system for doctors and hospitals. changing demographics, medical advances and epidemiological challenges including social and health inequalities also be addressed with high priority. this case study provides the background and experience of the development of uhc over the past century and a half, with lessons learned for consideration in how-and what-is done to achieve this goal. most industrialized countries have implemented national health programs such as health insurance systems or national health services. each system developed in the political, social, and historical context of the country-and continues to evolve. medium-and lowincome countries are also struggling to achieve universal access to care and health for all by expanding primary health care and social security plans which provide benefits to workers and for certain vulnerable populations-primarily mothers and children. as they move up the scale of economic development, developing countries must also address the problem of how to decrease morbidity and mortality, achieve equity in access to health care, and expand the funding basis for health care through national health insurance. some countries experience rapid economic development, but lag behind in directing increased national wealth towards improving health status. this is often due to a lack of focused political commitment, trained policy analysts, and cultural adaptation to the crucial importance of public health. each national health system has its own characteristics and challenges. systems management requires continuous evaluation based on welldeveloped information systems, trained health management personnel, societal involvement through all levels of government, as well as the private sector, professional organizations and advocacy groups. there is no defined "gold standard" plan for providing universal access to health care that is suitable for all countries. each country develops and modifies a program of national health appropriate to its own political and cultural needs and available resources. however, there are evolving patterns in health care organization, so that networking within and between countries ensures that they can-and do-learn from one another (box . ). barriers to necessary health care can be geographic, ethnic, cultural, social, lack of information and awareness, psychological, financial, and poverty. removing financial barriers to care is necessary and constructive, but not sufficient to address the health problems of individuals and of a society. equity in financial access with universal coverage is vital to population and individual health since anyone can have serious illness at any time. but equally important, long-term preventive care and health promotion are essential to good population and individual health standards. inequities exist in all societies, but many countries have successfully reduced these by poverty alleviation, job creation, education, and other programs that reduce interregional, socioeconomic, and demographic differences in health. special attention to high-risk groups in a population is essential. groups at-risk may be based on age, gender, ethnicity, genetic legacy, occupation, risky lifestyle, location of residence, religion, sexual orientation, economic status, or other factors that increase susceptibility to disease, premature death, or disability. services must be based on need and not only demand, which can escalate costs by over-servicing. health systems planning needs to promote access to patient care, but also those services that reach the entire population, especially people at high risk who are often least able to seek and access appropriate care. a program that provides equal access for all may not achieve the objective of better health for the population unless accompanied by other box . key elements of national health systems . a tradition of government and nongovernmental initiatives to improve health of the population. . public administration and regulation; public-private partnerships. . intersectoral cooperation with education, social services and the private sector. . demographic, economic, and epidemiologic monitoring. . health targets monitored with accessible data systems. . public health programs, including strong elements of health promotion. . universal coverage by public insurance or service system. . access to a broad range of health services. . strategic planning for health and social policies. . monitoring health status indicators. . recognition of special needs of high-risk groups and related issues. . portability and accessibility of benefits when changing employer or residence. . efforts to reduce inequity in regional and socio-demographic accessibility and quality of care. . adequacy of financing. . cost containment. . efficient use of resources for a well-balanced health system. . consumer satisfaction and choice of primary care provider. . provider satisfaction and choice of referral services. . promotion of high-quality service. . promote patient and staff safety. . comprehensive public health and health promotion programs. . comprehensive primary, secondary, and tertiary levels of medical care. . well-developed information and monitoring systems. . continual policy and management review. . promotion of standards and accreditation of services, professional education, training, research. . governmental and private provision of services. . decentralized management and community participation. . assurance of ethical standards of care for all. . conduct epidemiological, basic sciences and health systems research. . preparation for mass casualties from disasters and terrorism. important governmental, community and personal self-care activities. these include enactment and enforcement of environmental and occupational health laws, food safety, nutrition standards, clean water, improved rural care, higher educational levels, and provision of health information to the public. additional national programs are needed to promote health generally and to reduce specific risk factors for morbidity and mortality. responsibility for health lies not only with medical and other health professionals, but also with governmental and voluntary organizations, the community, the family, and the individual. individual access to an essential "basket of services" as a prepaid insured benefit is fundamental to a successful national health program. each country addresses this issue according to its means and traditions, but cost-effective evidence-based methods of meeting a countrys epidemiologic and demographic needs should be prioritized. coverage and payments for heart transplantation, for example, may be beyond the means of a health system, but early and aggressive management of hypertension, smoking, poor diet, physical inactivity, and rapid care for acute myocardial infarction are effective in saving lives at modest cost and containing the need for more intrusive health care interventions. prevention is cost-effective and should be integral to the development of service priorities within the insured benefits with incentives included in the "basket of services". globalization affects health systems around the world not only in the ease of spread of infectious diseases, but in increased access to modern preventive, diagnostic, treatment modalities. access to antiretroviral drugs has dramatically changed the face of hiv/aids globally, including in low-income countries with support of international and bilateral donors. the same is true for vaccines, including the mmr (measles, mumps, rubella, doses), hib (hemophilus influenza b), rotavirus, pneumococcal pneumonia and hpv (human papillomavirus) vaccines, which will save millions of children's lives and foster well being in the coming decade. information technology, migration of medical professionals, and internalization of educational standards are all global health issues affecting national health systems. health systems in all countries are facing common problems in population health, with rising population age, hypertension, obesity and diabetes prevalence, and rising health care costs. health systems research capacity is important in each country as it attempts to cope with rapid changes in population health and individual health needs with limited resources. development of research capacity enables improved capacity of decision-makers for informed, cost-effective decisions. in developing countries, low levels of funding for health in general-including research-impede evidence-based health system development and training of the new health workforce. strengthening reporting systems of data aggregation, as well as economic and epidemiologic analysis, are vital for health policy and management. national health systems from germany, uk, canada, us and russia are presented here as representing major models of organization. these organizational models influence health care system formulation in both developing and developed countries, as well as for countries restructuring their health services. health care systems and financing are under pressure everywhere, not only to assure access to health for all citizens, but also to keep up with advancing medical technology, and contain the cost increase at sustainable levels. because a health system is judged by more than its cost and measure of medical services, indicators of health status of the population, as well as morbidity and mortality are vital and should be available for the public through community organizations and the media. this topic has developed a complex terminology of its own. the world health organization (who) helps development of national health systems as shown in box . . universal health coverage is defined as ensuring that all people have access to needed health promotion, preventive, curative and rehabilitative health services, of sufficient quality to be effective, while also ensuring that people do not suffer financial hardship when paying for these services. g good health is essential to sustained economic and social development and poverty reduction. g access to needed health services is crucial for maintaining and improving health. g at the same time, people need to be protected from being forced into poverty because of the cost of health care. g a well-functioning health system working in harmony is built on having: trained and motivated health workers; a well-maintained infrastructure; a reliable supply of medicine and technologies; backed by adequate funding; strong health plans; evidence-based policies. who assists in creating resilient health systems by supporting countries to: g "develop, implement, and monitor solid national health policies, strategies and plans. g assure the availability of equitable integrated people-centered health services at an affordable price. g facilitate access to affordable, safe, and effective medicine and health technologies. g strengthen their health information systems and evidence-based policy-making, and to provide information and evidence on health-related matters." source: world health organization. health systems. available at: http://www.who.int/ healthsystems/about/en/ (accessed may ). health systems are meant to improve health and quality of life, as measured by quantitative and qualitative methods. the human development index (hdi) provides a standard method of comparison which combines many health and social indices into a summary figure for social development of countries. these include life expectancy at birth, gross domestic product (gdp) per capita, child mortality, education and others. table . shows life expectancy, still a valued health status indicator, for some industrialized, mid-level, and developing countries. comparisons between countries health indicators are useful to portray relative international health status among nations. the foundations of public responsibility for health care systems go back to ancient greece and rome where city states employed municipal doctors to service the poor and slaves. in the medieval and renaissance periods, monasteries and nunneries provided charitable care to the poor while professional guilds provided prepaid medical care and other social benefits to members and their families. these later evolved into the friendly (benevolent) societies, as mutual benefit programs that provided for burials, pensions, and payment for health services for members. in the twentieth century, these developed through collective bargaining into health insurance plans through private or professionally sponsored insurers, and labor unionÀsponsored health plans. governmental responsibility for health systems evolved in public health and health protection systems in the nineteenth and twentieth centuries and continues to evolve to face new challenges as well as preventive and treatment capacities. the health systems described highlight the unique and common features of national health systems in the search for "health for all", and policies for making health a priority in resource allocation, policy priority for human rights, and for socioeconomic development. figure . indicates the À trends in total health expenditures as percent of gross domestic products of selected countries in the european region of who. german and swedish expenditures rose to between % and %, in the united kingdom to over % while israel is relatively stable under % and the russian federation expenditures rose to % of gdp. germany's health care system today is characterized by participation as well as sharing of decision-making powers between the states (la¨nder), the federal government and civil society organizations. since , statutory health insurance (shi) has been mandatory for all citizens and permanent residents pay a uniform contribution of . percent of their income (gesetzliche krankenversicherung) with sickness funds (krankenkassen, january ). shi covers percent of the population, who have the right to choose their preferred sickness fund for a comprehensive range of services. the sickness funds are linked to associations of physicians accredited to treat patients covered by shi. private health insurance (phi) covers percent of the population for designated groups such as civil servants. others ( %) such as the military are included in other specific governmental programs. since the s financial incentives are being introduced to improve quality and efficiency of care along with beneficiaries right to choose between sickness funds increasing competition and a market orientation. hospitals are paid by diagnosis related groups (drgs)-i.e., payment by diagnostic category rather than hospital length of stay, adopted from us experience. physicians are paid by a capitation system-i.e., a fixed payment for each person registered for care with a doctor for a fixed period of time (as opposed to fee-for-service) in the doctor's medical associations. longterm care is covered by a federal mandatory program. germany expends . percent of gdp ( ) on health, one of the highest levels among eu members, with percent from public sources and percent privately sourced. in , germany had . acute care beds per , beds per population, nearly percent above the rate for the original eu countries ( . per , ). of these, percent of beds were in publicly owned, percent in private nonprofit, and percent in private for-profit hospitals. busse et al. ( ) describes reforms since its founding in gradually achieving universal coverage. the system is also seeking greater cost effectiveness as compared to neighboring countries. in europe, many countries developed taxation or social security models based on the bismarckian approach, with compulsory contributions by workers and their employers to a national social security system. this then financed approved services usually paid through private medical practice with fee-for-service payment. many european countries and japan gradually developed similar forms of compulsory health insurance for workers and their families following world war i, or later after world war ii, expanding to universal coverage health insurance systems. this model is used in france, belgium, the netherlands, japan, switzerland, and latin america as well as post-soviet health reforms and countries of eastern europe (cee). the israeli system, adopted in , based on the bismarckian model is mandatory national health insurance in which everyone must choose one of four long-standing sick funds now called health organizations. they compete for members, and are paid a per capita sum for which they are obliged to provide comprehensive services including hospital, primary care, and preventive services. the services improved vastly under national health insurance, with services kept up to date with annual additions to the statutory "basket of services." health statistics show israel as among the top countries for life expectancy, with rapidly falling mortality from strokes, coronary heart diseases, and cancers. consumer satisfaction is high, maternal and child health are stressed, a low hospital bed to population ratio, while health expenditures are relatively modest and a stable per capita health expenditure just under eight percent of gdp (lancet ). william beveridge was born in in bengal, india, where his father was a judge in the indian civil service. he trained as a lawyer coming to prominence in the british liberal government of À when he advised david lloyd george (chancellor of the exchequer from to , prime minister from to ) on old age pensions and national insurance. in , initiated by lloyd-george, influenced by the german compulsory health insurance scheme, the liberal government of great britain introduced the national health insurance act. it was compulsory for all wage earners between and years of age. this was a two-part plan based on a worker and employer contributory system for both unemployment insurance and for medical care for workers and their families. administration was through approved mutual benefit societies (the friendly societies), some based on insurance companies, and others by professional associations and trade unions. general practitioner services were paid on a capitation basis rather than a salary, preserving their status as self-employed professionals. initially this plan covered one-third of the population increasing to half by , however there was disruption due to mass unemployment during the great depression starting in and continuing to the late s. in the early days of world war ii, the british government established a national emergency medical service for hospitals in preparation for the anticipated large-scale civilian casualties that were expected during the blitz bombing by nazi germany. this established national health planning and rescued many hospitals from near bankruptcy due to the effects of the great depression in the united kingdom (uk). during world war ii, at the behest of prime minister winston churchill, beveridge developed a postwar social reconstruction program. the beveridge report of , social insurance and health services, outlined the concept of a future welfare state including a national health service, placing medical care in the context of general social policy for the total population. the wartime government coalition approved the principle of a national health service, which had wide public support, despite opposition from the medical association. in , the newly elected labour government of clement attlee took up the recommendations of beveridge to introduce the national insurance act ( ) as a comprehensive system of unemployment, sickness, maternity, and pension benefits funded by employers, employees and the government. the national health service (nhs) act was instituted in under the leadership of aneurin bevan, against continued opposition from medical organizations, as a universal state health service in britain. the nhs provides a nationally tax-based financed, universal coverage system providing free care by general practitioners, specialists, hospitals, and public health services. this includes diagnosis and treatment of illnesses at home or in hospital, including dental and optometric care. the original nhs structure was divided into three separate services: hospital, general practitioner, and community health services. the hospital and specialist services were under the authority of regional boards. general practitioners worked under national contracts, and community health services, such as public health, home nursing and health visitors, midwives, maternal-and child care, came under the control of the county and city local authorities. all units reported to the minister of health and his staff. the hospital bed supply in the uk in was just under half the rate in france and one third of the rate of beds in germany per , population. hospital based specialists are salaried but highly independent; general practitioners ran their own practices and provided the foundation of the nhs system. over time, this tripartite structure evolved to some degree of integration of gp and community health services, along with hospitals under hospital trusts reporting to regional health authorities. the nhs, with periodic reforms, is still in place in the uk and well accepted by the population and-over time-even by conservative governments and by the medical profession. there are differences between the nhs systems of the uk: england, scotland, wales and northern ireland each operate their own nhs, albeit with funding and structure of the central nhs. regional disparities in health indicators still exist despite changes in funding giving greater resources within regions (north-south divide) of england; each of the four has their own, policy directions. social class and geographic inequities in health within the nhs have been recognized since the s with a series of reports and analyses showing large gaps in life expectancy, avoidable (i.e., preventable) mortality between the south and north of england and even more so with scotland and significantly poorer health indicators. the marmot report on inequalities from indicated the scope of the problem: "people living in the most deprived neighborhoods will on average die seven years earlier than people living in the richest neighborhoods. even more disturbing, people living in poorer areas not only die sooner, but spend more of their lives with disability-an average total difference of years. the review has estimated the cost of health inequalities in england: productivity losses of d À billion every year; lost taxes and higher welfare payments in the range of d À billion per year; and additional nhs healthcare costs well in excess of d . billion per year." the "beveridge model" is a term used for the national health service model, which has since been adopted by many european countries and should be regarded as a strong model for countries reforming their universal health care systems, such as spain and italy. the scottish nhs diverges from the central english nhs in addressing inequalities by a focus on the health sector as the sole responsibility for reduction of inequalities. the english nhs and other government agencies see the problem more broadly and adopted poverty-fighting measures with some success in improving mortality and morbidity social and health disparities since . the nhs system remains generally popular in providing health security for all, and reaching good outcome measures despite regional inequities. no change of governing political party has led to dismantling the nhs for a privatized health system over the seven decades since its inception. canada: national health insurance tc (tommy) douglas was born in falkirk, scotland and immigrated at the age of with his working class family to winnipeg, manitoba, canada. he developed osteoarthritis and the doctors were going to amputate his leg as the family lacked funds for long-term medical care. his leg was saved by a senior surgeon who refused the amputation. this made tommy a lifelong advocate and fighter for publicly administered, universal health care for all. he became a baptist minister and entered politics winning the saskatchewan general election of for the ccf party in a massive victory. it was the first democratic socialist government elected in north america. he held the office for years, during which time he pioneered many major social and economic reforms. canada (population . million) is a federal state and a constitutional monarchy with parliamentary systems at national and provincial/territorial levels. health is primarily a provincial responsibility, but federal funding and standards play an important role in the canadian health system. local authorities also carry out many primary public health services including sanitation, water safety, and supervision of food safety, among other responsibilities. the provinces/territories are responsible for the funding of hospital, community, home and long-term care, as well as mental and public health services. starting in the s, federal grants-in-aid were given to the provinces/ territories for categorical health programs, such as cancer and public health services programs. since the sars (severe acute respiratory syndrome) epidemic in , the canadian federal government has increased its capacity in public health with a new federal department of public health, regional laboratories and encouragement of many schools of public health across the country. canada's national health program evolved as a system of provincial health insurance with federal government financial support and standards. initiatives for national health insurance in canada go back to the s, but definitive action occurred only after world war ii. the federal government regulates drug and medical device safety, funds research and provides services to the native indigenous population groups, the military, rcmp (royal canadian mounted police) and federal prison inmates. services for veterans were later transferred to provincial medicare programs. the development of national health insurance was largely due to the bitter experience of the great depression of the s, a strong agrarian cooperative movement, and the collective wish for a better society following world war ii. in , the social democratic cooperative commonwealth federation (ccf) party under the leadership of tommy douglas formed the government of saskatchewan, a large wheat-growing province of one million people on the western prairies. the national universal health insurance program evolved from the provincial initiatives led by tommy douglas, now considered "the father of canada's universal medicare plan." douglas established the saskatchewan hospital insurance and diagnostic services act in under provincial public administration. in a federal cost-sharing formula began providing approximately percent cost-sharing with greater levels of funding going to the poorer provinces. by , all provinces and two territories had implemented hospital insurance plans, in a twotiered national health insurance plan-i.e., universal provincial/territorial health plans with federal standards and cost-sharing. in , again in saskatchewan, the medical care insurance plan (medicare) was implemented after a bitter doctors' strike. in , the federal government appointed a royal commission on health services (the hall commission) which in recommended adoption of the saskatchewan model across the country with federal support and standards. the saskatchewan plan was rapidly followed by similar plans in other provinces encouraged by generous federal costsharing. the federal government cost-shares provincial and territorial programs. provinces/territories must adhere to the standards of the canada health act ( ), which defines services to be covered for hospital, diagnostic, and physician services. there is federal funding support for provincial/territorial public health, long-term care, home care and community mental health services. this federal legislation was expanded to provide co-funding for provincial/territorial medicare plans, which over a short period brought all canadians into provincially administered systems of publicly financed health care, while retaining the private practice model of medical care. hospital care is provided mostly through non-profit, non-governmental hospitals. developed over the period À , the provincial/territorial health insurance plans were promoted by federal governmental cost-sharing, political support, and national standards. the plans were initially financed by taxation and premiums, but later solely by general tax revenues with federal support under the canada health act of . federal standards required the provincial plans to be: publicly administered; comprehensive in coverage of health services; universal; portable across provinces; and, accessible without user fees. federal reimbursement to the provinces/territories initially covered percent of national average medical care expenditures per capita and percent of the actual expenditures by each individual province. this provided higher-than-national-average rates of support to poorer provinces as well as portability between provinces/territories. by , all provinces had implemented such plans, and a high degree of health services equity was achieved across the country. care is provided by private medical practitioners on a fee-for-service basis under negotiated medical fee schedules with no extra billing allowed. hospitals are operated by nonprofit voluntary, religious organizations or municipal authorities, with payment by block budgets. per capita spending on health in canada is relatively modest in comparison with that of the us, but above oecd averages. public spending as a percent of total health expenditures is close to the oecd average (see box . ). this medicaretype plan was later adopted in a number of other countries including australia. medicare is still popular in canada, with support from all political parties and by most medical professionals. medicare and federal cost-sharing weighed in favor of the poorer provinces, allowing these to catch up in health care services and standards with the richer provinces. the canadian health program differs substantively from those of the united kingdom and the united states. health systems are important in the political and cultural life of a country. each within its own tradition is attempting to ensure population health through public or private means, to constrain the rate of cost increases. comparisons using various health indicators can be controversial, but the canadian universal health service or insurance coverage seems to have improved the health status of the population more rapidly than similar indicators for the total us population, but not necessarily for all segments of the population. after decades of focus on developing national health insurance, canada became a leading innovator in health promotion prevention (see chapter ) . the canadian health program established universal coverage for a comprehensive set of health benefits without changing the basic practice of medicine from individual medical practice on a fee-for-service basis. poorer provinces were able to use the federal cost-sharing mechanism to raise standards of health services, and a high degree of health services equity was achieved across the country. rapid increases in health care costs led to a review of health policies in (the federalÀprovincial committee on the costs of health services). the resulting report stressed the need to reduce hospital beds and develop lower-cost alternatives to hospital care, such as home-based care and long-term care. federally-led initiatives during this period extended coverage to include home-based care and long-term nursing home care, while restricting federal participation in cost-sharing to the rate of increases in the gross national product (gnp). since then, many provincial and federal reports have examined the issues in health care and recommended changes in financing, cost-sharing, hospital services, development of primary care, and other community services. in , a new approach to health was outlined by the federal minister of health, marc lalonde, in a landmark public policy document, a new perspective on the health of canadians. this report described the health field theory in which health was seen as a result of genetic, lifestyle, and environmental issues, as well as medical care itself. as a result, health promotion became a feature of canadian public policy, with the objective of changing personal lifestyle habits to decrease cross-cutting risky behaviors such as smoking, obesity, and physical inactivity. the pioneering work in nutrition from the national nutrition survey published in led to the adoption of federal mandatory enrichment regulations for basic foods with essential vitamins and minerals. this and other initiatives in the s led to the ottawa charter on health promotion (see chapter ) , which has had a global impact with the foundation of health promotion as a crucial new aspect of public health and health system policy. the canadian health system being primarily the responsibility of the provinces/territories had a down side. during the sars pandemic of , the provinces dealt with it and were found to be lacking strong public health institutions adequate to the task. following high level reviews of the sars episode the federal government established a cdc-like institution, regional laboratories capable of infectious disease challenges and eight schools of public health across the country to ensure continuing development of a competent public health workforce. universal health care needed to be supplemented by introduction of lalonde-initiated health promotion and equally so a strong microbiologic public health component to ensure rapid and competent responses to new emerging health challenges. how does the canadian public view the universal public single payer medicare run by the provinces with federal guidelines and cost-sharing program? despite complaints, mostly from us sources, the canadian public appreciates their health protection very much. in , the canadian broadcasting corporation (cbc) television conducted a program over many months called "the greatest canadian," with candidates and advocates. this included a call to all people in canada to nominate their greatest canadian. canadians from coast to coast were asked to vote and chose tommy douglas, known as the "father of medicare" and selected by national polling as "the greatest canadian of all time." the canadian public is proud of their medicare plan, and appreciates the security and social protection as a great achievement for everyone in the country. australia, taiwan, and south korea have adopted national health insurance systems similar to the canadian model. the us (population million, gdp per capita usd $ , in ) has a system of government based on the federal constitution, with states each having its own elected government. the constitution gives primary responsibility for health and welfare to the states, while direct federal services are provided to armed forces, veterans, and indigenous (native) americans. the federal government has established a major leadership role in national health by the development of national standards, national regulatory powers, funding, and information systems. the federal level has many governmental structures for regulation of food, drugs, and environment, as well as for research, public health services, training programs and health insurance systems for the elderly and the poor. the us has the world's costliest health care system with over percent health insurance coverage, but universal access remains elusive, and population health indicators are well below many less-wealthy countries. however, the us has through trial and error experimentation made major contributions to the content and organization of public health systems, which are important for strengthening health systems in medium-and low-income countries as well as influencing countries with universal health systems (see chapter ) . clearly, the us can learn from other countries as well (see box . ) . in , the federal government established the us marine hospital service to provide hospitals for sick and disabled merchant seamen. this later became the uniformed us public health service commissioned corps (usphs) headed by the surgeon general ( ). services were added for native americans, military personnel and their families (through the veterans affairs department), the food and drug administration (fda), the national institutes of health (nih), the centers for disease control (cdc) and many other world class federal programs of research, service and teaching. other departments and legislation were added to promote nutrition and hygiene, establish state, municipal, and county health departments, and regulate drugs and health hazards. in , the sheppard-towner act established the federal children's bureau that administered grants to assist states to operate maternal and child health programs. from the s, labor unions won health insurance benefits through collective bargaining, which became the main basis for prepayment for health care in the united states until today. in , the committee on the costs of medical care recommended a universal national health program. this initiative was set aside during the great depression of À . the us social security act (ssa) of was introduced by president franklin d. roosevelt as part of the "new deal" to alleviate the mass suffering of the people during this very traumatic period in the us (and europe). the ssa was intended to include national health insurance, but this part of the ssa was set aside largely due to strong opposition of the insurance industry and the organized medical profession. the ssa provides financial benefits for widows, orphans, and the disabled, as well as pensions for the elderly, and provided a base for future reform including health insurance. with the outbreak of world war ii, a significant percentage of eligible military recruits were found unfit for compulsory service due to preventable health conditions. this, and the wish to maintain population health, led president roosevelt to initiate regulations in for fortification of "enriched" foods reaching a majority of the population including salt with iodine, flour with iron and vitamin b complex, and milk with vitamin d. during world war ii ( À ), governmental health insurance was provided to many millions of americans serving in the armed forces, along with their families. at the same time, health benefits through voluntary insurance for workers were vastly expanded in place of wage increases and this became the major method of prepayment for health care for a majority of the population. at the end of the war, millions of veterans were eligible for health care through the veterans administration (va), which established a national network of federal hospitals and primary care services. in , president truman attempted to bring in national health insurance, but the legislation (the wagner-murray-dingell bill) failed in the us congress. one section of the bill was approved, enabling the federal government to initiate a program to upgrade country-wide hospital facilities, while limiting the beds to population ratio, under the hill-burton act (see chapter ) . legislation also provided massive federal funding for the newly established national institutes of health (nih) to fund and promote research to strengthen public and private medical schools, teaching hospitals, and research facilities. in , president truman established the federally-assisted school lunch program through the department of agriculture bringing nutritious meals to many (millions increasing from million in to million in ) of school children throughout the us. in the s, the federal government also established the centers for disease control and prevention (cdc) and increased assistance for state and local public health activities and encouraged expansion of schools of public health across the country. in the us during the s through to the s, rapid health cost increases were attributed to many factors including the lack of a national health insurance mechanism. the plethora of health insurance systems fostered high costs and restrictions on access due to pre-existing conditions. other factors for rapid cost increases included an increasing elderly population, high levels of morbidity in the poor population, the spread of aids, rapid innovation and costly medical technology, specialization, high laboratory and diagnostic imaging costs, and large-scale public investment in medical education, research and health facility construction. the us system includes a mix of public health insurance and service programs (medicare, medicaid, veterans administration, indian health services, and military health coverage) which provide for a significant part- . percent in -of the us population. however, the majority ( %) is covered by the private insurance industry through employer-employee contracts which developed rapidly as the dominant health insurance sector with minimal government regulation. the cost of private health insurance to employers included in labor contracts of their employees and pensioners has become very high. in , general motors reported to a senate hearing that the cost of health insurance per car produced was double the direct cost of labor and more than the cost of steel per car. this impinged on competitiveness in price with for example with japan which has a successful universal governmental health insurance plan with public-private mix of services. the affordable care act (aca) introduced by president barack obama in brought some million previously uninsured persons into public and private insurance, increased governmental regulation to ensure fair pricing and payment and, especially, to abolish the past abuses of the "pre-existing condition" exclusions from insurance. other equally important factors were high levels of preventable hospitalization, institutional orientation of the health system, high administrative costs due to multiple private billing agencies in the private insurance industry, high incomes especially for specialist physicians, and high medical malpractice insurance costs. the pressure for cost constraint came from government, industry, and the private insurance industry. (see chapter ). private medical practice, with payment by fee-for-service, was the major form of medical care in the us until the s. most hospitals were operated through a mix of nonprofit agencies, including federal, state, and local governments, and voluntary and religious organizations, but a growing percentage are privately owned, for-profit (from . % of beds in to . % in ). in an effort to contain costs, the diversity of insurance systems promoted experimentation with organizational systems. health maintenance organizations (hmos) and other forms of managed care systems grew rapidly to become the predominant method of organizing health care in the united states. prepaid group practice (pgp) originated from private companies contracting to provide medical care, especially in remote mining camps and construction sites. in the s, new york city sponsored the health insurance plan of greater new york to provide prepaid medical care for residents of urban renewal and low-income housing areas. this was later extended to include organized union groups such as municipal employees and garment industry workers. pgp became best known in the kaiser permanente network developed for workers of henry j. kaiser industries, at the boulder dam and grand coulee dam construction sites in the s. kaiser permanente health plans now provide care for millions of americans in many other states. initially opposed by the organized medical profession and the private insurance industry, pgp gained acceptance by providing high-quality, less-costly health care. this became attractive to employers and unions alike, and later to governments seeking ways to constrain increases in health costs. since the s, the generic term health maintenance organization (hmo) was promoted by the federal government in the hmo act by president richard nixon in . hmos, which operate their own clinics and staff (i.e., the staff model), or through contracts with medical groups as preferred provider organizations (ppos), have become an accepted, if criticized, part of medical care in the united states and an important alternative to fee-for-service, private practice medicine. in , . million americans were registered in hmo plans or . percent of the total us population. in recent years, the terms accountable care organizations (aco), patient-centered medical home (pcmh) and population health management system (phms) have come into wide use to denote organizations that take responsibility for comprehensive care for enrolled patients, with payment based on a form of capitation rather than fee-for-service. acos are present in all states, washington, dc, and puerto rico, with the population covered increasing from . million in to . million in . the aco comes in different models, but many include a hospital base and may be linked to independent practice associations (ipas), and specialty groups, or hospital medical staff organizations, or in a network of hospitals linked with other providers as an organized delivery system. these are not-for-profit group practices led by doctors who are salaried and subject to rigorous annual professional review. this model may be adaptable on a wider scale to improve quality and cost effective care to improve health of americans. in , a prospective payment system, called diagnosis-related groups (drgs), was adopted for medicare, to encourage more efficient use of hospital care, with payment by categories of diagnosis. the drg is a classification system, for inpatient stays, categorizing possible diagnoses into more than major body systems and subdivides them into almost groups for the purpose of medicare reimbursement. this replaced the previous system of paying by the number of hospital days, or per diem or by itemized billing which encouraged longer hospital stays. drgs provided incentives for hospitals to diagnose and treat patients expeditiously and effectively. payment for medicare and medicaid patients shifted to this method placed the public insurance plans in a stronger position for payments to hospitals. in many states this has also become standard for patients with private health insurance as well. during the late s, the term managed care was introduced, expanding from hmos of the kaiser permanente type to include both non-profit and for-profit systems. these include independent practice associations (ipas), which operate with physicians in private practice, and preferred provider organizations (ppos), which provide insured care by doctors and other providers associated with the plan to the enrolled members or beneficiaries at negotiated prices. the drg payment system and hmos or managed care systems reduced hospital utilization. while total costs of health care increased in this period, without reduction of hospital utilization the increase would have been considerably higher. in , president clinton tried to introduce a health plan based on federally administered compulsory universal health insurance through the place of employment. a state could opt to form its own health insurance program including through its own department of health. physicians could contract with health insurance plans to provide care on a fixed-fee schedule, or in hmos, whether based on group or individual practice. the clinton health plan failed in congress mainly due to well financed opposition by the insurance industry and the organized medical community. in addition, opposition was also widespread among the majority of the population who already had good insurance benefits under their employment-based health insurance plans or medicare. their interest was in keeping the status quo so that the bill was defeated. following the failure of the clinton national health insurance proposal, managed care experienced tremendous growth. managed care systems have been able to cut costs in health care in ways that the us government could not. in the us as a whole, in addition to the nearly million persons enrolled in hmos, another million persons are enrolled in ppos, with percent of medicaid and percent of medicare beneficiaries in various "managed care plans". the search for cost containment led to the development of a series of important innovations in health care delivery, payment, and information systems. hmos demonstrated that good care provision can be operated efficiently with lower hospital admission rates than care provided on a fee-for-service basis. the managed care systems brought about profound changes in health care organization in the united states. in , president barack obama established the patient protection and affordable care act/health care and education reconciliation act of , widely known as the affordable care act (aca or obamacare) bringing health insurance to millions of previously uninsured americans when it went into effect in (see box . ). the aca requires most companies to cover their workers, and mandates that everyone has coverage or pay a fine. aca also requires insurance companies to accept all newcomers, regardless of any preexisting conditions, and assists people unable to afford insurance. this legislation covers young people under their parents' health insurance plans until the age of , covering . million young americans. it eliminated other limits on coverage, allowing those who had already reached a lifetime limit to be eligible for coverage. the affordable care act introduced discounts as large as percent for pharmaceuticals for seniors. health care reform is currently a contentious issue with the donald trump government planning to repeal the obama health care reforms to be replaced with a plan still under development. us health care spending increased from . percent of gdp in to . percent in , threatening the ultimate insolvency of medicare and cutbacks in medicaid in the near future. lack of universal access and the empowerment it potentially brings encourages an alienation or non-engagement with early health care for the socially disadvantaged sector of the population. this promotes inappropriate reliance on emergency department care and hospitalization in response to under-treated health needs. with large numbers of uninsured persons and many others lacking adequate health insurance, access and utilization of preventive care are below the levels needed to achieve social equity in health in the us. this is especially true for maternal-and child-health and for chronic diseases such as diabetes, hypertension, cancer, and heart disease. infant mortality rates in the united states vary greatly by race and ethnicity. as measured by the infant mortality rate, the rate among non-hispanic black mothers was . times higher than the rate for white non-hispanic mothers. a significantly higher rate of infant mortality exists among puerto rican and american indian populations compared with the national average. cdc reports that maternal mortality rates have increased in the united states between and from . to . per , live births possibly due to changes in reporting and increase in chronic illnesses and influenza during pregnancy particularly in the african american population. in , the department of health and human services (dhhs) released healthy people with two main goals: "increase the quality and years of healthy life" and "eliminate health disparities." these goals focus on specific areas developed by over national membership organizations and state health, mental health, substance abuse, and environmental agencies. many states have adopted use of these targets as their own measures of health status and performance. the us public health service, in cooperation with the national center for health statistics, regularly make available a wide set of data for updating health status and process measures relating to these national health goals. various preventive health initiatives are in place to try to alleviate health disparities, which successfully improved immunization coverage of us infants to meet national health targets, as well as for lead and other efforts directed toward poor population groups. in , a program called racial and ethnic adult disparities in immunization initiative was introduced in order to improve influenza and pneumococcal vaccinations among minorities aged and over. the us department of agriculture's women, infants and children (wic) program enables millions of poor americans to have good nutritional security. the wic program covers pregnant women, breastfeeding women (up to infant's first birthday), non-breastfeeding postpartum women (up to months after the birth of an infant or after pregnancy ends) and infants and children (up to their fifth birthday). wic serves percent of all infants born in the united states. the benefits include: supplemental nutritious foods, nutrition education and counseling at wic clinics, screening, and referrals to other health, welfare and social services such as completion of immunization and special needs counseling. school lunch programs are widespread under a federally assisted meal program operating in over , public and non-profit private schools and residential child care institutions, providing nutritionally balanced, low-cost or free lunches to more than million children each school day in . nutrition support for pregnant women and children in need, alleviates some of the ill effects of poverty in the united states, but lack of health insurance affects these groups severely especially in chronic disease, trauma, and other diseases of poverty. health disparities are a complex problem that goes beyond the issue of uninsured americans. low-income and illegal immigrants face challenges to access medical insurance. new immigrants must wait five years before they are eligible for medicaid. the structure of the medical system plays an important role in an individual's ability to obtain medical care. this includes convenience of making an appointment, office hours, waiting times, and transportation. a lack of health literacy also plays a role in an individual's ability to seek medical attention. individuals not fluent in english experience communication gaps. in , it was estimated that an excess of usd $ billion a year is spent on health care in the united states as a result of low health literacy. in certain areas of the country, medical facilities are scarce. minorities are under-represented in medical professions. black, latino, and native american populations make up approximately six percent of the physician workforce, although these populations represent over percent of the population in the united states. health disparities remain an important social and political issue in the united states. the office of minority health (omh) of the department of health and human services was established in to address issues of health disparities among racial and ethnic minorities. important health disparities exist in america in relation to region of residence, with the southern states having high rates of obesity, stroke, and coronary heart disease mortality, which are thought to be due to customary diets rich in fatty and salty foods. state health departments will need to address these issues in order to reduce gaps in life expectancy due to lifestyle factors which are grounded in tradition and poverty as well as lack of health insurance. one of the main goals of healthy people is to eliminate health disparities. the us has developed extensive information systems of domestic and international importance. the cdc publishes the mmwr (morbidity and mortality weekly report), which sets high standards in disease reporting and policy analysis. the us national center for health statistics (nchs), the health care financing administration (hcfa), the us public health service (usphs), the food and drug administration (usfda), the national institutes of health (nih), and many nongovernmental organizations (ngos) carry out data collection, publication, and health services research activities important for health status monitoring. national nutrition surveillance and other systems of health status monitoring are reported in the professional literature and in publications of the cdc. national monitoring of hospital discharge information facilitates the understanding of patterns of utilization and morbidity. these information systems are vital for epidemiologic surveillance and managing the health care system. us surgeon general reports have an important influence on health systems not only in the united states, but also internationally. the cdc created the national center for public health informatics (ncphi) in to provide leadership and coordination of shared systems and services, to build and support a national network of integrated, standards-based, and interoperable public health information systems. this is meant to strengthen capabilities to monitor, detect, register, confirm, report, and analyze data, as well as provide feedback and alerts on important health events. this will enable partners to communicate evidence that supports decisions that impact health. electronic medical and personal health records are now widely used. these protect patient privacy and confidentiality, and serve legitimate clinical and public health needs. media coverage of health-related topics is extensive, and is important to promote health consciousness in the public. however, the sheer volume of information may make it difficult to discern which information is most relevant, and due to misinformation on internet sites, can also create opposition to public health initiatives such as the refusal to vaccinate children. public levels of health knowledge grow steadily, but vary widely by social class and educational levels. in , the us surgeon general's report healthy people set a series of national health targets for a wide variety of public health issues. the program defined objectives in program areas within the three categories of prevention, protection, and promotion. these goals and objectives were formulated based on research and consultation by experts in different fields who participated in a conference by the us public health service. consensus is based on position papers, studies, and conferences involving the national governmental health agencies, the national academy of science institute of medicine, and professional organizations such as the american academy of pediatrics (aap), the us preventive health services task force, and the american college of obstetrics and gynecology (acog). many private individuals and organizations contribute to this effort, including state and local health agencies, representatives of consumer and provider groups, academic centers, and voluntary health associations. these targets are periodically assessed as performance indicators of the us health system and then updated. progress made during the s included major reductions in death rates for three of the leading causes of death: heart disease, stroke, and unintentional injuries. infant mortality decreased, as did the incidence of vaccine-preventable infectious diseases. the latest iteration, healthy people , identifies national health priorities. it strives to increase public awareness and understanding of the determinants of health, disease, disability, and opportunities for progress. it defines measurable objectives and goals for federal, state, and local authorities in the areas of health promotion, health protection, preventive services, surveillance and data systems, and age-related and special population groups. the final reviews of healthy people showed significant decreases in mortality from coronary heart disease and cancer. healthy people renews this effort to establish national targets which are adopted by state level governments and strongly influence policy in health insurance systems. the us has managed to achieve many of the targets set by the surgeon general's healthy people report. at the same time, the average annual increases in health care expenditures in the united states slowed markedly from the À period with average annual increases of . percent, falling to under percent annually between and . this is partly due to lower general inflation rates (, %), but also cost-containment measures being adopted by government insurance (medicare and medicaid) programs, the health insurance industry, the growth of managed care, and rationalizing the hospital sector by downsizing and promoting lower-cost alternative forms of care. national health insurance was delayed by congressional rejection of the clinton health plan. president barack obama's affordable care act (aca) provided millions of previously uninsured americans health insurance within better regulated private insurance or in state-run medicaid plans, but in is facing "repeal and replace" efforts by the president trump administration and republican congress. a number of possibilities exist to extend health insurance coverage: state health insurance initiatives with federal waivers and cost-sharing; a federal single payer universal coverage plan based on the federal medicare model or a federal-state medicaid model. the us health system is often called a costly and inefficient nonsystem. there are many stakeholders and providers, high costs, and poorer population health results than those achieved in other industrialized countries such as britain, germany, and canada. the health system is diffused with high levels of coverage for diverse insurance plans through employment-based insurance along with publicly financed and administered health insurance (e.g., medicare, medicaid, aca). inequalities are a significant health challenge in the us along with the uninsured, poverty, aging of the population, rising levels of obesity and diabetes. the principle of universal access through public insurance for all is still a highly politicized issue in the united states, although public acceptance seems to be gradually growing. the us has a reputation for good to outstanding quality of medical care, but for those without insurance, services are limited to hospital emergency care only. important ethnic, social, and regional inequities in health status are still present, but not necessarily greater than in countries with universal access health care plans such as the uk nhs. further, there are many parallel programs in the united states that have important positive public health content, such as universal school lunch programs, nutrition support for poor women, infants, and children (the wic program); food stamps for the working poor; fortification of basic foods, free care for the uninsured in emergency departments, medicare for the elderly, medicaid for the poor, and aca coverage for the near-poor. box . shows the challenges of the us health system. despite rapid increases in health care expenditures during the s and s, despite improved health promotion activities and rapidly developing medical technology, the health status of the american population g preventive programs strong tradition; screening for cancer; smoking reduction; food fortification, school lunch programs; nutrition support for poor pregnant women and children (wic); g hospitals obliged to provide emergency care to all regardless of insurance status, citizenship, legal status or ability to pay has improved less rapidly than that in other western countries and universal coverage has not been achieved. us performance measures are lower than many middle-and high-income countries with much lower per capita health expenditures, including measures such as infant mortality rates and life expectancy. infant mortality in the us remains high in comparison to oecd countries and ranks th among all countries in (estimated). even the rate of infant mortality of the white population of the united states was higher than that of countries that spent much less per person and a lesser percentage of gnp per capita on health care. life expectancy at birth in the united states in was below that of countries, just behind costa rica, portugal and slovenia. in , the us life expectancy at birth was . years, well below the oecd average of . years. social inequities in these health status indicators are further evidence of failures of the united states health system to reach its full potential, despite its being the costliest system in the world and its high quality for those with access (commonwealth fund, ) . the advent of the aca (obamacare) introduced in brought health insurance to millions of americans, but is challenged as unaffordable. the us still lacks a universal single payer health plan of canadian or european tradition, but the aca is a huge step forward in america where the working poor are in large measure excluded from access to health care except for emergencies. the struggle for universal access and cost containment are still formidable political and societal challenges for the united states. in , following the russian revolution, the soviet union (ussr) introduced its national health plan for universal coverage within a state-run system of health protection. the soviet model, designed and implemented by nikolai semashko, provided free health care for all as a governmentfinanced and -organized service. it brought free health services to the population, with a system of primary-and secondary-care based on the principles of universal and equitable access to care through district organization of services. it achieved control of epidemic and endemic infectious diseases and expanded services into the most remote areas of the vast under-developed country. this model was also applicable in countries included in the ussr following world war ii until the collapse of the ussr. the model developed in the former soviet union in by semashko brought free health care with governmental management by republic and regional authorities according to national norms set out by the ministry of finance. since the s health care became available for all with mostly underdeveloped basic infrastructure for health care including human resources. the semashko plan provided universal access to preventive and curative care, and control of infectious disease in a uniform plan, with many republics previously having only primitive care available, achieving national standards of services and improved health indicators. since the s, an "epidemiologic transition" was occurring characterized by declining mortality from infectious diseases and rising death rates from non-infectious diseases. life expectancy increased since , still remains far below levels in many medium-income developed countries. the transition in health systems following the collapse of the soviet union in took different paths for the socialist central and eastern european countries (cee) as compared to the core countries of the soviet union, called the commonwealth of independent states (cis). the cee countries moved rapidly to dismantle their soviet, centrally managed sanitary-epidemiological system (sanepid) system with decentralization while retaining universal coverage with central funding, but with local authority participation in some cases. most cee and cis countries have introduced health insurance systems, with more out-of-pocket payments (both formal and informal), and efforts to strengthen primary health care, with family medicine delivered by general practitioners. in most cases central authorities also maintained responsibility for epidemiological surveillance and environmental monitoring with some transferring responsibilities for environmental health in other ministries. the cee and cis countries maintained similar levels of health expenditures as percent of gdp between six and seven percent over the past decade, while the original european union (eu) countries reached an average of percent of gdp. the cis acute care hospital bed capacity ratio declined to six per population in far higher than cee countries (declined to . per ), which were higher than the western countries, although all country groups were declining (see chapter ) . the importance of these differences lies in the fact that total resources allocated for health in the soviet system was relatively low while the allocation allowed hospital care to consume some percent of total expenditures compared with less than percent in western countries. the outcome of this allocation of resources was weakness in development of primary care, prevention and community care in favor of an over-developed hospital bed supply. the russian federation adopted a mandatory health insurance (mhi) plan in to open up additional funding for health care in the face of severe governmental funding constraints. it remains a highly centralized system and is struggling to provide universal access to basic care. despite this, death rates from avoidable causes such as stroke and coronary heart disease have declined in the past decade and life expectancy has risen modestly, but remaining far below western as well as former socialist countries of central and eastern europe. developing national health systems with universal access has been a long process in high-income countries and is an important goal for all countries including medium-and low-income countries to promote improving access to health for the total population. the commonwealth fund published an outstanding international profile of selected health care systems in highincome countries ( ) including: australia, canada, china, denmark, england, france, germany, india, israel, italy, japan, the netherlands, new zealand, norway, singapore, sweden, switzerland, and the united states. global spending on health is expected to increase from us$ . trillion in to $ . (uncertainty interval . À . ) trillion in (in purchasing power parity-adjusted dollars). we expect per-capita health spending to increase annually by . % ( . À . ) in high-income countries, . % ( . À . ) in upper middle-income countries, . % ( . À . ) in lower middle-income countries, and . % ( . À . ) in low-income countries. low-and medium-income countries face major difficulties in developing universal health coverage, especially in terms of financial and professional resources. a study of global health care financing (dielman et al lancet ) reported on health expenditures from countries, including public, donor, and private ("out of pocket") payments between and . high-income countries spent more, and mostly from public sources, increasing expenditures by an estimated three percent per year. medium income countries increased their health spending more than three-four percent per year and low-income countries by two percent. economic development was positively associated with total health spending and a gradual shift away from a reliance on development assistance and out-of-pocket spending towards government spending. in , . percent of all health spending was financed by the government, although in low-income and lower-middleincome countries, percent and percent of spending was out-of-pocket, . percent and three percent respectively was with development assistance. recent growth in development assistance for health has been tepid. between and , it grew annually at . percent, and reached usd $ Á billion in . nonetheless, there is a great deal of variation revolving around these averages. in countries spending less than five percent of gdp on health, included many in asia, the middle east and sub-saharan africa (institute of health metrics and evaluation, ). while there is wide variation in health spending in low-and lowermiddle-income countries and there is overall increased spending in absolute terms, there is still a heavy reliance on out-of-pocket spending and development assistance, which itself is growing very slowly. this indicates that medium-and low-income countries are not providing the financial means to develop universal health access insurance plans. economic growth also does not translate into adequate funding for universal health care without dramatic changes in policy and decreased dependency on donor aid. international agencies-such as who-are promoting the search for ways to provide universal and equitable care, while controlling costs and improving efficiency in low-and middle-income countries. the universal declaration of human rights, article states: "( ) everyone has the right to a standard of living adequate for the health and well-being of himself and of his family, including food, clothing, housing and medical care and necessary social services, and the right to security in the event of unemployment, sickness, disability, widowhood, old age or other lack of livelihood in circumstances beyond his control. ( ) motherhood and childhood are entitled to special care and assistance. all children, whether born in or out of wedlock, shall enjoy the same social protection." the universal declaration of human rights specific inclusion of access to medical care for all should be seen as a priority in planning universal health insurance (uhi) for promotion of access to health needs for remote rural populations as well as urban poor, and displaced persons. this also applies to conditions of warfare, civil strife, natural disasters as well as incitement to and actual genocide. as said previously, the global consensus of the mdgs ( À ) and the sdgs ( À ) have undertaken to implement key elements of this important declaration. it is easier to be pessimistic than optimistic in the potential for success, but the significant achievements of the mdgs in poverty reduction, educational equity between the genders and in reduction of child and maternal mortality as well as in control of hiv, malaria and tuberculosis are signs of important progress and future possibilities. national governments must take up the financial burdens and management of expanding health systems as well as contributory advances in education, environment and other government sectors toward achieving these goals. bilateral aid and international donors are vital, but they cannot achieve or sustain all this without national commitments and resources. national health systems are essential to provide universal access to health care, but must be developed recognizing that restraint in increasing costs, equity in access and quality, as well as efficiency and effectiveness in use of resources are vital to achieve health targets and equity in population health. in the united states, a study of ethnic differences in utilization of services among medicare beneficiaries who have the same entitlements show significant differences indicating lesser use of preventive services such as mammography and higher rates of lower limb amputation for diabetes indicating poorer management of diabetes. studies in the united kingdom also show sharp differences in mortality rates by region of residence that correlate with socioeconomic gradations. universal access alone does not guarantee equality so that the design of service systems needs to take into account differing needs of groups or regions at higher risk and greater need. universal access by itself is important, but not sufficient to reduce inequalities, which have more complex needs than medical care alone. universal coverage health insurance must be developed with great care to avoid mistakes made in many countries in previous decades of promoting rapid increase in health expenditures to the benefit of the middle class while rural and poor urban populations linger in relatively poor health. a universal health insurance plan without strong incentives for prevention and community health will find itself in a trap of punishing the poor for the benefit of the rich. population health experience of the past century has shown the power of public health, in all its aspects, to raise life expectancy and quality, yet inequalities still plague all health systems. this provides an ethical challenge in planning, resource allocation and political support. beyond financing and resource allocation, there are many "nontariff" barriers to health. even in highly developed national health systems, social class, place of residence, education level, and ethnicity play significant roles in morbidity and mortality rates. addressing important health risk factors other than medical or hospital care is vital. the disease-risk factors of diet, smoking, physical fitness, nutrition status including obesity, and untreated hypertension. such conditions are not necessarily managed even where all residents of a country are insured for health care. social class, ethnic and regional differences in morbidity and mortality exist due to povertyassociated factors, such as insecurity, lack of control over one's life, lack of financial means or knowledge to purchase healthy foods, as well as fear, loneliness and depression. these are issues that are important and must be addressed in public health policy to reduce inequalities in health and the achievement of national health goals and equity. models of financing of universal health insurance include a variety of methods: general taxation; social security by employee-employer payments through payroll deductions; private insurance under contracts between employee and employer; and private out-of-pocket payments. taxation financing can be mainly through progressive income tax, resource taxes, surcharges or "sin taxes" (e.g., on cigarettes, alcohol, gasoline) and excise taxes along with local property and business licensing taxation where local authorities have a management role. funding by general tax revenues at national or state levels or shared between the two levels provides for more local administration while sharing in costs may be the most equitable way of raising funds. many countries use social security systems based on employerÀ employee contributions to pay for health services. the who, the world bank and oecd promote universal health insurance (uhi) for middle-income countries. the advantage will be to reduce the heavy burden of out-of-pocket payments, which are percent of health expenditures in many emerging countries. universal health insurance provides security for individuals and families against catastrophic health events, for regular medical and hospital care, and for ageing populations with increasing health needs. oecd recommends increasing health expenditures, which improves life expectancy, and to allow uhi implementation. even a percent increase in national health spending has been shown to reduce child mortality across many countries. universal health insurance must include promotion of greater efficiency in health care, such as shifting of services from hospital care to outpatient and primary care along with community and home-based care (see chapter ) . the process requires developing new health care provider roles with emphasis on outreach to groups with greater than average need, promoting public health and preventive care such as for underserved rural or urban communities or groups at special risk for disease such as cardiovascular disease (cvd) and diabetes, making use of epidemiologic and sociologic health data and information systems. universal health insurance undoubtedly contributes to improving health indicators such as life expectancy by coverage of the total population, systematizing financing of the health system and providing access to the population. however, without good management of resource allocation, universal health insurance cannot guarantee achievement of important health targets. allocation of resources is a fundamental problematic aspect of universal health insurance. national health policy governing universal health insurance must invest adequately in health promotion and disease prevention in order to reduce excessive allocation and utilization of hospital care. continuous monitoring and evaluation are essential to a health system, but not only for traditional outcome indicators, such as infant, child and maternal mortality rates, and disease-specific mortality rates. these are all valuable indicators of population health, but not sufficient. input, process and outcome indicators are important and necessary to include, such as supply and distribution of resources e.g., primary care, maternity centers, hospital beds; process measures e.g., immunization rates, incidence of vaccine-preventable diseases, growth patterns and anemia rates in infancy and childhood, food fortification, micronutrient supplements to risk group, prenatal delivery and neonatal care. outcome measures include prevalence of disabling conditions morbidity and mortality rates. disability adjusted life years (dalys) and quality adjusted life years (qalys) help change the emphasis from mortality to quality of life measures as part of the evaluation. national health systems require data systems that generate information needed for this continuous process of monitoring. monitoring of hospitalizations, length of stay, health-care facility acquired (nosocomial) infection, readmission rate by diagnosis and many more indicators, compliance with standards of care such as in infection control, surgical and maternal mortality, including infection and error rates, and other qualitative measures are now part of monitoring and payment systems. high-quality academic centers are needed for training epidemiologic, sociologic, and economic analyses professionals as well as health system managers and to carry out the studies and research vital for health progress. health systems are large-scale employers and among the largest economic sectors in their respective countries, with À percent of gdp in middle-and high-income countries and, therefore, a major factor in the total national economy. but the gap between countries is very high. many countries have per capita spending of less than usd $ per year, so that inadequate resources prevent people from receiving quality health care, without unaffordable out of pocket expenditures. in contrast, in many high-income countries annual health expenditures are above usd $ , per capita. donor aid to low-income countries from bilateral or international agencies or other donors rose rapidly from with an estimated $ billion usd to a peak of usd $ billion in , with only a modest change up to . low-income nations, many of which are undergoing important economic development, are under-spending in national allocations to the health sector and remain highly reliant on international aid. a goal of five to six percent of gdp spent on health is widely regarded as a minimum to provide the health care needed in any country. a study published in lancet by the institute for health metrics and evaluation, indicates that only one of low-income countries, and out of of middle-income countries, are expected to meet the target of five percent. low rates of national health expenditures in countries will be a serious limiting factor in improved health and universal access, especially if preventive care is unable to compete for resources as compared to clinical and hospital services. all countries face problems of financing, cost constraint, overcoming structural inefficiencies, and funding incentives for high quality and efficiency in health services. national health systems are necessarily complex, but go well beyond medical and hospital care. the quality of the community infrastructure-sewage, water, roads, communication, urban planning-social support such as pensions and welfare for the disabled, widows, orphans and others in need are essential for population health. attention to the quantity and quality of food (i.e., food and nutritional security), levels of education, and professional organization are all parts of this continuum. national health systems are not only a matter of adequacy and methods of financing and assuring access to services; they must also address health promotion, national health targets, and adapt to the changing needs of the population, the environment, and with a broad intersectoral approach to health of the population and the individual. the structure, content, and quality of a health system plays a vital role in the social and economic development of a society and its quality of life. universal access is increasingly widely accepted as essential to reduce the social inequalities in health. even when income gaps are high. however, vulnerable populations with higher levels of risk than those of the general population are still relatively deprived even under classical universal insurance systems. the key common factors of elevated vulnerability are poverty, isolation by geographic location, physical access by reasons of residency location, ethnicity, education and institutional barriers which reduce access. these inequality factors are the achilles heel of classical universal health insurance and service systems most of which have sought health promotion measures. there can be little doubt that universal access to health insurance or service systems reduces inequalities, but they require imaginative and outreach-oriented approaches to reach those urban and rural poor, people of aboriginal descent, those with an income lower than the poverty threshold, the unemployed, the homeless, and those who have not completed secondary education. societal programs to increase family disposable income for the poor are effective in reducing the health inequities. the two are complementary and equally important in social policy. in the united states more than ten percentages of the population are without any, or have inadequate, health insurance. loss of health coverage with change of place of employment and the rapidly increasing cost of private health insurance generated widespread pressure for a national health program. the business community, too, loses confidence in voluntary health insurance as costs of health insurance mounted rapidly and as a cost of employment in an increasingly harms the competitive international business climate. narrow planning for health systems ignores this message at the risk of missing their targets of improved health indicators, such as those adopted by the united nations-i.e., the millennium development goals and sustainable development goals. the mdgs and sdgs represent a growing movement of globalization of health with economic and political dimensions and greater stress on human rights to health policy. they are particularly relevant to lmics (low-and middle-income countries), but high-income countries have health inequalities that require new approaches based on outreach poverty abatement, and health promotion concepts. mdgs and sdgs presented a challenge to establish common data systems for performance measures to monitor effectiveness of policies and programs. this helps to build capacity for target-oriented health planning in low-and middle-income countries (lmics). a holistic view of health for all must take into account the many reasons for health disparities and disadvantage to the poor in health status. insurance to pay for doctors, hospitals, laboratories and imaging centers is necessary, but not sufficient, to raise population health standards for all. the "nontariff barriers"-i.e., issues beyond payment for services which may be addressed with incentives in payment systems, not only to reduce hospital length-of-stay, but to reduce health-care acquired infections, reaching out to chronically ill people with health promotion measures such as nutritional support, pneumonia and influenza immunization, hypertension control, cancer screening, and many other features of public health promotion. since the s, when bismarck introduced national health insurance in germany as part of social security with funding though sick funds, many countries have grappled in unique ways with developing health care systems. national health insurance systems developed through social security and social welfare systems, by national health insurance, or options to provide access to health services. in canada national health insurance provides universal coverage through national support for provincial health plans, paid for by general taxation, with national criteria. in the united states, president lyndon johnson established social security-based health insurance for the elderly and the poor through amendments to the social security act of , and president barack obama extended health insurance through the affordable care act of . the uk national health service-with the northern ireland, scottish and welsh nhs run semi-independently-was established in , providing a state-run system of medical, hospital, preventive, and community health care. though not discussed here, nordic and other european health systems provide universal coverage with involvement from all three levels of government, but over percent of expenditures are funded through public sources. in denmark, norway and sweden county councils are central to funding and management; in finland, the municipalities provide most of the health care. the former socialist countries have gone through painful periods of transition. many of these countries have developed free-market systems with dynamic growth in national economies along with health system reform. health systems in transition have adapted with great gains in longevity and reduced mortality from preventable diseases in many former socialist countries in central and eastern europe. others have had difficulties addressing the "missed epidemiologic transition" from infectious disease to control of noncommunicable disease but have begun to make progress in the st century. globally, public and private donor partnerships have emerged to help the poorest countries cope with overwhelming health problems of raising immunization coverage levels, reducing child and maternal mortality, managing hiv, tuberculosis, malaria, diarrheal and respiratory diseases and vaccinepreventable diseases in keeping with the mdgs based on a consensus of all member nations of the un. the objectives and specific targets included: reducing poverty, improving equal access of boys and girls to primary education, reducing child and maternal mortality, managing significant diseases such as hiv, tuberculosis, and malaria, along with improving the environment. reaching the targets for achieving these goals depends on developing infrastructures of health systems that provide access for all and distribution to meet geographic and social inequities in health. each country needs to develop its own system, but can learn from the experience of others. the purpose of this case study is to highlight the unique and common features, including positive and negative lessons learned from national health systems. observing and learning can help in defining needs for countries lacking but aspiring to achieve universal health systems, including positive and negative challenges. universal access is an important means of assuring that the economic barrier is removed for the total population, leading to increased access to medical and hospital services for those previously lacking the means to reach these services. universal access systems have been achieved in most industrialized countries. however, the us has not achieved this goal even with, by far, the highest health expenditures of oecd countries. this is due mainly to political gridlock despite success with its single payer system for medicare for the elderly. for low-income countries, the rates of health expenditures at present and forecast for the coming decades will be insufficient to achieve universal access systems. there must be a fundamental political change in national policies with health as a higher priority for funding and leadership. universal healthcare access is still a work in progress. the goal of universal access is a worthy one: to make health care accessible to all. the advent of universal access, however, is not assured given low levels of funding in many countries most in need of improved access but strengthening health systems: the role and promise of policy and systems research. geneva: global forum for health research alliance for health systems policy and research. world health organization. what is health policy and systems research (hpsr)? . geneva: world health organization achieving a high-performance health care system with universal access: what the united states can learn from other countries health spending in the united states and the rest of the industrialized world the publicÀprivate pendulum-patient choice and equity in sweden uk health dividesÀwhere you live can kill you disease and disadvantage in the united states and in england lessons from the east-china's rapidly evolving health care system the affordable care act at five years gatekeeping in health care the organization of personal health services. milbank quart noncommunicable diseases: stepping up the fight: how the russian federation is collaborating with other commonwealth of independent states' countries comparing health systems in four countries: lessons for the united states germany: health system review germany and health : statutory health insurance in germany: a health system shaped by years of solidarity, self-governance, and competition how canada compares: results from the commonwealth fund international health policy survey of primary care physicians healthy people : topic areas at a glance. national center for health statistics, last reviewed national health expenditure fact sheet, last modified health and health care in israel: an introduction. lancet. . special series international health care system profiles international profiles of health care systems united kingdom: health system review reforming the russian health care system the fragmentary federation: experiences with the decentralized health system in russia health care reform: lessons from canada ata international conference on primary health care the development of social security in america. social security administration national spending on health by source for countries between regional health inequalities in england. uk office for national statistics, department of health health care systems in the eu: a comparative study. directorate general for research systems science for universal health coverage health systems special edition. health systems: more evidence, more debate evolution and patterns of global health financing À : development assistance for health, and government, prepaid private, and out-of-pocket health spending in countries reforming sanitaryepidemiological service in central and eastern europe and the former soviet union: an exploratory study effects of race and income on mortality and use of services among medicare beneficiaries global health: a pivotal moment of opportunity and peril a systematic review of studies comparing health outcomes in canada and the united states how does the quality of care compare in five countries? financing global health : development assistance, public and private health spending for the pursuit of universal health coverage disease control priorities in developing countries kaiser family foundation. us global health policy strengthening health systems to provide rehabilitation services a new perspective on the health of canadians. ottawa, on: department of national health and welfare, a new perspective on the health of canadians. ottawa, on: department of national health and welfare access to care, health status, and health disparities in the united states and canada: results of a cross-national population-based survey social medicine vs professional dominance: the german experience universal health care: lessons from the british experience a system in name only-access, variation, and reform in canada's provinces the unequal health of europeans: successes and failures of policies a comparative analysis of health policy performance in european countries nordic health systems: recent reforms and health policy challenges. copenhagen: who regional office for europe on behalf of the european observatory on health systems and policies the history of health care in canada the marmot review final report: fair society, healthy lives a precious jewel-the role of general practice in the english nhs canada health system review reinventing public health: a new perspective on the health of canadians and its international impact international health care systems international profiles of health care systems the global campaign for the health mdgs: challenges, opportunities, and the imperative of shared learning red medicine: socialized health in soviet russia measuring the health of nations: updating an earlier analysis organization for economic cooperation and development (oecd) . oecd reviews of health care systems organization for economic cooperation and development (oecd) organization of economic cooperation and development (oecd) organization of economic cooperation and development (oecd) improving health services delivery in developing countries: from evidence to action russian federation. health system review health reform in central and eastern europe and the former soviet union national health systems of the world national health systems throughout the world building on values: the future of health care in canada comparing health and health care use in canada and the united states a survey of primary care physicians in countries ):w Àw . available at rocky road from the semashko to a new health model universalism, responsiveness, sustainability-regulating the french health care system integrated ambulatory specialist care-germany's new health care sector ethics of resource allocation and rationing medical care in a time of fiscal restraint-us and europe addressing the epidemiologic transition in the former soviet union: strategies for health system and public health reform in russia the new public health brave new world: the welfare state united nations human development report transforming our world., agenda items and sustainable development goals. goals to transform our world healthy development. the world bank strategy for health, nutrition, and population results spotlight on nutrition: unlocking human potential and economic growth world bank life expectancy at birth, total (years) world health organization. global health observatory. world health statistics : monitoring health for the sdgs everybody's business: strengthening health systems to improve outcomes: who's framework for action. geneva: world health organization world health report : working together for health. geneva: world health organization health systems: improving performance european health report : charting the way to well-being. copenhagen: world health organization research for universal health coverage world health organization. european health for all database (hfadb) world health organization. health systems: health system financing universal health coverage: sustainable development goal , health relying heavily on donors and out-of-pocket payments. the devil is in the details. . universal health insurance (uhi) or national health service systems are essential for advancing population health and should be give high priority in policy and funding by national governments and international aid agencies in middle-and low-income countries in the coming decades. . universal health insurance or service systems cannot be expected to succeed without continuing development of public health and health promotion as equal needs for population health and to achieve sdgs. . all countries seeking health development will need to raise public support for financing health systems by raising health expenditures to more than five -six percent of gdp. . all countries addressing these issues should endeavor to expand training to include bachelor and master degree training in public health and health systems management in order to raise the professional leadership and management levels to lead in the complexities of health systems in the challenges ahead. health promotion to hospice care on par with acute and rehabilitation care hospitals as essential, but managed so as to avoid unnecessary economic domination of the health system and potentially damaging health-care infections and trauma. . reaching out to populations-at-risk and in need of preventive care and health promotion by multi-professional and paraprofessional teamse.g., community health workers, is vital to address chronic care needs and prevent their complications, for remote villages or urban poverty areas, or to groups of people with chronic disease conditions. . health information systems including development and implementation of epidemiology and information technology for monitoring of disease and quality of care require emphasis. . immunization and nutritional support for prevention of infectious diseases, chronic diseases and micronutrient deficiency conditions are crucial for population health and should be given high priority in health system development. . health policy management is vital to achieving universal health coverage to advance population health, but it must be seen as part of health in all strategies and the sdgs to be effective within financial limitations and cost restraint. . health promotion must be developed in all its aspects to raise population and professional awareness with educational and legal means to reduce risk factors in population health. health systems to promote efficient use of resources and achievement of specified health targets? . what methods may be incorporated into national health systems to promote quality of care? . how can developing countries achieve universal health care, and at the same time work toward national health targets such as upgrading maternal and child heath, control of infectious diseases and preventing chronic diseases? . how can low-income countries address the low public expenditure on health to reduce dependence on global financial aid for sustainable development goals (sdgs)? key: cord- - ra uda authors: snowden, frank m. title: emerging and reemerging diseases: a historical perspective date: - - journal: immunol rev doi: . /j. - x. . .x sha: doc_id: cord_uid: ra uda summary: between mid‐century and , there was a consensus that the battle against infectious diseases had been won, and the surgeon general announced that it was time to close the book. experience with human immunodeficiency virus/acquired immunodeficiency syndrome, the return of cholera to the americas in , the plague outbreak in india in , and the emergence of ebola in zaire in created awareness of a new vulnerability to epidemics due to population growth, unplanned urbanization, antimicrobial resistance, poverty, societal change, and rapid mass movement of people. the increasing virulence of dengue fever with dengue hemorrhagic fever and dengue shock syndrome disproved the theory of the evolution toward commensalism, and the discovery of the microbial origins of peptic ulcer demonstrated the reach of infectious diseases. the institute of medicine coined the term ‘emerging and reemerging diseases’ to explain that the world had entered an era in which the vulnerability to epidemics in the united states and globally was greater than ever. the united states and the world health organization took devised rapid response systems to monitor and contain disease outbreaks and to develop new weapons against microbes. these mechanisms were tested by severe acute respiratory syndrome in , and a series of practical and conceptual blind spots in preparedness were revealed. in the long contest between humans and microbes, the years from mid-century until marked a distinctive era. in those euphoric decades, there was a consensus that the decisive battle had been joined and that the moment was at hand to announce the final victory. almost as if introducing the new period, the us secretary of state george marshall declared in that the world now had the means to eradicate infectious diseases from the earth. marshall's view was by no means exceptional. for some, in the early postwar years, the triumphant vision applied primarily to a single disease. the heady goal arose first of all within the field of malariology, where the rockefeller foundation scientists fred soper and paul russell thought that they had discovered in ddt (dichlorodiphenyltrichloroethane) a weapon of such unparalleled power that it would enable the world to eliminate the ancient scourge forever. with premature confidence in , russell published man's mastery of malaria ( ), frank m. snowden in which he envisaged a global spraying campaign that would free mankind from malaria -cheaply, rapidly, and without great difficulty. rallying to russell's optimism, the world health organization (who) adopted a global campaign of malaria eradication with ddt as its weapon of choice. the director of the campaign, emilio pampana, elaborated a one-size-fits-all program of eradication through four textbook steps -'preparation, attack, consolidation, and maintenance' ( ). russell's followers alberto missiroli, the director of the postwar campaign in italy, and george macdonald, the founder of quantitative epidemiology, reasoned that so signal a victory over mosquitoes could be readily expanded to include the elimination of all other vector-borne tropical diseases, ushering in what missiroli called a contagion-free eden, where medicine would make man not only healthy but also happy ( ) ( ) ( ) . if malariologists, who dominated the international public health community, launched the idea of the final conquest of infectious diseases, it rapidly developed into the prevailing orthodoxy. e. harold hinman, chief malariologist to the tennessee valley authority and member of the who expert committee on malaria, extrapolated from the conquest of malaria to the conquest of all contagion in his influential work world eradication of infectious diseases ( ) . aidan cockburn, a distinguished epidemiologist at johns hopkins and advisor to the who, gave expression to this new creed in his revealingly titled work the evolution and eradication of infectious diseases ( ) . as cockburn noted, '''eradication'' of infectious disease as a concept in public health has been advanced only within the past two decades, yet it is replacing ''control'' as an objective' ( ) . although not a single disease had yet been destroyed by his time of writing in , cockburn believed that the objective of eradication was 'entirely practical,' not just for individual illnesses but for the whole category of communicable diseases. indeed, he argued, 'it seems reasonable to anticipate that within some measurable time, such as years, all the major infections will have disappeared' ( ) . by that time, he explained, 'the major infections of today should have disappeared, and only remaining should be their memories in textbooks, and some specimens in museums. . . . with science progressing so rapidly, such an end-point is almost inevitable, the main matter of interest at the moment is how and when the necessary actions should be taken' ( ) . cockburn's timetable of total eradication by was, in fact, too slow for some. just a decade later, in , the australian virologist and nobel laureate frank macfarlane burnet went so far as to proclaim, together with his colleague david white, that 'at least in the affluent west,' the grand objective had already been reached. 'one of the immemorial hazards of human existence has gone,' he reported, because there is a 'virtual absence of serious infectious disease today' ( ) . the who also saw the entire planet as ready to enter the new era by the end of the century. meeting at alma ata in , the world health assembly adopted the goal of 'health for all, ' ( ) . what could possibly have led to such overweening confidence in the power of science, technology, and civilization to vanquish communicable disease? one factor was historical. in the industrialized west, rates of mortality and morbidity from infectious diseases began to plummet in the second half of the th century, in large part as a result of 'social uplift' -dramatic improvements in wages, housing, diet, and education. at the same time, developed nations erected the solid fortifications of sanitation and public health: sewers, drains, sand filtration, and chlorination of water as defenses against cholera and typhoid; sanitary cordons, quarantine, and isolation against bubonic plague; vaccination against smallpox; and the first effective 'magic bullet' -quinine -against malaria. meanwhile, improvements in the handling of food, pasteurization, retort canning, and the sanitation of seafood beds, yielded major advances against bovine tuberculosis (tb), botulism, and a variety of food-borne maladies. already by the early th century, therefore, many of the most feared epidemic diseases of the past were in headlong retreat for reasons that were initially more empirical and spontaneous than the result of the application of science. science, however, soon added new and powerful weapons. the foundational work of louis pasteur and robert koch had established the biomedical model of disease that promoted unprecedented understanding and yielded a cascade of scientific discoveries and new sub-specialties (microbiology, immunology, parasitology, and tropical medicine). the dawn of the antibiotic era with penicillin and streptomycin provided means to treat syphilis, staph infections, and tb. the development of a series of vaccines dramatically lowered the incidence of smallpox, pertussis, diphtheria, tetanus, rubella, measles, mumps, and polio. ddt seemed to furnish a means to abolish malaria and other insect-borne pathogens. by the s, therefore, scientific discoveries had provided effective weapons against many of the most prevalent infectious diseases. extrapolating from such dramatic developments, many concluded that it was reasonable to expect that communicable diseases could be eliminated one at a time until the vanishing point was reached. indeed, the worldwide campaign against smallpox provided just such an example when the who announced in that the disease had become the first ever to be eradicated by intentional human action. those who asserted the doctrine of the conquest of infection viewed the microbial world as largely static or only very slowly evolving. for that reason, there was little concern that the victory over existing infections would be challenged by the appearance of new diseases for which humanity was unprepared and immunologically naive. falling victim to historical amnesia, they ignored the fact that the last years even in the west had been punctuated by the appearance of a series of catastrophic new diseases: bubonic plague in , syphilis in the s, cholera in , spanish influenza in - . macfarlane burnet in this regard was typical. burnet was a founding figure in evolutionary medicine who acknowledged, in theory, the possibility of the emergence of new diseases as a result of mutation. but, in practice, he believed that such appearances are infrequent and that they occur only at such distant intervals as to occasion little concern. 'there may,' he wrote, 'be some wholly unexpected emergence of a new and dangerous infectious disease, but nothing of the sort has marked the last fifty years' ( ) . the notion of microbial fixity, that the diseases that we have are the ones that we will face, even underpinned the international health regulations adopted in (ihr ) , which specified that the three great epidemic killers of the th century were the only diseases requiring notification: plague, yellow fever, and cholera. the regulations gave no thought to what action would be required if an unknown but deadly and transmissible new microbe should appear ( , ) . if belief in the stability of the microbial world was one of the major articles of faith underpinning the eradicationists' vision, a second misplaced evolutionary idea also played a crucial role. this was the doctrine that nature was fundamentally benign. over time, eradicationists believed, the pressure of natural selection would drive all communicable diseases toward a decline in virulence. the principle was that excessively lethal infectious diseases would prevent their own transmission by prematurely destroying their hosts. the long-term tendency, the proponents of victory asserted, is toward commensalism and equilibrium. new epidemic diseases are virulent almost by accident as a temporary maladaptation, and they therefore evolve toward mildness, ultimately becoming readily treatable diseases of childhood. examples were the evolution of smallpox from variola major to variola minor; the transformation of syphilis from the fulminant 'great pox' of the th century into the slow-acting disease of today; and the transformation of classic cholera into the far milder el tor biotype. similarly, the doctrine held a priori that, in the family of four diseases of human malaria, the most virulent, i.e. falciparum malaria, was an evolutionary newcomer relative to the less lethal vivax, ovale, and malariae malaria, which were believed to be older and to have evolved toward commensalism. against this background, the standard textbook of internal medicine in the eradicationist era, the th edn of harrison's principles of internal medicine of , claimed that a feature of infectious diseases is that they 'as a class are more easily prevented and more easily cured than any other major group of diseases' ( , ) . the most fully elaborated and most cited theory of the new era was the 'epidemiologic transition' or 'health transition' theory represented by abdel omran, professor of epidemiology at johns hopkins, in and refined by him in and . omran's theory of the transition was an account of the encounter of human societies with disease in the modern period. according to omran and his followers in such journals as the health transition review, humanity has passed through three eras of modernity in health and disease. although omran is ambiguous about the precise chronology of the first era, the 'age of pestilence and famine,' it is clear that it lasted until the th century in the west and was marked by malthusian positive checks on demography: epidemics, famines, and wars. there followed the 'age of receding pandemics' that extended from the mid- th century until the early th in the developed west and until later in non-western countries. during this period there was a declining mortality from infectious diseases in general and from tb in particular. finally, after world war i in the west and after world war ii in the rest of the globe, humanity entered the 'age of degenerative and man-made diseases.' whereas in the earlier stages of disease evolution, social and economic conditions played the dominant role in determining health and the risk of infection, in the final phase medical technology and science played a major part. in this period, mortality and morbidity from infectious diseases have been progressively replaced by the rise of degenerative diseases such as cardiovascular disease, cancer, diabetes, and metabolic disorders, by man-made diseases such as occupational and environmental illnesses, and by accidents ( ) ( ) ( ) . adopting the perspective of 'health transition' theory, us surgeon general julius b. richmond announced in that infectious diseases were simply the 'predecessors' of the degenerative diseases that succeed and replace them. the course of nature, in his view, was simple, unidirectional, and benign ( ) . if memory of the power of public health and science provided a major impetus to overconfidence, forgetfulness also played a vital role. us surgeon general william steward reported in that the time had come to 'close the book on infectious diseases.' this view was profoundly eurocentric. even as medical experts in europe and north america snowden Á emerging and reemerging diseases r the authors journal compilation r blackwell munksgaard immunological reviews / declared final victory, infectious diseases remained the leading cause of death worldwide, and nowhere more disastrously than in the poorest and most vulnerable countries of africa, asia, and latin america. while the tb sanatoria were closing their doors in the developed north, the disease continued its ravages in the south. indeed, the disease continued to ravage the marginalized underclasses of the north itself: the homeless, prisoners, intravenous drug users, immigrants, and racial minorities. as paul farmer has argued, tb was emphatically not disappearing; it was just that the bodies it affected were either distant or hidden from sight ( , ) . indeed, in the best estimates suggest that there are more people ill with tb today than at any time in human history and that nearly two million will die of it during the course of the year ( , ) . ultimately, by the early s, the eradicationist position became untenable. rather than witnessing the rapid fulfillment of the prediction that science and technology would eliminate all infectious diseases from the globe, the industrial west discovered that it remained painfully vulnerable and to a degree that had seemed unimaginable. the decisive event, of course, was the arrival and upsurge of human immunodeficiency virus (hiv)/acquired immunodeficiency syndrome (aids). aids was first recognized as a new disease entity in , and its etiologic pathogen was identified in . by the end of the decade, it was clear that hiv/aids embodied everything that the eradicationists had considered unthinkable. aids was a new infectious disease for which there was no cure, it reached the industrial world as well as developing countries, and it unleashed in its train a series of exotic additional opportunistic infections. furthermore, it had the potential to become the worst pandemic in history as measured not only by mortality and suffering but also by its profound social, economic, and security consequences. from the front lines of the battle against aids, a series of voices sounded the alarm in the s about the severity of the new threat. most famous of all was the case of the us surgeon general c. everett koop, who became the chief federal spokesman on the disease. in he produced the brochure understanding aids and took the pioneering step of having it mailed to all million households in the nation ( ) . working in greater obscurity in sub-saharan africa, peter piot, who later directed unaids, warned in that aids in africa was not a 'gay plague' but an epidemic of the general population. he warned that it was transmitted by heterosexual as well as homosexual intercourse and that in fact it affected women more readily than men. the warnings of the s, however, were confined to the issues of aids: they did not directly confront the larger issue of eradicationism or announce a new era in medicine and public health. that task fell first to the national academy of science's institute of medicine (iom) and its landmark publications on emerging diseases that began in with emerging infections: microbial threats to health in the united states ( ) . once raised by the iom, the cry of alarm was taken up widely and almost immediately: by the centers for disease control and prevention (cdc), which devised its own response to the crisis in and founded a new journal emerging infectious diseases devoted to the issue; by the national science and technology council (nstc) in ; and by of the world's leading medical journals that agreed to take the unprecedented step by which each devoted a theme issue to emerging diseases in january , which they proclaimed 'emergent diseases month' ( ) ( ) ( ) . in , in addition, president bill clinton ( ) issued a fact sheet entitled 'addressing the threat of emerging infectious diseases' in which he declared them 'one of the most significant health and security challenges facing the global community.' there were also highly visible hearings on emerging infections in the us congress ( ) . in opening those hearings before the senate committee on labor and human resources, senator nancy kassebaum, the committee chairperson, noted, new strategies for the future begin with increasing the awareness that we must re-arm the nation and the world to vanquish enemies that we thought we had already conquered. these battles, as we have learned from the year experience with aids, will not be easy, inexpensive, nor quickly resolved. ( ) finally, to attract attention at the international level, the who, which had designated april of each year world health day, declared that the theme for was 'emerging infectious diseases -global alert, global response' with the lesson that in a global village, no nation is immune ( ) . in addition to the voices of scientists, elected officials, and the public health community, the popular press gave extensive coverage to the new and unexpected danger, especially when the lesson was driven home by three events of the s that captured attention worldwide. the first was the onset of a large-scale epidemic of asiatic cholera in south and central america, beginning in peru in and rapidly spreading across the continent until cases and deaths were reported in countries ( ) . since the americas had been free of the disease for a century, the arrival of the unwelcome visitor reminded the world of the fragility of painfully won advances in public health. because cholera is transmitted by the contamination of food and water by fecal matter, it is a 'misery thermometer' -an infallible indicator of societal neglect and substandard living conditions ( ) . its outbreak in the west late in the th century, therefore, caused shock and a sudden awareness of unexpected danger. indeed, the press informed its readers of the 'dickensian slums of latin america,' where the residents of lima and other cities drew their drinking water directly from the 'sewage-choked river rimac' and similarly polluted sources ( , ) . who director-general hiroshi nakajima proclaimed the south american epidemic an 'emergency situation. ' the second news-catching event in the matter of epidemic diseases was the outbreak of plague in the indian states of gujarat and maharashtra in september and october . the final toll for the epidemic was limited - cases and deaths were reported ( ) . nevertheless, the news that plague had broken out in both bubonic and pneumonic forms unleashed an almost biblical exodus of hundreds of thousands of people from the industrial city of surat. it cost india an estimated $ . billion in lost trade and tourism, and it sent waves of panic around the world. the disproportionate fear, as the new york times explained, was due to the fact that the very word plague was explosively charged. it evoked cultural memories of the black death that killed a quarter of the population of europe in the th century. india's plague, the paper continued, 'is a vivid reminder that old disease, once thought to have been conquered, can strike unexpectedly anytime, anywhere' ( ) . the third major epidemic shock of the s was an outbreak of the frightening disease of ebola hemorrhagic fever at the city of kikwit, zaire (now democratic republic of the congo), in . cholera claimed international attention because of the numbers of those it afflicted, even though it had a low case fatality rate if treated early. plague demanded attention because of its all too familiar potential. ebola, by contrast, did not inspire terror by giving rise to a major epidemic: it infected only people between january and july . nor did it create fear because of historical memories of disaster since it was a new disease first recognized in . nevertheless, ebola set off a tidal wave of fear -a 'modern nightmare' in the words of le monde -across the globe. the reasons were that it dramatically revealed the lack of preparedness of both industrial and developing nations to deal with a public health emergency. it ignited primordial western fears of the jungle and of untamed nature, and it fed on racial anxieties about 'darkest' africa. as a result, a prominent aspect of the kikwit outbreak was its capacity to generate what the journal of infectious diseases termed 'extraordinary' and 'unprecedented' press coverage that amounted at times to the commercial 'exploitation' of human misery and a 'national obsession' ( ) . descending onto the banks of the kwilu river, the world's tabloids stressed in vivid hyperbole that ebola was a zoonotic disease that had sprung directly from the jungles of africa as a result of the encounter between native charcoal burners and monkeys and now threatened the west. in the revealing headline of the daily telegraph of sydney, 'out of the jungle a monster comes' ( ) . even the most legitimate investigators, however, were disturbed to discover that ebola had eluded public health attention for weeks between the death of the index case on january and the notification of the international community on april , despite the fact that the disease had left clusters of severely ill and dying patients in its train. with such a porous surveillance network in place, ebola aroused the fear that it might spread unnoticed km from kikwit to kinshasa, and then throughout the world by means of the zairian capital's intercontinental airport. there the virus could be loaded on board as 'a ticking, airborne time bomb' ( ) . most of all, however, the kikwit outbreak commanded attention because ebola is almost invariably fatal and because its course in the human body is excruciating, dehumanizing, and dramatic. commenting on the scenes that he had observed in zaire, the author richard preston explained on television at the height of the outbreak that the mortality rate among sufferers was % and that there was no known remedy or prophylactic. he continued: the victims suffer what amounts to a full-blown biological meltdown. . . . when you die of ebola, there's this enormous production of blood, and that can often be accompanied by thrashing or epileptic seizures. and at the end you go into catastrophic shock and then you die with blood pouring out of any or all of the orifices of the body. and in africa where this outbreak is going on now, medical facilities are not all that great. i've had reliable reports that doctors . . . were literally struggling up to their elbows in blood -in blood and black vomit and in bloody diarrhea that looks like tomato soup, and they know they're going to die. ( ) in combination with the announcement by scientists that the world was highly susceptible to new pandemics of just such infections, these events on three continents generated hordes, and of nature exacting its revenge for human presumption. as forrest sawyer reported on abc news, 'once the western world thought it was safe from these invisible killers. not anymore. we are now biologically connected in a web or a net.' in addition, there was an outpouring of films devoted to the possibility of pandemic disaster such as wolfgang petersen's thriller outbreak and of widely read books on the same theme, including richard preston's best-seller, the hot zone; laurie garrett, the coming plague: newly emerging diseases in a world out of balance; and william close, ebola. in the words of david satcher, director of the cdc, the result was the 'cnn effect' -the perception by the public that it was at immediate risk even at times when the actual danger was small ( ) . in this climate of anxiety, the term 'emerging and reemerging diseases' was coined for the iom by joshua lederberg, winner of the nobel prize for medicine, to mark a new era. lederberg defined these disease entities as follows: 'emerging infectious diseases are diseases of infectious origin whose incidence in humans has increased within the past two decades or threatens to increase in the near future' ( ) . emerging diseases were those that, like aids and ebola, were previously unknown to have afflicted humans; reemerging diseases, such as cholera and plague, were familiar scourges whose incidence was rising, or whose geographical range was expanding. lederberg's purpose in devising a new category of diseases was to give notice that the age of euphoria was over. instead of receding to a vanishing point, he declared, communicable diseases 'remain the major cause of death worldwide and will not be conquered during our lifetimes . . . we can also be confident that new diseases will emerge, although it is impossible to predict their individual emergence in time and place' ( ) . indeed, the contest between humans and microbes was a darwinian contest with the advantage tilted toward the microbes. the stark message of the iom was that, far from being secure from danger, the united states and the west were at greater risk from contagious and epidemic diseases than at any time in history. an important reason for this new vulnerability was the legacy of eradicationism itself. the belief that the time had come to close the books on infectious diseases had produced a pervasive climate that critics labeled variously as 'complacency,' 'optimism,' 'overconfidence,' and 'arrogance.' the conviction that victory was imminent had led the industrial world to premature and unilateral disarmament. assured by a consensus of the leading medical authorities for years that the danger was past, federal and state governments in the united states dismantled their public health programs dealing with communicable diseases and slashed their spending. at the same time, investment by private industry on the development of new vaccines and classes of antibiotics dried up, the training of health care workers failed to keep abreast of new knowledge, vaccine development and manufacture were concentrated in fewer laboratories, and the discipline of infectious diseases struggled to attract its aliquot share of research funds and of the best minds. at the nadir in , the united states spent only $ million for infectious disease surveillance as public health officials prioritized other concerns -chronic diseases, substance abuse, tobacco use, geriatrics, and environmental issues. for these reasons, the assessment of american preparedness to face the challenges of the new era was disheartening. in the words of the cdc in : the public health infrastructure of this country is poorly prepared for the emerging disease problems of a rapidly changing world. current systems that monitor infectious diseases domestically and internationally are inadequate to confront the present and future challenges of emerging infections. many foodborne and waterborne disease outbreaks go unrecognized or are detected late; the magnitude of the problem of antimicrobial drug resistance is unknown; and global surveillance is fragmentary. ( ) more bluntly, michael osterholm, the minnesota state epidemiologist, informed congress in that, 'i am here to bring you the sobering and unfortunate news that our ability to detect and monitor infectious disease threats to health in this country is in serious jeopardy. . . . for twelve of the states or territories, there is no one who is responsible for food or water-borne disease surveillance. you could sink the titanic in their back yard and they would not know they had water' ( ) . a striking example of the effects of complacency on infectious disease is the case of tb in new york city. tb had once been the leading cause of death in the city, but improvements in hygiene and education, followed by the discovery of streptomycin, led to the conviction by the middle of the th century that the disease was on the verge of being entirely conquered. as a result, funding was diverted, and demonstrably effective tb programs were dismantled although the social determinants of the disease worsened dramaticallyimmigration, crowding, homelessness, and rates of incarceration. meanwhile, hiv/aids continued to provide large numbers of patients with compromised immunity. as a result, the risk of infection increased, while access to health care became increasingly difficult, and the city experienced a remarkable and entirely preventable resurgence of the 'white plague,' primarily among african american and hispanic residents. between and , the numbers of cases tripled, while drug resistance developed as a significant additional problem. new york city led the way in a national resurgence of tb as cases increased by % between and . overweening confidence led directly and rapidly to a local epidemic and a partial reversal nationally of decades of tireless campaigning ( ) . if the experience of the united states with tb suggests how fragile advances in health remained even in the industrial world, the situation in developing countries was still more disquieting. there, progress toward the germ-free eden during the eradicationist era was nil. in david satcher's uncompromising observation, 'persons living in tropical climates are still as vulnerable to infectious disease as their early ancestors were' ( ) . the critique of years of hubris went deeper than just a protest against a decline in vigilance. in addition, the theorists of emerging diseases argued that, unnoticed by the eradicationists, society since world war ii had changed in ways that actively promoted the emergence and reemergence of epidemic diseases. one of the leading features most commonly cited was the impact of globalization in the form of the rapid mass movement of goods and populations. as william mcneill noted in plagues and peoples ( ) , the migration of people throughout history has been one of the most dynamic factors affecting the balance between microbes and man. humans are permanently engaged in a kind of war in which the social and ecological conditions that they create exert powerful evolutionary pressure on micro-parasites. by mixing gene pools and by providing access for microbes to populations of non-immunes living in conditions in which the microbes thrive, globalization gave microorganisms a powerful advantage. in the closing decades of the th century and the early years of the st, the speed and scale of this phenomenon amounted to a quantum leap, as . billion passengers boarded airplanes in ( , ) . in the words of the popular press, the daily movement of people around the globe by airplane means that a disease breaking out today in kikwit can arrive in new york, mumbai, and mexico city tomorrow. the numbers of voluntary travelers, moreover, are massively supplemented by millions of involuntary refugees and displaced persons in flight from warfare, famine, and religious, ethnic, or political persecution. for lederberg and the iom, these rapid mass movements have tilted the advantage in favor of microbes, 'defining us as a very different species from what we were years ago. we are enabled by a different set of technologies. but despite many potential defenses -vaccines, antibiotics, diagnostic tools -we are intrinsically more vulnerable than before, at least in terms of pandemic and communicable diseases' ( ) . after globalization, the second factor most frequently underlined was demographic growth, especially because this growth occurred in circumstances that were the delight of microorganisms and of the insects that often transmit them. in the postwar era, population has soared above all in the poorest and most vulnerable regions of the world, with the global urban population growing at four times the rate of the rural. its hallmark has been wholesale, chaotic, and unplanned urbanization, led by the resource-poor nations of sub-saharan africa, which is the most rapidly urbanizing region on the planet ( ) . the results have been escalating poverty, widening social inequality, the birth of 'megacities' exceeding million inhabitants, and the spawning of teeming peri-urban slums without sanitary, educational, or other infrastructures. such places were ready-made for ancient diseases to expand, as cholera demonstrated in the shantytowns and barrios of cities like lima, mexico city, and rio de janeiro, where millions lived without sewers, drains, secure supplies of drinking water, or appropriate waste management. already in the th century, cholera had flourished in the conditions created in european cities by rapid and unplanned urbanization. in the final decades of the th century and the start of the st, a much larger process on a global scale reproduced in the cities of africa, asia, and latin america the anomalous sanitary conditions propitious for cholera ( ) . another clear indication of socio-economic conditions in these new urban ecosystems is the appearance of trench fever (bartonella quintana) among the inhabitants of homeless shelters in north american cities. trench fever first emerged in the filth and crowding of soldiers in the trenches of the western front in the first world war, when millions of combatants were infected by the lice that covered their bodies. bartonella quintana, however, had never been documented apart from the vermin and the grime of wartime. the reemergence of the disease in urban america is therefore a clear measure of the insalubrious conditions of marginalized populations among the urban poor ( , ) . here too in urban poverty were the social determinants that made possible the global pandemic of dengue fever that began in and has continued unabated until today, when . billion people are at risk every year and - million people are infected. dengue is the ideal type of an emerging disease. an arborovirus transmitted primarily by the highly urban, daybiting, and domestic aedes aegypti mosquito, dengue thrives in crowded tropical and semi-tropical slums whenever there is standing and unregulated water. it breeds abundantly in gutters, uncovered cisterns, unmounted tires, stagnant puddles, and plastic containers, and it takes full advantage of societal neglect and the absence or cessation of vector control programs. particularly important for the theorists of 'emerging diseases' was the manner in which dengue demonstrated the hollowness of the reassuring dogma that infectious diseases evolve inexorably toward commensalism and reduced virulence. the dengue virus is a complex of four closely related serotypes (den- , den- , den- , and den- ) that have been known to infect humans since the th century. until , however, dengue infections in any geographical area were caused by a single virus that gave rise to a painful illness marked by fever, rash, headache behind the eyes, vomiting, diarrhea, prostration, and joint pains so severe that the infection earned its nickname 'break-bone fever.' but 'classical' dengue was a self-limiting disease that was followed by lifelong immunity. the movement and mobility of populations, however, have allowed all four serotypes to spread indiscriminately around the globe, so that for the first time individuals who have already experienced infection with one dengue virus can subsequently be infected with one or more of the others, as there is no crossover immunity from one serotype to another. through mechanisms that are still imperfectly understood, the disease is much more severe in patients suffering re-infections with different serotypes. instead of becoming milder, therefore, dengue has become a growing threat, giving rise to far more frequent outbursts and to sudden, devastating epidemics in which large numbers of patients suffer the severe and often lethal complications of dengue hemorrhagic fever (dhf) and dengue shock syndrome (dss) that were once unknown. in the americas, the first modern epidemic of dengue fever broke out in in cuba, producing cases, of whom suffered dhf and dss ( ) . moreover, since the dengue vectors a. aegypti and aedes albopictus are present in the united states, scientists at the national institute of allergy and infectious diseases (niaid), such as its director anthony fauci, have noted that dengue fever has broken out in both hawaii and puerto rico, and that they see no inherent reason it could not include the continental united states in its ongoing global expansion ( ) . dengue therefore demonstrates the following important evolutionary lessons: (i) infectious diseases that do not depend on the mobility of their host for transmission (because they are vector-borne, waterborne, or foodborne) are not under selective pressure to become less virulent; (ii) overpopulated and unplanned urban or peri-urban slums provide ideal habitats for microbes and their arthropod vectors; and (iii) modern transportation and the movements of tourists, migrants, refugees, and pilgrims facilitate the process by which microbes and vectors gain access to these ecological niches. paradoxically, the very successes of modern medical science also prepared the way for the emergence of new infections. by prolonging life, medicine gives rise to ever larger numbers of elderly people with compromised immune systems. as part of this process, significant numbers of immunocompromised populations have appeared at earlier ages as well-diabetics, cancer and transplant patients undergoing chemotherapy, and aids patients whose lives have been radically extended by antiretroviral treatment. furthermore, such people are frequently concentrated in settings where the transmission of microbes from body to body is amplified, such as hospitals, facilities for the elderly, and prisons. the proliferation of invasive procedures has also increased the opportunities for such diseases. modern nosocomial infections emerged in these conditions, and have become a major problem of public health as well as an ever growing economic burden. of these infections, the so-called 'superbug' staphylococcus aureus -the leading cause of nosocomial pneumonia, of surgical site infections, and of nosocomial bloodstream infections -is the most important and widespread. a recent study notes that in the united states by : each year approximately two million hospitalizations result in nosocomial infections. in a study of critically ill patients in a large teaching hospital, illness attributable to nosocomial bacteria increased intensive care unit stay by days, hospital stay by days, and the death rate by %. an earlier study found that postoperative wound infections increased hospital stay an average of . days. ( ) a further threatening byproduct of the advance of medical science is the development of ever increasing antimicrobial resistance. already in his nobel prize acceptance speech, alexander fleming, who discovered penicillin, the first antibiotic, issued a prophetic warning. penicillin, he advised, needed to be administered with care, because the bacteria susceptible to it were likely to develop resistance. the selective pressure of so powerful a medicine would make it inevitable. echoing fleming's warning, the emerging diseases theorists argue that antibiotics are a 'non-renewable resource' whose duration of benefit is biologically limited. by the late th century, this prediction was reaching fulfillment. on the one hand, the discovery of new classes of antimicrobials had slowed to a trickle, especially in a market in which profit margins are compressed by competition, by regulations requiring large and expensive clinical trials before approval, and by the low tolerance for risk on the part of regulatory agencies charged with the safety of the public. on the other hand, while antiinfective development stagnates, many microorganisms have evolved extensive resistance. as a result, in one telling metaphor, physicians are rapidly emptying their quiver, and the world stands poised to enter the postantibiotic era ( ) . some of the most troubling examples of the emergence of resistant microbial strains are the emergence of plasmodia that are resistant to all synthetic antimalarials, of s. aureus that is resistant both to penicillin and to methycillin (mrsa), and of strains of mycobacterium tuberculosis that are resistant not only to first-line medications (mdr-tb) but to second-line medications as well (xdr-tb) ( ) . antimicrobial resistance has become a global crisis, and many anticipate the early appearance of strains of hiv, tb, staph a, and malaria that are not susceptible to any available therapy. in part the problem of antimicrobial resistance is a simple result of darwinian evolution. as a rand corporation study ( ) notes, there are tens of thousands of viruses and species of bacteria that are capable of infecting human beings, and many of them replicate and evolve billions of times in the course of a single human generation. evolutionary pressures, in this context, work to the long-term disadvantage of human beings. but unwise human actions have dramatically hastened the process. farmers spray crops with pesticides and fruit trees with antibiotics, and they add subtherapeutic doses of antibiotics such as virginiamycin and avoparcin wholesale to animal feed to prevent disease, promote growth, and increase the productivity of chickens, pigs, and feedlot cattle. indeed, half the world output of antimicrobials by tonnage is used in agriculture ( ) . at the same time, the popular confidence that microorganisms will succumb to a chemical barrage has led to a profusion of antimicrobials in domestic settings where they serve no purpose ( ) . physicians, pressured to give priority in clinical settings to the immediate risk of individual patients over the long-term interest of the species and to meet patients' expectations, have succumbed to profligate prescribing fashions, administering antibiotics even for non-bacterial conditions for which they are unnecessary or entirely useless. the classic case in this regard is the pediatric treatment of otitis media (or middle ear infection), for which the overwhelming majority of practitioners in the s prescribed antibiotics, even though two-thirds of the children derived no benefit from the medication. widespread possibilities of self-medication in countries with few regulations or through opportunities created by the internet amplify the difficulties. in the case of diseases such as malaria and tb that require a long and complicated therapeutic regimen, there is also the issue of patients who interrupt their treatment after the alleviation of their symptoms instead of persevering until their condition is cured. here the problem is not the overuse but the underuse of antibiotics. sometimes described as simple non-compliance by patients, the issue in fact raises complex questions of education, poverty, and lack of access to health care. here the who strategies of dots (directly observed treatment short course) and dots-plus are helpful but cannot solve the underlying problems. a further issue raised by the new era was the overly rigid conceptualization of disease by the eradicationists, who drew too sharp a distinction between chronic and contagious diseases. infectious diseases, it became clear during the s, are a more expansive category than scientists previously realized because many diseases long considered noninfectious in fact have infectious origins. in demonstrating these causal connections, the decisive work was that of the australian nobel laureates barry j. marshall and robin warren with regard to peptic ulcers in the s. peptic ulcers are a significant cause of suffering, cost, and even death, as one american in develops one during the course of a life time, over one million people are hospitalized by them every year, and die. marshall noted in his acceptance speech for the nobel prize in , however, that the chronic etiology of peptic ulcer in the s was universally accepted as scientific truth. in his words, 'i realized that the medical understanding of ulcer disease was akin to a religion. no amount of logical reasoning could budge what people knew in their hearts to be true. ulcers were caused by stress, bad diet, smoking, alcohol and susceptible genes. a bacterial cause was preposterous.' what marshall and warren were able to demonstrate, therefore, was a medical watershed. they proved, in part by means of an auto-experiment, that the bacterium helicobacter pylori was the infectious cause of the disease and that antibiotics rather than diet, lifestyle change, and surgery were the appropriate therapy ( ) . this insight led to the realization that many other non-acute diseases, such as certain forms of cancer, chronic liver disease, and neurological disorders, are due to infections. human papillomavirus, for instance, is thought to give rise to cervical cancer, hepatitis b and c viruses to chronic liver disease, campylobacter jejuni to guillain-barré syndrome, and certain strains of escherichia coli to renal disease ( , ) . there are indications as well that infections serve as an important trigger to atherosclerosis and arthritis, and there is a growing recognition that epidemics and the fear that accompanies them leave psychological sequelae in their wake, including posttraumatic stress ( , ) . this understanding of these processes is what some have termed finally, and most emphatically, the concept of emerging and reemerging diseases was intended to raise the most important threat of all -that the spectrum of diseases that humans confront is broadening with unprecedented and unpredictable rapidity. the number of previously unknown conditions that have emerged to afflict humanity since exceeds , with a new disease discovered on average more than once a year. the list includes such frightening names as hiv, hantavirus, lassa fever, marburg fever, legionnaires' disease, hepatitis c, lyme disease, rift valley fever, ebola hemorrhagic fever, nipah virus, west nile virus, sars (severe acute respiratory syndrome), bovine spongiform encephalopathy, avian flu h n , chikungunya virus, and group a streptococcus -the so-called 'flesh-eating bacterium.' skeptics argue that simply to list the diseases that have emerged since s gives the misleading impression that diseases are emerging at an accelerating rate. this impression, they suggest, is largely an artifact of heightened surveillance and improved diagnostic techniques rather than a new development. the who has countered that not only have diseases emerged at record rapidity as one would expect from the transformed social and economic conditions of the postwar world, but also that they gave rise between the years and to a record worldwide epidemic events ( ) . the most recent and comprehensive examination of the question ( ), published in february in nature, involved the study of emerging infectious disease (eid) 'events' between and , controlling for reporting effort through more efficient diagnostic methods and more thorough surveillance. the conclusion was that, 'the incidence of eid events has increased since , reaching a maximum in the s. . . . controlling for reporting effort, the number of eid events still shows a highly significant relationship with time. this provides the first analytical support for previous suggestions that the threat of eids to global health is increasing' ( ) . there are no rational grounds, the public health community concluded, to fail to expect that as diseases emerge in the future, some of them will be as virulent and as transmissible as hiv or the spanish influenza of / . discussion has therefore shifted dramatically from the question of whether new diseases will emerge and old ones resurge to the issue of how the international community can best prepare to face them. in the stark words of the us department of defense, 'historians in the next millennium may find that the twentieth century's greatest fallacy was the belief that infectious diseases were nearing elimination. the resultant complacency has actually increased the threat' ( ) . a major aspect of the official response to the challenge of emerging and reemerging diseases is that microbes now are regarded as threats to the security of states and to the stability of the international order. for the first time, therefore, not only public health authorities but also intelligence agencies and conservative think tanks have classified infectious diseases as a 'non-traditional threat' to national and global security. they assumed therefore the task of envisaging the future and the challenge that communicable diseases would play. here a turning point was the central intelligence agency (cia)'s national intelligence estimate (nie) for ( ) , which was devoted to the danger posed by disease and presented defense against epidemic diseases as a major security goal for the united states. as a document, nie - d ( ) was divided into four major sections: alternative scenarios, impact, implications, and discussion. in the first section, the cia attempted to outline three possible scenarios for the course of infectious diseases over the next years: (i) the optimistic contemplation of steady progress in combating communicable disease; to (ii) the forecast of a stalemate with no decisive gains either by microbes or by humans in their long war of attrition; and (iii) the consideration of the most pessimistic prospect of deterioration in the position of humans, especially if the world population continues, as seems probable, to expand and if megacities continue to spring up with their attendant problems of crowding, sanitation, and unprotected drinking water. unfortunately, the cia regarded the optimistic first case as extremely unlikely. the probable course of events, in its view, is that americans will die from infectious diseases every year or considerably more if a pandemic of influenza or of a still unknown disease occurs, if there is a dramatic decline in the effectiveness of antiretroviral treatments for hiv/aids. only toward the end of the years did the report foresee possible advances due to enhanced public health initiatives, the development of new drugs and vaccines, and economic development ( ) . against this background, the succeeding sections on 'impact' and 'implications' outlined a series of likely economic, social, and political results that would occur in the new age of increasing disease burdens. in the most afflicted regions of the world, such as sub-saharan africa, the report anticipated 'economic decay, social fragmentation, and political destabilization.' the international consequences of these developments would be growing struggles to control increasingly scarce resources, accompanied by crime, displacement, and the degradation of familial ties. disease, therefore, would heighten international tensions while it weakened forces, such as international peacekeepers, who might otherwise have played a larger role in controlling regional tensions. us or european military forces deployed abroad in support of humanitarian or other operations would be at high risk. because the economic and social consequences of increasing burdens of communicable diseases in the developing world are certain to impede economic development, the nie also predicted that democracy would be imperiled, that civil conflicts and emergencies would multiply, and that the tensions between north and south would deepen. three years later, motivated by the cia's report, an influential national security think tank, the rand corporation, turned to the intersection of disease and security when it attempted to provide 'a more comprehensive analysis than has been done to date, encompassing both disease and security' ( ) . in so doing, it envisaged even more somber probabilities than the cia in the new global environment. the rand corporation intelligence report the global threat of new and reemerging infectious diseases: reconciling u.s. national security and public health policy ( ) had two leading themes. the first was that in the postwar era there was a sharp decline in the importance of direct military threats to security. the second was that there is a corresponding rise in the impact of 'non-traditional challenges,' of which diseases are the major but inadequately recognized component. it has always been accepted, the report stressed, that diseases kill and undermine the quality of individual lives. in addition, it was essential to recognize that the transition to the era of emerging and reemerging diseases marked the opening of a period in which infectious diseases would profoundly affect the ability of states to function and to preserve social order. the most striking portion of the global threat of new and reemerging infectious diseases ( ) was its imagining of a probable scenario in which south africa could become the first modern state to fail specifically because of infectious diseases in general and the hiv/aids pandemic in particular. as the report explained, 'the contemporary hiv/aids crisis in south africa represents an acute example of how infectious diseases can undermine national resilience and regional stability.' in absolute numbers, south africa has the highest number of hiv-positive inhabitants in africa - . million people in , or % of the country's adult population. already, such extreme prevalence of the disease has pervasive impacts, affecting all aspects of south african security. but south africa is just emerging from the first phase of the aids pandemic and is therefore far from experiencing the full effects of the crisis, which even in the absence of resistance to antiretroviral therapy, is expected to produce patients with hiv and with full-blown aids by . in these circumstances, over a quarter of the economically active population will have the disease, causing severe skill shortages, creating poverty, destroying economic development, undermining participation in political life, and giving rise to more than two million orphans who will be impoverished, uneducated, and easily drawn into crime and prostitution. the effects will also be deeply felt in the military, the police, and the legal system, which will be severely deprived of manpower and unable to function just as social tensions deepened. 'the net effect,' it concluded, 'will be entirely negative for south africa's civil stability, possibly reducing the country to widespread social anarchy within the next five to twenty years.' this disturbing outcome, moreover, could be hastened by the public health policies of president thabo mbeki, who espoused the theories of the aids denier peter duesberg and rejected the link between the hiv virus and the disease. the point the rand corporation stressed most about south africa, however, was that it was simply a dramatic illustrative example. what was occurring there as a result of hiv/aids could happen without warning elsewhere. 'a crisis of similar proportions,' it explained, 'could therefore break out in any country at any time.' indeed, in the context of a growing danger of bioterrorist attack, such an outbreak could be launched intentionally. it was precisely this point -the growing vulnerability of all in the age of globalization -that led the world community, the european union, and individual nations to rearm in preparation for the inevitable threats to come. in the new climate of preparedness, the united states took a prominent role, beginning almost immediately in the aftermath of the iom report. in the cdc -the chief monitoring agency -drafted a strategic plan that it then updated in , while niaid -the principal basic research center -established a research agenda. both agencies' plans were endorsed by the white house, where the nstc under the chairmanship of vice president al gore issued a 'fact sheet: addressing the threat of emerging infectious diseases,' which in turn was backed by a presidential decision directive of june , . the result, as gore explained, was the first national policy by the united states to confront the international problem of infectious diseases ( ) . the essential starting point of the plan envisaged by the cdc, niaid, and the white house was the iom's description of the darwinian struggle under way between humans and microbes. in the iom's analysis of that struggle, microbes possess formidable advantages. they outnumber human beings a billionfold, they enjoy enormous mutability, and they replicate, in lederberg's estimate, a billion times more quickly than man, with generations measured in minutes rather decades. in terms of natural evolutionary adaptation, therefore, microbes are genetically favored to win the contest. in lederberg's observation, 'pitted against microbial genes, we have mainly our wits' ( ) . taking this iom analysis as its starting point, the american response to the new challenge is best seen as the attempt to organize and deploy human wit, backed by newly found financial resources, to counter the microbial genetic challenge ( ) . the white house 'fact sheet' declared in clear alarm that, 'the national and international system of infectious disease surveillance, prevention, and response is inadequate to protect the health of u.s. citizens.' to remedy the situation, the white house established six policy goals, as follows: . strengthen the domestic infectious disease surveillance and response system, both at the federal, state, and local levels and at ports of entry into the united states, in cooperation with the private sector and with public health and medical communities. . establish a global infectious disease surveillance and response system, based on regional hubs and linked by modern communications. . strengthen research activities to improve diagnostics, treatment, and prevention, and to improve the understanding of the biology of infectious disease agents. . ensure the availability of the drugs, vaccines, and diagnostic tests needed to combat infectious diseases and infectious disease emergencies through public and private sector cooperation. . expand missions and establish the authority of relevant us government agencies to contribute to a worldwide infectious disease surveillance, prevention, and response network. . promote public awareness of eids through cooperation with non-governmental organizations and the private sector ( ) . in pursuit of goals , , and , nih funding was doubled between and . niaid established a research agenda to develop new weapons to combat epidemic diseases, giving rise to an explosion in knowledge while publications on infectious diseases burgeoned. indeed, the agency director, anthony s. fauci, claimed in that hiv/aids in particular has become the most extensively studied disease in human history. niaid's priority is the development of safe and effective vaccines and medications to combat hiv/aids, malaria, tb, and influenza. to that end, it has evaluated over hiv vaccine candidates, funded clinical trials, and developed antiretroviral medications. in the field of malariology, it has completed the genomic sequencing of plasmodium falciparum and of the feared malaria vector anopheles gambiae with the expectation that this genetic knowledge is the first step toward the capacity to design anti-malarial drugs, vaccines, and pesticides. the work of the federal agency, moreover, has been complemented by the work of private organizations such as the bill and melinda gates foundation, and university laboratories ( ) . at the same time that niaid stressed basic research, the cdc developed a defensive strategy against emerging pathogens in compliance with goal of the president's directive. the cdc articulated its plan in two seminal works published in and . there it articulated its objectives in four principal areas: surveillance; applied research; prevention and control; and the enhancement of the infrastructure and trained personnel needed for diagnostic laboratories at the federal, state, local, and international levels. in addition, the atlanta-based agency strengthened its links with the international public health community and with other surveillance agencies such as the fda and the department of defense. it enhanced its capacity to respond to outbreaks, and it launched the journal emerging infectious diseases as a forum to pool information on communicable diseases. it sponsored a series of major international conferences on the topic of emerging and reemerging diseases, beginning in with the participation of representatives from all states and countries. the cdc initiatives were widely regarded as a model for the establishment of surveillance and response capabilities in other countries as well ( , ) . at the global level, the un and its agency who also took major steps to strengthen international preparedness for the ongoing siege by microbial pathogens. a first step was the creation in of the disease-specific organization unaids with the function of raising awareness, mobilizing resources, and monitoring the pandemic. funding levels in the fight against the disease increased from $ million in to nearly $ billion a decade later ( ). a further step was that like the united states, the united nations announced that it regarded infectious diseases as threats to international security. in acknowledgement of this new development, the security council took the unprecedented step in june of devoting a special session to the hiv/aids crisis. the session adopted a 'declaration of commitment on hiv/aids: global crisis -global action.' the declaration declared the global epidemic a 'global emergency and one of the most formidable challenges to human life and dignity' ( ) . five years later, in june , the general assembly reaffirmed its commitment to the campaign, and adopted the ' political declaration on hiv/aids,' whose chief goal was the establishment of national campaigns to improve access to care and treatment ( ). a third step was the establishment of a new set of international sanitary regulations -ihr ( ) -to replace the outdated ihr ( ). whereas the old framework was disease-specific and required notification only in the event of plague, yellow fever, and cholera, the new rules required notification for any 'public health emergency of international concern,' thereby including unknown pathogens and emerging infections. the regulations specified the nature of the 'events' that should trigger international concern. they also committed all of the who member states to improve their capacity for surveillance and response and to designate 'national ihr focal points' as the units responsible for providing notification while requiring, in exchange, that the who provide assistance to member states in fulfilling their obligations ( , ) . in addition, recognizing that microbes do not acknowledge political frontiers, ihr ( ) called for effective responses wherever necessary to contain an outbreak on the basis of realtime epidemiological evidence instead of concentrating on taking defensive measures at international borders. finally, the who organized a rapid response capacity with the necessary supporting infrastructure. this was the global outbreak alert and response network (goarn), which was established in with the goal of ensuring that even most resource-poor countries would have access to the experts and resources needed to respond to an epidemic emergency. to that end, goarn pooled the resources of countries and organized experts in the field. in addition, it stockpiles vaccines and drugs, and supervises their distribution during epidemic events. between its founding and , goarn responded to outbreaks and attempted to learn from experience by establishing protocols to standardize such matters as field logistics, security, communication, and the deployment of field teams ( ). in addition to goarn, the who set up surveillance systems specifically designed to deal with pandemic influenza, which the un agency determined as its most feared security threat. these disease-specific networks are (i) the global influenza surveillance network, which provides recommendations twice a year on the appropriate vaccine for the subsequent influenza season by collecting samples from patients in countries and forwarding them to who collaborating laboratories for analysis, and (ii) flunet, which compiles the surveillance data thus collected to establish a global real-time early-alert system for the disease ( , ) . in practice, the first test of the effectiveness of the new structures was the sars pandemic of / -the first major emerging disease threat of the st century. after first appearing in the chinese province of guangdong in november , it erupted as an international health threat in march , when the who received notification and declared a global travel alert. between march and the declaration on july that the disease had been contained, sars affected people, caused deaths, brought international travel to a halt in entire regions, and cost $ billion in gross expenditure and business losses to asian countries alone. as retrospective studies have demonstrated, sars presented many of the features that most severely expose the vulnerabilities of the global system: sars is a respiratory disease capable of spreading from person to person without a vector; it has an asymptomatic incubation period of more than a week; it generates symptoms that closely resemble those of other diseases; it takes a heavy toll on caregivers and hospital staff; it readily spreads unobserved aboard aircraft; and it has a case fatality rate of %. at the time this new disease appeared, moreover, its causative pathogen (sars-associated coronavirus) was unknown, and there was neither a diagnostic test nor a specific treatment. for all of these reasons, it dramatically confirmed the iom's prediction that all countries were more vulnerable than ever to eids. sars demonstrated no predilection for any region of the globe and was no respecter of prosperity, education, technology, or access to health care. indeed, after its outbreak in china, sars spread by airplane primarily to affluent cities such as singapore, hong kong, and toronto, where it struck relatively prosperous travelers and their contacts, hospital workers, patients, and hospital visitors, rather than targeting the poor and the marginalized. more than half of the recognized cases occurred in well-equipped and technologically advanced hospital settings such as the prince of wales hospital in hong kong, the scarborough hospital in toronto, and the tan tock seng hospital in singapore ( , , ) . in terms of response to the crisis, the sars outbreak demonstrated and vindicated the reforms taken on both the national and international levels. after the debacle of chinese obfuscation at the start of the epidemic, national governments cooperated fully with ihr ( ). the world's most equipped laboratories and foremost epidemiologists, working in realtime collaboration via the internet, succeeded, with unprecedented speed, in identifying sars-cov in just weeks. at the same time the newly created goarn, together with such national partners as the canadian public health intelligence network, the cdc, and the who global influenza network, took rapid action to issue global alerts, monitor the progress of the disease, and supervise containment strategies before the disease could establish itself endemically. ironically, given the high-tech quality of the diagnostic and monitoring effort, the containment policies were based on traditional methods dating from the public health strategies against bubonic plague by the th century and the foundation of epidemiology as a discipline in the th. these measures were case tracking, isolation, quarantine, the cancellation of mass gatherings, the surveillance of travelers, recommendations to increase personal hygiene, and barrier protection by means of masks, gowns, gloves, and eye protection ( ) . although sars affected countries and every continent, the containment operation coordinated by goarn successfully limited the outbreak overwhelmingly to hospital settings with only sporadic community involvement, so that by july the who could announce that the pandemic was over. although sars tested the newly established global defenses against emerging diseases and the protective ramparts withstood the challenge, doubts relentlessly surfaced. the chinese policy of concealment between november and march had placed international health in jeopardy and revealed that even a single weak link in the response network could undermine the ihr ( ) system. indeed, resourcepoor countries that were compliant with the new framework of obligations nonetheless found it difficult or impossible to maintain the surveillance effort for the full -month duration of the emergency. still more tellingly, it was also clear that a major factor in the containment of sars was simple good fortune. the world was lucky that sars is spread by droplets and therefore requires extended contact for transmission, unlike classic airborne diseases such as influenza and smallpox. it was, relatively, much easier to contain, because except in the infrequent and still poorly understood case of so-called 'super shedders,' it is not readily communicable from person to person. as poorly transmissible as it was, however, sars exposed the absence of 'surge capacity' in the hospitals and health care systems of the prosperous and well-resourced countries it affected. the events of thereby raised the specter of what might have happened had sars been pandemic influenza, and if it had traveled to resource-poor nations at the outset instead of mercifully visiting cities with well-equipped and well-staffed modern hospitals and public health care systems. furthermore, sars arrived in peacetime rather than in the midst of the devastation and the dislocations of war. in that respect, too, it did not repeat the challenge of the spanish lady of - . the physician paul caulford, who fought the sars epidemic in the front lines at scarborough hospital in toronto, raised these matters. in december , after the passing of the emergency, he reflected: sars must change us, the way we treat our planet, and how we deliver health care, forever. will we be ready when it returns? sars brought one of the finest publiclyfunded health systems in the world to its knees in a matter of weeks. it has unnerved me to contemplate what the disease might do to a community without our resources and technologies. without substantive changes to the way we manage the delivery of health care, both locally and on a worldwide scale, we risk the otherwise preventable annihilation of millions of people, either by this virus, or the next. ( ) at the end of the victory over sars, the nagging question therefore remains: even after the impressive efforts at rearmament since , how prepared is the international community for upcoming emerging diseases? have we been forever changed? the reforms introduced since the iom report in have been profound and important. indeed, the manner in which the international community responded to sars was innovative and, in the circumstances, highly successful. there is, however, a disconcerting sense of a systematic blindness in the responses -at all levels -to the crisis described by the iom, the cia, the rand corporation, the who, and the white house. what has been done has been necessary but probably far from sufficient. some of the issues raised by those who sounded the alarm have been forcefully addressed, but others have been largely ignored. the responses to date have fit into two chief categories, both of which are essential and both of which were evident during the sars pandemic. the first is reactive: the ability to respond rapidly and effectively to the outbreak of new epidemic threats. through a series of initiatives, the years since have witnessed the establishment of organized networks for gathering public health intelligence, of an international legal framework to structure emergency interventions, and of well equipped response teams of experts to contain and monitor outbreaks. if one were to compare outbreaks of infectious diseases to forest fires, the world has provided itself with surveillance satellites, advanced communications infrastructures, and a well-equipped fire department. one could question details of the response to sars, such as implementation lapses that risked the spread of the disease from the hospital environment into the community, but overall the world's 'dress rehearsal' demonstrated far-sighted planning and coordination beyond anything ever attempted before on an international scale. the second category of initiatives is proactive and scientific: the attempt to discover new weapons to attack microbial threats. after half a century of dwindling resources for the fight against infectious diseases, the scientific and public health communities have successfully aroused worldwide awareness of the threat to health and security. they have, at least initially, attracted new levels of funding for basic research from both public and private sources, and they have set research agendas. the result has been an explosion of knowledge, grants, and publications with priority given to genomic approaches to microbes and vectors, to the development of vaccines, and to the search for new medications and diagnostic tools. naturally there are grounds for criticism of various aspects of these initiatives. there is, for example, general agreement that overall levels of funding remain inadequate to the extent of the crisis and that after initial enthusiasm, governments have not continued to increase their support. there are also reasonable grounds for disagreement as to the relative distribution of research efforts, with discussion, for example, about the balance struck between research against hiv/aids and that against such other major diseases as malaria, tb, and pandemic influenza. some have also questioned whether developing vaccines is the right paradigm on all fronts. for example, should priority be given to those diseases for which the human immune response gives grounds for optimism thaton the basis of historical experience -a safe and effective vaccine can be developed (e.g. influenza and dengue)? or should other strategies be followed with respect to diseases for which the human immune response makes the development of a vaccine a far more arduous and unpredictable endeavor (e.g. cholera and malaria)? nevertheless, although there is no basis for false confidence, global research efforts have been galvanized, and major advances have been made in the field of infectious diseases in comparison with the early decades after world war ii. there is also a consensus that the effort to find vaccines and medicines is vital and that it must be enhanced in order to replenish the quivers of clinicians and public health officials. what is more troubling in principle is that there are also systematic blind spots -areas of danger raised by those who first sounded the tocsin regarding emerging diseases that have not been addressed at all or only marginally and sporadically. broadly speaking, the global community has chosen to address those issues for which scientific and technological responses are appropriate, while giving little sustained priority to what might be termed the social, economic, and environmental determinants of infectious disease. here there is a considerable irony. the founding figures of the modern concept of emerging and reemerging diseases such as joshua lederberg and robert shope stressed that epidemics do not strike societies randomly or in accord with the caprices of angry gods. diseases instead reflect the relationships that human beings establish with one another and with the natural and built environments. they then spread by taking advantages of the fault lines created by demography, poverty, environmental degradation, warfare, mass transportation, and societal neglect. the very beginning of the iom's discussion of the new dangers was the recognition that our new vulnerability is not accidental but is the logical result of the type of society that we have become. in defining this vulnerability in a keynote speech in , for instance, lederberg stated: to our disadvantage, we have crowding; we have social, political, economic, and hygienic stratification. we have crowded together a hotbed of opportunity for infectious agents to spread over a significant part of the population. this condensation, stratification, and mobility is unique, defining us as a very different species from what we were years ago. ( ) if our problem results from 'condensation, stratification, and mobility,' there is a disturbing silence in the government response. ironically, the various agencies -niaid, the cia, the department of defense -tasked by the presidential directive with augmenting american preparedness in the fight against infectious diseases neither mention socioeconomic factors nor elaborate a long-term strategy to address them. the call to action aroused the will to find new means to attack microbes and their vectors, and to contain disease outbreaks in human populations, but not to ameliorate the underlying conditions that have made modern societies vulnerable in the first place. three crucial examples illustrate the problem. the first is condensation or the press of overpopulation. clearly unrestrained demographic growth as the world population approaches seven billion strains all resources, degrades the environment, gives rise to the megacities and peri-urban slums where dengue, tb, and cholera thrive, drives populations to intrude into forests where they are exposed to new zoonotic infections, and overwhelms educational, housing, and hygienic infrastructures. here, the medical and public health communities agree, is a driving factor in the new human vulnerability to emerging diseases. the remedies, moreover, are already known, involving voluntary universal access for women to family planning education and technologies. one of the few forums even to raise the issue was the 'first international conference on women and infectious diseases' held in atlanta, february - , , where it was noted that, 'women's health, in and of itself, rarely has been at the forefront of international development programs or national health planning and policies' ( ) . in the field of infectious diseases, this lacuna is especially glaring because women are, as the conference stressed, more susceptible to infections than men, both for biological reasons and due to their caregiving roles and their relative burden of unemployment and poverty. women, moreover, suffer more serious complications from infectious diseases, above all during pregnancy. a second illustration is stratification, the burden of poverty and inequality. nearly all of the leading studies on emerging diseases regard poverty and its sequelae of poor diet, substandard housing, lack of education, and inadequate access to health care as one of the chief determinants of epidemic disease. poverty prevents people from taking measures to protect their own health, it undermines the immune system, it complicates access to safe water supplies, it leads to overcrowding in unhygienic housing, and it creates patterns of labor mobility and migration that compromise health. health care workers and clinicians recognize the link between inadequate resources and disease, with the result that many of the leading epidemic infections are widely termed 'diseases of poverty' ( ) . the issue therefore surfaces in who campaigns to combat the three most important contemporary epidemics: hiv/aids, malaria, and tb. as the report addressing poverty in tb control stated: poverty is the greatest impediment to human and socioeconomic development. the united nations and its specialized agencies are focusing on poverty reduction as a leading priority. in the health sector, poverty represents a principal barrier to health and health care and, consequently, the world health organization has committed to integrate the promotion of pro-poor policies throughout its work. ( ) the reduction of extreme poverty and hunger also form part of the un 'millennium development goals' to be achieved by . except for exhortation and moral suasion, however, it is not clear that the who has developed specific plans to tackle the problem of poverty as a primary determinant of public health, and the promotion of greater equality is entirely ignored. more strikingly, neither issue forms part of the strategic public health thinking of the united states. american analyses recognize poverty as a factor creating an environment favorable for infectious diseases, but they avoid both poverty and inequality as matters of practical health policy. here is the antithesis of the strategic recommendation of the south african pediatrician nulda beyers, who commented: the western cape is in some ways a model of tb epidemiology . . .. tb is almost non-existent in the white population, but in the black and coloured populations, where unemployment is running at %, and malnutrition and crowded slum housing are the norm, tb deaths can reach per . if i had to put my money on only one option -science or social upliftthere is no doubt that social uplift would have the bigger impact. ( ) poverty, moreover, reinforces both condensation and mobility. poverty creates a vicious downward spiral by interacting with population pressure because impoverished women are unable to practice effective family planning. the population explosion of the st century is based in the poorest regions of the planet. given a free and informed choice, privileged families in the industrial world limit their fertility. at the same time, however, poverty also augments vulnerability to infectious disease by setting in motion great streams of mobile people -the poor who become migrants, refugees, and displaced persons, and who then crowd into slums, mining compounds, refugee camps, and homeless shelters. these are people who are at disproportionately high risk of falling ill and of transporting their microbial burden with them. finally, there is the question of access to care. here the position of the leading figures in the campaign to recognize the importance of emerging and reemerging diseases is strangely contradictory. the iom examined the managed care revolution in the united states and the implications of for-profit medicine for the preparedness of the nation to face infectious diseases ( ) . by , managed care already enrolled million americans and therefore dominated health care delivery. the performance of the managed care revolution, however, did not inspire the iom. on the contrary, it produced a list of the major problems that, in its view, managed care created for public health. this list was lengthy and devastating. according to the iom, managed care creates severe public health difficulties because it does the following: (i) it places such strict controls on reimbursements that it becomes an impediment to effective collaboration with the public health community; (ii) it lowers costs by fostering management of infectious diseases by nonspecialists; (iii) it promotes the shift from inpatient to outpatient treatment, where there are neither the specialists nor the infrastructure to diagnose or contain infectious diseases; (iv) it proliferates bureaucratic complexities that complicate prompt response to disease outbreaks; (v) it reduces the commitment to training and research; and (vi) it encourages excessive antibiotic use ( ) . by leaving tens of million of people in the united states without insurance coverage and therefore without effective access to care, for-profit medicine effectively removes them from the disease surveillance network. to the extent that uninsured people avoid care entirely or seek it only at a late stage of their illness, the prompt information on which effective public health depends is undermined. in addition, excluding people from coverage drives them further into poverty and creates an underclass of the marginalized. finally, managed care relentlessly cuts costs by squeezing out of the system the surge capacity on which populations depend in the event of a disease outbreak. nevertheless, despite these observations, the iom reached perfectly anodyne conclusions. it did not conclude that only a system that guaranteed universal access is compatible with defense against infectious disease threats. instead, it lamely urged a deeper partnership between the managed care industry and public health officials. for these reasons, one can only conclude that we are not, in fact, forever changed. on the contrary, on both the national and international levels the response to the challenge of emerging disease threats remains partial with major gaps that are potentially costly in terms of human life and suffering. the united states and the world health community have established a sophisticated and necessary rapid response system. they have also proclaimed -and partially funded -a new commitment to basic research aimed at finding new antimicrobial weapons. they have not, however, systematically addressed the underlying causes for the new vulnerability. man's mastery of malaria textbook of malaria eradication 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diseases preventing emerging infectious diseases: a strategy for the st century. atlanta: us department of health and human services declaration of commitment on hiv/aids global public health security who. international health regulations flunet as a tool for global monitoring of influenza on the web global surveillance, national surveillance, and sars bell dmworld health organization working group on international and community transmission of sars. public health interventions and sars spread sars: aftermath of an outbreak infectious disease as an evolutionary paradigm steps for preventing infectious diseases in women targets now set by g countries to reduce ''diseases of poverty addressing poverty in tb control: options for national tb control programmes tuberculosis experts back social reform managed care systems and emerging infections: challenges and opportunities for strengthening surveillance, research and prevention key: cord- -djkljey authors: druckman, james n.; klar, samara; krupnikov, yanna; levendusky, matthew; ryan, john barry title: how affective polarization shapes americans’ political beliefs: a study of response to the covid- pandemic date: - - journal: nan doi: . /xps. . sha: doc_id: cord_uid: djkljey affective polarization – partisans’ dislike and distrust of those from the other party – has reached historically high levels in the united states. while numerous studies estimate its effect on apolitical outcomes (e.g., dating and economic transactions), we know much less about its effects on political beliefs. we argue that those who exhibit high levels of affective polarization politicize ostensibly apolitical issues and actors. an experiment focused on responses to covid- that relies on pre-pandemic, exogenous measures of affective polarization supports our expectations. partisans who harbor high levels of animus towards the other party do not differentiate the “united states’” response to covid- from that of the trump administration. less affectively polarized partisans, in contrast, do not politicize evaluations of the country’s response. our results provide evidence of how affective polarization, apart from partisanship itself, shapes substantive beliefs. affective polarization has political consequences and political beliefs stem, in part, from partisan animus. a defining feature of st century american politics is the rise of affective polarizationthe tendency of partisans to dislike, distrust, and avoid interacting with those from the other party (iyengar, sood, and lelkes ) . today, such partisan discord has reached record high levels (pew research center ) and it affects many apolitical aspects of our lives: for example, where we shop, our friendships, and our romantic lives (for a review, see iyengar et al. ) . but how does affective polarization affect our politics? surprisingly, we do not know much about this relationship: "little has been written on this topic (i.e., the political effects), as most studies have focused on the more surprising apolitical ramifications" (iyengar et al. , ) . here, we investigate one aspect of that puzzle: how does affective polarization shape our policy beliefs? demonstrating this relationship is fundamental to our understanding of how policy preferences develop, particularly in our present political moment. if affective polarization shapes issue beliefs, it would ( ) constitute direct evidence that citizen polarization matters for politics and ( ) suggest that policy attitudes stem partially from animus, rather than simply from more substantive rationales (cf. fowler ). the scarcity of work documenting such an effect, however, reflects the extreme difficulty of doing so. issue positions are endogenous to partisan animus: elite polarization drives both affective polarization (rogowski and sutherland ; webster and abramowitz ) , as well as issue positions (via cue-taking, see lenz ) . unsurprisingly, those who are more affectively polarized tend to also hold more polarized issue positions (e.g., bougher ), so it is unclear whether the relationship between issue positions and affective polarization is a causal one or rather a product of other factors that jointly lead to both outcomes. to unpack these effects, one would need a measure of affective polarization taken prior to the emergence of an issue, something that is impossible to predict and thus difficult to accomplish. the covid- pandemic, however, presents us with a means of doing so. because the virus and resulting pandemic was completely novel when it emerged in early , partisans did not have prior beliefs about it and their pre-covid levels of affective polarization cannot be affected by how elites acted during the crisis. a pre-covid measure of affective polarization, therefore, allows us to determine the relationship between partisan animus and beliefs about the pandemic. this not only enables us to uniquely isolate whether affective polarization shapes policy attitudes, but it also provides essential insight into the covid- crisis. if affective polarization divides the public, it creates hurdles for policymakers as they develop strategies to combat the pandemic now and in the future. it is not simply that there are partisan divides on the severity and handling of the crisis (e.g., gadarian, goodman, and pepinsky , and mccarthy ) , but rather that dislike of the opposition, at least in part, drives such gaps. this implies that policymakers and communicators must not only find substantive policies that bridge differing partisan priorities, but they also must find a way to vitiate partisan animus, a much more difficult task. it also is extremely difficult to experimentally manipulate levels of affective polarization due to extensive pre-treatment and ceiling effects among the more politically engaged segments of the public (see pew research center ). how does affective polarization shape responses to the crisis? a long line of political science research suggests that partisanship shapes how people interpret the political world (bartels ) , and how they assess credit and blame for governments' responses to crises (malhotra and kuo ) . the covid- pandemic has been no exception, with surveys highlighting large partisan gaps in the perceived seriousness of the crisis, actions taken in response to it, and assessments of blame for the outcome (allcott et al. ; gadarian et al. ) . much like other policies, even health pandemics have become partisan issues in the contemporary usa. at first blush, it might seem clear that partisan animus would lead to clear divides on political issues. yet, as we noted above, simply because partisans take different positions on issues does not mean that these positions are a function of affective polarization: for example, partisans might hold differential factual beliefs about the world (gerber and green ; fowler ) or have different underlying values (goren ) . in the case of covid- , republicans might see different information about the pandemic, or they might value economic stability more than democrats do, both of which would lead to partisan differences even in the absence of animus. given the existing evidence, we cannot conclude that affective polarization drives partisan differences in response to the pandemic. but there is reason to think that affective polarization, apart from partisan identification itself, can influence individuals' policy beliefs. specifically, affective polarization, perhaps ironically, will not affect politicized aspects of the issue. rather, political divisions in these areas manifest regardless of the level of polarization. when issues are already politicized, even those with low levels of affective polarization see them through a partisan lens. affective polarization rather politicizes ostensibly neutral targets, leading affectively polarized individuals to see apolitical topics through the prism of partisanship. we focus here on how americans evaluate the country's national covid- response. a unified response to this pandemic is central to ensuring collective success in defeating it. if affective polarization divides democrats from republicans, then it becomes more difficult to move forward with a coherent policy to address the crisis. prior work on attributions shows that partisan labels shape evaluations of government actors: individuals express greater confidence in, and more positive evaluations of, co-partisans (e.g., malhotra and kuo ; healy et al. ). this should straightforwardly apply to covid- . here, we compare beliefs about "president trump's" response to the pandemic to beliefs about the "united states'" response to it. the former clearly invokes a highly politicized (and polarizing) individual. the latter is a more neutral entity; also, using the nation as a whole primes national identity, which should mute the effects of partisanship (levendusky ) . further, evaluations of how one's country is handling the crisis are important as they tell us about cross-national assessments of governmental response to covid- (dryhurst et al. ). while we expect there to be a partisan split in response to president trump's handling of the crisis, it should not be driven by affective polarization, as all citizens will divide along party lines in response to such a politicized figure. asking about the country, however, need not evoke a partisan responsethere is no reason for democrats overall to evaluate the united states' response poorly whereas there is a clear partisan reason for them to evaluate trump's response poorly (and similarly for republicans in terms of no need to politicize the us response). this leads to our first hypothesis. h : democrats (republicans) will be less (more) critical of the united states' response to covid- , relative to trump's response to covid- , all else constant. we expect that affectively polarized partisans will politicize references to the country, seeing the national response through a partisan lens. this will lead them to equate the "united states" with the federal governmentand hence president trumpsimilarly to how affectively polarized citizens politicize trust in the government as a whole (hetherington and rudolph ) . for affectively polarized individuals, partisanship is chronically accessible and shapes their views of ostensibly neutral, or even potentially unifying, targets. they will see the "united states" as synonymous with, or at least similar to, "president trump," thereby politicizing it. they want to signal their partisan identity whenever possible (to make sure to distinguish themselves from the other side). h : as affective polarization increases, democrats (republicans) will be more (less) critical of the united states' response to covid- , all else constant. a consequence of h is that the treatment effect predicted in h will decrease or disappear among affectively polarized individuals since they view all targets politically (corollary ). in short, corollary follows logically from h and h (i.e., we expect a treatment effect that will shrink as affective polarization increases). our hypotheses concern democrats and republicans and, as such, do not apply to pure independents; we thus follow other work on affective polarization and exclude pure independents from our analyses (druckman and levendusky ). we pre-registered this exclusion and our hypotheses prior to the completion of data collectionspecifically stating the hypotheses in terms of corollary (for democrats and republicans)at: https://aspredicted.org/ pd i.pdf. a copy of our stage manuscript written prior to the data analysis is available at the dataverse link: https://doi.org/ . /dvn/slduut. we also test an alternative hypothesis, suggested by a reviewer but not initially pre-registered, that a measure of partisanship as a social identity moderates the treatment effect. partisanship as a social identity is a construct that captures the extent to which one feels as if he or she belongs to the party (e.g., when talking about the party, how often does the individual use "we" instead of "they," see huddy, mason, and aarøe ). while a plausible alternative, we did not pre-register this idea as our theory focuses on the out-party animus nature of affective polarization (which partisan social identity lacks). that negativity, we suspect, drives partisans to politicize issues to signal their partisan identities and differentiate themselves from the other side they dislike. we present these results here in the interest of transparency. issues of endogeneity make it difficult to determine whether affective polarization shapes responses to covid- or any other issue. a correlation between contemporaneous affective polarization and covid- opinions could stem from polarization causing beliefs about covid- , or from elite debates about covid- heightening affective polarization. we need data that measure affective polarization before people form issue opinionsin this case, prior to the outbreak of covid- . to circumvent this problem, we rely on a survey of a representative sample of , participants conducted in the summer of (from july , to july , ), prior to the emergence of covid- as an issue. in our pre-registration document, we stated that our initial sample included more than , individuals; however, prior to launching data collection, we realized that numerous respondents had not answered relevant affective polarization measures in our initial survey. as a result, the relevant re-contact sampling frame (who had answered the key affective polarization measure) was , . hence, there is a discrepancy here with the pre-registration sampling frame number (see supplementary information [si] for more details on this original study). the summer survey included four canonical measures of affective polarization (druckman and levendusky ): feeling thermometer ratings toward the parties (i.e., a scale where indicates very cold feelings and indicates very warm feelings), the degree to which respondents trust out-partisans versus in-partisans, trait ratings of opposing partisans (i.e., asking how well adjectives like patriotic, open-minded, etc. apply to out-partisans), and social distance measures that ask people how comfortable they would be to have a friend or neighbor from the other party, or how happy they would be if they had a child who married someone from the other party. we aggregate these items to form a measure of affective polarization (α = . ), looking specifically at out-party animus (e.g., lau et al. ) . we scale this measure to lie between and , with higher values indicating greater animosity for the other party. due to the timing of our measure of affective polarization, we can be confident that it is unrelated to the politics surrounding covid- , thereby allowing us to draw causal inferences about its effects on covid- beliefs. the summer survey also included a four-item scale to measure partisanship as a social identityincluding questions about the importance of one's party, how well the party label describes the individual, the use of the word "we" when thinking of the party, and the extent one thinks of him/herself as being in that party. this scaled measure (α = . ) enables us to test the aforementioned alternative hypothesis put forth by a reviewer. we re-interviewed these same respondents in the spring of (from april , to april , ), measuring their assessments of the handling of the covid- crisis to isolate the causal impact of affective polarization. a total of , participants completed the re-interview for a re-contact rate of % (see si for more details on the sample demographics). the re-interview survey included one measure of affective polarizationthe feeling thermometer itemand we find, consistent with prior work (alwin ; beam et al. ) , that it is relatively stable over time: there is a correlation of . between the original and re-interview outparty thermometer evaluation. this gives us confidence that the affective polarization measures from the pre-covid- surveys serve as valid and reliable measures of exogenous affective polarization. the covid- survey included an experiment to test our hypotheses. specifically, we randomly assigned participants to one of two conditions where they assessed the response to the covid- pandemic. one group was asked about president trump's response, while the other was asked about the united states' response. in each condition, we measured assessments on three items: ( ) confidence to address the pandemic (e.g., how confident are you that the trump administration/united states can limit the impact of the virus), ( ) response to the past preparation for the current outbreak (i.e., disagreement or agreement that president trump/the united states should have done more to prepare for the outbreak), and ( ) preparation for potential future outbreaks (i.e., disagreement or agreement that president trump/the united states should be doing more to prepare for the possibility of a future outbreak). if the results are consistent with our hypotheses, we should observe the following pattern of results. first, in line with hypothesis , we would observe that participants from different political parties offer differential evaluations of the targets (e.g., republicans being more favorable about trump than the united states). next, we expect to see that affective polarization moderates this relationship with a significant interaction between the us treatment and affective polarization (hypothesis ). finally, we also expect that affectively polarized individuals do not differentiate in their assessments of president trump and the united states, meaning that we may not observe any treatment effects among those who are most affectively polarized (corollary ). in short, we expect that those who are not affectively polarized will differentiate evaluations of president trump and the united statesviewing the superordinate category of the united states as something distinct from partisanship. in contrast, those who are more affectively polarized will politicize that superordinate construct, creating a divide even on an ostensibly apolitical target. the questionnaire for both surveys is provided in si . once we exclude pure independents, as explained above and in accordance with prior work, our dataset includes , partisans. we create a scale (ranging from - , with higher values indicating more approval/confidence) from our three evaluation measures (α = . ; see si for results presented separately for each measure). to test the first hypothesis, we run a model that includes only a variable for treatment assignment (y i β β united states i ε i ), where y i is respondent i's attitude about the response to the pandemic and united states i is an indicator for whether respondent i was asked about the united states' handling of the crisis (versus trump's). to test our second hypothesis, as well as the corollary, we run the we note, however, that one respondent did not answer any of our main outcome measures. the items also scale well if we look at the experimental conditions separately (α = . for the trump condition and α = . for the united states condition), or at the parties separately (α = . for democrats and α = . republicans). following regression: y i β β united states i β ap i β united states i × ap i ε i , where the additional variable, ap i , is the participant's level of affective polarization (measured in ). in table , we present the results separately for democrats and republicans, as we have separate expectations for the parties. we begin with the democrats and turn first to the test of hypothesis (table , model ). we see that democrats offer more favorable evaluations of america's response to covid- when asked about the united states' response relative to trump's response (difference of . , p < . for a one-tailed test). this follows from hypothesis : when asked about the response in the context of the united states, rather than the president, democrats are overall more positive. we next turn to our test of hypothesis (table , model ). here, we see a significant interaction between affective polarization and treatment assignment. turning to the substantive effects of this interaction, we see outcomes that are consistent with our predictions. first, increases in affective polarization among democrats have a significant, negative effect on evaluations of the response to covid- in both conditions. when participants are asked about the united our pre-registration stated that we would only run the second model, which contains the interaction between affective polarization and treatment. at the suggestion of a reviewer on the initial pre-registered report, we present both models as it provides a direct test of the treatment not conditioned by affective polarization. as per our prior note, we see in table , model , the treatment variable is significant as is the coefficient on the interaction term. an analysis of the marginal effect of the treatment shows that the treatment has a statistically significant effect at the . level in a one-tailed test when the affective polarization variable ranges from to about . . states, increases in affective polarization lower evaluations of the country's response by - . (p < . ); when participants are asked about trump, increases in affective polarization lower evaluations by - . (p < . ). this is in line with hypothesis , which posits that as affective polarization increases, democrats will become more negative toward the american response. the results for republicans are nearly identical but in the opposite direction, as expected. first (table , model ), republicans exhibit a lower evaluation of america's response to covid- when the target is the united states as opposed to trump (- . , p < . ). this result is in line with hypothesis . next, we again see a significant interaction between affective polarization and treatment in table , model . following hypothesis , as affective polarization increases, republicans become less critical of the american response in the united states ( . , p < . ); they also become less critical of trump response ( . , p < . ). we next consider another set of results suggested by corollary , which we present in figure . in this figure, we plot the predicted values for each party, for each experimental condition at different levels of affective polarization. in the united states treatment, democrats with low levels of polarization evaluate america's response to covid- at . , substantially surpassing the evaluations in the trump treatment ( . ). this difference between treatments is significant allowing us to reject the null hypothesis of no difference ( . , p < . ). yet, the democratic lines converge as polarization increases such that at the highest level of polarization, the united states and trump scores are extremely similar (respectively at . and . ) and we cannot reject the null hypothesis of no difference ( . , p = . ). in sum, highly polarized democrats' evaluations of "the united states" response are not statistically different from their evaluations of the "trump" response. in both cases, they politicize the potentially superordinate target. we see similar dynamics among republicans. republicans with low levels of affective polarization report higher evaluations of the american response in the trump condition than in the united states condition such that we can reject the null hypothesis of no difference ( . versus . , difference of − . , p < . ). yet the evaluations of the targets converge for republicans who are high in affective polarization and we cannot reject the null hypothesis of no difference (respectively, to . and . , difference of − . , and p = . ). the figure makes clear that affective polarization has a causal impact on political assessments, leading partisans to politicize evaluations even in cases with an, ostensibly, neutral target. this is concerning insofar as affective polarization leads partisans to split the effects of increasing polarization by treatment have overlapping confidence intervals, suggesting they are likely not statistically distinguishable from each other. again, we can see support for hypothesis with the significant effect of the treatment variable in model . the effects of increasing polarization by treatment have overlapping confidence intervals, suggesting they are not statistically distinguishable from each other. in si , we present some exploratory analyses these show the results are robust to the inclusion of a host of control variables. one intriguing exploratory finding is the least polarized democrats evaluate the response in the trump condition at virtually the same level as the least polarized republicans, perhaps reflecting a low levels of partisan reasoning. also, the least polarized republicans have much less favorable evaluations of the united states than the least polarized democrats when evaluating the country overall, undermining confidence in the national response which ideally would connect all citizens. finally, we turn to the aforementioned alternative hypothesis, offered by a reviewer, that the moderator is partisanship as a social identity rather than affective polarization. to test this, we run the interactive models from table but instead of our affective polarization measure, we include a partisanship as a social identity measure. we provide these results in table . we find the results do not replicate with that construct, suggesting that it is affective polarization generating our effects (as we pre-registered). the distinct results likely stem from the fact that partisanship as a social identity does not have an out-party animus component, which is what politicizes beliefspushing individuals to want to affirm their partisan identity and reject the other side. the rise in affective polarization has captured the attention of scholars, pundits, and citizens, yet we know little about its political effects and especially its effect on political issues. our study is the first to use a clearly exogenous measure of affective polarization to show how partisan animus shapes respondents' beliefs about a political issue. specifically, we show that affective polarization has little effect on already politicized issues, but it politicizes ostensibly neutral or apolitical ones. this makes clear that affective polarization or "political tribalism" is much more than mere reflections of policy preferences (fowler ) . it also highlights the reciprocal relationship between affective and ideological polarization, and it suggests that the two are quite intimately linked. our study also has implications for the ongoing response to the covid- pandemic. even ostensibly neutral communications become politicized by those who are highly polarized, thereby necessitating additional techniques to de-polarize them (e.g., bi-partisan endorsements; see bolsen et al. ) . in particular, it suggests that superordinate appeals to the nation ( van bavel et al. ) are ineffective for those who are most polarized, and hence policymakers need to craft strategies to appeal directly to them and work on de-polarization strategies rather than appeals to a shared identity. beyond this particular pandemic, our results speak more to the power of affective polarization to politicize novel issues and ongoing political debates. partisans who are more affectively polarizedwho are also more politically engagedpoliticize neutral issues and will polarize on most topics with only weak elite cues. our findings constitute the first evidence that affective polarization has clear policy implications as it divides opinion on those political issues that appear non-partisan or even apolitical. it highlights the importance of efforts to de-polarize partisans, as it may be the only route to coherent policy agendas. supplementary material. to view supplementary material for this article, please visit https://doi.org/ . /xps. . conflict of interest. this research is financially supported by the northwestern university, the university of pennsylvania, and the university of arizona. none of the authors have a financial conflict of interest, hold an office that creates a conflict of interest, or has a relative that creates a conflict of interest. no other party has the right to review paper prior to 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eric taylor; schertzer, robert; greenfeld, liah; hughes, chris; miller‐idriss, cynthia title: covid‐ , nationalism, and the politics of crisis: a scholarly exchange date: - - journal: nations natl doi: . /nana. sha: doc_id: cord_uid: nj ub in in this article, several scholars of nationalism discuss the potential for the covid‐ pandemic to impact the development of nationalism and world politics. to structure the discussion, the contributors respond to three questions: ( ) how should we understand the relationship between nationalism and covid‐ ; ( ) will covid‐ fuel ethnic and nationalist conflict; and ( ) will covid‐ reinforce or erode the nation‐state in the long run? the contributors formulated their responses to these questions near to the outset of the pandemic, amid intense uncertainty. this made it acutely difficult, if not impossible, to make predictions. nevertheless, it was felt that a historically and theoretically informed discussion would shed light on the types of political processes that could be triggered by the covid‐ pandemic. in doing so, the aim is to help orient researchers and policy‐makers as they grapple with what has rapidly become the most urgent issue of our times. covid- reinforce or erode the nation-state in the long run? together, these questions allow the contributors to reflect on how covid- may affect nationalism and the nation-state and how these core aspects of politics will in turn shape the response to covid- . the first question asks contributors to explain how they understand nationalism, how it may shape the response to covid- and whether covid- will in turn impact on nationalism. in their replies, greenfeld, hughes and miller-idriss discuss the ways in which nationalism is shaping the response to the pandemic. greenfeld argues that ethnic nationalism is a key variable shaping the responses of many states to covid- when compared with previous pandemics such as h n . miller-idriss strongly agrees and points out that states led by populist nationalists are faring much worse than others. hughes picks up on these themes by arguing that the medical and health care response is being 'weaponized' to support nationalist aims. on the other hand, the contributors argue that covid- will also shape nationalism. on this point, woods and schertzer put forward a typology for analysing how the pandemic could affect the development of nationalism, arguing that it could be constitutive, amplifying or transformative. ultimately, among these three possible trajectories, they argue that the most likely impact of the pandemic will be to amplify existing ethnic and national cleavages. miller-idriss joins woods and schertzer in highlighting this amplifying effect by pointing to rising anti-immigrant, xenophobic and conspiratorial anti-state sentiments in many states in the wake of covid- . hughes takes a slightly different view here by drawing attention to the potential for covid- to act as a transformative moment in chinese nationalism that revolves around pride for containing the virus. the second question asks contributors to reflect upon one of the most pressing issues on people's minds today-the potential for covid- to trigger and enflame ethnic and national conflict. several commentators have already raised the possibility of large-scale global warfare, given parallels to the decades following the spanish flu in and the economic ruin of the interwar period. however, there are many different types and levels of conflict: ethnic and national conflict has external (interstate) and internal (intrastate) dimensions, and it runs the gamut from largely peaceful political conflict to outright violence and warfare (schertzer & woods, ) . in their responses, the contributors consider these differing dimensions of conflict. focusing on the potential for covid- to exacerbate conflict between china, hong kong and taiwan, hughes notes how the pandemic has already provided the chinese government with a pretext for accomplishing its nationalist aims of integrating the territories with the mainland. on the other hand, hughes observes that taiwan has also used covid- to secure greater visibility in the international arena. this, in turn, risks drawing in more state actors, to become a larger interstate conflict between china and the west, particularly with the united states. on this score, greenfeld agrees that covid- risks amplifying conflict between china and the united states. greenfeld also comments on the possibility of the pandemic amplifying ethnic nationalism leading to the persecution of ethnic minorities. miller-idriss similarly focuses on the potential for covid- to increase persecution of minorities, noting the rise in anti-asian racism in the united states. however, for miller-idriss, it is in the fragile states of the global south where the risks of nationalist and ethnic conflict are greatest. for their part, woods and schertzer discuss many of these same themes, highlighting the specific risks that occur when a "politics of blame" is combined with nationalism. they argue that this combination can increase the risks of conflict with individuals and communities who are perceived as 'others.' finally, the third question asks contributors to project forward and reflect on whether the pandemic will have a lasting impact on the building block of our international order-the nation-state. as noted above, covid- arrived in a world where nationalism, trade protectionism and migration controls were on the ascent. it is possible that the pandemic will amplify these forces, leading nation-states to turn further inward. at the same time, the global nature of the virus may force international collaboration to mount an effective response. among these possible futures, no matter how much upheaval that may be caused by covid- , greenfeld doubts that it will shake the ideal of the nation-state as a vehicle for securing the identity and dignity of its citizens. quite the opposite, greenfeld suggests that the pandemic will work to erode global institutions. here, hughes broadly agrees with greenfeld, while also highlighting the ways in which the response to the pandemic could be used as a cover to strengthen the nation-state. hughes also warns that even the scientific community may not be immune to a process of nationalization. miller-idriss parts ways from greenfeld and hughes by suggesting that while the powerful nation-states may be strengthened by covid- , it is likely that the pandemic will erode the more fragile states of the global south. woods and schertzer pick up on this theme, while also pointing to a range of potential threats that covid- may throw at the nation-state, whether "from above" by neo-imperialisms or "from below" by new nationalist movements. however, while these threats may undermine some individual nation-states, they argue, like greenfeld, that this will not necessarily erode the potency of the nation-state as an idea. to answer these questions, as any question regarding the relationship between nationalism and other phenomena, it is necessary, first, to have a clear understanding of how cultures and societies function and evolve, in general, and of the nature of the cultural and social phenomenon of nationalism, specifically. to address these issues in , or so words fully is impossible, so i shall only state the empirical conclusions of my investigations and proceed on this basis. even these introductory remarks, however, must be introduced with a methodological consideration. when i am talking about a clear understanding, i do not mean to say "my understanding"; this would be tantamount to a chemist, for instance, saying "my understanding of gas is such and such," presuming that someone else's understanding is expected to be different. rather, assuming that cultures, societies and nationalism, just like gases, are empirical phenomena, i am approaching social and historical facts, following classical methodological recommendations, as things, without any prejudgement (bloch, ; durkheim, ) . the cultural (social, political, economic, etc.) process occurs simultaneously on the level of the individual mind and the collective level of the surrounding culture and consists of the constant give and take between these two levels. every collective trend begins with a new individual experience, to which the mind will react using existing cultural resources, but the reaction may be creative, that is, unpredictable. if the experience is sufficiently provocative and common, a new interest may transform this creative individual reaction into a shared ideal, eventually resulting in a new way of thinking and acting, that is, give rise to a new social institution, adding to the cultural resources and changing the institutional structure-the nature-of a society (greenfeld, (greenfeld, , (greenfeld, , . this, in most basic terms, is how societies change and evolve, in general, and how nationalism evolved, in particular. in regard to nationalism, specifically, one must keep in mind the following. (a) it is a historical, modern phenomenon: before the th century, there were no nations. (b) it is essentially a way of thinking, the basis of any institutional structure-thinking that the social world is naturally divided into sovereign communities of fundamentally equal members (communities called nations) and that a just society, consistent with the human nature, therefore, is an egalitarian society based on the principles of popular sovereignty. (c) as a result, nationalism implies democracy, every nation being a democratic society by definition. (d) the democratic/national principles of fundamental equality of membership and popular sovereignty can be interpreted and implemented differently, producing several types of nationalism: not every nationalism is ethnic. in the monotheistic civilization alone, in which ethnic nationalism is indeed the most common type, there exist two other types of nationalism: individualistic nationalism (such as the original english one) and collectivistic-civic nationalism (such as the french). (e) the broad appeal of nationalism is due to the fact that fundamental equality of membership in the nation and the consciousness of popular sovereignty dignify personal identities of members of the nation (greenfeld, ) . in this framework, we can examine the relationship between nationalism and covid- . let us begin with the possible effects of nationalism on the course of the pandemic. the course of the pandemic was certainly affected by the ways it was handled in different countries, and the way it was handled, i would argue, was a direct function of nationalism, specifically, of the national conflict between china and the united states. what leads me to say this? the comparison between coronavirus and previous pandemics: be it h n , sars, mers, ebola, hiv-aids of the recent decades, or such historically remote lethal attacks of infectious disease as the spanish flu of the last century or the plague (black death) in the middle ages. none of the previous pandemics involved worldwide lockdowns, cessation of normal activities and massive statesponsored and state-controlled mitigation. both the black death, which, incidentally, also came from china, and the spanish flu were incomparably more lethal than coronavirus: the plague would kill one in two people, %, in settlements it reached; if one contacted it, the fatality rate was between % and %. yet, only a few governments, such as that of the city of milan, ruled by a most brutal dictator, attempted to mitigate (benedictow, ) . of course, one can argue, no government at the time but a brutal dictatorship in a small city-state had the means to control its population (and the spread of the disease) to the extent that nationstates of today have. but this cannot be said of the influenza of and even less of recent pandemics (sars, h n , etc.), when the means of disease control at the disposal of governments were identical to what they are now. sars and h n , for instance, were at least as frightening as coronavirus (snowden, ) . but no worldwide panic ensued. neither the world economy nor that of any separate nation came to a standstill. one may argue that all of the recent pandemics proved far less devastating than was originally expected. but mitigation of coronavirus on a massive, coordinated scale began before it was known how devastating it might be (which is still not really known): reports that china was investigating a respiratory illness in wuhan appeared only on december , . the chinese government imposed a lockdown on the -million-large city of wuhan on january , . on january , when only one case of infection on the american soil was identified, the coronavirus task force was created in the united states, and on january , a ban on travel from china was imposed. closure of inessential businesses and schools, stay-at-home orders and construction of new medical coronavirus-ready facilities in record-breaking times followed. although the response of some other countries (japan, south korea and taiwan in the immediate vicinity of china, but also italy) was independent, most of the world was directly influenced by the reaction of china and the united states. within the first two months of the pandemic, economies contracted around the world, registering negative growth, unemployment skyrocketed, lives were universally disrupted, leaders interpreting this as they would results of a war on domestic soil and publics taking this in stride as they would indeed a war effort. what was different in the cases of h n , for instance, and coronavirus in the first two months of the declared pandemic? nothing. the difference in the reaction was not a function of the known difference in the nature or threat of the virus; it was a function of a difference in the political configuration of the world at the two points in time when the virus appeared. in april , when h n was first reported, the united states was still the one uncontested (though resented and attacked) superpower in the world. no nation yet took the place of the soviet union vis-à-vis it, challenging its position as the world's leader and arbiter. the superiority, the dignity and authority of the united states were beyond competition, if not beyond idle question. in , this was definitely not so. china, which only announced its nationalism in at its coming out party during the beijing olympics, has been steadily and at an increasing speed gaining on the united states in this competition in the past years, and the chief american national interest-the interest in superiority, dignity and authority-was now at stake. chinese leadership used coronavirus (whether intentionally or not) to challenge the united states to a single combat, so to speak. could you match us, president xi essentially offered, in containing a pandemic? the united states could no more disregard this challenge than it could disregard the sputnik in . and so, the public health race started: who could build a larger hospital in a shorter period of time, produce more ppe, administer more tests, stop outbreaks sooner and ensure more cooperation from the population? what could the rest of the world do, but follow the example of the two giants, disputing who would preside over it past ? now let us address the question of the possible effects of the pandemic on nationalism. would it, for instance, strengthen nationalist and especially ethnic-nationalist conflicts? given the news reaching us from washington and beijing, it seems clear that it has strengthened the nationalist conflict between the united states and china, which is as momentous as a nationalist conflict for the world today, as the nationalist conflict between the united states and russia (ruling over the soviet union) was at the time of the cold war. it is also quite clear that the pandemic had brought to the surface the nationalist conflicts within the eu, undermining the confidence in globalization in the one region which has been seen by experts as its empirical proof-the proof that human society was becoming transnational, transcending its national stage and moving towards a global community-and even among its staunchest erstwhile supporters. the universal reversion to nationalist policies and defence of particularistic national interests at the expense of transnational solidarity during the pandemic, however, only proved that rumours of nationalism's demise in the core western european nations have been grossly exaggerated. widespread manifestations of euroscepticism, such as strong national feeling in france, italy, the netherlands and so on, or even brexit, have not been regarded by theorists of globalization as an empirical contradiction of their theoretical position, but as proof of reactionary, right-wing or even extreme right political agenda of populist leaders and benighted, false consciousness among their uneducated followers. now it is obvious to all that the theorists were wrong (though how long this would remain obvious is another question): thanks to the pandemic, globalization today no longer seems the obvious current stage of human development, and nationalism no longer appears as the stage obviously transcended. nationalism in western europe (in distinction to central and eastern europe, for instance) has traditionally not been ethnic however, but rather individualistic, as in britain, or collectivistic-civic, as in france, italy and spain. would the pandemic fuel ethnic nationalist conflicts? the psychological foundation of ethnic nationalism is ressentiment, that is, existential envy, which is most efficiently assuaged by the humiliation to the point of elimination of the envied other; therefore, ethnic nationalism is inherently aggressive (greenfeld, ; greenfeld & chirot, ) . where it exists, anything can serve as fuel for ethnic aggression. the pandemic has already added to anti-semitic conspiracy theories (very much in line with medieval poisoning of the wells narrative born during the black death) in palestine and among certain publics in europe (adl, ). anti-semitism, of course, is the most deeply embedded institution (established way of thinking and acting) in the monotheistic world, predating nationalism by many centuries-and for this reason offering a particularly virulent and reliable channel of expression to ethnic nationalism-but one can imagine temporary flare-ups of less widespread ethnonational hostilities, in which a group identifies the object of ethnic national antagonism as the carrier of the virus. and, finally, will covid- reinforce or erode nation-state-that is, nationalism, nationalist institutions-in the long run? leaving aside the question of what can be said about the long run, in general, we should consider this in the wider framework of processes involved in social change, briefly sketched above. to use the most striking example of the social disruption caused by a sudden assault of infectious disease, the black death, the plague might have disrupted the medieval society of orders and shaken this social structure. land became cheap and labour dear, which allowed people from the lower classes to behave as if they belonged to the upper ones and encouraged intermarriage between poor noblemen and daughters of rich commoners. however, as with a dilapidating building, the unravelling of society did not in itself provide any orientation for reconstruction. the thinking remained the same, and for several centuries after the plague years of - , the reconstruction took the form of piecemeal patch-ups: sumptuary laws characterized the period, reflecting both that the old order was unravelling and that the only way society was imagined was exactly as it had been before the pandemic (cantor, ; cohn, ; herlihy, ) . only when reality was reimagined and new (national, as it happened) consciousness appeared did the direction of reconstruction became clear and set. institutions, which, as already durkheim emphasized, are just established ways of thinking and acting, are never stable-they are always in the process of waxing and waning, strengthening, weakening and modifying. conceptualization-ways of thinking, that is, to use weber's terminology, ideals, especially if encoded in laws, sacred texts, whether religious or secular, such as the american declaration of independence, popular and high culture, and so on-is always their strongest feature, but can rapidly be abandoned, if the interests supporting these ideals disappear. the interest behind nationalism and its institutions (e.g., nation-state)-dignity of personal identityis alive and well. covid- also ranged behind it the essential material interests (health, life and livelihood), pointing at the same time to the inability of transnational institutions-globalization-to serve these interests. it is transnational institutions, rather than nation-state, that are likely to fall victim to the pandemic. i would like to interpret the three questions as addressing national identity, policy-making and state-building, respectively. greenfeld is right to highlight how covid- has been politicized by growing tensions between the united states and china over a range of issues. this can be explored further by looking at the way in which covid- is being used in a process of mutual identity construction, which makes it impossible for medicine and science to be politically neutral. a good starting point is the naming of the virus. who has been aware that identifying the geographical origin of a virus can provoke a backlash against members of a particular religious or ethnic community since , at least, when it produced guidelines that call on governments to avoid this (who, ) . the convention was breached when the trump administration saw political mileage in using labels such as "wuhan virus" and "china virus" instead of the neutral name "covid- ," leading the chinese government to castigate it as suffering from an "ideological virus" (people's daily, ; wang, ) . this is despite the fact that the chinese government had already used the name "wuhan virus" to imply that the epidemic was a localized outbreak. it may be true, as greenfeld points out, that there has been an unprecedented scale of international coordination to contain covid- , but the history of pandemics shows that measures to control movement can be used to form national identity. this actually goes back to the age of empire, when thousands of muslim pilgrims were detained under sanitary controls imposed on the red sea area. in contrast, few people called for the quarantine of lawrence of arabia or other allied soldiers returning from the middle east in world war i (chase-levenson, ). a similar dynamic can be seen when various countries responded to covid- by imposing bans on travel from china in february , motivating the chinese government and commentators to make accusations of racial prejudice. beijing's ambassador to israel even went so far as to liken the closure of borders to the turning away of jewish refugees during the holocaust, which the embassy had to quickly retract (the guardian, ). this is typical of the process by which governing elites use the spectre of the external enemy, or the "other," to build national identity, that woods and schertzer draw attention to. at present, china and the united states are clearly using covid- in this way. this is illustrated by the controversy that blew up when the wall street journal published an article titled "china is the real sick man of asia" in february (mead, ) . china reacted by expelling three of the newspaper's reporters, while its foreign ministry warned that it "must be held responsible for what it has said and done," to which us secretary of state mike pompeo responded that "mature, responsible countries understand that a free press reports facts and expresses opinions." it is also important acknowledge that the pandemic is being used for a more positive construction of identity. this is quite clear in the way that the chinese government is using its apparently successful containment of the pandemic to propagate the superiority of the "china model" of politics, after the legitimacy of the chinese communist party (ccp) was badly dented by the early mismanagement of the crisis. by describing the campaign in terms of a "people's war," it can also be linked with the narrative of the ccp's "salvation of the nation" from japanese aggression and misrule by the nationalists in the s and s. one of the most disturbing aspects of the covid- crisis is the way in which it is used to weaponize medicine in ethnic and nationalist conflicts. this is most evident in the ccp's attempts to exert control over territories that are central to its nationalist mission. it could already be seen in the summer of . during that time, medics were subjected to police intimidation, arrest and surveillance as they came to the aid of citizens who were injured in demonstrations against the introduction of a law to extradite residents to mainland china, according to dr darren mann's eyewitness testimony before the house of lords on december , . such behaviour is in breach of the principle that access to treatment is a universal right without distinction of race, religion, political belief and economic or social condition, as enshrined in the who charter. this was already a strong deterrent to demonstrators when beijing took advantage of a ban on mass gatherings in the territory to impose a national security law in may , which will criminalize criticism of the ccp as unpatriotic and secessionist. when demonstrators defied the ban, they were condemned as a "political virus" (scmp, ). the use of covid- to fuel a nationalist conflict can also be observed in china's insistence that taiwan should be excluded from who, on the grounds that it is a part of china, despite its excellent record in containing the pandemic. it is too early to know how covid- will shape taiwan's identity politics, but the same situation during the sars epidemic of - allowed its incumbent president to use the "chinese plague" to galvanize flagging support in the polls by holding a referendum on demanding representation in international organizations, which helped him to win re-election in . given that an opinion poll conducted before the virus hit taiwan shows that the proportion of the population who self-identify as taiwanese has already risen to a new high of %, while % identify as both taiwanese and chinese (pew, ), taiwan's current president can gain substantial political capital by ramping up the campaign for who representation. the potential for covid- to fuel a nationalist conflict is further heightened when such issues become part of global and regional geopolitics. this is deepening as taiwan gains substantial support from other democratic states, while china appears to be taking advantage of the health crisis to step up its naval and air force intrusions into the waters around the island and into the south china sea. this growing linkage of the pandemic with the national security of the united states and china creates a context within which individuals in both countries are likely to be harassed as carriers of covid- , especially in the context of the rising populism that is highlighted by miller-idriss. this can be seen in the united states, where anybody deemed to be "chinese" due to their east asian features has become more liable to be harassed and assaulted. in china, where popular nationalism has long been used by the ccp as a source of legitimacy, xenophobia been fed by the narrative that the party is fighting and winning a "war" against a virus that was sent by the united states and is being spread by foreigners. there have been particularly serious cases of racism towards africans, due to the erroneous belief that they are unhygienic carriers. while miller-idriss is right to point to the ways in which covid- has been used to fuel anti-government extremism and conspiratorial sedition, it is also possible to find examples where civil society actors have criticized its use for nationalistic purposes: some reporters and editors at the wall street journal signed a letter calling for the "sick man" headline to be changed and for an apology to be made; chinese commentators have pointed out that it was their own intellectuals who began to refer to their country as a "sick man," going as far back as the defeat of the qing empire by japan in . such voices will remain marginal compared with the advocates of nationalism, however, unless covid- gives medical science sufficient authority to force the kind of cooperation between states that will weaken national sovereignty. history provides little evidence to support this prospect, however. from the coordination of quarantine procedures between the italian city-states down to today's who, contagious diseases have allowed governments to steadily accrue power over their citizens. china's use of information and communications technology to surveil its citizens as it manages covid- marks a new stage in this process. the dangers posed to civil liberties in democratic systems are also shown by cases such as the use of mobile telephones to identify and trace a disproportionate number of south korea's lgbt community, who face serious discrimination as a result. the state will become even more powerful if covid- justifies the introduction of new barriers to migration and the targeting of border health checks according to the national origins of travellers. the current crisis also shows how disease can be used not only to undermine the authority of scientists and medics, as miller-idriss points out, but also to turn them into political actors and national symbols. most controversial is the casting of dr li wenliang, as a "martyr" after he died from the virus, despite having been detained and disciplined by the authorities for trying to warn his colleagues at the early stage of the outbreak in wuhan. he the harnessing of scientists and medics to the nation-state can even be traced back to the china's first international conference, a meeting of epidemiologists in to discuss a pneumonic plague that had killed some , people in manchuria. to be sure that a "chinese" scientist should play a leading role, the qing empire appointed dr wu lien-teh ( - as its representative, despite the fact that he was born in malaysia and was thus a subject of the british empire. having been on the receiving end of the racism of european scientists and diplomats, wu was happy to lead a project that was partly seen as a way to prevent japan and russia from using the plague to assert their growing control over manchuria (wu, ) . he would go on to become an authority in the emerging international health system, challenge british interests in malaya by establishing an anti-opium society, campaign to remove racial discrimination in the provision of public services, and co-author a history of chinese medicine (wu & wong, ) . members of the scientific community can thus be agents of nationalism as much as they can be a force for cooperation. the latter becomes less likely as the decoupling of the united states and china requires them to prove their loyalty or face accusations of subterfuge or even espionage. the need for states to ensure self-sufficiency and reliable partnerships for the supply of essential medicines and protective equipment is also leading to the securitization of health, which will accelerate the deglobalization of trade and the movement of people. the recent decision of the united states to withdraw from who due to its handling of the pandemic thus looks more like a throwback to the years when sovereignty trumped international cooperation and brought down the league of nations than a world in which the nation-state is in decline. i thus agree with greenfeld that transnational institutions are more likely than the nation-state to be damaged by the pandemic. there are several dimensions to the relationship between nationalism and covid- that ought to be disentangled, but first, let me be clear about how i understand the concept of nationalism itself and the version of it i analyse here. nationalism is an exclusionary political project to make the state congruent with the nation (fox and miller-idriss ) . this can take many forms, from fully secessionist and independence movements to xenophobic and antiimmigrant expressions within an existing state. the current form of nationalist governance that we have seen emerge in several global states is what i call populist nationalism. populism is both a schema (way of thinking) and a rhetorical strategy that pits the ordinary, pure people against the corrupt elites (bonikowski, ; canovan, ; brubaker, ; miller-idriss ; mudde, ; müller, ) . populist nationalism, in turn, extends this pure people-nefarious elite dichotomy to a framing in which all "others" pose an essential threat to the pure nation and its ordinary people. only a stronger state, so the argument goes, can protect the nation from the growing danger posed by immigrants, ethnic others, non-christian religions and more. this is what jan kubik ( ) calls a "thick" form of populism, in contrast to mudde's ( ) description of populism as having a thin ideology. others have described "thick" populism using slightly different terms, such as rogers brubaker's classification of vertical and horizontal dimensions of populism, where the vertical dimension positions the people against the elite and the horizontal dimension creates intense polarization and fixed boundaries between groups of people (brubaker, ; berezin, ; kubik, ; miller-idriss, ) . populist nationalism is the form and expression of nationalism that i refer to in this essay, although i will also use the shorthand "nationalism" to refer to it. with this understanding of nationalism, i return to the relationship between nationalism and covid- . i suggest that there are at least three major impacts to explore. first, early indicators suggest that there is a direct impact of populist nationalism on the public health, infection rates and mortality rates of covid- . as i write this, several of the countries in the world with the highest covid- infection rates are led by populist nationalist leaders-including the united states, brazil and the united kingdom. the united states alone is responsible for over a quarter each of covid- infections and deaths globally, although the us population represents only . % of the global population (see world health organization, , online; united states census bureau, , online). why would populist nationalism itself be detrimental to a public health crisis? one reason is that populist nationalists' attacks on the "corrupt elite" have gone well beyond critiques of political leaders and opponents to include other "elite" experts, academics and scientists, as evidenced by a rejection of climate science and global environmental agreements, for example. undermining and delegitimizing scientific expertise and global cooperation and information sharing makes it significantly more difficult to convince the public of the benefits of shelter in place orders or practices to reduce the spread of the disease. in the case of covid- , populist nationalist leaders are thus more likely than other national leaders to reject scientists' advice, attack global organizations like who, promote scientifically unproven and potentially harmful treatments for covid- and reject scientifically proven practices like wearing masks in public. populist nationalist anti-elite and antiscience sentiments have undoubtedly led to higher covid- infection and mortality rates as a result. populist nationalists do not only attack and undermine scientific expertise, of course. the purity of the people, within populist nationalist frames, rests both in contrast to corrupt elites and to racial, ethnic, religious and immigrant "others." this is where the second impact of nationalism on covid- outcomes becomes clear. across europe and north america, there has already been a documented rise in xenophobic, anti-immigrant, anti-asian and anti-semitic hate during the global pandemic. the us administration's insistence on using the term "wuhan virus" or "chinese virus" is one of "many strategies of apportioning the blame for the (spread of the) virus to a specific place/country and to construct the disease as a foreign-grown threat to the nation" (nossem : ). in the united states alone, over , anti-asian hate incidents were reported within the first weeks of a new website established by asian american and pacific islander civil rights groups (lee & yadav, ) , to name just one example (see stop aapi hate reporting center, n.d. online) . such xenophobic expressions of nationalism are part of a clearly documented, pre-covid- rise in far right and extremist hate and the legitimation of white supremacist extremism (ebner, ; miller-idriss, mudde ) . white identity and the need for its protection and defence is a common thread across white supremacist and white nationalist beliefs and practices (belew, ) . during the covid- pandemic, these expressions have found a home in the circulation of memes and social media commentary that scapegoat entire populations as being responsible for the virus and its spread (see anti-defamation league, ) . dehumanizing language about "dirty" immigrants carrying disease has accompanied immigration bans along with border closures, asylum application denials, deportations and more, even while the practices of local "native" populations that rapidly spread the virus in local churches, parties, funerals, ski lodges and more have continued in more or less unchecked ways. at the extreme fringe, moreover, there are clear risks that the covid- era will help reinforce white supremacist extremists' sense of white victimhood and concomitant emotional appeals to protect, defend and take heroic action to restore sacred national space, territory and homelands (miller-idriss, ) . the third impact that has emerged as a result of the relationship between nationalism and covid- is the rise in anti-government extremism and conspirational sedition (finkelstein et al., ) . anti-government and apocalyptic far right extremists have rapidly grown in online and offline presence across the united states and europe, in part through organized protests against state and national shelter in place orders. calls for violent uprising against the state, political opponents and law enforcement-resulting in part from widely circulating misinformation and disinformation about governments' responses to covid- -have already inspired several violent attacks on law enforcement and at least two planned or enacted plots against hospitals. the growing popularity of conspiracies about a "deep state" and an apparent new convergence among anti-government groups across the political spectrumincluding anti-vaxxers and flat earthers, qanon conspiracy theorists, guns' rights advocates, patriot militias and white supremacist extremists-have created a combustive mix that brings a high risk of serious violence, particularly as we head into a likely second wave of spiking infections and shut downs in the fall of . conspiracy theories about governments' and corporations' plans to use a vaccine to microchip, neuter or control citizens are also circulating widely in extremist circles, which suggests that nation-states have a significant implementation challenge ahead of them even after a vaccine is successfully produced. covid- is likely to fuel ethnic and nationalist conflict in several ways. in the global north, as discussed above, rising xenophobia, conspiracy-fueled anti-asian and anti-semitic violence and anti-immigrant hate are already prevalent during the covid- pandemic. the potential short-and long-term impacts of school and university closures on youth radicalization are also significant. in the united states alone, over million youth in the primary, secondary and postsecondary systems are currently affected by school and college closures. this has led to massive increases in online engagement in ways that create incalculable risks of engagement with extremist material and recruiters. shortly after the pandemic began, us federal law enforcement issued warnings about the increased risk of child exploitation as a result of highly online youth presence, combined with reduced parental/caregiver supervision and lessoned interactions with other trusted adult networks, including teachers, coaches, youth group leaders and adult relatives outside the home (federal bureau of investigation, , online). similar risks exist for online radicalization (e.g., see state of new jersey office of homeland security and preparedness, ). the impact of extraordinary amounts of time spent online during the covid- pandemic-along with a risk in the drivers and grievances that create susceptibility to radicalization, such as anxiety, uncertainty, isolation and lack of purpose-will be clearer as time passes, but should be understood for now as a high-risk situation related to potential future violent extremism and terror. in the global south, covid- will potentially exacerbate ethnic tensions or fuel new ones in already-fragile states. a heightened lack of trust between local communities and governments or international organizations is part of the problem-in some cases, caused by very real abuses and instances of violence perpetrated by some frontline police and military responders during covid- curfew enforcement. in places where trust in governments is already low, or where there are existing grievances about inequitable distribution of resources, uneven responses in health care provision or distribution of resources can fuel ethnic conflict. these vertical tensions (between communities and authorities) are matched by deeper horizontal tensions between ethnic groups as shelter-in-place orders have reversed gains that had been made through promising communal engagement programmes that brought people together across dividing lines. as families retreat into ethnic communities, the fragile bonds from emerging crossethnic forms of engagement and cooperation are at risk. finally, both kinds of tensions-vertical and horizontal-are further heightened through the actions of bad actors who have circulated unreliable sources of information, disinformation, misinformation and conspiracy theories about the virus. some campaigns have targeted ethnic minorities through labels like the "rohinga virus," the "muslim virus" or the "refugee virus," aiming to produce fear and uncertainty and incite conflict (see search for common ground, n.d.). i would expect to see splintering on this question, for several reasons. one has to do with the issues of trust in government discussed above. in countries where the national response has strengthened public trust in the government-such as germany and new zealand-the nation-state will likely be strengthened. but in places where trust is weakened as a result of the government's response to covid- , including in the united states but also in more fragile states in the global south, the nation-state will likely be further eroded. the widespread circulation of misinformation, disinformation and conspiracy theories related to the virus and a covid- vaccine will also exacerbate declines in the nation-state's power, particularly in states where elected officials have failed to counter or have actively supported some conspiracy theories, even prior to covid- (see rosenblum & muirhead, ) . the same is likely true for the ways that covid- has illuminated existing disparities in health care provision across ethnic and racial groups. the drastically different infection and mortality rates for minorities compared with whites in the united states, for example, make it clearer than ever that the nation-state does not serve all its people equally. the uneven loss of life for black americans and communities of colour should be a wake-up call to nationstates and their citizens about the need for systematic change in social services and health care provision, as well as the need to address ongoing legacies of structural racism and discrimination. i would argue that the extent to which nation-states respond to these grievances will play a big part in whether the pandemic ultimately is a strengthening or a weakening force for the nation-state more generally. finally, increases in ethnic group conflict and political or ethnic group polarization and hate in the wake of covid- continue will also likely have differential impacts, depending on how states react. countries whose local, regional and national leadership firmly and unequivocally condemns hate and scapegoating related to the virus may be able to come out of the pandemic with stronger and more resilient communities and nation-states. but in places where political leaders ignore or exacerbate these tensions and contribute to further polarization, it is hard to see how covid- will not contribute to the further decline of the nation-state and the people's identification with it. we approach all three questions through a lens that conceives of the covid- pandemic as a crisis. this enables us to construct a typology of the differing ways that crises can impact the development of nationalism. we then use this typology to frame our discussion of how the pandemic could shape nationalism and how nationalism in turn could shape the response to the pandemic. covid- constitutes a severe global threat. it has significant potential to trigger multiple, cascading crises in nearly every aspect of our lives. in addition to the presence of a threat, crises typically involve systemic disruption, uncertainty and stress (brecher, ; quarantelli & dynes, ; rosenthal et al., ) . as a result of this widespread upheaval, crises have a high potential for triggering change (falleti & lynch, : . the concept of crisis has not been a specific focus in the field of nationalism studies. that being said, events that could readily be defined as crises, such as warfare, revolution or economic catastrophe, have been central to research on nationalism. this literature suggests that crises can impact the development of nationalism in three distinct ways: they can be ( ) constitutive, ( ) amplifying, or ( ) transformative crises as constitutive events. crises, particularly those that are associated with revolution, can be constitutive events in the formation of new nationalisms. indeed, the french revolution of is often depicted as the formative event for the worldwide spread of nationalism. during a revolution, the struggle against perceived illegitimate rule can provide a catalyst for the emergence of nationalist sentiment-the idea that "we" constitute our own nation and therefore ought to have political autonomy (see hobsbawm, ; bell, ) . similarly, warfare can be a powerful catalyst for the emergence of nationalist sentiment through conflict with a common threat (hutchinson, , pp. - ) . crises as amplifying events. crises can also have an amplifying effect on existing nationalisms. as such, they can reinforce both solidarity and division within and between national communities. solidarity is often expressed through a "rally around the flag effect," in which people unite under national leaders during the crisis (brody & shapiro, ; mueller, ; oneal, lian, & joyner, ) . nationalism can also provide a collective cipher for succour and inspiration during a crisis, whereby myths, symbols and practices associated with past crises are "rediscovered" and applied to the new crisis (hutchinson, ) . the crisis might also give rise to new cultural content and practices, which can further reinforce solidarity (hutchinson, ) . however, the inevitable search for responsibility that accompanies a crisis can also amplify divisions with perceived malevolent "others," both within and outside the national community. thus, during a crisis, it has been widely observed that attacks against internal minorities tend to surge, while the potential for conflict with external adversaries is heightened. crises as transformative events. as much as crises can amplify existing nationalisms, they can also be transformative. for example, crises can lead to new configurations of cultural boundaries between who is perceived to belong and who does not. previously excluded minorities might be incorporated into the national "we" as they make common cause against the threat. for example, the war against a genocidal germany was an important catalyst for the increased social inclusion of jews in america (alexander, : chapter ) . however, by the same token, minorities that were once included, or at least tolerated, might now be excluded if they become associated with the new threat. thus, after the terrorist attacks of september , muslims in the west became the new significant "others" (byng, ; poynting & mason, ) . in the international sphere, perceptions of who is the "friend" and "foe" can also undergo reconfiguration during a crisis. this occurred, for example, in the dramatic reversal of how the west perceived the soviet union following the world war ii. so, which of these potential pathways might nationalism take in the wake of covid- ? it is too early to tell whether this pandemic will be a constitutive event for the rise of new nationalisms. the same goes for whether it will have a transformative impact. there are signs of a potential "hamiltonian" moment in europe with the agreement between germany and france to pursue a € bn aid package for the eu, but there are no guarantees that all member states will agree to the proposal, nor whether this will persuade the citizens of those states to relinquish their national identities in favour of a pan-european identity. nevertheless, in some instances, there are early signals that covid- could move the boundary of who belongs and who does not. in the united kingdom, the importance of ethnic minorities to the nation has been made salient through their increased visibility in the professions on the frontlines of the struggle against the pandemic (hirsch, ) . this is also happening in canada, where leaders are considering making asylum seekers permanent residents to recognize their work in long-term care facilities (seidle, ) . but these are only two examples and it is still early days; in many other cases, we are seeing the opposite happen where migrants are being targeted. we therefore think that among the three pathways we described, the most likely impact of covid- will be to amplify existing nationalisms. there are already indications that covid- is amplifying nationalism across numerous contexts. most national leaders are enjoying a surge of support. myths and symbols related to how nations endured past crises, such as warfare, have been rediscovered and repurposed by national leaders in order to inspire their constituents as they confront the pandemic. new collective rituals have also emerged, such as weekly national "clapping" for key workers in the united kingdom, or the newly founded national days of mourning in spain. but this amplifying effect has not been entirely solidary. for example, in the united states, there has been a surge in racist attacks against asian americans (tavernise & oppel, ) . meanwhile, as we discuss in our response to question , it is fuelling division in the international sphere. the divisive othering and attribution of responsibility that stem from a crisis can increase the likelihood of intrastate political conflict, but not necessarily lead towards interstate violence. the splitting of populations into categories of "us" and "them" is central to nationalism. as fredrik barth ( ) points out in relation to ethnic identity, it is through contact with "others" that we construct a sense of "our" group. this othering tends to also entail a moralizing process that glorifies "us" and vilifies "them" (schertzer & woods, a) . and therein lies the rub: at times of crisis, this tendency can propel ethnic and national conflict because it creates logics that rationalize violent or discriminatory practices against perceived malign or corrupted "others." this is because nationalism provides a cultural roadmap for attributing responsibility for a crisis, in the sense that it is typically the vilified "others" that shoulder the blame. with covid- , attributing responsibility to an "other" is somewhat indirect, because ultimately, the responsibility lies with a virus rather than human actors. covid- is an "invisible enemy," as donald trump likes to quip. in this regard, the pandemic is akin to a natural disaster. but even natural disasters typically provoke efforts to attribute responsibility to human actors-to lay blame at the feet of an individual, group or institution for failing to act appropriately (bucher, ; yates, ) . this process of attributing blame can be highly conflictual. as the conflict takes shape, it tends to align with and amplify existing cleavages (tilley & hobolt, ) . for example, after hurricane katrina, an emotive struggle over responsibility ensued that ultimately enflamed a longer running conflict over the place of african americans in america (eyerman, ) . similar processes are emerging in relation to covid- . the pandemic is amplifying nationalist sentiment (see legrain, ) , which is precipitating a "politics of blame." this is particularly visible in relations between the united states and china. as hughes discusses in this exchange, a relationship that was already strained is now rapidly worsening, as the two countries blame one another for the pandemic. there is a fear that these political disputes may lead towards violent conflict. the vastly simplified argument here is that covid- creates a series of economic, social and political crises that increases incentives and opportunities for interstate conflict. and when rising nationalism is added to the mix, it increases the probability that leaders will opt for war (see hutchinson, ) . in our view, this account gives too much power to nationalism as the key driver of conflict. we know many of the conditions and logics that drive interstate warfare, and covid- does not necessarily lead us down these pathways. as others have argued, the pandemic has created significant logistical issues for mass troop mobilization, it has shaken the confidence of states and leaders and there is no necessary link between economic downturns and warfare-recessions are a bad predictor of interstate conflict (posen, ; walt, ) . while nationalism can shape decisions and introduce irrationality, it does not necessarily have the structuring power to overcome the current barriers to interstate warfare. the view that increasing nationalist sentiment will inevitably lead to violent conflict also oversimplifies nationalism. this logic assumes that nationalism is always dangerous and illiberal, which in our view is an outmoded that builds on a normative distinction between bad (ethnic) and good (civic) forms of identity. what is more likely is that covid- will amplify internal ethnic divisions within states. the process of othering, the search for blame and the calls to protect our "own" are driving a dynamic whereby foreigners and migrants are being targeted in many states. as miller-idriss details in her contribution, asians in western countries are suffering racist and violent attacks as perceived stand-ins, carriers and collaborators of the "silent enemy." migrants are facing hostility as potentially dangerous vectors of the virus and threats to the host society. asylum seekers are being denied entry into many countries or held in dangerous camps where they are at greater risk of contracting covid- . in short, some ethnic divisions within states are becoming increasingly salient. this type of internal ethnic conflict is not directly attributable to the pandemic. rather, it reflects how the internal dynamics of a national community are shaping the response of leaders and the public at a time of crisis. political culture matters in how covid- is shaping nationalism: it is the nation's cultural and political characteristics that are driving the emergent dynamics of conflict. these dynamics are not necessarily marching us down a path towards interstate violence, but they are making existing ethnic divisions within and between nations more salient. the nation-state has a privileged position in our political order. the international system is based upon the idea that political communities, called nation-states, deserve autonomy. the logic of nationalism provides legitimacy to this order: it is because states protect and represent a nation that they have sovereignty (mayall, ) . at first blush, we might expect that a global pandemic would erode the status and autonomy of nation-states: international collaboration and a pooling of resources are necessary to combat the virus. and yet, nation-states are leading the response to covid- , while the legitimacy of international organizations like the who is being questioned. given these early trends, and what we know about the endurance of nation-states, in our view, covid- will likely reinforce the nation-state. the early signals point towards a trend of nation-states greatly increasing their power in the face of covid- . they are reinforcing borders, curtailing migration, limiting internal population movements, spending vast amounts of money on economic stimulus and increasing surveillance of citizens. many of these moves have come at the cost of individual liberty and privacy (economist, ) . some of these measures will be relatively short lived, and others will likely be difficult to roll back. regardless, these patterns recentre the state in our lives. they bring the state back into view as a powerful actor (skocpol, ) . but these developments are about more than simply expanding the administrative capacity of states-they also reinforce the nationalist idea that they represent "nations." leaders and publics alike have embraced the rationale that increased state authority and power is necessary to protect the safety and way of life of the nation. this rationale is evident in the competition over medical supplies, which is increasingly nationalist in tone (goodman, thomas, wee, & gettleman, ) . european union states have worked against one another by limiting the export of protective equipment to other members in need. the united states has taken actions to limit the export of protective equipment to canada. conflicts over the production and distribution of an eventual vaccine are already taking shape. rather than concerted international collaboration and coordination, we are seeing increasingly protectionist approaches driven by the logic of the nation-state. at the same time, the nation-state is facing threats-from below and from above. there is an argument that substate national movements may use covid- to push for greater autonomy. this could trigger renewed instability, particularly in multinational states. but the evidence so far suggests the contrary. many multinational states are seeing a remarkable degree of pan-national solidarity. both dynamics are playing out now in the united kingdom: an early surge in solidarity across the union is increasingly diverging along national lines, with scotland, wales and northern ireland adopting different approaches to the pandemic. however, even if covid- does destabilize multinational states through national minority mobilization, this does not completely threaten the idea of the nation-state. national minorities seeking independence are not working to undermine the international society of nation-states; they are working to join it (williams & schertzer, , p. ). covid- may also threaten the nation-state from above. the economic and political crises that it will inevitably trigger can create opportunities for powerful nation-states to extend their influence over less powerful ones. in this regard, the pandemic may enable new forms of imperialism, undermining the status and sovereignty of nationstates. there are clear parallels supporting this argument: "foreign aid" provided by powerful states and institutions during past crises often belied thinly veiled forms of neo-colonialism (see charbonneau, ; fieldhouse, ; langan, ) . but even a resurgent imperialism may not undermine the idea of the nation-state system. history can serve as a guide. during the "cold war," the idea of the sovereign nation-state was strengthened. despite the widespread influence of the united states and soviet union, the idea that the world was fundamentally composed of sovereign nation-states did not diminish. therefore, we tend to agree with greenfeld that the covid- pandemic will not diminish the nation-state system in the long run. if we are right-if covid- reinforces the nation-state-then there are some potential perils. the amplification of power and autonomy of nation-states, paired with limited checks and accountability, may have long-lasting effects for privacy, security and democracy. people are rightly fearful that newly emboldened nation-states may hinder the necessary international collaboration to manage the pandemic. but this fear rests on a false dichotomy: a strengthened nation-state is not irreconcilable with strong international collaboration-quite the opposite (schertzer & woods, b) . the security and autonomy afforded by the nation-state can allow actors to engage in meaningful international collaboration. the establishment and growth of our key international institutions and related norms principally stem from actions taken by states, often following major crises. if this collaboration can be 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'u.s. and world population clock will a global depression trigger another world war? foreign policy speech of is indigeneity like ethnicity? theorizing and assessing models of indigenous political representation who issues best practices for naming new human infectious diseases online. who coronavirus disease (covid- ) dashboard plague fighter: the autobiography of a modern chinese physician history of chinese medicine: being a chronicle of medical happenings in china from ancient times to the present period attributions about the causes and consequences of cataclysmic events covid- , nationalism, and the politics of crisis: a scholarly exchange key: cord- -cfoq r i authors: tian, peng-fei; jin, yu-lan; xing, gang; qv, ling-ling; huang, yao-wei; zhou, ji-yong title: evidence of recombinant strains of porcine epidemic diarrhea virus, united states, date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: cfoq r i to investigate the evolutionary process by which porcine epidemic diarrhea virus (pedv) in the united states hypothetically descended from strains in china, we analyzed pedv-positive samples collected in china during january –july . recombination in strain sublineages was likely associated with identification of pedv in the united states in . to investigate the evolutionary process by which porcine epidemic diarrhea virus (pedv) in the united states hypothetically descended from strains in china, we analyzed pedv-positive samples collected in china during january -july . recombination in strain sublineages was likely associated with identification of pedv in the united states in . phacoronavirus that causes enteric disease in swine. the disease, ped, is characterized by acute vomiting and watery diarrhea and causes high mortality rates in newborn piglets ( ) . ped was first reported in in the united kingdom and was soon identified in many european and asian countries ( , ) . variant pedv strains that were fatal to young pigs, initially isolated during late in china and southeast asia ( , ) and in may in the united states ( , ) , have posed a serious threat to the pork industry. incidence of pedv-associated large-scale outbreaks of diarrheal disease in china was reported at %- % in suckling piglets ( , ) and outbreaks in the united states had spread to states by february (http://www.aasv. org/news/story.php?id= ), causing numerous deaths in neonatal piglets ( , , , ) . how the virus entered the united states remains unknown. a phylogenetic analysis based on available fulllength genomic pedv sequences indicated that all pedv strains were classified into distinct genogroups: g and g ( ) . pedv field strains isolated before and the derived vaccine strains were in the g genogroup, whereas all the new pedv strains isolated since in china and the united states (us pedv) are in g . the us pedv sequences were > % identical to strains found in china in the subgroup g a, suggesting their origin. in particular, the us pedv are most closely related to strain ah , which was isolated in eastern china and was proposed to have come from multiple recombination events among g lineages of pedv ( ) . divergence of pedv is driven by genetic recombination, as in other coronaviruses ( ) . details of recombination events in the process are needed to investigate origins. to investigate the evolutionary process by which us pedv strains hypothetically descended from precursors in china, we conducted a molecular epidemiologic analysis using pedv-positive samples collected from eastern china since . a total of fecal and intestinal samples were collected from pigs with typical ped symptoms on farms in provinces of eastern china during january -july . the rate of pedv-positive samples was . % ( / ) as had been determined by using reverse transcription pcr (rt-pcr) specific for the spike (s) gene ( ) . from the positive samples, we selected representative samples (table) to examine. using rt-pcr, we determined the sequences of the full-length genomic cdna for the strain ch/zjcx- / , identified the spike (s) gene for strains ch/ zjqz- w/ and ch/zjdx- / , and identified the region encoding structural protein genes by an order of ′-s-orf -e-m-n- ′ ( ′-spike protein-open reading frame -envelope-membrane-nucleoprotein- ′) for the remaining strains. all primers were designed based on the pedv mn strain (genbank accession no. kf ). we purified and cloned pcr products into a vector using ta cloning. we used vector nti software (http://www. lifetechnologies.com/us/en/home/life-science/cloning/ vector-nti-software.html) to assemble and analyze the sequences. we performed multiple alignments of s-orf -e-m-n, s, orf , m, n, and full-length genomes with available sequences from asia and the united states ( , , , ) and performed phylogenetic analyses using the mega . program (http://www.megasoftware.net/) with the neighbor-joining method. similar to most of the sequences recently documented in pedv strains in china and the united states, the s genes of the samples have a , -nt sequence that, compared with the prototype cv strain, shows . %- % sequence identities, and contain notable insertions at amino acids (aa) - (igen) and (n) and a deletion of aa (gk) at aa positions and at the n terminus ( ) . a phylogenetic analysis comparing s genes showed that, based on the complete genome (online technical appendix figure , wwwnc.cdc.gov/eid/article/ / / - -techapp .pdf), all strains were classified into the same group corresponding to g . however, it is notable that the chinese sublineage (branch) most closely related to the us pedv strains did not include the ah strain. instead, this sublineage contained the strain ch/zmdzy/ and other strains determined in this study. analyses of the phylogenetic trees constructed on the basis of the s-orf -e-m-n genes ( figure) , orf or m (online technical appendix figure ) also indicated that the ah strain was not closely related to the us branch, relative to the sublineage represented by strains ch/zmdzy/ , ch/ hubwhyq/ , ch/jxzs- l/ , and ch/jxzs- l/ (designated the zmdzy sublineage hereafter; figure) . the exception is the n gene-based tree, in which the ah was grouped more closely to the sublineage associated with the united states than the strains in the designated zmdzy sublineage (online technical appendix figure ). the relationship of the ah strain with the pedv strains identified in china, the united states, south korea, and belgium (online technical appendix figure ) in nonstructural protein genes was also determined by generation of phylogenetic trees based on orf ab, orf a, and orf b genes, respectively. in accordance with the results from the n gene and the pedv genotyping based on the full-length genomes ( ), the ah strain in these trees was most closely related to the us strains (online technical appendix figure ). therefore, the strains ah and ch/zmdzy/ displayed different phylogenetic relationships in different genome regions. overall, the ah strain was clustered closely with the us strains in the orf ab and the n gene region, whereas the zmdzy sublineage was clustered closely with the us strains in the s-orf -e-m region. to accurately determine how the us strains are related to strains ah and the zmdzy sublineage, we performed a recombination analysis using the recombination detection program and available pedv sequences ( ) . we used a multiple-comparison-corrected p-value cutoff of . in all methods. recombination events were identified by methods (recombination detection program, geneconv, bootscan, maxchi, chimaera, and siscan) when the us pedv sublineage represented by the mn strain was used as a query. by bootstrap analysis, putatively major recombination breakpoints were detected at nucleotides , , and (online technical appendix figure ), which generated regions: covered the ′ half of orf a, complete orf b, and the n terminus of the s (first , nt); the other spanned partial s, orf , e, m, and partial n (first nt) between the strain ah (as the major parent) and the zmdzy sublineage (as the minor parent). although the second region (partial s-orf -e-m-partial n) of the us strains is associated with the zmdzy sublineage, the source of genetic material in this region is not known, because none of the pedv strains in this sublineage had a highly identical sequence to the consensus sequence of the us strains. it is possible that the other recombination breakpoints exist within the s gene, according to the bootstrap supports in this region, which may be determined by future study with available new sequence data. we showed that the emergent us pedv strains are possibly descendent of major lineages derived from the zmdzy sublineage and ah through recombination. our study provides further information on the origin of the us pedv in . we identified s-orf -e-m-n genes, s genes, and full-length genomic cdna of pedv from pedv-positive samples collected in eastern china. comparative genomic, phylogenetic, and recombination analyses using new and known sequence data demonstrated that the ah strain is likely not the direct progenitor of emergent us pedv strains during . it is possible that replacement of a region within the partial s-orf -e-m-partial n region of the ah strain with a corresponding fragment close to the zmdzy sublineage (including several newly identified strains) resulted in a recombinant strain related to emergence of this virus in swine in the united states. other unidentified recombination events and accumulation of adapted mutations within the structural protein genes were also likely involved in this process. porcine epidemic diarrhoea virus: a comprehensive review of molecular epidemiology, diagnosis, and vaccines a new coronavirus-like particle associated with diarrhea in swine isolation and characterization of a variant porcine epidemic diarrhea virus in china chinese-like strain of porcine epidemic diarrhea virus complete genome sequence of porcine epidemic diarrhea virus strain usa/colorado/ from the united states origin, evolution, and genotyping of emergent porcine epidemic diarrhea virus strains in the united states outbreak of porcine epidemic diarrhea in suckling piglets emergence of porcine epidemic diarrhea virus in the united states: clinical signs, lesions, and viral genomic sequences pathology of us porcine epidemic diarrhea virus strain pc a in gnotobiotic pigs recombination, reservoirs, and the modular spike: mechanisms of coronavirus cross-species transmission multiplex reverse transcription-pcr for rapid differential detection of porcine epidemic diarrhea virus, transmissible gastroenteritis virus, and porcine group a rotavirus isolation and characterization of porcine epidemic diarrhea viruses associated with the disease outbreak among swine in the united states recombination detection and analysis using rdp key: cord- -ynqxgyw authors: epstein, jay s.; jaffe, harold w.; alter, harvey j.; klein, harvey g. title: blood system changes since recognition of transfusion‐associated aids date: - - journal: transfusion doi: . /trf. sha: doc_id: cord_uid: ynqxgyw nan the fact that transfusions could transmit infectious diseases, namely, bacterial infections, syphilis, and hepatitis, was recognized before taa with progressive interventions dating back to the dawn of blood banking. donor testing for antibodies to syphilis began in . bacterial infections, a major threat at the time of world war ii, were later decreased by cold storage of whole blood and red blood cells (rbcs) in plastic containers. , in the s, transfusion-associated hepatitis (tah) was largely prevented by near elimination of paid donation through product labeling to identify paid collections, concurrent with testing for hepatitis b virus (hbv) infections. however, the medical importance of the residual hepatitis risk, mostly attributed to non-a, non-b hepatitis (nanbh), was recognized slowly. with the acute threat of bacterial infections largely controlled, syphilis effectively prevented, and the full consequences of nanbh transmission unappreciated, the blood community in the late s was more focused on systemic issues of economic competition and supply instabilities than on transmissible disease. then came aids! aids was first reported as a "gay-related immune deficiency" in , but soon was identified in other risk groups including sex workers, haitian entrants to the united states, and injection drug users. , evidence for transfusion transmission emerged in when a few cases of aids were reported in hemophilia patients and later in transfusion recipients. however, despite a number of high-level federal meetings, actions by the national government to contain the aids risk from transfusion were not undertaken until . although transfusion transmission of hiv undoubtedly took place at least years before the recognition of taa due to the very long asymptomatic period of the disease, the delay in a response to taa subsequent to these initial reports of disease in persons with hemophilia and transfusion recipients also contributed to the aids tragedy. rage within the hemophilia community, due both to the fact of transmission of a fatal infection and to the failure of authorities to provide adequate warnings and preventions, was expressed in a demand for a congressional investigation. members of congress instead directed the department of health and human services (hhs) to look into the matter. this was accomplished through a contract with the institute of medicine (iom) to study the evolving hiv-related events impacting blood safety and the decision-making process in this crisis period. in its report, entitled "hiv and the blood supply: an analysis of crisis decision making ( )," the iom found no wrongdoing by organizations or officials, but identified failed opportunities to better protect public health. these failures to act more rapidly and aggressively in the face of taa were seen to unmask an underlying weakness in the ability of federal agencies to address a new threat in the face of substantial scientific uncertainty. this weakness was attributed to systemic deficiencies, primarily of leadership and coordination. in particular, the iom criticized the federal agencies for lack of top-level leadership needed to overcome inherent bureaucratic inertia; absence of a systematic approach within advisory committees sufficient to maintain their focus; over dependency on the regulated industry as a source of data given the inherent conflict of interest; and failure to engage in forward thinking both with respect to new technologies and emerging safety threats. as a consequence, the risk of taa was severely underestimated; patients and care providers were not suitably warned of the risk; and resistance to a change in the status quo caused delayed intervention. in a set of recommendations directed primarily at federal agencies, the iom called for a more responsive and integrated decision-making process including establishment of a blood safety council reporting to a designated blood safety director within hhs and a standing "expert panel" to assure communication of blood product risks and alternatives to their use both to care providers and to the public. specifically to the food and drug administration (fda), the iom recommended that, "where uncertainties or countervailing public health concerns preclude eliminating potential risks, the fda should encourage, and where necessary require, the blood industry to implement partial solutions that have little risk of causing harm." while not itself a mandate, the iom's admonition that the fda should institute measured precautions in the face of uncertainty has become a dominant factor in blood safety decision making. a more vigilant and proactive fda approach to blood safety unfortunately has had the unintended consequence of dramatically increasing the manufacturing costs and therefore the price of blood. the hhs response to the iom report established a new landscape for federal oversight of the blood system, which continues to the present day. the present structure includes the assistant secretary for health (ash) as the blood safety director; heads of public health service and related agencies as members of a blood, organ and tissue safety executive council (botsec); and an hhs secretary's advisory committee for blood and tissue safety and availability (formerly the advisory committee for blood safety and availability). the ash is the acknowledged national blood safety director with final responsibility and authority for decisions regarding blood safety and availability. an interagency blood, organ and tissue safety working group meets monthly by teleconference, more often when necessary, and the botsec meets approximately quarterly face to face with the ash to provide information and guidance regarding current and emerging issues involving the nation's blood supply. unlike fda's blood products advisory committee, whose function is to provide external scientific advice relevant to regulation, the secretary's advisory committee is empowered to discuss broad legal, ethical, social, and economic issues affecting the blood system. to give voice to patient concerns, both advisory committees seat voting representatives of communities that have been particularly affected by taa. additionally, in response to a series of congressional hearings, reports from the government accountability office, and the iom study, the fda developed and hhs subsequently adopted a comprehensive "blood action plan" designed to address the identified shortcomings, to ensure greater coordination among the department's public health agencies, and to increase the effectiveness of the fda's scientific and regulatory activities. notably, the post-taa era has witnessed an aggressive effort by the fda to improve blood safety through enforcement of cgmp in blood product collection and processing aligned with the model of pharmaceutical manufacturing and a more formal relationship than blood establishments experienced in the past. the fda initiative also involved promotion of automation to reduce human errors, including use of validated blood bank software. an intensive program of field inspections designed to assure universal regulatory compliance of blood collection establishments resulted in a number of court-enforced voluntary injunctions (consent decrees). known and emerging infectious threats to blood safety have continued to demand attention in the post-taa era, repeatedly testing whether the lessons of taa were learned. are we prepared to deal with potential threats from bioterrorism agents? how much effort should be expended to prepare for an outbreak of chikungunya virus that might never happen? what should we do about pandemic influenza and middle east respiratory syndrome coronavirus in the absence of studies to establish the presence or absence of viremia in the course of the infections? does it make sense to screen all blood donations when risks of babesiosis and dengue are seasonal and geographical? what changes to the current paradigm of donor screening and testing can be considered when pathogen reduction becomes available for all blood components? more generally, as we become increasingly proactive in addressing infectious risks, are we misdirecting resources that could be better spent to improve blood safety in other ways? readers of this commentary are encouraged to ask themselves whether the lessons of taa have been optimally incorporated during the decades of challenge and response that followed. a sentinel event in the history of blood safety was the recognition and response to taa. although the etiology remained unknown, the report of aids in three persons with hemophilia a in july suggested a blood-borne pathogen as the causative agent. these three individuals were reported to be heterosexual, had no other known aids risk factors, and had all received frequent administration of factor viii concentrate. the evidence for transmission of the "aids agent" through blood was further strengthened in december by the report of a -month-old infant in san francisco who had developed unexplained immunodeficiency after transfusion of multiple blood products to treat erythroblastosis fetalis. one of the blood donors was a man who was healthy at the time of donation, but subsequently died of aids. to address the possibility that aids was associated with the receipt of blood and blood products, the centers for disease control and prevention (cdc) convened a meeting on january , , with participation by the fda, the national hemophilia foundation, blood banking officials, and patient advocacy groups. from the cdc perspective, the purpose of the meeting was to discuss how to reduce the risk of aids in transfusion recipients and persons with hemophilia in the absence of a test for the etiologic agent. several possible strategies were presented, including deferral of blood donations by persons known to be at increased risk for aids and the use of surrogate tests to identify persons at increased risk of transmission, such as those with detectable antibody to hepatitis b core antigen (anti-hbc) or low cd /cd t-cell ratios. however, the meeting turned into a contentious debate about the existence of aids in transfusion recipients and persons with hemophilia, and no agreement was reached on a risk reduction strategy. on march , , the us public health service published the first recommendations for prevention of aids. among the recommendations was a statement that, "as a temporary measure, members of groups at increased risk for aids should refrain from donating plasma and/or blood." in addition to persons with clinical evidence of aids and their sexual partners, those considered to be at increased risk included "sexually active homosexual or bisexual men with multiple partners; haitian entrants to the united states; present or past abusers of iv drugs; patients with hemophilia; and sexual partners of individuals at increased risk for aids." at the time, these recommendations were controversial. in particular, restricting blood donation by homosexual men was seen as a civil rights issue, and deferring donations by haitian entrants undoubtedly led to discrimination against haitian americans. from a public health perspective, however, these measures were needed to increase blood safety. with the identification of hiv, screening of donated blood and plasma became possible. bulk preparations of the virus, known at the time as htlv-iii, were provided by the national cancer institute to diagnostics companies for the development of antibody detection tests. the first such screening test, developed by abbott laboratories, was approved by the fda in march . because of concerns that persons would donate blood for the purpose of learning their hiv infection status, the cdc funded the first alternative hiv test sites, where individuals could obtain free and confidential testing. blood banks also established the option of confidential unit exclusion to allow persons who had donated blood to confidentially indicate that the blood should not be used for transfusion. a watershed event in blood safety was the statement by the fda commissioner at a september workshop that nucleic acid technology should be implemented to close the window period for hiv detection by serology. this technology had been considered too costly and cumbersome for practical application in blood banking. the introduction of direct testing for hiv in donor blood, first by p antigen assays, which proved largely unproductive, and then by nucleic acid tests (nats) for viral rna, which proved beneficial, put to rest a decade of concern about residual hiv risk from donations in the -to -week infectious "window period" before seroconversion dependent on the sensitivity of different screening tests. the successful adaptation of nat to donor screening, including testing of specimens in small pools of to , established a new era in risk reduction from transfusiontransmitted viral diseases. in addition to increasing the safety of transfused blood, hiv antibody screening of donors led to "lookback" programs in which recipients of previous unscreened donations from infected donors were identified. these recipients were found to be at substantial risk for infection. , although no effective treatment was available at the time, infected recipients could be counseled to reduce the risk of hiv transmission to others. another retrovirus, htlv-i, was also found to cause disease, including adult t-cell leukemia or lymphoma and htlv- associated myelopathy or tropical spastic paraparesis. the virus can be transmitted by transfusion of cellular blood products, but not plasma fraction or plasma derivatives. in november , the fda issued guidance recommending antibody testing of donated whole blood and cellular components for htlv-i. because of a high degree of sequence homology, the currently approved htlv-i screening assay also detects antibodies to htlv-ii, a virus with transmission routes similar to htlv-i but with less clear disease associations. although not fda approved, western blot and pcr tests can be used to distinguish between the two viruses. world war ii led to recognition of the frequent occurrence of hepatitis among military personnel through the confluence of contaminated water, massive immunizations, and for the first time, blood transfusion. it was during this time that food-and water-borne "infectious hepatitis" was distinguished from parenterally transmitted "serum hepatitis" and these entities were later termed hepatitis a and b, respectively. in , beeson reported seven cases of jaundice occurring to months after transfusion of blood or plasma. a dramatic outbreak of hepatitis involving , us soldiers was traced to serum-contaminated preparations of yellow fever vaccine, which conclusively documented parenteral transmission. decades later, this outbreak was shown by seeff and colleagues to be due to the hepatitis b virus. the us army extensively studied serum hepatitis during and after the war and characterized both the epidemiology and the resultant disease, but could not identify the causative agent. the etiologic breakthrough began in the early s with the discovery of the australia antigen by blumberg and coworkers at the national institutes of health (nih). this single finding changed the course of hepatitis history when in , the australia antigen was shown by the blumberg group to be associated with viral hepatitis and then by prince and colleagues to be specifically associated with hepatitis b. in england, dane and coworkers showed by immune electron microscopy that the australia antigen represented the envelope protein of hbv and it was renamed the hepatitis b surface antigen (hbsag). the serologic distinctions between hepatitis a and b were further solidified by the controversial, but definitive prospective studies by krugman and colleagues at the willowbrook state school. the us government played a pivotal role in these momentous events, first through the initial discovery of the australia antigen in the intramural program at nih and then through extensive grant support of the blumberg laboratory at the institute for cancer research in philadelphia. in the late s and early s, prospective studies at the nih clinical center revealed several critical elements of tah, including: . that the primary risk factor for tah was the use of paid donor blood confirming earlier studies; in , this led to an fda mandate requiring the labeling of paid donor blood, which effectively resulted in the near-universal adoption of blood collection only from unpaid volunteers, one of the most important transfusion-transmitted infectious disease interventions ever implemented. . that hbsag testing of blood donors was effective even when using insensitive techniques such as agar gel diffusion and counterelectropherseis; nationwide testing for hbsag was delayed until more practical and confirmable assays were introduced in . volunteerism and first-generation hbsag screening reduced the incidence of tah from % to approximately % and that this massive reduction was more dependent on the donor source than on blood screening because hbv was shown to account for less than % of total tah. feinstone and coworkers at nih, it became evident that hav was not responsible for the residual cases of tah, giving rise to the cumbersome, but nonpresumptive designation nanbh. while intensive efforts to isolate the nanbh agent in the decade from to were unsuccessful, studies at the nih and cdc revealed that the agent was small, lipid-enveloped and most similar to the small rna alpha and flaviviruses. [ ] [ ] [ ] despite the absence of a specific test for detecting the nanbh agent, tah incidence declined because of the more judicious use of blood fostered by the recognition that nanbh could result in cirrhosis and death and by the devastating consequences of transfusion-transmitted hiv. further, in the absence of specific nanbh assays, surrogate assays were advocated. the transfusion transmitted virus study, supported by the national heart, lung and blood institute, published a retrospective analysis of a prospective study that showed that alanine aminotransferase (alt) testing of donors might effect a % reduction in tah incidence. this was confirmed by a similar analysis of the nih prospective tah study, but implementation of alt donor screening at the nih failed to demonstrate the predicted benefit. similar retrospective testing of the transfusion transmitted virus study and the nih prospective studies suggested that anti-hbc testing might result in a % to % reduction in tah, and this fostered the voluntary introduction of alt and anti-hbc donor testing in to ; the fda recommended routine donor testing for anti-hbc in . although anti-hbc screening was introduced specifically to detect hbv carriers who were hbsag negative (now termed occult hepatitis b), it also served as a surrogate for nanb carriers and for seronegative hiv carriers because of overlapping transmission routes. had anti-hbc surrogate testing been introduced in the early s it presumably would have prevented some cases of transfusion-transmitted aids and nanbh. this delayed implementation was the basis for extensive litigation, but also served as the driver for the iom recommendation of invoking the "precautionary principle" when weighing new donor screening interventions and this precautionary approach has significantly improved transfusion safety. industry has played a major role in hepatitis prevention, first by developing increasingly sensitive assays for hbsag, by developing nucleic acid detection assays for all the major viruses, and particularly by cloning the nanb agent. the latter was a monumental achievement by chiron corporation in collaboration with dan bradley at the cdc. using the then-novel technique of expression cloning, these investigators identified a single clone among millions tested that reacted with serum from patients with nanbh. houghton and associates at chiron then "walked" the genome, characterized an antigen derived from the nonstructural region of the viral genome, and developed an antibody assay to detect this viral protein. studies at the nih confirmed that the cloned agent, designated hepatitis c virus (hcv), was detected in virtually all nanbh cases and identified an implicated donor in near % of these cases. first-generation anti-hcv testing was introduced in and secondgeneration assays in . prospective studies at the nih clinical center documented the virtual eradication of tah by ; mathematical modeling after the introduction of nat screening in predicts that the current risk of transfusion-related hepatitis c is approximately one case in every million transfusions, approximately the same risk as being hit by lightning. west nile virus (wnv) was first identified in the united states in after an outbreak of encephalitis in newyork. four cases of unexplained fever and encephalitis in recipients of organ transplants from a common donor proved to be caused by wnv and raised the possibility of transmission through blood transfusion. initial efforts to screen blood donors using signs and symptoms of wnv infection proved ineffective. in , a total of cases of human illness were reported, and at least people contracted wnv through transfusion, six of whom died. the rapid expansion of wnv across the united states and reported to botsec by the cdc lent urgency to developing a screening test before the next epidemic season. the fda requested that industry develop such a test; the national heart, lung and blood institute provided $ . million in research support; the american red cross provided , archived specimens; and the fda facilitated rapid national test implementation and ultimate approval. although development of blood screening tests usually takes years, the nat assay for wnv was available for the epidemic season, building on technology platforms already developed for hiv and hcv. west nile virus was the first acute infection with a short asymptomatic viremia and an epidemic spread to warrant routine donor testing and demonstrated a successful collaboration of government, blood collectors, and the diagnostics industry. , a footnote to the wnv screening success was the recognition that testing of pooled samples was insufficiently sensitive to detect low-titer viremia in blood donations, including in the infectious preseroconversion donations commonly encountered during epidemic spread. however, universal testing of individual units in nonepidemic areas nationwide was inefficient and costly. this problem was solved through a novel strategy of triggering individual testing based on the yield of pool testing. this approach effectively detected and interdicted approximately potentially infectious blood donations during to . the emergence of variant creutzfeldt-jakob disease (vcjd) in the united kingdom and france first reported in posed what has been arguably the most challenging blood safety problem for decision makers since the beginning of the aids epidemic. like aids, vcjd presented a new disease with unknown transmission dynamics, the potential for transmission through blood transfusion, the recognition of a novel infectious agent (prions), and near invariable fatality. vcjd was linked to bovine spongiform encephalopathy, a disease recognized in the united kingdom since , so the incubation period of the disease was assumed to be lengthy. the scope of the epidemic was and remains unknown. , for prions, unlike for bacteria and viruses, no technology for developing diagnostic or screening assays was available. the fda established a transmissible spongiform encephalopathies advisory committee to assure focused, objective, and transparent input to its decision making. based on the available epidemiologic data in , the fda recommended that blood components collected from donors diagnosed with vcjd be withdrawn and developed a mathematical model for indefinite donor deferral based on geographic exposure (donors who resided in the united kingdom for a total of months or more, between and ) that eliminated an estimated % of donor exposuredays to bovine spongiform encephalopathy in the united kingdom with a projected loss of approximately % of donors, which was considered a difficult balance of safety and supply, necessitating close monitoring of the blood supply. based on continuing surveillance of vcjd, the geographic exclusion was expanded in , providing approximately a % reduction in total risk-weighted person-days of donor exposure to bovine spongiform encephalopathy in western europe including the united kingdom with an estimated total donor loss of approximately %. the question of blood transmission was answered when the united kingdom reported four cases of vcjd infections associated with blood transfusion that occurred between and . all four recipients had received transfusions of nonleukoreduced rbcs between and , which confirmed the long incubation. only time will tell whether the steps taken in the united states will prove both warranted and sufficient, but the policy reflects adoption of a "partial solution" when it appears to reduce risk and an attempt to act expeditiously and responsibly with a benefit-to-risk model to address risk in the face of scientific uncertainty. chagas disease, caused by the protozoa trypanosoma cruzi, affects an estimated million people globally; an estimated , people in the united states and canada are infected. most infections are found in immigrants from latin america. whereas most new infections are vector borne, transmission by blood transfusion is well recognized. six transmissions had been reported in the united states before the ability to screen blood donors. as early as , the fda blood products advisory committee recognized that while only % to % of those infected with t. cruzi develop symptomatic disease, the infection is lifelong in the absence of early treatment and can be fatal. in view of increasing immigration to the united states from endemic regions, the blood products advisory committee recommended testing donors when a suitable test became available. donor history screening proved insufficiently sensitive and specific. not until was a test found suitable for licensure. shortly thereafter, the major blood collectors undertook universal donor screening for antibodies to t. cruzi. in retrospect, an earlier study in los angeles and miami suggested that seropositivity did not equate with infectivity; none of recipients of blood from a subsequently identified seropositive donor had evidence of infection. two years of screening in the united states established that whereas the seroprevalence may be as high as in , donors in some regions, infections confirmed by lookback studies are rare. , reexamination by the fda of its decision to recommend universal donor screening led to a novel policy of once-in-a-lifetime donor testing based on the demonstrated rarity of acute or incident t. cruzi infections in us donors. anthrax: bioterrorism, public concern, and the blood supply anthrax is caused by infection with a spore-forming gram-positive bacterium bacillus anthracis found globally in temperate zones, but uncommon in the united states. only seven cases of cutaneous anthrax had been reported to the cdc between and when in an outbreak of bioterrorism-related anthrax resulted in confirmed or suspected cases including five fatalities. this episode raised public concern about the blood supply during a period of high anxiety regarding threats of bioterrorism. bacteremia is present during fulminant cutaneous and respiratory anthrax; however, bacteremia in asymptomatic individuals has not been described. the period between exposure to b. anthracis and development of clinical anthrax is reported as to days but may be as long as days. little information exists regarding transmission via blood transfusion from an asymptomatic individual who has been exposed to b. anthracis. no such cases have been reported and no licensed diagnostic or blood donor screening test exists. the fda received several inquiries regarding the risk to the blood supply from donors in direct contact with material contaminated with b. anthracis. after consulting with experts at the cdc, the nih, and the us army medical research institute for infectious diseases, the fda issued guidance regarding measures to reduce possible risk for transmission of anthrax from blood. the guidance did not recommend any changes to standard donor screening and blood collection procedures, but emphasized that standard blood collection procedures already in place include deferral of any donor who is not in good health at the time of donation. nevertheless, to address public concerns as well as the dearth of scientific information regarding blood transmission, the fda provided prudent but specific recommendations concerning donors with a confirmed medical diagnosis of anthrax or proven colonization with b. anthracis and provided criteria for product quarantine and retrieval related to reports of postdonation illness. in , the journal science reported that a gamma retrovirus, xenotropic murine leukemia virus-related virus (xmrv) was isolated from blood in two-thirds of patients diagnosed with chronic fatigue syndrome (cfs) and, most alarmingly, in . % of healthy subjects. a second article reported a related retrovirus (pmlv) with an even higher prevalence of . % among blood donors. these reports generated enormous public interest and concern. given the possibility that xmrv could be transmitted by transfusion, immediate calls arose to screen blood donors for signs and symptoms of cfs and to test donations for xmrv. at the same time, intensive efforts were being undertaken worldwide to resolve this potential safety concern. a federal interagency working group met repeatedly by teleconference and electronic communication, and laboratories within the cdc, nih, and fda invested resources into investigating discrepant laboratory results. additionally, representatives of the cdc, the fda, and the intra-and extramural programs at the nih participated in a public-private interorganizational task force assembled within days by the aabb (formerly american association of blood banks). the result was voluntary implementation of an interim aabb recommendation that blood collectors should "actively discourage potential donors who have been diagnosed by a physician with cfs, chronic fatigue and immune dysfunction syndrome, or myalgic encephalomyelitis from donating blood" and ultimately definitive laboratory evidence that xmrv or pmlv bore no association with cfs and posed no threat to the blood supply. , ongoing threats and challenges several infectious threats are currently challenging federal decision makers. bacterial contamination of platelets is a clearly identified risk that is being addressed with "partial solutions," culture, and point-of-issue serologic testing. hepatitis e virus is known to be transfusion transmitted, but potential disease burden has not been defined. the geographic and travel exclusions to limit the risk of malaria transmission continue to be refined pending development of screening assays or pathogen reduction technology. surveillance for the coronaviruses responsible for severe acute respiratory syndrome and middle east respiratory syndrome is active and the possibility that these agents as well as pandemic influenza and monkey pox might be transfusion transmitted or disrupt blood donation is unresolved. the possibility of seasonal and geographic-based donor screening with validated tests for dengue and babesiosis has been modeled even as pilot studies of screening assays are ongoing. , pathogen reduction technology offers an alternative approach to risk mitigation. such technology would change the riskbenefit paradigm both for the known infectious agents and for those likely to threaten the blood supply in the future. federal decision makers are involved in deter-mining when and how this technology should be applied to the nation's blood and blood components. the federal response to transfusion-transmitted infections has evolved dramatically since the emergence of hiv as a transfusion-transmitted infection. the philosophy of risk management has become more precautionary and patient focused, yet still data driven. regulation of notfor-profit blood collectors has become more formal and stringent. manufacturers of blood components are now held accountable for meeting cgmp standards similar to those that apply to the manufacture of medical devices and pharmaceutical-type drugs. a new and arguably more responsive federal structure for addressing issues of blood safety and availability has been adopted. the decisionmaking structure places a premium on clear lines of authority, internal and public communication, flexibility, and coordination among the federal agencies with major roles in blood safety. federal agencies have encouraged public discourse through workshops, joint initiatives with industry, and participation in public-private partnerships with professional societies and blood collectors. these adjustments have allowed federal agencies to respond with appropriate urgency to the differing situations posed by emerging infectious agents in the era since recognition of taa years ago. hiv's leading men years after hiv discovery: prospects for cure and vaccine epidemiologic notes and reports pneumocystis carinii pneumonia among persons with hemophilia a possible transfusion-associated acquired immune deficiency syndrome (aids)-california the hazards of blood transfusion in historical perspective transfusion-associated infections: years of relentless challenges and remarkable progress syphilis: a disease of direct transfusion hiv and the blood supply: an analysis of crisis decision making. washington dc: institute of medicine national academy press staff costs associated with the implementation of a comprehensive compliance program in a community blood center risk-based decision-making for blood safety: preliminary report of consensus conference us department of health and human services. improving blood safety and supply in the u.s the efficiency of hiv p antigen screening of us blood donors: projections versus reality risk of human immunodeficiency virus infection from blood donors who later developed the acquired immunodeficiency syndrome risk of human immunodeficiency virus (hiv) transmission by blood transfusions before the implementation of hiv- antibody screening guidelines for counseling persons with human t-lymphotropic virus type i (htlv-i) and type ii (htlv-ii) jaundice occurring one to four months after transfusion of blood or plasma: report of seven cases a serologic follow-up of the epidemic of post-vaccination hepatitis in the united states army a "new" antigen in leukemia sera australia antigen and acute viral hepatitis immunologic distinction between infectious and serum hepatitis virus-like particles in serum of patients with australia-antigen-associated hepatitis infectious hepatitis: evidence for two distinctive clinical, epidemiological, and immunological types of infection posttransfusion hepatitis after open-heart operations serum hepatitis from transfusions of blood posttransfusion hepatitis after exclusion of the commercial and hepatitis b antigen positive donor hepatitis a: detection by immune electron microscopy of a virus-like antigen associated with acute illness transfusion-associated hepatitis not due to viral hepatitis type a or b posttransfusion non-a, non-b hepatitis: physiochemical properties of two distinct agents inactivation of hepatitis b virus and non-a, non-b virus by chloroform determining the size of non-a, non-b hepatitis virus by filtration the chronic sequelae of non-a, non-b hepatitis serum alanine aminotransferase of donors in relation to the risk of non-a, non-b hepatitis in recipients: the transfusion-transmitted virus study the relationship of donor transaminase (alt) to recipient hepatitis: impact on blood transfusion services hepatitis c virus and eliminating post-transfusion hepatitis hepatitis b virus antibody in blood donors and the occurrence of non-a, non-b hepatitis in transfusion recipients: an analysis of the transfusion-transmitted virus study antibody to hepatitis b core antigen as a paradoxical marker for non-a, non-b hepatitis agents in donated blood isolation of a cdna clone derived from a blood-borne non-a, non-b viral hepatitis genome an assay for circulating antibodies to a major etiologic virus of non-a, non-b hepatitis detection of antibody to hepatitis c virus in prospectively followed transfusion recipients with acute and chronic non-a, non-b hepatitis and update on west nile virus infections in recipients of blood transfusions west nile virus transmission investigation team. transmission of west nile virus through blood transfusion in the united states in as west nile virus season heats up, blood safety testing lags behind west nile virus among blood donors in the united states screening the blood supply for west nile virus rna by nucleic acid amplification testing triggers for switching from minipool testing by nucleic acid technology to individual-donation nucleic acid testing for west nile virus: analysis of data to inform decision making transmissible spongiform encephalopathies estimation of epidemic size and incubation time based on age characteristics of vcjd in the united kingdom uncertainty due to model choice in variant creutzfeldt-jakob disease projections guidance for industry: revised preventive measures to reduce the possible risk of transmission of creutzfeldt-jakob disease (cjd) and variant creutzfeldt-jakob disease (vcjd) by blood and blood products transfusion transmission of human prion diseases transfusion-associated chagas disease (american trypanosomiasis) in mexico: implications for transfusion medicine in the united states guidance for industry: use of serological tests to reduce the risk of transmission of trypanosoma cruzi infection in whole blood and blood components intended for transfusion trypanosoma cruzi in los angeles and miami blood donors: impact of evolving donor demographics on seroprevalence and implications for transfusion transmission epidemiological and laboratory findings from years of testing united states blood donors for trypanosoma cruzi the united states trypanosoma cruzi infection study: evidence for vector-borne transmission of the parasite that causes chagas disease among united states blood donors anthrax as a biological weapon: medical and public health management. working group on civilian biodefense summary of notifiable diseases-united states detection of an infectious retrovirus, xmrv, in blood cells of patients with chronic fatigue syndrome detection of mlv-related gag gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors absence of evidence of xenotropic murine leukemia virus-related virus infection in persons with chronic fatigue syndrome and healthy controls in the united states xenotropic murine leukemia virus-related virus (xmrv) and blood transfusion: report of the aabb interorganizational xmrv task force failure to confirm xmrv/mlvs in the blood of patients with chronic fatigue syndrome: a multi-laboratory study a multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus aabb bacterial contamination task force. survey of methods used to detect bacterial contamination of platelet products in the united states in seroprevalence and incidence of hepatitis e virus infection in german blood donors dengue viremia in blood donors identified by rna and detection of dengue transfusion transmission during the dengue outbreak in puerto rico babesia microti real-time polymerase chain reaction testing of connecticut blood donors: potential implications for screening algorithms protecting the blood supply from emerging pathogens: the role of pathogen inactivation emerging infectious agents and the nation's blood supply: responding to potential threats in the st century none. key: cord- -cslrz yp authors: ehnert, karen; galland, g. gale title: border health: who's guarding the gate? date: - - journal: vet clin north am small anim pract doi: . /j.cvsm. . . sha: doc_id: cord_uid: cslrz yp changes in the global trade market have led to a thriving international pet trade in exotic animals, birds, and puppies. the flood of animals crossing the united states' borders satisfies the public demand for these pets but is not without risk. imported pets may be infected with diseases that put animals or the public at risk. numerous agencies work together to reduce the risk of animal disease introduction, but regulations may need to be modified to ensure compliance. with more than , dogs and , wildlife shipments being imported into the united states each year, veterinarians must remain vigilant so they can recognize potential threats quickly. the global trade market, the ease of transporting animals across continents and around the world, lower production costs in foreign countries, and market demand have resulted in a thriving pet trade of exotic animals, birds, and puppies, both purebred and small mixed breeds. the flood of animals crossing the united states' borders satisfies the public demand for these pets but is not without risk. trade barriers have been disappearing, creating a global marketplace. improved transportation networks allow travelers, trade goods, and animals to move across continents or the globe in a single day. improved communication and expanded use of the internet for commerce simplify the connection between consumers and suppliers worldwide. these changes have created an environment in which a new global pet trade thrives. between and , the uruguay round of the general agreement on tariffs and trade was held. the trade negotiations led to the creation of the world trade organization (wto) in and the reduction of tariffs, import limits, and quotas over the next years. agricultural product trade was liberalized, and guidelines on the trade of animals and animal products were created by the office international des epizooties. the wto operates under the principle that imported products be treated as favorably as domestic goods, but countries are permitted to take measures to protect humans and animals. these changes in trade regulations seem to have expanded the global market. the volume of world trade increased threefold from through , and the export value of goods from asia increased fivefold. exotic pet ownership is on the rise in the united states, resulting in an increased trade in live animals. the number of united states households owning reptiles increased from , in to . million in , and from to the numbers of pet birds, rodents, fish, turtles, and lizards have risen. importers, both legal and illegal, have stepped forward to meet this demand. in the early s, united states imports and exports accounted for % of the total world trade of approximately reptile species listed under the convention on international trade in endangered species of wild fauna and flora (cites). in the united states, the annual volume of live animal imports has roughly doubled since . there were , wildlife shipments in , with a declared value of more than $ . billion. from through , annual increases in wildlife trade ranged from % to %. from through , approximately , animals were imported into the united states each day. the number of animals being imported illegally is difficult to estimate. wildlife smuggling is very profitable and is estimated to bring in more than $ billion each year. interpol estimates that wildlife smuggling ranks third on the contraband list of items of value, behind drugs and firearms. customs officers have found animals stuffed in clothing, bags, containers, compartments in cars, and even inside artificial limbs. animal smuggling is likely to continue until the penalties outweigh the profits. starting in , the los angeles county veterinary public health and rabies control program (vph-rcp) noticed a sharp increase in puppies being imported from overseas, with an accompanying increase in public interest regarding how to import puppies for resale. individuals have reported that imported puppies could be sold for much more than their purchase price and shipment costs (vph-rcp, unpublished data). a kennel in los angeles county is selling yorkshire terrier puppies imported from south korea for $ to $ each. puppies smuggled from mexico often are sold for $ to $ cash. small purebred or crossbred puppies are very popular, and there is a lack of local breeders to meet the demand. the public's demand for small, cute puppies continues to stimulate the business and increase profits to puppy importers. requirements for importing animals into the united states can be found in the regulations of several federal agencies and reflect the mission of each agency. in , the lacey act became the first federal law protecting wildlife, by prohibiting the interstate movement and importation of wildlife species. additionally, the lacey act prohibits the importation of wildlife that has been determined to be injurious to people, agriculture, horticulture, forestry, or wildlife in the united states in , the bureau of fisheries and the bureau of biological survey was consolidated to create the united states fish and wildlife service (usfws) in the department of the interior, with the mission of conserving and protecting wildlife and plants. in , the endangered species act was passed to protect endangered or threatened species. the usfws also enforces requirements for cites, an international agreement between governments to ensure that international trade in wild animals and plants does not threaten the existence of those species. lists of endangered or threatened species covered under cites can be found in appendices i, ii, and iii of the agreement. usfws regulations require that all wildlife species imported for commercial, noncommercial, scientific, or personal use be declared at the time of import, be cleared by the usfws, and enter the united states through a designated port. in most cases, the importer must have a usfws permit. , if the species is covered under cites, the shipment also must be accompanied by a current cites certificate. the us department of agriculture (usda) animal and plant health inspection service (aphis) was established in to protect united states agriculture, consolidating the functions of previous animal and plant bureaus within the usda. the basis for aphis came from the usda's first regulatory program, the veterinary division, established in . in , the veterinary division became the bureau of animal industry, which was created by congress to promote research in livestock diseases, enforce animal import regulations, and regulate the interstate movement of animals. in , the usda's agriculture research service replaced the bureau of animal industry. in , the agriculture research service became the animal and plant health service (aphs), and in the meat and poultry inspection divisions of the consumer and marketing service were added, changing aphs to aphis. since , several changes have occurred, including the establishment of the food safety and quality service, known today as usda's food safety and inspection service, the transfer of the animal quarantine inspection activities at ports of entry from the veterinary services division to the plant protection division in , and the movement of the port inspection activities to the department of homeland security in . [ ] [ ] [ ] usda, aphis veterinary services limits the importations of animals, animal products, and plants based on the risk to agriculture. examples of these activities are controlling the importation of hoofed stock from countries in which foot and mouth disease is endemic or birds from countries that are experiencing outbreaks of highly pathogenic avian influenza (h n ) in poultry. importation of livestock or other hoofed stock, birds, dogs, or other animals may require a permit and possibly quarantine in a usda facility before the shipment is allowed to enter the united states. the animal welfare act was passed in to require minimum standards of animal care for animals that are used in research, bred for sale or exhibition, or transported commercially. aphis' animal care program enforces the provisions of the animal welfare act and the horse protection act, which was passed by congress in . the animal care program ensures that all animals are transported at the proper ages, in proper crates, and in appropriate conditions in accordance with the animal welfare act. the animal care program does not have regulations specific to importation of animals. the centers for disease control and prevention (cdc) of the department of health and human services has regulations prohibiting or controlling the importation of a variety of species of animals and animal products based on a specific threat to human health. for example, dogs entering the united states from countries reporting cases of rabies need proof of a current rabies vaccination, or the importer must sign an agreement to confine the animal until appropriate vaccinations can be obtained and then for an additional days after vaccination. the importation of nonhuman primates has been regulated since , limiting their importation specifically to purposes of science, education, or exhibition and requiring that importers be registered by the cdc. in , importation of civets was banned because these animals were considered to be an amplifying host or vector for severe acute respiratory syndrome (sars). in , the importation of african rodents was banned in response to an outbreak of monkeypox in the united states associated with imported gambian pouched rats. customs and border protection (cbp), located in the department of homeland security, is the first line of defense at the border to ensure that animals and animal products are being imported in accordance with all federal agency regulations. additionally, cbp has the authority to levy a fee on imported animals or products for commercial use, in accordance with the tariff codes. animal importation regulations change often, reflecting any new disease threats that arise, and imported animals may require permits or approvals from a variety of agencies. individuals planning to import animals should check with the usda, cdc, usfws, and cpb to make certain that all required documents are obtained before an animal is brought to the united states. in california, the number of legally documented dog imports began increasing in ( fig. ) . in , most imported dogs were single imports. some were personal pets; others were purebred dogs that had been purchased from an overseas breeder. few dogs were imported for resale. in , the number of imports of multiple puppies per shipment began to increase. the number of puppies imported into california through airports has increased from multidog imports documented in to in and in . each shipment contained as many as puppies. such large numbers of puppies are being imported for resale and not as personal pets. a similar increase was seen nationally. an estimated , dogs were imported into the united states in , with , lacking proof of valid rabies vaccinations, mostly because they were too young to be vaccinated. in california, most of the imported puppies were destined for los angeles county (fig. ) , and the most common countries of origin were mexico and canada (fig. ) . many dogs also were imported from asia, europe, south america, and russia. in los angeles county, many puppies were imported from south korea by pet stores or kennels. the most common breed imported was yorkshire terrier, followed by maltese, bulldogs, and poodles (fig. ) . as the number of shipments containing more than one dog increased, tracking puppies became increasingly more difficult in los angeles county. initially, several shipments went to local pet stores, but as los angeles county vph-rcp staff began enforcing postimportation quarantines until days after the puppies received their rabies immunization, shipments became harder to locate. puppies were sold before individual dog import multiple dog import vph-rcp visits, incorrect addresses were indicated on the cdc confinement agreement form, and individuals refused entrance onto their properties. in addition, some importers provided falsified rabies certificates, and puppies were not available for inspection. this problem was not limited to los angeles county. new york city sent out a veterinary alert in to notify veterinarians that puppies were being imported from rabies-endemic countries and that some were being sold without completing the mandated confinement. the cdc noted more than confinement agreement violations among imported dogs in . during the past few years, illegal shipments of puppies also have become a problem. the los angeles county vph-rcp and animal law enforcement agencies throughout california began receiving reports in that individuals were purchasing puppies in mexico and selling them in california. these puppies were advertised in free classified ads and were delivered to the purchaser at a public location, or they were sold directly from vehicles in shopping center parking lots. generally, the purchaser was required to pay cash and had no way of contacting the seller after purchase. many of the puppies were ill and died a short time after being sold to unsuspecting buyers (personal communication, captain aaron reyes, southeast area animal control authority, december , ) . in early , animal law enforcement agencies and three health agencies, including the los angeles county vph-rcp, formed the border puppy task force (bptf) to assess this growing and disturbing trend. in december , animal law enforcement officers worked alongside cbp agents for a -week period, examining and documenting animals entering from mexico through two california border crossings. more than puppies were examined during this operation; many were found huddled together in cardboard boxes in car trunks or wrapped in towels and stuffed under seats (fig. ) . only a few puppies were confiscated because of illness. most were allowed to enter california after a cdc confinement order was issued. these numbers indicate that , or more puppies may be imported each year through the two california-mexico border crossings investigated, and few are confined as required by federal law to protect against introduction of rabies. following the joint investigation, the bptf held a news conference and conducted media interviews to educate the public about the risks associated with illegally imported puppies. buyers were encouraged not to purchase puppies if the seller required cash and required that the puppy be delivered to its new owner in a public place, such as a restaurant or shopping center parking lot. individuals whose puppy became ill or died shortly after purchase were encouraged to report the matter to the bptf for follow-up investigation of illegal importers. in and , the bptf identified continued transport of puppies across the same border crossings. the cdc has responded to complaints about large-volume shipments of puppies intended for immediate resale and the need for additional regulations to prevent the introduction of zoonotic diseases into the united states by publishing an advance notice of proposed rulemaking on july , . public comments were solicited until december and are being evaluated. stakeholders were asked questions such as should the cdc establish a minimum age for importation of dogs, cats and ferrets? should imported animals have a unique identifier (microchip, tattoo)? should a valid international health certificate be required? should the importation of dogs, cats and ferrets be restricted to ports staffed by cdc quarantine personnel? these changes could have a major impact on the legal and illegal international puppy trade. until the regulations are revised, however, the flow of puppies into the united states is likely to continue. the worldwide movement of animals increases the potential for the spread of diseases that pose a risk to human and animal health. , animals are imported into the united states for use as pets, food and other animal products, scientific research, and exhibition in zoos. dogs and cats are allowed to enter the country without health certificates and, if the owners sign a confinement agreement as described previously, without proof of rabies immunization. even if a pet is ill on arrival, it may be allowed in, with a recommendation that the owner take the pet to a veterinarian for examination. many of the exotic animals are wild caught, and often there is no requirement that they be screened for zoonotic disease before or after arrival in the united states. global trade of animals creates circumstances in which diseases that generally are not found in the united states may be introduced. on the first world rabies day, september , , the cdc reported that the canine strain of rabies had been eliminated from the united states the importation of dogs from rabies-enzootic countries represents a risk for reintroducing canine rabies. , imported dogs have been found to be infected with rabies , , , on several occasions. in , a -month-old puppy imported from mexico into new hampshire became ill weeks after its arrival. the dog began whimpering and had tremors in one leg for days. it then developed urinary and fecal incontinence and finally excessive salivation. the owners took the puppy to a veterinarian, who suspected rabies based on the puppy's history and clinical signs. the puppy was euthanized, tested, and found to be rabid. seventeen people had been exposed, including the owner's classmates, partygoers, and a babysitter. in , a -month-old ill puppy was imported from thailand through the los angeles international airport and was allowed to enter the country. it had been evaluated by several veterinarians in thailand for a respiratory illness and had begun vomiting while in flight. the owner took the puppy to three veterinary clinics as she traveled to her home in northern california. the puppy was aggressive and seemed to have pain along its back. obvious neurologic signs did not develop until it was seen at the third veterinary clinic. at that point, the puppy was euthanized and tested positive for rabies (thai canine variant). numerous people had been exposed, and individuals required postexposure prophylaxis. more recently, in , a puppy imported from india by a washington state veterinarian developed rabies after being adopted by another veterinarian and taken to alaska. the puppy became ill days after arrival from india, with at least one episode of regurgitation. it then bit one of the veterinarians and another dog. clinic staff noticed it gnawing on its kennel, resulting in bleeding gums. even so, another veterinarian completed a health certificate for the puppy, and a third veterinarian transported it to alaska. the day after arriving in alaska, the puppy developed neurologic signs and died. the puppy was tested and found to be rabid (indian canine rabies variant); eight individuals received rabies postexposure prophylaxis. previous documented vaccination does not always negate the risk of imported rabies. in , a dog developed rabies months after being imported from cameroon. the dog had been vaccinated against rabies twice in west africa and once after arriving in the united states the owners took the dog to an animal hospital after it developed paralysis of the lower jaw. the dog was docile and ambulatory. it was discharged with a diagnosis of ''viral infection,'' and the owner was directed to force feed it. the dog was seen at two different clinics over days and finally was euthanized and tested for rabies. it was found to have a west african dog strain of rabies. thirty-seven individuals received postexposure prophylaxis after potential exposures to the dog during its illness and the weeks before the onset of clinical signs. in , an ill cat from mexico also was allowed to enter the country through los angeles international airport. the cat was seen by three veterinarians before being euthanized and testing positive for rabies. other countries have reported imported rabies cases. france has identified several cases of rabies in dogs imported illegally from morocco through portugal or spain by car. [ ] [ ] [ ] in and again in , three cases of canine rabies were reported in imported dogs. in , belgium and germany also reported rabies in dogs imported illegally from morocco. , imported dogs may carry other diseases, such as screwworm, , that pose risk to both animals and humans. screwworm infestation begins when a female fly lays eggs on a superficial wound. unlike typical maggots that feed on dead tissue, the screwworm feeds on living tissue. one female fly may lay up to eggs at a time and as many as eggs during a -day lifespan. the eggs hatch into larvae that burrow into the wound and begin feeding on living flesh. after feeding for to days, the larvae drop off and burrow into the soil, where they pupate. the adult screwworm fly emerges and then mates after to days. in the first day or two of screwworm infection, the clinical signs include a slight motion inside the wound and possibly a serosanguineous discharge and a distinctive odor. by the third day, the larvae may be seen easily. in dogs, the larvae often tunnel under the skin, and there may be a large pocket of larvae with only a small opening in the skin. the deep burrowing is distinctive of screwworms, because other types of maggots are surface feeders and feed on dead tissue. if screwworms are left untreated, animals may die of secondary infection or toxicity within to days of infection. daily wound treatment and larvicidal insecticides are necessary to control the screwworm larvae. in , astute veterinarians in mississippi and massachusetts identified screwworm larvae in imported dogs. , both new world (cochliomyia hominovorax) and old world (chyrsoma bezziana) screwworm myiasis are considered foreign animal diseases in the united states and are reportable within hours of diagnosis. new world screwworms were eradicated from the united states in . the old world screwworm had never been seen in this country until it was found in a -year-old dog imported from singapore to massachusetts in october . in september , a -year-old dog was imported from trinidad and entered the country through the miami airport. it was seen by a mississippi veterinarian days after arrival for ocular damage caused by larval infection. in both cases, the practitioners recognized that the larvae seemed unusual and submitted specimens for identification. their quick action prevented these insects from becoming established, which could have resulted in the united states livestock industry suffering $ million in production losses. imported dogs may introduce other non-native pathogens to the united states. in , a dog imported from england to canada was found to be infected with angiostrongylus vasorum, a nematode parasite of the pulmonary arteries and right heart of dogs and wild carnivores. this parasite is enzootic among dogs in areas of europe and uganda but is not considered established in north america. in , an investigation in french guiana, south america, determined that a dog imported from france in had leishmania infantum and subsequently spread the infection to a second dog. imported wild or exotic animals also pose a risk to human and animal health. bats have been associated with rabies virus and related lyssaviruses, nipah and hendra viruses, and a sars-like virus of bats. a highly pathogenic strain of the influenza virus, h n (hpai), first appeared in asia in and subsequently spread to russia, europe, and parts of africa. live bird markets, trade, wild birds, and illegal bird importation probably all contributed to the spread of the disease. , in , two crested hawk-eagles that had been smuggled into europe from thailand were seized at the brussels international airport. although neither appeared ill, they were euthanized and were found to be infected with hpai. bird smuggling continues to be a problem in the united states. from through , federal authorities intercepted individuals attempting to smuggle commercial quantities of live birds into the united states from mexico. before being arrested, one individual had illegally transported between and , exotic birds, valued at more than $ . million, across the border. smuggled birds are not quarantined, screened, or treated as required by federal law. in addition to avian influenza, smuggled birds may carry exotic newcastle disease, a foreign animal disease that is lethal to poultry, , or avian chlamydiosis, a zoonosis that people can contract through contact with pet birds. rodents, rabbits, and pocket pets also may pose a risk to human and animal health. in may and june , the first cluster of human monkeypox cases in the united states was reported. many of the patients developed a febrile vesicular rash after having contact with prairie dogs that had acquired the infection through contact with a shipment of african rodents at a wholesale pet store. the prairie dogs exhibited anorexia, wasting, sneezing, coughing, swollen eyelids, and ocular discharge. ultimately, there were confirmed and probable human cases of monkeypox during this outbreak. the traceback investigation showed that rodents imported from africa were held in the same area as prairie dogs before being shipped to other distributors and, ultimately, to many pet stores. the frequent mixing of species in the wildlife trade arena creates an opportunity for cross-species transmission and the introduction of new diseases to domesticated animals, wildlife, and humans. in addition to zoonotic threats, imported animals may pose a risk to agriculture. rabbit hemorrhagic disease (rhd) first was identified in china in . rhd is a highly contagious calicivirus that kills up to % of infected animals. infected rabbits often develop a blood-tinged foamy nasal discharge, severe respiratory distress, and/or convulsions before death. in % to % of the rabbits, clinical signs do not progress as rapidly but may include jaundice, malaise, weight loss, and eventually death in to weeks. this disease has spread to europe, asia, australia, new zealand, and cuba but still is considered a foreign animal disease in the united states. outbreaks of rhd occurred in the united states in , , and . the outbreak of rhd occurred at a rabbitry in indiana after the owner purchased rabbits from a flea market in kentucky. following the introduction of the new rabbits, nearly half of his herd died, and the remaining animals were euthanized to contain the outbreak. the source of the infection never was determined. imported exotic pets also may carry parasites that could pose a public health or agricultural health threat. in , florida animal health officials detected exotic ticks on a leopard tortoise that contained cowdria ruminantium, the cause of heartwater disease in ruminants. summary imported dogs bring the risk of the reintroduction of canine rabies, screwworm, and other diseases. exotic birds pose a risk for avian influenza, exotic newcastle disease, and psittacosis. rodents have been a source of imported monkeypox, and turtles can carry ticks that spread heartwater disease. regulations are in place to reduce the risk of diseases that pose a threat to public health and agriculture from imported animals. changes to the regulations are being proposed to define better the united states entry and follow-up requirements. veterinarians play an essential role in preventing the transmission of zoonotic disease between animals and the public and are on the front line dealing with imported animals. they should be aware of and compliant with state and local regulations and play an active role in educating and advising clients regarding the risk of importing an animal. veterinarians should be vigilant when examining new puppies. many imported dogs never are confined properly or inspected for infectious diseases, and many diseases may not be detected readily in imported dogs. with the current rabies vaccination requirements in the united states, most veterinarians have never seen a pet with rabies and do not consider rabies in the differential diagnosis. additionally, early signs of rabies may be very subtle and may not be recognized readily. it is important to keep rabies on the differential list, especially if the pet is known to have been or is suspected of having been imported. additional training in recognizing emerging infectious diseases may be helpful. veterinarians should contact their local health department immediately about any potential rabies cases or suspicious illness, especially in imported animals. a veterinarian could be the one who prevents the next outbreak. broken screens: the regulation of live animal importation in the united states the economic implications of greater global trade in livestock and livestock products the impact of diseases on the importation of animals and animal products global change and human vulnerability to vector-borne diseases results of the avma survey of companion animal ownership in us pet-owning households the reptile and amphibian communities in the united states all creatures great and small: wildlife smuggling ''not worth the risk''. us customs today akc dog registration statistics office of law enforcement about the u.s. fish and wildlife service convention on international trade in endangered species. wild fauna and flora convention on international trade in endangered species. wild fauna and flora. the cites appendices office of law enforcement. importing and exporting your commercial wildlife shipment animal and plant health inspection service. about usda, history of aphis animal and plant health inspection service. import export, animal and animal product import information, live animals animal and plant health inspection service. animal welfare centers for disease control and preventiondivision of global migration and quarantine. importation of pets, other animals, and animal products into the united states importing into the united states, a guide for commercial importers importation of dogs into the united states: risks from rabies and other zoonotic diseases. zoonoses public health veterinary alert # south east area animal control authority (seaaca) foreign quarantine regulations, proposed revision of hhs/cdc animal-import regulations rabies in a puppy imported from india to the usa impact of globalization and animal trade on infectious disease ecology notice to readers: world rabies day epidemiologic notes and reports imported dogs and cat rabies rabies in a puppy imported to california from thailand an imported case of rabies in an immunized dog canine rabies in france promed mail. rabies, canine-france ( ): investigation. promed mail an imported case of canine rabies in aquitaine: investigation and management of the contacts at risk rabies news archives germany, hamburg ex morocco is it just another worble? california veterinarian dangerous screwworm species found in u.s., poses little threat. dvm newsmagazine the center for food security & public health. screwworm myiasis screwworm found in mississippi dog angiostrongylosis with disseminated larval infection associated with signs of ocular and nervous disease in an imported dog first report of leishmania infantum in french guiana: canine visceral leishmaniasis imported from the old world bats: important reservoir hosts of emerging viruses summary of avian influenza activity in europe disease intelligence for highly pathogenic avian influenza highly pathogenic h n influenza virus in smuggled thai eagles exotic parrots confiscated from smugglers returned to mexico. press release investigation of an outbreak of velogenic viscerotropic newcastle disease in pet birds in michigan, indiana, illinois and texas phylogenetic relationships among highly virulent newcastle disease virus isolates obtained from exotic birds and poultry from to detection of chlamydiosis in a shipment of pet birds, leading to recognition of an outbreak of clinically mild psittacosis in humans monkeypox transmission and pathogenesis in prairie dogs the detection of monkeypox in humans in the western hemisphere spectrum of infection and risk factors for human monkeypox a pandemic strain of calicivirus threatens rabbit industries in the americas rabbit hemorrhagic disease evidence of cowdria ruminantium infection (heartwater) in amblyomma sparsum ticks found on tortoises imported into florida the authors thank dr. ben sun and sharon ernst who provided data on cdc confinement agreements completed for dogs imported into california. key: cord- -r m o dp authors: hourdel, véronique; kwasiborski, aurelia; balière, charlotte; matheus, séverine; batéjat, christophe frédéric; manuguerra, jean-claude; vanhomwegen, jessica; caro, valérie title: rapid genomic characterization of sars-cov- by direct amplicon-based sequencing through comparison of minion and illumina iseq (tm) system date: - - journal: front microbiol doi: . /fmicb. . sha: doc_id: cord_uid: r m o dp global human health is increasingly challenged by emerging viral threats, especially those observed over the last years with coronavirus-related human diseases, such as the severe acute respiratory syndrome (sars) and the middle east respiratory syndrome (mers). recently, in late december , a novel betacoronavirus, sars-cov- , originating from the chinese city of wuhan, emerged and was then identified as the causative agent of a new severe form of pneumonia, covid- . real-time genome sequencing in such viral outbreaks is a key issue to confirm identification and characterization of the involved pathogen and to help establish public health measures. here, we implemented an amplicon-based sequencing approach combined with easily deployable next-generation sequencers, the small and hand-held minion sequencer and the latest most compact illumina sequencer, the iseq (tm) system. our results highlighted the great potential of the amplicon-based approach to obtain consensus genomes of sars-cov- from clinical samples in just a few hours. both these mobile next-generation sequencers are proven to be efficient to obtain viral sequences and easy to implement, with a minimal laboratory environment requirement, providing useful opportunities in the field and in remote areas. global human health is increasingly challenged by emerging viral threats, especially those observed over the last years with the severe acute respiratory syndrome (sars) and the middle east respiratory syndrome (mers) caused by coronaviruses. recently, in late december , a novel betacoronavirus, sars-cov- , originating from wuhan, hubei province, china, emerged and was identified as the causative agent of a new form of severe pneumonia, named coronavirus disease (covid- ) zhou et al., ) . the outbreak spread further to europe and america mid-march to become a global public health emergency, with the vast majority of countries and territories reporting confirmed cases. by june , , the number of confirmed cases in the world has increased to over , , (dong et al., ) . sars-cov- , an enveloped positive-sense (+) single-stranded (ss) rna virus, is a new member of the coronaviridae family, betacoronavirus genus, and the seventh coronavirus known to infect humans. genetically distinct from sars-cov and mers-cov, sars-cov- was included in the monophyletic clade , within subgenus sarbecovirus, due to its closest sequence similarity with chinese bat sars-like coronaviruses (lu et al., ; wu et al., ; ye et al., ) . despite its rna proofreading capacity during replication like all members of the coronaviridae family, sars-cov- could nevertheless acquire some nucleotide mutations along the genome, allowing for tracking its spread and thus clade definition. the implementation of short turnaround time and userfriendly sequencing tools in affected regions to track the spread, analyze variants, and identify clusters of transmission of emerging viruses, like sars-cov- , is becoming essential. although whole genome sequencing of viral pathogens has become a routine procedure in epidemiological monitoring and surveillance, these molecular investigations essential for public health support are still challenging in remote areas with poor technical resources. thus, the development of easily deployable viral genome toolkits can be proposed to rapidly obtain sars-cov- genomic sequence data in the field without the requirement to send biological samples to suitably equipped and reference laboratories. these molecular investigations also depend on efficient and direct sequencing of viral material from clinical samples, i.e., often with low viral genetic loads and a high concentration of contaminant host nucleic acid background. to circumvent this difficulty, different techniques of enrichment can be achieved, either directly through laborious and timeconsuming culture isolation or, even better, the use of specific primers targeting the whole genome of the virus (houldcroft et al., ) . moreover, specific amplification-based approaches are proven successful since they can generate sufficient quantities of the genetic material needed for next-generation sequencing (quick et al., ) . recently, mobile next-generation sequencers have provided new opportunities in infectious diseases diagnostics and surveillance, such as the rapid sequencing of viral genomes during outbreaks. the pocket size nanopore technology sequencer minion (oxford nanopore technologies, ont) is portable and field-deployable and enables real-time outbreak surveillance of threatening pathogens, such as ebola, lassa, and zika viruses (faria et al., ; hoenen et al., ; kafetzopoulou et al., ) . similarly, the recent illumina iseq tm system is the most compact, accessible, and affordable next-generation illumina sequencer. this easy-to-use system is ideal for small whole-genome sequencing, e.g., viruses, and specific genomic targeted approaches (colman et al., ) . in this study, we aimed at implementing an ampliconbased sequencing approach to obtain sars-cov- consensus genomes directly from clinical specimens, adaptable into the field conditions, with the two easily manageable nextgeneration sequencers, the nanopore minion and the illumina iseq tm system. we also evaluated the performance of these two sequencers, in terms of ease of use, hands-on time, simplification of the sequencing process, and capacity for realtime genome sequencing in settings lacking laboratory resources for outbreak response. the two samples used in this study were sputum (cibu- and cibu- ) vero e cells (mycoplasma-free) seeded in -well plates ( × cells/well) were cultured in dmem (dulbecco's modified eagle medium; thermo fisher scientific, united states) containing % ps (penicillin , u/ml; streptomycin , µg/ml) and supplemented with % fbs (fetal bovine serum). samples were diluted : in dmem % ps without fbs and supplemented with µg/ml tpck-trypsin (sigma-aldrich, united states), added to the cell monolayers and incubated for h at • c in the presence of % co . the inoculum was then removed and replaced with fresh dmem % ps containing µg/ml tpcktrypsin. after incubation for days at • c in the presence of % co , cells were observed for the presence of a cytopathic effect (cpe) under the microscope, and culture supernatants were harvested, aliquoted, and stored at − • c. total rna from clinical samples was extracted using the nucleomag kit on the kingfisher automate (macherey nagel, germany) and from isolates using the nucleospin dx virus (macherey nagel, germany), following the manufacturer's instructions. sputum specimens and respective isolates rna extracts were tested with the sars-cov- real-time rdrp gene duplex reverse transcription (rt)-pcr developed by the french national reference center for respiratory viruses and the real-time e gene rt-pcr from the charité protocol (see who coronavirus disease covid- technical guidance: laboratory testing for -ncov in humans, available from https://www.who. int/docs/default-source/coronaviruse/whoinhouseassays.pdf). samples were considered sars-cov- positive if at least two out of three sars-cov- gene targets were detected by the rt-pcr assays. for each sample, the protoscript ii first strand cdna synthesis kit (new england biolabs, neb, united states) was used to obtain single-strand cdna from rna extracts using random hexamers. rt was performed at • c for min and • c for min. pools of specific primer sets were used to generate amplicons from the cdna using the q hot start high-fidelity dna polymerase (neb, united states) (supplementary table) . these multiplex primer sets (divided into two separate pools) were designed using the primal scheme software on the sars-cov- reference sequence (genbank accession number nc_ ) to sequentially amplify , bp using the following pcr conditions: • c for s, cycles of • c for s, • c for min, and ended by • c for min. clean-up of pcr products was performed with ampure xp magnetic beads (beckman coulter, united states). the quantity of amplicons was measured with the qubit . fluorometer using the dsdna hs assay kit (thermo fisher scientific, united states), and the quality was assessed by electrophoresis in e-gel r ex % agarose (invitrogen r ) and visualized with e-gel powersnap electrophoresis system (invitrogen r ). the amplicons obtained from the two clinical samples and their corresponding isolates were normalized to equal concentrations, multiplexed (x ), and sequenced using the minion and illumina iseq tm system (figure ). library preparation for the minion sequencing was performed using the ligation sequencing kit sqk-lsk and natives barcoding kits exp-nbd /exp-nbd (ont) according to the manufacturer's instructions and modifications as per quick et al. ( ) . briefly, pcr amplicons pools were end-repaired and da-tailed using an ultraii end prep reaction module (neb, united states) followed by ligation of native barcodes using the nebnext ultraii ligation module (neb, united states). all the pooled barcoded libraries were purified using ampure xp beads (beckman coulter) followed by adapter ligation with the nebnext ultraii ligation module. library clean-up was performed using ampure xp beads and short fragment buffer (sfb) and then eluted in µl of ont's elution buffer. the library was loaded onto an r . flow cell (flo-min ) and sequenced on a minion mk b device within h (figure ). ont minknow software (version . . ) was used to collect raw data and perform basecalling (guppy v . ). the rampart tool (read assignment, mapping, and phylogenetic analysis in real time) developed by the artic network has been used to visualize genome coverage in real time and reference matching for each barcode. from the fastq files, only reads with a minimum q score of were selected for the analysis. data were demultiplexed using the guppy_barcoder with the option require_barcodes_both_ends to figure | sars-cov- next-generation sequencing workflow, from the sample to sequence analysis. created with biorender.com. frontiers in microbiology | www.frontiersin.org ensure barcodes are present at each end of the fragment. the reads were filtered on the expected length of amplicons. reads between and , base pairs were kept; thus, potential chimeric reads were removed. selected reads were mapped against sars-cov- reference (nc_ ) using minimap (v . ) (li, ) . samtools (v . ) were used to sort the aligned bam files, to obtain coverage data and a consensus sequence. alignment statistics were also calculated with samtools. data were manually inspected using tablet (v . ) (milne et al., ) . the appropriate volume of each pool of amplicons was adjusted to have a total quantity of ng of amplicon input ( ng of each) per sample. the sequencing-ready libraries were prepared using the nextera dna flex prep kit (illumina, united states). the libraries were qualified on an agilent technologies bioanalyzer using a high-sensitivity dna chip following the manufacturer's instructions and quantified with the qubit . fluorometer using the dsdna hs assay kit (thermo fisher scientific, united states). the resulting libraries were sequenced using the iseq tm system (illumina, united states) and in two multiplexed runs were performed generating × bp read length data during a h run time (figure ). to remove low quality reads, trim off low-quality and contaminant residues, and filter out duplicated reads, fqcleaner v. . . was used, with phred quality score of . filtered reads were mapped against sars-cov- reference (nc_ ) using burrows-wheeler aligner mem algorithm (bwa-mem) (v . . ). samtools (v . ) was used to sort bam files and to generate alignment statistics, coverage data, and a consensus sequence. data were manually inspected using tablet (v . ) (milne et al., ) . the two sputum samples cibu- and cibu- , were tested with the specific sars-cov- real-time rt-pcr protocol. they were both found positive with the three sars-cov- gene targets. the threshold cycle (ct) values for cibu- and cibu- were respectively - and - for the rdrp gene duplex and and for the e gene. the two clinical specimens were also inoculated on vero e cells, and after incubation for days, a clear cytopathic effect was observed. culture supernatants of the first passage were harvested and tested for the presence of the virus with the specific sars-cov- real-time rt-pcr protocol. the ct values of the two corresponding isolates cibu- c and cibu- c were respectively - and - for the rdrp gene duplex and and for the e gene, confirming the isolation of sars-cov- . as soon as the first sars-cov- reference genome was released in genbank (nc_ ), we designed two sets of primers to generate a tiling path along the genome using the primal scheme tool. the full-length genome was amplified directly from the rna extracts from the clinical samples and the corresponding isolates, to obtain pcr products overlapping by bp and covering the entire , bp viral genomic sequence. thirtysix amplicons, split into two pools, were successfully generated for each specimen with a size expected range between and , bp (with an average length of bp) and controlled by gel electrophoresis. the amplicons obtained from the two clinical samples cibu- and cibu- were multiplexed and sequenced using the minion platform with r . . flow cell during h. the minion run produced , and , raw reads with a good quality score, respectively, for the two clinical samples, with an average of , bp read length. thus, the mapping against wuhan sars-cov- reference (nc_ ), by using minimap , retrieved , ( . %) and , ( . %) reads, respectively, for the two clinical samples ( table ) . the run yielded a median read depth of x and , x for the two clinical samples, respectively (table and figure ) , with the average base error rate ranging between . and . %. a near fulllength consensus sequence of , and , bp was generated for cibu- and cibu- , respectively. in the same way, a h minion run, applied to the two corresponding isolates cibu- c and cibu- c , produced , and , high-quality raw reads, respectively, with an average of , bp read length ( table ) . the run yielded a median read depth of , x and , x for the two isolates, respectively (table and figure ) . the mapping against wuhan sars-cov- reference (nc_ ) using minimap used . % of raw reads in both cases and allowed to generate the genome consensus sequence of , and , bp, for the two isolates, respectively. regardless of using a read depth cutoff of x or x, we obtained around and % of sars-cov- genome coverage, for the clinical samples, respectively. the genome coverage variation between both clinical samples reflected the initial viral load difference, which was even more marked at x (table ) , as is the difference between the median read depths. however, due to the high sequencing error rate around %, we observed that a reliable consensus sequence should be analyzed at a minimum depth coverage at x, or even x for some nucleotides. conversely, the genome coverage for the isolates was quite similar, with at x . % and . %, respectively ( table ) . for the clinical sample with the lower viral load cibu- , the genome coverage was significantly improved by the isolation step, less so for the second clinical sample with a very low ct value (figure ) . concerning the bioinformatics analysis, the rampart tool (read assignment, mapping and phylogenetic analysis in real time) developed by the artic network was helpful and time-saving to visualize genome coverage in real time and allowed to stop the run when sufficient data were generated. globally, using our amplicon-based approach, combined with the minion platform, we were able to obtain the near fulllength genome of the studied viral specimens in around h, from samples to sequences data. (figure ) . these observed variations in read depth are the direct consequence of the variable amplification efficiency of the primer pairs used in the multiplex pcr pool, impacted by the viral load of the samples as well as the secondary structures of the viral genome which affect primer binding. these results underlined that high-quality sequences could be obtained with greater samples multiplexing. using an amplicon-based approach, combined with the iseq tm system platform, we were able to obtain the near full genome of the studied sars-cov- in around h. viral consensus genomic sequences were rapidly and easily obtained for the two sars-cov- clinical specimens and their respective isolates, by using the two different sequencing platforms, minion and iseq tm system. we noted that the sequences obtained for the same specimen are identical, regardless of the sequencer used. sequence analysis of the sars-cov- consensus genomes showed that they belong to the proposed phylogenetic clade a , which is consistent with the phylogenetic analysis of the other human french sars-cov- sequences (gámbaro et al., ) . compared to the wuhan reference sequence (nc_ ), the viral genomic sequences cibu- and cibu- (gisaid accession numbers epi_isl_ and epi_isl_ ) display seven and six nucleotide mutations, respectively. both share five nucleotide mutations (c t, c t, c t, a g, and g t), among which three have led to amino acid mutations p l in orf ab, d g in s, and q h in orf a. it is noteworthy that the mutation d g in the spike glycoprotein is specific of clade a , encompassing most of the french sars-cov- sequences. the cibu- additionally contains two more mutations in orf ab, c t (t i) and c t, whereas the cibu- includes an additional one, c t. comparison of the genomes obtained for the clinical specimens and their respective isolates show that the sequences are strictly identical, suggesting that culture of the sars-cov- on vero e cells did not induce any molecular change, at least during the first passage. with many challenges still to be overcome in real-time genomics in rapid-response diagnostics, we evaluated the performances of these both mobile benchtop instruments. while the library preparation time is similar (approximately h) between the two approaches and require the same benchtop laboratory equipment (figure ) , the minion is more efficient and versatile in terms of run time, with the procurement of robust results after - h, compared to an incompressible run time of h for the iseq tm system. it is important to take into account the thawing time of the illumina cartridge reagents which takes at least h in comparison to the immediately available minion loading reagents which are stored at room temperature. minion needs a powerful laptop computer and a stable broadband internet connection, whereas illumina system is stand-alone at least in the first bioinformatics steps, as basecalling and demultiplexing. concerning the sequencers themselves, the two systems are equivalent in terms of ease of use and maintenance and are therefore both suitable for experiments in resourcelimited settings. the read length was fixed to nt by the illumina chemistry, and nanopore reads were longer and entirely covered the length of the generated amplicons with an average of , nt, after trimming with porechop (table ) . while ont improved sequencing accuracy, a still relatively high error rate of the minion raw reads (around %) was noticed in comparison with illumina ones (around . %), requiring a higher read depth to obtain a confident consensus sequence. overall, for each sample, we obtained a better coverage of the genome with the illumina approach, and this as early as x of read depth. by comparing minion and iseq tm system produced consensus genomes, we observed that the necessary coverage threshold is higher for minion than for iseq tm system. novel mammalian coronaviruses are regularly identified and involved in epidemics and severe diseases, such as sars-cov, which emerged in southern china in (drosten et al., ) , and mers-cov, first described in saudi arabia in and still circulating (song et al., ) . at the source of viral outbreaks, readily adaptable methods with rapid turn-around times are necessary for pathogen identification, surveillance programs, and public health strategies. whole genome sequencing with next-generation sequencers is now widely used in specialized laboratories, which have required equipment and long experience for this implementation. however, it is also essential that this approach is accessible at the pen-side of infected humans to investigate outbreaks in remote areas. in this regard, we therefore evaluated two space-saving and easily portable next-generation sequencers, minion and iseq tm system, through the current pandemic of covid- . although the initial investment gives an advantage to the minion, the cost of reagents on the other hand is similar, and both approaches require the identical minimum of laboratory equipment to generate the libraries. by using the primal scheme software on the first released sars-cov- reference sequence, we immediately developed an amplicon-based approach to sequence around , bp amplicons on our small portable sequencers. it has been reported that the ampliseq panel proposed by artic network, based on amplicons, may lead to coverage bias due to dimer formation between primers (itokawa et al., ) . our choice to produce longer amplicons, with lower number of primers, could be more efficient. nevertheless, for all the specimens, the extremities of the genome could not be obtained. as often in the genome sequencing of singlestrand rna viruses, the ' and ' non-coding regions are quite difficult to directly acquire, which would rather require an approach such as rapid amplification of cdna ends pcr (race-pcr). we successfully proved that such targeted approach performs well directly with clinical samples. the counterpart of this workflow requires prior knowledge of the pathogen but, on the other hand, could be promptly adapted to all viruses of interest, including those with very large genomes. we found that viral genomic sequencing, even with low-throughput sequencers, could be performed with high confidence and be achieved directly from clinical specimens with significantly shortened run time. although higher samples multiplexing is suitable, these relatively low throughput sequencers can also run economically with a small number of samples, which is a great advantage when the information is needed as quickly as possible. both sequencers generated the correct consensus genomes, with a slightly lower coverage for minion and a higher error rate than the iseq tm system. however, we were able to obtain the genome of the studied specimens in around h with the minion, illustrating the quasi real-time sequencing capacity to effectively support health authorities. the main defect of the iseq tm system finally lies in its run time. nanopore is regularly considered to have the advantage over other technologies of high portability and fast turnaround time (gardy and loman, ) . it should be noted that today illumina offers a sequencer, which tends toward the same interesting features, while maintaining the high quality of the reads, which is at the origin of illumina's success. the minion retains the advantage of greater versatility, with the possibility of analyzing data in true real time, particularly with tools such as rampart, and thus being able to stop the run after a few hours as soon as the amount of data is sufficient. concerning the further generation of the alignment of amplicon reads against the reference and the variant calling, both devices usually offer tools in the cloud, such as local run manager (dna amplicon analysis module) for iseq tm system, and epi me for minion. in outbreak situations, these two sequencers therefore make rapid sequencing accessible to a very large number of laboratories, requiring a minimum of molecular biology skills. nevertheless, the improvement of the dedicated bioinformatics user-friendly resources should still be developed to take into account the low network and informatics resources in the field. in conclusion, our investigation led to the development of an amplicon-based sequencing approach and the characterization of the viral genome as sars-cov- within a few hours, adaptable in field conditions, with two easily manageable next-generation sequencers, the nanopore minion and the illumina iseq tm system. they provide faster and more cost-effective small-scale runs, which avoid outsourcing for laboratories in remote areas, and allow control of the whole sequencing process. the minion and iseq tm system bring the power of next-generation sequencing to virtually any laboratory, with amplicon-based whole-genome sequencing protocols rapidly transposable to all molecular investigations of epidemic prone pathogens. the datasets generated for this study can be found in online repositories. the names of the repository/repositories and accession number(s) can be found in the article/supplementary material. ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. vh performed all the data analysis. ak and cb conducted the experiments. vh, ak, cb, jv, and vc conceived the study. vh, ak, cb, and vc analyzed the results and prepared the manuscript. sm, cb, and j-cm provided scientific guidance. all authors reviewed the manuscript. this work was made possible thanks to financial support obtained through the «urgence nouveau coronavirus» fundraising campaign of institut pasteur. this project also received funding from the french institut carnot pasteur "microbes et santé" (anr carn - ) and institut carnot "france futur Élevage" (anr carn - ), in the framework of the field project. whole-genome and targeted sequencing of drug-resistant mycobacterium tuberculosis on the iseq and miseq: a performance, ease-of-use, and cost evaluation an interactive web-based dashboard to track covid- in real time identification of a novel coronavirus in patients with severe acute respiratory syndrome mobile real-time surveillance of zika virus in brazil introductions and early spread of sars-cov- in france towards a genomics-informed, real-time, global pathogen surveillance system nanopore sequencing as a rapidly deployable ebola outbreak tool clinical and biological insights from viral genome sequencing a proposal of alternative primers for the artic network's multiplex pcr to improve coverage of sars-cov- genome sequencing. biorxiv metagenomic sequencing at the epicenter of the nigeria lassa fever outbreak minimap : pairwise alignment for nucleotide sequences genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding using tablet for visual exploration of second-generation sequencing data multiplex pcr method for minion and illumina sequencing of zika and other virus genomes directly from clinical samples from sars to mers, thrusting coronaviruses into the spotlight a new coronavirus associated with human respiratory disease in china zoonotic origins of human coronaviruses a pneumonia outbreak associated with a new coronavirus of probable bat origin we acknowledged all the members of the laboratory for urgent response to biological threats (institut pasteur) who are involved in the covid- diagnosis and india leclercq for her support in viral isolation. the supplementary material for this article can be found online at:https://www.frontiersin.org/articles/ . /fmicb. . /full#supplementary-material key: cord- -m hqxna authors: beck, teresa l.; le, thien-kim; henry-okafor, queen; shah, megha k. title: medical care for undocumented immigrants: national and international issues date: - - journal: physician assist clin doi: . /j.cpha. . . sha: doc_id: cord_uid: m hqxna the number of undocumented immigrants (uis) varies worldwide, and most reside in the united states. with more than million uis in the united states, addressing the health care needs of this population presents unique challenges and opportunities. most uis are uninsured and rely on the safety-net health system for their care. because of young age, this population is often considered to be healthier than the overall us population, but they have specific health conditions and risks. adequate coverage is lacking; however, there are examples of how to better address the health care needs of uis. family foundation, health coverage of immirgants: https://www.kff.org/disparitiespolicy/fact-sheet/health-coverage-of-immigrants/) and % are adults between the ages of and years. more than million people in the united states are the us-born children of uis. about half of uis are of mexican origin; however, these numbers have declined over the last years, from more than million to . million as of . california, texas, and florida have the largest numbers of uis, and nevada has the largest share, making up % of the state's population. [ ] [ ] [ ] [ ] the issue of uis is not unique to the united states. internationally, the united nations population division estimates that there are million to million unauthorized immigrants worldwide, and although most are in the united states, proportionally continental europe has a larger share. although uis have a variety of reasons to migrate, from safety concerns to economic incentives, addressing the health needs of these populations come with unique challenges and solutions. this article provides an overview of challenges in addressing their health needs, existing methods for accessing care, health conditions specific to this population, and potential solutions to consider in both the national and international contexts, specifically in europe. despite the better health status of the younger ui population, this advantage deteriorates over increasing time spent in the united states. various factors from socioeconomic status to fear of deportation affect the ui population's health both domestically and internationally and deter uis from seeking care. the ui population is often of lower socioeconomic status, which adds to the difficulties accessing health care. given that most of the federal insurance plans are unavailable to the ui population, uis are susceptible to higher out-of-pocket costs for care. in addition, because of undocumented status, they may not have sick leave days and may have difficulty negotiating time off from work to seek care. decreased proficiency in the language of the host country and fear of deportation may also present barriers to health care for uis. studies have shown that patients with limited english language proficiency (lep) are at higher risk of poor health and have decreased access to health care. patients who have lep had increased difficulty in understanding their health status as well as accessing preventive services. fear of deportation may lead to the avoidance of seeking care and risk of severe health complications, and this also affects health care for us-born children of uis. in addition, shame and discrimination are common feelings experienced by the ui population and contribute to poor access to health care globally. many of these issues in health care are not unique to the united states. in a study by chauvin and colleagues, % of the ui population in europe had access to health coverage, and, of those, only about % had true access because of barriers such as administrative difficulties, limited language proficiency, and lack of awareness of available services. of the main reasons for lack of access, administrative difficulties in obtaining health care and finances were cited as the most common. france and belgium were found to have the most complicated systems for obtaining health care and, for those who had access, the fear of deportation or imprisonment was prevalent. the patient protection and affordable care act (aca), passed in , required most us citizens and legal residents to have health insurance, and resulted in the expansion of medicaid in states. uis are not eligible for medicaid or state-based exchanges under this law. thus, although the number of overall uninsured in the united states has decreased, it is mostly us citizens and legal residents who have gained access to health insurance. in , congress approved the emergency medical treatment and labor act (emtala), requiring hospitals to provide services for active labor and emergency care regardless of insurance and immigration status. in addition to emtala, there is emergency care under medicaid, which is currently the only federal insurance that is available to uis. emergency medicaid covers patients in active labor and those with acute medical emergencies. it may only be used to stabilize patients and may not cover patients for services after the patient has been stabilized. federal provisions available to uis include prenatal care and care for children funded by maternal and child health block grants and the supplemental food program for women, infants and children. in , the children's health insurance program (chip) was expanded under the chip reauthorization act (chipra). in , federal funding for chip was expanded to states, which included the standard medicaid benefit package such as the early and periodic screening, diagnostic, and treatment services for medically necessary mental health and dental services, vaccinations and prescription drugs, and access to medical specialists and hospital care and services. although these resources are available for a vulnerable subset of uis, there are few resources that exist for sick, nonpregnant adults. federally qualified health centers (fqhcs) are community health centers that receive federal grant funding to support care to the uninsured without regard for immigration status. there are approximately health centers operating around the country, providing primary health care, dental, mental health, and pharmacy services on a sliding-scale basis. in addition, there are many low-cost and free community clinics that rely on private donations and volunteers to provide services to those who cannot afford to pay. europe faces similar challenges regarding access to health care for its ui population. the platform for international cooperation on undocumented migrants (picum) reported that italy and spain provided the widest coverage for ui with universal access to health care. germany, greece, sweden, and switzerland only cover emergency care for uis. table provides an overview of access to care for uis in europe. there is ongoing political debate in the united states regarding health care services for uis. those in opposition maintain that using taxpayer-funded services to support individuals who enter and remain in the united states illegally undermines the legal system. however, some scholars and legislators have argued that it is both unethical and impractical to deny access to health care services for illegal immigrants living in the united states. they view health care as a basic human right and an obligation of a just society to provide health care for everyone. leading medical professional societies such as the american medical association (ama), american college of physicians (acp), the american academy of family physicians (aafp), and the american nurses association (ana) reaffirm the position that all individuals living in the united states, regardless of their immigration status, should have access to quality health care, including the opportunity to purchase insurance. these leaders maintain that providing this population with access to health insurance is an evidence-based way to reduce health care costs. [ ] [ ] [ ] another argument, from a cost perspective, is that many uis will benefit from preventive care and early treatment of chronic diseases before they advance to lifethreatening and costly complications. , proponents of this strategy advocate for improving health literacy and vaccination rates, and offering health screenings to the ui population to try to prevent long-term adverse health outcomes and control cost. moreover, uis may harbor infections such as tuberculosis (tb), which, when undetected, can easily be transmitted to the general public, thus posing a public health risk. in contrast, some have argued that treating uis creates more expenditures for the united states while saving their countries of origin the costs of providing health care. furthermore, they argue that sharing inadequate health care resources with uis will reduce the availability of those scarce resources for us citizens. in the last decades, several states have attempted to advance legislation designed to deny uis access to publicly funded health services. one such initiative was california's proposition . this law, later deemed unconstitutional, required health care professionals to verify immigration status and report uis to authorities. in addition, some believe that continued unabated treatment of uis is an incentive for persistent violation of the immigration laws and threatens national security in the post- / era. proponents of this argument suggest that denying health care to uis will discourage others from attempting to immigrate without proper documentation. there are significant gaps in the literature on the health status of the ui population. immigrants in general, and the undocumented in particular, report lower levels of cancer, heart disease, arthritis, depression, hypertension, and asthma than do the native born. factors thought to contribute to lower rates of reported chronic diseases include the young immigrant population and the process of migration, which, especially in cases of undocumented individuals, positively selects for those healthy enough to make the often arduous journey (ie, the so-called healthy immigrant effect). , in addition, little is known about the long-term health of the children of uis, particularly related to the adverse effects of inadequate prenatal care and the stressors related to undocumented status, which has been shown to negatively affect children regardless of their own legal status. most of the emergency health care services used by uis are for childbirth. a study of emergency medicaid expenditures for undocumented and recent immigrants in north carolina between and found that more than % of health care spending was related to childbirth and complications of pregnancy. of the remaining health care expenditures, one-third was spent on the treatment of acute injuries and poisoning, possibly related to exposure to pesticides or other toxins in the workplace. these uses of health care services reflect not only the young age of most uis but also the type of work that they perform. beyond pregnancy and acute injury, chronic renal failure, cerebrovascular disease, and heart disease were major contributors to emergency medicaid use. various factors associated with undocumented status are thought to erode the health advantage of the undocumented at a faster rate than their documented counterparts. specifically, limited access to quality health care; increased vulnerability caused by low income and occupational status; and the stressors associated with undocumented status, such as fear of deportation, have been implicated. in addition, uis with chronic and infectious medical conditions are negatively affected because of poor access to care. [ ] [ ] [ ] perinatal health of undocumented women and their us-born children is a specific area of concern. consistent with much of the health literature, several studies have found that undocumented women engage in few health risk behaviors while pregnant and seem to have low rates of low-birth-weight or preterm babies. [ ] [ ] [ ] [ ] however, the beneficial effects of better health behaviors during pregnancy are counteracted by the effects of lower rates of prenatal care among uis. poor (and late) prenatal care has been associated with higher risk for adverse perinatal outcomes. , in addition, stressors related to undocumented status, such as fear of deportation or experiences of discrimination and stigma, may adversely affect the physical and emotional health of uis, with potential consequences for their us-born children. , findings from a qualitative study of immigrant families experiencing the arrest of at least parent by immigration authorities, showed an increase in the children's behavioral problems, speech and developmental concerns, and declines in school performance. there is a public health concern over uis bringing infectious diseases into the united states. legal immigrants and refugees are required to have a medical examination for migration to the united states, while they are still overseas. this examination is the responsibility of the centers for disease control and prevention (cdc), which provide instructions to the panel physicians who conduct the medical examinations. the procedure consists of a physical examination, an evaluation (skin test/chest radiograph examination) for tb, and a serologic evaluation for syphilis. requirements for vaccination are based on recommendations from the advisory committee on immunization practices. individuals who fail the examination because of certain health-related conditions are not admitted to the united states. such conditions include drug addiction or communicable diseases of public health significance, such as tb, syphilis, gonorrhea, leprosy, and a changing list of current threats such as polio, cholera, diphtheria, smallpox, or severe acute respiratory syndromes. there is a growing concern that uis crossing into the united states illegally could bring any of these threats. the most prevalent infectious diseases are hepatitis b, latent and active tb, filariasis, intestinal helminth infections, malaria, intestinal protozoa infections, hepatitis c, other nonparasitic infections, sexually transmitted diseases, and human immunodeficiency virus. little is known about the mental health issues of uis. however, the literature suggests that uis have a unique risk profile that may contribute to different mental health outcomes compared with their documented counterparts. themes specific to uis include failure in the country of origin, dangerous border crossings, limited resources, restricted mobility, marginalization/isolation, stigma/blame and guilt/shame, vulnerability/exploitability, fear and fear-based behaviors, and stress and depression. one study compared the diagnoses and mental health care use of undocumented latin american immigrants ( %) with those of documented ( %) and us-born latin americans ( %) treated in this clinical setting. the undocumented latin americans were more likely to have a diagnosis of anxiety, adjustment, and alcohol abuse disorders. the uis also had a significantly greater mean number of concurrent psychosocial stressors compared with documented immigrants and us-born groups, and they were more likely to have psychosocial problems related to occupation, access to health care, and the legal system. other studies have shown increasing rates of substance abuse, binge-eating, and conduct disorders among uis residing longer in the united states. the european immigrant population comes from many different countries, with a heavy concentration from countries in africa, the middle east, and the former soviet union. the most commonly reported health care problems in this undocumented migrant population include mental health, infectious and sexually transmitted diseases, and reproductive health. concerns about human trafficking, particularly of women and children, for commercial sexual exploitation or forced labor or slavery are more prominent in europe. despite the contentious debate over the aca, a consensus has emerged that strengthening primary care will improve health outcomes and restrain the growth of health care spending. supporting evidence comes from studies of primary care as an orientation of health systems and as a set of functions delivered by a usual source of care. although methodological concerns exist, many observational studies in the united states have found that regions with higher primary care physician-to-specialist ratios have better health outcomes, including lower mortality; fewer emergency department visits, hospitalizations, and procedures per capita; and lower costs. international comparisons between industrialized countries also suggest that countries with higher ratings of primary care orientation experience better health care outcomes and incur lower health care costs than countries with lower degrees of primary care orientation. these finding suggest that reducing barriers to primary care for uis may ultimately improve the quality and cost of delivering health care for all countries struggling to manage their growing immigrant populations. several us cities and states with large immigrant populations have attempted to address their health care needs by providing access to primary care. new york city has the nation's largest public health system, composed of the health and hospitals corporation (hhc) and community health care association of new york state, whose members include fqhcs and migrant health programs. these organizations provide much of the health care for uninsured and undocumented patients. both systems rely on medicaid (and, to a lesser extent, medicare) reimbursements. they also depend on federal disproportionate share hospital funding and other sources of state indigent care pool funding. in addition to primary and preventive health care, hhc ambulatory centers offer uninsured patients access to on-site pharmacies and referrals to medical specialists and diagnostic and other services located in hhc medical centers. california offers a medi-cal health insurance plan that provides a full range of lowcost health care options for uninsured californians, with some benefits provided regardless of immigration status. in addition, kaiser permanente offers a child health program for uninsured california children younger than years who do not have access to medi-cal or other coverage, regardless of immigration status. my health la (mhla) is a no-cost health care program that offers comprehensive health care for low-income, uninsured los angeles county residents, regardless of immigration status or medical condition. it offers care through community clinic medical home sites, where patients receive primary and preventive health care services and some diagnostic services. los angeles county department of health services facilities also provide county clinic medical home sites, plus emergency, diagnostic, specialty, inpatient services, and pharmacy services. healthy san francisco (hsf) is a low-income program for san francisco county residents regardless of employment status, immigration status, or medical condition. unlike mhla, hsf charges a participation fee and point-of-service fee to all patients except for those at less than % of the federal poverty level and those who are homeless. the harris county health system, which includes the city of houston, texas, offers access care, a financial assistance program open to uninsured and undocumented harris county residents, and provides access to discounted health care at more than community clinics, a dental clinic, and surgical and other subspecialty clinics. the harris health system has a dialysis clinic as well as a long-term care facility. in massachusetts, all immigrants are eligible for some form of health coverage. there is application for all available programs, including the insurance marketplace. mass health limited is the state version of emergency medicaid. it is available to uis and some immigrants who are prucol (permanent residence under color of law), defined as aliens who are living in the united states with the knowledge and permission of the federal government, and whose departure the agency does not contemplate enforcing. in nevada, the nonprofit access to healthcare network (ahn) offers medical discount programs, specialty care coordination, a health insurance program, nonemergency medical transportation services, a pediatric hematology/oncology practice, and a toll-free statewide call center. ahn has , members, more than half of whom are presumed to be undocumented. a study by hacker and colleagues identified areas to address barriers to care for uis: advocacy for policy, insurance options, expansion of the safety net, training of providers, and education of uis on navigating the system ( table ) . nearly all industrialized countries provide some form of government-supported health care to all of its residents, including those who are undocumented (see table ). although countries in the european union have significantly fewer uis, their models may offer insights on the options and challenges of addressing this health care dilemma facing the united states. medical care for uis is a complex area involving challenges for accessing care, barriers in financing care, and unique medical conditions. fear, stigma, cost, and cultural barriers often prevent uis from seeking medical care. uis make up a small but substantial portion of the population in the united states and internationally, and there is an emerging interest in finding solutions to address their health care needs. in the united states, cities with large numbers of immigrants have models that provide health care to their uninsured regardless of immigration status, and could potentially be expanded to other areas of the country experiencing increasing growth of their immigrant populations. international approaches may also inform on policies to address the health care needs of uis. 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utilization of mental health services among undocumented immigrant latinos primary care: a critical review of the evidence on quality and costs of health care undocumented immigrants and access to health care in new york city: identifying fair, effective, and sustainable local policy solutions: report and recommendations to the office of the mayor of key: cord- -jcpyrlw authors: lichtenstein, bronwen title: from “coffin dodger” to “boomer remover”: outbreaks of ageism in three countries with divergent approaches to coronavirus control date: - - journal: j gerontol b psychol sci soc sci doi: . /geronb/gbaa sha: doc_id: cord_uid: jcpyrlw objectives: this article compares responses to coronavirus control in australia, the united kingdom, and the united states, countries in which public ageism erupted over the social and economic costs of protecting older adults from covid- . methods: thirty-five ( ) newspapers, media websites, and current affairs magazines were sourced for the study: for australia, for the united kingdom, and for the united states. searches were conducted daily from april to june , using key words to identify age-related themes on pandemic control. results: despite divergent policies in the countries, ageism took similar forms. public responses to lockdowns and other measures cast older adults as a problem to be ignored or solved through segregation. name-calling, blame, and “so-be-it” reactions toward age vulnerability were commonplace. policies banning visits to aged care homes angered many relatives and older adults. indefinite isolation for older adults was widely accepted, especially as a vehicle to end public lockdowns and economic crises. discussion: older adults have and will continue to bear the brunt of covid- in terms of social burdens and body counts as the pandemic continues to affect people around the globe. the rhetoric of disposability underscores age discrimination on a broader scale, with blame toward an age cohort considered to have lived past its usefulness for society and to have enriched itself at the expense of future generations. many people view covid- as an "older adult" problem (fraser et al., ) . from health advisories on age vulnerability, to the ghettoizing of older adults for risk mitigation, ageist rhetoric has been a dominant theme for pandemic control. as a social fact, ageism has roots in the postindustrial era, where age-graded subgroups (e.g., "employees" and "retirees") emerged to meet the specialized demands of modern society (hagestad and uhlenberg, ; north and fiske, ) . the "us" and "them" narratives arising from this development prompted sociologist james coleman ( ) to claim that age segregation is the root cause of ageism. this article analyzes covid- -related discourse in three countries in which age segregation is a core principle of mitigation policies and is a contested space in terms of "people first" or "economy first" responses to managing the pandemic. ageism has infused medical decision making for covid- . a rhetoric of disposability has surfaced in questions about who should live or die when medical resources are scarce, hospital systems overwhelmed, and covid- roils the globe. older patients are deemed disposable when " [they] are not being resuscitated and die alone without appropriate palliative care. . ." (nacoti et al., ) . italy, spain, brazil, united kingdom, and some u.s. states have faced this reality. but even when covid- is largely contained, as in australia, new zealand, taiwan, and vietnam, medical rationing by age and morbidity is mooted in "what if" or second wave scenarios in which curative therapies and vaccine are still elusive. even caring messages create them-and-us dichotomies in which being older is a separate country, to use hagestad and uhlenberg's ( ) phrasing, and, in ayalon et al.'s ( ) analysis, a clearly defined outgroup in terms of health policies to isolate older adults. this research brief examines public ageism in official statements and debates over managing the crisis in three english-speaking countries with different approaches to coronavirus control. the first country (australia, population million) enacted timely control measures for covid- and has flattened the curve to a large extent. in both the united states (population million) and united kingdom (population . million), control measures were tardy and death rates among the highest in the world (worldometer, ) . all three countries adopted age-segregated policies in order to protect older adults on a temporary (if long-lasting) basis until a "cure" was found. the primary sources for this analysis include major broadsheets such as the age and sydney morning herald in australia; the guardian (and three tabloids, daily mail, the telegraph, and the sun) in the united kingdom; and the new york times and the washington post in the united states. thirty-five ( ) newspapers, media websites, and current affairs magazines were sourced for the study: for australia, for the united kingdom, and for the united states. (australia has a smaller population compared to the united kingdom and united states, and its media resources are fewer.) nonprint sources include the australian broadcasting commission (abc), the british broadcasting commission (bbc), health policy platforms (e.g., center for disease control and prevention [cdc]), and advocacy websites for older adults in each country. daily searches for source material were conducted from april to june , a period of widespread panic over mounting illness and the global death toll. the task for this brief was to examine these newspaper and media sites by matching keywords such as age/d, older, elderly, elders, seniors, pensioners, and grandparents with terms such as "covid- ," "sars-cov- ," "pandemic," and "coronavirus" to identify relevant policies and debates over coronavirus control. this targeted approach yielded three main themes for the analysis: lockdown of aged care homes, indefinite stay-at-home orders, and controversy over herd immunity. a fourth theme-access to ventilators-was salient in the early days of the pandemic but did not relate directly to initiatives for covid- control and was not included for analysis. the following paragraphs describe the results of the three themes. news items and postings on age segregation peaked in march-april , when cases were surging, officials were scrambling, and people feared the onslaught of a deadly virus that seemed out of control. on the first theme (lockdown of aged care homes), official policies in the three countries were similar in one respect: nursing home visits would be curtailed because of the high risk of death among residents who contracted the virus. table presents relevant news excerpts and postings for each country, as organized by government policy, aged care policy, and public responses to walling off older adults from the outside world (ayalon et al., ) . only a few responses are included to meet the word limits of this brief. table shows that visitors to aged care homes were officially banned in the united states, but not in australia and the united kingdom, which permitted family visits to some extent. australia's low infection rate could account for the difference in that country, although the aged care industry took issue with the government and itself instituted a total ban with strong support from the general public (karp, ) . the united kingdom's aged care industry also rejected the government's decision to allow healthy visitors and banned everyone without exception. in the united states, the industry followed cdc advice to ban all visitors; many families could not visit their relatives prior to death. family members in the three countries expressed grief and outrage at being denied access to their loved ones; they cited neglect and lack of institutional oversight of residents in their absence. the second theme (isolating older adults) affected anyone over in australia and in the united kingdom (table ) . "older" was defined as over in the united states, where restrictions were laxer and policies varied from state to state. in both australia and the united states, advocacy groups for older adults published stricter guidelines than their governments. only the united kingdom's national pensioners' convention adopted a softer policy after angry pushback from members about self-isolating for months on end. in all three cases, older adults were depicted as demented or medically compromised, despite a large majority rating their own health as good or excellent in recent studies (graham, ) . older adults were also deemed irresponsible. in the united states and united kingdom, they were scolded for ignoring health warnings to keep away from other people (chakelian, ; peterson, ) . a different story emerged from survey research in which older respondents proved more fearful of covid- than younger people, and less willing to visit grocery stores, friends' homes, crowded parties, and restaurants during lockdown (pew research center, a, b). terms such as "boomer remover," "boomer ( ) united kingdom: over s must self-isolate for up to four months. • official statement: "pensioners will be told to stay in their homes for months as part of a 'war-time-style' isolation plan to combat the coronavirus" (health secretary matt hancock, quoted in the sun news, march , ). • advocates' response: "the possibility of long-term selfisolation for our age group is unprecedented and hugely concerning. the main feedback we have heard from our members covers multiple worries about the impact and indeed the feasibility of social distancing" (national pensioners' convention website, march , ). • readers' response: "if i, (elderly and very spritely) choose to continue to lead a normal life and i contract covid- , i will either recover or die at home"; "at least if we die at home rather than in hospital then we have the consolation of not unduly affecting health authority statistics"; "i shall carry on as normal. i shall also ignore any rules about over- s staying in because they are being made by people who won't have to follow them" (chatroom postings, the telegraph, march , ). ( ) united states: self-isolation for up to two years, if necessary. • official statement: "older adults and people with underlying conditions should stay home as much as possible" (centers for disease control and prevention [cdc], april , ). • advocates' response: "the cdc recommends that those age and older avoid crowds, and that those in a community with an outbreak stay home as much as possible" (american association of retired persons [aarp] website, april , ). • public response: "you know what i'd really like to do right now if i'm being honest? i'd like to find a bat and ball and go break a few windows" ( -year old op-ed writer, washington post, may , ). "covid- killing me isn't my biggest concern. boredom, depression, or general frustration is"; "i have been alone for days and weeks before that. i am lonely and need human contact" (chatroom postings, the new york times, march , ). doomer," "yolo grandparents," "grey shufflers," and "moldy oldies" illustrate the degree to older people were denigrated in covid- -related postings and (occasionally) news sources analyzed for this brief. the third theme ("herd immunity") was the most contentious of the three topics, with fierce debate over whether lockdowns to protect vulnerable people were worth the cost to society (table ) . explicit in this debate was the assumption that covid- should be allowed to run its course, a proposition in which the majority, or "herd" of survivors (presumed to be immune), constitutes a shield to prevent the virus from regaining a foothold (rossman, ) . the problem with this proposition relates to uncontrolled illness and death until (or if) immunity is achieved. out of the three countries, australia alone rejected herd immunity as inhumane and morally unacceptable. protecting lives was the more important goal in australia, and strict lockdown was the way to achieve it. this people-first strategy was not without detractors who believed that herd immunity per se would protect the economy from collapse and the planet from environmental disaster. supporters of herd immunity referenced nationally scarring events, such as australia's bush fires, floods, droughts, and dust storms of . older readers expressed dismay at being deemed disposable and culled from society in survival-ofthe-fittest fashion. support for herd immunity faded in the wake of containment, reemerging only briefly in reference to second-wave threats and the cost of protecting ". . . older australians over who aren't worth as much as younger australians" (smith, ) . the united kingdom adopted herd immunity on ideological (libertarian) grounds with a caveat to protect older adults through self-isolation. an editorial in the guardian proclaimed: "the concept [of the free-born englishman] was fundamental to the government's decision-making in the crucial months of february and march [ ] ." this modified approach was abandoned when caseloads and death rates rose to alarming levels (worldometer, ) , nursing homes became hotbeds of disease, and hospitals were stretched to capacity (matthews, ) . proponents of the strategy offered familiar arguments about culling unproductive bodies from society but differed from their australian counterparts by claiming that herd immunity was a rational course of action in pandemic conditions (conn and lewis, ) . detractors expressed alarm at sacrificing older people to the tory government's pro-market policies and brexit machinations. as shown in the table, older adults had mixed feelings about being sequestered indefinitely under the government's modified plan, but abandonment, loneliness, and despair were evident in comments and postings in news sources used for this brief. the united states did not initially enact a policy of herd immunity, although bureaucratic delays, lack of testing, and official temporizing (schneider, ) were no match for a fast-moving viral foe. covid- soon became the leading cause of death in the united states (dowdy and ( ) australia: herd immunity rejected on moral grounds. • official statement: "we've seen what herd immunity has done in other parts of the world, so we won't be doing that" (deputy chief medical officer paul kelly, quoted on abc news, april , ). • herd immunity proponents: "we've grown too big for our own good, now nature replies by thinning us out a bit. at the end of all this, we will be stronger as a group, with the elderly and sick no longer being a burden" (chatroom posting, sydney morning herald, april , ). "provide government support to help the s+ stay at home but don't wreck the economy along with millions of jobs and lives" (letter to the age, march , ). • older readers: "we've faced our inevitable mortality, but i really don't enjoy being treated as one of the expendable"; "us older people are getting a bad rap. we have been blamed for grinding our social and economic system to a standstill" (the age, march , ). ( ) united kingdom: herd immunity until april (replaced by lockdowns). • official statement: "our aim is to build up herd immunity, so more people are immune to this disease and we reduce the transmission, at the same time protect those who are most vulnerable to it" (chief science advisor patrick vallance, quoted in the guardian, march , ). • herd immunity proponents: "pensioners? meh, they've had a good run"; "old people are an increasing burden, but must our young be the ones to shoulder it?" (postings to the guardian, april & may , d'souza, ). states belatedly imposed restrictions and lockdowns to flatten the curve, but with financial disaster looming, president trump urged american "warriors" to self-sacrifice for the economy (nakamura, ) . there was little question about which warriors would be sacrificed after a texas official proclaimed: "lots of grandparents would rather die than see health measures damage the us economy" (beckett, ) . the easing of state and municipal lockdowns left older adults to their own devices, perhaps to self-isolate indefinitely. america's debate over herd immunity erupted most strikingly at state capitols, where armed protesters demanded an end to lockdown orders in multistate demonstrations. protest signs evoked herd immunity with: "my virus, my choice"; "my right to die"; "sign up to die for the economy"; "natural immunity over manmade poison"; and even "sacrifice the weak." on the american association of retired persons' [aarp] website, worried retirees pondered their future as untouchables in covid- society. posters to other forums debated the pros and cons of isolating older people, with herd immunity proponents offering the harshest views of older adults as a drain on society. in counterpoint, "prophet of honor" voiced this experience of being rendered invisible in age-segregated america: my granddaughter ( ) was driving me home from chemo when i suggested she stop at a liquor store so i could get a couple of bottles of louis jadot to go with sunday dinner. she got my wheelchair out and we went inside. the clerk looked at me and then said to her "you know it's not safe to bring people like him out in public?" as if i were some "object." concern is all well and good, but don't overdo it (posted to thorbecke, ). the three countries in this brief have adopted different approaches to covid- control. at time of writing, the coronavirus is mostly contained in australia, but the united kingdom, and especially the united states, continue to experience severe outbreaks of the disease (worldometer, ) . each country has treated older adults as a special class for coronavirus control, and age-centric debates over who should live, die, and self-isolate have reflected widespread panic over rising death tolls. this focus can be explained, in part, by the twinning of "elderly" with "economy" in speeches about coronavirus control and in debates about herd immunity to avert economic catastrophe. australia alone diverged from herd immunity and relied on health expertise after witnessing the tragic death toll of other countries. with lower birthrates, smaller households, and older populations than in less developed regions of the world (united nations, ), these countries have gravitated toward institutionalizing older adults, prompting claims that age segregation is the root cause of ageism (coleman, ; hagestad and uhlenberg, ) . official policies to isolate older adults during covid- have accelerated this process. ageism has been blamed for islands of death in nursing homes (mueller, ) , and for a spike in intergenerational animosity, as captured in internet epithets such as "grandma/grandpa killer," boomer remover," and "boomer doomer" (pre-covid- ; "coffin dodger"). these hostile ageisms contrast with government bromides about protecting older adults, stereotyped as frail, incompetent, and obsolete prior to the pandemic (chonody, ) . the architects of benevolent ageism in the three countries failed to anticipate how sequestration exposed residents to covid- in aged care settings, where they were concentrated and infected in large numbers. this out-of-sight out-of-mind response also underscored support for herd immunity and opposition to public lockdowns. chonody ( ) argued that "us" versus "them" ageism reflects a fear of mortality and an effort to cope though avoidance, blame, and other tactics. the comparative approach to analyzing covid- related responses in australia, the united kingdom, and united states has highlighted a rhetoric of disposability and blame for an age cohort considered to have enriched itself at the expense of the climate, progress toward social equality, and the well-being of future generations (harris, ; whelan, ) . the analysis has also identified explicit name-calling and the infantilization of older adults for their vulnerability to covid- . this response has served to obscure systemic failures in timely and effective responses to covid- in the united kingdom and united states, where cost-cutting and small-government ideologies have undermined public health capability and created of a spectacle of death for the ages (lawrence et al., ; schneider, ) . age discrimination therefore occurs on multiple levels for older adults who will continue to bear the brunt of covid- in terms of social burdens and body counts as the pandemic continues its grim march across the globe. none declared. aging in times of the covid- pandemic: avoiding ageism and fostering intergenerational solidarity all the psychoses of us history": how america is victim-blaming the coronavirus dead. the guardian yolo grandparents" and "immortal boomers": are older people less afraid of coronavirus? the new statesman positive and negative ageism: the role of benevolent and hostile ageism the asymmetric society documents contradict uk government stance on covid- "herd immunity early herd immunity against covid- : a dangerous misconception ageism and covid- : what does our society's response say about us? why so many americans rate their health as good or even excellent. kaiser health network the social separation of old and young: a root of ageism coronavirus has deepened prejudice against older people. the guardian essential poll: two thirds of australians back aged-care homes on covid- visitor bans. the guardian how a decade of privatization and cuts exposed england to coronavirus. the guardian britain drops its go-it-alone approach to coronavirus. foreign policy on a scottish isle, nursing home deaths expose a covid- scandal. the new york times at the epicenter of the covid- pandemic and humanitarian crises in italy: changing perspectives on preparation and mitigation trump labels americans as "warriors" in risky push to reopen admid pandemic. the washington post an inconvenienced youth? ageism and its potential intergenerational roots frustrated millennials say they can't get their ageing parents to cancel their cruises, stop going to church, and take coronavirus seriously. business insider younger americans view coronavirus outbreak more as a major threat to finances than health can herd immunity really protect us from coronavirus? world economic forum failing the test -the tragic data gap undermining the u.s. pandemic response the ugly and dangerous debate simmering in australia i'm scared": how coronavirus is delivering a double blow for older americans department of economic and social affairs what is "boomer remover" and why is it making people so angry? newsweek covid- coronavirus pandemic none declared. key: cord- -byyx y authors: ryan, jeffrey r. title: seeds of destruction date: - - journal: biosecurity and bioterrorism doi: . /b - - - - . - sha: doc_id: cord_uid: byyx y this chapter provides the reader with an understanding and appreciation for the scope and importance of biological threats and the opportunity to see where they may be and have become the desire of terrorist groups and the makings of weapons of mass destruction. the history of biological warfare is covered in depth. these major events are important in helping us understand the issues related to using biological substances against an adversary. the difference between biosecurity and biodefense are explained and then related to homeland security and homeland defense, respectively. this chapter also details how expensive these programs are, with nearly $ billion having been spent on civilian biodefense since fiscal year in the united states alone. as discussed herein, there is a significant difference in the reality and the potential of bioterrorism. bioterrorism on a large scale is a low-probability event. bioterrorism on a small scale is a fairly routine occurrence with little potential. biological threats remain very much in the news. recent examples, such as laboratory incidents, the ebola outbreak of , and other emerging threats, are covered in this chapter. the dawning of the st century will be characterized as the age of terrorism. terrorism has affected most of us in one way or another. the shocking images of the september , , attacks remind us of just how dramatic and devastating terrorism can be. in most developed countries, the concept of bioterrorism and many of the words associated with it are widely recognized. in the united states, bioterrorism became a household word in october , when bacillus anthracis (the causative agent of anthrax) spores were introduced into the us postal service system by several letters dropped into a mailbox in trenton, new jersey (see fig. . ). these letters resulted in deaths from pulmonary anthrax and other cases of inhalation and cutaneous anthrax (thompson, ) . in the weeks and months that followed, first responders were called to the scene of thousands of "white powder" incidents that came as a result of numerous hoaxes, mysterious powdery substances, and just plain paranoia (beecher, ) . public health laboratories all over the united states were inundated with samples collected from the scene of these incidents. testing of postal facilities, us senate office buildings, and news-gathering organizations' offices occurred. between october and december the centers for disease control and prevention (cdc) laboratories successfully and accurately tested more than , samples, which amounted to more than million separate bioanalytical tests (cdc, ) . henceforth there has been a national sense of urgency in preparedness and response activities for a potential act of bioterrorism. humankind has been faced with biological threats since we first learned to walk upright. in his thought-provoking book guns, germs and steel, dr. jared diamond points out the epidemiological transitions we have faced since we were hunters and gatherers. more than , years ago the human experience with biological peril was mostly parasitic diseases that only affected individuals. after that, human societies began to herd and domesticate animals. the development of agriculture allowed for population growth and a shift from small tribal bands to a concentration of people into villages. larger groups of people could stand up to smaller elements, thereby enabling them to successfully compete for resources and better defend the ground that they held. agriculture also brought some deadly gifts: animal diseases that also affected man (zoonotic diseases), outbreaks of disease due to massing of people and lack of innate immunity, and a growing reliance on animal protein (diamond, ) . for ages human societies and cultures have been looking for a competitive advantage over their adversaries. advances in weapons of all types and explosives allowed military forces to defeat their enemies overtly on the battlefield and covertly behind the lines. technologies leading to nuclear, biological, and chemical weapons have also been exploited. indeed, each has been used legitimately and illegitimately on different scales to bring about a change in the tactics, the military situation, or the political will to face an enemy in battle. biological agents are no exception to this rule. as such, biowarfare (biological warfare) has a historical aspect to it that must be considered here because advances in the use of biological agents over the last century are one of the main reasons why bioterrorism exists today. when president richard m. nixon said, in november , that "mankind already holds in its hands too many of the seeds of its own destruction," he was signing an executive order putting an end to the united states' offensive capabilities for waging biowarfare. it is arguable that this statement foretold the potential doom we might all face when then state-of-the-art technologies became commonplace techniques in laboratories all over the world today. this chapter accordingly derives its name from the preceding quote and should serve to remind the reader that the seeds we sowed so long ago have now sprouted. the question remains: how shall they be reaped? bioterrorism is the intentional use of microorganisms or toxins derived from living organisms to cause death or disease in humans or the animals and plants on which we depend. biosecurity and biodefense programs exist largely because of the potential devastation that could result from a large-scale act of bioterrorism. civilian biodefense funding (cbf) reached an all-time high after the anthrax attacks of . conversely, the reality of the situation is that these well-intended programs cost taxpayers billions of dollars each year. rapid detection biothreat pathogen tools are available to assist responders with on-site identification of a suspicious substance. in addition, biosecurity and biodefense are "big business" in the private sector. security measures to protect agriculture and certain vulnerable industries from acts of bioterrorism and natural biological threats are also in place. detailed reports published in the journal biosecurity and bioterrorism (schuler, ; lam et al., ; sell and watson, ) show that us government cbf between fiscal year (fy) and fy amounted to more than $ billion. comparing fy to fy , there was an increase in cbf from $ million to $ . billion. the departments of health and human services and homeland security, which together account for approximately % of the fy request, have remained relatively constant in their funding. other agencies, most notably the department of agriculture and the environmental protection agency, have been more variable. these two agencies saw increased budget requests in fy , focusing on programs that protect the nation's food and water supplies. civilian biodefense spending, not including special allocations for project bioshield, reached a consistent level of approximately $ billion from fy to fy (sell and watson, ) . refer to table . for a summary of the cbf budget for fy - . bioshield is a program that was designed to give the united states new medical interventions (eg, vaccines, treatments) for diseases caused by several biothreat pathogens. when bioshield was conceived, it cost us taxpayers a total of $ . billion, which was metered out to the department of health and human services over a -year period. reports surfaced that suggest bioshield funds were being squandered and that few useful products were realized (fonda, ) . however, biothreat pathogen research and product development for unusual or rare diseases is fraught with numerous hurdles. this program will be addressed in chapter biosecurity programs and assets. the us postal service spent more than $ million developing and deploying its biohazard detection system (bds). at the peak of its utilization, the us postal service was spending more than $ million each year to operate and maintain the system. the bds is used only to provide early warning for the presence of a single biothreat pathogen, anthrax. furthermore, the system screens letter mail that comes from sources such as mailboxes and drops, which accounts for approximately % of all letter mail volume (schmid, ) . this model program and the technology it uses will be covered extensively in chapter consequence management and a model program. all of this seems rather incredible when comparing the level of funding given to one of the greatest biological threats of our time, the human immunodeficiency virus (hiv), which causes aids. an estimated . million people are currently living with hiv in the united states, with approximately , new infections occurring each (nih, ) compared with the $ . billion level of funding it receives for biodefense (sell and watson, ) . before delving into the subtleties of biosecurity and biodefense, one should explore the historical aspects of the use of biological agents in warfare and terrorism. the history presented here is not all inclusive. rather, it is a fair assessment of key events and characterizations that can be examined in other more comprehensive documents. pathogens and biological toxins have been used as weapons throughout history. some would argue that biological warfare began when medieval armies used festering corpses to contaminate water supplies. over several centuries this evolved into the development of sophisticated biological munitions for battlefield and covert use. these developments parallel advances in microbiology and include the identification of virulent pathogens suitable for aerosol delivery and large-scale fermentation processes to produce large quantities of pathogens and toxins. however, the history of biological warfare is shrouded by several confounding factors. first, it is difficult to verify alleged or attempted biological attacks. these allegations might have been part of a propaganda campaign, or they may have been due to rumor. regardless, some of the examples we have been given cannot be supported by microbiological or epidemiologic data. in addition, the incidence of naturally occurring endemic or epidemic diseases during that time complicates the picture so that attribution is impossible (christopher et al., ) . more important, our awareness that infectious diseases are caused by microbes does not go back very far in human history. germ theory, or the fact that infectious diseases are related to and caused by microorganisms, emerged after through the independent works of pasteur, lister, and koch (tortora et al., ) . therefore how could the attacking or defending commander know that the festering corpses might cause disease when people at that time thought that epidemics were related to "miasmas," the smell of decomposition, or heavenly "influences"? one need only consider the origin of certain disease names to appreciate this confusion. for instance, malaria gets its name from malaria, or "bad air" (ie, swamp gases; desowitz, ) . it was not until that we learned that the etiologic agents of malaria are protozoans in the genus plasmodium. the name influenza refers to the ancient belief that the disease was caused by a misalignment of the stars because of some unknown supernatural or cosmic influence (latin influentia). it was not until that we learned the flu was caused by the influenza virus (potter, ) . regardless of the lack of awareness of germs at the time, a few of the historic reports about the use of biological weapons in battle are worth noting here: • in the th century bc, assyrians poisoned enemy wells with rye ergot, a fungus. • in the th century bc, scythian archers tipped their arrows with blood, manure, and tissues from decomposing bodies. • in ad , attackers hurled dead horses and other animals by catapult at the castle of thun l'eveque in hainault (northern france). castle defenders reported that "the stink and the air were so abominable…they could not long endure" and negotiated a truce. • in ad at karlstein in bohemia, attacking forces launched the decaying cadavers of men killed in battle over the castle walls. they also stockpiled animal manure in the hope of spreading illness. however, the defense held fast, and the siege was abandoned after months. russian troops may have used the same tactic using the corpses of plague victims against the swedes in . • in ad the spanish contaminated french wine with the blood of lepers. • in the mid- s a polish military general reportedly put saliva from rabid dogs into hollow artillery spheres for use against his enemies. • francisco pizarro reportedly gave smallpox virus-contaminated clothing to south american natives in the th century. • in a letter dated july , , general jeffrey amherst, a british officer, approved the plan to spread smallpox to delaware indians (robertson, ) . amherst suggested the deliberate use of smallpox to "reduce" native american tribes hostile to the british (parkman, ). an outbreak of smallpox at fort pitt resulted in the generation of smallpox-contaminated materials and an opportunity to carry out amherst's plan. on june , , one of amherst's subordinates gave blankets and a handkerchief from the smallpox hospital to the native americans and recorded in his journal, "i hope it will have the desired effect" (sipe, ). • the same tactic was used during the civil war by dr. luke blackburn, the future governor of kentucky. dr. blackburn infected clothing with smallpox and yellow fever virus, which he then sold to union troops. one union officer's obituary stated that he died of smallpox contracted from his infected clothing (guillemin, ) . as previously mentioned, scientists discovered microorganisms and made advances toward understanding that a specific agent causes a specific disease, that some are foodborne or waterborne, that an agent can cycle through more than one species, and that insects and ticks are the vectors of disease. furthermore, medical professionals established that wars, famines, and poverty opened populations to the risk of epidemics. once these links were established, we learned that we could apply control and intervention methods. scientific knowledge about disease transmission coupled with social stability and active public health campaigns aided human survival. it subsequently became possible for advanced populations to protect their citizens from the burden of some of the most insidious infectious diseases, such as plague, cholera, diphtheria, smallpox, influenza, and malaria. these epidemics swept across nations in previous centuries, hitting hardest in crowded urban centers and affecting mostly the poor (guillemin, ) . at the opening of the industrial revolution, public health in cities had improved, water and food sources were monitored by the state, and vaccines and drug therapies were being invented as further protection. with many childhood diseases conquered, more people were living longer, and they were now dying of more "civilized" diseases such as cancer, heart disease, and stroke (diamond, ) . in underdeveloped nations, public health did not develop; hence, epidemics were prevalent and continued to be devastating. the dichotomy between developed and developing nations remains marked by generally good health versus widespread, preventable epidemics (guillemin, ) . as western nations were taking advantage of innovations in public health and medicine to mitigate epidemics, their governments invented biological weapons as a means of achieving advantage in warfare (diamond, ) . the german military has the dubious honor of being the first example of using biological weapons following a state-sponsored program. however, during world war i, they used disease-causing organisms against animals, not people. the goal of their program was to interrupt the flow of supplies to the allied frontlines. to do this they targeted the packhorses and mules shipped from norway, spain, romania, and the united states. in , dr. anton dilger, a german-american physician, developed a microbiology facility in washington, dc. dilger produced large quantities of anthrax and glanders bacteria using seed cultures provided by the imperial german government. at the loading docks, german agents inoculated more than animals that were destined for the allied forces in europe (wheelis, ) . from the german perspective, these attacks violated no international law. in addition, these activities were dwarfed by the atrocities of chemical warfare that was being waged on both sides of the line. to counter the german threat and explore the potential of air warfare the french sought to improve their integration of aerosols and bombs. at the same time as the french were signing the geneva protocol, they were developing a biological warfare program to complement the one they had established for chemical weapons during world war i (rosebury and kabat, ) . after world war i the japanese formed a "special weapons" section within their army. the section was designated unit . the unit's leaders set out to exploit chemical and biological agents. in they expanded their territory into manchuria, which made available "an endless supply of human experiment materials" (prisoners of war) for unit . biological weapon experiments in harbin, manchuria, directed by japanese general shiro ishii, continued until . a post-world war ii autopsy investigation of victims revealed that most were exposed to aerosolized anthrax. more than prisoners and chinese nationals may have died in unit facilities. in the japanese military poisoned soviet water sources with intestinal typhoid bacteria at the former mongolian border. during an infamous biowarfare attack in , the japanese military released millions of plague-infected fleas from airplanes over villages in china and manchuria, resulting in several plague outbreaks in those villages. the japanese program had stockpiled kg of anthrax to be used in specially designed fragmentation bombs. in , shortly before the battle of stalingrad, on the german-soviet front, a large outbreak of tularemia occurred. several thousand soviets and germans contracted the illness. some estimate that more than % of the victims had inhalation tularemia, which is rare and considered to be evidence of an intentional release. it was determined later that the soviets had developed a tularemia weapon the prior year (alibek and handelman, ) . during world war ii the allies had great fear of german and japanese biological weapons programs. their fears were sparked by sketchy reports that the japanese had an ongoing effort, and british intelligence suggested that germany might soon target britain with a bomb packed with biological agents. on the basis of these fears, great britain began its own bioweapons program and urged officials in the united states to create a large-scale biological warfare program. on december , , the us government convened a secret meeting at the national academy of sciences in washington, dc. the meeting was called to respond to great britain's request. army officers had urgent questions for an elite group of scientists. only a few months before, the president of the united states had grappled with the issue of biological weapons. president franklin d. roosevelt stated that "i have been loath to believe that any nation, even our present enemies, would be willing to loose upon mankind such terrible and inhumane weapons." secretary of war, general henry stimson, thought differently: "biological warfare is…dirty business," he wrote to roosevelt, "but…i think we must be prepared." president roosevelt approved the launch of the united states' biological warfare program. for the first time us researchers would be trying to make weapons from the deadliest germs known to science. in spring the united states initiated its bioweapons program at camp detrick (now fort detrick), maryland. the program focused primarily on the use of the agents that cause anthrax, botulism, plague, tularemia, q fever, venezuelan equine encephalitis, and brucellosis. production of these agents occurred at camp detrick, maryland, and other sites in arkansas, colorado, and indiana. the british had made two primary requests of us: ( ) to mass produce anthrax spores so that they could be placed in bomblets and stored for later deployment against the germans in retaliation for any future strike and ( ) the british supplied us with the recipe to make botulinum toxin and wanted to see if we could mass produce it. naturally the entire program was wrapped in a cloak of secrecy. fig. . is a collage of some important facilities built at camp detrick to produce and test bioweapons formulations. the british program focused on the use of b. anthracis (anthrax) spores and their viability and dissemination when delivered with a conventional bomb. gruinard island, off of the coast of scotland, was used as the testing site for formulations. at the time british scientists believed that the testing site was far enough from the coast to not cause any contamination of the mainland. however, in there was an outbreak of anthrax in sheep and cattle on the coast of scotland that faced gruinard. as a result, the british decided to stop the anthrax testing and close down the island site. despite the cessation of experiments, the island remained contaminated for decades until a deliberate and extensive decontamination program rendered the island inhabitable again. the us bioweapons program continued to grow in scope and sophistication. much of this was prompted by fear of a new enemy: the threat of communism, the soviet union, and its allies. experiments to test bioweapons formulations were routinely performed on a small scale with research animals. however, more comprehensive field and laboratory studies were performed with human research volunteers exposed to actual live agents and some situational scenarios using surrogate nonpathogenic bacteria to simulate the release of actual pathogens inside of buildings or aimed at cities. in researchers from detrick visited the pentagon on a secret mission. disguised as maintenance workers, they released noninfectious bacteria into the duct work of the building to assess the vulnerability of people inside large buildings to a bioweapons attack. the pentagon trial was considered to be a success because it revealed that germs could be formulated and released effectively for a small-scale act of sabotage. however, there was considerable doubt that biological weapons could be effective against a target the size of a city. accordingly, several tests were conducted on american cities (miller et al., ) . in the us army admitted that there were intentional releases of noninfectious bacteria in bioweapons experiments (cole, ) . one such trial took place in san francisco in september , when a us navy ship sailed a course adjacent to the golden gate bridge to release a plume of seemingly nonpathogenic bacteria (serratia marcescens). this trial was intended to simulate the dispersion of anthrax spores on a large city. on the basis of results from monitoring equipment at locations around the city, the army determined that san francisco had received enough of a dose for nearly all of the city's , residents to inhale at least of the particles. although the researchers believed that what they were releasing was harmless, one report shows that people reported to area hospitals with severe infections because of the release of this agent, of which was fatal (cole, ) . three years later, bioweapons experts took their secret exercises to st. louis and minneapolis, two cities that resembled potential soviet targets, where sprayers hidden in cars dispersed invisible clouds of harmless bacillus spores. in nonpathogenic bacillus globigii spores were released into the new york subway system using a broken light bulb to demonstrate the ability of a specific formulation to make its way from a central point source to both ends of the system in less than an hour. revelations of these experiments became known in when a senate subcommittee panel heard testimony from pentagon officials (us department of the army, dtic b l, ) . until that point, neither us citizens nor their representatives in washington knew anything about the american germ program. after nearly decades of secret research aimed at producing the ultimate biological weapons and stockpiling them for use against our enemies, president richard nixon surprised the world by signing an executive order that stopped all offensive biological agent and toxin weapon research and ordered all stockpiles of biological agents and munitions from the us program be destroyed. accordingly, on november , , he uttered these historic words in a speech to the nation on …biological warfare-which is commonly called "germ warfare. " this has massive unpredictable and potentially uncontrollable consequences. it may produce global epidemics and profoundly affect the health of future generations. therefore, i have decided that the united states of america will renounce the use of any form of deadly biological weapons that either kill or incapacitate. mankind already carries in its own hands too many of the seeds of its own destruction. subsequently, in the united states and many other countries were signatories to the convention on the prohibition of the development, production and stockpiling of bacteriological (biological) and toxin weapons and on their destruction, commonly called the biological weapons convention. this treaty prohibits the stockpiling of biological agents for offensive military purposes and forbids research into offensive use of biological agents. although the former soviet union was a signatory to the biological weapons convention, its development of biological weapons intensified dramatically after the accord and continued well into the s. in late april , an outbreak of pulmonary anthrax occurred in sverdlovsk (now yekaterinburg) in the former soviet union. soviet officials explained that the outbreak was due to ingestion of infected meat. however, it was later discovered that the cause was from an accidental release of anthrax in aerosol form from the soviet military compound , a soviet bioweapons facility. (this event is examined thoroughly in chapter case studies as a case study to demonstrate the potential of weaponized anthrax.) the robust bioweapons program of the soviet union employed more than , people. building at koltsovo was capable of manufacturing tons of smallpox virus each year. in kirov, the soviets maintained an arsenal of tons of weaponized plague bacterium. by soviet anthrax production capacity reached nearly tons a year. in the later part of the s the russians disassembled their awesome bioweapons production capacity and reportedly destroyed their stocks. as the soviet union dissolved, it appeared that the threat of biowarfare would diminish. however, the age of bioterrorism emerged with the anthrax attacks of . in addition, the us department of state published a report in that affirmed that six countries had active bioweapons programs. table . summarizes some of these events. biodefense programs and initiatives come out of a sense of vulnerability to biowarfare potentials. bioterrorism is deeply founded in what has been gained from active biowarfare programs (miller et al., ) . in the early s the leftist terrorist group, the weather underground, reportedly attempted to blackmail an army officer at fort detrick working in the research institute of infectious diseases (usamriid). the group's goal was to get him to supply organisms that would be used to contaminate municipal water supplies in the united states. the plot was discovered when the officer attempted to acquire several items that were "unrelated to his work." several other attempts are worth mentioning here: • in members of the right-wing group order of the rising sun were found in possession of - kg of typhoid bacteria cultures that were allegedly to be used to contaminate the water supplies of several midwestern cities. anton dilger produces anthrax and glanders bacterium to infect horses intended for the warfront. notable and documented use of bacteria against animals. june , delegates in switzerland create a geneva protocol banning the use of chemical and bacteriological methods of warfare. first international effort to limit use of biologicals in warfare. the japanese army gives general ishii control of three biological research centers, including one in manchuria. most despicable character in bioweapons history gets his start. great britain begins taking steps toward establishing its own biological weapons research project. allies start to develop a program. july nixon announces that the united states will renounce the use of any form of deadly biological weapons that either kill or incapacitate. the end of an era in us offensive biological weapons research, production, and storage. april , the biological weapons convention, which bans all bioweapons, is completed and opened for signature. seventy-nine nations signed the treaty, including the soviet union. march , the biological weapons convention officially goes into force; the us senate also finally ratifies the geneva protocol. political will to ban biological weapons on the international front. april nearly people die from an accidental release of anthrax spores in the soviet city of sverdlovsk. the united states suspects that anthrax bacterial spores were accidentally released from a soviet military biological facility. the rajneeshees contaminate food with salmonella bacterium in a small town in oregon to influence local elections. these small-scale incidents keep us mindful that some biological agents are easy to acquire and utilize in crimes and small-scale acts of terrorism. salmonella bacteria in a small town in oregon. it was the largest scale act of bioterrorism in us history. more than cases of salmonellosis resulted from the salad bar contamination. it was later discovered that the rajneeshees wanted to influence the local county elections. cult members obtained the salmonella strain through the mail from american type culture collection and propagated the liquid cultures in their compound's medical clinic. • in a home laboratory producing botulinum toxin was discovered in paris. this laboratory was linked to a cell of the german-based bäder meinhof gang. • in minnesota, four members of the patriots council, an antigovernment extremist group, were arrested in for plotting to kill a us marshal with ricin. the group planned to mix the homemade ricin with a chemical that speeds absorption (dimethylsulfoxide) and then smear it on the door handles of the marshal's car. the plan was discovered and all four men were arrested and the first to be prosecuted under the us biological weapons anti-terrorism act of . • in aum shinrikyo, a japanese doomsday cult, became infamous for an act of chemical terrorism when members released sarin gas into the tokyo subway. what many people do not know about the group is that it developed and attempted to use biological agents (anthrax, q fever, ebola virus, and botulinum toxin) on at least other occasions. despite several releases, it was unsuccessful in its use of biologicals. this program is examined more thoroughly in chapter case studies. • several small-scale incidents involving the biological poison ricin (refer to fig. . mississippi man was convicted of crimes related to these incidents and sentenced to years in prison. • in a philadelphia man sent a romantic rival a scratch-and-sniff birthday card laced with ricin. in he was convicted on several charges related to the incident and subsequently received a sentence of - years in prison. on june , , president george w. bush uttered these remarks from the white house at the signing of hr , the public health security and bioterrorism response act of : bioterrorism is a real threat to our country. it' s a threat to every nation that loves freedom. terrorist groups seek biological weapons; we know some rogue states already have them…it' s important that we confront these real threats to our country and prepare for future emergencies. it is clear that september and the anthrax attacks of sent the country to war and sparked several initiatives against all forms of terrorism. biological agents have some unique characteristics that make weaponizing them attractive to the would-be terrorist. most biological weapons are made up of living microorganisms, which means that they can replicate once disseminated. this possibility amplifies the problem and the effect of the weapon in several ways. first, some agents are capable of surviving in various different hosts. the target might be humans, but the disease may manifest in other animal hosts, such as companion animals (pets). in doing so, the problem may be more difficult to control. second, when people become infected with a disease-causing organism, there is an incubation period before signs of illness are apparent. during this incubation period and the periods of illness and recovery, the pathogen may be shed from the victim, causing the contagion to spread (a possibility only with diseases that are transmitted from person to person). there is no rule of thumb for how many people might be infected from a single patient. however, the nature of contagion clearly compounds the problem well beyond the initial release of the agent. in this instance the initial victims from the intentional outbreak become more weapons for the perpetrator, spreading the problem with every step they take. as grigg et al. ( ) stated so precisely in their paper, "when the threat comes from the infected population, selfdefense becomes self-mutilation." the would-be terrorist could surely derive great pleasure from watching government officials and responders tread on the civil liberties of such victims as they attempt to limit the problem from spreading among the population. making an effective biological weapon is no easy undertaking. the process and complexity depends largely on the pathogen selected to be "weaponized." if the pathogen is a spore-forming bacteria, such as b. anthracis (the causative agent of anthrax), there are five essential steps: germination, vegetation, sporulation, separation, and weaponization. the first three steps are designed to get small quantities of seed stock to propagate into a starter culture, grow them to a significant stage of growth in the proper volume, and turn those active cells into spores. the goal of the last two steps is to separate the spores from the dead vegetative cells and spent media. all five steps have dozens of secondary steps. in addition, each of the five steps requires a fairly sophisticated and well-equipped laboratory if the goal is to develop a sizable quantity of refined materials. weaponization is a term that applies to the processes necessary to purify, properly size, stabilize, and make biological agents ideally suited for dissemination. stabilization and dissemination are important issues because of the susceptibility of the biological agents to environmental degradation, not only in storage but also in application. these issues are problems whether the end use is for biological weapons, pharmaceuticals, cosmetics, pesticides, or food-related purposes. the susceptibility of the organisms to inactivation by the environment varies with the agent. as an example, anthrax spores released into the environment may remain viable for decades, whereas plague bacterium may survive for only a few hours. loss of viability or bioactivity is likely to result from exposure to physical and chemical stressors, such as exposure to ultraviolet radiation (sunlight), high surface area at air-water interfaces (frothing), extreme temperature or pressure, high salt concentration, dilution, or exposure to specific inactivating agents. this requirement of stabilization also extends to the methods of delivery because the organisms are very susceptible to degradation in the environments associated with delivery systems. the primary means of stabilization for storage or packaging are concentration; freeze drying (lyophilization); spray drying; formulation into a stabilizing solid, liquid, or gaseous solution; and deep freezing. methods of concentration include vacuum filtration, ultrafiltration, precipitation, and centrifugation. freeze drying is the preferred method for long-term storage of bacterial cultures because freeze-dried cultures can be easily dehydrated and cultured via conventional means. freeze-dried cultures may remain viable for more than years. deep freezing of biological products is another long-term storage technique for species and materials not amenable to freeze drying. the method involves storage of the contained products in liquid nitrogen freezers (− °c/− °f) or ultralow-temperature mechanical freezers (− °c/− °f). culturing viruses is a more costly and tenuous process because host cells are required for viral propagation. this means that cultures of host cells must be kept alive, often in an oxygen-deficient and temperature-stable atmosphere. in some cases, viruses may be more fragile when deployed as weapons, some becoming inactive on drying. biological toxins can be difficult to produce and purify, each requiring its own special set of circumstances. two specific examples are covered in subsequent chapters when those agents are discussed in detail. however, past bioweapons programs have determined that these agents are most effective when prepared as a freeze-dried powder and encapsulated. biological attacks by a terrorist group are apparently not easy to conduct or a practical option. if they were easy or practical, then many terrorist groups and hostile states would have done so long ago and frequently. our experience today with acts of biological terrorism has to do mainly with small-scale, limited attacks. however, if one were to acquire the means to produce the weapons, as described here, or purchase viable, sophisticated materials on the black market, a small group of persons could bring about the infection of a large percentage of targeted persons. clinical illness could develop within a day of dispersal and last for as long as - weeks. in a civil situation, major subway systems in a densely populated urban area could be targeted for a biological agent strike, resulting in massive political and social disorganization. it would take little weaponized material to bring about the desired effect. looking at this potential comparatively on a weight-toweight basis, approximately g of b. anthracis (anthrax) spores could kill as many people as a ton of the nerve agent sarin. with bioweapons in hand, small countries or terrorist groups might develop the capability to deliver small quantities of agents to a specific target. under appropriate weather conditions and with an aerosol generator delivering -to -μm particle-sized droplets, a single aircraft could disperse kg ( lb) of anthrax over a -km area ( , acres) and theoretically cause million deaths in a population density of , people/km (us dod, ada , ). much has been made of the potential of aerosolized powders and respiratory droplets in factual and fictitious biothreat scenarios. the largest infectious disease outbreak in the history of the united states occurred in april . the event was caused by an accidental waterborne contamination. the outbreak of cryptosporidiosis, which occurred in the greater milwaukee area, was estimated to have caused more than , people to become ill with gastroenteritis among a population of . million (mackenzie et al., ) . approximately people were hospitalized and about people died as a result of the outbreak. the milwaukee outbreak was attributed to failure of filtration processes at one of the two water treatment plants that served the city. several deficiencies were found at the plant, including problems relating to a change in the type of water treatment chemicals used for coagulation of contaminants before the filtration step. weather conditions at the time were unusual, with a heavy spring snowmelt leading to high source water turbidity and wind patterns that may have changed normal flow patterns in lake michigan, the raw water source for the city. describe the fundamental difference between biodefense and biosecurity. the secrecy of bioweapons programs of the previous century has been uncloaked. some of the most insidious disease agents ever to afflict humans, animals, and plants have been mass produced and perfected for maximum effectiveness. terrorist groups and rogue states may be seeking to develop bioweapons capabilities. these significant developments in bioweapons gave military leaders and politicians cause for great concern over the past few decades. the military necessity to protect the force and defend the homeland is the goal of a good biodefense program. simply put, biodefense is the need for improved national defenses against biological attacks. these are national programs, mostly planned and carried out by military forces and other government agencies. initially, biodefense programs require an intelligence-gathering capability that strives to determine what may be in the biological weapons arsenal of an aggressor. intelligence is needed to guide biodefense research and development efforts aimed at producing and testing effective countermeasures (ie, vaccines, therapeutic drugs, and detection methods). in addition, a real-time reporting system should be developed so that officials can be informed about an emerging threat before an agent has a chance to affect armed forces and millions of people in the homeland. the development of integrated systems for detecting and monitoring biological agents is instrumental to this goal. although most biodefense initiatives rest with the military, civilian government agencies contribute greatly to the biodefense posture. this is evident by the increases in cbf over the past few years and will be discussed in great detail in part iv of this book. on the other hand, biosecurity refers to the policies and measures taken for protecting a nation's food supply and agricultural resources from accidental contamination and deliberate attacks of bioterrorism. as i sit here today writing the second edition of this book, i am reflecting on the most recent concerns that we have for biological threats in modern society. for what it is worth, we seem to be much less concerned about acts of bioterrorism and/or biowarfare than we were - years ago. instead i see a great deal of concern, and rightfully so, for emerging infectious diseases and reemerging biological threats. we are also keenly aware of the accidental release of biological agents from research and reference laboratories. to illustrate these points we will briefly discuss four items of international interest that have been emphasized in the media: accidental shipment of live anthrax-positive controls samples, the / ebola outbreak in west africa, cases of middle east respiratory syndrome coronavirus (mers-cov) in south korea and saudi arabia, and a massive outbreak of highly pathogenic avian influenza (hpai). as previously mentioned, concerns for biological threat led to a wellspring of funding (nearly $ billion in years) for civilian biodefense programs in the united states. with all of this money the united states was able to build tremendous capabilities to detect and diagnose the agents and the diseases, respectively. with this money a few medical countermeasures (vaccines and treatments) were developed and produced. centers of excellence were funded and highly secure containment (biosafety level ) laboratories were built. with these new programs, testing modalities, and laboratories came the need to provide a ready supply of positive control agents and contracting opportunities for private biotechnology firms. as one very recent example, the us army laboratory in dugway proving grounds, utah, provided positive control samples of anthrax (b. anthracis) spores to public and private laboratories. before shipment, the spores had been propagated in the army laboratory and were exposed to gamma radiation to ensure no living spores were in the vials being provided. upon receipt of the samples, one laboratory in maryland questioned the integrity of the contents of the vial they received because there was no "death certificate" accompanying the samples. out of an abundance of caution they removed a small portion of the vial and streaked it onto sheep blood agar plates. to their amazement, several days later the plates showed growth and tested positive for anthrax. they immediately notified the cdc and the army. the cdc initiated an investigation and notified the media of the incident. the investigation showed that the living anthrax samples had been shipped to laboratories in us states and other countries (usa today, ) . once again the seeds of our destruction are sprouting, and some are of the opinion that we are our own worst enemy. more than laboratory incidents involving potential bioterror germs were reported to federal regulators during through . ebola virus was first discovered in in the sudan and zaire. ebola virus exists naturally in fruit bats, with sylvatic transmission to other mammals and sometimes humans when they consume raw or undercooked meat from an infected animal. infection with ebola virus in humans leads to severe viral hemorrhagic fever (vhf), which is often fatal (cdc, ) . in march an outbreak of ebola virus disease (evd) began in guinea, a western african nation. public health agencies at all levels failed to react quickly to the outbreak and it quickly spread to urban areas in liberia and sierra leone. subsequently, evd spread to nigeria and senegal. international air travel brought evd to the united states and europe, although the number of cases was very small and the threat was stamped out with ample infection control procedures in health-care facilities and aggressive public health measures for those exposed to actual case patients (cdc, ) . this is the largest outbreak of evd in history. at the time of this writing, the outbreak has been quelled by a "better late than never" effort. volunteers and medical relief groups from the united states and other countries received special training and deployed to west africa to help identify cases and treat the victims (see fig. . ) . however, new cases continue to be reported from guinea and sierra leone. as of june , , there have been , evd cases (suspect, probable, and confirmed) worldwide with approximately deaths; this equates to a % mortality rate (who, a) . to most the threat of ebola virus remains distant and out of mind. however, the stark reality is that international travel can interject evd into any populace on any continent within a matter of days. no country, person, or organization is immune to this threat. what makes evd such a great concern? first, ebola virus is a us health and human services category a agent. it meets all of the criteria for such a designation. evd results in high morbidity and mortality. evd requires special preparedness measures for public health and health care. evd is spread from person to person. evd can lead to panic and social disruption (cdc, ) . with this outbreak in particular, we are seeing all four criteria fulfilled. to make things worse, there is no food and drug administration (fda)-approved vaccine for humans and no fda-approved drug for treating vhf case patients. in a health-care setting, evd patients receive supportive care (hydration therapy) and rarely experimental drugs (cdc, ) . perhaps the only good thing to come from this outbreak is the development of a vaccine for ebola virus. there are currently three vaccine candidates undergoing phase iii clinical trials in west africa (who, b) . a case study on this outbreak is offered in chapter case studies of this book. how have international and national attitudes toward the biological threat changed since the early post- / era? include some discussion about the reality of versus the potential for biological threats. mers-cov (see fig. . ) was recognized by the world health organization (who) as a newly emerging pathogen in (berry et al., ) . the initial case where virus isolation and characterization came from occurred in jeddah, saudi arabia. subsequent infections were reported in middle eastern countries (jordan, qatar, and the united arab emirates), with a few cases also identified in europe, north africa, and the united states. mers-cov leads to severe respiratory illness in susceptible patients and is spread through person-to-person contact. ( ). the program had been designed to educate participants who would be deployed as members of the west african ebola response team as to the proper protocols to be followed when treating evd patients. the two participants were displaying the personal protective equipment worn by treatment specialists who would be interacting with evd patients. courtesy of the cdc/nahid bhadelia, md. south korea has recently been the epicenter of the largest outbreak of mers-cov outside of the middle east, reporting cases and deaths (who, c). the outbreak in south korea was traced to a single infected traveler. once again, this demonstrates the vulnerability to unexpected outbreaks of unusual diseases that all countries share in this highly mobile world. a report from a joint who-south korean investigation of this outbreak identified several reasons for the severity of the outbreak in south korea. these include a lack of awareness among health-care workers and the general public about mers-cov, the practice of "doctor shopping" (seeking care at multiple hospitals), people visiting infected patients in multibed hospital rooms, substandard infection control and prevention measures in health-care facilities, and contact of infected mers-cov patients in crowded emergency rooms. nearly all of the country's confirmed mers-cov patients were infected while seeking care or visiting hospital patients (boston globe, ) . more about mers-cov and other emerging pathogens is in chapter category c diseases and agents. hpai has been very much in the news since when the novel strain h n jumped from domestic bird populations (poultry) to humans in south east asia (ryan, ) . h n was very much feared by public health and government officials for its pandemic potential. since there have only been approximately cases of h n infection in humans, with a mortality rate of approximately % (hhs, ) . since that time, numerous other novel strains have emerged. in fact, a novel h n arose out of swine in and was the cause of a mild pandemic in humans. more recently, the novel strains h n and h n have been found to be the cause of major morbidity and mortality in poultry operations (chicken and turkey) in the united states, with detections affecting more than million birds (usda, ) . refer to fig. . for a graphic representation of this outbreak. the financial impact on the poultry growers and the egg and meat industry has been enormous. more can be found on this topic in chapter recent animal disease outbreaks and lessons learned. from this first chapter we can now understand and appreciate the scope and importance of biological threats and see where they may be and have become the desire of terrorist groups and the makings of weapons of mass destruction. biowarfare has a history. the major events are important in helping us understand the issues related to using biological substances against an adversary. we now know the difference between biosecurity and biodefense and can relate them to homeland security and homeland defense, respectively. we also know how expensive these programs are because nearly $ billion has been spent on civilian biodefense since fy in the united states alone. as discussed herein, there is a significant difference in the reality and the potential of bioterrorism. bioterrorism on a large scale is a low-probability event. bioterrorism and biocrimes on a small scale (eg, small amount of ricin directed at one or a few individuals) are fairly routine occurrences with little potential. biological threats remain very much in the news. recent examples, such as laboratory incidents, the ebola outbreak of / , the outbreak of mers-cov in south korea, and the hpai outbreak affecting poultry in the united states, make us aware that we must remain vigilant and utilize the biosecurity and biodefense programs to help us identify and respond to these accidental exposures and emerging threats. • biodefense. the collective efforts of a nation aimed at improving defenses against biological attacks. within these efforts are programs and agencies working toward increasing data collection, analysis, and intelligence gathering. the intelligence is applied to programs aimed at mitigating the effects of bioweapons by developing vaccines, therapeutics, and detection methods to increase the defensive posture. ultimately, biodefense initiatives protect the military forces and the citizens from the effects of biological attack. • biosecurity. the policies and measures taken for protecting a nation's food supply and agricultural resources from accidental contamination and deliberate attacks of bioterrorism. • bioterrorism. the intentional use of microorganisms or toxins derived from living organisms to cause death or disease in humans or the animals and plants on which we depend. bioterrorism might include such deliberate acts as introducing pests intended to kill us food crops; spreading a virulent disease among animal production facilities; and poisoning water, food, and blood supplies. • biowarfare, also known as germ warfare. the use of any organism (bacteria, virus, or other disease-causing organism) or toxin found in nature as a weapon of war. it is meant to incapacitate or kill an adversary. • pathogen. a specific causative agent of disease, mostly thought of as being an infectious organism (eg, bacteria, virus, rickettsia, protozoa). • weaponization. when applied to biologicals, the term implies a process of taking something natural and making it harmful through enhancing the negative characteristics of it. with biological agents, one might weaponize the agent by making more lethal, more stable, and more easily delivered or disseminated against an intended target. there is considerable debate about the use of this term. • zoonotic disease. an animal disease that may be transmitted to humans. • how was the decision made to begin the us biological weapons program? • what are the significant events in the history of biowarfare? what makes them significant? • when president nixon said that "mankind already holds in its hands too many of the seeds of its own destruction" in november , what did he mean by that? • weaponizing a biological agent is easy to do, right? • no one knows exactly who perpetrated the anthrax attacks of , and there has been no repeat of them since. why do you think we have seen no repeat of the anthrax attacks since ? the center for arms control and nonproliferation has an online course in biosecurity. type the url that follows into your internet browser and click on view course and select unit : "the history of biological weapons." the six sections in this unit provide an excellent overview and reinforce the material presented in the subheading about the history of biowarfare: www.armscontrolcenter.org/resources/biosecurity_course. the cdc's emergency and preparedness website offers a segmented video short lesson on the history of bioterrorism. the seven sections give a general overview on bioterrorism and separate vignettes on anthrax, plague, tularemia, vhfs, smallpox, and botulism: www.bt.cdc.gov/training/historyofbt. biohazard: the chilling true story of the largest covert biological weapons program in the world-told from the inside by the man who ran it. random house forensic application of microbiological culture analysis to identify mail intentionally contaminated with bacillus anthracis spores identification of new respiratory viruses in the new millennium. viruses south korea faulted on mers response biological warfare: a historical perspective clouds of secrecy. the army's germ warfare tests over populated areas the malaria capers: more tales of parasites and people, research, and reality guns, germs and steel: the fates of human societies medical aspects of chemical and biological warfare: a textbook in military medicine inside the spore wars. controversial contracts, bureaucratic bungling-the fed's biodefense drug program is a mess. how did it go so wrong? time the biological disaster challenge: why we are least prepared for the most devastating threat and what we need to do about it scientists and the history of biological weapons. a brief historical overview of the development of biological weapons in the twentieth century billions for biodefense: federal agency biodefense funding, fy -fy a massive outbreak in milwaukee of cryptosporidium infection transmitted through the public water supply germs: biological weapons and america's secret war the conspiracy of pontiac and the indian war after the conquest of canada a history of influenza rotting face: smallpox and the american indian pandemic influenza: emergency planning and community preparedness postal testing increasing five years after anthrax deaths billions for biodefense: federal agency biodefense budgeting, fy -fy federal agency biodefense funding, fy -fy the indian wars of pennsylvania killer strain: anthrax and a government exposed microbiology. an introduction ebola virus disease update on avian influenza findings the militarily critical technologies list part ii: weapons of mass destruction technologies h n avian flu (h n bird flu). available at hundreds of bioterror lab mishaps cloaked in secrecy army lab lacked effective anthrax-killing procedures for years biological and toxin weapons: research, development and use from the middle ages to world health organization ebola vaccines, therapies and diagnostics middle east respiratory syndrome coronavirus (mers-cov) -republic of korea key: cord- -yyh kikb authors: hossain, liaquat; karimi, faezeh; wigand, rolf t.; crawford, john w. title: evolutionary longitudinal network dynamics of global zoonotic research date: - - journal: scientometrics doi: . /s - - -y sha: doc_id: cord_uid: yyh kikb at global and local levels, we are observing an increasing range and rate of disease outbreaks that show evidence of jumping from animals to humans, and from food to humans. zoonotic infections (i.e. hendra, swine flu, anthrax) affect animal health and can be deadly to humans. the increasing rate of outbreaks of infectious diseases transferring from animals to humans (i.e. zoonotic diseases) necessitates detailed understanding of the education, research and practice of animal health and its connection to human health. these emerging microbial threats underline the need to exploring the evolutionary dynamics of zoonotic research across public health and animal health. this study investigates the collaboration network of different countries engaged in conducting zoonotic research. we explore the dynamics of this network from to based on large scientific data developed from scopus. in our analyses, we compare several properties of the network including density, clustering coefficient, giant component and centrality measures over time. we also map the network over different time intervals using vosviewer. we analyzed publication records. we found united states and united kingdom as the most collaborative countries working with and other countries in and cases, respectively. our results show increasing close collaboration among scientists from the united states, several european countries including united kingdom, italy, france, netherland, switzerland, china and australia with scientists from other parts of the world. united states, several european countries including united kingdom, italy, france, netherland, switzerland, china and australia with scientists from other parts of the world. background zoonosis can be referred to as the transmissible diseases between vertebrate animals and humans (who ) , which comprises % of emerging infectious diseases (taylor et al. ) . therefore, successful management of zoonotic diseases risks and outbreaks require the understanding of the complex interaction network of humans, animals and their living environments (who b) . previous bibliometric studies on relevant topics either investigated specific infectious diseases such as acquired immune deficiency syndrome (aids) (patra and chand ; uthman ) , tuberculosis (ramos et al. ) , and malaria (garg et al. ) or examined infectious diseases in general (bliziotis et al. ; ramos et al. ramos et al. , takahashi-omoe and omoe ) . the latter studies examined the research productivity and contribution of different countries and regions of the world in infectious diseases showing a gradual increase in research on infectious diseases in the us, the eu and other regions in the world. our investigation focuses on the contribution and collaboration of countries in exploring the intersection between animal and human health. we provide an investigation of the dynamics of zoonotic research networks over years by constructing and using large scientometric data. the study first explains the process of developing scientometric data for exploring research collaboration on this topic. these data are based on the extracted publication information from elsevier's scopus in the span of - . it proceeds with exploring these data by extracting a bibliometric networks (i.e. countries network). several social network measures such as network density and centrality are employed to analyze this network. the countries collaboration trend, network maps and measures, and their dynamics over this period of time are then discussed. elsevier's scopus (www.scopus.com) as one of the main sources of bibliometric data covering the greatest number of journals romo-fernández et al. ) is used to build the database of this study. the search for publications has been carried out with search queries using combinations of keywords including ''coordination, collaboration, cooperation, communication, preparedness, surveillance, emergency response, crisis management, containment, recovery, zoonotic, zoonosis, animal human, disease outbreak, illness outbreak, epidemic, pandemic and social network'' occurring in the articles' titles, abstracts and keywords. this initial set of keywords was selected after consulting with two experts in the field. the focus of the keywords was on three concepts including coordination, zoonotic diseases, and disease outbreaks at the various stages of disease prevention, detection, effective response and elimination. the publications information [e.g., author(s), document title, year, source title, citation count, source and document type, affiliations, publisher] were extracted using scopus export option. the publications used in the subsequent analysis were restricted to the ones in english. it is theoretically possible to miss out certain publications in the search process explained earlier. in order to minimize any missed out document and to account for any important keyword that was not included in the first stage, another set of keywords were identified to run a second round of search. as such, in the second stage, the keywords used in the extracted publications from the first stage were analyzed for their frequency. the frequency analysis of the keywords included identifying the most frequent ''single word'' and ''multiple words'' keywords. the latter keywords were the original keywords used by the authors and the former keywords were produced by splitting the ''multiple words'' ones. table shows the top ten most frequent ''single and multiple words'' keywords. another set of keywords including ''avian influenza, west nile virus, h n , control, risk'' were used in combination with ''coordination, collaboration, cooperation, communication, preparedness, surveillance, emergency response, crisis management, containment, recovery, outbreak, epidemic, pandemic and social network'' for a second round of search for publications ( search queries). the keywords that were too generic or used in the previous stage such as virus were not included in this round of search. the extracted publication data from this round was added to the previous results. the search span in both stages consisted of the period from to . the search for the publications was conducted in july . the two rounds of search resulted in publications of different types (e.g., article, conference paper, review) after filtering the publications with the same title. an application program was developed to extract bibliometric networks from these data, discussed in the next section. at least four bibliometric networks can be built using the database of publications developed in this study including networks involving authors, keywords, countries, and affiliations. figure shows these networks. in order to build these network (i.e. identify the links between the nodes) from the information available in the database, an application program is written in matlab. the algorithm of this application is explained here for the co- authorship network. the process of building the other networks including co-word, countries, and affiliation uses the same algorithm. there is a co-authorship relation between two authors if they wrote a document together. as such, in social network terms, there is a link (edge) from node a (author a) to n ode b (author b). to map the data exported from scopus into a co-authorship network, the following algorithm was developed where its variables are presented below: • max-no-papers maximum number of papers in the database with known authors • max-no-aut-paper maximum number of authors in a paper in the database • max-no-authors maximum number of authors in the database • list-all-authors a list containing the name of all the authors in the database • list-max-no-authors-per-paper a list indicating the maximum number of authors for each paper in the database • list-all-papers-with-all-their-authors a list of all authors for each paper in the database • co-authorship-initial a matrix with the size of (max-no-papers, max-no-aut-paper) that its cell (i,j) indicates whether author j in list-all-authors participated in writing paper i in the database • weighting a matrix with its cell (i,j) indicating the number of papers wrote by authors i and j in list-all-authors • co-authorship a matrix with its cell (i,j) indicating whether authors i and j in list-all-authors wrote a paper together or not in order to build the network of collaborating countries, the affiliation records of each publication were processed to extract the countries cited. in table below, we show some examples of the affiliation records in the database. the name of the countries, when reported, appears at the end of the record. in order to extract the countries associated with each publication, the steps explained below were followed: • reverse the affiliation record string, • count the number of characters till the first occurrence of a space (e.g., x characters), • extracting the first ''x'' characters identified in the previous step from the reversed string, • reverse the string extracted in step three which gives the name of the country reported. publications contained no affiliation information. these publications were excluded from the countries network analysis. further data cleaning process in this stage included identifying the variations in the name of the countries reported (e.g., united states, usa, us, united kingdom, uk) and unifying them. if an affiliation entry did not include the name of the country or useful information (e.g., the name of an institution) to search for the correct country of origin, it was excluded from further analysis ( publications). some other cases of data cleaning included finding the relevant country associated with a university, institution, company, state, or city where the name of the country was missing. this resulted in publications to carry out the data analysis. in this study, we apply the following network measures to perform our analysis: the density measure ''describes the general level of linkage among the points in a graph'' (scott , p. ) . in social network analysis terms, this is the number of links in a network, expressed as a proportion of the maximum possible number of links (scott ) . the density of a network increases as the number of linkages between its nodes grows. the densest network (with all its nodes linked together) has a density of and the least dense network (with no node linkage) has a density of . degree centrality- freeman ( ) defined degree centrality of a node as the number of its adjacent nodes. two nodes are adjacent if an edge links them together. therefore, degree centrality of a node counts the number of other nodes that are directly connected to it. the closeness centrality of a node is the sum of the graph-theoretic distances of that node to all other nodes in the network. the distance of a node from another is the length of the shortest path (geodesic path) between them (borgatti ; freeman ). normalized closeness centrality value of a node is calculated by dividing the number of all other nodes in the network by the sum of the distances of the node to all others (freeman ; leydesdorff ). the betweenness centrality of a node is defined as the frequency with which it settles in the shortest path connecting any other pair of nodes in the network (freeman ) the giant component in many cases, large and complex networks are seen to have a connected component that includes a substantial portion of the nodes in those networks. this connected component is referred to as the giant component. if a network has a giant component, it is usually only one (easley and kleinberg ) . the clustering coefficient of a node (e.g., node a) refers to the probability that two randomly selected adjacent nodes of a are adjacent to each other. in other words, it is the fraction of the pairs of a's adjacent nodes that are linked together (easley and kleinberg, ) . clustering and mapping vosviewer . . is used for displaying the structure of countries network. vosviewer provides both mapping and clustering of networks (especially bibliometric networks) in a unified approach as an alternative to combing the mapping and clustering techniques with different assumptions. its clustering technique is based on a weighted and parameterized variation of modularity-based clustering, and it uses visualization of similarities (vos) as its mapping technique . vos is a distance-based mapping technique rather than a graph-based one. while in the latter technique the distance between two nodes is not necessarily meaningful, in the former technique this distance represents the strength of their relationship (van eck and waltman ). vosviewer provides different visualizations of networks. in the label views, the size of a nodes' circle and label portray its importance. larger circles and labels represent more important nodes in terms of their weight (van eck and waltman ). the weight of the nodes in the countries networks in our study are determined based on the number of other countries associated with them and the strength of the associations. the color of the circles also depicts the cluster the node belongs to (van eck and waltman ) . the density view is helpful for identifying the most important areas of a map. in this view, the nodes are represented with the same label structure as the label view. the color of the point a node is placed in depends on the number of nodes around that point and their weights (i.e. their density). more nodes with greater weight neighboring a node lead to greater density for that node. according to the default color scheme used by vosviewer, three color (redgreen-blue) represent density where red and blue are assigned to the highest and lowest densities respectively (van eck and waltman ). as shown in fig. , the trend of publications on zoonotic research has been increasing since . while before , the number of extracted publications is constantly low, an increasing trend starts after that. this increase in the number of publications continues gradually and accelerates after . this observation provides three time intervals to examine detail changes in the collaboration networks including - , - , and - . the dynamic analysis in this study focuses on the last two time intervals as the number of publications in the first period is limited. another interesting point of time in fig. is . up to this year the number of publications is increasing but this upward trend halts here with occasional rises. to have a better understanding of the possible underlying reasons for such a trend in the zoonotic research output, the frequency of zoonotic research publications and who's disease outbreak news per year (who a) since are depicted in fig. . three highest points of disease outbreak news occurred in [due to suspected severe acute respiratory syndrome (sars) pandemic], (due to avian influenza pandemic) and (due to h n pandemic). after , with sars and avian influenza pandemics, the publications on zoonotic research grew rapidly, and then started to decline after , but again raised in with the spread of the h n pandemic to decrease again with the reduction in the disease outbreak incidences. it seems that the output of scientific research in the zoonotic disease outbreaks have reached a saturation level since and only occurrence of global disease outbreaks triggers increases in quantity of the related publications. as such, the changes of zoonotic research collaboration networks will also be examined for another two periods including - and - . table also shows the top ten journals publishing on this topic over the years examined in this study, in which emerging infectious diseases, veterinary record, euro surveillance: european communicable disease bulletin, and plos one hold the first three positions. countries collaboration trend figure below illustrates the changes in collaboration among the countries over time in terms of the number of collaborating countries, distinct collaboration links between them, and total number of collaboration links per year. the first instances of international collaboration start from and steadily increase although the number of collaboration links among countries experiences some rises and falls over the years. the highest amount of collaborations ( distinct links and total occurrences) takes place in among countries. in , the amount of collaborations drops to distinct collaboration ties while the number of participating countries increases to . since - the collaborating countries consist of - countries which are nearly % of all the countries ( ) in our database. in other words, the countries collaboration network at its most collaborative status comprises half of the publishing countries. in addition, the trend of recruiting more collaborating countries each year although is overall growing; its pace slows down after . however, the number of collaboration links between the present countries and the frequency of such collaborations shows fast increase (with occasional declines). as such, it seems that after the community of collaborating countries is more focused on having more collaboration with other existing countries in the community and strengthening these collaborative relationships. countries network measures and maps over time table demonstrates the measures of countries network in different periods. in the first period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , the density of the network is very low ( . %) indicating that a limited number of all possible collaboration links among countries are realized (see fig. a ). in addition, the high clustering coefficient ( . %) implies the high possibility of collaboration among two adjacent countries of a third country. figure a , pertaining to this period, illustrates this implication in the form of several triangles in the network. the network also has a giant component and several other small components. the network's degree of centrality is average ( . %). as shown in fig. a , the countries are gathered around a few central nodes in the network including the united states and united kingdom. they also possess the largest fig. countries network map during ( - ) and ( - ) . a label view of countries network ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , b label view of countries network ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) labels. south africa, germany, and italy (overlaid by germany in the map illustration), and france are the next countries with large labels which indicate their importance in the zoonotic research in this period. there is also a split evident in the map which separates countries around united states from countries around united kingdom. in other words, there is low density between the two areas. this is an implication of less collaboration among these two important areas of the network. in the second period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , the density of the network has improved (almost doubled) although it is still low. there is also a slight improvement in the clustering coefficient value ( . %). the degree centrality shows considerable improvement ( . %). as shown in fig. b , the countries are coming closer together compared to the previous period. the network closeness and the betweenness have decreased. the high value of closeness ( . %) and low value of betweenness ( . %) measures implies the low distance between the countries. the network measure for the whole period of time is similar to the second time period, which is expected given that most of the publications belong to this period. similar trend in the values of the network measures are observed in the other two periods ( - and - ) . the interesting observation here together with the information from fig. is the high value of clustering coefficient ( . %), density ( . %) and degree centrality ( . %) in - period which indicates the high probability that two collaborators of a country will be collaborating with each other and countries having more collaborations and collaborators. these values are higher than the seven years before . in other words, in the recent years, the countries were putting more effort in strengthening their relationship with more other countries (see figs. a, b) . the label views of the network in the whole period (fig. a) shows that united states and united kingdom are the major collaborating countries. italy, france and netherlands are the next main countries. as evident in the density view (fig. b) , united states and united kingdom are depicted in red indicating their high density; although united kingdom is nearer to other moderate density areas of the map while united states is placed farther from this part of the map. these countries as well as the others shown in red or orange comprise the important part of the world in terms of research, publication, and collaboration on zoonotic research. top collaborating countries table lists the countries with or more total collaborations and the corresponding number of countries they collaborated with. according to this list, united states and united kingdom are the first and second most collaborative countries working with and other countries in and cases, respectively. in addition, the number of countries they collaborate with exceeds the others. italy, france and netherland are the next most collaborative countries; although france's collaborating countries ( ) are slightly more than italy ( ). this result complements previous studies on the output of infectious disease research community. previous studies show that the united states and the western european countries productivity exceed the other countries in terms of publication on infectious disease research (bliziotis et al. ; takahashi-omoe and omoe ) , and united kingdom, france, and germany lead the european countries in terms of number of publication on this topic (ramos et al. (ramos et al. , ). our results show a similar pattern in terms of collaboration efforts on zoonotic research. the united states, united kingdom, france, italy and netherlands are the leading collaborative countries in zoonotic research. table presents the list of the strongest collaboration links among the countries. strength of a collaboration link is defined as the frequency of its occurrence during the years. - and - - - dynamic analysis during the period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , united states, united kingdom, germany, italy, and south africa are the top collaborating countries. in the second period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) , the number of collaborators and frequency of collaborations increase. while the united states and united kingdom still hold their position at the top of the list of most collaborative countries, some changes are observed in the countries that follow them. south africa is no longer among the top countries. italy, france and netherlands have progressed further up the list. china, australia and switzerland also managed to appear among the top ten collaborating countries (see table for further details). to identify their collaboration growth rates, first the average amount of collaboration for each country in each of two time periods (av = total collaborations/years) are calculated which is presented in table . the growth rate is then obtain as the quotient of the second and first periods' average collaborations (growth rate = av /av ). if a country did not have any collaboration in the first period its average collaboration for the second period is considered as the growth rate. the collaboration growth rates of the countries are identified for the - and - periods as they represent more recent data compared to the other time periods ( - and - ) examined in this study. nigeria, mexico, portugal, egypt and singapore collaboration growth rates exceed the other countries. this study provides longitudinal analysis of countries networks of zoonotic research during - based on large scientific data developed from scopus. the overall properties of these networks as well as their dynamics over these years are examined in detail. the countries network shows steady increase in collaboration among different countries. the united states is the most collaborative country having links with countries and total instances of collaborations. several european countries including united kingdom, italy, france, netherlands, switzerland, germany and belgium are among the top ten collaborating countries. china and australia are also among the ten most collaborating countries. nevertheless, the density of the network is still low which means that limited numbers of countries are collaborating. however, this trend is improving such that almost half of the countries had at least one collaboration link in the recent years. in addition, in spite of the recent lower rate of addition of more countries into the network, within the current network, the countries are increasingly initiating new collaborations as well as enhancing these collaborating relations (strengthening them). conflict of interest none. investigating attachment behavior of nodes during evolution of a complex social network: a case of a scientific collaboration network evolutionary dynamics of scientific collaboration networks: multi-levels and cross-time analysis worldwide trends in quantity and quality of published articles in the field of infectious diseases networks, crowds, and markets: reasoning about a highly connected world centrality in social networks conceptual clarification bibliometrics of global malaria vaccine research betweenness centrality as an indicator of the interdisciplinarity of scientific journals hiv/aids research in india: a bibliometric study. library and information science research publication of european union research on infectious diseases a bibliometric overview of infectious diseases research in european countries a bibliometric analysis of tuberculosis research indexed in pubmed co-word based thematic analysis of renewable energy social network analysis: a handbook worldwide trends in infectious disease research revealed by a new bibliometric method risk factors for human disease emergence software survey: vosviewer, a computer program for bibliometric mapping vosviewer manual a unified approach to mapping and clustering of bibliometric networks zoonoses and the human-animal-ecosystems interface no. key: cord- -nm wct authors: neville, ron; neville, jemma title: what can health care professionals in the united kingdom learn from malawi? date: - - journal: hum resour health doi: . / - - - sha: doc_id: cord_uid: nm wct debate on how resource-rich countries and their health care professionals should help the plight of sub-saharan africa appears locked in a mind-set dominated by gloomy statistics and one-way monetary aid. having established a project to link primary care clinics based on two-way sharing of education rather than one-way aid, our united kingdom colleagues often ask us: "but what can we learn from malawi?" a recent fact-finding visit to malawi helped us clarify some aspects of health care that may be of relevance to health care professionals in the developed world, including the united kingdom. this commentary article is focused on encouraging debate and discussion as to how we might wish to re-think our relationship with colleagues in other health care environments and consider how we can work together on a theme of two-way shared learning rather than one-way aid. health is global. health is local. health is individual. how should health care professionals conceptualize and then act on the need to manage their individual patients as best they can in a local and personal context, while taking account of the globalization of many aspects of society, including health? how can we solve the conundrum of acting both locally and globally to help patients? health has become a global issue because viruses such as hiv and sars do not respect international borders [ , ] . the failure of immunization delivery in one country can precipitate the return of a disease in surrounding countries, as the recent example of polio in nigeria shows [ ] . malaria eradication schemes in one area are ineffective unless neighbouring countries adopt similar strategies [ ] . access to uncontaminated water is a fundamental prerequisite for good health. conflict zones, water supply dis-putes and lack of engineering infrastructure prevent large areas of the world's population from achieving a reasonable health status [ ] . availability of trained health care staff is inequitable across urban and rural areas, across borders and regions. staff recruiting policy in one country can destabilize health care provision in another country. for example, the united kingdom's importing nurses to support the expansion of care homes for the elderly led to a further exodus of trained nursing staff from southern africa [ ] . the availability and supply of modern pharmaceuticals has become an issue of international concern, particularly with regard to antiretroviral hiv drugs. seemingly simple solutions to global inequality of supply, such as the free provision of high-quality pharmaceuticals manufactured in the developed world, have been blighted by the reappearance of the same drugs sold back into the developed world and also by the appearance of poor-quality counterfeit products [ ] . the emergence of the internet as the dominant source of educational support in both the developed and the developing world has fostered a culture and understanding of global health issues [ ] . social networking and more formalized institutional links are gradually raising awareness of the need to appreciate the similarities and shared ambitions of health professionals worldwide. many professionals now have experience of working in more than one country and have an unmet aspiration to work and help their colleagues in other health care environments. the old-fashioned model of "colonial aid" or project-specific nongovernmental organization (ngo) work based on a "donor and recipient" model is becoming discredited. one-way aid donation is sometimes not only ineffective, it can have a detrimental effect. in resource-poor countries, one-way aid can encourage dependence, present an opportunity for corruption, replicate systems of inappropriate training and encourage urbanization of resources and personnel, leading to emigration of trained personnel [ ] . increasing cooperation between different health care systems should be a two-way dialogue of support rather than a one-way flow of aid. just as technology companies can learn practical solutions emerging from resource-poor countries, so too can health care professionals learn from their colleagues. increased opportunity for travel and networking by means of the internet and low-cost telephone options have raised awareness of the potential for health care professionals in different environments to share experiences, learning and skills. such learning and sharing have the potential to help affluent countries just as much as resource-poor ones. the establishment of a project to twin scottish general practices with malawian clinics and a recent fact-finding visit prompted our colleagues to challenge us on the assertion that learning can be two-way [ ]. this article outlines some of the areas where health care professionals in the united kingdom can learn from malawi. both scotland and malawi enjoy almost universal access to primary care, free at the point of delivery. both countries have a well-developed structure of primary care. in the united kingdom, this is based around the national health service and the general practitioner (gp) list system. in malawi, health ministry clinics provide a backbone of primary, public health and maternity services in urban townships and rural population centres. there is a modest level of private health care provision and a sub-stantial contribution from various ngos -largely of a thematic nature -for example hiv, malaria or tuberculosis (tb) care. the health ministry has a very clear policy for health care delivery, including public health. there is a well-organized structure of district health offices (dho) with a chain of command, although not always accompanied by the logistic or fiscal capability to implement policy. the medical records system in the united kingdom, despite an investment of several billion pounds sterling in hardware and software support, remains fragmented and inefficient [ ] . a rather turgid debate rumbles on about whether patients can be trusted to hold or gain access to their records [ ] . in malawi all citizens are issued with a "health passport" for a token fee. this is a small paper booklet with customized versions for children and women of childbearing age (additional file ). the health passport is treated with reverence, but some copies succumb to loss, falling in the fire or getting wet in the rainy season. many malawians store the health passport in the plastic bags commonly used for weighing sugar. the booklet provides a complete and integrated record of immunizations, preventive health care priorities, major medical morbidities and a continuation record of clinical encounters. in the united kingdom we could learn from this experience by taking patient responsibility for records systems seriously, whether paper or electronic. we could also learn to use an integrated record to encompass primary and secondary care and preventive health care. fundamentally, taking steps to further involve patients in the management of their own health care records will increase the perception of transparency in the clinician/patient relationship and maintain trust. the malawian health care system has to prioritize which patients are suitable for expensive treatments, including antiretroviral therapy for hiv or anti-tb therapy. in order to be accepted on to a treatment programme, patients have to give a commitment to try to maintain their nutrition, take their medication as directed and be present for follow-up appointments. to facilitate these, patients must nominate a "guardian" -usually a close family member. the guardian must then accept responsibility for ensuring that the patient takes the right sort of nutritious food, checks medication compliance and makes sure the patient is present for follow-up. some clinics even provide a shelter and cooking facilities for the guardians [ ] . in the united kingdom it would of course be unacceptable to deny patients treatment because they were unable to produce a guardian or make a promise to comply with therapy, but there are lessons to be learnt from the malawian policy. patients in the united kingdom requiring treatment for hiv, hepatitis b or c or tb also need to maintain good nutrition, comply with medication regimes and be present for regular follow-up. a voluntary guardian system might well be acceptable to united kingdom patients and have the potential to favourably alter clinical outcome. it is the norm in antenatal and intrapartum care for united kingdom patients to be accompanied by a "guardian" (usually their partner). supportive partners may welcome an opportunity to become more involved in care and may be receptive to being given enhanced responsibility. perhaps the care of people with long-term health conditions is where the guardianship model could be most useful. the clinical outcome in people with diabetes, arthritis, ischaemic heart disease and chronic obstructive pulmonary disease (copd) depends on good nutrition, medication compliance and follow-up care according to management guidelines [ ] . again the experience of mentoring suggests that developing and formalizing support for patients may improve outcome. there is research evidence to suggest that clinical outcomes in cancer care can be enhanced if patients are "mentored": supported by volunteers or fellow sufferers [ ] . this support could be formalized to include a "guardian" commitment to provide good nutrition and assist with medication compliance and follow-up appointments. it would be interesting to tease out the relative contribution that shared responsibility and family support make to clinical care in the resource-rich developed world. with the decline of infectious diseases in the developed world due to improved hygiene, provision of fresh water and improved nutrition, less emphasis is now placed on public health initiatives. there is an apparent disconnect between care providers and those engaged in public health. very few front-line health care professionals in the united kingdom perceive themselves as having a direct public health role. the situation in malawi is very different, because of the high and visible presence of infectious diseases affecting the population. gps and midwives in the united kingdom might wish to re-learn outreach and public health skills. in malawi, clinical officers make direct and immediate contact with their public health outreach colleagues if they suspect a water source is contaminated or an open case of tb is present in the community. in the united kingdom, we might wish to reconsider how health professionals use their atrophied public health skills to tackle preventable problems such as smoking, excess alcohol consumption, poor dietary habits and lack of exercise [ ] . an accepted task of malawian midwives and clinical officers is to teach groups of patients about important public health matters such as condom use, good nutrition and obtaining fresh water. this teaching can include a dance or a song in keeping with local or village custom of conveying a message to peers. patients in the united kingdom would certainly remember a smoking cessation advice session that included singing and dancing with their doctor or nurse. while not advocating that the nhs provide dancing sessions en masse, the message is clear. engaging with local communities requires the use of communications media tailored to the target audience. in the united kingdom, one in three hiv-seropositive persons is unaware of his or her status [ ] . despite public health efforts to increase the uptake of testing, and despite the availability of retroviral therapy, testing for hiv still carries a stigma in the united kingdom health system. many patients are reluctant to turn to mainstream health facilities, such as their own gp, and turn instead to more secretive and less personal forms of care, such as genitourinary medicine clinics. in malawi, hiv testing is available in health ministry clinics and is voluntary, linked with counselling, hence vct. "vct" has entered the everyday vocabulary of malawians because clinics display signs and an ongoing poster campaign helps to dispel stigma. crucially, testing is available on demand with the result available quickly, sometimes on the same day. it is remarkable that a developed, resource-rich health care system such as the united kingdom's nhs still persists with the archaic practice of keeping patients waiting at least a week to receive a result. the malawian experience of destigmatizing and simplifying on-the-spot testing may be relevant to persons at risk in the united kingdom [ ]. the outcome for premature babies in resource-poor countries used to be very unfavourable. in south america, the "kangaroo care" model was developed. premature babies are placed between their mother's breasts. a woollen hat is provided to minimize heat loss through the baby's scalp, and the mother's body acts as an incubator (additional file ). breast milk is expressed directly into the baby's mouth, or onto cotton wool and then squeezed gently into the baby. "kangaroo care" can keep vulnerable premature babies alive in environments where incubators and tube feeding are not available [ ] . in malawi, maternity units have a "kangaroo care" section. mothers are assisted by their "guardians", usually a grandmother. they take it in turn to nurse the baby. while one is lying with the baby in the "kangaroo" position, the other prepares food and talks with other mothers and midwives. every so often they exchange roles. there may be aspects of kangaroo care applicable to intermediate-level, special-care baby support in the transition from high-dependency, extreme-premature incubator support to low-level support with parental involvement. a feature of clinic work in malawi is the set protocols for managing likely presenting problems. these are reminiscent of guidelines and flowcharts displayed in accident and emergency departments [ ] . perhaps all health care professionals should accept that it is good and accepted practice to constantly refer to protocols, and to share with patients an openness to consulting guidelines. a feature of malawian health care is drop-in youth centres. such centres are located within or close by health facilities and, unlike in the united kingdom, are not separated and delivered by different agencies across the health and social service divide. empowering young people through social responsibility, care for the elderly, sports and employment training is a message as relevant in europe as in africa [ ] . student nurses in malawi have to offer health educational group sessions as part of their training. this requires a high level of communication skill and an ability to cast aside inhibition to make sure an important health message is conveyed (additional file ). there are opportunities for malawian nurses to share this expertise with their more reserved colleagues in the united kingdom. while sitting in on clinics, we were struck by the attitudes of patients and staff. acceptance of adversity, perhaps borne out of experience of hunger or lack of resources, allowed a health care system to cope with large numbers of patients every day. it was culturally unacceptable to make a fuss and so health care staff members were able to concentrate on seeing ill people in order of clinical need rather than according to who protested the loudest or booked in first. in a clinical system of high throughput, rapid diagnosis and lack of treatment options, complaining was seen as futile. we found the lack of privacy during consultations unsettling, particularly when two or more consultations took place in the same room or the same space outdoors. our "prudishness" became a source of some amusement in an environment where attending to one's toileting needs was often a public matter. in malawi, international nurses day is celebrated each year, complete with the "nurses' pledge, prayer and song" [ ] . these feature the core values of nursing and are matters of intense pride for nurses. it is interesting to speculate whether nurses in the united kingdom are sufficiently proud of their hard work to sing a song about it in front of their patients. malawian clinics fly the national flag and are proud to be associated with the ministry of health. it is doubtful whether united kingdom clinics feel a similar need to be associated with the nhs. perhaps endless changes of health service administration have dampened enthusiasm for united kingdom staff to take pride in their institutions. health care in malawi is underresourced. patients die needlessly due to lack of adequate medical facilities. life expectancy is short. resource problems mean that malawi lags behind almost all other countries in measures of clinical outcome. but therein lies a paradox: the so-called "worse" can teach the so-called "best" many lessons. perhaps we should look to our colleagues in malawi and other resource-poor environments to help us reconnect with the core values of patient autonomy, simple recordkeeping, careful use of resources, adherence to protocols, innovation to tackle health education, integration of public health with clinical care and above all, professional pride in caring for patients. the barriers to change within each health care environment appear to be very different. clearly, increased monetary resources are needed in malawi. increased pay for staff, availability of medicines and equipment delivered uncritically could destabilize a system that can count organized primary care linked to public health as major assets. "westernization" of health care has the inherent risk of promoting consumerism, urbanization and hospital care -none of which is likely to raise the health outcomes for the majority of the population, who live by subsistence agriculture based around village communities with strong family ties. the united kingdom has recently learnt the painful lesson that increased monetary input does not directly correlate with improved health outcome. the major challenges facing the health of people in the united kingdom are linked to lifestyle. imaginative ways for families and communities working together to reduce smoking, increase exercise levels, improve nutrition and extend family support are more likely to yield dividends than increased gdp spent on hospitals. so what can health care professionals based in the united kingdom and other resource-rich environments learn from malawi? behind the gloomy statistics and cynicism about whether one-way aid works, there is an opportunity for dialogue locally and globally. at the very least, health care professionals in the united kingdom might want to debate and discuss what global and local health is about. our malawian colleagues can contribute and share in that debate. we can all learn global lessons to apply locally. malawi national strategy for sustainable development polio cases rise in nigeria as vaccine is shunned for fear of aids is malaria eradication possible? editorial. the lancet water and sanitation nurse recruitment and international migration closing the affordability gap for drugs in lowincome countries development aid: manna or myth? the lancet nhs misses target for introducing electronic records involving patients in checking the validity of the nhs shared record: a single practice pilot the twinning of scottish general practices and malawian clinics: the provision of email and internet services communication, quality of life and age: results of a -year prospective study in breast cancer patients php?option=com_content&view=article&id= :access-toclean-water-and-sanitation-a-human-rights-issue&catid= hiv statistics in the uk the scottish government funds the twinning of scottish and malawian clinics project. the authors thank all the health care staff and patients in malawi for telling them about their lives and their work. copd: chronic obstructive pulmonary disease; dho: district health office; gdp: gross domestic product; hiv: human immunodeficiency virus; ngo: nongovernmental organization; sars: severe acute respiratory syndrome; tb: tuberculosis; uk nhs: united kingdom national health service; vct: voluntary counselling and testing. the authors declare that they have no competing interests. the idea, drafts and completion of the article are the equal work of both authors. key: cord- -b iy w l authors: brown, clive m.; aranas, aaron e.; benenson, gabrielle a.; brunette, gary; cetron, marty; chen, tai-ho; cohen, nicole j.; diaz, pam; haber, yonat; hale, christa r.; holton, kelly; kohl, katrin; lee, amanda w.; palumbo, gabriel j.; pearson, kate; phares, christina r.; alvarado-ramy, francisco; roohi, shah; rotz, lisa d.; tappero, jordan; washburn, faith m.; watkins, james; pesik, nicki title: airport exit and entry screening for ebola — august–november , date: - - journal: mmwr morb mortal wkly rep doi: nan sha: doc_id: cord_uid: b iy w l in response to the largest recognized ebola virus disease epidemic now occurring in west africa, the governments of affected countries, cdc, the world health organization (who), and other international organizations have collaborated to implement strategies to control spread of the virus. one strategy recommended by who calls for countries with ebola transmission to screen all persons exiting the country for "unexplained febrile illness consistent with potential ebola infection." exit screening at points of departure is intended to reduce the likelihood of international spread of the virus. to initiate this strategy, cdc, who, and other global partners were invited by the ministries of health of guinea, liberia, and sierra leone to assist them in developing and implementing exit screening procedures. since the program began in august , an estimated , travelers, of whom approximately , were en route to the united states, have departed by air from the three countries with ebola transmission. procedures were implemented to deny boarding to ill travelers and persons who reported a high risk for exposure to ebola; no international air traveler from these countries has been reported as symptomatic with ebola during travel since these procedures were implemented. on december , , this report was posted as an mmwr early release on the mmwr website (http://www.cdc.gov/mmwr). in response to the largest recognized ebola virus disease epidemic now occurring in west africa, the governments of affected countries, cdc, the world health organization (who), and other international organizations have collaborated to implement strategies to control spread of the virus. one strategy recommended by who calls for countries with ebola transmission to screen all persons exiting the country for "unexplained febrile illness consistent with potential ebola infection." exit screening at points of departure is intended to reduce the likelihood of international spread of the virus. to initiate this strategy, cdc, who, and other global partners were invited by the ministries of health of guinea, liberia, and sierra leone to assist them in developing and implementing exit screening procedures. since the program began in august , an estimated , travelers, of whom approximately , were en route to the united states, have departed by air from the three countries with ebola transmission. procedures were implemented to deny boarding to ill travelers and persons who reported a high risk for exposure to ebola; no international air traveler from these countries has been reported as symptomatic with ebola during travel since these procedures were implemented. on october , , after the first imported ebola case was identified in the united states, an enhanced u.s. entry screening program was started at five international airports as an added measure to identify travelers from the three countries with widespread ebola transmission who might have been exposed to ebola within days before arrival or who currently had signs or symptoms of ebola. entry screening first began at john f. kennedy international airport (jfk) in new york city, then newark liberty international airport (ewr), washington-dulles international airport (iad), chicago o'hare international airport (ord), and hartsfield-jackson atlanta international airport (atl). this program also allowed federal authorities to educate travelers, obtain their contact information, and link them with state and local partners to facilitate health monitoring, as appropriate, and prompt referral for care if they became ill. of , travelers screened during october -november , ( . %) were referred to cdc public health officers for additional evaluation, and seven ( . %) of the were symptomatic and referred for medical evaluation ( table ) . none of the seven were diagnosed with ebola. the , travelers arrived in the united states after transit in at least one other country and had final destinations in states; the most common destinations were new york ( %), maryland ( %), pennsylvania ( %), georgia ( %), and virginia ( %) (figure) . entry screening provided public health departments with contact information for travelers to facilitate monitoring and provided an added layer of protection for the u.s. public. on august , , the international health regulations emergency committee determined that the ebola outbreak in west africa met the conditions for a public health emergency of international concern ( ). the committee advised that who member states with ebola transmission "should conduct exit screening of all persons at international airports, seaports and major land crossings, for unexplained febrile illness consistent with potential ebola infection." to advise on exit screening and other border control measures, cdc deployed staff members to liberia and guinea, beginning august , and to sierra leone, beginning august . in response to the importation of a case of ebola into nigeria with subsequent spread among health care workers and in the community, a cdc team was deployed to nigeria on august . who recommends that exit screening consist of a health questionnaire, a temperature measurement, and, if there is a fever, an assessment of the likelihood of the fever being caused by ebola ( ). according to who recommendations, ebola patients or contacts, or persons with an illness consistent with ebola, should not be allowed to travel unless the travel is part of an appropriate medical evacuation. cdc worked with in-country partners (e.g., ministries of health and airport authorities) to enhance exit screening procedures; recommendations were tailored to each country's needs to address critical gaps identified in their exit screening processes and procedures. activities included developing and delivering training on the signs and symptoms of ebola, exit screening procedures and documentation, and appropriate use of personal protective equipment. cdc also worked to conduct train-the-trainer sessions to ensure that the exit screening activities in place could be sustained. to help countries with no ebola transmission detect and manage ebola cases at points of entry, cdc developed templates and materials that other countries could consider and adapt as needed.* to estimate the number of travelers to the united states from the three countries most affected by ebola, cdc used flight data software from diio llc (reston, virginia). during august-october , approximately , travelers departed the three most affected countries (guinea, liberia, and sierra leone) by air; approximately , of these travelers were en route to the united states. procedures were implemented to deny boarding to ill persons and persons reporting a high risk of exposure to ebola. no traveler who was denied boarding for fever or other symptoms or reported exposures has been reported as diagnosed with ebola. of those who were permitted to travel, none are known to have had ebola symptoms during travel and none have been subsequently diagnosed with ebola. two travelers to the united states, who were not symptomatic during exit screening and travel, became ill with ebola after arrival. since july , cdc has enhanced its routine procedures for detecting ill travelers entering the united states at airports by providing additional guidance and training to partners, including u.s. customs and border protection (cbp), which inspects all arriving travelers seeking admission into the united states, airlines, airport authorities, and emergency medical service units at airports; the training covers recognizing possible signs of ebola in travelers and reporting suspected cases to cdc. on october , , cdc, in partnership with cbp, further enhanced efforts to identify ill travelers and travelers possibly exposed to ebola by initiating an additional screening measure for travelers arriving from guinea, liberia, or sierra leone. although identification of ill travelers remains an important goal of u.s. entry screening, enhanced entry screening also has four broader objectives: ) to identify, on their arrival in the united states, travelers who might be ill with ebola or who might have had exposure to ebola, ) to ensure that these travelers are directed to medical care, if needed, ) to provide travelers with information on reporting fever and other symptoms to public health authorities, and ) to rapidly provide the travelers' contact information to public health authorities for active or direct active monitoring. † cdc and cbp began enhanced entry screening at jfk on october and on october at four other airports (ewr, iad, ord, and atl). together, the five airports are estimated to handle % of all travelers arriving in the united states who had been in liberia, sierra leone, and guinea within the previous days. six days later, the department of homeland security exercised its authority to direct passengers flying from the three countries to arrive in the united states at one of the five airports with enhanced screening. . † with active monitoring a state or local public health authority assumes responsibility for establishing regular communication with persons whom were possibly exposed to ebola, including checking daily for symptoms and fever. with direct active monitoring the public health authority conducts active monitoring through direct observation. for each person arriving from one of these three countries, cbp provides health information developed by cdc that includes facts about ebola, symptoms to look for and what to do if symptoms develop, a wallet card, and information for clinicians to manage travelers who seek medical attention. each traveler also receives a digital thermometer § and instructions on how to use it. travelers are screened with questions about symptoms and potential exposure risks, temperature checks (using noncontact thermometers), and visual observation for other symptoms of ebola. if travelers have self-reported or measured fever or other symptoms or have been in a situation where exposure to ebola could have occurred, cbp officers refer them to cdc public health officers stationed at the airport for further evaluation. public health risk assessment of travelers is based on cdc-issued guidance ( ), which classifies potentially exposed persons into three risk categories, whether symptomatic or not: high risk, some risk, and low (but not zero) risk. the guidance provides recommendations for the monitoring of these persons and their safe movement to avoid potential exposure of others during commercial travel (e.g., by airplane, ship, train, or long-distance bus). cdc officers determine whether travelers can continue to their destinations, and whether transport to a hospital for medical evaluation of symptomatic travelers is needed. cdc coordinates disposition of symptomatic travelers and those in the high and some risk categories with the appropriate state health department at the time of assessment. persons identified as at high risk for exposure to ebola would not be allowed to travel further on public conveyances. all travelers in the three risk categories are referred for continued monitoring and support to a local health department based on their travel destination. contact information for travelers arriving from countries with widespread ebola transmission is entered into a database and transmitted to states through cdc's epidemic information exchange (epi-x), a secure notification system. once the states receive the travelers' contact information, public health authorities can initiate appropriate monitoring and movement restrictions based on risk. of the , arriving in the u.s. from countries with widespread ebola transmission who have been screened, % were adults aged ≥ years, and % had reportedly worked in a health care facility or laboratory in a country with widespread ebola transmission. according to flight data, it is estimated that less than . % of total arrivals to the u.s. arrive from the three countries. among the , screened travelers, ( . %) were referred to cdc public health officers; of these, seven ( . %) were referred for medical evaluation ( table ) . of the persons interviewed by cdc for evaluation, all were health care workers, of whom were determined to be in the low (but not zero) risk category ( ); nine of the were laboratory workers, all of whom were placed in the low (but not zero) risk category. since entry screening started, no traveler has been placed in the high risk category; one person became symptomatic after travel and was diagnosed with ebola days after arrival in the united states. as of november , , approximately , cases of ebola have been reported by who. of the four cases reported by the united states, two were among travelers from countries with widespread ebola transmission. the first of these was a traveler from liberia ( ) who had no fever or declared symptoms or exposures at his exit screening in liberia, was not symptomatic during travel, and developed symptoms after arrival in the united states. the second travel-related case was in a health care worker who returned from guinea and who did not have symptoms during exit screening at departure, during travel, or at entry screening on arrival in the united states before developing ebola. effective exit screening procedures in countries with widespread transmission of ebola helped instill confidence that persons symptomatic with ebola would be unlikely to travel. humanitarian assistance is vital for combating the ebola epidemic and reducing the risk for the disease being exported. airport exit or entry screening might not identify asymptomatic infected persons without recognized or declared exposures ( ). screening of travelers at departure from countries with widespread ebola transmission and upon arrival in the united states is part of a comprehensive and layered strategy to protect travelers and u.s. communities and also includes ) communicating to the traveling public by way of travel health alerts and other travel guidance posted online (at http:// www.cdc.gov/travel), ) denial of boarding to ill persons before travel, ) reporting of persons who become ill onboard u.s.bound airlines, and ) monitoring for days after the last possible exposure of persons from countries with widespread ebola transmission, based on their exposure risk category by u.s. public health authorities. on november , , cdc and cbp also began screening for ebola travelers from the west african nation of mali upon entry to the united states after reports of confirmed cases in that country. in the united states, entry screening enables public health authorities to identify persons arriving from countries with widespread ebola transmission and provide them with public health guidance about how to monitor themselves for symptoms of ebola, as well as the tools with which to monitor themselves, links to public health authorities, and information needed to contact public health or medical authorities if they develop a fever or other symptoms. together, the combined exit and entry screening processes achieve the following six outcomes; they: ) prevent travel by ill persons from countries with widespread ebola transmission until they have had appropriate medical evaluation, ) reduce the likelihood of a traveler from a country with widespread ebola transmission becoming ill during travel, ) allow the quick identification of any illness in persons arriving from countries with widespread ebola transmission, ) limit contact of persons being evaluated for ebola with other persons, ) facilitate rapid and appropriate clinical care for ill travelers, and ) provide the arriving traveler with public health education and links with public health authorities. although the magnitude of the current ebola outbreak in west africa has challenged established approaches, isolation of cases and contact tracing remain essential to contain the disease and prevent spread to other counties. outbreak responses to severe acute respiratory syndrome ( ), pandemic influenza a(h n ) ( , ) and middle east respiratory syndrome-coronavirus ( ) have demonstrated that, in an increasingly connected world, no destination is safe from the importation of emerging pathogens as long as pathogens are spreading anywhere in the world. cdc has worked with international partners to establish and strengthen exit screening at ports of departure in-country and with domestic partners to conduct entry screening upon arrival into the united states. the goal and potential benefit of exit and entry screening at international borders encompasses more than identification of ill travelers at those borders. using these processes to educate each traveler and then link the traveler to public health authorities for the duration of the incubation period is of critical importance to facilitate rapid detection of illness and implementation of appropriate public health control measures. the world health organization (who) recommends that countries with ebola transmission screen all persons exiting the country for febrile illness consistent with potential ebola infection. who recommends that exit screening consist of a health questionnaire, a temperature measurement, and, if there is a fever, an assessment of the likelihood of the fever being caused by ebola. according to who recommendations, ebola patients or contacts, or persons with an illness consistent with ebola, should not be allowed to travel unless the travel is part of an appropriate medical evacuation. this report describes results of the use of exit and entry screening processes as part of a comprehensive strategy to reduce the likelihood that symptomatic travelers board commercial flights and cause transmission of ebola. to date, there has been no indication of a risk for ebola disease transmission related to international air travel. of the , persons screened for ebola after arriving in the united states from guinea, liberia, and sierra leone, none were symptomatic during travel. a total of were referred to cdc public health officers for additional evaluation, and seven of the were found to be symptomatic and referred for medical evaluation; none had ebola. these processes help to maintain confidence that air travel is safe from ebola, identify potentially ill or exposed travelers, educate and inform the traveler, link the traveler with public health authorities for the duration of the incubation period, and facilitate the rapid detection of illness and implementation of appropriate public health control measures. state and local public health authorities are provided with timely information on arrivals from countries with widespread ebola transmission to facilitate active or direct active monitoring based on travelers' risk categorizations. world health organization guidance for monitoring and movement of persons with potential ebola virus exposure ebola virus disease cluster in the united states s. airport entry screening in response to pandemic influenza: modeling and analysis sars: an emerging global microbial threat modeling the epidemic waves of ah n / influenza around the world international flight-related transmission of pandemic influenza a(h n )pdm : an historical cohort study of the first identified cases in the united kingdom first confirmed cases of middle east respiratory syndrome coronavirus (mers-cov) infection in the united states, updated information on the epidemiology of mers-cov infection, and guidance for the public, clinicians, and public health authorities global migration task key: cord- -c nf vb authors: hallowell, benjamin d.; carlson, christina m.; jacobs, jesica r.; pomeroy, mary; steinberg, jonathan; tenforde, mark w.; mcdonald, emily; foster, loretta; feldstein, leora r.; rolfes, melissa a.; haynes, amber; abedi, glen r.; odongo, george s.; saruwatari, kim; rider, errin c.; douville, gina; bhakta, neenaben; maniatis, panagiotis; lindstrom, stephen; thornburg, natalie j.; lu, xiaoyan; whitaker, brett l.; kamili, shifaq; sakthivel, senthilkumar k.; wang, lijuan; malapati, lakshmi; murray, janna r.; lynch, brian; cetron, martin; brown, clive; roohi, shahrokh; rotz, lisa; borntrager, denise; ishii, kenta; moser, kathleen; rasheed, mohammad; freeman, brandi; lester, sandra; corbett, kizzmekia s.; abiona, olubukola m.; hutchinson, geoffrey b.; graham, barney s.; pesik, nicki; mahon, barbara; braden, christopher; behravesh, casey barton; stewart, rebekah; knight, nancy; hall, aron j.; killerby, marie e. title: severe acute respiratory syndrome coronavirus prevalence, seroprevalence, and exposure among evacuees from wuhan, china, date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: c nf vb to determine prevalence of, seroprevalence of, and potential exposure to severe acute respiratory syndrome coronavirus (sars-cov- ) among a cohort of evacuees returning to the united states from wuhan, china, in january , we conducted a cross-sectional study of quarantined evacuees from repatriation flight. overall, of evacuees completed exposure surveys and submitted upper respiratory or serum specimens or both at arrival in the united states. nearly all evacuees had taken preventive measures to limit potential exposure while in wuhan, and none had detectable sars-cov- in upper respiratory tract specimens, suggesting the absence of asymptomatic respiratory shedding among this group at the time of testing. evidence of antibodies to sars-cov- was detected in evacuee, who reported experiencing no symptoms or high-risk exposures in the previous months. these findings demonstrated that this group of evacuees posed a low risk of introducing sars-cov- to the united states. to determine prevalence of, seroprevalence of, and potential exposure to severe acute respiratory syndrome coronavirus (sars-cov- ) among a cohort of evacuees returning to the united states from wuhan, china, in january , we conducted a cross-sectional study of quarantined evacuees from repatriation flight. overall, of evacuees completed exposure surveys and submitted upper respiratory or serum specimens or both at arrival in the united states. nearly all evacuees had taken preventive measures to limit potential exposure while in wuhan, and none had detectable sars-cov- in upper respiratory tract specimens, suggesting the absence of asymptomatic respiratory shedding among this group at the time of testing. evidence of antibodies to sars-cov- was detected in evacuee, who reported experiencing no symptoms or high-risk exposures in the previous months. these findings demonstrated that this group of evacuees posed a low risk of introducing sars-cov- to the united states. suspending operation of buses, subways, and ferries within the city ( ) . as of january , a total of confirmed covid- cases had been reported in china ( ) . after china enacted the travel ban, the us department of state planned evacuation flights for us citizens and other third country nationals in wuhan. we describe the demographic and clinical characteristics, potential exposures to sars-cov- , personal protective measures implemented, and sars-cov- real-time reverse transcription pcr (rrt-pcr) and serologic test results for evacuees from repatriation flight from wuhan. these data can be used to better determine sars-cov- epidemiology, including assessing the point prevalence of past and current sars-cov- infections in this cohort and identifying factors associated with infection in this cohort. these findings can also be used to help estimate the initial risk for transmission to contacts in the united states posed by evacuees from wuhan and are relevant to current and future implementation of public health control measures, such as isolation and quarantine. we investigated quarantined evacuees from a january , , repatriation flight from wuhan to the united states. before the flight departed wuhan, evacuees were evaluated to ensure that they had no fever or respiratory signs/symptoms. at arrival in the united states and again at the quarantine facility, evacuees were asked to complete a us traveler's health declaration form disclosing any symptoms; they were also screened for illness and fever, asked about symptoms in the past hours, and asked about any high-risk exposures (including working in or visiting healthcare settings; caring for or visiting persons with fever, respiratory illness, or a confirmed covid- diagnosis; or visiting any live animal markets) in wuhan in the past days. those who reported symptoms or high-risk exposures were evaluated by a cdc quarantine medical officer, who determined if they required further evaluation and isolation from the quarantined cohort. nasopharyngeal and oropharyngeal swab samples and serum specimens were obtained from participating evacuees when they arrived at the quarantine station in the united states. as part of quarantine procedures, evacuees were actively monitored for fever and respiratory signs/symptoms for days after departure from wuhan; any evacuee in whom either fever or respiratory signs/symptoms developed during this time was evaluated for covid- ( ) , and additional nasopharyngeal and oropharyngeal specimens were collected ( , ). all specimens were collected, processed, and shipped to cdc for testing ( , ). presence of sars-cov- in nasopharyngeal and oropharyngeal swab samples was confirmed by rrt-pcr detection of viral rna in respiratory specimens ( ). serum specimens were initially tested for sars-cov- antibodies by sars-cov- elisa (appendix , https://wwwnc.cdc.gov/eid/ article/ / / - -app .pdf). we asked evacuees to complete a detailed, selfadministered survey during the flight from wuhan (appendix , https://wwwnc.cdc.gov/eid/ article/ / / - -app .pdf). the survey captured information on demographics, clinical signs/ symptoms, travel outside of hubei province, face mask use, limitation of time spent in public, and past high-risk exposures (including contact with confirmed covid- case-patients; persons with fever, acute respiratory illness, or both; healthcare and laboratory facilities; and animals and live animal markets). we assessed high-risk exposures over the past weeks and the past months. we compared high-risk exposures over the past weeks with rrt-pcr results for persons who provided an upper respiratory specimen (because days was the upper end of the estimated incubation period for covid- [ , ] ). we also compared high-risk exposures over the past months with the serologic test results for evacuees who provided a serum sample (because sars-cov- had probably been circulating for the months before their departure [ ] ). we entered survey responses into redcap electronic data capture tools hosted at cdc ( ) , and all entries were verified by a second reviewer for accuracy and completeness. data were analyzed by using sas software version . (sas institute, inc., https://www.sas.com). cdc determined that this investigation was public health surveillance (us department of health and human services, title code of federal regulations , protection of human subjects). evacuees' participation in the collection of biological specimens and the survey was voluntary. at the time of arrival in the united states, no evacuee had a measured fever or reported any signs or symptoms that required further evaluation. of the evacuees, completed surveys; % ( / ) of respondents provided a nasopharyngeal sample, an oropharyngeal sample, or of each for sars-cov- rrt-pcr testing, and % ( / ) provided a serum sample for testing. the median age of all evacuees was (range - ) years, and % ( / ) were male (table ) . most were either asian ( %, / ) or white ( %, / ). one evacuee reported having had close contact with a person with laboratory-confirmed co-vid- in the previous weeks. specifically, reported exposures included direct physical contact, being within feet of the person while that person was coughing or sneezing, taking an object handed from or handled by the person, and traveling in the same vehicle as the person (table ) . no other evacuees reported exposure to a person with laboratory-confirmed covid- in the previous months. however, % ( / ) reported having had close contact with a person with fever, acute respiratory illness, or both in the previous weeks and % ( / ) in the previous months (table ) . one evacuee had visited a live animal market in the previous weeks and % ( / ) in the previous months. three percent ( / ) of evacuees had visited settings with nondomesticated live animals in the previous weeks and % ( / ) in the previous months. one percent ( / ) of evacuees had had direct physical contact with a nondomesticated live animal (both instances with stray dogs) in the previous weeks. no additional evacuees had had direct physical contact with a nondomesticated live animal in the previous months. during the previous month, after hearing about covid- cases in wuhan, % ( / ) of evacuees reported having limited their time in public in wuhan, including avoiding public gatherings ( %), public transportation ( %), and all public settings (e.g., grocery stores or restaurants; %) ( table ). in addition, in the previous month, after hearing about covid- cases in wuhan, % of evacuees reported having worn a face mask while in public spaces. this finding represented a significant increase from the % of evacuees who reported having worn a face mask while in public spaces in the previous months (mcnemar test statistic . ; p< . ). five percent ( / ) of evacuees reported having experienced signs or symptoms associated with covid- (measured or subjective fever, cough, shortness of breath) in the previous weeks, and % ( / ) reported signs/symptoms associated with covid- in the previous months. one evacuee who reported signs/symptoms associated with covid- in the previous weeks sought medical care, and no evacuee required hospitalization while in wuhan (table ) . sars-cov- was not detected by rrt-pcr in any of the nasopharyngeal or oropharyngeal swab specimens collected from unique evacuees ( provided nasopharyngeal and oropharyngeal samples, nasopharyngeal sample only, and oropharyngeal sample only). during the -day quarantine period, fever developed in evacuees; additional nasopharyngeal and oropharyngeal swab specimens were collected and tested, and sars-cov- was not detected in either specimen type. one evacuee showed serologic evidence of a past sars-cov- infection. serum from that person had antibodies against sars-cov- at titers of determined by elisa and determined by microneutralization test. this person was male, was in the - -year age group, was traveling without any family members, and reported no signs/symptoms associated with covid- in the past months. he reported no high-risk exposures (including exposure to or contact with live animals, live animal markets, persons known to be ill with covid- , or persons with fever or acute respiratory signs/symptoms). he reported that since early january he had spent limited time out in public, including avoiding public transport, avoiding public gatherings, and not attending school/university. elisa results for the remaining serum specimens measured sars-cov- antibody titers at < , and the samples were therefore considered seronegative. our report on sars-cov- prevalence, seroprevalence, and potential exposures among evacuees returning from wuhan is part of the public health response enacted to slow transmission of sars-cov- in the united states. although this population of evacuees is probably not representative of all wuhan residents in terms of risk of acquiring sars-cov- infection, our results indicate limited exposure to sars-cov- among this group of early evacuees from wuhan. compared with previously reported covid- case-patients in wuhan, our population was younger (median vs. years of age) and their reported frequency of potential sars-cov- exposures was lower, including exposure to persons with respiratory signs/symptoms, work-associated healthcare exposures, and exposure to live animal markets ( ) . of note, although our questionnaire covered exposure to animals and animal markets, most transmission within wuhan during the evacuees' relevant exposure period before the repatriation flight to the united states was probably human-to-human ( , ) . our study population, which consisted predominantly of us expatriates, probably had other factors that reduced their risk for exposure and were not documented as part of our investigation. for example, it is possible that the expatriates' households in wuhan were smaller than other households in wuhan, which has been associated with a lower risk for transmission ( ) ( ) ( ) ( ) ; however, because we did not document household size in our investigation, we cannot show such an association. nearly all evacuees took preventive measures to limit potential exposure to sars-cov- while in wuhan. however, % of evacuees did have direct contact with persons who had fever or acute respiratory illness. previous investigations among evacuees traveling from wuhan to germany and japan detected sars-cov- rna in asymptomatic persons ( , ) , suggesting that symptom-based screening alone may not be effective for detecting sars-cov- infection. evacuees in our study underwent intensive screening such that no evacuee had signs/symptoms at the time of evacuation and none had detectable sars-cov- in upper respiratory tract specimens, suggesting the absence of asymptomatic respiratory shedding among this group at the time of testing. in addition, no sars-cov- was detected in respiratory specimens from the evacuees in whom fever developed during quarantine. the lack of sars-cov- detection in asymptomatic travelers at the time of testing and in the travelers in whom fever developed could result from a lower risk for exposure among this group compared with wuhan residents or other reported evacuees ( , ) . the elisa and microneutralization tests used in this investigation have produced robust responses to serum from confirmed sars-cov- patients (b. freeman et al., unpub data, https://www.biorxiv. org/content/ . / . . . v ). although evacuees reported signs/symptoms associated with covid- (subjective fever, cough, or shortness of breath) in the previous months, none were seropositive for sars-cov- . in contrast, an antibody response was detected in person who did not report illness in the previous months, indicating past sars-cov- infection, suggestive of past asymptomatic or mildly symptomatic infection. the overall seroprevalence of % suggests a low level of exposure to sars-cov- over the preceding months in wuhan. however, a lack of antibody response may not mean an absence of past infection; serologic responses were not always found in persons with mild middle east respiratory syndrome coronavirus illness and positive rrt-pcr results for that virus ( ) . future serologic testing among co-vid- case-patients may be useful for determining whether persons with asymptomatic or mild cov-id- disease become seropositive. efforts by this cohort to limit their exposure by limiting their time in public may have helped prevent infection, even in a city with extensive ongoing community transmission. because sars-cov- seems to be transmitted primarily through respiratory droplets, limiting time in public may have helped prevent infection because proximity to infected persons is needed for virus transmission ( ) . before the evacuees in our study departed wuhan, china was implementing measures to control sars-cov- by suspending public transport and vehicle traffic and canceling lunar new year gatherings ( ) . cdc currently recommends that all persons wear cloth face coverings in public; the purpose is to help protect others from potential droplet exposure, not to protect the persons wearing the face coverings ( ) . thus, although % of evacuees reported mask use after hearing about covid- in wuhan, individual mask use probably had minimal effect on their individual risk of acquiring infection. information about virus prevalence, seroprevalence, and possible sars-cov- exposures in this population of evacuees has the potential to inform current and future quarantine and isolation policies. in this population, who underwent intensive screening and monitoring, we detected no evidence of current infection with sars-cov- and very limited evidence of past infection. other than the evacuees included in our study, cases of covid- were detected in the united states during quarantine of later cohorts of evacuees after signs/symptoms developed and the evacuees underwent testing, demonstrating the value of quarantine and active monitoring of evacuees to detect covid- cases ( ) . emerging infectious diseases • www.cdc.gov/eid • vol. , no. , september limited to persons who submitted serum specimen. ¶limited to persons who reported an occupation (other than student, stay-at-home parent, or retired). #limited to persons - years of age and those reporting student as occupation. our investigation has limitations. first, the survey was self-administered and based on self-report; therefore, questions were open to interpretation and subject to reporting bias. because respiratory specimens from asymptomatic persons were collected at a single point in time, we are unable to show whether asymptomatic shedding might have occurred later during quarantine. also, rrt-pcr assays and serologic tests are inherently limited by their individual sensitivity and specificity; however, we believe that the limitations of test specificity and sensitivity across this population of evacuees were minimal. in addition, because only serum specimen was taken at the time of us arrival, we were unable to detect antibodies that may have developed later. as of may , a total of , , covid- cases had been confirmed in the united states, including in repatriated persons ( cases in returned evacuees across flights from hubei province and cases from the diamond princess cruise ship) ( ) . initial efforts to slow introduction of sars-cov- to the united states began in january and included quarantine of persons with high-risk exposures, screening of travelers at airports, and isolation and contact tracing of confirmed case-patients ( ) . our investigation demonstrated that this group of evacuees posed a low risk of introducing sars-cov- to the united states, and their exposure to sars-cov- in wuhan was probably limited. these results should help inform public health guidance on quarantine and isolation measures for travelers arriving from high-risk areas and further characterize the epidemiology of this emerging virus. table . signs/symptoms, clinical course, and past medical history for evacuees reporting illness who were on a repatriation flight from wuhan, china, to the united states in early * no./total no. 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thank the following members of the riverside university system: josephine cortez, anthony martinez, brianna anderson, hanh nguyen, kim clifton, vanessa arreola, jarrett herbst, jide adeyeye, stephanie loe, geoffrey leung, mike mesisca, gregory harriman. we also thank the cdc covid- patient under investigation team. at the time of the study, dr. hallowell was an epidemic intelligence service officer in the division of viral diseases, national center for immunization and respiratory diseases, cdc. his research interests include epidemiology of infectious diseases, vaccines, and public health. key: cord- -sxl g p authors: mathews, fiona title: chapter zoonoses in wildlife: integrating ecology into management date: - - journal: adv parasitol doi: . /s - x( ) - sha: doc_id: cord_uid: sxl g p zoonoses in wildlife not only play an important ecological role, but pose significant threats to the health of humans, domestic animals and some endangered species. more than two‐thirds of emerging, or re‐emerging, infectious diseases are thought to originate in wildlife. despite this, co‐ordinated surveillance schemes are rare, and most efforts at disease control operate at the level of crisis management. this review examines the pathways linking zoonoses in wildlife with infection in other hosts, using examples from a range of key zoonoses, including european bat lyssaviruses and bovine tuberculosis. ecologically based control, including the management of conditions leading to spill‐overs into target host populations, is likely to be more effective and sustainable than simple reductions in wildlife populations alone. bovine tuberculosis. ecologically based control, including the management of conditions leading to spill-overs into target host populations, is likely to be more effective and sustainable than simple reductions in wildlife populations alone. parasites and pathogens in wildlife are a natural part of biodiversity. an abundance of theoretical studies indicate that they have key roles in ecological and processes, including the regulation of population size may and anderson, ) and the maintenance of genetic diversity (may and anderson, ; read et al., ) . occasional field experiments have also demonstrated impacts of sublethal infections on reproductive rates (munger and karasov, ) and susceptibility of wildlife to predation (hudson et al., ) . yet the vast majority of empirical studies consider wildlife pathogens and parasites only if they threaten the health of humans or their domestic animals, and often overlook their natural history. partly this reflects the priorities of funding agencies; and their concerns are not trivial. more than % of emerging (or re-emerging) pathogens of humans are thought to have wild animals as their natural reservoirs (taylor et al., ) . examples include sars-cov (severe acute respiratory syndrome coronavirus), avian influenza a (h n ) virus (bird flu), nipah virus, hantavirus and west nile virus. the economic imperative for controlling zoonoses that affect domestic stock can be very strong. for example, bovine tuberculosis (btb) in the united kingdom undoubtedly has a reservoir in wild badger populations, and the direct cost of the disease to agriculture is projected to reach £ billion by (department for environment, food and rural affairs (defra), ). it has been recognised relatively recently that disease can also pose a serious threat to the survival of endangered wildlife (lyles and dobson, ; may, ; smith, ) . this can either be through direct mortality, where losses are greater than the birth rate, or through effects on birth rate, longevity and survival, which suppress the population size to a level that renders it susceptible to extinction by stochastic effects (table . ). generalist pathogens with a wide host range are particularly problematic, since even virulent species can persist in alternative hosts while driving the rare host to extinction (begon and bowers, ) . although remaining low on the list of priorities compared with other threats such as habitat loss, efforts are therefore sometimes now made to control infectious diseases for conservation reasons. examples of recent successes include the control of canine distemper virus in black-footed ferrets (mustela nigripes) (williams et al., ) , and rabies in african wild dogs (lycaon pictus) (hofmayer et al., ) and ethiopian wolves (canis simensis) (haydon et al., ) . in europe alone, there are at least zoonotic parasites and pathogens in wildlife that are known to be important either to public health or the agricultural economy (artois et al., ) . for many other infectious agents, such as cryptosporidium parvum, the epidemiological role of wildlife is unknown. despite the many attempts to control zoonoses in wildlife, the success rate is poor. typically, measures are adopted as crisis management (usually in the form of culling) following an outbreak, with little understanding of the ecology of species or its relationship to the pathogen. crisis management also means that proper scientific designs with appropriate controls are often lacking; it is therefore difficult to evaluate the effectiveness of a given intervention. even where there is a long history of attempts to control a disease through the management of a wildlife reservoir, the results have not been encouraging. for example, efforts over the last years to control btb in cattle in the united kingdom by culling of badgers has failed to yield significant benefits, with analyses of the recent randomised controlled trial of badger culling concluding that culling could not contribute meaningfully to future control strategies for btb (donnelly et al., ) . similarly, the culling of foxes has been discounted as a means of rabies control in western europe (blancou et al., ) . however, success has been achieved through the use of widespread vaccination (administered via bait) (aubert, ) . rabies is currently the only example of a widespread strategy of vaccination being favoured over the control of the host species (artois et al., ) . this review considers the ecology of zoonoses in wildlife and the links between infection in wildlife and humans or livestock. it proposes that a shift to ecologically based control, explicitly considering the natural history of wildlife hosts and their pathogens, is crucial in minimising the risk presented to humans, domestic animals and endangered species from zoonoses. this approach will also yield benefits for the conservation and welfare status of wild animals. notwithstanding the complexities of specific relationships, the probability of a zoonosis being passed from wildlife into another host population, be it humans, domestic stock or an endangered wild species, is always influenced by several key parameters. these are the intensity of infection in the reservoir hosts; the size, or depending on the case, the density, of the infected host population; the degree and nature of the contact between infected individuals (or infectious particles in the environment such as infected faeces); and the susceptibility of the in-contact animal. (for indirectly transmitted parasites and pathogens, the role of vectors and/or intermediate hosts must also be considered.) whether the zoonosis persists after initial invasion is also determined by the new host's population size. a great variety of models has been developed to describe the transmission dynamics of macro-and microparasites, taking into account the nuances of particular host and parasite population structures (diekmann and heesterbeek, ; heesterbeek and roberts, ; scott, ; scott and smith, ). yet empirical research has lagged behind the theoretical advances. the legacy of researchers like elton and chitty (chitty, (chitty, , elton, ; elton et al., elton et al., , , who sought not only to describe pathogens but to understand their ecological role, has not been sustained. (there are a few notable exceptions, including the long-term studies of small mammals in the north of england (beldomenico et al., a,b; feore et al., ) ; rodent reservoirs of hantavirus in the united states (calisher et al., ; mills et al., ) and macroparasite infections in laboratory models (ehman and scott, ; scott, ; scott and anderson, ; scott and smith, ) .) this deficiency was noted in a key text in the field in (grenfell and dobson, ) and again in the follow-up publication in (hudson et al., ) . we lack even species lists of parasites and pathogens for most, if not all, wild animals. while pathogens that affect international trade are reported to the world organization for animal health (oie), and many of these affect wildlife (see artois et al., ) for the lengthy list of those likely to affect wildlife in europe), there is no agreed systematic programme of surveillance (kulken et al., ) . even where programmes exist, they lack integration with surveillance in humans and domestic animals at both local and international scales. disease surveillance in wildlife is usually driven by outbreaks in humans or domestic animals (childs, ) . virulent pathogens are, therefore, more likely to be detected than more benign ones (williamson et al., ) . such studies are also, by their nature, not designed to screen for a range of pathogens, so opportunities to investigate the epidemiology and ecology of coinfections are often lost. systematic surveillance of representative samples of the population is difficult and time consuming. yet prevalence estimates can be seriously skewed if the only data available are derived from passive surveillance of carcasses. not only are estimates likely to be too high if they are based on samples of wildlife found dead or sick by the public, but even road kills and game bags are likely to over-represent certain population classes (such as dispersing juvenile male mammals) and animals in compromised health. disease-responsive surveillance also offers little information on the frequency with which transfer events are likely to occur. for example, many of the 'spectacular' epidemics derived from bat viruses, such as hendra virus, nipah virus, sars-cov-like virus, have been observed only a small number of times. we do not know why this should be the case. is transfer of zoonoses from bats to terrestrial vertebrates generally rare due to a lack of appropriate contact? or is there regular inter-specific transmission of other viruses but these go undetected because they lack the extreme pathogenicity of hendra and nipah viruses to stimulate screening efforts? pro-active surveillance of wildlife and of apparently healthy human or livestock populations could help answer these questions. structuring and species specificity of a pathogen in wildlife hosts? screening for european bat lyssaviruses in europe is an exemplary case of research stimulated by public health concerns. the first recorded european bat rabies case was in hamburg in and several other cases were identified subsequently (king et al., ). yet surveillance of bats was not really pursued until a woman in denmark was bitten by a serotine bat (eptesicus serotinus) infected with european bat lyssavirus (eblv ). since then more than rabies-positive bats have been identified across europe; the vast majority being serotine bats infected with eblv- (harris et al., ) . in the united kingdom, screening efforts were intensified following the death of a man in scotland from eblv- in , after apparent contact with many bats in the united kingdom and europe (fooks et al., ) . in contrast with classical rabies (rabv) there is now good evidence that at least some bats (and possibly other animals) can produce neutralising antibodies and survive eblv infection for at least years (serra-cobo et al., ; van der poel et al., ) , and experimental models suggest that eblv- might be inherently less virulent than eblv- (vos et al., ) . eblv- also appears to have a much more restricted geographical range than eblv- , and small numbers of positive bats have been identified in the united kingdom, switzerland, the netherlands, denmark and germany (department for environment, food and rural affairs (defra), ; racey et al., ; vos, ; vos et al., ) . these cases have all been in the closely related daubenton's (myotis daubentoni) and pond bats (m. dasycneme). structuring of eblvs therefore is apparent from these data both across geographical areas and across species. the serotine bat occurs over most of europe, extending north to latitude (england south of the wash estuary, denmark and southern sweden); daubenton's bats are common across europe; and the pond bat is present in a wide band across central and eastern europe (between and latitude; absent from the united kingdom (schober and grimmberger, ) ). yet neither eblv- nor eblv- appears throughout their hosts' ranges. some suggest that in the case of eblv- , this may be because long-distance travel is uncommon in serotines, the primary host (vos et al., ) . yet the species is widely distributed, and it is unlikely that there are gaps between populations that could not be travelled with relative ease; dispersing movements of up to km have also been recorded (hutterer et al., ) . interestingly, eblv- also appears to have a patchy distribution, despite its host species, at least in continental europe, being migratory over long distances (vos, ) . whether the geographical distribution is, in reality, less patchy than it currently appears requires co-ordinated surveillance effort and a willingness by statutory authorities to publish test results even if they are negative. it is clear that active surveillance (systematic screening of bats in the wild) has been undertaken in a few countries only, and passive surveillance (submission of dead bats by members of the public for screening) has involved few, if any, animals in a number of european countries, including portugal, ireland, greece, the czech republic and slovakia (racey et al., ) . a range of european bats, most of which are common and widespread, has been identified as having active eblv infections in addition to the key hosts (table . ). it is striking then that the vast majority of reported cases come from just three species. undoubtedly, the numbers of bats of each species submitted by the public does not match their abundance in the wild, but is influenced by the closeness of their contact with humans (and their cats, which are a major cause of bat mortality). for example, few woodland specialists have been submitted, whereas bats that frequently roost in houses, particularly pipistrelles, long-eared bats and possibly serotines, are over-represented (harris et al., ) . even active surveillance does not attempt comprehensive surveys of all species in proportion to their abundance: instead, it focuses on the three species already identified as being important sources of eblvs, potentially failing to estimate properly the prevalence in others. despite these limitations, the data clearly suggest that species partitioning occurs. the common pipistrelle bat is known to be susceptible to experimental infection with eblv- (kuzmin and botvinkin, ) . yet none of the more than , pipistrelles (p. pipistrellus and also p. pygmaeus, which is cryptic with p. pipistrellus) surveyed in the netherlands, france and the united kingdom (harris et al., ; picard-meyer et al., ; van der poel et al., ) has proved positive for the virus. whether structuring across bat species driven by differing immunoresponsiveness to particular eblv types, by a lack of transmission opportunities or by other mechanisms, is unclear. multi-species summer, and particularly hibernation, roosts are known, though the amount of inter-specific direct contact appears to vary by season and species. for example, bats in houses and trees tend to use single-species roosts, even if more than one species is present at the site (park et al., ) . there may be more potential for inter-specific contact at key underground sites used by bats. in a survey of more than , bats of different species roosting in caves in turkey, it was noted that multi-species clusters frequently occurred in the post-hibernation season, but not during hibernation; and the horseshoe bats (rhinolophus spp.) only ever formed single-species clusters (furman and Ö zgü l, ) . many bat species also use swarming sites-enclosed areas often in and around caves-for display purposes. at these sites, hundreds or thousands of bats of mixed species congregate (glover and altringham, ; parsons et al., ) . the amount of contact, for example, via urine or aerosol droplets, between species at these events is unknown. more field research is needed to investigate the opportunities for disease transmission across bat species, and across geographical barriers. interestingly, in the united kingdom, only a single case of exposure to eblv- has been found (the test was able to detect exposure rather than live virus), whereas in other european countries with eblvs, the apparently more pathogenic eblv- is more common (defra, ; racey et al., ; vos, ) . to date, seven daubenton' bats (myotis daubentoni) in the united kingdom have been found to have eblv- infection (defra, ) , the latest case being diagnosed in may . it is notable that although a low prevalence (around %) of seropositivity was detected during active surveillance of daubenton's bats in scotland, live virus was not isolated from any of them (brookes et al., ) . similar results were found in an active-surveillance study in spain, which found that up to % of individuals in some colonies were seropositive for eblv- , but the prevalence of active infection was less than . % (serra-cobo et al., ) . it is currently difficult to interpret these results, but the vertical transmission of antibodies, as well as acquired immunity, is a possibility. while it is clear that eblv- and eblv- can cause deaths in unvaccinated humans, whether natural immune responses and cryptic recovery (i.e., without the virus having invaded the central nervous system and become symptomatic) are possible remains unknown. it is unfortunate that there was been no serological testing of bat workers in the united kingdom to establish the natural prevalence of neutralising antibodies to eblvs prior to . since that date, following the fatality in scotland from eblv- , it has been officially recommended that bat handlers be vaccinated against rabies. the take-up rate of vaccination has been very high. this understandable management of the public-health crisis means that it is now not possible to gather information that would have helped indicate the pathogenicity of eblv- to humans, and also whether exposure was more widespread than the single fatal case. it certainly appears that despite other species being susceptible in experiments, natural spillover into other non-bat hosts to produce clinical symptoms is rare, with the only known case for eblv- being a single stone marten . there are no reports of spill-over for eblv- . the apparently simple task of establishing the prevalence of a pathogen in wild animals can be fraught with difficulty. even assuming that a reasonably random cohort can be sampled, there is usually no opportunity to repeat 'live-tests' in cases of diagnostic uncertainty. establishing values for other key parameters is equally problematic. fundamental data on the sex-and age-distributions of infection are often not recorded. sometimes this is because the surveys (particularly for 'crisis management') were not designed with research in mind. sometimes it is practically difficult for the data to be acquired. bats, for example, can live more than years, yet it is impossible in the absence of long-term banding studies on the particular population being surveyed, to judge the age of animals with much greater accuracy than 'juvenile', 'young of the year', and 'adult'. weight is frequently used as a surrogate for age or maturity, particularly in studies of rodents, but there can be difficulties in distinguishing age from dominance effects, since both are correlated with body mass. the size of the population (or its density) is also often estimated with huge margins of error, as surveyors simply lack the time to undertake detailed ecological studies in addition to collecting clinical samples. distinguishing between different burdens of infection (particularly for macro-parasites) and stages of infection (particularly for micro-parasites) is frequently overlooked. this makes it difficult to use the data to parameterise epidemiological models. for example, animals infected with btb but in which the bacilli are encysted present no risk of transmission at that particular time point, yet these groups are often combined when data from post-mortem examinations are used. the fact that the disease may reactivate at some future time (measured by the overall prevalence) is not relevant to the calculation of the basic reproductive rate of the disease r . by conducting large-scale surveys of representative populations of wildlife on british farms, workers were able to build deterministic models to investigate the likelihood of the disease persisting in each host species. initially they assumed that no between-species transmission was present. using the prevalence of infectious individuals, together with field data on population structure and density derived from the same sites, they computed the basic reproductive number r for each of the species. the analyses showed that even when the maximum likely prevalence was assumed (based on the upper % confidence limit), the r (the basic reproductive rate of the disease) ranged from just . in wood mice to . in rats. (the lower confidence intervals for prevalence always gave r values that were < . ; mathews et al., b .) it is therefore unlikely that the disease would persist within single-host systems in the wild: the animals are unable to pass on the infection to their conspecifics at a rate high enough to maintain the disease. the findings are robust to underdiagnosis of infection: to affect the r materially, the prevalences would need to be have been underestimated very substantially. if, instead of single-host models, we assumed multiple-host systems, then higher prevalences should have been observed in the field than those recorded. alternatively, to achieve the prevalences seen in reality, the withinspecies transmission rate would have to be even lower than the very low value calculated. they have therefore been able to conclude that multi-species transmission of btb within farmland wildlife communities appears unlikely. perhaps the best example of long-term epidemiological studies in wildlife leading to epidemiological models of value to human health comes from studies of hantavirus infection in the united states. large-scale studies of several thousand rodents were conducted by four separate research teams, but were co-ordinated by common methodologies (calisher et al., ; easterbrook et al., b; glass et al., ; mills et al., ) . using longterm datasets, with repeated trapping at set grids, the teams were able to explore key components of the transmission pathway. seropositivity was higher in males and in heavier animals, suggesting horizontal transmission among adult males. decreasing prevalence with age among the youngest deer mice suggests that infected dams confer passive immunity to pups. in the main host of sin nombre virus, the deer mouse (peromyscus maniculatus), gender, age, wounding, season and local relative population densities were linked with the period prevalence of antibody (used as a marker of infection). nevertheless, antibody prevalence and some of the risk factors associated with antibody prevalence, such as relative population density, gender bias and prevalence of wounding, varied significantly among sites and even between nearby trapping arrays at a single site. this suggests that local micro-site-specific differences play an important role in determining relative risk of infection in rodents and, consequently, in humans. these data are now being used in spatially explicit models of the risk of human disease outbreaks (eisen et al., ) . as described for bat lyssaviruses, the contact rates between infectious and susceptible individuals (or a vector and a susceptible) is a critical step in the transmission pathway. yet compared with the effort that goes into improving, for example, the accuracy of a diagnostic test, very little attention is paid to measuring it in the field. this failure may offer some explanation for the difficulties faced in attempted disease control programmes. for example, disease is a primary threat to the survival of the critically endangered ethiopian wolf (canis simensis). since the early s, outbreaks of rabies and canine distemper virus (cdv) have had significant impacts on wolf population dynamics randall et al., randall et al., , . these diseases are maintained in local domestic dog populations, and a programme of dog vaccination was therefore introduced in , with the aim of reducing the population of susceptible dogs and hence the risk of transmission to wolves. attempts were made to achieve coverage of more than % of susceptible dogs during annual vaccination campaigns. this was not an easy task since dogs in ethiopia are used for guarding cattle and are not tame. rabies vaccines have high efficacy, and in theory, this level of coverage should prevent rabies outbreaks % of the time (coleman and dye, ; world health organization, ) . over , vaccinations have taken place, and at least initially, the number of rabies cases in dogs declined (randall et al., ) . nevertheless, a rabies outbreak occurred in wolves in , and could be linked with more than sympatric dogs with clinical symptoms consistent with rabies . mathews has, therefore, been analysing the reasons for the apparent failure of the vaccination strategy, focusing on the population dynamics of the domestic dogs, using data collected by the ethiopian wolf conservation programme. the key factor appears to be the growth of the dog population, which, as in other african countries, is keeping pace with, or even outstripping, human populations (cleaveland et al., ; rhodes et al., ) . eighty-six percent of all households owned dogs, rising to . % in rural areas. virtually nothing is known about the true contact rate between domestic dogs and ethopian wolves. it is clear that interactions do occur as wolf-dog hybrids are seen. we might speculate that diseased dogs, and aggressive dogs that are difficult to vaccinate, might be even more likely to interact with wolves than would healthy ones. some data are available on the demography of the dogs surrounding the bale mountains national park-one of the strongholds of the remaining ethiopian wolf population-as a result of a questionnaire survey administered by the ethiopian wolf conservation programme. the rate of increase in the dog population size appears to be around % per annum, and the turnover rate is also high. this creates a constant influx of new susceptibles into the dog population. it is difficult to keep pace with these, given the financial and logistical constraints on the numbers of visits veterinarians can make to each village. there also appears to be some geographical clustering of vaccination effort, and the implications of pockets of unvaccinated dogs on the probability of rabies transmission to wolves is currently being explored. the vast majority of efforts to control zoonoses in wildlife hosts, rather than in domestic animals, rely on culling strategies. in simple terms, the idea is to depress the population of the reservoir host to a level at which the disease can no longer be sustained, because the density of infected and susceptible hosts is too low. few of these culling programmes have systematically examined either the total population size or the level of population reduction likely to be required to achieve the desired endpoint. even where this has been done, it can be difficult practically, as with vaccination, to achieve the level of coverage desired. the strategy to control btb in badgers and cattle in the united kingdom has had the culling of badgers as its cornerstone for more than years. when it became evident that gradual badger culling was having little or no impact on the incidence of the disease in cattle, a formal review of the programme was introduced, culminating in a large-scale randomised trial of badger culling. this has demonstrated that there is no clear-cut reduction in btb in cattle. on the contrary, whereas the incidence of btb in farms at the centre of km badger culling zones fell by around %, the incidence in farms up to km away from the borders of these zones increased by around % (donnelly, ) . similar results were found in comparable areas where clusters of badgers were removed reactively, following nearby outbreaks of btb in cattle (donnelly et al., ) . at least part of the explanation for the failure to achieve effective btb control is likely to be the alteration in contact rates between infected and susceptible badgers, and also between infected badgers and cattle, as a result of the culling. there has been only one detailed study of m. bovis epizootiology in undisturbed badgers (culling having been suspended at the site, woodchester park in gloucestershire, england in ; delahay et al., ) . this study showed that btb does not spread rapidly at high incidence through badger populations, but rather is distributed patchily among a minority of individuals. social groups are relatively stable, and long-term dispersal movements are uncommon, though shorter movements do occur more regularly (rogers et al., ; vicente et al., ) . there is a correlation between rates of inter-group movement and the incidence of new infections (rogers et al., ; vicente et al., ) . while spatial clusters of infection exist, there is no strong synchrony between neighbouring groups, suggesting that there is only limited transmission between adjacent social groups (delahay et al., ) . both individuals and groups are more likely to be incident cases where the social group was diminishing in size, although there is no apparent relationship with group size itself, suggesting that it is the change in group size, and possibly the associated social dynamics, that influences disease risk (vicente et al., ) . badger culling operations have clear impacts on the behavioural ecology of the survivors. woodroffe et al. ( ) found that badger social group ranges increased among survivors within reactive and pro-active culling areas and along the perimeters of pro-active culling areas. their finding, at a large scale, accords closely with the observations of of individual and group behaviour in two zones of badger removal in england, as well as those of o' corry-crowe et al. ( ) in ireland. in all cases, the spatial organisation of social groups was considerably altered following the culls, with a large increase in the extent of overlaps between social groups (e.g., fig. . ) . the numbers of ranges with which each group overlapped also increased. there was a rather chaotic alteration in population densities (e.g., fig. . ) . in the examples shown, culling was conducted in , largely targeting areas of highest badger density (in effect, the largest social groups). one year later badger density was, unsurprisingly, lower in the culled areas, whereas there had been some increases elsewhere. in , although the population as a whole had not grown, the density remained low, or even fell further, in two removal areas, but increased elsewhere. by and , the distribution of badgers in the study area was radically different from that at the outset, with some previously high density, but culled, areas remaining depauperate . thus, while the population density recovered as a whole, the badgers built up in a different place. this sort of radical redistribution has not been reported in undisturbed populations. the changes have not only implications for absolute contact rates, but also the nature of contacts. for example, bite-wounds-an important route of btb transmission-were more common in the macdonald et al. ( ) study following social perturbation. (post-cull) figure . badger social territories before and after the selective removal of social groups following btb incidents in local farms. social structure also plays an important role in hantavirus transmission. in deer mice, both wounding and sin nombre virus antibody prevalence increased with mass. although it occurred in both sexes, the a c e b d badgers removed in bro increase was much more pronounced in males. wounding was more frequent in adult males than in adult females, and adults had more wounds than juveniles. the highest rate of infection was seen in individuals with the most wounds. similarly, in rats (rattus norvegicus) hantavirus infection (seoul virus) was associated with both wounding and elevated testosterone levels (easterbrook and klein, ; easterbrook et al., a) . it is therefore evident that changes to social structure-for example, by the removal of a dominant male-could have important implications for the epidemiology of a disease. rather than attempt to control disease by vaccination or culling, an alternative approach is to understand the factors leading to disease outbreaks in the first place and to manage these (dobson, ) . habitat changes that lead to alterations in population structure or migratory patterns, for example, are likely to affect the risk of zoonotic disease transmission (dobson and may, ) . the effect of habitat fragmentation on disease processes has rarely been investigated, but it has recently been shown that trypanosoma cruzi infection rates are higher in fragmented than continuous atlantic forest (vaz et al., ) ; and the risk of lyme disease in new york is also apparently increased by fragmentation (allan et al., ) . interestingly, the division of endangered ethiopian wolf population into small sub-populations, joined by habitat corridors, has been shown to allow rabies control to be achieved using a low-coverage vaccination strategy (haydon et al., ) . the strategy operates by eliminating the largest outbreaks of disease, and so enhances meta-population persistence, rather than by the conventional objective of reducing the reproductive number of the disease to less than one (haydon et al., ) . human activities that artificially increase, rather than decrease, animal densities also influence disease processes. these increases can be the result of losses of absolute habitat area, or from the provision of supplementary food or water. in the united states, the practice of supplementary feeding of house finches and white-tailed deer has lead to an increase in the incidence of mycoplasmal diseases and btb, respectively (hartup et al., ; schmitt et al., ) , presumably because of greater opportunities for disease transmission, and possibly also immunosuppressive effects of aggression at the feeding sites. btb has also been an intractable problem in the british cattle herd, with the incidence rising inexorably since . with a cull of badgers recently being ruled out, somewhat controversially, as offering no meaningful contribution to the long-term control of the disease (donnelly et al., ) , it is worth asking whether consideration of the ecology of the badgers and cattle might help generate workable solutions. over the past years, along with the increase of btb, there has also been an increase in badger densities, and it is likely that this contributes at least in part to the disease in cattle. so why have badger populations risen? might the answer lie in changes in land use? macdonald and newman ( ) speculate on a possible role for climate change, with milder winters and hence greater earthworm availability improving survival rates. changes could also have occurred in the susceptibility of badgers to btb and/or of cattle to btb. for example, the average milk production of a dairy cow rose from , l in to , l in (farm animal welfare council, ) , possibly to the detriment of the animal's immune status. similarly, stress resulting from cull-associated social perturbations, or from other changes to habitat, food availability or population density, may have influenced the innate immune response of badgers. little is known of the physiological responses of free-living wild mammals to poor environmental quality or other potential stressors. an argument has been made for polychlorinated biphenyls (pcbs) and other pollutants contributing to phocine distemper outbreaks (ross et al., (ross et al., , , but this is has been questioned (o'hea, ) . while the role of toxicants is not clear, recent work indicates that high population densities in wild field voles is associated with compromise in haematological and immunological indices. poor body condition appeared to affect the inflammatory response (as indicated by lower neutrophil and monocyte peaks) and lower immunological investment (as indicated by lower lymphocyte counts (beldomenico et al., a,b) . i have found, with co-worker jon blount, preliminary evidence of increased oxidative stress (measured by serum malondialdehyde concentration) among non-infected badgers from farms with recent btb in cattle, compared with those at sites free of btb ( fig. . ). there is also a considerable literature from farm (moberg and mench, ) , laboratory (galloway and handy, ) , and free-living aquatic animals (liney et al., ) showing that environment has a strong impact on stress responses, and that these can lead to pathological and pre-pathological alterations in immune function and overall health status. while it might be difficult to intervene directly to reduce the causes of stress in animals, ecologically based interventions that reduce both disease susceptibility and the opportunities for transmission may be possible. for example, in a study of british farms it has been shown that habitat management and cattle herd size were strongly associated with the risk of btb in dairy cattle (mathews et al., a) . reduced risk of btb was associated with the management of farmland in ways favourable to wildlife, including greater hedgerow availability, a lack of gaps in hedgerows, increasing hedgerow width and the presence of ungrazed wildlife strips adjacent to hedgerows. all of these measures are encouraged by recent european common agricultural policy reforms ( ) . broadly, habitat could influence cattle contact rates or be associated with agricultural management practices in ways relevant to btb transmission (such as reduced herd size). favourable habitat may lower the susceptibility of badgers to btb or reduce the number of inter-group excursions; alternatively, cattle on hedgerow-rich farms may be at reduced risk of ingesting contaminated soil. taking for simplicity just one of the parameters contributing to the effects-the total length of hedgerow-an increase of km/ ha was associated with a decrease in the odds of btb by about . % ( % confidence interval . % increase to . % decrease) in univariate analysis. in absolute terms, this equates to the annual risk of btb changing from the current rate of . % ( , confirmed incidents in , herds in ) to . % ( , incidents) for herds in the west of england if a policy of moderate hedgerow density increase were adopted. this would mean a reduction of infected herds per year. by comparison, systematic badger culling appears able to reduce the odds of btb by a maximum of about % and may even increase the prevalence in neighbouring areas (donnelly et al., ) . change in land use has also been linked to the emergence of two henipaviruses, nipah virus and hendra virus in the s, and land use management may therefore offer part of the solution. both viruses appear to be asymptomatic in their natural hosts, fruit bats (genus pteropus). they are amplified in domestic animals, pigs and horses, respectively, where they cause mortality, and can then be passed on to humans (chua et al., ; halpin et al., ) . the closeness of rna sequence match between pteropus sp., livestock and human isolates of each virus suggests that a sudden change in virulence is a less likely explanation of their rapid emergence into domestic animals and humans than is the ecological change that have affected the habitat of their natural hosts. many flying fox species are in decline, with roosting and feeding sites being deforested, and converted to agricultural or urban use. a number of hypotheses have been proposed to explain exactly how nipah virus emerged (see breed et al., ) , all of which involve the establishment of piggeries in previously forested regions still used by fruit bats (chua et al., ) . increased contact rates are also the likely explanation for the emergence of hendra virus in australia, with many pteropus populations having relocated into urban areas (hall and richards, ) . with no vaccine available, and pteropus in need of conservation, ecologically based strategies to limit contact rates between bats and livestock offer the best prospects of controlling the disease (field and mackenzie, ) . managing the risks from zoonoses to the health of humans and domestic animals is complex. it is also fundamentally important: virtually all emerging infectious diseases have originated in wildlife. superficially, the simplest method of control is via a reduction in reservoir host-disease prevalence, this being achieved by culls of host populations. however, effective reductions in population densities can be difficult to achieve in practice and may be undesirable where the target is of conservation concern. for example, most bat species are threatened, and yet they appear to be particularly important sources of emerging viruses (calisher et al., ; 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bullataradis (monogenea) on guppies (poecilia reticulata) regulation of mouse colony abundance by heligmosomoides polygyrus parasitic and infectious diseases: epidemiology and ecology european bat lyssavirus infection in spanish bat populations animal disease and conservation risk factors for human disease emergence characterisation of a recently isolated lyssavirus in frugivorous zoo bats effects of habitat fragmentation on wild mammal infection by trypanosoma cruzi social organization and movement influence the incidence of bovine tuberculosis in an undisturbed high-density badger meles meles population european bat lyssaviruses-an ecological enigma susceptibility of ferrets (mustela putorius furo) to experimentally induced rabies with european bat lyssaviruses (eblv) canine distemper in black footed ferrets (mustela nigripes) from wyoming the analysis and modelling of british invasions who expert consultation on rabies. first report. who technical report series . who effects of culling on badger meles meles spartial organisation: implications for the control of bovine tuberculosis key: cord- -zkk d gd authors: muzumdar, jagannath m.; cline, richard r. title: vaccine supply, demand, and policy: a primer date: - - journal: j am pharm assoc ( ) doi: . /japha. . sha: doc_id: cord_uid: zkk d gd objective: to provide an overview of supply and demand issues in the vaccine industry and the policy options that have been implemented to resolve these issues. data sources: medline, policy file, and international pharmaceutical abstracts were searched to locate academic journal articles. other sources reviewed included texts on the topics of vaccine history and policy, government agency reports, and reports from independent think tanks. keywords included vaccines, immunizations, supply, demand, and policy. study selection: search criteria were limited to english language and human studies. articles pertaining to vaccine demand, supply, and public policy were selected and reviewed for inclusion. data extraction: by the authors. data synthesis: vaccines are biologic medications, therefore making their development and production more difficult and costly compared with “small-molecule” drugs. research and development costs for vaccines can exceed $ million, and development may require years or more. strict manufacturing regulations and facility upgrades add to these costs. policy options to increase and stabilize the supply of vaccines include those aimed at increasing supply, such as government subsidies for basic vaccine research, liability protection for manufacturers, and fast-track approval for new vaccines. options to increase vaccine demand include advance purchase commitments, government stockpiles, and government financing for select populations. conclusion: high development costs and multiple barriers to entry have led to a decline in the number of vaccine manufacturers. although a number of vaccine policies have met with mixed success in increasing the supply of and demand for vaccines, a variety of concerns remain, including developing vaccines for complex pathogens and increasing immunization rates with available vaccines. new policy innovations such as advance market commitments and medicare part d vaccine coverage have been implemented and may aid in resolving some of the problems in the vaccine industry. c urrently, vaccine-preventable disease levels are at near record lows. this was not the case at the beginning of the th century, when infectious diseases were the greatest threat to public health and the leading cause of death in the united states and elsewhere. during that period, few effective treatments or measures were available for preventing large numbers of deaths from these diseases, despite the fact that in , edward jenner performed the western world's first vaccination. during the th century, the "golden age" of vaccines witnessed the development and acceptance of vaccines for diphtheria (discovered in , but not used widely until the s), tetanus toxoids ( ), influenza vaccine (first used in ), polio vaccine with inactive virus ( ) and live attenuated virus ( ), measles ( ) , and combination measles-mumps-rubella (mmr) vaccine ( ) . estimates indicate that these vaccines have prevented more than million deaths per year worldwide from infectious diseases. vaccines have been well documented as one of the greatest achievements of medicine and are among the most cost-effective interventions in public health. for example, zhou et al. evaluated the economic impact of the routine u.s. childhood immunization schedule. they reported that for every dollar invested in childhood vaccination against nine vaccine-preventable diseases, $ . was saved in direct medical care costs. further, when indirect benefits were taken into account, such as parental absenteeism costs incurred in caring for ill chil- synopsis: supply and demand issues in the vaccine industry and the policy options that have been implemented to resolve these issues are reviewed in the current work. although vaccines have been responsible for some of the greatest successes in public health, the vaccine market is fragile and requires both supply-and demand-side interventions. vaccine availability has been limited by the number of suppliers, high research and development and production costs, and safety problems leading to increased regulatory requirements. demand for vaccines has been constrained by rapidly increasing vaccine costs, financing issues that have hindered efforts to achieve targets set for population immunization rates, and parental attitudes regarding the safety and efficacy of vaccine products. analysis: to date, a patchwork of policies to make the vaccine market more attractive for private firms and to increase patient access to these products has been implemented by the u.s. government and private philanthropies. according to the authors, an integrated policy approach that preserves incentives for market entry and innovation in the vaccine industry while addressing parental vaccine concerns and increasing immunization funding and reimbursement for both providers and patients is needed. dren, the amount saved rose to $ . . salo et al. assessed the cost effectiveness of influenza vaccination of children aged months to years and found that influenza vaccination for healthy children (all age groups) was more effective and less costly than not vaccinating children against influenza. these findings are due in part to the fact that many vaccines result in long-term or lifelong protection of the recipient and people they contact. through the process of "herd immunity" and "herd effect," a vaccines protect not only those who receive them but also those who cannot or do not receive the vaccine because of medical conditions, parental indifference, or religious or philosophical objections to vaccinations. , ( a the probability of unvaccinated individuals contracting a disease when part of a larger group with a certain seroprevalence [herd immunity] is called the herd effect.) however, of note, if a susceptible person strays outside the herd or if the herd changes, that person is still susceptible. compared with pharmaceutical products, the number of lives saved per invested dollar is substantial. economists have reported that this increased life expectancy has made a considerable contribution to economic growth. , in fact, it has been argued that more than one-half of the growth in real income in the first half of the th century is attributable to the declining mortality associated with the discovery of vaccines. , mass immunization programs have resulted in % eradication of smallpox from the world, elimination of diphtheria and polio, and % eradication of measles, mumps, and rubella in the united states. haemophilus influenzae type b (hib) vaccines have been successful in reducing childhood mortality. in addition, vaccination of healthy adults has resulted in decreased work absenteeism and decreased use of health care resources, including less use of antibiotics. , nevertheless, this success of vaccines is threatened because of several factors. problems related to vaccine research and development (r&d), manufacturing complexities, supply and distribution, safety issues, and financing have become areas of major concern. symptoms of this crisis include a decline in the number of vaccine producers from in to in and a decline in the number of licensed vaccine products from in to in . (some of these are combination products.) , eight of these vaccine products are currently produced by five major companies: sanofi pasteur, chiron (a business unit of novartis vaccines and diagnostics), glaxosmithkline, merck vaccines & infectious diseases, and wyeth vaccines. should any one of these suppliers cease production, it could take years for a replacement vaccine to be licensed and become available publicly. beginning in late , the united states faced shortages of of the recommended childhood vaccines. affected vaccines included diphtheria-tetanus-acellular pertussis (dtap), mmr, varicella, and pneumococcal conjugate vaccines. suspension of production of pedvaxhib and comvax by merck and a subsequent voluntary recall of certain lots of both vaccines on december , , led to a considerable disruption in the supply of hib-containing vaccines. thus, the dearth of suppliers appears to have affected the stability of vaccine supply. compounding these problems, the epidemiology of several diseases is changing. west nile virus killed at least people in the united states in , and cases of dengue fever, formerly known only in tropical areas, have been reported in texas. the centers for disease control and prevention (cdc) received reports of , cases of malaria in among individuals in the united states or its territories. this total represents an increase of . % from the , cases reported for . with rapid intercontinental transportation and a larger global population, diseases can travel and spread to many countries in little time. cdc issued a health advisory on april , , regarding a measles outbreak in arizona that was linked to importation of the measles virus from switzerland. the first case, with rash onset on february , , occurred in an adult visitor from switzerland who was hospitalized with measles and pneumonia. in another dramatic example, severe acute respiratory syndrome spread from asia to north america quickly, eventually infecting , people worldwide, of whom died, when a -year-old woman carried the infection from hong kong to toronto, where it eventually caused deaths. , objectives the current report seeks to provide an overview of the vaccine industry and public policy affecting it. specifically, we sought to ( ) highlight issues faced by vaccine manufacturers that make the vaccine industry a unique segment of the prescription drug industry, ( ) provide an overview of the vaccine market with regards to vaccine supply and demand, and ( ) provide an overview and critical evaluation of policy options proposed and implemented by various parties to address vaccine supply and demand problems. this research consists of a narrative literature review and critical analysis of the information retrieved. search criteria were limited to english language and human studies. keywords used for the search included vaccines, immunizations, supply, manufacturing, demand, policies, and push-pull solutions. indices such as medline, policy file, and international pharmaceutical abstracts were searched and the results augmented with reports produced by government agencies (e.g., government accountability office) and independent think tanks. a variety of sources were reviewed, including reports from academic journals and current texts on vaccine history and policy. articles pertaining to vaccine demand, supply, and public policy were selected and reviewed for inclusion in the current work. vaccines are biologics that introduce "weakened or killed disease-causing bacteria, viruses, and/or their components" or toxoids into a person or animal to stimulate an immune reaction that the body will remember if exposed to the same pathogen in the future. this unique property sets them apart from other segments of the pharmaceutical industry, such as "small-molecule" or products derived from traditional organic chemistry methods and from other biologically derived products used in a therapeutic capacity. as such, when a private firm considers entering the vaccine market, they face several important barriers to entry, some of which are shared with these product segments and others that are unique to vaccines. these are discussed in detail below. new vaccines begin with the recognition of an infectious disease burden worth preventing. basic research regarding pathogens and immune responses, often funded by the national institutes of health (nih), vaccine manufacturers, and nonprofit organizations such as the bill & melinda gates foundation, is performed mainly at universities. certain vaccines for yellow fever, typhoid, and anthrax are funded and developed in the department of defense. before entering clinical trials, prototype vaccines undergo toxicology testing that is conducted in a good laboratory practice-compliant laboratory. private firms then build on this knowledge to develop clinically feasible vaccine products and shepherd them through clinical testing. the vaccine's manufacturer then must submit a biological license application (bla) to the food and drug administration (fda) for evaluation and approval before marketing. the approval process tests extensively for safety and efficacy, along with purity and absence of contaminants. if data raise serious concerns about product safety or efficacy during any phase, fda may request additional information or studies or may halt ongoing clinical studies. the entire research, development, and approval process may require years or more. estimates of the cost of this process range from $ million to $ million ($us ). , table summarizes information on the different phases in vaccine research. manufacturing complexities. although vaccine manufacturing regulation originally was controlled by the u.s. public health service under the biologics control act of , this authority now rests with fda. the majority of vaccines approved by fda are manufactured from live (attenuated) or killed (inactivated) organisms. some are based on partially purified components of an organism such as diphtheria and tetanus, and a handful are recombinantly produced, such as the hepatitis b vaccine. vaccines are manufactured by at least three methods: egg-based (e.g., influenza vaccine), cell-derived (e.g., polio vaccine), or recombinant (e.g., hepatitis b vaccine). for bacterial vaccines, the bacterial pathogens are grown in bioreactors using media developed for optimizing the yield of the antigen (e.g., hib) ( figure ). as such, small deviations in the manufacturing process can have a major impact on the potency and/or purity of these products. thus, fda production facility requirements are rigorous, and these stringent regulatory hurdles add to the production costs of vaccines. because new vaccines generally are more complex than older products, vaccine suppliers face increasingly stringent regulation of manufacturing facilities even after a vaccine is approved. suppliers undergo frequent inspections of their production facilities by each country in which the vaccine product is licensed and by fda. individual product batches require separate approval for release, and slight modifications reviews vaccine policy to production processes or the packaging of products may trigger expensive and time-consuming product reviews. fda also requires frequent upgrades of vaccine production facilities to reflect state-of-the-art manufacturing processes. recently, fda quality control inspections led to merck's recall of . million doses of childhood vaccines to protect against meningitis, pneumonia, and hepatitis b because of contaminated manufacturing equipment. , the recall involved lots of the hib vaccine pedvaxhib and two lots of a combination vaccine for both hib and hepatitis b sold under the brand name comvax. most vaccine manufacturers are profit-seeking firms, not public health agencies. as such, they are not obligated to develop vaccines. these manufacturers face the decision of whether to invest large amounts of capital in vaccine r&d for a small portion of the global pharmaceutical market representing approximately . % of all pharmaceutical revenues. most vaccines are not "blockbuster" pharmaceuticals that yield large profits or returns on investment. although pharmaceuticals in the aggregate are a large market representing approximately $ billion annually ($us ) worldwide, sales of vaccines are estimated at just $ . billion to $ billion per year, with about one-quarter of total sales in the united states. this $ -billion market is controlled primarily by the five major manufacturers. moreover, most vaccines are used at most several times in a lifetime, whereas therapeutic biologics and small-molecule drugs often are used every day. thus, markets for small-molecule and biotechnology drugs treating chronic diseases are considerably more attractive to investors than vaccines. safety concerns, both real and unsubstantiated, continue to be a threat to the present vaccine market. vaccines are biologics and therefore are more difficult to produce with consistent precision than small-molecule drugs. they are subject to variability in the manufacturing process and require careful handling. despite intensive quality regulation, the biologic nature of vaccines, inherent uncertainties in manufacturing, and safety concerns make vaccine manufacturers targets for tort litigation for patients suffering an illness after vaccination. a surge of lawsuits in the s resulted in serious concerns regarding the supply of the dtap combination vaccine, as well as other vaccines. concerns have been raised in the united states regarding the safety of thimerosal, which is a mercury-containing preservative used in some vaccines. another concern is with the false association of mmr combination vaccine and autism in children. however, to date, studies have not shown an association between neurodevelopmental disorders and thimerosal. , in addition, no evidence has been found demonstrating a link between vaccination with the mmr vaccine and autism in children. rotashield, a rotavirus vaccine licensed in , was permanently withdrawn in when it was found to cause a rare but serious intestinal obstruction in some recipients. these safety concerns have been a reason for a change in the attitudes of some parents regarding having their children immunized. taken together, liability issues and safety concerns provide important disincentives to manufacturers considering developing and manufacturing vaccines. immunization rates for recommended vaccines among children in the united states have been consistently high. the immunization regimen was simple, costs incurred were small, and many (if not most) public schools required proof of immunization as a condition of attendance. , most children received vaccines from private practitioners with their parents paying for this service through third-party insurance or out of pocket. underprivileged children often received free immunizations from local health departments, with costs paid from general revenue funds at the local and state level. in the s, the cost of recommended immunizations began to increase, primarily as a result of the introduction of table displays a comparison of the costs for recommended vaccines for children to years of age for and . according to the national immunization survey (nis) for children, although the number of children vaccinated had reached record highs, for some vaccines, coverage among children was lower and varied with poverty level. also, according to recent cdc data, substantial gaps continue to remain in vaccination coverage for adults. these shortcomings may be due in part to the increasing costs of vaccines. given the increasing costs associated with vaccination and the increasing number of vaccine doses, financing for this service has taken on greater importance. currently, u.s. vaccine financing is a joint responsibility shared by the private and public sectors. as of , more than one-half of the vaccines recommended for children were purchased through federal contract, whereas vaccines for adults typically are covered by private insurance. private health plans often have insurance coverage for vaccines. however, some children enrolled in private health plans do not have coverage for vaccines and are considered underinsured for immunization. finally, some studies have shown that health care provid-ers have concerns regarding the costs of purchasing and administering vaccines and their level of reimbursement from public and private insurers. providers must order and purchase many vaccines (e.g., influenza) months before they are administered, resulting in substantial capital outlay coupled with delayed reimbursement. recently, freed et al. conducted a survey exploring physicians' perspectives on reimbursement for childhood immunizations. approximately one-half of the study respondents reported financial reasons and low profit margins from immunizations as factors affecting their purchase and administration of vaccines. these authors concluded that physicians who provide vaccines to children and adolescents are dissatisfied with third-party reimbursement levels and the increasing financial strain on their practices from immunizations. thus, increasing vaccine prices, a greater number of vaccine doses, and declining provider reimbursement for these products appear to be factors constraining both patient and provider demand for these products. parental beliefs regarding vaccine safety and efficacy have led to a decrease in the demand for recommended vaccines. , - for example, kennedy et al. reported that % of parents with a child still living at home in were opposed to compulsory vaccination laws and that this opposition was associated significantly with beliefs in the safety and efficacy of vaccines. in an analysis of the - nis, gust et al. found that more than % of parents had delayed their child's for recombinant vaccines, this involves many unit operations of column chromatography and ultrafiltration. formulated vaccine may include an adjuvant to enhance the immune response, stabilizers to prolong shelf life, and/or preservatives to allow multidose vials to be delivered. reviews vaccine policy first vaccination and that % had refused vaccination. concerns about vaccine safety were associated significantly with both of these behaviors. as described above, at least two important positive externalities (i.e., benefits accruing to individuals other than the original supplier and patient) can be attributed to vaccines: ( ) vaccination helps protect even those individuals not receiving the vaccine by reducing the transmission of a given disease and ( ) reductions in the burden of infectious disease in the th century have been linked to considerable economic expansion during that period. however, vaccine manufacturers cannot capture these third-party benefits. this problem, together with other supply-side (e.g., barriers to entry) and demand-side (e.g., vaccine financing) issues have resulted in market failure (i.e., a quantity and variety of vaccine products supplied that is below the social optimum) in the vaccine market. thus, both government policy makers and various health philanthropies have implemented a number of proposals aimed at overcoming these issues. these policies can be described as either "push" or "pull" strategies. push strategies seek to address supply-side issues in the vaccine market by providing direct assistance to ease the burden of research, development, and production costs, whereas pull strategies are designed to manipulate demand for vaccines, thereby improving the likelihood of a return on investment by increasing the number of immunizations administered. thus, push mechanisms can be thought of as funding inputs, while pull mechanisms can be thought of as paying for outputs. financial incentives. large, government-funded research and academic institutions play a vital role in basic vaccine research. public funding of vaccine discovery and early developmental efforts coupled with tax subsidies to private firms can reduce manufacturers' upfront financial outlays substantially and alter return on investment calculations for vaccine research favorably. , for example, nih sponsors approximately one-third of all vaccine-related basic research. most of this funding is in the form of grants to academic institutions and health-related agencies. the bioshield act of (p.l. - ) conferred more authority and leadership in the vaccine development effort on the national institutes of allergy and infectious diseases (niaid). the law increased the federal share of bioterrorism projects and allowed niaid to hire technical experts and to award grants and contracts for advancing r&d efforts for specific vaccines. to date, funds from the act have provided support for the r&d of new smallpox and anthrax vaccines. after the bioshield act, in , congress enacted the pandemic and all-hazards preparedness act (p.l. - ). this act gave authority for the advanced development and acquisitions of medical countermeasures to the biomedical advanced research and development authority. fda fast-track mechanism. the fda modernization act of (p.l. - ) directed fda to issue guidance describing its policies and procedures pertaining to fast-track products. fda's fast-track mechanism is designed to facilitate the development and expedite the review of new vaccines intended to treat serious or life-threatening conditions. the mechanism emphasizes early communication between the manufacturer and fda. this allows the manufacturer and fda to discuss development plans and strategies that can improve the efficiency of preclinical studies of the drug and focus efforts on the design of the major clinical efficacy studies before a formal submission of a bla. this early interaction can help clarify goals and plan early for obstacles that might delay approval decisions for a new vaccine. biovest international inc.'s biovaxid (a therapeutic vaccine focused on follicular non-hodgkin's lymphoma) and intracel's oncovax vaccine (designed to prevent recurrence in stage colon cancer) are recent examples of vaccines that have been granted fast-track status. fda accelerated approval. for certain biological products that are being tested for treatment of a serious or life-threatening illness, fda regulations allow "accelerated approval" of the biologic product based on the biologic products' "meaningful therapeutic benefit over existing treatments." , fda grants this approval on the basis of adequate and well-controlled clini- cal trials establishing that the biological product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. for example, in an effort to meet the increasing need for a flu vaccine, the fda approved fluarix, an influenza vaccine for adults that contains inactivated virus through this mechanism. the manufacturer demonstrated that after vaccination with fluarix, adults made levels of protective antibodies in the blood that fda believes are likely to be effective in preventing influenza. fluarix was the first vaccine approved using the accelerated approval process. fda priority review. under the fda modernization act, reviews for new drug applications (ndas) or blas are designated as either standard or priority. the review period changes depending on the designation given to the drug. drugs given a standard designation usually require months to more than year for review. the priority designation can, however, shorten the anticipated amount of time until approval decision from months to months for some products. the priority review process begins only when a manufacturer officially submits a bla (or an nda). priority review, therefore, does not alter the steps taken in a vaccine's development or testing for safety and effectiveness. merck's human papillomavirus vaccine-the first developed to prevent cervical cancer-was evaluated and approved in months under the priority review process. liability protections and safety solutions. because pharmaceutical manufacturers have expressed liability concerns as an important reason for abstaining from vaccine development, proposals addressing these concerns have been seen as necessary incentives to participation in vaccine development. in response to the safety concerns and the lawsuits against vaccine manufacturers, congress enacted the national childhood vaccine injury act of (p.l. - ). this legislation established the vaccine injury compensation program in , which ensures that individuals or families of individuals who may have been injured as a result of a routinely recommended vaccine are quickly, easily, and appropriately compensated. an individual claiming injury or death from a vaccine files a petition for compensation with the court. the petition is reviewed to determine whether it meets the criteria for compensation. a vaccine injury table lists and explains injuries/conditions that are presumed to be caused by vaccines. it also lists time periods in which the first symptom of these injuries/conditions must occur after receiving the vaccine. to qualify for compensation, a petitioner must show that an injury found in the vaccine injury table occurred or must prove that the vaccine caused the condition. a case found eligible for compensation is scheduled for a hearing to assess the amount of compensation. most noncompensable claims receive awards for attorney fees and costs. congressional approval of this act also set in motion the vaccine adverse event reporting system for monitoring vaccine adverse events. the homeland security act of (p.l. - ) protects manufacturers and health care workers who administer the smallpox vaccine from tort liability and restricts the liability assumed by the united states to negligence of those parties. the smallpox emergency personnel protection act of (p.l. - ) created a mechanism to compensate individuals who, in response to a secretarial request for smallpox vaccine preparedness, are injured by the vaccinia virus used in the smallpox vaccine. vaccine recipients and individuals contacted by them are eligible for medical care expense reimbursement, lost income benefits, and death benefits, administered through the health resources and services administration. the public readiness and emergency preparedness act of , (p.l. - ) is a tort liability shield that immunizes vaccine manufacturers, distributors, program planners, and administrators. the act protects these entities from financial risk in the event of any loss related to the manufacture, testing, development, distribution, administration, and use of countermeasures against chemical, biological, radiological, and nuclear agents of terrorism, epidemics, and pandemics. public-private partnerships. donors, foundations, and other partners have created a public-private partnership known as the global alliance for vaccines and immunization (gavi), the mission of which is to save children's lives and protect people's health through the widespread use of vaccines. as a gavi partner, the bill and melinda gates foundation has invested millions of dollars in r&d for vaccines for diseases such as malaria and human immunodeficiency virus, currently the leading killers of children and adults around the world. gavi has established public-private partnerships to accelerate late-stage development and introduction of priority vaccines against disease such as rotavirus and pneumococcus. stockpiles. stockpiles are, put simply, an artificial enhancement to current market demand levels in anticipation of periods when supply will be insufficient to meet demand. government funding of vendor-managed stockpiles of childhood vaccines ensures that some excess vaccine supply is always available to buffer supply problems when they occur. currently, the united states has a large enough stockpile of smallpox vaccine to vaccinate every person in the country who might need it in the event of an emergency. the government also expects to stockpile nearly million doses of an investigational vaccine against pandemic influenza, and studies are under way to develop mechanisms that could stretch that supply to cover more than one-third of the population. cdc also maintains a large anthrax vaccine stockpile. advance market commitments. advance market commitments involve donors who commit to buying yet-to-be-developed vaccines in bulk for poor nations if drug makers are able to deliver a vaccine that meets specifications and a price can be settled on in advance. supporters of advance market commitments range from the gavi partners to pope benedict xvi. donors have agreed to test this mechanism for a vaccine for pneumococcal disease. to date, the gates foundation, the united kingdom, italy, canada, norway, and russia have committed a total of $ . billion for the project. vaccine bonds. the united kingdom has taken a lead in promoting an international financing facility for immunization (iffim) iffim has raised more than $ billion in capital markets to immunize poor children in developing nations against reviews vaccine policy vaccine-preventable diseases. iffim plans to invest $ billion over the next decade to immunize million people who would not otherwise be protected from diseases that no longer represent public health threats in developed countries. the iffim mechanism concentrates on the funding for vaccine research by using long-term government commitments as security bonds issued in the capital markets. the cash received for the bonds then can be used for research and future purchase of vaccines. whenever the bonds are issued, iffim pays bondholders a modest rate of interest. as money pledged by donor governments becomes available gradually over years, these funds will be used to repay the capital value of the bonds. iffim was able to double the resources gavi has been able to allocate-$ . million in compared with $ . million in . vaccine financing programs. historically, the u.s. immunization system has been financed through public-private sector partnerships. the public sector purchases vaccines for approximately % of the birth cohort. section (a federal discretionary grant program to all states), the vaccines for children (vfc) act of (p.l. - ), and state funds are major public sector sources for vaccine financing. private sector vaccine purchases are covered through private health insurance and account for % to % of the pediatric vaccines sold annually in the united states. the federal government has played an evolving role in building the immunization structure in the united states. the earliest legislation pertaining to vaccine financing is the social security act of . title v of this act pertains to immunization services for children and their mothers. in , congress enacted the vaccine assistance act (section of the public health service act). this legislation provided grants to social service agencies and local health departments for immunization infrastructure and vaccine purchases. however, barriers to immunization access still remained in some areas as a result of considerable variability in immunization efforts by state and local governments. the deficiencies in this legislation were highlighted by the measles epidemic of - , which involved more than , cases and led to deaths. , substantial numbers of unimmunized preschool children, particularly in inner-city areas, contributed to this event. to ensure that vulnerable children had more reliable access to vaccines, the government refocused their funding resources on helping individual states in building immunization infrastructure. vfc is a state-operated federal entitlement program that provides free advisory committee on immunization practices-recommended vaccines to children years of age or younger who are uninsured, alaska native or native american, eligible for medicaid, or receive their vaccines in a federally qualified health center. at the state level, funds are earmarked for vaccine purchase and immunization programs. state funds also have been used to purchase vaccines for children and adolescents not eligible for vfc. a combination of vfc, state/local, and section program funds (i.e., vfc only, vfc and underinsured, vfc and underinsured select, universal, and universal select) has been used by a number of states to purchase all recommended vaccines for children in the state, including the privately insured. many states use universal programs that expand the eligibility for vfc vaccines by supplementing vfc purchases at federally discounted prices. the universal purchase states have been successful in raising vaccination rates among the underinsured and increasing access to newer and more expensive vaccines for children without insurance. however, criticisms of the universal purchase programs have been raised, including ( ) vaccine manufacturers' claims that universal purchase programs unfairly provide for the purchase of all vaccines at lower government contract prices, thus eliminating the private market for vaccines and decreasing revenue; ( ) although immunization charges are reduced under this program, patients still pay for the vaccine administration fee; and ( ) some contend that taxpayer money should not be spent to provide free vaccines for children whose insurance would otherwise pay for it. state medicaid and state children's health insurance program funds also are provided for vaccine purchase, although the level of medicaid funding varies from state to state. in contrast to vaccine coverage for children, adults are far less likely to be covered for immunization services and frequently face a problem of underinsurance. the federal medicare program covers some immunizations for all eligible beneficiaries through the medicare part b program. the selected immunizations include influenza, pneumococcal, and hepatitis b vaccinations. certain other vaccines (e.g., tetanus toxoid) also are covered if their administration is considered necessary in the treatment of another covered illness. the part d program generally covers those vaccines not available for reimbursement under medicare parts a or b when administration is reasonable and necessary for the prevention of illness. private insurance coverage of immunizations for working-age adults varies widely by the type of health plan. for example, health maintenance organizations typically have the highest coverage levels, while preferred provider organizations and indemnity plans historically have covered immunization services less frequently. by saving millions of lives and millions of dollars, vaccines have been responsible for some of the greatest successes in public health. however, the struggle against infectious disease is a continual process requiring new vaccines for the challenges that may confront human health in the future. the vaccine market is fragile and requires both supply-and demandside interventions. vaccine availability has been limited by the number of suppliers, high r&d and production costs, and safety problems leading to increased regulatory requirements. demand has been constrained by rapidly increasing vaccine costs, financing issues that have constrained efforts to achieve targets set for population immunization rates, and parental attitudes regarding the safety and efficacy of vaccine products. to date, the u.s. government, in concert with private philanthro-vaccine policy reviews pies, has implemented a patchwork of policies to make the vaccine market more attractive for private firms and to increase access to these products for individuals. we would argue that what is needed is an integrated policy approach that preserves incentives for market entry and innovation in the vaccine industry while simultaneously addressing parental vaccine concerns and increasing immunization funding and reimbursement for both providers and patients. year legislation description the vaccine act the first federal law dealing with patient protection and therapeutic substances. an agent to be appointed for preserving the genuine vaccine matter and to furnish the same to any citizen of the united states, whenever it may be applied for, through the medium of the post office. packets not exceeding half an ounce and relating to vaccination to go free of postage to and from the agent. biologics control act in addition to the testing of the final product, this act also mandated the testing and control of manufacturing materials and establishments. vaccine assistance act (section of the public health service act) infrastructure support for preventive health services such as immunization activities, including vaccine purchase assistance, is provided under section of the public health service act. national childhood vaccine injury act ensures that children who might be injured as a result of a routinely recommended vaccine are quickly, easily, and appropriately compensated. this act set into motion vaers for monitoring vaccine adverse events. vaccines for children act state-operated federal entitlement program that provides free acip-recommended vaccines to eligible children through age years. fda modernization act: fast-track mechanism the mechanism is designed to facilitate the development and expedite the review of new potential vaccines intended to treat serious or life-threatening conditions. fda modernization act: priority review reviews for ndas or blas are designated as either standard or priority. the review period changes depending on the designation given to the drug. homeland security act protects manufacturers and health care workers who administer the smallpox vaccine from tort liability and restricts that liability assumed by the united states to negligence of those parties. smallpox emergency personnel protection act mechanism to compensate individuals who, in response to a secretarial request for smallpox vaccine preparedness, are injured by the vaccinia virus used in smallpox vaccines. vaccine recipients and their contacts are eligible for medical care expense reimbursement, lost income benefit, and death benefits, administered through hrsa. project bioshield act increased the federal share of bioterrorism projects and allowed niaid to hire technical experts and to award grants and contracts for advancing the research and development efforts in vaccine areas. pandemic and all-hazards preparedness act intended to improve u.s. public health and medical preparedness and response capabilities for emergencies, whether deliberate, accidental, or natural. public readiness and emergency preparedness act tort liability shield intended to protect vaccine manufacturers, distributors, program planners, and administrators of vaccines from financial risk in the event of a loss from vaccines. abbreviations used: acip, advisory committee on immunization practices; bla, biological license application; hrsa, health resources and services administration; nda, new drug application; niaid, national institutes of allergy and infectious diseases; vaers, vaccine adverse event reporting system. immunizations in the united states: success, structure, and stress the vaccine industry: does it need a shot in the arm? national health policy forum vaccines: the controversial story of medicine's greatest lifesaver. part ii vaccine manufacturing: challenges and solutions economic evaluation of the -vaccine routine childhood immunization schedule in the united states cost-effectiveness of influenza vaccination of healthy children herd immunity and herd protection vaccines in the public eye demographic change and economic growth in east asia the health and wealth of nations vaccination greatly reduces disease, disability, death and inequity worldwide the health of nations: the contribution of improved health to living standards impact of vaccines universally recommended for children: united states, - . mmwr morb mortal wkly rep effectiveness and cost-benefit of influenza vaccination of healthy working adults: a randomized control trial vaccines for preventing influenza in healthy adults financing vaccines: in search of solutions that work putting markets to work in vaccine manufacturing why are pharmaceutical companies gradually abandoning vaccines? centers for disease control and prevention. vaccines & immunizations: immunization news strengthening the supply of routinely recommended vaccines in the united states: recommendations from the national vaccine advisory committee red book online: special alert: hib shortage vaccine shortages: history, impact, and prospects for the future reuters health information. tropical dengue fever may threaten u.s.: report. accessed at malaria surveillance: united states epidemiological and genetic analysis of severe acute respiratory syndrome just the facts: vaccines provide effective protection and fda makes sure they are safe crs report for congress: vaccine policy issues the epidemiology of rotavirus diarrhea in the united states: surveillance and estimates of disease burden vaccine product approval process the price of innovation: new estimates of drug development costs the fragility of the us vaccine supply merck recalls childhood vaccine financing vaccines in the st century lessons learned: new procurement strategies for vaccines: final report to the gavi board early thimerosal exposure and neuropsychological outcomes at to years neuropsychological performance years after immunization in infancy with thimerosal-containing vaccines autism's false prophets: bad science, risky medicine, and the search for a cure withdrawal of rotavirus vaccine recommendation financing immunizations in the united states vaccine shortages: history, impact, and prospects for the future national, state, and local area vaccination coverage among children aged - months: united states new data show unacceptably low adult immunization rates and that adults unaware of infectious disease threat. accessed at www.reuters.com/article/pressrelease/ idus + epidemiology: infectious diseases: preparing for the future gaps in vaccine financing for underinsured children in the united states estimating medical practice expenses from administering adult influenza vaccinations primary care physician perspectives on reimbursement for childhood immunizations qualitative analysis of mothers' decision-making about vaccines for infants: the importance of trust vaccine beliefs of parents who oppose compulsory vaccination parents with doubts about vaccines: which vaccines and reasons why cost-benefit analysis: concepts and practice crs report for congress: rs project bioshield project bioshield: protecting americans from terrorism department of health and human services. pandemic and all-hazard preparedness act guidance for industry, fast track drug development programs: designation, development, and application review biovest moves to fast track with cancer vaccine fda grants "fast track" designation for the development of oncovax government printing office. cfr subpart e: accelerated approval of biological products for serious or life-threatening illnesses cfr -code of federal regulations title fda approves new influenza vaccine for upcoming flu season fast track, priority review and accelerated approval fda licenses new vaccine for prevention of cervical cancer and other diseases in females caused by human papillomavirus department of health and human services, health resources and services administration. national vaccine injury compensation program (vicp). accessed at www.hrsa.gov/vaccinecompensation crs report for congress: rl , homeland security act of : tort liability provisions crs report for congress: rl , smallpox vaccine injury compensation public readiness and emergency preparedness act questions and answers. accessed at www.hhs.gov/disasters/emergency/manmadedisasters/bioterorism/medication-vaccine-qa.html accessed at www.gavialliance.org the problems and promise of vaccine markets in developing countries department of health and human services. cdc efforts in implementing a smallpox vaccination program builds stockpile of vaccine for flu pandemic why a market-driven vaccine plan faces big obstacles vaccine bonds provide model for other aid projects. accessed at www.medscape.com/viewarticle/ gavi alliance announces dramatic funding boost for hib vaccine assuring vaccination of children and adolescents without financial barriers: recommendations from the national vaccine advisory committee (nvac) measles surveillance: united states accessed at www. cdc.gov/vaccines/programs/vfc childhood vaccine supply policy impact of north carolina's universal vaccine purchase program by children insurance status adult immunization. accessed at www.cms.hhs.gov/adultimmunizations instructions: the assessment test for this activity must be taken online; please see "cpe processing" below for further instructions. there is only one correct answer to each question. this cpe will be available at www.pharmacist.com no later than july , . . which of the following is the process by which vaccines protect not only those who receive them but also those who cannot or do not receive the vaccine? a. passive immunization b. active immunization c. herd to obtain . contact hour of continuing pharmacy education credit ( . ceus) for "vaccine supply, demand, and policy: a primer," go to www.pharmacist.com and take your test online for instant credit. cpe processing is free for apha members and $ for nonmembers. a statement of credit will be awarded for a passing grade of % or better. you have two opportunities to successfully complete the posttest. pharmacists who complete this exercise successfully before july , , can receive credit.the american pharmacists association is accredited by the accreditation council for pharmacy education as a provider of continuing pharmacy education. the acpe universal activity number assigned to the program by the accredited provider is - - - -h -p."vaccine supply, demand, and policy: a primer" is a home-study continuing education activity for pharmacists developed by the american pharmacists association. key: cord- -n r n authors: sheikh, jamila; wynn, bridget a.; chakraborty, rana title: nutritional care of the child with human immunodeficiency virus infection in the united states: a historical and contemporary perspective date: - - journal: health of hiv infected people doi: . /b - - - - . - sha: doc_id: cord_uid: n r n in well-resourced settings, early infant diagnosis and administration of life-saving antiretrovirals (arvs) have significantly improved clinical outcomes in pediatric human immunodeficiency virus (hiv) infection. the dramatic increase in survival rates is associated with enhancements in overall quality of life, which reflect a multidisciplinary, holistic approach to care. current optimism starkly contrasts with the outlook and prognosis two decades ago, when failure to thrive and wasting syndrome from uncontrolled pediatric hiv infection resulted from poor oral intake, malabsorption, chronic diarrhea, and a persistently catabolic state. the tenets of care developed from that era still hold true in that all infants, children, and adolescents with hiv require comprehensive nutritional services in addition to effective combination antiretroviral therapy (cart). this chapter will review the principles of nutrition in the pre- and post-cart eras and discuss the etiologic factors associated with malnutrition, with an emphasis on interventions that have favorably impacted the growth and body composition of infants, children and adolescents with hiv. the global pandemic of human immunodeficiency virus (hiv) infection has had grave consequences in the lives of affected infants, children, and adolescents, with more than % of infant and child mortality attributed to hiv infection in endemic locations [ ] . in settings where voluntary and public resources are insufficient to provide long-term care, millions of children initially cared for by relatives have now been orphaned. however, many guardians themselves get sick or become overwhelmed by the number of dependents for whom they have to provide care. the growing number of street children and child-headed households are often the outcomes of a chain of events that begin with the hiv infection of a mother, her partner, or both. in the united states, perinatal transmission has decreased to such a significant extent that current estimates indicate less than infants born with hiv annually [ , ] . with the implementation of recommendations for universal prenatal hiv counseling and testing, antiretroviral (arv) prophylaxis, scheduled cesarean section delivery, and avoidance of breastfeeding, the rate of transmission events has decreased to less than % in the united states and europe [ ] [ ] [ ] [ ] [ ] . however, there remains an unacceptable annual rate of newly diagnosed hiv- infections among infants in the united states, with the persistence of marked racial and economic disparities [ ] . most pediatric hiv infections (> %) are caused by vertical transmission, with events more common to areas where antenatal hiv seroprevalence is high [ ] ; countries in sub-saharan africa and in south, east, and southeast asia account for more than % of the pregnant women needing arvs to prevent vertical transmission. however, global rates of new hiv infections and prevalence among young people have fallen in many countries, likely due to reductions in vertical transmission rates and improvement in access to effective cart, which has decreased secondary transmission events. a clinical overview perinatal infection occurs at a time of relative immunologic immaturity. the inability to control viremia exposes the thymus and other lymphoid tissue to hiv- -mediated destruction at a time of active thymopoiesis and lymphopoiesis [ ] . given that the virus is transmitted from the mother and that the degree of human leukocyte antigen class i sharing between mother and infant is high, the virus could evade the protective immune response of the newborn, which results in accelerated disease progression [ ] . in contrast to adults, hiv- -related symptoms, cd + t cell depletion, or both develop in most untreated vertically infected children within the first few years of life [ ] . in addition, plasma hiv- ribonucleic acid (rna) levels remained elevated over the first years among infants [ ] and do not decrease to less than copies/ml through at least the third year of life [ ] . the prolonged elevation of plasma hiv- rna levels may be related to the kinetics of viral replication, the size of the pool of host cells that are permissive to viral replication, and immature virus-specific immune responses. ii . nutrition and lifestyle the infection in perinatally infected infants and children progresses more rapidly than in adults. although % of the world's population with hiv- infection comprises children, % of all aids deaths were previously in this group. early studies before the era of cart indicated that a subset of children (~ %) progressed very rapidly to aids within year. the median time to aids for the remaining % was years [ ] . in adults, opportunistic infections (ois) are often secondary to the reactivation of pathogens acquired before hiv infection. in contrast, in infants and children with vertical infection, ois often reflect primary acquisition of host pathogens during ongoing hiv replication and advancing immunosuppression. for example, young children with active tuberculosis more often present with miliary disease. without effective cart, the most common ois in children include serious bacterial infections such as pneumonia and bacteremia. common copathogens and ois that are difficult to eradicate without successful immune reconstitution include chronic mucosal or disseminated infections with herpesviruses, namely, cytomegalovirus (cmv), herpes simplex virus (hsv), human herpes virus (hhv ) and varicella zoster virus (vzv). primary disseminated and reactivated tuberculosis is a major cause of morbidity and mortality among children with hiv in communities where infection with the pathogen is endemic. disseminated disease with mycobacterium avium complex may occur in children with hiv and advanced immunologic deterioration. pneumocystis jiroveci (formerly carinii) pneumonia (pcp) is a common and serious oi associated with a high mortality rate. pneumonia most often manifests between and months of age in infants with vertically acquired hiv infection. candidiasis (topical, oral, esophageal, and tracheobronchial) is the most common fungal infection in these children. causes of acute and chronic central nervous system (cns) infections include those caused by cryptococcus neoformans, and toxoplasma gondii. less commonly observed ois include cryptosporidiosis and systemic fungal infections. clinical presentations include hepatosplenomegaly, failure to thrive, oral candidiasis, recurrent diarrhea, parotitis, cardiomyopathy, hepatitis, nephropathy, developmental delay, encephalopathy, lymphoid interstitial pneumonitis, recurrent bacterial infections, and specific malignancies. malignancies include non-hodgkin b-cell burkitt-type lymphomas, leiomyosarcomas, and kaposi sarcoma, which are commonly described in children with hiv who are of sub-saharan african ethnicity. in the united states, in clinical practice, the number of ois seen in children with hiv has decreased, reflecting the widespread use and administration of effective cart regimens. however, ois continue to be the presenting symptom of hiv infection in infants due to lack of antenatal testing in mothers or in adolescents and young adults who are increasingly infected through horizontal transmission. the intestine is a primary target organ for hiv. hiv infection causes a depletion of cd + t lymphocytes in gut-associated lymphoid tissue, including selective loss of a subset of t helper cells called th lymphocytes, which are important in gut mucosal containment of extracellular pathogens such as salmonella typhimurium. th cells are lost early in retroviral infection and are not replenished over time. this depletion impairs long-term gastrointestinal (gi) mucosal integrity and permeability, causing increased bacterial translocation and immune activation. the intestinal mucosa is also the main reservoir of hiv in the body despite effective virologic suppression with cart. among untreated children with hiv, as many as % will have one or more intestinal disorders at a given time, with iron malabsorption present nearly % of the time [ ] . hiv enteropathy is secondary to direct hiv-mediated injury and indirect immune-mediated injury to the gi tract mucosa in the absence of specific opportunistic enteropathogens, perhaps reflecting selective loss of th lymphocytes. hiv enteropathy can occur in children and adolescents at all stages of hiv infection. clinical manifestations include chronic diarrhea, increased intestinal permeability, malabsorption, and malnutrition. histologic changes include lymphocytic infiltration of the gi tract mucosa, villous atrophy and blunting, and crypt hyperplasia [ , ] . a direct cytopathic effect of hiv on the intestinal mucosa is supported by the observation that clinical signs and symptoms improve after initiation of effective cart in association with virologic suppression and immune reconstitution of cd + t cells [ ] . acute, recurrent, and chronic diarrhea associated with malabsorption and growth impairment frequently occur in children with untreated hiv infection and advancing immunosuppression. commonly identified infective enteropathogens include bacteria (salmonella, shigella sp.), viruses (including rotavirus, adenovirus, cmv), parasites (entamoeba, giardia, cryptosporidia, microsporidia, isospora), and opportunistic fungi [ ] . in children with hiv, frequent and persistent watery diarrhea is the most common presentation of cryptosporidial, microsporidial, and isosporidial infections, associated with abdominal cramps, fever, vomiting, anorexia, weight loss, and poor weight gain [ ] . untreated chronic severe diarrhea may cause malnutrition, failure to thrive, severe dehydration, or a combination of all these problems. gi tract disease caused by cmv may include esophagitis, gastritis, pyloric obstruction, hepatitis, pancreatitis, colitis, ascending cholangitis and cholecystitis. signs and symptoms may include nausea, vomiting, dysphagia, epigastric pain, icterus, and watery diarrhea. stools may be bloody. sigmoidoscopy in cmv colitis provides nonspecific results, showing diffuse erythema, submucosal hemorrhage, and diffuse mucosal ulcerations. specific causes of diarrhea in representative adult subjects with aids are presented in table . [ ] . data reflect prospective follow-up of , participants in the swiss hiv cohort study; diarrheal episodes were evaluated by standardized stool examination, with intestinal infections diagnosed in less than % of chronic diarrheal episodes [ ] . the site and severity of infection vary according to the infecting organism. oral mucosal ulcerations secondary to infectious agents such as candida albicans, cmv, or hsv cause inflammation and pain during swallowing or after eating, which may lead to reduced oral intake. opportunistic enteropathogens such as cryptosporidium, cmv, and microsporidia [ ] may affect the hepatobiliary system and pancreas in addition to the gi tract, resulting in vomiting, abdominal pain, and malabsorption. in resource-limited settings, disease with mycobacterium tuberculosis is the most common cause of death in subjects with hiv. hiv and tuberculosis (tb) accelerate disease progression and mortality and are associated with marked clinical wasting; the extent of wasting is related to the severity of tb [ ] . the largest proportion of newly diagnosed children with hiv in many us centers are foreign born and at higher risk of prior and potentially ongoing exposure to tb. tb is almost always transmitted to children by an adult, most commonly a household contact, and the infection in children is primary infection rather than reactivated disease as in adults. there should be an increased index of suspicion of tb infection and disease in children with hiv, particularly in the context of clinical wasting and a low threshold for empiric antituberculosis therapy, even when diagnostic investigations fail to identify a tb-causing organism. the combination of underlying hiv infection, nutritional status (particularly protein-energy malnutrition), and host immunity are inextricably interdependent. in the united states, prior to the widespread administration of effective cart, the predominant effect of advancing immunosuppression on nutritional status in children with hiv was wasting and negative energy balance, which predicted both morbidity and mortality [ ] . in the pre-cart era, ois were major precipitants of weight loss, necessitating prevention or prompt diagnosis and treatment to prevent wasting and to promote weight recovery [ ] . growth in children with hiv was persistently below normal standards, with reduced height and weight velocities, compared with hiv-exposed but uninfected children. in , the centers for disease control and prevention (cdc) defined wasting in children younger than age years as ( ) persistent weight loss of more than % of baseline; ( ) downward crossing of at least two percentile lines on the weight-for-age chart in a child aged year or older; or ( ) less than the th percentile on the weight-for-height chart on two consecutive measurements at least days apart, plus chronic diarrhea or documented fever for at least days, whether intermittent or constant [ ] . in addition to ois, other etiologies that contribute to abnormal growth in untreated hiv infection in children include a synergistic combination of inadequate dietary intake, gi malabsorption, increased energy utilization, and socioeconomic adversity. the prevalence of malnutrition in children with hiv varied among centers in the united states with up to - % of children followed up in pediatric hiv programs having demonstrable evidence of protein-energy malnutrition, which, in turn, exacerbated the immunosuppressive effects of hiv [ ] . common patterns of wasting included an early decline in weight and height in the first months of life or early linear stunting with a normal weight-to-height ratio. progressive wasting with low weights and heights were also well recognized and more commonly associated with infectious enteropathogens. sequential follow-up demonstrated that growth in children with untreated hiv infection remained below growth in age-matched and gender-matched uninfected controls. malabsorption also results in macronutrient and micronutrient deficiencies. micronutrient deficiencies are widespread and compound the effects of hiv infection in children. deficiency can manifest in conditions such as fatigue, reduced learning ability due to anemia (iron deficiency), and impaired immunity [ ] . such deficiencies reflect inadequate nutrient intake and the consequences of excessive losses due to ois, diarrhea, and malabsorption, as previously described. other micronutrients that can also be malabsorbed resulting in deficiency include vitamin b , folic acid, thiamine, zinc, selenium, calcium, and magnesium, and fat-soluble vitamins a and d [ ] . the evidence base for the specific effect of micronutrient supplementation in children with hiv is limited, but a recent cochrane review of studies with , participants made the following key recommendations for practice. benefits of periodic vitamin a supplementation in children over months of age with hiv infection in resource-limited settings were supported by data from three african trials and were consistent with evidence of benefits of supplementation in uninfected children. zinc supplements reduced diarrheal morbidity and had no adverse effects on disease ii. nutrition and lifestyle progression in a single safety trial in south african children. children with hiv should therefore receive zinc supplements in the management of diarrhea and severe acute malnutrition in the same way as uninfected children with the same conditions. the review emphasized that micronutrient deficiencies and immune dysfunction in children with hiv would only be restored with effective suppression of hiv replication [ ] . cart consists of drugs that target the life cycle of hiv at specific enzymes or receptors to inhibit replication thereby preserving or restoring immune function. specific goals of administration of cart include maximally reduction of the plasma viral load below the limit of detection (< copies/ml), prevention of a selection of drug-resistant strains and maintenance of good immunologic status (repopulation with cd + -naïve t cells), and prevention of clinical disease progression and ois. clinical trials of cart in infants and children with hiv have demonstrated dramatic reductions in morbidity and mortality (> - %) in the united states since widespread implementation from onward, so the vast majority of infants and children with hiv- can now be expected to survive to adulthood [ , ] . five classes of arv drugs are commonly available for hiv therapy. two classes target the enzyme reverse transcriptase-non-nucleoside reverse transcriptase inhibitors (nrtis) and the non-nrtis. a third class-protease inhibitors (pis)-target viral protease, whereas integrase inhibitors target that corresponding enzyme. in addition, ccr inhibitors target the viral co-receptor ccr on permissive target cells. hiv- mutability is largely the result of errors introduced into the viral genome during replication. the hiv genome is approximately , nucleotides long, and each new virion has an average of one mutation. this results in a large pool of quasi-species of viral variants that are incapable of productive infection but some of which may provide an adaptive benefit, for example, the development of art resistance, to the virion. drug-resistance of the virus can develop during cart administration because of poor adherence, a regimen that is not potent, or a combination ii. nutrition and lifestyle of these factors resulting in incomplete virologic suppression. in addition, primary drug resistance may occur in arv-naive infants and children who can become infected with the resistant virus. aggressive, multidrug cart as early in infection as possible, with daily adherence for an indefinite period, is advocated to fully suppress viral replication and to preclude the selection or emergence of resistant viral variants. resistance testing has enhanced the ability to choose effective initial regimens as well as second-or third-line regimens. therapeutic strategies continue to focus on timely initiation of arv regimens that are capable of maximally suppressing viral replication in order to prevent disease progression, preserve or restore quantitative and qualitative immunologic function, and reduce the development of drug resistance [ ] . difficulties with long-term adherence to cart-particularly in infants and children because of variable drug administration, absorption, and metabolism; pretreatment with maternal cart and vertical transmission of drug-resistant virus; acceptability and palatability of medications; and refrigeration of syrup formulations in warm climates-are all well documented. long-term follow-up of infected infants and children involves longitudinal determinations of prognostic markers, including number and percentage of cd t cells, and viral load [ ] . such parameters provide a useful framework for the time to initiate and change therapy but involve frequent venipuncture in minors. long-term toxicities include lipodystrophy syndrome [ ] and lipid abnormalities, cardiomyopathy, mitochondrial toxicity and lactic acidosis, renal tubular acidosis [ ] , hypersensitivity reactions, and cns toxicity. fortunately, the availability of new drugs and drug formulations has led to the use of more potent regimens with reduced short-term toxicity, lower pill burden, and less frequent medication administration, all factors that are associated with better adherence and outcomes. enteral [ , ] or parenteral supplementation and appetite stimulants [ ] can improve the nutritional status and weight in children with untreated hiv infection but have little effect on the growth velocity of height. however, effective virologic suppression with cart was shown to improve mean weight, weight for height, and muscle mass in children with hiv, in whom pi-based therapy was initiated and maintained for a median of months. these effects were independent of virologic suppression and improved cd t-lymphocyte counts [ ] . these findings were also noted in the pediatric aids clinical trial group study, which ii. nutrition and lifestyle found that pi therapy improved both weight and height z-score annually, after adjusting for cd cell count, age, gender, and race [ ] . in the era of cart, following the introduction of pi-containing regimens, hiv-associated mortality decreased by greater than - %, with significant declines in opportunistic and related infections [ , ] . these encouraging outcomes have been tempered by the side effects associated with arvs. altered body composition, lipid abnormalities, and abnormal regulation of glucose metabolism are consequences that result in an increased risk of cardiovascular disease, reflecting complications of inflammation with uncontrolled hiv infection and the specific arv drugs as outlined. in children, adolescents, and adults, a clear syndrome of abnormal fat redistribution or lipodystrophy and metabolic changes associated with administration of cart is well described. patterns of lipodystrophy vary from peripheral fat wasting, or lipoatrophy, in the face, extremities, and buttocks to central fat accumulation, or lipohypertrophy, in the abdomen, dorsocervical spine regions (buffalo hump), and breasts. both conditions may occur alone or in combination [ , ] and can be difficult to assess in a growing child or adolescent, since changes in body fat occur normally during childhood and puberty [ ] . lipodystrophy in children with hiv is clinically evaluated by examination or self-report and has been documented to be as high as % [ ] . dual-energy x-ray absorptiometry (dexa) quantifies total, trunk, and limb fat. observational studies in children with lipodystrophy show decreased total and extremity fat and a greater trunk-to-extremity fat ratio in children with hiv compared with uninfected children [ , ] these changes are drug specific and associated with duration of therapy, with prolonged treatment and older age more likely to result in lipodystrophy. treatment with nrtis, including stavudine (d t), zidovudine (azt), and didanosine (ddi), is associated with a lower percentage of extremity fat and higher percentage of trunk fat and trunk-to-extremity fat ratio even after adjustment for wasting and stunting [ , ] . these changes in body fat distribution often cannot be reversed even after switching to less lipodystrophic arv regimens. in cohorts of children receiving a pi regimen, higher rates of dyslipidemia have been documented, with higher fasting lipids, cholesterol, and triglycerides. lipodystrophy in patients results in much higher waist-tohip ratios and elevated fasting insulin levels and blood pressure, which ii. nutrition and lifestyle are all significant risk factors for cardiovascular disease [ ] . for children without lipodystrophy, up to one fifth show symptoms of dyslipidemia. in summary, when selecting arv regimens, care must be taken to consider the above life-long side effects and their consequences. at a time when newer less lipodystrophic first-line regimens, including tenofovir, abacavir, ritonavir-boosted pis (atazanavir and darunavir), and the integrase inhibitors, most with the added advantage of once daily administration, are available in the united states, regimens that include zidovudine, didanosine, and stavudine should be prescribed less often to children with hiv to reduce these potential long-term toxicities. metabolic syndrome reflects a series of clinical conditions, including elevated triglyceride, low levels of high-density lipoprotein (hdl) cholesterol, hyperglycemia and insulin resistance, increased body fat distribution around the waist, and high blood pressure, all of which collectively increase the risk of cardiovascular disease. in individuals with hiv, the prevalence of metabolic syndrome is higher than in the general population and estimated to be - % [ , ] . although uncontrolled hiv in the absence of cart can cause low hdl cholesterol and high triglycerides, as discussed previously, arvs also induce body fat redistribution in conjunction with metabolic changes. earlier pis, including treatment doses of ritonavir (without boosting other pis), nelfinavir, and ritonavir-boosted lopinavir (kaletra) were documented to increase lipid plasma concentrations, including serum triglycerides, cholesterol, low-density lipoprotein (ldl) cholesterol, and apolipoprotein e and to lower hdl. virologic control with the newer pis, integrase inhibitors, tenofovir, and abacavir may be associated with increases in serum hdl, in the absence of these metabolic complications. when compared with population norms, children with hiv were noted to have lower-than-expected bone mineral density (bmd) for their age and gender that may have been associated with delays in growth, sexual maturity, duration of hiv infection, ethnicity, and disease severity [ ] . a more recent large study of american children and adolescents with hiv, aged - years, showed that males with hiv had significantly lower bmd at tanner stage compared with uninfected males [ ] . reduced bmd secondary to cart administration was first described in from dexa scans in vertically infected children, with the severity of osteopenia directly related to lipodystrophy [ ] . however, a longitudinal study from in dutch children showed an association between longer cart duration and increases in spinal bmd z-scores [ ] . lopinavir-ritonavir ii. nutrition and lifestyle [ ] , full-dose ritonavir [ ] , and tenofovir [ ] are associated with lower bmd in children. the principles of maintaining good bone health in youth with perinatal hiv infection is the same as those recommended for all youth in general. adolescents should therefore receive at least , mg calcium per day and at least iu vitamin d per day through their diet, by supplementation, or both [ ] . immune reconstitution inflammatory syndrome (iris) is a diseasespecific inflammatory response that can occur after treatment with arvs is initiated, reinitiated, or changed, resulting in effective virologic suppression and immune reconstitution of naïve and memory cd + t cells. iris has been noted to occur in children who begin art while they have severe malnutrition, are severely immunosuppressed [ ] , or both. risk factors therefore include a low cd nadir and high viral load levels prior to the initiation of cart. these children and adolescents often have numerous documented ois before, during, and after cart initiation [ ] . further research is needed to reduce complications and to optimize clinical management when they do occur. the interaction between hiv infection and nutrition is of great importance, and these two factors are interdependent, since strategies to improve nutritional status both quantitatively and qualitatively have been demonstrated to have a beneficial effect on clinical outcome and the immunologic course of the hiv infection. through the course of their disease, infants and children with hiv have numerous nutritional needs, which reflects, as previously described, impaired absorption, decreased oral intake, and increased nutrient requirements. specific adverse outcomes secondary to specific nutritional deficiencies include the inability to achieve normal weight for height; malnutrition and wasting; growth failure and stunting; and neurocognitive, neurodevelopmental, and oral motor delay often from hiv encephalopathy. early nutrition intervention is, therefore, essential and must be addressed simultaneously with the administration of cart, antimicrobial prophylaxis, and neurodevelopmental interventions. collectively, a ii. nutrition and lifestyle multidisciplinary approach is most effective in improving health outcomes and overall quality of life. in the pre-cart era, the nutritional causes of malnutrition reflected ( ) decreased oral intake caused by anorexia and by oral and esophageal lesions often from opportunistic pathogens, ( ) gastroesophageal reflux and aspiration, ( ) regression or nonattainment of key developmental milestones associated with oromotor dysfunction and impaired mastication, ( ) malabsorption, ( ) increased energy requirements and metabolism from ois with associated negative energy balance, ( ) vomiting and diarrhea from gastrointestinal (opportunistic) enteropathogens, and ( ) indirect immune-mediated enteropathy. at a time when effective cart was unavailable and faced with a debilitating catabolic disease and rapid disease progression in infants and children with hiv, nutritional interventions that were developed in the early s by pediatric providers targeted four key areas: . prompt management of diarrhea. in addition to isolation of opportunistic enteropathogens and prescribing appropriate antimicrobials for infectious etiologies, management of diarrhea mandates assessment of hydration status and rehydration by the oral or intravenous route. modification of diet in the setting of underlying food intolerance such as lactose or fat malabsorption, including pancreatic enzyme supplementation; and vitamin and mineral supplementation. other recommendations included introduction of a mechanical soft diet and nutritional supplementation. . management of nausea and vomiting. in addition to appropriate antiemetic agents, treatment also included recommendation of small frequent meals, liquid intakes between meals, and nutritional supplementation. . management of anorexia included small nutrient dense foods, nutritional supplementation, and appetite stimulants such as megestrol acetate. these early nutrition needs related to the unique physiologic demands for growth and development, so even today, interventions should be individualized according to the child's specific needs and relate to disease stage, gastrointestinal function, and growth [ ] . as a corollary, the energy and protein requirements for infants and children with hiv have not yet been established because individual needs vary, depending on age, growth, and the clinical and immunologic status that may increase energy and protein needs. infants and children with hiv who have slow weight gain are often prescribed high-protein, high-calorie diets. if nutritional needs are not met through a typical high-calorie, high-protein diet, then additional support may include oral nutritional supplements and overnight feeding through nasogastric or gastrostomy-tube feedings. a commercial formula with intact protein may be appropriate for children without underlying gastrointestinal pathology. infants and children with hiv who have gastrointestinal malabsorption should receive a semi-elemental formula to maximize absorption. elemental formulas are typically prescribed when semi-elemental formulas are not tolerated. infants and children with hiv who are unable to consume adequate calories orally often benefit from supplemental tube feeding. enteral tube feeding supplementation improves weight gain in children with hiv who have growth failure [ , ] . nasogastric tube feedings should be initially attempted and include night-time feedings, which allow the child to eat normally throughout the day. complications relating to nasogastric tube feedings include sinusitis and the technical inability of the caregiver to place the tube or administer the feedings [ ] . if delivery of feedings through a nasogastric tube improves growth, then placement of a more permanent device such as a gastrostomy tube should be considered. enteral supplementation with gastrostomy feeding has improved nutrition in a number of chronic childhood illnesses by providing adequate energy intake to promote weight gain when oral intake is poor. miller et al. [ ] first investigated the effects of gastrostomy tube feeding on weight gain, height, body composition, immune parameters, morbidity, and mortality in on children with hiv. weight z-scores before therapy were - . and had decreased to - . on initiation of nasogastric feedings. gastrostomy tube feedings significantly improved weight z-scores to get back to baseline approximately months after initiation of feeding. significant predictors of response to gastrostomy tube feedings included higher cd counts at initiation and lower weight-for-height z-scores at baseline. these findings suggested that early intervention during acute weight loss offers the best chances of improving weight in children with hiv. children with the greatest improvement in weight after gastrostomy tube placement spent less time in hospital and had a greater likelihood of survival compared with children who did not gain weight [ ] . this small but important study demonstrated that early nutritional intervention improved quality of life and reduced morbidity in children with hiv at a time when effective cart was unavailable. in the cart era, compliance with medical therapy is often improved with more reliable delivery of arvs through the gastrostomy tube and is associated with improved cd t-lymphocyte counts, virologic suppression, and improved longitudinal growth. guarino et al. tested the hypothesis that nutritional support improves intestinal and immune functions in italian children with hiv; received enteral nutrition through continuous feeding, and received total parenteral nutrition. the authors documented a significant increase in cd cell count, xylose levels, and body weight in those receiving enteral nutrition, suggesting that nutritional intervention may restore intestinal absorption and increase cd cell numbers if initiated early in the course of pediatric hiv infection [ ] . enteral feeding is preferred over parenteral nutrition to preserve the gut structure. parenteral nutrition should be used only in those children unable to tolerate or gain weight on enteral supplementation, those who have recurrent or chronic biliary tract or pancreatic disease, and those who have intractable diarrhea with weight loss [ ] . megestrol acetate is an oral synthetic progesterone used since the early s as an appetite stimulant. weight gain tends to be associated with increase in body fat rather than muscle. clarick et al. investigated the effects of megestrol acetate treatment on weight gain and linear growth in children with hiv who had growth failure. the average duration of the study was months. the study concluded that megestrol acetate was associated with weight gain but not linear growth during the treatment period. after the megestrol acetate treatment was discontinued, poor weight gain and weight loss were again noted [ ] . given the dramatic reductions in morbidity and mortality and the improved longitudinal growth in children with hiv in the united states since the widespread implementation of effective cart, megestrol acetate and other therapeutic agents (including growth hormone and the anabolic steroid oxandrolone) are prescribed very rarely, if at all, to subjects with hiv. in the s and early s, the devastating effects of hiv infection on the health of infants, children, and adolescents became apparent and required a rapid and effective response globally. over time, in the united states, with the introduction of arvs, the clinical manifestations associated with hiv infection as well as its treatment were seen to increase, driven by the short-and long-term toxicities of these new formulations in combination. in children with hiv, these manifestations reflected metabolic changes; wasting and stunting from gastrointestinal dysfunction were most often described in the s, but new clinical concerns in the early s were related to altered body composition, lipid abnormalities, and abnormal regulation of glucose metabolism. these complications were often attributed to the first-generation nrtis and pis. the longterm cardiovascular risks of these arvs on subjects with hiv are still unknown. after , newer pis and integrase inhibitors became more widely available and appear to have fewer metabolic adverse effects, although ongoing surveillance of these arvs and tenofovir will be important to evaluate incidences of renal tubular dysfunction and bmd. in the course of the changes in art over the previous two decades, optimal nutritional support has continued to be a cornerstone of pediatric and adolescent hiv care, applying the same principles developed from the early s to effectively support infants, children, and adolescents with hiv. these principles include ongoing comprehensive nutritional assessments and follow-up. when cart providing effective viral suppression was unavailable, enteral and parenteral support was associated with improved weight and body composition and overall survival and is still a key part of care for children and adolescents who present with advanced hiv disease. in addition, periodic vitamin a supplementation in children with hiv who are older than months of age is supported by clinical trials in africa. children with hiv should also receive zinc supplements in the management of diarrhea and severe acute malnutrition in the same way as uninfected children with the same conditions. investigators should continue to study the effects of oral hypoglycemic agents, lipidlowering medications, and lifestyle changes on cardiovascular risk factors in patients with lipodystrophy and hyperlipidemia at this time when obesity has become endemic in many communities in the united states. this unfortunate development on long-term health also has implications for children and adolescents with hiv across the united states. nevertheless, the overall outlook for children with hiv has improved significantly since the s, as reflected in the reduced rates of morbidity and mortality and improved quality of life. perhaps a measure of the latter is the overall medication burden. figure . is a child's medications, as shown by oleske et al. [ ] . figure . shows the pill burden for a number of adolescent patients in the united states in . the last paragraph of dr. oleske's article still relevant for . to quote directly, "compassionate, comprehensive, and coordinated clinical care services are required for all hiv-infected infants and children through adolescence. we must not underestimate their needs. as we improve their longevity with advances in primary hiv therapies, we must not let quality of life suffer due to a lack of nutritional intervention." global, regional, and national causes of child mortality in : a systematic analysis achievements in public health reduction in perinatal transmission of hiv infection-united states recent trends in the incidence and morbidity that are associated with perinatal human immunodeficiency virus infection in the united states combination antiretroviral strategies for the treatment of pregnant hiv- -infected women and prevention of perinatal hiv- transmission european collaborative study mother-to-child transmission of hiv infection in the era of highly active antiretroviral therapy the high number of medications for an adolescent with hiv in the slew of daily medications for a -year-old long-term surviving patient with perinatally acquired hiv in included: zidovudine (azt), didanosine (ddi), trimethoprim/sulfamethoxazole (tmp/smx), fluconzol, megase, prednisone, acyclovir, dapsone, biaxin, zalcitabine (ddc), albuterol, isonicotinylhydrazine (inh), rifampin, ranitidine (zantac) two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal hiv transmission: a randomized trial low rates of mother-to-child transmission of hiv following effective pregnancy interventions in the united kingdom and ireland earlier initiation of art and further decline in mother-to-child hiv transmission rates racial/ethnic disparities among children with diagnoses of perinatal hiv infection - states towards universal access: scaling-up priority hiv/ aids interventions in the health sector hiv- infection in children: a clinical and immunologic overview evolution and transmission of stable ctl escape mutations in hiv infection the european collaborative study association of human immunodeficiency virus (hiv) load early in life with disease progression among hiv-infected infants the relationship between serum human immunodeficiency virus type (hiv- ) rna level, cd lymphocyte percent, and long-term mortality risk in hiv- -infected children management of gastrointestinal disorders in children with hiv infection hiv enteropathy: crypt stem and transit cell hyperproliferation induces villous atrophy in hiv/microsporidia-infected jejunal mucosa enteropathies in the developing world: neglected effects on global health ritonavir combination therapy restores intestinal function in children with advanced hiv disease aetiology and management of malnutrition in hiv-positive children nutritional aspects of hiv-infected children receiving highly active antiretroviral therapy enteric infections and diarrhea in human immunodeficiency virus-infected persons microsporidia infection in patients with human immunodeficiency virus and unexplained cholangitis nutritional status in malawian patients with pulmonary tuberculosis and response to chemotherapy prospective analysis of patterns of weight change in stage iv human immunodeficiency virus infection nutrition in paediatric hiv infection magnitude of body-cell-mass depletion and the timing of death from wasting in aids centers for disease control and prevention revised classification system for human immunodeficiency virus infection in children less than years of age unicef tracking progress on child and maternal nutrition: a survival and development priority micronutrient supplementation for children with hiv infection incidence of opportunistic and other infections in hiv-infected children in the haart era declines in mortality rates and changes in causes of death in hiv- -infected children during the haart era hiv- drug resistance in hiv- -infected children in the united kingdom from national study of hiv in pregnancy and childhood collaborative hiv paediatric study increased lipodystrophy is associated with increased exposure to highly active antiretroviral therapy in hiv-infected children persistent non-gastrointestinal metabolic acidosis in pediatric hiv- infection gastrostomy tube supplementation for hiv-infected children effect of enteral tube feeding on growth of children with symptomatic human immunodefi-� ciency virus infection megestrol acetate treatment of growth failure in children infected with human immunodeficiency virus the effect of protease inhibitors on growth and body composition in hiv-infected children impact of protease inhibitor-containing combination antiretroviral therapies on height and weight growth in hiv- -infected children prevalence, evolution and risk factors for fat atrophy and fat deposition in a cohort of hiv-infected men and women pediatric hiv/aids cohort study. body fat distribution in perinatally hiv infected and hiv-exposed but uninfected children in the era of highly active antiretroviral therapy: outcomes from the pediatric hiv/aids cohort study regional body fat distribution in relation to pubertal stage: a dual-energy x-ray absorptiometry study of new zealand girls and young women european paediatric lipodystrophy group antiretroviral therapy, fat redistribution and hyperlipidaemia in hiv-infected children in europe morphologic and metabolic abnormalities in vertically hiv-infected children and youth longitudinal changes in regional fat content in hiv-infected children and adolescents the metabolic syndrome in hiv predictors of bone mineral density in human immunodeficiency virus- infected children total body and spinal bone mineral density across tanner stage in perinatally hiv-infected and uninfected children and youth in pactg bone mineral loss through increased bone turnover in hiv-infected children treated with highly active antiretroviral therapy bone mineral density increases in hiv-infected children treated with longterm combination antiretroviral therapy antiviral therapy and bone mineral measurements in hiv-infected youths comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in hiv-infected adults: -week results from the assert study vitamin d status in children and young adults with perinatally acquired hiv infection severe malnutrition and metabolic complications of hivinfected children in the antiretroviral era: clinical care and management in resourcelimited settings historical perspectives on the evolution in understanding the importance of nutritional care in pediatric hiv infection effects of nutritional rehabilitation on intestinal function and on cd cell number in children with hiv key: cord- - ja o sa authors: maloney, susan a.; weinberg, michelle title: prevention of infectious diseases among international pediatric travelers: considerations for clinicians date: - - journal: semin pediatr infect dis doi: . /j.spid. . . sha: doc_id: cord_uid: ja o sa an estimated . million children travel overseas annually. infectious disease risks associated with international travel are diverse and depend on the destination, planned activities, and baseline medical history. children have special needs and vulnerabilities that should be addressed when preparing for travel abroad. children should have a pretravel health assessment that includes recommendations for both routine and special travel-related vaccination; malaria chemoprophylaxis, if indicated; and prevention counseling regarding insect and animal exposures, food and water safety, and avoiding injuries. special consideration should be given to children with chronic diseases. families should be given anticipatory guidance for management of potential illnesses and information about the location of medical resources overseas. susan a. maloney, md, mhsc,* and michelle weinberg, md, mph* an estimated . million children travel overseas annually. infectious disease risks associated with international travel are diverse and depend on the destination, planned activities, and baseline medical history. children have special needs and vulnerabilities that should be addressed when preparing for travel abroad. children should have a pretravel health assessment that includes recommendations for both routine and special travelrelated vaccination; malaria chemoprophylaxis, if indicated; and prevention counseling regarding insect and animal exposures, food and water safety, and avoiding injuries. special consideration should be given to children with chronic diseases. families should be given anticipatory guidance for management of potential illnesses and information about the location of medical resources overseas. semin pediatr infect dis : - . t he volume of international travel has increased tremendously during the past decade. nearly . million u.s. residents traveled overseas in . approximately percent of u.s. residents traveled to destinations other than europe; these destinations included almost million trips to asia, more than . million trips to south and central america, . million trips to the middle east, and , trips to the african continent. an estimated percent to percent of adult travelers report health problems during international travel; percent to percent of travelers seek medical care during travel, . percent to percent are hospitalized abroad, . percent to . percent require emergency evacuation, and in , die. , infectious diseases are a major cause of morbidity among international travelers. [ ] [ ] [ ] [ ] [ ] an estimated percent of persons traveling annually from industrialized to developing countries develop travelers' diarrhea. [ ] [ ] [ ] [ ] [ ] [ ] [ ] malaria is a less frequent but potentially life-threatening problem for travelers; an estimated , north american and european travelers contract malaria annually. other infectious diseases reported in travelers include hepatitis a and b, sexually transmitted diseases, animal bites with risk of rabies, typhoid, cholera, legionellosis, human immunodeficiency virus (hiv) infection, and meningococcal disease. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] less specific information is available on the number of children traveling internationally or living abroad. extrapolating from overseas travel data for u.s. residents, one can estimate conservatively that at least . million children travel overseas annually (ie, % of the . million u.s. residents traveling internationally in reported traveling with children). information on the causes of serious morbidity and mortality among pediatric travelers is more limited. [ ] [ ] [ ] [ ] available data include a -year prospective hospital-based study in the united kingdom of children evaluated for fever who had traveled recently to the tropics. in this study, children with a median age of years (range, months to years) met the study entry criteria. fourteen of these children had nonspecific, self-limited illnesses of presumed viral origin, and children had conditions requiring hospital management and antimicrobial therapy. conditions requiring hospital management included four cases of malaria ( of plasmodium falciparum, and of plasmodium vivax malaria), three cases of bacillary dysentery, two cases each of dengue and typhoid fever, and one case each of acute hepatitis a infection, pneumonia (unspecified), pneumocystis carinii pneumonia (in a child with newly diagnosed hiv infection), bacterial lymphadenitis, streptococcal throat infection, and acute myeloid leukemia; no deaths occurred. in another retrospective study of travelers' diarrhea among swiss children who had visited the tropics or subtropics, pitzinger and coworkers found incidence rates of percent, . percent, . percent, and percent in children aged years or younger, to years, to years, and years and older, respectively. other authors have reported substantial health risks for pediatric travelers from noninfectious causes such as injuries, including automobile accidents and drowning. children have special needs and vulnerabilities that should be considered when preparing for travel abroad, and all children should have a pretravel health assessment performed. depending on the destination and the vaccinations needed, this assessment should be conducted up to months before travel. the pretravel assessment should include an evaluation of the child's medical history and immunization status, as well as a detailed review of the trip itinerary, including travel destinations, planned activities, type of accommodations (eg, hotel chains, residing with local families, camping), extent of contact with the local populations, and exposure to animals. special consideration should be given to children who have chronic diseases, such as diabetes, cardiac abnormalities, or immunocompromising conditions, in terms of vaccine recommendations and travel risks and precautions. parents should be advised to carry a summary of their child's medical history, treatment record, and all required prescription medications. during the assessment, the caregiver should ensure the following: ) the child has received up-to-date and appropriate vaccinations (both routine and special travel-related vaccines); ) the child has received appropriate malaria and other chemoprophylaxis regimens tailored for use in pediatric travelers; ) prevention counseling, particularly in the areas of insect barriers, food and water safety, and injury avoidance, has been given; and ) anticipatory guidance for managing potential illnesses (eg, diarrhea and dehydration) and seeking medical resources overseas has been provided. vaccination for international travel is among the most critical and complex components of the pretravel health assessment for children, and a careful review of both recommended routine childhood vaccinations and required and recommended travel-related vaccinations should be undertaken. pediatric travelers must have their routine immunizations brought up-to-date, as many vaccine-preventable diseases (vpds) are more prevalent in developing countries than in the united states. for example, diphtheria and pertussis are prevalent in eastern europe and many developing countries, and measles still is endemic in much of the developing world. hepatitis b, haemophilus influenzae type b, streptococcus pneumoniae, and varicella also are endemic in many developing countries. further, although worldwide polio eradication efforts have decreased the number of countries where travelers are at risk for acquiring polio (with most poliovirus transmission now occurring in large endemic areas in south asia and sub-saharan africa), polio outbreaks still occur; in july , outbreaks of vaccine-derived poliovirus type were reported in the dominican republic and haiti. , trip activities also may increase the risk of contracting infectious diseases such as measles; in both and , epidemiological investigations identified numerous cases of serologically confirmed measles among internationally adopted children and their new parents and siblings, who had traveled to china to accompany them home. , in addition, travel in large groups on conveyances such as cruise ships can facilitate transmission of vpds. parents should check their own immune status because travel with children can increase risk of exposure to vpds. if travel to developing countries is planned, assuring immunity is imperative, and accelerated schedules should be considered. depending on the travel destination and itinerary, routine vaccinations may need to be accelerated to maximize protection, particularly against polio, diphtheria/tetanus/pertussis, and measles (for example, measles vaccination may be recommended for children younger than months of age). guidelines for standard and accelerated schedules for routine childhood immunizations and special precautions and recommendations for immunocompromised children are available in the american academy of pediatrics, "red book: report of the committee on infectious diseases," and on web sites of the centers for disease control and prevention (cdc). common travel-related vaccines for children the most recent requirements and recommendations for travel-related vaccinations by specific geographic destinations can be obtained from cdc, "health information for international travelers" (the "yellow book"), and from cdc travelers' health internet and other travel-related web sites (see also table , international travel health information resources for web sites). the united states does not require arriving travelers to have any vaccinations for entry or return into the united states. some other countries may require proof of vaccination against yellow fever for entry, especially if the traveler is arriving from a country where yellow fever is endemic. yellow fever vaccine is available only from certified yellow fever vaccination centers; providers can refer to the following cdc yellow fever vaccine registry to locate certified centers in their areas: http://www .ncid.cdc.gov/travel/yellowfever. saudi arabia requires meningococcal vaccine for travelers to the hajj in mecca. some countries have required previous vaccination for cholera, but currently no countries require it, and the vaccine is not available in the united states. table provides general guidelines and indications for use of selected common travel-related vaccines, based on u.s. recommendations; world health organization (who) recommendations may differ. , hepatitis a is endemic in most of the world, and travelers are at risk in any area where sanitation is poor. vaccination is recommended for pediatric travelers aged years or older who will be visiting countries with intermediate to high endemicity (areas other than the united states, canada, australia, new zealand, western europe, and scandinavia). studies have demonstrated that protective antibody titers weeks after the patient has received the first dose of hepatitis a vaccine range from percent to percent; after weeks, protective antibody titers were present in percent to percent of vaccinees. intramuscular immunoglobulin is recommended for immunoprophylaxis against hepatitis a in children younger than years of age. in addition, for children years of age or older who are departing less than weeks after receiving a vaccination, immunoglobulin and vaccine can be given concurrently at different sites to ensure optimal protection. meningococcal disease occurs sporadically worldwide. epidemic disease has been reported in india, saudi arabia, and sub-saharan africa; indeed, recurrent epidemics of meningococcal disease occur in sub-saharan africa, mainly from december to june (the dry season). serogroup a is the most common cause of epidemics outside the united states, but serogroup c and other serogroups have been associated with epidemics. serogroup w- meningococcal infections among travelers returning from saudi arabia after visiting mecca during the hajj also have been reported recently. [ ] [ ] [ ] the meningococcal vaccine available in the united states is the quadrivalent polysaccharide a/c/y/w- , which is recommended for pediatric travelers years or older who are visiting sub-saharan africa during the dry season, or any country where an epidemic caused by a vaccine serogroup is occurring. the vaccine can be administered to children younger than years of age, but their immunologic response may be limited to serogroup a only. yellow fever occurs year-round in predominately rural areas of sub-saharan africa and south america; in recent years, outbreaks have been increasing. recently, yellow fever has reemerged in brazil, raising concern about increased risk in other areas of latin america and raising the possibility of transmission of yellow fever in urban areas. although a rare occurrence, yellow fever continues to be reported among travelers, particularly unvaccinated travelers, and can be fatal. prevention measures against yellow fever should include the use of personal protection measures against mosquitoes and vaccination. yellow fever vaccine is considered a relatively safe and effective vaccine. however, the vaccine has been found to be associated with an increased risk of developing encephalitis and other severe reactions in young infants. the vaccine should not be used in children younger than months of age. it should be used with caution in children to months of age, and after discussion with a travel medicine expert to weigh risks and benefits. medical waivers can be given to children who are too young for vaccination and to those who have other contraindications to vaccination, such as immunodeficiency. recently, reports have raised concern about possible rare instances of yellow-fever vaccine-associated neurotropic and viscerotropic disease, and these adverse events are being investigated. [ ] [ ] [ ] [ ] in the interim, cdc has stated that given the risk of serious illness and death caused by yellow fever, evidence of increasing transmission of the disease, and the known effectiveness of the vaccine, clinicians should continue to use yellow fever vaccine to protect travelers. however, cdc recommends that healthcare providers carefully review travel itineraries to ensure that yellow fever vaccine be given to only people traveling to areas where yellow fever is endemic or areas where there is reported yellow fever activity. , japanese encephalitis (je) is a viral infection transmitted by culex mosquitoes, which bite from dusk to dawn. je occurs year-round in tropical regions, and primarily from may through october in temperate zones. risk is greatest for travelers to rural asia, where the mosquito breeds in rice fields and other agricultural areas. je is associated with a high casefatality rate and severe neurological sequelae, especially among young children and the elderly. vaccination should be considered for pediatric travelers who are year of age or older and who will visit and reside in areas where je is endemic or epidemic, especially during transmission season, or for pediatric travelers whose activities include trips to rural farming areas. short-term travelers (Ͻ days) who visit only major urban areas are at lower risk for acquiring je and generally do not need to be vaccinated. rabies occurs worldwide. in certain areas of the world, including parts of brazil, bolivia, colombia, ecuador, el salvador, guatemala, india, mexico, nepal, peru, the philippines, sri lanka, thailand, and vietnam, canine rabies remains highly endemic. rabies also occurs in other wild animals, including bats. rabies vaccine should be considered for children visiting rabies-endemic countries for longer than month; undertaking extensive outdoor activities, such as backpacking or camping; or traveling to areas where access to health care is limited. to reduce the risk of acquiring rabies, children and their families should be counseled to stay away from stray dogs and other animals, especially if traveling to latin america, asia, or africa. typhoid vaccine is recommended for pediatric travelers visiting developing countries, especially for prolonged peri-ods of time, or traveling outside the usual tourist destinations. parents should be cautioned, however, that vaccination is not percent effective, and safe food and water precautions should be followed. influenza vaccine should be considered for children with chronic diseases and others at increased risk for developing complications of influenza if they are traveling to the tropics or to the southern hemisphere from april through september. in addition, influenza risk has been shown to be increased in destinations and on conveyances having large groups of tourists and in destinations with influenza outbreaks occurring, and, therefore, vaccination also should be considered in these circumstances. lastly, bacille calmette-guerin (bcg) vaccine is a live vaccine prepared from attenuated strains of mycobacterium bovis; bcg is used primarily in young infants to prevent disseminated and other forms of life-threatening diseases caused by tuberculosis (tb), such as tuberculous meningitis. bcg is recommended by the who for administration at birth; in the united states, bcg is recommended only in limited circumstances, such as unavoidable risk of exposure to m. tuberculosis. vaccination of a young pediatric traveler (non-hiv-infected and with negative tb skin test) might be considered, therefore, if travel is planned for a long-term stay in a country with high tb prevalence and prolonged contact with active tb cases is considered a potential problem. , bcg vaccine can be obtained from the canadian subdivisions of aventis pasteur or organon. more generally, children traveling to countries with high prevalence of tb should be given a skin test before and after travel to document possible exposure to tb. u.s. children who had traveled within the previous months to countries with a high prevalence of tb were reported to be . times more likely to have positive tb skin tests than were children who lived in the same u.s. areas but had not traveled. a recent review of malaria cases among u.s. civilians (adults and children) reported that the largest percentage of cases ( . %) occurred among persons who were visiting friends or relatives in malarious areas. retrospective reviews of malaria in children also have found that a substantial proportion of cases occurred among recent immigrants and among children of former immigrants who had traveled to visit their family's country of origin. , preventing malaria in pediatric travelers young children and nonimmune persons of any age are at greater risk for the development of severe complications from malaria; the substantial proportion of u.s. malaria cases reported in children underscores the importance of having strategies for the prevention of malaria. the prevention of malaria in pediatric travelers depends first on obtaining current and accurate information about the risk of contracting malaria in proposed travel destinations and determining if planned activities and season of travel place the traveler at increased risk of exposure. information on geographic and country-specific risks regarding malaria is available from multiple sources (see table , international travel health information resources). prevention strategies for pediatric travelers are two-fold: personal protection measures against mosquitoes and antimalarial chemoprophylaxis. the first mainstay of prevention is appropriate and effective use of personal protection measures to avoid being bitten by anopheles mosquitoes, which typically are evening and nighttime feeders. these measures include wearing clothing that reduces the amount of exposed skin (such as long-sleeved shirts, long pants tucked into socks, and hats) and, whenever possible, remaining in wellscreened or enclosed air-conditioned areas. travelers staying overnight in facilities without air conditioning or screens should use insecticide-treated mosquito nets over the beds. during the evening, insecticide also can be sprayed inside rooms. another important measure of personal protection is appropriate use of insect repellent, such as n,n-diethylmetatoluamide (deet), on exposed skin. the american academy of pediatrics has recommended using repellents with less than percent deet for infants and children. deet should not be used in children younger than months of age or applied to hands, mouth, or near the eyes of young children. despite the demonstrated efficacy of these measures, studies have found only percent of adult travelers with malaria reported using insect protection methods, and only percent took recommended chemoprophylaxis. the second mainstay of preventing the acquisition of malaria is chemoprophylaxis. the selection of the appropriate drug for antimalarial chemoprophylaxis must be based on numerous factors, including the most recent information available about the prevalence of malaria in the proposed travel destinations; trip itinerary; age, weight, and medical history of the traveler; personal preference regarding frequency of dosing and duration of chemoprophylaxis on trip return; and cost of medication. cdc provides resources with guidance on appropriate use and recommended regimens for antimalarial chemoprophylaxis (see table , international travel health information resources). figure outlines an algorithm for determining appropriate antimalarial chemoprophylaxis regimens for pediatric travelers. because the distribution of drug-resistant malaria is evolving constantly, clinicians should obtain the most recent information about the risk of malaria and zones of drug resistance before prescribing chemoprophylaxis for malaria. the first decision point in selecting appropriate antimalarial chemoprophylaxis is whether travel is occurring in a region of chloroquine-sensitive or -resistant malaria. for travel to areas with chloroquine-sensitive malaria, chloroquine is the drug of choice for antimalarial chemoprophylaxis. plasmodium ovale, plasmodium malariae, and most p. vivax are widely sensitive to chloroquine; however, chloroquine-resistant p. vivax is an emerging problem and has been reported from guyana, new guinea, india, myanmar (burma), and areas of indonesia. in addition to chloroquine-resistant p.vivax, chloroquine-resistant p. falciparium has been reported from these areas, and, consequently, chloroquine would not be recommended for chemoprophylaxis for travelers to these regions. if the traveler is visiting a region with chloroquine-resistant malaria, the next decision point is whether travel will include regions with chloroquine-resistant malaria only or both chloroquine-and mefloquine-resistant malaria. chloroquine-resistant p. falciparium is widespread and exists in all malaria-endemic areas except mexico, the caribbean, central america west of the former panama canal zone, argentina, and parts of the middle east and china. in some regions, p. falciparum may be resistant to both chloroquine and mefloquine; these areas currently are limited to the borders of thailand with myanmar (burma) and with cambodia, in the western provinces of cambodia, and in the eastern states of myanmar. , for travel to areas with chloroquine-resistant malaria, currently the three antimalarial chemoprophylaxis options are: mefloquine (lariam; hoffman-laroche, nutley, nj), atovaquone-proguanil (malarone; glaxo wellcome, research triangle park, nc), or doxycycline. cdc no longer recommends the use of chloroquine/proguanil for chemoprophylaxis for chloroquine-resistant areas. for travel to areas with chloroquine-and mefloquine-resistant malaria, either atovaquone-proguanil or doxycycline can be used. when antimalarial chemoprophylaxis options are being evaluated, each medication should be reviewed for contraindications and weight and age restrictions (see table , antimalarial chemoprophylaxis regimens for pediatric travelers). chloroquine is relatively well tolerated in children. in the united states, chloroquine is available in tablet form; in europe and other countries, it also is available as a syrup. mefloquine can be used safely in children weighing less than kilograms and may be useful for longer trips because it is administered once weekly. however, it must be continued for weeks after leaving the malarious area, and no liquid preparation is available. doses for children are one-quarter, one-half, and three-quarters of a tablet, depending on weight. few data are available on the use of atovaquone-proguanil in children weighing less than kilograms; however, studies are in progress. for children weighing more than kg at risk for acquiring chloroquine-resistant p. falciparum infection, atovaquone-proguanil can be advantageous for short trips because it is started to days before the trip and can be stopped days after the trip. it is available in pediatric tablet form. doxycycline is contraindicated in children younger use in areas with chloroquine-resistant and mefloquine-resistant malaria gi symptoms, photosensitivity may decrease the effectiveness of oral contraceptives *despite the use of chloroquine as an antimalarial chemoprophylaxis agent for decades and the use of high-dose chloroquine for certain chronic diseases, the literature is inconclusive regarding the potential risk of retinopathy associated with long term use of chloroquine for antimalarial prophylaxis. retinopathy rarely has been reported in patients on weekly prophylaxis. retinopathy appears to be related to dosage and accumulated dosage. than years of age because of concerns about the propensity of tetracycline to stain growing teeth or potentially to affect developing bones. for older children, doxycycline must be administered daily and continued for weeks after departing the malarious area. primaquine may be used as an option for primary prophylaxis in special circumstances. clinicians should contact cdc malaria branch for additional information (see table ). primaquine also can be used for terminal prophylaxis to decrease the risk of occurrences of relapses of p. vivax and p. ovale. , another aminoquinoline, tafenoquine, which is a long-acting primaquine analog, is undergoing investigation and may become approved for malaria chemoprophylaxis indications in the future. the importance of recommending appropriate antimalarial chemoprophylaxis regimens for travelers cannot be overemphasized. a review of malaria cases among u.s. civilians in found that close to percent had not taken any chemoprophylaxis and another percent had not taken the cdc-recommended drug for the area visited. in retrospective reviews of pediatric malaria cases, between and percent of cases had received no or inadequate chemoprophylaxis. , indeed, the inappropriate use of antimalarial chemoprophylaxis has been shown to be an important cause of mortality and serious morbidity among travelers. from through early , cdc received reports of seven u.s. travelers who died from malaria after using inappropriate chemoprophylaxis. all these travelers had received prescriptions for chloroquine for travel to areas with widespread chloroquine resistance. among cases of imported malaria with information about chemoprophylaxis during through early , ( %) took no chemoprophylaxis, and ( %) took an inappropriate chemoprophylaxis regimen. in addition to being given preventive therapy, parents should be counseled in signs and symptoms of malaria infection in children, such as fever, headaches, vomiting, diarrhea, and myalgias. delays in recognition and treatment of malaria are associated directly with increases in morbidity and mortality rates; therefore, prompt and appropriate initiation of effective therapy is paramount. because the epidemiology of many diseases is evolving, prevention hinges on clinicians' knowledge about current information regarding risks and outbreaks in travel destinations. a variety of pathogens are being recognized increasingly as emerging infectious diseases among travelers. in addition to malaria, other vector-borne infectious diseases are among the important diseases for consideration in travelers. dengue is one of the most important vector-borne viral infections worldwide and is endemic in asia, the south pacific, africa, latin america, and the caribbean. epidemics of dengue hemorrhagic fever, the more severe clinical form of dengue fever, occur every to years in southeast asia and are an emerging problem in latin america. recently, outbreaks of dengue fever occurred in hawaii and along the u.s. and mexico border. [ ] [ ] [ ] worldwide, an estimated to million cases of dengue fever occur annually; of these cases, , to , are dengue hemorrhagic fever. every year, cases of dengue fever among u.s. travelers are reported to cdc. dengue is transmitted primarily by day-biting aedes aegypti mosquitoes, which breed in flower vases, barrels, and discarded tires that collect water. transmission occurs in rural and urban areas, but the risk is greatest in urban areas. prevention should focus on protection against mosquito bites. travelers to risk areas should be counseled to apply repellent during the day, even while visiting cities. no vaccine is available, and prior infection with one of the four serotypes does not protect against infection with another serotype. the risk of developing dengue hemorrhagic fever actually may increase with subsequent infection with a different serotype. infections with african trypanosomiasis (sleeping sickness), a parasitic infection transmitted by the bite of a tsetse fly, occasionally have been reported among travelers. infection can result in severe neurological sequelae and is percent fatal if untreated. in , significant increases in the number of cases were reported among u.s. and european travelers to game parks in tanzania and kenya. between and , an imported case occurred on average every to years; however, in , seven cases were reported among u.s. travelers. , schistosomiasis, another parasitic infection caused by flukes that live part of their life cycle in fresh water snail hosts, affects more than million people worldwide. schistosomiasis has been reported among travelers to endemic areas of the africa, asia, south america, and the caribbean who participated in high-risk activities, such as swimming or wading in fresh water. , , children and their families should be counseled against swimming or wading in fresh water in risk areas. tick-borne encephalitis is transmitted primarily by the bite of ixodes ticks. it also can be transmitted by ingestion of unpasteurized dairy products from infected livestock. transmission occurs during summer months in western and central europe, scandanavia and parts of the former soviet union. persons who will be traveling for longer than weeks in endemic rural areas or travelers who will be engaging in high-risk activities, such as camping, should be considered for vaccination. the vaccine is not available in the united states but can be obtained in europe. examples of recent outbreaks or cases of unusual pathogens affecting travelers include fungal organisms (such as histoplasmosis and coccidioidomycosis), leptospirosis, and leishmaniasis. histoplasmosis is a fungal infection acquired by inhalation of spores, usually through exposure to bat, bird, or chicken droppings in barnyards and caves. the organism is endemic in the united states, latin amer-ica, eastern asia, parts of europe, africa, and australia. coccidioidomycosis, a fungal infection associated with inhalation of soil from high-risk areas, is endemic in the southwestern united states and latin america. both infections can cause a spectrum of illnesses from asymptomatic infection to acute pulmonary infection to severe, disseminated disease, especially in immunocompromised persons. several outbreaks of histoplasmosis have been reported among groups of u.s. visitors who entered a cave with bats in costa rica (cdc, unpublished data), ecuador, peru, and nicaragua. recently, more than college students became infected with histoplasmosis during a spring break trip to acapulco, mexico. two outbreaks of coccidioidomycosis have been reported among youth missionary groups involved in construction work in mexico. , most of these fungal outbreaks have two common features: high-risk, group activities and high attack rates, even in young, nonimmunocompromised individuals. because no vaccine is available, prevention involves counseling travelers to avoid exposure or to use special masks for high-risk individuals who cannot avoid exposure. leptosporosis is a zoonotic infection that is transmitted by exposure to water or soil contaminated with organisms excreted by domestic and wild animals. outbreaks have been reported among whitewater rafters in costa rica and among athletes from countries who participated in the eco-challenge multisport expedition race in borneo, malaysia in . because no vaccine against leptospirosis exists, persons engaging in high-risk activities should be counseled to avoid exposure to water that may be contaminated or to wear protective clothing. leishmaniasis, a parasitic infection transmitted by the bite of a sand fly, can lead to cutaneous or visceral infection. it has been reported among students who traveled to the rain forest in costa rica and among other travelers. the appropriate use of insect repellent and other personal protection measures against sand fly bites is the only prevention tool that is available. in , we experienced the global spread of a novel coronavirus, sars cov, which causes severe acute respiratory syndrome (sars); in many locations, the introduction of disease by ill travelers was followed by spread to healthcare workers and household contacts. during the course of approximately months, more than persons were infected with the virus and more than persons died. the majority of cases occurred in adults, and pediatric patients appeared to have a milder clinical course. , the united states was relatively spared during the outbreak, reporting a total of suspect or probable cases, with only eight laboratory-confirmed cases and no attributable deaths. however, during the sars outbreak, at least suspect or probable sars cases were investigated in the united states among children recently adopted from china and their family members. although none of these cases ultimately was laboratoryconfirmed, these findings demonstrate unique risks for pediatric travelers and their families and highlight the need for clinicians to be knowledgeable of emerging infectious diseases and recommended travel precautions. one of the most difficult tasks faced by international travelers of any age is ensuring the safety of food and water. travelers' diarrhea, caused by ingestion of contaminated food and water, affects between approximately to percent of adult travelers, and it is the most frequent health problem reported by travelers to developing countries. in terms of children, a retrospective study conducted by pitzinger and coworkers among swiss children who had visited the tropics or subtropics reported similar incidence rates of traveler's diarrhea in children: percent, . percent, . percent, and percent in children aged to years, to years, to years, and years and older, respectively. in this study, the authors also found that small children ( to years) most frequently were affected with travelers' diarrhea and that the clinical course tended to be more severe and prolonged when compared with older pediatric age groups. overall, children were found to have longer-lasting illness than that in adults, with an average duration of days for all children combined and days for small children. enteric pathogens typically are isolated from approximately to percent of stool specimens from adult travelers with diarrhea; in the remainder, usually no pathogen is isolated. escherichia coli, especially enterotoxigenic e. coli (etec), is the most common overall cause of travelers' diarrhea (although incidence can vary by destination), followed by camplobacter spp., salmonella spp., and shigella. other etiologic agents include pathogenic bacteria such as aeromonas and plesiomonas, protozoa (eg, giardia lamblia, entamoeba histolytica, crypotospiridium spp., and cyclospora cayetanensis), viruses such as rotavirus or norwalk-like viruses, and rarely helminthes. numerous risk factors for traveler's diarrhea also have been identified and include the consumption of certain high-risk foods (raw foods such as meats, seafood, and vegetables, unpasteurized dairy products, and ice and tap water) and travel to certain destinations. , destinations generally considered to have a high risk for travelers' diarrhea include latin america, africa, asia, and the middle east; low-risk travel destinations include north america, northern europe, australia, and new zealand. location of food preparation also is a recognized risk factor for traveler's diarrhea, with a higher risk shown for travelers eating from street vendors and in local restaurants and a lower risk for those eating in luxury hotels and private homes. counseling about food and water precautions to prevent traveler's diarrhea and anticipatory guidance to assure successful management of diarrhea are important parts of the pediatric pretravel assessment. in areas where access to bottled water is poor, water may be boiled for minute (or for minutes at altitudes greater than m [ feet]). these procedures will kill bacterial, parasitic, and viral pathogens. chemical disinfection with iodine is an alternative method for water treatment when it is not possible to boil water; however, this method cannot be relied on to kill cryptosporidium unless the water stands for minutes before drinking. chlorine also can be used for chemical disinfection, but its germicidal activity varies with ph, temperature, and the organic content of the water; it can, therefore, provide less consistent levels of disinfection in many types of water. portable filters are available and provide various degrees of protection against microbes. parents of pediatric travelers also should be counseled on the importance of advance planning for food and beverage items, especially for infants and young children. breast-feeding infants are considered relatively safe from travelers' diarrhea; for infants receiving formula, formula concentrate and powdered forms are the most convenient for travel, but a clean water supply must be available, or water must be boiled or chemically disinfected before preparation. for feeding toddlers and for older children, the travel adage of "boil it, cook it, peel it, or forget it" applies. travelers should avoid eating dairy products, including cheese and ice cream, because they often are unpasteurized. when a pediatric traveler develops diarrhea, oral rehydration solution to maintain hydration is the treatment of choice. parents also should be educated about the signs of mild, moderate, and severe dehydration and instructed in management of diarrhea, especially oral rehydration therapy. antimotility agents, such as lomotil (active ingredient, diphenoxylate; pfizer inc, new york, ny) and imodium (active ingredient, loperamide; mcneil-ppc, inc., ft washington, pa), are not recommended in children because of potential toxic megacolon and toxicity (extrapyramidal symptoms with diphenoxylate). empiric treatment of traveler's diarrhea with antimicrobial agents, typically ciprofloxacin, because of resistance to other agents such as trimethoprim-sulfamethoxazole, is used for adults. few studies of empiric antimicrobial treatment have been performed in children, and it is not a routinely recommended intervention for children. parents should be advised that severe diarrhea requires urgent medical attention, especially in younger pediatric travelers. prophylaxis for travelers' diarrhea with medications such as bismuth subsalicylate (the active ingredient in pepto-bismol; proctor & gamble, cincinnati, oh) is not recommended because of the potential accumulation of salicylate. prophylactic regimens with antimicrobial agents also are not recommended in children; the benefits usually are outweighed by potential risks, including allergic drug reactions, antimicrobial-associated colitis, and emergence of antibiotic-resistant strains. moreover, limited information is available about destination-specific antimicrobial resistance patterns. clinicians need to provide pediatric travelers and parent(s) with up-to-date and accurate international travel health information and recommendations for preventing illness. increasingly, the internet and computer-based travel resources are being used by practitioners and consumers alike because they provide current information that can be used to counsel and treat international travelers appropriately and effective-ly. a summary of some selected travel health resources that can be useful for providing information on health risks in specific travel destinations and current travel health recommendations (including immunizations and chemoprophylaxis) is provided in table . in addition, if health care provided overseas is not covered by a family's health insurance company, insurance can be purchased from several companies and can include airlift/medical evacuation. the u.s. embassy or consulate can provide names and addresses of english-speaking healthcare providers in the travel destination if medical evaluation is needed abroad. this information can be obtained before departure from embassy internet sites or by calling the embassy. in addition, names of physicians abroad also can be obtained from some worldwide directories, including those of the international society of travel medicine, at www.istm.org. travelers' and immigrants' health health problems after travel to developing countries a cumulative review of studies on travelers, their experience of illness and the implications of these findings illness associated with travel travelers' diarrhea: epidemiology, microbiology, prevention, and therapy health risks abroad: general considerations travelers diarrhea: approaches to prevention and treatment epidemiologic studies of travelers diarrhea, severe gastrointestinal infections, and cholera update on prevention of malaria in travelers pre-exposure rabies prophylaxis for travellers: are the benefits worth the cost legionnaires' disease on a cruise ship linked to the water supply system: clinical and public health implications - meningococcal disease among travelers returning from saudi arabia-united states update: assessment of risk for meningococcal disease associated with hajj absence of neiserria meningitidis w- electrophoretic type during the haj hiv- and hiv- infections among u.s. peace corps volunteers returning from west africa hiv infections, needlesticks and sexual behavior among dutch expatriates in sub-saharan africa meningococcal disease in travelers: vaccination recommendations risk of infection and other sexually transmitted diseases in travelers reported cholera in the united states memish z: meningococcal disease and travel typhoid fever in the united states, - group a meningococcal carriage in travelers returning form saudi arabia should travellers in rabies endemic areas receive pre-exposure rabies immunization febrile illness in successive cohorts of tourists to a hotel on the italian adriatic coast: evidence of a persistent foci of legionella infection risk of hepatitis b for travelers epidemiology and prevention of hepatitis a in travelers imported malaria in children in the uk epidemiology of travel-related morbidity and mortality in children prospective, hospital based study of fever in children in the united kingdom who had recently spent time in the tropics incidence and clinical features of traveler's diarrhea in infants and children prevention: health information for international travel update: outbreak of poliomyelitis-dominican republic and haiti centers for disease control and prevention: measles outbreak among internationally adopted children arriving in the united states, february centers for disease control and prevention: multistate investigation of measles among adoptees from china investigation and management of infectious diseases on international conveyances (airplanes and cruiseships redbook: report of the committee on infectious diseases world health organization: international travel and health: vaccination requirements and health advice. world health organization aedes aegypti, dengue and re-urbanization of yellow fever in brazil and other south american countries: past and present situation and future perspectives fever and multisystem organ failure associated with d- yellow fever vaccination: a report of four cases centers for disease control and prevention: fever, jaundice, and multiple organ system failure associated with d-derived yellow fever vaccination centers for disease control and prevention: yellow fever vaccine information statement cruise ships: a travel destination for high-risk passengers and the global spread of new influenza viruses prevention: the role of bcg vaccine in the prevention and control of tuberculosis in the united states: a joint statement by the advisory council for the elimination of tuberculosis and the advisory committee on immunization practices mycobacterium tuberculosis infection after travel to or contact with visitors from countries with a high prevalence of tuberculosis malaria surveillance-united states malaria surveillance-united states pediatric malaria in insecticide-treated bednets reduce mortality and severe morbidity from malaria among children follow safety precautions when using deet on children imported malaria: prospective analysis of problems in diagnosis and management malaria chemoprophylaxis in the age of drug resistance. i. currently recommended drug regimens delayed onset of malariaimplications for chemopropylaxis in travelers pediatric imported malaria in new york: delayed diagnosis prevention: malaria deaths following inappropriate malaria chemoprophylaxis-united states centers for disease control and prevention: travelers' health notice: dengue fever dengue surveillance in texas risk factors in dengue shock syndrome african trypanosomiasis in u.s. travelers: american society of tropical medicine and hygiene th annual meeting tropneteurop: outbreak of african trypanosomiasis among travelers to the serengeti national park in tanzania schistosomiasis in lake malawi schistosomiasis in travelers and expatriates control and prevention: cave-associated histoplasmosis-costa rica bat-associated histoplasmosis in returning travelers: case presentation and description of a cluster acute histoplasmosis in spelunkers returning from mato grosso an outbreak of acute febrile illness among travelers to nicaragua centers for disease control and prevention. outbreak of acute respiratory febrile illness among college students outbreak of coccidioidomycosis in washington state residents returning from mexico coccidioidomycosis in travelers returning from histoplasmosis: protecting workers at risk, revised guidelines for preventing histoplasmosis centers for disease control and prevention: outbreak of acute febrile illness among participants in ecochallenge sabah -malaysia lesion on the arm of a returning traveler a novel coronavirus associated with severe acute respiratory syndrome children hospitalized with severe acute respiratory syndrome-related illness in toronto infants born to mothers with severe acute respiratory syndrome travelers' diarrhea: epidemiology and clinical aspects information sources in travel medicine key: cord- -x ktas authors: thomaier, l.; teoh, d.; jewett, p.; beckwith, h.; parsons, h.; yuan, j.; blaes, a. h.; lou, e.; hui, j. y. c.; vogel, r. i. title: emotional health concerns of oncology physicians in the united states: fallout during the covid- pandemic date: - - journal: medrxiv : the preprint server for health sciences doi: . / . . . sha: doc_id: cord_uid: x ktas introduction: cancer care is significantly impacted by the coronavirus disease (covid- ) pandemic. our objective was to evaluate the effect of the pandemic on the emotional well-being of oncology providers across the united states and explore factors associated with anxiety and depression symptoms. methods and materials: a cross-sectional survey was administered to united states cancer-care physicians recruited over a two-week period ( / / - / / ) using snowball-convenience sampling through social media. symptoms of anxiety and depression were measured using the patient health questionnaire (phq- ). results: of participants, ( . %) completed the phq- : mean age . +/- . years; . % female; all oncologic specialties were represented. the rates of anxiety and depression symptoms were . % and . %, respectively. demographic factors associated with anxiety included female sex, younger age, and less time in clinical practice. perception of inadequate ppe ( . % vs. . %, p= . ) and practicing in a state with more covid- cases ( . % vs. . %, p= . ) were associated with anxiety symptoms. factors significantly associated with both anxiety and depression included: degree to which covid- has interfered with the ability to provide treatment to cancer patients and concern that patients will not receive the level of care needed for non-covid- illness (all p-values < . ). conclusion: the prevalence of anxiety and depression symptoms among oncology physicians in the united states during the covid- pandemic is high. our findings highlight factors associated with and sources of psychological distress to be addressed to protect the well-being of oncology physicians. by early april , the coronavirus disease (covid- ) pandemic resulted in over , cases and over , deaths in the united states. its burden on the healthcare system cannot be overstated. the pandemic has led to drastic changes in the delivery of health care: the creation of additional surge capacity for covid- patients, and in oncology specifically, changes in work schedules and roles, rapid implementation of telehealth, delays of procedures, treatments, and ambulatory visits, suspension of clinical trials, changes in endof-life care, and implementation of policies on the usage of personal protective equipment (ppe). additionally, while cancer is considered a potential risk factor for covid- , it is not yet clear to what extent cancer increases the risk of being infected with covid- , or of developing complication in its disease course, though studies are starting to be published. [ ] [ ] [ ] these many changes and uncertainties in oncology practice affect individuals with cancer and their treating physicians. however, other than a few editorials or commentaries, , no research to date has focused on the emotional well-being of physicians delivering cancer care in the united states. while increased emotional strain and post-traumatic stress symptoms have been reported in covid- frontline healthcare workers [ ] [ ] [ ] , potential effects of the pandemic on other providers, such as oncologists, have received less attention. the drastic change in oncology practice due to covid- and the uncertainty of its impact on the outcome of vulnerable cancer populations may cause significant stress among oncologists. we sought to evaluate the effect of the covid- pandemic on the emotional health of oncology physicians across the united states and explore factors associated with anxiety and depression symptoms. we conducted a cross-sectional anonymous online survey among physicians who treat individuals with cancer in the united states. the study was reviewed and approved by the university of minnesota institutional review all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint board. eligibility criteria included: ≥ years, ability to read/write in english, and being a physician (md or do) currently residing and providing cancer treatment to patients in the united states. individuals were recruited over a two-week period (march , -april , ) using snowball convenience sampling through social media (twitter, facebook, linkedin). survey items included demographics, measures of clinical practice, concerns about covid- , effects of the pandemic on treatment decision-making and practice, and emotional well-being, using redcap for data collection and storage. all questions were optional. we used the patient health questionnaire (phq- ), a brief validated self-report screener to measure symptoms of depression and anxiety over the past two weeks. potentially clinically relevant anxiety and depression symptoms were calculated using established cut-points of participant characteristics and responses were summarized using descriptive statistics, reporting means, standard deviations, and absolute and relative frequencies. we explored the associations of demographic, clinical practice, and covid- related factors with self-reported depression and anxiety by comparing those with and without symptoms using chi-squared tests and fisher's exact tests as appropriate for categorical variables, and t-tests assuming unequal variances for continuous variables. p-values < . were considered statistically significant. data were analyzed using sas . (cary, nc). a total of individuals started the survey; were screened out as not eligible ( not physicians who offer cancer treatments to patients, not practicing in the united states). of eligible participants, ( %) completed the phq- questions for inclusion in this analysis. approximately two-thirds ( . %) of respondents were female and the mean age was . ± . years (table ) . just over half of respondents reported having all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint minor children living with them, with females reporting this only slightly more than males ( . % vs. . %, p= . ). respondents practiced across states with all oncologic specialties represented. physicians reported treating a wide range of cancer types; the most common cancers treated were breast ( . %), colon ( . %), melanoma ( . %), rectal ( . %) and pancreatic ( . %). more than half practiced in an academic setting, in a large city or its suburb, and at large or medium sized hospitals. most ( . %) respondents were practicing in states with at least , confirmed covid- cases at the time of the survey ( table ). the majority ( . %) reported being moderately or extremely concerned about getting covid- and . % considered themselves to be at high-risk for developing serious illness from covid- . physicians reported covid- had affected their ability to provide treatment to cancer patients to a moderately severe degree ( . ± . ; severity range - ). a majority were moderately or extremely concerned about transmitting covid- to a patient ( . %) and the inability for their patients to receive the adequate level of care for a severe illness other than covid- ( . %). almost two-thirds ( . %) of oncology physicians in this study reported anxiety symptoms (table ) . demographic characteristics associated with anxiety included being female, younger age, and fewer years in clinical practice. further, many items related to perceived covid- risks were associated with anxiety, including practicing in a state with > covid- cases ( . % vs. . %, p= . ) or having inadequate ppe access ( . % vs. . %, p= . ). almost one-quarter ( . %) of respondents reported depression symptoms. while approximately a third who reported anxiety symptoms also reported depression symptoms ( . %), almost all who reported depression symptoms were also anxious ( . %). asian-indian physicians were more likely to report depression ( . %) than non-hispanic white ( . %) or other race/ethnicity physicians ( . %; p= . ). both anxiety and depression were associated with being moderately or extremely concerned about getting covid- , transmitting it to a family member or a patient, or inability for a patient to access an adequate level of care for a serious non-covid- related illness (all p< . ). all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint oncology physicians report significant anxiety and depression symptoms during the covid- pandemic in the united states. importantly, the perceived degree of interference with clinical practice along with personal concerns about covid- were significantly associated with both anxiety and depression. previous studies from wuhan, china have shown evidence of the high prevalence of distress, anxiety, and depression in covid- "frontline" personnel, including nurses and physicians. , risk factors for emotional health symptoms included female sex, nursing profession, working on the "frontline," and working in wuhan, china. while it is not difficult to explain the pandemic's effects on the mental health of frontline healthcare workers, it is equally important to understand how the physician-based workforce and hospital care capabilities for other specialties have been affected. oncology physicians have historically been more susceptible to burnout. and could be at even higher risk of distress during a crisis such as covid- . wu et al. recently published a comparison of oncology physicians and nurses who were either working in oncology or dispatched to the "frontline". those continuing to work in their usual capacity with uninfected cancer patients surprisingly had a greater frequency of burnout symptoms. our findings of high anxiety among oncologists and the association of these symptoms with concerns about covid- and patients getting adequate care for non-covid- conditions are consistent with that study. strengths of this study include the national sample of oncologists treating a wide range of cancers at a time the pandemic was evolving in the united states. limitations include its survey-based design, social media recruitment, and high proportions of surgeons and females; these respondents may not fully represent all oncologists practicing in the united states. we also chose to focus on physicians as they are heavily involved in treatment decision-making for oncology patients, however, we would expect similar results for advanced practice providers in oncology settings as well. these data may also under-report emotional symptoms due to all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint social desirability bias. finally, we do not know the rates of anxiety and depression among these oncologists prior to the pandemic and cannot infer these high rates were directly caused by the pandemic. the prevalence of anxiety-related symptoms we observed among oncology physicians in the united states is alarming. these findings support a recent call to action to address burnout, prior to the pandemic, to protect the mental health of all oncologists in order to preserve their ability to deliver high quality and efficient care to cancer patients at a time of unprecedented uncertainty . further studies are needed to identify the sources of psychological distress and assess the efficacy of interventions for physicians during and after the covid- pandemic. we have made tremendous strides in cancer care over the past few decades and to lose oncologists to burnout and its sequelae will be an extra insult to the already tragic situation of cancer and covid- . all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . https://doi.org/ . / . . . doi: medrxiv preprint all rights reserved. no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted june , . . centers for disease control and prevention managing cancer care during the covid- pandemic: agility and collaboration toward a common goal cancer patients in sars-cov- infection: a nationwide analysis in china risk of covid- for patients with cancer covid- and cancer: lessons from a pooled meta-analysis between scylla and charybdis -oncologic decision making in the time of covid- . the new england journal of medicine understanding and addressing sources of anxiety among health care professionals during the covid- pandemic impact on mental health and perceptions of psychological care among medical and nursing staff in wuhan during the novel coronavirus disease outbreak: a crosssectional study factors associated with mental health outcomes among health care workers exposed to coronavirus disease a comparison of burnout frequency among oncology physicians and nurses working on the front lines and usual wards during the covid- epidemic in wuhan research electronic data capture (redcap) -a metadata-driven methology and workflow process for providing translational research informatics support an ultra-brief screening scale for anxiety and depression: the phq- the patient health questionnaire- : validity of a two-item depression screener anxiety disorders in primary care: prevalence, impairment, comorbidity, and detection addressing burnout in oncology: why cancer care clinicians are at risk, what individuals can do, and how organizations can respond a call to action: ethics committee roundtable recommendations for addressing burnout and moral distress in oncology no reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity key: cord- - hc lbi authors: jamieson, denise j.; ellis, jane e.; jernigan, daniel b.; treadwell, tracee a. title: emerging infectious disease outbreaks: old lessons and new challenges for obstetrician-gynecologists date: - - journal: american journal of obstetrics and gynecology doi: . /j.ajog. . . sha: doc_id: cord_uid: hc lbi objective the purpose of this study was to summarize recent high-profile infectious disease threats that have affected the united states: severe acute respiratory syndrome, west nile virus, and anthrax. study design a systematic review was conducted with the use of medline searches, searches of the centers for disease control and prevention website, and review by experts at the centers for disease control and prevention. results the emerging infectious diseases pose very different threats: severe acute respiratory syndrome is a newly identified pathogen that caused an international pandemic; the west nile virus investigation involved an old pathogen that was identified in a new location; and the anthrax attacks involved the intentional introduction of a pathogen. conclusion all outbreaks highlight the importance of obstetrician-gynecologists keeping current with new information as it emerges. in this global environment, it is likely that novel disease threats will continue to emerge in the united states. the long and prominent role of infectious diseases in obstetrics and gynecology is well documented. references to puerperal sepsis date back to hippocrates' time, with his writings containing references to ''childbed fever.'' epidemics of puerperal sepsis at lying-in hospi-tals were not uncommon throughout the th and th centuries. thanks to the astute clinical observations of physicians such as dr oliver wendell holmes and dr ignaz semmelweis, by the end of the th century, the importance of hand washing and aseptic technique in obstetrics was recognized and contributed to substantial declines in puerperal sepsis rates. , with the advent of effective antibiotic therapy in the s, deaths from puerperal sepsis further declined. throughout most of the th century, overall infectious disease mortality rates declined precipitously because of numerous developments in medicine and public health, which included dramatic improvements in the safety of the water and food supply; advances in vector control, sanitation, and housing; the development of effective and available vaccinations; and the introduction and widespread use of antibiotics. the nation's overall success in combating infectious diseases led to widespread optimism that infectious diseases no longer posed a credible threat to health. this sentiment was summarized by surgeon general william stewart in who stated that ''the time has come to close the book on infectious diseases. we have basically wiped out infection in the united states.'' however, this optimism was short-lived. by the end of the th century, it was clear that infectious disease morbidity and death, whether naturally occurring or intentionally inflicted, were still very much with us. at the turn of the st century, we are faced with an emergence of new infectious disease threats within medicine, many of which may directly or indirectly affect the practice of obstetrics and gynecology. the emergence and spread of microbial threats is driven by a complex set of factors that includes the evolution of microbes under selective pressures; changes in climate, weather, and ecosystems; increased speed and scope of global travel and commerce; alterations in human susceptibility; and in some cases, criminal intent to harm. in , the centers for disease control and prevention (cdc) launched a plan to ''combat today's infectious diseases and prevent those of tomorrow'' with the publication of their report titled, ''addressing emerging infectious disease threats: a prevention strategy for the united states.'' this strategy, updated in , outlines a plan for building ''a stronger, more flexible us public health system that is well-prepared to respond to known disease problems, as well as to address the unexpected, whether it is an influenza pandemic, a disease caused by an unknown organism, or a bioterrorist attack.'' there is a clearly defined role for obstetriciangynecologists in the strategy to address emerging infectious diseases in the united states. in fact, diseases of pregnant women and newborn infants are of the areas that are targeted specifically in the cdc plan. in their role as frontline clinicians, they may be among the first to encounter patients with novel infectious diseases. for example, of the patients with lab-confirmed severe acute respiratory syndrome (sars) in the united states were pregnant women. as demonstrated by the clinical examples outlined later, astute clinicians are often responsible for first detection of clusters of infection or unusual presentations that prove to be emerging infectious diseases. furthermore, frontline clinicians such as obstetrician-gynecologists are a critical control point in the control and prevention of infectious diseases. they must know how to rapidly gather data and respond appropriately, and they may be required to respond rapidly to inquiries from their patients, particularly when the outbreak of the emerging infectious disease receives widespread media attention. in addition, they may need to address infectious disease risks within their practices, such as the isolation of clinic patients with rash or respiratory symptoms. this systematic review summarizes recent, highprofile infectious disease threats that have affected the united states: ( ) sars, ( ) west nile virus, and ( ) anthrax. for each of these infectious disease threats, this review provides a narrative of how and why this infection emerged and was identified and includes the role of individual clinicians and public health professionals. specific concerns for obstetrician-gynecologists that include issues that are relevant for pregnant women are addressed. relevant literature in the infectious diseases of interest was identified by searching medline ( medline ( - with the following key words (last accessed: : sars, west nile virus, and anthrax. the search was limited to english language. these searches identified , , and citations, respectively. the titles of all articles were reviewed by of authors (j.e.e.; d.j.j.), and the relevant articles were reviewed in more detail (ie, abstract and/or full manuscript). to ensure that articles that focus specifically on pregnancy issues were not overlooked, combinations of the following key words were also searched with pubmed: sars and pregnancy; west nile virus and pregnancy; and anthrax and pregnancy. for these searches, non-english articles were included, if the abstract was in english. these searches resulted in , , and articles for sars, west nile virus, and anthrax, respectively. the full manuscripts for all of these articles were read and reviewed. morbidity and morality weekly reports were searched by title on the cdc website (www.cdc.gov/ mmwr) with the same keywords (sars, west nile virus, and anthrax), which resulted in , , and mmwr publications, respectively. the summaries from these manuscripts were reviewed, and relevant articles were read and reviewed in full. cdc experts for each of the outbreaks of interest reviewed the manuscript and the references that were cited to identify any potential omissions. although an extensive literature search was undertaken for this systematic review, this review is not meant to summarize all that is known about the infectious diseases that are covered. rather, it is meant to provide a brief summary of the outbreaks to orient the reader and to highlight some lessons learned and to focus on some important aspects of the outbreaks that are of particular relevance for practicing obstetrician-gynecologists. on february , , a -year-old physician who was traveling from the guangdong province of china spent night on the ninth floor of what came to be known as ''hotel m'' in hong kong. this physician, who had been providing care for patients in guangdong province where an outbreak of respiratory disease among approximately patients had been reported, had been ill for approximately week with similar respiratory symptoms. [ ] [ ] [ ] at least guests of this hotel, including guests who also stayed on the ninth floor of ''hotel m,'' became infected with the mysterious respiratory disease, which was later named sars. these infected hotel guests then traveled on to other countries and transported the disease with them, effectively serving as index patients for the outbreaks of sars in a variety of countries, which included vietnam, singapore, canada, ireland, and the united states. , , , within months, o cases of sars and o deaths in countries would be reported to the world health organization (who) and represented the first pandemic of the st century. because of unprecedented international scientific, medical, and public health collaboration and cooperation, the global response to sars was extraordinarily rapid and effective , ; by july , , the who had announced that the global outbreak of sars had been contained. because of the potential for rapid international spread of sars, a rapid, effective, and coordinated global response was required. within the first weeks of march, the who established a multicenter laboratory network for the study of sars. by the third week in march, a novel coronavirus was identified in patients with sars. , shortly thereafter, the full genome of the sars-associated coronavirus was mapped, and it was announced that this coronavirus was the causative agent of sars. , in the meantime, under the leadership of the who, teams of epidemiologists from a wide variety of international agencies including the us cdc were dispatched around the world to investigate the origins, transmission, clinical characteristics, and risk factors for sars. based on epidemiologic data, including seroprevalence studies, strong evidence emerged that suggested that caged, exotic animals that are sold in markets in guandong province served as the likely source of the sars coronavirus, which then spread to persons who were handling and selling these animals. , , the primary mode of sars transmission was identified as contact with large respiratory droplets from symptomatic individuals. , however, initial infection control recommendations accounted for potential airborne transmission as well. therefore, a multifaceted approach to disease control was required, and a wide variety of infection control measures were instituted rapidly. [ ] [ ] [ ] in the healthcare setting, infection-control practices were enhanced and included provision of personal protective equipment and training of healthcare workers in respiratory and hand hygiene. specifically, healthcare workers should wear gloves, gown, mask, and eye protection. these recommendations combine elements of contact, droplet, and airborne infection-control precautions. additionally, patients with sars were grouped together and isolated in the hospital. ideally, sars patients should be placed in private rooms, which maintain the negative pressure, and the number of healthcare workers who care for the patient and the number of visitors should be limited. in some places, specifically designated clinics and hospitals were set up to care only for patients with sars. , , , it is important for healthcare workers to be aware that viremia with sars coronavirus peaks later in the illness course than other similar-appearing respiratory infections, such as influenza. this means that the transmission of sars may be more likely to days after illness onset at the point at which a sarsinfected patient requires hospital admission and in some cases intubation. to control transmission in the larger community, public education, contact tracing and quarantine of contacts, surveillance at border crossings (such as health declaration forms and fever monitoring), and travel advisories and restrictions were instituted. in mid march, the who issued an unprecedented emergency global travel advisory that recommended postponement of all but essential travel to high-risk sars areas. in addition to the epidemiologic descriptions, the clinical course of sars also was elucidated rapidly. , , , , , , [ ] [ ] [ ] [ ] [ ] infected persons typically experience the rapid onset of fever and other prodromal symptoms (such as myalgia, malaise, and headache). a nonproductive cough is also common, and shortness of breath generally develops later. the presence of rhinorrhea makes the diagnosis of sars less likely. other findings that are characteristic of sars include lymphopenia and elevated lactate dehydrogenase levels and pulmonary infiltrates on chest imaging. a patient's condition may deteriorate rapidly, exhibiting oxygen desaturation and adult respiratory distress syndrome, and require ventilatory support. in patients with suspected sars, a workup for known causes of communityacquired pneumonia should be performed, and specimens should be collected for sars testing. serum samples from patients with sars often show appropriate acuteand convalescent-phase immunoglobulin g antibodies with a sars-specific enzyme-linked immunosorbent assay. standard regimens for community-acquired pneumonia should be instituted, and supplemental oxygen should be used as needed. the patient's condition may deteriorate rapidly because of progressive respiratory failure and may require admission to an intensive care unit and mechanical ventilation. although the antiviral drug ribavirin has been used extensively to treat sars outside the united states, there are no data that demonstrate its efficacy. , because ribavirin is known to be teratogenic and embryocidal in animal studies, ribavirin is not recommended for treatment of sars in pregnant women. although there were reports of pregnant women with sars from several countries, the number of reported cases is too small to permit any definitive conclusions as to whether sars was more or less severe among pregnant women as compared with nonpregnant women. among the cases of sars that have been reported among pregnant women, there were no reports of perinatal transmission of sars. [ ] [ ] [ ] [ ] [ ] [ ] the largest case series of pregnant women with sars was from hong kong; pregnant patients, including pregnant healthcare workers, with sars were admitted to public hospitals in hong kong. three of the pregnant patients with sars died, for a case fatality rate of %. seven of the pregnant women with sars were infected in the first trimester, and of the women were infected in the second or third trimester. among the women who were infected in the first trimester, women had spontaneous abortions, and women had induced abortions. of the women who were infected later in pregnancy, women underwent preterm cesarean delivery ( - weeks of gestation) for worsening maternal hypoxemia; of the women who underwent cesarean delivery subsequently died. although the number of evaluated patients was small, pregnant women with sars were more likely to require admission to the intensive care unit, to experience renal failure and disseminated intravascular coagulopathy, and to die than nonpregnant control subjects. followup information was reported for the liveborn infants who were born to pregnant women who were infected with sars during the second or third trimesters. there was no clinical or laboratory evidence of sars among the infants, despite a systematic search for perinatal transmission that included serial reverse transcriptasepolymerase chain reaction assays, viral cultures, and paired serologic titers. there were also cases of pregnant women with sars from mainland china , and cases from the united states. , , notably, of the persons with laboratory-confirmed sars in the united states were pregnant women. a -year-old pregnant woman at weeks of gestation had traveled from the united states to hong kong and then to guangdong province to visit family members. she stayed on the same floor of ''hotel m'' during the same time as the year-old ill physician who is credited with infecting the other guests. on return to the united states, she was hospitalized for pneumonia and required mechanical ventilation. serum specimens were positive for the sars coronavirus antibody. she was delivered at weeks of gestation by cesarean delivery for placenta previa. the infant appeared uninfected by sars, although specimens were not obtained for testing. , the second case involved a -year-old woman at weeks of gestation who also traveled to hong kong during the sars epidemic. after recovering from her illness, she had a relatively unremarkable pregnancy. at weeks of gestation, she had preterm labor and spontaneous rupture of membranes and underwent an emergency cesarean delivery because of fetal distress. the infant appeared normal, and no virus was detected in stool samples. for obstetrician-gynecologists, there are several important lessons from the sars pandemic. although the united states was spared relatively during this outbreak, the global response to this outbreak may provide important clues about how to respond to future health threats. during an outbreak of a disease like sars in which nosocomial spread plays an important role, the implications for a busy obstetric unit that provides urgent medical care on a -hour basis to primarily healthy pregnant women and their newborn infants are enormous. staff from several large obstetric units in toronto , and hong kong [ ] [ ] [ ] provided detailed reports about the challenges that they faced responding to sars, an emerging infectious disease about which very little was known. in a toronto hospital, the timing was ideal because the obstetrics unit was able to move into a newly designed facility with separate entrances, elevators, and air handling systems. staff were instructed to use appropriate personal protective equipment (masks, face-shield or eye protection, gown, non-latex gloves), and all patients and visitors wore masks. in addition, visitors were limited to visitor during labor and delivery, and no visitors were allowed after the delivery. the length of the postpartum stay was decreased, and after discharge women were instructed to stay at home under quarantine for days. all physicians and healthcare workers were asked to observe work quarantine and were allowed to go directly to work and home with minimal contact with the public. , in hong kong, obstetric services were transferred to a hospital that was separate from where sars cases were being treated. women were discharged sooner after delivery, and all nonessential obstetric services (such as routine ultrasound examinations and prenatal diagnosis) were suspended temporarily. [ ] [ ] [ ] the basic principles of the responses in toronto and hong kong included keeping healthy pregnant women away from potentially infectious sars cases. in august , a physician in queens was caring for patients who had been hospitalized with encephalitis and muscle weakness. because of concerns about the unusual nature and pattern of the illness, the physician contacted the local health department. the health department followed up and found additional cases of similar illness in the area, and further investigation revealed several interesting epidemiologic clues: the patients lived within a square mile area of each other; all of the patients participated in outdoor activities such as gardening in the evenings, and culex mosquito breeding sites and larvae were found in the patients' yards and neighborhoods. further surveillance of local hospitals revealed a total of patients who had been hospitalized with a similar illness. subsequently, west nile virus was isolated both in birds in this area and in the ill patients. the rapid identification and control of this outbreak, which represents the first recognized outbreak of west nile virus in the western hemisphere, is a tribute to the astute observations of a front-line clinician combined with the rapid response of the public health system. as described in the editorial accompanying the case series of the patients who were hospitalized with west nile virus in new york city, ''the discovery that a cluster of cases of encephalitis in the new york city area in the summer of was caused by the west nile virus, was a masterstroke of medical detection, combining features of a berton roueche story, a michael crichton novel, and alfred hitchcock's the birds.'' west nile virus is a single-stranded mosquito-borne flavivirus with a predilection for the human nervous system, which accounts for the neurologic sequellae often associated with infection. the virus was identified originally in the west nile region of uganda in . a variety of bird species serve as the natural reservoir for the virus, and the virus is transmitted to humans by mosquitoes that bite both birds and humans. since the first reports in , west nile virus has now spread to at least states and has accounted for o , reported cases. [ ] [ ] [ ] most individuals who are infected with the virus are either asymptomatic or experience a mild illness, typically with symptoms of headache, fever, and rash. a small proportion (approximately %) of infected individuals will have severe disease that includes encephalitis, meningitis, or acute flaccid paralysis. laboratory diagnosis is based on serologic evidence; immunoglobulin m (igm) antibody to west nile virus can be detected in the blood or cerebrospinal fluid. because igm does not readily cross the blood-brain barrier, detection in the cerebrospinal fluid is diagnostic of west nile virus meningoencephalitis. however, there is some cross-reactivity with other flaviviruses, such as st. louis encephalitis virus. despite a variety of antiviral and other agents that have been used empirically, there is currently no known effective treatment for infection with west nile virus. therefore, treatment is generally supportive. , west nile virus and pregnancy a probable case of intrauterine transmission and a possible case of transmission from breastfeeding have been reported. a -year-old woman at weeks of gestation was hospitalized with severe headache and fever and subsequently experienced weakness and pain in her legs with documented involvement of the lower motor neurons on electromyelography. west nile virusspecific igm antibodies were detected in her serum and cerebrospinal fluid. at weeks of gestation, she was delivered of a live infant with bilateral chorioretinitis and cystic destruction of cerebral tissue. igm antibodies were detected in the infant's serum and cerebrospinal fluid. one of laboratories detected west nile virus in placental samples. , these findings are consistent with transplacental transmission of west nile virus from the mother. although other possible reasons for these congenital abnormalities were not detected, a causal relationship between the neurologic abnormalities and the west nile virus infection has not been proved. although several other cases of documented west nile virus infection during pregnancy have been reported, none of these other reports have documented transplacental transmission. [ ] [ ] [ ] in some cases, the workup of the infants after birth was not complete. for example, a woman with a history of chronic hypertension and sickle cell trait was diagnosed at weeks of gestation with west nile virus meningoencepalitis. her pregnancy was further complicated by superimposed preeclampsia, and delivery was induced at weeks of gestation for fetal growth restriction. at birth, the infant appeared normal and did well clinically, although no serologic testing of the infant for west nile virus was performed. in this case, the mother may have been at greater risk for complications from infection with west nile virus because of her underlying medical conditions. for example, hypertension may facilitate the passage of the neurotropic west nile virus across the blood-brain barrier and result in increased rates of menigoenchephalitis. it is also likely that the hypertension contributed to the fetal growth restriction, although it is possible that fetal infection with west nile virus also may have contributed to the impairment of fetal growth. in addition to transplacental transmission, a probable case of breastfeeding transmission has also been reported. shortly after delivery, a woman in michigan required a postpartum blood transfusion and received units of packed red blood cells from a donor who was infected with west nile virus. nine days after receiving the contaminated blood, the woman experienced west nile virus meningoencephalitis that was documented by west nile virus-specific igm from cerebrospinal fluid. the woman breastfed her infant for the first days after delivery, and west nile virus was isolated from her breastmilk on day . although the infant remained asymptomatic, west nile virus-specific antibody was isolated from the infant, which suggests likely west nile virus transmission through breastfeeding. transmission of west nile virus through blood transfusion has been well documented. , clinicians who care for patients with encephalitis after blood transfusion should consider west nile virus, and, if it is identified, immediately should notify public health officials to initiate measures to prevent additional cases. to avoid west nile virus infection, the cdc recommends that pregnant women avoid exposure to mosquitoes, including wearing protective clothing and avoiding outdoor activities during peak mosquito feeding times, usually dawn and dusk. in addition, pregnant and lactating women should use insect repellant that contains n,n-diethyl-m-tolumide (deet). when used according to the labeling instructions, deet can be used safely by pregnant and lactating women. safety information about deet comes largely from animal toxicity studies and from a malaria clinical trial in thailand in which pregnant women applied deet daily and no serious maternal or neonatal adverse effects were reported. for pregnant women with unexplained fever, mental status changes, meningitis, encephalitis, or acute flaccid paralysis, obstetrician-gynecologists should consider the diagnosis of west nile virus and should test maternal samples for west nile virus (serum and cerebrospinal fluid, if indicated). however, screening of asymptomatic pregnant women is not recommended. if west nile virus infection in pregnancy is diagnosed, the case should be reported to the health department and the cdc. the cdc has set up a registry for pregnant women who have been infected with west nile virus; since , the cdc has been tracking o infected pregnant women. during pregnancy, a detailed ultrasound examination of the fetus to evaluate for structural abnormalities should be considered no sooner than to weeks after the onset of symptoms. after birth, the infant who is born to a woman who was infected with west nile virus during pregnancy should be evaluated thoroughly. the cdc recommends that this neonatal workup include the following procedures: thorough physical examination that includes comprehensive neurologic assessment and a hearing examination; testing serum of the infant for west nile virus-specific igm and igg antibodies; examination of placenta by a pathologist; and storage of the entire placenta, a portion of the umbilical cord, and umbilical cord serum. in cases of spontaneous or induced abortion, it is recommended that products of conception be tested for evidence of west nile virus infection. although anthrax is believed to be one of the egyptian plagues at the time of moses, this ancient disease was not very active in the arena of modern medicine until relatively recently. the anthrax attacks of changed the us experience with anthrax and rapidly accelerated scientific knowledge and medical expertise in this area. in the fall of , letters that contained anthrax spores were mailed to several locations through the us postal service. on october , , the first recognized case of inhalational anthrax in the united states since the s was reported; a -year-old man who had been exposed to a contaminated letter was hospitalized in palm beach county, florida. this was the first documented case of anthrax in the united states to result from an intentional human act. at least letters with bacillus anthracis spores were sent to florida, new york city, and washington dc - that resulted in the contamination of postal facilities, us senate offices, and other locations and resulted in confirmed or probable cases of anthrax and deaths. , as a result of the anthrax attacks, o , people received antibiotics for possible exposure to anthrax spores. the cdc recommends either ciprofloxacin or doxycycline orally for days for postexposure prophylaxis to b anthracis spores. anthrax is an infection caused by b anthracis, an aerobic, spore-forming, nonmotile, gram-positive rod. because of their resistance to drying, heat, ultraviolet light, gamma radiation, and many disinfectants, the spores have been developed as biologic weapons by a number of nations. a bioweapons factory in the former soviet union accidentally released anthrax spores in , which resulted in at least cases of anthrax and deaths. there are at least clinical manifestations of anthrax: cutaneous, inhalational, and gastrointestinal. naturally occurring anthrax results from contact with anthrax-infected animals or animal products; the disease most commonly occurs in grazing animals that are infected after ingesting spores from the soil. , once inhaled, the b anthracis spores are deposited in alveolar spaces where they are engulfed by macrophages. the engulfed spores are then transported to the pulmonary lymphatics where they germinate. the initial symptoms of inhalational anthrax resemble those of a viral upper respiratory tract infection, typically with fever, nonproductive cough, headache, myalgias, and malaise. , the second stage of illness is often characterized by the rapid onset of dyspnea, respiratory failure, massive septicemia, and the development of hemorrhagic thoracic lymphadenitis and mediastinitis, which often can be visualized on chest imaging as a widened mediastinum. case fatality rates with inhalational anthrax are high and require the prompt initiation of aggressive antibiotic treatment. the cdc guidelines for treatment of inhalational anthrax include combination therapy with doxycycline or ciprofloxacin in conjunction with another active antimicrobials such as clindamycin for days. accurately diagnosing anthrax requires a high index of suspicion on the part of the clinician, because patients initially have flu-like ''illness.'' during the anthrax attacks of , the observations of a number of astute frontline clinicians and laboratory workers led to the rapid and correct diagnoses that allowed many others to receive rapid prophylaxis and treatment. for example, the diagnosis of the index case in west palm beach county was facilitated by the observations of an astute clinician who suspected anthrax on the basis of large gram-positive bacilli in the cerebrospinal fluid of a patient with a clinical course that was compatible with inhalational anthrax and by the subsequent analysis by laboratory staff who recently had undergone bioterrorism preparedness training. the clinical and epidemiologic details of this index case were disseminated rapidly through the media, the internet, and public health agencies such as the cdc. the worldwide literature that describes cases of anthrax in pregnancy is limited. two cases of cutaneous anthrax in the third trimester have been described in turkey in . a -year-old woman at weeks of gestation experienced a submandibular eschar with extensive edema. she had reported flaying a cow the previous week. she was treated presumptively with penicillin and prednisolone and recovered within days. b anthracis was isolated subsequently from the lesion. she was delivered of a healthy infant at weeks of gestation. a -year-old woman at weeks of gestation had a weeping lesion on her right elbow from which b anthracis was later identified. she was treated with penicillin and recovered. she was delivered of a healthy infant at weeks of gestation. although both these cases resulted in spontaneous preterm delivery shortly after infection, a causal link between anthrax infection in pregnancy and preterm delivery cannot be made on the basis of these descriptive cases. at least cases of intestinal anthrax in pregnancy have been reported. a -year-old pregnant indian woman experienced gastrointestinal symptoms and abdominal distention after ingesting improperly cooked beef. fluid from peritoneal lavage revealed b anthracis. despite antibiotic treatment and supportive care, the woman died hours after admission. in iran, a -year-old woman had abdominal pain and distension at - weeks of gestation. she underwent surgery for a presumptive diagnosis of ruptured ovarian cyst. at the time of surgery, massive edema of the intestines, ascites, and a large retroperitoneal hemorrhage were noted; the patient died hours after surgery. b anthracis was isolated subsequently from intestinal tissue and from the ascites. it was assumed that this woman, who handled sheep and goats, contracted gastrointestinal anthrax from ingestion of contaminated meat. the correct diagnosis was missed because of her pregnancy. an unusual case of fatal anthrax infection of the uterus was also reported from iran. it is thought that the anthrax was introduced into the uterus by an attempt at illegal abortion with a dirty stick. during the anthrax attacks of , recommendations about how to implement postexposure prophylaxis regimens for asymptomatic pregnant women needed to be developed rapidly. the cdc guidelines for prophylaxis evolved during the outbreak and require that clinicians and public health officials consult the cdc website for regular updates. both the american college of obstetricians and gynecologists and the cdc recommend that asymptomatic pregnant and lactating women with exposure to b anthracis receive days of antibiotic prophylaxis, as recommended for nonpregnant adults. the antimicrobial of choice is ciprofloxacin, a fluoroquinolone. although fluoroquinolones are not used generally during pregnancy and lactation because of a possible association with arthropathy in animal studies, therapeutic doses of ciprofloxacin are unlikely to pose a substantial teratogenic risk. , in instances in which the specific b anthracis strain has been shown to be penicillin-susceptible, initiating or changing to prophylaxis with amoxicillin can be considered. doxycycline should be used with caution in pregnant women because it may cause fetal toxic effects such as defective dental enamel and depressed bone growth. in addition, the use of doxycycline in pregnant women infrequently has been associated with hepatic necrosis. however, the risks of anthrax must be balanced against the risks of doxycycline; in some cases, the use of doxycycline in pregnant women may be appropriate. , , an inactivated cell-free anthrax vaccine that has been shown to confer immunity in animal models has been licensed for use in the united states since . in it was mandated that all us military personnel receive it because of concerns about potential exposure to anthrax from biologic weapons. in march , this vaccination program was curtailed because of a shortage of vaccine, because there is only manufacturing facility in the united states. currently, only those military personnel who are assigned to high-threat areas routinely receive the vaccine. in addition, the vaccine can be used as an adjuvant to postexposure regimens. in terms of safety of vaccine for women of reproductive age, a recent report analyzed pregnancy rates and adverse birth outcomes among women at military bases in georgia. among women, at least women received at least dose of anthrax vaccine. there was no significant difference in pregnancy rates or adverse birth outcomes between vaccinated and unvaccinated women. however, with only pregnancies, there was inadequate power to detect differences in adverse birth outcomes. in addition, the department of defense used computerized medical records to conduct a preliminary evaluation of the use of anthrax vaccine in the first trimester of pregnancy. because of limitations in the medical record system, it was determined that a more systematic evaluation with the use of original medical records would be required before conclusions could be drawn. in the meantime, the department of defense policy continues to exclude pregnant women from anthrax vaccination programs. the emerging infectious disease threats that are described in this systematic review pose very different and novel health threats: sars is a newly identified pathogen that caused an international pandemic; the west nile virus investigation involved an old pathogen that was identified in a new location; and the anthrax attacks involved the intentional introduction of a pathogen. sars and west nile virus highlight the importance of international travel and commerce in the spread of disease. the identification of west nile virus highlights the importance of astute clinicians recognizing and responding to unusual disease patterns. all outbreaks highlight the importance of obstetrician-gynecologists and other clinicians keeping up-to-date with new information as it emerges. it is interesting to note that some of the same strategies that were identified by the work of dr semmelweis and others, such as hand hygiene, are as effective today for the prevention of the transmission of emerging infections like sars as they were for the prevention of puerperal sepsis in the th century. for obstetrician-gynecologists, the basic approach to the appreciation of a novel or emerging infection should be similar to the approach that is taken with any patient, that is taking a careful history and performing a complete physical examination, evaluating the patient frequently, and always keeping a high degree of clinical suspicion, particularly when something about the clinical picture just does not seem ''right.'' although a clinician may not pick up that ''something is just not right'' on the first time seeing the patient, the clinical picture will evolve over time. it may be that a patient does not respond to therapy as expected or that additional information that was missed initially begins to emerge (eg, recent travel, sick contacts, unusual pets, hobbies, activities). unusual patterns of disease, such as atypical patterns of person, place, and time, may be clues to clinicians that a novel disease or intentional act of bioterrorism may be involved. for example, influenzalike illness in the summer (unusual timing of disease) or an outbreak of chickenpox among adults (unusual persons involved) may be clues that point to alternate diagnoses or explanations. during an outbreak, the cdc offers interim guidance on diagnosis, treatment, and other clinical information for clinicians that is reviewed regularly and updated on the internet (www.cdc.gov). information about specimen collection and availability of diagnostic testing can also be found on the cdc website. physicians who detect unusual clusters of disease are encouraged to first contact their local or state health department, which may then also contact the cdc for further information or assistance. in addition, there are also two -hour telephone hotlines for physicians: one hotline with general information about a variety of current health topics ( - - ) and one hotline for communicating with the cdc director's emergency operations center, which is set up for reporting urgent health emergencies or unusual clusters of illness ( - - ). in this global environment, it is likely that novel disease threats will continue to emerge in the united states. as primary providers of healthcare for women, obstetrician-gynecologists will likely be called on to assist in responding to and controlling these threats to public health. practicing obstetricians and 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systemic findings west nile virus meningoencephalitis during pregnancy west nile virus encephalitis during pregnancy west nile virus infection: a pediatric perspective west nile virus infection transmitted by blood transfusion transmission of west nile virus from an organ donor to four transplant recipients interim guidelines for the evaluation of infants born to mothers infected with west nile virus during pregnancy deet: a review and update of safety and risk in the general population deet-based insect repellents: safety implications for children and pregnant and lactating women safety of the insect repellent n,n-diethyl-mtoluamide (deet) in pregnancy index case of fatal inhalational anthrax due to bioterrorism in the united states death due to bioterrorism-related inhalational anthrax: report of patients bioterrorism on the home front: a new challenge for american medicine clinical presentation of inhalational anthrax following bioterrorism exposure: report of surviving patients anthrax as a biological weapon, : updated recommendations for management investigation of bioterrorism-related anthrax, united states, : epidemiologic findings update: investigation of bioterrorism-related anthrax and adverse events from antimicrobial prophylaxis anthrax crisis in washington dc: pharmacists' role in screening patients and selecting prophylaxis anthrax as a biological weapon: medical and public health management: working group on civilian biodefense update: investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy anthrax during pregnancy: case reports and review anthrax peritonitis case records of the pahlavi hospitals updated recommendations for antimicrobial prophylaxis among asymptomatic pregnant women after exposure to bacillus anthracis management of asymptomatic pregnant or lactating women exposed to anthrax fluoroquinolone toxicity profiles: a review focusing on newer agents teratogenic effect of drugs: a resource for clinicians teris safety of the new quinolones in pregnancy updated recommendations for antimicrobial prophylaxis among asymptomatic pregnant women after exposure to bacillus anthracis relationship between prepregnancy anthrax vaccination and pregnancy and birth outcomes among us army women status of us department of defense preliminary evaluation of the association of anthrax vaccination and congenital anomalies epidemiologic clues to bioterrorism key: cord- -y z l ji authors: carter-pokras, o.; hutchins, s.; gaudino, j.a.; veeranki, s.p.; lurie, p.; weiser, t.; demarco, m.; khan, n.f.; cordero, j.f. title: the role of epidemiology in informing united states childhood immunization policy and practice date: - - journal: ann epidemiol doi: . /j.annepidem. . . sha: doc_id: cord_uid: y z l ji one of the ten greatest public health achievements is childhood vaccination because of its impact controlling and eliminating vaccine-preventable diseases (vpds). evidence-based immunization policies and practices are responsible for this success and are supported by epidemiology that has generated scientific evidence for informing policy and practice. the purpose of this report is to highlight the role of epidemiology in the development of immunization policy and successful intervention in public health practice that has resulted in a measurable public health impact: the control and elimination of vpds in the united states. examples in which epidemiology informed immunization policy were collected from a literature review and consultation with experts who have been working in this field for the past years. epidemiologic examples (e.g., thimerosal-containing vaccines and the alleged association between the measles, mumps, and rubella (mmr) vaccine and autism) are presented to describe challenges that epidemiologists have addressed. finally, we describe ongoing challenges to the nation’s ability to sustain high vaccination coverage, particularly with concerns about vaccine safety and effectiveness, increasing use of religious and philosophical belief exemptions to vaccination, and vaccine hesitancy. learning from past and current experiences may help epidemiologists anticipate and address current and future challenges to respond to emerging infectious diseases, such as covid- , with new vaccines and enhance public health impact of immunization programs for years to come. epidemiology is the foundation of effective immunization policy and practice in the united states . epidemiologic methods, such as surveillance of vaccine-preventable diseases (vpds) and vaccination coverage, risk factor identification for both disease and lack of vaccination, community intervention and effectiveness studies, and assessment of access to and quality of vaccination services have contributed to the historic reduction or elimination of many vpds in the united states and the americas. epidemiology has contributed to immunization policy and practice at most levels of the immunization field--from vaccine development to ensuring that vaccines reach those who need them and result in the desired public health impact, disease control, and when feasible, disease elimination. for example, surveillance and studies of childhood infectious diseases provide the basis of morbidity and mortality data used to make j o u r n a l p r e -p r o o f immunization was selected as an example for examination of epidemiology in informing public health policy and practice because childhood immunization is one of the ten greatest public health achievements in the united states--it saves lives and is cost-effective. , - a study of . million children years of age or younger born during - found that routine childhood vaccination prevented million cases of illnesses and , premature deaths from vpds, resulting in a net savings of an estimated $ billion in direct medical costs and $ . trillion in societal costs to the united states. , this paper highlights the role of epidemiology in immunization policy development and public health practice that have led to major reductions in vpds. the success of childhood immunization programs has resulted from coordinated efforts that began with a rigorous science base--including epidemiologic methods and studies--that informed decision-making, led to public health policy, and continues to guide immunization services delivery. the working definition for policy in this paper is one generally used in public health: "a law, regulation, procedure, administrative action, incentive, or voluntary practice of governments and other institutions." this definition can be further summarized as described by torjman: "those decisions that seek to achieve a desired goal that is considered to be in the best interest of all members of society." j o u r n a l p r e -p r o o f through this examination of how epidemiology contributed to the successes, we also highlight lessons learned from immunization policy and practice that may be applicable to other public health programs, particularly those priorities delineated in healthy people . the united states has a robust policy-making apparatus for immunization policy development that supports all stages, from vaccine development to immunization practice. many stakeholders in the public and private sector are engaged at each step--from the consideration of candidate vaccines to vaccination of children once the food and drug administration (fda) (figure ) license new vaccines. many groups share responsibility in program implementation at the state, local, and even the health care office level in order to ensure high vaccination coverage, and reduction and control of vpds. vaccine development requires a large and diverse research infrastructure with funding from public and private sectors that begins by identifying diseases suitable for vaccine development ( figures and ) . once a candidate vaccine is developed, rigorous testing for safety, tolerability, immunogenicity, and efficacy follows with phase i, ii and iii clinical vaccine trials ( figure ). the private sector funds most clinical trials to demonstrate the safety, tolerability, immunogenicity, and efficacy of a candidate vaccine while the public sector funds vaccine development for selected vaccines and establishes priorities for vaccine development. developing new vaccines is an expensive and high-risk proposition, estimated to cost up to $ million dollars per vaccine and is a lengthy process, often taking more than a decade to bring a vaccine from development to market. the fda in the united states plays a key role in j o u r n a l p r e -p r o o f examining a candidate vaccine for its composition and source and the methods used for, and findings from,testing the vaccine's safety, purity and potency. only after the fda reviews and accepts the evidence from these initial steps, will it further examine evidence from human clinical trials about safety, tolerability, immunogenicity, and efficacy for the candidate vaccine in humans after finding a candidate vaccine to be safe and efficacious in humans, fda can then proceed to issue a license for the manufacture and commercial distribution for the vaccine ( figure ). , once the fda approves a vaccine, advisory committees such as the advisory committee on immunization practices (acip) recommend whether a new vaccine targeted for children and adults should be included in its recommended schedules for routine immunization ( figure ). , state and local immunization programs and health care providers play major roles in ensuring that vaccine coverage of a new vaccine quickly reaches high levels, and that established vaccines maintain a high coverage level needed to reduce or control vpds. professional organizations, such as the american academy of pediatrics (aap), the american academy of family physicians (aafp), and the american college of physicians (acp), make recommendations to their members on best practices to ensure high vaccination coverage and, in collaboration with the acip, recommend a schedule of routine immunization. government programs and insurance companies have a major role in the financing of vaccine purchase, and access to those vaccines. insurance companies cover many immunizations through their health care coverage plans. government programs, such as the vaccines for children program (vfc), provide targeted funding to cover costs for all acip-recommended vaccines for uninsured and underinsured children ages years and younger. many stakeholders from federal, state and local agencies, health plans, hospitals, clinics, employers, health care providers and philanthropic organizations play key roles in the implementation and day-to-day operation of the united states j o u r n a l p r e -p r o o f immunization system. the complex infrastructure of laws, regulations, funding streams, and programs continues to be informed by a spectrum of diverse epidemiologic surveillance and studies. we now describe some key elements of the federal agencies and respective advisory committees that inform immunization policy development. the national vaccine program office (nvpo), provides strategic leadership and coordination among federal agencies and other stakeholders to help reduce the burden of preventable infectious diseases. nvpo and national vaccine advisory committee (nvac) were established to comply with section of the public health service act. , nvpo obtains advice from the national vaccine advisory committee (nvac), which recommends approaches to control and prevent human infectious diseases through vaccine development, and provides advice on prevention of adverse reactions to vaccines ( figure ). , one example of nvac's key role was during and after the time of the major measles resurgence of the s was when it issued a call for action to eliminate endemic measles in the united states by using epidemiological evidence to improve childhood vaccination along with simultaneous monitoring of burden of measles. use of scientific evidence by nvac and the advisory committee for immunization practices' (acips') is a strong example of how epidemiology has contributed to the development of evidence-based national policy and has strengthened the immunization system in the united states. , , this example is discussed later in the article. j o u r n a l p r e -p r o o f as mentioned earlier, in the united states, vaccine development is supported by a combination of public and private sector research. in the public sector, the federal government through the united states department of defense, the national institutes of health, and other agencies within the department of health and human services (hhs) funds vaccine development. vaccine manufacturers invest significantly in all phases of vaccine development. the fda is the government regulatory agency that approves vaccines for commercial use. the sponsor of a vaccine submits the required documentation on safety, efficacy, and other aspects of the candidate vaccine to the fda. following internal reviews, the proposal is presented to the vaccines and related biological products advisory committee (vrbpac) (figure ), which then makes recommendations for licensing and additional data requests based on this evidence. the fda administrator makes the decision to approve the candidate vaccine based on the recommendation of the advisory committee. if approved, a vaccine license is issued with specific indications, precautions and contraindications. the advisory committee on immunization practices (acip), provides advice and guidance to the director of the centers for disease control and prevention (cdc) regarding use of vaccines and related agents for control of vaccine-preventable diseases in the civilian population of the united states ( figure ). , once a vaccine is licensed, and following a comprehensive review of the scientific evidence, the acip recommends vaccines for routine use and provides guidance on vaccine administration schedules likely to achieve the best levels of disease protection. years. , [ ] [ ] [ ] the increased availability and recommendations for more childhood vaccines represent remarkable achievements of the maturing immunization system of the united states to prevent vaccine preventable diseases, but have contributed to growing concerns about vaccine safety acceptability. [ ] [ ] [ ] [ ] [ ] the community preventive services task force, established by hhs in , develops guidance on community-based approaches to increase vaccination coverage based on available scientific evidence. , , this taskforce has provided evidence-based guidance for effective community-based approaches to reach and sustain high vaccination coverage ( figure ). effective strategies recommended include "multi-component" efforts such as combining health care system and community interventions together, use of client reminder/recall and provider reminder systems, use of client incentives, use home visits, and implementing state or local school immunization requirements for attendance. from this point on, we use the terms, "surveillance" and "monitoring" interchangeably to refer to the ongoing, systematic collection, analysis, interpretation, and dissemination of data regarding a health-related event for use in public health action to reduce morbidity and mortality and to improve health in contrast to "point in time" epidemiologic studies and outbreak investigation data use. vpds and reports national summaries of notifiable diseases, a regular feature in the mmwr. , cdc also monitors sporadic, endemic, epidemic and pandemic disease incidence overall and among population sub-groups to target and improve disease prevention and control efforts, including national elimination and global eradication initiatives. the recognition that hpv and hepatitis b vaccines can prevent cancer, has led to the inclusion of cancer and more recently precancerous disease surveillance and registries as data sources for monitoring the impact of vaccines in reducing cervical and liver cancer, respectively. [ ] [ ] [ ] [ ] since the s, after the resurgence of measles, the national immunization survey (nis) has been measuring immunization coverage at national and state levels using standardized methods. the nis originally targeted children - months of age, but now includes adolescents in a module designated as nis-teen. , the nis (preschool child) and nis-teen are multi-modal telephone-based surveys of parents with provider verification of immunization records. the nis has been essential in monitoring coverage for new vaccines as they are incorporated into the recommended immunization schedule. ensuring the safety of vaccines is a key component of table, those affected can apply for compensation through a streamlined process that avoids lengthy litigation. , immunization policy, practice, and epidemiology are necessarily intertwined. epidemiology informs policy and strategies to be incorporated into immunization practice through a process j o u r n a l p r e -p r o o f that begins with the consideration of what diseases may be preventable by a vaccine and continues with the identification of evidence-based strategies to effectively ensure high immunization coverage and optimally control or eliminate vpds. the development of childhood vaccines is preceded by collection and analysis of epidemiological data on the incidence of vpd-related conditions, disease morbidity and mortality, and evidence that infection confers protection against recurrence of the disease ( figure ). a recent example of this process related to the severity of varicella disease including mortality among adults in the united states prior to development of the varicella vaccine. also, as we write during the current pandemic, we are seeing unprecedented international scientific efforts to respond to the widespread community transmission of the novel coronavirus, sars-cov- , and the resulting waves of suffering and death related to covid- . these field clinical trials provide efficacy data and additional safety data about candidate vaccines. , these clinical trials are developed using rigorous epidemiologic methods, which include identifying the targeted trial population, randomization of participants to vaccination or placebo/alternative comparator groups, surveillance of the disease targeted by the vaccine, and monitoring of adverse events following vaccine administration. there are many examples of how epidemiologic evidence from vpd surveillance systems and outbreak investigation have contributed to better understanding of vaccine effectiveness and have led to changes in recommendations of vaccine administration. following introduction of a new vaccine, it is necessary to measure its population effectiveness in reducing the incidence of the targeted condition. results from ongoing surveillance of vpds and studies of reported outbreaks also provide opportunities to investigate waning vaccine immunity, reduced vaccine effectiveness, and gaps in vaccination due to missed opportunities to vaccinate during clinical encounters and/or vaccine hesitancy. the contribution of epidemiologic studies is evident, for example, in the development of recommendations for pertussis vaccines. studies of several pertussis outbreaks provided evidence that adults and adolescents were sources of disease transmission to young children, and that previously vaccinated adolescents were responsible for school outbreaks because of waning immunity. these findings led to additional child dose recommendations and the development of a new acellular vaccine booster recommended for adolescents and adults. [ ] [ ] [ ] the evidence of both waning immunity and that vaccinated pregnant women were able to provide passive immunity to their developing fetuses, also led to recommendations for routine tetanus and influenza vaccination for pregnant women. , epidemiologic studies of measles outbreaks led to the recognition that measles vaccination before months of age was associated with lower vaccine effectiveness. this was the basis for the acip recommendation that the first measles dose be administered on or after months of age. similarly, evidence from outbreaks among college students and school children showed insufficient effectiveness of a single measles dose to provide herd immunity. this led to recommendations for two doses of measles vaccines, one at - months and a second at to years of age. , other examples include a study of pertussis risk relative to the receipt and time since vaccination of the fifth dose of diphtheria and tetanus toxoids, and acellular pertussis vaccine (dtap) during an outbreak, and the role of varicella surveillance leading to change in immunization schedule from a single varicella dose to a two-dose schedule. epidemiologic studies have been used to evaluate new, and untested outbreak control interventions, such as evaluating recommendations to health care providers to vaccinate children using cdc's minimum immunization intervals during pertussis outbreaks and to use a third vaccination, during recent upsurges in mumps outbreaks. from to , the united states experienced a major nationwide resurgence of measles, which was detected by cdc's measles surveillance. the response to these events perhaps provides the best case-study of how epidemiologic evidence has informed, refined, and redirected united states immunization policy and practice. examination of reasons for the resurgence identified two kinds of outbreaks: ( ) large outbreaks among unvaccinated preschoolaged children, mainly in large urban centers, and ( ) smaller outbreaks among vaccinated children who, we know retrospectively, needed a second dose of a measles-containing vaccine. , additional analyses showed that unvaccinated preschool-aged outbreaks affected mostly young minority children in urban areas, with african american, latino, and american indian/alaska native children who contracted measles at rates three to times higher than white children did. the nvac examined evidence that pointed to challenges in the united states immunization system that likely contributed to the measles resurgence and to low immunization coverage rates that were well below healthy people objectives for preschool children. low vaccination coverage was primarily attributed to barriers in access to vaccination services or to missed opportunities to vaccinate by health care providers. , cost of vaccine was a key risk factor for uninsured or underinsured children. studies indicated that children visiting health care providers did not always receive all the recommended vaccines they were due, suggesting that missed opportunities to vaccinate were also important risk factors. , , - nvac's report concluded that immunization services needed to be enhanced and expanded. to guide efforts to increase vaccination rates, the report recommended that a national, standardized surveillance system to track age-appropriate immunization coverage across jurisdictions was necessary. this led to the creation of the national immunization survey to track the uptake of new childhood vaccines and monitor vaccination rates among young children - months of j o u r n a l p r e -p r o o f age to guide initiatives to more completely vaccinate these children with all recommended vaccines. , [ ] [ ] [ ] [ ] [ ] the key nvac findings and recommendations were published in , in what is now considered a report of historic significance. the nvac recommendations were embraced by policy makers and resulted in the launch of the childhood immunization initiative (cii). the cii, a presidential initiative, included several key elements: ( ) improving access to immunization services, ( ) developing immunization information systems, ( ) providing free vaccines to uninsured children (the vaccines for children program), and ( ) creating the national immunization program at cdc, now within the national center for immunization and respiratory diseases. improved access to immunization services improving access required addressing missed opportunities for immunizations. at the time, there were differences in recommendations between the acip, the american academy of pediatrics (aap) and the american academy of family practice (aafp). a major accomplishment of the cii was harmonizing the childhood immunization schedule jointly endorsed by acip, aap, and aafp, revisions of which have become a well-established convention and practice standard since . [ ] [ ] [ ] to address missed opportunities, programs targeted health care providers to remind them to make every child's medical visit, including acute and chronic care visits, a vaccination visit. tools are now available to health care providers to help them assess and improve immunization practices and identify ways to eliminate missed opportunities for vaccination at their offices. immunization registries or immunization information systems (iis) before the cii, most parents did not know the immunization status of their child. use of completed immunization cards and access to scattered immunization records among child providers were very limited and there were no electronic medical records that would allow clinicians to accurately assess immunization status at every visit (something particularly difficult at emergency room visits). immunization registries were developed to assist in the immunization assessment at each health j o u r n a l p r e -p r o o f care visit. by the mid- s, provider-based and population-or community-based immunization registries, now called immunization information systems (iis), were created for use by health providers to address immunization record scatter across clinics. iis are powerful and effective tools that provide timely access to immunization status at the point of care and have reduced missed opportunities by targeting under-vaccinated children for vaccination reminders and recalls, even before the introduction of electronic health record (ehr) systems. , [ ] [ ] [ ] as new vaccines were added to the immunization schedule, the combined series have been expanded. table includes a glossary of selected measures of vaccine completeness. , the acip expansion of recommended vaccines to adolescents and adults led to upgrades of the nis to specifically measure vaccination coverage for adolescents, including tetanus-diphtheriaacellular pertussis (tdap) and meningococcal conjugate vaccine (menacwy), by creating the nis -teen module in . , , in , monitoring for human papillomavirus (hpv) vaccination was added. like the original preschool child nis, this nis adolescent module includes provider-verified receipt of vaccines rather than relying on self-reported vaccination and provides data at state and selected local levels. vaccination coverage among young children and adolescents is found in figure and tables and . the end of the th century and the subsequent decades of the st century have witnessed further declines and the control of many vpds. polio has been eliminated from the americas and most of the world and it is near eradication worldwide. diseases like diphtheria, tetanus, measles, in spite of the retraction, this article created major concerns among parents considering vaccinating their children and continues to affect vaccination coverage of the mmr vaccine. a large epidemiologic study in denmark provided strong evidence of a lack of association between mmr and autism. similarly, a study in the united kingdom did not find any association between mmr and autism. the institute of medicine in the united states examined all available evidence and concluded that there was no evidence to link mmr vaccination and autism. the consequences of the subsequently retracted wakefield article include dramatic initial declines in mmr vaccination coverage in some countries. there were numerous resulting outbreaks of measles and mumps in the united kingdom, france, and elsewhere. [ ] [ ] [ ] [ ] surveillance documented that, in , the united states experienced cases in states, the largest number of measles cases since endemic measles was eliminated in . nis has also confirmed other study findings that suggest that those who intentionally delayed vaccination are significantly more likely to have heard or read unfavorable information about vaccines than parents who did not intentionally delay. additionally, parents who intentionally delayed due to vaccine safety or efficacy concerns were significantly more likely to seek information from the internet rather than from a health care provider compared with parents who delayed because of child illness. differences by race have been documented in j o u r n a l p r e -p r o o f these analyses--the percentage of parents who intentionally delayed immunizations was highest among white, non-hispanics ( . %), american indian/alaska natives ( . %), followed by asians ( . %), hispanics ( . %), and blacks ( . %). further analyses are needed to evaluate which parental, community and other characteristics and risk factors underlie these notable differences by racial/ethnic groups in childhood vaccine delays, for example examining how differences in historical experiences with vpds and trust may influence vaccine decision making among different groups. findings about intentional delays in immunization among some -year-old children and the ability of parents to claim religious or philosophical exemptions raise questions about the influence of the ease of parent claims in some states and higher state vaccination exemption rates. one study found that states enacting stricter exemption policies tend to have lower rates of exemptions. in recent years, congress and states, such as california, vermont, utah, washington and oregon, have passed or attempted to pass laws to modify or eliminate the use of non-medical exemptions. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] these policy initiatives are being met with public controversy and opposition by nationally-organized and grassroots groups communicating vaccine safety, civil liberty, other concerns, and also anti-vaccine sentiments. [ ] [ ] [ ] [ ] [ ] the legal viability and public health effectiveness of these more restrictive strategies remain to be determined. early studies of california's non-medical exemption elimination show that, while non-medical exemptions declined, geographic clustering of these exemptions remained leaving populations of students at-risk for vpds in a number of communities. [ ] [ ] [ ] epidemiological studies clearly play a key role in monitoring changing child immunization coverage, non-medical exemptions to school immunization requirements and other measures of vaccine hesitancy trends and the impact of policy changes and the interventions to address them. another important immunization practice issue is addressing differences in vpd morbidity and disparities in vaccination coverage among special populations. epidemiological studies proved to be particularly relevant when examining the impact of haemophilus influenzae type b (hib) and hepatitis a (hepa) vaccines on the american indian/alaska native (ai/an) population. the introduction of the hib vaccine significantly reduced hib incidence in ai/an children. surveillance proved to be critical in demonstrating a greater response with the first dose of the polyribosylribitol phosphate conjugated to the meningococcal outer membrane protein (prp-omp)-containing hib vaccines for ai/an infants providing earlier protection. in fact, when alaska switched from prp-omp to non-omp vaccine during a vaccine shortage, ai/an hib incidence increased. , again, epidemiological evidence was important to guide immunization practice. besides experiencing higher hib disease incidence, ai/an children historically had more than a five-fold higher incidence of hepa virus infection and were experiencing frequent large-scale outbreaks every - years. with the implementation of routine hepa vaccination in among high-risk populations (e.g., ai/ans), disease incidence and outbreak disparities were completely eliminated. as another special population, the amish were the last group to experience a polio outbreak in the united states. in , pennsylvania noted an increase in hib disease among amish preschool children. an epidemiologic study of hib carriage showed high levels of hib carriage and low vaccination coverage among amish households. a study among amish parents who did j o u r n a l p r e -p r o o f not vaccinate their children found that only % identified personal-belief objections as a factor, % reported that vaccination was not a priority compared with other daily activities, and % would vaccinate children if offered locally. these findings encouraged the state to target hib vaccination programs to amish communities and craft specific educational messages to amish parents leading to a reduction in hib disease in this special population. these examples show how public health used epidemiologic surveillance to document increases in disease incidence and disparities in vaccination coverage in special populations in order to respond with targeted interventions to address these problems and achieve disease prevention successes. epidemiologists are improving their methods to track new vaccine uptake, especially for newer vaccines including the multi-dose human papillomavirus (hpv) vaccine to prevent cervical cancer and the tdap booster for adolescents and adults. the hpv vaccine experience epidemiologists have looked closely at the factors associated with rates of hpv vaccine initiation and completion to examine vaccine uptake and acceptance. observed differences pointed out that further research was needed to better understand population-specific barriers to completion of the hpv series. monitoring hpv uptake, first among adolescent girls and later among adolescent boys, epidemiologists focused on identifying risk factors associated with low hpv vaccination.a telephone survey of mothers of - -year-old girls found that the predominant perception was that their daughters were at low risk for hpv infections and hpv-related diseases. findings also showed that mothers and their health care providers lacked sufficient knowledge about hpv disease and hpv vaccines. many mothers also reported that they believed that their daughters were currently too young to receive the hpv vaccine although receipt might be more acceptable at later ages. also, mothers reported significant concerns about the long-term safety of these vaccines. the most commonly identified reasons for mothers accepting these vaccines for their daughters included: their perceptions that their daughters were at high risk for acquiring hpv; their beliefs that the vaccine had a favorable safety profile; their intentions to prevent cervical j o u r n a l p r e -p r o o f cancer among their daughters and protect them against cancer; their own personal experience with hpv infection or hpv-related diseases; and their recalling strong physician recommendations to vaccinate their daughters. these findings have been shaping the messages and strategies to promote hpv vaccination with a stronger focus on the cancer prevention benefit of this vaccine. as in other countries, the impact of the covid- pandemic on the united states immunization system and policies is starting to become apparent as covid- continues to rapidly spread across communities. since public health authorities across the united states have needed to urgently implement non-pharmaceutical public health disease containment measures (e.g., shelter-in-place, postponements of noncritical health care visits), early epidemiological studies are already documenting a dramatic decline in ordering and administration of childhood vaccines, vfc clinic capacity to vaccinate children, and immunization coverage rates for vpds. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] rapid development of new covid- vaccines is an imperative because of the severe consequences of covid- disease, which is disproportionately impacting people over years of age, people with heart disease, diabetes, other chronic diseases, essential service workers and populations of color. [ ] [ ] [ ] [ ] however, as new vaccines for covid- are being developed and tested, new reports also suggest the emergence of major challenges for new covid- vaccination uptake. [ ] [ ] [ ] several reports state that that up to % percent of polled respondents were hesitant about accepting new covid- vaccines when they become available. , j o u r n a l p r e -p r o o f previous epidemiological studies have shown that after vaccine supply chain disruptions and shortages have occurred, uptake of vaccine may slowly recover and could remain persistently lower than prior uptake well behind recommended target coverage rates when supplies become available. re-engaging patients for clinical preventive services and increasing vaccination among people who have previously declined or fallen behind schedule during and after the covid- crisis are critical strategies to prevent other vpd outbreaks, which could further strain our health care system, emergency response systems, and economy and, thus, slow economic and societal recovery from the pandemic. [ ] [ ] [ ] with delays in vaccinations, vaccine hesitancy and upcoming seasonal influenza transmission, during the pandemic, we face new challenges that risk losing historical achievements in individual and community health and new unknown risks of further preventable illnesses, disabilities and death. , [ ] [ ] [ ] [ ] previous epidemiologic evidence suggests that by reducing the incidence of vpds such as influenza and pneumococcal disease, we also would reduce burden on the health care facilities that are already under pressure in communities responding to the waves of covid- outbreaks and community-wide transmission. immunization policy makers, public health practitioners and health care providers must plan new immunization initiatives that include proactively and transparently gaining back the trust of an already skeptical public whose trust in public health and health care advice during this pandemic have been sorely tested. , [ ] [ ] [ ] epidemiologic surveillance, research and program evaluation will be essential nationally, regionally and within communities to guide needed interventions that successfully respond to these new public health challenges. more challenging is the ongoing need to develop new, specific vaccines for emerging diseases with high morbidity and mortality and rapid spread as real-time countermeasures, notable at the time of this writing during the covid- pandemic. [ ] [ ] [ ] [ ] , especially challenging is that currently governments are usually the sole funding source for vaccine development unless commercial manufacturers offer to help and see financial and other incentives including the potential for more routine population-wide use. [ ] [ ] [ ] [ ] [ ] [ ] [ ] to be ready to respond effectively to the eventuality of new, emergent vaccine-preventable outbreaks and community-wide biological attacks, policy makers, health officials, legislators and other stakeholders can work together to ensure that policies are in place to expedite development of new vaccines, ensure vaccine safety and efficacy, and determine appropriate resources in a timely fashion. public/private partnerships can be developed to meet the demands for research and development of new vaccines and to establish capacity for production. additional public health system capacity across all levels and communities could be enhanced and sustained in order to address mass vaccine distribution and administration by health care providers, vaccination monitoring, disease surveillance, and program and policy evaluations to meaningfully inform policy and program decisions in realtime. j o u r n a l p r e -p r o o f uniform, quick, appropriate and timely reporting of disease cases and adverse events by physician offices, hospitals, laboratories, schools or other institutions such as child-care and correctional facilities can be more firmly established. enhanced electronic reporting from electronic laboratory and health record systems, data analyses and information dissemination can be enhanced to function more rapidly in real-time. rapid surveillance using electronic data is needed to provide more timely and accurate situational status assessments, target services and improve response time to public health emergencies. epidemiologists can expand their use of methods from other public health disciplines, such as community-based participatory research, qualitative research, rapid-cycle quality improvement work and evaluation methods to better identify vaccine acceptance disparities and differences in perceptions, knowledge, attitudes, and beliefs among specific populations, including providers. interventions that overcome the barriers and address the needs of special populations can be developed, implemented, evaluated and disseminated. epidemiology remains essential for informing policy and programmatic practice decision making to prevent and respond to vpds. epidemiologic studies of the large united states measles resurgence identified major factors by further identifying determinants of low vaccination coverage. these efforts were crucial for focusing policies and programmatic strategies at national, state and local levels. surveillance and epidemiologic research have also been essential in monitoring the impact of vaccinations on infectious disease incidence and vaccine acceptance j o u r n a l p r e -p r o o f by clinicians, parents and patients. while epidemiology has positively influenced changes in immunization policy and led to historic reductions in vpds, the reduction of vpd incidence has created new challenges in our ability to help parents and providers understand why vaccines remain essential. recent developments 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diseases: exploring the public health successes and challenges. testimony before the committee on health, education, labor and pensions, united states senate group shape vaccine delivery working group. from refrigerator to arm: issues in vaccination delivery vaccine refusal, mandatory immunization, and the risks of vaccine-preventable diseases. the new england journal of medicine > polio: > mmr: > hib: > hepb: > varicella abbreviations: dtp/dtap = diphtheria and tetanus toxoids and whole cell pertussis vaccine or diphtheria and tetanus toxoids and acellular pertussis vaccine mmr = measles-mumps-rubella vaccine hib = haemophilus influenzae type b vaccine hep b = hepatitis b vaccine; varicella= varicella vaccine; and pcv = pneumococcal conjugate vaccine abbreviations: dtp/dtap = diphtheria and tetanus toxoids and whole cell pertussis vaccine or diphtheria and tetanus toxoids and acellular pertussis vaccine mmr = measles-mumps-rubella vaccine hib = haemophilus influenzae type b vaccine hepb = hepatitis b vaccine varicella=varicella vaccine pcv = pneumococcal conjugate vaccine hepa = hepatitis a vaccine *selected vaccines and dosages are in accordance with immunization objectives from healthy people and follow the cdc's recommended immunization schedule for children and adolescents ages years or younger : : *: : : ) includes ≥ doses of dtap, ≥ doses of poliovirus vaccine, ≥ dose of measles-containing vaccine, the full series of hib (≥ or ≥ doses, depending on product type figure . vaccine coverage among preschool-aged children -united states abbreviations: dtp/dtap = diphtheria and tetanus toxoids and whole cell pertussis vaccine or diphtheria and tetanus toxoids and acellular pertussis vaccine mmr = measles-mumps-rubella vaccine hib = haemophilus influenzae type b vaccine hep b = hepatitis b vaccine; varicella= varicella vaccine pcv = pneumococcal conjugate vaccine rv = rotavirus vaccine hep a = hepatitis a vaccine + from the united states immunization survey note: no data are available for - . children in the united states immunization survey and national health interview survey were ages - months centers for disease control and prevention. coverage among children - months by state, hhs region, and the united states national, regional, state, and selected local area vaccination coverage among adolescents aged - years -united states centers for disease c, prevention. benefits from immunization during the vaccines for children program era -united states race/ethnicity non-hispanic white *selected vaccines and dosages are in accordance with immunization objectives from healthy people and follow the cdc's recommended immunization schedule for children and adolescents aged years or younger. , **includes those with >= doses, and those with doses when the first hpv vaccine was initiated prior to age years and there was at least five months minus four days between the first and second dose. ***among adolescents with no history of varicella. † numbers in parentheses refer to the number of doses of that vaccine being reported in this figure. key: cord- -i ayr authors: perez, andres m.; linhares, daniel c. l.; arruda, andreia g.; vanderwaal, kimberly; machado, gustavo; vilalta, carles; sanhueza, juan m.; torrison, jerry; torremorell, montserrat; corzo, cesar a. title: individual or common good? voluntary data sharing to inform disease surveillance systems in food animals date: - - journal: front vet sci doi: . /fvets. . sha: doc_id: cord_uid: i ayr livestock producers have traditionally been reluctant to share information related to their business, including data on health status of their animals, which, sometimes, has impaired the ability to implement surveillance programs. however, during the last decade, swine producers in the united states (us) and other countries have voluntarily begun to share data for the control and elimination of specific infectious diseases, such as the porcine reproductive and respiratory syndrome virus (prrsv). those surveillance programs have played a pivotal role in bringing producers and veterinarians together for the benefit of the industry. examples of situations in which producers have decided to voluntarily share data for extended periods of time to support applied research and, ultimately, disease control in the absence of a regulatory framework have rarely been documented in the peer-reviewed literature. here, we provide evidence of a national program for voluntary sharing of disease status data that has helped the implementation of surveillance activities that, ultimately, allowed the generation of critically important scientific information to better support disease control activities. altogether, this effort has supported, and is supporting, the design and implementation of prevention and control approaches for the most economically devastating swine disease affecting the us. the program, which has been voluntarily sustained and supported over an extended period of time by the swine industry in the absence of any regulatory framework and that includes data on approximately % of the sow population in the us, represents a unique example of a livestock industry self-organized surveillance program to generate scientific-driven solutions for emerging swine health issues in north america. although porcine reproductive and respiratory syndrome (prrs) is one of the most important economic constraints to pork production in the us ( , ) , reporting of prrs outbreaks is not mandatory in the country. in the absence of a regulatory framework, prrs control and elimination actions are voluntary. at the field level, producers and veterinarians make decisions that seek to maximize profit while keeping the necessary standards for animal health and welfare. however, individual-level decisions may lead to complex and diverse epidemiological scenarios at a regional level. because of the epidemiological features of prrs virus (prrsv) transmission, such as high levels of disease incidence, high variability and rapid mutation of the virus, intensiveness of production, and, in some cases, vertical integration of the industry, and limitations of current preventive and control methods, there is not much hope for disease control if programs are not simultaneously implemented at local (i.e., production system level) and regional levels (i.e., state or county levels) ( ) ( ) ( ) ( ) . the perception that regional approaches are required to control the disease has led to the implementation of at least voluntary regional prrsv control or elimination projects in the us and canada ( ) . none have succeeded in eliminating prrsv regionally, and, arguably, most seem to have had limited success on significantly controlling the disease. part of the limited progress on those regional projects may be attributed to inconsistencies in regional biosecurity compliance and suboptimal biosecurity of swine operations, incomplete regional producer participation, poor standardization, and availability of information on pathogen monitoring and surveillance systems, including lags in detection and communication about outbreaks ( ) . lack of progress of regional control and eradication projects may also be at least in part associated with limited funding for disease and insufficient coordination of control activities. in contrast, one may argue that it is unknown what the epidemiological situation of the disease would be in the absence of those voluntary programs, and thus, the effectiveness of their implementation is debatable and subject to speculation. nevertheless, veterinarians and producers from individual farms and production companies, generically referred to as "production systems, " still need to make decisions intended to maximize their results ( ) using the information available to them, which may lead to scenarios that are not compatible with disease control at a regional level. the tension between "individual" and "common" good leads to a complex relation of behaviors and attitudes, resembling a "game." in this "game, " certain "players" (production systems) make decisions that may be conditional to the decisions made by other "players, " which, in turn, may result in a change of decisions taken by other "players." this "game, " which in social economics corresponds to a concept referred to as "game theory" ( , ), soon becomes dynamic, and the conditions required to control the disease at a regional level become, at minimum, difficult to reach. thus, prrsv control at the regional level becomes challenging, and often depends on regional leadership. if short-and long-term values of participation are not quantified and clear, it is unlikely that progress will be made. many stakeholders have perceived the social nature of prrsv control at the regional level in the us. spontaneous initiatives intended to voluntarily share knowledge have emerged in the country with the objective of promoting a greater good, i.e., control of a disease that affects the industry as a whole, even if such sharing may represent a potential risk or loss to their individual interest. here, we review the largest voluntary initiative for data sharing among us swine producers, including a summary of its design and governance, and highlighting a number of epidemiological features of the disease that the project helped to elucidate over the last years. the ultimate objective of this voluntary program is to build the capacity to respond in the event of an emerging disease, while supporting the prevention and control of endemic diseases of swine, such as prrsv. since the late 's, prrsv has been consistently generating losses in the us swine industry. thanks to an effective collaboration between researchers, swine veterinarians, and swine producers, epidemiological characteristics of the disease were uncovered and preventive and control measures were implemented. despite important improvements from a bioexclusion, biomanagement, and biocontainment standpoint, the virus continues to persist in us swine herds. because there has historically been no documentation of disease occurrence metrics through space and time, the industry could not systematically assess whether the current situation was better or worse compared to previous years, generating uncertainty and speculation. based on this knowledge gap and the need to further understand the epidemiology of the disease at larger spatial and temporal scales, a group of producers and practitioners decided to voluntarily share breeding herd prrsv status for their respective production systems. through weekly reporting, practitioners updated their respective prrsv breeding herds' status, making the estimation of weekly cumulative incidence reports possible. the product of this effort was then shared back to participants in the form of weekly reports. reports included information on disease prevalence, disease incidence, and proportion of herds in each prrsv status. reports also included benchmarking comparing numbers of participants to aggregated results from other participants in the database. the program's name changed through time and it is currently referred to as the morrison's swine health monitoring project (mshmp), in recognition of the late dr. robert morrison, who was the driving force leading the inception and organization of the program. compared to regional control projects, the mshmp is larger, including information from reproduction farms (sow farms, multipliers, genetic nuclei) in a number of regions, whereas regional control projects are typically smaller, limited to a geographical area, and including also information nurseries, growers, and finishers. mshmp participants have agreed that prrsv incidence graphs generated by their voluntary collaboration would be shared with the industry for benchmarking, disease monitoring, and promoting participation. in , the project included production systems that provided data related to prrsv breeding herd status, location, and prrsv interventions on a regular basis. those systems represented approximately one million sows, which at the time, accounted for roughly % of the total us breeding herd based on usda estimates ( ) . in , porcine epidemic diarrhea virus (pedv) and porcine delta-coronavirus (pdcov) emerged in the us swine population ( , ) . this dramatic and dynamic situation provided an opportunity for producers to continue working together, and therefore pedv and pdcov were added to the list of diseases being monitored and reported on a voluntary basis ( ) . over the years, others were prompted to join the project, which ultimately increased the representativeness of the database and thus provided a more accurate benchmark for the industry. senecavirus a and pathogens associated with central nervous system disease were later added to the list of pathogens reported to mshmp. at the time when this manuscript was written in february , production systems, accounting for ∼ % of the us sow population, continue to provide their data for the benefit of the industry (figure ). briefly, after each participant has voluntarily agreed to participate, a participation form and a data privacy agreement are signed prior to data acquisition. then, farm-level information, such as location, herd size, farm type (e.g., farrow-to-wean, farrow-to-feeder, farrow-to-finish), genetic level (e.g., multiplier or commercial herd) and air filtration status is provided by each participant and stored in a central database housed at the university of minnesota. one person within each participating system serves as point of contact for the project, becoming responsible for data sharing in direct communication with the mshmp's data coordinator. each week, participants share the list of sow farms that have changed their status, either worsening (e.g., outbreaks) or improving (e.g., ceased shedding or completed elimination). once the information is received by the mshmp data coordinator, it is reviewed for quality control and entered into the main database. data are then used to estimate measures of disease occurrence such as incidence and prevalence. for incidence, a graph featuring the weekly and yearly cumulative incidence is presented. incidence data are also used to create an exponentially weighted moving average graph, in which the magnitude and duration of the outbreak is graphed through time. additionally, that figure depicts a threshold level (upper confidence limit of the two lowest seasons in the previous years) that marks the start and end of epidemic periods. the prevalence graph for prrsv is based on a classification from the american association of swine veterinarians (aasv), in which each prrsv sow herd status is defined ( ) . the mshmp report is comprised of pages including participant logos and supporting/funding sources (page ), the aggregate incidence and prevalence graphs for prrsv (page ) and pedv (page ), the seneca valley virus and atypical central nervous system case counts (page ), a space for sharing the latest developments in swine related research referred to as "science page" (page ), and the names and affiliations of all the individuals that receive the public report (page ). additional pages are shared with the project participants referring only to their own systems, and including incidence and prevalence graphs for both prrsv and pedv. since its inception in , the mshmp has played a critical role in providing data that scientists translated into science-driven solutions to help the us swine industry mitigating prrsv impact. here, we summarize some important swine disease features that the mshmp has helped to elucidate and that promoted engagement and participation among producers. for the last years ( - ), prrsv has maintained stable incidence levels on an annual basis, with an increase in the number of outbreaks, colloquially referred to as "prrs season, " consistently starting between mid-october to mid-november ( ) . the only period that showed a substantial different incidence, compared to other periods, was in - , when pedv was first detected in the us ( ) . however, seasonal dynamics seemed to differ across different states, with minnesota, north carolina, and nebraska having more consistent seasonality than iowa, and illinois. furthermore, there seems to be a secular pattern in the southern and southeastern regions of the country, with large epidemics occurring every - years ( , ) . prrsv impact may be mitigated by implementing certain management strategies mshmp investigators developed herd-level metrics of success of prrsv control and elimination programs, such as timeto-stability (tts), time to baseline productivity (ttbp), and total loss per thousand sows. those metrics were used to compare the effect of multiple aspects or interventions on breeding herds affected with prrsv. prrsv-infected breeding herds achieved stability (i.e., producing prrsv-negative piglets) significantly sooner, compared to other strategies, when they had reported a prior infection (i.e., existing partial herd immunity) and implemented herd closure (i.e., temporary interruption of replacement breeding stock introduction), and/or used wild type live virus inoculation as part of load-closeexpose programs. specifically, tts was weeks sooner for breeding herds adopting live-virus inoculation (lvi) as part of a load-close-expose program compared to those that used mlv vaccination protocols. conversely, herds using mlv achieved ttbp weeks sooner, and lost , piglets/ , sows less than herds using lvi. altogether, economic analysis revealed an advantage for herds using mlv compared to lvi ( , ) . more recently, mshmp data have been used to estimate the breeding herd prrs time-to-stability of a subset of breeding herds from six production systems that used similar testing criteria. a total of breeding herds in the midwestern us participated in this study, which accounted for ∼ , sows. these herds reported prrs outbreaks between and . breeding herds that had prrsv outbreaks during the spring and summer had a significantly longer tts than herds that had outbreaks during the fall and winter. in addition, there was a significant difference between tts between production companies suggesting that there are particular factors within production systems that may drive viral persistence in breeding herds ( ) . the mshmp has been used to provide incidence data that helped to estimate the cost of prrs, as part of various projects aimed at monitoring prrs impact over time. those data have helped in part to demonstrate that the annual cost of prrs to the us swine industry has decreased $ . million from october ($ . million) to october ($ . million) ( ), partially possibly due to increased number of breeding herds constantly immunizing sows with attenuated prrs virus vaccines (figure ) , which has been associated with reduced production losses ( ) . some have suggested that, coincidently with the dissemination of research results demonstrating the impact of control measures on tts, the proportion of sow farms in the mshmp that have implemented vaccine-based control strategies substantially increased, suggesting that producers may have seen some value in the adoption and implementation of those research findings in the field (figure ) . noteworthy, however, it is also possible that the shift may be explained, at least in part, by other factors that were not formally assessed such as, for example, ped emergence in the country. in any case, data provided by participants has allowed mshmp to compile and visualize the rate at which different control strategies have been adopted by participants. swine farm density has long been recognized as an important indicator for the risk of farms becoming infected with prrsv and pedv, even though the relative contribution of different routes of infection remain debated among swine practitioners and producers. through the use of historical mshmp data along with publicly available datasets, insights on environment-related factors that could affect the risk of prrsv outbreaks were assessed. swine sites located in regions with higher land slopes, and swine sites surrounded by trees and herbaceous coverage were protected from reporting a prrsv outbreak compared to sites located in regions with lower land slopes and regions characterized by cultivated areas, respectively ( ) . however, the effects of slope may not be consistent across all regions, and may depend on the specific topography of the area ( ) . precipitation, temperature, and land cover were all contributors for prrsv spatial risk, with specific contribution amounts varying according to "subregion" in the us ( ) . for pedv, temperature, wind speed, and vegetation have been identified as important modulators of risk, even in swine-dense areas ( ) . taken together, these results demonstrate that, even for highly intensive pig production, environmental factors play an for the past several decades, epidemiological modeling has been an important tool for understanding and predicting the spread of infectious diseases. the availability of farm-level outbreak data through mshmp, combined with data on animal movements between farms ( ) , has enabled some of the first data-informed epidemiological models in the us swine industry. the availability of prrsv genetic sequences from farms that became infected [see for example, ( ) ] allowed for the model to be fit to the observed spatiotemporal dynamics of the unfolding ped epidemic in ( ) . data on which and when farms become infected also has opened the possibility of using this rich database to develop predictive models that could be used to forecast when a farm is expected to be at high risk. the potential for forecasting was initially explored using ped incidence data ( ) . animal movement data available within the mshmp was combined with environmental risk factors within a km radius around breeding farms to identify major drivers of ped outbreaks, which included the total numbers of pig movements into neighboring farms, regional hog density, environmental, and weather factors such as vegetation, wind speed, temperature, and precipitation, and topographical features such as slope. results suggest that ped occurrence may be predictable with an acceptable (i.e., > %) level of accuracy, which eventually may lead to the design and implementation of a near real-time forecasting system for these diseases. the us swine industry continues to reach important production levels together with expanding their breeding and growing herds. infectious diseases are one of the most important limiting factors as they deteriorate performance and increases production costs. furthermore, foreign animal diseases are of concern for the industry as they could potentially affect the industry's export market. therefore, the us swine industry continues to work closely with researchers to seek answers and implement procedures to mitigate the burden of endemic diseases, while building capacity to respond against emerging and foreign animal diseases. a program like mshmp, which its foundation is trust and voluntary participation, has had an important impact on the surveillance of pathogens for the national industry. an academic institution-led program has motivated producer and veterinarian collaboration for the greater good of the industry. reasons why producers and veterinarians have been willing to share their data are difficult t to assess. initially, there was an intention to standardize data collection and sharing, to improve situational awareness and facilitate the decision-making process considering the epidemiological situation of the disease in near real time and in the entire region, rather than on their own farms and systems only. however, motivation declines with time, and it is important to demonstrate the added value of the effort. in that regards, even though shared data are private and managed only by the mshmp team, producers and veterinarians still obtain a benefit because important outputs, that help inform their decisions, are routinely shared with them. prrsv has been used as a way to bring the industry together and build the methodology to create a program that has the potential to be adaptable to other diseases. mshmp has demonstrated over the years that voluntary organization of swine producers and practitioners toward a common goal resulted in a powerful initiative that outweighed initial concerns about own data protection. most importantly, such voluntary collaboration has also led to collaborative research involving a number of higher education institutions in the us that helped to elucidate some of the most important epidemiological features of endemic swine diseases in the us, and ultimately, provided a substantial support to the mitigation of disease impact in the country. the evolution of analytical capabilities for big data analysis is expected to result in novel and innovative tools that will allow for the routine analysis of big datasets, such as that collected in the mshmp. the promotion of social initiatives, intended to promote data sharing and self-organization of producers, along with the application of those novel analytical techniques, may help to reshape in the near future the landscape of coordinated activities to promote the prevention and control of food animal diseases worldwide. assessment of the economic impact of porcine reproductive and respiratory syndrome on swine production in the united states assessment of the economic impact of porcine reproductive and respiratory syndrome virus on united states pork producers results of a control programme for the porcine reproductive and respiratory syndrome in the french 'pays de la loire' region control and elimination of porcine reproductive and respiratory syndrome virus the ever-expanding diversity of porcine 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syndrome virus epidemics in a cohort of sow herds in the united states estimation of time-dependent reproduction numbers for porcine reproductive and respiratory syndrome (prrs) across different regions and production systems of the united states. front vet sci time-series analysis for porcine reproductive and respiratory syndrome (prrs) in the united states comparison of time to prrsv-stability and production losses between two exposure programs to control prrsv in sow herds effect of immunologic solutions on sows and gilts on time to stability, and production losses in breeding herds infected with - - prrsv factors affecting porcine reproductive and respiratory syndrome virus time-to-stability in breeding herds in the midwestern united states transbound annual prrs costs fall $ . million-productivity gains blunt the impact of prrs on the u land altitude, slope, and coverage as risk factors for porcine reproductive and respiratory syndrome (prrs) outbreaks in the united states predicting outbreaks of porcine epidemic diarrhea virus through animal movements and spatial neighborhoods surveillance of porcine reproductive and respiratory syndrome virus in the united states using risk mapping and species distribution modeling characterization of swine movement in the united states and implications for disease control porcine reproductive and respiratory syndrome virus outbreak role of animal movement and indirect contact among farms in transmission of porcine epidemic diarrhea virus the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © perez, linhares, arruda, vanderwaal, machado, vilalta, sanhueza, torrison, torremorell and corzo. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- - niaplc authors: schrag, stephanie j.; brooks, john t.; van beneden, chris; parashar, umesh d.; griffin, patricia m.; anderson, larry j.; bellini, william j.; benson, robert f.; erdman, dean d.; klimov, alexander; ksiazek, thomas g.; peret, teresa c.t.; talkington, deborah f.; thacker, w. lanier; tondella, maria l.; sampson, jacquelyn s.; hightower, allen w.; nordenberg, dale f.; plikaytis, brian d.; khan, ali s.; rosenstein, nancy e.; treadwell, tracee a.; whitney, cynthia g.; fiore, anthony e.; durant, tonji m.; perz, joseph f.; wasley, annemarie; feikin, daniel; herndon, joy l.; bower, william a.; kilbourn, barbara w.; levy, deborah a.; coronado, victor g.; buffington, joanna; dykewicz, clare a.; khabbaz, rima f.; chamberland, mary e. title: sars surveillance during emergency public health response, united states, march–july date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: niaplc in response to the emergence of severe acute respiratory syndrome (sars), the united states established national surveillance using a sensitive case definition incorporating clinical, epidemiologic, and laboratory criteria. of , unexplained respiratory illnesses reported by state and local health departments to the centers for disease control and prevention from march to july , , a total of ( %) met clinical and epidemiologic sars case criteria. of these, ( %) were probable cases with radiographic evidence of pneumonia. eight ( %) were laboratory-confirmed sars-coronavirus (sars-cov) infections, ( %) were sars-cov negative, and ( %) had undetermined sars-cov status because of missing convalescent-phase serum specimens. thirty-one percent ( / ) of case-patients were hospitalized; none died. travel was the most common epidemiologic link ( / , %), and mainland china was the affected area most commonly visited. one case of possible household transmission was reported, and no laboratory-confirmed infections occurred among healthcare workers. successes and limitations of this emergency surveillance can guide preparations for future outbreaks of sars or respiratory diseases of unknown etiology. in response to the emergence of severe acute respiratory syndrome (sars), the united states established national surveillance using a sensitive case definition incorporating clinical, epidemiologic, and laboratory criteria. of , unexplained respiratory illnesses reported by state and local health departments to the centers for disease control and prevention from march to july , , a total of ( %) met clinical and epidemiologic sars case criteria. of these, ( %) were probable cases with radiographic evidence of pneumonia. eight ( %) were laboratory-confirmed sars-coronavirus (sars-cov) infections, ( %) were sars-cov negative, and ( %) had undetermined sars-cov status because of missing convalescent-phase serum specimens. thirty-one percent ( / ) of case-patients were hospitalized; none died. travel was the most common epidemiologic link ( / , %), and mainland china was the affected area most commonly visited. one case of possible household transmission was reported, and no laboratory-confirmed infections occurred among healthcare workers. successes and limitations of this emergency surveillance can guide preparations for future outbreaks of sars or respiratory diseases of unknown etiology. t he emergence of severe acute respiratory syndrome (sars) presented a challenge to public health and healthcare delivery systems worldwide. the previously unknown respiratory syndrome was characterized by nonspecific clinical symptoms, was highly transmissible in some circumstances, did not respond to antimicrobial therapy, and could rapidly progress to severe respiratory dis-tress and death. sars appears to have originated in guangdong province, china; however, the global importance of this illness was not recognized initially by local health authorities. when the world health organization (who) issued a historic global alert about cases of severe atypical pneumonia on march , , the outbreak had spread through international travel from guangdong province to at least hong kong and hanoi, vietnam. there was an urgent global need for diagnosis of the etiologic agent, detection and containment of probable cases, guidance on the healthcare management of patients and potentially exposed persons, identification of measures to prevent and control infections, and timely public health communications to a wide range of audiences. on march , , the u.s. centers for disease control and prevention (cdc) launched an emergency public health response and established national surveillance for sars to identify case-patients in the united states and determine if domestic transmission was occurring. we describe the surveillance system established to detect sars in the united states, focusing on its design, challenges, and modifications that occurred as the outbreak evolved, and characteristics of the case-patients identified. such information is critical for preparing for possible future outbreaks of sars or other emerging microbial threats with nonspecific respiratory symptoms. cdc's initial surveillance definition for a suspect case of sars (table ) was based on a definition first published by who ( ). these definitions specified clinical criteria and required a potential exposure to sars (epidemiologic link). who categorized all cases with x-ray or autopsy evidence of pneumonia or respiratory distress as probable, and all others meeting the case definition were classified as suspect cases. cdc initially categorized all cases as suspect, but on april , , cdc adopted who's suspect and probable classifications ( ) . sars-affected areas that constituted an epidemiologic link changed throughout the outbreak, requiring continual modification of the case definition. cdc considered an area sars-affected if evidence of documented or suspected community transmission existed. regions were removed from the list of sars-affected areas when cdcissued travel alerts or advisories were discontinued, which meant that the area had reported no new cases of sars for days. on april , , after a new coronavirus (sars-cov) was identified as the etiologic agent of sars ( ) ( ) ( ) ( ) , the case definition was changed to incorporate criteria for laboratory-confirmed illness ( ) . laboratory criteria were refined near the end of the outbreak, resulting in the final case definition on july , (tables and ) ; revision of the requirements for a convalescent-phase serum specimen from to days after illness onset was not applied retrospectively, consistent with the instructions accompanying release of this case definition. this definition also introduced an exclusion criterion for suspect or probable case-patients confirmed negative for sars-cov infection. in this analysis, we did not apply this exclusion criterion to allow for a complete presentation of suspect and probable cases captured and monitored by national surveillance. does not apply to serum samples collected before july , . testing results from serum samples collected before july , and between and days after symptom onset are acceptable and will not require collection of additional sample > days after symptom onset. g factors that may be considered in assigning alternate diagnoses include strength of epidemiologic exposure criteria for sars, specificity of diagnostic test, and compatibility of clinical presentation and course of illness for alternative diagnosis. case-patients were eligible for inclusion if they were u.s. residents and were present in the united states during some of their illness. non-u.s. residents who became ill or in whom sars was diagnosed while they were in the united states were monitored as patients of special interest until april , , after which they were included in surveillance. u.s. citizens who were not present in the united states for any period of their illness were not included in surveillance. national surveillance began on march , , days after cdc initiated its emergency response. the analysis in this report covers the period march through july , , weeks after who declared the global outbreak over. case definitions were distributed to state and local health departments through cdc's epidemic information exchange (epi-x), a secure communications network for public health professionals, and through cdc's health alert network. case definitions were also posted on a cdc web site dedicated to sars. a case report form was developed to collect demographic and clinical data as well as information about epidemiologic links. this form was also distributed through epi-x and by electronic mailings by the council of state and territorial epidemiologists (cste) to its membership. the case report form was modified as the outbreak evolved. at the beginning of the outbreak, health departments were requested to report to cdc all respiratory illnesses that they thought should be evaluated for sars. although the communication chain for reporting these illnesses to health departments varied by state, all health departments relied on passive reporting from clinicians rather than actively seeking to identify potential cases. cdc hosted weekly teleconferences with state and local health departments to address developing issues related to the domestic surveillance and response. an atlanta-based cdc team received illness reports by telephone or fax. state and local health department personnel collected data, completed case report forms, and determined case status in consultation with cdc. when a patient met the case definition, data about that person were added to a "line list," which was updated and analyzed daily. hospitalized case-patients were actively monitored to establish outcomes, as were persons who had pending data that could alter case status. illnesses that failed to meet the case definition on subsequent investigation (e.g., patient's travel history clarified) were removed from the line list. the data collection system at both the health departments and cdc was paper-based rather than electronic or online. epidemiologic data were entered at cdc into an electronic database that was merged with laboratory data. state and local health departments were asked to collect acute-and convalescent-phase serum and stool specimens and nasopharyngeal or oropharyngeal swab samples from all case-patients. before the cause of sars was established, specimens were tested for a wide array of bacterial and viral pathogens at cdc. after sars-cov was discovered, serum specimens were tested for sars-cov antibodies, and respiratory and stool specimens were tested for sars-cov by polymerase chain reaction (pcr) ( ). diagnostic testing was initially centralized at cdc. later, reagents for sars-cov antibody and nucleic acid testing were made available to state public health laboratories and the laboratory response network ( ) . to meet u.s. food and drug administration requirements for the use of nonlicensed tests in these laboratories, cdc developed informed-consent documents and informational materials that clinicians used when collecting specimens for sars-cov testing from their patients. case-patients were classified as confirmed, negative, or undetermined for sars-cov infection (tables and ). on july , , the -day period required for convalescent-phase specimens was extended to days for newly identified cases on the basis of evidence that seroconversion sometimes occurred after day ( ) . during the course of the outbreak, testing for alternative causes that could fully explain patient illness was ordered at the discretion of local clinicians, and sars was often excluded on the basis of local interpretations of test results. many of these illnesses were never reported to cdc. diagnostic testing for alternative agents was performed at cdc early in the outbreak. in addition, evaluation of acute ( ). a rise in igg antibody titers of twofold or more between acute-and convalescentphase serum pairs was considered positive for a pneumococcal exposure or event. chlamydia igg and igm antibodies were measured by using a microimmunofluorescent antibody assay (focus technologies, cypress, ca). l. pneumophila antibodies were measured by using an indirect immunofluorescent antibody assay ( ) . specific igg antibodies to the respiratory viruses (excluding influenza) were measured by using an indirect enzyme immunoassay panel, following procedures previously described for hmpv ( ) . a rise in igg antibody titers of fourfold or greater between acute-and convalescent-phase serum pairs was considered positive for recent virus infection. serologic analysis for influenza was performed by hemagglutination-inhibition assay. all serum specimens were treated with receptor-destroying enzyme to remove nonspecific inhibitors before testing ( ) . specimens from some or all of the following sources were tested by pcr for evidence of bacterial or viral infection: bronchoalveolar fluid, sputum, tracheal aspirates, nasal washings, and nasal, nasopharyngeal, and oropharyngeal swab samples. all the bacterial methods used have been described previously ( , ( ) ( ) ( ) except the l. pneumophila real-time pcr assay (online appendix). total nucleic acid was extracted from µl of specimen by using the qiaamp virus biorobot mdx kit (qia-gen inc., valencia, ca). reverse transcriptase (rt)-pcr assays for influenza a and b viruses; respiratory syncytial virus; human parainfluenza viruses , , and ( ) ; and hmpv ( ) were performed as previously described. rt-pcr assays for adenovirus and picornavirus (inclusive of rhinovirus and enterovirus) were performed by using these same amplification conditions with primer pairs to the con- from had chest x-ray evidence of pneumonia and were classified as probable case-patients. eight case-patients ( %) were confirmed to be positive for sars-cov, ( %) were confirmed to be negative for sars-cov by serologic testing, and ( %) had undetermined sars-cov status because of the absence of convalescent-phase serum samples. cases were reported from states and puerto rico, with the highest case counts in california ( ), new york ( ), and washington ( ) ; no cases were reported from states or the district of columbia (figure ). of the eight confirmed sars-cov-positive casepatients, all had radiographic evidence of pneumonia and six were identified in the first month of surveillance (table ). five traveled to hong kong, two to toronto, and one to singapore. further case details have been presented elsewhere ( ) ( ) ( ) ( ) . among the eight confirmed sars-cov-positive case-patients, seven had illnesses that were associated solely with travel to an affected area. although the eighth case-patient traveled with her spouse (subsequently confirmed as a case-patient) to an affected area (hong kong, where both stayed in a hotel in which intense local transmission occurred [ ]), the epidemiologic link was classified as close contact because the onset of illness occurred days after the couple's return to the united states ( , ) . the median age of all suspect and probable casepatients was years (range months to years), and % were male ( travel to an affected area was the most commonly reported epidemiologic link ( % of cases). mainland china was the most frequent destination ( % of travelers), followed by hong kong ( %), and toronto ( %); % of case-patients traveled to more than one affected area. the frequency of travel to china, hong kong, and toronto among sars case-patients is shown by date of illness onset in figure ; the periods during which these areas were considered sars-affected for surveillance purposes are also shown. no healthcare workers with suspect or probable sars (n = ) were confirmed to be sars-cov positive; ( %) were confirmed sars-cov negative, and the remainder had undetermined sars-cov status. the only possible case of recognized secondary transmission was between the married couple described above. the number of illnesses reported was highest during the first weeks of surveillance and varied over the course of the outbreak (figure ). among suspect and probable cases, the completeness of critical surveillance variables related to case definition and severity of illness was as follows: date of symptom onset, %; radiologic chest imaging for pneumonia, %; hospitalization status, %; hospital discharge date for admitted case-patients, %; and healthcare worker as occupation, %. although collection of convalescent-phase sera was essential for assessing infection with sars-cov, samples needed for definitive laboratory determination of case status were not obtained from % of patients (probable case-patients: %; suspect case-patients: %; chi-square = . ; p = . ). sensitivity refers to the proportion of sars-cov cases in the population that were detected by the surveillance system ( ) . because sars-cov confirmatory laboratory testing was performed only on patients identified by the surveillance system, we cannot evaluate sensitivity for the system overall. if we limit analysis to the population of suspect and probable cases with definitive laboratory results (n = ), we can evaluate the sensitivity of the probable case definition; all the confirmed sars-cov-positive patients (n = ) had been classified as probable cases, leading to a sensitivity of %. the predictive value positive refers to the proportion of reported cases that actually have the health-related event under surveillance (sars-cov infection). the predictive value positive among cases with definitive laboratory results was % ( / ). the predictive value positive among the probable cases with definitive laboratory results was %. the united states was one of many countries reporting sars cases to who, which established international case definitions and reporting standards. although flexibility was limited by the need to maintain harmonized international surveillance, u.s. surveillance remained flexible enough to incorporate frequent modifications rapidly. for example, when mainland china was added to the list of sars-affected areas, within hours, case-patients who traveled to provinces other than guangdong were added to the line list, and travel to mainland china quickly became the most common travel exposure (figure ). the median time between symptom onset and reporting suspect or probable cases to cdc decreased during the first weeks of national surveillance from to days. after week , the median time to national reporting increased to a median of days, with % ( / ) of cases reported > days after illness onset. data on date illness was reported to local and state health departments were not collected. among the suspect and probable case-patients for whom serologic or pcr testing was performed at cdc, ( %) demonstrated evidence of at least one alternative respiratory infection. among specimens tested, picornavirus (enterovirus/rhinovirus) was the most common pathogen identified ( of , %), followed by human influenza a or b virus ( / [ %]) and m. pneumoniae ( / , %; table ). patients with probable and suspect cases of sars were equally likely to have an alternate cause identified ( % each). sars-cov-negative casepatients and those with unknown sars-cov status were also equally likely to have an alternate cause identified ( % and %, respectively). adequate specimens were available for only two of the eight sars-cov-positive case-patients, one of whom also showed a fourfold or greater rise in antibodies to influenza b. during the u.s. emergency public health response to sars, > , unexplained respiratory illnesses were reported by state and local health departments to cdc. countless additional illnesses were investigated and rapidly ruled out for sars by state and local health departments. despite the large surveillance burden, discovery of the etiologic agent for sars and development of effective diagnostic tests showed that the united states experienced limited sars activity during the global outbreak, similar to much of europe, africa, australia, and south america. there was no evidence of community transmission in the united states even though sars-affected countries were common travel destinations for u.s. residents. investigation of close contacts of the eight u.s. sars-cov-infected patients yielded one instance of secondary domestic transmission, although travel-related exposure cannot be definitively excluded for this case ( , ) , and the source of exposure is considered undetermined by who. in addition, no healthcare workers identified by national surveillance had laboratory evidence of sars infection, despite evidence of unprotected exposures to confirmed case-patients ( ) . while effective surveillance and timely infection-control measures likely helped limit transmission, why the united states experienced few sars-cov infections despite opportunities for importation and spread remains unclear. national surveillance during the emergency response met important surveillance objectives. it identified illness clusters for further investigation, tracked progression of the epidemic in the united states, and facilitated specimen collection from suspect and probable case-patients for sars diagnosis. this surveillance allowed for rapid and frequent updates to the healthcare and public health communities and to the public on the status of the outbreak. despite these successes, the system had several important limitations. like all passive systems, it relied on astute healthcare providers to detect and report illnesses that might have been sars. the lack of a rapid diagnostic test that could reliably diagnose sars-cov infection during the early phase of illness increased the workload and anxiety of clinicians, public health personnel, patients, their contacts, and the general public. frequent, labor-intensive contact with healthcare providers was needed to obtain updated clinical information for reported case-patients. as a result, classification of patients as suspect and probable case-patients was dynamic and often changed as new information became available. this situation sometimes created seeming discrepancies between national and state and local health department case counts, which in turn complicated public communication. the evolution of the worldwide outbreak required frequent modifications of the case definition, and establishing consistent criteria to define a sars-affected area on the basis of community transmission was difficult. finally, the paper-based reporting system increased the difficulty of reporting to cdc and delayed timeliness of reports, and the resulting database did not allow states immediate access to their own information. the time between disease onset and reporting to cdc increased in the latter phase of the outbreak. this increased reporting lag may reflect the growing surveillance workload as the outbreak progressed, delays in reporting until alternative diagnoses were evaluated, or a decreasing sense of urgency fueled by low disease rates and low likelihood of confirmed sars among u.s. case-patients and lack of evidence for community transmission. the value of remaining vigilant throughout all stages of an outbreak should not be underestimated. it was critical in the context of this outbreak that infection-control measures be rapidly implemented for all suspect and probable case-patients since a single case in any area could quickly have a global impact. evidence from toronto, hong kong, hanoi, singapore, and taiwan suggests that in some circumstances a single patient led to a large number of secondary cases and chains of transmission ( , ) . moreover, although most patients with sars show radiographic evidence of pneumonia, as was observed for all the confirmed u.s. case-patients with sars-cov disease, in an outbreak setting, heightened vigilance and infection-control measures should be maintained for suspect as well as probable case-patients because of growing evidence that a small proportion of patients may not exhibit evidence of pneumonia and because features of pneumonia often do not develop until days - of illness ( , ) . the timeliness of infection-control measures implemented for u.s. casepatients could not be assessed because relevant data were not collected as part of national surveillance. the clinical signs and symptoms of sars infections are similar to that of other respiratory illnesses. empiric management of patients with respiratory illness, limited state and local capacity to perform reliable respiratory diagnostics, and lack of national surveillance for respiratory syndromes, such as pneumonia, complicated the challenge of rapid identification of sars patients. comprehensive testing for a variety of respiratory pathogens among patients with suspect and probable cases found that % had evidence of a possible infection with bacterial and viral respiratory pathogens other than sars-cov. our finding that one case-patient with confirmed sars-cov also tested positive for influenza b infection is consistent with accumulating evidence that co-infections involving sars-cov and other bacterial or viral respiratory pathogens occur ( , ) . this underscores the importance of obtaining convalescent-phase serum samples to make final determinations about infection with sars-cov and of maintaining infection-control measures despite identification of alternative agents. moreover, in determining alternative diagnoses, the strength of the epidemiologic exposure criteria for sars, the specificity of the diagnostic test, and the compatibility of the clinical signs and symptoms and course of illness for the alternative diagnosis should be taken into account (tables and ) . testing for respiratory pathogens could not be completed until after the outbreak; this precluded timely re-assessment of case-patients to determine if an agent other then sars-cov was most likely responsible for the clinical illness. to help facilitate more timely diagnostic evaluation, cdc plans to develop real-time pcr assays for important respiratory pathogens for use by public health laboratories. improving local capacity for diagnosing respiratory illness should strengthen national preparedness for respiratory illness threats. in june , the council of state and territorial epidemiologists (cste) added respiratory illness due to sars-cov to the list of nationally reportable diseases. cdc has adopted the case definitions detailed in the cste position statement ( ) . this new definition, which was updated again on october , , will improve the predictive value positive of national surveillance by considering "reports under investigation" that require monitoring and infection control as separate from cases of confirmed sars-cov disease that will be reported to the national system. the statement sets the stage for future sars surveillance. cdc has developed a sars preparedness plan for the united states that outlines in more detail recommendations for surveillance ( ); as part of preparedness efforts, a web-based surveillance module for sars-cov disease reporting is now in place. in the absence of recognized sars cases, initial surveillance will likely consist of sentinel case detection with a focus on unexplained illnesses in healthcare workers and travelers returning from areas that were affected by sars in the recent global outbreak. because hospitals experienced high rates of transmission in affected areas, infection-control teams may additionally institute passive or active surveillance for pneumonia or fevers among staff and patients, combined with diagnostic testing for sars-cov. the intensity of surveillance efforts will need to be tailored to the degree of local transmission within both the community and healthcare facilities. contact tracing should rapidly identify possible early cases of secondary sars and any unrecognized sources of infection for persons without epidemiologic links. challenges remain, including how best to allocate limited public health resources for preparedness planning in light of the world's limited experience with sars infections and how to synchronize national case definitions and reporting requirements with the systems established by international agencies, such as who. although whether sars will become a recurring problem is unclear, lessons learned while preparing for that eventuality will be important for other global infectious disease outbreaks. update: severe acute respiratory syndrome-united states identification of a novel coronavirus in patients with severe acute respiratory syndrome a novel coronavirus associated with severe acute respiratory syndrome coronavirus as a possible cause of severe acute respiratory syndrome identification of severe acute respiratory syndrome in canada updated interim surveillance case definition for severe acute respiratory syndrome (sars)-united states the laboratory response network for bioterrorism update: severe acute respiratory syndrome-worldwide and united states validation of immunoglobulin g enzyme-linked immunosorbent assay for antibodies to pneumococcal surface adhesin a in the diagnosis of pneumococcal pneumonia among adults in kenya hospital-laboratory diagnosis of legionella infections human metapneumovirus infections in young and elderly adults concepts and procedures for laboratory-based influenza surveillance. atlanta: who collaborating center for the surveillance, epidemiology, and control of influenza application of a nested, multiplex pcr to psittacosis outbreaks development of taqman probe-based pcr with customized internal controls for detecting mycoplasma pneumoniae and m. fermentans. abstracts of the th general meeting of the development and evaluation of real-time pcr-based fluorescence assays for detection of chlamydia pneumoniae genescan reverse transcription-pcr assay for detection of six common respiratory viruses in young children hospitalized with acute respiratory illness severe acute respiratory syndrome (sars) and coronavirus testing-united states update: severe acute respiratory syndrome-united states update: severe acute respiratory syndrome-united states update: outbreak of severe acute respiratory syndrome-worldwide updated guidelines for evaluating public health surveillance systems: recommendations from the guidelines working group lack of sars in u.s. healthcare workers despite opportunity for transmission (abstract lb- ) alexandria (va): idsa update: severe acute respiratory syndrome-toronto, canada severe acute respiratory syndrome-singapore prevalence of asymptomatic infection by severe acute respiratory syndrome coronavirus in exposed healthcare workers (abstract k- c) asymptomatic severe acute respiratory syndrome-associated coronavirus infection. emerg infect dis [serial online utility of sensitive molecular testing to evaluate suspect sars cases in california (abstract v- ) occurrence of respiratory co-infections in persons suspected of having sars. abstract k- d public health guidance for community-level preparedness and response to severe acute respiratory syndrome (sars) we thank the state and local health departments and healthcare providers in the medical community whose efforts were the foundation for domestic sars surveillance and reporting. we are grateful especially for the contributions made by the council of key: cord- -zkxyxiv authors: crabtree, scott j.; cohen, stuart h. title: the role of multidisciplinary infection prevention teams in identifying community transmission of sars-cov- in the united states date: - - journal: infection control and hospital epidemiology doi: . /ice. . sha: doc_id: cord_uid: zkxyxiv this case study highlights the role of a multidisciplinary infection prevention team in the identification of the first community-transmitted sars-cov- case at a large, tertiary referral center in the united states. by rounding on the hospital units such teams can serve vital infection prevention, antibiotic stewardship, and disease surveillance functions. to the editor-the first case cluster of what would be later called coronavirus disease (covid- ) was reported in wuhan, china, on december , . by january , , the first imported case in the united states was identified in a returning traveler. the first community-transmitted case of covid- was not identified in the united states until february , , at the university of california davis medical center (ucdmc) in sacramento, california, in a patient without known travel to china or contacts with a known patient with covid- . prior to this, the centers for disease control and prevention (cdc) guidance had recommended sars-cov- testing only in these patient populations. through the coordinated efforts of ucd's multidisciplinary infection prevention (ip) program, the patient was identified as a possible covid- case and obtained sars-cov- testing. on february , , the case patient presented to a local community hospital with complaints of a flu-like illness. she decompensated shortly after her admission, requiring intubation, vasopressors, and progressively greater ventilatory support. arrangements were therefore made to have her transferred to ucdmc for the possible initiation of extracorporeal membrane oxygenation for acute respiratory distress syndrome. she arrived at ucdmc on hospital day (hd ). on hd , ucdmc's ip team conducted its weekly rounds in the medical intensive care unit. the ip team is a multidisciplinary team of an infectious diseases (id)-trained physician, an id-trained pharmacist, an ip nurse, and a unit nurse champion (table ) . this team rounds daily in a different icu with a recurring weekly schedule for individual units. during rounds, each patient is reviewed through the electronic medical record and via discussion with the bedside nurse to evaluate for possible infection prevention and antimicrobial stewardship interventions. efforts are focused on reducing unnecessary lines and devices, ensuring appropriate use of isolation precautions, and improving antibiotic utilization. recommendations are given directly to the bedside nurse when applicable or are later directed to the primary physician. at times, patients with complicated, presumed infectious processes are also referred to the infectious diseases consultation service for further evaluation. rounds typically require an hour daily, depending on the complexity of the patient population and the size of the unit. these teams have been active at ucdmc since the beginning of and are considered an important arm of ucdmc's ip program. at this point, the patient remained intermittently febrile but stable on the ventilator with an improving pao /fio and minimal respiratory secretions. laboratory testing was remarkable, with a white blood cell count of . cells/mm ( . % lymphocytes), sodium of mmol/l, and worsening creatinine of . mg/dl. computed tomography images of the chest showed confluent consolidative and ground glass opacities in the right upper and (to lesser extent) middle lobes. testing for common respiratory pathogens was negative. she had been in good health prior to her illness, with no significant travel or exposure histories. the patient's case was discussed with her bedside nurse, who confirmed that sars-cov- was considered by her primary team, but given the absence of exposures, testing for this agent was not pursued. we then made the decision for the bedside nurse to further clarify patient's occupational, travel, and potential exposure histories with her family, with plans for the ip team to reassess later that morning. the patient's bedside nurse subsequently reported that the patient worked in the service industry and had had direct and close interaction with multiple individuals on a daily basis. one of these individuals had returned from china a few weeks prior and was briefly detained by customs upon arrival. no further details of this encounter were available. the community in which she worked was located southwest of sacramento near a local air force base, where a number of diplomatic evacuees had been in recent quarantine. we then elected to review her case with the director of hospital epidemiology and infection control, and we collectively decided that, despite the absence of clear exposure risks, given her clinical picture and its unknown cause, testing for sars-cov- would be requested through the county public health officer. this request was first denied due to the patient's not meeting the cdc's criteria for a person under investigation (pui), but days later (on hd ) was granted by the cdc. on hd , nasopharyngeal rt-pcr results returned positive for sars-cov- . due to ongoing critical illness, the id consultation service made a request to the food and drug administration for compassionate-use remdesivir, which was granted that same day. the first dose was administered on hd . on hd , the patient was extubated, and on hd she was discharged home. antimicrobial stewardship "handshake" rounds, involving the regular in-person interaction between stewardship teams and frontline providers, were first rolled out at children's hospital colorado in , with good results. such rounds have been associated with sustained improvements in antibiotic utilization, high critical-care physician satisfaction, and improved and timely id consultation. similar ip-focused multidisciplinary teams have been shown to reduce the rate of catheter-associated urinary tract infections and central-line-associated bloodstream infections. however, given that this strategy is only a recent development, further research is needed to better appreciate its impact and to optimize this practice. this case highlights an additional and critical surveillance role that a multidisciplinary ip team can provide, especially in times of emerging infectious disease. due to the identification of this case, the cdc reviewed and later revised its pui case definition, with widespread impact on the management of the covid- epidemic within the united states. undiagnosed pneumonia-china (hubei) first case pf - novel coronavirus in the united states intervention and acceptance rates support handshake-stewardship strategy sustainability of handshake stewardship: extending a hand is effective years later attitudes and perceptions amongst critical care physicians towards handshake antimicrobial stewardship rounds a handshake from antimicrobial stewardship opens doors for infectious disease consultation the effect of interdisciplinary team rounds on urinary catheter and central venous catheter days and rates of infection a community transmitted case of severe acute respiratory distress syndrome due to sars cov in the united states acknowledgments. we would like to thank janet peterson, felicidad loomis, and shavinderpal sanga for their roles in the care of this patient and their contribution to the multidisciplinary ip team.financial support. no financial support was provided relevant to this article. all authors report no conflicts of interest relevant to this article. key: cord- -fan rta authors: childs, j.e.; krebs, j.w.; real, l.a.; gordon, e.r. title: animal-based national surveillance for zoonotic disease: quality, limitations, and implications of a model system for monitoring rabies date: - - journal: prev vet med doi: . /j.prevetmed. . . sha: doc_id: cord_uid: fan rta surveillance for zoonotic diseases among wildlife is a research and public health challenge. the inherent limitations posed by the requisite human–animal interactions are often undefined and underappreciated. the national surveillance system for animal rabies in the united states was examined as a model system; reporting of animal rabies is legally mandated, each case of rabies is laboratory confirmed, and data have been consistently collected for more than years. factors influencing the monthly counts of animal rabies tests reported during – were assessed by univariate and multivariable regression methods. the suitability of passively collected surveillance data for determining the presence or absence of the raccoon-associated variant of rabies within states and within individual counties was assessed by determining critical threshold values from the regression analyses. the size of the human population and total expenditures within a county accounted for % and %, respectively, of the variance in testing. the annual median number of rabies tests performed was seven for counties without rabies, for counties with non-raccoon rabies, and for counties with raccoon rabies. active surveillance may be required in locales with sparse human populations when a high degree of confidence in the status of rabies is required. the systematic collection of surveillance data on infected or diseased wildlife at the national level is extremely rare. systematic surveillance at the national level requires a central authority which receives standardized reports of incident cases of disease or infection occurring among wildlife within geographically and politically defined surveillance units during specified time intervals which are generated by regional veterinary or public health officials. ideally, reporting by local authorities would be legally mandated and standardized and suspected cases of disease would be confirmed by clinical samples tested at a diagnostic laboratory using validated methods. epidemiologists at the central authority would collate and analyze the regional data to provide local authorities with a comprehensive national report on disease activity. recent experiences with avian influenza virus a, subtype h n (ellis et al., ) , sars coronavirus (lau et al., ) , and the henipaviruses (mackenzie, ) have focused attention on the possible benefits of collecting epidemiologic information on virus maintenance within wildlife populations serving as reservoir hosts. as national data on domestic and wild animal rabies has been systematically collected from individual counties within each state in the united states for more than years this system provides an excellent model to explore the strengths and limitations of animalbased surveillance for a viral zoonosis. furthermore, reporting of animal and human rabies is legally mandated by each state and territory within the united states centers for disease control and prevention, ) and each case of animal rabies is confirmed by laboratory testing prior to being reported to the federal centers for disease control and prevention (cdc) as part of the national notifiable disease surveillance system (centers for disease control and prevention, ) . as post-exposure measures dictated for humans and domestic animals are often based on the results from standardized laboratory testing for the presence of rabies viral antigen or rna in brain tissue from a suspect rabid animal (trimarchi and smith, ) , diagnostic testing is an essential activity and integral to rabies prevention (gordon et al., ) . it is important to note that public health officials and veterinary health officials define surveillance and monitoring systems differently. a passive surveillance system as defined by public health practitioners is ''. . . one in which a health jurisdiction receives disease reports from physicians, laboratories, or other individuals or institutions as mandated by state law'' (birkhead and maylahn, ) . the closest corresponding system in veterinary public health is considered an active monitoring and surveillance system and is defined as ''an active collection of data for any monitoring and surveillance system (moss) is the systematic collection or regular recording of cases of a designated disease or group of diseases for a specific goal of monitoring or surveillance'' (salman, ) . as the animal rabies surveillance system was designed to protect human health, is mandated by law, and is coordinated by a federal public heath agency, the cdc, the term surveillance system is used herein rather than moss. national surveillance data for animal rabies have proved invaluable for mapping the approximate geographic boundaries of areas affected by specific rabies virus variants krebs et al., ) , documenting county-specific levels of rabies activity (childs et al., ) , and projecting epidemic spread russell et al., russell et al., , . with the increasing use of oral rabies vaccine (orv) to control and contain wildlife rabies in the united states (steelman et al., ; kemere et al., ; slate et al., ) national surveillance data have assumed a new importance in identifying the boundaries of areas affected by wildlife rabies. however, the suitability of the national surveillance system to pinpoint areas affected by rabies is often assumed without regard for the limitations inherent in the systematic collection of information requiring numerous levels of human-animal interaction. human-animal interactions begin at the local level where individual citizens are involved in the reporting of a suspicious animal and local authorities are required to procure and ship a specimen to a state laboratory. once an animal specimen arrives at the state laboratory a decision is made concerning testing; specimens from animals not directly involved in a potential human or domestic animal rabies exposure are typically excluded from testing (wilson et al., ; torrence et al., ; fischman et al., ; gordon et al., ) . counts of rabies test results reported as national surveillance data are, therefore, the endpoint of a required activity and these data provide an important index as to the level and epidemiologic characteristics of rabies activity within the surveillance-unit of the individual county (wilson et al., ; fischman et al., ; childs et al., ; gordon et al., ) ; no other independent source of information on wildlife rabies exist. irregularities in reporting of animal rabies at the county-level is widely acknowledged (torrence et al., ; fischman et al., ; moore, ; mondul et al., ) , but factors contributing to this variability have not been assessed. similarly, no effort has been made to assess the relative suitability of national surveillance data to determine the presence or absence of a specific variant of rabies virus within a specific county. herein, factors affecting the annual number of laboratory rabies tests performed by a county were assessed and the suitability of this activity for determining the presence or absence of raccoon rabies was evaluated. national surveillance data from to were analyzed if submitted from a state affected by the unique variant of rabies virus associated with raccoons (procyon lotor) (smith et al., ; smith, ) . nineteen states met the inclusion criterion; alabama, connecticut, delaware, florida, georgia, maine, maryland, massachusetts, north carolina, new hampshire, new jersey, new york, ohio, pennsylvania, rhode island, south carolina, virginia, vermont, and west virginia. monthly surveillance reports of laboratory-confirmed cases of animal rabies, identified by standardized methods (trimarchi and smith, ) , included the species name or common name of taxonomically related groups (e.g. ''bat''), the date of diagnostic testing, and the county of origin. states are only required to report positive results (i.e. rabid animals), however, since cdc had requested ''complete'' reporting of both positive and negative laboratory results. a rough gauge of the quality of the crude surveillance data submitted by states was set to determine if ''adequate'' surveillance (who, ; advisory committee on immunization practices, ; oie, ) was occurring within a state; specifically, how confident should health practitioners be that raccoon-associated rabies was absent if no rabies or no raccoon rabies was reported from a state or county. the criterion used to operationally define adequate state reporting required that the annual number of negative test results reported had to equal or exceed the annual number of positive (i.e. rabid) results; years in which ! % of the reported rabies tests were negative are referred to as ''complete reporting years''. states contributing < % complete reporting years over the -year study were discussed, but their counties were excluded from detailed analyses. the outcome modeled was the median annual number of animals (log transformed) reported from individual counties within a state or among all counties in the affected region during - (childs et al., ; gordon et al., ) . additional analyses stratified counties into five categories to examine surveillance specific to raccoon rabies in more detail: counties with no reported rabies, counties reporting rabies but not raccoonassociated rabies, counties reporting raccoon-associated rabies, counties with a state diagnostic laboratory (laboratory county), or counties without a state diagnostic laboratory (non-laboratory county). nine covariates were evaluated. three demographic variables, log county area, log county human population and county human population density evaluated the association of human population size or density on numbers of animals tested for rabies per county; three demographic variables, percentage of college graduates per county, percentage of persons living below the poverty level per county, and log total annual county expenditures, were selected to provide an index of the socio-economic features of individual counties; and three covariates, distance (km) to the nearest testing laboratory, latitude, and longitude, provided information on the absolute location of county and relative distance to a county rabies testing facility. epidemics of raccoon-associated rabies were previously shown to vary along a north-south gradient in the united states (childs et al., ) . various multivariable linear regression models were constructed using a stepwise selection procedure in sas, which retained variables significant at p < . (sas institute, ) . demographic data came from the u.s. census (u.s. census bureau, ). latitude, longitude, and distance data were calculated from county centroids using sas geographic information service software (sas institute, ) . testing of residuals by cook's distance and dffits was performed as warranted (neter et al., ) . bonferroni adjustments of alphas for multiple comparisons were made as warranted (rothman and greenland, ) . three states contributed insufficient numbers of complete reporting years (< over the -year study interval) and were excluded from further analyses: florida ( complete years), georgia ( ), and delaware ( ) (fig. a) . only three ( . %) of florida's counties and ( . %) of georgia's counties ever submitted complete surveillance reports (fig. a) . the final data set contained counties within states and generated , county-years of complete rabies test reporting (table ). the number of complete reporting years submitted by a given state ranged from six to ten years; complete reporting from all states occurred only in ( fig. a and b) . the median number of rabies tests reported per county-year ranged from to (fig. ) . the overall median percentage of rabid animals testing positive per county-year was . % (n = ; fig. c , table ). counties reporting no rabies reported the lowest median of seven animals tested for rabies per year (interquartile range [iqr] , ) and a the independent city of baltimore was omitted, and its reports were assigned to the county of the same name. b the independent cities of charlottesville, covington, emporia, falls church, harrisonburg, lexington, manassas, manassas park, martinsville, norton, poquoson, staunton and winchester had no reports and were omitted. the independent cities of fairfax, bedford, franklin, and roanoke were omitted, and their reports were assigned to counties of the same names. counties with rabies-but not raccoon-associated rabies-reported a median of (iqr , ) . counties with raccoon-associated rabies reported significantly more rabid animals, median = (iqr , ), than other counties (table ). laboratory counties (n = ) among of states reported the highest median annual number of (iqr , ) animals tested (fig. and table ); the non-laboratory counties reported a significantly lower annual median of (iqr , , p < . ). the median annual percentages of animals testing rabid were indistinguishable between laboratory and non-laboratory counties ( . % and . %; table ). univariate analyses revealed that county human population size accounted for > % (adjusted p < . for each state) of total variance in the median number of animal rabies tests reported per county-year within each state; r values exceeded % for of states. similarly, median annual county expenditures within each state accounted for > % ( p < . ) of total variance in the median number of animal rabies tests per county-year for of states. other covariates accounting for > % of the variance among rabies tests performed were county human population density, percentage college graduates and percentage of the population below the poverty level. results from stratified analyses were, with a single exception, completely concordant with state county-level analyses; total county expenditures explained a higher percentage of the variance ( %) among laboratory counties than did human population size ( %). in regional univariate analyses of all counties human population size accounted for % of the variance in the animals tested per county-year and total county expenditure accounted for % of the variance. the estimated minimum number of humans in a county and minimum threshold of county expenditures required for any animal to be tested for rabies was persons or $ , , ( fig. a and b) . multivariable regression models separately assessed the association of human population size and total county expenditures on total animal rabies tests reported per county as colinearity (r = . ) precluded their simultaneous inclusion in models. county human population size accounted for %- % of the variance in median number of animals tested per county-year in stratified county analyses and % in the regional analysis (table ) . similarly, county expenditures explained %- % variance in stratified county analyses and % in the regional analysis (table ) . covariates other than human population size and total county expenditures explained < . %- % of the total variance in multivariable models (table ). residual diagnostics indicated that none of the multivariable models violated assumptions of normalcy or variance in the error term, with the exception of the regional model containing county expenditures; as only one outlying county was influential no changes were made in this individual model. the median number of rabid raccoons reported per county-year was significantly correlated (r = . ) with the total number of raccoons tested; the ''required'' minimum number of raccoons tested to detect a single rabid raccoon was approximately . . mapping the locations of the counties testing < . raccoons per year indicated that most of the counties reporting no rabies present or no raccoon-variant associated rabies were outside the known endemic area of raccoon-associated rabies or in states (maine and new york) at the boundary of the expanding wavefront of the raccoon rabies epidemic in (fig. a) . however, counties with low annual rates of testing raccoons were also evident within endemic regions of raccoon-associated rabies and were common throughout regions rabies reported, rabies reported but not among raccoons, and no rabies reported. areas of low reporting and of special interest as sites of oral rabies vaccine (orv) delivery are circled. (b) counties reporting > . and . raccoons tested for rabies, the suggested threshold needed to on average detect a single rabid raccoon. enlarged circled areas indicate regions with low rabies reporting considered to be at risk for rabies introduction through long distance translocation. immediately adjacent to known epidemic or endemic activity in ohio, west virginia, and alabama (fig. b) . national surveillance for animal rabies within the united states provides sufficient information to map regions of endemic rabies where different virus variants circulate among terrestrial carnivore hosts and these data can accurately predict which variant is responsible for most rabies within a given county (mcquiston et al., ; . however, the presence or absence of rabies in a given county in which no rabid animals are reported and few are tested cannot be determined by the boundaries of endemic rabies drawn from surveillance reports submitted by other counties in the region: it is impossible to differentiate whether the absence of rabies reports reflects inadequate levels of surveillance or the genuine absence of disease. the world health organization, the world organization for animal health and the cdc (who, ; advisory committee on immunization practices, ; oie, ) , state that ''adequate surveillance,'' as indicated by sufficient animal testing and reporting, are prerequisites to a country being considered ''rabies-free.'' similar criteria can be applied to state reporting and in the cdc requested that states submit the results from all rabies tests performed to specifically assess the adequacy of surveillance coverage. however, cursory examination of surveillance reports from states submitted from to , using an index of ! % negative test results as an operational measure of adequate surveillance, revealed three states where insufficient laboratory test data precluded interpretation of the absence of rabies reporting; other states had a varied record of complete reporting. the operational criteria for adequate reporting used herein was liberal, chosen to capture states where limited resources may preclude testing of animals other than those directly involved in a potential rabies exposure to a human or domestic animal. when raccoon rabies is epidemic in a state the percentage of raccoons testing rabid can approach % in a given year (beck et al., ; fischman et al., ) ; the overall percentage of rabid animals will be diluted by negative results from other species and will fall below % (gordon et al., ) . as no guidelines exist as how to define adequate surveillance this arbitrary, but transparent, measure was selected as an initial reference value that in the future may be further reassessed and refined. inadequate surveillance for rabies may be of little concern if a non-reporting county is surrounded by counties where raccoon rabies has already been reported, as raccoon rabies can be assumed to be present. however, if the county reporting no rabies is situated in the path of a spreading epidemic and is proximate to counties recently reporting raccoon rabies then the issue of adequate surveillance becomes highly relevant. the need to know the status of rabies within a specific locale is crucial when planning for rabies control as when geographically-targeted rabies intervention, such as orv, is being considered to interrupt the spread of epidemic raccoon rabies into previously unaffected counties (slate et al., ) . whether the absence of rabies testing, or extremely low levels of testing, reflect actual circumstances (i.e. no wildlife biting humans or domestic animals, therefore no testing) or insufficient surveillance is difficult to decipher. however, a consistent positive association has been documented between the likelihood of detecting rabies in the reservoir host species and the total number of animal rabies tests performed (wilson et al., ; torrence et al., ) . regression analysis of the number of rabid raccoons detected per number of animal rabies tests performed in the townships of connecticut revealed a strong positive association (r = . ; p < . ), nearly identical to the value obtained herein (r = . ; p < . ). the robustness of this association across different geographic scales ( townships versus eight counties) is consistent with results indicating that the percent of rabid animals identified becomes stable above a critical number of animal tests (fig. c) . this asymptotic relationship was well illustrated by the differences in median numbers of animals tested per county-year in laboratory counties ( animals) and non-laboratory counties ( ) where the percentage of rabid animals was identical ( . % and . %). the numbers of animals tested for rabies and reported through surveillance were positively and strongly associated with human population size or, alternatively, median annual expenditures in the individual county. county human population density was a less important factor than absolute population size. counties with high human densities contain urban centers, which support lower densities of wildlife reservoirs of rabies virus. although urban parks can support some of the highest densities of raccoons recorded (riley et al., ) , indices of raccoon population size and distribution indicate this species is absent or rare in the most densely populated areas of cities (anthony et al., ) . the numbers of animals submitted for rabies testing suggests human or domestic animal contact with rabid animals is frequency dependent, based on the prevalence of rabies among animal populations and the absolute number of persons, rather than dependent on human population density. in regions where orv is being used to form a vaccine barrier (foroutan et al., ; slate et al., ) counties that are proximate to other counties with endemic or epidemic raccoon variant rabies are at risk for rabies even if no wildlife rabies had been previously detected, as exemplified by the sudden appearance of a focus of raccoon rabies in townships > km west of the ohio orv barrier; raccoon rabies had not been previously detected in the affected townships or in intervening townships immediately to the west of the orv barrier (lake county general health district, ; russell et al., ; slate et al., ) . the large numbers of counties reporting low numbers of raccoons tested for rabies proximate to the orv barrier in ohio and west virginia (rabies management, a , b ) pose a potential surveillance problem. in high risk counties active surveillance should be considered as a complement to the passive surveillance system in place. the high probability of rabies introduction through long distance dispersal or translocation of infected animals poses one of the greatest threats to effective rabies control programs. there is a well established history of long-distance translocations of infected raccoons spreading raccoon-associated rabies virus into areas not immediately adjacent to known endemic foci (nettles et al., ; russell et al., ; smith et al., ) . long distance translocations created epidemic foci in advance of the traveling wavefront of epidemic raccoon rabies in connecticut . potential routes of raccoon rabies spread from breech points in the ohio orv barrier have been identified, and coupled with active surveillance programs, these methods can improve rapid detection and help target remedial intervention activities (russell et al., . this study had several limitations. the most obvious is reliance on the relative qualities of surveillance data from a broad region to reach conclusions on the level of rabies surveillance activity within specific states and counties. there are no additional independent sources of animal rabies data available to assess the completeness of rabies reporting, therefore, the comparative approach was used to evaluate the adequacy of existing surveillance activities. furthermore, this study pooled county reports submitted from - and levels of raccoon rabies varied within each county during this interval (childs et al., ; gordon et al., ) . a study looking specifically at reporting trends during differing stages of the raccoon epidemic among counties would be useful. this study identified several factors influencing national surveillance for animal rabies. many factors are likely to influence any systematic effort to assess infection or disease among wildlife species serving as reservoir hosts for zoonotic pathogens. the complex web of human-animal interactions required to generate each surveillance datum will limit the completeness of any animal-based surveillance system. within the united states both the number of persons and the resources available were significantly associated with surveillance activity. however, local county features also influenced the rate of rabies testing. variation in complete reporting of test results complicated unambiguous interpretation of the presence or absence of raccoon-associated rabies in specific areas. it is certain that any other animal-based surveillance program that relies on citizen participation will encounter similar issues and limitations. advisory committee on immunization practices land use associations and changes in population indices of urban raccoons during a rabies epizootic an epizootic of rabies in maryland, - principles and practice of public health surveillance case definitions for infectious conditions under public health surveillance national association of state public health veterinarians, inc. 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severe acute respiratory syndrome coronavirus-like virus in chinese horseshoe bats emerging zoonotic encephalitis viruses: lessons from southeast asia and oceania epidemiologic characteristics of rabies virus variants in dogs and cats in the united states trends in national surveillance for rabies among bats in the united states spatial diffusion of raccoon rabies in pennsylvania, usa applied linear regression models terrestrial animal health code usda rabies management national program. united states department of agriculture population density, survival, and rabies in raccoons in an urban national park modern epidemiology predictive spatial dynamics and strategic planning for raccoon rabies emergence in ohio a priori prediction of disease invasion dynamics in a novel environment animal disease surveillance and survey systems; methods and applications status of oral rabies vaccination in wild carnivores in the united states predicting the spatial dynamics of rabies epidemics on heterogeneous landscapes assessing the role of long-distance translocation and spatial heterogeneity in the raccoon rabies epidemic in connecticut molecular epidemiology antigenic characteristics of isolates associated with a new epizootic of raccoon rabies in the united states bait delivery for oral rabies vaccine to gray foxes epidemiology of raccoon rabies in virginia, to diagnostic evaluation profiles of general demographic characteristics emergence of raccoon rabies in connecticut, - : spatial and temporal characteristics of animal infection and human contact the authors thank the state and territorial health departments, agriculture departments, and laboratories for their contributions of rabies surveillance data. this work was supported in part by u.s. department of agriculture grant ca to emory university. key: cord- -dvlnx z authors: park, jewel; rhim, hye chang title: consequences of covid- on international medical graduates and students applying to residencies in the united states date: - - journal: korean j med educ doi: . /kjme. . sha: doc_id: cord_uid: dvlnx z nan the coronavirus disease (covid- ) pandemic has necessitated unprecedented measures to contain the virus, including restricting foreigners from entering the united states. since january , , several presidential proclamations have sequentially restricted the entry of foreign nationals from china, iran, and much of europe; and as of march , the department of state has temporarily suspended routine visa services at all us embassies and consulates [ ] . previous immigration restrictions, such as presidential proclamation in , had already raised concerns about hindering the entrance of international medical graduates (imgs), who constitute % of the physician workforce in the united states [ ] . according to the national resident matching program (nrmp), also known as the match, approximately , non-us imgs, in addition to , us imgs, apply for residencies in the united states every year, citing various reasons such as greater professional opportunities, a better training environment, or political stability [ ] . the application process for imgs is complex and rigorous, often requiring several years after graduation from medical school, and it is inherently unpredictable, with only % of applicants matched successfully [ ] . thus, the process is especially vulnerable to perturbations such as the current pandemic, and the consequences will negatively affect not only the flow of the physician workforce into the united states, but also the career fulfillment of imgs and bilateral exchange of knowledge between the united states and other countries [ ] . while the negative impacts of the pandemic on the residency application process may be minimal if the pandemic is controlled in the near future, estimates suggest the spread of covid- in the united states will peak in june , and due to the risk of rebound transmission, widespread social distancing will need to be maintained for at least months, until vaccines are available to immunize the population [ ] . here, we summarize the potential consequences of the covid- pandemic on the process of medical residency applications for current imgs and international medical students (imss) and recommend measures that can be taken to minimize the disruption to their participation in us healthcare. many steps in the process of residency application for imgs require that applicants be physically present in the united states, such as the step clinical skills (cs) and step exam, and complete residency interviews. also, although it is not compulsory, many imgs participate in observerships/externships or research in the united states to increase their competitiveness. all these activities can be severely affected by the current travel restrictions. step cs exam is particularly important. given the unavoidable human-to-human contact that takes place during the exam, the united states medical licensing examination (usmle) program has closed all of its five test centers as of march , , and plans to reopen them on june at the earliest [ ] . while the usmle program, after reopening, "will open additional testing appointments to help meet increased, timesensitive testing demands," not only is there a possibility that the reopening will be significantly delayed given the uncertain trajectory of the current pandemic, but a great practical difficulty is likely to arise in the plan to offer additional appointments, as the number of trained standardized patients (sps) is limited and may even decrease if sps decline to participate due to health concerns. this problem is especially significant because step cs testing appointments are already notorious for being extremely limited and completely fill up at least to months in advance. moreover, score reporting can take up to months, which means that test appointments have to be scheduled very early on to meet the deadlines set by residency programs. the process is even more complicated for non-us imgs, who have to apply for a visa just to take the exam. with the current suspension of visa services, many imgs will find it difficult to secure a date that will enable them to meet the deadlines, and consequently, they may have to forego applying for the match. since the trajectory of the current pandemic is unpredictable, a delay in reopening the usmle test centers seems inevitable. therefore, plans for reopening should be prepared and announced in a timely manner to avoid critical disruptions to the application process. alternatively, authorities may consider granting a temporary waiver in the match for step cs qualification to allopathic us medical students, for whom the need for the accreditation has comparatively less utility given the first-time pass rate of % [ ] ; this will solve the issue of the limited availability of step cs test appointments, which is currently putting us and international applicants alike at risk of not meeting the application deadline. for imss who have yet to graduate, the cancellation of visiting electives in the united states is the gravest concern. due to safety concerns arising from the covid- pandemic, many medical schools in the united states have cancelled clinical rotations and stopped receiving visiting students. as of april , , out of the schools that reported their policies on visiting students to the association of american medical colleges, schools are not receiving visiting students [ ] . it is uncertain when these medical schools will start receiving visiting medical students again. in addition to the well-recognized advantage of participating in visiting electives for successful candidacy in the match [ ] , visiting electives benefit step reporting from three-digit scores to a pass/fail grade is expected to increase the importance of visiting electives and letters of recommendation for imss, since they now have lost one important objective measure attesting to their clinical competency [ ] . applying to a visiting elective in the united states is already a difficult and stressful process for imss, due to visa issues, financial burdens, incompatibility with the home institution's curriculum, and the extremely limited number of schools that offer visiting electives to international students (just before the pandemic, only medical schools offered spots for imss from institutions without affiliation agreements). since many imss solidify their intent to practice medicine in the united current outbreak of coronavirus disease long-term potential implications of immigration barriers for medical education international medical graduates in the usa: a qualitative study on perceptions of physician migration easing international medical graduates' entry into us training the importance of international medical graduates in the united states covid- response team, imperial college london. impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and healthcare demand united states medical licensing examination. covid- updates and resources conducting a high-stakes osce in a covid- environment governor murphy signs executive order to remove barriers to health care professionals joining new jersey's covid- response and provide protections for front line health care responders national resident matching program. nrmp faqs during covid- pandemic the usmle step cs: time for a change association of american medical colleges. vslo program updates the impact of visiting student electives on surgical match outcomes change in reporting of usmle step scores and potential implications for international medical graduates acknowledgements: none. key: cord- -w sk m authors: caduff, carlo title: what went wrong: corona and the world after the full stop date: - - journal: med anthropol q doi: . /maq. sha: doc_id: cord_uid: w sk m this article examines the global response to the covid‐ pandemic. it argues that we urgently need to look beyond the virus if we want to understand the real seriousness of what is happening today. how did we end up in a space of thinking, acting, and feeling that has normalized extremes and is based on the assumption that biological life is an absolute value separate from politics? the author suggests that today's fear is fueled by mathematical disease modeling, neoliberal health policies, nervous media reporting, and authoritarian longings. it is as though mankind had divided itself between those who believe in human omnipotence (who think that everything is possible if one knows how to organize masses for it) and those for whom powerlessness has become the major experience of their lives. ---hannah arendt the measures that governments across the world have taken to contain the spread of coronavirus disease are massive and unprecedented. as a result of these measures, life has come to an almost complete standstill, with many countries under lockdown. never in the history of humanity have such drastic interventions into the lives of populations occurred in the name of health on such a scale and in such a short period of time. as a result of the world's largest and perhaps most stringent lockdown, millions of daily wage laborers have lost their source of income in india. health care workers have been attacked and evicted from their homes because they are seen as potential spreaders of contagious disease (kalra and ghoshal ) . neighborhoods have been scared into panic when an ambulance appears on the street. due to the sudden ban on any form of transportation, migrant workers have been stranded between the cities where they used to work and the villages where their families are living (daniyal et al. ) . cancer patients have been unable to receive essential medical care because they cannot reach the hospital. it is the poor, the marginalized, and the vulnerable who are most affected by drastic measures, exacerbating already existing inequalities. in kenya, the police enforced a coronavirus curfew using teargas and excessive force against presumable violators of lockdown law (namwaya ) . in bangladesh, the government created a special unit to monitor social media and arrest people for spreading "misinformation" about the virus (hrw ). in hungary, parliament passed a law allowing prime minister orbán to limit freedom of speech, defer elections, and suspend rules and regulations by decree (gebrekidan ) . in india, state governments released companies from the purview of labor laws, including occupational health laws, to stimulate the economy (sharma ) . in lebanon, the currency collapsed, leaving % of the population in need of food aid (chulov ) . in the united states, over million people have filed for unemployment benefits (rushe and aratani ) . unfortunately, as of the writing of this article, many things remain completely unknown in this pandemic despite intensive investigation. for example, we don't know what helped contain the outbreak in china, and particularly whether government interventions reduced the spread of the virus or if the virus burned out there before moving on to other susceptible populations. the fact is: we simply don't know. nevertheless, many actors and institutions have proceeded as if they did know, imposing extreme measures that have affected billions of people and that have pushed societies to the edge of collapse by creating poverty, hunger, misery, debt, and unemployment. today, many wonder how we ended up where we are. how was it possible for a virus to trigger such a massive response that continues to threaten society and the economy, with so little discussion about the costs and consequences of extreme measures? why is there widespread agreement that aggressive interventions to "flatten the curve" were necessary and justified? it seems that this unprecedented public health experiment occurred without sufficient consideration of the social, political, and economic consequences. the failure to consider the impact of extreme measures that have become the norm in many places in the covid- pandemic has been stunning. the destruction of lives and livelihoods in the name of survival will haunt us for decades. the coronavirus disease outbreak seems to have started in the chinese city of wuhan in december . in january, the chinese government put wuhan and other major cities in the province under lockdown. a lockdown of million people "is unprecedented in public health history, so it is certainly not a recommendation the who has made," dr. gauden galea, the world health organization's (who) representative in beijing, emphasized at the time (reuters ). in other provinces, the chinese government implemented tailored measures, including factory shutdowns and school closures, but not a lockdown or restriction of movement to limit the spread of disease. major media outlets in the united states called china's locked-city strategy deployed in and around wuhan "harsh," "extreme," "severe," and "controversial," emphasizing that it offered "no guarantee of success" (qin et al. ) . a new york times article noted that "china is trying to halt a coronavirus outbreak using a tactic … with a long and complicated history fraught with social, political and ethical concerns" (levenson ) . experts quoted in the article called the lockdown of cities "an unbelievable undertaking" that would be "patently unconstitutional in the united states." "that type of thing," said james hodge, a professor of law, "is obviously an excessive response." another expert cited in the article, historian howard markel, pointed to the "darker side of quarantine-its use as a social tool rather than its scientific use as a medical tool." in the united kingdom, newspaper articles suggested that the chinese government would not be able to keep the city of wuhan "closed for business indefinitely" (graham-harrison ). in february, the virus continued to circulate and soon appeared in other countries. in march, the who declared the covid- outbreak a global pandemic. despite the criticism of china's approach, a crude and extreme version of lockdown became the international norm promoted by experts, officials, and the media across the world. concerns with the dark side of quarantine faded rapidly. a few countries like south korea veered from this norm and chose instead a classic infectious disease intervention: test-trace-isolate, with a highly centralized approach to public health intelligence gathering. emphasizing mass testing and meticulous contact tracing to interrupt the chain of transmission, south korean health officials closed schools and managed the crisis successfully without any lockdowns or roadblocks, and few restrictions of movement. significantly, south korea learned from earlier outbreaks of infectious disease (sars in particular), and imposed central control, used digital technologies, and enforced quarantines, and it witnessed one of the lowest covid- mortality rates. by the end of april , around , cases of infection had been detected there, but only people had died. germany developed its own testing protocol, which was published on january by the who (beaumont ) . when the first case was detected on january , germany launched mass testing, systematic contact tracing, and early hospitalization, keeping the mortality rate low and hospitals functional even when cases of infection increased (mohr and datan-grajewski ) . health officials relied on an extensive network of laboratories and were able to conduct over , sars-cov- (covid- ) tests per week (buck ) . along with south korea, germany put testing and contact tracing at the heart of the response. despite the who's emphasis on testing and south korea's and germany's early success in reducing the spread of the virus, most countries considered testing at scale as a low priority and relied on an extreme version of the chinese approach of lockdown. however, in china, the approach was tailored and regionalized; as a who report noted, "specific containment measures were adjusted to the provincial, county and even community context, the capacity of the setting and the nature of novel coronavirus transmission there" (who ). the lockdown focused on the major cities in the most affected province, constraining the life of million people in a country of . billion. in other words, it was a limited lockdown affecting % of china's total population. in contrast to the tailored and regionally differentiated intervention that sought to minimize the socio-economic impact of the response, many other governments across the world imposed nationwide lockdowns that went far beyond china's locked-city approach. in practice, these lockdowns amounted to curfews (often legalized after the fact by emergency laws). italy was the world's first country with a nationwide lockdown/curfew. many countries followed suit, partly motivated by shocking images of overwhelmed hospitals in italy's north and partly driven by a disease model report released in the united kingdom a few days after italy's surprising national lockdown announcement . this moment of shock and surprise triggered a chain reaction in the pandemic response. the horizon shifted, the inconceivable became possible, and life suddenly felt surreal. the u.k.'s disease model garnered a lot of attention, creating a sense of urgency that amplified the political pressure because the numbers were alarming . published by a group of experts without peer review on an institutional website, the report compared covid- with the great pandemic of , which killed over million people worldwide and suggested, without any evidence, that sars-cov- was "a virus with comparable lethality to h n influenza in ." most frightening in all this was not so much the lethality of the sars-cov- virus but the license to rush forward with predictions, abandon basic standards of science, and make dramatic claims to scare people. for covid- , the report predicted , deaths in the united kingdom and . million deaths in the united states. it presented possible strategies to reduce the impact of the pandemic, but the focus was exclusively on "non-pharmaceutical interventions." there was no discussion of testing and contact tracing. a proven public health strategy known to be effective was systematically sidelined in one of the most influential reports to emerge in the covid- pandemic. significantly, the report claimed to focus on "feasibility" of measures and promoted the idea that systematic suppression of transmission would work best-in other words, lockdowns. however, it excluded from any consideration the social, political, and economic implications of lockdowns, noting that "no public health intervention with such disruptive effects on society has been previously attempted for such a long duration of time." in addition to ignoring testing and contact tracing as a possible strategy, disregarding the social, political, and economic implications of lockdowns, and conceding that there is no "easy policy decision to be made," the authors of the report felt confident enough to claim that "suppression" was the "preferred policy option" and the "only viable strategy" that countries across the world needed to implement "imminently." the lockdowns that were required for suppression would need to be maintained "until a vaccine becomes available" (which they predicted to be "potentially months or more"). a crude, extreme, and ultimately unsustainable version of the chinese approach became the international norm. shutting down society and the economy until a preventive medical treatment becomes available was advanced as an appropriate response and the only possible way of dealing with the crisis, despite the costs and consequences. italy figured as an important but fundamentally ambivalent model, shifting the locked-city into a locked-country approach. the italian scenario was sobering and frightening but also inspiring and motivating. to avoid italy's disaster, governments appropriated the italian approach of mass confinement and rigid restriction of movement as a one-size-fits-all intervention. in many places throughout the world, including italy and france, the locked-country approach took a militarized form with massive deployment of the police to enforce lockdown restrictions. the locked-country approach seemed to obviate the necessity of justifying a differentiated strategy that might have looked unequal and unfair and that might have intensified social and political conflicts along multiple internal fractures and fault lines. to avoid the political fallout of a differentiated strategy, which would have required systematic testing, government officials in europe and elsewhere invoked the politically expedient image of a total threat and suggested that "we are all in the same boat" and that "we are all in this together." the idea that regional lockdowns would not be possible and that it was best to treat the virus as a global threat that would uniformly impact all people involved conjuring an image of a united nation confronting a total threat that required everyone's sacrifice. this image relied on a false assumption of equality. solidarity came to mean not mutual support in a situation of uneven risk, but rather generalization of a sense of danger across a national population perceived as a homogeneous body under attack. the ideology of national pandemic solidarity-putting everybody under confinement and treating everyone the same-obscured the reality that lockdowns mean different things to different people, and that not everyone is equally exposed or equally vulnerable. both the virus and the lockdown disproportionately affected those who were already vulnerable along lines of age, class, and race. dramatic references to the magnitude of the threat served as justification for nationwide lockdown policies. this extreme and unprecedented blanket approach systematically imposed on entire populations was driven by a number of factors that variously prevailed in different countries across the world: a growing sense of panic, constant media sensationalism, deep authoritarian longings, increasing political pressure to contain the spread of the virus, disturbing accounts of overwhelmed hospitals unable to cope with the surge of patients, misleading mortality calculations, and, most importantly, a trust in the power of mathematical disease modeling. throughout the covid- pandemic, there has been an abiding assumption among observers and the public that it is clear what is happening; that everyone knows what is going on because everyone can see it on television. however, what an endless stream of media reports from around the world have continued to obscure is the fact that it is impossible to know what is happening in a population when there is no systematic testing. the lack of testing created a void that was filled by the flexible evidence of disease modeling. in the absence of robust data, disease modeling emerged as the presumably best and only available science to inform policy. media hyperbole focused on absolute numbers independent of context and made covid- deaths politically visible. flexible disease modeling (often based on data derived from viruses such as influenza) took the place of accurate epidemiological surveillance. scientific papers published online without peer review made scary projections and painted a grim picture. widely reported simulation models created shock effects that shaped government policies. a narrow focus on numbers played an important role in understandings of the magnitude of the threat, fueling fear and panic in the absence of actual evidence. a distinct imaginary took hold, "the imaginary of an unprecedented event," which seemed to require an unprecedented response (kelly ). there was a widespread sense, among experts and the media, that the sars-cov- virus was much more lethal than influenza. that this pandemic was different from influenza and thus necessitated a different approach was typically claimed on the basis of the case-fatality rate, the number of deaths as a subset of those infected with sars-cov- . the casefatality rate played a crucial role in the justification of the public health experiment now unfolding before our eyes. estimates of the case-fatality rate initially varied hugely from . % to %. in an article published in the lancet, scientists claimed the case-fatality rate could even be as high as % (baud et al. ). in early march , the who directorgeneral stated that the case-fatality rate for sars-cov- was . %. he added: "by comparison, seasonal flu generally kills far fewer than % among those infected." whatever the estimates, the fact remains that it is impossible to calculate the case-fatality rate in the absence of systematic testing. given the lack of evidence, the only scientifically valid statement at the time would have been to say that we simply don't know how lethal the virus is. early on in this pandemic, it became clear that over % of infected people were experiencing no symptoms at all at the time of testing (gudbjartsson et al. ) . this means that a surveillance regime where only people with symptoms were tested will automatically exclude a large number of infections. additionally, patients with symptoms are much more likely to die than asymptomatic people. the result is an exaggerated case-fatality rate. testing strategies differed across countries and changed within countries over time. for example, on february , , the italian ministry of health published a revised policy for testing, prioritizing patients with severe clinical symptoms (and thus higher chances of dying). this change in policy resulted in an apparent increase in the case-fatality rate of . % on february to . % on march (onder et al. ) . suddenly, the virus seemed to have become much more deadly. however, this increase was a numerical illusion-a statistical artifact. there was no change in the lethality of the virus. changes in testing policy occurred in many countries and even across regions where different tactics for counting deaths were used. in china, test-positive asymptomatic patients were excluded from being counted as cases of infection (wu et al. ) . in belgium, deaths were counted independent of any testing (schultz ) . of % of all deaths, only . % turned out to be confirmed by laboratory test as covid- positive. almost half of all victims were merely suspected to be linked with the virus but had never actually been tested. there was and remains no agreement among experts and officials on what counts as a death caused by the virus. in italy, covid- -related deaths were defined as those occurring in test-positive patients, "independently from preexisting diseases that may have caused death" (onder et al. ) . this is particularly concerning in terms of data quality because the vast majority of deaths occur in patients who are older than with one or more comorbidity. test-positive patients who die because of heart disease or terminal cancer are not necessarily dying because of sars-cov- infection. yet they appear in the statistics of some countries. this confusion between patients who die with the virus and those who die from it has had an impact on the data and their quality, making comparisons between countries impossible. further, almost all tests that are done use rna tests, which can detect an infection only as long as the virus is present in the body. these tests, however, cannot tell whether a person had the virus in the past. only serological tests for antibodies against the virus can provide an accurate picture of how many people have been infected in a given population. and yet, such systematic serological studies were and are missing. given the lack of testing and taking into account the role of selection bias, the large number of asymptomatic cases, the confusions in case definitions, the changes in testing policies, and the difficulty of knowing who is dying with versus dying from the disease, the denominator for calculating actual death rates cannot be reliably determined. without a denominator, it is mathematically impossible to calculate the case-fatality rate. nevertheless, despite the lack of data, experts, officials, and the media have remained transfixed by the assumption of clarity and reliability of numbers, and they continued to circulate wild estimates, unleashing a pandemic of scary charts with exponential curves. over the last weeks of march, more and more testing was done globally, and more testing continues as of the time of this publication. not surprisingly, estimates of the case-fatality rate have come down significantly, because the denominator has gone up due to the increase of testing. in iceland, % of the population has been tested using rt-pcr-based tests independent of symptoms, suggesting a case-fatality rate of . %. this figure is six times lower than who's official estimate for covid- . the center for evidence-based medicine at the university of oxford noted that if one assumes that % of iceland's population is infected, then the corresponding infection-fatality rate would be . %. a study using both rt-pcr-based and serological tests conducted in one of germany's most affected regions indicated a case-fatality rate of . % and an infection-fatality rate of . % (streeck et al. ) . we know from epidemics and pandemics of the past that the case-fatality rate is often massively overestimated at the beginning of an outbreak because case detection is limited, largely based on hospital patients and typically biased toward the severest cases of disease. when the h n swine flu pandemic occurred in , the estimated case-fatality rate varied between . % to . % in the first weeks of the outbreak. in , a decade after the pandemic, the who reported that the swine flu pandemic turned out to have a case-fatality rate of . %. this means that the actual casefatality rate was five times lower than the lowest estimate. social science scholarship has shown how numbers can deceive. numbers have the ability to reveal as well as conceal. therein lies their magic. they appear as seemingly neutral bearers of truth. they offer a sense of mathematical precision, making things seem more certain than they actually are and displacing attention away from the conditions under which they were produced. abstracting from limitations on the conditions of their production and treating numbers as absolute is dangerous because it makes things comparable that are not comparable, because it suggests scientific knowledge where there is lack of evidence, and because it creates the sense of a major threat obscuring the differential nature of risk. what using numbers this way fails to account for is the fact that not everyone is at risk in the same way. among the more interesting figures of the sars-cov- pandemic is the number of deaths per million inhabitants per country. this number is probably more reliable than the case-fatality rate because deaths are less likely to be missed (ignoring for now the case of belgium and the difficulty of defining deaths caused by sars-cov- ) and because the denominator, a country's population, is known. here are the current numbers of deaths per million inhabitants for five countries as of may , : spain: italy: france: germany: south korea: the staggering differences between countries cannot solely be explained by demography or rates of infection (some countries seem to have more infected people per million inhabitants than others and so might be overwhelmed, though this is also a question of time-how many cases per week per region). what the differences might reveal (and it is important to note that they may well change) is that some health care systems are able to deal with the crisis in a better way than others. the structural fragilities of an underfunded, understaffed, overstretched, and increasingly privatized and fractured health care system contribute to higher mortality rates (adams ) . in a sense, each society has the mortality it deserves (canguilhem : ) . where medical care is easily accessible, with sufficient and well-trained staff, and with capacity flexibility, patients are more likely to receive better care and survive. in this sense, it matters that spain turns out to have beds per , inhabitants, italy . , france , germany , and south korea . . although beds per inhabitants is a crude indicator, it is noteworthy that germany can rely on over , staffed intensive care beds, out of which only , were occupied in early april (see mohr and datan-grajewski ) . this at a time when there were more cases in germany than in france and the united kingdom and slightly less than in spain and italy. germany's was clearly not a health care system overwhelmed by a sudden surge of patients. ironically, organizations such as the oecd frequently scolded germany's health care system in the past for "oversupply" of hospital beds and its "inability" to "rationalize hospital capacity" (kumar and schoenstein ) . this means that the case-fatality rate is not just dependent on the biological nature of the virus and the age and health profile of the population (people most at risk of death are older than with one or more comorbidity). the case-fatality rate also depends on systematic testing, meticulous contact tracing, well-trained health care workers, nursing homes with adequate resources, and the ability of the health care system to cope with the crisis (excess as well as surge capacity) and provide high-quality medical care, particularly keeping medical workers safe and healthy. in this sense, the pandemic has and will continue to brutally expose policy failures and structural health care system deficits. the situation in many hospitals in italy, spain, and france is troubling, especially in densely populated areas. but it is important to understand why some of these highly visible institutions of care were overwhelmed. lombardy, italy's most affected region, has long been an experimental site for health care privatization: community-centered care "has been all but wiped out" (bagnato ) . the lack of general practitioners and the defunding and low emphasis on community care have increased the pressure on hospitals in urban centers. these hospitals have neither excess nor surge capacity to cope with a sudden rise in demand. over the past five years, hospitals across europe held numerous strike actions "with doctors and health workers complaining of funding cuts, a government reduction in the number of beds and a serious lack of medical staff leading to dire working conditions for emergency room staff" (chrisafis ). hospital systems in italy, spain, and france were on the brink of collapse even before the virus arrived. the most telling demonstration of the structural contradictions of pandemic preparedness under neoliberalism occurred, not surprisingly, in the united states. as american newspaper articles reported, hospitals across the country deferred regular medical services to free up space, equipment, and staff for the pandemic response. when patients started to avoid hospitals due to fear of infection, a main source of income was drastically cut off, "causing huge losses that have forced some hospitals to let go of health care workers as they struggle to treat infected patients" (harris and schneider ). facing a "financial nightmare," hospitals filled their intensive care units with patients who did not really need intensive care so that they could charge more and make up for the financial loss. additionally, administrators cut salaries, laid off hundreds of staff, and sent others on unpaid leave, weakening the health care system further in the midst of the pandemic response. when a new virus appears, things start to fall apart. once everyone gets scared, extreme measures are implemented, in a more or less improvised manner, and trillions of dollars, euros, and pounds are pumped into the economy to make up for the loss. once the worst is over, however, the normal crisis continues, and the structural fragilities remain (caduff ) . this pandemic will haunt us all for decades in ways that we can barely imagine at this point. the nature and sheer scale of the interventions that we have witnessed are staggering, and the consequences-social, political, and economic-remain unforeseeable. there are no systematic accounts of the implications and repercussions seen so far, nor do we have any idea about the number of indirect deaths due to the lockdowns/curfews, the social distancing and the self-isolation. we have yet to see a realistic plan that would outline how we might learn to live with a virus that is unlikely to disappear any time soon (sullivan and chalkidou ) . in the meantime, i suggest that we reframe the corona conversation to cut through the confusion and dimness that is pervading this pandemic in the following ways: the emergence of new viruses in human populations is normal. it has happened before; it will happen again. coronaviruses are common and circulate widely in humans. they have infected people and killed thousands year after year, especially in winter. worldwide, between , to , people die from influenza viruses every year. the sars-cov- virus has killed , people so far. there is no doubt, sars-cov- is causing a serious infectious disease, but so far it is still in the range of what we observe in terms of mortality during a severe influenza season. the main difference is the speed of infection, the clinical picture of the disease, and the impact on demographically older populations causing massive compression of morbidity and mortality that is overwhelming weak health care systems with no excess and little surge capacity. the influenza pandemic killed between and million people worldwide, and the influenza pandemic killed between and million people. as of the writing of this article, covid- has killed , people, according to the official numbers. clearly, the world has witnessed worse pandemics, including . million deaths due to tb each year, , deaths due to hiv infections each year, and , deaths due to malaria, all preventable and treatable conditions. this observation does not mean that influenza and covid- are clinically similar or that nothing should be done to contain the spread of sars-cov- and mitigate the consequences. however, it raises the question of why fear and panic are spreading like wildfire, provoking such extreme measures, and why experts and government officials are willing to mount an unprecedented effort for sars-cov- but have never considered similar interventions for the , - , people who die every year due to influenza. influenza is a relatively well-known virus. to say that sars-cov- is an unknown virus doesn't automatically justify the most extreme measures that the world has ever seen. what makes this pandemic unprecedented is not the virus but the response to it. extreme measures to contain the spread of the virus have resulted in extreme fallouts. it is difficult to overestimate what we are witnessing today. the pandemic response has pushed the world into a space of fragility and uncertainty. there hovers a "perhaps" over everything now (caduff ) . blinded by the urgency of the immediate moment, the response has created an opening for actors and institutions to push agendas and reorder the world. we will grapple for years to come with the changes that are happening today. the response to the disease is driven by a fantasy of control that overestimates and overreacts. this fantasy has caused and is causing enormous harm. it is unrealistic, misleading, and bound to fail. a pandemic like this cannot be controlled; it can only be managed. if we keep using words such as control, we are only setting ourselves up for disappointment. this pandemic is far from having found a language that is adequate to the problems it is posing. we urgently need new concepts but seem to have little imagination. the urgency of the crisis has displaced reliance on basic standards for quality and control of quality of scientific research. papers are published without peer review. claims are made without evidence. perhaps not surprisingly, given the fragile health care infrastructures in some countries, speed appears to be more important than quality, rigor, and integrity. underscrutinized science, lack of data, speculative evidence, strong opinions, deliberate misinformation, exaggerated mortality rates, the / news media attention, and the rapid spread of dramatic stories on social media have led to poor political choices and major public anxiety. we are afraid of covid- . we are not afraid of influenza. we see one thing as a public health emergency and another as a fact of life. today, we are learning an old insight the hard way: not every life and not every death are equal. some deaths are more important than others, drawing more attention, triggering a bigger response and mobilizing more resources. in the covid- pandemic, the belief seems to have taken root that health is an absolute value and that every life needs to be saved by all means. meanwhile, millions of people are dying of influenza, tb, hiv, malaria, and diarrhea, not to mention chronic diseases and accidents. there seems to be less political urgency for these preventable deaths. some health care systems were overwhelmed in this pandemic. others were not. for decades, governments have underfunded, understaffed, and privatized health care systems across the world, and these trends have exacerbated the impact of the pandemic. the response to sars-cov- took a particular shape, converging in extreme measures that have become the norm in many countries. questions that remain include: was it the only possible way of managing the crisis? why has a crude version of china's approach become the dominant model? at the heart of this pandemic was and is the widespread assumption that there were and are no alternatives to extreme measures implemented on entire populations with little consideration of cost and consequences. this is not true. as some countries have shown, adequate testing and less drastic policies of social distancing work well to manage the pandemic. it seems that some officials saw covid- as a disease that could be contained. as the who director-general suggested in early march , "we don't even talk about containment for seasonal flu-it's just not possible. but it is possible for covid- ." this perception may have contributed to the radically different approach seen across many countries. the idea of "flattening the curve" is often seen as the optimal solution, but there is no guarantee that the effort to do this will actually impact the total number of deaths over the long run of the disease's presence in any community. it may ultimately simply spread the same number of deaths over a longer period of time and thus perhaps reduce the pressure on hospitals but not overall mortality. nationwide lockdowns are not a solution. they prevent infection as long as they are in place, but they also keep people susceptible. this is particularly concerning in a pandemic where the virus has become endemic. once lockdowns are lifted, the number of infected people may well rise again later. this is why it has been so hard for countries who adopted this strategy to return to normal life-the strategy is not sustainable over the long run. as andrea bagnato noted about the stay-at-home strategy: "it is not in the harshness of its lockdown, but in the effectivity of separating the infected from the non-infected, that china's response has excelled: a centralized system of dedicated structures (called fangcang) was built in no time, where all patients and their contacts were treated and divided in four groups according to severity. instead, lombardy simply closed everything down. and it becomes clearer by the day that the main landscapes of infection were not public spaces, but hospitals, retirement homes, workplaces, and indeed private homes" (bagnato ). in germany, % of the people who died due to covid- are years or older (mohr and datan-grajewski ) . a majority of the patients who died have one or more underlying health condition such as hypertension, diabetes, cardiovascular disease, chronic respiratory disease, or cancer. this means that the pandemic is killing predominantly people with an already reduced life expectancy. the key question then becomes excess deaths-the difference between the statistically expected number of deaths and actually occurring deaths over a period of time. there is no doubt that there will be excess deaths due to covid- , but it is unclear how large that number will be. the pandemic response has produced a substantial rise in the number of people who now live with untreated illness. prohibition of public transport has made it difficult for patients and staff to reach hospitals. patients with conditions other than covid- avoid doctors because they are afraid of getting infected. emergency room attendance dropped substantively the world over. cancer referrals decreased and cancer screening services stopped entirely. rural health services in countries such as india crashed. essential public health programs have been paused; many resources have been reallocated. this means that patients are neglected, receiving no or less medical care, leading to untreated illness and a rise in mortality. a virus causes disease, not hunger. it is not the pandemic, but the response to it that threatens the livelihood of millions of people. in many countries, both rich and poor, the trends are shocking. in india, children die of starvation. farmers commit suicide because they are unable to harvest crops. stranded daily wage laborers drop dead after walking hundreds of miles. the poor, marginalized, and vulnerable bear the brunt of the pandemic response. the lockdown is a political mechanism not simply for the prevention but for the redistribution of negative effects. lockdowns shift negative effects away from hotspots of public attention to places where they are less visible and presumably less serious. in this way, they are part and parcel of a politics of inequality. this pandemic is not just about health, it is about fear, and the objects that are singled out and then made the ground and motivation of systematic thought and action. to be afraid has become an obligation, a responsibility, a duty. people are afraid not just because of what they experience but because they are told to be afraid and encouraged to inhabit the world with fear of "foreign bodies" and "invisible enemies." public discourse is highly moralized. looking for someone to blame, individuals are exposed as "super-spreaders" responsible for the rising number of cases. on social media, "lockdown warriors" accuse citizens of lack of patriotism and failure to "do their duty" in the face of danger. in this highly moralized public discourse, life is considered an absolute value that can justify almost every form of disciplinary intervention in the name of health. public health needs to be front and center in any infectious disease intervention. investing in strong public health infrastructures should happen even when there is no pandemic. mathematical disease modeling cannot replace systematic epidemiological surveillance on the ground. the most effective way to manage an infectious disease outbreak is to test, trace, and isolate. interventions need to be phased over time; they need to be dynamic, regionally targeted and risk based. all interventions must take into account the social, political, and economic impact, as well as the indirect impact on other health conditions. interventions that do this will create management strategies that work to minimize collateral damage. absolute numbers cannot be used for policy, they only fuel fear and panic. national lockdowns are not a solution. they protect people temporarily, but they also leave them susceptible. once restrictions are lifted, cases of infection are likely to increase again. there is no exit from the pandemic; there is only an exit from the response to it. we are still at an early stage of understanding how best to clinically manage covid- both as a disease and as a risk factor to potentially vulnerable populations. it is vital to find better ways of sharing quality data and effective practice to ensure health systems learn and adapt quickly. what this pandemic shows is a lack of preparedness. this will come as a surprise, given the billions of dollars, euros, and pounds that were spent over the last years on pandemic preparedness, including experience with past epidemics and pandemics such as ebola and swine flu. how can it be that hospitals ran out of n masks in week one? where did all the billions spent on preparedness go? outsourced production capacity and insufficient stockpiles of personal protective equipment put nursing home residents, community health care workers, and hospital staff at risk, weakening health care systems further. key preparedness concepts need to be at the heart of the response. fifteen years of pandemic preparedness seem to have evaporated into thin air in this pandemic. instead of activating existing plans and drawing on concepts such as the pandemic severity assessment framework, countries imposed a massive, untested, and unproven generic lockdown with unforeseeable social, political, and economic repercussions. sars-cov- is less lethal than every single scenario exercise that has been conducted for preparedness planning by governments and non-governmental organizations in europe and america. it will be important to understand why key preparedness concepts were sidelined in this pandemic, despite the attention that preparedness received and the substantial resources it consumed for over a decade. the fear of death is powerful in societies eager to repress the inescapable reality of death. in such a context, it is important to flatten the curve of extreme speaking, feeling, and acting. what was and will always be urgently needed is moderation and perspective. to continue to engage in today's competition for ever more extreme predictions is dangerous. it will only support those who ignored the virus initially and who are more than willing to blame it now for the mess. equally dangerous is a public health populism of clapping hands that leaves out any consideration of the social, political, and economic costs and consequences of sweeping interventions. attempts to obscure political failures are growing rapidly. those who contribute to extreme predictions and apocalyptic readings of the current situation are only contributing to the obfuscation of the policy failures and underlying structural issues that are responsible for many of today's problems. there are already attempts in countries such as the united kingdom and the united states to rewrite failure as success. not surprisingly, governments are calling on citizens to participate in public performances, demonstrate national unity in the face of danger, and celebrate collective strength and resolve. fighter jets soaring through the sky and helicopters showering rose petals on "frontline warriors" are militarized state spectacles. but health care workers deserve more than patriotic feelings and symbolic gestures; they deserve better health care policies. to challenge and critique now is essential. the story of how the chinese approach became a model for generic lockdowns in the global north and then exported to countries in the global south is important to note, particularly considering the dramatic consequences for millions of people struggling to survive without any source of income. ironically, these extremely restrictive lockdowns were sometimes demanded by people eager to criticize the authoritarianism of the chinese state. across the world, the pandemic unleashed authoritarian longings in democratic societies, allowing governments to seize the opportunity, create states of exception and push political agendas. commentators have presented the pandemic as a chance for the west to learn authoritarianism from the east. this pandemic risks teaching people to love power and call for its meticulous application. pandemic time is an auspicious time for all kinds of political projects. as a result of the unforeseeable social, political, and economic consequences of today's sweeping measures, governments across the world have launched record stimulus bills costing trillions of dollars, pounds, pesos, rand, and rupees. earmarked predominantly for individuals and businesses, these historic emergency relief bills are pumping staggering amounts of money into the economy, but, ironically, they are not intended to strengthen the public health infrastructure or improve medical care. the trillions that governments are spending now as stimulus packages surpass even those of the financial crisis and will need to be paid for somehow. today, there is a massive global recession in the making. if austerity policies of the past are at the root of the current crisis with overwhelmed health care systems in some countries, the rapidly rising public debt is creating the perfect conditions for more austerity in the future. the pandemic response will have major implications for the public funding of education, welfare, social security, environment, and health in the future. if you think something good will come out of this crisis, you should think again. today we are just driving faster and with a much bigger car, but it is the same road with the same destination. wolf bukowski notes that the political discussion in italy is now dominated by an "uncritical 'responsibility'" that cannot find a place outside the imperative to contain the virus. "the right intuition that 'we should not question the reality of the epidemic' shifts all too easily into 'we should not question the government's response to the epidemic'" (bukowski ). in such a context, any control intervention imposed by the state is perceived as lawful, and no democratic discussion and debate appears necessary ("let the experts speak!"). in other places, critique has become difficult for other reasons. the tragedy of today's political moment in the united states, the united kingdom, and brazil is that right-wing politicians pushed many into embracing measures that one thought were only possible in authoritarian regimes. here, an engagement in critical analysis has become almost impossible because it is seen as playing into the hands of trump, johnson, and bolsonaro, political figures who seem unconcerned with public health and the staggering inequalities that afflict our world and whose public statements have reached an unmatched level of ignorance and incompetence. however, it is important to understand that the strategic combination of confusion, contradiction, and the play of extreme opposites is foundational for authoritarian rule. everything that instills a sense of disorder and that intensifies the crisis magnifies the desire for decisive action. in this article, i have tried to carve a path through the morass of fear, panic, and desire for control to see how one can sustain a critical analysis of the pandemic response. as scholars and citizens, we have the obligation to think beyond the crisis, create openings in the world, and consider, critically and democratically, how we want to govern ourselves. as veena das underscores, it is important that we do not let our "love for the subtle and nuanced understanding of issues disappear on the grounds of needs for the rough and the ready in an emergency" (das ) . the pandemic and the response to it will require us to reimagine lives, rebuild conditions of existence, and find better ways of doing science and politics. like every engagement in a serious pedagogical project, it will entail a reconsideration of the objects we desire. today's fear is fueled by four main forces: mathematical disease modeling-a flexible and highly adaptable tool for prediction, mixing calculations with speculations, often based on codes that are kept secret and assumptions that are difficult to scrutinize from the outside. neoliberal policies-systematic disinvestments in public health and medical care that have created fragile systems unable to cope with the crisis. nervous media reporting-an endless stream of information, obsessed with absolute numbers, exploiting the lack of trust in the health care infrastructure and magnifying the fear of collapsing systems. authoritarian longings-a deep desire for sovereign rule, which derives pleasure from destruction and tries to push the world to the edge of collapse so that it can be rebuilt from scratch. this set of forces inspires thought, action, and passion in powerful ways. energized by the thrilling experience of witnessing "history in the making," actors and institutions have seized the opportunity to reorder the world, push political agendas in the name of survival, and shape life for years to come. the pandemic has become an auspicious moment to change the rules of engagement and expand the scope of scientific, medical, and political authority over bodies and populations. it is an occasion to publish papers and make dramatic statements, to feel relevant and important to the world, and enjoy the moment in the limelight. in the midst of death and destruction, the pandemic creates opportunities for innovation, domination, and profit-making. this unexpected opening connects elites in science, politics, and the media, releasing shocks of information, instruction, and command that are pushing hard against our confined, anxious, restless bodies. mathematical disease modeling, neoliberal policies, nervous media, and authoritarian longings fuel a fatal spiral centered around the fear of collapse. this fear is now literally in the air; it moves in and out of us with every breath; it operates as animating medium of our intense isolation and immobility. pandemic fear is unnerving and mentally exhausting. yet for those who embrace the feeling, it has the power of sustaining a state of excitement-excitement derived from the secret pleasure of spoiling a precious thing, wasting enormous resources, and engaging in an all-consuming project with total dedication. what we might call the provocation of the crisis-its intensification, expansion, and totalization beyond any notion of utility-seems so excessive and extreme that it borders on sheer madness. what could be more dangerous, more daring, more exciting than a walk on the wild side, an excursion to the other side of reason? melodramatic phrases such as "beating the virus," "winning the war," and "defeating the darkness" are rhetorically powerful and contagious. equally popular notions like "corona heroes" and "lockdown warriors" are symptoms of overidentification in a hegemonic discourse of power. all these terms reveal how this pandemic is "fabulously textual, through and through," and, at the same time, is lacking a source of symbolization strong, creative, and disturbing enough to move our engagement with the world beyond the most conventional of tropes (derrida ) . the language that we are asked to adopt today, in the midst of this outbreak, is contaminated with words that are stiff, stale, and corrupt like putrid air. given that so much of today's response is based on and driven by mathematical disease modeling and that millions of lives and livelihoods are being destroyed before our eyes, it is not an option anymore to exclude the "externalities" of a pandemic response that lacks imagination and that has resorted to the crudest interventions of all: the full stop. for those with permanent jobs, a comfortable couch, and no daycare duties, this unforeseen interruption may feel like a gift, a welcome relief from the non-stop world of global capitalism. but for millions of people living in less privileged parts of the planet, the pause button spells unemployment and hunger, not breaktime and downtime. without income, food, and access to basic health care, people are not making the most of the confinement outside in the garden; they are desperate and dying. we urgently need to look beyond the virus if we want to understand the real seriousness of what is happening today. how did we end up in this strange space of thinking, acting, and feeling that has normalized extremes and that is based on the assumption that biological life is an absolute value separate from politics? never has it been more important to insist that another politics of life is possible. the latest imperial college disease model report summarizes the staggering blindness that has prevailed in this pandemic: "we do not consider the wider social and economic costs of suppression, which will be high" (walker et al. ) . the time to suppress the costs of suppression and cast the consequences of interventions as an externality to model-based policy is over. these claims are utterly misleading, ignoring the influenza pandemics of and , including the hiv/aids pandemic, ebola, and many other infectious disease outbreaks that have killed millions of people worldwide with no vaccine available. last but not least, the toll of covid- is not even close to the toll of the influenza pandemic. . the report distinguishes between two strategies these days i sometimes catch myself wishing to get the virus-in this way, at least the debilitating uncertainty would be over… a clear sign of how my anxiety is growing is how i relate to sleep. till around a week ago i was eagerly awaiting the evening: finally, i can escape into sleep and forget about the fears of my daily life… now it's almost the opposite: i am afraid to fall asleep since nightmares haunt me in my dreams and awaken me in panic-nightmares about the reality that awaits me disasters and capitalism … and covid- . somatosphere website staying at home. e-flux real estimates of mortality following covid- infection. the lancet coronavirus testing: how some countries got ahead of the rest. the guardian website germany's coronavirus anomaly controllo e autocontrollo sociale ai tempi del covid- the pandemic perhaps: dramatic events in a public culture of danger the normal and the pathological french medics warn health service is on the brink of collapse. the guardian website anger and poverty grip lebanese city. the guardian as covid- pandemic hits india's daily-wage earners hard, some leave city for their home towns. scroll.in website facing covid- : my land of neither hope nor despair no apocalypse, not now impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and health care demand. imperial college website for autocrats and others corona virus is a chance to grab even more power. the new york times website wartime conditions" as global coronavirus deaths reach . the guardian website spread of sars-cov- in the icelandic population cash-starved hospitals and doctor groups cut staff amid pandemic. the washington post bangladesh: end wave of covid- "rumor" arrests. human rights watch website indian doctors evicted over coronavirus transmission fears, says medical body. the wire website, march ebola vaccines, evidentiary charisma and the rise of global health emergency research managing hospital volumes germany and experiences from oecd countries scale of china's wuhan shutdown is believed to be without precedent. the new york times so stark ist die krankenhaus-auslastung mit corona-patienten. mdr website kenya police abuses could undermine coronavirus fight. human rights watch website . case-fatality rate and characteristics of patients dying in relation to covid- in italy china tightens wuhan lockdown in "wartime" battle with coronavirus. the new york times website shows commitment to contain virus: who representation in china. reuters website us unemployment rises another m, bringing total to m since pandemic began. the guardian website india moves big labour law changes to limit coronavirus impact others make these changes. financial express website why belgium's death rate is so high: it counts lots of suspected covid- cases. npr website vorläufiges ergebnis und schlussfolgerungen der covid- case-cluster-study urgent call for an exit plan: the economic and social consequences of response to covid- pandemic. centre for global development website the global impact of covid- and strategies for mitigation and suppression who. . report of the who-china joint mission on coronavirus disease (covid- estimating clinical severity of covid- from the transmission dynamics in wuhan, china is barbarism with a human face our fate? critical inquiry blog stavrianakis, nancy tamini, and laurence tessier. i am particularly grateful for conversations with richard sullivan. maria josé de abreu insisted i start writing and put thoughts on paper. for suggestions, i would like to thank the editor of medical anthropology quarterly, vincanne adams, and the two anonymous reviewers. none of these colleagues and friends are responsible for the arguments in this article. key: cord- -e koo authors: shank, nancy title: a review of the role of cost–benefit analyses in - - diffusion date: - - journal: american journal of preventive medicine doi: . /j.amepre. . . sha: doc_id: cord_uid: e koo context the - - helpline is a social services innovation that has spread rapidly throughout the u.s. policy diffusion theory suggests that policymakers seek to reduce uncertainty by anticipating the effects of a proposed innovation through tools such as cost–benefit analyses. few policy diffusion studies have examined use of information, such as cost–benefit analyses, in the diffusion process. the purpose of this study is to examine how cost–benefit analyses were used during the rapid diffusion of - - across states. the paper also describes components of - - cost–benefit analyses. evidence acquisition in , cost–benefit analyses of - - and substantive citations of them were identified through scholarly key word searches using academic search premier and web of science, general internet searches using google search terms, and communications with academicians and - - practitioners through personal contact and e-mail discussion groups. to be included in this study, documents had to be related to - - helplines, present information about their costs and benefits, and be formal documents. the documents were catalogued and analyzed for cost–benefit analyses or references to analyses, and stated purpose. evidence synthesis of the documents that met eligibility inclusion criteria, nine were original cost–benefit analyses and ten referenced analyses conducted for other jurisdictions. conclusions the diffusion of - - helplines in the u.s. has been influenced by interjurisdictional exchange of cost–benefit analyses, in both the creation of original analyses and/or the referencing of previous work. i n , the federal communication commission (fcc) set aside the three-digit dialing code - - for community services information and referral. in the decade since, use of - - has spread to each of the states, washington dc, and puerto rico. there are problem/need categories of information and referral provided by - - s (table ). although call proportions vary from state to state, health and mental health calls typically account for % to % of calls. - increasingly, - - helplines are serving as public information points for health concerns including severe acute respiratory syndrome (sars), west nile, and flu shots. these helplines also have participated in community health prevention outreach to vulnerable populations to promote smoking cessation programs, mammography, adult human papillomavirus (hpv) vaccination, and paps. despite the rapid adoption of - - helplines across the u.s., there has been limited scholarly attention paid to this social services innovation. cost-benefıt analyses (cbas), often sponsored by advocates for - - , informed policymakers about likely economic impacts. it is well known in the - - community that cbas conducted for one jurisdiction were sometimes used by other jurisdictions as evidence of a positive economic benefıt. however, no systematic documentation has been conducted on the use of - - cbas from one jurisdiction to take action in another jurisdiction. moreover, there is little guidance in the academic literature generally that documents information flows between jurisdictions in the policy diffusion process. the present study addresses this gap by using - - as a case study to document possible use of cbas done by one jurisdiction to justify policy action about - - in other jurisdictions. this paper also describes use of cba for understanding components of - - and provides one case example of components of a - - cba. the fırst - - started in atlanta ga in . the ability to offer information and referral services through a threedigit dialing code was embraced by organizations across the u.s., who successfully banded together to petition the fcc to reserve - - nationwide for community information and referral. the fcc gave states the responsibility of determining what organization(s) would be responsible for delivering the service. for most states, this determination would be made by a public service or public utility commission. in a limited number of states, the determination was made by a legislative body or delegated to a coalition of information and referral organizations. states have varied in whether they have staged approval for - - geographically or done so in a single action. some states, such as michigan, nebraska, and california, have staged - - successively within their state, adding regions over a number of years. other states, such as hawaii and texas have assigned - - responsibility across their state in a single action. once authorized, - - services typically have been responsible for developing their funding and implementing the service. a limited number of - - services receive substantial state support, but most rely primarily on a combination of public and private support. the - - s have not addressed funding and implementation challenges in isolation. several national not-for-profıt organizations have promoted - - nationally. notably, united way worldwide and the alliance of information and referral systems (airs) have jointly championed - - development. united way worldwide used its nationwide network of united way member agencies to advocate at the national and local levels for adoption of and funding for - - s across the u.s. airs, the association of information and referral organizations, leveraged its network and incorporated - - into its professional standards and certifıcations. these two national organizations, along with local - - s, worked with legislators to propose federal funding through the calling for - - act. the act would have provided substantial federal funds to support - - s throughout the u.s. although the act was not passed, several - - s successfully received targeted congressional appropriations. united way worldwide and airs have served as networks for information sharing about the costs and benefıts of - - , typically by equipping local - - supporters who were in contact with their state and local policymakers. airs and united way worldwide publicized documents and toolkits with information about the service's costs and benefıts through e-mail discussion groups, at national conferences, and through personal communications. in , united way worldwide also commissioned a cba for adoption of - - across the entire u.s. airs' and united way worldwide's dissemination strategies appear to have promoted sharing of cbas in states through local - - supporters. one national - - leader reflected on a typical encounter of a - - supporter with a state policymaker (anonymous, personal communication, ): the rote question [asked by state policymakers] was often "have you done a cost-benefıt analysis?" . . . [the] answer would be, "not yet, although we would be willing to develop one if you could help with the funding of the study. however, cost-benefıt documents have been published by texas and nebraska [for example]. would you like to review those?" types of cost analyses include cbas, cost-effectiveness analyses, cost-utility analyses, and cost-feasibility analyses. cbas judge the worth of a policy based on its economic impact by assigning and comparing the costs of the inputs to the value of the outcomes. cbas have been used in a variety of human service settings, such as education, corrections, poison control centers, services for people with dementia, and health promotion. proponents of cbas claim that the economic valuation of policies provides objective criteria with which to make decisions. they claim that the valuations are transparent methods used to weigh relevant factors. critics charge that it is impossible to monetize all inputs and outcomes of a proposed program and therefore cost analyses ignore important intangible outcomes. despite ongoing debate about cbas, they continue to be a popular tool considered by policymakers. cost-benefıt analyses have been used by advocates of - - to demonstrate its worth. some jurisdictions have developed cbas, and others simply have cited the results of other jurisdictions' analyses. there has been limited scholarly work examining - - cbas. , only two peer-reviewed articles were found that explored costs and/or benefıts of - - s. the fırst focused solely on the benefıts that - - s offer to communities and described the challenges and approaches to quantifying those benefıts. that study was not an analysis of a specifıc - - service; rather, it was an overview of the types of benefıts - - s accrue and a description of how those benefıts might be measured. the second article documented potential costs and benefıts at the individual, organizational, and societal levels and incorporated a temporal dimension to benefıts calculation (i.e., short-, medium-, and long-term). neither of the scholarly articles calculated the costs and benefıts of a specifıc - - service or reviewed the role of cbas in the diffusion of - - across the u.s. policy diffusion has been a topic of keen interest to scholars over the past several decades. researchers seek to explain why some governments adopt innovative public policies whereas other jurisdictions do not. walker's seminal work defıned a policy innovation as any program new to a government, regardless of how many other governments may have adopted it. for him, and the researchers who have followed his lead, it is not the novelty of the idea but the fact that it is new to the jurisdiction that qualifıes it as an innovation. many diffusion researchers have examined the interdependence of governmental bodies when making policy decisions, recognizing that policymakers do not enact policy in isolation. policymakers reduce the risk of making bad decisions by relying on a variety of sources, including those used by policymakers in other jurisdictions. , based in rogers's broader theory of diffusion of innovation, policy diffusion describes how policymakers opportunistically scan their environment for new ideas or solutions to problems. when an idea is identifıed, it is subjected to an information-gathering and testing period. during this period, policymakers may seek to reduce the risk of unexpected consequences by looking to the experiences of others. researchers hypothesize that jurisdictions emulate each other for four reasons: ( ) policymakers face a problem and use solutions already developed by others as a decision-making shortcut; ( ) policymakers want to remain competitive with other states to provide a good economy and quality of life for residents; ( ) policymakers want to conform to the norms of other states or the expectations of the federal government; or ( ) policymakers respond to public pressure from citizens and media. , researchers have studied diffusion in the context of a wide range of policies including lotteries, gaming, school choice, end of life, water fluoridation, living wills, antismoking, and hmos. policymakers may learn of innovations from policy networks, professional associations, epistemic communities, nongovernmental organizations, think tanks, and the media. this transfer of information may take place through face-to-face communications, but it also may occur through documentary and informal evidence. formally documented expert-based information, such as cost analyses, may be particularly desired and persuasive when policymakers are developing policy decisions. , despite the important and powerful role of such information, researchers have noted that few policy diffusion studies have focused on the use of information in the diffusion process. the present study addresses this gap by examining the use of information produced through a popular policy tool (i.e., cbas) in the rapid spread of - - in the u.s. both scholarly and gray literatures were searched. documents identifıed through the searches were included in the current study if they were related to - - , examined - - costs and benefıts, and were formal documents (e.g., not simply website narrative). excluded from the study were analyses not specifıc to - - , information sources that were not formalized, or that presented costs or benefıts only in a very general way. information collected from each document included the author, title, publisher, year of publication, and how costs and benefıts were monetized. the documents were coded independently so no test of inter-rater reliability was required. scholarly literature was identifıed through computerized searches using academic search premier (asp) and web of science (wos). the searches were conducted for the presence of keywords in scholarly, peer-reviewed publication abstracts prior to march . each database was searched using keyword combinations of: and cost; - - and cost; - - and call center; and call center; - - and human services; and human services; human services and telephone; information and referral and human services; and telephone and community-based services. of the articles returned by the searches (duplicates included), were found by asp and through wos. only one of the articles met the eligibility criteria for the present study. gray literature was searched in three ways: ( ) through existing lists of cbas; ( ) via personal communications; and ( ) using internet searches. lists of cbas were obtained from airs, united way worldwide, and the center for excellence in cancer communication research at washington university in st. louis. personal communications in the form of e-mail inquiries were sent on april , , and june , , to - - administrators and staffers through two e-mail discussion groups: the airsnetworker (approximately recipients) and the - - discussion-l list ( recipients). the e-mails requested cost-benefıt or cost-effectiveness analysis, or any other type of analysis that attempted to compare the costs of - - s to positive outcomes. the third information source was web searches. searches were conducted using the terms - - cost benefıt, cost benefıt, feasibility study, and - - business plan. the search identifıed documents for inclusion in the study. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] only one document was found through the scholarly database search, whereas the remaining were identifıed through the gray literature search. three documents were from national organizations: two from united way worldwide and one from the national aging information and referral support center. eleven documents covered an entire state or area within a state, with some states represented by multiple documents (number denoted parenthetically): arkansas, california, hawaii, kentucky, maryland, michigan ( ), nebraska, oregon, pennsylvania ( ), texas ( ), and washington ( ). approximately half (nϭ ) of the eligible documents were original cbas. all but one of the cbas were conducted at the state level. of the documents, six were identifıed as cbas, , - two were identifıed as valuation documents, , and one was identifıed as a business plan. table lists the cbas in chronologic order based on publication date. the analyses included those that were developed prior to delivery of - - services (relying on speculative projections) and those developed after - - had been established (incorporating actual delivery experience in projections). two studies, the texas study and the nebraska study, predated the ruling by the fcc. the remaining seven studies were conducted in the years following the fcc designation. five cbas were conducted prior to their states' authorization, and three were conducted subsequent to state authorization. the studies conducted prior to - - authorization within their state were texas ( ); ne- according to the documents, the purpose of these analyses was to estimate the value of the existing service. the national study ( ) was conducted following the fcc decision, but prior to widespread adoption of - - across the u.s. several of the prospective cbas compared varying service-delivery structures. for example, the nebraska study compared three models of situating call centers (i.e., single statewide center, six regional centers open / , and six regional centers operating weekdays and one becoming the overnight and weekend center). in other studies where information and referral services (e.g., texas, ) or actual - - s were already in place (e.g., michigan, ), existing call volumes and organizational structures were analyzed. in all of the cbas, except maryland's, benefıts outweighed costs. (maryland projected a slightly higher per capita cost and monetized a smaller number of benefıts than did other states). some of the cbas were used as models or information sources for work done in subsequent cost analyses. for example, both the maryland and arkansas studies explicitly mentioned that they used aspects of the nebraska study. the texas study and the national study shared several authors and featured similar valuation approaches. the washington study reviewed benefıts that were quantifıed in the maryland and nebraska studies. the hawaii study referenced arkansas, maryland, michigan, and the national analyses. the analyses across the nine cbas varied in depth and scope of costs and benefıts. moreover, there were variations in which costs and benefıts were monetized or simply described in nonmonetary terms. for the purpose of illustration, the costs and benefıts identifıed in texas's cba are listed in table . costs. all the cbas, except the washington study, monetized the costs of implementing - - . none of the analyses presented nonmonetized costs, suggesting that the authors believed all - - costs were able to be valued fınancially. of the monetized costs, most of the studies (maryland, michigan, national, nebraska, texas and ) divided costs into start-up costs and ongoing costs. the arkansas (pre-implementation) and hawaii (post-implementation) studies made no distinction. start-up costs included such items as capital expenses for hardware, software, telephony, databases, and offıce furnishings. the nebraska study also included training as a start-up cost. all studies, except the washington study, calculated operating expenses. operating expenses included personnel costs; materials and supplies; travel; facilities rental; promotion/marketing; training; insurance; technology (e.g., telecommunications, hardware and software); professional services (e.g., legal, information technology, telecommunications, accounting); and equipment. benefits. both monetized and nonmonetized benefıts were reported in most studies. many of the studies categorized monetized benefıts. for example, the texas studies examined benefıts to individuals, government, and society, whereas the nebraska and arkansas studies categorized benefıts to individual citizens, employers, human service providers, planners, and funders. the most commonly monetized benefıts included call avoidance for other three-digit numbers (e.g., , ); personal and professional time-savings in locating services; call avoidance for community human service programs; cost avoidance for needing redundant information and referral lines that could be handled by - - ; improved productivity for providers; tax dollars recovered to the community through referrals to volunteer tax-assistance programs; and cost avoidance for more-expensive interventions that could be addressed through less-expensive programs (e.g., nursing homes, early intervention). most studies also included nonquantifıed benefıts. the most-frequently mentioned nonquantifıed benefıts were reduced frustration for individuals seeking services, reduced cost of services, cost avoidance of more-expensive interventions that could be addressed through lessexpensive programs, improved information about service coverage and needs, and reduced toll-free lines sponsored by governments. some studies did not quantify benefıts that were quantifıed by other studies. for example, the nebraska, national, arkansas, and michigan studies monetized the benefıt of avoiding redundant information and referral calls, whereas maryland mentioned call avoidance as a benefıt but did not attempt to value it. ten documents referred to other jurisdictions' - - cbas and did not present original analyses ( table ). most of the documents (nϭ ) were local or state-focused. two had a national focus. the remaining study was a combination of a national and municipal focus. the experience of other states appears to have been important as most of the reports explicitly stated their desire to learn from other states who had implemented - - . two states (michigan and pennsylvania) did not have state authorization for - - at the time of publication of the documents referring to others' cbas. one state (washington) had authorized a third party to make a decision about what organization would be authorized to operate their - - , but at the time of the statewide plan ( ), had not made an assignment. the one local plan (peninsulas region of washington) had received state authorization to operate a - - but had not yet implemented the service. two states (california and kentucky) had achieved authorization of at least one - - within their boundaries at the time of publication, but only approximately one half of their state's populations had access to - - . most often, the results of other jurisdictions' cbas were reported as a net monetary value. for example, the california study is typical in referring to the national study's fınding that the net present value to the nation over years of complete - - coverage would be $ million. five of the documents reported the results of only one of the cbas (table ) . four studies mentioned two analyses. one study mentioned three analyses. the most-frequently reported analysis was the national analysis, which was reported in eight of the documents. the nebraska analysis was cited in seven reports. one report mentioned the texas analysis. essentially, it appears that the case for - - was established by , as none of the cbas published after were referenced in other documents. many of the documents presented the challenge of identifying fınancial support for - - services. for example, pennsylvania's plan states that building a - - network: requires a signifıcant long-term commitment from state government as well as ongoing support from a broad mixture of private sources-united ways, private foundations and business-and local funding obtained by the regional - - call centers from both public and private sources. an important but largely unexamined question in policy diffusion is how information is used by jurisdictions throughout the policy diffusion process. researchers increasingly are viewing products of policy analyses as contributing to wider processes beyond that for which they originally were authored. , the present study provides evidence that specifıc results produced by cbas were used in the rapid diffusion of - - s across the u.s. the current study begins to fıll a gap in policy diffusion research, because there has been little documentation of the use of information by others. the results illustrate policy information sharing through the example of cbas in the diffusion of - - . as one national leader in - - commented (anonymous, personal communication, ): some leaders in the political sphere and/or major internal government administrators liked to know that they could be a trailblazer in their state with some security that other states had adopted it and that studies were available to back it up. there are several limitations to the present study. first, archival evidence was the sole source of information. thus, study scope limited to documented analyses and their mention in formal documents by other jurisdictions. this approach prevents exploration of the comparative valance of cbas in relation to other information policymakers may have accessed. therefore, this study is not able to describe the persuasiveness of cbas results in the results of the current study point to areas for future research and practice. the rapid diffusion of - - s suggests that the national network of - - s was an effective channel for sharing policy-relevant information. this raises further research questions: what contributed to the effıcacy of this diffusion process? how might the network be used to spread future policy innovations? does diffusion theory help us understand the mechanisms associated with early and late adoption of policies like - - ? why have certain groups not adopted - - ? these questions may benefıt from both qualitative and quantitative (e.g., mixed-methods) approaches. understanding the potential inequities in policy diffusion will be important. diffusion theorists have posited that jurisdictions' internal characteristics (e.g., socioeconomics of the intended population) and propinquity to other innovators are related to likelihood to adopt, suggesting that isolated, economically disadvantaged areas may be less likely to adopt policy innovations, such as - - . , data from united way worldwide indicate that rural communities may be disproportionately represented in areas without - - . rural areas tend to have greater need for, but fewer, social services. this leads to the disquieting possibility that the areas whose residents could most benefıt from - - services may be the very ones lacking access. future research should explore disparities in adoption and access to innovative social policies such as - - , as well as to understanding the mechanisms by which successful adoption is accomplished. as a result, research will benefıt policymakers, policy implementers, and other practice-based professionals who are striving to accelerate the uptake of life-saving - - services. a practical implication of the present study is that - - s are able to work together to share information and mobilize quickly, despite the fact that - - s are not a single national body but rather a collection of independent organizations. there is promising evidence, for example, in the realm of disaster response and recovery, that - - s together form an effective national network that is able to meet unanticipated surges of need. , , , in their role in providing health-related information and referral, and in their emerging role as a proactive source for promoting community and individual health, the - - network comprises an effective vehicle for diffusing new practices. further, - - and health practitioners may fınd fertile ground for furthering mutual goals by working together. united way/airs . nationwide status. us.org/status.htm airs: i&r problem/ needs national categories - - texas. - - texas information and referral network action summary united way of pennsylvania. ways - - works proactive screening for health needs in united way's - - information and referral service the role of information in the policy process: implications for the examination of research utilization in higher education policy - - state by state: a periodic report on the national implementation of three digit-accessed telephone information and referral services indiana partnership, inc. fact sheet - - in the mid south delta: a collective case study collectivecasestudy/ - - % in% the% mid% south% delta % collective% case% study.pdf advancing the common good: united way policy agenda for the th congress cost-effectiveness analysis: methods and applications economic techniques the state of cost-benefıt and costeffectiveness analyses in education does cost-benefıt analysis or self-control predict involvement in bullying behavior by male prisoners? cost-benefıt analysis of a regional poison control center cost-benefıt analysis of assistive technology to support independence for people with dementia-part : development of a methodological approach to the enable cost-benefıt analysis a fınancial cost-benefıt analysis of a health promotion program for individuals with mobility impairments examining the potential benefıts of a - - system: quantitative and other factors - - information services: outcomes assessment, benefıt-cost analysis, and policy issues the diffusion of policy diffusion research. psweb.sbs.ohio-state the diffusion of innovation among the american states diffusion of innovations adoptions as policy innovations: an event history analysis innovations and diffusion models in policy research explaining the diffusion of innovation types amongst high and low innovative localities: a test of the berry and barry model disentangling diffusion: the effects of social learning and economic competition on state policy innovation and expansion policy networks and innovation diffusion: the case of state education reforms promoting a "good death": determinants of painmanagement policies in the u fluoridation: diffusion of an innovation among cities innovation and reinvention in state policymaking: theory and evolution of living will laws the mechanisms of policy diffusion interstate professional associations and the diffusion of policy innovations introduction: epistemic communities and international policy coordination non-governmental policy transfer: the strategies of independent policy institutes international organizations as teachers of norms: the united nations educational, scientifıc, and cultural organization and science policy interstate communication among state legislators regarding energy policy innovation expert-based information and policy subsystems: a review and synthesis information sources in state legislative decision making the value of a comprehensive texas information and referral network final report: survey of existing i&r services and a nebraska system cost/benefıt analysis the value of a comprehensive texas information and referral network maryland - - : benefıts and costs of a - - system for maryland national benefıt/cost analysis of three digit-accessed telephone information and referral services: fınal report win - - : performance evaluation and cost-benefıt analysis of - - i&r systems arkansas system cost/benefıt analysis benefıt/cost analysis of aloha united way's program michigan - - . michigan - - business plan aging network involvement in civil society consulting group llc, venture architects. washington information network business plan. win .org/docs/ win wabusinessplan.pdf united way - - of the peninsulas business plan - - california. - - california partnership business plan michigan association of united ways. michigan - - business plan united way of southeastern pennsylvania. policy brief: how does reduce state spending? . . . /communityimpact/publicpolicy/ does save taxpayers kg pennsylvania - - . pennsylvania - - business plan united way of america. - - fact sheet kentucky - - . kentucky - - strategic business plan after hurricanes, support grows for call service policy analysis for what? the effectiveness of nonpartisan policy research organizations the diffusion of policy innovations-an experimental investigation putting the - - coverage map in context department of agriculture. rural income, poverty, and welfare: summary of conditions and trends after the storms: - - stories from the hurricane season. united way of america trial by fıre: how - - 's regional response to the southern california wildfıres underscored the need for a statewide network publication of this article was supported by funding from the national cancer institute (nci) and the offıce of behavioral and social science research (obssr) of the nih (hhsn p).ns has received consulting fees from the alliance of information and referral systems and united way worldwide, the lead national organizations in the development of - - in north america. key: cord- -tnde jp authors: jewell, jennifer s; farewell, charlotte v; welton-mitchell, courtney; lee-winn, angela; walls, jessica; leiferman, jenn a title: mental health during the covid- pandemic in the united states: online survey date: - - journal: jmir form res doi: . / sha: doc_id: cord_uid: tnde jp background: the covid- pandemic has had numerous worldwide effects. in the united states, there have been . million cases and nearly , deaths as of october , . based on previous studies of mental health during outbreaks, the mental health of the population will be negatively affected in the aftermath of this pandemic. the long-term nature of this pandemic may lead to unforeseen mental health outcomes and/or unexpected relationships between demographic factors and mental health outcomes. objective: this research focused on assessing the mental health status of adults in the united states during the early weeks of an unfolding pandemic. methods: data was collected from english-speaking adults from early april to early june using an online survey. the final convenience sample included us residents. the -item survey consisted of demographic questions, mental health and well-being measures, a coping mechanisms checklist, and questions about covid- –specific concerns. hierarchical multivariable logistic regression was used to explore associations among demographic variables and mental health outcomes. hierarchical linear regression was conducted to examine associations among demographic variables, covid- –specific concerns, and mental health and well-being outcomes. results: approximately % ( / ) of the us sample was aged ≥ years. most of the sample was white ( / , %), non-hispanic ( / , %), and female ( / , %). participants reported high rates of depression ( / , %), anxiety ( / , %), and stress ( / , %). older individuals were less likely to report depressive symptomology (or . , p<. ) and anxiety symptomology (or . , p<. ); in addition, they had lower stress scores (– . points, se . , p<. ) and increased well-being scores ( . points, se . , p<. ). individuals who were no longer working due to covid- were . times more likely to report symptoms of depression (p=. ), had a . -point increase in stress (se . , p=. ), and a . -point decrease in well-being scores (se . , p=. ) compared to individuals who were working remotely before and after covid- . individuals who had partial or no insurance coverage were - times more likely to report depressive symptomology compared to individuals with full coverage (p=. and p=. , respectively). individuals who were on medicare/medicaid and individuals with no coverage were . and . times more likely to report moderate or severe anxiety, respectively (p=. and p=. , respectively). financial and food access concerns were significantly and positively related to depression, anxiety, and stress (all p<. ), and significantly negatively related to well-being (both p<. ). economy, illness, and death concerns were significantly positively related to overall stress scores (all p<. ). conclusions: our findings suggest that many us residents are experiencing high stress, depressive, and anxiety symptomatology, especially those who are underinsured, uninsured, or unemployed. longitudinal investigation of these variables is recommended. health practitioners may provide opportunities to allay concerns or offer coping techniques to individuals in need of mental health care. these messages should be shared in person and through practice websites and social media. the covid- pandemic has produced over million confirmed cases and over . million confirmed deaths worldwide as of october , [ ] . of these, nearly . million cases are in the united states, with nearly , deaths [ ] . in addition to health impacts, many have raised the alarm about the potential for a widespread global mental health crisis as a result of the pandemic [ ] [ ] [ ] [ ] . specific groups may be at increased risk for adverse mental health outcomes, such as frontline health care workers [ ] and those that have experienced illness or death of family, friends, or coworkers. many more are likely to experience distress as a result of economic hardship, disruption to social networks, and work-and school-related changes due to the protracted crisis. elevated rates of depression and anxiety have been documented following stressors such as disease outbreaks, including the - ebola crisis in west africa, among caretakers, survivors, their immediate contacts, and others [ , ] . in addition, epidemics such as sars and hiv have been associated with depression and other mental health concerns among various groups [ ] [ ] [ ] [ ] [ ] [ ] . the current pandemic is likely to be associated with similar mental health outcomes, as a result of potential exposure to stressors including loss of loved ones, economic hardship, social isolation, and childcare responsibilities following school and day care closures. countless businesses across the united states closed in an attempt to protect workers, limit transmission of the coronavirus, and allow health care systems to keep pace with the needs of those requiring hospital care. with the exception of essential services, much of the economy has come to a virtual standstill, resulting in unprecedented rates of unemployment [ ] . financial struggles, including job loss and food insecurity, are known risk factors for mental illness, particularly anxiety, depression, and suicide [ , ] . in most us states, nonessential workers have been required to stay at home for several weeks. many states have had stay-at-home orders in place for longer periods of time. although there is an easing of movement restrictions in some areas within the united states, many people are still concerned about the potential safety risks of resuming prepandemic levels and types of activities. as a result, so-called "social distancing" continues for many in the united states. physical distancing requirements (eg, social distancing) have the potential to limit physical and social contact, disrupt prepandemic social networks, and undermine the potential for social support at a time when it may be needed most. this may result in an increase in loneliness and social isolation. across numerous studies, social isolation has been associated with increased morbidity and mortality, with an increase in coronary heart disease, stroke, and poor mental health outcomes such as depression and anxiety [ ] [ ] [ ] [ ] [ ] . the increase in financial and familial struggles for some families may have exacerbated the negative effects of strict social distancing measures and overall trauma. although studies examining the mental health impacts of covid- are limited, findings from a few recent studies indicate that many in the united states are experiencing significant and worsening mental health difficulties during the pandemic [ ] . a review of the emerging literature regarding the effects of the pandemic suggests that symptoms of anxiety and depression are common [ ] . in one study [ ] , which used a representative sample and compared recent mental health concerns to those in , large increases in mental health distress were noted. younger people, those with children in the household, married individuals, and asians appeared to be faring worse than others [ ] . authors suggested these findings may reflect economic hardship, but more research is needed to understand factors contributing to greater difficulties in some groups than others. the current study examines demographic differences in mental health and well-being outcomes and specific sources of concern that impact these outcomes among a us sample of adults surveyed between april and june , , immediately following business closures and movement restrictions. this study may bring to light additional factors related to mental health during the pandemic and fill gaps in the current literature. specifically, several covid- -specific concern-related items that have not been previously assessed were included in the current analyses. these findings have the potential to inform current intervention efforts as well as new initiatives, with the potential to mitigate suffering and bolster resilience during the ongoing pandemic. the mental health and wellbeing survey during covid- pandemic received ethical approval from the colorado multiple institutional review board (comirb protocol # - ). survey data was collected between april and june , . a snowball sampling technique was used. this survey was advertised on facebook and instagram via paid targeted advertising. in addition, it was sent out via listservs and other media including centers for disease control and prevention (cdc) prevention research centers, american public health association mental health section, colorado public radio, university of colorado research announcements, and the university of south florida. study data were collected and managed using redcap electronic data capture tools hosted at the university of colorado [ ] . redcap (research electronic data capture) is a secure, web-based application designed to support data capture for research studies, providing the following features: ( ) an intuitive interface for validated data entry, ( ) audit trails for tracking data manipulation and export procedures, ( ) automated export procedures for seamless data downloads to common statistical packages, and ( ) procedures for importing data from external sources. participants consented digitally before beginning the survey. additionally, participants in the initial survey were given the opportunity to opt in to future surveys to collect longitudinal data. a participation incentive in the form of a drawing for one of two $ gift cards was offered. adults aged ≥ years were eligible to take the english-language survey, regardless of country of residence. there were no exclusion criteria beyond ability to provide consent. although data was collected from an international sample initially, most of the participants were residing in the united states. as a result, only data from the us subsample is included in the present analyses. the final us sample consisted of individuals. the -item survey consisted of demographic questions, mental health and well-being measures, coping mechanisms, and questions gauging covid- -specific concerns. demographic questions included age, race/ethnicity, gender, work status, household size, and insurance coverage. the survey also included four mental health and well-being scales measuring well-being, depression, anxiety, and stress. the short warwick-edinburgh mental wellbeing scale (swemwbs) was used as a continuous measure of well-being. it has high internal consistency and convergent validity with other measures of life satisfaction and physical and mental health (α=. in this sample). the swemwbs has a range of - , with higher scores indicating higher well-being [ ] . the patient health questionnaire- (phq- ) was used as a brief measure of depression (α=. in this sample). the phq- has a sensitivity of % and a specificity of % for major depression. the phq- has a range of - and was dichotomized for analyses using a cutoff score of ≥ [ , ] . generalized anxiety disorder (gad) was assessed using the gad- , which has a sensitivity of % and a specificity of % (α=. in this sample). the gad- has a range of - , and moderate or severe anxiety was based on a cut-off of ≥ [ ] . lastly, stress was assessed using a validated -item continuous measure with response options ranging from "not at all" to "very much" stress "these days" (elo stress-symptoms item). this stress item has demonstrated construct, content, and criterion validity for group-level analysis [ ] . the survey included a coping checklist, comprised of behavioral items with an additional "other" option, to ascertain which types of coping were most common (eg, exercise, engaging with media, engaging remotely with family/friends). the survey items examining covid- -specific concerns included questions about personal financial impact, food security, economic impact, and risk of serious illness or death (in participants or others known to participants) related to covid- . questions were phrased in the following manner: "how concerned are you about... [the financial impact current events may have on your family]?" data were exported from redcap into spss (version ; ibm corp) for analyses. data cleaning included testing of assumptions, exploration of outliers, and missingness for all key variables. as all key variables had less than % missing data and data were missing completely at random (χ = . , p=. ), listwise deletion was used in all analyses. univariate and bivariate analyses were conducted. two proportion z tests were also used to calculate differences between responses (%) to the phq- and gad- and national prevalence data. an independent sample t test was run to compare the sample average for the warwick wellbeing score with a nationally representative sample. two hierarchical multivariable logistic regression models were run (logistic regression models and ) to explore associations among demographic variables, depression (not depressed versus depressed), and anxiety (no or mild anxiety versus moderate or severe anxiety) outcomes. hierarchical regression was used to investigate if specific sources of concern (eg, financial concern, illness-related concern) were related to the outcome measures after controlling for demographic characteristics of the analytical sample. for categorical variables, well-established cutoffs based on representative us samples were used. all demographic variables were added simultaneously to each model, after which unique sources of concern were entered into models (logistic regression models and ) to see which sources of concern predicted depression and anxiety outcomes after controlling for demographics. r values, odds ratios, and p values for logistic regression models are presented. next, two hierarchical linear regression models were run (linear regression models and ) to explore associations between demographic variables and stress and well-being outcomes. in total, unique sources of concern were entered into models (linear regression models and ) to see which sources of concern predicted stress and well-being outcomes after controlling for demographics. unstandardized coefficients, p values, and adjusted r values are reported for all linear regression models. alpha (α) was set at . . linear regression models for the well-being and stress outcomes are presented in table . an increase in age decade was associated with a . -point decrease in stress score (se . , p<. ) and a . -point increase in well-being score (se . , p<. ). on average, individuals who did not have insurance reported a . -point higher stress score (se . , p=. ) and a . -point lower well-being score (se . , p<. ). no longer working due to covid- was associated with a . -point increase in stress score and . -point decrease in well-being score compared to individuals who were working remotely before and after covid ("no change" group; se . , p=. ; se . , p=. ). males also reported significantly lower stress scores compared to females (b= . , se . , p<. ). financial concerns and food access concerns were significantly and positively related to depression, anxiety, and stress (all p<. ) and significantly negatively related to well-being (both p<. ). economy-, illness-, and death-related concerns were significantly and positively related to overall stress score after controlling for all demographic variables (all p<. ). additional analyses were considered, including investigating the effects of race/ethnicity and parenthood status. the cell sizes for these variables were too small to conduct analyses. table . logistic regression models showing associations between depression (models and ), anxiety (models and ), demographic variables, and sources of concern (n= ). the imposed social distancing experienced by many throughout the united states undoubtedly contributed to numerous shortand long-term negative effects within the population. this survey aimed to identify the impact of the covid- pandemic and imposed social distancing on mental health among us residents within a small window of time during which many businesses were closed and many individuals were out of work. based on the findings associated with this convenience sample, when compared to prepandemic representative population-level data in the united states, it appears that mental health declined overall during the late spring of . prevalence rates of both depressive symptoms and anxiety symptoms were notably higher than national prepandemic averages. in addition, mental well-being significantly decreased, and stress levels were elevated in this sample. these findings support early evidence that the effects of the pandemic on mental health are significant [ ] . the findings from the regression analyses suggest that age may be an important factor in considering mental health impacts of the pandemic. as age increased, anxiety symptoms, depression symptoms, and stress decreased, and well-being increased. this effect may be explained by stress on younger individuals due to inconsistent income or parenting-related obligations; however, these relationships could not be analyzed due to small cell sizes. based on a review of the limited literature specifically related to the covid- pandemic, rajkumar [ ] found that older adults were at greater risk for mental health concerns [ ] . no other studies we reviewed found a relationship with age. further research should be conducted to determine mental health risks relative to age and associated factors during the covid- pandemic. findings from this study suggest loss of work due to pandemic-related closures greatly increased the odds of depression symptoms when compared to individuals who did not experience a change in their employment (were working remotely both before and after closures began). loss of employment was also related to increased stress levels and decreased mental well-being. this could indicate a segment of the population that may require additional support to overcome mental health challenges during the pandemic. economic crises have been tied to poor mental health outcomes in numerous studies [ , ] . employment, in contrast to unemployment, has been linked to decreased mental illness, including depression and anxiety, and increased mental well-being [ ] . job instability, including moving from a permanent position to a temporary position, has been linked to increased mental illness [ ] . public health officials should make targeted efforts to reach out to the segment of the population that completely lost the ability to work during social distancing regulations. these individuals may need aid that extends beyond financial support. partial and no insurance coverage was associated with increased odds of depression symptoms when compared to fully insured individuals. this finding supports previous evidence that increased health care coverage reduces the prevalence of undiagnosed and untreated depression [ ] . individuals with limited health coverage also had higher stress scores and lower well-being scores. a similar effect was seen with moderate to severe anxiety. this finding was particularly pronounced in the uninsured population. the effects of partial or no insurance coverage on mental health may be exacerbated by the circumstances of the pandemic. those with no insurance demonstrated extremely high odds of anxiety symptoms. this is likely related to concern about what would happen to them if they contracted covid- . practitioners working with uninsured and partially insured individuals should take note of potentially decreased mental health in this population. although these practitioners may not have the ability to affect their patients' insurance status or concerns about the potential financial burden of contracting covid- , they do have the opportunity to encourage low-or no-cost coping methods that may decrease depressive and anxiety symptomatology. several other factors demonstrated relationships with mental health. males reported significantly lower stress levels than females. this is consistent with findings on gender and stress [ ] . this difference in stress levels may be due to gender differences in coping with stressful situations and differences in hormonal responses to stressful events [ ] . increased family financial concern and family food access concern were positively related with depression symptoms, anxiety symptoms, and stress, and negatively related to well-being. in addition, concern about the economy, illness-related concern, and death-related concern were positively related to stress scores. the financial concern and food security findings are consistent with previous work investigating this relationship [ , ] . each of the relationships between the concern items and mental health variables is consistent with expected outcomes from the covid- pandemic [ ] . practitioners may wish to ask their patients about specific concerns that they may be experiencing during this time. using a sliding scale for medical fees and having referrals and information about different types of aid available (eg, food banks and local, state, and federal funds) may reduce the mental burden on some individuals. practitioners are also in the best position to convey accurate information about covid- risk status and effective protective measures. information of this type can be conveyed in person or online through practice websites and social media. this reliable information may counteract the concern of illness and death and reduce poor mental health outcomes. there are noteworthy limitations to this study. the convenience sample was primarily insured, non-hispanic, white, and female, which may have led to results that are not generalizable to the broader population of us adults. minority populations tend to experience the effects of trauma to a greater degree than others. given the results seen in this study in a non-hispanic white population that is primarily insured, it is reasonable to assume that minority populations may be impacted to an even greater degree than what was demonstrated in this study. particular care should be taken to measure and address these concerns in future studies. in addition, due to the small number of african americans in this sample, we were not able to explore the relationship between race and mental health, a limitation that should be prioritized for exploration in follow-up research. in addition, the sample did not include a representative percentage of young people or individuals with children. given the age effects in this study, further investigation is encouraged to determine the effect of age on mental health outcomes during the pandemic. the results of this study are based on a comparison with prepandemic norms, which may not be representative of the morbidity of these mental health conditions in peripandemic or postpandemic times. functional impairment was not measured. therefore, assumptions about the impact of negative mental health symptomatology in the peripandemic period cannot be made. furthermore, the survey was conducted online, which likely inadvertently excluded individuals that do not have access to or are uncomfortable with the internet. the strengths of this study include the large sample, which consisted of respondents from of states in the united states. this survey was also developed and launched early in the pandemic's course through the united states. therefore, it likely captured early mental health responses that later surveys may not have captured. these responses included both mental health struggles and positive mental health indicators. this study was designed with a follow-up in mind. respondents to this survey were asked if they would be willing to participate in a follow-up survey at a later date. this will allow for longitudinal data collection at multiple time points as social distancing restrictions change throughout the united states. our findings suggest that many us citizens, particularly non-hispanic, white, insured individuals, are experiencing high stress, depressive, and anxiety symptomatology. practitioners, including health care workers and mental health specialists, can be a resource for those struggling with mental health concerns during the pandemic. these messages should not only be made in person, but also through practice websites and social media accounts. the overwhelming amount of information available to the public regarding covid- makes it difficult to delineate accurate information from inaccurate information [ ] . practitioners have a preexisting rapport with their patients that they should use to shift the balance toward accurate information. this patient-provider relationship may engender trust that does not exist with larger health or government entities. practitioners should capitalize on this rapport to convey accurate, timely information regarding risk factors, protective measures, coping techniques, financial relief, and food banks. policy makers should encourage growth in areas of mental health support that are most feasible during this time. telemental health, for example, has been shown to be highly effective, cost-efficient, and accessible, especially in isolated communities [ ] . online mental health assessments and self-directed mental health interventions have also been widely introduced in china, with their effectiveness remaining to be seen [ ] . future research should continue to track the mental health effects of the pandemic as it progresses. there may be future waves of illness that impact social distancing recommendations and requirements. these, in turn, may impact mental health. longitudinal investigation of these effects is recommended. future studies should make concerted efforts to obtain a representative sample. representative state-specific samples are available through various entities for a fee. in addition, specific outreach to underrepresented populations is recommended. knowledge of these fluctuations in 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lancet psychiatry this study was supported by nih/ncrr colorado ctsi grant number ul rr . its contents are the authors' sole responsibility and do not necessarily represent official national institutes of health (nih) views. research, is properly cited. the complete bibliographic information, a link to the original publication on http://formative.jmir.org, as well as this copyright and license information must be included. key: cord- -ff mr a authors: almutlak, mohammed; li, jennifer y.; bin helayel, halah; fairaq, rafah title: future of corneal donation and transplantation: insights from covid- pandemic date: - - journal: cornea doi: . /ico. sha: doc_id: cord_uid: ff mr a nan o n march , , the world health organization declared covid- a pandemic, a mere months after the first case of this novel coronavirus was reported in wuhan, china. the gravity of the disease and its rapid global spread have been alarming; the global incidence of the disease has exceeded , , with over , deaths. it has profoundly affected governments, societies, and the day-to-day lives of individual citizens. moreover, it has strained all aspects of health care throughout the world, with corneal transplantation and eye banking being no exception. early on, in the pandemic, with little data available about this new disease and its effect on ocular tissue, eye bank associations around the world rapidly put into place new screening recommendations to reduce the yet unknown risk of donor-recipient transmission during corneal transplantation. in the united states, the eye bank association of america (ebaa) released its first screening recommendations on february , . this early advisory, based in part on the guidance from the us center for disease control on patient screening, included recommendations to defer ocular donors with the diagnosis of covid- , the presence of signs and symptoms of covid- , any history of close contact with a confirmed covid- case, or any history of travel to endemic areas. by mid-march, covid- was spreading rapidly throughout the united states. concerns about the asymptomatic transmission of covid- , the lack of adequate testing, the potential overwhelming of our healthcare system, and the need to conserve essential medical supplies led to drastic shutdown measures in the united states and throughout the world. the ebaa covid- screening recommendations continued to evolve to keep pace with the rapidly changing nature of the pandemic with updates released on march , , and april , . with so many unknowns, the donor screening recommendations were extremely conservative, resulting in significant donor deferrals. fortunately, this decrease in ocular donors corresponded with a recommendation from the american academy of ophthalmology on march , , for immediate cessation of any ophthalmic treatment other than urgent or emergent care. in the matter of a week, ophthalmic care in the united states virtually ground to a halt, including elective corneal transplantation. in a survey conducted by the ebaa of the us eye banks, the volume of tissue distributed for corneal transplantation procedures declined to approximately % and % of the normal volume for domestic surgeries and % and % of the normal volume for international surgeries in march (with eye banks reporting) and april ( eye banks reporting), respectively (k. corcoran, personal communication, july , ). as covid- restrictions were gradually lifted throughout the united states in may and june, elective surgeries including corneal transplantation procedures resumed and, according to the same ebaa survey, were at approximately % of their usual volume by the beginning of june ( eye banks reporting) and % by the beginning of july ( eye banks reporting). in an effort to keep up with the increased demand for corneal tissue as stayat-home restrictions lifted, the ebaa covid- screening recommendations were cautiously adjusted in mid-may to increase the donor pool safely, but there remains a reduction of % to % in donors because of covid- screening rule outs. for corneal surgeons in the united states, this reduction of potential donors will likely not be felt as acutely as in the rest of the world. in , , corneal transplants were supplied by the us eye banks. the us surgeons performed , ( . %) of those corneal transplants, and a third of the tissue recovered, over , donor corneas, was exported to international recipients. even with a reduction of the donor pool in the united states, the eye banks will likely be able to meet the surgical demand domestically. however, the aq : amount of tissue being distributed for corneal transplantation internationally has yet to recover since covid- remaining low at % and % of the prepandemic volume in june and july, respectively. the potential ramifications worldwide of fewer available donor corneas must not be overlooked. even before the covid- pandemic, there was a severe imbalance between corneal tissue supply and demand. in , gain et al found that at least . % of the world's population had almost no access to corneal tissue, and for every corneas needed, only was available. it can be expected that this imbalance will be further aggravated by the pandemic. a decrease in corneal donors throughout the world because of covid- , combined with a decline in the number of donor corneas being exported from countries such as the united states, will potentially lead to severe corneal tissue shortages around the world. additional challenges may await eye banks in their efforts to resume regular operations as quickly as possible. in addition to a decreased donor pool, decreased airline flights may make it more difficult to import or distribute tissue particularly internationally. shortages of supplies may strain eye bank operations especially as covid- numbers continue to increase in many places. eye banks may also struggle to keep preservation times low because the current ebaa covid- screening recommendations frequently necessitate review by eye bank medical directors for donor eligibility, which may delay the release of tissue. donor testing for severe acute respiratory syndrome-coronavirus- (sars-cov- ), if performed, will further add cost and time to the distribution of corneal tissue while potentially providing a false sense of security because testing has not been validated for cadaveric samples and have varying rates of false-negative results. eye banks may start to see push back from surgeons who are noticing a difference in donor tissue characteristics compared with what they were used to pre-covid in part because of the decreased volume of available tissue and the increased time required for donor tissue screening. for now, though, this is the state of eye banking in the era of covid- . current screening recommendations seem appropriate, given what we know, and are allowing eye banks to sustain operations as safely as possible. fortunately, to date, there have been no reported cases of recipient-donor sars-cov- transmission through human cell or tissue. adding to this reassurance is a recent study by bayyoud et al that did not detect sars-cov- rna in corneal tissues (epithelium, stroma, and endothelium) or in the anterior chamber fluid or conjunctival tissue of covid- patients' postmortem, although the sample size was small. however, if the pandemic lingers and a shortage of corneal tissue become more acutely felt, the debate on routine donor testing will, no doubt, come to the foreground. at this time, donor testing is not advocated by either the ebaa or the us food and drug administration for the reasons previously stated. unfortunately, serologic testing for covid- antibodies is inappropriate for screening active infection in donors, and covid- reverse transcriptase polymerase chain reaction testing availability continues to vary from community to community, as does the ability to obtain results in a timely manner. at the end of the day, more research must be conducted on the true risk of viral transmission through donor corneal tissue. it is said that nothing brings people together more than a crisis, and it is now more important than ever that we come together in support of our eye banks. in the absence of a vaccine, eye banks must continue to take extra measures not only to provide safe corneal tissue but also to ensure the health of their workforce with adequate social distancing measures and personal protective equipment; all the while, they have to navigate the economic impact of lost revenue from fewer donor corneas being transplanted. countries that rely heavily on international tissue imports should begin to focus on expanding local tissue donation and procurement. at a time like this, we must all become advocates for corneal donation in our own communities and for our local eye banks. surgeons should remember and take to heart the lessons learned from the corneal preservation time study by accepting donor corneas with longer preservation times and remembering that neither donor age nor preoperative donor endothelial cell counts have been shown to affect graft success ; now is not the time to be a "picky" surgeon. ultimately, by emphasizing the gift of donation and the role and impact eye banks make in the management of corneal blindness, we can inspire cooperation among all stakeholders. driven by humanity's strongest drive, the instinct to survive, we can improve our resilience and emerge stronger from this pandemic. who-director-general-s-opening-remarks-at-themedia-briefing-on-covid a novel coronavirus from patients with pneumonia in china coronavirus update (live) global alliance of eye bank associations. coronavirus (covid- ) and ocular tissue donation eye bank association of america. covid- updates important coronavirus updates for ophthalmologists eye bank association of america global survey of corneal transplantation and eye banking absence of severe acute respiratory syndrome-coronavirus- rna in human corneal tissues updated information for human cell, tissue, or cellular or tissuebased product (hct/p) establishments regarding the coronavirus disease effect of cornea preservation time on success of descemet stripping automated endothelial keratoplasty: a randomized clinical trial donor, recipient, and operative factors associated with graft success in the cornea preservation time study key: cord- -uy f f o authors: nara, peter l.; nara, deanna; chaudhuri, ray; lin, george; tobin, greg title: perspectives on advancing preventative medicine through vaccinology at the comparative veterinary, human and conservation medicine interface: not missing the opportunities date: - - journal: vaccine doi: . /j.vaccine. . . sha: doc_id: cord_uid: uy f f o abstract vaccination has historically and remains one of the most cost-effective and safest forms of medicine today. along with basic understanding of germ theory and sanitation, vaccination, over the past years, has transformed lives and economies in both rich and poor countries by its direct impact on human and animal life—resulting in the eradication of small pox, huge reductions in the burden of previously common human and animal diseases such as polio, typhoid, measles in human medicine and contagious bovine pleuropneumonia, foot-and-mouth disease, screwworm and hog cholera and the verge of eradicating brucellosis, tuberculosis, and pseudorabies in veterinary medicine. in addition vaccination along with other animal production changes has provided the ability to produce otherwise unaffordable animal protein and animal health worldwide. the landscape however on which vaccinology was discovered and applied over the past years, even in the past years has and is undergoing continuous change. for vaccination as a public health tool to have its greatest impacts in human and veterinary medicine, these great medical sciences will have to come together, policy-relevant science for sustainable conservation in developing and developed countries needs to become the norm and address poverty (including lack of basic health care) in communities affected by conservation, and to consider costs and benefits (perceived or not) affecting the well-being of all stakeholders, from the local to the multinational. the need to return to and/or develop new education-based models for turning the tide from the heavily return-on-investment therapeutic era of the last century into one where the investment into the preventative sciences and medicine lead to sustainable cultural and cost-effective public health and economic changes of the future is never more evident than today. the new complex problems of the new millennium will require new educational models that train para- and professional people for thinking and solving complex inter-related biological, ecological, public-, political/economic problems. the single profession that is best positioned to impact vaccinology is veterinary medicine. it’s melding with human medicine and their role in future comparative and conservation-based programs will be critical to the successful application of vaccines into the st century. vaccination has historically and remains one of the most cost-effective and safest forms of medicine today. along with basic understanding of germ theory and sanitation, vaccination, over the past years, has transformed lives and economies in both rich and poor countries by its direct impact on human and animal life-resulting in the eradication of small pox, huge reductions in the burden of previously common human and animal diseases such as polio, typhoid, measles in human medicine and contagious bovine pleuropneumonia, foot-and-mouth disease, screwworm and hog cholera and the verge of eradicating brucellosis, tuberculosis, and pseudorabies in veterinary medicine. in addition vaccination along with other animal production changes has provided the ability to produce otherwise unaffordable animal protein and animal health worldwide. the landscape however on which vaccinology was discovered and applied over the past years, even in the past years has and is undergoing continuous change. for vaccination as a public health tool to have its greatest impacts in human and veterinary medicine, these great medical sciences will have to come together, policy-relevant science for sustainable conservation in developing and developed countries needs to become the norm and address poverty (including lack of basic health care) in communities affected by conservation, and to consider costs and benefits (perceived or not) affecting the well-being of all stakeholders, from the local to the multinational. the need to return to and/or develop new education-based models for turning the tide from the heavily return-on-investment therapeutic era of the last century into one where the investment into the preventative sciences and medicine lead to sustainable cultural and cost-effective public health and economic changes of the future is never more evident than today. the new complex problems of the new millennium will require new educational models that train para-and professional people for thinking and solving complex inter-related biological, ecological, public-, political/economic problems. the single profession that is best positioned to impact vaccinology is veterinary medicine. it's melding with human medicine and their role in future comparative and conservation-based programs will be critical to the successful application of vaccines into the st century. published by elsevier ltd. the new millennium did not bring the anticipated global internet technology shutdown however, it has brought with and heralded a time of significant change, opportunity and challenges. i and my co-authors goal in this overview are to celebrate, provocate, instigate innovate and activate those in society who are in interested to contributing to the betterment of human and animal health through vaccination. for vaccination to have its greatest chance of working policy-relevant science for sustainable conservation in developing countries needs to address poverty (including lack of basic health care) in communities affected by conservation, and to consider costs and benefits (perceived or not) affecting the wellbeing of all stakeholders, from the local to the multinational. the need to return to and/or develop new education-based models for turning the tide from the heavily return-on-investment therapeutic era of the last century into one where the investment into the pre-ventative sciences and medicine lead to sustainable cultural public health and economic changes of the future is never more evident than today. if the article gets the attention of researchers, educators/teachers, funders, policy makers, economists and the general public in both developed and developing countries to become involved in finding collaborative solutions to the conservation crisis than we will consider it a success. vaccination has and remains one of the most cost-effective and safest forms of medicine toward improving health today. along with basic understanding of germ theory and sanitation, vaccination, over the past years, has transformed lives in both rich and poor countries-resulting in the eradication of smallpox and huge reductions in the burden of previously common diseases such as polio, typhoid and measles. immunization is particularly well suited to all countries including those with weak health systems, because it requires relatively less training and equipment and does not depend on skilled diagnosis, long-term drug regimens or extensive medical care. immunization and sanitation remain as the most important public health modality responsible for improving the gnp of developing countries through additional gains in healthier children who are better educated and grow up to impact on their productivity. like schoolchildren, healthier workers have better attendance rates and are more energetic and mentally robust. workers in healthy communities, moreover, need to take less time off to care for sick relatives. body size, which is greatly influenced by one's health during childhood, has been found to have large impacts on long-term productivity. recent economists [ ] have calculated that a -year increase in life expectancy improves labor productivity by %. despite the weakness of health systems in many developing countries, three-quarters of the world's children now receive a standard package of childhood vaccines through the who/unicef expanded program on immunization to protect them against diphtheria, tetanus, pertussis, polio, measles and neonatal tuberculosis [ ] . these vaccines currently save an estimated million lives a year -almost , lives a day -and protect millions more from illness and permanent disability, thus providing as mentioned above a healthier cohort of people to contribute to the economic development of the nation. the full package of basic vaccines (diphtheria, tetanus, pertussis, polio, measles and neonatal tuberculosis) costs less than $ per year of life saved in poor countries. "life-years" and "year of life" consistently refer to disability-adjusted life-years (dalys). interventions are generally considered extremely costeffective if the cost per year of life is less than $ . by comparison, antiretroviral treatment for hiv/aids-an intervention that donors widely support in the developing world costs up to five times as much at $ to $ per life-year saved; by way of comparison, in the us and the uk medical interventions are considered cost effective at $ , to $ , per life-year saved [ , [ ] [ ] [ ] . the week during the conference in amsterdam it was reported that "vaccine-preventable deaths reach new low in u.s." as reported in a federal report released tuesday, november , people readily associate the role of veterinarians with private veterinary practice focused on pets and farm animals, but the true dimensions and contributions of veterinary medicine are much broader and reflect expanding societal needs and contemporary challenges to animal and human health and to the environment [ ] . veterinary medicine has responsibilities in biomedical research; ecosystem management; public health; food and agricultural systems; and care of companion animals, wildlife, exotic animals, and food animals. the expanding role of veterinarians at cdc reflects an appreciation for this variety of contributions. veterinarians' educational background in basic biomedical and clinical sciences compare with that of physicians. however, unlike their counterparts in human medicine, veterinarians must be familiar with multiple species, and their training emphasizes comparative medicine. veterinarians are competent in preventive medicine, population health, parsitology, zoonoses, and epidemiology, which serve them well for careers in public health. the history and tradition of the profession always have focused on protecting and improving both animal health and human health [ ] . since , a total of diseases have been eliminated from equine, poultry, and livestock populations in the united states [ ] . the elimination of these livestock diseases, along with outstanding research in animal health, is key to the remarkable gains in the efficiency of u.s. animal production [ ] . partly as a consequence, u.s. residents spend only approximately % of their disposable income on food, whereas residents in other countries pay three or four times more [ ] . although this achievement is recognized to have added billions of dollars to other parts of the u.s. economy, its success in allowing the u.s. public access to a nutritious, affordable, and sustainable food supply -also important for the public's health and well-being -is far less appreciated. the success of the national brucellosis and tuberculosis elimination campaigns has benefited not only the u.s. livestock industries but also human health by substantially reducing these zoonotic threats in animals. additional public health contributions can be attributed to the food safety and inspection service of the u.s. department of agriculture (usda), which has substantially reduced the burden of food-borne illnesses, improved food safety, and eliminated other zoonotic threats. over the years, cdc has worked closely with usda and the food and drug administration to improve the safety of u.s. foods and reduce antimicrobial resistance in pathogens that infect both humans and animals. veterinary scientist and veterinarians within the health and human services serve in many critical capacities. veterinary officers in the commissioned corps work throughout the u.s. department of health and human services and in other federal agencies. most veterinary officers are assigned to the cdc, nih, fda, usda, epa, ogha, ndms and state department. other veterinarians and veterinary scientists function as medical research scientists post-doctoral nih/nci fellows, principal investigators, some specializing in lab animal medicine and providing critical lab animal health infrastructure and support, design of animal models for human disease in most of the hhs institutes. some are part of the hhs national disaster medical services and were deployed as the veterinary medical assistant teams (v-mats) and supported the search and rescue in the world trade disaster. additionally, since , the avma and the college of american pathologists have been working together to create a standard nomenclature that would allow veterinarians, physicians, and other medical professionals to create electronic medical records that use a common language. the systematized nomenclature of medicine, snomed, was initially created by the college for human medicine but has sincethrough the partnership with avma -expanded to include veterinary terms. on july , , the department of health and human services announced it would make snomed available nationally at no charge, a step toward instituting a standardized electronic medical records system. the hhs signed a -year, $ . million contract with the college to license snomed and make it available nationally. the national library of medicine is administering the program. prior to the hhs's agreement with the avma, practitioners in areas of practice nationally on the front line of surveillance would have had to pay a $ to $ annual registration fee to access snomed. the cdc has expanded the role, scope, and influence of veterinarians and veterinary scientists and epidemiologists in public health since its inception in [ ] . early in the history of cdc, veterinarians in the u.s. public health service and the cdc veterinary public health division helped reduce zoonotic diseases, especially rabies and food-borne illnesses [ ] . today, veterinarians serve throughout cdc in positions that address not only infectious diseases but also the entire spectrum of public health challenges: environmental health, chronic diseases, human immunodeficiency virus infection and acquired immunodeficiency syndrome, injuries, immunizations, laboratory animal medicine, global health, migration and quarantine, health education, and bioterrorism. veterinarians contribute as epidemiologists, laboratory scientists, policymakers, researchers, and surveillance experts and in environmental and disease prevention and control programs both domestically and globally. at cdc, veterinarians have participated in the epidemic intelligence service since [ ] . forty-one states now have state veterinary public health officials. in , almost students and faculty attended the first veterinary student day at cdc; in april , cdc will co-host an inaugural conference with the association of schools of public health and association of american veterinary medical colleges. in addition, cdc has been recognized as a world association for animal health collaborating center for emerging and re-emerging zoonoses. the cdc publication, emerging infectious diseases, has highlighted zoonotic diseases in nearly every issue to zoonotic diseases and has devoted an annual issue in each of the previous years. the cdc has provided an important scientific forum for zoonotic disease research and programs both domestically and globally and should serve as a template for the nih, as will be discussed later in this paper (section . ), for moving these highly trained and broad-based medical skill set professionals from a more decentralized setting into a central institute at the nih. benjamin franklin's famous quote, "an ounce of prevention is worth a pound of cure" was actually fire-fighting advice-he founded the first fire fighting organization in philadelphia, its obvious application to medicine, although obvious, has not been a mainstay of heavily invested research and development in human health practices. many of the leading causes of death and disability in the united states can be prevented [ ] . primary prevention can prevent or arrest the disease process in its earliest stages by promoting healthier lifestyles or immunizing against infectious disease [ ] . secondary prevention, by detecting and treating asymptomatic risk factors or early asymptomatic disease, can substantially reduce subsequent morbidity or mortality. the human and veterinary clinician plays a pivotal role in both primary and secondary prevention. health professionals deliver vaccinations, screen for modifiable risk factors such as high blood pressure and high cholesterol, counsel patients about smoking and other behavioral risk factors, provide screening tests for early detection of cancer and other chronic conditions, and advise patients about the benefits and risks of preventive therapies such as postmenopausal hormone replacement therapy. the preventative health care landscape has changed in some regards in the years since the u.s. preventive services task force (uspstf/task force) was first established in to provide advice about prevention for health professionals. prevention became more of an integral component of primary health care [ ] . delivery of clinical preventive services such as immunizations, mammograms, and cholesterol screening has risen steadily over the past two decades (national center for health statistics [ ]). roughly % of employers now include well-child visits, childhood immunizations, screening tests, and adult physical examinations among covered health benefits, compared to less than half that did so in [ ] . interest in prevention grew significantly among the public, clinicians, educators, employers, and policymakers [ ] and health plans and individual clinicians were increasingly being held more accountable for the quality of the preventive care they provide to their patients [ ] . at the close of the th century, health care costs in the united states continued to rise steadily, accounting for . % of the gross domestic product in [ ] , and debate on health care funding for the aging american population intensified. no doubt fueled by the incredibly imbalanced historic spending in preventative healthcare of cents for every cents spent for curative treatment [ ] . numbers are harder to come by for recent years, but given the spiraling costs of treatment since it is likely that this ratio has gone down considerably since then-possibly grossly estimated to be closer to : today. in this environment, preventive services often compete with one another and with diagnostic-and treatment-oriented care for increasingly constrained resources [ ] . while preventive services are often believed to save costs, delivery of most preventive services, with few exceptions (e.g. some immunizations), incurs net costs [ ] . evidence that us society clearly favors the cure (or treat) approach to disease over prevention can be shown in the following ways. first, though there is a shortage of preventive medicine specialists (public health, general preventive medicine, occupational medicine, and aerospace medicine physicians), in the us the number of residents in training in was less than . % of all residents, not sufficient for replacement or to fill the expanding demand for the specialty's skills and talents [ , ] . second, preventive medicine residencies and subspecialties in human and veterinary medicine are generally found in only graduate medical education programs not financed by cms or mainstream academic training programs. third, we believe that our preventive acts are only statistical, whereas our curative acts are certain. this mistaken belief perhaps derives from our sense that we have more control over cure outcomes than prevention outcomes-we think that we do cure, whereas we only facilitate prevention. this notion of doing vs. facilitating is an important one, because if we believe that our curative actions are more effective than our preventive ones then we will more likely act toward the more effective. the editor of the british medical journal, fiona godlee, expressed this well when she states, "because it is acted on healthy people, preventive medicine needs even stronger supporting evidence on benefits and harms than therapeutic interventions" [ ] . thus substantial gaps in the delivery of effective preventive care in the united states remained, however, because clinicians continued to face many of the same barriers that originally spurred the formation of the first uspstf. identifying effective interventions were and are difficult in prevention, where prospective controlled trials are often difficult to conduct. these studies come from the field of epidemiology which has changed remarkably during its growth in the past quarter century. one of those changes has been a mixed blessing of ever-increasing specialization among its practitioners at the cost of the generalist. this phenomenon has shaped the field and a partial explanation for this trend is found in the decline in the availability of training funds not focused on specific and general disease areas. without returning to the training of general conservation-medicine based epidemiologists, the needed trend associations and study designs that are needed to show the economic and public health returns related to preventative practices field will not be realized and in addition lose some of its ability to quickly respond to new and expected emerging public health challenges. conflicting recommendations from different organizations, further exacerbated by the advocacy positions of some groups, leave many clinicians uncertain about what to do. clinicians facing increasing time pressures in practice may question the value of some routine preventive interventions, as may employers and other payers struggling with accelerating health care costs. although more prevention information is reaching the public, the messages conveyed are often inconsistent and increasingly colored by commercial self-interest. clinicians may feel compelled to provide unproven or ineffective services because patients demand them or they fear being sued, but patients may find that insurance coverage for individual preventive services, especially new technologies, is inconsistent. the importance of clarifying what we know and do not know about the effectiveness of specific preventive services is as important in as it was in . although the uspstf was disbanded in with the release of the guide, the need to keep pace with the rapid growth in scientific evidence led to convening a second panel in . the second uspstf was smaller, with only members, eight of whom were primary care physicians. it refined the previous group's methods for reviewing evidence and making recommendations, and expanded the scope of topics. it adopted policies for disclosure of conflicts arising from financial interests, funding sources, or other affiliations. the work of the second uspstf was marked by strengthened ties with both federal and nongovernmental partners, including primary care subspecialty societies. the work of the second uspstf culminated in the publication of the second edition of the guide in , which covered over interventions in areas. by the time the second edition of the guide appeared, the environment for preventive medicine and evidence-based medicine had changed dramatically. managed care organizations, which had emerged as a dominant paradigm for delivering and paying for health care, included some preventive care among basic covered services more commonly than had traditional fee-for-service insurance. at the same time, the heightened competition spurred by managed care brought increased attention to costs and value of treatments with less attention given to prevention. the guide was frequently cited by health plans and systems of care in defending their health maintenance programs and benefits packages, and its recommendations informed many of the health plan employer data and information set (hedis) quality measures developed by the national committee on quality assurance for evaluating health plan performance but not integrated into cost saving practices by the insurance companies. the rapid progress towards universal vaccination coverage in the s and s has slowed in recent years. unicef funding for vaccination fell from $ million to $ . million between and [ , ] . global coverage of the diphtheria, tetanus, and pertussis (dtp ) vaccine has been at around % since [ ] . fifty-seven developing countries have yet to eliminate neonatal tetanus, and , babies died of the disease in . ten developing countries reported cases of polio in june , despite the massive (and largely successful) global effort to eradicate the virus [ , , ] . sixty-two percent of countries, meanwhile, had still not achieved full routine immunization coverage in , with gavi estimating that at least . million additional infants need to be reached to achieve full coverage. there are several factors behind this loss of momentum. although dramatic progress has been made in increasing worldwide vaccination coverage from below % to above %, the task has inevitably become harder now that the easiest-to-reach populations have been vaccinated. because these communities are more elusive, the average cost per vaccination has increased, and it may be that other apparently cheaper health interventions have become more attractive. there are many practical problems impeding vaccine delivery. delivering vaccines to patients requires functioning freezers and reliable transport to move the vaccines from port to clinic; clinics refrigerators (which in turn require a constant supply of energy); good roads and with access to people who need to be immunized; parents who know the value of vaccination; trained medical staff to deliver the dose; and sterile syringes. only % of vaccineimporting countries could guarantee vaccine safety and quality [ ] , while a further study of developing countries found that at least half of injections were unsafe [ , [ ] [ ] [ ] [ ] . the third factor behind the lack of progress in recent years is political. political disruptions have affected coverage in some areas. in somalia and congo, for example, where vaccination rates have fallen rapidly in the past decade, war and social breakdown have impeded public health campaigns, despite "vaccination days" in congo that temporarily halted fighting. gauri et al. have found that the quality of institutions and governance are positively correlated with vaccination coverage [ , ] . politics in the developed world have also played a part. according to a report by the us institute of medicine, in the us vaccine industry was forced to stop offering low-price vaccines to develop-ing countries following congressional hearings that "savaged" the industry for "allegedly subsidizing vaccines for the poor children of the world by charging high costs to us families and taxpayers". as the institute of medicine points out, this move was based on a flawed premise, as the us vaccines would have been developed anyway to protect american children and travelers. public perceptions of vaccination change-as coverage spreads through a community and it reaches a point at which those who are unvaccinated are highly unlikely to catch a disease because herd immunity has set in. at this juncture, it may be more rational for an individual to refuse vaccination in order to avoid any risk of side effects. with the oral polio vaccine, for example, there is a one in a million chance of paralysis, and in societies where mass vaccination has eliminated the disease, the risk of paralysis is greater than that of catching polio itself. what had once been a public and private good is now a public good but a private risk. as more and more people choose to avoid this risk, of course, overall coverage rates decline, and the community is once again exposed to the threat of the disease. public perceptions have been influenced by vaccine scares. controversy and the attendant bad publicity about the safety of vaccines have been abetted by incidents such as the withdrawal of half the us supply of flu vaccines in due to contamination at the manufacturer [ ] . in addition, alarms over the safety of vaccines such as that for measles, mumps and rubella (mmr), which some believe to cause autism, have further fanned the anti-vaccine movement's flames [ ] . in the us, disputes continue to rage about the scientific basis of such claims, but the preponderance of the evidence, according to the us centers for disease control (cdc), says that the mmr vaccine is safe [ ] . in response to these types of controversies in the us, the institute of medicine has called for independent oversight of vaccine safety studies to ensure the fairness and openness of the vaccine safety datalink program, which is overseen by the cdc. as one can see there are many complex factors that have to be considered when bringing vaccination programs into existence. the impact of vaccination of animal diseases on agriculture is typically assessed in quantitative terms-lost revenues; costs of eradication, decontamination, and restocking; and the numbers of affected farms, animals and humans. this approach can be applied universally to all outbreaks in all countries because it normally reflects the hard data supplied by large commercial operations and the estimates by relevant governmental agencies of small farmer impact [ ] . when used exclusively, however, it fails as a barometer, because it does not and cannot factor in the multi-dimensional character of major disease events-and the accompanying societal effects that often get lost when it comes to assessing the damage in developing countries. the quantitative approach must also be interpreted, and cannot be used "as is" for comparing impacts in developed and developing countries. further, while export trade losses in a developing country may be small in terms of the dollar amount, the impact upon its pre-epidemic market share is inevitably greater and more persistent. other impacts such as effects on human health and community stability tend to be more visible and last longer in developing countries, particularly at the village level where animal are husbanded primarily for the benefit of the immediate family, and often in impoverished circumstances [ ] . the consequences of animal diseases in domesticated birds and livestock can be complex and generally go well beyond the immediate effects on affected producers. these diseases have numerous impacts, including: • productivity losses for the livestock sector (e.g. production losses, cost of treatment, market disturbances). • loss of income from activities using animal resources (in such sectors as agriculture; energy; transportation; tourism). • loss of well-being of human beings (morbidity and even mortality rates; food safety and quality). • prevention or control costs (production costs; public expenditure). • suboptimal use of production potential (animal species, genetics, livestock practices). the most direct economic impact of animal diseases is loss of production and/or productivity, and ensuing income losses for farmers [ ] . however, if the economy depends on one or some of the vulnerable products, the impacts can be serious, and local food security can be threatened. the economic impact also depends on response strategies adopted by farmers and possible market adjustments. if the farm economy is diversified or if there are other opportunities to generate income, the impacts can be mitigated. the economic impact also depends on response strategies adopted by farmers and possible market adjustments. the loss of the farmer's "well-being" will generally be lower than the value of the lost product, except where the farmer has few alternatives or is wholly dependent on the affected product, which is quite often the case in developing countries. direct losses are the result of the disease itself (they may be very high when mortality rates are between and %), or from animal health measures (stampingout policies) [ , ] . in vietnam, one of the countries most seriously affected by the avian flu, almost million birds - % of the country's poultry population -had to be destroyed at an estimated cost of us $ million ( . % of gnp) [ ] . the smaller scale producers lost the least in absolute terms, but the most in relative terms, as the outbreak resulted in losses equivalent to upwards of times their daily income (from us $ a day or less). in africa, abortions caused by the rift valley fever virus not only affect birth rates, but also push human consumption of milk downward in the year following an outbreak [ ] . in the dairy farming sector in kenya, it is estimated that losses in milk production accounted for % of all losses caused by an outbreak of foot-and-mouth disease in the s. direct costs are generally well below the indirect costs of animal diseases and are directly linked to the rapid containment of outbreaks: case studies have shown that early detection and the implementation of appropriate measures in the event of an outbreak are essential to help minimize direct losses as much as possible. conversely, inappropriate control and eradication measures are at the root of such endemic situations, which are much more difficult, and infinitely more costly, to keep under control or eradicate. the livestock sector plays a significant role in the economic development of many countries and vaccination can serve as one of the most important means of assuring its health. as such the cost of not developing new and important or properly applied vaccines can have tremendous economic consequences. the production of meat and other animal-based food items generates income, jobs, and foreign exchange for all stakeholders in the animal industries. consequently, an epizootic which could have been otherwise mitigated by vaccination can affect the industry's upstream (inputs, genetic resources) and downstream activities (slaughterhouses, butchering operations, processing, marketing) in terms of jobs, income for the stakeholders in the industry, or market access. a survey by the food and agriculture organization of the united nations (fa ) on avian flu revealed that in the most seriously affected regions of indonesia, % of permanent workers at industrial or commercial farms lost their jobs [ ] . similarly, an outbreak of contagious bovine pleuropneumonia in botswana led to the destruction of more than , animals in the most seriously affected province, and the immediate closure of the export slaughterhouse, which employed persons. owing to the catalyst role of livestock raising in the rural economy as a whole, the costs of the indirect effects of these measures were later estimated to be seven times higher than the costs caused by direct losses [ ] . in vietnam, % of the poorest segment of the population, for which poultry farming accounts for - % of household income, is particularly vulnerable to income losses caused by avian flu. the fao and world organization for animal health (oie) estimate that between one-third and one-half of the populations living in the most seriously affected areas of southeast asia depend on poultry farming for at least a part of their income [ , ] . in france, the leading european poultry producer, it is estimated that farmers affected by the crisis lost % of their income in months (between january and march ). the effects of the production losses are also linked to price variations, which are caused by supply and demand (im)balances. depending on the market, prices can rise sharply (consumer product on the domestic market) or plummet (product banned for export but cleared for consumption on the domestic market, product deemed too dangerous for human consumption or perceived as such). in brazil, where % of products are exported, the price of a day-old chick, an early indicator of a possible change in production, reportedly fell by %. and even in cases where the country is not infected, market uncertainties and the fall in prices prompted the largest producers to cut back production by % this year. loss of access to, or the opportunity to access, regional and international markets generally have more significant economic implications than just production losses. in / , the rift valley fever outbreaks in east africa seriously affected pastoral economies in somalia, with a decline of more than % in exports (which generate more than % of foreign exchange in "somali land"), following an embargo declared by saudi arabia on all animal products from the horn of africa [ , ] . conversely, the world bank has reported that eradication of certain major diseases to facilitate access to "high value" export markets can provide considerable benefits. loss of access to, or the opportunity to access, regional and international markets generally have more significant economic implications than just production losses. uruguay is a good example of a country that gained access to a lucrative market after eradicating foot-and-mouth disease. beef exports increased in volume by more than % and in value by % after the oie declared uruguay to be officially foot-and-mouth disease-free without vaccination in . access to the u.s. market (where prices are double those of the domestic market) provides uruguay with additional revenue to the tune of us $ million each year. a medium-term analysis showed that access to "pacific rim" markets would generate additional revenue of us $ million each year, and yet, before the disease was eradicated, uruguay had been spending (only) us$ million to us $ million each year on vaccines to combat foot-and-mouth disease. in this case, control costs would account for less than % of the revenue generated by exports alone [ ] . animal diseases that could be controlled by vaccination can have major effects on food availability and quality for poor communities. it is well known that agriculture plays an important role in the generation of income and jobs in other sectors but the closeness of this interdependence became particularly obvious during recent epizootics. for pastoral societies, animal husbandry contributes directly and indirectly to food security and to nutrition as a source of quality proteins, vitamins and trace elements, traction, and com-mercially tradable products [ , ] . certain diseases could have significant repercussions on food supply and the nutrition of poor communities that do not have readily available substitute products, which could therefore lead to famine (rinderpest for example). poultry meat is the primary animal protein in africa (which has little to begin with) and the indispensable source of discretionary income for the survival of millions of small farmers. the high mortality rates as a result of avian flu, which is extremely pathogenic, and the sanitary slaughter of poultry would therefore have a negative impact on the food available to the entire population, as well as on rural revenue. furthermore, developing or transition countries which generally have poor public health systems are particularly at risk from zoonoses making vaccination against these diseases particularly important to target. in / a major rift valley fever epidemic in egypt resulted in , human cases and fatalities [ , ] . twenty years later, a new epidemic affected over , persons in east africa, and persons succumbed to the hemorrhagic form of the disease. but zoonoses also affected industrialized countries with high health standards as was the case with the bovine spongiform encephalopathy crisis in europe [ ] . food-borne diseases (over have been classified) are a major source of acute gastroenteritis (which costs the netherlands us $ million per year) and the cause of major morbidity with fatalities among children in the third world [ ] . in the specific case of a pandemic, most of the economic loss is caused by the increase in morbidities and fatalities in the human population and its repercussions on the world economy. the most recent estimates suggest that the "spanish" influenza in caused the death of million persons, that is, . % of the population at the time. the most obvious economic losses were the reduction in quantity and productivity of the workforce, and according to the experts, in the case of a pandemic could represent times more than all the other losses combined [ ] . another category of economic impact is linked to individual strategies to avoid contamination-or to survive possible contamination. the example of the severe acute respiratory syndrome (sars) clearly shows the sharp drop in demand in the services sector (tourism, public transport, retail trade, hospitality and food services) resulting from the combined efforts of individuals to avoid any close contact [ ] . based on the experience with severe acute respiratory syndrome in south-east asia, the world bank thinks that an avian flu pandemic could result in a % loss of the world's gross domestic product and cost the world economy us $ billion in the space of year. the losses are difficult to calculate and would undoubtedly be much more significant in light of the extremely high mortality rates in developing countries which do not have good health care systems. the impact of animal diseases on the tourism and leisure sectors could also be quite significant. the negative effect of foot-and-mouth disease in the united kingdom on these two sectors amounted to us $ billion because of restrictions on access to rural areas and represented more than half of the total cost of the disease [ ] . the federation of american scientists' animal health/emerging animal diseases (ahead) project proposed a major program in sub-saharan africa to detect and document the extent of infectious diseases shared by farm and wild animals, and to supply treatment, prevention and control services to remote communities that have previously been neglected by other programs, both national and international. this program, international lookout for infectious animal disease (iliad), was implemented in south africa [ ] . at the core of iliad is the need for a permanent and sustainable regional program of in situ surveillance designed to detect, monitor, treat, prevent and control infectious diseases with the goals of increasing livestock production in remote farming communities, protecting the health of wild species, building indigenous physical and professional resources, and introducing communications and epidemiology information technologies. transmission of infectious diseases is rampant in remote communities in the sub-saharan region, just as they once were in the united states and as they always are wherever poverty and farming co-exist. diseases shared by wild, farmed and captive/bred animals, and by animals and humans, suppress food production, frustrate species preservation efforts and greatly affect public health. detection, prevention and control of these diseases are an essential element in expanding trade, improving nutrition, exploiting ecotourism and ensuring food security. iliad is structured in the investor mode-an international consortium of donor groups providing short-term developmental assistance with program direction and oversight provided by veterinary diagnostic, public policy and epidemiology experts representing the sub-saharan africa partnership members-the renowned onderstepoort veterinary and exotic disease institutes (ovi) and tuskegee university (tu), and fas-ahead. given positive assessments of the benefits of the program after years, national or provincial institutions will integrate some or all of the activities into their official veterinary and agricultural activities. it is difficult to calculate the cost of the public's loss of confidence in animal industries in their countries, or of an importer country towards the veterinary services of the exporter country. animal diseases can have major effects on food availability and quality for poor communities. consumers' obsessive fear of bovine spongiform encephalopathy (mad cow disease), fed by the media and which a good communication strategy could have prevented, would have tremendous social repercussions on a europe still reeling from long term economic repercussions. in italy, the baseless perception of a food risk related to avian flu coupled with low confidence in public health services eventually resulted in a % reduction in the consumption of poultry and eggs. the loss of confidence by an importer country can trigger a lasting embargo and major economic and social repercussions (arabian peninsula embargo on the horn of africa, affected by the rift valley fever virus). loss of access to, or the opportunity to access, regional and international markets generally have more significant economic implications than just production losses. animal diseases might also have indirect long-term impacts, affecting deferred productivity. this is the case for example of the reduction in the fertility rate of long-cycle species, the effects of which span periods of - years [ ] . in short, the long-term costs of a slow response are rarely taken into account. economic analyses focus primarily on the effects of the outbreaks and rarely take into account the long-term effects of an endemic situation (characterized by less virulent outbreaks which recur for several years). this is the case of classic swine fever in haiti where recurrent outbreaks reduced the usage rate by %, which for pig farmers meant a loss of revenue of us $ . million per year [ ] [ ] [ ] . with major crisis, long-term impacts would make themselves felt, since the additional costs of financing prevention and control measures would lead to an equivalent reduction in savings and investments. for example, the analysis of the global impact of the avian flu crisis in europe was complicated by outbreaks of foot-and-mouth disease in brazil, the largest global exporter of beef and poultry. it is therefore easy to imagine what the combination of these two events would mean in terms of the upward push of prices of all meats, similar to what occurred in with north american beef and bovine spongiform encephalopathy. the european union, a net importer of beef, especially from brazil, would see an increase in the price of beef in its internal markets stemming from the embargo imposed on brazilian beef because of the foot-and-mouth disease. it must be pointed out that the crises could have a cumulative impact, particularly since they are amplified by the effects of globalization the following example therefore illustrates the ripple, spillover and remote effects: in the united states, where % of oleaginous and cereal production is geared towards animal production. an epizootic which reduces animal production by % would have the immediate consequence of the loss of , jobs, a surplus of . ton in cereals and oleaginous products, a % reduction in world trade and, crises in other producing countries. in , nearly americans out of every , died each year of infectious disease. laurie garrett, author of "the coming plague: newly emerging diseases in a world out of balance", writes that in the postwar environment, powerful medical weaponry (antibiotics, vaccines, water treatment, anti-malaria drugs) gave scientists confidence that they could significantly control and/or eradicate infectious disease from viral, bacterial or parasitical sources. in the late s, the surgeon general of the usa, william h. stewart, said that ". . .it was time to close the book on infectious diseases and pay more attention to chronic ailments such as cancer and heart disease." a measure of that success came towards the end of the s, when the world realized that smallpox had become the first disease to be eradicated from the human species. such halcyon days from the s to the early s are but a memory. by , the numbers were down to per , . the "health for all" accord, signed in , set a goal of the year for eliminating many international scourges. but amid all this optimism, the numbers started rising. in , people per , died and we know the rest of the story, . . . or do we? the grandiose optimism rested on two false assumptions; that microbes were biologically stationary targets, that for the most part human and other animal diseases were for the most part limited to those species and geographically sequestered. scientists have witnessed an alarming mechanism of microbial adaptation and change, anything but stationary, microbes and the insects, rodents and other animals that transmit them are in a constant state of biological, ecological flux and evolution [ ] . according to the u.k. centre for tropical veterinary medicine, - % of all the known species of infectious organisms that affect human health (causing a quarter of the world's deaths) can be transmitted by animals. approximately of these infectious organisms are linked to diseases that have only recently emerged, or have increased in severity (and geographic distribution) in recent years. who averages outbreak investigations every year, and around will require an international response. more than new and highly infectious diseases have been identified in the last years. furthermore, known strains of diseases such as tuberculosis, many species of gram positive and negative bacteria as well as many parasites, e.g. malaria, food animal coccidia have developed resistance to various classes of antibiotics, while old diseases have reappeared, such as cholera (in angola, with deaths), yellow fever (new cases recently reported in guinea, sudan, mali, and senegal), plague, dengue fever, meningitis, hemorrhagic fever, measles, mumps, rubella and diphtheria. there are emerging diseases just among marine life, reports the book conservation medicine, and these include tuberculosis in fur seals and chlamydiosis in sea turtles. more staggering than these cited numbers in living animals including humans are those coming out of the microbial genetic sequencing and diversity studies involving the oceans. recent data in this field suggest that the oceans of the world contains approximately ( ) phage particles or virions (cf. million metric tons), much of it turning over once per day and most likely be a regular source for current and future zoonotic and human infections. this vast mutation engine, even if one assumes a minimal mutation rate, generates the equivalent of hundreds of new complete human genomes per day. a -l sample of surface seawater was concentrated; ∼ × ( ) viral particles, the dna once randomly sheared and cloned yielded , fragments for sequencing. data analysis showed that most of the sequences were from previously unknown viruses. approximately . % of the total sequence samples overlapped, suggesting that the marine viral community was highly diverse. a unique mathematical analysis further suggested that approximately ( ) different new viral types may be present. it is obvious from this most recent description that complex and confounding zoonotic interactions can be expected to occur as ecosystems become concentrated and/or diluted during the upcoming environmental and ecological change. this will require a new breed of medical scientists that have foregone the days of super-and sub-specialization and are now grounded in both depth and broad general eco-and bio-medical systems training. few people recognize the broad range of clinical and basic veterinary research and its many important contributions to society in the realms of public health and food safety, vaccination, fertility, drug and vaccine development, surgical techniques and biodegradable materials, space medicine, animal health and welfare, and comparative medicine [ ] . opportunities in veterinary research include comparative studies with animals that shed light on human health problems; the development of tools to better detect, prevent, and control zoonotic diseases (that spread from animals to humans); the establishment of scientifically based policies for the humane treatment of animals; and the development of measures to secure and protect the nation's food supply and farm-animal economy from a potential act of bioterrorism [ , ] . the new complex problems of the new millennium will require new educational models that train para-and professional people for thinking and solving complex inter-related biological, ecological, public-economic problems. the single profession that is most centered on the new paradigm is veterinary medicine. the three major disciplines within veterinary medicine and research -public health, comparative clinical and basic medicine, and animal health -are closely intertwined [ , ] . for example, research in comparative medicine contributes to animal health through the development of preventive medicine and treatment. the study of wildlife diseases contributes not only to wildlife health and conservation, but also to public health because many animal diseases can spread to humans. therefore, collaborative and interdisciplinary research is crucial in translating scientific advances from one traditional discipline to another. however, interdisciplinary research is in many cases hampered by administrative, funding, and cultural barriers between institutions. furthermore, agencies that support veterinary research have specific missions. funding to support proposed interdisciplinary research can be difficult to obtain when it is partially related to the mission of several agencies but does not perfectly fit the mission of any one agency. the future requires the veterinary research community to encourage research funders to develop a long-term interagency strategy for veterinary research [ , , ] . in , rudolph virchow, the father of comparative medicine, stated, "between animal and human medicine there are no dividing lines-nor should there be. the object is different but the experience obtained constitutes the basis of all medicine" [ ] . sir william osler ( - ), considered the best-known physician in the english-speaking world at the turn of the century, called the "most influential physician in history" is quoted as saying "veterinary medicine and human medicine complement each other and should be considered as one medicine." dr. calvin schwabe, a retired uc davis professor of veterinary medicine who pioneered the use of human disease tracking techniques in the study of animal illnesses, a global authority on animal diseases that are communicable to human beings and was an early visionary in a field that today is marked by the emergence of pathogens such as avian influenza, mad cow disease and sars. in , dr. schwabe established the department of epidemiology and preventive medicine at the uc davis school of veterinary medicine-the first of its kind in the world at a vet school. the author of more than publications, he promoted the concept of "one medicine," which attempts to bring the fields of human and animal health care together. to this goal in june of the american veterinary medical association (avma) announced that in partnership with the american medical association (ama) there was an adopted resolution calling for collaboration on a one health initiative. the two national, medical organizations will work collaboratively on areas of mutual medical interest, such as pandemic influenza, bioterrorism risks, biomedical research and will be charged with developing strategies to promote collaboration among the various health science associations, colleges, government agencies and industries. a quote from a ama board member, duane m. cady, md "new infections continue to emerge and with threats of cross-species disease transmission and pandemic in our global health environment, the time has come for the human and veterinary medical professions to work closer together for the greater protection of the public health in the st century," the avma policies supporting the concept of "one health" include: furthermore to strengthen this initiative and give it a renewable funding foundation, it would be recommended to move toward, the creation of: ( ) a specific focus at the national institutes of health (nih) on integrated veterinary research via the roadmap initiativemore specifically to create or combine existing potions of institutes into an institute of comparative medicine (icm); ( ) a joint interagency collaborative programs could also be established to enhance interdisciplinary collaborative research and have either re-routed an/or new congressionally supported intra-mural and extra-mural funding program; and ( ) while working out and introducing the legislative changes for the icm the nih should create a veterinary liaison with all the current institutes like the veterinary-medicine and public-health liaison at the centers for disease control and prevention (cdc) in which a veterinarian, dr. lonnie j. king, was selected to head up the agency's national center for zoonotic, vector-borne, and enteric diseases-a relatively recent creation, the center is dedicated to understanding infectious disease ecology and will help to ensure integration of veterinary and human medical research. the american veterinary medical association, with information provided by many other organizations and institutions, conservatively estimates a current deficit of public health veterinarians (e.g. usda food safety and animal disease control, homeland security, research on domestic and foreign animal diseases, wildlife disease control, laboratory animal care and research) and is expected to increase possibly to , by as the human population increases without intervention. comparably the health resources and services administration (hrsa) in the u.s. department of health and human services (dhhs) released a report in , projecting a shortfall of approximately , physicians in [ ] . if current trends continue, the full time equivalent (fte) physician supply is projected to grow to , by , while demand for physicians will increase to , due to the growth and aging of the u.s. population (physician workforce policy guidelines, ). the report projects shortages will be in greatest in non-primary care specialties. it has been over years since the federal government has allocated funds to increase the number of veterinarians and physicians that graduate each year. to begin to alleviate this problem the veterinary workforce expansion act (s. /h.r. ), which is currently being considered by the united states house of representatives and senate would provide an average of $ million per year for the next years in the form of competitive grants to help increase the number of veterinarians entering public practice. if passed and funded, this bill would allow the nation's veterinary schools and other institutions training public health veterinarians to apply for competitive grants to increase capacity in the form of classrooms, teaching laboratories, research facilities, and administrative space. this bill would be vital to the nation's ability to protect human and animal health, as veterinarians are often the first line of defense for both. the text of the bill can be found at: http://thomas.loc.gov by searching by the bill numbers listed above. a list of co-sponsors to the bill can also be found via that site by selecting the link entitled "bill summary & status". over the past century, humanity has had a devastating impact on the earth's wildlife and ecosystems. we are in fact living through the largest mass extinction since the end of the dinosaurs million years ago. unless effective solutions are found, this new century will see the demise of countless more species and pristine ecosystems, particularly in the tropics. the global society, and what surrounds and influences it, are in profound change. these changes will have very significant impacts on future veterinary medicine and veterinary medical education. there are major demographic, political, environmental, disease, technological, and economic influences, all forcing changes onto society. a few examples illustrate the point [ ] . • with immigration into north america accelerating, combined with a declining birth rate, the ethnic diversity in society will continue to increase, with the associated impact on values. • in , for the first time in history, urban people will outnumber rural people. • political destabilization, inflamed by bio-terrorism and religious fanaticism, is expected to increase. • changes in the atmosphere are causing powerful shifts in the environment (melting of the ice caps, rising sea levels) and in the climate (hurricanes, flooding). • global water shortages, especially in heavily populated areas, will soon approach critical levels. to information and service (http://www.jvmeonline.org/cgi/ content/full/ / / #b #b ). • consumer spending power in emerging economies will go from $ trillion to $ trillion by , but the gap between rich and poor is increasing. how will these changes alter the needs of society? how must academic veterinary medicine adapt to prepare veterinarians to respond to these new needs? clearly, humanity has yet to find a way to live on planet earth in a potentially sustaining manner where by stabilizing flora and fauna remain intact to promote healthy ecosystems diversity for all species including our very ownhumans. for example, it is estimated that the equivalent of six earths would be needed to sustain the current world's population if people everywhere consumed natural resources at the rate we do in the united states. it is interesting to think that vaccination directly or indirectly impacts six of the seven united nations millennium goals. understanding and coping effectively with an emerging crisis may sometimes require the birth of action-oriented "crisis disciplines." conservation medicine: ecological health in practice brings together an impressive group of experts from diverse specialties medicine, veterinary science, conservation biology, epidemiology, parasitology, public health, and others) to examine the links among human health, wildlife health, and ecosystem health and begin to address questions like: • how factors such as climate change, endocrine disruptors, and toxic microalgae affect wildlife and human health; • the importance of biodiversity for human health (as medical models, sources of medicines, factors in the ecology of infectious diseases, and indicators of environmental quality), with a review of biodiversity-related biomedical research projects funded by the national institutes of health from to ; • how the health of rainforest-dwelling peoples depends on such diverse factors as forest integrity, floods, seasonality, community organization, education, gender dynamics, national budgets, and global markets; • how wildlife health relates to environmental security; • the health hazards of ecotourism; • the causes and impacts of emerging infectious diseases of humans and wildlife; • how the health of terrestrial and marine animals and ecosystems are monitored, and descriptions of innovations using stool dna and retrovirus evolution as markers of animal population dynamics, stool hormones to indicate species stress, and animal behaviors as proxies for the health of ecosystems; • how habitat fragmentation and reduced biodiversity can increase the risk of lyme disease infection; • how land use changes such as deforestation and water projects influence the ecology of malaria and other vector-borne infections; • how ecological health and wildlife disease are managed in national parks; • the role of zoos in the recovery and conservation of endangered species; • how reducing the burden of infectious disease among park workers in africa could prevent a devastating epidemic among the world's remaining mountain gorillas; • how efforts to control livestock diseases are affecting wildlife health and ecosystems in botswana; • teaching ecosystem health in an undergraduate medical curriculum. more than one billion poor people in asia and africa are closely linked with animals for their livelihoods and they pay a really high tribute to different animal diseases-one can easily demonstrate that improving animal-health mechanisms at the national and local level, and decreasing this weight of animal diseases, will lead very quickly to the alleviation of poverty for this class of people. the world organization of animal health (oie) brings together chief veterinary officers from countries in an effort to create global standards of animal health and animal welfare robust enough to withstand the daunting challenges of worldwide commerce. with an annual budget of around $ million, it is a significantly smaller organization that its human-health counterpart, the world health organization, which has some $ billion a year expenditure on its programs. last year, over billion food animals were produced worldwide to help feed a population of billion people, resulting in trillions of pounds of animal products distributed worldwide and projections for show that demand for animal products will increase by %, especially in developing countries. this poses unprecedented risks for human safety and will require a closer linking of the two agencies. along with those core concerns, oie also addresses farming practices, analyzes import risks, and mediates bilateral trade disputes among its member countries. among its most important achievements in recent years, has been the eradication of rhinderpest, a centuries-old intestinal disease also known as "cattle plague in some countires." in the early s, rhinderpest wiped out upwards of $ million worth of african livestock, contributing to widespread human famine. in general professional students of veterinary and human medicine are exposed more likely to a more scientifically exposed than a politically exposed culture. animal and human health policies must be science-based the rallying cry that is heard from animal and human health professionals around the world. the second verse of this mantra is often 'science, not politics', as if science is unquestionably 'good' and politics 'evil'. antipathy toward politics is worn as a badge of honor. the crowning moment frequently comes with the proclamation, 'i am a scientist, i want nothing to do with politics. ' the phrase 'science-based' infers that the underlying justification of animal/human health policy is derived from knowledge gathered through the systematic observation of, or experimentation with, phenomena. scientific knowledge implies the compilation and analysis of data by individuals with advanced education in specific disciplines. scientists seek facts, the fundamental truths which explain the world around us. at face value, the 'science, not politics' paradigm has a great deal of appeal. however, the very notion of fundamental truth is illusory, as scientific knowledge changes frequently with new observations and experiments. furthermore, conjecture and refutation characterize the scientific method, with disagreement and debate the recognized features of scholarly pursuit. scientists often reach conflicting interpretations of observational and experimental data. consequently, individual scientists may champion different, even diametrically opposed, sets of ideas and principles, so that any number of alternatives may be justified as 'science-based'. finally, animal health professionals typically consider only the biological and physical sciences as 'true sciences', dismissing the social sciences. politics reflect the human need for organization of authority, whether in public or private life. politics exist whenever two or more people come together. the terms 'office politics' and 'family politics' are recognized as clearly as the collective activities surrounding local or national governance. politics exist even in science, affecting scientific organizations, refereed publications and academe. indeed, politics are inescapable. all public courses of animal/human health action adopted by governments emerge from the interplay of science and politics. the policy-making process is governed by rules and regulations, affected by the organizational culture of the government agencies involved, and constrained by legal authorities, political correctness and resource availability. the animal/human health policy-making process involves consideration of current biological and physical scientific knowledge. policy decisions also consider social science factors including ideologies, economics and public opinion. hence the etiology of animal/human health policy is multifactorial. the current older traditional schools of veterinary and human medicine and future schools of "one medicine" will need to include leadership, economics and local, state, national and international governances courses and better training in mechanisms of public policies and rule making. epidemiologists accept the concept of multifactorial etiology as a basic tenet. we discuss disease in terms of agent, host and environment interactions. the practice of applied epidemiology demands a breadth of knowledge and the ability to work in interdisciplinary teams. the more complex the problem, the greater the demand for additional knowledge and insights. veterinary and human epidemiologists study risk factors for disease in animal/human populations and develop strategies for health promotion and disease control [ ] . unfortunately these are done frequently in a vacuum when in fact the two are inter-related and contributing to the observed and at the time undiagnosed disease spectrum however, animal/human health problems cannot be resolved by consideration of biological and physical factors alone. the veterinary and human (someday to become one and the same) epidemiologist working with field problems soon recognizes the critical role played by people in animal/human health issues. applying epidemiological principles to animal/human disease prevention requires consideration of social issues such as attitudes toward animals, cultural and religious mores, and individuals' willingness and capability to implement the prevention strategies. implementing prevention on a national scale brings additional factors into the equation such as availability of resources, adequacy of veterinary services, and animal health infrastructure, among others. therefore, animal health policy development and imple-mentation require attention to macroepidemiology, the study of all of the economic, social and political inputs which affect the distribution and impact of animal or human disease at the national level [ , ] . the low hanging fruit of yesterdays fields of microbiology, zoonotic and emerging infectious diseases, immunology, antibiotic sensitivity, vaccine development, oncology, anti-viral drugs, public health, ecology, environment, human and animal health, to name a few have been picked. today comparative and interdisciplinary research is critical to translating scientific advances from one discipline or species to another and providing new insights into human health problems. scientific fields such as laboratory animal medicine, pathology, immunology, biophysics, mathematics, bioinformatics, genetics, molecular biology and toxicology, when combined with veterinary medicine, have proven especially relevant to success in biomedical research. veterinarians also have contributed to public health through the care of companion animals. fifty-seven percent of all u.s. households own a dog, cat, or both. in addition, millions of exotic animals, birds, and reptiles are kept as pets [ ] . although pets enrich the lives of humans, they also potentially can threaten public health. veterinarians help educate the public about prevention of zoonoses; vaccinate large numbers of pets for zoonotic diseases, such as rabies and leptospirosis; and reduce the level of ecoparasites that can transmit human diseases and intestinal worms, such as roundworms and hookworms, which can cause serious health problems in humans. the , private-practice veterinarians in the united states form a valuable front line for detecting adverse health events, reducing zoonotic diseases, and delivering public health education. because veterinarians work at the interface of human, animal, and environmental health, they are uniquely positioned to view this dynamic through the lens of public health impact. significant changes in land use, expansion of large and intensified animal-production units, and microbial and chemical pollution of land and water sources have created new threats to the health of both animals and humans [ ] . because animals share human environment, food, and water, they are effective sentinels for environmental, human, and public health problems, including bioterrorism. concerns are increasing about antimicrobial resistance of pathogens, waste and nutrient management, and potential runoffs into streams, rivers, and oceans. food animal and wildlife populations are inextricably linked to some environmental problems. together these have led to creation of a new scientific discipline called conservation medicine and ecosystem health, and veterinarians are assuming a leadership role in the field [ ] . several decades ago, special factors came together to create a new epidemiologic era characterized by increases in emerging and reemerging zoonoses [ ] . humans, animals, and animal products now move rapidly around the world, and pathogens are adapting, finding new niches, and jumping across species into new hosts. in , approximately billion food animals were produced to help feed a world population of . billion persons; the united nations' food and agriculture organization estimates that demand for animal protein will increase by % by , especially in developing countries [ ] . the lessons learned from severe acute respiratory syndrome, west nile virus, monkeypox, and avian influenza are reminders of the need to view diseases globally; integrate animal and public health surveillance, epidemiology, and laboratory systems; and create new strategic partnerships among animal, human, and public health professions [ , ] . veterinarians are essential to the detection and diagnosis of and response to these threats and are integral to first-line defense and surveillance for bioterrorism agents. the convergence of human and animal health drove creation of the newly proposed national center for zoonotic, vector-borne, and enteric diseases. plans are being completed to establish several multidisciplinary state-level zoonosis research and development centers. the veterinary profession has recently gained a important foothold on the health and human services government research institutes at the cdc and evolved in prominence as a member of the health professions and has established its importance and usefulness to human and public health. it is hoped and expected that with the developing visions and challenges outlined in this overview we will see the continued melding of veterinary and human medicine to create new educational programs and tools for developing future leaders for solving globally some of the most challenging public and animal health, ecosystem, and conservation problems of the st century. the value of vaccination world health organization. measles deaths drop dramatically as vaccine reaches world's poorest children the value of vaccination: a global perspective intervention cost-effectiveness: overview of main messages the costs and benefits of front-loading and predictability of immunization. cgd working paper veterinarians in population health and public practice: meeting critical national needs cattle, priests and progress in medicine veterinary medicine: an illustrated history committee on assessing the nation's framework for addressing animal diseases. national research council. animal health at the crossroads: preventing, detecting, and diagnosing animal diseases veterinary medicine and public health at cdc the th anniversary of the veterinary medical corps officers of the u.s. public health service veterinarians and public health: the epidemic intelligence service of the centers for disease control and prevention actual causes of death in the united states primary care: balancing health needs, services, and technology mercer survey of employer-sponsored health plans recommendations to the congressional prevention coalition: nine high-impact actions congress can take to protect and promote the nation's health hedis : the health plan employer data and information set and the health accounts team health spending in : signals of change effectiveness in disease and injury prevention estimated national spending on prevention-united states disease prevention research at nih: an agenda for all. workshop j: prevention strategies, economic realities, and identification of prevention research needs dissecting cost-effectiveness analysis for preventive interventions: a guide for decision makers us graduate medical education editor's choice: preventive medicine makes us miserable immunization in developing countries: its political and organizational determinants progress towards immunization goals : summary presentation of key indicators global market-global 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veterinary science committee on increasing veterinary involvement in biomedical research. national research council. national need and priorities for veterinarians in biomedical research animal agriculture and the global food supply. task force report . ames, iowa: council for agricultural science and technology council on graduate medical education. physician workforce policy guidelines for the u.s. for towards a better map: science, the public, and the media. economic and social research council the general epidemiologist: is there a place in today's epidemiology? misleading media reporting? the mmr story vaccine delays hit chiron's recovery. la times ten great veterinary public health/preventive medicine achievements in the united states advance market commitments: a policy to stimulate investment in vaccines for neglected diseases historical comparisons of morbidity and mortality for vaccine-preventable diseases in the united states priorities in developing countries surveillance and monitoring systems for animal health programs and disease surveys committee on assessing the nation's framework for addressing animal diseases, national research council. animal health at the crossroads: preventing, detecting, and diagnosing animal diseases. washington sustainable agriculture solutions (sas)-action report the annual report the annual report understanding and improving health and objectives for improving health. vols an agenda for action: veterinary medicine's crucial role in public health and biodefense and the obligation of academic veterinary medicine to respond investing in health immunization at a glance immunization at a glance world development indicators polio eradication website, global case count measuring the national economic benefits of reducing livestock mortality the primary author wishes to acknowledge and dedicate this paper to the late dr.'s jonas salk and maurice hilleman whose lifetime experiences and contributions are unprecedented in medicine and vaccinology and whom personally encouraged and instilled in me during numerous public and private discussions and meetings the importance of working in and helping to advance the field of vaccinology for the betterment of global human and animal health. key: cord- -jqlz yt authors: katz, sophie e.; williams, derek j. title: pediatric community-acquired pneumonia in the united states changing epidemiology, diagnostic and therapeutic challenges, and areas for future research date: - - journal: infectious disease clinics of north america doi: . /j.idc. . . sha: doc_id: cord_uid: jqlz yt community-acquired pneumonia (cap) is one of the most common serious infections in childhood. this review focuses on pediatric cap in the united states and other industrialized nations, specifically highlighting the changing epidemiology of cap, diagnostic and therapeutic challenges, and areas for further research. pneumonia is an infection of the lower airways (distal bronchi and alveoli) caused by both viruses and bacteria. community-acquired pneumonia (cap) specifically refers to clinical signs and symptoms of pneumonia acquired outside a hospital setting. it is one of the most common serious infections in childhood, accounting for more than , deaths among children younger than years of age in . although the rate of mortality due to cap is much lower in the developed world compared with the developing world, cap continues to account for a significant proportion of health care visits and hospitalizations in high-income countries. this review focuses on pediatric cap in the united states and other industrialized nations, specifically highlighting the changing epidemiology of cap, diagnostic and therapeutic challenges, and areas for further research. in the united states, cap accounts for approximately million outpatient visits annually and is among the most common causes for hospitalization, with approximately , pediatric hospitalizations annually (annual incidence of . - . hospitalizations per , children). [ ] [ ] [ ] the highest rate of health care utilization occurs in children younger than years of age and decreases with increasing age in the pediatric population. children with pneumonia most often present with fever, tachypnea, and other signs of respiratory distress ( table ) . signs and symptoms may include tachypnea, cough, dyspnea, retractions, grunting, hypoxemia, abdominal pain, or lethargy, and physical examination findings of decreased breath sounds, crackles, rales, or wheezing on auscultation of lung fields. many of these findings overlap with other acute lower respiratory tract diseases (eg, asthma and viral bronchiolitis), and identifying children with pneumonia based only on clinical signs and symptoms is sometimes difficult. as a result, chest radiographs are commonly used to confirm the diagnosis. even when a chest radiograph reveals an infiltrate, however, it is sometimes difficult to differentiate between consolidation representing pneumonia and atelectasis commonly seen in children with asthma or bronchiolitis. as a result, variation in chest radiograph interpretation is common and may contribute to antibiotic overuse. , for this reason, the guideline developed by the pediatric infectious diseases society (pids) and infectious diseases society of america (idsa) discourages use of chest radiographs in children with suspected uncomplicated pneumonia in an outpatient setting. chest radiographs are recommended in children who are hospitalized with hypoxemia or respiratory distress and in those with suspected complications, such as parapneumonic effusions, necrotizing pneumonia, or pneumothorax ( fig. ) . chest ultrasound is most often used for evaluating local complications, such as parapneumonic effusion and empyema, but recent studies have demonstrated high sensitivity ( %- %) and specificity ( %- %) for detecting lung consolidation compared with chest radiography. [ ] [ ] [ ] [ ] [ ] additional benefits of chest ultrasound include a lack of ionizing radiation and availability in most emergency department settings. an important limitation of ultrasound is that evaluation and interpretation are highly operator dependent. thus, despite these promising early studies, large-scale, pragmatic studies are needed to better evaluate the effectiveness of this imaging technique versus standard chest radiography. pneumonia is a heterogeneous disease caused by a variety of pathogens, including viruses and bacteria. historically, cap was largely considered a bacterial process, most often due to streptococcus pneumoniae, haemophilus influenzae, streptococcus pyogenes, and staphylococcus aureus. [ ] [ ] [ ] [ ] [ ] the introduction of routine childhood vaccination against both streptococcus pneumoniae and h influenzae, however, has dramatically reduced disease caused by these pathogens. at the same time, highly sensitive molecular diagnostics for viral respiratory pathogens have heightened awareness of the impact of viruses as a cause of cap. a study by michelow and colleagues exemplifies pre-pneumococcal conjugate vaccine (pcv) era etiology studies. that study used traditional culture methods, pneumolysin-based polymerase chain reaction (pcr) assays, viral direct fluorescent antibody tests, and serologic tests for viruses, mycoplasma spp, and chlamydia spp to identify pathogens in hospitalized children with radiographically confirmed lower respiratory infections at a single institution. a majority of patients ( %) were noted to have infection with typical respiratory bacteria (most commonly, streptococcus pneumoniae, detected in % of children with documented bacterial disease), with viruses identified in % of children. a -valent pcv (pcv ) targeting the most common clinically important pneumococcal serotypes was introduced into the united states childhood immunization schedule in . rates of invasive pneumococcal disease caused by pcv serotypes in children less than years of age plummeted from an average of . cases to . cases per , population within years after the introduction of pcv . by , hospitalization rates for cap and pneumonia-associated complications among young children decreased by % and %, respectively. , despite these declines, disease caused by nonvaccine serotypes soon emerged, and rates of complicated pneumonia increased, prompting introduction of an expanded, -valent pct (pcv ) into the us childhood immunization program in . since that time, hospitalization rates decreased from . per , admissions in the pre-pcv era to . per , admissions in the post-pcv era, and rates of complicated pneumococcal pneumonia decreased significantly. pneumonia etiology in the post-pneumococcal conjugate vaccine era the multicenter centers for disease control and prevention (cdc) etiology of pneumonia in the community (epic) study was a prospective, population-based surveillance study of greater than pediatric cap hospitalizations in the united states conducted from to . this study used serology and nasopharyngeal pcr to identify different viruses, culture-based methods and whole-blood pcr (pneumococcal lyt-a) to identify typical bacteria, and nasopharyngeal pcr to identify atypical bacterial pathogens. viruses were identified in greater than % of children, whereas bacteria were identified in only % of children (fig. ) . the most common viral pathogens included respiratory syncytial virus (rsv), human rhinovirus, human metapneumovirus, and adenovirus, all detected in greater than % of children. rsv, adenovirus, and human metapneumovirus were more commonly identified in children younger than years of age compared with older children. bacteria were identified in approximately % of children in the cdc epic study, although streptococcus pneumoniae was only identified in % of children, further underscoring the impact that pcv has had on the epidemiology of pediatric cap. mycoplasma pneumoniae was the most frequently identified bacterial pathogen, detected in % of children, including % of school-aged children, but only % of children younger than years of age. other bacteria were identified in % or less of children. importantly, % of children in the cdc epic study had no pathogen identified, highlighting the continued need for enhanced diagnostics and novel pathogen discovery techniques. other pathogens that are less commonly seen among us children include mycobacterium tuberculosis, fungi, burkholderia cepacia, aspergillus fumigatus, and pseudomonas aeruginosa and usually occur in patients with underlying risk factors, such as immunocompromising conditions; chronic conditions, such as cystic fibrosis and spinal muscular atrophy; or history of international travel ( table ) . these pathogens should also be suspected in patients who experience treatment failure for more common etiologic agents. the pids/idsa cap guideline recommends obtaining blood cultures in children hospitalized with cap. , , in this setting, however, blood cultures identify a pathogen in only % to % of children with cap. [ ] [ ] [ ] [ ] blood cultures are more often positive in children with parapneumonic effusion, ranging from % to %. , , in the outpatient setting, blood cultures are not routinely recommended, because positivity rates are low and results are unlikely to change management. regardless, despite group b streptococci neonatal pneumonia and sepsis. neonatal pneumonia and sepsis. gram-negative enterics neonatal pneumonia and sepsis. potential pathogens in aspiration pneumonia. cause of afebrile pneumonia in young infants < mo of age. anaerobes (oral flora) potential pathogens in aspiration pneumonia. legionnaires' disease. rare in children but associated with community outbreaks. exposure to contaminated artificial freshwater systems. coxiella burnetti q fever. exposure to wild and domesticated herbivores or unpasteurized dairy (eg, cattle, sheep, and goats). also potential bioterrorism agent. psittacosis. bird (eg, pet birds and pigeons) exposure. tularemia. rabbit exposure. yersinia pestis pneummonic plague. rodent flea exposure. anthrax. woolsorter's disease. wild and domesticated herbivore (eg, cattle, sheep, goats) exposure. also potential bioterrorism agent. leptospirosis. exposure to urine of wild and domestic animals carrying the bacterium. rare in us children. usually associated with high-risk exposures. brucellosis. exposure to wild and domesticated animals or unpasteurized dairy (eg, cattle, sheep, pigs, goats, deer, and dogs). histoplasmosis. exposure to bird or bat droppings (eg, poultry/ bird roosts and caves). endemic to eastern and central united states. blastomycosis. environmental exposure to fungal spores (wooded areas). endemic to southeastern and midwestern united states. cryptococcosis. exposure to soil contaminated with bird droppings. significant pathogen nearly exclusively among immunocompromised. their low yield, blood cultures currently provide the best opportunity to identify typical bacterial pathogens in most children with cap. diagnostic yield of blood cultures can be optimized by restricting their use to those patients with increased pretest probability of having a positive culture, such as those who are severely ill or have parapneumonic effusion. [ ] [ ] [ ] isolation of pathologic organisms occurs significantly less frequently in patients exposed to antibiotics before specimen collection. , studies have also demonstrated increased yield of blood cultures with each additional milliliter of blood drawn. [ ] [ ] [ ] obtaining adequate weight-based blood volumes is also associated with lower rates of blood culture contamination, for reasons yet unknown. , contamination rates can also be minimized by adhering to proper sterile collection methods. , , cultures of the lower respiratory tract pleural fluid cultures are positive in up to % of cases and should be performed whenever pleural fluid is obtained. , , , [ ] [ ] [ ] the invasive methods associated with sampling the pleural space, however, make it impractical to obtain pleural fluid specimens except when dictated for clinical care. bronchoalveolar lavage is rarely indicated in cap, except in instances of lack of response to therapy, very severe pneumonia, or immunocompromised hosts in whom opportunistic pathogens are suspected. sputum cultures are of low diagnostic yield in children, due to the inability of most young children with pneumonia to produce an adequate sputum sample. pretreatment with antibiotics further hinders diagnostic yield. induced sputum has been explored as an opportunity to collect sputum samples in young children, although utility is limited by frequent detection of upper respiratory tract bacteria and similar rates of recovery of pathogens in pneumonia cases compared with children without pneumonia. , molecular diagnostics pneumococcal urinary antigen testing is often used in the evaluation of pneumonia in adults. in children, however, detection of streptococcus pneumoniae urinary antigen is associated with false-positive results due to high rates of nasopharyngeal colonization. , more recently, a serotype-specific urinary antigen detection method has been developed and validated in adults with pneumonia ; whether or not this test could prove useful in children remains to be determined. although not widely used in clinical settings, whole-blood pneumococcal pcr (lyt-a) has been used in epidemiologic studies, including epic and pneumonia etiology research for child health (perch). potential benefits include improved sensitivity, rapid turnaround time, and less influence of antibiotic pretreatment compared with culturebased methods. , in the epic study, . % of children tested were pcr-positive for streptococcus pneumoniae, whereas blood cultures were positive for pneumococcus in only % of children (p<. ). in the perch study, children with pneumonia ( . %) were pneumococcal pcr-positive, whereas only children (denominator not provided) had a positive blood culture for streptococcus pneumoniae. moreover, although prior studies demonstrated % specificity of lyt-a pneumococcal pcr from the blood, the perch study also identified pneumococcal dna in the blood of control children ( . %). thus, although pneumococcal pcr may increase rate of detection over blood culture, suboptimal test specificity hampers interpretation. pcr also increases yield for pleural fluid specimens. in a study evaluating archived pleural fluid specimens from pediatric patients with cap, a pathogen was detected in % of samples using pcr compared with only % of samples when using conventional culture methods (p<. ). the most frequent pathogen detected using pediatric community-acquired pneumonia both methods was streptococcus pneumoniae, % using pcr and % using conventional culture. the next most frequent pathogens identified were streptococcus pyogenes ( % using pcr and % using conventional culture) and s aureus ( % using pcr and % using conventional culture). this study also highlighted the potential for bias with respect to pathogen identification introduced when relying on culture alone for epidemiologic studies, because penicillin-resistant pneumococcal isolates and s aureus were more likely to be positive in culture, whereas other serotypes of streptococcus pneumoniae and bacterial pathogens commonly susceptible to penicillins were more commonly identified by pcr. up to two-thirds of children younger than years are colonized in the upper respiratory tract with common bacterial pathogens known to cause pneumonia, and pcr from the upper respiratory tract is not a reliable method for ascertaining bacterial etiologies of pneumonia. a possible exception is m pneumoniae, which has not previously been considered a frequent colonizer of the upper respiratory tract. consistent with this theory, the cdc epic study demonstrated that although m pneumoniae was detected in % of children with pneumonia, fewer than % of controls had evidence of m pneumoniae. in contrast, a cross-sectional, observational study in the netherlands of asymptomatic children and children with symptoms of upper and lower respiratory tract infection detected m pneumoniae dna not only in % of symptomatic children but also in % of asymptomatic children. given the conflicting results of these studies and the increasing commercial availability of m pneumoniae pcr tests, caution is warranted when interpreting test results in the clinical setting. in contrast to bacteria, pcr testing for viruses from upper respiratory samples has largely replaced culture and serology-based methods to investigate pneumonia etiology, owing to superior sensitivity, rapid turnaround time, and ability to identify viruses that are difficult to grow in culture. a major concern, however, is whether lower respiratory tract disease can be attributed to a viral pathogen detected in the upper airway. the scope of the problem is well illustrated in a study conducted by self and colleagues that compared pcr detections of viruses from the upper respiratory tract among children with cap and healthy, asymptomatic children enrolled in the cdc epic study. overall, approximately % of asymptomatic children had or more viruses detected compared with approximately % of children with cap. detection of most viruses was higher among children with cap compared with asymptomatic controls, including influenza ( % vs %), rsv ( % vs %), and human metapneumovirus ( % vs %), with attributable fractions greater than % for all. conversely, rhinovirus was detected at a similar frequency in both children with cap and asymptomatic children ( % vs %; attributable fraction %; % ci, % to %). attributable fractions for other viruses studied ranged from % to %. thus, although some viruses detected in the upper airway likely reflect lower airway disease (eg, rsv, influenza, and human metapneumovirus), detection of other viruses must be interpreted with caution. as proposed for adults, investigating viral loads may further help to differentiate disease versus asymptomatic colonization. because sensitive methods of diagnosing viral infections have become more widely available, the recognition of viral and bacterial coinfection has also increased. it is well known that upper tract disease with respiratory viruses often precedes the development of bacterial pneumonia. [ ] [ ] [ ] although it is not always clear if a virus detected in the upper airway represents prior or concurrent infection in a subject with bacterial pneumonia, studies suggest that viral-bacterial codetections are associated with a more severe clinical course compared with single viral or bacterial detections. [ ] [ ] [ ] the association between influenza and coinfection with pneumococcal or staphylococcal pneumonia is perhaps the best described of these viral and bacterial coinfections. , elevated leukocyte count was traditionally considered to be associated with serious bacterial infection, but the specificity of leukocyte count in making the diagnosis of bacterial pneumonia in children is poor, and the degree of elevation does not reliably distinguish between viral and bacterial pneumonia. , - as such, routine measurement of leukocyte count is likely not beneficial. more recent biomarkers used in the detection of pneumonia include c-reactive protein (crp) and procalcitonin (pct). these biomarkers may perform better than leukocyte count for identifying bacterial infections, , , although identifying relevant clinical cutpoints remains a challenge. to evaluate the impact of crp in the etiologic diagnosis of pneumonia, a meta-analysis of studies with more than children with viral or bacterial causes of cap demonstrated that crp levels greater than or equal to mg/l to mg/l were associated with only a % positive predictive value for identifying children with bacterial pneumonia. pct is a peptide precursor of calcitonin and is produced by c cells in the thyroid gland and by neuroendocrine cells in the lung and intestine. levels are usually undetectable in healthy individuals but increase in response to systemic inflammation. cytokines typically associated with bacterial infection enhance pct release, whereas interferons, which are more often associated with viral infections, inhibit pct release. , thus, much interest has been directed at pct as a potential biomarker for bacterial disease. among hospitalized children enrolled in the cdc epic study, a pct cutoff value of . ng/ml demonstrated a sensitivity of % and specificity of % for cap caused by typical bacterial pathogens. the study also found that higher pct levels were associated with more severe disease. multiple studies have shown utility in using pct levels to guide antibiotic initiation and duration. [ ] [ ] [ ] [ ] [ ] [ ] biomarker studies using transcriptomics show promise for enhancing diagnostic capabilities by using host responses to identify possible pathogens and study disease severity. [ ] [ ] [ ] [ ] transcriptomics uses gene expression profiling to measure the activity or expression of thousands of genes at once, thereby creating a global picture of cellular activity. profiles of peripheral blood leukocytes in patients with lower respiratory tract infection can accurately distinguish influenza viral infection from bacterial infection and predict disease severity. host transcriptional profiling has also been shown useful in distinguishing symptomatic rhinovirus infection from incidental detection in children. these promising studies will likely add much to the understanding of pneumonia etiology and outcomes, although much work remains prior to translating these new technologies to the bedside. several prognostic models are available for adults with pneumonia, , and their application has been shown to contribute to improved outcomes. unfortunately, no analogous models have been validated in children, a recognized key knowledge gap. recently, williams and colleagues derived prognostic models to identify risk for severe outcomes among children with cap; each model demonstrated good predictive accuracy (concordance index . - . ) . in that study, extremes of age, vital signs, chest indrawing, and radiographic infiltrate pattern ranked among the most important predictors of disease outcomes. although these models require further validation, their use could reduce variability and improve care for children with pneumonia. although viruses are a major cause of childhood pneumonia, a majority of children with pneumonia receive antibiotics. pneumonia is associated with more antibiotic use in us pediatric hospitals than any other condition. when antibiotics are indicated, amoxicillin or ampicillin is recommended as first-line therapy in most children (table ) . prior to release of the national guideline, however, broader-spectrum third-generation cephalosporins and macrolides were commonly used. to date, the impact of the national guideline on prescribing has been mixed. approximately years after guideline publication, penicillin use increased approximately . % and cephalosporin use decreased approximately . % across tertiary care children's hospitals in the united states, although substantial variability was noted across institutions. similar variability persists in the outpatient setting. antimicrobial stewardship programs, local clinical practice guidelines, and quality improvement methods all play important roles in raising awareness of these recommendations and reducing unnecessary and inappropriate antibiotic use. , , current practices for treatment of uncomplicated cap generally use -day to -day antibiotic courses, although large pediatric randomized controlled studies are currently evaluating the safety and efficacy of shorter courses of antibiotics, a united kingdom community-acquired pneumonia study (cap-it) and the us phase iv double-blind, placebo-controlled, randomized trial short course outpatient therapy of community acquired pneumonia (scout-cap). , consideration of alternative etiologies, such as s aureus, is warranted in children with severe or rapidly progressive disease, extensive local complications, or poor treatment response. s aureus is an uncommon cause of cap, detected in only % of children hospitalized with pneumonia. thus, to preserve the effectiveness of antistaphylococcal antibiotics, care must be taken when considering when to use these agents empirically, and efforts to de-escalate therapy whenever possible should be emphasized. although m pneumoniae is a frequent cause of cap in children, it is impossible to reliably distinguish this pathogen from other common causes of pneumonia. questions regarding the utility of currently available pcr tests for m pneumoniae, as outlined previously, further complicate treatment considerations. moreover, azithromycin use is associated with the development of multidrug resistance. , perhaps the most important consideration governing when to use macrolide therapy, however, is that currently available studies have failed to consistently demonstrate their benefit in children with pneumonia. despite advances in recent years, cap continues to cause significant morbidity and mortality and poses diagnostic and therapeutic challenges. vaccination against haemophilus influenzae type b and streptococcus pneumoniae has greatly reduced invasive disease rates caused by these pathogens, and the introduction of molecular diagnostics has highlighted the important role that respiratory viruses play in disease pathogenesis while also introducing new challenges. this updated understanding brings into question whether all children with cap would benefit from antibiotic therapy, and if so, which therapies might be most effective. limitations of current diagnostics, however, impede advances toward addressing these important questions. biomarkers and host responses to infection are current areas of intense study that may facilitate a deeper understanding of pneumonia etiology and disease outcomes. as this important work progresses, future epidemiologic studies using state-of-the-art diagnostics will continue to serve an important role in informing understanding of the changing epidemiology of cap. british thoracic society guidelines for the management of community acquired pneumonia in children: update world health organization ambulatory visit rates and antibiotic prescribing for children with pneumonia community-acquired pneumonia requiring hospitalization among u.s. children national hospitalization trends for pediatric pneumonia and associated complications healthcare cost and utilization project (hcup) the management of communityacquired pneumonia in infants and children older than months of age: clinical practice guidelines by the pediatric infectious diseases society and the infectious diseases society of america disagreement in the interpretation of chest radiographs among specialists and clinical outcomes of patients hospitalized with suspected pneumonia prospective evaluation of point-of-care ultrasonography for the diagnosis of pneumonia in children and young adults ultrasound diagnosis of pneumonia in children lung ultrasound for the diagnosis of pneumonia in children: a meta-analysis lung ultrasound as first-line examination for the diagnosis of community-acquired pneumonia in children performance of chest ultrasound in pediatric pneumonia etiology of community-acquired pneumonia in hospitalized children epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children etiology and treatment of communityacquired pneumonia in ambulatory children etiology of community-acquired pneumonia in children based on antibody responses to bacterial and viral antigens etiology of childhood pneumonia: serologic results of a prospective, population-based study incidence of pneumococcal disease due to non-pneumococcal conjugate vaccine (pcv ) serotypes in the united states during the era of widespread pcv vaccination decline in pneumonia admissions after routine childhood immunisation with pneumococcal conjugate vaccine in the usa: a time-series analysis population snapshot of emergent streptococcus pneumoniae serotype a in the united states pneumococcal pneumonia requiring hospitalization in us children in the -valent pneumococcal conjugate vaccine era the contribution of blood cultures to the clinical management of adult patients admitted to the hospital with communityacquired pneumonia: a prospective observational study utility of blood cultures in pediatric patients found to have pneumonia in the emergency department prevalence of bacteremia in hospitalized pediatric patients with community-acquired pneumonia blood cultures in the emergency department evaluation of childhood pneumonia blood culture in evaluation of pediatric community-acquired pneumonia: a systematic review and meta-analysis molecular analysis improves pathogen identification and epidemiologic study of pediatric parapneumonic empyema diagnosis of bloodstream infections in children reducing blood culture contamination in the emergency department: an interrupted time series quality improvement study reducing the blood culture contamination rate in a pediatric emergency department and subsequent cost savings the effect of antibiotic exposure and specimen volume on the detection of bacterial pathogens in children with pneumonia influence of antibiotics on the detection of bacteria by culture-based and culture-independent diagnostic tests in patients hospitalized with community-acquired pneumonia effect of number of blood cultures and volume of blood on detection of bacteremia in children effects of volume and site of blood draw on blood culture results bacteremia among children admitted to a rural hospital in kenya how reliable is a negative blood culture result? volume of blood submitted for culture in routine practice in a children's hospital an epidemiological investigation of a sustained high rate of pediatric parapneumonic empyema: risk factors and microbiological associations parapneumonic empyema in children: decortication hastens recovery in patients with severe pleural infections predictive factors of morbidity in childhood parapneumonic effusion-associated pneumonia: a retrospective study role of bronchoalveolar lavage in the diagnosis of pulmonary infiltrates in immunocompromised patients limited utility of polymerase chain reaction in induced sputum specimens for determining the causes of childhood pneumonia in resource-poor settings: findings from the pneumonia etiology research for child health (perch) study the diagnostic utility of induced sputum microscopy and culture in childhood pneumonia evaluation of a rapid immunochromatographic test for detection of streptococcus pneumoniae antigen in urine samples from adults with community-acquired pneumonia evaluation of binax now, an assay for the detection of pneumococcal antigen in urine samples, performed among pediatric patients validation of an immunodiagnostic assay for detection of streptococcus pneumoniae serotype-specific polysaccharides in human urine comparison of the effect of antibiotic treatment on the possibility of diagnosing invasive pneumococcal disease by culture or molecular methods: a prospective, observational study of children and adolescents with proven pneumococcal infection determining the microbiological cause of a chest infection detection of pneumococcal dna in blood by polymerase chain reaction for diagnosing pneumococcal pneumonia in young children from low-and middle-income countries pneumococcal dna is not detectable in the blood of healthy carrier children by real-time pcr targeting the lyta gene the descriptive epidemiology of streptococcus pneumoniae and haemophilus influenzae nasopharyngeal carriage in children and adults in kilifi district carriage of mycoplasma pneumoniae in the upper respiratory tract of symptomatic and asymptomatic children: an observational study respiratory viral detection in children and adults: comparing asymptomatic controls and patients with communityacquired pneumonia frequent detection of respiratory viruses without symptoms: toward defining clinically relevant cutoff values seasonal invasive pneumococcal disease in children: role of preceding respiratory viral infection respiratory viruses predisposing to bacterial infections: role of neuraminidase outbreak of pneumonia in a long-term care facility: antecedent human parainfluenza virus infection may predispose to bacterial pneumonia critically ill children during the - influenza pandemic in the united states coinfection with staphylococcus aureus increases risk of severe coagulopathy in critically ill children with influenza a (h n ) virus infection viral-bacterial coinfection affects the presentation and alters the prognosis of severe community-acquired pneumonia insights into the interaction between influenza virus and pneumococcus complications and associated bacterial coinfections among children hospitalized with seasonal or pandemic influenza erythrocyte sedimentation rate, white blood cell count and serum c-reactive protein in assessing etiologic diagnosis of acute lower respiratory infections in children clinical features and inflammatory markers in pediatric pneumonia: a prospective study the utility of biomarkers in differentiating bacterial from non-bacterial lower respiratory tract infection in hospitalized children: difference of the diagnostic performance between acute pneumonia and bronchitis diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review association of c-reactive protein with bacterial and respiratory syncytial virus-associated pneumonia among children aged < years in the perch study the utility of serum c-reactive protein in differentiating bacterial from nonbacterial pneumonia in children: a meta-analysis of children procalcitonin as a biomarker in respiratory tract infection in vitro and in vivo calcitonin i gene expression in parenchymal cells: a novel product of human adipose tissue procalcitonin accurately identifies hospitalized children with low risk of bacterial community-acquired pneumonia effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (prorata trial): a multicentre randomised controlled trial procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis procalcitonin guidance to reduce antibiotic treatment of lower respiratory tract infection in children and adolescents (propaed): a randomized controlled trial procalcitonin measurements for guiding antibiotic treatment in pediatric pneumonia whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection superiority of transcriptional profiling over procalcitonin for distinguishing bacterial from viral lower respiratory tract infections in hospitalized adults association of rna biosignatures with bacterial infections in febrile infants aged days or younger rhinovirus detection in symptomatic and asymptomatic children: value of host transcriptome analysis gene expression patterns in blood leukocytes discriminate patients with acute infections a prediction rule to identify low-risk patients with community-acquired pneumonia smart-cop: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia predicting severe pneumonia outcomes in children identifying targets for antimicrobial stewardship in children's hospitals impact of a national guideline on antibiotic selection for hospitalized pneumonia variability in antibiotic prescribing for community-acquired pneumonia effectiveness of antimicrobial guidelines for community-acquired pneumonia in children quality improvement methods increase appropriate antibiotic prescribing for childhood pneumonia cap-it: efficacy, safety and impact on antimicrobial resistance of duration and dose of amoxicillin treatment for young children with community-acquired pneumonia (cap): a randomised controlled trial placebo-controlled, randomized trial to evaluate short course vs. standard course outpatient therapy of community acquired pneumonia in children (scout-cap) active bacterial core surveillance team. outpatient antibiotic prescribing and nonsusceptible streptococcus pneumoniae in the united states mycoplasma pneumoniae infections-does treatment help? treatment of mycoplasma pneumonia: a systematic review the authors thank kathryn edwards, md, and ritu banerjee, md, phd, vanderbilt university medical center, for their critical review and input during article preparation.pediatric community-acquired pneumonia key: cord- -k imddzr authors: siegel, jane d.; rhinehart, emily; jackson, marguerite; chiarello, linda title: guideline for isolation precautions: preventing transmission of infectious agents in health care settings date: - - journal: am j infect control doi: . /j.ajic. . . sha: doc_id: cord_uid: k imddzr nan . clinical syndromes or conditions warranting additional empiric transmission-based precautions pending confirmation of diagnosis table . infection control considerations for highpriority (cdc category a) diseases that may result from bioterrorist attacks or are considered bioterrorist threats table . recommendations for application of standard precautions for the care of all patients in all health care settings table . components of a protective environment . the transition of health care delivery from primarily acute care hospitals to other health care settings (eg, home care, ambulatory care, freestanding specialty care sites, long-term care) created a need for recommendations that can be applied in all health care settings using common principles of infection control practice, yet can be modified to reflect setting-specific needs. accordingly, the revised guideline addresses the spectrum of health care delivery settings. furthermore, the term ''nosocomial infections'' is replaced by ''health care-associated infections'' (hais), to reflect the changing patterns in health care delivery and difficulty in determining the geographic site of exposure to an infectious agent and/ or acquisition of infection. . the emergence of new pathogens (eg, severe acute respiratory syndrome coronavirus [sars-cov] associated with sars avian influenza in humans), renewed concern for evolving known pathogens (eg, clostridium difficile, noroviruses, communityassociated methicillin-resistant staphylococcus aureus [ca-mrsa]), development of new therapies (eg, gene therapy), and increasing concern for the threat of bioweapons attacks, necessitates addressing a broader scope of issues than in previous isolation guidelines. . the successful experience with standard precautions, first recommended in the guideline, has led to a reaffirmation of this approach as the foundation for preventing transmission of infectious agents in all health care settings. new additions to the recommendations for standard precautions are respiratory hygiene/cough etiquette and safe injection practices, including the use of a mask when performing certain highrisk, prolonged procedures involving spinal canal punctures (eg, myelography, epidural anesthesia). the need for a recommendation for respiratory hygiene/cough etiquette grew out of observations during the sars outbreaks, when failure to implement simple source control measures with patients, visitors, and health care workers (hcws) with respiratory symptoms may have contributed to sars-cov transmission. the recommended practices have a strong evidence base. the continued occurrence of outbreaks of hepatitis b and hepatitis c viruses in ambulatory settings indicated a need to reiterate safe injection practice recommendations as part of standard precautions. the addition of a mask for certain spinal injections grew from recent evidence of an associated risk for developing meningitis caused by respiratory flora. . the accumulated evidence that environmental controls decrease the risk of life-threatening fungal infections in the most severely immunocompromised patients (ie, those undergoing allogeneic hematopoietic stem cell transplantation [hsct] ) led to the update on the components of the protective environment (pe). . evidence that organizational characteristics (eg, nurse staffing levels and composition, establishment of a safety culture) influence hcws' adherence to recommended infection control practices, and thus are important factors in preventing transmission of infectious agents, led to a new emphasis and recommendations for administrative involvement in the development and support of infection control programs. . continued increase in the incidence of hais caused by multidrug-resistant organisms (mdros) in all health care settings and the expanded body of knowledge concerning prevention of transmission of mdros created a need for more specific recommendations for surveillance and control of these pathogens that would be practical and effective in various types of health care settings. this document is intended for use by infection control staff, health care epidemiologists, health care administrators, nurses, other health care providers, and persons responsible for developing, implementing, and evaluating infection control programs for health care settings across the continuum of care. the reader is referred to other guidelines and websites for more detailed information and for recommendations concerning specialized infection control problems. part i reviews the relevant scientific literature that supports the recommended prevention and control practices. as in the guideline, the modes and factors that influence transmission risks are described in detail. new to the section on transmission are discussions of bioaerosols and of how droplet and airborne transmission may contribute to infection transmission. this became a concern during the sars outbreaks of , when transmission associated with aerosol-generating procedures was observed. also new is a definition of ''epidemiologically important organisms'' that was developed to assist in the identification of clusters of infections that require investigation (ie multidrug-resistant organisms, c difficile). several other pathogens of special infection control interest (ie, norovirus, sars, centers for disease control and prevention [cdc] category a bioterrorist agents, prions, monkeypox, and the hemorrhagic fever viruses) also are discussed, to present new information and infection control lessons learned from experience with these agents. this section of the guideline also presents information on infection risks associated with specific health care settings and patient populations. part ii updates information on the basic principles of hand hygiene, barrier precautions, safe work practices, and isolation practices that were included in previous guidelines. however, new to this guideline is important information on health care system components that influence transmission risks, including those components under the influence of health care administrators. an important administrative priority that is described is the need for appropriate infection control staffing to meet the ever-expanding role of infection control professionals in the complex modern health care system. evidence presented also demonstrates another administrative concern: the importance of nurse staffing levels, including ensuring numbers of appropriately trained nurses in intensive care units (icus) for preventing hais. the role of the clinical microbiology laboratory in supporting infection control is described, to emphasize the need for this service in health care facilities. other factors that influence transmission risks are discussed, including the adherence of hcws to recommended infection control practices, organizational safety culture or climate, and education and training. discussed for the first time in an isolation guideline is surveillance of health care-associated infections. the information presented will be useful to new infection control professionals as well as persons involved in designing or responding to state programs for public reporting of hai rates. part iii describes each of the categories of precautions developed by the health care infection control practices advisory committee (hicpac) and the cdc and provides guidance for their application in various health care settings. the categories of transmission-based precautions are unchanged from those in the guideline: contact, droplet, and airborne. one important change is the recommendation to don the indicated personal protective equipment (ppe-gowns, gloves, mask) on entry into the patient's room for patients who are on contact and/or droplet precautions, because the nature of the interaction with the patient cannot be predicted with certainty, and contaminated environmental surfaces are important sources for transmission of pathogens. in addition, the pe for patients undergoing allogeneic hsct, described in previous guidelines, has been updated. five tables summarize important information. table provides a summary of the evolution of this document. table gives guidance on using empiric isolation precautions according to a clinical syndrome. table summarizes infection control recommendations for cdc category a agents of bioterrorism. table lists the components of standard precautions and recommendations for their application, and table lists components of the pe. a glossary of definitions used in this guideline also is provided. new to this edition of the guideline is a figure showing the recommended sequence for donning and removing ppe used for isolation precautions to optimize safety and prevent self-contamination during removal. appendix a provides an updated alphabetical list of most infectious agents and clinical conditions for which isolation precautions are recommended. a preamble to the appendix provides a rationale for recommending the use of or more transmission-based precautions in addition to standard precautions, based on a review of the literature and evidence demonstrating a real or potential risk for person-to-person transmission in health care settings. the type and duration of recommended precautions are presented, with additional comments concerning the use of adjunctive measures or other relevant considerations to prevent transmission of the specific agent. relevant citations are included. new to this guideline is a comprehensive review and detailed recommendations for prevention of transmission of mdros. this portion of the guideline was published electronically in october and updated in november (siegel jd, rhinehart e, jackson m, chiarello l and hicpac. management of multidrug-resistant organisms in health care settings, ; available from http://www.cdc.gov/ ncidod/dhqp/pdf/ar/mdroguideline .pdf), and is considered a part of the guideline for isolation precautions. this section provides a detailed review of the complex topic of mdro control in health care settings and is intended to provide a context for evaluation of mdro at individual health care settings. a rationale and institutional requirements for developing an effective mdro control program are summarized. although the focus of this guideline is on measures to prevent transmission of mdros in health care settings, information concerning the judicious use of antimicrobial agents also is presented, because such practices are intricately related to the size of the reservoir of mdros, which in turn influences transmission (eg, colonization pressure). two tables summarize recommended prevention and control practices using categories of interventions to control mdros: administrative measures, education of hcws, judicious antimicrobial use, surveillance, infection control precautions, environmental measures, and decolonization. recommendations for each category apply to and are adapted for the various health care settings. with the increasing incidence and prevalence of mdros, all health care facilities must prioritize effective control of mdro transmission. facilities should identify prevalent mdros at the facility, implement control measures, assess the effectiveness of control programs, and demonstrate decreasing mdro rates. a set of intensified mdro prevention interventions is to be added if the incidence of transmission of a target mdro is not decreasing despite implementation of basic mdro infection control measures, and when the first case of an epidemiologically important mdro is identified within a health care facility. this updated guideline responds to changes in health care delivery and addresses new concerns about transmission of infectious agents to patients and hcws in the united states and infection control. the primary objective of the guideline is to improve the safety of the nation's health care delivery system by reducing the rates of hais. instruct symptomatic persons to cover mouth/nose when sneezing/ coughing; use tissues and dispose in no-touch receptacle; observe hand hygiene after soiling of hands with respiratory secretions; wear surgical mask if tolerated or maintain spatial separation, . feet if possible. *during aerosol-generating procedures on patients with suspected or proven infections transmitted by respiratory aerosols (eg, severe acute respiratory syndrome), wear a fittested n or higher respirator in addition to gloves, gown, and face/eye protection. -proper construction of windows, doors, and intake and exhaust ports -ceilings: smooth, free of fissures, open joints, crevices -walls sealed above and below the ceiling -if leakage detected, locate source and make necessary repairs d ventilation to maintain $ air changes/hour d directed air flow; air supply and exhaust grills located so that clean, filtered air enters from one side of the room, flows across the patient's bed, and exits on opposite side of the room d positive room air pressure in relation to the corridor; pressure differential of . . pa ( . -inch water gauge) d air flow patterns monitored and recorded daily using visual methods (eg, flutter strips, smoke tubes) or a hand-held pressure gauge d self-closing door on all room exits d back-up ventilation equipment (eg, portable units for fans or filters) maintained for emergency provision of ventilation requirements for pe areas, with immediate steps taken to restore the fixed ventilation system d for patients who require both a pe and an airborne infection isolation room (aiir), use an anteroom to ensure proper air balance relationships and provide independent exhaust of contaminated air to the outside, or place a hepa filter in the exhaust duct. ( ) reaffirm standard precautions as the foundation for preventing transmission during patient care in all health care settings; ( ) reaffirm the importance of implementing transmission-based precautions based on the clinical presentation or syndrome and likely pathogens until the infectious etiology has been determined ( table ) ; and ( ) provide epidemiologically sound and, whenever possible, evidence-based recommendations. this guideline is designed for use by individuals who are charged with administering infection control programs in hospitals and other health care settings. the information also will be useful for other hcws, health care administrators, and anyone needing information about infection control measures to prevent transmission of infectious agents. commonly used abbreviations are provided, and terms used in the guideline are defined in the glossary. medline and pubmed were used to search for relevant studies published in english, focusing on those published since . much of the evidence cited for preventing transmission of infectious agents in health care settings is derived from studies that used ''quasiexperimental designs,'' also referred to as nonrandomized preintervention and postintervention study designs. although these types of studies can provide valuable information regarding the effectiveness of various interventions, several factors decrease the certainty of attributing improved outcome to a specific intervention. these include: difficulties in controlling for important confounding variables, the use of multiple interventions during an outbreak, and results that are explained by the statistical principle of regression to the mean (eg, improvement over time without any intervention). observational studies remain relevant and have been used to evaluate infection control interventions. , the quality of studies, consistency of results, and correlation with results from randomized controlled trials, when available, were considered during the literature review and assignment of evidencebased categories (see part iv: recommendations) to the recommendations in this guideline. several authors have summarized properties to consider when evaluating studies for the purpose of determining whether the results should change practice or in designing new studies. , , this guideline contains changes in terminology from the guideline: . the term ''nosocomial infection'' is retained to refer only to infections acquired in hospitals. the term ''health care-associated infection'' (hai) is used to refer to infections associated with health care delivery in any setting (eg, hospitals, long-term care facilities, ambulatory settings, home care). this term reflects the inability to determine with certainty where the pathogen was acquired, because patients may be colonized with or exposed to potential pathogens outside of the health care setting before receiving health care, or may develop infections caused by those pathogens when exposed to the conditions associated with delivery of health care. in addition, patients frequently move among the various settings within the health care system. of infectious agents, a susceptible host with a portal of entry receptive to the agent, and a mode of transmission for the agent. this section describes the interrelationship of these elements in the epidemiology of hais. i.b. . sources of infectious agents. infectious agents transmitted during health care derive primarily from human sources but inanimate environmental sources also are implicated in transmission. human reservoirs include patients, [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] hcws, , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and household members and other visitors. [ ] [ ] [ ] [ ] [ ] [ ] such source individuals may have active infections, may be in the asymptomatic and/or incubation period of an infectious disease, or may be transiently or chronically colonized with pathogenic microorganisms, particularly in the respiratory and gastrointestinal tracts. other sources of hais are the endogenous flora of patients (eg, bacteria residing in the respiratory or gastrointestinal tract). [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] i.b. . susceptible hosts. infection is the result of a complex interrelationship between a potential host and an infectious agent. most of the factors that influence infection and the occurrence and severity of disease are related to the host. however, characteristics of the host-agent interaction as it relates to pathogenicity, virulence, and antigenicity also are important, as are the infectious dose, mechanisms of disease production, and route of exposure. there is a spectrum of possible outcomes after exposure to an infectious agent. some persons exposed to pathogenic microorganisms never develop symptomatic disease, whereas others become severely ill and even die. some individuals are prone to becoming transiently or permanently colonized but remain asymptomatic. still others progress from colonization to symptomatic disease either immediately after exposure or after a period of asymptomatic colonization. the immune state at the time of exposure to an infectious agent, interaction between pathogens, and virulence factors intrinsic to the agent are important predictors of an individual's outcome. host factors such as extremes of age and underlying disease (eg, diabetes , , human immunodeficiency virus/acquired immune deficiency syndrome [hiv/ aids], , malignancy, and transplantation , , ) can increase susceptibility to infection, as can various medications that alter the normal flora (eg, antimicrobial agents, gastric acid suppressors, corticosteroids, antirejection drugs, antineoplastic agents, immunosuppressive drugs). surgical procedures and radiation therapy impair defenses of the skin and other involved organ systems. indwelling devices, such as urinary catheters, endotracheal tubes, central venous and arterial catheters, [ ] [ ] [ ] and synthetic implants, facilitate development of hais by allowing potential pathogens to bypass local defenses that ordinarily would impede their invasion and by providing surfaces for development of biofilms that may facilitate adherence of microorganisms and protect from antimicrobial activity. some infections associated with invasive procedures result from transmission within the health care facility; others arise from the patient's endogenous flora. clothing, uniforms, laboratory coats, or isolation gowns used as ppe may become contaminated with potential pathogens after care of a patient colonized or infected with an infectious agent, (eg, mrsa, vancomycin-resistant enterococci [vre], and c difficile ). although contaminated clothing has not been implicated directly in transmission, the potential exists for soiled garments to transfer infectious agents to successive patients. i.b. .b. droplet transmission. droplet transmission is technically a form of contact transmission; some infectious agents transmitted by the droplet route also may be transmitted by direct and indirect contact routes. however, in contrast to contact transmission, respiratory droplets carrying infectious pathogens transmit infection when they travel directly from the respiratory tract of the infectious individual to susceptible mucosal surfaces of the recipient, generally over short distances, necessitating facial protection. respiratory droplets are generated when an infected person coughs, sneezes, or talks , or during such procedures as suctioning, endotracheal intubation, [ ] [ ] [ ] [ ] cough induction by chest physiotherapy, and cardiopulmonary resuscitation. , evidence for droplet transmission comes from epidemiologic studies of disease outbreaks, [ ] [ ] [ ] [ ] from experimental studies, and from information on aerosol dynamics. , studies have shown that the nasal mucosa, conjunctivae, and, less frequently, the mouth are susceptible portals of entry for respiratory viruses. the maximum distance for droplet transmission is currently unresolved; pathogens transmitted by the droplet route have not been transmitted through the air over long distances, in contrast to the airborne pathogens discussed below. historically, the area of defined risk has been a distance of , feet around the patient, based on epidemiologic and simulated studies of selected infections. , using this distance for donning masks has been effective in preventing transmission of infectious agents through the droplet route. however, experimental studies with smallpox , and investigations during the global sars outbreaks of suggest that droplets from patients with these infections could reach persons located feet or more from their source. it is likely that the distance that droplets travel depends on the velocity and mechanism by which respiratory droplets are propelled from the source, the density of respiratory secretions, environmental factors (eg, temperature, humidity), and the pathogen's ability to maintain infectivity over that distance. thus, a distance of , feet around the patient is best considered an example of what is meant by ''a short distance from a patient'' and should not be used as the sole criterion for determining when a mask should be donned to protect from droplet exposure. based on these considerations, it may be prudent to don a mask when within to feet of the patient or on entry into the patient's room, especially when exposure to emerging or highly virulent pathogens is likely. more studies are needed to gain more insight into droplet transmission under various circumstances. droplet size is another variable under investigation. droplets traditionally have been defined as being . mm in size. droplet nuclei (ie, particles arising from desiccation of suspended droplets) have been associated with airborne transmission and defined as , mm in size, a reflection of the pathogenesis of pulmonary tuberculosis that is not generalizeable to other organisms. observations of particle dynamics have demonstrated that a range of droplet sizes, including those of diameter $ mm, can remain suspended in the air. the behavior of droplets and droplet nuclei affect recommendations for preventing transmission. whereas fine airborne particles containing pathogens that are able to remain infective may transmit infections over long distances, requiring aiir to prevent its dissemination within a facility; organisms transmitted by the droplet route do not remain infective over long distances and thus do not require special air handling and ventilation. examples of infectious agents transmitted through the droplet route include b pertussis, influenza virus, adenovirus, rhinovirus, mycoplasma pneumoniae, sars-cov, , , group a streptococcus, and neisseria meningitides. , , although rsv may be transmitted by the droplet route, direct contact with infected respiratory secretions is the most important determinant of transmission and consistent adherence to standard precautions plus contact precautions prevents transmission in health care settings. , , rarely, pathogens that are not transmitted routinely by the droplet route are dispersed into the air over short distances. for example, although s aureus is transmitted most frequently by the contact route, viral upper respiratory tract infection has been associated with increased dispersal of s aureus from the nose into the air for a distance of feet under both outbreak and experimental conditions; this is known as the ''cloud baby'' and ''cloud adult'' phenomenon. [ ] [ ] [ ] i.b. .c. airborne transmission. airborne transmission occurs by dissemination of either airborne droplet nuclei or small particles in the respirable size range containing infectious agents that remain infective over time and distance (eg, spores of aspergillus spp and m tuberculosis). microorganisms carried in this manner may be dispersed over long distances by air currents and may be inhaled by susceptible individuals who have not had face-to-face contact with (or even been in the same room with) the infectious individual. [ ] [ ] [ ] [ ] preventing the spread of pathogens that are transmitted by the airborne route requires the use of special air handling and ventilation systems (eg, aiirs) to contain and then safely remove the infectious agent. , infectious agents to which this applies include m tuberculosis, - rubeola virus (measles), and varicella-zoster virus (chickenpox). in addition, published data suggest the possibility that variola virus (smallpox) may be transmitted over long distances through the air under unusual circumstances, and aiirs are recommended for this agent as well; however, droplet and contact routes are the more frequent routes of transmission for smallpox. , , in addition to aiirs, respiratory protection with a national institute for occupational safety and health (niosh)-certified n or higher-level respirator is recommended for hcws entering the aiir, to prevent acquisition of airborne infectious agents such as m tuberculosis. for certain other respiratory infectious agents, such as influenza , and rhinovirus, and even some gastrointestinal viruses (eg, norovirus and rotavirus ) , there is some evidence that the pathogen may be transmitted through small-particle aerosols under natural and experimental conditions. such transmission has occurred over distances . feet but within a defined air space (eg, patient room), suggesting that it is unlikely that these agents remain viable on air currents that travel long distances. aiirs are not routinely required to prevent transmission of these agents. additional issues concerning small-particle aerosol transmission of agents that are most frequently transmitted by the droplet route are discussed below. although sars-cov is transmitted primarily by contact and/or droplet routes, airborne transmission over a limited distance (eg, within a room) has been suggested, although not proven. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] this is true of other infectious agents as well, such as influenza virus and noroviruses. , , influenza viruses are transmitted primarily by close contact with respiratory droplets, , and acquisition by hcws has been prevented by droplet precautions, even when positive-pressure rooms were used in one center. however, inhalational transmission could not be excluded in an outbreak of influenza in the passengers and crew of an aircraft. observations of a protective effect of ultraviolet light in preventing influenza among patients with tuberculosis during the influenza pandemic of - have been used to suggest airborne transmission. , in contrast to the strict interpretation of an airborne route for transmission (ie, long distances beyond the patient room environment), short-distance transmission by small-particle aerosols generated under specific circumstances (eg, during endotracheal intubation) to persons in the immediate area near the patient also has been demonstrated. aerosolized particles , mm in diameter can remain suspended in air when room air current velocities exceed the terminal settling velocities of the particles. sars-cov transmission has been associated with endotracheal intubation, noninvasive positive pressure ventilation, and cardiopulmonary resuscitation. , , , , although the most frequent routes of transmission of noroviruses are contact and foodborne and waterborne routes, several reports suggest that noroviruses also may be transmitted through aerosolization of infectious particles from vomitus or fecal material. , , , it is hypothesized that the aerosolized particles are inhaled and subsequently swallowed. roy this conceptual framework can explain rare occurrences of airborne transmission of agents that are transmitted most frequently by other routes (eg, smallpox, sars, influenza, noroviruses). concerns about unknown or possible routes of transmission of agents associated with severe disease and no known treatment often result in the adoption of overextreme prevention strategies, and recommended precautions may change as the epidemiology of an emerging infection becomes more well defined and controversial issues are resolved. i.b. .d.ii. transmission from the environment. some airborne infectious agents are derived from the environment and do not usually involve person-to-person transmission; for example, anthrax spores present in a finely milled powdered preparation can be aerosolized from contaminated environmental surfaces and inhaled into the respiratory tract. , spores of environmental fungi (eg, aspergillus spp) are ubiquitous in the environment and may cause disease in immunocompromised patients who inhale aerosolized spores (through, eg, construction dust). , as a rule, neither of these organisms is subsequently transmitted from infected patients; however, there is well-documented report of person-to-person transmission of aspergillus sp in the icu setting that was most likely due to the aerosolization of spores during wound debridement. the pe involves isolation practices designed to decrease the risk of exposure to environmental fungal agents in allogeneic hsct patients. , , , [ ] [ ] [ ] [ ] environmental sources of respiratory pathogens (eg, legionella) transmitted to humans through a common aerosol source is distinct from direct patient-to-patient transmission. i.b. .e. other sources of infection. sources of infection transmission other than infectious individuals include those associated with common environmental sources or vehicles (eg, contaminated food, water, or medications, such as intravenous fluids). although aspergillus spp have been recovered from hospital water systems, the role of water as a reservoir for immunosuppressed patients remains unclear. vectorborne transmission of infectious agents from mosquitoes, flies, rats, and other vermin also can occur in health care settings. prevention of vectorborne transmission is not addressed in this document. this section discusses several infectious agents with important infection control implications that either were not discussed extensively in previous isolation s vol. no. supplement guidelines or have emerged only recently. included are epidemiologically important organisms (eg, c difficile), agents of bioterrorism, prions, sars-cov, monkeypox, noroviruses, and the hemorrhagic fever viruses (hfvs). experience with these agents has broadened the understanding of modes of transmission and effective preventive measures. these agents are included for information purposes and, for some (ie, sars-cov, monkeypox), to highlight the lessons that have been learned about preparedness planning and responding effectively to new infectious agents. i.c. . epidemiologically important organisms. under defined conditions, any infectious agent transmitted in a health care setting may become targeted for control because it is epidemiologically important. c difficile is specifically discussed below because of its current prevalence and seriousness in us health care facilities. in determining what constitutes an ''epidemiologically important organism,'' the following criteria apply: d a propensity for transmission within health care facilities based on published reports and the occurrence of temporal or geographic clusters of more than patients, (eg, c difficile, norovirus, rsv, influenza, rotavirus, enterobacter spp, serratia spp, group a streptococcus). a single case of health care-associated invasive disease caused by certain pathogens (eg, group a streptococcus postoperatively, in a burn unit, or in a ltcf; legionella spp, , aspergillus spp ) is generally considered a trigger for investigation and enhanced control measures because of the risk of additional cases and the severity of illness associated with these infections. i.c. .a. clostridium difficile. c difficile is a sporeforming gram-positive anaerobic bacillus that was first isolated from stools of neonates in and identified as the most frequent causative agent of antibioticassociated diarrhea and pseudomembranous colitis in . this pathogen is a major cause of health care-associated diarrhea and has been responsible for many large outbreaks in health care settings that have proven extremely difficult to control. important factors contributing to health care-associated outbreaks include environmental contamination, persistence of spores for prolonged periods, resistance of spores to routinely used disinfectants and antiseptics, hand carriage by hcws to other patients, and exposure of patients to frequent courses of antimicrobial agents. antimicrobials most frequently associated with increased risk of c difficile include third-generation cephalosporins, clindamycin, vancomycin, and fluoroquinolones. since , outbreaks and sporadic cases of c difficile with increased morbidity and mortality have occurred in several us states, canada, england, and the netherlands. [ ] [ ] [ ] [ ] [ ] the same strain of c difficile has been implicated in all of these outbreaks; this strain, toxinotype iii, north american pulsedfield gel electrophoresis (pfge) type , and polymerase chain reaction (pcr)-ribotype (nap / ), has been found to hyperproduce toxin a (a -fold increase) and toxin b (a -fold increase) compared with isolates from other pfge types. a recent survey of us infectious disease physicians found that % of the respondents perceived recent increases in the incidence and severity of c difficile disease. standardization of testing methodology and surveillance definitions is needed for accurate comparisons of trends in rates among hospitals. it is hypothesized that the incidence of disease and apparent heightened transmissibility of this new strain may be due, at least in part, to the greater production of toxins a and b, increasing the severity of diarrhea and producing more environmental contamination. considering the greater morbidity, mortality, length of stay, and costs associated with c difficile disease in both acute care and long-term care facilities, control of this pathogen is becoming increasingly important. prevention of transmission focuses on syndromic application of contact precautions for patients with diarrhea, accurate identification of affected patients, environmental measures (eg, rigorous cleaning of patient rooms), and consistent hand hygiene. using soap and water rather than alcohol-based handrubs for mechanical removal of spores from hands and using a bleachcontaining disinfectant ( ppm) for environmental disinfection may be valuable in cases of transmission in health care facilities. appendix a provides for recommendations. i.c. .b. multidrug-resistant organisms. in general, mdros are defined as microorganisms-predominantly bacteria-that are resistant to or more classes of antimicrobial agents. although the names of certain mdros suggest resistance to only a single agent (eg, mrsa, vre), these pathogens are usually resistant to all but a few commercially available antimicrobial agents. this latter feature defines mdros that are considered to be epidemiologically important and deserve special attention in health care facilities. other mdros of current concern include multidrug-resistant streptococcus pneumoniae, which is resistant to penicillin and other broad-spectrum agents such as macrolides and fluroquinolones, multidrug-resistant gram-negative bacilli (mdr-gnb), especially those producing esbls; and strains of s aureus that are intermediate or resistant to vancomycin (ie, visa and vrsa). mdros are transmitted by the same routes as antimicrobial susceptible infectious agents. patient-to-patient transmission in health care settings, usually via hands of hcws, has been a major factor accounting for the increase in mdro incidence and prevalence, especially for mrsa and vre in acute care facilities. [ ] [ ] [ ] preventing the emergence and transmission of these pathogens requires a comprehensive approach that includes administrative involvement and measures (eg, nurse staffing, communication systems, performance improvement processes to ensure adherence to recommended infection control measures), education and training of medical and other hcws, judicious antibiotic use, comprehensive surveillance for targeted mdros, application of infection control precautions during patient care, environmental measures (eg, cleaning and disinfection of the patient care environment and equipment, dedicated single-patient use of noncritical equipment), and decolonization therapy when appropriate. the prevention and control of mdros is a national priority, one that requires that all health care facilities and agencies assume responsibility and participate in community-wide control programs. , a detailed discussion of this topic and recommendations for prevention published in is available at http:// www.cdc.gov/ncidod/dhqp/pdf/ar/mdroguideline . pdf. i.c. . agents of bioterrorism. the cdc has designated the agents that cause anthrax, smallpox, plague, tularemia, viral hemorrhagic fevers, and botulism as category a (high priority), because these agents can be easily disseminated environmentally and/or transmitted from person to person, can cause high mortality and have the potential for major public health impact, might cause public panic and social disruption, and necessitate special action for public health preparedness. general information relevant to infection control in health care settings for category a agents of bioterrorism is summarized in table . (see http:// www.bt.cdc.gov for additional, updated category a agent information as well as information concerning category b and c agents of bioterrorism and updates.) category b and c agents are important but are not as readily disseminated and cause less morbidity and mortality than category a agents. health care facilities confront a different set of issues when dealing with a suspected bioterrorism event compared with other communicable diseases. an understanding of the epidemiology, modes of transmission, and clinical course of each disease, as well as carefully drafted plans that specify an approach and relevant websites and other resources for disease-specific guidance to health care, administrative, and support personnel, are essential for responding to and managing a bioterrorism event. infection control issues to be addressed include ( ) identifying persons who may be exposed or infected; ( ) preventing transmission among patients, hcws, and visitors; ( ) providing treatment, chemoprophylaxis, or vaccine to potentially large numbers of people; ( ) protecting the environment, including the logistical aspects of securing sufficient numbers of aiirs or designating areas for patient cohorts when an insufficient number of aiirs is available; ( ) providing adequate quantities of appropriate ppe; and ( ) identifying appropriate staff to care for potentially infectious patients (eg, vaccinated hcws for care of patients with smallpox). the response is likely to differ for exposures resulting from an intentional release compared with a naturally occurring disease because of the large number of persons that can be exposed at the same time and possible differences in pathogenicity. various sources offer guidance for the management of persons exposed to the most likely agents of bioterrorism. federal agency websites (eg, http://www. usamriid.army.mil/publications/index.html and http:// www.bt.cdc.gov) and state and county health department websites should be consulted for the most upto-date information. sources of information on specific agents include anthrax, smallpox, [ ] [ ] [ ] plague, , botulinum toxin, tularemia, and hemorrhagic fever viruses. , i.c. .a. pre-event administration of smallpox (vaccinia) vaccine to health care workers. vaccination of hcwsl in preparation for a possible smallpox exposure has important infection control implications. [ ] [ ] [ ] these include the need for meticulous screening for vaccine contraindications in persons at increased risk for adverse vaccinia events; containment and monitoring of the vaccination site to prevent transmission in the health care setting and at home; and management of patients with vaccinia-related adverse events. , the pre-event us smallpox vaccination program of is an example of the effectiveness of carefully developed recommendations for both screening potential vaccinees for contraindications and vaccination site care and monitoring. between december and february , approximately , individuals were vaccinated in the department of defense and , in the civilian or public health populations, including approximately , who worked in health care settings. no cases of eczema vaccinatum, progressive vaccinia, fetal vaccinia, or contact transfer of vaccinia were reported in health care settings or in military workplaces. , outside the health care setting, there were cases of contact transfer from military vaccinees to close personal contacts (eg, bed partners or contacts during participation in sports such as wrestling ). all contact transfers were from individuals who were not following recommendations to cover their vaccination sites. vaccinia virus was confirmed by culture or pcr in cases, of which resulted from tertiary transfer. all recipients, including breast-fed infant, recovered without complications. subsequent studies using viral culture and pcr techniques have confirmed the effectiveness of semipermeable dressings to contain vaccinia. [ ] [ ] [ ] [ ] this experience emphasizes the importance of ensuring that newly vaccinated hcws adhere to recommended vaccination site care, especially those caring for high-risk patients. recommendations for pre-event smallpox vaccination of hcws and vacciniarelated infection control recommendations are published in the morbidity and mortality weekly report, , with updates posted on the cdc's bioterrorism website. i.c. . prions. creutzfeldt-jakob disease (cjd) is a rapidly progressive, degenerative neurologic disorder of humans, with an incidence in the united states of approximately person/million population/year. , cjd is believed to be caused by a transmissible proteinaceous infectious agent known as a prion. infectious prions are isoforms of a host-encoded glycoprotein known as the prion protein. the incubation period (ie, time between exposure and and onset of symptoms) varies from years to many decades. however, death typically occurs within year of the onset of symptoms. approximately % of cjd cases occur sporadically with no known environmental source of infection, and % of cases are familial. iatrogenic transmission has occurred, with most cases resulting from treatment with human cadaver pituitary-derived growth hormone or gonadotropin, , from implantation of contaminated human dura mater grafts, or from corneal transplants. transmission has been linked to the use of contaminated neurosurgical instruments or stereotactic electroencephalogram electrodes. [ ] [ ] [ ] [ ] prion diseases in animals include scrapie in sheep and goats, bovine spongiform encephalopathy (bse, or ''mad cow disease'') in cattle, and chronic wasting disease in deer and elk. bse, first recognized in the united kingdom in , was associated with a major epidemic among cattle that had consumed contaminated meat and bone meal. the possible transmission of bse to humans causing variant cjd (vcjd) was first described in and was subsequently found to be associated with consumption of bse-contaminated cattle products primarily in the united kingdom. there is strong epidemiologic and laboratory evidence for a causal association between the causative agent of bse and vcjd. although most cases of vcjd have been reported from the united kingdom, a few cases also have been reported from europe, japan, canada, and the united states. most persons affected with vcjd worldwide lived in or visited the united kingdom during the years of a large outbreak of bse ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) and may have consumed contaminated cattle products during that time (see http://www.cdc.gov/ncidod/ diseases/cjd/cjd.htm). although there has been no indigenously acquired vcjd in the united states, the sporadic occurrence of bse in cattle in north america has heightened awareness of the possibility that such infections could occur and have led to increased surveillance activities. updated information may be found at http://www.cdc.gov/ncidod/diseases/cjd/cjd.htm. the public health impact of prion diseases has been reviewed previously. vcjd in humans has different clinical and pathologic characteristics than sporadic or classic cjd, including ( ) younger median age at death ( [range, to ] vs years), ( ) longer median duration of illness ( months vs to months), ( ) increased frequency of sensory symptoms and early psychiatric symptoms with delayed onset of frank neurologic signs; and ( ) detection of prions in tonsillar and other lymphoid tissues, not present in sporadic cjd. similar to sporadic cjd, there have been no reported cases of direct human-tohuman transmission of vcjd by casual or environmental contact, droplet, or airborne routes. ongoing blood safety surveillance in the united states has not detected sporadic cjd transmission through blood transfusion; - however, bloodborne transmission of vcjd is believed to have occurred in patients in the uited kingdom. , the following fda websites provide information on steps currently being taken in the united states to protect the blood supply from cjd and vcjd: http://www.fda.gov/cber/gdlns/cjdvcjd.htm and http:// www.fda.gov/cber/gdlns/cjdvcjdq&a.htm. standard precautions are used when caring for patients with suspected or confirmed cjd or vcjd. however, special precautions are recommended for tissue handling in the histology laboratory and for conducting an autopsy, embalming, and coming into contact with a body that has undergone autopsy. recommendations for reprocessing surgical instruments to prevent transmission of cjd in health care settings have been published by the world health organization (who) and are currently under review at the cdc. questions may arise concerning notification of patients potentially exposed to cjd or vcjd through contaminated instruments and blood products from patients with cjd or vcjd or at risk of having vcjd. the risk of transmission associated with such exposures is believed to be extremely low but may vary based on the specific circumstance. therefore, consultation on appropriate options is advised. the united kingdom has developed several documents that clinicians and patients in the united states may find useful (see http://www.hpa.org.uk/infections/topics_az/cjd/ information_documents.htm). i.c. . severe acute respiratory syndrome. sars is a newly discovered respiratory disease that emerged in china late in and spread to several countries. , in particular, mainland china, hong kong, hanoi, singapore, and toronto have been significantly affected. sars is caused by sars-cov, a previously unrecognized member of the coronavirus family. , the incubation period from exposure to the onset of symptoms is typically to days, but can be as long as days and in rare cases even longer. the illness is initially difficult to distinguish from other common respiratory infections. signs and symptoms usually include fever above . c and chills and rigors, sometimes accompanied by headache, myalgia, and mild to severe respiratory symptoms. a radiographic profile of atypical pneumonia is an important clinical indicator of possible sars. compared with adults, children are affected less frequently, have milder disease, and are less likely to transmit sars-cov. , [ ] [ ] [ ] the overall case fatality rate is approximately %; underlying disease and advanced age increase the risk of mortality (see http://www.who.int/csr/sarsarchive/ _ _ a/en/). outbreaks in health care settings, with transmission to large numbers of hcws and patients, haa been a striking feature of sars; undiagnosed infectious patients and visitors have been important initiators of these outbreaks. , [ ] [ ] [ ] the relative contribution of potential modes of transmission is not known precisely. there is ample evidence for droplet and contact transmission; , , however, opportunistic airborne transmission cannot be excluded. , [ ] [ ] [ ] [ ] [ ] , for example, exposure to aerosol-generating procedures (eg, endotracheal intubation, suctioning) has been associated with transmission of infection to large numbers of hcws outside of the united states. , , , , therefore, aerosolization of small infectious particles generated during these and other similar procedures could be a risk factor for transmission to others within a multibed room or shared airspace. a review of the infection control literature generated from the sars outbreaks of concluded that the greatest risk of transmission is to those who have close contact, are not properly trained in use of protective infection control procedures, and do not consistently use ppe, and that n or higher-level respirators may offer additional protection to those exposed to aerosol-generating procedures and high-risk activities. , organizational and individual factors that affect adherence to infection control practices for sars also were identified. control of sars requires a coordinated, dynamic response by multiple disciplines in a health care setting. early detection of cases is accomplished by screening persons with symptoms of a respiratory infection for history of travel to areas experiencing community transmission or contact with sars patients, followed by implementation of respiratory hygiene/cough etiquette (ie, placing a mask over the patient's nose and mouth) and physical separation from other patients in common waiting areas. the precise combination of precautions to protect hcws has not yet been determined. at the time of this publication, the cdc recommends standard precautions, with emphasis on the use of hand hygiene; contact precautions, with emphasis on environmental cleaning due to the detection of sars-cov rna by pcr on surfaces in rooms occupied by sars patients; , , and airborne precautions, including use of fit-tested niosh-approved n or higher-level respirators and eye protection. in hong kong, the use of droplet and contact precautions, including the use of a mask but not a respirator, was effective in protecting hcws. however, in toronto, consistent use of an n respirator was found to be slightly more protective than a mask. it is noteworthy that no transmission of sars-cov to public hospital workers occurred in vietnam despite inconsistent use of infection control measures, including use of ppe, which suggests other factors (eg, severity of disease, frequency of high-risk procedures or events, environmental features) may influence opportunities for transmission. sars-cov also has been transmitted in the laboratory setting through breaches in recommended laboratory practices. research laboratories in which sars-cov was under investigation were the source of most cases reported after the first series of outbreaks in the winter and spring of . lessons learned from the sars outbreaks are useful in devising plans to respond to future public health crises, such as pandemic influenza and bioterrorism events. surveillance for cases among patients and hcws, ensuring availability of adequate supplies and staffing, and limiting access to health care facilities were important factors in the response to sars. guidance for infection control precautions in various settings is available at http://www.cdc.gov/ncidod/sars. i.c. . monkeypox. monkeypox is a rare viral disease found mostly in the rain forest countries of central and west africa. the disease is caused by an orthopoxvirus that is similar in appearance to smallpox but causes a milder disease. the only recognized outbreak of human monkeypox in the united states was detected in june , after several people became ill after contact with sick pet prairie dogs. infection in the prairie dogs was subsequently traced to their contact with a shipment of animals from africa, including giant gambian rats. this outbreak demonstrates the importance of recognition and prompt reporting of unusual disease presentations by clinicians to enable prompt identification of the etiology, as well as the potential of epizootic diseases to spread from animal reservoirs to humans through personal and occupational exposure. only limited data on transmission of monkeypox are available. transmission from infected animals and humans is believed to occur primarily through direct contact with lesions and respiratory secretions; airborne transmission from animals to humans is unlikely but cannot be excluded, and may have occurred in veterinary practices (eg, during administration of nebulized medications to ill prairie dogs ). in humans, instances of monkeypox transmission in hospitals have been reported in africa among children, usually related to sharing the same ward or bed. , additional recent literature documents transmission of congo basin monkeypox in a hospital compound for an extended number of generations. there has been no evidence of airborne or any other person-to-person transmission of monkeypox in the united states, and no new cases of monkeypox have been identified since the outbreak in june . the outbreak strain is a clade of monkeypox distinct from the congo basin clade and may have different epidemiologic properties (including human-to-human transmission potential) from monkeypox strains of the congo basin; this awaits further study. smallpox vaccine is % protective against congo basin monkeypox. because there is an associated case fatality rate of , %, administration of smallpox vaccine within days to individuals who have had direct exposure to patients or animals with monkeypox is a reasonable policy. for the most current information on monkeypox, see http://www.cdc.gov/ncidod/mon keypox/clinicians.htm. i.c. . noroviruses. noroviruses, formerly referred to as norwalk-like viruses, are members of the caliciviridae family. these agents are transmitted via contaminated food or water and from person to person, causing explosive outbreaks of gastrointestinal disease. environmental contamination also has been documented as a contributing factor in ongoing transmission during outbreaks. , although noroviruses cannot be propagated in cell culture, dna detection by molecular diagnostic techniques has brought a greater appreciation of their role in outbreaks of gastrointestinal disease. reported outbreaks in hospitals, and large crowded shelters established for hurricane evacuees has demonstrated their highly contagious nature, their potentially disruptive impact in health care facilities and the community, and the difficulty of controlling outbreaks in settings in which people share common facilites and space. of note, there is nearly a -fold increase in the risk to patients in outbreaks when a patient is the index case compared with exposure of patients during outbreaks when a staff member is the index case. the average incubation period for gastroenteritis caused by noroviruses is to hours, and the clinical course lasts to hours. illness is characterized by acute onset of nausea, vomiting, abdominal cramps, and/or diarrhea. the disease is largely self-limited; rarely, death due to severe dehydration can occur, particularly in elderly persons with debilitating health conditions. the epidemiology of norovirus outbreaks shows that even though primary cases may result from exposure to a fecally contaminated food or water, secondary and tertiary cases often result from person-to-person transmission facilitated by contamination of fomites , and dissemination of infectious particles, especially during the process of vomiting. , , , , , , , widespread, persistent, and inapparent contamination of the environment and fomites can make outbreaks extremely difficult to control. , , these clinical observations and the detection of norovirus dna on horizontal surfaces feet above the level that might be touched normally suggest that under certain circumstances, aerosolized particles may travel distances beyond feet. it is hypothesized that infectious particles may be aerosolized from vomitus, inhaled, and swallowed. in addition, individuals who are responsible for cleaning the environment may be at increased risk of infection. development of disease and transmission may be facilitated by the low infectious dose (ie, , viral particles) and the resistance of these viruses to the usual cleaning and disinfection agents (ie, they may survive , ppm chlorine). [ ] [ ] [ ] an alternate phenolic agent that was shown to be effective against feline calicivirus was used for environmental cleaning in one outbreak. , there are insufficient data to determine the efficacy of alcohol-based hand rubs against noroviruses when the hands are not visibly soiled. absence of disease in certain individuals during an outbreak may be explained by protection from infection conferred by the b histo-blood group antigen. consultation on outbreaks of gastroenteritis is available through the cdc's division of viral and rickettsial diseases. i.c. . hemorrhagic fever viruses. hfv is a mixed group of viruses that cause serious disease with high fever, skin rash, bleeding diathesis, and, in some cases, high mortality; the resulting disease is referred to as viral hemorrhagic fever (vhf). among the more commonly known hfvs are ebola and marburg viruses (filoviridae), lassa virus (arenaviridae), crimean-congo hemorrhagic fever and rift valley fever virus (bunyaviridae), and dengue and yellow fever viruses (flaviviridae). , these viruses are transmitted to humans through contact with infected animals or via arthropod vectors. although none of these viruses is endemic in the united states, outbreaks in affected countries provide potential opportunities for importation by infected humans and animals. furthermore, there is a concern that some of these agents could be used as bioweapons. person-to-person transmission has been documented for ebola, marburg, lassa, and crimean-congo hfvs. in resource-limited health care settings, transmission of these agents to hcws, patients, and visitors has been described and in some outbreaks has accounted for a large proportion of cases. [ ] [ ] [ ] transmission within households also has been documented in individuals who had direct contact with ill persons or their body fluids, but not in those who did not have such contact. evidence concerning the transmission of hfvs has been summarized previously. , person-to-person transmission is associated primarily with direct blood and body fluid contact. percutaneous exposure to contaminated blood carries a particularly high risk for transmission and increased mortality. , the finding of large numbers of ebola viral particles in the skin and the lumina of sweat glands has raised concerns that transmission could occur from direct contact with intact skin, although epidemiologic evidence to support this is lacking. postmortem handling of infected bodies is an important risk for transmission. , , in rare situations, cases in which the mode of transmission was unexplained among individuals with no known direct contact have led to speculation that airborne transmission could have occurred. however, airborne transmission of naturally occurring hfvs in humans has not been documented. a study of airplane passengers exposed to an in-flight index case of lassa fever found no transmission to any passengers. in the laboratory setting, animals have been infected experimentally with marburg or ebola virus through direct inoculation of the nose, mouth, and/or conjunctiva , and by using mechanically generated viruscontaining aerosols. , transmission of ebola virus among laboratory primates in an animal facility has been described. the secondarily infected animals were in individual cages separated by approximately meters. although the possibility of airborne transmission was suggested, the investigators were not able to exclude droplet or indirect contact transmission in this incidental observation. guidance on infection control precautions for hvfs transmitted person-to-person have been published by the cdc , and by the johns hopkins center for civilian biodefense strategies. the most recent recommendations at the time of publication of this document were posted on the cdc website on may , . inconsistencies among the various recommendations have raised questions about the appropriate precautions to use in us hospitals. in less developed countries, outbreaks of hfvs have been controlled with basic hygiene, barrier precautions, safe injection practices, and safe burial practices. , the preponderance of evidence on hfv transmission indicates that standard, contact, and droplet precautions with eye protection are effective in protecting hcws and visitors coming in contact with an infected patient. single gloves are adequate for routine patient care; doublegloving is advised during invasive procedures (eg, surgery) that pose an increased risk of blood exposure. routine eye protection (ie goggles or face shield) is particularly important. fluid-resistant gowns should be worn for all patient contact. airborne precautions are not required for routine patient care; however, use of aiirs is prudent when procedures that could generate infectious aerosols are performed (eg, endotracheal intubation, bronchoscopy, suctioning, autopsy procedures involving oscillating saws). n or higher-level respirators may provide added protection for individuals in a room during aerosol-generating procedures ( table , appendix a). when a patient with a syndrome consistent with hemorrhagic fever also has a history of travel to an endemic area, precautions are initiated on presentation and then modified as more information is obtained ( table ) . patients with hemorrhagic fever syndrome in the setting of a suspected bioweapons attack should be managed using airborne precautions, including aiirs, because the epidemiology of a potentially weaponized hemorrhagic fever virus is unpredictable. numerous factors influence differences in transmission risks among the various health care settings. these factors include the population characteristics (eg, increased susceptibility to infections, type and prevalence of indwelling devices), intensity of care, exposure to environmental sources, length of stay, and frequency of interaction between patients/residents with each other and with hcws. these factors, as well as organizational priorities, goals, and resources, influence how different health care settings adapt transmission prevention guidelines to meet their specific needs. , infection control management decisions are informed by data regarding institutional experience/epidemiology; trends in community and institutional hais; local, regional, and national epidemiology; and emerging infectious disease threats. i.d. . hospitals. infection transmission risks are present in all hospital settings. however, certain hospital settings and patient populations have unique conditions that predispose patients to infection and merit special mention. these are often sentinel sites for the emergence of new transmission risks that may be unique to that setting or present opportunities for transmission to other settings in the hospital. i.d. .a. intensive care units. intensive care units (icus) serve patients who are immunocompromised by disease state and/or by treatment modalities, as well as patients with major trauma, respiratory failure, and other life-threatening conditions (eg, myocardial infarction, congestive heart failure, overdose, stroke, gastrointestinal bleeding, renal failure, hepatic failure, multiorgan system failure, and extremes of age). although icus account for a relatively small proportion of hospitalized patients, infections acquired in these units account for . % of all hais. in the national nosocomial infection surveillance (nnis) system, . % of hais were reported from icu and high-risk nursery (neonatal icu [nicu]) patients in (nnis, unpublished data). this patient population has increased susceptibility to colonization and infection, especially with mdros and candida spp, , because of underlying diseases and conditions, the invasive medical devices and technology used in their care (eg central venous catheters and other intravascular devices, mechanical ventilators, extracorporeal membrane oxygenation, hemodialysis/filtration, pacemakers, implantable left-ventricular assist devices), the frequency of contact with hcws, prolonged lengths of stay, and prolonged exposure to antimicrobial agents. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] furthermore, adverse patient outcomes in this setting are more severe and are associated with a higher mortality. outbreaks associated with various bacterial, fungal, and viral pathogens due to common-source and person-to-person transmissions are frequent in adult icus and pediatric icus (picus). , [ ] [ ] [ ] [ ] [ ] [ ] i.d. .b. burn units. burn wounds can provide optimal conditions for colonization, infection, and transmission of pathogens; infection acquired by burn patients is a frequent cause of morbidity and mortality. , , the risk of invasive burn wound infection is particularly high in patients with a burn injury involving . % of the total body surface area (tbsa). , infections occurring in patients with burn injuries involving , % of the tbsa are usually associated with the use of invasive devices. mssa, mrsa, enterococci (including vre), gram-negative bacteria, and candida spp are prevalent pathogens in burn infections, , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and outbreaks of these organisms have been reported. [ ] [ ] [ ] [ ] shifts over time in the predominance of pathogens causing infections in burn patients often lead to changes in burn care practices. , [ ] [ ] [ ] [ ] burn wound infections caused by aspergillus spp or other environmental molds may result from exposure to supplies contaminated during construction or to dust generated during construction or other environmental disruption. hydrotherapy equipment is an important environmental reservoir of gram-negative organisms. its use in burn care is discouraged based on demonstrated associations between the use of contaminated hydrotherapy equipment and infections. burn wound infections and colonization, as well as bloodstream infections, caused by multidrug-resistant p aeruginosa, acinetobacter baumannii, and mrsa have been associated with hydrotherapy; thus, excision of burn wounds in operating rooms is the preferred approach. advances in burn care (specifically, early excision and grafting of the burn wound, use of topical antimicrobial agents, and institution of early enteral feeding) have led to decreased infectious complications. other advances have included prophylactic antimicrobial use, selective digestive decontamination, and use of antimicrobial-coated catheters; however, few epidemiologic studies and no efficacy studies have been performed to investigate the relative benefit of these measures. there is no consensus on the most effective infection control practices to prevent transmission of infections to and from patients with serious burns (eg, single-bed rooms, laminar flow, and high-efficiency particulate air [hepa] filtration, or maintaining burn patients in a separate unit with no exposure to patients or equipment from other units ). there also is controversy regarding the need for and type of barrier precautions in the routine care of burn patients. one retrospective study demonstrated the efficacy and cost-effectiveness of a simplified barrier isolation protocol for wound colonization, emphasizing handwashing and use of gloves, caps, masks, and impermeable plastic aprons (rather than isolation gowns) for direct patient contact. however, to date no studies have determined the most effective combination of infection control precautions for use in burn settings. prospective studies in this area are needed. i.d. .c. pediatrics. studies of the epidemiology of hais in children have identified unique infection control issues in this population. , , [ ] [ ] [ ] [ ] [ ] pediatric icu patients and the lowest birth weight babies in the nicu monitored in the nnis system have had high rates of central venous catheter-associated bloodstream infections. , ) . close physical contact between hcws and infants and young children (eg. cuddling, feeding, playing, changing soiled diapers, and cleaning copious uncontrolled respiratory secretions) provides abundant opportunities for transmission of infectious material. such practices and behaviors as congregation of children in play areas where toys and bodily secretions are easily shared and rooming-in of family members with pediatric patients can further increase the risk of transmission. pathogenic bacteria have been recovered from toys used by hospitalized patients; contaminated bath toys were implicated in an outbreak of multidrug-resistant p. aeruginosa on a pediatric oncology unit. in addition, several patient factors increase the likelihood that infection will result from exposure to pathogens in health care settings (eg, immaturity of the neonatal immune system, lack of previous natural infection and resulting immunity, prevalence of patients with congenital or acquired immune deficiencies, congenital anatomic anomalies, and use of life-saving invasive devices in nicus and picus). there are theoretical concerns that infection risk will increase in association with innovative practices used in the nicu for the purpose of improving developmental outcomes, such factors include cobedding and kangaroo care, which may increase opportunity for skin-to-skin exposure of multiple gestation infants to each other and to their mothers, respectively; although the risk of infection actually may be reduced among infants receiving kangaroo care. children who attend child care centers , and pediatric rehabilitation units may increase the overall burden of antimicrobial resistance by contributing to the reservoir of ca-mrsa. [ ] [ ] [ ] [ ] [ ] [ ] patients in chronic care facilities may have increased rates of colonization with resistant garm-negative bacilli and may be sources of introduction of resistant organisms to acute care settings. i.d. . nonacute health care settings. health care is provided in various settings outside of hospitals, including long-term care facilities (ltcfs) (eg nursing homes), homes for the developmentally disabled, behavioral health service settings, rehabilitation centers, and hospices. in addition, health care may be provided in non-health care settings, such as workplaces with occupational health clinics, adult day care centers, assisted-living facilities, homeless shelters, jails and prisons, school clinics, and infirmaries. each of these settings has unique circumstances and population risks that must be considered when designing and implementing an infection control program. several of the most common settings and their particular challenges are discussed below. although this guideline does not address each setting, the principles and strategies provided herein may be adapted and applied as appropriate. i.d. .a. long-term care. the designation ltcf applies to a diverse group of residential settings, ranging from institutions for the developmentally disabled to nursing homes for the elderly and pediatric chronic care facilities. [ ] [ ] [ ] nursing homes for the elderly predominate numerically and frequently represent longterm care as a group of facilities. approximately . million americans reside in the nation's , nursing homes. estimates of hai rates of . to . per resident-care days have been reported, with a range of to per resident-care days in the more rigorous studies. [ ] [ ] [ ] [ ] [ ] the infrastructure described in the department of veterans affairs' nursing home care units is a promising example for the development of a nationwide hai surveillance system for ltcfs. lctfs are different from other health care settings in that elderly patients at increased risk for infection are brought together in one setting and remain in the facility for extended periods; for most residents, it is their home. an atmosphere of community is fostered, and residents share common eating and living areas and participate in various facility-sponsored activities. , because able residents interact freely with each other, controlling infection transmission in this setting can be challenging. a residents who is colonized or infected with certain microorganisms are in some cases restricted to his or her room. however, because of the psychosocial risks associated with such restriction, balancing psychosocial needs with infection control needs is important in the ltcf setting. , , , ) and bacteria, including group a streptococcus, , b pertussis, nonsusceptible s pneumoniae, , other mdros, and c difficile ). these pathogens can lead to substantial morbidity and mortality, as well as increased medical costs; prompt detection and implementation of effective control measures are needed. risk factors for infection are prevalent among ltcf residents. , , age-related declines in immunity may affect the response to immunizations for influenza and other infectious agents and increase the susceptibility to tuberculosis. immobility, incontinence, dysphagia, underlying chronic diseases, poor functional status, and age-related skin changes increase susceptibility to urinary, respiratory, and cutaneous and soft tissue infections, whereas malnutrition can impair wound healing. [ ] [ ] [ ] [ ] [ ] medications (eg, drugs that affect level of consciousness, immune function, gastric acid secretions, and normal flora, including antimicrobial therapy) and invasive devices (eg, urinary catheters and feeding tubes) heighten the susceptibility to infection and colonization in ltcf residents. [ ] [ ] [ ] finally, limited functional status and total dependence on hcws for activities of daily living have been identified as independent risk factors for infection , , and for colonization with mrsa , and esbl-producing klebsiella pneumoniae. several position papers and review articles provide guidance on various aspects of infection control and antimicrobial resistance in ltcfs. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] the centers for medicare and medicaid services has established regulations for the prevention of infection in ltcfs. because residents of ltcfs are hospitalized frequently, they can transfer pathogens between ltcfs and health care facilities in which they receive care. , [ ] [ ] [ ] [ ] this also is true for pediatric long-term care populations. pediatric chronic care facilities have been associated with the importation of extendedspectrum cephalosporin-resistant, gram-negative bacilli into a picu. children from pediatric rehabilitation units may contribute to the reservoir of community-associated mrsa. , [ ] [ ] [ ] i.d. .b. ambulatory care. over the past decade, health care delivery in the united states has shifted from the acute, inpatient hospital to various ambulatory and community-based settings, including the home. ambulatory care is provided in hospital-based outpatient clinics, nonhospital-based clinics and physicians' offices, public health clinics, free-standing dialysis centers, ambulatory surgical centers, urgent care centers, and other setting. in , there were million visits to hospital outpatient clinics and more than million visits to physicians' offices; ambulatory care now accounts for most patient encounters with the health care system. adapting transmission prevention guidelines to these settings is challenging, because patients remain in common areas for prolonged periods waiting to be seen by a health care provider or awaiting admission to the hospital, examination or treatment rooms are turned around quickly with limited cleaning, and infectious patients may not be recognized immediately. furthermore, immunocompromised patients often receive chemotherapy in infusion rooms, where they stay for extended periods along with other types of patients. little data exist on the risk of hais in ambulatory care settings, with the exception of hemodialysis centers. , , transmission of infections in outpatient settings has been reviewed in studies. [ ] [ ] [ ] goodman and solomon summarized clusters of infections associated with the outpatient setting between and . overall, clusters were associated with common source transmission from contaminated solutions or equipment, were associated with person-to-person transmission from or involving hcws, and were associated with airborne or droplet transmission among patients and health care workers. transmission of bloodborne pathogens (ie, hbv, hcv, and, rarely, hiv) in outbreaks, sometimes involving hundreds of patients, continues to occur in ambulatory settings. these outbreaks often are related to common source exposures, usually a contaminated medical device, multidose vial, or intravenous solution. , [ ] [ ] [ ] [ ] [ ] in all cases, transmission has been attributed to failure to adhere to fundamental infection control principles, including safe injection practices and aseptic technique. this subject has been reviewed, and recommended infection control and safe injection practices have been summarized. airborne transmission of m tuberculosis and measles in ambulatory settings, most often emergency departments, has been reported. , , , , [ ] [ ] [ ] measles virus was transmitted in physicians' offices and other outpatient settings during an era when immunization rates were low and measles outbreaks in the community were occurring regularly. , , rubella has been transmitted in the outpatient obstetric setting; there are no published reports of varicella transmission in the outpatient setting. in the ophthalmology setting, adenovirus type epidemic keratoconjunctivitis has been transmitted through incompletely disinfected ophthalmology equipment and/or from hcws to patients, presumably by contaminated hands. , , , [ ] [ ] [ ] [ ] preventing transmission in outpatient settings necessitates screening for potentially infectious symptomatic and asymptomatic individuals, especially those at possible risk for transmitting airborne infectious agents (eg, m tuberculosis, varicella-zoster virus, rubeola [measles]), at the start of the initial patient encounter. on identification of a potentially infectious patient, implementation of prevention measures, including prompt separation of potentially infectious patients and implementation of appropriate control measures (eg, respiratory hygiene/cough etiquette and transmission-based precautions) can decrease transmission risks. , transmission of mrsa and vre in outpatient settings has not been reported, but the association of ca-mrsa in hcws working in an outpatient hiv clinic with environmental ca-mrsa contamination in that clinic suggests the possibility of transmission in that setting. patient-to-patient transmission of burkholderia spp and p aeruginosa in outpatient clinics for adults and children with cystic fibrosis has been confirmed. , i.d. .c. home care. home care in the united states is delivered by more than , provider agencies, including home health agencies, hospices, durable medical equipment providers, home infusion therapy services, and personal care and support services providers. home care is provided to patients of all ages with both acute and chronic conditions. the scope of services ranges from assistance with activities of daily living and physical and occupational therapy to the care of wounds, infusion therapy, and chronic ambulatory peritoneal dialysis. the incidence of infection in home care patients, other than that associated with infusion therapy, has not been well studied. [ ] [ ] [ ] [ ] [ ] [ ] however, data collection and calculation of infection rates have been done for central venous catheter-associated bloodstream infections in patients receiving home infusion therapy [ ] [ ] [ ] [ ] [ ] and for the risk of blood contact through percutaneous or mucosal exposures, demonstrating that surveillance can be performed in this setting. draft definitions for home care-associated infections have been developed. transmission risks during home care are presumed to be minimal. the main transmission risks to home care patients are from an infectious home care provider or contaminated equipment; a provider also can be exposed to an infectious patient during home visits. because home care involves patient care by a limited number of personnel in settings without multiple patients or shared equipment, the potential reservoir of pathogens is reduced. infections of home care providers that could pose a risk to home care patients include infections transmitted by the airborne or droplet routes (eg, chickenpox, tuberculosis, influenza), skin infestations (eg, scabies and lice), and infections transmitted by direct or indirect contact (eg, impetigo). there are no published data on indirect transmission of mdros from one home care patient to another, although this is theoretically possible if contaminated equipment is transported from an infected or colonized patient and used on another patient. of note, investigations of the first case of visa in home care and the first reported cases of vrsa , , , found no evidence of transmission of visa or vrsa to other home care recipients. home health care also may contribute to antimicrobial resistance; a review of outpatient vancomycin use found that % of recipients did not receive prescribed antibiotics according to recommended guidelines. although most home care agencies implement policies and procedures aimed at preventing transmission of organisms, the current approach is based on the adaptation of the guideline for isolation precautions in hospitals, as well as other professional guidance. , this issue has proven very challenging to the home care industry, and practice has been inconsistent and frequently not evidence-based. for example, many home health agencies continue to observe ''nursing bag technique,'' a practice that prescribes the use of barriers between the nursing bag and environmental surfaces in the home. although the home environment may not always appear clean, the use of barriers between noncritical surfaces has been questioned. , opportunites exist to conduct research in home care related to infection transmission risks. i.d. .d. other sites of health care delivery. facilities that are not primarily health care settings but in which health care is delivered include clinics in correctional facilities and shelters. both of these settings can have suboptimal features, such as crowded conditions and poor ventilation. economically disadvantaged individuals who may have chronic illnesses and health care problems related to alcoholism, injected drug use, poor nutrition, and/or inadequate shelter often receive their primary health care at such sites. infectious diseases of special concern for transmission include tuberculosis, scabies, respiratory infections (eg, n meningitides, s pneumoniae), sexually transmitted and bloodborne diseases (eg, hiv, hbv, hcv, syphilis, gonorrhea), hepatitis a virus, diarrheal agents such as norovirus, and foodborne diseases. , [ ] [ ] [ ] [ ] a high index of suspicion for tuberculosis and ca-mrsa in these populations is needed; outbreaks in these settings or among the populations they serve have been reported. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] patient encounters in these types of facilities provide an opportunity to deliver recommended immunizations and screen for m tuberculosis infection, along with diagnosing and treating acute illnesses. recommended infection control measures in these nontraditional areas designated for health care delivery are the same as for other ambulatory care settings. therefore, these settings must be equipped to observe standard precautions and, when indicated, transmission-based precautions. as new treatments emerge for complex diseases, unique infection control challenges associated with special patient populations must be addressed. i.e. . immunocompromised patients. patients who have congenital primary immune deficiencies or acquired disease (eg. treatment-induced immune deficiencies) are at increased risk for numerous types of infections while receiving health care; these patients may be located throughout the health care facility. the specific immune system defects determine the types of infections most likely to be acquired (eg, viral infections are associated with t cell defects, and fungal and bacterial infections occur in patients who are neutropenic). as a general group, immunocompromised patients can be cared for in the same environment as other patients; however, it is always advisable to minimize exposure to other patients with transmissible infections, such as influenza and other respiratory viruses. , the use of more intense chemotherapy regimens for treatment of childhood leukemia may be associated with prolonged periods of neutropenia and suppression of other components of the immune system, extending the period of infection risk and raising the concern that additional precautions may be indicated for select groups. , with the application of newer and more intense immunosuppressive therapies for various medical conditions (eg, rheumatologic disease, , inflammatory bowel disease ), immunosuppressed patients are likely to be more widely distributed throughout a health care facility rather than localized to single patient units (eg, hematologyoncology). guidelines for preventing infections in certain groups of immunocompromised patients have been published previously. , , published data provide evidence to support placing patients undergoing allogeneic hsct in a pe. , , in addition, guidelines have been developed that address the special requirements of these immunocompromised patients, including use of antimicrobial prophylaxis and engineering controls to create a pe for the prevention of infections caused by aspergillus spp and other environmental fungi. , , as more intense chemotherapy regimens associated with prolonged periods of neutropenia or graft-versus-host disease are implemented, the period of risk and duration of environmental protection may need to be prolonged beyond the traditional days. i.e. . cystic fibrosis patients. patients with cystic fibrosis (cf) require special consideration when developing infection control guidelines. compared with other patients, cf patients require additional protection to prevent transmission from contaminated respiratory therapy equipment. [ ] [ ] [ ] [ ] [ ] such infectious agents as b cepacia complex and p aeruginosa. , , , have unique clinical and prognostic significance. in cf patients, b cepacia infection has been associated with increased morbidity and mortality, [ ] [ ] [ ] whereas delayed acquisition of chronic p aeruginosa infection may be associated with an improved long-term clinical outcome. , person-to-person transmission of b cepacia complex has been demonstrated among children and adults with cf in health care settings , and from various social contacts, most notably attendance at camps for patients with cf and among siblings with cf. successful infection control measures used to prevent transmission of respiratory secretions include segregation of cf patients from each other in ambulatory and hospital settings (including use of private rooms with separate showers), environmental decontamination of surfaces and equipment contaminated with respiratory secretions, elimination of group chest physiotherapy sessions, and disbanding of cf camps. , the cystic fibrosis foundation has published a consensus document with evidence-based recommendations for infection control practices in cf patients. i.f. new therapies associated with potentially transmissible infectious agents i.f. . gene therapy. gene therapy has has been attempted using various viral vectors, including nonreplicating retroviruses, adenoviruses, adeno-associated viruses, and replication-competent strains of poxviruses. unexpected adverse events have restricted the prevalence of gene therapy protocols. the infectious hazards of gene therapy are theoretical at this time but require meticulous surveillance due to the possible occurrence of in vivo recombination and the subsequent emergence of a transmissible genetically altered pathogen. the greatest concern attends the use of replication-competent viruses, especially vaccinia. to date, no reports have described transmission of a vector virus from a gene therapy recipient to another individual, but surveillance is ongoing. recommendations for monitoring infection control issues throughout the course of gene therapy trials have been published. [ ] [ ] [ ] i.f. . infections transmitted through blood, organs, and other tissues. the potential hazard of transmitting infectious pathogens through biologic products is a small but ever-present risk, despite donor screening. reported infections transmitted by transfusion or transplantation include west nile virus infection, cytomegalovirus infection, cjd, hepatitis c, infections with clostridium spp and group a streptococcus, malaria, babesiosis, chagas disease, lymphocytic choriomeningitis, and rabies. , therefore, it is important to consider receipt of biologic products when evaluating patients for potential sources of infection. i.f. . xenotransplantation. transplantation of nonhuman cells, tissues, and organs into humans potentially exposes patients to zoonotic pathogens. transmission of known zoonotic infections (eg, trichinosis from porcine tissue) is of concern. also of concern is the possibility that transplantation of nonhuman cells, tissues, or organs may transmit previously unknown zoonotic infections (xenozoonoses) to immunosuppressed human recipients. potential infections that potentially could accompany transplantation of porcine organs have been described previously. guidelines from the us public health service address many infectious diseases and infection control issues that surround the developing field of xenotransplantation; policies and procedures that explain how standard precautions and transmission-based precautions are applied, including systems used to identify and communicate information on patients with potentially transmissible infectious agents, are essential to ensure the success of these measures. these policies and procedures may vary according to the characteristics of the organization. a key administrative measure is the provision of fiscal and human resources for maintaining infection control and occupational health programs that are responsive to emerging needs. specific components include bedside nurse and infection prevention and control professional (icp) staffing levels, inclusion of icps in facility construction and design decisions, clinical microbiology laboratory support, , adequate supplies and equipment including facility ventilation systems, adherence monitoring, assessment and correction of system failures that contribute to transmission, , and provision of feedback to hcws and senior administrators. , , , the positive influence of institutional leadership has been demonstrated repeatedly in studies of hcws' adherence to recommended hand hygiene practices. , , , , , [ ] [ ] [ ] [ ] [ ] [ ] health care administrators' involvement in the infection control processes can improve their awareness of the rationale and resource requirements for following recommended infection control practices. several administrative factors may affect the transmission of infectious agents in health care settings, including the institutional culture, individual hcw behavior, and the work environment. each of these areas is suitable for performance improvement monitoring and incorporation into the organization's patient safety goals. , , , ii.a. .a. scope of work and staffing needs for infection control professionals. the effectiveness of infection surveillance and control programs in preventing nosocomial infections in ust hospitals was assessed by the cdc through the study on the efficacy of nosocomial infection control (senic project) conducted between and . in a representative sample of us general hospitals, those with a trained infection control physician or microbiologist involved in an infection control program and at least infection control nurse per beds were associated with a % lower rate of the infections studied (cvc-associated bloodstream infections, ventilator-associated pneumonias, catheter-related urinary tract infections, and surgical site infections). since the publication of that landmark study, responsibilities of icps have expanded commensurate with the growing complexity of the health care system, the patient populations served, and the increasing numbers of medical procedures and devices used in all types of health care settings. the scope of work of icps was first assessed in - by the certification board of infection control, and has been reassessed every years since that time. , [ ] [ ] [ ] the findings of these analyses have been used to develop and update the infection control certification examination, which was first offered in . with each new survey, it becomes increasingly apparent that the role of the icp is growing in complexity and scope beyond traditional infection control activities in acute care hospitals. activities currently assigned to icps in response to emerging challenges include ( ) surveillance and infection prevention at facilities other than acute care hospitals (eg, ambulatory clinics, day surgery centers, ltcfs, rehabilitation centers, home care); ( ) oversight of employee health services related to infection prevention (eg, assessment of risk and administration of recommended treatment after exposure to infectious agents, tuberculosis screening, influenza vaccination, respiratory protection fit testing, and administration of other vaccines as indicated, such as smallpox vaccine in ); ( ) preparedness planning for annual influenza outbreaks, pandemic influenza, sars, and bioweapons attacks; ( ) adherence monitoring for selected infection control practices; ( ) oversight of risk assessment and implementation of prevention measures associated with construction and renovation; ( ) prevention of transmission of mdros; ( ) evaluation of new medical products that could be associated with increased infection risk (eg, intravenous infusion materials); ( ) communication with the public, facility staff, and state and local health departments concerning infection control-related issues; and ( ) participation in local and multicenter research projects. , , , , , none of the certification board of infection control job analyses addressed specific staffing requirements for the identified tasks, although the surveys did include information about hours worked; the survey included the number of icps assigned to the responding facilities. there is agreement in the literature that a ratio of icp per acute care beds is no longer adequate to meet current infection control needs; a delphi project that assessed staffing needs of infection control programs in the st century concluded that a ratio of . to . icp per occupied acute care beds is an appropriate staffing level. a survey of participants in the nnis system found an average daily patient census of per icp. results of other studies have been similar: per beds for large acute care hospitals, per to beds in ltcfs, and . per in small rural hospitals. , the foregoing demonstrates that infection control staffing no longer can be based on patient census alone, but rather must be determined by the scope of the program, characteristics of the patient population, complexity of the health care system, tools available to assist personnel to perform essential tasks (eg, electronic tracking and laboratory support for surveillance), and unique or urgent needs of the institution and community. furthermore, appropriate training is required to optimize the quality of work performed. , , ii.a. .a.i. infection control nurse liaison. designating a bedside nurse on a patient care unit as an infection control liaison or ''link nurse'' is reported to be an effective adjunct to enhance infection control at the unit level. [ ] [ ] [ ] [ ] [ ] [ ] such individuals receive training in basic infection control and have frequent communication with icps, but maintain their primary role as bedside caregiver on their units. the infection control nurse liaison increases the awareness of infection control at the unit level. he or she is especially effective in implementating new policies or control interventions because of the rapport with individuals on the unit, an understanding of unit-specific challenges, and ability to promote strategies that are most likely to be successful in that unit. this position is an adjunct to, not a replacement for, fully trained icps. furthermore, the infection control liaison nurses should not be counted when considering icp staffing. there is increasing evidence that the level of bedside nurse staffing influences the quality of patient care. , adequate nursing staff makes it more likely that infection control practices, including hand hygiene, standard precautions, and transmission-based precautions, will be given appropriate attention and applied correctly and consistently. a national multicenter study reported strong and consistent inverse relationships between nurse staffing and adverse outcomes in medical patients, of which were hais (urinary tract infections and pneumonia). the association of nursing staff shortages with increased rates of hai has been demonstrated in several outbreaks in hospitals and ltcfs, and with increased transmission of hepatitis c virus in dialysis units. , , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] in most cases, when staffing was improved as part of a comprehensive control intervention, the outbreak ended or the hai rate declined. in studies, , the composition of the nursing staff (''pool'' or ''float'' vs regular staff nurses) influenced the rate of primary bloodstream infections, with an increased infection rate occurring when the proportion of regular nurses decreased and that of pool nurses increased. ii.a. .c. clinical microbiology laboratory support. the critical role of the clinical microbiology laboratory in infection control and health care epidemiology has been well described , , [ ] [ ] [ ] and is supported by the infectious disease society of america's policy statement on the consolidation of clinical microbiology laboratories published in . the clinical microbiology laboratory contributes to preventing transmission of infectious diseases in health care settings by promptly detecting and reporting epidemiologically important organisms, identifying emerging patterns of antimicrobial resistance, and assessing the effectiveness of recommended precautions to limit transmission during outbreaks. outbreaks of infections may be recognized first by laboratorians. health care organizations need to ensure the availability of the recommended scope and quality of laboratory services, a sufficient number of appropriately trained laboratory staff members, and systems to promptly communicate epidemiologically important results to those who will take action (eg, providers of clinical care, infection control staff, health care epidemiologists, and infectious disease consultants). as concerns about emerging pathogens and bioterrorism grow, the role of the clinical microbiology laboratory assumes ever-greater importance. for health care organizations that outsource microbiology laboratory services (eg, ambulatory care, home care, ltcfs, smaller acute care hospitals), it is important to specify by contract the types of services (eg, periodic institution-specific aggregate susceptibility reports) required to support infection control. several key functions of the clinical microbiology laboratory are relevant to this guideline: ii.a. . institutional safety culture and organizational characteristics. safety culture (or safety climate) refers to a work environment in which a shared commitment to safety on the part of management and the workforce is understood and maintained. , , the authors of the institute of medicine's report titled to err is human acknowledged that causes of medical error are multifaceted but emphasized the pivotal role of system failures and the benefits of a safety culture. a safety culture is created through ( ) the actions that management takes to improve patient and worker safety, ( ) worker participation in safety planning, ( ) the availability of appropriate ppe, ( ) the influence of group norms regarding acceptable safety practices, and ( ) the organization's socialization process for new personnel. safety and patient outcomes can be enhanced by improving or creating organizational characteristics within patient care units, as demonstrated by studies of surgical icus. , each of these factors has a direct bearing on adherence to transmission prevention recommendations. measurement of an institution's culture of safety is useful in designing improvements in health care. , several hospitalbased studies have linked measures of safety culture with both employee adherence to safe practices and reduced exposures to blood and body fluids. [ ] [ ] [ ] [ ] [ ] [ ] [ ] one study of hand hygiene practices concluded that improved adherence requires integration of infection control into the organization's safety culture. several hospitals that are part of the veterans administration health care system have taken specific steps toward improving the safety culture, including error-reporting mechanisms, root cause analyses of identified problems, safety incentives, and employee education. [ ] [ ] [ ] ii.a. . adherence of health care workers to recommended guidelines. hcws' adherence to recommended infection control practices decreases the transmission of infectious agents in health care settings. , , [ ] [ ] [ ] [ ] [ ] several observational studies have shown limited adherence to recommended practices by hcws. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] observed adherence to universal precautions ranged from % to %. , , , , the degree of adherence often depended on the specific practice that was assessed and, for glove use, the circumstance in which the practice was applied. observed rates of appropriate glove use has ranged from a low of % to a high of %. however, % and % adherence with glove use have been reported during arterial blood gas collection and resuscitation, respectively, procedures in which considerable blood contact may occur. , differences in observed adherence have been reported among occupational groups in the same health care facility and between experienced and nonexperienced professionals. in surveys of hcws, self-reported adherence was generally higher than actual adherence found in observational studies. furthermore, where an observational component was included with a self-reported survey, self-perceived adherence was often greater than observed adherence. among nurses and physicians, increasing years of experience is a negative predictor of adherence. , education to improve adherence is the primary intervention that has been studied. whereas positive changes in knowledge and attitude have been demonstrated, , no or only limited accompanying changes in behavior often have been found. , self-reported adherence is higher in groups that received an educational intervention. , in one study, educational interventions that incorporated videotaping and performance feedback were successful in improving adherence during the study period, but the long-term effect of such interventions is not known. the use of videotaping also served to identify system problems (eg, communication and access to ppe) that otherwise may not have been recognized. interest is growing in the use of engineering controls and facility design concepts for improving adherence. whereas the introduction of automated sinks was found to have a negative impact on consistent adherence to handwashing in one study, the use of electronic monitoring and voice prompts to remind hcws to perform hand hygiene and improving accessibility to hand hygiene products increased adherence and contributed to a decrease in hais in another study. more information is needed regarding ways in which technology might improve adherence. improving adherence to infection control practices requires a multifaceted approach that incorporates continuous assessment of both the individual and the work environment. , using several behavioral theories, kretzer and larson concluded that a single intervention (eg, a handwashing campaign or putting up new posters about transmission precautions) likely would be ineffective in improving hcws adherence. improvement requires the organizational leadership to make prevention an institutional priority and integrate infection control practices into the organization's safety culture. a recent review of the literature concluded that variations in organizational factors (eg, safety climate, policies and procedures, education and training) and individual factors (eg, knowledge, perceptions of risk, past experience) were determinants of adherence to infection control guidelines for protection against sars and other respiratory pathogens. surveillance is an essential tool for case finding of single patients or clusters of patients who are infected or colonized with epidemiologically important organisms (eg, susceptible bacteria such as s aureus, s pyogenes [group a streptococcus] or enterobacter-klebsiella spp; mrsa, vre, and other mdros; c difficile; rsv; influenza virus) for which transmission-based precautions may be required. surveillance is defined as the ongoing systematic collection, analysis, interpretation, and dissemination of data regarding a health-related event for use in public health action to reduce morbidity and mortality and to improve health. the work of ignaz semmelweis delineating the role of person-toperson transmission in puerperal sepsis is the earliest example of the use of surveillance data to reduce transmission of infectious agents. surveillance of both process measures and the infection rates to which they are linked is important in evaluating the effectiveness of infection prevention efforts and identifying indications for change. , [ ] [ ] [ ] [ ] the study on the efficacy of nosocomial infection control (senic) found that different combinations of infection control practices resulted in reduced rates of nosocomial surgical site infections, pneumonia, urinary tract infections, and bacteremia in acute care hospitals; however, surveillance was the only component essential for reducing all types of hais. although a similar study has not been conducted in other health care settings, a role for surveillance and the need for novel strategies in ltcfs , , , and in home care [ ] [ ] [ ] [ ] have been described. the essential elements of a surveillance system are ( ) standardized definitions, ( ) identification of patient populations at risk for infection, ( ) statistical analysis (eg, risk adjustment, calculation of rates using appropriate denominators, trend analysis using such methods as statistical process control charts), and ( ) feedback of results to the primary caregivers. [ ] [ ] [ ] [ ] [ ] [ ] data gathered through surveillance of high-risk populations, device use, procedures, and facility locations (eg, icus) are useful in detecting transmission trends. [ ] [ ] [ ] identification of clusters of infections should be followed by a systematic epidemiologic investigation to determine commonalities in persons, places, and time and to guide implementation of interventions and evaluation of the effectiveness of those interventions. targeted surveillance based on the highest-risk areas or patients has been preferred over facility-wide surveillance for the most effective use of resources. , however, for certain epidemiologically important organisms, surveillance may need to be facility-wide. surveillance methods will continue to evolve as health care delivery systems change , and user-friendly electronic tools for electronic tracking and trend analysis become more widely available. , , individuals with experience in health care epidemiology and infection control should be involved in selecting software packages for data aggregation and analysis, to ensure that the need for efficient and accurate hai surveillance will be met. effective surveillance is increasingly important as legislation requiring public reporting of hai rates is passed and states work to develop effective systems to support such legislation. the education and training of hcws is a prerequisite for ensuring that policies and procedures for standard and transmission-based precautions are understood and practiced. understanding the scientific rationale for the precautions will allow hcws to apply procedures correctly, as well as to safely modify precautions based on changing requirements, resources, or health care settings. , , - one study found that the likelihood of hcws developing sars was strongly associated with less than hours of infection control training and poor understanding of infection control procedures. education regarding the important role of vaccines (eg, influenza, measles, varicella, pertussis, pneumococcal) in protecting hcws, their patients, and family members can help improve vaccination rates. [ ] [ ] [ ] [ ] education on the principles and practices for preventing transmission of infectious agents should begin during training in the health professions and be provided to anyone who has an opportunity for contact with patients or medical equipment (eg, nursing and medical staff; therapists and technicians, including respiratory, physical, occupational, radiology, and cardiology personnel; phlebotomists; housekeeping and maintenance staff; and students). in health care facilities, education and training on standard and transmission-based precautions are typically provided at the time of orientation and should be repeated as necessary to maintain competency; updated education and training are necessary when policies and procedures are revised or when a special circumstance occurs, such as an outbreak that requires modification of current practice or adoption of new recommendations. education and training materials and methods appropriate to the hcw's level of responsibility, individual learning habits, and language needs can improve the learning experience. , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] education programs for hcws have been associated with sustained improvement in adherence to best practices and a related decrease in device-associated hais in teaching and nonteaching settings , and in medical and surgical icus (coopersmith, # ) . several studies have shown that in addition to targeted education to improve specific practices, periodic assessment and feedback of the hcw's knowledge and adherence to recommended practices are necessary to achieve the desired changes and identify continuing education needs. , [ ] [ ] [ ] [ ] [ ] the effectiveness of this approach for isolation practices has been demonstrated in the control of rsv. , patients, family members, and visitors can be partners in preventing transmission of infections in health care settings. , , - information on standard precautions, especially hand hygiene, respiratory hygiene/cough etiquette, vaccination (especially against influenza), and other routine infection prevention strategies, may be incorporated into patient information materials provided on admission to the health care facility. additional information on transmission-based precautions is best provided when these precautions are initiated. fact sheets, pamphlets, and other printed material may include information on the rationale for the additional precautions, risks to household members, room assignment for transmission-based precautions purposes, explanation of the use of ppe by hcws, and directions for use of such equipment by family members and visitors. such information may be particularly helpful in the home environment, where household members often have the primary responsibility for adherence to recommended infection control practices. hcws must be available and prepared to explain this material and answer questions as needed. hand hygiene has been frequently cited as the single most important practice to reduce the transmission of infectious agents in health care settings , , and is an essential element of standard precautions. the term ''hand hygiene'' includes both handwashing with either plain or antiseptic-containing soap and water and the use of alcohol-based products (gels, rinses, foams) that do not require water. in the absence of visible soiling of hands, approved alcohol-based products for hand disinfection are preferred over antimicrobial or plain soap and water because of their superior microbiocidal activity, reduced drying of the skin, and convenience. have been associated with a sustained decrease in the incidence of mrsa and vre infections primarily in icus. , , [ ] [ ] [ ] [ ] the scientific rationale, indications, methods, and products for hand hygiene have been summarized in previous publications. , the effectiveness of hand hygiene can be reduced by the type and length of fingernails. , , individuals wearing artificial nails have been shown to harbor more pathogenic organisms, especially gram-negative bacilli and yeasts, on the nails and in the subungual area compared with individuals with native nails. , in , the cdc/hicpac recommended (category ia) that artificial fingernails and extenders not be worn by hcws who have contact with high-risk patients (eg, those in icus and operating rooms), due to the association with outbreaks of gram-negative bacillus and candidal infections as confirmed by molecular typing of isolates. , , , [ ] [ ] [ ] [ ] the need to restrict the wearing of artificial fingernails by all hcws who provide direct patient care and those who have contact with other high-risk groups (eg, oncology and cystic fibrosis patients) has not been studied but has been recommended by some experts. currently, such decisions are at the discretion of an individual facility's infection control program. there is less evidence indicating that jewelry affects the quality of hand hygiene. although hand contamination with potential pathogens is increased with ring-wearing, , no studies have related this practice to hcw-to-patient transmission of pathogens. ppe refers to various barriers and respirators used alone or in combination to protect mucous membranes, airways, skin, and clothing from contact with infectious agents. the choice of ppe is based on the nature of the patient interaction and/or the likely mode(s) of transmission. specific guidance on the use of ppe is provided in part iii of this guideline. a suggested procedure for donning and removing ppe aimed at preventing skin or clothing contamination is presented in figure . designated containers for used disposable or reusable ppe should be placed in a location convenient to the site of removal, to facilitate disposal and containment of contaminated materials. hand hygiene is always the final step after removing and disposing of ppe. the following sections highlight the primary uses of and criteria for selecting this equipment. ii.e. . gloves. gloves are used to prevent contamination of hcw hands when ( ) anticipating direct contact with blood or body fluids, mucous membranes, nonintact skin and other potentially infectious material; ( ) having direct contact with patients who are colonized or infected with pathogens transmitted by the contact route (eg, vre, mrsa, rsv , , ); or ( ) handling or touching visibly or potentially contaminated patient care equipment and environmental surfaces. , , gloves can protect both patients and hcws from exposure to infectious material that may be carried on hands. the extent to which gloves will protect hcws from transmission of bloodborne pathogens (eg, hiv, hbv, hcv) after a needlestick or other puncture that penetrates the glove barrier has not yet been determined. although gloves may reduce the volume of blood on the external surface of a sharp by % to %, the residual blood in the lumen of a hollow-bore needle would not be affected; therefore, the effect on transmission risk is unknown. gloves manufactured for health care purposes are subject to fda evaluation and clearance. nonsterile disposable medical gloves made of various materials (eg, latex, vinyl, nitrile) are available for routine patient care. the selection of glove type for nonsurgical use is based on various factors, including the task to be performed, anticipated contact with chemicals and chemotherapeutic agents, latex sensitivity, sizing, and facility policies for creating a latex-free environment. , [ ] [ ] [ ] for contact with blood and body fluids during nonsurgical patient care, a single pair of gloves generally provides adequate barrier protection. however, there is considerable variability among gloves; both the quality of the manufacturing process and type of material influence their barrier effectiveness. whereas there is little difference in the barrier properties of unused intact gloves, studies have shown repeatedly that vinyl gloves have higher failure rates than latex or nitrile gloves when tested under simulated and actual clinical conditions. , [ ] [ ] [ ] [ ] for this reason, either latex or nitrile gloves are preferable for clinical procedures that require manual dexterity or will involve more than brief patient contact. a facility may need to stock gloves in several sizes. heavier, reusable utility gloves are indicated for non-patient care activities, such as handling or cleaning contaminated equipment or surfaces. , , during patient care, transmission of infectious organisms can be reduced by adhering to the principles of working from ''clean'' to ''dirty'' and confining or limiting contamination to those surfaces directly needed for patient care. it may be necessary to change gloves during the care of a single patient to prevent cross-contamination of body sites. , it also may be necessary to change gloves if the patient interaction also involves touching portable computer keyboards or other mobile equipment transported from room to room. discarding gloves between patients is necessary to prevent transmission of infectious material. gloves must not be washed for subsequent reuse, because microorganisms cannot be removed reliably from glove surfaces, and continued glove integrity cannot be ensured. furthermore, glove reuse has been associated with transmission of mrsa and gram-negative bacilli. [ ] [ ] [ ] when gloves are worn in combination with other ppe, they are put on last. gloves that fit snugly around the wrist are preferred for use with an isolation gown, because they will cover the gown cuff and provide a more reliable continuous barrier for the arms, wrists, and hands. proper glove removal will prevent hand contamination (fig ) . hand hygiene after glove removal further ensures that the hands will not carry potentially infectious material that might have penetrated through unrecognized tears or that could have contaminated the hands during glove removal. , , ii.e. . isolation gowns. isolation gowns are used as specified by standard and transmission-based precautions to protect the hcw's arms and exposed body areas and prevent contamination of clothing with blood, body fluids, and other potentially infectious material. , , , [ ] [ ] [ ] the need for and the type of isolation gown selected is based on the nature of the patient interaction, including the anticipated degree of contact with infectious material and potential for blood and body fluid penetration of the barrier. the wearing of isolation gowns and other protective apparel is mandated by the occupational safety and health administration's (osha) bloodborne pathogens standard. clinical and laboratory coats or jackets worn over personal clothing for comfort and/or purposes of identity are not considered ppe. when applying standard precautions, an isolation gown is worn only if contact with blood or body fluid is anticipated. however, when contact precautions are used (ie, to prevent transmission of an infectious agent that is not interrupted by standard precautions alone and is associated with environmental contamination), donning of both gown and gloves on room entry is indicated, to prevent unintentional contact with contaminated environmental surfaces. , , , the routine donning of isolation gowns on entry into an icu or other high-risk area does not prevent or influence potential colonization or infection of patients in those areas, however. , [ ] [ ] [ ] [ ] isolation gowns are always worn in combination with gloves, and with other ppe when indicated. gowns are usually the first piece of ppe to be donned. full coverage of the arms and body front, from neck to the mid-thigh or below, will ensure protection of clothing and exposed upper body areas. several gown sizes should be available in a health care facility to ensure appropriate coverage for staff members. isolation gowns should be removed before leaving the patient care area to prevent possible contamination of the environment outside the patient's room. isolation gowns should be removed in a manner that prevents contamination of clothing or skin (fig ) ; the outer, ''contaminated'' side of the gown is turned inward and rolled into a bundle, and then discarded into a designated container for waste or linen to contain contamination. ii.e. . face protection: masks, goggles, and face shields. ii.e. .a. masks. masks are used for primary purposes in health care settings: ( ) placed on hcws to protect them from contact with infectious material from patients (eg, respiratory secretions and sprays of blood or body fluids), consistent with standard precautions and droplet precautions; ( ) placed on hcws engaged in procedures requiring sterile technique, to protect patients from exposure to infectious agents carried in the hcw's mouth or nose; and ( ) placed on coughing patients to limit potential dissemination of infectious respiratory secretions from the patient to others (ie, respiratory hygiene/cough etiquette). masks may be used in combination with goggles to protect the mouth, nose, and eyes, or, alternatively, a face shield may be used instead of a mask and goggles to provide more complete protection for the face, as discussed below. masks should not be confused with particulate respirators used to prevent inhalation of small particles that may contain infectious agents transmitted through the airborne route, as described below. the mucous membranes of the mouth, nose, and eyes are susceptible portals of entry for infectious agents; other skin surfaces also may be portals if skin integrity is compromised (by, eg, acne, dermatitis). , [ ] [ ] [ ] [ ] therefore, use of ppe to protect these body sites is an important component of standard precautions. the protective effect of masks for exposed hcws has been demonstrated previously. , , , procedures that generate splashes or sprays of blood, body fluids, secretions, or excretions (eg, endotracheal suctioning, bronchoscopy, invasive vascular procedures) require either a face shield (disposable or reusable) or a mask and goggles. [ ] [ ] [ ] [ ] , , , , the wearing of masks, eye protection, and face shields in specified circumstances when blood or body fluid exposure is likely is mandated by osha's bloodborne pathogens standard. appropriate ppe should be selected based on the anticipated level of exposure. two mask types are available for use in health care settings: surgical masks that are cleared by the fda and required to have fluid-resistant properties, and procedure or isolation masks. ,# to date, no studies comparing mask types to determine whether one mask type provides better protection than another have been published. because procedure/isolation masks are not regulated by the fda, they may be more variable in terms of quality and performance than surgical masks. masks come in various shapes (eg, molded and nonmolded), sizes, filtration efficiency, and method of attachment (eg, ties, elastic, ear loops). health care facilities may find that different types of masks are needed to meet individual hcw needs. ii.e. .b. goggles and face shields. guidance on eye protection for infection control has been published. the eye protection chosen for specific work situations (eg, goggles or face shield) depends on the circumstances of exposure, other ppe used, and personal vision needs. personal eyeglasses and contact lenses are not considered adequate eye protection (see http://www.cdc.gov/ niosh/topics/eye/eye-infectious.html). niosh guidelines specify that eye protection must be comfortable, allow for sufficient peripheral vision, and adjustable to ensure a secure fit. a health care facility may need to provide several different types, styles, and sizes of eye protection equipment. indirectly vented goggles with a manufacturer's antifog coating may provide the most reliable practical eye protection from splashes, sprays, and respiratory droplets from multiple angles. newer styles of goggles may provide better indirect airflow properties to reduce fogging, as well as better peripheral vision and more size options for fitting goggles to different workers. many styles of goggles fit adequately over prescription glasses with minimal gaps. although effective as eye protection, goggles do not provide splash or spray protection to other parts of the face. the role of goggles in addition to a mask in preventing exposure to infectious agents transmitted through respiratory droplets has been studied only for rsv. reports published in the mid- s demonstrated that eye protection reduced occupational transmission of rsv. , whether this was due to the prevention hand-eye contact or the prevention of respiratory droplet-eye contact has not been determined. however, subsequent studies demonstrated that rsv transmission is effectively prevented by adherence to standard precautions plus contact precautions and that routine use of goggles is not necessary for this virus. , , , , it is important to remind hcws that even if droplet precautions are not recommended for a specific respiratory tract pathogen, protection for the eyes, nose, and mouth using a mask and goggles or a face shield alone is necessary when a splash or spray of any respiratory secretions or other body fluids is likely to occur, as defined in standard precautions. disposable or nondisposable face shields may be used as an alternative to goggles. compared with goggles, a face shield can provide protection to other facial areas besides the eyes. face shields extending from the chin to crown provide better face and eye protection from splashes and sprays; face shields that wrap around the sides may reduce splashes around the edge of the shield. removal of a face shield, goggles, and mask can be performed safely after gloves have been removed and hand hygiene performed. the ties, earpieces, and/or headband used to secure the equipment to the head are considered ''clean'' and thus safe to touch with bare hands. the front of a mask, goggles, and face shield are considered contaminated (fig ) . ii.e. . respiratory protection. the subject of respiratory protection as it applies to preventing transmission of airborne infectious agents, including the need for and frequency of fit testing is under scientific review and was the subject of a cdc workshop. respiratory protection currently requires the use of a respirator with n or higher-level filtration to prevent inhalation of infectious particles. information about respirators and respiratory protection programs is summarized in the guideline for preventing transmission of mycobacterium tuberculosis in health care settings. respiratory protection is broadly regulated by osha under the general industry standard for respiratory protection ( cfr . ), which requires that us employers in all employment settings implement a program to protect employees from inhalation of toxic materials. osha program components include medical clearance to wear a respirator; provision and use of appropriate respirators, including fit-tested niosh-certified n and higher-level particulate filtering respirators; education on respirator use, and periodic reevaluation of the respiratory protection program. when selecting particulate respirators, models with inherently good fit characteristics (ie, those expected to provide protection factors of $ % to % of wearers) are preferred and theoretically could preclude the need for fit testing. , issues pertaining to respiratory protection remain the subject of ongoing debate. information on various types of respirators is available at http://www.cdc.gov/niosh/ npptl/respirators/respsars.html and in several previously published studies. , , a user-seal check (formerly called a ''fit check'') should be performed by the wearer of a respirator each time that the respirator is donned, to minimize air leakage around the face piece. the optimal frequency of fit testing has not been determined; retesting may be indicated if there is a change in wearer's facial features, onset of a medical condition that would affect respiratory function in the wearer, or a change in the model or size of the respirator that was initially assigned. respiratory protection was first recommended for protection of us hcws from exposure to m tuberculosis in . that recommendation has been maintained in successive revisions of the guidelines for prevention of transmission of tuberculosis in hospitals and other health care settings. , the incremental benefit from respirator use, in addition to administrative and engineering controls (ie, aiirs, early recognition of patients likely to have tuberculosis and prompt placement in an aiir, and maintenance of a patient with suspected tuberculosis in an aiir until no longer infectious), for preventing transmission of airborne infectious agents (eg, m tuberculosis) remains undetermined. although some studies have demonstrated effective prevention of m tuberculosis transmission in hospitals in which surgical masks instead of respirators were used in conjunction with other administrative and engineering controls. , , the cdc currently recommends n or higher-level respirators for personnel exposed to patients with suspected or confirmed tuberculosis. currently, this recommendation also holds for other diseases that could be transmitted through the airborne route, including sars and smallpox, , , until inhalational transmission is better defined or health care-specific ppe more suitable for preventing infection is developed. wearing of respirators is also currently recommended during the performance of aerosol-generating procedures (eg, intubation, bronchoscopy, suctioning) in patients with sars-cov infection, avian influenza, and pandemic influenza (see appendix a). although airborne precautions are recommended for preventing airborne transmission of measles and varicella-zoster viruses, no data are available on which to base a recommendation for respiratory protection to protect susceptible personnel against these infections. transmission of varicella-zoster virus has been prevented among pediatric patients using negativepressure isolation alone. whether respiratory protection (ie, wearing a particulate respirator) will enhance protection from these viruses has not yet been studied. because most hcws have natural or acquired immunity to these viruses, only immune personnel generally care for patients with these infections. [ ] [ ] [ ] [ ] although there is no evidence suggesting that masks are not adequate to protect hcws in these settings, for purposes of consistency and simplicity, or because of difficulties in ascertaining immunity, some facilities may require the use of respirators for entry into all aiirs, regardless of the specific infectious agent present. procedures for safe removal of respirators are provided in figure . in some health care settings, particulate respirators used to provide care for patients with m tuberculosis are reused by the same hcw. this is an acceptable practice providing that the respirator is not damaged or soiled, the fit is not compromised by a change in shape, and the respirator has not been contaminated with blood or body fluids. no data are available on which to base a recommendation regarding the length of time that a respirator may be safely reused. sharps-related injuries. injuries due to needles and other sharps have been associated with transmission of hbv, hcv, and hiv to hcws. , the prevention of sharps injuries has always been an essential element of universal precautions and is now an aspect of standard precautions. , these include measures to handle needles and other sharp devices in a manner that will prevent injury to the user and to others who may encounter the device during or after a procedure. these measures apply to routine patient care and do not address the prevention of sharps injuries and other blood exposures during surgical and other invasive procedures addressed elsewhere. [ ] [ ] [ ] [ ] [ ] since , when osha first issued its bloodborne pathogens standard to protect hcws from blood exposure, the focus of regulatory and legislative activity has been on implementing a hierarchy of control measures. this has included focusing attention on removing sharps hazards through the development and use of engineering controls. the federal needlestick safety and prevention act, signed into law in november , authorized osha's revision of its bloodborne pathogens standard to more explicitly require the use of safety-engineered sharps devices. the cdc has provided guidance on sharps injury prevention, , including guidelines for the design, implementation and evaluation of a comprehensive sharps injury prevention program. ii.f. . prevention of mucous membrane contact. exposure of mucous membranes of the eyes, nose, and mouth to blood and body fluids has been associated with the transmission of bloodborne viruses and other infectious agents to hcws. , , , the prevention of mucous membrane exposures has always been an element of universal precautions and is now an element of standard precautions for routine patient care , and is subject to osha bloodborne pathogen regulations. safe work practices, in addition to wearing ppe, are designed to protect mucous membranes and nonintact skin from contact with potentially infectious material. these include keeping contaminated gloved and ungloved hands from touching the mouth, nose, eyes, or face and positioning patients to direct sprays and splatter away from the caregiver's face. careful placement of ppe before patient contact will help avoid the need to make adjustments to ppe and prevent possible face or mucous membrane contamination during use. in areas where the need for resuscitation is unpredictable, mouthpieces, pocket resuscitation masks with -way valves, and other ventilation devices provide an alternative to mouth-to-mouth resuscitation, preventing exposure of the caregiver's nose and mouth to oral and respiratory fluids during the procedure. ii.f. .a. precautions during aerosol-generating procedures. the performance of procedures that can generate small-particle aerosols (aerosol-generating procedures), such as bronchoscopy, endotracheal intubation, and open suctioning of the respiratory tract, have been associated with transmission of infectious agents to hcws, including m tuberculosis, sars-cov, , , and n meningitidis. protection of the eyes, nose, and mouth, in addition to gown and gloves, is recommended during performance of these procedures in accordance with standard precautions. the use of a particulate respirator is recommended during aerosol-generating procedures when the aerosol is likely to contain m tuberculosis, sars-cov, or avian or pandemic influenza viruses. ii.g. . hospitals and long-term care facilities. options for patient placement include single-patient rooms, -patient rooms, and multibed wards. of these, single-patient rooms are preferred when transmission of an infectious agent is of concern. although some studies have failed to demonstrate the efficacy of single-patient rooms in preventing hais, other published studies, including one commissioned by the aia and the facility guidelines institute, have documented a beneficial relationship between private rooms and reduced infectious and noninfectious adverse patient outcomes. , the aia notes that private rooms are the trend in hospital planning and design. however, most hospitals and ltcfs have multibed rooms and must consider many competing priorities when determining the appropriate room placement for patients (eg, reason for admission; patient characteristics, such as age, gender, and mental status; staffing needs; family requests; psychosocial factors; reimbursement concerns). in the absence of obvious infectious diseases that require specified airborne infection isolation rooms (eg, tuberculosis, sars, chickenpox), the risk of transmission of infectious agents is not always considered when making placement decisions. when only a limited number of single-patient rooms is available, it is prudent to prioritize room assignments for those patients with conditions that facilitate transmission of infectious material to other patients (eg, draining wounds, stool incontinence, uncontained secretions) and those at increased risk of acquisition and adverse outcomes resulting from hais (due to, eg, immunosuppression, open wounds, indwelling catheters, anticipated prolonged length of stay, total dependence on hcws for activities of daily living). , , , , , single-patient rooms are always indicated for patients placed on airborne precautions in a pe and are preferred for patients requiring contact or droplet precautions. , , , , , during a suspected or proven outbreak caused by a pathogen whose reservoir is the gastrointestinal tract, the use of single-patient rooms with private bathrooms limits opportunities for transmission, especially when the colonized or infected patient has poor personal hygiene habits or fecal incontinence, or cannot be expected to assist in maintaining procedures that prevent transmission of microorganisms (eg, infants, children, and patients with altered mental status or developmental delay). in the absence of continued transmission, it is not necessary to provide a private bathroom for patients colonized or infected with enteric pathogens as long as personal hygiene practices and standard precautions (especially hand hygiene and appropriate environmental cleaning) are maintained. assignment of a dedicated commode to a patient, and cleaning and disinfecting fixtures and equipment that may have fecal contamination (eg, bathrooms, commodes, scales used for weighing diapers) and the adjacent surfaces with appropriate agents may be especially important when a single-patient room cannot be assigned, because environmental contamination with intestinal tract pathogens is likely from both continent and incontinent patients. , the results of several studies that investigated the benefit of a single-patient room in preventing transmission of c difficile were inconclusive. , [ ] [ ] [ ] some studies have shown that being in the same room with a colonized or infected patient is not necessarily a risk factor for transmission; , - however, for children, the risk of health care-associated diarrhea is increased with the increased number of patients per room. these findings demonstrate that patient factors are important determinants of infection transmission risks. the need for a single-patient room and/or private bathroom for any patient is best determined on a case-by-case basis. cohorting is the practice of grouping together patients who are colonized or infected with the same organism to confine their care to a single area and prevent contact with other patients. cohorts are created based on clinical diagnosis, microbiologic confirmation (when available), epidemiology, and mode of transmission of the infectious agent. avoiding placing severely immunosuppressed patients in rooms with other patients is generally preferred. cohorting has been extensively used for managing outbreaks of mdros, including mrsa, rotavirus, and sars. modeling studies provide additional support for cohorting patients to control outbreaks; - however, cohorting often is implemented only after routine infection control measures have failed to control an outbreak. assigning or cohorting hcws to care only for patients infected or colonized with a single target pathogen limits further transmission of the target pathogen to uninfected patients, , but is difficult to achieve in the face of current staffing shortages in hospitals and residential health care sites. [ ] [ ] [ ] however, cohorting of hcws may be beneficial when transmission continues after implementing routine infection control measures and creating patient cohorts. during periods when rsv, human metapneumovirus, parainfluenza, influenza, other respiratory viruses, and rotavirus are circulating in the community, cohorting based on the presenting clinical syndrome is often a priority in facilities that care for infants and young children. for example, during the respiratory virus season, infants may be cohorted based solely on the clinical diagnosis of bronchiolitis, due to the logistical difficulties and costs associated with requiring microbiologic confirmation before room placement and the predominance of rsv during most of the season. however, when available, single-patient rooms are always preferred, because a common clinical presentation (eg, bronchiolitis), can be caused by more than infectious agent. , , furthermore, the inability of infants and children to contain body fluids, and the close physical contact associated with their care, increases the risk of infection transmission for patients and personnel in this setting. , ii.g. . ambulatory care settings. patients actively infected with or incubating transmissible infectious diseases are frequently seen in ambulatory settings (eg, outpatient clinics, physicians' offices, emergency departments) and potentially expose hcws and other patients, family members, and visitors. , , , , , in response to the global outbreak of sars in and in preparation for pandemic influenza, hcws working in outpatient settings are urged to implement source containment measures (eg, asking coughing patients to wear a surgical mask or cover coughing with tissues) to prevent transmission of respiratory infections, beginning at the initial patient encounter, , , as described in section iii.a. .a. signs can be posted at the facility's entrance or at the reception or registration desk requesting that the patient or individuals accompanying the patient promptly inform the receptionist of any symptoms of respiratory infection (eg, cough, flulike illness, increased production of respiratory secretions). the presence of diarrhea, skin rash, or known or suspected exposure to a transmissible disease (eg, measles, pertussis, chickenpox, tuberculosis) also could be added. prompt placement of a potentially infectious patient in an examination room limits the number of exposed individuals in the common waiting area. in waiting areas, maintaining a distance between symptomatic and nonsymptomatic patients (eg, . feet), in addition to source control measures, may limit exposures. however, infections transmitted through the airborne route (eg, m tuberculosis, measles, chickenpox) require additional precautions. , , patients suspected of having such an infection can wear a surgical mask for source containment, if tolerated, and should be placed in an examination room (preferably an aiir) as soon as possible. if this is not possible, then having the patient wear a mask and segregating the patient from other patients in the waiting area will reduce the risk of exposing others. because the person(s) accompanying the patient also may be infectious, application of the same infection control precautions may be extended to these persons if they are symptomatic. , , family members accompanying children admitted with suspected m tuberculosis have been found to have unsuspected pulmonary tuberculosis with cavitary lesions, even when asymptomatic. , patients with underlying conditions that increase their susceptibility to infection (eg, immunocompromised status , or cystic fibrosis ) require special efforts to protect them from exposure to infected patients in common waiting areas. informing the receptionist of their infection risk on arrival allows appropriate steps to further protect these patients from infection. in some cystic fibrosis clinics, to avoid exposure to other patients who could be colonized with b cepacia, patients have been given beepers on registration so that they may leave the area and receive notification to return when an examination room becomes available. ii.g. . home care. in home care, patient placement concerns focus on protecting others in the home from exposure to an infectious household member. for individuals who are especially vulnerable to adverse outcomes associated with certain infections, it may be beneficial to either remove them from the home or segregate them within the home. persons who are not part of the household may need to be prohibited from visiting during the period of infectivity. for example, in a situation where a patient with pulmonary tuberculosis is contagious and being cared for at home, very young children (age under years) and immunocompromised persons who have not yet been infected should be removed or excluded from the household. during the sars outbreak of , segregation of infected persons during the communicable phase of the illness was found to be beneficial in preventing household transmission. , several principles guide the transport of patients requiring transmission-based precautions. in the inpatient and residential settings, these include the following: . limiting transport of such patients to essential purposes, such as diagnostic and therapeutic procedures that cannot be performed in the patient's room. . when transport is necessary, applying appropriate barriers on the patient (eg, mask, gown, wrapping in sheets or use of impervious dressings to cover the affected areas) when infectious skin lesions or drainage are present, consistent with the route and risk of transmission. . notifying hcws in the receiving area of the patient's impending arrival and of the necessary precautions to prevent transmission. . for patients being transported outside the facility, informing the receiving facility and the medi-van or emergency vehicle personnel in advance about the type of transmission-based precautions being used. for tuberculosis, additional precautions may be needed in a small shared air space, such as in an ambulance. cleaning and disinfecting noncritical surfaces in patient care areas is an aspect of standard precautions. in general, these procedures do not need to be changed for patients on transmission-based precautions. the cleaning and disinfection of all patient care areas is important for frequently touched surfaces, especially those closest to the patient, which are most likely to be contaminated (eg, bedrails, bedside tables, commodes, doorknobs, sinks, surfaces and equipment in close proximity to the patient). , , , the frequency or intensity of cleaning may need to be changed, based on the patient's level of hygiene and the degree of environmental contamination and for certain infectious agents with reservoirs in the intestinal tract. this may be particularly important in ltcfs and pediatric facilities, where patients with stool and urine incontinence are encountered more frequently. in addition, increased frequency of cleaning may be needed in a pe to minimize dust accumulation. special recommendations for cleaning and disinfecting environmental surfaces in dialysis centers have been published previously. in all health care settings, administrative, staffing, and scheduling activities should prioritize the proper cleaning and disinfection of surfaces that could be implicated in transmission. during a suspected or proven outbreak in which an environmental reservoir is suspected, routine cleaning procedures should be reviewed, and the need for additional trained cleaning staff should be assessed. adherence should be monitored and reinforced to promote consistent and correct cleaning. us environmental protection agency-registered disinfectants or detergents/disinfectants that best meet the overall needs of the health care facility for routine cleaning and disinfection should be selected. , in general, use of the existing facility detergent/disinfectant according to the manufacturer's recommendations for amount, dilution, and contact time is sufficient to remove pathogens from surfaces of rooms where colonized or infected individuals were housed. this includes those pathogens that are resistant to multiple classes of antimicrobial agents (eg, c difficile, vre, mrsa, mdr-gnb , , , , , , ). most often, environmental reservoirs of pathogens during outbreaks are related to a failure to follow recommended procedures for cleaning and disinfection, rather than to the specific cleaning and disinfectant agents used. [ ] [ ] [ ] [ ] certain pathogens (eg, rotavirus, noroviruses, c difficile) may be resistant to some routinely used hospital disinfectants. , , [ ] [ ] [ ] [ ] [ ] [ ] the role of specific disinfectants in limiting transmission of rotavirus has been demonstrated experimentally. also, because c difficile may display increased levels of spore production when exposed to non-chlorine-based cleaning agents, and because these spores are more resistant than vegetative cells to commonly used surface disinfectants, some investigators have recommended the use of a : dilution of . % sodium hypochlorite (household bleach) and water for routine environmental disinfection of rooms of patients with c difficile when there is continued transmission. , one study found an association between the use of a hypochlorite solution and decreased rates of c difficile infections. the need to change disinfectants based on the presence of these organisms can be determined in consultation with the infection control committee. , , detailed recommendations for disinfection and sterilization of surfaces and medical equipment that have been in contact with prion-containing tissue or high risk body fluids, and for cleaning of blood and body substance spills, are available in the guidelines for environmental infection control in health care facilities and in the guideline for disinfection and sterilization. medical equipment and instruments/devices must be cleaned and maintained according to the manufacturers' instructions to prevent patient-to-patient transmission of infectious agents. , , , cleaning to remove organic material always must precede highlevel disinfection and sterilization of critical and semicritical instruments and devices, because residual proteinacous material reduces the effectiveness of the disinfection and sterilization processes. , noncritical equipment, such as commodes, intravenous pumps, and ventilators, must be thoroughly cleaned and disinfected before being used on another patient. all such equipment and devices should be handled in a manner that will prevent hcw and environmental contact with potentially infectious material. it is important to include computers and personal digital assistants used in patient care in policies for cleaning and disinfection of noncritical items. the literature on contamination of computers with pathogens has been summarized, and reports have linked computer contamination to colonization and infections in patients. , although keyboard covers and washable keyboards that can be easily disinfected are available, the infection control benefit of these items and their optimal management have not yet been determined. in all health care settings, providing patients who are on transmission-based precautions with dedicated noncritical medical equipment (eg, stethoscope, blood pressure cuff, electronic thermometer) has proven beneficial for preventing transmission. , , , , when this is not possible, disinfection of this equipment after each use is recommended. other previously published guidelines should be consulted for detailed guidance in developing specific protocols for cleaning and reprocessing medical equipment and patient care items in both routine and special circumstances. , , , , , , in home care, it is preferable to remove visible blood or body fluids from durable medical equipment before it leaves the home. equipment can be cleaned onsite using a detergent/disinfectant and, when possible, should be placed in a plastic bag for transport to the reprocessing location. , although soiled textiles, including bedding, towels, and patient or resident clothing, may be contaminated with pathogenic microorganisms, the risk of disease transmission is negligible if these textiles are handled, transported, and laundered in a safe manner. , , key principles for handling soiled laundry are ( ) avoiding shaking the items or handling them in any way that may aerosolize infectious agents, ( ) avoiding contact of one's body and personal clothing with the soiled items being handled, and ( ) containing soiled items in a laundry bag or designated bin. if a laundry chute is used, it must be maintained to minimize dispersion of aerosols from contaminated items. methods of handling, transporting, and laundering soiled textiles are determined by organizational policy and any applicable regulations; guidance is provided in the guidelines for environmental infection control in health care facilities. rather than rigid rules and regulations, hygienic and common sense storage and processing of clean textiles is recommended. , when laundering is done outside of a health care facility, the clean items must be packaged or completely covered and placed in an enclosed space during transport to prevent contamination with outside air or construction dust that could contain infectious fungal spores that pose a risk for immunocompromised patients. institutions are required to launder garments used as ppe and uniforms visibly soiled with blood or infective material. little data exist on the safety of home laundering of hcw uniforms, but no increase in infection rates was observed in the one published study, and no pathogens were recovered from home-or hospital-laundered scrubs in another study. in the home, textiles and laundry from patients with potentially transmissible infectious pathogens do not require special handling or separate laundering and may be washed with warm water and detergent. , , the management of solid waste emanating from the health care environment is subject to federal and state regulations for medical and nonmedical waste. , no additional precautions are needed for nonmedical solid waste removed from rooms of patients on transmission-based precautions. solid waste may be contained in a single bag of sufficient strength. the combination of hot water and detergents used in dishwashers is sufficient to decontaminate dishware and eating utensils. therefore, no special precautions are needed for dishware (eg, dishes, glasses, cups) or eating utensils. reusable dishware and utensils may be used for patients requiring transmission-based precautions. in the home and other communal settings, eating utensils and drinking vessels should not be shared, consistent with principles of good personal hygiene and to help prevent transmission of respiratory viruses, herpes simplex virus, and infectious agents that infect the gastrointestinal tract and are transmitted by the fecal/oral route (eg, hepatitis a virus, noroviruses). if adequate resources for cleaning utensils and dishes are not available, then disposable products may be used. important adjunctive measures that are not considered primary components of programs to prevent transmission of infectious agents but nonetheless improve the effectiveness of such programs include ( ) antimicrobial management programs, ( ) postexposure chemoprophylaxis with antiviral or antibacterial agents, ( ) vaccines used both for pre-exposure and postexposure prevention, and ( ) screening and restricting visitors with signs of transmissible infections. detailed discussion of judicious use of antimicrobial agents is beyond the scope of this document; however, this topic has been addressed in a previous cdc guideline (http://www.cdc.gov/ncidod/dhqp/pdf/ar/ mdroguideline .pdf). ii.n. . chemoprophylaxis. antimicrobial agents and topical antiseptics may be used to prevent infection and potential outbreaks of selected agents. infections for which postexposure chemoprophylaxis is recommended under defined conditions include b pertussis, , n meningitides, b anthracis after environmental exposure to aeosolizable material, influenza virus, hiv, and group a streptococcus. orally administered antimicrobials also may be used under defined circumstances for mrsa decolonization of patients or hcws. another form of chemoprophylaxis involves the use of topical antiseptic agents. for example, triple dye is routinely used on the umbilical cords of term newborns to reduce the risk of colonization, skin infections, and omphalitis caused by s aureus, including mrsa, and group a streptococcus. , extension of the use of triple dye to low birth weight infants in a nicu was one component of a program that controlled a long-standing mrsa outbreak. topical antiseptics (eg, mupirocin) also are used for decolonization of hcws or selected patients colonized with mrsa, as discussed in the mdro guideline , [ ] [ ] [ ] [ ] ii.n. . immunoprophylaxis. certain immunizations recommended for susceptible hcws have decreased the risk of infection and the potential for transmission in health care facilities. , the osha mandate requiring employers to offer hbv vaccination to hcws has played a substantial role in the sharp decline in incidence of occupational hbv infection. , the routine administration of varicella vaccine to hcws has decreased the need to place susceptible hcws on administrative leave after exposure to patients with varicella. in addition, reports of health care-associated transmission of rubella in obstetric clinics , and measles in acute care settings demonstrate the importance of immunization of susceptible hcws against childhood diseases. many states have requirements for vaccination of hcws for measles and rubella in the absence of evidence of immunity. annual influenza vaccine campaigns targeted at patients and hcws in ltcfs and acute care settings have been instrumental in preventing or limiting institutional outbreaks; consequently, increasing attention is being directed toward improving influenza vaccination rates in hcws. , , , [ ] [ ] [ ] transmission of b pertussis in health care facilities has been associated with large and costly outbreaks that include both hcws and patients. , , , , , , , hcws in close contact with infants with pertussis are at particularly high risk because of waning immunity and, until , the absence of a vaccine appropriate for adults. but acellular pertussis vaccines were licensed in the united states in , for use in individuals age to years and the other for use in those age to years. current advisory committee on immunization practices provisional recommendations include immunization of adolescents and adults, especially those in contact with infants under age months and hcws with direct patient contact. , immunization of children and adults will help prevent the introduction of vaccine-preventable diseases into health care settings. the recommended immunization schedule for children is published annually in the january issues of the morbidity and mortality weekly report, with interim updates as needed. , an adult immunization schedule also is available for healthy adults and those with special immunization needs due to high-risk medical conditions. some vaccines are also used for postexposure prophylaxis of susceptible individuals, including varicella, influenza, hepatitis b, and smallpox vaccines. , in the future, administration of a newly developed s aureus conjugate vaccine (still under investigation) to selected patients may provide a novel method of preventing health care-associated s aureus (including mrsa) infections in high-risk groups (eg, hemodialysis patients and candidates for selected surgical procedures). , immune globulin preparations also are used for postexposure prophylaxis of certain infectious agents under specified circumstances (eg, varicella-zoster virus, hbv, rabies, measles and hepatitis a virus , , ). the rsv monoclonal antibody preparation palivizumab may have contributed to controlling a nosocomial outbreak of rsv in one nicu, but there is insufficient evidence to support a routine recommendation for its use in this setting. ii.n. , , , and sars , [ ] [ ] [ ] . effective methods for visitor screening in health care settings have not yet been studied, however. visitor screening is especially important during community outbreaks of infectious diseases and for high-risk patient units. sibling visits are often encouraged in birthing centers, postpartum rooms, pediatric inpatient units, picus, and residential settings for children; in hospital settings, a child visitor should visit only his or her own sibling. screening of visiting siblings and other children before they are allowed into clinical areas is necessary to prevent the introduction of childhood illnesses and common respiratory infections. screening may be passive, through the use of signs to alert family members and visitors with signs and symptoms of communicable diseases not to enter clinical areas. more active screening may include the completion of a screening tool or questionnaire to elicit information related to recent exposures or current symptoms. this information is reviewed by the facility staff, after which the visitor is either permitted to visit or is excluded. family and household members visiting pediatric patients with pertussis and tuberculosis may need to be screened for a history of exposure, as well as signs and symptoms of current infection. potentially infectious visitors are excluded until they receive appropriate medical screening, diagnosis, or treatment. if exclusion is not considered to be in the best interest of the patient or family (ie, primary family members of critically or terminally ill patients), then the symptomatic visitor must wear a mask while in the health care facility and remain in the patient's room, avoiding exposure to others, especially in public waiting areas and the cafeteria. visitor screening is used consistently on hsct units. , however, considering the experience during the sars outbreaks and the potential for pandemic influenza, developing effective visitor screening systems will be beneficial. education concerning respiratory hygiene/cough etiquette is a useful adjunct to visitor screening. ii.n. .b. use of barrier precautions by visitors. the use of gowns, gloves, and masks by visitors in health care settings has not been addressed specifically in the scientific literature. some studies included the use of gowns and gloves by visitors in the control of mdros but did not perform a separate analysis to determine whether their use by visitors had a measurable impact. [ ] [ ] [ ] family members or visitors who are providing care to or otherwise are in very close contact with the patient (eg, feeding, holding) may also have contact with other patients and could contribute to transmission in the absence of effective barrier precautions. specific recommendations may vary by facility or by unit and should be determined by the specific level of interaction. there are tiers of hicpac/cdc precautions to prevent transmission of infectious agents, standard precautions and transmission-based precautions. standard precautions are intended to be applied to the care of all patients in all health care settings, regardless of the suspected or confirmed presence of an infectious agent. implementation of standard precautions constitutes the primary strategy for the prevention of health care-associated transmission of infectious agents among patients and hcws. transmission-based precautions are for patients who are known or suspected to be infected or colonized with infectious agents, including certain epidemiologically important pathogens, which require additional control measures to effectively prevent transmission. because the infecting agent often is not known at the time of admission to a health care facility, transmission-based precautions are used empirically, according to the clinical syndrome and the likely etiologic agents at the time, and then modified when the pathogen is identified or a transmissible infectious etiology is ruled out. examples of this syndromic approach are presented in table . the hicpac/cdc guidelines also include recommendations for creating a protective environment for allogeneic hsct patients. the specific elements of standard and transmission-based precautions are discussed in part ii of this guideline. in part iii, the circumstances in which standard precautions, transmission-based precautions, and a protective environment are applied are discussed. tables and summarize the key elements of these sets of precautions standard precautions combine the major features of universal precautions , and body substance isolation and are based on the principle that all blood, body fluids, secretions, excretions except sweat, nonintact skin, and mucous membranes may contain transmissible infectious agents. standard precautions include a group of infection prevention practices that apply to all patients, regardless of suspected or confirmed infection status, in any setting in which health care is delivered (table ). these include hand hygiene; use of gloves, gown, mask, eye protection, or face shield, depending on the anticipated exposure; and safe injection practices. also, equipment or items in the patient environment likely to have been contaminated with infectious body fluids must be handled in a manner to prevent transmission of infectious agents (eg, wear gloves for direct contact, contain heavily soiled equipment, properly clean and disinfect or sterilize reusable equipment before use on another patient). the application of standard precautions during patient care is determined by the nature of the hcw-patient interaction and the extent of anticipated blood, body fluid, or pathogen exposure. for some interactions (eg, performing venipuncture), only gloves may be needed; during other interactions (eg, intubation), use of gloves, gown, and face shield or mask and goggles is necessary. education and training on the principles and rationale for recommended practices are critical elements of standard precautions because they facilitate appropriate decision-making and promote adherence when hcws are faced with new circumstances. , [ ] [ ] [ ] [ ] [ ] [ ] an example of the importance of the use of standard precautions is intubation, especially under emergency circumstances when infectious agents may not be suspected, but later are identified (eg, sars-cov, n meningitides). the application of standard precautions is described below and summarized in table . guidance on donning and removing gloves, gowns and other ppe is presented in figure . standard precautions are also intended to protect patients by ensuring that hcws do not carry infectious agents to patients on their hands or via equipment used during patient care. , , the strategy proposed has been termed respiratory hygiene/cough etiquette , and is intended to be incorporated into infection control practices as a new component of standard precautions. the strategy is targeted at patients and accompanying family members and friends with undiagnosed transmissible respiratory infections, and applies to any person with signs of illness including cough, congestion, rhinorrhea, or increased production of respiratory secretions when entering a health care facility. , , the term cough etiquette is derived from recommended source control measures for m tuberculosis. , the elements of respiratory hygiene/cough etiquette include ( ) education of health care facility staff, patients, and visitors; ( ) posted signs, in language(s) appropriate to the population served, with instructions to patients and accompanying family members or friends; ( ) source control measures (eg, covering the mouth/nose with a tissue when coughing and prompt disposal of used tissues, using surgical masks on the coughing person when tolerated and appropriate); ( ) hand hygiene after contact with respiratory secretions; and ( ) spatial separation, ideally . feet, of persons with respiratory infections in common waiting areas when possible. covering sneezes and coughs and placing masks on coughing patients are proven means of source containment that prevent infected persons from dispersing respiratory secretions into the air. , , , masking may be difficult in some settings, (eg, pediatrics), in which case the emphasis by necessity may be on cough etiquette. physical proximity of , feet has been associated with an increased risk for transmission of infections through the droplet route (eg, n meningitidis and group a streptococcus ) and thus supports the practice of distancing infected persons from others who are not infected. the effectiveness of good hygiene practices, especially hand hygiene, in preventing transmission of viruses and reducing the incidence of respiratory infections both within and outside [ ] [ ] [ ] health care settings is summarized in several reviews. , , these measures should be effective in decreasing the risk of transmission of pathogens contained in large respiratory droplets (eg, influenza virus, adenovirus, b pertussis, and m pneumoniae ). although fever will be present in many respiratory infections, patients with pertussis and mild upper respiratory tract infections are often afebrile. therefore, the absence of fever does not always exclude a respiratory infection. patients who have asthma, allergic rhinitis, or chronic obstructive lung disease also may be coughing and sneezing. although these patients often are not infectious, cough etiquette measures are prudent. hcws are advised to observe droplet precautions (ie, wear a mask) and hand hygiene when examining and caring for patients with signs and symptoms of a respiratory infection. hcws who have a respiratory infection are advised to avoid direct patient contact, especially with high-risk patients. if this is not possible, then a mask should be worn while providing patient care. iii.a. .b. safe injection practices. the investigation of large outbreaks of hbv and hcv among patients in ambulatory care facilities in the united states identified a need to define and reinforce safe injection practices. the outbreaks occurred in a private medical practice, a pain clinic, an endoscopy clinic, and a hematology/oncology clinic. the primary breaches in infection control practice that contributed to these outbreaks were reinsertion of used needles into a multiple-dose vial or solution container (eg, saline bag) and use of a single needle/syringe to administer intravenous medication to multiple patients. in of these outbreaks, preparation of medications in the same workspace where used needle/syringes were dismantled also may have been a contributing factor. these and other outbreaks of viral hepatitis could have been prevented by adherence to basic principles of aseptic technique for the preparation and administration of parenteral medications. , these include the use of a sterile, single-use, disposable needle and syringe for each injection given and prevention of contamination of injection equipment and medication. whenever possible, use of single-dose vials is preferred over multiple-dose vials, especially when medications will be administered to multiple patients. outbreaks related to unsafe injection practices indicate that some hcws are unaware of, do not understand, or do not adhere to basic principles of infection control and aseptic technique. a survey of us health care workers who provide medication through injection found that % to % reused the same needle and/or syringe on multiple patients. among the deficiencies identified in recent outbreaks were a lack of oversight of personnel and failure to follow up on reported breaches in infection control practices in ambulatory settings. therefore, to ensure that all hcws understand and adhere to recommended practices, principles of infection control and aseptic technique need to be reinforced in training programs and incorporated into institutional polices that are monitored for adherence. iii.a. .c. infection control practices for special lumbar puncture procedures. in , the cdc investigated cases of postmyelography meningitis that either were reported to the cdc or identified through a survey of the emerging infections network of the infectious disease society of america. blood and/or cerebrospinal fluid of all cases yielded streptococcal species consistent with oropharyngeal flora and there were changes in the csf indices and clinical status indicative of bacterial meningitis. equipment and products used during these procedures (eg, contrast media) were excluded as probable sources of contamination. procedural details available for cases determined that antiseptic skin preparations and sterile gloves had been used. however, none of the clinicians wore a face mask, giving rise to the speculation that droplet transmission of oralpharyngeal flora was the most likely explanation for these infections. bacterial meningitis after myelography and other spinal procedures (eg, lumbar puncture, spinal and epidural anesthesia, intrathecal chemotherapy) has been reported previously. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] as a result, the question of whether face masks should be worn to prevent droplet spread of oral flora during spinal procedures (eg, myelography, lumbar puncture, spinal anesthesia) has been debated. , face masks are effective in limiting the dispersal of oropharyngeal droplets and are recommended for the placement of central venous catheters. in october , hicpac reviewed the evidence and concluded that there is sufficient experience to warrant the additional protection of a face mask for the individual placing a catheter or injecting material into the spinal or epidural space. there are categories of transmission-based precautions: contact precautions, droplet precautions, and airborne precautions. transmission-based precautions are used when the route(s) of transmission is (are) not completely interrupted using standard precautions alone. for some diseases that have multiple routes of transmission (eg, sars), more than transmission-based precautions category may be used. when used either singly or in combination, they are always used in addition to standard precautions. see appendix a for recommended precautions for specific infections. when transmission-based precautions are indicated, efforts must be made to counteract possible adverse effects on patients (ie, anxiety, depression and other mood disturbances, - perceptions of stigma, reduced contact with clinical staff, [ ] [ ] [ ] and increases in preventable adverse events ) to improve acceptance by the patients and adherence by hcws. iii.b. . contact precautions. contact precautions are intended to prevent transmission of infectious agents, including epidemiologically important microorganisms, which are spread by direct or indirect contact with the patient or the patient's environment as described in section i.b. .a. the specific agents and circumstance for which contact precautions are indicated are found in appendix a. the application of contact precautions for patients infected or colonized with mdros is described in the hicpac/cdc mdro guideline. contact precautions also apply where the presence of excessive wound drainage, fecal incontinence, or other discharges from the body suggest an increased potential for extensive environmental contamination and risk of transmission. a single-patient room is preferred for patients who require contact precautions. when a single-patient room is not available, consultation with infection control personnel is recommended to assess the various risks associated with other patient placement options (eg, cohorting, keeping the patient with an existing roommate). in multipatient rooms, $ feet spatial separation between beds is advised to reduce the opportunities for inadvertent sharing of items between the infected/colonized patient and other patients. hcws caring for patients on contact precautions wear a gown and gloves for all interactions that may involve contact with the patient or potentially contaminated areas in the patient's environment. donning ppe on room entry and discarding before exiting the patient room is done to contain pathogens, especially those that have been implicated in transmission through environmental contamination (eg, vre, c difficile, noroviruses and other intestinal tract pathogens, rsv). , , , , , , iii.b. . droplet precautions. droplet precautions are intended to prevent transmission of pathogens spread through close respiratory or mucous membrane contact with respiratory secretions as described in section i.b. .b. because these pathogens do not remain infectious over long distances in a health care facility, special air handling and ventilation are not required to prevent droplet transmission. infectious agents for which droplet precautions are indicated are listed in appendix a and include b pertussis, influenza virus, adenovirus, rhinovirus, n meningitides, and group a streptococcus (for the first hours of antimicrobial therapy). a single-patient room is preferred for patients who require droplet precautions. when a single-patient room is not available, consultation with infection control personnel is recommended to assess the various risks associated with other patient placement options (eg, cohorting, keeping the patient with an existing roommate). spatial separation of $ feet and drawing the curtain between patient beds is especially important for patients in multibed rooms with infections transmitted by the droplet route. hcws wear a mask (a respirator is not necessary) for close contact with infectious patient; the mask is generally donned on room entry. patients on droplet precautions who must be transported outside of the room should wear a mask if tolerated and follow respiratory hygiene/cough etiquette. iii.b. . airborne precautions. airborne precautions prevent transmission of infectious agents that remain infectious over long distances when suspended in the air (eg, rubeola virus [measles], varicella virus [chickenpox], m tuberculosis, and possibly sars-cov), as described in section i.b. .c and appendix a. the preferred placement for patients who require airborne precautions is in an aiir, a single-patient room equipped with special air handling and ventilation capacity that meet the aia/facility guidelines institute standards for aiirs (ie, monitored negative pressure relative to the surrounding area; air exchanges per hour for new construction and renovation and air exchanges per hour for existing facilities; air exhausted directly to the outside or recirculated through hepa filtration before return). , some states require the availability of such rooms in hospitals, emergency departments, and nursing homes that care for patients with m tuberculosis. a respiratory protection program that includes education about use of respirators, fit testing, and user seal checks is required in any facility with aiirs. in settings where airborne precautions cannot be implemented due to limited engineering resources (eg, physician offices), masking the patient, placing the patient in a private room (eg, office examination room) with the door closed, and providing n or higher-level respirators or masks if respirators are not available for hcws will reduce the likelihood of airborne transmission until the patient is either transferred to a facility with an aiir or returned to the home environment, as deemed medically appropriate. hcws caring for patients on airborne precautions wear a mask or respirator, depending on the disease-specific recommendations (see section ii.e. , table , and appendix a), that is donned before room entry. whenever possible, nonimmune hcws should not care for patients with vaccine-preventable airborne diseases (eg, measles, chickenpox, smallpox). diagnosis of many infections requires laboratory confirmation. because laboratory tests, especially those that depend on culture techniques, often require or more days for completion, transmission-based precautions must be implemented while test results are pending, based on the clinical presentation and likely pathogens. use of appropriate transmission-based precautions at the time a patient develops symptoms or signs of transmissible infection, or arrives at a health care facility for care, reduces transmission opportunities. although it is not possible to identify prospectively all patients needing transmission-based precautions, certain clinical syndromes and conditions carry a sufficiently high risk to warrant their use empirically while confirmatory tests are pending (see table ). icps are encouraged to modify or adapt this table according to local conditions. transmission-based precautions remain in effect for limited periods (ie, while the risk for transmission of the infectious agent persists or for the duration of the illness (see appendix a). for most infectious diseases, this duration reflects known patterns of persistence and shedding of infectious agents associated with the natural history of the infectious process and its treatment. for some diseases (eg, pharyngeal or cutaneous diphtheria, rsv), transmission-based precautions remain in effect until culture or antigen-detection test results document eradication of the pathogen and, for rsv, symptomatic disease is resolved. for other diseases (eg, m tuberculosis), state laws and regulations and health care facility policies may dictate the duration of precautions. in immunocompromised patients, viral shedding can persist for prolonged periods of time (many weeks to months) and transmission to others may occur during that time; therefore, the duration of contact and/or droplet precautions may be prolonged for many weeks. , [ ] [ ] [ ] [ ] [ ] [ ] the duration of contact precautions for patients who are colonized or infected with mdros remains undefined. mrsa is the only mdro for which effective decolonization regimens are available. however, carriers of mrsa who have negative nasal cultures after a course of systemic or topical therapy may resume shedding mrsa in the weeks after therapy. , although early guidelines for vre suggested discontinuation of contact precautions after stool cultures obtained at weekly intervals proved negative, subsequent experiences have indicated that such screening may fail to detect colonization that can persist for . year. , [ ] [ ] [ ] likewise, available data indicate that colonization with vre, mrsa, and possibly mdr-gnb can persist for many months, especially in the presence of severe underlying disease, invasive devices, and recurrent courses of antimicrobial agents. it may be prudent to assume that mdro carriers are colonized permanently and manage them accordingly. alternatively, an interval free of hospitalizations, antimicrobial therapy, and invasive devices (eg, or months) before reculturing patients to document clearance of carriage may be used. determination of the best strategy awaits the results of additional studies. see the hicpac/cdc mdro guideline for a discussion of possible criteria to discontinue contact precautions for patients colonized or infected with mdros. although transmission-based precautions generally apply in all health care settings, exceptions exist. for example, in home care, aiirs are not available. furthermore, family members already exposed to diseases such as varicella and tuberculosis would not use masks or respiratory protection, but visiting hcws would need to use such protection. similarly, management of patients colonized or infected with mdros may necessitate contact precautions in acute care hospitals and in some ltcfs when there is continued transmission, but the risk of transmission in ambulatory care and home care has not been defined. consistent use of standard precautions may suffice in these settings, but more information is needed. a pe is designed for allogeneic hsct patients to minimize fungal spore counts in the air and reduce the risk of invasive environmental fungal infections (see table for specifications). , [ ] [ ] [ ] the need for such controls has been demonstrated in studies of aspergillosis outbreaks associated with construction. , , , , as defined by the aia and presented in detail in the cdc's guideline for environmental infection control in health care facilities, , air quality for hsct patients is improved through a combination of environmental controls that include ( ) hepa filtration of incoming air, ( ) directed room air flow, ( ) positive room air pressure relative to the corridor, ( ) well-sealed rooms (including sealed walls, floors, ceilings, windows, electrical outlets) to prevent flow of air from the outside, ( ) ventilation to provide $ air changes per hour, ( ) strategies to minimize dust (eg, scrubbable surfaces rather than upholstery and carpet, and routinely cleaning crevices and sprinkler heads), and ( ) prohibiting dried and fresh flowers and potted plants in the rooms of hsct patients. the latter is based on molecular typing studies that have found indistinguishable strains of aspergillus terreus in patients with hematologic malignancies and in potted plants in the vicinity of the patients. [ ] [ ] [ ] the desired quality of air may be achieved without incurring the inconvenience or expense of laminar airflow. , to prevent inhalation of fungal spores during periods when construction, renovation, or other dust-generating activities that may be ongoing in and around the health care facility, it has been recommended that severely immunocompromised patients wear a high-efficiency respiratory protection device (eg, an n respirator) when they leave the pe. , , the use of masks or respirators by hsct patients when they are outside of the pe for prevention of environmental fungal infections in the absence of construction has not been evaluated. a pe does not include the use of barrier precautions beyond those indicated for standard precuations and transmission-based precautions. no published reports support the benefit of placing patients undergoing solid organ transplantation or other immunocompromised patients in a pe. these recommendations are designed to prevent transmission of infectious agents among patients and hcws in all settings where health care is delivered. as in other cdc/hicpac guidelines, each recommendation is categorized on the basis of existing scientific data, theoretical rationale, applicability, and, when possible, economic impact. the cdc/hicpac system for categorizing recommendations is as follows: category ia. strongly recommended for implementation and strongly supported by well-designed experimental, clinical, or epidemiologic studies. category ib. strongly recommended for implementation and supported by some experimental, clinical, or epidemiologic studies and a strong theoretical rationale. category ic. required for implementation, as mandated by federal and/or state regulation or standard. category ii. suggested for implementation and supported by suggestive clinical or epidemiologic studies or a theoretical rationale. no recommendation; unresolved issue. practices for which insufficient evidence or no consensus regarding efficacy exists. health care organization administrators should ensure the implementation of recommendations specified in this section. agents into the objectives of the organization's patient and occupational safety programs. assume that every person is potentially infected or colonized with an organism that could be transmitted in the health care setting and apply the following infection control practices during the delivery of health care. iv.a. . during the delivery of health care, avoid unnecessary touching of surfaces in close proximity to the patient to prevent both contamination of clean hands from environmental surfaces and transmission of pathogens from contaminated hands to surfaces. airborne precautions does not need to wear a mask or respirator during transport if the patient is wearing a mask and infectious skin lesions are covered. category ii v.d. . exposure management immunize or provide the appropriate immune globulin to susceptible persons as soon as possible after unprotected contact (ie, exposure) to a patient with measles, varicella, or smallpox: category ia d administer measles vaccine to exposed susceptible persons within hours after the exposure or administer immune globulin within days of the exposure event for high-risk persons in whom vaccine is contraindicated. , - d administer varicella vaccine to exposed susceptible persons within hours after the exposure or administer varicella immune globulin (vzig or an alternative product), when available, within hours for high-risk persons in whom vaccine is contraindicated (eg, immunocompromised patients, pregnant women, newborns whose mother's varicella onset was , days before or within hours after delivery). , - d administer smallpox vaccine to exposed susceptible persons within days after exposure. vi. protective environment (see table airborne infection isolation room (aiir). formerly known as a negative-pressure isolation room, an aiir is a single-occupancy patient care room used to isolate persons with a suspected or confirmed airborne infectious disease. environmental factors are controlled in aiirs to minimize the transmission of infectious agents that are usually transmitted from person to person by droplet nuclei associated with coughing or aerosolization of contaminated fluids. aiirs should provide negative pressure in the room (so that air flows under the door gap into the room), an air flow rate of to air changes per hour (ach) ( ach for existing structures, ach for new construction or renovation), and direct exhaust of air from the room to the outside of the building or recirculation of air through a highefficiency particulate air filter before returning to circulation. ( ambulatory care setting. a facility that provides health care to patients who do not remain overnight; examples include hospital-based outpatient clinics, non-hospital-based clinics and physician offices, urgent care centers, surgicenters, free-standing dialysis centers, public health clinics, imaging centers, ambulatory behavioral health and substance abuse clinics, physical therapy and rehabilitation centers, and dental practices. bioaerosol. an airborne dispersion of particles containing whole or parts of biological entities, including bacteria, viruses, dust mites, fungal hyphae, and fungal spores. such aerosols usually consist of a mixture of monodispersed and aggregate cells, spores, or viruses carried by other materials, such as respiratory secretions and/or inert particles. infectious bioaerosols (ie, those containing biological agents capable of causing an infectious disease) can be generated from human sources (eg, expulsion from the respiratory tract during coughing, sneezing, talking, singing, suctioning, or wound irrigation), wet environmental sources (eg, high-volume air consitioning and cooling tower water with legionella) or dry sources (eg, construction dust with spores produced by aspergillus spp). bioaerosols include large respiratory droplets and small droplet nuclei (cole ec. ajic ; : - ) . caregiver.. any person who is not an employee of an organization, is not paid, and provides or assists in providing health care to a patient (eg, family member, friend) and acquire technical training as needed based on the tasks that must be performed. cohorting. in the context of this guideline, this term applies to the practice of grouping patients infected or colonized with the same infectious agent together to confine their care to one area and prevent contact with susceptible patients (cohorting patients). during outbreaks, health care personnel may be assigned to a cohort of patients to further limit opportunities for transmission (cohorting staff). colonization. proliferation of microorganisms on or within body sites without detectable host immune response, cellular damage, or clinical expression. the presence of a microorganism within a host may occur with varying durations but may become a source of potential transmission. in many instances, colonization and carriage are synonymous. droplet nuclei. microscopic particles , mm in size that are the residue of evaporated droplets and are produced when a person coughs, sneezes, shouts, or sings. these particles can remain suspended in the air for prolonged periods and can be carried on normal air currents in a room or beyond, to adjacent spaces or areas receiving exhaust air. engineering controls. removal or isolation of a workplace hazard through technology. an airborne infection isolation room, a protective environment, engineered sharps injury prevention device, and a sharps container are examples of engineering controls. epidemiologically important pathogen. an infectious agent that has one or more of the following characteristics: ( ) readily transmissible, ( ) a proclivity toward causing outbreaks, ( ) possible association with a severe outcome, and ( ) difficult to treat. examples include acinetobacter spp, aspergillus spp, burkholderia cepacia, clostridium difficile, klebsiella or enterobacter spp, extended-spectrum beta-lactamaseproducing gram-negative bacilli, methicillin-resistant staphylococcus aureus, pseudomonas aeruginosa, vancomycin-resistant enterococci, vancomycin-resistant staphylococcus aureus, influenza virus, respiratory syncytial virus, rotavirus, severe acute respiratory syndrome coronavirus, noroviruses, and the hemorrhagic fever viruses. hand hygiene. a general term that applies to any one of the following: ( ) handwashing with plain (nonantimicrobial) soap and water, ( ) antiseptic handwashing (soap containing antiseptic agents and water), ( ) antiseptic handrub (waterless antiseptic product, most often alcohol-based, rubbed on all surfaces of hands), or ( ) surgical hand antisepsis (antiseptic handwash or antiseptic handrub performed preoperatively by surgical personnel to eliminate transient hand flora and reduce resident hand flora). health care-associated infection (hai). an infection that develops in a patient who is cared for in any setting where health care is delivered (eg, acute care hospital, chronic care facility, ambulatory clinic, dialysis center, surgicenter, home) and is related to receiving health care (ie, was not incubating or present at the time health care was provided). in ambulatory and home settings, hai refers to any infection that is associated with a medical or surgical intervention. because the geographic location of infection acquisition is often uncertain, the preferred term is considered to be health care-associated rather than health care-acquired. healthcare epidemiologist. a person whose primary training is medical (md, do) and/or masters-or doctorate-level epidemiology who has received advanced training in health care epidemiology. typically these professionals direct or provide consultation to an infection control program in a hospital, long-term care facility, or health care delivery system (also see infection control professional). health care personnel, health care worker (hcw). any paid or unpaid person who works in a health care setting (eg, any person who has professional or technical training in a health care-related field and provides patient care in a health care setting or any person who provides services that support the delivery of health care such as dietary, housekeeping, engineering, maintenance personnel). hematopoietic stem cell transplantation (hsct). any transplantation of blood-or bone marrow-derived hematopoietic stem cells, regardless of donor type (eg, allogeneic or autologous) or cell source (eg, bone marrow, peripheral blood, or placental/umbilical cord blood), associated with periods of severe immunosuppression that vary with the source of the cells, the intensity of chemotherapy required, and the presence of graft versus host disease (mmwr ; : rr- ). high-efficiency particulate air (hepa) filter. an air filter that removes . . % of particles . . mm (the most penetrating particle size) at a specified flow rate of air. hepa filters may be integrated into the central air handling systems, installed at the point of use above the ceiling of a room, or used as portable units (mmwr ; : rr- ). home care. a wide range of medical, nursing, rehabilitation, hospice, and social services delivered to patients in their place of residence (eg, private residence, senior living center, assisted living facility). home health care services include care provided by home health aides and skilled nurses, respiratory therapists, dieticians, physicians, chaplains, and volunteers; provision of durable medical equipment; home infusion therapy; and physical, speech, and occupational therapy. immunocompromised patient. a patient whose immune mechanisms are deficient because of a congenital or acquired immunologic disorder (eg, human immunodeficiency virus infection, congenital immune deficiency syndromes), chronic diseases such as diabetes mellitus, cancer, emphysema, or cardiac failure, intensive care unit care, malnutrition, and immunosuppressive therapy of another disease process [eg, radiation, cytotoxic chemotherapy, anti-graft rejection medication, corticosteroids, monoclonal antibodies directed against a specific component of the immune system]). the type of infections for which an immunocompromised patient has increased susceptibility is determined by the severity of immunosuppression and the specific component(s) of the immune system that is affected. patients undergoing allogeneic hematopoietic stem cell transplantation and those with chronic graft versus host disease are considered the most vulnerable to health care-associated infections. immunocompromised states also make it more difficult to diagnose certain infections (eg, tuberculosis) and are associated with more severe clinical disease states than persons with the same infection and a normal immune system. infection. the transmission of microorganisms into a host after evading or overcoming defense mechanisms, resulting in the organism's proliferation and invasion within host tissue(s). host responses to infection may include clinical symptoms or may be subclinical, with manifestations of disease mediated by direct organisms pathogenesis and/or a function of cell-mediated or antibody responses that result in the destruction of host tissues. infection control and prevention professional (icp). a person whose primary training is in either nursing, medical technology, microbiology, or epidemiology and who has acquired specialized training in infection control. responsibilities may include collection, analysis, and feedback of infection data and trends to health care providers; consultation on infection risk assessment, prevention, and control strategies; performance of education and training activities; implementation of evidence-based infection control practices or those mandated by regulatory and licensing agencies; application of epidemiologic principles to improve patient outcomes; participation in planning renovation and construction projects (eg, to ensure appropriate containment of construction dust); evaluation of new products or procedures on patient outcomes; oversight of employee health services related to infection prevention; implementation of preparedness plans; communication within the health care setting, with local and state health departments, and with the community at large concerning infection control issues; and participation in research. certification in infection control is available through the certification board of infection control and epidemiology. infection control and prevention program. a multidisciplinary program that includes a group of activities to ensure that recommended practices for the prevention of health care-associated infections are implemented and followed by health care workers, making the health care setting safe from infection for patients and health care personnel. the joint commission on accreditation of healthcare organizations requires the following components of an infection control program for accreditation: ( ) surveillance: monitoring patients and health care personnel for acquisition of infection and/or colonization; ( ) investigation: identification and analysis of infection problems or undesirable trends; ( ) prevention: implementation of measures to prevent transmission of infectious agents and to reduce risks for device-and procedure-related infections; ( ) control: evaluation and management of outbreaks; and ( ) reporting: provision of information to external agencies as required by state and federal laws and regulations (see http://www.jcaho.org). the infection control program staff has the ultimate authority to determine infection control policies for a health care organization with the approval of the organization's governing body. long-term care facility (ltcf). a residential or outpatient facility designed to meet the biopsychosocial needs of persons with sustained self-care deficits. these include skilled nursing facilities, chronic disease hospitals, nursing homes, foster and group homes, institutions for the developmentally disabled, residential care facilities, assisted living facilities, retirement homes, adult day health care facilities, rehabilitation centers, and long-term psychiatric hospitals. mask. a term that applies collectively to items used to cover the nose and mouth and includes both procedure masks and surgical masks (see http://www.fda. gov/cdrh/ode/guidance/ .html# ). multidrug-resistant organism (mdro). in general, a bacterium (excluding mycobacterium tuberculosis) that is resistant to or more classes of antimicrobial agents and usually is resistant to all but or commercially available antimicrobial agents (eg, methicillin-resistant staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing or intrinsically resistant gram-negative bacilli). nosocomial infection. derived from greek words, ''nosos'' (disease) and ''komeion'' (to take care of), refers to any infection that develops during or as a result of an admission to an acute care facility (hospital) and was not incubating at the time of admission. personal protective equipment (ppe). a variety of barriers used alone or in combination to protect mucous membranes, skin, and clothing from contact with infectious agents. ppe includes gloves, masks, respirators, goggles, face shields, and gowns. procedure mask. a covering for the nose and mouth that is intended for use in general patient care situations. these masks generally attach to the face with ear loops rather than ties or elastic. unlike surgical masks, procedure masks are not regulated by the food and drug administration. protective environment. a specialized patient care area, usually in a hospital, with a positive air flow relative to the corridor (ie, air flows from the room to the outside adjacent space). the combination of high-efficiency particulate air filtration, high numbers (. ) of air changes per hour, and minimal leakage of air into the room creates an environment that can safely accommodate patients with a severely compromised immune system (eg, those who have received allogeneic hemopoietic stem cell transplantation) and decrease the risk of exposure to spores produced by environmental fungi. other components include use of scrubbable surfaces instead of materials such as upholstery or carpeting, cleaning to prevent dust accumulation, and prohibition of fresh flowers or potted plants. quasi-experimental study. a study undertaken to evaluate interventions but do not use randomization as part of the study design. these studies are also referred to as nonrandomized, pre-/postintervention study designs. these studies aim to demonstrate causality between an intervention and an outcome but cannot achieve the level of confidence concerning an attributable benefit obtained through a randomized controlled trial. in hospitals and public health settings, randomized control trials often cannot be implemented due to ethical, practical, and urgency reasons; therefore, quasi-experimental design studies are commonly used. however, even if an intervention appears to be effective statistically, the question can be raised as to the possibility of alternative explanations for the result. such a study design is used when it is not logistically feasible or ethically possible to conduct a randomized controlled trial, (eg, during outbreaks). within the classification of quasi-experimental study designs, there is a hierarchy of design features that may contribute to validity of results (harris et al. cid : : . residential care setting. a facility in which people live, minimal medical care is delivered, and the psychosocial needs of the residents are provided for. respirator. a personal protective device worn by health care personnel over the nose and mouth to protect them from acquiring airborne infectious diseases due to inhalation of infectious airborne particles , mm in size. these include infectious droplet nuclei from patients with mycobacterium tuberculosis, variola virus [smallpox], or severe acute respiratory syndrome and dust particles that contain infectious particles, such as spores of environmental fungi (eg, aspergillus spp). the centers for disease control and prevention's national institute for occupational safety and health (niosh) certifies respirators used in health care settings (see http://www.cdc.gov/niosh/topics/respirators/). the n disposable particulate, air-purifying respirator is the type used most commonly by health care personnel. other respirators used include n- and n- particulate respirators, powered air-purifying respirators with high-efficiency filters, and nonpowered fullfacepiece elastomeric negative pressure respirators. a listing of niosh-approved respirators can be found at http://www.cdc.gov/niosh/npptl/respirators/disp_part/ particlist.html. respirators must be used in conjunction with a complete respiratory protection program, as required by the occupational safety and health administration, which includes fit testing, training, proper selection of respirators, medical clearance, and respirator maintenance. respiratory hygiene/cough etiquette. a combination of measures designed to minimize the transmission of respiratory pathogens through droplet or airborne routes in health care settings. the components of respiratory hygiene/cough etiquette are ( ) covering the mouth and nose during coughing and sneezing, ( ) using tissues to contain respiratory secretions with prompt disposal into a no-touch receptacle, ( ) offering a surgical mask to persons who are coughing to decrease contamination of the surrounding environment, and ( ) turning the head away from others and maintaining spatial separation (ideally . feet) when coughing. these measures are targeted to all patients with symptoms of respiratory infection and their accompanying family members or friends beginning at the point of initial encounter with a health care setting (eg, reception/triage in emergency departments, ambulatory clinics, health care provider offices). (srinivasin a iche ; : ; http://www.cdc.gov/flu/ professionals/infectioncontrol/resphygiene.htm). safety culture. shared perceptions of workers and management regarding the level of safety in the work environment. a hospital safety climate includes the following organizational components: ( ) senior management support for safety programs, ( ) absence of workplace barriers to safe work practices, ( ) cleanliness and orderliness of the worksite, ( ) minimal conflict and good communication among staff members, ( ) frequent safety-related feedback/training by supervisors, and ( ) availability of ppe and engineering controls. source control. the process of containing an infectious agent either at the portal of exit from the body or within a confined space. the term is applied most frequently to containment of infectious agents transmitted by the respiratory route but could apply to other routes of transmission, (eg, a draining wound, vesicular or bullous skin lesions). respiratory hygiene/cough etiquette that encourages individuals to ''cover your cough'' and/or wear a mask is a source control measure. the use of enclosing devices for local exhaust ventilation (eg, booths for sputum induction or administration of aerosolized medication) is another example of source control. standard precautions. a group of infection prevention practices that apply to all patients, regardless of suspected or confirmed diagnosis or presumed infection status. standard precautions represents a combination and expansion of universal precautions and body substance isolation. standard precautions are based on the principle that all blood, body fluids, secretions, excretions except sweat, nonintact skin, and mucous membranes may contain transmissible infectious agents. standard precautions include hand hygiene and, depending on the anticipated exposure, use of gloves, gown, mask, eye protection, or face shield. in addition, equipment or items in the patient environment likely to have been contaminated with infectious fluids must be handled in a manner to prevent transmission of infectious agents (eg, wear gloves for handling, contain heavily soiled equipment, properly clean and disinfect or sterilize reusable equipment before use on another patient). surgical mask. a device worn over the mouth and nose by operating room personnel during surgical procedures to protect both surgical patients and operating room personnel from transfer of microorganisms and body fluids. surgical masks also are used to protect health care personnel from contact with large infectious droplets (. mm in size). according to draft guidance issued by the food and drug administration on may , , surgical masks are evaluated using standardized testing procedures for fluid resistance, bacterial filtration efficiency, differential pressure (air exchange), and flammability to mitigate the risks to health associated with the use of surgical masks. these specifications apply to any masks that are labeled surgical, laser, isolation, or dental or medical procedure (http://www.fda.gov/cdrh/ode/guidance/ .html# ). surgical masks do not protect against inhalation of small particles or droplet nuclei and should not be confused with particulate respirators that are recommended for protection against selected airborne infectious agents (eg, mycobacterium tuberculosis). other species s use contact precautions for diapered or incontinent persons for the duration of illness or to control institutional outbreaks. giardia lamblia s use contact precautions for diapered or incontinent persons for the duration of illness or to control institutional outbreaks. noroviruses s use contact precautions for diapered or incontinent persons for the duration of illness or to control institutional outbreaks. persons who clean areas heavily contaminated with feces or vomitus may benefit from wearing masks, because virus can be aerosolized from these body substances; , , ensure consistent environmental cleaning and disinfection with focus on restrooms even when apparently unsoiled. , hypochlorite solutions may be required when there is continued transmission. [ ] [ ] [ ] alcohol is less active, but there is no evidence that alcohol antiseptic handrubs are not effective for hand decontamination. cohorting of affected patients to separate airs paces and toilet facilities may help interrupt transmission during outbreaks. rotavirus c di ensure consistent environmental cleaning and disinfection and frequent removal of soiled diapers. prolonged shedding may occur in both immunocompetent and immunocompromised children and the elderly. also for asymptomatic, exposed infants delivered vaginally or by c-section and if mother has active infection and membranes have been ruptured for more than to hours until infant surface cultures obtained at to hours of age negative after hours of incubation. susceptible hcws should not enter room if immune caregivers are available; no recommendation for face protection of immune hcws; no recommendation for type of protection (ie, surgical mask or respirator) for susceptible hcws. in an immunocompromised host with varicella pneumonia, prolong the duration of precautions for duration of illness. postexposure prophylaxis: provide postexposure vaccine as soon as possible but within hours; for susceptible exposed persons for whom vaccine is contraindicated (immunocompromised persons, pregnant women, newborns whose mother's varicella onset is # days before delivery or within hours after delivery) provide vzig, when available, within hours; if unavailable, use ivig. provide airborne precautions for exposed susceptible persons and exclude exposed susceptible health care workers beginning days after first exposure until days after last exposure or if received vzig, regardless of postexposure vaccination. variola (see smallpox) vibrio parahaemolyticus (see gastroenteritis) vincent's angina (trench mouth) s viral hemorrhagic fevers due to lassa, ebola, marburg, crimean-congo fever viruses s, d, c di single-patient room preferred. emphasize: use of sharps safety devices and safe work practices, hand hygiene; barrier protection against blood and body fluids on entry into room (single gloves and fluid-resistant or impermeable gown, face/eye protection with masks, goggles or face shields), and appropriate waste handling. use n or higher-level respirator when performing aerosol-generating procedures. largest viral load in final stages of illness when hemorrhage may occur; additional ppe, including double gloves, leg and shoe coverings may be used, especially in resource-limited settings where options for cleaning and laundry are limited. notify public health officials immediately if ebola is suspected. , , , also see table *type of precautions: a, airborne precautions; c, contact; d, droplet; s, standard; when a, c, and d are specified, also use s. y duration of precautions: cn, until off antimicrobial treatment and culture-negative; di, duration of illness (with wound lesions, di means until wounds stop draining); de, until environment completely decontaminated; u, until time 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keratoconjunctivtis in a pediatric unit due to adenovirus type a large outbreak of epidemic keratoconjunctivitis: problems in controlling nosocomial spread nosocomial transmission of cryptococcosis cryptococcal endophthalmitis after corneal transplantation probable transmission of norovirus on an airplane centers for disease control and prevention. prevention of hepatitis a through active or passive immunization: recommendations of the advisory committee on immunization practices (acip) hepatitis a outbreak in a neonatal intensive care unit: risk factors for transmission and evidence of prolonged viral excretion among preterm infants excretion of hepatitis a virus in the stools of hospitalized hepatitis patients hospital outbreak of hepatitis e herpes simplex virus infections neonatal herpes infection: diagnosis, treatment and prevention human metapneumovirus infection in the united states: clinical manifestations associated with a newly emerging respiratory infection in children 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recent outbreak of adenovirus type infection in a chronic inpatient facility for the severely handicapped an outbreak of multidrugresistant pneumococcal pneumonia and bacteremia among unvaccinated nursing home residents human-to-human transmission of rabies virus by corneal transplant human rabies prevention, united states, : recommendations of the advisory committee on immunization practices (acip) rhinovirus and the lower respiratory tract concurrent outbreaks of rhinovirus and respiratory syncytial virus in an intensive care nursery: epidemiology and associated risk factors rhinovirus infection associated with serious lower respiratory illness in patients with bronchopulmonary dysplasia nosocomial ringworm in a neonatal intensive care unit: a nurse and her cat nosocomial transmission of trichophyton tonsurans tinea corporis in a rehabilitation hospital molecular epidemiology of staphylococcal scalded skin syndrome in premature infants an outbreak of fatal nosocomial infections due to group a streptococcus on a medical ward an outbreak of group a streptococcal infection among health care workers clusters of invasive group a streptococcal infections in family, hospital, and nursing home settings isolation techniques for use in hospitals us government printing office rethinking the role of isolation practices in the prevention of nosocomial infections the authors and hicpac gratefully acknowledge dr larry strausbaugh for his many contributions and valued guidance in the preparation of this guideline. the mode(s) and risk of transmission for each specific disease agent listed in this appendix were reviewed. principle sources consulted for the development of disease-specific recommendations for the appendix included infectious disease manuals and textbooks. , , the published literature was searched for evidence of person-to-person transmission in health care and non-health care settings with a focus on reported outbreaks that would assist in developing recommendations for all settings where health care is delivered. the following criteria were used to assign transmission-based precautions categories: d a transmission-based precautions category was assigned if there was strong evidence for person-to-person transmission via droplet, contact, or airborne routes in health care or non-health care settings and/or if patient factors (eg, diapered infants, diarrhea, draining wounds) increased the risk of transmission. d transmission-based precautions category assignments reflect the predominant mode(s) of transmission. d if there was no evidence for person-to-person transmission by droplet, contact or airborne routes, then standard precautions were assigned. d if there was a low risk for person-to-person transmission and no evidence of health care-associated transmission, then standard precautions were assigned. d standard precautions were assigned for bloodborne pathogens (eg, hbv, hcv, hiv) in accordance with cdc recommendations for universal precautions issued in . subsequent experience has confirmed the efficacy of standard precautions to prevent exposure to infected blood and body fluid. , , additional information relevant to use of precautions was added in the comments column to assist the caregiver in decision-making. citations were added as needed to support a change in or provide additional evidence for recommendations for a specific disease and for new infectious agents (eg, sars-cov, avian influenza) that have been added to appendix a. the reader may refer to more detailed discussion concerning modes of transmission and emerging pathogens in the background text and for mdro control in the mdro guideline. key: cord- -sbppgkza authors: donohoe, holly; pennington-gray, lori; omodior, oghenekaro title: lyme disease: current issues, implications, and recommendations for tourism management date: - - journal: tour manag doi: . /j.tourman. . . sha: doc_id: cord_uid: sbppgkza lyme disease is a bacterial infection spread through the bite of an infected tick. in the last few decades, the number and spatial reach of new cases has increased globally and in the united states, lyme disease is now the most commonly reported vector-borne disease. despite this evolving public health crisis, there has been little-to-no discussion of the implications for tourism supply and demand. this paper reviews the scientific literature to identify lyme disease risk factors and the implications for tourism management are discussed. the major contribution of this paper is a set of recommendations for tourism managers who may be tasked with mitigating the risks for visitors and employees as well as the potential impacts of lyme disease on destination sustainability. lyme disease is the world's fastest growing vector-borne zoonotic disease with cases reported in over countries and endemic foci in north america, europe, and asia (who, ) . the world health organization (who, ) reports that the risk is generally low except for those travelling to rural areas, particularly campers, hikers, and workers in countries or areas at risk. however, this assessment may give a false sense of security for people working or travelling in areas where the risk of lyme disease is uncertain and it may breed complacency amongst those responsible for occupational, travel, or public health. the northeastern united states is traditionally defined as the endemic global center for lyme disease and the public health risk is highest in this area. in , systematic surveillance for lyme disease was initiated by the u.s. centers for disease control and prevention (cdc, a), with states reporting cases. in a standardized case definition was approved and by , the number of cases reported had increased over percent (cdc, b; ciesielski et al., ) . the cdc ( a) states that only percent of lyme disease cases are being recorded which translates into approximately , estimated cases in the united states each year (fig. ) . a majority ( percent) have been concentrated in the northeast, yet cases have been reported in every state and in many countries around the world and their geospatial analysis reveals that lyme disease has extended well beyond traditionally defined endemic areas (cdc, b; diuk-wasser et al., ) . lyme disease case rates have been increasing exponentially at the global scale while in the united states it has become the number one and most medically significant vector-borne infectious disease (abbott, ; piesman & eisen, ) . while it is possible to surmise that better diagnostics and increased reporting are responsible for case rate trends in the united states and other parts of the world, case rates vary because of social, environmental, and economic variables such as climate and ecological change, tick and host species range expansion, human demographics and behaviour, land use patterns, clinical practice, disease reporting standards, surveillance technologies, and true incidence (daniels, falco, schwartz, varde, & robbins, ; grenfell & harwood, ; horowitz et al., ) . lyme disease is caused by borrelia burgdoferi e a bacterial pathogen transmitted to humans through the bite of an infected tick. the pathogen is sylvatic; meaning that it cycles between wild animal hosts and vectors. humans are not the primary host and as such are usually incidental or dead-end hosts. although the symptoms have been observed since the th century, it has only been or so years since the etiological agent and the primary vector(s) for lyme disease were recognized and their medical significance reported. the infection is characterized by a distinctive bull's eye rash that occurs in e percent of patients (cdc, ) . from the early symptoms of fever, headache, muscle and joint pain to the more serious symptoms such as cognitive impairment, cardiac abnormalities, arthritis, and paralysis, the impacts on individual health are noteworthy (who, ) . diagnosis is completed through a clinical examination and confirmed through serological tests and treatment consists of oral or intravenous antibiotics. currently, there is no vaccine available for human use but several are available for veterinary use (willadsen, ) . although the medical and scientific communities have been pursuing the problem for years, tourism has been slow to recognize that lyme disease can affect both tourism supply and demand. in the supply context, outdoor workers in endemic areas are at increased risk because of their frequent exposure to ticks and tick habitat (piacentino & schwartz, ) . antecedent studies have established that outdoor workers are up to times more likely to be infected than the general population (bowen, schulze, hayne, & parkin, ; smith et al., ) . given that a proportion of individuals employed in the tourism, parks, and outdoor recreation sectors are required to spend some to all of their time working outdoors, the potential threat to individual and industry health is cause for concern. for those infected, days to weeks of sick time may be required to complete treatment and the medical costs can be significant. in addition to the social costs, the u.s. department of labor reports that workplace illnesses have a major impact on an employer's economic sustainability and profit margin. the annual number of nonfatal illnesses has been estimated at , with direct cost of $ billion and indirect costs of approximately $ billion (leigh, ) . direct costs include workers' compensation payments, and it is estimated that employers pay $ billion per week for direct workers' compensation costs (u.s. department of labor, ) . workers' compensation covers less than percent of these costs, so all members of society share the economic burden. indirect costs include but are not limited to training replacement employees, implementation of corrective measures, lost productivity, and costs associated with lower employee morale and absenteeism. the direct medical costs associated with lyme disease in the united states are estimated at . billion dollars annually but the true cost of lyme disease is the profound impacts on personal health and well-being (maes, lecomte, & ray, ; magnarelli, ; zhang et al., ) . from a demand perspective, the who reports that the risk to those travelling to endemic areas of the world is generally low but nonetheless, they warn travellers to avoid tick-infested areas and tick exposure on their dedicated lyme disease webpage for international travellers (http://www.who.int/ith/diseases/lyme/en). when outdoor activities are planned during a trip to an endemic area for tick-borne disease, a tourist is at risk and the who's assessment can be misleading (falco & fish, ; hayes, ; raoult et al., ; smith et al., ) . their risk can be magnified because tourists may not have all of the necessary information or access to resources that would enable them to make informed decisions regarding lyme disease prevention before and during travel (jonas, mansfeld, paz, & potasman, ; kelly-hope, purdie, & kay, ) . for tourists who are aware of health risks before choosing a destination, s€ onmez and graefe ( ) and kozak, crotts, and law ( ) report that perceived risk can be a strong predictor for avoiding certain regions or changing travel plans. dixon et al. ( ) report that the macroeconomic consequences of a health threat or crisis are highly sensitive to demand-side effects such as the reductions in international tourism and leisure activities that result from elevated risk perceptions. for example, during the severe acute respiratory syndrome (sars) pandemic, traveller's health risk perceptions had a significant effect on international tourism demand. over cases and deaths in countries were reported in with a majority of cases occurring in asia (who, ) . the initial spread of sars was exponential with predictive models showing that if uncontrolled, a majority of people would become infected wherever it was introduced (dye, ) . air travel to areas affected by the advisories decreased dramatically during the epidemic (kuo, chen, tseng, ju, & huang, ; zeng, carter, & de lacy, ) . in east asia, tourist arrivals dropped by percent during the month of april compared to the same period in , with china, hong kong, singapore, and vietnam reporting the greatest losses (pine & mckercher, ; wilder-smith, ) . growth of the broader travel and tourism economy, which measures visitor spending and capital investment around the world, slowed to . percent down from percent in previous years and international arrivals fells . percent (world travel and tourism council, ) . while lyme disease is certainly not a pandemic and it cannot be spread person to person, like sars and other infectious disease risks, it can prompt fear and anxiety that most certainly can affect a traveller's perceptions and by extension; it can affect their travel choices and behaviours (birnbrauer, pennington-gray, & donohoe, ). herrington's ( ) national survey of american risk perceptions regarding ticks and lyme disease found perceived risk to be a predictor of behavioural change. those who had seen ticks, had heard about lyme disease, were concerned about being bitten, or knew someone who had lyme disease were more likely to engage in tick-bite prevention such as avoiding tick habitat and wearing insect repellent. brewer et al.'s ( ) research confirms that higher risk judgements encourage people to engage in protective behaviour, indicating a causal relationship between perceived risk and behaviour modification. although empirical research has yet to confirm as much, lyme disease beliefs and attitudes have likely been having an impact on the decision-making processes and behaviours of outdoor workers, recreationists and travellers (hanson & edelman, ) . knowing that lyme disease poses a real and growing threat to the tourism industry, the purpose of this paper is to first, review the scientific literature to identify lyme disease risk factors and second, to critically assess the implications for tourism management. a search for scholarly journal articles about lyme disease was performed using pubmed, proquest global, and google scholar on july , . the search parameters were narrowed to identify articles where "lyme disease" occurred in the title then additional words were added to winnow down the results to relevant articles: "travel", "tourism", "recreation(al)", "park(s)", "occupation(al)", "risk", and "prevention" (table ) . no temporal restrictions were used. after removing duplicates, unique scholarly articles were identified and reviewed. the search for articles with "lyme disease" and "travel" or "tourism" resulted in articles in all three search engines. the fact that lyme disease has not been examined in the context of tourism and travel is no surprise because the tourism domain has not traditionally focused the research lens on health risks. there is a research and knowledge gap regarding health risk generally and lyme disease specifically, as well as their potential and real impacts on the tourism industry. it should be noted that a similar pubmed search using "tick-borne disease" and "tourism" yielded papers dealing with other tick-borne diseases that occur independent of or in conjunction with lyme disease. anaplasma, babesia, bartonella, ehrlichia, and rickettsia for example, may be just as significant as lyme disease in some parts of the world yet they are equally underappreciated in the travel and tourism context. these papers were consulted in the preparation of this paper and they are also included in the analysis that follows. when "recreation/al" and "parks" was added to the search, articles were identified, of which were case or exploratory studies of ixodes scapularis tick populations and their hosts in select recreational parks in canada (morshed, scott, fernando, mann, & durden, ; scott et al., ) , italy (curioni et al., ) , and the united states (daniels et al., ; falco & fish, ; lane et al., ) . two articles surveyed parks visitors (hallman, weinstein, kadakia, & chess, ) and recreational destination workers (rees & axford, ) about their lyme disease knowledge, tickexposure, tick-bite prevention behaviours and/or clinical history with the disease. of the articles where "occupation(al)" or "work(er)" appeared, the majority were seroprevalence studies of individuals working in the forestry, parks, land management, and agricultural sectors in various locations around the world (e.g. cisak, w ojcik-fatla, zają c, sroka, & dutkiewicz, ; goldstein et al., ; guy, bateman, martyn, heckels, & lawton, ; nakama, muramatsu, uchikawa, & yamagishi, ; smith et al., ; stanchi & balague, ) . one study from the united states reported the results of a survey of workers regarding their knowledge of lyme disease and their behaviour regarding tick-bite prevention and one article provided a comprehensive review of the occupational risks (piacentino & schwartz, ) . over articles were found that contained "lyme disease" and "risk" in the title. a majority of these articles assumed a natural science perspective (i.e. epidemiology, medicine, microbiology, and zoology) and reported on the spatial and temporal factors affecting ticks, the causative agent e the borrelia pathogen(s), host species, environment, and human exposure (e.g. allan, keesing, & ostfield, ; glass et al., ; guerra et al., ; maher, nicholson, donnelly, & matyas, ; ogden et al., ) . a minority of the papers focused on behavioural risks and a review of these papers revealed a consensus that human exposure to ticks is the central risk factor for infection (e.g. diuk-wasser et al., ; fish, ) while knowledge and prevention act as risk mediators (e.g. mckenna, faustini, nowakowski, & wormser, ; smith, wileyto, hopkins, cherry, & maher, ) . articles that contained the key word "prevention" did so primarily as a recommendation for public agencies responsible for reducing the burden of infection. piesman and eisen ( ) and poland ( ) provide a review of lyme and tick-borne disease prevention strategies and mowbray, amlôt, and &rubin ( ) provide a review of education and communication interventions to prevent tick-borne disease. a critical synthesis of this body of research was completed to identify lyme disease risk factors as they have potential implications for tourism management. it is the aforementioned factors e exposure, knowledge, and personal protection behaviour -that comprise the discussion in the sections that follow. . . tick exposure i. scapularis or the blacklegged tick is the primary vector for lyme disease in the united states. in the united states and other areas of the world, dozens of tick species have been implicated in the spread of lyme and lyme-like borrelia pathogens to humans and animals (e.g. barbour, maupin, teltow, carter, & piesman, ; burgdorfer, ; clark, ; clark, leydet, & hartman, ; harrison et al., ; mather & mather, ; nakao, miyamoto, & fukunaga, ; piesman & sinsky, ; piesman, clark, dolan, happ, & burkot, ) . epidemiological studies have explored the relationship between ticks, climate, seasonality, host species, and disease risk in a variety of local or regional contexts (e.g. estrada-peña, ; sumilo et al., ; wielinga et al., ) . predictive models have been developed using remote sensing, satellite imagery, geographical information systems, and advanced statistical analysis (e.g. daniels et al., ; diuk-wasser et al., ; werden et al., ) . the research indicates that vegetation and climate are the two central predictors of suitable/unsuitable habitats for tick species and it is therefore possible to identify high-risk areas and potential emergent areas for lyme disease. the areas with the highest risk for human exposure are those that contain suitable tick habitat, ticks capable of transmitting the lyme disease pathogen, and have high host activity (gray et al., ; schulze, jordan, & hung, ) . empirical approaches have laid the groundwork for a better understanding of the relationship between environmental factors and tick distribution. however, they fail to account for the vital role that human behaviour plays in the disease transmission process. the global increase in interaction between humans and wildlife through population growth, economic development, and an increasingly mobile society that brings people into endemic areas for work and leisure is amplifying personal risk (kollaritsch et al., ; quine et al., ; rizzolli, hauffe, vourc'h, neteler, & rosa, ) . the rapid expansion of the tourism industry and air travel is of concern as the importation of pathogens and vectors by travellers (purposefully or not) and specifically ticks and tick-borne disease pathogens is a real threat to human and ecological health (e.g. daugschies, ; hall, ; holzer, ; schuster et al., ) . european case reports demonstrate statistical relationships between outdoor recreation in tick-infested forests and tick-borne disease infection (e.g. daniel, danielov a, k rí z, jirsa, & no zi cka, ; kahl & radda, ; sumilo et al., ) . early case studies in the united states failed to show a significant increase in risk associated with outdoor recreation (e.g. bowen et al., ; ciesielski et al., ; falco & fish, ) but smith et al.'s ( ) research found that persons who had spent more than h per week in outdoor activities in endemic areas were . times more likely to test positive for lyme disease. since the s, a small body of literature has evaluated the occupational risk for lyme disease. in new york, schwartz and goldstein et al. ( ) confirmed that lyme disease is a hazard of outdoor work and a study in new jersey found that outdoor workers were nearly five times more likely to have contracted lyme disease than indoor workers (bowen et al., ) . in the broader international and tickborne disease contexts, the research shows similar relationships between tick exposure and infection. in lithuania, motiejunas, bunikis, barbour, & sadziene ( ) report that those at highest risk for a tick-borne disease (established through seropositivity testing) are outdoor workers ( percent tested positive/n ¼ ). recent case studies in europe (e.g. bartosik, sitarz, szyma nska, & buczek, ; bochnickova & szilagyiova, ; franke, hildebrandt, meier, straube, & dorn, ; jameson & medlock, ) confirm that ticks, lyme and other tick-borne disease pathogens are common across europe and they pose a significant occupational risk to outdoor workers. two studies in poland involving serological testing of both ticks and humans confirmed that those who perform work in forest environments are regularly exposed to tick-borne disease pathogens and as such, are at a higher risk of infection. two dutch studies of lyme disease seroprevalence in outdoor workers showed a statistically significant risk (or, . ; percent ci, . e . and or, . ; percent ci, . e . ) relative to the control group (kuiper et al., ; van charante, groen, mulder, rijpkema, & osterhaus, ) . in , piacentino and schwartz published a meta-analysis of articles on the occupational risk of lyme disease and report that the scientific evidence demonstrates that those who work outdoors in endemic areas are at an increased risk for contracting lyme disease because of their exposure to ticks. it is evident in this body of literature that exposure to ticks is the single most significant human risk factor and the first line of defence against tick bites should be avoidance of these areas completely or seasonally (during periods of high tick activity), or where appropriate, control of the tick population. given the geospatial expansion of tick species, increasing human mobility and encroachment into tick habitat, and the attendant expectation that future interactions between humans and ticks are likely to increase, vigilance and on-going monitoring is required as new and extant tick-borne pathogens pose potential threats to public health. lyme disease risk is magnified when individuals are not aware of the risks, do not mitigate risks, are not familiar with infection signs and symptoms, and do not know where to seek information or support . it is widely accepted that knowledge plays an important role in mediating lyme disease risk as it is a pivotal precursor to preventative behaviour (piacentino & schwartz, ; poland, ). herrington's ( ) national survey found that a majority of americans know about ticks and the risks they present to human health. in the tourism and recreation context, hallman et al. ( ) found that over percent of people surveyed at three state parks in new jersey reported knowing about lyme disease and could name at least one bite prevention strategy (table ). in recreational and agricultural settings in poland, bartosik et al. ( ) found that workers do not know about the health risks associated with ticks and they are not protecting themselves against tick bites while at work. in the forestry sector, cisak et al. ( ) found that workers possess only basic tick-borne disease knowledge. in france, a study of nearly outdoor workers revealed that a majority would like to have access to educational materials so that they can make informed decisions about tick-bite prevention (thorin et al., ) . it is difficult to draw conclusions on the basis of the limited study of lyme and associated tick-borne disease knowledge, but the literature suggests that knowledge varies geographically and although it has not yet been correlated, it may be that knowledge is higher in areas where lyme and/or other tick-borne diseases are endemic and therefore the risk is higher and investments in educational interventions may be greater. in the latter case, the science appears more developed and it suggests that educational interventions do influence an individual's lyme disease knowledge. for example, gould et al. ( ) evaluated resident behaviours following an intensive community-wide education program and found that percent were aware of the risks and were taking steps to prevent tick exposure. gray et al. ( ) assessed knowledge of lyme disease among a sample of students before and after an educational intervention and found that general knowledge of ticks and lyme disease improved. jenks and trapasso ( ) found that knowledge of tick removal and the signs and symptoms of infection improved following a one-on-one educational intervention by a physician. maher et al. ( ) measured the impact of a lyme disease education program for children in the united states and found that participants had more knowledge of ticks and more confidence in their ability to do a tick check. fox ( ) reports that individuals were more knowledgeable about wearing protective clothing following an educational intervention while knowledge of other personal protection measures was not significantly changed. this body of work provides empirical evidence that the communication of objective and clear messages about tick-borne disease and tick exposure can be effective for increasing public knowledge as well as an individual's ability to make informed decisions about personal protection. concomitantly, prevention investments specifically targeted at increasing public knowledge are an important risk mediator because knowledge can empower the individual to choose to engage in personal protection behaviours. not knowing about lyme disease is most certainly a risk factor for those living or visiting endemic areas for work or leisure. it is widely accepted in the health risk literature that behaviour plays an important role in minimizing disease risk . behavioural modification related to lifestyle, hygiene, and personal protection is the primary method for the prevention of infectious diseases where prophylactics are unavailable. for example, noroviruses are the most common cause of epidemic gastroenteritis on cruise ships and they are responsible for at least percent of all gastroenteritis outbreaks worldwide (goodgame, ; hall et al., ) . hand hygiene (washing with soap and water) is the single most important method for preventing infection and controlling transmission (hall et al., ) . to prevent mosquito-borne infectious diseases such as dengue fever and west nile virus, personal protection through the use of insect repellents and the avoidance of outdoor activity during peak mosquito feeding times is recommended in conjunction with communitybased chemical and biological control investments (renganathan et al., ) . in the case of malaria, the use of insecticide-treated bed nets has been shown to minimize human-vector contact and the incidence of infection by up to percent (choi et al., ) . in the absence of a lyme disease vaccine for human use, the u.s. centers for disease control ( a) recommends personal protection measures for avoiding tick bites and infection: ( ) avoid tick areas; ( ) avoid direct contact with ticks; and ( ) remove ticks from your body (table ). if tick habitats cannot be avoided, there are simple things that individuals can do to minimize the risk for tick bites and pathogen exposure (see table ). wearing protective clothing mechanically decreases direct skin exposure and wearing light-coloured clothing makes it more likely that the tick will be detected and removed before it finds a feeding site (garcia-alvarez, palomar, & oteo, ) . repellents containing deet (n, n-diethylmeta-toluamide) applied to skin and permethrin-based insecticides applied to clothing have been shown to effectively decrease the risk of tick bites and they are reasonably safe to use (patey, ; piesman & eisen, ) . recently, vaughn et al. ( ) evaluated the protective effectiveness of factory-based and longlasting permethrin (insecticide) treated uniforms among a cohort of outdoor workers in north carolina. the incidence of workrelated tick bites reported by the treatment group was significantly lower than the control group and the treated uniform prevented % of tick bites. the results indicate that long-lasting permethrin impregnated uniforms can be highly effective for deterring tick bites for up to one year. if a tick bite should occur, the tick should be removed using the proper technique of grabbing the tick close to the skin and pulling gently upward with tweezers (tick removal guide: http://www.cdc. gov/ticks/removing_a_tick.html). the tick should be saved in a sealed container and provided to a physician for testing when the victim seeks medical attention (due, fox, medlock, pietzsch, & logan, ; garcia-alvarez et al., ) . in this regard, knowing the early signs and symptoms of infection are important for early diagnosis and treatment (symptom guide: http://www.cdc.gov/ ticks/symptoms.html). it is important to note that not all bites will result in infection because not all lyme disease transmissioncapable ticks carry the pathogen. and, the public health risk for lyme disease is affected by spatiotemporal patterns of the tick vector, its life stage, preferred host species (i.e. mice, deer), as well as seasonality, climate, and a range of other environmental factors (adelson et al., ; diuk-wasser et al., ; ostfeld et al., ; qui, dykhuizen, acosta, & luft, ; schulze, jordan, schulze, mixson, & papero, ) . it is equally important to note that while numerous personal protection strategies have been recommended by public health authorities (table ) , they vary in cost, acceptability, and effectiveness, and their uptake has been universally poor (corapi et al., ) . research in areas where lyme disease is endemic has demonstrated that despite adequate knowledge about its symptoms and transmission, individuals are not taking action to protect themselves from the risk of infection. in the tourism and recreation context for example, hallman et al. ( ) reported that over percent of visitors surveyed in new jersey state parks could name at least one tick bite prevention measure but a majority ( percent) took no precautions. shadick, daltroy, phillips, liang, & liang ( ) study of residents and visitors to martha's vineyard in massachusetts found that knowledge about lyme disease alone was not a predictor for protective behaviours and visitors were less likely to protect themselves than residents. a similar study conducted ten years later found that visitors to nantucket (located next to martha's vineyard) were significantly more likely to take precautions when visiting if they had been exposed to a lyme disease education program while on the ferry to this island destination . in the united kingdom, a study of early lyme disease patients found that participants were more likely to perform tick checks, monitor for symptoms, and seek medical attention after a countryside visit (i.e.) rather than take precautions before and during the potential exposure (marcu, barnett, uzzell, vasileiou, & susan, ) . those who regularly frequented the countryside were the least likely to perform during-visit precautions (marcu et al., ). herrington's ( ) national survey of americans found that despite knowing about lyme disease risk, a majority ( percent) of those surveyed were not taking action to prevent tick bites. conversely, gould et al.'s ( ) study of knowledge, attitudes, and behaviours of connecticut residents e a highly endemic area of the united states, found that percent knew some to a lot about lyme disease, percent felt they were very or somewhat likely to get lyme disease in the coming year, percent used personal protective behaviours to prevent lyme disease, and percent reported using environmental tick controls (e.g. pesticide application on personal property). in the occupational context, "adherence to national institute for occupational safety and health-recommended tick bite prevention methods is poor" in the united states and the same is suggested in the literature for other parts of the world (vaughn et al., : ) . in poland for example, cisak et al. ( ) found less than percent of the forestry workers they surveyed were practising tick-bite prevention. bartosik et al. ( ) found that high-risk workers do not possess knowledge of the potential consequences of a tick bite, are unlikely to take protective measures beyond insect repellent application, and those from urban areas were less likely to protect themselves. the mixed results from the study of residents, visitors, and outdoor workers suggest that a variety of factors are influencing the adoption of personal protection and that more research is needed to better understand how they vary spatially, temporally, socioeconomically, or otherwise (bayles, evans, & allan, ) . a limited number of controlled trials have attempted to empirically measure the relationship between knowledge, tick-bite prevention, and seropositivity (laboratory confirmed measure of infection). daltroy et al. ( ) conducted a randomized trial of a lyme disease educational program whereby approximately , visitors to nantucket -a high-risk area in massachusetts, were provided with educational materials before arriving. after their visit, study participants reported their tick-bite prevention while in nantucket and provided a blood sample for serological screening. the study found that visitors who were knowledgeable about lyme disease were significantly more likely to practice tick-bite prevention during their visit and were also significantly less likely to be infected with lyme disease during their stay. at months post visit, participants self-reported that they had been infected with lyme disease and of these were confirmed by physicians. the analysis showed lower rates of self-reported illness among those who received educational materials and long-term visitors (> weeks) were more likely to have lower relative risk than short-term visitors. similarly, malouin et al. ( ) assessed the impact of a lyme disease educational campaign in maryland and found a significant difference between the intervention and non-intervention control group in terms of knowledge and the self-reported use of prevention methods but no significant serological difference between groups was observed. in their study of outdoor workers in new york state, schwartz and goldstein ( ) found that when workers were knowledgeable and they practised personal protection, the occupational risk for lyme disease infection was significantly diminished (as measured by tick exposure odds ratios). a recent study looked at a variety of environmental and behavioural/ personal risk factors for seropositivity and found that exposure and age were associated with positive lyme serology and wearing protective clothing was significantly associated with negative serology (finch et al., ) . this lean body of literature suggests that taking action to prevent tick bites before, during, and after visiting a natural and/or known tick area (see table ) can be effective for preventing lyme disease and that knowledge is a precursor to the adoption of personal protection behaviours (beaujean, bults, van steenbergen, & voeten, ) . this finding is congruent with theoretical explanations found in the health education literature. the health belief model was one of the first theories of health behaviour and it remains one of the most widely recognized and applied in the field. the model suggests that an individual's readiness to take action, is influenced by their beliefs about their susceptibility to a health threat, perceptions of the benefits of taking action to prevent it versus the perceived barriers to taking action, and confidence in their ability to take action (self-efficacy) (rosenstock, ) . this model has been used to better understand an individual's decisionmaking and behaviours related to infectious disease risk (e.g. glanz, rimer, & viswanath, ; harrison, mullen, & green, ; janz & becker, ) and recently it has been shown to be useful for understanding the grey area between tick-borne disease knowledge and personal protection behaviour (e.g. bayles et al., ; beaujean, et al., ) . in the same vein, the theory of planned behaviour posits that behaviour can be deliberative and planned and that an individual's attitude toward a behaviour, the perceived control they have over a behaviour, as well as normative beliefs and subjective norms act to shape an individual's behaviours (ajzen, (ajzen, , . theory of reasoned action suggests that a person's behaviour is determined by his/her intention to perform the behaviour and that this intention is, in turn, a function of his/her attitude toward the behaviour and his/her subjective norm (fishbein & ajzen, ) . the difference between these two theories being that the former suggests that attitude and control are predictors of behavioural intention and action while the later suggests behavioural intention is the most important determinant of behaviour (madden, ellen, & ajzen, ) . while knowledge about a health threat is a precursor to an individual's transition from knowledge to action, there are numerous theories and models that posit a variety of factors to explain the adoption [or not] of health risk prevention behaviours. concomitantly, it must be acknowledged that theories such as these do not capture or model the complexity of behavioural change in the context of health and wellbeing. if it were a simple equation (e.g. increased knowledge of health risk ¼ behavioural change), then nearly everyone would lead healthy lifestyles, they would protect themselves against health risks, and many illnesses would be non-existent. however, it is not as simple as a linear or causal relationship and there are many factors that affect health behaviour. for example, marcu et al. ( ) and beaujean et al. ( ) report that individuals don't comply with tick bite prevention recommendations because they interfere with their enjoyment of the outdoors (e.g., they refuse to wear long clothes on a hot day), they believe the risk of tick bites is low (perceived susceptibility), they do not believe that the recommendations are effective (e.g., insect repellent does not always prevent bites), and they are not confident in their ability to identify a tick or a tick bite. in this case, an improved understanding of the individuals and segments at risk for lyme and other tick-borne diseases as well as the factors that do or do not influence their behaviours is needed to inform the development of targeted and tailored public health interventions (bayles et al., ; beaujean et al., ; mowbray et al., ) . the epidemiological evidence is strongly indicative of a causeeffect relationship between tick exposure and lyme disease infection. although the science is embryonic when it comes to the relationship between knowledge, personal protection behaviour, and lyme disease risk, it certainly suggests that these factors can act as risk moderators and mediators. short of major changes in tick ecology, vaccine availability, tick control, and human behaviour, predictive models suggest that lyme disease will continue to be a public health threat in an increasing number of areas around the world. when we examine this issue through a tourism lens, it is clear that lyme disease is posing a real and growing threat to both supply and demand in endemic and emergent areas of the world. decisions regarding the primary prevention of vector-borne diseases such as lyme disease are as a matter of course, made at the national, state, or regional level and do not involve tourism industry stakeholders but should. in the past, a plethora of methods for large-scale lyme disease prevention including vaccines, biological and chemical tick control methods have been adopted by government agencies at a variety of scales (garcia-alvarez et al., ) . in , the united states federal drug administration (fda) approved the lymerix™ vaccine and the cdc advisory committee on immunization practices (acip) recommended vaccination for those living in high risk areas (nigrovic & thompson, ) . although it was shown to reduce new infections in vaccinated adults by percent, the manufacturer voluntarily withdrew the product from the market in amidst reports of side-effects, a government investigation, a class-action lawsuit, negative media coverage, and declining sales (nigrovic & thompson, ) . in the absence of a human vaccine, a variety of chemicals have been used to reduce the overall tick population but the effect has proven short-lived, their use impractical on a largescale basis, and chemical resistance has been observed in tick species (george, ) . wildlife management has been explored as a less-toxic alternative but attempts to limit the primary host population through hunting, landscape modifications, and movement restrictions (e.g. fencing) have produced mixed results and they too are impractical on a large-scale basis (heymann, ; piesman & eisen, ) . while these interventions may have blunted the tick population and pathogen lifecycle, "they have clearly not been sufficient to lower the number of [lyme] cases, and the epidemic continues to gain momentum" (hayes & piesman, : . given that these efforts have not yet achieved the desired end, willadsen ( : ) argues that "the achievement of the full potential of vaccination, the application of biocontrol agents and the coordinated management of the existing technologies all pose challenging research problems." with an eye to the future, scholars are expressing hope that the development and application of new scientific tools and technologies (i.e. molecular techniques) will have the capacity to revolutionize tick control methods and policies into the future or better yet, they will manifest an effective human vaccine (garcia-alvarez et al., ; sonenshine, kocan, & de la fuente, ; willadsen, ) . in the absence of such a vaccine or other suitable prophylactic and effective tick control methods, piesman and eisen ( : ) argue that lyme disease education is the single most important area in which public health agencies, employers, and other stakeholders can invest to reduce the burden of infection. they argue that the next logical step in prevention is to "ensure ready access to objective information empowering the individuals de facto responsible for control of ticks and tick-borne diseases to make rational and informed decisions regarding their personal risk of exposure to tick-borne pathogens and to take appropriate actions to mitigate risk of tick bites and pathogen exposure." in the united states for example, the cdc has an active tick-borne disease prevention program with a dedicated focus on lyme disease and many state health agencies have developed similar public health education programs. however, they fail to account for the unique characteristics of tourists who may not be familiar with the local area and health risks, and they are unlikely to know where to seek local health risk information. the implications are such that the tourism industry and the tourists upon which it depends are left vulnerable to the real and perceived risk of lyme disease. perhaps it is best that disease prevention be left in the hands of public health experts, but this does not negate the role that tourism bodies can play, in partnership with public health and other organizations, to address the growing lyme disease problem in many parts of the world. it is recommended that tourism industry associations, destination management organizations (dmo), and convention and visitors bureaus (cvb) for example, represent the industry's unique interests, characteristics, needs, and concerns in the public health decision-making forum at national, state, and regional levels (e.g. form a task group). and it is important that these same industry stakeholders assume a leadership role in the dissemination and operationalization of any public health interventions that affect those providing travel and tourism services and those consuming them. when considering the day-to-day management of tourism in high-risk destinations and emergent areas for lyme disease, parsons ( ) and pennington-gray et al. ( ) recommend that managers take a proactive rather than reactive management approach to potential health threats so that they can mitigate the risks and deal with the threat more effectively. ritchie ( ) and pennington-gray, thapa, kyriaki, cahyanto, and mclaughlin ( ) recommend the development of a multi-phase management plan to help destinations and/or attractions, accommodations, and other servicing businesses avoid or limit the severity of the threat's impact on supply and demand. the plan should address: ( ) how to prevent the threat, ( ) what to do in the event of, and ( ) how to recover. in the later cases, generalizable tourism crisis management guidance is available in the literature (e.g. faulkner, ; ritchie, ; young & montgomery, ) . in the specific lyme disease context, it is strongly recommended that tourism managers become informed and take action to protect visitors and employees from the risk of acquiring lyme and other tick-borne diseases. public health authorities should be consulted about the risks for tick-borne disease in the area and any potential "hotspots" for high tick activity and disease risk should be identified and marked. for example, brochures could be provided to visitors upon entry into state or national parks and warning signs could be posted at trail heads, picnic areas, or other high human activity areas where the risk for a tick encounter exists. similarly, park managers could provide brochures and workshops to employees so that they can be made aware of the risks and the ways to protect themselves and park visitors. in endemic areas, travellers arriving by air or ferry or other could be provided with an informative pamphlet in arrival, departure, or visitors centres. public health authorities and local pest management experts should be consulted when making tick control decisions at tourism attractions so as to avoid costly, illegal, or harmful mistakes. where it is feasible or appropriate, tourism managers should seek out a biological tick control expert to recommend strategies for tick and/or wildlife control (e.g. deer fencing). for example, removing leaf litter and cutting back tall grass and brush in high human activity areas is a simple and low cost way to reduce ticks and tick encounters in tourism destinations. it is also recommended that tourism management stakeholders seek out educational materials from public health authorities and make them available to employees and visitors. in the united states, the cdc has a free toolkit that includes downloadable fact sheets in english, spanish, and portuguese and pamphlets and trail signs can be ordered free of charge (http://www.cdc.gov/lyme/toolkit/index. html). in michigan, the public health authority has made available a downloadable fact sheet entitled "preventing lyme disease in recreational camp settings" that provides recommendations for staff and visitor protection (http://www.michigan.gov/documents/ emergingdiseases/camp_guidelines_ _ .pdf). the california department of public health has developed an interactive website to provide information about infected ticks as part of its statewide vector-borne disease surveillance program. the data on the map represents ticks collected and tested by the california department of public health as well as vector control and public health agencies in the state (http://cdphgis.maps.arcgis.com/apps/socialmedia/ index.html?appid¼ d fb d f d a acb d ). this website is a useful model for developing publicly available risk maps for tick-borne diseases in other areas of the world. tourism managers can provide invaluable information to surveillance programs such as the one in california by reporting tick encounters and providing ticks collected in and around tourism attractions to the local authorities for testing. this information is valuable because it can inform public health authorities about emerging outbreaks and it is a pragmatic way in which the tourism industry can take an active role in the monitoring of tick-borne diseases on a local-to-global scale. the world health organization ( ) published the international travel and health book and it contains authoritative information about the geographical distribution, risk for travellers, and recommended precautions for lyme disease and a myriad of other health risks (http://www.who.int/ith/en/). on a biannual basis, the cdc (cdc & brunette, ) publishes health information for international travel or the "yellow book" as it is commonly known (http://www.cdc.gov/features/yellowbook). while it is written primarily for health practitioners, international corporations, volunteer organizations, travel industry professionals, and travellers often refer to this book for recommendations for addressing health risks and international travel. making the aforementioned resources available to employees and visitors by providing copies onsite or sharing the web links to these multimedia resources would enable access to authoritative information before, during, and after travel. tourism managers can use existent resources such as the ones mentioned and/or they can invest in the development of their own communication plan and tools so as to account for the unique risks, visitor or employee demographics, or other conditions specific to their site. for example, rocky mountain national park developed a downloadable brochure that details the health risks and unique ecology associated with ticks in the park (http://www. nps.gov/romo/planyourvisit/upload/ticks_ .pdf). it is also recommended that an occupational risk workshop or training module be offered so as to improve employee knowledge of the risks and the action they can take to prevent the disease and educate visitors. it must be stressed that regardless of the intervention, whether it be tick control or educational programs, tourism management stakeholders should consult and collaborate with travel health experts and public health authorities if we are to make any gains in tackling this health and safety issue. there is a role for tourism and it is recommended that tourism stakeholders partner with appropriate agencies and organizations, become active in local surveillance efforts, and co-develop educational or other interventions. this breadth of expertise and perspective is required for addressing and yielding positive results with respect to the complexity that is lyme and tick-borne disease control. this paper has critically reviewed and synthesized the literature concerned with lyme disease and three human risk factors have been identified. exposure was confirmed to be the only prognostic factor for infection while knowledge and personal protection behaviour were identified as mediating risk factors. the review noted that the research concerned with these risk factors is lean albeit evolving and there is much to be learned from all relevant scientific domains from anthropology, to entomology, to pathology, to zoology. by extension, there is a lot of work required to translate science into real-world solutions. piesman and eisen ( : ) state this future research need succinctly: "academic research on tick-borne diseases must be brought into the real world and effective methods for the prevention of tick-borne disease must be made cheap, easy, and safe." research funding is best spent developing a vaccine but until such a vaccine is deemed safe for widespread use or an effective tick control method is developed, research concerned with the aforementioned risk factors is needed to better inform public health interventions targeting the minutiae of human behaviour. in the tourism context, we must first expand beyond our geographical understanding so that we can better understand the spatial reach of lyme disease and destinations at-risk. risk maps are commonly used as a decision support tool by public health agencies, the medical community, and those who are tasked with protecting individual or community health. while the cdc ( ) makes an updated national risk map (based on surveillance data) available every few years, there is much for the tourism industry to learn from the fine-scale surveillance and mapping of disease epidemiology, tick populations, human behaviour, and the environment. as previously stated, tourism managers can play an active role in disease surveillance by monitoring and reporting what is happening on the ground at tourism attractions and destinations. in the global context, understanding has been constrained by research primarily focused on north america and europe. future research should focus on other endemic and emergent areas of the world. specific attention should be paid to destinations where nature-based activities are the primary touristic attraction as the potential impact of lyme and other tick-borne diseases could be significant for destination sustainability. research is also needed to better document and predict the scale and scope of the lyme disease risk associated with human activities and behaviours. in completing this review, it is apparent that behavioural research is an important but inadequately studied aspect of lyme disease prevention. activity-based risk research has focused on outdoor activities generally and outdoor work and outdoor recreation specifically. future research should focus on identifying differences, if at all, between different kinds of outdoor work and/or outdoor recreation activities. insight into these differences would certainly help tourism managers categorize the risks and plan accordingly. decisions concerning personal protection against lyme disease are made at the individual level yet little is known about perceptions of risk and other potential catalysts for protective behaviour. future research should focus on identifying unknown factors and better understanding known factors as well as their influence on an individual's choice to engage in protective behaviour. in the tourism context, the catalyst(s) may be different between the general population, tourists, and outdoor workers and this certainly requires research investments if the industry is to plan a response. future research should also be concerned with improving our very limited understanding of the impacts that lyme disease is having on the tourism industry. based on this review, we can surmise that it is having an impact on employee health, travel choices, and the economic sustainability of tourism in endemic areas but empirical research is needed to identify the scale and scope of past, present, and future impacts. theoretically driven research is needed to improve our knowledge of the relationships between public health, tourism, and the natural environment so that tourism management stakeholders can be empowered to be active agents in evolving and transdisciplinary efforts to prevent, manage, and recover from lyme disease outbreaks. holly donohoe, ph.d. is an assistant professor in the department of tourism, recreation and sport management at the university of florida. central to her research are critical examinations of tourism planning, management and marketing while evaluation science and its use of select methods and techniques for risk, impact, and policy analysis are considered her realm of expertise. current research includes projects related to vector-borne diseases and their impact on the tourism industry. studies range from baseline studies of public awareness, the analysis of public health and tourism crisis management policy frameworks, to the assessment of occupational risk for tourism a nd re creation prof essionals in at-risk environments. dr. lori pennington-gray is the director of the tourism crisis management institute at the university of florida. she received her ph.d from michigan state university ( ), her ms from the pennsylvania state university ( ) and her bs from waterloo university in canada ( ) . she has expertise in tourism marketing, planning and development, policy and crisis management. she has been involved with a number of tourism studies globally and has worked with a number of countries on tourism policy initiatives. dr. pennington-gray has published more than refereed articles, has brought in more than $ m in external research dollars and made over presentations. dr. pennington-gray teaches both undergraduate and graduate students the concepts of tourism policy, planning, marketing and crisis management. oghenekaro omodior, is a doctoral student in the department of tourism, recreation and sports management at the university of florida. he received his undergraduate training in medical laboratory sciences and a master of science degree in clinical biochemistry from olabisi onabanjo university in nigeria and masters of public health from the university of south carolina. karo's research is concerned with spatial patterns and public health impacts of vector-borne and emerging infectious diseases on tourism and outdoor recreation. he is a fellow 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uniforms: a randomizedcontrolled trial for tick bite prevention tick control: thoughts on a research agenda geography, deer, and host biodiversity shape the pattern of lyme disease emergence in the thousand islands archipelago of ontario longitudinal analysis of tick densities and borrelia, anaplasma, and ehrlichia infections of ixodes ricinus ticks in different habitat areas in the netherlands international travel and health international travel and health: lyme borreliosis (lyme disease crisis management and its impact on destination marketing: a guide for convention and visitors bureaus short-term perturbations and tourism effects: the case of sars in china economic impacts of lyme disease key: cord- - a i h authors: bittle, james l.; muir, susie title: vaccines produced by conventional means to control major infectious diseases of man and animals date: - - journal: advances in veterinary science and comparative medicine doi: . /b - - - - . - sha: doc_id: cord_uid: a i h publisher summary this chapter reviews the development of some of vaccines and their use in controlling such major diseases as diphtheria, rinderpest, newcastle disease, smallpox, pertussis, yellow fever, rabies, etc. park–williams number (pw ) strain is used to make diphtherial toxoid for vaccines. as a source of toxin, it is rendered nontoxic by incubation with formalin under alkaline conditions. the product's retention of antigenicity, enabling it to induce antitoxin antibodies, makes it an excellent pediatric vaccine. vaccine against rinderpest virus was developed by koch in by administering bile from infected cattle. animals that survived were permanently immune. formalin- and chloroform-inactivated vaccines were developed using tissues from the infected animals. for the control of newcastle disease, a number of attenuated live-virus vaccines have been developed which are widely used to control the disease. the bl strain, the lasota strain, and the f strain are used to immunize birds of all ages by different routes, including by addition to drinking water and by spraying. protection against rabies correlates with sn antibody, which can be assessed by a number of tests. pasteur's classical vaccine, developed from infected spinal cord tissue dried at room temperature for – days, was given in a series of – inoculations beginning with material dried the longest and progressing through material dried for only days. the first parvovirus shown to be a filterable agent was feline panleukopenia virus (verge and christoforoni, ) , which was not characterized until much later (johnson, a,b; johnson et al., ) . the virus affects most members of the family felidae, causing enteritis and bone marrow hypoplasia that results in severe leukopenia. the virus infects kittens in utero and postnatally causes cerebellar hypoplasia and ataxia (kilham and margolis, ) . immunization. the first panleukopenia vaccines were produced by infecting susceptible cats and harvesting their tissues. filtrates from these tissue suspensions were treated with chemical inactivants such as formalin. two inoculations of this type of vaccine produced longlasting protection (leasure et al., ; enders and hammond, ) . however, subsequent vaccines, produced in primary feline kidney cell culture and inactivated with formalin, proved safer and more effective (bittle et al., ; davis et al., ). an attenuated live-virus vaccine was also very effective in inducing immunity and protection (slater and kucera, ) . concern for the wide-scale use of an attenuated live-virus vaccine centers on the premise that shedding may spread the virus to other species, possibly allowing the emergence of pathogenic variants in these species. attempts to immunize cats orally with attenuated live-virus vaccines have not been successful, but intranasal aerosol application has been effective (scott and glauberg, ; schultz et al., ) . three members of the parvovirus family are known to infect dogs: minute virus of canines, a defective canine adeno-associated virus, and the pathogenic canine parvovirus. canine parvovirus is related to feline panleukopenia virus and may have originated from one of the mammalian parvoviruses. in young dogs, the virus causes leukopenia and severe intestinal disease with necrosis of crypt epithelium in the small intestine. myocarditis occasionally develops, causing sudden heart failure in young dogs. in an epizootic of this disease occurred in the united states, causing high mortality (eugester, ) . immunization. because of the close relationship between feline panleukopenia virus and canine parvovirus, inactivated feline panleukopenia vaccine initially was used to protect susceptible dog populations (appel et al., a) . later, inactivated and attenuated vaccines produced with the canine virus proved to be much more effective (pollack and carmichael, ; appel et al., b) . these parvovirus vaccines have been formulated with other vaccines, including canine distemper and canine adenovirus vaccines, and are administered routinely to young dogs. porcine parvovirus has a distant serologic relationship to other parvoviruses, but it causes disease only in swine. the virus, which is widespread, causes abortions, fetal death, and infertility in sows infected early in gestation. immune sows reinfected during gestation give birth to normal piglets. immunization. numerous reports have shown the effectiveness of inactivated porcine parvovirus vaccines in swine (suzuki and fujsaki, ; mengeling et al., ; wratthal et al, ; fujisaki et al., ; joo and johnson, ) . for example, mengeling et al. ( ) demonstrated the value of a vaccine in which the virus was inactivated with acetylethyleneimine. an attenuated live-virus vaccine has been described (paul and mengeling, ) in which a porcine isolate was attenuated by - passages in a swine testicular cell line. this vaccine effectively induced antibodies and protected challenged animals. the vaccine virus did not cross the placenta; however, it did kill fetuses when inoculated in utero. the virus was shed in feces, and so could be transmitted to unvaccinated animals. the inactivated vaccines now used in united states have been effective in controlling porcine parvovirus infection. vaccination is recommended for gilts and sows before breeding. adenoviruses cause significant disease in dogs, foxes, and man, but have also been isolated from cattle, swine, goats, sheep, horses, turkeys, and chickens, where they produce mild infections, mainly associated with the respiratory and intestinal tracts. there are at least different adenoviruses, of which occur in man. each adenovirus has a narrow host range. there are two canine adenoviruses. canine adenoviruses (cav- ) causes infectious canine hepatitis, which at one time was widespread, but now has been controlled by vaccination. infected dogs also develop corneal opacities following this infection, as a result of the formation of immune complexes and uveitis within the anterior chamber of the eye (carmichael et al., ) . in foxes, cav- produces a rapidly fatal encephalitis. canine adenovirus (cav- ) causes respiratory disease in dogs, but neither hepatitis nor encephalitis in dogs or foxes. the respiratory disease varies depending on the strain of virus and bacterial superinfection. cav- may be transmitted by aerosol, whereas cav- is spread by other direct means such as contact with urine or saliva from infected animals. cav- and cav- are oncogenic in experimentally infected hamsters (sarma et al., ; dulcac et al., ) . immunization. dogs that recover from natural cav- infection are immune for a long period. the first cav- vaccines were produced by formalin inactivation of tissue homogenates from infected dogs. cav- was first adapted to tissue culture by cabasso et al. ( ) and by fieldsteel and emery ( ) . the latter modified the virus by serial passage in porcine and canine tissue cultures; the resulting vaccine immunized dogs and did not produce clinical signs of infection except for occasional corneal opacity similar to that caused by natural infection. dogs immunized with cav- vaccines are also protected against cav- (appel et al., ) . the immunity produced by the attenuated live-virus cav- vaccines is long lasting and has drastically reduced the incidence of the canine disease. although cav- is closely related to cav- , when it is inoculated parenterally into dogs, it does not cause disease, although the virus is shed from the respiratory tract (appel et al., ) . such dogs become immune to both cav- and cav- . an attenuated live-virus vaccine containing cav- is now being widely used in place of older cav- vaccines (bass et al., ) ; this has resulted in a much lower incidence of corneal opacity in recipients. however, because of the oncogenicity of adenoviruses in other hosts, the respiratory shedding of cav- virus should be a concern. in man, adenoviruses mainly produce disease of the respiratory tract which varies in severity depending on the virus and the age of infected individuals. the viruses cause acute pharyngitis in infants and children, pharyngitis and conjunctivitis in children, and acute respiratory disease (ard) in military recruits and institutionalized young adults. pneumonia may also occur, expecially following ard. a vaccine consisting of adenovirus types , , and , grown in monkey kidney cell culture and inactivated with formalin, was introduced in for use in u.s. military recruits. the vaccine was effective in reducing ard in this population (sherwood et al., ) . however, the vaccine was withdrawn from use in because of concern for possible oncogenicity of the adenoviruses, and of the sv virus present in the monkey kidney cell culture. a subsequent adenovirus, type , was passed in human tissue and was, therefore, devoid of sv genomic material. this virus, encapsulated in enteric-coated capsules, proved to be a safe and effective vaccine edmonson et al., ). an adenovirus vaccine, prepared in the same way and given simultaneously with adenovirus vaccine, was equally effective (top et al., ) . the administration of a vaccine with only one of these viruses was not effective in controlling ard caused by any of several different adenoviruses, but formulation of a vaccine with both viruses proved to be broadly cross-protective and have had a major influence in controlling ard in u.s. military recruits. over herpesviruses produce disease in man and animals. these viruses have an affinity for epithelial tissues and nervous system tissues. these tropisms lead to specific disease syndromes involving the respiratory and urogenital tracts, and the central and peripheral nervous systems. the viruses often cause persistent infections, which can be latent and can be reactivated. herpesvirus disease are generally much more severe in young humans and animals. some herpes-viruses, including epstein-barr virus (ebv) in humans and marek's disease virus in fowl, are associated with malignancies. the presence of specific antibodies may prevent or modify the clinical disease but does not prevent infection. vaccines have been developed for those herpesviruses causing major diseases in animals; however, despite the seriousness of human herpesvirus diseases, including those caused by herpes simplex virus, ebv virus, cytomegalovirus, and varicella virus, progress has been slow in developing vaccines for humans. this stems from concern over possible persistence and oncogenicity of vaccine viruses. in the past few years, several attenuated live-virus varicella vaccines have been tested and found safe and efficacious (takahashi et al., ; asano et al., ; arbeter et al, ) . since the initial recognition of infectious bovine rhinotracheitis (ibr) in the early s and the later recognition of another manifestation of the disease, infectious pustular vulvovaginitis, this bovine herpesvirus has been acknowledged as a major problem in livestock. the respiratory disease varies from mild to severe, and herd mortality can be as high as % in an acute outbreak. the virus may cause abortions in pregnant cattle, and the genital disease results in a chronic vulvovaginitis but not abortions, apparently due to a lack of viremia. immunization. attenuated live-virus vaccines were developed by serial passage of field isolates in bovine kidney cell cultures. such vaccine viruses have reduced virulence when administered intranasally and do not produce disease when administered parenterally york et al., ) . vaccine virus does not spread from vaccinated to unvaccinated contact animals. the widescale use of such vaccines has controlled this disease effectively. when administered by the intranasal route (todd et al., ) , these vaccines had the advantage of producing more rapid protection, but long-term protection was no greater than with perenterally administered vaccines (mckercher and crenshaw, ) . because of the possibility that the attenuated live-virus vaccines given parenterally might cause abortion, their use has been restricted to nonpregnant animals. a formalin-inactivated vaccine has also been developed, but requires multiple inoculations, and the serum neutralizing (sn) antibody response is low (matsuaba et al., ) . however, inactivated vaccines are used especially in dairy cattle because of concern that the attenuated live-virus vaccines may cause abortion. four herpesviruses affect horses: equine rhinopneumonitis virus (ehv- ) causes abortion which may be epizootic, and also, occasionally, rhinopneumonitis; ehv- is cytomegalovirus found in buffy coat cells of most horses, but its role in causing disease is unknown; ehv- causes equine coital exanthema, a urogenital tract disease; and ehv- is the main cause of equine rhinopneumonitis. ehv- and - are related antigenically, whereas types and are distinct (sabine et al., ; studdert and blackney, ) . immunization. the first vaccine for equine rhinopneumonitis was developed by doll and bryans ( ) , who adapted an ehv- isolate to suckling hamsters. this vaccine produced a mild disease, but induced protective immunity against the more serious respiratory disease and abortion that occurs in older animals. however, this vaccine sometimes caused abortions, and the virus was known to spread from vaccinated to unvaccinated horses. a more attenuated strain of ehv- has been used widely and is considered to be reasonably effective (mayr, ) . this strain was attenuated by passage in hamsters and in pig kidney cell culture before adaptation to an equine cell line (gerber et al., ) . this vaccine induces low levels of sn antibodies, and protects against respiratory disease but not against abortion. a formalin-inactivated vaccine, emulsified in an oil adjuvant, has also been found safe and effective in preventing respiratory disease. this vaccine, in controlled field trials, lowered the abortion rate significantly (bryans, ; bryans and allen, ) . the attenuated live-virus and the inactivated vaccines contain only ehv- , but apparently there is enough cross-protection induced by repeated vaccinations to protect against the ehv- respiratory disease. this herpesvirus is unusual in that it occurs naturally in many species-cattle, sheep, goats, swine, dogs, cats, rats, and mice. it produces a fatal disease in all of these species except adult swine, in which the disease is mild. in each species except swine the primary sign is intense puritis resulting in the animal biting the affected area. infection rapidly spreads to the central nervous system, leading to paralysis and death. in adult swine, the signs of infection are mild, usually of a respiratory nature, but abortions follow in approximately % of pregnant sows. in young pigs, especially neonates, the infection may be fatal. since the disease is prevalent only in swine, this is the only animal for which a vaccine has been developed. in examining a virulent strain of pseudorabies virus, bartha and kojnok ( ) found two plaque sizes. the small plaque size variant, called k, occurred naturally and had reduced virulence for rabbits. further studies with this strain passaged in chick embryo or calf testicle cell culture produced a safe vaccine for swine. one dose induced partial immunity and a second dose yielded good immune responses in all recipients. mcferran and dow ( ) adapted the Κ strain to vero cells and showed that one dose of a vaccine prepared from this passage material was protective. pigs vaccinated with this vaccine did not shed the virus. although the vaccine did not prevent infection, it prevented clinical disease. this attenuated live-virus vaccine is used widely. feline rhinotracheititis virus, which was first isolated in , produces a widespread respiratory disease in cats (crandell and maurer, ) . the virus may also cause fetal death. immunization. an attenuated live-virus vaccine was developed by passage of a field isolate in feline kidney cells (bittle and rubic, ) . the vaccine is given parenterally and is safe and effective (scott, ) . low levels of sn antibodies persist for at least months. vaccinated cats are resistant to intranasal instillation of virulent virus; they may be reinfected, but do not develop clinical disease (bittle and rubic, ; kahn et al., ) . the vaccine has controlled this important respiratory pathogen and, when combined with a feline calicivirus vaccine, has drastically reduced the incidence of respiratory disease in this species. this herpesvirus is highly contagious and causes lesions in the larynx, trachea, and bronchi of infected fowl. the infection causes the formation of an exudate that produces the characteristic respiratory distress and rattling in severely affected birds. birds that recover from this disease are immune for a long period, but may remain as carriers and a source of virus for reinfection of flocks. immunization. the earliest method of immunization was developed by beaudette and hudson ( ) , who applied virulent virus from tracheal exudate to the mucosa of the bursa of fabricius and the cloaca with a stiff brush. this produced a local infection and a solid systemic immunity. the use of fully virulent virus caused occasional outbreaks of disease, particularly when the scarification was not properly done or insufficient virus was present, and birds did not become immune. the virus was propagated on the chorioallantoic membrane of embryonated eggs by burnet ( ) , and this became a source of vaccine material. other methods of vaccination involved intranasal instillation (benton et al., ) and feeding in drinking water (zamberg et al., ) . attenuated strains of ltv have been developed by serial passage in cell culture (gelenczei and marty, ) and by feather follicle passage (molgard and cavett, ) . attenuated strains isolated from outbreaks or selected from passage are now used in preference to virulent virus. marek's disease virus causes lymphoproliferative disease in chickens, occurring in three forms: neural, ocular, and visceral (the latter mainly in young birds) (sevoian and chamberlain, ; biggs and payne, ) . sevoian was the first to provide evidence that marek's tumors were caused by a virus and were transmissible. the virus has been established as a gamma herpesvirus (churchill and biggs, ; soloman et. al., ) . immunization. fatalities from marek's disease caused major economic losses in the poultry industry until a vaccine was developed for its control. this was accomplished by churchill et al. ( ) , who attenuated by serial passage a virus isolated from chickens that is parenterally administered at day of age. thereafter, okazaki et al. ( ) selected a herpesvirus from turkeys (hvt) that was relatively avirulent in chickens, and zander et al. ( ) and schat and calnek ( ) , selected a natural avirulent strain from chickens. these three vaccines are effective, but the hvt strain has been more widely used because it can be obtained from infected cells and can be lyophilized (calnek et al., ) . the vaccines are given parenterally to chicks at hatching and produce good protection ( - %) against virulent virus challenge (purchase et al., ) . viruses of the family poxviridae infect most domestic animals and man. from the standpoint of immunoprophylaxis, the most important poxviruses are: orthopoxvirus, smallpox (variola), mousepox (ectromelia); avipoxvirus, fowlpox, pigeonpox; capripoxvirus, sheeppox, goatpox; leporipoxvirus, myxomatosis virus; parapoxvirus, contagious pustular dermatitis virus. all these poxviruses cause serious disease in their primary host species and some may infect other species. each of the poxviruses causes characteristic vesicular lesions on the skin and mucous membranes, with the exception of myxomatosis virus which produces hyperplastic lesions in the form of myxomas and fibromas. ectromelia (mousepox) is caused by a virus closely related to vaccinia virus and produces a serious disease of laboratory mice. vaccination with vaccinia apparently will reduce the morbidity and mortality of mousepox in a colony, but it will not prevent infection and may act to maintain a silent reservoir of virus (buller and wallace, ) . sheeppox is one of the most serious pox diseases, occurring in europe, the middle east, and africa, but it is controlled by vaccination (aygun, ; sabban, ) . goatpox occurs mainly in the middle east and africa; a goatpox vaccine has been reported to also immunize against sheeppox (rafyi and ramyar, ) . contageous pustular dermatitis virus is unrelated to sheeppox, but causes a pox-like disease in young lambs in which vesicles form around the skin of lips, nostrils, and eyes. boughton and hardy ( ) showed that animals could be protected by scarification with dried contageous pustullar dermatitis virus material similar to that use with vaccinia. myxomatosis virus causes a fatal disease of domestic rabbits and may be spread by direct contact or by blood meals of insects such as mosquitos and fleas (myers et. al., ) . mckercher and saito ( ) developed a safe and efficacious attenuated live-virus vaccine by passage of the virus in rabbit kidney cell culture. this virus, once the cause of epidemics that decimated entire cities, has now been eradicated. the control was brought about by worldwide vaccination and isolation of infected persons. another factor in the control of smallpox was that variola virus had no other host except man. immunization. material from lesions of smallpox-infected individuals had been used for centuries to infect susceptible persons so they would develop a mild form of the disease and become resistant. this variolation was dangerous but much safer than natural exposure to the smallpox virus. jenner ( ) practiced an improved form of this method by using cowpox virus (vaccinia) to inoculate susceptible persons, as described in chapter . most vaccinia vaccines were produced by scarifying the skin of a calf with infected material and harvesting the lymph from the crusted lesions as aseptically as possible. this was stored in % glycerol to stabilize the virus and preservatives were added to destroy bacteria. sheep and rabbits were also used similarly for vaccine production. vaccinia virus was also adapted to grow in embryonated eggs (goodpasture et al., ) . vaccinia virus is very stable, can be produced at a low cost, and is simple to administer. these factors played a major role in allowing the wide-scale use of vaccinia for the eradication of smallpox. fowlpox virus occurs mainly in chickens and produces pox lesions on the wattles, comb, mouth, nostrils, and eyes. the disease is spread mainly by direct contact with infected birds and blood-sucking parasites such as mosquitoes. although it is a fairly resistant virus, it is not otherwise very transmissible. immunization. fowlpox vaccine was originally made by scarifying cockrel combs with virulent virus and harvesting the exudate. johnson ( ) demonstrated that dried exudate would produce immunity when scarified in the wing web or applied to the thigh skin free of feathers. fowlpox virus was later cultivated on the chorio allontoic membrane by goodpasture et al. ( ) and used as a source of vaccine material. later the virus was adapted to tissue culture. an attenuated live-virus fowlpox vaccine produced in cell culture may be used in -day-old chicks (siccardi, ) . another vaccine, an attenuated strain (hp- ) developed by mayr et al. ( ) , is given orally to -day-old chicks, then repeated after to months. hepadnaviridae is a new-found family of viruses containing hepatitis Β virus of man as well as three similar but distinct viruses that infect woodchucks, beechey ground squirrels, and pekin ducks. these viruses have many of the same ultrastructural, molecular, and biological features and their surface antigens cross-react to a small, variable degree. the host range appears to be specific for each virus. hepatitis Β infects man and certain higher primates, including the chimpanzee and gibbon. infection with these hepadnaviruses results in subacute hepatitis, which often becomes progressive and chronic. the most important of these viruses is hepatitis Β virus, which produces a chronic disease in man (blumberg et al., ; prince, ) . hepatitis Β virus is transmitted by blood, saliva, and semen, but also from mother to offspring, the latter route accounting for as much as one-third of persistent infections. the disease is usually selflimiting, but in - % of patients the infection becomes chronic, with the virus persisting in a carrier state. there are over million chronic carriers of this virus worldwide. a late sequela in chronic carriers is hepatocellular carcinoma. it is estimated that - % of malignancies in africa are the result of hepatitis b-induced oncogenesis. immunization. the development of a vaccine for hepatitis Β was hampered by the difficulty of growing the virus in cell culture. krugman et al. ( ) was the first to show that hepatitis Β virusinfected serum could be heat-inactivated and retain its antigenicity. they also showed that this inactivated serum given parenterally could protect subjects exposed to virulent hepatitis Β virus. this led to the use of plasma from infected but healthy virus carriers as the source of antigen. carriers produce large quantities of the hepatitis Β virus, along with its outer coat protein. by purifying and inactivating the coat protein, a safe and effective vaccine was developed (hilleman et al., ) . the coat protein, naturally formed into -nm particles, was purified by ammonium sulfate concentration, isopycnic banding, rate zonal separation and enzymatic digestion. the purified protein particles were then inactivated with : formalin. the particles induce good levels of protective antibody when given in a series of three injections (symuness et al., ) . however, the high cost of this vaccine has limited its use. newer vaccines produced by recombinant dna methods are now being used, as described in other chapters. the four genera in the family picornaviridae are: aphthovirus, rhinovirus, enterovirus, and cardiovirus. viruses in the first three genera cause important diseases in domestic animals and man, whereas viruses in the fourth infect rodents. the picornaviruses in general have a primary affinity for superficial tissues especially of the digestive and respiratory tracts. viruses in the first three genera also have an ability to mutate, thus yielding many serotypes. rhinoviruses cause clinical disease in man, horses, and cattle. no vaccines have been developed for the infections of humans because of the multiplicity of viral serotypes. the number of serotypes in horses (three) and cattle (two) is fewer; nevertheless, no vaccines are available. over enteroviruses exist; of these, vaccines have been developed only for poliomyelitis viruses, avian encephalomyelitis, and duck hepatitis viruses. other viruses in this group either are of low pathogenicity or the number of serotypes is so large as to preclude the development of vaccines. the exception is human hepatitis a virus, which causes a serious disease and has one serotype; the development of both inactivated virus and attenuated live-virus vaccines is in progress (hilleman et al., ; provost et al., ) . fmd was the first animal disease shown to be caused by a virus (loeffler and frosch, ) . fmd viruses cause one of the most economically important diseases of animals and its control is critical to the world's supply of animal protein. the viruses are widespread and occur in many cattle producing regions of the world. the viruses also affect other cloven-footed animals including sheep, swine, and goats. fmd virus infection produces vesicles on oral mucous membranes, including the tongue, gums, and dental pads, but also on the skin including the interdigital spaces and teats. these vesicles on the mucous membranes coalesce and erupt, leaving large denuded areas. the mucous membrane and skin lesions can incapacitate an animal for weeks, thus severely disrupting its productivity. the viruses are highly contagious and persist for long periods in infected animals. animals that recover from natural infection are immune for approximately one year. vallee and carre ( ) showed that there was more than one fmd virus; seven serotypes with over subtypes have now been identified, making the development of effective vaccines difficult. immunization. the first fmd vaccine for cattle was reported in and consisted of a formalinized emulsion of vesicular epithelium (vallee et al., ) . a similar but improved version called the schmidt-waldmann vaccine followed and contained vesicle material from the tongue epithelium of infected cattle. this material was treated with formalin and used with aluminum hydroxide (schmidt, ; waldmann and klobe, ) . another advance was described by frenkel ( ) , who infected superficial layers of bovine tongue epithelium in culture and inactivated the newly replicated virus with formalin to produce a more uniform product. although this method is used today in some areas of the world, most fmd vaccines are now produced by growing the virus in baby hampster kidney cells (mac-pherson and stoker, ; mowat and chapman, ; capstick et al., ) . the imines replaced formalin as an inactivant in most fmd vaccines after brown et al. ( ) showed that viral inactivation was more complete, and safer vaccines could be produced by this process. all inactivated fmd vaccines contain more than one serotype, including the serotypes most common in the area in which the vaccines are to be used. although inactivated vaccines that are produced and used properly can effectively lead to the control fmd, their stability could be improved, thereby lowering their cost. this is discussed further in the chapter by brown. attenuated live-virus fmd vaccines have been developed (henderson, ) but are not used because of the fear that the virus might persist in animals and in meat and milk products from animals (hyslop, (hyslop, - . there are three polio viruses and minor variants of each. the viruses infect man by entry into the upper alimentary tract, infecting cells, and spreading via the blood to the central nervous system, producing neuronal destruction in the medulla and spinal cord. the degree of paralysis that follows infection depends on such factors as virus strain and virus tropism. the vast majority of persons infected with wild polio viruses show no apparent clinical disease. paralysis occurs only in an estimated % of infected individuals; polio virus is responsible for at least % of cases. immunization. early attempts to develop inactivated poliovirus vaccines were hampered by not knowing that there are three distinct viruses. the differentiation of the three viruses by bodian ( ) and kessel and pait ( ) was a major step toward controlling the disease. enders et al. ( ) found that poliovirus would grow in extraneural tissues of human origin and thus laid the groundwork for the development of poliovirus vaccines. the first vaccine (salk) contained all three polio viruses grown in monkey kidney cell culture and inactivated with formalin (salk et al., ) . this vaccine, introduced in , reduced the incidence of paralytic poliomyelitis - % where it was used; however, multiple doses were required and intestinal tract infection was not prevented, thus allowing the virus to continue to spread. there was an intense effort in the s to develop an attenuated live-virus vaccine that could be administered orally, and could protect the intestinal tract, thus breaking the chain of transmission. koprowski, sabin, and cox each developed vaccine strains of reduced neurovirulence that underwent extensive laboratory and field studies (koprowski et al., ; sabin, ; cox et al., ) . the strains developed by sabin were finally licensed in the united states; they produced rapid immunity as well as protection of the intestinal tract while preventing spread to unvaccinated, susceptible persons in contact with vaccinées. this improved the overall level of immunity in communities. with the widescale use of oral poliomyelitis vaccine, the incidence of paralytic disease in the united states has dropped to less than cases per year. the occasional reaction to the attenuated vaccine is discussed in the chapter by hogle and filman. avian encephalomyelitis was first discribed and shown to have a viral etiology by jones ( jones ( , . the virus is widespread and affects young chickens ( - weeks old). characteristic clinical signs are ataxia and tremors of the head and neck. extensive neuronal degeneration occurs in the anterior horn of the cord and in the medulla and pons. the virus may affect older laying birds, causing a drop in egg production. flocks that have survived an outbreak or subclinical infection during the growing period are resistant to further infection (schaaf and lamoreux, ) . moreover, infected chickens - weeks of age undergo only mild disease, providing an opportunity for vaccination (schaff, ) . calnek and taylor ( ) successfully immunized immature birds with an attentuated live-virus vaccine delivered in drinking water. a number of vaccines have been developed including the strain (calnek, ) , the nsw- strain (westbury and senkovic, ) , the philips duphar strain (folkers et al., ) , and a strain grown in chicken pancreas cell culture (miyamae, ) . inactivated ae virus vaccines have been developed for use in susceptible breeding flocks that are in production (schaaf, ; calnek and taylor, ; butterfield et al., ; macleod, ) . two viruses in the family caliciviridae cause significant disease in animals, vesicular exanthema virus in swine and sea lions and feline calicivirus. caliciviruses have also been isolated from humans, calves, reptiles, nonhuman primates, birds, dogs, and fish, but do not produce significant disease in these animals. vesicular exanthema virus caused a disease in swine closely resembling fmd (traum, ) . eradication of this disease followed the discovery that the main source of contagion was uncooked infected meat in garbage fed to swine, and the consequent enforcement of garbage cooking laws. fastier ( ) first isolated a calicivirus from a domestic cat and showed that it produced an upper respiratory tract infection. a large number of viral isolates, with different neutralization patterns, were made from clinically ill cats (crandell et al., ; bittie et al., ) . these serotypes were later shown to have a common antigen and are now considered a single serotype (povey and ingersoll, ) . this virus is widespread, having been isolated from cats in many countries. the virus produces a disease that is generally mild, but, if allowed to progress, the lesions may extend from the upper respiratory tract into the lung causing pneumonia and death (kahn and gillespie, ) . immunization. cats that recover from natural infection and have neutralizing antibodies can be reinfected, but they do not have recurrent clinical disease. an attenuated live-virus calicivirus vaccine has been prepared by serial passage at low temperature; this vaccine virus produces only mild clinical signs in recipients (bittle and rubic, ) . this attenuated live-virus vaccine is administered parenterally; it induces high levels of neutralizing antibody and protects vaccinated cats challenged intranasally with both homologous and heterologous strains (kahn et al., ; scott, ) . immunity from vaccination persists for at least months and probably longer. the calicivirus is combined with feline rhinotracheitis and feline panleukopenia to make a multivalent vaccine that is routinely used in domestic cats (bittle and rubic, ) . inactivated vaccines have also been licensed and are used in multivalent vaccines. the family reoviridae is divided into three genera: reovirus, rotavirus, and orbivirus. infections cause by member viruses are common in mammals and birds. reoviruses are commonly isolated from dogs, cats, sheep, cattle, horses, mice, rats, rabbits, birds, and man. only in birds is the disease serious enough to warrant control with vaccines. the reoviruses are commonly found in sewage, and the mode of transmission is thought to be the fecal-oral route. avian reovirus. in chickens and turkeys, reoviruses produce a widespread disease called viral arthritis (tenosynovitis). this disease of the synovial membranes, tendon sheaths, and myocardium was first recognized by dalton ( ) and by olsen and solomon ( ) . viral arthritis occurs primarily in meat-producing birds, and in acutely affected flocks there is a high rate of condemnation. there are at least five avian reovirus serotypes, but they are antigenically unrelated to the mammalian reoviruses. immunization. vaccination of breeding stock is an effective way to control viral arthritis. van der heide et al. ( ) used an attenuated live-virus vaccine and cessi and lombardini ( ) used an inactivated vaccine in laying hens to protect chicks with maternal antibody. this eliminated transmission and protected susceptible day-old chicks. rotaviruses produce acute gastroenteritis in many species, especially in newborns, including newborn calves, foals, lambs, piglets, puppies, monkeys, and humans. the clinical signs are similar in all species; in each there is acute diarrhea followed by dehydration and rapid loss of weight. secondary bacterial infection may exaggerate the symptoms and also cause pneumonia. the viruses infect epithelial cells of villi, causing desquamation and loss of absorptive function, resulting in diarrhea, rapid dehydration, and emaciation. secretory antibody is very important in protecting the epithelial surface of the small intestine (snodgrass and wells, ) ; antibody contained in colostrum is protective when in high titer. a. bovine rotavirus. bovine rotovirus causes a rapidly spreading disease in neonatal calves (mebus, ) . the antigenic relationship of the bovine rotavirus and other rotaviruses isolated from children, calves, piglets, mice, and foals is very close (woode et al., ) . immunization. an attenuated live-virus vaccine developed by mebus et al. ( ) is administered in two doses to cows prior to calving. this is meant to stimulate colostral antibody, which is passed on to the nursing calves. this vaccine has also been combined with an attenuated live-virus coronavirus vaccine and entero-toxigenic e. coli vaccine to prevent calf scours. b. porcine rotavirus. leece et al. ( ) isolated a rotavirus from piglets with fatal diarrhea. additional reports of this disease showed that it was widespread and warranted the development of a vaccine for its control. immunization. early attempts to immunize pigs by oral administration of a bovine attenuated live-virus rotavirus vaccine were unsuccessful (leece and king, ) . presently an attenuated porcine rotavirus vaccine containing two serotypes, a and a , is licensed in the united states and is being used in combination with a transmissible gastroenteritis (tge) vaccine. the vaccines are administered to pregnant sows by both parenteral and oral routes. at least two doses of vaccine are given orally, and weeks before farrowing, and one dose is given parenterally week before farrowing. this induces antiviral colostral antibody for the protection of suckling piglets. the member viruses of this genus replicate in arthropods as well as in vertebrates. the most important viruses are the bluetongue viruses, and african horse sickness viruses. colorado tick fever virus, the only virus in this genus that infects man, is transmitted by the bite of infected ticks. the disease is usually benign, and infection produces long-lasting immunity. a. bluetongue virus. bluetongue viruses infect ruminants and are transmitted by culicoides gnats. the most serious disease is in sheep, which develop fever, depression, oral lesions, pneumonia, and lame-ness. mortality can be high, especially in lambs. ewes infected early in gestation may produce lambs with hydrocephalus and other congenital deformities. although cattle rarely have clinical bluetongue disease, in utero transmission can occur, resulting in congenital deformities. of the distinct bluetongue viruses, occur in the united states. infection with one bluetongue virus confers resistance to reinfection with that same virus for several months, but cross-protection against infection with other viruses is minimal. a multivalent attenuated live-virus vaccine developed in south africa by serial passage of several different viruses in sheep proved difficult to standardize. a more uniform vaccine was later developed by alexander et al. ( ) ; it contained strains of at least five viruses, attenuated by passage in chick embryos, and gave broad protection against the multiple viruses seen in the field. a similar vaccine was developed by mckercher et al. ( ) , who isolated bluetongue virus in the united states and also attenuated a strain of serotype by serial passage in chick embryos (mckercher et al., ) . recently mcconnell and livingston ( ) have been attempting to incorporate more bluetongue virus strains into multivalent attenuated live-virus vaccines. inactivated vaccines for bluetongue would have the advantage of greater safety than attenuated live-virus vaccines. they would eliminate the possible chance of reversion to virulence, and the chance of vaccine-associated abortion and birth defects. such vaccines are under development (stott et al., ) . . african horse sickness virus. african horse sickness virus causes an acute disease in equine animals in africa, the middle east, and asia. it was shown to be caused by a virus (mcfadyean, ) and has been more thoroughly characterized by breeze et al. ( ) . the viruses are transmitted to horses by culicoides species and affect principally the vasculature of the respiratory tract causing edema of the lungs, head, and neck. the viruses also cause cardiac lesions. immunization. some animals that recover from natural infection may be reinfected, so immunity is not permanent. a spleen pulp vaccine inactivated with formalin was made by dutoit et al. ( ) and administered in multiple doses. later, an attenuated live-virus vaccine was developed by serial intracerebral passage of a field isolate in mice (alexander and dutoit, ) . however, because there are nine african horse sickness viruses, it has been necessary to adapt each to mice and to combine them in a polyvalent vaccine. such vaccine has been effective in protecting horses. the virus that causes ibd was first isolated by winterfield and hitchner ( ) using embroyonated eggs. it causes a disease of chickens in commercial poultry-producing areas. the virus affects mainly young birds - weeks of age, with clinical signs of diarrhea and dehydration. the lesions arise in lymphoid tissues such as the bursa of fabricius, thymus, and spleen, producing immunosupression with the associated opportunistic infections. immunization. both attenuated live-virus and inactivated vaccines have been developed to control ibd. the vaccines are used mainly for immunizing breeder flocks to confer passive immunity through the yolk sac of the egg. maternal antibody protects chicks for - weeks. if breeder flocks are boosted with oil-adjuvant-inactivated vaccines, maternal antibody may last longer. there are several types of attenuated live-virus vaccines with varying degrees of virulence. these vaccines are administered in water, etc., to chicks from day to - weeks of age in broiler-breeder flocks, followed by vaccination with an inactivated product at approximately - weeks of age (lukert and hitchner, ). the four genera in the family togaviraidae are: alphavirus, pestivirus, rubivirus, and arterivirus. each of these genera contain important pathogens. the alphavirus genera include: all cause encephalitis in horses and humans. in horses, the mortality rate of eee in over %, and that from wee is about - %. the main mode of transmission is by culicine mosquitoes; however, vee has been transmitted from horse to horse by contact with body fluids. immunization. infections with togaviruses produce viremia, longterm humoral antibody responses, and immunity. early vaccines were made from formalin-inactivated infected animal brain tissue. the cultivation of both wee and eee in the chick embryo by higbee and howitt ( ) made possible the development of successful inactivated vaccines (beard et al., ) . more recent vaccines for wee and eee are produced in tissue culture. an attenuated live-virus vee vaccine, first developed for humans, is also used for horses in endemic areas (berge et al., ; mckinney et al., ) . the vaccine virus is grown in primary chick embryo cell cultures; it induces long-lasting immunity. an inactivated vee vaccine has also been developed and is combined with wee and eee vaccines in a trivalent formulation. a. hog cholera (hc) virus. hog cholera virus and bovine virus diarrhea (bvd) virus antigenically are closely related pestiviruses, but are specific in the diseases they cause in swine and cattle, respectively. hc virus produces an acute febrile disease marked by multiple hemorrhages, necrosis, and infarcts in internal organs. lethargy, vomiting, and encephalomyelitis are seen in a high percentage of infected animals during an outbreak and mortality is high. immunization. passive protection with convalescent swine serum from swine has been used effectively for short-term control of outbreaks for many years (dorset et al., ) . antiserum and either virulent or partially attenuated virus strains were also used to establish active immunity. although there is only one antigenic type of hc virus, variant biotypes have arisen that are more difficult to protect against with standard vaccines. the presence of neutralizing antibody correlated well with protection. an inactivated virus vaccine prepared from defibrinated swine blood taken during the acute phase of the disease and treated with crystal violet or phenol was safe, but required multiple doses (mcbryde and cole, ) . attenuation of hc virus was first accomplished by passage in rabbits (baker, ; koprowski et al., ) . tissue culture attenuated live-virus vaccines eventually replaced the rabbit vaccine; the latter produced a rapid and long-lasting immunity. a large number of different attenuated live-virus hc vaccines with different characteristics have been used over the years, but residual pathogenicity, shedding, and spread of vaccine viruses have remained problems. a vaccine containing bvd virus was tested in swine, based on evidence that this virus could block replication of hc virus (sheffy et al., ) . however, the bvd vaccine did not protect against all strains of hc virus (tamoglia et al., ) . formerly, control of hc was difficult because hc virus persists in infected meat scraps fed to swine in uncooked garbage. however, since no vaccines have been used in the united states. by controlling the transport of swine and cooking all garbage used as feed, the disease has been eradicated from the united states, and several european countries. b. bovine virus diarrhea (bvd) virus. bvd virus causes a widespread disease of cattle, especially in young stock. clinical signs, which vary in severity, include scouring, ulcerations of the oral cavity, and abortion. young animals that recover often remain stunted and unproductive for long periods. bvd viral strains differ in their cytopathic effects in tissue culture; cattle infected with noncytopathogenic strains during the first months of gestation can transmit the virus to the fetus, which may be born viremic and immunologically tolerant. later exposure to cytopathogenic strains, naturally or by vaccination, can cause offspring to develop the more severe form of the disease (bolin et al., ) . a cytopathogenic strain of virus isolated from a calf and designated oregon (c v) strain (gillespie et al., ) became less pathogenic for calves after passages in bovine kidney tissue culture . this has been the standard vaccine strain and has been used widely for many years. for cattle never exposed to bvd antigen, this vaccine strain is safe and effective; however, persistently infected cattle may react strongly to vaccination with the cytopathic strain of bvd virus, causing a mucosal disease syndrome. it is important to identify and eliminate persistently infected cattle from herds. rubella virus. in man, rubella virus causes a generally mild exanthematous disease, with malaise and respiratory symptoms. complications include arthritis, thrombocytopenia purpura, and encephalitis. gregg's observation ( ) that rubella virus produces fetal abnormalities if infection occurs early in pregnancy emphasized the destructive effects of this virus and the need to develop a means to protect against infection. immunization. natural exposure to rubella virus evokes nasopharyngeal antibody, which is important in preventing reinfection. antibody, especially igg antibody in mother's plasma, is important in preventing fetal infection. two groups isolated rubella virus in tissue culture (parkman et al., ; weller and nova, ) , allowing the first attempts to develop vaccines. both inactivated and attenuated live-virus vaccines were tried before the latter evolved as superior products. the attenuated live-virus vaccines were developed using different cell culture systems, including monkey kidney (parkman et al., ) , duck embryo (buynak, ), rabbit kidney (peetermans and huygelen, ) , canine kidney (musser and hilsabeck, ) , and human diploid cells (plotkin, ) . the vaccines now being used are more than % effective in inducing protective levels of antibody that persist for at least years. the annual incidence of rubella in the united states has dropped from , reported cases in to less than in . equine arteritis virus. equine arteritis virus was first isolated by doll et al. ( ) . the disease caused by this virus is characterized by edema of limbs, stiffness, and swelling in the tissues surrounding the eye, and abortion. immunization. horses that recover from infection develop longlasting immunity. an effective attenuated live-virus vaccine was developed by serial passage of bucyrus field strain virus in primary equine and rabbit kidney cell culture and an equine dermal cell line (doll et al., ; wilson et al., ; mccollum, ). the vaccine has been shown in challenge trials to protect recipients for as long as months (mccollum, ) ; it does not cause any clinical manifestations and it is not spread to susceptible horses in contact with vaccinated recipients. yellow fever virus causes acute hepatitis and hemorrhagic fever in man, characterized by jaundice, shock, and renal damage. transmission is by mosquitoes belonging to the aedes genus throughout tropical areas of south america and africa. the virus is maintained in a transmission cycle between mosquitoes and monkeys, with man being infected when he enters a territory in which the monkey-mosquito cycle exists. immunization. an attenuated live-virus yellow fever vaccine was developed by passage of the virulent asibi strain in mouse brain and cell culture until it had lost its pathogenicity for monkeys and man (theiler, ) . the vaccine virus, termed d, is propagated in embryonated eggs. the vaccine, given as a single dose, is extremely safe and efficacious, providing immunity for at least years. the family orthomyxovirus comprises the influenza viruses, the cause of acute, highly contagious respiratory disease in man, horses, swine, and birds. two structural viral proteins (nf and m) divide this family into three distinct genera: a, b, and c. the viruses, especially influenza a virus, undergo genetic réassortaient, which allows variant viruses to emerge. two viral proteins, the hemagglutinin and neuraminidase, both located on the surface of virions, are important in inducing immunity. vaccines have been widely used for controlling influenza with reasonably good success. since immunity is more closely related to local secretory iga antibody than to serum antibody, it is difficult to stimulate and maintain protection with the presently used inactivated vaccines. with human infections, the type a viruses undergo occasional antigenic shifts and drifts, after which the antigens in the vaccine may not be representative of those viruses found in the field. this potential antigenic variability, as well as animal reservoirs for this virus, are responsible for the pandemics associated with this virus. as an example, the acute respiratory disease of swine caused by a type a strain of virus was first recognized in during the human influenza epidemic and is believed to have been transmitted from swine from humans. both swine and humans are susceptible to the swine virus. however, the disease in swine occurs sporadically and has not been enough of a problem to warrant the use of vaccines in that species. influenza is a respiratory infection with systemic manifestations that include fever, chills, muscular aches, etc. the severity of the disease depends on the virus strain and the susceptibility of the population. persons that have recovered from an influenza infection are usually immune to rechallenge with the homologous virus. however, the change of a few amino acids in hemagglutinin may give rise to antigenic drift and reinfection of populations. immunization. because of the epidemic threat of influenza viruses, careful surveillance for new strains is carried out in many parts of the world. the strains that public health officials predict will be the cause of the next winter's epidemics are then scheduled for vaccine production. for vaccine production, virus is grown in the allantoic cavity of embryonated eggs and is purified and concentrated by zonal centri-fugation. the virus is inactivated with formalin, ß-propiolactone, or irradiation. the quantity of viral antigen per dose is standardized before use. the vaccine usually contains several type a viruses and a type Β virus. these inactivated whole virus vaccines produce protective levels of antibody in approximately % of primed recipients and in % of the unprimed recipients. antibody levels are maintained for approximately year in primed individuals. attenuated live-virus influenza vaccines have been used extensively in the ussr with varying results. problems of adverse reactions, inconsistent potency, and questionable appropriateness of strains make it difficult to evaluate the effectiveness of these vaccines. more recent attempts to develop attenuated live-virus vaccines involve genetic reassortment, a method that offers considerable promise (reviewed by wright and karzon, ) . influenza in horses resembles the disease in man and swine. the two type a influenza viruses of importance in the horse are: a/equi l/prague/ type and a/equi /miami/ type . the disease spreads rapidly through susceptible horses, and those that recover are protected for only a short time. recovery from infection with one virus type does not provide immunity against the other. immunization. vaccines for equine influenza are produced in essentially the same manner as human influenza vaccines. formalinactivated vaccines contain both equine type and viruses and one of several adjuvants, as described by bryans et al. ( ) . vaccines of this type are widely used and effectively control equine influenza. the family paramyxoviridae contains several viruses that cause significant disease in animals. the family is composed of three genera that include the following viruses for which vaccines have been developed. these viruses are transmitted by the respiratory route and are antigenically rather stable. parainfluenza viruses infect humans, rodents, swine, dogs, and cattle. these viruses, by themselves, cause mild upper respiratory tract disease, but when combined with other viral and bacterial pathogens may cause a more severe syndrome. parainfluenza types , , , and a/ b infect humans, especially young children. type is considered the most pathogenic, causing a bronchitis and pneumonitis. vaccines for parainfluenza of rodents (sendai virus infection), dogs (canine parainfluenza), and cattle (bovine parainfluenza) have been developed. there is no licensed parainfluenza vaccine for man. a. sendai virus. sendai virus, first isolated during attempts to recover human respiratory viruses in mice (kuroya et al., ) , is a parainfluenza type virus that causes respiratory disease in mice, rats, hamsters, and swine. the disease occurs either in an acute-short duration form or a chronic-persistent, clinically inapparent form. spread is by either direct contact or by aerosol. in mouse colonies, this disease is difficult to control because the virus is so highly infective. immunization. formalin-inactivated vaccines have been effective in controlling the disease in mice and rats (fukumi and takeuchi, ; eaton et al, ; tsukui et al, ) . additionally, a temperature-sensitive mutant strain of sendai virus has been used as an aerosol-delivered vaccine in mice. it suppresses virus replication, but the vaccine virus spreads throughout the colony and makes it difficult to monitor for wild virus strains (kimura et al, ) . b. canine parainfluenza virus. outbreaks of mild respiratory disease in laboratory dogs have been attributed to parainfluenza type virus (binn et al, ; crandell et al, ) . when other respiratory agents such as mycoplasma and bordetella bronchiseptica were given intranasally after exposure to this parainfluenza virus, more severe respiratory signs occurred (appel and percy, ) . this encouraged efforts to develop a vaccine for canine parainfluenza virus. immunization. an attenuated live-virus parainfluenza vaccine has been shown to protect dogs against aerosol challenge with virulent virus (emery et al, ) . the vaccine produces no untoward effects and has been combined with canine distemper and canine adenovirus vaccines in multivalent formulations. c. bovine parainfluenza virus. a parainfluenza type virus isolated from cattle can also cause mild respiratory disease (reisinger et al, ) . the virus, when combined with other respiratory pathogens including pasteurella and infectious bovine rhinotracheitis virus, causes the severe pneumonia syndrome, called "shipping fever." immunization. an attenuated live-virus parainfluenza type vaccine administered parenterally induces good levels of antibodies and affords protection against experimental challenge (mohanty and lillie, ; thorsen et al., ) . this vaccine has been combined with infectious bovine rhinotracheitis virus and bovine virus diarrhea vaccines in multivalent formulations. an inactivated vaccine, requiring two inoculations, induces high hemagglutination-inhibition titers and lessens the severity of the disease in cattle challenged with the same virus (gale et al., ) . mumps virus causes an acute infection in man with parotitis as the main clinical manifestation, although the central nervous system and other organs including the testes and ovaries can be affected. mumps virus has a limited host range; in addition to man, only certain monkey species and laboratory rodents can be infected. immunization. recovery from natural infection with mumps virus confers long-term immunity. early experiments with formalininactivated virus derived from infected parotid glands of monkeys showed that monkeys and humans could be immunized (enders et al., ; stokes et al., ) . habel ( ) found that chick embryo grown virus could be inactivated with ultraviolet light or formalin and would induce protection in monkeys. a similar vaccine was later shown to induce protection in man (habel, ; henle et al., ) . poor antibody responses to multiple inoculations of this type of vaccine encouraged the search for a more effective vaccine. a mumps virus strain ( jeryl lynn) has been attenuated by passage in chick embryos (weibel et al., ) . the vaccine is immunogenic in - % of subjects, and neutralizing antibodies persist for at least years. the annual incidence of mumps in the united states has been reduced from , cases in to less then , in by application of this vaccine. as presently used, mumps vaccine is combined with measles and rubella vaccines in a pediatric formulation called mmr. newcastle dibcctse is one of the most serious widespread diseases affecting poultry. the disease was first described by kranevelt ( ) and shortly thereafter by doyle ( ) , who named it after the area in england where an outbreak occurred and showed that its cause was a filterable virus. the disease has several forms causing mainly respiratory, enteric, and central nervous system manifestations. the morbid-ity and mortality vary depending on the virus strain. burnet ( ) described the hemagglutinating property of the virus, which has been very helpful in its quantitation and immunodiagnosis. immunization. a number of attenuated live-virus vaccines have been developed which are widely used to control the disease. the bl strain (hitchner and johnson, ) , the lasota strain (winterfield et al., ) , and the f strain (asplin, ) are used to immunize birds of all ages by different routes, including by addition to drinking water and by spraying. vaccines containing inactivated virus do not produce long-lasting immunity but may be used in certain situations when only short-term immunity is needed, such as when boosting immunity is needed in laying flocks. increasing the antigen content and using oil-emulsion adjuvants improves the quality of these inactivated vaccines (stone et al, ; zanella and marchi, ) . measles is a highly contagious disease of humans, occurring mostly in children, causing exanthemata and sometimes more serious manifestations including encephalomyelitis. the virus has two principal immunogens, the hemagglutinin and the fusion protein (norrby et al., ) . the immunity produced by natural infection is long lasting. immunization. the growth of measles virus in chick embryo fibroblasts by enders and peebles ( ) paved the way for the development of vaccines. a formalin-inactivated measles virus vaccine was shown to induce partial immunity. however, some vaccinated children later exposed to measles virus, either naturally or as attenuated live-virus measles vaccine, developed atypical measles (atypical rashes, edema of hands and feet, and respiratory disease). it was later found that formalin-inactivated vaccine failed to stimulate antibody to the fusion protein: consequently the virus could spread from cell to cell, causing the atypical manifestations of disease (norrby et al., ). an attenuated live-virus vaccine was developed from the edmonston strain of measles virus by passage first in human cell culture, then in the amnionic sac of embryonated hen's eggs, and finally in chick embryo cells (milovanovic et al., ) . this vaccine (enders passage level b) was effective in inducing immunity but produced some adverse effects (katz and enders, ; stokes et al., ) . further attenuation by growth at lower temperature yielded an equally effective vaccine that produced fewer side effects (schwarz, ; hilleman et al., ) . attenuated live-virus measles vaccine has been combined with mumps and rubella vaccines. measles vaccine usage has reduced the incidence of measles in the united states from , cases in to , in . canine distemper virus affects most carnivores, causing respiratory, gastrointestinal, and central nervous system disease. the mortality rate in dogs is about %. dunkin and laidlaw ( ) first described the disease in detail and confirmed the viral etiology proposed earlier by carre ( ) . immunization. dunkin ( , a,b) prepared a vaccine by treating virus derived from spleens of infected dogs with formalin. initial administration of this vaccine, followed weeks later with a small dose of virulent virus, usually produced only a mild disease with solid immunity. this approach was replaced with inactivated virus vaccines, given in multiple doses, which served as the main means of controlling the disease from to . green ( ) serially passaged canine distemper virus in ferrets and produced the first attenuated live-virus vaccine; however, this vaccine caused disease in some dogs. the adaptation of canine distemper virus to the chorioallantoic membrane of embryonated eggs by haig ( ) was a major step in developing an attenuated live-virus vaccine. cabasso and cox ( ) applied this method and after passages showed that the virus lost virulence for ferrets but retained its immunizing property for dogs. rockborn ( ) adapted a strain of canine distemper virus to cell culture, and this method is now widely used to produce attenuated live-virus vaccines. rinderpest is an acute highly contagious disease of ruminants characterized by erosions and necrosis of the intestinal mucosa. the disease is epizootic in parts of africa and asia, causing great losses of cattle and buffalo. immunization. koch in developed one of the first means of immunizing cattle against rinderpest by administering bile from infected cattle. animals that survived were permanently immune. formalin-and chloroform-inactivated vaccines were developed using tissues from infected animals. these vaccines were safe, but required two or three doses and protection lasted less than a year (walker et al., ) . rinderpest virus has been adapted to several foreign hosts, including goats (daubney, ) and rabbits (nakamura et al., ) and has been attenuated by passage in these animals. tissues of these animals have been used to produce vaccines in many countries. however, on continued passage, the seed strains tend to lose their immunogenicity, and vaccines become contaminated with adventitious agents from the foreign host. the kabete strain of rinderpest virus was adapted to grow on the chorioallantoic membrane of embryonated eggs, becoming attenuated for cattle after passages . this vaccine and another containing a lapinized strain of virus adapted to embryonated eggs have been used widely in africa (nakamura and miyamoto, ) . more recently, the kabete strain was adapted to bovine kidney cell culture and after passages became avirulent for cattle. this vaccine strain is safe and efficacious in most cattle breeds (plowright and ferris, ) . protection persists for at least years. over million doses of this vaccine have been used in africa, with good success (maurer, ) . bovine rsv produces a rhinitis and catarrhal bronchiolitis in cattle (mohanty et al., ; jacobs and edington, ; paccaud and jacquier, ) . the virus appears to be widespread having been isolated in europe, the united states, and asia. human and bovine virus are related antigenically (paccaud and jacquier, ) ; however, the cattle virus is not known to infect man. immunization. nasal secretory antibody is protective but the disease may occur in the presence of serum antibody. an inactivated bovine rsv vaccine is combined with vaccines for infectious bovine rhinotracheitis, bovine virus diarrhea, and bovine parainfluenza components in a multivalent formulation. the efficacy of the rsv component in this formulation is unclear. of the viruses in the family rhabdoviridae that cause disease in man and domestic animals, the most important is rabies virus. others include vesicular stomatitis viruses (vsv) and bovine emphemeral fever virus (befv). vsv occurs sporadically and epizootically, affecting horses, cattle and swine in the united states. there is a formalininactivated vaccine (gearhart et al., ) , but it is used rarely. befv is an arthropod-transmitted disease of cattle occurring mainly in africa, but also in asia and australia; it is controlled by immunization with attenuated live-virus vaccines (van der westhuizen, ; inaba et al, ; spradbrow, ; theodoridis et al, ) . rabies is an infection of the central nervous system; the disease can occur in most mammals and is usually fatal. there are only a few documented cases of human survivors. after isolating the virus, pasteur ( ) developed a vaccine for its control. historically rabies virus has been considered as a single serotype. but now shared antigens have been found in other viruses in africa of which two, mokola and duvenhage, may be associated with human disease (shope et al. y ) . mokola virus causes a rabies-like disease in dogs and cats in zimbabwe (foggin, ) . immunization. protection against rabies correlates with sn antibody, which can be assessed by a number of tests. pasteur's classical vaccine, developed from infected spinal cord tissue dried at room temprerature for - days, was given in a series of - inoculations beginning with material dried the longest and progressing through material dried for only days (pasteur ) . even though the last inoculum was virulent enough to cause rabies, the earlier inoculations conferred sufficient immunity to protect the recipients. this method of producing a vaccine was successful in most instances but caused the disease occasionally and was eventually replaced by chemically inactivated vaccines prepared from infected brain tissue. although effective, these vaccines gave rise to undesirable side-effects because they contained a myelin-related encephalitogen present in brains from mature animals. substitution of brain tissue from immature animals such as suckling mice, rats, and rabbits with their lesser myelin antigenic content greatly reduced these post-vaccination reactions. the adaptation of the flury strain of rabies virus to growth in chick embryos led to the development of attenuated live-virus vaccines produced in this tissue (leach and johnson, ; koprowski and cox, ; black, , ) . the growth of rabies virus in tissue culture has further improved rabies vaccines (kissling, ; cabasso et al., ; emery et al., ; brown et al., ; fenje, ; abelseth, ). yet, despite their benefits, the attenuated rabies vaccines occasionally caused rabies, particularly in cats. therefore, suckling mouse brain and tissue culture again became the substrates of choice to produce inactivated rabies virus vaccines for animals. in humans the requirement for a safe substrate is more exacting than in animals. for this reason, duck embryos proved better than brain tissue to produce rabies virus (peck et al., ) . after inactivation with ß-propriolactone (bpl), this virus was an improved product for humans, although the allergenic effects from duck embryo tissue still present a problem. therefore the adaptation of the pm rabies virus strain to human diploid cells and inactivation with bpl (wiktor et al., ) was a further improvement. this vaccine is less reactive and more effective for pre-and post-exposure use in humans than any other yet made (bahmanyar et al., ) . a similar vaccine produced in bhk cells is also beneficial in animals. retroviruses have an rna genome, a portion of which encodes the unique enzyme reverse transcriptase. this enzyme imparts to retroviruses the ability to make rna-directed dna copies of their genome, which can then act as a transposable element and can be integrated into the host cell dna. thus, once a cell is infected, it may escape immune surveillance and destruction and the host animal may be infected for life. the retroviruses thus constitute a considerable challenge to traditional vaccine approaches, as discussed further in the chapters by arlinghaus and by nathanson and gonzalez-scarano. many retroviruses infect mammalian species, from mouse to man. most notable are the c-type retroviruses, including the primate, murine, and feline leukemia viruses, as well as human t-cell leukemia viruses types i and ii; the b-type retroviruses, particularly mouse mammary tumor virus; and the lentiviruses, including caprine infectious anemia virus, visna virus, equine infectious anemia virus, feline immunodeficiency virus, bovine immunodeficiency virus, and human immunodeficiency viruses (hiv- and hiv- ). in recent years, as hiv has become a major threat, massive efforts have been directed to developing an efficacious vaccine. so far, all attempts have met with failure. in fact, there are only two retrovirus vaccines that have been proven effective: a formalin-inactivated whole virus preparation of the primate saids type d retrovirus, which is capable of protecting monkeys from a lethal challenge (marx et al., ) , and the commercially available vaccine for feline leukemia. felv commonly infects cats in urban areas, usually by the oralnasal route. kittens under months of age are particularly susceptible. about % of infected cats develop persistent anemia from which myeloproliferative disease and hypoplastic anemia may follow. the immunosuppression caused by felv infection may predispose to severe chronic opportunistic infections. because cats that develop neutralizing antibody are usually immune to infection, vaccines have been developed and tested with that goal in mind. immunization. the problem in developing a vaccine for feline leukemia was to find immunogens that could be used without exposing animals to oncogenic materials. early studies with inactivated whole virus were unsuccessful (yohn et al., ) . although attenuated live-virus vaccines induce sufficiently high levels of neutralizing antibodies to be protective ( jarrett et al., ; pedersen et al., ) , their oncogenic potential makes them unacceptable. efforts to develop vaccines containing only viral proteins, such as envelope protein, have had variable results. however, cultivation of felv in fl transformed cells, followed by treatment to release viral and cell proteins, yields a vaccine that stimulates antibodies to both viral and cell membrane components. a commercial vaccine using this method of antigen production has been approved for use in the united states; it is based on studies done by olsen and lewis ( ) . subsequently, the efficacy of this vaccine has been disputed (pederson and ott, ) . viruses in the family coronaviridae cause important diseases including avian infectious bronchitis, transmissible gastroenteritis of swine (tge), feline infectious peritonitis (fip), and human coronavirus infections. other coronaviruses may cause disease in calves, dogs, mice, rats, turkeys, horses, and parrots, but the diseases are of less importance. coronavirus diseases usually follow a similar pattern, except for fip. fip is a chronic debilitating disease manifested as fibrinous peritonitis and pleuritis. the infection may be inapparent, but is fatal in a small proportion of infected cats. the immune response to fip virus seems to mediate the disease; the immune response is not protective and antibody levels are higher in diseased animals. immune complexes have also been demonstrated in renal glomeruli of cats with fip. bovine coronavirus causes acute diarrheal disease in neonatal calves (mebus et al., ). an attenuated live-virus vaccine is being used in combination with an attenuated live-virus rotavirus vaccine to control calf diarrhea. the vaccine is administered to pregnant cows near the end of gestation and stimulates colostral antibodies that offer protection to nursing calves. with the exception of avian infectious bronchitis, most coronavirus infections have been difficult to control with vaccines. perhaps this is because primary lesions are in mucous membranes of the respiratory and gastrointestinal tracts, sequestered from immune reactivity. coronaviruses produce about % of common colds in man, second only to rhino viruses. there are two groups of human coronaviruses that are antigenically distinct. ibv is a highly contagious respiratory infection of young chickens. the virus may also infect older birds, causing a decrease in egg production. the disease was first shown to be caused by a virus by bushnell and brandley ( ) . beaudette and hudson ( ) propagated the virus in chick embryos, making possible the quantification of the virus and the means for attenuation. there are a number of serotypes of ibv, making the development of an effective vaccine difficult. immunization. immunity following natural infection may last up to year, depending on the serotype and the severity of challenge. van roekel et al. ( ) first developed an immunization procedure; he used a field strain of virus to infect -to -week-old birds before they start to lay, inoculating a few of the birds and allowing infection to spread naturally through the flock. today, there are a number of attenuated live-virus vaccines licensed in the united states. there is good protection ( - %) against homologous virus strains and about % against heterologous strains (hofstad, ) . reduced pathogenicity may be associated with reduced immunogenicity, so a balance must be maintained. the attenuated live-virus vaccines are administered by the usual labor-saving devices of spraying, dusting, or placing the vaccine in drinking water. the wide-scale use of ibv vaccines has significantly reduced the economic loss caused by this disease. tge is an often fatal disease of pigs under weeks of age. the main lesion is enteritis, resulting in malabsorption, diarrhea, and dehydration. tge virus is serologically related to fip virus, but the diseases have entirely different characteristics. there is one serotype of tge virus and one serotype of fip virus. high levels of maternal tge antibody in sows' colostrum protect piglets if fed continuously. immunity of this type has been produced by feeding sows tissues containing virulent tge virus several weeks prior to gestation. the effects of this virus are relatively mild in older animals. attenuated live-virus vaccines administered parenterally to pregnant swine in the latter part of the gestation period produce colostral antibodies. apparently, in sows previously exposed to tge, this vaccine produces sufficient immune responsiveness to be of value. the vaccine is also used orally in pigs - days old to induce local immunity. the effectiveness of this use of the vaccine has not been thoroughly demonstrated. the genus corynebacterium is a heterogeneous grouping with its species placed together largely on the basis of similar cell wall components (goodfellow and minnikin, ) . these species share a basic cell wall chemistry (barksdale, ) of which the mycolic acids (silva and ioneda, ) , especially trehalose dimycolate, are frequently used as potent adjuvants in immunization protocols. two corynebacteria-c. pyogenes and c. pseudotuberculosis-are important in veterinary medicine. the former is frequently associated with ruminate suppurative conditions and abscesses, but it rarely affects man. infections with this organism are sporadic, because it is an opportunist that gains entry through wounds and abrasions. it may also be seen as a secondary invader in devitalized tissues; e.g., vaccination site abscesses. the efficacy of vaccines, toxoids, and antisera against c. pyogenes is equivocal; little is known about immunity to the bacterium. corynebacterium pseudotuberculosis causes caseous lymphadenitis of goats and sheep. it is recognized as a worldwide problem and a serious cause of economic loss to the goat industry (burrell, ; ashfaq and campbell, ) . as with c. pyogenes, the responsible bacterium, c. pseudotuberculosis, is primarily an opportunist entering wounds or abrasions, where it causes local inflammation before settling in the regional lymph nodes. immunization. cell-mediated immunity is necessary for acquired resistance and protection against c. pseudotuberculosis (jolly, ; tashjian and campbell, ; irwin and knight, ) . killed and autogenous vaccines and a toxoid vaccine have been used in attempts to immunize against the bacterium (cameron, ; brogden et al., ; nairn et al., ; burrell, ; anderson and nairn, ; brown et al., ) ; however no one vaccine has proven highly efficacious. diphtheria, characterized by the formation of a tightly adherent pseudomembrane on the pharyngeal mucous membranes of the throat and trachea, is a highly contagious disease of man caused by the bacterium c. diphtheriae. the bacterium can also be isolated from the pharyngeal mucosa of normal individuals. the organism produces a lethal protein exotoxin (gill and pappenheimer, ; collier and kandel, ) . immunization. successful immunization against c. diphtheriae actually protects against the diphtherial exotoxin. because diphtheria toxin is produced in high yield by the park-williams number strain (pw ), pw is used to make diphtherial toxoid for vaccines. as a source of toxin it is rendered nontoxic by incubation with formalin under alkaline conditions. the product's retention of antigenicity, enabling it to induce antitoxin antibodies, makes it an excellent pediatric vaccine. it is commonly utilized in combination with antigens from c. tetani and b. pertussis. the most important species of the bacillus genus, b. anthracis, is the organism responsible for the disease anthrax in both man and animals. anthrax was the first bacterial disease ever to be reported, being described by davaine in . koch in reproduced the disease via animal inoculation and in pasteur successfully vaccinated against anthrax. in animals, natural infection usually occurs by ingestion of spores that germinate in the mucosa of the esophagus or the intestinal tract. herbivorous animals, especially cattle, horses, sheep, and goats, are highly susceptible to the disease, usually the result of grazing in infected pastures or consuming infected foods. in man, anthrax is manifested in three forms: cutaneous (malignant carbuncle), pulmonary (woolsorter's disease), and gastrointestinal with cutaneous being the most common. death results from the combined effects of an extracellular toxic protein complex (vodkin and leppla, ) comprised of three components: edema factor, protective antigen, and lethal factor (leppla, ; stephen, ) . effective vaccines require all three components. immunization. the attenuated pasteur vaccine has been supplanted in veterinary medicine by stable spore vaccines, carbo-zoo vaccine, or stern vaccine (jackson et al., ) prepared from avirulent, nonencapsulated variants of b. anthracis. the viable bacterial spores are suspended in % saponin. immunity is attributed to the development of antibodies to the toxins released from growing bacteria. vaccines of killed bacteria provide little immunity, since no bacterial toxins are produced; hence, no antitoxin antibodies are generated. purified protective antigen (complex toxin) is both antigenic and immunogenic and has been used as a vaccine for humans. it is prepared by aluminum potassium sulfate precipitation of sterile b. anthracis culture filtrates and has proven highly efficacious. erysipelothrix is found in soil, water, and decaying vegetative material and carcasses. the major species of interest is e. rhusiopathiae, which has serotypes (norrung, ) . the bacterium, most notable for causing swine erysipelas, is capable of invading the tissues of both man and animal. fatally affected animals develop welt-like, discolored cutaneous lesions, and numerous hemorrhagic lesions in thoracic and abominai viscera; chronic debilitating arthritis predominates in surviving animals. immunization. the principal vaccines used to control erysipelas are formalin-killed, alum-adsorbed, whole-cell culture vaccines. these combinations of soluble bacterial glycoprotein and whole killed bacterial cells are usually produced from strains of serotype , which possess highly antigenic soluble cell wall glycoproteins. animals immunized with cell-free culture fluids develop agglutinins to the whole bacteria (white and verway, ) . such vaccines are highly effective in controlling swine erysipelas. the pathogenic clostridia invade both man and many animal species of veterinary interest, in which they cause such diseases as tetanus (c. tetani), gas gangrene (c. perfringens, c. septicum, c. oedematous), botulism (c. botulinum), enterotoxemia, and dysentery (c. perfringens). the clostridia are widely distributed in soil and water and are common inhabitants of the intestinal tracts of animals and humans. additionally, the bacteria can often be isolated from infected wounds. vaccination is not routinely practiced against all clostridial organisms, notably c. botulinum. the toxins of c. botulinum, which exert their effects upon the nervous system (schantz and sugiyama, ) , are as potent as those of c. tetani. the lethal dose of the toxin, however, is less than that required to induce an antibody response. clostridium perfringens has five serotypes, a-e, classified according to the production of lethal exotoxins. types a and c are pathogenic for man, whereas all five serotypes can affect animals (see table i ). immunization. the exotoxins of c. perfringens are antigenic proteins that can be detoxified for use in vaccines. the existence of common capsular antigens, which elicit cross-reactions between the serotypes, demonstrates the considerable heterogeneity of this group. ewes and lambs are frequently vaccinated against c. perfringens enterotoxemias. effective vaccines employ type-specific alum- precipitation or formalinized toxoids (smith and matsuoka, ; kennedy et al, ) . clostridium tetani elaborates potent neurotropic exotoxins (tetanospasmin and tetanolysin) that may be lethal for susceptible species such as man, horses, mules, swine, cattle, and sheep. birds are not naturally susceptible to the bacterium. tetanus toxin is one of the most poisonous toxins known. it acts only on the nervous system and its effect characteristically causes spastic paralysis and generalized convulsions. immunization. protective antitoxin blood levels are obtained by immunizing both humans and susceptible animals with alumprecipitated or absorbed tetanus toxoid (chodnik et al., ) . ramon and lemetayer ( ) first introduced the concept of active immunization against tetanus when they used formalinized tetanus toxoid precipitated with alum to vaccinate horses. clostridium tetani vaccines are very effective at inducing long-lasting immunity in both man and domestic animal species. a serious, often fatal disease has been successfully controlled with these vaccines. clostridium novyi possesses four antigenic types, a, b, c, and d; type a is the most common clinical pathogen. types a and Β are responsible for gas gangrene both in man and animals (elder and miles, ) . in areas where sheep simultaneously carry a heavy liver-fluke infestation, exposure to c. novyi is often associated wtih hepatic necrosis and subcutaneous edema. migrating flukes produce foci of hepatic necrosis suitable for the germination of spores and the subsequent elaboration of lethal toxins (williams, ) . immunization. effective vaccinations for c. novyi in animals employ chemically inactivated, detoxified, and adjuvanted suspensions of alum-precipitated formalinized whole broth cultures. clostridium chauvoei, which is the etiologic agent for the disease "blackleg" and is pathogenic for animals only, occurs primarily in ruminant species. protective antigens and toxins with hemolytic and necrotizing activity are formed in susceptible animals ( jayaraman et al., ) . the necrotizing toxin may effect fatal toxemia with degenerative foci of myonecrosis. immunization. immunity to c. chauvoei can be produced via vaccination with its alum-precipitated formalinized cultures (chandler and gulasekhuram, ) . clostridium septicum, in contrast to c. chauvoei, is pathogenic for both man and animal. in man, it is associated with gas gangrene and in affected animals, primarily ruminants, it is the agent most closely identified with the diseases malignant edema and braxy. the organism produces four lethal necrotizing, hemolyzing toxins that cause an increase in capillary permeability and myonecrosis. immunization. immunity to c. septicum is induced with injection of formalinized bacterial cultures. the antitoxin provides homologous protection and additionally protects against c. chauvoei. animals are often vaccinated with mixtures of clostridial species; i.e., novyi, chauvoei, septicum, perfringens, and sordelli in one combination vaccine. these are highly efficacious vaccines and are routinely used in veterinary medicine. although infections with mycobacterium tuberculosis primarily occur through inhalation of the tubercle bacillus, ingestion of large numbers of the bacilli in contaminated milk or infectious sputum can readily produce disease in susceptible species. the bacterium is pathogenic in man, but can also cause disease in monkeys, pigs, and occasionally in cattle, dogs, and parrots. the disease may be asymptomatic or produce severe, debilitating pulmonary lesions. if infection is not restricted by the immune system, the disease may be fatal (comstock, ; bloom and godal, ) . since bacteriocidal mechanisms of the normal macrophage prevent m. tuberculosis from multiplying intercellularly (goren, ; goren et al., ) , protective immunity depends on cell-mediated immunity (lagrange, ) . mycobacterium bovis, closely related to m. tuberculosis, and m. avium causes disease primarily in cattle and birds. they can, however, be contagious to man, sheep, and pigs. immunization. immunoprophylaxis for tuberculosis is based on vaccination with an attenuated, relatively avirulent strain of m. bovis that does not produce lesions. the strain is known as bcg or the bacillus of guérin ( , ) . worldwide, this is one of the most widely used human vaccines, as it has proven efficacious in controlling a severe disease. additionally, bcg has been used for nonspecific enhancement of resistance against tumors and other infec-tions. the cell wall of m. tuberculosis is a potent immunostimulant when used in freund's adjuvant. although streptococci may be normal inhabitants of the gastrointestinal tract, they may also be pathogenic for both man and animals. on the basis of characteristic cell wall components, the streptococci are traditionally divided into lancefield groupings (lancefield, ) . streptococcus agalactiae, a streptococcus group Β organism, causes severe mastitis in the bovine species and has been identified as a major cause of serious neonatal infections in man (eickoff et al., ) . capsular antigens form the four major type-specific antigens (la, lb, ii, and iii), with type iii organisms being most commonly associated with neonatal meningitis. in infants, early-onset disease occurs within the first days of life and is characterized by sepsis and pneumonia. the mortality rate is high. late-onset disease occurs around month of age and is characterized by meningitis (einstein et al., ) . immunization. there is a direct correlation between the absence of maternal igg antibody to type iii antigen and the incidence of neonatal infection. thus, susceptibility to the bacterium is related to the absence of significant levels of maternal serum antibody being transferred transplacental^ to the fetus. current vaccine developments are directed toward maternal immunization with type iii antigen (einstein et al., ) . streptococcus pneumoniae, the etiologic agent of pneumococcal pneumonia in human infants and adults, may cause septicemia, meningitis, and inner ear infections. aerosol transmission of the bacterium, often in association with viral upper respiratory infections, is the major mode of transmitting s. pneumoniae infections. streptococcus pneumoniae possesses a capsular polysaccharide capable of deterring phagocytosis, thus enhancing the virulence of the bacterium. of over types of the bacterium identified, serotypes are most frequently associated with the disease. a polyvalent pneumococcal vaccine prepared from soluble purified capsular polysaccharides of the most predominant s. pneumoniae serotypes has proven effective in adults. the capsular polysaccharides are well-tolerated and highly immunogenic; signifi-cant rises in protective serum antibody titers are achieved following vaccination (kasper et al., ) . however, vaccination of infants has not proven beneficial, because they develop no higher antibody titers to the bacteria than do unvaccinated infants (ginsburg, ) . enterotoxigenic pathogenic strains of escherichia coli may cause severe, potentially fatal, diarrheal disease in both man and domestic species, particularly neonatal cattle and swine. the capsular (k) antigens are cell-surface proteins and/or polysaccharides associated with virulence. the k antigen mediates adhesion to the microvillus of intestinal epithelial cells; production and release of enterotoxin follow (bywater, ; lonroth et al., ) . escherichia coli neonatal enteritis of newborn calves is also a serotype-specific disease (myers and guinée, ) . ail important colostral antibodies in both swine and cattle are anti-k antibodies (usually k ) (myers and guinée, ; moon et ah, ) . immunization. vaccination of gilts, sows, heifers, and cows with vaccines prepared from the k or other pilus-associated antigens has reduced morbidity and mortality from e. coli nec natal enteritis of newborn piglets and calves (nagy et ah, ; rutter, ; kohler et ah, ; childrow and porter, ; myers and guinée, ) . to prepare the porcine vaccines, bacterial strains specific for the herds to be vaccinated are used to immunize animals weeks prior to parturition, thereby generating specific, protective colostral antibodies. recombinant dna technology, discussed in the chapter by collett has introduced the potential to construct e. coli vaccine strains that would afford considerably better protection than those currently available. salmonella species are a major cause of invasive enteric infections in humans and domestic animals, with domestic poultry constituting the largest reservoir of salmonella organisms in nature. normally, infection occurs through the oral route. salmonella is a facultative intracellular pathogen; therefore, cell-mediated immunity is more important than humoral immunity in resistance to the disease, salmonellosis (fields et ah, a,b; dougan et ah, ; woolcock, ) . salmonella typhi, the only salmonella species that has a capsular polysaccharide (vi antigen), is the etiologic agent of typhoid fever, a serious and common disease in underdeveloped areas (edelman and levine, ) . this pathogen infects humans only; there is no suitable animal model for typhoid fever. immunization. few vaccines have been developed for salmonella, and most are of low efficacy with undesirable side-effects. live vaccines are more effective than killed ones in promoting better immunity (levine et ah, ; dougan et ah, ; roantree, ) . with respect to s. typhi, vaccines containing the inactivated bacteria offer only limited and transient protection with undesirable side-effects (levine, et ah, ) . the attenuated strain of s. typhi, ty- a, requires multiple doses to achieve - % protection (hirschel et ah, ) . consequently, typhoid fever has not been controlled by immunization, although the vi antigen has recently been hailed as the agent of a preventative vaccine (robbins and robbins, ) without adverse side-effects (acharya et ah, ) . yersinia pestis is the etiologic agent of plague or "black death" in man, a highly fatal disease with fever and purulent lymphadenopathy. although not a disease of domestic animals, rats, ground squirrels, and other rodents may be affected. the bacterium is spread by the rat flea, xenopsylla cheopis, from rat to rat and from rat to man. immunization. the most widely used vaccine for the prevention of y. pestis infection is haffkine's vaccine, first developed in . this vaccine is prepared from heat and phenol-killed virulent cultures. formalin-killed virulent bacteria are also successful, as are living avirulent strains (grasset, ) . the is no evidence that any vaccine protects against pneumonic plague, the most contagious and fatal form of the disease. furthermore, vaccine protection is only recommended for plague research workers. disease control is primarily dependent upon eradication of rodent carriers of y. pestis. pasteurella multocida and p. haemolytica are common commensals of the mucous membranes of the respiratory tract and oropharynx of healthy cattle, sheep, swine, dogs, and cats. when the bacteria multiply unchecked, they can penetrate the oral and/or respiratory mucosa, where they quickly grow and overpower the host's defense systems. pasteur first described this bacterium as the etiologic agent of fowl cholera; it is also associated with bovine pneumonia, swine plague, and an epizootic hemorrhagic septicemia in ungulates. the bacterium's heat-stable antigens have been used as serologic indicators in the gel diffusion precipitin test to define its serotypes (brogden et al., ) . immunization. pasteur's successful bacterial vaccine to fowl cholera, and the first vaccine ever used, consisted of avirulent cultures of the p. multocida attenuated by prolonged growth on artificial medium. killed p. multocida vaccines are prepared from virulent immunogenic strains of the bacterium. the organisms are suspended in formalinized saline, incorporated into an adjuvant, and injected subcutaneously (heddleston et al., ) . these vaccines induce substantial immunity to fowl cholera. additionally, live vaccines for oral administration have been developed for use in the poultry industry (dougherty et al., ; heddleston et al., ; oison, ; bierer and derieux, ) . pasteurella multocida is usually mixed with modified live or killed bovine rhinotracheitis virus, parainfluenza virus, bovine viral diarrhea virus, and p. hemolytica bacteria in combination vaccines to protect against pasteurella pneumonia in cattle. bovine pneumonic pasteurellosis (shipping fever) is a severe fibrinous pneumonia of feedlot cattle usually associated with biotype a, serotype infections with this organism. immunization. administration of either killed or live vaccines has been of limited efficacy in controlling shipping fever. partial protection from experimental disease follows immunization of cattle with either live p. haemolytica by aerosol or parenteral routes confer et al., ) or lyophilized p. haemolytica vaccines consisting of chemically altered, streptomycin-dependent, or modified live organisms given intramuscularly or intradermally (confer et al., ) . humoral antibody responses appear to correlate strongly with protection against experimental disease (confer etat., ; mckinney et al., ) . for example, purified p. haemolytica lipopolysaccharide stimulates specific antibody formation and has protected calves challenged with the bacterium from developing the disease (hilwig et al., ) . these obligate parasites, restricted to respiratory and pharyngeal mucous membranes, cause important diseases in porcine (h. pleuropneumonia, h. suis, andi/. parasuis), equine (h. equigenitalis), bovine (h. somuns), and avian (h. gallinarum, h. paragallinarum) hosts. most hemophilus species require two factors, hemin (x) and nicotinamide adenine dinucleotide (v), for growth. antigens associated with protection and virulence have been described fori/, paragallinarum (yamamoto, ) , the etiologic agent of infectious coryza in chickens. birds that have recovered from natural infection possess varying degrees of immunity to re-exposure (page et al., ) ; immunity is serotype-specific. adjuvanted vaccines containing multiple bacterial serotypes are prepared from chicken embryos or formalinized bacterial broth cultures and are effective vaccines in preventing infectious coryza in chickens. this bacterium is the etiologic agent of the porcine disease, contagious pleuropneumonia, which is characterized by severe multifocal, necrotizing pneumonia with venous thrombosis and associated serofibrinous pleuritis (didier et al., ) . the disease is of considerable economic importance to the swine industry, being most prevalent in situations where swine are raised under intensive management conditions. hemophilus pleuropneumoniae possesses major and minor antigens that are both common and serotype specific (gunnarson et al., ; gunnarson, ; mittal et al., ) . since high antibody titer apparently provides little protection from the disease, cell-mediated immunity may be important in protection from infection (rapp and ross, ; rosendal et al., ) . immunization. no adequate immunoprophylaxis against contagious pleuropneumonia is currently available, although many vaccines have been tried (nielsen, ; henry and marstellar, ; christensen, ; masson et al., ) . prior infection with one serotype provides protection from heterologous serotypes (nielsen, ) . the bacterial strains used in vaccines are serotype specific and, while not preventing the disease, can reduce its severity (christensen, ) . hemophilus somnus is the cause of infectious meningoencephalitis, a disease with low morbidity but high mortality in cattle. whole or sonicated bacterial cells and bacterial protein are immunogenic (noyer et al., ) and efficacious bacterins foster protective immunity in calves (williams et al., ) . the bacterins of h. somnus, adjuvanted with aluminum hydroxide, are prepared from highly immunogenic strains of the bacterium and grown in serum-free media for use as vaccines. the species in this genera, b. pertussis, b. bronchiseptica, and b. parapertussis, can be either parasites or, as in swine and dogs, common inhabitants of the upper respiratory tract. these small, serologically related bacilli produce a dermonecrotic toxin. infection is by aerosol transmission with bacteria adherent to tracheal cilia (bemis et al., ) . local, not serum, antibody concentration is important in clearance of the infection. the etiologic agent of whooping cough, Β. pertussis, produces two distinct hemagglutinins, leukocytosis-promoting factor-hemagglutinin (lpf-ha) and filamentous hemagglutinin (fha), and various toxins (pertussis toxin [pt] and dermonecrotic toxin). fha is involved in bacterial adherence to the respiratory mucosa, whereas pt is believed to be the major protective (sato and sato, ) and pathogenic antigen (steinman et al., ) . immunization. although efficacious, the safety of the human vaccines currently in use, suspensions of killed whole cells containing protective antigens, is open to question (robinson et al., ) . undesirable side-effects such as screaming, collapse, encephalopathy, and other serious neurological complications have been reported in association with b. pertussis vaccinations (dick, ) . the potencies of whole cell vaccines correlate with the antigenic content of pt (reiser and germanier, ) . bordetella bronchiseptica is an obligate parasite of the upper respiratory tract of both dogs and pigs. in dogs the bacterium frequently invades the lungs as a sequela to canine distemper (caused by a morbillivirus), causing an often fatal bronchopneumonia. the bacterium is also associated with mild to severe tracheobronchitis, "kennel cough," in dogs (bemis et al., ) . in pigs, a deformation of the bony structures of the nasal area (atrophic rhinitis) and reduction of the total volume of nasal turbinates commonly follow the bacterial infection (ross et al., ) . degenerative changes in the osteoblasts and osteocytes may be caused by elaboration of a dermonecrotic toxin (dnt), which is released from b. bronchiseptica after colonization or multiplication of the organisms on the nasal mucosa (nakai et al., ) . the release of dnt from p. multocida type d is thought to exacerbate the disease. immunization. vaccines to control canine b. bronchiseptica infections are commonly incorporated into combination packages containing attenuated live-virus canine distemper, and canine adeno and parainfluenza viruses. to control atrophic rhinitis, avirulent live, or inactivated organisms alone or in combination with p. multocida, erysipelothrix rhusiopathiae and!?, coli have been utilized in vaccines. the organisms in this group, b. abortus, b. suis, Β. melitensis, Β. canis, and b. ovis, cause the disease brucellosis in domestic animals and man. the bacterium may localize in the reproductive tract which, in the female, can lead to fetal death with subsequent abortion. brucellosis, due to b. abortus or b. melitensis, is a zoonotic disease, readily transmitted from animal to man. the potentially severe consequences of brucellosis, fetal death and abortion, in the pregnant cow and epididymitis and sterility in the bull result in significant economic loss to the cattle industry. the primary source of infection is infected animals, whose mammary and/or genital secretions may contain the bacterium. calves can become infected in utero; however, the main portals of infection are oral mucosa, nasopharynx, and conjuctiva of exposed animals. immunity to b. abortus is dependent upon cell-mediated immunity, as the presence of serum antibodies, although a significant indicator of infection, does not correlate with the immune status of the host (fitzgeorge et al., ; kaneene, et al., ; swiderska et al., ; montaraz and winter, ) . most humans who contract brucellosis have been exposed either to b. melitensis, the etiologic agent of malta or mediterranean fever, or b. abortus. brucella melitensis, found in the milk of infected sheep and goats, may produce fatal disease when ingested by humans. brucellosis of sheep and goats mimics the disease as it is seen in cattle, with fetal death and abortion occurring in ewes and does and epididymitis in rams and billies. brucella ovis infects sheep, causing late fetal death and abortion in pregnant ewes and epididymitis in rams, such as b. abortus does in cattle. immunization. brucella abortus (strain ) is currently used as the vaccine of choice for control of brucellosis of cattle in the united states. this is a viable, smooth strain that, while posing virtually no threat for cattle, may cause disease in man. the major objections to the vaccine are this pathogenicity for humans and the difficulty of differentiating vaccinated from naturally infected animals since persistent serum antibodies are induced by the vaccine. killed b. melitensis in adjuvant or live avirulent strains have been used for vaccines to induce a high degree of immunity in sheep and goats. brucella ovis bacterins in adjuvant, as well as b. melitensis vaccines, have been used to protect animals from the disease b. ovis causes, since the antigens of these two pathogens are cross-protective (diaz et al., ) . pathogenic members of this genus are associated with venereal disease, fetal death, and abortion in cattle. this bacterium is transmitted to uninfected cattle by coitus or artificial insemination and is an obligate parasite of the genital tract. immunization. stimulation of opsonizing antibodies of the igg class by systemic vaccination with adjuvanted vaccines is effective in preventing natural infection in bulls (bouters et al., ) and infertility in cows (corbeil et al., ; hoerlin and kramer, ) , and prevents the carrier state (wilkie and winter, ). unlike c. fetus venerealis, this bacterium is contracted by ingestion and is not transmitted venereally. both sheep and cattle can be infected; however, the disease is most severe in pregnant ewes, which undergo a high percentage of abortions or premature births within a flock. immunization. in sheep, vaccination with polyvalent adjuvanted vaccines is efficacious in preventing disease (thompson and gilmour, ) . the most important organism of this genus, v. cholera, causes severe, acute enteritis in humans and nonhuman primates. the etiologic agent of cholera in humans, v. cholera, causes a potentially fatal diarrheal disease. infection results in the production of a powerful enterotoxin in the small intestine, which stimulates an increase in cyclic amp in intestinal epithelial cells and causes a profuse outpouring of isotonic fluids. vibrio possesses immunogenic heat-labile flagellar (h) protein and heat-stable (o) lipopolysaccharide somatic antigens. the cholera toxin is immunologically and functionally similar to the heat-labile enterotoxin of e. coli (yamamoto et al., ) . it consists of six light subunits (l) that assist in toxin adherence to intestinal cell receptors and one heavy subunit (h), which is the toxic entity. immunization. present cholera vaccines are administered by parenteral or oral routes. parenteral vaccines consist of formalin/phenolinactivated bacteria, whereas oral vaccines employ killed or live bacteria. vaccines given by either route provide protection for approximately - months. the predominant immune mechanism is antibacterial rather than antitoxic (levine et al., ) ; antibacterial antibodies prevent attachment of the bacterium, whereas antitoxic antibodies inhibit toxin adherence to cell receptors. because current vaccines often produce adverse side-effects (feeley, ) , synthetic and semi-synthetic vaccines are currently under investigation. for the latter, a nonpyrogenic, bivalent cell-surface protein-polysaccharide conjugate is being investigated (kabir, ) . h. leptospira spp. the pathogenic genera of this family can penetrate the gastrointestinal mucosa and abraded epidermis. leptospires are transmitted through contact with the urine of animal carriers, either directly or in contaminated water or soil. rodents are the primary reservoir of the bacteria which, due to its ability to synthesize urease, colonizes the renal nephron and subsequently is shed into the urine. leptospirosis causes economically serious disease in cattle and swine by causing fetal death, abortion, and infertility. recovery from infection with one serotype lends immunity only to that serotype. this immunity is predominantly humoral, since agglutinins (igm) are responsible for the initial clearance of the bacteria; neutralizing antibodies (igg) are also protective (hanson, ; negi et al., ) . canine leptospirosis infections may be severe, occurring more commonly in male dogs than in females. man is a dead-end host for leptospires; infection in man is accidental and usually related to occupational exposure. immunization. killed, multivalent, leprospira vaccines protect against clinical disease in cattle and swine; however, in pigs, immunity does not protect against renal colonization (stalheim, ) . dogs can be vaccinated successfully with formalin or phenol-killed vaccines that contain antigens from the two most common infecting serotypes, l. canicola and l. icterohemorrhagica (kerr and marshall, ) . vaccines for humans, prepared from chemically inactivated cells of leptospires, have been used extensively in certain areas of the world. neisseria meningitidis neisseria meningitidis is a frequent cause of endemic purulent meningitis in human infants and adults, although the incidence of the disease is substantially higher in young infants (hoffman, ) . bacterial invasion of the meninges is usually hematogenous from the upper respiratory tract and is a life-threatening affliction. neisseria meningitidis has been classified into at least nine groups (a, b, c, w- , x, y, z, l, -e) on the basis of its capsular polysaccharides (morse, ) . immunization. protection against meningococcus meningitis results primarily from the presence of antibodies against the capsular polysaccharide of n. meningitidis (frasch et al., ) . group a and c polysaccharide vaccines are especially effective against disease in children over two years of age and in adults. epidemic typhus fever has afflicted mankind since ancient times. it is an acute highly infectious disease with the potential for explosive epidemics in man. significant outbreaks of the disease have been intimately associated with war and famine. the disease is characterized by sustained high fevers, headache, panencephalitis, a diffuse maculopapular skin rash, and toxic vascular damage. the fatality rate may be high. the etiologic agent, r. prowazeki, is transmitted from person to person by the human body louse pediculus humanus corporis. infection is established by inoculating infected louse feces into the skin by scratching. immunization. although no etiologic relationship has been demonstrated between r. prowazeki and the bacterial strain proteus x , these two species share a common polysaccharide antigen (castaneda, ) . the sera of infected typhus patients agglutinates proteus x and this test is now standard (weil-felix reaction) for diagnosis of the acute disease. additionally, r. prowazeki has two major antigenic components-one heat labile and the other heat stable (craigie et al., ; topping et al., ) . typhus fever vaccine contains killed organisms propagated in the yolk-sac membranes of developing chick embryos (cox, ) . this vaccine not only diminishes the symptoms of typhus in immunized persons, but it also greatly reduces the mortality rate (gilliam, ) . the usefulness of the attenuated (madrid Ε strain) vaccine is hampered because, under appropriate conditions, the strain may revert to virulence (brezina, ) . the prokaryotes proc. world vet. congress, th proc. annu. conf. aust. vet. assoc tuberculosis in bacterial infections in humans: epidemiology and control symposium on rickettsial diseases vm/sac new trends and developments in vaccines vaccines ' : modern approaches to new vaccines principles and practice of cholera control vaccines ' proc. natl. acad the prokaryotes proc. natl public health rep viral hepatitis viral hepatitis proc. west. states food anim. conf vaccination against foot and mouth disease an inquiry into the cause and effects of the vanidae vaccinae vaccines ' a system of bacteriology the mycobacteria: a source book proc. natl. acad. sei. u.s.a. diseases of poultry bovine medicine and surgery proc. int. conf. equine infect. dis proc. annu. conf. aust. vet. assoc proc. natl. acad. sei. u.sa. proc. conf. res. work. anim. dis vaccines ' proc. th annu. meet. u.s. livestock sanit. assoc proc. natl. acad proc. th annu. meet. u.s. livestock sanit. assoc the virus in yellow fever proc. int. vet. congr vaccines ' diseases of poultry were useful references in writing this chapter. key: cord- -nzc itk authors: baker, marissa g.; peckham, trevor k.; seixas, noah s. title: estimating the burden of united states workers exposed to infection or disease: a key factor in containing risk of covid- infection date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: nzc itk introduction: with the global spread of covid- , there is a compelling public health interest in quantifying who is at increased risk of contracting disease. occupational characteristics, such as interfacing with the public and being in close quarters with other workers, not only put workers at high risk for disease, but also make them a nexus of disease transmission to the community. this can further be exacerbated through presenteeism, the term used to describe the act of coming to work despite being symptomatic for disease. quantifying the number of workers who are frequently exposed to infection and disease in the workplace, and understanding which occupational groups they represent, can help to prompt public health risk response and management for covid- in the workplace, and subsequent infectious disease outbreaks. methods: to estimate the number of united states workers frequently exposed to infection and disease in the workplace, national employment data (by standard occupational classification) maintained by the bureau of labor statistics (bls) was merged with a bls o*net survey measure reporting how frequently workers in each occupation are exposed to infection or disease at work. this allowed us to estimate the number of united states workers, across all occupations, exposed to disease or infection at work more than once a month. results: based on our analyses, approximately % ( . m) of united states workers are employed in occupations where exposure to disease or infection occurs at least once per week. approximately . % ( . m) of all united states workers are employed in occupations where exposure to disease or infection occurs at least once per month. while the majority of exposed workers are employed in healthcare sectors, other occupational sectors also have high proportions of exposed workers. these include protective service occupations (e.g. police officers, correctional officers, firefighters), office and administrative support occupations (e.g. couriers and messengers, patient service representatives), education occupations (e.g. preschool and daycare teachers), community and social services occupations (community health workers, social workers, counselors), and even construction and extraction occupations (e.g. plumbers, septic tank installers, elevator repair). conclusions: the large number of persons employed in occupations with frequent exposure to infection and disease underscore the importance of all workplaces developing risk response plans for covid- . given the proportion of the united states workforce exposed to disease or infection at work, this analysis also serves as an important reminder that the workplace is a key locus for public health interventions, which could protect both workers and the communities they serve. to estimate the number of united states workers frequently exposed to infection and disease in the workplace, national employment data (by standard occupational classification) maintained by the bureau of labor statistics (bls) was merged with a bls o*net survey measure reporting how frequently workers in each occupation are exposed to infection or disease at work. this allowed us to estimate the number of united states workers, across all occupations, exposed to disease or infection at work more than once a month. based on our analyses, approximately % ( . m) of united states workers are employed in occupations where exposure to disease or infection occurs at least once per week. approximately . % ( . m) of all united states workers are employed in occupations where exposure to disease or infection occurs at least once per month. while the majority of exposed workers are employed in healthcare sectors, other occupational sectors also have high proportions of exposed workers. these include protective service occupations (e.g. police officers, correctional officers, firefighters), office and administrative support as covid- spreads globally, there is public health importance in characterizing the role of the workplace in disease transmission, given the variety of work tasks that could promote the spread of infectious disease (e.g., interfacing with customers, patients, and co-workers; preparing food), and the role of the workplace in spreading previous epidemics or pandemics [ , ] . it is known that those working in healthcare settings face increased exposure to agents causing infectious diseases such as sars-cov- , but may also have better infectious disease protection plans and policies than other occupational settings, potentially limiting the transmission of disease to community members [ ] . while important, these measures may be inadequate for the effective prevention of infection for such high risk occupations, especially when they are working with inadequate ppe stockpiles, and the hospitals are overwhelmed due to heavy patient loads [ ] . nearly % of confirmed covid- cases in wuhan, china (as of february , ) were in healthcare workers, indicating the workplace is a potential location of transmission even among workers who are trained to protect themselves from biological hazards [ ] . however, other occupational groups which may have more sporadic exposure to infectious or disease-causing agents may not have the same level of planning, or even think that an infection disease control plan is warranted for their workplace. of the first covid- cases confirmed in singapore, had probable relation to occupational exposure, including workers in retail stores and casinos, domestic workers, a tour guide, taxi and private hire car drivers, security guards, and workers at the same construction site, further exemplifying the role of the workplace in transmitting disease [ ] . understanding the burden of occupational exposure to infection and disease, including how many workers are potentially exposed and what occupations they work in, allows for upstream prevention measures, both at the workplace (e.g. developing appropriate infectious disease response plans, integrating infectious disease trainings into other workplace trainings, developing workplace policies that can support a workforce potentially exposed to sars-cov- ) and regulatory levels (e.g. increased access to paid sick leave, hazard pay for those exposed during a pandemic, etc.). these workplace and regulatory policies will be valuable in helping reduce the transmission of infectious disease from and within the workplace, and their importance may be realized with burden estimates previously, state-level employment data were utilized to estimate the number of workers exposed to a host of occupational exposures in united states federal region x (washington, oregon, idaho, alaska), spanning chemical, physical, ergonomic, and psychosocial hazards [ ] . here, utilizing the same data analysis methods as previously detailed in doubleday et al., the number of workers across the united states exposed to disease or infection at work more than once a month is estimated. despite some of the inherent limitations in using these existing data sources, we believe this analysis is valuable for informing risk assessments and prompting protective actions that occupational sectors and regulatory agencies can take during infectious disease outbreaks, such as covid- . two sources of data were utilized for this analysis, and are detailed below. united states employment data was obtained from the bureau of labor statistics (bls) occupational employment statistics database [ ] . the most current employment data at the time of analysis was from may , and is organized by standard occupational classification codes ( soc). soc codes are hierarchical, ranging from two-digits (major group code) to six digits (detailed occupation code), with the six-digit codes being the most detailed [ ] . to estimate exposure to disease and infection in the workplace, we used data within the o � net database. o � net is a job characterization tool, generated from survey data, with rich information on tasks performed, skills needed, and job characteristics for different occupations, in order to inform job seekers or researchers [ ]. as nearly six-digit soc occupations are updated each year, the entire o � net database is completely refreshed every few years [ ] . between and , nearly , employees from , workplaces had responded to o � net questionnaires. o � net uses a deliberate survey sampling scheme, to ensure representation of workers from across the united states, across organizations of different size, and from both government and private workers. for small socs where it may be hard to find respondents, and to complement data from job incumbents, o-net also relies on occupational analysts and occupational experts to answer questionnaires. o � net does not collect data from military occupations; thus, soc codes beginning with "military specific occupations" are not included in o � net data. similarly, employment numbers for "military specific occupations" is not reported in the bls occupational employment statistics database. no other soc codes are excluded from the o � net database, but two soc codes were not included in the measure utilized for this analysis, which were for the occupations of "rock splitters, quarry" and "timing device assemblers and adjusters" employing , and persons in the united states, respectively [ ] . to characterize frequency of workplace exposure to infectious disease, we used the following o � net question: "how often does your current job require you be exposed to diseases or infections?" respondents, who take the survey online or on paper, could select from the following frequencies of exposure: never; once a year or more but not every month; once a month or more but not every week; once a week or more but not every day; every day [ ] . respondents are given little context when completing the survey, with interpretation of the question up to the respondent. within o � net, these data are converted to a - score, representing weighted-average frequency of the metric for each soc code. for this analysis, occupations were retained that had a score of - , representing exposure to disease/infection more than once a month. soc codes were merged with the national employment data to calculate the total number of workers employed in the occupations with exposure to disease/ infection at more than once a month. all data analysis was conducted using the statistical software package r version . . . as of may , there were a total of . million persons employed in the united states in employer-employee arrangements counted by bls. of these . million workers, an estimated . % ( , , ) were employed in occupations where exposure to disease or infection occurs more than once a month. as of may , % ( , , ) of the united states workforce was employed in occupations where exposure to disease or infection occurs at least once a week. table summarizes the number and proportion of workers exposed more than once a week and more than once a month by major occupational sectors (two-digit soc). both healthcare practitioner and technical occupations, and healthcare support occupations have more than % of workers exposed more than once a month, and more than % of workers exposed more than once a week. other notable major occupation groups with high proportion of exposure are protective service occupations ( % exposed more than once a month, including police officers, firefighters, transportation security screeners), personal care and service occupations ( % exposed more than once a month, including childcare workers, nannies, personal care aides), and community and social services occupations ( . % exposed more than once a month, including probation officers, community health workers, and social and human health assistants). the % of office and administrative support occupations with exposure to disease or infection more than once a month are patient representatives, couriers and messengers, and medical secretaries. the nearly % of workers exposed in business and financial operation table . number and percent of workers exposed to infection or disease more than one time per month, and more than one time per week, by major ( -digit) standard occupational classification code (soc). exposure to infection/disease in the workplace occupations are compliance specialists, which includes environmental compliance specialists and coroners. the full o � net dataset, ranking the frequency of exposure for each soc is publicly accessible online [ ] , as is employment and wage data [ ] . as these databases are periodically updated, they should be referenced for information on frequency of exposure for a specific occupation. during an infectious disease outbreak, the workplace can play an important role in both spreading the disease [ , ] and helping to stop the spread of disease through workplace practices and policies [ , ] . understanding the wide range of occupations that could be exposed to infection or disease due to work activities is important for planning risk management and communication to workers, in addition to prioritizing workplace response plans. this analysis estimates that the number of workers who face frequent exposure to an infection or disease at work; estimates of the number of workers who fall ill due to such exposures are not possible in this analysis. however, a primary goal of public health, especially in the face of a global pandemic, is to prevent the spread of disease. therefore, understanding how many workers are frequently exposed, and what occupations they represent, is an important first step in being able to prompt and enact risk reduction strategies prior to disease transmission occurring, and illness manifesting. thus, the results reported here have important public health implications. several limitations must be emphasized. exposure to disease or infection in the workplace, and resultant transmission into the community, is dependent on many factors which were not able to be investigated in this analysis. this includes number of contacts that worker has with the public, workplace emphasis on and access to handwashing, number of interactions with bodily fluids, existing hygiene and cleaning practices in the workplace, availability of appropriate personal protective equipment (ppe) etc. while certainly this could vary between occupations, many of these factors would also vary within occupations, and none of these data were captured with the o � net data. presenteeism, reporting to work despite being symptomatic for disease, is common in the workplace, and is another contributor to the transmission of infectious disease, and potentially to the spread of epidemics or pandemics [ , ] . one analysis examined the role of workplace transmission in the h n pandemic, estimating that about million employees in the united states worked while infected, and that these workers may have caused the infection of as many as million of their co-workers [ ] . access to paid leave, which could ameliorate the financial burden of staying home while sick, varies substantially by occupation, industry, employer, location, and worker sociodemographic profile (e.g., race/ethnicity) [ , ] . workers without access to paid leave have higher rates of presenteeism, and are less likely to receive preventative health services such as getting flu shots [ ] . occupational sector also influences rates of presenteeism, with studies from various countries showing higher rates of presenteeism among workers in healthcare, public service, and educational sectors, as these essential services often do not have substitute workers available [ ] [ ] [ ] . indeed, a recent systematic review identified occupation type as one of the strongest predictors of presenteeism [ ] . as many of these sectors are already exposed to disease due to work activities, it is important that disease response plans for these sectors include not only control methods to reduce exposures at work, but also contingency plans to ensure sick workers do not come back to work with disease. this could be accomplished through cross-training, providing extra paid sick leave during this time, ensuring flexible working conditions, and ensuring substitute workers are identified to fill in if essential workers fall ill. importantly, o � net data are also subject to misclassification and undercounting. o � net data were generated from self-reported subjective questionnaires and therefore are subject to bias and misclassification. respondents may not realize they are exposed to infection or disease at work unless they are in a workplace where these hazards are communicated to them and protective equipment is provided (e.g., healthcare sectors) leading to potential differential misclassification across occupational groups. workers could also be reporting expose to disease or infection that occurs while commuting to work (particularly by public transportation), leading to additional misclassification. additionally, information from the o � net database is applied at the occupation-level, and therefore does not account for within-job exposure variation [ ] . many workers are not included in the o � net and bls data sources, including independent contractors (which includes "gig economy" workers), domestic workers, self-employed, undocumented, and continent workers. these workers may be uniquely susceptible to exposure at work due to limited ability to take time off if they or a family member is ill [ ] . in sweden and norway, higher rates of presenteeism (coming to work when sick) were found among low-income and immigrant workers [ ] . this further emphasizes the importance of continuing to develop occupational surveillance systems that capture exposures and outcomes experienced by these undercounted groups, as well as ensure worker protections extend to protect these undercounted workers. in conclusion, our analysis shows that a large proportion of the united states workforce, across a variety of occupational sectors, are exposed to disease or infection at work more than once a month. these are workers that public health should consider especially at risk for covid- , due to frequent exposure to disease and infectious agents. however, it should be noted that there are many other workers that could also be exposed to sars-cov- , or encourage the spread of covid- , such as workers who are not given access to flexible working, workers who do not feel they can take sick time if they or a family member is sick, workers who do not have access to paid sick leave, or workers that perform essential services and do not have access to substitute workers. work presented here 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social, economic, and labor policies on occupational health disparities paid sick leave and preventive health care service use among u.s. working adults job stress and presenteeism among chinese healthcareworkers: the mediating effects of affective commitment sickness presenteeism at work: prevalence, costs and management presenteeism exposures and outcomes amongst hospital doctors and nurses: a systematic review use of o*net as a job exposure matrix: a literature review at work but ill: psychosocial work environment and well-being determinants of presenteeism propensity sickness presenteeism in norway and sweden the authors gratefully acknowledge annie doubleday for developing the r code that supported this analysis. key: cord- - t authors: oppong, joseph r. title: globalization of communicable diseases date: - - journal: international encyclopedia of human geography doi: . /b - - - - . -x sha: doc_id: cord_uid: t fueled by globalization and human behavior, communicable diseases pose a serious threat to humankind despite unparalleled technological advances. new viruses and devastating communicable diseases such as ebola and zika are emerging; diseases previously considered eradicated such as measles are reemerging, while antibiotic resistance is increasing to dangerously high levels worldwide. increased human population and accelerated global travel make local outbreaks instant global threats. researchers are concerned that an avian influenza outbreak could kill many more people when it emerges because of the absence of immunity and human travel interaction patterns. yet the threat of communicable disease varies by geographic location—where you live matters. this entry examines the spatial patterns of familiar communicable diseases, including the syndemic of human immunodeficiency virus (hiv) and tuberculosis, as well as new diseases such as ebola, zika, and dengue. it highlights the huge potential of mapping communicable disease genotypes while raising the alarm on the urgent need for effective global disease surveillance systems and new tools for fighting communicable diseases. because communicable diseases do not respect political boundaries, global cooperation is vital to prevent this threat to humankind. rates are much lower, increasing numbers of people are living with hiv/aids, and prevalence is particularly high among subpopulations such as blacks, men who have sex with men, and intravenous drug users. at the end of , about . million people were living with hiv globally, with . million cases in sub-saharan africa, a region with % of the world's population, and % of the world's children living with the disease. hiv prevalence rates vary widely between african countries, ranging from a low of less than % of the adult population in senegal and somalia to more than % in south africa and zambia. but the world's most affected region remains southern and eastern africa where an estimated . million people were living with hiv in , % of them being female. the region also had % of the global total of new hiv infections, but only % of the people living with hiv in the region were accessing antiretroviral therapy in . women are more vulnerable and thus more severely affected than are men, and at much younger ages. the major driving forces of hiv/aids include poverty and economic inequality which necessitate transactional sex, and gender inequality enshrined in cultural practices such as widow inheritance. global efforts to control the disease through improved testing and supply of inexpensive medications and other programs are beginning to yield positive results including plummeting death rates, and unaids has set a goal of ending aids by . tuberculosis (tb) is an airborne respiratory disease caused by mycobacterium tuberculosis. tb bacilli are propelled into the air when people who are sick with pulmonary tb cough, sneeze, talk, or during normal breathing. inhaling even a small number of these airborne bacilli is enough to cause infection. most exposed persons never become ill but develop latent tb. an important minority ( %- %) progress from latent to active tb due, for example, to immunosuppression from coinfection with the hiv. despite treatment advances, tb remains an uncontrolled communicable disease worldwide and about million persons are diagnosed and million die yearly. currently, more than % of the global tb burden occurs within developing countries due to widespread hiv/aids infection, crowding, medication shortages, and poor healthcare programs. in developed countries, newly diagnosed tb occurs most frequently among foreign-born immigrants, and native-born homeless who typically live in extremely crowded and unsanitary conditions. for example, in germany and france immigrants are three times and six times, respectively, more likely to be diagnosed with tb than are native-born persons. in , countries in eastern and southern africa (angola, ethiopia, kenya, lesotho, mozambique, namibia, south africa, tanzania, zambia, and zimbabwe) were listed among the countries with the highest tb burden. the two epidemicsdhiv/aids and tbdare intertwined in such a catastrophic way that they have been termed syndemic. hiv is now associated with epidemic outbreaks of tb, multidrug-resistant tb (mdrtb), and extensively drug-resistant tb (xdr-tb). similarly, tb is now the leading cause of death in hiv-positive adults, and in , people living with hiv were times more likely to have tb worldwide. polio is a viral disease that is usually spread through fecal contaminated water and food. early symptoms of infection include fatigue, fever, vomiting, headache and pain in the neck, and extremities. the virus invades the nervous system and can cause paralysis in hours. incubation takes between and days, but a person begins to shed the virus in their stool - days before, and - weeks after the onset of symptoms. a small minority of cases ( . %- %) result in paralysis, and at least % of cases occur in children - years old. because most infected people have no symptoms at all while spreading the highly contagious virus for weeks, once introduced, polio usually infects many people before an outbreak is detected. polio provides an illustrative example of the challenges in global disease control. once considered almost eradicated worldwide, polio resurged not only in the six countries with endemic polio (nigeria, india, pakistan, niger, afghanistan, and egypt) but transmission was reestablished in an additional six countries (burkina faso, central african republic, chad, cote d'ivoire, mali, and sudan). despite massive efforts, total eradication continues to be an elusive goal. the global campaign to eradicate polio by suffered a severe setback when parts of northern nigeria rejected the polio vaccine because muslim clerics claimed that it causes infertility and spreads hiv/aids and cancer. from those few states, polio spread through large parts of the country, neighboring countries, and eventually to saudi arabia through nigerian muslims on pilgrimage to mecca. indonesian muslims, who were exposed during their pilgrimage in mecca, carried the disease with them to indonesia where it became reestablished. polio reminds us that global cooperation is critical for controlling communicable diseases. sexual behavior of travelers is contributing to spatial mixing of different strains of sexually transmitted pathogens worldwide. consequently, sexually active travelers risk being infected with new strains of known sexually transmitted infections. for example, gonorrhea, which causes an estimated million cases worldwide each yeardabout , in the united statesdis becoming more and more resistant to antibiotics. early in , a superresistant strain was reported in the united kingdom, diagnosed in a man, who developed symptoms after sexual contact with a woman in southeast asia. the bacterial infection was resistant to the two major antibiotics for treating the diseasedazithromycin and ceftriaxone. this case confirms one major concern for sexually active humanity: drug-resistant gonorrhea is spreading around the globe. long known to be endemic in africa, southeast asia, and the pacific islands, zika virus (zikav) was first identified in brazil in (where it threatened cancellation of the rio olympics) and subsequently spread throughout the region of the americas. zikav is spread primarily by the mosquito vector, aedes aegypti, and also by sexual contact, blood transfusion, and congenitallydfrom a pregnant woman to her unborn baby during pregnancy or around birth. symptoms include mild rash, fever, red eyes, body pains, and headache. infection during pregnancy can cause miscarriage; congenital microcephalydbabies with abnormally small heads; or other serious brain anomalies. in , a total of , noncongenital zikav disease cases were reported in the united states, mostly in travelers returning from zikav-affected areas, but local mosquito-borne transmission increased. no local mosquito-borne transmission has been reported in the continental united states in . despite the presence of aedes aegypti in multiple states, other environmental conditions (e.g., use of air conditioning and window screens and temperate climate) likely limit the transmission risk in us states. as of march , a total of countries globally had reported local mosquito-borne zikav transmission. determining accurately the complete global burden of zikav disease is extremely difficult due to significant underreporting. because disease is often clinically mild, patients might not seek medical care. among those who do, the disease may be easily mistaken for another illness with similar presentation (e.g., dengue or chikungunya virus disease), testing may not be available or requested, and diagnosed cases may not be reported. severe acute respiratory syndrome (sars) illustrates how migration facilitates the spatial spread of disease. from its source, guangdong province in south china, sars spread initially to hong kong, from where it diffused worldwide. when it was over, a total of probable cases and deaths had been reported in countries. the devastation of sars followed a path of spatially linked places and people facilitated by international travel. canadians returning from asia imported sars into canada. the first cases involved a canadian family of hong kong descent who lived in toronto. a -year-old woman and her husband traveled to hong kong and stayed at a hotel where a cluster of persons with suspected or probable sars are known to have stayed. two days after returning home, the woman developed what is now known as sars and died. several family members who had close contact with the index case then developed sars symptoms, and one was later admitted to a hospital that subsequently became the epicenter for the toronto outbreak. sars killed canadians, caused illness in hundreds more, paralyzed a major segment of ontario's healthcare system for weeks, and put more than , residents of the greater toronto area in quarantine. dengue is transmitted by the mosquitoes aedes aegypti and aedes albopictus, which are found throughout the world. in many parts of the tropics and subtropics, dengue is endemic, that is, it occurs every year, usually during a season when aedes mosquito populations are high, often when rainfall is optimal for breeding. these areas are, however, additionally at periodic risk for epidemic dengue, when large numbers of people become infected during a short period. dengue epidemics require a coincidence of large numbers of vector mosquitoes, large numbers of people with no immunity to one of the four virus types (denv , denv , denv , denv ), and the opportunity for contact between the two. although aedes are common in the southern united states, dengue is endemic in northern mexico, and the us population has no immunity, dengue transmission in the continental united states is low primarily because contact between people and the vector is too infrequent to sustain transmission. today about . billion people, or % of the world's population, live in areas with a risk of dengue transmission. dengue is endemic in at least countries in asia, the pacific, the americas, africa, and the caribbean. the world health organization (who) estimates that to million infections occur yearly, including , dhf cases and , deaths, mostly among children. chikungunya virus is most often spread to people by aedes aegypti and aedes albopictus mosquitoes, the same mosquitoes that transmit dengue virus. chikungunya was first described during an outbreak in southern tanzania in . the name "chikungunya" derives from a word in the kimakonde language, meaning "to become contorted," and describes the stooped appearance of sufferers with very debilitating joint pain that usually lasts for a few days or may be prolonged to weeks. occasional cases of eye, neurological, and heart complications have been reported, as well as gastrointestinal complaints. outbreaks have occurred across africa, asia, europe, and the indian and pacific oceans. in the late , chikungunya virus was found for the first time in the americas on islands in the caribbean. there is no vaccine to prevent or medicine to treat chikungunya virus infection. the symptoms of chikungunya are similar to those of dengue and zika. some communicable diseases originate in animals and occasionally mutate to infect humans. an excellent example is avian influenza. it occurs naturally among wild birds; they shed it in their saliva, nasal secretions, and feces, but usually do not get sick from it. domesticated birds, including chickens, ducks, and turkeys, become infected through contact with contaminated surfaces, birds, or their secretions. human contact with infected birds or contaminated surfaces produces infection, but human-to-human spread of avian influenza viruses is rare, typically limited, and unsustained. symptoms of avian influenza in humans include fever, cough, sore throat, muscle aches, eye infections, severe respiratory diseases, and other life-threatening complications. human influenza virus refers to those subtypes (currently h n , h n , and h n ) that spread widely among humans. in the united states, human flu kills , people and hospitalizes more than , people every year. research continues into new vaccines to counter a possible flu pandemic, but unfortunately, current vaccine production methods require an outbreak before an effective vaccine can be developed and even then it takes between and months. to avoid a global pandemic of flu virus, new vaccine technologies are required, to respond quickly and effectively to new challenges of communicable disease outbreaks. ever since the seminal work of dr. john snow, mapping has been a key tool in fighting communicable diseases. thanks to recent technological advances, particularly in geographic information system (gis), the role of mapping in disease tracking, surveillance, and control has burgeoned. recent examples include west nile virus and tb control. cromley and mclafferty provide an excellent overview of gis applications in public health generally. one particularly fascinating recent development is mapping genotypes of communicable disease. each disease-causing organism has a specific phenotype, and the species members have a more unique genotype. tools exist for separating and categorizing disease organisms with these more unique genotypes into groups based on their genetic structure (isolates). two people with identical or matching isolates indicate recent transmission from a common source; unique isolates indicate remote transmission from a different source. analyzing and mapping these genotypes allows researchers to distinguish between not just disease species (phenotype) but also locate areas with high incidence and different strains of the disease, including recent versus remote transmission of disease. areas with high rates of clustered genotypes indicate ongoing transmission (i.e., an outbreak), whereas multiple unique isolates indicate infections that were acquired elsewhere (are imported). moonan et al. based a recently successful tb intervention on geographically targeted screening of clustered tb isolates. because it assumed that persons with clustered strains of disease from geographically related areas represent ongoing community transmission that can be identified and interrupted through treatment, the study focused resources on zip codes with high incidence and clustered isolates. during the -month intervention, the number of cases of tb decreased from . cases per screenings to . cases per . the rate of developing latent tb infection fell from . to . per person-years of exposure. the intervention was successful because it distinguished between high incidence areas with high and low levels of clustered strains and deployed resources not just on the basis of incidence but on the basis of genotype. since unique isolates represent remote transmission, location-based screening in areas with high rates of unique isolates would be less likely to identify either persons with active tb or recent acquired latent tb infection and thus not as cost-effective. despite their incredible potential, these approaches are rarely employed in developing countries where they are most needed. before the measles vaccine existed, out of every children got the disease before age and million people died from it every year. similarly, small pox killed out of every people and left survivors with unsightly scars. sadly, as vaccinations have successfully eliminated such previously deadly or terribly debilitating diseases, people have become indifferent or even hostile to them. the number of parents refusing to vaccinate their children, and the surge in the opposition to vaccines, in general, what has been termed the anti-vaccination movement, particularly in developed countries, should be a major concern. recent measles outbreaks in the united states, the united kingdom, and france should be a shocking reminder that surging opposition to vaccines surely paves the way for the return of deadly diseases. communicable diseases remain a major threat to humankind. effective surveillance and response remain our best protection against these deadly threats. unfortunately, surveillance remains poor and rudimentary in areas where outbreaks are most likely. strengthening the health and surveillance systems of poor developing countries is critically important because communicable diseases do not respect political boundaries. sadly, as vaccinations have successfully eliminated previously deadly or terribly debilitating diseases, people have become indifferent or even hostile to vaccinations, making it more likely the deadly diseases return. global cooperation is vital to prevent this threat to humankind. see also: diffusion; health geography; medical geography. clinical features and short-term outcomes of patients with sars in the greater toronto area mycobacterium tuberculosis complex genetic diversity: mining the fourth international spoligotyping database (spoldb ) for classification, population genetics and epidemiology controlling tuberculosis in the united states recommendations from the american thoracic society, cdc, and the infectious diseases society of america severe acute respiratory syndrome the pristine myth: the landscape of the americas in international travel and sexually transmitted disease the burden of dengue and chikungunya worldwide: implications for the southern united states and california update: noncongenital zika virus disease cases d u.s. states and the district of columbia tuberculosis in canada annual report on tuberculosis cases zika virus disease in travelers returning to the united states continued transmission of zika virus in humans in west africa, - a brief history of evolving diagnostics and therapy for gonorrhea: lessons learned the anti-vaccination movement: a regression in modern medicine zika virus transmissiondregion of the americas place and health: towards a reformed medical geography putting health and health care into place: an invitation accepted and declined to reform is not discard: a reply to paul hiv and tuberculosis: a deadly human syndemic tuberculosis: epidemiology of the disease in canada a reformed medical geography reconsidered using gis technology to identify areas of tuberculosis transmission and incidence what is the outcome of location-based targeted tuberculosis screening based on universal genotyping? foreign-born status and geographic patterns of tuberculosis in tarrant county the global health threat of african urban slums: the example of urban tuberculosis commentary on kearns's 'place and health: toward a reformed medical geography epidemiology of tuberculosis in the united states on the mode of communication of cholera the risk of cancer associated with specific mutations of brca and brca among ashkenazi jews travel and the introduction of human immunodeficiency virus type non-b subtype genetic forms into western countries molecular detection and genotyping of pathogens: more accurate and rapid answers dead crow reports and location of human west nile virus cases who guidelines for the global surveillance of severe acute respiratory syndrome (sars) global polio eradication initiative. health and medical geography specialty group of association of american geographers the impact of globalization on infectious disease emergence and control: exploring the consequences and opportunities, workshop summary -forum on microbial threats key: cord- -ltjurdrq authors: acheson, d.w.k. title: food and waterborne illnesses date: - - journal: encyclopedia of microbiology doi: . /b - - . - sha: doc_id: cord_uid: ltjurdrq there are many different biological, chemical, or radiological agents that when added to food can result in many different types of illness. some may be rapidly fatal; others require long-term exposure to result in illness. some lead to short-term illness and others result in long-term complications. the universe of such agents and situations is enormous. this article summarizes some of the principal foodborne microbiological agents that clinicians and those involved with public health have to deal with. while the range of agents is broad and the list is long there are several basic mechanisms such as ingestion of preformed toxins or toxin production once a microbe is present in the intestine that facilitate sorting these agents into some logical framework. however, at the end of the day it is always key to think about ingested agents as a cause for illness, whether that illness be confined to the intestinal system or more systemic. in principle all foodborne illness is preventable and of the key messages to consumers and health care professionals is to know if you or your patient is at greater risk from foodborne illness. if one is dealing with an ‘at risk’ patient, it is important they be educated on what foods to avoid and what precautions to take to minimize the likelihood of acquiring a foodborne illness. while treating most foodborne illness is straightforward, prevention is clearly the path of choice. the topic under discussion is foodborne illness. while there are many causes of foodborne illness the focus of this text is on microbes. the text approaches the issues by discussing illness due to toxins preformed in foods and toxins made once the microbes have been ingested, illness due to other mechanisms that affect the gastrointestinal tract, and finally foodborne illness that has manifestations other than purely gastrointestinal. a wide variety of the common foodborne pathogens is discussed, with a brief description of what they are, the types of illness they cause, and the kinds of food most frequently associated with them along with some commentary with regard to treatment. food-and waterborne illness typically brings to mind the image of an individual who develops an acute gastrointestinal illness following exposure to contaminated food or water. however, the definition of illness that may be attributed to food or water is broad and encompasses exposure to toxins, carcinogens, metals, prions, allergens, and other factors, in addition to the classic infective pathogens. as reviewing each of these agents in detail is beyond the scope of this article, our focus will be on foodand waterborne infections only; an extensive list of foodborne pathogens is given in table . this article discusses the current epidemiology of foodborne illness, provides an overview of the various toxins and organisms considered to be the more important foodborne agents, and discusses some preventative approaches that can be used to help ensure consumers stay safe with regard to the food they prepare and eat at home. the clinical symptoms, treatment, and long-term consequences of various foodborne infections are also briefly reviewed. foodborne illness typically consists of acute gastrointestinal upset with nausea, vomiting, diarrhea, and abdominal cramps. typically, symptoms resolve without the need for significant medical intervention and without long-term consequence. however, on occasion foodborne infection causes severe illness or death. unfortunately, in the early stages of illness, differentiating between a patient with an inconsequential infection and the patient who may develop life-threatening sequelae can be difficult. some systemic consequences of infection occur several days or weeks after the initial exposure. examples include the hemolytic uremic syndrome (hus) secondary to shiga toxin-producing escherichia coli (stec), the development of guillain-barré syndrome (gbs) after campylobacter infection, and the association of a number of enteric bacterial pathogens with reactive arthritis and postinfectious irritable bowel syndrome. the true burden of foodborne illnesses in the united states and in other parts of the world is largely unknown; however, the number of suspected deaths worldwide from foodborne pathogen exposure is staggering. several million children die each year worldwide from acute diarrheal disease and resulting dehydration, the majority of which is likely due to contaminated food or water. in the united states, until recently, we had very little data on the numbers and outcomes of foodborne infection. the development of the foodborne diseases active surveillance network (foodnet) in by the centers for disease control and prevention (cdc) has provided, for the first time, the opportunity to determine the epidemiology of foodborne disease in the us population. foodnet is the (eip) , and is a collaborative venture with eip program sites, the us department of agriculture (usda), and the food and drug administration (fda). foodnet performs populationbased active surveillance for confirmed cases of campylobacter, e. coli o :h , listeria, salmonella, shigella, vibrio, yersinia, and hus, as well as cryptosporidium and cyclospora infections. in , surveillance occurred within a defined population of . million americans using information from clinical microbiology laboratories in ten states. foodnet monitors only confirmed cases of diarrheal infection, missing cases that never present to medical attention. however, through additional surveys, foodnet has the capacity to determine the frequency of diarrhea and the number of physician visits within the study population. utilizing foodnet and other data, the cdc provides our current best estimate of the true burden of foodborne infections in the united states. mead and his colleagues from the cdc estimate that there are million illnesses, hospitalizations, and deaths annually due to foodborne infections. this means that, on average, somewhere between one in three and one in four americans will have a foodborne infection each year. while these data provide an excellent estimate of disease prevalence in the united states, they also illustrate some major gaps in our knowledge of foodborne infections. specifically, determining attribution can be very difficult. for example, in the context of sporadic infections, the precise food that has caused the illness and the point at which the food was contaminated are usually unknown. or indeed whether the infection was acquired through person-to-person spread or by some other route is difficult to ascertain. also, in million cases, or % of the estimated million infections each year, no specific pathogen is identified. disease due to unidentified agents results in hospitalizations and deaths, which begs the question as to whether these are due to known pathogens or foodborne infections yet to be discovered. our ignorance as to the cause of more than % of the estimated foodborne illness is a daunting problem. however, many new agents have been discovered and linked to foodborne disease in the last years. table offers a list of some recently described food-and waterborne pathogens, some are new pathogens and others are agents previously recognised but infrequently linked to illness or considered nonpathogenic. for example, campylobacter jejuni was once thought to be an unusual cause of bacteremia but is now known to be one of the most frequent bacterial causes of enteritis in the united states. in , the most recent year for which preliminary foodnet data are available, the cdc confirmed laboratory-confirmed cases of infections from the foodnet sites. incidence varied dramatically between the foodnet sites. for example, campylobacter affected . per people in georgia and . per in california. salmonella infections varied from . per in oregon to . per in georgia. though the explanation for these geographic differences is unknown, they seem to suggest true regional variation of foodborne pathogens. another trend observed in foodnet data was the preponderance of cases in the young and elderly. in , foodnet identified cases of hus in children aged below years (rate: . per children); ( %) of these cases occurred in children aged below years (rate: . ). across all age groups, clinical outcomes differed by pathogen. while the total number of listeria monocytogenes and e. coli o :h infections were less than for some of the other pathogens, they were associated with much higher hospitalization rates and death rates than any of the other bacterial pathogens monitored (table ) . table reflects the lack of correlation between the propensity for an organism to cause disease and its propensity to result in the death of the patient. since foodnet began to operate in , the accumulated data have also revealed a seasonal trend, with a spike in infection with the three major pathogens (salmonella, c. jejuni, and e. coli o :h ) during the summer months (figure ) . the summer predominance of bacterial foodborne infections is likely multifactorial. clearly, warmer weather allows for more rapid bacterial growth on food that is improperly refrigerated. consumer habits also change in the warmer months, with more picnics and barbecues, contributing to problems with keeping food refrigerated, increased risk of cross contamination, and so on. foodnet surveillance effectively monitors trends in the rates of infection over time and there have been a number of changes since foodnet surveillance began, with the estimated annual incidence of several infections changing significantly from baseline to (figure decreased significantly ( % ci ¼ - %). in contrast, significant increases in incidence compared with baseline occurred for salmonella enteritidis ( %, ci ¼ - %), salmonella newport ( %, ci ¼ - %), and salmonella. javiana ( %, ci ¼ - %). the estimated incidence of salmonella heidelberg and salmonella montevideo did not change significantly compared with baseline. while foodnet produces excellent data on the epidemiology of foodborne illness overall, it has several important areas of weakness. it does not survey for many of the common foodborne pathogens, including viruses, which are thought to cause the vast majority of foodborne illness. similarly, it does not address the cause of illness in patients who do not have a stool sample sent for analysis: those who either do not seek medical care or do seek care but do not have a stool sample analyzed. in an adjunctive study reported by the cdc, % of residents interviewed through random phone consultations reported an episode of diarrhea during the previous month. this translates to . episodes of diarrhea per person per year, which if multiplied roughly by the population of the united states, represents million diarrheal cases per year. in this study, merely % of those with a diarrheal episode sought medical care, and of those, only % reported submitting a stool sample for culture. thus, our best data on the causes of acute gastrointestinal disturbance from foodnet surveillance are based on cultures of less than % of diarrheal episodes. nonetheless, despite the current limitations of our evaluation of foodborne illness, the endeavors of state, local, and federal authorities have been critical to improving our knowledge of disease frequency, pathogen epidemiology, and the establishment of control systems to limit food contamination. the knowledge gained from foodnet surveillance allows for targeted efforts to improve food safety and education. as noted previously, the diversity of foodborne pathogens listed in table is far too extensive to be discussed completely within the scope of this article. in the following sections therefore, many of these microbial agents will be discussed briefly with a focus on typical modes of transmission, the foods they frequently contaminate, and the specific serious consequences that may ensue from infection. although foodborne agents cause disease by a wide variety of mechanisms, the mode of infection often falls into one of the following three categories: ( ) ingestion of preformed toxins produced by bacteria in food prior to consumption; ( ) infection with pathogens present in food which, following ingestion, produce toxins in the gastrointestinal tract; and ( ) infection with organisms having various virulence factors that permit the microbes to be invasive, cause local damage, or create physiologic perturbations that result in clinical disease. of the three mechanisms, the preformed toxin is the most consistently transmitted via food. as each toxigenic organism requires a specific environment to stimulate toxin production, each has a predilection for certain types of food. as a result, different types of foods confer different risks for toxin ingestion. the major toxins of the common foodborne pathogens are discussed in detail in the next few sections and were reviewed by sears and kaper in . c. botulinum produces one of the best-known and deadly preformed toxins. the organism's natural habitat is soil, and therefore, its spores frequently contaminate fresh fruits and vegetables. commercial food sources have been occasionally implicated, but the majority of outbreaks have been traced to home-canned foods, especially vegetables, fruits, fish, and condiments. recent outbreaks have been attributed to chili, carrot juice, and home-prepared fermented tofu. generally the disease is rare, and in the united kingdom, only cases have been recognized between and . a recent report from the united kingdom provides a brief review of c. botulinum and foodborne botulism as well as descriptions of the six episodes ( cases with three deaths) of this disease that occurred in the united kingdom between and . to prevent botulism, the clostridium spores must be destroyed by heating food to a temperature of c for min, usually with the aid of a pressure cooker. in an anaerobic environment with a ph above . , any surviving spores will germinate and produce their deadly toxins. there are seven antigenically distinct types of botulinum toxin, each of which is designated by a letter, a-g. types a, b, e, f, and g are associated with human disease, with type a accounting for about % of outbreaks and type b %. once ingested, the toxin is absorbed through the proximal small intestine and spreads via the bloodstream to the peripheral cholinergic nerve synapses where it irreversibly blocks acetylcholine release. a flaccid paralysis results, with cranial nerves affected first, followed by respiratory muscle paralysis and death if left untreated. the diagnosis of botulism is clinical and treatment should be initiated prior to confirmation with laboratory data, as the traditional mouse bioassay for toxin detection requires days for final results. samples such as food, vomitus, serum, gastrointestinal washings, and feces are all reasonable specimens to test. newer pcr-and enzyme immunoassay-based detection methods are now being used. early in the course of disease, treatment may include emetics or gastric lavage to remove unabsorbed toxin. a trivalent (a, b, e) horse serum antitoxin decreases the progression and duration of paralysis, but it does not reverse existing paralysis. pentavalent and heptavalent antitoxins are also being investigated. human botulism immune globulin intravenous (big-iv) may also be beneficial. botulism carries a significant mortality rate, of up to %, with type a toxin. of those who survive the acute phase of illness, most recover completely. see later in the article for a discussion of infant botulism, which is a similar condition but not due to preformed toxin. a second well-known group of preformed toxins are those produced by s. aureus. s. aureus produces a variety of enterotoxins, defined by their antigenicity as enterotoxins a-h. staphylococcal enterotoxins a through g are responsible for % of staphylococcal food poisoning outbreaks. on rare occasions, other staphylococcal species, including coagulase negative staphylococci, have been found to produce similar enterotoxins. the toxins are small proteins with similar tertiary structures and biologic activity, including superantigen properties. ingestion of as little of - ng of toxin is considered sufficient to cause disease in humans. compared with botulinum toxin, staphyloccocal toxins are not inactivated by heating or boiling; nor are they susceptible to ph extremes, proteases, or radiation. as a result, once formed in food, these toxins are almost impossible to remove. the mechanism through which the toxin acts is not fully understood, but is suspected to be via stimulation of the autonomic nervous system and gut inflammation. as the toxin is not absorbed systemically, protective immunity is not induced following exposure. typically, patients become symptomatic between and h after ingestion of the food containing staphylococcal enterotoxin, with nausea ( - %), vomiting ( %), and abdominal cramps ( - %). diarrhea occurs in a large proportion of patients ( - %), but fever is rare. treatment of affected individuals is supportive and symptoms usually abate within days. there is no need to treat with antibiotics directed toward s. aureus. s. aureus is present in the mucous membranes and skin of most warm-blooded animals. food is most often contaminated with s. aureus through the fingers or nose of a food worker. the toxin is produced when contaminated food is stored at room temperature for a sufficient length of time to allow the organism to grow and produce toxin. the bacterial population must be greater than organisms per gram of contaminated food before appreciable amounts of toxin will be produced to elicit illness. a number of different foods have been associated with staphylococcal food poisoning, including egg products, cooked meat products, poultry, tuna, mayonnaise, and particularly cream-filled desserts and cakes. this disease is more frequently associated with food from the home or a service establishment rather than commercially prepared food. it has also occasionally occurred in large outbreaks with thousands of affected individuals. a third example of preformed toxins are those of b. cereus, a gram-positive, spore forming aerobe that causes two distinct clinical syndromes: a short-incubation period emetic syndrome and a long-incubation period diarrheal syndrome. the organism is known to produce up to three enterotoxins. cereulide and the tripartite hemolysin bl have been identified specifically as emetic and diarrheal toxins, respectively. nonhemolytic enterotoxin, a homologue of hemolysin bl, has also been associated with the diarrheal syndrome. the toxins associated with the diarrheal illness are not preformed but produced by the organism during the vegetative growth phase in the small intestine. the emetic toxin, named cereulide, is thought to be an enzymatically synthesized peptide produced as the organism grows in food, especially starchy foods such as rice and pasta. like staphylococcal toxin, cereulide is resistant to heat, ph variation, and proteolysis, and is therefore rarely destroyed during food preparation. its exact pathogenic mechanism remains unknown, but it has been shown to stimulate the vagus afferent by binding to the -ht receptor. the emetic syndrome presents much like s. aureus-related foodborne disease, occurring - h after exposure and causing nausea and vomiting. fever is not characteristic of the illness and full recovery usually occurs. diagnosis can be made by finding the organism in the food or vomitus of the patient, or through detection of the emetic toxin through bioassays or the enterotoxins by commercial immunoassays. new approaches include the use of real-time pcr to detect cereulide-producing b. cereus genes in potentially contaminated food. derived from various types of food, a number of naturally occurring toxins may cause human foodborne illness. many are associated with consumption of seafood contaminated by algae. others are due to fungal contamination of food or inherent to certain fruits and vegetables. scombroid poisoning typically occurs after the ingestion of spoiled, dark-fleshed fish, especially tuna and mackerel. the clinical symptoms of poisoning, including flushing, headache, palpitations, dizziness, nausea, vomiting, and diarrhea, are attributable to excess levels of histamine present in temperature-abused fish. histamine is produced by bacterial metabolism of the amino acid histidine in fish muscle. bacterial replication and histamine production occur when fish is not frozen promptly after being caught or is stored at room temperature for several hours. symptoms of intoxication begin within minutes to several hours following ingestion. most resolve fully within hours, but, occasionally, bronchospasm or circulatory collapse may occur. the diagnosis is clinical, and treatment consists of antihistamines. elevated histamine levels in the contaminated fish or the patient's serum may be diagnostic, but few laboratories, other than regulatory laboratories, are equipped to undertake this analysis. ciguatera poisoning is due to the ingestion of neurotoxins from tropical and subtropical marine fin fish, including mackerel, groupers, barracudas, snappers, amberjack, and triggerfish. it affects individuals yearly, mainly in the caribbean and south pacific islands. the toxin is produced in reef algae, the dinoflagellates (e.g., gambierdiscus toxicus). it spreads through the food chain via consumption of smaller organisms and fish by larger predators, accumulating at dangerous levels in the flesh of large fish. two groups of compounds are implicated in ciguatera fish poisoning: the lipid-soluble ciguatoxins, which activate nerve synapse sodium channels, and the water-soluble maitotoxin, which induces neurotransmitter release by binding to calcium channels. in humans, these toxins cause gastrointestinal symptoms - h after ingestion, including nausea, vomiting, and watery diarrhea. neurologic symptoms follow, with weakness, heat-cold temperature reversal, vertigo, ataxia, paresthesias, and dysathesias of the perioral region, palms, and soles. death and serious cardiovascular complications are uncommon. most symptoms resolve within a week, but neurologic symptoms can persist for months. the diagnosis of ciguatera is clinical; however, the toxin can be detected in fish using a mouse bioassay or newer enzyme immunoassays. five main types of shellfish poisoning have been described: paralytic, neurotoxic, diarrheic, amnestic, and azaspiracid. like ciguatera, illness is due to toxins generated by algae, usually dinoflagellates, which accumulate in the shellfish. the paralytic variant of shellfish poisoning is due to saxitoxin, an agent that blocks neuronal sodium channels and prevents propagation of the action potential. clinically, this results in a rapid-onset, life-threatening paralysis. brevitoxin, the agent responsible for neurotoxic shellfish poisoning, also binds sodium channels but does not cause paralysis; instead, it produces a clinical syndrome similar to but less severe than ciguatera. symptoms of nausea, vomiting, and paresthesias occur within hours of exposure and resolve completely within days. diarrheic shellfish poisoning causes gastrointestinal disturbance with nausea, vomiting, and diarrhea. the toxin acts by increasing protein phosphorylation. amnestic shellfish poisoning, also known as toxic encephalopathic poisoning, causes outbreaks of disease in association with consumption of mussels. manifestations include nausea, vomiting, diarrhea, severe headache, and, occasionally, memory loss. the toxin domoic acid is a glutamate receptor agonist that causes excitatory cell death. diagnosis of human illness due to shellfish toxins is clinical based on symptom profile and prompt onset of symptoms after shellfish consumption. the exception to this is amnestic poisoning, which may not cause symptoms until - h after exposure. the toxins can be detected using either mouse bioassays or high-performance liquid chromatography (hplc), but this is done primarily for research purposes or in monitoring. owing to the serious consequence of shellfish poisoning, large-scale surveillance systems for contamination of shellfish populations have been implemented. tetrodotoxin is present in certain organs of the puffer fish and if ingested can cause rapid paralysis and death. symptoms may occur in as little as min or after several hours. the illness progresses from gastrointestinal disturbance to almost total paralysis, cardiac arrhythmias, and death within - h after ingestion of the toxin. the diagnosis is clinical and based on history of exposure. mouse bioassays and hplc have been used to detect tetrodotoxin in food. aflatoxins are produced by certain strains of fungi (e.g., aspergillus flavus and aspergillus parasiticus) that grow in various types of food. most human exposure occurs through mold-contaminated corn or nuts, especially tree nuts (brazil nuts, pecans, pistachio nuts, and walnuts), peanuts, and other oilseeds. because mycotoxins can be produced prior to or after harvest, eliminating them from food is nearly impossible. aflatoxin b is the most common and toxic, but there are several types of toxins (b , g , and g ). they are potent mutagens and carcinogens, with b causing deoxyribonucleic acid (dna) damage in the p tumor suppressor gene. exposure to the aflatoxin predisposes the patient to hepatocellular carcinoma, especially in conjunction with chronic hepatitis b infection. with a high ingested dose of aflatoxin, a condition known as aflatoxicosis may occur, characterized by fever, jaundice, abdominal pain, and vomiting. aflatoxin exposure is common in asia and parts of africa but uncommon in the united states. the diagnosis is clinical, but assays to detect the toxins in food exist. serum and urine markers have also been developed to quantify exposure. vibrios currently, there are over vibrio species, a group of gram-negative marine organisms, most of which are not human pathogens. the most common and severe human illness is caused by vibrio cholerae o , the species responsible for seven cholera pandemics. the previous six were caused by the 'classic' biotype and the seventh pandemic, which began in , was caused by the 'el tor' biotype. in the united states, cholera is mainly acquired through consumption of gulf coast seafood or through foreign travel. a clean water supply is critical to cholera prevention, as the organism is resistant to washing, refrigeration, and freezing of a wide variety of seafood and fresh produce. because stomach acidity does kill many of the organisms, more than v. cholerae are usually required for infection; those with decreased gastric acidity may be infected with lower doses. the incubation period is usually - days, but may be as short as a few hours or as long as days. infection causes voluminous watery diarrhea. hypotension and shock may result within the first h of infection. the primary virulence factor is the cholera toxin, which targets an intestinal g-protein, producing cyclic adenosine monophosphate (camp). the increase in camp produces watery diarrhea by inhibiting intestinal sodium absorption and increasing chloride and bicarbonate secretion. the toxin is transmitted to the organism via a bacteriophage. indeed, in recent years a new pathogen, v. cholerae o , evolved in the indian subcontinent. non-o strains were not previously associated with human epidemics, but this pathogen appears to have acquired the cholera toxin and other virulence factors through horizontal transmission and bacteriophage infection. vibrio parahaemolyticus also inhabits marine environments and is acquired principally through the ingestion of raw shellfish. this vibrio has been a major foodborne pathogen in japan, but is less common in the united states. in recent years there has been global dissemination of v. parahaemolyticus serotype o -k . infection is characterized by diarrhea, abdominal cramps, nausea, and vomiting, with fever and chills present in about % of cases. dysentery occurs in a minority of patients, more often in children than in adults. occasionally, wound infections and septicemia occur. symptoms may appear in as little as h, but are typically present - h after exposure. disease is attributed to a kda protein called thermostable direct hemolysin (tdh). the gastroenteritis is usually self-limiting. patients require fluids, and antibiotics may be useful if intestinal symptoms persist. vibrio vulnificus is another free-living estuarine organism that is frequently isolated from shellfish, most often acquired through raw oyster or clam consumption. it is the most common life-threatening vibrio infection in the united states. individuals with diabetes, immunosuppressive disorders, and liver disease including hemochromatosis and alcoholic liver disease are especially susceptible to infection. in these groups the case fatality ratio may exceed %. infection presents with fevers, chills, nausea, vomiting, and diarrhea. hypotension and sepsis ensue. large hemorrhagic bullae erupt and progress to necrotic ulcers. v. vulnificus is an encapsulated organism, thereby resistant to the bactericidal activity of normal human serum. the pathogenesis of v. vulnificus is not well understood but has been summarized recently by gulig and colleagues. the organisms are sensitive to the amount of transferrin-bound iron in the host, which may explain the increased susceptibility in patients with hemochromatosis. definitive diagnosis may be made from blood, stool, or wound cultures. due to the severity of infection, antibiotics should be initiated promptly. v. vulnificus is susceptible to many antimicrobials, including tetracycline, ciprofloxacin, trimethoprim-sulfamethoxazole, ampicillin, and chloramphenicol. clostridium perfringens is an anaerobic, spore-forming, gram-positive rod associated with two distinct types of foodborne disease. the species has been divided into five distinct types, a-e. type a causes the majority of human infections and is usually linked to the consumption of meat or poultry (typically high-protein foods) that have been stored between and c for more than h. at this temperature, clostridial spores germinate and begin vegetative growth. at an infective dose of vegetative cells, ingested clostridial spores transiently colonize portions of the intestine and produce enterotoxin. ingestion of preformed toxin or nongerminated spores will not usually result in disease. the enterotoxin (cpe) is a heat-labile kda protein encoded by the cpe gene. c. perfringens types a, c, and d all carry this gene, but for unclear reasons only type a is frequently associated with foodborne disease. cpe functions by a complex mechanism, inserting itself into the host cell membrane and altering membrane permeability. clinically, diarrhea and severe abdominal cramps develop - h after exposure; vomiting and fever are less common. diagnosis is complicated by the presence of c. perfringens in the bowel microflora of many asymptomatic individuals. however, a number of tests are able to detect the enterotoxins in stool, including enzyme immunoassays or latex agglutination. c. perfringens type c causes the second distinct foodborne illness, mainly in developing countries. it causes a necrotizing enterocolitis seen in the context of malnutrition. the type c strains produce enterotoxin and type 'a' and 'b' toxins. the b toxin appears to be responsible for the cell necrosis associated with infection. as the b toxin is inactivated by intestinal proteases, illness occurs in patients in whom these enzymes are inadequate (e.g., in malnutrition) or in the presence of trypsin inhibitors found in undercooked pork or sweet potatoes. infant botulism results from the germination of ingested spores of botulinum toxin-producing clostridia that colonize the large intestine. the spores germinate within the intestine and produce botulinum toxin. of the various potential environment sources such as soil, dust, and foods, honey is the one dietary reservoir of c. botulinum spores that has definitively been linked to infant botulism by both laboratory and epidemiological studies. children aged months are very susceptible to developing infant botulism. honey continues to be an important exposure source in young infants and cases continue to occur. jars of honey bear a label advising parents to not feed honey to children less than months old. the two main e. coli species associated with foodborne illness are stec and enterotoxigenic e. coli (etec). the former are relative newcomers to the scene of foodborne pathogens. the first stec to be associated with disease in humans was e. coli o :h following two outbreaks of hemorrhagic colitis in . since then, at least different serotypes of stec have been associated with clinical disease and have become recognized as the most common cause of hus. not all stec have been associated with human illness and the more virulent forms are often referred to as enterohemorrhagic e. coli (ehec) that are characterized by having the ability to attach and efface intestinal epithelium, produce shiga toxins (stx), and carry a specific plasmid. stec bacteria colonize the intestinal tracts of many mammalian species, particularly ruminants (cattle, sheep, and goats). most human illness is due to the ingestion of contaminated bovine products, but an increasing number of reports associate infection with fecally contaminated fresh produce (lettuce, alfalfa sprouts, unpasteurized apple cider, spinach) and water. one of the key virulence factors of stec is bacteriophage-encoded stx. the two main types are stx and stx , but there are at least five subtypes of stx (stx , c, d, e, and f). the infectious dose of some stec (e.g., o :h ) is known to be very low, in the region of - organisms. symptoms typically develop - days after ingestion, but may occur in as little as day or as long as days. nonbloody or bloody diarrhea is the primary acute manifestation. treatment of stec and its major complications is currently largely supportive. controversy exits as to the role of antibiotics, with concern that treatment of pediatric patients with certain antimicrobials (e.g., fluoroquinolones and trimethoprim-sulfamethoxazole) may actually increase the likelihood of serious complications such as hus. several recent reviews relating to foodborne e. coli infections have been written, and the reader is referred to them for more details. a well-described example of a long-term consequence following infection with a foodborne and waterborne pathogen is the hus resulting from stec infection. in the united states, . % of patients will require a renal transplant following hus. in up to % of patients with hus, the pancreas is also damaged, causing some patients to develop permanent diabetes mellitus. etec infection is a common cause of disease in developing countries, and is frequently associated with travelers' diarrhea. etec are transmitted through contaminated water and food and have caused a number of large outbreaks in the united states; however, their importance in sporadic disease is not known. incubation periods range from h to days, and typical symptoms are abdominal discomfort and watery, nonbloody diarrhea without fever. etec have two significant virulence characteristics: the ability to colonize the intestine and the capacity to produce enterotoxins. a variety of colonization factor antigens (cfa) and two different types of toxins, known as heatstable (st) and heat-labile (lt) toxins, have been found in etec. the st group consists of small peptides that effect intracellular concentrations of cyclic guanosine monophosphate (gmp). the lt toxins are structurally and functionally much like the cholera toxin. oral rehydration is the mainstay of treatment and is often life saving for infants. antibiotic therapy is not routinely required. salmonella salmonella are one of the most common causes of foodborne illness in humans. they can be divided into two broad categories: those that cause typhoid and those that do not. the typhoidal salmonella, such as s. typhi and s. paratyphi, colonize humans and are acquired through the consumption of food or water contaminated with human fecal material. the much larger group of nontyphoidal salmonella are found in the intestines of other mammals and, therefore, are transmitted through food or water that has been contaminated with fecal material from a wide variety of animals and poultry. more than serovars of salmonella are differentiated by their somatic (o) antigens and flagellar (h) antigens. in the united states, most typhoid is the result of food contamination by an asymptomatic chronic carrier, or from foreign travel. typhoid fever continues to be a global health problem, but is uncommon in the united states; only outbreaks occurred between and . in contrast, the number of cases of nontyphoidal salmonella increased steadily over the last four decades. s. enteritidis infection due to contamination of hen eggs is a particular problem, with an estimated contamination rate of in eggs. the bacteria penetrate intact eggs lying in fecal material or infect them transovarially before the shell is formed. other common sources of nontyphoidal salmonellosis are inadequately pasteurized milk, foods prepared with raw eggs, meat, poultry, and fecally contaminated fresh produce. the infectious dose of s. typhi is thought to be around organisms. typhoid infection is characterized by high fevers, abdominal discomfort, and a rose-colored macular rash. the infective dose of nontyphoidal salmonella may vary from < to depending on the host, the food vehicle, and the type of salmonella. these species tend to cause bloody or nonbloody diarrhea, fever, nausea, vomiting, and abdominal discomfort. in all types of salmonella the most critical virulence determinant is their ability to cross the intestinal epithelium and cause invasive disease. the most pressing problem regarding salmonella is the emergence of multidrug-resistant strains. for example, s. typhimurium phage type dt is resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline. in europe quinolone-resistant strains of salmonella have been detected. campylobacter, which was not recognized as a foodborne pathogen until the mid s, is now one of the most common bacterial foodborne infections diagnosed in the united states. campylobacter are gram-negative, spiral, microaerophilic organisms. two species of campylobacter, c. jejuni and c. coli, are responsible for the vast majority of human disease, with c. jejuni causing % of infections and c. coli near %. campylobacter fetus, campylobacter upsaliensis, campylobacter hyointestinalis, and campylobacter lari have occasionally been associated with gastroenteritis. in human studies, infectious doses as low as organisms may result in disease, and one drop of chicken juice may contain infectious organisms. campylobacter are more frequently associated with sporadic disease than with outbreaks, and person-to-person spread does not appear to be common. c. jejuni and c. coli are intestinal commensals in many animals and birds, including domestic pets. the main vehicle for human infection is poultry, but other raw meats, milk, and water have also been implicated. surface water can be contaminated with campylobacter and waterborne outbreaks have been reported. the pathogenicity of campylobacter depends on its motility; in vitro, nonmotile strains are not capable of invading intestinal epithelial cells. typical infection causes diffuse colonic inflammation with marked inflammatory cell infiltration of the lamina propria, which may be mistaken for inflammatory bowel disease. symptoms usually occur within - days after exposure, but may occur as quickly as h or as late as days. high fevers, headache, and myalgias may precede the onset of nausea, vomiting, and diarrhea. the diarrhea may be loose and watery or grossly bloody. abdominal cramps and pain may predominate. interestingly, the disease is sometimes biphasic, with an apparent settling of symptoms after - days followed by a recrudescence. local complications resulting from direct spread of the organisms from the gastrointestinal tract are rare and include cholecystitis, hepatitis, acute appendicitis, and pancreatitis. the case fatality rate is low, approximately . per infections. however, long-term complications may occur including gbs. gbs affects - persons per in the united states each year, or less than person per infected. a recent article by hughes and cornblath address this issue and they point out that about a quarter of patients with gbs have had a recent c. jejuni infection, and that axonal forms of the disease are especially common in these people. the pathogenesis of injury is molecular mimicry, in which the immunologic response to the core oligosaccharides of campylobacter lipopolysaccharide cross-react with a variety of neuronal glycosphingolipids. up to % of individuals affected by gbs require mechanical ventilation, and another % will have permanent neurologic deficits. the overall risk of developing gbs following campylobacter infection is considered to be in . the percent of cases of gbs linked to prior infection with campylobacter is estimated to be - %. at least campylobacter serotypes have been associated with gbs, but serotype o: is thought to be the most common association. the interval between infection and the development of gbs may be as short as week or as long as . those with a rapid onset of gbs are suspected to have had prior exposure to the critical campylobacter serotypes and therefore primed for a rapid immune response. diagnosis of campylobacter is confirmed by stool culture. pcr and enzyme immunoassays are now available and may become useful for species-specific antigen detection. as with salmonella, a growing number of campylobacter are developing antimicrobial resistance. fluoroquinolones are generally very active against campylobacter when they are susceptible, and there was a period when it appeared that these would be the drugs of choice. however, the increasing problems with fluoroquinolone resistance now makes fluoroquinolones much less desirable and not a drug of choice in first-line therapy. in sweden, quinolone resistance in clinical isolates of c. jejuni increased more than fold in the early s; macrolide resistance is also increasing. of the three members of the genus yersinia, y. enterocolitica and y. pseudotuberculosis are considered to be foodborne pathogens, whereas y. pestis is typically not. overall, yersinia cause less foodborne illness than salmonella or campylobacter, and the majority of isolates in food, environmental samples, and human stool are nonpathogenic species. y. enterocolitica is divided into biogroups, with more than 'o' antigens used to designate strains. most human disease is associated with serotypes o , o , o , or o . y. enterocolitica is an invasive organism. all pathogenic strains carry a plasmid pyv, coding for the virulence proteins yersinia outer proteins (yops) and adhesin a (yada), which block phagocytosis, opsonization, and complement activation; and yersinia enterotoxin (yst), invasin (inv), and attachment-invasion proteins (ail), which mediate invasion and serum resistance. a variety of tests, including pcr and dna hybridization, congo red absorption, salicin fermentation, and esculin hydrolysis, can be used to determine if a strain is pathogenic. y. enterocolitica infection results in mesenteric lymphadenitis, enteritis, and diarrhea. most infections are selflimited, but symptoms can be prolonged, lasting several weeks or longer. complications such as ulceration and intestinal perforation may occur. the classic long-term complication following yersiniosis is the development of reactive arthritis, occurring most commonly in patients who are hla-b -positive. although antibiotic therapy is not routinely required, many antimicrobials are effective; ceftriaxone or fluoroquinolones are recommended for serious infection. yersinia infection is most frequently associated with raw or undercooked pork consumption. swine are the major reservoir of these organisms, though pathogenic human strains have been found in sheep, dogs, cats, and wild rodents. milk is a frequently reported source, and since y. enterocolitica can survive and indeed multiply in milk at c, small numbers of organisms can become a significant health threat, even if the milk is refrigerated. six serotypes and four subtypes of y. pseudotuberculosis have been described, but serotype o is associated with about % of human disease. the clinical picture is similar to that of y. enterocolitica. l. monocytogenes is a pathogen of great concern because of the high mortality rate associated with infection. listeriosis is the major concern from exposure to l. monocytogenes and although rare and usually occurring only in high-risk populations ( cases per year estimated to occur in the united states) is associated with high morbidity and mortality rates, with a case fatality rate of over %. of the seven listeria species, only l. monocytogenes is a significant human pathogen. it is common in the environment, present in soil, water, on plants, and in the intestinal tracts of many animals. thirty-seven different types of mammals, at least species of birds, and between and % of humans are carriers of listeria. although the organism is readily killed by heat and cooking, the fact that it is ubiquitous makes recontamination a real risk. of particular concern is that the organism is able to grow and multiply at refrigerator temperatures in certain foods, so even minor contamination of a product may result in high levels of bacteria after extended storage. the infectious dose is not known, with some studies suggesting it may be as high as organisms, and others suggesting that it may be as low as several hundred. the more critical determinant of listeria infection is likely individual susceptibility, with the elderly, pregnant women, the immunocompromised, and newborns having higher rates of infection and higher mortality rates. foods associated with listeriosis include unpasteurized milk, soft cheeses (e.g., feta, camembert, and brie), coleslaw, smoked seafood, luncheon meats, and hot dogs. human infection occurs sporadically and in outbreaks. infected individuals suffer a mild, transient gastroenteritis - days after contaminated food is consumed. most immunocompetent adults have no further symptoms. susceptible individuals may suffer, after a period of days, fevers and mylagias, septicemia, meningitis, or encephalitis. pregnant women have a -fold increased risk of infection, and transplacental transmission may cause spontaneous abortion, premature birth, neonatal sepsis, and meningitis. once the diagnosis is established, l. monocytogenes is readily treated by penicillins or aminoglycosides. l. monocytogenes has also been associated with febrile gastroenteritis and is linked with a variety of food items. generally, such episodes are self-limiting and do not lead to listeriosis. it is unclear how frequently l. monocytogenes causes enteritis since it is not an organism that is routinely looked for in this context. shigellae are unusual in that they are not present in fecal material from animals such as poultry, beef, and pork, and are therefore not transmitted in the same manner as nontyphoid salmonella, campylobacter, or e. coli. instead, these bacteria are highly host adapted, infecting only humans and some nonhuman primates. transmission occurs when a food product is contaminated by human fecal material. there are four different species of shigella (s. dysenteriae, s. flexneri, s. sonnei, and s. boydii) and all cause human disease. in the united states and other developed countries, most infection is due to s. sonnei, though s. flexneri is also common. one of the most striking features of shigellosis is the very small inoculum of organisms required to cause disease: as few as - of the most virulent genus, s. dysenteriae, are sufficient to cause dysentery in healthy adult volunteers. this low infectious dose permits person-to-person spread, with % of persons in a household becoming infected when an index case is identified in a family. given that these organisms are not typically present in food other than through human contamination -either directly during food preparation or indirectly from contamination with human fecal materialall shigellosis could be considered to be due to person-toperson spread. a variety of foods have been implicated in shigellosis including salads (potato, tuna, shrimp, macaroni, and chicken), raw vegetables, dairy products, poultry, and common-source water supplies. shigella often cause bloody diarrhea. some species carry stx and may cause hus like e. coli o :h . treatment with antibiotics shortens the duration of fever, diarrhea, and bacteremia, and reduces the risk of lethal complications. it also shortens the duration of pathogen excretion in stool, thereby limiting the spread of infection. a recent concern, however, is the increasing antibiotic resistance of shigella species. antibiotic resistance occurs quickly in shigella, attributed to horizontal transfer of resistance genes on integrons. multidrug-resistant isolates have been discovered in several developing countries. e. sakazakii is a motile, peritrichous, gram-negative rod that was previously referred to as a 'yellow-pigmented enterobacter cloacae'. e. sakazakii is a recently identified foodborne pathogen that has been implicated most frequently in causing illness in neonates and children from days to years of age. a recent review by bowen and braden of cases indicated that e. sakazakii has a mortality rate of - %. twelve infants had bacteremia, thirty-three had meningitis, and one had urinary tract infection. most newborns with e. sakazakii infections die within days of infection. death is usually attributed to sepsis, meningitis, or necrotizing enterocolitis. the case fatality rates vary from to %. sources of e. sakazakii associated with infant infections have not been identified in many cases; however, epidemiological investigations have implicated rehydrated powdered infant formula as well as equipment and utensils used to prepare rehydrated formula in hospital settings. enteroinvasive e. coli (eiec) is not frequently recognized as a foodborne pathogen, but infection has been linked to water and other foods such as cheese. eiec causes morbidity and mortality in young children in developed countries, but is a more important pathogen in developing countries due to poor hygiene and sanitation. a number of prominent serogroups found to be eiec have been described, including o , o , o , o , o , o , o , and o . clinically, eiec produces disease similar to shigellosis, with watery diarrhea or dysentery. eiec should be considered in those subjects with dysentery and substantial fecal leukocytes, in whom other invasive organisms have been ruled out. enteropathogenic e. coli (epec), like shigella species, is transmitted mainly by the fecal-oral route from one infected individual to another. epec has no known animal reservoir and is transmitted via food and water once contaminated by an infected person. epec is a major cause of infantile diarrhea worldwide, but mostly affects the developing world. the organisms have caused major outbreaks in various developed countries, but their role in sporadic disease is unknown because we lack routine diagnostic testing for these bacteria. clinically, epec infection presents with a watery, nonbloody diarrhea. low-grade fever and vomiting are common. in the developing world, mortality rates may be high, especially among infants. enteroaggregative e. coli (eaec) get their name from the way in which they adhere to epithelial cells in culture, in a 'stacked brick' pattern. these bacteria have been associated with acute or persistent diarrhea among immunocompromised patients and in developing countries. currently, there is no known animal reservoir for eaec, and fecal-oral spread from one person to another is considered to be the usual route of transmission. as with epec, contamination of food and water from infected individuals is probably important. in hiv patients with persistent eaec-associated diarrhea, antibiotic treatment has resulted in clearing of the organisms and in improvement in symptoms, suggesting that these bacteria are true pathogens, but they may be more opportunistic than other foodborne bacteria. aeromonads are gram-negative, facultatively anaerobic, motile, oxidase-positive bacilli that have been associated with foodborne illness. they are present in soil, freshwater, and sewage, and can contaminate fresh produce, meat, and dairy products. the infection rate tends to peak during the summer months. of the various species, aeromonas hydrophila, aeromonas caviae, aeromonas veronii, and aeromonas jandaei are most frequently associated with acute enteritis and foodborne infections. all typically cause persistent watery diarrhea. patients often have abdominal pain and dysenteric-like symptoms can occur, but fecal leukocytes and red cells are usually absent from stool. nausea, vomiting, and fever may occur in up to % of patients. infection is usually self-limiting and full recovery occurs in most healthy individuals without antimicrobial therapy, often making the diagnosis of academic interest only. the exception may be the patient with persistent diarrhea in whom no other cause has been identified. a number of protozoa have been associated with consumption of contaminated food and water. according to a review by karanis and colleagues, at least waterassociated outbreaks of parasitic protozoan disease have been reported. giardia lamblia and cryptosporidium parvum account for the majority of outbreaks ( , . and , . %, respectively), entamoeba histolytica and cyclospora cayetanensis were the etiological agents in nine ( . %) and six ( . %) outbreaks, respectively, while toxoplasma gondii and isospora belli were responsible for three outbreaks each ( . %) and blastocystis hominis for two outbreaks ( . %). balantidium coli, the microsporidia, acanthamoeba, and naegleria fowleri were responsible for one outbreak each ( . %). however, questions remain in the literature as to whether some of these less frequently seen agents are truly the cause of illness or simply 'detected at the time'. c. parvum is an apicomplexan protozoan parasite that causes diarrhea in both immunocompetent and immunocompromised individuals. its pathogenic potential in immunocompromised patients first became evident during the early acquired immunodeficiency syndrome (aids) epidemic. its ability to affect healthy individuals was confirmed in , when more than people in milwaukee developed cryptosporidiosis as a result of contaminated municipal drinking water. cryptosporidia are typically waterborne, but foodborne and person-toperson spread have occurred. the primary reservoirs are bovine and human. symptoms tend to occur days after ingestion of the oocysts. once ingested, the oocysts release four sporozoites, which then attach to and invade intestinal epithelial cells, especially in the jejunum and ileum. as a result, infection may be missed by diagnostic evaluation such as endoscopy. the diagnosis is made by a modified acid-fast or kinyoun stain for oocysts in the stool, or using commercially available immunofluorescence assays. typically, cryptosporidiosis causes watery diarrhea, abdominal cramping, nausea, and vomiting. fever is infrequent. in the immunocompetent, infection is selflimiting and recovery is the rule after a week or two. immunocompromised hosts do not clear the infection, and malabsorption may become a significant and lifethreatening problem. unfortunately, there is no known treatment for c. parvum infection, and current methods of water purification are ineffective for removal of the organism from the public water supply. g. lamblia is probably the most common enteric protozoan worldwide. though it may not cause dramatic enteric disease and has few systemic complications, giardiasis can lead to profound malabsorption and misery. only g. lamblia is known to infect humans. like other enteric protozoa, it is transmitted via the fecal-oral route and is most commonly spread through contaminated water. disease is caused by ingestion of cysts, which excyst in the proximal small intestine and release trophozoites. the trophozoites divide by binary fission and attach intimately to the intestinal epithelium via a ventral disk. the infectious dose is as low - cysts. clinical symptoms vary greatly; infection may be asymptomatic, or at the other extreme, may result in substantial abdominal discomfort, chronic diarrhea, protein-losing enteropathy, and intestinal malabsorption. g. lamblia can be diagnosed by fecal microscopy looking for either cysts or trophozoites. currently, many laboratories use commercially available kits utilizing either fluorescence microscopy with specific antibodies or enzyme immunoassays. metronidazole is the drug of choice for treatment. e. histolytica is the second leading cause of parasitic death in the world, with more than deaths annually. it is spread through fecal contamination of food and water or by person-to-person contact. amebic cysts are the infectious agent. they may survive for weeks in an appropriate environment. following ingestion, they pass unharmed through the stomach, travel to the small intestine, and excyst to form trophozoites. the trophozoites then colonize the large bowel and either multiply or encyst, depending on local conditions. the trophozoites invade the colonic epithelium, resulting in ulceration of the mucosa and amebic dysentery. they may also spread hematogenously to the portal circulation, causing parenchymal liver damage and amebic abscesses. the onset of symptoms in amebic dysentery may be gradual, initially presenting with mucoid stools and constitutional symptoms before progressing to bloody stools, abdominal pain, and fever. amebic abscesses may develop months to years after exposure. there are two types of entamoeba: e. histolytica is pathogenic while e. dispar is a commensal. microscopic examination of the stool has been the standard technique used to diagnose amebic dysentery, but this technique cannot distinguish between the two species. in the patient with classic symptoms of amebic dysentery, this distinction may not be important. however, elisa and stool pcr techniques are now commercially available and allow specific identification of e. histolytica. once the diagnosis is made, in the united states, metronidazole is the only drug available for treatment. in invasive amebic infections metronidazole should be followed by a luminal agent such as paromomycin or iodoquinol to eliminate bowel colonization by cysts. c. cayetanensis has caused a number of outbreaks in north america associated with consumption of imported raspberries in - . cyclospora has also been associated with basil and snow peas, undercooked meat and poultry, and contaminated drinking and swimming water. in immunocompetent patients, cyclospora infection results in self-limiting diarrhea with nausea, vomiting, and abdominal pain. in immunocompromised patients there can be a chronic cycle of diarrhea with anorexia, malaise, nausea, and abdominal discomfort followed by transient remissions. infection is diagnosed through detection of oocysts in stool by direct stool microscopy and oocyst autofluorescence. the infection can be treated successfully with trimethoprim-sulfamethoxazole. t. gondii is an intracellular pathogen that invades the human host from the gastrointestinal tract and causes symptomatic or asymptomatic toxoplasmosis. the vast majority of persons infected with t. gondii are asymptomatic. however, there is a risk of reactivating infection at a later time should the individual become immunocompromised. this is especially a concern in patients with aids. there is a greater risk of this when the cd lymphocyte count falls below cells/ml. primary maternal infection during pregnancy can be transmitted to the fetus and can result in serious sequelae and there are an estimated - cases of congenital toxoplasmosis in the united states each year. felines of all types are the only animals in which t. gondii can complete its reproductive cycle; thus cats are a major source of infection. with regard to foods, humans may become infected from consuming undercooked contaminated meat from an infected animal or from consuming food that has been contaminated in the environment with oocysts in the soil and then not cooked (e.g., fresh produce). according to cdc, viruses account for many more cases of foodborne infection than bacterial causes. viral syndromes range from simple gastroenteritis to life-threatening hepatitis. viruses contaminate both food and water, but they do not reproduce in these media; nor do they produce toxins. several viruses, such as the noroviruses, cause large outbreaks, while others are only associated with sporadic disease. the difficulty in diagnosing viral illness has precluded the acquisition of large amounts of epidemiologic data. however, the advent of rapid tests such as enzyme immunoassays is beginning to change this and will eventually lead to a better understanding of the epidemiology and disease burden caused by the various foodborne viral pathogens. noroviruses (genus norovirus, family caliciviridae) are a group of related, single-stranded rna, nonenveloped viruses that cause acute gastroenteritis in humans. norovirus is the official genus name for the group of viruses provisionally described as 'norwalk-like viruses' (nlv). noroviruses are the principal cause of epidemic, nonbacterial gastroenteritis in the united states. mead and colleagues estimate these viruses cause million infections, hospitalizations, and deaths annually. norwalk virus (now called norovirus) was first described after a large outbreak in . noroviruses have been associated with many large outbreaks in cruise ships, nursing homes, banquet halls, and other institutional settings. the primary source of infection is feces-contaminated drinking water, but the virus may also be spread through food that has been stored or washed in contaminated water or handled by an infected food service worker. noroviruses are highly contagious, with fewer than viral particles sufficient to cause disease, and are resistant to freezing, heating, ph extremes, and disinfection. symptoms tend to occur h after exposure and consist of vomiting and diarrhea. the diarrhea is watery without red cells, leukocytes, or mucus. the disease is usually selflimiting, resolving in - days without long-term sequelae. diagnosis can be made using transmission electron microscopy to find norovirus particles in stool, vomitus, or food. serologic testing, enzyme immunoassays, and pcr techniques also establish the diagnosis. the only treatment required is to prevent dehydration. handwashing will have a significant impact on the spread of the infection. a number of other viruses have also been associated with outbreaks of acute enteritis and are suspected to be spread through the fecal-oral route. table includes a list of potential foodborne viruses: rotavirus, enteric adenovirus, saporo-like viruses, coronaviruses, toroviruses, reoviruses, and the smaller-sized viruses such as caliciviruses, astroviruses, parvoviruses, and picobirnaviruses. all cause a similar acute illness with a self-limiting noninflammatory, watery diarrhea. hepatitis a is an rna virus, belonging to the family picornaviridae, with a worldwide distribution. it is spread via the fecal-oral route through contaminated food and water, and person-to-person spread. in sporadic infections, up to - % of susceptible household contacts of the affected individual are infected with hepatitis a. large outbreaks have been traced to a variety of foods including contaminated water, shellfish, milk, potato salad, and fresh fruits. one of the largest outbreaks in the united states was in from green onions. symptoms develop days after exposure on average, with a range of - days. the lengthy incubation period complicates tracing the source of infection. during the incubation period and the first week of acute illness, hepatitis a virus can usually be detected in stool. therefore, there is a prolonged phase when an individual is asymptomatic, but may transmit the disease to others, a significant concern in relation to food workers and foodborne transmission. an inactivated viral vaccine was licensed in and the cdc and the american academy of pediatrics have been implementing an incremental hepatitis a immunization strategy for children since then. in endemic countries, childhood infection and immunity are almost universal; childhood disease tends to be asymptomatic. in the united states, disease typically occurs after foreign travel to an endemic region. it may present with fever, jaundice, fatigue, abdominal pain, nausea, and diarrhea. diagnosis of the acute infection may be established serologically and treatment is supportive. an immune globulin may also be used for pre-or postexposure prophylaxis. hepatitis e virus was first described in after an epidemic affecting individuals occurred in kashmir, causing cases of fulminant hepatic failure and deaths. it is a small rna virus from the caliciviridae family usually transmitted through contaminated drinking water. hepatitis e is responsible for most of the epidemics of hepatitis in the developing world and is transmitted through contaminated water. it is the major etiological agent for acute hepatitis and acute liver failure in endemic regions. it causes severe liver disease among pregnant females and patients with chronic liver disease. person-to-person spread occurs rarely, with secondary attack rates of . - . % in household contacts of infected individuals. foodborne spread has not yet been documented. hepatitis e is endemic to india, southeast and central asia, parts of africa, and mexico. it has an incubation period of - weeks, although most people develop symptoms around days postexposure. clinically, the disease is similar to hepatitis a, with constitutional symptoms followed by jaundice. most patients recover, but mortality rates of up to % have been reported, with pregnant women at higher risk. the diagnosis is made serologically. hepatitis e vaccines remain experimental. preventing illness in the first place is clearly the most desirable approach when dealing with food safety and foodborne illness and there are many approaches to take with regard to prevention. prevention is particularly important when it comes to individuals who are young, elderly, or have compromised immune systems, and there are a number of steps that can be undertaken to minimize the potential risk. at the outset, it is important to recognize that certain groups are at much greater risk than others. this is well illustrated in the context of listeriosis in which the likelihood of developing illness varies in relation to a variety of underlying conditions ( table ) . for example, there is a times greater risk of a transplant patient becoming sick from listeriosis as compared to an individual under the age of with no underlying medical conditions. according to the council for agricultural science and technology (cast), a majority of foodborne illnesses can be attributed to improper food-handling behaviors (tables and ). leading causal behaviors are failure to ( ) hold and cool foods appropriately, ( ) practice proper personal hygiene, ( ) prevent cross-contamination, ( ) cook to proper internal temperatures, and ( ) procure food from safe sources. information related to the proper handling of food can be found at www.foodsafety.gov. risk assessment of listeria monocytogenes in ready-to-eat foods. technical report (microbiological risk assessment series; no. ), food and agriculture organization of the united nations and the world health organization, . behaviors that % of a national panel of food safety experts (n ¼ ) rated as being of special importance to pregnant women and/or infants and young children, with those rated as important to both groups presented first. table consumer food-handling behaviors of special importance to elderly and immune compromised individuals elderly and immune compromised individuals avoid soft cheeses, cold smoked fish, and cold deli salads l. monocytogenes avoid hot dogs and lunchmeats that have not been reheated to steaming hot or f store eggs and poultry in the refrigerator salmonella enteritidis avoid raw or partially cooked eggs, foods containing raw eggs. cook eggs until both the yolk and white are firm. use a thermometer to make sure that foods containing eggs are cooked to . c ( f) cook shellfish until the shell opens and the flesh is fully cooked; cook fish until flesh is opaque and flakes easily with a fork nlv obtain shellfish from approved sources nlv; vibrio species avoid eating raw or undercooked seafood/shellfish (clams, oysters, scallops, and mussels). cook fish and shellfish until it is opaque; fish should flake easily with a fork. when eating out, order foods that have been thoroughly cooked and make sure they are served piping hot behaviors that % of a national panel of food safety experts (n ¼ ) rated as being of special importance to the elderly and/or immunocompromised individuals, with those rated as important to both groups presented first. emerging infections; enteropathogenic infections; epidemiological concepts and historical examples; global burden of infectious diseases antimicrobial resistance in nontyphoidal salmonella campylobacter jejuni infections: update on emerging issues and trends infections of the gastrointestinal tract invasive enterobacter sakazakii disease in infants food poisoning exotoxins of staphyloccocus aureus guillain-barré syndrome escherichia coli o :h and other shiga toxin producing e. coli strains waterborne transmission of protozoan parasites: a worldwide review of outbreaks and lessons learnt enterohaemorrhagic escherichia coli in human medicine food-related illness and death in the united states diarrheagenic escherichia coli pathogenesis and diagnosis of shiga toxin-producing escherichia coli infections salmonella typhimurium dt : a virulent and drug resistant pathogen bacillus cereus food poisoning and its toxins enteric bacterial toxins: mechanisms of action and linkage to intestinal secretion the enteric toxins of clostridium perfringens fish and shellfish poisoning key: cord- -la vi j authors: brower, jennifer l. title: the threat and response to infectious diseases (revised) date: - - journal: microb ecol doi: . /s - - - sha: doc_id: cord_uid: la vi j the threat from microorganisms is complex, and the approaches for reducing the challenges the world is facing are also multifaceted, but a combination approach including several simple steps can make a difference and reduce morbidity and mortality and the economic cost of fighting infectious diseases. this paper discusses the continually evolving infectious disease landscape, contributing factors in the rise of the threat, reasons for optimism, and the policies, technologies, actions, and institutions that might be harnessed to further reduce the dangers introduced by pathogens. it builds upon and updates the work of other authors that have recognized the dangers of emerging and re-emerging pathogens and have explored and documented potential solutions. in just the past year, the united states has been bombarded with headlines on the dangers of infectious diseases: "hiv 'epidemic' triggered by needle-sharing hits scott county, indiana [ ] ;" "american with ebola now in critical condition [ ] ;" "seasonal flu vaccine even less effective than thought: cdc [ ] ;" "'superbug' outbreak at california hospital, more than exposed [ ] ;" "deadly cre bugs linked to hard to clean medical scopes [ ] ;" "painful virus [chikungunya] sweeps central america, gains a toehold in u.s. [ ] . " the ebola outbreak that began in and the measles outbreak initiated at disney world in particular brought the threat of "exotic" infectious diseases back to the american and global consciousness. this coupled with the fact that the most commonly circulating strains of the influenza a virus h n drifted [ ] from that used in the - influenza vaccines serve as reminders that the threat from microorganisms is continuously evolving and is persistent. the threat of emerging and re-emerging pathogens has been discussed in the scientific literature, the medical community, by policy makers, and the general public over the past years, but much of the discussion was among directly affected populations and their caregivers. general interest flourished after a series of events in the s and early s. in , a report by russian general kuntsevich followed by boris yelstin's decree in april of that year to end all offensive biological weapons programs revealed that the former soviet union had an extensive biowarfare program and that facilities and expertise still existed which would enable russia to unleash deadly pathogens on the world [ ] . in when shoko asahara, the spiritual leader of a japanese religious cult, was arraigned, the magnitude of the organization's attempts to deploy anthrax in was exposed [ ] . in october , the united states was transfixed by the first bioterrorism attacks on its own soil: envelopes containing bacillus anthracis spores were sent through the mail to targets ranging from media companies to government officials [ ] . five people died and thousands were treated with prophylactic antibiotics. the attacks and other attempted and planned attacks, along with widely publicized outbreaks such as west nile virus in [ ] and severe acute respiratory syndrome (sars) in [ ] , brought the topic of infectious disease to the forefront. in addition, more incessant threats such as influenza and lower respiratory infections continue to kill and cause economic harm through lost productivity and hospitalizations. furthermore, zoonotic diseases such as salmonella and listeria, which represent more than two-thirds of emerging and re-emerging diseases [ ] , raise the visibility of the economic and human and animal health issues caused by pathogens. in april , the sabra dipping company voluntarily recalled about , cases of hummus potentially contaminated with listeria monocytogenes. at the same time, blue bell recalled nearly products also similarly contaminated. while there were no known casualties as a result of the sabra contamination, authorities in kansas and texas reported that three deaths in each state might be attributed to the blue bell incident [ ] . the threat from microorganisms is complex, and the approaches for lowering the challenges the world is facing are also multifaceted, but several simple steps can make a difference. this paper will discuss the emerging infectious disease landscape, contributing factors in rise of the threat, reasons for optimism, and the actions, policies, technology, and institutions that might be harnessed to further reduce the dangers introduced by pathogens. it builds upon the work of other authors who have recognized the dangers of emerging and re-emerging pathogens and have explored and documented potential solutions [ ] [ ] [ ] . microorganisms pose health and economic threats and may pose a strategic threat if a large percentage of the population is overcome or if the potential transmission of infectious diseases across borders causes an increase in tension among state allies or enemies. one organism alone, clostridium difficile, is estimated to cost the united states between $ and $ billion per year [ ] , with its primary impact on american children [ ] . initially identified in the early s as a commensal organism in the digestive tract, c. difficile infection (cdi) has only been recognized as a significant threat to pediatric health over the last decade [ ] . the threat to both children and adults is global. infections since have become more common, more acute, less treatable by standard therapy, and more likely to reoccur [ ] . initially, the c. difficile infections were associated with the use of the antibiotic clindamycin, but fluoroquinolones and cephalosporins are currently the more likely cause of disturbed gut microbiota, which increasingly lead to colonization with ribotype , a severe variant of c. difficile [ ] . according to the centers for disease control and prevention (cdc), emerging infectious diseases are those "whose incidence in humans has increased in the past two decades or threatens to increase in the near future [ ] ." while there may be debate about the specifics, for the purposes of this article, re-emerging and emerging diseases are distinguished as follows: re-emerging diseases are those that were known to impact humans or animals in the past and were thought to be brought under control with zero or few infections in the past several decades. these include infections resulting from changes or evolution of existing organisms and changes in the geographic distribution of an organism or populations affected by the organisms. previously unrecognized (in the past several decades) infections are considered emerging. according to this definition, c. difficile would be considered an emerging pathogen as its dangers were not recognized when it was first identified. other outbreaks and trends of concern include the following: tuberculosis (tb), while no longer among the leading causes of death in , was still among the leading causes, killing over , people in [ ] . in the united states, while overall tb incidence is decreasing, it is still a large problem for foreign-born residents and for the homeless population at a cost of nearly $ million per year [ ] . lyme disease caused by the spirochete borrelia burgdorferi was recently recognized as an epidemic. the disease is difficult to diagnose, causes long-term disability if untreated, and may impact as many as , people in the united states [ ] . more than % of lyme disease patients continued to exhibit symptoms after six months, and for % of infected people, symptoms continued for more than three years [ ] . the spread of diseases such as multidrug resistance acinetobacter in at-risk populations is also of increasing concern. "within the last years, members of the bacterial genus acinetobacter have risen from relative obscurity to be among the most important sources of hospital-acquired infections. the driving force for this has been the remarkable ability of these organisms to acquire antibiotic resistance determinants, with some strains now showing resistance to every antibiotic in clinical use [ ] ." acinetobacter resistance to drugs such as imipenem and ampicillin/sulbactam increased % from to [ ] . leptospirosis, one of the most widely distributed zoonotic diseases worldwide, is an emerging public health concern particularly in large urban centers of developing countries [ ] . it is also important in the united states in humans, pets, and wildlife. experts believe incidence in humans is underreported, but the cdc estimates that - leptospirosis cases occur annually with approximately half of those in hawaii [ ] . in , triathletes in illinois were exposed to leptospirosis of which became symptomatic [ ] , representing the largest human outbreak in the united states. recently, cases in pets have caused concern in california [ ], michigan [ ], and florida [ ] . more than a quarter of the tested deer population in michigan was infected with the disease [ ] . west nile virus (wnv) is another zoonotic disease of concern, and the us population and health practitioners have become more aware of this disease over the past decade. birds carry the virus, which is then transmitted by mosquitoes to humans, horses, and other mammals. disease symptoms range from fever to neurological complications, such as encephalitis or meningitis. mortality is observed mostly in older and immunocompromised individuals. in , wnv was introduced to the united states, and its range soon extended across north america [ ] . not only is the number of wnv outbreaks increasing but also novel strains are emerging, which display higher virulence. wnv has also developed sophisticated avoidance mechanisms to avoid its elimination [ ] . noroviruses are the leading cause of foodborne disease outbreaks worldwide and may soon eclipse rotaviruses as the most common cause of severe childhood gastroenteritis, because rotavirus vaccine use is becoming more prevalent [ ] . norovirus rapidly undergoes genetic mutations and recombinations so that new epidemic strains are constantly evolving. although norovirus infection is generally not fatal, infections in children, the elderly, and the immunocompromised can cause morbidity and even death. research into a vaccine or treatment has been impeded by the lack of a cell culture or small animal model. however, vaccines based on norovirus capsid protein virus-like particles show potential and may become broadly available through transgenic expression in plants [ ] . vibrio vulnificus, a common gram-negative bacterium in warm coastal waters globally, is an emerging pathogen [ , ] . up to million vulnerable americans are at risk when consuming raw or improperly prepared seafood tainted with v. vulnificus which can cause primary septicemia [ ] . additionally, all individuals are at risk of serious wound infection that may lead to secondary septicemia [ , ] . even with antibiotic treatment, half of patients may die from primary septicemia and a quarter from secondary [ , ] . other environmental organisms of concern include the waterborne pathogen that causes legionnaires' disease, legionella bacterium; naegleria fowleri, which causes amebic meningoencephalitis; other mycobacterium (hospital environment) such as mycobacterium abscessus and m.massiliense in lung disease; the mosquitoborne chikungunya virus and the tickborne bourbon virus. in addition to causing acute illness, research has uncovered links between infectious diseases and cancer. in one study by wu et al. [ ] , researchers found measurable differences in fecal microbiota between healthy individuals and those with colorectal cancer as determined by pyrosequencing of the s rrna gene v region. as early as , researchers found that hepatitis b surface antigen (hbsag) carriers had a greater incidence of primary hepatocellular carcinoma (phc) than among non-carriers [ ] . the list of emerging and re-emerging pathogens could fill up a tome. these organisms vary in virulence and distribution, but all of them share common characteristics in that the incidence or virulence or both are increasing and humans must find methods of preventing, detecting, and treating them. to combat infectious disease, it is important to understand the factors that are working to increase the occurrence and severity of infections. human behavior has a large impact on the creation of environments where microorganism can evolve and mutate. these changes can sometimes make organisms more infectious and/ or virulent. examples include the following: antibiotics in the environment through overuse and misuse; changes in sexual norms; patterns of drug use and incarceration; global climate change; human incursion into new environments; and changing patterns of human interactions with wild and domesticated animals; expanding travel patterns; vaccination avoidance; and population concentrations in large cities. recent cases are used to illustrate how differences in human behavior have modified the threat from bacteria and viruses. the problem of antibiotic resistance is threefold: there has been a rise in the number or identification of resistant bacterial strains; the pipeline for the development of new medicines to treat infection dried up significantly over the past years; and the most significant problem is the lack of stewardship of existing antimicrobials. these issues have led to a reduction in the efficacy and number of responses available to physicians and their patients. the biological processes that lead to resistance are extremely complicated and not fully understood, resulting in sometimes limited progress in the control and treatment of resistant microorganisms and the diseases they cause [ ] despite recognition of the problem nearly a century ago. davies and davies [ ] compiled a list of "suberbugs," which have increased pathogenicity and are more impervious to treatment. their list includes the following: multidrug-resistant (mdr) m. tuberculosis; nosocomial (hospital-linked) infections with acinetobacter baumannii, burkholderia cepacia, campylobacter jejuni, citrobacter freundii, clostridium difficile, enterobacter spp., enterococcus faecium, enterococcus faecalis, escherichia coli, haemophilus influenzae, klebsiella pneumoniae, proteus mirabilis, pseudomonas aeruginosa, salmonella spp., serratia spp., staphylococcus aureus, staphylococcus epidermidis, stenotrophomonas maltophilia, and streptococcus pneumoniae. their list does not include the new delhi metallo-beta-lactamase- (ndm- ) resistant strains discussed below. as the authors point out, in addition to the direct human toll, treatment is often more costly [ ] when resistant organisms are involved. in fact, the issue has become so acute that new terms have developed over the past decades: microorganisms that are pan-drug resistant (pdr) or extremely drug resistant (xdr). one of the most widely dispersed antibiotic resistant organisms is m. tuberculosis. worldwide, this organism is often resistant to multiple drugs, and in , completely drug-resistant forms of tuberculosis were reported in citizens of four countries: afghanistan, azerbaijan, iraq, and iran [ ] . in many organisms, such as enteric bacteria which are acquired both in community and hospital settings, resistance (often to β-lactam antibiotics in this case) spreads through horizontal gene transfer on plasmids; however, there have been no documented cases of this in tuberculosis, where all resistance occurs by spontaneous mutation [ ] . multidrug resistant pseudomnas aeruginosa is also of concern as it is deadly and widespread [ , ] . m. tuberculosis is one example of the multitudes of resistant organisms. other widespread and dangerous bugs include staphylococcus aureus ( . per inpatient prevalence rate in [ ] ) and c. difficile (in us hospitals in , c. difficile was the most commonly reported pathogen causing . % of health careassociated infections and staphylococcus aureus caused the second highest percentage, . %. klebsiella pneumoniae and klebsiella oxytoca . % and escherichia coli . % followed closely behind [ ] ). at a single hospital in and , resistant acinetobacter baumannii infected . % of patients who were not previously infected [ ] . infections with resistant organisms are harder to control; standard treatments are less effective; illness and hospital stays are longer; and mortality is higher. gram-positive organisms resistant to antibiotics were the first concern, but resistance in gramnegative organisms emerged: gram-negative bacteria resistance increases faster than in gram-positive bacteria [ ] , and there are fewer antibiotics in the pipeline that work against gram-negative bacteria [ ] . cosgrove et al. [ ] performed a meta-analysis of studies published between and on the impact of methicillin resistance on mortality. these studies included nearly patients, a third of whom were infected with methicillin resistant staphylococcus aureus (mrsa). mortality was significantly lower in the group infected with susceptible bacteria. in another study, cosgrove's group found that mrsa bacteremia also increased median length of hospital stay by almost % and not surprisingly (given the longer stay), increased hospital charges from an average of $ , to $ , [ ] . a prospective study found similar results in hemodialysis patients at the duke university hospital [ ] as did a study on orthopedic patients [ ] . vancomycin-resistant enterococci (vre) [ ] and enterobacter species resistant to third generation cephalosporins [ ] showed a similar trend; however, penicillin-and cephalosporin-resistant streptococcus pneumonia results were dissimilar, and the authors surmised that this might be due to the specific use of vancomycin [ ] . chemicals in daily use may also change microorganism susceptibility to antimicrobial agents. for instance, it has been regularly demonstrated in the laboratory that resistance to triclosan, an antimicrobial agent used in many household products including hand sanitizer, and crossresistance to antimicrobials increases with use of triclosan containing products; however these results have not yet been observed in the community. based on the available evidence, the risk of potential antimicrobial resistance outweighs the benefit of widespread triclosan use in antimicrobial soaps [ ] . resistance is not something that can be conquered: bacteria with their relatively short lifespans can mutate quickly; however, with knowledge of the , resistance genes of types [ ] , it may be possible to stay one step ahead of resistance and find new ways to treat bacterial infections. other changes that have impacted infectious disease distribution and prevalence are changes in sexual norms, drug use, and incarceration. needle sharing itself can spread infections, and the use of drugs can affect sexual and risk taking behavior which can put people in jeopardy [ ] . while homophobia is decreasing in the united states and worldwide, homophobia has been one of the major social determinants of infection particularly with hiv/ aids and other sexually transmitted diseases. for example, men sleeping with men accounted for % of new hiv infections in [ ] . historical legal restrictions, which are now being relaxed in this decade, had ostracized gay people, limiting their self-identification and therefore efforts to target gay communities for education and prevention as well as diagnosis and treatment efforts. injecting drug users account for % of new hiv infections often due to inadequate access to sterile needles and syringes and addiction treatment programs [ ] . as noted below, drug use also changes behavior which also leads to increased transmission. drug use and incarceration patterns go largely hand-in-hand. in part because of the united states hard line on drug use, united states incarceration rates are the highest in the world with minorities accounting for a disproportionate percent of the prison population. incarceration rates disrupt community and sexual relationships and compound poverty issues, amplifying the exposure of communities and individuals to hiv infection and other infections [ ] . in a second example, methamphetamine use has been shown to affect a person's judgment and may lead to unsafe behaviors such as reduced condom use, multiple partners, and increased drug injection. methamphetamines also increase physical susceptibility because their use dries mucosa intensifying chafing and abrasions, which, in turn, allow microorganisms to enter the body during sexual and other activity [ , ] . aquaculture contributes to the pollution of rivers, bays, and even our oceans with antibiotics and antibiotic resistance genes (args). from china to the united states, antibiotics and args have been found in surface water of all types. for example, in the coastal water of the bohai bay, china, fluoroquinolones, macrolides, sulfonamides, tetracyclines and chloramphenicoles, and polypeptides were found at concentrations up to several micrograms per liter with higher concentrations where human activity was concentrated [ ] . in a review, comparing aquaculture and land animal production with the respect to type, mechanism, and quantity of antibiotic resistance, done, venkatesan, and halden [ ] found that aquaculture was similar to terrestrial agriculture in terms of the resistance mechanisms, that antibiotics used in aquaculture are important in human health, and that pathogens isolated from the farmed fish were resistant to multiple antibiotics. due to improper use and disposal of antibiotics, the presence of antibiotic-resistant organisms and genes in natural waterbodies, wastewater, and treated municipal water has been widely demonstrated and reviewed [ ] [ ] [ ] [ ] . without additional treatment, this water is commonly used on crops; humans and animals then consume the products, and serious outbreaks have occurred that are difficult to treat because the microorganisms do not respond to commonly used antibiotics [ ] [ ] [ ] [ ] . pruden et al. [ ] found concerning levels of args in colorado (united states) dairy lagoon water, irrigation ditch water, river sediments, treated drinking water, and recycled wastewater. ramsden et al. [ ] similarly found antibacterial resistance in municipal wastewater treatment plants. zuccato et al. [ ] discovered that the concentrations of atenolol, bezafibrate, clofibric acid, cyclophosphamide, diazepam, erythromycin, furosemide, lincomycin, oleandomycin, ranitidine, salbutamol, spiramycin, and tylosin were in the nanogram per liter range in river or drinking water or river sediments in several sites in italy. munir et al. [ ] examined the presence of antibiotic-resistant genes and bacteria in several types of wastewater effluents in michigan and found that advanced water treatment systems such as membrane bioreactors were significantly more effective than conventional wastewater treatment at removing the tetracycline-resistant gene teto and sulfonamide-resistant gene (sul-i) as well as tetracycline and sulfonamide-resistant bacteria. anaerobic digestion and lime stabilization treatment of wastewater was more effective than the conventional dewatering and gravity thickening methods for removing antibiotic-resistant genes and bacteria [ ] . burch et al. [ ] were able to significantly reduce the concentrations of the args tet(a), tet(w), and erm(b) using conventional wastewater treatment (aerobic); however, removal of inti required batch treatment, while the others required relatively long-term semi-continuous treatment. tet(x) increased in concentration. according to the world bank, nearly million travelers visited the united states and approximately one billion people traveled globally in [ ] . the incidence of tuberculosis in the united states is largely due to foreign visitors and citizens and residents born in other countries [ ] . another, travel related resistance threat emerged in the united states in when three patients were reported to have the gene for new delhi metallo-beta-lactamase (ndm- ), an enzyme that destroys beta-lactam antibiotics including commonly used penicillins, cephalosporins, and carbapenems. the first case was reported in india in [ ] , and to date, india and pakistan have reported the most instances of ndm- , but the gene is spreading globally, and cases have now been detected in many countries, including great britain, canada, sweden, australia, japan, and the united states. antibiotics are widely used in india and some researchers [ ] have demonstrated that overuse of carbapenems led to the development of ndm- [ ] . research also points to medical tourism as a cause [ ] [ ] [ ] [ ] . ndm- is a newly identified problem, only recognized since about december in the medical literature, but it is only one example of diseases transmitted through medical tourism which is defined as travel to a country to get medical care that is not available or is more expensive in one's own country. precise data on the economic value and the number of patients seeking medical procedures are not easily available. in , smith et al. [ ] estimated that approximately four million patients crossed borders seeking treatment. in , guidelines to unify definitions of medical tourism and methodologies for reporting its extent were published and accuracy of the types and amounts of medical tourism may improve in the near future [ ] . a greater potential threat is related to the increasing travel of immunocompromised patients. lortholary et al. [ ] illuminated the fact that as more and more people are living with hiv, having organ transplants, using immunodilators, or suffering from diabetes, more individuals are infected when traveling. the authors suggested preparations and responses to prevent severe illnesses when traveling. infections spread within the united states from travel as well. for example, during the period from through , cryptococcus gattii infections were reported to the cdc. c. gattii, an environmental fungus typically prevalent in tropical and sub-tropical regions, can cause an uncommon infection of the lungs and/or the central nervous system in those who inhale the fungus. more than % of the cryptococcosis cases occurred in people who had traveled to the pacific northwest. the infection was fatal for % of the patients [ ] . many factors have reduced the number of new antibiotics approved in the united states each year as well as reduced domestic production including demanding food and drug administration (fda) regulations, the cost and time to market of development, the consolidation in the pharmaceutical industry, and the lack of financial impetus to produce and distribute antibiotics, which are generally used on a one-off basis versus drugs used to treat chronic conditions such as statins, viagra, and allergy medications. in a may speech, janet woodcock, the director of the center for drug evaluation and research (cder), acknowledged that new antibiotics were not sufficient to address growing antibiotic resistance and that fda's approach to approval was a significant factor [ ] . the fda introduced new regulations for clinical trials at the beginning of the twenty-first century, which led to a cooling of antimicrobial development in the pharmaceutical industry [ ] . first, the newly required approach doubled the cost of phase iii clinical trials, already a substantial barrier for development. in phase iii, it is expected that testing will include pairs of relatively large (usually > total subjects per study) groups of people conducted for the selected pathogen at the relevant body location(s). this has become challenging as new antibiotics focus on particular pathogens including resistant pathogens, making it difficult to enroll large numbers of patients [ ] . in part because of the cost of the new regulations, eli lilly, bristol-myer squib, glaxo smithkline, proctor and gamble, roche, and wyeth left the development business [ , ] . in addition, while the amount of antibiotics prescribed has continued to grow, the market value has not changed and was estimated at $ billion in [ ] as compared to a $ . billion market in for statins alone [ ] . companies are getting out of the market because the regulatory burden is high, antimicrobials are typically used for short periods of time, public pressure is building to lower use, and the medicines are often subject to price controls outside of the united states [ , ] . while development has slowed, in the past years, new antibiotics have been brought to market. two approved more recently, fidaxomicin and bedaquiline, have new modes of action. fidaxomicin was shown to effectively treat c. difficile [ ] . because the financial incentives are few, much antibiotic production has been outsourced from the united states to india, china, and other countries where labor, raw material, and energy costs are lower [ ] . in fact, it has been more than years since the active ingredient for penicillin was last manufactured in the united states. this presents a significant strategic problem for the united states in the case of an outbreak, particularly during times of conflict or worldwide scarcity. global climate change is increasingly accepted as causing extreme, unusual weather patterns [ ] . changing weather patterns can impact the presence of infectious agents in many ways. for instance, in may and june , an initially unidentified disease killed ten people in the four corners region of arizona and new mexico. at the outset, % of the patients died of the infection, and after the medical staff developed enhanced protocols, the death rate was only reduced to %. scientists isolated a hantavirus [ ] , and later, researchers determined that an unusually wet spring led to increased rodent carrier density which in turn impacted human infection rates; however, these factors alone are not enough to explain persistent hantavirus infection in the southwestern united states [ ] . ecosystem changes and human interactions with the environment may increase the transmission of infectious disease [ ] . for instance, three studies found robust correlations between the threat to humans from west nile virus and low bird diversity in the united states [ ] [ ] [ ] . the spread of emerging infectious diseases among animals has significant human health and economic costs. zoonotic diseases kill more than two million people per year and transmission occurs from both wild and domesticated animals [ ] . halsby et al. [ ] reviewed the english literature with respect to infectious diseases caused by pet store animals and found discussions of infections related to pet shops. the most commonly observed diseases were salmonellosis and psittacosis: other diseases such as tularemia were also identified. the human animal interaction has impacted civilization throughout history. according to daszak et al. [ ] , "parallels between human and wildlife emerging infectious diseases (eids) extend to early human colonization of the globe and the dissemination of exotic pathogens. in the same way that spanish conquistadors introduced smallpox and measles to the americas, the movement of domestic and other animals during colonization introduced their own suite of pathogens. the african rinderpest panzootic of the late s and s is a paradigm for the introduction, spread, and impact of virulent exotic pathogens on wildlife populations. this highly pathogenic morbillivirus disease, enzootic to asia, was introduced into africa in . the panzootic front traveled km in years, reaching the cape of good hope by , extirpating more than % of kenya's buffalo population and causing secondary effects on predator populations and local extinctions of the tsetse fly." more recently, bovine tuberculosis, while responsible for only cases of human tuberculosis in the uk, prompted the slaughter of tens of thousands of cattle in the first decade of the twenty-first century [ ] . in , throughout the united states, domestic poultry and wild birds have been suffering from a highly pathogenic strain of avian influenza (hpai) h [ ] . through june , , more than million birds were put to death. the cost of the government response is tagged at $ million primarily to fund the work of staffers and contractors [ ] . on the commercial side, analysts used economic models and found that for a million dollars in direct losses there are $ . million in overall economic losses. in mid-may direct losses in poultry production were estimated at $ million leading to overall losses of more than $ million [ ] . transmission to humans in the united states has not been detected, although related viruses have caused serious illness and death around the world [ ] . typically, people have focused on wildlife diseases that affect human health and agriculture. recently, researchers, policy makers, and others have begun to pay attention to wildlife infectious diseases, because a number of endangered species including birds, amphibians, and invertebrates [ ] are impacted [ ] . human's changing relationship with the environment "deforestation and ensuing changes in land use, human settlement, commercial development, road construction, water control systems (dams, canals, irrigation systems, reservoirs), and climate, singly, and in combination have been accompanied by global increases in morbidity and mortality from emergent parasitic disease [ ] ." lyme disease is a prime example of how human destruction of the environment (forests) can lead directly to increased risk for disease exposure. allan, keesing, and ostfeld [ ] found that as forest patch size decreased ioxdes nymphal infection prevalence and nymphal density with increased, resulting in a noticeable rise in the density of infected nymphs and concluded that habitat fragmentation affects human health. as humans change or destroy the local environment, they tend to interact with or disturb wildlife populations, creating further instances for exposure to infectious diseases. goldberg et al. [ ] found increased rates of interspecific gastrointestinal bacterial exchange between people and nonhuman primates when humans visited chimpanzee and ape habitats. chimpanzees carried antibiotic-resistant bacteria although there had never been treatment with antibiotics. many of the factors discussed above coexist to increase the threat from microorganisms. the antivaccine lobby, especially in the united states, has led to a significant decline in the vaccination rates of infants and children, particularly among specific demographics despite the overwhelming success of vaccines in the fight against vaccine-preventable diseases. for instance, in (pre-vaccine), , cases of measles were reported with mortalities. in , there were cases of measles but no deaths. similarly in , cases of diphtheria were reported resulting in deaths. in , there were no reported cases of diphtheria [ ] . up to two % of parents in the united states refuse vaccination completely for their children with up to % more who are cautious or elect to delay vaccination [ ] . the reduction in vaccination coverage is typically attributed to the lack of perceived threat due to the success of vaccination, combined with false medical research and media reporting [ ] . the reduction in vaccination rates has resulted in the highest number of cases of measles in the united states since it was declared eliminated in [ ] . while native measles has been eliminated in canada, several measles cases are imported each year by international travelers and due to inadequate vaccination, these cases often lead to secondary spread. in the first five months of , cases in five provinces from known importations occurred through infected travelers arrived from the philippines, india, the united states, thailand, pakistan, italy, and the netherlands [ ] . travel patterns in canada are exemplary of much of the world. in years, international travel (excluding travel to the united states) more than doubled from . million to million trips [ , ] . if the antivaccine trend does not abate, and in conjunction with widespread global travel, the threat from diseases once thought under control may pose a significant threat to the population. influenza outbreaks kill and hospitalize more than , americans each year. the predominant strategy in the united states is to encourage all eligible populations to get vaccinated; however, for the - flu season, more than half of influenza a (h n ) viruses had drifted from the h n vaccine virus. this mismatch leads to decreased vaccine effectiveness [ ] . it may also discourage individuals from getting the flu vaccine in the future. population growth, urbanization, and travel along with deterioration in public health infrastructure have contributed to the resurgence of infectious diseases. dengue fever provides a prime example of the intersection of the triad. while dengue viruses were dispersed throughout the tropics in the first half of the twentieth century, epidemics were infrequent because urban populations were comparatively small, and the viruses and mosquito vectors were transported on ships versus the air transport of today. the travel of both goods and people during world war ii set the stage for the spread of dengue fever. in the post war era with unparalleled urban growth and travel, serious epidemics occurred more frequently. scarcely years later, dengue hemorrhagic fever became a principal cause of hospitalization and mortality in the pediatric population throughout southeast asia [ ] . with respect to the intentional use of microorganisms as a weapon, the united states and the world have an outmoded threat-view focused on soviet era biological weapons, but travel, medicine abuse, and the lack of a us capability to approve and manufacture new antimicrobial and antiviral agents have changed many dimensions of the threat as discussed above. with the dissolution of the soviet union, the fact that the us biological weapons program ended decades ago, and the intellectual, medical, manufacturing, and weaponization knowledge needed to start a bioweapons program, the threat from naturally occurring organisms is far greater than the threat of bioterrorism or biowarfare in . the threats of infectious diseases dwarf that of terrorism and other asymmetric threats to human life. approximately three million people died in due to lower respiratory infections [ ] , and infectious diseases are the major cause of death of children under five. "the most important pathogens are rotavirus for diarrhea and pneumococcus for lower respiratory infections [ ] ." however, there is hope that new antibiotics will be identified and developed. recent research such as that performed by ling et al. [ ] found new ways to identify antibiotics [ ] in the environment and companies are beginning to invest again. under the direction of dr. kim lewis, ling and colleagues identified teixobactin. to do this, the team used the novel screening method to examine , strains. in both in vitro and in vivo tests, teixobactin was demonstrated to be operative, without major side effects, against the organisms that cause common illnesses such as pneumonia, tuberculosis, and staph infection, diseases which sicken more one million americans yearly. while teixobactin was effective against diseases of public health concern, it was ineffective against gram-negative bacteria. teixobactin binds on several targets triggering cell wall break down. the ability to bind on multiple sites lessens the chance of early teixobactin resistance. in addition to developing the new antibiotic, the researchers commercialized the screening technology, which can examine organisms that cannot typically be cultured in the lab [ ] . researchers are also developing techniques to enhance the impact of probiotics in fighting infections and other diseases such as cancer [ ] . while recent events bring the threat of microorganisms to the forefront of the public mind, the work of doctors, researchers, public health professionals, and other experts have continued unabated for decades. these attempts include scientific, technological, policy, and commercial attempts to reduce or eliminate the deaths and other losses caused by pathogens. to a large extent, these efforts have succeeded. in , the average lifespan in the united states was . for men and . for women, and one of the predominant causes of death was infectious disease. by the end of the century, lifespan had increased to . for men and . for women [ ] . in , infectious diseases accounted for more than half of all deaths: in , this percentage was reduced tenfold [ ] . the increases in life expectancy have been distributed across the world, although some areas have benefitted more than others from breakthroughs in sanitation, nutrition, and medical advances. one of the primary contributors to the reduction in the death rate was the reduction of infant deaths due to infectious diseases. prior to the mid- s, infectious disease played the predominant role in infant mortality with half of the (out of ) infant deaths due to pathogens [ , ] . by , the united states infant mortality rate had decreased to . per live births [ ] . also in the united states, in the midnineteenth century, foodborne and waterborne diseases such as typhoid, cholera, and dysentery resulted in deaths per , . these diseases were eliminated in the united states by the early s [ ] . one noteworthy exception to the steady progress in increased life expectancy is due to an infectious disease: hiv/aids decreased life expectancy dramatically in parts of africa over the past years [ ] . the leading causes of death and illness have shifted from infectious and parasitic diseases to noncommunicable diseases and chronic conditions. with the introduction of widespread antibiotics [ , ] in the s and antivirals in the late s [ ] , a new era of public health was ushered in, and the death rate due to infectious diseases accounted for less than % of mortality worldwide [ ] ; however, the optimism was short lived. even before there was prevalent proof that bacteria could quickly evolve to thwart antibiotics, evidence indicates that bacteria exhibit resistance in nature even without human pressure [ ] ; however, mechanisms of resistance impacting disease treatment were first noticed in the late s with regards to the use of sulfonamides [ ] . due to overuse, underuse, and incorrect disposal, antibiotic resistance has become a worldwide threat to public health [ ] . in addition, the cost and difficulty in developing new antibiotics has stunted the pipeline. finally, environmental [ ] , behavioral, and other physical and cultural changes have fostered situations where new pathogens can emerge and old enemies reemerge or spread to new locations. global climate change is altering where species thrive, and more localized or temporary changes modify infectious disease risk to humans as well. while ndm- strains are difficult to treat, many of them remain sensitive to an older, seldom used antibiotic, colistin, or aztreonam [ , ] years, clinical trial number n c t ; a n d s a f e t y, to l e r a b i l i t y, a n d immunogenicity study of a clostridium difficile toxoid vaccine in healthy adult volunteers, clinical trial number nct (a total of studies were found on www. clinicaltrials.gov when searching for 'c. difficile vaccine [ ] .' improvements are needed in dosage and timing to achieve high level immunity, however the investment required is large with estimates ranging from $ , , to $ , , [ ] to take a vaccine or antibody, respectively, through clinical trials. until a vaccine is developed, antibiotics will be used to treat infections. fidaxomicin, the first new antibiotic approved by the fda to treat cdi was approved in may . it was shown to be as effective as oral vancomycin, previously the only fdaapproved therapy for mild-to-moderately severe cdi. vancomycin is expensive and resistance in enterococci is a concern. oral metronidazole has been used by the medical community off label (it was approved for the treatment of certain anaerobic bacteria and parasites); however, relapse was observed in a quarter of patients within a month following treatment. fidaxomicin, in addition to being as effective as standard treatment, is a narrow spectrum antibiotic, allowing patients to maintain healthy native gut microbiota [ , ] . on a larger scale, according to the world health organization (who), hiv mortality was reduced from . million in to . million in , and diarrhea fell from one of the top five causes of death to number seven, with a similar number of deaths to hiv/aid in [ ] . tuberculosis distribution has declined since the turn of the century, in part because of the reach of the who's directly observed therapy short-course strategy and the implementation of the stop tb partnership plan [ ] . malaria cases and mortality has been meaningfully reduced by over cases and four million people respectively over the years between and through the use of artemisinin-based drugs, distribution of insecticide-treated bed nets, and indoor residual spraying of insecticide [ ] . this demonstrates that research, infrastructure, and other health-based investments have improved prevention and response to infectious diseases. all of this comes at a cost: between and governments including the united states, the uk, australia, canada, france, and germany and large non-profits and international institutions such as the gates foundation and the global fund contributed more than $ billion to the fight against hiv/ aids and nearly $ billion for international maternal and child health, which is in large part funding for vaccination [ ] . in addition, president obama has recognized that infectious diseases pose a national security threat. on september , , in his weekly address [ ] , the president stated, "so this is an epidemic that is not just a threat to regional security-it's a potential threat to global security if these countries break down, if their economies break down, if people panic. that has profound effects on all of us, even if we are not directly contracting the disease. and that's why, two months ago, i directed my team to make this a national security priority." because the challenges of new and re-emerging infections are complicated, a combination of science and technological advances, policy initiatives, and cooperative institutions are required. to make a significant difference, the united states and other countries must invest in technology and have systems capable of making these advancements available to those who need them, build technology development, and public health infrastructure; put in place policies and institutions that encourage these investments both in the public and private sectors. the success of programs such as the malaria initiative that combine these approaches is self-evident, but more needs to be done. an illustrative, but not complete, discussion of recent and additional proposals/initiatives is below. the united states, other countries, states, and international institutions have taken many steps to combat the threat. below are many of the important efforts and characteristics needed for resilience to the microbial threat. most importantly, it is critical to have a well-defined leader who is responsible for directing and monitoring progress as well as communicating risks. in president obama's september executive order [ ] , he directed the "national security council staff, in collaboration with the office of science and technology policy, the domestic policy council, and the office of management and budget to coordinate the development and implementation of federal government policies to combat antibiotic-resistant bacteria [ ] ." the president also created both a task force and an advisory council; however, he did not put a single individual in charge. identifying and developing a central, qualified, trusted person in charge of coordinating the investments in research, infrastructure and outreach; policies to incentivize behaviors to improve medicine development, infection control in medical and community settings; and communicate risks and responses in a directed and trusted manner at the federal government level, will enhance accountability and the likelihood of success. during times of low or chronic threat (e.g., flu season), the named person can develop a trusted relationship with the public, the medical and public health communities, the pharmaceutical industry, the defense department, international peers, and others involved in infectious disease response and defense. this is particularly difficult in diverse countries with divided political parties. a history of purposeful and innocent ethical lapses and scientific mistakes have contributed to a lack of trust such as the inaccurate flu vaccine in the - season and the confusing messages from the texas hospital and the cdc on ebola in . when a man traveled from africa and came down with a high fever and other symptoms, he was sent home by the hospital with antibiotics for two days [ ]: ebola was not well diagnosed in texas. one of the last trusted public health officials was the surgeon general under ronald reagan, dr. c. edward koop. by the time he stepped down in , he had become a household name, a rare distinction for a public health administrator. "dr. koop issued emphatic warnings about the dangers of smoking, and he almost single-handedly pushed the government into taking a more aggressive stand against aids [ ] ." dr. anthony fauci, director of the united states national institutes for allergy and infectious disease, has been a source of trusted and accurate infectious disease related information recently with regards to the ebola outbreak of . fauci is a natural leader for the us infectious disease/public health message, "he is someone who is really trusted by all the different organizations and people surrounding the aids challenge, ranging from the scientific community, the academic community and the activist community," according to louis sullivan, m.d., secretary of health and human services during the first bush administration and president emeritus of morehouse school of medicine in atlanta. "i don't know of anyone as broadly accepted by all those disparate groups [ ] ." the head of the cdc can also be a valuable spokesperson, but the cdc may have lost some of the public's trust during the ebola crisis [ ] . to centralize response, president obama appointed rob klain as the ebola coordinator. he was neither a doctor nor a scientist, and he left the job after six months, while ebola was still spreading in africa. while additional capability was developed at medical centers in the united states under klain's tenure, there were few noticeable signs of progress; he was not open to the media [ ] ; and likely as a result, was not embraced by the public. if the president chose a well-respected individual with healthcare and pharmaceutical industry expertise to serve in the white house to coordinate policies, funding and messages from nih, the cdc, the department of defense, the state department, state public health agencies, and other national and international institutions involved in the chain of prevention, detection, and treatment of infectious disease, it would be optimal. critical manufacturing capabilities have moved overseas, particularly to india and china. the us government could provide tax and other incentives and clear policies for approval for drugs, biologics, and manufacturing facilities to get manufacturing of key ingredients back to the united states. this would allow a faster and more certain response in times of emergency and the allow the government to initiate emergency medicine production under president obama's march executive order [ ] -national defense resources preparedness for manufacturing and distribution of medicines during times of crisis and the defense production act of as amended [ ] . international institutions are making significant efforts in preventing, detecting and responding to infectious diseases, and the continued work and support through the who, un, nato, the pan american health organization, the g , the cdc global health initiative, and other domestic and international bodies will improve international surveillance, reporting, prevention, and response. mechanisms for early reporting would avoid punishment such as travel bans for acknowledgement of dangerous infectious diseases within countries' borders. in addition, leaders in the united states would work to develop trusted relationships with peers in other countries. with more us foreign aid directed towards building public health infrastructure, the funds would have the primary impact of bolstering response and reducing transmission and casualties from infectious diseases within a country and secondary impacts of stabilizing societies (studies have shown that countries with healthy populations are more stable [ ] ). these outcomes would result in a safer and more secure world as there would be reduced disease transmission across borders. there are many existing global and domestic health initiatives such as the following: [ ] . lessons learned from this work can be utilized to further the goals of improving prevention and response to infectious disease. a research and response focus on diseases we encounter in the modern era as opposed to an emphasis on old soviet threats (unless the intelligence community identifies specific threats in the areas of bioterrorism and biowarfare) would enhance prevention and response capacities and funnel limited resources to current health and disease issues. preparations for naturally occurring outbreaks will not only prevent deaths year to year, but will also help exercise countries to fight intentionally introduced diseases by developing policies, procedures, infrastructure, and new technologies that foster quick innovation and therefore response to any microorganism, natural or manmade. each day, there are technological advances for preventing and combatting infectious diseases in addition to the progress specifically in medical research. for instance, adoption of advanced wastewater treatment systems can reduce exposure to antibiotics and args. this can be accomplished by tax incentives and partial payment by the federal government when wastewater treatment systems are replaced and advanced systems are used. in , $ billion federal dollars were spent on water utilities (water supply or treatment) accounting for approximately one quarter of public infrastructure spending [ ] . state and local governments spent $ billion for the operation and maintenance of infrastructure double the spending on capital improvements ($ billion). "although state and local governments rely primarily on their own revenues to purchase capital, federal grants also are an important source of funds. since , federal grants have accounted for one-third or more of the capital spending on infrastructure by states and localities. that share was considerably larger from the mid- s through the mid- s as a result of federal support for water utilities after passage of the clean water act in [ ] ." a renewal of this investment, with a focus on improving water treatment to remove antibiotics, args and other pollutants and destroying resistant organisms, would expand the positive results. regulations limiting the concentrations of antibiotics and args in treated municipal water, if enacted, in concert with meaningful financial penalties for those violating these standards, may significantly reduce the risk of population exposure. this can be difficult because the source of the contamination is often hard to identify. current antiviral drugs have several disadvantages including their specificity, toxicity and expense. researchers at the charles draper stark laboratories developed draco (double-stranded rna activated caspase oligomerizer). in lab-grown cells, draco killed different viruses, including ones that cause the common cold, influenza, polio and dengue fever with minimal effects on healthy cells [ ] ; however, there is still much work to be done before this drug can be fda approved and used by the general public. vectored vaccines use a live-vaccine made with a partial pathogen. they have been developed against sars-cov and demonstrated in mice, but the safety of vesicular stomatitis virus vaccine (vsv) in humans requires further research. newcastle disease virus, a host range-restricted virus, has been developed as a vaccine vector for intranasal immunization against emerging pathogens [ ] . science informs advances in drug development. for instance, authors reviewed a variety of genome sequence and gene knockout data for acinetobacter spp., with a focus on the critical systems to find the most appropriate sequences to target for therapies [ ] . this is just one early example in the explosive field of bioinformatics. in , in recognition of the importance of bioinformatics as a tool to diagnose and develop therapeutics for infectious diseases, the national institute of allergy and infectious diseases established four bioinformatics resource centers (brcs) to collect, store, and share bioinformatics information on bacteria, viruses, eukaryotic pathogens, and invertebrate vectors of human pathogens. as with the factors involved in the rise of the threat the responses are interrelated. the fda is, and must continue to, evolve its policies and regulations in the approval process so that research can proceed to the stage where drugs and biologics are ready for human use. this is discussed in more detail in the policies section below. because infectious diseases do not respect borders, it is in the strategic interest of the united states, the european union, and other countries with developed public health systems to invest in global public health infrastructure. this requires both a long-term investment as well as an acute response capability. president obama recognized both of these in the fall of . first on september , at the global health summit, president obama discussed long-term capacity building: "we, collectively, have not invested adequately in the public health capacity of developing countries." "this speaks to a central question of our global age-whether we will solve our problems together, in a spirit of mutual interest and mutual respect, or whether we descend into the destructive rivalries of the past. when nations find common ground, not simply based on power, but on principle, then we can make enormous progress. [ ] " a few weeks later, president obama discussed the acute strategic needs, "as i have said from the start of this [ebola] outbreak, i consider this a top national security priority. this is not a matter of charity-although obviously the humanitarian toll in countries that are affected in west africa is extraordinarily significant. this is an issue about our safety [ ] ." the president also signed the executive order on combating antibiotic-resistant bacteria in september of [ ] . recent outbreaks of diseases thought banished from the united states demonstrate the need for full vaccination. several communities resist vaccination, and incentives to vaccinate will increase population safety and prevent those who cannot be vaccinated from coming down with vaccinepreventable diseases. one common incentive is the requirement to be vaccinated to enter public school. waivers can be sought, but to boost the vaccination rates, state and local governments can reduce the numbers of exemptions provided. mississippi has already followed this course, and it has the highest vaccination rates in the united states. other potential policies include requiring exemption forms to be filed yearly; requiring parents to complete an education component; and requiring private as well as public school children to be vaccinated [ ] . several states are implementing one or more related measures. while only four states do not recognize a religious exemption from vaccinations, states do not allow exemptions for personal reasons (all states allow exemptions for medical reasons). in part due to the measles outbreak, on july of california will eliminate all non-medical vaccine exemptions. pennsylvania is also pondering eliminating personal exemptions. colorado has made the exemption process more burdensome [ ] . dina fine maron of scientific american [ ] suggested the following common sense approach: improved education and communication, sustain and enhance immunization outreach, maintain vigilance and rapidly contain imported infections. anthony fauci proposed partnerships, among government, industry, and academia to develop additional timely solutions to the threat of new and resurgent infectious diseases [ ] . one example of a successful academia-industry partnership is the response to the hiv/aids epidemic. aids was first recognized in the early s and the death rate steadily increased through the mid- s when it was recognized as a worldwide epidemic. research at and collaboration among academic institutions (including wayne state university) and investment by the public and private sectors (burroughs wellcome which later became glaxosmithkline) led to the development of the antiretroviral treatments used today. the partnerships transformed a deadly infection into a principally chronic disease within two decades [ ] [ ] [ ] . partnerships now work to ensure prevention, testing, distribution of anti-hiv/aids drugs and treatment worldwide. over the years fda has introduced innovations for the development and approval of pharmaceuticals including fast track, parallel track, orphan drugs, surrogate endpoints, noninferiority [ ] . according to the fda guidance [ ] , a non-inferiority (ni) study is used to demonstrate that the degree of inferiority of the drug being tested as compared to the control (an already approved drug) is less than the noninferiority margin. recently, to facilitate the development of biopharmaceuticals, a cross-industry group, including members from astra zeneca, university of texas medical school houston and smaller pharmaceutical companies, proposed a tiered evidence-based regulatory approach. in this approach tier a is the typical large phase iil approach and tier d is equivalent to the animal rule, which states that "for drugs developed to ameliorate or prevent serious or life threatening conditions caused by exposure to lethal or permanently disabling toxic substances, when human efficacy studies are not ethical and field trials are not feasible, fda may grant marketing approval based on adequate and well-controlled animal efficacy studies when the results of those studies establish that the drug is reasonably likely to produce clinical benefit in humans [ ] ." tiers b and c rely heavily on preclinical data and combined animal and human pharmacokinetic and pharmacodynamic (pk-pd) data fully integrated into a limited clinical program [ ] . in the c. difficile study discussed above, suggestions for prevention include: limit contact, limit inappropriate antibiotic usage, and increase surface cleaning. handwashing with soap from dispensers with sealed refills instead of open refillable dispensers can lower the risk of infection [ ] and is just one example of a common sense technique to prevent the spread of many bacterial infections. another common sense response is increased monitoring. cryptosporidium parvum did not appear to pose a risk until , people became ill, and approximately people died of cryptosporidiosis in milwaukee's water service area in . today, regulators and public health scientists are trying to identify microbes that pose a similar risk in the future. if these microbial contaminants occur in raw water supplies, they may need monitoring and treatment prior to these waters entering the potable water distribution system. the contaminant candidate list (ccl) developed by the united states environmental protection agency outlines a series of biological contaminants of concern that are not currently regulated but may pose a threat. should these contaminants move from the ccl to a regulatory framework, water supply utilities will incur added monitoring and testing of their water supply sources, and potentially added monitoring and treatment costs in their operations, but safety will likely increase as a result of these expenditures. the article discusses many of the problems and solutions due to emerging pathogens with a focus on the impact and response in the united states. these challenges are exacerbated in less well-off countries with poor sanitation, lack of access to preventative health care, unstable governments, or weak public health infrastructure. awareness is key, and this and other articles are working to spread the message. the threat from emerging diseases is continuously evolving as evidenced by the recent appearance of the zika virus. while the virus itself was isolated from the zika forest in uganda in the first half of the twentieth century, it did not begin to take a serious human toll until when it traveled from the pacific islands to brazil [ ] : it is now considered a global threat, with its vector, the aedes species mosquito living on all continents [ ] . there have been more than one million cases in brazil, and researchers noticed a surge in fetal microcephaly, a small head size for gestational age and sex indicating issues with brain growth, in zika-prone locations [ ] . it is now widely accepted that maternal infection with zika can lead to serious consequences for a fetus. for most infected, the effects will be minimal, but in addition to the fetal effects guillain-barre increases have been associated with zika infections. reliable diagnosis is not yet widely available, but reverse-transcriptase polymerase chain reaction (rt-pcr) testing of serum in the first seven days after symptom onset or igm-capture enzyme-linked immunosorbent assay (mac-elisa) analysis of samples are the most promising methods [ ] . animal models for further research, therapeutics and vaccines are required [ ] to stop the negative impacts of the disease since the vector is widespread and difficult if not impossible to eradicate. the general growing awareness of the threat posed by infectious disease because of travel, urbanization and all of the other factors described above combined with the serious consequences, primarily for pregnant mothers and their fetuses led to one of the fastest global responses to an infectious disease in the history of humankind. on april , , president obama announced that he would direct $ million in federal dollars remaining from the fund to fight ebola to fight the zika virus. the money will primarily be used for cdc and nih research on the virus, its role in birth defects, and vaccines for prevention. funds will also go to the formation of cdc response teams. this funding falls short of the $ . billion in emergency money president obama initially requested, and the shortfall is likely to delay a complete, effective response. internationally, the who designed and disseminated a global strategic response framework and joint operations plan, which can be accessed at http://www.who. int/emergencies/zika-virus/response/en/ . compare this to the response to polio, an enterovirus that causes few symptoms in the vast majority of cases, but can cause paralysis and even death in - % of cases. though poliovirus circulated in the population for hundreds of years, it did not reach 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bulk-soap-refillable dispensers zika virus the global distribution of the arbovirus vectors aedes aegypti and ae albopictus acknowledgments dr. ralph mitchell inspired me to look at the world in a new way, from the perspective of the tiny organisms that make the world what it is, but also threaten that world. key: cord- -w oeoxq authors: haischer, michael h.; beilfuss, rachel; hart, meggie rose; opielinski, lauren; wrucke, david; zirgaitis, gretchen; uhrich, toni d.; hunter, sandra k. title: who is wearing a mask? gender-, age-, and location-related differences during the covid- pandemic date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: w oeoxq masks are an effective tool in combatting the spread of covid- , but some people still resist wearing them and mask-wearing behavior has not been experimentally studied in the united states. to understand the demographics of mask wearers and resistors, and the impact of mandates on mask-wearing behavior, we observed shoppers (n = ) entering retail stores during periods of june, july, and august . approximately % of the june sample wore a mask. at that time, the odds of an individual wearing a mask increased significantly with age and was also . x greater for females than males. additionally, the odds of observing a mask on an urban or suburban shopper were ~ x that for rural areas. mask mandates enacted in late july and august increased mask-wearing compliance to over % in all groups, but a small percentage of resistors remained. thus, gender, age, and location factor into whether shoppers in the united states wear a mask or face covering voluntarily. additionally, mask mandates are necessary to increase mask wearing among the public to a level required to mitigate the spread of covid- . wearing a mask in public is currently a controversial and politicized issue in the united states, even with case evidence from other countries that face coverings help to control the spread of coronavirus disease (covid- ) [ ] . as taiwan, hong kong, south korea, and other countries with almost universal masking have been some of the most successful at reducing daily case and death rates [ , ] , the united states has largely trended in the other direction, setting national and state records for daily new cases of covid- at the end of june . as of september , the united states had recorded more than seven million confirmed cases and over , deaths [ ] . despite the controversy around masking, transmission of covid- (caused by the virus sars-cov- ) occurs primarily through respiratory particles from infected individuals and even asymptomatic cases can be contagious [ ] . experts in aerosol science, virology, infectious diseases, and epidemiology acknowledge the potential for a a a a a airborne transmission of the virus [ ] . thus, without a vaccine in distribution, masks are one of the few control measures available for protection against the virus because they serve as a physical barrier between people [ , ] . not only do masks protect the wearer from droplets and some smaller airborne particles, but they also provide source control, stopping particles coming from a wearer. study of the filtration efficiency of different fabrics has shown that even cotton weaves and blends can block viral transmission [ ] , so masks can be made virtually cost-free with household materials. while up to % of person-to-person transmission of the virus may occur through asymptomatic individuals [ ] , many people who have been infected with covid- experience significant functional complications within their organ systems. in children and young adults, the disease appears to be mild, but even among previously infected collegiate athletes, potentially life-altering inflammation within the cardiovascular system was detected [ ] . thus, even fit young adults are not immune to the harm that the virus can cause within the human body. systemically, cardiovascular [ ] , neurological [ ] , hepatic [ ] , renal [ ] , and respiratory [ ] complications of the virus have been reported across most age groups. older adults however are the most likely to experience severe outcomes, with one study showing that % of hospitalized individuals were at least years old [ ] . furthermore, % of hospitalized cases were men in this study, and consistent with a meta-analysis showing that males are at greater risk for severe outcomes from covid- [ ] . overall, death rate increases drastically with age and comorbid conditions, and mortality among hospitalized cases may be as high as % [ ] . new data is also emerging that suggests previously asymptomatic or "mild" cases are experiencing debilitating negative effects months after infection [ ] [ ] [ ] [ ] . given the easy transmission of this debilitating virus from person-to-person and the lifechanging complications across populations, mask wearing is demonstrated to be a very effective and proactive public health tool that will save lives and lessen future public health burden. though the evidence of the efficacy and importance of masks is clear, store policies and public mandates requiring masks in america have been met with protests [ ] and, in rare cases, violence [ , ] . public health research shows these measures may already have reduced cases in the united states by , through may nd [ ] , but the messaging from top-level government officials has been inconsistent [ ] and polling suggests that a sizeable portion of the general population are still going out in public without masks [ , ] , though self-reported behavior is not always reliable. a previous meta-analysis concluded that women were % more likely than men to engage in nonpharmaceutical protective behaviors (e.g. mask wearing) during epidemics and pandemics [ ] , and in the covid- pandemic women report wearing masks more often than men [ ] , despite the fact that male sex may be a risk factor for more severe outcomes of the disease [ ] . older adults are at higher risk for more severe cases of covid- [ , ] , so it is reasonable to expect that this demographic may wear masks more than younger individuals. mask wearing by retail shoppers may also vary by location, in that groups that report greater resistance to mask wearing may be more concentrated outside of urban areas [ ] . specifically, rural areas tend to have higher concentrations of conservative-leaning voters [ ] who are reported to be more resistant to wearing a mask [ ] . while the initial outbreak in the united states was primarily in cities, rural counties have also some of the highest case rates in the united states per capita [ ] . this geographical spread is particularly concerning given that populations that live in non-metropolitan areas are more vulnerable to covid- [ ] and highlights the need to study pandemic-related health behaviors like masking in rural locations. learning what demographic groups are wearing masks and how mask mandates impact behavior among these groups will help officials to better target public health messaging that promotes the practice among groups with lower usage. to facilitate greater understanding and reliable experimental data on whether gender, age, location, and the presence of mask mandates influence mask wearing in the united states, we conducted a direct observational study at retail stores in wisconsin. observations occurred between june and august . from june th to august rd , , the -day average case rate in wisconsin more than doubled ( to cases) and the percentage of positive cases had increased from . % to . % [ ] . thus, during this period, many major retail chain [ ] and wisconsin state [ ] mask mandates were enacted, allowing for study of mask wearing before and after these regulations went into effect. the primary aim of our study was to determine mask use by gender expression, estimated age, and location. we hypothesized that, without a mandate, mask use among females would be greater than males across all age groups and locations. additionally, that mask use would be greater among older adults (> years old) than middle-age ( - years old) and young individuals ( - years old) and would be less in rural than in urban or suburban areas. a secondary aim of this project was to revisit stores on dates near the implementation of store and state mask mandates to characterize how mask-wearing behavior changes in response to these requirements. we addressed our primary aim by visiting different retail locations across five different counties in southeastern wisconsin. retail stores selected for observation were based largely on geographical spread across milwaukee and the surrounding areas. in the interest of exploring mask wearing among urban, suburban, and rural stores, we designated a center point of the city (united states postal service main office; w st. paul ave, milwaukee, wi, usa) and recorded the linear distance of each store to the city center. based on distance, stores were then placed into urban (< . km from city center; n = , . ± . km to city center), suburban ( . - . km; n = , . ± . km), and rural (> . km; n = , . ± . km) store groups. visits to stores (n = ) occurred at various times between am and pm (june rd - th , ) and lasted at least minutes (average = min), with observers recording data with writing utensil and paper or mobile device. to address our secondary aim, stores were revisited and data was collected in the same manner on dates shortly before store or state mandates were implemented (n = ; july th - st , ), when there was a store mandate but not a state mandate (n = ; july nd -july st , ), and after the wisconsin state mandate began (n = ; august st - rd , ). note that the overlap in the secondary visit dates is related to corporate differences in the dates mask mandates began at various stores. stores consisted of grocery and other large big-box retail stores and shoppers were not aware they were being observed. children under the estimated age of two were not recorded and estimated age categories were defined as young = - years old, middle age = - years old, older: > years old. these ranges reflect the substantial increase in stratified death rates for individuals - and - years old when compared to prior age groups ( ) . for all observations that were collected, summary sheets were crosschecked by other observers. all procedures involved public observation or accessed public information and did not require review by an institutional review board. to determine the impact of gender, age, location, and their interactions on mask wearing during the initial visit period (june rd - th , ), multiple logistic regression analysis was performed. sixty individuals who were wearing their mask or face covering improperly (not over nose and mouth) were recorded but excluded from this analysis as they could not be grouped into a dichotomous outcome (mask/no mask). after excluding these individuals, observations remained for the analysis, and gender expression, age, and location independent variables were dummy coded and entered into a backward elimination procedure with their associated interactions (gender-age, gender-location, age-location, and gender-age-location). limit for variable removal and test classification cutoff were set at . and . , respectively. adjusted odds ratios (aor) are expressed with respect to reference groups (gender: male, age: young, location: rural) with % confidence intervals and significance was determined at p < . . percentage data including incorrect mask wearers from the initial visit (june rd - th , ) was used to compare to later data (july th -aug rd , ) and evaluate the changes in maskwearing behavior in response to mask mandates. all analyses were performed with either microsoft excel (microsoft, redmond, wa, usa) or ibm statistical package for social sciences version (ibm, armonk, ny, usa). over the course of visits, individuals were observed entering retail stores. of the individuals we observed during the first round of data collection that could be grouped into a dichotomous outcome (mask/no mask) (fig ) , . % were wearing a mask or face covering with the general trend across gender, age, and location largely aligning with our original hypotheses (table ) . females wore masks . % more than males (fig a) . additionally, masks were seen at a higher percentage in older than middle-age (+ . %) and young (+ . %) individuals (fig b) . urban and suburban mask wearing was similar but was much lower at rural stores (suburban: - . %; urban: - . %; . ± . km) (fig c) . regression analysis revealed that gender, age, and location all significantly impact the odds of an individual being observed to wear a mask (p < . ; fig ) . results indicate the odds of a female wearing a mask are significantly greater than males (aor = . , % ci = . - . ). odds are also greater for middle age (aor = . , % ci = . - . ) and older adults (aor = . , % ci = . - . ) than younger individuals. the odds of observing someone in urban (aor = . , % ci = . - . ) or suburban (aor = . , % ci = . - . ) areas wearing a mask is also much higher than in rural locations, reflecting the much lower prevalence of masks seen at rural stores. the significant age-location interaction effect (p < . ) is largely driven by differential changes in mask-wearing behavior between older adults and the other age groups (fig d) . while estimating age and gender is an obvious limitation of this study, the sample was large (~ , observations) increasing the study power to offset the effect of variability from the estimations. currently, no peer-reviewed and direct-observational studies of mask wearing are available for comparison to our study findings. preprint study akin to ours also reflects alarming and similarly low percentages of mask wearing in wisconsin [ ] . additionally, our data can be discussed in relation to national polls and surveys that addressed mask wearing at about the same time. a may-to-june survey of adults in wisconsin and four other surrounding states indicated . % always wear a mask when they leave home [ ] , and data in our study lends credibility to this number. notably, other regions of the united states surveyed reported different habits ( . - % mask usage) so direct observational studies in other parts of the country would be beneficial to confirm national variability when mask mandates are not in place. another poll conducted in mid-april indicated that only % of adults always wear a mask or face covering when outside the home [ ] , so perhaps usage nation-wide has gradually improved even when masks are not required. women also reported wearing a mask more often than men. so why are men wearing masks in public places less than women? perhaps masks are viewed as a sign of fragility or weakness among some men in the usa, as suggested in previous preprint work [ ] . in this case, public health messaging that focuses on aligning masks with masculinity would likely be beneficial to improve usage among males in the united states. alternatively, women may be more likely to protect themselves and others by wearing a mask because they handle the majority of caregiving within families [ ] , or because of awareness of the preexisting gender inequalities in social, political, and economic systems that have been further amplified due to the pandemic [ ] . it is not surprising that our june data showed that older individuals wear masks more than middle-age and young people because older adults are at higher risk for more severe cases of covid- . however, the low percentage of young individuals wearing a mask combined with their potential to be asymptomatic [ ] creates problems for case containment. a key and underreported benefit of masks is source control, so mask wearing is important across all age groups. lower-risk individuals put older adults and those with preexisting conditions of all ages at risk of severe illness by not wearing a mask due to the potential for asymptomatic viral transmission. one of the most interesting findings of the current study is the evidence of drastically different mask-wearing behavior in rural areas compared with urban and suburban shoppers when mask requirements are not in place. the odds of urban and suburban shoppers wearing a mask was about x greater than for rural store-goers during our june data collection period, possibly reflecting the fact that individuals shopping in rural areas perceive lower risk. however, it has been previously reported that mask-wearing habits do not appreciably differ between counties with low and high numbers of covid-related deaths [ ] . further, while living population density may be lower in rural regions, the size of retail stores is relatively uniform. thus, differences in the density of shoppers in stores across regions is likely far less than the actual population density differences reflect. understanding why rural shoppers may resist the use of masks more than shoppers in other areas is an important issue because the health care system in these areas of the united states may be less equipped to handle large spikes in cases. rural residents may also need to travel further for emergency care, putting them at greater risk for severe consequences of infection. for these reasons, public health messaging that promotes masks in rural communities is critically important. by the last week of july , for stores with no mask mandate, wearing increased to about % overall (fig ) . this may reflect some improvement in voluntary compliance, as many stores had announced mandates to be enforced at later dates. thus, some individuals may have been moved to comply due to the prospect of needing to wear a mask for future shopping trips. within these data there were no discernable age-related differences, but it was still evident that more females ( . %) were wearing masks than males ( . %). data after store and the wisconsin state mask mandates began shows mask wearing increased to over % overall (fig ) . modeling studies suggest mask usage needs to be to nearly universal to have a significant effect on the epidemiological curve [ , ] , and our results emphasize that mask mandates are necessary to approach this goal. if public officials do not enact these mandates the welfare of shoppers will continue to be left to retail corporations. while retail store mandates obviously improve mask-wearing compliance among shoppers, our data may indicate that that store regulations could be slightly less effective than mandates enacted by government as a slightly higher percentage of individuals were observed correctly wearing masks after a state mandate began ( % vs % with store mandate only). mask mandates obviously improve usage, but it deserves mention that a small percentage of the population still resist masks even with retail store and government regulations in place. though it may be argued that some shoppers might have a health condition that precludes wearing a mask, the centers for disease control and prevention only recommend against mask wearing if an individual has trouble breathing or is unable to remove a face covering without assistance [ ] so it is improbable that this is a valid explanation for all of the mask resistors observed with a state mandate ( %; fig ) . mask-wearing mandates are necessary to reduce person-to-person transmission of covid- and save lives as a portion of the general public will resist wearing masks in retail stores without them. even with mandates in place, some individuals still resist or wear them incorrectly, putting employees, other shoppers, and themselves at risk due to the potential for viral transmission from asymptomatic carriers [ , ] . encouraging voluntary compliance to mask wearing is critical so that retail employees do not have to play the role of "mask police", risking verbal or physical abuse from resistant shoppers. close encounters (within six feet) are a great risk to adjusted odds ratios (aor) and % confidence interval plots of mask usage for gender expression, age, and location during the initial data collection period from june rd - th , . odds ratios are expressed in relation to reference groups (gender: male; age: young; location: rural). https://doi.org/ . /journal.pone. .g who is wearing a mask? employees if the resistor without a mask is infected. though some stores provide masks to shoppers after entering, there is still a short period that these individuals are inside of the store without masks on. as the possibility of aerosolized transmission of covid- was recently confirmed [ ] , every breath and word spoken without a mask on (or without one covering mouth and nose) and especially indoors, increases risk of aerosolized virus spread. thus, it is critical to wear a mask from entrance to exit of any public indoor space. to further reduce the number of individuals entering without a mask, stores may benefit from providing masks to shoppers that need them outside of the entrance, where possible. averting cases of covid- will save lives so wearing a mask is a public health service and should not be viewed as a symbol of fragility of the individual. wearing a mask is not about stopping transmission of all cases but minimizing case rates and lessening the public health burden. importantly, the long-term effects of covid- are still unknown so mask wearing is also vital to reduce burden from future comorbidities that may result within individuals who were infected. masks are an essential public health intervention for combatting the pandemic, and only % of individuals observed in our june sample were wearing a mask when entering a retail store. this is less than half the percentage needed to have a significant effect on the reducing the mask-wearing compliance was poor in june but had improved immediately before mandates began. compliance rose to > % with a mandate in place across all demographics, but a small percentage of the population still resisted. the overlap in "before" and "with store mandates" dates is related to corporate differences in the dates mask mandates began. https://doi.org/ . /journal.pone. .g spread of covid- [ , ] . males, younger individuals, and shoppers in rural communities were observed wearing masks less than other groups. however, with store mandates and a state-wide mandate to wear a mask, we showed that mask-wearing compliance rose to over % in all groups, including those that resisted mask wearing in june. as officials around the united states continue to debate mask mandates at local and state levels, our data indicated that mandates are necessary to ensure mask-wearing compliance among the public meets the minimum threshold to take control of the covid- pandemic. our data also highlights that a portion of the general population does not follow public health recommendations without them. furthermore, even with mandates in place a portion of shoppers (~ %) still resist or wear masks ineffectively. individual shoppers may consider this information to evaluate the potential risks of in-person shopping based on store and local mask policies, location, and the age and gender of the store's clientele. our findings are also important to inform policy makers that mask mandates are necessary to improve compliance to a level that can help flatten the epidemiological curve, saving lives and decreasing burden on the united states health care system. supporting information s file. june observations raw data. its contains raw data for the initial data collection period in june. (xlsx) s file. july and august observations raw data. its contains raw data for the second data collection period in july and august. the species severe acute respiratory syndrome-related coronavirus: classifying -ncov and naming it sars-cov- reducing transmission of sars-cov- a modelling framework to assess the likely effectiveness of facemasks in combination with 'lock-down' in managing the covid- pandemic united states coronavirus info; c temporal dynamics in viral shedding and transmissibility of covid- enviromental health matters initiative face coverings for the public: laying straw men to rest face masks for the public during the covid- crisis physical distancing, face masks, and eye protection to prevent person-to-person transmission of sars-cov- and covid- : a systematic review and meta-analysis. the lancet estimating the generation interval for coronavirus disease (covid- ) based on symptom onset data cardiovascular magnetic resonance findings in competitive athletes recovering from covid- infection cardiovascular complications in covid- neurologic manifestations of hospitalized patients with coronavirus disease manifestations and prognosis of gastrointestinal and liver involvement in patients with covid- : a systematic review and meta-analysis incidence of acute kidney injury in covid- infection: a systematic review and meta-analysis. crit care coronavirus in china features of , uk patients in hospital with covid- using the isaric who clinical characterisation protocol: prospective observational cohort study risk factors of critical & mortal covid- cases: a systematic literature review and meta-analysis pathophysiology, transmission, diagnosis, and treatment of coronavirus disease (covid- ) gemelli against covid- post-acute care study group. persistent symptoms in patients after acute covid- from 'brain fog' to heart damage, covid- 's lingering problems alarm scientists covid- : what do we know about "long covid the lasting misery of coronavirus long-haulers. nature anti-vaccine activists, mask opponents target public health officials-at their homes. los angeles times black mayor of kansas city says he was called n-word, received death threat over mask rule. nbc news mcdonald's customer attacks drive-through worker over safety rule community use of face masks and covid- : evidence from a natural experiment of state mandates in the us mixed messaging on masks set u.s. public health response back. npr the northeast leads the country in mask-wearing. cnn new april guidelines boost perceived efficacy of face masks a meta-analysis of the association between gender and protective behaviors in response to respiratory epidemics and pandemics older adults and covid- republicans, democrats move even further apart in coronavirus concerns how the rural-urban divide became america's political fault line latest map and case count rural america is more vulnerable to covid- than cities are, and it's starting to show. the conversation wisconsin department of health services covid- : wisconsin summary data mcdonald's joins walmart and dozens of other chains with mask mandates emergency order # : relating to preventing the spread of covid- by requiring face coverings in certain situations. the state of wisconsin office of the governor use of face coverings by the public during the covid- pandemic: an observational study the effect of messaging and gender on intentions to wear a face covering to slow down covid- transmission geographies of care and responsibility united nations secretariat. the impact of covid- on women age-dependent effects in the transmission and control of covid- epidemics bidirectional impact of imperfect mask use on reproduction number of covid- : a next generation matrix approach. infectious disease modeling this simple model shows the importance of wearing masks and social distancing. the conversation considerations for wearing masks viable sars-cov- in the air of a hospital room with covid- patients key: cord- -n cfs ku authors: kading, rebekah c.; cohnstaedt, lee w.; fall, ken; hamer, gabriel l. title: emergence of arboviruses in the united states: the boom and bust of funding, innovation, and capacity date: - - journal: trop med infect dis doi: . /tropicalmed sha: doc_id: cord_uid: n cfs ku mosquito-borne viruses will continue to emerge and generate a significant public health burden around the globe. here, we provide a longitudinal perspective on how the emergence of mosquito-borne viruses in the americas has triggered reactionary funding by sponsored agencies, stimulating a number of publications, innovative development of traps, and augmented capacity. we discuss the return on investment (roi) from the oscillation in federal funding that influences demand for surveillance and control traps and leads to innovation and research productivity. while outbreaks of infectious diseases are devastating to human and animal populations, surges in private and public funding for outbreak pathogens have positively influenced research and innovation. contemporary outbreak response efforts now incorporate digital media; electronic surveillance tools; mathematical modelling; sequencing; and teams of experts that include anthropologists, social scientists, and other diverse disciplinarians [ ] . outbreak stimulus funding leads to increased scientific productivity on outbreak pathogens, and incites innovation [ ] . for example, an innovation workshop convened after an anthrax bioterrorism attack in , to discuss new surveillance and pathogen detection approaches [ ] . the ebola grand challenge program, funded by the us centers for disease control and prevention (cdc), united states agency for international development (usaid), the united states executive office, and the department of defense, provided financial backing to innovative projects to improve the response to ebola outbreaks. these projects included protective suits, health care and technology solutions, and decontaminants [ ] . the usaid zika grand challenge program in received over applications and provided million dollars to innovative ideas to address zika virus transmission [ ] . currently, during the covid- pandemic, innovations are emerging such as new ventilators, drones delivering medical supplies, and the use of artificial intelligence in medicine [ ] [ ] [ ] [ ] . ideally, these scientific advances will aid in combatting the current epidemic as well as fuel innovation in preparedness for future emerging disease events, leading to return on investment (roi). the introduction and spread of numerous mosquito-borne viruses around the globe has also shepherded a wave of innovation to improve upon industry-standard sampling techniques that more efficiently capture the target vector species, physiological cohort, or virus-infected population of vectors [ ] . ramirez et al. [ ] recently reviewed traditional surveillance approaches in the context of novel innovations that have advanced surveillance capacity, including pathogen surveillance from sugar feeding vectors, next-generation sequencing (edna (environmental dna) for presence or absence of vectors in habitats), and xenosurveillance for vectors and pathogens. additionally, modernized sampling strategies have also been expanded to incorporate technical advancements in such areas as infrared scanning, citizen science, and drones [ ] [ ] [ ] [ ] . driving the introduction and incorporation of novel trapping approaches to surveillance programs is the persistent emergence of mosquito-borne pathogens. many arboviruses cause a significant disease burden to the public each year. west nile virus (wnv) (introduced in ), st. louis encephalitis virus (slev), jamestown canyon virus (jcv), la crosse encephalitis virus (lacv), eastern equine encephalitis virus (eeev), and powassan (powv, tick-borne) are tracked through the cdc database, arbonet [ ] . in the last several years, incidence of jcv and powv has been increasing [ ] [ ] [ ] [ ] . additionally, a multistate outbreak of eeev occurred in the northeastern us in , in which the reported cases far exceeded the historical average of around eight cases/year [ ] . through the first half of the th century, western equine encephalitis virus (weev) was also widespread and caused significant morbidity and mortality in humans and horses; however, this virus has largely disappeared from most areas over the past several decades for unconfirmed reasons, with the last human case in the united states reported in [ , ] . in , chikungunya (chikv) was first reported in the americas, followed by zika virus (zikv) two years later [ , ] . these virus invasions came during a time of increasing dengue virus (denv) incidence, range expansion, and replacement of dominant serotypes in different geographic areas [ ] [ ] [ ] . the pan american health organization (paho) reported a % increase in the number of dengue cases, from , , between and to , , between and [ , ] . intensive transmission of aedes-borne viruses in the americas coupled with the expanding range of ae. aegypti mosquitoes presents a continual threat of these viruses gaining a foothold in the united states as well [ ] [ ] [ ] . to date, cases of denv, zikv, and chikv in the united states have predominately been traveler-associated, with the exception of local transmission of zikv in florida and texas during [ , ] . when a mosquito-borne virus rapidly spreads around the world and becomes a public health emergency of international concern, federal agencies allocate substantial funds to fight the virus. in the u.s., congress approves these funding packages, such as the $ . billion for zika virus in september, [ ] . this stimulus funding provides agencies such as the national institutes of health (nih), the centers for disease control and prevention (cdc), and the national science foundation the resources to allocate funds to public health agencies and researchers to enhance outbreak surveillance and response efforts. as a proxy for this federal spending allocated to different emerging arboviruses, we used the nih reporter search query to estimate the funding of projects related to the emergence of wnv, chikv, and zikv. we used the key words of ''west nile virus", ''chikungunya virus", and ''zika virus" in the search feature which queries all project titles, abstracts, and scientific terms. to compare these invasive mosquito-borne viruses to those endemic to the united states, we also included three endemic mosquito-borne viruses that have resulted in continual transmission, including human disease, in the last several decades. these additional virus searches were performed for ''eastern equine encephalitis virus", ''st louis encephalitis virus", and ''la crosse encephalitis virus". the search for st. louis encephalitis virus returned more projects with ''st" than with ''saint". the search was performed on may , and we included all years from - in each search. nih-funded projects have a record for each fiscal year of a project (e.g., a -year nih r has five records). the projects include international and national investigators and project locations. the search for wnv resulted in records for a total of $ , , , in funding; chikv matched records for $ , , in funding; and zikv matched records for $ , , , in funding ( figure ). the search for eeev matched records for a total of $ , , in funding; slev matched records for $ , , in funding; and lacv matched records for $ , , in funding ( figure ). the rise in nih-funded projects for the invasive arboviruses rose quickly following their introduction into the u.s., especially for zikv. the nih-funding for endemic arboviruses was steadier over the time year period, especially for lacv. records for $ , , in funding ( figure ). the rise in nih-funded projects for the invasive arboviruses rose quickly following their introduction into the u.s., especially for zikv. the nihfunding for endemic arboviruses was steadier over the time year period, especially for lacv. in response to wnv and zikv, the cdc supports detection and response capacity to local agencies by providing states epidemiology and laboratory capacity (elc) cooperative agreements with all states and us territories. for the first five years following the introduction of wnv into the u.s., the cdc issued elc funds which were reduced in . a survey by the council of state and territorial epidemiologists in showed several enhancements to surveillance, laboratory, and control capacity that were made possible as the result of elc funding [ ] . however, after yearly reductions in elc funds, a survey in revealed many of these programs had reduced or lost surveillance and response measures [ ] . despite this lack of sustained funding and reduced infrastructure, wnv continues to have periodic large epidemics [ ] . the advent of chikv and zikv to the americas caught many u.s local, state, and federal agencies off guard with a lack of knowledge of, lack of surveillance of, or inability to control aedes (stegomyia) mosquitoes. once again, along with the nih who spent over $ million in on zikv-related projects, the cdc administered $ million in supplementary zika elc stimulus funds to states to help programs re-bound and shift from a culex-centric focus to aedes [ ] . this pulse in funding helped improve the surveillance and control of aedes mosquitoes, although the fading of zika virus in the national news and the reduction of these elc funds [ ] has resulted in many programs again reducing their capacity. in response to wnv and zikv, the cdc supports detection and response capacity to local agencies by providing states epidemiology and laboratory capacity (elc) cooperative agreements with all states and us territories. for the first five years following the introduction of wnv into the u.s., the cdc issued elc funds which were reduced in . a survey by the council of state and territorial epidemiologists in showed several enhancements to surveillance, laboratory, and control capacity that were made possible as the result of elc funding [ ] . however, after yearly reductions in elc funds, a survey in revealed many of these programs had reduced or lost surveillance and response measures [ ] . despite this lack of sustained funding and reduced infrastructure, wnv continues to have periodic large epidemics [ ] . the advent of chikv and zikv to the americas caught many u.s local, state, and federal agencies off guard with a lack of knowledge of, lack of surveillance of, or inability to control aedes (stegomyia) mosquitoes. once again, along with the nih who spent over $ million in on zikv-related projects, the cdc administered $ million in supplementary zika elc stimulus funds to states to help programs re-bound and shift from a culex-centric focus to aedes [ ] . this pulse in funding helped improve the surveillance and control of aedes mosquitoes, although the fading of zika virus in the national news and the reduction of these elc funds [ ] has resulted in many programs again reducing their capacity. (figures , ) . the yearly pattern in publications for these three arboviruses closely matches the total funding by nih, although publications reported on web of science include publications by international authors funded by different international sponsors. publications including the endemic arboviruses as keyword searches have slowly increased over the last years, but the scale of the increase in publications for invasive arboviruses is much greater. along with the pulse in funding and attention by media and the public, surges in peer-reviewed publications occur following the emergences of arboviruses. to quantify these publications, we performed a "basic search" of the web of science core collection for the key words of "west nile virus", "chikungunya virus", and "zika virus". as with the nih reporter search, we included "eastern equine encephalitis virus", "st louis encephalitis virus", and "la crosse encephalitis virus". the search for st. louis encephalitis virus returned more publications with "st" than with "saint". the year range for the search was to , and the search was conducted on may . the results yielded , records for wnv; for chikv; for zikv; for eeev; for slev; and for lacv (figures and ) . the yearly pattern in publications for these three arboviruses closely matches the total funding by nih, although publications reported on web of science include publications by international authors funded by different international sponsors. publications including the endemic arboviruses as keyword searches have slowly increased over the last years, but the scale of the increase in publications for invasive arboviruses is much greater. the evolution of mosquito trapping tools targeting culex and aedes mosquitoes has followed suit, being driven by the emergence of these viruses, the resulting resources generated by federal agencies, and consumer demand. to visualize trends in trap usage over time, we evaluated bioquip products sales data in each main trap category between and ( figure ). as the united states has experienced emergences and threats of first culex and now also aedes-borne viruses, innovations to traditional mosquito trapping tools targeting these vector groups have arisen, with the proportion of sales in different categories fluctuating over time in response to arbovirus outbreak and funding availability (figure ). the diversity of traps sold by bioquip products also increased substantially from two categories in to nine categories by (figure ) as new innovations came to market. undoubtedly, the surge of aedes-borne viruses in particular during this time period has influenced the development and sales of novel traps targeting ae. aegypti mosquitoes. the cdc light trap has become an industry standard for collection of mosquitoes for the purposes of arbovirus surveillance. the similar evs (encephalitis vector survey) trap [ ] is also routinely used for arbovirus surveillance and operates on a similar principle as the cdc light trap using light and carbon dioxide (co ) as attractants. between and , trap sales were the evolution of mosquito trapping tools targeting culex and aedes mosquitoes has followed suit, being driven by the emergence of these viruses, the resulting resources generated by federal agencies, and consumer demand. to visualize trends in trap usage over time, we evaluated bioquip products sales data in each main trap category between and ( figure ). as the united states has experienced emergences and threats of first culex and now also aedes-borne viruses, innovations to traditional mosquito trapping tools targeting these vector groups have arisen, with the proportion of sales in different categories fluctuating over time in response to arbovirus outbreak and funding availability (figure ). the diversity of traps sold by bioquip products also increased substantially from two categories in to nine categories by (figure ) as new innovations came to market. undoubtedly, the surge of aedes-borne viruses in particular during this time period has influenced the development and sales of novel traps targeting ae. aegypti mosquitoes. and zikv to the americas (figure ) . similarly, gravid aedes traps (gat) [ , ] were introduced between and . conceptually based on traditional gravid traps [ ] , these traps do not require electricity to function. gat sales quickly grew to approximately % of the traps sold by bioquip in ( figure ). the insectazooka© and the prokopak aspirator [ ] are lightweight, portable field aspirators developed as an alternative to backpack models. these devices facilitate the collection of resting and engorged mosquitoes from indoor and outdoor resting sites. the cdc light trap has become an industry standard for collection of mosquitoes for the purposes of arbovirus surveillance. the similar evs (encephalitis vector survey) trap [ ] is also routinely used for arbovirus surveillance and operates on a similar principle as the cdc light trap using light and carbon dioxide (co ) as attractants. between and , trap sales were dominated by suction traps using light and co as attractants, and gravid traps, largely for culex vectors of wnv and slev. due to the sustained threat of wnv year after year [ ] , traps targeting culex vectors are expected to remain a mainstay in the industry. several specific innovations have either improved the functionality of the standard light trap or targeted different physiological cohorts of mosquitoes. in , bioquip released the first commercially available light-emitting-diode (led) cdc-style light trap with customizable colors (figure ). bayonet mounted led chips were also available to replace the white incandescent lights in existing cdc style light traps. the passive box trap offered an alternative to cdc light traps, by providing a co -baited trap that was not reliant on a power source and could be used to sample arbovirus vectors in more remote areas [ ] . a collapsible passive trap was also developed to address portability issues [ ] . a photo switch option also added to light traps, allowing researchers the flexibility to set traps when convenient and conserve battery power. finally, the cdc resting trap was introduced in for the purpose of collecting blood-engorged mosquitoes to determine vertebrate host utilization [ ] . passive and resting traps represent a smaller proportion of sales over the last several years, suggesting their utility may be serving the research community as opposed to being integrated into large-scale operational surveillance activities. surveillance for viruses transmitted by ae. aegypti mosquitoes requires very different tools and strategies than for those used for culex-borne viruses. these urbanized, day-biting, container-breeding mosquitoes are generally not attracted to the suction and gravid traps that are so efficient at catching culex mosquitoes [ ] . the growing need for traps that effectively collected aedes mosquitoes led to the innovation of the bg sentinel mosquito trap in (biogents ag, regensburg, germany) [ ] , among others. bg sentinel traps began selling at bioquip in , and sales comprised approximately % of the total traps sold by bioquip in following the introduction of chikv and zikv to the americas (figure ) . similarly, gravid aedes traps (gat) [ , ] were introduced between and . conceptually based on traditional gravid traps [ ] , these traps do not require electricity to function. gat sales quickly grew to approximately % of the traps sold by bioquip in ( figure ). the insectazooka© and the prokopak aspirator [ ] are lightweight, portable field aspirators developed as an alternative to backpack models. these devices facilitate the collection of resting and engorged mosquitoes from indoor and outdoor resting sites. the emergence of mosquito-borne viruses has occurred repeatedly in recent decades, and studies predict that these emergences will continue. much of our response to these events is reactionary, triggered by the increase in attention, funding, publication, innovation, and preventive measures for public health. the long-term impact or return on investment of outbreak spending is evidenced by scientific advancements (publications) and innovation, but we advocate for a more sustainable, economical, and effective approach by minimizing the oscillations of boom and bust in funding and capacity for mosquito-borne viruses. our goal should be to optimize the cost-effectiveness of budgetary spending by adopting resource allocation for biosecurity threats that maximize benefits while minimizing the total cost given anticipated expenditures incurred in the event of mosquito-borne viral outbreaks [ , ] . outbreak science: recent progress in the detection and response to outbreaks of infectious diseases infectious disease outbreak research: insights and trends innovative surveillance methods for rapid detection of disease outbreaks and bioterrorism: results of an interagency workshop on health indicator surveillance a grand challenge for development combating zika | grand challenge for development | u.s. agency for international development james dyson designed a new ventilator in days. he's making , for the pandemic fight targeted applications of unmanned aerial vehicles (drones) in telemedicine will blood-bearing delivery drones transform disaster relief and battlefield medicine? available online how innovation is helping mitigate the coronavirus threat searching for the proverbial needle in a haystack: advances in mosquito-borne arbovirus surveillance determining mosquito distribution from egg data: the role of the citizen scientist detection of plasmodium berghei infected anopheles stephensi using near-infrared spectroscopy rapid, noninvasive detection of zika virus in mosquitoes by near-infrared spectroscopy project premonition project: field trials of a robotic smart trap for mosquito identification and bionomics west nile virus and other nationally notifiable arboviral diseases-united states neuroinvasive arboviral disease in the united states powassan virus disease in the united states jamestown canyon virus disease in the united states- - notes from the field: multistate outbreak of eastern equine encephalitis virus-united states summary of notifiable diseases-united states continued evidence of decline in the enzootic activity of western equine encephalitis virus in colorado arboviral diseases branch, national center for emerging and zoonotic infectious diseases, cdc notes from the field: chikungunya virus spreads in the americas-caribbean and south america first report of autochthonous transmission of zika virus in brazil trends in patterns of dengue transmission over years in a pediatric cohort study in nicaragua the history of dengue outbreaks in the americas history, epidemiology and diagnostics of dengue in the american and brazilian contexts: a review region of the americas (by country and subregion) - past and future spread of the arbovirus vectors aedes aegypti and aedes albopictus multiple introductions of the dengue vector, aedes aegypti, into california global expansion and redistribution of aedes-borne virus transmission risk with climate change assessing real-time zika risk in the united states congress approves $ . billion in zika funding assessing capacity for surveillance, prevention, and control of west nile virus infection-united states national capacity for surveillance, prevention, and control of west nile virus and other arbovirus infections-united states cdc. statistics & maps | west nile virus | cdc awards nearly $ million to continue the fight against zika cdc. elc -year focus, funding, and impact | dpei | cdc a miniature battery powered co baited light trap for mosquito borne encephalitis surveillance a simple non-powered passive trap for the collection of mosquitoes for arbovirus surveillance development, optimization, and field evaluation of the novel collapsible passive trap for collection of mosquitoes the centers for disease control and prevention resting trap: a novel device for collecting resting mosquitoes mosquito ecology: field sampling methods field evaluation of effectiveness of the bg-sentinel, a new trap for capturing adult aedes aegypti (diptera: culicidae) development of the gravid aedes trap for the capture of adult female container-exploiting mosquitoes (diptera: culicidae) an improved autocidal gravid ovitrap for the control and surveillance of aedes aegypti a revised version of the cdc gravid mosquito trap a new, cost-effective, battery-powered aspirator for adult mosquito collections budgeting and portfolio allocation for biosecurity measures-kompas cost-benefit analysis for biosecurity decisions the viewpoints described herein represent those of the authors and not necessarily their institutions or funding agency. the authors declare no conflict of interest. the funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. key: cord- -hsnz qry authors: bhattacharjee, barnali; acharya, tathagata title: “the covid- pandemic and its effect on mental health in usa – a review with some coping strategies” date: - - journal: psychiatr q doi: . /s - - - sha: doc_id: cord_uid: hsnz qry the covid- pandemic has resulted in enormous losses in terms of human lives and economy in united states. the outbreak has been continuing to heavily impact the mental health of people. developing key strategies to prevent mental illnesses is extremely important for the well-being of people. a survey conducted during the last week of march showed that % of americans felt that their lives were impacted by the outbreak, which was a % increase from the survey conducted only weeks earlier. the results show a positive correlation between covid- infections/casualties and growing public concern. these observations suggest possible increase in mental health illnesses in united states as a consequence of the pandemic. the authors review a recently published model on covid- related fear among the people. the fear of being infected or dying from the disease is one of the most significant causes of mental health disorders. loss of employment or the fear of losing employment is another major concern leading to mental illnesses. several unique strategies to prevent or mitigate mental illnesses are discussed. the covid- epidemic started at wuhan, china and within a few months became a global pandemic. the world health organization (who) declared the covid- outbreak as a public health hazard of international concern on january , [ ] . at this time, regions in china had reported infections and the total number of cases exceeded that for the severe acute respiratory syndrome (sars). on the same day, united states centers for disease control and prevention (cdc) confirmed the first case of person to person transmission in united states. on january , health and human services (hhs) declared coronavirus a public health emergency in united states. again, on the same day, cdc issued a federal quarantine for weeks affecting american evacuees from wuhan, china [ ] . the first covid- death in united states of america was reported on february , . over the next days, the virus hit united states of america especially hard resulting in , deaths and over . million infections. during pandemics it is common for healthcare professionals and scientists to primarily focus on the pathogen to study its mechanism with an aim of containing it and treating the disease. under these conditions, the secondary effects such as the effect of the pandemic on human psychiatry tend to be neglected [ ] . historically, disease outbreaks and epidemics have been known to cause mental illnesses. for instance, during the korean mers outbreak, patients who were isolated for hemodialysis reported high levels of stress [ ] . in addition, several reports exist where high levels of post-traumatic stress disorders (ptsd) were reported due to isolation following a major traumatic event such as an act of terrorism, natural calamity, or a disease outbreak [ ] [ ] [ ] . in this article, the authors critically examine the onset of the pandemic in united states of america focusing on its effect on the mental health of american people. the authors discuss various strategies to overcome the mental health challenges associated with both the outbreak and response. the covid- pandemic in united states figure shows the number of covid- cases in united states from beginning through may , [ ] . figure shows the total number of covid- deaths in united states respectively between february , and may , . the total number of covid- cases and deaths started increasing rapidly from march , . currently, the total number of covid- deaths in united states has already crossed , . may , with the increase in the number of covid- cases in united states from march through april , there has been a rise in fear in the minds of people. in addition to the uncertainties caused by the disease itself, people have been experiencing additional insecurities due to conflicting and dubious information about disease transmission, inadequate control measures, and lack of efficient therapeutic mechanisms. non availability of adequate protective gear for healthcare professionals has created additional barriers [ , ] . besides, the lockdown required to slow down the spread of the disease has resulted in tremendous losses to the economy resulting in widespread loss of employment. all of the factors mentioned above contribute towards mental health disorders among people. kaiser family foundation (kff) conducts health tracking polls in united states. there were two such polls conducted: (a) march - , , and (b) march - , . following are some of the findings from the two polls [ ] [ ] [ ] : (a) the poll conducted on march - , reported % of americans expressing that their lives were disrupted "a lot" or "some" by the covid- outbreak. this is a % increase from the poll conducted weeks earlier [ ] . (b) while % of the adults expressed concerns over being exposed to coronavirus while they were at work, % were worried that they or someone in their family would be sick from coronavirus [ ] . (c) about % worried that their investments would be negatively impacted by coronavirus for a long time [ ] . (d) while % worried that the economic downturn due to coronavirus would cause them to lose their jobs, % worried that they would lose income due to workplace closure or reduced work hours [ ] . psychiatric quarterly (e) about % were worried that the worst from the outbreak was yet to come [ ] . the above findings are directly related to the sharp increase in covid- cases and covid- related deaths in united states during the same period as indicated by figs. and . this suggests that the covid- pandemic and its effect on the economy in united states may lead to an increase in mental health illness in the country. in order to completely assess the effect of the covid- outbreak on the mental health, it is important to learn about the population groups susceptible to mental health illnesses: (a) elderly people: elderly people are particularly prone to mental illness during the current pandemic. over the past years in united states, the population age group and above increased from . healthcare is the fastest growing sector of the us economy [ ] . (d) children and teenagers: children and teenagers are prone to mental disorders during the current situation. in united states, the population group under years of age has increased from . million in to . million in [ ] . (e) people with past and family psychiatric history: people with past and family psychiatric history are particularly prone to mental illnesses. currently . % of american adult population has been experiencing mental health problems. this is equivalent to million people in united states [ ] . the pandemic and the associated economic downturn may trigger mental disorders of varying complexity within the american society. some of the common mental disorders may be classified as (i) psychotic disorders, (ii) mood disorders, and (iii) anxiety disorders [ ] . psychotic disorders are characterized by significant impairment of reality testing, and may be classified as disorders such as schizophrenia, schizophreniform disorders, schizoaffective disorders, brief psychotic disorders, and delusional disorders. schizophrenia is usually diagnosed through two or more of the following disorders being present for significant amount of time through a period of month. these disorders may be delusions, hallucinations, formal thought disorder, anhedonia, and avolition. anhedonia is the inability to feel pleasure and avolition is associated with decrease in motivation to perform selfdirected purposeful activities. schizophrenia is characterized by at-least months of continuous disturbance. the influenza pandemic of was caused by an influenza a viral strain. several reports exist that related the pandemic to onset of schizophrenia among the people [ ] [ ] [ ] . schizophreniform disorder is similar to schizophrenia with the exception that the episode of the disorder lasts for at least month but less than months. brief psychotic disorder is similar to schizophrenia, and is characterized by delusions, hallucinations, formal thought disorder, and avolition. the duration of this disorder is at least day but is less than month. schizoaffective disorder is characterized by delusions, hallucinations, formal thought disorder, anhedonia, and avolition. this may also be accompanied by a major mood episode and an uninterrupted period of illness. these are also characterized by delusions or hallucinations for weeks or more in the absence of a major mood episode during the period of illness. delusional disorder is associated with the presence of one or more delusions through a period of month or more. however, the other criteria for schizophrenia are never met. in addition to psychotic disorders, mood disorders may be very common among people during an outbreak [ , ] . these are characterized by combination of symptoms comprising a predominant mood state of abnormal quality and duration. mood disorders can be classified as mood episodes and mood disorders. major depressive mood episode is associated with symptoms such as depressed mood throughout the day, markedly diminished interest and pleasure, significant and unintentional weight loss, decrease or increase in appetite, or insomnia through a -week period. a manic episode is associated with a distinct period of persistent and abnormally elevated, expansive or irritable mood which may lead to increased goaldirected activity or energy lasting more than a week. this is also present through most part of the day. major depressive disorders are characterized by the depressive mood episodes which are not accounted for by schizoaffective disorder and are not superimposed on other diseases such as schizophrenia or schizophreniform disorder. persistent depressive disorders are characterized by depressed mood for most of the day, for more days than not, for a duration of years or more. these disorders are also associated with lack of appetite or overeating, insomnia or hypersomnia, fatigue, low self-esteem, poor concentration, and feeling of hopelessness. depressive disorders are twice as prevalent in females as in males. the peak prevalence age of depressive disorders is - years. recent stressors associated with the covid- pandemic such as illnesses, social isolation, depressive home environment, and financial hardship can cause depressive disorders. during previous influenza outbreaks, anxiety disorders have been reported in some articles [ , ] . anxiety disorders may result in social or occupational functioning being impaired. possible forms of anxiety disorders resulting from the covid- pandemic may be as follows: . panic disorder: this is characterized by an abrupt surge of intense fear and discomfort which may reach its peak within a few minutes. panic disorders are also characterized by symptoms such as palpitations and accelerated heart rate, perspiration, trembling, shortness of breath, feelings of choking, nausea or abdominal distress, dizziness, derealization, or depersonalization. this disorder is twice or thrice as common in women than in men. the average age of onset is early to mid- s. agoraphobia: this is determined by conspicuous fear of two or more of the following: using public transportation, being in open spaces, standing in a line or being in a crowd, or being outside of the home alone. the fear or anxiety may be persistent and may last for months or more. during the current covid- pandemic, social distancing has been suggested as an effective method to stop the disease from spreading. however, long-term social distancing may lead to agoraphobia among people. . obsessive-compulsive disorder: the obsessions are defined by recurrent and persistent thoughts or images that are experienced sometimes during the period of disturbance. these obsessions are intrusive and unwanted and cause distress and anxiety in most individuals. in the covid- pandemic, people are required to wash their hands as often as possible. however, excessive handwashing may develop into an obsessive-compulsive disorder among many. . phobic disorder: phobic disorders are associated with either specific phobia or social phobia. social phobia is defined as marked and persistent fear of situations where one is exposed to unfamiliar people or possible scrutiny by others. the current situation during the covid- pandemic and pro-longed social distancing although necessary, may facilitate social phobia among people. . post-traumatic stress disorder: post-traumatic stress disorder may result from someone being exposed to actual or threatened death, serious injury, or sexual violence either through direct experience, or by witnessing the event in another person. the disorder may also be developed in a person when they learn about the trauma occurring to someone they know. the increasing number of covid- deaths as shown by fig. may result in widespread post-traumatic stress disorders among people. . substance-related and addictive disorders: these are neurobiological disorders that involve compulsive seeking and usage of drugs and alcohol, despite adverse consequences with loss of control over drug and alcohol. substance abuse is common during disease outbreaks and pandemics [ , ] . a recent report suggests as many as , americans being at risk of dying from drug/alcohol abuse or suicide due to coronavirus related despair [ ] . . illness anxiety disorder: this is a disorder that is defined as the preoccupation of fear of having a serious disease to the point of causing significant impairment. a person may engage in maladaptive behavior such as excessive physical checking or total healthcare avoidance. this disorder can continue for a duration longer than months and the usual onset is in the s or s. . sleep disorders: adequate sleep is extremely necessary for normal functioning of human body. sleep deprivation can lead to cognitive impairment and increased mortality. several reports suggest that influenza disease outbreaks lead to chronic sleep disorders [ , ] . . eating disorders: eating disorders are characterized by persistent disturbance of eating that impairs functioning of health. anorexia nervosa is an eating disorder where people develop unwarranted fear of being overweight and as a result may severely impair their health by starvation and over-exercise. binge-eating disorder is associated with eating much more rapidly than normal and eating until one feels uncomfortably full. bulimia nervosa is a disorder characterized by recurrent episodes of overeating, and a recurrent inappropriate compensatory behavior in order to prevent weight gain, such as self-induced vomiting, fasting, excessive exercise, and inappropriate use of laxatives. a recent article argued that fear experiences during the current pandemic may be modeled as a relationship between four interrelated dialectical domains such as: (i) fear of/for the body (ii) fear of/for significant others (iii) fear of knowing/not knowing (iv) fear of taking action/fear of inaction [ ] . in the following section, the authors discuss strategies that may be useful towards preventing/mitigating mental illnesses due to the above-mentioned fears. fear of/for the body is associated with the fear of being infected and ultimately dying from the infection. the fear of being infected may be managed by curtailing physical contact. however, the authors recommend keeping close contact with family and friends through electronic and social media. a recent study suggested facetime being useful to reduce behavioral problems in nursing home patients suffering from dementia during the current covid- crisis [ ] . fear of/for significant others relates to a person's worries regarding being infected by or infecting his/her significant others. likewise, the fear of taking action/inaction is related to consequences related to human interpersonal behavior during the pandemic. for instance, a person's sense of visiting and caring for his elderly parents may interfere with his fear of infecting them. people are therefore deprived of their normal roles of caring for or being cared for by their significant others, which may lead to sense of solitude. one way of preventing solitude is by developing a supportive network where people may share each other's worries and discuss strategies. the authors suggest healthy expression of emotions and thoughts as a way of avoiding mental illnesses as they should avoid suppression of sadness or anxiety during the current crisis period. the fear of knowing/not knowing concerns with the limited availability of information regarding the disease. often times inadequate knowledge leads to misinformation and unnecessary panic among the people. therefore, people should limit their exposure to pandemicrelated news because too much information may lead to the anxiety disorders mentioned above [ ] . the pandemic and the corresponding economic downturn have resulted in unemployment, and this may lead to both anxiety and psychotic disorders among the people [ ] . in many cases long term unemployment can lead to disruption of family life resulting in divorce [ , ] . it is believed that fear of losing employment can be minimized through positive thinking. in the unfortunate event of loss of employment, a person may focus on improving his/her qualifications and skills that make him/her more marketable to the industry. the authors suggest maintaining healthy eating and sleeping habits as effective methods towards preventing mental illnesses during the current outbreak. a previous research has reported mindful eating being useful towards reducing depressive symptoms [ ] . several previous reports have shown direct relationships between maintaining a healthy sleep cycle and avoiding mental illnesses [ ] [ ] [ ] [ ] . performing yoga have been proven to be beneficial towards managing mental health [ ] [ ] [ ] . a previous study reported the effectiveness of managing trauma using yoga due to separate conditions which included unprecedented natural disasters such as tsunami [ ] . the authors suggest practicing yoga and meditation to manage mental health during the current covid- crisis. the center for disease control (cdc) has published several guidelines for coping with the pandemic [ , ] . among these are guidelines that are relevant to healthcare professionals and responders. responding to the covid- crisis could take an extremely heavy emotional toll on healthcare professionals. the healthcare professionals during the current pandemic are in the 'war zone' attending infected patients. often, healthcare workers have to take very difficult decisions such as allocating scant resources to patients that are equally needy. therefore, in addition to the risk of being infected, the healthcare professionals are subjected to secondary traumatic stress. secondary traumatic stress reactions result from direct exposure to another individual's traumatic experiences. such traumatic experiences among healthcare workers may cause 'moral injury' or mental illnesses. moral injury is defined as the psychological distress that arises from actions or lack of actions and violates a person's moral or ethical code [ ] . the authors suggest that healthcare professionals in the country should regularly monitor their own secondary mental traumatic stress symptoms such as fear, withdrawal, and guilt. they should allow more time for themselves and their families to recover from responding to the pandemic. the healthcare workers should be made aware of the current grim situation in hospitals. they also need to be prepared for the moral dilemma that they may be facing at work. the government should take adequate measures to prepare and train healthcare professionals for their work and associated challenges to reduce the risk of mental health illnesses among them [ ] . the healthcare professionals should be provided with a complete and honest assessment of the situations that they may have to face. forums such as schwartz rounds should be designed to help the healthcare workers safely discuss and share the emotional challenges associated with caring of patients [ ] . reports suggest that support from immediate supervisors, colleagues, and line managers protects mental health of professionals [ ] . medical health care professionals who are either too busy to attend meetings or avoid them altogether may need help and the immediate supervisors may need to identify such situations. finally, during an outbreak, in addition to being subjected to uncertainty, job demands, and the fear of infecting their family members, the healthcare workers may also experience social stigmatization on certain occasions [ , ] . stigmatization can significantly hamper the work performances of healthcare professionals. in the current situation, the government and the people of the country should strongly support healthcare workers in order to help them perform to the best of their abilities. first case of novel coronavirus in the united states secretary azar declares public health emergency for united states for novel coronavirus. in: us department of health and human services pandemic fear" and covid- : mental health burden and strategies inevitable isolation and the change of stress markers in 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diagnosis of ptsd and severe mental illness yoga for rehabilitation: an overview yoga for anxiety: a systematic review of the research evidence effect of iyengar yoga on mental health of incarcerated women: a feasibility study managing mental health disorders resulting from trauma through yoga: a review airborne or droplet precautions for health workers treating covid- ? covid- stress, coping, and adherence to cdc guidelines managing mental health challenges faced by healthcare workers during covid- pandemic risk factors for post traumatic stress disorder amongst united kingdom armed forces personnel reflection for all healthcare staff: a national evaluation of schwartz rounds social stigma during covid- and its impact on hcws outcomes publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations barnali bhattacharjee completed her undergraduate degree in medicine and surgery (mbbs) from gauhati medical college, india in . through the next years, she worked as a medical and health officer employed by the state of assam in india acharya has a phd in mechanical engineering from louisiana state university. he is presently working as an assistant professor at california state university, bakersfield. he has research interests in several areas of engineering including thermo-fluid applications into medicine key: cord- -xihpfidg authors: ford, julian d.; grasso, damion j.; elhai, jon d.; courtois, christine a. title: social, cultural, and other diversity issues in the traumatic stress field date: - - journal: posttraumatic stress disorder doi: . /b - - - - . -x sha: doc_id: cord_uid: xihpfidg this chapter describes how the impact of psychological trauma and posttraumatic stress disorder (ptsd) differ, depending on individual differences and the social and cultural context and culture-specific teachings and resources available to individuals, families, and communities. a social-ecological framework is used to differentiate the impact of exposure to traumatic stressors and the development of (or resistance to) ptsd, based on the individual’s or group’s (i) personal, unique physical characteristics, including skin color, racial background, gender, and sexual orientation; and (ii) family, ethnocultural, and community membership, including majority or minority group status, religious beliefs and practices, socioeconomic resources, and political and civic affiliations. while personal, familial, social, and cultural factors can be a positive resource contributing to safety and well-being, they also can be a basis for placing the person, group, or entire community or population in harm’s way or at heightened risk of developing ptsd. this is an adaptive response in one sense, providing an awareness and readiness to respond should the genocide or any associated forms of stigma, discrimination, or violence ever recur with impunity. however, it can also become a form of persistent hypervigilance similar to that seen in ptsd, placing a strain upon the individual's or group's daily life that may compromise their well-being. our discussion of the impact of exposure to traumatic stressors and ptsd on ethnoracial groups and individuals whose forebears have experienced historical trauma will bear this fact in mind. in addition, gender-based biases and beliefs, many of which are based on longstanding religious and cultural traditions, have caused women to be systematically discriminated against and subject to routine physical and sexual assault. genderbased discrimination and violence against females (whether intra-or extrafamilial) have been so widespread as to be implicated in what kristof and wudunn ( ) term "gendercide." in their recent book, they cite examples of selective abortions based on a fetus's gender and differential nutrition and care beginning in infancy also based on gender preference. they are then often followed by lifelong major disparities in education and restricted role and career opportunities for females as compared to males. unfortunately, even today, with all the advances that have occurred predominantly in western societies, these same issues remain in place around the world. the increased recognition of the underclass status of the majority of women and girls and the discrimination they face, along with the violence perpetrated against them (often seemingly with impunity), in countries around the world (whether industrialized and "advanced," or relatively primitive) has led to the recent development of major initiatives against global violence and discrimination against women. malala yousafzai, who was shot by the taliban for her espousal of universal education for girls, was awarded the nobel peace prize, the youngest recipient to date. the brutality of the attack against her was shocking, yet it served to highlight the traumatic threat to which many girls and women across the world are exposed when targeted for hateful acts by those who believe this is necessary to maintain the status quo and the subservience of females. discrimination and violence based on sexual orientation and transgender/intergender status are yet other sources of traumatic victimization that must be well recognized. sexual orientation is both a personal and social characteristic that is more complex than the gender that a person inherits based on inborn sexual characteristics. when socially ascribed gender and culturally promulgated expectations for gender-based activities, such as mating, are a mismatch to an individual's sense of his or her own true sexual preferences and identity, the conflict can be psychologically devastating. global initiatives therefore are underway to prevent or ameliorate the adverse impact of discrimination, stigma, and violence based on sexual orientation and identity providing an essential foundation for the basic liberties, freedom from assault, and the right to marry to gay, lesbian, bisexual, and transgendered (glbt) individuals. it should also be noted that boys and men are also subject to abuse and assault at rates that are not yet adequately researched. males may be more subject to violence when they are in a position of vulnerability of some sort due to being a member of a group that is targeted and/or of lesser status/lesser strength. depending on social, cultural, and other diversity issues in the traumatic stress field their cultural background and its traditions and beliefs, individuals may also have "multiple vulnerability status"-that is, to be members of more than one group or to have characteristic that cause them to be even more susceptible to discrimination or victimization (i.e., adolescent black male in the united states; a baby born with physical or developmental disabilities in a culture that endorses selective resources to the ablebodied; a gay man or lesbian woman of color in a highly homophobic and racist society). age is yet another vulnerability factor dimension that has not received adequate recognition, with individuals at either end of the life span as most vulnerable. research has substantiated that children and adolescents are the most at-risk segment of the population globally (finkelhor, ) . victimization of the elderly and the lessabled/disabled members of the population is now documented as widespread in many societies and is increasingly under investigation. like other forms of abuse, victimization of the elderly and less-abled is often based on the victim's relative degree of dependence and his powerlessness to defend himself. the extent and impact of exposure to traumatic stressors experienced by each of these vulnerable populations is discussed in this chapter, as are the efforts of international non-governmental organizations (ngos) to provide them with resources to reduce their exposure to traumatic stressors or to mitigate the adverse effects of traumatic exposure and ptsd (box . ). box . key points . culture, ethnicity, gender, sexual orientation, and disability are potential sources of resilience, but they also may lead to chronic stressors such as social stigma, discrimination, and oppression, which can increase psychological trauma and ptsd. . cumulative adversities are faced by many persons, communities, ethnocultural minority groups, and societies that may lead to-as well as worsen the impact of-ptsd: • persons of ethnoracial minority backgrounds; • persons discriminated against due to gender or sexual orientation; • persons with developmental or physical disabilities; • economically impoverished persons and groups, including the homeless; • victims of political repression, genocide, "ethnic cleansing," or torture; • persons chronically or permanently displaced from their homes and communities due to catastrophic armed conflicts or disasters. . members of ethnoracial minority groups have been found to be more likely in some cases to develop ptsd than other persons, but in other cases they are less likely to develop ptsd (e.g., persons of asian or african descent). . members of ethnoracial minority groups often encounter disparities in access to social, educational, economic, and health care resources; it is these disparities that are the most likely source of the increased vulnerability of these persons to psychological trauma and ptsd. (continued ) to psychological trauma in the immediate or most distant past, or both. psychological trauma and ptsd occur across the full spectrum of gender, racial, ethnic, and cultural groups in the united states (pole, gone, & kulkarni, ) . psychological trauma and ptsd are epidemic internationally as well, particularly for ethnoracial minority groups (which include a much broader range of ethnicities and cultures and manifestations of ptsd than typically recognized in studies of ptsd in the united states; de jong, komproe, spinazzola, van der kolk, & van ommeren, ; de jong, komproe, & van ommeren, ) . the scientific and clinical study of ptsd and its treatment among gender and ethnoracial majority and minority groups is of great importance, especially given the disparities, adversities, and traumas to which they have been subjected historically (miranda, mcguire, williams, & wang, )-and to which they are still exposed in health and health care, education and income, and adult criminal and juvenile justice (ford, ) . although latinos (and possibly african americans) persons are at greater risk than european americans for ptsd based on available research findings (pole, gone, & kulkarni, ) , it is possible that the elevated prevalence may be due to differences in the extent or types of exposure to psychological trauma (including prior traumas that often are not assessed in ptsd clinical or epidemiological studies; eisenman, gelberg, liu, & shapiro, ) or to differences in exposure to other risk or protective factors such as poverty, education, or gender-based violence (turner & lloyd, , . in addition, there is sufficient diversity (in norms, beliefs, values, roles, practices, language, and history) within categorical ethnocultural groups such as african americans or latinos to call into question any sweeping generalizations about their exposure and vulnerability or resilience to psychological trauma (pole et al., ) . race, ethnicity, gender and sexual identity, and culture tend to be described with shorthand labels that appear to distinguish homogeneous subgroups but that actually obscure the true heterogeneity within as well as between different groups (marsella, friedman, gerrity, & scurfield, ) . one partial antidote for this problem is for clinicians and researchers to be curious about these issues and to ask study participants or clinical patients to self-identify their own racial, ethnic, and cultural background and to essentially educate them about their unique characteristics and associated belief systems and traditions (brown, ; brown, hitlin, & elder, ) . it also is important to carefully assess factors that are associated with differential exposure to adverse experiences (such as racial-ethnic discrimination) or differential access to protective resources (such as income, health care, education, police protection), rather than assuming that each member of an ethnocultural group is identical on these crucial dimensions. however, when systematic disparities in exposure to stressors or deprivation of resources are identified for specific groups, such as persons from indigenous culturesthe original inhabitants of a geographic area who have been displaced or marginalized by colonizing national/cultural groups-are found to have a generally increased risk of discrimination, poverty, addiction, family violence, and poor health (harris et al., ; liberato, pomeroy, & fennell, ) , it is crucial not to mistakenly conclude that those persons are less resilient than others when they are confronted with traumatic stressors. commonly, the very opposite is true: persons and groups who are subjected to chronic stressors or deprivations tend to be more resilient than others, but they also are more exposed to and less protected from traumatic stressors (pole et al., ) . racism and associated discrimination and mistreatment are particularly chronic stressors faced by many members of ethnoracial and other minority groups. racism may constitute a form of psychological trauma in and of itself, increasing the risk of exposure to psychological trauma, and exacerbating its impact by increasing the risk of ptsd (ford, ) . as of yet, few systematic studies have directly examined racism as a risk factor for exposure to psychological trauma, although the connection is increasingly recognized (carter & forsyth, ; hunter & schmidt, ; miller, ) . perhaps, the holocaust and other forms of genocide have been the most investigated to date. studies of survivors of the holocaust and other types of ethnic annihilation provide particularly graphic and tragic evidence of the infliction of psychological trauma en masse in the name of racism (staub, ; yule, ) . studies are needed that systematically compare persons and groups who are exposed to different types and degrees of racism in order to test whether (and under what conditions) racism is a form of, or leads to exposure to other types of, traumatic stressors (ford, ) . when racism leads to the profiling and targeting of ethnoracial minority groups for violence, dispossession, dislocation, or annihilation, the risk of ptsd increases in proportion to type and degree of the traumatization involved (pole et al., ) . for example, studies based in the united states (pole et al., ) and internationally (macdonald, chamberlain, & long, ) suggest that racial discrimination may have played a role in placing military personnel from ethnoracial minority groups at risk for more extensive and severe combat trauma exposure. one study found that self-reported experiences of racial discrimination increased the risk of ptsd among latino and african american police officers (pole, best, metzler, & marmar, ) . another study with asian american military veterans from the vietnam war era showed that exposure to multiple race-related stressors that met ptsd criteria for psychological trauma was associated with more severe ptsd than when only one or no such race-related traumas were reported (loo, fairbank, & chemtob, ) . this study more precisely operationalized racism than any prior study, utilizing two psychometrically validated measures of race-related stressors and ptsd. however, as in the pole et al. ( ) study, the stressors/traumas and ptsd symptoms were assessed by contemporaneous self-report, so the actual extent of racism experienced by the participants cannot be definitely determined. the loo et al. ( ) study also did not control for traumatic stressor exposure other than that which was related to racism. in order to extend the valuable work these studies have begun, it will be important to utilize measures based on operationally specific criteria for categorizing and quantifying exposure to discrimination (e.g., wiking, johansson, & sundquist, ) as a distinct class of stressors that can be assessed separately as well as concurrently with exposure to psychological trauma. research also is needed to determine to what extent the adverse outcomes of racial disparities are the direct result of racism as a stressor (e.g., racially motivated stigmatization, mistreatment, subjugation, and deprivation resulting in personal and community depression and destabilization), as opposed to the indirect effects of racism (such as microaggressions that accrue over time). racism can also indirectly reduce access to protective factors (adequate nutrition and other socioeconomic and community resources) that protect against the adverse effects of stressors (such as poverty, pollution, disaster) and traumatic stressors (such as accidents, crime, or violence). hurricane katrina and its aftermath provided just such an example. it is important to determine whether ptsd is the product of either the direct or indirect effects of racism, or both, particularly given its demonstrated association with other psychiatric conditions (such as depression, anxiety, and addiction) and with increased risk of physical illness (such as cancer and cardiovascular disease) in ethnoracial minorities (e.g., among american indians; sawchuk et al., ) . education is a particularly relevant example of a socioeconomic resource to which ethnoracial minorities often have restricted access as that as a protective factor mitigating against the risk of ptsd (dirkzwager, bramsen, & van der ploeg, ) and overall health status (wiking et al., ) . racial disparities in access to education are due both to direct influences (such as lower funding for inner-city schools that disproportionately serve minority students) and indirect associations with other racial disparities (such as disproportionate juvenile and criminal justice confinement of ethnoracial minority persons). racial disparities in education are both the product of and a contributor to reduced access by minorities to other socioeconomic and health resources (such as income, health insurance, adequate nutrition) (harris et al., ) . when investigating risk and protective factors for ptsd, it is essential therefore to consider race and ethnicity in the context not only of ethnocultural identity and group membership but also of racism and other sources of racial disparities in access to socioeconomic resources. although all ethnoracial minority groups tend to be disproportionately disadvantaged with regard to the more privileged majority population, particularly severe disparities in access to vital resources often are complicated by exposure to pervasive (both intrafamilial and community) violence and by the loss of ties to family, home, and community. when family and community relationships are severed-as occurs with massive political upheaval, war, genocide, slavery, colonization, or catastrophic disasters-racial and ethnocultural groups may find themselves scattered and subject to further victimization and exploitation. for example, there continue to be massively displaced populations in central and south america, the balkans, central asia, and africa. when primary social ties are cut or diminished as a result of disaster, violence, or political repression, the challenge expands beyond survival of traumatic life-threatening danger to preserving a viable life, community, and culture in the face of lifealtering losses and suppression of those very factors needed to maintain (garbarino & kostelny, ; rabalais, ruggiero, & scotti, ) . ethnoracial groups that have been able to preserve or regenerate core elements of their original cultural norms, practices, and relationships within intact or reconstituted families may actually be particularly resilient to traumatic stressors and protected against the development of ptsd. for example, persons of asian or african descent have been found to be less likely than those of other ethnocultural backgrounds to develop ptsd. whether this is due to factors other than ethnicity per se, such as having cultural practices and beliefs that sustain family integrity and social ties, is a question that has not been scientifically studied and should be a focus for research (pole et al., ) . a recurring theme is that the psychological trauma inflicted in service of racial discrimination may lead not only to ptsd but also to a range of insidious psychosocial problems that result from adverse effects upon the psychobiological development of the affected persons. when families and entire communities are destroyed or displaced, the impact on the psychobiological development of children and young adults may lead to complex forms of ptsd that involve not only persistent fear and anxiety but also core problems with relatedness and self-regulation of emotion, consciousness, and bodily health that are described as "complex ptsd" (herman, ) or "disorders of extreme stress" (de jong et al., ) . a critical question not yet answered by studies of ptsd and racial discrimination (pole et al., ) and race-related stress (loo et al., ) , as well as by the robust literature that shows evidence of intergenerational transmission of risk for ptsd (kellerman, ) , is whether racism constitutes a "hidden" (crenshaw & hardy, ) or "invisible" (franklin, boyd-franklin, & kelly, ) form of traumatization that may be transmitted across generations. recent research findings demonstrating highly adverse effects of emotional abuse in childhood (teicher, samson, polcari, & mcgreenery, ) are consistent with a view that chronic denigration, shaming, demoralization, and coercion may constitute a risk factor for severe ptsd and associated psychobiological problems. research is needed to better describe how emotional violence or abuse related to racism may (along with physical violence) constitute a form of traumatic stress and how this may adversely affect not only current but also future generations. a fully articulated conceptual model for the scientific study and social/clinical prevention and treatment of the adverse impact of psychological trauma and ptsd requires principles and practices informed by this diversity of factors, rather than a "black and white" view of race, ethnicity, or culture that misrepresents the individual's and group's heritage, nature, and needs. treatment preferences, in terms of characteristics of the therapist as well as the therapy model, differ substantially not only across but also within ethnoracial groups (pole et al., ) . as a result, it is not possible as yet-and may never be possible-to precisely prescribe how best to select or train therapists and design or adapt therapies to fit different ethnocultural groups and the individuals within them. a culturally competent (brown, (brown, , a (brown, , b approach to treating ptsd (ford, ) begins with a collaborative discussion in which the therapist adopts the stance of a respectful visitor to the client's outer and inner world-clarifying the client's expectations and preferences, and the meaning of sensitive interpersonal communication modalities (such as spatial proximity, gaze, choice of names, private versus public topics, synchronizing of talk and listening, use of colloquialisms, providing advice or education). ptsd therapists thus must avoid stereotypic assumptions and become both a host and guest in the client's psychic world in order to ensure that assessment and treatment are genuinely collaborative and sensitive to each client's ethnocultural traditions, expectations, goals, and preferences (parson, ; stuart, ) . at times, it is helpful to involve other members of the family or culture in assisting with the treatment. religious beliefs and spirituality are other dimensions of culture that have not yet been given sufficient focus in most psychotherapy but must also be assessed and understood by the therapist (walker, courtois, & aten, ) . cultural competence means many things to many people, and unfortunately, it is often mistakenly equated with being of the same racial, ethnic, cultural, religious, or national background as the persons involved in a study or receiving services, or knowing in advance exactly what each person believes and expects, how they communicate with and are most receptive to learning from others, and what their experience has been in relation to sensitive matters such as psychological trauma or ptsd. this is likely to be a serious mistake for several reasons. sharing some general racial, ethnic, cultural, or national features (or an apparently identical language or religion) is not synonymous with shared identity, knowledge, or history. even persons from as virtually identical backgrounds as monozygotic twins raised in the same family have substantial differences in physical and temperamental characteristics as well as often quite distinct social learning histories, and thus rarely if ever can reliably read one another's minds or exactly know one another's vulnerabilities and strengths. therefore, cultural competence should not be defined in terms of stereotypic assumptions about identity or prescience but instead based upon a respectful interest in learning from each person and community what they have experienced and how they understand and are affected by psychological trauma and ptsd. we should also note that the idioms of distress can differ by culture and tradition. professionals from industrialized nations and anglo cultures must be cautious and respectful in working with individuals and communities from other cultures that are challenged by ptsd in the aftermath of exposure to violence or disasters. before offering or providing education or therapeutic assistance, it is essential to become aware of how the potential recipients understand and prefer to communicate about traumatic stress and the process of healing from traumatization. the implication for psychometric assessment of psychological trauma and ptsd with clients of ethnocultural minority groups (hall, ; marsella et al., ) is that it is essential to carefully select protocols that do not confront individuals with questions that are inadvertently disrespectful of their values or practices (e.g., including peyote as an example of an illicit drugs in a native american tribe that uses it for religious rituals), irrelevant (e.g., distinguishing blood family from close friends in a group that considers all community members as family), or incomplete (e.g., limiting health care to western medical or therapeutic services, to the exclusion of traditional forms of healing). a systematic assessment of trauma history and ptsd thus should include not only a recitation of events in a person's life and symptomatic or resilient responses in the aftermath but how the person interpreted these events and reactions based on their cultural framework, beliefs, and values (manson, ) . interventions for prevention or treatment of ptsd typically have been developed within the context of the western medical model (parson, ; but see andres-hyman, ortiz, anez, paris, & davidson, ; hinton et al., ; hwang, , for examples of culturally sensitive adaptations). evidence-based ptsd treatment models are not necessarily incompatible with culturally specific healing practices and have in common the goal of fostering not just symptom reduction but a bolstering of resilience and mastery (see chapters and ). the integration of culturally specific methods and rituals in prevention or treatment interventions for ptsd, however, requires careful ethnographic study (i.e., observing and learning about the values, norms, beliefs, and practices endorsed and enforced by different cultural subgroups and their particular idioms (ways of describing and explaining) traumatic stress and ptsd) so the ptsd clinician and researcher can truly work collaboratively withrather than imposing external assumptions and standards upon-the members of the wide range of ethnic and cultural communities. in most cultures, girls and women are subject to discrimination in the form of limitations on their access to crucial socioeconomic resources. women earn - % lower wages or salaries than men in most job classes in the united states (http://www.payequity.org/info.html) and europe (http://www.eurofound.europa.eu/ewco/ / / es i.htm). although girls and women are approaching parity with boys and men in access to education in most areas of the world (and exceed the enrollment of boys or men in secondary and college/university education), in sub-saharan africa and asia, women and girls are as much as % less likely to be able to enroll in education and to have achieved literacy as adults (http://www.uis.unesco.org/template/ pdf/educgeneral/uisfactsheet_ _no% _en.pdf). girls and women also may be systematically subjected to extreme forms of psychological and physical trauma as a result of their gender being equated with second-class citizenship and social norms that permit or even encourage exploitation. sexual exploitation of women and girls is an international epidemic, including abuse and molestation, harassment, rape and punishment of rape victims, forced marriage, genital mutilation, and sex trafficking or slavery (box . ). physical abuse or assault of women and girls is tolerated-and in some cases actually prescribed as a form of social control-in both mainstream cultures and subcultures that span the globe and include most religions and developed as well as developing or preindustrial societies. similar potentially traumatic forms of violence are directed at many glbt persons as a result of both formal and informal forms of social stigma and discrimination. epidemiological studies have been conducted with samples of glbt youth (d'augelli, grossman, & starks, ) and adults (herek, ) in the united states, suggesting that they are often subjected to potentially traumatic violence as a result of their nontraditional sexual orientation and behavior. instances of violence specifically related to sexual orientation include: • - % of gay men and % of lesbians who were physically assaulted in the past year; • - % of glb adults who were subjected to actual or threatened violence toward their person or a property crime at some point in their lives; • - % of glb adolescents reported past incidents of physical or sexual violence. in contrast to the general pattern of stigma-related violence being directed toward girls and women, gay and bisexual boys (d'augelli et al., ) and men (herek, ) were more likely to report violent victimization or threats than lesbian or bisexual women or girls. the findings from the survey of glb adolescents suggest that stigma and victimization begin early in life, with physical and sexual attacks occurring as early as ages - years old. one in eleven glb adolescents met criteria for ptsd, box . "making the harm visible": sexual exploitation of women and girls women from every world region report that the sexual exploitation of women and girls is increasing. all over the world, brothels and prostitution rings exist underground on a small scale, and on an increasingly larger scale, entire sections of cities are informally zoned into brothels, bars, and clubs that house, and often enslave, women for the purposes of prostitution. the magnitude and violence of these practices of sexual exploitation constitute an international human rights crisis of contemporary slavery. in prostitution: a form of modern slavery, dorchen leidholdt, the coexecutive director of the coalition against trafficking in women, examines the definitions of slavery and shows how prostitution, and related forms of sexual exploitation, fit into defined forms of slavery. in some parts of the world, such as the philippines, prostitution is illegal but well entrenched from providing "recreational services" to military personnel. in "blazing trails, confronting challenges: the sexual exploitation of women and girls in the philippines," aida f. santos describes the harmful conditions for women and girls in prostitution in the philippines, with problems related to health, violence, the legal system, and services. in other regions, such as northern norway, organized prostitution is a more recent problem, stemming from the economic crisis in russia. in "russian women in norway," asta beate håland describes how an entire community is being transformed by the trafficking of women for prostitution from russia to campgrounds and villages across the border in norway. political changes combined with economic crises have devastated entire world regions, increasing the supply of vulnerable women willing to risk their lives to earn money for themselves and their families. aurora javate de dios, president of the coalition against trafficking in women, discusses the impact of the southeast asian economic crisis on women's lives in "confronting trafficking, prostitution and sexual exploitation: the struggle for survival and dignity." economic globalization controlled by a handful of multinational corporations located in a few industrialized countries continues to shift wealth from poorer to richer countries. in her paper "globalization, human rights and sexual exploitation," aida f. santos shows us the connection between global economics and the commodification and sexual exploitation of women and girls, especially in the philippines. structural adjustment programs implemented by international financial institutions impose loan repayment plans on poor countries, which sacrifice social and educational programs in order to service their debt to rich nations and banks. fatoumata sire diakite points to structural adjustment programs as one of the factors contributing to poverty and sexual exploitation in her paper "prostitution in mali." zoraida ramirez rodriguez writes in "report on latin america" that the foreign debt and policies of the international monetary fund are primary factors in creating poverty for women and children. these forces leave women with few options, increasing the supply of women vulnerable to recruitment into bride trafficking and the prostitution industry. (continued ) social problems such as sexual and physical abuse within families force girls and women to leave in search of safety and a better life, but often they find more exploitation and violence. physical and sexual abuse of girls and women in their families and by intimate partners destroys girls' and women's sense of self and resiliency, making them easy targets for pimps and traffickers who prey on those who have few options left to them. these factors are evident in many of the papers from all world regions in this volume, such as jill leighton and katherine depasquale's, "a commitment to living," and martha daguno's, "support groups for survivors of the prostitution industry in manila." government policies and practices also fuel the demand for prostitution, as they legalize prostitution or refuse to enforce laws against pimps, traffickers, and male buyers. in making the harm visible, we see how countries with governmental structures and ideological foundations as different as the netherlands and iran, both promote and legalize sexual violence and exploitation of girls and women. in "legalizing pimping, dutch style," marie-victoire louis exposes the liberal laws and policies that legalize prostitution and tolerate brothels in the netherlands. at the other extreme, religious fundamentalists in iran have legalized the sexual exploitation of girls and women in child and temporary marriages and the sexual torture of women in prison. sarvnaz chitsaz and soona samsami document this harm and violation of human rights in "iranian women and girls: victims of exploitation and violence." global media and communication tools, such as the internet, make access to pornography, catalogs of mail-order brides, advertisements for prostitution tours, and information on where and how to buy women and girls in prostitution widely available. this open advertisement normalizes and increases the demand by men for women and girls to use in these different forms of exploitation. donna m. hughes describes her findings on how the internet is being used to promote the sexual exploitation of women and children in "the internet and the global prostitution industry." in this milieu, women and girls become commoditiesbought and sold locally and trafficked from one part of the world to another. how do we make the harm of sexual exploitation visible? in a world where sexual exploitation is increasingly normalized and industrialized, what is needed to make people see the harm and act to stop it? the women in making the harm visible recommend four ways to make the harm of sexual exploitation visible: listen to the experiences of survivors, expose the ideological constructions that hide the harm, expose the agents that profit from the sexual exploitation of women and children, and document harm and conduct research that reveals the harm and offers findings that can be used for policy initiatives. reprinted with permission from the introduction to making the harm visible, edited by d. hughes - times the prevalence of children (copeland, keeler, angold, & costello, ) and adolescents (kilpatrick et al., ) in national samples in the united states. although gender and sexual orientation may seem intuitively to be simpler phenomena than race or ethnicity, in reality they are quite complex in terms of referring to not just biological characteristics but many aspects of psychological identity and social affiliations. being a female or a male, let alone gay, lesbian, bisexual, or transgendered/ intergendered, means many different things to different people. although more stable than changeable, sexual orientation and even gender may be changed for the same person over time. it is inaccurate to assume that all or even most people of a given gender or sexual orientation are identical or even similar without careful and objective assessment of how they view themselves and how they actually act, think, and feel. in relationship to psychological trauma and ptsd, therefore, the broad generalizations that have been suggested by research concerning gender and sexual orientation relate more to the way in which people of a gender or sexual orientation are generally viewed and treated (which varies, depending on the society and culture) than to inherent qualities of a given gender or sexual orientation (which is highly individual across all societies and cultures). the finding that girls and women are more often subjected to sexual and intrafamilial traumatic stressors, while boys and men more often experience physical, accidental, combat, and assaultive traumatic stressors is consistent with stereotypic sex roles that are found in many (but not all) cultures that assign females to the role of subservient helper and caregiver, while males are assigned to the role of leader and warrior. there are biological foundations for these differences-such as due to distinct levels of the sex-linked hormones estrogen and testosterone, and brain chemicals that differentially affect females and males (oxytocin and vasopressin; see chapter ). however, biology need not dictate a person's or a group's destiny, so it is inaccurate to assume that males or females must always fill these sex role stereotypes, particularly when there are severe adverse consequences, such as the epidemics of abuse of girls and women and of boys and men killed as violent combatants or as the "spoils of war." stereotypes can be even more insidious and damaging in relation to sexual orientation. only in the past decades has homosexuality been rescued from the status of a psychiatric disorder (as it was in the first three editions of the diagnostic and statistical manual). stigma and harassment evidently are still experienced, potentially with traumatic results when violent acts are tolerated or even encouraged, by glbt adults and youth. it is not surprising that the prevalence of ptsd is greater among persons with other than heterosexual sexual identities, and the extent to which this is the result of the pernicious stigma directed at such individuals in most cultures or of outright traumatic violence, or both, remains to be tested. persons with physical or developmental disabilities are another group of persons who unfortunately may be subjected to stigma and discrimination. physical disabilities are more common in developing countries than in more industrialized and affluent nations in which medical technology and accident and illness prevention have reduced the risk of severe injury or genetically based physical disabilities (mueser, hiday, goodman, & valentini-hein, ) . persons with physical disabilities may be at risk for exposure to traumatic accidents or maltreatment as children and as adults due to limitations in their abilities to care for themselves and live independently, particularly if they have cognitive impairment due to conditions such as mental retardation or serious mental illness. only one study that examined the prevalence of exposure to potentially traumatic events among physically disabled persons could be located. that was a national survey of women with physical disabilities by the center for research on women with disabilities (nosek, howland, & young, ) . on the one hand, the study found that disabled women were no more likely to report exposure to physical or sexual abuse than women without physical disabilities. however, in more detailed interviews with a subsample, more than % reported instances of abuse, on average two incidents per woman (each often lasting for a lengthy time period). for example, the report provides verbatim quotations: more than half of all respondents ( % with disabilities, % with no disability) reported a history of either physical or sexual abuse, or both, which is a substantially higher prevalence than that reported in epidemiological surveys of nationally representative samples of women. notably, women with disabilities were more likely than women without disability to report emotional abuse from a caregiver or family member and to have experienced all forms of abuse for a longer time period than women without disability. although ptsd was not assessed, women younger than years old with spina bifida ( %), amputation, traumatic brain injury (tbi), or multiple sclerosis (> %) were highly likely to be diagnosed with depression than women with no disability. in light of the extensive histories of potentially traumatic abuse and of depression, it appears that women with physical disabilities-particularly those in early to midlife adulthood with disabilities that involve progressive deterioration or mental or psychological disfiguration-may be at risk for having experienced traumatic interpersonal violence and other forms of abuse and suffering from undetected ptsd. tbi is a special case of physical disability because it involves physical injury that specifically compromises mental functioning. tbi ranges from mild (no more than minutes of unconsciousness and hours of amnesia) to severe (coma of at least hours or amnesia for more than hours). studies with adults and children of both genders who have sustained tbi demonstrate that they are as likely to develop ptsd as persons in equally severe accidents or assaults who have not (mcmillan, williams, & bryant, ) . fewer studies have been conducted with persons with severe than mild tbi, but they have not been found to be less likely to develop ptsd, as was originally hypothesized-due to not being able to experience or later recall the psychologically traumatic aspects of the injury as vividly as a person who does not lose consciousness or have amnesia. a subsequent study confirmed that adults with tbi were less likely to report acute traumatic stress symptoms immediately after the injury and to recall having felt helpless when interviewed several weeks later but that months after the accident, they were equally likely to report ptsd symptoms as injury survivors with no tbi (jones, harvey, & brewin, ) . tbi definitely exacerbates, and indeed may cause, ptsd, as tragically is illustrated by the extremely high estimates of prevalence of ptsd among military veterans of the iraq and afghanistan wars with tbi. thus, ptsd warrants careful assessment when tbi has occurred. concerning developmental disabilities, similarly, only one published study of ptsd could be located (ryan, ) . in that study, adults receiving services for learning disability were more likely than other adults (kessler, sonnega, bromet, & hughes, ) to report exposure to traumatic stressors ( % prevalence, on average two past traumatic events). however, they had no greater risk than adults in the general population when exposed to traumatic stressors. the most frequently reported types of traumatic exposures were multiple experiences of sexual abuse by multiple perpetrators (commonly starting in childhood), physical abuse, or life-threatening neglect. traumatic losses involving a caregiver or close relative or friend (including witnessing the death in several instances (such as witnessing a sibling dying in a fire, a close friend die during a seizure or an accident, or a parent commit suicide by shooting himself in the head with a gun)) were also reported by at least % of the participants. most of the learning-disabled adults who met criteria for ptsd had been referred for treatment for violent or disruptive behavior, typically with no psychiatric diagnosis or a diagnosis of schizophrenia, autism, or intermittent explosive disorder. when ptsd was diagnosed, major depression was a frequent comorbid disorder; yet, neither ptsd nor depression typically had been identified prior to the clinical assessment study. the findings of this study suggest that adults with developmental disorders often have been targets for abuse or neglect in childhood or have sustained severe traumatic losses and that their ptsd and depression tend to go undiagnosed as clinicians make their behavioral difficulties the focus of treatment services (box . ). poverty is an adverse result of having low "social status." this does not mean that a person or group is objectively deficient but rather that he or she is identified socially and politically as either not deserving or not possessing the social mandate to have access to resources such as money, safety, housing, transportation, health care and nutrition, education, and gainful employment. kubiak's ( ) social location theory states that each individual possesses identities within their society that are defined ( ) show the adverse impact of undetected ptsd: "a -year-old girl with a learning disability has suffered early abuse of a physical and sexual nature, including neglect. she presented [for medical evaluation] in early childhood with behavioral problems of aggression. she settled in a residential school from age to before an act of arson. she later revealed that she had experienced inappropriate sexual behaviors with peers at school. she complained of intrusive thoughts and images, along with depressive symptoms. at times she shows sexually inappropriate behavior and self-harm." "a -year-old man with a moderate learning disability who had been sexually assaulted by a care[giver] presented [for medical evaluation] in [an] acute state with disturbance of appetite, sleep, loss of skills, and emotional numbness, but the abuse was revealed only months later. on being exposed to the perpetrator at a later date, he showed a deterioration in mental state with acute symptoms of anxiety, and later developed a depressive disorder requiring medication. his level of functioning never returned to that prior to the traumatic event." a third case illustrates the therapeutic gains that a ptsd perspective can provide: a -year-old woman with learning disabilities and pervasive developmental disorder had been diagnosed at age with schizophrenia and subsequently had been diagnosed with schizoaffective disorder, bipolar disorder, and borderline personality disorder. for years after the first psychiatric diagnosis and hospitalization, she had been psychiatrically hospitalized more than times due to episodes of acute suicidality complicated by auditory command hallucinations (i.e., she believed she was hearing voices telling her to kill herself) and compulsive self-harm behavior (she used sharp objects to cut virtually every area on both arms and legs). treatment included high doses of antipsychotic, antiseizure, antidepressant, and antianxiety medications and two courses of electroconvulsive therapy, with periods of relative stabilization sufficient for her to live in an assisted living residential home and on two occasions to live in an independent apartment with in-home daily case management and nursing care. each period of improvement was relatively brief, lasting no longer than - months, at which time she experienced severe worsening in the apparently psychotic, depressive, and anxiety symptoms, requiring multiple rehospitalizations and progressive loss of social and cognitive abilities. for several years, family therapy was conducted, and the patient's history of traumatic stressors was assessed gradually in order not to lead to further destabilization. in addition to potential episodes of sexual assault as an adolescent and young adult, her mother disclosed that her biological father had been severely domestically violent during the patient's first years of life, until the mother ended that relationship. when ptsd was confirmed and accepted by the treatment team and the patient and her family as the primary diagnosis, the patient felt that she finally understood why she was experiencing the cyclic surges in distress and was able to utilize affect by factors such as their race, socioeconomic class, gender, age, residential status, and legal status. the greater the number of oppressed identities that one possesses, the more likely one will be "poor," including not only low income but also living in neighborhoods plagued with high crime, gang violence, abandoned buildings, drugs, teen pregnancy, high unemployment rate, underfunded schools, housing shortage, food of limited nutritional value, and unresponsive police. thus, poverty fundamentally is a breakdown of the social order as well as a resultant deprivation of resources for some people. the relationship between low income and exposure to psychological trauma and ptsd has been studied primarily in relationship to women and families, including those who currently have stable housing and those who do not. morrell-bellai, goering, and boydell ( ) identify poverty as a core risk factor for homelessness, because the socioeconomic benefits provided by a diminishing societal safety net and the typically insufficient employment wages provided by marginal jobs force people to rely on an increasingly limited pool of subsidized housing or to become homeless. associated risk factors include a lack of education, lack of work skill, physical or mental disability, substance abuse problem, minority status, sole support parent status, or the absence of an economically viable support system (fischer & breakey, ; morrell-bellai et al., ) . snow and anderson ( ) found that the most common reasons for homelessness reported in a survey of men and women living "on the street" were family-related problems such as marital breakup; family caregivers becoming unwilling or unable to care for a mentally ill or substance-abusing family member; escape from a dysfunctional and/or abusive family; or not having a family to turn to for support. poverty and homelessness involve a vicious cycle in which socioeconomic adversities are compounded by the experience of homelessness, leading to psychological disaffiliation, hopelessness, and loss of self-efficacy, and often substance dependence (bentley, ; hopper & baumohl, ; morrell-bellai et al., ) -which thus tends to perpetuate poverty and homelessness. a recent study by frisman, ford, lin, mallon, and chang ( ) reported that % of a sample of very low-income homeless women caring for children had experienced at least one type (and on average, five different types) of psychologically traumatic events, usually repeatedly and over long periods of time, with one in three having experienced full or partial ptsd at regulation skills (taught using dialectic behavior therapy and trauma affect regulation: guide for education and therapy; see chapter ). over the next year, her medications were carefully reduced to the lower therapeutic range for attentional problems and anxiety, with a sustained improvement in mood and social and cognitive functioning such that she was able to successfully work as a skilled volunteer in an assisted living center for older adults. some time in their lives. in addition, ford and frisman ( ) found that one in three of these homeless women with children had experienced a complex variant of ptsd involving problems with dysregulated affect or impulses, dissociation, somatization, and alterations in fundamental beliefs about self, relationships, and the future (i.e., "complex ptsd" or "disorders of extreme stress"; ford, ) . more than half of the sample had a history of either or both ptsd and its complex variant. exposure to violence and other forms of victimization begins in childhood for many homeless individuals, in part due to their exposure and the vulnerability of their living conditions (north, smith, & spitznagel, ) . rates of childhood physical abuse as high as % among homeless adolescents have been reported (maclean, paradise, & cauce, ) , and this figure may be on the low end. extremely poor women, whether homeless or not, have elevated rates of lifetime ptsd or other mental illness, and a history of such disorders is associated with having grown up in family and community environments with violence, threat, and anger (bassuk, dawson, perloff, & weinrub, ; davies-netzley, hurlburt, & hough, ) . however, homelessness per se may confer additional risk: homeless mothers and their children have higher lifetime rates of violent abuse and assault than equally impoverished housed mothers (bassuk et al., ) . thus, poverty puts people at risk for traumatic violence, but not having a stable residence compounds this risk and the likelihood of developing ptsd. victims of political repression, genocide ("ethnic cleansing"), and torture when political power is used to repress free speech and citizens' self-determination, there is an increase in the risk to members of that nation or community and its neighbors and associates of psychological trauma. domestic violence (see box . ) is a microcosm that shares much in common with large-scale political repression, because physical, psychological, and economic power is used to entrap, systematically break down, and coercively control the thoughts as well as the actions and relationships of the victim. on a larger scale, political repression involves similar psychological (and often physical as well) assaults by the people and institutions in power on the people, families, communities, and organizations that are deprived of access to political power and socioeconomic resources-and therefore also on their fundamental freedoms and values. without access to self-determination and the resources necessary to sustain independence, people are vulnerable to not just traumatic exploitation and violence but also to the traumatic loss of their intimate relationships, their families, their way of life, and their values (box . ). genocide (also described as "ethnic cleansing") involves the planned and systematic elimination of an entire collectivity of people, based on discrimination against them. historically, genocide has occurred often when conquering nations not only dominated and subjugated other nations but sought to eradicate their core culture and its leaders and teachers and to kill off or enslave the entire population. examples in the twentieth century include the armenian genocide in turkey, the holocaust box . the lost boys of sudan: complex ptsd in the wake of societal breakdown in the book what is the what?, by dave eggers ( ), valentino achak deng (a fictional character based upon a real person) provides an autobiography that includes his trials and tribulations in his current home in atlanta, georgia, after a traumatic journey of many years as a "lost boy" fleeing from his family's home in a rural village in southern sudan to refugee camps in ethiopia and kenya. valentino graphically describes a relentless series of traumatic experiences that include his village becoming a war zone, the deaths of family and friends, starvation and continual threats of being killed while traveling by foot with thousands of other "lost" children to escape sudan, witnessing brutal acts of violence by children as well as adults (e.g., a boy beating another boy to death in a fight over food rations), and being robbed and beaten unconscious in his own home in atlanta by a predatory african american couple. valentino is a good example of a person who suffers from chronic and complex ptsd, yet is extremely articulate, intelligent, and resourceful. valentino struggles with both unwanted memories and the need to keep his memories so that he ultimately can make sense of what has happened to him: what is the what? by writing his autobiography, he did what the therapy for children or adults with ptsd is intended to do: making sense of, rather than attempting to avoid, memories and reminders of traumatic experiences as a part-albeit horrible or tragic-of one's complete life story (see chapters and ). for example, in trauma-focused cognitive behavior therapy, the therapist helps the child to write (or in other creative ways to depict, such as by drawing pictures; using puppets, dolls, or action figures; or using collage or music) a "story" of what happened to them before, during, and after traumatic experience(s) and to share this "story" with a parent who can help the child with feelings of guilt and fear so that the traumatic memory can be "over" in the child's mind. because valentino was not able to get that kind of help, his autobiography as an adult (the book) is a kind of second attempt to achieve a sense of resolution by telling his story. but we see how this is very difficult to do when current life involves new problems and dangers that interfere with achieving a sense of safety. whether valentino succeeds in achieving some degree of emotional resolution about what he and his loved ones have suffered is an open question. what is clear is that he never stops trying to do so. it also is apparent that valentino's ethnic identification and heritage as an african man from the dinka tribe is very important as a protective factor enabling him to retain a small but significant fragment of his sense of personal identity and his intimate ties to his family and community. he experiences an odyssey as a victim fleeing the scene of horrific trauma, an initially reluctant but eventually drug-induced savage combatant, and a refugee "stranger in a strange land" when he is able to escape to what seems like an entirely different planet in the cosmopolitan urban setting of atlanta and the southern united states. it is the psychological trauma that he experiences on this odyssey, and the chronic stressors and societal breakdown and oppression that led him-and millions of others of all ages and a multiplicity of ethnocultural groups-on this journey of crisis and survival, and not his ethnicity or cultural background that is responsible for the profound symptoms of ptsd that he develops. inflicted on jewish people in europe by the nazis, the "ethnic cleansing" in bosnia and serbo-croatia in the s, and the massacres and mass starvation and epidemics perpetrated in rwanda in , in sudan beginning in , and in somalia, kenya, and zimbabwe most recently. genocide was first used as a term in by raphael lemkin, combining the words genos, from the greek for "race" or "kind," and cidere, which is latin and can be translated as "kill" (brom & kleber, ) . in , the term was adopted by the united nations general assembly and defined by the united nations convention on the prevention and punishment of the crime of genocide (cppcg) as follows: gregory stanton, the president of genocide watch, described " stages of genocide"; http://www.genocidewatch.org/aboutgenocide/ stagesofgenocide.htm. accessed / / : . classification-earliest stage, dividing people into "us" and "them" (the victim group). . symbolization-assigning particular symbols to designate the victim group members. . dehumanization-equating certain people with subhuman animals, vermin, or insects. . organization-militias or special units created for the purpose of genocide. . polarization-broadcasting of propaganda aimed at marginalizing the out-group. . preparation-out-group members are physically separated or confined in a "ghetto." . extermination-murder, starvation, infection, or other forms of inflicting pain and death. . denial-refusal to accept responsibility or admit wrongdoing, maintaining the self-righteous position that the victim group deserved annihilation and were subhuman. these stages are approximate and vary in each separate incident, but they demonstrate how genocide differs from other forms of even very horrific violence (such as war) because the aim is not simply to subdue, harm, or exploit but to dehumanize, exterminate, and annihilate. genocide thus involves several traumatic features, including loss of self-worth and allegiance to core values and institutions; prolonged pain and suffering; bereavement; terror and horror of annihilation; injury; helplessness while witnessing demeaning, cruel, and violent events; and confinement. survival responses to genocide are described by brom and kleber ( ) as: … a narrowing of functioning and awareness in order to maximize the chances of survival [often involving] psychic closing off (also called robotization-that is, acting and feeling emotionally and mentally empty or on "automatic pilot" like a "robot"), [and] regression-that is, feeling, thinking, and acting like a child (or in the case of children, like a much younger age than actual chronological age). often victims also experience a strong dependence on perpetrators who decide on life and death. the "muselman effect" … manifested by complete physical decrepitude, apathy, slowing of movement, and gradual disintegration of personality (including loss of the capacity for rational reasoning) may result when individuals have been exposed to long-term and extreme circumstances. an additional phenomenon that is well documented is the so-called "death imprint" resulting when substantial witnessing of death continues to haunt the survivor. these reactions closely parallel the symptoms of both asd (such as dissociation and regression) and ptsd (such as intrusive reexperiencing and emotional numbing). the adverse long-term effects of experiencing genocide are severe and pervasive. more than one in three survivors become clinically depressed and develop ptsd. the social support of caring family members (and for children, parents, or other caregivers) and relationships and activities that individuals to retain their spiritual or religious beliefs and their sense of self-respect are crucial protective factors against ptsd and depression. however, even the most resilient and socially supported person is likely to experience distressing memories and survivor guilt years or even decades later. studies with elderly holocaust survivors who are physically and emotionally very hardy (often well into their s and s) have documented significant persisting emotional distress and ptsd symptoms or more years later (brom & kleber, ) . moreover, the offspring of holocaust survivors with ptsd are more likely than offspring whose parents do not have ptsd to themselves experience ptsd as adults (yehuda et al., (yehuda et al., , . genocide often involves physical hardships that compromise physical health and may lead to long-term illnesses and depletion of the body's immune system. for example, the physical exertion and pain involved in torture, untreated physical illnesses, insufficient sleep, starvation, exposure to extreme temperatures, and forced labor may accelerate the aging process (brom & kleber, ) . genocide also often includes separating individuals from their families and community groups. this not only deprives the survivor of crucial social support but engenders a sense of isolation, distrust, and shame and of being permanently psychologically damaged (herman, ) . survivors also are faced with a choice of holding to their allegiance to their family, nation, culture, and racial identity, despite the punishment inflicted by the perpetrators, or abandoning these basic commitments and rejecting themselves and people like them. faced with this impossible choice (as epitomized in william styron's classic novel, sophie's choice), survivors often believe that they failed utterly and let down not only themselves but their family and culture no matter how resiliently they coped and the integrity of their efforts. survivor guilt is an expression of a sense of grief, powerlessness, and failure, including questioning why they survived and others did not. torture. torture is a terrible special case of political repression that involves "malicious intent and a total disregard for the recipient's dignity and humanity. thus, torture is among the most egregious violations of a person's fundamental right to personal integrity and a pathological form of human interaction" (quiroga & jaranson, ) . the united nations (un) office of high commissioner for human rights established a "convention against torture and other cruel, inhuman or degrading treatment or punishment (cat)," which has been endorsed by nations and defines torture as follows: for the purpose of this convention, the term "torture" means any act by which severe pain or suffering, whether physical or mental, is intentionally inflicted on a person for such purpose as obtaining from him or a third person information or a confession, punishing him for an act he or a third person has committed, or is suspected of having committed, or intimidating or coercing him or a third person, or for any reason based on discrimination of any kind, when such pain or suffering is inflicted by, or at the instigation of, or with the consent or acquiescence of, a public official or other person acting in an official capacity. it does not include pain or suffering arising only from, inherent in, or incidental to lawful sanctions. (http://www.unhchr.ch/html/menu /b/h_cat .htm accessed / / ) an amnesty international worldwide survey found that % of countries practice torture systematically, despite the absolute prohibition of torture and cruel and inhuman treatment under international law. torture may be euphemistically referred to as "enhanced interrogation techniques" and condoned in order to obtain "intelligence" from designated enemies of the nation, although this is completely prohibited by the un resolution (quiroga & jaranson, ) . widespread controversy has attended the use of such techniques by the us central intelligence agency in response to the september , , terrorism incidents, controversy that peaked in with the presidential decision to close the guantanamo bay military prison, and the release of the us senate report revealing and questioning the legality and morality of torture tactics used in interrogation and incarceration. basoglu, livanou, and crnobaric ( ) , in a sample from the balkan war ( - ) studied from to , showed that the torture need not inflict physical pain in order to produce ptsd. psychological assessment of torture survivors was systematized by the istanbul protocol, a manual on the effective investigation and documentation of torture and other cruel, inhumane, or degrading treatment or punishment that includes modules for medical, psychological, and legal professionals united nations resolution / on december , (quiroga & jaranson, ) . the psychological problems most often reported by torture survivors are emotional symptoms (anxiety, depression, irritability/aggressiveness, emotional liability, self-isolation, alienation from others, withdrawal); cognitive symptoms (confusion/disorientation, memory and concentration impairments); and neuro-vegetative symptoms (lack of energy and stamina, insomnia, nightmares, sexual dysfunction) (quiroga & jaranson, ) . the most frequent psychiatric diagnoses are ptsd and major depression, other anxiety disorders such as panic disorder and generalized anxiety disorder, and substance use disorders. longer-term effects include changes in personality or worldview, consistent with complex ptsd (quiroga & jaranson, ) . the greater the degree of distress and loss of sense of control during torture, the greater the likelihood of ptsd and depression. resilience, through being able maintain a sense of personal control, efficacy, and hope while enduring torture, is associated with less distress during torture and lower risk of ptsd (quiroga & jaranson, ) . social, cultural, and other diversity issues in the traumatic stress field however, quiroga and jaranson ( ) cited a study by olsen showing that years after torture, physical pain was still prevalent even if torture was primarily psychological in nature. based on this finding and related studies, they conclude the following (p. ): the most important physical consequence of torture is chronic, long-lasting pain experienced in multiple areas of the body. all [physical] torture victims show some acute injuries, sometimes temporary, such as bruises, hematomas, lacerations, cuts, burns, and fractures of teeth or bones, if examined soon after the torture episode. permanent lesions, such as skin scars on different parts of the body, have been found in % to % of torture victims. … falanga, beating the sole of the feet with a wooden or metallic baton, has been studied extensively. survivors complain of chronic pain, a burning sensation. … acute renal failure secondary to rhabdomyolysis, or destruction of skeletal muscle, is a possible consequence of severe beating involving damage to muscle tissue. this condition can be fatal without hemodialysis. … a severe traumatic brain injury that is caused by a blow or jolt to the head or a penetrating head injury may disrupt the function of the brain by causing a fracture of the skull, brain hemorrhage, brain edema, seizures, and dementia. the effects of less severe brain injury have not been well studied. treatment for torture survivors must be multidisciplinary and involves a long-term approach. several treatment modalities have been developed, but little consensus exists concerning the standard of practice, and treatment effectiveness has not been scientifically validated by treatment outcome studies (quiroga & jaranson, ) . a key element that is widely agreed upon is to pay careful attention to not inadvertently replicating in benign ways aspects of torture in the treatment (such as by pressing a survivor to recount traumatic memories without the survivor's informed and voluntary consent; by encouraging or discouraging political, family, and social activities except as initiated by the survivor; or by behaving in authoritarian ways rather than seeking to be collaborative with the survivor). it also is best to use medical, psychiatric medication, and psychotherapy modalities to address the ptsd symptoms of impaired sleep, nightmares, hyperarousal, startle reactions, and irritability. quiroga and jaranson ( ) also recommend using groups for socializing and supportive activities to reestablish a sense of family and cultural values, and supporting the traditional religious and cultural beliefs of the survivor. currently, nearly torture survivor treatment centers exist worldwide, of them accredited by the international rehabilitation council of torture victims (quiroga & jaranson, ) . most of these centers also involve the survivors' families and communities in developing shared approaches to recovery and reparation of the harm done to all. the controversy concerning the use of torture on detainees in the so-called "war on terror" has led to deep concern on the part of not only the public at large but specifically by mental health professionals. the issue is that psychiatry and psychology professionals who are in the military or consult to the military have been involved in the detention and interrogation of suspected terrorists at high-security facilities such as the military base at guantanamo bay and the military prison in iraq, abu ghraib. as a result, guidelines for mental health professionals working in these or similar facilities in which prolonged detention and interrogation may involve practices that constitute torture have been developed by a special committee of the american psychological association's division ( ) on trauma psychology (box . ). the apa council of representatives … included in its "unequivocal condemnation" all techniques considered torture or cruel, inhuman or degrading treatment or punishment under the united nations convention against torture and other cruel, inhuman, or degrading treatment or punishment; the geneva conventions; the principles of medical ethics relevant to the role of health personnel, particularly physicians, in the protection of prisoners and detainees against torture and other cruel, inhuman, or degrading treatment or punishment; the basic principles for the treatment of prisoners, the mccain amendment, the united nations principles on the effective investigation and documentation of torture and other cruel, inhuman, or degrading treatment or punishment an "absolute prohibition against mock executions; waterboarding or any other form of simulated drowning or suffocation; sexual humiliation; rape; cultural or religious humiliation; exploitation of fears, phobias, or psychopathology; induced hypothermia; the use of psychotropic drugs or mind-altering substances; hooding; forced nakedness; stress positions; the use of dogs to threaten or intimidate; physical assault, including slapping or shaking; exposure to extreme heat or cold; threats of harm or death; isolation; sensory deprivation and overstimulation; sleep deprivation; or the threat [of these] to an individual or to members of an individual's family. psychologists are absolutely prohibited from knowingly planning, designing, participating in, or assisting in the use of all condemned techniques at any time and may not enlist others to employ these techniques. we have come to the conclusion that the united states' harsh interrogationdetention program is potentially trauma-inducing both in general (e.g., indefinite detention, little contact with lawyers, no contact with relatives or significant others, prolonged absence of due process, awareness that other prisoners have been tortured, lack of predictability or control regarding potential threats to survival or bodily integrity) and in terms of some of its specific components (e.g., prolonged isolation, waterboarding, humiliation, painful stress positions). in other words, these potentials for trauma extend beyond the narrow procedures that meet international definitions of torture. the evidence for risk of psychological trauma to detained enemy combatants is particularly compelling and well grounded in formal research, but there is also suggestive anecdotal and theoretical evidence of trauma induction in interrogators and the broader society. we were particularly struck by the fact that the potentially traumatic elements include not only activities designed to extract information from prisoners but also much of the detention process as it is currently conceived, beyond much oversight, or compliance with international law. given the pervasiveness of these traumatogenic elements, it is questionable whether psychologists can function in these settings without participating in, or being adversely affected by, heightened risk for trauma. nonetheless, as a group of psychologists with expertise in preventing traumatic stress and ameliorating debilitating posttraumatic sequelae, we believe that certain steps could … minimize the risk of psychological trauma. they are as follows: . we believe that the risk of traumatic stress and negative posttraumatic sequelae will be reduced if psychologists adhere to both the apa ethical standards and subsequent refinements of apa policies pertaining to interrogation, detention, and torture. such adherence would be more likely if the apa ethics code were revised to incorporate, as enforceable standards, the specific interrogation and torture-related policy refinements that have occurred since . psychologists should promote situations that maintain the risk of traumatic stress at acceptably low levels and avoid situations that heighten the risk for traumatic stress occurring. among other things, this means that psychologists should not provide professional services in secret prisons that appear to be beyond the reach of normal standards of international law or in settings in which torture and other human rights abuses have been credibly documented to be permitted on the basis of local laws. it also suggests that psychologists should not support or participate in any detention or interrogation procedure that constitutes cruel or inhumane treatment or that otherwise has been shown to elevate risk of traumatic stress (e.g., prolonged isolation). . if psychologists work in settings in which detention and interrogations are conducted, then they should conduct or seek an assessment of the potential traumatic features of the treatment of detainees before, during, and after interrogation. this assessment can be informal or formal, depending on whether other systems of oversight are in place. this assessment should include an examination of the social psychological factors that could elevate risk of trauma. because not all psychologists have expertise in assessing traumatic stress risk and/or social psychological (continued ) factors, the assessment should be conducted by psychologists who have this specific expertise. such assessments could inform decisions not only by psychologists but also by others working in facilities in which detention and interrogation occur. it is recommended therefore that apa advocate for appropriate governmental authorities to appoint an independent oversight committee for each facility of this type and that the oversight committees include psychologists identified by apa as having relevant expertise. . if psychologists work in settings in which risk of traumatic stress is found to be elevated then they should (i) formally recommend alterations that could reduce the traumatogenic potential of the detention and interrogation process (n.b. some recommendations may be aimed at policy makers rather than local authorities); (ii) conduct or seek an assessment of posttraumatic stress symptoms and associated features (e.g., depression, dissociation) in detainees, interrogators, and other directly or indirectly involved staff; (iii) recommend appropriate psychological interventions for any detainees or personnel found to be suffering from clinically significant psychological difficulties; and (iv) refuse to participate in any activities that significantly increase risk of traumatic stress. if a psychologist working in such settings does not have specific expertise required to meet some of the above recommendations, then she or he should consult with psychologist(s) who have this expertise to make the appropriate determination. . because some detainee abuses have been credibly linked to an absence of appropriate training and/or expertise, psychologists should advocate for, participate in designing, and/or assist with providing appropriate and comprehensive training to all personnel involved in interacting with detainees. this training should include (i) clear ethical guidelines emphasizing the prohibition of causing harm and the importance of protecting detainee rights, (ii) a research-based overview of the nature and consequences of traumatic stress and posttraumatic impairment as they relate to the interrogation and confinement process and all parties involved in layperson terms with practical implications, and (iii) detailed review of research on false confessions, in layperson terms, with practical implications for enhancing the validity and utility of information gathered in the course of interrogation and detention. because not all psychologists have expertise in these specific matters, apa should develop standardized training materials that cover the current state of psychological knowledge and practices on these important topics, and ensure that these materials are regularly updated by qualified psychologists in consultation with experts from other fields such as law enforcement, the military, and human rights. . because protecting human rights reduces the risk for traumatic stress and posttraumatic impairment, psychologists should collaborate with legal, military, and other colleagues to advocate for due process for all detainees, including providing clear guidelines about finite lengths of detention prior to formal hearing or trial and enforcing the recent supreme court decision to reinstate habeas corpus and other international standards of human rights. psychologists' support for these actions should not come from a blanket support for adherence to law but rather from an informed judgment that these … laws reduce the risk for harm. psychologists should be prepared to disagree with any future international laws or us supreme court decisions that heighten risk for traumatic stress. box . continued . psychologists should support increased transparency during the detention and interrogation process. such increased transparency could reduce the likelihood of traumatizing practices, increase the likelihood that traumatizing practices will be identified and stopped as early as possible, and protect ethical psychologists and other workers within the system from being falsely accused of acting unethically. we recognize that this recommendation raises an apparent conflict with the goal of secrecy commonly endorsed by national security organizations. we concur that full transparency is unreasonable and counterproductive. yet, we do believe that increased transparency is a safeguard against traumatizing practices. though the details of resolving this conflict are beyond the scope of this task force's expertise, we believe that reasonable, knowledgeable intelligence experts, in consultation with psychologists, can construct a system of oversight that will both retain credible independence from the military chain of command and guard classified information. one suggestion may be to establish a greater presence of psychological expertise within a framework of oversight protection. . if psychologists are going to continue to be involved in interrogations, then it will be important to continue to segregate the function of interrogation consultant from that of mental health provider to reduce risk of perceived or actual betrayal by the detainee. it is unknown whether betrayal of trust due to dual roles can constitute a direct form of traumatization under these circumstances, but it is likely that betrayal in this context could exacerbate traumatic stress that occurs of other aspects of detention and interrogation (especially in light of the ways that such detention appears to disrupt attachment as outlined in the body of our report). maintaining separate roles also may enable the psychologist to more effectively assist detainees with traumatic stress reactions by fostering a trusting therapeutic relationship. . psychologists should advocate for extra protections for detainees who are from vulnerable populations such as minors, ethnic minorities, or other groups that have limited access to socioeconomic or political resources or are potentially subject to societal discrimination or prejudice because such groups may be more likely to receive coercive interrogations and/or excessive force and less likely to be sympathetically viewed by the general public. for this purpose, psychologists may work within sponsor/authorizing organizations to institute developmental, gender, and culture sensitivity trainings for interrogators and should review evidence concerning the impact of different forms of traumatic stressors and differential sensitivity to the interrogation/detention setting/process on different (and particularly vulnerable) ages, genders, and cultural backgrounds. such psychologists should, to whatever extent possible, guard against such information being used to exploit vulnerable populations and instead emphasize ways to enhance safety and psychological wellbeing in the interrogation process. if psychologists lack relevant expertise to meet the recommendations, … they should seek or advocate for outside expert consultation. . psychologists should collaborate with colleagues from a variety of professions and organizations, including the military and intelligence organizations, to conduct ethical research on several aspects of the detention and interrogation process, especially its potential for inducing trauma. recent reviews suggest that most of the interrogation procedures used today have not received recent rigorous study (intelligence science board, ) . furthermore, very little of the recent study has been directed toward understanding the psychological effects of interrogation on not only the detainees but also the people working within and outside the interrogation and detention system. political violence not only leads to traumatic harm to people while they are living in their communities but also often when victims are forced to flee their homes either to another country or while remaining within their country. refugees are defined by the united nations high commissioner for refugees (unhcr) as persons who have left their nation of origin to escape violence. article one of the united nations convention relating to the status of refugees defines a refugee as someone who "owing to well-founded fear of being persecuted for reasons of race, religion, nationality, membership of a particular social group or political opinion, is outside the country of his nationality and is unable or, owing to such fear, is unwilling to avail himself of the protection of that country; or who, not having a nationality and being outside the country of his former habitual residence as a result of such events, is unable or, owing to such fear, is unwilling to return to it" (unhcr, p. ; http:// www.unhcr.org/home/publ/ b e ea .pdf; accessed . . ). therefore, refugees are distinct from both legal and illegal immigrants, economic migrants, environmental migrants, and labor migrants (weine, ) . refugees must involuntarily leave home, community, and family and friends, often with limited resources or preparation and usually without knowing whom they can trust and where they can find safe passage and a safe haven. thus, both prior to and during the displacement, refugees often suffer psychologically traumatic experiences, including having their community or homes attacked or destroyed due to war; racially, genderbased, or ethnically targeted genocide or terrorism; institutionally orchestrated deprivation and violence; along with torture, atrocities, rape, witnessing violence, fear for their lives, hunger, lack of adequate shelter, separation from loved ones, and destruction and loss of property (weine, ) . estimating the number of refugees is very difficult. a minimum estimate that is probably much lower than the actual number is calculated by the united nations based on the number of persons in resettlement camps or individually recognized by a host country. based on this definition, there were million refugees worldwide in (www.unhcr.org) (figure . ). in côte d'ivoire, and was quickly followed by others in libya, somalia, sudan, and elsewhere. in all, . million people were newly displaced, with a full , of these fleeing their countries and becoming refugees. " saw suffering on an epic scale. for so many lives to have been thrown into turmoil over so short a space of time means enormous personal cost for all who were affected," said the unhcr antónio guterres. "we can be grateful only that the international system for protecting such people held firm for the most part and that borders stayed open. these are testing times." worldwide, . million people ended either as refugees ( . million), internally displaced ( . million), or in the process of seeking asylum ( , ). despite the high number of new refugees, the overall figure was lower than the total of . million people, due mainly to the offsetting effect of large numbers of idps returning home: . million, the highest rate of returns of idps in more than a decade. among refugees, and notwithstanding an increase in voluntary repatriation over levels, was the third lowest year for returns ( , ) in a decade. viewed on a -year basis, the report shows several worrying trends. one is that forced displacement is affecting larger numbers of people globally, with the annual level exceeding million people for each of the last years. another is that a person who becomes a refugee is likely to remain one for many years-often stuck in a camp or living precariously in an urban location. of the . million refugees under unhcr's mandate, almost three-quarters ( . million) have been in exile for at least years awaiting a solution. overall, afghanistan remains the biggest producer of refugees ( . million), followed by iraq ( . million), somalia ( . million), sudan ( , ), and the democratic republic of the congo ( , ) . around four-fifths of the world's refugees flee to their neighboring countries, reflected in the large refugee populations seen, for example, in pakistan ( . million people), iran ( , ) , kenya ( , ), and chad ( , many people displaced from their communities by violence remain in their home country. they are not considered refugees, but "idps": "people or groups … who have been forced to leave their homes" due to "armed conflict, situations of generalized violence, violations of human rights, or natural-or human-made disasters, and who have not crossed an international border" (www.unhcr.org). as of , there were more than three times as many idps as refugees, an estimated million worldwide, million social, cultural, and other diversity issues in the traumatic stress field due to armed conflict and million due to mass natural disasters (www.unhcr.org). between one and more than million idps were known to be in several countries in , including colombia, congo, iraq, somalia, sudan, and uganda. azerbaijan, cote due n'orde, and sri lanka had more than , known idps each. at least another million persons are considered "stateless"-that is, to not be citizens of any nation, in . nepal and bangladesh have the majority of the stateless persons in the world, although nearly million persons in those two countries were made citizens in . palestine and iraq are the other countries with large numbers of stateless persons. there may be millions more stateless individuals, because only countries assisted the united nations in its census of stateless persons in (www.unhcr.org). the impact of forced displacement often is not just extremely stressful but traumatic. refugees, idps, and stateless persons have few protections and often must live in confined camps or crowded public shelters, where they are vulnerable to assaults (including rape), robbery, and illness. many have witnessed horrific violence associated with wars, genocide, or other forms of mass armed conflict that caused them to flee. loss of family and friends due to violence or illness is common, as well as due to being separated with no way to communicate. studies have documented high prevalence levels of ptsd and depression among refugees or idps from armed conflicts in central america, southeast asia, the middle east, and the balkans (fazel, wheeler, & danesh, ; marshall, schell, elliott, berthold, & chun, ) at least times higher than the - % prevalence estimates from epidemiological surveys (see chapter ). ptsd prevalence estimates that are more than three times higher than these very high levels, as high as - %, have been reported among disabled central american refugees (rivera, mari, andreoli, quintana, & ferraz, ) and among afghan mothers (seino, takano, mashal, hemat, & nakamura, ) . other studies have more specifically investigated physical displacement in the traumatic stress experienced by refugees. displacement may involve many stressors, and a research review found that "living in institutional accommodation, experiencing restricted economic opportunity, [being] displaced internally within their own country [or] repatriated to a country they had previously fled or whose initiating conflict was unresolved" were particularly problematic. this review of reports involving , participants ( , refugees and , persons who were not displaced) showed that displacement alone was associated with more severe mental health problems, including ptsd (porter & haslam, ) . in contrast to most research findings on the etiology (see chapter ) and epidemiology (see chapter ) of ptsd, "refugees who were older, more educated, and female and who had higher predisplacement socioeconomic status and rural residence also had worse outcomes" (porter & haslam, , p. ) . people become "internally displaced" as often due to mass natural disasters as to armed violence. in the united states, several hundred thousand people had to leave the new orleans area following hurricane katrina in august . almost , received medical care at american red cross shelters within the next month (mills, edmondson, & park, ) . many displaced persons already were severely disadvantaged due to living in poverty (roughly % of the population of new orleans), having limited access to quality health care, and exposure to community violence (mills et al., ) . in a study of adult evacuees from new orleans and surrounding parishes ( % men, average age years old, % black, % low income (annual income less than $ , ), % reporting a prehurricane psychiatric disorder ( % depression, % anxiety disorder, % bipolar disorder)), most ( %) waited several days to be evacuated, and a majority reported sustaining minor to severe injuries ( %) and mild to severe illness ( %) in the hurricane or evacuation process. one in seven lost a loved one due to death in the hurricane or its aftermath, and most ( %) were separated from a family member for a day or more. many ( %) lost their home, two-thirds of whom were without property insurance. almost two in three ( %), particularly women, people with a prior psychiatric disorder, and those who recalled feeling their lives were in danger during the hurricane or its aftermath, were injured physically, or felt they had limited control over their current life circumstances, reported symptoms sufficient to qualify for a diagnosis of asd. natural disasters of several magnitudes greater have occurred in less developed and affluent areas of the world. for example, the tsunami that struck on december , , in the wake of the sumatra-andaman earthquake killed an estimated , people along the coastlines of the indian ocean, including , indonesians. another half a million indonesians were displaced from their communities. studies of survivors of this tsunami from indonesian areas such as aceh and north sumatra (frankenberg et al., ) , as well as from thailand (van griensven et al., ) and sri lanka (hollifield et al., ) , have demonstrated that posttraumatic stress, anxiety, and depression are suffered by hundreds of thousands, and perhaps millions, of people who experienced psychological trauma due to the tsunami (box . ). box . refugee posttraumatic stress in the wake of mass natural disaster frankenberg et al. ( ) reported a unique study of the impact of a massive natural disaster: the indian ocean tsunami that struck the day after christmas . unlike most research on mental health after disasters, this study began with a survey of a representative sample of persons in the host country (indonesia) almost years before the disaster. this "national socioeconomic survey (susenas)" provided a registry of respondents and predisaster data on health and socioeconomic characteristics of people throughout indonesia. the "study of the tsunami aftermath and recovery (star)" attempted to recontact , persons interviewed in communities by the susenas. the study also was able to determine the extent of damage caused to each community by the tsunami. the researchers got data from the national aeronautics and space administration's moderate resolution imaging spectroradiometer sensor collected year prior to the tsunami, and again immediately after the tsunami, to assess the degree to which the pretsunami ground cover visible in the first image had been replaced by bare earth in the second image. communities with at least % loss of ground cover were classified as heavily damaged ( % of the surveyed communities). those with some loss of ground cover were categorized as moderately damaged ( % of all locales), and % with no loss of ground cover were classified as undamaged by the tsunami. community leaders' and field observers' estimates of damage strongly correlated (r= . and . ) with these satellite-based estimates. one in three of the survey respondents (average age years old) heard the tsunami wave or people screaming. fewer sustained injuries ( %), lost a spouse ( %), lost a parent or child ( %), or witnessed family or friends "struggle or disappear" ( %), but % lost a family member or friend, % lost their home, and % lost their farming land, livestock, or equipment. posttraumatic stress was assessed by asking every respondent years or older to answer seven of the items from the ptsd checklist (see chapter ), as follows: since the tsunami, have you ever experienced (never, rarely, sometimes, or exposure to probable traumatic stress due to hearing the wave or screams, being injured, or seeing friends or family members "struggle or disappear," doubled the severity of pcl-c scores. consistent with this finding, compared to the sleep difficulties reported before the tsunami, after the tsunami, there was a large increase in the likelihood of sleep difficulties only in the most heavily damaged areas. pcl-c scores increased the most in the worst damaged locales, followed by the moderately damaged ones, with little change in the nondamaged communities. pcl-c scores averaged . , . , and . for the heavily, moderately, and undamaged areas, respectively, at the time of the interview and had been % higher at their peak after the tsunami (based on respondents' recollections). this is consistent with other studies that have reported persistent ptsd symptoms among the worst exposed persons but a substantial decline in ptsd symptom severity over time even among heavily exposed persons (see chapter ). women reported higher pcl-c scores than men, but primarily only in the heavily damaged areas. age was a factor in all communities: persons younger than years reporting an increase after the tsunami and persons years and older reporting lower pcl-c scores after the tsunami. interestingly, respondents who had a parent alive before the tsunami had lower pcl-c scores after the tsunami, but marital status, education, and income were not related to posttsunami pcl-c scores. property damage also correlated with posttsunami pcl-c scores. (continued ) as frankenberg et al. ( ) noted, these findings probably understate the severity and widespread nature of the harm, including posttraumatic stress, caused by a massive disaster such as this tsunami. however, the study provides the strongest evidence to date that a disaster that is not only life threatening for many but that displaces tens or hundreds of thousands of persons from their homes, families, neighbors, and way of life has the strongest adverse impact on communities that are most directly affected. another study (van griensven et al., ) conducted weeks after the tsunami in six southwestern provinces of thailand (where more than persons died or were unaccounted for and another were injured) included random samples of displaced persons and nondisplaced persons from the most heavily hit area and persons from less damaged areas. even though the extent of death and destruction was less in the worst-hit areas of thailand than in indonesia, symptoms of ptsd were reported by % of displaced and % of nondisplaced persons in the most damaged area of thailand (and by % in the less damaged areas). anxiety or depression symptoms were reported by three times as many persons, with similar proportions depending on displacement and the severity of damage to the community. thus, this study adds to the findings of the study from indonesia by demonstrating that displacement from home and community was a factor in ptsd and related symptoms soon after a mass natural disaster. the thailand study also resurveyed participants from the worst-damaged area months later ( months after the tsunami) and confirmed that displaced persons continued to be more likely than nondisplaced persons to suffer from ptsd, anxiety, and depression symptoms. consistent with other studies (ford, adams, & dailey, ) of postdisaster recovery (including the indonesia study), as the first anniversary of the disaster approached, about % of each group had recovered sufficiently to no longer report severe symptoms. whereas the indonesia study examined the extent of damage to participants' homes and (for most) the source of their incomes (farmland, animals, and equipment), the thailand study inquired directly as to whether respondents had lost their source of income and found that loss of livelihood was the strongest correlate of ptsd, anxiety, and depression symptoms. thus, the thailand study showed that losing not only home or community but also one's ability to generate an independent income through gainful work may contribute to the development and persistence of ptsd and related anxiety and depression symptoms. the defining characteristics of becoming a refugee in the wake of disaster therefore include (i) exposure to life-threatening catastrophe; (ii) loss of or separation from family and friends, (iii) loss of home and community; and (iv) loss of one's personal or family livelihood. each of these factors may result in acute posttraumatic distress, and the combination of several places people at risk for persistent ptsd. as weine ( ) describes, resettlement of refugees is a substantial challenge not only for displaced persons themselves but also for the host country. relatively stable and affluent countries in asia (such as pakistan, due to afghan refugees), the middle east (such as lebanon and syria, due to palestinian refugees), and africa (such as kenya and south africa), as well as most european and british commonwealth nations and the united states, have had a large influx of refugees. the half of all refugees who are resettled in cities experience economic pressures due to poverty and low-wage work and must live in communities that are crowded, segregated economically and culturally, and often adversely affected by crime, gangs, drugs, aids, and troubled schools (weine, ) . another half of all refugees are resettled in suburban and rural areas, which are more isolated (www.unhcr.org). in either case, refugees often face prolonged separations from family, friends, and loved ones, as well as the burden of having to find a way to subsist while saving money to bring others to their new home and to provide support to those back home who have stayed behind. refugee children have additional needs and challenges, including having to survive life-threatening experiences without adult help or guidance and then, if they are fortunate enough to be permanently resettled, having to return to being a "child" with a new family, community, and culture (henderson, ) . refugee children often display not only the symptoms of ptsd but also behavior problems (such as control, aggression, or defiance of authority), profound bereavement, and developmental, learning, or educational delays or deficits that are understandable in light of their often chronic deprivations before and during displacement. however, children also can be particularly resilient in the face of the psychological losses and traumas of being a refugee, and often they are a key source of hope for their families in the resettlement process (weine, ) . many refugees have opportunities to receive mental health services, either in the context of a refugee camp or after resettlement, but many do not seek or utilize these services. survival; getting stable and predictable access to food, money, housing, transportation, and safety; renewing communication with friends and family; and sustaining or regaining connection to cultural and religious traditions, values, and practices may take precedence over mental health treatment (and may in fact be the best form of therapy for many, under the circumstances). in resettlement settings, clinical treatment for refugee trauma is typically organized through refugee mental health clinics or specialized torture victim treatment centers, with services including crisis intervention, psychopharmacology, individual psychotherapy, group psychotherapy, and self-help groups and activities (weine, ) . to deliver culturally appropriate services, many programs involve traditional healers, socialization or mutual support groups, multifamily groups, and culturally based activities (weine, ) . services also tend to be provided by staff who themselves are members of the refugees' ethnic community, in collaboration with traumatic stress specialists and mental health professionals. the traditional model of western professional "expert" doctor or consultant who unilaterally tells local staff or clients how best to do assessment, diagnosis, or treatment has been justly criticized as culturally insensitive and potentially harmful rather than helpful (weine, ) . instead, the joint experience and expertise of the refugee client, local professional and paraprofessional alike, traditional healers, and traumatic stress professionals are taken together in a team approach that validates the client's and local helpers' cultures and traditions. this approach enhances the providers' ability to make a true cross-cultural assessment of symptoms and diagnoses, to adapt interventions to reflect different cultural beliefs and practices, and to engage not just individual clients but families and communities in recovery from ptsd. such an approach is consistent with new theoretical views of refugee traumatic stress, which include "the concepts of cultural bereavement, cultural trauma, family consequences of refugee trauma, community trauma, and social suffering" (weine, ) . this more culturally grounded view of refugees' experiences of traumatic stress and recovery from ptsd has led to the development of innovative therapy approaches (such as incorporating personal testimony and reconciliation into treatment) that address refugees' psychological vulnerabilities but strongly acknowledge their (and their families' and communities') hopes and strengths (weine, ) . when mass catastrophes, whether human-made or "acts of god" in origin, including natural disasters such as tsunamis, tornadoes, hurricanes, floods, or earthquakes, or public health emergencies, such as aids, severe acute respiratory syndrome (sars), pandemic influenza, ebola, or human-made disasters such as terrorist attacks, airline crashes, ferry capsizes, and train derailments, cause tens or hundreds of thousands or even millions of people and families to experience psychological trauma, the resultant suffering and needs are generally beyond the capacities of traditional mental health services and other forms of government-sponsored services. ngos play a critical role supporting and assisting persons and communities affected by catastrophic disaster or violence, including providing psychological support through clinical and nonclinical behavioral health services (hamilton & dodgen, ) . ngo responses to the mental health needs of mass-disaster survivors are based on the core belief that "all disasters are local" (hamilton & dodgen, ) . this means that local responders such as law enforcement, police, emergency medical teams, and professionals from the health care facilities, schools, and government are invariably first on the scene and frequently remain involved for months or years afterward. when insufficient resources are available, a local community may request help from the country, state, or provincial governments, which in turn may request regional or national assistance from both government and private sectors. for that reason, ngos that provide assistance following disasters, such as the american red cross, the national voluntary organizations active in disaster (nvoad), the united way, and the salvation army do so through their local chapters, which organize the initial relief efforts to provide shelter, food, legal aid, health and mental health care, and humanitarian assistance. organized in , nvoad is the umbrella organization coordinating all disaster relief services provided by volunteer organizations such as the american red cross throughout the united states. ngos also work closely with faith-based organizations (fbos) in the united states (such as catholic charities united states, church world service, lutheran disaster response, national association of jewish chaplains) within the national response framework of the federal emergency management agency (fema), which guides the nation's "all-hazards incident response" (hamilton & dodgen, ) . for example, american red cross disaster mental health (dmh) volunteers provide mental health services to people in shelters, while the church of the brethren provides crisis intervention to young children through their disaster child care program (hamilton & dodgen, ) . the american red cross is the most widely recognized ngo providing dmh services in the united states. in , congress chartered the american red cross to "carry on a system of national and international relief in time of peace" to reduce and prevent the suffering caused by national calamities program (hamilton & dodgen, ) . in , the american red cross established a formal dmh services program and began training licensed and certified mental health professionals to volunteer and assist other red cross workers to cope with and recover from the traumatic stress (or "vicarious trauma") of their disaster relief work. initially only licensed psychologists and social workers were permitted to become red cross dmh volunteers, but recently professionals from other disciplines, such as psychiatry and masters-level marriage and family therapy or counseling professions, also have become eligible. the american red cross has set up formal agreements with the american psychiatric association, the american psychological association, the national association of social workers, the american counseling association, and the american association of marriage and family therapy. the agreements provide that in the event of a mass disaster, the red cross will notify each professional associations to put out a call to their memberships for professionals who have completed red cross preparatory training and who can take time out from their ordinary work to serve as dmh volunteers for weeks or more at red cross disaster services sites. the american red cross sets up and oversees family assistance centers for disaster-affected communities, provides crisis and grief counseling through its dmh volunteers, and coordinates with federal agencies such as fema and the national transportation safety board (for airline or mass transportation disasters) to provide child care services and interfaith memorial services. the red cross also works closely with disaster-focused ngos such as the national organization for victim assistance, disaster psychiatry outreach, and the international critical incident stress foundation, inc. (icisf). founded in , the icisf trains mental health professionals, emergency responders, clergy, and chaplains to conduct critical incident stress management (see chapter ) teams to support disaster services personnel. in , the american red cross broadened the scope of dmh services to include assisting disaster-affected persons who are seeking red cross assistance, as well as red cross volunteers. all dmh volunteers now are trained in psychological first aid (see chapter ) so that they will provide mental health services to disaster victims in an appropriately circumscribed manner that is therapeutic without attempting to conduct psychotherapy at a disaster relief site. two other freestanding programs participating in a dmh response are the green cross assistance program, which provides trained traumatology specialists and the association of traumatic stress specialists, an association of mental health professionals and paraprofessionals who assist survivors of psychological trauma (hamilton & dodgen, ) . a number of us ngos also work internationally to provide psychosocial support and traumatic stress counseling to survivors of disasters and mass conflicts. these include the international services of the american red cross, the united methodist committee on relief, church world services, green cross, action aid-the united states, the american refugee committee, the center for victims of torture, and doctors without borders (hamilton & dodgen, ) . the international federation of red cross and red crescent societies also assist many nations' red cross organizations in serving their own and neighboring countries. a analysis by the united states homeland security institute found that fbos and ngos had a significant beneficial impact during and after hurricanes katrina and rita, with mental health and spiritual support among types of services (hamilton & dodgen, ) . the study reported that while fbos and ngos faced significant limitations and challenges in providing services, mental health and spiritual support was one of the three best-applied special practices, particularly services designed to preserve family unity within disaster relief shelters. hamilton and dodgen ( , p. ) describe how ngos can work together to meet critical needs in times of mass crisis, using the september , , terrorist attacks in new york, washington, and pennsylvania, as a case in point: local mental health providers working in mental health settings mobilized quickly, but needs were expected to surpass local capability. the american red cross dispatched dmh providers from local and adjacent communities to provide mental health support and stress reduction assistance. national volunteers recruited from across the country arrived within a few days to augment that mission. concurrently, icisf-trained volunteers, some of whom were already part of military mental health systems, also arrived to provide assistance. other agencies, such as fbos, also organized support for victims. in washington, the military was the gatekeeper for volunteers and worked closely with the american red cross to coordinate mental health support. in new york, civilian authorities collaborated with the american red cross. as family assistance centers were set up to aid grieving families, national dmh volunteers continued providing mental health support. because the terrorist attacks created a crime scene, access was controlled and ngos needed official standing to provide assistance. incorporating lessons learned from / , a similar event today would be different in several ways: all ngos and government agencies would organize their response under the national incident management system (nims) and the nrf, thus creating a more centralized, coordinated response and reducing overlapping or competing activities on the part of nvoads. because of ongoing coordination and outreach efforts since / , a greater array of disciplines and specific types of expertise would be available through ngos. the benefits of these efforts were seen during the responses to hurricanes katrina and rita in . personal and community characteristics that reflect ethnocultural, national, gender, age, and disability factors are crucial in defining the identity of every human being. when traumatic stress occurs in a person's or community's life, its impact is influenced by these identity factors. when identity is used as a basis for stigma, discrimination, or socioeconomic disadvantage, those stressors compound the effect of traumatic stressors and can be traumatic in and of themselves. by addressing the vulnerability that this combination in a scientifically and clinically responsible manner (alcantara, casement, & lewis-fernandez, ; c'de baca, castillo, & qualls, ; ghafoori, barragan, tohidian, & palinkas, ) to assist rather than stigmatize persons and communities (ruglass et al., ) , the traumatic stress professional can play a crucial role in our society's quest for social justice. 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presently the per capita mortality rate is over /million, respectively . and times higher compared to canada and germany. as we enter fall , the us is enduring ongoing outbreaks across large regions of the country. moreover, within the us, an early and persistent feature of the pandemic has been the disproportionate impact on populations already made vulnerable by racism and dangerous jobs, inadequate wages, and unaffordable housing, and this is true for both the headline public health threat and the additional disastrous economic impacts. in this article we assess the impact of missteps by the federal government in three specific areas: the introduction of the virus to the us and the establishment of community transmission; the lack of national covid- workplace standards and enforcement, and lack of personal protective equipment (ppe) for workplaces as represented by complaints to the occupational safety and health administration (osha) which we find are correlated with deaths days later (ρ = . ); and the total excess deaths in to date already total more than , , while covid- mortality rates exhibit severe—and rising—inequities in race/ethnicity, including among working age adults. the united states (us) has been among those nations most severely affected by the first-and subsequent-phases of the pandemic of covid- , the disease caused by sars-cov- . with only % of the worldwide population, the us has seen about % of covid- deaths. despite formidable advantages in resources and expertise, presently the per capita mortality rate is over /million, respectively . and times higher compared to canada and germany [ , ] . as we enter fall , the us is enduring ongoing outbreaks across large regions of the country. moreover, within the us, an early and persistent feature of the pandemic has been the disproportionate impact on populations already made vulnerable by racism and dangerous jobs, inadequate wages, and unaffordable housing, and this is true for both the headline public health threat and the additional disastrous economic impacts [ ] [ ] [ ] [ ] [ ] [ ] . the newly issued federal healthy people framework (released on august , ) [ ] , sets the nation's objectives for the next decade, with the first two overarching goals being: ( ) "attain healthy, thriving lives and well-being free of preventable disease, injury, and premature death" and ( ) "eliminate health disparities, achieve health equity, and attain health literacy to improve the health and well-being of all." the third is: "create social, physical and economic environments that promote attaining the full potential for health and well-being for all" [ ] . in the case of covid- , the us has missed the mark on all three goals. in the following we document critical federal missteps in protecting the nation, with an eye towards guiding a better response. we start with how community transmission in the us became established in the spring. we then document complaints submitted to the us occupational safety and health administration by us workers regarding their risk of exposure to covid- at work, a key site of transmission, and compare the temporal relationship of these complaints to covid- cases and deaths. we conclude with an empirical analysis of excess mortality and age-specific racial/ethnic inequities in covid- mortality. living graffiti at jamaica pond (boston, ma): early may, while covid- lockdown underway --"we cannot direct the wind, but we can adjust the sail" (photograph taken by n. krieger) to prevent or delay establishment of the virus, many countries have implemented symptom screening at ports of entry, sometimes together with quarantine of travelers. such measures have enabled singapore, hong kong, and taiwan to avoid large early outbreaks, despite having been at high risk of introductions due to the volume of travelers from wuhan (hubei province, china), the initial epicenter of the pandemic. in the us, control of borders, including in relation to public health, rests with the federal government, an authority assumed since the founding of the country [ ] [ ] [ ] [ ] [ ] . the administration implemented a travel ban affecting only non-us travelers from china on january , , without any mandatory symptom screening at entry or quarantine of travelers, despite the virus at this time already known to be present in italy, iran, spain, germany, finland, and the united kingdom. similarly, selective restrictions on travel from europe were only instituted a full weeks later, on march , , at which point deaths had been reported in italy alone (by contrast, on january , china had reported deaths). none of these restrictions applied to returning us citizens or permanent residents, despite their potential exposure to sars-cov- [ ] . hence there were ongoing opportunities for introductions of the virus to the us from europe. consistent with this, phylogenetic studies have found repeatedly that the great majority of sars-cov- introductions to the us were viral lineages circulating in europe [ ] . a study of the genomic epidemiology of the early pandemic in the boston area estimated a total of independent importations from europe, of which occurred prior to march [ ] [ ] [ ] . imports included a superspreading event at a conference on february - leading to more than known infections among attendees or their contacts. the index cases were two international business travelers. this introduction is estimated to be the direct ancestor of % of sampled genomes not associated with the conference, including samples from outbreaks in homeless shelters, so it is reasonable to suggest that this introduction alone hastened the establishment of the virus in the region and the scale of the subsequent surge of infections. as has been previously shown, by early march the most likely source of introduction to a region was from elsewhere in the united states [ ] . this shows that any action to delay or prevent introductions would need to be at the national level, and while the window for effective action was brief, it was missed. symptom screening alone is unlikely to provide a significant barrier to a virus like sars-cov- that is capable of presymptomatic transmission [ ] , but may be an effective component of mitigation if supplemented by a coherent central strategy to delay case importation. while like-for-like comparisons of government responses to covid- should be interpreted with caution, the benefits of such an approach are well-illustrated by australia: like the us, australia is a large and well-developed economy with major metropolitan cities, substantial international travel, and wide variations in population density. also similar to the us, important elements of pandemic response were devolved to individual states, but border control is the responsibility of the central federal government. australia had reported confirmed cases on march when it imposed a closure of its borders to non-australian citizens, which was augmented by a mandatory -day, supervised quarantine in a hotel for all international arrivals (including australian citizens), aggressive testing and contact tracing, and population-wide adherence to social distancing guidelines [ ] . following these local containment measures australia saw no explosive covid- case surges through the southern hemisphere winter. despite a recent burst of domestic transmission in the state of victoria that resulted in the immediate re-imposition of a statewide lockdown and interstate movement restrictions [ ] , at present (early september ) australia reports . deaths/million persons, in comparison with the us report of deaths/million persons [ ] . this is the difference between establishing effective national border policies and failing to do so. the pandemic has presented different risks and rates of exposure to different sectors of us society, at different times and in different places. health care and other essential workers who continued to work while much of the country was shut down, who work in close quarters or have contact with the public as part of their job-e.g., in transportation, critical manufacturing, food and agriculture, grocery stores, and pharmacies-have faced a greater risk of exposure and infection from covid- . [ ] [ ] [ ] [ ] [ ] . despite the designation of these workers as "essential," an important federal failure has been the lack of standards requiring systematic collection of data on covid- cases or deaths by industry and occupation. nevertheless, information available from case reports, state health departments, media reports, and other sources show: large numbers of cases among health care workers and first responders; major outbreaks in meatpacking, and poultry plants [ ] ; outbreaks among prison staff (above and beyond inmates); and numerous cases in transportation, warehousing, and other essential industries, as well as in public-facing occupations (e.g., grocery stores and retail) [ ] . people infected at work expose their household members-and if they are low-wage workers, they are more likely to live in crowded housing with inadequate ventilation, which increases the risk of transmission and decreases the options for people who are ill to self-isolate [ , , [ ] [ ] [ ] . the federal government could have limited transmission of sars-cov- at the workplace in multiple ways. one is through its unparalleled purchasing power and ability to invoke the defense production act and ensure equitable supply and distribution of ppe. however supplying ppe was delegated to a variety of actors: state and city governments, large hospital chains, and in some cases small networks of clinics [ ] . second, the federal government could have established mandatory universal paid sick leave for those unable to work due to covid- , but it did not. the congressional mandate for h of paid covid-related leave covered only some groups of workers. third, the federal government could have mandated standards for occupational exposures, but it failed to act, even as some us states have done so. to date, the federal occupational safety and health administration (osha) has not issued any emergency or permanent standard specific to covid- exposure at the workplace; additionally, as of august , , federal osha, which oversees enforcement of osha standards in states, had issued only four citations related to covid- [ ] . moreover, the total number of federal osha inspections (of any kind) during has been reduced by twothirds, compared to the same period in prior years [ ] . several of the states with approved state osha plans have taken stronger regulatory and enforcement action than federal osha to protect workers from exposure to sars-cov- . for example, virginia issued a comprehensive emergency temporary standard on sars-cov- on july , , and the state of michigan has issued multiple executive orders on worker protection from covid- enforced through the michigan state osha plan [ , ] . the california, nevada, and minnesota state osha plans have all issued numerous citations under other existing standards to protect workers from covid- [ ] . however, in most states little regulatory or enforcement action has been taken by either the federal government or the state to address workplace exposures to the virus [ , ] . while there have been few federal osha citations, worker complaints to osha that raise concerns about workplace conditions and exposure to covid- can serve to estimate hazards of exposures and risks of infection as reported by workers themselves. to our knowledge, these data have not been analyzed in relation to the population burdens of covid- [ ] . figure shows the volume of osha complaints (federal and state combined), broken down by four industries (manufacturing, retail, healthcare and social assistance, and other up to september th ). the total number of national complaints is shown, as are the numbers of complaints for the four main geographical regions of the country. covid- mortality data from confirmed cases is also shown. figure in turn presents results of the time-series analysis using osha complaints volume, as a function of time, as a predictor and confirmed covid- cases and covid- deaths as the response variables. specifically, we identified the best time lag that predicts each response variable-using osha complaints as a predictor-by calculating the pearson correlation between multiple lags for each response variable and osha complaints. two findings stand out: ( ) the curve of the osha complaint data resembles an epidemic curve (fig. ) , and ( ) the complaints predate covid- deaths (fig. ) . at the national level, the osha complaints were best correlated with (a) covid- deaths days later ( = . ), and (b) covid- new confirmed cases days later ( = . ). across all four subregions-northeast, south, midwest, west-of the country, osha complaints foreshadowed covid- deaths by . - weeks, with moderate to high correlations ( . to . ). correlations with cases, however, are notably weaker in regions other than the north-east, which may be unsurprising given the volume of cases there in the spring. in general the variation in rates by geographic region and industry is substantial and mirrors the course of the pandemic-notably when considering individual industries the strongest correlation observed was between complaints in the health care and social assistance sector and deaths days later ( = . ) . regional correlations between complaints and reported covid- cases and covid- deaths (fig. ) suggest complaints reflect local responses to awareness of pandemic activity. these patterns point to a lack of learning from experiences across states, and the lack of enforced federal standards. according to osha covid- enforcement data, as of september , , federal osha had opened inspections for only out of worker complaints ( . %) received related to covid- [ , ] . during this same time period, the state osha plans had opened inspections in response to , covid- complaints received- . % of worker complaints for covid- [ , ] . these results further suggest that osha complaints have the potential to be used, in a prospective manner, to predict changes of covid- activity as an additional data source in early warning systems such as those as described in [ ] . we cannot determine the extent to which patterns of osha complaints reflect growing awareness of the pandemic and the need for adequate protection, or whether they are more direct indicators of failures that causally contributed to workplace, family, and community spread. but findings do suggest that expressed worker concerns may be an indicator of real risks, and failure to respond is a missed opportunity to intervene to mitigate disease transmission in the workplace and, in turn, the community at large. while there is not a consistent definition of "essential workers," data suggest that people in this category disproportionately are low-income, are people of color, rely on public transportation, and live in crowded housing [ , , [ ] [ ] [ ] . they also have more underlying disabilities and less access to care, which underscores the importance of mitigating exposures to sars-cov- in the workplace. work is a key exposure risk, and to date, federal policies regarding covid- and workplaces have chiefly aimed to limit the liability of employers, rather than to protect employees through, for example, mandating that employers develop an infection control plan [ ] . in the following section we consider the consequences in terms of excess all-cause mortality and racial/ethnic inequities in covid- mortality. beyond the number of confirmed covid- deaths in the us (more than , as of / / , estimates of excess deaths (comparing the same calendar period for to the average annual deaths for - and controlling for population growth) provide a powerful way to gauge the excess mortality due to covid- . excess mortality may be due directly to the infection or be due to delays in seeking care for non-covid illnesses or injuries; this measure also takes into account potential reductions in mortality (e.g., due to lower air pollution during the economic lockdown) as well as the seasonality of death rates [ ] [ ] [ ] . in table , we show the results of four different approaches, ranging from more to less conservative, that have been used to estimate the excess number of deaths and the excess death rate (per , person-years (p-y)), in relation to us mortality data as of september , [ ] [ ] [ ] [ ] . no matter which method is used, the estimated excess number of deaths, ranging from , to , , is already greater than the outer margin of what the federal government stated, on april , , would be the upper limit of the expected death toll, i.e., , [ ] [ ] [ ] . we additionally estimated an annual excess age-standardized death rate of . per , p-y ( % ci . - . ) based on the difference in age-standardized mortality rates for vs - , (as opposed to scaling the estimated excess death count by the population as in table ). this estimate is almost double that of the third leading cause of death in the us, i.e., unintentional injuries, for which the annual age-standardized death rate was / , p-y in (the most recent year available) [ ] . the number of excess deaths in ( , ) is already well over half the number of cancer deaths for all of ( , ) [ ] . it should be obvious that given that the pandemic is not over, and transmission continues in much of the country, these numbers can only increase. australia is again instructive, as it exhibits very little excess mortality. the most recent report from the australian bureau of statistics states, " , doctor certified deaths occurred between january and may and were registered by june. this compares to a baseline average of , over the past years" [ ] . this translates to an excess of only deaths in australia. in contrast, the us, with a population times greater, has times more excess deaths. if the us has struggled with national pandemic response, it is instructive to compare with europe. like the us, european nations are advanced economies with substantial resources. unlike the us, they are themselves independent nation states, with no overarching federal coordination, and the continent is far more densely populated than the us and has an older population. some european nations have suffered even higher per-capita mortality from the pandemic so far than the us, among them italy and spain (hit hard early in the spring) and the united kingdom. in contrast others such as germany (like the us a federal nation with extensive porous land borders) have far less covid- related mortality, and relatively little excess mortality overall including in the most at-risk age groups [ , ] . in contrast with the us, european nations have seen few subsequent surges over the summer after initial introductions were controlled, even if cases are increasing once more in many countries. however, the overall all-cause mortality for the continent as a whole through the end of july, when outbreaks were still ongoing across the south of the us, is estimated to be % lower than the us [ ] . we must also consider outcomes other than death. while sars-cov- is a virus that spreads via the respiratory route, it causes a systemic infection with commensurate potential for diverse long term sequelae, including important outcomes such as stroke in young, otherwise healthy adults [ ] , and multisystem inflammatory syndrome in children (mis-c), a condition similar to kawasaki syndrome that is associated with pediatric sars-cov- infection [ ] . if an extremely large number of infections are permitted, even rare chronic outcomes will leave a large burden on healthcare after the pandemic. as of august , , the number of confirmed cases in the us equaled . million-almost on par with the population of massachusetts ( . million) [ ] . [ ] . if % of the million cases were so afflicted, the number of persons ( , ) would exceed the national estimate for the number of us women diagnosed with breast cancer ( , ) [ ] . the proportion of long-term effects of one kind or another is unknown, but it is increasingly recognized as a source of serious concern [ , ] . finally, despite the initial federal failure to report covid- data by race/ethnicity [ ] , a combination of specific studies, state reporting, investigative journalism, and data trackers has revealed that a persistent feature of the pandemic has been the existence of racial/ethnic inequities in cases, hospitalizations, and mortality, especially with regard to increased risk among us black, latinx, and american indian/alaska native populations compared to the us white non-hispanic population [ - , , , , ] . what is less appreciated is that racial/ethnic inequities in covid- mortality rates, especially among younger working-age adults, are increasing over time, especially among the latinx and american indian/alaska native populations. these table estimation of excess deaths during the us covid- pandemic, comparing weekly death counts to the corresponding average annual - deaths, using different methods a as of september , (source: centers for disease control and prevention) a method : sum up over weeks and then age-standardize using the direct method method : count only age strata and weeks where the excess is greater than zero, and set weeks where the excess in the age stratum is less than zero to zero method : we compare to the upper bound on the average deaths for - , but once again ignore weeks where the excess in the age stratum is less than zero b age-standardized excess rate per , person-years is computed based on dividing the age-specific excess count of deaths under the four methods by the age-specific population person-time (taking into account the age-specific population counts and the elapsed time since january , ), weighting by the year standard million, and summing over age categories c age-standardized cumulative incidence proportion per , population (i.e. a risk per capita) is computed based on dividing the age-specific excess count of deaths under the four methods by the age-specific population count in , weighting by the year standard million, and summing over age categories trends are evident in fig. , which we generated using cdc data for february through september th, (with . % of deaths assigned a race/ethnicity) [ , ] . specifically, the racial/ethnic inequity in age-standardized mortality rate ratios, compared to white non-hispanics, increased over time for the five calendar periods displayed (february -may , may -june , june -july , july -august , august -september , and september -september ) among working age adults (ages - ) who were categorized as black non-hispanic (p value for trend < . ), hispanic (p < . ), and american indian/alaska native (p < . ).the estimates we report, moreover, are likely to be conservative because classification of covid- deaths in part depends on testing, and inequities in access to testing, especially affecting low-income communities of color, would deflate their reported covid- mortality rates [ , ] . moreover, the elevated mortality risk on the order of -to tenfold among persons under age shown in fig. is unlikely to be explained by pre-existing co-morbidities, because the documented racial/ethnic mortality rate ratios for major chronic conditions (including cardiovascular disease, diabetes, and cancer) among adults under age are around twofold or less [ , , ] . in closing, we have documented key points at which the us federal government has failed to take the actions and collect the data needed to protect the us population from covid- and the attendant toll on population health and health inequities. despite the understandable dismay at the state of the pandemic in the united states, it is not too late to make a difference, and that difference starts with the implementation of apt policies. those policies are too numerous to list here but have been amply documented in publications from organizations such as the center for global development, which identified many of the relevant challenges early in the pandemic, stating in february: "there is an urgent but closing window to prepare for large-scale spread of the disease in the us and elsewhere. this paper recommends actions to address pressing gaps in us and global preparedness in the event that covid- cannot be contained and sustained human-to-human transmission occurs beyond china" [ ] . the national association of county and city health officials has made the urgency of maintaining health equity in an emergency preparedness plan, as have local health officials [ , ] . perhaps most poignantly, a "pandemic playbook" produced by the national security council in "repeatedly (advises) officials to question the numbers on viral spread, ensure appropriate diagnostic capacity and check on the us stockpile of emergency resources" [ ] . what we have seen is the consequence of not heeding that advice. all cases and deaths cannot be prevented-that clearly is not possible with a novel pandemic-but the evidence suggests that ineffective national policies and responses [ ] , especially as compared to those of other wealthy nations or compared to the intricate preparation and planning by previous administrations of both parties, have been driving the terrible toll of covid- and its inequities in the us. this country-and its political leaders, who bear responsibility-can and must do better. open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/ . /. reported cases and deaths by country, territory, or conveyance the racial time bomb in the covid- crisis what the data show: the pandemic seems to be hitting people of color the hardest. the atlantic racism in the time of covid- . interdisciplinary association for population health science the fierce urgency of now: closing glaring gaps in us surveillance data on covid- population health in the time of covid- : confirmations and revelations. milbank quarterly enough: covid- , structural racism, police brutality, 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affiliations we would like to thank ziba cranmer and gowtham asokan, with bu spark! (boston university, massachusetts), for their advice, early on, regarding accessing and exploring the osha complaint data. we would also like to thank lawson ung (hsph) for advice on the nature of the australian pandemic response. we would like to thank and acknowledge dr. mary t. bassett (director, françois-xavier bagnoud (fxb) center for health and human rights at harvard university and fxb professor of the practice of health and human rights, harvard t.h. chan school of public health) for her intellectual leadership for prior work, in which she involved nk and jtc, on the importance of analyzing age-specific racial/ethnic inequities in covid- mortality, and which has influenced the approach taken for this paper. we would also like to thank pamela waterman (hsph) for her influence on the paper's analytic orientation and also for her role in facilitating team meetings and communication. we have written permission to acknowledge all of the individuals listed. authors' contributions w.p. hanage co-conceptualized the paper, led its writing, and helped frame the analyses and interpret results. c. testa co-conceptualized the analyses, helped obtain the data and conducted the data analyses for the occupational health and health inequities sections, and contributed to manuscript preparation. j. chen co-conceptualized the analyses, helped obtain the data and helped oversee the data analyses and interpretation for the occupational and health inequities sections, and contributed to manuscript preparation. p. seminario, e. pechter, and l. davis led acquisition and interpretation of the osha complaint data, and contributed to manuscript preparation. m. santillana co-conceptualized and assisted with implementing the analyses and interpreting them and contributed to manuscript preparation. n. krieger initiated the paper, led assembling the team, contributed to framing the paper and drafting each section, and guided the data acquisition, data analyses, and data interpretation for the sections pertaining to occupational health and health inequities. all co-authors contributed to the final manuscript and approved its content before submission. key: cord- -v c vda authors: istúriz, raul e.; torres, jaime; besso, josé title: global distribution of infectious diseases requiring intensive care date: - - journal: critical care clinics doi: . /j.ccc. . . sha: doc_id: cord_uid: v c vda this article describes infectious diseases that are of special importance to intensivists. the emphasis on epidemiology notwithstanding, it also addresses clinical, diagnostic, and treatment issues related to each infection described. the discussion avoids terrorism-related aspects of these infections, because they were very well covered in the october issue of the critical care clinics. of standardized definitions in different areas of the world, and the lack of large-scale studies based on significant cohorts, do not permit epidemiologic certainty [ ] . estimates of the epidemiology of sepsis published rely mostly on discharge diagnosis data. annual incidence is high in the united states, around per , population and mortality is also high, % to % [ , ] . morbidity and mortality depend on the characteristics of the host and the infecting microbe. in terms of incidence and mortality, the situation regarding sepsis and severe sepsis in such areas as latin america [ ] , africa [ ] , and asia [ ] may be worse than in developed countries. although the average age of patients with the diagnosis of sepsis at the time of discharge is years, the attack rate is very high in children (over cases per , population per year), and low-weight newborns have the highest incidence. both incidence and mortality decrease after age year to increase gradually up to adulthood. infection originates in the lungs, abdomen, urinary tract, and skin in most studies [ ] [ ] [ ] [ ] . ventilatorassociated pneumonia is a leading cause of death from hospital-acquired infections in the icu setting [ ] . bacteremic patients frequently evolve and develop sepsis, severe sepsis, and septic shock with correspondingly increasing mortality [ ] . in adults, both in the united states and europe, most (around %) patients admitted in icus with the diagnosis of sepsis have already been hospitalized for other causes and come from the hospital wards [ , ] . severe bacteremia and sepsis caused by the classic pathogens neisseria meningitidis and streptococcus pyogenes is rarely found now, and has been replaced by sepsis caused by commensal microbes, which infect individuals with conditions that compromise their skin and mucosal barriers or their immune systems. advances in surgical techniques including transplant medicine, and increased survival of patients with trauma, splenectomy, and neutropenias are, in part, caused by advances in the treatment of sepsis associated with these conditions. in % of the patients no responsible microorganism is isolated, in most the organism isolated from blood or the infection site was one that usually does not cause infection in healthy persons, and frequently the infection is polymicrobial [ , ] . although for many years gram-negative bacteria were found in most bacteremic patients with severe sepsis, the percentage of cases associated with blood isolation of gram-positive pathogens has increased in the last decades and now staphylococcus aureus, coagulase-negative staphylococci, and enterococci are responsible for % to % of the cases. another recent tendency is to isolate fungi ( %- %), notably species of candida [ , ] . difficult-to-treat pathogens include pseudomonas aeruginosa, acinetobacter species, klebsiella pneumoniae, enterobacter species, resistant enterococci, and methicillin-resistant s aureus. a new syndrome of severe necrotizing pneumonia produced by infection by community-acquired methicillin-resistant s aureus led to icu admissions because of the severe manifestations [ ] . the organism is now also considered a hospital pathogen [ ] . the cumulative economic impact of resistant bacteria is enormous [ ] . candidemia commonly originates from catheters in colonized patients. species of candida, some resistant to antifungals, can spread by hematogenous seeding to lungs, liver, spleen, cardiac structures, bone, skin, and eyes. mortality is substantial. the introduction of new classes of antibiotics and antifungals, such as the oxazolidinones, the glycylglycines, and the equinocandins, has improved the ability to treat resistant pathogens. malaria continues to represent a leading cause of disease burden, in terms of death and disability, in a substantial part of the world. about % of the world's population lives in countries of africa, asia, central america, oceania, and south america where the disease is endemic. globally, . to . million malaria-related deaths occur annually. children are the worst affected group, especially children aged months to years. it may cause as many as % of all deaths in children in some endemic regions of sub-saharan africa. additionally, almost every country in the world experiences imported malaria. approximately cases and deaths caused by malaria are diagnosed every year in the united states. most of them ( %) are acquired outside the country. over half the cases originate from africa. plasmodia metabolize hemoglobin and other red blood cell proteins to create a toxic pigment called ''hemozoin.'' the parasites derive their energy solely from glucose, which they metabolize times faster than the red blood cells they inhabit; hypoglycemia and lactic acidosis are common findings. anemia is caused by lysis of both infected and uninfected red blood cells, suppression of hematopoiesis, and increased clearance of red blood cells by the spleen. over time, malaria infection may induce thrombocytopenia and hepatosplenomegaly. of the four species of plasmodium known to infect man, p falciparum is the most important. this is because the parasite is not only capable of infecting red cells of all ages and causing heavy parasite loads, but it also induces the production of proteinaceous knobs that bind to endothelial cells. these cytoadherent infected red blood cells tend to clump together within the small blood vessels in many organs and tissues, accounting for much of the damage incurred by the parasite. to a large degree, the damage observed in malaria by p falciparum seems to be related to damage inflicted by the host against itself, in response to the parasite. this is thought to be related to release of tumor necrosis factor; up-regulation of tumor necrosis factor receptors (type ); and consequent expression of adhesion molecules (intercellular adhesion molecule , especially). infected cells stick to endothelium using a large malarial protein called pfemp , which binds cd or thrombospondin. because p falciparum malaria is a potentially life-threatening disease, close clinical and laboratorial monitoring of patients is necessary. moreover, reliable criteria for icu admission should be defined and risk factors identified (box ). in children, the complications of severe malaria include metabolic acidosis, often caused by hypovolemia; hypoglycemia; lactic acidosis; severe anemia; seizures; and increased intracranial pressure. in adults, renal failure and pulmonary edema are more common causes of death. in contrast, concomitant bacterial infections occur more frequently in children and are associated with mortality in them. admission to critical care units or icus may help reduce the mortality, and the frequency and severity of sequelae related to severe malaria [ , ] . the mortality in acute renal failure without dialysis is % to %. early diagnosis of established renal failure and institution of dialysis are important in preventing mortality. a rapidly rising creatinine level is the most sensitive indicator of the need for dialysis. peritoneal dialysis reduces mortality, but hemofiltration is even more effective and is associated with an improved outcome [ ] . early icu monitoring should be attempted, especially under the following conditions: lack of clinical response to antimalarial treatment within hours or any signs of neurologic disturbance (hypoglycemia excluded). prospective multicenter trials and guidelines for supportive intensive care are urgently needed [ ] . the mortality can be reduced by early recognition of the features of severe malaria; prompt administration of appropriate antimalarials; and treatment of complications, preferably in an icu setting. clinicians must have a high index of suspicion, especially with travelers who have recently visited endemic areas. a high standard of nursing care and continued observation in the acute stage of the disease are important for reducing mortality [ ] . leptospirosis is a widespread infection transmitted among animals and occasionally from animals to humans. direct exposure to urine of infected animals or urine-contaminated water and soil, through recreational or occupational activities, represents the main source of infection for humans. in general, occupations with a greater risk include dairy farmers, sewer workers, and soldiers. the most common source of exposure in some developed countries is the dog or other household pets, followed by livestock, rodents, and other wild animals [ ] . although the distribution of leptospirosis is worldwide, tropical regions bear the brunt of its impact. moreover, the environmental conditions prevalent in most tropical and subtropical regions, including abundant rainfalls, nonacidic soil, and high temperatures, along with numerous natural water courses and an abundant biodiversity, are particularly favorable for the transmission of leptospira infection. the icteric form or weil's syndrome is associated with severe hepatic malfunction; marked jaundice; hemorrhages; and cardiac, hemodynamic, pulmonary, and neurologic alterations. weil's syndrome has a high mortality rate. frequently, serum bilirubin levels are above mg per cm . although hepatic malfunction is not a major cause of death, it is associated with a higher incidence of complications and higher mortality. renal involvement in severe leptospirosis is characterized by an increase in urea and creatinine levels, elevation of the sodium excretion fraction, and nonspecific abnormal findings in the urinalysis. these include leukocyturia, hematuria, proteinuria, and crystalluria. oliguria occurs with variable frequency. acute renal failure may be aggravated by hemodynamic alterations, such as dehydration and arterial hypotension. notably, metabolic acidosis occurs more frequently in oliguric patients [ ] . the use of dialysis methods to manage acute renal failure highly improves the survival of patients with severe leptospirosis [ ] . clinical cardiac involvement is frequent as a consequence of the concurrent myocarditis. metabolic disturbances, such as hypokalemia, may aggravate this condition. the most common manifestations are ekg alterations and cardiac arrhythmia. hemorrhagic phenomena are relatively common, and may occur in the skin, mucosae, or internal organs. over the past decade, pulmonary hemorrhage has been increasingly recognized throughout the world as a grave manifestation of leptospirosis. pulmonary hemorrhages may vary from ordinary hemoptoic sputum to massive pulmonary hemorrhage. gastrointestinal hemorrhages with variable degrees of severity may also occur, manifesting as melena, hematemesis, and enterorrhagia. pulmonary involvement is characterized by the presence of hemorrhagic interstitial pneumonia, with diffuse or localized pulmonary infiltrates. respiratory failure with decreased arterial pao is attributed to impaired oxygen diffusion at the alveolar-capillary membrane level as a result of edema and blood leakage into the pulmonary interstitium. leptospirosis associates with high lethality when complicated with organ dysfunction (r %). poor prognostic factors are male gender, alcohol dependence, age o years, a high multiple organ dysfunction score, acute respiratory distress syndrome, presence of metabolic acidosis, and need for mechanical ventilation. timely intervention and intensive therapy, however, may be lifesaving [ , ] . the excess morbidity and mortality associated with influenza epidemics and the increased hospitalization costs are secondary to severe cases of the disease [ ] . primary influenza pneumonia, secondary bacterial pneumonia, and mixed viral and bacterial pneumonia are critical human features of influenza virus infection. although children are among the groups most at risk for developing influenza and its complications and are more likely to spread the infection to others, complications of seasonal influenza occur most frequently among patients older than years and those with chronic comorbidities including diseases of the cardiovascular or pulmonary system, diabetes mellitus, hemoglobinopathies, renal insufficiency, and immunosuppression. pregnancy may also pose an added risk. recent information suggests that at least some avian influenza viruses may cause life-threatening and lethal disease in individuals without predisposing factors [ ] . other than differences in neuraminidase, the viral features that might make them more pathogenic for humans are unknown. despite the fact that influenza is in general worldwide in distribution, it tends to occur in partially confined outbreaks in communities of varying sizes with the prevalence of one viral strain. primary influenza pneumonia, more commonly caused by influenza a virus, is not common, but no reliable information exists as to the exact prevalence of complicated disease [ ] . estimates vary, but studies of sequential epidemics suggest an overall complication rate of close to %. complicated respiratory influenza begins abruptly with typical features of seasonal disease but progresses rapidly and relentlessly to the adult respiratory distress syndrome. diagnosis may be made aided by the epidemiology, rapid tests, viral isolation, culture, polymerase chain reaction, and serology, but in clinical practice is seldom documented on time for effective therapeutic measures to be taken. sputum bacteriology is not helpful. chest radiography typically shows bilateral infiltrates without consolidation, but localized pneumonia with segmental unilateral infiltrates occurs. there is no response to antibiotic treatment and mortality is high. pathology shows diffuse pneumonia with hemorrhage, hyaline membranes but little inflammation. the m ion channel inhibitors amantadine and rimantadine have activity against strains of influenza a but not b or c viruses. they are not active against the current h virus strain that threatens to become the precursor of the next pandemic. the neuraminidase inhibitors, extremely active against all influenza a strains, remain active against influenza b strains and the avian viruses of all neuraminidase subtypes, but resistant strains have been described. clinical information supporting the efficacy of antiviral drugs in severe influenza pneumonia is not available, and recommendations are made based on case reports. secondary bacterial pneumonia is usually suspected when a patient experiences an exacerbation of fever and respiratory symptoms after a period of improvement from influenza like-illness. this biphasic evolution may not be present. bacterial pneumonia may coincide with viral pneumonia in mixed viral and bacterial pneumonia. it may also be clinically indistinguishable from pneumonia in the absence of viral infection and separation is difficult during an influenza outbreak. streptococcus pneumoniae, haemophilus influenzae, s aureus, mycoplasma pneumoniae, and other pathogens can be responsible. severe acute respiratory syndrome is a serious, infectious, pulmonary illness that jumped species from semidomesticated animals to humans, and spread from china and hong kong in late . most of the affected individuals were cared for in china ( ) and hong kong ( ). cases were treated in countries including vietnam, singapore, thailand, taiwan, and canada, most in intensive care settings. approximately months after the first case, a coronavirus was identified as the causative organism [ ] . severe acute respiratory syndrome's main symptoms include high fever, myalgia, cough, and dyspnea progressing to the adult respiratory distress syndrome and multiple organ dysfunction [ ] . reverse-transcriptase polymerase chain reaction serology and culture are possible but have shortcomings making routine clinical use difficult. there is no specific anticoronavirus therapy and supportive care remains the principal therapeutic alternative. rivabirin and corticosteroids have been used but their efficacy has not been established. mortality is around %. infection control practices are extremely important in halting the progression of an outbreak. generalized tetanus, a protein-toxin mediated neurologic disorder caused by clostridium tetani, an obligate anaerobic, motile gram-positive rod with terminal spores has traditionally been, and continues to represent despite effective vaccine a common cause of intensive care admissions that are long and are associated with high mortality [ ] and cost. the global incidence of tetanus has been estimated at about million cases per year. in the united states the reported cases and deaths from tetanus have decreased substantially since the s because of successful vaccination efforts [ ] . the risk of developing clinical tetanus after an acute puncture or laceration is higher in patients older than years, a reflection of waning immunity, with a significant proportion of cases occurring in women [ ] , and a low mortality rate. injection drug users are a growing population at risk [ ] . in sharp contrast, the epidemiology of generalized tetanus in developing countries, where mortality figures may be up to times higher, follows closely the problem of lack of immunization efforts. in some areas, neonatal tetanus, occurring in the offspring of unvaccinated women, causes approximately % of the cases and mortality. even worse, mothers with a past history of babies suffering neonatal tetanus accounted for more than one third of all cases in one study [ ] . the disease is seen predominantly in rural areas, in areas where soil is cultivated, and in tropical regions or in summer months in template regions. in developed countries, neonatal tetanus must still be suspected, especially in populations that avoid standard vaccination and prenatal care. tetanus is one of the few diseases that are diagnosed only on clinical grounds (the only major differential diagnosis is strychnine poisoning), but in some difficult cases electromyography may assist the clinician. treatment, details of which are beyond the scope of this article, includes supportive therapy, attention to several clinical manifestations, and passive immunization. the role of antibiotics against c tetani remains controversial. mortality, even in experienced icus, may reach % in severe cases. tetanus is an inexcusable disease [ ] , because it is preventable with a three-dose series of an inexpensive and safe toxoid. the expanded program on immunization should be reinforced whatever the area of the world and age group. although the toxin produced by clostridium botulinum is structurally and functionally similar to that of c tetani, its clinical effects are entirely different, and in a sense opposite. whereas tetanus toxin produces muscular rigidity and spasms, botulinum toxins produce muscle weakness. human botulism also has a worldwide distribution, and foodborne disease is usually present in outbreaks. the epidemiology is different from that of tetanus and, at least in the united states, parallels the presence of the toxin type present in the spores of the environment [ ] . in countries and societies around the world, such as alaska, china, egypt, and mozambique, botulism may be linked to food preparation techniques [ ] [ ] [ ] [ ] [ ] [ ] , in others to religious practices [ ] . infant botulism, acquired through the consumption of spores rather than toxin and commonly attributed to consumption of honey and other sources [ ] , may present with constipation, feeding problems, hypotonia, and a weak cry. respiratory assistance is necessary when upper airway obstruction ensues; this is commonly followed by respiratory insufficiency of long duration [ ] . relapses have been described. clinically, and shortly after toxin ingestion, adult patients remain mentally intact but develop symmetric descending weakness acutely in the absence of fever or sensory deficit outside of the eyes [ ] . nausea, dry mouth, and diarrhea may accompany the neuropathy. several autonomic problems may also be present [ ] . patients requiring mechanical ventilation may necessitate long periods of treatment in the icu setting [ ] and prolonged intubation [ ] . toxin type may predict clinical manifestations [ ] ; disease caused by toxin a tends to be more severe than disease caused by toxin b. diagnosis must be suspected clinically, and is easier during an outbreak; the edrophonium test can be helpful to exclude myasthenia gravis and the absence of tick attachment helps rule out tick paralysis. the guillain-barreś yndrome and the miller fisher variant, the eaton-lambert myasthenic syndrome, acute poliomyelitis, and magnesium intoxication are in the usual differential diagnosis. anaerobic cultures and botulism toxin assays of serum, intestinal content, and suspect foodstuffs are useful when available as are electromyographic studies, especially the painful repetitive nerve stimulation. treatment consists of supportive care, including ventilator assistance, antitoxin treatment or human botulism immune globulin (for infant botulism), and surgical cleansing of wounds. laxatives are important to eliminate active luminal toxin. patient recovery is slow and muscular weakness and neuropsychiatric sequelae may remain. application of all aspects of correct food handling protocols remains the best prophylactic measure against botulism. an effective vaccine for widespread use is sorely needed. the epidemiology of human rabies closely follows that of animal rabies and is only partially understood [ ] . the degree of development of nations may predict the local transmission patterns. in general, in areas where dogs are not immunized, canine rabies exists, and most human cases result from dog bites. in contrast, in areas with successful immunization programs, most human cases derive from exposure to wild animal species. globally, rabies virus has a broad host range. dogs account for % of animal rabies and are the major reservoir, terrestrial mammals for %, and bats for %. although canine rabies is now rare in latin america, it remains uncontrolled in areas of africa and asia. other wild animals, such as mongooses in africa and asia, skunks, gray and red foxes, raccoons (the principal reservoir in the united states), coyotes, and jackals in america, europe, africa, and asia are reservoirs. ninety-nine countries reported animal rabies in ; reported having no cases [ ] . in the united states, the domesticated animal that causes more cases in humans is the cat, followed by the dog. cattle, equines, sheep, goats, and pigs also transmit rabies variants. in a wide variety of species of insectivorous bats, rabies occurs in north america, europe, africa, asia, and australia. no history of bite is obtained in a substantial proportion of bat-associated human rabies [ ] . worldwide, as many as , individuals die yearly and million receive postexposure prophylaxis. most of the doses of vaccine used for postexposure prophylaxis carry a risk of neurologic adverse effects. rabies virus is transmitted from salivary secretion through contact (usually bite) with an infected animal [ ] . after a variable incubation period, the virus replicates locally and later reaches entry into the central nervous system through centripetal motion in peripheral nerves. it causes encephalitis, leading to an almost invariably lethal, progressive neurologic disease, characterized by agitation, upper neuron motor paralysis, impaired responses to external signals, and other abnormal neurologic signs. infection of the salivary glands and possibly other tissues during the clinical stage leads to shedding of rabies virions and potential transmission. corneal and other organ transplant has been responsible for rare human-to-human transmission [ ] . the finding of rabies virus antibodies in the cerebrospinal fluid in a patient with encephalitis is diagnostic of rabies; reverse-transcriptase polymerase chain reaction in saliva and skin biopsy sample of the neck have high sensitivity for detection of genetic rabies virus material. brain tissue is used for postmortem definitive diagnosis. once clinical rabies develops, there is no specific treatment and despite optimal intensive care, almost all patients gradually die. even if intensive ventilatory support is applied, many complications develop. the survival, without the use of rabies vaccine, of a -year-old girl in whom clinical rabies developed month after she was bitten by a bat made news in june [ ] . she was treated by induction of coma and was supported in an icu environment while receiving ketamine, midazolam, ribavirin, and amantadine. the patient was discharged after days of hospital care. after months, she exhibited choreoathetosis, dysarthria, and unsteady gait. the same treatment protocol, modified for specific complications, has been applied to at least two more rabies patients but survival has not been achieved. the pre-exposure vaccination of high-risk individuals is strongly recommended, as is postexposure prophylaxis [ ] . they are very effective and constitute specific measures. acute bacterial meningitis remains an important cause of morbidity, mortality, and neurologic sequelae in the world. given the problems with reporting, it is unlikely that the world prevalence of the disease is less than the best united states estimates of approximately cases per , population per year. in areas of brazil, the attack rate might be as high as cases per , population per year. meningitis epidemics have a strong environmental component in africa, with the most severe epidemics occurring in the sahelian region known as the meningitis belt [ ] . mortality varies, but has been estimated between % and %. in countries where h influenzae vaccine coverage in children approaches that of developed societies, three major epidemiologic changes have occurred in regards to community-acquired bacterial meningitis: ( ) there has been a dramatic decrease in meningitis caused by h influenzae, ( ) bacterial meningitis has become a disease of adults, and ( ) s pneumoniae is the leading cause of meningitis. penicillin resistance may be very high [ ] . other bacterial pathogens responsible are n meningitidis, group b streptococci, and listeria monocytogenes. nosocomial bacterial meningitis also is a major problem, with case fatality ratio of approximately %. the case fatality rate for meningitis caused by enterobacteriaceae is much higher, approaching %. factors involved in the pathogenesis of meningitis include the ability to colonize mucosal surfaces, intravascular survival, meningeal invasion, and survival in the subarachnoid space. once replication is established in meningeal tissues, alterations in the blood-brain barrier, increased intracranial pressure, alterations in cerebral blood flow, and neuronal injury develops. severe neurologic damage and mortality to the host are the consequences. patients present with headache, fever, nuchal rigidity, and signs of cerebral dysfunction. kernig's or brudzinski's signs might be present on physical examination. prompt analysis of cerebrospinal fluid including cultures (and blood cultures) typically confirms the clinical diagnosis and guides empiric therapy. gram stain and culture are positive in up to % of the cases. dexamethasone plus age and immune status-dependent bactericidal empiric or specific antimicrobial therapy with penetration into the cerebrospinal fluid must be started at appropriate doses immediately. in patients with increased intracranial pressure, several methods are available to intensivists effectively to reduce pressure. the timely use of pneumococcal, meningococcal, and h influenzae vaccines is advocated. viral hemorrhagic fevers are a heterogeneous group of severe, life-threatening viral diseases [ ] that have as a common base a degree of vascular instability and permeability and decreased vascular integrity resulting in bleeding. thrombocytopenia may be a feature that aggravates the bleeding tendency. with the exception of dengue and possibly yellow fever, travel to rural areas is a frequent epidemiologic clue to the diagnosis. the diseases are mentioned as they occur or threaten to occur in nature and some only briefly, highlighting the epidemiologic features that might make an intensive care specialist come in contact with them. dengue fever and dengue hemorrhagic fever (dhf) are increasingly important public health problems in the tropics and subtropics. dengue has been called the most important mosquito-transmitted viral disease in terms of morbidity and mortality. about to billion people live in areas where dengue is endemic. the disease is now found in more than countries throughout the americas, africa, the eastern mediterranean, southeast asia, and the western pacific. an estimated to million cases of dengue fever and , to , cases of dhf are officially notified annually; however, the true incidence is not known. case fatality rates vary from % to % in some asian countries to . % in the americas [ , ] . in a small proportion of cases, the virus causes increased vascular permeability that leads to a bleeding diathesis or disseminated intravascular coagulation characteristic of dhf. secondary infection by a different dengue virus serotype has been confirmed as an important risk factor for the development of dhf. in % to % of dhf cases, the patient develops shock, known as the ''dengue shock syndrome.'' worldwide, children younger than years comprise % of dhf subjects; however, in the americas, dhf occurs in both adults and children [ ] . patients with dhf who develop signs of dehydration, such as tachycardia, prolonged capillary refill time, cool or blotchy skin, diminished pulse amplitude, altered mental status, decreased urine output, rise in hematocrit, narrowed pulse pressure, or hypotension, require admission for intravenous fluid administration. patients with shock may be classified into one of two groups according to the pulse pressure at admission. those with pulse pressure o and % mm hg are considered of moderate severity, whereas patients with pulse pressure % mm hg are considered to have severe shock [ ] . the following types of patients are at risk, so attending staff must be particularly alert: young infants ! year old dhf grade iv or prolonged shock overweight patients patients with massive bleeding patients with changes of consciousness (encephalopathy) patients with underlying diseases (eg, thalassemia, g- -pd deficiency, congenital heart disease, and so forth) referred patients these patients need special laboratory investigations because they may have complications, such as internal bleeding; severe hypoglycemia; electrolyte imbalance (hyponatremia, hypocalcemia); metabolic acidosis; liver failure; and renal failure. to assess a patient's condition, the following laboratory tests are considered essential: hematocrit blood gases and serum electrolytes studies liver function tests platelet count, prothrombin and thrombin time, and partial thromboplastin time dengue shock syndrome, being a medical emergency, must be dealt with promptly by administering intravenous fluid to increase plasma volume. patients, particularly children, may emerge in and out of shock during a -hour period. the patient must be monitored around the clock by medical staff. blood pressure, pulse, and respiration must be recorded every minutes (or more frequently, if required) until shock is overcome. hematocrit or hemoglobin levels have to be checked every hours for the first hours, and then every hours until stable. a fluid balance sheet must be maintained. it should contain details of the type of fluid and rate and volume of its administration. the volume and frequency of urine output must also be recorded here. most children with dengue shock syndrome respond well to cautious treatment with isotonic crystalloid solutions. early intervention with colloid solutions is not generally indicated. the fluid regimen of ringer's lactate at ml/kg over a period of hours is now supported by strong prospective evidence and should be recommended for children with moderately severe shock. for those with severe shock, the situation is less straightforward, and clinicians must continue to rely on personal experience, local availability of particular products, and cost. minor advantages in initial recovery has been observed with starch, and significantly more adverse reactions were associated with dextran, so if the use of a colloid is considered necessary, starch may be the preferred option [ , ] . yellow fever follows different transmission patterns in areas of sub-saharan africa and south america. in africa the epidemiology of yellow fever has been from outbreak to epidemic in nature. some studies have estimated that epidemics of the last two decades have been large [ ] . in south america, in sharp contrast, a low-grade endemic situation exists, with few cases reported per year, usually in young men, from rural forest areas in a jungle cycle. the potential for urbanization by migration of infected individuals to cities and for large-scale epidemics caused by the presence of vectors in those cities in both areas of the world exists. yellow fever varies greatly in clinical presentation and severity, from an asymptomatic infection; to undifferentiated febrile illness; to a typical biphasic (infection plus intoxication) illness; to a severe hemorrhagic fever with high mortality. the abrupt onset of fever, headache, myalgia, and hepatitis accompanied by leucopenia and albuminuria is typical but may not be present in all patients. prostration is common in severe disease and may progress to stupor and coma. patients must be treated in an intensive care facility and isolated from mosquitoes. hypotension and shock, renal failure, and metabolic acidosis are poor prognostic signs. severe yellow fever is a very serious disease, with case fatality ratios of % to %. secondary bacterial infections worsen the prognosis of many patients but are amenable to treatment. laboratory confirmation of yellow fever, serologically or from tissue samples, is very important epidemiologically and must be pursued. supportive measures are used as needed, but no treatment protocols or affective antiviral drugs have been developed. survival is associated with lifelong immunity. an arenavirus, lassa virus causes endemic and epidemic disease in nigeria, sierra leone, guinea, liberia, and possibly other areas of west africa [ ] . the virus reaches humans endemically year round and epidemically during dry seasons from rodents by aerosolized small particles. it can also be transmitted by close interhuman contact and by nosocomial exposure. the number of cases in africa is unknown, but in endemic countries, lassa fever is a common cause of admission. estimates place in tens of thousands of cases annually in africa. a febrile disease contrasts with dengue fever in its gradual onset, followed by severe fatigue and prostration. a maculopapular rash might be present or noted. bleeding is seen in % to % of the cases. elevated transaminase levels predict adverse outcomes, and are considered an indication for ribavirin treatment. convalescence is slow and associated with bilateral deafness in a significant number of cases. progress has been made toward a vaccine [ ] . diseases seen in rural areas of south america [ ] caused by junin, machupo, sabia, and guanarito arenaviruses have so far been local public health problems. clinically, they are similar to lassa fever but thrombocytopenia and central nervous system dysfunction are more common and severe. intensive care specialists outside of these areas are unlikely to see patients, but should suspect the diagnosis of the south american hemorrhagic fevers given the right epidemiologic exposures, which with the exception of sabia virus occur after contact with wild rodents in rural agricultural areas. hantavirus pulmonary syndrome is a disease that predominates in south (andes virus) and north america (sin nombre virus), in china, and in russia (seoul virus) [ ] . laboratory rats may be infected and transmit disease to humans. hantavirus epidemics have been associated with seasons or years of increased rodent populations. the viruses, basically parasites of wild rodents, produce severe pulmonary edema (secondary to increased vascular permeability), hemoconcentration, and shock in humans. the disease commonly starts with severe myalgia and abdominal pain. severe hypoxia and shock are managed in the icu and, if the patient survives, reversion of the vascular leak permits complete recovery. diagnosis is based on the fact that igm and igg antibodies are present very early in the illness and can be measured by elisa on admission. reverse-transcriptase polymerase chain reaction in blood samples and immunohistochemical staining of tissues may detect hantavirus. treatment consists of judicious administration of fluids, cardiotonic drugs, and other supportive measures. other viral hemorrhagic fevers of interest, but unlikely to be treated in icus outside of discrete areas of the world are crimean-congo fever, ebola and marburg virus hemorrhagic fevers, kyasanur, and omsk. laboratory confirmation is very important. approximately % of patients who develop symptoms of acute hepatitis without pre-existing liver disease progress to severe acute, so-called ''fulminant liver failure'' (flf) with hepatic failure (defined as the presence of encephalopathy) within weeks of the onset of symptoms. the term ''acute liver failure'' is used to describe the onset of encephalopathy within weeks of the onset of jaundice. there are considerable geographic variations in the etiology of acute and flf. the most common causes in japan and asia are related to viral hepatitis. hepatitis e is the leading cause in india, whereas hepatitis b virus infections are the leading cause in france and japan [ ] . temporal changes in the etiology of flf are evident. drug-induced (acetaminophen toxicity) fulminant hepatic failure is currently a leading cause of liver failure in western developed countries [ ] . many viruses other than hepatitis also are recognized causes of flf in childhood, including epstein-barr virus; cytomegalovirus; paramyxovirus; varicella-zoster virus; herpesvirus types , , and ; parvovirus; and adenovirus [ , ] . hepatitis b virus is the most common cause of flf in endemic areas. recognized sources of infection include women with positive antihepatitis b antigen who give birth, and carriers of subdeterminants of hepatitis b surface antigen who donate blood. hepatitis a virus infection is a well-known cause of flf in individuals of all ages, with an estimated prevalence rate of . % to %. diagnosis of hepatitis a virus infection is made by the presence of anti-hepatitis a virus igm in the patient's serum [ ] . the risk of developing flf is generally low but there are groups with higher risks. pregnant women with acute hepatitis e virus infection have a risk of flf of around %, with a mortality of %. the risk of developing flf in hepatitis a virus infection increases with age and with pre-existing liver disease. fulminant hepatitis b is seen in adult infection but it is relatively rare [ , ] . the pathogenesis of flf usually initiates with the exposure of a susceptible person to an agent capable of inducing severe hepatic injury, even though the exact etiology remains undisclosed in most cases of flf. similarly, the pathophysiologic mechanism involved in the occurrence of hepatic encephalopathy in children with flf has not been fully defined [ ] . viral agents may cause damage to hepatocytes either by direct cytotoxic effect or as a result of hyperimmune response. apparently, the interaction between the infectious agent and the host determines the incidence of flf. fulminant hepatic failure is an uncommon but devastating illness in which the liver fails in a short period of time (! weeks in the initial definition [ ] ) in the absence of chronic liver disease. it must be distinguished from the much more common acute decompensation that develops abruptly and without warning in patients with chronic liver disease. in fulminant hepatic failure, mortality rate is higher and significant morbidity results from cerebral edema and intracranial hypertension, which are rare in patients with chronic disease. fulminant hepatic failure is defined by the development of coagulopathy and encephalopathy and is associated with rapid progression of multiple organ system failure. acetaminophen has surpassed viral hepatitis as the leading cause of fulminant hepatic failure in the united states and accounts for % and perhaps as much as % of the cases [ , ] . mortality rate is high but recovery is possible in % to % of patients with supportive care. the decision to proceed to liver transplantation is complicated. although the course may be protracted, recovery is usually complete. liver transplantation remains the sole lifesaving option for many patients. patients who have fulminant hepatitis have a mortality of up to % 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fulminant hepatitis medical progress: acute liver failure fulminant hepatic failure key: cord- -erdwejd authors: diaz, j. h. title: global climate changes and international trade and travel: effects on human health outcomes date: - - journal: encyclopedia of environmental health doi: . /b - - - - . - sha: doc_id: cord_uid: erdwejd there is now near-unanimous scientific agreement that greenhouse gas emissions generated by human activities have increased global temperatures and changed the earth's climate. there is, however, no universal agreement on how rapidly, regionally, or asymmetrically the earth will warm; or on the true impact of global warming on infectious disease outbreaks and natural disasters and their inevitable public health outcomes. in addition, many other factors influence the emergence and reemergence of infectious diseases in a changing environment including international trade and travel, exotic eating habits, lifestyle and residential choices, host susceptibility, and microbial adaptation. the ultimate effects of climate changes and the increased distribution of pathogens by international trade and travel will not be limited to infectious disease outbreaks in immunologically naïve populations but will also impact world food production and quality, air quality, drinking water availability and quality, immigration, urban relocation, and civil unrest. despite the uncertainties in outcomes and their magnitudes, the active responses to climate changes in a global economy must include combinations of environmental, political, regulatory, socioeconomic, and public health measures. the ultimate effects of global warming on rainfall, drought, and tropical cyclone activity will have farreaching human health impacts, not only on weatherrelated infectious disease outbreaks but also on world food production and supplies, access to safe drinking water, and mass population relocations. a more frequent drought-monsoon cycle supports outbreaks of malaria transmitted by water surface ovipositing anopheles species mosquitoes and dengue and chikungunya fever outbreaks transmitted by container-breeding aedes species mosquitoes. as nighttime temperatures increase and glaciers and permafrost retreat into the highlands, the geographic distribution ranges of mosquito and tickborne diseases extend to higher altitudes and to new regions in formerly disease-free areas with competent insect vectors. this article will explore the influences of free trade and international travel on public health outcomes in a warming world with a global economy. the interrelationships of climate change, international commerce, free trade, and international travel on observed human health consequences many factors will influence the onset of emerging and reemerging infectious disease outbreaks including climatic and ecosystem changes, new vector-pathogen relationships, human health behaviors, and human host susceptibilities. emerging infectious diseases may be defined as those that have recently appeared in human populations, have expanded their ranges of distribution, or threaten to increase their prevalences and distribution ranges in the near future. today most emerging infectious diseases arise in the natural environment as zoonoses, such as hantavirus pulmonary syndrome and severe acute respiratory syndrome (sars); or adopt a competent, new insect vector, such as aedes albopictus, a new mosquito vector for dengue and chikungunya viruses ( figure ). reemerging infectious diseases may be defined as those whose pathogenesis, clinical manifestations, and treatment strategies are well known but have reemerged as public health threats, often with increased antimicrobial drug resistances, such as multidrug resistant tuberculosis and methicillin-resistant staphylococcus aureus. in addition to climatic, ecologic, and microbial factors, other significant factors that influence the emergence and reemergence of infectious diseases include international trade and air travel, the globalization of agriculture and food production, exotic eating habits, lifestyle, and residential choices. the worldwide spread of the asian tiger mosquito, a. albopictus, by imported tire shipments on container ships from southeast asia has introduced a new secondary (to aedes aegypti) vector for dengue fever into the tropical americas and chikungunya fever in india and indian ocean islands (figure ). accessible airline connections now permit infected individuals to travel anywhere in the world in less than h, delivering human reservoirs of malaria, dengue, west nile virus, and chikungunya fever to new temperate areas for autochthonous or local transmission by new and adaptable mosquito vectors, often recent air or sea arrivals themselves. west nile virus was most likely imported to the united states in through air by the arrival in new york city of either an infected passenger or an infected culex species mosquito from an endemic region of east africa or the middle east. by , competent local culex vectors had initially established a mobile reservoir for west nile virus in wild birds in wet, warming ecosystems that began to move the virus rapidly across the united states from new york to the west coast. the initial wild animal reservoir for introduced west nile virus in the united states was so specific that it targeted only birds of the family corvidae, especially crows and jays. by , west nile virus infections were reported in other wild and domestic animals and humans across the continental united states and had caused over cases of meningoencephalitis with deaths (case fatality rate (cfr) ¼ . %). the major mosquito vectors of emerging and reemerging infectious diseases are featured in table . there were many historical examples of the international transport of human pathogens or their vectors by world exploration and trade that preceded any significant impact from recent climatic changes by centuries. prominent examples included the introduction of syphilis in the americas by european explorers, the spread of bubonic plague to europe by genoans returning from wars in the middle east, and the introduction of yellow fever carriers and mosquito vectors in the americas by west african slave traders. some recent examples of the international transport of pathogens or their vectors include the expanded global distribution ranges of plasmodium falciparum and p. vivax malaria and neuroangiostrongyliasis (nas) caused by the rat lungworm, angiostrongylus cantonensis. the most common reasons for malaria to occur in the industrialized nations of north america and europe where malaria was once endemic are also related to international air travel and include airport malaria and imported malaria. although similar subtropical ecosystems will support malaria reintroduced into formerly endemic regions such as the southern united states and the northern mediterranean, the exact impact of warming temperatures and greater precipitation on expanded malaria distribution ranges worldwide remains uncertain. nevertheless, malaria has become endemic at higher alpine altitudes in east africa and in south america. airport malaria is defined as the intercontinental transfer of malaria through the introduction of an infective anopheline mosquito vector into a nonendemic disease area with a changing ecosystem that supports the vector-pathogen relationship. however, imported malaria is defined as the intercontinental transfer of malaria by the movement of a parasitemic person to a nonendemic disease area with locally competent anopheline vectors in a welcoming ecosystem. airport malaria is acquired through the bite of an infected tropical anopheline mosquito within the vicinity of an international airport. the malaria-infected mosquito vector is a new arrival on an international flight from a malaria-endemic region. climate change has now expanded the geographic distribution of malaria-endemic regions and extended the length of seasonal malaria transmission cycles in endemic regions, so more arrivals of malaria-carrying mosquitoes are anticipated. how often do infected mosquitoes travel by air from tropical disease-endemic nations to capital cities in industrialized nations with disease-supporting warming ecosystems? in , random searches of arriving airplanes at gatwick airport in london found that of airplanes from tropical countries contained mosquitoes, some of which were female anopheles species capable of transmitting malaria. after the female anopheles species mosquito leaves the aircraft, she may survive long enough, especially during temperate periods, to take a blood meal and transmit malaria pathogens, usually in the vicinity of an international airport. after one or more figure the female aedes albopictus, or asian tiger mosquito, has been disseminated in coastal temperate zones worldwide by global trade and has genetically adapted to become a competent new vector for dengue and chikungunya viruses. reproduced from cdc image, available at http://www.dpd.cdc.gov/dpdx. blood meals, female mosquitoes seek a water surface to lay their eggs. all female mosquitoes lay their eggs in standing water, either on the surface or just below. the anopheline vectors of malaria prefer to lay eggs in drainage ditches, marshy areas, and puddles. the culicine vectors of west nile virus, dengue, and chikungunya fever prefer to lay their eggs in containers that trap freshwater, such as flower pots and even discarded tires. climate changes, particularly warming nighttime temperatures and increased precipitation, offer several selective advantages to all mosquito species including ( ) a longer reproductive life and a prolonged breeding season, ( ) opportunities for more blood meals during gestation, ( ) plenty of standing water surfaces for egg laying, and ( ) a faster egg hatch over days and not weeks. as international air travel between malaria-endemic nations and malaria nonendemic nations increases, cases of airport malaria have increased. in , two cases of p. falciparum malaria were diagnosed in persons without histories of travel to malaria-endemic regions living and km from gatwick airport. hot, humid weather in britain may have facilitated the survival of imported, infected anopheline mosquitoes. during the summer of , six cases of airport malaria were diagnosed in the vicinity of charles de gaulle airport near paris. four of the patients were airport workers, infected at work, and the others were residents of villeparisis, a small town approximately . km away from the airport. to reach villeparisis, the infected anopheline mosquitoes were thought to have hitched a car ride with airport workers who lived next door to two of the patients. in addition to airport malaria transmitted by infected mosquito air travelers, many countries throughout the developed world are reporting an increasing number of cases of imported malaria because of the great increase in long-distance air travel by infected passengers. malaria cases imported from africa to the united kingdom rose from in to in . in , an italian woman was infected with malaria following a bite from a local, malaria-competent vector, anopheles labranchiae. this species had been a common malaria vector in italy until the country was declared malaria free in . the local mosquito responsible for transmitting malaria was thought to have acquired the parasite after biting a parasitemic girl who had recently arrived in italy from india. airport malaria was ruled out in this case because of the great distance from the nearest international airport. this case illustrated the ease with which imported malaria may be reestablished in a formerly endemic nation with a warming climate, competent local anopheline vectors, and a humid and wet ecosystem that supports vector-host-parasite relationships. in the united states, recent outbreaks of presumed local or autochthonous mosquito-borne malaria transmission have been reported in california, following the immigration of agricultural workers from malaria-endemic areas of mexico. in , a p. vivax malaria outbreak resulted in cases, in mexican migrant workers, over a -month period. epidemiological and microbiological investigations later confirmed secondary spread from infected immigrants to other immigrants and local residents transmitted by local malaria-competent, anopheline vectors. prevention and control strategies for airport and imported malaria should include early case definition, case confirmation, and treatment; strengthened vector surveillance to detect the potential for autochthonous transmission; and drainage of potential mosquito breeding and egg-laying surface water sites. although the relationships among infected vector importation, index case immigration, reclaimed disease ecosystems, and malaria transmission are complex, future attempts to control and eradicate airport and imported malaria should be based on an understanding of disease transmission mechanisms and an appreciation that climate and ecosystem changes can support reemerging local mosquito-borne infectious diseases, especially malaria, dengue, chikungunya fever, and west nile virus (table ) . in addition to commercial, business, and recreational international air travel, infectious diseases may also be transmitted by sea from endemic to nonendemic nations with warming ecosystems that will support host-pathogen relationships. infected arthropod vectors, infected animal hosts, especially rodents, and even virulent microbes travel well at sea, especially in hot and humid ship cargo holds and in cargo containers. recent outbreaks of cholera in ecuador and peru have followed increased shipping trade with southeast asia, where vibrio cholerae is endemic in coastal estuaries. traceback investigations have demonstrated that container vessels pump in contaminated saltwater ballast into their hulls in their homeports for smoother transoceanic sailing and then discharge the ballast before unloading in distant ports with warming estuaries. such practices can effectively import cholera bacteria, marine viruses, and harmful algae to new, warming marine ecosystems and fisheries causing microbial and algal toxin contamination of shellfish beds and regional fisheries. the exotic pet trade, exotic cuisines, adventure travel, and emerging infectious diseases in the developed world the helminthic infections that can cause eosinophilic meningitis (em), neuroangiostrongyliasis (nas) and gnathostomiasis (gns), and chagas disease, an arthropod-borne zoonosis, share many of the characteristics of emerging infectious diseases supported by free trade in a warming world. nas is now endemic in hawaii and some coastal us cities following the us importation of nas by stowaway rodent hosts on cargo ships from china and southeast asia of the causative parasite, a. cantonensis, or rat lungworm. the intentional introduction of an intermediate a. cantonensis host, the giant african land snail (achatina fulica), to control insect pests on us farmlands and to serve as exotic pets for home terrariums also imported the unwelcome parasites to us ecosystems by paratenic or transporting hosts. gnathostoma spinigerum-induced gns has been recently recognized as an emerging imported disease in the united kingdom. since g. spinigerum is endemic in central and south america, most notably in mexico, gns may soon become another emerging potential cause of em in north america, given the adventurous and exotic eating habits of north americans abroad. the reduviid insect vectors of chagas disease have now moved from the rural areas of latin america into cities and coastal resort areas frequented by international travelers. the vectors have also migrated northward into the temperate areas of the midsouthern united states and have established a trypanosoma cruzi zoonosis among wild animals and some domestic animals kenneled outdoors as far north as virginia. the exotic pet trade and the importation of infectious diseases: monkeypox and neuroangiostrongyliasis in addition to a. cantonensis-infected african giant snails, the exotic pet trade has also imported monkeypox to the united states in pet rodents. in , cases of monkeypox were reported among three midwestern us states (illinois, indiana, and wisconsin). fortunately, there were no deaths, but patients were hospitalized for supportive treatment, including a child with encephalitis. the monkeypox virus, a smallpox-like orthomyxovirus, was first isolated in the congo river basin of west africa in . after an incubation period of - weeks, monkeypox is characterized by a prodrome of headache, fever, fatigue, and backache, followed by a characteristic rash. the monkeypox rash is similar to smallpox with evolving macules, vesicles, and pustules that crust over and heal within - days (figure ) . unlike smallpox, pronounced lymphadenopathy is usually present and complications may include pneumonia and encephalitis. although person-to-person transmission may occur, infection is usually transmitted by contact with contaminated animals. the cfr ranges from % to %, with higher cfrs in young children. traceback investigations of the us monkeypox outbreak revealed that all patients had had contact with pet animals: patients had contacts with pet prairie dogs, with a pet rabbit, and with a pet imported giant gambian rat, cricetomys gambianus. the source of the monkeypox virus introduced into the united states was later identified as infected giant gambian rats imported from ghana to texas and sold to an illinois pet distributor, who housed the animals together before sale to pet shop owners and others. although the monkeypox virus is endemic in west african river basins, including the gambia and congo, the humid river bottomland ecosystems of the mississippi-missouri-ohio river basins of the central united states will support the transmission of the virus from imported rodents to domestic rodents, especially prairie dogs and squirrels, and to rabbits (figure ) . the close contact between pet owners and their pets permitted the transmission of the zoonotic infection, for which there is no specific treatment, to humans. regulations now prohibit the importation of african rodents into the united states, and sentinel monitoring systems of local rodents for monkeypox infections have now been initiated. like the rat lungworm, the monkeypox virus may become an unwelcomed, but established, zoonosis in the united states as a result of relaxed free trade regulations, especially of the exotic pet trade, and a welcoming, warming riverbottomland ecosystem. a. cantonensis, the rat lungworm, was first described in china in , living in the pulmonary arteries of rats. the first human infection was reported from taiwan in . the life cycle is complex and involves a rodent definitive host and an appropriate mollusk intermediate host, usually land snails or slugs (figure ) . adult worms mature in rat brains, enter the central circulation, and mate in the pulmonary arteries producing eggs. the eggs become first-stage larvae that penetrate pulmonary vessels to access the respiratory tree, where they are coughed up, swallowed, and excreted in feces. these second-stage larvae must be consumed by land snails or slugs to mature into infective third-stage larvae, be eaten by rodents, and maintain the parasite's life cycle. man becomes a dead-end host by consuming raw intermediate mollusk hosts, or food items contaminated by their slime, or by consuming raw, crustacean (shrimp, crabs, fish, and frogs) transport, or paratenic, hosts that consumed infected mollusks. in man and paratenic hosts, the neurotropic larvae migrate to the cns (neural larva migrans) seeking to mature into young adults as in rat brains but eventually die causing em. a. cantonensis is enzootic throughout southeast asia, most indian and pacific ocean islands, including the hawaiian islands, many caribbean islands, and has even been reported in new orleans, louisiana. the global spread of the parasite resulted from international trade, parasite-infested rat stowaways disembarking container ships, and the intentional introduction of giant african land snails as biological controls and exotic pets. in , a. cantonensis was isolated from % of norway rats, rattus norvegicus, trapped in new orleans, louisiana, between april and february . in , a case of a. cantonensis-induced em was reported from new orleans in an -year-old male who presented with a -week history of headache, stiff neck, low-grade fever, and myalgias. he admitted eating a raw snail from the street on a dare a few weeks earlier. a second presumed autochthonous case of a. cantonensis infection was reported from south louisiana in in a -year-old man who presented with neck and backaches, myalgias, and paresthesias. he admitted having consumed, on a dare, two raw legs from a green tree frog, hylidae cinerea, days before symptom onset. a. cantonensis was responsible for an outbreak of nas in us travelers returning from jamaica to chicago in , who had consumed romaine lettuce. the lettuce food vector was actually imported to jamaica from the united states and presumably contaminated somewhere in between with snails or slugs or their secretions containing infective a. cantonensis larvae. in summary, there is now ample clinical, epidemiological, parasitological, and immunological evidence that an a. cantonensis zoonosis has been established in the continental united states and in the caribbean in rats, mollusks, and paratenic frog hosts as a direct result of international commerce. although cases of nas are rarely confirmed by the identification of a. cantonensis larvae or adults in the cns, most cases can now be confirmed serologically and epidemiologically; the reported cfr in us cases is relatively low ( . %); and most patients recover completely, even without specific antihelminthic treatment. the most effective prevention and control strategies for nas include ( ) educating citizens and travelers in endemic areas that snails, slugs, freshwater fish and shrimp, frogs, and crabs must be cooked, not marinated or refrigerated, before being eaten; ( ) washing all vegetables thoroughly before eating them uncooked; ( ) washing hands thoroughly after handling pet african land snails or cleaning out their terrariums; ( ) reducing and controlling the definitive host rodent populations with rodenticides; ( ) reducing and controlling snail and slug paratenic host populations with molluscicides; and ( ) policing and restricting the exotic pet trade. originally confined to southeast asia and japan, gns is acquired by eating raw or undercooked foods, infected with third-stage larvae of the roundworm, g. spinigerum. g. spinigerum is a common roundworm of wild and domestic cats, dogs, and other carnivores that coils within submucosal tumors in the stomach of definitive hosts, mates, and releases eggs in the host's feces. the eggs embryonate into first-stage larvae in fresh or brackish water ecosystems and are ingested by small crustacean intermediate hosts, which become prey for larger humans are incidental hosts, passage of larvae in humans has never been documented, and humans do not transmit either a cantonensis or a. costancensis causes eosinophilic meningitis, a meningoencephalitis characterized by eosinophils in the cerebrospinal fluid (csf). common in parts of southeast asia and pacific islands, africa and the canbbean. causes eosinophilic enteritis, an eosinophilic inflammation of the mesenteric arterioles of the ileocecal region of the gastrointestinal tract that mimics appendicitis. common in parts of central and south america eggs hatch in the lungs, and first-stage larvae are passed in rodent feces (a. cantonensis) third-stage larvae are ingested by rats first-stage larvae infect snails and slugs. slugs and snails are intermediate hosts, and after two molts, the larvae reach the infective (third) stage. humans become infected through food containing third-stage (infective) larvae. food items may include uncooked or undercooked snails or slugs, infected paratenic hosts (i.e., crabs, freshwater shrimp), and raw vegetables contaminated with snails or slugs. eggs hatch in the lungs, and first-stage larvae are passed in rodent feces (a. cantonensis) figure the life cycle of the rat lungworm, angiostrongylus cantonensis, which causes eosinophilic meningitis (a), is compared to the life cycle of angiostrongylus costaricensis, which causes eosinophilic enteritis (b). reproduced from cdc image, available at http:// www.dpd.cdc.gov/dpdx. predators including fish, shrimp, crabs, crayfish, frogs, and snakes ( figure ). the larvae mature into infective thirdstage larvae in these transport or paratenic hosts, encyst in tissues, but do not develop into adults, unless the paratenic hosts are consumed by definitive carnivorous hosts. once infective larvae are consumed by predators, they will mature into adults in the stomach and restart the parasite's life cycle ( figure ). since humans are not the natural definitive hosts, infective larvae consumed by humans in raw foods will not develop into adults but will penetrate the gastrointestinal tract and migrate hematogenously causing cutaneous or visceral larva migrans in any organ system. typically, the most common foods containing infective larvae have included fish, shrimp, crab, crayfish, frog, snake, and chicken. however, most human cases have followed consumption of raw or citrus-marinated fish (ceviche) or shellfish. in , gns caused by g. spinigerum was first recognized as an emerging imported helminthic infection in the united kingdom in a case series of patients treated over a -month period. in this series, the median incubation period was months; peripheral eosinophilia was present in ( %) of the patients, and was not a reliable screening tool; and cases presented with a myriad of symptoms ranging from migratory cutaneous swellings (also known as yangtze edema in asia, or nodular eosinophilic migratory panniculitis in the united states) to eosinophilic gastritis. today, gns remains relatively common in southern china, thailand, and bangladesh; is becoming more common throughout latin america and the caribbean; and is most often described in the united states in southeast asian immigrants. a diagnosis of gns should now be considered for all patients with a history of travel to endemic regions and migratory cutaneous swellings, eosinophilic gastritis, or a combination of cutaneous swellings with any manifestation of neural larva migrans, especially eosinophilic meningoencephalitis and migratory radicular pain or radiculomyelitis. neural gns has also caused radiculomyeloencephalitis and subarachnoid hemorrhage. most fatal cases of gns have been associated with neural larva migrans and em, with eosinophils comprising over % of the cerebrospinal fluid (csf) cell count. prevention and control strategies for gns include ( ) educating citizens and travelers in endemic areas that fish, shrimp, crayfish, frogs, crabs, chicken, and snakes must be cooked thoroughly first and not eaten raw, marinated, or refrigerated and ( ) seeking medical care immediately for evaluation of persistent nonspecific gastrointestinal illnesses or migratory subcutaneous swellings. regional warming in northern latitudes and adventure travel in the americas: t. cruzi and chagas disease (american trypanosomiasis) chagas disease, or american trypanosomiasis, is an arthropod-borne protozoan infectious disease endemic throughout most of the americas, caused by the trypanosome, t. cruzi, and transmitted to man by reduviid, or kissing, bugs ( figure ) . the life cycle of t. cruzi is depicted in figure . reduviid bugs, specifically the triatomines (phylum insecta, order hemiptera, family reduviidae, subfamily triatominae), transmit several strains of wild animal t. cruzi among many nonspecies-specific wild mammalian reservoir hosts throughout the americas (figure ). there are also many competent species of reduviid vectors capable of transmitting zoonotic wild strains of t. cruzi to domestic animals and man throughout the americas (figure ) . like malaria and west nile virus, chagas disease may also be transmitted congenitally and by blood transfusion and organ transplantation. unlike malaria and west nile virus, however, chagas disease was recently found to be transmitted by the ingestion of infected triatomines, which poses special risks to international travelers who eat or drink unpasteurized foods made from palm oils or raw sugarcane. in its world health report, the world health organization (who) noted that chagas disease caused more deaths from parasitic disorders than any other parasitic disease in latin america, and that t. cruzi was responsible for the third greatest number of parasitic infections in the world following malaria and schistosomiasis. chagas disease is now the most common cause of myocarditis worldwide, and chagasic heart failure has become an increasingly common indication for heart transplantation in the americas. since reduviid bites occur at nighttime and are either painless, possibly from combinations of salivary local anesthetics and anticoagulants, or associated with pruritus. the localized pruritus only serves to induce rubbing and scratching by sleepy victims, effectively dispersing infective trypomastigotes across bite-damaged epidermal surfaces or adjacent mucoepidemal junctions. since there is no vaccine to prevent chagas disease and current chemotherapy is limited to only two drugs, most efficacious only in the earliest stages of acute or reactivated t. cruzi infections, the best preventive strategies for chagas disease in travelers to the americas should be directed at ( ) the education of travelers to t. cruzi-endemic areas of the americas in the transmission risks of chagas disease; ( ) a recommendation for sleeping under pyrethroid-impregnated insect nets, especially when staying overnight in thatched and mudwalled huts or unmortared cabins; and ( ) a recommendation to travelers to drink only bottled, boiled, or pasteurized beverages; to avoid all local brews, especially those made from local palm trees and sugarcane; and to avoid chewing on unwashed sugarcane stems or palm hearts and avoid using unwashed sugarcane stems as swizzle sticks for beverages. several components of climate change, particularly warming temperatures and more frequent drought-rainy season cycles, have supported the success of new vectorpathogen relationships, as in airport and imported malaria transmission. some insect vectors, particularly mosquitoes, have been given selective advantages by climate change, free trade, and air travel. introduced pathogens from tropical regions, such as the monkeypox virus and the rat lungworm, have found new animal reservoirs in warming ecosystems north of the equator. how should humankind respond to climate change and its inevitable impact on biological systems and the quality and safety of human life? the united nations, through its agencies and panels, such as the who and ipcc, has taken the lead in directing appropriate international responses that will include combinations of environmental, political, regulatory, socioeconomic, and public health measures. such measures must include limiting anthropogenic greenhouse gases, fostering renewable energy resources, improving natural disaster forecasting, developing drought and disease-resistant food crops, recognizing the disease potential of introduced pathogens in a warming world, instituting sentinel monitoring for infectious diseases in animals and man, and developing primary prevention strategies for climate change-related infectious disease outbreaks and extreme weather events. primary prevention strategies for emerging infectious diseases should include new vaccines for avian influenza, sars, and west nile virus. primary injury prevention strategies for extreme weather events figure triatoma infestans, a common reduviid vector of trypanosoma cruzi among animals and humans in the americas. reproduced from cdc image, available at http:// www.dpd.cdc.gov/dpdx. should include early warning systems for heat waves, floods, tornadoes, tsunamis, and tropical cyclones. developing global climate anomalies suggest potential disease risks for chikungunya outbreaksfthe globalization of vectorborne diseases wildlife, exotic pets, and emerging zoonoses climate change and human health how environmental exposures influence the development and exacerbation of asthma climate change: the public health response climate change: synthesis report, ar syr summary for policymakers wildlife as a source of zoonotic infections world health assembly : climate change and health global environmental change and health: impacts, inequalities, and the health sector climate change and human health: present and future risks dengue and hemorrhagic fever: a potential threat to public health in the united states improved surface temperature prediction for the coming decade from a global climate model what makes ticks tick? climate change, ticks, and tick-borne diseases emerging tick-borne infections: rediscovered and better characterized, or truly new? emerging infectious diseases, an online journal published by the united states centers for disease control and prevention financial support was provided by departmental and institutional sources. the author has no conflicts of interest to disclose. key: cord- -lrbi authors: childs, james e. title: pre-spillover prevention of emerging zoonotic diseases: what are the targets and what are the tools? date: journal: wildlife and emerging zoonotic diseases: the biology, circumstances and consequences of cross-species transmission doi: . / - - - - _ sha: doc_id: cord_uid: lrbi the uneven standards of surveillance, human- or animal-based, for zoonotic diseases or pathogens maintained and transmitted by wildlife h r s, or even domestic species, is a global problem, readily apparent even within the united states, where investment in public health, including surveillance systems, has a long and enviable history. as of , there appears to be little scientific, social, or political consensus that animalbased surveillance for zoonoses merits investment in international infrastructure, other than the fledgling efforts with avian influenza, or targeted nontraditional avenues of surveillance and research. individual humans sickened or killed by an unknown infectious cause potentially indicate a zoonotic disease emergence has occurred, but, by themselves, are insufficient to document any instance of emergence. incident cases of a new zoonotic disease must come to the attention of local authorities and then be the target of clinical, epidemiologic, and microbiologic research prior to any determination that an outbreak was caused by an emerging or reemerging pathogen. satisfactory fulfillment of koch's postulates is a daunting process, involving the diagnosis of human disease, i.e., the isolation of the infecting pathogen in cell culture; the molecular and antigenic characterization of pathogens obtained from human or animal tissues; and establishing the novel pathogen's causal role as etiologic agent ). these endeavors link forever an instance of emergence with a single time point and place, a pinpoint and date on a map [fig. . in institute of medicine ( ) ]. such an accounting system is necessary, but belies the dynamic ongoing process of disease emergence. as with the invading species that perishes on a foreign shore before being identified and labeled by a knowledgeable biologist, countless cases of zoonotic disease go unrecognized and uncatalogued. these missing data limit comparative analyses of the qualities of successful invading species to the far larger outgroup of pathogens for which there are limited or negative, i.e., not detected, data (daszak et al. ; cleaveland et al. ; dobson and foufopoulos ; kolar and lodge ; see the chapter by cleaveland et al., this volume) . irrespective of the limitations of such studies, coherent trends and suites of plausible traits associated with successfully emerging pathogens have been derived from comparative studies (dobson and foufopoulos ; cleaveland et al. ; see the chapters by cleaveland et al. and holmes and drummond, this volume) , but offer little guidance on how and where to focus attention (but see the chapters by daszak et al. and merianos, this volume) . zoonotic viral emergences surprise even the scientists who are most knowledgeable within a subject area. witness the identification of a novel hantavirus causing fatal disease in the southwestern united state, after decades of search for pathogenic hantaviruses in the united states (leduc et al. ) , and the discovery of a novel lyssavirus causing a disease indistinguishable from rabies, in supposedly rabies-free australia (hooper et al. ) . although the process of zoonotic pathogen emergence often begins with identification of a case or cluster of human disease, surveillance and monitoring systems are ill equipped to detect and then characterize the unknown (see the chapters by merianos and by stallknecht, this volume) . once a new zoonotic disease is identified and a case definition is established, the systematic collection of information on incident cases of human disease is used to generate information in a usable form, through appropriate data analytic and publication processes conducted through personnel working through a central repository. when the information is disseminated back to health professionals, from the federal government to individual practitioner level, a surveillance system is established. the country of occurrence, the morbidity and mortality, and the preexisting public health infrastructure, mixed with a good portion of serendipity, influence the likelihood of detecting a newly emerged zoonosis. surveillance for zoonotic pathogens is largely based on detecting illness or infection in homo sapiens (see the chapters by merianos and by stallknecht, this volume); humans serve as the sentinel species for zoonotic agents maintained in transmission cycles in which, fortunately, they rarely play other than an incidental role as a dead-end host. a variety of surveillance systems and data sources have been successfully, if sometimes unintentionally, employed to monitor existing zoonotic diseases or to detect new diseases (table ). an example of a serendipitous outcome stemming from syndrome-based surveillance for a specific disease occurred in new york city in , with the implementation of a system to detect bioterrorism-related cases of anthrax (centers for disease control and prevention ; buehler et al. ; paddock et al. ) . the putative anthrax case definition included a febrile illness accompanied by either a rash or eschar. rickettsialpox, caused by rickettsia akari , had been an endemic, legally mandated reportable disease in new york city since the mid- s (huebner and jellison ; huebner et al. ), but since the s the median number of annual cases reported was approximately . the classical presentation of rickettsialpox includes a fever and one or more eschars at the bite sites produced by the infected mite vector transmitting r. akari . over an -month interval, cases of rickettsialpox were diagnosed through the syndromic-based anthrax-surveillance system in new york city; tissue biopsies from patients yielded the first isolates of r. akari from the united states in more than years . although rickettsialpox was a known entity, anthrax surveillance highlighted the underappreciated level of disease caused by this endemic zoonosis. surveillance systems designed to detect and monitor a specific animal disease have also uncovered novel zoonotic pathogens. in the united states, two previously unknown rhabdoviruses have been isolated from dead birds collected for monitoring and forecasting wnv activity (eidson et al. b (eidson et al. , c mostashari et al. ; garvin et al. ; travassos da rosa et al. ) . while in australia, laboratory workup of a sick pteropid bat collected in conjunction with hendra virus (hev) investigations following an outbreak of disease affecting horses and humans in halpin et al. ) yielded a new lyssavirus , australian bat lyssavirus (abl), closely related to rabies virus (fraser et al. ; gould et al. a) . within months of the isolation of abl, this virus was demonstrated to be the cause of fatal encephalitis in humans (gould et al. b) ; until this time no rabies had been reported from australia. effective, but informal, surveillance systems can be implemented rapidly following the identification of a novel zoonotic disease emergence within countries with a highly developed public health infrastructure. the interplay of factors influencing initial detection and later development of systematic surveillance are illustrated by the outbreak of hantavirus pulmonary syndrome (hps) in the southwestern united states in may . an indian health service physician noted a temporally and spatially linked cluster of cases of a severe, kitala et al. b often fatal, respiratory disease, affecting previously healthy, young-adult navajo indians residing on a reservation (duchin et al. ) . the physician notified local authorities and subsequently cdc was invited by state officials to help investigate the growing number of fatalities. testing of patient sera at cdc revealed the presence of antibodies reactive with hantaviral antigens . facilitated by epidemiologic knowledge of hantaviruses and hantaviral diseases occurring in eurasia, rapid progress was made in uncovering the natural history of this mysterious new disease. in a matter of weeks, investigators confirmed the disease was clinically distinct from eurasian disease (moolenaar et al. ) , that the etiologic agent was a new hantavirus , sin nombre virus (nichol et al. ) , and the reservoir host (h r ; for definition of terminology see the chapter by childs et al., this volume) was a species of new world rodent, peromyscus maniculatus (childs et al. ) . a relatively crude but effective national surveillance program, capitalizing on media interest in the hps outbreak, was established by june . six months later, private citizens or their physicians had reported and submitted clinical specimens for diagnostic testing from persons; confirmed hps cases were identified from states outside of the four-state region where the initial outbreak was localized (tappero et al. ) . this impromptu surveillance system was highly successful in rapidly identifying the widespread geographic distribution and sporadic incidence of hps cases throughout much of the western united states. once a zoonotic disease is characterized, formal, systematic surveillance efforts can be initiated at the state or national level in countries possessing the requisite infrastructure. national surveillance programs coordinated through cdc, with rare exceptions, focus on the systematic collection of data on human disease. national surveillance and the global network for monitoring influenza a activity among humans is the outstanding example of a system integrating epidemiologic data with the collection and characterization of influenza viral subtypes circulating throughout the world (centers for disease control and prevention d; cox et al. ) . the unquestioned value of the global influenza surveillance program rests with the vaccines produced. each year's new influenza vaccines are based on determinations of the currently circulating influenza subtypes and divining which subtypes should be incorporated into next season's vaccine cocktail. a global early warning system to detect zoonotic pathogens transmitted to humans was launched in july by the un food and agriculture organization (fao) and the world health organization (who) in collaboration with the world organization for animal health (formerly the office of international epizooties or oie) (http://www.who.int/mediacentre/news/new/ /nw /en). specifically mentioned as examples are bse and sars; data from infected and diseased humans and animals will be gathered and assessed jointly. plans to develop a global animal-based influenza surveillance program exist (centers for disease control and prevention d; stohr ) . it remains unclear if animal-based influenza surveillance will extend beyond domestic poultry and livestock to wild waterfowl and shorebird h r s, although this latter activity is strongly endorsed melville and shortridge ; see the chapter by webby et al., this volume). surveillance for zoonotic diseases among wildlife, as opposed to domestic animals and livestock, falls through the cracks of both veterinary and human health practices (see the chapter by stallknecht, this volume). reviews of animal health monitoring systems mention wildlife disease surveillance only in passing and largely in reference to the difficulties of establishing population estimates (denominator data) for defining rates, such as disease incidence, or the obstacles to developing systematic surveillance programs coordinating with human disease surveillance (ingram et al. ; see the chapters by daszak et al., merianos, and by stallknecht, this volume) . most regional or state systems collecting information on wildlife diseases are passive surveillance systems. passive surveillance in the united states, as defined by public health professionals, is the systematic collection of data on human diseases, reportable through legal mandate in most states, obtained within specified time frames on conditions listed by national notifiable disease surveillance system (nndss) (teutsch ) ; data are reported to cdc by electronic submissions via the national electronic telecommunications system for surveillance (netss) (teutsch ) . international regulations require reporting on quarantinable conditions, such as plague, yellow fever, cholera, and sars (teutsch ; centers for disease control and prevention b) . diseases covered by the nndss are established through collaborations of the council of state and territorial epidemiologists (cste) with the cdc and the nationally reportable diseases are reviewed at -year intervals, at which time case definitions are established or modified (centers for disease control and prevention ). by virtue of the population estimates provided by the us census, human surveillance data collected via nndss are population-based. summary statistics on nationally notifiable disease are published weekly in morbidity and mortality weekly report (mmwr) and summarized in annual reports (centers for disease control and prevention c). in contrast, for wildlife and domestic animal diseases, the oie, situated in paris, france, determines diseases reportable by its member counties (thiermann ) . the diseases are divided into two lists: list a diseases are of major importance in international trade of animals or animal products and have the potential for very serious and rapid spread irrespective of national borders; list b diseases are of public health importance within counties (thiermann ; http://www.oie.int). within the united states, mandated reporting of animal diseases varies by state, and voluntary reporting by professionals is a major component of data collection (salman ) . at the federal level, information is collected by the animal and plant health inspection service (aphis) of the department of agriculture (usda). given the lack of accurate population estimates for many domestic animals and livestock, passive veterinary surveillance is not population-based. surveillance for wildlife diseases exists at some level in most developed countries. as with human, surveillance, the infrastructure for receiving, typing, and storing animal specimens and the diagnostic laboratory capacity for establishing diagnoses are minimal prerequisites (see the chapter by stallknecht, this volume). within north america, the canadian cooperative wildlife health center (ccwhc), supported by the four canadian veterinary schools, was established in to promote nationwide surveillance of wildlife diseases. in canada, disease detection is carried out by a wide range of professional and voluntary field personnel, including hunters, and specimen diagnosis is conducted at provincial and federal veterinary laboratories. the central repository for data is the ccwhc, which disseminates surveillance information to persons responsible for wildlife programs and policies, and to the public (leighton et al. ). in the united states, states have often taken the lead in monitoring wildlife diseases, such as wnv among dead birds, arboviral infections among sentinel bird flocks (mostashari et al. ; eidson et al. a; komar ) , and transmissible spongiform encepahlopathy (tse) associated with elk and whitetailed deer (williams and miller ) . in several states, notably california and florida, surveillance for arbovirus activity using sentinel flocks of birds have documented trends in the enzootic activity of western equine encephalomyelitis (wee), st. louis encephalitis (sle), and eastern equine encephalomyelitis (eee) linked to climatic and local weather patterns (reeves ; shaman et al. ; day ; barker et al. ) . surveillance for viruses transmitted from wildlife h r s to domestic poultry and livestock, such as avian influenza a, subtypes of which infect and cause disease in humans (kermode-scott ; fouchier et al. ) , is conducted through the usda. additionally, the usda conducts mandated surveillance for zoonotic infections of livestock, such as bse, anthrax, and bovine tuberculosis (tb) (anonymous b; myers et al. ) . regional activities monitoring wildlife diseases, especially among game animals, such as white-tailed deer ( odocoileus virginianus ), exist through cooperative efforts involving research and educational institutions, state fish and game departments, and hunters. a successful example is the southeastern cooperative wildlife disease study (scwds) maintained at the university of georgia, where programs collect regional data on wildlife, ectoparasitic and endoparastic infestations, and microbiologic and serologic evidence of past or current infections. historical collections and independently funded research programs through scwds recently led to the rapid elucidation of the natural history of emerging tick-borne zoonoses caused by bacteria in the genera ehrlichia and anaplasma (davidson et al. ; little et al. ; lockhart et al. lockhart et al. , ; see the chapter by paddock and yabsley, this volume) . wildlife disease monitoring in sweden and northern europe has existed since the s, relying heavily on the cooperation and interest of hunters in the collection and submission of samples from game animals (mörner ; mörner et al. ) . surveillance for wildlife diseases in the uk and ireland has included bovine tb maintained by badgers (see the chapter by palmer, this volume); current plans call for increased surveillance of wildlife, notably birds for wnv, in england and wales (griffin et al. ; gormley and costello ; crook et al. ; duff et al. ; see the chapter by palmer, this volume). short-term studies of wildlife h r s are the most common survey methods employed in response to specific instances of emergence or spread of zoonotic disease. following an outbreak of human monkeypox in several us states (centers for disease control and prevention a; see the chapter by regnery, this volume), local populations of indigenous north american rodents were captured and examined for infection from areas around animal-holding facilities housing african rodents imported for the pet-trade and implicated as the source of monkeypox virus (cunha ; check ) . native american ground squirrels, coincidentally housed in the same buildings with the african rodents and purchased as pets, were implicated as the source of monkeypox virus transmitted to humans (guarner et al. ; see the chapter by regnery, this volume). short-lived studies identifying rabid raccoons were undertaken in ohio, following the first reported case of raccoon-variant rabies in that state (stefanak et al. ) . testing of trapped and road-killed raccoons helped define the geographic extent of the enzootic area of raccoon rabies in the state in preparation for the deployment of an oral rabies vaccine (orv) in an effort to prevent the westward expansion of epizootic raccoon rabies into ohio and west to other states (kemere et al. ; foroutan et al. ; aphis wildlife services factsheet ) . long-term prospective studies of zoonotic pathogens circulating within wildlife h r s are critical to understanding factors mediating irregular increases and declines within animal populations, which can drive the risk of spillover to humans. the varying population dynamics of zoonotic pathogens and their h r s are, in some instances, as with rabies virus, driven by pathogen-induced host mortality (anderson et al. ; childs et al. ; coyne et al. ) ; the risk of rabies virus spillover to domestic animals is closely, but not perfectly, mirrored by the temporal dynamics within the wildlife h r (gordon et al. ) . examples of systematic wildlife disease studies that have exceeded several years in duration are few. one ongoing example is the investigations of the population dynamics of rodent h r s and snv and other hantaviruses in the southwestern united states, which were established in the mid- s following the outbreak of hps. replicated and coordinated studies among universities in several states, using similar methodologies for population sampling, virological testing, and data management (mills et al. ) , have provided a wealth of information critical for unraveling aspects of the transmission and maintenance of hantaviruses (mills et al. a (mills et al. , b . the knowledge base established by these efforts allowed increasingly elaborate hypotheses developed from field observations to be tested. the modalities of hantaviral transmission were assessed by application of microsatellite markers to genetically identify familial relationships among individual mice; related male p. maniculatus were more likely to be snv-infected (root et al. ) , providing clues to the chain of transmission events contributing to the male bias in hantaviral infection documented by several descriptive studies (mills et al. a ). ongoing research is providing clues as to the critical h r population size required to sustain hantavirus transmission and is exploring the phenomenon of snv disappearance and reemergence in h r populations , possibly through snv maintenance within refugia of a special nature . these ongoing studies spanning more than years, have been sufficient to capture occurrences and effects of environmental drivers, such as el niño southern oscillation (enso), which occurs at semi-predictable intervals of approximately - years (chen et al. a ). enso is a principal indicator of global climate which modifies local weather patterns; increasing rainfall associated with enso is hypothesized to drive a trophic cascade of events (polis et al. ) , ultimately leading to increases in local h r populations and increased risk of hps (glass et al. ; hjelle and glass ) . remote sensing and gis techniques, coupled to a household-based case-control methodology assessing rodent abundance around residences of hps cases , predicted where p. maniculatus would be more abundant at future case houses. analyses of annual satellite images to detect local environmental conditions supportive of rodent hr population growth has proven an effective tool for predicting the qualitative level of risk (low, moderate, high) for hps over a sizable region of the southwestern us (glass et al. ) . educational recommendations and field trials of rodent-proofing methods were incorporated into the long-term investigations (glass et al. ) , to provide readily available control measures in anticipation of increased risk of hps ). animal-based surveillance is a process inherently different from human-based surveillance (table ) . with the exception of surveillance efforts targeting livestock and poultry, run through the center for animal health surveillance of the usda (king ) , no formal sampling methodology exists for estimating animal population sizes at the regional or continental level (see the chapter by stallknecht, this volume). wildlife population estimates at the continental scale are few and generally restricted to tractable populations associated with conservation efforts, with the possible exception of national waterfowl surveys , or national hunter-or road-killed indices of white-tailed deer populations (hayne ). targeted ecologic studies directed at species that are endangered or threatened have in several instances provided population-based information complementing the objectives of wildlife disease research. the most notable examples involve species that are relatively easy to observe or for which population-based indices exist, such as carcass, nest, or scat counts (leroy et al. ) . where estimates of animal numbers have been enumerated, the impact of fatal zoonotic viruses indicate certain wildlife species could serve as sentinels for monitoring viral activity; species conservation activities can provide leverage to any additional surveillance investment (see the chapter by daszak et al., this volume) . examples include great apes killed by ebola virus (leroy et al. ; walsh et al. ; see the chapters by gonzales et al., this volume), and rabies induced mortality among african wild dogs (kat et al. ; gascoyne et al. b; burrows ) , and ethiopian (whitby et al. ; sillero-zubiri et al. ) and artic wolves (ballard and krausman ; weiler table key differences in the terms "passive surveillance" and "active surveillance" and methods of data collection as used and defined by veterinary and human health professionals surveillance system or manner of data collection veterinary health a human public health b passive "the passive collection of data involves the reporting of clinical or subclinical suspect cases to the health authorities by health care professionals at their discretion." "a passive surveillance system is one in which a health jurisdiction receives disease reports from physicians, laboratories, or other individuals or institutions as mandated by state law." legally mandated, systematically collected within specified time frames, voluntarily reported to cdc not population-based specified by state and federal officials within the national notifiable disease surveillance system (nndss). population-based by virtue of the us census active "an active collection of data for any monitoring and surveillance system (moss) is the systematic collection or regular recording of cases of a designated disease or group of diseases for a specific goal of monitoring or surveillance." "in contrast, an active surveillance system is established when a health department regularly contacts reporting sources (e.g., once per week) to elicit reports, including negative reports (no cases)." key characteristics not necessarily mandated by law not necessarily mandated by law population-based population-based collects negative data a quoted from salman ( ) b quoted from birkhead and maylahn ( ) et chapman ) . for other wildlife, the lack of population estimates precludes estimation of basic epidemiologic parameters, including rates such as incidence or mortality; these capabilities are beyond those of any existing surveillance system for a wildlife zoonosis. novel animal-based surveillance and control programs are being planned for zoonotic agents, such as bse, sars-cov and influenza a subtypes which have realized or potential pandemic importance to humans or domestic animals (http://www.who.int/mediacentre/news/new/ /nw /en). the ultimate h r s for these agents includes domestic and wild animal species. for example, the h r s for influenza a subtype h ni are among wild waterfowl and shorebirds, and perhaps other avian types, although, domestic chickens and other poultry serve as both the first secondary host (h s ) or intermediate host (h i )(see the chapter by childs et al., this volume, for description of terms) and can develop as a novel h r (see the chapter by webby et al., this volume). experts within the who and elsewhere, acknowledge a need ". . . to get rid of the natural reservoir of h n , but we need to do it safely" (quote attributed to klaus stohr, project leader of who's global influenza program; cited in abbott and pearson [ ] ). however, even rough plans of how such an immense undertaking will be designed and integrated into the countries of greatest significance in asia are lacking. even when infection within an animal h r or h s is relatively detectable, national surveillance programs for monitoring morbidity and mortality among wildlife and establishing the etiologic cause of infection through a system of diagnostic laboratories are rare (see the chapter by stallknecht, this volume). if the zoonotic agent is a pathogen of domestic livestock, formal surveillance can target abattoirs or production facilities where food animals are processed, as is the major emphasis of bse surveillance conducted both in the united states by the usda (kellar and lees ; anonymous b ) and within european countries ). among wildlife, animal rabies is the only disease within the nndss for which time-series data of reasonable duration, more than years, quantity and quality has been systematically collected from all us states and territories . animal-based surveillance for pathogens causing emerging zoonotic diseases in humans is often hampered by the lack of clinical signs in infected individuals of the h r (table ) . where zoonotic viruses cause fatal disease among wildlife and domestic animal h r s, h s s, or h i s, tracking the spread of these agents is a simpler matter, although this remains a formidable challenge within countries lacking basic surveillance infrastructure. tracking the spread of influenza a subtype h n of domestic chickens, ducks, and some wild waterfowl in southeastern asia (chen et al. b; li et al. ; lu et al. ; see the chapter by webby et al., this volume), wnv in north america (garvin et al. ; guptill et al. ; walsh et al. ; larkin ) , ebola virus in central africa (leroy et al. (leroy et al. , walsh et al. ; see the chapter by gonzales et al., this volume), and rabies virus in north america, europe, and southern africa (sabeta et al. ; childs et al. ; gordon et al. ; see the chapter by nel and rupprecht, this volume) has been facilitated by the mortality these viruses cause in wildlife and domestic species. national surveillance for animal rabies is a model public health activity. as the cdc is charged with promotion of human health and disease prevention and control, animal-based rabies surveillance data are well integrated into national, state, and local human and veterinary public health programs . a brief examination of the objectives, types of data collected, and the practical use of the information disseminated through the national animal rabies surveillance program is illustrative of the potential benefits accrued from an animal-based surveillance system. surveillance for animal rabies collects information on the current status and level of rabies activity among wildlife and domestic animals at the county level within individual states. monthly counts of rabid animals, and from some states the tally of negative results, designated to the level of animal species or taxonomic group, are submitted to the cdc ). surveillance information is analyzed, summarized, and disseminated back to the data providers in a timely manner through publications ) and additional communications, which are updated annually, such as the compendium of animal rabies prevention and control (centers for disease control ). surveillance data on animal rabies are sufficiently detailed and accurate to allow human and veterinary health professionals to anticipate levels of rabies activity at the county or regional level, permitting some future planning for preventative activities, including procurement of human vaccine and human rabies immunoglobulin (hrig) for postexposure treatment of potentially exposed persons (centers for disease control and prevention b; advisory committee on immunization practices ); increasing vaccination levels of dogs and cats; and initiation of targeted control efforts to vaccinate wildlife using orv kemere et al. ) . several species of terrestrial carnivore, raccoons ( procyon lotor ), red foxes ( vulpes vulpes ), and striped skunks ( mephitis mephitis ) serve as h r s for particular genetic variants of rabies circulating in the continental us; numerous rabies virus variants are also associated with different species of bats (messenger et al. ) . rabies virus variants can be differentiated by limited sequence analysis or monoclonal antibody methods and the enzootic area where rabies variants overlap the geographic range of their terrestrial mammalian hosts can be reasonably determined . time-series surveillance data on wildlife rabies, analyzed by statistical algorithms defining and demarcating intervals of increased (epizootic) or diminished (interepizootic or enzootic) rabies activity, provide results concordant with predictions and outcomes based on numerical solutions to mathematical models of the population dynamics of rabies virus within a single h r species anderson et al. ; coyne et al. ). time-series analyses have defined the temporal dynamics of disease in a wildlife h r guerra et al. ) and demonstrated the close association of this relatively predictable process to the risk of rabies spillover to domestic animals (gordon et al. ). furthermore, these data can inform epidemiologic simulations and models predicting epizootic rabies spread (russell et al. , and have been modified to forecast the savings accrued by preventing rabies spread through the application of orv (gordon et al. ) . additionally, local data have provided the raw material to explore formal methodologies for demonstrating and assessing the impact of long-distance translocations (ldts) of infected animals on the rate and pattern of rabies spread in heterogeneous environments . the availability of remotely sensed or digitized maps, coupled with gis-assisted partitioning of landscapes into habitats of varying quality, allow explorations of the impact of landscape heterogeneity on the characteristics of epizootics and the pattern of epizootic wavefront spread (jones et al. ; smith et al. ) . such analyses have been used to assess where remedial prevention activities should be focused when breaches in orv barriers occur and where active surveillance might be considered as a complement to passive data collection where fine-scale knowledge of the presence of rabies is needed to guide interventions . however, rabies surveillance reveals several inherent difficulties to conducting any form of wildlife-based disease surveillance and offers a sobering view of the hurdles to be overcome when considering such programs in other locations for other diseases. animal rabies surveillance was implemented to provide humans with a measure of rabies risk in their communities and, other than relative species counts over years, there is no information on the incidence or impact of rabies in any animal community. the nature of the human-animal interactions required by an animal-based surveillance system provides a distorted image of rabies as a community process (fig. ) . biases inherent to data collected by animal rabies surveillance at the national level stem from the requirement of human participation in each step of the process culminating in a rabies diagnosis in an animal ( fig. a ; gordon et al. ) . the impact of human demography, measured as absolute population size per county, on the surveillance process is sufficient to account for fully % of the variation in total animal specimens tested for rabies (fig. b; childs et al. ) . total county expenditure is almost as strong a predictor, accounting for % of the variation in total animal tests performed. pathobiologic features of rabies, human behavior, and the expense associated with diagnostic testing of specimens skew the types of animals observed, harvested, and tested for rabies. medium-to-large-sized mammals are more likely to be observed by humans and reported to wildlife control officials. in a typical surveillance year, small terrestrial mammals, predominantly rodents, but some insectivores, weighing less than kg account for less than . % of the total animals tested and diagnosed as rabid (real and childs ) , although small mammals provide the greatest species diversity and the overwhelming abundance of individuals and biomass of many mammalian communities (bourliere ) . rodents are fully susceptible to rabies infection and are capable of transmitting the virus to other species (childs et al. ; winkler et al. ) ; in some countries, rodents have been implicated in natural maintenance cycles of the virus (summa et al. ; verlinde et al. ) . a major sampling bias occurs at the level of the rabies diagnostic laboratory where, in an effort to save money on personnel time and diagnostic reagents, rabies testing is typically restricted to specimens from animals directly involved fig. a , b (continued) data integrating test outcome with information on the type of animal and date and place of origin produced at the state level and submitted to cdc. b although data on each of the events partitioned in (a) are unavailable, a surrogate value of population size is used to measure the importance of human interaction in generating surveillance data, assuming that increasing numbers of humans increase the likelihood of many of the events in (a) occurring. there is a strong association between the absolute numbers of humans resident in the smallest surveillance unit (us census figures), a county within a state, and the total numbers of animals tested for rabies from that surveillance unit. the relationship is a power function in which human population size accounts for % of the variance in median total tests conducted for rabies conducted over a decade from counties in a region affected by the raccoon variant of rabies virus. " " " " " " " " " " h o x h k xh n x fig. a, b the process of wildlife-and animal-based surveillance is interactive, involving multiple, and frequently independent, interactions between humans and wildlife to generate a single datum captured. panel a depicts some examples of these interactions, which could be assigned a probability if information were available, between private citizens and local and federal agencies in the route to generating a datum on animal rabies. each process involves some interaction with an animal, a tissue sample taken from the animal, test material derived from the sample, an outcome derived from the sample at the diagnostic laboratory, and the in the potential exposure of humans or domestic animals to rabies virus (fig. a) ; other specimens go untested (torrence et al. ; wilson et al. ). many of these limitations and biases will be generic problems confronting any effort to monitor wildlife species anywhere in the world. the most widespread approaches to zoonotic disease control completely ignore the ecology of wildlife and pathogen maintenance and transmission and, therefore, the potential for interrupting pathogen transmission prior to human spillover. instead, prevention and control strategies focus on defensive measures for the human h s . national institutions charged with strategic planning for emerging diseases or intentional releases of zoonotic agents have emphasized improving diagnostic capabilities for detecting human infections, modifying the immune status of human or domestic animals through vaccines, producing better antiviral or antibacterial drugs, and enhancing human-based surveillance as an early warning system (fauchi ; centers for disease control and prevention ). with the possible exception of extensive human vaccination, each of these approaches target post-spillover events and none of these avenues of research will have the slightest impact on reducing the risk of additional emergence of viruses or other pathogens from wildlife. the current fixation on human vaccines, human diagnostics, human drugs, and human-based surveillance is the legacy of past successes. landmark achievements for zoonotic disease prevention include vaccines for yellow fever and rabies, and other vaccines of human or veterinary importance exist, or are being developed, for tick-borne encephalitis, rift-valley fever, arboviral encephalitides, sars, ebola hemorrhagic fever, hps, and many others (chang et al. ; cox et al. ; lau ; custer et al. ; matsuoka et al. ; nalca et al. ; warfield et al. ; hjelle ; tomori ; tesh et al. ; stephenson ; monath et al. ; huang et al. ) . new antiviral drugs can be designed, created, and screened with far better efficiency than at any time in the past and novel candidates and methodologies for improving the delivery of drugs to infected cells are in development (oxford et al. ; duzgunes et al. ; wu et al. ; pastor-anglada et al. ) . additionally, traditional measures of case isolation, contact-tracing, and quarantine of exposed persons, banning of public gatherings, or curtailing individual access to international travel have proved highly effective in controlling the spread of zoonotic diseases with pandemic potential, as with sars (zhong ; anderson et al. ; speakman et al. ; see the chapter by wang and eaton, this volume) (fig. ) . but sars-cov is not influenza a. methods relying on increasing social distance are unlikely to prevent the spread of humanadapted pandemic influenza a mills et al. ) . aerosol transmissibility of influenza virus in the subclinical patient precedes clinical signs by h (mills et al. ; fraser et al. ) , unlike the coincidence of clinical disease with the onset of infectiousness with sars-cov . influenza a vaccine production capacity and antiviral medication stockpiles to combat influenza spread are insufficient even in wealthy developed countries (mills et al. ). can we continue to prepare and respond to such pathogens by strictly defensive measures aimed at the human h s ? so given the proven record of achievement of a medical or technological approach to defending humans from invasion by infectious organisms, is there much to be gained by examining processes, antecedent to human spillover, for potential vulnerabilities and as intervention targets, as a complement to ongoing efforts to improve human-based disease prevention activities? the answer is yes, but a qualified yes. simply saying we need such systems glosses over the myriad of obstacles in developing programs. designing and implementing wildlife-based surveillance and targeted interventions will not be achieved in the short term and establishing the infrastructure to support these efforts would be difficult and expensive (see the chapter by merianos, this volume). the maintenance and transmission cycles of zoonotic viruses within wildlife h r s offer many of the same targets for control as do human-based interventions, with the notable exception that population culling can be exploited for control of animal reservoirs, intermediate host populations and arthropod vector species. the ultimate prevention strategy for zoonotic agents affecting humans is to abrogate or greatly reduce cross-species transmission by disrupting transmission and maintenance cycles of zoonotic viruses within the h r . (introduction of refractory genes into h v s, endosymbionts) physical/temporal barriers table ). animal quarantine, isolation of animals exposed to a pathogen, and legal bans to trade in animals or animal products originating from countries with enzootic disease act to increase social distance and decrease the likelihood of contacts between infected and susceptible hosts. immunocontraception of h r s to reduce population size or genetic modification of h v s to render vector populations refractory to infection may play a role in prevention in the future. human vaccination, treatment, and the prophylactic use of drugs are defensive measures that may prevent or reduce spillover and post-spillover spread, but will not reduce the likelihood of contact between infected h r and individual humans. (modified from childs ) however, rarely has the full force of human scientific creativity and funding been directed at understanding and interrupting vulnerable infectious processes prerequisite to, but intermediate from, the immediate circumstances leading to human infection. the most widespread approach to zoonosis control is the culling or killing of individuals of h r s, h v s, or h i s, either through selected culling (largely restricted to domestic animals) or indiscriminate population reduction (wobeser ). the most common example of culling is the use of insecticides to control h v populations and nuisance populations of mosquitoes (thier ; leprince and lane ; mount et al. ) ; however, issues related to human and environmental health have limited enthusiasm for this type of control in many circumstances. culling of wildlife h r populations has been adopted, or is planned, to curtail transmission of several viral and bacterial zoonotic pathogens to humans or domesticated livestock, although the record of population control as an effective prevention strategy limiting spillover is mixed (wobeser ; see the chapter by palmer, this volume). targeted reduction of specific h r populations for control of rabies virus variants has been employed in europe and north america. on both continents, programs have targeted red foxes (muller ; debbie ) and in north america raccoon and skunk populations have been targeted (rosatte et al. ; debbie ) . efforts are ongoing in central and south america to reduce vampire bat populations in an effort to curtail the enormous economic loses sustained from vampire-bat transmitted rabies to cattle. anticoagulants applied topically or systemically by direct inoculation into livestock are the major methods of vampire bat control (crespo et al. ; fornes et al. ; thompson et al. ). however, wildlife culling to control rabies has been deemed largely unsuccessful or unnecessary given the intensive use of orv to vaccinate susceptible h r s (centers for disease control and prevention b; macinnes et al. ; aubert b; brochier et al. ; slate et al. ) . however, mathematical modeling of different control strategies frequently identifies a combination of vaccination and targeted culling as the optimal strategy for rabies control (smith and wilkinson ; anderson et al. ) . culling has recently been halted as a control measure for badgers serving as h r s for bovine tb in england (roper ; gormley and costello ; see the chapter by palmer, this volume), although in ireland data suggest badger culling is an effective measure in reducing the incidence of tb in cattle herds (griffin et al. ) . the removal of some , badgers in england from to failed to curb bovine tb spread among cattle (delahay et al. ) . vaccination of badgers against tb is now being investigated as a part of an integrated control program that includes targeting specific sites for control and different herd management practices for high-risk regions (white and benhin ) . china initiated culling of live captured and breeding stocks of several species of carnivores, the masked palm civet ( paguma larvata ), the raccoon dog ( nyctereutes procyonoides ), and the chinese ferret badger ( melogale moschata ), implicated in the transmission of sars-cov to humans (watts ; zhong ) . the who questioned the appropriateness of culling wildlife species (parry ) and it is now appears that wild carnivores are not the actual h r for sars-cov. current information suggests that bats of the genus rhinolophus are the h r for ancestral coronaviruses giving rise to sars-cov capable of infecting wild carnivores and humans ; see the chapter by wang and eaton, this volume). irrespective of the culling of farm-raised animals, the enormous illegal trade in wildlife will continue to stock the wet markets of china, vietnam, and other southeastern asian countries, with meat and other animal products from wild carnivores and other wildlife species prized for their culinary and medicinal properties (bell et al. ; yiming and dianmo ) . control of emerging zoonotic agents circulating among domestic poultry, livestock, and companion animals is often more finely targeted at specific infected subpopulations or demographic cohorts than methods applied to wildlife. for example, the mass elimination of seropositive dogs in brazil has been used in control programs for zoonotic visceral leishmaniasis; although evidence suggests dog control has failed to reduce the number of human leishmaniasis cases (moreira et al. ) . different culling strategies have been used for the control of bse. herd culling involves destroying entire herds of cattle from which an index case of bse originated; birth cohort culling targets the subpopulation of cattle born during a specific interval of time and considered at greatest risk for having acquired bse before the prohibition of feed containing cattle-derived offal; maternal culling destroys offspring borne to high-risk cows as the risk of vertical transmission of bse is approximately % (anonymous ) ; a final subpopulation considered to be at high risk, but difficult to identify operationally, is the feeding cohort. in the uk selected culling of birth cohorts (years - ) and maternal cohorts have been the major methods employed (donnelly et al. ) , involving destruction of more than , animals (anonymous ) . france, portugal, and ireland have employed mainly herd culling, with some maternal culling in france, with the destruction of approximately , , , , and , cattle, respectively (anonymous, ) . additional culling methods may be employed as surveillance data accumulate . switzerland and belgium have adopted both herd and birth cohort culling, with , and , animals destroyed as of , respectively (heim and murray ; anonymous ) . culling of domestic poultry is the primary means of control for pathogenic influenza a subtypes, some considered to have pandemic potential as human viruses. millions of chickens and other poultry were killed in hong kong in an attempt to prevent the spread of influenza a subtype h n (watts a; tam ) , and in over million chickens were killed in eight southeast asian nations as the threat of a human pandemic looms (watts a; abbott and pearson, ; see the chapters by merianos and webby et al., this volume). in april , canada ordered the killing of million chickens and other poultry to contain an outbreak of influenza h n ; year earlier, the netherlands culled million chickens to control an outbreak of a related influenza subtype, h n (stegeman et al. ) . livestock culling resulting in major economic losses accompanied the outbreak of niv affecting swine and humans in malaysia in (stegeman et al. ; paton et al. ; see the chapter by merianos, this volume), where more than million swine were culled (lam and chua ; uppal ) . nipah virus has since re-emerged in malaysia, precipitating new rounds of culling (ahmad ) . export bans and culling have enormous economic impacts and emerging zoonotic viruses, such as influenza h n , niv, wnv, and sars-cov, confront the stake holders in a global economy with unprecedented new risks (james ; von overbeck ) . in the future, population reduction by immune contraceptive programs could be used among certain populations of h r s or h i s (ferro ; miller and killian ; lurz et al. ) (fig. ) . there are ethical and practical limits as to how culling is, and will be, employed, as populations of game species and other wildlife species considered ecologically and esthetically important will be off limits, even if the species serves as h r for a zoonotic pathogen. exceptions occur where species overabundance becomes a nuisance problem or threatens vulnerable environments, as with white-tailed deer ( odocoileus virgineanus ) in suburban environments or feral horses on barrier islands or federally controlled lands. in such instances, immune contraception may become the population reduction method of choice (kirkpatrick et al. ) . where critical species within a community become environmentally destructive when overabundant, as with elephants within the confines of protected game reserves, controlled culling through hunting could generate income for indigenous peoples, but plans to use immune contraception may present a more acceptable choice (fayrer-hosken et al. ; delsink et al. ) . the second major approach to zoonotic pathogen control is through vaccination of individuals in the target h r or h i populations. wildlife vaccination is currently limited to few species, although new vaccines are under development (table ) . japanese encephalitis virus (jev) transmission to humans often requires mosquito vectors which initially obtain a viremic bloodmeal from a swine h i , alternatively referred to as an amplifying host (daniels et al. ) ; vaccination of domestic swine to interrupt jev transmission has been attempted (daniels et al. ; ueba et al. ) . similarly, vaccines for chickens serving as the h r of influenza a virus subtypes are being employed to remove the intermediary avian host most closely associated with virus transmission to humans (lee et al. ; ellis et al. b) . intermediate or amplifying vertebrate h s s, once infected by contact with a h r , can directly transmit zoonotic viruses to the humans h s , as occurred with hev and niv transmission from pteropid bats initially to horses and swine (hooper et al. ; selvey et al. ; field et al. ; uppal ; see the chapters by daniels et al. and field et al., this volume) (fig. ) . however, the wildlife vaccine with the widest distribution and greatest proven effectiveness is orv for red foxes and raccoons. the orv most commonly in use for rabies control targeting wild carnivores is a recombinant vaccinia virus vaccine expressing the rabies virus glycoprotein gene (v-rg) (rupprecht et al. (rupprecht et al. ; orv was the first live-recombinant vaccine to be released in the field ). the vaccine is distributed in plastic sachets, often covered with a polymer containing additives designed to preferentially attract the target h r (linhart et al. (linhart et al. , , although nontarget species find these vaccine-laden baits attractive (olson and werner ) . millions of orv doses have been delivered to control red fox rabies in europe and raccoon rabies in the united states (aubert a (aubert , b slate et al. ); orv has eliminated or reduced red fox rabies in many countries in western europe aubert b) . in the united states, deployment of orv to reduce enzootic levels of rabies, such as gray fox-associated rabies in texas (steelman et al. ) , or to develop immune barriers to the spread of raccoon variant rabies and coyote/ dog variant rabies, in ohio, west virginia, and pennsylvania (the ohio barrier), and in texas, respectively (foroutan et al. ; farry et al. ; slate et al. ) , have established zones where herd immunity is sufficiently high that rabies virus transmission is interrupted. the ohio barrier was effective in preventing or reducing raccoon rabies cases west of the vaccination border to a sporadic few, but after - years of success, a serious breach of the ohio barrier, km west of the vaccine zone, sparked what appears to be a new epizootic focus anonymous. a) . rapid and extensive remedial vaccination was employed and will be essential to contain this new focus from rapidly expanding into a full-blown epizootic .this long-term approach to rabies control is expensive and demands sustained public commitment (kemere et al. ; foroutan et al. ; gordon et al. ) ; however, the alternative public health activities required should raccoon rabies become enzootic, are perhaps more expensive and also require sustained support (gordon et al. ) . although the risk for human exposure to vaccinia virus in orv exists, relatively few instances of human exposure have been reported (gordon et al. ) . in the united states, a case of systemic vaccinia occurred in a pregnant women after she was bitten by her pet dog while trying to remove a vaccine sachet from the dog's mouth . if ever fully developed and employed, genetic manipulation of h v populations, or endosymbionts of h v populations to establish vector refractoriness to infection by a zoonotic pathogen (scott et al. ; rasgon et al. ; olson et al. ; blair et al. ) , will theoretically disrupt the transmission chain leading to human infection (fig. ) . if refractory gene penetrance into a h v population is complete, a pathogen could suffer extinction; if partial, the effect would be a mirror image to partial vaccine coverage of humans. both strategies would reduce the probability of contact (see the chapter by real and biek, this volume) between an infectious vector and a susceptible human host, one reducing the proportion or number of infected vectors, the other decreasing the number or proportion of susceptible humans. as yet genetic engineering methods have no proven practical value in zoonotic disease control. quarantine of animals arriving into a country from foreign countries, where certain diseases are enzootic, has a long history (gensini et al. ) . for example, dogs traveling from the united states to the uk were subject to a -month quarantine as part of the uk's rabies prevention law; proof of vaccination and a positive serologic test now suffice (shaw et al. ; fooks et al. ) . national legislation can attempt to reduce within-country movement of species recognized to be h r s of zoonotic viruses. laws pertaining to translocations of rabies h r s were passed following the outbreak of a coyote/dog variant of rabies virus in florida following importation of infected coyotes from texas (centers for disease control and prevention ). the cdc imposed a ban on the importation of african rodents destined for the us pet trade after the introduction of monkeypox virus and the outbreak of human monkeypox that resulted from transmission of virus through an indigenous north american rodent h i infected by virus spillover where housed in the same building with the african rodents (centers for disease control b; see the chapter by regnery, this volume). on the same day as the cdc ban was announced, the food and drug administration initiated regulatory control of interstate transport of prairie dogs in an effort to limit further spread of monkeypox to humans and potentially other susceptible species (see the chapter by regnery, this volume). in a similar attempt to control the transmission of sars-cov, china passed laws prohibiting trade in certain carnivore species following the outbreak of sars (zhong ) . international laws pertaining to facilitating animal trade, while reducing the risk of exporting diseased animals or animal products, were established by the sanitary and phytosanitary measures, the sps agreement, coincident with establishment of the world trade organization (wto) in (zepeda et al. ) . the international standards are set by the oie (oie ) . national prohibitions have been instituted by various nations, as exemplified by bans on importing cattle or cattle products from countries where bse has been detected, listed, and updated on the usda website (http://www.aphis.usda.gov/lpa/issues/bse/trade/ bse_trade_ban_status.html), and bans to importing poultry from countries with enzootic avian influenza (hall ) , also listed on the usda website (http:// www.aphis.usda.gov/lpa/issues/ai_us/ai_trade_ban_status.html). public health professionals have lamented the years of budgetary neglect that have weakened our federal and state infrastructure for conducting surveillance (bryan et al. ) . national capacities to collect surveillance data of quality, which can inform prevention and intervention planning, are not developed over a year or even a decade. any diminishment in support for human-based surveillance activities is a poor prognostic for implementing novel activities, such as designing and implementing regional programs to study zoonotic pathogens within their wildlife h r s, as any of these efforts require the same long-term, continuous support. the united states has already lost much of its capacity to train scientists whose interests span field biology and laboratory sciences; the calls for increased training is a shrill mantra falling on deaf ears (institute of medi-cine , medi-cine , , centers for disease control and prevention ) . even the emergences of sars-cov, hiv, wnv, influenza a subtype h n , snv, and niv have generated little movement toward training, encouraging, or promoting our professional capacity to explore the intricacies by which such pathogens have evolved and are maintained within their wildlife hosts; but by in large, the national response has been a handful of ro s and a few training grants in vector-borne diseases and disease ecology. additionally, there has been little success at cross-training of public health and veterinary professionals at the doctoral level; schools of public health tend to have few veterinarians as full-time faculty members, although at the postdoctoral level programs such as the epidemiologic intelligence service (eis) at cdc recruit veterinarians with each class. as of july , a joint and coordinated effort to establish an international surveillance network for the monitoring of animals and humans for zoonotic pathogens, or diseases caused by them, has been announced by the who and faso in collaboration with the oie (http://www.who.int/mediacentre/news/ new/ /nw /en). the nature of this effort and details concerning program implementation in countries lacking adequate surveillance infrastructure have yet to be announced; any assessment of such a program designed to provide an early warning system for zoonotic pathogen emergence may be years in coming. the role of veterinary medicine and veterinary epidemiology in support of the sps agreement is severely hampered by the inequality of services available among nations (zepeda et al. ) . developing nations face an enormous challenge to develop surveillance and monitoring systems, diagnostic laboratories, and the coordinating infrastructure to assure the validity and quality of the process for any domestic animal and livestock disease, much less emerging zoonoses (zepeda et al. ) . the bias toward human-based surveillance and post-spillover treatment of infected humans is firmly institutionalized, and too often the mission-boundaries of federal agencies preclude coordinated advancement toward any integrative policy. as an example of the problems inherent to different federal agencies' ability to cross traditional boundaries to promote integration of human and veterinary epidemiology is illustrated by a report issued by cdc in morbidity and mortality weekly reports in response to the discovery of bse in cattle in the united states: "the occurrence of bse in the united states reinforces the need for physicians to be aware of the clinical features of variant creutzfeldt-jakob disease (vcjd) and to arrange for brain autopsies in all decedents with suspected or probable cjd to assess the neuropathology of these patients" (centers for disease control a). although efforts of the usda to trace the origins of the infected animal were briefly alluded to in this report, the final recommendation focusing on the human consequences of bse missed an opportunity to re-emphasize the critical component of veterinary surveillance. perhaps a report, written in collaboration with the usda, could have highlighted the means by which bse surveillance in cattle was to be enhanced. research focusing on wildlife h r s and the human-wildlife interface is most often funded through year-to-year contracts or limited grants to research institutions, which often lack the infrastructure to preserve data, specimens, and, too often, trained investigators for durations exceeding the length of a grant. in addition, if there are no programs in place to disseminate and use the information generated by disparate research efforts, the results from such studies will remain within the confines of some academic journal, rather than translated into recommendations to prevent or reduce the risk of human disease. currently, any products or recommendations stemming from such studies have little chance of diffusing into the public health culture (childs , in press) . the same problem exists with theoretical or mathematical approaches to infectious disease epidemiology. once mathematical models are developed and validated by use of existing data sets (russell et al. coyne et al. ; childs et al. ) , the route to integrating insights gleaned from mathematical approaches into public health practice or specific control activities is unclear. mathematical modeling as an aid to assist policy decisions has come under severe criticism from practicing veterinary professionals operating on the front lines of disease control. the disparate interpretations of the success of mathematical models in forming an effective control policy for an animal-disease disease outbreak are clearly illustrated by postcrisis reviews of the foot-andmouth-disease (fmd) outbreak in the uk in . proponents and authors of models saw the utility and predictions of models validated (woolhouse ) , while some veterinary practitioners and epidemiologists saw little to no benefit in the models as applied in a real-time crisis (salman ) . the serious and widening gulf between mathematical modeling and public health practice requires a systematic and purposeful effort on both sides to bridge these differences (childs , in press ). if communications fail, the danger exists for one class of professional to dismiss the efforts of the other as either irrelevant or hopelessly unsophisticated. whose problem is it? national and international long-range translocations of infected animals have played an extensive role in the emergence of viral zoonoses. the phenomenon is so common that it must be considered in conjunction with any control strategy based on legal restrictions to animal movement, bans to trade in wildlife, or when constructing vaccination barriers to limit pathogen spread. instances of transcontinental zoonotic viral spread reinforce the significance of ldts and the recommendation that contingencies for their occurrence should be included in any strategic plan for zoonotic disease control. in , sars spread around the world in a matter of months, eventually affecting countries on every populated continent (heymann ) . in , monkeypox was introduced into the united states along with a shipment of african rodents destined for the pet trade (cunha ; centers for disease control and prevention a; see the chapter by regnery, this volume). in , wnv was recorded in the new world for the first time, introduced into new york city by an infected vector or human host (lanciotti et al. ; kilpatrick et al. ) . in , singapore experienced outbreaks of niv infection among abattoir workers after importing swine from malaysia (chew et al. ; see the chapter by field et al., this volume) . the impact of a within-country ldt is well illustrated by the spread of raccoon rabies from a focus identified in the late s along the virginia-west virginia border, a focus likely seeded by the translocation of raccoons incubating rabies from an enzootic region of raccoon-associated rabies virus in the southeastern united states (nettles et al. ) . the resulting rabies epizootic, as the disease spread into mid-atlantic and northeastern states, was one of the most extensive and intensive wildlife epizootics recorded (childs et al. ; . a rabid bat stowaway onboard a ship originating from the west coast of the united states was discovered in hawaii, which is a rabies-free state (centers for disease control and prevention ); other instances of ldts of rabid bats, some transcontinental, have been reviewed (constantine ) . at a finer scale, quantitatively defined instances of raccoon rabies epizootic foci developing in advance of the epizootic wavefront in connecticut indicate local translocations influenced the spatial pattern of raccoon rabies spread through that state . the instance of a rabies virus variant of coyotes/domestic dogs from texas being introduced into florida with transported coyotes was described previously (centers for disease control and prevention ). without adequate compensation for losses accrued through culling or exportation bans, countries attempting to implement animal-based surveillance programs for domestic species, much less wildlife, are likely to encounter problems with voluntary reporting (see the chapter by merianos, this volume). in some instances, the mere threat of culling, as with swine in areas of malaysia affected by niv, can promote epidemic spread as farmers disperse valuable animals to protect their livelihood (chua ; see the chapter by field et al., this volume) . in addition to the enormous economic losses facing individuals whose animals are killed or whose products cannot be sold, the consequences of reporting an outbreak of a new zoonotic disease can be politically unattractive, inviting delays in reporting, as may have occurred with sars in china (enserink ) . other hidden costs associated with zoonotic disease outbreaks may persist through the burden of surveillance and animal testing (bradley and liberski ) and the loss to veterinary services (bennett and hallam ) . before implementation of any control activity, such as culling or vaccination, it is essential that the target species has been accurately and irrefutably identified as the h r or h i of importance. identification of a h r requires establishing epidemiologic plausibility using definable criteria, such as the temporal and spatial association of putative h r s to pathogen spillover, and molecular epidemiologic data linking virus recovered from a h s to virus circulating among h r s (haydon et al. ; childs ) . china initiated culling of some species of carnivores and other wildlife intended for human consumption (watts b) , although no sars-cov has yet been isolated from wild civets obtained directly from the field (bell et al. ; guan et al. ) . in , a putative h r for coronaviruses ancestral to those isolated and characterized from humans and palm civets was identified among three species of bats of the genus rhinolophus ; see the chapter by wang and eaton, this volume). molecular sequencing of sars-cov from bats, palm civets, and humans indicates a common ancestor with rapid positive selection for virulent viral subtypes infecting humans and civets (song et al. ; see the chapter by wang and eaton, this volume). removing carnivores near the top of ecological food chains can have many unforeseen, and in certain circumstances, potentially disastrous, consequences. by diluting, or severing important links in community processes, culling of top-level carnivores can cause changes in species richness and diversity in communities and increases in prey populations (ostfeld and holt ; ostfeld and keesing ) , including wild rodent h r s of other potentially dangerous zoonotic agents, such as borrelia burgdorferi and the arenaviruses and hantaviruses (logiudice et al. ; mills and childs ) . use of methods designed to control one species, such as anticoagulants topically applied to cattle to reduce vampire bat populations, can reduce populations of ecologically important species of bats unintentionally dosing themselves when roosting with vampire bats in confined spaces (mayen ; martinez-burnes et al. ) . contrast the purposeful and highly successful surveillance for animal rabies with activities targeting other known or potential pandemic zoonotic threats with wildlife h r s. subtypes of hiv i and hiv ii have emerged independently from primate sivs on at least eight independent occasions (hahn et al. ; b. hahn, personal communication to jec) . the number of sivs described among nonhuman primates in africa, as of , was approximately (apetrei et al. ). rapid replication, high mutability, and the elevated rates of recombination of lentiviruses (zhuang et al. ; see the chapter by holmes and drummond, this volume) virtually assures that new strains of siv-hiv will make the journey out of africa. there appears to be little systematic effort to enhance or build the basic infrastructure in regions of west africa that could begin to conduct surveillance for new emerging hivs at the human level or monitor the dynamics of transmission of diverse and genetically chimerical sivs transmitted among nonhuman primates. detection of spumaviruses among hunters, although uncommon (~ %), signify the extent to which humans are exposed and infected with diverse primate retroviruses (wolfe et al. ) . although some of the countries of importance are war zones and politically unstable, it is unclear that given an improving situation, surveillance for sivs spilling over to humans would be regarded as a priority among funding institutions concentrating on hiv vaccine trials. how are we surveilling and preparing for the next pandemic of influenza? currently influenza a subtype h n has a limited capacity for cross-vertebrate class transmission from birds to mammals, although infection is frequently fatal to humans once spillover succeeds sturm-ramirez et al. ; claas ; tran et al. ; see the chapter by webby et al., this volume). monitoring avian h n subtypes has been, and continues to be spotty, and largely limited to domestic poultry in which infection is often fatal to chickens and to a lesser extent ducks ). recombination of waterfowl influenza viruses within a domestic duck h r may have been the origin of highly pathogenic subtypes of h n for chickens (chen et al. b; tumpey et al. ; guan et al. guan et al. , , and successive isolates of h n from domestic ducks over time indicate increasing virulence for mammals (chen et al. b; guan et al. a guan et al. , b . domestic geese may serve a role as an independent h r for recombinant wild waterfowl-goose influenza h n subtypes and help drive the rapid evolution of highly pathogenic viruses of ducks and chickens chen et al. b ). yet the ultimate origin of h n and other influenza subtypes, h n and h n , occurring among domestic poultry and representing human threats choi et al. ) , is the diverse species of waterfowl, shorebirds, and possibly other avian types in which these various influenza subtypes circulate, often with minimal morbidity (see the chapter by webby et al., this volume). surveillance for influenza subtypes among wild waterfowl and other migratory birds is spotty (krauss et al. ; campitelli et al. ; de marco et al. ; hatchette et al. ) and largely restricted to local or regional populations, as occurs in north america and italy (krauss et al. ; slemons et al. ; hatchette et al. ; campitelli et al. ; de marco et al. ; ellis et al. a; stallknecht et al. ). the who has proposed establishing an animal influenza network to develop and coordinate research on the ecology and molecular biology of animal influenza viruses and integrate these animal-based activities with the global surveillance program for human influenza (stohr ) ; presumably emphasis will be placed on wild waterfowl and other migratory birds, in addition to domestic poultry and livestock. the uneven standards of surveillance, human-or animal-based, for zoonotic diseases or pathogens maintained by wildlife h r s, or even domestic species (zepeda et al. ) , is a global problem, readily apparent even within the united states, where investment in public health, including surveillance systems, has a long and enviable history (thacker ) . as of , there appears to be little scientific, social, or political consensus that animal-based surveillance for zoonoses merits investment in international infrastructure. however, this trend may be changing with the recent announcement of the proposal to develop a global early warning system for certain zoonotic agents or disease to be coordinated by the who, fao, and oie. technologically advanced solutions to addressing vector-borne or zoonotic disease transmission, such as genetic manipulation of mosquitoes or immunocontraception aimed at target vertebrate hosts, may involve good science, but whether these approaches represent good public health is highly debatable (scott et al. ; furguson et al. ) . novel schemes of preventing spillover of human pathogens from animal h r s can only spring from improving our understanding of the ecological context and biological interactions of pathogen maintenance among h r s. there are no easy solutions to preventing spillover and there is no reason to expect we will ever predict the wheres and whys of new emergences of zoonotic diseases (see the chapters by cleaveland et al. and daszak et al., this volume) . inevitably, the major issue arises of where surveillance and research efforts should focus, and there are many areas worthy of consideration. where the intent exists to improve global surveillance for specific zoonoses of animals, such as influenza a, every possible effort should be made to bring in new ideas and to set a standard of excellence that will encourage additional forays into these areas. as a speculative example, the ability to genetically modify plants to produce viral antigens of potential vaccine quality (castle and dalgleish ) may provide a tool to reach wild waterfowl that gather in vast numbers in specific staging areas during migration. could influenza a subtype h n genes be introduced into corn (tacket et al. ; lamphear et al. ), a favorite food of virtually all waterfowl and poultry, and would such a vaccine immunize sufficient numbers of waterfowl to reduce the susceptible population if widely dispersed among migratory staging areas? would there be a payoff from large investments to improve surveillance and knowledge of known or potential zoonotic pathogens circulating among wildlife h r populations? no one knows, but the alternative is to continue to rely on disease detection among sentinel humans. our ongoing experience with hiv, the looming threat of pandemic influenza, and the myriad of other zoonotic virus emergences in the last few years inform us of the outcomes we can expect by relying on detection of post-spillover events. efforts to create a knowledge base of the ecology of zoonotic viruses and other pathogens are not without precedent. a glimpse at the enormous achievements in the field and laboratory by scientists connected to the rockefeller foundation virus program should convince even skeptical readers of the value of an integrated research approach, without adherence to rigid disciplinary boundaries (theiler and downs ) . public health judges its great achievements not by damage control, but permanent prevention or, ultimately, eradication of disease threats. when any zoonotic disease or agent shows up in a human, to a great degree, we have failed; in some notorious instances, such as with hiv, it will already be too late to halt a pandemic's spread. we are aware of the consequences and the difficulties in combating 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hot spots key: cord- -uiezqa p authors: tessler, hannah; choi, meera; kao, grace title: the anxiety of being asian american: hate crimes and negative biases during the covid- pandemic date: - - journal: am j crim justice doi: . /s - - - sha: doc_id: cord_uid: uiezqa p in this essay, we review how the covid- (coronavirus) pandemic that began in the united states in early has elevated the risks of asian americans to hate crimes and asian american businesses to vandalism. during the covid- pandemic, the incidents of negative bias and microaggressions against asian americans have also increased. covid- is directly linked to china, not just in terms of the origins of the disease, but also in the coverage of it. because asian americans have historically been viewed as perpetually foreign no matter how long they have lived in the united states, we posit that it has been relatively easy for people to treat chinese or asian americans as the physical embodiment of foreignness and disease. we examine the historical antecedents that link asian americans to infectious diseases. finally, we contemplate the possibility that these experiences will lead to a reinvigoration of a panethnic asian american identity and social movement. introduction covid- (or the coronavirus) is a global pandemic that has affected the everyday lives of hundreds of millions of people. at the time we write this, there have been over four million cases across over countries worldwide (pettersson, manley, & hern, ) . moreover, pervasive stay-at-home orders and calls for social distancing, as well as the disruptions to every facet of our lives make it difficult to overstate the importance of covid- . as the beginning of the outbreak has been traced to china (and wuhan in particular), both in the united states and elsewhere, people who are chinese or seen as east asian have become associated with this contagious disease. early reports in the united states were often accompanied by stock photos of asians in masks (burton, ; walker, ) . many of the first reports labeled the disease as the "wuhan virus," or "chinese virus," and the trump administration has also used these terms (levenson, ; maitra, ; marquardt & hansler, ; rogers, jakes, & swanson, ; schwartz, ) . news media coverage in the united states focused on the hygiene of the seafood market in wuhan and wild animal consumption as a possible cause of coronavirus (gomera, ; mackenzie & smith, ) . memes and jokes about bats and china flooded social media, including posts by our peers online. these reports provide the american public a straightforward narrative that focuses on china as the origin of covid- . in this paper, we review current patterns of hate crimes, microaggressions, and other negative responses against asian individuals and businesses during the covid- pandemic. these hate crimes and bias incidents occur in the landscape of american racism in which asian americans are seen as the embodiment of china and potential carriers of covid- , regardless of their ethnicity or generational status. we believe that asian americans not only are not "honorary whites," but their very status as americans is, at best, precarious, and at worst, in doubt during the covid- crisis. we suggest that what we witness today is an extension of the history of asians in the united states and that this experience may lead to the reemergence of a vibrant panethnic asian american identity. as of early may , there have been over . million individuals who have tested positive for and over , deaths from covid- in the united states alone and the numbers are growing rapidly every day ("cases in the u.s.," ). although researchers have traced cases of the virus in the united states to travelers from europe (gonzalez-reiche et al., ) and to travelers within the united states (fauver et al., ) , some members of the general public regard asian americans with suspicion and as carriers of the disease. on april th, , nbc news reported that % of americans have personally witnessed someone blaming asians for the coronavirus (ellerbeck, ) . the covid- pandemic has revealed the negative perceptions of asian americans that have long been prevalent in american society. many individuals in the united states see the virus as foreign and condemn phenotypically asian bodies as the spreaders of the virus (ellerbeck, ) . consistent with claire jean kim's theory on racial triangulation (kim, ) and the concept of asians as perpetual foreigners (ancheta, ; saito, ; tuan, ; e. d. wu, ) , we posit that during covid- , the racial positionality of asian americans as foreign and other persists, and that this pernicious designation may be a threat to the safety and mental health of asian americans. they are not only at risk of exposure to covid- , but they must contend with the additional risk of victimization, which may increase their anxiety. historically, from the late th through the mid twentieth century, popular culture and news media portrayed asians in america as the "yellow peril," which symbolized the western fear of uncivilized, nonwhite asian invasion and domination (okihiro, ; saito, ) . it is possible that the perceived threat of the yellow peril has reemerged in the time of covid- . the spread of the coronavirus and the increased severity of the pandemic has caused fear and panic for most americans, as covid- has brought about physical restrictions and financial hardships. so far, forty-two states have issued stay-at-home orders, which has resulted in % of the american population facing restrictions that impact their daily lives (woodward, ) . novel efforts to end the pandemic across the states have led businesses to shut down. as a result, more than million people in the united states have filed for unemployment since the onset of the coronavirus crisis (gura, ) . because this virus has been identified as foreign, for some individuals, their feelings have been expressed as xenophobia, prejudice, and violence against asian americans. these negative perceptions and actions have gained traction due to the unprecedented impact covid- has on people's lives, and institutions such as uc berkeley have even normalized these reactions (chiu, ) . however, racism and xenophobia are not a "natural" reaction to the threat of the virus; rather, we speculate that the historical legacies of whiteness and citizenship have produced these reactions, where many individuals may interpret asian americans as foreign and presenting a higher risk of transmission of the disease. already, the fbi has issued a warning that due to covid- , there may be increased hate crimes against asian americans, because "a portion of the us public will associate covid- with china and asian american populations" (margolin, ) . news reports, police departments, and community organizations have been documenting these incidents. evidence suggests that the fbi's warning was warranted. based on reporting from stop aapi hate, in the one-month period from march th to april rd, there were nearly alleged instances of anti-asian bias (jeung & nham, ) . the reported incidents have been concentrated in new york and california, with % of the reports hailing from california and % of reports from new york, but asian americans in states across the nation have reported incidents (jeung & nham, ) . there have been a large number of physical assaults against asian americans and ethnically asian individuals in the united states directly related to covid- . while the majority of americans are sheltering-in-place and staying at home, % of the selfreported anti-asian incidents have taken place outside people's private residences, in grocery stores, local businesses, and public places (jeung & nham, ) . we suggest that these hate crimes and other incidents of bias have historical roots that have placed asians outside the boundaries of whiteness and american citizenship. in addition, we believe that the current covid- crisis draws attention to ongoing racial issues and provides a lens through which to challenge the notion of america as a post-racial society (bonilla-silva, ) . one of the incidents under investigation as a hate crime includes the attempted murder of a burmese-american family at a sam's club in midland, texas (yam, a) . the suspect said that he stabbed the father, a four-year-old child, and a twoyear-old child because he "thought the family was chinese, and infecting people with coronavirus" (yam, a) . police are investigating numerous other physical incidents including attacks with acid (moore & cassady, ) , an umbrella (madani, ) , and a log (kang, ) . there have been a number of physical altercations at bus stops (bensimon, ; madani, ) , subway stations (parnell, ) , convenience stores (oliveira, ) , and on the street (jeung & nham, ; sheldon, ) . asian americans are also reporting physical threats being made against them (driscoll, ; parascandola, ) . based on stop aapi hate statistics, asian americans filed reports of physical assaults in four weeks (jeung & nham, ) , and it is likely that other asians have not reported their experiences out of fear or concern about the legal process. in addition to the physical attacks and threats against asian americans, individuals have also filed reports of vandalism and property damage targeted at asian businesses. one korean restaurant in new york city had the graffiti "stop eating dogs" written on its window (adams, ) . perpetrators have also made explicit references to covid- in their vandalism, where phrases such as "take the corona back you ch*nk" (goodell & mann, ) , and "watch out for corona" (wang, ) have been documented on asian-owned restaurants. some of these incidents were not reported to the police and therefore will not be investigated as hate crimes, as business owners reasoned that it would be difficult to track the vandals (adams, ; buscher, ) . these incidents of vandalism demonstrate the association some people make between asian american businesses and covid- . beyond the narrow definition of the incidents that can be classified as punishable hate crimes, asian americans have also documented a large number of alleged bias and hate incidents. stop aapi hate reports indicate that % of coronavirus discrimination against asian americans has involved verbal harassment, with over incidents of verbal harassment reported in just four weeks (jeung & nham, ) . in addition, there have been over reports of asian americans being coughed or spat on. one prevalent theme in the verbal incidents is the linking of asian bodies to covid- , where the aggressors are purportedly calling asians "coronavirus," "chinese virus," or "diseased," and telling them that they should "be quarantined," or "go back to china" (adl ). in all of these incidents, the perpetrators consistently use anti-asian racial slurs (buscher, ; goodell & mann, ; sheldon, ) . this hateful language that targets all asians (and not just chinese americans) demonstrates the racialization of asian americans. the threat of a global pandemic to people's everyday lives is something that most americans have not experienced before. however, the act of interpreting the current national crisis as an external threat and ascribing this danger to chinese bodies and more broadly asian bodies should not surprise scholars of asian americans. in fact, this deeply-rooted cognitive association of asian americans to asia and to disease has a long history. hence, we examine the phenomenon of xenophobia against asian americans in the context of historical racial dynamics in the united states. race has been posited as a socio-historical concept, and while many race scholars in the united states have focused on the black/white binary, others have documented how asian americans have also been racialized over time (omi & winant, ) . these scholars have examined how the racialization of asian americans has developed in relation to african americans and white americans (bonilla-silva, ; kim, ) . one of the dominant stereotypes of asian americans is that they are perpetual foreigners, where individuals directly link phenotypical asian ethnic appearance with foreignness, regardless of asian immigrant or generational status (ancheta, ; tuan, ; f. h. wu, ) . this stereotype is longstanding in american history and has forcefully re-emerged during the covid- crisis. the perception of an asianlooking person as simultaneously chinese, asian, and foreign underscores how this racial categorization affects all asian americans. thus, we suggest that the concept of asian american panethnicity (okamoto & mora, ) may be particularly applicable during the covid- pandemic. the legacy of white supremacy equates white bodies with purity and innocence, while nonwhite bodies are designated as unclean, uncivilized, and dangerous. white supremacy and its tactic of othering asian bodies has been a consistent recurrence over earlier pandemics. dating back to the nineteenth century, the bubonic plague was framed as a "racial disease" which only asian bodies could be infected by whereas white bodies were seen as immune (randall, ) . in , honolulu officials quarantined and burned chinatown as a precaution against the bubonic plague (mohr, ) . in , san francisco authorities quarantined chinatown residents, and regulated food and people in and out of chinatown, believing that the unclean food and asian people were the cause of the epidemic (shah, ; trauner, ) . the history of the yellow peril has continued throughout the th and st centuries in the embodied perceptions of asian immigrants as the spreaders of disease (molina, ) . more recently, during the sars (severe acute respiratory syndrome) epidemic, the discourse in the united states focused on chinatown as the epicenter of the disease (eichelberger, ) . studies suggest that % of americans reported avoiding asian businesses and asian americans experienced increased threat and anxiety during sars (blendon, benson, desroches, raleigh, & taylor-clark, ) . we suspect the negative impact of covid- on asian americans has been far greater than the impact of sars. in new york city's chinatown, restaurants suffered immediately after the first reports of covid- , as some restaurants and businesses experienced up to an % drop in profits for the two months prior to march th, far before any stayat-home orders were given (roberts, ) . when moral panic arises, foreign bodies, typically the undesirable and "un-american" yellow bodies, may be seen as a threat that can harm pure white bodies. the cycle of elevated risk, followed by fearing and blaming what is foreign is not just limited to disease outbreaks, but also occurs during economic downturns. in , vincent chin was beaten to death by two men who blamed him for the influx of japanese cars into the united states auto market. vincent chin was attacked with racial slurs and specifically targeted because of his race. although chin was chinese american, in the minds of these two men, he represented the downturn of the auto industry in detroit and the increased imports of japanese automobiles (choy & tajima-pena, ) . similarly, after the / attacks in the united states, retaliatory aggressions were not limited to attacks against arabs or muslims (perry, ) . violence and hatred against the perceived enemy resulted in incidents targeting sikhs, second and third generation indian americans, and even lebanese and greeks (perry, ) . more recently, the hate crime murder of srinivas kuchibhotla, an indian immigrant falsely assumed to be an iranian terrorist and told "get out of my country" before being shot to death, illustrates the association between racialized perceptions of threat and incidents of violence (fuchs ) . with the covid- pandemic, violent attacks and racial discrimination against asian americans have emerged as non-asian americans look for someone or something asian to blame for their anger and fear about illness, economic insecurity, and stay-at-home orders. the current perceptions of china and more broadly east asia as both economic and public health threats have made chinese and east asians in america fearful for their own safety. some asian americans have made efforts to hide their asian identity or assert their status as american in an attempt to prevent hate crime attacks (buscher, ; tang, ) . while this tactic may be effective on the individual level, it does not modify the positionality of asian bodies during covid- . the attempt to distinguish asian americans from asians who are foreign nationals misses the fact that in the united states, being asians and being foreign are inextricably bound together. after world war ii, news media and local organizations encouraged chinese americans to distinguish themselves from the japanese, and similarly encouraged japanese americans to show their americanness and patriotism to gain acceptance by the white majority (e. d. wu, ) . muslim and sikh americans displayed american flags after / to show that they were not a threat to the united states, and more recently there has been a movement to celebrate sikh captain america (ishisaka, ) . former presidential candidate andrew yang suggested that asian americans fight against racism by wearing red white and blue and prominently displaying their americanness (yang, ) . in many of these situations, these strategies did not directly address the problems of racism and xenophobiathey simply shifted the blame towards another group. disease does not differentiate among people based on skin color or national origin, yet many asian americans have suffered from discrimination and hatred during the covid- pandemic. although the threat of the virus is real for all americans, asian americans bear the additional burden of feeling unsafe and vulnerable to attack by others. the link between covid- and hate crimes and bias incidents against asian americans is indicative of the widespread racial sentiments which continue to be prominent in american society. while some scholars have gone as far as to regard asian americans as "honorary whites" (tuan, ) , the current covid- crisis has made markedly clear this is an illusion, at best. there are a number of reasons why the racial dynamics of anti-asian crimes during covid- should be examined more closely. first, the majority of incidents and attacks have occurred in diverse metropolitan areas such as new york city, boston, and los angeles. these are spaces that most americans have traditionally regarded as more liberal and tolerant of difference than other parts of the united states. in new york city alone, from the start of the covid- outbreak through april , the nypd's hate crime task force has investigated fourteen cases where all the victims were asian and targeted due to coronavirus discrimination (nypd, ) . the remarks of a kansas governor that said his town was safe "because it had only a few chinese residents" (lefler & heying ) offers one explanation for the high concentration of racial incidents in large cities with sizable asian populations, but we think that this is not sufficient in explaining the data so far. future research should track racial bias and hate crimes more systematically in order to further our understanding of how demography and urbanicity influence these incidents. second, these hate crimes have increased the anxiety of asian americans during already uncertain times, with many fearful for their physical safety when running everyday errands (tavernise & oppel jr., ). asian americans are now self-conscious about "coughing while asian" (aratani, ) , and concerned about being targeted for hate crimes (liu, ; wong, ) . there is evidence to suggest that asian americans under-report crimes (allport, ) , and some recent immigrants may lack an understanding of the legal system and process of reporting crimes, particularly in the case of hate crimes. therefore, scholars should take additional care to document and analyze these incidents and their effects on asian american communities across the united states. the possible upward trend of anti-asian bias incidents and hate crimes is indicative of the growth of white nationalism and xenophobia. the image of a disease carrier with respect to covid- is bound in asian bodies and includes assumptions about race, ethnicity, and citizenship. as vincent chin, srinivas kuchibhotla, the burmese-american family, and many others have shown us, the level of fungibility in terms of how asian ethnicities are perceived can be deadly. it does not matter if the person is from china, of chinese origin, or simply looks asianthe perpetrators of this violence see all of these bodies as foreign and threatening. while there have been numerous instances of anti-asian bias and crime, there have not been similarly patterned anti-european tourist incidents or an avoidance of italian restaurants, suggesting that covid- illuminates the particular racialization of disease that extends beyond this virus, and further back in american history. already there has been substantial news coverage of these anti-asian crimes, which suggests that people are paying attention to this issue, and police departments are actively investigating many of these incidents. activists and community organizations have started online campaigns such as #washthehate and #hateisavirus to combat anti-asian racism during this time. the bbc has documented distinct news articles covering alleged incidents of discrimination since the onset of the covid- pandemic (cheung, feng, & deng, ) . in addition, the chinese for affirmative action and asian pacific policy and planning council have created a platform where individuals can record incidents of racism and coronavirus discrimination. the reporting of hate crimes during covid- is superior to the reports of these types of incidents during the sars outbreak (leung coleman, ; washer, ) . although the federal government response has been limited compared to the hate crime prevention initiatives after / and sars, in may , the commission on civil rights agreed to take on the demands proposed by a group of democratic senators in a letter requesting a stronger response to the anti-asian hate crimes and discrimination during covid- (campbell & ellerbeck, ; yam, b) . similar to the murder of vincent chin, which served to ignite an asian american activist movement, we hypothesize that the racial incidents against asian americans during the covid- pandemic may encourage the political mobilization of a panethnic asian american movement. at the same time, we believe that the incidents that are classified as "hate crimes" and "bias incidents" based on legal definitions do not fully capture the extent or pervasiveness of racist and xenophobic thoughts against asian americans. we encourage future scholars to more closely examine the culturally embedded racial logics that lead to these incidents, rather than focusing solely on the incidents themselves as the object of analysis. the hate crimes against asians in the time of covid- highlight the ways that asian americans continue to be viewed as foreign and suspect. this may be an additional burden on asian americans beyond the anxiety, economic instability, and the risk of illness all americans have experienced during covid- . racist graffiti scrawled on michelin-starred west village korean restaurant reports of anti-asian assaults, harassment and hate crimes rise as coronavirus spreads. anti-defamation league racial violence against asian americans race, rights, and the asian american experience coughing while asian": living in fear as racism feeds off coronavirus panic. the guardian cops bust suspect accused of coronavirus-related hate crime on asian man public's response to severe acute respiratory syndrome in toronto and the united states from bi-racial to tri-racial: towards a new system of racial stratification in the usa racism without racists: color-blind racism and the persistence of racial inequality in the united states why asians in masks should not be the "face" of the coronavirus reality is hitting me in the face: asian americans grapple with racism due to covid- federal agencies are doing little about the rise in anti-asian hate coronavirus: what attacks on asians reveal about american identity. bbc news uc berkeley apologizes for coronavirus post listing xenophobia under 'normal reactions' to the outbreak update: racist death threats lodged against seymour restaurant. valley independent sentinel sars and new york's chinatown: the politics of risk and blame during an epidemic of fear over percent of americans have witnessed covid- bias against asians, poll says coast-to-coast spread of sars-cov- in the united states revealed by genomic epidemiology kansas man sentenced to life for killing indian engineer in a bar accessed how to prevent outbreaks of zoonotic diseases like covid- introductions and early spread of sars-cov- in the new york city area take the corona back you ******: yakima police investigate racist graffiti at asian buffet. yaktri news u.s. jobless claims reach million since coronavirus hit, wiping out all gains since sikh captain america fights intolerance and bigotry. the seattle times incidents of coronavirus-related discrimination asian americans feel the bite of prejudice during the covid- pandemic the racial triangulation of asian americans kansas official: pandemic isn't a problem here because there are few chinese people. the kansas city star coronavirus is inspiring anti-asian racism: this is our political awakening stop trying to make "wuhan virus" happen being asian american in the time of covid- . the daily nexus covid- : a novel zoonotic disease caused by a coronavirus from china: what we know and what we don't woman needed stitches after anti-asian hate crime attack on city bus, nypd says the wuhan virus is finally awakening europe to china's imperialism. the federalist fbi warns of potential surge in hate crimes against asian americans amid coronavirus us push to include "wuhan virus" language in g joint statement fractures alliance plague and fire: battling black death and the burning of honolulu's chinatown fit to be citizens? public health and race in los angeles brooklyn woman burned outside home in possible acid attack nypd announces citywide crime statistics for margins and mainstreams: asians in american history and culture brute attacks, shouts at asian man, , in vancouver racial formation in the united states asian man spit on, threatened in nyc coronavirus hate crime coronavirus-inspired crook robs woman of cellphone, spews hate hate and bias crime: a reader tracking coronavirus' global spread black death at the golden gate: the race to save america from the bubonic plague as covid- spreads, manhattan's chinatown contemplates a bleak future trump defends using 'chinese virus' label, ignoring growing criticism. the new york times model minority, yellow peril: functions of foreignness in the construction of asian american legal identity media called coronavirus "wuhan" or "chinese coronavirus" dozens of times contagious divides girl charged with racially assaulting asian woman over coronavirus from guns to gopros, asian americans seek to deter attacks the chinese as medical scapegoats in san francisco forever foreigners or honorary whites? the asian ethnic experience today news outlets contribute to anti-asian racism with careless stock photos on coronavirus coverage. media matters for america vandals tag downtown asian restaurant with racist message representations of sars in the british newspapers for asian americans, there are two pandemics: covid- and daily bigotry about % of americans have been ordered to stay at home. this map shows which cities and states are under lockdown the color of success: asian americans and the origins of the model minority where are you really from? asian americans and the perpetual foreigner syndrome uc berkeley health account calls xenophobia a "common reaction" to coronavirus civil rights commission agrees to senate democrats' call for action against anti-asian racism andrew yang: we asian americans are not the virus, but we can be part of the cure publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations hannah tessler is a phd student in sociology at yale university. her research focuses on race, ethnicity, and sociology of education meera choi is a phd student in sociology at yale university. her research focuses on the intersection of family and culture grace kao is chair and ibm professor of sociology and faculty director of education studies at yale university. she is the immediate past vice president of the acknowledgements we gratefully acknowledge support from the faculty of arts and sciences, the macmillan center, and the council for east asia at yale university. we are also grateful for the support of the laboratory program for korean studies through the ministry of education of the republic of korea and the korean studies promotion service of the academy of korean studies (aks- -lab- ). key: cord- -w q o wc authors: pendell, dustin l.; marsh, thomas l.; coble, keith h.; lusk, jayson l.; szmania, sara c. title: economic assessment of fmdv releases from the national bio and agro defense facility date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: w q o wc this study evaluates the economic consequences of hypothetical foot-and-mouth disease releases from the future national bio and agro defense facility in manhattan, kansas. using an economic framework that estimates the impacts to agricultural firms and consumers, quantifies costs to non-agricultural activities in the epidemiologically impacted region, and assesses costs of response to the government, we find the distribution of economic impacts to be very significant. furthermore, agricultural firms and consumers bear most of the impacts followed by the government and the regional non-agricultural firms. scientific laboratories designed to study diseases are not completely risk free, and the possibility exists that accidents of nature or deliberate acts of terror might cause the spread of a disease that the facility is trying to prevent. on the one hand animal and human health officials in the united states are interested in preventing the introduction and spread of diseases like ebola, rift valley fever or highly pathogenic avian influenza, while on the other hand scientists within the united states need small quantities of these materials for study and to develop response strategies should an outbreak occur. it is a tenuous balancing act with tradeoffs that can be staggering varying in outcomes and economic value. this study considers a timely and relevant case, food-and-mouth-disease (fmd), in one such facility, the national bio and agro defense facility (nbaf). we couple outcome from plume and epidemiological models with an economic model to calculate the potential economic consequences of several critical types of accidental releases from a research facility. the approaches used here are likely to have application for other diseases and research facilities, and in providing a monetary estimate of the risks posed by such facilities that can be compared against the benefits of better preparedness. in , manhattan, kansas was selected as the site for the new national bio and agro defense facility. it is intended to replace the current research facility at plum island animal disease the united states were zoonotic, a disease that is transmissible between animals and humans, with % originating from wildlife [ ] . trends suggest that the frequency of emerging infectious diseases will continue to increase, especially with the growing interface between humans, animals, and wildlife [ ] . potential transmission and spread of foreign animal diseases (fad) and zoonotic diseases are driven by some of the same forces that propel the global economy. globalization has increased both international trade and human mobility. as the world human population and standard of living continues to grow, there is, and will be a continued increase in demand for protein from livestock. the united nations world tourism organization [ ] forecasts a to % increase over s record one billion international tourist arrivals worldwide in . the economic losses associated with emerging, highly contagious fads and zoonotic diseases can be significant. according to the world bank [ ] , the direct costs (e.g., costs to public and animal health services and producer compensation for culled animals) and indirect costs (e.g., trade and tourism) of outbreaks during the s surpassed $ billion and $ billion, respectively. hosono et al. [ ] estimated that the - nipah virus outbreak in malaysia resulted in $ million in losses from culled animals and $ million in indirect effects. the severe acute respiratory syndrome (sars) outbreak in east asia and canada resulted in estimated losses of $ to $ billion [ ] . in the fmd outbreak in the uk that lasted more than days in duration, over six million animals were culled with estimated losses of $ billion to $ billion [ ] . animal agriculture is important to the u.s. economy as it is a primary source of food and nutrition, a major contributor to exports, and it is valued at $ billion [ ] . with such a vital industry, the united states needs to position itself to defend against the threat of fads and zoonotic diseases. to do so, a modern biocontainment laboratory that is capable of conducting research and developing vaccines against such diseases is required, yet the united states does not currently have one. in , in the homeland security presidential directive (hspd- ): defense of united states agriculture and food, the administration showed the need for such a facility: "the secretaries of agriculture and homeland security will develop a plan to provide safe, secure, and state-of-the-art agriculture biocontainment laboratories that research and develop diagnostic capabilities for foreign animal and zoonotic diseases" [ ] . there are foot-and-mouth disease virus incidents known or believed to have been released over the past years from biocontainment research laboratories worldwide, including czechoslovakia, demark, germany, spain, russia, united kingdom, and united states [ ] . because of potential release and subsequent consequences of a contagious infectious disease, proper analyses and reviews must be conducted before constructing a new state-of-the-art biocontainment research facility. homeland security [ ] has noted that piadc is at "the end of its lifecycle and is too small to meet the nation's research needs". it is the intent that nbaf will: ( ) replace and enhance the current research at piadc; ( ) enhance research capabilities diagnosing foreign animal, emerging and zoonotic diseases in large animal livestock; ( ) develop new vaccines and other countermeasures for large animal livestock; ( ) train veterinarians and animal agricultural specialists in preparing for and responding to animal diseases; and ( ) give the united states its only bsl- research capacity of high-consequence diseases affecting large animal livestock. because of two government accountability office [ , ] reports, the fy dhs appropriation act (p.l. - ) would not allow funds to be made available for construction of nbaf until it completed a site specific risk assessment to be reviewed by the national academies of sciences [ ] . following the appropriations act of , dhs commissioned the site-specific biosafety and biosecurity mitigation risk assessment in , including a review by the national academy of sciences (nas). in the nas review, they noted several shortcomings in the site specific risk assessment (ssra), including an inadequate qualitative risk assessment, underestimation of the risk of a pathogen release and transmissions, and methodological flaws of the plume and epidemiological modeling [ ] . to address these shortcomings, dhs conducted an updated site-specific biosafety and biosecurity mitigation risk assessment in [ ] , which was also reviewed by the national academy of sciences [ ] . the information from initial risk assessment completed in was used in altering the design of nbaf and changing the standard operating procedures, personnel training, and emergency response planning. for example, the initial design of nbaf would withstand wind speeds of miles per hour [ ] . following the updated risk assessment, the design of nbaf was modified to conform to nuclear regulatory standards and withstand with up to miles per hour [ ] . to assess the economic impacts of unintentional fmdv releases from nbaf, we follow [ , , [ ] [ ] to link supply shocks from an animal disease spread model with a multi-commodity, multi-market partial equilibrium model. this is supplemented with a regional input-output economic model to capture impacts on allied and associated businesses [ , ] . additional economic shocks include domestic and international markets, which are discussed in detail below. government costs associated with controlling and eradicating and fmd outbreak are calculated as well. the epidemiological disease spread model used in this study is the north american animal disease spread model (naadsm). naadsm is a spatial, stochastic, state-transition simulation model that simulates highly contagious animal diseases [ ] . naadsm has been used in numerous studies to evaluate the impacts of highly contagious animal diseases in various countries including several economic impact studies [ - , , - ] . the naadsm framework requires extensive parameterization including information on animal population (e.g., location, production type, size of herd), disease manifestation (e.g., latently infected), disease transmission (e.g., direct, indirect, and aerosol), disease detection, surveillance, and control (e.g., animal movements, traceability, and vaccination). the parameters can take on an integer value (e.g., number of herds destroyed per day), probability (e.g., probability of infection given exposure to an infected herd), probability density function (e.g., length of time that an infected herd is subclinically infectious) or relational function (e.g., probability of detecting an infectious herd, which is a function of clinical signs being observed and being reported to authorities once clinical signs have been observed). the parameters are developed through literature searches, research, and expert opinions. given the epidemiological output is exogenous input into the economic model, and not the primary focus of this paper, the reader is referred to dhs [ , section . . ] for complete documentation of the parameter values used in this study. naadsm is simulated times for each scenario to generate a distribution of disease spread outcomes. in addition to the uncertainty resulting from the stochastic disease spread model, different starting locations for infection are also incorporated to better reflect uncertainty. unlike previous studies which pick a specific starting location (e.g., cow-calf operation or feedlot operation) to model the consequences of an fmd outbreak, this study includes all possible starting locations (e.g., cow-calf operations, feedlot operations, etc.) for each release scenario. in other words, for each starting location the fmd outbreak is modeled and the consequences are ranked. it is then possible to report the outbreak consequences at the probability levels (e.g., p , p , and p ) for the different starting locations. agricultural firms and consumers. a quarterly multi-market partial equilibrium simulation model is used to assess how unintentional releases of fmdv would impact u.s. agricultural producers and consumers. this study utilizes an updated version of the paarlberg et al. [ ] partial equilibrium model. the partial equilibrium model includes major agricultural sectors along vertical and horizontal market chains beginning with livestock and grain production to meat processing and the final consumer, including both domestic and international. exogenous, production, domestic demand, and international trade, shocks resulting from an fmd outbreak are incorporated into the model as percentage changes from the baseline. the economic model then solves for the percent changes in the endogenous variables (prices and quantities) for each quarter. the percent changes in the endogenous variables are then applied to a baseline defined by the observed data for the first quarter of through the fourth quarter of of no-disease. this results in estimated changes in per capita consumer welfare and changes in quasi-profits and captured by returns to capital and management. parameters for the partial equilibrium model include livestock-feed balance information, revenue and factor shares, and elasticities. the livestock-feed balance information, revenue shares, and factor shares are retained as defined in [ ] . the retail elasticity values for final meat demand for beef, pork, and poultry [ ] , lamb [ ] , and milk [ ] are updated for this study. substitution elasticities for derived demand and trade elasticities remained unchanged. producer expectations regarding expected future returns are modeled as naïve expectations [ ] . livestock supply, use, and price data, as well as forage prices are from the livestock marketing information center [ ] . coarse grains, wheat, rice, and the soybean complex supply, use, and price data are from outlook reports and data prepared by the usda-economic research service [ ] . total quarterly use was generated by feed balance equations from which data on animal numbers are combined with standard feeding practices to produce quarterly amounts of forage and pasture. hay, corn silage, and sorghum silage production is reported by the national agricultural statistics [ ] . uncut grazed pasture is imputed for quarters and . international trade data are derived from lmic [ ] , usda-ers [ ], and foreign agricultural service [ ] . information concerning the crop policy mechanisms are from provisions of the federal agriculture improvement and reform act of [ ] and the farm act [ ] . regional non-agricultural sector. assessing the costs and disruptions to the non-agricultural activities in the epidemiologically impacted region can be very important [ , ] . thompson et al. [ ] estimates that the direct losses of tourism following the uk fmd outbreak were equal to the losses to the agricultural sector, excluding the producer compensation from the government. furthermore, the indirect effects to tourism were more than times larger when compared to the indirect effects to agriculture. the regional impacts in this study are estimated using an input-output model which is a system of equations that describe the flow of income and product throughout an economy. specifically, the bureau of economic analysis's regional input-output modeling system (rimsii) is used because they provide a well-accepted and validated methodology to evaluate these impacts. moreover, the input-output industrial multipliers provide the flexibility to define the states defined by the disease spread model. rimsii integrates the input and output relationships of approximately u.s. industries and regional economic accounts. the final-demand multipliers for output are used to estimate the indirect economic activity generated by a specific economic activity in a region. thus, the intent of using the rimsii data is to measure the effects of an fmd outbreak on the non-agricultural regional economy. calculations are structured to remove duplication or double counting of losses. the indirect effects evaluated include: ( ) the effect of culling and destroying animals on the non-agricultural regional economy (e.g., retail trade); ( ) the economic implication of a travel ban that would limit recreational and non-essential travel in and out of a region; and ( ) the indirect effects from the stimulus to the region created by the expenditures during government eradication and clean-up efforts. travel bans, resulting in reduced tourism, are another important source of potential economic losses for the impacted region [ ] . travel bans composed of transit and ground transportation; spectator sports; hotels and motels; and food and drink services are evaluated. the economic impact from the loss in travel expenditures can be measured using rimsii [ ] . total domestic travel expenditures for overnight trips and day trips of over miles in were obtained from the u.s. statistical abstract produced by the u.s. census bureau by state. however, the rimsii data separates the economic effects of various forms of travel (table ) . thus, using data on the percentage allocations of travel expenditures from the bureau of labor statistics, expenditures are allocated by category for each state in the study region [ ] . while not insignificant, travel and tourism is not a dominant sector in the region. kansas, nebraska, and oklahoma each constitute less than % of the u.s. domestic travel visits and expenditures ( . % combined). travel and tourism are more important in texas, colorado and missouri which contribute . %, . % and . % of domestic travel visits and expenditures, respectively. travel expenditures, by state, for trips of over miles were obtained from the u. s. census bureau. additionally, the u.s. bureau of labor statistics reports the percentage of allocations of travel expenditures. thus, using data on the percentage allocations of travel expenditures, expenditures were allocated by category (e.g., air transportation) for each state in the study region [ ] ). it appears likely that in major outbreaks travel restrictions to non-agricultural events will be lifted after two quarters so a maximum reduction of % of annual travel is realized. for outbreaks of less than two quarters, the travel reduction is computed from the number of days the outbreak lasts as a percentage of a full year's reduction. typical government costs associated with eradicating an fmd outbreak are calculated. these costs include appraisal, cleaning and disinfection, disposal, euthanasia, indemnification, quarantine, surveillance, and vaccination. indemnification payments reflect the value of culled animals at average market prices in the first quarter of prior to an fmdv release. table reports the government costs used in this study which are based on published literature [ ] [ ] and the non-indemnification costs per animal are consistent in magnitude with those reported by abdalla et al. [ ] . an fmd outbreak would result in shocks to production, domestic demand, and international trade [ , , ] . these shocks are expressed as percentage changes for each quarter and incorporated into the economic model. production (supply) shock. output from the disease spread model is used to estimate the production or supply shocks. specifically, the number of animals culled by production type, by quarter is used to calculate the percentage reduction in supply. additionally, two emergency vaccinations scenarios are assumed: vaccinate-to-kill and vaccinate-to-live. no federal vaccination policy for fmd exists in the u.s. and no definitive precedent was uncovered in previous studies. after discussions with members of a u.s. government review panel, the vaccinationto-live and vaccination-to-kill policies were defined for this study as initial assessment. it is realized that different assumptions concerning a vaccination policy could be made (see [ ] ). for outbreaks < days, the vaccinate-to-kill scenario is assumed where all vaccinated animals are assumed to be culled. for outbreaks > days, it is assumed that culling of the vaccinated cattle will occur until the th day of the outbreak and then afterwards, any vaccinated cattle in the queue to be culled or newly vaccinated cattle will not be culled and remain in the cattle inventory. depending on the scenario (vaccinate-to-kill or vaccinate-to-live), the number of animals culled and/or animals vaccinated listed in table and table are used in calculating the production shock, respectively. domestic demand shock. there are anticipated decreases in consumer demand, even though fmd does not pose a human health concern. as such, reduction in u.s. consumer demand is incorporated to allow variations in the level of consumer perception of food quality [ ] . these domestic demand shocks represent the share of the u.s. population decreasing consumption of a final good and provide a policy instrument by which to manage impacts on final demand. because there have been no fmd events on the u.s. mainland since , it is [ ] . given the above information, domestic demand shocks are specified for fmd across the scenarios. based on the epidemiological output (see table ) smaller (larger) outbreaks coincided with outbreaks that lasted shorter (longer) than one quarter. consequently, following an fmd outbreak lasting less than one quarter, it was assumed that % of people would refrain from consuming beef, pork, and lamb while . % would stop consuming milk and dairy products during the outbreak. this is consistent with consumer reactions to food safety events reported in [ , ] . in the second quarter, domestic consumer demand for beef, pork and lamb declined by . % and was fully recovered (i.e., % decline) for dairy and milk products. it is assumed that consumer demand for meat products would be fully recovered by the third quarter. in outbreaks lasting more one quarter, it was assumed that % of domestic consumers would refrain from consuming beef, pork and lamb while % would stop consuming milk and dairy products during the outbreak. following the end of the outbreak, it was assumed that domestic consumer demand would decrease by % for one quarter and . % for another quarter for beef, pork, and lamb. consumer demand for dairy and milk products would decline by . % for one quarter following the outbreak. international trade shock. the magnitude and duration of trade shocks assumed in this study are based on observations from previous events in throughout the world, including the united states. in and , due to isolated incidences of bse, the u.s. and canada faced complete bans on beef in major overseas markets while beef and cattle imports and exports continued among the north america free trade agreement countries (canada, mexico, and the united states) under a variety of restrictions [ ] . the united states has experienced a long recovery relative to pre-outbreak trade status as a result the isolated bse events. u.s. beef exports, as a percentage of beef production was . % in , dropped dramatically to . % in , and recovered to . % in [ ] . a review of previous literature is useful in identifying plausible time lengths defining trade bans for our fmd scenarios. the eu imposed a one year ban on the uk following its fmd outbreak. rich and winter-nelson [ ] analyzed the - fmd outbreaks in the southern cone of south america and concluded short lived impacts on exports to argentina, brazil, and uruguay. randolph, morrison, and poulton [ ] assumed a month ban on exports during fmd outbreaks in zimbabwe. nogueira et al. [ ] and tozer et al. [ ] apply to year trade bans for hypothetical fmd outbreaks in mexico and australia, respectively. although the actual length of export restrictions will depend upon the actual product, disease, trade agreements, and countries involved, these observations provide valuable information on trade bans. given the information above, trade shocks are created in the following manner. first, % of all u.s. exports of beef, pork, lamb meat, cattle, swine, and sheep are halted during the full quarter of the outbreak and for one quarter after the last case appears. this assumes some processed/cooked beef is still exported after the outbreak. the interruption of exports for one quarter beyond the end of the outbreak (and for two quarters beyond the end of the outbreak when emergency vaccination without slaughter is practiced) is consistent with world organization for animal health (oie) guidelines and practices (chapter . ) during fmd outbreaks [ ] . second, after the additional quarter ended with no fmd reported, it is assumed that gradual recovery of u.s. exports will occur until it reaches the baseline levels. full recovery is assumed to occur in approximately two years following one full quarter after the outbreak is eradicated. for fmd, the duration of the outbreak becomes a critical element in determining the economic effects from trade disruptions. the region of focus for this study includes seven states: colorado, iowa, kansas, missouri, nebraska, oklahoma and texas. in this region agriculture is economically important, especially for livestock. in , cattle and calves are the most valuable agricultural commodity in four states in the study [ ] . all seven states are in the top cattle and calves inventory with . million head ( . % of total u.s. inventory) located in those seven states. texas, nebraska, kansas, iowa, and colorado are the five largest states with cattle on feed; almost million head on january , [ ] . furthermore, hogs are recognized as one of the top five commodities those states. total hog and pig inventory on december , for the region was . million head ( . % of total u.s. inventory). . percent of total u.s. sheep and lamb inventory ( . million head) occurred in those seven states on january , [ ] . additionally, a significant percentage of state farm receipts in this region are derived from dairy. a unique feature of this study when compared with previous work is the size of the livestock population and number of herds. most hypothetical fmd studies in the united states focus on a small region at the state or county level [ , , , , [ ] [ ] . with nearly . million head and . million herds, this study contains one of the largest, if not the largest, number of susceptible animals/herds of any fmd economic modeling study ( table ). the exact farm locations are not available in the united states. location data typically exists for medium and large sized operations. smaller operations were accounted for by incorporating locations from a dataset developed by lawrence livermore national laboratory (llnl) using the nass agricultural census data from [ ] .the production types used in naadsm are adjusted to allow for use in the partial equilibrium economic model. the production types required by the partial equilibrium economic model are beef cattle, dairy, slaughter cattle, swine and sheep. as such, the production types used in naadsm (listed in table ) are adjusted as follows: cow-calf + beef (backyard) = beef cattle; dairy = dairy; feedlot (small) + feedlot (large) = beef slaughter; swine = swine (small) + swine (large) + swine (backyard); goats + sheep + small ruminants (backyard) = sheep. as with any contagious disease research laboratory, there are multiple mechanisms and pathways in which a pathogen might be released from a containment laboratory. such pathways include: liquid (e.g., through a drain), solid waste (e.g., carcass disposal system), fomite and vectors (e.g., clothing, mosquito), and aerosol (e.g., air filtration system). although protocols to reduce the risk of infectious material leaving the laboratory exist, it is impossible to eliminate all of the risk associated when dealing with highly contagious pathogen research. thus, four plausible unintentional introduction events of the fmdv are evaluated. these events with examples of actual releases include: in august , an fmd outbreak occurred near pribright, uk. according to defra [ ] , it has been suggested that the probable cause of the outbreak was due to leaking drainage pipes at the institute for animal health, a zoonotic disease research laboratory. in september , an air leak in a gasket around a research laboratory door was the cause of in an internal release of fmdv at piadc [ ] . this scenario represents the virus accidentally released through an aerosol. in august , several steers at piadc were found to contain a different strain of fmdv than the vaccine research being conducted. although the actual cause of this outbreak was never determined, it is likely a laboratory worker carried and transmitted the virus to steers [ ] . although no know natural disaster has resulted in a release of fmdv, it is plausible that such an event could occur as tornados, on average, are reported with nautical miles of nbaf each year [ ] . on june , , an enhanced fujita tornado touched down in manhattan, kansas, including on the campus of kansas state university, which is where nbaf will be located. each of the four release scenarios have differing: ( ) probabilities of an event occurring, ( ) amount of fmdv released, and ( ) the means by which the virus is transported in the environment. thus, this information is used to calculate the probability that any given premises becomes infected with fmdv. further details about the different release mechanisms can be found in [ ] pages - and - . additionally, the first three events represent unannounced events while the latter scenario represents an announced event. it is important to distinguish between these two types of unintentional releases as an unannounced release could continue to spread the fmdv until the disease is identified and confirmed by officials. in the event of an announced released, control and mitigation plans (e.g., animal movement bans, increased surveillance, etc.) could be immediately implemented, potentially reducing the impacts. the results from the disease spread model are summarized in tables and . results are reported for the distribution of outcomes at th , th , and th percentiles of outbreaks based on animals culled. this provides a range of consequences that may arise from an fmd outbreak. to better reflect uncertainty inherent in the potential different outbreak starting locations (i.e., cow-calf operation, feedlot, etc.), additional consequences are reported for the th , th , and th percentiles based on location of the index case. for example, p /p implies the th percentile of epidemiological output based on culled animals and the th percentile of epidemiological output based on starting location. in all release events, there were several assumptions regarding vaccinations including: ( ) an emergency vaccination program was implemented after the first animal was infected; ( ) the fmd vaccination supply was not a limiting constraint; ( ) a km vaccination ring was employed; ( ) all animals that were vaccinated were culled unless the outbreak lasted longer than quarters, at which the culling of vaccinated animals ceased at the end of the nd quarter. those animals that were vaccinated and not culled remained in the inventory. in the aerosol, liquid waste, and transference release events, there are scenarios in which the outbreak lasted less than quarters (i.e., vaccinate-to-kill policy); of those scenarios were less than days in duration (table ) . additionally, the number of animals culled in those scenarios generally was less than . million head. the remaining scenarios were a vaccinate-tolive policy and ranged in duration from to days. the number of animals culled ranged between . and . million head for the longer duration scenarios. the tornado release event results have one noticeable difference: the upper bound of animals culled and duration of outbreaks was smaller when compared to the other three release events, but the lower bound was much higher. in other words, the th percentile of epidemiological output resulted in . million head culled with a duration of days, which is much larger than the other three release events ( table ). the number of animals culled and length of the outbreak for the th percentile of epidemiological output scenario was . million head and days. although the duration of days was the same as other three release event scenarios, the number of animals culled was much smaller in the th percentile scenario. the impacts at the th percentile were larger due to the initial spread of the virus by the tornado. because this release event is in effect a self-announcement, mitigation and control plans are put into place immediately and a higher probability of observing and reporting the disease by a producer, which can be seen at the th percentile of epidemiological output based on culled animals. the numbers of livestock vaccinated follow a similar pattern as duration and number of animals culled. the p /p and p /p scenarios result in the smallest and largest number of vaccinations administered, respectively ( table ). the fewest vaccines administered are in the liquid waste release event for p /p while the p /p scenario for the transference release scenario results in over million vaccinations. to determine the total economic impact for a scenario, the changes in producer returns to capital and management and consumer welfare, government indemnification and non-indemnification expenditures, and the costs to the non-agricultural regional sector were summed together. liquid waste release. losses for the liquid waste release scenario range from $ to $ , million in damage ( table ). the th percentile epidemiological output and th and th location quartiles resulted in no detection and spread of fmd (table ) . thus, no economic damages were incurred. in the p /p scenario ( th percentile in epidemiological output and th percentile for starting location), changes in producer returns to capital and management were a decline of $ , million while changes in consumer welfare increased by $ , million. the positive effect on consumers was a result of a small production shock, small table . agricultural and regional non-agricultural impacts and government costs of hypothetical fmd outbreak (millions $). producer returns to capital and management indemnification non-indemnification regional non-agriculture impacts liquid waste adverse reactions from consumers, and trade sanctions. in other words, it is possible for consumers of meat and dairy products to benefit from an fmd outbreak, if it is small in nature and consumer reactions are limited because of trade sanctions on agricultural exports leads to oversupply and reduce u.s. meat and dairy prices [ , , [ ] [ ] . producer and consumer impacts for p /p are similar in size to p /p while the remaining distribution of epidemiological and starting location impacts range from declines of $ , to $ , million and declines of $ , to $ , million for producers and consumers, respectively. in all release event scenarios, the negative impacts to consumers are smaller than that of the producers. the regional non-agricultural effects were negative and range from $ to losses of $ , billion (table ). although government indemnification payments replace the value of lost livestock, it is not enough to offset the full economic impact on the region. the government costs associated in eradicating an fmd outbreak range from $ to $ , million with to percent of that due to indemnity payments (table ) . table summarizes the distributional cumulative economic impact across the entire study period for the liquid waste release (beginning in and ending in ). however, consequences of disease outbreaks are inherently dynamic in nature with benefits and costs accruing differently to producers and consumers across time, and this interplay has important policy implications [ ] . fig illustrates the changes in producer returns to capital and management by agricultural sector across time for the p /p liquid waste scenario. after an outbreak is announced there is an immediate negative effect on the swine and beef cattle sectors of about $ , million. this is due to the loss of livestock, meat, and dairy export markets, reduced demand for red meat and dairy products by domestic consumers, and culled animals. when the outbreak is officially declared over (the th quarter), the beef cattle sector's producers returns to capital and management has rebounded to the pre-outbreak levels while the swine sector's recovery to pre-disease outbreak levels occurs approximately four quarters later (the th quarter). this result is mostly due to the amount of exports lost by both sectors; approximately % and % of u.s. beef and swine production in was exported, respectively. after the th quarter, beef producers experience positive returns, and do so for the next quarters, primarily a result of lower grain and forage prices, consumer demand fully recovering, and the gradual recovery of export markets. swine producers also have positive gains, but not as large of gains as the beef cattle producers. losses to the meat processing sector's returns to capital and management decline from the onset of the outbreak until the peak in the th quarter, where the loss in that quarter is approximately $ , billion (fig ) . these losses are a result of lower beef prices due to the oversupply of beef (i.e., loss of the export markets). similar to the meat processing, producer returns to management and capital in the crops sector decline. however, the losses in the crops sector are more severe and continue to decline until the th quarter. these losses (which include grains, forage, and pasture) are a result of less demand from fewer cattle and swine. additionally, the grains prices were far above u.s. government support levels, thus, price support payments had little, if any, effect. both the meat processing and crops sectors producer returns do not fully recover to pre-disease levels by the th quarter. although producer returns to capital and management for the remaining sectors (eggs and layers, dairy cattle and milk, lambs and sheep, and soybean processing) are positive or negative, they are very small. table reports aggregate changes in producer returns to capital and management across the quarters by sector. this perhaps gives the best overview of the impacts to the agriculture industry in this hypothetical fmd outbreak. additional liquid waste scenarios reported in dhs [ ] remain qualitatively similar, but do vary according to the degree of the outbreak. aerosol release. in the event of an accidental release of the fmdv through an aerosol, the total economic impacts range from losses of $ , million to $ , million ( table ). the range of losses to the agricultural producers was $ , million for the p /p scenario to $ , million for the p /p scenario. the small localized fmd outbreaks that lasted less than a quarter in duration, p /p , p /p , and p /p scenarios, resulted in gains to consumers of about $ , million. the p /p scenario resulted in a decline in consumer welfare of $ , million while the remaining scenarios saw much larger declines in consumer welfare ranging from $ , to $ , million because of the duration of the outbreak and number of animals culled and vaccinated. the government indemnification costs range from $ million for the p /p scenario to $ , million for the p /p scenario. the non-indemnification costs are smaller with a range of $ million to $ , million. finally, the impacts to the regional non-agricultural sectors are declines of $ million to $ , million across the scenarios. the distribution of losses by production type across time is qualitatively similar to the liquid waste scenario described above. transference release. because the duration of the fmd outbreaks and number of animals culled and vaccinated are similar to the aerosol scenarios, the total economic impacts of the transference release scenarios are similar to impacts of an aerosol release, including the distribution of impacts by production types across time. losses to producers range from $ , million to $ , million while changes in consumer welfare are a positive $ , million to a negative $ , . government indemnification and non-indemnification costs range from $ million and $ million to $ , million and $ , million, respectively. regional nonagricultural impacts range from $ million to $ , million in the losses resulting from hypothetical fmd outbreaks. tornado release. tornado events are unlike the previous releases because of immediate, widespread dispersion and the events are effectively self-announced. the economic impacts were estimated in the event the fmdv is released because a tornado comprises the containment laboratories at nbaf. with a tornado release event, the duration of an outbreak under the p / p scenario is days compared to , , and days in the liquid waste, aerosol, and transference scenarios, respectively. additionally, the number of animals culled in the p /p scenario is significantly higher when compared to the other three release scenarios (approximately . million more animals are culled). thus, the lower end of the range of total economic impacts for this scenario is much larger because more animals are culled and the duration is longer at the lower end of the distribution (p /p ). although the impacts are larger at the lower end of the distribution, the impacts at the upper end of the distribution (p /p ) are smaller because fewer animals are culled. the total economic impacts range from losses of $ , million to $ , million. similar to the aerosol and transference release events, producers lose along the entire distribution of outcomes. however, consumers do not gain in any at any point along the distribution. when compared to the other three release events, the range of government costs is smaller. however, the p /p scenario has much larger government costs while the p /p costs are smaller for both indemnification and non-indemnification. the lower and upper ends of the distribution for regional non-agricultural impacts are losses of $ million and $ , million, respectively. united states animal agriculture is becoming a highly integrated and global system that is very important both domestically and internationally. this complex system combined with the increasing frequency of emerging infectious disease threatens the stability of the u.s. economy, food security, and livestock and public health. this economic analysis is part of a congressionally mandated site specific risk assessment, which links outcomes from plume and epidemiological models to risk outcomes. this study examines the economic consequences of foot-and-mouth disease virus (fmdv) releases from a national disease research facility. specifically, we investigate the economic impacts to consumers and firms, costs to the government, and disruptions to non-agricultural regional sectors. outcomes of the site-specific risk assessment have been and are currently being implemented in the form of feedback into the planning and construction process of the national bio-and agro defense facility (nbaf), along with improvements in scientific and economic modeling. given the projected investment costs of over $ billion and the risks related to potential foreign animal and zoonotic disease releases, feedback into the planning and construction of the facility is critical to enhance future food security. unlike previous studies that focused on various alternate mitigation strategies, this study focuses on potential animal disease releases from nbaf. the release events modeled include aerosol, liquid waste, and transference (unannounced release events) and a tornado (announced release event). indeed, differences in the distribution of economic consequences arise between the unannounced and announced events. mitigation controls used includes stamping out, vaccinate-to-live and vaccinate-to-kill. although this is not a definitive study of fmd vaccination, the economic consequences from the selected scenarios are informative to government planners and policy makers. schroeder et al. [ ] find that emergency vaccination can be a cost effective mitigation tool that can help reduce the spread of disease. they conclude that a high-capacity emergency vaccination program together with large vaccination zones results in significant savings to consumers, producers, and the government. total losses for the reported fmdv release events range from about $ billion to $ billion in damages. producer effects are always negative due to lost output and reduced prices and share the largest burden in losses. consumers realize negative or positive effects primarily contingent upon the size of the outbreak, export losses, and assumed demand shocks. regional non-agricultural losses and government indemnification (non-indemnification) costs are much smaller than the producer and consumer impacts, ranging from $ million to over $ , million and from $ million to nearly $ , million ($ million to over $ , million) across the scenarios, respectively. these economic impacts across the four release events are similar, except for the tornado release event. because the tornado release event is effectively an announced event and the virus dispersion is greater, lower bound economic losses are much larger than the unannounced releases while the upper bound of the economic consequences is much smaller. several additional key insights are identified. first, it is important to integrate time into the economic analysis, as livestock are durable goods. costs and benefits evolve over time in response to producer decisions, consumer reactions, and international trade responses by trading partners. second, disaggregation among production types is vital to link epidemiological to economic models. furthermore, this allows for additional analysis on how the different production sectors are impacted. third, size of the outbreak and duration of trade sanctions are important. fourth, the timing of identifying an fmdv release (announced vs. unannounced) is important and has differing economic consequences. similar to all hypothetical foreign animal disease studies that report economic consequences, they are conditional in nature. not only are they conditional on the available information and modeling assumptions, but they are conditional on an outbreak occurring. while it is plausible that fmdv releases may arise from nbaf, estimated probabilities of the sequence of events leading to an outbreak are not large [ ] . nevertheless, as actual events and empirical evidence demonstrate, fmd events are low probability high cost events that deserve continued vigilance and research to mitigate the consequences. this study is not without limitations. total costs could be overestimated if, for example, the impact of tourism is diverted to different areas or the purchase delayed/deferred. however, the estimated costs provide plausible estimates using standard economic techniques. the modeling approach assumes homogenous commodities and goods, including beef. fmd outbreaks are treated as shocks to economic system and are not endogenous to the model. trade is not differentiated among trading partners, but rather differentiated by domestic and international markets. capacity constraints need to be investigated for processing infected animals, as well as capital constraints. nevertheless, the modeling framework provides the appropriate fidelity to assess economic consequences. this study does raise questions for future research. first, additional research needs to be completed on vaccination strategies and capacity constraints. second, trade sanctions and trade agreements need to be studied further. third, government costs and the structure of government costs should be examined to better understand the nature of public expenditures. fourth, potential benefits resulting from research, diagnostic tests, and training of personnel would have positive impacts. the extent of those benefits needs to be investigated. fifth, sensitivity analysis on the economic 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mad-cow disease food and rural affairs (uk defra). family food-data sets disease-related trade restrictions shaped animal product markets in and stamp imprints on evaluating equity impacts of animal disease control: the case of foot and mouth disease in zimbabwe foot-and-mouth disease and the mexican cattle industry domestic and trade impacts of foot and mouth disease and bse on the australian beef industry terrestrial animal health code usda-national agricultural statistics service (nass). various livestock and animals reports. washington, d.c epidemic and economic impacts of delayed detection of foot-and-mouth disease: a case study of a simulated outbreak in california emergency vaccination to control foot-and-mouth disease: implications of its inclusion as a u.s. policy option developing livestock facility type information from usda agricultural census data for use in epidemiological and economic models foot and mouth disease : a review and lessons learned pendell initiated this research while he was at colorado state university. the authors would like to thank philip paarlberg and national academies committee members for helpful comments. key: cord- -a wl f authors: lawler, j. j.; spencer, b.; olden, j. d.; kim, s.-h.; lowe, c.; bolton, s.; beamon, b. m.; thompson, l.; voss, j. g. title: . mitigation and adaptation strategies to reduce climate vulnerabilities and maintain ecosystem services date: - - journal: climate vulnerability doi: . /b - - - - . - sha: doc_id: cord_uid: a wl f abstract increasing temperatures and altered precipitation regimes associated with human-caused changes in the earth s climate are having substantial impacts on ecological systems and human well-being. maintaining functioning ecosystems, the provision of ecosystem services, and healthy human populations into the future will require integrating adaptation and mitigation strategies. adaptation strategies are actions that help human and natural systems accommodate changes. mitigation strategies are actions that reduce anthropogenic influences on climate. here, we provide an overview of what will likely be some of the most effective and most important mitigation and adaptation strategies for addressing climate change. in addition to describing the ways in which these strategies can address impacts to natural and human systems, we discuss the social considerations that we believe must be incorporated into the development and application of mitigation or adaptation strategies to address political situations, cultural differences, and economic limitations. adaptation adjustment in natural or human systems in response to actual or expected climatic stimuli or their effects, which moderates harm or exploits beneficial opportunities. various types of adaptation can be distinguished, including anticipatory and reactive adaptation, private and public adaptation, and autonomous and planned adaptation (ipcc ) . climate change a significant and lasting change in the statistical distribution of weather patterns over periods ranging from decades to millions of years. we focus largely on changes in temperature and precipitation, as they are changing in many regions and have direct impacts on ecosystems and human well-being. mitigation actions that reduce the effects of humans on the climate. resilience amount of change a system can undergo without changing state (ipcc ) . sensitivity it is the degree to which a system is affected, either adversely or beneficially, by climate-related stimuli. the effect may be direct (e.g., a change in crop yield in response to a change in the mean, range, or variability of temperature) or indirect (e.g., damages caused by an increase in the frequency of coastal flooding due to sealevel rise) (ipcc ) . vulnerability the degree to which a system is susceptible to, or unable to cope with, adverse effects of climate change, including climate variability and extremes. vulnerability is a function of the character, magnitude, and rate of climate variation to which a system is exposed, its sensitivity, and its adaptive capacity (ipcc ) . virtually all regions of the earth are experiencing rapid changes in temperature, precipitation, and/or other aspects of climate. human-caused changes in the earth's climate are greatly altering ecological systems, with consequences for human well-being. for example, recent studies have documented shifts in the distribution of plants and animals, advances in the timing of key ecological processes, and extinctions of wildlife populations and species that are likely linked to recent increases in temperature (parmesan ) . such changes are creating regional combinations of environmental conditions that, within the next - years, may have no current-day analog. the resulting changes in ecosystem function will undoubtedly affect the provision of ecosystem services for human communities. maintaining or increasing ecosystem services into the future will require integrating adaptation strategies (actions that help human and natural systems accommodate changes) and mitigation strategies (actions that reduce anthropogenic influences on climate) ( figure ). mitigation strategies are those that reduce the magnitude of climate change that will occur. the vast majority of these strategies involve either reducing greenhouse gas (ghg) emissions or sequestering carbon, although they can address any human climate forcing. by contrast, adaptation can be defined as alterations to human or natural systems that are designed to reduce the negative impacts ofor exploit the opportunities created byclimate change (ipcc a) . adaptation strategies are much more varied than mitigation strategies, as they are more often specific to particular systems or locations. mitigation and adaptation strategies designed to address changes in climate may have additional positive or negative effects on ecosystem functioning, ecosystem services, and human well-being. for example, replacing fossil fuels with renewable energy sources reduces ghg emissions while simultaneously reducing air pollution, acid rain, and smog, as well as asthma and respiratory ailments of humans. conversely, coastal armoring, the building of seawalls, breakwaters, and jetties, may reduce damage to built structures from the combined effects of sea-level rise and storm surges but such actions can negatively affect coastal ecosystems. in this chapter, we provide an overview of what will likely be some of the most effective and most important mitigation and adaptation strategies for addressing changes to the climate system stemming from increased ghg emissions. we attempt to cover the entire spectrum of life, from plants and animals to humans, as well as the geophysical properties of our planet that support these organisms. in relation to human populations, we focus primarily on human health as an index of well-being. we also introduce concepts of climate justice. many of our examples are taken from the united states, although we also include other regions of the world in our analysis as appropriate. we discuss various ways in which mitigation and adaptation strategies can help reduce the magnitude and the impacts of the changes we are likely to experience, as well as improve human health and directly or indirectly affect ecosystem functions and services. finally, although our analysis sets priorities and orders of importance for an ideal world unimpeded by political considerations, cultural differences, or economic limitations, we include a discussion of the social considerations that we believe must be incorporated into the development and application of mitigation or adaptation strategies. in the following sections, we briefly discuss what will likely be some of the most effective mitigation strategies for addressing climate change, largely focusing on strategies to reduce co and other ghg emissions ( table ) . we have grouped these strategies into five categories: transportation, shelter, food, energy, and carbon storage and bioengineering. although we focus on mitigation strategies that will reduce the magnitude of future climatic changes, we also discuss how these strategies can improve ecosystem functioning and, in some cases, human health. transportation, the movement of people and goods, significantly impacts climate through the emission of ghgs. in , transportation accounted for % of the world's energy-related ghg emissions and road transportation represented % of the total carbon dioxide (co ) emissions from transportation (ipcc b) . in addition to being a major source of emissions, transportation also significantly affects ecosystem functions and services. pollution from vehicles affects ecosystem services such as clean air and water directly, and indirectly through impacts on the plants and animals that regulate ecosystem function. as species are lost from or move into ecosystems the functioning of those systems can change, resulting in altered ecosystem services. human health is likewise affected by pollution from vehicles (e.g., through chronic lung disease). transportation networks and moving vehicles also fragment landscapes, reducing the flows of energy and biota resulting in isolated populations and potentially making these populations vulnerable to extirpation and impairing ecosystem functions. mitigation strategies that address transportation can be placed into three basic categories: those that increase the efficiency of particular transportation approaches, those that result in a shift in the mode of transportation, and those that reduce the amount of transportation that is needed. here, we briefly table examples of mitigation strategies aimed at reducing ghg emissions or, in the case of the last category, sequestering carbon to reduce co concentrations in the atmosphere mitigation strategies barriers to implementation a large reduction in ghg emissions can be accomplished by increasing the fuel efficiency of vehicles. for example, increasing the efficiency of light-duty vehicles (cars and small trucks) has the potential to reduce their carbon emissions by up to % by (ipcc b) . such efficiencies can be attained by a combination of reducing vehicle weights, increasing aerodynamics, increasing engine efficiency (particularly diesel engine efficiency), and increasing the use of biofuels and electric and hybrid vehicles. in , the international energy association projected that the proportion of transportation energy supplied by biofuels could be increased to % (iea a) . although there is good evidence of successful biofuel markets and programs (e.g., ethanol from sugarcane in brazil, goldemberg ) , there are also negative consequences of increased biofuel production for biodiversity and carbon storage (fargione et al. ; fletcher et al. ) . one opportunity for transportation mitigation strategy is the promotion of behavioral changes of drivers. efficiency of road vehicles could be improved by - % by changes in driving styles, improved maintenance, more efficient tires, reduced idling, and traffic design and maintenance (ipcc b). a second approach to reducing emissions and many of the other effects of transportation involves changing the ways in which people and goods are moved. one such approach is to increase the use of public and human-powered transportation. increasing the amount of walking, biking, and use of public transit will depend largely on the available infrastructure and the capacity to provide it. supporting the development of 'walkable' cities and neighborhoods, bike-friendly roadways and bike paths, carpooling and car-sharing programs, and efficient and safe mass transit are all approaches for shifting the mode of urban transport. present transportation alternatives vary by country, with europe, japan, and many developing countries having the highest levels of public transportation use, and the united states having the greatest use of personal automobiles. in some developing countries, such as vietnam or china, personal automobile use is a recent phenomenon, and personal motorized transport is a high aspiration because it conveys increased social status. this disparity in the historical development of the transportation sector will mean that mitigation strategies, barriers, and solutions will have to be location specific and may be dynamic over time. in addition to the reduction in emissions and the other environmental benefits of shifts to more human-powered transportation, such changes also have clear human health benefits resulting from increased exercise, weight management, and decreases in air pollution (nemet et al. ) . simultaneously improving the quality of public transport and leapfrogging transport-intensive stages of economic growth is needed in many countries to increase higher levels of mass transit use and human-powered transportation (wright and fulton ) . further reductions in emissions can be made by changing modes of transport for other transportation such as moving more freight by train and ship and less by truck. the third way to reduce transportation-related ghg emissions is to reduce the amount of transportation that is needed. decreasing the demand for transportation largely involves changes in human behavior, urban and landscape planning, and changes in technology. sprawling, low-density urban neighborhoods, such as those found in the united states, perpetuate automobile dependency and transform ecologically functional landscapes into subdivisions. compact, highdensity communities with local urban centers allow residents to work and live in close proximity, and help build social capital among residents and protect natural areas. in conjunction with human-centered transportation infrastructure such as sidewalks, bike lanes, and public transportation, compact neighborhoods reduce car dependency while simultaneously improving the physical fitness of residents. public green space and urban forests sequester carbon while improving air quality and mental well-being. increased vegetation, shade trees, and less asphalt combat urban heat-island effects and reduce energy demand for cooling buildings. advances in communication technologies also have the potential to reduce the need for transportation. the internet, online meeting, document sharing, and conference tools have led to an increase in telecommuting and web-based meetings. similarly, online meetings have begun to replace some inperson meetings and have the potential to dramatically reduce air travel, which can account for a significant portion of an individual's carbon footprint (fox et al. ). the most significant barriers to implementing mitigation strategies in the transportation sector are long-established personal transportation behaviors and the lack of government interest or capacity to invest in new technologies. changing the way and the amount that people move around will be very difficult. in the united states and elsewhere, people's relationships with the automobile involve issues of convenience, independence, safety, and social status. changing these relationships will involve making forms of public transportation more convenient, more effective, and more appealing. rising fuel costs and commute times may provide some opportunity for implementing transportation-based mitigation strategies. failing automobile industries and economic crises may provide another. similar to the projects undertaken by the civilian conservation corps in the united states in the depression of the s, modern-day work relief programs could be used to transform transportation systems. short of such crises, major changes in transportation will take a combination of regulatory action, education, and incentive programs. housing is one of the most idiosyncratic and regionally variable aspects of human culture. the design of structures is dependent on local climate, land access, available materials, and regional architectural histories. much of the recent human-caused change in climate stems, in large part, from the way we design, construct, and inhabit the built environment. the following section focuses on a representative selection of design strategies that mitigate the built environment's contribution to carbon emissions and, in many cases, provide cobenefits to human health and local/regional ecological resilience. building material extraction can have profound impacts on ecosystems and ecosystem services. mining degrades natural landscapes, destroys habitat, pollutes freshwater environments, and can expose human populations to toxins. poorly managed lumber extraction leads to deforestation, eliminates suitable habitats, erodes soils, and diminishes the earth's carbon sequestration capacity. mines that observe best management practices such as land reclamation have fewer negative impacts on climate, local ecosystems, and human health. sustainably harvested lumber can act as a long-term carbon sink and contribute to the productive and ecological resilience of forests. rapidly renewable lumber alternatives such as bamboo can offset the demand for slow-growing trees species, rebuild soils, and set the stage for reforestation. however, as with any renewable resource, expanding the production of bamboo in monocultures has the potential to eliminate and/or degrade existing ecosystems. eight percent of annual carbon emissions worldwide can be attributed to building material extraction, production, transportation, and installation (mazria and kerschner ) . choosing building materials with low embodied energy (the cumulative energy of extraction, production, transport, installation, and disposal) and/or that use alternative energy sources reduces the building sector's carbon footprint. locally sourced materials produce fewer carbon emissions than those transported long distances and both durable materials and those with recycled content help reduce demand for virgin materials. fully recyclable materials can be reprocessed and repurposed with low energy inputs indefinitely. removing toxic compounds from material production processes and building products facilitates the recycling or biodegradation of building components. it also helps prevent air and waterborne industrial pollution and associated human illness. in some cases, it may be possible to choose building materials that actually sequester more carbon than is emitted in their production. the production of portland cement, the most commonly used cement in construction, is a relatively large source of co emissions. magnesium oxide-based cement is as strong as normal portland cement, but can be manufactured at low temperatures using renewable energy sources. magnesium oxide is an abundant mineral and is easily recyclable (smith ) . as it cures, it absorbs more co than is released during its production, resulting in a net negative carbon budget. the average lifespan of buildings in the united states is less than years (o'connor ) . design for adaptationdesign that easily accommodates changes in configuration and useextends the life of buildings and stems demand for new construction and virgin materials. when buildings are ultimately decommissioned, design for disassembly facilitates the breakdown and reuse of their constituent components. both design for adaptation and design for disassembly act upstream from recycling as part of a multicyclic system that repositions well-weathered buildings and building materials as resources rather than wastes, reducing carbon emissions in the process. building operations such as heating, cooling, and lighting account for % of electricity consumption in the united states (mazria and kerschner ) . passive design strategies can drastically reduce a building's dependence on carbon-intensive energy production. in cold climates, airtight, well-insulated building envelopes can work in tandem with building orientation, thermal mass, and passive solar radiation to provide thermal comfort and reduce heating bills. in hot climates, external shading, light colored/reflective roofs and walls, and passive ventilation strategies can reduce cooling loads. daylighting strategies such as light shelves and shallow floor plans bring natural light into interior spaces, reducing the demand for electrical lighting while, at the same time, contributing to the well-being and productivity of building occupants. similar to the use of building materials to sequester more carbon than they produce, buildings can generate more energy than they consume. buildings equipped with photovoltaics, wind turbines, and fuel cells are some of the energy producing technologies that make this possible. recent advances in computer-aided design software help designers address building performance issues early in the design process and optimize building design for energy use and production. improvements in digital monitoring and analysis allow occupants to scrutinize building performance and optimize energy use once buildings are operational. in the future, smart buildings and systems will likely respond dynamically to human occupation, weather, daily cycles, and seasonal change, further reducing their energy footprint. compact communities (discussed in the transportation section, above), land-use planning, and high-density zoning have the potential to reduce co emissions, reduce sensible and latent heat fluxes, and improve human health and ecosystem function. centralized infrastructure and zoning laws that segregate industrial, commercial, agricultural, and residential land use can be beneficial to public health within localities. however, these practices also create a cognitive disconnect between human action and its environmental consequences. they facilitate the transfer of local environmental burdens to regional and global scales, contribute to climate change, and undermine the health of vulnerable populations. integrated land use and responsibly managed distributed ecological infrastructure have the potential to safeguard public health without the transference of environmental burdens. synthesizing commercial, industrial, agricultural, and residential precincts, reimagining landscape as infrastructure, and bringing utilities into the public realm raises awareness about the causal relationships that link human activities, environmental degradation, and human health. urban agriculture, for example, reduces dependence on carbonintensive industrial food production, minimizes the carbon footprint of food transport, teaches urbanites how to grow their own food, and provides nutrition to communities. carbon-conscious materials, regenerative buildings, compact communities, and integrated landscapes have the potential to mitigate the worst effects of climate change. their success will depend on the ability to implement them not only in developed countries but also in the burgeoning cites of the global south. we must adapt these strategies to diverse climates, contexts, and cultures and pursue them in tandem with issues of economic development and social equity. in modern history, land distribution and regulation have always been the prerogative of governments. for this reason, national, regional, and local governments have a large role to play in housing mitigation strategies. governments control land-use planning, zoning, and building-code regulations. the ability to act on the mitigation strategies identified above, therefore, is largely dependent upon the regulatory and enforcement environment in a region. in a democratic society, these will in turn be dependent upon the inclination and ability of the state to assume progressive and proactive attitudes toward mitigation. agriculture releases considerable amounts of ghgs into the atmosphere. in , it accounted for - % of the total global anthropogenic ghgs including approximately % of nitrous oxide (n o) and % of methane (ch ) of the anthropogenic totals (rosenzweig and tubiello ; smith et al. ; burney et al. ) . land-use change, nitrogenous fertilizer applications, livestock production, rice farming, and biomass burning are among the major direct sources of ghg emissions. indirect sources of ghgs from agriculture include the production and/or applications of fertilizers and pesticides, the operation of farm machinery, and the transportation of agricultural products (burney et al. ). there are multiple opportunities for mitigating climate change impacts through modifications in agricultural practices and food consumption. with respect to agricultural production, mitigation strategies include soil carbon sequestration and the reduction of ghg emissions through altered production methods. with respect to food consumption, society can mitigate the impacts of climate change through changes in diet and by reducing the amount of transportation needed to deliver food (e.g., increasing local food production). below, we discuss several of these mitigation strategies. the topic of increasing local food production is covered in previous sections on transportation and shelter. unlike housing, food is a sector that is potentially much more amenable to individual decision-making and personal choice. this will depend on the relative proportion of food in a household budget. while americans spend only % of their incomes on average on food, the figure for indonesia is %. this indicates that people from wealthy countries would have greater flexibility to support alternative and nonindustrial agriculture through consumer preferences than those from countries where food is a larger part of household budgets. agricultural and degraded soils can act as large carbon sinks with the potential to sequester - gt of carbon globally (lal ) . soil organic carbon (soc) is the major component ( %) of this large soil carbon pool (lal ) . soc accumulation is facilitated by adding biomass to the soil and minimizing soil disturbances. the increased soc improves the physical, chemical, and biological properties of the soil and in turn enhances crop productivity, water holding capacity, and land sustainability under a low-input cropping system. several agricultural practices facilitate accumulation and retention of soc in cropland soils, e.g., conservation tillage, mulches, cover crops, manuring, crop rotations, and agroforestry (lal ) . the benefits of these agricultural practices go beyond carbon sequestration. they have the potential to reduce erosion, limit positive feedbacks in drought cycles, and benefit human health. over the past years, % of the world arable land has been taken out of production as a result of erosion (pimentel ) . conventional agricultural practices involving frequent tillage result in soil erosion, which in turn increases concentrations of airborne particulates. these particles can carry pathogens causing infectious diseases and can provide positive feedbacks to drought conditions. recent climate modeling has demonstrated a positive feedback in the 'dust bowl' drought of the s in the united states (schubert et al. ; cook et al. ). cook et al. ( ) discovered that a reduction in vegetation cover and the addition of eroded soil dusts to the air resulted in a high temperature anomaly over the northern united states and intensified the drought. as a result of the dust bowl, more than % of the surveyed farms comprising . million acres were seriously eroded, and the economic loss was valued close to us$ million (aaas ) . a combination of warming, drought, and conventional agricultural practices together have the potential to re-create the dust bowl of the s in the great plains of the united states (rosenzweig and hillel ) . the livestock industry is a main contributor to three major climate-related problems associated with global food systems: ghg emissions, reactive nitrogen mobilization, and plant biomass appropriation (pelletier and tyedmers ) . increases in livestock production and meat consumption are also blamed for the evolution of new and virulent emergent diseases. any improvement in the environmental sustainability of livestock production will concurrently have a benefit for human health. pelletier and tyedmers ( ) estimated that globally the livestock sector contributed % of anthropogenic ghg emissions, % of reactive nitrogen mobilization, and consumed % of human-appropriated biomass as of . reduction in ghg emissions in agriculture can be achieved by developing strategies involving improved production efficiency, land-use changes, cropland and rangeland management, and livestock and manure management (rosenzweig and tubiello ; smith et al. ; burney et al. ; pelletier and tyedmers ) . for example, enhancing production efficiency through agricultural intensification has been credited with the avoidance of gt of carbon emission globally since (burney et al. ). this figure highlights that the investment in agricultural research to improve the environmental sustainability of global food production systems (i.e., livestock, crop, and aquatic systems) should be a prioritized mitigation strategy (lobell et al. ; burney et al. ; steinfeld and gerber ) . another mitigation strategy to reduce emissions involves shifting livestock production regimes from ruminants to more efficient and lower impact monogastric species (e.g., poultry), well-managed fisheries and aquaculture, and promoting plant-based protein sources (pelletier and tyedmers ; steinfeld and gerber ) . changing livestock production from ruminants to monogastric animals and reducing livestock production overall both require significant changes in diet in many parts of the world. this is, of course, where tradition and culture play an important role, yet it is not impossible to induce dietary changes. initiatives that reduce the consumption of meat could have dramatic effects on ghg emissions particularly in developed countries (mcmichael et al. ) . such policies would also reduce impacts on ecosystems and promote other ecosystem services such as a reduction in the clearing of amazonian rain forests, reduced nitrogen deposition, and a reduction in the application of high-phosphate fertilizers used to grow feed. reduced meat consumption could also improve human health in developed countries particularly when coupled with incentive structures and educational measures to replace high-fat, sugar-rich foods with more complex diets based on plant proteins. reduced red meat consumption will likely lower the risk of obesity, diabetes, and several types of cancer (and specifically colorectal cancer), and may reduce the risk of ischemic heart disease (mcmichael et al. ) . a shift from meat-based proteins to plant-based proteins has the potential to substantially increase the total food calories available for consumption worldwide. worldwide educational efforts, altered trade policies, shifts in farm subsidies, public health campaigns and new environmental stewardship programs will be needed to achieve a fundamental change in the consumption of meat to achieve large-scale cobenefits for the environment and human health. energy consumption and production affect carbon emissions, which in turn affect human health and ecosystem functioning and services. these effects can be divided into the influence of energy consumption and production. while human well-being is in many ways positively affected by the increased availability of energy, there are also negative health effects resulting from the energy consumption and production. below, we describe potential mitigation strategies for the energy sector. the us energy information administration reports on energy consumption in the united states in four sectors: residential, commercial, transportation, and industrial. in , consumption across the four sectors accounted for , , , and % of overall energy consumption, respectively (us energy information administration ). overall energy consumption, as well as co emissions from energy consumption, continues to rise. total us co emissions from energy consumption were million metric tons of carbon in and million metric tons in (research and innovation technology administration ). reducing ghg emissions through declining energy consumption can be accomplished through a combination of technological advances and changes in human behavior (including the adoption of new or alternative technologies). several mitigation strategies for addressing energy consumption have been provided in the previous sections on transportation and shelter. in addition to those strategies, increasing the efficiency of appliances and lighting is likely to provide significant reductions in ghg emissions. the most efficient appliances in use today use half to one-fifth of their most inefficient counterparts currently in use (ipcc b) . in developed countries, substituting smaller and more efficient refrigerators, washing machines, and other appliances for less efficient ones can substantially reduce energy use. in addition, in developed countries, improvements in the efficiency of electronic devices with inefficient standby modes and power supplies (or more simply unplugging these devices when not in use) can significantly reduce energy consumption. in developing countries where biomass (e.g., wood, dung, and charcoal) is used for cooking fuel, substantial reductions in ghg emissions and improvements in human health may be attained by increasing the efficiency of biomass stoves, fostering a shift to cleaner burning liquid and gaseous fuels, and improving access to electricity (ipcc b). significant reductions in emissions can also be made through the use of more efficient lighting. the emissions from electric lighting worldwide are equivalent to roughly % of those generated by light passenger vehicles (iea b). substituting more efficient lighting technology (e.g., compact fluorescent bulbs and occupancy detectors) can reduce residential energy use by a factor of four or five (ipcc b). programs designed to increase the energy efficiency of appliances, vehicles, and lighting (e.g., the energy star and vehicle fuel economy (cafÉ)) also have the potential to reduce ghg emissions. although such programs have not decreased energy use in the united states, they may be partially responsible for halting the growth of per capita energy consumption (us energy information administration ). methods for reducing the impacts of energy production on atmospheric co concentrations, human health, and the environment focus primarily on improvements in an increased generation of renewable energy. renewable energy sources include those based on waves and tides, biofuels, solar, wind, and hydropower. a shift to renewable energy sources has great potential to reduce ghg emissions, reduce impacts on ecosystems and ecosystem services, and improve human health. nonetheless, the production of renewable energy will have adverse effects on some ecosystems. below, we discuss some of the benefits and potential side effects of some sources of renewable energy. in regions of large tides and tidal currents, such as the united kingdom, tidal energy could supply as much as % of the country's energy supply (blunden and bahaj ) . two types of systems are in use or are proposed, the tidal barrage and tidal turbines. tidal barrages allow water to flow into a bay or estuary during flood tide, then they release the water back during ebb tide. as water is released it flows through turbines generating energy. the impact of barrages on fish may be substantial (aprahamian et al. ) . power can also be extracted in the marine environment by turbines in regions of high wave and current energy. however, the ecological impact of the extraction of energy in highly energetic environments is not clear (shields et al. ) . the effects of such installations include alteration of benthic (ocean bottom) environments through changes in sediment transport and detrimental impacts on intertidal species through altered currents and nutrient flows. biofuels (discussed briefly in section . . . transportation) include corn-and sugarcane-based ethanol, woodbased methanol, biodiesel from soy, rapeseed oil, and switchgrass. biomass is also used in cofiring (combining with coal or other fossil fuels in the burning process) or burned alone as a fuel. crops can be grown explicitly for biofuels, or residues from farming or forestry can be used as biofuels. biofuels can also be converted into gasses and then used to fuel gas engines. nonetheless, many biofuels require significant amounts of land and water to grow them, which brings fuel production into conflict with food production as well as potentially result in a climate effect from the alteration in the surface fluxes of heat and moisture into the atmosphere. in addition, fuel plants may not be as effective as others at absorbing ghgs, and more natural lands converted to agriculture for biofuels will result in increased erosion, decreased water quality, and a loss of wildlife habitat and biodiversity. solar energy can be used to generate electricity, heat water, and heat buildings and can be a highly effective form of renewable energy in some regions. although photovoltaic power generation only accounted for . % of world power production as of , expansion is occurring at roughly % per year, largely in developing countries (ipcc b) . hot water production is the second single largest use of energy in residences in both the united states and china. solar water heating is a cost-effective alternative to other fuel sources in many locations. similarly, passive solar heating of buildings (mentioned in the section . . . shelter) is an effective heating measure in many regions. finally, solar energy can be used to generate power with solar thermal electric plants that focus solar rays to heat a liquid, which is then used to generate electricity. passive solar space heating and hot water production likely have the lowest environmental costs. decentralized photovoltaic use on residences and buildings incurs environmental costs in terms of the production process, but likely have few other negative effects. conversely, photovoltaic fields and solar thermal electric plants can have large footprints, adversely affecting plant and animal habitat. like solar power, wind-generated power is more effective in some areas than others. wind produced . % of global electricity in but has been growing at a rate of approximately % per year since (ipcc b ). there are potential adverse effects on birds, through collision, displacement due to disturbance, barrier effects, and habitat loss, with more research needed in all areas (drewitt and langston ; fox et al. ). in addition, the impact of wind turbines on views is perceived to be a substantial barrier to implementation in some communities (wolsink ) . as of , hydropower accounted for % of global electricity (ipcc b) . together, large hydropower plants and small and micro hydropower systems can supply power to large municipalities and isolated rural communities with relatively few emissions. hydropower is not carbon neutral, however, and some studies have estimated significant emissions from hydropower reservoirs (ipcc b) . in addition, dams and reservoirs fragment river networks, alter natural flows of water and sediments, and change stream temperatures. these effects are discussed in section . . . human-dominated systems. there are several other major renewable energy sources including nuclear, hydrogen, and geothermal. as with the renewable sources described above, there are both benefits and costs to using these other renewable energies. most of the mitigation strategies discussed above are focused on reducing ghg emissions. additional strategies can be used to increase carbon sequestration, removing co from the atmosphere. below, we discuss a few strategies that have been proposed for increasing carbon sequestration and storage as well as much riskier geoengineering proposals. deforestation is one of the largest sources of emission accounting for over gt co per year in (stern ) . although there are many other uses of natural resources that result in carbon emissions, here we focus on mitigation strategies that focus on deforestation. given the slow rate at which trees absorb carbon dioxide, simply planting new trees in place of those removed does not immediately offset the removal of a tree. a more rapid approach to mitigation is to reduce deforestation. unlike the majority of emissions that emanate from industrialized countries, most emissions from deforestation are generated by developing countries. deforestation also itself alters the climate system (pielke et al. ). reduced emissions from deforestation and forest degradation (reddþ) is a program of the united nations that seeks to mitigate climate change by providing incentives to conserve forest cover. given recognized challenges in redd (dickson et al. )including country by country differences in who owns the forest, who should receive the monetary benefits of preserving the forest, and the reliance of various indigenous groups on forests for livelihood and cultural identitythe program was modified to reddþ in to minimize negative consequences and respect the rights of indigenous peoples and members of local communities (kanninen et al. ) . assumed cobenefits include the suite of ecosystem services such as watershed protection; reduction of soil erosion; flood control; provision of fuel, timber, and foods; and cultural and spiritual amenities for local communities. biodiversity is presumably also enhanced by protecting natural systems. it is possible that forest-dependent communities will be able to maintain access to forests through this initiative. potential coharms are increased demand for conversion of other ecosystems if forests are protected, replacement of mixed stands with plantations, and benefits accruing to those not responsible for care and maintenance of the forests. prevention of deforestation mitigates atmospheric co concentrations by preventing the release of stored carbon that occurs when forests are harvested and protecting forest stands that absorb carbon, as well as limits changes in surface energy and water fluxes. as of , south america and africa continue to have the largest net loss of forests and large decreases in carbon storage (fao ) . although tropical forests have been the focus of early redd efforts, recent evidence indicates that a large amount of carbon can be stored in mangrove forests (donato et al. ) , peatlands (dise ) , and boreal forests (carlson et al. ) , making these potential targets for conservation efforts. urban forests have also been largely neglected as a potential carbon sink. escobedo et al. ( ) review the services and disservices of urban forests combined with human health and pollution mitigation as well as carbon sequestration. in some locations, urban forests are on par with other techniques for carbon sequestration and reduction. in addition to capturing carbon in plants, it may be possible to increase carbon storage in the water and in the earth's crust with various methods. these proposed approaches are still on the scientific fringe and considered to be highly unproven and/or potentially quite risky. one such approach is to capture carbon in the oceans through iron fertilization. in regions of the ocean where there are ample nutrients to drive primary production (photosynthesis) but observations show that chlorophyll is relatively low, the lack of iron is thought to limit the productivity. over the last two decades, several experiments have attempted to determine whether the addition of elemental iron into the water could cause an increase in algal production and ultimately, as photosynthesis fixes carbon into organic molecules that then sink, the sequestration of carbon in deep ocean sediments. however, the results of these experiments are mixed (de baar et al. ) , with the export of carbon being difficult to assess and likely quite modest. at the same time, the impacts on local ecosystems and thus ultimately fisheries in potentially highly productive regions of the subpolar oceans are not yet known. other carbon sequestration approaches have also been proposed including pumping air down into the oceans, injecting carbon into the ground, and incorporating biochar into soils. given the magnitude of projected changes in climate and the difficulty in implementing meaningful mitigation measures, some scientists have argued for large-scale efforts to reduce the amount of incoming solar radiation. these approaches are collectively referred to as geoengineering. at present, these approaches are unproven, risky, and, at best, will only address some of the impacts of the human influence on climate. one such geoengineering approach would inject sulfate aerosols into the stratosphere. these aerosols would reflect incoming solar rays and reduce warming. although such an approach might reduce average global temperatures, it would also likely decrease average global precipitation (bala et al. ) as well as alter atmospheric and ocean circulation patterns. for a given change in radiative forcing, solar forcing is more effective at changing the hydrological cycle than forcing from carbon dioxide owing to differences in the surface latent heat (and thus evaporation) response. while the impact of carbon dioxide fertilization could increase net primary production in terrestrial ecosystems (govindasamy et al. ) , ecosystems could continue to be vulnerable due to changes in water resources. in addition, solar radiation management would not address the potentially significant problem of ocean acidification to marine ecosystems. the majority of both natural and human systems will have to adapt to climate change in some form or the other. a broad array of adaptation strategies has been proposed for reducing the impacts of climate change in both more natural systems and human communities (ipcc a; heller and zavaleta ) ( table ) . many of these strategies are either general concepts or strategies that apply to most ecosystems and regions. we begin by describing general concepts and strategies. we then describe some of the strategies that have been proposed for four broad types of ecosystems including freshwater, terrestrial, coastal, and human-dominated systems. for the freshwater, terrestrial, and coastal systems, we focus on strategies that would lessen negative impacts of changing climate on ecosystem functioning and ecosystem services. for the human-dominated systems, we discuss the ways that some of the most often discussed strategies for climate adaptation in these systems will impact (either negatively or positively) ecosystem functioning and the provision of ecosystem services in these and in surrounding areas. developing adaptation strategies to address future shifts in climate will require expanding the temporal and spatial scales of plans, policies, and management (kareiva et al. ; lawler three-year, -year, and even -year plans will fail to address many climate impacts. future planning will need to address both short-term and long-term changes in systems. to address long-term changes, plans and policies will need to look at least years into the future and will be more useful if they look ahead or more years for many ecosystems and ecosystem services. it will often also be necessary to expand the spatial scale at which systems are managed and policies and plans are developed. as species move and ecosystems change, it will be necessary to think well beyond neighborhood, park, refuge, state, or even national boundaries. planning will need to occur at multiple, integrated scales and will need to involve local, regional, and sometimes national participants (kareiva et al. ) . while expanding the temporal and spatial scale of climate adaptation strategies, it will be necessary to keep in view local histories, politics, and economies. scale and locality also play a formative role for issues of 'environmental' or 'climate' justice. environmental justice describes the tendency for poor communities to be more vulnerable to environmental degradation. poor communities tend to bear not only the unequal burden of polluting, destructive, and destabilizing industries but also a disproportionate share of the blame for environmental destruction and responsibility for ameliorating environmental change. for example, polluting industries are often located in poor communities due to cheap land values and the inability of poor communities to politically resist their presence, or a desire to develop jobs at any cost. for instance, swidden agriculturalists in southeast asia have been blamed for forest fires despite satellite data pinning large fires to governmentsponsored oil palm plantations (harwell ) and southeast asian fishers living near toxic riparian runoff from mining have been blamed for polluting local waters by cyanide fishing (lowe ) . the broad spatial scales that are required to address the effects of a changing climate necessitate cooperation and coordination among managers, planners, and policy makers from different jurisdictions, agencies, and management units (kareiva et al. ) . they require agencies with diverse mandates and cultures to work together in ways that they have not done in the past. as an example, the us climate change science program is a federal organization that reaches across federal agencies. the broad scale of climate impacts also requires cooperation across sectors of society and different types of organizations including nongovernmental organizations, local and regional governments, citizen groups, and industry. the us fish and wildlife service's landscape conservation cooperatives are an example of a system designed to bring together diverse groups of scientists, stakeholders, policy makers, and managers to, in part, address climate change. in addition, as emissions from one locale affect the climate in other locales, addressing the global nature of climate change will involve cooperation at an international level (hannah ) . although, as the above examples demonstrate, some regional, national, and international efforts have been put in place to foster collaboration, more such efforts will need to be made to adequately address climate change. in addition to cooperation among scientific and political leaders, local and regional stakeholders need to work together as a unified force for social and environmental change. representatives from the global north need to appreciate perspectives emanating from the global south and vice versa. climate adaptation can be brought into many other environmental and social justice agendas among community advocacy groups and should not remain the purview of the community of knowledge leaders with scientific expertise. there are three fundamental approaches to managing systems in a changing climatepromoting resistance, resilience, and transition. resistance-based adaptation strategies focus on maintaining the current state of a system in the face of climate change or climate-driven changes in the environment. building a seawall to prevent erosion as sea levels rise and storm surges intensify is an example of a resistance-based adaptation strategy. resilience can be defined as the ability of a species or system to return to its current state following a perturbation (e.g., holling ) . resilient systems will be able to maintain ecosystem functions and processes and avoid a transition to a new state as climates change. most of the discussion of climate adaptation to date has focused on managing ecosystems for resistance or resilience. most of the general adaptation strategies discussed below and the more specific strategies discussed for each of the four types of ecosystems are intended to increase resilience. the magnitude and rate of projected climatic changes over the coming century will likely make both resistance-and resilience-based strategies insufficient or ineffective in the long run. managing many systems will require promoting change to a new state. strategies for promoting change in human-dominated systems may include planting new crops, redesigning road networks, and relocating people. strategies for fostering change in more natural systems include assisted colonization of threatened plants and animals (see below) and shifting management efforts from one species to another. the outcomes of these more aggressive and forward-looking strategies will be more uncertain, and their implementation will be more controversial. change is especially hard in social contexts where it is uncomfortable, disadvantageous, expensive, or where the old system is remunerative or beneficial to elites, decision makers, or other small influential groups. adaptive management is a flexible approach to managing a system in which the management actions are treated as largescale experiments (holling ; walters and hilborn ) . it is an iterative process in which the system is monitored following the initial management action and new actions (again treated as experiments) are designed and implemented in response to the results of the initial actions. adaptive management was conceived for managing highly uncertain systems, and thus it has great potential for managing systems in a changing climate (arvai et al. ) . adaptive management approaches designed to address climate change will likely have four basic steps (kareiva et al. ) : ( ) assessing the potential impacts of climate change on the system in question, ( ) designing management actionsin the form of experiments with testable hypotheses or predictionsto address the potential impacts, ( ) monitoring the system for climatic changes and system responses, and ( ) using the results of the monitoring to evaluate the effectiveness of the management actions and redesign them as necessary before repeating the four steps. it is generally accepted that more diverse systems are more resilient to environmental change than less diverse systems. thus, restoring or protecting the biological diversity of a system will likely increase resilience of that system to climate change (glick et al. ). this diversity can be in the form of species diversity, environmental diversity, or genetic diversity (schindler et al. ) . a second, general approach to increasing resilience of species and systems involves reducing the impacts of other factors that reduce the overall resilience of the species or system. for individual species, this might mean reducing harvest, restoring or protecting habitat, eliminating diseases, or reducing human interactions. for ecosystems, this may mean reducing pollutants, restoring vegetation, reducing human use, and controlling invasive species. as climates change, many species need to move to track suitable climatic conditions and changing habitats. in some cases, it may be possible to facilitate movement by increasing connectivity of freshwater and terrestrial landscapes (see sections . . . freshwater systems and . . . terrestrial systems). however, many species with limited dispersal abilities or that face significant barriers to dispersal will be unable to respond to changing climates. assisted colonization is one strategy that has been proposed for facilitating climate-driven range shifts (hunter ; mclachlan et al. ); also referred to as managed relocation and assisted migrationassisted colonization is the translocation of species outside their native range to facilitate movement in response to climate change. the concept is controversial for both ethical and ecological reasons. some researchers have highlighted the potential for negative, ecological, evolutionary, and economic impacts, as well as ethical concerns (ricciardi and simberloff ; sax et al. ). advocates argue that assisted colonization will be essential for cases in which species will have to move to find suitable environments but will be unable to do so, that many of the potential risks are overblown, and that guidance can be developed for the strategic and informed use of assisted colonization. several decision-making frameworks and prioritization strategies for applying assisted colonization have been proposed (hoegh-guldberg et al. ; richardson et al. ). although assisted colonization will likely be a useful strategy in many systems, there will be specific factors and risks that will need to be considered for particular systems (e.g., in freshwater systems, olden et al. ). virtually all freshwater systems are already impacted by human activities (e.g., vörösmarty et al. ) . under current climate projections, virtually all freshwater ecosystems will face significant impacts by the middle of this century. most of these impacts will be detrimental from the perspective of existing freshwater ecosystems and the human livelihoods and communities that depend upon them (poff et al. ) . discussions have broadly focused on rising water and air temperatures, increasing and decreasing precipitation, increasing evapotranspiration, and changing regimes of groundwater and surface runoff. there are four basic types of adaptation strategies that have been proposed for addressing these impending impacts. we define these as ecological water management, connectivity, protected areas, and restoration strategies. below, we briefly describe some of the specific strategies that have been proposed in each of these areas. increased water scarcity associated with decreased precipitation and increased warming in some regions is likely to prompt the modification of dams and reservoirs to improve storage capacity (see section . . . . managed aquatic systems). traditional water management has generally sought to dampen the natural variability of river flows to attain steady and dependable water supplies for domestic and industrial uses, irrigation, navigation, and hydropower, and to moderate extreme water conditions such as floods and droughts (postel and richter ) . however, the extraordinary species richness and productivity characteristic of freshwater ecosystems is strongly dependent upon, and attributable to, the natural variability of their hydrologic conditions. thus, large changes to natural flow regimes can have large impacts on species, ecosystems, and society (postel and carpenter ; iucn ; wcd ) . the water needs of humans and natural ecosystems are commonly viewed as competing. however, water managers and political leaders increasingly recognize that there are limits to the amount of water that can be withdrawn from freshwater systems before their natural functioning and productivity, native species, and the array of goods and services they provide are severely degraded ). this has led to a growing realization that society derives substantial benefits both from out-of-stream extractions of water as well as by maintaining adequate flows of water within freshwater ecosystems. in recent years, the water needs of river ecosystems are receiving increasing attention in water-supply planning, offering hope that many rivers can be protected before their health and ability to provide important goods and services is seriously compromised by water development. restoring or protecting some semblance of the natural river flow conditions necessary to support ecosystem function (called environmental flows) into the future is one of the most important climate change adaptation strategies for flowing waters. recent regulatory mandates and policy decisions calling for restoring and preserving environmental flows have led to a reexamination of dam operations for better protection of river health (watts et al. ) . for example, the south african national water act ( ) calls for the creation of a reserve of water in each river basin to meet both basic human needs and protect river ecosystem health. similarly, other national directives and international agreements such as the water framework directive of the european union are providing mechanisms for river protection, including the provision of adequate environmental flows (postel and richter ) . maintenance of environmental flows (flows that sustain river ecosystems) is likely to be the highest priority adaptation response for freshwater ecosystems in most contexts. this will require policies and implementation mechanisms to protect (and, if necessary, restore) flows now, and to continue to provide environmental flow regimes under changing patterns of runoff associated with climate change. as air and water temperatures warm, many freshwater species will be forced to rapidly adapt to their new environments, to migrate to more suitable habitats, or face extinction (heino et al. ). responses of aquatic organisms to climate change will be constrained because they are limited to dispersal along pathways of connected water. consequently, the linear nature of river systems makes them highly prone to fragmentation from waterfalls, dams, and water withdrawals. such fragmentation can not only limit dispersal and the ability of species to track climate change but also disrupt the completion of life cycles for many freshwater organisms. for many streams, especially in arid and semiarid ecosystems, there is concern that more frequent and severe droughts will lead to the building of more dams and water diversions, further fragmenting stream networks (seager et al. ) . increasing the connectivity of freshwater systems is one key way to help aquatic systems adapt to climate change. species responses to climate change will be limited by human-engineered structures, including hundreds of thousands of dams, diversions, and impassable road culverts that exist globally (nilsson and schopfhauser ) . in the united states alone, there are over large dams and an estimated . million or more small impoundments that disrupt the dispersal of aquatic organisms. in recent decades, however, new water laws and programs have helped to increase habitat connectivity by removing or modifying human barriers to movement in river systems. increasingly, small dams and diversions are being removed for a number of ecological, social, and economic reasons, including the enhancement of longitudinal connectivity for fish migration (stanley and doyle ) . similarly, temporary barriers such as impassable culverts under roadways are being modified to allow for easier recolonization and movement of fishes (roni et al. ) . although this management strategy may promote the adaptive capacity of species to respond to climate change, the removal of such obstructions can simultaneously increase the risk of invasion by nonnative species and associated diseases, which are major threats to ecosystem structure and function. in fact, the conversion of culverts into permanent barriers has been a common management approach to protect isolated native populations from invasive species spreading upstream (fausch et al. ). given the complexities of promoting the movement of native species while concurrently limiting the spread of invasive species, it is unlikely that the removal of barriers to enhance habitat connectivity will be a successful adaptation strategy in all areas for reducing the impacts of climate change on ecosystem function. in addition to restoring or protecting environmental flows and increasing connectivity within stream networks, it may be necessary to protect the species themselves to allow them to move through or persist in more intensely managed landscapes. in aquatic ecosystems, this may involve increasing the size of existing reserves or creating new protected areas that encompass important freshwater resources and allow for native species and assemblages to persist into the future (abell et al. ) . such acquisitions and agreements ideally would capture a large portion of the geographical, ecological, and geophysical range of multiple species, thus increasing opportunities for organisms to adapt and evolve to changing environmental conditions. protected areas have historically been a cornerstone of terrestrial conservationand are discussed in much more detail in that section, below. nonetheless, protected areas will likely play a major role in protecting aquatic species as climate change and areas could easily be prioritized to provide protection for both terrestrial and aquatic systems in a changing climate (abell et al. ). projected increases in air temperatures, combined with reduced snowpack, earlier onset of spring peak flows, and lower summer baseflows, will have direct implications for the thermal regimes of streams and rivers (poff et al. ) . the ecological implications of stream warming are significant. water temperature directly influences the metabolic rates, physiology, and life histories of aquatic species and helps determine rates of important ecological processes such as nutrient cycling and productivity. in general, warming will produce a general shift in species distribution poleward with extinctions and extirpations of cold-water species at lower latitudes and range expansion of warm-water (often invasive species) and cool-water species into higher latitudes. restoring and protecting riparian vegetationthe trees and shrubs that grow along the banks of rivers and streamshas the potential to reduce stream temperatures in certain places. recent modeling suggests that riparian habitat restoration can play an important role in offsetting the effects of climate change. battin et al. ( ) used a series of linked models of climate, land cover, hydrology, and salmon population dynamics to investigate the impacts of altered stream flow and temperature on the effectiveness of proposed habitat restoration efforts designed to recover chinook salmon populations in the pacific northwest of the united states. this study showed that in the absence of habitat restoration, basin-wide spawning populations would decline by an average of - % by . by contrast, they found large increases in juvenile rearing capacity associated with proposed riparian habitat restoration, which limited climate-induced declines to % according to one climate model and increased salmon abundance by % according to another model. however, the model results showed that not all expected climate impacts could be mitigated entirely. in relatively narrow streams, reforestation was predicted to decrease water temperatures by increasing shading, but in wide, main-stem reaches where most chinook salmon spawn, riparian vegetation had a minor effect on water temperature. in addition to restoring riparian areas, targeted protection of forested riparian buffers using fencing to stop livestock from entering the stream and trampling/grazing vegetation or conservation easements to eliminate farming activities may also help to reduce stream temperatures. the many adaptation strategies that have been proposed for addressing climate change in terrestrial systems can be loosely grouped into three categoriesthose that involve protected lands and conservation planning, those that address connectivity, and those that are more species or site specific in nature. protecting land is arguably one of the most effective ways of conserving biodiversity and terrestrial ecosystem services. it is generally assumed that lands that are selected to protect today's species and ecological systems will protect those species and systems into the future. climate change brings this assumption into question. as climates change and species distributions shift, species will move into and out of reserves. changes in species composition, the timing of ecological events, and the rates of ecosystem processes will result in changes in the functioning of ecosystems and the services they provide. many proposed adaptation strategies address these challenges by augmenting current protected areas with additional reserves, parks, and preserves (heller and zavaleta ; lawler ). these strategies range from broad calls for more protected lands to more sophisticated recommendations about how to select new lands or design new reserves to better protect biodiversity and ecosystem services as climates change. a number of strategies have been proposed for determining where to put new protected lands to best address the effects of climate change. some of the simplest strategies involve placing reserves at the poleward or elevational boundaries of the range limits of specific species (peters and darling ) , at major transitions between vegetation formations (halpin ) , or at the core of species environmental distributions (araújo et al. ) . others have proposed placing reserves between existing reservesin the hopes that those new reserves will act as stepping stones allowing species to better move from reserve to reserve. yet another recommendation involves placing reserves across strong environmental gradients. reserves that span many different environments will potentially allow species to shift their distributions without leaving the reserve. in addition to these simple rules of thumb for placing reserves to address climate change, many more sophisticated approaches to selecting areas for new reserves have been proposed. for example, modeled climate-driven shifts in species distributions can be used to select new reserves that will protect biodiversity today and into the future (hannah et al. ; vos et al. ; hole et al. ). although this approach may prove useful for some species and systems, care must be taken in the use of the models developed to project species range shifts. there are many uncertainties associated with the models themselves and the climate projections on which they rely. another proposed approach to building a reserve network that will be resilient to climate change involves protecting environments in lieu of protecting species and systems. this approach has been referred to as 'protecting the ecological stage.' this analogy implies that the species and the ecological systems are players and that the soils and topography of a region form the stage on which they interact and evolve. by protecting a suite of diverse environments, it is assumed that one will protect the areas where new ecological systems can develop as climates change (anderson and ferree ; beier and brost ) . similarly, others have suggested that more resilient reserve networks will be those that include a diversity of current climates (pyke and fischer ) . although climates will change, many of the climate gradients generated by latitudinal and topographic patterns will remain. thus, a set of reserves that protects a diversity of climates today will likely protect a diversity of climates in the future. at least one recent study has applied the concept of protecting environments (topographies, soils, and climate gradients) to a reserve-selection problem (schloss et al. ) . one last approach to building a resilient reserve network in a changing climate involves placing reserves in areas that are likely to serve as climate refugia. refugia are areas that are projected to experience minimal climatic changes and/or have cooler microclimates (saxon et al. ; hansen et al. ; shoo et al. ) . one potential opportunity for climate change adaptation is to consider people as an essential component of species conservation and climate adaptation. while reserve and park systems have a long history of alienating local people, using violence and other coercive measures to separate people and wildlife, in this case, local livelihoods are also threatened by climate change. this provides an opening for a new approach to conservation and a new discourse on the relationship between local people and wildlife. as for freshwater systems, improving the connectivity of the terrestrial landscape will be critical for addressing climate change. in response to historical climatic changes, many species shifted their rangesmoving toward the equator as ice sheets advanced and moving poleward as the ice sheets retreated. today's species will have a much harder time responding to current and impending climatic changes. present-day landscapesunlike the landscapes of the distant pastare fragmented by roads, agricultural fields, and residential development. given that many species will have trouble moving across these human-dominated landscapes, it will be essential to reconnect fragmented landscapes to allow species to respond to shifting climates. not surprisingly, improving landscape connectivity was the most often recommended climate change adaptation strategy in a recent review of the literature (heller and zavaleta ). many of the recommendations for increasing connectivity involve designing corridors that connect current protected lands. traditionally, such corridors have been designed for particular focal species, and they have connected reserves or remaining fragments of habitat. however, corridors that facilitate species ranges shifts and the reshuffling of ecosystems will need to connect what is habitat for a species today with an area that may become habitat in the future. in this way, corridor design will need to evolve to address climate change. one such approach to developing corridors for addressing climate change involves basing the corridors on environmental gradients instead of on the current vegetation (which is often used as a measure of habitat) (beier and brost ) . another approach uses projected changes in climate to orient corridors (ackerly et al. ) . a third method involves using modeled shifts in species distributions to identify potential routes that species would need to take to move from currently suitable climates to places where climates will likely be suitable in the future (williams et al. ; rose and burton ) . these three approaches are based on different assumptions and have different levels of associated uncertainty. in general, the uncertainty increases with the intensity of modeling required to identify the corridor, and thus the first of the three approaches has the least inherent uncertainty and the last of the three has the most. although corridors may be useful for some species, they will not be feasible or effective in all places or for all species. in addition to designing corridors to facilitate species movements, it will likely be necessary to improve the permeability of the landscape in general (franklin and lindenmayer ). increasing landscape permeability will involve changing the way we use and manage the landscape. changes in forest harvest practices from clear-cuts to selective, retention harvests can increase the connectivity of forested landscapes. landscape planning and zoning for residential development can reduce landscape fragmentation. windbreaks, fencerows, and crop choices can be used to increase the connectivity of agricultural lands. at a finer scale, choices of landscaping plants, road placement, and wildlife over-and underpasses can increase landscape permeability. protected lands and connectivity increase species ability to adapt to changing climates at relatively large spatial scales. in general, they address species movements. adaptation strategies are also needed at finer scales. in particular, strategies are needed that address individual species and ecosystems. many of these finer scale approaches tend to involve reducing temperatures or otherwise offsetting the exposure to the changes in climate or climate-driven changes in environmental conditions. for example, it may be possible to reduce temperatures by restoring vegetation to provide shade (wilby et al. ; wilby and perry ) . it may be possible to reduce the impacts of changing fire regimes through forest management practices. fire suppression policies, may, for example, have particularly severe ramifications in a climate in which fires will generally be larger and more frequent. it may also be feasible to provide supplemental water for particularly vulnerable plants or animals in times of drought or during heat waves. similarly, shade shelters could be provided to help some animals weather heat waves in extreme climates. although some of these strategies may prove useful in the short term, many will be neither cost-effective nor long-term solutions. another system-specific approach to addressing climate change involves altering species composition or community structure in a way that allows a system to better cope with climatic changes. for a forested system, this may mean planting new species or planting seeds of the same species that have a different genetic makeup (millar et al. ; glick et al. ). likewise, for grasslands and shrublands, this may mean choosing different species or strains for restoration purposes. moreover, it may mean facilitating the transformation of an ecosystemfor example from a shrubland to a woodland or from a shrubland to a grassland. in many cases, the first species to move into these transitioning systems may be invasive species. facilitating the transition to a new state using species native to the region may, in many cases be preferable to having new systems dominated by invasive species. these extreme cases will require ex situ conservation strategies, including seed banking and captive breeding to ensure the long-term survival of the species. the interface between the land, sea, and air found in coastal areas is a high-energy system subject to storms, winds, and tides. it is also where the majority of protein comes from in many regions of the world. many vital ecosystem services are provided along coastal margins of continents and islands. fringing coral reefs and mangrove forests buffer wave energy, which reduces erosion along the coast. these systems also provide critical habitat for many species, especially nursery areas for provisional services such as fisheries. in many areas, sea-level rise and associated storm surges will make it difficult to protect these systems and the services they provide. nonetheless, there are two main approaches that will likely prove most useful in coastal systems: building resilience through protection and restoration and facilitating the transition to new ecosystems. one of the more beneficial ways, from both an environmental and economic standpoint, to adapt to predicted changes from climate change is by protecting and restoring natural systems that provide multiple ecosystems services. this would include protection of human infrastructure from sea-level rise and increased inundation. protection and restoration of natural buffers such as barrier islands, mangroves, and coral reefs not only require little financial construction and maintenance but also maintain the wealth of ecosystem services associated with these systems, which include nursery and rearing habitat for many commercial seafood stocks such as fish and shrimp, recreational and cultural opportunities for humans, and protection from inundation. some natural protection features such as sea ice cannot be maintained in the face of increasing temperatures. in alaska, the loss of sea ice and melting of permafrost due to warming ocean and air temperatures has exposed the shore to wave energy that used to be absorbed or damped by sea ice or frozen soils. undoubtedly, ecosystem services that depended on that sea ice protection have also been lost. many regions have seen a huge decrease in the area covered by mangroves as coastal areas are drained and mangroves removed for aquaculture. worldwide, it is estimated that more than % of mangrove forests have been destroyed or converted to other uses. on a local scale, many areas have lost all of their mangroves. this loss destroys a wide range of ecosystem services provided by these forests, which range from carbon sequestration to flood protection, spawning, and rearing grounds for many fish and other marine species. restoring mangrove forests results in increased storm surge protection for natural and human coastal systems, provides nursery habitat for many commercially important fisheries, and stores sediments that may damage offshore coral reefs. worldwide, corals exhibit well-documented environmental adaptability over time scales of weeks to thousands of years. corals are actually two creatures that live together in a symbiotic relationship. zooxanthellae are the algal component of corals that provide nutrients generated from photosynthesis to the animal component. different zooxanthellae species and different species of corals in general have differential environmental tolerances. for example, some corals near the arabian peninsula exist under conditions of salinity and temperature that are greater than near-term predicted future average salinities and temperatures resulting from climate change. these adaptive changes likely operate on a decadal time scale. thus, in some cases, it may be possible to identify particular species or zooxanthellae and algal combinations that are more resilient to warming. protecting coral reefs from other stressors such as excess sediment and/or nutrient and pollutant inputs from terrestrial sources and unregulated diving can increase the coral's ability to adapt to increased water temperatures. technological adaptation measures include using sprinklers to create roughened sea surface to decrease light penetration or covering reefs with shade cloth to limit bleaching of corals. as sea levels rise, many coastal systems will need to migrate inland. when there are extensive human uses of coastal space or urban buildup, space for ecosystem recovery and migration of species will not be available. providing space for the migration of biotic elements of the coastal system at the same time as when human populations are forced to move would provide cobenefits for coastal life and human communities. ecosystems will usually adjust to changing salinities and water levels, and the services provided by the system will be maintained where conditions are suitable. for example, in , a subdivision east of houston in baytown, texas, was bought out, the structures removed, and the entire area restored to coastal wetlands. a more extreme example of planned retreat is the maldive islands. their current plan is to exploit the current coastal amenities, primarily beaches and coral reefs; secure capital with which to train younger citizens; and prepare them for relocation to other countries such as india, sri lanka, and australia. in the short term, there are negative consequences to ecosystem services due to commercial and touristic exploitation, but in the long run, by abandoning the islands, the system will be able to come to a new ecological state. in some cases, removing human infrastructure will be a necessary but insufficient means of fostering landward shifts in coastal systems. in such cases, it may be necessary to facilitate the shift in natural systems and stabilize soils by planting more coastal species inland as water levels rise. such actions have been taken as part of the alligator river climate change adaptation project on the north carolina coast in the southeastern united states poulter ) . here we describe some of the adaptation strategies that have been proposed for built environments, agricultural systems, and managed freshwater systems. we explicitly focus on how the most commonly proposed strategies could affect associated ecosystems. the severity of climate change impacts will depend, in large part, on our ability to transform the built environment in response to changing conditions. the following section discusses some of the climate change adaptation strategies that will likely take place in built environments and the effects that these strategies may have on ecosystem functions and services. we briefly discuss human migrations, flood control, sea-level rise, increased water storage, and urban heat-island effects. perhaps the most basic form of climate change adaptation involving the built environment is human migration. vulnerable populations will be forced to abandon their homes, relocate, and rebuild. they will displace resident populations and open up the possibility of conflict in the process. the bulk of climate change-related human migration that is already occurring involves movement from rural areas to cities in developing countries. unplanned urban growth will fuel the expansion of informal urban settlements, and by ,  people, one-third of the world's population, may inhabit urban slums. in both rural and urban environments, proactive planning and resettlement strategies that identify populations at risk and relocate them stand to drastically reduce long-term human hardship stemming from climate change. they can also protect vital ecosystems from the degradation associated with unplanned development. however, resettlement can have profound negative impacts. poorly executed, it can degrade indigenous culture, undermine traditional livelihoods, destroy social networks, and deepen poverty by distancing poor communities from employment opportunities. given these dangers, in some cases, it is preferable to fortify communities against climate change impacts in place. this approach introduces improvements to infrastructure and housing, builds upon the prior efforts of communities, and preserves social networks. in many regions, climate change will result in increased rainfall and flooding. conventional approaches to storm water management rely on defensive hard structures. water runs from impermeable concrete and asphalt surfaces into storm drains, culverts, and concrete embankments. rivers are straightened, channelized, and isolated from their natural floodplains to accommodate human settlement. as flood events become more intense and frequent with climate change, storm water management strategies must evolve. rather than take a defensive stance, they should promote the coexistence of humans, habitat, and water. soft infrastructure or low-impact development strategies, such as permeable paving, green roofs, green walls, rain gardens, bioswales, and constructed wetlands offer a promising alternative to conventional storm water infrastructure. they promote groundwater recharge, reduce flooding, and improve water quality with downstream benefits to aquatic habitats. in areas of severe flood risk, resettling residents on higher ground and reintroducing rivers to their floodplains protects human populations, dissipates flood energy, and creates wetland habitat. through temporal landuse practices such as intermittent farming, floods become an asset rather than a threat, depositing sediments that enrich agricultural lands. by , rising sea levels may displace as many as million people (myers ) . like conventional storm water infrastructure, conventional seawall infrastructure relies on defensive hard structures. as sea levels rise, existing levees will become obsolete. here again, soft-infrastructure strategies offer a promising alternative. graduated transitions from sea to land including manmade offshore islands, expansive shallows, and coastal marshes act as buffers for storm surge better equipped to absorb the impacts of extreme weather events. they provide habitat for marine species and, in coastal cities, public space for recreation when conditions permit. in places like coastal peru and sub-saharan africa, disappearing glaciers and reduced precipitation will increase the frequency, duration, and impacts of drought, undermining food and water security. a number of interventions in the built environment can help communities cope with water scarcity. increasing water storage at scales ranging from dams to urban reservoirs and household rainwater barrels helps bolster water supplies during prolonged dry periods. in coastal areas, desalination plants and, in select localities of south america and africa, fog harvesting may prove to be viable alternative water sources. ecological sanitation technologies such as dry toilets and gray water wetlands conserve potable water for drinking and, as part of a network of integrated ecological infrastructure systems, irrigate and provide nutrients for urban farms and forests. they also help prevent contamination of local water bodies, preserving their viability as sources of potable water and ecological integrity. further impacts of, and opportunities associated with, these various adaptation strategies are discussed in the sections . . . . and . . . . . cities in developed countries are on average - c hotter than the surrounding countryside (un human settlements programme ). higher urban temperatures increase energy use, degrade urban air quality, raise the temperature of urban storm water runoff, and contribute to general discomfort, respiratory illnesses, heat stroke, and other heat-related illnesses. warming in conjunction with increased urbanization will amplify urban heat-island effects and their associated impacts. several strategies can help reduce urban temperatures. at the scale of the site, urban trees with high, dense canopies, strategically planted around buildings, in parking lots, and along streets permit the passage of air, shade heat-absorbing surfaces, and cool the atmosphere through evapotranspiration. they also reduce the temperature of runoff water. green roofs perform a similar function on roof surfaces. buildings and landscapes constructed from materials with high solar reflectance or albedo absorb less heat and reduce urban temperatures. at a larger scale, streets oriented parallel (or up to ) to prevailing winds, permeable networks of public open space, strategically situated low-rise buildings, and gaps between high-rise structures increase the air permeability of urban environments. increased temperatures and changes in precipitation regimes are likely to have negative impacts on global food security by worsening the existing regional disparities between developing and developed countries (easterling et al. ; rosenzweig and tubiello ) . this is supported by the prediction that a moderate warming accompanied with elevated co concentrations is likely to lead to an increase in crop productivity of developed countries in temperate mid and high latitudes, whereas even a slight increase in temperature could damage crops that are already growing at supraoptimal temperatures in countries located in tropical, low latitudes (easterling et al. ; easterling ) . as in other systems, even with significant mitigation efforts, adaptation strategies will be necessary to address the impacts of climate change on agriculture. adaptation strategies for more resilient agricultural systems may include altering the timing and location of cropping, switching crop species and cultivars, selecting livestock breeds, crop rotations, and efficiently using and managing water resources. these types of adaptation strategies have been referred to as autonomous strategies (easterling ) . implementing some of these strategies, such as changing the type of livestock that is grazed or changing crop rotations could have profound effects on ecosystem functioning. however, in general, these types of adaptation strategies will have environmental impacts smaller than more intensive strategies that are designed to transform systems. for many agricultural systems, the magnitude of climatic changes will necessitate more intensive planned adaptation strategies that foster significant transformations of systems or infrastructures (easterling ) . such intensive strategies will be particularly important for sub-saharan africa and south asia where climate will have major impacts on agriculture (lobell et al. ; nelson et al. ). these planned adaptation options include developing new infrastructure (e.g., irrigation infrastructure, transport and storage infrastructure, and efficient water use and reuse technologies), investing in new technical and management options (e.g., crop and livestock improvement, enhancing germplasm), shifts in the distribution of agriculture (e.g., abandoning some areas and farming new lands), and building the capacity to make continuing adjustments. here, we discuss two of these strategiesimproving crop performance and water conservationin more detail. stresses on crops due to extreme heat and pest and pathogen pressures are likely to increase with climate change (deutsch et al. ; battisti and naylor ) . multiple adaptation options are available for improving crop performance in the face of such climate-driven stresses. first, in conjunction with conventional breeding, crop improvement through genetic engineering is seen as an effective adaptation tool in a changing climatealthough public opinion is often divided on the use and consequences of genetically engineered crops (macdiarmid ; jones ) . a second approach involves maintaining crop genetic diversity by, for example, collecting and storing the diversity of current cultivars or local landraces. a third adaptation strategy involves exploiting symbiotic relationships between crops and other organisms. for example, it has been shown that numerous fungal and bacterial endophytes confer stress tolerance to heat, drought, salinity, and pathogen attacks (rodriguez et al. ; rodriguez et al. ), and others promote growth and fix atmospheric nitrogen xin et al. ). other strategies include the application of kaolin particle films to reduce heat stress and photoinhibition and to mitigate pest damage (glenn et al. ; glenn ) as well as the incorporation of biochar into soils to confer numerous agronomic benefits that enhance crop performance and stress tolerance (marris ) . irrigated agriculture accounts for about % of the world's freshwater withdrawals (rosegrant et al. ). with increasing global population, the demand for irrigated agriculture will continue to increase globally because realized crop yields normally increase considerably with irrigation. adaptation strategies that foster more efficient use of water in agriculture will be critical for achieving global food security while conserving water in a changing climate. these strategies will include institutional water management reform, economic incentives for efficient water use, and infrastructure investment for efficient irrigation and water delivery systems (rosegrant et al. ). the 'virtual water' trade through crop products from water-abundant to water-deficit areas should be considered as one of the key adaptation options to climate change (rosegrant et al. ; easterling ) . improving crops for higher water-use efficiency (i.e., greater yield with less water use) should be a goal for genetic, ecological, and agronomic options of adaptation discussed above. alternative strategies of increasing water storage capacity with dams and increasing the number of stream diversions for agriculture will, in contrast, have significant impacts on aquatic ecosystems (see the section . . . . managed aquatic systems). as discussed above, changes in temperature and precipitation are likely to lead to changes in the demand for water. projected climatic changes will likely lead to increased demands for residential use, irrigated agriculture, hydropower production, and carbon capture and storage technologies. in some regions, current water management may not adequately cope with the impacts of changing precipitation regimes and increased evaporation on the reliability of water supply, flood risk, health, agriculture, energy generation, and freshwater ecosystems (palmer ) . adaptation strategies designed to address water management for human uses will either directly or indirectly affect ecosystem functioning and ecosystem services. in addition to the adaptation strategies for addressing water demands for agriculture and residential use (addressed to some extent in sections . . . . and . . . . ), other important adaptation strategies for managed aquatic systems that will impact ecosystem functions and services include increased extraction of groundwater, improving storage capacity by building or modifying dams and reservoirs, desalination of seawater, and expansion of rainwater storage and water transfer (bates et al. ; hirji and davis ) . improving storage capacity by building or modifying dams and reservoirs is likely to be one of the most common regional responses to decreased water availability and increased demand for water. the great utility of running water has resulted in the extensive exploitation of streams and rivers by humans throughout the world, a process greatly facilitated by the construction of hundreds of thousands of dams globally (nilsson et al. ) . by capturing high river flows and releasing the water in a carefully controlled manner, dam managers can deliver steady and dependable water supplies to downstream areas, protect settlements from floods, or generate power. although human manipulation of the world's river flows has provided many societal benefits, it has also caused considerable ecological damage and the loss of important ecosystem services valued by society (baron et al. ) . flow regulation for hydropower and storage, diversion for human use, and extraction of groundwater connected to stream systems often significantly affect the natural seasonal and interannual variation in river flow, commonly referred to as the natural flow regime (poff et al. ) . a natural flow regime is needed to sustain the complex riverine and riparian ecological functions and processes that support native biodiversity and provide myriad ecological services including maintaining water quality, recharging groundwater, and nutrient cycling (naiman et al. ) . facing an ominous future of increasingly severe watersupply shortages in many areas of the world, social planners and government leaders are exploring strategies for ensuring that enough water of sufficient quality is available for use by future generations. human demands for water are expected to increase under a warmer climate, exacerbating current management problems. increasing demands for irrigation and industrial cooling water could conflict with the increasing demands for municipal water supplies resulting from urban growth. climate-induced changes to water availability and increasing human demand for water are likely to prompt the construction or modification of dams and reservoirs to improve storage capacity and enhance water security (wcd ; palmer ). for instance, by storing water in reservoirs, water managers capture high flows during wet years or seasons to supplement water supplies at drier times, thereby maximizing the reliability of water supplies and certain economic benefits each year. for regions where increases in runoff variability or more prolonged drought conditions are associated with climate change, the pressure to build watersupply reservoirs will be great. although the construction of additional dams and reservoirs will undoubtedly provide many societal benefits, a rich body of scientific knowledge has shown that river regulation also causes considerable ecological damage and the loss of important ecosystem services valued by society (baron et al. ; postel and richter ) . river ecosystem health deteriorates when natural flows of water, sediments, and organic materials through a river system are substantially disrupted or modified by human activities (poff et al. ; richter et al. ) . river damming and associated environmental alteration is now widely recognized as a leading cause of declines in freshwater biodiversity globally (bunn and arthington ) . dams have also been implicated in the loss of commercial fisheries in many estuaries and coastal areas, and in the degradation of other natural ecosystem products and services worldwide (wcd ) . in addition, reservoirs increase the loss of water due to evaporation. finally, as mentioned above, reservoirs emit substantial quantities of carbon dioxide and methane into the atmosphere (st. louis et al. ) , and therefore, the creation of additional reservoirs is likely to further promote climate change. in many regions, impending water shortages will also lead to greater interest in desalination as a technique for tapping into the vast and infinitely tempting water supplies of the sea. recent improvements in reverse osmosis technology, coupled with the rising cost and increasing unreliability of traditional water supplies both currently and projected in the future, are making desalination a water-supply option with major plants in operation, in planning, or under consideration in europe, north africa, north america, australia, china, and india. like most large-scale industrial processes, making water has a number of actual or potential impacts on aquatic goods and services (wwf ) . emerging issues include significant cost and pollution emitted by desalination plants and the mostly unknown, but potentially substantially, effects on freshwater and coastal ecosystems. intake pipes can remove larvae and small marine organisms, and discharge from desalination plants can elevate levels of salt and other constituents of seawater such as boron; dead sea life, which consumes oxygen while decomposing; chemicals added to change the composition of the water for processing, as well as reducing contamination and clogging of filters and membranes; corrosion byproducts; and the heat added for or during processing. finally, water manufacturing is an energy-intensive process. although increasing ghg concentrations and the resulting increasing temperatures are global phenomena, the globe will often be an inappropriate scale for developing mitigation and adaptation strategies. human activities generate differential risks and vulnerabilities that vary with location due to differences in social, political, cultural, and economic conditions (beck ) . although, in one sense, all people are vulnerable to catastrophic climate change, at another more fundamental level, the risk of climate change impacts (along with blame and responsibility) are unevenly distributed. we can begin to think of the unequal distribution of the vulnerability to climate change as a scale issue. mitigation and adaptation strategies can be applied at multiple, and often overlapping, scales. at the finest scale, the development of mitigation strategies will depend on local leadership and the attitudes of local populations and individuals toward climate change. at national and international levels, mitigation efforts will be organized through large and formal programs and institutions (e.g., un-redd). although some adaptation strategies will be national and international in nature, much adaptation will take place at finer scales of communities and regions. a hallmark of climate change as a global phenomenon is that leadership and coordination across local, national, and international scales is important for ameliorating its effects. in turn, coordination across scales will entail understanding local climate risks and local and regional understandings of the causes of climate change and the costs and benefits of different mitigation and adaptation strategies. the effectiveness of any mitigation or adaptation strategy (building codes, population planning, dietary changes, etc.) depends on its acceptance in local, regional, and national communities. social impediments to adoption of climate change strategies include ideological outlooks, structural constraints, and cultural barriers. for example, free-market ideologies can impede the ability of governments to invest in alternative energies; agricultural subsidies and corporate monopolies on agricultural inputs may create structural barriers to alternative agriculture; and cultural norms for relative water and energy use, family size, or the flavor and texture of food can inhibit conservation of resources and changes in diet. there is a clear disparity between societies that have contributed the most to ghg emissions and those that will likely suffer the direst consequences of climate change. at the international level, efforts to shift blame from the activities of the rich to the actions of the poor have been used to shirk the responsibility to mitigate climate change and to impede the development of global mitigation strategies. the dispute between the global north and south over who caused climate change and who must now take responsibility for mitigation is by now well known. countries in the global south argue that northern countries have already developed their economies relying on fossil fuel consumption and now, when it is their turn to develop, they are asked to put restrictions on their energy consumption and natural resource use. meanwhile, the united states has used the reluctance of developing countries to cap emissions as an excuse for inaction on its part. mitigation and adaptation activities that do not take globally inequalities in wealth, resources, and adaptive capacity into account, or insist on 'equality' in action in a demonstrably unequal world cannot be effective. addressing population growth clearly plays a key role in both mitigation and adaptation strategies. however, focusing on population size while ignoring global patterns in the consumption of resources and the distribution of wealth will result in failed policies and strategies. the world's human population is approaching  , and a growing population inevitably means greater demand for the numerous goods and services supported by terrestrial and aquatic ecosystems. while the availability of resources has seemingly stretched beyond the direst predictions of several decades ago, the crisis of overconsumptionnamely, of coal and other fossil fuels that produce ghgs and contribute to climate changeis simultaneously becoming clearer. while trends over the past several decades suggest that population growth is a significant driver of co emissions (bongaarts ; dietz and rosa ) , it is also true that urbanization, aging, and changes in household size similarly affect energy use and emissions (mackeller et al. ; cole and neumayer ) . particular point sources of ghg emissions from energy consumption in developed countries, like the internationally managed oil fields of nigeria or emissions from the recent iraq war, which since has released over million metric tons of carbon dioxide, the equivalent of adding million new cars to american roads (reisch and kretzmann ) , should bear at least as much scrutiny as the desires of third world women and men to bear children. an overarching emphasis on population detracts from a nuanced understanding of the multiple drivers of ghg emissions. it will be ineffective to focus on the effects of climate change on ecosystems without considering the concurrent effects on human well-being and vice versa. disparities in climate change risk and human health often overlap, and human health and environmental health are intricately intertwined. although diseases are often approached as singular phenomena, good models exist that demonstrate the interactive effects of multiple morbidity factors on health outcomes and disease trajectories. for example, interactions between acquired immune deficiency syndrome and tuberculosis, or diabetes and severe acute respiratory syndrome, have synergistic impacts on patients that must be understood together. likewise, social attributes, like poverty or exposure to racism, interact with disease conditions to increase the damaging effects of disease. such interactions have the potential to influence the effects of climate change on disease movement and clustering, disease interactions, and the impact of climate change on global health (baer and singer ) . human action and human vulnerability to such interactions between climate, disease, and the environment are structured by social and economic inequality, and thus mitigation and adaptation strategies will need to take these inequalities into account. what is clear from a social and political perspective on mitigation and adaptation is that no one set of mitigation or adaptation strategies will be applicable to all people in all places. suggested approaches to either mitigation or adaptation will involve costs and benefits that are unequally distributed across nations, populations, and societies. there will, for example, always be those who can escape pollution with air filters and private vehicles, use air conditioning to 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us online workers in times of covid‐ date: - - journal: tijdschr econ soc geogr doi: . /tesg. sha: doc_id: cord_uid: py lbg we draw on data from the online labour index and interviews with freelancers in the united states securing work on online platforms, to illuminate effects of the covid‐ pandemic. the pandemic's global economic upheaval is shuttering shops and offices. those able to do so are now working remotely from their homes. they join workers who have always been working remotely: freelancers who earn some or all of their income from projects secured via online labour platforms. data allow us to sketch a first picture of how the initial months of the covid‐ pandemic have affected the livelihoods of online freelancers. the data shows online labour demand falling rapidly in early march , but with an equally rapid recovery. we also find significant differences between countries and occupations. data from interviews make clear jobs are increasingly scarce even as more people are creating profiles and seeking freelance work online. we combine data from the online labour index (oli) and an interview-based panel study of freelance workers in the united states to provide insight into the changes in online labour markets relative to the ongoing pandemic arising from the global spread of the novel coronavirus, covid- . we do so to contribute evidence and insight to the ways in which a global pandemic appears in the localised context of one of the economies most impacted. the freelance workers that are the focus of this analysis are those taking on projects and contracts for knowledge work: technology support, software development, bookkeeping, accounting, web content, writing and editing, and other types of cognitive work. the growth in online labour markets, and the project-or task-based structure of freelance labour, provides a unique window into effects of a pandemic on work. the oli provides a global perspective; the panel study provides for a more localised set of insights. we pursue this work recognising that as the scope and breadth of the global covid- pandemic continues to grow, the implications to workers and labour markets grow more profound. even conservative estimates of a contained global outbreak are showing significant global macroeconomic impacts (mckibbin & fernando ) . similarly, models at the country level are showing serious economic impacts (atkeson ) . early research is also showing distinct demographic and industry differences in the impact of the pandemic (wenham et al. ; stephany et al. ) . building on the emerging covid- related research, we examine a specific subset of labour markets -the online labour market and its workers -to understand the near-term impacts of the pandemic. online freelancers are in precarious work arrangements generally, and the pandemic presents a particularly challenging scenario to them for at least three reasons. first, the online nature of their work makes them susceptible to greater competition (dunn ) . second, freelance work is project-based: there is little to no commitment between employer and worker beyond the specifics of the project's contract (wood et al. ) . finally, in many countries their status as independent contractors leaves online freelancers in vulnerable positions especially during economic downturns. for example, in the united states, benefits such as health care are tied to formal, full-time employment and are not provided to freelancers. indeed, in comparison with many industrialised countries, there are relatively fewer labour and employment regulations governing non-standard work arrangements in the united states (ilo ; mckay et al. ). on the one hand, online labour markets could be experiencing a boost in demand as companies move operations online. on the other hand, the sharp economic downturn could be causing companies to reduce the use of online labour platforms alongside other types of non-standard work. we address this issue by examining recent changes in the global demand for online labour. and while viruses may be blind to nation-states, policies and interventions are nation-state specific. cross-national comparisons can therefore provide insight on the economic implications of specific policies and interventions. research has already begun to understand the economic implications of country specific interventions (e.g. thunstrom et al. ) . in this initial rapid analysis, we therefore use quantitative data to examine changes in the demand for online labour in three important regional economies with different countermeasures towards the pandemic: united states, germany, and south korea. the data show distinctly different geographic patterns between countries, with us data showing a particularly acute drop in demand for workers, with a simultaneously sharp increase in supply of available workers. the data also make clear that not all occupations in the united states are experiencing the shocks similarly. tech and software development occupations show a significant increase in both online labour demand and number of registered profiles. because of the significant market shock evident in the united states and its notable occupational differences, we complement the quantitative view with interviews with us-based online freelance workers, helping us to understand the significance, implications and lived experiences of the market shock to online freelance workers. online labour platforms are websites that mediate between buyers and sellers of remotely deliverable cognitive work (horton ) . the clients range from individuals and early-stage startups to fortune companies (corporaal & lehdonvirta ). the sellers are either self-employed independent contractors, or people in regular employment who earn additional income by moonlighting as freelancers via the internet. the platforms match clients and workers using a variety of mechanisms, such as allowing clients to post projects for bidding, and allowing freelancers to post resumes for clients to evaluate. besides matching, the platforms also handle contracting, time tracking, monitoring, billing, and dispute resolution, allowing the entire relationship to be carried out remotely. online labour platforms can be further subdivided into freelancing platforms (e.g. upwork, toptal, fiverr) where payment is on an hourly or milestone basis, and microtask platforms (e.g. amazon mechanical turk) where payment is on a piece rate basis (lehdonvirta ) . of these, freelancing platforms appear to be much larger in terms of user numbers (kässi & lehdonvirta ) . online labour platforms are also sometimes called online gig platforms, but they are conceptually distinct from local gig economy platforms such as uber or deliveroo, which involve physical on-site service delivery (wood et al. ) . the global market for online labour has grown approximately per cent over the past three years (kässi & lehdonvirta ) . but as the covid- pandemic is hitting the world's economies, causing a massive rise in unemployment in the united states, it is pertinent to ask how the pandemic is affecting the market for online labour. pandemic's potential effects on online labour demand -there are several potential mechanisms through which the pandemic could be causing a positive demand shock for online labour. the pandemic appears to be forcing companies in affected countries to shift from collocated office work towards home-based remote working arrangements, known in previous literature as telework (huws et al. ) or telecommuting (mokhtarian, ) , and now colloquially referred to as 'work from home'. the pandemic is also likely pushing companies to increase the use of virtual collaboration as a substitute to travel and face-to-face meetings. telework and virtual collaboration have been slowly and unevenly gaining in popularity already since their introduction in the early s. now, there appears to be an unprecedented surge of interest towards them. for instance, interest in remote working and related search terms in google search approximately tripled from its pre-pandemic baseline to march (clement ) . the stock market value of teleconferencing software company zoom video communications approximately doubled in the same time period. given this surge of interest in remote work and virtual collabouration, it is conceivable that remote-by-design online labour markets could be seeing a significant demand boost. companies looking to engage new contractors might now favour remote online contractors hired through web-based platforms over on-site contractors hired through conventional staffing agencies. already before the pandemic, many skilled workers located in rural areas of the united states appear to have successfully used online labour markets to remotely access opportunities in urban areas . it is also possible that some companies might be moving existing contractor relationships to online labour platforms, in what is known as the 'bring your own freelancer' model (corporaal & lehdonvirta ) . platforms provide features for monitoring and managing contractors remotely, which can partly substitute for the missing in-person controls ). shortterm contractors are typically subject to more performance-and outcome-based controls than regular employees, whose loyalty may be sought with cultural and incentive-based controls (ouchi ) . furthermore, the pandemic and the switch to remote work and virtual collaboration might also be creating additional demand for certain types of labour, some of which is supplied through online labour platforms. in particular, it is conceivable that there is a significant positive demand shock for information technology contractors who can help companies set up and maintain remote work and virtual collaboration infrastructure, and provide training on their use. systems integration work and database management work might also increase as organisational reliance on systems over in-person interactions increases. large firms often have existing it services outsourcing providers, but small-and medium-sized companies may be turning to online labour platforms for these needs (bunyaratavej et al. ) . however, it is also conceivable that the pandemic could be causing a significant reduction in demand for online labour, through a few possible mechanisms. online labour is part of the broader category of non-standard work, which includes other independent contractors and temporary workers. many companies in the united states use non-standard workers as a flexible buffer that can be rapidly reduced in economic downturns to protect core workers (kalleberg ) . online labour can also be seen as a form of outsourcing , which is likewise something that companies can adjust to respond to changing demand. given that the pandemic and its public policy responses have in many countries already resulted in a general economic downturn of historic proportions, it is conceivable that companies could be cutting their use of online labour platforms to engage contractors. already before the pandemic it was apparent that demand in the online labour market was very responsive to events such as public holidays (kässi & lehdonvirta ) , and workers felt that demand for their services could fluctuate a lot (lehdonvirta ) . two opposing effects of the covid- pandemic on demand for online freelance labour are thus conceivable. on the one hand, to the extent that online labour is a substitute to onsite labour, we can expect to see an increase in demand. the technical and organisational effort involved in switching to remote operations might also cause an increase in the demand for specific types of online labour, especially it services. we will refer to all these demand-increasing mechanisms collectively as the distancing bonus. on the other hand, to the extent that online labour is a complement to general economic activity, we can expect to see a decrease in demand, as companies facing declining revenues reduce non-essential spending, including external online contractors. we refer to this as the downscaling loss. pandemic's potential effects on online labour supply -the pandemic can also be expected to have a significant impact on the supply of labour on online labour markets. the supply generally speaking consists of two margins: the number of workers offering their services through online platforms, and the number of hours that they are willing to supply (horton ) . the number of workers offering services online might conceivably increase, because the pandemic and its countermeasures have led to record-high unemployment in many countries, freeing up skilled workers (del rio-chanona et al. ) . workers who were already offering a small number of hours online on top of their regular work (i.e. moonlighting; pesole et al. ) might increase the hours offered as a result of being laid off. on the other hand, workers who are not laid off from their regular jobs might decrease the number of hours they supply through online labour markets, to signal loyalty to their employers. both moonlighters as well as existing full-time online freelancers might also decrease the hours supplied online as a result of falling ill or having increased care and housework duties, as schools and daycare centres close or family members fall ill. geographic and temporal variation in the effects -the pandemic's possible positive and negative effects on online labour supply and demand are likely to vary across space and time, for a variety of reasons. some reasons have to do with the dynamics of the pandemic itself. the pandemic unfolds in phases, from initial discovery to growing spread and eventual public and private countermeasures, followed by an easing up of the countermeasures and possible additional waves of infection (bedford et al. ). owing to differences in initial entry time, infection rates, and response speed, different countries are at different phases, with different impacts on economic activity. country differences in public and private countermeasures, severity of the epidemic, and underlying economic conditions are also likely to generate geographic variation in effects seen in online labour markets (ilo ). moreover, dynamics of the online labour market itself provide plenty of reasons to expect geographic differences (beerepoot & lambregts ) . generally speaking, a clear global north--global south trade pattern is evident in online labour markets, where the majority of employers are located in high-income countries (kässi & lehdonvirta ) while most workers are located in low-and middle-income countries ). different employer countries have different demand profiles in terms of the occupations they are buying from online labour platforms, although these differences are surprisingly small (kässi & lehdonvirta ) . changes in supply and demand in different countries are ultimately reflected in the global aggregate online labour supply and demand. although there is evidence of preference and discrimination in online labour markets (galperin & greppi ) , overall the market functions globally, with workers with similar skills and experience considered reasonably good substitutes for each other regardless of location the resulting overall effects on the market have substantive policy implications. if and when online labour demand experiences a distancing bonus effect while supply remains relatively constant, then the growing online labour market could offer an avenue for laid-off workers to recover some of their earnings. but if the downscaling loss effect dominates and/ or the market is flooded with additional labour supply, then people thus far earning their main income through online labour platforms are likely to join the ranks of self-employed people urgently in need of financial assistance. in the following section we present a rapid initial quantitative assessment of which effects dominate, across time and selected countries. we draw on the oli for a first quantitative assessment of how online labour markets are affected by the covid- pandemic. the oli is an index that measures the utilisation of online labour platforms over time and across countries and occupations (kässi & lehdonvirta ) . it serves a similar function as conventional labour market statistics on new vacancies. the index is constructed by continuously collecting data on tasks and projects posted on major online labour platforms in near real-time. the results of the oli are published as an open data set and an interactive online visualisation, updated daily (http://ilabo ur.oii. ox.ac.uk/onlin e-labou r-index /). in this rapid initial assessment, we examine the effects of the pandemic on the aggregate global market, followed by three important regional economies. finally, we present additional analyses pertaining to the united states. as discussed in the literature review, online labour markets have a distinct geography. our data allows us to provide a detailed picture of how the demand for online labour is geographically distributed on the platforms monitored by the oli. as shown in figure , the largest share of online labour demand originates from employers based in the united states, who posted per cent of all projects recorded in . the second largest buyer country for online freelance work is the united kingdom ( %), followed by india ( %). europe excluding the united kingdom generates per cent of online labour demand, with germany as the biggest demander in this group. only three per cent of the demand for online workers comes from the entirety of africa. given these very uneven geographies of online labour demand, it is fair to assume that global developments on online labour markets are often driven by buyers from the united states. changes in online labour demand -over the past several years, the oli has shown a clear seasonal pattern: demand drops during the year-end holiday season, and then rises again to reach a plateau in february, which normally persists until may. however, as figure shows, this is not the case in . by mid-march, when the world health organisation declared that covid- had become a pandemic, the oli was in deep decline, in comparison to and . this finding indicates that the downscaling loss effect may be dominating over the distancing bonus effect. however, in early april the oli began to rise again, surpassing by far the usual level of previous years by the end of april. this observation, on the other hand, indicates that at this stage of the pandemic, the distancing bonus may have started to dominate over the downscaling loss. to further examine this fast-changing dynamic, we are interested in examining the biggest demander country, the united states. however, the united states was not the first economy to be impacted by the pandemic and its countermeasures. it is useful to contrast it with other important regional economies with different covid- trajectories and responses. in this study, we limit ourselves to examining three important regional economies: germany, south korea, and the united states as the three economies confronted the pandemic at different points in time and opted for different countermeasures. figure shows a cross-country comparison of online labour demand from germany, south korea and the united states. each country shows a distinct pattern. south korea was one of the first economies that had to face the consequences of covid- early in . demand from south korea fell from mid-february to mid-march, but bounced back rapidly in late march. demand from germany similarly fell from february to march, and experienced a more modest rebound in april. demand from the united states started falling roughly two weeks later than the demand from south korea and germany and fell furthest, but by early may was close to reaching pre-crisis levels again. (normile ) . germany established early and localised testing, which allowed the government to impose only relatively moderate restrictions and to permit local business to open again in the beginning of april. demand from the united states can also be seen bouncing back from mid-april onwards, even though restrictions remained largely in place. this could reflect businesses adjusting to the new normal of remote work, rather than a return to pre-pandemic operations. given the particularly clear drop in demand for online labour from the united states, we are interested in how this drop may vary across different types of work. the oli categorises online labour into six different occupations: clerical and data entry, professional services, software development and technology, creative and multimedia, sales and marketing support, and writing and translation. for a more detailed description of these categories, see kässi and lehdonvirta ( ) . as figure shows, not all occupations have experienced a drop in demand. demand in creative and multimedia or sales and marketing support has shrunk significantly as the pandemic has unfolded. but requests for projects in the software development and technology category remain largely unaffected. this finding is consistent with an interpretation that companies are cutting non-essential freelance contracts, such as marketing and sales campaigns, while maintaining freelance outsourcing that is essential for continued business operations, such as tech support and database management. the figures are also consistent with the idea that the rapid push towards videoconferencing and other remote operations across companies has created additional demand for freelance it specialists who are able to help with this. changes in online labour supply -the oli does not provide us with a direct measure of labour supply, but we are able to observe the number of registered worker profiles on a smaller set of online labour platforms. this can be used as an imperfect proxy for the number of workers offering services through online labour platforms. we are not able to observe changes in the number of hours the workers are supplying. an increase in the number of registered freelancer profiles in the united states is evident since the beginning of april. in particular, as shown in figure , a very significant number of new freelancers have registered in the software development and technology category. other occupations do not show a similar increase in registered workers. this is consistent with an interpretation that recently laid-off workers across the economy are not registering en masse on online labour platforms to attempt to make up for lost income. some workers are probably doing so, but to some extent the increased supply in the software development and technology category might also be attributable to the pull of increased opportunities due to growing demand. in sum, while we observe a downscaling loss for most online labour occupations in the united states, software and tech jobs appear to profit from a distancing bonus effect. however, even in this category labour supply growth in the united states appears to have outpaced labour demand growth, suggesting that the workers are likely to be experiencing a tight market. to better understand the workers' experiences, we draw on data from an ongoing panel study in the united states that relies on structured interviews to provide insights on how these trends are being manifested through the lived experiences of workers. our interview data come from an ongoing panel study of freelance workers who are located in the united states and seeking work online via the online labour platform upwork (see http://upwork.com). upwork is one of many online labour platforms and routinely seen as a dominant player. the focus on upworkers serves as a window into the career plans and work strategies of freelance workers seeing work online. the study is designed around a carefully constructed sample of people who pursue freelance work as a primary or secondary source of income, and reflect a range of work types, skill levels, experience online, gender, ethnicity and success with this work. participants are hired and paid as they would for other jobs found on upwork. once hired, participants complete a ' survey that provides us an overview of their working plans, outcomes and experiences and a ' interview. the interview builds on the survey data and follows a carefully designed protocol of semi-structured questions. interviews are done by one of the six members of the digital work research group, a joint effort of syracuse university and skidmore college, both in new york state. the research team members were trained on the protocol and meet frequently and routinely to review the protocol, the data, and pursue interim analyses (as is customary in field studies). beginning in mid-march , we asked freelancers how they were faring in the face of the covid- pandemic. since then, we have done interviews. for this paper, we completed an interim analysis of these freelancers, reviewing the transcripts of the interview, drawing on the field notes, and looking to secondary sources for additional insight. specific to comparing with the oli, the panel study design and this initial analysis, relies on the job classifications provided by upwork, grouped into three broader categories (see table for summary statistics): . administrative work to include: accounting, customer service, translation, editing. in the oli, this category roughly responds to the occupations 'writing and translation', 'professional services', and 'clerical and data entry'. . technology work to include: web, mobile and standard programming, engineering and architecture, data and analytics, it and networking. in the oli, this category roughly responds to the occupation 'software development and tech'. . creative work to include: design, graphics, sales and marketing, writing, and some oneoffs like crisis response public-relations. in the oli, this category roughly responds to the occupations 'creative and multimedia', 'writing and translation', and 'sales and marketing support'. data from the panel study provide substantial evidence in support of downscaling loss effects. the freelancers with whom we spoke report that there are fewer jobs being posted. freelancers who have long-standing clients tell us these clients are pausing current projects and not adding new projects. furthermore, freelancers indicate that there are many more people bidding for the jobs: sometimes six times more than even a month ago (e.g. + bids now, versus five bids). this seems to align very well with the data presented in figure . freelancers are also reporting that in response to the increased number of people seeking work online, they are having to bid on more jobs to keep securing work, and often are bidding for work below their target salary rates, and even below minimum wage rates. while each freelancer's situation is unique, work-seeking strategies in our initial analysis, seem to be externally focused. that is, while many have relied on existing relationships, their predictability of these relationships producing work are now more tenuous. in turn, freelancers indicated that they are diversifying and applying to different type of work, increasing the number of jobs they simultaneously are bidding for, bidding for lower paying contracts and lowering their hourly rates. from this initial analysis we see little evidence of distancing bonus effects in the united states across the platforms broadly, although we see initial evidence of distancing bonus effects at the occupation level. at first these changes were not affecting one broad category of work more than another. by april , those respondents in creative spaces (marketing, design, web content) noted work was slowing dramatically, while work supporting digital infrastructure (web services, backend web work) was steady or even increasing, corroborating with the data in figure . this suggests that clients are starting to look into the concerning future and prioritising basic operations over customer-facing efforts. beyond these insights on distancing bonus and downscaling loss effects, two additional observations from our interviews warrant mention. first, these us-based freelancers are reporting changes in their life worlds that are reshaping their labour strategies and working arrangements. nearly all of the respondents report spouses and partners being laid off or having to work from home, and that their children are now at home for schooling. these changes are requiring the freelancers to alter their own working arrangements and work availabilitywith most having less time to pursue work. the scope of these changes is increasing each week, and the changes are becoming more impactful as the economy continues to slow down. the current arrangements are no longer new, not yet normal, and uncertainty clouds things. these changes dampen the ability of workers to take on typical work loads, providing some opportunity for new entrants. finally, every one of the participants in the panel study is casting an increasingly worried eye on the longer term as the economic slowdown in the united states continues to press on most but the wealthy. panel data make clear that fewer than per cent of our respondents have health care: a profoundly disturbing finding given that many of their spouses and partners are losing jobs. panel data also make clear that fewer than per cent of our respondents had more than a few weeks of savings: seven weeks into massive social distancing and million people losing their jobs, these workers are exhausting these reserves, well before the economic crisis is over. taken together, the low number of freelancers with healthcare, and savings, showcases the precarity of the workspace and amplifies the implications of the changes to the online labour markets as demonstrated above. findings suggest the downscaling loss effect may be dominating over the distancing bonus effect. at the same time, the number of workers seeking income through online labour platforms is increasing. this, in turn, suggests freelancers earning their income through online labour platforms are more likely to see a tighter market and larger variations in their income in the face of a more uncertain online labour market. for the us-based freelancers with whom we spoke, their situation is further complicated by the structural and legal landscape they face. to wit, their employment classification (as independent contractors) restricts access to social policies that could serve as a social safety net (e.g. access to healthcare and unemployment benefits). the broad and chaotic response by the united states' federal government in the face of the economic crisis is more poignant for freelance workers as their status relative to what counts as work often means they are not able to access unemployment benefits and may not be eligible for the stimulus checks associated with the cares act. given the social and labour policies, significant market shocks, like the pandemic, make visible the risks associated with non-standard work arrangements in the united states. these risks may be one of the reasons why the oli figures for the united states vary so much more than do those of south korea and germany. while this analysis has focused on the united states, to fully understand the nuances and differences in the online labour market, future analysis exploring other countries is essential. furthermore, the data also only provide a freelancer perspective, so understanding changes and behaviors of clients (employers) and their impact (and how they're impacted) would provide an important perspective in the market dynamics discussed here. we see value in the further interrogation of the downscaling loss and distancing bonus effects from other analytic perspectives to include temporality, geography, and demography. the magnitude of downscaling and distancing are likely to change over time, as the pandemic and its consequences unfold. moreover the effects are likely to vary across geography, due to national differences in economic structures, the phase and severity of the pandemic, and countermeasures adopted. we also see distinct differences in demands for different occupations. considering the gendered and racial differences in occupations (e.g. women, for example, are overrepresented in the sales and creative occupations and minorities are overrepresented in service occupations, see https://conte xts.org/blog/inequ ality -durin g-the-coron aviru s-pande mic/#rea), we then may see certain groups disproportionately affected. as can be seen, one possible roadmap for near-term research related to the pandemic can be: (i) the examination in the differences driven by occupation; (ii) analysis of the differences in country-level trajectories; and (iii) further investigation of gender and racial disparities found in freelance work. these implications illustrate the questions that emerge from this early view into changes in the online labour markets for freelance work arising from the global pandemic. at a broader level, the covid- pandemic produces a unique window of opportunity to gauge the interdependencies between the online labour market and the regular economy. initially, the sharp decline in the online labour market closely mirrored the broader labour market. as the pandemic has continued, our analysis shows a rebound in the online labour market. this not only suggests that online labour markets can transcend its traditionally complementary role in the broader markets, but may play a key role in bridging gaps in the broader economy caused by sudden economic shocks. we speculate this is being manifested in at least three ways. first, firms are using more project-based work, which is more conducive to the use of freelancers. second, firms are increasingly becoming more accustomed to distributed and remote working arrangements, which is also more conducive to freelancers. while both of these are independent of the current pandemic, they are macro-level changes in employment relations that we see as catalysts to the increases in the demand for online freelancers. third, online platforms allow people to more easily seek freelance work, which blurs the boundaries between online and traditional labour markets. as a more efficient matching system for work, online labour markets help to alleviate the friction associated with job searches and allow workers to seek work beyond their local geography. all of these things allow online labour markets to normalise more quickly during periods of economic shock. as the evidence in our analysis suggests, the online labour market demand has recovered, and in some occupational areas has surpassed, relative to pre-pandemic levels. the raw data (used in figure ) are collected by periodically sampling workers from four major online labour platforms: fiverr, freelancer, guru, and peopleperhour what will be the economic impact of covid- in the us? rough estimates of disease senarios covid- : towards controlling of a pandemic competition in online job marketplaces: towards a global labour market for outsourcing services? global networks icts and the urban-rural divide: can online labour platforms bridge the gap? information, communication, & society, - conceptual issues in services offshoring research: a multidisciplinary review interest in remote working related search terms during covid- outbreak platform sourcing: how fortune firms are adopting online freelancing platforms supply and demand shocks in the covid- pandemic: an industry and occupation perspective digital work: new opportunities or lost wages? geographical discrimination in digital labour platforms. in: m digital economies at global margins online labour markets telework: towards the elusive office flexible firms and labour market segmentation: effects of workplace restructuring on jobs and workers online labour index: measuring the online gig economy for policy and research flexibility in the gig economy: managing time on three online piecework pplatforms. new technology, work and employment the global platform economy: a new offshoring institution enabling emerging-economy microproviders available at <https://assets.aspen insti tute. org/conte nt/uploa ds/ / /autom ation -and-a-chang ing-econo my_the-case-for-action the global macroeconomic impacts of covid- : seven scenarios defining telecommuting. transportation research record coronavirus cases have dropped sharply in south korea. what's the secret to its success a conceptual framework for the design of organisational control mechanisms platform workers in europe the corisk-index: a data-mining approach to identify industry-specific risk assessments related to covid- in real-time the benefits and costs of using social distancing to flatten the curve for covid- covid- : the gendered impacts of the outbreak networked but commodified: the (dis)embeddedness of digital labour in the gig economy we thank raghav raheja (syracuse university) and gabrielle vaccaro (skidmore college) for their central role in the qualitative data collection efforts. likewise, we would like to acknowledge dr. otto kässi for engineering most of the oli data collection infrastructure. about of do: acceptances and declinations are tracked. research guidelines require paying those who agree to this job even if they do not finish: this work is voluntary and they can cease working at any time. about in begin, but do not finish. all who begin are rated five stars (as performance ratings matter greatly for online workers). many of those who have completed the work leave a positive review of the work. there are no negative reviews. . for example, there are active sub-threads for experiences with platform work, generally, and upwork, specifically, to be found in the online platform reddit, as well as facebook groups devoted to both. . upwork changes its categorisation of workers from time to time, making classification a challenge. . cares act, see: https://www.congr ess.gov/ bill/ th-congr ess/senate-bill/ /text?q=produ ct+update. key: cord- -l zqci authors: holschbach, chelsea l.; peek, simon f. title: salmonella in dairy cattle date: - - journal: veterinary clinics of north america: food animal practice doi: . /j.cvfa. . . sha: doc_id: cord_uid: l zqci as an infectious, contagious pathogen, salmonella is probably rivaled by only bovine viral diarrhea virus in its ability to cause clinical disease, such as enteritis, septicemia, pneumonia, and reproductive losses. the increasing prevalence of salmonella, particularly salmonella dublin, on dairies presents new challenges to producers and veterinarians. no current discussion of bovine salmonellosis is complete without acknowledging the increasing public health concern. increasing antimicrobial resistance among enteric pathogens brings the use of antimicrobials by veterinarians and producers under ever stricter scrutiny. this article provides a comprehensive review of salmonella etiology, prevalence, pathogenesis, diagnostics, treatment, and control. facet to salmonellosis on many modern dairies. the ability to establish lifelong infection, characterized by an asymptomatic carrier status, with intermittent periods of bacteremia and intermittent shedding, challenges control of this serotype. enteric infection with other non-host-adapted serotypes, particularly in calves, can also be associated with true bacteremia, sepsis, and high mortality rates. no current discussion of bovine salmonellosis could be complete without acknowledging the increasing public health concern regarding its relevance as an important zoonosis, the risk that contaminated dairy and dairy beef products can pose to human health, and, just as important, the reality that increasing antimicrobial resistance among zoonotic enteric pathogens such as salmonella brings the use of antimicrobials by veterinarians and producers under ever stricter scrutiny. salmonella is a genus of gram-negative, facultative anaerobic bacteria that belong to the family of enterobacteriaceae. there are recognized species within the genus: s enterica and salmonella bongori. s enterica can be further divided into subspecies, s enterica subspecies enterica being the most relevant in dairy cattle. more than serovars (serotypes), differentiated by their antigenic composition, have been identified. serovars are based on the somatic (o), flagellar (h), and capsular (vi) antigens. most human and veterinary diagnostic laboratories have phenotypically divided salmonella isolates into serogroups based on detection of the o lipopolysaccharide and h flagellar antigens, historically by agglutination methods. , although these traditional serotyping techniques have formed the basis of human and veterinary diagnostic practice for salmonellosis for several decades, they are labor intensive and time consuming, typically taking at least hours. with the advent of more advanced molecular diagnostic methods, genetic approaches to serotyping are beginning to supercede traditional tests. in general, these methods use of types of targets for serotype determination, the first are indirect targets, which use random surrogate genomic markers known to be associated with certain serotypes, and the second method uses direct targets requiring the use of highly specific genetic determinants of a particular serotype. the latter typically involve the rfb gene cluster responsible for o somatic group antigen synthesis and the flic and flib genes encoding the flagellar antigens of salmonella. genomic sequencing is becoming increasingly common for the identification and serotyping of salmonella isolates. , the hope is that, with diminishing costs and continued refinement, more rapid, accurate genoserotyping will improve diagnostic and surveillance efforts for both public health and veterinary purposes. most commonly, clinical bovine isolates have been divided by their o antigens, and serovars are further grouped into serogroups assigned to an early letter of the alphabet (eg, a, b, c, d, and e). by current convention, salmonella isolates are referred to by their serovar/serogroup classification (eg, s enterica subspecies enterica serovar typhimurium, is abbreviated to salmonella typhimurium). despite the diversity of serovars, relatively few are of clinical importance among cattle. the majority of cattle isolates are salmonella of types b, c, and e, which are non-host specific, or salmonella dublin (type d), which is the host-adapted serovar in cattle. the isolation of salmonella from the feces of dairy cows or calves as well as the environment on dairy farms is increasingly common. as part of the united states department of agriculture's national animal health monitoring system (nahms) dairy holschbach & peek study, fecal samples were collected from approximately healthy cows on each of dairy operations across states. forty percent of the dairy operations had at least cow that was salmonella positive on fecal culture. of the roughly healthy cows sampled, % were fecal culture positive. compared with the dairy nahms study, the percentage of salmonella-positive operations had doubled and the percentage of positive cows had more than doubled. for the study, when environmental sampling was performed in conjunction with individual cow sampling, the number of dairies with a positive salmonella culture increased to nearly %. within the study, the most frequently isolated salmonella serotypes included salmonella cerro, salmonella kentucky, salmonella montevideo, and salmonella muenster. these serotypes fall within groups k, c , c , and e, respectively. in a comprehensive study of more than dairy herds in the northeastern united states in , fecal samples were collected from female dairy cattle for salmonella culture based on a suspicion of clinical disease. salmonella was found in % of the dairy herds monitored for approximately year over the course of the study. the herd-level incidence rate was approximately positive herds per herdyears; however, just % of the positive study herds accounted for more than % of the clinical salmonella cases. the predominate serotype identified was salmonella newport, accounting for % of the cases, followed by salmonella typhimurium, accounting for nearly % of cases. clustering of disease among herds was consistent with another us prevalence study that found that % of the enrolled dairy farms accounted for more than % of the salmonella-positive fecal and environmental samples. in this study, sampling of conventional and organic herds on occasions over a period of year resulted in detection at least salmonella-positive fecal sample on more than % of farms ( / ). serogroup e was the most commonly identified serogroup in fecal samples, although serogroup b was the most common isolate across farms, with % of fecal-positive farms having at least serogroup b isolate. data from a more recent study demonstrated that of the nearly salmonella isolates identified at the national veterinary services laboratory from clinical and nonclinical case submissions, the most common serotype was salmonella dublin ( %) followed by salmonella cerro ( %) and salmonella typhimurium ( %). a retrospective study of s enterica isolates submitted to the wisconsin veterinary diagnostic laboratory from to parallels the findings from the national veterinary services laboratory. of the nearly isolates identified, salmonella dublin was the most prevalent serotype identified, accounting for a total of isolates ( % of total). along with dublin, salmonella cerro ( %), newport ( %), montevideo ( %), kentucky ( %), and typhimurium ( %) comprised the top most commonly isolated sertotypes. the emergence of salmonella dublin as one of the most commonly isolated serotypes is of major concern for the dairy industry. as the host-adapted strain of salmonella in cattle, animals infected with salmonella dublin can become chronic, subclinical carriers that have the potential to shed large numbers of organisms into the environment. these carriers also play an important role in maintaining infection within a herd by shedding not only in feces, but also in milk and colostrum. salmonella infections are well-known for their association with clinical signs of enterocolitis, septicemia, and abortion in dairy cattle. pneumonia is an increasingly common manifestation of salmonella dublin infection in calves , and worth bearing in mind when dealing with mild, moderate, or severe respiratory disease on heifer rearing facilities. whether or not this merely represents hematogenous localization of the salmonella in dairy cattle organism to the lungs in much the same way that is seen with septic arthritis, for example, or a more specific organ tropism for the lungs by this serovar is uncertain. however, personal observations by one of the authors and many others suggest that this particular clinical manifestation of salmonella dublin infection is increasingly common during the late nursing and postweaning period. salmonella infection is most commonly transmitted by fecal-oral contamination from other livestock, rodents, birds, or by feeding contaminated protein source animal byproducts. given the increased frequency with which the organism can be isolated on dairy farms, from both symptomatic and asymptomatic cattle, it is reasonable to assume that fecal-oral spread from other cattle is the most common means of spread on modern dairies. older literature establishing that aerosol transmission was possible in closely confined, penned calves would also seem to be currently relevant with respect to the spread of certain salmonella serotypes, especially salmonella dublin, on endemic heifer rearing facilities. , in both calves and adults, those factors that determine pathogenicity and whether or not clinical disease is seen include virulence of the serotype, dose of inoculum, degree of immunity (passive or adaptive) or previous exposure of host to the serotype, and other stressors currently affecting the host. the organism will less frequently penetrate ocular or nasal mucous membranes. the most detailed studies of the pathogenesis of bovine salmonellosis infection come from the literature describing enteric infection via the oral route, mainly in calves. [ ] [ ] [ ] once ingested, salmonella attaches to mucosal cells and is capable of destroying enterocytes. attachment is increased if gastrointestinal stasis is present or the normal flora has been disturbed or is not yet established, as is the case in neonates. the organism penetrates through the enterocytes to the lamina propria of the distal small intestine and colon, where they stimulate an inflammatory response or are engulfed by macrophages and neutrophils. once salmonellae have gained entry to mononuclear phagocytes, they can be rapidly disseminated throughout the body. salmonellae have a predilection for lymphoid tissues, invading through m-cells, and are found in the highest numbers in the peyer patches and mesenteric lymph nodes. from here, the organism often enters the lymphatics and may eventually lead to bacteremia. , experimental studies have also shown that oral exposure can lead to infection and systemic dissemination via pharyngeal lymphoid tissue (tonsils) without the need for true enteric infection. salmonellae are capable of surviving and multiplying in numerous host tissues, often as facultative intracellular bacteria in macrophages and reticuloendothelial cells. these characteristics guard them against the hosts' normal defense mechanisms and potentially facilitate true bacteremia. the virulence mechanisms of salmonellae are, therefore, composed of their ability to invade the intestinal mucosa, locate to and multiply within the lymphoid tissues, and to evade host defense mechanisms. enterocolitis caused by salmonella spp. is due to inflammation with subsequent maldigestion and malabsorption, and to a lesser extent from secretory mechanisms. , inflammation in the colon leads to the commonly observed fresh blood in the feces of both adults and calves. the diarrhea caused by salmonella spp. is principally mediated by the host inflammatory reaction to the infection. to establish infection, enteropathogens such as salmonella must first be able to overcome those host factors that resist colonization of the gut, principle among these being a fairly dense gut microbiota, which secrete a variety of bacteriocins, antibiotics, and colicins that hinder enteropathogen growth. there is increasing evidence that many enteropathogens, including salmonellae, are not able to colonize the gut in the face of a normal microbiota and hence factors that negatively influence this key component of resistance are important in the predisposition to enteric disease. once salmonella density reaches a critical threshold (about colony-forming units per gram in the case of salmonella typhimurium in mice), then a sufficient number of organisms can invade the gut epithelium by first docking with and then invading the epithelial cells. at a molecular level, salmonella typhimurium does this by specific bacterial adhesins for attachment and then a secretion system that injects a cocktail of bacterial toxins (the type iii secretion system) that enables the bacterium to reach the lamina propria. damaged gut cells are expelled into the lumen, as part of the host defense system, giving rise to some of the clinical signs of salmonellosis and a profound inflammatory response is initiated via interleukin- within to hours after infection. there are molecular reasons that underscore the clinical observation that differences in pathogenicity between serotypes exist. some strains of salmonella dublin and salmonella typhimurium, for example, have a virulence plasmid (carrying the spv gene) that facilitates survival of the organism within phagocytes, partly perhaps explaining the increased association of these serotypes with clinical disease in calves and adults. the ease with which genes can be transferred between salmonella and other members of the enterobacteriaceae also provides a rational explanation for the transfer of antimicrobial resistance. precise and eloquent experimental data on the mechanisms by which salmonella infection can lead to reproductive loss and abortion are hard to find. clinically, abortions are most common when serotypes b, c, or d are involved and it makes intuitive sense that abortion in cattle infected with salmonella spp. could arise through several different mechanisms. septicemia could lead to seeding of the fetus and uterus, causing fetal infection and death. , the fact that diagnostic post mortem investigations of aborted fetuses can often recover the organism from fetal samples supports this possibility. endotoxemia leading to inflammatory mediator release might also cause luteolysis secondary to prostaglandin release. high fevers or hyperthermia could also play a role in prostaglandin release or cause abortion through more direct fetal injury. cows may abort at any stage of gestation, but expulsion of the fetus is most common at to months of gestation. , a definitive diagnosis of salmonella infection in the live animal involves detection of the organism, most commonly by aerobic culture. although a clinical history of febrile illness accompanied by hemorrhagic enteritis and anorexia may be suggestive in either calves or adults, there is a sufficient differential diagnosis list in both age groups that diagnostic sampling must be performed. when reproductive losses are encountered in pregnant cattle, unless there are concurrent cases of bloody diarrhea, the clinical signs are even less definitive for salmonellosis and the differential list even longer. for hemorrhagic enteritis in adults, the differential list principally includes winter dysentery and bovine viral diarrhea virus infection; in calves, depending on age, such a presentation merits consideration of several viral (rotavirus, coronavirus), protozoal (cryptosporidium, eimeria), and bacterial causes (escherichia coli, clostridium perfringens). however, one should not rely on the presence of blood in the stool; many cases of enteric salmonellosis present without this clinical finding. remarkable variation in clinical severity will occur based on serovar virulence, host immunologic status, and inoculating dose. in calves, death may occur owing to septicemia before diarrhea salmonella in dairy cattle becomes obvious or a significant clinical abnormality. in large free stall dairies, it is increasingly common to encounter salmonella infection as an endemic challenge with clinical presentations that are highly variable, ranging from the classic textbook description of reproductive losses and enteric disease in adult cattle through to lower impact problems with fevers of unknown origin, little to no diarrhea, and only modest consequences in terms of appetite and milk yield reduction. because salmonella organisms are easily and rapidly out competed by other fecal gram negatives, the majority of diagnostic laboratories use enrichment media such as tetrathionate or selenite broth to improve the chances of salmonella growth and then plate these enriched samples onto selective media such as brilliant green or xylose lysine deso-oxycholate agar. veterinarians working in the field are advised to contact their local diagnostic laboratory for assistance with sample handling, processing, and submission before investigating either individual or group problems with enteric disease suspicious for salmonella infection. it is frequently worthwhile to place samples directly into enrichment media before submission to improve the chances of positive culture and to keep samples chilled until they arrive at the diagnostic laboratory. disadvantages of fecal culture include the fact that shedding can be sporadic, even in true infections (certainly when one considers the sensitivity of bacterial culture) and that, in the face of an ongoing outbreak, one can occasionally encounter clinically normal calves and adults who shed the organism but never develop any clinical signs. the latter situation may still provide useful information, however, both from the perspective of deciding which animals merit treatment but also from the broader standpoint of identifying an enteric pathogen that should never be trivialized or considered a commensal. however, the general pattern is that subclinically or persistently infected cattle shed low numbers of organisms, whereas clinically ill or acutely infected animals may excrete higher numbers in feces. when the clinical suspicion of salmonella is high, a single negative culture is not sufficient to rule out infection. as mentioned, fecal samples should be submitted to qualified diagnostic laboratories that are equipped to culture enteric pathogens and with careful attention to sample handling. although culturing of individual cow fecal samples is the most common method used to assess individual and herd salmonella status, it can be expensive and time consuming, especially in larger herds. in a study comparing individual, pooled, and composite fecal samples, it was found that composite fecal sampling was more sensitive at the sample level than the other methods, primarily because of the increased number of cattle sampled indirectly through this method. hence, if one is merely trying to obtain a yes or no answer or identify and track specific serovars, or antimicrobial susceptibility patterns over time, composite fecal samples are typically collected from areas on dairy operations where manure accumulates from a majority of adult animals, such as holding pens, alleyways, and lagoons. newer techniques for diagnosing salmonella are based on detection of genetic material from the bacteria, that is, polymerase chain reaction (pcr) techniques. , these techniques are generally thought to be more sensitive than culture, but have the disadvantage that subsequent serotyping is not always possible. both species-specific (s enterica) and individual serotype pcr tests are available at some, but not all, veterinary diagnostic laboratories within the united states. there are main pcr methods: the traditional pcr and the real-time pcr. in the traditional pcr method, the test result is qualitative (yes or no). in real-time pcr, a threshold cycle (ct-value) gives a quantitative value of dna in the sample; the ct-value is inversely correlated with the starting concentration of the target dna; hence, the lower the ct number the more salmonella dna there will be in the sample. at the current point in time, only a few veterinary diagnostic laboratories offer both species-specific and serotype (usually salmonella dublin) assays for use with biological samples such as feces, milk, or tracheal and bronchoalveolar lavage fluid. the advantage is a quicker turnaround time and the potential for greater sensitivity, although parallel cultures are still necessary for in vitro antibiograms to be performed to aid treatment decisions (dr keith poulsen, wisconsin state veterinary diagnostic laboratory, personal communication, ). it is possible that, in the near future, pcr assays may become used for environmental samples although these can contain so many potential pcr inhibitors and out-competing organisms that sensitivity and specificity may be lost. the use of pcr methodology to investigate contamination of milk is also of increasing relevance, potentially for veterinarians, but also from the public health perspective. certain serovars, notoriously salmonella dublin, but also to include salmonella typhimurium and newport, can be found in the milk or colostrum of infected lactating animals. although conventional pasteurization should kill the organism, there is an understandable desire for food safety reasons to use highly sensitive methods to detect the organism after harvest. although fecal culture remains the gold standard at most laboratories, blood culture, a culture of transtracheal wash or bronchoalveolar lavage fluid, and joint fluid may all be useful choices for individuals experiencing bacteremic salmonellosis. the propensity for bacteremia in neonatal calves with salmonellosis makes aseptically obtained aerobic blood cultures a particularly useful diagnostic sample to consider in valuable animals. , culture of these nonfecal samples is far less likely to be diagnostically valuable in adults, although pcr methods on such samples may potentially improve sensitivity in the future. although gross post mortem findings of severe, diffuse, fibrinonecrotic ileotyphlocolitis with watery, often bloody content are highly suggestive, they are neither consistent enough or definitive for enteric salmonella infection in calves or adults. however, in both calves and adults, necropsy material can provide excellent diagnostic material for the definitive diagnosis of salmonella infection. in all age groups, it is advised to obtain numerous samples from the gastrointestinal tract (ileum, cecum, colon), mesenteric lymph node, and gall bladder (bile is a particularly useful sample), as well as lung tissue, especially when consideration of salmonella dublin is warranted, as increasingly is the case. because veterinarians are rarely only interested in the diagnosis of salmonella infection during a field necropsy, one may need to take multiple samples from such sites and handle the samples specifically as described to enhance the chances of a positive salmonella culture. culture remains the most common method used by most diagnostic laboratories to confirm salmonella infection in post mortem samples. samples from abortion cases that may have been caused by salmonella, should include fluid or tissue from both the dam and the fetus. most salmonella-associated abortions are in the last trimester so there will be a fetus to work with, preferably relatively fresh depending on the delay before the fetus is discovered. samples from the dam might include milk or colostrum, serum, and feces. feces and milk can be screened via culture or pcr, whereas the serum sample can be used for salmonella dublin serology (described elsewhere in this article). providing the fetus is not severely autolyzed, heart blood, abomasal contents, and intestinal or biliary samples might be useful but diagnostically veterinarians are all too commonly challenged by the "freshness" of an abortus. as is true of many enteritis investigations, with abortion cases veterinarians are typically attempting to submit samples that might reveal one of many possible infectious etiologies and it may be simpler to submit the entire fetus if this can be done in a timely manner. environmental sampling on dairy farms and heifer rearing facilities has largely been a research tool rather than a clinically applicable procedure. however, quite a lot of information has been learned regarding areas of large free stall facilities where positive salmonella cultures can often be repeatedly obtained either in herds with or without known clinical disease. , not surprisingly, areas of high traffic use and density and where sick cows and cows soon to calve are located are frequently discovered to yield positive cultures. just as was discussed under individual cow fecal sampling, veterinarians are advised to seek the input of the laboratory to which they are going to submit samples before obtaining on-farm environmental specimens. the use of buffered peptone water or more specific enrichment broths before submission may improve chances of salmonella being isolated from heavily contaminated samples. drag swabs, milk filters, and even absorbent socks worn over shoes, as have been used for environmental sampling in poultry houses, can be used. proof of current infection with salmonella dublin can be achieved via conventional culture with serotyping or pcr methodologies if available. , in addition, both in the united states and several countries in europe it is also currently possible to use an enzymelinked immunosorbent assay (elisa) to measure the level of antibodies directed against o-antigens from salmonella dublin in blood and milk. in this way, one can measure the humoral immune response as an indicator of current or previous infection. , some laboratories report the elisa result as a semiquantitative percentage value, giving an optical density reading referable to a standard set of controls. in addition, elisa tests can also be used for individual or bulk tank milk sample screening, and have come to be used quite extensively in countries such as denmark, where active surveillance programs for this serovar are in effect. , sensitivity for the serum elisa is considerably higher than fecal culture for the identification of salmonella dublin infected cattle, and as a diagnostic test the serum elisa is reported to perform best when used in animals between and months of age (box ). treatment fluid therapy is the mainstay of treatment for cattle with enteric salmonellosis. the type of fluid and route of administration is based on the severity of clinical signs box salmonella diagnostic testing options individual animal fecal culture using enrichment and selective media. composite fecal sampling. salmonella polymerase chain reaction (feces, milk, tracheal or bronchoalveolar lavage fluid). blood, transtracheal wash, bronchoalveolar lavage, or joint fluid culture when bacteremia is suspected in calves. culture of post mortem samples: gastrointestinal tract, mesenteric lymph node, bile, and lung. salmonella dublin enzyme-linked immunosorbent assay: serum or milk. and the economic value of the animal. in calves with acute, severe diarrhea showing signs of hypovolemic shock, intravenous fluid therapy using a balanced electrolyte solution, such as lactated ringers, is necessary. , in severely depressed or comatose animals, resuscitative fluids, such as hypertonic saline, are indicated. if administered, hypertonic saline, dosed at - ml/kg, should always be followed with isotonic crystalloids or water to replace the "borrowed" water from the intracellular space. dextrose supplementation can be a critical part of the intravenous fluid therapy plan for calves with salmonellosis, not only because of poor feed intake, but because of the increased risk of hypoglycemia that may accompany septicemia. calves that are ambulatory, have a suckle, and are only moderately dehydrated can often be managed with oral fluids. calves and even adult cattle can develop severe metabolic acidosis with peracute salmonella infections and intravenous bicarbonate-rich fluids should be considered when profound depression or shocklike signs accompany diarrhea. oral electrolyte solutions have proven to be helpful in correcting mild to moderate dehydration; however, depending on the degree of bowel inflammation, fluid absorption and digestion may be altered. fluid therapy for adult cattle in the field setting can prove to be more challenging owing to the sheer volume of fluid needed in cases of severe dehydration. hypertonic saline followed by at least gallons of oral electrolytes or water, either consumed voluntarily or given by orogastric tube, is a highly efficient method of fluid resuscitation in adult cattle. in valuable calves or adults, colloids (plasma or hetastarch) are often indicated as a result of hypoproteinemia secondary to albumin loss from the gastrointestinal tract. synthetic colloids, such as hetastarch, are a more reasonably priced option, but only augment colloidal pressure. plasma has the added benefit of immunoglobulins and acute phase proteins, which provide therapeutic benefits in septic or inflammatory conditions. antimicrobial therapy for the treatment of salmonellosis was, is, and probably always will be, controversial. of utmost concern is the potential for the creation of antibiotic-resistant strains of salmonella that may present a risk to humans or animals in the future. although antimicrobial therapy may aid in clinical recovery, it has also been criticized as failing to limit fecal shedding or to impart a positive effect on the duration of fecal shedding. in truth, this criticism is largely extrapolated from research in other species. in cattle, the effect of prior antibiotic use on fecal shedding may be age variable, with research identifying that the risk of fecal shedding after antibiotic treatment is greater for adults and heifers than in calves. however, the risk of true bacteremia in calves with enteric salmonellosis is substantial, justifying the use of antimicrobials in patients of this age. bacteremic spread of the organism can result in concurrent disease in multiple organs, such as pneumonia, arthritis, and meningitis. the presence of these clinical infections should always merit antimicrobial administration. the comparative risks for such systemic complications in adults are less than in calves, making the routine use of antimicrobials in mature animals less justifiable. if possible, antimicrobial selection should be based on culture and susceptibility of the salmonella isolate. the dilemma faced by practitioners is frequently that real-time decisions regarding antimicrobial use and selection have to be made in advance of any definitive microbiologic data. some guidelines regarding salmonella susceptibility can be provided, however. according to the nahms study, isolates were found to be most resistant to tetracycline, streptomycin, ampicillin, and ceftiofur, but were frequently sensitive to aminoglycosides, fluoroquinolones, and trimethoprim-sulfas. to the us readership, these lists will not provide much comfort because of restrictions on antimicrobial use under the current animal medicinal drug use clarification act. fluoroquinolones and certain sulfonamides may not be used extra-label in the united states. additionally, there is a voluntary ban on the use of aminoglycosides, such as gentamicin and amikacin, in food-producing animals because of long-term tissue residues. as of , the extra-label use of ceftiofur in regard to dose, route, and frequency of administration is also prohibited. owing to the facultative intracellular nature of the organism, it is also worth bearing in mind that antimicrobial penetration into the cell can be limited, even for antimicrobials that show in vitro efficacy. when chosen, antibiotic therapy should be continued for at least to days in cases of acute or peracute salmonellosis. appropriate withdrawal times should be observed for all antimicrobial usage and animal medicinal drug use clarification act guidelines followed at all times. for questions regarding extended withdrawal times and extralabel use of antimicrobials, us readers are advised to contact the food animal residue avoidance database. in addition to crystalloid fluid therapy, colloid administration when indicated by hypoproteinemia, and responsible, legal, and signalment appropriate selection of antibiotics, the third and final component of therapy for salmonellosis is antiinflammatory use. the inflammatory cascade triggered by local or systemic infection with salmonella is a critical component of the pathogenesis of this organism and culminates in many of the clinical signs observed. direct endotoxin-mediated effects alongside the host systemic inflammatory response are major components of many calf and adult salmonella infections that can be mitigated, at least in part, by the use of nonsteroidal antiinflammatory drugs. cattle may be dosed with flunixin meglumine at . mg/kg of body weight intravenously every hours and then tapered to . mg/ kg every hours, or the medication discontinued after the patient stabilizes. label use of flunixin meglumine includes dosages of up to . mg/kg in the united states. prolonged administration of nonsteroidal antiinflammatory drugs, particularly at the higher dose or in the face of dehydration, can lead to abomasal ulceration and renal papillary necrosis. , , in rare circumstances, some clinicians elect to administer "shock" doses of corticosteroids, but this measure would be uncommon in either general or referral practice. soluble prednisolone sodium succinate would be the preferred agent in such circumstances. from both the literature and personal experience, it seems that not only are herd epidemics becoming more common, but perhaps more worryingly the disease has become endemic on an increasing number of facilities. endemicity is obviously problematic with any serovar, but is inevitable when the herd prevalence of salmonella dublin infection increases. frequently, the disease becomes a cyclical problem responsible for a spectrum of illness that varies from the more classic presentations described through to milder illness perhaps characterized by fever, looser than normal stool, and mild production loss. depending on the interaction of general cow health, other concurrent stressors, climatologic stress, and the level of fecal-oral challenge at any one time, adult cows may or may not become clinically ill. transition cow management becomes an important factor in whether or not new infections are acquired and subsequently result in clinical illness in the late dry and early lactation period, a time when cattle may be at their most susceptible to infectious disease. as with any fecally-orally spread organism, control strategies are broadly speaking simple to describe, but not necessarily so easy to put into place for many dairies. larger herd size, crowded husbandry, and free stall housing all contribute to an increased propensity for exposure to contaminated manure, and although purchased feedstuffs are still occasionally incriminated as a means by which new salmonella infections are introduced onto farms, as are rodent and bird populations, the major source of infection are other cattle shedding the organism in their feces. the high likelihood of feces being contaminated with salmonella organisms on many diaries should mitigate against the spreading of manure on fields that are to be used for forages, or common use equipment for manure handling and feed distribution. evidence suggests that heating of manure to greater than c for more than days, alongside aeration of composted manure using straw, markedly and significantly reduces the number of salmonella organisms, although it is uncertain how practical this information is to larger dairies with modern large-volume manure handling systems. peculiarly, and perhaps rather worryingly, study looking at risk factors for increased antimicrobial resistance among salmonella isolates on dairy farms identified the use of composted manure for bedding as a significant problem. the most directly applicable research regarding modern manure handling systems and survival of salmonella organisms under natural rather than laboratory conditions demonstrated that a multiple-drug-resistant strain of salmonella newport survived for less than hours in a compost pile at c, but would survive for more than months and more than months in an effluent lagoon and field soil, respectively. once salmonellosis has been confirmed in adult cattle, there are a number of further investigative and control measures that may be implemented. these measures do not differ according to serotype, but there are some specific challenges concerning the host adapted serovar salmonella dublin that will be discussed in a later section. it is prudent to consider the possible source(s) of the infection. although commodities, especially protein feed sources, and wild bird and rodent populations have been incriminated in many texts over the years, it seems quite uncommon these days for a single point source event to have introduced the infection onto a dairy de novo. environmental sampling of feed, water, and storage facilities can be helpful in identifying contamination in this regard, but if, as is commonly the case on larger dairies, management continues to purchase replacement animals or expand from other herds, it seems inevitable from prevalence data that the infection will be introduced via infected cattle and their feces. in all probability, many "new" outbreaks are likely surges in clinical disease and new infections in a herd where the infection already existed but hitherto had remained subclinical. factors in transition cow management that reduce immunologic competence or increase exposure risk, are likely to contribute to the onset of clinical disease in such circumstances. the isolation of affected animals and strict attention to hygiene are pieces of advice routinely given but difficult to implement on large dairies. the numbers of affected animals can be overwhelming and lactating cows have to be milked at least twice a day, requiring them to walk and congregate in frequently trafficked areas and holding pens for the parlor into which they release enormous numbers of organism whenever they defecate. avoidance of common use equipment for manure handling and feed distribution have already been mentioned, but should be in place on well-managed dairies anyway. sick, transition, and maternity animals should never be housed together, but unfortunately are for convenience on many occasions; this condition merely ensures exposure of the most susceptible animals to those most likely to be contagious. cleaning and disinfection of the environment are also important, but again somewhat intimidating in the context of a larger dairy. proper cleaning and disinfection of the environment and equipment after a salmonella outbreak can, however, be critically important in decreasing the risk of disease transmission to both cattle and humans. cleaning is defined as the removal of all visible debris and is arguably the most important step in decontamination of animal environments. even the best disinfectants will be minimally effective when used in the presence of organic matter, such as feces and bedding material. not only does cleaning remove the physical barrier between disinfectants and the organism, but it also removes a majority of the organisms so that fewer need to be killed by the disinfectants. this is especially helpful with fecally-orally spread infections like salmonella. where the infectious dose is relatively high (often in the order of - organisms , ). livestock trailers, maternity and calf pens, feeding equipment, and other areas suspect of being contaminated with salmonella should be the main focus for cleaning and disinfection. although high-power washing can be quite helpful in removing organic debris, its use is not recommended because of the risk of cross-contamination of the environment, and splashing and aerosolization of contaminated material, which can lead to human and animal infection. , power washing also fails to remove biofilm, which is an essential and vital component to proper cleaning. in place of power washing, hand-held foamers can be used to apply alkaline detergent and acid rinses for cleaning. the wisconsin veterinary diagnostic laboratory has formulated a cleaning and disinfecting protocol specifically for premises with confirmed salmonella, which can be found at www.wvdl.wisc.edu. a recent paper examining disinfection efficacy against several common bacterial pathogens in a large animal hospital environment showed an approximately % reduction in colony-forming units per milliliter of s enterica when either an accelerated hydrogen peroxide or peroxy monosulfate disinfectant product was used via a mist application technique, provided adequate cleaning was performed first. as with antimicrobial drugs, disinfectants have a spectrum of activity that can be highly variable between disinfectant classes. examples of disinfectants commonly used in veterinary medicine include bleach (sodium hypochlorite), quaternary ammonium, phenols, and peroxides. bleach is rapidly inactivated by organic debris, but has a broad spectrum of activity. quaternary ammonium has moderate activity in organic debris and is effective against gram-negative bacteria, such as salmonella. the principle advantage of phenols is better activity in organic debris. peroxides are increasingly used for environmental disinfection, footbaths, and environmental misting and fogging, , and are perceived as being more environmentally friendly than chemicals such as phenols and bleach. chlorine dioxide is a powerful oxidant as well as disinfectant, and it can be used to remove and prevent biofilm formation. its use in the dairy industry is becoming more common. current recommendations from the wisconsin state veterinary diagnostic laboratory are for its use in solution at ppm. although rarely done on farm, the effectiveness of environmental cleaning and subsequent disinfection for salmonella control can be assessed by postdisinfection sampling. ongoing efforts at animal isolation and environmental hygiene will be important because shedding of salmonella will continue for many weeks after the initial cases have seemingly resolved. with respect to control, shedding continues periodically for the life of the animal in the case of salmonella dublin. once salmonella has been identified on a farm, veterinarians and management should increase awareness of the public health risk among workers and revisit personal hygiene, protective clothing, and appropriate disinfectant footbath use for employees. if time and labor resources are limited, then concentrating cleaning and disinfection efforts toward highrisk groups (transition cows, maternity pen) and high use traffic areas may be a reasonable compromise. inevitably, the identification of salmonella infection in adult cows or calves will lead to a conversation about vaccine use as a preventative strategy. many farms have at one time or another tried a commercially available or autogenous salmonella vaccine as an adjunct component of control. the safety and efficacy of autogenous products are questioned by many academicians, but individual experiences are sometimes compelling, at least in the short term in the face of an outbreak. as with other infectious contagious diseases such as infectious bovine keratoconjunctivitis, when any vaccine product is used during an outbreak it is impossible to know whether improvement was associated with vaccine use or natural immunologic exposure and protective antibody responses. the most commonly used product in the united states currently for the control of salmonellosis in adults is a siderophore receptor/porin vaccine derived from salmonella newport (salmonella newport bacterial extract, zoetis animal health, parsippany, nj). it is administered to dry cows as an initial injection series and boostered annually. it can, however, be given at any stage of lactation or to heifers. it will not prevent infection, but has been associated with an amelioration in disease severity. it does result in demonstrable antibody levels in colostrum when administered twice during the dry period, although the protective effect of these antibodies against challenge postnatally in calves at this time is unknown. the efficacy of other gram-negative core vaccines to prevent or decrease salmonella disease, such as the j product (enviracor, zoetis animal health) or endovac-bovi (immvac, columbia, mo), which are specifically marketed for protection against coliform mastitis, is highly debatable. the maintenance of good general health, excellent hygiene, and particular attention to the well-being of late gestation and early lactation animals are all critical components of salmonella control. a closed herd is ideal, but rarely achieved, making exposure to the organism inevitable on most dairies. prompt diagnosis, treatment, and isolation are important during an outbreak in adult cattle and environmental sampling to include bulk tank milk and high-risk housing areas should now be considered a routine part of disease prevention and surveillance. many of the important components of adult cow control programs mentioned in the previous section overlap with specific measures recommended for calves. an article in a previous volume of this journal provided an excellent review of control measures specific to calves. as in adult herds, endemic disease is increasingly common among calves. commercial heifer rearing facilities that manage preweaned calves from as young as a few hours of age onward, sourced and transported from multiple farms of origin, create a high-risk environment for the acquisition and spread of neonatal salmonellosis. adequate passive transfer, although imperative for rearing healthy calves, is not an absolute guarantee for protection from salmonella infection. fecal-oral transmission is a prime means of spread for enteric and septicemic salmonella infection in calves, but one must be mindful of the risk posed by other secretions such as colostrum, unpasteurized milk, and respiratory secretions, especially in the case of salmonella dublin. hygiene, isolation, and treatment principles for calves, calf housing, and personnel working with calves are very similar to those discussed in the adult section. special consideration should be given to fecal contamination of milk, milk replacer, colostrum, feeding equipment, and starter rations as a means of cross-infection. periodic environmental sampling of equipment such as nipple feeders, buckets, and housing can be valuable tools to trouble shoot outbreaks and improve quality control and prevention efforts. milk and colostrum are effective enrichment media for salmonella, so sampling these sources should be done "as fed" rather than as initially mixed or prepared. the increased availability of colostrum pasteurizers has added a very helpful tool to control not only salmonella dublin, but also other serotypes that can also be found in colostrum. maternity area hygiene and management are extremely important salmonella in dairy cattle in the control of neonatal salmonellosis. decreasing the postpartum exposure to the dam reduces the chances of immediate infection. a rather alarming recent publication has identified that true vertical transmission in newborn calves is documented with several serovars common to cattle in the united states. if further studies confirm this finding, it would add yet another serious challenge to the control of salmonellosis in calves. because exposure of calves to salmonella is very likely in the commercial dairy environment, management efforts should be directed toward limiting dose and maximizing health and disease resistance in the young replacement animal population. there are no revelations within this advice, but just as occurs with adult cattle, the degree to which farms are able to dedicate personnel and time may only be prioritized in the midst of, or immediately after, an outbreak of clinical disease. prompt diagnosis, separation, and treatment are important, but group housing of calves can quickly create a "perfect storm" for contagious disease spread. as with adults, vaccination and immunization with modified live or killed (autogenous or commercially available) products is often part of the control and prevention measures instituted. there is very little evidence to support effective control of salmonella infection in calves via passive transfer from immunized dams with any type of vaccine although the siderophore/porin product mentioned in the previous section in adults will stimulate colostral antibody. salmonella is predominantly cleared by cellular immune responses and humoral antibody alone may not provide satisfactory protection. vaccine use in calves is best considered when management efforts at control and prevention have already been put in place, or if these have been implemented but found to make little difference in the pattern or severity of disease. autogenous products derived from a specific serovar isolated from clinical cases must be used very carefully owing to the risk of anaphylactic reactions, and only from reputable biologic manufacturers. similarly, caution is advised regarding modified live vaccine use in calves owing to the potential for adverse reactions. killed vaccines have performed inconsistently in the small number of trials carried out in the past in calves. , comments regarding salmonella dublin control the increasing prevalence of salmonella dublin infection in the us dairy industry , and its unique status as the host adapted serovar of s enterica subspecies enterica in cattle merit some more specific attention. for readers who wish more, and a greater in-depth discussion of this serovar, we refer you to the excellent primary sources and review paper authored by dr liza nielsen from denmark who, together with her international collaborators, has published a great deal of excellent work, particularly as it applies to disease impact as well as control and surveillance strategies. , , , , [ ] [ ] [ ] within the european community, especially within the scandinavian countries, there are currently several active surveillance and certification programs that are designed to control, and potentially eradicate salmonella dublin infection in cattle herds. it is doubtful whether the immediate future holds much promise for such coordinated efforts within the us dairy industry, but there are undoubtedly useful lessons to be learned from experiences in other countries. all of the control measures described in this article for adults and calves can be applied to salmonella dublin infection, just as they can to other serovars. however, the serologic response to salmonella dublin, and the ability to measure that as a potential surrogate marker of the carrier status, opens up possibilities for identification and control. currently within the united states, the serologic test for salmonella dublin is available commercially through the animal health diagnostic center at cornell university and can be applied to either blood (serum) or bulk tank milk samples. it is important to recognize that a single time point positive test result does not confirm the carrier status, but indicates an antibody response owing to previous exposure, current infection, or passively derived antibody in a calf less than months of age. repeated individual animal sampling at specified intervals can be used during surveillance programs to identify animals that are likely to be carriers based on the persistence of an elisa positive result with a high optical density reading. , , using the data generated by nielsen as a guide, the animal health diagnostic center at cornell university categorizes a carrier as any animal that has strong positive serum elisa results over an -month period (dr belinda thompson, personal communication). from the currently available literature it does not seem to be possible to predict or estimate what percentage of infected calves or adults will go on to become true carriers, although the number is probably quite low. in herds classified as being endemic for salmonella dublin in denmark, the seroprevalence is highly variable but may only be at % of the whole herd, with a higher proportion of infection in young stock compared with adults. reinfection of previously infected and seemingly recovered animals also seems to be possible when individuals are followed over long periods of time. some of these subsequent infections may also result in the development of carrier status (dr belinda thompson, personal communication). bulk tank samples can be used for periodic milking herd surveillance, or, if applied to selected milking groups, to identify whether salmonella dublin has been introduced into a herd or is present in a particular population of cattle within the herd. from epidemiologic data, it seems that the risk of becoming a carrier after infection is greater for calves and for adults infected around the time of calving. another study shows that salmonella dublin infection in endemic herds can be reduced when an individual employee was dedicated to colostrum administration to newborn calves and calving cows were moved into a specific maternity pen before calving. a number of epidemiologic investigations in endemic salmonella dublin herds in scandinavia have identified risk factors and important control points for eradication of infection. , [ ] [ ] [ ] [ ] many of the risk factors and management tools demonstrated to improve control of salmonella dublin infection are intuitively sensible and relevant to other salmonella serovars. improving the likelihood of control is associated with avoiding cattle purchases from other farms and ensuring good calving area management and individual calf-rearing practices with solid, not permeable, barriers between calves. aggressive culling programs are not practical in situations where prevalence is high and may only become reasonable once new calf infections are serologically proven to decline to very low, or absent, levels. , it may be difficult for some producers and heifer rearers to instigate all of the management changes and practices that have been successful in european countries, but readers are directed to information available through the animal health diagnostic center at cornell university website for very helpful guidelines concerning control of salmonella dublin. in the united states, there is a commercial live salmonella dublin vaccine (entervene d, boehringer ingelheim vetmedica, st. joseph, mo) that is being used as a component of salmonella dublin control on many farms. the product is administered parenterally to newborn calves to stimulate an immune response before initial exposure to the pathogen. the goal is to prevent the serious health consequences of natural infection as well as the development of the carrier status in what is the most susceptible population of animals within endemic herds. however, when given according to label instructions the product will interfere with serologic testing, giving a false-positive result at up to months of life. furthermore, the product can be associated with fatal anaphylactic reactions in some recipient calves. these reactions seem to be more common in endemic herds than in naïve ones. this product can stimulate colostral antibody production when given to dry cows and was not associated with any adverse reactions when given to late pregnant animals. the vaccinated cohort in this study were from a farm with no clinical history of salmonellosis in recent years. whether this colostral antibody might provide protection against neonatal infection is currently unknown. herd biosecurity? maintain a closed herd. if purchasing cattle, ensure a negative serologic test from individual animals or a negative bulk tank milk test from the herd of origin within the last months. maintain separate maternity and sick cow pens. have separate equipment for feed and manure handling. dedicate personnel to solely work with high-risk or sick cattle versus neonates. salmonellosis not only can cause severe disease in cattle, but also poses a significant zoonotic risk. farm workers, calf handlers, and their families are clearly at risk of becoming infected by salmonella spp. during outbreaks of clinical illness, but the risk of exposure goes far beyond farm workers or veterinarians with direct animal contact during outbreaks of disease. asymptomatic shedding of salmonella, a characteristic of salmonella dublin infection, but also an issue with many other common bovine serovars such as newport and typhimurium, creates risk for people in direct contact with the animal, its feces, or milk. , , however, the majority of human salmonellosis cases do not derive from direct animal contact, but are instead acquired through foodborne exposure. so-called nontyphoidal salmonellosis is one of the leading causes of acute bacterial gastroenteritis in humans in the united states, responsible for an estimated . million cases of illness annually. the predominant risk for zoonotic salmonellosis from cattle lies in exposure to contaminated meat from beef, which would include dairy beef and cull dairy cows, typically via fecal contamination of the carcass at the time of slaughter. [ ] [ ] [ ] although salmonella mastitis is extremely uncommon, shedding of the organism in milk is not, and its presence has been documented in bulk tank milk in several studies. - a positive bulk tank or milk filter sample may represent fecal contamination, true lactational shedding, or a combination of both. conventional pasteurization should kill the organism, provided effective temperature and duration are reached. it is important to consider the diagnostic procedure performed to identify the salmonella in bulk tank or milk filter samples when interpreting these studies. studies using pcr , , rather than culture will detect a greater prevalence of salmonella-contaminated samples because of genomic material from both live and dead organisms in the sample. side-by-side comparisons of conventional culture and pcr using the same samples have been performed and show that approximately one-quarter ( . % vs . %) of those bulk tank samples that are pcr positive for s enterica will be positive by culture. true "dairy" products actually account for only a small percentage of human salmonellosis in the united states, and many of these outbreaks are due to the consumption of raw milk and raw milk products. , bacterial antimicrobial resistance represents an important current and future problem in infectious disease public health. concerns regarding zoonotic salmonella infections have been amplified in recent years by the emergence of multiple drug-resistant strains of several s enterica serovars associated with cattle. [ ] [ ] [ ] [ ] it is generally accepted that antimicrobial-resistant bacteria are produced, maintained, and disseminated as a result of selection pressure introduced by the use of antimicrobial drugs. suspected principal foci of selection pressure include use of antimicrobials for the treatment of humans and in food-producing animals for treatment or prevention of disease and growth promotion. , modern molecular methods combined with other conventional techniques such as pulse field gel electrophoresis can be used to investigate the origins of foodborne human enteric disease and the role of antimicrobial use in cattle with the occurrence of multiple drug-resistant salmonella infection in humans. at this point in time, there are few published studies establishing such links from "farm to fork." a recent extensive systematic literature review of publications on the effect of antimicrobial use in agricultural animals on drug-resistant foodborne salmonellosis in humans from to concluded that, although antibiotic use in cattle increased the likelihood of colonization in the host, there were no studies that traced antimicrobial-resistant salmonella in humans back to the farm. the antimicrobials of choice for treating bacterial gastroenteritis in humans are generally the fluoroquinolone, ciprofloxacin, for adults and the cephalosporin, ceftriaxone, for children. , at issue today is whether the veterinary analogs of these drugs may be responsible for the emergence of antimicrobial resistance in foodborne pathogens like salmonella. the mechanism by which s enterica typically acquires antimicrobial resistance to fluoroquinolones differs quite markedly and, importantly, from that by which resistance to cephalosporins develops. specifically, fluoroquinolone resistance is usually acquired through clonal dissemination of salmonella isolates with mutations in chromosomally encoded resistance genes. cephalosporin resistance usually is obtained via independent acquisition of mobile genetic elements via plasmids and transposons. further work is needed in this area to determine whether there is a connection between veterinary use of ceftiofur and the emergence of ceftriaxone resistance in salmonella spp. although ceftriaxone-resistant salmonella typhimurium has been documented in cattle, other larger studies have demonstrated little to no resistance to this particular third-generation cephalosporin in cattle sourced serovars despite more common resistance to other cephalosporins. , although it is now years old, interested readers are directed to the excellent review of antimicrobial resistant salmonella in dairy cattle by alexander and colleagues. in a more recent publication, a significant decrease was observed in antimicrobial resistance among dairy cattle salmonella isolates in the northeastern united states. many practitioners and diagnostic laboratories will be very familiar with the wide variety of antimicrobial sensitivity patterns demonstrated by different s enterica serovars obtained from individual animal and environmental samples. certain serovars seem to be more commonly associated with greater in vitro resistance than others. the paper by cummings and colleagues demonstrated a decrease in resistance trends between and . it was postulated that this might have been related to an increase in the prevalence of the serovar cerro in fecal samples from their study population. the biggest concern arises with serovars that have historically been more common in dairy cattle and that are associated with human disease outbreaks, such as newport and typhimurium. in particular, several human foodborne outbreaks caused by salmonella typhimurium dt of dairy or beef origin that are characteristically resistant to the antibiotics ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline have been reported. , an interesting and rigorously investigated example of zoonotic multiple drug resistant salmonella from cattle is provided by the wisconsin experience with salmonella heidelberg over the last years. since , the wisconsin state veterinary diagnostic laboratory (wvdl), in conjunction with human and veterinary health organizations throughout wisconsin, have been tracking a multidrug-resistant strain of salmonella heidelberg, a group b serovar (dr keith poulsen, wvdl personal communication). as of november , there were confirmed human infections from different wisconsin counties. upon questioning, more than % of the infected individuals reported purchasing holstein bull calves from livestock dealers or sale barns. during and , the wvdl also isolated several multidrug-resistant salmonella heidelberg isolates from calves located mostly in wisconsin. pulse-field gel electrophoresis and whole genome sequencing of isolates indicated that the human and bovine isolates were very closely related. this strain of salmonella heidelberg is highly pathogenic and multidrug resistant. only antimicrobial drug is an effective treatment option for human cases and no effective, legal (united states) options exist for cattle (dr keith poulsen, wvdl, personal communication). as the application of modern molecular techniques becomes more commonplace, it is probable that diagnostic and surveillance efforts will place food animal species and production methods under greater scrutiny with respect to zoonotic enteric diseases. increased awareness, rigor, and possibly limitations regarding antimicrobial use in food animals should not be surprising outcomes. large animal internal medicine escherichia, shigella, and salmonella methodologies for salmonella enterica subsp. enterica subtyping, gold standards and new methodologies the validation and implications of using whole genome sequencing as a replacement for traditional serotyping for a national salmonella reference laboratory salmonella serotype determination utilizing high throughput genome sequencing data biosynthesis of o-antigens: genes and pathways involved in nucleotide sugar precursor synthesis and o-antigen assembly sequence invariance of the antigen-coding central region of the phase i flagellar filament (flic) gene among strains of salmonella typhimurium the salmonella in silico typing resource (sistr): an open web-accessible tool for rapidly typing and subtyping draft salmonella genome assemblies infectious diseases of the gastrointestinal tract united states department of agriculture (usda). salmonella, listeria and campylobacter on us dairy operations united states department of agriculture (usda). e.coli o :h and salmonella status on dairy farms. fort collins (co): usda-aphis-vs-ceah the incidence of salmonellosis among dairy herds in the northeastern united states prevalence of salmonella spp on conventional and organic dairy farms salmonella serotypes isolated from animals in the united states antimicrobial resistance patterns of bovine salmonella enterica isolates submitted to the wisconsin veterinary diagnostic laboratory: - histopathology case definition of naturally acquired salmonella enterica serovar dublin infection in young holstein cattle in the northeastern united states review of pathogenesis and diagnostic methods of immediate relevance for epidemiology and control of salmonella dublin in cattle transmission of salmonellae among calves penned individually aerosol infection of calves and mice with salmonella typhimurium salmonella in calves cross protective immunity conferred by a dna adenine methylase deficient salmonella eneterica serovar typhimurium vaccine in calves challenged with salmonella serovar newport contribution of salmonella typhimurium virulence factors to diarrheal disease in calves salmonella infections in cattle salmonellosis in calves -the effect of dose rate and other factors on the transmission salmonella typhimurium diarrhea reveals basic principles of enteropathogen infection and disease-promoted dna exchange the roles of inflammation, nutrient availability and the commensal microbiota in enteric pathogen infection an nk cell perforin response elicited via il- controls mucosal inflammation kinetics during salmonella gut infection methods for the cultural isolation of salmonella comparison of individual, pooled, and composite fecal sampling methods for detection of salmonella on u.s. dairy operations development and evaluation of a real time multiplex polymerase chain reaction procedure to clinically type prevalent salmonella enterica serovars validation of a h real time pcr method for screening of salmonella in poultry fecal samples real time pcr method for detection of salmonella spp. in environmental samples recombinant plasmid based quantitative real time pcr analysis of salmonella enterica serotypes and its application to milk samples isolation of salmonella spp. from the environment of dairies without any clinical history of salmonellosis cattle and environmental sample level factors associated with the presence of salmonella in a multi-state study of conventional and organic dairy farms age stratified validation of an indirect salmonella dublin serum elisa for individual diagnosis in cattle humoral antibody responses to experimental and spontaneous salmonella infections in cattle measured by elisa factors associated with variation in bulk tank milk salmonella dublin elisa odc% in dairy herds simulation model estimates of test accuracy and predictive values for the danish salmonella surveillance program in dairy herds disease management of dairy calves and heifers effect of previous antimicrobial treatment on fecal shedding of salmonella enterica subsp. enterica serogroup b in new york dairy herds with recent salmonellosis pathogen reduction in minimally managed composting of bovine manure survival characteristics of salmonella enterica serovar newport in the dairy farm environment farm level associations with the shedding of salmonella and antimicrobial resistant salmonella in us dairy cattle salmonella transmission through splash exposure during a bovine necropsy comparison of disinfectant efficacy when using high-volume directed mist application of accelerated hydrogen peroxide and peroxymonosulfate disinfectants in a large animal hospital passive immunity stimulated by vaccination of dry cows with a salmonella bacterial extract evidence supporting vertical transmission of salmonella in dairy cattle salmonella typhimurium infection in calves: protection and survival of virulent challenge bacteria after immunization with live or inactivated vaccines immunization of calves against salmonellosis effect of prevention of salmonella dublin exposure of calves during a one-year control programme in danish dairy herds dynamic changes in antibody levels as an early warning of salmonella dublin in bovine dairy herds gross margin losses due to salmonella dublin infection in danish dairy cattle herds estimated by simulation modelling salmonella dublin infection in dairy cattle: risk factors for becoming a carrier a questionnaire study of associations between potential risk factors and salmonella status in swedish dairy herds culling decisions of dairy farmers during a -year salmonella control study salmonella dublin infection in young dairy calves: transmission parameters estimated from field data and an sir model nyschap recommendations for the control of salmonella dublin in dairy calf and heifer raising operations characterization of the serologic response induced by vaccination of late gestation cows with a salmonella dublin vaccine the effect of clinical outbreaks of salmonellosis on the prevalence of fecal shedding among dairy cattle in new york human multi-drug resistant salmonella newport infections food related illness and death in the united states animal sources of salmonellosis in humans outbreak of multi-drug-resistant salmonella enterica serotype typhimurium definitive phage type infection linked to commercial ground beef, northeastern united states highly resistant salmonella newport-mdrampc transmitted through the domestic us food supply: a foodnet case -control study of sporadic salmonella newport infections antimicrobial resistance of salmonella enterica isolates from bulk tank milk and milk filters in the united states prevalence of salmonella enterica, listeria monocytogenes and escherichia coli virulence factors in bulk tank milk and in line filters from us dairies prevalence of salmonella enterica in bulk tank milk from us dairies as determined by polymerase chain reaction factors associated with salmonella presence in environmental samples and bulk tank milk from us dairies a survey of foodborne pathogens in bulk tank milk and raw milk consumption among farm families in pennsylvania antimicrobial resistance trends among salmonella isolates obtained from dairy cattle in the northeastern united states prevalence of antimicrobial resistance among salmonella on midwest and northeast dairy farms ceftriaxone-resistant salmonella infection acquired by a child from cattle antimicrobial resistance and serotype prevalence of salmonella isolated from dairy cattle in the southwestern united states antimicrobial resistance of commensal escherichia coli from dairy cattle associated with recent multiresistant salmonellosis outbreaks effects of antimicrobial use in agricultural animals on drug resistant foodborne salmonellosis in humans. a systematic literature review nontyphoidal salmonellosis ceftiofur resistant salmonella strains isolated from dairy farms represent multiple widely distributed subtypes that evolved by independent horizontal gene transfer antimicrobial resistant salmonella in dairy cattle in the united states analysis of antimicrobial resistance genes detected in multi-drug resistant salmonella enterica serovar typhimurium isolated from food animals key: cord- - a jxl authors: cohn, amanda c.; broder, karen r.; pickering, larry k. title: immunizations in the united states: a rite of passage date: - - journal: pediatr clin north am doi: . /j.pcl. . . sha: doc_id: cord_uid: a jxl today, vaccination is a cornerstone of pediatric preventive health care and a rite of passage for nearly all of the approximately , infants born daily in the united states. this article reviews the us immunization program with an emphasis on its role in ensuring that vaccines are effective, safe, and available and highlights several new vaccines and recommendations that will affect the health of children and adolescents and the practice of pediatric medicine in future decades. we must plan for the future, because people who stay in the present will remain in the past. -abraham lincoln in , when jenner showed successful inoculation of humans with cowpox to protect them from the devastation of smallpox, a revolution in science and medicine began [ ] . more than centuries later, immunizations were hailed as one of ''ten great public health achievements'' of the twentieth century [ , ] . today, vaccination is a cornerstone of pediatric preventive health care and a rite of passage for nearly all of the approximately , infants born daily in the united states. immunizations have had a profound impact on the health of children, adolescents, and adults in the united states (table ). the most extraordinary success of immunizations was the worldwide eradication of smallpox. declared in , smallpox eradication was achieved through an unprecedented collaborative international initiative, led by the world health organization, establishing an example for other vaccine-preventable diseases [ ] . vaccination since has led to elimination of wild-type poliomyelitis and indigenous measles in the united states, both major causes of pediatric morbidity and mortality in the prevaccine era [ , ] . an integral part of achieving these successes was establishment of a federal immunization infrastructure, which followed the introduction of polio vaccination in the s [ ] . immunization programs, legislation, and funding mecha- nisms are now in place to ensure that immunizations are accessible to all children. as a result, coverage levels for most routinely recommended childhood vaccines in the united states are approaching or have surpassed the us department of health and human services healthy people goal of % coverage [ ] . immunizations have changed the scope of pediatric practice in the united states. pediatric residents now infrequently encounter varicella, which in the s was commonplace. likewise, although haemophilus influenzae type b (hib) was the leading cause of meningitis in young children before availability of hib vaccines in , most newly trained pediatricians will never see a case of invasive hib [ ] . this article reviews the us immunization program with an emphasis on its role in ensuring that vaccines are effective, safe, and available and highlights several new vaccines and recommendations that will affect the health of children and adolescents and the practice of pediatric medicine in future decades. childhood and adolescent immunization schedule the centers for disease control and prevention (cdc), american academy of family physicians, and american academy of pediatrics (aap) annually publish a childhood and adolescent immunization schedule. the advisory committee on immunization practices (acip), with input from many liaison organizations, periodically reviews the schedule to ensure consistency with new vaccine developments and policies [ ] . the first combined immunization schedule was published in and recommended six vaccines containing antigens against nine infectious diseases [ ] : diphtheria and tetanus toxoids and whole-cell pertussis vaccine (dtp); tetanus and diphtheria toxoids (td); measles, mumps, and rubella vaccine (mmr); hib; oral polio vaccine (opv); and hepatitis b virus vaccine. ten years later in february , there were ten vaccines against [ ] . before a vaccination becomes part of routine clinical pediatric practice, three steps need to be taken: ( ) the fda must license the vaccine, ( ) the acip and the committee on infectious diseases of the aap and aafp must recommend the vaccine for use, and ( ) the vaccine must be subsidized to cover children without private health insurance. numerous government and partner organizations participate in bringing a vaccine from the bench into the clinic. table provides links where information about these organizations can be obtained. before fda licensure, a new vaccine goes through to years of preclinical testing and clinical trials, costing pharmaceutical companies millions of dollars in new development costs. before testing the vaccine in humans, a company files an investigational new drug application with the fda followed by three phases of clinical trials that are performed to study vaccine safety, immunogenicity, and efficacy (table ) [ ] . after completion of the prelicensure clinical trials, the manufacturer files a biologics licensure application (bla), and the fda, with input from its advisory committee, determines if data support vaccine safety, immunogenicity, and efficacy ( fig. ) [ ] . after licensure, monitoring for rare adverse events continues for some vaccines through formal phase iv trials conducted by the fda and manufacturer. after fda licensure of a new vaccine, information about the vaccine is reviewed by the acip. the acip comprises voting members appointed by the secretary of the department of health and human services. in addition, several professional medical and public health groups and industry representatives participate in acip discussions. to formulate recommendations, the acip establishes subject-specific working groups to review and synthesize data months to ensuring that all us children and adolescents, regardless of health insurance status or income level, have access to recommended immunizations requires a complex system of financing comprised of private and public funding mechanisms (table ). in , % of us children received vaccines purchased through the public sector, and % received vaccines purchased through the private sector. most of the public-purchase vaccines are financed through the vaccines for children (vfc) program, an entitlement program established in as part of the social security act [ , ] . other government funding mechanisms include section of the public health service act of , a federal grant program, and state and local government funding. these programs provide support for states to provide immunizations to children who do not qualify for the vfc program but who are not covered by private insurance. fourteen states, referred to as ''universal'' purchase states, use a combination of federal and state funding to purchase and distribute vaccines recommended for children to all immunization providers in private and public sectors. the remaining states purchase vaccines for uninsured and underinsured chil- immunizations in the us dren who are not eligible for vfc. in addition, insurance provides vaccines for children in the private sector. as the number of vaccines has increased and the scope of the immunization program has expanded, new challenges have emerged. the increasing cost of vaccines, vaccine shortages, and immunization safety are important concerns the immunization program will continue to address in coming years. the rising cost of fully immunizing a child in the united states is due to the increasing number of vaccines and the increasing price of existing vaccines. the estimated cost of completing the childhood immunization series through years of age in was $ . per child at the government-purchasing rate. the cost of immunizing a child through years of age in was $ per child for all vaccines, not including influenza vaccine [ ] . increasingly, state and local health departments are required to make difficult choices about which vaccines to purchase using public funds, including section grant funds. the recommendation in to vaccinate routinely with pcv doubled the cost of immunizing a child. section and state funding have not been adequate to cover pcv for underinsured children in many states, including of the universal purchase states. the addition of new, effective childhood and adolescent vaccines to the schedule has the potential to create serious funding challenges in the future. despite the increasing costs of immunization programs, numerous studies have shown that vaccination continues to be a cost-effective public health intervention. these studies show the need to continue to identify adequate funding sources to support immunization recommendations [ ] [ ] [ ] [ ] . an institute of medicine (iom) report on vaccine financing released in concluded, ''alternatives to current vaccine pricing and purchasing programs are required to sustain stable investment in development of new vaccine products and attain their social benefits for all'' [ ] . in addition to the increasing cost of vaccines, an unparalleled number of vaccine shortages in the united states has had a substantial impact on vaccine delivery. from through , vaccine shortages and changes in routine recommendations occurred for of the diseases for which childhood and adolescent vaccination is recommended (fig. ) [ ] [ ] [ ] [ ] [ ] [ ] . the shortages affected millions of children and health care providers, even triggering suspension of vaccine school entry requirements [ , ] . two vaccine shortages (pcv and tetanus and diphtheria toxoids [td]) lasted nearly years, one (pcv ) occurred twice [ ] , and one (inactivated influenza vaccine, - season) halved the us influenza vaccine supply virtually overnight [ , ] . the causes of these widespread vaccine shortages are multifactorial. one important long-term factor is the decrease in number of vaccine manufacturers of childhood vaccines routinely recommended in the united states. in , a federal immunization working group expressed concern about the stability of the us vaccine supply in the setting of ''a steady attrition of specific pharmaceutical manufacturers from the entire field of biologics'' [ ] . in , six manufactures produced the six vaccines. in , although four vaccines (pcv , varicella, influenza, and mcv ) have been added to the recommended schedule, the number of manufacturers decreased to five. in addition, there are single manufacturers for four of the childhood and adolescent vaccines (mmr, varicella, pcv , and mcv ). in response to concerns over fragility of the us vaccine supply, the general accounting office and national vaccine advisory committee conducted in-depth reviews of the vaccine shortages and concluded that future disruptions in vaccine supply are likely to continue, and proposed solutions [ , ] . vaccines are administered routinely to healthy children and must uphold a scrupulously high safety standard; however, no vaccine is completely safe. in , the national childhood vaccine injury act was passed creating a compensation program for families affected by childhood vaccine-associated adverse events. several other government programs and committees to ensure the safety of the vaccine supply also were created by this act ( table ) . as many vaccine-preventable diseases approach or reach elimination in the united states, continuing to balance the risks and benefits of each vaccine becomes increasingly important [ ] . opv, formerly recommended for routine use in the united states, was associated with vaccine-associated paralytic poliomyelitis ( case among . million vaccine doses distributed). this rare adverse event was no longer considered acceptable after elimination of polio in the united states [ ] . in , the acip recommended using ipv for all doses of polio vaccine. public perceptions of vaccine safety are a challenge to the continued success of the vaccination program. new parents and younger physicians grew up without appreciation of the morbidity and mortality of immunizations in the us several vaccine-preventable diseases. risk or perception of risk for adverse events becomes an important concern. two current prominent public vaccine safety concerns are the perceived causal association between mmr and autism and thimerosal-containing vaccines and autism. as a result of heightened concerns about safety, in the cdc and national institutes of health commissioned the iom of the national academy of science to convene an immunization safety review committee [ ] . between and , this independent expert committee published eight reports related to immunization safety concerns. the committee has made recommendations in the areas of public health response, policy review, research, and communications (box ). with respect to autism, the iom concluded that the body of epidemiologic evidence favors rejection of a causal relationship between the mmr vaccine and autism. the committee also concluded that there is no relationship between thimerosal-containing vaccines and autism [ ] . none of the eight iom reports recommended a policy review of the current vaccine recommendations or change in the immunization schedule. to help ensure safety of vaccines, a robust infrastructure consisting of several systems has been established to monitor vaccine safety after vaccine licensure. the vaccine adverse event reporting system, operated jointly by cdc and fda, is a national passive surveillance system used to detect early warning signals and generate hypotheses about possible new vaccine adverse events or changes in frequency of recognized events [ ] . intussusception associated with receipt of rotavirus vaccine, leading to the withdrawal of the vaccine from the market in , was an adverse event detected by the vaccine adverse event reporting system [ , ] . a third system is the vaccine safety datalink, which consists of large linked databases from health maintenance organizations. associations between serious medical events and immunizations can be evaluated through the vaccine safety datalink. the newest system is the clinical immunization safety assessment centers network, which consists of selected clinical academic medical centers in partnership with cdc to study the pathophysiology of vaccine reactions and develop clinical management protocols for affected patients [ ] . these systems are crucial to the vitality and strength of the us immunization program. since its inception, the major focus of the us immunization program has been on vaccinating infants and young children. of the vaccines routinely recommended for children and adolescents, only two, td vaccine and the mcv , are recommended for all adolescents [ ] . in , as a result of growing concern about morbidity associated with vaccine-preventable diseases in the hard-to-reach adolescent population, the acip recommended expanding efforts to immunize adolescents ( - years old) by establishing a routine vaccination visit at to years old [ ] . in addition to providing td and previously missed vaccinations, the report emphasized that this visit should be used to provide other important preventive health services. the anticipated addition of several new adolescent vaccines to the recommended schedule has stimulated a reappraisal of the approaches that most effectively and efficiently would increase the proportion of adolescents who receive newly recommended vaccines and develop ways to integrate these approaches with other adolescent health, education, and development programs. similar to all aspects of clinical medicine, immunization recommendations continuously change as new vaccines are licensed and new information becomes available. since , several new vaccination recommendations were implemented for existing and new vaccines. notable examples are pcv and the hepatitis b vaccine; new recommendations for both have affected children and health care providers. several vaccines with expected fda licensure in the near future likely will alter the us immunization program and preventive health care practices ( table ). vaccines with a pediatric or adolescent focus under review by the acip are relevant to the prevention of pertussis, human papillomavirus (hpv), influenza, varicella, and rotavirus. this section presents a summary of these vaccines in addition to information on pcv , hepatitis b vaccine, and mcv . the potential impact of vaccines on the distant horizon also will be highlighted. emphasis is on how recent and upcoming policy decisions might affect children and adolescents, health care providers, and society during the next decade. pcv was recommended for routine use in infants in the united states beginning in . before introduction of pcv , streptococcus pneumoniae (pneumococcus) was a leading cause of infectious morbidity in young children in the united states, annually causing approximately , cases of invasive disease in children younger than years old, including cases of meningitis and deaths. in addition, the burden of pneumonia without bacteremia, otitis media, and sinusitis was substantial [ ] . after introduction of routine pcv vaccination, the incidence of invasive pneumococcal disease declined dramatically, especially in children younger than years old [ ] [ ] [ ] . active us population-based surveillance data show that within years of pcv licensure, the rate of invasive pneumococcal disease in children younger than years old declined by % [ ] . in tandem with the decrease in invasive disease, data suggest the incidence of pneumococcal noninvasive disease, including otitis media, also decreased [ , ] . in addition to decreasing the burden of pediatric pneumococcal disease, pcv may have an impact on reducing pediatric antibiotic prescriptions and procedures such as blood cultures in young, febrile children [ ] . the decline in invasive pneumococcal disease is beyond what would be expected from childhood vaccination, given vaccine efficacy and pcv coverage data, suggesting that herd immunity may play a role in protecting unimmunized people from invasive disease [ ] . reduced nasopharyngeal carriage of vaccinecontaining serotypes in vaccinated children is believed to contribute to development of herd immunity against pneumococcus. rates of invasive pneumococcal disease seem to be declining among some unvaccinated groups after implementation of universal infant pcv vaccination. in addition, postlicensure surveillance data suggest a decrease in antibiotic-resistant strains of s. pneumoniae [ , ] . because pcv includes only of the more than serotypes of pneumococcus, there is theoretical concern that serotype replacement might occur in highly vaccinated populations. one study noted an increase in the proportion of cases of invasive pneumococcal disease resulting from nonvaccine serotypes, but the total number of cases was not changed [ ] . this study supports the need for continued pneumococcal surveillance in the post-pcv era [ ] . hepatitis b vaccine holds a unique place in the us immunization schedule because they are the only vaccines licensed for neonates and the only licensed vaccine that prevents cancer. the continued evolution of hepatitis b vaccine recommendations reflects many of the challenges associated with vaccines that will be licensed in the near future. before , an estimated , to , people in the united states were infected annually with hepatitis b virus, including approximately , children [ ] . although most vaccine-preventable diseases are spread via contact or airborne droplets, hepatitis b infection is spread via exposure to infected blood or blood products, sexual contact, and injection devices. much of the transmission of hepatitis b in adults is silent; there is no accompanying rash or symptoms. although adults have a % chance of developing chronic hepatitis b virus infection, infants infected perinatally who do not receive hepatitis b immunoglobulin and vaccine at birth have a % chance of developing chronic infection. twenty-five percent of these infections lead to hepatocellular carcinoma [ ] . the complexity of hepatitis b transmission required a vaccination strategy to protect infants and high-risk adults from infection. the first acip hepatitis b recommendation in was to vaccinate groups known to be at high risk for hepatitis b virus infection, such as health care workers, men who have sex with men, and intravenous drug users [ ] . in , the acip expanded recommendations to include infants born to mothers who were hepatitis b surface antigen (hbsag) positive. recognition of the difficulty in identifying mothers infected with hepatitis b led to a recommendation in to test all women for hbsag during the prenatal period. vaccinating high-risk groups continued to be difficult because no foundation existed to vaccinate adolescents and adults who already were participating in high-risk activities. in , a universal infant vaccination strategy was instituted to achieve the goal of reducing transmission of hepatitis b virus [ ] . it is recommended that the first dose be given at or before months of age with a preference for all infants to receive the first dose at birth. neonatal vaccination works by protecting the infant from contracting hepatitis after vertical or horizontal exposure. giving all infants the birth dose protects infants whose mothers were not tested for hbsag during pregnancy. infant vaccination eventually will provide protection against hepatitis b virus to adolescents who may engage in high-risk activities before exposure. from to , rates of hepatitis b virus infection in children and adolescents younger than years old declined more than % in the united states [ ] . from to , approximately to cases of invasive meningococcal disease occurred annually in the united states [ ] . the case-fatality ratio for meningococcal disease is approximately %, and severe sequelae (eg, neurologic disability, limb loss) occur in approximately % of survivors [ ] . nasopharyngeal carriage of neisseria meningitidis occurs in approximately % to % of the us population [ ] . transmission is through direct contact with respiratory tract droplets of infected individuals. infants younger than year of age have the highest rates of meningococcal disease, with an annual incidence of . cases per , population during [ ] . during the s, incidence rates of meningococcal disease increased among adolescents and young adults [ ] . evidence also showed that college freshmen living in dormitories have a modestly increased risk of meningococcal disease ( . cases per , ) compared with other persons the same age [ ] . a meningococcal polysaccharide (mps) vaccine containing the antigens of serogroups a, c, y, and w has been used in the united states since licensure in . this vaccine protects against the serogroups that cause approximately two thirds of meningococcal disease that occurs in persons to years old in the united states. more than half of cases in infants are due to serogroup b, however, for which a licensed vaccine does not exist in the united states [ ] . similar to other polysaccharide vaccines, mps induces a t cell-independent immune response resulting in poor long-term immunity and inconsistent immunogenicity in children younger than years old. an additional shortcoming is that mps does not reduce nasopharyngeal carriage or induce herd immunity [ ] . before february , mps vaccine was recommended for groups at high risk for meningococcal disease and for outbreak control. educating college freshmen about the potential for the mps vaccine to prevent severe infection also was recommended. some states required proof of vaccination or vaccine waiver for entry into colleges and universities [ ] . employing the same technology used to develop pcv , a meningococcal serogroup c conjugate vaccine was licensed in the united kingdom in . the vaccine was introduced into the routine infant schedule, with catch-up vaccination for older children and adolescents. in the years after introduction of infant meningococcal conjugate vaccine, the incidence of serogroup c meningococcal disease declined by % in vaccinated persons and at least % in unvaccinated persons, suggesting the vaccine produced herd immunity [ ] . in the united states, a quadrivalet meningococcal conjugate vaccine (serogroups a, c, y, and w- ) (mcv ) was licensed on january , , for use in persons to years old. during prelicensure clinical trials, immune responses to mps and mcv were similar in adolescents and adults. because mcv induces t cell-mediated immunity, the duration of protection is thought to be longer than immunity produced by mps. on february , , the acip voted to recommend that mcv be administered universally to adolescents ages to and around years of age, and college freshmen living in dormitories; a vfc resolution also was passed. with the addition of mcv to the immunization schedule, a new era of adolescent vaccination was launched. in the united states, meningococcal conjugate vaccines for use in children younger than years of age are under study. pertussis remains endemic in the united states despite high immunization coverage rates of infants and young children [ ] . immunity to pertussis wanes approximately to years after vaccination, and loss of immunity seems to play a major role in the continued circulation of pertussis [ ] . in and , , and more than , cases of pertussis were reported to the cdc, respectively [ ] . much of the reported increase is thought to be due to increasing physician recognition of pertussis as a nonspecific, persistent cough illness in adolescents and adults, coupled with increasing use of polymerase chain reaction testing for diagnosis of all age groups. how much of the reported increase is due to enhanced surveillance or improved diagnostic methodology is unclear. one study suggested that a true increase in the incidence of pertussis disease occurred in young infants in the united states between and [ ] . the burden of pertussis disease in adolescents is substantial. of the reported cases of pertussis in the united states in , % were in adolescents; the true number of cases is likely to be much higher (cdc, unpublished data). although pertussis is rarely life-threatening in adolescents, the morbidity and societal costs associated with adolescent pertussis disease are important [ ] . in a canadian study, % of adolescents with pertussis reported a cough duration of at least weeks [ ] . paroxysms, shortness of breath, posttussive vomiting, and difficulty sleeping occur commonly in adolescents with pertussis disease [ , ] . to reduce pertussis disease in adolescents, some countries have recommended an adolescent booster dose. in summer , two manufacturers submitted blas to the fda for use of adolescent and adult pertussis vaccines in the united states (tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine adsorbed (tdap). the bla indication for one vaccine includes persons to years old, and the other includes persons to years old. policymakers are reviewing several strategies for pertussis vaccination in adolescents and adults. a cost-benefit analysis in the united states found universal vaccination for persons to years old to be the most economic strategy [ ] . the expected impact of adolescent pertussis vaccination would be to reduce the risk of pertussis in vaccinated adolescents. ideally, another public health goal of pertussis vaccination is to reduce transmission to infants younger than months old who have not completed the primary vaccination series and are at highest risk of death from pertussis. the role of an adolescent vaccination program in reducing transmission to infants is unknown. vaccinating mothers and other close family members of young infants, referred to as a ''cocoon strategy,'' is one method under consideration to decrease pertussis transmission to infants. one study suggested that adult family members are the most frequently identified source for pertussis transmission to infants [ ] . universal replacement of the td booster given every years with tdap is another strategy being discussed. finally, vaccinating women during pregnancy and vaccinating neonates against pertussis have been raised as potential strategies to improve control of pertussis, although pertussis vaccines for these indications are unlikely to be licensed in the united states in the near future [ , ] . more than types of papillomaviruses have been recognized on the basis of dna sequence analyses [ ] . papillomaviruses are ubiquitous, have been detected in a wide variety of animals and humans, and are specific to their respective hosts. hpv is associated with a variety of clinical conditions that range from benign skin and mucous membrane lesions to cancer. most hpv infections are benign. clinical manifestations with the most frequently associated hpv type are as follows: skin warts (types , , , and ), recurrent respiratory papillomatosis (types and ), condyloma acuminata (types and ), and cervical cancer (types , , , , and ) . based on the association of hpv with cervical cancer and precursor lesions, hpvs can be grouped into low-risk and high-risk hpv types [ ] . in the united states and europe, hpv accounts for approximately % of the cases of cervical cancer, with types , , and accounting for an additional % to % of cases [ ] . hpv is one of the most common causes of sexually transmitted diseases in men and women worldwide, causing almost all of the morbidity and mortality associated with cervical cancer [ ] . epidemiologic studies have shown that the risk of contracting genital hpv infection and cervical cancer is related directly to sexual activity. several specific factors increase the risk of becoming infected with hpv, including multiple sexual partners at any time, having sex with a person who has had multiple sexual partners, sexual activity at an early age, presence of other sexually transmitted diseases, and hpv type. vaccination against high-risk hpv types could reduce substantially the incidence of cervical cancer. administration of hpv- vaccine has been shown to reduce the incidence of hpv- infection and hpv-related cervical intraepithelial neoplasia [ ] . in addition, a bivalent hpv vaccine was efficacious in preventing persistent cervical infections with hpv- and hpv- and associated cytologic abnormalities and lesions [ ] . currently, two hpv vaccines are in the final stages of phase iii testing. one vaccine contains hpv types , , , and , and the second hpv vaccine contains types and . applications for licensure are expected to be filed with the us fda in late or . rotavirus is a common cause of gastrointestinal tract illness in young children. by years of age, nearly all children test seropositive for rotavirus, indicating previous infection. in the united states, rotavirus disease leads to an estimated , clinic visits, , to , hospital admissions, and to deaths annually [ ] . the first rotavirus vaccine was licensed in the united states in and was removed from the market and from the immunization schedule in because of an association with intussusception. this vaccine was a tetravalent rhesus human reassortant vaccine [ , ] . currently, several other rotavirus vaccines are in different stages of development. two late-stage vaccines have completed phase iii clinical trials. one vaccine is derived from a monovalent human strain, and the other is a pentavalent bovine-human reassortant vaccine. large-scale phase iii trials did not show an association of these vaccines with intussusception, but postlicensure monitoring is planned. in january , mexico became the first country to make a new rotavirus vaccine available. the company has filed license applications in more than other countries outside the united states. the manufacturer of the second rotavirus vaccine plans to release it first in the united states after licensure by the us fda. after licensure in the united states, educational efforts that address identifiable barriers to achieving practitioner advocacy and patient acceptance will be necessary to ensure implementation of rotavirus vaccine recommendations [ ] . ensuring physician acceptance of the vaccine is critical to achieving high coverage levels [ ] . varicella vaccine, licensed for use in the united states in , is a live, attenuated virus vaccine developed from the vesicles of a healthy infected child with chickenpox. this vaccine is recommended as a single dose for children months to years old. susceptible persons years old or older should receive two doses administered weeks apart. before varicella vaccine became widely used, varicella was one of the most recognizable rashes seen by pediatricians and was associated with , hospitalizations and deaths in the united states each year [ ] . in , the vaccine had % coverage levels, resulting in a significant decrease in mortality, morbidity, and hospitalizations attributable to varicella [ ] . breakthrough varicella infections in vaccinated children occur in % of children exposed to varicella. breakthrough infections usually are mild (b lesions), however, with few complications [ ] . vaccinated children with mild disease were only one third as contagious as children with moderate-to-severe disease, whether they were vaccinated or unvaccinated. vaccine effectiveness for prevention of moderate disease (n lesions and complications requiring a visit to a clinician) was % [ ] . a second dose of varicella vaccine has been approved by the fda and is being considered for the routine childhood vaccination schedule. the impact of varicella vaccine on the incidence of zoster infections in adults in the united states is unknown. varicella vaccine may protect children receiving the vaccine from zoster when they become adults. studies suggest, however, that continued exposure to varicella protects latently infected adults [ ] . vaccination in children could lead to an increase in zoster incidence in unvaccinated adults because exposure to varicella-infected children has declined, but zoster surveillance is limited. a vaccine to prevent herpes zoster in adults is under investigation. since the worldwide influenza pandemic of that caused an estimated to million deaths, the control of influenza circulation has been a major challenge to clinicians and public health experts. the threat of an unpredictable influenza pandemic and the concern about avian influenza heighten the importance of preventing morbidity and mortality caused by epidemics of influenza disease in the united states, which cause more than , hospitalizations and more than , deaths annually [ ] . implementing the expansion of influenza vaccine recommendations to -to -month-old children and prioritizing vaccine during influenza vaccine shortages are important issues the us immunization program faces regarding influenza prevention. influenza virus contains eight major proteins, including hemagglutinin (ha), which controls viral penetration and attachment, and neuraminidase (na), which controls viral particle release and spread. influenza strains are identified by type (a, b, and c) and by subtype categorized by ha and na. there are different ha and different na subtypes. major changes in ha and na, called antigenic shifts, are associated with emergence of novel influenza viruses to which little or no immunity exists in the exposed population. antigenic shifts were the cause of the three influenza pandemics in the twentieth century (table ) [ ] . minor changes in ha and na, called antigenic drifts, define the influenza viruses that circulate each year. influenza vaccines are developed yearly based on antigenic drifts. worldwide surveillance established by the world health organization allows predictions to be made regarding antigenic drifts, which enables vaccine to be updated before the start of an influenza season. recommendations for which influenza strains should be included in the vaccine are made in early spring before influenza season. three influenza types are formulated and combined to make a new trivalent vaccine each year. two types of influenza vaccines are licensed for use in the united states. one is an inactivated vaccine recommended for persons months of age in highrisk groups and their close contacts. the second is a cold adapted, live, nasally administered vaccine licensed for healthy people to years of age, including close contacts of high-risk persons. the acip and aap recommended in to expand influenza vaccine recommendations to include all children to months old and household contacts of children up to months old as well as to continue immunization of all children in high-risk groups. this recommendation was made based on epidemiologic data showing that healthy children in this age group are at high risk of hospitalization from influenza, and that deaths in this age group occur [ ] [ ] [ ] [ ] . more than reports of pediatric influenzaassociated deaths during the - influenza season stimulated the addition [ ] . the influenza vaccine is unique to the recommended childhood and adolescent immunization schedule because it is the only vaccine that requires a visit during a certain time of year and that requires annual immunization. even if the circulating strains of virus are the same as the year before, an annual booster is necessary to retain immunity. in addition, children months to years old are recommended to have two doses of influenza vaccine administered month apart if they previously have never been vaccinated for influenza [ ] . adding influenza into the childhood schedule is challenging for public health officials and primary care physicians developing programs to attain high coverage rates in children to months old. vaccine development is expanding to include products against cancers, chronic diseases, and other infectious diseases. vaccines against inflammatory diseases for which an infectious cause has not been identified, such as multiple sclerosis and rheumatoid arthritis, are being developed as therapeutic vaccines. scientists effectively are using new biologic tools to improve existing vaccines. new technologies also are being used to improve vaccine delivery systems, producing better combination, oral, and intranasal vaccines. the science behind new vaccines continues to advance at a remarkable pace, driven by an evolving understanding of the cellular and molecular processes involved in different responses of the immune system [ ] . many infectious organisms have evolved over thousands of years to evade this immune response. adjuvants to vaccines are now being used not only to create an immune response, but also to focus the immune response down a desired path [ ] . dna vaccines, plasmids of dna encoding the desired antigen, also are being developed with the intention of simplifying vaccine production and eliminating the possible risk of organism reversion [ ] . as was true during the time of jenner, vaccines continue to push the frontiers of science and medicine. in , the iom published a report prioritizing development of vaccines to be used in the united states. the iom committee considered vaccines that could be licensed within years directed against conditions of domestic health importance [ ] . health benefits of these vaccines were measured by a standard health outcome measure, quality-adjusted life years gained. these vaccines were placed into categories of most favorable to least favorable (box ). since publication of this report, pcv has been licensed for infants beginning at months of age (most favorable category), and hpv vaccine (more favorable category) and rotavirus vaccine administered to infants (favorable category) are on the near horizon as discussed in this article. since release of this report, several organisms not included on the iom list have emerged or became larger public health threats, including west nile virus, metapneumovirus, methicillin-resistant staphylococcus aureus, the coronavirus associated with severe acute respiratory syndrome box . institute of medicine report on vaccines for the twenty-first century most favorable: vaccination strategy would save money cytomegalovirus vaccine administered to -year-olds influenza virus vaccine administered to the general population (once per person every years) insulin-dependent diabetes mellitus therapeutic vaccine multiple sclerosis therapeutic vaccine rheumatoid arthritis therapeutic vaccine group b streptococcus vaccine given to women during first pregnancy and to high-risk adults streptococcus pneumoniae vaccine given to infants and -year-olds more favorable: vaccination strategy would incur small costs (b$ , ) for each qaly* chlamydia vaccine administered to -year-olds helicobacter pylori vaccine administered to infants hepatitis c vaccine administered to infants herpes simplex virus vaccine administered to -year-olds hpv vaccine administered to -year-olds melanoma therapeutic vaccine mycobacterium tuberculosis vaccine administered to highrisk populations neisseria gonorrhoeae vaccine administered to -year-olds respiratory syncytial virus vaccine administered to infants and -year-olds favorable: vaccination strategy would incur moderate costs (n$ , but b$ , ) per qaly gained parainfluenza virus vaccine administered to infants and women during their first pregnancy rotavirus vaccine administered to infants group a streptococcus vaccine administered to infants group b streptococcus vaccine given to high-risk adults and low utilization in -year-olds or women during their first pregnancy (sars), and avian influenza virus (h n ). the ongoing outbreak of h n influenza in asia, associated with high mortality rates, has stimulated research of a vaccine that has the potential to thwart a possible major influenza pandemic. circulating h n viruses may adapt to humans through genetic mutation or reassortant with human influenza strains, allowing for human-to-human transmission, facilitated by the fact that most humans lack preexisting immunity owing to lack of previous exposure [ ] . these emerging infectious diseases and the need to prevent them add further complexity to immunization schedules of the future. until the twentieth century, approximately half of children in the united states died as a result of childhood illness. until the s, infectious diseases were the leading cause of death in the united states. in the first edition of the red book published by the aap in january , chapters dealt with infectious diseases, ranging from the common cold to smallpox. except for pertussis, diphtheria, and less favorable: vaccination strategy would incur significant costs (n$ , -n$ million per qaly gained) borrelia burgdorferi vaccine given to resident infants born in and immigrants of any age to geographically defined highrisk areas coccidioides immitis vaccine given to resident infants born in and immigrants of any age to geographically defined highrisk areas enterotoxigenic escherichia coli vaccine administered to infants and travelers epstein-barr virus vaccine administered to -year-olds histoplasma capsulatum vaccine given to resident infants born in and immigrants of any age to geographically defined highrisk areas neisseria meningitidis type b vaccine given to infants shigella vaccine given to infants and travelers or travelers only * quality-adjusted life year (qaly) takes into account quantity and quality of life generated by health care interventions. qaly is calculated by placing a weight on time in different health states. the cost per qaly is the cost required to generate year of perfect health. data from www.iom.edu/vaccinepriorities. tetanus, and smallpox, active immunization was not available for the other conditions in this edition. currently, active immunization exists for of the diseases contained in the eight pages of the red book, and one disease, smallpox, has been eradicated. since then, many other infectious disease have emerged or reemerged, including sars, hiv, west nile virus, metapneumovirus, avian influenza, and methicillin-resistant s. aureus. many of these conditions are expected to be controlled in the future by immunizations. as the recommended childhood and adolescent immunization schedule continues to expand, the us immunization program will be challenged to integrate novel immunization strategies into the current immunization infrastructure. the impact of future vaccines in the united states will be more difficult to calculate because they will prevent fewer deaths than vaccines in the past. the cost of these vaccines will continue to increase, and funding support will be challenged. the risk of adverse vaccine events will have to be weighed against the risk of the disease if not vaccinated. pediatric health care providers face a growing complexity of problems in children, including injury, obesity, asthma, and mental health and behavioral disorders. as the cost and complexity of the childhood and adolescent immunization schedule increase, considering the role of immunizations within the context of other preventive health interventions and overall societal values becomes increasingly important. immunizations are one of the most effective clinical preventive services in pediatric practice [ ] . despite the challenges facing the us immunization program, immunizations will likely remain on the list of great public health accomplishments of the twenty-first century, and the legacy of jenner will continue. smallpox and its eradication. geneva who ten great public health achievements, united states impact of vaccines universally recommended for children-united states measles elimination in the united states epidemiology of poliomyelitis in the united states one decade after the last reported case of indigenous wild virus-associated disease healthy people : national health promotion and disease prevention objectives haemophilus influenzae invasive disease in the united states, - : near disappearance of a vaccine-preventable childhood disease recommended childhood and adolescent immunization schedule-united states advisory committee on immunization practices, american academy of pediatrics, american academy of family physicians, national immunization program development of pediatric vaccine recommendations and policies vaccination policies and programs: the federal government's role in making the system work financing immunizations in the united states cost-effectiveness of a routine varicella vaccination program for us children projected cost-effectiveness of pneumococcal conjugate vaccination of healthy infants and young children priorities among recommended clinical preventive services cost-effectiveness of hepatitis b virus immunization strengthening the supply of routinely recommended vaccines in the united states: recommendations from the national vaccine advisory committee centers for disease control and prevention. 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control and prevention. poliomyelitis prevention in the united states: updated recommendations of the advisory committee on immunization practices (acip) immunization safety review: committee reports. washington, dc national academy of sciences understanding vaccine safety information from the vaccine adverse event reporting system withdrawal of rotavirus vaccine recommendation rotavirus vaccine for the prevention of rotavirus gastroenteritis among children: recommendations of the advisory committee on immunization practices (acip) safety of immunizations centers for disease control and prevention. immunization of adolescents: recommendations of the advisory committee on immunization practices, the american academy of pediatrics, the american academy of family physicians, and the american medical association preventing pneumococcal disease among infants and young children: recommendations of the advisory committee on immunization practices (acip) postlicensure surveillance for 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hepatitis b vaccination-united states acute hepatitis b among children and adolescents-united states opportunities for control of meningococcal disease in the us prevention and control of meningococcal disease and meningococcal disease and college students: recommendations of the advisory committee on immunization practices (acip) active bacterial core surveillance report, emerging infections program network changing epidemiology of pertussis in the united states: increasing reported incidence among adolescents and adults final: reports of notifiable diseases trends in pertussis among infants in the united states societal costs and morbidity of pertussis in adolescents and adults morbidity of pertussis in adolescents and adults evaluation of strategies for use of acellular pertussis vaccine in adolescents and adults: a cost-benefit analysis infant pertussis: who was the source? new pertussis vaccination strategies beyond infancy: recommendations by the global pertussis initiative pertussis vaccination strategies for neonates-an exploratory costeffectiveness analysis human papillomavirus and cervical cancer safety and immunogenicity trial in adult volunteers of a human papillomavirus l virus-like particle vaccine a controlled trial of a human papillomavirus type vaccine efficacy of a bivalent l virus-like particle vaccine in prevention of infection with human papillomavirus types and in young women: a randomised controlled trial intussusception among recipients of rotavirus vaccine: reports to the vaccine adverse event reporting system intussusception among infants given an oral rotavirus vaccine available at: www.pediatrics. aappublications.org/cgi/reprint/ / /e ?maxtoshow=&hits= &hits= &resultformat= &author =iwamoto&searchid= _ &stored_search=&firstindex= &sortspec= relevance&journalcode=pediatrics varicella disease after introduction of varicella vaccine in the united states contagiousness of varicella in vaccinated cases: a household contact study contacts 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potentially pandemic h n influenza virus in eastern asia key: cord- -t l zii authors: mayer, j.d. title: emerging diseases: overview date: - - journal: international encyclopedia of public health doi: . /b - - . - sha: doc_id: cord_uid: t l zii emerging infectious diseases are diseases that are either new, are newly recognized, or are increasing in prevalence in new areas. resurgent diseases are also usually grouped in this category, as is antimicrobial resistance. these diseases have been given formal recognition in the past two decades, although a historical outlook demonstrates that the phenomenon has probably been persistent, although largely undetected, through recorded history. emergence has accelerated recently, driven by factors such as demographic change, land use change, increased rapidity and frequency of intercontinental transportation, and other mostly social trends. continued infectious disease emergence poses, and will continue to pose, significant challenges for public health and for basic science. emerging and re-emerging infectious diseases have been major features of contemporary societies. indeed, there is evidence that history has been characterized by the constant interplay of humans and pathogens (mcneill, ) . however, it is impossible to say when the terms 'emerging infection' or 'emerging infectious diseases' were first used to describe new infectious diseases, or diseases that meet the criteria that are described in this article. the belief in the s that the threat of infectious diseases had been eliminated in developed countries was unfounded. a broader view of history would have demonstrated this. one possible reason for the optimism is that the s was a decade of optimism in general. in the united states, social programs were instituted to address inequities; humankind had not only orbited the earth, but landed on the moon; the gains of science and technology were impressive; economic expansion was equally impressive; poliomyelitis had been all but eliminated in the united states; and the sense of 'control' was widespread. beyond the borders of the united states, however, in africa, asia, latin america, and elsewhere, malaria proved to be a huge challenge to life, although its prevalence was decreasing, and diarrheal diseases continued to take their toll, particularly among the young. transportation links created the potential for transmission of infection between tropical regions and developed countries such as the united states. the potential for new diseases to emerge in the united states was there, and it took just a few years until this happened, catching the medical and public health communities by surprise. in discussions of emergence, both 'emerging infections' and 'emerging infectious diseases' are commonly found. while the two are closely related, they are not synonymous. an infection does not necessarily represent a state of disease. 'infection' suggests that an agent (usually a microbe) has become resident in the host. usually that agent is replicating in the host. however, the host need not show any sign of disease, in the sense that it can conduct its normal activities without hindrance. 'disease' is a state in which the normal functioning of the host is impaired, and both signs and symptoms are present -indeed, they are what limit normal function. an infectious disease is therefore a disease that is due to a pathogen. appeared de novo, or are being experienced in a region with greater intensity, or for the first time. some authors have used a more specific definition of emerging to diseases and have specified five types of emerging diseases: ( ) diseases that arise de novo, ( ) diseases that are newly recognized, ( ) diseases that have not previously existed in a specific area, ( ) diseases that had not yet made a species jump to humans until the present, and ( ) diseases that are increasing in prevalence. there are other definitions as well. the simplest definitions are frequently the most useful, and thus morse's definition will be used in this article. re-emerging infectious diseases are frequently thought of as being closely related phenomena to emerging infectious diseases. whereas emerging diseases denote diseases that are being experienced for the first time in a given location, re-emerging diseases are diseases that are reappearing in regions from which they have disappeared. usually eradication is due to deliberate efforts on the parts of government and public health agencies. for example, malaria control programs following the end of world war ii were instrumental in the elimination of malaria from some areas of the world, such as italy and spain. sometimes, malaria eradication was eliminated as part of multisector development programs. for example, the tennessee valley authority, created during the s primarily for flood control, hydroelectric power, and economic development, also had an explicit aim of malaria control. this resulted in the drainage of most swamps, and the elimination of malaria from this part of the united states. just as malaria was disappearing from many regions in the s, the next decade saw the resurgence of malaria, and the global prevalence of malaria has been increasing ever since. there are multiple reasons for this. these include anopheline spp. resistance to ddt, banning of ddt because of suspected environmental effects, and the development of resistance to chloroquine. malaria, then, is a re-emerging disease. another is tuberculosis. in many societies, tb had been nearly eliminated, but with the appearance of hiv/aids, immunocompromised individuals were much more susceptible to tb reactivation. tb, therefore, is also considered to be a re-emerging disease. the public and the medical and public health communities gradually came to realize that their complacency over the potential threat of infectious diseases was misplaced, and that new and emerging diseases constituted one foci of concern over health threats to the public. this change in attitude came gradually, and can be thought of as a series of historical 'moments,' each of which refocused attention on infectious diseases. while it is impossible to be exhaustive here, this section takes a roughly chronological approach in describing the events that led the public and professional communities to realize that infectious diseases had not been 'conquered.' the bicentennial of the united states was celebrated in , and there were many gala events around the nation in july. one was the meeting of the pennsylvania chapter of the american legion. the events surrounding this meeting were the first to bring the attention of both the population and the broad scientific and medical communities to the argument that infectious diseases in the united states had been 'conquered,' and both alarmed the public and aroused the curiosity of the scientific and medical communities because this appeared to be a new disease. indeed, before legionellosis was identified and antimicrobial treatment identified, legionellosis was called a 'monster disease. ' over members of the american legion who had attended the meeting developed an unusual respiratory illness, and it became clear that it was of bacterial etiology, although it was initially thought to be viral, due to its close clinical resemblance to influenza. approximately people died as a result of this outbreak. however, two things remained unclear. first, the pathogen could not be identified with conventional methods, and second, no common source of exposure could be identified initially, although the fact that the number of incident cases followed a typical epidemic curve suggested very strongly that there was some sort of common exposure to the pathogen. the news media seized upon this medical 'mystery,' and the public knew that they were dealing with an unknown infectious disease. this constituted a historical moment in contemporary american history, because it had been decades since something like this had happened. six months later, the bacterium was finally identified. legionella was not a new bacterium. stored samples from outbreaks as early as tested positive for legionella spp. however, the bacterium had not been identified in these outbreaks because it had not yet been described and characterized. in retrospect, most renowned is an outbreak that occurred in pontiac, michigan in , although the symptoms were milder than in the legionella outbreak in philadelphia. in fact, mild legionellosis with a nonpneumonic form is often called 'pontiac fever.' this is not the place to review the epidemiology, pathophysiology, and clinical aspects of legionellosis in depth. briefly, though, it usually has an acute onset, and is usually caused by legionella pneumophila, although other species are also pathogenic. in fact, there are species of the genus, and numerous serotypes. epidemiologically, l. pneumophila is by far the dominant species in human disease. the major reservoirs are bodies of freshwater, and the main mode of transmission is through small droplets that are inhaled from the environment. in the philadelphia outbreak, the source was finally traced to the air conditioning system in the hotel in which most attendees were lodged; the attendees were inhaling small particles in certain parts of the building. dozens of subsequent outbreaks have been traced to similar mechanisms. these have been not only air conditioners but also shower heads, aerosolizers in sinks, and whirlpools. virtually anything that aerosolizes fresh water is a potential mechanism by which legionellosis may be transmitted. symptoms of classic legionnaires disease are nonspecific and include fever, malaise, headaches, and myalgias. frequently, rigors will develop, as will a productive cough (in about half the cases). dyspnea (shortness of breath) is almost invariably present, and chest pain is common, as is a relative bradycardia for the elevated temperature. there are a number of abnormalities in laboratory tests, and chest films are markedly abnormal. a urine antigen test is available for one serotype, so laboratory diagnosis must frequently rely on more complex and time-consuming laboratory methods such as dfa. sputum cultures or cultures from bronchoalveolar lavage have been the mainstay of laboratory diagnosis. since laboratory methods do not show a definitive diagnosis until a minimum of days following onset, diagnosis is usually made on clinical grounds, and treatment is initiated based upon index of suspicion. erythromycin proved to be effective in , and other macrolides (azithromycin, clarithromycin) are highly effective. tetracycline and doxycycline are frequently used, as are the fluoroquinolones, such as levofloxacin. in hosts who are not immunocompromised, the prognosis is generally positive. there is no doubt that legionellosis was an emerging disease when it was first identified. its particular significance lies in its historical context -in the fact that this was the first occurrence that began shaking the optimism of the s and early s that infectious diseases had been conquered, and also in the fact that the etiology of an obviously infectious syndrome with a reasonably high case fatality ratio remained unknown for a number of months. chronologically, the next event to bring infectious disease to the attention of the public was another emerging infectious syndrome. in late and , a number of women in the united states became seriously ill with a syndrome characterized by high fever, shock, rash, hypotension, and capillary leak. this syndrome had been first described as such years earlier, although in retrospect it had been noted in the medical literature in the s. the paper identified toxic shock syndrome in males, females, and children -and the females were both menstruating and not menstruating. the outbreak was associated with menstruating women, many of whom were using superabsorbent tampons. although this was a major risk factor in the - outbreak, much of the public and many physicians were under the erroneous impression that toxic shock syndrome (tss) was necessarily associated with menstruating women who were using superabsorbent tampons. although tss is not necessarily associated with menstruating women, this does remain a risk factor in the epidemiology of tss. as with legionnaires disease, tss was a rare disease, yet the public's perception of it was out of proportion to its true prevalence -the risk was exaggerated. this is something that social scientists have called the 'social amplification of risk' in the context of new events that are potentially dangerous, but that nonetheless carry with them a low risk. amplification takes place as a result of media coverage, and as a result of intrapsychic processes that tend to amplify the threat of novel threats when the locus of control over the event is external to the individual. during the outbreak of toxic shock syndrome, newspapers were full of stories about tss and the sometimes deadly consequences of developing the syndrome. these were frequently on 'page above the fold' and necessarily caught the attention of the public. the same was true of television news. once this outbreak of tss appeared to be concentrated in one single group -menstruating women using superabsorbent tampons -the general public's fear of tss began to diminish, and the federal government mandated the withdrawal of those tampons from the market. the number of incident cases began a rapid decline, and was back to baseline of about cases per year by . some reports demonstrated that there was a decrease in the use of all tampons -not just superabsorbent tampons. it was already known in that toxic shock syndrome was caused by staphylococci (specifically, s. aureus). in these cases, treatment is threefold: removal of the tampon, indwelling tampon, or other hypothesized environmental cause; aggressive fluid resuscitation; and rapid use of antistaphylococcal antibiotics. other bacterial species can cause toxic shock syndrome. in rare cases, other staphylococcus species have been associated with toxic shock syndrome, and because they are coagulase-negative, they are difficult to treat. at this time, coagulase-negative staphylococci constitute the most common cause of hospital-acquired bacteremia. this sometimes results in endocarditis, and usually the only effective treatment is surgical valve replacement, particularly in the case of those who have had earlier valve replacement. aggressive antibiotic therapy is occasionally effective. should toxic shock syndrome be considered to be an emerging disease? it certainly was in , when the public was so concerned with its appearance. now, in , years after it was first described, this label is more questionable. what was most significant about toxic shock syndrome, however, was its historical significance. it followed the outbreak of legionnaires disease so closely that it turned the public's attention, once again, to infectious diseases, and to infectious diseases that had been unknown. it also reminded the biomedical community that infectious diseases had not been conquered. the issue at the time was whether legionnaires disease and toxic shock syndrome were anomalies, whether the assumption of the conquest of infectious diseases had clearly been erroneous, or whether these two outbreaks were harbingers of a new stage in 'epidemiologic history'a historical period during which emerging infections would become common and would catch the attention of the public, the public health community, the medical community, and government agencies. the public health and medical communities were divided on this. it would soon become clear, however, that the latter would hold true -that emerging infectious diseases would come to the forefront of public health, epidemiology, and the medical community. in the cases of legionnaires disease and tss, the social amplification of risk exaggerated perceived threats. nonetheless, the public became more attentive to infection. two other phenomena would solidify this attention. one was the appearance of hiv/aids in the united states, and the other was public attention that was drawn to hemorrhagic fevers, mostly in africa. the details of hiv/aids are covered elsewhere in this encyclopedia, and there will be no attempt here to duplicate this material. rather, this discussion concentrates on the significance of hiv/aids. when hiv/aids first appeared in several urban areas in the united states in , it appeared to be an anomalous syndrome. it was not called 'aids' until , when the centers for disease control (cdc) gave the syndrome that label. in the same year, researchers at cdc also linked one of the pathways of transmission to blood and blood products, causing a great deal of public concernif it was possible to contract aids through a frequently used medical practice, it had the potential of affecting millions of people. until then, aids was thought to be restricted to the gay community. in , blood banks were warned by the cdc that blood and blood products could definitely transmit aids, and surgeons and other medical personnel began rethinking the criteria necessary for transfusion. by , it was clear that the exponential increase in the number of incident cases was a definite trend. in and , two teams discovered that the pathogen causing aids was viral, and although it had a different nomenclature at first, there was a great deal of relief that the causal agent had been discovered. it is an interesting study in the sociology of science to analyze the competing claims by luc montagnier at the institut pasteur and robert gallo in the united states concerning their respective claims that they discovered hiv. it is now clear that montagnier discovered the virus. shortly after the virus was discovered and characterized, an antibody test was developed to detect hiv in vivo. this was quickly used to screen blood products as well as to detect hiv in individuals. whereas some people decried the slowness of the u.s. government's response to hiv, the time from the first presentation of a group of males with kaposi's sarcoma or oral thrush until the antibody test for a recently identified virus was only years. granted, the president of the united states, ronald reagan, had not even mentioned aids, and funding was less impressive than it could have been, but the time was quite short. the real challenge with hiv has been to find an effective vaccine, or to find a 'cure,' although antivirals have been effective in suppressing viral load in the majority of cases since - . the prevalence and mortality data are well-known. the best estimates are that globally, over million people are living with hiv/aids, and approximately million have died of hiv/aids. currently, about - million of those living with hiv/aids are women, and in developing countries, particularly in sub-saharan africa, hiv/aids is becoming, increasingly, a disease of women. currently, approximately two-thirds of those living with hiv/aids are in sub-saharan africa, but the increasing prevalence and incidence of hiv/aids in asia -and particularly, in india and china -are making east asia and south asia regions of tremendous concern. this is because each country has over billion people, and the prevalence rates do not have to be high to result in large numbers of infected people. the global significance of hiv/aids is that it, by itself, has altered demographic trends, and the political economy of nations and regions, not to mention the human suffering that this disease has exacted. in botswana and swaziland, for example, the gains in life expectancy during the th century have not only been completely reversed, but the life expectancy at birth is lower now than it was at the beginning of the th century. in the context of this article, hiv/aids is an emerging infectious disease par excellence. a generation ago, it was literally unheard of. now in all developed countries and in many developing countries, hiv/aids shapes many behaviors, is responsible for significant stigma, is feared, and causes a significant percentage of deaths. globally, hiv/aids is the fourth leading cause of death, although in many parts of africa, it is the leading cause of death. hiv/aids is an emerging infectious disease because of the historical rapidity with which it moved from an unknown localized zoonotic complex in west and central africa to the most prevalent infectious disease in the world. while the scientific evidence suggests that there were a number of species jumps of both hiv- and hiv- that occurred in africa, these were so localized and the societies isolated enough from the rest of the world that hiv went unnoticed. thus, it appeared as though the disease went from nonexistence to a major pandemic in a matter of a few years. and there is another major significant dimension. since hiv/aids appears to have originated in africa -'out there,' away from northern europe and north america -some have argued that hiv/aids acquired a certain nefariousness -a disease emerging from the dark, foreign, isolated jungle -the stereotypical cauldron of new diseases. viral hemorrhagic fevers have been in the public eye since , when there was a major outbreak of a hemorrhagic fever in the jos plain of nigeria. the disease came to be called lassa fever, caused by an arenavirus (lassa) that seemed particularly undesirable to the public. the virus is named after the town in which this outbreak occurred. like all hemorrhagic fevers, including dengue in some cases, one of the characteristics of lassa fever is that it can disturb the clotting/coagulation mechanism, resulting in disseminated intravascular coagulation (dic) and diffuse hemorrhage. the outbreak was publicized in the united states through the news media, perhaps because it was an 'exotic' or newsworthy event, and once again, the social amplification of risk was responsible for exaggerated fears of 'what if it spreads here?' that this outbreak occurred in sub-saharan africa, which, in the eyes of the north american public, may have been thought to be all 'jungle' (the jos plain is not rain forest) probably also contributed to the amplification of risk. serologic tests demonstrate that exposure to lassa virus is common in west africa. for example, in parts of nigeria, seroprevalence is positive in % of those tested; in sierra leone, the figure varies from - % depending on the region (richmond and baglole, ) . it is now known that humans are dead-end hosts, and that the rat species mastomys natalensi is the natural host. these rats are extremely common throughout sub-saharan africa. people become infected by inhaling aerosols from rat excreta, and risk is increased by eating them, which is a very common practice in west africa. modern modes of travel have allowed infected individuals who are either symptomatic or asymptomatic at time of entry to travel to other continents, where they require treatment for lassa fever. these cases have not been numerous, but cases have appeared in the united states and japan, as well as in several european countries. this has caught some clinicians unprepared, since they were not trained in tropical medicine and were unaware of how to diagnose or manage a viral hemorrhagic fever. the prevalence rate of lassa fever is much higher than was initially thought. in one series, lassa fever accounted for % of adult deaths in sierra leone, and as many as % of hospital admissions (richmond and baglole, ) . following the outbreak in , it took some time to investigate adequate treatment protocols, but now, aggressive fluid replacement and the use of antiviralsparticularly ribavarin -are the treatments of choice. ebola hemorrhagic fever and closely related marburg virus are both single-stranded rna viruses, as are other viruses that cause hemorrhagic fevers. ebola and marburg are filoviruses; ebola virus is actually a genus and there are four species. it was first described in the sudan in , and estimates are that mortality from this virus has now exceeded people. the case fatality ratio exceeds %, and may be as high as % in some cases. transmission is different than lassa fever. it is usually through direct contact with blood and bodily secretions from individuals who are ill with ebola fever, or from nonhuman primates who are also infected. evidence points to bats as the natural reservoir of ebola virus, but this is not certain. in several studies, however, bats have been shown to be infected by the virus (leroy et al., ) . this is highly suggestive, but it is not conclusive proof. like so many other viral hemorrhagic fevers, the symptomatology of ebola is very nonspecific and typical of viral syndromes in general. the clinician needs to have a high index of suspicion. at this point, the only certain treatment is supportive, and from a public health point of view, quarantine is of the utmost importance, since ebola fever is so contagious. this was well-documented by the news media in the outbreak in kikwit, democratic republic of the congo (drc, then zaire) in . this was so well-documented that once again it led to exaggerated perceptions of risk, with overtones of the 'exotic disease' from sub-saharan africa and its possible spread to the united states. recent advances in understanding the pathogenesis of ebola and the role of proinflammatory cytokines has led to the use of some recombinant products that block the progression of the inflammatory cascade to dic in some animal models. nonetheless, this approach has not been used in humans as of . there are three notable points that need to be mentioned concerning ebola. first is that it appears to be increasing in prevalence in africa. this may be because detection is better and the disease has been better described, both epidemiologically and pathophysiologically. second is that there is significant concern that ebola virus could be used as a biological weapon. it has thus been placed on the highest level (category a) of potential biological weapons by the cdc. finally, ebola, more than any other emerging infectious disease, typifies in the mind of the public the sort of dangerous, threatening disease risk that is associated with tropical areas, the 'jungle,' and the threats that are associated with a more interconnected world. bovine spongiform encephalopathy (bse), or 'mad cow disease' in nontechnical terms, is another infectious disease that focused public awareness on emerging infections. the pathogen in this case was unusual not only in the sense that it had not been described elsewhere, but also because the whole class of pathogens -prionshave been very rare. like another neurologic disease, kuru, bse turned out to be due to a prion. essentially, prions are very simple since they are just unusually folded and self-replicating proteins. they cannot even be described as organisms. the source of the prion is not known, although many speculate that it is somehow derived from sheep infected with scrapie. in , an unusual disease seemed to be affecting cattle in the united kingdom, and by the end of the year, over cattle had died because of spongiform encephalopathy. since it was apparent that the disease was contagious, over million cattle were intentionally slaughtered to limit contagion and ensuing effects on the cattle industry. by the mid- s, there was a clear epidemiologic association between bse and a variant of a neurodegenerative disease in humans that had been described in the middle of the th century: creutzfeldt-jakob disease (cjd). however, there were some notable differences between cjd and the disease that was affecting humans in the s. the median age of this new syndrome was much younger than in classical cjd; the median duration of survival from onset of symptoms was longer than in classical cjd; and pathological differences and differences on mri were apparent with this new variant. accordingly, the cjd associated with bse first was named 'new variant creutzfeldt-jakob disease' or 'nvcjd;' as time progressed, nvcjd was renamed 'variant cjd' or 'vcjd.' although there were very few cases of vcjd in the uk human population, the threat of this disease was great according to public perception. according to the world health organization (who), as of november , there had been cases of vcjd in the united kingdom, six in france, and one each in several other countries (who, ) . nearly all of those with vcjd died or would die within years. because of the realistic fear of contagion, several steps have been taken to limit the spread of vcjd. feeding practices for cattle have changed so that it is no longer legal to feed animal protein that might contain any tissues proximal to the central nervous system to other cattle. in the united kingdom, there was a ban on cattle over months old from entering the commercial food supply. in the united states, individuals who have lived in the united kingdom or who have spent more than months in the united kingdom are banned from being blood donors on the assumption that they might have consumed infected beef during their stay(s) in the united kingdom. a ban was instituted on importing cattle and cattle feed from the united kingdom, and, occasionally, from canada, in an attempt to prevent bse from spreading to the united states (kuzma and ahl, ) . while the number of incident cases of vcjd and bse have decreased in a typical epidemic curve pattern, the effects of the bse 'scare' have been tremendous. the very credibility of the uk government was threatened. the whole cattle and meat industries were severely hurt. on the other hand, surveillance techniques and understanding of cattle food chains were vastly improved. severe acute respiratory syndrome (sars) proved to be of great import in both the public awareness of emerging infectious diseases and in the testing and real-time construction of both domestic and international systems of public health surveillance and response. it was particularly important in terms of public awareness because it spread very rapidly on the international and intercontinental scales. sars apparently began as a few cases of a viral pneumonia in guangdong province in southeastern china in late . however, this was not immediately apparent to the global public health communities because it was not publicized by the chinese government. what catapulted sars to international attention in the media and in the public health community was the appearance and rapid increase of incident cases in guangdong in february (zhao, ) . sars spread rapidly to hong kong, where contact tracing eventually identified one night in a specific hotel where the index case stayed as being the epidemic focus. the index case infected at least others who were in the hotel at one time or another during that night. sars spread from hong kong to other areas of hong kong and to singapore, vietnam, and canada (toronto, ontario). the spread of all these cases has been traced to airplane travel, followed by localized spread by an index case. a case definition was developed based upon clinical presentation, which typically consisted of fever, initially, followed by lower respiratory signs and symptoms, sometimes resulting in acute respiratory distress syndrome and respiratory distress typical of acute lung injury as a response to the inflammatory cascade. just over cases were identified worldwide, and died, for a case fatality ratio just < %. a disproportionate degree of contagion occurred in intensive care units and areas of hospitals in which hospital personnel were exposed to respiratory excretions; close proximity -within m -to an infected patient who was undergoing endotracheal intubation was the single greatest risk factor for contracting sars. local measures to control the spread of sars consisted largely of quarantine and containment. in china, for example, separate quarters for sars patients were constructed very rapidly. in singapore, arriving and departing passengers were required to pass through automated temperature detectors, and anybody with a fever was required to undergo further medical evaluation. the same was true at most points of entry in most developed countries. since most cases were contracted in hospitals and health facilities, rigorous contact control procedures were instituted, and in some cases, hospitals were closed to visitors and new admissions. the identification of the pathogen causing sars constitutes a textbook example of how international cooperation in science and public health may occur when the willpower is there and the scientific capability exists. by mid-march , many leading laboratories with advanced virologic capabilities had agreed to cooperate in a network that was coordinated by the world health organization. within weeks, a pathogen was identified as a novel coronavirus, using a combination of methods: molecular polymerase chain reaction, culture, and electron microscopy, and shortly thereafter, the criteria of koch's postulates were met. thus, the evidence was quite clear that the new coronavirus was the pathogen. the virus was named the sars coronavirus, or, almost always, sars cov. the ecology of sars was not understood as quickly as the pathogen was identified. some features were identified within a number of months. first was the phenomenon of superspreaders, which is a concept that previously had received scant attention. in this case, it became apparent that a small number of individuals spread sars to a disproportionately large number of people. it is not clear whether this is because of behavioral factors, host-pathogen interaction, or environmental factors. what is fairly clear is that were it not for superspreaders, the epidemic would not have affected nearly as many people as it did. this is because the r , or number of people who one individual could infect, was inflated by superspreaders. thus there was a domino effect of contagion. in , bats were identified as the reservoir of sars cov. there had previously been some speculation about bats being the reservoir, but there was no solid evidence, and the reservoir had been a mystery. some had suggested that proximity of people to avian species could possibly be a factor in the pathogenesis of sars, because of the importance of this process in avian influenza. however, this turned out not to be the case with sars. sars is a prototype of an emerging infectious disease (berger et al., ) . there is no evidence that sars cov existed in the human population prior to the outbreak of late - . the specific syndrome surprised the public health and medical communities, yet its general features did not, and the emergence of new diseases had been a familiar concept since the u.s. institute of medicine report of . at the same time, the rapidity of the appearance of sars and its very rapid spread at every scale fueled public apprehension, and even hysteria in some cases. evidence exists that history has been punctuated by relatively regular influenza epidemics and pandemics. the rapidity of epidemic spread, leading to pandemics, is largely determined by the velocity of the prevailing transportation modes. severe epidemics and pandemics are caused by genetic shift, whereby the viral genome expressing surface antigens (hemagglutinin and neuraminidase) undergoes relatively major change. relatively minor epidemics occur because of genetic shift, in which the surface antigens undergo minimal yet detectable changes in their configuration. following genetic shift, people have minimal immunity to the virus, and are susceptible. in one sense, each year influenza constitutes an emerging infection, because the precise genome of the influenza viruses and the surface antigens undergo change. similarly, whenever a pandemic occurs, influenza represents a more significant emerging infection. on the other hand, influenza represents a disease entity that is not new to the population. thus, it is a matter of semantics whether to consider influenza to be an emerging infection. avian influenza may constitute the next serious pandemic threat. it has been known for decades that genetic reassortment occurs in southeastern china because of the proximity of humans, avian species, and swine. an unusual number of influenza epidemics appear to arise there. however, the concern over avian influenza arises from a slightly different situation. it has been known for some time that no less than influenza subtypes -different configurations of surface antigens -can infect aquatic bird species. it has been wellestablished that several of these subtypes can infect humans, although recent experience suggests that all subtypes that circulate in avian species may have the potential to infect humans. this is one of the reasons that has given rise to concern over the possibility of an avian influenza pandemic. this theoretical concern moved closer to reality in hong kong in , when one influenza strain (h n ) was transmitted directly from poultry to humans. this took place in 'wet markets' -markets in which live poultry are densely packed, and where people co-mingle with their intended purchases. the transmission in appears to have been limited: only cases were confirmed. however, the case fatality ratio was high. six of the people died. transmission also occurred with another strain - h n -in , and in and there was widespread transmission and mortality among chickens in hong kong. because of a concern over possible transmission to humans, and because of the devastating economic potential in the poultry industry, containment of this epidemic in poultry was partly obtained by the slaughter of millions of chickens and other poultry. avian influenza viruses have shown some propensity, since , for transmission to humans. so far, human cases of influenza that have been identified as avian strains have been limited to approximately , and these have all been in asia. human-to-human transmission has been implicated in only a few cases. if this is the case, what is the concern over avian influenza? because of the tendency for influenza viruses to mutate, many virologists and epidemiologists predict that there is a high likelihood that a mutation could occur that would facilitate human-to-human transmission of h n and other avian subtypes that have been transmitted to humans. if this occurs, then there is little doubt that this strain would spread rapidly among the human population, and would spread locally, nationally, and between continents in a manner similar to sars. other epidemiologists and virologists are more circumspect in their predictions, and argue that the probability of a mutation that would increase the propensity of avian influenza to spread from human to human is unknown. a minority of authorities argue that the probability is low. thus, in assessing the overall threat of avian influenza, the crucial question is whether the virus will spread readily from human to human. at this point (mid- ) , it is unknown whether this will occur. however, it is prudent public health policy to bolster surveillance systems, and governments are stockpiling neuraminidase inhibitors, which are medications that can moderate the course of influenza if taken early in the course of clinical disease, or sometimes prevent the onset of symptoms if taken prophylactically. similarly, there has been great emphasis on vaccine development and stockpiling. in response to growing public concern over emerging infectious diseases, both domestically and internationally, as well as to both interest and concern in the medical and public health communities, a major conference on emerging viruses was held at rockefeller university in . the conference was cosponsored by several government agencies. the conference participants reached many conclusions, but two of them were that emerging infections had become a major focus for scientific research and that emerging infectious diseases had become and would remain a major public health challenge for the united states. accordingly, the institute of medicine of the national research council of the united states took a proactive role and sought funding for a major study of emerging infections. the study was funded by a number of government units, and in early , a high-powered committee met in washington for the first time to: identify significant emergent infectious diseases, determine what might be done to deal with them, and recommend how similar future threats might be confronted to lessen their impact on public health. (institute of medicine, : vi) the committee issued a report in that quickly became a standard scientific and policy reference on emerging infectious disease. emerging infections: microbial threats to health was the first major comprehensive discussion of how emerging infections arise, and how they might be addressed by the public health community. the committee also identified the six 'factors' or causes of emergence. briefly, the factors that this committee identified were the following: human demographics and behavior; technology and industry; economic development and land use; international travel and commerce; microbial adaptation and change; and the breakdown of public health measures. it is notable that five of these six factors are social factors that are consequences of changes in society. even microbial adaptation and change, such as the development of antimicrobial resistance as a response to selective pressure, has a large behavioral dimension. this is partly a response to a technical innovation -the development of antimicrobials -and partly a response to a behaviorthe prescribing of those antimicrobials. of course, one dimension of this factor is the nonselective and improper prescribing of antimicrobials. this has several dimensions: the prescription of antibiotics when none are needed, the prescription of broad-spectrum antibiotics when narrowspectrum antibiotics are sufficient, the free availability of antibiotics in many developing countries on the street and in pharmacies where no prescription is needed, and the free use of late-generation antibiotics in the food industry to promote the growth of cattle, chickens, and other animals intended for human consumption. so, in fact, all of the six factors of emergence are social and behavioral in nature. it is ironic that despite the fact that both institute of medicine reports concluded that the major causes of emergence have been social, there have been very few social analyses of emerging infections. for example, emerging infectious diseases, a new journal founded in in response to the growing importance of emerging infections, has an explicit aim of including a social understanding of emerging infections in its contents, yet there have been very few articles written by social scientists in this journal, and very few articles with any social content have been published. the main point is that the overwhelming understanding of emerging infections has been 'biomedical.' this is not a criticism of either the journal or of any field in public health or medicine. in large part, this is the result of the sociology of knowledge and science. for whatever reason, few social scientists have become involved in research on emerging infections, whereas the same cannot be said about chronic diseases. some researchers have asked the question of why emerging infectious diseases are emerging now and in the societies where they are emerging, and have sought a more contextual understanding of emerging infections. david bradley asks a very penetrating question: [a]ttaching a microbiological label to an outbreak. . .does not answer either the micro-scale questions such as ''why is there an outbreak here, now, of this size, affecting these people?'' nor does it answer the macro-questions such as ''why are there more (or fewer) outbreaks this decade than last?'' nor does it answer the question ''what drives the overall worldwide trends in such problems?'' (bradley, : ) for example, a number of individuals have argued that emerging infections may represent another stage in the epidemiologic transition. our understanding of emerging infections has not been totally devoid of social analysis. inequality and poverty have become a major focus for the social analysis of health and disease. the argument is that through a complicated series of pathways that are yet to be fully understood, both poverty and inequality result in poor health status. this has not been applied extensively to emerging infectious diseases, although paul farmer's ( ) insightful work has been applied to emerging infections. in his critical analysis of emerging infection, farmer asks, ''emerging for whom?'' in other words, the diseases that westerners might label as emerging may have been present or endemic in poorer societies for a long time: if certain populations have long been afflicted by these disorders, why are the diseases considered ''new'' or ''emerging''? is it simply because they have come to afflict more visible -read more ''valuable'' persons? this would seem to be an obvious question from the perspective of the haitian or african poor. (farmer, : ) in other words, farmer argues, the concept of emerging infectious diseases is one of epistemology -the theory of knowledge. how do emerging diseases come to be categorized as 'emerging'? by implication, many of these diseases have been present in poorer societies for a long time. the evidence affirms this. hiv was probably present in small foci in central africa for decades to centuries; ebola was similarly endemic in west africa for an unknown period, as was lassa fever. what is novel about the past few decades is greater interconnection between places, allowing diseases, and news of diseases, to spread; better methods of detection; and changing settlement geographies that have brought people into different forms of contact with animal reservoirs. the root cause of the infectious disease emergence is human action, both intentional and unintentional. most of this action is the result of cumulative individual acts on a mass scale. for example, the mass urbanization of society in poorer countries is the sum of millions of individuals who move from rural to urban areas. this is largely the result of the perceived economic opportunities in urban areas, and the 'push' factor of lack of opportunity in rural areas. yet, taken together, millions of individual moves result in urbanization, and this urbanization facilitates the spread of diseases by the respiratory route, the fecal-oral route, and many other modes of transmission. the institute of medicine committee also developed a set of policy recommendations. these concentrated in two areas: the need for vastly increased resources for interdisciplinary training in infectious diseases because of the depleted workforce resources in this area; and the need to develop new surveillance and public health response systems, since the committee had determined that emerging infections did, indeed, constitute a major public health threat to the united states. this report was issued with a great deal of publicity. the u.s. public's attention was already focused on emerging infectious diseases as a result of legionnaires disease, viral hemorrhagic fevers, and toxic shock syndrome. now there was a major quasi-governmental report by a group of the nation's leading scientists who issued the sobering conclusion that: even with unlimited funds, no guarantee can be offered that an emerging microbe will not spread disease and cause devastation. (institute of medicine, : ) part of the institute's report identified specific microbes and diseases that could possibly threaten public health in the future. three of these were e. coli :h , cryptosporidiosis, and hantavirus. the report was prescient, because within a few years there were serious outbreaks of all of these. in , which was the year after the iom report was issued, there was a major outbreak of cryptosporidiosis on the south side of milwaukee, wisconsin. it caused diarrhea, ranging from mild to severe, in over people. cryptosporidium parvum is a protozoan parasite; evidence in animal models is that ingestion of even one oocyst can result in severe gastrointestinal symptoms. in humans, as few as oocysts can produce these effects (king and monis, ) . it is impervious to usual methods of water treatment, and only recently has an effective medication become available. the milwaukee outbreak was probably due to groundwater absorption of cattle feces, subsequent runoff due to both heavy rains and snow melting, transport of the oocysts to river tributaries, and movement of the oocysts into lake michigan, which serves as the water supply for the south side of milwaukee. the filtration plant for that water was ineffective in eliminating the oocysts. many of these events are putative, but together they constitute a logical chain. meanwhile, research is still proceeding on the ecology of cryptosporidiosis. understanding is progressing, but it is still incomplete. e. coli :h was also mentioned in the iom report as being an emerging disease. in january , the washington state department of health ascertained that an outbreak of :h was occurring in the state, and this outbreak was associated with having eaten at jack in the box fast-food restaurants. subsequently, it became apparent that the epidemic was not limited to washington, but also included idaho and nevada. the epidemiologic investigation of this outbreak was intricate, and implicated a chain of events. first, because meat inspection in the united states was inadequate, one theory is that e. coli :h from the bowels of cattle had gotten into meat that was sent to market when cattle were slaughtered, and the bowel was probably nicked or severed. another is that under stress, cattle defecate over one another, and fecal matter from one cow can contaminate the hides of other cattle. second, when this meat was ground into hamburger, it increased the surface area of the meat by several orders of magnitude, thereby allowing the pathogen a great deal of exposure. third, once this hamburger meat was shipped to jack in the box restaurants, it appears that hamburgers were being systematically undercooked, below industry standards. this allowed the e. coli to survive and enter the hosts' systems. the consequences of such infection can be severe, and were in , with those who were symptomatic frequently suffering from bloody diarrhea, fever, cramps, and, in the worst case, hemolytic uremic syndrome. the pathogenesis of this disease was only partially understood in , but understanding is more complete in . the third disease that was mentioned in the iom report that occurred shortly after its publication was hantavirus. in may , in the four corners area of arizona, new mexico, california, and utah, several males who were otherwise in good health developed a sudden serious respiratory disease that was thought to be a rapidly progressing acute respiratory distress syndrome, since this was the immediate cause of death. however, it was noted that these cases had formed a cluster, and investigators tried to find some sort of common source to explain a possible environmental exposure to explain this serious and sometimes fatal syndrome. though hantavirus had never been described in the united states, serologic tests in patients showed a surprising seropositivity to hantavirus. it was apparent that this was the pathogen that had caused the dozen deaths associated with the outbreak. the chain of events that led up to the outbreak is now fairly clear. winter was unusually warm in the four corners area as a result of el nino, and the spring was also unusually rainy. these two conditions led to the rapid and plentiful growth of pinon trees, which provided food for a number of rodents. there is consensus that the deer mouse (peromyscus maniculatus) population increased by an order of magnitude. testing demonstrated that about % of the mice that were trapped after this epidemic were infected with hantavirus, and studies demonstrate that households from which infected individuals came were far more likely to have heavy rodent infestations than were households of controls. more rigorous studies eventually showed that transmission occurred from rats to humans, and that many of the cases, in this instance, were associated with crawling under houses and other places in which rodent exposure was likely to occur. by , many of the predictions of the first institute of medicine report ( ) had been realized, and understanding of emerging infectious diseases had improved. there was greater focus on globalization as a process of disease spread, and the attacks on the world trade center and pentagon on september , focused attention on terrorism. a new institute of medicine committee was formed to consider the nature of microbial threats and emerging diseases, and the report of this committee was issued in (institute of medicine, ) . this report represented a rethinking of the factors of emergence, and presented a more nuanced understanding of the causes of emerging diseases, most of which were still social at one level or another. bioterrorism ('intent to harm') was specifically mentioned as a factor of emergence, as was lack of political will. policy recommendations for surveillance, response, and training were more detailed than in the report, and there was a more urgent tone to the need to respond to emerging threats. in this report, the emphasis on biological and social interaction was strong: genetic and biological factors allow microbes to adapt and change, and can make humans more or less susceptible to infections. changes in the physical environment can impact on the ecology of vectors and animal reservoirs, the transmissibility of microbes, and the activities of humans that expose them to certain threats. human behavior, both individual and collective, is perhaps the most complex factor in the emergence of disease. emergence is especially complicated by social, political, and economic factors. . .which ensure that infectious diseases will continue to plague us. (institute of medicine, : ) increasing resistance to antibacterials, antivirals, and other antimicrobials is frequently grouped under the heading of 'emerging infections.' resistance is certainly a constantly growing and very major public health problem, but this is of importance to emerging infections only in the sense that diseases that were once highly treatable with first-and second-generation antimicrobials are no longer treatable by them. the selective pressures exerted by antimicrobials have made numerous pathogens resistant to even the newest antimicrobials due to mechanisms that are now understood. for example, many respiratory pathogens are no longer treatable by b-lactam antibiotics since their b-lactam rings are cleaved by b-lactamases. there are fluoroquinolone-resistant strains of neisseria gonorrhoeae, resistant strains of staphylococcus aureus, and so on. the problem is most severe in hospitals, where severe infections once responsive to vancomycin are now resistant to this glycopeptide. several new antimicrobials have been developed, in part to address vancomycin resistance, but resistance to these medications developed within a few years of their introduction. thus, antimicrobial resistance is both a community problem and a hospital problem. there is great concern over multiple drug-resistant tuberculosis, which is defined as tuberculosis that is resistant to two first-line medications, and extensively resistant tuberculosis, which has a more complex definition specifying several medications. there is not space in this article to explore antimicrobial resistance in greater depth. the relationship between people and pathogens has been an integral part of history, and will continue to be. the progress in the diagnosis, detection, and clinical management of infectious diseases has been substantial. indeed, fauci ( ) has gone so far as to argue that: the successful diagnosis, prevention, and treatment of a wide array of infectious diseases has altered the very fabric of society, providing important social, economic, and political benefits. nonetheless, infectious diseases, aggregated together, constitute the second leading cause of death worldwide, and in many regions, they account for the dominant cause. moreover, emerging diseases will continue to emerge, because of constantly changing social and demographic conditions, as well as selective pressures. the prototypical emerging infectious disease, hiv/aids, has an uncertain future in the long run. perhaps a vaccine will be developed that will be inexpensive, and perhaps distribution systems will be developed that will transport the vaccine to points of demand. perhaps antiretrovirals will become extremely inexpensive, and perhaps the failure rate for antimicrobials of % will be overcome. however, it is unlikely under present conditions that all of these improvements will occur. thus, the future of hiv/aids is more sobering. the same is true of antimicrobial resistance. in an age of optimism when antimicrobials were developed and used successfully -perhaps the first years of antimicrobial use -concern over resistance was minimal. however, the fact that organisms adapt to changing environmental conditions and threats is something that has not been realized only recently. the inevitability of adaptation is undeniable, and the only way to meet the challenges of resistance is through a combination of appropriate antimicrobial use (including the use of narrow-spectrum antibiotics as soon as possible in the clinical course of an individual) and the development of new antimicrobials, as well as new understanding in the physiology and genetics of microorganisms, which might lead to the development of new technologies in addressing the pathogenic basis of disease. see also: aids, epidemiology and surveillance; antimicrobial resistance; severe acute respiratory syndrome (sars); transmissible spongiform encephalopathies; tuberculosis: overview; west nile disease. acromegaly a condition produced by overproduction of growth hormone, leading to excessive growth of the hands, feet, and jaw in postpubertal individuals and giantism in prepubertal children. adrenal glands two endocrine organs situated above the kidneys that make a series of hormones: cortisol (stress hormone), aldosterone (salt-retaining hormone), and catecholamines (stress hormones). autoimmunity a situation in which part of the body, often an endocrine organ, is recognized as 'foreign,' triggering an immune response that tends to lead to destruction of the endocrine gland. cushing syndrome excessive production of cortisol with loss of the normal circadian variation leading to weight gain, hypertension, and type diabetes mellitus. g protein proteins within the cell that transfer the hormone message from the receptor to specific parts of the cell. graves disease a combination of thyroid overactivity due to an autoimmune disorder and eye problems. hypothalamus part of the brain containing control centers for appetite, thirst, and pituitary hormone secretion. pituitary major regulator of hormone production. secretion of hormones regulated by the hypothalamus. severe acute respiratory syndrome (sars): paradigm of an emerging viral infection new and resurgent infectious: prediction, detection, and management of tomorrow's epidemics infections and inequalities: the modern plagues infectious diseases: considerations for the st century emerging infections: microbial threats to health in the united states microbial threats to health critical processes affecting cryptosporidium oocyst survival in the environment living with bse fruit bats as reservoirs of ebola virus plagues and peoples factors in the emergence of infectious diseases lassa fever: epidemiology, clinical features, and social consequences variant creutzfeldt-jakob disease sars molecular epidemiology: a chinese fairy tale of controlling an emerging zoonotic disease in the genomics era the coming plague: newly emerging diseases in a world out of balance new and resurgent infections: prediction, detection, and management of tomorrow's epidemics the changing face of disease: implications for society the challenge of emerging and re-emerging infectious diseases an emptying quiver: antimicrobial drugs and resistance the politics of emerging and resurgent infectious diseases disease in evolution: global changes and emergence of infectious diseases endocrine diseases: overview p c hindmarsh key: cord- - kpn db authors: weinstein, robert a.; singh, kamaljit title: laboratory-acquired infections date: - - journal: clin infect dis doi: . / sha: doc_id: cord_uid: kpn db laboratory-acquired infections due to a wide variety of bacteria, viruses, fungi, and parasites have been described. although the precise risk of infection after an exposure remains poorly defined, surveys of laboratory-acquired infections suggest that brucella species, shigella species, salmonella species, mycobacterium tuberculosis, and neisseria meningitidis are the most common causes. infections due to the bloodborne pathogens (hepatitis b virus, hepatitis c virus, and human immunodeficiency virus) remain the most common reported viral infections, whereas the dimorphic fungi are responsible for the greatest number of fungal infections. because of the increasing attention on the role of the laboratory in bioterrorism preparation, i discuss the risk of laboratory-acquired infection with uncommon agents, such as francisella tularensis and bacillus anthracis. physicians who care for a sick laboratory worker need to consider the likelihood of an occupationally acquired infection while advising exposed laboratory workers about postexposure prophylaxis. in addition, physicians should be aware of the importance of alerting the laboratory if infection with a high-risk agent is suspected. formed with a sputum specimen and returned a positive result for sars coronavirus. additional epidemiologic investigation revealed that the laboratory where he worked was also involved in research on sars coronavirus and that one of the cell cultures of west nile virus was contaminated with the same infecting strain of sars coronavirus. although this case represents an exceptional event, it serves to highlight the inherent risk posed to laboratory workers by virtue of their occupation. infectious diseases specialists may be asked to evaluate an ill laboratory worker. this article provides a framework for assessment of such patients by reviewing the published literature on infections acquired in the clinical diagnostic laboratory. laboratory infections due to a wide variety of bacteria, viruses, rickettsiae, fungi, and parasites have been described in the literature. the largest survey of infections was reported in by pike [ ] , who found that laboratory-acquired infections were due to agents, although agents accounted for % of the cases (table ) [ , ] . at least deaths have resulted from laboratory-acquired infection [ , ] . however, care should be taken in the interpretation of historical surveys, because some infections (e.g., q fever, venezuelan equine encephalitis, and dermatomycoses) occurred predominantly in research and animal laboratories, and many of these infections (e.g., psittacosis and typhoid) were reported before [ , ] . surveys of diagnostic laboratory workers in the united kingdom conducted since have reported that tuberculosis and enteric infections (especially shigellosis) were the most common laboratory-acquired infections [ , ] . a follow-up survey of uk laboratories from - reported that gastrointestinal infections predominated, particularly shigellosis [ ] . similar results were obtained from a survey of clinical microbiology laboratories in utah from the period - , with shigellosis reported to be the most common laboratory-acquired infection [ ] . these results suggest a shift in the pattern of laboratoryacquired infections, with enteric infections predominating. however, no denominator data have been provided that would help determine the actual risk or incidence of infection for laboratory workers. in a - survey of clinical laboratory directors who participate in clinmicronet, an online forum sponsored by the american society of microbiology, % of laboratories reported the occurrence of at least laboratory-associated infection (table ) [ ] . the most common laboratory-acquired infections were shigellosis, brucellosis, and salmonellosis. in contrast, the highest incidences of infection were associated with brucella species ( cases per , laboratory technologists, compared with . cases per , persons in the general population) and neisseria meningitidis ( . cases per , laboratory technologists, compared with . cases per , persons in the general population). of note, the annual number of laboratory-acquired infections has steadily decreased since [ , ] . for example, survey results from the united kingdom from the period - found an infection incidence of . cases per , person-years, compared with an incidence of . cases per , person-years during the period - [ , ] . this finding undoubtedly reflects an improved awareness of the hazards of working with infectious agents and placement of a greater emphasis on laboratory safety, such as through the use of personal protective equipment. in addition, there have been improvements in laboratory design, such as the use of laminarflow biological safety cabinets (bscs), which provide unidirectional airflow that entraps any aerosolized particles in the airstream and subsequently into air filters [ ] . bacteria account for the largest proportion of infections ( %) in diagnostic laboratories, with over different species reported [ ] . below, i highlight common causes of infection that are currently of most concern. brucella species. brucellosis continues to be the most frequently reported laboratory-associated bacterial infection [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in the united states, brucella infection is one of the most common laboratory-acquired infections, accounting for % of laboratory-acquired bacterial infections and % of deaths due to laboratory infection [ ] . aerosolization is the major source of transmission, but the bacterium can also be transmitted via direct contact. however, in many reported cases, it has not been possible to accurately determine the mechanism for transmission. the disease has also affected janitors and persons who have made brief visits to the laboratory [ ] . person-to-person transmission is rare, although a case of brucella infection transmitted from a laboratory worker to a spouse has been documented, presumably through sexual intercourse [ ] . although no controlled studies have been performed to assess the benefit of postexposure prophylaxis (pep), it should be considered for laboratory workers who have high-risk exposure to brucella species (e.g., because of direct manipulation of brucella cultures outside of laminar-flow bscs). doxycycline (or trimethoprim-sulfamethoxazole for pregnant women) and rifampin have been frequently used for pep [ , ] . in a report from canada, laboratory workers were exposed to brucella melitensis, which had been isolated from a patient from india with a draining chest sinus. six laboratory workers were offered pep with doxycycline ( mg twice daily) and rifampin ( mg daily) for weeks. only person declined pep; weeks after exposure, the technologist developed fever (temperature, р Њc), and sets of blood cultures confirmed brucellosis. none of the other laboratory workers developed infection or evidence of seroconversion. follow-up serologic tests should be performed for all exposed individuals, probably every fortnight for the first months, then every month for an additional - months [ , ] . n. meningitidis. sejvar et al. [ ] examined the risk of laboratory-acquired n. meningitidis infection using postings on listservs, to obtain reports of laboratory-acquired meningococcal disease occurring worldwide during the period - . sixteen cases of probable laboratory-acquired meningococcal disease were identified, including cases in the united states. nine cases ( %) were due to serogroup b, and ( %) were due to serogroup c. overall, cases ( %) were fatal. all cases occurred among clinical microbiologists and were likely due to exposure to aerosols containing n. meningitidis. the calculated attack rate was cases per , microbiologists, compared with an attack rate of . cases per , persons among the general population. the results of this analysis suggest that laboratory-acquired meningococcal disease represents a significant occupational hazard to clinical microbiologists. although primary prevention of laboratory-acquired meningococcal disease should focus on appropriate handling and manipulation of cultures in a laminar-flow bsc, all laboratory microbiologists should be offered the tetravalent vaccine [ ] . it will decrease-but not eliminate-the risk of infection, because it is less than % effective and does not provide protection against serogroup b [ ] . microbiologists who inadvertently manipulate invasive n. meningitidis isolates on an open bench-top in a manner that could result in aerosolization should consider pep with either a single -mg dose of ciprofloxacin or mg of rifampin given twice daily for days [ ] . mycobacterium tuberculosis. early surveys of laboratoryacquired tuberculosis found an incidence of tuberculosis among laboratory personnel - times greater than that in the general population [ , ] . however, unless there is some accident to which the infection can be traced, it is difficult to state with certainty that tuberculosis was laboratory acquired, because of the potential for exposure outside of the workplace and the long incubation period before symptomatic disease develops. m. tuberculosis can be isolated from a variety of clinical spec-imens, and manipulation of specimens or cultures that generate aerosols is the most important risk factor for acquiring tuberculosis in the laboratory. the high infectivity of m. tuberculosis is related to the low infective dose for humans ( % infective dose, ! bacilli) [ ] . the use of laminar-flow bscs for aerosol-generating manipulations with biosafety level у practices and fit-tested respirators with n- rating should be routinely used [ , ] . laboratory personnel should undergo an annual mantoux purified protein derivative skin test or an interferong release assay to demonstrate conversion. persons with positive test results should be evaluated for active tuberculosis by chest radiography. in the event of accidental exposure, laboratory workers should be tested and months after the accident, and persons with new conversion should be offered prophylaxis [ ] . francisella tularensis. f. tularensis is a fastidious, gramnegative coccobacillus that is infrequently encountered in the clinical microbiology laboratory, but it has gained increased importance because of its possible use as a bioterrorism agent [ ] . the greatest hazard to laboratory workers is from exposure to infectious aerosols from manipulation of cultures. clinicians should be aware that, although patients with tularemia, brucellosis, or endemic mycoses do not pose a communicable disease risk to health care workers, specimens obtained from these patients pose a significant threat to laboratory workers. shapiro et al. [ ] described laboratory workers who were exposed to f. tularensis after clinicians failed to notify the laboratory about a suspected case of pneumonic tularemia in a -year-old man who eventually died. blood cultures, sputum cultures, and autopsy pleural fluid were all positive for gramnegative coccobacilli, which failed to grow on sheep blood agar and macconkey agar and were initially misidentified as haemophilus species. eleven laboratory workers and autopsy personnel with high-risk exposure to f. tularensis received pep with doxycycline ( mg twice daily for days), with no resulting infections. to minimize the risk of exposure of laboratory workers, any suspicion about infection with a high-risk pathogen should be immediately communicated to the laboratory. this practice not only protects the staff but also benefits the patient, because a faster and more directed laboratory evaluation can be initiated. bacillus anthracis. before the outbreak of bioterrorism-related anthrax in the united states, anthrax was an uncommon illness in the united states [ ] . in march , the centers for disease control and prevention were alerted about a laboratory worker who had received a diagnosis of cutaneous anthrax [ ] . one day after he had cut himself over the right jaw while shaving, the patient assisted a coworker in moving vials of b. anthracis from the laminar-flow bsc in the main laboratory to a freezer. the patient had handled the vials with- out gloves but washed his hands with soap and water. over the next days, the cut over the laboratory worker's jaw increased in size, and he developed low-grade fever, cervical lymphadenopathy, and cellulitis around the scab. cultures of specimens from beneath the scab were positive for b. anthracis, and the patient was treated with intravenous ciprofloxacin and doxycycline and discharged while receiving ciprofloxacin. epidemiologic investigation of this case revealed that the tops of the vials tested positive for b. anthracis. although all specimen processing surfaces were decontaminated with % bleach solution, storage vials were sprayed with % isopropyl, because bleach caused labels to become dislodged. this case brings the number of cases of bioterrorism-related anthrax identified since october to and is the first laboratory-acquired case of bioterrorism-related anthrax. enteric pathogens. salmonellosis is one of the most common reported infections in published surveys [ , , , , ] . blaser et al. [ ] reported cases of laboratory-acquired typhoid fever in the united states over a -month period from to , representing . % of the sporadic cases of typhoid fever reported in the united states. of particular concern was that a number of cases occurred in individuals who had not directly worked in the microbiology laboratory, including cases in family members of a microbiologist who worked with salmonella culture, of which proved to be fatal. in fact, ty-phoid fever has accounted for more reported fatalities than any other laboratory-acquired infection [ ] . of note, many earlier reported cases of typhoid fever were associated with mouth pipetting and handling of proficiency test strains-practices which are now avoided [ , , ] . in recent surveys, shigella species was the most frequently identified agent of laboratory-acquired infection [ ] [ ] [ ] . one explanation for the large number of reported cases of laboratory-acquired shigellosis is that shigella species are more virulent and require a much lower inoculum to cause illness. however, it is also probably true that microbiology laboratory staff who develop diarrhea are more likely to attempt to establish a cause for their illness, compared with the general population. a number of other enteric pathogens have also been identified as less common causes of laboratory-acquired infection, including clostridium difficile and escherichia coli o :h [ , ] . viral agents transmitted through blood and bodily fluids cause most of the laboratory-acquired infections in diagnostic laboratories and among health care workers [ ] . although the viral hemorrhagic fevers incite the most fear and dominate the imagination of the media and public, the viruses responsible are rare causes of laboratory infection [ , ] . however, there is always the possibility that an agent not previously seen may be encountered. this occurred in , when workers were infected while handling tissue specimens from african green monkeys, with deaths resulting [ ] . the causative agent was named marburg virus, after the town in germany where most cases occurred. of the common blood-associated viruses, hepatitis b virus (hbv) is the most common cause of laboratory-acquired infection [ ] . the incidence of hbv infection among all health care workers in the united states is estimated to be . - . infections per workers, which is - times than the level for the general population [ ] . it is encouraging that, in the most recent surveys of laboratory-acquired infections in the united kingdom, there were no reported cases of hbv infection among laboratory workers [ , ] . this finding is probably related to the use of universal precautions when handling blood specimens, improvements in needleless devices, and the availability of immunization. because hepatitis b is a vaccine-preventable disease, all laboratory workers should be offered the hepatitis b vaccine without charge. nonimmunized laboratory workers who have percutaneous, ocular, or mucous membrane exposure to contaminated blood should receive pep with hepatitis b immunoglobulin and vaccine [ ] . during - , there were confirmed cases of acute hepatitis c reported to the centers for disease control and prevention, with occupational exposures ( . %) to blood [ ] . however, there are few data on the incidence of hepatitis c among laboratory workers, and only single case reports in surveys have been performed in the united states and the united kingdom [ ] [ ] [ ] . human immunodeficiency virus (hiv) infection associated with exposure to contaminated blood or body fluids probably causes the greatest concern. the risk of hiv transmission after a percutaneous exposure to hiv-infected blood has been estimated to be ∼ . %, and the risk has been estimated to be ∼ . % after exposure to a mucous membrane [ , ] . data on occupational transmission of hiv from the period - revealed a total of health care workers in the united states with occupationally acquired hiv infection; % of these health care workers were laboratory workers [ ] . in the event of laboratory-based exposure from a source person with hiv infection, or if information suggests the likelihood that the source person is hiv infected, immediate referral to employee health for hiv pep should be sought [ ] . the dimorphic fungi blastomyces dermatitidis, coccidioides immitis, and histoplasma caspsulatum are responsible for the majority of laboratory-acquired fungal infections in the united states (table ) [ , , ] . although cutaneous infections due to accidental inoculation are documented, most laboratory-acquired infections are caused by inhalation of infectious conidia from the mold form, resulting in pulmonary infection. the mere lifting of a culture plate lid often suffices to cause the release of large numbers of conidia, and should a sporulating culture be dropped, millions of conidia would be dispersed. the risk of infection in the mycology laboratory probably is low, because handling of specimens is done in laminar-flow bscs, and culture plates are secured with shrink seal to prevent accidental opening. however, a greater risk of infection is likely on the aerobic culture bench, because colonies of b. dermatitidis and c. immitis can grow on routine media and may be visible within - days. it cannot be overemphasized that clinicians who suspect a dimorphic fungal infection should immediately alert the microbiology laboratory. laboratory-acquired parasitic infections are uncommon in the diagnostic microbiology laboratory [ , , ] . approximately cases of laboratory-acquired infection, with a variety of blood and intestinal protozoa, have been reported (table ) [ , ] . most of these cases occurred in research and reference laboratories. readers are referred to the review by herwaldt [ ] . fifty-two cases of malaria among laboratory workers and health care workers have been reported, with cases reviewed by herwaldt [ ] ; cases were due to plasmodium cynomolgi, cases were due to plasmodium vivax, and cases were due to plasmodium falciparum [ , ] . most of the cases of p. vivax and p. falciparum infection occurred among health care workers and laboratory workers rather than among researchers and resulted from needlestick injuries that occurred while obtaining blood or preparing blood smears from patients [ ] . infection due to intestinal protozoa are uncommon in clinical diagnostic laboratories [ ] . one case of giardiasis was reported in a clinical laboratory technologist who processed specimens, many of which were in leaky containers. one case of isospora belli infection occurred in a technologist who examined numerous stool specimens from a patient infected with i. belli. laboratory-acquired infection represents an occupational hazard unique to laboratory workers, especially those in the microbiology laboratory. exposures may occur inadvertently, may not even be recalled, or may result from lapses in technique leading to accidental inoculation. however, not every exposure results in infection. a risk assessment for infection based on the host's immune system, mechanism of the exposure, infectious dose of the exposure, virulence of the agent, use of personal protective equipment, and immunization status needs to be performed. the accurate quantification of such risk is unfortunately difficult, because there is no systematic reporting system that monitors the number of laboratory-related exposures and infections. the centers for disease control and prevention has recently convened a committee to address these issues that will, i hope, provide evidence-based guidelines on exposure risk and use of pep. laboratory associated infections and biosafety laboratory-acquired severe acute respiratory syndrome laboratory-associated infections: summary and analysis of cases past and present hazards of working with infectious agents laboratory-associated infections: incidence, fatalities, causes and prevention continuing importance of laboratoryacquired infections incidence of tuberculosis, hepatitis, brucellosis and shigellosis in british medical laboratory workers infections in british clinical laboratories, - a survey of infections in united kingdom laboratories, - infections acquired in clinical laboratories in utah bacterial and fungal infections among diagnostic laboratory workers: evaluating the risks evidence-based biosafety: a review of the principles and effectiveness of microbiological containment measures prevention of laboratoryacquired brucellosis analysis of risk factors for laboratory-acquired brucella infections the spanish co-operative group for the study of laboratory-acquired brucellosis. laboratory-acquired brucellosis: a spanish national survey laboratory-acquired brucellosis brucella abortus infection acquired in microbiology laboratories exposure of hospital personnel to brucella melitensis and occurrence of laboratory-acquired disease in an endemic area epidemiology of laboratory-associated infections laboratory infections due to brucella person-to-person transmission of brucella melitensis brucellosis in pregnant women assessing the risk of laboratoryacquired meningococcal disease laboratory-acquired meningococcal disease-united states centers for disease control and prevention. prevention and control of meningococcal disease: recommendations of the advisory committee on immunization practices (acip) incidence of tuberculosis among workers in medical laboratories centers for disease control and prevention and national institutes of health. biosafety in microbiological and biomedical laboratories mycobacterium: general characteristics tularemia as a biological weapon: medical and public health management exposure of laboratory workers to f. tularensis despite a bioterrorism procedure the sverdlovsk anthrax outbreak of suspected cutaneous anthrax in a laboratory worker-texas fatal salmonellosis originating in a clinical microbiology laboratory acquisition of typhoid fever from proficiency testing specimens acquisition of typhoid fever from proficiency testing specimens nosocomial and laboratory-acquired infection with escherichia coli o zur atiologie einer unbekanten, von affen ausgegangen menschlichen infektionskrankheit the risk of hepatitis b infection among health care professionals in the united states: a review surveillance for acute viral hepatitis-united states occupational risk of human immunodeficiency virus infection in healthcare workers: an overview italian study group on occupational risk of hiv infection. the risk of occupational human immunodeficiency virus in health care workers surveillance for occupationally acquired hiv infection-united states updated us public health service guidelines for the management of occupational exposures to hiv and recommendations for postexposure prophylaxis laboratory-acquired parasitic infections form accidental exposures potential conflicts of interest. k.s. has served on the speakers' bureau for wyeth. key: cord- - dup sr authors: lu, victor m.; menendez, ingrid; levi, allan d.; komotar, ricardo j. title: letter to the editor: lessons to learn from the coronavirus disease (covid- ) pandemic for international medical graduate applicants and united states neurosurgery residency programs date: - - journal: world neurosurg doi: . /j.wneu. . . sha: doc_id: cord_uid: dup sr nan t he opportunity to participate in a neurosurgery residency program within the united states is highly sought after by both american and international medical graduates (imgs). estimates suggest %e % of all residents in u.s. neurosurgery residency programs are indeed imgs, , typically supported by either a j- (exchange) or h -b (work) visa. in light of the current covid- pandemic, a number of changes affecting the visa process in the united states has revealed particular immigration policies that are subject to change without notice. sudden changes can affect when an incoming img resident can expect to start and therefore when a u.s. neurosurgery program can expect to have its full complement of residents. we highlight herein the key lessons learned from the current pandemic for potential img neurosurgery applicants and programs to consider. these will ensure both applicants and programs are better equipped to withstand any sudden changes to immigration conditions in the future. . applicants should plan to be in the united states before match day. in the early stages of the covid- pandemic, multiple countries, including the united states, installed travel bans both in and out of the country. the number of possible flights to the united states decreased, including from lebanon and india, the largest contributors of img residents to u.s. neurosurgery programs. in this scenario, all successful img applicants would not have been able to physically reach their program were they not in the united states before these changes, impacting their application for various licenses and completion of scheduled orientations needed to legally commence residency. therefore, being present in the united states before match day is recommended to ensure that if an img candidate is successful, changes in travel policies and plans will not impact their ability to start residency on time. . programs should not solely rely on premium processing for h -b visas. as lockdowns in the united states began, the u.s. citizenship and immigration services suspended premium processing of h -b visas, which would have greatly impacted incoming img residents. this is because the time between match day and the start of the residency program is typically months, and the time for h -b petitions preecovid- required months on average to be approved. premium processing was the sole avenue in which these petitions could have been approved within the -month turnaround, as it expedites the process. yet, with the suspension of h -b processing, incoming img residents and programs would have had no choice but to delay their start date for an uncertain period of time waiting for their h -b to be approved. . applicants and programs should always have immigration and visa support. the most recent presidential executive order in response to covid- suspended the entry of all j- and h -b visa holders from overseas entirely until the end of . although this occurred in june , if it had occurred earlier, then any new img resident residing outside the united states would not have been eligible to enter the united states until , and perhaps even apply for visa support then. it is difficult for a lay person to interpret if neurosurgery would have satisfied the sole exception to this order that those "involved with the provision of medical care to individuals who have contracted covid- and are currently hospitalized" would be allowed entry at the discretion of the customs officer. this is why accessible and contemporary immigration and visa support is crucial for any incoming img resident and program to properly interpret these caveats. . applicants and programs should start preparing as soon as possible. an inevitable consequence of this covid- pandemic is the backlog of visa petitions that have accumulated in the time of lockdown. this will likely lead to longer processing times for months once all the executive orders are completed. if the order is extended further beyond into , who is to say new incoming img residents will need to apply for visas even earlier to ensure maximum time is given for their visa support to be approved. moving forward, the impact of the backlog could even last up until the time img neurosurgery residents need to renew their visas, as neither the j- nor h -b lasts for years. early preparation will allow imgs and programs the best chance to ensure any possible delays in processing do not impact the start or continuation of training for img residents. the current covid- pandemic has shed light on how difficult the immigration process can be for prospective img applicants and u.s. neurosurgery programs, as well as how unpredictable it can be. given both the short turnaround from match day to the start of residency, as well as the -year duration of neurosurgery residency, there are multiple considerations future img applicants, current img residents, and programs should prepare for to ensure that their application, training, and service are not compromised. informed preparation will serve all involved well to be better equipped to withstand any sudden changes to immigration circumstances in the future, even after the pandemic has abated. the path to u.s. neurosurgical residency for foreign medical graduates: trends from a decade geographic distribution of international medical graduate residents in u.s. neurosurgery training programs citizens: beirut international airport closure embassy and consulates in india. status of repatriation flights to the united states uscis announces temporary suspension of premium processing for all i- and i- petitions due to the coronavirus pandemic proclamation suspending entry of aliens who present a risk to the u.s. labor market following the coronavirus outbreak conflict of interest statement: the authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.https://doi.org/ . /j.wneu. . . . key: cord- -lyewg c authors: bloomfield, sally f.; aiello, allison e.; cookson, barry; o'boyle, carol; larson, elaine l. title: the effectiveness of hand hygiene procedures in reducing the risks of infections in home and community settings including handwashing and alcohol-based hand sanitizers date: - - journal: am j infect control doi: . /j.ajic. . . sha: doc_id: cord_uid: lyewg c infectious diseases (id) circulating in the home and community remain a significant concern. several demographic, environmental, and health care trends, as reviewed in this report, are combining to make it likely that the threat of id will increase in coming years. two factors are largely responsible for this trend: first, the constantly changing nature and range of pathogens to which we are exposed and, secondly, the demographic changes occurring in the community, which affect our resistance to infection. this report reviews the evidence base related to the impact of hand hygiene in reducing transmission of id in the home and community. the report focuses on developed countries, most particularly north america and europe. it also evaluates the use of alcohol-based hygiene procedures as an alternative to, or in conjunction with, handwashing. the report compiles data from intervention studies and considers it alongside risk modeling approaches (both qualitative and quantitative) based on microbiologic data. the main conclusions are as follows: ( ) hand hygiene is a key component of good hygiene practice in the home and community and can produce significant benefits in terms of reducing the incidence of infection, most particularly gastrointestinal infections but also respiratory tract and skin infections. ( ) decontamination of hands can be carried out either by handwashing with soap or by use of waterless hand sanitizers, which reduce contamination on hands by removal or by killing the organisms in situ. the health impact of hand hygiene within a given community can be increased by using products and procedures, either alone or in sequence, that maximize the log reduction of both bacteria and viruses on hands. ( ) the impact of hand hygiene in reducing id risks could be increased by convincing people to apply hand hygiene procedures correctly (eg, wash their hands correctly) and at the correct time. ( ) to optimize health benefits, promotion of hand hygiene should be accompanied by hygiene education and should also involve promotion of other aspects of hygiene. the effectiveness of hand hygiene procedures in reducing the risks of infections in home and community settings including handwashing and alcohol-based hand sanitizers there can be no doubt that advances in hygiene during the th and th centuries, along with other aspects of modern medicine, have combined to improve both the length and quality of our lives. however, since the middle of the th century, following the development of vaccines and antimicrobial therapy, and with serious epidemics of the ''old'' infectious enemies such as diphtheria, tuberculosis, and others apparently under control, hygiene has tended to lose its prominent position, and the focus of concern has shifted to degenerative and other chronic diseases. nowhere has the decline in concern about hygiene been more evident than in the home and community. however, whereas advances in medicine and public health seemed, at one time, to offer the possibility that infectious diseases (id) might soon be a thing of the past, it is now clear that this is not the case. in the past years, concern about id and the need for prevention through home and community hygiene has moved steadily back up the health agenda. between and , deaths attributable to id increased by % in the united states alone, representing the third leading cause of death among us residents. two factors are largely responsible for this trend: first, the constantly changing nature and range of pathogens to which we are exposed and, secondly, the changes occurring in the community, which affect our resistance to infection. to what extent our more relaxed attitudes to hygiene practice have contributed to these trends is not known, but poor hygiene is a significant factor for a large proportion of the gastrointestinal (gi), skin, and respiratory tract (rt) infections, which make up the greatest part of the id burden. prior to approximately , common pathogens such as rotavirus, campylobacter, legionella, escherichia coli (e coli) o , and norovirus were largely unheard of. whereas methicillin-resistant staphylococcus aureus (mrsa) and clostridium difficile (c difficile) were once considered largely hospital-related problems, this is no longer the case. now, community-associated mrsa (ca-mrsa) strains are a major public health concern in north america and, increasingly, in europe. most recently, the severe acute respiratory syndrome (sars) outbreak and concerns about avian flu have raised awareness of the potential for transmission of respiratory viruses via hands and surfaces. demographic trends mean that the proportion of the population in the community who are more vulnerable to infection is increasing, whereas trends toward shorter hospital stays and care in the community also demand increased emphasis on care of ''at-risk'' groups in the home who require protection from infection. in assessing the potential for reducing id transmission through hygiene practice, it is recognized that contaminated hands and failure to practice hand hygiene are primary contributors. in this report, we review the evidence base related to the impact of hand hygiene in reducing transmission of id in the home and community. this report focuses on developed countries, most particularly north america and europe, within the context of renewed public health concerns about ids and their impact on health and well-being. the review also evaluates the use of alcohol-based hand hygiene procedures as an alternative to, or in conjunction with, handwashing. these products are defined by a number of different terms in europe and north america (hand sanitizers, handrubs, and others). for the purposes of this report, we will refer to them as alcohol-based hand sanitizers (abhs). although this report focuses primarily on the home, it is recognized that the home forms a continuum with public settings such as schools, offices, and public transport and cannot be considered totally in isolation. nevertheless, the hand hygiene practice framework proposed in this review is largely also applicable to ''out of home'' settings. this report compiles data from intervention studies and considers it alongside risk modeling approaches based on microbiologic data. currently, there is a tendency to demand that, in formulating evidence-based policies and guidelines, data from intervention studies should take precedence over data from other approaches. although there are those who still adhere to this, it is accepted increasingly that, as far as hygiene is concerned, because transmission of pathogens is highly complex and involves many different pathogens each with multiple routes of spread, decisions regarding infection control must be based on the totality of evidence including microbiologic and other data. this document is intended for infection control and public health professionals who are involved in developing hygiene policies and promoting hygiene practice for home and community settings, including those involved with food and water hygiene, care of domestic animals, pediatric care, care of elderly adults, and care of those in the home who may be at increased risk for acquiring or transmitting infection. the purpose of the review is to provide support for those who work at the interface between theory and practice, particularly those involved in developing policies for the home and community, by providing a practical framework for hand hygiene practice together with a comprehensive review of the evidence base. in recent years, a significant amount of research has been done to identify strategies for changing hygiene behavior. whereas those who manage hygiene improvements often choose to promote hygiene by educating people on the links between hygiene and health, one of the lessons that has been learned is that traditional (cognitive) approaches can raise awareness but do not necessarily achieve the desired effects. if practices such as handwashing are to become a universal norm, a multidimensional promotion that engages the public is needed to persuade people to change their behavior. although we recognize that this aspect is fundamental, it is outside the scope of this report and is reviewed elsewhere. [ ] [ ] [ ] [ ] [ ] whereas, in the past, research and surveillance largely focused on health care-associated and foodborne illnesses, increasing resource is now being allocated to generating data that give a better view of the extent to which infections are circulating in the community; how they are being transmitted; and how this varies from one region, country, or community to another. although the data in the following section represent a useful overview, we note that the data collection methods differed significantly from one study to another, which means that comparisons from different geographic locations must be interpreted with care. current trends in communicable ids in europe are described in more detail in the recent ( ) european communicable disease epidemiological report from the european centre for disease prevention and control (ecdc). infectious gi disease and hygiene foodborne disease. rates of foodborne illness remain at unacceptably high levels, despite the efforts of food producers to ensure the safety of the food supply. raw meat and poultry and fruits and vegetables bought at retail premises may be contaminated with pathogens. good hygiene practices during food preparation in the home are therefore essential in preventing cross contamination of prepared foods from raw foods and preventing contamination of food by infected household members or domestic animals. the european food standards agency (efsa) report and the ecdc report cite campylobacteriosis as the most reported animal infection transmitted to humans. in , reported campylobacter infections increased by . % compared with the previous year, rising to an incidence rate of . cases per , people. the efsa states that the source of most human campylobacter infections is related to fresh poultry meat. on the other hand, salmonella infections fell by . % in to an incidence of . cases per , ( , reported cases). the world health organization (who) report concluded that approximately % of reported foodborne outbreaks in the who european region over the past decade were caused by food consumed in private homes. the report cites several factors as ''critical for a large proportion of foodborne diseases'' including use of contaminated raw food ingredients, contact between raw and cooked foods, and poor personal hygiene by food handlers. united kingdom data show that food poisoning notifications reached a peak in - and has since declined but remains in excess of , per year. in reality, the burden of food poisoning is much higher because most cases go unreported; according to the uk food standards agency, the true number of cases is approximately . million per year. in , mead et al reported on food-related illness in the united states, using data from a range of sources including national surveillance and community-based studies. they estimated that foodborne illness in the united states causes million illnesses, , hospital admissions, and deaths each year. most frequently recorded pathogens were campylobacter, salmonella, and norovirus, which accounted for . %, . %, and . %, respectively, of estimated foodborne illnesses. data suggest that the total number of reported outbreaks has not declined substantially in recent years, ranging from to outbreaks and between , and , cases per year for the years to . other infectious gi disease. from recent investigations, it is now recognized that a substantial proportion of the total infectious gi disease burden in the community is because of person-to-person spread within households, particularly for viral infections, where it is most often the cause. person-to-person transmission in the home can occur by direct hand-to-mouth transfer, via food prepared in the home by an infected person, or by transmission because of aerosolized particles resulting from vomiting or fluid diarrhea. apart from transmission by inhalation of airborne particles, these infections are preventable by good hygiene practice. the who report stated that, of the total gi infection outbreaks (including foodborne disease) reported in europe during and , % and %, respectively, were due to person-to-person transmission. in the united kingdom, it is estimated that up to % of gi infection results from person-to-person tranmsission. a study of united kingdom outbreaks suggested that % of salmonella outbreaks and more than half of e coli o outbreaks are transmitted by nonfoodborne routes. national surveillance systems vary in their methods of data collection but mostly focus on foodborne disease. inevitably, this means that data on gi illnesses relate mainly to large foodborne outbreaks in restaurants, hospitals, and others, whereas sporadic nonfoodborne cases in the general community go largely unreported. in the united kingdom, even when ''household'' outbreaks are reported, they mostly involve home catering for parties and other functions and are therefore mainly foodborne outbreaks. because milder cases of gi illness often go unreported, this means that the overall gi infection burden, particularly that which is not foodborne, is unknown; the most informative data on the overall burden of infectious gi illness (both foodborne and nonfoodborne) in the community come from various community-based studies, which have been carried out in europe and the united states and are reviewed below. two large community studies have been carried out in europe: one in the united kingdom and the other in the netherlands. the uk study, carried out from to involving , participants in the community presenting to general practice, estimated that only of cases of gi illness is detected by surveillance. the study indicated that as many as in people in the general uk population develop gi illness each year, with an estimated . million cases occurring annually of which about % are nonfoodborne. , it was estimated that, for every reported case of campylobacter, salmonella, rotavirus, and norovirus, another . , . , , and cases, respectively, occur in the community; based on the number of laboratory reports, it is possible to estimate the true number of infections occurring in the community (table ) . from the community study carried out in the netherlands between and , it was estimated that approximately in . people experience a bout of infectious gi disease each year. campylobacter was detected most frequently ( % of cases), followed by ghiardia lamblia ( %), rotavirus ( %), norovirus ( %), and salmonella ( %). relative to the population of the netherlands ( million), , norovirus gastroenteritis cases occur annually. the us study of mead et al, which also included data from community-based studies, indicated that the total number of cases of infectious gi illness annually is approximately million (of which approximately % are nonfoodborne). they estimated that the number of episodes of acute gastroenteritis per person per year is approximately . . from the available data, the authors were also able to estimate the proportion of total episodes that were nonfoodborne. as shown in table , by far the most frequently reported causes of gi illness were norovirus, rotavirus, and campylobacter. for campylobacter, e coli, and norovirus, a significant proportion of cases was estimated as nonfoodborne, whereas, for hepatitis a (hav), shigella, and rotavirus, almost all cases were estimated as nonfoodborne. for salmonella on the other hand, only % of cases were considered as nonfoodborne. davis et al reviewed outbreaks of e coli o related to family visits to animal exhibits. indications are that norovirus is now the most significant cause of infectious gi illness in the developed world, both outbreak related and endemic. , currently, we are seeing increased outbreaks of norovirus, a major concern in japan and also in europe. expert opinion is that norovirus strains now circulating are more ''virulent'' and more easily spread from person to person via hands and surfaces or during food handling. infection with hav is common worldwide, and adenovirus is also a frequent cause of gastroenteritis. c difficile-associated disease now occurs with increasing frequency in the community, in which it usually affects persons receiving antibiotic therapy but also healthy individuals. recently, a new strain ( ) of c difficile has emerged in north america, causing infections in the community among individuals with no predisposing factors. a recent study indicated that exposure to a family member with helicobacter pylori gastroenteritis was associated with a . -fold increased risk of infection in another family member and that infection most usually involved person-to-person transmission, associated with conditions of crowding and poor hygiene. using data from the e coli o :h outbreak in in the united states associated with contaminated spinach, seto et al developed a model that showed that secondary person-to-person transmission was similar to that in previous e coli outbreaks ( %). the model suggests that even a modestly effective hygiene promotion strategy to interrupt secondary transmission (prevention of only %- % of secondary illnesses) could result in a reduction of % to % of symptomatic cases. respiratory tract infections are largely caused by viruses. in the united states, viruses account for up to % of respiratory infections. the common cold is reported to be the most frequent, acute infectious illness to humans. data from the united states suggest that the mean number of respiratory illnesses experienced per year in adults is approximately . to . , and, in children under years of age, it is approximately . to . . approximately % of upper rt infections are caused by rhinoviruses. other species causing acute rhinitis are coronaviruses, parainfleunza viruses (piv), respiratory syncytial viruses (rsv), and adenoviruses. although colds are generally mild and self-limiting, they represent a significant economic burden because of loss in productivity and medical costs. furthermore, secondary infections produce complications, such as otitis media, sinusitis, or lower respiratory infections including pneumonia, with its risk of mortality, particularly in elderly adults. several studies have demonstrated that colds are also a trigger for asthma. rsv is the major cause of viral rt infection in young children worldwide. child day care attendance in north america caries with it a very high risk of rsv infection within the first years of life and accounts for . % to . % of hospitalized infants in the united states. influenza is a more serious rt illness, which can cause complications that lead to increased physician visits, hospitalization, and death, the risks being highest among persons aged . years, children aged , years, and persons who have medical conditions (eg, diabetes, chronic lung disease). [ ] [ ] [ ] influenza must also be considered in terms of days absent from work and school and pressure on health care services. an important aspect of influenza is the threat associated with the emergence of novel subtypes capable of causing an influenza pandemic. according to bridges et al, influenza epidemics in the united states result in an annual average of , deaths and , hospitalizations; among those with influenza who belong to an ''at-risk'' group, a significant proportion develop pneumonia, and up to in can die of related complications. in europe, the - influenza season annual report showed that, of countries, recorded what is regarded as high activity ( up to influenza-like or acute respiratory illnesses per , population). although data indicating the role of hands and other surfaces in the transmission of colds have been available for some time, it is only in the last few years that there has been any real awareness that hands and surfaces may also be a transmission route for flu viruses. evidence that measures such as hand hygiene can reduce spread of rt infections comes from the sars outbreaks in hong kong, which coincided with the latter part of influenza season, when it was observed that, as extensive personal and community public health measures took place, influenza case numbers fell significantly, more so than usual for the time of year. skin and wound infections are common in the home and community, but most are self-limited. because these infections, apart from s aureus infections go unreported, little or no data are available on the burden of skin and wound infections in the community. s aureus is the most common cause of infections of skin and soft tissue, which, in a small proportion of cases, lead to the development of bacteremia or pneumonia. serious infections usually occur in health care facilitiesin patients who are immunocompromised-in which s aureus is mostly usually associated with wounds and intravenous devices and in which the antibioticresistant strain, mrsa, is a major concern. infected patients discharged from hospitals and health care workers (hcws) caring for mrsa-infected patients can bring mrsa into the home and pass it on to healthy family members, who become colonized, thereby spreading the organism into the community and facilitating the circulation of these strains. [ ] [ ] [ ] mrsa colonization in an individual can persist for up to months. , in recent years, mrsa has been increasingly found to cause infections in healthy members of the community without apparent risk factors. these ca-mrsa strains are different from health care-associated (hca) mrsa strains and are a concern because they equally infect children and young adults. these strains primarily cause skin and soft tissue infections but can also cause invasive infections such as sepsis, pneumonia, and osteomyelitis, which is some cases can be fatal. some ca strains are known to produce panton-valentine leukocidin (pvl), which has been implicated as a virulence factor, although opinion is, however, divided as to whether this is the case; whereas some studies support this notion, others do not. in the united states, ca-mrsa is now a significant concern. ca-mrsa strains have also now been detected in france, switzerland, germany, greece, the nordic countries, australasia, the netherlands, and latvia. in the united kingdom, cases of ca-mrsa and pvlproducing strains have been reported, but the number of reported cases is still small. , within the global population that affect our resistance to infection.''at-risk'' groups cared for at home include not only newborn infants whose immune system is not fully developed but also the rapidly increasing elderly population whose immune system is declining. ''atrisk'' groups include patients discharged recently from hospital, immunocompromised family members, and family members with invasive devices such as catheters. it also includes people whose immunocompetence is impaired as a result of chronic and degenerative illness or because they are undertaking certain drug therapies. all of these groups, together with those who carry hiv/aids, are increasingly cared for at home by a caregiver, who may be a household member. a survey of the united states and european countries-germany, the netherlands, and the united kingdom-suggests that up to in of the population belongs to an ''at-risk'' group (table ) . the data suggest that between % and % of the population of these countries are . years of age. in an intervention study of patients with aids, it was found that patients assigned to the intensive handwashing intervention group developed fewer episodes of diarrheal illness ( . . vs. . . new episodes of diarrhea, respectively, during a -year observation period. gi pathogens are now implicated as causative or contributory factors in the development of cancers and other chronic conditions; examples include hepatitis b virus (hepatocelluar carcinoma), h pylori (peptic ulcer disease), and campylobacter jejuni (guillain barré syndrome). foodborne illness has been estimated to result in chronic sequelae in % to % of cases ; a european commission report cites evidence of chronic disease, such as reactive arthritis, following % of salmonella cases, with % of e coli o cases progressing to serious and even fatal complications. even mild viral infections can be predisposing factors to more severe and possibly fatal secondary bacterial infections. in devising a strategy for home hygiene and producing hygiene practice advice, the international scientific forum on home hygiene (ifh) has developed an approach based on risk management that involves identifying the ''critical control points'' for preventing the spread of id in the home. risk management (also known as hazard analysis critical control points [haccp] ) is now the standard approach for controlling microbial risks in food and other manufacturing environments and is becoming accepted as the optimum means to prevent such risks in home and hospital settings. the key feature of the ifh approach is that it recognizes the need to look at hygiene from the point of view of the family and the total range of problems it faces to reduce id risks, including food hygiene, personal hygiene (particularly hands) and hygiene related to the general environment (toilets, baths, hand basins, surfaces, and others), domestic animals, and family members at increased risk. adopting a holistic approach makes sense because all these issues are interdependent and based on the same underlying microbiologic principles. haccp also forms the basis for developing an approach to home hygiene that can be adapted to meet differing needs. indeed, it is only by adopting such a holistic approach that the causal link between hands and infection transmission in the home can be addressed properly because hand hygiene is a central component of all these issues. the ifh risk management approach to hygiene starts from the principle that pathogens are introduced continually into the home by people (who may have infection or may be asymptomatic), food, and domestic animals and also sometimes via the water or the air. additionally, sites at which stagnant water accumulates, such as sinks, toilets, waste pipes, or items, such as cleaning or face cloths, readily support microbial growth and can become a primary reservoir of infection; although microbial species are mostly those that represent a risk to vulnerable groups, primary pathogens can also be present. so long as there are people, pets, and food in the home, there will always be the risk of pathogenic microbes. in many homes, there will also be at least one family member who is more susceptible to infection for one reason or another. within the home, there is a chain of events, as described in fig , that results in transmission of infection from its original source to a new recipient. to an extent, we can limit the exit and entry of pathogens from and into the body, but the link that we have most control over is that related to the ''spread of pathogens.'' the spread of infection can be interrupted by good hygiene practice, which includes adherence to hand hygiene recommendations and cleaning and disinfecting contaminated environmental surfaces. the risk-based approach to home hygiene is described in more detail by bloomfield and scott and bloomfield. they suggest that sites and surfaces in the home should be categorized into main groups: reservoir sites, reservoir/disseminators, hands and hand and food contact surfaces, and other surfaces. risk assessment is then based on the frequency of occurrence of pathogenic contamination at that site, together with the probability of transfer from that site such that family members may be exposed. this means that, even if a particular environmental site is highly contaminated, unless there is a high probability of transfer from that site, the risk of infection transmission is low. from this, it is possible to determine the ''critical control points'' for preventing spread of infection. the data suggest the following: d for reservoir sites such as the sink waste pipes or toilets, although the probability of contamination (potentially pathogenic bacteria or viruses) is high, the risk of transfer is limited unless there is a particular risk situation (eg, a family member with enteric infection and fluid diarrhea, when toilet flushing can produce splashing or aerosol formation that can settle on contact surfaces around the toilet). , d by contrast, for reservoir sites such as wet cleaning cloths, not only is there high probability of significant contamination, but, by the very nature of their usage, they carry a high risk of disseminating contamination to other surfaces and to the hands. d for hands and hand contact and food preparation surfaces, although the probability of contamination is, in relative terms, lower, it is still significant, for example, particularly following contact with contaminated food; people; pets; or other contaminated surfaces such as door, faucet, and toilet-flush handles. because there is a constant risk of spread from these surfaces, hygiene measures are important for these surfaces. d for other surfaces (floors, walls, furniture, and others), risks are mainly due to pathogens such as s aureus and c difficile, which survive under dry conditions. because the risks of transfer and exposure are relatively low, these surfaces are considered low risk, but where there is known contamination, for example, soiling of floors by pets, crawling infants may be at risk. cleaning can also recirculate dust-borne pathogens onto hand and food contact surfaces. overall, this approach allows us to rank these various sites and surfaces (fig ) according to the level of transmission risk; this suggests that the ''critical control points'' for breaking the chain of infection are the hands, together with hand and food contact surfaces, cleaning cloths, and other cleaning utensils. however, although this is a useful ''rule of thumb'' ranking, it is not a constant. for example, although risks from toilets, sinks, floors, and others relate mainly to the relatively lower risk of transfer from these sites to hands, hand and food contact surfaces, and cloths, this risk can increase substantially during occasions when an infected family member has fluid diarrhea or when a floor surface is contaminated with vomitus, urine, or feces. in the following section, we evaluate data indicating the extent to which the hands, both alone and in combination with other surfaces, are responsible for the spread of infection. the criteria for assessing causal inference of a link between hygiene practice and id risk reduction have been reviewed by aiello and larson. establishing the potential health impact of a hygiene intervention such as hand hygiene requires examination of the evidence related to a range of criteria that should include the strength, consistency, and temporality (cause and effect) of the association, together with data on plausibility (biologic or behavioral rationale) and biologic gradient. aiello and larson recognize that, although a single factor such as the hands may be a ''sufficient cause'' of infection transmission, spread of infection frequently involves a number of ''component causes,'' which, together or independently, work to determine the overall risk. the risk assessment approach, as outlined above, indicates that the ''critical control points'' or ''component causes'' of infection transmission in the home are the hands, together with hand and food contact surfaces and cleaning cloths. based on plausibility, the role of the hands relative to other surfaces can be understood by mapping the potential routes of spread of gi, rt, and skin infections in the home as shown in fig . this suggests that, for all groups of infections, the hands are probably the single most important transmission route because in all cases they come into direct contact with the known portal of entry for pathogens (the mouth, nose and, conjunctiva of the eyes) and are thus the key last line of defense. figure shows, however, that, although in some cases the hands alone may be ''sufficient cause'' for transmission of an infection (eg, from an mrsa carrier, to hands, to the wound of a recipient), in other cases transmission involves a number of component causes (eg, from contaminated food, to a food contact surface, to hands, to the mouth of a recipient). what this means is that the transmission risk via the hands also depends on the extent to which surfaces become contaminated with pathogens during normal daily activities, ie, the risk of hand-to-mouth transfer will be increased if extensive transfer from raw food to food preparation surfaces also occurs. defining the importance of hand hygiene relative to other hygiene practices, such as surface and cloth hygiene, is difficult because of the close interdependence of these factors. although the focus of this review is the prevention of infection through hygiene practice, fig shows that in some cases airborne transmission can operate independently, without involving the hands, whereas, for gi infection, transmission can operate independently via food. although handwashing intervention studies provide data supporting the causal link between hand contamination and id transmission, defining the importance of hand hygiene relative to other hygiene practices, such as surface and cleaning cloth hygiene, or the risks associated with airborne transmission is difficult because of the close interdependence of these factors. currently, such assessments can only be made on a qualitative basis, using microbiologic data (as in the following section) together with some limited epidemiologic data. in this section, we present epidemiologic and microbiologic data to support the causal relationship between hygiene and id risk. because the risks of hand transfer increase as the risks of contamination of other surfaces increases, data related to relevant surfaces are also included. in recent years, a range of studies has been published, many related specifically to the home, which indicate the extent to which id agents occur and are spread in home and community settings during normal daily activities and their potential to cause infection. these studies include assessments of frequency occurrence of sources of pathogens in the home, their rate of ''shed'' from an infected source into the environment, their rate of die away on hands and other surfaces, their rate of transfer via the hands to the mouth, nose, conjunctiva, and others and/or to ready-to-eat foods, and their the infectious dose. the infectious dose (ie, the number of particles to which the recipient is exposed), their immune status, and the route by which they are infected are key factors that determine the infection risk. the ''infectious dose'' varies for different pathogens and is usually lower for people who are ''at-risk'' than for healthy household members. transmission of infectious gi disease. risks from exposure to gi pathogens via the hands. as shown in fig , exposure to gi pathogens can occur by direct hand-to-mouth contact or indirectly via contaminated food. in the home, food can be contaminated either directly by an infected food handler or indirectly by cross contamination via hands and surfaces from another source, which may be contaminated food, another infected household member (or carrier), or a household pet or farm animal. hand-to-mouth contact is a frequent occurrence, particularly among children; a study of mouthing behavior in young children showed that children , months of age exhibit the highest frequency, with events/hour; for children . months of age, this was reduced but was still of the order of events/hour. the potential for transmission of pathogens from hands to ready-to-eat foods is supported by a number of studies: d in a model domestic kitchen, % of food preparation sessions using campylobacter-contaminated chicken resulted in positive campylobacter isolations from prepared salads, cleaning materials, and food contact surfaces. d bidawid et al , showed that touching lettuce with finger pads contaminated with hav and feline calicivirus (fcv), used as a surrogate for norovirus, for seconds resulted in transfer of . % and %, respectively, of the virus. based on the load for hav in feces ( to viral particles/g), an estimated particles were transferred to the lettuce. d rusin et al showed that, when volunteers' fingertips were inoculated with a pooled suspension of micrococcus luteus (m luteus), serratia rubidea (s rubidea), and bacteriophage prd- and held to the lip area, transfer rates were . %, . %, and . %, respectively. as stated above, the infection risk from oral consumption depends on the number of bacterial cells or viral particles that are consumed. table shows that, for many of the commonly occurring gi pathogens, the infectious dose is relatively small. sources and spread of gi pathogens to the hands. figure illustrates that the risk of exposure to gi pathogens via the hands depends on the extent to which these pathogens are brought into the home (either by infected people or pets or via contaminated food) and the extent to which they are spread via hands and other surfaces and by airborne transmission. relevant data from various sources, as summarized below, suggest that exposure to gi pathogens via the hands is a frequent occurrence during normal daily activities and that the numbers of organisms transferred by handto-mouth contact can be well within the numbers required to cause infection. household members who are infected, or who are carriers, are a primary source of infection in the home. pathogens that can be carried persistently by otherwise healthy people include salmonella species and c difficile. approximately % of adults (mainly those . years of age), and up to two thirds of babies, are known to carry c difficile in their gut, although it is not known what proportion are toxin producing. people or animals that carry gi pathogens shed large numbers of organisms in their feces or when they vomit. a single vomiting incident following norovirus infection may produce million viral particles, and, at the peak of a rotavirus infection, . virions may be excreted per gram feces. surfaces in the home may become contaminated by enteric organisms that are aerosolized during vomiting or by transfer of vomitus and fecal matter via hands. viruses aerosolized from flushing the toilet can remain airborne long enough to contaminate surfaces throughout the bathroom. infectious agents introduced into the home via food include salmonella, campylobacter, listeria, and e coli o . a variety of foods can act as a source of these organisms, including meat, fish and poultry products, dairy products, fruits, and vegetables. organisms in particles, and moisture or juices, from food will contaminate any surface they come into contact with. an salmonella species up to but could be as low as - cells. contamination may be amplified by transfer to foods, which are then stored incorrectly. campylobacter species organisms can result in human illness. oral dose for e coli may be as little as cells. in one outbreak, a median dose of , organisms per hamburger was reported. norovirus - units or even less. may be as few as particles. ward et al showed that of adults became infected after consuming rotavirus ( particles) picked up from a contaminated surface via the hands. efsa survey of salmonella in chicken indicates significant differences among eu member states, with isolation rates between % and . %; the level reported for the united kingdom was . % to . %. the efsa also reported that up to % of samples from fresh poultry were positive for campylobacter. in the united states, more than half of raw chicken is estimated to be contaminated with camplylobacter. chapman et al showed that . % to . % of meat products purchased from uk butchers were positive for e coli o . in a recent study in canada, c difficile was isolated from % of samples of retail ground meat purchased over a -month period, and isolates were toxigenic. the home is frequently a shelter to a range of different pets; more than % of homes in the englishspeaking world have cats and dogs, with million cats and dogs in the united states. in the united states, up to % of dogs may carry campylobacter, and % to % may carry salmonella ; cats are also carriers of these organisms. carriage of c difficile in household pets is quite common; up to % of pets are affected, although these mostly involve noncytotoxigenic strains. kramer et al, sattar et al, and rzezutka and cook reviewed data showing that gi pathogens can survive on surfaces for several hours and, in some cases, days, particularly on moist surfaces, although infectivity depends on the numbers that survive (table ) . studies to quantify transfer between hands, foods, and kitchen surfaces , showed that transfer rates were highly variable, ranging from as high as % to as low as %. transfer to hands was highest from nonporous surfaces but lower from surfaces such as carrots, sponges, and dishcloths (, %). rusin et al sampled volunteers hands after touching surfaces contaminated with m luteus, s rubidea, and phage prd- . activities included wringing out a dishcloth/sponge, turning off a faucet, cutting up a carrot, making hamburger patties, holding a phone receiver, and removing laundry from the washing machine. transfer efficiencies for the phone receiver and faucet were % to % and % to %, respectively. paulson showed that, when gloved hands were contacted for to seconds with surfaces such as cutting boards and doorknobs contaminated with fcv (log . particles), the log number of particles recovered from hands was . to . . these laboratory studies are supported by a range of field studies showing spread via the hands and other surfaces during normal daily activities: d following preparation of salmonella and campylobacter-contaminated chickens in domestic kitchens, these species were isolated from . % of hands and hand and food contact surfaces. isolation rates were highest for hands, chopping boards, and cleaning cloths ( %, %, and %, respectively, of surfaces sampled). d in homes containing an infant recently vaccinated for polio (during which time shedding occurs in feces), virus was isolated from % of bathroom, living room, and kitchen surfaces. most frequently contaminated were hand contact sites such as bathroom taps, door handles, toilet flushes, soap dispensers, nappy changing equipment, and potties. d following handshaking with a volunteer whose hands were contaminated from touching a viruscontaminated door handle, successive transmission from one person to another could be followed up to the sixth person. d where fingers were contacted with noroviruscontaminated fecal material, the virus was consistently transferred via the fingers to melamine surfaces and from there to hand contact surfaces, such as taps, door handles, and telephone receivers. contaminated fingers sequentially transferred the virus to up to clean surfaces. d a study with fcv showed survival for up to days on telephone buttons and receivers, for or days on computer mouse, and for to hours on keyboard keys and brass disks representing faucets and door handles. the time for % virus reduction was , hours on computer keys, mouse, and brass disks; to hours on telephone receivers; and to hours on telephone buttons. d in homes of infants with recurrent c difficile infection, % of environmental surfaces were positive for c difficile, and of other household members carried c difficile in stool. in a control home with no household carriers, none of environment samples were positive for c difficile. d in out of homes in which there was a salmonella case, the causative species was isolated from fecal soiling under the flushing rim and scale material in the toilet bowl for up to weeks after notification of infection. flushing toilets seeded with salmonella enteritidis resulted in contamination of hand contact surfaces such as toilet seats and toilet seat lids. these represent recent examples of studies that have been reported. these and other studies are also reviewed elsewhere. , [ ] [ ] [ ] in developing hygiene policies for preventing gi infections, one of the difficulties is assessing risks associated with hand transmission relative to other risks such as inadequate cooking or storage of food or inhalation of infected vomit particles. gillespie et al reported an evaluation of reported outbreaks linked to uk households for to that suggested, of the % of outbreaks designated as foodborne, cross contamination was implicated in % of outbreaks compared with % and % of outbreaks for which inadequate storage and cooking, respectively, were thought to be the cause. there were no data to suggest what percentage of cross contamination events involved the hands, and gillespie et al expressed concern that most of the reported outbreaks were linked to home catering, thus not necessarily representative of normal daily routine. aerosol transmission can result from settling on hand and food contact surfaces, but, for norovirus, infection can sometimes result from direct inhalation of infected particles of vomit by people immediately adjacent to the person who vomits. the potential for airborne transmission of norovirus was demonstrated in studies in a restaurant and a primary school, in which close proximity to infected persons in the immediate aftermath of a vomiting attack was identified as a risk factor. , transmission of rt infections. the last years have seen an unprecedented global focus on developing strategies for preventing transmission of influenza. the who is taking a lead on pharmaceutical interventions such as vaccines and antivirals but has also made recommendations for other interventions, which include highlighting the importance of hygiene, and in particular hand hygiene, in minimizing spread in the home and community. risks from exposure to respiratory pathogens via the hands. as shown in fig , exposure to rt viruses can occur either by inhalation of infected mucous or inoculation of the nasal mucosa or eyes with viruscontaminated hands, which then cause infection via the mucous membranes and upper rt. rhinovirus and rsv are deposited into the front of the nose or into the eye (where they pass down the lacrymal duct), either on the end of the finger or possibly sometimes in aerosolized droplets. rubbing the eyes and nose with the fingertips is a common occurrence; hendley et al found that in . attendees of hospital rounds rubbed their eyes, and % picked their nose, within a -hour observation period. a review of the data (table ) suggests that the infectious dose for respiratory viruses is relatively small. alford et al suggest that aerosolized doses of as little as tcid (tissue culture infective dose) of influenza virus could infect volunteers. evidence for transmission of rhinovirus and rsv infections via contaminated hands comes from a number of studies: d a number of studies have demonstrated that selfinoculation by rubbing the nasal mucosa or conjunctivae with rhinovirus-contaminated fingers can lead to infection. , over a period of years, gwaltny and hayden performed intranasal challenges on healthy young adults who had no antibody to the challenge, and infected ( %). after handling contaminated coffee cups and other objects, more than % of subjects developed infection. hall et al showed that volunteers touching contaminated objects and/or the fingers of symptomatic individuals had a higher attack rate of colds if they touched their eyes or nose. d in a -year family trial, hendley and gwaltney found that prophylactic treatment of mothers' fingers with iodine reduced the incidence of rt infections. when illness occurred in the family, mothers were instructed to dip their fingers in iodine upon awakening in the morning, then every or hours or after activities that washed the iodine from the skin. the secondary attack rate in mothers was % in the iodine group and % in placebo families. no infections occurred in mothers after exposures to an infected index case in the iodine group, compared with infections after exposures in the placebo group. d hall et al showed that infected infants excrete prodigious amounts of rsv in their nasal secretions for several days and that rsv could be recovered from hands that had touched surfaces contaminated with secretions from infected infants. hall and douglas found that close contact with symptomatic infants who were producing abundant secretions, or their immediate environment, was necessary for infection. sources and spread of rt pathogens to the hands. figure illustrates that the risk of exposure to rt pathogens via hands depends on the extent to which these pathogens are spread from an infected person during normal daily activities. relevant data come from various sources and are summarized below. taken together, the data suggest that, when a household member is infected, exposure of other household members via hands is likely to occur during normal daily activities and that the numbers of organisms involved are within those required to initiate infection if transferred to the eyes or nose. people infected with cold viruses shed large quantities of virus-laden mucus. droplets of nasal secretions generated by coughing, sneezing and talking can travel over a distance . m to contaminate surrounding surfaces. , , [ ] [ ] [ ] up to infectious influenza particles per milliliter has been detected in nasal secretions. the mean duration of a cold is . days. viral shedding may occur to hours before illness onset but generally at lower titers than during the symptomatic period. titers generally peak during the first to hours of illness and decline within several days, with titers low or undetectable by day . children can shed virus for up to weeks, whereas immunocompromised people may continue to shed virus for weeks to months. infectious material can also be deposited directly on hands and tissues during sneezing and blowing the nose. contamination of hands can occur by handshaking or touching contaminated surfaces. pathogens shed into the environment from these sources can survive for significant periods and are readily spread around the home to and from the hands and via handkerchiefs and tissues, tap and door handles, telephones, or other hand contact surfaces: d gwaltney and hendley demonstrated that most subjects with experimental colds had rhinovirus on their hands and that virus could be recovered from % of plastic tiles they touched. for people with rhinovirus colds, virus was found on % of hands and % of objects in their immediate environment. opinion as to the importance of the hands relative to the airborne route for transmission of rhinovirus colds is divided. some investigators , , , maintain that contamination of the hands followed by inoculation of the eyes or nose is of paramount importance; in fact, gwaltney et al found that it was exceedingly difficult to transmit virus orally or by kissing and found little evidence of droplet or droplet nuclei transmission. , others maintain that the evidence favors droplet and droplet nuclei transmission as the most important mode of spread. for rsv, there is general agreement that the hands are the primary route for the spread of infection. , , for influenza, although more data are needed, it is increasingly accepted that not only airborne (both true airborne transmission involving droplet nuclei [, mm in diameter] and ''droplet transmission'' involving droplets . mm that deposit onto surfaces quite rapidly) but also surface (including hand) transmission come into play. , , the relative contribution of each mode of transmission is unknown but appears to vary depending on the circumstances, symptoms, respiratory tract loads, and the viral strain. data from animal studies and influenza outbreaks suggest that droplets generated when infected persons cough or sneeze are the predominant mechanism of airborne transmission, although data supporting droplet nuclei spread are also available. , [ ] [ ] [ ] it is possible, however, that influenza is less transmissible via hands and surfaces compared with rhinovirus and others because of its lower ability to survive outside a human or animal host. data suggest that, to some extent, airborne droplets and droplet nuclei cause infection as a result of settling on hand contact surfaces. the frequent occurrence of diarrhea and the detection of viral rna in fecal samples tested suggest that the h n influenza virus may replicate in the human gut and could be a source of transmission via hands and surfaces. at present, however, it is thought that this is unlikely. the growing evidence base related to the survival, transmission, and human exposure to rt viruses via hands and other surfaces is also reviewed elsewhere. , , , , , transmission of skin and wound infections. risks from exposure to skin and wound pathogens via the hands. as shown in fig , exposure to skin pathogens such as s aureus can occur via the hands. exposure can produce colonization and/or infection that usually occurs in areas in which there are cuts, abrasions, and others that damage the integrity of the skin. where there are predisposing factors, the numbers of organisms required to produce infection may be relatively small. marples showed that up to cells may be required to produce pus in healthy skin, but as little as may be sufficient in areas in which the skin is occluded or traumatized. risks associated with exposure to hca-mrsa and ca-mrsa are different. hca-mrsa usually affects elderly adults and those who are immunocompromised, particularly those with surgical or other wounds or who have indwelling catheters. for ca-mrsa, those at particular risk appear to be younger, generally healthy people who practice contact sports or other activities that put them at higher risk of acquiring skin cuts and abrasions. us experience suggests that ca-mrsa may be more virulent than other strains and is easily transmissible within households and community settings (eg, schools, day care centers, sport teams) in which skin-to-skin contact or sharing of contaminated items (eg, towels, sheets and sport equipment) are vehicles for person-to-person transmission. a case-control study involving cases of mrsa in a us prison showed that inmates who washed their hands # times per day had an increased risk for mrsa infection compared with inmates who washed their hands . times per day. sources and spread of skin and wound pathogens to the hands. figure illustrates that the risk of exposure to skin pathogens via the hands depends on the extent to which people or animals colonized or infected with pathogenic strains are present in the home and the extent to which these pathogens are spread during normal daily activities. transfer of skin pathogens to the hands can occur either by direct contact with an infected source or indirectly via hand contact surfaces or the surfaces of clothing or household linens. relevant data, as outlined below, suggest that, when there is a person in the home who is infected or colonized with s aureus, exposure of other household members as a result of transfer via hands, surfaces, clothing, and others is likely to occur during normal daily activities and that the numbers of organisms involved are within the numbers of particles that could initiate an infection in a susceptible recipient. a study by kluytmans et al suggests that s. aureus is carried as part of the normal body flora in up to % of the general population, although a us study suggests that the carriage rate is much less ( . %). in the united kingdom, indications are that the proportion of the general population carrying antibiotic-resistant strains of s aureus (either hca-or ca-mrsa) is somewhere between . % and . %, the majority being carriers of hca-mrsa who are . years of age and/or have had recent association with a health care setting. although cases of ca-mrsa and pvlproducing mrsa have been reported, indications are that the prevalence of mrsa and pvl-producing strains circulating in the community is currently very small. in the united states, although it is concluded that colonization rates for mrsa in the community are still low, it is nonetheless thought to be increasing. , graham et al report on an analysis of - data from the national health and nutrition examination survey (nhanes) to determine colonization with s aureus in a noninstitutionalized us population. from a total of participants, it was found that . % were colonized with s aureus, of which . % were colonized with mrsa. of persons with mrsa, half were identified as strains containing the sccmec type iv gene (most usually associated with ca-mrsa), whereas the other half were identified as strains containing the sccmec type ii gene (most usually associated with hca-mrsa). several other investigators have examined the epidemiology of mrsa in the us community; differences in the data suggest a sporadic distribution of ca-mrsa, with carriage rates ranging from % to % in baltimore, atlanta, and minnesota up to % to % for an apparently healthy population in new york. domestic pets can also be a source of s aureus, including mrsa and pvl-producing strains. [ ] [ ] [ ] [ ] [ ] manian described dog owners suffering from persistent mrsa infection, who suffered relapses whenever they returned home from the hospital; further investigation revealed that the dog was carrying the same strain of mrsa. people who carry s aureus can shed the organism in large numbers most usually associated with skin scales. kramer et al review data showing that s aureus (including mrsa) can survive on dry surfaces for periods from days up to months. scott and bloomfield showed that, during a -hour drying period, up to % of s aureus inoculated onto laminate could be transferred to fingertips by contact. transfer to fingertips also occurred when a cloth contaminated with s aureus was used to wipe a clean surface. studies in health care settings, as reviewed by bloomfield et al, found that transmission of the mrsa strain from an index case to siblings and the mother occurred at least times, and one family member was colonized for up to months or more. these represent recent examples of studies that show survival and transfer of mrsa around the home. these and other studies are also reviewed by bloomfield et al. intervention studies to establish the causal link between hand hygiene and infectious disease in the home and community both observational and interventional study designs have been used to assess the relationship between hand hygiene and id transmission. by definition, observational studies are not randomized and must utilize careful methods to preserve internal validity. control of confounding and the potential for selection, recall, and other biases are also a concern, for example, individuals who wash their hands less frequently are also less likely to report symptoms. intervention studies on the other hand compare infection rates in groups in which handwashing is, or is not, promoted. intervention studies employing randomization of treatment groups have been considered the ''gold-standard'' in terms of reducing selection biases. these studies have the ability to ensure that randomized groups are similar, apart from treatment allocation and differences that occur by chance. for these reasons, we limit discussion to intervention studies, focusing on gi and rt illnesses, because these are the most common infectious illness symptoms in home and community settings. a range of intervention studies have been carried out to evaluate the causal link between handwashing and id transmission and have been reviewed in a series of papers to assess the consistency and strength of the link. [ ] [ ] [ ] overall, these studies indicate a strong and consistent link between handwashing and gi disease and a significant link between handwashing and rt illnesses. for the most part, these studies have been carried out in child day care centers, schools, and military and other public settings in which the outcome is often measured against a high baseline level of infection. relatively few studies have been carried out in household settings in the united states and europe. difficulties associated with studying households in developed areas include fewer children under the age of years, higher level of hygiene infrastructure, and difficulties in collecting data. given that there are likely fewer susceptible individuals clustered within household settings, the prevalence of gi and rt illnesses is relatively much lower, making it more difficult to detect a significant influence of hand hygiene on the occurrence of illness. whereas some intervention studies are not relevant to this review and have been omitted, others give useful insight into the potential impact of handwashing in the home and in the general community. studies that are included have been selected on the basis of whether transmission routes are likely to reflect those in the home, most particularly whether the relative rates of transmission via these routes (as shown in fig ) are likely to be similar. for this reason, studies on gi infection in developing countries have been excluded; in these settings, limited access to sanitation means that rates of direct hand-to-mouth transmission from feces is high relative to other routes of transmission (eg, person-to-person transmission via hands, or inadequate food hygiene), compared to settings with adequate water and sanitation in which transmission is more likely to involve person-to-person transmission and transmission via food, rather than direct feces-to-hand-to-mouth. for gi illnesses, we have, therefore, focused on studies carried out in developed country communities, although, even for studies such as those in child daycare centers, in which food preparation is not undertaken by study participants, the data probably reflect mainly the impact on person-to-person transmission. for rt infections, studies conducted in both developed and developing countries are included on the basis that relative rates of airborne transmission versus transmission via hands are likely to be similar regardless of setting. in a recent review, aiello et al assessed the relationship between handwashing and gi outcomes focusing on studies conducted in north america and europe. table summarizes studies providing an effect estimate (risk ratio, rate ratio, and others) as well as % confidence intervals ( % ci). in all of the studies, handwashing with soap was the factor studied, although in some, this was combined with hygiene education measures. all studies assessing handwashing and hand hygiene education were conducted in school or day care settings. among the studies in table , the reduction in gi illness associated with handwashing ranged from % to %. however, of the studies were not statistically significant, including the study that identified a value of %. the studies that gave statistically significant results all describe reductions close to %. overall, these reviews suggest a consistent causal relationship between handwashing and reduction in gi illness, although the findings are less consistent and of a lesser magnitude than in lesser developed settings in which studies considered statistically significant suggested reductions from % to %. in assessing rt infections, the reviews of aiello and larson and aiello et al, mentioned above, they reported that hand hygiene (handwashing, education, and waterless hand sanitizers) can reduce the risk of respiratory infection by % ( % ci: %- %). these investigators have now updated their estimate with further, more recent, studies that, when all studies are taken together, give a pooled impact on respiratory infection of %. based on these studies, table summarizes the results of community-based interventions (excluding health care-related and military settings) on rt illnesses. most studies were conducted in economically developed countries ( %, / ). the range of reduction in illness was % to %, but only % ( / ) of the studies were statistically significant. the results suggest that hand hygiene education and promotion of handwashing can reduce rates of rt illnesses, but the impact is less than for gi infections, although it must be borne in mind that the available data are more limited. there are also several studies of handwashing that do not distinguish between gi and rt outcomes. , , these studies measure outcomes such as illness-related absenteeism, making it difficult to assess the impact on specific disease etiologies. of these studies, only one reported a significant reduction ( %). two were conducted in day care centers, and was conducted in an elementary school. all studies were conducted in economically developed areas (united states, sweden, and israel). , , several methodologic issues must be considered for these studies. studies that use randomization are more likely to produce study groups with similar baseline characteristics. surprisingly, % of the studies in tables and did not randomize. in some studies, randomization may not be an option (eg, in community settings) because the intervention is too complicated to randomize to multiple groups rather than assigning it to a single geographic area. controlling for potential confounding variables is also an important issue, for example, if a study did not control for age and included adults as well as children, the effect of a hygiene intervention may be diluted because adults are at lower risk for diarrheal disease compared with children. in randomized studies, adjustment for confounding in the statistical analysis may not be required if potential confounders associated with intervention and control groups appear balanced, for example, randomization of households in the same geographic area may produce intervention and control arms with the same age distributions, hygiene habits, and health profiles. as summarized in table , of the studies, only % ( / ) reported controlling for at least potential confounding factor. although masking (also known as blinding) can be difficult to implement in hygiene studies because subjects, observers, and interviewers are usually aware of the intervention status, a few studies ( / ) were able to employ masking to reduce knowledge of the intervention. masking can reduce biases associated with knowledge of intervention, including changes in behaviors, practices, and data collection methods. for intervention studies, disregarding clustered sample design may cause bias. for example, a handwashing program in a day care center may affect a child's risk of disease through its individual-level effect (the effect of handwashing of a child on his or her own risk of disease) and through its group-level effect (the effect of centerwide handwashing on risk of disease, even if the child is not following the handwashing program). clustered interventions must take into account the grouped data structure in subsequent analyses or must analyze data at the in the section above, which describes the development of a risk-based approach to home hygiene, we evaluated how pathogens are introduced into the home and the chain of events that can lead to healthy household members becoming infected. an assessment of the microbiologic data related to each stage of the infection transmission cycle suggests that the critical control points for preventing the spread of infection in the home are the hands, hand contact surfaces, food contact surfaces, and cleaning cloths and utensils. intervention at the appropriate time (eg, during raw food handling, rather than as part of daily routine cleaning) is an equally fundamental part of a riskbased approach to hygiene. in practice, pathogens may be transmitted by more than one route, and it is impossible to achieve % hand hygiene compliance. therefore, interventions to reduce id transmission in the home must be multifaceted. key to preventing infection transmission via the hands (and other surfaces) is the application of effective hygiene procedures. because the evidence reviewed in the earlier sections shows that the ''infectious dose'' for many common pathogens such as campylobacter, norovirus, and rhinovirus can be very small ( - particles or cells), intuitively one must argue that, in situations in which there is significant risk, the aim should be to get rid of as many organisms as possible from critical surfaces. organisms can be removed from hands and other surfaces by the following: d physical removal using soap or detergent-based cleaning; or d microbes can be killed in situ by applying a disinfectant or sanitizer. in principle, handwashing using soap or detergent and water mechanically dislodge organisms, but, to be effective, it must be applied in conjunction with a rubbing process that maximizes release of microbes from the skin and a rinsing process that washes the organisms off the hands. although elimination of transient contamination from the hands by the application of a hygiene procedure is plausible, the evidence considered below suggests that, in practice, procedures vary considerably in the extent to which they achieve this. in this section, data on the efficacy of hand hygiene procedures are summarized. a range of test methods has been used to measure the efficacy of hand hygiene products and procedures. although these methodologies yield valuable data, the results can vary considerably depending on the method used. in , sickbert-bennet et al produced a study, based on published literature and their own data, which indicated that factors that affect efficacy measurements are as follows: use of experimental contamination versus normal flora, application method of test organism, type of hand hygiene agent, concentration of active ingredient, volume, duration of contact and application method of the agent, and study method (in vivo panel test vs in vitro suspension test). interpretation of data is made difficult by failure to compare multiple agents in the same study; because of these limitations, comparisons of results from different studies must be interpreted with care. in vivo ''panel test'' studies of the effectiveness of handwashing. in europe, the efficacy of handwashing is established by panel tests that determine the reduction in the number of organisms released from artificially contaminated hands. the test applicable to handwash products is the committee european normalisation hygienic handwash test en . in this test, e coli is inoculated onto the hands and dried. the handwash product is applied to the hands with a rubbing action for either seconds or minute. the residual number of bacteria present on the hands is assessed pre-and postwash by a rinse sampling process and the log reduction determined. to make a claim that a product is a hygienic handwash, it must produce a log reduction in release of e coli from the hands at least equivalent to that produced by a reference soft soap product (mean, . log in minute; range, . - . ). in the united states, handwashing is evaluated by a similar panel test using serratia marcescens as the product, when evaluated by this method, must produce a -log reduction after minutes. a range of studies, based on these methodologies, has been carried out to determine the efficacy of handwashing, and are reviewed by boyce and pittet, kampf and kramer, and sickbert-bennet et al. from their assessment, kampf and kramer estimated that handwashing produced a mean reduction of up to . log within minute. data from individual studies are summarized in table and suggest that, for e coli, the greatest reduction is achieved within the first seconds, ranging from . to . log after seconds to . to . log after seconds. extending the washing time to minute produces a reduction of . to . log, but increasing the process for more than minute does not appear to gain any additional reduction. relatively few data are available on the effectiveness of handwashing in removal of viruses, but the available data (table ) suggest that handwashing may be less effective for viruses compared with bacteria. although panel test data suggest that handwashing efficacy is similar across a range of bacterial species, some field-based studies suggest that efficacy can vary quite significantly. in some cases, organisms can be attached to the hands too firmly and may not be removed by handwashing. a study of the spread of salmonella and campylobacter from contaminated chickens via hands during handling and preparation in a kitchen showed that, although campylobacter were efficiently released from the hands by a second rub and rinse process, a -minute process was necessary to eliminate salmonella. the hand rinsing process is also important; cogan et al showed that, following preparation of salmonella and campylobacter-contaminated chickens in domestic kitchens, . % of hands and hand and food contact surfaces still showed evidence of contamination even after participants had carried out a washing-up routine with detergent and hot water and then used a cloth to wipe surfaces. sites contaminated most frequently were hands ( %); dishcloths, utensils, and tap handles ( %); and sink surrounds ( %). these results were confirmed in further studies , in which, after cleaning up with a typical routine involving a bowl of hot soapy water and a cloth, although isolation rates from hands of participants were % ( / ) for campylobacter, % ( / ) of participants still had salmonella on their hands, and, on occasions, counts recovered were . colony-forming units. in a further study in which participants cleaned up in the same way but then rinsed their hands under running water for seconds, no samples were positive for campylobacter. however, % ( / ) still had low numbers of salmonella isolated from their hands. larson et al showed that the quantity of soap ( ml and ml) used can also have an impact on the microbial reduction achieved by handwashing. bidawid et al , studied the impact of handwashing in preventing transfer of hav and fcv from artificially contaminated finger pads to pieces of lettuce (table ). touching the lettuce for seconds resulted in transfer of . % and %, respectively, of the virus. when finger pads were washed before the lettuce was touched, the amount of virus transferred was reduced to . % and . %, respectively. amounts of hav and fcv remaining on treated finger pads were . % and %, respectively. surprisingly, virus transfer to lettuce when the finger pads were rinsed with water alone was between % and . %, depending on the volume of water used for rinsing. barker et al showed that a thorough -minute handwash with soap was sufficient to eliminate norovirus from fecally contaminated hands to levels that gave negative reverse-transcription polymerase chain reaction assays. however, schurmann and eggers concluded that enteric viruses, particularly poliovirus, may be more strongly bound to the skin and that the inclusion of an abrasive substance in handwash preparations is needed to achieve effective removal. handwashing was also found to be ineffective in eliminating adenovirus from hands of a physician and patients. for handwashing, a hand-rubbing time of seconds with soap is generally recommended, although the data in table indicate that seconds to minute is needed to achieve the optimum of -to -log reduction. in practice, it is doubtful whether people comply with even a -second handwash, although there are few data to confirm this. a study of healthy another study with office workers and students showed a mean log prewash count of . compared with . postwash. kampf and kramer also reviewed studies from health care settings in which increased bacterial counts were found on the hands after handwashing, and handwashing failed to prevent transfer of bacteria from hands to surfaces. although there are no data available to confirm this, increases in contamination may result from sweating induced by hot water, which flushes resident bacteria from the sweat glands onto the hand surface or aids detachment of bacteria attached to skin scales. it is important to bear in mind that, although soap and water removes contamination from the hands, soap itself has a limited antimicrobial effect, which means that contamination will be transferred to the sink. hospital studies show that pseudomonas aeruginosa and burkholderia cepacia can form reservoirs of contamination in sink waste pipes and can be a source of infection at times when splashes of contaminated water come in contact with hands. mermel et al reported that hands of hcws became recontaminated from faucet handles during a shigella outbreak. soap bars also have the potential to spread contamination from person to person via the hands. efficacy of abhs abhs are formulations that contain either ethanol propanol or -propanol or a combination of these products. their antimicrobial activity is attributed to their ability to denature proteins. although products containing % to % alcohol are most effective, higher concentrations are less effective because proteins are not easily denatured in the absence of water. a range of in vivo and in vitro studies have been carried out to determine the effectiveness of abhs and are reviewed by boyce and pittet, kampf and kramer, and sickbert-bennet et al. in vivo panel testing of abhs. in europe, the efficacy of abhs is established by panel tests that determine the reduction in the number of organisms released from artificially contaminated hands. the test applicable to abhs is the committee european normalisation hygienic handrub test en . in this test, e coli is inoculated onto the hands and dried. the sanitizer is applied to the hands with a rubbing action for a specified period. the residual number of bacteria present on hands is assessed pre-and posttreatment by a rinse-sampling process and the log reduction determined. to claim that a product is a hygienic handrub, it must produce a log reduction at least equivalent to that produced by a reference product containing % vol/vol -propanol (mean, . log in minute; range, . - . ). in vivo panel testing against bacterial strains. data from in vivo panel tests, summarized in table , indicate that abhs show good and rapid activity against bacterial stains such as e coli and s aureus. efficacy is at least as good, if not better, than that achieved by handwashing with soap (table ) ; log reductions obtained after a -second contact period were of the order of . to . or more compared with . to . for a -second handwashing process. boyce and pittet conclude that, typically, log reductions of the release of test bacteria from artificially contaminated hands average . log after seconds and . to . log after minute. paulson et al compared the efficacy of abhs containing % ethanol (contact time minutes) with handwashing against s marcescens, which showed that handwashing ( seconds rubbing followed by seconds rinsing) produced a log reduction of . compared with . for the abhs. hammond et al recorded a . -log reduction for % ethanol against s marcescens in seconds using the astm method. sickbert-bennet et al, however, showed that exposure of s marcescens to % to % ethanol for seconds produced only a . -to . -log reduction compared with . -log reduction for handwashing for seconds, when tested by the astm method. leischner et al carried out in vivo tests that showed that alcohol gels were significantly less effective against c difficile spores ( . -to . -log reduction) compared with handwashing with chlorhexidine soap ( . -log reduction). residual spores were readily transferred by handshaking following abhs use. the reduction in spore counts is higher than expected in view of their known resistance to alcohol and may result from the friction associated with application of the gel rather than a bactericidal action; kampf and kramer state that water alone can produce a reduction of . to . log within minute for e coli. using the standard astm method, sickbert-bennet et al evaluated the effect of exposure time and volume of product used on the efficacy of % ethanol. they showed that the use of g of the abhs produced a higher log reduction compared with g ( . -to . -log reduction compared with . -to . log reduction). rubbing the hands until dry ( - minutes) was more effective compared with a -second application ( . -to . -log reduction compared with . -to . -log reduction). two recent field studies indicate that an abhs is equally or slightly more effective than handwashing in reducing bacterial contamination on hands. davis et al compared the reduction of bacterial counts on hands using soap and water or a % ethanol-based hand sanitizer (contact time seconds) after animal handling at a us livestock event. there was no significant difference in the distribution of log reductions obtained using abhs compared with handwashing; log reductions in total count ranged from . to . and . to . for total coliforms. traub-dargtz et al carried out a study at clinics in canada to evaluate the efficacy of handwashing compared with use of abhs ( % ethanol, contact time - seconds) on veterinary staff performing routine equine physical examinations. mean bacterial load on hands increased by . and . log (for the clinics, respectively) as a result of handling the animals, whereas the mean log reduction produced by handwashing with soap was less than . , compared with . and . log (for the clinics, respectively) produced by abhs. in vivo panel testing against viral strains. a number of in vivo studies have been carried out to determine the efficacy of abhs in reducing the release of viruses from hands. test methods were variants of the method of ansari et al or the astm e method, in which the virus is applied to the fingertips and the efficacy of the product in reducing the numbers of viral particles recoverable from the hands determined. the residual number of viral particles present on the hands is assessed pre-and posttreatment and the log reduction determined. data collated by boyce and pittet (table ) indicate that ethanol at % to % produces a . -to . -log reduction against a range of viruses, the extent of the reduction depending on the viral strain, the nature and concentration of the alcohol, and contact time. data indicate that activity of abhs against viral strains is less than against bacterial strains and that ethanol has greater activity against viruses than -propanol. however, all of the strains referred to in table are nonenveloped viruses, which are known to be more resistant to disinfectants than enveloped viruses. as far as hand hygiene in the home and community is concerned, however, this is key because many of the viral strains responsible for hygiene-related id commonly occurring in community settings (rotavirus, norovirus, rhinovirus, and adenovirus) are nonenveloped. that having been said, the data suggest that, although nonenveloped viruses such as hav and enteroviruses (eg, poliovirus) require % to % alcohol to be reliably inactivated, studies by sattar et al in a number of these studies, handwashing with soap was also investigated. these studies , , showed that the action of abhs against hav, polio, and rotavirus was significantly better than that achieved by handwashing with soap. however, in the test model used by ansari et al and mbithi et al, inoculated fingertips are exposed to soap solution or abhs by inverting them over a vial containing the product. in practice, handwashing involving rubbing and rinsing is likely to remove larger numbers of organisms from hands. in a further experiment, ansari et al also demonstrated that -propanol ( %) was more effective ( . % reduction after seconds) than liquid soap ( % reduction) against rotavirus. mbithi et al showed that the log reduction of polio and hav virus ( . - . ) by application of % ethanol was sufficient to prevent transfer to another surface via the fingertips. using similar methodology, bidawid et al , studied the impact of ethanol hand sanitizers in preventing transfer of hav and fcv from artificially contaminated finger pads to pieces of lettuce. results (table ) show that touching the lettuce for seconds resulted in transfer of . % and %, respectively, of the virus. when finger pads were treated with % ethanol or % ethanol (contact time seconds) before the lettuce was touched, the amount of virus transferred was reduced to . % and . %, respectively, for hav and . % and . %, respectively, for fcv. although both % and % alcohol produced significant reductions in virus transfer, significant amounts of virus were found to remain on treated finger pads. in all cases, treatment with ethanol was less effective than handwashing. kampf and kramer and boyce and pittet suggest that, to achieve satisfactory activity against nonenveloped viruses, higher alcohol concentrations and extended contact times are needed. absolute ethanol reduced viral release from hands by . log, % ethanol by . log, and absolute -propanol by . log but with a contact time of minutes. schurmann and eggers concluded that high alcohol-concentration products are effective against enteroviruses only under favorable conditions (large disinfectant/ virus volume ratio, low protein load). other studies also demonstrate superior activity of high ethanol concentrations against nonenveloped viruses such as polio, hav, and adenovirus. , in vitro testing against bacteria, viruses, and fungi. whereas in vivo tests can be used to indicate the efficacy of products under use conditions, in vitro suspension tests are used to establish whether efficacy extends to a broad range of organisms. in vitro testing bacterial and fungal strains. alcohols have excellent and rapid activity against gram-positive and gram-negative vegetative bacteria and fungi when tested in vitro. , a study by fendler et al (table ) shows the efficacy of an abhs containing % ethyl alcohol against a range of bacterial and fungal species, giving -to -log reduction in to seconds. in vitro testing against viral strains. data, as reviewed by boyce and pittet, confirm that enveloped viruses such as herpes, influenza, piv, and rsv are very susceptible to alcohols. data from individual studies (table ) suggest that activity against enveloped viruses is equivalent to that against bacterial strains. however, in agreement with in vivo data, alcohols tend to be less effective against nonenveloped viruses, although this is not the case for all strains. fendler et al confirmed good activity for ethanol ( %) against piv and herpes viruses (. -log reduction in seconds) and some, but relatively less, activity against the nonenveloped rhinovirus, cocksackie virus, adenovirus, and hav ( -to -log reduction in seconds). hammond et al showed . -log reduction against herpes and influenza virus but also . . -log reduction against rhinovirus type . there are no data on efficacy against rotavirus in vitro. in vitro tests suggest that alcohols are relatively effective against fcv, although gehrke et al (table ) found that -propanol was more effective than -propanol and ethanol. it was also found that these alcohols were less effective against fcv at % than at % and %. at this concentration ( %), -propanol, -propanol, and ethanol produced log reductions of only . , . , and . , respectively. by contrast, duizer et al showed that % ethanol produced less than a -log reduction for fcv after minutes and a -log reduction after minutes. these data are confirmed by a further study (mcneil-ppc unpublished) using in vitro suspension test methods as used to generate data in table . the data (table ) show that % ethanol gave a to -log reduction in seconds against a range of nonenveloped viruses including not only rsv, piv, and influenza a and b but also against some strains of rhinovirus and echovirus. efficacy of abhs under conditions of soiling. alcohols are considered inappropriate when hands are visibly dirty or soiled because they fail to remove soiling. however, in a number of in vitro studies, in which the efficacy of abhs was determined in the presence and absence of soil ( % fetal calf serum or . % bovine serum albumin), soil produced little or no loss of efficacy. , larson and bobo showed that, in the presence of small amounts of protein material (eg, blood), ethanol and -propanol were more effective than soap in reducing bacterial counts on hands. using the astm method, sickbert-bennet et al showed that applying protein to hands did not produce any significant reduction in efficacy of abhs or handwashing but produced a modest but significant increase; log reductions for handwashing were . to . and . to . in the absence and presence of protein, respectively. log reductions for abhs were . to . and . to . in the absence and presence of protein, respectively. one of the problems in developing hygiene promotion policies is the lack of quantitative data on the relative health impact of different hygiene interventions. although intervention studies yield quantitative data on health impact, as discussed in section . , the reliability of these estimates is difficult to confirm. by contrast, in vivo and in vitro tests are more economic to perform and can be used to determine relative efficacy of different procedures but give no assessment of how the contamination reduction on hands correlates with health impact. in an attempt to overcome these problems, haas et al have applied the technique of quantitative microbial risk assessment (qmra) to estimate the relative health benefits resulting from use of different hygiene procedures. this approach involves using microbiologic data from the published literature related to each stage of the infection transmission cycle to calculate infection risk. in a recent study, these investigators developed a model for studying the effect of hand contact with ground beef during food preparation, which was used to study the impact of handwashing and use of abhs in preventing subsequent transference from the hands to the mouth compared with no handwashing. pathogenic e coli and e coli o :h were selected for this study because it is known from other investigations that handling ground beef during home food preparation poses a risk of infection with e coli. to perform the risk assessment, data on the density of pathogens in ground beef, transference from beef to hands, removal by handwashing or abhs, rate of transfer from hand to mouth, and infectivity of ingested pathogens were obtained from the literature and, after screening for data quality, were used to develop probability distributions. for assessing log reductions produced by hand hygiene procedures, only in vivo panel testing data were considered. the median log reduction used in these calculations was . (range, . - . ) for handwashing and . (range, . - . ) for abhs. table shows the estimates of the infection risk from handling raw beef, as obtained from the analysis. the authors note that these risks are conditional in the sense that they quantify the risk to an individual who has handled ground beef and who engages in hand-to-mouth activity. the probability that an individual will engage in such behavior is not known, and, therefore, a direct comparison with actual disease rates cannot be made. however, with some plausible assumptions, it was assessed that, assuming that there are million individuals in the united states, each of whom handles ground beef once per month, this results in . contacts per year. assuming that % of these individuals contact hand to mouth after handling ground beef, this amounts to . incidents per year. for e coli o :h , using the median risk, this would result in an estimate ranging from . infections per year if all individuals washed their hands with soap following contact with ground beef to . infections per year if no handwashing is done. this would equate to a % median risk reduction for handwashing compared with no handwashing. if an abhs was used, this would result in an estimate of . infections per year if all individuals used abhs following contact with ground beef. this would equate to a . % median risk reduction for use of abhs compared with handwashing. this study follows an earlier study by haas et al to calculate risks associated with hand-to-mouth transfer after diaper changing of a baby infected with shigella. based on this model, it was calculated that the probability of acquiring infection was between of and of for those who used handwashing with soap after changing diapers. this was based on panel test data conclude that quantitative microbial and id risk models offer a useful tool to assess the relative extent to which different hygiene procedures can impact on id risks. they concede, however, that, although risk modeling represents a promising approach, there are limitations to most models because of the multifactorial nature of infection transmission, the dynamic environment in which transmission takes place, and the paucity of data to specify model parameters. in an earlier section, we evaluated intervention study data to assess the strength of the causal link between hand hygiene and id transmission. in this section, we use these data to evaluate the effectiveness of handwashing as a hygiene measure and in relation to the effectiveness of using abhs as an adjunct or an alternative to handwashing. despite the methodologic limitations, the collective weight of evidence from intervention and microbiologic studies described earlier suggests that handwashing with soap can have a significant impact in reducing the incidence of gi and rt infection. the data, however, show that the health impact from handwashing promotion varies significantly according to the setting and outcome. statistically significant reductions ranged from % to % for gi illness and % to % for rt illness. although all studies were carried out in settings such as day care centers and schools, we believe that the modes of transmission in these settings and the relative rates of transmission of rt and gi infections are likely to reflect those occurring in the home. in , meadows and le saux published a review of the effect of rinse-free hand sanitizers in elementary schools over a -year period. they concluded, however, that the data were of poor quality and that more rigorous intervention trials are needed. in a more recent study, aiello et al examined the epidemiologic evidence for a relationship between waterless hand sanitizers and infections in the community setting over several decades. in table , we present the studies that specifically examined abhs. only studies with an effect estimate and % ci are presented. the type and content of the abhs varied across studies, for example, one study reported the use of a % isopropyl alcohol rinse and another study utilized an alcohol-based foam sanitizer. however, most studies used alcohol-based gels or other alcohol-based emollients. the alcohol content included ethanol and -propanol at concentrations ranging from % to %. of the intervention studies, were conducted in the united states ( %, / ) and in finland ( %). most were conducted in child day care centers, elementary schools, or universities ( %, / ), and one was conducted in the household ( %, / ). outcomes included gi-related illnesses/symptoms and/or upper rt-related illnesses/symptoms examined as separate outcomes or in combination with other infectionrelated symptoms as part of a school absence-related definition of ''infectious-illness.'' of the studies, % ( / ) reported significant results for at least one age group or outcome. the effect was stronger in younger compared with older age groups for studies providing age stratified data. the reduction in gi illness ranged from % to % for the intervention studies that examined gi illnesses as separate outcomes. [ ] [ ] [ ] of these, all but one showed statistically significant reductions. the study by uhari et al showed a significant reduction in gi illness only among children # years of age. all but one of these studies was conducted in child care settings. when evaluated separately, reductions in gi illness appeared more robust compared with the findings for upper rt illness. for upper rt illness, the reduction in infectious illness/symptoms ranged from % to %. only of the studies ( %) examining upper rt illness as a main outcome reported a statistically significant reduction. uhari et al reported a % reduction in rt illnesses among children # years of age, but no significant effect in older children. white et al reported a % reduction in upper rt illness among students using abhs in residence halls. however, this study suffered from several methodologic shortcomings, including lack of control for clustered units, no randomization, no masking, and no monitoring of product use. all but one of the intervention studies included a hygiene education component, but, in of these studies, this was only provided in the intervention arm. the level of education varied widely, ranging from basic information on when to use the abhs (ie, after sneezing and coughing, after use in the restroom, before lunch) to in-depth education programs and biweekly instructional material designed to educate families on hand hygiene and infection transmission. in all studies, abhs was promoted as a supplement to handwashing, or as an alternative to handwashing when soap was unavailable, and it is likely that the hygiene education would have had the effect of encouraging more frequent handwashing as well as use of abhs. although almost all studies indicated that hygiene education combined with promotion of abhs can reduce the risks of gi or rt illness, only studies allowed any assessment of the independent effect of the abhs. of these studies, both studies showed a significant reduction in illness-related absences ( % and %, respectively), but it is not clear whether the illnesses were predominantly gi or rt because these studies used a loose definition of absence-related illnesses. sandora et al was the only study carried out in the household setting and, of all the studies, reported the highest reduction for gi illness. the trial involved families with children enrolled in child care centers. intervention families received a supply of abhs and biweekly hand hygiene educational materials for months; control families received only materials promoting good nutrition. a total of gi illnesses occurred during the study; % were secondary illnesses. the secondary gi illness rate was significantly lower ( %) in intervention families compared with control families (see table ). a total of rt illnesses occurred during the study; % were secondary illnesses. although rt illness rates were not significantly different between groups, families with higher abhs usage had marginally lower rt illness rate than those with less usage ( % reduction). sandora et al suggested that the difference may be due to heightened diligence associated with using abhs after a gi-related incident compared with an rt incident, such as sneezing. overall, based on relatively limited data available, the results in table suggest that the impact of abhs promotion, as part of a hygiene education and promotion program in reducing the incidence of gi infections in young children, is similar to that observed for promotion of handwashing with soap. promotion of abhs in this manner also produced some reduction in the incidence of rt infections, which was less than that associated with promotion of handwashing alone. assessing whether there might be an added health benefit of using abhs above and beyond the effect of hygiene education is hampered by the fact that most studies used hygiene education and abhs in the intervention arm but did not provide an educational component to the control arm. several important methodologic issues were evident, although more recent studies have improved designs and conduct. in most studies, either parents or school personnel provided information on id among children in the study populations. in all but one study, the parents, participants, or personnel monitoring and reporting infections were not masked as to their own or their child's intervention status. although masking of participants and interviewers to the intervention status is important, because it might influence reporting, it is often difficult to conduct masked hygiene interventions and may not be ethical. sandora et al determined that it was neither feasible nor ethical to mask subjects or interviewers because it is difficult to devise a formulation that could act as a ''placebo'' for abhs, and using a placebo abhs product might endanger the control group via inadequate hand hygiene. in many of the abhs studies, especially the recent ones, efforts were made to control for potential confounding factors. however, many of the studies did not collect information on baseline hand hygiene practices (nor methods and frequency of cleaning/disinfecting soiled/contaminated environmental surfaces in homes) as well as abhs use. the studies also excluded participants who reported current abhs use in the home. furthermore, participants were asked to refrain from using abhs in settings outside the home. these are all important design strategies minimizing bias associated with noncompliance or differential usage. two of the intervention studies failed to use systematic monitoring for hygiene practices, such as frequency of hand-sanitizing episodes, frequency of handwashing, or duration of handwashing. , this is especially concerning because the study by sandora et al suggests that the quantity of abhs influences the risk of infection in a dose-response manner. moreover, if frequency of handwashing and abhs use is not recorded, it is impossible to isolate the independent effects of abhs from that of handwashing on infection rates. in these studies of abhs use, surveillance measures included calculating use from monthly demand, total amount supplied, observation by research assistants, participant report, and reported use by primary caregivers in households. , , , , overall, the microbiologic data, together with the intervention study data (both those involving abhs as well as those involving handwashing) as presented in this review, provide consistent evidence of a strong causal link between hygiene and the spread of infection in the home and community, and suggest that probably the single most important route for the spread of infection is the hands. if the data from intervention studies (summarized in table ) are an accurate reflection of the true picture, it is suggested that, for up to % of gi illnesses, the hands are the ''sufficient,'' or a ''component'' (see earlier for definitions), cause of spread of infection. this correlates with microbiologic and other data reviewed in this report, which suggest that, although there is a tendency to assume that gi infections are mostly foodborne and result from inadequate cooking and inadequate storage of food, in reality, most gi infections in the home result from person-to-person spread or contamination of ready-to-eat foods within the home, much of which involves the hands as the sufficient or a component cause. for rt illnesses, the intervention study data (summarized in table ) suggest that transmission via hands could be a sufficient or component cause of up to % of illnesses; whereas there has been a tendency to assume that the lower impact of hand hygiene on rt compared with gi infections is due to the fact that spread of rt pathogens is mainly airborne, the microbiologic and other data in this review correlate with the intervention data in suggesting that, for rt infections commonly circulating in the community, such as rhinovirus and rsv, the hands are the major route of spread. although up to % to % reduction in id risk was observed in some intervention studies, in other studies the reduction was much less. this variability could well be due to methodologic issues but could also be due to other factors within and between study communities. one possibility is that it relates to differences in the range of pathogens with differing modes of spread prevalent in different study groups, which means that hand hygiene has greater impact in some intervention groups than others. alternatively, the differences may reflect differing levels of hand hygiene compliance in different intervention groups. in some studies, the quality of the hygiene education, the manner in which the hygiene promotion was conducted, and the enthusiasm with which it was received may have given the intervention group a better understanding of what was required, with the result that they used better hygiene technique and were more likely to apply it at critical times. although there are no intervention study data to confirm this, the microbiologic data together with the qmra assessments suggest that even a relatively modest increase in log reduction on hands within a population could produce a significant increase in the health impact of a hand hygiene promotion campaign, which could, in turn, be achieved by addressing the issues in the next sections. although panel tests carried out under controlled conditions showed that handwashing can reduce the numbers of bacteria and some viruses on the hands by up to -to -log within seconds to minute, in practice it is doubtful whether people wash their hands properly, even for the prescribed period of seconds, to achieve this. at present, there is a paucity of data on the efficacy of handwashing in relation to how people actually wash their hands on a day-to-day basis, both in the duration of handwashing and handwashing technique; in most of the intervention studies described earlier no attempt was made to time handwashes or to determine residual levels of contamination on the hands after handwashing. microbiologic data suggest that, for some pathogens (eg, salmonella), mechanical removal by handwashing alone is inefficient. these data, together with the results of in vivo panel testing of the effectiveness of handwashing and of abhs, as described above, question the efficacy of handwashing in community-based groups and suggest that more work is needed to determine the efficacy of hand hygiene procedures under conditions normally encountered in the home and how hand hygiene procedures could be improved. for abhs, in vivo and in vitro testing suggest that these formulations are highly effective against bacterial pathogens and can produce a . -log reduction on hands within seconds and . -to . -log reduction after a -minute application against a wide range of species including salmonella. it is possible, however, that the potential for increased benefits against bacterial infections compared with handwashing may be offset by reduced efficacy against important nonenveloped viruses such as rotavirus, some strains of rhinovirus, and possibly also norovirus. it has been argued that the higher impact of abhs interventions against gi compared with rt infections is due to the fact that rt infections are predominantly viral. however, because the intervention data indicate that handwashing also supports a stronger reduction in gi diseases compared with rt diseases, this seems unlikely. some studies suggest that, to achieve satisfactory activity that includes all types of viruses, higher concentrations up to % ethanol should be advised. other studies suggest that the efficacy of abhs may be increased by increasing the volume of agent applied to the hands. in formulating policies for hand hygiene, it would be convenient to be able to define what represents a ''safe'' residual level of contamination on the hands after hand hygiene, ie, sufficient to prevent infection transmission, but, because the infectious dose varies from one species to another and is dependant on the immune status of the recipient, this approach is untenable. the qmra approach, as outlined earlier in this review, however, demonstrates that strategies that produce an increase in the log reduction on hands from to to are accompanied by a significant incremental reduction in the risk of infection in a given population and could thus be worthwhile. this suggests that the health impact from promoting hand hygiene could be increased by developing and promoting procedures for use in the home and community that increase the log reduction of contamination on the hands. this involves identifying products and procedures (both soap-based and waterless products or wipes) that achieve high levels of removal and/or ''kill'' (alone or in combination) of the full range of gram-negative and gram-positive bacteria and enveloped and nonenveloped viruses and that deliver hand hygiene under conditions that people are prepared to employ in their busy and mobile daily lives. it also suggests that, particularly for ''high-risk'' situations as outlined below, there is advantage to be gained by promoting handwashing followed by use of abhs to increase the log reduction. applying hand hygiene at the correct time: the need for hygiene education the data presented in this review suggest that the favorable health impact from promoting hand hygiene could be further increased by getting people to practice hand hygiene not just more frequently but also at the right time. a number of studies show the relatively poor understanding of the principles of hygiene that is present in the community. this may be one of the factors responsible for the higher risk reductions observed in intervention studies of gi compared with rt infections. for example, knowledge regarding the need for handwashing after coughing or sneezing may not be as pervasive as knowledge about handwashing after defecation, and it may be that people understand better when to wash their hands during food-associated activities but not, for example, while handling contaminated tissues. although some intervention studies described in this review involved a component of education, it was not possible to determine the extent to which hygiene education that enhanced people's understanding of infection transmission also enhanced health outcome. because visible soiling is an unreliable indicator of the presence of pathogens on the hands, people are unlikely to wash their hands at the correct time unless they have been taught to do so or have some awareness of the chain of infection transmission in the home, ie, they are aware of when their hands may be contaminated. whereas risks associated with food handling are largely confined to defined periods of time, for rt and skin infections (and person-to-person transmission of gi infection), the risk is ongoing and involves a large proportion of our ongoing daily activities. thus, whereas it is possible for hand hygiene advice associated with food hygiene to be rule based, this is not the case for other types of infections. in the event of a flu pandemic, the advice issued by the uk health protection agency to ''wash hands frequently'' is unlikely to be effective unless people have some idea of the times when their hands are likely to be contaminated with flu virus. although current thinking about hygiene promotion tends toward a view that the most effective way to change behavior is by mass social marketing of single rule-based hygiene messages, the data presented in this review suggest that the complexity and shifting nature of the id threat is such that a rule-based approach to hygiene is inadequate to meet current public health needs. the need is for an approach founded on awareness of the chain of infection transmission and how it differs for different groups of infections. hygiene education needs to be consistently incorporated as part of hand hygiene promotion programs if people are to properly understand the risks and adapt their behavior accordingly. based on the data presented in this review, we propose that, in promoting hand hygiene, significant improvements in health impact could be achieved by giving better guidance to people, first, on how to choose the best methods for hand hygiene (handwashing and/or use of abhs) based on the situation and showing them how to apply it properly and why this is important. secondly, it means stressing when it is important to apply hand hygiene, ie, what are the risk situations or critical control points at which hand hygiene needs to be applied. although the level of risk varies according to the occupants of the home (eg, presence of children, pets, ill people) and their immune status, based on the risk assessment approach as outlined earlier in this review, the critical control points or situations in which hand hygiene is indicated are as follows: d after using the toilet (or disposing of human or animal feces); d after changing a baby's diaper and disposing of the feces; d immediately after handling raw food (eg, chicken, raw meat); d before preparing and handling cooked/ready-to-eat food; d before eating food or feeding children; but also d after contact with contaminated surfaces (eg, rubbish bins, cleaning cloths, food contaminated surfaces); d after handling pets and domestic animals; d after wiping or blowing the nose or sneezing into the hands; d after handling soiled tissues (self or others', eg, children); d after contact with blood or body fluids (eg, vomit and others); d before and after dressing wounds; d before giving care to an ''at-risk'' person; and d after giving care to an infected person. in choosing the appropriate option for hand hygiene, there are possibilities: either handwashing with soap, use of abhs (or other effective waterlessbased sanitizers), or handwashing followed by use of abhs. a possible framework for informing appropriate choice according to the particular situation is outlined in fig . this suggests that, in situations in the home and community that are ''standard risk'' (perhaps better described as situations not specifically regarded as ''high risk''), either handwashing or use of abhs may be chosen. within this, however, there are factors that advise, or in some cases dictate, choice, for example, handwashing is only an option when there is access to soap and water, whereas use of abhs is not an option when hands are heavily soiled (although people are likely to choose handwashing in this situation, prompted by the need to ''clean'' their hands). as discussed previously, there will always be situations in the home in which there is increased risk, either because there is a known source of infection or someone who is at increased risk of becoming infected. these situations are summarized in table . these situations may relate to activities that are carried out routinely in the home, such as handling of raw meat and poultry, or involve household members such as pregnant women or young babies who are otherwise healthy but at increased risk of (or from) infection. they also relate to ''nonroutine'' situations such as a person in the home who is infected with a cold, or norovirus or other gi infections, or to situations in which there is someone who is at increased risk of infection as a result of underlying illness, immunosuppressive drug treatment, or needing catheter or wound care. although much of the ''health care'' carried out at home is done by trained caregivers, increasingly, there are situations in the home in which simple but risky actions are carried out by household members. in all of these ''increased risk'' situations, as outlined in table , it is suggested that handwashing followed by use of an abhs should be encouraged. in persuading people to change behavior, one of the key factors is ''removing barriers to action.'' lack of convenient access to a sink is a significant barrier to compliance, and time pressure is a barrier to getting people to wash their hands thoroughly. a key benefit of abhs is that they offer the means to apply hand hygiene in situations in which there is limited or no access to a soap and water. in home care situations, abhs offer an alternative to handwashing in situations in which other pressures mitigate against finding the time to visit the bathroom for handwashing, for example, when caring for a baby in the nursery or a sick person. they also offer a substitute for handwashing in ''out of home'' settings such as offices and public places, such as public transport or animal exhibits, at which access to soap and water is a particular problem and all of which offer frequent opportunities for hand transmission of infection. promoting use of abhs has the potential to get people to undertake hand hygiene more frequently and at critical times. in response to concerns about the possibility of a flu pandemic, the centers for disease control and prevention recommend the use of abhs for use as an alternative to handwashing. in the event of a flu pandemic, it seems particularly important to encourage people to adopt good hand hygiene in public places. in health care settings, links between use of abhs and increased hand hygiene compliance and reduced infection rates has been observed. in applying the framework outlined in fig , our intention is that this should not be regarded as an ''either handwashing or abhs'' situation; the fundamental aim should be to encourage more people to undertake hand hygiene procedures wherever possible at critical times. in view of the fact that hands are part of a complex system of infection transmission pathways, it must also be considered whether hand hygiene can, or should, be promoted in isolation. because people are reluctant to comply with handwashing, together with the microbiologic data showing the potential for transfer via hand and food contact surfaces and cloths to hands, which increase as the frequency occurrence of contamination of these surfaces increases, it would seem that, to maximize the health impact from hand hygiene promotion, it should be s vol. no. supplement combined with promotion of hygiene in general, including hygienic cleaning of critical surfaces. if nothing else, this could raise awareness that hand contamination can arise from touching apparently clean surfaces. we are concerned that emphasis on handwashing alone without putting it within the context of other aspects of hygiene is encouraging the perception that handwashing is all that is required, ie, ''if you wash your hands you won't get sick.'' the aim of this report has been to review the evidence base for hand hygiene and develop a practical framework from it for promoting an effective approach to hand hygiene in home and community settings. provision of detailed guidelines for hand hygiene is outside the scope of this review. for such guidelines the reader is referred to the ifh guidelines and training resource on home hygiene. as part of its work in promoting home hygiene, the ifh has produced ''guidelines for prevention of infection and cross infection in the domestic environment'' and ''recommendations for selection of suitable hygiene procedures for use in the domestic environment.'' , these documents are based on the concept of a risk-based approach and give detailed guidance on hand hygiene in the context of all aspects of home hygiene including food hygiene, general hygiene, personal hygiene, care of pets, and others. most recently, the ifh has also produced a teaching/self-learning resource on home hygiene. this is based on the ifh guidelines and recommendations but is designed to present home hygiene theory and practice in simple practical language that can be understood by those with relative little infection control training or background. infectious diseases circulating in the community remain a significant concern, both in developed and developing countries. the global burden of id accounts for over million deaths annually but, whereas the majority of deaths occurs in the developing world, infection also causes approximately % of deaths in developed countries. although mortality from id has declined in the developed world, trends in morbidity suggest a change in the pattern of id rather than declining rates. several demographic, environmental, and health care trends, as reviewed in this report, are combining to make it likely that the threat of id will increase in coming years, rather than decline. one such factor is the rising proportion of the population in the community who are more vulnerable to infection. an important part of current european and us health policy is commitment to shorter hospital stays. a key requirement is to ensure that the increased health provision at home is not accompanied by an increase in id risks; otherwise, the cost savings gained by care in the community are likely to be overridden by costs of rehospitalization. even for the ''healthy community,'' id represents a significant economic burden because of absence from work and school and added health care costs. secondary infections can produce complications, and some infections may be associated with the development of diseases such as cancer or other chronic conditions, which can manifest at a later date. those responsible for ensuring that the public are protected from infection in health care facilities are now realizing that their ability to manage the problem is hampered by spread of pathogens such as mrsa, c difficile, and norovirus in the community and the home, and the number of infected people or carriers who come into their facilities, and are looking for ways to address this by engaging the public to adopt more rigorous standards of hygiene. one of the things that is apparent from newly emerging data, and that is reflected in this review, is the extent to which common infections circulating in the community are hygiene related. this suggests, in turn, that hygiene promotion could have a significant benefit in terms of improved public health and well-being; in particular, the data highlight the extent to which viruses (norovirus, rotavirus, rhinovirus, influenza, and other viruses) are responsible for hygiene-related diseases now circulating in the community. the main conclusions from this review are as follows: d id circulating in the home and community is a serious public health problem in the developed as well as the developing world. d good hygiene practice is key to reducing the burden of id in the home and community. d hand hygiene is a key component of good hygiene practice in the home and community and can produce significant benefits in terms of reducing the incidence of infection, most particularly for gastrointestinal infections but also for respiratory tract and skin infections. d decontamination of hands can be carried out either by handwashing with soap or by the use of waterless hand sanitizers, which achieve a log reduction in bacterial and viral contamination on hands by the removal of contamination or by killing the organisms in situ. the health impact of hand hygiene within a given community can be increased by using products and procedures, either alone or in sequence, that maximize the log reduction of both bacteria and viruses on hands. d the impact of hand hygiene in reducing id risks could be increased by convincing people to apply hand hygiene procedures correctly (eg, wash their hands correctly) and at the correct time. d to optimize health benefits, promotion of hand hygiene must be accompanied by hygiene education and should also involve promotion of other aspects of hygiene, for example, surface and cloth hygiene. this report highlights a number of areas in which additional data are needed: d further studies are needed to characterize the frequency of, and factors associated with, id transmission in noninstitutional settings such as the home. d 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handwashing behaviour guidelines for prevention of infection and cross infection the domestic environment recommendations for selection of suitable hygiene procedures for use in the domestic environment home hygiene-prevention of infection at home: a training resource for carers and their trainers memorandum on the threat posed by infectious diseases. need for reassessment and a new prevention strategy in germany. rudolf schulke foundation. wiesbaden: mph-verlag gmbh the authors thank dr. michele pearson, centers for disease control and prevention, atlanta, ga, for her very valuable and extensive contributions to the preparation of this review. key: cord- -lsuwsm authors: jackson, michael l.; neuzil, kathleen m.; thompson, william w.; shay, david k.; yu, onchee; hanson, christi a.; jackson, lisa a. title: the burden of community-acquired pneumonia in seniors: results of a population-based study date: - - journal: clin infect dis doi: . / sha: doc_id: cord_uid: lsuwsm background. pneumonia is recognized as a leading cause of morbidity in seniors. however, the overall burden of this disease—and, in particular, the contribution of ambulatory cases to that burden—is not well defined. to estimate rates of community-acquired pneumonia and to identify risk factors for this disease, we conducted a large, population-based cohort study of persons aged ⩾ years that included both hospitalizations and outpatient visits for pneumonia. methods. the study population consisted of , seniors enrolled at group health cooperative who were observed over a -year period. pneumonia episodes presumptively identified by international classification of diseases, ninth revision, clinical modification codes assigned to medical encounters were validated by medical record review. characteristics of participants were defined by administrative data sources. results. the overall rate of community-acquired pneumonia ranged from . cases per person-years among persons aged – years to . cases per person-years among those aged ⩾ years. in this population, . % of all pneumonia episodes were treated on an outpatient basis. in multivariate analysis, risk factors for community-acquired pneumonia included age, male sex, chronic obstructive pulmonary disease, asthma, diabetes mellitus, congestive heart failure, and smoking. conclusions. on the basis of these data, we estimate that roughly , cases of community-acquired pneumonia occur annually among seniors in the united states and that ∼ of every persons aged ⩾ years will have a new episode of community-acquired pneumonia each year. the risk of pneumonia increases markedly with age, and pneumonia is a leading cause of death among seniors [ , ] . in the united states, an estimated , hospitalizations for community-acquired pneumonia (cap) [ ] and , deaths attributed to pneumonia and influenza occur among seniors every year [ ] . despite the importance of cap in this population, information on the epidemiology of cap among seniors in the united states is limited. in particular, because many prior studies of pneumonia have included only hospitalized patients, the increasingly important contribution of outpatient disease is not well defined. to better assess the burden of cap in seniors and to iden-bases that record immunizations, medication prescriptions, radiographic test reports, and international classification of diseases, ninth revision, clinical modification (icd- -cm)-coded diagnoses associated with outpatient visits and hospitalizations. each member also has a paper medical record that included copies of hospital admission and discharge summaries and outpatient and emergency department visit notes. hospitalizations for pneumonia among the study population had been identified and validated as part of a prior study of pneumococcal vaccine effectiveness [ ] . in that study, hospitalizations assigned a discharge diagnosis of pneumonia (icd- -cm codes - . ) or streptococcal or pneumococcal bacteremia (icd- -cm codes . , . , . , . , and . ) were selected for chart review. cases of nosocomial pneumonia, defined as cases in which pneumonia symptoms developed after hospitalization or in which the patient had been hospitalized in the previous days, were excluded. a confirmed episode of cap involving hospitalization was defined by an indication that, at the conclusion of their clinical evaluation, the treating physicians considered pneumonia to be the etiology of the presenting illness. episodes of pneumonia treated on an outpatient basis were presumptively defined by an outpatient or emergency department visit with a pneumonia icd- -cm code that was associated with both prescription of antibiotics and obtainment of a chest radiograph within days after the visit. an outpatient episode of cap was defined as confirmed if the chart review indicated that pneumonia was the most likely diagnosis attributed to the illness by the treating physician and if the patient had not been hospitalized in the prior days. definition of baseline covariates. to assess potential risk factors for pneumonia among the study population, a series of baseline covariates was defined from ghc administrative data sources and the regional cancer registry. these variables include ischemic cardiac disease, congestive heart failure, chronic obstructive pulmonary disease (copd), asthma without copd, renal disease, stroke, dementia, lung cancer, serious nonlung cancer, other cancer, diabetes mellitus, receipt of prednisone, receipt of other immunosuppressive medications, pneumonia hospitalization in the year prior to cohort entry, use of home oxygen, and receipt of home health care. the full definitions of these variables are provided in table a in appendix a. smoking status was defined on the basis of data routinely collected at ghc during outpatient visits [ ] . information on smoking status was missing for % of study subjects. these subjects differed in several characteristics from persons with known smoking status. alternate analyses were conducted that excluded persons who were missing smoking information, but because the results did not vary substantially from the results of analyses of the entire study population, the results presented include persons with and persons without smoking data. rates of pneumonia. crude event rates were calculated by dividing the number of cases by the cumulative person-time in each age-and sex-specific stratum. crude event rates were based on all events occurring during the study period and could include multiple events per person. to examine seasonal variation in pneumonia rates, biweekly crude rates were calculated by dividing the number of cases occurring in -week intervals by the cumulative person-time in each interval. we plotted these rates over time and compared the pattern of variation during and outside of influenza seasons with the pattern of proportionate mortality from pneumonia and influenza in the united states, as defined by national vital statistics data [ ] . influenza seasons were defined on the basis of local and national surveillance data [ ] [ ] [ ] [ ] . statistical analysis. differences in rates were assessed using the x test. multivariate cox proportional hazards models [ ] were used to evaluate the association of baseline covariates with the time to first of each outcome event during the study period. additional models were fit to test for the presence of an interaction between age or sex and other covariates with the risk of pneumonia. the attributable risk, attributable risk percentage, population-attributable risk, and population-attributable risk percentage of cap cases associated with smoking were all calculated by comparing the crude rates of cap in current smokers with the rates of cap in former smokers and those who have never smoked using standard formulas [ ] . the cohort consisted of , persons who contributed , person-years of observation during the study period. overall, % of the subjects were male, % were aged - years at baseline, and % were aged - years at baseline (table ). hospitalizations for pneumonia. a total of hospitalizations associated with a pneumonia icd- -cm code among persons were identified. information on ( %) of these events was available for review. of these events, were readmissions for pneumonia and were episodes of nosocomially acquired pneumonia. of the remaining hospitalizations, a clinical diagnosis of cap was confirmed for ( %); cohort members accounted for these cases. an additional confirmed hospitalizations for pneumonia were identified by chart review of hospitalizations associated with a bacteremia icd- -cm code. thus, confirmed capassociated hospitalizations among persons were identified during the study period. a total of episodes of presumptive outpatient pneumonia among persons were identified on the basis of administrative data, and records of ( %) of these events were available for review. of these events, episodes were excluded because a record of care for a respiratory illness was not verified, and were excluded because the respiratory illness was associated with a hospitalization. of the remaining events, a diagnosis of cap was confirmed for ( %), which occurred among cohort members. rates of cap and the percentage of cases resulting in hospitalization increased with age (table ). the rate of pneumonia was consistently higher among men than among women, across all age groups and for both hospitalized patients and outpatients with pneumonia, although the difference was not always statistically significant. overall, . % of cap episodes were treated on an outpatient basis. among persons aged у years, the rate of cap was . events per person-years, which is roughly episode of pneumonia for every persons per year. among persons hospitalized for cap, . % died within days after hospital admission. among outpatients with pneumonia, . % died within days after the first diagnosis. overall, . % of all the deaths in the cohort during the study period occurred within days after a cap diagnosis. we found that the peak rates of all cap (both hospitalizations and outpatient visits for pneumonia) coincided with periods of influenza viral circulation (figure ). in addition, the seasonal pattern of cap in our study population closely mirrored the temporal pattern of the percentage of deaths attributed to pneumonia and influenza nationally. similar seasonal patterns were seen in analyses restricted to either outpatients or hospitalized patients, and the proportion of pneumonia episodes requiring hospitalization did not vary between influenza and noninfluenza periods, either for the cohort overall or by age group (data not shown). the attributable risk for smoking among the study cohort was . cap events per person-years, and the attributable risk percentage for smoking was . %. that is, assuming there is a causal relationship between smoking and cap, we estimate that ∼ % of episodes of pneumonia among smokers were due to smoking. the population-attributable risk for smoking (among the population of persons with smoking data) was . cap events per person-years, and the population-attributable risk percentage for smoking was . %. that is, among the population of persons with smoking data, ∼ % of pneumonia events were due to smoking. there was no significant difference in the attributable risks of smoking across age groups or between men and women. in multivariate analysis, age, male sex, current smoking, diabetes mellitus, congestive heart failure, lung cancer, serious nonlung cancer, copd, asthma without copd, dementia, stroke, receipt of prednisone, use of home oxygen services, greater number of outpatient visits, and hospitalization for pneumonia in the year prior to the study start date were independently associated with risk of all cap (table ) . in general, indicators of chronic illness at baseline were more strongly [ ] [ ] [ ] [ ] . for comparison, the biweekly proportion of all deaths in the united states attributed to pneumonia and influenza (p&i), as reported by national vital statistics data, is also presented [ ] . associated with risk of hospitalization for pneumonia than of outpatient visits for pneumonia. the variable most strongly associated with all cap was copd. there was no significant interaction between age or sex and other covariates on risk of pneumonia. to our knowledge, this is the first contemporary study to assess rates of both hospitalizations and outpatient visits for pneumonia among community-dwelling seniors in the united states, and it provides, to our knowledge, the only populationbased assessment of risk factors for cap among seniors in the united states. our study builds on previous population-based studies of hospitalizations and outpatient visits for cap conducted among communities in finland [ , ] and among the ghc population in the s and early s [ ] , each of which had substantially fewer seniors in their study populations. extrapolating our age-specific rates to the population of seniors in the united states who were not in nursing homes, as reported in census data [ ] , we estimate a disease burden of , cases of cap treated on an outpatient basis and , cases of cap resulting in hospitalization, for a total of , cases of cap. these rates also indicate that ∼ of every persons aged у years will have a new episode of cap each year. our rates of hospitalizations for cap are consistent with those reported by marston et al. [ ] in a centers for disease control and prevention-sponsored prospective study of radi-ographically confirmed hospitalization for cap patients in counties in ohio in . after adjusting for differences in the age distribution of persons aged у years in the study populations, our age-adjusted hospitalization rate of . cases per person-years was nearly identical to the rate of . cases per person-years among community-dwelling seniors reported by marston et al. [ ] . the ohio study did not, however, include an assessment of outpatient visits for cap, which is particularly important, given the trend towards outpatient treatment that has occurred over the past decades. we found that, even among persons aged у years, nearly one-half ( . %) of cap events were treated on an outpatient basis. inclusion of outpatient episodes allows a more comprehensive estimate of the burden of disease and a more accurate assessment of risk factors for cap. persons with chronic conditions who develop cap are more likely to be hospitalized for treatment than are persons without chronic conditions. this means that assessments restricted to hospitalizations for cap will likely overestimate the association of those conditions with the risk of cap. the availability of administrative data on the ghc population allowed us to define the presence of underlying conditions consistently across the study population. because of this, we were able to assess the independent association of those characteristics with risk of pneumonia in multivariate analyses. as previously reported among adults, we found that copd, immunosuppression, smoking, and congestive heart failure were all independently associated with disease risk among sen- iors [ ] [ ] [ ] [ ] [ ] . in addition, we also found that diabetes, lung cancer, serious nonlung cancer, and previous hospitalizations for pneumonia were also risk factors for cap among elderly persons. in this cohort, rates of cap were higher in men than in women, and male sex was a risk factor for cap even after adjusting for age, smoking, and the presence of chronic medical conditions. a survey of hospitalizations associated with a pneumonia icd- -cm code reported in medicare claims [ ] found a significantly higher risk among men than among women, as did a follow-up assessment of the risk of a hospitalization associated with a pneumonia diagnosis among participants of the first national health and nutrition examination survey (nha-nes i) [ ] . neither of these studies assessed whether male sex was associated with pneumonia after adjusting for other risk factors, so it was not clear in these studies whether male sex was simply a marker for a higher prevalence of other risk factors. a population-based study involving elderly persons in finland found that crude cap rates did not differ between men and women and that male sex was not significantly associated with cap after accounting for age and certain chronic medical conditions and risk factors, including asthma, receipt of immunosuppressive therapy, and heart disease [ ] . because our study population was much larger than that of the finnish study, we have more power to detect an independent risk of cap associated with male sex if such a risk truly exists. however, it is possible that the difference in risk we observed could be the result of confounding by factors unmeasured in our population. we found that current smokers were at an increased risk of hospitalization for cap, which is consistent with previous reports. previous case-control studies have shown that smoking is associated with an increased risk of pneumonia [ , ] . one study has reported that, among adults who quit smoking, the excess risk of cap appears to have decreased years after quitting [ ] . we estimate that, among elderly smokers, nearly one-third of pneumonia episodes can be attributed to smoking, suggesting that smoking cessation could potentially reduce the risk of cap among smokers by an important degree. among our study population, the seasonal pattern of pneumonia closely followed the pattern of pneumonia and influenza mortality nationally. correlations between rates of hospitalization for acute respiratory disease and patterns of influenza activity have been reported in adult populations in other geographic areas [ ] [ ] [ ] . the - influenza season is recognized as having been more severe than the several preceding seasons [ ] , and timing of the peak rate of cap for the elderly ghc population in this study period closely matched the peak proportional pneumonia and influenza mortality rates in the united states, occurring in late december and early january . this correlation suggests that data from health management organizations (hmos) on pneumonia-related hospitalizations and outpatient visits could be an additional method for identifying periods of influenza virus circulation or quantifying the severity of influenza seasons. rates of cap in this population were high, especially among some subgroups of subjects, such as those aged у years, and there was close correlation with influenza virus circulation. this is despite the fact that vaccination rates for both influenza and pneumococcal polysaccharide vaccines were high in this population. annual influenza vaccination rates among the study population were %, and % of subjects received pneumococcal vaccine either prior to or during the study period, emphasizing the need for other measures for preventing pneumonia in seniors. the burden of illness could potentially be reduced by the availability of other vaccines, such as pneumococcal conjugate vaccines or vaccines effective against human metapneumovirus or respiratory syncytial virus infection. alternatively, increased emphasis on other strategies to reduce the risk of influenza infection, such as vaccination of caregivers and household contacts, could potentially impact disease risk. one limitation of this study is the possible underascertainment of pneumonia events, because our case finding was primarily restricted to medical encounters assigned a pneumonia icd- -cm code, and so would not capture pneumonia episodes associated exclusively with other diagnosis codes. for outpatient pneumonia, we would also have missed episodes in which a chest radiograph was not ordered. we cannot estimate the extent to which underascertainment may have influenced our results. however, this problem is likely to be more significant for pneumonia treated on an outpatient basis (in which a health care provider may only see a patient early in the course of the illness and assign a diagnosis before the evaluation has been completed) than in cases in the hospital setting (in which the discharge diagnoses are assigned at the end of the hospital stay and should represent a more complete assessment of the illness episode). a second limitation is that the study population includes enrollees of a single health maintenance organization in a single geographic area, and the findings may not be generalizable to the us population as a whole. as noted above, however, our age-standardized rate of cap-related hospitalizations was essentially identical to that observed in the study of cap in ohio [ ] . this similarity, along with the close correspondence between the observed rates over time in our study and the national proportional rates of mortality due to pneumonia and influenza, suggest that our study population is not dissimilar from the elderly population of the united states as a whole. our method for detection of both hospitalizations and outpatient visits for cap among a defined population of hmo enrollees has several advantages for conducting pneumonia surveillance. this type of surveillance can identify high-risk subgroups, can track trends in pneumonia incidence over time, and is suitable for both prospective and retrospective studies. surveillance of this type would be particularly useful for studying the effect of new vaccines or the introduction of new pathogens, such as severe acute respiratory syndrome coronavirus, on rates of pneumonia. incidence of communityacquired pneumonia requiring hospitalization. results of a populationbased active surveillance study in ohio. the community-based pneumonia incidence study group deaths: final data for hospitalized community-acquired pneumonia in the elderly: age-and sex-related patterns of care and outcome in the united states deaths: preliminary data for effectiveness of pneumococcal polysaccharide vaccine in older adults vital statistics mortality data, multiple cause detail update: influenza activity-united states and worldwide, - season, and composition of the - influenza vaccine update: influenza activity-united states and worldwide, - season, and composition of the - influenza vaccine update: influenza activity-united states and worldwide, - season, and composition of the - influenza vaccine update: influenza activity-united states and worldwide, - season, and composition of the - influenza vaccine time-dependent covariates in the cox proportionalhazards regression model epidemiologic methods: studying the occurrence of illness incidence of communityacquired pneumonia in the population of four municipalities in eastern finland clinical efficacy of pneumococcal vaccine in the elderly: a randomized, single-blind populationbased trial rates of pneumonia during influenza epidemics in seattle census briefs: the years of age and older population prospective study of pneumonia hospitalizations and mortality of us older people: the role of chronic conditions, health behaviors, and nutritional status risk factors for community-acquired pneumonia in adults: a population-based case-control study risk factors for community-acquired pneumonia diagnosed upon hospital admission. british thoracic society pneumonia study group risk factors for community-acquired pneumonia diagnosed by general practitioners in the community risk factors for pneumonia in the elderly proportion of community-acquired pneumonia cases attributable to tobacco smoking serious morbidity and mortality associated with influenza epidemics acute respiratory disease hospitalizations as a measure of impact of epidemic influenza influenza-associated morbidity and mortality in young and middle-aged women financial support. vaccine safety datalink contract with the america's health insurance plans, funded by the centers for disease control and prevention.potential conflicts of interest. k.m.n. has received grant support from aventis-pasteur. l.a.j. has received grant support from aventis-pasteur and has served as a consultant to chiron vaccines. all other authors: no conflicts. key: cord- - vp authors: thombs, brett d.; kwakkenbos, linda; henry, richard s.; carrier, marie-eve; patten, scott; harb, sami; bourgeault, angelica; tao, lydia; bartlett, susan j.; mouthon, luc; varga, john; benedetti, andrea title: changes in mental health symptoms from pre-covid- to covid- among participants with systemic sclerosis from four countries: a scleroderma patient-centered intervention network (spin) cohort study date: - - journal: j psychosom res doi: . /j.jpsychores. . sha: doc_id: cord_uid: vp introduction no studies have reported mental health symptom comparisons prior to and during covid- in vulnerable medical populations. objective to compare anxiety and depression symptoms among people with a pre-existing medical condition and factors associated with changes. methods pre-covid- scleroderma patient-centered intervention network cohort data were linked to covid- data from april . multiple linear and logistic regression were used to assess factors associated with continuous change and ≥ minimal clinically important difference (mcid) change for anxiety (promis anxiety a v . ; mcid = . ) and depression (patient health questionnaire- ; mcid = . ) symptoms, controlling for pre-covid- levels. results mean anxiety symptoms increased . points ( % confidence interval [ci] . to . ). depression symptom change was negligible ( . points; % ci - . to . ). compared to france (n = ), adjusted anxiety symptom change scores were significantly higher in the united kingdom (n = ; . points, % ci . to . ), united states (n = ; . points, % ci . to . ), and canada (n = ; . points, % ci . to . ). odds of ≥ mcid increase were . for the united kingdom ( % ci . to . ) but not significant for the united states ( . , % ci . to . ) or canada ( . , % ci . to . ). older age and adequate financial resources were associated with less continuous anxiety increase. employment and shorter time since diagnosis were associated with lower odds of a ≥ mcid increase. conclusions anxiety symptoms, but not depression symptoms, increased dramatically during covid- among people with a pre-existing medical condition. the sars-cov- coronavirus disease (covid- ) pandemic has caused more than , deaths and has had devastating health, social, political, and economic consequences worldwide. there are expected to be serious mental health implications during and beyond the initial outbreak, but their degree and nature are not well understood. [ ] [ ] many cross-sectional studies report percentages of participants above cutoff thresholds on mental health symptom questionnaires during covid- . such percentages, however, vary substantially across otherwise similar populations even in normal times. furthermore, they tend to dramatically overestimate prevalence obtained from validated methods, and there is too much heterogeneity to correct for differences statistically. , thus, studies that directly evaluate changes are needed. based on a living systematic review, , as of june , , only studies had compared mental health prior to and during covid- . four studies of university students suggest small increases in depression but minimal or no increases in anxiety. a united kingdom general population study found small increases in general mental health symptoms but did not differentiate between anxiety and depression symptoms. no studies had evaluated mental health changes among people at risk of covid- complications due to pre-existing medical conditions. furthermore, despite important differences in pandemic responses across countries, no studies had compared mental health changes between countries. people with the autoimmune disease systemic sclerosis (ssc; scleroderma) are representative of patients with pre-existing medical conditions that put them at risk during covid- . more than % have interstitial lung disease, many are frail, and use of immunosuppressant drugs is common. , the scleroderma patient-centered intervention network (spin) cohort routinely collects mental health outcomes at -to -month intervals. [ ] [ ] [ ] the spin covid- cohort was initiated to collect data during covid- and allows j o u r n a l p r e -p r o o f journal pre-proof comparison of mental health symptoms prior to and during covid- for participants enrolled in both cohorts. our objective was to compare anxiety (promis anxiety a v . scale , ) and depression (patient health questionnaire- ) symptoms before and after onset of covid- among people with ssc, including ( ) continuous score changes; ( ) proportion with change scores of at least one minimal clinically important difference (mcid); ( ) proportion initially under a cutoff threshold who changed by at least mcid and reached the threshold; and ( ) factors associated with changes, including country, comparing results from canada, france, the united kingdom, and the united states. this was a longitudinal study that linked pre-covid- data from the spin cohort - to data collected from a sub-cohort during the baseline assessment of the associated spin covid- cohort between april , and april , using the same measurement scales. person-level, deterministic linking was used with participant email addresses as the indentifier. the full protocol for the spin covid- cohort and the present study, which provides more detail on the methods and measures, is available online (https://osf.io/kbncx/). anxiety symptoms. the promis anxiety a v . scale , includes items asking participants, in the past days, how often: ( ) "i felt fearful"; ( ) "i found it hard to focus on anything other than my anxiety"; ( ) "my worries overwhelmed me"; and ( ) "i felt uneasy". items are scored - with response options "never" to "always". higher scores represent more anxiety. possible raw scores range from to . raw scores are converted into t-scores standardized from the general us population (mean = , standard deviation = ). a change of . t-score points was selected to represent the mcid and a threshold for identifying people with at least moderate symptoms of t-score ≥ . promis anxiety a v . has been validated in ssc , and is included in all -month spin cohort assessments. depressive symptoms. the eight-item phq- measures depressive symptoms over the last weeks with item scores from (not at all) to (nearly every day) and higher scores representing more depression. possible total scores range from to . the mcid has been estimated to be . points, and a threshold of ≥ is commonly used to identify people who may have depression. the phq- , which is assessed every months in the spin cohort, performs equivalently to the phq- , which has been shown to be valid in ssc. descriptive statistics are presented as mean (standard deviation) for continuous variables and numbers (percentages) for categorical variables. changes in anxiety and depression symptoms were described: ( ) continuously with t-scores or raw scores, in terms of mcids, and with a hedges g standardized mean difference effect size, all with % confidence intervals (cis); ( ) as the proportion of participants whose symptoms worsened or improved, separately, by at least mcid, with % cis; and ( ) as the proportion initially below a t-score of on the promis anxiety a v . or a score of on the phq- who increased by at least mcid j o u r n a l p r e -p r o o f and reached the threshold score, with % cis. for proportions, % cis were generated based on agresti and coull's approximate method for binomial proportions. we conducted two sets of sensitivity analyses for symptom changes. first, for both anxiety and depressive symptoms, we compared change to scores from assessments done months, have you seen any of the following health professionals to address a mental health concern?"), and financial resource adequacy (continuous). all analyses were conducted using stata (version ) with -sided statistical tests and p < . significance level. changes included exclusion of participants from australia, because only would have been eligible; removal of covid- infection from model covariates, since only participants reported a positive test; and addition of sensitivity analyses. additionally, we controlled for baseline anxiety or depression symptom scores to ensure that factors associated with change were not confounded with initial symptom level differences. the spin patient advisory board (https://spinsclero.com) reviews all spin research, including the present study, and advises the spin steering committee to ensure that spin research addresses the needs of people with ssc. additionally, members of the study-specific spin covid- patient advisory team was involved in each stage of the present study, including designing the spin covid- cohort, selecting outcomes for assessment, interpreting results, and providing comments on the present manuscript. as shown in table , anxiety symptoms increased more than a full mcid ( . points, % ci . to . ). increases by country were . points ( % ci . to . ) for france, . points for canada ( % ci . to . ), table as shown in table ). we found that anxiety symptoms increased substantially compared to before the covid- pandemic among vulnerable persons with a pre-existing medical condition, ssc, whereas depressive symptom changes were minimal. overall, mean change on the promis anxiety a v . was . points, greater than the mcid of points. approximately % of participants experienced an increase of  mcid. results differed, however, by country. anxiety symptoms increased by approximately points among participants from france, points among participants from canada, points among participants from the united kingdom, and points among participants from the united states. in multivariable analysis, compared to france, participants from the united kingdom, united states, and canada scored . , . , and . points higher. participants from the united kingdom also had odds of over twice as likely to have increased by  mcid. overall, depression symptoms changed negligibly, but this was also associated with country with increases higher by approximately points in the united kingdom and point in canada and the united states, though this was not statistically significant for the united states. the only other variable that was consistently associated with symptoms of anxiety and depression was adequacy of financial resources, which was significantly associated with better outcomes for continuous anxiety symptoms and both continuous depression symptoms and odds of an increase in depression symptoms of  mcid. our study is one of the first to report mental health symptom changes during covid- in a vulnerable population with a pre-existing medical condition and the first to compare symptom changes across countries. compared to studies of university students, which suggest that depressive symptoms have increased by a small amount and anxiety minimally or not at all, , we found that depressive symptoms changed minimally, but anxiety symptoms, on average, increased substantially. this may relate to the differential effect that covid- is having on increases in anxiety and depression symptoms were associated with country with large magnitudes in some cases. comparing across countries is fraught with complexities. one possible explanation may relate to the coherence of governmental and civil responses in the countries we studied. indeed, editorials in the lancet have described the american response as "inconsistent and incoherent" and the uk's national response as "astonishingly haphazard." france undertook some of the most restrictive measures internationally to attempt to reduce the spread of the virus, which may have reduced fear, relatively, among people vulnerable due to medical conditions. canadian provinces were somewhat less restrictive but were generally consistent with a high level of political consensus on measures that have been taken. the consistent finding that symptoms were associated with adequacy of financial resources to meet current needs underlines the financial implications of the pandemic and the role of economics in mental health. all of the countries with participants in our study have provided aid packages, - and findings from our study would seem to emphasize the importance of economic supports for those in need. this is the first study to compare mental health outcomes among people vulnerable during covid- due to a pre-existing medical condition. the spin cohort is a well-characterized, ongoing cohort, and people with ssc are representative of other patient groups who are vulnerable during covid- . there are also limitations to consider. first, the spin cohort is a convenience sample, although participant characteristics are similar to other large ssc cohorts. second, participants complete questionnaires online, which may reduce generalizability. third, it j o u r n a l p r e -p r o o f journal pre-proof was not possible to capture and include local variables, such as the degree participants' communities were affected or whether public health interventions were consistently followed in those communities. nonetheless, data were collected at a time when social isolations were generally at their most conservative. finally, different mcid values may be chosen. the -point mcid we used for anxiety symptoms was conservative; others have recommended mcids of to points, and it is possible that we may have underestimated the degree of patient-important change. in sum, we compared mental health symptoms prior to and during the covid- outbreak among people vulnerable due to a pre-existing medical condition. we found that anxiety symptoms increased substantially and that the magnitude was associated with country; increases were highest in the united states and united kingdom and more moderate in france and canada. there were minimal differences in depressive symptoms during covid- compared to pre-covid- . these findings, which differ from early reports of results from younger adults, for instance, and suggest that the nature of mental 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information system (promis) developed and tested its first wave of adult self-reported health outcome item banks the phq- as a measure of current depression in the general population classification criteria for systemic sclerosis: an american college of rheumatology/european league against rheumatism collaborative initiative who timeline -covid- . world health organization consumer financial protection bureau. cfpb financial well-being scale: scale development technical report comparative responsiveness and minimally important difference of common anxiety measures validity of two new patient-reported outcome measures in systemic sclerosis: patient-reported outcomes measurement the patient health questionnaire anxiety and depression scale (phq-ads): initial validation in three clinical trials accuracy of patient health questionnaire- (phq- ) for screening to detect major depression: individual participant data meta-analysis equivalency of the diagnostic accuracy of the phq- and phq- : a systematic review and individual participant data meta-analysis comparison of the phq- and ces-d depression scales in systemic sclerosis: internal consistency reliability, convergent validity and clinical correlates approximate is better than "exact" for interval estimation of binomial proportions reviving the us cdc offline: covid- -what countries must do now oxford covid- government response tracker a rare moment of crosspartisan consensus: elite and public response to the covid- pandemic in canada. can j . economic impact payments virus aid package beats financial crisis stimulus which countries have applied measures like stimulus checks and how much? protocol for a partially nested key: cord- -csy fekx authors: cohen, alan b. title: living in a covid‐ world date: - - journal: milbank q doi: . / - . sha: doc_id: cord_uid: csy fekx nan politicians and scientists over control of the narrative. misinformation abounds regarding the virus, its origins, preventive measures to contain it, and the prospects for cures and vaccines. equally damaging is the false dichotomy that permeates the public debate over whether it is more important to restore the economy or mitigate the pandemic. the enormous political and economic pressure to "re-open" the country to commerce and "normal" activity has caused virtually all states to relax "stay-at-home" orders and other restrictions intended to control the virus' spread. however, public health experts remain concerned that these activities may generate new surges in the numbers of confirmed cases, hospitalizations, and deaths. there is no denying that we now live in a covid- world-one fraught with constant uncertainty about personal safety as well as our collective health and economic well-being. those affected the most by the pandemic-low-income individuals and communities of color-also are the most disadvantaged by poverty and other social determinants of health. as we begin to chart a path toward recovery, we need to recognize the interconnection between health equity and economic security. economic recovery in the absence of an equitable health care system will only perpetuate longstanding historical injustices. however, a reformed health care system that truly embraces and pursues equity in health outcomes will serve the needs of all americans and instill hope in the future. this transformation will take time, effort, and resources, and it will test the patience and resolve of many as they adapt to living in a covid- world. what, then, might this journal do in the present situation? throughout its history, the milbank memorial fund has been dedicated to connecting leaders with the best available evidence and experience. in that same spirit, the quarterly has been committed to applying the best empirical research to practical policymaking regarding population health. we intend to pursue that goal in the current crisis, publishing original research and insightful perspectives that advance knowledge in the field and serve the public interest. this month, we will announce a call for papers regarding policies and practices as they relate to the covid- pandemic, with an eye toward improving future decisionmaking and avoiding the mistakes and pitfalls of the recent past. stay tuned-details to follow. this issue of the quarterly contains a mix of articles, some targeted to the covid- pandemic and others spanning our ongoing areas of editorial interest. in "detailing the primary care imperative"-the third installment in our milbank classics series-james perrin celebrates the enduring wisdom of barbara starfield, leiyu shi, and james macinko in their landmark article, "contribution of primary care to health systems and health." perrin emphasizes the important characteristics of primary care-first contact care, holistic person-focused care over time, comprehensive care, and coordinated care-that emerged from this work and have become ingrained within primary care medical homes across the nation. he critically examines the progress made by the united states in the years since the publication, citing notable improvements but also pointing out the lingering weaknesses and obstacles to fulfillment of starfield's original vision for primary care. in two complementary milbank quarterly perspectives, nason maani and sandro galea explore the long-term negative effects of the united states' failure to invest in the nation's infrastructure to address both population health and public health. in "covid- and underinvestment in the health of the us population," they identify the underlying conditions of the us population that have made americans particularly susceptible to the spread of the virus, including inequitable socioeconomic conditions, long-entrenched racial and ethnic divides, poor treatment of marginalized populations, and a mismatch between health care needs and access to care. in "covid- and underinvestment in the public health infrastructure of the united states," the authors examine trends in public health funding, noting the chronic underfunding of state public health departments and reductions in federal funding of public health in favor of commitments to build hospital infrastructure and support biomedical research. these trends, they assert, have hampered the nation's ability to respond appropriately to the covid- crisis. to counter these problems, they call for a sustained federal commitment for a centrally coordinated and accountable public health infrastructure coupled with acknowledgment by policymakers that social determinants are the foundational causes of health and that the health of all citizens is a public good that can lead to economic security. as states look for novel ways to provide affordable health insurance to their citizens, several are implementing initiatives that test the concept of a "public option" to compete with private insurance within the affordable care act marketplaces. in a new milbank quarterly perspective, michael sparer evaluates reform efforts in two states: washington state, which enacted a "public option," and new mexico, which failed in its effort to enact a medicaid buy-in. sparer compares the two approaches, finding that federal funding remains central to expanded coverage and that the line between the aca public expansion and the commercial marketplaces has become blurred, posing significant challenges to state policymakers. he contends that washington state's initiative will be important to follow as a redefined "public option" that potentially might serve as a politically viable model for health reform. the democratic presidential election campaign stirred contentious debate over potential health reform-pitting single payer medicare for all plans against incremental changes to the affordable care act. with joe biden as the presumptive democratic nominee, the likely path for democrats will be modest and incremental. in a new milbank quarterly perspective, tsung-mei cheng draws upon the work of her late husband and health policy collaborator, uwe reinhardt, with particular attention to possible lessons for the united states from germany's all-payer health care system. the perspective is a tribute to the legacy of reinhardt, who for more than four decades illuminated the fields of health economics and health policy with his penetrating insight and witty commentary that always offered object lessons for policymakers and researchers alike. in a sweeping review, cheng defines allpayer systems and their advantages, compares health care spending in the united states with that in several other nations, provides a detailed description of germany's all-payer system, and concludes with lessons for the united states. both she and reinhardt believe that germany's system could serve as a model to help bend the cost growth curve and expand coverage, while also creating a kinder health care system for all americans. in an original research article, that also is the subject of a milbank quarterly in conversation podcast this month (see https://www.milbank. org/quarterly/milbank-quarterly-podcast/), emilie courtin and colleagues address the question of "can social policies improve health? a systematic review and meta-analysis of randomized trials." their comprehensive review and meta-analysis of these experiments in the united states find suggestive evidence of health benefits associated with investments in early life, income support, and health insurance policies. however, many of the studies are underpowered to detect health impacts and are at risk of bias. they recommend that future social policy experiments be better designed to measure and evaluate health outcomes. how to prioritize interventions with intertwined threats and costs poses great challenges for decision makers in large urban counties. in "which priorities for health and well-being stand out after accounting for tangled threats and costs? simulating potential intervention portfolios in large urban counties," bobby milstein and jack homer use county health rankings data for a predefined peer group of urban counties to identify cross-impacts among threats to health and wellbeing. adding appropriate time delays, they develop a dynamic model of these cross-impacts and simulate each of the counties over years to assess the likely impact of potential interventions for outcomes that include years of potential life lost, the fraction of adults in fair-poor health, and total spending on urgent services. the combined portfolio of interventions yields improvements by year that are considerably greater than those at year . poverty reduction and social support are the most highly ranked interventions. they suggest that a significant concentration of resources in a regional portfolio ought to go toward these strongest contributors for equitable health and well-being. in a rapidly changing health care environment, primary care leaders need training to enhance their practice-level leadership skills. in "leading innovative practice: leadership attributes in leap practices," benjamin crabtree and colleagues review the literature on leadership from the perspective of complex adaptive systems, and identify nine leadership attributes thought to support practice change. they apply these attributes to practices that rank high on a practice learning and leadership scale from the learning from effective ambulatory practice (leap) project to see whether and how the attributes manifest in highperforming innovative practices. all nine attributes identified from the literature are evident and seem important during a time of change and innovation. the authors argue that complexity science offers a hypothesized developmental model in which some attributes are foundational and necessary for the emergence of others. policymakers need to evaluate integrated care programs to identify and manage conflicts and tensions between a program's aims and the context in which it operates. in "rethinking integrated care: a systematic hermeneutic review of the literature on integrated care strategies and concepts," gemma hughes and colleagues report on a systematic review of literature covering integrated care strategies and concepts. their analysis includes comparing heterogeneous strategies and concepts, developing a taxonomy of the literature, and generating a new interpretation of those strategies. common across empirical and conceptual work is a concern with unity in the face of fragmentation. however, the authors find that integrated care programs do not necessarily lead to intended changes in experiences and outcomes, which they attribute, in part, to significant misalignment between the aspiration for unity underpinning conceptual models on the one hand and the multiplicity of practical application of strategies to integrate care on the other. they conclude that models of integrated care need to be valued for their heuristic rather than predictive powers. community-engaged research (cenr) aims to engender meaningful academic-community partnerships to increase research quality and impact, and to improve individual and community health through the uptake of evidence-based practices. in "measuring community-engaged research contexts, processes, and outcomes: a mapping review," tana luger and colleagues describe a mapping review aimed toward helping partnerships find and select measures to evaluate cenr projects and characterize areas where further development of measures is needed. the authors identify multiple measures of context (factors to support effective academic-community collaboration), process (measures of group dynamics and trust), and outcomes (impacts such as benefits and challenges of cenr participation). they find substantial variation in how academic-community partnerships conceptualize and define even similar domains. they advocate a hybrid approach in which partnerships discuss common metrics and develop locally important measures to address cenr's multiple goals. the flint, michigan, water crisis-a manmade tragedy that exposed thousands of children and adults to excessive lead levels in the city's drinking water-has been well documented. a major factor explaining why the crisis unfolded as it did is the complexity of the laws regulating how government agencies maintain and monitor safe drinking water. peter jacobson and colleagues analyze "the role of the legal system in the flint water crisis" by examining the legal arrangements governing public health and safe drinking water, and the degree of legal preparedness among governmental officials. their analysis reveals flaws in both the legal structure and the implementation of the laws that failed to stop the crisis while simultaneously exacerbating it substantially. they recommend that policymakers examine the legal framework in their jurisdictions and take appropriate steps to avoid similar disasters. precision medicine depends on new technologies that measure specific biomarkers, which theoretically will lead to more accurate diagnosis and targeted treatment. owing to the disruptive nature of these technologies, they often require radical changes to clinical practice and service organization. in "personalized medicine, disruptive innovation, and 'trailblazer' guidelines: case study and theorization of an unsuccessful change effort," alex rushforth and trisha greenhalgh describe a case study of an attempt by academic researchers to radically change asthma management in the united kingdom using a precision medicine biomarker. the authors employ a wide-ranging data set that includes documents, interviews, and ethnographic observation. they find that, despite efforts by the academic researchers to engage in clinical guideline development for primary care clinicians, practitioners working outside tertiary referral centers do not accept the vision of precision medicine as inscribed in the guideline for various reasons. they believe that "trailblazer" guidelines, based on new, disruptive technologies, may catalyze practice change only in a limited way for interested individuals and groups, and that, in the absence of broader professionally led change efforts, may be strongly resisted. in closing, we wish to inform readers that scholarly opinions will no longer appear in the print edition of the quarterly. all opinions will appear exclusively on our website (https://www.milbank.org/quarterly/ the-milbank-quarterly-opinions/). we invite you to visit the website, where you will find recent opinions by contributing writers lawrence gostin, sara rosenbaum, and joshua sharfstein as well as guest opinions by sherry glied and others on various topics of interest. he could have seen what was coming: behind trump's failure on the virus lives were lost' as warnings went unheeded, whistleblower tells house centers for disease control and prevention. coronavirus disease : cases in the u.s covid- forecasts the employment situation million americans now unemployed as another million file for benefits. the guardian the u.s. was beset by denial and dysfunction as the coronavirus raged trump's aggressive advocacy of malaria drug for treating coronavirus divides medical community trump abandoned it -and science -in the face of covid- during coronavirus pandemic, governors' leadership is critical. the philadelphia inquirer states relax coronavirus restrictions as u.s. fitfully seeks steps toward normalcy covid- and racial/ethnic disparities key: cord- -ji jbct authors: morens, david m.; folkers, gregory k.; fauci, anthony s. title: the challenge of emerging and re-emerging infectious diseases date: - - journal: nature doi: . /nature sha: doc_id: cord_uid: ji jbct infectious diseases have for centuries ranked with wars and famine as major challenges to human progress and survival. they remain among the leading causes of death and disability worldwide. against a constant background of established infections, epidemics of new and old infectious diseases periodically emerge, greatly magnifying the global burden of infections. studies of these emerging infections reveal the evolutionary properties of pathogenic microorganisms and the dynamic relationships between microorganisms, their hosts and the environment. merging infections (eis) can be defined as "infections that have newly appeared in a population or have existed previously but are rapidly increasing in incidence or geographic range" . eis have shaped the course of human history and have caused incalculable misery and death. in , a new disease -acquired immune deficiency syndrome (aids) -was first recognized. as a global killer, aids now threatens to surpass the black death of the fourteenth century and the - influenza pandemic, each of which killed at least million people , . of the 'newly emerging' and 're-emerging/resurging' diseases that have followed the appearance of aids (fig. ) , some have been minor curiosities, such as the cases of monkeypox imported into the united states , whereas others, such as severe acute respiratory syndrome (sars), which emerged in the same year , have had a worldwide impact. the anthrax bioterrorist attack in the united states falls into a third category: 'deliberately emerging' diseases. eis can be expected to remain a considerable challenge for the foreseeable future. here we examine the nature and scope of emerging and reemerging microbial threats, and consider methods for their control. we emphasize that emergence results from dynamic interactions between rapidly evolving infectious agents and changes in the environment and in host behaviour that provide such agents with favourable new ecological niches. about million (> %) of million annual deaths worldwide are estimated to be related directly to infectious diseases; this figure does not include the additional millions of deaths that occur as a consequence of past infections (for example, streptococcal rheumatic heart disease), or because of complications associated with chronic infections, such as liver failure and hepatocellular carcinoma in people infected with hepatitis b or c viruses (fig. ) . the burden of morbidity (ill health) and mortality associated with infectious diseases falls most heavily on people in developing countries , and particularly on infants and children (about three million children die each year from malaria and diarrhoeal diseases alone ). in developed nations, infectious disease mortality disproportionately affects indigenous and disadvantaged minorities . eis have been familiar threats since ancient times. they were once identified by terms such as ȕșȓȖș ȝ (loimos) , and later as 'pestilences' , 'pestes' , 'pests' and 'plagues' . many examples can be cited in addition to the black death and the influenza pandemic, such as certain biblical pharaonic plagues and the unidentified plague of athens, which heralded the end of greece's golden age . the age of discovery, starting in the fifteenth century, was a particularly disastrous period with regard to the spread of infectious diseases. importation of smallpox into mexico caused - million deaths in - , effectively ending aztec civilization , . other amerindian and pacific civilizations were destroyed by imported smallpox and measles [ ] [ ] [ ] [ ] [ ] . historians have referred to these events as apocalypses and even as genocide . for centuries, mankind seemed helpless against these sudden epidemics. but the establishment of the germ theory and the identification of specific microbes as the causative agents of a wide variety of infectious diseases [ ] [ ] [ ] led to enormous progress, notably the development of vaccines and ultimately of antimicrobials . in fact, the era of the identification of microbes had barely begun when optimists at the end of the nineteenth century predicted the eradication of infectious diseases . by the s, which witnessed the widespread use of penicillin, the development of polio vaccines and the discovery of drugs for tuberculosis, complacency had set in , and in , the us surgeon general stated that "the war against infectious diseases has been won" . some experts remained sceptical, aware of recurrent lessons from history. they were less persuaded by successes than alarmed by failures such as the lack of progress against infections in the developing world and the global spread of antimicrobial resistance. richard krause, then the director of the us national institute of allergy and infectious diseases, warned in (ref. ) that microbial diversity and evolutionary vigour were still dynamic forces threatening mankind. as krause was completing his book the restless tide , aids -one of history's most devastating pandemics -was already insidiously emerging. the emergence of aids led to renewed appreciation of the inevitability and consequences of the emergence of infectious diseases [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in the past years, some of the factors that resulted in aids have also led to re-emergences of historically important diseases such as cholera, diphtheria, trench fever and plague. many re-emergences have been catalysed by wars, loss of social cohesion, and natural disasters such as earthquakes and floods, indicating the importance not only of microbial and viral factors, but also of social and environmental determinants [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the challenge of emerging and re-emerging infectious diseases the classification of eis as 'newly emerging' , 're-emerging/resurging' or 'deliberately emerging' is useful because the underlying causes of emergence and the optimal prevention or control responses frequently differ between the groups. newly emerging infections are those that have not previously been recognized in man. many diverse factors contribute to their emergences (see box ); these include microbial genetic mutation and viral genetic recombination or reassortment, changes in populations of reservoir hosts or intermediate insect vectors, microbial switching from animal to human hosts, human behavioural changes (notably human movement and urbanization), and environmental factors. these numerous microbial, host and environmental factors interact to create opportunities for infectious agents to evolve into new ecological niches, reach and adapt to new hosts, and spread more easily between them. any discussion of recent eis must begin with the human immunodeficiency virus (hiv) that causes aids. hiv has so far infected more than million people worldwide . before jumping to humans an estimated - years ago , perhaps as a consequence of the consumption of 'bush meat' from non-human primates, hiv- and hiv- had ample opportunity to evolve in hosts that were genetically similar to man (the chimpanzee, pan troglodytes, and the sooty mangabey, cercocebus atys). but hiv/aids might never have emerged had it not been for disruptions in the economic and social infrastructure in post-colonial sub-saharan africa. increased travel, the movement of rural populations to large cities, urban poverty and a weakening of family structure all promoted sexual practices, such as promiscuity and prostitution, that facilitate hiv transmission [ ] [ ] [ ] [ ] . such complex interactions between infectious agents, hosts and the environment are not unique to the epidemiology of hiv/aids. the examples cited below further illustrate how changes in population density, human movements and the environment interact to create ecological niches that facilitate microbial or viral adaptation. some infectious agents that have adapted to non-human hosts can jump to humans but, unlike hiv, are not generally transmitted from person to person, achieving only 'dead end' transmission. infections in animals that are transmitted to humans (zoonoses), and those transmitted from one vertebrate to another by an arthropod vector (vector-borne diseases), have repeatedly been identified as ranking among the most important eis , . examples include the arenavirus haemorrhagic fevers (argentine, bolivian, venezuelan and lassa haemorrhagic fevers) and hantavirus pulmonary syndrome (hps). viruses in these groups have co-evolved with specific rodent species whose contact with humans has increased as a result of modern environmental and human behavioural factors. farming, keeping domestic pets, hunting and camping, deforestation and other types of habitat destruction all create new opportunities for such infectious agents to invade human hosts [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the first epidemic of hps, detected in the southwestern region of the united states in (ref. ) , resulted from population booms of the deer mouse peromyscus maniculatis, in turn caused by climate-related and recurrent proliferation of rodent food sources. increased rodent populations and eventual shortages of food drove expanded deer mouse populations into homes, exposing people to virus-containing droppings. the - malaysian nipah virus epidemic further illustrates the influence of human behaviours and environmental perturbations on newly emerging human infections. pigs crammed together in pens located in or near orchards attracted fruit bats whose normal habitats had been destroyed by deforestation and whose droppings contained the then-unknown paramyxovirus. virus aerosolization caused infection of pigs, with overcrowding leading to explosive transmission rates and ultimately to infections in pig handlers. variant creutzfeldt-jakob disease (vcjd) is another example of a zoonotic disease emerging in humans. vcjd is caused by the humanadapted form of the prion associated with the emerging epizootic (large-scale animal outbreak) of bovine spongiform encephalopathy (bse) figure global examples of emerging and re-emerging infectious diseases, some of which are discussed in the main text. red represents newly emerging diseases; blue, re-emerging/resurging diseases; black, a 'deliberately emerging' disease. adapted, with permission, from ref. . epizootic/vcjd epidemic, primarily affecting great britain, probably resulted from the now-abandoned practice of supplementing cattle feed with the pulverized meat and bones of previously slaughtered cattle. bse itself is suspected to have emerged because of even earlier use of cattle feed containing the agent of sheep scrapie, a prion disease recognized by farmers more than years ago . alarmingly, the new bse prion has become uncharacteristically promiscuous: unlike most known prions, it readily infects multiple species in addition to humans. this suggests the possibility of further emerging diseases associated with prions with currently unknown transmissibility to humans . the recent reports of variant strains of the bse prion suggest that the bse agent could be a more serious threat than other animal prions. infectious agents indirectly transmitted to or between humans by way of human-modified environments account for other emerging zoonoses, as well as certain non-zoonotic diseases, which are discussed below. for example, legionnaires' disease, first identified in , is caused by legionella pneumophila, whose emergence as a human pathogen might not have occurred were it not for the environmental niche provided by air-conditioning systems . campylobacter jejuni and shiga-toxin-producing escherichia coli (e. coli o :h and other agents of haemolytic-uraemic syndrome) infect agricultural animals, gaining access to humans through food, milk, water or direct animal contact. other enteric pathogens, such as the vibrios causing classical cholera (re-emerging; see below) and serogroup o cholera, and the zoonotic protozoa cryptosporidium parvum and cyclospora cayetanensis , seem to have come from environmental or animal organisms that have adapted to human-to-human 'faecal-oral' transmission through water. some eis come from microorganisms that once caused familiar diseases, but which now cause new or previously uncommon diseases. streptococcus pyogenes caused a fatal pandemic of scarlet and puerperal fevers between and (ref. ) . scarlet fever, then the leading cause of death in children, is now rare, but has been largely supplemented by other streptococcal complications such as streptococcal toxic shock syndrome, necrotizing fasciitis and re-emergent rheumatic fever . when new microbes are discovered, their emergences as disease-causing pathogens may be delayed. for example, in , robert koch was unable to show that the newly discovered koch-weeks bacillus caused serious disease. more than a century later, a fatal ei dubbed brazilian purpuric fever was linked to virulent clonal variants of haemophilus influenzae biogroup aegyptius (the koch-weeks bacillus) . although the bases of emergences of new and more severe diseases caused by s. pyogenes and h. influenzae biogroup aegyptius are not fully known, in both cases complex microbial genetic events are suspected. the distinctive clonal variants associated with severe h. influenzae biogroup aegyptius disease have been shown by pcr (polymerase chain reaction)-based subtractive genome hybridization to contain not only a unique plasmid, but also unique chromosomal regions, some of which are encoded by bacteriophages . this research has narrowed the search for virulence determinants to unique proteins, some of which may have been acquired from other organisms by horizontal gene transfer. streptococcus pyogenes has been studied more extensively, but the basis of severe disease emergence seems to be more complex than for h. influenzae biogroup aegyptius. many factors associated with streptococcal virulence have been identified in strains bearing the m surface protein as well as in other m protein strains, among them bacteriophage-encoded superantigen toxins and a protein known as sic (streptococcal inhibitor of complement), which seems to be strongly selected by human host mucosal factors. several lines of evidence suggest that changes in streptococcal virulence reflect genetic changes associated with phage integration, large-scale chromosomal rearrangements and possibly the shuffling of virulence cassettes (clusters of genes responsible for pathogenicity), followed by rapid human spread and immune selection , . infectious agents that are associated with chronic diseases are one of the most challenging categories of newly emerging (or at least newly appreciated) infections. examples include the associations of hepatitis b and c with chronic liver damage and hepatocellular carcinoma, of certain genotypes of human papillomaviruses with cancer of the uterine cervix, of epstein-barr virus with burkitt's lymphoma (largely in africa) and nasopharyngeal carcinoma (in china), of human herpesvirus with kaposi sarcoma, and of helicobacter pylori with gastric ulcers and gastric cancer [ ] [ ] [ ] . some data even suggest infectious aetiologies for cardiovascular disease and diabetes mellitus , major causes of death and disability worldwide. other associations between infectious agents and idiopathic chronic diseases will inevitably be found. re-emerging and resurging infections are those that existed in the past but are now rapidly increasing either in incidence or in geographical or human host range. re-emergence is caused by some of the factors that cause newly emerging infectious diseases, such as microbial evolutionary vigour, zoonotic encounters and environmental encroachment. re-emergences or at least cyclical resurgences of some diseases may also be climate-related -for example, the el niño/southern oscillation (enso) phenomenon is associated with resurgences of cholera and malaria . the impact of both new and re-emerging infectious diseases on human populations is affected by the rate and degree to which they spread across geographical areas, depending on the movement of human hosts or of the vectors or reservoirs of infections. travel has an important role in bringing people into contact with infectious agents . an increase in travel-associated importations of diseases was anticipated as early as , when commercial air travel was still in its infancy . this has since been demonstrated dramatically by an international airline hub-to-hub pandemic spread of acute haemorrhagic conjunctivitis in (ref. ) , by epidemics of meningococcal meningitis associated with the hajj, and more recently by the exportation of epidemic sars (a newly emerging disease) from guangdong province, china, to hong kong, and from there to beijing, hanoi, singapore, toronto and elsewhere (fig. ) . the persistent spread of hiv along air, trucking, drug-trafficking and troop-deployment routes is a deadly variation on this theme [ ] [ ] [ ] . plasmodium falciparum malaria was neglected for several decades, but is now among the most important re-emerging diseases worldwide (fig. ) . years of effective use of dichlorodiphenyltrichloroethane (ddt) led to the abandonment of other mosquito-control programmes, but the insecticide fell into disuse because of mosquito resistance and concerns about the insecticide's potentially harmful effects on humans and wildlife. consequently, malaria has re-emerged, and the situation has been worsened by the development of drug resistance to chloroquine and mefloquine . research efforts focus on the development of vaccines and new drugs, and on re-establishing public health measures such as the use of bed nets. tuberculosis is one of the most deadly re-emerging diseases (fig. ) . the discovery of isoniazid and other drugs initially led to effective tuberculosis cures, empty sanitoria and the dismantling of public health control systems in developed nations. consequently, by the s, when tuberculosis had re-emerged in the era of hiv/aids, local and state health departments in the united states lacked field, laboratory and clinical staff and so had to reinvent tuberculosiscontrol programmes . the remarkable re-emergence of tuberculosis was fuelled by the immune deficiencies of people with aids, which greatly increases the risk of latent mycobacterium tuberculosis infections progressing to active disease, and being transmitted to others. inadequate courses of anti-tuberculosis therapy compound the problem, leading to the emergence and spread of drug-resistant and multidrug-resistant strains , and a need for more expensive treatment strategies such as directly observed therapy. it has been known for over a century that tuberculosis is a disease of poverty, associated with crowding and inadequate hygiene. the continuing expansion of global populations living in poverty makes tuberculosis more difficult to control. . immune deficiency associated with aids, and with chemotherapy for cancer, immune-mediated diseases and transplantation, has contributed to an enormous global increase in the numbers of immunosuppressed people over the past few decades (probably more than % of the world's population), setting the stage for the re-emergence of many opportunistic infections. hiv, which has infected more than million people globally , is the largest single cause of human immune deficiency and markedly increases vulnerability to a wide range of opportunistic pathogens, including pneumocystis carinii, various fungi, tuberculosis, protozoa and herpesviruses . breakthroughs in cancer therapy and in immunosuppressive therapies used to treat immune-mediated diseases and for transplantation , can also leave patients susceptible to opportunistic infections. human organ transplantation adds a further risk of infection with undetected pathogens in donor tissues, and transplantation of animal organs introduces the risk of transmission to humans of animal microbes . the emergence of zoonotic and vector-borne diseases can also be associated with human behaviours and environmental perturbation. although west nile virus is now a major epidemiological concern in the developed world, dengue remains the most significant and widespread flavivirus disease to have emerged globally . a - epidemic in hawaii -fortunately without fatalities -is a reminder that dengue has also re-emerged in locations once considered to be dengue-free. usually transmitted by aedes aegypti mosquitoes, dengue has recently been transmitted by aedes albopictus -a vector switch of potential significance with respect to dengue re-emergence . in the americas, including many us southern states, a. albopictus has been spreading into areas where a. aegypti mosquitoes are not found, and persisting for longer seasonal periods, putting tens of millions more people at risk of dengue infection. dengue re-emergence is further complicated by disturbing increases in a serious and formerly rare form of the disease, dengue haemorrhagic fever (dengue shock syndrome being its highly fatal form). these severe complications are thought to result from the evolution of dengue viruses to escape high insight review articles nature | vol | july | www.nature.com/nature population immunity, seen in increased viral virulence and human immunopathogenesis due to antibody-dependent enhancement of viral infection . cholera is also of interest, not only as an important cause of mortality, but also because of the complexity of factors that determine its re-emergence. both virulent and avirulent strains of these zoonotic bacteria are maintained in the environment and are rapidly evolving in association with phyto-and zooplankton, algae and crustaceans. such environmental strains seem to act as reservoirs for human virulence genes (for example, genes for the phage-encoded cholera toxin and the toxin-coregulated pilus (tcp) factor associated with attachment), and to undergo gene transfer events that lead to new strains containing further virulence gene combinations. these result in periodic cholera emergences that cause epidemics and pandemics . thus, although the disease we know as cholera has appeared to be clinically and epidemiologically stable at least since the third pandemic (in the s), modern evidence suggests that such apparent stability masks aggressive bacterial evolution in complex natural environments. influenza a viruses, which are endemic gastrointestinal viruses of wild waterfowl, have evolved elaborate mechanisms to jump species into domestic fowl, farm animals and humans. periodic gene segment reassortments between human and animal viruses produce important antigenic changes, referred to as 'shifts' . these can lead to deadly pandemics, as occurred in , , and (refs , ) . in intervening years, shifted viruses undergo continual but less dramatic antigenic changes called 'drifts' , which allow them partially to escape human immunity raised by previously circulating influenza viruses. influenza drift is an evolutionary success story for the virus. influenza a has a seemingly inexhaustible repertoire of mutational possibilities at several critical epitopes surrounding the viral haemagglutinin site that attaches to human cells. it remains something of a mystery how zoonotic influenza viruses mix with each other and with human strains to acquire the additional properties of human virulence and human-to-human transmissibility. before , mild cases of human disease associated with avian influenza viruses were occasionally reported . these events have become more frequent, sometimes resulting in severe cases of disease and death. avian influenza has recently made dead-end jumps to humans -for example, the hong kong outbreak of the newly emergent h n influenza, the h n epidemic in the netherlands, the - h n and h n epizootics in asia and elsewhere, and occasional cases of h n disease (fig. ) . meanwhile, back-switches of human h n viruses have emerged in pigs, from which both doubly mixed (pig-human) and triply mixed (pig-human-avian) viruses , have been isolated. such enzootic/zoonotic mixing is suspected to have occurred in the influenza pandemic of - , which was caused by an h n virus with an avian-like receptor-binding site . the predicted virulence genes of this virus are now being sought from -year-old pathology specimens and from frozen corpses . the implications of interspecies genetic mixing for future influenza pandemics are troubling. although much remains speculative about how influenza viruses emerge and spread, it seems clear that the process is driven by prolific and complex viral evolution (genetic reassortment and mutational 'drift'), interspecies mixing and adaptation, and ecological factors that bring humans into contact with animals and each other. by whatever means new influenza virus pandemic strains emerge, they eventually reach a critical threshold of human transmission beyond which epidemic and pandemic spread follows mathematically predictable patterns. the dynamics and determinants of such epidemic development have been studied since the nineteenth century for several infectious diseases. for influenza, both historical and prospective epidemics have been described or predicted using deterministic and stochastic mathematical models, often with surprising accuracy when compared with actual epidemic data. more complicated mathematical models that describe how diseases spread by means other than personto-person aerosol transmission have generally been less successful in describing and predicting epidemics, but have nonetheless been helpful in planning public health responses to epidemics caused by hiv , vcjd and other diseases. mathematical modelling is also used to determine the impact of emerging epidemics. for example, it has been difficult to estimate overall influenza mortality because fatal infections are often neither diagnosed nor accurately recorded in hospital records and death certificates, especially in the elderly. recent epidemiological attempts to obtain improved influenza mortality estimates from seasonal excess mortality data have indicated that influenza mortality may be insight review articles nature | vol | july | www.nature.com/nature greater than was previously suspected, because influenza deaths are frequently coded under seemingly unrelated categories such as cardiovascular diseases. the same approaches also show that other influenza-like deaths may actually be due to other agents, such as respiratory syncytial virus (rsv), a common childhood virus that in the past decade has emerged as a major cause of adult mortality . deliberately emerging microbes are those that have been developed by man, usually for nefarious use. the term 'deliberately emerging' refers to both naturally occurring microbial agents such as anthrax , and to bioengineered microorganisms such as those created by the insertion of genetic virulence factors that produce or exacerbate disease. deliberately emerging microbes include microorganisms or toxins produced in a form that would cause maximal harm because of ease of dissemination, enhanced infectivity or heightened pathogenicity . as concepts, bioterrorism and biowarfare are probably not new. the alleged catapulting of plague-ridden corpses over enemy walls in the siege of caffa (the modern crimean port of feodosia, ukraine) and the dispatch of smallpox-impregnated blankets to indians by british officers in the seven years war ( - ) have frequently been cited as examples of bioterrorism or biowarfare , . two modern attacks have been well documented. in , an oregon religious cult spiked restaurant salad bars with salmonellae in an attempt to sway a local election . a anthrax attack , in which a terrorist mailed anthrax-spore-filled letters to prominent figures, including two us senators, resulted in illness in at least people and the death of five of these individuals. public alarm was elevated by the knowledge that bacillus anthracis is a common and easily obtainable enzootic and soil organism found in laboratories worldwide, and that scientific technology had increased its lethality: the spores had been weaponized by being concentrated, finely milled and packed with a dispersal agent to increase their capacity to disseminate . the united states, the united kingdom, the soviet union and other nations once had sophisticated offensive bioweapons programmes that included the production of weaponized anthrax spores . soviet scientists continued to produce large quantities of organisms adapted for biowarfare and bioterror -among them the agents of smallpox, plague, tularaemia and marburg virus -for several years after their signing of the bioweapons and toxins treaty convention in , which forbade such activities . by , the soviet programme was annually producing , tonnes of weaponized anthrax spores, packing them into warheads and other delivery devices . before the anthrax attacks , the us scientific community had for several years been bolstering its biodefence research capacity. the anthrax attacks greatly accelerated this expansion as part of a national defence plan, which includes efforts to provide a knowledge base for the development of effective countermeasures against agents of bioterror, such as diagnostics, therapeutics and vaccines, and to translate this knowledge into the production and delivery of such measures . bioterror agents have been grouped into three categories of risk . the six category a agents (anthrax, smallpox, plague, tularaemia, viral haemorrhagic fevers and clostridial botulinum toxin) are given top priority because they are highly lethal and readily deployed as weapons. category b and c agents include food-borne and water-borne organisms that incapacitate but usually do not kill. infectious diseases will continue to emerge and re-emerge, leading to unpredictable epidemics and difficult challenges to public health and to microbiology and allied sciences. surveillance and response, the key elements in controlling eis, be they naturally occurring or deliberately engineered, depend on rapid clinical diagnosis and detection and containment in populations and , which along with state and local health departments and other agencies have been making significant strides in national surveillance-response capacity. the enormous influx of us government-funded research resources (largely through the national institutes of health) and public health resources (mainly through the cdc, and state and local public health agencies) in response to the increased threat of a bioterrorist attack will fortify the response capabilities related to all eis. however, it is clear that surveillance and other activities that traditionally fall within the domain of public health are not in themselves sufficient to adequately address the problem of eis. of critical importance are basic, translational and applied research efforts to develop advanced countermeasures such as surveillance tools, diagnostic tests, vaccines and therapeutics . genomics, proteomics and advances in nanotechnology are increasingly being exploited in diagnostic, therapeutic and microbial research applications, and in rational drug and vaccine design. direct and computational structural determination , prediction of protein-protein interactions between microorganisms and drugs, and sophisticated bioinformatics techniques support research in all of the above areas. these technologies have led to numerous advances in real-world utility against eis, most notably in the development of more than antiretroviral drugs that can effectively suppress hiv replication. where they are available and properly used in hiv-infected individuals, these medications have dramatically reduced hiv morbidity and mortality . gene-and protein-based microarrays can be used to detect pathogen signals, to monitor resistance to anti-infective agents, to characterize host gene responses to recent infections, and to facilitate the development of new drugs and vaccines . basic and applied research together have provided promising new vaccine platforms, such as recombinant proteins, immunogenic peptides, naked dna vaccines, viral vectors of extraneous genes encoding immunogenic proteins (including chimaeras), replicons and pseudovirions . many novel vaccine candidates are now being developed against eis such as hiv, ebola virus, west nile virus, dengue, the sars coronavirus, tuberculosis and malaria. of particular note are novel tuberculosis vaccines that recently entered clinical trials -the first time in more than years that new approaches to vaccination for tuberculosis have been assessed in humans . chimaeric flavivirus vaccines for west nile virus, dengue and japanese encephalitis virus are effective in animal models and are in various stages of clinical testing . our growing understanding of the human immune system is also helping to accelerate vaccine development. this is especially true in the case of innate immune responses, which are evolutionarily older, less specific and faster-acting than the adaptive responses that have been the traditional targets of vaccines . as we learn more about innate immunity and its relationship with the adaptive immune system, opportunities to create more effective vaccine adjuvants will emerge. for example, synthetic dna sequences that contain repeated cpg motifs mimic the stimulatory activity that bacterial dna fragments exert on the innate immune system. these sequences show promise as vaccine adjuvants that accelerate and augment immune responses . we can anticipate more progress of this kind as we continue to delineate the complex interactions between innate and adaptive immune responses. the sequencing of the human genome, the genomes of six other animals, including the mouse, and those of microbial vectors and microbes themselves (for example, p. falciparum and its mosquito vector, anopheles gambiae), have elevated microbiology to a wholegenome level. the ability to sequence microbial genomes in a few days or less, and to examine host-vector-microbe interactions at both the genome level and at the tertiary protein structural level, will help us to understand the molecular mechanisms that underlie the pathogenesis of infectious disease and host defences, including resistance and immune evasion. these advances will facilitate the development of new countermeasures. other fertile areas of research include the use of geographical information systems and satellite imaging to support field study and epidemic prevention (for example, predicting hps and rift valley fever epidemics in indigenous areas by satellite imagery of water and vegetation related to animal reservoir and vector prevalence). underlying disease emergence are evolutionary conflicts between rapidly evolving and adapting infectious agents and their slowly evolving hosts. these are fought out in the context of accelerating environmental and human behavioural alterations that provide new ecological niches into which evolving microbes can readily fit. it is essential that broadly based prevention strategies, as well as new and improved countermeasures (that is, surveillance tools, diagnostics, therapeutics and vaccines), be continually tested, refined and upgraded, requiring a strengthened relationship between public health and basic and clinical sciences. the challenge presented by the ongoing conflict between pathogenic microorganisms and man has been well summarized by a noted champion of the war on eis, joshua lederberg: "the future of microbes and mankind will probably unfold as episodes of a suspense thriller that could be entitled our wits versus their genes" . the global scientific and public health communities must confront this reality not only with wit, but also with vision and sustained commitment to meet a perpetual challenge. in figure of this review, the pie chart was drawn incorrectly, with the wedge sizes not in proportion to the total size. the correct figure is shown below. asthma and chronic obstructive pulmonary disease . million factors in the emergence of infectious diseases the wordsworth encyclopedia of plague and pestilence updating the accounts: 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to encapsulated strains of haemophilus influenzae identification and characterization of genomic loci unique to the brazilian purpuric fever clonal group of h. influenzae biogroup aegyptius: functionality explored using meningococcal homology group a streptococcus: allelic variation, population genetics, and host-pathogen interactions genome sequence of a serotype m strain of group a streptococcus: phage-encoded toxins, the high-virulence phenotype, and clone emergence identification of herpesvirus-like dna sequences in aids-associated kaposi's sarcoma microbes and malignancy: infection as a cause of human cancers helicobacter pylori-associated diseases current clinical topics in infectious diseases vol el niño and health epidemiology in relation to air travel acute haemorrhagic conjunctivitis: dealing with a newly emerging disease two worlds of malaria research toward vaccines against malaria the global situation of mdr-tb staphylococcus aureus resistant to vancomycin -united states methicillin (oxacillin)-resistant staphylococcus aureus strains isolated from major food animals and their potential transmission to humans the crisis in antibiotic resistance surveillance for aids-defining opportunistic illnesses, - . mmwr (cdc surveillance summary no. ss- ) infections in patients with cancer undergoing chemotherapy: aetiology, prevention, and treatment impact of current transplantation practices on the changing epidemiology of infections in transplant recipients xenotransplantation: public health risks -patient vs. society in an emerging field the outbreak of west nile virus infection in the new york city area in outbreak of west nile infection west nile virus: epidemiology and ecology in north america dengue and dengue haemorrhagic fever antibody-dependent enhancement of infection and the pathogenesis of viral disease molecular ecology of toxigenic vibrio cholerae the next influenza pandemic: lessons from hong kong a molecular whodunit avian influenza viruses infecting humans structure of the uncleaved human h haemagglutinin from the extinct influenza virus the origin of the pandemic influenza virus: a continuing enigma potential impact of low-efficacy hiv- vaccines in populations with high rates of infection short-term projections for variant creutzfeldt-jakob disease onsets mortality associated with influenza and respiratory syncytial virus in the united states the chilling true story of the largest covert biological weapons program in the world -told from the inside by the man who ran it (random house document zur geschichte des schwarzen todes. mitgetheilt und eingeleitet smallpox and the indians in the american colonies a large community outbreak of salmonellosis caused by intentional contamination of restaurant salad bars biodefence on the research agenda: the world needs new and creative ways to counter bioterrorism threats in bioterrorism: i. cdc category a agents world health organization. consensus document on the epidemiology of severe acute respiratory syndrome (sars) preventing emerging infectious diseases: a strategy for the st century (department of health and human services protein structure prediction and structural genomics guidelines for using antiretroviral agents among hiv-infected adults and adolescents new technology platforms in the development of vaccines for the future the jordan report: th anniversary adjuvants of immunity: harnessing innate immunity to promote adaptive immunity recent advances in the discovery and delivery of vaccine adjuvants the value of complete microbial genome sequencing (you get what you pay for) the authors thank r. m. krause for helpful discussions, and j. weddle for graphic design. the authors declare that they have no competing financial interests.insight review articles key: cord- -efv ovx authors: reicher, stephen; stott, clifford title: on order and disorder during the covid‐ pandemic date: - - journal: br j soc psychol doi: . /bjso. sha: doc_id: cord_uid: efv ovx in this paper, we analyse the conditions under which the covid‐ pandemic will lead either to social order (adherence to measures put in place by authorities to control the pandemic) or to social disorder (resistance to such measures and the emergence of open conflict). using examples from different countries (principally the united kingdom, the united states, and france), we first isolate three factors which determine whether people accept or reject control measures. these are the historical context of state‐public relations, the nature of leadership during the pandemic and procedural justice in the development and operation of these measures. second, we analyse the way the crisis is policed and how forms of policing determine whether dissent will escalate into open conflict. we conclude by considering the prospects for order/disorder as the pandemic unfolds. . for instance , snowden, ( ) documents how, during the cholera epidemic in italy, restrictions on burials led to attacks on health workers and the police. in general terms, then, we need to understand what determines whether a pandemic leads to greater social cohesion or greater social conflict? the question is equally pertinent when it comes to the current pandemic. we have seen high levels of adherence to lockdown measures and a remarkable flowering of mutual aid groupsin britain alone more than , groups involving some million people (butler, ) . we have also seen discord and overt conflict between the public and authoritiesin france, italy, brazil, and the united states, for example. so what determines why and when cohesion gives way to conflict, social order to social disorder? the origins of order let us turn first to the question of 'order'. more specifically, we focus here on whether the public accept without dissent the things that governments demand of them. in the context of covid- , why do people tolerate restrictions on their everyday lives, such as lockdown? the question of why people obey authorities is one of the most famous in the history of psychology. it is exemplified by the popularity and notoriety of milgram's yale obedience studies (milgram, ) . yet, milgram's work is more influential as a demonstration of how far some people will go in obeying an authority figure than as an explanation of this phenomenon. indeed, milgram's 'agentic state' account of obedience is little more than tautologysuggesting that we obey authority because we enter a state where we focus uniquely on obeying authority and hence automatically obey orders. our recent re-analyses suggest a very different story. obedient participants, we argue, should be understood as 'engaged followers' reicher et al., ) . far from being passive in the presence of an authority, they make an active ideological choice to work with the experimenter to advance the scientific enterprisesomething they see as a noble cause. moreover, we suggest this does not happen by accident. it is a result of active 'identity leadership' by the experimenter who actively seeks to bring about such shared identification between himself and the participant in the cause of science. this conclusion chimes with that from the work of tyler and colleagues on why people obey the law (tyler, )the so-called 'group engagement' model (tyler & blader, ) . they show that adherence depends upon whether people see themselves and authoritiesparticularly the policeas part of a common in-group. they too focus on the antecedents of such shared identity, but the emphasis is less on leadership than on procedural justice in the interactions between authorities and their publics. it is by giving people voice, by treating them fairly and with respect, that a sense of being part of a common group is created. this in turn legitimates laws and regulations and increases adherence to them (bradford, murphy & jackson, ) . more recent research suggests that the potency of procedural justice lies not simply in creating an in-group relationship between authorities and citizens but in establishing the authorities as prototypical in-group members acting for and serving the interests of the group (radburn & stott, ; radburn, stott, bradford & robinson, ; stott et al., ) . this work puts flesh on john turner's suggestion that the procedural justice framework 'points to a whole range of other factors relevant to identification with authorities and acceptance of their control as an ingroup norm (e.g. the ideology and goals of group members, the social comparative context, their history of success or failure for the group, the degree to which the authorities are perceived as more or less prototypical of the relevant identity) ' ( , p. ) . echoing turner, we suggest that, in addition to leadership and procedural justice, historical and structural context is a third antecedent of shared in-group identity and hence of adherence to authority. let us now briefly consider the significance of these three factors in the covid- pandemic. we use, as an example, the united kingdomwhere levels of adherence to restrictions have been consistently high. clearly, given that we are still in the midst of the pandemic and do not yet have the luxury of prolonged reflection or comprehensive data, our argument is more illustrative than definitive. but still, it is worth considering whether we can make sense of what we know thus far. first, regarding historical context, britain has a long tradition of treating state intervention as progressive and in the interests of the general populationwhich even if not a consistent reality, serves as a potent national myth (rollings, ) . politically, this is expressed in the idea that policing is not an imposition from the centre but rooted in local consent (channing, ) . economically, it is encapsulated in the idea of welfarism (page & silburn, ) . institutionally, it is exemplified by the nhs, invoked as a centrepiece in danny boyle's pageant of britishness for the opening ceremony of the london olympics and currently occupying an almost deified status. additionally, there are also powerful historical myths of state and society joining as one in times of national crisis as exemplified in the notion of a 'blitz spirit' and of the king and queen remaining in london to share the plight of the people during ww (calder, ) . these historical myths are potent sources for the ways contemporary social realities are broadly understood, and social relations are defined in the present. but they are not so much determining cultural presences as rhetorical resources that can be drawn uponand indeed need to be actively invokedif they are to influence our understanding of covid- , our relationship to authority during the pandemic and our responses to their policies. this takes us to the second antecedent of shared identity: leadership. there are already many controversies about the leadership of the uk government during this crisis and no doubt they will grow in time: did they tarry too long in declaring lockdown and have they shown sufficient diligence in developing testing and in securing protective equipment for frontline workers? nonetheless, government ministers and government information services have, increasingly over time, framed the crisis in inclusive national termsa 'we' thing that incorporates government and people in common cause . and indeed the queen, in her address to the nation on th april, invoked the myth of a 'blitz spirit' to ground her calls for national solidarity, notably by finishing with a reference to vera lynn's most famous of all ww songs: 'we will meet again'. but the rhetoric of 'togetherness' is of little use and may indeed be undermined when it is not matched by practices which make it possible for us to come together. otherwise, the words will be seen as hypocrisy and will only serve to undermine a sense of equity and trust in authority. at this point, we are back in the territory of procedural justicethe third antecedent of identification with authorityalbeit with a critical twist. that is, it is important that fairness is not just a matter of rhetoric and the process by which regulations are introduced but that it extends to the ways in which those regulations impact on people in practice (armaline, sanchez & correia, ; epp, maynard-moody & haider-markel, ) . once again, there is already criticism of government support to enable everyone to observe lockdown as too little and too late. and again, there will be more. there is little doubt that the poor and precarious are less able to stay at home, even if they are as motivated as the rich and secure to do so (atchison et al., ) . the evidence is clear that the poor (and bame people) are getting infected and dying at far higher rates than the affluent (pidd, barr & mohdin, ) . but first, the united kingdom does have a range of welfare provisions including free universal health care. second, even if insufficient, nonetheless unprecedented financial measures have been implemented to help people to stay off work during the pandemic: a boost in welfare payments, a state guarantee to replace % of lost wages and of lost income for the self-employed. this has been high enough to secure high levels of trust in government and support for lockdown even amongst those suffering from it (duffy & allington, ) . enough, for now at least (as we write at the start of may), to secure the social order. let us turn next to the question of 'disorder' and more specifically to protests against government social distancing measures and to anti-authority rioting in the context of the pandemic. if a facilitative historical context, inclusive leadership, and the legitimacy of authority (cf. bottoms & tankebe, ) are critical to creating shared identity and maintaining social order, what happens when these factors are absent? let us answer that question primarily by reference to the usa where (unlike in the united kingdom) there have been multiple protests against lockdownbut additionally by addressing the unrest that has occurred in various other countries such as italy, brazil, and france. the caveats we expressed concerning our analysis of the uk case obviously apply here as well. as before, we shall start with the historical relationship between state and people. gary wills starts his history of this relationship in the united states with a famous quotation: 'henry david thoreau put in extreme form what many americans want to believe: "i heartily accept the motto: 'the government is best which governs least'"' ( , p. ). the country, after all, was born in a revolution against what was seen as an alien and tyrannical state, and this attitude of suspicion remained attached to any state power. to this day, the right to bear arms (as articulated in the nd amendment to the constitution) is seen by many as a necessary counterbalance to such tyranny. in this context, any and all state intervention has the potential to be rejected as unacceptable and anti-american. once again, however, these beliefs do not exert a spontaneous influence. they have to be invoked, applied to the current context, and used to mobilize people against antipandemic measures such as lockdown. anti-state leadership is critical and, remarkably, it was provided by the right-wing populist head of state, us president donald trump. he directly referenced the anti-state principles on which 'this country' was built in order to criticize anti-pandemic measures. he praised protestors against lockdown as 'responsible', and he tweeted 'liberate minnesota!' followed by 'liberate michigan' and then 'liberate virginia and save your great nd amendment. it is under siege!' (embury-dennis, ). finally, the huge structural inequalities in the united states, the fact that less than half of poorer workers get any sick pay, that . million people have no health cover, and that % of americans could not find $ to cover an emergency (vesoulis, ) , combined with the fact million americans became unemployed in march and (santhanam, , have led to great hardship in the period of lockdown. this creates a context in which a sizeable pool of people is amenable to being mobilized by antilockdown leadership. in the poor south, for instance, % of people support trump on the pandemic over their own state governors (santhanam, ) . while, as yet, there are no systematic analyses of those who are protesting, anecdotal reportsalong with scrutiny of the chants and the placards displayed in protestssuggest a combination of 'liberty' and 'hardship' concernsa leadership and organization rooted in traditional antistate conservatism gaining some traction amongst those alienated from the authorities by economic suffering. as stocpol puts it: 'we've got a. . . combination of top-down influence from high-dollar organizations and some genuine energy at the grassroots level' (cited in illing, ) . in suggesting that all three factorsanti-state historical context, anti-state leadership, and inequitycontribute to the emergence of disorder, we do not suggest they are all equivalent or all necessary for protest to emerge. thus, events in america show how history and leadership can facilitate the emergence of an understanding that pandemic measures are unfair and unjustan illegitimate imposition by an alien authority that is acting against us rather than for and with us. however, events elsewherewe shall focus particularly on franceshow that such an understanding can arise directly from government measures that are experienced as inequitable and the ways that those who then challenge these measures are treated by the police. the lockdown in france took effect on march . this was in the context of the longstanding 'yellow vest' movement. as jetten et al. ( ) show, a sense of popular alienation from a state out of touch with the sufferings of ordinary people intertwined with the notoriously aggressive heavy handedness of french policing to drive the movement towards violent protest and sustain these protests across time and location. these features were then reproduced within the lockdown itself. as elsewhere, the lockdown exacerbated inequalities of class and 'race', making it particularly difficult for poor ethnic minority members to adhere to the regulations and stay at home (willsher & harrap, ) . the state responded with heavy-handed repression. anyone leaving their home has been required to carry a time-stamped certificate that has to be produced on demand. infringement carries penalties of heavy fines or even up to six-year imprisonment for the crime of 'endangerment'. by st april, just sixteen days after the control measures were introduced, the french police had already carried out . million controls and issued , fines (statista, ) compared to less than , across the one month following the imposition of control measures in the united kingdom. (npcc, ) . just one week into lockdown, french media began to report that the police were experiencing difficulties in enforcing such repressive measures especially in the poorer and ethnically mixed paris suburbs (keiger, ) , themselves historically areas of antipolice sentiment and rioting (body-gendrot, ) . then, early in the morning of th april, in the paris suburb of villeneuve-la-garenne, a local man of arab decent riding a motorcycle was injured when he collided with the open door of an unmarked police car. the incident was immediately interpreted by many as just another example of police brutality and rioting developed across the next four days, spreading into four suburbs across paris and with additional incidents reported across france (willsher, ) . what we see here is a classic pattern of crowd violence. a background of structural inequalities leading to alienation from authority, a pattern of antagonistic interactions with the police such that they become the concrete face of the 'other', a specific incident which is understood to exemplify the illegitimacy of the police, and then a spread of violence to other sites where locals share such a view of the police (ball et al, ; drury et al, ; stott et al, ) . the critical point is to understand how the distal determinants of conflict (which lie in the interaction of general structural inequalities and specific policies such as lockdown) interact with the proximal determinants (which lie in indiscriminate and repressive forms of policing, and in the spiral of negative interactions with particular sectors of the public that are initiated by such repression). it is only by developing such an understanding of how disorder occurs that we can learn how to preserve public order. we began this paper by asking what determines whether a pandemic brings people together with authorities so as to maintain order or else pushes them apart and creates disorder. our answer has been at two levels. on the one hand, we must look at the combination of historical context and contemporary leadership which determine whether people will mobilize around perceived inequities to challenge authority and disregard the regulations they seek to impose. on the other hand, we have pointed to the specific role of policingspecifically repressive policingin escalating dissent into open violence. both are key domains for further investigation. nonetheless, even if the details of our analysis are necessarily provisional at this stage of events, it is clear that disorder is a complex phenomenon which requires a combination of structural, political, and interactional factors to occur. consequently, lack of disorder might tell us that not all is bad, but it does not tell us that all is well either. nor does it allow us to be complacent. that is certainly true of the situation in the united kingdom. as we have indicated, there are major structural inequalities which are reflected in the disproportionate death rates of poor and bame people. equally the leadership and the political response to the pandemic may have done just enough to preserve cohesion, but there are more and more voices expressing concerns about the inefficiencies and inequities of current government policiesand these may grow as the situation develops. finally, the policing response may have largely concentrated on the three es of engaging, explaining, and encouraging the public to adhere to government measures (such as lockdown) before reverting to the fourth eenforcement (npcc, a). but the pattern has not been consistent across the country. all in all, we cannot rest on our laurels. unless we are clearly seen to do more in the longer term to make a priority of addressing the structural inequalities; unless more steps are taken to make it possible for those in precarious positions to cope with lockdown and other measures; unless the focus of the police and other agencies is more firmly focussed on enabling rather than enforcing coherence, then the precious and fragile social consensus that we have enjoyed thus far could always give way to social conflict. stephen reicher, phd (conceptualization; writingoriginal draft) clifford stott (conceptualization; writingreview & editing). the biggest gang in oakland': rethinking police legitimacy perceptions and behavioural responses of the general public during the covid- pandemic: a cross-sectional survey of uk adults who controls the city? a micro-historical case study of the spread of rioting across north london in public disorder and globalisation police legitimacy and the authority of the state officers as mirrors: policing, procedural justice and the (re) production of social identity nhs coronavirus volunteers frustrated at lack of tasks. the guardian, rd may the myth of the blitz the police and the expansion of public order law in britain the black death and the burning of the role of social identity processes in mass emergency behaviour: an integrative review social scaffolding: applying the lessons of contemporary social science to health, public mental health and healthcare a social identity model of riot diffusion: from injustice to empowerment in the london riots the accepting, the suffering and the resisting: the different reactions to life under lockdown coronavirus: trump doubles down on call for supporters to 'liberate' democratic states from lockdown. the independent. th april rethinking the nature of cruelty: the role of identity leadership in the stanford prison experiment there is no anti-lockdown protest movement. vox, nd april how economic inequality fuels the rise and persistence of the yellow vest movement france'sd downward spiral of coronavirus repression. the spectator obedience to authority police chiefs welcome positive start to recruitment drive engage, explain, encourage, enforce -applying the four 'e's. retrieved from https:// www.college.police.uk/what-we-do/covid- /documents/engage-explain-encourage-enf orce-guidance.pdf british social welfare in the twentieth century calls for health funding to be prioritised as poor bear brunt of covid- . the guardian, st may the social psychological processes of 'procedural justice': concepts, critiques and opportunities when is policing fair? groups, identity and judgements of the procedural justice of coercive crowd policing engaged followership and engaged fellowship working toward the experimenter: reconceptualizing obedience within the milgram paradigm as identification-based followership mad mobs and englishmen policing the coronavirus outbreak: processes and prospects for collective disorder butskellism, the postwar consensus and the managed economy despite economic hardship, most americans not ready to reopen, poll says. pbs the impact of plague in tudor and stuart england naples in the time of cholera number of controls carried out and fines issued during the containment linked to the coronavirus epidemic (covid- ) in france between the roots of evil the evolving normative dimensions of 'riot': towards an elaborated social identity explanation keeping the peace' social identity, procedural justice and the policing of football crowds explaining the nature of power: a three-process theory why people obey the law: procedural justice. legitimacy, and compliance the group engagement model: procedural justice, social identity, and cooperative behavior coronavirus may disproportionally hurt the poor -and that's bad for everyone a necessary evil disruption on streets of france as lockdown tensions rise. the guardian in a paris banlieue, coronavirus amplifies years of inequality. the guardian, th april all authors declare no conflict of interest. no data available. key: cord- -hqtb a c authors: tan, tina q; kullar, ravina; swartz, talia h; mathew, trini a; piggott, damani a; berthaud, vladimir title: location matters: geographic disparities and impact of coronavirus disease (covid- ) date: - - journal: j infect dis doi: . /infdis/jiaa sha: doc_id: cord_uid: hqtb a c the covid- pandemic in the united states has revealed major disparities in the access to testing and messaging about the pandemic based on the geographic location of individuals, particularly in communities of color, rural areas, and areas of low income. this geographic disparity, in addition to deeply rooted structural inequities, have posed additional challenges to adequately diagnose and provide care for individuals of all ages living in these settings. we describe the impact that covid- has had on geographic disparate populations in the united states and share our recommendations to what might be done to ameliorate the current situation. coronavirus disease has emerged as the worst global pandemic in the last years, with almost million diagnosed cases and over , deaths as of september , . covid- has exerted a devastating toll across all communities. however, disparity exists between low and middle-high income geographies in the level of care available to patients with covid- . an analysis of deaths in massachusetts found an increase in excess deaths in the early days of covid- . mortality was % greater in cities and towns "with higher poverty, higher household crowding, higher percentage of populations of color, and higher racialized economic segregation" compared to those with the lowest levels of those measures. a striking example of the impact of geography on covid- disease is the navajo nation, which has reported the highest per capita covid- rate in the united states with a rate of , cases per , people compared to new york state, new jersey, or the united states with rates of , cases/ , , , cases/ , , and cases/ , , respectively. in memphis, data reveal that most covid- testing occurs in the predominantly white and well-off suburbs, not the majority african american, lower-income neighborhoods. , further, testing rates are lowest in states designated as being unhealthy (based on factors such as life expectancy, population living at or below the poverty level, and number of low birth weight infants). this approach is problematic because the populations in these states have higher rates of chronic conditions that increase the risk of serious complications and death from covid- , such as heart disease, chronic respiratory diseases, and diabetes. these disparities in testing rates are concerning because delays in testing increase the chance of a surge in silent spread and severe covid- cases in states among rural and lower-income populations. in this viewpoint, we will discuss the geographic disparities that exist during this pandemic and provide our recommendations on what can be done to change the current paradigm. a c c e p t e d m a n u s c r i p t there is a wide disparity in covid- testing by geographic area. such disparities may stem from a lack of: hospitals and health care facilities, walk-in testing sites, access to transportation to drive-up testing sites, and lack of information regarding availability of testing. although urban sites may have public transportation and walk-in testing facilities, communities in rural areas or low income settings are challenged by limited access to individual/private transportation or walk-in testing locations. a recent analysis highlighted that geographic access to covid- testing sites is as uneven as access to overall health care, with higher travel times to covid- test sites in rural counties and in counties with a larger non-white or uninsured population, suggesting that covid- cases are potentially under-counted and under-reported in these areas. some of these limitations may be unique to communities in specific geographic areas, including areas with a large amish or mennonite population (where access to healthcare facilities is limited), native american communities, and other socially isolated communities. testing for novel diseases and information regarding how to access testing needs to be made widely available with resources tailored to the needs of the persons residing in the community, to avoid stigma associated with a new disease. it is critical that jurisdictions expand public health and commercial laboratory testing in all communities regardless of geography. innovative methods of testing, such as mobile testing units or home testing kits, should also be considered. while transportation may pose unique challenges to accessing testing, accurate information about the pandemic may not be disseminated to communities further away from urban settings and in isolated communities. these populations may consider pandemics more of an "urban disease" and less relevant for rural settings with lower population density and access to covid- testing has been limited across the united states with testing practices varying across different local and regional areas and across age groups. in many areas of the country, prioritization for testing has been limited to persons who are symptomatic. in general, many studies report that persons ≤ years of age are more likely to be asymptomatic or have milder symptoms. therefore, they may not meet the testing criteria even if there has been significant exposure, leading to limited number of tests provided to children relative to the % of the population that they comprise. although the risk of severe based on antibody seroprevalence studies, it is estimated that the total number of persons in the u.s. infected with covid- is at least times higher than the current number of confirmed cases, indicative of significant undertesting in pediatric and adult populations alike. [ ] [ ] [ ] because of the lack of testing, the proportion of infants, children, adolescent and young adults infected with covid- who are potentially at risk for developing serious or life-threatening illness remains unclear. the limited access to testing is significantly worse for those who live in rural areas and low income settings, inhabited by a disproportionate number of socio-economically disadvantaged whites, african americans, and latinx populations. programs focused on increased testing of children, utilizing community centers, places of worship, and schools, are needed, especially with schools reopening. the covid- pandemic initially impacted the most densely populated areas in the united states particularly large urban areas in which health systems endured waves of cases that overwhelmed resources including hospital beds, personal protective equipment, intensive care capacity, ventilators, and personnel. it appeared that more rural communities had initially been less directly impacted. however, as social distancing recommendations around the country have relaxed and as access to testing has started to increase, rural populations have become more vulnerable to new surges of infection. those living in rural communities may not have experienced the first hand perception of threat and may be less likely to maintain strict adherence to precautions such as social distancing and wearing of masks. the major concern for covid- infections in rural populations, in which % of the u.s. a c c e p t e d m a n u s c r i p t population reside, is that healthcare systems are less equipped for high capacity and high acuity care. non-metropolitan hospitals have fewer intensive care unit beds ( . versus . beds per , population), fewer intensive care resources, and less access to id subspecialists. a study looking at the distribution of u.s. id specialists found that of the , u.s. counties, , counties ( . %) do not have a single id physician. furthermore, individuals living in rural areas are more likely to be older and have underlying conditions that place them at an increased risk for severe infection. therefore, outbreaks in rural areas have the potential to overwhelm the limited healthcare resources available. potential action items to ease the burden include: equipping previously non-icu areas to function as icus, expansion of in-hospital tele-health capabilities for subspecialty consults, and having state licensing boards allow qualified physicians and nurses to temporarily staff rural hospitals in an outbreak. the covid- pandemic has accentuated longstanding racial/ethnic disparities in healthcare access and outcomes in the united states particularly in regard to geographic locations in rural and remote areas and low income settings. as rural and urban geographic areas remain interconnected, health policymakers and government authorities need to develop emergency and preparedness plans that address the limited access to covid- testing, effective means of communication, provider shortage, and lack of healthcare facilities and intensive care units in rural areas. these geographically distant and isolated spots of covid- transmission can become fertile grounds for resurgence of the pandemic. the authors have no conflicts of interest to disclose. financial support: no funding was received. m a n u s c r i p t covid- and the unequal surge in mortality rates in code measures of poverty, household crowding, race/ethnicity, and racialized economic segregation racial disparities emerge in tennessee's testing for covid- data on covid- cases in unhealthier states have lower covid- testing rates rural america could be the region hardest hit by the covid- outbreak geographic access to united states sars-cov- testing sites highlights healthcare disparities and may bias transmission estimates characteristics and outcomes of children with coronavirus disease (covid- ) infection admitted to us and canadian pediatric intensive care units hyperinflammatory shock in children during covid- pandemic. the lancet acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov- pandemic multisystem inflammatory syndrome related to covid- in previously healthy children and adolescents multisystem inflammatory syndrome in u.s. children and adolescents covid- possible striking more children than expected covid- in children in the united states: intensive care admissions, estimated total infected, and projected numbers of severe pediatric cases in disease in children -united states hospitalization rates and characteristics of children aged ≤ years hospitalized with laboratory-confirmed covid- -covid-net, states state-level data report seroprevalence of antibodies to sars-cov- in sites in the united states cdc los alamos national laboratory covid- confirmed and forecasted case data covid-= fears diminish in many rural areas american hospital capacity and projected need for covid- patient care | health affairs where is the id in covid- ? the authors would like to thank the staff of the infectious diseases society of america (idsa) for their assistance with preparing this manuscript. a c c e p t e d m a n u s c r i p t a c c e p t e d m a n u s c r i p t key: cord- -eslgz ka authors: chomel, bruno b.; belotto, albino; meslin, françois-xavier title: wildlife, exotic pets, and emerging zoonoses date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: eslgz ka most emerging infectious diseases are zoonotic; wildlife constitutes a large and often unknown reservoir. wildlife can also be a source for reemergence of previously controlled zoonoses. although the discovery of such zoonoses is often related to better diagnostic tools, the leading causes of their emergence are human behavior and modifications to natural habitats (expansion of human populations and their encroachment on wildlife habitat), changes in agricultural practices, and globalization of trade. however, other factors include wildlife trade and translocation, live animal and bushmeat markets, consumption of exotic foods, development of ecotourism, access to petting zoos, and ownership of exotic pets. to reduce risk for emerging zoonoses, the public should be educated about the risks associated with wildlife, bushmeat, and exotic pet trades; and proper surveillance systems should be implemented. deforestation, development of human habitat, and mining activities have been suggested as risk factors associated with the reemergence of vampire bat rabies in humans in the amazon basin. in , persons died of rabies transmitted by vampire bats, mainly in brazil ( cases) and colombia ( cases) ; only human cases of rabies were transmitted by dogs in all latin america ( ) . a similar trend was again observed for . when fi rst described in , kyasanur forest disease was restricted to a much smaller area ( square miles) in india than the actual , square miles of endemic zone ( ) . this tickborne disease occurs in evergreen rain forests interspersed with deciduous patches and clearings for rice cultivation and human habitations. forest workers are particularly at risk; their mortality rates may reach %. in , a major epidemic occurred during which several monkeys died, , humans were infected, and humans died. the outbreak occurred in previously undisturbed forest where some ha were clearcut to establish a cashew tree plantation. most of the human patients were immigrant laborers employed to clear the forest ( ) . as many as , human cases occur each year, and this number has increased in the past years. most cases occur during the dry season (january-may), when nymphal activity is maximal. such a zoonosis is a good example of deforestation and agricultural development leading to human habitat expansion into natural foci of a viral infection. because cleared areas were widely used for grazing of cattle, a major host for adult ticks, these areas favored the proliferation of the tick haemaphysalis spinigera. conversely, the reduction of traditional agricultural land and its replacement with forested areas, home to the main reservoirs and hosts of borrelia burgdorferi, in association with the settlement of persons in periurban areas, led to a considerable increase in human cases of lyme disease in the united states ( ) . an estimated . million wild ruminants, major amplifi ers for adult ixodes scapularis ticks, live in north america ( ) . from an estimated - million white-tailed deer inhabited north america before the arrival of europeans, the deer population was greatly reduced by habitat loss and unrestricted hunting. however, by the mid- th century, the population was restored throughout north america, and an estimated - million white-tailed deer are believed to inhabit the united states alone. in many areas of the eastern united states, populations have soared to previously unattained levels (www.aphis.usda.gov/ws/nwrc/is/living/deer.pdf). human activities may also be a source of wildlife infection, which could create new reservoirs of human pathogens. the recent outbreak of tuberculosis caused by mycobacterium tuberculosis in suricats and mongooses was one of the fi rst documented spillovers of a human disease within a wildlife population ( ) . banded mongooses were observed feeding regularly at garbage pits and were therefore exposed to human excretions and any infectious material from tuberculosis-infected humans. the emergence of argentine hemorrhagic fever in eastcentral argentina during the s, and its expansion to north-central argentina, has been directly linked to development of agricultural activities (mainly corn growing) that sustain the virus's main reservoir, the corn mouse (calomys musculinus). caused by the junin virus, argentine hemorrhagic fever affects primarily adult male agricultural workers, mainly during the harvest season ( ) . in the late s and early s, a rabies epidemic occurred in free-ranging greater kudus (tragelaphus strepsiceros) in namibia ( ) . the kudu population had increased considerably in response to favorable conditions and human-made environmental changes. suitable conditions for transmission in the kudu population after initial infection by rabid carnivores are provided by the social behavior of kudus, such as browsing on thorny acacia trees and resultant lesions in the kudus' oral cavity, and excretion of relatively high titers of virus in the saliva of infected animals ( ) . the outbreak of nipah virus infection in malaysia during - , which caused human cases of viral encephalitis and a % mortality rate, was also the result of several major ecologic and environmental changes associated with deforestation and expansion of nonindustrial pig farming in association with production of fruit-bearing trees ( ) . such combination led to infection of pigs, which developed respiratory and neurologic symptoms after indirect exposure to infected fruit bats that shed the virus. the sick pigs were a subsequent source of human infection ( ) . farming of wild animal species led to reemergence of zoonoses such as bovine tuberculosis in captive deer populations. deer at low population densities on natural range are less likely to be affected to any major extent by disease. however, disease becomes a factor in intensive management of deer ( ) . reemergence of zoonotic diseases that had been controlled from their domestic animal reservoirs is also of major concern. wildlife may become new reservoirs of infection and may recontaminate domestic animals; examples include bovine tuberculosis in the united kingdom associated with mycobacterium bovis infection in badgers (meles meles) ( ) and brucellosis in outdoor-reared swine in europe that resulted from spillover from the wild boar brucellosis (brucella suis biovar ) reservoir ( ) . wildlife trade provides mechanisms for disease transmission at levels that not only cause human disease out-breaks but also threaten livestock, international trade, rural livelihoods, native wildlife populations, and ecosystem health ( ) . worldwide, an estimated , primates, million birds, , reptiles, and million tropical fi sh are traded live each year ( ) . international wildlife trade is estimated to be a us $ -billion industry ( ) . translocation of wild animals is associated with the spread of several zoonoses. rabies was introduced in the mid-atlantic states in the s when hunting pens were repopulated with raccoons trapped in rabies-endemic zones of the southern united states ( ) . in eastern europe, raccoon dogs (nyctereutes procyonoides) are becoming a new reservoir for rabies, in addition to the established red fox reservoir, as raccoon dogs have spread into new habitats from accidental release of animals raised for fur trade ( ) . brush-tailed possums (trichosurus vulpecula) from tasmania were introduced into new zealand to establish a new species of fur-bearing animals. the translocated population proliferated and is now estimated to be > million, of which %- % are possibly infected by m. bovis, a permanent threat to the cattle-and deer-farming industries ( ) . translocation of hares from central and eastern europe for sporting purposes led to several outbreaks of tularemia, introduction of b. suis biovar to western europe, and subsequent encroachment of this brucellosis strain into the wild boar population of western europe ( ) . during - , b. suis biovar infections were reported in > outdoor-rearing pig farms in france ( ) . illegal trade can also be a possible source of human infection. in march , psittacosis developed in several customs offi cers in antwerp, belgium ( ) . a customs officer had been hospitalized with pneumonia days after exposure to parakeets illegally imported by an indian sailor. the risk of contracting psittacosis was . × higher for offi cers exposed to parakeets > hours than for those exposed only briefl y. similarly, a highly pathogenic avian infl uenza a h n virus from crested hawk eagles smuggled into europe by air travel has been isolated and characterized ( ); fortunately, however, screening of human and avian contacts indicated that no dissemination had occurred. another risk factor related to the emergence of zoonotic diseases from wildlife has been the considerable increase in consumption of bushmeat in many parts of the world, especially central africa and the amazon basin, where - . million tons and - million kilograms, respectively, are consumed each year ( ) . the simian foamy virus has been identifi ed as a zoonotic retrovirus that infects people who have direct contact with fresh nonhuman primate bushmeat; this fi nding indicates that such zoonoses are more frequent, widespread, and contemporary than previously appreciated. similarly, new retroviruses, human t-lymphotropic virus types and were found in persons who hunt, butcher, or keep monkeys or apes as pets in southern cameroon ( ) . the combination of urban demand for bushmeat (a multibillion-dollar business) and greater access to primate habitats provided by logging roads has increased the amount of hunting in africa, which has increased the frequency of human exposure to primate retroviruses and other disease-causing agents. similarly, several outbreaks of ebola virus in western africa have been associated with consumption of bushmeat, mainly chimpanzees that were found dead ( ) . traditional and local food markets in many parts of the world can be associated with emergence of new zoonotic diseases. live animal markets, also known as wet markets, have always been the principal mode of commercialization of poultry and many other animal species. such markets, quite uncommon in the united states and, until recently, in california, are emerging as a new mode of commercialization within specifi c ethnic groups for whom this type of trade assures freshness of the product but raises major public health concerns. the avian infl uenza epidemic, which began in southeast asia in and recently spread to other parts of the world, is directly related to infected birds sold live in traditional markets. live bird markets facilitate the spread of this avian h n virus by wild birds ( ) . similarly, the newly discovered severe acute respiratory syndrome-associated coronavirus was linked to trade of live, wild carnivores, especially civets, in the people's republic of china ( ). however, recent data suggest that civets may be only amplifi ers of a natural cycle involving trade and consumption of bats ( ) . trichinellosis has long been associated with consumption of undercooked meat from wild animals, such as bears, and now consumption of uncooked meat from deer and wild boar has recently been associated with emergence of severe cases of hepatitis e in hunters in japan ( ) . industrialized nations' new taste for exotic food has also been linked with various zoonotic pathogens or parasites, such as protozoa (toxoplasma), trematodes (fasciola sp., paragonimus spp.), cestodes (taenia spp., diphyllobothrium sp.), and nematodes (trichinella spp., anisakis sp., parastrongylus spp.). adventure travel is the largest growing segment of the leisure travel industry; growth rate has been % per year since (adventure travel society, pers. comm.). this type of travel increases the risk that tourists participating in activities such as safaris, tours, adventure sports, and extreme travel will contact pathogens uncommon in industrialized countries. the most commonly encountered rickettsial infection in travel medicine is african tick bite fever, caused by rickettsia africae and transmitted in rural sub-saharan africa by ungulate ticks of the amblyomma genus; > imported cases have been reported from several continents during the past few years ( ) . most patients are infected during wild game safaris and bush walks. moreover, because ecotourism is becoming increasingly popular with international travelers, more cases of imported rickettsioses are likely to occur in europe, north america, and elsewhere in years to come. cercopithecine herpesvirus (herpes b virus) is an alpha herpesvirus endemic to asian macaques, which mostly carry this virus without overt signs of disease. however, zoonotic infection with herpes b virus in humans usually results in fatal encephalomyelitis or severe neurologic impairment ( ) . herpes b virus has been implicated as the cause of ≈ cases of meningoencephalitis in persons who had direct or indirect contact with laboratory macaques. a survey of workers at a balinese hindu temple, a major tourist attraction where macaques roam free, showed that contact suffi cient to transmit b virus occurred commonly between humans and macaques. furthermore, ( . %) of macaques at that location had antibodies to herpes b virus ( ) . petting zoos, where children are allowed to approach and feed captive wildlife and domestic animals, have been linked to several zoonotic outbreaks, including infections caused by escherichia coli o :h , salmonellae, and coxiella burnetii ( ) . more than outbreaks of human infectious diseases associated with visitors to animal exhibits were identifi ed during - ( ) . in an outbreak of salmonellosis at a colorado zoo, cases (most of them in children) were associated with touching a wooden barrier around the komodo dragon exhibit. salmonella organisms were isolated from case-patients, a komodo dragon, and the wooden barrier. children who did not become infected were more likely to have washed their hands after visiting the exhibit ( ) . exposure to captive wild animals at circuses or zoos can also be a source of zoonotic infection. twelve circus elephant handlers at an exotic animal farm in illinois were infected with m. tuberculosis, and had signs consistent with active disease after elephants died of tuberculosis. medical history and testing of the handlers indicated that the elephants had been a probable source of exposure for most of the infected persons ( ) . after an m. bovis outbreak in rhinoceroses and monkeys at a zoo in louisiana, animal handlers, previously negative for tuberculosis, had positive test results ( ) . exotic pets are also a source of several human infections that vary from severe monkeypox related to pet prairie dogs or lyssaviruses in pet bats to less severe but more common ringworm infections acquired from african pygmy hedgehogs or chinchillas. epidemiologic and animal traceback investigations confi rmed that the fi rst community-acquired cases of monkeypox in humans in the united states ( cases) resulted from contact with infected prairie dogs that had been housed or transported with african rodents imported from ghana ( ) . similarly, an outbreak caused by francisella tularensis type b occurred among wild-caught, commercially traded prairie dogs; f. tularensis antibodies in exposed person documented the fi rst evidence of tularemia transmission from prairie dog to human ( ) . african pygmy hedgehogs have been implicated in human salmonellosis cases in the united states and canada ( ) . in the united states, the number of commercialized reptiles, especially iguanas, imported per year has increased considerably to ≈ million. the number of human cases of salmonellosis, especially in very young children, increased dramatically in parallel with iguana pet ownership. the centers for disease control and prevention estimates that ≈ % of human infections with salmonellae in the united states are associated with having handled a reptile. most iguanas have a stable mixture of salmonella serotypes in their intestinal tract and intermittently or continuously shed salmonella organisms in their feces ( ) . eight cases of rabies caused by a new rabies virus variant were reported in the state of ceará, brazil, from through . marmosets (callithrix jacchus jacchus) were determined to be the source of exposure. these primates are common pets; most cases occurred in persons who had tried to capture them, and case was transmitted by a pet marmoset ( ) . in , encephalitis was diagnosed in an egyptian rousette bat (rousettus egyptiacus) that had been imported from belgium and sold in a pet shop in southwestern france. the pet bat was infected with a lagos bat lyssavirus and resulted in the treatment of exposed persons (y. rotivel, pers. comm.). emerging infectious diseases have a major effect on human health and can create tremendous economic losses. animals, particularly wild animals, are thought to be the source of > % of all emerging infections ( ) . leading factors for emergence of zoonoses are unbalanced and selective forest exploitation and aggressive agricultural development associated with an exponential increase in the bushmeat trade ( ) . similarly, the increase of ecotourism, often in primitive settings with limited hygiene, can be associated with the acquisition of zoonotic agents. therefore, development of appropriate programs for surveillance and for monitoring emerging diseases in their wildlife reservoirs is essential. most animal pathogens for which surveillance programs exist relate to farm animals, and few or no programs are specifi cally aimed at wildlife. two different but complementary approaches are ) to monitor the pres-ence of specifi cally identifi ed pathogens that have emerged as human pathogens and ) to investigate in a given wildlife species the presence of known or unknown infectious agents. furthermore, conservation of habitat biodiversity is critical for preventing emergence of new reservoirs or amplifi er species. key measures for reducing the dispersion of emerging zoonoses include sustainable agricultural development, proper education of tourists about the risks of outdoor activities, and better control of the live animal trade (exotic pets, wet markets, bushmeat). public health services and clinical practitioners (physicians, veterinarians) need to more actively educate the public about the risks of owning exotic pets and adopting wild animals. as suggested by kuiken et al. ( ) , it is time to form "a joint expert working group to design and implement a global animal surveillance system for zoonotic pathogens that gives early warning of pathogen emergence, is closely integrated to public health surveillance and provides opportunities to control such pathogens before they can affect human health, food supply, economics or biodiversity." major tasks that should be taken by the international community include better integration and coordination of national surveillance systems in industrialized and developing countries; improved reporting systems and international sharing of information; active surveillance at the interface of rural populations and wildlife habitats, especially where poverty and low income increase risks for pathogen transmission; training of professionals, such as veterinarians and biologists, in wildlife health management; and establishment of collaborative multidisciplinary teams ready to intervene when outbreaks occur. dr chomel is director of the world health organization/pan american health organization collaborating center on new and emerging zoonoses at the university of california, davis. his research focuses on zoonotic infections, especially those caused by bartonella spp., in domestic animals and wildlife and their effects on human health. risk factors for human disease emergence conservation medicine and a new agenda for emerging diseases update: multistate outbreak of monkeypox-illinois emerging or reemerging bacterial zoonoses: factors of emergence, surveillance and control diseases of humans and their domestic mammals: pathogen characteristics, host range and the risk of emergence the value of wildlife wildlife trade and global disease emergence bushmeat hunting, deforestation, and prediction of zoonoses emergence epidemiologic situation of human rabies in latin america in the encyclopedia of arthropod-transmitted infections emerging bacterial zoonotic and vector-borne diseases. ecological and epidemiological factors wildlife diseases and population medicine mycobacterium tuberculosis: an emerging disease of freeranging wildlife arenaviruses other than lassa virus rabies in the kudu antelope (tragelaphus strepsiceros) anthropogenic environmental change and the emergence of infectious diseases in wildlife advances in health and welfare of farmed deer in new zealand bovine tuberculosis and badger blame from the discovery of the malta fever's agent to the discovery of a marine mammal reservoir, brucellosis has continuously been a re-emerging zoonosis exotic-pet trade disease risks associated with wildlife translocation projects epidemiological surveillance of rabies in lithuania from to a psittacosis outbreak in customs offi cers in antwerp (belgium) highly pathogenic h n infl uenza virus in smuggled thai eagles emergence of unique primate t-lymphotropic viruses among central african bushmeat hunters isolation and phylogenetic characterization of ebola viruses causing different outbreaks in gabon transmission of avian infl uenza viruses to and between humans bats are natural reservoirs of sars-like coronaviruses complete or near-complete nucleotide sequences of hepatitis e virus genome recovered from a wild boar, a deer, and four patients who ate the deer rickettsioses and the international traveler b-virus (cercopithecine herpesvirus ) infection in humans and macaques: potential for zoonotic disease human exposure to herpesvirus b-seropositive macaques reports of zoonotic disease outbreaks associated with animal exhibits and availability of recommendations for preventing zoonotic disease transmission from animals to people in such settings an outbreak of salmonellosis among children attending a reptile exhibit at a zoo mycobacterium tuberculosis infection as a zoonotic disease: transmission between humans and elephants epizootic of mycobacterium bovis in a zoologic park first reported prairie dog-to-human tularemia transmission hedgehog zoonoses prevalence of fecal shedding of salmonella organisms among captive green iguanas and potential public health implications alves araujo fa, de mattos ca public health: pathogen surveillance in animals key: cord- -bakwk tm authors: fauver, joseph r.; petrone, mary e.; hodcroft, emma b.; shioda, kayoko; ehrlich, hanna y.; watts, alexander g.; vogels, chantal b.f.; brito, anderson f.; alpert, tara; muyombwe, anthony; razeq, jafar; downing, randy; cheemarla, nagarjuna r.; wyllie, anne l.; kalinich, chaney c.; ott, isabel m.; quick, joshua; loman, nicholas j.; neugebauer, karla m.; greninger, alexander l.; jerome, keith r.; roychoudhury, pavitra; xie, hong; shrestha, lasata; huang, meei-li; pitzer, virginia e.; iwasaki, akiko; omer, saad b.; khan, kamran; bogoch, isaac i.; martinello, richard a.; foxman, ellen f.; landry, marie l.; neher, richard a.; ko, albert i.; grubaugh, nathan d. title: coast-to-coast spread of sars-cov- during the early epidemic in the united states date: - - journal: cell doi: . /j.cell. . . sha: doc_id: cord_uid: bakwk tm the novel coronavirus sars-cov- was first detected in the pacific northwest region of the united states in january , with subsequent covid- outbreaks detected in all states by early march. to uncover the sources of sars-cov- introductions and patterns of spread within the united states, we sequenced nine viral genomes from early reported covid- patients in connecticut. our phylogenetic analysis places the majority of these genomes with viruses sequenced from washington state. by coupling our genomic data with domestic and international travel patterns, we show that early sars-cov- transmission in connecticut was likely driven by domestic introductions. moreover, the risk of domestic importation to connecticut exceeded that of international importation by mid-march regardless of our estimated effects of federal travel restrictions. this study provides evidence of widespread sustained transmission of sars-cov- within the united states and highlights the critical need for local surveillance. a novel coronavirus, known as sars-cov- , was identified as the cause of an outbreak of pneumonia in wuhan, china, in december (gorbalenya et al., ; wu et al., ; zhou et al., ) . travel-associated cases of coronavirus disease were reported outside of china as early as january , , and the virus has subsequently spread to nearly all nations (world health organization, a ). the first detection of sars-cov- in the united states was a travel-associated case from washington state on january , (centers for disease control and prevention, a) . the majority of early covid- cases in the united states were ( ) associated with travel to a ''high-risk'' country or ( ) close contacts of previously identified cases according to the testing criteria adopted by the centers for disease control and prevention (cdc) (centers for disease control and prevention, b) . in response to the risk of more travel-associated cases, the united states placed travel restrictions on multiple regions with sars-cov- transmission, including china on january , iran on february , and europe on march (taylor, ) . however, community transmission of sars-cov- was detected in the united states in late february, when a california resident contracted the virus despite meeting neither testing criterium (moon et al., ) . from march - , , the number of reported covid- cases in the united states rapidly increased from to , , and the virus was detected in all states (dong et al., ) . it was recently estimated that the true number of covid- cases in the united states is likely in the tens of thousands (perkins et al., ) , suggesting substantial undetected infections and spread within the country. we hypothesized that, with the growing number of covid- cases in the united states and the large volume of domestic travel, new united states outbreaks are now more likely to result from interstate rather than international spread. because of its proximity to several high-volume airports, southern connecticut is a suitable location in which to test this hypothesis. by sequencing sars-cov- from local cases and comparing their relatedness to virus genome sequences from other locations, we used ''genomic epidemiology'' (grubaugh et al., a) to identify the likely sources of sars-cov- in connecticut. we supplemented our viral genomic analysis with airline travel data from major airports in southern new england to estimate the risk of domestic and international importation therein. our data suggest that the risk of domestic importation of sars-cov- into this region now far outweighs that of international introductions regardless of federal travel restrictions and provide evidence for coast-to-coast sars-cov- spread in the united states. to delineate the roles of domestic and international virus spread in the emergence of new united states covid- outbreaks, we sequenced sars-cov- viruses collected from cases identified in connecticut. our phylogenetic analyses showed that the outbreak in connecticut was caused by multiple virus introductions and that most of these viruses were related to those sequenced from other states rather than international locations ( figure ). we sequenced sars-cov- genomes from nine of the first covid- cases reported in connecticut, with sample collection dating from march - , (data s ). these individuals are residents of eight different cities in connecticut. according to the connecticut state department of public health, none of the cases were associated with international travel. using our amplicon sequencing approach, ''primalseq'' (grubaugh et al., b; quick et al., ) , with the portable oxford nanopore technologies (ont) minion platform, we generated the first sars-cov- genome approximately h after receiving the sample (ct-yale- ), demonstrating our ability to perform near-real-time clinical sequencing and bioinformatics. our complete workflow included rna extraction, pcr testing, validation of pcr results, library preparation, sequencing, and live base calling and read mapping. we shared the genomes of these viruses publicly as we generated them (gisaid epi_isl_ - ). we combined our genomes with other publicly available sequences for a final dataset of sars-cov- genomes ( figure ; data s ). the dataset can be visualized on our ''community'' nextstrain page (https://nextstrain.org/community/ grubaughlab/ct-sars-cov- /paper ). we built phylogenetic trees using a maximum likelihood reconstruction approach, and we used shared nucleotide substitutions to assess clade support ( figure ; data s ). our first nine sars-cov- genomes clustered into three distinct phylogenetic clades, indicating multiple independent virus introductions into connecticut. our sars-cov- genome ct-yale- clusters closely with other viruses sequenced from asia (china), whereas the close genetic relatedness of genomes from europe and washington state in the clade that contains ct-yale- makes it difficult to track the origins of this virus ( figure a ). regardless, neither the ct-yale- nor the ct-yale- covid- cases were travel-associated, which indicates that these patients were part of domestic transmission chains that stemmed from undetected introductions. the other seven sars-cov- genomes clustered with a large, primarily united states clade, within which the majority of genomes were sequenced from cases in washington state ( figure b ). because of a paucity of sars-cov- genomes from other regions within the united states, we could not determine the exact domestic origin of these viruses in connecticut. we also cannot yet determine whether the higher number of substitutions observed in ct-yale- and ct-yale- ( figure b ) compared with the other connecticut virus genomes within this clade was the result of multiple introductions or of significant undersampling. however, given that seven of our nine connecticut sars-cov- genomes fell within this clade versus the many other international clades, these were most likely the result of a common domestic source(s) rather than repeated international introductions. importantly, our data indicate that, by early to mid-march, there had already been interstate spread during the early covid- epidemic in the united states. our phylogenetic analysis shows that the covid- outbreak in connecticut was driven, in part, by domestic virus introductions. to compare the roles of interstate and international sars-cov- spread in the united states, we used airline travel data and the epidemiological dynamics in regions where travel routes originated to evaluate importation risk. we found that, because of the large volume of daily domestic air passengers, the dominant ll a b figure . the covid- outbreak in connecticut is phylogenetically linked to sars-cov- from washington (a) we constructed a maximum-likelihood tree using global sars-cov- protein coding sequences, including sequences from covid- patients identified in connecticut from march - , . the total number of nucleotide differences from the root of the tree quantifies evolution since the putative sars-cov- ancestor. we included clade-defining nucleotide substitutions to directly show the evidence supporting phylogenetic clustering. the number of sars-cov- genomes used in this phylogenetic tree from each location is shown in parentheses. (b) we enlarged the united states clade consisting primarily of sars-cov- sequences from washington state and connecticut. the map shows the location and number of sars-cov- genomes that cluster within this clade. the minion sequencing statistics are enumerated in data s , and the sars-cov- sequences used and author acknowledgments can be found in data s . a root-to-tip plot showing the genetic diversity and substitution rate of the data can be found in figure s . the genomic data can be visualized and interacted with at https://nextstrain.org/community/grubaughlab/ct-sars-cov- /paper . importation risk into the connecticut region switched from international to domestic by early to mid-march ( figure ). we first estimated daily passenger volumes arriving in the region from the five countries (china, italy, iran, spain, and germany) and out-of-region states (washington, california, florida, illinois, and louisiana) that have reported the most covid- cases to date (figures a- d ). by march , the five countries comprised % of reported non-united states cases, whereas the five states comprised % of reported domestic cases outside of connecticut and new york. to this end, we collected passenger volumes arriving in three major airports in southern new england: bradley international airport (bdl; hartford, connecticut), general edward lawrence logan international airport (bos; boston, massachusetts), and john f. kennedy (b) we selected three international airports in the region that are commonly used by connecticut residents: hartford (bdl), boston (bos), and new york (jfk). we used data from january to march to estimate relative differences in daily air passenger volumes from the selected origins to the airport destinations. these daily estimates were then combined by either international or domestic travel. (c and d) the cumulative number of daily covid- cases were divided by , population to calculate normalized disease prevalence for each international location (china, italy, iran, spain, and germany) (c). the cumulative number of daily covid- cases were divided by , population to calculate normalized disease prevalence for each international location (washington, california, florida, illinois, and louisiana) (d). (e) we calculated importation risk by modeling the number of daily prevalent covid- cases in each potential importation source and then estimating the number of infected travelers using the daily air travel volume from each location. the data, criteria, and analyses used to create this figure can be found in data s . ll international airport (jfk; new york, new york; figure b ). because travel data for are not yet available, we calculated the total passenger volume from each origin and destination pair between january and march , and estimated the number of daily passengers. we found that the daily domestic passenger volumes were $ times greater than international in hartford, $ times greater in boston, and $ times greater in new york in our dataset ( figure b ). by combining daily passenger volumes ( figure b ) with covid- prevalence at the travel route origin (figures c and d) and accounting for differences in reporting rates, we found that the domestic and international sars-cov- importation risk started to increase dramatically at the beginning of march ( figure e ). without accounting for the effects of international travel restrictions, our estimated domestic importation risk from the selected five states surpassed the international importation risk by march . using previous assumptions around travel restrictions (chinazzi et al., ) , we also modeled two scenarios where federal travel restrictions reduced passenger volume by % and by % from the restricted countries ( figure e ). because of the overall low prevalence of covid- in china, we did not find any significant effects of travel restrictions from china that were enacted on february (data s ). also, we did not find significant changes to the importation risk following travel restrictions from iran on march , likely because of the relatively small number of passengers arriving from that country (data s ). although we did find a dramatic decrease in international importation risk following the restrictions on travel from europe (march ), this decrease occurred after our estimates of domestic travel importation risk had already surpassed that of international importation ( figure e ). the dramatic rises in domestic and international importation risk preceded the state-wide covid- outbreak in connecticut ( figure e ), and the recent increase in risk of domestic importation may give rise to new outbreaks in the region. the combined results of our genomic epidemiology and travel pattern analyses suggest that domestic spread recently became a significant source of new sars-cov- infections in the united states. we find strong evidence that outbreaks on the east coast (connecticut) are linked to outbreaks on the west coast (washington), demonstrating that trans-continental spread has already occurred. as of march , there are more than , sars-cov- genomes sequenced from around the world, including more than from the united states (https:// nextstrain.org/ncov); however, most of the latter were obtained from a small number of states. therefore, we cannot determine the exact origins of the viral introductions into connecticut. recent domestic travel history of the nine reported cases was not available, but it is unlikely that all of the infections originated in washington state. furthermore, because of low genetic diversity between these early sequences from connecticut and washington, we cannot yet quantify the rate at which the virus may be spreading between the united states coasts or whether an introduction from a common source is responsible for phylo-genetic grouping. there are likely other large, multi-state phylogenetic sars-cov- clades that exist in the united states. as testing capacity increases and more viral genome sequences become available from new locations, more granular reconstructions of virus spread throughout the united states will be possible (grubaugh et al., a) . specifically, elucidating the phylogenetic relationship of viral genomes collected in connecticut to those collected in neighboring states, especially states with a high burden of disease, like new york, will improve our understanding of critical interstate dynamics. our estimates of domestic importation risk are likely conservative despite some important limitations of our air travel analysis. because we do not have access to current airline data, we could not exactly quantify the effect of government restrictions on international travel. in addition, even without explicit government restrictions, general social distancing and work-fromhome guidelines are reducing all airline travel. by using airline data available from , we did not account for these decreases in our international or domestic travel patterns. although such variations may lower our domestic risk estimates, we also did not account for the large volumes of regional automobile and rail travel, especially along the corridor that connects massachusetts, new york, new jersey, pennsylvania, and washington d.c. to connecticut. we do not believe that connecticut is more closely connected to its neighbors than states in other regions of the country. therefore, our risk estimates indicate that this interconnectedness will perpetuate the domestic spread of sars-cov- and that domestic spread will likely become the primary source of new infections in the united states. we argue that, although simplistic, our model demonstrates the urgent need to focus control efforts in the united states on preventing further domestic virus spread. as this epidemic progresses, domestic introductions of the virus could undermine control efforts in areas that have successfully mitigated local transmission. in china, local outbreak dynamics were highly correlated with travel between wuhan and the outbreak dynamics therein during the early months of the epidemic . similarly, if interstate introductions are not curtailed in the united states with improved surveillance measures, more robust diagnostic capabilities, and proper clinical care, quelling local transmission within states will be a sisyphean task. we therefore propose that a unified effort to detect and prevent new covid- cases will be essential for mitigating the risk of future domestic outbreaks. this effort must ensure that states have sufficient personal protective equipment, sample collection materials, and testing reagents because these supplies enable effective surveillance. finally, state-and local-level policymakers must recognize that the health and well-being of their constituents are contingent on that of the nation. if spread between states is now occurring, as our results indicate, then the united states will struggle to control covid- in the absence of a unified surveillance strategy. detailed methods are provided in the online version of this paper and include the following: the authors of this study would like to acknowledge s. cordey, i. eckerle, and l. kaiser from geneva university hospital for directly sharing their genome sequence data with our team; everyone who openly shared their genomic data on genbank and gisaid (authors listed in data s ); d. a.l.w. is the principal investigator on a research grant from pfizer to yale university and has received consulting fees for participation in advisory boards for pfizer. received: march , revised: april , accepted: april , published: may , this study did not generate new unique reagents, but raw data and code generated as part of this research can be found in the supplemental files, as well as on public resources as specified in the data and code availability section below. the accession number for the sars-cov- sequence data reported in this paper is ncbi bioproject:prjna and gisaid: epi_isl_ - . sequencing data have been made available via sra. data used to create the figures can be found in the supplemental files. the interactive nextstain page to visualize the genomic data can be found at: https://nextstrain.org/ community/grubaughlab/ct-sars-cov- /paper . the raw data, results, and analyses can be found at: https://github.com/ grubaughlab/ct-sars-cov- . residual de-identified nasopharyngeal samples testing positive for sars-cov- by reverse-transcriptase quantitative (rt-q)pcr were obtained from the yale-new haven hospital clinical virology laboratory or the connecticut state department of public health. in accordance with the guidelines of the yale human investigations committee and the connecticut state department of public health, this work with de-identified samples is considered non-human subjects research. all samples were de-identified before receipt by the study investigators. sample collection and processing samples for this study were collected during an early testing phase by the connecticut state department of public health or the yale clinical virology laboratory at the yale school of medicine. none of the cases that we sequenced in this study were associated with international travel. all samples included in this study had ct values less than , sufficient volume of rna for library preparation, and were collected by march . as early samples were crucial for validating pcr diagnostics in multiple laboratories, the number of samples meeting these criteria were limited. nasopharyngeal swabs were collected from patients presenting with symptoms of sars-cov- infection at multiple medical centers in connecticut. these patients are all connecticut residents, but we do not have access to location data associated with each of these early sars-cov- genomes to avoid patient identification. swabs were placed in virus transport media (bd universal viral transport medium) immediately upon collection. samples ( ml) were subjected to total nucleic acid extraction using the nuclisens easymag platform (biomé rieux, france) at the yale clinical virology laboratory. the recommended cdc rt-qpcr assay was used to test for the presence of sars-cov- rna (centers for disease control and prevention, c). a total of samples from different individuals met our inclusion criteria and were selected to to move forward with next generation sequencing (ngs). of these, we were successfully able to generate sequencing libraries from nine samples. sars-cov- positive samples were processed for ngs using a highly multiplexed pcr amplicon approach for sequencing on the oxford nanopore technologies (ont; oxford, united kingdom) minion using the v primer pools (quick et al., ) . sequencing libraries were barcoded and multiplexed using the ligation sequencing kit and native barcoding expansion pack (ont) following the artic network's library preparation protocol (v primers) (quick, ) with the following minor modifications: cdna was generated with superscriptiv vilo master mix (thermofisher scientific, waltham, ma, usa), a total of ng of each sample was used as input into end repair, end repair incubation time was increased to min followed by a : bead-based clean up, and blunt/ta ligase (new england biolabs, ipswich, ma, usa) was used to ligate barcodes to each sample. cdna synthesis and amplicon generation was performed concurrently for each sample. samples were processed by ct value to reduce the likelihood of contamination from high titer samples to low titer samples. barcoding, adaptor ligation, and sequencing was performed on samples with ct values between - (low titer group) prior to samples with ct values below (high titer group) (data s ). two samples, yale- and yale- , were diluted : in nuclease-free water prior to cdna synthesis. a no template control was created at the cdna synthesis step and amplicon generation step to detect cross-contamination between samples. controls were barcoded and sequenced with both the high and low titer sample groups. a total of ng of the low titer group was loaded onto a minion r . . flow cell and sequenced for a total of . h and generated . million reads. the flow cell was nuclease treated, flushed, and primed prior to loading ng of the high titer group library. these samples were sequenced for a total of h and generated . million reads (data s ). the rampart software from the artic network was used to monitor the sequencing run to estimate the depth of coverage across the genome for each barcoded sample in both runs https://github.com/artic-network/rampart). following completion of the sequencing runs, .fast files were basecalled with guppy (v . . , ont) using the high accuracy module. basecalling was performed on a single gpu node on the yale hpc. consensus genomes were generated for input into phylogenetic analysis according to the artic network bioinformatic pipeline (artic network). variants in the consensus genomes were called using nanopolish per the bioinformatic pipeline (loman et al., ) . amplicons that were not sequenced to depth of x were not included in the final consensus genome, and these positions are represented by stretches of nnn's (data s ). to investigate the origin and diversity of sars-cov- in connecticut, we compiled a dataset of our nine genomes with another representative sample of sars-cov- genomes that were available from genbank (https://www.ncbi.nlm.nih.gov/genbank/ sars-cov- -seqs/) and gisaid (https://www.gisaid.org/). see data s for a list of sequences and acknowledgments to the originating and submitting labs. no data that was only released on gisaid was used without consent from the authors (see acknowledgments). we aligned consensus genomes using the augur toolkit version . . (hadfield et al., ) . specifically, we aligned sequences using mafft (katoh et al., ) , masked sites at the and ends of the alignment as well as a small number of sites that likely vary due to assembly artifacts (see https://github.com/nextstrain/ncov), and reconstructed a phylogeny using iq-tree (nguyen et al., ) . these trees are further processed using augur and treetime to add ancestral reconstructions . the tree is rooted on the ancestor of the two genomes ''wuhan-hu- / '' and ''wuhan/wh / .'' sequences in this sample differ from the root by or fewer nucleotide substitutions. bootstrap values are not a meaningful measure of branch support in this case. here, many of the branches are supported by one substitution, which would correspond to a bootstrap support of . . for a branch supported by two substitutions the bootstrap support value would correspondingly be . . given this approximate one-to-one mapping between bootstrap values and the number of substitutions, we directly show mutations supporting the major splits in the tree as it is more informative. the substitutions defining these clades are compatible with the tree topology and are not homoplastic. the probability that all clade defining substitutions arose multiple times independently in a manner compatible with the tree topology is vanishingly small. for example, with a rate of nucleotide substitutions per month in a genome of length approximately ' bases, the probability of this happening for any pair of six sister clades within a month time frame is < . . a root-to-tip plot can be found in figure s . the data can be visualized at: https://nextstrain.org/community/grubaughlab/ct-sars-cov- /paper . daily covid- cases from international locations were obtained from the european centre for disease prevention and control via our world in data (https://ourworldindata.org/coronavirus-source-data). international data were accessed on march , . daily covid- cases from connecticut and other u.s. locations (washington, california, florida, illinois, and louisiana) were obtained from the repository (https://github.com/cssegisanddata/covid- ) hosted by the center for systems science and engineering (csse) at johns hopkins university (dong et al., ) . these represent the international and out-of-region domestic (i.e., excluding new york, massachusetts, and new jersey) locations with the most reported covid- cases. to investigate the domestic and international spread of sars-cov- , we obtained air passenger volumes from the international air transport association (iata; http://www.iata.org/). iata data consist of global ticket sales, which account for true origins and final destinations, and represents % of all commercial flights. we obtained the monthly number of passengers traveling by air from five international (china, italy, iran, spain, and germany) and five u.s. locations (washington, california, florida, illinois, and louisiana) to airports that are commonly used by connecticut residents: bradley international airport (bdl, hartford, connecticut; ranked rd in u.s. in yearly passenger volume; https://www.faa.gov/airports/planning_capacity/passenger_allcargo_stats/passenger/), general edward lawrence logan international airport (bos, boston, massachusetts; ranked th), and john f. kennedy international airport (jfk, new york, new york; ranked th). air passenger data from is not currently available; thus, we used data from january to march to represent general trends in passenger volumes, as done previously (bogoch et al., ) . we took the average of the -month passenger volumes to estimate the daily number of travelers entering each airport from the specified origin. to account for passenger reductions following u.s. government alerts and restrictions (taylor, ) , we modeled two scenarios: a % reduction in passenger volume and a % reduction in passenger volume. these thresholds were determined based on previously reported estimates and assumptions around travel restrictions (chinazzi et al., ) . we estimated the true number of incident cases per day by adjusting the number of reported incident cases to reflect the ascertainment period and reporting rate using: where c t is the number of reported incident cases of covid- on day t, d is the number of days from symptom onset to testing, and r is the reporting rate. we assumed a constant ascertainment period of d = days between symptom onset and testing (ferguson et al., ) . because of the evidence of pre-symptomatic transmission (tindale et al., ) , we also assumed that cases become infectious one day before symptom onset. to account for substantial uncertainty around reporting rates, we assigned different reporting rates to ll e cell , - .e -e , may , please cite this article in press as: fauver et al., coast-to-coast spread of sars-cov- during the early epidemic in the united states, cell ( ), https://doi.org/ . /j.cell. . . article individual locations based on the testing criteria enacted in that location (niehus et al., ) . for each country and state, we first extracted testing criteria from the department or ministry of health website. we assumed that countries or states with similar testing criteria policies captured similar proportions of true infections. using the respective testing criteria, we categorized countries or states as having narrow, moderate, or broad testing levels. we then assigned reporting rates to each testing level by using the mean and % confidence interval of the reporting rate estimated by nishiura et al. ( ) : . ( % ci = . - . ). the reporting rate for the broadest testing level, r = . , also corresponded to the reporting rate in mainland china (chinazzi et al., ) . we thus assigned iran, florida, washington, and illinois to a ''narrow'' testing level (r = . ); spain, italy, and louisiana to a ''moderate'' testing level (r= . ); and china, germany, and california to a ''broad'' testing level (r = . ; data s , ''testing-criteria''). to estimate the number of prevalent infectious individuals on day t (p t ), we multiplied the number of incident infections up to day t by the probability that an individual who became infectious on day i was still infectious on day t: where g(t-i) is the cumulative distribution function of the infectious period. we modeled the infectious period as gamma distribution with mean days and standard deviation . days which aligns with other modeling studies (prem et al., ; zhao et al., ) . we assumed that cases would not travel once they were diagnosed and therefore removed them from our estimate of infectious travelers (t t ): ði i À c i + d + Þð À gðt À iÞÞ + x tÀ i = tÀ i i ð À gðt À iÞÞ + i t eq. the first term of equation accounts for the assumption that some cases had been diagnosed by day t and thus would not travel. the second and third terms capture cases who are infectious on day t and have not yet been diagnosed. we calculated daily risk of importation as a function of the population-adjusted density of infectious travelers and passenger volume: where t t is the number of infectious travelers on day t, pop a is the population of location a, and n t is the number of passengers traveling from each location to southern new england on day t. we summed the calculated risk across the three airports (bdl, bos, jfk) and then across domestic and international travelers to arrive at our final estimates. the maps presented in our figures were generated using shape files from natural earth (http://www.naturalearthdata.com/). the basemaps are open source and freely available to anyone. statistical analyses were performed using r version . . (r core team, ) and are described in the figure legends and in the method details. cell , - .e -e , may , e please cite this article in press as: fauver et al., coast-to-coast spread of sars-cov- during the early epidemic in the united states, cell ( ), https://doi.org/ . /j.cell. . . figure s . root-to-tip plot showing the evolutionary rate of the sars-cov- genomes in our dataset, related to figure ll article potential for global spread of a novel coronavirus from evaluating and reporting persons under investigation (pui) coronavirus disease (covid- ) cdc -novel coronavirus ( -ncov) (real-time rt-pcr diagnostic panel) the effect of travel restrictions on the spread of the novel coronavirus (covid- ) outbreak an interactive web-based dashboard to track covid- in real time impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and healthcare demand tracking virus outbreaks in the twenty-first century severe acute respiratory syndrome-related coronavirus: the 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estimating unobserved sars-cov- infections in the united states the effect of control strategies that reduce social mixing on outcomes of the covid- epidemic in wuhan ncov- sequencing protocol v multiplex pcr method for minion and illumina sequencing of zika and other virus genomes directly from clinical samples r: a language and environment for statistical computing (r foundation for statistical computing) treetime: maximum-likelihood phylodynamic analysis a timeline of the coronavirus pandemic. the new york times transmission interval estimates suggest pre-symptomatic spread of covid- novel coronavirus ( -ncov) situation report- coronavirus disease (covid- ) situation report- a new coronavirus associated with human respiratory disease in china a mathematical model for estimating the age-specific transmissibility of a novel coronavirus a pneumonia outbreak associated with a new coronavirus of probable bat origin article star+methods key resources table resource availability lead contact further information and requests for data, resources, and reagents should be directed to and will be fulfilled by the lead contact, nathan d. grubaugh (nathan.grubaugh@yale.edu key: cord- -zt o co authors: sovacool, benjamin k.; furszyfer del rio, dylan; griffiths, steve title: contextualizing the covid- pandemic for a carbon-constrained world: insights for sustainability transitions, energy justice, and research methodology date: - - journal: energy research & social science doi: . /j.erss. . sha: doc_id: cord_uid: zt o co abstract the global covid- pandemic has rapidly overwhelmed our societies, shocked the global economy and overburdened struggling health care systems and other social institutions around the world. while such impacts of covid- are becoming clearer, the implications of the disease for energy and climate policy are more prosaic. this special section seeks to offer more clarity on the emerging connections between covid- and energy supply and demand, energy governance, future low-carbon transitions, social justice, and even the practice of research methodology. it features articles that ask, and answer: what are the known and anticipated impacts of covid- on energy demand and climate change? how has the disease shaped institutional responses and varying energy policy frameworks, especially in africa? how will the disease impact ongoing social practices, innovations and sustainability transitions, including not only renewable energy but also mobility? how might the disease, and social responses to it, exacerbate underlying patterns of energy poverty, energy vulnerability, and energy injustice? lastly, what challenges and insights does the pandemic offer for the practice of research, and for future research methodology? we find that without careful guidance and consideration, the brave new age wrought by covid- could very well collapse in on itself with bloated stimulus packages that counter sustainability goals, misaligned incentives that exacerbate climate change, the entrenchment of unsustainable practices, and acute and troubling consequences for vulnerable groups. the global covid- , or coronavirus disease, pandemic has overwhelmed our societies, shocked the global economy, thrown energy markets into disarray and overburdened struggling health care systems and other social institutions around the world. unlike earlier modern disease outbreaks such as severe acute respiratory syndrome (sars), swine flu (h n ), or ebola, the covid- virus is very easily transmitted by person-to-person contact. further, it has no known preexisting immunities, it is spread by people that do not appear to be sick, and the ratio between infections and fatalities is very high, particularly for older people and people with preexisting medical conditions. in medical terminology, society is undergoing a global pandemic with an immunologically naïve population. when addressing a group of sustainable development and medical professionals in april , columbia university professor jeffrey sachs estimated that the virus that causes covid- (i.e. sars-cov- ) could infect half the world's population within the next few years [ ] . although the global response to covid- may not be fully commensurate to the severity of the challenge, it has nevertheless disrupted longstanding notions of human resilience, disease preparedness, and even global health governance [ ] . national and subnational responses to the disease have often been far-reaching and at times transformative, including not only mandatory lockdowns, quarantines and restrictions on travel but key interventions such as evacuations, the distribution of hygiene and sanitation kits, and the suspension of all public visitors. some countries have utilized mass surveillance (as well as tracking and contact tracing apps) to monitor symptoms within their populations, funded community participation in the development and distribution of personal protective equipment, or participated in the design of intersectoral and transnational cooperation and aid packages. more than $ trillion in fiscal support measures had been announced by governments globally as of june to mitigate the economic impact from the pandemic, particularly impacts from the lockdown measures implemented to prevent spread of the disease [ ] . these relief packages amount to nearly % or more of gdp in germany, japan and the united states, with the united states alone signing a massive $ trillion covid- emergency bill and stimulus package in march [ ] . the european union set up a € billion coronavirus response investment initiative to provide liquidity to small businesses and the health care sector [ ] . the united kingdom also has invested heavily, launching a furlough program where the government paid the wages of . million affected workers (one quarter of the workforce) at a cost of more than £ billion with an additional £ billion in loans to businesses [ ] . initial assessments of the economic consequences of the pandemic are sobering, with estimations of a global gdp contraction of . % in [ ] , global trade shrinking by % [ ] and as many as million people losing their jobs [ ] . although the impacts of covid- on health systems and national economies are heavily covered in the media, and oft debated in the public, the implications of the disease for energy and climate policy are more prosaic. this special section of energy research & social science seeks to offer more clarity on the emerging connections between covid- and topics such as energy supply and demand, energy governance, future low-carbon transitions, social justice, and even the practice of research methodology. it features articles that ask, and answer: what are the known and anticipated impacts of covid- on energy demand and climate change? how has the disease shaped institutional responses and energy policy frameworks, especially in places such as africa where covid- is negatively affecting ongoing efforts to achieve access to modern energy? how will the disease impact ongoing patterns of innovation, social practices and future transitions, including not only adoption of renewable energy but also the electrification of mobility and mobility-as-a-service? how might the disease, and social responses to it, exacerbate underlying patterns of energy poverty, energy vulnerability, and energy injustice? lastly, what challenges and insights does the pandemic offer for the practice of research, and for research methodology? although ostensibly never intended as measures to reduce energy consumption, air pollution, or climate change directly, responses to the virus have had substantial connections with energy demand and greenhouse gas emissions. the most prominent drivers of these have been mandatory lockdowns or quarantines for households (people are only permitted to leave for essential reasons) and the related severe restrictions on travel. in late april , more than half of the entire global population ( %) was under some form of a coronavirus lockdown, with their movement actively restricted and controlled by their respective governments. the share of energy use that was exposed to containment measures reached % [ ] . as the top panel of fig. indicates, the largest lockdowns were in india, china, and the united states. one article calculated that more people were in lockdown due to covid- than were alive during world war ii [ ] . as the other panels of fig. indicate, more than countires had travel restrictions in place due to coronavirus in late march and the number of commerical flights has plummeted dramatically. abu-rayash and dincer (this volume [ ] ) add that road transport is also down significanty given the large number people forced to stay at home. they further show that in canada not only did civil aviation activities drop by % compared to business-as-usual in late , but also military aviatation activities were down by a significant % in . they also projected that for , greenhouse gas emissions for the canadian transport sector will be nearly % lower than than in . covid- has not only affected travel and the energy involved in providing it, but also global energy supply chains and the viability of energy firms. writing in this volume [ ] , hosseini argues that the most affected renewable energy sector has been solar energy and remarks that indeed, "the covid- pandemic has struck the renewable energy manufacturing facilities, supply chains, and companies and slowed down the transition to the sustainable energy world". the causes behind such shifts are manifold: governments have understandably redistributed public funding to combat the disease in a way that leaves less available for renewable energy incentives and tax credits. various renewable energy technology suppliers have placed staff on furlough and also adopted austerity measures and reduced operating capacity. projected installations are down significantly over earlier forecasts; one investment bank in the united states predicted residential-solar installations to fall by % year-over-year in the second quarter of and by % in the fourth quarter of . this reinforces the projections provided by irena that total new solar pv capacity additions in will be roughly on par , but this is as much as % below earlier expectations stated by several industry organizations [ ] . the off-grid renewable energy sector could face even more dire circumstances, with the world bank noting that the pandemic has seriously disrupted electrifications efforts, meaning that sdg (that encompasses universal energy access by ) is now unlikely to be met [ ] . it is in this context that mark mccarthy akrofi and colleagues (this volume [ ] ) caution that the pandemic could "reverse the enormous progress that off-grid energy companies have made to bring power to some million people in the last decade." solar pv alone is responsible for employing about % of the entire african workforce but solar firms and enterprises are already being forced to cut jobs, lay off staff, and confront declining liquidity. due to a strong dependence on imported solar pv technology from china, where manufacturing has declined due to the pandemic, dramatic reductions on future installed solar capacity are also projected for countries such as india [ ] . covid- is affecting global fossil fuel markets as well. hosseini (this volume [ ] ) adds that the coronavirus has disrupted global oil markets far more than any geopolitical event has (such as an embargo from opec), weakening the ability of oil suppliers to control markets and driving down natural gas spot prices into the $ /mmbtu (million british thermal units) range. although geopolitical tensions between saudi arabia and russia played an early role in the oil price collapse [ ] , demand destruction due to covid- has indeed been the driving force. jefferson (this volume) [ ] writes "in the run-up to the collapse of crude oil prices in early it was primarily a division between russia and saudi arabia within opec which appeared to be the main force at work, but then the covid- pandemic took over, followed by us oil prices turning negative in april , as may contracts expired and traders had to offload stocks with ongoing storage becoming extremely limited." he further states that despite the stimulus and recovery packages being offered by many nations, "there will be many oil sectors incurring losses, from us shale oil and canadian tar sands producers, to many standard crude oil exporters incurring problems with production equipment access and costs, or experiencing lack of competitiveness in key markets." recent data from the international energy agency confirms this point, noting severe reductions in global demand for oil and natural gas (see fig. ). although not representative of all countries and regions, the special section does feature some deep and nuanced assessments of the particular impacts the pandemic is having on national energy supply or demand. nima norouzi and colleagues (this volume) [ ] intimately trace the impacts of the virus where it first emerged in wuhan, china, looking at how it impacted not only national energy demand, but also precipitated steep declines (and future uncertainty) in patterns of electricity consumption and oil consumption, industrial productivity and energy markets. they specifically propose a methodology for analyzing such patterns during periods in which historical data becomes inaccurate because of a crisis event such as covid- . azzam abu-rayash and colleagues (this volume) [ ] closely analyze the impacts of the pandemic on electricity demand in ontario, canada, where they calculate declines in electricity consumption during april of about % or , gw and note distinct changes in demand patterns due to quarantine and travel restrictions. this corresponds with some positive externalities as well, including greenhouse gas emission reductions of , tons of co equivalent attributed to covid- with a monetary value of $ , for the month of april . fig. shows a similar trend in europe, with significant (and positive) reductions in air pollution noted across france, italy, and spain, largely from the curtailment of road transport. abouzar estebsari and colleagues (this volume [ ] ) offer a well-reasoned explanation for why related reductions in electricity demand occurred, having analyzed patterns of electricity demand in spain, italy, belgium and the united kingdom (countries with more severe covid- movement restrictions) as well as the netherlands and sweden (countries with less restrictive measures). they found that during the second week of april only in sweden demand remained more or less the same (actually rising slightly) relative to a reference week in . significant reductions were experienced in spain ( %), italy ( . %), belgium ( . %), the uk ( . %) and even the netherlands ( . %) due to covid- . the ramifications of covid- extend well beyond the avoided energy consumption and emissions associated with travel and household lockdowns; they are also drastically shaping the strength (or erosion) of some energy institutions and policy frameworks. for instance, the pandemic is having a particularly pronounced effect on institutions and policy frameworks in africa, even though it is not (at the time of this writing) a major center of infections or death. mulualem gebreslassie (this volume) [ ] writes that the closure of energy intensive businesses and industries in africa has meant a positive shift in that states can now provide scarce energy services to homes or national health care systems. as they conclude, the pandemic "may even convince the african continent to rethink and clear the way for investing more in clean and reliable energy resources and make business processes easy for those who are interested to enter the renewable energy sector." mark mccarthy akrofi and colleagues (this volume [ ] ) add that african states are already rushing to intervene and stimulate recovery but do not specifically address how stimulus packages will influence the clean energy transition. further research therefore needs to examine how government stimulus can strengthen the renewable energy sector via various aid packages, economic incentives, and monetary and fiscal incentives-efforts müller et al. note are all broadly consistent with many national policy frameworks across the continent [ ] . as already stated, the pandemic has significantly disrupted lives, businesses, and economies. furthermore, it could culminate in lasting effects on social norms and practices. to contextualize this claim, consider that the global response to covid- has necessitated unprecedented levels of coordination and information sharing with the intent of ultimately curtailing outbreaks and minimizing harm [ ] . this has occurred at multiple levels of society at once across many different types of institutions-making it what the nobel laureate elinor ostrom would have called "organizational multiplicity" and a "polycentric" phenomenon [ , ] . fig. displays the variety of messages received about covid- merely by the lead author, including those from the mass media (covid- dominated headlines in the uk for weeks), companies and travel providers, national government, grocery stores, universities, restaurants, social groups and charities, and even churches. this phenomenon parallels what scholar eve kosofsky sedgwick terms the "christmas effect" [ ] to describe the way that major parts of western society come together and speak "with one voice" for the christmas holiday. for it is annually during the christmas season that churches build nativity scenes and hold a greater number of masses; state and federal governments establish school and national holidays; the media run major advertising campaigns; and social events and domestic activities align. whenever society combines institutional inertia in this manner, it can exert profound and lasting influence over patterns of behavior, transcending individual firms and people. although certainly not festive, the "coronavirus effect" may be just as effective as the "christmas effect." such messages and strategies of communication underscore an immense amount of coordination across diverse and heterogeneous actors and organizations. the resulting messages were persistent, coming repeatedly and daily. they were prominent, in many times coming from sources people trust. they were multifaceted, coming from many sectors beyond health care including not only those in fig. , but also the mayor of london sadiq khan, banks, libraries, political groups, airlines, friends, and family. one of the authors even had his "smart printer" send an automated email about ink delivery during the pandemic, as well as six emails from his dentist about dental hygiene during the pandemic. and the messages were personal, often prescribing very specific actions or recommendations (about washing, essential travel, social distancing, self-quarantining, and mask wearing) connected to personal health and calling for immediate changes in behavior and practice. given the coronavirus' ability to achieve this "christmas effect," hundreds of millions of people immediately adopted the new behavior of "social distancing," with fig. showing its adoption in india, the united states, the united kingdom and singapore. when making the predictions mentioned in the introduction, jeffrey sachs even remarked that "we should expect to change our behaviors not just during this pandemic but perhaps forever." indeed, wisdom kanda and colleagues (this volume [ ] ) argue that in the context of sustainability transitions, the pandemic is causing "disruptive" change not only by potentially accelerating transformations in incumbent socio-technical systems, but also by also affecting emergent innovations and niches. in the mobility sector, they discuss how in finland and sweden the virus has weakened the push for mobility-as-a-service efforts (given they involve sharing rides, not ideal in an environment of social distancing) but had less impact on the push for electric vehicles (given they permit individualized, private transport). they therefore suggest that the impacts of covid- on mobility practices and transitions are important research streams moving forward. caroline kuzemko and colleagues (this volume [ ] ) take an even broader and more holistic view of the ways the pandemic can place pressure on sustainability transitions in the near-term and the longterm. they argue that covid- can alter the scope and pace of energy systems change with declining electricity demand and prices, the disruption of supply chains, and possible rebounds associated with recovery and stimulus packages. it could also shift financial investment flows away from incumbent industries and carbon intensive fuels. the pandemic is changing multi-scalar policy and politics by calling into question longstanding conventions about globalization and interconnectivity, as well as freedom of movement and geopolitical tensions between groups such as the united states and china or the united states and the world health organization. the pandemic is lastly transforming social and political practices, especially those related to telework/working from home as well a preferred modes of travel given the near-term focus on social distancing. here they warn that the lasting imprint of the pandemic is uncertain, with the potential that it entrenches unsustainable practices (such as driving a car) perhaps as great as its ability to introduce more sustainable practices (such as walking). they raise the critical question of whether there will be an acceleration of pre-pandemic drivers for sustainability across the dimensions they consider or whether momentum for sustainability will be lost as pandemic recovery plans are rolled out. kester et al. recently refer to this as the "dialectic" nature of future sustainability transitions, given they can reinforce dominant practices as much as they can reform existing ones [ ] . even electric mobility, an innovation kanda and colleagues noted may ultimately be less affected by the pandemic, has unclear and highly differentiated impacts on sustainability as noted in table . this means the adoption of electric vehicles is neither good nor bad in sustainability terms, it instead depends on how such innovations are governed and managed across areas such as vehicle use, daily life, social identity and systemwide environmental effects. the covid- pandemic has equally compelling linkages with energy crises, energy poverty, energy vulnerability and energy injustice. kathleen brosemer and colleagues (this volume [ ] ) write that the pandemic will only "illuminate and compound existing crises in energy sovereignty." it is worsening already terrible inequalities in health care access among the navajo nation in the united states, where hospitals were overburdened before covid- outbreaks with caring for indigenous peoples harmed from coal mining and extraction as well as increases in kidney disease and cancer that resulted from many years of living next to abandoned uranium mines. the pandemic is compounding environmental injustices as covid- most affects those with preexisting medical conditions, and yet decades of poor environmental and air quality leave minority groups at heightened risk of having those conditions. it is undermining the ability of energy firms to guarantee the provision of energy access and modern energy services in times of austerity and uncertainty. it is lastly serving as a mechanism for powerful incumbent interests to usurp various regulatory processes that back their own narrow interests at the expense of the public good. one particular example is enbridge "taking advantage of divided public attention and a fraught financial situation during the covid- crisis to push forward permit applications" for a major change in the routes of one of their pipelines. such attempts at regulatory manipulation are not limited to north america; kalyani writes how vested interests in india were using the pandemic as an excuse to increase employment in the coal and gas sectors, even though these sectors operate contrary to india's stated climate policies [ ] . paolo mastropietro and colleagues (this volume [ ] ) add that "the covid- pandemic and the consequent lockdown exacerbated energy poverty and insecurity worldwide." however, they also note that the collective response from policymakers has been to attempt to safeguard vulnerable citizens by an array of protection measures including: • disconnection bans; • energy bill deferral and payment extension plans; • enhancement of energy assistance programs; • energy bill reductions or cancellations; • support measures for commercial and small industrial activities; • creation of funds and other support measures to suppliers. after reviewing the global prevalence of these measures, they conclude that two are "best" at minimizing vulnerability: direct energy assistance programs and bans on disconnections, the latter being the most widespread measure introduced by governments during the pandemic. matthew henry and colleagues (this volume [ ] ) take an equally useful global analytical lens, reinforcing the recent call for a "just transition." this debate about a "just transition" is ongoing across many countries and provinces, with at least national commissions, policies, or task forces in place across canada, china, czech republic, germany, ghana, indonesia, new zealand, scotland, south africa, spain, the united states and vietnam. as table indicates, a "just transition" is backed by powerful coalitions and groups around the world. as henry and colleagues note, a just transition intends to ensure that as global society decarbonizes, it does not leave anyone behind. efforts must be made to offer income support for workers during the full duration of transition, to tailor local economic development tools for affected communities, and to offer realistic training or retraining programs that lead to decent work. they worry, however, that both the covid- pandemic and the global fall in oil prices could complicate ongoing attempts to realize a just transition-especially since the pandemic has resulted in the loss of more than , clean energy jobs and halted momentum in the push for solar energy and wind energy. they conclude however that the covid- crisis represents "a unique opportunity to adopt just transition principles into community and economic recovery efforts." the insights offered by this special section are not just topical or thematic. they also relate to the very art and craft of undertaking research, with some interesting insights for research design and research methodology. both jefferson (this volume [ ] ) and kanda and colleagues (this volume [ ] ) note how scholars, especially those designing energy programs (such as the global energy assessment) or utilizing table the differentiated impacts of electric mobility and electric vehicles on sustainability. strengthens sustainability weakens sustainability vehicle uptake evs substitute for conventional cars and motorcycle. evs increase car-based mobility by drawing people away from active and public modes of transport. evs used more in intermodal (active and public transport) systems and in combination with measures to discourage car use. evs encourage excessive driving and are bought as second or third (luxury) cars. evs increase the use of car sharing/ride sharing schemes. evs increase the preference for private, single-occupancy driving practices. evs are a wakeup call to address private vehicle use if alternatives are available -public transport, shared services etc. evs, through their cheaper variable costs, enable longer distances, thus supporting urban sprawl. they also compete with public transport and shared services. evs allow for more family time as commutes are part of office hours. evs allow office hours to be extended to include commuting time. expression of gender evs and ev marketing break with gender distinctions through alternative design, comfort and ease of operations. evs and ev marketing reinforce stereotypical car images of masculinity (large, sporty, pickup trucks) or femininity (small, quiet, early generation evs). evs and ev marketing point to new stereotypes around responsible and sustainable car use. evs and ev marketing reinforce stereotypical car discourses of joy and notions of freedom. evs break with class distinctions, as low variable costs enable more mobility for all. evs reinforce class/wealth distinctions as high capital costs imply that only rich can afford them and their benefits. evs, through their broad deployment, signal a need for more efficient low-carbon propellants, alternative modes of transport, less mobility and spur pro-environmental behavior in other sectors evs have lower emissions, which lead to rebound effects: more miles travelled, heavier vehicles, more private vehicles. this is especially relevant if the ecosystem around evs fails to materialize, e.g. no battery recycling, only dump charging, nonrenewable electricity, etc. oil independence evs minimize and signal lower oil/gas consumption, which reduces dependency among households and non-oil producers on oil companies and oil producing countries. evs cause a reduction in demand for oil, which reduces the oil price and makes fueling conventional vehicles cheaper. lower oil prices also reduce oil sector investments and thereby limit production to a smaller group of oil producing countries (those with low variable costs) and counterintuitively increasing oil dependence on a smaller group of countries. evs are designed and promoted by sustainably oriented firms with a focus on innovation and entrepreneurship. evs are co-opted and marginalized by transnational conglomerates with little desire for social change. source: authors modification from kester et al [ ] . selected organisations and movements supporting a "just transition" in . conceptual frameworks (such as the multi-level perspective) need to better account for epidemics and pandemics as landscape shocks. the persistence, prominence, multifaceted and personal nature of effective messaging about the virus (discussed in section ) also remind us about the importance of recognizing culture [ , ] whenever researchers engage in communication or outreach. fig. even shows the adapting to local culture of messages about social distancing and wearing masks. for instance, images about the virus in the western state of colorado (in the united states) feature skis and cowboys-symbols well embedded in local culture. lucha libre in mexico has played a relevant role in its culture since the late s, mainly due to its masked wrestlers, who have incorporated their own family traditions, beliefs and fears into the design of their masks [ ] . the louvre abu dhabi similarly adapted their messages about the pandemic to feature culturally appropriate attire for women, e.g. abayas on images of women performing social distancing. michael fell and colleagues (this volume [ ] ) suggest that the pandemic represents not only an existential threat to society, but also a threat to the practice of research, given that it calls into question the internal and external validity of our findings in the academy. this includes both the validly of research done before the pandemic (given that society may never be the same after) and the future robustness of any research conducted during the pandemic (a situation of extreme anxiety and stress far removed from "normal" life, potentially making findings less stable over time). they argue that covid- changes the context for research as it creates an environment that may be unprecedented and highly unusual compared to future years. they note the pandemic is reconfiguring demographics in rapid and unforeseen ways, with advanced morbidity and mortality and differentiated effects across age, gender, or ethnicity. they argue (much as we have in section ) that the pandemic is altering behaviors and daily routines; changing perceived personal and cognitive constraints and feelings; putting pressure on exiting social norms and identities; and materially changing homes and workplaces. taken together, these features of covid- may demand that we rethink in meaningful ways the design of future studies, how we determine demographically representative samples, how we collect data, how we interpret findings, and how we translate those findings into recommendations. such considerations are timely and relevant given the explosion of covid- publications that have appeared since the start of the pandemic. nearly , papers on the pandemic were published between february and may alone, and , of these were released through the preprint servers biorxiv, medrxiv and arxiv [ ] . chen and colleagues (this volume [ ] ) further these themes in their work on acceptance of and willingness to pay (wtp) for home energy management systems (hems) during the covid- pandemic in new york, usa. they note that the pandemic is having a distinct effect on survey participants with social-psychological variables, such as attitude toward hems and social norms, arising as important factors for explaining technology adoption intention. they also affirm some of the points raised by fell et al. about the unique situation survey respondents have found themselves in. many reported feeling "anxious" and others suggested that they felt they had a high chance of getting infected by coronavirus themselves-a salient message considering that the survey was conducted in new york, one of the global epicenters of the disease. the authors indicate that they hope that their survey results offer a "foundation for researchers to conduct larger-scale energy studies by considering the opportunities to build transdisciplinary collaborations through integrated methods and matching datasets." this might include future work on cultural differences in social distancing, how energy burdens are framed and distributed, what constitutes healthy built-home environments, and other social-psychological factors including perceived fairness or social networking. marius schwarz and colleagues (this volume [ ] ) offer additional insights regarding the impacts of the pandemic on research methodology that are perhaps obvious but nonetheless highlight important and perhaps persistent trends. they argue that covid- is opening up new ways of doing research, of being an academic, of collecting data and attending conferences. they argue "the pace with which researchers adopted digital formats for conferences, lectures, and meetings showed that currently available tools can substitute many of the physical interactions at work. it also showed that academics are willing to use digital tools for scientific exchange." the pandemic has showcased that academics and those in higher education can quickly and creatively change how they deliver lectures and are accessible to students; how they give guest seminars and discuss findings; even how they may interview for jobs, do research interviews, and host online workshops. they hope that "going digital" in many of these formats and contexts will continue, given the generally positive nature of the energy or carbon savings involved [ ] . they further suggest that such digital modes of interaction could come to substitute for physical modes in how academics work in groups, hold team meetings, and socially network. situated at the nexus of the covid- pandemic, energy systems, and climate change, this special section has revealed the complex, and often shifting, contours of how the disease is shaping global patterns of energy consumption, policymaking, and governance. it is altering the desirability of some emerging innovations and sustainability transitions, and heightening concerns over energy vulnerabilities and injustices. it is even challenging in fundamental ways how future energy and climate researchers go about their work. as table reveals, these intersections can be weighty and protean, but they are also perilous and precarious. for every noted positive intersection with some aspect of stainability or doing research, or benefit, we see an almost equally salient negative intersection, or risk. take one of these examples: lowering demand for, and prices of, fossil fuels. is this a blessing-foretelling that fossil fuels are becoming unviable-or a curse-cementing fossil fuels as cheap and abundant sources of energy to be utilized for many years to come? potently, it is the aspect of energy justice and vulnerability that particularly has more negative intersections (risks) than positive ones (benefits). covid- , as various authors presented in this special section, represents a strategic opportunity to work in parallel on designing and implementing economic and social recovery programs and advancing the global climate agenda towards a just transition. what is also evident from the special section is the multi-scalar and multifaceted nature of social responses to the pandemic, which have created a "christmas effect" or "coronavirus effect" of: • instructing people how to immediately alter and change their routines and practices in response to a crisis (e.g., social distancing, wearing masks, quarantining, and handwashing); • bolstering the strength and resilience of infrastructure and institutions (e.g., of hospitals and medical research institutions); • building capacity to monitor and manage emergency measures (e.g., trace infections, test people); • properly financing social responses in ways commensurate to a grand challenge (e.g., donations to national health services or the world health organization); • restoring economic activity gradually and via approaches that are backed by science (e.g., mandatory lockdowns and partial reopening, deployment of government rescue and stimulus funds); • harnessing innovation and rapidly developing critical new technologies (e.g., new therapeutics and vaccines); • utilizing a variety of trusted institutions and individuals to convey information and messages (e.g., the cdc, major news outlets, doctors and medical professionals); • while undertaking these steps, protecting the vulnerable (e.g., those with preexisting conditions, the unemployed and/or the indigent). although the impacts from the pandemic have so far been far from equitable or welcomed by the majority of people, this list of actions does offer a possible recipe for how future energy and climate planning could proceed as well, if policymakers and planners see the opportunity to transform social practices and institutions as much as the pandemic has. this could help achieve a "christmas" or "coronavirus" effect for energy and climate policy that encompasses: table the dialectic or dualistic impacts the covid- pandemic can have on energy and climate sustainability and research. energy and climate impacts of the virus -sharp reductions in travel related energy consumption and carbon emissions -immediate reductions in electricity consumption -depression of fossil fuel markets (particularly coal, oil and gas) -immediate reductions in global air pollution -redistribution of scarce energy resources in african nations to homes or national health care system -acceleration of african stimulus packages for low-carbon transitions -disruption of clean energy jobs -disruption of clean energy supply chains -risk of real and substantial rebounds in consumption accelerated by stimulus and recovery packages -disruption of off-grid energy markets and eroded progress on energy access programs -potentially bolstered trends in the electrification of private transport -shifted financial and investment flows away from carbon intensive assets -transformed social and professional practices in ways that are less energy intensive (e.g., working from home, walking, cycling) -undercutting of demand-side innovations such as ridesharing or mobility-as-a-service -dis-incentivizing mass-transit and public transport due to social distancing norms -calling into question the increasing interconnectivity and globalization of socio-technical systems -accelerating a geopolitical divide between the united states and other actors (e.g. china, world health organization) connections with energy justice an vulnerability -implementation of a variety of emergency protective measures including bans on disconnection and targeted assistance packages -increased attention to the principles of a "just transition" and the need for stimulus packages to be low-carbon and equitable • instructing people how to immediately reduce their carbon footprints (e.g. using energy efficient technologies in their homes, eating less meat, avoiding air travel [ ] ); • bolstering infrastructure, institutions and industrial strategy (e.g.. incentives for clean energy manufacturing and deployment including wind turbines, solar panels, electric vehicles [ ] ); • building capacity to mitigate, monitor and manage emergency measures (e.g., tracking plans for universal energy access and sdg , deployment of micro grids, bans on disconnection [ ] ); • properly financing social responses in ways commensurate to the challenge (e.g., substantially increase funding for national and multinational climate and development organizations or green investment banks, investment for deployment of low-carbon technologies and infrastructure [ , ] ); • restoring economic activity gradually and via approaches that are backed by science (e.g., development pathways synchronized to the ndcs of the paris accord or the findings of the ipcc, investment of economic stimulus funds in low-carbon technologies, green new deals [ ] [ ] [ ] ); • harnessing innovation and the development of new technologies (e.g., the next generation of transport fuels, energy storage, smart grids or hydrogen fuel cells) [ ] [ ] [ ] ; • utilizing trusted institutions and individuals to convey persistent and repeated information, messages and narratives in ways that resonate with audiences (e.g., major news outlets, the ipcc, governments, major corporations, churches, restaurants and celebrities sent persistently through various media channels) [ ] [ ] [ ] [ ] ; • while undertaking these steps, protecting the vulnerable (e.g., households in energy or mobility poverty, marginalized groups or indigenous peoples) [ ] [ ] [ ] [ ] . if such actions were taken in concert, progress on energy and climate would likely outpace all previous targets and milestones, rather than remaining chronically underfunded, underperforming and continually lagging behind expectations. both of these core findings-that covid- matches its promise of change with precariousness about the direction it goes, and that covid- responses offer a possible template for future energy and climate action-remind us that we remain at a critical but fragile crossroads. as much as we see great progress in efforts toward ameliorating the covid- crisis, we also see the same types of hindrances that have plagued progressive energy policy and climate action. specifically, lack of attention to warnings about a potential crisis, delayed responses to building evidence of crisis onset, nationalism at the expense of the global good, politics overshadowing social welfare, marginalized populations (e.g., people of low socio-economic status, or people in low and middle income countries) experiencing adverse consequences at higher rates, conspiracy theories and fatigue of mitigation measures. as fig. both comically and tragically seeks to depict, climate change is akin to a perpetual pandemic, but one that multiplies threats in steeper and more severe ways than covid- or its economic consequences. markard and rosenbloom have the right of it when they write that unlike the pandemic, "climate change, in particular, threatens the very basis for continued human prosperity and requires an equal, if not greater, societal mobilization" [ ] . hence, the opportunities emerging from the pandemic for energy systems and climate policy can be secured or squandered. without careful guidance, governance and consideration, the brave new age wrought by covid- could very well collapse in on itself with bloated stimulus packages, misaligned incentives, the embedding of unsustainable practices, and acute and troubling consequences for vulnerable groups. ssdn: epidemiology and economics of covid covid- gives the lie to global health expertise world economic outlook: the great lockdown trump signs $ trillion coronavirus stimulus bill jobs and economy during the coronavirus pandemic uk furlough scheme spending exceeds billion pounds trade set to plunge as covid- pandemic upends global economy more people are now in 'lockdown' than 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and australia the misallocation of climate research funding the green new deal in the united states: what it is and how to pay for it canada's green new deal: forging the socio-political foundations of climate resilient infrastructure? a post mortem of the green deal: austerity, energy efficiency, and failure in british energy policy critical perspectives on disruptive innovation and energy transformation innovating innovation-disruptive innovation in china and the lowcarbon transition of capitalism are low-carbon innovations appealing? a typology of functional, symbolic, private and public attributes credibility, communication, and climate change: how lifestyle inconsistency and do-gooder derogation impact decarbonization advocacy climate change strategic narratives in the united kingdom: emergency, extinction,effectiveness using stories, narratives, and storytelling in energy and climate change research greenberg energy policy and research: the underappreciation of trust advancing an energy justice perspective of fuel poverty: household vulnerability and domestic retrofit policy in the united kingdom mobility justice in low carbon energy transitions justice, social exclusion and indigenous opposition: a case study of wind energy development on the isthmus of tehuantepec energy justice discourses in citizen deliberations on systems flexibility in the united kingdom: vulnerability, compensation and empowerment a tale of two crises: covid- and climate the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. key: cord- - vlxa i authors: williamson, e. d.; westlake, g. e. title: vaccines for emerging pathogens: prospects for licensure date: - - journal: clin exp immunol doi: . /cei. sha: doc_id: cord_uid: vlxa i globally, there are a number of emerging pathogens. for most, there are no licensed vaccines available for human use, although there is ongoing research and development. however, given the extensive and increasing list of emerging pathogens and the investment required to bring vaccines into clinical use, the task is huge. overlaid on this task is the risk of anti‐microbial resistance (amr) acquisition by micro‐organisms which can endow a relatively harmless organism with pathogenic potential. furthermore, climate change also introduces a challenge by causing some of the insect vectors and environmental conditions prevalent in tropical regions to begin to spread out from these traditional areas, thus increasing the risk of migration of zoonotic disease. vaccination provides a defence against these emerging pathogens. however, vaccines for pathogens which cause severe, but occasional, disease outbreaks in endemic pockets have suffered from a lack of commercial incentive for development to a clinical standard, encompassing phase iii clinical trials for efficacy. an alternative is to develop such vaccines to request us emergency use authorization (eua), or equivalent status in the united states, canada and the european union, making use of a considerable number of regulatory mechanisms that are available prior to licensing. this review covers the status of vaccine development for some of the emerging pathogens, the hurdles that need to be overcome to achieve eua or an equivalent regional or national status and how these considerations may impact vaccine development for the future, such that a more comprehensive stockpile of promising vaccines can be achieved. globally, there are a number of emerging and re-emerging pathogens. some of these cause endemic disease in regions of the globe, where they are maintained in zoonotic reservoirs and transmitted to man either by direct or indirect contact. for most of the emerging pathogens there are no licensed vaccines available for human use, although there is ongoing research and development. however, given the extensive and increasing list of emerging pathogens and the time and investment required to bring vaccines into clinical use, the task is huge. overlaid on this task is the risk of anti-microbial resistance (amr) acquisition by micro-organisms which can endow a relatively harmless organism with pathogenic potential. furthermore, climate change also introduces a challenge by causing some of the insect vectors and environmental conditions prevalent in tropical regions to begin to spread out from these traditional areas, thus increasing the risk of migration of zoonotic disease. vaccination provides a defence against these emerging pathogens. however, to date, vaccines for pathogens which cause severe, but occasional, disease outbreaks in endemic pockets have suffered from a lack of commercial incentive for development to a clinical standard. while approval of vaccines for diseases caused by such pathogens would clinical and experimental immunology review article series editor: e diane williamson make a significant impact on disease outbreaks, taking niche vaccines into clinical development, including phase iii clinical trials for efficacy, requires a large investment in time and money. an alternative is to develop such vaccines to request us emergency use authorization (eua), or an alternative status in the united states, canada and european union (eu) making use of a considerable number of alternative regulatory mechanisms that are available prior to licensing, so that the products are deployable at the first indications of a disease outbreak. this review covers the status of vaccine development for some of the emerging pathogens, the hurdles that need to be overcome to achieve eua or an equivalent regional or national status and how these considerations may impact vaccine development for the future, such that a more comprehensive stockpile of promising vaccines can be achieved. pathogens which are classed as emerging or re-emerging are identified through global surveillance programmes and organizations such as the world health organization (who). although labelled 'emerging', most of these pathogens are not new and have either been quiescent in the environment until the conditions are opportune to emerge or have evolved from a parent organism to adapt to the prevailing conditions. thus, there is an intricate relationship between the environment, the climate, wildlife and human existence and lifestyle. the coronaviruses exemplify this point: the ancestral virus possibly existed approximately years ago [ ] . coronaviruses have a wide species range infecting birds, bats, chickens, pigs, dogs, cats and rodents [ ] . however, the first human coronavirus was described only in the s [ , ] , and the coronavirus causing severe acute respiratory syndrome (sars) was discovered only in [ ] [ ] [ ] , while that causing middle east respiratory syndrome (mers) first emerged in [ ] . it is likely that warm-blooded flying birds and bats have co-evolved with the coronaviruses to aid dissemination [ ] . for example, sars is thought to have first infected old world bats, then spreading to horseshoe bats [ ] , civets and finally to man [ ] . in the outbreak of sars in china and adjacent countries, phylogenetic analysis suggested that the virus spread from bats to humans, possibly through the intermediary civet species. neither bats or civets showed any clinical signs of infection, and it is thought that bats are the main zoonotic reservoirs for the virus [ ] . organizations such as the who, national institutes for allergy and infectious diseases (niaid) and the us centers for disease control (cdc) publish lists of emerging pathogens which may be viral, bacterial or rickettsial in nature. the who priority list contains viruses which have been prioritized as the most likely to cause epidemics and for which the who will establish a blueprint programme for accelerated research and development (r&d) [ ] . the list published in february is shown in table . niaid [ ] and cdc [ ] also publish lists of pathogens of priority which comprise bacteria and viruses, but categorize these into three groups depending on pathogenicity, accessibility and the availability of vaccines and therapies. all the viruses listed by the who also occur on these lists, alongside bacterial pathogens of concern. one of these is yersinia pestis, causative of bubonic and pneumonic plague, which is recognized by all three bodies (who, cdc, niaid) as a current priority following the exceptionally large and serious outbreak between september to april in madagascar [ ] , where the disease is endemic. in addition, niaid recognizes the added threat to human health posed by the acquisition of amr by pathogens and who has also published a priority list [ ] of bacterial species for which r&d is required to develop new antibiotics (table ) . globally, there are many regions of endemic disease which are maintained by reservoirs of zoonotic pathogens in the local wild animal species. these pathogens comprise viral, bacterial and rickettsial species and some have complex lifecycles, infecting an environmental (e.g. standing water) or animal reservoir and then being transmitted either by direct contact with man or indirectly, via an insect (e.g. mosquito) or mammalian (e.g. bat, civet, camel) vector, to man, from which they may be spread by human-tohuman transmission. (fig. ). an example of a serious and widespread bacterial infection is mosquito-transmitted plasmodium falciparum, causing malaria in many tropical regions. malaria causes significant morbidity and co-morbidity in these regions in which it is endemic. due to the complex life cycle of the causative bacterium, it has been challenging to achieve a vaccine for malaria. the most advanced candidate is the rts,s/as vaccine [ ] , which is undergoing a pilot implementation in three countries in sub-saharan africa, with a view to determining its impact on disease prior to a wider implementation [ ] . despite the availability of approved vaccines [ , ] , typhoid fever and cholera remain significantly debilitating enteric diseases in regions of the world where hygienic living conditions are poor and there is little access to health care. both infections are caused by bacteria (salmonella typhi and vibrio cholera, respectively) which exist in contaminated water and food. tuberculosis (tb) is a respiratory infection which is widespread globally. caused by mycobacterium tuberculosis, and transmitted to man from zoonotic reservoirs (badgers, cattle) with a high potential for subsequent human-to-human transmission, tb is prevalent in susceptible individuals living in overcrowded conditions [ ] . although the bcg vaccine has been in routine use for many years, variable efficacy has been reported, depending on region of use [ , ] with - % reported in the united kingdom but lower levels in equatorial countries. the emergence of multi-drugresistant tb (mdr tb) in recent years raises the bar for treatment of this disease and makes a high level of vaccine efficacy even more important [ ] . examples of zoonotic reservoirs which maintain endemic viral diseases are numerous and are summarized in table . in particular, viral endemic disease is caused by the coronaviruses (mers and sars) in saudi arabia and the eastern mediterranean countries; and by the lassa arenavirus, which is endemic in west african countries and caused a serious outbreak of lassa fever in nigeria in [ ] ; other viruses which are endemic and cause viral haemorrhagic fever include dengue, which is widespread in tropical and subtropical regions worldwide [ ] , the filoviruses (ebola and marburg) which have a zoonotic reservoir in bats in sub-saharan africa [ ] ; and yellow fever virus, which is prevalent in africa, central and south america and the caribbean [ ] . interestingly, the same mosquito (aedes aegypti) which spreads yellow fever virus also transmits the dengue, chikungunya and zika viruses [ ] . chikungunya virus has a widespread distribution in africa, asia, india and south america and with occasional cases in europe, and causes a debilitating, but rarely fatal, disease [ ] . zika virus emerged in brazil in [ ] , although it was first detected in monkeys in uganda as early as [ ] , and the first documented human case occurred in nigeria in [ ] . the large brazilian outbreak of zika viral disease culminated in , with thousands of cases reported [ ] . rift valley fever virus (rvfv) is another zoonotic virus which is endemic in sub-saharan africa and primarily infects cattle, sheep and goats, but can be transmitted to man by mosquito bite to cause an acute fever [ ] . an example of a bacterium which has been classed as a re-emerging pathogen and which is endemic in global regions is y. pestis, causative of plague. bubonic [ ] [ ] [ ] . over thousands of years, y. pestis has evolved away from the enteric yersinia species to become a lethal flea-transmitted bacterium [ ] . it is transmitted to man, typically from a zoonotic reservoir in infected rats or other rodents (e.g. ground squirrels or prairie dogs), by flea-bite to cause bubonic plague [ ] (fig. ). if not detected and treated, this can develop into either septicemic plague or the most serious form of all, a secondary pneumonic plague. in turn, individuals with pneumonic plague can transmit this by aerosol droplet to others, to establish a primary pneumonic plague infection. each year, a few cases of plague are also reported in the southwestern united states, where the disease has been endemic in the rodent population since the late s [ ] . as well as infecting the rodent population, infected fleas can spread y. pestis to other wildlife species (e.g. rabbits/hares or, rarely, domesticated animals [ ] ) which, in turn, raises the potential of transmission to man by inhalation to cause a primary pneumonic plague. in endemic areas, outbreaks of plague are often associated with seasonal environmental changes, causing rodents to stray closer to human habitation. the plague outbreak in madagascar during / was particularly serious, with an estimated cases and deaths ( · % fatality rate) [ ] . this outbreak was approximately sixfold greater than usual, with an unusual predominance of pneumonic, rather than bubonic plague. although y. pestis is susceptible to antibiotics, such as the aminoglycosides (gentamycin, streptomycin), the fluoroquinolones (e.g. ciprofloxacin) or tretracyclines (e.g. doxycycline) [ ] , these need to be administered very early to a suspected plague case, and ideally before symptoms emerge. additionally, there have been reported instances of antibiotic resistance including to multiple antibiotics [ , ] . hence, there is a clear and increasingly urgent need for an efficacious vaccine. other bacterial endemic diseases include melioidosis and glanders which, although not caused by zoonotic pathogens, are endemic in southeast asia where the bacteria reside in soil and are transmitted to humans through occupational exposure, e.g. working in paddy fields [ ] . another bacterial disease which is endemic in the northern hemisphere is tularaemia, caused by the bacterium francisella tularensis, which has zoonotic reservoirs in the rabbit, hare and rodent populations in the south, central and western united states and is transmitted to man by ticks and biting flies [ ] . rickettsial species, such as coxiella burnetii, causative of q-fever, comprise bacteria which exist within another cell, and as such q-fever is contracted when humans are exposed to aerosolized droplets from the urine, milk, faeces or birth detritus from infected sheep, goats and cattle [ ] . for all these pathogens, there is a requirement for efficacious approved vaccines to curtail or prevent regular disease outbreaks. for some of these pathogens (e.g. rvfv, cchf) there are vaccines [ ] , but these are not widely available [ ] or have been used and withdrawn for safety or regulatory reasons (e.g. the live vaccine strain for tularaemia) [ ] or they are not universally suitable, requiring a screening test prior to administration due to the potential for a hypersensitivity response (as for the vaccine for q-fever) [ ] . there is no readily available licensed plague vaccine, although a series of killed whole cell vaccines (kwcv) has been produced and used in the past, mainly in the biodefence context (reviewed in [ ] ). additionally, live attenuated plague vaccines, derived from an attenuated mutant strain as the ev series, have been used in the former ussr (fussr) and are still used in asia, notably in russia and china [ , ] . ev , the most commonly cited of these, provides protective efficacy against plague, but is licensed for human use only in countries of the fussr and is documented to cause serious adverse effects in non-human primates and malaise and adverse effects in human vaccinees [ ] . whatever the context, all these diseases would be positively impacted by the availability of efficacious and approved vaccines. however, to a greater or lesser extent they are all niche diseases with no major commercial incentives to drive vaccine development programmes. this is a space that non-governmental organizations (ngos) such as the coalition of epidemic preparedness innovations (cepi) [ ] and global vaccine alliance (gavi) [ ] have entered and they are supporting vaccine efforts for some of the diseases listed above. additionally, philanthropic funders such as the gates foundation are supporting vaccine r&d efforts [ ] . in the united kingdom, and subsequent to the ebola outbreak in west africa, vaccine networks for human and veterinary vaccines have formed to prioritize vaccine efforts in these respective contexts [ ], while the department of health, together with innovate uk, has supported r&d of vaccine candidates for the prioritized pathogens [ ] . as a result of these global initiatives, a number of candidate vaccines are being developed for emerging bacterial and viral pathogens, examples of which, although by no means exhaustive, are cited here [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . who reports ongoing global vaccine r&d efforts [ ] and also tracks the progress of clinical trials for emerging pathogens [ ] . here it may be worth drawing a distinction between prophylactic vaccination, i.e. general use prophylaxis (gup), given routinely and not necessarily in the face of specific, predicted outbreaks, in contrast to post-exposure prophylactic (pep) vaccination, to be given after a suspected exposure to a pathogen, or to ring-fence an outbreak or, indeed, post-exposure therapeutic (pet) vaccination, to be given after an actual exposure. in the pep and pet contexts, the benefit of vaccination vastly outweighs the risk of disease (i.e. the risk : benefit ratio is low), while in the prophylactic context the risk : benefit ratio may be greater than, or equal to, · ). for infections with short incubation times, e.g. less than h, as for pneumonic plague, pep or pet vaccination may only be useful if administered under antibiotic cover. in the united states, once a vaccine candidate has been thoroughly tested for safety in non-clinical models, and in an escalating-dose, statistically powered, phase i design in the clinic, from then on it may be possible to pursue approval for an eua, rather than pursue the full-length pathway to biological licensing authorization (bla). this can enable the earlier availability of vaccines for use in endemic regions. however, it should be noted that eua is only available through the food and drug agency (fda) in the united states. some alternative regulatory mechanisms that may be considered prior to licensing are outlined below. from the discovery phase to the clinic, vaccine development requires the completion of a series of steps represented as a generic outline in fig. . the regulatory agencies lay down specific guidance for these steps [ , ] and this review presumes no authority in this regard, but seeks to give a generalized overview of a generic vaccine development process. exit from the discovery and preclinical phases requires substantive data demonstrating immunogenicity and efficacy in at least one suitable animal model(s). where possible, efficacy in the animal model should be demonstrated by direct exposure to the pathogen concerned. technology transfer for manufacture under good manufacturing practice (gmp) will require a demonstration of known provenance of all essential materials required in the manufacture of the vaccine candidate. this includes seed stocks of cell lines from which recombinant proteins may be expressed, e.g. escherichia coli, human embryo kidney cells, baculovirus, tobacco mosaic virus; or seed stocks of attenuated vaccine vectors, e.g. viral vectors such as adenovirus, vesicular stomatitis virus, modified vaccinia ankara; or bacterial vaccine vectors, e.g. salmonella, listeria; the genetic constructs cloned into the cell line in question; all culture media and components and all formulations and excipients. transfer of the manufacturing process to gmp may include scale-up and conversion to, for example, fermentation conditions, or to plant-based, mammalian cell line or insect cell line expression on an expanded scale. this transfer will probably require the demonstration of consistency between consecutive batches at gmp, which will also enable the development of scaled-up downstream processing methodology. vaccine components (the drug substance) from these batches may be formulated (the drug product) as required and used in safety/toxicology studies and for immunogenicity/efficacy in an appropriate second animal model, which will be as representative as possible of the human response. the second animal model is often, but not necessarily, a non-human primate, and the selection of this second model will depend entirely on the vaccine indication. there will also be a requirement to generate sufficient stability data on both the drug substance and the drug product and to demonstrate that the drug product is stable for at least the duration of the intended phase i clinical trial under prevalent conditions in that location. clearly, extended stability testing under a range of conditions, including accelerated conditions (high ambient temperature and relative humidity), will also be required to progress the vaccine through development. as well as determining its stability, both the drug substance and product will require characterization for properties such as identity, purity, isoelectric point, osmolality, endotoxin levels and potency, to demonstrate consistency between batches and to allow for release of these for clinical trials. it is essential to ensure safety of the drug product before entering a clinical trial, and the drug product may be tested in suitable small animal models for the absence of adverse effects under conditions of repeated dosing at the anticipated human dose level, as well as in the intended human schedule, but at multiples of the anticipated human dose-level. the use of rodent models (mouse or rat) for this testing allows for sufficient statistical powering of such safety/toxicological testing. if the clinical trial is to be conducted in women of child-bearing age, it may be necessary to carry out reproductive toxicology testing of the drug product; in this case it may be necessary also to use a sensitive rabbit model and to administer the vaccine to pregnant rabbits to screen for adverse effects in the mother and potential teratogenic effects in the f generation. the national regulatory authority will expect to review the existing safety data and outlines of further protocols to be used. a review of all the data pertaining to the candidate vaccine will be required by the regulators in order to proceed to a clinical trial. depending on the specific requirements of the regulatory authorities in the country of origin/manufacture of the vaccine and also the intended location of the clinical trial, this may take the form of an investigator's brochure, protocol and summaries of manufacturing, non-clinical and clinical data in a clinical trial application (for the european medicines agency, ema) or an investigational new drug (ind) application (e.g. us fda). other international regulators (e.g. in canada, japan and china) will have variations on the documentation required. in the united states, the alternative approaches to full marketing approval that are available for vaccines under development and which may be considered through the fda are to either request an eua or to request expanded access (ea), sometimes called compassionate use. the eua is issued in support of potential and actual public health, military and domestic emergencies involving chemical, biological, radiological and nuclear agents (cbrn), including emerging infectious diseases, e.g. pandemic influenza. such fda-approved medical products which may be stockpiled for use in emergencies are referred to as medical countermeasures (mcm) and include biological products, e.g. vaccines, drugs and devices. specifically, the eua authority is separate and distinct from use of an investigational medical product held under an ind and must be able to treat serious or life-threatening diseases or conditions. in contrast, ea submissions are for products used under an ind or a protocol (treatment plan), or submitted as a protocol amendment to an existing or new ind. the ea categories cover use under either an individual patient ind or protocol, individual emergency ea use, or ea for an intermediate-size population or for widespread use (large populations). other us regulatory programmes for biologicals and drugs to treat serious or life-threatening conditions include fast-track designation, breakthrough therapy designation, accelerated approval pathway and priority review designation. in canada, access to drugs through special access programmes (saps) exists for serious and life-threatening conditions, when marketed alternative products are not available or unsuitable and evidence supports the intended use. priority review of marketing submissions and 'notice of compliance with conditions' for such products may also be considered and granted by health canada. in the european union, the ema supports early patient access to new medicines and which are eligible for a marketing authorization application under the centralized procedure and either target unmet medical needs or those which have a major public health interest. the ema has launched a priority medicines (prime) scheme to facilitate early dialogue and support the development of medicines that target unmet medical needs and which promotes an accelerated regulatory assessment. in addition, the prime scheme is intended for seriously debilitating or life-threatening diseases, compassionate use of unauthorized medicines for patients with an unmet medical need (when no satisfactory treatment is available in the european union) and also provides conditional marketing authorization. the regulation and rules of access to compassionate use programmes varies between national government authorities across eu member states. in the united kingdom, the early access to medicines scheme (eams) gives patients with life-threatening or debilitating conditions access to innovative medicines without marketing authorization, but for which there is a clear medical need. a two-stage evaluation process initially considers promising innovative medicine (pim) designation before an eams scientific opinion. also in the united kingdom, the potential supply of unlicensed medicinal products (specials) may be considered by the medicines and healthcare products regulatory agency (mhra) for the importation of medicines that have marketing authorization status from countries outside the united kingdom and european union. where there is an unmet need of priority to the who for a new vaccine, the who may establish a blueprint programme [ ] . as vaccine candidates for the specific blueprint programme advance through the development process, and particularly when they have attached clinical data, the who may run a prequalification check to determine whether the candidate meets their requirements on behalf of un agencies that will ultimately purchase vaccines [ ] . to do this, who will engage with subject matter experts to draft and publish a target product profile (tpp) for a vaccine requirement. who will use its scientific advisory group of experts (sage) to review vaccine candidate performance against the tpp and to prequalify a vaccine candidate(s) which fulfils the tpp. assuming that the preclinical safety and toxicology testing has been satisfactory, a protocol for phase i testing of the vaccine candidate may be submitted to the regulatory authorities for approval. the primary objective of the phase i clinical trial is to test the vaccine candidate for safety in informed and consenting adult volunteers who will be selected according to pre-agreed inclusion/exclusion criteria. as this is the first time the candidate is being used in man, the phase i trial is typically small and cautious. if a range of dose-levels is being tested, it may be necessary to dose a sentinel group of single subjects from each arm of the study to assess safety through week of immunization and starting at the lowest level before proceeding to the next level. the data from the sentinel group would be reviewed before proceeding with the main study. then the first cohort would be dosed at the lowest level before proceeding to the next level, and so on. volunteers will be closely monitored for adverse effects in the clinic at each dosing time-point and will typically maintain a diary at home to record any symptoms arising between time-points. an independent safety monitoring panel, including medically qualified personnel, will be required to monitor the reporting of adverse effects. volunteers may also be blood-sampled to assess vaccine immunogenicity from baseline and serial samples, and depending on vaccine type may be required to supply additional samples which can be collected non-invasively, e.g. saliva/stool samples. all volunteers may be followed up for a pre-agreed period on completion of the study, to check for latent adverse events and to monitor, e.g. for maintenance of circulating antibody titres or memory response to the vaccine. the second phase of clinical trials typically allows for an enlarged study to assess vaccine safety and to monitor immunogenicity. during this phase, significantly expanded cohorts of volunteers may be dosed with vaccine at doselevel(s) selected as optimum from the phase i trial and can be monitored for safety and a more detailed immunogenicity assessment, which may include assays of both serological and cellular memory responses. once again, volunteers may be blood-sampled for baseline and serial serum/plasma samples, and depending on vaccine type may be required to supply additional samples which can be collected non-invasively, e.g. whole blood/saliva/stool. in the event that a phase iii trial for efficacy is not feasible, for ethical or practical reasons, it may be necessary to plan a blood-sampling regimen in the volunteers which will enable sufficient sample volumes to be available for animal rule studies (discussed below). if sufficient safety data are gained from a phase ii trial, the regulatory authorities may be able to consider the vaccine for eua. the third phase of clinical trials is typically designed to assess efficacy. however, where this is not feasible for either practical/logistical or ethical reasons, phase iii could be regarded as a further, significantly enlarged trial for vaccine safety with adequate follow-up of vaccinated volunteers. a phase iii field trial of vaccine efficacy may be feasible in the event of an anticipated seasonal outbreak, in which case vaccination could be given prophylactically and well in advance. as long as effective biosurveillance programmes are in place to instigate a rapid response to new infections in an unvaccinated placebo cohort, the latter group may be included in a prophylactic efficacy trial. conversely, reactive mode vaccination in the context of an actual outbreak is likely to be more complicated, as it would be unethical to omit anyone at risk of infection from the vaccination programme. hence, sufficient safety data on the candidate vaccine would be required in case of need to administer it to pregnant/nursing mothers, children and elderly people as well as to the general adult population. additionally, it may be necessary to administer an adjunct to the vaccine, such as an appropriate antibiotic, to both cohorts (vaccinated and placebo). whatever the context, careful consideration of the trial design needs to be made and approved by the regulators to achieve adequate statistical powering and to determine the need to provide supplementary antimicrobial therapy, and also the need for a placebo cohort. after the anthrax letters incident in the united states in in which anthrax was released through the postal system, resulting in five fatalities and widespread anxiety [ ] , the fda issued the animal rule (fda cfr) [ ] to expedite the development of vaccines and therapies for biothreat agents for which it is neither feasible nor ethical to carry out phase iii efficacy studies in man. in this situation, the animal rule makes provision for the substitution of animal efficacy data for human efficacy data. the animal efficacy data should demonstrate a reasonable likelihood that the candidate vaccine or therapy would be efficacious in man [ ] . the animal efficacy data should be provided ideally from more than one animal model, or from one model only if that model is well-characterized and authentically represents the human disease syndrome [ ] . in addition, the fda may require supporting data to include pharmacokinetic/pharmacodynamic (pk/pd data) and a determination of the pathophysiological mechanism of action of the biothreat agent and a 'reasonable understanding' of the protective mechanism of the proposed vaccine or therapy. thus, if the candidate is a vaccine, a reasonable understanding of the protective mechanism(s) being invoked by it requires an identification of the immune correlates of protection. immune parameters which correlate with protection in the selected animal models may include the total titre of circulating antibody induced to the vaccine and the determination of a minimum cut-off titre required to confer protection. alternatively, the titre of functional or neutralizing antibody within that total may provide the correlate, particularly where the neutralization of specific virulence factors produced by the biothreat agent is identified and quantifiable [ ] . for some vaccines, the induction of a cellular memory response instead of, or in addition to, circulating antibody will provide the correlate. this is measurable by the ex-vivo recall response of peripheral blood mononuclear cells (pbmcs) on stimulation with the vaccine antigen(s) [ ] . in the absence of direct efficacy testing in the human vaccinee, the immune correlate identified above provides a surrogate marker of efficacy. if this is a functional antibody, the titre induced in man needs to be compared with the titre required in the animal model(s) to provide protection. this can be achieved, for example, by the in-vitro neutralization of a specific virulence factor, or by a competitive enzyme-linked immunosorbent assay (elisa), where the test antibody is competed with a known neutralizing antibody for binding to the target antigen or by the passive transfer of antibody from a human vaccinee into a naive animal, followed by pathogen challenge [ ] . whatever the immune correlate may be, its effect would be expected to follow the pattern shown in fig. , where as the value increases, the likelihood of death in the vaccinee decreases [ ] . thus, vaccine efficacy = relative reduction in risk of death = − (% of vaccinated subjects at < protective level) (% of unvaccinated subjects at< protective level) . although a number of immunotherapies and pretreatments have been licensed under the animal rule, the first vaccine to be licensed in these circumstances is 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emergence of sars review of bats and sars naiad/nih priority list of pathogens. available at cdc priority list of pathogens. available at the plague outbreak in madagascar: data descriptions and epidemic modelling who priority list of bacteria rts,s malaria vaccine efficacy and immunogenicity during plasmodium falciparum challenge is associated with hla genotype malaria vaccine implementation programme (mvip) -programme advisory group vaccines for preventing typhoid fever global economic evaluation of oral cholera vaccine: a systematic review diagnosis and treatment of tuberculosis: latest developments and future priorities efficacy of bcg vaccine in the prevention of tuberculosis variation in protection by bcg: implications of and for heterologous immunity drug-resistant tb: deadly, costly and in need of a vaccine genomic analysis offers insight into nigeria lassa fever outbreak ecological niche modeling for filoviruses: a risk map for ebola and marburg virus disease outbreaks in uganda sep yellow fever in africa and the americas: a historical and epidemiological perspective zika, chikungunya and dengue: the causes and threats of new and re-emerging arboviral diseases chikungunya: bending over the americas and the rest of the world the zika virus epidemic in brazil: from discovery to future implications zika: the origin and spread of a mosquito-borne virus zika virus outbreak of zika virus infections the pathogenesis of rift valley fever ecologic features of plague outbreak areas, democratic republic of the congo mechanism study on a plague outbreak driven by the construction of a large reservoir in southwest china (surveillance from - ) the natural history and incidence of yersinia pestis and prospects for vaccination yersinia pestis, the cause of plague, is a recently emerged clone of yersinia pseudotuberculosis plague into the st century yersinia pestis: examining wildlife plague surveillance in china and usa cat-transmitted fatal pneumonic plague in a person who travelled from colorado to arizona cdc plague treatment transferable plasmid-mediated resistance to streptomycin in a clinical isolate of yersinia pestis resistance of yersinia pestis to antimicrobial agents melioidosis in thailand: present and future tularemia transmission to humans: a multifaceted surveillance approach airborne geographical dispersal of q fever from livestock holdings to human communities: a systematic review and critical appraisal of evidence current status of rift valley fever vaccine development the use of veterinary vaccines for prevention and control of rift valley fever: memorandum from who/fao meeting protection induced by a francisella tularensis subunit vaccine delivered by glucan particles standardized guinea pig model for q fever vaccine reactogenicity plague vaccine development: current research and future trends developing live vaccines against plague russian vaccines against especially dangerous bacterial pathogens cepi new vaccines for a safer world about gavi, the vaccine alliance vaccine delivery:bill and melinda gates foundation dual route vaccination for plague with emergency use applications immunogenicity and safety of subunit plague vaccine: a randomized phase a clinical trial rift valley fever mp- vaccine phase clinical trial: safety, immunogenicity and genetic characterisation of virus isolates development of vaccines against cchf virus a monovalent chimpanzee adenovirus ebola vaccine boosted with mva effect of dengue serostatus on dengue vaccine safety and efficacy non-neutralising antibodies elicited by recombinant lassa-rabies vaccine are critical for protection against lassa fever chadox and mva based vaccine candidates against mers-cov elicit neutralising antibodies and cellular immune responses in mice vaccine and therapeutic options to control chikungunya virus chikungunya vaccines in the pipeline a bacteriophage t nanoparticle based dual vaccine against anthrax and plague who: health products in the pipeline for infectious diseases world health organization. who vaccine pipeline tracker yjurcmg xwo kvuyedybmzdcxqbyjgdczm/pubhtml# fda guidances for vaccine development vaccines for emerging pathogens: from research to the clinic. part regulatoryinformation/guidances/vaccines/default.htm ema guideline for vaccine development who guidance for clinical evaluation of vaccines who vaccine standards: vaccine prequalification. available at the anthrax vaccine and research: reactions from postal workers and public health professionals code of federal regulations (cfr) cfr . - . evidence needed to demonstrate effectiveness of new drugs when human efficacy studies are not ethical or feasible predictive models and correlates of protection for testing biodefence vaccines first vaccine approval under the fda animal rule the authors declare no competing interests. key: cord- -xi zy ow authors: allam, zaheer title: the third days: a detailed chronological timeline and extensive review of literature documenting the covid- pandemic from day to day date: - - journal: surveying the covid- pandemic and its implications doi: . /b - - - - . - sha: doc_id: cord_uid: xi zy ow this chapter surveys the global unfolding of events during the third days of the covid- pandemic that originated from china. the third days of the unfolding of the events showcased how city-wide lockdowns were started to be considered globally, the moving of the epicenter from china to europe, and major industries being impacted worldwide. to document this, an extensive review of the literature provides a daily overview of the situation covering health, economic, political, and social perspectives and outlines key events during the unfolding of the pandemic. this chapter surveys, and establishes a chronological timeline of the outbreak from day to day , covering issues appertaining to health policy and dwells into socioeconomic measures and impacts during the unfolding of the pandemic. the past days of the covid- pandemic had been eventful, as the reality of the disease was clear globally, where no single continent had been spared. the next days (day to day ) were marked with major milestones, challenging and most trying in different spheres of life as is demonstrated in succeeding sections. to start with, during this period, the number of confirmed cases increased from slightly above , to a high of million and counting (spotlight, ) , with the number of casualties increasing from deaths to over , deaths across the globe by the end of the days. in addition, the number of affected countries increased from countries to countries and territories (worldometer, ) . another change that was witnessed within the third days is the shifting of the covid- pandemic epicenter from europe to the united states, where the numbers of confirmed cases in the country, beingdby that timedmore than a quarter of the confirmed cases in the rest of the world (kirby and stewart, ). as the impacts of the coronavirus continued to be felt, there was evidence of an economic downturn in different countries, including in developed economies, where the number of people filing for unemployment claims increased. due to the economic hardships, it became apparent that many countries were trying to ease the lockdown restrictions to allow for reopening of economies, but in a gradual and cautious manner to avoid the reemergence of cases. it is within these days that governments were seen to propose economic stimulus packages to bail out their citizens and economies, including companies that were already struggling due to reduced activities. at the same time, due to the economic and social strives, there was evidence of political tension between countries as they trade blame on responsibilities toward containing the coronavirus before it spread, and become global pandemic (business davidson, a; smith, ) . during these days, it also became clear that the world was a long way before a vaccine could be developed and thus, the demand for personal protective equipment (ppes) would continue, and we see countries and regions formulating policies to control the exportation of ppes and medical supplies to other countries. with the increasing scarcity of ppes and other basic, medical essentials, these were seen to rely on the world health organization (who) and well-wishers for the supplies. within these days, there is also evidence of there was no safe-haven against coronavirus, as even those in cruise ships and aircraft carriers were infected and with cases in such places spreading faster (cna, c; gajanan and mansoor, ; kaneko and kim, ; willsher and sabbagh, ) . it also dawned that even those in positions of power and authority are not immune to the virus, where some even succumbed to their injuries. within these days, it also became apparent that every single sector is highly dependent on the health sector, as those like sports and entertainment, religious sectors and others remained "grounded" with some high profile events such as professional football leagues, olympics, and wrestling being canceled, postponed, or suspended indefinitely (bbc sport, ; cacciola and deb, ; schad, ) . during this period also, it becomes apparent that it is possible for technology companies to set aside their competition and come together for the common goal of humanity (apple, ) . therefore, even as events of these third days had been devastating and heartbreaking, there is much that humanity can learn, and have learned, and going forward, even after the covid- is finally phased out, as people, governments, regions, and economies embark on rebuilding, some of the positives that have been learned will need to be kept alive. the following sections document the unfolding of the pandemic. during this month, every effort counted in the fight against the spread of covid- , and this was emphasized by the events of march . on this day, finally, the who conceded that without a doubt, coronavirus amounted to a global pandemic (who, ad) . the build-up to this global pandemic announcement saw a national wide lockdown declared in italy on th following an uncontrollable and astronomic increase in the number of new cases and deaths in the country (bbc, c) . following this, the country was beginning to experience unprecedented abandonment by its neighbors and country members of the eu who had continued to issue a travel advisory to their citizens against traveling into or from italy (gov.uk, a) . unsurprisingly, by th, all eu member states had experienced the outbreak of the covid- disease, and most of the first cases were related to travelers fleeing italy after the situation therein started to worsen (who, ad) . in north america, the situation in the united states was also getting out of hand, with over states including arizona, washington d.c., michigan, colorado, vermont and rhode island, and others declaring states of emergency (razek, ) . here, on march , the united nations headquarters in new york closed its doors to the public for fear of spreading the virus (krisel, ). as the situation escalated, with over confirmed cases in the country, and over deaths from the virus, the national basketball association (nba), one of the most popular and fancied sporting activity in north america abruptly suspended its season, as of march , when a player of the utah jazz tested positive for coronavirus, just before their game with oklahoma city began (cacciola and deb, ) . these unfolding attracted a host of intervention measures in the country to ensure people would observe the health guidelines, especially by staying at home and keeping social distancing. first, on march , vice president pence announced that medical insurance companies had agreed to waive all copayments on covid- testing and also extended their coverage for the treatment of the disease (office of the president, b). similarly, the country, through homeland security, announced a level travel advisory and subsequently temporarily restricting entry to all foreign travelers from china, iran, and certain countries of europe. the restrictions also demanded that all american citizens and legal permanent residents and their immediate families returning from countries already affected by the virus must undergo a self-quarantine for a minimum of days upon arrival (homeland security, ) . this announcement was affirmed by the oval office address by president trump stating that travel advisory applied to all the countries in the schengen area (collinson, ) . the decision by trump was disapproved by the eu leaders (gaouette et al., ) . elsewhere, to control and reduce the spread of the virus, the schooling system in different countries was seen to be disrupted. as of march , a un report indicated that about % of students across the globe were out of school and this included countries like italy, czech republic, part of spain (madrid region), greece, and austria among many others that took the decision of closing the school to protect students and their families, as a mean to comply with who's health guidelines (who, p) . surprisingly, as countries hastened to close down schoolsdhighlighting the worsening of this situation, reports from china indicated that normalcy was returning to a point that some schools were reopening especially in qinghai province (cgtn, ) . in regard to financing efforts against this disease and supporting technological advancement in the development of test kits and vaccine development, on march , the bill & melinda gates foundation, mastercard, and wellcome together committed approximately $ million (bill and melinda gates foundation, ). on the same date, the coalition for epidemic preparedness innovations on its part committed an extra $ . million to render the organization's total investment in vaccine development to $ . million, with the funds expected to help both the company novavax and the university of oxford to research and develop a vaccine for this disease (kff, ). furthermore, on march , the united kingdom announced more funding ($ . million) , this time from its national budget to aid vulnerable countries in their efforts against covid- (gov.uk, b) . two days after declaring the coronavirus a global pandemic, circumstances in the western part of the globe have led the who to make another declaration; this time, the new epicenter of the outbreak of coronavirus was europe (who, ae). this announcement was not surprising as of then, italy was already overwhelmed ( , cases and deaths already) (snuggs, ) , and spain had in the day declared a state of emergency (cnbc, ) . things in other member countries of the union were also worsening, with the region recording over deaths in a span of h from the disease, and over new cases in the same period (who, c) . and surprisingly, from the situation report by the who (who, c), all the cases in each of these countries were of local transmission; thus, warranting the decision different countries were making to restrict movements, and where possible, instituting total lockdowns like the case of italy. on the western side of the globe, more states in the united states were declaring a state of emergencies, restricting the number of people in gatherings, closing all learning institutions, and restricting movements among other things. these happenings were more pronounced on march , and when the worse came to worst, present donald trump, under the robert t. stafford disaster relief and emergency assistance act (stanford act), declared a state of national emergency (office of the president, a). by then, the number of cases in the united states had increased to and those who died from the disease reached deaths, with transmission happening locally (who, j) . in total, the global number of confirmed cases had reached a high of , cases, with of those reported in the past h. of the sum, , had been confirmed from countries, of which were reporting their first cases. the remaining cases were reported in china, where situations were coming back to normal, with only new cases reported in the populous country, and deaths were reported in the -h period. wuhan, the former epicenter only recorded five confirmed cases (reuters, c) . outside china, the deaths increased by , raising the total tally to cases (who, c). following these unprecedented unfolding globally, economies were facing numerous challenges, as most economic activities had stalled or were nonexistent. for instance, in the united states, the stock exchange recorded the lowest point, only reminiscence with situations of (mccabe and ostroff, ). for this reason, different agencies introduced financial packages to offer some support. for instance, the adb announced a $ million package that could be accessed by companies to supply critical essentials for combating covid- (adb, ) . in europe, the european bank for reconstruction and development is reported to have approved a $ . billion financial package to help companies in the region to remain afloat during this period the region was experiencing the most trying moment in the recent history (williams, ) . amid the challenges of covid- and its impacts, some countries like taiwan found some solace in the use of technology to track and instill the mandatory quarantine, especially for those coming from certain areas. with technology, enforcement officers were able to know those who were flaunting rules and their whereabouts, and this helped reduce the spread of the virus, despite it being just kilometers from china where things were worse some days ago (yun, ) . in europe, there was some use of technology, especially mobile apps, that helped in mapping and tracking cases, and to bolster this even further, the european commission (ec) was offering funding to a tune of v m ($ . ) for start-ups or small medium enterprises (smes) developing technologies with capacities to treat, test, monitor, or offer other aspects that could help in the fight against covid- (euroean commission, a). in the past month since the first case was confirmed in africa, the number of countries affected in the continent increased to by march , with seven reporting their first case in a span of h. also, a week prior, the number of cases in the continent was only , but they increased to with six deaths reported to have been imported, except for south africa, algeria, senegal, and cameroon (who, k) . in europe, most countries were receiving unprecedented numbers of new cases, especially in italy, spain, france, and germany, which recorded , , , , and new cases, respectively, and almost all cases in most of these eu countries were locally transmitted (who, k). the number of deaths in the region was also rising with italy losing people in a single day (snuggs, ) , while spain lost , france , and the united kingdom lost lives. in germany, which was reported to have embarked on mass testing as early as the situation warranted so, the number of deaths was relatively low (only two reported by th) (who, k) . following the dire state in the region, the european commission published guidelines (euroean commission, b) on the exportation of ppes out of the region. among such guidelines were the restriction of exportation of the said equipment unless with express green light from the eu member states. however, the eu was categorical that the measures taken were only within a specified period, especially during that period when those ppes were greatly needed locally; and thus, it was not a total ban on export, which would contravene the region's international obligations in matters of trade (euroean commission, b) . in the middle east, the severity of the disease was still present in iran, which until th had a total of , confirmed cases and deaths, with a high of deaths having been reported in a period of h. the situation in other countries within the region was controlled with only deaths reported ( in iraq, in lebanon, and in bahrain). in the american region, only a few confirmed cases were reported, and only deaths were reported in ecuador. however, the government there continued to institute proactive response measures to ensure the spread would be contained. for instance, the cdc announced that no gathering would be allowed in the united states that have more than people, thus putting into disarray functions such as weddings, concerts, and sporting events among others that are known to attract a large crowd (the new york times, a). more states declared a state of emergencies, while more schools in different states (more than states), including new york city with over . students (shapiro, ) calling for the closure of schools. one major news in the united states on that day was the negative test results for the country's president, who a few days ago had some contact with a brazilian official who turns positive after the testdprompting president trump to undergo testing (education week, ) . in other places, country borders were being closed. for instance, after confirming their first covid- cases, kazakhstan and uzbekistan closed their borders (reuters, j) . colombia also closed its border with venezuela, while turkey, with one of the leading airline services globally, suspended flights to nine european countries (liptak, ) . lebanon reported to have called for a -day lockdown in the entire country to curb the spread of the virus, which for the past week had claimed the lives of three people (france , b). the other goods news of the day came from south korea, which had shown a great resolve in bringing down the number of new cases, and this was bearing fruits after it implemented a number of strategies that involved the use of advanced technologies. first, it adopted the use of drive-thru clinics where people could be tested within min and receive their results the following day. this allowed them to test over people per hour, as there were such clinics countrywide, where six people were being tested in an hour per clinic (choon, ) . the strategy also reduced local transmissions as contacts were greatly reduced. the country also implemented the use of mobile apps to enforce quarantines and track the spread of the virus (park, ) . the success of the drive-thru clinics and apps were later adopted by the united states and germany (yamey, on th, the health landscape in different regions changed even further, with the western pacific region having the highest number of confirmed cases, mostly because of china. the european region was on its knees, health-wise, with , confirmed cases, with of these being reported in a single day. the number of deaths in this region had also increased by to take the region's tally to deaths. both north and south american regions had cases, and a total of deaths ( deaths reported in a day). the african and the south-east asia regions were relatively saved until then, with only and confirmed cases, respectively, and total deaths for both regions being (who, l). following the dire need in the european region, the eu closed its borders except for essential travels. russia also closed its borders, only allowing its citizens and legal permanent residents to travel back. spain was also reported to have instituted border restrictions for all noncitizens and residents. in france, besides instituting border restrictions like a majority of its eu counterparts, it also announced a countrywide lockdown, which meant that no gathering of any size would be allowed, with people expected to remain at home with some exceptions (onishi and méheut, ) . similar events of widespread lockdowns and border restrictions were also observed in latin america, with countries such as venezuela and peru leading the cue in countrywide lockdowns. colombia and costa rica also instituted border restrictions and control. however, brazil, which by then (march ) had the most confirmed cases in the region, overlooked all the measures that the rest of the world were implementing, and had a section of its population (supporters of their president; jair bolsonaro) demonstrate against his opponents (harris and schipani, ) . in iran, the government was forced to release over , prisoners as a way of curbing the spread of the virus in the country, which was already at alarming levels (hawkins, ) . as the global social fabric was being dismantled by the disease, its impacts were being felt in the economic sphere. for instance, on th, the airline industry in the united states was seeking government financial assistance of up to $ billion to help them remain afloat (sider and mann, ) . the dow jones industry also recorded its historical low after dropping . points; the worst day crash since the "black monday" crash (millhiser, ) . following those uncertainties and the threat covid- posed to the global fabric, a number of well-wishers and philanthropists were seen to be in the frontline of helping countries win this war. on th, the jack ma foundation donated assorted ppes and testing kits to the united states , which greatly needed these following the increasing demand, and the disruption of supply chain following the slow activities in china. on th, the world bank group committed another $ billion to help in the fight against the diseases (the world bank, b), while on the same day, bloomberg philanthropies gave a financial package of $ million, especially to help low-x and middleincome economies (bloomberg philanthropies, ). as the dark crowd of coronavirus continued to spread in italy, its impacts were becoming evident, as in a month, the number of deaths ( ) in the country surpassed those in china ( ) since the onset of the outbreak to march (quinn, b) . its health sector was completely overwhelmed with images of dejected nurses trending on social media, and while that was happening, china reported no new confirmed cases attributable to local infection, as the new cases that it confirmed were suspected to have been imported from other countries (siobhán o'grady et al., b) , as it had started to ease its border restrictions. the number of new cases in italy also increased by cases, bringing their country total to , , becoming the second most affected country after china. as for the european regions, italy recorded a total of over , cases on both th . the number of deaths for both days totaled , far much more than the rest of the regions combined. in the americas, new cases on th were : almost double of what was recorded the previous day ( new cases on th). the eastern mediterranean region recorded new cases to push their region total to , , and the number of deaths in the region reached after ( died on th), with most of these coming from iran. in total, the global confirmed cases had increased to , cases on th after , more cases were reported. the number of total deaths globally increased by a total of to reach a global tally of cases (who, m). on local scenes, the disease affected some prominent people, celebrities, and sports personalities. for instance, in the us nba teams, denver nuggets (wimbish, ), los angele lakers (whitcomb, b) , philadelphia ers (zagoria, ) , and boston celtics (ward-henninger, ) reported that each had some of their players confirmed positive, but they decline to give the names of those players. on the same land, congress representatives, ben mcadams (d-utah) and mario diaz balart of florida, confirmed that they had also contracted the disease (helsel, ) . in washington, two employees of the world bank group tested positive on the th with fears that more could have been affected. on the th, there were reports that prince albert of monaco also tested positive for covid- (romo, ) . another person is the executive director of the world food program, david beasley, who also tested positive after returning from canada (world food program, ) . to respond to the numerous cases and scenarios prompted by the covid- case, different regions, individual countries, and agencies adopted different and diverse measures. for instance, in india, the government was reported to have banned any export of ppes, ventilators, and certain medications and supplements as such were not enough locally (suneja, ) . in addition to this, to reduce further spread, especially from imported cases, it closed its borders for incoming flights (business today, b). in the united states, the number of interventions was observed, for instance, the two june scheduled party primaries in connecticut were postponed (pramuk and dzhanova, ) . president trump also signed into law the family first coronavirus response act that would see most americans receive a family relief of $ . the act also gave $ billion to be accessed by smes (erica werner et al., ) . the university of hong kong received $ , from the coalition for epidemic preparedness innovations to continue with vaccine testing for covid- (galford, ) . on the th, the rockefeller foundation committed a $ million to assist in response to covid- , especially in cities such as nairobi, new york, washington, bangkok, and bellagio (rockefeller foundation, ). since the onset of the coronavirus, there had been a theory that it was mostly affecting older people, but the who debunked this, by indicating that data on those affected in different countries and regions have shown that a significant proportion of those in hospitals are aged below years; hence, calling the younger generation to be also extra cautious. the organization also launched a health alert messaging services through whatsapp and facebook, demystifying the importance of technology in the fight against covid- , especially in sharing data and information (who, d). the organization also reported that it had reached an agreement with different producers in china who were ready to supply the organization with ppes, so that it could continue supporting countries in need of such across the world (schnirring, ) . while that was going on, they delivered an extra . million laboratory test kits for covid- to different parts of the world (watts and simon, ) . there was also news that first vaccine trials had begun, and the who together with its partners was to organize an international study dubbed solidarity trial in different countries aimed at trying different treatments that could be adopted to win over covid- (who, d) . regarding the reports on the spread and impacts of the coronavirus on this day (march ), the situation reported by world health organization indicated that the world was still in great danger of recording even more cases. for instance, italy reported the single largest number of deaths, where people died, and those confirmed increasing to , cases. in the united states, the cdc indicated that it had confirmed a total of , cases (cdc, ). as that was happening, president trump invoked the defense production act, to force general motors (gm) to produce ventilators to fill the gap after the situation in the hospital become dire (haynes, ) . on this, earlier on the day, gm rejected the move, prompting the president to apply his executive authority on them, and the new york governor equated the ventilators to missiles during world war ii (klein and raju, ) . the controversies in the united states were not over as it was reported that canada, through its prime minister, justin trudeau, would return all asylum seekers to the united states (austen, ). elsewhere, cuba invoked border restrictions for all noncitizens and nonresidents. it had delayed this decision to "keep its key tourism industry alive," but the threat of the coronavirus forced the president to take that crucial and bold decision (france , a). as time passes, the spread of the coronavirus virus took hold across the globe. on march , the who declared the virus outbreak as a global pandemic, and days later (on th), the director-general declared that the "pandemic is accelerating" (chappell, ) . and true to his word, in the past days, the number of new confirmed cases each day were averaging , new cases, to push the global total to , confirmed cases. the number of new deaths in those days was also increasing at an average of almost each day, and by rd, the total number of deaths had reached , globally (who, n). of great concern on those numbers is that most of them were coming from the european region, which by rd had reached a high of , confirmed cases and total deaths. the only regions that had shown a lot of resilience were the african region with only total confirmed cases and total reported deaths. the south-east asia region was also relatively spared having confirmed only cases and total deaths. the region of americas was showing worrisome trends, having reported a high of , new cases in a single day (march ) to push its total tally of confirmed cases to , cases and a total tally of deaths ( deaths) reported in a single day (who, n). while a majority of countries, especially in europe writhed in desperation from the impacts of covid- , china reported a third consecutive day with no local new case of coronavirus (the straits times, c). this meant that they could slowly transition back to their previous economic routine, and it also gave hope to those whose situation was worsening. in the other regions, including africa where confirmed cases were low, they were responding to the spread by escalating lockdowns and border restrictions (aljazeera, b) . other countries followed this trend. for instance, on march e , bolivia (reuters, b) , greece (stamouli, ), cuba (oppmann, ) , and the united kingdom (sparrow et al., ) imposed total lockdown in their countries (aljazeera, b) . egypt on the other hand called off all religious activities in mosques and churches for days (mourad, ) . during this period still, other countries including pakistan (reuters, n), vietnam, singapore (benner, ), uae, panama (aljazeera, b) , india, nigeria (reuters, m), and zimbabwe (the citizen, ) closed their borders to all foreign travels and nonresidents and banned international flights to or from their soils for a minimum of days. germany, on the other hand, banned gatherings of more than two persons, as cases in the country started to soar, while on the same day, spain extended the state of emergency for more days, as the situation internally was getting out of hand, with thousands hospitalized, and cases soaring each day (picheta, ) . the decision taken by each individual country was meant for the good of the citizens, but such also had a far-reaching impact on the economy. for instance, the banning of the international flights in these days, and others that had been instituted earlier mean that sectors such as tourism, hospitality industry, and others are grounded, with millions of workers employed in those sectors uncertain of what the future holds. in such circumstances, governments were forced to rely on external organizationsdlike the jack ma foundation, which on nd delivered a consignment of assorted ppes, and test kits to african countries to fight the covid- (meseret and meldrum, ). on rd, the world bank group's president was also pleading with bilateral creditors to extend debt relief to low-income economies to help them build some capacity that could allow them to fight the disease (bank, ) . while this was going on, african finance ministers were pleading for a $ billion economic stimulus in addition to the suspension of external debt to allow their individual countries to fight the coronavirus pandemic (uneca, ). china's progression toward containing the virus received a boost after the province of hubei was freed from the lockdown after almost months since the lockdown was instituted (associated press, ). it was a relief to the residents who, for such a long period, lived in fear and uncertainty of when they would return to their previous routines. the good news was that wuhan, the first epicenter of coronavirus was to open a month later, as the number of new cases had reduced significantly. in the last h, the entire country of china reported on new cases, of which, cases were reported to have been imported (cna, a). the number of deaths had also increased, with seven reported in the city of wuhan (the star, ) . the other good news came from germany where the chancellor's, angela merkel, the first test came back negative for coronavirus, but would undergo the same process a few days later to confidently confirm this result (mischke, ) . the fear that she would have contracted the disease came after a doctor who had attended her turned positive, forcing the chancellor into a safety procedure of self-isolation (mischke, ) . the day however did not present the good news to everyone, especially to governments, health workers, and security forces implementing lockdowns and other measures in different countries and to the general global population. on this, in the past h alone, the number of newly laboratory-confirmed cases neared , and the deaths on a single day accumulated to globally (cna, a). the most unfortunate report on this is that half of the new cases and deaths reported came from european countries ( , cases and deaths), with the american regions also experiencing a high of , new cases and deaths (who, e). regarding the accumulation of confirmed cases, it took at least months for cases to climb to , confirmed, and only days to reach , cases. from here, it only took days for the global total to surpass , confirmed cases, and even more startling, only days for the total to reach almost , confirmed cases. such trends prompted the international olympics committee and japan's olympic authority, led by prime minister shinzo abe, to postpone the olympics scheduled for summer to as more countries had expressed their fears of the virus (ramsay, ) , while others cited lack of preparation and other technicalities (aarons, ) . they also prompted the prime minister of india, narendra modi, to lock down the country for days, only a day after the later declared an immediate grounding of all flights in or out of india (shroff, ) . new zealand also went into lockdown (bbc, e), as australia announced a ban on all overseas travel (whiteman and sharma, ) . while in the united states, a troop of , us national guards was mobilized in states to help in response to the disease (gresik and altman, ), as it had already infected more than , people countrywide. while those were being mobilized, three of their colleagues in the navy (sailors) contracted the virus, when an aircraft carrier they were boardingdtogether with approximately other peopledset sail from vietnam. by now, the situation of covid- globally reached fever-pitch where the u.n. secretary-general antónio guterres argued that the disease was ravaging the whole of humanity, with approximately one-third of the population experiencing one or more covid- -related restriction (unicef, ). following this, there was shortages in all sectors, with the who warning that already, the world was facing a "significant shortage" of assorted medical supplies. on the social sphere, there was a shortage in the health sector prompting the un to launch a $ billion financial package on march targeting global humanitarian responses, especially to be advanced to vulnerable countries (un secretary-general, ). with the funds, those countries would manage to bolster their laboratory equipment, build and increase available sanitation (handwashing) stations, and increase medical supplies among other things. besides the financial package, the who was calling on developed economies to assist african countries with health machines such as ventilators and respirators as the continent cannot satisfy the demand for such, especially if cases of covid- were to increase (ighobor, ). those calls and interventions come at a time when most countries, especially in europe and america, were experiencing one of the darkest moments of their history. for instance, in spain, as of th, the number of reported deaths ( deaths) surpassed those reported in china ( ). but still, italy was leading in the number of people who had died with a total of , with having died in a span of only h. france had also started to lose a significant number of people as a result of the covid- , with already having succumbed in the past h. the islamic state of iran and the united states were also affected with (total deaths ) and (total deaths ) deaths having died in the past h. in regard to the number of confirmed cases, which were averaging , cases per day in the past days, the global total had increased to , by th according to the who data. africa was still showing some resilience despite reports of weak health system, with only deaths reported coming from confirmed cases across the globe (who, o). the economic situation globally was worsening, but even more in the united states where it was reported that by march , over . million american had filed for their employment benefit (casselman et al., ) ; a figure that is thought to be the highest in the history of the country. this could be attributed to the increasing number of people who were contracting the coronavirus especially in new york, which had become the epicenter of the outbreak in the northern american region, with the united states having more cases than any other country (kirby and stewart, ; the new york times, b). but, fortunately, the trump administration's stimulus plandworth $ trilliondwas unanimously passed the senate (carney, ) , thus allowing the government to offer some financial support, especially to those who continued to lose their livelihoods. elsewhere, more countries were responding to the pandemic by instituting lockdowns or other strict measures that would somehow suppress the local transmission. on this, on march , panama was reported to have suspended any form of domestic flights , days after, it had suspended international flights (aljazeera, b) . in thailand, the government declared a state of emergency forcing more areas within the country to shut down (techakitteranun, ) , while iraq and lebanon extended their curfews by days in each country. in russia, moscow shut down all forms of businesses and activities for a week (march to april ), except for essential businesses such as pharmacies and grocery stores (astapkovich, ) . the highlight of the day was the testing positive for coronavirus of uk prime minister boris johnson, which he announced to the world via a video on twitter (bbc, g). he reported that, henceforth, he would be in self-isolation and will continue working from. but, while this was breaking news, the greatest and most unfortunate news came from italy and spain. in spain, it had earlier been reported that it had recorded the highest number of deaths in a single day ( ) (rtve, ), but later only italy released its official report of the day where it indicated that approximately (who later reported (who, f)) people had died within a span of only h. italy had also confirmed new cases while spain reported new cases bringing the total confirmed cases to , and , cases, respectively. however, the united states reported the highest number of new confirmed cases ( , ), taking its total tally to , according to the data by who (who, f) but according to the us cdc data (cdc, ), the total number of cases reported in the country by th had reached , , thus leading globally. in the middle east, iran was reporting the highest numbers of new cases, with cases reported within h and new deaths during the same period (who, f). other countries in the region were relatively calm with no other reporting more than a cases a day. in africa, algeria reported the highest number of deaths ( ) (who, f) while south africa reported the first death from the virus. this death and the increasing number of confirmed cases in the country prompted the government to announce a -week nationwide lockdown (neuman, b) . elsewhere, china reported new cases and new deaths, in what seemed like a signal to a second wave of infection. following this, the government announced a ban on all foreigners, suspecting that they were the cause of this new trend in rise of cases, as out of those new cases, none were from local transmission (bbc, a; mai, ) . on the same date, the african development bank (afdb) provided aid to the continent with a $ billion social bond targeted to economic and social sectors facing stiff challenges from the impacts of covid- (afdb, ). at the same time, the who announced that the vaccine trial dubbed solidarity trialdthat it had announced about on march dwas to begin shortly, with the first trials administered to patients drawn from norway and spain, but overall, the trials would be extended to more than countries that had agreed to be part of the program (who, af). in the united states, the food and drug administration authorized the use of a -min diagnostic kit for coronavirus intended to speed-up the testing process, but a shortage of necessary equipment for collecting specimens was feared to derail the use of this kit (azad, ) . on the same land, donald trump, president of america, signed the $ trillion stimulus that was passed the previous day by the senate (foran et al., ) . even as the month of march came to an end, the incidences related to covid- continued almost unthwarted. for instance, the number of new confirmed cases for the past days has been increasing at an average of above , each day, and the number of deaths occurring each day likewise increased at an average of deaths. within the days, the total number of confirmed cases globally increased from , das captured by the who on march (who, f)dto , by march . another astonishing occurrencedespecially on march dwas the number of people that died in a single day in both spain and italy, which recorded and new deaths, respectively (who, p) . this happened while the number of patients being admitted to different hospitals in both countries exceeded their bed capacity and human resources allocation (cheng, ) . the united states was also going through thick and thin, as the number of new cases in the country continued to soar at alarming rates. even in africad which had shown some levels of resilience against the spread of this pandemicdthe numbers for the past days seemed to increase at an average of almost daily, with egypt, algeria, and south africa being the most affected (who, q) . in fact, the who's director-general highlighted the plight of the global health system and argued that there was a chronic global shortage of medical supplies such as ppes, ventilators, and other basic amenities required to saving lives (who, af). these unfolding events were happening amidst numerous responses and interventions both at local, regional, and international levels by government, international organizations like the who, the world bank, and others. among the new interventions that countries were implementing include the extension of the social distancing guidelines in the united states by president donald trump until the end of the following month (april ), and perhaps with a possible extension to june (shear, ) . the country had also accelerated the testing of individuals, and by th, the president announced that over one million people had been tested despite earlier hiccups in regard to faulty testing kits (tirrell et al., ) . in africa, on th, nigeria was reported to have directed the cessation of movement in two of its most populous cities, lagos and abuja, to reduce the chances of importation of the coronavirus to rural areas (akwagyiram, a) . in mexico, in a bid to reduce the soaring confirmed cases and growing number of deaths as a result of covid- , the government declared a health emergency (reuters, l) . in portugal, the government had resulted in treating everyone including foreigners with pending applications as permanent residents of the country so they could access public health facilities without encountering hitches (reuters, o) . but despite all those negatives, there was good news from the city of wuhan, which after undergoing a "dark moment" in the past months, saw authorities relaxing some quarantine measures, including rail services in and out of the city, meaning that people could eventually access the rest of the country (beaumont, ) . authorities in the province of hubei also announced that they would allow domestic flights to resume in all airports, except tianhe international airport in wuhan (xinhua, c) . the other goods news is that on , the bill & melinda gates foundation, wellcome, and mastercard together granted three institutions (the university of washington, university of oxford, and la jolla institute for immunology) financial support worth $ million to facilitate clinical trials for immunotherapies they were developing (mastercard, ) . in the wake of the new months, the reality of devastation of the covid- in different countries, regions, and globally was becoming clear. for instance, in spain, by april , the number of those affected reached , . but, by then, italy had more than these cases with , confirmed cases, while the united states, which had become the new epicenter, had , confirmed cases, as per the cdc data (cdc, ), while the who reported , (who, r). regionally, cases in europe reached more than half a million people ( , ), where , of those had succumbed to the virus. the region of the americas was the second most affected with a total of , confirmed cases and deaths. the western pacific region was the third hardest hit, with , infected and deaths. the eastern mediterranean regions had , confirmed cases and recorded deaths, while the african region had confirmed cases and reported deaths from the virus. overall, the global total number of confirmed cases had reached , , and an addition of , from the previous reported numbers. the number of deaths had also reached , , with a high of dying in the past h (who, r). by april , the global total exceeded the , , mark as per the john hopkins data, ncov .live, and other websites, but who reported the total numbers at , confirmed cases (who, g). the reality was reflected in the economic sector with the world bank reporting that the impacts of covid- pandemic would force more than million people into poverty (the world bank, a) . the reality of this statement was affirmed in the happenings in the united states, where it was reported that in a period of just week, . million more people filed for unemployment benefits, taking the number of those who had filed for the benefits to over million people (long and dam, a) . the same trends of unemployment were also being experienced in austria where the unemployment levels jumped to % in the country within the months since the onset of the pandemic (reuters, a) . the said reality prompted several unprecedented actions in different countries and organizations. for instance, on april , the un announced the postponement of the climate conference (cop ) scheduled for november due to covid- (un, ) . in the sporting world, the all england club announced that the wimbledon tennis tournament was canceled due to covid- , and this was the first time since world war ii that the championship was called off. on the same day, the health minister in italy announced that the countrywide lockdown would continue to be in force until the th of the month as the number of confirmed cases, and deaths continued to increase (reuters, i). the announcement was also confirmed by the country's prime minister giuseppe conte said that the situation in the country forced him to sign the decree to extend the measures (orihuela et al., ) . the same measures were taken by germany. on april , more actions continued, with saudi arabia extended its curfew to h on its most visited and the holiest cities in islam: mecca and medina (aljazeera, c) . a similar action was taken in thailand involving the entire country, with exception of medical personnel, and those transporting essential products, and for people moving to quarantine or health facilities (the nation, ). peru and panama establish a different strategy for reducing the number of people outside by imposing a gender divide, where certain days were set aside for only men and the others for men. this way, it would be impossible for those living together leaving their homes together (aquino and moreno, ). in the united states, the white house was encouraging people going out to wear masks (sun and dawsey, ) , and this came while most of the citizens were trying to come to terms with stay-at-home orders that had been declared in almost states in the country (nottingham, ) . the highlight of the day is the worsening health status of the uk prime minister boris johnson, prompting him to be moved into intensive care. he was taken to hospital in london the previous day (april ), after the covid- symptoms persisted, days after he tested positive (bbc, g). on the same day, in the same country, new deaths were reported, taking the country's total death toll to while the total number of confirmed cases increased to , after new cases were reported in a period of h. within the european region, the total number of confirmed cases had increased to , after , more cases were reported in a span of h. the number of deaths also had increased by a total of deaths to take the total tally for the region to , , and these were far much more than the total deaths of all other regions combined. on the same day, the united states reported , new cases to take their country's total to , (who, s) and also reported a high of deaths increasing the total deaths recorded in the country to , while other data showed that deaths had reached , (siobhán o'grady et al., a) . in the previous day (april ), it had reported cases and , new cases; the highest reported data in the region since the onset of the pandemic (who, a). as these occurred, president trump reported that hydroxychloroquine, an antimalaria drug, could be used against covid- (crowley et al., ) . in the middle east, the total number of confirmed cases in iran increased to , after more people tested positive. globally, the total confirmed cases stood at , , and the total deaths reported were , (who, s). in africa, where cases had started to increase significantlydreaching and deaths, it was reported that the former libya prime minister mahmoud jibril died of coronavirus the previous day after fighting the covid- disease for approximately weeks (aljazeera, d). in china, which reported new cases and only deaths, fears were that the country would be experiencing asymptomatic transmissions of the virus; hence, the increase in newly reported cases. these were experienced though the country had already introduced border restrictions with other countries, and following the fear of asymptomatic cases, the government vowed to tighten border control measures even further (zhang and munroe, ) . the most astonishing news reported on april was that of the positive testing for coronavirus of four tigers and three lions in the bronx zoo, bringing the total number of cats reported to have contracted the virus to (daly, ) . this raised alarms as no known research had shown that the virus could be passed from humans to animals. this far, a report by the who indicated that more than % (approximately . billion) of students globally have had to remain at home following the closure of school. to offer some intervention on this, the organization, together with unicef and the international publishers association, launched the "read the world" initiative to allow student access learning materials even during the difficult times (who, a). in the sporting sector, to safeguard the lives of participants and to comply with the health guidelines of social distancing and others, the open golf championship was called off; being the second time, it was canceled since during the ww (the open, ). after days of uncertainties, the chinese authorities finally lifted the lockdown on wuhan as promised, after the city successfully saw a reduction in the number of new confirmed cases for the coronavirus (aljazeera, a) . in fact, the report from the entire country was that the new cases that were being reported were all imported ones, and the government had vowed to take extra measures to control its borders (zhang and munroe, ) . the good news on the country is that on the previous day (april ), despite reporting new confirmed casesdwhich were all imported, the country reported zero death for the first time since it started publishing figures of the death related to covid- (who, b) . even on th, the number of new cases was only : all imported and only two deaths. the situation was, however, totally different in other regions, especially in europe where france, on a single day, reported new deaths to push its total death toll to , , while those whose tests turned positive in the past h increased by to take the country's total to , (who, t) . this total was however smaller compared to germany, italy, and spain whose totals had increased to , , , , and , cases, respectively. belgium and the netherlands also witnessed an increase in the number of deaths with and new recorded deaths, respectively (who, b). on this, despite germany having more confirmed cases, it had managed to keep the death toll relatively low, with reports showing that it is due to the mass testing initiative it had embarked on; thus, cases were getting identified before becoming critical (perrigo, ) . until eighth, it had only lost people, while its european counterparts were worse off (who, t) . the other nation that saw the number of casualty increase was the u.s, which, since a few days ago had started to witness numerous deaths, and confirmed cases. on this day, the country lost lives to the disease, and , were the newly confirmed cases taking the country's total to , , according to who data (who, t), but the uscdc reported the total number as , cases (cdc, ), where the difference could be due to difference in reporting time between who on central european time (cet) and us edt time zones. while this was happening, the country's president, donald trump who had frequently attacked the who for failing in its mandate in detecting the virus earlier threatened to withdraw funding to the agency (sevastopulo and manson, ) . he categorically said that the organization had withheld information about the virus and was wrong about the outbreak in china (davidson, a) . but, in a quick rejoinder, the who's director-general warned that it would be disastrous to politicize the fight against the pandemic (wise, ) . following the health situation in france, authorities announced that they were imposing a ban on daytime outdoor exercise in paris, which had allowed its citizens to enjoy despite the country being on lockdown (bbc, f). on the same day (april ), the egyptian authorities announced that the ban on mosques and churches would still continue even during the ramadan period as the country was still facing the challenge of coronavirus, with new cases increasing and more deaths being witnessed (egypt independent, ) . in the asian region, japan joined the list of many other countries who had declared a state of emergency as the number of cases in the country had started to rise in the month (rich et al., ) . in singapore, to contain the spread of the covid- , the health minister gan kim yong announced that the government was banning any form of social gathering whether at home or in public (zhang, ) . the ban came just a day after a motion to outlaw social gathering in the country was rushed and passed to the law in parliament the previous day. elsewhere, as the impacts of the virus continued to be felt, the wellness trust, on april , started an initiative aimed to raise a minimum of $ billion from the private sector by the end of april to fill the financial gap being experienced in search vaccines, drugs, and tests for covid- (wellcome, ) . a similar initiative dubbed "afrochampions initiative" was launched by african union and africa centres for disease control and prevention to raise over $ million for medical responses, with $ million required urgently for the same purpose (africanews, ) . after spending three nights in the intensive care unit, the uk prime minister boris johnson was finally discharged from the unit and transferred to a normal ward where he recovered. in fact, it was reported that he could manage short walks, though he needed some time to feel better (the sun, ) . while the report of his improvement was encouraging, it was not the case for over families in the country, from england who had lost their loved ones as a result of the disease on that particular day. in italy, a total of people lost their lives on th (who, h), while had died the previous day (who, u) . in total, the number of deaths in italy had reached a high of , by th with of these being doctors who had contracted the virus while in line of duty (aljazeera, g) . in spain, hopes of flattening the curve were high after the country saw a decline in the number of deaths for the third consecutive day (landauro and keeley, ) . however, the number of new cases in the country was increasing and had climbed to , cases after more cases were confirmed on th. the renewed hope was also being experienced in china after it continued to witness a reduced number of deaths in the country, as well as more recoveries, which had reached , (regencia et al., ) . while that was happening, the spread of the virus has gone as far as in deep rural areas where a -yearold boy from the indigenous tribe of yanomami found in brazil, amazon forest was confirmed with the coronavirus on t th, and on th, unfortunately, he passed away (phillips, ) . another rare place where the virus was reported was in the cook county jail in chicago where new cases involving inmates and staff were reported (whitcomb, a) . in america still, the number of death from covid- were increasing at an alarming rate, where new deaths were reported on th (who, h) and more had died the previous day (who, u). following these increases, with most of them coming from new york cities, the state had resulted in burials in mass graves as the numbers kept on increasing (anderson, ) , with its confirmed cases being more than any other country globally (bbc, d) . the situation in the united states prompted the german foreign minister to criticize the us handling of the virus (connor, ) . another rare place that was affected by coronavirus is a french navy airplane carrier, where servicemen tested positive to covid- (aljazeera, e) . as the cases globally increased to over . million people, the economic impact of the virus continued to bite. for instance, in the united states, another . million people filed for unemployment claims bringing the total number of those in the same predicaments into almost million in only weeks (long and dam, b) . in vietnam, it was reported that the country was in dire need of almost $ billion to caution its economy against the budget deficit that continued to widen (reuters, r) . albania was also trending on a tight economic path, prompting it to seek financial support from the imf, which extended a loan of $ . million (imf, ) . in zimbabwe, following the ban on all international flights in or out of the country, air zimbabwe sent its employees on leave, which was, unfortunately, unpaid (the herald, ). on the same continent, senegal adopted a directly opposite approach of protecting its workers against being laid off by companies in excuse of the covid- crisis (france-presse, ). on other news, there were reports that google and apple would cooperate to develop a mobile app that would help in tracking coronavirus spread (apple, ) . although that was good news especially coming from the tech world, in singapore, the use of technology faced concerns when online learning platforms that the government had initiated were suspended after the video conferencing zoom platform was hacked during a learning session, and the hackers displayed explicit images to the students (lee, ) . although the death tolls in at least four countries crossed the , mark, others have witnessed significant declines in the number of new cases being reported daily, and thus planning to ease lockdown stances and other strict measures that had been put in place. until april , countries like the united states ( , deaths), spain ( , deaths), italy ( , deaths), and france ( , deaths) were most affected, with the situation in the united kingdom worsening ( , ) (who, w). indeed, a report by the office for national statistics highlighted that uk numbers were underreported by %, the number in the country would be reading over , cases (bruce, ) . on this, it was highlighted that the number of deaths reported did not reflect the actual number represented in over care homes, where most of the elderly population were (mcintyre and duncan). although those numbers are many, there was hope in spain and italy as the number of deaths kept on decreasing each day, and from the report, these were optimistic that they would ease their stand on lockdowndspain by end of june (bbc, h). on this, other more countries including greece (by may ) (tugwell, ) , portugal (by may ), australia (had already started by then), pakistan, and austria (with already thousands of shops reopened (niesner and murphy, )) were considering this move (dw, ). although those countries were eager to lift lockdown measures, germany was considering reintroducing it after community infection cases over the past few days started to rise after the country had cautiously tried to ease the lockdown (mayberry et al., ) . in moscow, president putin strengthened the lockdown measures until may to counter the rising cases of infections (davidson, b) . similar measures were also being taken in china, in the heilongjiang province bordering russia, where cases were reported on april , where chinese nationals who had fled to russia tried to return home (wu, ) . following this, the cases in the province increased to , and chinese authorities in the province promised to reward locals who would report the "illegal migrants" (the straits times, b). georgia, on its part, was planning to lock down four of its largest cities, including its capital tbilisi for days as local transmission started to increase with the county's total cases reaching (who, w), an addition of more confirmed cases (who, v) . on the economic front, the imf warned that the global economy would shrink by approximately % following unprecedented measures like lockdowns, and ban on transportations, and closing down of manufacturing and other industries (rapperport and smialek, ) . in a way to ease the economic pressure, president donald trump started issuing stimulus checks to americans, amid some delays after he realized that his name did not appear on the checks (rein, ) . the situation of the economy is also pointed by activities in heathrow airports where passenger demands were expected to reduce by almost % this month (april), after having plummeted by % last month and cargo volume reduced by . % (rojas, ) . the economy was worsening also for the who after president trump retaliated that he was halting funds to the agency following its mismanagement of the coronavirus (mayberry et al., ) . on the societal fronts, the racial discrimination of blacks in china continued, with the mcdonald outlets in china forced to apologize after the store displayed posters banning black people from accessing the china store (folley, ) . elsewhere, turkey was planning to temporarily release over , inmates, after getting approval from parliament to ease overcrowding; thus, void the risk of coronavirus infection in the facilities (wilks, ) . as of th, covid- had spread to countries and territories across the globe with over , , confirmed cases and , deaths reported. of those cases and deaths, % were reported in europe, while more than % of the remaining cases ( , confirmed cases and , deaths) reported in regions of the americas. the eastern mediterranean region had , confirmed cases and deaths while the south-east asia region had a count of , confirmed cases and deaths. africa, which had started to experience some significant increase in infections, had , confirmed cases with of those newly reported and deaths of which of those occurred in a span of h (who, aa). still in africa, it was noted that out of the countries that had reported cases of covid- were drawn from the western and central part of the continent, and who officials reported that they had teams on the ground to establish the real reason why this was happening (who, ac) . of the total reported deaths, the highest number occurred in the united states with a high of deaths, while the united kingdom had the second tally of the day with cases. france had cases while italy and spain, two countries that had for past days shown remarkable improvement, had and cases, respectively (who, aa). on th, the french navy reported that an airplane carrier had soldiers affected, and in less than a week, on th, the number of those had increased to a total of (willsher and sabbagh, ). although reports in the health sector showed that the world was still unsafe, as had also been warned by the who, other issues were coming up in other sectors. for instance, in japan, whose total confirmed cases tallied to dwhich included three cabinet officialsd and the number of deaths increasing to , the prime minister shinzo abe declared a nationwide state of emergency (mccurry, ) . he also advanced a handout worth u , to every resident of the country regardless of their economic status to caution them during the period of this emergency (the japan times, a). in the united states, on the same day, . million people filed unemployment claims bringing the total number of those in this situation to more than million people in a period of only weeks (long, ) . following this, president donald trump unveiled guidelines aimed to help some economic activities in the country to resume, but he left the final decision of opening the economy, by easing the restrictions on each individual state, to the individual state governors (white house, ). in germany, after experiencing prior issues after easing lockdown measures resulted to increased number of confirmed cases, the government was planning to reopen the economy as from april by allowing some nonessential stores to open and also allowing schools to resume as from may (morris and beck, ). in brazil, president jair bolsonaro fired the minister for health after the minister insisted on strict social isolation guidelines, a move that the president was against. unfortunately, the president had been seen to have regularly downplayed the outbreak of the virus in his country despite the country having , confirmed cases and deaths by april (quinn, a) . in sports, following the situation in france, the tour de france scheduled for june and july was postponed to a tentative date between th august and th september, as the government banned public gatherings to reduce the spread of the coronavirus (tour de france, ). for world wrestling entertainment, the company was planning to lay off some employees including wrestlers and producers such as kurt angle (russell, ) . the move was to caution the company against the financial decline it was facing following the impacts of the pandemic. after months of extreme pressure, anxiety, and uncertainties, wuhan settled and revised its official data relating to the coronavirus. after the review, the death toll from the covid- pandemics increased by % meaning that its number increased from deaths to deaths, pushing the country total by april to deaths. the errors in reporting were attributed to delays, omissions, and incorrect reporting that are understandable following all the many things that are happening during that period (neuman, a) . the number of reported deaths also increased in the african continent after more deaths were reported, taking the total tally to , while new confirmed cases increased by , pushing the continent's total to , , according to africa centres for disease control and prevention (africa cdc) (xinhua, a) , but data by the who for the same period show a total of , cases and deaths (who, x) . death tolls were rising by higher margins in the european regions and had exceeded , deaths, from , , cases reported in the region. this increase, observed throughout spain and italy, however, continued to experience improvements with death rates reducing each day. the united kingdom, france, and belgium still reported increasing numbers of deaths ( , , and , respectively) . however, the united states still leads in the number of confirmed cases ( , on april ) and death tolls ( on the same day) per day for more than two consecutive weeks (who, x) . globally, the total number of cases had increased to a high of over . million, with the number of deaths exceeding , by april (who, x) . despite the risk of the disease being live, the orthodox churches in georgia were observed to flaunt the state of emergency declaration to hold easter masses, where hundreds of congregants attended (antidze, ) . in the united states, a day after the president had outlined a set of rules for reopening the economy, but left the final say on the hands of the governor, some protesters were observed in states of michigan, minnesota, and ohio and others, calling their governors to lift the restrictions in their states (gabbatt, ) . at the same time, texas governor is said to have signed an executive order to allow a reopening as from may (office of the texas governor, ). this was happening, even as the us secretary of defense extended the travel ban for one more month to void the earlier expiry scheduled for may ; thus, showing that the country was still not ready to ease the restrictions it had set. further south, in chile, the government started issuing "immunity cards" for all those who had infected and recovered from the virus. with the card, these could comfortably return to their work stations (thomson, ) . as this was happening, the number of cases in the country rose to , , taking the country as the third most affected in latin america (who, x) . however, the who, through dr. michael ryan, one of the executive directors, warned that there was no evidence that those who were recovering from covid- were developing any immunity that could prevent them from being reinfected (who, ab) . during the same press conference, the director-general emphasized that as chinese authorities allowed the wet market to reopen, they would ensure conformity to food safety and highest levels of hygiene and that the law banning any trade in wildlife for food was to be implemented strictly to save the world from future pandemics like the coronavirus (who, ab). elsewhere, more countries were slowly and cautious easing restrictions, with france allowing visitors to care homes, albeit some conditions (dodman, ). croatia also eased some restrictions allowing people to travel within their districts. in other countries such as the united kingdom and zimbabwe, the lockdown measures were to remain intact until when the government is confident the situations are controlled (today, b) . in saudi arabia, despite the start of ramadan, the top religious authorities of the country were recommending people to pray at home to reduce the spread of the virus among the faithful (reuters, p) . this was necessary, as already, deaths were not sparing countries' leadership. for instance, in nigeria, president buhari's chief of staff, abba kyari became the latest topranking official to die from covid- (akwagyiram, b) . a similar case was reported in guinea where a top official and ally of the president alpha condé also died (afp, a). within a period of h (april e ), the number of infections globally increased from . million cases to over . million, while the number of deaths increased to above , globally (reuters, g) . in europe, the number of those infected increased over this period to over . million, with a daily average increase of approximately , new cases, while the number of new deaths in the areas also increased by an average of above each daydtaking the total deaths in the region to , according to data by the who (who, y). in the american regions, cases increased by an average of , confirmations pushing the total confirmed cases to , cases (who, y). the number of deaths increased to approximately , by april , with a majority of these reported in the united states, which was the new epicenter for the coronavirus. the eastern mediterranean region had its total confirmed cases increase to , cases with people dying from covid- . the western pacific region had a total of , cases after new cases were confirmed while the number of deaths increased to . the south-east asia region and african regions, though have had their cases increase, have shown remarkable levels of resilience despite having some of the weakest health systems. their total confirmed cases increased to , and , cases, respectively, while the number of people who succumbed to the covid- in the regions increased to and deaths, respectively, (who, y) . following the unprecedented increase of infections in the united states, president donald trump had reported on april that he would be signing an executive order to suspend immigration to the united states for the next days. and, true to his word, on st, he signed the order meaning that green card recipients would be blocked from moving into the country, with only workers holding nonimmigrant visas allowed (nick miroff et al., ) . he supported his decision by arguing that the unprecedented effects on covid- had pushed many americans out of jobs, and he would wish to see them access the available job opportunities without having to compete with migrants (nick miroff et al., ) . and to ensure that job opportunities would be available, on the same day, his office and congressional leaders agreed on a $ billion small business and hospitals stimulus package, that now only awaited approval from the house of representatives (roberts, ) . in africa, south africa took a similar approach of bailing out the economy by unveiling a $ billion relief plan that would also aid the most vulnerable in the society during the period that the country was struggling with increasing cases of coronavirus and the lockdown measures (channelstv, ) . the economic struggles saw iran start to reopen its economy with major shopping centers in the capital tehran being the first (press, ) . similar actions were observed in israel, which eased lockdown restrictions to allow small shops and stores to open and allow people to move around, but on condition mask-wearing in public (haaretz, ) . this came as the number of recoveries in those countries started to increase, while the death toll contained (efrati and rabinowitz, ). in the poorest countries in the world, the world bank supported the pandemic bond, launched in , with an amount of $ . million to assist nations from the impacts of covid- (baker, ) . this came as the un world food programme warned that the impacts of covid- would result in the doubling of world hunger, representing a total of million people (anthem, ) . the economy was however not worsening for individuals only, but on this day, it was seen to have particularly worsened for us oil-producing economies and companies, with the prices per barrel going down to $ , a historical event that has never happened (suleymanova, ). the only sector that was seen to be doing well, especially in the united states is the gaming industry, probably due to the "stay-at-home" orders and also due to the closure of schools. but, while the market increased, there were fewer games produced due to the impacts sparked by the coronavirus (schreier, ) . the other sector that was seen to benefit from the impacts of covid- was the environment, where it was reported that following the reduced activities in the manufacturing and transport sector, less emissions ( % drop) are expected during the year (marchand and faigle, ). as over countries continued to fight the spread, and the impacts of covid- in their countries, the united states was the most hit with over , cases and over , reported deaths as up to april . the new cases in the country had increased at an average number of approximately , (cdc, ). as the number of cases continued to increase, and other more "staying-at-home" measures following the lockdowns in different states, the number of those filing for unemployment claims continued to increase with over . million additional claims reported over the past week, which was the fifth consecutive week since this trend started (lambert, ) . these new numbers raised the total of those who had filed for their employment benefits to over million people (chaney and guilford, ) . outside the united states, there were mixed responses to the virus. some were seen to ease and lift the lockdown and subsequent measures they had implemented, while others were seen to be in haste to institute those measures. for instance, in the netherlands, after experiencing some "relative calm" over the past weeks in respect to infections in the country, its number had started to rise with new deaths averaging over each day and reaching a high of deaths and , confirmed cases by april (who, z). to minimize further infection, a stern decision was taken to ban any form of public gather until september ( months extension) the first of such a ban globally. that means that events such as sports, music festivals, and religious grouping would not be resuming anytime soon (reuters, e) . but, it was not the only one extending such measure as in pakistan, the lockdown was extended by two more weeks until may , as the country was still experiencing increasing numbers of local transmission of the virus, and the lockdown extension would somehow reverse these trends (cherian, ) . indonesia also joined the list of those that were strengthening their measures after the government announced that it would be temporarily suspending nonessential domestic and international air and sea travel until the end of may to curtail the spread of the coronavirus in the country (bangkok post, ) . others that extended their lockdown include liberia (garda, ) , lebanon (reuters, k) , and czech, which sought parliamentary intervention to allow the extension of the state of emergency until may (xinhua, b) . on the same breath, some countries and states in the united states started easing restrictions to allow the reopening of their economy. these include states such as georgia, oklahoma, and others in the united states, which took these decisions despite the disapproval of president trump (smith, ) . belgium was ready to start reopening some businesses and schools as from may, but gradually and cautiously (martens, ) . although countries were reacting to covid- situations in different ways, some unfortunate news besides new cases and deaths were also reported. for instance, in the united kingdom, which had seen the confirmed cases increase significantly and the number of deaths rising to beyond , there were reports that among the dead were national health service personnel who had paid the ultimate price in a bid to save their country from the pandemic (express and star, ) . in bangladesh, it was reported that frontline doctors had tested positive for the coronavirus due to strains that the covid-i had put on the healthcare system, with most of those in the frontline experiencing a shortage of ppes, test kits, and hospital beds, among other basic essentials (mahmud, ) . elsewhere in japan, after a dreadful experience with the diamond princess cruise ship, on st, another fateful incidence involving an italian cruise ship (costa atlantica) happened in nagasaki shipyard (the japan times, b). it started when one of the crew members tested positive for coronavirus, while of his colleagues were also showing signs, especially high fever. the following day, after contact tracing from the first confirmed cases, another cases tested positive (the straits times, a). h later, another people tested positive (kaneko and kim, ) and by th, a total of people; all crew members were confirmed as testing positive (cna, b) . following this, the japanese government stated that it would test people, out of the who were on board the cruise ship and those who turned negative would be repatriated back to their home countries. as the fifth month, since the onset of the coronavirus, is almost over, the number of those confirmed to have contracted the virus increased to over million people globally, and at least , were reported to have succumbed to the disease. over the same period, of the million, over , patients had recovered (spotlight, ). one country where success against covid- have, and continued to be celebrated, was in wuhan, hubei province, china, where healthy officials reported that they had treated all cases and those who recovered were discharged from hospital (o'donnell, ) . in fact, as previously reported, the restrictions and lockdown in the provinces were lifted including in wuhan, on april (aljazeera, a) . following this, on rd, china pledged additional funding, amounting to $ million, to the who (shih, ) , as already, it could manage the few cases emerging, and the funds could help other areas that were experiencing high pressure from the pandemic. in the new cases, between th and th, china was reported to have only recorded a total of new cases and asymptomatic cases, but no death was reported in the days (who, i). as cases in china reduced, those in the european region seemed to have continued increasing reaching a high of , , cases after the addition of , new cases on th, and the number of deaths increased to , . in the american region, the number of cases was , , and , deaths reported, according to data by the who (who, i). the eastern mediterranean, western pacific, and south-east asia regions had , , , , and , confirmed cases, respectively. the african region continued to show high levels of resilience with only , confirmed cases and deaths reported (who, i). but as the number of cases continued to increase, reports of more countries planning to ease up the lockdown also increased. as of th, italy and spain, two of the most affected countries by the covid- pandemic, with cases of death in each exceeding , (italy , deaths, spain , ) unveiled plans of how they would open up their country as from may . in italy, according to prime minister giuseppe conte, the manufacturing industry would gradually open as from may , but schools would remain closed for three more months until september (kayali, ) . in spain, people would be allowed to walk out for physical activities, but social distancing will have to be observed, as infections in the country were still real (reuters, q) . saudi arabia is another country that considered lifting the nationwide curfew, except for mecca, which remained under -h curfew (aljazeera, h). in germany, after easing the restrictions a few days ago, it is reported that volkswagen was gearing to resume production in their wolfsburg factory on april (allan, ) , the same decision was also taken by bmw company and other companies such as mercedes, jaguar land rover, and others reopening in a few days (reuters, f) . this came as some protests were witnessed in berlin as people demanded the easing of lockdown measures to allow them to return to work (reuters, d) . in the united states, as some states started reopening businesses, the airline industry, which was yet to resume, received support funds amounting to $ . billion -taking their bailout total from the us treasury to $ . billion, with the first disbursement received on april (landay and shephardson, ) . although those countries were gearing to resume business, others insisted on strict measures as cases continued to rise. for instance, the united kingdom maintained the lockdown as it was still not safe from the virus infections (bbc, i). sri lanka also extended the lockdown in the country to counter the increasing number of cases (afp, b). honduras was even considering extending the lockdown by at least one more week until may (reuters, h) . in india, prime minister modi urged his citizens to piously adhere to the nationwide lockdown to contain the rising cases that came amid the month-long curfew (the straits times, d). by april , it became official that the number of covid- infection cases had exceeded the million (the who reported . million cases and , deaths) people and caused the death of over , people globally. of the confirmed cases, over million were reported in the united states while a quarter of reported deaths from the virus coming from the united states. the number of deaths in the country ( , ) even surpassed the total of those who died during the vietnam war between and , where nearly , people died (woodward, ) . in new york, it was reported that for every four people, one of them had contracted the coronavirus. this is after almost , cases had been confirmed, and more than , deaths were reported in the city alone. these numbers in the united states eclipse those of other reported regions. for instance, as of th, the total number of reported cases in africa ( , ) was far much less than the total number of deaths ( , ) reported in the united states on the same day. in addition, they were more than the total number of deaths ( , ) in italy and the united kingdom, which were leading in terms of reported deaths in europe (worldometer, ) . to reduce these unprecedented trends, some states in the united states started testing for asymptomatic residents such as delivery drivers, rideshare drivers, and others. this came as most of the states were planning to reopen by easing the lockdown restrictions, amidst opposition from president trump, and the latest, judge clay jenkins of dallas county, who mentioned the solution, for now, was to follow science and people to stay at home (holcombe, ) . besides the united states, other countries that are yet to experience some reductions in a number of cases include russia, where president vladimir putin stated that the country was bracing for a new and grueling phase of the pandemic (llyushina, ) . his statement came at a time when the number of confirmed cases had continued to stabilize, and the country performed significantly well to reduce casualties. italy, though determined to ease its lockdown restrictions, was experiencing some new cases, with its numbers reaching beyond the , mark. according to the who, africa, eastern europe, latin america, and parts of asia were still not yet out of risk; hence, caution was required even as some actions such as easing the restriction were being taken. this came as eu experts warned that the world would have to wait longer for the vaccine, which would not be ready until the end of , especially considering the cost implications, and other processes that have to be accomplished (cullen, ) . in relation to this, in new york city, it was reported that medical personnel had started testing famotidine; an over-thecounter heartburn medication could cure covid- (lentile, ) . this came as human trials had also started in germany where biontech, a pharmaceutical company was testing its vaccine on volunteers, with participants already having received the dose as from april (aljazeera, f) . as solutions for the covid- continued to be sought, some diplomatic disharmony was witnessed when india canceled orders for , rapid test kits from china after claiming that they were "faulty," and also went forth to withdraw some of the kits that were already in use in several states (bbc, b) . china responded harshly and claimed that it was unfair and irresponsible for india to label chinese products as "faulty" (business today, a). in sports, following the unseen end for the pandemic, french authorities stated that there was no hope for "big sporting affairs" to come back until september in the years, thus, throwing the french football season in disarray, thus, causing them to be canceled (aarons and lowe, ) . the cancellation came as other countries like germany had already announced that the football season (bundesliga) would return in a date to be confirmed albeit under closed doors (bassell, ) . regarding the olympics, the olympics international committee stated that it would cancel the event coming in the next year if the pandemic would not have ended (schad, ) . olympics must be delayed to ensure french football season will not resume but la liga has new hope of restart adb to provide $ million to support strained supply chains in fight against covid- african development bank launches record breaking $ billion "fight covid- leading member of guinea government dies from coronavirus sri lanka extends virus lockdown coronavirus e africa: african union and african private sector launch covid- response fund nigeria orders -day cessation of movement in lagos, abuja to fight coronavirus nigerian president's chief of staff dies from coronavirus china's wuhan ends coronavirus lockdown but concerns remain coronavirus: travel restrictions, border shutdowns by country curfew in mecca, medina extended to hours over coronavirus former libya prime minister mahmoud jibril dies from coronavirus france reports covid- cases on board aircraft carrier germany company begins human trials of coronavirus vaccine one hundered italian doctors have died of coronavirus saudi arabia partially lifts curfew except in mecca volkswagen restart production as european car factories reopen burials on new york island are not new, but are increasing during pandemic risk of hunger pandemic as covid- set to almost double acute hunger by end of hundreds of parishioners attend orthodox easter vigil in georgia apple and google partner on covid- contact tracing technology ( ) china to end lockdown of coronavirus-hit hubei province; wuhan to open next month moscow shuts down all non-essential shops & restaurants to stop spread of covid- trudeau says canada will return asylum seekers to fda authorizes -minute coronavirus test poorest countries finally set to get world bank pandemic bond funds indonesia bans air, sea travel until june over virus fears world bank group president malpass: remarks to the development committee bundesliga return in may now looks inveitable but fans far from happy coronavirus travel: china bars foreign visitors as imported cases rise coronavirus: india cancels order for "faulty coronavirus: italy extends emergency measures nationwide coronavirus: new york has more cases than any country bbc. ( e) coronavirus: new zealand announces lockdown coronavirus: paris bans daytime outdoor exercise coronavirus: prime minister boris johnson tests positive coronavirus: spain plans return to 'new normal' by end of coronavirus: uk must find 'new normal' to ease lockdown e raab formula e: china race called off amid coronavirus outbreak wuhan eases quarantine as coronavirus cases in us pass , singapore closes borders to keep virus at bay, but no shutdown bill & melinda gates foundation, wellcome, and mastercard launch initiative to speed development and access to therapies for covid- uk coronavirus death toll could be far higher than previously shown coronavirus crisis: china fumes over icmr clampdown on 'faulty' rapid testing kits, calls it 'unfair business today. ( b) coronavirus outbreak: india bans international flights till suspends season after player tests positive for coronavirus senate unanimously passes $ t coronavirus stimulus package it's a wreck': . million file unemployment claims as economy comes apart coronavirus disease : cases in the us china's first batch of schools reopens in qinghai province available at south africa president ramaphosa unveils $ bn covid- relief plan coronavirus: who head says nations must attack as 'pandemic is accelerating europe's hospitals among the best but can't handle pandemic pakistan extends lockdown for days, until may south korea throws up innovative tech solutions in coronavirus fight. available at: straitstimes. com/asia/east-asia/south-korea-throws-up-innovativetech-solutions china's imported covid- cases spike as fears grow of second wave covid- tally rises to on italian cruise ship in japan cruise ship stranded by covid- fears to dock in cambodia spain impose nationwide lockdown due to virus, closes all stores except groceries and pharmacies trump address sparks chaos as coronavirus crisis deepens germany's maas: trump coronavirus response took 'too long ignoring expert opinion, trump again promotes use of hydroxychloroquine coronavirus vaccine won't be ready until end of under "most optimistic seven more big cats test positive for coronavirus at bronx zoo donald trump stokes fresh coronavirus row as wuhan reopens global covid- cases near million as putin warns russia faces 'extraordinary' crisis devil's dilemma': france lifts ban on nursing home visits as some warn against relaxing rules coronavirus: what are the lockdown measures across europe? available at map: coronavirus and school closures israel reverses the trend: more coronavirus recoveries than new cases mosques to remain closed, charity iftar tables banned in ramadan negotiations intensify on capitol hill over massive stimulus legislation as coronavirus fallout worsens applications welcome from startups and smes with innovative solutions to tackle coronavirus outbreak commission publishes guidance on export requirements for personal protective equipment the nhs workers who have died during the coronavirus pandemic mcdonald's apologizes after store in china displayed sign banning black people trump signs historic $ trillion stimulus after congress passes it friday senegal bans layoffs during coronavirus crisis cuba closes borders to non-residents over virus: president lebanon announces two-week lockdown over coronavirus us anti-lockdown rallies could cause surge in covid- cases, experts warn cruise ship docks in mexico, passengers allowed to disembark after being denied entry in jamaica, cayman islands amied coronavirus fears cepi invests $ , into potential covid- vaccine from university of hong kong european union leaders denounce trumps coronavirus travel restrictions liberia: president extends lockdown measures for two weeks from april /update foreign travel advice: italy uk helps world's poorest countries withstand the economic disruption of coronavirus latest guard update: more than , troops mobilised for covid- response a fine for not wearing a mask: these are israel's new coronavirus regulations bolsonaro defies coronavirus to rally against congress coronavirus: iran release , prisoners in bid to tackle spread of virus trump invokes defense production act to force gm to make ventilators dallas county judge opposes governor's plan to reopen and calls for residents to follow science and stay home fact sheet: dhs notice of arrival restrictions on china, iran and certain countries of europe together we can with the war against covid- ) imf executive board approves us$ . million in emergency support to albania to combat italian cruise ship in japan has coronavirus cases italy and spain announce plans to ease coronavirus lockdowns further cepi approves $ . m in additional funding for coronavirus vaccine research, bringing total to $ how new york became the epicenter of america's coronavirus crisis ventilators are to this war what missiles were to world war ii un headquarters closes to public as coronavirus precaution real unemployment rate soars past %dand the u.s. has now lost . million jobs spain sees slowing coronavirus toll, holds virtual easter parades airlines receive extra $ . billion in payroll support singapore stops zoom for home-schooling after hacking report famotidine trial underway in nyc for covid- treatment trump declares national emergency e and denies responsibility for coronavirus testing failures russia will "face a new and grueling phase of the pandemic now has million unemployed, wiping out a decade of job gains america is in a depression. the challenge now is to make it short-lived america is in a depression. the challenge now is to make it short-lived hundreds of doctors in bangladesh infected with coronavirus coronavirus: beijing's ban on foreign travellers comes into force months after it criticised other countries for 'isolating china will coronavirus reduce emissions long term? available at belgium to gradually ease virus lockdown in first half of may covid- therapeutics accelerator awards $ million in initial grants to fund clinical trials coronavirus crisis 'like no other' as cases near m: live updates stocks plunge % in dow's worst day since japan declares state of emergency over coronavirus care homes and coronavirus: why we don't know the true uk death toll as virus spreads, africa gets medical supplies from chinese billionaire the dow jones had its biggest point drop in history monday angela merkel's first coronavirus test result is negative panama suspends domestic flights to curb the spread of coronavirus: civil aviation authority germany to reopen schools, shops after 'fragile' success egypt shuts mosques and churches over coronavirus fears china raises wuhan death stats by half to account for reporting delays and omissions goes into -week lockdown trump to suspend immigration to u.s. for days, citing coronavirus crisis and jobs shortage austria reopens thousands of shops in first loosening of coronavirus lockdown nearly % of americans have been ordered to stay at home office of the president. ( a) letter from president donald remarks by president trump and vice president pence at a coronavirus briefing with health insurers governor abbott issues executive order establishing strike force to open texas coronavirus-press-conference- apr .pdf?sfvrsn¼ bd c cd_ cuba is going under lockdown over coronavirus concerns italy joins germany in prolonging lockdown to quell outbreak covid- : how a phone app is assisting south korea enforce self-quarantine measures why is germany's coronavirus death rate so low? available at first yanomami covid- death raises fears for brazil's indigenous peoples spain to extend coronavirus state of emergency as deaths soar connecticut becomes latest state to postpone primary as coronavirus spreads iran begins to open its economy despite fears of second wave of infection brazil's populist president ousted his respected health minister while continuing to downplay the coronavirus pandemic italy's coronavirus death toll surpasses china's japanese pm and ioc chief agree to postpone olympics until ) i.m.f. predicts worst downturn since the great depression states have declared a state of emergency due to coronavirus global coronavirus death toll exceeds , : live updates unprecedented move, treasury orders trump's name printed on stimulus checks austrian joblessness hits record despite government bit to avoid layoffs bolivia postpones elections, announces nationwide -day quarantine to stem spread of coronavirus china's coronavirus epicenter reports just five cases, beijing tomb-sweepers urged to stay back dozens of protesters were arrested in berlin on saturday for flouting lockdown rules and staging a demonstration against lockdown measures dutch extend ban on major public events until sept europe restarts car factories amid uncertain demand global coronavirus cases pass . million as u.s. tally surpasses , honduras extends coronavirus curfew by one week to may italy's coronavirus lockdown measures to be extended to april : minister kazakhstan, uzbekistan close borders after first coronavirus cases kazakhstan-uzbekistan-close-borders-after-first-coronaviruscases-iduskbn ex lebanon advised to extend coronavirus lockdown to may mexico declares health emergency as coronavirus death toll rises nigeria closes land borders to fight coronavirus spread pakistan suspends internationa flights for two weeks portugal to treat migrants as residents during coronavirus crisis saudi top religious authority recommends home prayers in ramadan amid coronavirus spain to allow outdoor exercise if coronavirus cases contine to fall vietnam in talks to borrow $ billion as budget deficit seen widening japan declared a coronavirus emergency. is it too late? available at us senate approves $ bn funding for small businesses rockefeller foundation. ( ) the rockefeller foundation commits $ million in covid- assistance coronavirus: heathrow passenger demand to fall by more than % in april prince albert ii of monaco test positive for coronavirus the coronavirus map in spain: , dead and more than , infected wwe announces layoffs two days after florida deems company an 'essential business tokyo olympics will be canceled, not delayed, if coronavirus pandemic still poses threat in as italy covid- cases soar, who tackles ppe, test shortages gaming sales are up, but production is down donald trump threatens to freeze funding for who new york city public schools to close to slow spread of coronavirus trump extends social distancing guidelines through end of april china pledges additional $ million funding for world health organization india extends ban on international flights until airlines seek $ billion coronavirus aid package coronavirus deaths surpass , , hhs watchdog says american hospitals face 'severe' shortages of equipment, staff and tests china reports zero new local coronavirus infections; trump signs bill to ensure paid leave, other financial benefits too soon': trump disagrees with georgia governor's decision to reopen businesses coronavirus deaths in italy up by in a day to , global death toll from coronavirus tops greece to go into coronavirus-induced lockdown crash! us crude futures turn negative for first time in history white house expected to urge americans to wear face coverings in public to slow spread of coronavirus government bans exports of certain masks, ventilators, raw material for masks zimbabwe shuts borders after first coronavirus the herald. ( ) breaking: air zim sends workers on unpaid leave japan to declare nationwide state of emergency as virus spreads the japan times. ( b) one crew member tests positive, feverish on cruise ship in japan. available at the nation. ( ) pm announces pm to am nationwide curfew gives new guidelines, new york to close restaurants and schools and italian deaths rise the new york times. ( b) u.s. now leads the world in confirmed cases. available at statement from the r&a/the open in to be cancelled china reports newly imported covid- cases and one in wuhan cases-on-cruise-ship-docked-fo r-repairs. the straits times. ( b) china tightens russian border checks, approves experimental coronavirus vaccine china's imported coronavirus cases soar, no local transmission for third straight day the straits times. ( d) indian pm modi urges citizens to follow lockdown as coronavirus cases rise boris johnson's move from intensive care to a general ward is the lift britain needed world bank group increases covid- response to $ billion to help sustain economies world's first covid- immunity cards are coming to chile more than million people tested for coronavirus in us, but access varies from state to state georgia proposes -day lockdown of four cities including capital uk not thinking of easing virus lockdown measures yet: minister the tour de france greece to gradually start lifting lockdown measures on may . available at: greece to gradually start lifting lockdown measures on key cop climate summit postponed to 'safeguard lives secretary-general's remarks at launch of global humanitarian response plan for covid- african finance ministers call for coordinated covid- response to mitigate adverse impact on economies and society a global approach is the only way to fight covid- , the un says as it launches humanitarian response plan coronavirus: boston celtics guard marcus smart tests positive for covid- chinese businessman to donate , test kits and million masks to the world health organization has distributed . million coronavirus lab tests around the world global covid-zero initiative launched to fill $ bn shortfall for coronavirus response chicago's largest jail reports inmates, staff positive for coronavirus two los angeles lakers players have tested positive for covid- , team says president donald j. trump is beginning the next phase in our fight against coronavirus: guidelines for opening up america again australia bans overseas travel and extends social restrictions situation report - . available at who. ( b) coronavirus disease (covid- ): situation report - . available at who. ( c) coronavirus disease (covid- ): situation report - . available at who. ( d) coronavirus disease (covid- ): situation report - . available at who. ( e) coronavirus disease (covid- ): situation report - . available at who. ( f) coronavirus disease (covid- ): situation report - . available at who. ( g) coronavirus disease (covid- ): situation report - . available at who. ( h) coronavirus disease (covid- ): situation report - . available at who. ( i) coronavirus disease (covid- ): situation report - . available at who. ( j) coronavirus disease (covid- ): situation report - . available at who. ( k) coronavirus disease (covid- ): situation report - . available at who. ( l) coronavirus disease (covid- ): situation report - . available at who. ( m) coronavirus disease (covid- ): situation report - . available at who. ( n) coronavirus disease (covid- ): situation report - . available at who. ( o) coronavirus disease (covid- ): situation report - . available at who. ( p) coronavirus disease (covid- ): situation report - . available at who. ( q) coronavirus disease (covid- ): situation report - . available at who. ( r) coronavirus disease (covid- ): situation report - . available at who. ( s) coronavirus disease (covid- ): situation report - . available at who. ( t) coronavirus disease (covid- ): situation report - . available at situation report - . available at coronavirus disease (covid- ): situation report - who. ( w) coronavirus disease (covid- ): situation report - . available at who. ( x) coronavirus disease (covid- ): situation report - . available at who. ( y) coronavirus disease (covid- ): situation report - . available at who. ( z) coronavirus disease (covid- ): situation report - . available at who. ( aa) coronavirus disease (covid- ): situation report - . available at who. ( ab) covid- virtual press conference. available at who. ( ac) opening statement who director-general's opening remarks at the media briefing on covid- e who director-general's opening remarks at the media briefing on covid- e who director-general's opening remarks at the media briefing on covid turkey to free one-third of its prisoners to curb coronavirus ebrd unveils v billion emergency coronavirus financing package inquiry after of french aircraft carrier's crew catch coronavirus coronavirus: nuggets report member of organization tested positive for covid- who chief warns against 'politicizing' coronavirus unless 'you want to have more body bags world food programme. ( ) statement from wfp executive director david beasley report coronavirus cases remote chinese city hit by coronavirus after weeks of feeling safe africa's covid- death toll hits , , as confirmed cases rise to czech parliament oks extending state of emergency until except wuhan, china's hubei reopens domestic flights what the u.s. needs to do today to follow south korea's model for fighting coronavirus how taiwan is containing coronavirus despite diplomatic isolation by china three members of the philadelphia ers organization test positive for coronavirus china sees rise in asymptomatic coronavirus cases, to tighten controls at land borders key: cord- -xl fv qx authors: kahn, r. e.; morozov, i.; feldmann, h.; richt, j. a. title: th international conference on emerging zoonoses date: - - journal: zoonoses public health doi: . /j. - . . .x sha: doc_id: cord_uid: xl fv qx the th international conference on emerging zoonoses, held at cancun, mexico, – february , offered participants from countries, a snapshot of current research in numerous zoonoses caused by viruses, bacteria or prions. co‐chaired by professors heinz feldmann and jürgen richt, the conference explored topics: (i) the ecology of emerging zoonotic diseases; (ii) the role of wildlife in emerging zoonoses; (iii) cross‐species transmission of zoonotic pathogens; (iv) emerging and neglected influenza viruses; (v) haemorrhagic fever viruses; (vi) emerging bacterial diseases; (vii) outbreak responses to zoonotic diseases; (viii) food‐borne zoonotic diseases; (ix) prion diseases; and (x) modelling and prediction of emergence of zoonoses. human medicine, veterinary medicine and environmental challenges are viewed as a unity, which must be considered under the umbrella of ‘one health’. several presentations attempted to integrate the insights gained from field data with mathematical models in the search for effective control measures of specific zoonoses. the overriding objective of the research presentations was to create, improve and use the tools essential to address the risk of contagions in a globalized society. in seeking to fulfil this objective, a three‐step approach has often been applied: (i) use cultured cells, model and natural animal hosts and human clinical models to study infection; (ii) combine traditional histopathological and biochemical approaches with functional genomics, proteomics and computational biology; and (iii) obtain signatures of virulence and insights into mechanisms of host defense response, immune evasion and pathogenesis. this meeting review summarizes of the conference presentations and mentions briefly the articles in this special supplement, most of which were presented at the conference in earlier versions. the full affiliations of all presenters and many colleagues have been included to facilitate further inquiries from readers. addition to the summaries later of six presentations on this topic, this special supplement includes an article, monitoring of west nile virus infections in germany by dr. u. ziegler et al. which identified west nile virus (wnv) antibodies in migratory birds, but not in resident birds, in domestic poultry or in local horse populations throughout germany. the wnv antibody-positive species were found in birds that migrate to tropical africa or southern europe; however, wnv-specific rna could not be found in any of the samples. the conference opened with a presentation from professor m. a. diuk-wasser and her colleagues j. simpson and c. m. fosom-o'keefe (all yale school of public health, new haven, ct, usa) and g. molei, p. m. armstrong, and t. g. andreadis (center for vector biology and zoonotic species at the connecticut agricultural experiment station, new haven, ct, usa), ecology of west nile virus in the north-eastern united states. professor diuk-wasser began by noting that west nile virus (wnv) was introduced into new york city in by unknown means and was now considered endemic throughout the usa, with , human cases and , deaths in the usa since . it had been hypothesized that increased biodiversity leads to a decreased risk of exposure to zoonotic pathogens (keesing et al., ) . at issue is whether this 'dilution effect' or 'zooprophylaxis' for vector-borne pathogens applies only when vectors are generalist feeders, because the link between host diversity and pathogen transmission might break down when vectors exhibit host preferences. in the north-eastern united states, wnv perpetuates in an enzootic transmission cycle involving culex spp. mosquitoes and virus-competent avian hosts. previous studies had detected that a large proportion of c. pipiens and c. restuans bloodmeals were derived from american robins (turdus migratorius), suggesting a key role for this bird species in the wnv transmission cycle (kilpatrick et al., ; molaei et al., ) . the new haven-based research team tested for preferential feeding by conducting equal choice experiments (robins versus other bird species) (simpson et al., ) and by comparing the proportion of culex spp. bloodmeals acquired from robins to the proportion of robins in the local bird community. both methods indicated preferential feeding for robins. they were also able to identify robin communal roosts as amplification foci in greater new haven (diuk-wasser et al., ) . then, through field-informed mathematical modelling, they determined that host preferences were indeed key drivers of wnv transmission and that landscape attributes (such as urbanization) in combination with mosquito abundance and a measure of host community competence were the strongest predictors of pathogen prevalence (simpson et al., ) . thus, it was clear that pathogen prevalence and human risk of infection were best predicted by assessing the relative pathogen competence and attractiveness to vectors of all species in the host community, rather than using simple measures of biodiversity. in the next presentation, interactions among multiple tick-borne pathogens in a natural reservoir host, professor fish and his colleagues j. brown, m. fitzpatrick, s. usmani-brown, p. cislo and p. krause (yale school of public health, new haven, ct, usa) stressed that species interactions within a parasite community drive infection risk in a wildlife population (telfer et al., ) . at least five tick-borne pathogens are known to be transmitted by ixodes scapularis, the principal vector of lyme disease in the united states: (i) borrelia burgdorferi, an agent of lyme disease; (ii) anaplasma phagocytophilum, an agent of human anaplasmosis; (iii) babesia microti, an agent of human babesiosis; (iv) borrelia miyamotoi, an agent of relapsing fever; and (v) the powassan encephalitis virus. two or more of these pathogens can be transmitted either simultaneously by a single tick or sequentially by successive tick-bites, resulting in different permutations of mixed-infection studies. in the context of pathogen prevalence of ixodes scapularis nymphs, borrelia burgdorferi, has been found in . % of samples from the north-east and mid-western united states, while babesia miroti has been found in . % of samples from block island, rhode island. professor fish explained that several types of co-infections have been explored in an experimental system employing laboratory colonies of i. scapularis ticks and peromyscus leucopus white-footed mice, a natural reservoir host for these pathogens. outcomes of mixed infections in mice have been measured by r o , the fitness parameter and basic reproductive rate which indicates the number of secondary tick infections resulting from a primary infection (levin and fish, ) . the observed outcomes of dual mixed infections have been variable with both positive and negative effects on r o , while interactions have been mutual, unidirectional or null. these diverse pathogen interactions play an important role in determining the infection prevalence of host-seeking nymphs in nature, and consequently, in the risk of infection for humans. professor h. henttonen (finnish forest research institute, vantaa, finland) and his team h. leirs, e. r. kallio, k. tersago and l. voutilainen in collaboration with university of antwerp, belgium; university of liverpool, united kingdom; and the universities of helsinki and jyväskylä, finland, studied biome specific rodent dynamics and hanta epidemiologies in europe. their research sought to understand the main biomes and forest coverage in europe, the european hanta viruses and their carriers, and the biome specific dynamics of hanta virus carriers and the biome specific transmission dynamics and epidemiologies. within the bunyaviridae family of viruses, hantaviruses infect rodents (and insectivores) and cause haemorrhagic fever with renal syndrome (hfrs) in humans in the old world and hantavirus cardiopulmonary syndrome (hcps) in the new world. in a large european union project, eden (emerging diseases in a changing european environment, ), rodent-borne (robo) viral infections have been studied, along with tick-borne pathogens, leishmaniasis, west nile virus, malaria and rift valley fever. the most important aim of professor henttonen and his colleagues was to clarify the differences in boreal (northern) and temperate europe in the human epidemiology of nephropathia epidemica, by far the most common hantaviral disease in europe, caused by puumala hantavirus (puuv). the population dynamics of the host species, the bank vole, differ greatly in various parts of europe, driven by predation in the north and masting events in the temperate zone. consequently, the causes of rodent fluctuations are different. in addition, the role of landscape patterns (homogenous taiga vs. fragmented temperate forests) in rodent/virus dispersal is significant, as well as local environmental conditions (e.g. temperature and moisture), which affect virus survival outside the host. for example, in room temperature, puuv remains infectious for at least weeks outside the host, and possibly for much longer in cold temperatures and in moist conditions. these research findings are essential for human risk evaluation with regard to both long-term and seasonal occurrence of puuv in the environment. in spite of chronic infection of bank voles and the excretion of puuv in their faeces, urine and saliva, the shedding period is limited, which has significant implications for seasonal transmission dynamics in rodents. thus, within the same host/virus system, biomespecific puuv epidemiologies occur (kallio et al., ; tersago et al., ) , thereby highlighting the need for geographically comparative studies in europe (metla, ) . professor v. sambri and his team, p. gaibani, f. cavrini, a. m. pierro, m. p. landini and g. rossini (all regional centre for microbiological emergencies [crrem] , unit of clinical microbiology, st orsola-malpighi university hospital, bologna, italy) investigated usutu: a novel human pathogenic mosquito-borne flavivirus. this virus belongs to the japanese encephalitis serogroup within the mosquito-borne cluster of the genus flavivirus in the family flaviviridae. first isolated from mosquitoes of the genus culex in south africa in , the usutu virus (usuv) has since been isolated from mosquitoes, rodents and birds throughout sub-saharan africa and europe. the virus is thought to be maintained in nature in a mosquito-bird transmission cycle in areas with a minimum of at least ten hot days > °c, but no mammalian reservoir has yet been identified. professor sambri pointed out that it was not until september that usuv was found in the liver of a patient who underwent an orthotropic liver transplant (gaibani et al., ) . further study of the plasma and genome sequencing analysis confirmed the presence of usuv viremia. then usuv was detected in the livers of an additional four patients from the same area suffering from acute meningo-encephalitis during / . both serological assay and molecular assay have been used as new tools for the diagnosis of usuv infection. thus, it is now clear that usuv is a new emerging flavivirus pathogenic for humans. further studies are required to discover both the geographical distribution of this virus and the mechanisms by which humans acquire the virus. since this conference presentation, there has been increased awareness of the seriousness of usuv (vázquez et al., ) . according to the world health organisation (who) and unicef, . million children under the age of five die from diarrhoea annually (unicef/who, astroviruses cause infections within the small intestine and are associated with at least % of all sporadic cases and > % of all hospitalized cases. these rapidly evolving, nonenveloped, single-stranded rna viruses can be transmitted directly from infected individuals and animals, and indirectly through contaminated food and water. professor schultz-cherry's laboratory was the first to demonstrate that astroviruses induce diarrhoea by a novel mechanism: they possess an enterotoxin that disrupts intestinal epithelial barrier function independent of cellular damage or an inflammatory response (koci et al., ) . this occurs within h post-infection because of reorganization of the tight junction protein occludin and the actin cytoskeleton (moser et al., ) . in essence, within a complex pathogenic process, astroviruses cause diarrhoea by increasing intestinal barrier permeability. this is the first evidence showing that a viral coat protein is an enterotoxin. of great interest, the toxin can act independently of species barriers. given the increasing isolation of astroviruses from diverse species, there is increasing evidence that toxicogenic astroviruses could be associated with zoonotic disease. professor m. g. katze (department of microbiology and washington national primate research center, university of washington, seattle, wa, usa) set out a unifying approach to molecular biology in his presentation, systems and computational biology: emerging tools for exploring emerging viruses. he emphasized that modern day virologists and immunologists must do better in their search to understand how a virus kills and how effective vaccines can be developed, especially because traditional virology has yielded surprisingly little information about why some virus strains cause severe diseases while others remain innocuous. he pointed out that the case fatality rate for the influenza pandemic was about . % and that particular h n virus may have infected as much as one-third of the world's population. issues arise not only in understanding a virus, but also in understanding how hosts respond. for example, the virus infection resulted in very high expression of inflammatory, antiviral and immune cell genes very early in host infection (kash et al., ) . significant progress in overcoming existing and emerging viruses depends on biologists, mathematicians and computer specialists working together within a systems biology paradigm. such research begins with either in vitro studies of virus replication on cell lines or primary cell cultures, moving to nonhuman primate models of virus infection. then samples from the experiments are investigated at multiple time points and conditions; and high throughput data are then examined by data processing to prepare systematic evaluations of different host responses. data integration involving data analysis and modelling of key genes and pathways is then possible, followed by iterative processing of host perturbations and the use of viral mutants to discover specific applications to translational research. such a systems biology approach requires not only continuing experiments with virusinfected experimental systems but also significant efforts to maintain the hardware and software of an extensive laboratory computational infrastructure. it is this computing infrastructure, which permits the laboratory to go quickly from samples to pathway visualization, as the data analysis workflow moves from microarray images to gene expression data to pathway models. the mission of this virolab is to develop steadily over the years to come a virtual laboratory to confront the viruses involved in infectious diseases -influenza, ebola, marburg, hepatitis c, sars-cov, vaccinia, herpes simplex, west nile, hiv- , siv, measles, lassa, chikungunya and dengue fever. the three key characteristics of this integrated approach to so many infectious diseases are as follows: (i) to use cell culture, primary cells, nonhuman primate and human clinical models to study viral infection; (ii) to combine traditional histopathological, virological and biochemical approaches with functional genomics, proteomics and computational biology (haagmans et al., ); and (iii) to obtain signatures of virulence and insights into mechanisms of host defense response, viral evasion and pathogenesis (casadevaill et al., ) . for example, with the study of all respiratory viral diseases, a unifying hypothesis is that highly pathogenic respiratory viruses use both unique and common strategies to remodel the host cell to enhance virus replication, regulate disease severity and promote virus transmission (chang et al., ) . a highly significant new tool for studying these emerging viruses is next generation sequencing (ngs) which has already 'changed the way we think about scientific approaches in basic, applied and clinical research' to such an extent that 'the potential of ngs is akin to the early days of polymerase chain reaction (pcr), with one's imagination being the primary limitation to its use' (peng et al., ) . already, a good understanding of the 'timing' and extent of immune (innate)-mediated injury after virus infection has been achieved. furthermore, molecular 'disease' signatures associated with different pathogens in multiple animal species have been described at micro-rna, mrna, protein level, metabolite and lipid levels. such successful modelling of molecular events has made possible verifiable prediction about key nodes and bottlenecks, enabling the identification of novel host cell drug targets (diamond et al., ) . the translational impact of this research, in professor katze's view, will be immense, revealing a completely new and expanded host defense repertoire consisting of non-annotated noncoding rnas. despite all of these achievements, four crucial questions remain unanswered: (i) is systems biology too complicated and too expensive to become the pre-eminent approach in virology and immunology? (ii) are mathematicians and computer scientists up to the challenges? (iii) how will new technologies like next generation sequencing impact virus systems biology research, especially in the context of rna sequencing? (iv) how can new principal investigators best be identified and appointed? (virolab, ) . it has long been recognized that the emergence of any zoonoses is a complex process involving 'ecological interactions at the individual, species, community and global scale' (childs et al., , p. ) . this topic began with a presentation from professor a. a. aguirre that focused on the ecological framework in which any zoonotic disease should be considered. the role of bats as an important reservoir host for many dangerous zoonotic pathogens was then considered in some detail (cf. daniels et al., ; field et al., ; gonzalez et al., ; wang and eaton, ) . professor a. a. aguirre (department of environmental science and policy, george mason university and executive director, smithsonian-mason global conservation studies program, front royal, virginia, usa) presented emerging zoonotic diseases of wildlife: developing global capacity for prediction and prevention. he began by explaining that conservation medicine and more recently ecohealth have emphasized the need to bridge disciplines, thereby linking human health, animal health and ecosystem health under the paradigm that 'health connects all species in the planet' (aguirre et al., ) . in his view, the recent convergence of global problems such as climate change, biodiversity loss, habitat fragmentation, globalization, infectious disease emergence and ecological health demands integrative approaches breaching disciplinary boundaries. the international union for conservation of nature (iucn) maintains a red list of threatened species -an important initiative in view of the animal extinctions that have already occurred, of which . % were caused by disease (smith et al., ) . professor aguirre noted that the u.s. agency for international development (usaid) has been a major leader in the global response to the emergence and spread of highly pathogenic avian influenza (hpai). since mid- , it has programmed approximately $ million to build capacities in more than countries for monitoring the spread of hpai among wild bird populations, domestic poultry, and humans, and to mount a rapid and effective containment of the virus when it is found. recent analyses indicate that these efforts have contributed to significant downturns in reported poultry outbreaks and human infections and a dramatic reduction in the number of countries affected. furthermore, the usaid bureau for global health, office of health, infectious disease and nutrition (gh/hidn) recently funded two cooperative agreements, predict and respond, under its avian and pandemic influenza and zoonotic disease program to continue and expand this work. the goal of predict is to establish a global early warning system for zoonotic disease emergence that is capable of detecting, tracking and predicting the emergence of new infectious diseases in high-risk wildlife (e.g. bats, rodents and nonhuman primates) that could pose a major threat to human health. the goal of respond is to improve the capacity of countries in high-risk areas to respond to outbreaks of emergent zoonotic diseases that pose a serious threat to human health. the geographical scope of this expanded effort is directed to zoonotic 'hotspots' of wildlife and domestic animal origins (jones et al., ) . predict includes a program of smart (strategic, measurable, adaptive, responsive and targeted) surveillance that focuses on preventing the 'spilling over' from wildlife to humans or to halt these diseases rapidly after that spillover by understanding what factors induce emergence and rapidly identifying ways of prevention, control, and mitigation. the overall aim of smart is to promote an integrated, global approach to emerging zoonoses. this integration requires commitment from a broad coalition of partners and stakeholders including government agencies, universities and non-governmental organizations, collaborating for specific purposes and to generate in the future new international structures able to respond to these emerging zoonoses. with . billion animals being imported into the united states each year, as well as an extensive international trade in illegal animal exports ) and some % of emerging zoonoses worldwide having wildlife origins, professor aguirre stressed that ecohealth has become a necessity, not an optional policy goal. dr. g. a. marsh and his colleague dr. l.-f. wang (australian animal health laboratory [aahl], geelong, victoria, australia) began their presentation, bats: a mixed bag of new and emerging viruses, by pointing out that the ''old'' bat viruses were represented by many zoonotic pathogens, including rabies virus, yellow fever virus, st louis and japanese encephalitis viruses, and west nile virus. now bats have been identified as natural reservoirs for a number of new and emerging viruses -ebola virus, marburg virus, hendra virus and sars-like coronaviruses. there are some different bat species; and they often roost in high-density colonies of over one million flying mammals, which have, in a very real sense, been travelling for millions of years, exposing themselves to many pathogens; therefore, the resulting complexity is not surprising. key research questions include (i) why do bats seem to be able to co-exist with a great diversity of viruses without showing disease signs? (ii) what triggers the spillover of bat viruses into other animals? (iii) do bats control viral infection differently from other mammals? attempts to isolate viruses from bats have generally been unsuccessful. therefore, in an effort to improve the success rate for virus isolation, dr. marsh and his team have recently developed primary cell culture lines from numerous different species of bats (crameri et al., ) . the use of these bat cell lines, in combination with improved sampling techniques, has lead to recent isolation of hendra virus from a number of bat urine samples collected in several locations across queensland, australia, including those associated with human and horse virus spillover events (smith et al., ) . furthermore, this henipavirus surveillance program has led to the isolation of a number of novel viruses from two different virus families, whose zoonotic potential is not yet known. in an attempt to understand virus/host interactions, as well as to provide insight into the key factors involved in future spillover events, aahl has launched a number of international collaborative projects in south-east asia and ghana, west africa. c. kohl (sonntag et al., ) . the phylogenetic analysis of the genome sequence of bat adv- demonstrated a close relationship to canine adenovirus and (cadv- and cadv- ) (kohl et al., ) . the very similar genome organization supported the hypothesis of a shared ancient ancestor. interestingly, both cadvs are presenting untypical pathological features within the family adenoviridae. these adenoviruses were found to have an unusually broad host range and are causing a rather higher pathogenicity in a variety of carnivore hosts. the untypical pathological features might be understood as signs of a missing adaptation host and could provide a model to study ancient inter-species transmission events. this section of the conference addressed cross-species transmission of selected pathogens. in addition to the summaries below of three presentations on this topic, this special supplement includes an article, epidemiological survey of tryanosoma cruzi infection in domestic owned cats from the tropical southeast of mexico by dr. m. jiménz-coello et al. setting out how a significant public health problem in mexico has been caused by the crossspecies transmission of american trypanosomiasis (at) from triatomine bugs to domestic cats, representing a potential risk to humans. speaking on behalf of an extensive team of collaborators from a number of institutions -c. osborne, p. cryan, t. j. o'shea, l. m. oko, c. ndaluka, c. h. calisher, a. berglund, m. l. klavetter, r. a. bowen and k. v. homes -dr. s. r. dominguez (section on pediatric diseases, the children's hospital, university of colorado school of medicine, aurora, co, usa) began by noting that the first pandemic of the twenty-first century, the deadly sars virus, had its natural reservoir in bats. in his presentation, alphacoronaviruses in new world bats: prevalence, persistence, phylogeny and potential for interaction with humans, he suggested that bat coronaviruses (covs) may well be the ancestors of all group and covs. today bats had become a primary species encountered by humans in terms of potential exposure to significant disease agents. their research was tackling three important unanswered questions: (i) what is the prevalence and diversity of bat covs in new world bats? (ii) do bat covs persist in bat populations and/or individual bats? (iii) what are the potential interactions of infected bats with the human population? a -year study (osborne et al., ) had collected clinical and environmental samples from bats at rural sites and urban sites throughout colorado, as well as bat carcasses obtained from various counties throughout the state from the colorado department of public health and environment. of the , faecal or anal swab samples, , that is, %, were positive for cov rna. the highest prevalence of the virus was in juvenile bats; although rates of prevalence varied from year to year, late spring was the time when the virus peaked. although bat covs persisted within bat populations and their roosts, individually tagged cov-infected bats cleared their infections within weeks without apparent illness. new world bats of the same species in geographically distinct locations and over the course of several years harbour similar covs, and some new world bat covs may be able to infect bats of different genera. strikingly, bats, which had known or potential contact with humans, had a high prevalence of - % of cov infection. it is clear that significant opportunities exist for zoonotic transmission of coronaviruses from bats to humans and vice versa, especially as more than viruses have already been isolated from or detected in bat tissues. noting that many mammalian and avian species in addition to bats are susceptible to coronavirus infection, receptor proteins that include ace , apn and cea-cam . the recent emergence of sars coronaviruses from civets, bats and/or other reservoir species into humans depended upon a few amino acid substitutions in the receptor-binding domain (rbd) of s from the animal viruses that allowed them to recognize human ace instead of, or in addition to, receptors of their natural hosts (li, ) . alphacoronaviruses of pigs, cats, dogs and human coronovirus e use apn receptors of the host species, and all four viruses recognize feline apn (tusell et al., ) . in contrast, for human alphacoronavirus nl , the receptor-binding motif (rbm) with its three loops in the rbd binds specifically to human ace . in the rbds of the cat virus, fipv, professor holmes and her research team predicted three loops structurally similar to the nl rbms, and they constructed chimeric fipv rbds containing one, two or three rbms from nl . receptor-binding assays using enzyme-linked immunoassays (elisa), flow cytometry and co-immunoprecipitation identified three loops (rbms) in fipv rbd that are required for binding to feline apn. furthermore, substitution of only a few key amino acid residues within the rbms of fipv altered apn specificity and viral host range. thus, the emergence of alphacoronaviruses into new host species can occur when spontaneous mutations arise in the rbms that permit binding to variants of the apn receptor protein expressed by different host species. considering the interaction between human and swine h n viruses since , professor h. d. klenk (institute of virology, philipps university, marburg, germany) presented the mechanisms of pathogenicity and host adaptation of influenza viruses in the light of the new h n pandemic. he explained that there was now a clear scientific consensus that wild aquatic birds are the natural hosts for a large variety of influenza a viruses. occasionally these viruses are transmitted from this reservoir to other species, such as chickens, pigs and humans, leading to devastating outbreaks in domestic poultry and the possibility of human influenza pandemics. by the end of february , there had been , deaths, with the world health organization later confirming cases in countries and territories, with deaths in at least countries and territories before the spread of the h n virus diminished. however, professor klenk set out the evidence to support his view that the pathogenic and pandemic potential of this new h n virus is not yet exhausted. the host range and pathogenicity of any virus are polygenic traits depend on the interaction of different viral proteins with specific host factors. it has long been known that proteolytic activation and receptor specificity of the hemagglutinin (ha) are important determinants for pathogenicity and interspecies transmission, respectively. there is now considerable evidence that ha mutations altering receptor specificity and cell tropism of the pandemic influenza a virus (h n v) are linked to the d g amino acid substitution and are associated with a particularly severe outcome of infection (liu et al., ) . it should be remembered that the viral polymerase has to enter the nucleus of the infected cell to promote replication and transcription of the viral genome. adaptive mutations in polymerase subunits of avian viruses improve binding to importin alpha, a component of the nuclear pore complex in mammalian cells. as a result, nuclear transport of these proteins and efficiency of replication are enhanced. thus, the interaction of the viral polymerase with the nuclear import machinery is an important determinant of host range. some of the structural features typical for avian viruses have been preserved in the polymerase of the pandemic influenza a virus (h n v) suggesting that this virus has the potential to further adapt to humans. recent studies have shown that the ns protein, another important determinant of pathogenicity and host range, is sumoylated and that this modification enhances virus growth. interestingly, ns of h n v is not sumoylated (xu et al., ) . taken together, these observations support the view that the pathogenic and pandemic potential of the new virus is not yet exhausted. furthermore, because of the firm evidence of ha polymorphism in position , mutants and other mutations with altered receptor specificity will have to be closely monitored. in the subsequent discussion, it was noted that when a virus becomes highly pathogenic, this might block its spread if additional hosts are not readily available. furthermore, the role of co-infection with bacterial inflection was highly relevant in the - influenza pandemic and might well be relevant in a future pandemic. there have been at least three influenza pandemics every century since , with some evidence of earlier epidemics and pandemics after . in the cambridge world history of human disease, a. w. crosby ( ; p. ) has noted that although the black death and world wars i and ii killed higher percentages of the populations at risk, the - influenza pandemic was possibly 'in terms of absolute numbers, the greatest single demographic shock that the human species has ever received'. the summaries below of seven presentations on this topic highlight the diversity of influenza viruses in north america (cf. nelson et al., ) , while other relevant research has been published with respect to swine influenza viruses (sivs) in europe (kyriakis et al., ) . considerable research has now been carried out into how the highly pathogenic h n avian influenza virus spreads from wild birds and ducks to chickens and other species, including humans (rabinowitz et al., ; ma et al., ) . the studies of how influenza viruses can be genetically altered to become more transmissible have become a matter of much controversy palese and wang, ) . in addition, to the summaries below, this special supplement includes an article, lessons from emergence of a/goose/guangdong/ -like h n highly pathogenic avian influenza viruses and recent influenza surveillance efforts in southern china, in which dr. x.-f. wan has considered the emergence and ecology of influenza a viruses in southern china, especially the highly pathogenic h n virus. backed by an extensive team of collaborators, professor a. d. m. e. osterhaus (head, department of virology, erasmus medical centre, rotterdam, the netherlands) began his presentation, emerging and neglected influenza viruses, by explaining the complex aetiology of the influenza a, b and c viruses. while humans can serve as host species for all three viruses, influenza a can also be present in other mammals and avian species, influenza b in seals and influenza c in pigs. the severity of the disease is relatively high with influenza a, moderate with influenza b and low with influenza c, with the prevalence in humans high with both influenza a and b viruses, but lower with influenza c. furthermore, a clear distinction needs to be made between seasonal influenza, avian influenza and pandemic influenza. there are two different mechanisms of host adaptation -sequential mutations and genome reassortment. most recently, the new h n swine flu pandemic outbreak of drew attention to the speed with which an influenza virus could move around the world. however, the fact that this particular virus was not as virulent as first anticipated proved crucial in confronting the virus, even though it spreads rapidly among humans, unlike the much more virulent h n avian flu virus, from which more than people have died from more than verified cases from to (world health organization (who), ). although clinical evidence of h n avian influenza appears predominantly in diving ducks, a number of dabbling duck species -mallard, teal, wigeon and gadwall -appear to spread h n , generally acquired from wild birds, without showing major signs of disease. the likelihood of a major pandemic linked to h n has not decreased in the last years, even though publicity has certainly decreased. furthermore, professor osterhaus pointed out that the recent h n pandemic influenza outbreak indicated that the scientific community was wrong in its earlier belief that 'a pandemic strain could only arise from a subtype that had not previously been widely disseminated in humans [because] the h n virus has shown that human varieties characterized by different hemagglutinin (ha) molecules may follow separate lines of evolution and may generate potentially pandemic strains within an existing human ha subtype. hence, it is essential to develop methods for estimating how many antigenically different subtypes may reside within each ha type' (cf. rappuoli et al., ) . in the light of the continuing prevalence of many subtypes of influenza, there is a critical need for improved monitoring, especially in asia and africa, as part of a move from a reactive to a proactive approach, with greater research into the possibility of developing a universal vaccine. although there are increasing opportunities for virus infections to emerge and spread rapidly in our global society, new tools are being provided by research in molecular biology, epidemiology, genomics and bioinformatics. already early warning systems based on state of the art virus detection techniques, as well as targeted intervention strategies based on data about the mutual virus-host interaction have been instrumental in dealing with numerous viral threats, including sars and avian influenza. the extensive research of the department of virology at erasmus medical centre in rotterdam was highlighted by a further presentation, influenza pneumonia: the role of the alveolar macrophage, given by dr. d. van riel. highly pathogenic avian influenza (hpai) h n virus causes severe, often fatal, pneumonia in humans. the pathogenesis of hpai h n virus is not completely understood, although the alveolar macrophage (am) is thought to play an important role. the am resides in the pulmonary alveolus, the primary site of hpai h n virus replication in humans. it had been shown previously that hpai h n virus attaches abundantly to these am (van riel et al., ) . the aim of this study was to determine the response of primary human am to hpai h n virus, seasonal h n virus or pandemic h n virus, and to compare these responses with that of macrophages cultured from monocytes. hpaiv h n infection of am compared with that of macrophages cultured from monocytes resulted in a lower percentage of infected cells (up to % versus up to %), lower virus production and lower tnf-alpha induction. infection of am with h n or h n virus resulted in even lower percentages of infected cells (up to %) than with hpai h n virus, while virus production and tnf-alpha induction were comparable. in conclusion, this study revealed that macrophages cultured from monocytes are not a good model to study the interaction between am and influenza viruses. furthermore, the interaction between hpai h n virus and am could contribute to the pathogenicity of this virus in humans, because of the relatively high percentage of infected cells rather than virus production or an excessive tnf-alpha induction (van riel et al., ). one virus of each pair was wild type, while the other carried the h y na mutation conferring resistance to na inhibitor oseltamivir. within each pair, the wild-type and oseltamivir-resistant virus caused disease of equal severity in ferrets and replicated to comparable virus titers in the upper respiratory tract. then, to assess the fitness of drug-resistant h n influenza viruses, the research team considered virus-virus interactions within the host by co-inoculating ferrets with mixtures of the oseltamivirsensitive and oseltamivir-resistant h n viruses in varying ratios (e.g. / ; / ; / ; / ; / ). using this novel approach, they demonstrated that the proportion of a/vietnam/ / -h y clones tended to increase, while the proportion of a/turkey/ / -h y clones tended to decrease. their findings suggest that the h y na mutation can affect the fitness of two h n viruses differently and is dependent on background na sequence. dr. govorkova pointed out that antigenic and genetic diversity, virulence, the degree of na functional loss of h n virus and differences in host immune response can also contribute to such differences. therefore, the risk of emergence of drug-resistant influenza viruses with uncompromised fitness should be monitored closely and considered carefully in pandemic planning. in a collaboration with c. corzo, k. juleen and m. gramer they initiated an active surveillance program in healthy pigs in multiple sites in , during a period coincident with the emergence of the h n pandemic in humans. their study, active surveillance for influenza viruses in north america, presented an analysis from months of data which indicated that similar viruses can be detected in both active and passive surveillance schemes and that there has been an explosion of diversity in swine influenza viruses (siv) in the united states. not only were a number of pandemic h n infections in swine detected, but a number of pandemic/endemic swine virus reassortants were found, albeit from healthy animals (ducatez et al., ) . virologically, the pattern of disease surveillance grounded in the activities of state diagnostic laboratories collecting information from diseased animals is representative; however, epidemiologically this data from diseased animals is not representative. reverse zoonoses have had a huge impact on siv in the united states (vincent et al., ) , and the pandemic virus is now endemic. however, in considering whether any particular reassortment causes alarm, it must be acknowledged that there is not yet a good model of risk, so h , like h , is going to be found in pigs for some time to come, but the consequences of this diversity in siv are not yet clear. the extensive collaboration now taking place in the study of swine influenza was evident in the presentation vessel pendulum began by explaining the three elements of how swine could be considered as a mixing vessel for influenza a viruses as formally proposed by scholtissek et al. ( ) : (i) swine are susceptible to infection with influenza a viruses from avian and human viruses; (ii) the avian viruses can adapt within the pig, producing novel reassortants; and (iii) these reassortants can then be shed and are infectious to man. the goal of this presentation was to test the first part of the mixing vessel hypothesis, concerned with the susceptibility of swine to avian and human influenza viruses, making use of both mixing vessel studies in pigs and genetic markers to investigate adaptation. dr. lager noted that the emergence of the h n highly pathogenic avian influenza virus that can transmit from avian species directly to man, and the presumption that the h n influenza jumped from birds to man has expanded our understanding of the swine mixing vessel hypothesis as a potential, but not exclusive, source of human pandemic viruses (taubenberger et al., ) . moreover, the emergence of the pandemic h n virus has re-emphasised swine as a potential source of pandemic virus. in this study, all of the challenge viruses (avian h , h , h ) induced a similar effect in pigs; challenge viruses did replicate in pigs; the infections were subclinical with mild pneumonias; most infections resulted in seroconversion; and none of them transmitted to contact controls. this series of studies suggests pigs could be easily infected with avian viruses; however, an adaptation step is needed to generate fit viruses that transmit among swine. parallel studies are currently underway testing the susceptibility of pigs to human seasonal influenza viruses. future studies using reverse genetics could investigate potential genetic markers for adaptation of avian viruses to swine which may provide insight into the interspecies transmission of influenza viruses. a in this study, an attempt was made to recreate the pandemic virus by co-infecting cells (in vitro) or a group of pigs (in vivo) with eurasian (sp ) and north american triple reassortant (ks ) sivs (ma et al., a) . infected pigs were co-housed with two groups of sentinel animals to investigate virus maintenance and transmission. the origin of each gene segment of viruses was determined, which were isolated from supernatants collected from co-infected cells or nasal swabs and bronchioalveolar fluid samples collected from infected and sentinel animals. different reassortant viruses were identified from co-infected cell lines; however, no virus with the genotype of ph n was found. less reassortant viruses were found in the lungs of co-infected pigs in contrast to those in co-infected cells. interestingly, only the intact ks was detected from nasal swabs from the second group of sentinel pigs. these results demonstrated that multiple reassortant events can occur within the lower respiratory tract of the pig; however, only a specific gene constellation is able to be shed from the upper respiratory tract. however, in this study, it was not possible to generate the ph n constellation using co-infection with the techniques described above and previously (ma et al., b) . in . she began by reflecting on the ability of swine to act as a reservoir for many influenza viruses, becoming infected with low mortality, regardless of influenza virus strain. the objective of the study was to further understand the porcine response to influenza and to compare this response to other animals infected with the same virus. to accomplish this objective, they used statistical and functional analysis of global gene expression to compare host transcriptional response during acute infection by a contemporary h n pandemic influenza virus (a/california/ / ) in swine, non-human primates and mice. using their data, they compared and contrasted the biological pathways most significantly associated with gene expression changes during acute infection across these species. their goal was to leverage data collected in their previous studies (ma et al., ; safronetz et al., ) to better understand influenza virus pathogenesis through a cross-species analysis that considered three crucial questions: (i) which genes change over the course of acute infection? (ii) what are the top functions altered during infection? (iii) how does functional response compare across the three species? despite challenges to data integration and interpretation, including the differences in transcript representation and annotation on the microarrays for the different species, the researchers found notable differences in response to influenza in the lungs of the three species. although similar functional groups of genes changed with infection in all three species, the nature of that response was species specific. swine exhibited an elevated transcriptional response that tapered by resolution of influenza. mice exhibited a decrease in many acute phase and immune response genes quickly followed by a steady increase in expression. host response in macaques was most pronounced and maintained over time. in considering the transcription of immune-related genes in swine, mice and nonhuman primates, they found that although the number of immune-related genes changing in each species was similar, the precise genes changing were very different, with only immune response genes commonly differentially expressed across all three species. this suggested that the nature of immune response within each species may be quite different. in response to the perennial question after any scientific experiment, ''where do we go from here?'' they offered four ideas: (i) time series analysis could reveal unique response kinetics across species, thereby leading to targeted analysis; (ii) data integration across multiple data types, including transciptomics, proteomics, mirna and ngs could generate a more complex, multidimensional view of response; (iii) as annotation of the different species-specific genomes improves, this information could be integrated into future analyses, making a better understanding of the biological responses to infection possible; and (iv) the gathering of this additional information could empower more precise analysis on what makes each species uniquely susceptible or resistant to influenza. in the firm view of these particular six researchers, studies such as this are necessary for a deeper understanding of influenza pathogenesis and demonstrate the utility of systems biology in the study of emerging viruses. three relevant articles on this topic have been published below, highlighting the global dimensions of both infection and treatment, no matter where the virus first emerges. the need for geographical comparative studies of the emerging hantavirus, puumala hantavirus (puuv), has already been indicated by professor henttonen and his team in their presentation summarized earlier in the opening topic of this meeting review. in a further investigation into the same hantavirus, dr. eckerle and her colleagues have presented an article within this special supplement entitled atypical severe puumala hantavirus infection and virus sequence analysis of the patient and regional reservoir host. in this article, they focus on the difficulties in the diagnosis of and treatment for a single patient and performed virus sequence analysis showing regional clustering in reservoir and host. in their more wide-ranging conference presentation, they investigated cytokine expression in a cohort of patients hospitalized with acute severe hantavirus infection during an epidemic in germany in (cf. faber et al., ) . elevated proinflammatory cytokines during the early phase of disease compared to healthy controls and increase in immunosuppressive tgf-b from early to later phase of disease supported the hypothesis of an immune-mediated pathogenesis of puumala hantavirus (sadeghi et al., ) . this finding indicates that the immune status of the host for old-world hantaviruses plays an important role, not only the virus itself. in a further article published in this special supplement, how ebola virus counters the interferon system, a. kühl and s. pöhlmann have reviewed which components of the innate immune system could be effective against the zoonotic transmission of ebola virus (ebov) to humans, which results in severe haemorrhagic fever and high case-fatality rates. their focus is on how the interferon (ifn) system, as a key innate defense against viral infections, is targeted by distinct ebov proteins, and on how specific effector molecules of the ifn system could form a potent barrier against the spread of ebov in humans. finally, in lassa fever in west africa: evidence for an expanded region of endemicity, dr. n. sogoba and his colleagues h. feldmann and d. safronetz have stressed the importance of increased surveillance for lassa virus across west africa. the seven presentations summarized below cover a number of haemorrhagic fever viruses. for example, an important example of a highly contagious and life-threatening haemorrhagic fever virus is crimean-congo haemorrhagic fever virus (cchfv), caused by a tick-borne virus of the bunyaviridae family (elliott, ) , first recognized in the crimea in , with an identical virus isolated in the congo in ; the incidence and geographical spread of this disease with its high human fatality rate have increased significantly in the past years. however, the causes of this increase are not yet clear (maltezou and papa, ) . in the light of the need to develop new therapies and effective, safe vaccines, the next seven research presentations could prove to be of considerable significance, not only for cchfv, but also for the hendra, nipah, lujo and ebola viruses. although these viruses have certain common features in their causes and consequences, each haemorrhagic fever virus needs to be carefully studied as a distinct entity. dr (peyrefitte et al., ) . moreover, it has already been shown that cchfv causes liver damage in infected patients and in the animal model (bereczky et al., ) . the research objectives were to consider: (i) how does cchfv affect hepatocarcinoma cell lines? (ii) is cchfv able to enter and replicate into these cell lines? (iii) does cchfv modulate the in vitro cellular response? to better understand the cchfv pathogenesis in liver cells, they analysed in vitro the host response induced after cchfv infection in huh (unable to produce ifn-beta) and hep-g (capable of producing ifn-beta) cell lines. they noticed that while in huh , cchfv infection elicited at day a cytopathogenic effect, no visible effect was seen in cchfv-infected hepg . this intriguing feature led them to analyse the viral parameters expecting a differential cellular response. both cell lines were shown to be permissive to cchfv and with a high viral yield as monitored by plaque titration assay, genomic and antigenomic strand quantification. these cchfv-infected hepatocarcinoma cell lines induced only il- secretion. in addition, a pro-apoptotic effect was observed in huh but not in hepg . interestingly, no type-i ifn was detected for hep-g during the kinetic study, suggesting a strong inhibition of ifn secretion. they concluded that cchfv does enter and replicate in hepatocytes and that hepatocytes could be involved in cchf pathogenesis associated with antigen presenting cells for cchfv dissemination. while cchfv did not induce ifn-beta secretion in hepatocyte cell lines, cchfv did induce the secretion of il- in hepatocyte cell lines. furthermore, cchfv induced a higher secretion of il- in the apoptotic huh cell line than in the nonapoptotic hep-g cell line. thus, this research indicated that il- production and apoptosis seemed to be markers of cchfv pathogenesis in hepatocyte cell lines. professor t. w. geisbert (university of texas, medical branch, galveston, tx, usa) presented an evaluation of countermeasures against hendra and nipah viruses in nonhuman primate models. he pointed out that the henipaviruses, hendra virus (hev) and nipah virus (niv) are enigmatic emerging pathogens that can cause severe and often fatal neurologic and/or respiratory disease in both animals and humans. guinea pigs, hamsters, ferrets and cats have been evaluated as animal models of human hev infection. a research team led by professor geisbert recently evaluated african green monkeys as a nonhuman primate model for henipavirus infection and discovered that they are the first consistent and highly susceptible nonhuman primate models of hev and niv infection rockx et al., ) . the severe respiratory pathology, neurological disease and generalized vasculitis manifested in both hev-and nivinfected african green monkeys provides an accurate reflection of what is observed in henipavirus-infected humans. these nonhuman primate models were then employed to evaluate several post-exposure treatments including ribavirin (which did not work) and a human anti-henipavirus monoclonal antibody (which was successful). dr the research was motivated by the awareness that neutralizing antibodies are probably the major effectors against this viral infection. the rationale of using rv vectors for the development of a niv vaccine was fourfold: (i) rv-vectored vaccines are not pathogenic regardless of the route of administration or the immune status of the host; (ii) rv-based vaccines are very efficacious even after a single immunization by the oral route; (iii) rv-based vaccines have the ability to target macrophages and dendritic cells, to induce th t-cell response and are capable of inducing long-lasting immunity; and (iv) postexposure prophylaxis using recombinant rv vaccines is very effective, even when the cns is already infected (faber et al., a,b) . the niv g gene was inserted into the non-pathogenic rv vectors spbaangas or spbaangas-gas, resulting in spbaangas-ng or the double gas variant spbaan-gas-ng-gas, respectively. further research led to four significant conclusions: (i) there are no detectable amounts of niv g present in recombinant nivg-rv particles; (ii) the presence of an niv g gene does not increase, but rather decreases the pathogenicity of the recombinant viruses; (iii) priming with nivg-rv triggers a strong niv g-specific memory response, which correlates inversely with vaccine concentration used for the priming; and (iv) a single immunization with nivg-rv is probably sufficient to protect against a niv challenge infection. arenaviruses are rodent-borne bisegmented ambisense rna viruses, which include lassa fever virus, lymphocytic choriomeningitis (lcm) and tacaribe the index case for this acute febrile illness virus was a travel agent living on a farm during in lusaka, zambia, who infected a local cleaner, as well as a paramedic and a nurse in johannesburg, south africa, all of whom died, with the paramedic infecting a further nurse who was treated with ribavirin and survived . the name of the virus originated from the first two letters of the two key cities, lusaka and johannesburg. four of the five infected persons died of haemorrhagic fever-like symptoms paweska et al., ). viral genome sequencing revealed that this virus differed from other arenaviruses by at least % and is highly pathogenic, with a case fatality rate (cfr) of % paweska et al., ) . in view of the uniqueness and high virulence of lujo virus (ljv), the research team developed a reverse genetics system to study the molecular characteristics of this novel arenavirus. this system will facilitate studies of ljv biology, development of antiviral screening assays and pathogenesis studies in animal models. t. cutts (national microbiology laboratory, public health agency of canada, canadian science centre for human and animal health, winnipeg, manitoba, canada) with his colleagues s. theriault (chief, applied biosafety research program, same centre) and g. kobinger (chief, special pathogens program, same centre) presented cytofixÔ inactivation of veroe cells infected with zaire ebola virus (zebov) both in vitro and in vivo. first, it was pointed out that removing infected tissues from high-containment laboratories requires implementation of a number of different decontamination techniques to render the organism inert and is subject to flexibility according to the laws of the country in which the laboratory is located. according to the canadian biosafety guidelines th edition, an organism may be removed from containment once it has been rendered inert, but no procedure is in place to validate these biosafety guidelines, and it is up to the individuals to implement the relevant guidelines (public health agency of canada, , p. . chap. . . ). methods such as gamma irradiation, formalin fixation, acetone and methanol permeation, plus the use of various other chemical agents, are common practices to preserve cellular tissue or blood components and to inactivate organisms (elliott et al., ; mitchell and mccormick, ; preuss et al., ; villinger et al., ; sanchez et al., ) . such methods still raise questions as to their effectiveness or their redundancy. furthermore, these inactivation steps can lead to the alteration of the target organism possibly affecting the qualitative and quantitative results. the focus of the applied biosafety research program was to evaluate and develop technologies and procedures relevant to biocontainment in the context of the laboratory, as well as to prevent unintentional and intentional release of dangerous organisms into the environment. using the commercial product, cytofix/cytoperm tm from bd biosciences, this research sought to inactivate vero e cells which had been infected with the deadly zaire ebola virus (zebov). the aim of the research was to determine the effectiveness and duration of cytofix/ cytoperm for fixing the cellular material infected with zebov. the veroe cells were infected with the wildtype zebov and a mouse adapted zebov(mazebov) and assayed after a -min and -min exposure to cyto-fixÔ followed by neutralization. samples of blood from a non-human primate infected with zebov were drawn at dpi and assayed for effectiveness in the same manner as the in vitro studies with cytofixÔ. in addition, vero e cells infected with mazebov were treated in the same manner and injected into balb/c mice to compose the in vivo studies. cytoxicity and neutralization assays were used to determine the effect (if any) the treatment had on both the virus and the health of host cells. results of the tissue culture tcid assay showed that a -min exposure to cytofixÔ inactivated a large portion of the cells containing infectious virions, while after a -min exposure, no detectable levels of virus were observed. blood samples from the non-human primates showed similar results to the cell culture assay having no detectable virus from infected cells after min of exposure. in vivo studies with mice showed that both a min and -min exposure time to cytofixÔ had a % survival rate after days post-infection, while the positive controls succumbed after to dpi. because laboratories differ in their preferences of technique, the time of inactivation also varies. what this research demonstrated was the effectiveness of a quick procedure of min for inactivating viruses within cells infected with zebov, thereby rendering organisms safe to remove from containment. has not yet been linked with disease in humans, the presence of antibodies against rebov in people working closely with infected macaques and swine indicates that humans can be infected with this virus (miller et al., ; miranda et al., ; barrette et al., ). however, research has been hampered by the fact that the only available disease model for rebov to date has been cynomolgus macaques. seeking new rebov disease models, the research team assessed various rodent models -the balb/c mouse, hartley guinea pig, syrian hamster and stat )/) mouse that lacked the signal transducer and activator of transcription (durbin et al., ) . although virus replication occurred in guinea pigs and hamsters, progression to disease was only observed upon inoculation of stat )/) mice. despite certain drawbacks set out in the journal article, the stat )/) mouse can be used to investigate the determinants of differences in pathogenicity in various rebov strains, as well as to assess vaccination and antiviral therapies (miller et al., ; miranda et al., ; durbin et al., ; barrette et al., ; de wit et al., ) . the unity of human, animal and ecosystem health outlined by professor aguirre, as well as the interactions among multiple tick-borne pathogens in a natural reservoir host set out by professor fish and his research team, both summarized in topic above, highlight the necessity of cross-disciplinary collaboration in studying zoonotic bacterial diseases (daszak et al., , pp. - ) . such collaboration is especially important in studying tick-borne infectious disease, which emerged so extensively in the united states during the last three decades of the twentieth century (paddock and yabsley, , p. ) . now, in an article published in this special supplement, beyond lyme: etiology of tick-borne human disease with emphasis on the southeastern united states, drs. stomdahl and hickling have explained that tick distributions are in flux, especially in the south-eastern united states, requiring health providers to think 'beyond lyme' to identify the specific tick species that bite humans and the different pathogens these ticks carry. in an international context, drs. wood and artsob have set out the increasing importance of travel-associated rickettsioses in their article, spotted fever group rickettsiae: a brief review and a canadian perspective. in a third article published in this special supplement, drs. verma and stevenson present an article on epidemiology of leptospirosis with its one million cases worldwide. in leptospiral uveitis -there's more to it than meets the eye! they hypothesize in detail about how the eye inflammation uveitis is triggered and stress the impact that 'understanding how this bacterium is able to induce this inflammatory process will be a key to the better management and prevention of the disease'. this continuum of basic research leading to understanding a disease and then to managing that disease and finally to preventing it offers a pattern of scientific discovery that is relevant to many other emerging zoonotic diseases. opening his presentation, the foodborne pathogen campylobacter jejuni exploits mammalian host cell receptors and signaling pathways, professor konkel noted that the per cent of c. jejuni isolates that are resistant to antibiotics is continuing to increase and that c. jejuni infections are frequently associated with serious sequelae, including guillain-barré syndrome. it is well understood that infection with c. jejuni is often a consequence of eating foods contaminated with undercooked poultry. however, c. jejuni pathogenesis is a highly complex process that is dependent on many factors including motility, adherence, cell invasion, protein secretion, intracellular survival and toxin production. acute illness, characterized by the presence of blood and leucocytes in stool samples, is specifically associated with c. jejuni invasion of intestinal epithelial cells. dissecting bacteria-host cell interactions are critical to understanding the infection caused by c. jejuni. previous work has shown that maximal invasion of host cells by c. jejuni is dependent on synthesis of the c. jejuni cadf and flpa fibronectin (fn) binding proteins and requires the secreted campylobacter invasion antigens [cia(s)] (larson et al., ) . to test the hypothesis that maximal cell invasion requires specific signalling events, binding and internalization assays were performed in the presence of numerous inhibitors of cell signaling pathways. the research team found that c. jejuni cell invasion utilizes components of focal complexes (fcs), as invasion is significantly inhibited by wortmannin (an inhibitor of pi- kinase) and pp (a c-src inhibitor). they further demonstrated that a wild-type strain of c. jejuni results in the activation of the rho gtpase rac . these observations are consistent with the proposal that c. jejuni binding to host cell-associated fn and secretion of the cia proteins trigger integrin receptor activation, which in turn promotes intracellular signalling and actin cytoskeletal rearrangement. on the basis of these data, they concluded that c. jejuni utilizes a novel mechanism to promote host cell invasion. the research findings professor konkel presented were recently published in cellular microbiology (eucker and konkel, ) . simple, fast and specific tests for pathogen identification are essential for epidemiological investigation of numerous diseases. within the field of immunodiagnostics, a quantitative determination of either antibody or antigen by antigen-antibody interaction can be made by lateral flow tests (also known as a dipstick or rapid tests). dr. e. baranova and her colleagues p. solov'ev, n. kolosova and s. biketov (all state research center for applied microbiology, obolensk, russia) began the presentation, development of lateral flow tests for the fast identification of zoonotic disease agents, by pointing out that lateral flow (lf) tests can be used in the field, as a diagnostic tool that produces results that can be read visually by the naked eye within min after sample application. the creation of an algorithm for the development of an appropriate lf test to identify biopathogens requires the development of a target antigen, obtaining specific antibodies (biketov et al., ) and then creating a lf-test formulation to be trial tested. the target antigens must have the ability to induce species-specific antibodies, as well as be characterized by surface localization with multiple epitope presentation on the surface. the antibodies need to have a specificity and sensitivity sufficient for application in the lf detection format, as well as the capacity to be preserved after labelling with gold particles and after immobilization on a surface. over a period of months, the research team developed and tested in the field lf tests for the detection of bacillus anthracis, which causes anthrax, yersinia pestis, which causes bubonic plague, and francisella tularensis, which is the causative agent of tularaemia (or rabbit fever). all three of these lf tests have now been made available as commercial products and are being used throughout russia for the rapid identification of these dangerous pathogens. drs. j. d. trujillo and p. l. nara (center for advanced host defences, immunobiotics and translational comparative medicine, iowa state university, ames, iowa, usa) have developed and validated a new approach to the diagnosis of infectious agents. dr. trujillo explained that they are employing novel polymerase chain reaction (pcr)-based methods for the detection and differentiation of current and emergent mycoplasma species relevant to human and animal medicine and biodefense. their presentation, titled novel sybr Ò real-time pcr assay for detection and differentiation of mycoplasma species in biological samples from various hosts, began by explaining the relevance of mycoplasma species, which are endemic, strict or opportunistic pathogens in human and animal medicine. moreover, mycoplasma species are important re-emerging pathogens and foreign animal diseases. importantly, mycoplasma species are difficult to culture or are un-culturable, and thus are difficult to impossible to detect by conventional diagnostic methods. moreover, current pcr methods have limited breath of species detection and differentiation, requiring the use of species-specific assays that are costly and time-consuming. their goal was to develop a pilot mycoplasma genus diagnostic assay to validate the novel application of high-resolution melt (hrm) methodology for rapid, sensitive and cost-effective detection and differentiation of various pathogenic mycoplasma species. dr. trujillo presented the validation and utilization of sybr Ò green dye in real-time pcr (qpcr) mycoplasma detection and differentiation assay (panmyco qpcr). this pcr assay utilizes primers specific for this genus (modified from s. c. baird et al., ) . this pcr assay results in the generation of small dna fragments of various base pair lengths called pcr amplicons. each amplicon has a melt temperature (tm) that is determined following qpcr. sequence of amplicon representative of the mycoplasma species present defines the melt temperature (tm) and allows for the use of amplicons tm in species identification with limited resolution and excellent sensitivity. the panmyco qpcr assay has similar sensitivity to a conventional nested pcr assay for mycoplasma bovis with a linear detection range of one colony forming unit (trujillo et al., ). additional work presented described increasing species resolution of this assay, by defining unique melt profiles for each mycoplasma species amplicon utilizing precision melt software from biorad, ca, usa to perform hrm analysis. greater than different species of mycoplasma found in bovine, caprine, ovine, avian and porcine hosts have been characterized with the panmyco qpcr and hrm analysis. occasionally, this testing has resulted in the detection of multiple species in a single sample or discovery of novel or emergent mycoplasma species. this data analysis method allows for the sensitive detection and rapid differentiation of numerous mycoplasma species in many different hosts. dr. trujillo concluded that this novel real-time pcr assay can detect and potentially differentiate all known mycoplasma species. moreover, this presentation demonstrated the novel use of genus-specific sybr green pcr and hrm analysis for the detection, differentiation and discovery of medically important pathogens. several additional translational research projects have been launched to demonstrate the importance and utility of the pan myco qpcr assay in the context of infectious disease surveillance. one translational research project focuses on validation of this novel molecular methodology for field detection assays. there is increasing awareness of the need for improved laboratory investigation, risk assessment, contingency planning and simulation exercises to respond effectively to zoonotic diseases (lipkin, ; westergaard, a and b; escorcia et al., ) . in view of the need to research into and respond to so many emerging zoonoses, it is relevant to note the fourfold classification of emerging zoonoses proposed earlier by silvio pitlik: type : from wild animals to humans (hanta); type +: from wild animals to humans, with further human-to-human transmission (aids); type : from wild animals to domestic animals to humans (avian flu); and type +: from wild animals to domestic animals to humans, with further human-to-human transmission (sars) (kahn et al., : p. ) . confronting outbreaks of these emerging zoonoses is often possible with an imaginative combination of laboratory investigation and extensive fieldwork (borchert et al., ; robinson, ) . three distinctive articles appear below on outbreak responses to zoonotic diseases, highlighting the importance of linking together basic research, practical action and an integrated one health-oriented approach. in a. grolla and nine co-authors from eight different institutions in five different countries have explained how two mobile laboratories were set up and capable of running within < h of arrival, providing safe, accurate, rapid and reliable diagnostic services as the ebola zaire outbreak began in the democratic republic of the congo. finally, in emerging and exotic zoonotic disease preparedness and response in the united states: coordination of the animal health component, dr. r. l. levings has set out the integrated approach of emergency management and diagnostics, veterinary services, animal and plant health inspection service, united states department of agriculture in the prevention of, the preparedness for, the response to and the recovery from a zoonotic disease outbreak. in all three of these areas -basic research, practical action and an integrated one health-oriented approach -much has been achieved in recent years, but much also remains to be achieved as soon as possible. even when those diseases are not transmitted to humans, there are substantive challenges, as highlighted in the next case study by woods on combating brucellosis in cattle in zimbabwe. in a practical, problem-oriented presentation, dr. p. s. a. woods (veterinary public health section, faculty of veterinary science, university of pretoria, onderstepoort, south africa and university of reading) with r. s. beardsley (pharmaceutical health services research, school of pharmacy, university of maryland, baltimore, maryland, usa) and n. m. taylor (veterinary epidemiology and economics unit, school of agriculture, policy and development, university of reading, reading, united kingdom) asked can we increase farmers' perception of their brucellosis susceptibility to improve adoption of preventive behaviors amongst small-scale dairy farmers in zimbabwe? she explained the background to the problem, presented a model that was used to develop a strategy to confront the disease and then set out the results and recommendations of the research team. brucellosis is an extremely infectious bacterium that causes abortion in cows, different syndromes in other animal species and malaria-like undulant fever, arthritis, depression and epididymitis in people. however, it had been controlled in zimbabwe until when financial constraints forced the government veterinary services to curtail disease surveillance and discontinue free vaccinations. small-scale farmers did not seek vaccination from other sources, partly because they were unaware of the necessity of vaccination, and also at that time brucellosis was absent from small-scale farming areas. however, uncontrolled cattle movements from to linked to invasions of large-scale farms resulted in dispersal of possibly brucella-positive cattle and movement of the disease into small-scale herds. the result was that brucellosis became a potential problem in these herds and now presents a serious zoonotic threat. preventing brucellosis requires movement control to stop brucella-positive cattle entering an area, as well as live vaccine for female calves. although there is no human-to-human spread of the disease, it is essential that people do not handle new-born calves or abortions from brucella-positive cows, nor drink unpasteurized milk from brucella-positive cows (arimi et al., ) . in essence, reducing the risk of brucellosis requires that farmers adopt appropriate preventive behaviours, with these control efforts and changes in behaviour being communitydirected in order to be sustainable. it was this stress upon community direction that formed the basis for funding by the wellcome trust to investigate the hypothesis that the level of a farmer's knowledge about brucellosis would influence subsequent preventive behaviour. the approach, based partly on the 'health belief model' (rosenstock et al., ) was grounded in the expectation that each small-scale farmer would make health behaviour choices according to individual perceptions about the disease and personal beliefs about their abilities and the costs required to change the risks of their cattle and families acquiring the disease. in this project, the independent variable was the level of an individual farmer's knowledge about brucellosis, while the dependent variables were two key preventive behaviours -decreasing cattle disease by calfhood vaccination and preventing zoonotic disease by milk pasteurization. the research was carried out in partnership with a national network of small-scale dairy cooperatives with all activities conducted with existing local personnel. the aim was to tailor the educational program to the initial knowledge or awareness of each community of farmers, recognizing the considerable difference in knowledge levels between-and within communities. local teams, not outsiders, developed appropriate educational materials, targeting those with the lowest levels of knowledge. completed survey questionnaires indicated a significant relationship between the initial level of farmers' knowledge about brucellosis and their calf brucellosis vaccination practices. the range of brucellosis knowledge among some small-scale farmers in southern zimbabwe was considerable, with % of farmers being unaware of the disease, % having limited knowledge and % having good knowledge. however, even amongst those farmers with a relatively high level of knowledge, % of farmers had not vaccinated their calves at the time of the survey. furthermore, there was a disappointingly low uptake of milk boiling despite a significant increase in knowledge about raw milk as a mode of infection for humans. although the information sessions did increase farmers' awareness of the dangers of zoonotic brucellosis, an exaggerated perception of the effectiveness of calf vaccination decreased the likelihood of safe milk practices. this outcome indicated the importance of reaching the women who were responsible for milk and food preparation. ongoing research is investigating whether increasing the role of nurses and environmental health technicians to emphasize human infection and to reach different family members, within a research paradigm which combined veterinary and human medicine, would increase the uptake of milk hygiene practices. there is increasing awareness of the need to balance transparency with carefully designed information disclosure strategies in the face of sudden outbreaks of foodborne diseases (national research council, ; taylor, ) . both consumers and producers must be rapidly informed of any significant dangers with specific food products; however, considerable misinformation can be spread if laboratory results are incomplete or inconclusive (palm et al., ) . recent experience with e. coli-infected sprouts in germany and listeria-infected cantaloupes the united states has highlighted the difficulties in identifying the original source of a disease outbreak, as well as the swiftness with which an unexpected food-borne disease can cause sickness and death (armour, ; blaser, ; buchholz et al., ; frank et al., ) . it should be noted that that there was no easily identified zoonotic link in either of these two food-borne diseases derived from bacteria, which killed people in the united states and throughout europe during ; however, as professor c. kastner points out later, a significant number of these food-borne diseases do have a zoonotic origin (parker et al., ) . two articles linked to this topic are published in this special supplement. first, there is emerging antimicrobial resistance in commensal e. coli with public health relevance by dr. a. käsbohrer and her colleagues. their aim was to assess the prevalence of and trends in antimicrobial resistance through active monitoring programs along the food production chains for poultry, pigs and cattle, as well as to collect isolates for resistance testing and then select certain isolates for further phenotypic and genotypic characterization. the research team found alarming rates of resistance to antimicrobials in zoonotic bacteria and commensals, as set out in their article, which could compromise the effective treatment for human infections. this work provides a basis on which to improve both risk assessment and risk mitigation strategies in the face of the increasing antimicrobial resistance to zoonotic bacteria and parasitic organisms within both humans and animals. second, in american trypanosomiasis infection in fattening pigs from the south-east of mexico, m. jiménz-coello and her colleagues have investigated the extent to which the protozoa trypanosoma cruzi (t. cruzi) is presenting in fattening pigs in yucatan, mexico, threatening parasitic infections in animals destined for human consumption. tackling the question of how to refine national and international strategies to combat food-borne zoonotic diseases, professor c. kastner (food science institute, kansas state university, manhattan, kansas, usa) considered the public health and economic impact of foodborne zoonotic diseases. he began by noting that each year in the united states, according to statistics from the centers for disease control, million people become sick from food-borne diseases, , are hospitalized and , die. a significant portion of these diseases have a zoonotic origin, with extensive product recalls and domestic as well as international trade disruptions (fung et al., ) . therefore, more than years ago, the us department of agriculture established a food safety consortium ( ) which focuses on food-borne zoonotic diseases involving beef in kansas, pork in iowa and poultry in arkansas. the continuing aim of that consortium is to develop long-term control strategies that identify the critical control points and control technologies, as well as short-term strategies to address incidental contamination, whether accidental or intentional. the us livestock industry in general and kansas in particular are vulnerable to food-borne zoonotic diseases. for example, in kansas, sources of contamination include feed, feedlots (which vary in size from , to , head per lot) and packing plants (which vary in size from , to more than , head per day per plant). beef processing points where mixing of different ingredients occurs are the most critical points for both incidental and intentional contamination. in the light of these challenges, a biosafety level research facility, the biosecurity research institute (bri) ( ) has been built on the kansas state university campus, to evaluate strategies to detect and control food-borne zoonotic diseases from production through processing. furthermore, in minneapolis, minnesota, ncfpd (national center for food production defense, ) has been operational since as a department of homeland security center of excellence. ncfpd has adopted a systems approach whose goals include to: (i) ensure significant improvements in supply chain security, preparedness and resiliency; (ii) develop rapid and accurate methods to detect incidents of contamination and to identify the specific agent(s) involved; (iii) apply strategies to reduce the risk of food-borne illness because of intentional contamination in the food supply chain and to develop the tools to facilitate recovery from contamination incidents; (iv) deliver appropriate and credible risk communication messages to the public; and (v) develop and deliver highquality education and training programs to develop a cadre of professionals equipped to deal with future threats to the food system. these research centers are essential to minimize the threat of food-borne zoonotic diseases. t. cutts (national microbiology laboratory, public health agency of canada, canadian science centre for human and animal health, winnipeg, manitoba, canada) presented comparative inactivation studies of listeria monocytogenes at room and refrigeration temperatures on behalf of a research team that included b. carruthers, c.-l. cross, s. theriault (chief, applied biosafety research program, same center) and himself. listeria monocytogenes, a non-sporulating, gram-positive bacillus, is found chiefly in ruminants, but can affect all species and causes listeriosis, an infrequent but serious illness that affects the central nervous system of humans and domestic animals (bortolussi, ; chan and weidmann, ). listeriosis can be acquired from the consumption of contaminated foods and has an incubation period ranging from to days (bortolussi, ; chan and weidmann, ). because of this variable incubation period and the fact that listeriosis leads to a mortality rate of - %, the applied biosafety research program at the national microbiology laboratory of the public health agency of canada considered the significance of proper decontamination of listeria in food processing environments (chan and weidmann, ). the importance of this work is indicated by the fact that somewhere from to % of ready-to-eat foods are thought to be contaminated with listeria (public health agency of canada, and . recently, listeria monocytogenes has gained notoriety because of its ability to grow at the low temperatures, high salt and low ph used in food processing plants (bortolussi, ) . therefore, a study was undertaken to determine the bactericidal efficacy of various liquid disinfectants and the effect that low temperatures have on the ability of these disinfectants to inactivate l. monocytogenes at conditions found in food processing plants. at both room and refrigeration temperature ( °), ethanol, javex, su and peracetic acid (paa) products outperformed all others. surprisingly, there was no significant variation in performance at room temperature compared with refrigeration temperature. however, as some organisms undergo changes during a temperature shift, it is crucial to test each disinfectant at the temperature at which it will be employed. bleach was found to be effective but is toxic, corrosive and residue forming, while the paa and ethanol compounds do not form residues and are not corrosive. as a result of these studies, major canadian food-processing plants have changed their decontamination procedures and are no longer using quaternary ammonium compounds (quats), which were previously used extensively. positive relations have been built up between companies and laboratories, leading to more relevant laboratory studies and industrial applications (public health agency of canada, ). a prion (proteinaceous infectious particle) has been defined as a 'malformed version of a normal cellular protein that apparently ''replicates'' by recruiting normal proteins to adopt its form, [thus becoming] capable of infecting other cells of the same, or a different organism' (prusiner, ; thain and hickman, , p. ) . although two nobel prizes in medicine have been awarded for prion research, to carleton gajusek in and to stanley prusiner in , the precise nature of the infectious agent remains unclear to such an extent that controversy continues about whether a prion is solely protein (brooks, , pp. - ) . whatever the cause, prion diseases are fatal chronic neurological diseases that affect the brains and nervous systems of many mammals, including humans (imran and mahmood, ) . prions can be detected in tissues by a number of research techniques, including infective bioassay, animal inoculation, western blot and immunochemistry. it is clear that prions can cause spongiform encephalopathies within both humans and animals (e.g. creutzfeldt-jakob disease, kuru, scrapie, transmissible mink encephalopathy, feline spongiform encephalopathy and bovine spongiform encephalopathy) (blood et al., (blood et al., , p. . summaries of the three presentations below offer further insights into the nature of prion diseases. in prion diseases, professor j. j. badiola and dr. c. akin (university of zaragoza, zaragoza, spain) focused on the outbreak of bovine spongiform encephalopathy (bse) ('mad cow disease') in the united kingdom, which led to a better understanding of the epidemiology and molecular characteristics of the disease. epidemic bse affected mainly the united kingdom, with a total of , positive animals compared to , in all other member states of the european union (oie, ). control and eradication of transmissible spongiform encephalopathies (tses) became a priority, not only in europe, but throughout the world. in , a reinforcement of the passive surveillance program and the establishment of an active one were established by the european commission for all the european union member states (european commission, ) . passive surveillance, focused on animals with clinical signs of the disease, and active surveillance was carried out in the following target groups: healthy slaughtered, fallen stock, emergency slaughtered and animals culled under bse eradication. apart from these measures, specific risk materials (e.g. tonsils, intestines, spleen, spinal cord and skull, including the brain and eyes) were defined and prohibited from being included in the human food chain. moreover, a banning of all meat and bone meal for animal feed was established (european commission, ) . the result of these powerful eradication measures has been a rapidly decreasing number of new bse cases, with less than cases detected worldwide in , of which were in the european union (oie, ) . the impressive containment of bse in the united kingdom from , reported cases in to in is testimony to the determination with which scientists, politicians, civil servants and farmers have worked together to bring the disease under control. professor c. i. lasmézas (dept of infectology, the scripps research institute, scripps, florida, usa) began her presentation, zoonotic potential of new animal prion diseases: assessment in non-human primates, by noting that the first demonstration of the transmissibility of a prion disease to non-human primates (nhps) was made in by carleton gajdusek when he transmitted kuru to chimpanzees. since then, animal and human prion diseases have been transmitted to a range of nhps. cynomolgus macaques have shown the highest selectivity with regard to the prion strain by which they can be infected and therefore seem to be the species of choice to assess the risk that any given animal prion strain can be pathogenic for humans (lasmézas et al., ) . prions were thought to be very difficult to transmit from one species to another; however, the experience of studying scrapie highlights the difficulties inherent in studying prion diseases in the laboratory. scrapie had been transmitted orally to other ruminants (goats) but only intracerebral inoculations had successfully transmitted scrapie to monkey, mouse or mink. however, the oral transmission of bovine spongiform encephalopathy (bse) to domestic cats in forced a revision of this earlier belief. transmissions of bse have now occurred orally to sheep, goat, monkey, mink, cheetah, puma, cat and mouse. intracerebral transmission of bse has also occurred to pig. furthermore, intraspecies oral transmission of bse has taken place within numerous speciesmonkey, mink, sheep, goat, cow, hamster and mouse. vcjd (variant creutzfeldt-jakob disease) is a new human disease, which was caused by eating ruminant-derived food products contaminated with bse. vcjd poses a public health problem because of the absence of preclinical diagnostic test, the long incubation periods of prion diseases in humans (possibly extending up to years) and the transmissibility of the disease by blood transfusion. the research team at the french commissariat a l' energie atomique (cea) demonstrated that bovine spongiform encephalopathy (bse) was transmissible to macaques within years with a % infection rate and caused a disease indistinguishable from the human variant of creutzfeldt-jakob disease (lasmézas et al., ) . this provided a model to study carefully the peripheral pathogenesis of vcjd, the oral infectious dose of bse and evaluate the risk of human-to-human transmission of vcjd by blood transfusion (herzog et al., ) . further, the research team used the macaque model to assess the zoonotic potential of emerging forms of bse called l-or h-type. the l-type bse presents with higher pathogenicity to macaques than classical bse (comoy et al., ) . therefore, continued precautionary measures remain necessary to protect the human food chain. experiments are ongoing at the national institute of allergy and infectious disease, hamilton, montana, to assess the risk linked to chronic wasting disease that is spreading throughout the usa. the closing acknowledgements of professor lasmézas to other researchers indicated both the complexity and importance of continuing work in prion diseases. furthermore, since the cancun meeting further important research has been published (hamir et al., ) . infectivity distribution studies of animals infected with bse prions animals are a matter of considerable importance in seeking to elucidate the route of infectious prions from the gut to the central nervous system (cns) open questions about this lethal journey from the gut to the brain, including where in the gut the disease begins, the initial steps of the neuronal bse pathogenesis, the ascension of bse prions to the brain, the haematogenous spread and the centrifugal contamination of the periphery (buschmann and groschup, ; hoffmann et al., ) . the scale of the research task was indicated by the fact that , samples were collected per animal autopsy, leading to some , frozen samples collected and archived at the friedrich-loeffler-institut. tissue samples were collected from the gut, the central and autonomous nervous system (ans) of the challenged bovines and then examined for the presence of pathological prion proteins (prp sc ). there was some variation among different animals. however, a distinct accumulation of prp sc was observed in the distal ileum, confined to follicles and/or the enteric nervous system, in almost all animals . bse prions were found in the sympathetic nervous system starting from months post-inoculation (mpi) on as well as in the parasympathetic nervous system from mpi on (kaatz et al., ) . a clear dissociation of prion infectivity and detectable prp sc deposition was obvious in tongue (balkema- . the earliest presence of infectivity in the brainstem was detected at mpi, while prp sc -accumulation was detected first after mpi. in summary, these results deciphered for the first time the centripetal spread of bse prions along the ans to the cns starting already half way during the incubation period. bse prions spread in cattle from the gut to the brain along the sympathetic, parasympathetic and spinal cord routes, possibly in that order of importance. spinal cord involvement may even not be necessary at all, but bse infectivity in the form of prp sc spills over into the periphery already in the pre-clinical phase. the modelling and prediction of emerging zoonoses is a fast-growing field of considerable complexity. of the five papers relevant to this topic, two have been published in full below in this special supplement. dr. g. zanella and her colleagues consider modelling transmission of bovine tuberculosis in red deer and wild boar in normandy, france. their mathematical model of the mycobacterium bovis infection within and between species takes into account the transmission of m. bovis through infected offal -the viscera of animals killed by hunters and left behind. when an animal was hunted in the brotonne forest in normandy prior to , it was eviscerated in situ and only the carcass taken away, with the raw viscera left behind. since , offal disposal has been required in brotonne forest; however, the regulation has not always been observed by hunters (unpublished correspondence with g. zanella, - december, ) an important benefit of mathematical modelling is that it permits consideration of all the elements involved in disease transmission within a population, thereby complementing field data, as well as testing the effects of control measures. thus, the direct transmission of the m. bovis infection within the red deer and wild boar populations can be distinguished from indirect transmission through contaminated offal. the model indicates that offal destruction is the key factor in infection control for both red deer and wild boar. the authors conclude that, in principle, the structure of this model is relevant to the situations where dead animals play an important role in disease transmission between two or more species. in a further article published in this special supplement, constructing ecological networks: a tool to infer risk of transmission and dispersal of leishmaniasis, dr. c. gonzález-salazar and professor c. stephens set out the role of ecological networks as a powerful tool for understanding and visualizing inter-species ecological and evolutionary interactions. taking the example of leishmaniasis in mexico, they show that such networks can be used not only to understand potential ecological interactions between species involved in the transmission of the disease, but also to identify the potential role of the environment in disease transmission and dispersal. strikingly, they show how potential interactions can be inferred from geographical data, rather than by direct observation. their findings have led to the prediction of additional reservoirs in mexico of many new species, including bats and squirrels. the resulting model can be used to understand and map potential transmission risk, as well as construct risk scenarios for the dispersal of leishmaniasis from one geographical region to another. such a risk assessment tool for leishmaniasis will be especially useful in the light of the bill and melinda gates foundation decision in january to join with major pharmaceutical companies and the world health organization in targeting leishmaniasis as one of the neglected tropical diseases to receive improved drugs, diagnostics, vector control strategies and vaccines (bill & melinda gates foundation, ; boseley, ) . however, the possibility of new reservoirs suggests it is hard to imagine that leishmaniasis can be completely eradicated. nevertheless, it is increasingly clear that leishmaniasis has a disturbing capacity to jump from species to species, so efforts to control the disease must be given a high priority (unpublished correspondence with c. stephens, february , ; cf. flanagan et al., ) . it is difficult to model and predict the distribution and impact of a new emerging virus. for example, the emergence in november in europe of a midge-borne virus member of the bunyaviridae family, named schmallenberg virus after the location in germany where it was first detected, has caused serious birth defects in lambs, goats and cattle (ecdc, ) . scientists, farmers, veterinarians, public health officials and consumers are all confronted with the uncertainty inherent in facing a new animal pathogen (farmers weekly, ) . appropriately, at the same time as this new virus has emerged, the animal health and veterinary laboratories agency (ahvla) has set up a new independent advisory group to evaluate veterinary surveillance in england and wales, although their original intent was in part to consider funding reductions (trickett, ) . modelling risk factors for zoonotic influenza infections is challenging because the infections are often rare; the laboratory assays are often difficult and imprecise, and the most definitive studies require intensive resources. this was the view of professor g. c. gray (emerging pathogens institute and college of public health and health professions, university of florida, gainesville, florida, usa) in his presentation, modeling risk factors for zoonotic influenza infections in man: challenges and strategies for success. in particular, serologic detections of these infections in humans may be confounded by crossreacting antibody, waning antibody from the infection of interest, inaccurate matching of the enzootic pathogen and the laboratory strain, laboratory errors and weakly powered statistical comparisons. the underlying question which professor gray and his research team is tackling is: which human, animal and environmental factors predict disease? these three factors can be viewed as a venn diagram with its intricate interactions. like understanding cardiovascular disease, how a person acquires a zoonotic influenza infection is a complex process, and predictive laboratory assays are imprecise. for example, with avian influenza viruses (especially h n , popularly known as 'bird flu'), poultry veterinarians, turkey workers, hunters and people without indoor plumbing may be at increased risk of aiv infection but infections are rare. subclinical or mild infections do occur; and occasionally aiv causes severe disease in persons exposed to sick birds. although aiv transmission from human-to-human seems rare, further cohort studies and more sensitive serological assays are needed. a basic scientist often tests hypotheses by: (i) carefully setting up an experimental setting; (ii) isolating confounding factors; and (iii) looking for statistically significant associations with an outcome. such a process is not possible for a number of emerging disease problems such as human infections with swine influenza virus (siv). experimental studies are not possible. hence, epidemiologists must perform observational studies of people most likely to be infected with siv and by looking at possible risk factor associations, infer causality. one must first determine settings where the prevalence of siv in expected to be high and then study those workers. for example, sivs are often endemic in large-scale modern production facilities. risk factors for sow-herd siv seropositivity involve pig density, whether there is an external source of breeding pigs, the total animals on the site and the closeness of barns. similarly, risks factors for finisherherd siv positivity must be considered -the number of siv-positive sows, size of herd, pig farm density and farrow-to-finish type of farm (poljak et al., ) . however, siv surveillance in pigs is largely passive and voluntary, so recognizing which pig workers to study is a challenge. detection of siv infections in man often requires a sentinel event (e.g. human illness with pig exposure or sick pigs). as pigs do not always have clinical signs of novel virus infection and often there is no compensation system to protect pig farmers, the pork industry is reluctant to permit the study of their workers for siv infection (gray and baker, ) . therefore, these observational studies are currently very difficult. professor gray concluded by pointing out that although there are numerous challenges in conducting epidemiological studies for zoonotic influenza, there are six substantive ways to control confounding variables: (i) design every study carefully; (ii) use non-animal-exposed controls; (iii) employ validated laboratory assay using zoonotic influenza strains; (iv) use multivariate modeling to examine cross-reacting serologic responses due to human viruses and vaccines; (v) consider proportional odds modeling; and (vi) consider employing a second unique serologic test (see gpl, ) . with the support of co-authors from different institutions, dr. k. j. linthicum (united states department of agriculture, agricultural research service, center for medical, agricultural & veterinary entomology, gainesville, fl, usa) presented two case studies about forecasting emerging vector-borne diseases. dr. linthicum began by pointing out that global climate variability, often linked to el niño conditions, can be used to forecast emerging vector-borne disease spread in local areas (linthicum et al., ) . these forecasts are possible because specific pathogens, their vectors and hosts are sensitive to temperature, moisture and other ambient environmental conditions. with consistent and reliable satellite observations, global sea temperatures, climate and vegetation can be observed. first, temperature plays a major role in its impact on aides aegypti mosquitoes transmitting dengue haemorrhagic fever virus in southeast asia (linthicum et al., ) and possibly also on how ae. aegypti transmits chikungunya virus in africa and asia , as well as on how anopheles species mosquitoes transmit p. vivax malaria in the republic of korea. vectorial competence is dependent upon the extrinsic incubation (ei) period in the mosquito vector. the ei represents the time from ingestion of the virus while feeding on a viremic host to the virus arriving in the salivary glands. the shorter the ei period, which occurs during higher ambient temperatures, the greater the vectorial competence (garrett- jones and shidrawi, ) . if data are available for a specific local area on the daily humanbiting rate (ha) of the mosquitoes, the daily rate of blood feeding (a) and the length of the ei cycle (n), it is possible to calculate vectorial capacity (rattanarithikul et al., ) . second, accurate measurements and understanding of how exceptionally heavy rainfall and flooding affects aides and culex mosquitoes and the introduction of virusinfected mosquitoes into susceptible vertebrate hosts enables forecasts to be made about when and where rift valley fever (rvf) will develop in sub-saharan africa and middle east (anyamba et al., ) . outbreaks of rift valley fever are known to follow periods of widespread and heavy rainfall associated with the development of a strong inter-tropical convergence zone over eastern africa (davies et al., ) . during periods of elevated transmission, there is a significantly increased risk of globalization of these and other arboviruses; however, the forecasting methods described provide . - months early warning before an outbreak and provide ample time for disease mitigation before the first cases appear (anyamba et al., ) . furthermore, the emergence and expansion of a number of disease vectors (e.g. mosquitoes, mice, locust) often follow the trajectory of the green flush of vegetation in semiarid lands. the ability to predict periods of elevated risk enables better prevention, containment or exclusion strategies to be drawn up to limit globalization of emerging pathogens. thus, it has been possible for the food & agricultural organization (fao) to create a system of alerts -the emergency prevention system for transboundary animal and plant pests and diseases (empress, ) . subsequent to dr lithicum's presentation, significant further work has been done to provide a genome-scale overview of gene expression in the malaria-transmitting mosquito anopheles gambiae (maccallum et al., ) , as well as to expand the vectorbase website with regularly updated genome information on two other mosquito species, aedes aegypti and culex quinquefasciatus, and numerous other organisms, including the tick species ixodes scapularis (lawson et al., ; niaid, ) . the ultimate aim of this research is to create a database that will facilitate a systems-level view of gene expression for many different organisms. reflecting on the numerous types of statistical analysis that are used to estimate confidence intervals for proportions in scientific studies, dr. s. guillossou and his colleagues professors h. m. scott and j. a. richt (dept. of diagnostic medicine and pathobiology, college of veterinary medicine, kansas state university, manhattan, kansas, usa) utilized the final presentation of the conference, estimates of low prevalences and diagnostic test estimates: what confidence do we really have? to illustrate the differences, limits and sometimes chaotic behaviour of different statistical approaches. dr. guillossou pointed out that there were more than different methods for determining a % confidence interval of a proportion. he stressed that it is always important to report the method of statistical analysis being utilized. in his view, the agresti-coull interval approach presents a satisfactory compromise between computational requirements and coverage probability (newcombe, ; brown et al., ) . ideally, the effects of coverage probability should be estimated and the most appropriate method chosen before reporting the findings or using proportions as inputs in any epidemiological study. what did this th international conference on emerging zoonoses achieve? there was the opportunity to meet old friends and make new friends, to share one's academic work and to reflect on what lies ahead with emerging zoonoses. it is now clear that human medicine, veterinary medicine and environmental challenges are a unity which must be considered under the umbrella of 'one health' (one health initiative, ) . viruses are continuing to jump from animals to people with unexpected consequences, because the evolution of any virus is impossible to predict. even the recent relatively mild swine flu virus infected % of the human population and killed some , people globally -far less than would have been the case if the virus had mutated to a more deadly form, as might easily have happened. the reality is, as professor nathan wolfe, professor in human biology at stanford university, has commented: 'as a species, we're not that focused on the things that have the most potential to be devastating to us as a global population, such as viruses. unless people take these things seriously, we're going to look back and say we had all the tools necessary to try to address these risks, and we basically ignored them because they weren't dramatic like a car accident or a hurricane' (geddes, ; kahn, ; wolfe, ) . this conference, many others and the th international conference on emerging zoonoses to be held in in berlin, are aimed at creating, improving and using the tools essential to address the risks of viral contagions in a global society. none. the organizing committee of the conference wishes to acknowledge the excellent services of the conference organizers, target conferences of tel aviv, israel, and the welcome financial contributions of medimmune, boehringer ingelheim vetmedica gmbh, prionics ag, center of excellence for emerging and zoonotic animal diseases (ceezad) and national center for foreign animal and zoonotic disease defense (fazd), as well as the poster prize donated by wiley-blackwell. we are also grateful to the wiley-blackwell staff who have contributed so significantly to this special supplement, especially rachel robinson and peter tubman, as well as to dr. klaus osterrieder for his helpful comments and to the presenters who have approved or improved every summary in this meeting review. this material is based upon work supported by the u.s. department of homeland security under grant award number -st-ag . the views and conclusions contained in this supplement are those of the authors and should not be interpreted as necessarily representing the official policies, either expressed or implied, of the u.s. department of homeland security. additional funding has been provided by the kansas bioscience authority. conservation medicine: ecological health in practice prediction of a rift valley fever outbreak : prediction, assessment of the rift valley fever activity in east and southern africa - and possible vector control strategies climate teleconnections and recent patterns of human and animal disease outbreaks risk of infection with brucella abortus and escherichia coli o :h associated with marketing of unpasteurized milk in kenya fallout from listeria outbreak hits walmart: retail detection and identification of mycoplasma from bovine mastitis infections using a nested polymerase chain reaction bse infectivity in the absence of detectable prp(sc) accumulation in the tongue and nasal mucosa of terminally diseased cattle discovery of swine as a host for the reston ebolavirus crimean-congo hemorrhagic fever virus infection is lethal for adult type i interferon receptor-knockout mice the search and identification of the new bacillus anthracis exosporium antigen as immunodiagnostic target our approach: neglected diseases deconstructing a lethal foodborne epidemic saunders comprehensive veterinary dictionary outbreak description and lessons learned listeriosis: a primer drug companies join forces to combat deadliest tropical diseases genetic detection and characterization of lujo virus, a new hemorrhagic fever-associated arenavirus from southern africa interval estimation for a binomial proportion epidemic profile of shigatoxin-producing escherichia coli o :h outbreak in germany highly bovine spongiform encephalopathy-sensitive transgenic mice confirm the essential restriction of infectivity to the nervous system in clinically diseased cattle microbial virulence as an emergent property: consequences and opportunities physiology and genetics of listeria monocytogenes survival and growth at cold temperatures : a chemokine gene expression signature derived from meta-analysis predicts the pathogenicity of viral respiratory infections introduction: conceptualising and partitioning the emergence process of zoonotic viruses from wildlife to humans (base) transmitted from asymptomatic aging cattle to a primate establishment, immortalisation and characterisation of pteropid bat cell lines the cambridge world history of human disease infection and disease in reservoir and spillover hosts: determinants of pathogen emergence wildlife and emerging zoonotic diseases: the biology, circumstances and consequences of cross-species transmission collaborative research approaches to the role of wildlife in zoonotic disease emergence rainfall and epizootic rift valley 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campylobacter jejuni invasion of host cells by stimulating membrane ruffling regulation (ec) / of the european parliament and of the council of may laying down rules for the prevention, control and eradication of certain transmissible spongiform encephalopathies draft report on the monitoring and testing of ruminants for the presence of transmissible spongiform encephalopathies (tses) in the eu in immunogenicity and safety of recombinant rabies viruses used for oral vaccination of stray dogs and wildlife effective preexposure and postexposure prophylaxis of rabies with a highly attenuated recombinant rabies virus steep rise in notified hantavirus infections in henipaviruses: emerging paramyxoviruses associated with fruit bats anticipating the species jump: surveillance for emerging viral threats epidemic profile of shiga-toxin-producing escherichia coli :h outbreak in germany meat science and applications false-positive transcription-mediated amplification assay detection of west nile 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caatle an overview of human prion diseases global trends in emerging infectious diseases spread of classic bse prions from the gut via the peripheral nervous system to the brain what contagion missed : going viral emerging infections: a tribute to the one medicine, one health concept cyclic hantavirus epidemics in humans-predicted by rodent host dynamics meeting review ª blackwell verlag gmbh • zoonoses public health genomic analysis of increased host immune and cell death responses induced by influenza virus effects of species diversity on disease risk host heterogeneity dominates west nile virus transmission astrovirus induces diarrhea in the absence of inflammation and cell death genome analysis of bat adenovirus : indications of interspecies transmission comparative analysis of ebola virus glycoprotein interactions with human and bat cells virological surveillance and preliminary antigenic characterization of influenza viruses in pigs in five european countries from campylobacter jejuni secretes proteins via the flagellar type iii secretion system that contribute to host cell invasion and gastroenteritis bse transmission to macaques vectorbase: a data resource for invetebrate vector genomics inference between agents of lyme disease and human granulocytic ehrlichiosis in a natural reservoir host structural analysis of major species barriers between humans and palm civets for severe acute respiratory syndrome coronavirus infections climate and satellite indicators to forecast rift valley fever epidemics in kenya vector-borne diseases -understanding the environmental, human health, and ecological considerations, workshop summary pathogen discovery altered receptor specificity and cell tropism of d g hemagglutinin mutants isolated from fatal cases of pandemic a (h n ) influenza virus the pig as a mixing vessel for influenza viruses: human and veterinary implications pandemic h n virus causes disease causes upregulation of genes related to inflammatory and immune response, cell death, and lipid metabolism in pigs identification and characterization of a highly virulent triple reassortant h n swine influenza virus in the united states viral reassortment and transmission after co-infection of pigs with classical h n and triple-reassortant h n swine influenza viruses an expression map for anopheles gambiae crimean-congo hemorrhagic fever: epidemiological trends and controversies in treatment metla : finnish forest research institute update: filovirus infections among persons with occupational exposure to nonhuman primates seroepidemiological study of filovirus related to ebola in the philippines physicochemical inactivation of lassa, ebola, and marburg viruses and effect on clinical laboratory analyses host feeding patterns of culex mosquitoes and west nile virus transmission, northeastern united states the potential consequences of public release of food safety and inspection service establishment-specific service national center for food production defense spatial dynamics of humanorigin h influenza a virus in north american swine two-sided confidence intervals for the single proportion: comparison of seven methods geographical distribution of countries that reported bse confirmed cases since alphacoronaviruses in new world bats: prevalence, persistence, phylogeny, and potential for interaction with humans ecological havoc, the rise of the white-tailed deer, and the emergence of amblyomma amricanum-associated zoonoses in the united states : h n influenza: facts and fear molecular epidemiology of human pathogens: how to translate breakthroughs into public health practice development of an algorithm for assessing the risk to food safety posed by a new animal disease and investigation teams, and members of the outbreak control integrative deep sequencing of the mouse lung transcriptome reveals differential expression of diverse classes of small rnas in response to respiratory virus infection differential activation 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expression during early and late phase of acute puumala hantavirus infection pandemic swine-origin h n influenza a isolates show heterogeneous virulence in macaques filoviridae: marburg and ebola viruses the nucleoprotein as a possible major factor in determining host specificity of influenza h n viruses avian host-selection by culex pipiens in experimental trials vector host-feeding preferences drive transmission of multi-host pathogens: west nile virus as a model system evidence for the role of infectious disease in species extinction and endangerment reducing the risks of the wildlife trade identifying hendra virus diversity in pteropid bats new adenovirus in bats characterization of the influenza virus polymerase genes will the food safety modernization act help prevent outbreaks of foodborne illness? species interactions in a parasite community drive infection risk in a wildlife population hantavirus disease (nephropathia epidemica) in belgium: effects of tree seed production and climate new veterinary surveillance group set up'. farmers weekly sybr green real-time pcr detection and differentiation assay for mycoplasma species in biological samples mutational analysis of aminopeptidase n, a receptor for several group coronaviruses, identifies key determinants of viral host range : diarrhoea: why children are still dying and what can be done usutu virus -potential risk of human disease in europe markedly elevated levels of interferon (ifn)-c, ifn-a, interleukin (il)- , il- , and tumor necrosis factor-a associated with fatal ebola virus infection swine influenza viruses: a north american perspective bats, civets and the emergence of sars a foot and mouth disease simulation exercise involving the five nordic countries contingency planning: preparation of contingency plans what is the optimal therapy for patients with h n influenza assessment of rodents as animal models for reston ebolavirus writing committee of the second world health organization consultation on clinical aspects of human infection with avian influenza a (h n ) virus modification of non-structural protein of influenza a virus by sum key: cord- -dwfwwdbn authors: staat, dana d.; klepser, michael e. title: international adoption: issues in infectious diseases date: - - journal: pharmacotherapy doi: . /phco. . . sha: doc_id: cord_uid: dwfwwdbn international adoptions have become increasingly common in the united states. children awaiting international adoption and families traveling to adopt these children can be exposed to a variety of infectious diseases. compared with the united states, foreign countries often have different immunization practices and methods of diagnosing, treating, and monitoring disease. reporting of medical conditions can also differ from that of the united states. the prevalence of infectious diseases varies from country to country and may or may not be common among adopted children. the transmission of tuberculosis, hepatitis b, and measles from adopted children to family members has been documented. furthermore, infectious organisms (e.g., intestinal parasites), bacterial pathogens (e.g., bordetella pertussis and treponema pallidum), and viruses (e.g., human immunodeficiency virus and hepatitis viruses) may cause clinically significant morbidity and mortality among infected children. diseases such as severe acute respiratory syndrome or avian influenza have not been reported among international adoptees, but transmission is possible if infection is present. family members may be infected by others during travel or by their adopted child after returning home. families preparing to adopt a child from abroad should pay special attention to the infectious diseases they may encounter and to the precautions they should take on returning home. states citizens. if this number does not seem impressive, families in the united states adopted more than , children of foreign origin since . also striking is that, since , the number of international adoptions in the united states has increased by more than % (figure ). internationally adopted children originate from countries that unfortunately are often poor, developing, or war torn. their governments are often poorly equipped to manage the number of orphaned or abandoned children. as a result, they allow individuals from foreign countries to adopt these children. owing to changing economic, political, and social climates around the world, policies pertaining to foreign adoption in these countries are constantly changing. as a result, a country may have a liberal foreign adoption policy or high quota one year, but it may close its doors to adoption the next. figure highlights the effect of these changes on the origins of adopted children who were brought into the united states over the past decade. at present, more than % of internationally adopted children brought to the united states are from china, russia, and guatemala. the emergence of a disease or a medical condition sometimes overshadows the joy of bringing a new child into a family. family members traveling to a foreign country to complete an adoption are at risk for acquiring infectious diseases in that country. all too often, travelers, nontraveling family members, and other contacts are at risk for acquiring an infectious process because appropriate safeguards are not followed or considered. two published reports highlight the potential health risks associated with international adoption. , because of the devastation these diseases can cause and because of the ease with which many can be spread, health care practitioners must be familiar with medical obstacles associated with international adoptions. in addition, since many of these diseases can easily be prevented with vaccination, prophylaxis, and/or education, the pharmacist can play an integral part in minimizing the health risks of the families involved in these adoptions. internationally adopted children often enter the united states without a caregiver who is familiar with their medical history, vaccination status, or social experiences. this situation is in stark contrast to immigrant or refugee children, who often arrive with parents or other guardians. the absence of a parent or guardian is one reason why medical records of international adoptees are often incomplete. information regarding their family history, prenatal health, and birthing conditions are generally not available. even their exact date of birth is often unknown. adding to the confusion for adopting families is that medical terminology and medical practices vary widely depending on the country of origin. for example, a case-series review of preadoptive medical records showed that more than % of children from the former soviet union and eastern europe had several diagnoses suggestive of severe neurologic impairment. of interest, postadoptive evaluation in the united states failed to confirm the diagnoses in any of the children. in contrast, documentation of medical records is excellent for children from korea because of government-controlled adoption agencies. documentation from other countries, such as china or russia, is highly variable. in addition to confusion and uncertainty pertaining to diagnostic and medical terminology, adoptive parents and their medical consultants must be vigilant for errors in medical diagnoses and vaccination schedules in the medical records. examples of such errors are vaccinations that were apparently administered before the birth date of the adopted child. records that appear perfect, such as vaccinations given exactly - months apart, are often modified to align with current immunization schedules in the united states. in addition, descriptions of child development should be accepted cautiously. under close scrutiny, developmental milestones are often found not to match the child' s estimated age, or they are found to be virtually identical to those of other children from the same orphanage. the old adage applies: if it seems too good to be true, it probably is. immunization records for internationally adopted children are often unclear, incomplete, or even missing altogether. a retrospective analysis of internationally adopted children showed that % had no written records of immunizations given before their adoption. adopted children may have received vaccines of differing potencies or at different ages, or they may have been given a number of doses other than what is recommended in the united states. furthermore, in some countries, various vaccinations may be given at minimum intervals of weeks, as opposed to the weeks required in the united states. , as a result of these discrepancies in administration schedules, u.s. immigration officials may not accept documentation of previous vaccinations. another concern is that children adopted from orphanages or other large institutions are frequently severely malnourished or chronically ill. under these conditions, even if vaccines are administered appropriately, adequate immunity may not be observed owing to the child' s inability to mount an immune response. , for children who arrive in the united states with an unclear or questionable immunization status, serologic titers may need to be drawn to test their immunity. serologic titers were drawn in children adopted from china who had documented immunizations against tetanus, diphtheria, and poliomyelitis. the titers revealed that only % of the children were fully protected against each disease. although titers for diseases such as diphtheria or type-specific polio can be drawn, they are not routinely obtained. the infrequency with which these tests are performed may cause substantial expense and a delay in obtaining results. even if a child is reported to have had a specific primary disease that generally affords immunity, vaccinating the child may still be prudent because he or she might not have mounted an immune response or because the disease might have been misdiagnosed. furthermore, if no written documentation of vaccinations is available, appropriate vaccination series should be begun as soon as possible. also, vaccination should be considered missing if the documentation is only partial. examples are if names of the vaccine or if the vaccination dates are missing, if the vaccination record appears too good to be true, if the vaccinations are self-reported, or if the records appear questionable in any way. finally, vaccinations given at intervals of less than weeks should not be counted because this schedule may elicit suboptimal immune responses. in most instances, administering or readministering the vaccine series is easier than attempting to assess the child' s immune status. because other countries may focus on required vaccinations for diseases endemic to their region, clinicians should ensure that all vaccinations that the centers for disease control and prevention (cdc) and the advisory committee on immunization practices recommend are given to newly adopted children. vaccines most commonly omitted from foreign vaccination programs include those for haemophilus influenzae type b, hepatitis b, varicella, and measles, mumps, and rubella. catch-up or initial vaccination series should be given as soon as possible, unless the adopted child is acutely ill and has a high temperature. figures and show the cdc primary immunization schedule for and the catch-up schedule, respectively. , a good general rule is to revaccinate when in doubt. the risk of not vaccinating is generally greater than the risk of revaccinating. table illustrates the approach of the advisory committee on immunization practices and the american academy of family physicians to the evaluation and revaccination of internationally adopted children. in the united states, the occurrence of tuber-culosis has been steadily declining; however, this is not the case in many developing countries, where tuberculosis continues to be among the leading causes of death. many countries from which children are adopted, such as china, russia, korea, and vietnam, have a high rate of tuberculosis. as a region, southeast asia has the second highest incidence of tuberculosis in the world after africa. the incidence in africa is cases of tuberculosis/ , people, whereas in southeast asia it is cases/ , . in contrast, the incidence of tuberculosis in the americas is approximately cases/ , people. another consideration is that the worldwide occurrence of drug-resistant tuberculosis is increasing. according to the world health organization, more than , cases of multidrug-resistant tuberculosis have been reported. between and , almost every country the world health organization surveyed had documented cases. of all cases of tuberculosis in the united states, multidrug-resistant mycobacterium tuberculosis caused . %. multidrugresistant tuberculosis is most problematic in china, eastern europe, and russia. rates of resistance in russia and eastern europe are . - %, whereas rates in china range from . % in hong kong to . % in the henan province. in , a report described a -year-old child adopted from the marshall islands who had a diagnosis of extensive, bilateral, cavitary pulmonary tuberculosis. this child was not screened for tuberculosis before entering the united states. as a result, he transmitted m. tuberculosis to % of his direct contacts in rural north dakota. although active tuberculosis is infrequently reported among immigrant children, internationally adopted children are more likely than domestically adopted children to have active tuberculosis. the rate of tuberculosis among internationally adopted children is - times that among the general population of the united states. latent tuberculosis is more common among internationally adopted children than active tuberculosis. tuberculosis skin tests were positive in approximately . - % of internationally adopted children. , children who resided in orphanages had rates of latent tuberculosis higher than those of children who were raised in foster homes. a study of international adoptees revealed that ( %) who were screened with tuberculin skin testing were given a diagnosis of latent tuberculosis. of note, the high rate of positive results among internationally adopted children may be due to not only exposure to active cases of tuberculosis in their countries of origin but also vaccination with the bacillus calmette-guérin (bcg) vaccine, which is more common in developing countries than in the united states. routine screening for tuberculosis in internationally adopted children should include a tuberculin skin test administered by using the mantoux method. , , , testing should be performed regardless of the child's history of receiving the bcg vaccine. although the reaction to a tuberculin skin test due to the bcg vaccine cannot be distinguished from the reaction due to latent tuberculosis, immunity secondary to the bcg vaccine wanes over time. a health care professional should review the results - hours after the tuberculin skin test is performed. indurations of at least mm should be considered positive in a healthy child. in a child infected with human immunodeficiency virus (hiv), indurations of mm or larger require further evaluation. skin testing should be repeated after months in children in whom an induration of smaller than mm is elicited. this recommendation is based on the fact that children may not respond to the test because of other illness, malnutrition, or recent infection with tuberculosis without time to mount an adequate immune response. , in children with a positive tuberculin skin-test result, chest radiography and full physical examination should be performed to determine if they have active tuberculosis. also, in newborns with a recent history of bcg immunization, chest radiography and a tuberculin skin test should be done year after vaccination. , for the treatment of a child with active tuberculosis, physicians should select an antituberculosis regimen based on resistance patterns from the adopted child's country of origin. recommended treatment for active tuberculosis includes months of therapy: isoniazid, rifampin, and pyrazinamide given for months, then isoniazid and rifampin given for the last months. table shows common drugs and dosages used to treat tuberculosis. in the case of latent tuberculosis, children should be treated with a -month course of isoniazid - mg/kg/day (table ). if a patient cannot tolerate isoniazid or if he or she was exposed to a documented isoniazid-resistant strain of m. tuberculosis, rifampin - mg/kg/ day for months is an acceptable alternative (table ) . , close contacts and family members of internationally adopted children who have active tuberculosis should also undergo tuberculin skin testing performed with the mantoux method. hepatitis b is the most common chronic viral illness worldwide. although some patients infected with hepatitis b may never have symptoms, as many as % of children who acquire chronic hepatitis b eventually develop hepatocellular carcinoma or cirrhosis. children adopted from impoverished orphanages are at high risk of being infected with hepatitis b. hepatitis b is endemic in china and southeast asia, as well as in eastern europe (especially romania), most of the middle east, africa, and the amazon basin, among other regions. more than % of children adopted from romania have serologic evidence of past or present hepatitis b infection. institutionalized children usually acquire hepatitis b from vertical transmission (transmission at birth) or from the transmission of body fluids when living in close quarters with other infected individuals. overall, about % of international adoptees to the united states have a table provides information to guide the interpretation of serologic results. hepatitis b virus may incubate for as long as days; therefore, internationally adopted children should have their initial hepatitis b panel repeated approximately months after arriving in the united states. this testing may be deferred in children who are clearly immune or clearly infected. when the history of hepatitis vaccination is questionable or missing, children should receive the three-dose hepatitis b vaccination series. immunization does not harm a child with an active hepatitis b infection and may help a child with incubating disease avoid chronic disease. the risk of transmitting hepatitis b to household members is well documented, albeit low. , [ ] [ ] [ ] families of children adopted from asia with documented hepatitis b infection had a % occurrence of subsequent hepatitis b infection compared with a % risk in a control population. household members of any child with a positive hbsag result should be vaccinated if they have not completed the vaccination series. specific recommendations to guide therapy for children with acute hepatitis b infection are not readily available. lamivudine decreased serum dna levels of hepatitis b virus to below the limit of the research assay at the end of a -week trial ( % vs % with placebo) in children with chronic hepatitis b. interferon-alfa was relatively ineffective for chronic infections acquired during childhood. adefovir dipivoxil has yet to be studied in children. other promising treatments for hepatitis b, such as entecavir, tenofovir, clevudine, telbivudine, and pegylated interferon alfa- a, are in various stages of development and approval by the u.s. food and drug administration. efficacy and safety data for new agents to treat chronic hepatitis b infection in children have yet to be published, but these agents may be alternative treatments for hepatitis b in the future. as with hepatitis b, hepatitis a is endemic in many areas, such as southeast asia, china, and latin america. because hepatitis a is transmitted by means of the fecal-oral route, hepatitis a is commonly associated with areas that have poor sanitation and/or crowded living conditions. infection with hepatitis a is worrisome and may lead to fulminant hepatitis and death. hepatitis a is observed relatively infrequently among adopted children. owing to the low occurrence of infection, internationally adopted children generally do not have serology for hepatitis a tested unless they have symptoms suggestive of hepatitis. symptoms of hepatitis a, if manifested, may include jaundice and/or fever. no treatment for hepatitis a is available, and only supportive care is recommended. however, all individuals traveling to areas with high rates of hepatitis a should be given the hepatitis a vaccine, which consists of an inactivated virus. two doses of the vaccine should be administered at least months apart. one month after receiving the first dose of the vaccine, - % of adults develop protective antibodies. if an unvaccinated individual is exposed to hepatitis a, postexposure prophylaxis with immunoglobulin may be warranted. immunoglobulin should be given no more than weeks after exposure. hepatitis c among the general population, hepatitis c has a worldwide prevalence comparable to that of hepatitis b. however, among internationally adopted children, the prevalence of hepatitis c infection is not well documented but believed to be considerably lower than that of hepatitis b. according to limited serologic data, hepatitis c infection appears to be present in less than % of internationally adopted children. , therefore, routine screening of asymptomatic children for hepatitis c is usually not warranted. however, screening may be appropriate for children who have symptoms consistent with hepatitis, those whose mothers have a history of drug abuse, and those who come from areas with high frequency of hepatitis c. according to the world health organization, areas with the highest prevalence of hepatitis c are africa (rate of . %), the eastern mediterranean ( . %), and the western pacific ( . %). pertussis pertussis, or whooping cough, is a disease that clinicians in developed countries tend to overlook. pertussis appears to be mounting a comeback in both developed and developing countries. although the disease commonly occurs in unvaccinated individuals, its occurrence is also described among those who received the vaccine while they were malnourished or immunocompromised. in addition, data suggest that even those who were appropriately vaccinated may be at risk for acquiring infection with bordetella pertussis secondary to waning of their protective immunity. , in the united states, children receive a fourdose pertussis vaccination series as part of combined vaccination that includes diphtheria and tetanus. in contrast, foreign-born children may not receive vaccination against pertussis. in the absence of appropriate vaccination, these children are at increased risk for developing active disease. a -month-old infant adopted from russia had no record of being vaccinated against the disease. as a result, close contacts during travel and family members were all exposed to the disease. the cdc recommends that antimicrobial prophylaxis with erythromycin be given to any person who was exposed to an active case of pertussis, regardless of their immunization status. if an individual is thought to have pertussis and if the cough has lasted less than weeks, antimicrobial therapy is indicated. the drug of choice for pertussis is erythromycin. however, most data pertaining to the treatment of pertussis are decades old; therefore, most agents newer and better tolerated than erythromycin have not been thoroughly evaluated for this indication. despite the completion of only a few well-controlled clinical studies, azithromycin, clarithromycin, and trimethoprim-sulfamethoxazole appear to be appropriate treatment alternatives. , clinical data about fluoroquinolones and ketolides are lacking. although uncommon in the united states, the measles virus is common in countries from which children are adopted. in april , adoptions from an orphanage in china were temporarily suspended because of an outbreak of measles among adoptees from the hunan province. in , cases of measles were identified in children recently adopted from china and in their close contacts. measles was diagnosed in adopted children, along with two adoptive mothers who were born in the united states, a caregiver who lived with the adoptive family for week, and a sibling of a child adopted from china who never contracted the disease. based on the dates of infection, the measles exposure was determined to occur in china. this exposure was most likely from the orphanage, but it could have occurred during the screening period or during travel. the cdc launched a measles vaccination campaign at the infected orphanage, and adoptions resumed weeks after the last case of measles was reported. because measles is a major medical concern, children in the united states are routinely vaccinated against the disease, generally along with mumps and rubella in a combination vaccine. however, combination vaccines are not universally used. many countries immunize children with vaccines for only measles or for a combination of measles and rubella. as a result, adopted children may lack coverage against mumps, rubella, or both. therefore, information regarding the types and content of vaccines administered to the child should be obtained. also, because the child may lack immunoprotection and have active disease, family members of an internationally adopted child must have up-to-date immunization against measles, mumps, and rubella. the cdc recommends that adults born after receive at least one dose of the measles, mumps, and rubella vaccine unless they had a documented case of the measles. because of their high risk of acquiring measles, college students, international travelers, and health care workers should receive two doses of the vaccine given at least month apart. of note, pregnant women should not receive the measles, mumps, and rubella vaccine, and women should avoid pregnancy for months after receiving the vaccine. human immunodeficiency virus although the rate of infection with hiv in many developing countries is rising, hiv infection is infrequently noted among international adoptees. investigators reported that two ( . %) of internationally adopted children screened had hiv antibodies. of interest, both children subsequently had negative results for hiv with a polymerase chain reaction test. other investigators did not identify any internationally adopted children infected with hiv. , , one potential reason for the lack of hiv infections among adoptees is that preadoption screening has become widespread in eastern europe and in countries such as china. as a result, hivinfected children may be removed from the pool of children available for adoption. regardless of the results of preadoption screening, all children should be tested for hiv on their arrival to the united states, and they should be retested months later to determine if seroconversion occurred secondary to a recent hiv infection. syphilis, which is caused by the spirochete treponema pallidum, can be transmitted to children by means of sexual abuse or maternal transmission. eastern european nations have documented increases in the occurrence of congenital syphilis. in russia alone, the occurrence of congenital syphilis has doubled every year from - and reached a total of cases in . in contrast, less than . % of international adoptees test positive for syphilis. , , syphilis serology is required in the medical examination for united states visas, but regardless of the test results, internationally adopted children should be retested for syphilis on their arrival to the united states. treatment of syphilis may often be accomplished with one dose of benzathine penicillin. experts in the field of adoption medicine listed parasites second only to hepatitis b virus for their propensity to cause long-term problems in children. parasites may cause severe diarrhea, dehydration, and malnutrition in addition to chronic starvation. protozoa may be present in drinking water in undeveloped countries. institutions such as orphanages promote the transmission of parasites because of close contact, diminished immunity secondary to malnutrition, and inadequate treatment. although transmission of intestinal parasites from adopted children to families and other contacts is not reported, it is possible. in addition, appropriate diagnosis is essential for the well-being of the child. intestinal parasites can be found in - % of internationally adopted children. , the risk of being infected with intestinal parasites is higher in older children and children from eastern europe than in younger children and children from other areas of the world, such as china, korea, or guatemala. , , according to one group of investigators, % of romanian children older than months who were screened for intestinal parasites had evidence of infection. this rate was in contrast to % of infants aged months or younger. giardia lamblia is the intestinal parasite most frequently encountered among internationally adopted children; however, it is not uncommon for infected children to have more than five organisms. , symptoms are not reliable indicators of parasitic infection. other diseases, such as lactose intolerance or refeeding syndrome after starvation, may mimic infection with intestinal parasites. in all children, at least three fresh fecal specimens should be examined for parasites at intervals of no less than week. , , , rates of detection increase with the use of several specimens. if parasites are detected and treatment started, stools should be reexamined after each course of therapy because of the high prevalence of several infecting parasites. , scabies and lice scabies (sarcoptes scabiei) and lice (pediculus species) are common among internationally adopted children. a major risk factor for scabies and lice infestations is residence in an orphanage. investigators reported a greater than % rate of scabies or lice in adopted children, but documentation is limited. scabies is often difficult to identify among internationally adopted children, especially if they were partially treated or if they have numerous insect bites. some experts recommend treating any rash as if it were a scabies infection. general treatment with topical permethrin cream or shampoo is appropriate. severe acute respiratory syndrome an unusual pneumonia was first reported in the guangdong province of china in november and has since been referred to as severe acute respiratory syndrome (sars). the sars virus spread to more than people in countries and killed . the cause of the disease was determined to be a novel coronavirus similar to a virus seen in some animals consumed in china. the only other known coronaviruses cause the common cold. aggressive health measures have limited the occurrence of sars. since july , the end of the pandemic, additional cases of sars have been reported. although person-to-person transmission is possible, other sources of infection have been identified. transmission of the sars virus from an internationally adopted child to a prospective parent or other family member is possible; however, such a case has not been reported. children with sars typically have a minor respiratory illness compared with infected adults. during the initial sars outbreak, children accounted for a small number of reported cases. for prevention, the cdc recommends that travelers avoid areas where transmission is most likely to occur. these areas include hospitals treating patients with sars and live animal markets. frequent hand washing is also recommended. avian influenza involves a large number of influenza viruses that primarily affect birds and not humans. avian influenza type a/h n is a virulent form that can cause disease in humans. avian h n is believed to be primarily transmitted from direct bird-to-human contact and not from human-to-human contact. the concern is that the strain will mutate to a virulent strain that is easily transmitted from human to human. according to the world health organization, confirmed cases of avian influenza in humans have been documented from -november . countries that have had confirmed cases are vietnam ( cases, deaths), thailand ( cases, deaths), indonesia ( cases, seven deaths), cambodia (four cases, four deaths), and china (two cases, one death). to our knowledge, no internationally adopted children have yet to contract the virus. symptoms range from typical flu symptoms of fever, cough, sore throat, and muscle aches to eye infections, pneumonia, and respiratory distress. the antiviral drugs oseltamivir and zanamivir are expected to be used to treat avian influenza a, but their effectiveness is unclear. analysis of some strains of h n in revealed resistance to rimantadine and amantadine. a vaccine to prevent this virus is not yet available, but clinical trials to test a newly developed vaccine began in april . although requirements vary from country to country, most individuals considering an international adoption can plan to stay in their child's home country for several days to weeks. during this time, travelers may be exposed to a number of potential pathogens from a variety of sources, including water, food, children, and the environment. all people who plan to travel for the adoption should seek medical advice regarding immunizations and preventive therapy at least - weeks before traveling. in addition to consulting a travel medicine specialist, they may also seek advice from a physician specializing in adoption. many institutions now have an adoption medicine physician or clinic that is familiar with issues encountered when an international child is adopted. during the trip, travelers must follow general travel guidelines. for example, they should avoid ingesting tap water directly by drinking it or indirectly by eating uncooked foods that may have been cleaned with tap water or drinking beverages with ice. in addition, food parasites and bacteria may contaminate a variety of foods. therefore, it is prudent for them to avoid foods that were not properly cooked. the cdc recommends avoiding uncooked meat, fruits and vegetables, and milk products. mosquitoes and ticks may carry infectious diseases, such as malaria, yellow fever, and japanese encephalitis. , travelers to central america, south america, eastern europe, asia, and other areas of the world are at risk for contracting malaria. protective clothing (long pants, longsleeved shirts) should be worn, and topical insect repellents containing diethyltoluamide, or deet, should be used. prescription drugs may also be used to prevent malaria. most drugs should be started before the person travels and be continued after he or she returns to the united states. table presents malaria prevention options. because of concerns related to resistance, specific antimalarial treatment should be based on the country being visited. travelers should be familiar with the signs and symptoms of malaria, which may include chills, headache, fatigue, and muscle aches. immediate treatment should be sought at onset of these symptoms and continued for as long as year after travel to an endemic area. questions about malaria can be directed to the cdc web site (available from http://www. cdc.gov) or the cdc malaria hotline (telephone number - - - ). routine vaccinations and boosters should be current for all travelers and nontraveling family members. the recommended adult immunization schedule can be accessed through the cdc web site. vaccines usually administered in the united states, often in childhood, are directed against tetanus, diphtheria, pertussis, varicella, polio, hepatitis b, h. influenzae type b, pneumococcal disease, and measles, mumps, and rubella. a tetanus-diphtheria booster is recommended every years. table shows recommendations for specific vaccinations. suggestions for vaccination vary depending on the destination country. at this point, the only required vaccination is the yellow fever vaccination for travel to certain countries in sub-saharan africa and tropical south america. the u.s. government requires internationally adopted children to undergo physical examination before entering the country. this examination is not intended to ensure that the adopted child is completely healthy; rather, it is designed to ensure that the child will not harm residents of the united states. therefore, clinicians usually do not test for infectious diseases that are common in the united states or that are not transmitted by casual contact. table lists the components of the medical examination. parents should not rely on the medical examination to reveal all potential infections, and they should still seek medical care for their adopted child after they enter the united states. a physician should immediately examine acutely ill children or children who have serious chronic diseases on their arrival to the united states. children who appear healthy should see their physician within - weeks of their arrival for a comprehensive medical examination. , for screening, the american academy of pediatrics recommends hepatitis b serology, syphilis serology, hiv serology, mantoux intradermal skin testing for tuberculosis, stool examination for ova and parasites, and a complete blood cell count with red blood cell indexes. other ageappropriate tests may be indicated, depending on the country of origin and on the specific medical concerns associated with a particular child. the adoption of a child should be a joyous occasion. however, the detection of an illness in the adopted child or the acquisition of an for the safety and well-being of all those involved, the adoptive parents should be well informed about the potential infectious complications associated with international adoption. many infections can be avoided altogether, or the effect of disease can be minimized with proper travel planning and follow-up. despite the travel advice that adoptive parents receive from adoption agencies, simple measures, such as reviewing the child's vaccination status, are often overlooked. in addition, adoption agencies may not be helpful in interpreting preadoption medical reports. as health care providers, we can help these families prepare for their travel and homecoming by providing counseling and information about potential infectious diseases that they may encounter. children and adolescents younger than years are not required to undergo blood testing for syphilis and human immunodeficiency virus infection or chest radiography for tuberculosis unless the examining physician believes that they are likely to have been exposed. immigrant visas issued to orphans coming to the u measles outbreak among internationally adopted children arriving in the united states update: measles among adoptees from china-april preparing families for international adoption health of children adopted from the former soviet union and eastern europe: comparison with preadoptive medical records infectious disease and the internationally adopted child evaluating acceptability and completeness of overseas immunization records of internationally adopted children the immigrant, refugee, or internationally adopted child health care of the internationally adopted child part . before and at arrival into the adoptive home immunisation status of children adopted from china preparing to meet foreign bugs. travel, immigration, and international adoptions require special precautions recommended childhood and adolescent immunization schedule-united states recommended immunization schedule for children and adolescents who start late or who are more than month behind-united states general recommendations on immunization. recommendations of the advisory committee on immunization practices (acip) and the american academy of family physicians (aafp) table . tuberculosis cases, case rates per , population, deaths, and death rates per , population, and percent change: united states world health organization. the world health report preventing infectious diseases during and after international adoption world health organization. drug resistance: tuberculosis a prioritised research agenda for dots-plus for multidrug-resistant tuberculosis (mdr-tb) global trends in resistance to antituberculosis drugs. world health organization-international union against tuberculosis and lung disease working group on anti-tuberculosis drug resistance surveillance extensive transmission of mycobacterium tuberculosis from a child pediatric tuberculosis collaborative group. targeted tuberculin skin testing and treatment of latent tuberculosis infection in children and adolescents prevalence of infectious diseases among internationally adopted children mycobacterium tuberculosis infectious disease issues in internationally adopted children hepatitis b: no guarantee [families with children from china web site red book: report of the committee on infectious diseases the health of children adopted from romania basic skill in interpreting lab data transmission of hepatitis b virus from adopted asian children to their american families hepatitis a and b in the family unit: nonparenteral transmission by asymptomatic children adoption of children from countries with endemic hepatitis b: transmission risks and medical issues epivir-hbv (lamivudine) package insert world health organization, department of communicable disease surveillance and response prevention of hepatitis a through active or passive immunization: recommendations of the advisory committee on immunization practices (acip) health of children adopted from china changing epidemiology of pertussis in the united states: increasing reported incidence among adolescents and adults summary of notifiable diseases-united states pertussis in an infant adopted from russia guidelines for the control of pertussis outbreaks efficacy of short-term treatment of pertussis with clarithromycin and azithromycin azithromycin is as effective as and better tolerated than erythromycin estolate for the treatment of pertussis centers for disease control and prevention. measles: recommendations for prevention epidemiology and management of infectious diseases in international adoptees recent declines in reported syphilis rates in eastern europe and central asia: are the epidemics over? international adoptions. travelers' health: yellow book the severe acute respiratory syndrome severe acute respiratory syndrome. travelers' health: yellow book severe acute respiratory syndrome among children world health organization. cumulative number of confirmed human cases of avian influenza a/(h n ) reported to who avian influenza infection in humans centers for disease control and prevention. protection against mosquitoes and other arthropods. travelers' health: yellow book centers for disease control and prevention. malaria and travelers general recommendations for vaccination and immunoprophylaxis. travelers' health: yellow book the visa medical examination: the facts [families with children from china web site key: cord- -fv authors: cain, william e. title: american dreaming: really reading the great gatsby date: - - journal: society doi: . /s - - - sha: doc_id: cord_uid: fv f. scott fitzgerald’s the great gatsby ( ) is one of the best known and most widely read and taught novels in american literature. it is so familiar that even those who have not read it believe that they have and take for granted that they know about its main character and theme of the american dream. we need to approach the great gatsby as if it were new and really read it, paying close attention to fitzgerald’s literary language. his novel gives us a vivid depiction of and insight into income inequality as it existed in the s and, by extension, as it exists today, when the american dream is even more limited to the fortunate few, not within reach of the many. when we really read the great gatsby, we perceive and understand the american dimension of the novel and appreciate, too, the global range and relevance that in it fitzgerald has achieved. it is a great american book and a great book of world literature. was imperative to read spengler, to sympathize or revolt. it still remains so" (december , ) . retrospectively, fitzgerald could have felt that he must have been reading spengler in spengler in - because this german author's theory of historical degeneration matched the mood that pervades the great gatsby. the decline of the west is a perplexing, lurid text, imposing in manner, epic in scale, intermittently provocative, tedious as a whole. it is impossible to know which of its many sections seized fitzgerald, but the pages on "money" are a potent corollary to his inquiry into american wealth: we can imagine fitzgerald being engaged by them. spengler comments on the growth and expansion of the town, the city, and the accumulation and centrality of money there: as soon as the market has become the town, it is no longer a question of mere centers for streams of goods traversing a purely peasant landscape, but of a second world within the walls, for which the merely producing life "out there" is nothing but object and means, and out of which another stream begins to circle. the decisive point is this-the true urban man is not a producer in the prime terrene sense. he has not the inward linkage with soil or with the goods that pass through his hands. he does not live with these, but looks at them from outside and appraises them in relation to his own life-upkeep…. in place of thinking in goods, we have thinking in money. (vol. , ch. ; spengler's italics) about the enthralling daisy buchanan, gatsby says, "her voice is full of money," to which the narrator nick carraway responds, "that was it. i'd never understood before. it was full of money-that was the inexhaustible charm that rose and fell in it, the jingle of it, the cymbals' song of it" ( ; new york: scribner trade paperback, ). it is not charm alone that money supplies. it also engenders callous indifference; after gatsby's death, nick says about tom buchanan and daisy: "they were careless people, tom and daisy-they smashed up things and creatures and then retreated back into their money or their vast carelessness, or whatever it was that kept them together, and let other people clean up the mess they had made" ( ). wealth has hardened tom and daisy. they are careless, heedless, at a secure and indifferent distance from trouble, never facing the necessity to pay attention or minister to others. it is not that they are thoughtless but, rather, that they "think in money." about money, spengler continues: as the seat of this thinking, the city becomes the moneymarket, the center of values, and a stream of moneyvalues begins to infuse, intellectualize, and command the stream of goods…. only by attuning ourselves exactly to the spirit and economic outlook of the true townsman can we realize what they mean. he works not for needs, but for sales, for money. the business view gradually infuses itself into every kind of activity. at the beginning a man was wealthy because he was powerful-now he is powerful because he has money. (vol. , ch. ) tom does and does not fit spengler's discourse, for, though wealthy, he has inherited his money: he has no vocation or career and has not made anything. tom and daisy are profligate and irresponsible, leading lives that consist, in nick's phrase, of being "rich together" ( ). tom is a formidable physical specimen, as fitzgerald's first description of him, through nick, attests: he was a sturdy, straw haired man of thirty with a rather hard mouth and a supercilious manner. two shining, arrogant eyes had established dominance over his face and gave him the appearance of always leaning aggressively forward. not even the effeminate swank of his riding clothes could hide the enormous power of that body-he seemed to fill those glistening boots until he strained the top lacing and you could see a great pack of muscle shifting when his shoulder moved under his thin coat. it was a body capable of enormous leverage-a cruel body. ( ) tom inhabits a domineering body; his money is embedded in a proto-fascist mass of muscle. he vents a thuggish cruelty, as when he lashes out at his mistress myrtle wilson: "making a short deft movement, tom buchanan broke her nose with his open hand" ( ). fitzgerald was not a philosopher or cultural historian intent on composing encyclopedic arguments. wittgenstein, heidegger, joseph campbell, northrop frye, whittaker chambers, henry kissinger: these are among the figures, very different from fitzgerald, whom spengler influenced. but it is noteworthy that fitzgerald sent his letter to perkins, invoking spengler, in june . his career was faltering, and his effort to thrive as a hollywood screenwriter was failing. the nation remained afflicted by the great depression's tough times (unemployment was %), and the world was at war, with hitler on the march across western europe. the dunkirk evacuation was the first week of june. on june , the day of fitzgerald's letter to perkins, mussolini took italy into the war as an ally of germany. on this same day, the headline of the new york times was: "nazi tanks now within miles of paris." the german army entered paris on june , and france surrendered on june . the literary critic maureen corrigan has stated: "the great gatsby is the greatest… our greatest american novel" (so we read on: how the great gatsby came to be and why it endures, ) . like others, she relates it to the american dream, to american ideas and categories. yet so reflexive has this line of response become that it tends to operate at a remove from fitzgerald's line-by-line writing. if we aim to understand the rich american resonance of the great gatsby, its spengler-like dimension, and, ultimately, its universal range of reference, its impact on readers all across the globe, we must really read it. that we should really read the great gatsby: this sounds obvious. but do we do it? the great gatsby is a book that we assume we already are familiar with, that (so we dimly recall) was assigned to us long ago in high school, that we tell ourselves we must have read. it is akin to moby-dick, uncle tom's cabin, adventures of huckleberry finn, catch- , and other books that we know, or know about, even if we are not intimate with them or in fact have not actually read them. what we need to do, is to pause, take a breath, and approach fitzgerald's novel as if it were new to us. for instance, on the first night that nick attends one of gatsby's parties, he and his companion jordan baker intersect with "two girls in twin yellow dresses" who had met jordan a month ago: "you've dyed your hair since then," remarked jordan, and i started but the girls had moved casually on and her remark was addressed to the premature moon, produced like the supper, no doubt, out of a caterer's basket. with jordan's slender golden arm resting in mine we descended the steps and sauntered about the garden. a tray of cocktails floated at us through the twilight and we sat down at a table with the two girls in yellow and three men, each one introduced to us as mr. mumble. ( ) this passage has the playful exuberance that we associate with dickens, but it is more concise, subtle, and fleeting in its surreal, fantastical quality. we are invited to imagine the moon emerging like a felicitous treat from one of the caterer's baskets, and we watch the tray dawdle in the air as if on its own. this is fitzgerald's evocation of the magic, unreality, and impossibility of gatsby's project to reconnect with daisy. he gives us a controlled rhythm of sentences that amusingly climaxes with the three-man mr. mumble. after a date with jordan, nick returns to his modest house: "when i came home to west egg that night i was afraid for a moment that my house was on fire. two o'clock and the whole corner of the peninsula was blazing with light which fell unreal on the shrubbery and made thin elongating glints upon the roadside wires. turning a corner i saw that it was gatsby's house, lit from tower to cellar" ( ). fitzgerald is presenting an ostentatious effect-a house seemingly on fire, the peninsula blazing, and another house lit up from top to bottom. yet the word "unreal" exposes the illusory nature of the scene. it is amazing and not real, majestic and unnerving testimony to gatsby's imagination, to his yearning to journey backward in time so that he can rewrite the narrative of his and daisy's lives. such a keen image: the light sparking "glints," quick flashes, on the wires. the next day is the date for the afternoon tea that nick has arranged for gatsby's meeting with daisy. as always, in fitzgerald's description and dialogue there are bewitching phrases and images: "the rain cooled about half-past three to a damp mist, through which occasional thin drops swam like dew" ( ). then, daisy arrives: "is this absolutely where you live, my dearest one?" the exhilarating ripple of her voice was a wild tonic in the rain. i had to follow the sound of it for a moment, up and down, with my ear alone before any words came through. a damp streak of hair lay like a dash of blue paint across her cheek and her hand was wet with glistening drops as i took it to help her from the car. "are you in love with me," she said low in my ear. "or why did i have to come alone?" ( ) fitzgerald catches the coy theatricality in daisy's sense of herself. she knows how flirtatious she is, and she performs her attractiveness for nick's enjoyment. it is pleasing to him to observe the performance even as he is aware that daisy knows (and knows that he knows) that he is not in love with her. at the same time, daisy's quickness at producing this impression intimates her fragility, vulnerability, aloneness. who is daisy when she is not on stage? who is she really? gatsby, nick, and daisy enter and wander through gatsby's opulent mansion: "if it wasn't for the mist we could see your home across the bay," said gatsby. "you always have a green light that burns all night at the end of your dock" ( ). green is the color of life, renewal, nature, and energy; it is associated with growth, harmony, freshness, safety, fertility, and the environment. but green is also associated with money, finance, banking, ambition, greed, jealousy, and wall street. this duality makes green the appropriate color for the light that gatsby has gazed at: it has become a symbol for him, at a distance yet clandestinely close, his secret. the mist implies more than gatsby realizes. now at last, he is with daisy. but how clearly is he seeing her? "your home": gatsby does not register the implications of his words. tom is a brute, but he is daisy's husband, and they have a child. their luxurious, wasteful lifestyle, and tom's addiction to adultery: the cozy connotations of "home" do not flow from this family. but it is a family and they do have a home. this is the structure and history that gatsby thinks he can blot out. fitzgerald's next lines convey the depletion in gatsby even as, at this moment, he has daisy nearby and is making contact with her body: daisy put her arm through his abruptly but he seemed absorbed in what he had just said. possibly it had occurred to him that the colossal significance of that light had now vanished forever. compared to the great distance that had separated him from daisy it had seemed very near to her, almost touching her. it had seemed as close as a star to the moon. now it was again a green light on a dock. his count of enchanted objects had diminished by one. ( ) ( ) is gatsby feeling the self-questioning emotions that nick attributes to him? "possibly it had occurred to him": this brooding reflection on nick's part may disclose more about him than it does about gatsby. fitzgerald is communicating to us gatsby's glamor and nick's ambivalent interpretation of it, his projection from himself into the american dreamer whom he scrutinizes with fascination and disapproval. then, as the chapter draws to a close, the peculiar mr. ewing klipspringer plays the piano: in the morning in the evening, ain't we got fun-outside the wind was loud and there was a faint flow of thunder along the sound. all the lights were going on in west egg now; the electric trains, men-carrying, were plunging home through the rain from new york. it was the hour of a profound human change, and excitement was generating on the air. one thing's sure and nothing's surer the rich get richer and the poor get-children. in the meantime, in between time-( ) the tune accents the contrast between rich and poor, and combines the intonation of a loud wind and a counter-intuitive, faintly sounding thunder. fitzgerald gives us once again the imagery of light and electricity, and we hear in nick's voice that he is being mesmerized by a romantic, wistful imagination of his own. nick then turns to gatsby, who has on this fateful day reunited with daisy at last: as i went over to say goodbye i saw that the expression of bewilderment had come back into gatsby's face, as though a faint doubt had occurred to him as to the quality of his present happiness. almost five years! there must have been moments even that afternoon when daisy tumbled short of his dreams-not through her own fault but because of the colossal vitality of his illusion. it had gone beyond her, beyond everything. he had thrown himself into it with a creative passion, adding to it all the time, decking it out with every bright feather that drifted his way. no amount of fire or freshness can challenge what a man will store up in his ghostly heart. ( ) ( ) this sounds dead-on about gatsby, including his magnitude as a dreamer-the word "colossal" appears a second time. yet we should ask how much nick's response is the result of his own desires, hopes, and doubts. he is a reader as much as we are, a reader of gatsby who is struggling to understand this fabulously rich man who is captivating and mysterious, at once intriguing and absurd. nick reports gatsby's thoughts and feelings. is this perception or, again, is it projection? he sees bewilderment in the face and infers ("as though") that it signifies gatsby's uncertainty. the exclamation "almost five years" tells us what gatsby and nick, both of them, are likely to be marveling at. "there must have been," nick surmises: this is his interpretation of, his insistence on, the meaning for gatsby of the reunion with daisy. nick says that gatsby's dream about her and about himself and her as one, his "illusion," was so immense that, surely, she must have fallen short of embodying it. "tumbled" means to fall suddenly and helplessly; a sudden downfall, overthrow, or defeat. this is the verb that fitzgerald ties to daisy here, while he connects gatsby to "thrown himself," which implies someone who is passionate and, also, out of control, desperate. "every bright feather that drifted"-as if gatsby were so transfixed that he creatively works with the merest wisps that flutter by. "no amount of fire or freshness…": fitzgerald could have done without this sentence. it could feel tacked on, a sudden shift from the focus on gatsby himself. but fitzgerald deploys the sentence to point to nick as an interpreter who is stating the lesson that gatsby's dream illuminates for nick himself: "as i watched him he adjusted himself a little, visibly. his hand took hold of hers and as she said something low in his ear he turned toward her with a rush of emotion. i think that voice held him most with its fluctuating, feverish warmth because it couldn't be over-dreamed-that voice was a deathless song" ( ). fitzgerald was an avid reader of poetry, especially keats and shelley and others of the romantic and victorian periods. here, he may be alluding to the phrase "deathless song" as rudyard kipling uses it in "the last of the light brigade" ( ), which is itself a response to and revision of tennyson's "the charge of the light brigade" ( ). kipling's poem describes the fate of the neglected survivors: "though they were dying of famine, they lived in deathless song." gatsby served in combat in world war i, carnage and death enveloping him, entranced by the dream of re-crossing the atlantic to recover daisy. nick tells us what he sees as he looks at gatsby and daisy, but he cannot hear her words. fitzgerald could have written, "the voice…," but instead he writes, "i think that…," again dramatizing the impact of this moment on nick, the observer. fitzgerald brings the chapter to a close: they had forgotten me, but daisy glanced up and held out her hand; gatsby didn't know me now at all. i looked once more at them and they looked back at me, remotely, possessed by intense life. then i went out of the room and down the marble steps into the rain, leaving them there together. ( ) gatsby and daisy are reunited; nick is forgotten, isolated from them, the detail of the falling rain calling attention to his sense of forlorn separateness from them. "intense life" is a compact expressive term for his perception of this couple's exhilarating intimacy. it voices the feeling of being alive at the highest degree that dreamers long for, the dream for them becoming incredibly true. this intense life is not in nick himself. it is in his realization of a vital presence, overwhelming ("a rush of emotion"), miraculous, perhaps too great to be sustained for long, in gatsby and daisy. he is on the outside. when we read the great gatsby, we tend to highlight gatsby and his pursuit of daisy, and the conflict that arises between him and tom buchanan-two wealthy men, each determined to defeat his rival and claim exclusive ownership of the beautiful woman. but fitzgerald chose a first-person narrator, and, in certain respects, nick is the most interesting of the novel's characters. the action of the story that nick is telling took place in june-august , and it is now two years later. much time has passed, and he is back home in the midwest. we might consider how much we could recall of a stretch of incidents and persons, spanning three months, that occurred two years earlier. how trustworthy would our memory be? would we be creating-not so much remembering as inventing-as we reached backward in time to recollect our own and others' words and actions and relationships? when we really read the great gatsby, we should devote attention to nick, to his dreams (or their absence), and to his social and economic position. nick, we learn, is a yale graduate and a veteran of the war. at the outset, his tone is sometimes self-indulgently clever and sarcastic, irritating, even as all the while he-that is, the astute artist fitzgerald-is revealing his own entitled background and fine fortune. nick is not from a very wealthy family, but he is not from a poor one, either: my family have been prominent, well-to-do people in this middle-western city for three generations. the carraways are something of a clan and we have a tradition that we're descended from the dukes of buccleuch, but the actual founder of my line was my grandfather's brother who came here in fifty-one, sent a substitute to the civil war and started the wholesale hardware business that my father carries on today. ( ) nick says that the family tradition is that they descend from a line of scottish peers, a detail that he mentions with irony but that, at the same time, he did not need to mention at all. he has pride in his origins, his status and distinction, which he downplays and is wry about, but which matters to him. the carraways were immigrants, generations ago; they are not newly arrived on east coast shores. this is more than a family; in an american context, with its more compressed time-frame, it is a clan, a line. the founder of this family-line must have achieved a measure of success, his american dream, because when the civil war threatened him, he had the money to buy an exemption from service in the union army. he paid a substitute to risk mutilation or death in his place. after the war, nick was restless and, unlike the pioneers who journeyed westward, he moved in the opposite direction: i decided to go east and learn the bond business. everybody i knew was in the bond business so i supposed it could support one more single man. all my aunts and uncles talked it over as if they were choosing a prep-school for me and finally said, 'why ye-es' with very grave, hesitant faces. father agreed to finance me for a year and after various delays i came east, permanently, i thought, in the spring of twenty-two. ( ) nick is somewhat cavalier about turning to the bond business. he is not single-minded or ambitious, not motivated by a burning dream of his own. the fact that everybody he knew was in the bond business tells us about the types of people he and his supportive family are familiar with. nick then headed east, with a propitious advantage not available to others: his father agreed to finance him for a year. periodically, nick refers to the work he does, the people with whom he interacts, and his attitude toward them: i knew the other clerks and young bond-salesmen by their first names and lunched with them in dark crowded restaurants on little pig sausages and mashed potatoes and coffee. i even had a short affair with a girl who lived in jersey city and worked in the accounting department, but her brother began throwing mean looks in my direction so when she went on her vacation in july i let it blow quietly away. ( ) we hear nick's distaste as he reports that he consorted with clerks. he had a sexual affair; we do not know anything about it or even the girl's name-she is only a "girl," not a woman. her brother suspected that nick would take sexual advantage of his sister and then would dispense with her. nick's blithe tone of voice implies that indeed he would do something like this. to him, this young woman was merely a fling. nick adds that he "took dinner usually at the yale club," an experience he says he did not enjoy. but, nonetheless, he is a member of this club. further on, nick says that jay gatsby, then james gatz, had begun his studies at "the small lutheran college of st. olaf in southern minnesota," but had left it after just two weeks ( ). it is not only the very wealthy tom buchanan who benefits from privilege, but so does the ivy league graduate and yale club member nick. later, nick says: "the next april [ ] daisy had her little girl and they went to france for a year. i saw them one spring in cannes and later in deauville and then they came back to chicago to settle down" ( ). nick has the means to travel abroad and sojourn in resort towns on the french riviera and in normandy. he is among the fortunate few. nick's family, then, is prominent and well-to-do. tom's family is hugely rich; daisy's family has social standing and money. as for gatsby, born in north dakota: "his parents were shiftless and unsuccessful farm people-his imagination had never really accepted them as his parents at all" ( ). perhaps this is the trait in gatsby that for fitzgerald defines him as an american dreamer-imagination. it is imagination and tenacity, even ruthlessness, the willingness not only to move beyond one's origins but also to deny them. the greatest american dreamers say yes, but their power comes first from saying no. this is the insight that fitzgerald, writing during and about the s, establishes and explores. the american dreamer, as exemplified in the charismatic, crazy gatsby, strives for success, for self-realization, rushing forward. but this dream is propelled by the dreamer's disavowal of his or her past, the refusal to be that person: i cannot accept these parents, this upbringing. who i am, is intolerable to me, and i will not endure my existence in this paltry life: i will become someone else. when fitzgerald in the s was describing gatsby's dream, what were the conditions of american life that he witnessed? what was happening all around him? in the aftermath of the war, the u.s. economy in - had tumbled into a depression, especially in agriculture; the price of wheat plummeted by %, and cotton by %. the unemployment rate hit . % in . but, in a spectacular turnaround, it dropped to . % by the following year and was down to . % by . during the s, the gross domestic product (gdp) increased by %; annual per capita income did also, rising by %. as the scholar robert a. divine has noted: "the american people by the s enjoyed the highest standard of living of any nation on earth." propelled by commerce, industry, banking, and the stock market, the economy boomed from t at a growth rate of % per year. the u.s. accounted for nearly % of the world's industrial output. many americans at last had discretionary income, and, from shrewd marketers, they were receiving nonstop guidance about how to spend it. the historians george b. tindall & david e. shi explain: "more people than ever before had the money and leisure to taste of the affluent society, and a growing advertising industry fueled its appetites. by the mid- s, advertising had become both a major enterprise with a volume of $ . billion [$ billion today] and a major institution of social control." during the spending sprees of the s, americans could purchase cameras, wrist-watches, washing machines, and much else. from to , the number of telephones doubledthe word "telephone" occurs nineteen times in the great gatsby; the number of radios increased from , to million. by , " million people a week went to the moviesthe equivalent of half the nation's population" (steven mintz and randy roberts, hollywood's america, th ed., ). nick and tom attended yale. gatsby spent some weeks at oxford. daisy, meanwhile: we hear nothing about her education (which may have been entirely at home, with tutors). she has no interests other than travel and conspicuous consumption and display. the action of the novel takes place in ; the th amendment, giving women the right to vote, was ratified in august . there is no indication that this means anything to daisy. during the s,women began to benefit from greater freedom. divorce, for example, became easier. in , in every marriages ended in divorce; in , it was in . as the historian irwin unger has noted, in a typical woman's outfit consumed . yards of cloth; in , it required only seven yards. the ever-increasing popularity of movies and magazines also led to more attention to the right and best types of female behavior and appearance. as another historian, jane bailey, has said: by , hemlines were raised to below the knee; long curls gave way to short "bobbed" haircuts. pleasureseeking "flappers" (an english term once applied to prostitutes) drank, danced, and smoked their way through life. the heightened emphasis on female sexuality was not entirely emancipatory, however. as movies and magazines became more popular, standardized ideals of physical attractiveness took root. sales of cosmetics increased from $ million in to $ million in , as the goal of achieving perpetual youthfulness underwrote a cult of beauty and consumption. flappers' rejection of curves led to women binding their breasts and dieting to look boyish. the bathroom scale first appeared on the scene in the s, and cigarette ads targeted women with such slogans as "reach for a lucky instead of a sweet." daisy is slender, and she smokes. she also drinks alcohol, though, it seems, not to excess. this is in contrast to jordan baker's account of daisy's drunken state on the evening before her marriage to tom. too late, gatsby notified her that he was returning to the united states; by then committed to tom, she became "drunk as a monkey" ( ). this, in the story, was in june . prohibition went into effect in : it was illegal to manufacture, transport, or sell alcoholic beverages, and the consumption of alcohol, overall, declined. but drinking was common, and fashionable, for the middle and upper classes; at the expensive plaza hotel, tom takes out a bottle of whiskey, and daisy offers to make him a mint julep ( ). robert a. divine points out that "bootleggers annually took in nearly $ billion [$ . billion today], about two percent of the gross national product." gatsby is a bootlegger, a criminal: that is how he has amassed his fortune, supplemented by shady financial dealings with the gambler and gangster meyer wolfsheim. the s also marked the boom of the automobile-industry. henry ford had said: "i am going to democratize the automobile. when i'm through everybody will be able to afford one, and just about everyone will have one." when ford's model t was introduced in the early s, its cost was $ ; in , the cost of the model a, which replaced the model t, was $ . by , there were million registered passenger vehicles. automobiles abound in fitzgerald's book, and gatsby's car is the aristocrat among them, a radiant vehicle known to all: i'd seen it. everybody had seen it. it was a rich cream color, bright with nickel, swollen here and there in its monstrous length with triumphant hatboxes and supperboxes and tool boxes, and terraced with a labyrinth of windshields that mirrored a dozen suns. sitting down behind many layers of glass in a sort of green leather conservatory we started to town. ( ) tom and daisy have showy cars-and a chauffeur drives her to the tea at nick's where she meets gatsby ( ). meanwhile, the ineffectual gas-station man george wilson dreams that tom will bestow on him a car that the wealthy buchanans intend to get rid of; he appeals to tom, reminds him, and in response tom barks at him in annoyance. a monument to s' opulence and excess, there is, furthermore, gatsby's prodigious house, to the right of nick's place: "the one on my right was a colossal affair by any standard-it was a factual imitation of some hôtel de ville in normandy, with a tower on one side, spanking new under a thin beard of raw ivy, and a marble swimming pool and more than forty acres of lawn and garden" ( ). nick also visits the buchanan residence: their house was even more elaborate than i expected, a cheerful red and white georgian colonial mansion overlooking the bay. the lawn started at the beach and ran toward the front door for a quarter of a mile, jumping over sun-dials and brick walks and burning gardens-finally when it reached the house drifting up the side in bright vines as though from the momentum of its run. the front was broken by a line of french windows, glowing now with reflected gold, and wide open to the warm windy afternoon, and tom buchanan in riding clothes was standing with his legs apart on the front porch. ( ) fitzgerald foregrounds tom's truculent, conquest-seeking sexuality. later, we learn that he and daisy left chicago for this massive mansion in the east because of one of his sexual escapades ( ). the lifestyles of the rich and famous are maintained by innumerable workers-drivers, cooks, waiters, gardeners, servants. fitzgerald makes this crucial point often, as here, about gatsby's elaborate parties: "every friday five crates of oranges and lemons arrived from a fruiterer in new yorkevery monday these same oranges and lemons left his back door in a pyramid of pulp-less halves. there was a machine in the kitchen which could extract the juice of two hundred oranges in half an hour, if a little button was pressed two hundred times by a butler's thumb" ( - ). the butler, dehumanized, depersonalized, has been reduced to a thumb. gatsby does not give him a thought. this mansion-owner with the midas touch pays no more heed to his staff's mindnumbing routines than do the buchanans. fitzgerald perceived that the s economy was making american a new gilded age. at the beginning of the decade, president warren g. harding's principal cabinet member was secretary of the treasury andrew w. mellon, who cut personal income taxes to a maximum rate of %, lowered the estate tax, and repealed the gift tax. he also implemented steep tariffs and slashed federal spending. loyalists of big business were appointed to regulatory boards and agencies. corporate profits and stock dividends soared, rising far more rapidly than did the wages of workers. speaking in during his presidential campaign, herbert hoover declared: "we in america today are nearer to the financial triumph over poverty than ever before in the history of our land. the poor man is vanishing from us. under the republican system, our industrial output has increased as never before, and our wages have grown steadily in buying power." poor people were vanishing because no one was bothering to look for them. workers were losing power, and labor unions-a force during the era of eugene v. debs and the socialists and international workers of the world-suffered a falling off in their ranks. the historians tindall and shi point out: "prosperity, propaganda, welfare capitalism [i.e., bonuses, pensions, health and recreational activities in the workplace], and active hostility, combined to cause union membership to drop from about million in to . million in ." farmers had to deal with unstable prices, deep debts, foreclosures, and bankruptcies. farm exports fell as agriculture in europe was restored after the war; farm income in was billion; in , billion. what about african americans? nick refers to them several times, e.g., "as we crossed blackwell's island a limousine passed us, driven by a white chauffeur, in which sat three modish negroes, two bucks and a girl. i laughed aloud as the yolks of their eyeballs rolled toward us in haughty rivalry" ( ). in s new york city, few african americans were being escorted in limousines with white men as their drivers. most were sharecroppers in the south, under the sway of white landowners. falling prices for crops hurt them badly, and for many the s were harsh and unforgiving. hundreds of thousands of sharecroppers and other workers lost their jobs during this decade. many african-americans in the south migrated northward to new york, chicago, detroit, and other cities. they found employment but of an uneven and inadequate kind. much of the work they did was in the lowest-paying jobs; and they lived in segregated areas, in inferior-quality housing. as for other groups: a report on the condition of native americans found that half owned less than $ and that percent lived on less than $ a year. mexican americans, too, had failed to share in the prosperity. during the s, each year , mexicans migrated to the united states. most lived in conditions of extreme poverty. in los angeles the infant mortality rate was five times higher than the rate for anglos, and most homes lacked toilets. a survey found that a substantial number of mexican americans had virtually no meat or fresh vegetables in their diet; percent said that they could not afford to give their children milk. (digital american history, university of houston) by , the top % of the population owned % of all personal wealth. the top % owned %. only the top percent owned stocks. this was a decade of extreme income inequality, as fitzgerald confirms. there are the old money buchanans, the new money gatsby, the bond-businessman nick who is subsidized by his father; and then, on the other hand, there is the floundering, beaten-down george wilson, and, among many others alongside or lower down from him, the "finn" who works in nick's house as a maid-he never refers to her by name. in , economists concluded that a family of four needed $ per year [$ , today] for its basic necessities. even during this prosperous period, approximately % of american families did not reach this level of income. "the top . percent of american families in had an aggregate income equal to that of the bottom percent" (robert s. mcelvaine, the great depression, ) . also in , the stock market crashed, from in september to in july . banks failed; farmers lost their lands; factories and mines came to a stop. investments and savings were wiped out. farm income fell by %. foreign trade fell by %. by , personal income had declined by more than %. unemployment was %. in the automobile industry, production by fell to % of the total; the number of automobile workers fell to % of the total. by - , the average family income had collapsed to $ per year. there was no safety net. for much of the nation, financial prosperity and security were not achievable in the s, and by the s, except for the very fortunate, it had disappeared. so much for the american dream. but we should inquire into this american dream even more, this term to which the great gatsby is always linked. for it was in circulation not only during the s, but earlier as well. i have not been able to locate any book that has "american dream" in its title in the date range to . from to the present, by contrast, there are more than one hundred. still, the phrase does appear in various texts in the late th and early th centuries, and the implication is that people know what it means. a notable example is in an editorial in the montgomery advertiser, february , , urging the nation to be militantly ready and prepared for war: "if the american idea, the american hope, the american dream, and the structures which americans have erected, are not worth fighting for to maintain and protect, they were not worth fighting for to establish." zelda sayre was born in montgomery, alabama, in ; her father, anthony dickinson sayre ( - ), a lawyer, jurist, and democratic legislator, was appointed in to the state supreme court. i am sure that he read the montgomery advertiser; possibly he perused this editorial on a day when his daughter was at the breakfast table or in the living room with him. f. scott fitzgerald, commissioned as a second lieutenant, met zelda in montgomery in july ; this is altered slightly, but not significantly, in the novel-gatsby meets daisy in august , in louisville, kentucky. fitzgerald hence could feel the fervor of gatsby's dream because he had felt it strongly in himself. he craved success as a writer because through it he believed he could win zelda. his first novel, this side of paradise, was published on march , ; one week later, he and zelda were married. age twenty-four, fitzgerald had obtained the object that had enchanted him. by the early s, literary critics and scholars were regularly invoking "the american dream" in relation to the great soc gatsby, as did, for instance, marius bewley: "critics of scott fitzgerald tend to agree that the great gatsby is somehow a commentary on that elusive phrase, the american dream. the assumption seems to be that fitzgerald approved." to the contrary, says bewley: "the great gatsby offers some of the severest and closest criticism of the american dream that our literature affords…. the theme of gatsby is the withering of the american dream" ("scott fitzgerald's criticism of america," sewanee review, spring ). the american dream as aspiration and illusion had gained currency in the aftermath of world war ii and from the surge in the economy that boosted consumption in the s. the economy grew during this decade by %, and the median american family experienced an increase in purchasing power of %. unemployment was low, inflation was low. the critic sarah churchwell says: "it is not a coincidence that the great gatsby began to be widely hailed as a masterpiece in america during the s, as the american dream took hold once more, and the nation was once again absorbed in chasing the green light of economic and material success" (careless people: murder, mayhem, and the invention of the great gatsby, ). yet bewley refers to "withering," implying that the dream, as portrayed by fitzgerald, had in some earlier era flowered and flourished but had now shriveled and wizened. when was this era? the american dream was not widespread in the s, and it became even more restricted during the great depression decade. if there is a single main source for the term, it is james truslow adams's the epic of america, published in , six years after the great gatsby, and two years into the great depression, the high times for the fortunate in the s shattered. adams , born in brooklyn, was an excellent student in high school and college, but he faltered in his graduate studies in philosophy and history and found little satisfaction in publishing and finance. while living in new york with his father and sister, adams began to devote his time and energy to the writing of history, based in primary sources, rendered in an appealing, accessible style. adams's three-volume survey of the settlement of new england and its history to was a major success, and for this project and other books in the s he was widely praised. adams based the epic of america on his conviction that self-improvement and self-formation were the motive forces in american history. adams maintains that there has always been: … the american dream, that dream of a land in which life should be better and richer and fuller for every man, with opportunity for each according to his ability or achievement. it is a difficult dream for the european upper-classes to interpret adequately, and too many of us ourselves have grown weary and mistrustful of it. (adams's italics) he continues: "it is not a dream of motor cars and high wages merely, but a dream of a social order in which each man and each woman shall be able to attain to the fullest stature of which they are innately capable, and be recognized by others for what they are, regardless of the fortuitous circumstances of birth or position." adams states that the american dream is more than money and materialism: no, the american dream that has lured tens of millions of all nations to our shores in the past century has not been a dream of merely material plenty, though that has doubtless counted heavily. it has been much more than that. it has been a dream of being able to grow to fullest development as man and woman, unhampered by the barriers which had slowly been erected in older civilizations, unrepressed by social orders which had developed for the benefit of classes rather than for the simple human being of any and every class. and that dream has been realized more fully in actual life here than anywhere else, though very imperfectly even among ourselves. it has been a magnificent epic and dream, adams affirms. but he then asks, what about the american dream at present and in the future? if the american dream is to come true and to abide with us, it will, at bottom, depend on the people themselves. if we are to achieve a richer and fuller life for all, they have got to know what such an achievement implies. in a modern industrial state, an economic base is essential for all. we point with pride to our "national income," but the nation is only an aggregate of individual men and women, and when we turn from the single figure of total income to the incomes of individuals, we find a very marked injustice in its distribution. the concern that adams expresses is about income inequality-he saw it in the s, and again in the great depression decade. in this same year, , looking backward, fitzgerald wrote in an essay, "echoes of the jazz age": it ended two years ago, because the utter confidence which was its essential prop received an enormous jolt, and it didn't take long for the flimsy structure to settle earthward. and after two years the jazz age seems as far away as the days before the war. it was borrowed time anyhow-the whole upper tenth of a nation living with the insouciance of grand dukes and the casualness of chorus girls. but the moralizing is easy now and it was pleasant to be in one's twenties in such a certain and unworried time. the upper tenth troubles adams too, as he declares in a verdict that applies to the s, the s-and to where we are in the twenty-first century: there is no reason why wealth, which is a social product, should not be more equitably controlled and distributed in the interests of society. a system that steadily increases the gulf between the ordinary man and the super-rich, that permits the resources of society to be gathered into personal fortunes that afford their owners millions of income a year, with only the chance that here and there a few may be moved to confer some of their surplus upon the public in ways chosen wholly by themselves, is assuredly a wasteful and unjust system. it is, perhaps, as inimical as anything could be to the american dream. nick says about the very rich american dreamer gatsby: "he wanted nothing less of daisy than that she should go to tom and say: 'i never loved you'. after she had obliterated four years with that sentence they could decide upon the more practical measures to be taken" ( ). gatsby wanted money, an immense amount of it, which he procures by lawless means, so that he can capture daisy, who represents for him privilege and status. "obliterate": to remove utterly from recognition or memory; to remove from existence; to destroy utterly all trace, indication, or significance. it never occurs to gatsby to consider whether daisy, herself, wants to participate in his dream. he assumes that she does-and that she will immediately erase the fact that she has been and is married to tom and is the mother of a child. gatsby is blinded by his dream, and by money and the potency he believes that it gives him. at one point, in front of nick and jordan baker, daisy "got up and went over to gatsby and pulled his face down, kissing him on the mouth." she murmurs: "you know i love you" ( ). but for gatsby this will not suffice. he will not allow daisy to say that she once loved tom but now loves him. he commands her to negate the person she was, a person with a past and a memory of it. the money that gatsby has, and the magnitude of his hyperbolic purchases, should prove to her, so gatsby presumes, that he loves her and that she should join him in the story-line of their lives than he has constructed. gatsby does feel apprehension when daisy seems not to be falling into exact conformity with his image of her, to which nick replies: "i wouldn't ask too much of her," i ventured. "you can't repeat the past." "can't repeat the past?" he cried incredulously. "why of course you can!" he looked around him wildly, as if the past were lurking here in the shadow of his house, just out of reach of his hand. "i'm going to fix everything just the way it was before," he said, nodding determinedly. "she'll see." ( ) nick warns gatsby about the impossibility of this ultimatum, this imposition on daisy. but nick does not formulate his point in quite the correct terms-and gatsby does not discern the misleading nature of both nick's words and his own incredulous reply. gatsby does not want to "repeat" the past. his intention is not that at all. it is through money and rhetoric to obliterate the past, to write a new history on a blank page, as though the one there before had never existed. why not? if you have the money, you can do anything. fixing everything the way it was before: this links gatsby to meyer wolfsheim, who "fixed the world series" in ( ). it is criminal to recreate another person in the coercive manner that gatsby is committed to. fitzgerald intends for us to recognize that for gatsby "the way it was before" is not his dream. his dream is to make it the way it was not: he hates his past, and his money is his guarantee that he can dispense with the person he was and invite-that is, order-daisy to do the same. nick breaks from this dialogue to reflect on gatsby's obsession: "he talked a lot about the past and i gathered that he wanted to recover something, some idea of himself perhaps, that had gone into loving daisy. his life had been confused and disordered since then, but if he could once return to a certain starting place and go over it all slowly, he could find out what that thing was..." ( ; fitzgerald's ellipsis). nick's story is entwined with gatsby's. often it is difficult to know when nick is giving us an accurate impression of gatsby and when he is speculating about him. nick next proceeds to stage and paint the scene of gatsby's remembered vision of his momentous time with daisy: …one autumn night, five years before, they had been walking down the street when the leaves were falling, and they came to a place where there were no trees and the sidewalk was white with moonlight. they stopped here and turned toward each other. now it was a cool night with that mysterious excitement in it which comes at the two changes of the year. the quiet lights in the houses were humming out into the darkness and there was a stir and bustle among the stars. out of the corner of his eye gatsby saw that the blocks of the sidewalk really formed a ladder and mounted to a secret place above the trees-he could climb to it, if he climbed alone, and once there he could suck on the pap of life, gulp down the incomparable milk of wonder. ( ; fitzgerald's ellipsis) fitzgerald heightens nick's language, imbuing it with romance, melodrama, and phantasmagoric sublimity. this is far beyond anything that gatsby could articulate. it is sumptuous and strained, lavish and ridiculous: nick is appalled and seduced by the wealth-laden gatsby's effort to incarnate his daisy-inspired imagination. fitzgerald returns to this scene when nick once more tells the reader about gatsby's first experiences of daisy. he says that gatsby said: "she was the first 'nice' girl he had ever known. in various unrevealed capacities he had come in contact with such people but always with indiscernible barbed wire between. he found her excitingly desirable" ( ). an acute phrase: the "barbed wire" visible yet indiscernible, not to be seen. it is oracular for gatsby, who would take part in the argonne offensive in france ( ), one of the deadliest battles in u.s. military history, where there were labyrinthine networks of barbed wire in the killing zones. to pre-war gatsby, daisy is not only desirable but excitingly so: she arouses, stirs, stimulates him. she amplifies desire: "he went to her house, at first with other officers from camp taylor, then alone. it amazed him-he had never been in such a beautiful house before. but what gave it an air of breathless intensity was that daisy lived there-it was as casual a thing to her as his tent out at camp was to him" ( ). there is more here about the house than about daisy; it is not her, but the house to which gatsby (according to nick) attached the word "beautiful." this is where daisy lives, but the antecedent for "it" is "house"-that is, while daisy is special, it is the house itself that has "breathless intensity": "there was a ripe mystery about it, a hint of bedrooms upstairs more beautiful and cool than other bedrooms, of gay and radiant activities taking place through its corridors and of romances that were not musty and laid away already in lavender but fresh and breathing and redolent of this year's shining motor cars and of dances whose flowers were scarcely withered" ( ). nothing about daisy's appearance, not anything directly about her at all. the word "beautiful" reappears, but again not in reference to her but to the house. nick then returns to daisy: "it excited him too that many men had already loved daisy-it increased her value in his eyes. he felt their presence all about the house, pervading the air with the shades and echoes of still vibrant emotions' ( ). later, gatsby will insist that daisy obliterate, wipe out ( , ), her relationship with tom. but at this initial stage, her value to gatsby is increased because other young men have loved her. they confirm the rightness of gatsby's desire for her, intensifying it. the next passage takes us to the climax of gatsby's pursuit: but he knew that he was in daisy's house by a colossal accident. however glorious might be his future as jay gatsby, he was at present a penniless young man without a past, and at any moment the invisible cloak of his uniform might slip from his shoulders. so he made the most of his time. he took what he could get, ravenously and unscrupulously-eventually he took daisy one still october night, took her because he had no real right to touch her hand. ( ) gatsby is pretending to daisy to be someone he is not. in army uniform-another marvel, the cloak that is invisibleall of the officers are the same. gatsby can represent himself to daisy as better in status than he really is. deceiving her, he is playing a role; he knows (she does not know) who he is-the offspring of shiftless, unsuccessful parents whom he has repudiated. what makes the passage shocking is that, having deceived daisy, gatsby "takes" her sexually. he takes her, he took her; two lines later fitzgerald repeats, "he had certainly taken her." nick's account makes this sexual consummation not a loving one but an assault, a molestation, or worse. "ravenously" implies extreme hunger, being famished, voracious like a beast, intensely eager for gratification or satisfaction. "unscrupulously": without scruples, without conscience, unprincipled. is this love? if it is, it is expressed as if it were theft, a trespass, an act of resentment, of hate and self-hatred. fitzgerald could have written the passage differently, or not included it at all. this is what he wanted. when gatsby, his "taking" done, separates from daisy, "she vanished into her rich house, into her rich, full life leaving gatsby-nothing. he felt married to her, that was all" ( ). he feels married to her: it is hard to know what this means. for the main impression is one of coercion and grievance, of sexual violation. gatsby desires daisy. or, should we say that he despises her?-despises the socially privileged and wealthy? gatsby knows that daisy does not know who he is and would rebuff him if she did. his interaction with her has left him feeling cancelled out, null and void. "when they met again," says nick: two days later it was gatsby who was breathless, who was somehow betrayed. her porch was bright with the bought luxury of star-shine; the wicker of the settee squeaked fashionably as she turned toward him and he kissed her curious and lovely mouth. she had caught a cold and it made her voice huskier and more charming than ever and gatsby was overwhelmingly aware of the youth and mystery that wealth imprisons and preserves, of the freshness of many clothes and of daisy, gleaming like silver, safe and proud above the hot struggles of the poor. ( ) ( ) gatsby, objectifying daisy, values her silvery presence for its distance from futile poverty where dreams never come true. she is preserved in her wealth; she is imprisoned too, but the implication is that gatsby, by uniting himself to her, will liberate her along with himself. this is an impossible dream, as somewhere in his mind gatsby is aware. daisy is captivating but sullied in his eyes: he has tainted her by taking her. in a startling juxtaposition, fitzgerald passes from nick's description to gatsby's own colloquial speech: "i can't describe to you how surprised i was to find out i loved her, old sport. i even hoped for a while that she'd throw me over, but she didn't, because she was in love with me too. she thought i knew a lot because i knew different things from her.... well, there i was, way off my ambitions, getting deeper in love every minute, and all of a sudden i didn't care. what was the use of doing great things if i could have a better time telling her what i was going to do?" ( ) gatsby is acknowledging that, for him, the american dream is better talked about than experienced: he could have done great things but what is even better is the prospect of telling daisy that he will do them in the future. it might be better for gatsby never to do them, because if they were done, it would no longer be possible to talk about them, anticipate them, look forward to them. gatsby may realize that if he did great things, these would not make him happy. not doing them means not being disappointed. in the screenplay for his film adaptation of the great gatsby, , baz luhrmann revises the dialogue of this scene. gatsby says: "i knew it was a great mistake for a man like me to fall in love. a great mistake. i'm only …. i might still be a great man if i could only forget that i once lost daisy. but my life, old sport, my life has got to be like this…he draws a slanting line from the lawn to the stars." luhrmann is bringing out, putting into words, an insight into gatsby that fitzgerald glances at. gatsby reveals that he knows the mistake he made; in two senses, it is a "great" mistake. there is time for him to choose a different direction. money is not everything and neither is daisy, but gatsby cannot make this choice: he cannot forget that he lost daisy. does he want to possess her because he desires her, or does he desire her because he lost her? fitzgerald's exposition of, and inquiry into, the american dream, undertaken in , is psychologically complex, written in a suspenseful first-person form full of twists and turns, flash-forwards and flash-backs. fitzgerald criticizes delusion and illusion, yet from first to final page, his craftsmanship, his adroit literary language, is subtle and sensitive. he pays tribute to the american dream that he discredits, and we remain wedded to it. on the campaign train in iowa, , barack obama celebrated the american dream: as i've traveled around iowa and the rest of the country these last nine months, i haven't been struck by our differences-i've been impressed by the values and hopes that we share. in big cities and small towns; among men and women; young and old; black, white, and brown-americans share a faith in simple dreams. a job with wages that can support a family. health care that we can count on and afford. a retirement that is dignified and secure. education and opportunity for our kids. common hopes. american dreams. obama said that he, his grandparents, and other family members had achieved this dream, but that many americans were now finding their hopes for it to be unfulfilled: "while some have prospered beyond imagination in this global economy, middle-class americans-as well as those working hard to become middle class-are seeing the american dream slip further and further away." "you know it from your own lives," obama continued: americans are working harder for less and paying more for health care and college. for most folks, one income isn't enough to raise a family and send your kids to college. sometimes, two incomes aren't enough. it's harder to save. it's harder to retire. you're doing your part, you're meeting your responsibilities, but it always seems like you're treading water or falling behind. and as i see this every day on the campaign trail, i'm reminded of how unlikely it is that the dreams of my family could be realized today. obama told his audience-this was the basis for his campaign: "i don't accept this future. we need to reclaim the american dream." during his two terms, - , how well did president obama perform in his effort to restore and reanimate the american dream? in a study published in late , emmanuel saez and gabriel zucman concluded: "the share of wealth held by the top . percent of families is now almost as high as in the late s, when the great gatsby defined an era that rested on the inherited fortunes of the robber barons of the gilded age." they noted: the flip side of these trends at the top of the wealth ladder is the erosion of wealth among the middle class and the poor…. the growing indebtedness of most americans is the main reason behind the erosion of the wealth share of the bottom percent of families. many middle class families own homes and have pensions, but too many of these families also have much higher mortgages to repay and much higher consumer credit and student loans to service than before. ("exploding wealth inequality in the united states," washington center for equitable growth, october , ) preparing in for her presidential campaign, hillary clinton said: "we have to do a better job of getting our economy growing again and producing results and renewing the american dream so americans feel they have a stake in the future and that the economy and political system is not stacked against them." she had served as obama's secretary of state from to ; her promise to renew the american dream thus amounted to a critique of the administration that she had been part of. from - to - , hillary and bill clinton made more than $ million in lecture fees; in total, during these fifteen years after he left the white house, they made $ million. they led (and continue to lead) luxurious lives; they have a charitable foundation worth many millions; and their net worth (estimates vary) is somewhere in the $ million range. money "has always been passed down in families"-as fitzgerald shows through tom buchanan-"but today, across america, parents who can are helping their grown children in unprecedented ways" (jen doll, harper's bazaar, february , ). since , the clintons' daughter chelsea has served as a member of the corporate board of iac/interactivecorp, a media and investment company: she has received $ million in compensation. she has one qualification for this position: her parents. her wedding in cost $ million; for their new york city condo, she and her husband paid $ . million; they have a net worth in excess of $ million. hillary clinton lost the election in to donald trump, net worth, $ . billion, who had launched his campaign in june with a speech that concluded: trump: sadly, the american dream is dead. audience member: bring it back. trump: but if i get elected president i will bring it back bigger and better and stronger than ever before, and we will make america great again. during president trump's term, from forward, the numbers for growth, employment, and the stock market have been positive. vice president mike pence said, april , , that the american dream was "dying until president donald trump was inaugurated" in . trump's policies are generating jobs "at the fastest pace of all," pence emphasized, and this "gives evidence of the fact that the american dream is coming back." "was the american dream in trouble? you bet," pence said in an interview: "i really do believe that's why the american people chose a president whose family lived the american dream and was willing to go in and fight to make the american dream available for every american" (cnbc, april , ). donald trump jr. has said: "for the last years our biggest net export has been the american dream, but because of donald trump we've brought that american dream home, where it belongs" (june , ). eric trump, the second of the president's sons, echoes this claim: "we have achieved something that was incredible and something that is so much bigger than what we are and it shows that the american dream is alive and under him i think the american dream is going to be stronger than it was ever before" (fox business, september , ). on the other hand: in late , the census bureau reported: "the gap between the richest and the poorest u.s. households is now the largest it has been in the past years." "the most troubling thing about the new report," states the economist william m. rodgers iii, is that it "clearly illustrates the inability of the current economic expansion, the longest on record, to lessen inequality" (bill chappell, "u.s. income inequality worsens, widening to a new gap," npr, september , ). as for the record-setting stock market: in , % of americans owned stock; in , % do. this means that nearly half of the nation owns no stock-no mutual funds, no retirement funds. the top % of families with the highest income own, on average, $ , in stocks. among low-income workers, % of them do not have a retirement account or cannot afford to contribute to one. (allison schrager, quartz, september , ; gallup news, september , .) the authors of a report published in conclude: we live in an age of astonishing inequality. income and wealth disparities in the united states have risen to heights not seen since the gilded age and are among the highest in the developed world. median wages for u.s. workers have stagnated for nearly fifty years. fewer and fewer younger americans can expect to do better than their parents. racial disparities in wealth and well-being remain stubbornly persistent. in , life expectancy in the united states declined for the third year in a row, and the allocation of healthcare looks both inefficient and unfair. advances in automation and digitization threaten even greater labor market disruptions in the years ahead. ("forum on economics after neoliberalism," boston review, february , ) nevertheless, we dream on. in orlando, florida, june , , president trump announced his bid for reelection: our country is now thriving, prospering and booming. and frankly, it's soaring to incredible new heights. our economy is the envy of the world, perhaps the greatest economy we've had in the history of our country. and as long as you keep this team in place, we have a tremendous way to go. our future has never ever looked brighter or sharper. the fact is, the american dream is back, it's bigger and better, and stronger than ever, before. in , % of american workers made less than $ per hour. this places their income for the year below the federal poverty level. overall, "the number of people earning less than $ , accounts for . percent of the population." during the next five years, the job most in-demand, which will rise %, is home health-aide. its median salary is $ , . the reporter/journalist jeanna smialek observes that "unequal access to opportunities is now a global story. barriers vary by country, but children are generally more likely to earn incomes similar to their parents' in nations with higher income inequality." she comments further: "the graph of this relationship is often called a great gatsby curve, named after f. scott fitzgerald's novel about social mobility and its costs." the united states is "further toward the high-inequality, highimmobility end of the scale than other advanced economies." in the united states, says smialek, "higher incomeinequality goes hand in hand with lower upward-mobility," and she cites research by the economists raj chetty, nathaniel hendren, and others. hendren observes: "it just speaks to this kind of question: to what extent are we a country where kids have a notion of the american dream?" (bloomberg business week, march , ; see also john jerrim and lindsey macmillan, "income inequality, intergenerational mobility, and the great gatsby curve: is education the key?," social forces, december ). senator bernie sanders has spoken about the american dream. in , on the senate floor, he asked, "what happened to the american dream?", and he replied, "we are now the most unequal society" among all of the industrial nations. in his campaign for the nomination, sanders emphasized the crisis of income inequality, and he is emphasizing it even more. the son of jewish immigrants, a member of a family that struggled to pay the bills, sanders through hard work and education made it all the way to the u.s. senate; he now is "attempting to identify his own personal story with the american dream", a dream that, he contends, fewer and fewer americans can hope to achieve (walter g. moss, la progressive, march , ). on his campaign www-site, joe biden also presents himself as an embodiment of and proponent for the american dream: during my adolescent and college years, men and women were changing the country-martin luther king, jr., john f. kennedy, robert kennedy-and i was swept up in their eloquence, their conviction, the sheer size of their improbable dreams…. america is an idea that goes back to our founding principle that all men are created equal. it's an idea that's stronger than any army, bigger than any ocean, more powerful than any dictator. it gives hope to the most desperate people on earth. it instills in every single person in this country the belief that no matter where they start in life, there's nothing they can't achieve if they work at it. so too does senator elizabeth warren, and she has a proposal for reducing the inequality gap: i've got plans to put the american dream within reach for america's families-and a plan to pay for it with a two-cent wealth tax. a two-cent tax on fortunes of more than $ millionthe wealthiest . %can bring in the revenue we need to invest in universal child-care, public education, universal tuition-free public college and student debt cancellation for % of people who have it…. education was my ticket to live my dreams, and it's time we make that opportunity available to every family who wants it. (concord monitor, november , ) those at the top, the wealthiest americans: they are the most alarmed critics of the sanders and warren positions and proposals. hedge-fund manager leon cooperman, for instance, wailed about warren's intention to set new rules for wall street: "this is the fucking american dream she is shitting on" (politico, october , ). more temperately, he said: "let's elevate the dialogue and find ways to keep this a land of opportunity where hard work, talent, and luck are rewarded and everyone gets a fair shot at realizing the american dream." cooperman's net worth is $ . billion. critics of a tax increase on the very rich and of regulation that might lessen income inequality: these worried voices include michael bloomberg (net worth, $ . billion) and jeff bezos (net worth in , $ . billion; in , net worth, $ billion-the remainder after his wife received $ billion in their divorce settlement). the sports merchandise executive michael rubin (net worth, $ . billion) contends that boosting taxes on the super-rich "would have the exact opposite effect of what you want to happen…. what makes america great is that this is a true land for the entrepreneur…. what would happen is that people won't start businesses here anymore" (yahoo finance, january , ). mark cuban (net worth, $ . billion) weighs in: "i love entrepreneurship because that's what makes this country grow. and if i can help companies grow, i'm setting the foundation for future generations. it sends the message that the american dream is alive and well" (cnbc, march , ) . cuban endorsed hillary clinton in as the best advocate of (his phrase) "the american dream." she says that she is in favor of an estate tax, but as for a tax increase aimed at the very wealthy (like herself), she asserts that this would be "incredibly disruptive" (daily beast, july , ; business insider, november , ) . in , the world's wealthiest people added $ . trillion to their fortunes, increasing their collective net worth %, to at least $ . trillion. the twenty-six people at the top possess greater wealth than the . billion people in the bottom half of the world's population. in the united states, there are + billionaires. in a report, january , oxfam focused on this vast disparity and concluded: "extreme wealth is a sign of a failing system. governments must take steps to radically reduce the gap between the rich and the rest of society and prioritize the well-being of all citizens over unsustainable growth and profit." in the same month, many of the attendees at the world economic forum, "the most concentrated gathering of wealth and power on the planet," at their meeting in davos, switzerland, expressed a similar concern. kristalina georgieva, managing director of the international monetary fund, said: "the beginning of this decade has been eerily reminiscent of the s." in a report that was prepared for this meeting, the united states is at # in the world's social mobility index, behind, e.g., germany, france, canada, japan, and the united kingdom. one observer remarked: "canadians have a better shot at the american dream than americans do." (chloe taylor, cnbc, january , ; heather long, washington post, january , ; hanna ziady, cnn business, january , .) among americans, % say that there "is too much economic inequality." for young people, ages to , the figure rises to more than %. if there is a surprise in the polling, it is that only + percent say that reversing income inequality should be a "top priority." but the priorities they do emphasize, such as "creating affordable health care, fighting drug addiction, making college more affordable, fixing the federal budget deficit, and solving climate change"-all of these are connected to economic policy. people recognize this-which is why nearly % believe that the very wealthy should pay more in taxes (cnbc, january , ; npr, january , ). economists have demonstrated that inequality is higher today than it has been since the s, the decade of the great gatsby. in forbes magazine, for example, jesse colombo writes: "it's not fashionable to wear flapper dresses and do the charleston, but s-style wealth inequality is definitely back in style. america's ultra-rich haven't held as much of the country's wealth since the jazz age" (february , ). here are the conclusions presented in recent studies of the american dream: absolute mobility has declined sharply in america over the past half-century primarily because of the growth in inequality. socio-economic outcomes reflect socio-economic origins to an extent that is difficult to reconcile with talk of opportunity. your circumstances at birth-specifically, what your parents do for a living-are an even bigger factor in how far you get in life than we have previously realized. at least since the s, american have worried that the united states is no longer the "land of opportunity" it once was. data show a slow, steady decline in the probability of moving up…. millennials might be the first american generation to experience as much downward mobility as upward mobility. if fitzgerald were alive, he would see that the inequality he had depicted in the great gatsby has widened, that it is not a gap, but an abyss. all of this is true and crucially pertinent to fitzgerald's novel as we read it now. but he is saying even more in it, and here we need to move through and beyond american themes and the statistics that bear witness to them. for there is in the great gatsby a vision that exceeds money, inequality, and the american dream. i am referring in particular to the novel's final pages, to the elegiac, plaintive paragraphs that are familiar to many of us but that perhaps we have not really read. in them, fitzgerald is simultaneously american and global, national and international; he is transhistorical, universal. "these concluding lines are so impassioned and impressive," says the critic richard chase, "that we feel the whole book has been driving toward this moment of ecstatic contemplation, this final moment of transcendence" (the american novel and its tradition, ) . in the completed first draft, these lines are not at the end but, rather, at the close of the first chapter. fitzgerald made many revisions throughout his typed draft and page proofs. but he made very few changes in these paragraphs. what he did, was to relocate them. he wanted them to be the conclusion even as he knew that their melancholy intensity would be present in the mood and atmosphere of his story from the start. the mansion is empty. gatsby is dead and buried. soon nick will be leaving for the midwest: most of the big shore places were closed now and there were hardly any lights except the shadowy, moving glow of a ferryboat across the sound. and as the moon rose higher the inessential houses began to melt away until gradually i became aware of the old island here that flowered once for dutch sailors' eyes-a fresh, green breast of the new world. its vanished trees, the trees that had made way for gatsby's house, had once pandered in whispers to the last and greatest of all human dreams; for a transitory enchanted moment man must have held his breath in the presence of this continent, compelled into an aesthetic contemplation he neither understood nor desired, face to face for the last time in history with something commensurate to his capacity for wonder. ( ) these sentences are laden with loss and longing. but this is only one register of it, the tone of voice of the first-person narrator nick. fitzgerald's perspective is here as well, and he is more tough-minded in his judgments. the term "pandered" points us, ironically and critically, toward nick, toward the role he played in fostering gatsby's quest for daisy that culminated in the dreamer's death. nick's imagination expands as he moves centuries backward in time to the moment when long island was dense with forests and when dutch sailors first glimpsed it. for them, according to nick, it might have been the breath-taking prospect of a new beginning, an eden rediscovered, and he seems to share in this reverie. but fitzgerald knows that history was more complicated then, and that much has transpired since. in april , henry hudson, an english sea captain hired by the dutch east india company, undertook a voyage of exploration to north america to locate a sea and trade route to asia. by july, his eighty-foot ship with its crew of sixteen had reached nova scotia and shortly thereafter he arrived at present-day staten and long islands, and then travelled up the river that now bears his name. hudson grasped that here were lucrative possibilities for commerce, for money-making, for profit, especially in the fur trade. settlers began to arrive in - ; the first group consisted of thirty families. this dutch territory included manhattan, parts of long island, connecticut, and new jersey. in , peter minuit, director of the colony, with a payment of blankets, kettles, and knives, secured an alliance or treaty with the neighboring native americans. the dutch settlement was small, some people, in the midst of tribes that were sometimes in conflict with one another. relations between settlers and native americans were, at the outset, peaceful for the most part, but there was an attack on a dutch fort at albany, named fort orange, as early as .; bloody conflicts broke out in the s and into the s. the new netherland population was , with in new amsterdam at the southern tip of manhattan. also in , a dutch ship unloaded eleven slaves in new amsterdam, and others were brought up the coast from the caribbean. new amsterdam was built by slave labor, and by , one-third of the population was african. nick imagines dutch seamen looking from the outside in, but fitzgerald wants us also to be cognizant of the view from the inside out-nick himself is on the shore, looking outward. the enchantment, the awe, may have been thrilling for those on the outside who first experienced it, but in this novel filled with people of various races and ethnicities, fitzgerald presents a history that these men aboard ship did not know, did not possess but would inaugurate and sustain through dispossession, enslavement, battle, and war. fitzgerald calls attention to the deforestation of the land, the assault on it, the exploitation of it as it lay there ready to be taken. nick refers to the "fresh, green breast of the new world," an image that fitzgerald is connecting to the green light, beguiling and perilous, and to the terrible death of myrtle wilson, killed by daisy driving the car with gatsby next to her: the "death car" as the newspapers called it, didn't stop; it came out of the gathering darkness, wavered tragically for a moment and then disappeared around the next bend. michaelis wasn't even sure of its color-he told the first policeman that it was light green. the other car, the one going toward new york, came to rest a hundred yards beyond, and its driver hurried back to where myrtle wilson, her life violently extinguished, knelt in the road and mingled her thick, dark blood with the dust. michaelis and this man reached her first but when they had torn open her shirtwaist still damp with perspiration, they saw that her left breast was swinging loose like a flap and there was no need to listen for the heart beneath. the mouth was wide open and ripped at the corners as though she had choked a little in giving up the tremendous vitality she had stored so long. ( ) nick then says: and as i sat there brooding on the old, unknown world, i thought of gatsby's wonder when he first picked out the green light at the end of daisy's dock. he had come a long way to this blue lawn and his dream must have seemed so close that he could hardly fail to grasp it. he did not know that it was already behind him, somewhere back in that vast obscurity beyond the city, where the dark fields of the republic rolled on under the night. he broods his way into a final affirmation and tragic prophecy: gatsby believed in the green light, the orgastic future that year by year recedes before us. it eluded us then, but that's no matter-tomorrow we will run faster, stretch out our arms farther.... and one fine morning--so we beat on, boats against the current, borne back ceaselessly into the past. when we read the great gatsby, we inevitably think (as fitzgerald wants us to) about the american dream-what it was and is, and whether, if we are losing this dream, we might restore it in this twenty-first century riven by income inequality. but when we really read the great gatsby, we realize that fitzgerald has written both a great american novel and a great novel for the world. the great gatsby belongs with melville's moby-dick, dreiser's sister carrie, and ellison's invisible man-milestone american books that readers everywhere deeply respond to. fitzgerald compels all of his readers to reflect on what it means to be human, bodies ensnared by time, consumed by desires destined never to be fulfilled. the great gatsby is rooted in a time and place and nation: it is american through and through, and it is an essential guide to and diagnosis of the way we live now. but it is, furthermore, a literary work with an all-inclusive address that speaks to societies and cultures outside its american context. fitzgerald has a message about life in america and a message about life itself. he believes that life for all persons is the pursuit of happiness, not the achievement of it. most of us have faith in, we yearn for, a future of maximum well-being-not just a good life, but one so good that it overcomes and redeems, or seems to, the inexorability of death. this is the dream we cannot reach, a satisfaction that cannot be measured, a happiness that eludes us. if only, somehow, we could get to it, we would know immortality. we tell ourselves that we need to try harder and desire more intensely. then it will come. but it does not, and the "current" pulls us rearward, into oblivion. there is no religious comfort or consolation. we beat on, striving, not finding contentment. this is the only choice we have: amid a finite existence, we seek persons and objects that beckon to us, that we are convinced represent desires and dreams uniquely our own. the great gatsby is superior by far to everything that fitzgerald wrote before it, and nothing that he wrote after it, not tender is the night ( ) or the love of the last tycoon, comes close to it. everything that fitzgerald had, everything that he was, is in this novel. his self-destructive behavior, alcoholism, financial pressures, and the mental illness of his wife zelda denied him the luminous career that his astonishing talent seemed to promise. he died of a heart attack in december , age forty-four. in a letter in october to his daughter scottie, fitzgerald described to her "the wise and tragic sense of life": by this i mean the thing that lies behind all great careers, from shakespeare's to abraham lincoln's, and as far back as there are books to read-the sense that life is essentially a cheat and its conditions are those of defeat, and that the redeeming things are not "happiness and pleasure" but the deeper satisfactions that come out of struggle. having learned this in theory from the lives and conclusions of great men, you can get a hell of a lot more enjoyment out of whatever bright things come your way. the great gatsby dramatizes the myths and realities of this country and continent from the moment of the settlers' arrival and then onward to the s and to the present where we see the american dream broken by income inequality. but what may be even more remarkable is that, translated into fifty languages worldwide, the great gatsby transcends its national origin and setting. fitzgerald tells truths about the human condition, about desire, disappointment, and death. really read, it is about the american dream and much more. june : the pandemic that struck the united states and the world earlier this year has caused widespread illness and death, damaged the national and international economies, and created agonized uncertainty about the future. scholars and researchers are in agreement about one point at least: the pandemic has caused (and will continue to cause) the most harm among america's most vulnerable-the elderly, minorities, and low-income workers and their families. many have painted a bleak picture. alexis crow, for example, an expert in economics and finance, has noted: in the united states, the twinned health and economic crises resulting from coronavirus have laid bare several persistent issues in the socio-economic fabric of the country-and which also complicate the trajectory of sustainable growth for future generations. these issues include fiscal sustainability and ballooning deficits; income inequality and the vast disparity in livelihoods across the income distribution; the hollowing out of the mittelstand (small and medium enterprises); and the future of work and employment. (atlantic council, may , ) a report from the international monetary fund expresses a similar concern: the pandemic will leave the poor further disadvan-taged…. the inequality gap between rich and poor has widened after previous epidemics-and covid- will be no different…. if past pandemics are any guide, the toll on poorer and vulnerable segments of society will be several times worse. indeed, a recent poll of top economists found that the vast majority felt the covid- pandemic will worsen inequality, in part through its disproportionate impact on low-skilled workers. (world economic forum, may , ) the epidemiologist sandro galea, in his study of the national and international effects of coronavirus, has said: discussions about covid- pandemic's effects tend to focus either on public health or the economy, as if they were two separate matters. but they are linked, and not just by data about the disease's disproportionate impact on poor and minority populations. the worldwide economic devastation from lockdown policies is sending millions into povertyincreasing their exposure to potential covid- infection as well as to the deadly threat that comes simply from being poor. a central determinant of health is money-the ability to afford such basic resources as nutritious food, access to good medical care, safe housing, quality education, and the simple peace of mind that comes with having the means to weather sudden shocks…. less money generally means shorter, sicker lives, as reflected by the approximately -year gap in life expectancy between the richest and poorest americans. (washington post, may , ) david n. cicilline, a member of congress from rhode island, links the sickness and mortality rates of covid- to income inequality, and to the deterioration of the american dream: the global pandemic has laid bare the economic fragility of millions of american families. in the last few decades, the american middle class has been hollowed out. for millions of americans living paycheck to paycheck, the american dream-the ideal that in this country anything is possible, and everyone can achieve the security of a good life-is nearly unattainable. for decades, anyone taking a clear-eyed look into the economic well-being of our middle class would have seen the warning signs. but this public health crisis has uncovered an even deeper, more fundamental crisis for all to see. the united states is simply no longer the country of opportunity that we once were. (boston globe, may , ) in the midst of the pandemic, the nation also has been racked and torn apart by the death of george floyd, an african-american killed by white police-officer derek chauvin (three of his fellow officers assisted in the arrest) in minneapolis, minnesota, on may th. demonstrations and protests have taken place throughout the united states and abroad, with angry voices demanding action to bring an end to police brutality, systemic racism, poverty, income inequality, and the lack of equity in education and health care. many have spoken with extreme bitterness and indignation. kari winter, an american studies scholar and minneapolis-native, contends-and others have reiterated this indictment: when derek chauvin pressed his knee on george floyd's neck, he committed a brutal, horrific murder. he had three immediate collaborators, but they are not alone in their guilt. their behavior is enabled by the systemic rot of racism. four hundred years of white supremacy have put the american dream of democracy on life support…. when black lives don't matter, none of our lives matter. when black rights don't matter, the american constitution does not matter. freedom of the press? arrested. cruel and unusual punishment? celebrated. right to be secure in your person and house against unreasonable search, seizure or murder? smashed to smithereens. (university of buffalo news center, june , ; see also robin wright, "fury at america and its values spreads globally," the new yorker, june , ) in the great gatsby, with brilliant perception and understanding, fitzgerald examines and exposes the limitations of the american dream. it might crack and come apart in the years ahead in ways that would shock but not surprise him. this is the brutal end of the line for myrtle, a dreamer whose "tremendous vitality" links her to gatsby, possessed by the "colossal vitality" of the desire he stored so long for daisy. the great gatsby brims with violence. we hear about the civil war, the great war, race-war (tom buchanan's panic that "nordics" soon will be overwhelmed by "the colored empires key: cord- -b f z r authors: allam, zaheer title: underlining the role of data science and technology in supporting supply chains, political stability and health networks during pandemics date: - - journal: surveying the covid- pandemic and its implications doi: . /b - - - - . - sha: doc_id: cord_uid: b f z r this concluding chapter explores how data science and technology has been key in fighting covid- through early detection and in the devising of tools for containing the spread. interestingly, two precedence constraints are seen to emerge. first, data-driven modeling is the leading policy at an urban and national level, and second, legislations, which are being passed at record speed, will remain as a legacy postvirus. it is expected that those will accelerate the digital transition of communities for decades to come and lead to a resurgence of the smart cities concept which peaked in . this chapter thus outlines the increasing role of data science in health sciences, the need for more robust digital infrastructures, and the role of technology in supporting livability of communities and world order. in a period of just months, the global landscape had been overturned by the coronavirus, which was not seen as a threat in the initial stages when reports from started trickling from wuhan, china. in fact, for almost weeks after it was reported on december , , it had only affected people and had not spread to any other regions, or outside the city of wuhan. for this reason, even the world health organization hesitated to identify it as a public health emergency of international concern (pheic) (who, c) and as global pandemic (branswell, ) . but when it started to spread, first to neighboring regions, and to more parts of the china, and finally, to regions far and wide, it caused unprecedented panic and fears. worse still, the number of infections started to increase exponentially, with substantial numbers of deaths in different parts of the world. by the end of months, the disease, which was later renamed to covid- , had infected over million people and killed over , , with most of the deaths witnessed in the most developed regions and countries (sullivan et al., ) . worse still, it had sparked fear and panic on governments prompting them to institute some measures with far-reaching impacts on societies, economies, the political sphere, and also the environment. for the first time in history, numerous countries had instituted lockdowns in their countries (barry and jordans, ; bermingham, ) , imposed border restrictions, banned noncitizens or permanent residents from their countries, and grounded transportation networks. there have been also total suspension of flights, on both domestically and internationally (pham, ) , and unprecedented use of security forces in different countries to impose those measures. economies across the globe have been halted, with only a few sectors, more so those providing essential services allowed to perform. the measures have also been accused of disrupting of supply chain (cohen, ; oecd, ; shwartz, ) , thus prompting wide-scale scarcity of basic things including medical supplies that have been in great demand in different parts of the globe. socially, the emergence of covid- brought unprecedented pains, fears, agony, and disarray as people, in their thousands, and millions are hospitalized, others separated with their loved ones forever. in worse-case scenarios, in areas with high daily death rates, deaths from hospitals were buried in mass graves with relatives void of the opportunity to say good bye. the devastation has been even worse on those who traveled outside their countries, and with lockdowns and restricted transportation, people have had to remain displaced until such measures are eased or lifted. the measures that have been imposed in different countries have also seen unprecedented impacts on livability, especially in urban areas where people are forced to remain indoors, with limited supplies (nkengasong and mankoula, ; wearden and jolly, ) , with no social interactions, and with pressures from loss of jobs and source of their livelihoods. such have prompted social strives, where in different parts of the globe such as in india, the united states, and germany, residents of some towns called for lifting of lockdowns and other restrictions. such issues were arising when the united nations' world food programme had warned that the effects of covid- would result into increase in the number of acute hunger, affecting more than million people globally (anthem, ) . politically, as the covid- situation escalated, more political tensions were built. for instance, countries have been seen trading accusations as to the responsibility that each has played in escalating the situation. others such as china have been accused by countries such as the united states, germany, the united kingdom, spain, and even france of having mishandled the situation and failing to share conclusive information and data in time to allow others to prepare (bronstad, ; pleasance, ) . on other occasions, the united states has been blamed for instituting measures such as banning european travelers into the united states, also for banning exportation of medical supplies and other issues (larsen and gramer, ). in fact, with no immediate end on sight for this pandemic, there were fears that the tension may even escalate to dangerous heights, warranting interventions of international bodies. while the emergence of covid- had severely impaired the global systems, it however, exposed the importance and power of modern technologies in helping address events such as pandemics. for instance, in the first stages of the outbreak of this virus, when the chinese scientists and authorities and the who were trying to identify the virus (who, d), and whether it could have impacts beyond wuhan, a tech startup named bluedot was able to detect that the world was facing an outbreak, which may end up having global impact. using real-time data from different sources such as airlines ticketing and numerous news outlets, it made the prediction days earlier, before the who made the announcement (allam et al., ; bowles, ) . on the same, allam et al. ( ) highlighted that there was also another startup named metabiota that correctly predicted that the outbreak would spread to the neighboring regions in a matter of time, and a week later, the prediction came true as japan, thailand, singapore, and others that had been noted as potential target for the outbreak confirmed their first cases. besides those, even when countries went on lockdown, the use of technology became even more apparent, as devices such as drones, robots, sensors, smart helmets, and thermal detectors were widely used for different purposes such as delivery, identifying potential coronavirus virus cases and other purposes (who, b) . technologies such as artificial intelligence (ai), machine learning, natural language processing, and big data have also been instrumental in some countries in implementing quarantines, in search for vaccines and drugs and in helping reduce further spread of the virus. after such success on the use technology, it is incumbent upon different stakeholders in the global sphere to invest more resources in ensuring widespread of the same in different sectors; as going forward, the global systems will require a concerted effort to restore. for instance, in the economic front, there are signs that the world may be headed for a recession and that would have far-reaching impacts not only on the economies (africa renewal, ; statista, a statista, , b stephanie and gerstel, ; wang, ; wearden and jolly, ) but also on the environment. on this, with the use of technologies in sectors such as agriculture, manufacturing, energy production, and building and construction, it would be possible not only to revive the economies but also to void impacts on the environments. by ensuring continuity of the strides already made in different sectors, more so the environmental, the world may escape the dangers posed by climate change and others that are related to environmental sustainability (allam and jones, ) . with that background, this chapter will concentrate on discussing the role of technology and data science in supporting supply chains, economies, and political sustainabilities. the occasional occurrence of pandemics in the world is not unusual from a historical perspective. since time immemorial, humans have had to contend with these, but, fortunately, most of those remained local, especially due to a number of factors. first, the global population has been played a significant part in the spread of pandemics, and in earlier days, population were relatively smaller and people were sparsely distributed. secondly, the interaction between different groups of people from different countries and regions was limited as transportation infrastructures were not well developed, until recently. also, urbanization was not as pronounced as it is today, and this played a key role in preventing widespread. today, things are extremely different, as the population has already increased to . billion people, and it is projected to reach a high of . billion by and to . billion by (un, ). furthermore, technological advancement is at all-time high, and this has made interactions, communication, transportation, and research among other things more robust and efficient. these modern facts have made it possible for pandemics to be widespread and devastating. therefore, in the case of infectious diseases like the covid- , it is not surprising that they spread quite fast and impact numerous people and sectors in a short period of time. for instance, by the time of writing this chapter, the coronavirus had spread to over countries, infecting over million people and killed over people. it had also started to spark some political and economic tensions, besides impacting greatly the social aspects in every part of the globe. the technological advancement, however, cannot be overlooked on the lens of facilitating spread, but its greatest strength has been in controlling and preventing further spread and devastations. for instance, during the spanish flu outbreak ( e ), where technology was rudimentary, over million people lost their lives (martini et al., ) . however, as technology continued to advanced, including in the medical fields, the succeeding pandemic such as the e severe acute respiratory syndrome (sars) spread was effectively contained, and it only spread into countries and only infected people over that period. even other outbreaks such as the middle east respiratory syndrome (mers) (cdc, ), ebola (wojda et al., ) , zika (kazmi et al., ) , and influenza like the swine flu (aris-brosou et al., ) that have broken out did not have devastating impacts as compared with the spanish flu. in fact, even the hiv that emerged in the s, and is still present to date, has well been managed due to availability of technologies (the, ) . despite that, these have had some significant impacts on social and economic frontiers, which cannot be overlooked and which demand even further advancement in the medical field to help with the identification of outbreaks before they spread. one of the most novel ways of ensuring that future outbreaks can be contained is widespread application of data computation and analysis (allam and jones, ) , which already, as discussed in the previous section, was instrumental in making predictions about the outbreak and spread of covid- by bluedot and metabiota. in other fields such as climate change, the application of predictive technologies has been widely used, and these have had significant impacts in helping promote discourses on climate sustainability, emissions reduction, and the need to adopt alternative energy production (allam, a (allam, , b . while the use of technology is being promoted, it is not meant to debase the role of other players in the medical world, but such would supplement the efforts, by making the work of investigators, pharmacists, researchers, and others even more pronounced and with far-reaching outcomes. it would also help in hastening processes, making decisions, collecting data, and reducing human errors in interpretation of said data, thus reducing misdiagnosis and other such issues that have occasionally been witnessed in the medical field . such benefits are made even more robust by the availability of diverse data sources, data collecting technologies, and different data sharing platforms. for instance, with the increase of internet infrastructures, now supporting even g in some regions (o'mahony et al., ) , and with the availability of numerous smart, mobile devices such as phones, drone, wearable technologies, and cameras, data generation and sharing is becoming pronounced. similarly, the increase in number of social media platforms (cinnamon et al., ) , increased online news outlets, and mobile apps among others are helping in generating unprecedented amounts of data (allam, b) . the use of such apps has earlier been used, especially during the haiti earthquake and the cholera outbreak in the same country where health professionals collaborated with telecom companies such as digicel (largest telecompany in the country) to track the movement of people. this allowed for optimal resource management and also in deployment efforts of those offering different forms of assistance (bengtsson et al., ; lu et al., ) . even in the current pandemic, there is evidence of widespread use of technologies, besides what bluedot and metabiota did. in different parts of the globe, governments, telecoms, and startups have been seen to develop different apps and online tools such as trackers that have helped in tracking and mapping the spread of the disease (porterfield, ; voa student union, ; wakefield, b) . for instance, in south korea, it is reported that they developed a platform that allowed security and health personnel effectively impose quarantine and would warn them whenever individuals were flaunting such measures (park, ) . computation technologies were also widely used in china to combat the spread of covid- (chaturvedi, ) , and even as it continued to spread in other countries, we have seen rival tech companies such as apple and google collaborating to make tracking tools to aid in effective mapping and tracking of the spread of the virus (apple, ) . by tapping on these technologies, there are possibilities of enriching the available database such that even in the future, it would be easier to address emergencies of whatever nature. on this, the most promising thing with the use of data computation technologies is that data from different spheres could be collated and analyzed to reach an informed conclusion. this is how bluedot company made the prediction through the use of a wide expertise network as it hosts a rich expertise base comprising of meteorologists, software developers, data scientists, ecologists, geographers, epidemiologists, veterinarians, and others, thus allowing them to make informed conclusion, which are inspired by insights from the diverse backgrounds (bluedot, a (bluedot, , b . going further, even post-covid- , the role of computation technologies will continue, especially in reevaluating the policy responses, and hence help different stakeholders to identify areas of weakness and how such could be strengthened in case of similar future major disruptive events. following the numerous technological interventions initiated to combat the covid- pandemic, it is now evident that technology, especially related to data storage, data processing and sharing is part of the backbone of the health industry. this has been given the impetus by the happening in the technological sphere where much effort has been made in improving data collection methodologies, with the use of smart devices gaining traction. in regard to data storage, developments have been made significantly, where research is being performed to see whether it could be possible to store such in human genomes or proteins such that, in the future, unlimited amounts of data could be stored. in regard to data processing, as noted earlier, the medical field would benefit even further through the upcoming advancements in ai-driven tools, the advancement in machine learning technologies, and also the improvement in big data technologies. with these technologies, it will be possible to process vast amount of data, in real time and from diverse sources as noted earlier; hence, the insights and conclusion drawn from such will have far-reaching impacts. this far, in the medical field, with such technologies, there is evidence that it is now possible to perform noninvasive surgeries that reduce fatalities and also reduce healing time for patients, and such have proven beneficial (elrod, ) , especially during this period of covid- . others such as the d printing are gaining traction, especially in address complex medical issues, especially those requiring implantation of biomedical devices. according to javaid and haleem ( ), d printing is offering the possibility to have relatively smaller implant devices at the comfort of patients. in the case of covid- , already, with the available data, researchers have estimated and predicted the various case scenarios that different countries would face, especially in terms of fatality and recoveries, and infection, hence allowing all involved parties to prepare (giordano et al., ; tokars et al., ) . for instance, in the united states, using such computation, it was estimated that country may have an approximate death toll of , and have millions affected. and already, the number of infections in the country has clocked over million (cole et al., ) . when those technologies and many others are complemented by data computation, the medical field can be made to benefit even further, and already, market of those devices and the number of companies investing in the medical fields are increasing. in particular, with the notable achievements and recognition that data processing startups have gained over this period of covid- following the correct predictions made, the market for smart devices will continue to grow even further. on this, before the emergence of the pandemic, it had been projected that the number of internet of things (iot)e supported devices in the health industry would reach a total of billion devices by and billion devices by (digital information world, ), thus pushing the device market to us$ . billion (fortune business insight, ). mordo intelligence ( ) undervalues the market and argues that it will increase to a high of us$ . billion by from a high of us$ . billion report in . but in both predictions, it is true that the growth in the market is relatively high, at a compounded annual growth rate (cagr) of more than % each year. mordo intelligence ( ) credits such increase in number to factors such as the improvement in accuracy and connectivity that such devices have made possible in the healthcare sector and also the emergence of big data in healthcare such that any amount of data that such could generate would be stored and processed without fear of lack of storage. with the world focusing on statistical modeling for data gathering from the increasing covid- cases, and solutions driven from processing that data, it means that solutions derived may also be technologically driven. in fact, even as governments, scientists, agencies, individuals, and other stakeholders intensify the search for a vaccine and drug for this disease, already, as noted earlier, technological processes have managed to assist in reducing the spread of the virus. for instance, the example cited in the previous section about the use of mobile platforms in the republic of south korea to enforce quarantine is proof that technology holds a sizable share in bringing to an end the coronavirus menace and that of future pandemics. it is worth noting that using technology, the chinese authorities managed to identify the coronavirus genome sequence and posted the same on a public database where it could be accessed by all accredited researchers (ecdc, ). within no time, labs across the world had access to this, and they managed to clone it (scott et al., ) . through such public platforms, those labs shared information and data on all the experiments that failed, helping reduce repetition, and they are also helping researchers on areas to focus (ramiah, ) . in other cases, through statistical modeling, organizations, including the who and others, have been able to develop dashboards that are helping to track the spread of coronavirus, and these are providing people with real-time updates on what is happening across the globe (who, a). similarly, using these modeling, especially those that are ai driven, china managed to diagnose thousands of coronavirus cases, as these could read through thousands of ct scans in a record time with an accuracy level of over % (ramiah, ). this helped reduce time and also ease the pressure on the radiologists who were already overwhelmed due to the fast rates at which cases were being confirmed and hospitalized. an article posted in the university of copenhagen website (uoc, ) explains that ai will, in such cases, go ahead to predict the patients who may urgently be in need of ventilators, depending on severity of their case. ai-based machine learning and natural language processing have also been employed in health facilities in other countries with huge success rates (wright, ) , thus providing hope in the fight against the spread of the virus, and finally, finding a cure for the disease. but its most promising use, in respect to fighting the covid- pandemic, is its ability to crawl through the data pertaining to the , approved drugs already on the market and make predictions from over million possible pairs or over . billion triple-drug combinations. but with ai-powered technologies, researchers predict that possible combination of drugs; whether a part or triple that could go to human trials would take only few weeks. and, already, companies such as healx (earley, ) , exscientia (exscientia, ) , scipher medicine (wakefield, a) , and others are also in advanced stages of proposing possible drugs that could be repurposed and be tried as cures for covid- . outside the hospital environment, as noted in the previous chapters, giant corporations such as apple, google, alibaba, tencent, and others have been seen to develop apps and platforms that provide data sharing platforms, and such have helped in mapping areas where cases were spreading faster and where people could get help and get tested. all the data collected from these platforms and numerous others that are actively being used elsewhere across the globe would remain its usefulness, even post-covid- , but this will require a superior statistical modeling tools to manage the increasing magnitude of such data. in this case, therefore, it will not be farfetched to employ the services of ai-driven technologies such as machine learning, natural language processing, and others such as big data that have already proven capable of delivering quality statistical results in real time and with high levels of reliability. during the period where c vid- has engulfed the world and brought almost everything at a standstill, the role of data processing and sharing is not only being hailed in the health sector but also seen to be critical in other spheres such as the economy, society, and the environment. in the economic sector, there is much that the emergence of the coronavirus has prompted, especially with restriction on movements, grounding of transportation and lockdowns. firsts, as noted by the international labour organization (ilo, ), these measures meant to assist the health sector have transformed the way a majority of people work. on this, a portion of the workforce has managed to continue working from home via teleworking, or through other means. but a majority of the population, especially those in the informal sector, have had their routines greatly disrupted, with a majority globally already filling for unemployment claims. for instance, in the united states, in about weeks, from march to april , over million people filled unemployment claims (jones, ) , higher than the december recession where . million people filed similar claims (department of labor, ). such happenings have increased economic pressures on families, forcing them toward seeking family relief, and other social support systems to see them through the period of aforementioned restrictions. with the disruptions in the labor market, mahler et al. ( ) used data processing to showcase that the estimation on issues such as global poverty will tilt upward, whereas, in the absence of the coronavirus, this year ( ), the global poverty rate would have followed the projected historical trend that showed that it could decrease. but now, with the available data from over countries on those locked down, those losing their jobs and the disruption on other economic areas, it shows that the pandemic will push the poverty by around . % higher from rate, and . % higher from what had been predicted earlier (mahler et al., ) . data processing has also been used during this period to predict that the current health crisis could lead to a recession, where some experts argue that already, the recession has already started in the united states (stewart, ) . the disruptions in the economic sectors have not only prompted challenges on the economic front butalso raised concerns on the security sector, especially with countries seen to short-circuit and ban the exportation of health equipment of other countries. these have raised fears of lack of transparency, thus affecting global collaboration on the fight against the virus. in particular, the issue of data on infections, deaths, and medical supplies has sparked political tensions between different countries, even prompting accusations on independent bodies such as the who (sevastopulo and manson, ) . the need for transparency on data sharing on covid- has thus been emphasized by different global organizations like the united nations (un), world bank, and others (the world bank, ) . according to the world bank ( ), data transparency not only would help in reducing political tension and win over the coronavirus but is also prerequisite in weathering down the economic shocks affecting the global economy, especially by helping enhancing trust in governments, hence promoting investments especially post-covid- . in a bid to ensure that the issue of transparency, especially on the origin and the outbreak of the virus, is established, countries such as the united states have been seen to establish fact-finding committees, whereas others such as germany, sweden, and australia are considering doing the same in due course (amaro, ) . the need for reverse engineering as reported in an article posted in nature medicine (oppmann, ) is warranted by the lack of collaboration, especially by the chinese, whom the european union (eu) chief, ursula von der leyen, said need to be involved in the investigation of the origin of the virus, so that more understanding on the origins can be uncovered, leading to better preparations for future pandemics (amaro, ) . the first such reverse engineering was performed by researchers at peter doherty institute for infection and immunity in collaboration with royal melbourne hospital and university of melbourne where a copy of virus was grown in the lab from samples from an infected patient (reuters, ) . the need for participation of as many parties as possible is to elucidate the real origin of the virus, and issues that have raised numerous theories, where the united states claimed that it may have originated from a virology laboratory in wuhan, china (stanway, ; borger, ; law, ) . china strongly rejected this theory and is also backed by the who, which warned against blaming individual countries for the virus outbreak and spread since this would jeopardize the steps already in place to stop its spread (pérez-peña and mcneil, ) . the availability of diverse institutions, governments, and laboratories and hospitals participating in the fact finding about the coronavirus does not only offer hope and possibilities of gathering data across a diversity array of networks and regions, but also their findings would facilitate efforts of finding a cure for the virus. the identification of the genome sequencing of the virus, for instance, is a positive in the search for vaccines, and drugs, especially noting that these genome sequences are deposited in the public databases, where all researchers can access them. the same are also submitted to the "global initiative on sharing all influenza data" (gisaid) platform. as noted earlier, despite the controversies that are associated with the source of the virus, knowing the actual source would not only hasten in the development of the vaccine and cure but also help in winning back confidence of numerous stakeholders, whom, to this far, have shown dissatisfaction on how the whole issue of the pandemic has been managed. winning the confidence of everyone will help in further collaboration efforts in eliminating the virus, unlike the scenario where individual country is seen to be looking inwardly and applying their own policies, trials, and test, and treating information from other countries with suspicion. while the exploding demand for data-driven solutions at this particular period is all geared toward overcoming the spread and impacts of the coronavirus, this may spark and reignite the need for smart cities concepts, which peaked in (allam and newman, ; allam, ) . in the current dispensations, most of the digital solutions that cities across the world have been observed to be concentrating on is the health sector with the aim of containing any incidence of coronavirus, especially to prevent further spread (allam et al., ; allam and jones, ) . on this front, numerous devices and technologies, such as state-ofthe-art thermal imaging sensors, smart helmets with sensors, use of drones, robots, and mobile phone applications have been in use in this period to help in screening and providing contactless diagnosis against the virus. even postcoronavirus, such technologies will still remain relevant, as they also will be part of numerous other iot devices that are seen to be increasing, as the demand for smart solutions increases. on this, even before the emergence of coronavirus, the demand for smart cities, as expressed by mordor intelligence ( ), was growing, and this had catalyzed the demand for iot devices, which, by , were only . billion devices and had been projected to reach a high of . billion devices by , as the application of smart cities concept continued. besides this, the global market for the iot solutions had reached a high of over us$ billion by , and the projections were that it would cross us$ . trillion by (liu, ) . according to horwitz ( ) from cisco, currently, the number of iot-connected devices globally is over billion, and she also predicts that they would increase to over billion devices by , especially due to improvement in areas such as internet connectivity where many cities will have the g services by then. as those devices increase, the smart cities market will also continue to grow, and as smart cities association ( ) report showcases, it will improve from the $ billion valuation to over us$ . billion valuation by . on the above, though the outbreak of covid- may have somehow halted the attention on application of the smart cities concepts that different cities were piously pursuing, its management is seen to be prompting new legislations aimed at enhancing tech solutions to contain the spread, and most of these will survive postvirus. their enactment, therefore, does not only address the virus, but in the future, they will also add to the existing ones on urban livability, and ultimately, they will lead to better urban and policy decisions. in particular, those policies have formulated to guide in restricting movements, instituting guidelines, and containing the transport sectors, and others will have a positive bearing in the future in ensuring issues such as traffic congestion, supply of basic services, and provision of securities and other issues are maintained. this will be based on the increasing data that different cities are generating those measures that have been placed to contain covid- . for instance, das (philip james) explains how the university of newcastle is using smart technologies to track the adherence to social distancing measures in newcastle, and after analyzing the massive data (capturing over . billion individual events), the conclusion is that the sensors being used were able to give real-time data on how people were responding and also identified areas and issues prompting bottlenecks. on this, as noted by allam and jones ( ) , one of the issues that has appeared prominently in the course of containing the spread of covid- is the nationalistic approach, in decision-making where each country has been observed to look inward, with little regard to the plight of its neighbors. such an approach would be counterproductive in a smart cities concept, as the devices installed need to communicate with others within the network to ensure synchronization of data and information, hence reading to informed decisions and insight drawn after data analysis. with lockdowns, it has been evident that urban livelihood was to be negatively impacted, and in no time, this came to pass, with citizens in a number of cities in different countries protesting. this situation in cities is largely blamed on the haphazardly formulated policies that were mechanically enacted with little consideration of the negative impact that they would draw on locals. in most cities, despite the high population and density, government was seen to delay in implementing measures that would allow them to manage early detection, which would eventually help to reduce the number of local transmissions that prompted the lockdown. however, the blame is not all on government, for it also took time before it was established that the virus could be transmitted from one person to the other. therefore, in most cities, the lockdown came when local transmission had already spread. but while that is the case, local governments had the capacity to learn, especially by analyzing data of cities such as wuhan, which was affected first, and see how cases were spreading quickly and thus prepare effectively, especially by formulating restrictions measures that are more flexible, while being effective, for locals. such would have sufficed, as most urban cities are characterized of high-density and high-rise buildings, where during total lockdown, people would feel trapped, where grant ( ) supports that the planning of such leaves only a little or no open spaces where people could move out for recreation. but with prior planning, as was observed in france, people had opportunities to walk out, albeit under very strict conditions. but while things have been complicated by lockdowns, one take-home after the covid- is the need for intelligent urban planning principles, and this could be achieved by promoting decentralization, of some services, especially those that could be done achieved remotely as advised by shenker ( ) . already, this has been happening in this era of covid- , where some people have been able to work from home via live telecommunicating. there has also been a widespread use of digital transactions such as use of mobile money transactions, which could help in decentralizing the financial services. while the future postcovid is still uncertain, there are clear indications that the technological revolutions that were brought about to address it will remain as a legacy. there will be calls, soon enough, for communities, cities, and regions will use this momentum to craft more resilient fabrics while keeping in mind societal and economic equity in the process. eca estimates billions worth of losses in africa due to covid- impact redefining the smart city: culture, metabolism and governance. case study of port louis biotechnology to render future cities as living and intelligent organisms data as the new driving gears of urbanization artificial intelligence (ai) provided early detection of the coronavirus (covid- ) in china and will influence future urban health policy internationally climate change and economic resilience through 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( b) forecasted impact of coronavirus (covid- ) on gdp in italy q -q the global economic impacts of covid- the coronavirus recession is already here known global covid- deaths pass , e as it happened the global hiv/aids epidemic-progress and challenges transparency is key to weathering shocks, investing in growth, and enhancing trust in government the changing face of surveillance for health caredassociated infections world population prospects artificial intelligence to predict corona-patients' risk of needing ventilators phone apps in china track coronavirus coronavirus: ai steps up in battle against covid- coronavirus: tracking app aims for one million downloads china may adjust gdp growth target due to coronavirus imf: global economy faces worst recession since the great depression who. ( a) coronavirus disease (covid- ): situation report e who. ( b) novel coronavirus ( -ncov): situation report- . available at emergency committee regarding the outbreak of novel coronavirus ( -ncov) who timeline -covid- the ebola outbreak of e : from coordinated multilateral action to effective disease containment, vaccine development, and beyond ai becomes an ally in the fight against covid- key: cord- -wawui fd authors: tulchinsky, theodore h.; varavikova, elena a. title: communicable diseases date: - - journal: the new public health doi: . /b - - / - sha: doc_id: cord_uid: wawui fd publisher summary in a world of rapid international transport and contact between populations, systems are needed to monitor the potential explosive spread of pathogens that may be transferred from their normal habitat. the potential for the international spread of new or reinvigorated infectious diseases constitute threat to mankind akin to ecological and other man-made disasters. public health has addressed the issues of communicable disease as one of its key issues in protecting individual and population health. methods of intervention include classic public health through sanitation, immunization, and well beyond that into nutrition, education, case finding, and treatment, and changing human behavior. the knowledge, attitudes, beliefs, and practices of policy makers, health care providers, and parents is as important in the success of communicable disease control as are the technology available and methods of financing health systems. together, these encompass the broad programmatic approach of the new public health to control of communicable diseases. important for all health providers and public health personnel so as to be able to cope with the scale of these problems and to absorb new technologies as they emerge from scientific advances and experience, and their successful application. lived. it was to be observed, indeed, that it did not come straight on toward us; for the city, that is to say within the walls, was indifferently healthy still; nor was it got over the water into southwark; for though there died that week , of all distempers, whereof it might be supposed above died of the plague, yet there was but in southwark, lambeth parish included; whereas in the parishes of st. giles the agent-host-environment triad, discussed in chapter , is fundamental to the success of understanding transmission of infectious diseases and their control, including those well known, those changing their patterns, and those newly emerging or escaping current methods of control. infection occurs when the organism successfully invades the host body, where it multiplies and produces an illness. a host is a person or other living animal, including birds and arthropods, who provides a place for growth and sustenance to an infectious agent under natural, as opposed to experimental, conditions. some organisms, such as protozoa or helminths, may pass successive stages of their life cycle in different hosts, but the primary or definitive host is the one in which the organism passes its sexual stage. the secondary or intermediate host is where the parasite passes the larval or asexual stage. a transport host is a carrier in which the organism remains alive, but does not develop. an agent of an infectious disease is necessary, but not always sufficient to cause a disease or disorder. the infective dose is the quantity of the organism needed to cause clinical disease. a disease may have a single agent as a cause, or it may occur as a result of the agent in company with contributory factors, whose presence is also essential for the development of the disease. a disease may be present in an infected person in a dormant form such as tuberculosis, or a subclinical form, such as poliomyelitis or hiv. the virulence or pathogenicity of an infective agent is the capacity of an infectious agent to enter the host, replicate, damage tissue, and cause disease in an exposed and susceptible host. virulence is indicated by the severity of clinical disease and case fatality rates. the environment provides a reservoir for the organism, and the mode of transmission, by which the organism reaches a new host. the reservoir is the natural habitat where an infectious agent lives and multiplies, from which it can be transmitted directly or indirectly to a new host. the reservoir refers to the natural habitat of the organism, which may be in people, animals, arthropods, plants, soil, or substances in which an organism normally lives and multiplies, and on which it depends for survival or in which it survives in a dormant form. contacts are persons or animals who have been in association with an infected person, animal, or contaminated inanimate object, or environment that might provide an opportunity for acquiring the infective agent. persons or animals that harbor a specific infectious agent, often in the absence of discernible clinical disease, and who serve as a source of infection or contamination of food, water, or other materials, are carriers. a carrier may have an inapparent infection (a healthy cartier) or may be in the incubation or convalescent stage of the infection. communicable diseases may be classified by a variety of methods: by organism, by mode of transmission, by methods of prevention (e.g., vaccine preventable, vector controllable), or by major organism classification, that is, viral, bacterial, and parasitic disease. a virus is a nucleic acid molecule (rna or dna) encapsulated in a protein coat or capsid. the virus is not a complete cell and can only replicate inside a complete cell. the capsid may have a protective envelope of a lipid containing membrane. the capsid and membrane facilitate attachment and penetration of a host cell. inside the host cell, the nucleic molecule may cause the cell's chromosomes to be changed in its own genetic material or so that there is cellular manufacture and virus replication. viroids are smaller rna structures without capsids which can cause plant disease. prions are recently discovered (stanley prusiner, nobel prize, ) variants of viruses or viroids which are the infective agents cause of scrapie in sheep, and similar degenerative central nervous system diseases in cattle and in man (mad cow disease or creutzfeld-jakob disease in humans). bacteria are unicellular organisms that reproduce sexually or asexually, grow on cell-free media, and can exist in an environment with oxygen (aerobic) or in one lacking oxygen (anaerobic). some may enter a dormant state and form spores where they are protected from the environment and may remain viable for years. bacteria include a nucleus of chromosomal dna material within a membrane surrounded by cytoplasm, itself enclosed by the cellular membrane. bacteria are often characterized by their coloration under gram's stain, as gram-negative or gram-positive, as well as by their microscopic morphology, colony patterns on growth media, by the diseases they may cause, as well as by antibody and molecular (dna) marking techniques. bacteria include both indigenous flora (normal resident) bacteria and pathogenic (disease causing) bacteria. pathogenic bacteria cause disease by invading, overcoming natural or acquired resistance, and multiplying in the body. bacteria may produce a toxin or poison that can affect a body site distant from where the bacterial replication occurs, such as in tetanus. bacteria may also initiate an excessive immune response, producing damage to other body tissues away from the site of infection, e.g;, acute rheumatic fever and glomerulonephritis. parasitology studies protozoa, helminths, and arthropods that live within, on, or at the expense of a host. these include oxygen-producing, flagellate, unicellular organisms such as giardia and trichomonas, and amoebas such as entamoeba important in enteric and gynecologic disorders. sporozoa are parasites with complex life cycles in different hosts, such as cryptosporidium or malarial parasites. parasitic disease usually refers to infestation, with fungi, molds, and yeasts that can affect humans. helminths are worms that infest humans especially in poor sanitation and tropical areas. transmission of diseases is by the spread of an infectious agent from a source or reservoir to a person (table . ). direct transmission from one host to another occurs during touching, biting, kissing, sexual intercourse, and projection via droplets, as in sneezing, coughing, or spitting, or by entry through the skin. indirect transmission includes via aerosols of long-lasting suspended particles in air, fecal-oral transmission such as food and waterborne as well as by poor hygenic conditions with inanimate materials, such as soiled clothes, handkerchiefs, toys, or other objects. vector-borne diseases are transmitted via crawling or flying insects, in some cases with multiplication, and development of the organism in the vector, as in malaria. the subsequent transmission to humans is by injection of salivary gland fluid during biting, e.g., congenital syphilis, or by deposition of feces, urine or other material capable of penetrating the skin through a bite wound or other trauma. transmission may occur with insects as a transport mechanism, as in salmonella on the legs of a housefly. airborne transmission occurs inderectly via infective organisms in small aerosols that may remain suspended for long periods of time and which easily enter the respiratory tract. small particles of dust may spread organisms from soil, clothing, or bedding. vertical transmission occurs from one generation to another, or from one stage of the insect life cycle to another stage. maternal-infant transmission occurs during pregnancy (transplacental), delivery, as in gonorrhoea, breast-feeding, e.g., hiv, with transfer of infectious agents from mother to fetus or newborn. resistance to infectious diseases is related to many host and environmental factors, including age, sex, pregnancy, nutrition, trauma, fatigue, living and socioeconomic conditions, and emotional status. good nutritional status has a protective effect against the results of an infection. vitamin a supplements reduce complication rates of measles and enteric infections. tuberculosis may be present in an individual whose resistance is sufficient to prevent clinical disease, but the infected person is a cartier of an organism which can be transmitted to another or cause clinical disease if the person's susceptibility is reduced. immunity is resistance to infection resulting from presence of antibodies or cells that specifically act on the microorganism associated with a specific disease or toxin. immunity to a specific organism can be acquired by having the disease, that is, natural immunity, or by immunization, active or passive, or by protection box . vaccines and prevention "the greeks had two gods of health, aesculapius and hygeia, therapy and prevention, respectively. medicine in the twentieth century retains those two concepts, and vaccination is a powerful means of prevention. what follows is information on the vaccines that together with sanitation, make modem society possible, and that if wisely used will continue to bestow on mankind the gift of prevention, which according to proverb is worth far more than cure." source: plotkin, s. a., mortimer, e. a. . vaccines. second edition. philadelphia: wb saunders (with permission). infectious agent: a pathogenic organism (e.g., virus, bacteria, rickettsia, fungus, protozoa, or helminth) capable of producing infection or an infectious disease. infection: the process of entry, development, and proliferation of an infectious agent in the body tissue of a living organism (human, animal, or plant) overcoming body defense mechanisms, resulting in an inapparent or clinically manifest disease. antigen: a substance (e.g., protein, polysaccharide) capable of inducing specific response mechanisms in the body. an antigen may be introduced into the body by invasion of an infectious agent, by immunization, inhalation, ingestion, or through the skin, wounds, or via transplantation. antibody: a protein molecule formed by the body in response to a foreign substance (an antigen) or acquired by passive transfer. antibodies bind to the specific antigen that elicits its production, causing the infective agent to be susceptible to immune defense mechanisms against infections e.g., humoral and cellular. immunoglobulins: antibodies that meet different types of antigenic challenges. they are present in blood or other body fluids, and can cross from a mother to fetus in utero, providing protection during part of the first year of life. there are five major classes (igg, igm, iga, igd, and ige) and subclasses based on molecular weight. anfisera or antitoxin: materials prepared in animals for use in passive immunization against infection or toxins. source: jawetz, melrick, and adelberg, medical microbiology, . through elimination of circulation of the organism in the community. immunity may be by antibodies produced by the host body or transferred from externally produced antibodies. the body also reacts to infective antigens by cellular responses, including those that directly defend against invading organisms and other cells which produce antibodies. the immune response is the resistance of a body to specific infectious organisms or their toxins provided by a complex interaction of antibodies and cells including a. b cells (bone marrow and spleen) produce antibodies which circulate in the blood, i.e., humoral immunity; b. t cell-mediated immunity is provided by sensitization of lymphocytes of thymus origin to mature into cytotoxic cells capable of destroying virusinfected or foreign cells; c. complement, a humoral response which causes lysis of foreign cells; d. phagocytosis, a cellular mechanism which ingests foreign microorganisms (macrophages and leukocytes). surveillance of disease is the continuous scrutiny of all aspects of occurrence and spread of disease pertinent to effective control of that disease. maintaining ongoing surveillance is one of the basic duties of a public health system, and is vital to the control of communicable disease, providing the essential data for tracking of disease, planning interventions, and responding to future disease challenges. surveillance of infectious disease incidence relies on reports of notifiable diseases by physicians, supplemented by individual and summary reports of public health laboratories. such a system must concern itself with the completeness and quality of reporting and potential errors and artifacts. quality is maintained by seeking clinical and laboratory support to confirm first reports. completeness, rapidity, and quality of reporting by physicians and laboratories should be emphasized in undergraduate and postgraduate medical education. enforcement of legal sanctions may be needed where standards are not met. surveillance of infectious diseases includes the following: . morbidity reports from clinics to public health offices; . mortality reports from attending doctors to vital records; . reports from selected sentinel centers; . special field investigations of epidemics or individual cases; . laboratory monitoring of infectious agents in population samples; . data on supply, use, and side effects of vaccines, toxoids, immune globulins; . data on vector control activities such as insecticides use; . immunity levels in samples of the population at risk; . review of current literature on the disease; . epidemiologic and clinical reports from other jurisdictions. epidemiologic monitoring based on individual and aggregated reports of infectious diseases provide data vital to planning interventions at the community level or for the individually exposed patient and his contacts, along with other information sources such as hospital discharge data and monitoring of sentinel centers. these may be specific medical or community sites that are representative of the population and are able to provide good levels of reporting to monitor an area or population group. a sentinel center can be a pediatric practice site, a hospital emergency room, or other location which will provide a "finger on the pulse" to assess the degree and kind of morbidity occurring in the community. it can also include monitoring in a location previously known for disease transmission, such as hong kong in relation to influenza. epidemiologic analysis provided by government public health agencies should be published weekly, monthly, and annually and distributed to a wide audience of public health and health-related professionals throughout the country. feedback to those in the field on whose initial reports the data are based is vital in order to promote involvement and improved quality of data, as well as to allow evaluation of the local situation in comparison to other areas. in a federal system of government, national agencies report regularly on all state or provincial health patterns. state or provincial health authorities provide data to the counties and cities in their jurisdictions. such data should also be readily available to researchers in other government agencies, universities, and other academic settings for further research and analysis both on internet and hard-copy publications. notifiable diseases are those which a physician is legally required to report to state or local public health officials, by reason of their contagiousness, severity, frequency, or other public health importance (table . ). public health laboratory services provide validation of clinical and epidemiologic reports. they also pro- vide day-to-day supervision of public health conditions, and can monitor communicable disease and vaccine efficacy and coverage. in addition, they support standards of clinical laboratories in biochemistry, microbiology, and genetic screening. nosocomial or hospital-acquired infections constitute a major health hazard associated with care in institutions. in the united states, they occur in - % of hospital admissions and are the cause of lengthening of hospital stay and an estimated , deaths per year. in developing countries, nosocomial infection rates may occur in up to % of hospitalizations. this category of infectious disease most commonly includes infections of the urinary tract, surgical wounds, lower respiratory tract (pneumonias), and blood poisoning or septicemias. in the united states, up to % of hospital-acquired infections are caused by multidrug resistant organisms. staphylococcus infections resistant to many current antibiotics, for example, methicillin and vancomycin, are a notable cause of prolongation of hospitalization or even death. the increasing number of immunodeficient patients has increased the importance of prevention of nosocomial infections. where standards of infection control are lacking, in both developed and developing countries, hospital staff are vulnerable to serious infection. in developing countries, deadly new viruses, such as ebola and marburg viruses mainly affect nursing, medical, and other staff as secondary cases. surveillance and control measures are important elements of hospital management. hospital epidemiologists and infection control staff are part of modem hospital staffing. the cost to the health system of nosocomial infections is a major consideration in planning health budgets. reducing the risk of acquiring such infections in hospital justifies substantial expenditures for hospital epidemiology and infection control activities. with diagnostic related group payment for hospital care (by diagnosis rather than by days of stay) the good manager has a major incentive to ensure that the risk of nosocomial infections is minimized, since they can greatly prolong hospital stays, raising patient dissatisfaction and health care costs. an endemic disease is the constant usual presence of a disease or infectious agent in a given geographic area or population group. hyperendemic is a state of persistence of high levels of incidence of the disease. holoendemic means that the disease appears early in life and affects most of the population, as in malaria or hepatitis a and b in some regions. an epidemic is the occurrence in a community or region of a number of cases of an illness in excess of the usual or expected number of cases. the number of cases constituting an epidemic varies with the disease, and factors such as previous epidemiological patterns of the disease, time and place of the occurrence, and the population involved must be taken into account. a single case of a disease long absent from an area, such as polio, constitutes an epidemic, and therefore a public health emergency because a clinical case may represent a hundred carriers with nonparalytic or subclinical poliomyelitis. in the s, two to three or more cases of measles linked in time and place may be considered sufficient evidence of transmission and presumed to be an epidemic. a pandemic is occurrence of a disease over a very wide area, crossing international boundaries, affecting a large proportion of the population. each epidemic should be regarded as a unique natural experiment. the investigation of an epidemic requires preparation and field investigation in conjunction with local health and other relevant authorities. verification of cases and the scope of the epidemic will require case definition and laboratory confirmation. tabulation of known cases according to time, place, and person are important for immediate control measures and formulation of the hypothesis as to the nature of the epidemic. an epidemic curve is a graphic plotting of the distribution of cases by the time of onset or reporting, which gives a picture of the timing, spread, and extent of the disease from the time of the initial index cases and the secondary spread. epidemic investigation requires a series of steps. this starts with confirmation of the initial report and preliminary investigation, defining who is affected, determining the nature of the illness and confirming the clinical diagnosis, and recording when and where the first (index) and follow-up (secondary) cases occurred, and how the disease was transmitted. samples are taken from index case patients (e.g., blood, feces, throat swabs) as well as from possible vectors (e.g., food, water, sewage, environment). a working hypothesis is established based on the first findings, taking into account all plausible explanations. the epidemic pattern is studied, establishing common source or risk factors, such as food, water, contact, environment, and drawing a time line of cases to define the epidemic curve. how many are ill (the numerator) and what is the population at risk (the denominator) establish the attack rate, namely, the percentage of sick among those exposed to the common factor. what is a reasonable explanation of the occurrence; is there a previous pattern, with the present episode a recurrence or new event? consultation with colleagues and the literature helps to establish both a biological and epidemiologic plausibility. what steps are needed to prevent spread and recurrence of the disease? coordination with relevant health and other officials and providers is required to establish surveillance and control systems, document and distribute reports, and respond to the public's fight to know. the first reports of excess cases may come from a medical clinic or hospital. the initial (sentinel or index) cases provide the first clues that may point to a common source. investigation of an epidemic is designed to quickly elucidate the cause and points of potential intervention to stop its continuation. this requires skilled investigation and interpretation. epidemiologic investigations have defined many public health problems. rubella syndrome, legionnaire's disease, aids, and lyme and hantavirus diseases were first identified clinically when unusually large numbers of cases appeared with common features. the suspicions that were raised led to a search for causes and the identification of control methods. a working hypothesis of the nature of an epidemic is developed based on the initial assessment, the type of presentation, the condition involved, and previous local, regional, national, and international experience. the hypothesis provides the basis for further investigation, control measures, and planning additional clinical and laboratory studies. surveillance will then monitor the effectiveness of control measures. communication of findings to local, regional, national, and international health reporting systems is important for sharing the knowledge with other potential support groups or other areas where similar epidemics may occur. the centers for disease control and prevention (cdc), originally organized in as the office for malaria control in war areas, is part of the u.s. public health service. as of , the cdc had a budget of $ . billion, and employees include epidemiologists, microbiologists, and many other professionals. the cdc includes national centers for environmental health and injury control, chronic disease prevention and health promotion, infectious diseases, prevention services, health statistics, occupational safety and health, and international health. the epidemic intelligence service (eis) of the cdc in the united states is an excellent model for the organization of the national control of communicable diseases. young clinicians are trained to carry out epidemiologic investigations as part of training to become public health professionals. eis officers are assigned to state health departments, other public health units, and research centers as part of their training, carrying out epidemic investigation and special tasks in disease control. the cdc, in cooperation with the who, has developed and offers free of charge, a personal computer program to support field epidemiology, including epidemic investigations (epi-info), which can be accessed and down-loaded from the worldwide web. this program should be adopted widely in order to improve field investigations, to encourage reporting in real time, and to develop high standards in this discipline. cdc's morbidity and mortality weekly report (mmwr) is a weekly publication of the cdc's epidemiologic data, also available free on the internet. it includes special summaries of reportable infectious diseases as well as noncom- although an infectious disease is an event affecting an individual, it is communicable to others, and therefore its control requires both individual and community measures of protection. control of the disease is a reduction in its incidence, prevalence, morbidity, and mortality. elimination of a disease in a specified geographic area may be achieved as a result of intervention programs such as individual protection against tetanus; elimination of infections such as measles requires stoppage of circulation of the organism. eradication is success in reduction to zero of incidence of the disease and presence in nature of the organism, such as with smallpox. extinction means that a specific organism no longer exists in nature or in laboratories. public health applies a wide variety of tools for the prevention of infectious diseases and their transmission. it includes activities ranging from filtration and disinfection of community drinking water to environmental vector control, pasteurization of milk, and immunization programs (see table . ). no less important are organized programs to promote self protection, case finding, and effective treatment of infections to stop their spread to other susceptible persons (e.g., hiv, sexually transmitted diseases, tuberculosis, malaria). planning measures to control and eradicate specific communicable diseases is one of the principal activities of public health and remains so for the twenty-first century. treating an infection once it has occurred is vital to the control of a communicable disease. each person infected may become a vector and continue the chain of transmission. successful treatment of the infected person reduces the potential for an uninfected contact person to acquire the infection. bacteriostatic agents or drugs such as sulfonamides inhibit growth or stop replication of the organism, allowing normal body defenses to overcome the organism. bacteriocidal drugs such as penicillin act to kill pathogenic organisms. traditional medical emphasis on single antibiotics has changed to use of multiple drug combinations for tuberculosis and more recently for hospital-acquired infections. antibiotics have made enormous contributions to clinical medicine and public health. however, pathogenic organisms are able to adapt or mutate and develop resistance to antibiotics, resulting in drug resistance. wide-scale use of antibiotics has led to increasing incidence of resistant organisms. multidrug resistance constitutes one of the major public health challenges at the end of the twentieth century. antiviral agents (e.g., ribovarin) are important additions to medical treatment potential, as are "cocktails" of antiviral agents for management of hiv infection. antibiotic use is a health problem requiting attention of clinicians and their teachers as well as the public health community and health care managers, representing the interaction of health issues across the entire spectrum of services. organized public health services are responsible for advocating legislation and for regulating and monitoring programs to prevent infectious disease occurrence and/or spread. they function to educate the population in measures to reduce or prevent the spread of disease. health promotion is one of the most essential instruments of infectious disease control. it promotes compliance and community support of preventive measures. these include personal hygiene and safe handling of water, milk, and food supplies. in sexually transmitted diseases, health education is the major method of prevention. each of the infectious diseases or groups of infectious diseases have one or more preventive or control approaches (table . ). these may involve the coordinated intervention of different disciplines and modalities, including epidemiologic monitoring, laboratory confirmation, environmental measures, immunization, and health education. this requires teamwork and organized collaboration. very great progress has been made in infectious disease control by clinical, public health, and societal means since in the industrialized countries and since the s in the developing world. this is attributable to a variety of factors, including organized public health services; the rapid development and wide use of new and improved vaccines and antibiotics; better access to health care; and improved sanitation, living conditions, and nutrition. triumphs have been achieved in the eradication of smallpox and in the increasing control of other vaccine-preventable diseases. however, there remain serious problems with tb, stds, malaria, and new infections such as hiv, and an increase in multiple drug-resistant organisms. vaccines are one of the most important tools of public health in the control of infectious diseases, especially for child health. vaccine-preventable diseases ta b l e . annual incidence of selected vaccine-preventable infectious diseases in rates per , population selected years, united states, - disease the body responds to invasion of disease-causing organisms by antigenantibody reactions and cellular responses. together, these act to restrain or destroy the disease-causing potential. strengthening this defense mechanism through im-box . definitions of immunizing agents and processes vaccines: a suspension of live or killed microorganisms or antigenic portion of those agents presented to a potential host to induce immunity to prevent the specific disease caused by that organism. preparation of vaccines may be from: a. live attenuated organisms which have been passed repeatedly in tissue culture or chick embryos so that they have lost their capacity to cause disease but retain an ability to induce antibody response, such as polio-sabin, measles, rubella, mumps, yellow fever, bcg, typhoid, and plague. b. inactivated or killed organisms which have been killed by heat or chemicals but retain an ability to induce antibody response; they are generally safe but less efficacious than live vaccines and require multiple doses, such as polio-salk, influenza, rabies, and japanese encephalitis. c. cellular fractions usually of a polysaccharide fraction of the cell wall of a disease-causing organisms, such as pneumococcal pneumonia or meningococcal meningitis. d. recombinant vaccines produced by recombinant dna methods in which specific dna sequences are inserted by molecular engineering techniques, such as dna sequences spliced to vaccinia virus grown in cell culture to produce influenza and hepatitis b vaccines. toxoids or antisera: modified toxins are made nontoxic to stimulate formation of an antitoxin, such as tetanus, diphtheria, botulism, gas gangrene, and snake and scorpion venom. immune globulin: an antibody-containing solution derived from immunized animals or human blood plasma, used primarily for short-term passive immunization, e.g., rabies, for immunocompromised persons. antitoxin: an antibody derived from serum of animals after stimulation with specific antigens and used to provide passive immunity, e.g., tetanus. munization is one of the outstanding achievements of public health, as treatment of infectious diseases by antimicrobials is a major element of clinical medicine. immunization (vaccination) is a process used to increase host resistance to specific microorganisms to prevent them from causing disease. it induces primary and secondary responses in the human or animal body: a. primary response occurs on first exposure to an antigen. after a lag or latent period of - days (depending on the antigen) specific antibodies appear in the blood. antibody production ceases after several weeks but memory cells that can recognize the antigen and respond to it remain ready to respond to a further challenge by the same antigen. b. secondary (booster) response is the response to a second and subsequent exposure to an antigen. the lag period is shorter than the primary response, the peak is higher and lasts longer. the antibodies produced have a higher affinity for the antigen, and a much smaller dose of the antigen is required to initiate a response. c. immunologic memory exists even when circulating antibodies are insufficient to protect against the antigen. when the body is exposed to the same antigen again, it responds by rapidly producing high levels of antibody to destroy the antigen before it can replicate and cause disease. immunization protects susceptible individuals from communicable disease by administration of a living modified agent, or subunit of the agent, a suspension of killed organisms or an inactivated toxin (see table . ) to stimulate development of antibodies to that agent. in disease control, individual immunity may also protect another individual. herd immunity occurs when sufficient persons are protected (naturally or by immunization) against a specific infectious disease reducing circulation of the organism, thereby lowering the chance of an unprotected person to become infected. each pathogen has different characteristics of infectivity, and therefore different levels of herd immunity are required to protect the nonimmune individual. the critical proportion of a population that must be immunized in order to interrupt local circulation of the organism varies from disease to disease. eradication of smallpox was achieved with approximately % world coverage, followed by concentration on new case findings and immunization of contacts and surrounding communities. for highly infectious diseases, such as measles, immunization coverage of over % is needed to achieve local eradication. immunization coverage in a community must be monitored in order to gauge the extent of protection and need for program modification to achieve targets of disease control. immunization coverage is expressed as a proportion in which the numerator is the number of persons in the target group immunized at a specific age, and the denominator is the number of persons in the target cohort who should have been immunized according to the accepted standard: vaccine coverage = no. persons immunized in specific age group • no. persons in the age group during that year immunization coverage in the united states is regularly monitered by the national immunization survey by a household survey in all states, as well as selected urban areas considered to be at high risk for undervaccination. an initial telephone survey is followed by confirmation, where possible, from documentation from the parents or health care providers. the survey for july -june examined children born between august and november (i.e., aged - months, median age months). the results show improving coverage, with % having received three or more doses of dpt (diphtheria, pertussis, and tetanus), % with three or more doses of opv (oral polio vaccine), % with three or more doses of haemophilus influenzae, type b (hib), but only % with three or more doses of hepatitis b. however, only % had received all recommended vaccines at the recommended ages. eases that still cause millions of deaths globally each year. other important infectious diseases are still not subject to vaccine control because of difficulties in their development. in some cases, a microorganism can mutate with changes. viruses can undergo antigenic shifts in the molecular structure in the organism, producing completely new subtypes of the organism. hosts previously exposed to other strains may have little or no immunity to the new strains. antigenic drift refers to relatively minor antigenic changes which occur in viruses. this is responsible for frequent epidemics. antigenic shift is believed to explain the occurrence of new strains of influenza virus necessitating, for example, annual reformulation of the influenza vaccine associated with large scale epidemics and pandemics. new variants of poliovirus strains are similar enough to the three main types so that immunity to one strain is carded over to the new strain. molecular epidemiology is a powerful new technique used to specify the geographic origin of organisms such as poliomyelitis and measles viruses, permiting tracking of the source of the virus and epidemic. combinations of more than one vaccine is now common practice with a trend to enlarging the cocktail of vaccines in order to minimize the number of injections, and visits required. this reduces the number of visits to carry out routine immunization saving staff time and costs, as well as increasing compliance. there are virtually no contraindications to use of multiple antigens simultaneously. examples of vaccine cocktails include dpt (diphtheria, pertussis, and tetanus) in combination with haemophilus influenzae b, poliomyelitis, and varicella, or mmr (measles, mumps, and rubella) vaccines. interventions in the form of effective vaccines save millions of lives each year and contribute to improved health of countless children and adults throughout the world. vaccination is now accepted as one of the most cost-effective health interventions currently available. continuous policy review is needed regarding allocation of adequate resources, logistical organization, and continued scientific effort to seek effective, safe, and inexpensive vaccines for other important diseases such as malaria and hiv. new technology of recombinant vaccines, such as that of hepatitis b, holds promise for important vaccine breakthroughs in the decades ahead. internationally, much progress was made in the s in the control of vaccinepreventable diseases. at the end of the s, fewer than % of the world's children were being immunized. who, unicef, and other international organizations mobilized to promote an expanded programme on immunization (epi) with a target of reaching % coverage by . immunization coverage increased in the developing countries, preventing some million child deaths annually. bacillus calmette-gu rin (bcg) coverage rose from to %; poliomyelitis with opv (three doses) from to %, and tetanus toxoid for pregnant women from to %. since , there has been a decline in coverage in some parts of the world, mainly in sub-saharan africa. the challenge remains to achieve control or eradication of vaccine-preventable diseases, thus saving millions of more lives. part of the hfa stresses the epi approach, which includes immunization against diphtheria, pertussis, tetanus, po-liomyelitis, measles, and tuberculosis. an extended form of this is the epi plus program which combines epi with immunization against hepatitis b and yellow fever and, where appropriate, supplementation with vitamin a and iodine. the success in international eradication of smallpox is now being followed by a campaign to eradicate poliomyelitis and other important infectious diseases. diphtheria. diphtheria is an acute bacterial disease of the tonsils, nasopharynx, and larynx caused by the organism corynebacterium diphtheriae. it occurs in colder months in temperate climates where the organism is present in human hosts and is spread by contact with patients or carriers. it has an incubation period of - days. in the past, this was primarily an infection of children and was a major contributor to child mortality in the prevaccine and preantibiotic eras. diphtheria has been virtually eliminated in countries with well-established immunization programs. in the s, an outbreak of diphtheria occurred in the countries of the former soviet union among people over age . it reached epidemic proportions in the s, with , cases ( - ) with deaths in in russia alone. this indicates a failure of the vaccination program in several respects: it used only three doses of dpt in infancy; no boosters were given at school age or subsequently; the efficacy of diphtheria vaccine may have been low, and coverage was below %. efforts to control the present epidemic include mass vaccination campaigns for persons over years of age with a single dose of dt (diphtheria and tetanus) and increasing coverage of routine dpt vaccines to four doses by age years. the epidemic and its control measures have led to improved coverage with dt for those over years, and % coverage among children aged - months. who recommends three doses of dpt in the first year of life and a booster at school entry. this is considered by many to be insufficient to produce long-lasting immunity. the united states and other industrialized countries use a four-dose schedule and recommend periodic boosters for adults with dt. pertussis. pertussis is an acute bacterial disease of the respiratory tract caused by the bacillus bordetella pertussis. after an initial coldlike (catarrhal) stage, the patient develops a severe cough which comes in spasms (paroxysms). the disease can last - months. the paroxysms can become violent and may be followed by a characteristic crowing or high pitched inspiratory whooping sound, followed by expulsion of a tenacious clear sputum, often followed by vomiting. in poorly immunized populations and those with malnutrition, pneumonia often follows and death is common. pertussis declined dramatically in the industrialized countries as a result of widespread coverage with dpt. however, because the pertussis component of the vaccine caused some reactions, many physicians avoided its use, using dt alone. during the s in the united kingdom, many physicians recommended against vaccination with dpt. as a result, pertussis incidence increased with substantial mortality rates. this led to a reappraisal of the immunization program, with insti-tution of incentive payments to general practitioners for completion of vaccination schedules. as a result of these measures, vaccination coverage, with resulting pertussis control, improved dramatically in the united kingdom. pertussis continues to be a public health threat and recurs wherever there is inadequate immunization in infancy. a new acellular vaccine is ready for widespread use and will be safer with fewer and less severe reactions in infants, increasing the potential for improved confidence and support for routine vaccination. use of the new vaccine is spreading in the united states and forms part of the u.s. recommended vaccination schedule. tetanus. tetanus is an acute disease caused by an exotoxin of the tetanus bacillus (clostridium tetani) which grows anaerobically at the site of an injury. the bacillus is universally present in the environment and enters the human body via penetrating injuries. following an incubation period of - days, it causes an acute condition of painful muscular contractions. unless there is modem medical care available, patients are at risk of high case fatality rates of - % (highest in infants and the elderly). antitetanus serum (ats) was discovered in and during world war i, ats contributed to saving the lives of many thousands of wounded soldiers. tetanus toxoid was developed in . the organism, because of its universal presence in the environment, cannot be eradicated. however, the disease can be controlled by effective immunization of every child during infancy and school age. adults should receive routine boosters of tetanus toxoid once very decade. newborns are infected by tetanus spores (tetanus neonatorum) where unsanitary conditions or practices are present. it can occur when traditional birth attendants at home deliveries use unclean instruments to sever the umbilical cord, or dress the severed cord with contaminated material. tetanus neonatorum remains a serious public health problem in developing countries. immunization of pregnant women and women of childbearing age is reducing the problem by conferring passive immunity to the newborn. the training of traditional birth attendants in hygienic practice and the use of medically supervised birth centers for delivery also decreases the incidence of tetanus neonastorum. elimination of tetanus neonatorum by the year was made a health target by the world summit of children in . in that year, the number of deaths from neonatal tetanus was reported by unicef as , infants worldwide, declining to , in . immunization of pregnant women increased from under % in to % in - . despite progress, coverage is still too low to achieve the target of elimination. poliomyelitis. polio virus infection may be asymptomatic or cause an acute nonspecific febrile illness. it may reach more severe forms of aseptic meningitis and acute flaccid paralysis with long-term residual paralysis or death during the acute phase. poliomyelitis is transmitted mainly by direct person-to-person contact, but also via sewage contamination. large-scale epidemics of disease, with attendant paralysis and death, occurred in industrialized countries in the s and s, engendering widespread fear and panic and thousands of clinical cases of "infantile paralysis". growth of the poliovirus by john enders and colleagues in tissue culture in led to development of the first inactivated polio vaccine by jonas salk in the mid- s and gave hope and considerable success in the control of the disease. the development of the live attenuated oral poliomyelitis vaccine by albert sabin, licensed in , added a new dimension to its control because of the effectiveness, low cost, and ease of administration of the vaccine. the two vaccines in their more modern forms, enhanced strength inactivated polio vaccine (eipv), and triple oral polio vaccine (topv), have been used in different settings with great success. oral polio vaccine (opv) induces both humoral and cellular, including intestinal, immunity. the presence of opv in the environment by contact with immunized infants and via excreta of immunized persons in the sewage gives a booster effect in the community. immunization using opv, in both routine and national immunization days (nids) has proven effective in dramatically reducing poliomyelitis and circulation of the wild virus in many parts of the world. use of the enhanced strength ipv (eipv) produces early and high levels of circulating antibodies, as well as protecting against the vaccine-associated disease. in rare cases opv can cause vaccine-associated paralytic poliomyelitis (vapp), with a risk of case per , with initial doses, and case per over million with subsequent doses. approximately eight to ten cases of vapp occur annually in the united states, with clinical, ethical, and legal implications. use of ipv as initial protection eliminates this problem. experience in gaza and the west bank in the s and s, and later in israel, showed that a combination of ipv and opv is effective in overcoming endemic and imported poliovirus. opv requires multiple doses to achieve protective antibody levels. where there are many enteroviruses in the environment, as is the case in most developing countries, interference in the uptake of opv may result in cases of paralytic poliomeylitis among persons who have received or even doses of adequate opv. controversy as to the relative advantages of each vaccine continues. the opv program of mass repeated vaccination in control of poliomyelitis in the americas established the primacy of opv in practical public health, and the momentum to eradicate poliomyelitis is building. a combined schedule of ipv and opv would eliminate the wild virus and protect against vaccine-associated disease. the sequential use of ipv and opv was adopted as part of the routine infant immunization program in the united states in , but ipv alone was adopted in . there are concerns that exclusive use of either vaccine alone will not lead to the desired goal of eradication of polyomyelitis. progress in global eradication of polio has been impressive. global coverage of infants with three doses of opv reached % in as compared to % in . the african region of who had an increase in opv coverage from % in to % in . national immunization days (nids) were conducted in countries in and in , covering million children in . mopping up operations to reinforce coverage of children in still endemic areas is proceeding along with increased emphasis on acute flaccid paralysis (afp) monitoring. confirmed polio cases reported continued at - , per year in - . with continued national and international emphasis, and support of who, rotary international, unicef, donor countries, and others, there is a real prospect of a world without polio, if not by the year , then or shortly thereafter. measles is an acute disease caused by a virus of the paramyxovirus family. it is highly infectious with a very high ratio of clinical to subclinical case ratio ( / ). measles has a characteristic clinical presentation with fever, white spots (koplik spots) on the membranes of the mouth, and a red blotchy rash appearing on the rd- th day lasting - days. mortality rates are high in young children with compromised nutritional status, especially vitamin a deficiency. the measles virus evolved from a virus disease of cattle (rinderpest) some - years ago, becoming an important disease of humans with high mortality rates in debilitated, poorly nourished children, and significant mortality and morbidity even in industrialized countries. in the prevaccine era, measles was endemic worldwide, and even in the late s it remains one of the major childhood infectious diseases. it is one of the commonest causes of death for school age children worldwide. despite earlier predictions that measles deaths would be halved to , by , who reported . million measles deaths in that year and over million in . eradication in the first decade of the next century is a feasible goal, provided that there is an adequate international effort. measles immunization increased from under % worldwide in to % in - , but % in sub-saharan africa. single-dose immunization failed to meet control or eradication requirements even in the most developed parts of the world. a live vaccine, licensed in , was later replace by a more effective and heat stable vaccine, but still with a primary vaccination failure rate (i.e., fails to produce protective antibodies) of - %, and secondary failure rate (i.e., produces antibodies but protection is lost over time) of %. a two-dose policy incorporates a booster dose, usually at school-age, in addition to maximum feasible infant coverage of children in the - month period (timing varies in different countries). catch-up campaigns among schoolage children should be carried out until the routine two-dose policy has time to take full effect. nearly universal primary education in developing countries, offers an opportunity for mass coverage of school age children with a second dose of measles and a resulting increase of herd immunity to reduce the transmission of the virus. the two-dose policy adopted in many countries, should be supplemented with catch-up campaigns in schools to provide the booster effect for those previously immunized and to cover those previously unimmunized, especially in developing countries. the cdc considers that domestic transmission in the united states has been interrupted and that most localized outbreaks were traceable to imported cases. south america and the caribbean countries are now considered free of indigenous measles, based on their successful use of nids, although a large epidemic occurred in in brazil. it now appears that eradication has become a feasible target during the early part of the next century, with a strategy of levels of coverage in in-fancy with a two-dose policy, supplemented by catch-up campaigns to older children and young adults, and outbreak control. mumps. mumps is an acute viral disease characterized by fever, swelling, and tenderness usually of the parotid glands, but also other glands. the incubation period ranges between and days. orchitis, or inflammation of the testicles, occurs in - % of postpubertal males and oophoritis, or inflammation of the ovaries, in % of postpubertal females. sterility is an extremely rare result of mumps. central nervous system involvement can occur in the form of aseptic meningitis, almost always without sequelae. encephalitis is reported in - per , cases with an overall case fatality rate of . %. pancreatitis, neuritis, nerve deafness, mastiffs, nephritis, thyroiditis, and pericarditis, although rare, may occur. most persons born before are immune to the disease, because of the nearly universal exposure to the disease before that time. the live attenuated vaccine introduced in the united states in is available as a single vaccine or in combination with measles and rubella as the measlesmumps-rubella (mmr) vaccine. it provides long-lasting immunity in % of cases. mumps vaccine is now recommended in a two-dose policy with the first dose of mmr given between and months of age and a second dose given either at school entry or in early adolescence. mmr in two doses is now standard policy in the united sates, sweden, canada, israel, the united kingdom, and other countries. the incidence of mumps has consequently declined rapidly. local eradication of this disease is worthwhile and should be part of a basic international immunization program. rubella. rubella (german measles) is generally a mild viral disease with lymphadenopathy and a diffuse, raised red rash. low grade fever, malaise, coryza, and lymphadenopathy characterize the prodromal period. the incubation period is usually - days. differentiation from scarlet fever, measles, or other febrile diseases with rash may require laboratory testing and recovery of the virus from nasopharyngeal, blood, stool, and urine specimens. in , norman gregg, an australian ophthalmologist, noted an epidemic of cases of congenital cataract in newborns associated with a history of rubella in the mother during the first trimester. subsequent investigation demonstrated that intrauterine death, spontaneous abortion, and congenital anomalies occur commonly when rubella occurs early in pregnancy. congenital rubella syndrome (crs) occurs with single or multiple congenital anomalies including deafness, cataracts, microophthalmia, congenital glaucoma, microcephaly, meningoencephalitis, congenital heart defects, and others. moderate and severe cases are recognizable at birth, but mild cases may not be detected for months or years after birth. insulin-dependent diabetes is suspected as a late sequela of congenital rubella. each case of crs is estimated to cost some $ , in health care costs during the patient's lifetime. prior to availability of the attenuated live rubella vaccine in , the disease was universally endemic, with epidemics or peak incidence every - years. in unvaccinated populations, rubella is primarily a disease of childhood. in areas where children are well vaccinated, adolescent and young adult infection is more apparent, with epidemics in institutions, colleges, and among military personnel. a sharp reduction of rubella cases was seen in the united states following introduction of the vaccine in , but increased in , following rubella epidemics in - . a further reduction in cases was followed by a sharp upswing of rubella and crs in [ ] [ ] [ ] . an outbreak of rubella among the amish in the united states, who refuse immunization on religious grounds, resulted in cases of crs in . it is now thought that vaccination of sufficient numbers in the united states reduced circulation of the virus and protected most vulnerable groups in the population. in the past, immunization policy in some countries was to vaccinate school girls aged to protect them for the period of fertility. the current approach is to give a routine dose of mmr in early childhood, followed by a second dose in early school age to reduce the pool of susceptible persons. women of reproductive age should be tested to confirm immunity before pregnancy and immunized if not already immune. should a woman become infected during pregnancy, termination of pregnancy previously recommended is now managed with hyperimmune globulin. the infection of pregnant women during their first trimester of pregnancy is the primary public health implication of rubella. the emotional and financial burden of crs, including the cost of treatment of its congenital defects, makes this vaccination program cost-effective. its inclusion in a modem immunization program is fully justified. elimination of crs syndrome should be one of the primary goals of a program for prevention of vaccine-preventable disease in developed and developing countries. adoption of mmr and the two-dose policy will gradually lead to eradication of rubella and rubella syndrome. viral hepatitis. viral hepatitis is a group of diseases of increasing public health importance due to their large scale worldwide prevalence, their serious consequences, and our increasing ability to take preventive action. viral hepatic infectious diseases each have specific etiologic, clinical, epidemiologic, serologic, and pathologic characteristics. they have important short-and long-term sequelae. vaccine development is of high priority for control and ultimate eradication. hepatitis a. hepatitis a (hav) was previously known as infectious hepatitis or epidemic jaundice. hav is mainly transmitted by the fecal-oral route. clinical severity varies from a mild illness of - weeks to a debilitating illness lasting several months. the norm is complete recovery within weeks, but a fulminating or even fatal hepatitis can occur. severity of the disease worsens with increasing age. hav is sporadic/endemic worldwide. improving sanitation raises the age of exposure, with accompanying complications. it now occurs particularly in persons from industrialized countries when exposed to situations of poor hygiene, or among young adults when traveling to areas where the disease is en-demic. common source outbreaks occur in school-aged children and young adults from case contact, or from food contaminated by infected handlers. hepatitis a may be a serious public health problem in a disaster situation. prevention involves improving personal and community hygiene, with safe chlorinated water and proper food handling. hepatitis a vaccine has been recently licensed for use in the united states, and will probably soon be recommended for routine vaccination programs, as well as for persons traveling to endemic areas. hepatitis b. hepatitis b (hbv) once called serum jaundice, was thought to be transmitted only by injections of blood or blood products. it is now known to be present in all body fluids and easily transmissible by household and sexual contact, perinatal spread from mother to newborn, and between toddlers. however, it is not spread by the oral-fecal route. hepatitis b virus is endemic worldwide and is especially prevalent in developing countries. carrier status with persistent viremia varies from < % of adults in north america to % in some parts of the world. carders have detectable levels of hbsag, the surface antigen (i.e., australian antigen), in their blood. high risk groups in developed countries include intravenous drug users, homosexual men, persons with high numbers of sexual partners, those receiving tattoos, body piercing or acupuncture treatments, and residents or staff of institutions such as group homes and prisons. immunocompromised and hemodialysis patients are commonly carders of hbv. hbv may also be spread in a health system by use of inadequately sterilized reusable syringes, as in china and the former soviet union. transmission is reduced by screening blood and blood products for hbsag and strict technique for handling blood and body fluids in health settings. hbv is clinically recognizable in less than % of infected children but is apparent in - % of infected adults. clinically hbv has an insidious onset with anorexia, abdominal discomfort, nausea, vomiting, and jaundice. the disease can vary in severity from subclinical, very mild to fulminating liver necrosis, and death. it is a major cause of primary liver cancer, chronic liver disease, and liver failure, all devastating to health and expensive to treat. hepatitis b virus is considered to be the cause of % of primary cancer of the liver in the world and the most common carcinogen after cigarette smoking. the who estimates that more than billion people alive today have been infected with hbv. it is also estimated that million persons are chronic carriers of hbv, with an estimated - . million deaths per year from cirrhosis or primary liver cancer. this makes hepatitis b control a vital issue in the revision of health priorities in many countries. strict discipline in blood banks and testing of all blood donations for hbv, as well as hiv, and hepatitis c, is mandatory, with destruction of those with positive tests. contacts should be immunized following exposure with hbv immunoglobulin and hbv vaccine. the inexpensive recombinant hbv vaccine should be adopted by all countries and included in routine vaccination of infants. catch-up immunization for older children is also desirable. immunization programs should include those exposed at work, such as health, prison, or sex workers and adults in group settings. hbv immunization has been included in who's epi-plus expanded program of immunization. hepatitis c. first identified in , and previously known as non-a, non-b hepatitis, hepatitis c (hcv) has an insidious onset with jaundice, fatigue, abdominal pain, nausea, and vomiting. it may cause mild to moderate illness, but chronicity is common going on to cirrhosis and liver failure. the cdc estimates that million americans are chronically infected with hcv, with - , resulting deaths per annum, and the main cause of liver transplants. hcv is transmitted most commonly in blood products, but also among injecting drug users ( % of intravenous drug users were hcv positive in a vancouver study in ), and is also a risk for health workers. the disease may also occur in dialysis centers and other medical situations. person-to-person spread is unclear. prevention of transmission includes routine testing of blood donations, antiviral treatment of blood products, needle exchange programs, and hygiene. the who in has declared hepatitis prevention as a major public health crisis, with an estimated million persons infected worldwide ( ) , stressing that this "silent epidemic" is being neglected and that screening of blood products is vital to reduce transmission of this disease as for hiu hcv is a major cause of chronic cirrhosis and liver cancer. no vaccine is available at present, but an experimental vaccine is undergoing field trials. interferon and ribavirin treatment is reportedly effective in % of cases. hepatitis d. hepatitis d virus (hdv) also known as delta hepatitis, may be self-limiting or progress to chronic hepatitis. it is caused by a viruslike particle which infects cells along with hbv as a coinfection or in chronic carriers of hbv. hdv occurs worldwide in the same groups at risk for hbv. it also occurs in epidemics and is endemic in south america, africa, and among drug users. prevention is by measures similar to those for hbv. management for hdv is by passive immunity with immunoglobulin for contacts and high risk groups, and should include hbv vaccination as the diseases often coincide. there is currently no vaccine for hdv. hepatitis e. hepatitis e virus has an epidemiological and clinical course similar to that of hav. there is no evidence of a chronic form of hev. one striking characteristic of hev is its high mortality rate among pregnant women. the disease is caused by a viruslike particle with an incubation period of - days and is most common in young adults. sporadic cases as well as epidemics have been identified in india, pakistan, burma, china, russia, mexico, and north africa. hev results from waterborne epidemics or as sporadic cases in areas with poor hygiene, spread via the oral-fecal route. it is a hazard in disaster situations with crowding and poor sanitary conditions. prevention is by safe management of water supplies and sanitation. disease management is supportive care; passive immunization is not helpful and no vaccine is currently available. teria which causes meningitis and other serious infections in children under months of age. before the introduction of effective vaccines, as many as in children developed invasive hib infection. two-thirds of these had hib meningitis, with a case fatality rate of - %. long-term sequelae such as hearing impairment and neurological deficits occurred in - % of survivors. the first hib vaccine was licensed in , based on capsular material from the bacteria. extensive clinical trials in finland demonstrated a high degree of efficacy, but less impressive results were in seen in postmarketing efficacy studies. by , a conjugate vaccine based on an additional protein cell capsular factor capable of enhancing the immunologic response was introduced. several conjugate vaccines are now available. the conjugate vaccines are now combined with dpt as their schedule is simultaneous with that of the dpt. although the hib vaccine has been found to be cost-effective, despite initially being as costly as all the basic vaccines combined (i.e., dpt, opv, mmr, and hbv). for this reason, its use thus far has been limited to industrialized countries. the vaccine is a valuable addition to the immunologic armamentarium. it showed dramatic results in local eradication of this serious early childhood infection in a number of european countries and a sharp reduction in the united states. impressive field trials in the gambia showed a sharp reduction in mortality from invasive streptococcal diseases. the price of the vaccine has also fallen dramatically since the mid s. as a result, in , the world health organization recommended inclusion of hib vaccine in routine immunization programs in developing countries. influenza. influenza is an acute viral respiratory illness characterized by fever, headache, myalgia, prostration, and cough. transmission is rapid by close contact with infected individuals and by airborne particles with an incubation period of - days. it is generally mild and self-limited with recovery in - days. however, in certain population groups, such as the elderly and chronically ill, infection can lead to severe sequelae. gastrointestinal symptoms commonly occur in children. during epidemics, mortality rates from respiratory diseases increase because of the large numbers of persons affected, although the case fatality rates are generally low. over the past century, influenza pandemics have occurred in , , , and , while epidemics are annual events. the influenza pandemic of caused millions of deaths among young adults, by some estimates killing more than had died in world war i. it was the fear of recurrence of this pandemic which led the cdc to launch a massive immunization program in the united states in to prevent swine flu (the virus was a strain antigenically similar to that of the pandemic influenza) from spreading from an isolated outbreak in an army camp. the effort was stopped after millions of persons were immunized with an urgently produced vaccine when serious reactions occurred (guillain-barre syndrome, (i.e., a type of paralysis), and when no further cases of swine flu were seen. this demonstrated the difficulty of extrapolating scenarios from a historical experience. each year, epidemiologic services of the who and collaborating centers such as the cdc recommend which strains should be used in vaccine preparation for use among susceptible population groups. these vaccines are prepared with the current anticipated epidemic strains. the three main types of influenza (a, b, and c) have different epidemiological characteristics. type a and its subtypes, which are subject to antigenic shift, are associated with widespread epidemics and pandemics. type b undergoes antigenic drift and is associated with less widespread epidemics. influenza type c is even more localized. active immunization against the prevailing wild strain of influenza virus produces a - % level of protection in high risk groups. the benefits of annual immunization outweigh the costs, and it has proven to be effective in reducing cases of influenza and its secondary complications such as pneumonia and death from respiratory complications in high-risk groups. pneumococcal disease. pneumococcal diseases, which are caused by streptococcus pneumoniae, include pneumonia, meningitis, and otitis media. the capsular types of pneumococci selected out of known types of the organism for the vaccine are those responsible for % of pneumococcal pneumonia cases and - % of all pneumonia cases in the united states, and are responsible for some , deaths per year. this vaccine has been found to be cost-effective for high risk groups, including persons with chronic disease, hiv carriers, patients whose spleens were removed, the elderly, and those with immunosuppressive conditions. it should be included in preventive-oriented health programs, especially for long-term care of the chronically ill. because pneumococci cause bacterial meningitis, pneumococcal vaccine may be a future candidate for use in routine immunization programs for children (over age ). varicella is an acute, generalized virus disease caused by the varicella zoster virus (vzv). despite its reputation as an innocuous disease of childhood, varicella patients can be quite ill. a mild fever and characteristic generalized red rash lasts for a few hours, followed by vesicles occurring in successive crops over various areas of the body. affected areas may include the membranes of the eyes, mouth, and respiratory tract. the disease may be so mild as to escape observation or may be quite severe, especially in adults. death can occur from viral pneumonia in adults and sepsis or encephalitis in children. neonates whose mothers develop the disease within days of delivery are at increased risk with a case fatality rate of up to %. long-term sequelae include herpes zoster or shingles with a severely painful, vesicular rash along the distribution of sensory nerves, which can last for months. its occurrence increases with age and it is primarily seen in the elderly. it can, however, occur in immunocompromised children (especially those on cancer chemotherapy), aids patients, and others. some % of a population will experience herpes zoster during their lifetimes. reye's syndrome is an increasingly rare but serious complication from varicella or influenza b. it occurs in children and affects the liver and central nervous system. congenital varicella syndrome with birth defects similar to congenital rubella syndrome has been identified recently. varicella vaccine is now recommended for routine immunization at age - months in the united states, with catch-up for children up to age years and for occupationally exposed persons in health or child care settings. varicella vaccine is also recommended for nonpregnant women of child bearing years. cost-benefit studies indicate a : ratio if both direct and indirect costs are included (see chapter ). varicella vaccine is likely to be added to a "cocktail vaccine" containing dpt, polio (ipv), and hib. meningococcal meningitis. meningococcal meningitis, caused by the bacterium neisseria meningitides, is characterized by headache, fever, neck stiffness, delirium, coma, and/or convulsions. the incubation period is - days. it has a case fatality rate of - % if treated early and adequately, but rises up to % in the absence of treatment. there are several important strains (a, b, c, x, y, and z). serogroups a and c are the main causes of epidemics, with b causing sporadic cases and local outbreaks. transmission is by direct contact and droplet spread. meningitis (group a) is common in sub-saharan african countries, but epidemics have occurred worldwide. during epidemics, children, teenagers, and young adults are the most severely affected. in developed countries, outbreaks occur most frequently in military and student populations. in , meningococcal meningitis spread widely in the "meningitis belt" in central africa. epidemic control is achieved by mass chemoprophylaxis with antibiotics (e.g., rifampin or sulfa drugs) among case contacts, although the emergence of resistant strains is a concern. vaccines against serotypes a and c (bivalent) or a, c, w, and y are available. their use is effective in epidemic control and prevention institutions and military recruits, especially for a and c serogroups. vaccination is one of the key modalities of primary prevention. immunization is cost-effective and prevents wide-scale disease and death, with high levels of safety. despite the general consensus in public health regarding the central role of vaccination, there are many areas of controversy and unfulfilled expectations. a vaccination program should aim at % coverage at appropriate times, including infants, school children, and adults. immunization policy should be adapted from current international standards applying the best available program to national circumstances and financial capacities (table . ). public health personnel with expertise in vaccine-preventable disease control are needed to advise ministries of health and the practicing pediatric community on current issues in vaccination and to monitor implementation and evolution of control programs. controversies and changing views are common to immunization policy, so that discussions must be conducted on a continuing basis. policy should be under continuing review by a ministerially appointed national immunization advisory committee, including professionals from public health, academia, immunology, laboratory sciences, economics, and relevant clinical fields. bduring , the recommendation for polio virus was changed to doses of ipv in infancy. vaccine supply should be adequate and continuous. supplies should be ordered from known manufacturers meeting international standards of good manufacturing practice. all batches should be tested for safety and efficacy prior to release for use. there should be an adequate and continuously monitored cold chain to protect against high temperatures for heat labile vaccines, sera, and other active biological preparations. the cold chain should include all stages of storage, transport, and maintenance at the site of usage. only disposable syringes should be used in vaccination programs to prevent any possible transmission of blood-borne infection. a vaccination program depends on a readily available service with no barriers or unnecessary prerequisites, free to parents or with a minimum fee, to administer vaccines in disposable syringes by properly trained individuals using patientoriented and community-oriented approaches. ongoing education and training on current immunization practices are needed. incentive payments by insuring agency or managed care systems promote complete, on-time coverage. all clinical encounters should be used to screen, immunize, and educate parents/guardians. contraindications to vaccination are very few; vaccines may be given even during mild illness with or without fever, during antibiotic therapy, during convalescence from illness, following recent exposure to an infectious disease, and to persons having a history of mild/moderate local reactions, convulsions, or family history of sudden infant death syndrome (sids). simultaneous administration of vaccines and vaccine "cocktails" reduces the number of visits and thereby improves coverage; there are no known interferences between vaccine antigens. accurate and complete recording with computerization of records with automatic reminders helps promote compliance, as does co-scheduling of immunization appointments with other services. adverse events should be reported promptly, accurately, and completely. a tracking system should operate with reminders of upcoming or overdue immunizations; use mail, telephone, and home visits, especially for high risk families, with semiannual audits to assess coverage and review patient records in the population served to determine the percentage of children covered by second birthday. tracking should identify children needing completion of the immunization schedule and assess the quality of documentation. it is important to maintain up-to-date, easily retrievable medical protocols where vaccines are administered, noting vaccine dosage, contraindications, and management of adverse events. all health care providers and managers should be trained in education, promotion, and management of immunization policy. health education should target parents as well as the general public. monitoring of vaccines used and children immunized, individually and by category of vaccination can be facilitated by computerization of immunization records, or regular manual review of child care records. where immunization is done by physicians in private practice, as in the united states, determination of coverage is by periodic surveys. inspection of vaccines for safety, purity, potency, and standards is part of the regulatory function. vaccines are defined as biological products and are therefore subject to regulation by national health authorities. in the united states, this comes under the legislative authority of the public health service act, as well as the food, drug and cosmetics act, with applicable regulations in the code of federal regulations. the federal agency empowered to carry out this regulatory function is the center for drugs and biologics of the federal food and drug administration. litigation regarding adverse effects of vaccines led to inflation of legal costs and efforts to limit court settlements. the u.s. federal government enacted the child vaccine injury act of . this legislation requires providers to document vaccines given and to report on complications or reactions. it was intended to pay benefits to persons injured by vaccines faster and by means of a less expensive procedure than a civil suit for resolving claims. using this no-fault system, petitioners do not need to prove that manufacturers or vaccine givers were at fault. they must only prove that the vaccine is related to the injury in order to receive compensation. the vaccines covered by this legislation include dtp, mmr, opv, and ipv. development of vaccines from jenner in eighteenth century to the advent of recombinant hepatitis b vaccine in , and of vaccines for acellular pertussis, varicella, hepatitis a, and rotavirus in the s, has provided one of the pillars of public health and led to enormous savings of human life. vaccines for viral in-fections in humans for hiv, respiratory syncytial virus, papilloma, epstein-barr virus, dengue fever, and hantavirus are under intense research with genetic approaches using recombinant techniques. the potential for the future of vaccines will be greatly influenced by scientific advances in genetic engineering, with potential for development of vaccines attached to bacteria or protein in plants, which may be given in combination for an increasing range of organisms or their harmful products. recombinant dna technology has revolutionized basic and biomedical research since the s. the industry of biotechnology has produced important diagnostic tests, such as for hiv, with great potential for vaccine development. traditional whole organism vaccines, alive or killed, may contain toxic products that may cause mild to severe reactions. subunit vaccines are prepared from components of a whole organism. this avoids the use of live organisms that can cause the disease or create toxic products which cause reactions. subunit vaccines traditionally prepared by inactivation of partially purified toxins are costly, difficult to prepare, and weakly immunogenic. recombinant techniques are an important development for production of new whole cell or subunit vaccines that are safe, inexpensive, and more productive of antibodies than other approaches. their potential contribution to the future of immunology is enormous. molecular biology and genetic engineering have made it feasible to create new, improved, and less costly vaccines. new vaccines should be inexpensive, easily administered, capable of being stored and transported without refrigeration, and given orally. the search for inexpensive and effective vaccines for groups of viruses causing diarrheal diseases led to development of the rotavirus vaccine. some "edible" research focuses on the genetic programming of plants to produce vaccines and dna. vaccine manufacturers, who spend huge sums of money and years of research on new products, tend to work on those which will bring great financial rewards for the company and are critical to the local health care community. this has led to less effort being made in developing vaccines for diseases such as malaria. yet industry plays a crucial role for continued progress in the field. since the eradication of smallpox, much attention has focused on the possibility of similarly eradicating other diseases, and a list of potential candidates has emerged. some of these have been abandoned because of practical difficulties with current technology. diseases that have been under discussion for eradication have included measles, tb, and some tropical diseases, such as malaria and dracunculiasis. eradication is defined as the achievement of a situation whereby no further cases of a disease occur anywhere and continued control measures are unnecessary. reducing epidemics of infectious diseases, through control and eradication in selected areas or target groups, can in certain instances achieve eradication of the disease. local eradication can be achieved where domestic circulation of an organism is interrupted with cases occurring from importation only. this requires a strong, sustained immunization program with adaptation to meet needs of importation of carriers and changing epidemiologic patterns. smallpox was one of the major pandemic diseases of the middle ages and its recorded history goes back to antiquity. prevention of smallpox was discussed in ancient china by ho kung (circe ao ), and inoculation against the disease was practiced there from the eleventh century ad. prevention was carried out by nasal inhalation of powdered dried smallpox scabs. exposure of children to smallpox when the mortality rate was lowest assumed a weakened form of the disease, and it was observed that a person could only have smallpox once in a lifetime. isolation and quarantine were widely practiced in europe during the sixteenth and seventeenth centuries. variolation was the practice of inoculating youngsters with material from scabs of pustules from mild cases of smallpox in the hope that they would develop a mild form of the disease. although this practice was associated with substantial mortality, it was widely adopted because mortality from variolation was well below that of smallpox acquired during epidemics. introduced into england in (see chapter ) it was commonly practiced as a lucrative medical specialty during the eighteenth century. in the s, variolation was also introduced into the american colonies, russia, and subsequently into sweden and denmark. despite all efforts, in the early eighteenth century smallpox was a leading cause of death in all age groups. toward the end of the eighteenth century an estimated , persons died annually from smallpox in europe. vaccination, or the use of cowpox vaccinia virus to protect against smallpox, was initiated late in the eighteenth century. in , a cattle breeder in yorkshire, england, inoculated his wife and two children with cowpox to protect them during a smallpox epidemic. in , edward jenner, an english country general practitioner, experimented with inoculation from a milkmaid's cowpox pustule to a healthy youngster, who subsequently proved resistant to smallpox by variolation (see chapter ). vaccination, the deliberate inoculation of cowpox material, was slow to be adopted universally, but by , over , persons in england were vaccinated. vaccination gathered support in the nineteenth century in military establishments, and in some countries which adopted it universally. opposition to vaccination remained strong for nearly a century based on religious grounds, observed failures of vaccination to give lifelong immunity, and because it was seen as an infringement of the state on the rights of the individual. often the protest was led by medical variolationists whose medical practice and large incomes were threatened by the mass movement to vaccination. resistance was also offered by "sanitarians" who opposed the germ theory and thought cleanliness was the best method of prevention. universal vaccination was increasingly adopted in europe and america in the early nineteenth century and eradication of smallpox in developed countries was achieved by the mid twentieth century. in , the soviet union proposed to the world health assembly a program to eradicate smallpox internationally and subsequently donated million doses of vaccine per year as part of the million needed to promote vaccination of at least % of the world population. in , who adopted a target for the eradication of smallpox. a program was developed which included a massive increase in coverage to reduce the circulation of the virus through person-to-person contact. where smallpox was endemic, with a substantial number of unvaccinated persons, the aim of the mass vaccination phase was % coverage. increasing vaccination coverage in developing countries reduced the disease to periodic and increasingly localized outbreaks. in , countries were considered endemic for smallpox, and another experienced importation of cases. by , the number of endemic countries was down to , and by only countries were still endemic, including india, pakistan, bangladesh, and nepal. in these countries, a new strategy was needed, based on a search for cases and vaccination of all contacts, working with a case incidence below per , . the program then moved into the consolidation phase, with emphasis on vaccination of newborns and new arrivals. surveillance and case detection were improved with case contact or risk group vaccination. the maintenance phase began when surveillance and reporting were switched to the national or regional health service with intensive follow-up of any suspect case. the mass epidemic era had been controlled by mass vaccination, reducing the total burden of the disease, but eradication required the isolation of individual cases with vaccination of potential contacts. technical innovations greatly eased the problems associated with mass vaccination worldwide. during the s, there was wide variation in sources of smallpox vaccine. in the s, efforts to standardize and further attenuate the strains used reduced complication rates from vaccinations. the development of lyophilization (freeze-drying) of the vaccine in england in the s made a heat-stable vaccine that could be effective in tropical field conditions in developing countries. the invention of the bifurcated needle (bernard rubin ) allowed for easier and more widespread vaccination by lesser trained personnel in remote areas. the net result of these innovations was increased world coverage and a reduction in the spread of the disease. smallpox became more and more confined by increasing herd immunity, thus allowing transition to the phase of monitoring and isolation of individual cases. in the last case of smallpox was identified in somalia, and in the who declared the disease eradicated. no subsequent cases have been found except for several associated with a laboratory accident in the united kingdom in . the who recommends that the last stores of smallpox virus should be destroyed in . the cost of the eradication program was $ million or $ million per year. worldwide savings are estimated at $ billion annually. this monumental public health achievement set the precedent for eradication of other infectious diseases. the world health assembly decided to destroy the last two remaining stocks of the smallpox virus in atlanta and moscow in . destruction of the remaining stock was delayed in to because of concern that illegal stocks may be held by some states or potential bioterrorists for potential use in weapons of mass destruction, concern regarding the appearance of monkeypox and a wish to use the virus for further research. in , the who established a target of eradication of poliomyelitis by the year . global immunization coverage with three doses of opv increased from some % in to over % in , with a slight decline in the period - . support from member countries and international agencies such as unicef and rotary international has led to widescale increases in immunization coverage throughout many parts of the world. the world health organization promotes use of opv only as part of routine infant immunization or national immunization days (nids). this strategy has been successful in the americas and in china, but india and the middle east remain problematic. eradication of wild poliomyelitis by the year will require flexibility in vaccination strategies and may require the combined approach, using opv and ipv, as adopted in the united states in to prevent vaccine-associated clinical cases. the combination of opv and ipv may be needed where enteric disease is common and leads to interference in opv uptake, especially in tropical areas where endemic poliovirus and diarrheal diseases are still found. the world bank estimated that achievement of global eradication would save $ million annually in the united states alone. since the eradication of smallpox, discussion has focused on the possibility of similarly eradicating other diseases, and a list of potential candidates has emerged. some of these have been abandoned because of practical difficulties with current technology. diseases that have been under discussion for eradication have included measles, tb, and tropical diseases such as malaria and dracunculiasis. eradication of malaria was thought to be possible in the s when major gains were seen in malaria control by aggressive case environmental control, case finding, and management. however, lack of sustained vector control and an effective vaccine has prevented global eradication. malaria control suffered serious setbacks because of failure in political resolve and capacity to continue support needed for necessary programs. in the s and s, control efforts were not sustained in many countries, and a dreadful comeback of the disease occurred in africa and asia in the s. the emergence of mosquitoes resistant to insecticides, and malarial strains resistant to antimalarial drugs, have made malaria control even more difficult and expensive. renewed effort in malaria control may require new approaches. use of community health workers (chws) in small villages in highly endemic regions of colombia resulted in a major drop in malaria mortality during the s. the chws investigate suspect cases by taking clinical histories and blood smears. . scientific feasibility a. epidemiologic vulnerability; lack of nonhuman reservoir, ease of spread, no natural immunity, relapse potential; b. effective practical intervention available; vaccine or other primary preventive or curative treatment, or vectoricide that is safe, inexpensive, long lasting, and easily used in the field; c. demonstrated feasibility of elimination in specific locations, such as an island or other geographic unit. . political will/popular support a. they examine smears for malaria parasites and a diagnosis is made. therapy is instituted and the patient is followed. quality control monitoring shows high levels of accuracy in reading of slides compared to professional laboratories. in the late s, there was widespread discussion in the literature of the potential for eradication of measles and tb. measles eradication was set back as breakthrough epidemics occurred in the united states, canada, and many other countries during the s and early s, but regional eradication was achieved combining the two-dose policy with catch-up campaigns for older children or in national immunization days, as in the caribbean countries. tuberculosis has also increased in the united states and several european countries for the first time in many decades. unrealistic expectations can lead to inappropriate assessments and policy when confounding factors alter the epidemiologic course of events. such is the case with tb, where control and eradication have receded from the picture. this deadly disease has returned to developed countries, partly in association with the hiv infection and multiple-drug-resistant strains, as well as homelessness, rising prison populations, poverty, and other deleterious social conditions. directly observed therapy is an important recent breakthrough, more effective in use of available technology and will play a major role in tb control in the twenty-first century. a decade after the eradication of smallpox was achieved, the international task force for disease eradication (itfde) was established to systematically evaluate the potential for global eradicability of candidate diseases. its goals were to identify specific barriers to the eradication of these diseases that might be surmountable and to promote eradication efforts. the subject of eradication versus control of infectious diseases if of central public health importance as technology expands the armamentarium of immunization and vector control into the twenty-first century. the control of epidemics, followed by interruption of transmission and ultimately eradication, will save countless lives and prevent serious damage to children throughout the world. the smallpox achievement, momentous in itself, points to the potential for the eradication of other deadly diseases. the skillful use of existing and new technology is an important priority in the new public health. flexibility and adaptability are as vital as resources and personnel. selecting diseases for eradication is not purely a professional issue of resources such as vaccines and manpower, organization and financing. it is also a matter of political will and perception of the burden of disease. there will be many controversies. the selection of polio for eradication while deferring measles when polio kills few and measles kills many may be questioned. the cdc published criteria for selection of disease for eradication are shown in box . . the who, in a review of health targets in the field of infectious disease control for the twenty-first century, selected the following targets: eradication of chagas' disease by ; eradication of neonatal tetanus by ; eradication of leprosy by ; eradication of measles by ; eradication of trachoma by ; reversing the current trend of increasing tuberculosis and hiv/aids. in , a conference in atlanta, georgia, reviewed the subject, which is still very much in a state of flux. table . summarizes the selection of diseases which are presently seen as controllable and those considered to be potentially eradicable. the subject will be under review in the years ahead. mycobacterium tuberculosis in humans and m. bovis in cattle. the disease is primarily found in humans, but it is also a disease of cattle and occasionally other primates in certain regions of the world. it is transmitted via airborne droplet nuclei from persons with pulmonary or laryngeal tb during coughing, sneezing, talking, or singing. the initial infection may go unnoticed, but tuberculin sensitivity appears within a few weeks. about % of those infected enter a latent phase with a lifelong risk of reactivation. approximately % go from initial infection to pulmonary tb. less commonly, the infection develops as extrapulmonary tb, involving meninges, lymph nodes, pleura, pericardium, bones, kidneys, or other organs. untreated, about half of the patients with active tb will die of the disease within years, but modern chemotherapy almost always results in a cure. pulmonary tb symptoms include cough and weight loss, with clinical findings on chest examination and confirmation by findings of tubercle bacilli in stained smears of sputum and, if possible, growth of the organism on culture media, and changes in the chest x-ray. tuberculosis affects people in their adult working years, with - % of cases in persons between the ages of and . its devastating effects on the work force and economic development contribute to a high cost-effectiveness for tb control. the tubercle bacillus infects approximately . billion people in the world today, causing over million cases and nearly million deaths in . during , new cases of tb included . million ( %) in southeast asia and the western pacific regions of who, with . million cases in india, and . million in indonesia. by , the incidence of tb may increase to . million new cases per year, a % increase over . between and , who estimates there were million new cases of tb, of which million cases were in association with hiv infection. during the s, an estimated million persons died of tb, including . million with hiv infection. a new and dangerous period for tb resurgence has resulted from parallel epidemiologic events: first, the advent of hiv infection and second, the occurrence of multiple drug resistant tb (mdrtb), that is, organisms resistant at least to both isoniazid (inh) and rifampicin, two mainstays of tb treatment. mdrtb can have a case fatality rate as high as %. hiv reduces cellular immunity so that people with latent tb have a high risk of activation of the disease. it is estimated that hiv negative persons have a - % lifetime risk of tb; hiv positive people have a risk of % per year of developing clinical tuberculosis. drug resistance, the long period of treatment, and the socioeconomic profile of most tb patients combine to require a new approach to therapy. directly observed treatment, short-course (dots), has shown itself to be highly effective with patients in poor self-care settings, such as the homeless, drug users, and those with aids. the strategy of dots uses community health workers to visit the patient and observes him or her taking the various medications, providing both incentive, support, and moral coercion to complete the needed to month therapy. dots has been shown to cure up to % of cases, at a cost of as little as $ per patient. it is one of the few hopes of containing the tb pandemic. in , who released a new strategy for control of tuberculosis over the next decade. the plan calls for new guidelines for control, new aid funds for developing countries, and enlistment of ngos to assist in the fight. the new guidelines stress short-term chemotherapy in well-managed programs of dots, stressing strict compliance with therapy for infectious cases with a goal of an % cure rate. even under adverse conditions, dots produces excellent results. it is one of the most cost-effective health interventions combining public health and clinical medical approaches. tuberculosis incidence in the united states decreased steadily until , increased in , and has declined again since. from to , there was an excess of , cases over the expected rate if the previous decline in case incidence had continued. this rise was largely due to the hiv/aids epidemic and the emergence of mdrtb, but also greater incidence among immigrants from areas of higher tb incidence, drug abusers, the homeless, and those with limited access to health care. this is particularly true in new york city, where mdrtb has appeared in outbreaks among prison inmates and hospital staff. from to , tb incidence in the united states declined by % and in some states, including new york, by % or more. this turnaround was due to stronger tb control programs that promptly identified persons with tb and initiated and ensured completion of appropriate therapy. aggressive staff training, outreach, and case management approaches were vital to this success. concern over rising rates among recent immigrants and the continued challenge of hiv/aids and coincidental transmission of hepatitis a, b, and c among drug users and marginal population groups show that continued support for tb control is needed. bacillus calmette-gurrin (bcg) is an attenuated strain of the tubercle bacillus used widely as a vaccination to prevent tb, especially in high incidence areas. it induces tuberculin sensitivity or an antigen-antibody reaction in which antibodies produced may be somewhat protective against the tubercle bacillus in % of vaccinees. although the support for its general use is contradictory, there is evidence from case-control and contact studies of positive protection against tb meningitis and disseminated tb in children under the age of . in some developed, low-incidence countries, it is not used routinely but selectively. it may also be used in asymptomatic hiv-positive persons or other high risk groups. the bcg vaccine for tuberculosis remains controversial. while used widely internationally, in the united states and other industrialized countries, it is thought to hinder rather than help in the fight against tb. this concern is based on the usefulness of tuberculin testing for diagnosis of the disease. where bcg has been administered, the diagnostic value of tuberculin testing is reduced, especially in the period soon after the bcg is used. studies showing equivocal benefit of bcg in preventing tuberculosis have added to the controversy. while those in the field in the united states continue to oppose the use of bcg, internationally it is still felt to be of benefit in preventing tb, primarily in children. a metaanalysis of the literature of bcg carried out by the technology assessment group at harvard school of public health concluded: on average, bcg vaccine significantly reduces the risk of tb by %. protection is observed across many populations, study designs, and forms of tb. age at vaccination did not enhance predictiveness of bcg efficacy. protection against tuberculous death, meningitis, and disseminated disease is higher than for total tb cases, although this result may reflect reduced error in disease classification rather than greater bcg efficacy. [colditz et al., jama, .] box . control of tuberculosis . identifying persons with clinically active tb; . diagnostic methods--clinical suspicion, sputum smear for bacteriologic examination, tuberculin skin testing, chest radiograph; . case finding and investigation programs in high risk groups; . contact investigation; . isolation techniques during initial therapy; . treatment, mainly ambulatory, of persons with clinically active tb; . treatment of contacts; . directly observed treatment, short-course (dots), where compliance suspect; . environmental control in treatment settings to reduce droplet infection; . educate health care providers on suspicion of tb and investigation of suspects. currently, the who recommends use of bcg as close to birth as possible as part of the expanded programme of immunization (epi). tuberculosis control remains feasible with current medical and public health methods. deterioration in its control should not lead to despair and passivity. the recent trend to successful control by dots despite the growing problem of mdrtb suggest that control and gradual reduction can be achieved by an activist, community outreach approach. the who in made tb control one of its major priorities, expressing grave concern that the mdr organism, now widely spread in countries of asia, eastern europe, and the former soviet union, may spread the disease much more widely. the disease constitutes one of the great challenges to public health at the start of the new century. acute infectious diseases caused by group a streptococci include streptococcal sore throat, scarlet fever, puerperal fever, septicemia, ersypelas, cellulitis, mastoiditis, otitis media, pneumonia, peritonsillitis (quinsy), wound infections, toxic shock syndrome, and fasciitis, the "flesh eating bacteria." streptococcus pyogenes group a include some serologically distinct types which vary in geographic location and clinical significance. transmission is by droplet, person-to-person direct contact, or by food infected by carriers. important complications from a public health point of view include acute rheumatic fever and acute glomerulonephritis, but also skin infections and pneumonia. acute rheumatic fever is a complication of strep a infection that has virtually disappeared from industrialized countries as a result of improved standards of living and antibiotic therapy. however, outbreaks were recorded in the united states in , and an increasing number of cases have been seen since . in developing countries, rheumatic fever remains a serious public health problem affecting school age children, particularly those in crowded living arrangements. longterm sequelae include disease of the mitral and aortic heart valves, which require cardiac care and surgery for repair or replacement with artificial valves. acute glomerulonephritis is a reaction to toxins of the streptococcal infection in the kidney tissue. this can result in long-term kidney failure and the need for dialysis or kidney transplantation. this disease has become far less common in the industrialized countries, but remains a public health problem in developing countries. the streptococcal diseases are controllable by early diagnosis and treatment with antibiotics. this is a major function of primary care systems. recent increases in rheumatic fever may herald a return of the problem, perhaps due to inadequate access to primary care in the united states for large sectors of the population, along with increased social hygiene problems. where access to primary care services is limited, infections with streptococci can result in a heavy burden of chronic heart and kidney disease with substantial health, emotional, and financial tolls. measures to improve access to care and pub-lic information are needed to assure rapid and effective care to prevent chronic and costly conditions. zoonoses are infectious diseases transmissible from vetebrate animals to humans. common examples of zoonoses of public health importance in nonindustrialized countries include brucellosis and rabies. in industrialized countries, salmonellosis, "mad cow disease" and influenza have reinforced the importance of relationships of animal and human health. strong cooperation between public health and veterinary public health authorities are required to monitor and to prevent such diseases. brucellosis is a disease occurring in cattle (brucella abortus), in dogs (br. cahis), in goats and sheep (br. melitensis), and in pigs (br. suis). humans are affected mainly through ingestion of contaminated milk products, by contact, or inhalation. brucellosis (also known as relapsing, undulant, malta, or mediterranean fever) is a systemic bacterial disease of acute or insidious onset characterized by fever, headache, weakness, sweating, chills, arthralgia, depression, weight loss, and generalized malaise. spread is by contact with tissues, blood, urine, vaginal discharges, but mainly by ingestion of raw milk and dairy products from infected animals. the disease may last from a few days to a year or more. complications include osteoarthritis and relapses. case fatality is under %, but disability is common and can be pronounced. the disease is primarily seen in mediterranean countries, the middle east, india, central asia, and in central and south america. brucellosis occurs primarily as an occupational disease of persons working with and in contact with tissues, blood, and urine of infected animals, especially goats and sheep. it is an occupational hazard for veterinarians, packinghouse workers, butchers, tanners, and laboratory workers. it is also transmitted to consumers of unpasteurized milk from infected animals. animal vectors include wild animals, so that eradication is virtually impossible. diagnosis is confirmed by laboratory findings of the organism in blood or other tissue samples, or with rising antibody titers in the blood, with confirmation by blood cultures. clinical cases are treated with antibiotics. epidemiologic investigation may help track down contaminated animal flocks. routine immunization of animals, monitoring of animals in high risk areas, quarantining sick animals, destroying infected animals, and pasteurizing milk and milk products prevents spread of the disease. control measures include educating farmers and the public not to use unpasteurized milk. individuals who work with animals (cattle, swine, goats, sheep, dogs, coyotes) should take special precautions when handling animal carcasses and materials. testing animals, destroying carriers, and enforcing mandatory pasteurization will restrict the spread of the disease. this is an economic as well as public health problem, requiring full cooperation between ministries of health and of agriculture. rabies is primarily a disease of animals, with a variety of wild animals serving as a reservoir for this disease, including foxes, wolves, bats, skunks, and raccoons, who may infect domestic animals such as dogs, cats, and farm animals. animal bites break the skin or mucous membrane, allowing entry of the virus from the infected saliva into the bloodstream. the incubation period of the virus is - weeks; it can be as long as several years or as short as days, so that postexposure preventive treatment is a public health emergency. the clinical disease often begins with a feeling of apprehension, headache, pyrexia, followed by muscle spasms, acute encephalitis, and death. fear of water ("hydrophobia") or fear of swallowing is a characteristic of the disease. rabies is almost always fatal within a week of onset of symptoms. the disease is estimated to cause , deaths annually, primarily in developing countries. it is uncommon in developed countries. rabies control focuses on prevention in humans, domestic animals, and wildlife. prevention in humans is based on preexposure prophylaxis for groups at risk (e.g., veterinarians, zoo workers) and postexposure immunization for persons bitten by potentially rabid animals. because reducing exposure of pets to wild animals is difficult, immunization of domestic animals is one of the most important preventive measures. prevention in domestic animals is by mandatory immunization of household pets. all domestic animals should be immunized at age months and revaccinated according to veterinary instructions. prevention in wild animals to reduce the reservoir is successful in achieving local eradication in settings where reentry from neighboring settings is limited. since , the use of oral rabies immunization has been successful in reducing the population of wild animals infected by the rabies virus. rabies eradication efforts, using aerial distribution of baits containing fox rabies vaccine in affected areas of belgium, france, germany, italy, and luxembourg, have been underway since . the number of rabies cases in these affected areas has declined by some %. switzerland is now virtually rabies-free because of this vaccination program. the potential exists for focal eradication, especially on islands or in partially restricted areas with limited possibilities of wild animal entry. livestock need not be routinely immunized against rabies, except in high risk areas. where bats are major reservoirs of the disease, as in the united states, eradication is not presently feasible. salmonella, discussed later in this chapter under diarrheal diseases, is one of the commonest of all infectious diseases among animals and is easily spread to humans via poultry, meat, eggs, and dairy products. specific antigenic types are associated with food-borne transmission to humans, causing generalized illness and gastroenteritis. severity of the disease varies widely, but the diseases can be devastating among vulnerable population groups, such as young children, the elderly, and the immunocompromised. epidemiologic investigation of common food source outbreaks may uncover hazardous food handling practices. laboratory confirmation or serotypes helps in monitoring the disease. prevention is by maintaining high standards of food hygiene in processing, inspection and regulation, food handling practices, and hygiene education. bacillus anthracis causes a bacterial infection in herbivore animals. its spores contaminate soil, worldwide. it affects humans exposed in occupational settings. transmission is cutaneous by contact, gastrointestinal by ingestion, or respiratory by inhalation. it has gained recent attention (iraq, ) as a highly potent agent for germ warfare or terrorism. limited supplies of vaccine are available. creutzfeld-jakob disease is a degenerative disease of the central nervous system linked to consumption of beef from cattle infected with bovine spongiform encephalopathy. it is transmitted by prions in animal feed prepared from contaminated animal material and in transplanted organs. this disease was identified in the united kingdom linked to infected cattle leading to a ban on british beef in many parts of the world and slaughter of large numbers of potentially contaminated animals. the tapeworm causing diphyllobothriasis (diphyllobothrium latum) is widespread in north american freshwater fish, passing from crustacean to fish to humans by eating raw freshwater fish. it is especially common among inuit peoples and may be asymptomatic or cause severe general and abdominal disorder. food hygiene (freezing and cooking of meat) is recommended; treatment is by anthelminthics. leptospiroses are a group of zoonotic bacterial diseases found worldwide in rats, raccoons, and domestic animals. it affects farmers, sewer workers, dairy and abattoir workers, veterinarians, military personnel, and miners with transmission by exposure to or ingestion of urine-contaminated water or tissues of infected animals. it is often asymptomatic or mild, but may cause generalized illness like influenza, meningitis, or encephalitis. prevention requires education of the public in self protection and immunization of workers in hazardous occupations, along with immunization and segregation of domestic animals and control of wild animals. vector-borne diseases are a group of diseases in which the infectious agent is transmitted to humans by crawling or flying insects. the vector is the intermediary between the reservoir and the host. both the vector and the host may be affected by climatic condition; mosquitoes thrive in warm, wet weather and are suppressed by cold weather; humans may wear less protective clothing in warm weather. the only important reservoir of malaria is humans. its mode of transmission is from person to person via the bite of an infected female anopheles mosquito (ronald ross, nobel prize, ) . the causative organism is a single cell parasite with four species: plasmodium vivax, p malariae, p falciparum, and p ovale. clinical symptoms are produced by the parasite invading and destroying red blood cells. the incubation period of approximately - days, depending on the specific plasmodium involved. some strains of p vivax may have a protracted incubation period of - months and even longer for p ovale. the disease can also be transmitted through infected blood transfusions. confirmation of diagnosis is by demonstrating malaria parasites on blood smears. falciparum malaria, the most serious form, presents with fever, chills, sweats, and headache. it may progress to jaundice, bleeding disorders, shock, renal or liver failure, encephalopathy, coma, and death. prompt treatment is essential. case fatality rates in untreated children and adults are above %. an untreated attack may last months. other forms of malaria may present as a nonspecific fever. relapse of the p ovale may occur up to years after initial infection; malaria may persist in chronic form for up to years. malaria control advanced during the s- s through improved chlovaquine treatment and use of ddt for vector control with optimism for eradication of the disease. however, control regressed in many developing countries as allocations for environmental control and case findings/treatment were reduced. there has also been an increase in drug resistance, so that this disease is now an extremely serious public health problem in many parts of the world. the need for a vaccine for malaria control is now more apparent than ever. the world health organization estimated that, in , sub-saharan africa (ssa) had million new malaria cases, with % of children up to age . over million deaths occur annually from malaria more than two-thirds of them in ssa. large areas, particularly in forest or savannah regions with high rainfall, are holoendemic. in higher altitudes, endemicity is lower, but epidemics do occur. chloroquine-resistant p. falciparum has spread throughout africa, accompanied by an increasing incidence of severe clinical forms of the disease. the world bank estimates that % of all disability-adjusted life years (dalys) lost per year in ssa are from malaria, which places a heavy economic burden on the health systems. in the americas, the number of cases detected has risen every year since , and the who estimates there to have been . - . million cases in . the nine most endemic countries in the americas achieved a % reduction in malaria mortality between and . southeast asian region reports some . million cases of malaria in and deaths from tb. this accounts for more than one-third of all non-african malaria cases. there is an increase in resistant strains to the major available drugs and of the mosquitoes to insecticides in use. vector control, case finding, and treatment remain the mainstay of control. use of insecticide-impregnated bed nets and curtains, and residual house spraying, and strengthened vector control activities are important, as are early diagnosis and carefully monitored treatment with monitoring for resistance. control of malaria will ultimately depend on a safe, effective, and inexpensive vaccine. attempts to develop a malaria vaccine have been unsuccessful to date due to the large number of genetic types of p. falciparum even in localized areas. a colombian-developed vaccine is being field-tested with partial effectiveness. research in vaccines for malaria has also been hampered by the fact that it is a relatively low priority for vaccine manufacturers because of the minimal potential for financial benefit. research on malaria concentrates on the pharmacological aspects of the disease because of increasing drug resistance. in , who has initiated a new campaign to "roll back malaria" and maintain the dream of eradication in the future. effective low technology interventions include community-based case finding, early treatment of good quality, insecticide use, and vector control. the use of community health workers in endemic areas, has shown promising results. local control and even eradication can be achieved with currently available technology. this requires an integration of public health and clinical approaches with strong political commitment. the rickettsia are obligate parasites, i.e., they can only replicate in living cells, but otherwise they have characteristics of bacteria. this is a group of clinically similar diseases, usually characterized by severe headache, fever, myalgia, rash, and capillary bleeding causing damage to brain, lungs, kidneys, and heart. identification is by serological testing for antibodies, but the organisms can also be cultured in laboratory animals, embryonic eggs, or in cell cultures. the organisms are transmitted by arthropod vectors such as lice, fleas, ticks, and mites. the diseases caused millions of deaths during war and famine periods prior to the advent of antibiotics. these diseases appear in nature in ways that make them impossible to eradicate, but clinical diagnosis, host protection, and vector control can help reduce the burden of disease and deal with outbreaks that may occur. public education regarding self-protection, appropriate clothing, tick removal, and localized control measures such as spraying and habitat modification are useful. epidemic typhus, first identified in , is due to rickettsia prowazekii. spread primarily by the body louse, typhus was the cause of an estimated million deaths, i.e., during war and famine, in poland and the soviet union from - . untreated, the fatality rate is - %. typhus responds well to antibiotics. it is currently largely confined to endemic foci in central africa, central asia, eastern europe, and south america. it is preventable by hygiene and pediculicides such as ddt and lindane. a vaccine is available for exposed laboratory personnel. murine typhus is a mild form of typhus due to rickettsia typhi, which is found worldwide and spread in rodent reservoirs. scrub typhus, also known as tsutsugamushi or japanese river fever, is located throughout the far east and the pacific islands, and was a serious health problem for u.s. armed forces in the pacific during world war ii. it is spread by the rickettsia tsutsugamushi and has a wide variation in case fatality according to region, organism, and age of patient. rocky mountain spotted fever is a well-known and severe form of tick-borne typhus due to rickettsia rickettsii, occurring in western north america, europe, and asia. q. fever is a tick-borne disease caused by coxiella burnetii and is worldwide in distribution, usually associated with farm workers, in both acute and chronic forms. regular anti-tick spraying of sheep, cows, and goats helps protect exposed workers. protective clothing and regular removal of body ticks help protect exposed persons. arthropod-borne viral diseases are caused by a diverse group of viruses which are transmitted between vertebrate animals (often farm animals or small rodents) and people by the bite of blood-feeding vectors such as mosquitoes, ticks, and sandflies and by direct contact with infected animal carcasses. usually the viruses have the capacity to multiply in the salivary glands of the vector, but some are carried mechanically in their mouthparts. these viruses cause acute central nervous system infections (meningoencephalitis), myocarditis, or undifferentiated viral illnesses with polyarthritis and rashes, or severe hemorrhagic febrile illnesses. arbovirus diseases are often asymptomatic in vertebrates but may be severe in humans. over antigenetically distinct arboviruses are associated with disease in humans, varying from benign fevers of short duration to severe hemmorhagic fevers. each has a specific geographic location, vector, clinical, and virologic characteristics. they are of international public health importance because of the potential for spread via natural phenomena and modem rapid transportation of vectors and persons incubating the disease or ill with it, with potential for further spreading at the point of destination. arboviruses are responsible for a large number of encephalitic diseases characterized by mode of transmission and geographic area. mosquito-borne arboviruses causing encephalitis include eastern and western equine, venezuelan, japanese, and murray hill encephalitides. japanese encephalitis is caused by a mosquito-borne arbovirus found in asia and is associated with rice-growing areas. it is characterized by headache, fever, convulsions, and paralysis, with fatality rates in severe cases as high as %. a currently available vaccine is used routinely in endemic areas (japan, korea, thailand, india, and taiwan) and for persons traveling to infected areas. tick-borne arboviruses causing encephalitis include the powassan virus, which occurs sporadically in the united states and canada. tickborne encephalitis is endemic in eastern europe, scandinavia, and the former soviet union. an epidemic of mosquito-borne encephalitis in new york city in included cases and deaths, due to the west nile fever virus, never before found in the united states. other insect vectors. it affects animals and humans who are in direct contact with the meat or blood of affected animals. the virus causes a generalized illness in humans with encephalitis, hemorrhages, retinitis and retinal hemorrhage leading to partial or total blindness, and death ( - %). it also causes universal abortion in ewes and a high percentage of death in lambs. the normal habitat is in the rift valley of eastern africa (the great syrian-african rift), often spreading to southern africa, depending on climactic conditions. the primary reservoir and vector is the aedes mosquito, and affected animals serve to multiply the virus which is transmitted by other vectors and direct contact with animal fluids to humans. an unusual spread of rvf northward to the sudan and along the aswan dam reservoir to egypt in - caused hundreds of thousands of animal deaths, with , human cases and deaths. rvf appeared again in egypt in . this disease is suspected to be one of the ten plagues of egypt leading to the exodus of the children of israel from egypt during pharaonic-biblical times. in , an outbreak of rvf in kenya, initially thought to be anthrax, with hundreds of cases and dozens of deaths, was related to abnormal rainy season and vector conditions. satellite monitoring of rainfall and vegetation is being used to predict epidemics in kenya and surrounding countries. animal immunization, monitoring, vector control, and reduced contact with infected animals can limit the spread of this disease. arboviruses can also cause hemorrhagic fevers. these are acute febrile illnesses, with extensive hemorrhagic phenomena (internal and external), liver damage, shock, and often high mortality rates. the potential for international transmission is high. yellow fever. yellow fever is an acute viral disease of short duration and varying severity with jaundice. it can progress to liver disease and severe intestinal bleeding. the case fatality rate is < % in endemic areas, but may be as high as % in nonendemic areas and in epidemics. it caused major epidemics in the americas in the past, but was controlled by elimination of the vector, aedes aegypti. a live attenuated vaccine is used in routine immunization endemic areas and recommended for travelers to infected areas. determining the mode of transmission and vector control of yellow fever played a major role in the development of public health (see chapter ). in , the who reported , cases and , deaths from yellow fever globally. dengue hemorrhagic fever. dengue hemorrhagic fever is an acute sudden onset viral disease, with - days of fever, intense headache, myalgia, arthralgia, box . dengue fever and dengue hemorrhagic fever, dengue fever, a severe influenza-like illness, and dengue hemorrhagic fever are closely related conditions caused by four distinct viruses transmitted by aedes aegypti mosquitos. dengue is the world's most important mosquito-borne virus disease. a total of , million people worldwide are at risk of infection. an estimated million cases occur each year, of whom , need to be hospitalized. this is a spreading problem, especially in cities in tropical and subtropical areas. major outbreaks were reported in colombia, cuba, and many other locations in . source: world health organization. . world health report gastrointestinal disturbance, and rash. hemorrhagic phenomena can cause case fatality rates of up to %. epidemics can be explosive, but adequate treatment can greatly reduce the number of deaths. dengue occurs in southeast asia, the pacific islands, australia, west africa, the caribbean, and central and south america. an epidemic in cuba in included more than , cases, and deaths. vector control of the a. aegypti mosquito resulted in control of the disease during the s- s, but reinfestation of mosquitoes led to incresased transmission and epidemics in the pacific islands, caribbean, central and south america in the s and s. outbreaks in vietnam included , cases in , another , cases in , and a similar sized outbreak in . indonesia had over , cases in with deaths, and in over , cases (january-may) with at least deaths. in , epidemics of dengue were reported in fiji, the cook islands, new caledonia, and northern australia. the who estimates , deaths and . million cases worldwide in . monkeys are the main reservoir, and the vector is the a. aegypti mosquito. no vaccine is currently available, and management is by vector control. lassa fever. lassa fever was first isolated in lassa, nigeria, in and is widely distributed in west africa, with , - , cases and deaths annually. it is spread by direct contact with blood, urine, or secretions of infected rodents and by direct person-to-person contact in hospital settings. the disease is characterized by a persistent or spiking fever for - weeks, and may include severe hypotension, shock, and hemorrhaging. the case fatality rate is %. marburg disease. marburg disease is a viral disease with sudden onset of generalized illness, malaise, fever, myalgia, headache, diarrhea, vomiting, rash, and hemorrhages. it was first seen in marburg, germany, in , following ex-posure to green monkeys. person-to-person spread occurs via blood, secretions, organs, and semen. case fatality rates can be over %. ebola fever. ebola fever is a viral disease with sudden onset of generalized illness, malaise, fever, myalgia, headache, diarrhea, vomiting, rash, and hemorrhages. it was first found in zaire and sudan in in outbreaks which killed more than persons. it is spread from person to person by the blood, vomitus, urine, stools, and other secretions of sick patients, with a short incubation period. the disease has case fatality rates of up to %. an outbreak of ebola among laboratory monkeys in a medical laboratory near washington, d.c., was contained with no human cases. the reservoir for the virus is thought to be rodents. an outbreak of ebola in may in the town of kikwit, zaire, killed persons out of cases ( % case fatality rate). this outbreak caused international concern that the disease could spread, but it remained localized. another outbreak of ebola virus occurred in gabon in early , with cases, of whom had direct exposure to an infected monkey, the remainder by human-to-human contact, or not established; of the cases died ( %). this disease is considered highly dangerous unless outbreaks are effectively controlled. in zaire, lack of basic sanitary supplies, such as surgical gloves for hospitals, almost ensures that this disease will spread when it recurs. lyme disease is characterized by the presence of a rash, musculoskeletal, neurologic, and cardiovascular symptoms. confirmation is by laboratory investigation. it is the most common vector-borne disease in the united states, with , cases reported between and . it primarily affects children in the - age group and adults aged - . lyme disease is preventable by avoiding contact with ticks, by applying insect repellant, wearing long pants and long sleeves in infected areas, and by the early removal of attached ticks. several u.s. manufacturers produced vaccines which are approved for animal and human use. in the mid s, a mother of two young boys who were recently diagnosed with arthritis in the town of lyme, connecticut, conducted a private investigation among other town residents. she mapped each of the six arthritis cases in the town, cases which had occurred in a short time span among boys living in close proximity. this suggested that this syndrome of "juvenile rheumatoid arthritis" was perhaps connected with the boys playing in the woods. she presented her data to the head of rheumatology at yale medical school in new haven, who investigated this "cluster of a new disease entity." some parents reported that their sons had experienced tick bites and a rash before onset of the arthritis. a tick-borne, spiral shaped bacterium, a spirochete, borrelia burgdorferi, was identified as the organism, and ticks shown to be the vector. cases repond well to antibiotic therapy. in over , cases ( . per , ) were reported from states, an increase from , in and , in . cases were mainly located in the northeast, north central, and mid-atlantic regions. the disease accounts for over % of vector-borne disease in the united states and was the ninth leading reported infection in . lyme disease has been identified in many parts of north america, europe, the former soviet union, china, and japan. a newly licensed vaccine is effective for people exposed to ticks but not general usage. personal hygiene for protection from ticks and environmental modification are important to limit spread of the disease. source: cdc, , mmwr, : - ; and cdc, , mmwr, , no. . lyme disease website http://www.cdc.gov/ncidad/disease/lyme/lyme.htm medically important parasites are animals that live, take nourishment, and thrive in the body of a host, which may or may not harm the host, but never brings benefit. they include those caused by unicellular organisms such as protozoa, which include amoebas (malaria, schistosomiasis, amebiasis, and cryptosporidium), and helminths (worms), which are categorized as nematodes, cestodes, and trematodes. public health continues to face the problems of parasitic diseases in the developing world. increasingly, parasitic diseases are being recognized in industrialized countries. giardiasis and cryptosporidium infections in waterborne and other outbreaks have occurred in the united states. parasitic diseases are among the most common causes of illness and death in the world, e.g., malaria. milder illnesses such as giardiasis and trichomoniasis cause widespread morbidity. intestinal infestations with worms may cause of severe complications, although they commonly cause chronic low-grade symptomatology and iron deficiency anemia. echinococcosis (hydatid cyst disease) is infection with echinococcus granulosus, a small dog tapeworm. the tapeworm forms unilocular (single, noncompartmental) cysts in the host, primarily in the liver and lungs, but they can also grow in the kidney, spleen, central nervous system, or in bones. cysts, which may grow up to cm in size, may be asymptomatic or, if untreated, may cause severe symptoms and even death. this parasite is common where dogs are used with herd grazing animals and also have intimate contact with humans. the middle east, greece, sardinia, north africa, and south america are endemic areas, as are a few areas in the united states and canada. the human dis-ease has been eliminated in cyprus and australia. while the dog is the major host, intermediate hosts include sheep, cattle, pigs, horses, moose, and wolves. preventive measures include education in food and animal contact hygiene, destroying wild and stray dogs, and keeping dogs from the viscera of slaughtered animals. a similar, but multilocular, cystic hydatid disease is widely found in wild animal hosts in areas of the northern hemisphere, including central europe, the former soviet union, japan, alaska, canada, and the north-central united states. another echinococcal disease (echinococcus vogeli) is found in south america, where its natural host is the bush dog and its intermediate host is the rat. the domestic dog also serves as a source of human infection. surgical resection is not always successful, and long-term medical treatment may be required. control is through awareness and hygiene as well as the control of wild animals that come in contact with humans and domestic animals. control may require cooperation between neighboring countries. tapeworm infestation (taeniasis) is common in tropical countries where hygienic standards are low. beef (taenia saginata) and pork (t. solium) tapeworms are common where animals are fed with water or food exposed to human feces. freezing or cooking meat will destroy the tapeworm. fish tapeworm (diphyllobothrium latum) is common in populations living primarily on uncooked fish, such as inuit people. these tapeworms are usually associated with northern climates. toddlers are especially susceptible to dog tapeworm (dipylidium caninum), which is present worldwide, and domestic pets are often the source of oral-fecal transmission of the eggs. the disease is usually asymptomatic. similarly, dwarf tapeworm (hymenolepis nana) is transmitted through oral-fecal contamination from person to person, or via contaminated food or water. rat tapeworm (hymenolepis diminuta) also mostly affects young children. onchocerciasis (fiver blindness) is a disease caused by a parasitic worm, which produces millions of larvae that move through the body causing intense itching, debilitation, and eventually blindness. the disease is spread by a blackfly that transmits the larva from infected to uninfected people. it is primarily located in sub-saharan africa and in latin america, with over million persons at risk. control is by a combination of activities including environmental control by larvicidal sprays to reduce the vector population, protection of potential hosts by protective clothing and insect repellents, and case treatment. a who-initiated program for onchocerciasis control started in is sponsored by four international agencies: the food and agriculture organization (fao), the united nations development program (undp), the world bank, and who. it covers countries in sub-saharan africa, focusing on control of the blackfly by destoying its larvae, mainly via insecticides sprayed from the air. prevalence in was reported by who as over million persons. the program has been successful in protecting some million persons and helping . million infected persons to recover from this disease. who estimates that the program will have prevented , cases of blindness by the year and has freed million hectares of land for resettlement and cultivation. the program cost $ million. this investment is considered by the world bank to have a return of - % in terms of large scale land reuse and improved output of the population. a who program, the african program for onchocerciasis control (apoc), started in , uses a new drug (ivermectin) and selective vector control efforts by spraying. this involves countries in africa, and in a similar program in south america. see website http://www/who.int/ocp and is financed by many donor countries, internation organizations, merck & company, and ngos. dracunculiasis (guinea worm disease) is a parasitic disease of great public health importance in india, pakistan, and central and west africa. it is an infection of the subcutaneous and deeper tissues caused by a large ( cm) nematode, usually affecting the lower extremities and causing pain and disability. the nematode causes a burning blister on the skin when it is ready to release its eggs. after the blister ruptures, the worm discharges larvae whenever the extremity is in water. the eggs are ingested in contaminated water and the larva released migrate through the viscera to locate as adults in the subcutaneous tissue of the leg. incubation is about months. the larva released in water are ingested by minute crustaceans and remain infective for as long as a month. prevention is based on improving the safety of water supplies and by preventing contamination by infected persons. education of persons in endemic areas to stay out of water sources and to filter drinking water reduces transmission. insecticides remove the crustaceans. chlorine also kills the larvae and the crustaceans which prologue larval infectivity. there is no vaccine. treatment is helpful, but not definitive. dracunculiasis was traditionally endemic in a belt from west africa through the middle east to india and central asia. it was successfully eliminated from central asia and iran and has disappeared from the middle east and from some african countries (gambia and guinea). the world health organization has promoted the eradication of dracunculiasis. major progress has been made in this direction. worldwide prevalence is reported to have been reduced from million cases in to million in , , in , and , cases in . eradication was anticipated for the year , and in the who established a commission to monitor and certify eradication in formerly endemic areas. india's reported cases fell from , in to in , and the country was free of transmission in . in , formerly high prevalence countries such as kenya reported no cases in , while chad, senegal, cameroons, yemen, and the central african republic less than cases each. eradication of this disease appears to be imminent. the who eradication program was developed successfully as an independent program with its own direction and field staff, but further progress will require the integration of this program with other basic primary care programs in order to be self-sustaining as an integral part of community health. community-based surveillance systems for this disease are being converted to work for monitoring of other health conditions in the community. schistosomiasis (snail fever or bilharziasis) is a parasitic infection caused by the trematode (blood fluke) and transmitted from person to person via an intermediate host, the snail. it is endemic in countries in africa, south america, the caribbean, and asia. there are an estimated million persons infected worldwide and more than million at risk for the disease. the clinical symptoms include fever, nausea, vomiting, abdominal pain, diarrhea, and hematuria. the organisms schistosoma mansoni and s. japonicum cause intestinal and hepatic symptoms, including diarrhea and abdominal pain. schistosoma haematobium affects the genitourinary tract, causing chronic cystitis, pyelonephritis, with high risk for bladder cancer the ninth most common cause of cancer deaths globally. infection is acquired by skin contact with freshwater containing contaminated snails. the cercariae of the organism penetrate the skin, and in the human host it matures into an adult worm that mates and produces eggs. the eggs are disseminated to other parts of the body from the worm's location in the veins surrounding the bladder or the intestines, and may result in neurological symptoms. eggs may be detected under microscopic examination of urine and stools. sensitive serologic tests are also available. treatment is effective against all three major species of schistosomiasis. eradication of the disease can be achieved with the use of irrigation canals, prevention of contamination of water sources by urine and feces of infected persons, treatment of infected persons, destruction of snails, and health education in affected areas. persons exposed to freshwater lakes, streams, and rivers in endemic areas should be warned of the danger of infection. mass chemotherapy in communities at risk and improved water and sanitation facilities are resulting in improved control of this disease. leishmaniasis causes both cutaneous and visceral disease. the cutaneous form is a chronic ulcer of the skin, called by various names, e.g., rose of jericho, oriental sore, and aleppo boil. it is caused by leishmania tropica, l. brasiliensis, l. mexicana, or the l. donovani complex. this chronic ulcer may last from weeks to more than a year. diagnosis is by biopsy, culture, and serologic tests. the organism multiplies in the gut of sandflies (phlebotomus and lutzomi) and is transmitted to humans, dogs, and rodents through bites. the parasites may remain in the untreated lesion for - months, and the lesion does not heal until the parasites are eliminated. prevention is through limiting exposure to the phlebotomines and reducing the sandfly population by environmental control measures. insecticide use near breeding places and homes has been successful in destroying the vector sandflies in their breeding places. case detection and treatment reduce the incidence of new cases. there is no vaccine, and treatment is with specific antimonials and antibiotics. visceral leishmaniasis (kala azar) is a chronic systemic disease in which the parasite multiplies in the cells of the host's visceral organs. the disease is characterized by fever, the enlargement of the liver and spleen, lymphadenopathy, anemia, leukopenia, and progressive weakness and emaciation. diagnosis is by culture of the organism from biopsy or aspirated material, or by demonstration of intracellular (leishman-donovan) bodies in stained smears from bone marrow, spleen, liver, or blood. kala azar is a rural disease occurring in the indian subcontinent, china, the southern republics of the former u.s.s.r., the middle east, latin america, and sub-saharan africa. it usually occurs as scattered cases among infants, children, and adolescents. transmission is by the bite of the infected sandfly with an incubation period of - months. there is no vaccine, but specific treatment is effective and environmental control measures reduce the disease prevalence. this includes the use of antimalarial insecticides. in localities where the dog population has been reduced, the disease is less prevalent. sleeping sickness. sleeping sickness a disease caused by trypanosoma brucei, transmitted but the tsetse fly, primarily in the african savannahs, affecting cattle and humans. some million persons are at risk in sub-saharan africa. who reported , new cases, a total prevalence of , cases, and , deaths from this disease in . prevention depends on vector control, and effective treatment of human cases. chagas disease is a chronic and incurable vector and blood transfusion borne parasitic disease (trypanosoma cruzi) which causes disability and death. it affects some million persons mainly in latin america, with some , new cases and , deaths occurring annually. about % of affected persons develop severe heart disease. brazil, which accounts for % of the cases prevalent in latin america, achieved elimination of transmission in , after uruguay ( ) and venezuela ( ) and followed by argentina ( ) . elimination of transmission is projected by who by the year . control is difficult, but control measures include reducing the animal host and vector insect population in its habitat by ecological and insectiside measures, education of the population in prevention by clothing, bednets, and repellents, and with chemotherapy for case management. amebiasis. amebiasis is an infection with a protozoan parasite (entamoeba histolytica) which exists as an infective cyst. infestation may be asymptomatic or cause acute, severe diarrhea with blood and mucus, alternating with constipation. amebic colitis can be confused with ulcerative colitis. diagnosis is by microscopic examination of fresh fecal specimens showing trophozoites or cysts. transmission is generally via ingestion of fecal-contaminated food or water containing cysts, or by oral-anal sexual practices. amebiasis is found worldwide. sand filtration of community water supplies removes nearly all cysts. suspect water should be boiled. education regarding hygienic practices with safe food and water handling and disposal of human feces are the basis for control. ascariasis. ascariasis is infestation of the small intestine with the roundworm ascaris lumbricoides, which may appear in the stool, occasionally the nose or mouth, or may be coughed up from lung infestation. the roundworm is very common in tropical countries, where infestation may reach or exceed % of the population. children aged - years are especially susceptible. infestation can cause pulmonary symptoms and frequently contributes to malnutrition, especially iron deficiency anemia. transmission is by ingestion of infective eggs, common among children playing in contaminated areas, or via the ingestion of uncooked products of infected soil. eggs may remain viable in the soil for years. vermox and other treatments are effective. prevention is through education, adequate sanitary facilities for excretion, and improved hygienic practices, especially with food. use of human feces for fertilizer, even after partial treatment, may spread the infestation. mass treatment is indicated in high prevalence communities. pinworm disease or enterobiasis. pinworm disease (oxyuriasis) is common worldwide in all socioeconomic classes; however, it is more widespread when crowded and unsanitary living conditions exist. the enterobius vermicularis infestation of the intestine may be symptomless or may cause severe perianal itching or vulvovaginitis. it primarily affects schoolchildren and preschoolers. more severe complications may occur. adult worms may be seen visually or identified by microscopic examination of stool specimens or perianal swabs. transmission is by the oral-fecal ingestion of eggs. the larvae grow in the small intestine and upper colon. prevention is by educating the public regarding hygiene and adequate sanitary facilities, as well as by treating cases and investigating contacts. treatment is the same as for ascariasis. mass treatment is indicated in high prevalence communities. ectoparasites. ectoparasites include scabies (sarcoptes scabiei), the common bed bug (cimex lectularius), fleas, and lice, including the body louse (pediculus humanis), pubic louse (phthirius pubis), and the head louse (pediculus humanus capitis). their severity ranges from nuisance value to serious public health hazard. head lice are common in schoolchildren worldwide and are mainly a distressing nuisance. the body louse serves as a vector for epidemic typhus, trench fever, and louse-borne relapsing fever. in disaster situations, disinfection and hygienic practices may be essential to prevent epidemic typhus. the flea plays an important role in the spread of the plague by transmitting the organism from the rat to humans. control of rats has reduced the flea population, but during war and disasters, rat and flea populations may thrive. scabies, which is caused by a mite, is common worldwide and is transmitted from person to person. the mite burrows under the skin and causes intense itching. all of these ectoparasites are preventable by proper hygiene and the treatment of cases. the spread of these diseases is rapid and therefore warrants attention in school health and public health policy. legionnelae, a gram-negative group of bacilli, with species and many serogroups. the first documented case was reported in the united states in , and the first disease outbreak was reported in the united states in among participants of a war veterans convention. general malaise, anorexia, myalgia, and headache are followed by fever, cough, abdominal pain, and diarrhea. pneumonia followed by respiratory failure may follow. the case fatality rate can be as high as % of hospitalized cases. a milder, nonpneumonic form of the disease (pontiac fever) is associated with virtually no mortality. the organism is found in water reservoirs and is transmitted through heating, cooling, and air conditioning systems, as well as from tap water, showers, saunas, and jaccuzzi baths. the disease has been reported in australia, canada, south america, europe, israel, and on cruise ships. prevention requires the cleaning of water towers and cooling systems, including whirlpool spas. hyperchlorination of water systems and the replacement of filters is required where cases and/or organisms have been identified. antibiotic treatment with erythromycin is effective. leprosy (hansen's disease) was widely prevalent in europe and mediterranean countries for many centuries, with some , leprosaria in the year . leprosy was largely wiped out during the black death in the fourteenth century, but continued in endemic form until the twentieth century. leprosy is a chronic bacterial infection of the skin, peripheral nerves, and upper airway. in the lepromatous form, there is diffuse infiltration of the skin nodules and macules, usually bilateral and extensive. the tuberculoid form of the disease is characterized by clearly demarcated skin lesions with peripheral nerve involvement. diagnosis is based on clinical examination of the skin and signs of peripheral nerve damage, skin scrapings, and skin biopsy. transmission of the mycobacterium leprae organism is by close contact from person to person, with incubation periods of between months and years (average of - years). rifampicin and other medications make the patient noninfectious in a short time, so that ambulatory treatment is possible. multidrug therapy (mdt) has been shown to be highly effective in combating the disease, with a very low relapse rate. treatment with mdt ensures that the bacillus does not develop drug resistance. mdt is covering % of known cases in , according to who reports, as compared to only % in . the increase has been associated with improved case finding. bcg may be useful in reducing tuberculoid leprosy among contacts. investigation of contacts over years is recommended. the disease is still highly endemic primarily in five countries, india, brazil, indonesia, myanmar, and bangladesh, and is still present in some countries in southeast asia, including the philippines and burma, sub-saharan africa, the middle east (sudan, egypt, iran), and in some parts of latin america (mexico, colombia) with isolated cases in the united states. world prevalence has declined from . million cases in , . million in , to less than million cases in . the world health organization expects to eliminate leprosy as a public health problem by the year , defined as prevalence of less than per , population, or less than , cases. trachoma is currently responsible for million blind persons or % of total blindness in the world. the causative organism, chlamydia trachomatis, is a bacteria which can survive only within a cell. it is spread through contact with eye discharges, usually by flies, or household items (e.g., handkerchiefs, washcloths). trachoma is common in poor rural areas of central america, brazil, africa, parts of asia, and some countries in the eastern mediterranean. the resulting infection leads to conjuncfival scarring and if untreated, to blindness. who estimates there are million cases of active disease in endemic countries. hygiene, vector control, and treatment with antibiotic eye ointments or simple surgery for scarring of eyelids and inturned eyelashes prevent the blindness. a new drug, azithromycin, is effective in curing the disease. the who is promoting a program for the global elimination of trachoma using azithromycin and hygiene education in endemic areas. chlamydia (chlamydia pneumonia) is suspected of playing a role in coronary artery disease by intraarterial infection, with plaque formation and occlusion of the artery by thrombi consisting mainly of platelets. if borne out, this will provide potential for low cost intervention to reduce the burden of the leading worldwide cause of death. sexually transmitted diseases (stds) are widespread internationally with an estimated million new cases per year, with . million new cases, over million total cases, and . million deaths ( ), aids has captured world attention over the past decade. the global burden of stds is enormous (table . ), and the public health and social consequences are devastating in many countries. sexually transmitted diseases, especially in women, may be asymptomatic, so that severe sequelae may occur before patients seek care. infection by one std increases risk of infection by other diseases in this group. syphilis is caused by the spirochete treponema pallidum. after an incubation period of - days (mean - ), primary syphilis develops as a painless ulcer or chancre on the penis, cervix, nose, mouth, or anus, lasting - weeks. the patient may first present with secondary syphilis - weeks (up to weeks) after infection with a general rash and malaise, fever, hair loss, arthritis, and jaundice. these symptoms spontaneously disappear within weeks or up to months later. tertiary syphilis may appear - years after initial infection. complications of tertiary syphilis include catastrophic cardiovascular and central nervous system conditions. early antibiotic treatment is highly effective when given in a large initial dose, but longer term therapy may be needed if treatment is delayed. gonorrhea (gc) is caused by the bacterium neisseria gonorrhoeae. the incubation period is - days. gonorrhea is often associated with concurrent chlamydia infection. in women, gc may be asymptomatic or it may cause vaginal discharge, pain on urination, bleeding on intercourse, or lower abdominal pain. untreated, it can lead to sterility. in men, gc causes urethral discharge and painful urination. treatment with antibiotics ends infectivity, but untreated cases can be infectious for months. drug resistance to penicillin and tetracycline has increased in many countries so that more expensive and often unavailable drugs are necessary for treatment. prevention of gonococcal eye infection in newborns is based on routine use of antibiotic ointments in the eyes of newborns. chancroid. chancroid is caused by haemophilus ducreyi. in women chancroids may cause a painful, irregular ulcer near the vagina, resulting in pain on in-tercourse, urination, and defection, but it may be asymptomatic. in men it causes a painful, irregular ulcer on the penis. the incubation period is usually - days, but may be up to days. an individual is infectious as long as there are ulcers, usually - months. treatment is by erythromycin or azithromycin. herpes simplex. herpes simplex is caused by herpes simplex virus types and and has an incubation period of - days. genital herpes causes painful blisters around the mouth, vagina, penis, or anus. the genital lesions are infectious for - days. herpes may lead to central nervous system meningoencephalitis infection. it can be transmitted to newborns during vaginal delivery, causing infection, encephalitis, and death. cesarian delivery is therefore necessary when a mother is infected. anti-viral drugs are used in treatment, orally, topically, or intravenously. chlamydia. chlamydia is caused by chlamydia trachomatis. in women, it is usually asymptomatic but may cause vaginal discharge, spotting, pain on urination, lower abdominal pain, and pelvic inflammatory disease (pid). in newborns, chlamydia may cause eye and respiratory infections. in men, chlamydia causes urethral discharge and pain on urination. the incubation period is - days and the infectious period is unknown. treatment for chlamydia is doxycycline, azithromycin, or erythromycin. chlamydia infection, not necessarily venereal in transmission, may be transmitted to newborns of infected mothers. chlamydia pneumoniae, presently under investigation as a possible cause or contributor to coronary heart disease, and is widespread in poor hygenic conditions. trichomoniasis. trichomoniasis is caused by trichomonas vaginalis. the incubation period is - days (mean = ). in women, trichomoniasis may be asymptomatic or may cause a frothy vaginal discharge with foul odor, and painful urination and intercourse. in men, the disease is usually mild, causing pain on urination. treatment is by metronidazole taken orally. without treatment, the disease may persist and remain infectious for years. (hpv). it is a sporadic disease which may be associated with cervical neoplasia and cancer of the cervix. hpv includes many types associated with a variety of conditons. the search for a hpv vaccine to prevent cancer of the cervix looks promising. in areas where a full range of diagnostic services is lacking, a "syndromic approach" is recommended for the control of stds. the diagnosis is based on a group of symptoms and treatment on a protocol addressing all the diseases that could possibly cause those symptoms, without expensive laboratory tests and repeated visits. early treatment without laboratory confirmation helps to cure persons who might not return for follow-up, or may place them in a noninfective stage so that even without follow-up they will not transmit the disease. std incidence between and is shown in table . , with decline overall except around , with subsequent further fall in incidence. screening in prenatal and family planning clinics, prison medical services, and selected years - disease syphilis ( [ ] [ ] [ ] [ ] [ ] [ ] and subsequent decline by more than % in reported cases includes all three stages of the disease as well as congential syphilis. rates are cases per , population, rounded. in clinics serving prostitutes, homosexuals, or other potential risk groups will detect subclinical cases of various stds. treatment can be carried out cheaply and immediately. for instance, the screening test for syphilis costs $ . and the treatment with benzathine penicillin injection costs about $ . in . partner notification is a controversial issue, but may be needed to identify contacts who may be the source of transmission to others. control of stds through a syndrome approaach based on primary care providers is being promoted by who. health education directed at high risk target groups is essential. providing easy and cost-free access to acceptable, nonthreatening treatment is vital in promoting the early treatment of cases and thereby reducing the risk of transmission. promoting prevention through the use of condoms and/or monogamy requires long-term educational efforts that are now fostered by the hiv/aids pandemic. increased use of condoms for hiv prevention is associated with reduced risk of other stds. training medical care providers in std awareness should be stressed in undergraduate and continuing educational efforts including personal protection as care givers. human immunodeficiency virus (hiv) is a retrovirus that infects various cells of the immune system, and also affects the central nervous system. two types have been identified: hiv , worldwide in distribution, and the less pathogenic hiv , found mainly in west africa. hiv is transmitted by sexual contact, exposure to blood and blood products, perinatally, and via breast milk. the period of communicability is unknown, but studies indicate that infectiousness is high, both during the initial period after infection and later in the disease. antibodies to hiv usually appear within - months. within several weeks to months of the infection, many persons develop an acute self-limited flulike syndrome. they may then be free of any signs or symptoms for months to more than years. onset of illness is usually insidious with nonspecific symptoms, including sweats, diarrhea, weight loss, and fatigue. aids represents the later clinical stage of hiv infection. according to the revised cdc case definition ( ), aids involves any one or more of the following: low cd count, severe systematic symptoms, opportunistic infections such as pneumocystis pneumonia or tb, aggressive cancers such as kaposi's sarcoma or lymphoma, and/or neurological manifestations, including dementia and neuropathy. the who case definition is more clinically oriented, relying less on often unavailable laboratory diagnoses for indicator diseases. aids was first recognized clinically in in los angeles and new york. by mid- it was considered an epidemic in those and other u.s. cities. it was primarily seen among homosexual men and recipients of blood products. after initial errors, testing of blood and blood products became standard and has subsequently closed off this method of transmission. transmission has changed markedly since the initial onslaught of the disease, with needle sharing among intravenous drug users, heterosexual, and maternal-fetal transmission becoming major factors. comorbidity with other stds apparently increases hiv infectivity and may have helped to convert the epidemiology to a greater degree of heterosexual transmission. the disease grew exponentially in the united states (table . ), but incidence of new cases nas declined since . aids has become a major public health problem in most developed and developing countries, reaching catastrophic proportions in some sub-saharan african countries affecting up to % of the population. hiv-related deaths were the eighth leading cause of all deaths in in the u.s., the leading cause among men aged - years of age, and the fourth leading cause for women in this age group. by , aids had been diagnosed in , persons and , had died. it is estimated that up to million persons are hiv infected in the united states. globally, deaths from aids totalled . million in , with an estimated . million person having died from this pandemic up to . in , an estimated . million person were hiv infected with . million new infection in . the declining incidence of new cases in the industrialized countries may be the result of greater awareness of the disease and methods of prevention of transmission. improving early diagnosis and access to care, especially the combined therapy programs that are very effective in delaying onset of symptoms, are important parts of public health management of the aids crisis. until an effective vaccine is available, preventive reliance will continue to be on behavior risk-reduction and other prevention strategies such as needle and condom distribution among high risk population groups. throughout the world, hiv continues to spread rapidly, especially in poor countries in africa, asia, and south and central america. the united nations reports that million persons are living with hiv/aids, % of them in developing countries, where transmission is % by heterosexual contact. every day, more than persons are infected, including children. in thailand, person in is now infected. in sub-saharan africa person in is infected, and in some cities as many as person in carries the virus. estimations of new infections per year in sub-saharan africa range from to million persons, while in asia the range is from . to . million new infected persons per year. lessons are still being learned from the aids pandemic. the explosive spread of this infection, from an estimated , people in to an anticipated million persons hiv infected, shows that the world is still vulnerable to pandemics of "new" infectious diseases. enormous movements of tourists, business people, truck drivers, migrants, soldiers, and refugees promote the spread of such diseases. widespread sexual exchange, traffic in blood products, and illicit drug use all promote the international potential for pandemics. war and massive refugee situations promote rape and prostitution, worsening the aids situation in some settings in africa. hiv has arrived in almost every country. however, there is the somewhat hopeful indication that the rate of increase, has slowed in the united states. this may be an indication either of higher levels of self-protective behavior, or that the most susceptible population groups have already been affected and the spread into the general population is at a slower rate. it is also possible that this may yet prove to be only a lull in the storm, as heterosexual contact becomes a more important mode of transmission. the eleventh international conference on aids, held in vancouver, canada, in july , reported signs that combinations of several drugs from among a number of antiretroviral medications are showing promise to suppress the aids virus in infected people. at a current annual price of $ , - , per patient, these sums well beyond the capacity of most developing countries. development of methods of measuring the hiv viral load have allowed for better evaluation of potential therapies and monitoring of patients receiving therapy. in developed countries, transmission by blood products has been largely controlled by screening tests; transmission among homosexuals has been reduced by safe sex practices; transmission to newborns has been reduced by recent therapeutic advances. safe sex practices and condom use may have helped in reducing heterosexual transmission. further advances in therapy and prevention with a vaccine are expected over the next decade. the hiv/aids pandemic is one of the great challenges to public health for the st century due to its complexity, its international spread, its sexual and other modes of transmission, its devastating and costly clinical effects, and its impact on parallel diseases such as tuberculosis, respiratory infections, and cancer. the cost of care for the aids patient can be very high. needed programs include home care and community health workers to improve nutrition and self-care, and mutual help among hiv carriers and aids patients. the ethical issues associated with aids are also complex regarding screening of pregnant women, newborns, partner notification, reporting, and contact tracing, as well as financing the cost of care. diarrheal diseases are caused by a wide variety of bacteria, parasites, and viruses (table . ) infecting the intestinal tract and causing secretion of fluids and dis- solved salts into the gut with mild to severe or fatal complications. in developing countries, diarrheal diseases account for half of all morbidity and a quarter of all mortality. diarrhea itself does not cause death, but the dehydration resulting from fluid and electrolyte loss is one of the most common causes of death in children worldwide. deaths from dehydration can be prevented by use of oral rehydration therapy (ort), an inexpensive and simple method of intervention easily used by a nonmedical primary care worker and by the mother of the child as a home intervention. in , diarrheal diseases were the cause of almost million child deaths, but by this had declined to . million, largely under the impact of increased use of ort. diarrheal diseases are transmitted by water, food, and directly from person to person via oral-fecal contamination. diarrheal diseases occur in epidemics in situations of food poisoning or contaminated water sources, but can also be present at high levels when common source contamination is not found. contamination of drinking water by sewage and poor management of water supplies are also major causes of diarrheal disease. the use of sewage for the irrigation of vegetables is a common cause of diarrheal disease in many areas. salmonella are a group of bacterial organisms causing acute gastroenteritis, associated with generalized illness including headache, fever, abdominal pains, and dehydration. there are over serotypes of salmonella, many of which are pathogenic in humans, the most common of which are salmonella typhimurium, s. enteritidis, and s. typhi. transmission is by ingestion of the organisms in food, derived from fecal material from animal or human contamination. common sources include raw or uncooked eggs, raw milk, meat, poultry and its products, as well as pet turtles or chicks. fecal-oral transmission from person to person is common. prevention is in safe animal and food handling, refrigeration, sanitary preparation and storage, protection against rodent and insect contamination, and the use of sterile techniques during patient care. antibiotics may not eliminate the carrier state and may produce resistant strains. shigella are a group of bacteria that are pathogenic in man, with four groups: type a = shigella dysenteriae, type b = s. flexneri, type c = s. boydii, and type d = s. sonnei. types a, b, and c are each further divided into a total of serotypes. shigella are transmitted by direct or indirect fecal-oral methods from a patient or carrier, and illness follows ingestion of even a few organisms. water and milk transmission occurs as a result of contamination. flies can transmit the organism, and in nonrefrigerated foods the organism may multiply to an infectious dose. control is in hygienic practices and in the safe handling of water and food. escheria eoli e. coli are common fecal contaminants of inadequately prepared and cooked food. particularly virulent strains such as o :h can cause explosive outbreaks of severe (enterohemmorhagic) diarrhoeal disease with a hemolytic-uremic syndrome and death, as occurred in japan in with cases and deaths due to a foodborne epidemic. other milder strains cause travellers diarrhoea and nursery infections. inadequately cooked hamburger, unpasturized milk, and other food vectors are discussed under food safety in chapter . cholera is an acute bacterial enteric disease caused by vibrio cholerae, with sudden onset, profuse painless watery stools, occasional vomiting, and, if untreated, rapid dehydration, and circulatory collapse, and death. asymptomatic infection or carrier status, and mild cases are common. in severe, untreated cases, mortality is over %, but with adequate treatment, mortality is under %. diagnosis is based on clinical signs, epidemiologic, serologic and bacteriologic confirmation by culture. the two types of cholera are the classic and el tor (with inaba and ogawa serotypes). in , a large scale epidemic of cholera spread through much of south america. it was imported via a chinese freighter, whose sewage contaminated shellfish in lima harbor in peru (box . ). the south american cholera epidemic has caused hundreds of thousands of cases and thousands of deaths since . prevention requires sanitation, particularly the chlorination of drinking water, prohibiting the use of raw sewage for the irrigation of vegetable crops, and high standards of community, food, and personal hygiene. treatment is prompt fluid therapy with electrolytes in large volume to replace all fluid loss. oral rehydration should be accomplished using standard ort. tetracycline shortens the duration of the disease, and chemoprophylaxis for contacts following stool samples may help in reducing its spread. a vaccine is available but is of no value in the prevention of outbreaks. viral gastroenteritis can occur in sporadic or epidemic forms, in infants, children, or adults. some viruses, such as the rotaviruses and enteric adenoviruses, af- in the s, peruvian officials stopped the chlorination of community water supplies because of concern over possible carcinogenic effects of trihalomethanes, a view encouraged by officials of the u.s. environmental protection agency (epa) and the u.s. public health service. in january , a chinese freighter arrived in lima, peru, and dumped bilge (sewage) in the harbor, apparently contaminating local shellfish. consumption of raw shellfish is a popular local delicacy (ceviche) and associated with cases of cholera seen in local hospitals. contamination of local water supplies from sewage resulted in the geometric increase in cases, and by the end of the pan american health organization (paho) reported an epidemic of , cases and deaths. the epidemic spread to countries, and in there were a further , cases and deaths spreading over much of south america, continuing in . in the united states, cases of cholera were reported in ; of these, cases and death were among passengers of an airplane flying from south america to los angeles in which contaminated seafood was served. in , cases of cholera were reported in the united states which were unrelated to international travel. these occurred mostly among persons consuming shellfish from the gulf coast with a strain of cholera similar to the south american strain, also possibly introduced in ship ballast. cholera organisms are reported in harbor waters in other parts of the united states (promed, , promed, . fect mainly infants and young children, and may be severe enough to cause hospitalization for dehydration. others such as norwalk and norwalk-like viruses affect older children and adults in self-limited acute gastroenteritis in family, institution, or community outbreaks. rotaviruses cause acute gastroenteritis in infants and young children, with fever and vomiting, followed by watery diarrhea and occasionally severe dehydration and death if not adequately treated. diagnosis is by examination of stool or rectal swabs with commercial immunologic kits. in both developed and developing countries, rotavirus is the cause of about one-third of all hospitalized cases for diarrheal diseases in infants and children up to age . most children in developing countries experience this disease by the age of years, with the majority of cases between and months. in developing countries, rotaviruses are estimated to cause over , deaths per year. the virus is found in temperate climates in the cooler months and in tropical countries throughout the year. breastfeeding does not prevent the disease but may reduce its severity. oral rehydration therapy is the key treatment. a live attenuated vaccine was approved by the fda in and adopted in the u.s. recommended routine vaccination programs for infants. adenoviruses. adenoviruses, norwalk, and a variety of other viruses (including astrovirus, calcivirus, and other groups) cause sporadic acute gastroenteritis worldwide, mostly in outbreaks. spread is by the oral-fecal route, often in hospital or other communal settings, with secondary spread among family contacts. food-borne and waterborne transmission are both likely. these can be a serious problem in disaster situations. no vaccines are available. management is with fluid replacement and hygienic measures to prevent secondary spread. giardiasis. giardiasis (caused by giardia lamblia) is a protozoan parasitic infection of the upper small intestine, usually asymptomatic, but sometimes associated with chronic diarrhea, abdominal cramps, bloating, frequent loose greasy stools, fatigue, and weight loss. malabsorption of fats and vitamins may lead to malnutrition. diagnosis is by the presence of cysts or other forms of the organism in stools, duodenal fluid, or in intestinal mucosa from a biopsy. this disease is prevalent worldwide and affects mostly children. it is spread in areas of poor sanitation and in preschool settings and swimming pools, and is of increasing importance as a secondary infection among immunocompromised patients, especially those with aids. waterborne giardia was recognized as a serious problem in the united states in the s and s, since the protozoa is not readily inactivated by chlorine, but requires adequate filtration before chlorination. person-to-person transmission in day-care centers is common, as is transmission by unfiltered stream or lake water where contamination by human or animal feces is to be expected. an asymptomatic carrier state is common. prevention relies on careful hygiene in settings such as day-care centers, filtration of public water supplies and the boiling of water in emergency situations. cryptosporidium. cryptosporidium parvum is a parasitic infection of the gastrointestinal tract in man, small and large mammals and vertebrates. infection may be asymptomatic or cause a profuse, watery diarrhea, abdominal cramps, general malaise, fever, anorexia, nausea, and vomiting. in immunosuppressed patients, such as persons with aids, it can be a serious problem. the disease is most common in children under years of age and those in close contact with them, as well as in homosexual men. diagnosis is by identification of the cryptosporidium or-ganism cysts in stools. the disease is present worldwide. in europe and the united states, the organism has been found in < to . % of individuals sampled. spread is common by person-to-person contact by fecal-oral contamination, especially in such settings as day-care centers. raw milk and waterborne outbreaks have also been identified in recent years. a large waterborne disease outbreak due to cryptosporidium occurred in milwaukee in described in chapter . management is by rehydration and prevention is by careful hygiene in food and water safety. helicobacter pylori. helicobacter pylori, first identified in , is a bacterium causally linked to duodenal ulcers and gastritis, contributing to high rates of gastric cancer (chapter ). it is an important example of the link between infection and chronic disease. this has enormous implications for prevention of cancer of the stomach, chronic peptic ulcers and large-scale use of hospitals and other medical resources (see chapter ). the control of diarrheal diseases requires a comprehensive program involving a wide range of activities, including good management of food and water supplies, education in hygiene, and, particularly where morbidity and mortality are high, education in the use of oral rehydration therapy (ort). oral rehydration therapy (ort) is considered by unicef and who to have resulted in the saving of million lives each year in the s. proper management of an episode of diarrhea by ort (table . ), along with continued feeding, not only saves the child from dehydration and immediate death, but also contributes to early restoration of nutritional adequacy, sparing the child the prolonged effects of malnutrition. the world summit for children (wsc) in called for a reduction in child deaths from diarrheal diseases by one-third and malnutrition by one-half, with em- phasis on the widest possible availability, education for, and use of ort. this requires a programmatic approach. public health leadership must train primary care doctors, pediatricians, pharmacists, drug manufacturers, and primary care health workers of all kinds in ort principles and usage. they must be backed by the widest possible publicity to raise awareness among parents. oral rehydration therapy is an important public health modality in developed countries as well as in developing countries. diarrhoeal disease may not cause death as frequently in developed countries, but it is still a significant factor in infant and child health and, even under the most optimal conditions, can cause setbacks in the nutritional state and physical development of a child. use of ort does not prevent the disease (i.e., it is not a primary prevention), but it is excellent in secondary prevention, by preventing complications from diarrhoea, and should be available in every home for symptomatic treatment of diarrheal diseases. an adaptation of ort has found its place in popular culture in the united states. a form of ort, marketed as "sports drinks," is used in sports where athletes lose large quantifies of water and salts in sweat and insensible loss from the respiratory tract. the wider application of the principles of ort for use in adults in dry hot climates and in adults under severe physical exertion with inadequate fluid/salt intake situations requires further exploration. management of diarrheal diseases should be part of a wider approach to child nutrition. the child who goes through an episode of diarrheal disease may have a faltering in growth and development. supportive measures may be needed following the episode as well as during it. this involves providing primary care services that are attuned to monitoring individual infant and child growth. growth monitoring surveillance is important to assess the health status of the individual child and the child population. supplementation of infant feeding with vitamins a and d, and iron to prevent anemia are important for routine infant and child care, and more so for conditions affecting total nutrition such as a diarrheal disease. in the developing world, respiratory infections account for over one-quarter of all deaths and illnesses in children. as diarrheal disease deaths are reduced, the major cause of death among infants in developing countries is becoming acute respiratory infections (aris). in industrialized countries, aris are important for their potentially devastating effects on the elderly and chronically ill. they are also the major cause of morbidity in infants in developed countries, causing much anxiety to parents even in areas with good living conditions. cigarette smoking, chronic bronchitis, poorly controlled diabetes or congestive heart failure, and chronic liver and kidney disease increase susceptibility to aris. aris place a heavy burden on health care systems and individual families. improved methods of management of such chronic diseases are needed to reduce the associated toll of morbidity, mortality, and the considerable expenses of health care. acute respiratory infections are due to a broad range of viral and, to a lesser extent, bacterial infections. it is the latter which can progress to pneumonia with mortality rates of - %. acute viral respiratory diseases include those affecting the upper respiratory tract, such as acute viral rhinitis, pharyngitis, and laryngitis, as well as those affecting the lower respiratory tract, tracheobronchitis, bronchitis, bronchiolitis, and pneumonia. aris are frequently associated with vaccine-preventable diseases, including measles, varicella, and influenza. they are caused by a large number of viruses, producing a wide spectrum of acute respiratory illness. some organisms affect any part of the respiratory tract, while others affect specific parts and all predispose to bacterial secondary infection. while children and the elderly are especially susceptible to morbidity and mortality from acute respiratory disease, the vast numbers of respiratory illnesses among adults cause large-scale economic loss from work absence. bacterial agents causing upper respiratory tract infection include group a streptococcus, mycoplasma pneumonia, pertussis, and parapertussis. pneumonia or acute bacterial infection of the lower respiratory tract and lung tissue may be due to pneumococcal infection with streptococcus pneumoniae. there are known types of this organism, distinguished by capsule characteristics; account for % of pneumococcal infections in the united states. an excellent polyvalent vaccine based on these types is available for high risk groups such as the elderly, immunodeficient patients, and persons with chronic heart, lung, liver, blood disorders, or diabetes. opportunistic infections attack the chronically ill, especially those with compromised immune suystems, often with life-threatening aris. mycoplasma (primary atypical pneumonia) is a lower respiratory tract infection which sometimes progresses to pneumonia. tb and pneumonocytis carynia are especially problematic for aids patients. other organisms causing pneumonias include chlamydia pneumoniae, h. influenza, klebsiella pneumonia, escherichia coli, staphylococcus, rickettsia (q fever), and legionella. parasitic infestation of lungs may occur with nematodes (e.g., ascariasis). fungal infections of the lung may be caused by aspergillosis, histoplasmosis, and coccidiomycosis, often as a complication of antibiotic therapy. access to primary care and early institution of treatment are vital to control excess mortality from aris. in developed countries, aris as contributors to infant deaths are largely a problem in minority and deprived population groups. because these groups contribute disproportionately to childhood mortality, infant mortality reduction has been slower in countries such as the united states and russia than in other industrialized countries. the continuing gap in mortality rates between white and black children in the united states can, to a large extent, be attributed to aris and less access to organized primary care. children are brought to emergency rooms for care when the disease process is already advanced and more dangerous than had it been attended to professionally earlier in the process. many field trials of ari prevention programs have been proved successful involving parent education and training of primary care workers in early assessment and, if necessary, initiation of treatment. this needs field testing in multiple settings. reliance on vaccines to prevent respiratory infectious diseases is not currently feasible. aris are caused by a very wide spectrum of viruses, and the development of vaccines in this field has been slow and limited. the vaccine for pneumococcal pneumonia has been an important breakthrough, but it is still inadequately utilized by the chronically ill because of its limitations, costs, and lack of sufficient awareness, and it is too expensive for developing countries. improvements in bacterial and viral vaccine development will potentially help to reduce the burden of aris. a programmatic approach with clinical guidelines and education of family and care givers is currently the only feasible way to reduce the still enormous morbidity and mortality from aris on the young and the elderly. the success of sanitation vaccines and antibiotics led many to assume that all infectious diseases would sooner or later succumb to public health and medical technology. unfortunately, this is a premature and even dangerous assumption. despite the longstanding availability of an effective and inexpensive vaccine, the persistence of measles as a major killer of million children per year represents a failure in effective use of both the vaccine and the health system. the resurgence of tb and malaria have led to new strategies, such as managed or directly observed care, with community health workers to assure compliance needed to render the patient noninfectious to others and to reduce the pool of carriers of the disease. current successes in reducing poliomyelitis, dracunculiasis, onchocerciasis, and other diseases to the point of eradication has raised hopes for similar success in other fields. but there are many infectious diseases of importance in developed and developing countries where existing technologies are not fully utilized. oral rehydration therapy (ort) is one of the most cost-effective methods of preventing excess mortality from ordinary diarrheal diseases, and yet is not used on sufficient scale. biases in the financing and management of medical insurance programs can result in underutilization of available effective vaccines. hospital-based infections cause large-scale increases in lengths of stay and expenditures, although application of epidemiologic investigation and improved quality in hospital practices could reduce this burden. control of the spread of aids using combined medical therapies is not financially or logistically possible in many countries, but education for "safe sex" is effective. community health worker programs can greatly enhance tuberculosis, malaria, and std control, or in aids care, promote prevention and appropriate treatment. in the industrialized and mid-level developing countries, epidemiologic and demographic shifts have created new challenges in infectious disease control. prevention and early treatment of infectious disease among the chronically ill and the elderly is not only a medical issue, it is also an economic one. patients with chronic obstructive lung disease (copd), chronic liver or kidney disease, or congestive heart failure are at high risk of developing an infectious disease followed by prolonged hospitalization. public health has addressed, and will continue to stress the issues of communicable disease as one of its key issues in protecting individual and population health. methods of intervention include classic public health through sanitation, immunization, and well beyond that into nutrition, education, case finding, and treatment, and changing human behavior. the knowledge, attitudes, beliefs, and practices of policy makers, health care providers, and parents is as important in the success of communicable disease control as are the technology available and methods of financing health systems. together, these encompass the broad programmatic approach of the new public health to control of communicable diseases. in a world of rapid international transport and contact between populations, systems are needed to monitor the potential explosive spread of pathogens that may be transferred from their normal habitat. the potential for the international spread of new or reinvigorated infectious diseases constitute threat to mankind akin to ecological and other man-made disasters. the eradication of smallpox paved the way for the eradication of poliomyelitis, and perhaps measles, in the foreseeable future. new vaccines are showing the capacity to reduce important morbidity from rubella syndrome, mumps, meningitis, and hepatitis. other new vaccines on the horizon will continue the immunologic revolution into the twenty-first century. as the triumphs of control or elimination of infectious diseases of children continue, the scourge of hiv infection continues with distressingly slow progess an effective vaccine or cure for the disease it engenders. partly as a result of the hiv/ aids, tb staged a comeback in many countries where it was thought to be merely a residual problem. at the same time an old/new method of intervention using directly observed short-term therapy has shown great success in controlling the tb epidemic. the resurgence of tb is more dangerous in that mdrtb has become a widespread problem. this issue highlights the difficulty of keeping ahead of drug resistance in the search for new generations of antibiotics, posing a difficult challenge for the pharmaceutical industry, basic scientists as well as public health workers. the burden of infectious diseases has receded as the predominant public health problem in the developed countries but remains large in the developing countries. with increases in longevity and increased importance of chronic disease in the health status of the industrial and mid-level developing nations, the effects of infectious disease on the care of the elderly and chronically ill is of great importance in the new public health. long-term management of chronic disease needs to address the care of vulnerable groups, promoting the use of existing vaccines and antibiotics. most important is the development of health systems that provide close monitoring of groups at special risk for infectious disease, especially patients with chronic diseases, the immunocompromised, and the elderly. the combination of traditional public health with direct medical care needed for effective control and eradication of communicable diseases is an essential element of the new public health. the challenge is to apply a comprehensive approach and management of resources to define and reach achievable targets in communicable disease control. access to e-mail and the internet are vital to current practice of public health and nowhere is this more important than in communicable diseases. there are many such information sites and these will undoubtedly expand in the coming years. several sites are given as examples. the internet has great practical implications for keeping up to date with rapidly occurring events in this field. outstanding encyclopedia database on infectious diseases (available via mdcassoc@ix.netcom.com at reduced price for promed users, and free to sub-saharan african sites) promed is an excellent, free report on current events in communicable diseases internationally; join via owner-promed @usa recommended readings centers for disease control. . update: international task force for disease eradication addressing emerging infectious disease threats: a prevention strategy for the united states. executive summary update: trends in aids incidence--united states one thousand days until the target date for global poliomyelitis eradication tuberculosis morbidity--united states measles--united states, . morbidity and mortality weekly report national adult immunization awareness week--october - , recommended readings ; and influenza and pneumococcal vaccination levels among adults aged --- years impact of the sequential ipv/opv schedule on vaccination cover-agemunited states advances in global measles control and elimination: summary of the international meeting recommended childhood immunization schedulemunited states impact of vaccines universally recommended for childrenmunited states progress toward global poliomyelitis eradication global disease elimination and eradication as public health strategies childhood immunizations rotavirus vaccines: who position paper. weekly epidemiologic record infectious diseases of humans: dynamic and control vaccines and world health: science, policy, and practice control of communicable diseases manual jawetz, melnick and adelberg's medical microbiology, twenty-first edition preventive medicine and public health, second edition efficacy of bcg vaccine in the prevention of tuberculosis. meta-analysis of the published literature manson's tropical diseases vaccination and world health principles and practice oflnfectious diseases immunization of adolescents: recommendations of the advisory committee on immunization practices, the american academy of pediatrics, the american academy of family physicians and the combination vaccines for childhood immunization: recommendations of the advisory committee on immunization practices, the american academy of pediatrics, the american academy of family physicians and the poliomyelitis prevention: revised recommendations for use of inactivated and live oral poliovirus vaccines diphtheria outbreakmrussian federation rubella and congenital rubella syndrome~united states compendium of animal rabies control, : national association of state public health veterinarians progress toward elimination of haemophilus influenzae type b disease among infants and children in the united states tetanus surveillance~united states, - recommendations and reports--vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of measles: recommendations of the advisory committee on immunization practices national, state and urban area vaccination coverage levels among children aged - months~united sates varicella related deaths among children--united states progress toward global poliomyelitis eradication ten great public health achievements--united states a ten-year experience in control of poliomyelitis through a combination of live and killed vaccines in two developing areas measles control in developing and developed countries: the case for a two-dose policy integration of vitamin a supplementation with immunization. weekly epidemiological record update cholera--western hemisphere, . morbidity and mortality weekly 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drugs in the management of acute diarrhoea in children world health organization. . the malaria situation in aids: images of the epidemic. geneva: who. world health organization progress toward the elimination of leprosy as a public health problem the world health report : fighting disease, fostering development the world health report health for all in the twenty-first century. eb / . geneva: who. world health organization. . the world health report : life in the twenty-first century: a vision for all world health organization. . the world health report : making a difference key: cord- - ob okeh authors: feng, tianjun; keller, l. robin; wang, liangyan; wang, yitong title: product quality risk perceptions and decisions: contaminated pet food and lead‐painted toys date: - - journal: risk anal doi: . /j. - . . .x sha: doc_id: cord_uid: ob okeh in the context of the recent recalls of contaminated pet food and lead‐painted toys in the united states, we examine patterns of risk perceptions and decisions when facing consumer product‐caused quality risks. two approaches were used to explore risk perceptions of the product recalls. in the first approach, we elicited judged probabilities and found that people appear to have greatly overestimated the actual risks for both product scenarios. in the second approach, we applied the psychometric paradigm to examine risk perception dimensions concerning these two specific products through factor analysis. there was a similar risk perception pattern for both products: they are seen as unknown risks and are relatively not dread risks. this pattern was also similar to what prior research found for lead paint. further, we studied people's potential actions to deal with the recalls of these two products. several factors were found to be significant predictors of respondents’ cautious actions for both product scenarios. policy considerations regarding product quality risks are discussed. for example, risk communicators could reframe information messages to prompt people to consider total risks packed together from different causes, even when the risk message has been initiated due to a specific recall event. the year was called "the year of the recall" due to the recalls of pet food and children's toys in the united states. ( ) in particular, the pet food contamination crisis led to the widespread recall of more than , pet food products, mainly from menu foods, beginning in march . ( ) according to the u.s. food and drug administration (fda) newsletter, ( ) as of april , , the fda had received consumer reports of approximately , deaths of dogs and , deaths of cats with cases confirmed. further investigation revealed that, though not yet proven, the presence of melamine and melamine-related compounds, such as cyanuric acid, in the ingredients of the affected food appears to be the cause of kidney failure that killed thousands and sickened tens of thousands of pets. meanwhile, on august , , the toy-making giant mattel recalled , toys, including dora the explorer and sesame street toys, due to violations of lead paint standards, which was followed by a rash of toy recalls in august and september . ( ) children who suck on or ingest toys with high lead content may have elevated blood lead levels and may get lead poisoning. this can lead to learning and behavior problems, and at very high levels, seizures, coma, and even death (u.s. centers for disease control and prevention (cdc)). we are interested in how consumers perceive the quality risk of a product under threat of recall and how they make a decision about actions to take upon hearing news of an actual or threatened product recall. here, product quality risk refers to the risk of a product (e.g., health, financial, safety risk, etc.) caused to customers and generated by its inherent quality problems (e.g., in raw materials, ingredients, production, logistics, or packaging). we examine risk perceptions and decisions using the contaminated pet food and lead-painted toys as examples in the same study for a number of reasons. first, pets and children are vulnerable members of a household that adults have a responsibility to protect. second, both involved potentially serious health threats. third, the recalls occurred in the same time span. finally, both products originated in china and were destined for the u.s. market. for these two recalls, there was a great deal of media attention, including anecdotal stories of relatively extreme actions by consumers. for instance, in response to the recall of lead-painted toys, some parents were so concerned and scared that they tested all of their children's toys for lead and threw away the toys on the recall list. ( ) for regulators, consumers, and the companies in the supply chain for these products, it will be valuable to understand the components of people's reactions to such events. this line of work should be helpful in future recalls of other products to gain a quick understanding of likely patterns of consumer reactions. to explore risk perceptions of these two product recalls, we used two approaches that have been widely adopted in the risk perception literature. the first approach was to elicit judged probabilities of the adverse quality risk with respect to these two product recalls. ( , ) specifically, we elicited judged more information about children's risks and opportunities to manage them can be found at http://www.kidsrisk.harvard.edu/, a project created and directed by professor kimberly thompson at the harvard school of public health. the public tends to have different perceptions and attitudes toward risks faced by children and adults, respectively, ( ) and probably the same is true for humans and pets. in addition, while our study focused on making decisions on behalf of a child or a pet, similar decisions might also apply when made for adults (e.g., johnson et al.) . ( ) probabilities that ( ) a dog will die from eating contaminated dog food within the next month (in the case of the dog food recall) and ( ) an under-sixyear-old child will have elevated blood lead levels from playing with lead-painted toys within the next couple of months (in the case of the children's toys recall). we then examined biases in judged probabilities of quality risks of these two products due to using a packed frame (lumping together multiple items) or unpacked frame (listing items separately). we chose to investigate this since companies or regulators in future recall crises would have the ability to frame probability information and other messages using packed or unpacked probability frames. people tend to have an overall higher judged probability for a focal event's occurrence when the description of an event is unpacked into its individual components. ( − ) also tversky and kahneman ( ) showed that when a described specific case seems very representative of a general category, this "representativeness" may lead to higher judged probabilities. in this study, an adverse health effect from the recalled product may be incorrectly seen as more likely to occur than that same health effect from any cause. in the second approach, we applied the wellknown psychometric paradigm ( − ) developed by slovic and his colleagues to further examine risk perceptions of the two product recalls. this approach has been widely adopted to understand and predict people's responses to various risks by identifying similarities and differences among those risks. analyzing newly arising risks and comparing them with existing ones along a number of dimensions will help policymakers understand each new risk and potentially help the general public accurately perceive the risks. accordingly, we considered eight hazardous products and risky situations, including the two recalled products and six additional risks spanning sickness risks from food and nonfood consumer products, on seven qualitative rating scales. the six comparison risks include avian flu (because it poses severe health risks to both birds and humans), ( − ) mad cow disease (bovine spongiform studies of perceived health risks of various human food products have been done on modified food, ( − ) organic food and conventional food, ( − ) salmonella food poisoning, ( ) and general food safety issues. ( − ) little or no attention in this stream of work has been on pet food. perceived health and safety risks of technologies have been done on gene technology, ( ) biotechnology, ( ) nuclear power, ( ) environmental risk and technology, ( − ) and other technologies. ( ) , which has raised consumer anxiety about beef consumption, ( − ) severe acute respiratory syndrome (sars), contaminated spinach, smoking cigarettes, ( − ) and cell phone radiation. this allows us to establish the risk perception map, which helps investigate how these newly recalled products score on factors shown in the past to influence risk perception and how they compare with the six comparison risks. as discussed before, both recalled products originated in china. the well-documented country-oforigin literature emphasizes that a product's origin plays an important role in consumers' perceptions of the product. ( ) thus, we conjecture that the country of origin may influence risk perceptions of the two contaminated products. in this study, we examined this issue for four original sources of products (the united states, china, japan, and mexico). finally, it has been shown that risk perceptions influence people's decisions in risky situations. ( , ) accordingly, we examined people's actions in response to the product recalls. for example, a pet owner may choose to gain more information about the recalls before taking further actions, or a child's parents may decide to throw away all toys at home when they hear about the recall announcements. further, we identified the factors most predictive of their cautious actions. our survey had three versions depending on the information format of the focal events. table i shows the main difference between these three versions of the survey. first, we asked all participants to think about dogs that had eaten the contaminated dog food. in version a, one group of participants reported their estimate of the probability of one of those dogs dying due to eating the contaminated dog food. the version b group was asked what the probability is of one of those dogs dying (with no cause mentioned). in contrast, the version c group received an unpacked framing of the question in version b, in which they judged the probability of one of those dogs dying from eating contaminated food and then judged the probability of one of them dying from other causes. the question design of these three versions was similar for the scenario of lead-painted children's toys, except that we asked respondents to estimate the probability of one of those under-sixyear-old children having elevated blood lead levels (from playing with lead-painted toys, from unspecified causes, or from other causes). each participant received the same version of the questions for both the food and toy scenarios. all the other questions in the survey were the same across all participants, including questions on the characterization of perceived quality risks on various dimensions and on trust in the original sources of products. several other short questions were designed to measure participants' knowledge and actions toward the recalls of contaminated pet food and lead-painted children's toys. to identify there are several other causes that could lead to elevated blood lead levels for young children. according to the case studies from the u.s. center for disease control (cdc), the primary source of lead exposure to children in the united states is leadcontaminated household dust. landrigan ( ) claimed that childhood lead poisoning is the major factor that contributes to the costs of all pediatric environmental disease in the united states, which amount to approximately $ . billion every year. determinants that are significant predictors of respondents' potential actions, we also asked for information about demographic characteristics, such as gender and personal experience with dogs or cats. two hundred and five survey participants, ranging in age from to , were recruited from the human subject pool at the university of california, irvine. (in total, respondents, all enrolled in undergraduate classes, participated in our study. among them, five participants did not complete their survey and thus were removed from the data analysis.) they were randomly assigned to three groups of , , and participants for versions a, b, and c. note that college student samples have been used in several prior risk perception papers. ( − ) participants received one hour of course extra credit. table ii provides the demographic data. eighty-eight percent of the participants were female. approximately % of the respondents and their families have had - dogs and % of them have had more than two dogs. nearly % of the respondents do not have siblings under six years old, but % of them had been a babysitter. survey data were collected through surveymonkey.com, recorded in a microsoft excel spreadsheet and analyzed using the spss statistical software. participants took about to minutes to complete this online survey. statistical analyses included tests of differences in means, factor analysis, anova, multiple regression, and logistic regression. for comparability, a common set of independent variables was used to estimate all regression models. after reading a short description of both the food and toys recalls, respondents gave an estimate of how many dogs died in the united states from contaminated dog food in and how many undersix-year-old children got elevated levels of lead in their blood in the united states from playing with lead-painted toys in . the median responses on these two questions were , dogs (mean: , , sd: , ) and , children (mean: , , sd: , , ), respectively. note that for pet food, approximately , dog deaths were attributed to the contaminated food, according to the fda. the large standard deviations indicated that respondents held varied opinions about impact of the recalled products. trust in institutions is closely related to subjective risk judgments regarding human food quality risks. ( , , ) an individual who trusts less in institutions for food quality information tends to perceive a higher probability of risk. using three -point rating scales, we also asked questions related to participants' trust in institutions, information while this uneven gender distribution was partly due to the fact that female students account for a majority of the university's human subject pool, we believe that such a distribution would also hold for pet food and children's toy shoppers. participants selfselected the experiments they would participate in. those selecting our study were told: "we are conducting a study on how people react to product quality related crises, with a focus on the recent recalls of contaminated pet food and lead-painted children's toys." we further analyzed the relationship between participants' gender and their subjective probability judgment for all three versions, and we did not find significant differences. therefore, we conducted the analyses based on the pooled data from both male and female respondents. sufficiency, and overall concerns about these product quality risks, as shown in table iii . respondents had a fairly good level of trust in the information that the authorities provided on both food (mean = . out of , where is full trust) and toys (mean = . ), but did not think that they had fully received enough information for either recall (mean = . for food, and mean = . for toys). participants were highly concerned about the safety of dog food (mean = . ) and had significantly more concern about toys (mean = . , p < . ). since respondents had a relatively high level of trust in the authorities and concern about these products' safety, but felt they did not have enough information, government agencies and companies could provide people with more information to aid them in making more informed decisions. we first elicited judged probabilities in response to the two product recalls, which are shown in table iv . in survey version a, participants gave an estimate of the number of dogs dying from eating the food within the next month. for instance, if an estimate was , , this participant's judged probability of dogs dying from eating the contaminated food was % = , / , (i.e., participants were told in the survey to suppose that , dogs ate the same contaminated dog food). a similar structure was used for toys. thus, using version a, we elicited participants' subjective probabilities for the two scenarios and found that the mean judged probability of dogs dying from eating the contaminated food was . % and the mean judged probability of children having higher blood lead levels from lead-painted toys a version c (unpacked condition) had a significantly higher mean judged probability than version b (packed condition) at the % level using a t-test (p = . for contaminated dog food and p = . for lead-painted toys). was . %. we believe that our participants tended to overestimate their probability judgments for the potential adverse reactions with these two recalls. this is very likely due to the availability heuristic, ( ) which states that people predict the frequency and probability of an event by the extent to which occurrences of that event are easily "available" in memory. clearly, there was extensive media coverage on the two product recalls during the recall crisis and thus adverse examples could be readily brought to mind for respondents. note that a similar pattern has also been observed in the prior literature on risk perception. for example, by using a large-scale national survey, viscusi ( ) found that both smokers and nonsmokers significantly overestimated the lung cancer risk of cigarette smoking. interestingly, when participants focused on the adverse effects due to the recall event (version a), their answers were higher than when they considered all adverse effects from any cause (version b). this may be seen as falling prey to the representativeness according to the u.s. pet ownership & demographics sourcebook, ( ) there are approximately , , pet dogs in the united states, so roughly every fourth person owns a pet dog (the total population of the united states by july , was around , , based on the population estimates from the u.s. census bureau). the fda received reports that about , dogs died from eating contaminated food with cases confirmed, including the confirmed deaths of cats. assume that only . % of the dogs in the united states had eaten the contaminated dog food during the recall crisis in , which is a relatively low estimate since several major pet food manufacturers recalled more than , products, with most of the recalls coming from menu foods, the largest maker of wet dog and cat food in north america. then the "actual" probability of a dog dying from eating the contaminated food would be as low as . % (i.e., , / , = . %). as a result, respondents apparently generally overestimated the probability of a dog dying from eating the contaminated food. in the case of children's toys, although the real data about the number of under-six-year-old children who had elevated blood lead levels from playing with lead-painted toys during the recall were not available, we suspect that respondents' judged probabilities were higher than the actual probabilities. in , mattel inc., the world's largest toy company, recalled over million chinese-made toys, including dolls, cars, and action figures. from this, one might expect that at least several millions of children could have played with the lead-painted toys. on the other hand, there was very little news coverage on the reports of children's lead poisoning cases due to playing with the lead-painted toys in . consequently, we are led to believe that the actual probability of an under-six-year-old child having elevated blood lead levels from playing with lead-painted toys would be much lower than . %. we are grateful to an anonymous referee for this suggestion. it is possible that participants tend to err on the high side since pets and children are vulnerable in general and there is no cost to overestimating. heuristic of tversky and kahneman. ( ) more specifically, since the vivid and recent stories about product recalls seem to represent well the category of dog deaths or sources of lead paint for children, when people were asked just about adverse effects of the recall event in version a, the high representativeness of the recall to the category may have led to higher probability estimates. in contrast, in version b, the general set of causes of the adverse event may not have been very available in people's imagination, and thus their estimates for the probability of the larger category of adverse events from all causes may have been lower, since it might have been harder to bring to mind other instances of the adverse event not from the recalls. next, we examined biases in judged probabilities of quality risks of these two products due to using a packed frame or unpacked frame. in version b, participants estimated the number of those dogs dying within the next month. since those dogs might die from other possible causes in addition to the contaminated food in the next month (e.g., natural death from aging, dying from a car accident, etc.), version b is a packed frame of the focal event of death. in contrast, version c is an unpacked frame, in which participants explicitly provided an estimate of the number of those dogs dying from eating contaminated food and the number of those dogs dying from other causes. by comparing responses between versions b and c, we examine biases in probabilities due to packing or unpacking of the focal event. for children's toys, we asked respondents to think about those under-six-year-old children who played with the lead-painted toys. hence the focal event in the scenario of lead-painted toys is that an under-sixyear-old child has a higher blood lead level from any cause within the next couple of months. shown in table iv , in the packed condition (b) of the contaminated dog food scenario, the mean probability of dogs dying (from any cause) was . %, while the mean probability of dogs dying from any cause calculated by summing the responses for food-caused and other deaths in the unpacked condition (c) was significantly higher ( . %, t = . , d.f. = , p = . ). the pattern also held in the lead-painted toys scenario (t = . , d.f. = , p = . ). specifically, the mean probability in the packed condition and unpacked condition was . % and . %, respectively. so our result is consistent with support theory ( ) in that people tend to judge an overall higher probability when the description of the focal event is unpacked. this suggests that extensive recall publicity that may focus people's attention on the focal recall event, and thus lead them to mentally unpack adverse health effects into different causes, could lead to overestimating the actual probability. using the psychometric paradigm, we now examine the ratings on seven risk perception dimensions of eight hazardous products or risky situations, including contaminated dog food, lead-painted toys, contaminated spinach, avian flu, mad cow disease, sars, cell phone radiation, and cigarette smoking. we chose to examine contaminated spinach, since it is a contaminated food, like the dog food. we chose to examine sars, avian flu, and mad cow disease since they are health risks beginning in outbreaks outside of the united states with the potential to spread to the united states, like both the dog food and toys. (contaminated beef from mad cow disease could be seen as contaminated food or as a disease without the focus on food.) we chose to examine cell phones and smoking since they involve nonfood consumer products with ear/mouth/nose contact leading to possible adverse health effects, like the toys. for some items, we provided participants with a onesentence description. the seven -point psychometric scales reflecting risk characteristics have been used to characterize perception of risk in previous research. ( , ) the potential influence of these dimensions was suggested in early risk research, ( , ) verified by fischhoff et al. ( ) and applied widely in further work, such as slovic et al. ( ) and mcdaniels et al. ( ) table v describes the seven rating scales of controllability, dread, severity of consequences, voluntariness, known to the exposed, immediacy of effect, and risk newness. four items were described. the contaminated spinach outbreak occurred in september and people faced a risk of getting sick or even dying due to infection from eating uncooked spinach with e. coli bacteria. ( ) avian flu refers to an illness mainly caused by the influenza subtype h n virus adapted to birds and it could lead to clinically severe and fatal human infections through bird-to-human transmissions. ( ) mad cow disease, also known as bse, is a degenerative neurologic disease of cattle that affects the central nervous system and humans could have degeneration of physical and mental abilities, and ultimately die from eating contaminated beef. ( ) severe acute respiratory syndrome (sars) is a viral respiratory disease in humans caused by the sars coronavirus and this highly contagious virus could cause substantial illness and death among the general population. ( ) the mean ratings on the risk dimensions for the eight risks are shown in table vi . among the eight risks, contaminated dog food had the highest mean ratings on the - scale on the dimensions of unknown to the exposed (mean = . , where = precisely known to the dog owners) and newness (mean = . where = old), but the lowest mean ratings in terms of dread (mean = . , where = not dreaded). compared to other contaminated food for human consumption (i.e., spinach and beef), respondents viewed the risk of contaminated dog food to be the least dread. the lead-painted toys were the third most unknown (mean = . ), third most new (mean = . ), and second least dread (mean = . ). meanwhile, sars was rated to be the most uncontrollable risk (mean = . ), the most dread risk (mean = . ), the risk with the most fatal consequence (mean = . ), the most involuntary risk (mean = . ), and the risk of the most immediate effect (mean = . ). this was likely because of the extensive media coverage on the rapidly increasing number of infected cases and death during the outbreak of sars between november and july . in contrast, perhaps due to its prevalence in the general population, cigarette smoking received the lowest ratings on four scales, including controllability (mean = . ), voluntariness (mean = . ), known to the exposed (mean = . ), and newness (mean = . ). cell phone radiation was seen to be the least fatal (mean = . ) and to have its negative effect delayed the most (mean = . ). table vii provides the intercorrelations among the mean ratings of the seven risk characteristics. there were high associations between many scales and no association between a few others (e.g., dread and known to the exposed, r = . ). given that there were sufficiently high intercorrelations for several pairs of the seven risk characteristics, we conducted a principal component factor analysis with a varimax rotation to seek any key factors underlying the seven risk characteristics. the seven characteristics loaded onto the two factors displayed in table viii . the two orthogonal factors explained almost % of the variance, which was sufficiently high to account for the observed intercorrelations. factor was highly correlated with all risk characteristics except risk dread and severity of consequence. factor was highly correlated with both the risk's severity of consequence and risk dread, and moderately highly associated with risk controllability, though a little bit lower than the two risk characteristics mentioned above. thus, as used in the previous literature, we refer to factor as the "unknown risk factor" and factor as the factor of "dread risk." ( , ) following the procedures of slovic et al., ( ) we computed two factor scores for each risk item by weighting the ratings on each risk scale proportionally to the scale's importance in determining each factor and then summing across all scales. note that respondents' ratings on each risk dimension were recoded from the - scale into a scale with endpoints − and , with a midpoint , to highlight the relationship between responses and the scale midpoints. fig. depicts the relative position of each of the eight risks within the two-factor space, with factor on the vertical axis (i.e., "unknown risk") and factor on the horizontal axis (i.e., "dread risk"). this figure is also known as a risk perception map in the literature. ( , ) the upper extreme of factor is associated with risk being unknown, new, involuntary, uncontrollable, and having delayed consequences. items at the far right of factor are construed as dread, having fatal consequences, new, and uncontrollable. from fig. , we observe that contaminated dog food and lead-painted toys almost overlapped in the upper left quadrant, with both being perceived as moderately unknown and relatively neutral on the scale of dread to not dread risks. their location is similar to that found in prior work for lead paint. ( , ) cell phone radiation was also in this quadrant. the most extreme item in the upper right quadrant was sars, which was perceived as highly unknown and dread. in that quadrant, avian flu had a pattern similar to sars, except that it was seen as slightly less dread. one possible explanation is that both of them were contagious diseases and had recently broken out primarily in asia. the two contaminated human food items, mad cow disease (i.e., contaminated beef) and contaminated spinach, were also located in this upper right quadrant. respondents perceived nearly the same level of un-known risks for both contaminated human food and pet food and they considered contaminated human food to be more dread than contaminated dog food. cigarette smoking was located at the lower left quadrant, seen as rather known and slightly not dread. this is consistent with the pattern of smoking found previously. ( , ) finally, note that none of the eight items considered in this study was included in the lower right quadrant, in which risks were perceived to be known but dread (e.g., handguns were found to be located in this quadrant in prior research). ( , ) in this section, we examine country-of-origin effects on risk perceptions of the two contaminated products. specifically, using a -point scale, we asked participants to rate how much they trust products made in the united states, china, japan, and mexico in terms of health and safety risks, how much they are satisfied with those products in terms of a good affordable price with decent product quality, and how much they are satisfied with those products in terms of product quality. as shown in table ix , there were significant differences in the respondents' evaluations between the four countries for each of the three ratings scales above based on an anova. this is consistent with the literature that country of origin has a strong influence on perceived quality or product evaluation. ( , ) moreover, through tukey's tests, we found that for each of the three scales, the united states and japan on average received significantly higher ratings than both china and mexico. however, for each of the three scales, there was no significant difference between the two developed countries, the united states and japan. similarly, between the two developing countries, china and mexico, we might have found insignificant differences since china and mexico were the second a the hypothesis that the means of these three scales between the four countries are equal was rejected at the % level using anova. and third largest countries that the united states imported products from in , with each country accounting for . % and . % of the u.s. annual total imports, respectively (according to the u.s. census bureau, the year report of ). but, interestingly, we found that respondents had significantly higher (more favorable) ratings of products made in china than those of products made in mexico for all three rating scales despite the fact that the focus of our study was on recalled pet food and children's toys that were made in china. we provide an alternative explanation as follows. prior literature suggested that differences in economic development or industrialization levels are an important factor in accounting for the country-of-origin effect, that is, the higher the level of economic development or industrialization, the more favorable is the perception of the quality of its workers, as well as the perceived quality of its products. ( − ) despite the privileged tariff status set by the north american free trade agreement, mexico appears to be losing its u.s. export marketing shares; whereas with its accession to the world trade organization, china has played a very important role in today's world economy, that is, china has become the world's third largest economy since , behind only japan and the united states (cnn news, january , ). this might lead to a difference in people's perceived quality between products made in china and products made in mexico. more interestingly, we found that there was a significant difference in perception of products from asian countries between the asian-american and non-asian-american subjects. the general quality index of products from each country was considered by averaging respondents' ratings of products made in that country on the three scales above, where represents "do not trust/not satisfied," and represents "fully trust/satisfied." specifically, asian- nearly half of the respondents were asian americans in our study (note that according to the undergraduate profile of university of california, irvine, in fall , our sample was quite representative in terms of distribution by race). although we did not ask our subjects how long their family had been in the united states, one may expect a difference in risk perception based on how many years their family has been in the united states, or even a difference in risk perception among different generations of family members. wong-kim et al. ( ) suggested that length of stay in the united states and fluency with the english language affected people's beliefs. bonin et al. ( ) found that there was a difference in risk preference between first-generation immigrants (born abroad) and the second generation (born in the immigrated country). future studies could investigate this. american respondents had significantly lower general quality ratings of products made in china (mean = . ) than non-asian-american respondents (mean = . ) (p < . ). on the contrary, products made in japan received significantly higher ratings from asian-american respondents (mean = . ) relative to non-asian-american respondents (mean = . ) (p < . ). we did not find a significant difference in perceived quality of products made in the united states or mexico between these two groups. this finding makes a contribution to the country-of-origin literature and complements results from public opinion surveys. respondents' possible actions to deal with the product recalls are in table x . participants said they would take a variety of actions when they were asked what they would do with the pet food or the toys at home when they heard about recalls of contaminated pet food and lead-painted children's toys. the pattern was similar for food and toys in that the top three options for both scenarios included "check websites for more information," "read/listen to news coverage," and "throw away all dog food/toys," each of which had more than % of the respondents selecting it. (some participants provided other alternatives, such as "take dogs to the vet for checkup," "purchase dog food without contaminated ingredients," "test child for lead poisoning," "return item and ask for refund," "put them away for a period of time until i have more information about the topic," "sue toy makers if my child has been poisoned," etc.) this suggested that when faced with a product recall event, people may collect more information about the product itself before taking any further actions or simply proceed to take cautious actions (i.e., our results on perceptions of country sources are fairly consistent with other surveys of adult consumers in the united states. in the context of imported food, dewaal ( ) found of the survey respondents who answered a question to place countries/regions in order of concern from greatest to least concern, on average gave the order of china (greatest concern), mexico, european union, australia, canada (least concern). similarly, weise ( ) reported on a usa today/gallup poll of adults (who shop for groceries) showing that products "from china rank highest on those shoppers' suspicion scale: % are concerned about food from china, compared with % concerned about foods from mexico and % concerned about foods from the usa." what would you do with the dog food at your home when you heard that some dog food has recently been contaminated? check all that apply. • check websites for more information * % contaminated • throw away all dog food * % • read/listen to news coverage * % pet • talk with friends about what their experience is with this issue % • cook dog food from fresh ingredients % food • trust store to remove recalled items % • modify use (e.g., give food to bigger dogs, not puppies) % • other % what would you do with the toys at your home when you heard that some toys have recently been recalled due to lead-paint? check all that apply. • check websites for more information * % lead • read/listen to news coverage * % • throw away all toys * % painted • talk with friends about what their experience is with this issue % • test toys for lead % toys • trust store to remove recalled items % • wash toys % • modify use (e.g., give toys to bigger kids, not infants/toddlers) % • other % * actions in bold italic font were selected by more than % of respondents. dispose of the products before complete information has been obtained). we were interested in identifying the determinants of respondents' cautious actions to "throw away all dog food/toys." thus we developed two logistic regression models using maximum likelihood estimation to determine the factors most predictive of their cautious actions for both the contaminated dog food scenario and the lead-painted toys scenario based on the data in version a. table xi shows the results from the two logistic regression models. from this table, we can see that both models had moderate explanatory power in predicting respondents' actions to "throw away all dog food/toys." specifically, respondents' subjective probabilities were found to be a consistent predictor of their cautious actions to "throw away all dog food/toys" at the . level for both product scenarios (wald statistic = . , p = . for dog food, and wald statistic = . , p = . for toys). for example, respondents who had higher subjective probabilities were more likely to choose cautious actions, that is, throwing away all dog food/toys. several other factors were found to be significant predictors in specific product scenarios. in the logistic regression model for the dog food scenario, race was a significant predictor of throwing away all dog food at the . level (wald statistic = . , p = . ), that is, asian-american respondents were more likely to choose to throw away all dog food than non-asian-american participants. this is consistent with the previous country-of-origin finding that asian-american respondents perceived significantly lower quality for products made in china (where the recalled dog food was from) than their non-asian-american counterparts. two of the seven risk dimensions were found to be significant predictors of throwing away all dog food at the . level. dread was positively associated with throwing away all dog food (wald statistic = . , p = . ), which implies that respondents who perceived the risk of contaminated dog food to be more dread were more likely to take cautious actions. conversely, newness was negatively associated with this cautious action (wald statistic = . , p = . ), since, for a new risk, respondents might need to know more about it before they decide to throw away all dog food. respondents who more frequently wear a seatbelt when riding in a car were generally more cautious and more likely to choose to throw away all dog food (wald statistic = , p = . ). in the logistic regression model for the children's toys scenario, trust in authorities was positively associated with the cautious action of throwing away the toys (wald statistic = . , p = . ). this implies in the contaminated dog food scenario, the dependent variable is the action of "throw away all dog food." in the lead-painted toys scenario, the dependent variable is the action of "throw away all toys." b = do not trust/not satisfied; = fully trust/satisfied. we averaged respondents' ratings of products made in china on the three scales to be the general quality index of china in both logistic regression models. * significant at . level; * * significant at . level; * * * significant at . level. that respondents who had more trust in the product recall information provided by the government were more likely to adopt cautious actions against potentially contaminated products. the risk being known to those exposed was also found to be a significant predictor of the cautious action of throwing away all toys at the . level (wald statistic = . , p = . ). so, respondents who perceived the risk of lead-painted toys to be known precisely were more likely to throw away the toys. we examined both the pet food and children's toys product recalls in a single study since we felt that both would have similar response patterns, being products for protected household members where their adverse effects come from ingestion via the mouth. when participants focused on the adverse ef-fects due to just the recall event, their probability answers were higher than when they considered all adverse effects from any cause. so, when faced with a product recall event, extensive news coverage could make the public overestimate the actual probability for potential adverse outcomes. thus, companies or regulators could provide information about future recall risks by putting the current risk in perspective by lumping it with other similar risks. a focus on all risks might lead consumers to display less bias in their probability judgments. however, we also found that when risks are unpacked, the probability judgment is higher than when they are packed together. the challenge for risk communication is to reframe information messages to get people to consider total risks from different causes in a lumped together way, even when the risk message has been prompted by a specific recall event. our results also suggest that there might be a paradox in the value of information when people are faced with a product recall event. on one hand, we find that when a recall is publicized, it can lead to greater overestimation of the actual probability for potential adverse outcomes associated with the focal recall event. this implies that more information leads to an upward bias in people's subjective risk judgments. on the other hand, we found that "check websites for more information" is the option that people choose the most during the outbreak of a product recall. that is, more information is desirable for the general public before they make their product use/disposal/repurchase decisions. more empirical research is needed to examine this possible paradox in the effect of added information when product quality risks are involved. our results could also help policymakers frame additional information gathering efforts. questions that could be investigated regarding pet food and toy safety include: at what level of perceived risk would individuals call the emergency ( ) number or the poison control center? when would they use government resources to help mitigate risk? if the government or an agency recommended that they throw out the items, would they comply? are the respondents concerned about the businesses that might suffer from the recall? risk communication has also been examined from a sociological perspective. ( , ) for instance, mileti and fitzpatrick ( ) constructed a model to describe public perception and response to communication about natural hazards risks. they found that additional communications encouraged personal search for more information. more specifically, from the information processing perspective, people's response to hazard information can be divided into eight stages: ( − ) ( ) receiving the warning; ( ) understanding the warning; ( ) believing the warning; ( ) confirming the threat; ( ) personalizing the threat; ( ) determining whether or not protective action is needed; ( ) determining whether protective action is feasible; and ( ) taking protective action. note that although our work originated from a psychological perspective, our study does contribute to several stages in the above framework, such as stage (how probabilistic information is understood in different formats), stage (participants' trust in institutions), and stages , , and (analysis of participants' actions). our results on perceptions of toys with lead paint risks are timely since the united states has recently enacted higher safety standards for toys with lead paint risks via the consumer product safety improvement act (cpsia), which added certification and testing requirements for all products subject to cpsc standards or bans, including lead in paint on toys. this is consistent with consumers' opinions regarding lead paint in toys. however, the cpsc recently issued a one-year stay of enforcement until february , for certain testing and certification requirements of the cpsia for manufacturers and importers of regulated products, including products intended for children years old and younger. the stay of enforcement permitted toy providers to not have to prove they had tested their products, but they were still required to meet the lead standards. food safety also is a continuing public concern. at the national center for food protection and defense, founded in at the university of minnesota, researchers are working on developing best practices for effective risk communications related to potentially catastrophic food bioterrorism incidents from a practice-oriented viewpoint. they have developed a risk communication tool kit and several case studies, including one on the schwan's salmonella crisis ( ) and one on tainted strawberries. ( ) similarly, our findings on country of origin of products are timely, since the u.s. department of agriculture's mandatory country-of-origin labeling program's final regulation became effective on march , , requiring labels for meat, fish, fruits, vegetables, and some nuts. this recent labeling policy is also consistent with consumers' opinions. in addition, the american veterinary medical more specifically, lead paint in toys is of broad concern as demonstrated in the nationwide pew food safety survey ( ), where , u.s. adult interviewees were asked whether they considered "toys for children being made with unsafe materials, such as lead-based paint" to be a serious problem. fifty-seven percent said it was a "serious problem that is fairly common," and % said it was a "serious problem that rarely occurs." a larger percentage felt that toys were a fairly common serious problem than were prescription medications marketed prior to adequate testing ( %), fresh fruits and vegetables contaminated with bacteria that make them unsafe to eat ( %), or automobiles having flaws or faulty parts making them unsafe to drive ( %). for example, among u.s. respondents (who described themselves as interested in food safety) in an august u.s. food safety survey by the center for science in the public interest, . % were very concerned with the safety of domestically produced foods and . % were very concerned with the safety of imported foods. regarding u.s. food safety, % of the consumers in the dewaal ( ) survey were very supportive of association also approved policy changes on june , to use "pet food health claims" to replace the existing policy on "pet food therapeutic claims," which indicated the increasing attention on health aspects of pet food. during the summer of , there was a new food contamination outbreak of the salmonella saint paul strain in the united states, apparently from fresh vegetables. ( ) at first thought to be in tomatoes, later investigations pointed toward jalapeño or serrano peppers grown with contaminated water on a farm in the state of nuevo leon in northeastern mexico as the potential source. ( ) our work can help shed light on such an evolving issue in the multinational food supply chain, both by providing a template for future surveys on evolving risks and by examining our results on the pattern of responses for products from different countries (in this case from mexico) and where other contaminated food items fell in the factor analysis in fig. . contaminated spinach was near dog food on the vertical axis at moderately unknown risk and spinach was a bit more dread than dog food on the horizontal axis. mad cow disease was even more dread. for future recall events, an examination of where the new risk falls on these dimensions could aid in understanding how the public might react. following the recent media focus on product quality risks in the contaminated pet food and leadpainted toy recalls, we examined risk perceptions and decisions related to these two recalls. two approaches were used to explore risk perceptions of the product recalls. in the first approach, we elicited judged probabilities and found that people appear to have greatly overestimated the actual risks for both product scenarios. in the second approach, we applied the psychometric paradigm to examine risk perception dimensions among eight health risks. it was found that the contaminated dog food was most unknown, most new, but least dread. the lead-painted toys were the third most unknown, third most new, and second least dread. examining these results via factor analysis, we found that both contaminated dog food and lead-painted toys were near each other and near contaminated spinach and cell phone radiation in the two-factor space of the risk perception map, country-of-origin labeling. eighty percent would support more detailed labeling, down to region, country, state, and farm. and had similar patterns to what prior research found for lead paint. further, we found that the top three actions would be the same under the scenario of people hearing of pet and child risks: "check websites for more information," "read/listen to news coverage," and "throw away all dog food/toys." as could be expected, a higher subjective probability of quality risks was significantly associated with arguably more cautious actions, such as "throwing away all dog food/toys." taken together, our results suggest that educating consumers about product quality risks can ultimately help them make better informed decisions, based upon more realistic assessments of actual risks. the year of the recall fda limits chinese food additive imports food and drug administration (fda) news alert consumer product safety commission news. mattel recalls various barbie r accessory toys due to violation of lead paint standard valuation of childhood risk reduction: the importance of age, risk preferences, and perspective are adult patients more tolerant of treatment risks than parents of juvenile patients? risk analysis thomas tank engine toy recall angers parents violence risk assessment and risk 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dimensions of country-of-origin evaluations americans' attitudes toward immigrants and immigration: the role of values, social identification, and attitudinal ambivalence assessing cancer beliefs in a chinese immigrant community native-migrant differences in risk attitudes imported food: usda's options for change limited by statute and consumer confidence facing the unexpected: disaster preparedness and response in the united states from the margins to the mainstream? disaster research at the crossroads the causal sequence of risk communication in the parkfield earthquake prediction experiment an integrated model of risk perception and protective action: public response to tornado warnings behavioral foundations of community emergency planning communication of emergency public warnings: a social science perspective and state of the art assessment disasters by design: a reassessment of natural hazards in the united states lessons learned about protecting america's food supply, case studies in crisis communication crisis plans and interagency coordination: lessons learned from tainted strawberries in the school lunch program salmonella "smoking gun" located grown jalapeño and serrano peppers not connected to salmonella saintpaul outbreak the authors gratefully thank the editor michael greenberg, the area editor ann bostrom, and three anonymous reviewers for their extremely thoughtful and constructive reviews, which have significantly helped improve the article. portions of this work were supported by grants to professor tianjun feng from the national natural science key: cord- -s ale ko authors: grant, aubrey title: coronavirus, refugees, and government policy: the state of u.s. refugee resettlement during the coronavirus pandemic date: - - journal: world med health policy doi: . /wmh . sha: doc_id: cord_uid: s ale ko the novel coronavirus pandemic poses unique challenges to forcibly displaced populations around the world. months into the pandemic, countries are still scrambling to enact policies that mitigate the outbreak and minimize the strain on their health‐care infrastructures and economies. the united nations high commissioner for refugees continues to work with member states to provide guidance and assistance to those populations protected under their mandate. however, there is great concern regarding the ability to appropriately provide for displaced populations, as they tend to be hosted in areas that lack access to health care and proper hygiene materials. the situation has been exacerbated by the temporary suspension of refugee resettlement across the globe. in the united states, the trump administration has responded to the crisis by further eroding refugee and asylum resettlement programs and failing to properly protect the asylum seekers currently being detained. at the local level, resettled refugees and asylees have responded to the unique challenges posed by coronavirus by using their skillsets to provide assistance and services to community members in need. the coronavirus, and the trump administration's response, are likely to have long‐term negative impacts on refugee resettlement and asylum programs. the novel coronavirus pandemic poses unique challenges to forcibly displaced populations around the world. months into the pandemic, countries are still scrambling to enact policies that mitigate the outbreak and minimize the strain on their health-care infrastructures and economies. the united nations high commissioner for refugees (unhcr) continues to work with member states to provide guidance and assistance to those populations protected under their mandate. however, there is great concern regarding the ability to appropriately provide for displaced populations, as they tend to be hosted in areas that lack access to health care and proper hygiene materials. the situation has been exacerbated by the temporary suspension of refugee resettlement across the globe. in the united states, the trump administration has responded to the crisis by further eroding refugee and asylum resettlement programs and failing to properly protect the asylum seekers currently being detained. at the local level, resettled refugees and asylees have responded to the unique challenges posed by coronavirus by using their skillsets to provide assistance and services to community members in need. the coronavirus, and the trump administration's response, are likely to have long-term negative impacts on refugee resettlement and asylum programs. on march , , the world health organization recognized the novel coronavirus (covid- ) as a global pandemic (refugees international, n.d.) . at the time of writing, around countries have been affected by the virus (unhcr, b). coronavirus- times more deadly than influenza (krogstad, )-has placed an unprecedented strain on the world's most prosperous countries. governments have grappled with how to handle the challenges posed by the pandemic, urging people to stay home and practice social distancing in one form or another. medical professionals have made it clear that the coronavirus is a serious threat that should be taken seriously by all. however, the data show that the virus impacts certain populations disproportionately. for instance, forcibly displaced populations-including refugees, internally displaced persons, asylum seekers-may be particularly vulnerable to the coronavirus (refugees international, n.d.). forced migration is at record highs in , with around . million people around the world being forcibly displaced. about . million people are internally displaced within their country of origin, . million are forcibly displaced outside of their country of origin (identified as refugees), and . million are seeking asylum in another country (unhcr, ). the population protected by the unhcr has doubled since (unhcr, ) and around percent of refugees are displaced longer than years (unhcr, ). nearly percent of displaced populations are hosted in low-and middle-income countries (unhcr, b) and about percent of refugees live in cities with turkey hosting the largest refugee urban population (usa for unhcr, n.d.). around percent of refugees live in refugee camps, the largest of which are hosted in bangladesh, uganda, kenya, jordan, tanzania, and ethiopia (usa for unhcr, n.d.). each host country faces its own specific challenges in facing a global health crisis due to differences in size, housing infrastructure, and environment. as of march , , countries have been affected by coronavirus; of these countries host refugee populations (unhcr, b). the majority of refugees reside in countries with health-care systems that were already overwhelmed before the outbreak of coronavirus (united nations human rights office of the high commissioner, ). many refugees live in makeshift shelters or reception centers that are overcrowded, with limited access to healthcare services and clean water and/or sanitation (united nations human rights office of the high commissioner, ). against this backdrop, on march , , the unhcr announced that resettlement departures for refugees would be suspended temporarily (unhcr, a, para ). this response was spurred by actions resettlement countries were beginning to take to restrict the entry of international travelers to limit exposure to coronavirus, and out of concern for the safety and health of refugees during the resettlement process. on march , , in response to the unhcr refugee resettlement suspension, it was reported that the trump administration would be temporarily halting refugee admissions, effective march , (alvarez, ) . on march , the centers for disease control and prevention (cdc) issued an order halting the entry of any individual seeking asylum on the canadian or mexican borders due to public health concerns (cdc, ; cms, ; kanno-youngs, shear, & haberman, ). on april , , the cdc extended their march order to suspend entry of persons from "countries where an outbreak of a communicable disease exists" for a minimum of additional days (redfield, ) . two days later, on april , , president trump issued an executive order suspending all immigration to the united states for a minimum of days (trump, n.d.) . the new executive order continues to allow immigration into the united states through the special immigrant visa (siv) program for afghans and iraqis being persecuted for their affiliation with the u.s. military, in addition to allowing nonimmigrant visa entry for students, agricultural workers, religious workers, and high-tech workers (cms, ). these policy shifts and temporary bans have essentially ended refugee resettlement and asylum programs for the foreseeable future, leaving many refugees and asylum seekers in vulnerable, unsafe situations. as of april , , around , refugees had been resettled in the united states (cms, ); the annual ceiling of refugee admissions for set by the trump administration was , -a number the u.s. refugees admissions program (usrap) is unlikely to meet now. with the new restrictions in place, the only refugees currently being resettled are those deemed "emergency cases," or those being relocated from nauru, papua new guinea, and australia through the u.s. australian agreement (cms, ). prior to the coronavirus pandemic the trump administration's cuts to the resettlement program were drastic; the presidential determination of refugee admissions was the lowest in the usrap's history and constituted an percent decrease from the obama administration's presidential determination of , (krogstad, ) . in addition, denying asylum-seekers entry into the united states has created unsafe conditions along the border with mexico. a year ago, the trump administration instituted the migrant protection protocols (mpp), which required most individuals requesting asylum at the u.s. southern border wait in mexico while their case was reviewed (caldwell, ; cms, ) . since the program was enacted, around , individuals have had to wait in mexico for court rulings on their asylum cases (caldwell, ) . to date, there are roughly , cases pending and many others awaiting appeals' decisions (caldwell, ) . although immigrant court hearings have been suspended due to the coronavirus, for individuals in mexico under mpp, the executive office of immigration review (eoir) continues to hold hearings for detained immigrants (cms, ). the united states has the largest immigration detention apparatus in the world, detaining an average of , individuals a day (fox & mckenzie, ) . detention facilities are high-risk environments for communicable diseases; facilities often have unsanitary conditions, poor ventilation, and limited access to hygiene materials (kerwin, ) . in , immigration and customs enforcement (ice) reported around , immigrants had been quarantined across the united states due to outbreaks of the flu, mumps, and other communicable diseases (raff, ) . this is particularly concerning given that the mortality rate for coronavirus is times higher than the flu, and unlike the flu, there is no treatment for coronavirus (fox & mckenzie, ) . in a joint press release from the united nations human rights office of the high commissioner, the international organization for migration, world health organization and united nations high commissioner for refugees expressed concern for detained immigrants and urged governments to release detainees without delay (united nations human rights office of the high commissioner, ). medical professionals in the united states have called on ice to decrease detention populations by transitioning to community-based alternatives (kerwin, ) . as of april , , few detainees have been released and there has been limited testing for those detained. in addition, ice has not been transparent about coronavirus cases in detention facilities, failing to provide statistics on returnees who may have been infected during transit, or infected staff members working at private facilities-where over half of all detainees are held (kerwin, ) . in late march the united states congress passed three legislation packages in response to the pandemic, providing assistance to the health-care industry, businesses, and individuals. the federal legislative actions taken make refugees and immigrants eligible for some benefits and assistance programs. one of these benefits is the economic impact payment, which is distributed by the internal revenue service and is available to lawful permanent residents who classify as a "resident alien" for u.s. income tax purposes (refugee council usa, ). also, refugees and immigrants with work authorizations are eligible for state unemployment insurance and the new benefits instituted by the coronavirus aid, relief, and economic security act (cares act), including the pandemic emergency unemployment compensation, the pandemic unemployment assistance, and the federal pandemic unemployment compensation (refugee council usa, ). these programs offer much-needed relief for eligible immigrants, as foreign-born populations have been disproportionately impacted by the pandemic-induced recession (abraham, grant, spiegel, vazquez, & page, ; capps, batalova, & gelatt, ) . in addition, the cares act allocated $ million to the department of state's migration and refugee assistance (mra) account to provide services, including health care, for refugees both domestically and internationally (cms, ). at the local level, refugees and asylees have taken active roles and used their skills to help communities respond to the coronavirus. many refugees work in positions that have been deemed essential services during the pandemic. more than , refugees work in food processing, more than , work in grocery stores and food markets, and over , refugees work in restaurants and foodservice establishments (new american economy, ). the health-care sector has the second-largest workforce of refugees with . percent of refugees working in the industry (new american economy, ). in health care, refugees make up a significant percentage of frontline workers in states that have historically resettled large numbers of refugees, such as california, texas, and new york. coronavirus has stressed a health-care system that was already dealing with shortages in medical personnel across the united states (osorio, ) . the need for health-care workers prompted the state of new york to allow medical students to begin practicing earlier than previously allowed. in new jersey, governor phil murphy issued an order providing temporary medical licenses to physicians who have at least years' experience and who have practiced in the past five years (osorio, ) . the need for trained medical workers has led to an innovative collaboration in which the international rescue committee (irc)-a refugee resettlement agency-identifies foreign-trained immigrants and refugees currently residing in the united states so that they can be contacted if they meet eligibility requirements for temporary licenses (irc, a (irc, , b . this unique partnership should provide a significant boost to a strained health-care infrastructure, as it is estimated that , refugees and immigrant workers who obtained healthrelated degrees abroad had previously been unable to utilize their credentials in the u.s. health-care system (irc, a). aside from providing services as first responders or essential workers, some refugees have garnered community support to aid in coronavirus responses. in westchester county, ny, neighbors for refugees-a nonprofit organization that provides services aimed at empowering refugees as they transition to life in the united states (neighbors for refugees, a)-partnered with masks for new york to help address the shortage of personal protective equipment (ppe) for hospital workers (masks for ny, ). as a result of the partnership, recently resettled female refugees with seamstress experience, in collaboration with local community members, raised over , usd in three weeks and made around , masks for medical facilities around new york city (neighbors for refugees b). similarly, in dupage county, illinois, the re:new project-an organization in the chicago area that teaches refugee women english and sewing, while also employing them to craft artisan products-has transitioned their standard operations and begun making face masks following cdc guidelines for medical professionals (re:new project, ). even with shelter-in-place orders in effect, refugee artisans have continued their work from home and are able to make about masks a week, which are donated to medical facilities, nonprofit organizations, and retirement communities in need around chicago (nbc chicago, ) . in addition to working in essential services and helping to produce ppe, refugees have been involved in efforts to provide food for those in need during the pandemic. in baltimore, mera kitchen collective-founded in to empower refugee and immigrant women through food entrepreneurship (meehan, ; cassie, ) -has responded to the coronavirus pandemic by donating prepared meals to health-care workers and fellow baltimoreans in need (strickland, ) . mera kitchen's initial goal was to provide , meals; however, within days of starting the community meal initiative, the organization had received donations of more than , usd, enabling them to provide over , meals (mera kitchen, ; strickland, ) . aside from providing food aid, the organization has also been able to provide employment for individuals who were laid off due to the pandemic (mera kitchen, ) . similarly, adenah bayoh, a liberian refugee who now owns ihop restaurants in paterson, newark, and irvington, is providing free meals to those in need (hill, ) . families in new jersey will be able to pick up free pancakes and sandwiches from her restaurants until schools reopen (hill, ) . in addition, bayoh is working with irvington city council to provide free meals to seniors in the community (hill, ) . the pandemic policies enacted, and the suspension of immigration to the united states, will have long-lasting impacts on humanitarian immigration into the united states. since taking office, the trump administration has steadily dismantled and impeded immigration into the united states for the world's most vulnerable populations (alvarez, ; boghani, ; chishti & pierce, ; pierce, ) . the administration has touted their restrictive immigration policies as measures that are "restoring the rule of law," "securing our borders," and "protecting american workers" (the white house, n.d.). since the migrant crisis of , western governments have seen a surge of politicians and political parties that are xenophobic and intolerant of immigrants. in recent years, a wave of nationalism and populism has coursed through europe and the united states. president trump has used fears emerging during the pandemic to create policies and procedures that further restrict immigration and conflate immigrants with public safety or health concerns. it is likely that once countries begin to reopen following the coronavirus pandemic, some politicians will seize on temporary suspensions to further restrict immigration policies (yayboke, n.d.) . and once the refugee admissions program resumes the resettlement of refugees, it is likely that new procedures and protocols will be added to an already lengthy and intensive screening process. currently, health and security screenings for refugees take an average of years to complete. the future of refugee and asylum programs in the united states could be significantly altered in the coming year, partly due to the coronavirus, and partly due to policy shifts stemming from the november elections. aubrey grant, mpp, is a phd candidate at george mason university's schar school of policy and government, and a research assistant for the gender and policy center, fairfax dr. ms b , arlington, virginia, united states. the author is sincerely grateful to the reviewers for their thoughtful comments and feedback. conflicts of interest: none declared. corresponding author: aubrey grant, agrant @gmu.edu situational brief: asylum seekers, detained migrants, and documented/undocumented migrants in the united states during the covid- pandemic america's system for resettling refugees is collapsing refugee admissions to the us temporarily suspended a guide to some major trump administration immigration policies trump administration program nearly ended asylum. now, coronavirus has halted it covid- and unemployment: assessing the early fallout for immigrants and other u.s. workers mera kitchen empowers refugees through food entrepreneurship order suspending introduction of certain persons from countries where a communicable disease exists center for migration studies (cms). . covid- migration-related developments crisis within a crisis: immigration in the united states in a time of covid- importance of releasing asylum seekers from detention during the covid pandemic irc responds to president trump's planned executive order to halt immigration to the us online platform for refugees and immigrants in the united states seeking to citing coronavirus, trump will announce strict new border controls ice detention policies and practices fatally flawed key facts about refugees to the u.s about us baltimore's mera kitchen collective empowers immigrant women through food covid updates re:new project producing masks for organizations across chicago neighbors for refugees. b. refugee sewing initiative new american economy. . refugee workers on the frontlines and as essential workers immigrant doctors want to help fight covid- but are stymied by state licensing laws immigration-related policy changes in the first two years of the trump administration we are like sitting ducks extension of order suspending introduction of certain persons from countries where a communicable disease exists advocating for refugee resettlement and asylum refugees international. n.d. covid- and the displaced: addressing the threat of the novel coronavirus in humanitarian emergencies baltimore catering business has donated nearly , meals to families and healthcare workers immigration proclamation suspending entry of immigrants who present risk to the u.s. labor market during the economic recovery following the covid- outbreak united nations high commissioner for refugees (unhcr) united nations high commissioner for refugees (unhcr). a. iom, unhcr announce temporary suspension of resettlement travel for refugees united nations high commissioner for refugees (unhcr). b. coronavirus outbreak the rights and health of refugees, migrants and stateless must be protected in covid- response five ways covid- is changing global migration key: cord- - ey dv authors: seymour, i.j.; appleton, h. title: foodborne viruses and fresh produce date: - - journal: j appl microbiol doi: . /j. - . . .x sha: doc_id: cord_uid: ey dv nan raw and minimally processed fruits and vegetables are typically sold to the consumer in a ready-to-use or readyto-eat form. these products do not generally contain preservatives or antimicrobial agents and rarely undergo any heat processing prior to consumption. for many years raw fruits and vegetables have been implicated as vehicles for transmission of infectious micro-organisms. although fresh produce can support the growth and/or survival of many pathogenic bacteria there is little published information on the stability of human pathogenic viruses on these food products. viruses cannot grow in or on foods but may sometimes be present on fresh produce as a result of faecal contamination. this contamination can arise at source in the growth and harvesting area from contact with polluted water and inadequately or untreated sewage sludge used for irrigation and fertilization. alternatively, fruits or vegetables handled by an infected person might become contaminated with virus and transmit infection. the most frequently reported foodborne viral infections are viral gastroenteritis and hepatitis a: both have been associated with the consumption of fresh fruit or vegetables. in recent years it has been recognized that viruses are an important cause of foodborne disease. unlike bacteria, viruses do not grow or multiply in or on foods, but foods may become contaminated with human viruses and transmit infection. there are many groups of viruses which could contaminate food items, but the major foodborne viral pathogens are those that infect via the gastrointestinal tract, such as the gastroenteritis viruses and hepatitis a virus. it is these viruses that are the main subject of this review. viruses that infect via the gastrointestinal tract are excreted in faeces and may also be present in vomit. foods become contaminated either directly by infected people or through sewage pollution. those enteric viruses, which are commonly associated with foodborne outbreaks, either cannot be cultured in the laboratory or can only be cultured with dif®culty. hence information and experimental studies on survival and recovery of viruses from foods often relates to other virus types that are readily cultured. some of these viruses may be good models for important foodborne viral pathogens, but others may have widely differing characteristics. enteroviruses, such as coxsackieviruses and vaccine strains of poliovirus, have been used particularly. they infect via the gastrointestinal tract, occur in the environment as a result of sewage contamination and are relatively stable. however, there are very few published reports of foodborne outbreaks of illness caused by enteroviruses. there is the potential for contamination with other virus groups, such as respiratory viruses, although transmission to humans through foods has not been recognized. infrequently endogenous contamination of meat and milk can occur with viruses such as tick-borne encephalitis. such zoonotic infections have been reviewed by and need not be considered in this review. viruses are usually transmitted directly from person to person, but epidemiological and laboratory investigations indicate that viral diseases can on occasions be transmitted via foods, particularly those that are minimally processed. these include seafood, especially the bivalve molluscan shell®sh, and fresh fruits, vegetables and salad items. it might be expected that any virus that infects via the gastrointestinal tract could be foodborne. in practice, however, the most commonly reported foodborne viral infections are viral gastroenteritis and less frequently hepatitis a. it is believed that the incidence of both is greatly under reported, but for different reasons. viral gastroenteritis is a relatively mild disease and most people do not consult a medical practitioner; hence, the majority of cases are not investigated and are not reported. a recent national study funded by the department of health of infectious intestinal disease (iid) in the community indicated that for every case of iid detected by national laboratory surveillance, there are cases in the community. the study also concluded that a smaller proportion of cases due to common viral pathogens are reported than cases due to common bacterial pathogens (wheeler et al. ; food standards agency, ) . viral gastroenteritis has a short incubation period of ± days depending on the type of virus. this means that when cases are investigated, the possibility of foodborne transmission is likely to be considered. in contrast, hepatitis a is often a more severe disease and is more likely to be reported. however, the incubation period is ± weeks and hence an association with a food source is unlikely to be made, unless there is a very clearly de®ned outbreak. several different viruses cause gastroenteritis: the most important include rotavirus, the small round-structured viruses (srsv) otherwise known as norwalk-like viruses (nlv), astrovirus and adenovirus types and . however, in almost all foodborne outbreaks where a virus is identi®ed, it is an nlv. rotavirus and astrovirus are only rarely implicated. adenovirus has not been associated with food or waterborne transmission. viral gastroenteritis is usually regarded as a mild selflimiting disease lasting ± h. however, people can feel debilitated for or weeks, which has considerable economic implications in terms of working days lost and impaired performance. symptoms include malaise, abdominal pain, pyrexia, diarrhoea and/or vomiting. a range of symptoms occurring in an outbreak should alert investigators to the possibility of a viral cause. the viruses are usually transmitted by the faecal±oral route, but they are also present in vomitus. onset of viral gastroenteritis may be sudden and can commence with projectile vomiting. virus will be disseminated over a wide area in aerosol droplets, which is a particular hazard where food is being prepared * where the organism identi®ed in an outbreak was the main aetiological agent. outbreaks in which there was foodborne transmission followed by person-to-person transmission, but the proportion of each mode was unknown. data from phls communicable disease surveillance centre. and laid out. although most transmission is directly from person to person, contaminated food and water can give rise to common source outbreaks. the infective doses are not known, but the evidence from volunteer studies and the typically high attack rates observed in outbreaks suggest that they are very low (westwood and sattar ; caul et al. ) . for instance, it has been estimated that nlvs have an infective dose of between and virus particles (caul ; stolle and sperner ) . viruses account for % of foodborne and % of waterborne outbreaks occurring in england and wales reported to the phls communicable disease surveillance centre (cdsc) (appleton, ; o'brien et al. ) (table ) . a recent paper prepared by the public health laboratory service (phls) reported on the microbiological status of ready-to-eat fruit and vegetables between and in england and wales (o'brien et al. ) . fruit and vegetables accounted for á % ( / ) of the total foodborne outbreaks reported during that period. the most commonly identi®ed aetiological agent was the nlvs, which were linked to % of the outbreaks. the causative organism of a further % of outbreaks was reported as unknown, although the clinical and epidemiological features of these outbreaks suggested that the majority ( %) were also viral. . . norwalk-like viruses. this group of viruses infects all age groups. there is a variable incubation period of ± h, which is thought to be dose-dependent. it occurs all year round, although in temperate climates most infections occur over the winter months. these viruses are responsible for both sporadic cases of gastroenteritis in the community and for outbreaks in schools, hospitals, old people's homes, hotels and cruise ships. the national iid study indicated that viruses are the most common cause of iid in the community, with nlv the most frequently reported organism (wheeler et al. ; food standards agency, ) . from to , nlvs accounted for one-third of all gastroenteritis outbreaks reported to the phls communicable disease surveillance centre (cdsc) and the number of outbreaks of nlv gastroenteritis exceeded the number of outbreaks of salmonellosis. unlike the salmonellosis outbreaks, however, only % of the nlv outbreaks were known to be food or waterborne (appleton, ) . the virus is extremely infectious and secondary cases are a characteristic feature of foodborne outbreaks. therefore, it is not always possible to determine whether illness is acquired from a foodborne source or by person-to-person transmission (see table ). this accounts partly for underrecognition of the extent of foodborne transmission of these viruses. in a review of nlv (srsv) infection in england and wales between and by the phls, direct foodborne transmission could be ascertained in only % of outbreaks (dedman et al. ). there have been reports of outbreaks where nlvs have been epidemiologically associated with various items of fresh produce, such as washed salads (lieb ; lo et al. ) , imported frozen raspberries (ponka et al. ) , coleslaw (currier ) , green salads (grif®n et al. ) , fresh cut fruits (herwaldt et al. ) and potato salad (patterson et al. ) . the virus was discovered in by electron microscopy (kapikian et al. ) (fig. ). the ®rst virus originated from the town of norwalk in the united states, and became the prototype of the group. the name small roundstructured virus (srsv), which describes the morphology of the virus particle (caul and appleton , appleton, ) , was used in the united kingdom and elsewhere until recently. it has now been agreed informally by virologists working with this group to adopt the name norwalk-like virus, for the present, so as to bring some conformity to the nomenclature of these viruses. however, formal names have not yet been agreed by the international committee on virus nomenclature. the nlvs form a complex group of viruses. they have formally been classi®ed with the caliciviridae and are often referred to as human caliciviruses. they are split into two broad genogroups. most viruses in these two groups have the typical morphology of a ± nm diameter particle with an amorphous surface and ragged outline, as originally described for the srsv group (caul and appleton ) . within the caliciviridae there is a second genus of human gastroenteritis viruses, provisionally named sapporo-like viruses (slvs). the slvs have the morphology of classical caliciviruses and are genomically distinct from the nlvs . on sequencing, some strains with there are suggestions that the epidemiology of slvs differs from nlvs, in that slvs mainly cause infections of young children. it is not clear whether slvs are of signi®cance in foodborne infections and more studies are needed to clarify their role. genotypic analysis is being used increasingly to investigate the epidemiology of these two groups of viruses (fankhauser et al. ; maguire et al. ; hale et al. ; hedlund et al. ; koopmans et al. ) . there are several serotypes of human caliciviruses, which correspond broadly with the genotypic groups. most studies have been carried out with nlvs, and indicate that immunity is complex and short-lived (matsui and greenberg, ) . volunteer studies have shown that people can be infected repeatedly with the same virus strain (parrino et al. ; johnson et al. ). . . rotavirus. rotaviruses mainly infect young children . it is estimated that they cause one million deaths a year in children under years of age, mostly in developing countries. in developed countries deaths are relatively rare, but rotavirus gastroenteritis is the most frequent reason for admission of young children to hospital. rotaviruses consistently account for around % of all gastroenteritis viruses reported to cdsc, although this ®gure is probably biased by reports of hospitalized children, rather than the occurrence in the community, where nlvs are of greater signi®cance. foodborne and particularly waterborne spread are probably a signi®cant route of transmission in developing countries, but in developed countries reports are rare (table ) . . . astrovirus. the astroviruses form a morphologically distinct group of viruses, and are named from the ®ve-or six-point star seen by electron microscopy on the surface of some particles. astroviruses have mainly been associated with illness in young children, often under year of age. reports of astrovirus infection in older children and adults are infrequent, although outbreaks have been reported in the elderly. this may re¯ect testing policy: detection normally relies on electron microscopy, which is insensitive and often not performed on sporadic samples from adults. the use of more sensitive molecular detection methods is required to assess the incidence and epidemiology of these viruses. astroviruses have been seen in some adults following the consumption of shell®sh or contaminated water, but these incidents appear to be comparatively rare (kurtz and lee ; kurtz ) (table ) . there are two forms of enterically transmitted hepatitis ± hepatitis a and hepatitis e (cromeans et al. ). the most characteristic symptom of hepatitis a is jaundice, but milder symptoms of nausea and general malaise without jaundice are common. patients may feel unwell for several weeks, but recovery is complete. deaths are rare. some infections, particularly in children, may be asymptomatic. like viral gastroenteritis, transmission is by the faecal±oral route, but the primary site of viral replication is the liver. virus excretion may commence up to a week before symptoms are apparent, making control dif®cult. the epidemiology of foodborne hepatitis a is essentially similar to that of viral gastroenteritis. food-and waterborne outbreaks have been recognized for over years, but are infrequently reported. epidemiological evidence to link hepatitis infection to food and water sources is sparse, because of the long incubation period. between and , outbreaks occurring in england and wales were reported to cdsc, but only one of these was known to be foodborne. that outbreak was associated with shell®sh. from to , cdsc received laboratory-con®rmed reports of cases of hepatitis a. the source of most of these infections was unknown and just were recorded as foodborne. in the united states, the centers for disease control and prevention (cdc) placed hepatitis a as the sixth leading cause of foodborne disease from to (centers for disease control and prevention ) . outbreaks associated with fresh produce, particularly soft fruits and salads, have been reported from several countries. iceberg lettuce (rosenblum et al. ), strawberries (niu et al. ) , diced tomatoes (williams et al. ) and salad items (pebody et al. ) have all been implicated. a recent outbreak of hepatitis a in the united states was associated with consumption of food items containing frozen strawberries imported from mexico (anon ; cliver ) . in the united kingdom, outbreaks have been traced to frozen raspberries. there was evidence that the raspberries in these outbreaks were contaminated by infected fruit-pickers (noah ; reid and robinson ; ramsay and upton ) . there is only one serotype of hepatitis a. following infection immunity is lifelong. an effective vaccine is available. currently it is used for persons at high risk, such as travellers (department of health et al. ) . food packagers and food handlers in the united kingdom have not been associated with hav transmission suf®ciently often to justify routine immunization, except in outbreaks. the incidence of hepatitis a in developed countries has fallen in recent years and hence a susceptible population has built up. as endemic infection declines, it is possible that an increase in foodborne outbreaks will be seen. the yearround global distribution of fruit and vegetable products poses a risk of infection, particularly when these products are imported from countries with a high incidence of hepatitis a. hepatitis e has been associated with large waterborne outbreaks in some developing countries, notably in asia, africa and central america. foodborne transmission has been suggested, but not proved conclusively. illness appears more severe than hepatitis a, particularly in pregnant women where a death rate of ± % has been observed (cromeans et al. ) . the primary source of infection appears to be contaminated water rather than person-to-person spread. secondary person-to-person transmission is estimated at only á ± % (cromeans et al. ) . cases in the united kingdom are reported infrequently and are mainly imported from endemic areas. with the worldwide distribution of foods, vigilance should be maintained. viruses are very small micro-organisms, and basically comprise a nucleic acid core of either dna or rna, surrounded by a protein coat. they require living cells in order to replicate and generally have a very restricted host range. viruses do not multiply in foods or water, or in or on any other environmental sample. however, viruses can survive outside living cells and remain infectious. enteric viruses are hardy and survive well in the environment. these viruses survive on inanimate surfaces, on hands and in dried faecal suspensions (green et al. a; barry-murphy et al. ; bidawid et al. ; sattar et al. ) . lingering outbreaks have occurred in hospitals, in residential homes and on cruise ships, probably as a result of environmental contamination. nlvs have been detected by pcr in environmental swabs from hospital lockers and hotel carpets supposedly cleaned after incidents of vomiting (green et al. a) . the viruses survive just as well on kitchen surfaces and food preparation areas. in one reported outbreak, a kitchen worker vomited into a sink. the following day the sink, which had been cleaned with a chlorine-based disinfectant, was used for washing salad and an outbreak of gastroenteritis associated with nlvs ensued (patterson et al. ) . enteric viruses are acid stable and so are able to survive in the gastrointestinal tract. it is likely that they will survive food processes designed to produce the low ph that inhibits bacterial spoilage organisms (e.g. pickling in vinegar and fermentation processes that produce foods such as yoghurt). both nlvs and hepatitis a virus retain activity after exposure to acidity levels below ph scholtz et al. ) . most viruses remain infectious after refrigeration and freezing. frozen foods, that have not received further cooking, have been implicated in a number of incidents of viral gastroenteritis and hepatitis a (noah ; reid and robinson ; ramsay and upton ; niu et al. ) . gastroenteritis viruses and hepatitis a virus are inactivated by conventional cooking processes, but retain their infectivity after heating to °c for min parry and mortimer ; fleming et al. ; millard et al. ; slomka and appleton ) . it is uncertain whether they would be inactivated completely in some pasteurization processes. nlvs cannot be cultured in the laboratory and until recently detection relied on the use of electron microscopy. this technique is fairly insensitive and requires a minimum of virus particles per ml of sample. it has been used widely for detection of virus in faecal samples from patients, but cannot be used for looking for the lower concentration of virus particles present in contaminated food, water and environmental samples. sequencing of the genome of the norwalk virus has led to the development of pcr assays, with greatly enhanced sensitivity for virus detection . however, there is great genomic diversity among the nlvs and one set pcr primers will not detect all strains (norcott et al. ) . pcr assays are being used for the examination of food samples, particularly shell®sh, but far more complex nucleic acid extraction techniques are required than when working with clinical specimens from patients (atmar et al. ; green et al. b ). there are also greater problems with naturally occurring inhibitors to the pcr reaction in these types of samples. nlvs have been detected in samples of raspberries associated with an outbreak of gastroenteritis in quebec. sequence analysis demonstrated that the strain of nlv identi®ed in the raspberries was identical to that found in the patients (gaulin et al. ) . expression of recombinant virus capsids in yeast and insect cells is allowing the development of elisa-based diagnostic assays, but reagents are not widely available and so far the tests only detect a very limited number of nlv strains (jiang et al. ) . further development and more widespread use of elisa tests will greatly facilitate the detection of nlvs in clinical samples, although such tests may not be suf®ciently sensitive to detect virus in food samples. at the present time, pcr and elisa assays for nlvs are only available in specialist laboratories and are not used for the routine testing of food samples. commercial test kits are not yet available. rotavirus and astrovirus can both be grown in cell cultures in the laboratory. however, it is unreliable and time-consuming for isolation from primary specimens and is not normally used. rotavirus is frequently detected using commercial elisa or latex agglutination tests and pcr assays are available. rotavirus has been detected in lettuce (hernandez et al. ) and shell®sh samples, but it is not clear if these were of human origin. electron microscopy is still the most usual method for the detection of astroviruses, although pcr assays are used in a few laboratories. diagnosis of hepatitis a infection in patients is by detection of speci®c igm antibody, since virus excretion has largely ceased by the time illness becomes apparent. the virus can be cultured in the laboratory, but this is a long and unreliable procedure. in one outbreak at a summer camp in the united states, virus was isolated from the drinking water supply, but this took weeks. pcr assays have been developed and have been used for detecting virus in water, shell®sh and other food and environmental samples. due to the long incubation period of hepatitis a, food items are not usually available for testing, even if suspected as the source of illness. in particular, minimally processed fruits and vegetables have a short shelf life. there have been a few experimental studies to investigate seeding and recovery of viruses from fresh produce. transfer of hepatitis a virus to lettuce leaves has been investigated sattar et al. ) . rotavirus and poliovirus were recovered from the surface of vegetables in a method described by badawy et al. ( b) . average recovery rates of and %, respectively, were obtained from lettuce; however, recovery of rotavirus from non-leafy vegetables was lower, averaging %. ward et al. ( ) also recovered poliovirus and adenovirus from vegetable surfaces, obtaining mean ef®ciencies of approximately ± %. there is a need to develop more effective quantitative methods in order to assess the survival of viruses on fresh produce and to determine the decontamination ef®ciencies of current commercial washing systems for fruit and vegetables. fruits and vegetables may become contaminated with viruses in two ways. first, they may be contaminated in their growing area before harvest by coming into contact with inadequately treated sewage or sewage polluted water. secondly, contamination can arise during processing, storage, distribution or ®nal preparation either directly from infected people or by contact with a contaminated environment. in most outbreaks of foodborne viral disease involving fresh produce, it is not known whether contamination took place before, during or after harvest. guidelines issued by the world health organization state that fruits and vegetables to be eaten raw should not be fertilized with sewage or irrigated with contaminated water (beuchat ) . sewage sludge is sometimes applied to agricultural land, with the bene®t that useful plant nutrients and organic matter are recycled to the soil. however, the uk government is proposing more stringent controls for harvesting vegetables from land where conventionally processed sewage sludge is applied (adas, ) . the transmission of viruses is thought to be mainly by surface contamination. there are relatively few reported studies on the possible uptake of viruses within damaged plant tissues during primary growth. studies with poliovirus report that virus can in®ltrate into the roots and body of plants from the soil (oron et al. ) , but there is no evidence of illness from this source. viruses from sewage do not bind readily with soil particles and can enter groundwaters leading to contamination of water sources. the viruses causing gastroenteritis and hepatitis a appear to be extremely infectious in very low doses. large numbers of virus particles can be excreted in the faeces from an infected person. levels of the order of ± infective units per gram have been estimated (feachem et al. ) . poor personal hygiene is therefore a major route through which viruses can directly reach foods. virus can be transferred from faecally contaminated ®ngers to foods or to work surfaces and door handles. there is a signi®cant risk of contamination from ®eld workers who do not have adequate on-site toilet and hand-washing facilities. even when these facilities are put in place, the workers need to be supervised in such a way as to ensure that the facilities are used (cliver ) . in an outbreak of hepatitis a, associated with frozen raspberries, infection was con®rmed in a fruit picker on the farm where the raspberries were cultivated (ramsay and upton ). a number of outbreaks have also been linked to contamination of fresh produce from the vomitus of infected food handlers ). it has been suggested that between and million virus particles are liberated during vomiting (reid et al. ; caul ) . as well as direct transmission, aerosols produced by vomiting can contaminate exposed food, or surfaces with subsequent transfer to foods. human enteric viruses will potentially be present in any type of water contaminated by human faecal material and by sewage. the department of environment, transport and regions (detr) jointly with uk water industry research limited and the environment agency, recently commissioned four reviews on enteroviruses. these covered the source (sellwood et al. ) and survival (irving and morris ) in the environment and their fate through sewage treatment processes (merrett and weatherley ) . mounting evidence suggests that viruses can survive long enough and in high enough numbers to cause human diseases through direct contact with polluted water or contaminated foods (nasser ; bosch ) . irving and morris ( ) concluded that a thorough and valid assessment of the occurrence and signi®cance of viruses in natural waters is hampered by lack of reliable information. they suggested that this is due to inef®cient analytical techniques, and because different analytical methods have been used so that comparisons on survival data between different studies cannot be made. however, it does appear that different types of viruses are inactivated at different rates under identical conditions, and therefore no single microorganism can be expected to be an indicator for all viruses. temperature is an important factor, with low temperatures favouring viral survival in natural waters. raphael et al. ( ) found no signi®cant drop in rotavirus titre after days at °c in raw water, treated tap water or ®ltered water. however, a % drop in titre was observed after days at °c. astrovirus survival has been demonstrated in drinking water after days at °c (abad et al. b ). nasser et al. ( ) concluded that hepatitis a virus and poliovirus could survive in wastewater and groundwater for days or more at °c . hepatitis a virus and poliovirus were shown to survive in excess of one year in mineral water stored at °c (biziagos et al. ). hepatitis a virus can survive in fresh or salt water for up to a year (sobsey et al. ) . evidence suggests that adsorption of viruses to particulate matter and sediments confers substantial protection against inactivating in¯uences. salinity and ph do not appear to have a signi®cant direct effect on virus survival under conditions normally found in natural waters, but may have indirect effects by modifying interaction of viruses with particulates. there is some evidence that solar radiation promotes inactivation of viruses, but the effects have not been extensively studied. development of pcr-based assays has allowed the detection of nlvs in both river water and seawater wyn-jones et al. ) . in , an outbreak of nlv gastroenteritis occurred among canoeists and was associated with river water at a water sports centre (gray et al. ) . when hepatitis a virus was detected in lettuce from costa rica, it was suggested that the possible source of contamination was the discharge of untreated sewage into river water used to irrigate crops, which is common practice in some less well-developed countries (hernandez et al. ) . in another outbreak of hepatitis a, traced to commercially distributed lettuce or tomatoes, it was hypothesized that contamination may have occurred in the ®elds from dirty water used for growing or irrigation, or possibly from the use of night soil, although this was dif®cult to prove (rosenblum et al. ) . enteric viruses may contaminate soil through the land disposal of sewage sludge and dirty irrigation water. a number of research studies have investigated the survival of human pathogenic viruses in soils with con¯icting results. survival appears to depend on a number of different variables, particularly the growing season, soil temperature, rainfall, soil type and composition. for example, viable poliovirus was recovered from spray-irrigated soil after days during the winter season tierney et al. ) . this compared to a maximum survival period of only days during the summer, which suggested the higher temperature and solar radiation levels in the warmer seasons accelerated viral inactivation. the possibility also exists that viruses may be mechanically transmitted to fruits and vegetables during harvest. sadovski et al. ( ) noted the persistence of inoculated poliovirus in drip irrigation pipes and soil. moderate environmental conditions and alluvial-type soil, which restricts water in®ltration, enhanced viral recoveries in the upper soil layers. oron et al. ( ) found that relatively high soil temperature ( °c) and a low moisture content hindered poliovirus survival. wet soil conditions are frequently associated with low soil temperature. gerba ( ) reported that a large proportion of outbreaks of waterborne disease in the unite states resulted from contaminated groundwater. climate, the nature of the soil and the nature of the resident micro¯ora determine virus survival and retention within soil particles. both electrostatic and hydrophobic interactions are thought to contribute towards virus adsorption and are controlled by the characteristics of the soil. some investigations have focused on the survival of viruses on inanimate environmental surfaces such as stainless steel, glass and plastics. abad et al. ( ) observed that a range of enteric viruses, including hepatitis a virus and rotavirus, persisted for extended periods (greater than days) on several types of porous and nonporous surfaces. greater virus survival was noted at °c than at °c. the effect of relative humidity on survival of hepatitis a virus on nonporous surfaces has been investigated sattar et al. ) . at °c, relative humidity had little effect on survival time, but at °c survival was longest when relative humidity was low. it is apparent from the lingering outbreaks that have occurred on cruise ships that nlvs survive well on environmental surfaces. nlvs have been detected in swabs of lockers in hospital outbreaks and from hotel carpets (green et al. a; barry-murphy et al. ) . a disinfectant formulation is considered to be effective if it is capable of inducing a -fold ( á %) or greater reduction in the virus titre springthorpe et al. ) . experimental studies have shown that a free chlorine level of ppm reduced the infectivity titre by more than á % on stainless-steel disks v i r u s e s a n d f r e s h p r o d u c e contaminated with the enteric viruses coxsackievirus b and hepatitis a virus, and the respiratory viruses adenovirus type , parain¯uenza virus type and coronavirus e (sattar et al. ; mbithi et al. ). the virucidal action of sodium hypochlorite ( ppm at ph á ) was also tested against hepatitis a virus, human rotavirus and a bacteroides fragilis bacteriophage dried on polystyrene (abad et al. a ). overall, a less than -fold titre reduction was achieved for all the viruses examined. chlorine is a common disinfectant used by many fresh produce processors to wash fruits and vegetables (beuchat ; seymour ) . however, chlorine levels greater than ppm are thought to cause adverse discoloration (bleaching) and off avours in the ®nished product (hurst and schuler ) . survival times for some enteric viruses have been determined on a range of different fruit and vegetable commodities. it is dif®cult to draw conclusions from the different studies, since experimental conditions and methods varied. however, most of these studies report viability in excess of the product shelf life. konowalchuk and speirs ( ) established no signi®cant loss in coxsackievirus b titre when contaminated lettuce was stored for d under moist conditions at °c, but some inactivation took place during storage under dry conditions. they hypothesized that under conditions of low or no moisture the aqueous part of the virus inoculum evaporated leaving the virus exposed to air and/or salts. celery, lettuce and carrots stored at °c supported the survival of a range of enteric viruses for up to days (konowalchuk and speirs a) . badawy et al. ( a) indicated that rotavirus sa- (a simian rotavirus that can be cultured) survived on lettuce, radishes and carrots for up to days at °c. viral inactivation at room temperature ( °c) was signi®cantly greater than at °c; however, viable rotavirus sa- was still detected on lettuce after days. they concluded that the rough or irregular surfaces present on lettuce might offer some additional protection for virus particles. indeed, protected segments of plants such as the roots, closed leaves and internal fruit parts, may offer favourable conditions that increase survival time up to days (smith ) . viable poliovirus was recovered from ef¯uent spray-irrigated lettuce and radishes days after inoculation tierney et al. ) . sadovski et al. ( ) isolated polioviruses from cucumbers grown in ef¯uentirrigated soil for a full days after inoculation. oron et al. ( ) investigated the transmission of poliovirus from subsurface drip-irrigated soil to tomato plant leaves and tomato fruits. virus was not detected in the tomato fruits. however, a number of leaf samples were positive for poliovirus even though the virus was injected cm below the surface of the soil. this result suggests that poliovirus can penetrate into plant tissue through the root system. the lack of viable poliovirus in the tomato fruits may be due to the presence of antiviral substances as witnessed by other authors. chilled storage temperatures ( ± °c) typically retard respiration, senescence, product browning, moisture loss, and microbial growth in minimally processed fruits and vegetables, but may contribute to the survival and transmission of viruses to the human host. speirs ( b, ) described the potent antiviral properties of different fruit extracts at neutral ph, particularly strawberry. they found signi®cant differences in viral recovery on strawberries, cherries and peaches held in a humid atmosphere at °c. recoveries of coxsackievirus and echovirus were also greater than those of poliovirus and reovirus, although the authors did not offer an explanation for this result. most of the aqueous fruit extracts and infusions demonstrated notable antiviral properties. although the active compounds were not isolated, these agents could be phenolic in nature. in grapes, these chemicals are thought to be located primarily in the skin (konowalchuk and speirs ) . fruits and vegetables are known to contain a vast array of antimicrobial substances, particularly organic acids, phenolic and sulphur compounds and small polypeptide proteins. despite this, outbreaks of viral gastroenteritis and hepatitis a have been associated with fruits and fruit juices. in the absence of formal studies it could be inferred that the gastroenteritis and hepatitis a viruses are relatively resistant to these virucidal chemicals. in view of the increasing use of ready-to-eat vegetables sold in modi®ed atmosphere packaging (map), the survival of hepatitis a virus on lettuce in map, stored at room temperature and °c, has been investigated . survival at °c was the same in map as under normal conditions of packaging. at room temperature viral survival was slightly better in map containing higher carbon dioxide levels. it was suggested that enhanced virus survival might be due to inhibition of ethylene by carbon dioxide, resulting in reduced physiological spoilage of vegetables such as lettuce and possibly less toxic effects on the virus. studies have indicated that indigenous micro¯ora in the water environment are deleterious to survival of enteric viruses (raphael et al. ) . these ®ndings highlight the importance of avoiding contamination of food items before packaging in map . bardell ( ) studied the survival of herpes simplex virus type , suspended in saliva, on the skin of tomatoes and the upper surface of lettuce. although storage times of only h were studied, temperature was shown to have a signi®cant effect on virus titre. there was no loss of virus infectivity titre at °c compared to a -log reduction at room temperature ( ± °c). although not an enteric virus and not a virus that comes to mind as a possible foodborne infection, herpes viruses could invade through the mucous membranes of the mouth. most fruit and vegetable washing systems are designed to remove gross contamination such as dirt, insects, and foreign matter. however, they are reported to be less successful at removing microbial contaminants (beuchat ; seymour ) . vigorous washing of fruits and vegetables with clean potable water typically reduces the number of micro-organisms by ± -fold (beuchat ) and is often as effective as treatment with mg l ) chlorine, the current industry standard (elphick ; seymour ) . raw materials are typically immersed in cooled sanitized water and then dewatered to remove surface moisture and fruit and vegetable juices from the product (simons and sanguansri ) . product agitation is optimized by using water or air jets which enhance surface contact, carriage of product, and suspension of solids and vegetable debris (simons and sanguansri ) . there has been recent concern over the possible migration of bacterial pathogens into the core tissue of fruits and vegetables during washing. zhang and farber ( ) found that uptake of bacterial cells was associated with a negative temperature differential between the water and the product. however, the uptake of human viruses by fruits and vegetables under similar conditions has not been studied. lodging or attachment of microorganisms in tissue crevices may protect cells from direct contact with disinfectants and consequently aid in their survival (beuchat ) . recent studies by seo and frank ( ) found that escherichia coli o :h could survive in the stomata and on cut edges of lettuce following chlorine treatment. although there are no available data for viruses, cell surface structures are likely to offer some additional protection. numerous authors have reported on the ef®cacy of disinfectants for the inactivation of readily culturable human viruses using standard suspension tests, but data for gastroenteritis viruses and hepatitis a virus are lacking. the authors of this review were unable to ®nd any data on the effectiveness of disinfectants and processing aids for the decontamination of enteric viruses on fruits and vegetables. the most commonly used sanitizers and processing aids for cleaning fruits and vegetables are chlorine, chlorine dioxide, organic acids and surfactants, while ozone is receiving renewed interest. the mechanism of action of these disinfectants on viruses and their interaction with plant materials is poorly understood and there are con¯icting reports on their ef®cacy. there are no positive lists of permitted processing aids in the united kingdom or european community, although an inventory has been produced by the codex alimentarius commission (codex alimentarius general requirements, volume a, nd edition . fao/who isbn ± - ± ). directive / /ec of the european parliament contains a list of biocidal products, which have been approved and authorized for use. council regulation (eec) no. / highlights the food additives, processing aids and other substances permitted for the organic production of agricultural products. the use of chlorine, for the treatment of organically grown fruits and vegetables, has recently been banned in the united kingdom and the fresh produce industry is currently trying to ®nd viable and effective alternatives. chlorine is the most widely used disinfectant for washing fresh produce because it is relatively cheap, easy to use and exhibits rapid microbiological action in aqueous solution (elphick ) . the food and drug administration (fda) in the united states permits the use of chlorine as a disinfectant in wash, spray and¯ume waters in the raw fruit and vegetable industry (garret ) . however, in certain ec countries, chlorine is not permitted as a wash water additive. disinfectants such as chlorine and ozone have a strong af®nity for organic matter and are`used up' rapidly in wash tanks containing dirty produce. therefore, for any washing system, it is important to monitor and control the level of disinfectant at all times, to ensure that it is optimal. it is also imperative to maintain chlorine disinfectants within a suitable ph range (boyette et al. ) . chlorine-based disinfectants are usually considered to be the most effective against enteric viruses. however, nlvs and hepatitis a virus appear to be relatively resistant to chlorine (grabow et al. ; peterson et al. ; keswick et al. ) . nlvs are inactivated by mg chlorine l ) , which is the concentration used to treat a water supply after a contamination incident. in the united states a level of mg chlorine l ) with a contact time of min is recommended for inactivation of hepatitis a virus. in recent studies (doultree et al. ) feline calicivirus was shown to be surprisingly resistant to chlorine, requiring mg l ) freshly reconstituted granular hypochlorite for complete inactivation. clearly there is a need for further studies on disinfection of these persistent organisms. chlorine dioxide is not as susceptible to ph changes or the presence of organic matter as chlorine (simons and sanguansri ) . chlorine dioxide is unstable, must be generated on-site and can be explosive when concentrated. the oxidizing power of chlorine dioxide is reported to be about á times that of chlorine (beuchat ) . however, zhang and farber ( ) found no signi®cant difference in decontamination ef®ciency between chlorine and chlorine dioxide. several authors have reported the sensitivity of a range of animal viruses to chlorine dioxide (harakeh ; chen and vaughn ) although there is no information for nlvs and hepatitis a virus. organic acids can occur naturally in many fruits and vegetables and may retard the growth of some microorganisms and prevent the growth of others (beuchat ) . most of these acids behave primarily as fungistatic agents, while others are more effective at inhibiting bacterial growth. these include acetic, citric, succinic, malic, tartaric, benzoic, propanoic and sorbic acids. due to recent changes in legislation, washes and sprays containing organic acids are becoming more popular for the processing of organically grown fruits and vegetables. a number of products are now commercially available. however, scholtz et al. ( ) found that hepatitis a virus remained infectious for min at ph . nlvs and hepatitis a virus survive exposure to acidity levels below ph , while rotavirus is inactivated below ph and above ph palmer et al. ; weiss and clark ; scholtz et al. ) . viruses that infect via the gastrointestinal tract are acid stable since they have to survive the harsh low ph environment of the stomach. organic acids are therefore unlikely to have a signi®cant effect on the viability of hepatitis a virus and nlvs during the typically short contact times used for washing fruits and vegetables (seymour ) . several authors have reported the action of surfactants (wetting agents) in combination with disinfectants (adams et al. ; zhang and farber ) . however, these agents may reduce the antimicrobial effect of chlorine disinfectants and adversely affect product quality (adams et al. ). ozone is lethal to a wide variety of microorganisms, including enteric viruses (finch and fairbairn ) . it is a potent oxidizing agent, is very reactive and unstable, leaves no residues in water and naturally decomposes into ordinary oxygen. this absence of toxicity is one of its major advantages over chlorine disinfectants. ozone has recently been approved as a disinfectant for food applications in the united states (graham ) and industry suppliers are working to develop appropriate systems for fresh produce washing. ozone is unstable, cannot be stored and must therefore be generated on-site. however, due to perceived safety problems and a lack of information on the ef®cacy of ozone, this technology has not yet been readily taken up in europe. although ozone can be used safely, it can cause irritation of the eyes, headache, dryness of the throat, and coughing at exposure levels in the range of á ± á ppm (boisrobert et al. ). the occupational safety and health administration (osha) has set the permissible exposure limit of workers to ozone at á ppm if ozone is to be used in aqueous or gaseous form it is essential that the air is monitored for ozone and that suitable control measures are in place to remove it. the control of foodborne viral infection was considered in the report of the advisory committee on the microbiological safety of food ( ). sewage pollution is a major factor in the contamination of food and water. this is particularly pertinent to fruits and vegetables that will not be cooked before consumption. untreated or inadequately treated sewage discharged into natural waters can cause contamination of crops. sewage sludge is applied to agricultural land, with the bene®t that useful plant nutrients are recycled to the soil. in april , the agricultural development and advisory service (adas, uk) published the safe sludge matrix (adas, ) . this document gives clear guidance on the minimum acceptable level of treatment for any sewage sludge applied to agricultural land and provides a framework to ensure microbiological safety. as from december application of all untreated sludge on agricultural land used to grow food crops has been prohibited in the united kingdom. use on all agricultural land will be prohibited from the end of . untreated sludge is produced by either the primary settlement or secondary biological stages of sewage treatment. further processing may be undertaken to produce treated sludge, resulting in improved stability and a reduction in health hazards and odour problems. (maff ) . currently, treated sludge may be applied to land used for salad crops, but harvesting is not permitted for months. vegetables cannot be harvested for months. a -month harvest interval is required if enhanced treated sludge is used. all applications must comply with the sludge (use in agriculture) regulations and detr code of practice . these controls may help to reduce the risks of microbiological contamination of fruits and vegetables in the uk, but still do not address the potential problem of imported produce from countries with different standards for organic fertilisers or irrigation water. the other major source of contamination is from infected people handling food. people with symptoms should be excluded from food handling. however, food-handlers with only very minimal symptoms have been implicated in transmission of viral gastroenteritis. current recommendations state that food-handlers should be allowed to return to work h after symptoms have ceased. (phls ) . these recommendations appear to work satisfactorily, but were based on the rapid decrease in virus excretion observed by electron microscopy. using more sensitive pcr assays, nlvs can be detected for longer periods than electron microscopy and, in some instances, for up to a week after onset of symptoms. it is not clear if people shedding virus detectable by pcr are infectious, but recommendations on how long to exclude people from food-handling need to be kept under review. the main period of excretion for hepatitis a virus is before symptoms become apparent and therefore control is dif®cult. the wearing of disposable gloves is recommended if foods are to be manipulated by hand, but this does not prevent transfer of viruses to gloves by touching contaminated surfaces. if vomiting occurs, virus may be spread over a wide area in aerosol droplets. uncovered food that is not to receive cooking should be discarded. the environment should be thoroughly cleaned, including work surfaces, sinks and door handles. recent studies by the phls demonstrated the presence of virus on surfaces and materials that had been cleaned by recommended decontamination methods. this suggests that the current recommendations for the removal of nlvs from contaminated surfaces are inadequate (barry-murphy et al. ) . cliver ( ) advised thorough cooking of virus-contaminated foods. however, ready-to-eat fruits and vegetables are unlikely to withstand such harsh treatment and may show deleterious changes in sensory quality. larkin ( ) suggested a wash at °c for min to ensure the microbiological safety of fresh produce. he concluded that this heat treatment does not affect the appearance and taste of most fruits and vegetables provided the food is eaten within h. however, the majority of minimally processed fruits and vegetables require a shelf life in excess of day and therefore this heating step is not applicable. meticulous attention to good food handling practices and education is essential. there should be provision of adequate toilet and hand-washing facilities, not only in the catering and retail industry, but also for farm workers. there is an effective vaccine for hepatitis a and it has been suggested that food handlers should be vaccinated (cliver ) . epidemiological data currently suggest that food-handlers in the united kingdom do not pose a signi®cantly greater risk of transmitting hepatitis a infec-tion than other people, and use of vaccine in this group may not be cost-effective. no vaccines have been developed for nlvs but research studies with nlv recombinant capsid antigens offer the potential for future development of vaccines. there are challenges, however, in designing effective vaccines in that ®rst, there are multiple types of nlvs and secondly, the mechanisms for inducing immunity to these agents is poorly understood (estes et al. ) . fresh produce contributes to the transmission of viral infections. there is a lack of information on the survival of viruses on fresh produce related to shelf life and types of packaging. information is also lacking on the ef®ciency of current washing and decontamination processes for the removal of viruses. studies are therefore required to provide this information for nlvs and hepatitis a virus in particular. there is a need for information on rotaviruses and astroviruses. both these viruses have been implicated in foodborne and waterborne outbreaks in the united kingdom, although only very infrequently. the role and extent of food or waterborne transmission needs to be more clearly de®ned for both these viruses. the infectivity of nlvs and hepatitis a virus is dif®cult to study in the laboratory. nlvs cannot be cultured in vitro and culture techniques for hepatitis a virus are timeconsuming. other viruses that can be cultured readily have been used as models for these pathogens in a number of studies. although only the use of speci®c human pathogenic viruses will give clear and unequivocal data on survival, inactivation and removal, this is not always safe and practical. model systems using similar non-pathogenic human or mammalian viruses may be the most satisfactory alternative. for example, feline calicivirus has been used as a model system for nlvs in assessing the ef®cacy of commercially available disinfectants (doultree et al. ) . feline calicivirus was also used as a model for nlvs in another study on the heat treatment of shell®sh (slomka and appleton ) . this organism would appear to be a good candidate for virus studies on fresh produce. in order to undertake studies on the survival and removal of viruses, there is a need to develop better methods for inoculation and recovery of virus from a range of fresh produce items. there have been recent suggestions that faecal coliforms on fresh produce may be an indicator of the probable presence of enteric viruses. however, several authors have found no signi®cant correlation (keswick et al. ; le guyader et al. ) . despite the shortcomings of indicator organisms such as bacteriophages, there is a need for a safe and convenient model that can be used to help the food industry to assess and optimize new treatment processes. this is not intended as an indicator to monitor food samples directly. other studies have shown that the behaviour and survival of bacteriophages mimic human viruses more closely than bacteria and would be suitable for such purposes. the optimization of washing and decontamination processes to remove viruses from fruits and vegetables will ultimately contribute to the overall safety of these food products. survival of enteric viruses on environmental fomites disinfection of human enteric viruses on fomites factors affecting the ef®cacy of washing procedures used in the production of prepared salads the safe sludge matrix. ref: ampu /b/ anonymous (reported by: united states of america, calhoun department of public health) ( ) hepatitis a associated with consumption of 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of the food standards agency for the production of this paper (project: bo ). key: cord- -tq f d authors: weaver, scott c.; barrett, alan d. t. title: transmission cycles, host range, evolution and emergence of arboviral disease date: journal: nat rev microbiol doi: . /nrmicro sha: doc_id: cord_uid: tq f d many pandemics have been attributed to the ability of some rna viruses to change their host range to include humans. here, we review the mechanisms of disease emergence that are related to the host-range specificity of selected mosquito-borne alphaviruses and flaviviruses. we discuss viruses of medical importance, including venezuelan equine and japanese encephalitis viruses, dengue viruses and west nile viruses. rna viruses, including hiv , , dengue virus (denv) , and possibly the severe acute respiratory syndrome (sars) coronavirus [ ] [ ] [ ] , have caused recent pandemics by changing their host range to amplify in humans. mosquito-borne alphaviruses and flaviviruses belong to the arthropod-borne viruses (arboviruses), and both have a positive-sense single-stranded rna genome. most arboviral infections are asymptomatic, or present with an influenza-like illness. however, several mosquito-borne alphaviruses and flaviviruses are important human pathogens that cause central nervous system disease, coma or death (table ) . arboviruses require a host (usually a bird or small mammal) in which they replicate, and a vector, such as a mosquito, for transmission to other organisms. female mosquitoes ingest virus from the blood of an infected animal. on biting another animal the mosquito transfers the virus through saliva into the new host. birds are the most common arbovirus hosts, whereas humans and other animals such as horses are usually dead-end hosts -they do not transmit the virus to others in the 'herd', and cannot function as a reservoir for reinfection of mosquitoes. infection of dead-end hosts can, however, lead to clinical disease (table ) . in this review, we focus on selected viruses such as venezuelan equine and japanese encephalitis viruses (veev and jev, respectively), which cause epidemics by adapting to domestic animals and exploiting them as amplification hosts. we discuss other mosquito-borne viruses including west nile virus (wnv) and denv, which cause neurological disease. we consider the patterns and history of host-and geographical-range alterations that lead to disease emergence, and the experimental model systems that are used to study the evolutionary constraints on arbovirus host-range changes. venezuelan equine encephalitis (vee) was first recognized as a disease of horses, donkeys and mules in south america during the mid- s. the veev genome encodes four non-structural proteins that participate in genome replication and protein processing, and generates a subgenomic mrna ( s), which is translated into three main structural proteins. these structural proteins and the positive sense . -kb rna genome comprise virus particles. recently, interest in veev has been renewed, because it has been developed as an efficient, stable biological weapon that is infectious by aerosol and that is easily produced in large quantities . epidemiology of epizootics. veev was isolated in from a post-mortem brain specimen of a horse with encephalitis , , but it was only in the late s that the veev was identified as a cause of human diseasepresenting as a febrile illness, sometimes accompanied by neurological manifestations and occasional mortality , . until , periodic but unpredictable outbreaks of vee (some involving hundreds of thousands of equine and human cases) were mostly restricted to as well as in mexico and florida. these enzootic strains differed from the strains that were isolated during equine epizootics and epidemics; they were antigenically distinct and generated little or no viraemia in experimentally infected horses. it was therefore thought that enzootic strains were incapable of causing epidemics, although fatal infections documented in panama and mexico established their virulence as human pathogens , . in the late s, antigenic studies shed light on the relationship between epizootic and enzootic veev strains. the strains isolated during major epizootics were antigenically similar, and were classified into subtypes iab and ic. the enzootic strains were antigenically distinct from the epizootic strains and were more diverse. the enzootic strains were grouped into subtypes id-if and ii-vi, and were later classified as several different species , (table ) . as it was initially believed that enzootic veev strains were unrelated to vee outbreaks, because they were incapable of amplification in equines and were never isolated during major epidemics, the source of the subtype iab and ic strains that initiated vee epizootics and epidemics remained unknown . advances in viral molecular genetics, phylogenetic methodology and computational techniques have provided some answers. initially, rna oligonucleotide fingerprinting showed that some enzootic strains in subtype id were more closely related to certain subtype ic epizootic strains than was indicated by their antigenic properties . later, genome sequencing confirmed peru, ecuador, venezuela and colombia (fig. ) . (human cases were only recognized retrospectively for the earliest outbreaks.) widespread and long-lasting vee outbreaks did occur -one epizootic began in el salvador and guatemala in and spread through most of central america and mexico, reaching texas in the united states in . however, after , vee outbreaks and epizootic strains seemed to disappear for years. there were many reasons for this long period of viral inactivity. equine encephalitis has a high mortality rate, and those animals that survive usually produce protective neutralizing antibodies and are immune to reinfection , . insufficient populations of mosquito vectors also limited incidence of the disease. however, in , an outbreak of vee occurred in venezuela ( - venezuelan epizootic/epidemic) , and in , there were epizootics/epidemics in venezuela and colombia , as well as small equine epizootics in southern mexico in and (ref. ) . after identification of veev as a cause of human disease, experimental animal models revealed that equine infection results in a high titre viraemia; the animals therefore serve as highly efficient amplification hosts in the presence of abundant competent mosquito vectors . in agricultural settings, this efficient amplification facilitates human infection. at the same time, viruses with similar antigens, including the vee serocomplex of alphaviruses (fig. ) , were discovered in permanent sylvatic cycles in several tropical and subtropical regions of south and central america, requires knowledge of the host-range changes and their genetic basis. recently, the molecular changes that led to the evolution of epizootic strains from enzootic progenitors have begun to be determined. analysis of related enzootic id and epizootic ic strains from western venezuela facilitated the identification of putative genetic determinants of the epizootic phenotype . also, amino-acid sequences of the envelope glycoprotein revealed a common pattern of positive charge (arginine (arg) or lysine (lys)) substitutions in a region that was probably located on the surface of the viral particle, which might encode the antigenic determinants , . preliminary studies in which these mutations were introduced into the envelope protein of an enzootic id strain indicate that an arg or lys residue at amino-acid position is the main determinant of the equine viraemia phenotype. interestingly, these mutations also change the serotype from id to iab/ic, explaining the correlation between veev serotype and epizootic potential. this single amino-acid substitution, which has a major effect on the vertebrate host range, has resulted in the repeated occurrence of vee emergence over the past years. this period correlates with the introduction of equines into the new world from europe, and the establishment of equine populations that are large enough to mediate efficient amplification. rna viruses, including alphaviruses, have very high mutation frequencies because their error-prone rnadependent rna polymerases lack proof-reading ability . estimates of mutation frequency for a closely related alphavirus, eastern equine encephalitis virus (eeev), are approximately - substitutions per nucleotide. this indicates that the single mutation leading to the lys or arg substitution at position in the envelope glycoprotein e occurs regularly in nature, because veev populations in mosquitoes and vertebrate reservoir hosts usually exceed plaque-forming units (pfu) ml - . an interesting exception to the association between equine veev amplification and epizootic transmission is the recent mechanism of equine disease emergence in mexico . although phylogenetic studies support the recent acquisition of the equine virulence phenotype by local, enzootic subtype ie strains , , the link between neuroinvasion and viraemia -which occurs in all other epizootic strains (subtypes iab and ic)is broken in the mexican strains isolated from encephalitic horses in and . these veev strains cause equine encephalitis in the absence of high-titre viraemia, which indicates increased neurotropism, as high plasma levels of circulating veev are usually necessary for cerebral invasion . the lack of equine amplification by these strains probably explains their failure to spread to the united states and central america, despite similar ecological conditions and a geographical position in the path of the widespread - subtype iab outbreak. other epizootic amplification hosts are being sought in mexico to explain the sudden emergence of vee in , but selection by deforestation for adaption to an alternative, non-sylvatic vector may also be involved . this similarity . phylogenetic studies concluded that the enzootic subtype id strains were ancestors of the epizootic viruses -now known to have evolved independently on at least three occasions (fig. ) . this led to the prediction, in , that additional epizootics would follow despite a -year hiatus . in the case of the - venezuelan outbreak, and both mexican outbreaks, phylogenetic studies identified sympatric, closely related enzootic strains that seemed to represent the epizootic progenitors. the venezuelan/ colombian isolates were almost identical to strains isolated in the same regions during a - epizootic/epidemic, suggesting either release from a laboratory source or unprecedented genetic stability in a cryptic, natural transmission cycle . enzootic and epizootic strains of veev use different vertebrate hosts and mosquito vectors (box ) . therefore, understanding mechanisms of vee emergence by antigenic shifts and the acquisition of the equine viraemia phenotype sympatric having overlapping geographical distributions. - , , , , subtype iab - subtype iab , - , , , - , subtype iab - - , indicate that viral adaptation to epizootic mosquito vectors might also be important for vee emergence , . recently, these findings were extended to the subtype id enzootic viruses (putative epizootic progenitors), supporting the role of adaptation to mosquito vectors in vee emergence , . interestingly, the same genetic determinant, the e -spike envelope glycoprotein, seems to regulate adaptation to both mosquito and equine hosts . studies are now underway to determine if the same amino-acid substitutions mediate both host-range changes. veev emergence -unanswered questions. there are many important unanswered questions about veev emergence. why has only one of the closely related enzootic veev lineages (fig. ) apparently generated all epizootic iab and ic strains responsible for major outbreaks? do slight differences in the gene and protein profiles of other enzootic veev lineages prevent adaptation to equine hosts and/or epizootic vectors by altering the effect of minor genetic mutations? as equine populations decline in latin america, and human and domestic animal populations increase, will the scale and frequency of vee epizootics decrease? can humans or domestic animals such as cattle replace equines as amplification hosts? humans can sustain levels of viraemia similar to those of equines, but are probably mosquito host range and emergence. as well as adaptation to equine amplification,veev emergence from enzootic progenitors requires an alteration in the mosquitovector host range. all seven of the vector species identified in enzootic veev cycles are members of the culex (melanoconion) subgenus of mosquitoes, and all of these mosquitoes are also members of the spissipes section (comprising species) of this subgenus . the ecological and physiological properties that facilitate efficient transmission of enzootic veev by these mosquitoes are unknown, but might include their relative population stability, as they inhabit areas around permanent water sources. however, during outbreaks, floodwater mosquitoes of genera such as ochlerotatus (formerly named aedes) and psorophora -which show large seasonal changes in population density -are the main transmission vectors of epizootic veev. outbreaks often occur in desert-like habitats -such as the guajira peninsula of venezuela and colombia -at times of unusually heavy rain. similar climatic events might contribute to the emergence of other arboviruses such as rift valley fever virus, which, unlike veev, is efficiently maintained by transovarial transmission . studies showing that ochlerotatus taeniorhynchus (probably the most important epizootic vector in coastal outbreaks) has a higher oral susceptibility to epizootic (subtype iab) compared with enzootic (subtype ie) veev zoonotic pathogens or diseases that normally circulate among nonhuman animals but that can be transmitted to humans. figure) . veev adaptation to domestic amplification hosts (equines) requires mutations in the e gene that encodes the envelope glycoprotein. these mutations increase the level of host viraemia, and have occurred at least three times during the past century. this change is accompanied by an alteration in the veev serotype to iab or ic. adaptation to epizootic mosquito vectors also seems to accompany some veev outbreaks. dengue viruses have emerged as the most important human arboviral pathogens by altering their host range, from non-human primate enzootic reservoirs to humans, in an ecologically and separately evolving urban endemic transmission cycle (see figure) . the four dengue serotypes all emerged independently as human pathogens hundreds to thousands of years ago, when human populations had attained sufficient density to enable continuous horizontal transmission, probably supplemented by vertical transmission in mosquitoes. ochlerotatus and psorophora spp. (veev), culex tritaeniorhynchus, culex spp. human amplification (for example, urban dengue virus,yfv, chikungunya) spillover from enzootic cycle (for example, wnv, sylvatic dengue virus, yfv, veev) amplification in domestic animals (for example, epizootic veev, jev) (weev) habitats. the adaptation of these viruses to equine hosts would have profound public and veterinary health implications. the recombinant ancestors of weev are eeev-and sindbis-like alphaviruses, both of which use avian enzootic hosts. however, eeev, but not sindbis, causes equine and human encephalitis, indicating that the non-structural and/or capsid-protein genes or cis-acting rna sequences are important determinants of this pathogenic phenotype . although jev is an arbovirus, it is a member of the genus flavivirus, family flaviviridae. the genome of jev is similar to that of veev, as it comprises a singlestranded, positive-sense rna molecule, approximately , nucleotides in length. however, in contrast with alphaviruses, the flavivirus genome has no ′ poly(a) tail. structural proteins, including a single envelope protein, are encoded by the ′ quarter of the genome. japanese encephalitis -the disease. although japanese encephalitis (je) has been recognized as a disease since the s (ref. ), the jev was first isolated in in tokyo, japan, from the brain of a fatal human exposed to mosquito vectors less frequently than domestic animals , . cattle, dogs and other domestic animals are susceptible to infection with veev, but levels of viraemias are low, and adaptation would probably be required for amplification in these hosts. during , epidemic vee occurred in regions of venezuela lacking equine populations, but with abundant goats, sheep and people, implicating humans or other animals as amplification hosts (g. medina and n. perez, personal communication). can epizootic veev strains persist in nature in the absence of efficient equine amplification and transmission? is epizootic adaptation to equine and mosquito hosts species-specific, resulting in a loss of fitness for the sylvatic hosts that are required for permanent viral circulation? further research is needed to predict the future impact of vee, and to design effective measures to prevent and control natural emergence events and possible terrorist introductions. there are other interesting questions about eeev and western equine encephalitis virus (weev). unlike veev, these viruses do not amplify efficiently in equines (they produce low levels of viraemia), and epizootics involve avian hosts and usually occur only in close proximity to their enzootic swamp (eeev) or agricultural the level of viraemia is too low to infect mosquitoes. similarly, an unusually wide range of animals, including birds, dogs, bats and snakes are dead-end hosts that are unable to infect mosquitoes. pigs and birds are the major amplifying hosts of jev, although infection usually does not produce clinical disease. these animals do, however, develop high-titre viraemias, which provide an excellent source of infection for mosquitoes. in parts of asia where pigs are often kept adjacent to human dwellings, these animals are an important source of viral amplification and significantly enhance human exposure and infection. also, as most domestic pigs are slaughtered by months of age, annual birth cohorts provide a population of animals that are susceptible to infection . as jev does occur in areas of asia where pig populations are low, they are not essential hosts for the enzootic transmission cycle. interestingly, in central java, where there are few pigs, it seems that cattle, which are normally considered a dead-end host, might be involved in the natural transmission cycle of jev . migratory birds allow jev to travel large distances. unlike veev, there case of encephalitis . jev is the largest worldwide cause of epidemic encephalitis. the virus causes epidemics of paediatric encephalitis, mainly in india, korea, china, south-east asia and indonesia. owing to its large geographical range, more than two billion people are at risk of infection, and case-fatality rates often exceed %. approximately , cases occur each year, of which , are fatal; importantly, up to % of those who survive the disease suffer from neurological sequelae that last from months to years. the ratio of apparent to inapparent (asymptomatic) infection varies from in to in , depending on the geographical area. for example, in northern thailand, cases of encephalitis caused by jev have been diagnosed each year since the late s, with most cases occurring during the rainy season in june, july and august. the fatality rate of virologically confirmed cases is %, and, in thailand, about in humans that are infected with jev develop encephalitis. similar to veev, jev is also a veterinary problem and horses can succumb to encephalitis. however, unlike veev, equines are dead-end hosts for jev, as ie-pa -menaii ie-gu - u ie-gu - u ie-mx -oax ie-mx - ie-mx -oax ie-mx - - id- proven. the differences in jev genotypes might have arisen in response to geographical variation in mosquito vectors or amplifying hosts. the relevance to human disease of the genotypic and antigenic differences among jev strains is unknown. early genetic studies used rna oligonucleotide fingerprinting to identify genetic differences; however, determination of the nucleotide sequence of the first jev genome in (strain jaoars , genotype iii) facilitated comprehensive genetic studies. representative genomic sequences of the four genotypes have been determined, and results are consistent irrespective of the technique used (t mapping, partial or complete genome sequencing). the genotypes show different levels of geographical clustering (fig. ) . genotype i is found in australia, japan, korea, northern thailand and cambodia; genotype ii is found in australia, southern thailand, malaysia, sarawak and indonesia; genotype iii is found throughout asia and genotype iv is found only in indonesia. initial studies suggested that there were genetic differences between strains associated with endemic (round the year) disease in tropical regions of asia such as malaysia, indonesia and the philippines, compared with epidemic (summer-only) disease in temperate regions of asia (for example, japan, taiwan, korea and china). however, this has not been confirmed, and differences in endemic and epidemic disease are probably due to climatic variation. je is an emerging disease, and its geographical distribution is increasing. australia is the latest country in which jev has been isolated, and the virus was probably introduced by viraemic migratory birds or wind-borne infected mosquitoes. most phylogenetic studies of the genus flavivirus imply that the flaviviruses originated in africa and then spread to other continents . phylogenetic studies of jev reveal that genotype iv is most divergent, with up to % nucleotide and . % amino-acid variation compared with genotype i, whereas the other three genotypes differ by no more than % at the nucleotide and . % at the aminoacid levels . the phylogeny of jev (fig. ) indicates that genotype iv, which is found only in indonesia, is ancestral. genotypes ii and iii have also been found, sometimes concurrently, in the indonesia/malaysia region. introduction of jev into badu island in the torres straits, australia, in involved genotype ii, whereas the subsequent introduction of jev into northern australia in involved genotype i. genotype iii is most commonly isolated, and is found throughout asia (but not australia). similarly, genotype iii was the only genotype found in japan until , when genotype i was first isolated. overall, these results indicate that jev originated in the indonesia/malaysia region and subsequently spread to surrounding areas and countries. the rate of evolution of jev indicates that it is a relatively 'young' virus, with genotype iv diverging from the progenitor ancestral virus is no evidence that enzootic jev requires adaptation (mutation and selection for replication in pigs or birds) to initiate amplification in these epizootic amplification hosts. the principal vectors of jev are culex tritaeniorhynchus mosquitoes, and maximum virus isolation rates from mosquitoes occur during late july, concurrent with human and equine epidemics. in malaysia, both culex gelidus and c. tritaeniorhynchus are important vectors. other mosquito vectors include members of the aedes, anopheles, mansonia and armigeres species. antigenicity and genotype of jev. studies have indicated that there are antigenic and genetic differences among jev strains, with at least four genotypes and five antigenic subtypes [ ] [ ] [ ] . these genotypes and subtypes might correspond, although this has not been experimentally proteins (part a in figure) . during infection, two mrnas are synthesized -a full length mrna that forms the viral genome and a smaller mrna that is used to produce virion (part b, right) shows the rna genome in the centre surrounded by copies of the capsid protein, and the lipid-bilayer envelope, which is derived from the host-cell plasma membrane. the capsid protein is arranged into hexons and pentons on a t = lattice, which complements the organization of the envelope glycoproteins. the e envelope glycoproteins are parallel to the envelope and the e envelope glycoproteins form spikes on the surface. the e protein is believed to be the site of mutations that alter the host range of veev for equines and mosquitoes to mediate epizootic emergence, probably through cellular-receptor interactions. the nucleocapsid (part c) has capsid proteins arranged with t = icosahedral symmetry. the figure was reproduced with permission from ref . it is thought that migratory birds might be important in the emergence of jev. the asiatic cattle egret (bubulcus ibis coromandus) is an important amplifying host, and its geographical range increased in asia during the nineteenth century because of changes in agricultural practices . this coincided with the evolution and spread of recent jev genotypes. it is also tempting to hypothesize that the second world war had an important role in jev emergence, because isolation of jev strains had been restricted to japan prior to this conflict. some important questions remain. why is genotype iv restricted to the indonesian/malaysian region, whereas recent genotypes are geographically more widespread? genotype iv has only been identified once (in ), from five mosquito isolates, and its ability to cause human disease is unproven. although it is thought that genotype iv existed prior to , this has not been confirmed. the sequence of the structural protein genes of a strain (muar) from malaysia indicates that muar is ancestral to genotype iv and is a fifth genotype (fig. b) source of the virus, because humans only develop a low-titre viraemia and are therefore considered deadend hosts. bioterrorism is also an unlikely source, as the epicentre of the outbreak was in the queen's district of new york city, and the virus was transmitted by mosquitoes. one explanation is that wnv was introduced to new york by a viraemic animal that was subsequently bitten by a mosquito, which then spread the disease to humans. many exotic animal species, particularly birds, are imported into the united states through new york, and it is possible that an imported viraemic bird initiated transmission. alternatively, an infected migratory bird might have carried the virus to the united states. normally, migratory birds fly in a north-south direction, rather than in an east-west direction. the north-south route would imply that the virus entered the united states from central/south america. this seems unlikely, as wnv was only found in the southern united states at least one year after it was discovered in new york. another possibility is the east-west route. although this might also seem unlikely, vagrant racing-pigeons from europe occasionally appear in the united states. recently, the uk media reported that a homing pigeon called 'billy' was released in france en route to britain, but instead flew to new york . finally, an infected mosquito that was transported aboard an aircraft could have introduced wnv to the united states. aircraft departing from the middle east to the united states are not routinely treated with insecticide, and mosquitoes often enter aeroplanes -attracted by humans or bright light. phylogenetic studies using both complete and partial genome sequences have shown that the wnv strain found in new york in is most closely related to a israeli strain isolated from a goose, which indicates that the virus was recently introduced into the united states. this conclusion was supported by serological studies that showed a lack of anti-wnv antibodies in individuals living in new york prior to (ref. ). initial studies revealed that the nucleotide sequences of strains found on the eastern seaboard of the united states were similar to the prototype 'new york ' (ny ) strain isolated from a flamingo in the bronx zoo, and indicated that the ny strain spread westward in - . recent studies have shown that a genetic variant termed 'north america' has arisen since and has replaced ny as the dominant genotype present in north america . the 'north america' genotype only differs by . % from ny , but has characteristic nucleotide and amino-acid substitutions. other genetic variants have been identified, including a south-east coastal texas genotype that differs by . % from ny and by . % from 'north america', and a mexican genotype that differs by . % from ny (ref. ). overall, these data might indicate a lack of darwinian selection in the evolution of a particular genetic variant, and support genetic drift of the virus during its dissemination across north america. consistent with this hypothesis, the southeast coastal texas genotype was only isolated in from the texas-louisiana border, and might have become extinct. to date, there is no evidence for selection of any phenotypic differences among north american strains, and it remains to be seen if wnv will evolve towards reduced virulence as it adapts to new hosts in the western-hemisphere ecosystem. there are many hypotheses about the mechanism of wnv emergence in the united states. it is unlikely that viraemic human travellers are a each year . in urban settings, denvs are transmitted among human hosts by the peridomestic mosquito vectors aedes aegypti and aedes albopictus. however, studies of dengue virus ecology in sylvatic habitats of west africa and malaysia , have identified transmission cycles involving non-human primates as reservoir hosts and arboreal, tree-hole dwelling aedes (stegomyia) spp. as vectors. efficient inter-human denv transmission probably requires a human population of , to million people, a feature of urban civilizations that did not exist until about , years ago, and therefore the sylvatic cycle is probably ancestral . endemic/epidemic denv is therefore thought to have evolved in africa or asia from sylvatic viral forms. initial phylogenetic studies of both endemic/ epidemic and sylvatic strains of denv- showed evolutionary divergence of these ecologically distinct forms . recent studies indicate that epidemic/endemic forms of denv- , - and - , which now use humans as reservoir hosts, evolved independently from sylvatic progenitors in the past , years, accompanied by host-range changes from non-human primates to humans, and from arboreal aedes spp. to a. aegypti and a. albopictus vectors , (fig. ) . the highly efficient peridomestic transmission cycle -which is now independent of the ancestral sylvatic cycles -benefits greatly from the ecology of a. aegypti. this species lays its eggs in waterstorage containers and in refuse, it readily enters human habitations and it often takes several blood meals during each reproductive cycle for both egg production and nutrition. once infected, this competent vector transmits the virus to many human hosts , . interestingly, as with sylvatic denv, a. aegypti originated from another tree-hole-dwelling aedes mosquito which is found in sylvatic african habitats (aedes aegypti formosus) . however, the sylvatic african forms of denv do not use a. aegypti formosus as a principal vector, and this subspecies is relatively refractory to infection . yellow fever virus also uses a. aegypti aegypti as its main vector during african urban epidemics, but this cycle seems to be temporary and cannot be detected during inter-epidemic periods. it is not known why yfv has not adapted to a permanent human-a. aegypti endemic cycle, which would have devastating public health implications. the adaptation of rna viruses to new hosts is generally host-specific . the evolutionary hypothesis therefore predicts that a. aegypti and a. albopictus should have increased susceptibility for endemic/ epidemic denv compared with its sylvatic progenitors. recent experimental infection studies of populations of a. aegypti and a. albopictus support this hypothesis. when fed blood meals containing equivalent viral titres, the endemic/epidemic strains of denv- consistently infect a higher proportion of mosquitoes than sylvatic strains . if similar adaptation to human hosts occurred during denv evolution, differences in pathogenicity might be expected between the endemic and sylvatic denv strains. studies are required in regions of africa and asia, where humans are exposed to sylvatic infection, to confirm these differences. genetic north america. however, differences in surveillance and the high incidence of human infection through blood transfusion, mother-to-foetus transmission, transmission in breast milk and by organ transplantation have caused major public health concerns [ ] [ ] [ ] [ ] [ ] [ ] [ ] . an important question that remains unanswered is how wnv will adapt to new ecosystems in the new world. there are two main hypotheses based on comparisons with other members of the jev group members. first, wnv could become enzootic and endemic, similar to st louis encephalitis virus (slev), and cause limited human disease through spillover. alternatively, the virus could become epidemic, similar to asian strains of jev, and could cause annual outbreaks affecting large numbers of humans and animals. the 'explosive' nature of the north-american wnv epidemic as well as the equine and avian epizootics might reflect highly efficient enzootic amplification and avian virulence. north-american birds have probably not developed resistance to wnv because of low levels of viral exposure. virulence in the avian host might subsequently decline because of the strong selection for resistance to wnv resulting from high bird-mortality rates. if resistance is accompanied by a decline in viraemia levels, enzootic amplification could subside. then, spillover to humans and equines would diminish. the transport of wnv into latin america by migratory birds raises important questions about pre-existing human and avian immunity to other flaviviruses such as slev, denv, yfv and rocio virus. cross-reactive immunity could protect against wnv infection and/or disease, or could increase pathogenesis through immune enhancement, which is thought to contribute to the aetiology of dengue hemorrhagic fever. it is still not known if wnv and south american flaviviruses can share the same hosts and ecosystems (similar to wnv and slev in the united states). it is also not known how wnv will spread and cause human disease in the presence of flavivirus antibodies. competition between wnv and slev for avian hosts and mosquito vectors might be expected to result in competitive exclusion of one of these viruses . however, these viruses coexist in the southern united states where they seem to use the same avian hosts and vectors. low rates of immunity to slev in birds and low rates of infection in c. quinquefasciatus might indicate that host resources are not limiting factors, which could allow for indefinite coexistence. denvs (serotypes - ) are the most important arbovirus human pathogens, and are also unusual as they use humans as reservoir hosts (see further information in the online links box). during the past years, the prevalence of dengue fever, as well as lifethreatening dengue haemorrhagic fever and shock syndromes, has increased exponentially, with approximately , million people (two-fifths of the world's population) at risk, and about million cases recorded peridomestic in, and around, human habitations. cycles that rely on humans as exclusive reservoir hosts. (the smallpox virus has been eradicated from natural transmission by smallpox vaccine and, similarly, poliovirus is nearly eliminated worldwide.) however, any eradication programme would rely on an inability of the sylvatic strains to re-emerge -currently the likelihood of this is not known. studies are required to quantify the number of mutations leading to vector adaptation during emergence of urban dengue from ancestral sylvatic cycles. this will allow assessment of the frequency with which arboviruses can undergo host adaptation. these studies are important because denv vaccines are currently being developed that could eradicate urban malaysia -p - malaysia -p - malaysia -p - thailand -tc philippines - philippines - philippines -h- -p thailand -d sri lanka -s malaysia -p - indonesia - indonesia - tahiti - results . another arbovirus, vesicular stomatitis virus (vsv), can also adapt simultaneously to sandfly and vertebrate host cells, and the mutation rate of the virus in specialized compared to alternating-host passages is the same. this contradicts the hypothesis that arboviruses are constrained in their evolutionary potential . surprisingly, vsv populations that are specialized for replication in vertebrate cells showed fitnessincreases for replication in sandfly cells, indicating a lack of specificity in some adaptation events. further study of these model systems is needed to determine if alternating passages generate mutations that increase fitness in both cell types, or if they generate a polymorphic population with host-cell-specific adaptive mutations. recent in vivo experiments have produced results that contradict the cell-culture experimental models of arbovirus evolution. when veev was placed into a laboratory transmission cycle -consisting of ten cycles in hamsters alternating with ten cycles in a. aegypti mosquitoes -genetic stability of the virus isolates was observed, and virus fitness was either reduced or unchanged. however, specialization for replication in the hamster host resulted in rapid increases in virus fitness with many mutations, consistent with virus adaptation and evolutionary constraints imposed by the alternating-host cycle of arboviruses . cell-culture models probably do not fully reflect in vivo conditions, as artefacts (such as selection for virus binding to heparin sulphate) might distort results , . the development of experimental systems to study mechanisms of replication of these important human and animal pathogens in different hosts should reveal how these rna viruses emerge to cause disease in humans. although it is still unclear if there are common mechanisms of emergence of arboviruses, studies using molecular genetics and viral ecology should enable researchers to predict emergent strains. furthermore, common determinants of emergence could be used to develop rationally designed antiviral strategies. although host-range changes have occurred throughout arbovirus evolution, with important consequences for human health, the ease and frequency with which these events occur is unknown. viruses that have obligate alternating replication cycles in taxonomically disparate hosts -vertebrate and arthropod -should be compromised because they are 'generalists', owing to their fitness in both hosts. other viruses that use a single host as their main reservoir might be able to adapt more readily to related hosts. this might account for the slow rates of evolution of most arboviruses (approximately substitutions per nucleotide per year) compared with many single-host rna viruses (approximately - substitutions per nucleotide per year) . experimental cell-culture model systems have been developed to test this hypothesis, but results are only partially supportive. in vitro transmission cycles of eeev have been established by serial passage in vertebrate (baby-hamster kidney), or mosquito (a. albopictus c / ) cells . eeev has also been introduced into an alternating-host cycle of both cell types to mimic the natural transmission cycle. as predicted, virus-fitness increases occurred in both hosts following specialization. viruses that had specialized to one host type showed a decline in fitness in the alternate cells, as well as in comparable vertebrate or mosquito cells, consistent with specificity of adaptation during specialization. surprisingly, the alternating-host-cell cycles resulted in simultaneous adaptation to both cell lines, with increased levels of fitness comparable to those associated with host specialization, contradicting the hypothesis that arboviruses are limited in their adaptation potential by the alternating-host transmission cycle. however, specialization resulted in a larger number of mutations than alternating-host passages, consistent with the reduced rates of nucleotide-sequence changes typical of arboviruses. alternating passage of eeev in chicken and mosquito cell lines produced similar origin of hiv- in the chimpanzee pan 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abortion experiences and preferences of transgender, nonbinary, and gender-expansive people in the united states date: - - journal: am j obstet gynecol doi: . /j.ajog. . . sha: doc_id: cord_uid: cty uho background transgender, nonbinary, and gender-expansive (tge) people who were assigned female or intersex at birth experience pregnancy and have abortions. no data have been published on individual abortion experiences or preferences of this understudied population. objective(s) to fill existing evidence gaps on the abortion experiences and preferences of tge people in the united states to inform policies and practices to improve access to and quality of abortion care for this population. study design in , we recruited tge people assigned female or intersex at birth and aged years and older from across the united states to participate in an online survey about sexual and reproductive health recruited through the pride study and online postings. we descriptively analyzed closed- and open-ended survey responses related to pregnancy history, abortion experiences, preferences for abortion method, recommendations to improve abortion care for tge people, and respondent sociodemographic characteristics. results the majority of the , respondents were less than years of age. respondents represented multiple gender identities and sexual orientations and resided across all four united states census regions. overall, ( %) respondents had ever been pregnant; these reported total pregnancies, of which ( %) ended in abortion. for respondents’ most recent abortion, ( %) were surgical, ( %) were medication, and ( . %) used another method (primarily herbal). most recent abortions took place at or before nine weeks gestation (n= , %). if they were to need an abortion today, respondents preferred medication abortion to surgical abortion three to one (n= versus n= ), but ( %) respondents did not know which method they would prefer. reasons for medication abortion preference among the respondents included a belief that it is the least invasive method (n= , %) and the most private method (n= , %). to improve accessibility and quality of abortion care for tge patients, respondents most frequently recommended that abortion clinics adopt gender-neutral or gender-affirming intake forms, that providers utilize gender-neutral language, and that greater privacy be incorporated into the clinic. conclusion(s) these data contribute significantly to the evidence base on individual experiences of and preferences for abortion care for tge people. findings can be used to adapt abortion care to better include and affirm the experiences of this underserved population. transgender, nonbinary, and gender-expansive (tge) people experience pregnancy and need abortions. [ ] [ ] [ ] transgender is an umbrella term that describes a person whose gender identity (e.g., man, nonbinary, woman) differs from the sex they were assigned at birth (i.e., female, intersex, male) which is typically based on external genitalia. cisgender describes a person whose gender identity aligns with the sex they were assigned at birth. nonbinary and gender- expansive are also umbrella terms that describe gender identities that are not limited to man or woman -they could be a combination of both or neither. transgender people are thought to make up at least . % of the total united states population or . million people. this proportion may be higher among younger people, especially when including nonbinary and gender-expansive identities: a recent study found that % of - -year-olds identified as transgender, % identified as agender, bigender, genderfluid or genderqueer, and another % identified as unsure or questioning. in short, % of those in this age group identified as transgender or gender non-conforming. population level data do not exist on the number of tge people in the united states capable of pregnancy. the majority of tge individuals assigned female sex at birth do not have surgeries to remove their internal reproductive organs (i.e., uterus, ovaries, and fallopian tubes), , and some report having sperm-producing sexual partners. , , as a result, a substantial proportion of tge individuals assigned female sex at birth may need pregnancy and/or abortion care during their lives. similarly, people with intersex conditions or differences in sex development (dsd) -a heterogeneous group that may or may not also be tge identified -may also need pregnancy and/or abortion care during their lives. , although current studies estimate that one quarter of all (presumably cisgender) women will have an abortion in the united states, no corresponding population-level data exist on the j o u r n a l p r e -p r o o f abortion rate among tge people who can get pregnant. the best approximation, from all known abortion-providing facilities in the united states, estimated that there were between and transgender and nonbinary abortion patients nationwide in . this incidence estimate, however, is likely an underestimate as not all providers collected data on the patients' gender identities and/or sex assigned at birth -necessary to identify tge people. , several studies have published data on abortions experienced by tge people in the united states. , a survey of transgender and gender non-conforming adults who were assigned female sex at birth found that ( %) reported having at least one unplanned pregnancy, and of these, ( %) ended in abortion. in a mixed-methods study of masculine identified people who were assigned female sex at birth, ( %) participants reported lifetime pregnancies, of which ( %) ended in abortion. we are not aware of any studies that describe the abortion types that tge patients have had, the gestational ages at which abortion care was accessed, or preferences for abortion care. there are well-established barriers to general health care for tge people, including discrimination based on gender identity in clinics, limited provider knowledge, refusal of care provision, lower rates of insurance coverage than the general united states population, and more frequent discrepancies between gender presentation/identity and sex/gender indicated on administrative documents compared to cisgender women. [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] these barriers result in delays, denials, and extra charges for care. , , , these same barriers likely hinder access to abortion care. [ ] [ ] [ ] [ ] [ ] [ ] to begin addressing these barriers to care, foundational epidemiological data on abortion -a major pregnancy and reproductive health outcome -among tge individuals are needed to inform the adaptation of abortion care. stakeholders -including researchers, health care providers, and community members -have called for these data. , , design and format have been described in detail elsewhere. all survey questions allowed for a "prefer not to say" or "i don't know" response option to ensure completeness of responses. to prevent multiple responses from any participants, we enabled the "prevent ballot box stuffing" feature and reviewed participant ip addresses; ip address data were subsequently deleted. participants who completed the survey were entered into a randomized drawing to win a $ electronic gift card ($ , in gift cards were distributed in total). key variables included experiences with abortion, recommendations for improving abortion care, measures of abortion method preference, and respondent sociodemographic characteristics. to evaluate experiences of abortion, the survey included a pregnancy history module that prompted respondents to enter each pregnancy they had experienced. for each pregnancy, participants were asked whether they were trying to get pregnant and to indicate how each pregnancy had ended. for respondents that reported a prior abortion, survey questions assessed how many abortions and the types of abortions that they had experienced. for a respondent's most recent abortion, additional survey questions inquired about the abortion type and gestational age at which the abortion took place. among those who reported a prior abortion, respondents had the opportunity to indicate recommendations for improving abortion care from a list of ten options, including the option to write-in a recommendation. to measure abortion method preference, all respondents were asked: "if you needed an abortion now, what type of abortion would you prefer?" the response choices included "medication abortion", "surgical abortion", "not listed" (with an option to write-in a method), or "i don't know". the survey then prompted respondents to answer the question: "what are the main reasons that this is your preferred method of abortion?" respondents could select up to three options from a multiple- choice list of reasons related to method privacy, cost, accessibility, pain, familiarity, and more, including a write-in response. the full text of the survey has been published elsewhere. specific sociodemographic characteristics included age at the time of survey initiation, gender identity, sex assigned at birth, intersex identity, sexual orientation, race/ethnicity, education level, health insurance coverage, and region of residence. for gender identity, sexual orientation, and race/ethnicity, respondents could select all options that applied, or write-in their own option. proportion of the total number exposed to study information), and , from the pride study ( . % of pride participants likely eligible due to reporting female sex assignment at birth, or with missing data for assigned sex at birth). in response to a question on sex assigned at birth in this current survey, , of these , pride participants reported having been female sex assigned at birth, , reported male, eight each reported neither or preferring not to say, and did not respond to the question. approximately half of the pride participants who responded to this survey and reported having been female sex assigned at birth ( . %) identified as cisgender sexual minority women, and thus, their results are not presented here. among all respondents to the survey, , expressed a gender identity that aligned with the larger umbrella of tge and were female or intersex assigned at birth. the majority of these participants (n= , , %) were recruited through the pride study, and the rest from the general public (n= , %). details of study screening and recruitment are reported elsewhere. among the , participants, most were younger than years (median= ; table ). the most common gender identity was nonbinary ( %), followed by transgender man ( %), and genderqueer ( %); % of respondents reported more than one gender identity. most ( %) respondents reported having been female sex assigned at birth, with % identifying as intersex. respondents reported a range of sexual orientations, most frequently queer ( %), followed by bisexual ( %) and pansexual ( %). respondents were primarily white ( %), well-educated, and most ( %) had health insurance coverage. for the lifetime pregnancies reported across ( %) respondents, ( %) were retrospectively reported as unintended. of these ever-pregnant respondents, ( %) reported at least one pregnancy ending in abortion. these respondents reported a total of abortions. fifty-two respondents reported a single abortion, nine reported two abortions, and six reported three or more (table ) . for respondents' most recent abortion, ( %) were surgical, ( %) were medication, and ( . %) were another method (primarily herbal). nearly two thirds of respondents' most recent abortions took place at or before nine weeks gestation (n= , %) ( table ) . j o u r n a l p r e -p r o o f the respondents who reported a pregnancy ending in abortion offered gender-related recommendations to improve the abortion care experience as a tge person. specifically, respondents most frequently recommended that clinics adopt gender-neutral intake forms that are gender and sexual orientation affirming, and that staff utilize gender-neutral language (table ) . other respondent recommendations related to specific ideas for increasing the availability of affirming abortion care, as well as increasing patient privacy within and outside of abortion facilities. when asked about abortion method preference, respondents ( %) preferred medication abortion over surgical (n= , %) or an unlisted method (n= , %) (figure ) , while respondents ( %) did not know what type of abortion they would prefer. among the respondents who wrote-in an unlisted method, indicated that they would never get an abortion because of opposition to abortion or inability to get pregnant; five indicated that they would base the decision on the provider's recommendation; two stated that either method was fine; and two indicated a preference for an herbal method. while medication abortion was the most preferred method among both those who had experienced an abortion and those who had not ( % versus % respectively), a higher proportion of respondents who had experienced abortion reported a preference for surgical abortion than among respondents who had not experienced abortion ( % versus %); while a lower proportion of those who had experienced abortion did not know what type they would prefer ( % versus %). among the most recent abortions, % of people who preferred surgical abortion had obtained a surgical abortion, while only % of those who preferred medication abortion had obtained a medication abortion. overall, the most common reasons given for preferring medication abortion included "this method is the least invasive" (n= , %); "this method feels the most private" (n= , %); and "this method does not require anesthesia" (n= , %) ( table ). thirty-one respondents wrote-in a reason for preferring medication abortion, which included a desire to avoid interactions with medical providers where they could be misgendered or traumatized (n= , . %), and the ability to manage the abortion themselves in the privacy of their own homes without having to face protestors (n= , . %). among the respondents who indicated a preference for surgical abortion, the most common reasons included "i feel most comfortable with the type and number of medical staff present for this option" (n= , %); "this method would take the least amount of time (is fastest)" (n= , %); and "the method is the least painful" (n= , %) (table ) . write-in responses from participants who preferred surgical abortion included an aversion to the hormones contained in medication abortion (n= , %), a greater certainty that the abortion would be a success (n= , %), a desire to avoid passing the pregnancy at home (n= , %), and a sense that surgical would be less traumatizing than medication abortion (n= , %). these results demonstrate that tge people assigned female or intersex at birth in the united states have medication, surgical, and herbal abortions. respondents reported nearly one in five abortions occurring past the gestational limits for medication abortion ( weeks), which may account for the higher number of surgical abortions reported as compared to medication abortions, despite a three to one preference for medication abortion. notably, nearly one third of respondents did not know what type of abortion they would prefer if they were to need one today. to improve abortion care for tge patients, respondents recommended that abortion providers incorporate affirming intake forms into clinics and that staff and clinicians use gender-inclusive language. the primary limitation of this study is the lack of representativeness of the study population. because no known sampling frame exists for recruiting tge people assigned female or intersex at birth, we relied on convenience sampling. the extent to which these findings are generalizable to all tge people assigned female or intersex at birth is unknown. additionally, although ( %) respondents indicated a race or ethnicity other than "white", some racial and ethnic groups had low representation, and more specific studies focused on the experiences of tge people of color and the intersection of various sociodemographic characteristics is warranted. lower numbers of participants from multiple racial groups precluded our ability to assess if and how these abortion experiences and preferences represent a diversity of experiences -particularly when disparities in abortion care along racial lines are well established. these limitations are balanced by strengths. this is the first quantitative study to report on abortion experiences and preferences of tge people in the united states. further, the large number of respondents, several orders of magnitude larger than prior sexual and reproductive health studies among this population, , , , provides more descriptive information than previously available. the study was performed in a community-dwelling sample rather than a clinical sample. the survey instrument, as well as recruitment efforts, were co-created by our interdisciplinary research team in close collaboration with a community advisory team ; community engagement was essential to reaching respondents and to ensuring that the survey centered the experiences of the target populations. clinical implications the implications of these findings are that people of various gender identities and experiences have abortions, and thus abortion providers must ensure that systems serve the abortion needs of people with varying gender identities and experiences. revising clinic intake forms to assess capacity and desires for pregnancy in a gender-neutral way, as well as systematically incorporating similar questions into conversations between providers and patients, may help to identify patients capable of pregnancy and prompt pregnancy options counseling. , several studies evaluating clinician knowledge and comfort with care provision for tge populations found self-identified gaps in provider knowledge about tge health care, as well as a lack of confidence, sense of preparedness, or experience with providing care to these populations. - therefore, clinicians should seek out training on how to provide gender- affirming sexual and reproductive healthcare for tge patients to improve the appropriateness and quality of care. perhaps relatedly, many respondents in this study did not know which abortion type they preferred, suggesting that clinicians and counselors should incorporate more information about abortion options in conversations with tge patients, including advocating for and distributing abortion education materials that are inclusive of many genders, not only cisgender women. clinicians should also consider that reasons for preferring one method of abortion over another may differ for tge patients as compared to cisgender women patients. prior studies of abortion method preference among (presumably) cisgender women, although most published following the introduction of medication abortion in the united states, found that women's preferences for abortion were motivated primarily by fears of bleeding, complications, or anesthesia, as well as beliefs about which method was more "natural", and the time involved for either method. while tge respondents shared some reasons consistent with those reported by cisgender women previously, the importance of privacy and minimizing the invasiveness of the experience emerged more strongly among those who preferred medication abortion - considerations central to tge patients, a community commonly subjected to unnecessary medical questioning, exams, or even assault on the part of providers. despite a strong preference for medication abortion, more than twice as many respondents had accessed surgical abortion as compared to medication abortion. these data highlight a gap between preferred abortion method and obtained abortion method -a gap that future research should explore. further, while most respondents obtained an abortion prior to ten weeks gestation, one in five obtained an abortion ten weeks or later. future research should explore barriers and facilitators to abortion care generally as well as potential delays throughout the process of obtaining an abortion. finally, most abortion care research in the united states focuses almost exclusively on the experiences of cisgender women, despite these and other recent findings that demonstrate that tge people want, seek, and obtain abortions. these results emphasize the need for greater awareness and sensitivity to the inclusion of tge people in research on abortion preferences and experiences and there is growing operational guidance towards these aims. more support from the clinic staff more privacy within the clinic more support from my provider better pain management during abortion more time in recovery none of these j o u r n a l p r e -p r o o f what are the main reasons this is your preferred method of abortion? n % n % n % this method is the least invasive figure . abortion method preference among an online sample of transgender, nonbinary, or gender expansive people assigned female or intersex at birth in the united states (n= , ) family planning and contraception use in transgender men transgender abortion patients and the provision of transgender-specific care at non-hospital facilities that provide abortions contraceptive use and pregnancy intentions among 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hui, jane yuet ching; yuan, jianling; teoh, deanna; thomaier, lauren; jewett, patricia; beckwith, heather; parsons, helen; lou, emil; blaes, anne h.; vogel, rachel i. title: cancer management during the covid- pandemic in the united states: results from a national physician cross-sectional survey date: - - journal: am j clin oncol doi: . /coc. sha: doc_id: cord_uid: ohzkpbwy objectives: the coronavirus disease (covid- ) has significantly impacted health care delivery across the united states, including treatment of cancer. we aim to describe the determinants of treatment plan changes from the perspective of oncology physicians across the united states during the covid- pandemic. methods: participants were recruited to an anonymous cross-sectional online survey of oncology physicians (surgeons, medical oncologists, and radiation oncologists) using social media from march to april , . physician demographics, practice characteristics, and cancer treatment decisions were collected. results: the analytic cohort included physicians: ( . %) surgeons, ( . %) medical oncologists, and ( . %) radiation oncologists. in all, . % were practicing in states with to confirmed covid- cases as of april , , and . % were in states with > cases. most physicians (n= ; . % of surgeons, . % of medical oncologists, and . % of radiation oncologists) had altered cancer treatment plans. most respondents were concerned about their patients’ covid- exposure risks, but this was the primary driver for treatment alterations only for medical oncologists. for surgeons, the primary driver for treatment alterations was conservation of personal protective equipment, institutional mandates, and external society recommendations. radiation oncologists were primarily driven by operational changes such as visitor restrictions. conclusions: the covid- pandemic has caused a majority of oncologists to alter their treatment plans, but the primary motivators for changes differed by oncologic specialty. this has implications for reinstitution of standard cancer treatment, which may occur at differing time points by treatment modality. t he novel coronavirus (sars-cov- ) and subsequent disease (coronavirus disease ) was identified in wuhan, china, in december , and first reported in the united states on january , . since then, the number of covid- cases has continued to rapidly rise across the country, with a cumulative , confirmed cases and a total of , covid- deaths as of april , . early reports have also indicated that older adults or adults with underlying comorbid illness and/or suppressed immune response are more likely to be severely affected by concurrent with this new health threat, patients in the united states continue to be diagnosed with cancer. it is estimated that . million new cancer cases were diagnosed in in the united states, many of whom are currently receiving or will require treatment amid the crisis. the covid- pandemic poses a challenge for cancer patient management, due to the implementation of social distancing to reduce transmission of sars-cov- - and the depletion of health care resources and personal protective equipment (ppe) supplies. in march , the centers for medicare and medicaid services (cms) temporarily expanded coverage for beneficiaries to receive health care services through virtual visits to facilitate social distancing. in the same month, surgeons were advised by the us surgeon general and by the american college of surgeons (acs) to triage and postpone elective surgeries in order to conserve ppe and to prepare for a surge in covid- patients requiring all levels of care. professional societies such as the society of surgical oncology, the american society of clinical oncology (asco), the american society for radiation oncology, the american society of breast surgeons, and the society of gynecologic oncology (sgo), are also issuing recommendations regarding cancer care delivery during the pandemic. we sought to describe the determinants of oncology treatment plan changes from the physician perspective during the covid- pandemic. do) who treats cancer patients in the united states, physician age: years or older, and ability to read/write in english. individuals were recruited over a -week period (march to april , ) using snowball convenience sampling methods with social media platforms facebook (posting in national and minnesotan physician groups and various women physician groups), linkedin, and twitter (from university of minnesota masonic cancer center, american cancer society, and personal twitter accounts of the authors). invitations to participate in the survey were also posted on acs, asco, and sgo (physician-only) online discussion forums. in addition, emails with a survey link were sent by the american cancer society to cancer programs in the north region, covering states. survey data were collected and stored using redcap, a web-based data collection tool. measures survey items included demographics and measures of clinical practice size and location, personal concerns about covid- , effects of covid- pandemic on cancer patient treatment, sources of information about covid- , and emotional health. validated measures were used or modified as appropriate when possible. general demographic data on participants were obtained by self-report but no identifying data were collected. the number of covid- cases in each state was determined using data from the centers of disease control and prevention (cdc) as of april , , the half-way point during the study recruitment period. the categorization provided by the cdc resulted in groups to which respondents were assigned, based on the number of confirmed covid- cases in their state: to , to , to , and or more. physicians were asked whether they had to cancel/postpone/alter cancer treatments (surgery, chemotherapy, radiation therapy) and response options were "yes," "no," "no, but will have to reassess this," and "not applicable." physicians who answered "yes" were then asked to select reason(s) for altering cancer treatment plans from a list of prespecified options. physicians were asked to select all reasons that applied, rather than being limited to ascribing their decisions to a single motivation. the analyses for this study were limited to participants who provided their oncology specialty (surgical, medical, radiation). participant characteristics and responses were summarized using descriptive statistics. we assessed factors associated with treatment decision-making ("yes altered" vs. "no but plan to reassess") using χ tests and fisher exact tests as appropriate for categorical variables, and t tests assuming unequal variances for continuous variables. we also compared reasons for altered treatment plans by medical specialty using χ tests. data were analyzed using sas . (cary, nc), and p-values < . were considered statistically significant. a total of individuals clicked on the survey link and ( . %) were eligible physicians who proceeded on to the survey itself ( fig. ) . among eligible physicians, provided information about their medical specialty (surgical, medical oncology, radiation oncology, other), of which physicians reported "other" and were excluded from this analysis. in our study of oncology physicians, ( . %) were surgeons, ( . %) medical oncologists, and ( . %) radiation oncologists ( a majority of respondents were from states with > confirmed covid- cases (as of april , ), with . % practicing in states with to cases, and . % practicing in states with > cases. over half of the respondents ( . %) thought they had adequate ppe for clinical practice. there were no differences in the reported adequacy of ppe by the statewide number of confirmed covid- cases (p = . ). participants reported that the covid- pandemic has significantly interfered with their ability to provide treatment to active cancer patients (mean, . . on severity scale, from = no problem to = severe problem). of the respondents, ( . %) reported they have already altered treatment plans; respondents had not yet altered plans, and of these, ( %) planned to reassess. most ( . %) surgeons reported cancelling or postponing their patients' cancer surgery, with . % of those who delayed cases referring patients for alternative treatment in the meantime. similarly, a majority of medical oncologists ( . %) and radiation oncologists ( . %) reported altering their patients' chemotherapy and radiation therapy plans, respectively. most physicians in all specialties were concerned about their patients' risk of covid- exposure (table ). however, medical oncologists were more likely than surgeons or radiation oncologists to alter treatment plans due to this reason ( . % vs. . % vs. . %, respectively, p = . ). surgeons, more so than medical oncologists or radiation oncologists, were driven to alter cancer treatment plans by the desire to conserve ppe ( . % vs. . % vs. . %, respectively, p < . ), institutional mandates ( . % vs. . % vs. . %, p < . ), and professional medical organization recommendations ( . % vs. . % vs. . %, p < . ). radiation oncologists were more likely than surgeons or medical oncologists to alter treatment plans due to logistic concerns such as the new strict visitor policy ( . % vs. . % vs. . %, respectively, p = . ). though not statistically significant, radiation oncologists were also more likely than surgeons or medical oncologists to alter treatment plans due to concerns about exposure risk to health care workers ( . % vs. . % vs. . %, p = . ). we assessed physician demographic and practice factors associated with self-reported cancer treatment plan alteration by april , ( table ). the respondents who replied that they had not altered treatment plans and did not plan to reassess were excluded from this analysis. we found that female physicians ( . % vs. . %, p = . ) and physicians who practice in states with higher numbers of confirmed covid- cases ( . % > cases vs. . % to cases, p = . ) were more likely to have already altered their patients' cancer treatment plans compared with those who plan to reassess. those who treat hematologic malignancies were less likely to have altered their treatment plans compared with those who do not treat these malignancies ( . % vs. . %, p = . ). none of the other factors, including race/ethnicity, medical specialty, practice settings, hospital size, and perceived adequacy of ppe, were associated with the decision to alter treatment plans. of the physicians ( surgeons and medical oncologists) who reported they have not altered treatment plans and did not plan on reassessing, only practiced at an academic institution, and six practiced in a rural community or small city/ town. interestingly, of the physicians practice in states with > confirmed covid- cases, although data specific to their communities is unknown. at~ to weeks after the first confirmed case of covid- in the united states, we found that the majority of physicians had already altered the oncology treatment plans, including surgery, chemotherapy, and radiation therapy, for their patients. the sweep of the pandemic across the world has prompted rapid and drastic changes to many aspects of daily and professional life. physicians who are not considered frontline in diagnosing and managing covid- patients have nonetheless had to rapidly adapt to changes in medical practice and policies in order to continue to provide care for conditions other than covid- . these changes affect patients with cancer, who by the nature of treatment of this heterogenous disease require frequent clinical evaluation and yet are also at high risk for severe manifestations of covid- due to immunosuppression. it is too early to tell how cancer patients will be affected directly by the virus and also indirectly by the consequences of the pandemic. early data from china , suggest that cancer patients may be at increased risk of severe illness from covid- , though susceptibility may be attributable to age, underlying lifestyle differences such as smoking history, or presence of cancer. without definitive data, it is challenging for physicians to determine how to balance the risks of covid- exposure and the consequence of postponing or altering cancer treatment in their patients. many professional medical societies as well as recognized experts in the field have published recommendations [ ] [ ] [ ] [ ] [ ] and editorials on triaging and managing patients with cancer during this new health crisis. however, as with any patient management, there is no "one size fits all" algorithm. we did observe that physicians who practice in states with higher numbers of confirmed covid- cases were more likely to have altered their treatment plans but do not have longitudinal data to assess how case numbers affect cancer care. we found that the drivers for altering treatment plans differed by specialty of the oncology physician. for surgeons in particular, recommendations from professional medical societies played a significant role. various professional medical societies did differ in the timing and level of detail in their recommendations for managing cancer patients during covid- , and thus it is difficult to draw specific conclusions regarding the differences on reliance on these recommendations across medical specialties (surgery vs. medical oncology vs. radiation oncology), given that this is a single cross-sectional survey. however, our findings highlight the important roles that professional medical societies can play when we are confronted with a health crisis that reaches all disciplines. it is important that societies make recommendations in a timely manner, and also to update them frequently as needed even logistical and operational changes such as visitor restrictions and cancelation of patient accommodation/travel can have significant impact on the delivery of oncology care, particularly when multiple visits in succession are necessary. medical and radiation oncologists are having to take these factors into consideration when making treatment recommendations to cancer patients, especially for those who have transportation, mobility and/or financial challenges. finally, there is the concern about covid- exposure itself. most physician respondents of all specialties were concerned about their patients' risk of contracting sars-cov- . medical oncologists especially have had to weigh the risks of potentially immunosuppressive treatment against the cancer treatment benefits in this unprecedented context. furthermore, approximately half of our survey respondents also cited concerns regarding exposure risks to health care workers. cancer treatments involve interactions with multiple other health care workers, such as medical assistants, nurses, surgical technicians, nurse anesthetists, phlebotomy laboratory staff, radiation therapists, etc., in addition to physicians involved, which challenge the social distancing paradigm. we found that physicians who practice in states with a higher covid- case count were more likely to have already altered cancer treatment plans. this finding is in keeping with what we would have expected, as resources are more likely to be diminished in these states and physician concern heightened. we also observed that women were more likely to have already altered cancer-treatment plans. additional analysis of the selfreported reasons for altering treatment plans revealed no sex differences in the endorsements of the reasons listed in table . it is not readily apparent why women were more likely to have already altered treatment plans. when data for this analysis were collected, public health concerns many parts of the united states were primarily centered around an impending surge in covid- cases of uncertain magnitude; but in some states, covid- cases were already spiking. alterations to cancer care during this time have to be interpreted in the context of this sudden unprecedented health crisis and the surrounding uncertainty. in the long run, altered cancer treatment regimens will also have public health consequences. , cancer treatments and screenings that have been delayed but cannot be canceled will create a care backlog, and may negatively affect cancer outcomes in the future. by reducing the population's vulnerability to one threat, we inevitably risk increasing its vulnerability to other threats. cancer care recommendations going forward will likely change again as the balance of covid- versus cancer risks keeps shifting with time. there are several limitations to this study. because it is a survey-based study, there is an inherent response bias. it may be that physicians who have found that they have had to adjust their practice as a result of the pandemic were more likely to participate in this survey study. we chose a social media recruitment method in order to disseminate this survey to reach a broad audience quickly. however, because of this, we are unable to directly compare respondents with nonrespondents. to enhance response rate, certain known oncologic social media groups were targeted, further contributing to selection bias. this resulted in a disproportionately high number of respondents from minnesota. in contrast, new york, one of the states with the highest impact from covid- , had a low response rate. finally, there were more female than male respondents, which may have biased our findings; our finding that female physicians were more likely to have already altered treatment plans may have been driven by unmeasured confounding in our univariate analysis. because of the number of survey respondents, we were unable to perform multivariable analysis of these physician or practice factors to explore potential interactions. we were unable to assess specific aspects of treatment plan alterations with this current survey, beyond postponing surgeries, altering chemotherapy plans, and altering radiation therapy plans. we surveyed oncology physicians broadly across the united states, thus assuming that a broad range of cancer (and thus treatment) types would be included. while responses regarding specific procedures or chemotherapy regimens would be informative, our primary goal was to obtain a broad assessment while minimizing attrition during the survey. similarly, we did not assess whether and how telemedicine was adopted by oncology physicians given the recent cms expansion of virtual visit coverage. this would be an important topic for future work in the examination of how the covid- pandemic has affected cancer care in the united states. despite these limitations, we include a large population of oncology physicians currently treating cancer patients around the united states, identifying important treatment changes occurring during the covid- pandemic to allow for opportunities for ensure high quality cancer care for the . million individuals diagnosed with cancer in the united states last year. our findings suggest that as the number of cases of covid- fluctuates throughout different states and as professional or regulatory guidance changes, cancer treatment decision-making will likely similarly fluctuate and change. timely updates from professional organizations is extremely important in guiding our oncology physicians. future studies will no doubt look back on the covid- pandemic to examine the "fallout" of this pandemic as it relates to cancer patient screening, diagnosis, treatment, and outcome. this study provides a glimpse of the physician perspective early on in the covid- pandemic. cancer care treatment plan changes have occurred during the covid- pandemic. in addition to concerns regarding covid- exposure risks, physicians are having to weigh additional factors, such as conservation of ppe, external recommendations, and operational changes when deciding how to care for oncology patients during this health crisis. this has implications for how standard cancer care is reinstated after the pandemic has resolved. bold values indicate statistical significance (p < . ). *eight ( %) respondents said they have not altered treatment plans and did not plan on reassessing; they were excluded from this analysis. three respondents did not answer this question. †as of april , . covid- indicates coronavirus disease ; ppe, personal protective equipment. clinical features of patients infected with novel coronavirus in wuhan covid- ) cases in us centers for disease control and prevention. national vital statistics system. provisional death counts for coronavirus disease (covid- ). . available at covid- in critically ill patients in the seattle region-case series seer data submission, posted to the seer web site interventions to mitigate early spread of sars-cov- in singapore: a modeling study executive department state of california emergency executive order - directing minnesotans to stay at home how should us hospitals prepare for coronavirus disease (covid- )? medicare telemedicine health care provider fact sheet covid- : recommendations for management of elective surgical procedures covid- resources covid- patient care information available at: https://www. astro.org/daily-practice/covid- -recommendations-and-information/ clinical-guidance recommendations for prioritization, treatment, and triage of breast cancer patients during the covid- pandemic: executive summary. the american society of breast surgeons anti-cancer therapy and clinical trial considerations for gynecologic oncology patients during the covid- pandemic crisis. society of gynecologic oncology research electronic data capture (redcap)-a metadata-driven methodology and workflow process for providing translational research informatics support managing cancer care during the covid- . pandemic: agility and collaboration toward a common goal. j natl compr canc ne cancer patients in sars-cov- infection: a nationwide analysis in china clinical characteristics of covid- -infected cancer patients: a retrospective case study in three hospitals within wuhan risk of covid- for patients with cancer risk of covid- for cancer patients thoracic surgery outcomes research network inc. covid- guidance for triage of operations for thoracic malignancies: a consensus statement from thoracic surgery outcomes research network oncology practice during the covid- pandemic between scylla and charybdis-oncologic decision making in the time of covid- a war on two fronts: cancer care in the time of covid- we conducted a cross-sectional anonymous online survey study of physicians who treat cancer patients in the united states. the study was reviewed and deemed exempt by the university of minnesota institutional review board. all participants were provided with an information sheet about the study and confirmed eligibility before completing the online survey. eligibility criteria included being a physician (md or key: cord- - rd ul authors: smith, kristine m.; anthony, simon j.; switzer, william m.; epstein, jonathan h.; seimon, tracie; jia, hongwei; sanchez, maria d.; huynh, thanh thao; galland, g. gale; shapiro, sheryl e.; sleeman, jonathan m.; mcaloose, denise; stuchin, margot; amato, george; kolokotronis, sergios-orestis; lipkin, w. ian; karesh, william b.; daszak, peter; marano, nina title: zoonotic viruses associated with illegally imported wildlife products date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: rd ul the global trade in wildlife has historically contributed to the emergence and spread of infectious diseases. the united states is the world's largest importer of wildlife and wildlife products, yet minimal pathogen surveillance has precluded assessment of the health risks posed by this practice. this report details the findings of a pilot project to establish surveillance methodology for zoonotic agents in confiscated wildlife products. initial findings from samples collected at several international airports identified parts originating from nonhuman primate (nhp) and rodent species, including baboon, chimpanzee, mangabey, guenon, green monkey, cane rat and rat. pathogen screening identified retroviruses (simian foamy virus) and/or herpesviruses (cytomegalovirus and lymphocryptovirus) in the nhp samples. these results are the first demonstration that illegal bushmeat importation into the united states could act as a conduit for pathogen spread, and suggest that implementation of disease surveillance of the wildlife trade will help facilitate prevention of disease emergence. no adequate estimate of numbers of wildlife traded throughout the world exists given the large size and covert nature of the business. beyond the threats to conservation, the intermingling of wildlife, domestic animals and humans during the process of wildlife extraction, consumption, and trade can serve as a vessel for pathogen exchange [ ] . nearly % of emerging infectious diseases in humans are of zoonotic origin, the majority of which originate in wildlife [ , ] . therefore infectious diseases acquired from contact with wildlife, such as occurs via the wildlife trade, are increasingly of concern to global public health. trade in live animals and animal products has led to the emergence of several zoonotic pathogens, of which rna viruses are the most common. sars emerged as a respiratory and gastrointestinal disease in southwest china and within months had spread to other countries, eventually leading to , cases and deaths. masked palm civets (paguma larvata) traded in the markets of guangdong were found to be infected and a large proportion of the early cases were restaurant workers who bought and butchered wildlife from these markets [ ] . the united states is one of the world's largest consumers of imported wildlife and wildlife products [ ] . between and , approximately . billion live wild animals (around , , per year) were legally imported into the united states nearly % of which were destined for the pet industry [ ] , and an average of over million kilograms of non-live wildlife enter the united states each year [ ] . new york is the most frequently used port of entry into the united states, and in combination with los angeles and miami accounts for more than half of all known wildlife imports. imports most often refused entry (i.e., deemed to be illegal) into the united states included those from china, philippines, hong kong, thailand, and nigeria [ ] -countries with endemic pathogens such as highly pathogenic h n influenza virus, nipah virus, and simian retroviruses. health risks to the us public, agricultural industry, and native wildlife posed by the wildlife trade have generally not been quantified due to minimal surveillance of live animal imports and the absence of surveillance of wildlife product imports. despite this, known examples of disease introductions to the united states via the wildlife trade have included pathogens of risk to wildlife, livestock and public health such as amphibian chytridiomycosis, exotic newcastle's disease, and monkeypox, respectively. the monkeypox outbreak showed that a single shipment of infected animals can result in serious impact on public health, highlighting the challenges faced by agencies attempting to regulate both legal and illegal wildlife trade. the usda regulates certain exotic ruminant species, some birds, some fish, a few species of tortoise, hedgehogs, tenrecs, and brushtail possums for specific foreign animal diseases to protect agricultural health. in general, there is no current remit for usda to regulate species as potential threats to wildlife or public health. species restricted by centers for disease control and prevention (cdc) include certain turtles, nhps, bats, civets, and african rodents. hunting and butchering of bushmeat (for the purpose of this paper to be defined according to oxford dictionary as the meat of african wild animals) has been increasingly recognized as a source of disease emergence. harvest of nhp bushmeat and exposure to nhps in captivity have resulted in cross-species transmission of several retroviruses to humans including simian immunodeficiency virus (siv), simian t-lymphotropic virus (stlv), and simian foamy virus (sfv) [ , ] . while siv and stlv adapted to humans and spread to become the global pathogens human immunodeficiency virus (hiv) and human t-lymphotropic virus (htlv), less is known about the distribution and public health consequences of sfv infection [ ] . much of the bushmeat smuggled into the united states from africa by air passes through europe en route, although amount and characteristics of bushmeat reaching us borders is not well described. one study estimated that tons of bushmeat was imported every year into paris roissy-charles de gaulle airport in france on air france carriers alone [ ] . under the authority of the public health service act, the us department of health and human service (dhhs), cdc is responsible for preventing the introduction, transmission, and spread of communicable diseases, including those from animals or animal products to humans. cdc recognizes the potential public health risk posed by illegal trade in wildlife and regulations are in place that prohibit the importation of bushmeat products derived from cdc-regulated animals. to better understand and educate the public about risks to public health from smuggled bushmeat, beginning in cdc and inter-agency and non-governmental partners initiated a cooperative effort to assess those risks. this effort includes a pilot study to screen for evidence of zoonotic pathogens in cdc-regulated wild animal products. here we report finding sequences of simian retroviruses and herpesviruses in bushmeat confiscated at five us airports. this pilot study was initiated at john f. kennedy airport (jfk) in queens, ny, where cdc-regulated wildlife products were seized by us customs and border protection (cbp) between october to september . beginning in april , additional seizures from another four airports that receive international flights (philadelphia, washington dulles, george bush intercontinental-houston, and atlanta hartsfield-jackson international) were included in the study. illegally imported shipments were confiscated opportunistically and thus the pilot study established only the presence and not the prevalence of zoonotic agents in the specimens. site of origin and destination, flight data, mail shipment or carrying passenger identification, date of arrival, and date of sample collection were recorded for each confiscation. items were photographed and identified to genus and species if possible. biological samples were processed for aliquoting and storage at the cdc quarantine laboratory at jfk airport, and any remaining tissues were incinerated according to standard protocols. all items were sampled while wearing full personal protective equipment and sterile instruments were used to avoid cross-contamination. the freshest part of each item was located (muscle appearing red or raw, joint fluid, bone marrow, etc.) and several samples were taken from each item, placed in cryotubes, and preserved immediately in liquid nitrogen. an additional collection of bushmeat items was seized by us fish and wildlife service (usfws) at jfk airport in , and provided for this study by usfws and the united states geological survey national wildlife health center (nwhc). specimens included those central to a federal case against a person caught smuggling bushmeat into new york for resale [ ] . these samples had been stored at usfws forensic laboratories at uc from until , when they were shipped to the nwhc for processing as part of this study. all specimens were then stored at uc, and thawed at uc before processing at the nwhc. tissue dissection was performed as described above with some minor differences; . cm samples were preserved in ml nuclisens lysis buffer (biomerieux inc, cat# ) prior to immediate storage at uc. permission was obtained from the new york department of agriculture and markets to transfer the frozen specimens from jfk airport to cdc national center for hiv/aids, viral hepatitis, std, and tb prevention (nchhstp), and/or columbia university's center for infection and immunity (cii) for testing. when an assured gross identification of species could not be made, samples were genetically identified by phylogenetic analysis of mtdna genes, including cytochrome c oxidase subunits i and ii (cox / ), and/or cytochrome b (cytb) [ ] [ ] [ ] [ ] [ ] . nucleic acids were extracted from - mg of tissue using mechanical disruption (qiagen tissue lyser ii or next advance inc bullet blender), followed by proteinase k treatment until complete digestion of the tissue was achieved. purification of subsequent homogenates was performed using the qiagen all-prep dna and rna extraction kit or dneasy blood and tissue kits according to the manufacturer's instructions. nucleic acid quality was determined using the agilent bioanalyser (agilent rna nano ) or ß-actin pcr as previously described [ ] . samples were screened for multiple pathogens as described in detail elsewhere, including: leptospira and anthrax [ ] , herpesviruses [ ] , filoviruses [ ] , paramyxoviruses [ ] , coronaviruses [ ] , flaviviruses [ ] , orthopoxviruses [ ] and simian retroviruses (siv, stlv, sfv) [ ] [ ] [ ] [ ] [ ] [ ] . all pcr-amplified bands approximately the expected size were confirmed by sequencing. raw sequences were analyzed and edited in geneious pro v . . and mega . . multiple sequence alignments were constructed using clustalw and phylogenetic comparisons made using neighbor-joining (nj) and maximum likelihood (ml) algorithms. modeltest was used to select the most appropriate nucleotide substitution model. support for branching order was evaluated using , nonparametric bootstrap support. sequence identity was calculated using uncorrected p-distances in paup* and blast. from october to september , postal shipments confiscated at jfk airport were included in this study. from june to september , an additional passenger-carried packages confiscated at the four other international airports were sampled for this study. additional confiscations were made but were not included in this study due to poor condition of sample (e.g., severely degraded or chemically treated). in many cases multiple separate packages were included in a single shipment or carried by a single passenger. specimens varied in condition, including items that were fresh, raw transported in a cooler, lightly smoked, or well dried (fig. a-d) . most items contained moist inner tissue. rna quality was low with a predominance of degraded, low molecular weight fragments in the samples, while bactin sequences were detected in the nhp specimens suggesting the presence of amplifiable dna (data not shown). samples from approximately animals were included in this study, including nhps comprising chimpanzees (pan troglodytes), mangabeys (cercocebus spp.), and guenons (cercopithecus spp.; one of which was further analyzed and identified as cercopithecus nictitans, white-nosed guenon) all confirmed by phylogenetic analysis; and rodents comprised of cane rats (thryonomys sp.) confirmed by gross or phylogenetic analysis, suspected cane rats (based on gross identification), and rats (unknown species) confirmed by gross identification. the usfws specimens from included an additional nhp tissues from individual animals including baboons (papio sp.) and african green monkeys (agms; chlorocebus sp.) all confirmed by phylogenetic analysis. both sfv and herpesviruses were detected in the nonhuman primate bushmeat samples. all positive nhp samples are presented in table . all nhp samples were negative for siv and stlv sequences. all rodent samples were negative for leptospira, anthrax, herpesviruses, filoviruses, paramyxoviruses, coronaviruses, flaviviruses, and orthopoxviruses. sfv polymerase (pol, -bp) and long terminal repeat (ltr, , -bp) sequences were detected at cdc in tissues from one chimpanzee (bm ) and one mangabey (bm ). sfv ltr sequences were also identified in a second mangabey (bm ). blast analysis of the -bp pol sequences from bm and bm showed maximum nucleotide identity to sfvs from p. t ellioti and mangabey (cercocebus atys and cercocebus agilis), respectively. phylogenetic analysis of the two pol sequences with those available on genbank confirmed that the chimpanzee sfv was highly related to sfv from p. t. ellioti whereas the mangabey sfv clustered tightly with sfv from sooty mangabeys (cercocebus atys) ( figure ) . p. t. ellioti are endemic to west-central africa in nigeria and cameroon while cercocebus atys are found in west africa from senegal to ghana. phylogenetic analysis was not performed on ltr sequences since only limited sfv sequences in this region are available at genbank. blast analysis was similarly limited and gave the highest nucleotide identity to chimpanzee and mandrill (m. sphinx) sfv ltr sequences, respectively. the two ltr sequences from mangabeys (bm and bm ) were % identical to each other due to an -bp deletion in the ltr of bm and nucleotide substitutions. in the usfws samples sfv pol sequences were present in / baboons, and in / agms. the baboon sfvs shared . % nucleotide identity, and had - % nucleotide identity with the agm sfv. phylogenetic analysis of the short ( bp) pol sequences shows that the three baboon sfvs clustered together, yet separately from the agm sfv -suggesting some genetic relatedness that reflects host specificity as previously demonstrated [ ] (figure ). however, while the short baboon sfv pol sequences detected in this study clustered together, they did not cluster with other published sequences from baboons ( . - . % nucleotide identity). similarly the agm sequences did not cluster with published agm sequences ( . - . % nucleotide identity). these results may reflect poor phylogenetic signal from limited sequence data in this region. all simian dna samples from usfws were also screened for larger sfv pol sequences ( -bp) as done at the cdc but were found in only one baboon sample (cii- ). phylogenetic analysis of the larger pol sequence inferred a significant relationship to sfv from guinea baboons (p. papio) (figure ), which correlated with the origin of the shipment (guinea). our inability to detect larger pol sequences in other sfv-positive baboon and agm samples may be due to highly degraded nucleic acids in those specimens (confiscated in ) which limits detection of longer sequences. two genera of herpesvirus were detected in nhp specimens, including cytomegaloviruses (cmv; betaherpesvirus) and lymphocryptoviruses (lcv; gammaherpesvirus) ( table ) . cmv sequences from baboons cii- and cii- shared . . % nucleotide identity indicating they are likely to be the same virus. comparison of this virus with the cmv sequence from whitenosed guenon bm showed these two cmvs are % identical. overall, nucleotide sequence identity within the cmvs (for sequences included here) was shown to be . - % (m = . %). lcvs were detected in four agms, two baboons, and one mangabey. lcv sequences in agms cii- and cii- were . % identical and likely represent the same virus. a comparison of this virus with the other lcvs detected showed . - . % sequence identity. sequence identity for the entire lcv group was calculated to be . - % (m = . ). phylogenetic analysis confirmed the presence and phylogenetic relatedness of cmv and lcv in these nhp specimens (figure ). multiple viruses were detected within some samples. both lcv and sfv were detected in the bone marrow of agm cii- and muscle of mangabey bm (table ) . cmv, lcv, and sfv were detected in baboon cii- (table ) . new sfv, herpesvirus, and mtdna sequences identified in the current study have been deposited at genbank with the following accession numbers: jf -jf and jf -jf . sequences less than bp are available upon request. our study is the first to establish surveillance for zoonotic viruses in wild animal products illegally imported into the united states in an effort to prevent the transmission of infectious agents from these shipments. the restricted number of samples included in this study were tested for a limited range of pathogens only and thus presence of additional pathogens not included in this study cannot be ruled out. we identified four sfv strains and two different herpesviruses (in some cases in the same tissues) in smuggled nhp bushmeat. using phylogenetic analysis and gross examination, we were able to determine that bushmeat from nine nhp species and at least two rodent species were attempted to be smuggled into the united states. these results are consistent with the origin of the shipments from west africa and included species of conservation importance (p. papio, cercocebus atys, and p. t. ellioti are classified as ''near threatened'', ''vulnerable'', and ''endangered'', respectively by the international union for conservation of nature), suggesting more education efforts or harsher penalties are needed regarding the handling, consumption, and illegal transportation of products from wildlife of conservation concern. in addition, the finding of mangabey, guenon, and cane rat bushmeat in our study is consistent with that reported by chaber et al who found these and bushmeat from nine other species entering paris-charles de gaulle airport [ ] . our finding of sfv dna in smuggled nhp specimens comprising of four species (baboon, chimp, mangabey, and agm) is significant because sfv is a known zoonotic infection of humans exposed to nhps. however, the mode of transmission to humans is poorly understood and while most infected people reported sustaining a nhp exposure (mostly bites) others did not, suggesting a less invasive mode of infection is possible [ ] . these viruses are probably not easily spread from human-to-human, although persistent infection has been documented [ ] . several sfv-positive people reported donating blood while infected and because blood banks do not screen for sfv, secondary transmission via contaminated blood donations may be possible [ ] . further research into the possibility of secondary transmission of sfv is required. the finding of sfv dna in the bushmeat samples highlights a potential public health risk of exposure to these tissues along the hunting, transportation, and consumption continuum with multiple opportunities for primary transmissions. unlike most retroviruses whose rna genome is packaged in the viral particles, foamy viruses are unusual in that dna and/or rna can be present in the infectious virus particles. thus, finding of only dna does not exclude that sfv in these tissues is not infectious, especially in the more recently cdc confiscated items which contained fresher tissue compared to the usfws items confiscated in that were partially degraded at the time of analysis in . human infection with sfv is of further concern because increases in the pathogenicity of simian retroviruses following cross-species transmission have been documented (e.g., hiv- and hiv- ) [ , ] . however, the limited number of cases, short follow-up duration, and selection biases in the enrolling of healthy workers or hunters to identify cases all limit the identification of potential disease associations [ ] . although we did not find siv or stlv in the limited number of specimens in this study, these viruses have been found in high prevalences in nhp specimens at bushmeat markets and in hunted nhps [ , , ] . hiv- and hiv- emerged as a result of several spillover events of siv from chimpanzees and mangabeys, respectively, that were likely hunted for bushmeat in central and western africa [ ] . serosurveillance studies have shown thirtyfive different species of african nhps harbor lentivirus infections, with a prevalence of siv in up to % of free-ranging chimpanzees, and - % of free-ranging sooty mangabeys and green monkeys [ , , , ] . to date, four groups of htlv viruses found in humans are believed to have originated from corresponding stlv strains in nhp species (including mangabeys, baboons, and chimpanzees) via multiple transmission events [ ] . htlv- , closely related to stlv- group viruses, infects to million people worldwide and is spread from person to person via bodily fluids [ ] . these viruses are capable of causing leukemia, lymphoma and neurologic disease in humans [ ] . discoveries of htlv- and htlv- , and a novel stlv- strain were recently made in nhp hunters in cameroon [ ] , and % of hunted bushmeat in cameroon has been shown to be infected with stlv strains [ , ] . although imported wildlife products are often not in a freshly-killed state, many are not smoked or processed in any manner, thus screening of larger sample collections of smuggled bushmeat may reveal evidence of these viruses. like retroviruses, herpesviruses can cause long-term latent infections in their host. most herpesviruses are host-specific, yet particular strains are capable of causing severe disease in the nonhost, examples of which include agents of malignant catarrhal fever and herpes b virus [ , ] . cmvs are in the betaherpesvirus subfamily. human cmv is typically asymptomatic in humans, with the exception of immunocompromised persons. similarly, many nhps are asymptomatic hosts of cmv that do not typically infect other species, including humans. however, baboon cmv (bcmv), like that identified in our study, has been shown to replicate in human tissues in vitro as well as infect and replicate in humans following a bcmv-positive liver xenotransplant [ ] . lymphocryptoviruses (lcv) are in the gammaherpesvirus subfamily, and include human lcv, and epstein-barr virus (ebv), the agent of infectious mononucleosis. nearly % of adults in the united states have antibodies indicating exposure at some point to ebv. lcvs are typically asymptomatic in their host, with the exception of immunocompromised individuals who may develop b-cell tumors. although much less efficient, baboon lcv can infect human b cells in immunocompromised persons or in persons co-infected with ebv and replicate in ebv-immortalized b cells with the theoretical potential for viral recombination [ ] . however, it is unknown if the novel herpesviruses found in bushmeat specimens in our study can easily infect humans handling these tissues. systematic studies examining herpesvirus transmission risks associated with handling or consumption of infected animal tissues have not been reported. in addition, virus isolation was not performed in our study to determine the infectiousness of the specimens at the time of confiscation. in summary, our study establishes initial surveillance methodology to detect and identify zoonotic pathogens and species of origin of wildlife products entering the united states. while we were successful in demonstrating the presence of sfv and herpesviruses in bushmeat specimens, our pilot study was limited by the range, number, and variable condition of products available to us and was not intended to be a comprehensive review of presence or to measure prevalence of all pathogens imported in wildlife products. because our study only included a small number of cdcregulated species and excluded products of ungulate, carnivore, reptile, avian and other origin, as well as any live animal imports, all of which may carry zoonotic pathogens or diseases that threaten domestic livestock or native wildlife, in addition to the fact that virus isolation was not performed in our study to determine the infectiousness of the specimens at the time of confiscation, there is a large component of zoonotic disease risk assessment not included in this study. a further understanding of pathogen movements through the trade will only be recognized through broader surveillance efforts and pathogen identification and discovery techniques in wildlife and wildlife products arriving at us ports of entry so that appropriate measures can be taken to further mitigate potential risks. wildlife trade and global disease emergence host range and emerging and reemerging pathogens overviews of pathogen emergence: which pathogens emerge, when and why epidemiologic clues to sars origin in china united states fish and wildlife service office of law enforcement intelligence unit. us wildlife trade: an overview for reducing the risks of the wildlife trade molecular detection of viral pathogens simian t-cell leukemia virus (stlv) infection in wild primate populations in cameroon evidence for dual stlv type and type infection in agile mangabeys (cercocebus agilis) the scale of illegal meat importation from africa to europe via paris the problems and promise of dna barcodes for species diagnosis of primate biomaterials identification of mosquito blood meals using mitochondrial cytochrome oxidase subunit i and cytochrome b gene sequences ancient co-speciation of simian foamy viruses and primates universal primer cocktails for fish dna barcoding dna primers for amplification of mitochondrial cytochrome c oxidase subunit i from diverse metazoan invertebrates naturally acquired simian retrovirus infections in central african hunters molecular detection of anthrax spores on animal fibres detection and analysis of diverse herpesviral species by consensus primer pcr rapid molecular strategy for filovirus detection and characterization sensitive and broadly reactive reverse transcription-pcr assays to detect novel paramyxoviruses identification of a severe acute respiratory syndrome coronavirus-like virus in a leaf-nosed bat in nigeria identification of a kunjin/west nile-like flavivirus in brains of patients with new york encephalitis detection of orthopoxvirus dna by realtime pcr and identification of variola virus dna by melting analysis retroviral antibodies in indians the simian foamy virus type transcriptional transactivator (tas) binds and activates an enhancer element in the gag gene frequent simian foamy virus infection in persons occupationally exposed to nonhuman primates coinfection of ugandan red colobus (procolobus [piliocolobus] rufomitratus tephrosceles) with novel, divergent delta-, lenti-, and spumaretroviruses human foamy virus: further characterization, seroepidemiology, and relationship to chimpanzee foamy viruses myasthenia gravis accompanied by thymomas not related to foamy virus genome in belarusian's patients aids as a zoonosis: scientific and public health implications origins of hiv and the evolution of resistance to aids simian t-lymphotropic virus diversity among nonhuman primates in cameroon risk to human health from a plethora of simian immunodeficiency viruses in primate bushmeat chimpanzee reservoirs of pandemic and nonpandemic hiv- primate parasite ecology: the dynamics and study of host-parasite relationships new hosts for equine herpesvirus b-virus (cercopithecine herpesvirus ) infection in humans and macaques: potential for zoonotic disease detection of infectious baboon cytomegalovirus after baboon-to-human liver xenotransplantation infection of human b lymphocytes with lymphocryptoviruses related to epstein-barr virus we thank the usfws forensics laboratory, ashland, oregon, and nathan ramsay, usgs national wildlife health center for assistance with this study. we thank the contributions of ecohealth alliance's consortium for conservation medicine. use of trade names for identification only and does not imply endorsement by the us geological survey national wildlife health center, the department of health and human services, the public health service, or the centers for disease control and prevention. the findings and conclusions in this report are those of the authors and do not necessarily represent the views of the national wildlife health center or the centers for disease control and prevention. key: cord- -kt rqx m authors: laird, frank n. title: sticky policies, dysfunctional systems: path dependency and the problems of government funding for science in the united states date: - - journal: minerva doi: . /s - - - sha: doc_id: cord_uid: kt rqx m leaders of the scientific community have declared that american science is in a crisis due to inadequate federal funding. they misconstrue the problem; its roots lie instead in the institutional interactions between federal funding agencies and higher education. after world war ii, science policy elites advocated for a system of funding that addressed what they perceived at the time as their most pressing problems of science-government relations: the need for greater federal funding for science, especially to universities, while maintaining scientific autonomy in the distribution and use of those funds. the agencies that fund university research developed institutional rules, norms, and procedures that created unintended consequences when they interacted with those of american higher education. the project system for funding, justified by peer-review and coupled with rapidly increasing r&d budgets, created incentives for universities to expand their research programs massively, which led to unsustainable growth in the demand for federal research money. that system produced spectacular successes but also created the unintended longer-term problem that demand for science funding has grown more quickly than government funding ever could. most analysts neglect potentially painful reforms that might address these problems. this case demonstrates that successful political coalitions can create intractable long-term problems for themselves. leaders of the scientific community have declared that american science is in decline and that the united states is losing its global scientific and engineering preeminence as other countries invest in improving theirs. the purported consequences of this decline will be nothing less than economic stagnation and a loss of national security. a national academy of sciences (nas) study framed the problem with its title: rising above the gathering storm. the study concluded that if the united states does not fix the problem, then "[f]or the first time in generations, our children could face poorer prospects for jobs, healthcare, security, and overall standard of living than have their parents and grandparents" (p. ). the nas study identified many causes of the decline, from restrictions on immigration to k- education, but the heart of the matter was too little federal funding for research, especially for universities. what the nas study did not recognize is that those funding problems had arisen from deeply embedded institutional features of federal science policy, not a stingy congress. the fundamental problem is that interactions between federal agencies and higher education have led to unintended consequences, creating an induced demand for research and development (r&d) funding for universities that has increased more quickly than r&d budgets ever could. in turn, that imbalance has led to increasing pressure on scientists operating within that system (bok : - ; howard and laird ) . solving this problem requires challenging the core institutional features of the existing system. the historical development of that system reveals that the scientific community, especially in universities, has become dependent on a persistent but dysfunctional system (pierson : ) . that dysfunction arises from core features of the policy itself. science policy elites have sought, without success, simply to push aside the constraints of budget policy-making instead of changing those core features. the current american research funding system arose after world war ii. the story is well-known (see greenberg ; hart ; h.r. rpt. a; kleinman ) , but i summarize it here to analyze some under-appreciated features of science policy that have led to the current problems with the system. prior to the war, government-funded research was, in most fields, small, consistent with total federal spending, which was a small part of the economy (omb ) . while the new deal greatly expanded the overall role of the federal government, federal r&d funding did not partake in that growth. instead, it was the war that provided a critical juncture for science policy, a historical moment that made it possible to institute radically new policies, which set the stage for the creation of new peacetime institutional rules and norms that would "trigger a process of positive feedback" (pierson : , n. ) . creating new rules and norms required challenging entrenched views within the scientific community, as well as within the federal government. odd as it may seem today, before world war ii many leaders of the scientific community resisted increased federal funding out of fear that government control would accompany such funding (greenberg : - ) . moreover, conservative americans hostile to government programs in general included many people in the scientific and engineering community (hart , chap. ) . as a result, the american scientific community devoted to basic research ("pure science" in an earlier idiom) was small and, in most fields of science, a backwater compared to that in europe. in december , then-secretary of commerce herbert hoover bemoaned the state of pure science in america, blaming it on the heavy emphasis government and industry put on applied science. he estimated that government and industry together spent about $ million per year on applied science but that government and philanthropy together only spent about $ million on pure science (hoover : - ) . while hoover was president, - , he raised funding for pure science to about $ million, but during the new deal it fell back to the $ million range. during this era, american science faculty would often urge their best undergraduates to pursue phds in europe (greenberg : - ) . private firms focused on their immediate technological needs and so spent little on basic research. the federal government did have a few agencies with substantial r&d programs, but much of that money went to government facilities or private firms in the relevant industries (e.g. ruttan , chap. ) . only the department of agriculture had developed an extensive university-based research program (dupree [ ] : and ; h.r. rep a: - ) . during the s, some leaders within the scientific community argued that scientists could benefit from greater government support if scientists themselves had control over how the money was spent. karl compton, then president of both the massachusetts institute technology (mit) and the american institute of physics, argued that greater investments in science would benefit science and the larger society (compton : ) . compton compared government funding for research in the united states unfavorably with several other countries, including russia and japan, and concluded that "we have been more lucky than intelligent" (compton : ) . abraham flexner, director of the institute for advanced study, argued in for both greatly increased government support of basic research and scientific autonomy in his pamphlet the usefulness of useless knowledge. great practical benefits, he claimed, came from scientists who had no interest in the applications of their ideas, but whose ideas then provided the basis for important new technologies (flexner [ ] (baxter , chap. and appendices and ; zachary , chaps. - ) . bush oversaw an increase in funding for war-related r&d, including to universities, as osrd funding shot up from $ . million in fy to $ . million in fy (baxter : ) . by the end of the war, large contracts to universities had totaled $ . million (baxter : - ) . additional r&d funding came from the military directly. university scientists, who had spent years scrimping by on private philanthropy, suddenly saw what massive federal spending could do. this flood of money changed universities' relationship to the federal government and, though this funding was concentrated at a small number of universities, its effects spread much more widely. mit and the california institute of technology (cal tech) received, between them, $ . million of that $ . million total. nonetheless, scientists from many universities had the experience of working with generous federal funding because federal research administrators had quickly realized that some projects required large, centralized laboratories, but no single university had the staff to operate such labs. therefore, osrd officials persuaded many universities to release some of their scientists and engineers for the duration of the war to go work in large labs at a few key universities. by the end of the war, the radiation lab at mit had staff from different colleges and universities, was directed by a physicist from the university of rochester, and had only one mit faculty member on its steering committee (baxter : - ) . the same was true at the large labs at cal tech and harvard. in addition, many academic scientists took leave from their universities to work in the new national laboratories that the government had established to create nuclear weapons and similar projects. thus scientists and engineers from across academia experienced expansive federal funding. as james baxter, a senior official in osrd, put it, "money was never a limiting factor . . . as the agency grew, congress proved unfailingly generous" (baxter : ) . as the director of osrd, bush could fund any institution he wished using almost any contractual arrangement, and he experimented constantly with new procedures for distributing the money, in the process creating new institutional arrangements on the fly (baxter , chap. ) . these qualitative changes to federal science policy were just as important as the increasing budgets for laying the foundations for the post-war r&d funding system. new institutional rules determined which scientists or institutions would get federal money, who made those decisions, and based on what criteria. those rules became the focus of protracted and heated debate even before the war ended. starting in , senator harley kilgore (d-wv) introduced bills to create an agency for war-time and post-war r&d. kilgore's bills emphasized directing scientific research to national needs and having diverse constituencies involved in deciding which projects to fund. his bills drew strong opposition from the army, the navy, industrialists, scientific organizations, and, not least, from vannevar bush and his allies in and out of government. bush and kilgore differed fundamentally over key issues, especially about how much control scientists outside of government would exert over the distributions of federal r&d funds and toward what ends those funds would aim (kevles : - ) . these conflicts reflected fundamentally different visions of the role of the state among american political elites (hart , chap. ) and highlight how contingent the final result was. by bush quietly began planning for a new post-war system, convinced that the federal government should maintain substantial funding for scientists engaged in basic research. in he persuaded president roosevelt to request a report on postwar science policy, which bush and his staff then produced (zachary : - and endnote ). science: the endless frontier, released in , became the urtext of american science policy, even though bush did not get everything that he wanted in post-war science institutions. though different government agencies adopted different methods for distributing r&d funds, the overall system implemented key components of bush's vision, namely, greatly increased funding for science while allowing the scientific community outside of government to exercise substantial control over the allocation of the funds. bush, a skilled policy entrepreneur, framed his proposals in terms of the need for the united states to invest heavily in scientific research to maintain a strong military technological advantage, along with promoting prosperity and public health (hart : - ; zachary , chap. ) . during the war, bush's office had funded research that produced a remarkable array of technological innovations (baxter catalogs them) , which gave him considerable credibility with political elites thereafter. nonetheless, despite bush's influence, it took five years after the end of the war for congress to pass the legislation that created the national science foundation (nsf) due to intense political battles over the purpose and structure of post-war federal science funding, mainly with the allies of senator kilgore (h.r. rep. a; hart ; zachary ) . the final form of federal r&d funding, spread across multiple government agencies, was a hybrid system that resulted from a set of political compromises. some agencies adopted bush's ideas, while others used older systems of mission-oriented funding. the national institutes of health (nih), the newly-created nsf, and portions of other agencies emphasized funding mostly untargeted basic research. but this system is not the only way to fund science, as other countries and other u.s. government agencies, such as the departments of agriculture and defense, have demonstrated (h.r. rep. b; dupree [ dupree [ ] . to justify such public funding, bush and his allies needed to explain how untargeted research created tangible benefits for the country. absent such benefits, why should the government fund basic science at levels higher than those it provided for, say, the arts and humanities? the linear model of technological innovation, articulated in the s by flexner (( ) ) and others, provided that justification. that model stated that the country needed to support basic research as the "seed corn" that would give rise to new technologies. this model assumes that private firms will underinvest in basic research because its benefits are uncertain and long-term and because the firms cannot capture all the benefits of their investment. due to this classic example of a public goods market failure, the federal government must step in to provide that investment (brooks : - ; nelson : - ) . though bush himself knew that the linear model was far too simple to explain scientific and technological advances, he understood that it was a politically expedient way to justify government support for basic science, and science: the endless frontier embraced this model (zachary : ; h.r. rep a: - ) . proponents of the linear model claimed that government agencies should not try to pick the most "practical" basic research topics, since no one can predict which basic scientific results will lead to the most or most important technological applications. instead, the government should fund the "best" basic science. to operationalize this model of choosing the best science, agencies should fund individual projects, as opposed to providing steady funding to particular research programs or universities. this apparently mundane administrative procedure-providing funds to individual projects instead of particular people, programs, universities, or even geographic regions-became the truly disruptive institutional feature of post-war science policy. that a scientist worked at a prestigious university or had previously received government funding was no guarantee that he or she would continue to produce the best science, and funding by geographic regions or some other formula could deprive more deserving projects of funding if they fell outside the bounds of that formula. the only way to insure that money went to the best science was to subject every scientific effort, project by project, to rigorous review. no scientist or university could rest on its laurels or geographic good luck. not all federal funding agencies chose the project funding system, but those that did used peer review by scientists outside of government as their method for choosing the best projects to fund (polanyi for the classic justification of this procedure). whatever the strengths and weaknesses of peer review (smith : - for a review), it institutionalized the norm that the non-governmental community of scientists should have a major say over the distribution of research funds and justified autonomy for scientists who are conducting research (chubin and hackett : , - ) , making it part of the "social contract for science" (guston and keniston : - ) . unlike any other government distributional policy, science policy places much of the control of that distribution in the hands of those who, as a group, benefit from it. congress determines the budgets of the various agencies and so implicitly allocates funds among broad fields of science, but the peer-reviewed project system ensures that non-governmental scientists greatly influence who actually receives the funds. the policy advocates who promoted this system believed that it would convince scientists that government funding could come without intrusive government control. in terms of gaining acceptance among policymakers and the wider public, peer review justified the competitive project system, claiming that it removed bias from the system and promoted only the most meritorious projects. the competitive project system, in turn, created the institutional incentives that led to an imbalance in supply and demand for r&d funds. moreover, this system of funding science fit neatly into the ideological struggle of the cold war in that it rewarded individual excellence, independent of whoever happened to be in power in government at any given time (wolfe ) . the individual, competitive project grant became the dominant, though not only, funding mechanism the federal agencies have used to fund university research (h.r. rep. b , chapters and ). the project system of funding is now so deeply ingrained at american universities, so taken for granted, that it seems utterly natural, yet, coupled with greatly increased funding after world war ii, it radically changed the opportunities that universities faced. if federal funding could, in principle, go anywhere, and if that funding was increasing rapidly, then universities that had small research profiles could greatly increase their r&d activity and gain increased budgets, graduate programs, and prestige if they could successfully compete for such funding. also, because status accrued to universities that had high-profile research and graduate programs, many universities wanted to enter those ranks. as a result, since the end of the war, more universities have required their faculty to compete successfully for grants and publish their research in order to get hired and promoted (bok : - ) , thereby increasing the demand for research funds. this dynamic, a form of induced demand (ladd ) , planted the seeds of the current problems that science policy elites are labelling a crisis of funding. these new policies and institutional practices succeeded for decades after the war, thanks to dramatically increased federal funding for r&d, spurred in part by the security pressures of the cold war. competition with the soviet union ran along many dimensions, including scientific and technological supremacy. even agencies whose research had no military applications enjoyed growing budgets. the nih budget increased by more than a factor of in short order, shooting up from less than $ million in to more than $ million in (h.r. rep. a: ) . between and , total defense r&d rose by a factor of . in constant dollars, and total non-defense funding increased by a factor of . in the same period. (omb , table . ). yet even those rapid increases, almost tripling in real terms in less than ten years, looked meager compared to r&d budget growth after the soviet union launched sputnik on october , . though president dwight d. eisenhower was not particularly concerned about sputnik, other politicians and many segments of the media pushed the idea that the satellite demonstrated soviet technological superiority and posed a major threat to national security ("sputnik" ) . in response, congress accelerated r&d funding increases. between fiscal years and , defense r&d outlays went up by a factor of . in constant dollars, and real non-defense r&d spending shot up by a factor of . . even if one subtracts the space budget from the non-defense r&d total, the civilian r&d budget increased by a factor of . in real terms in that decade (omb , table . ). by total r&d funding reached $ . billion in nominal terms, more than quintupling in a decade. during the same period the overall federal budget did not increase dramatically, instead remaining a few percentage points above or below % of gdp (omb , table . ). federal spending on r&d increased from . % of federal outlays to . % (omb , table . ). it was a remarkable time to be a scientist in the united states. for more than years after world war ii, both scientists and science policy-makers could well believe that the american system for funding science was working splendidly. indeed, that system produced spectacular results. researchers in the united states came to dominate the international scientific community. since scientists working in the united states have won more than half of all the chemistry, physics, and medicine/physiology nobel prizes. although researchers in the european union and china both currently produce more papers than those in the united states, publications by americans dominate the measure of the most cited papers (national science foundation a, pp. o- , o- ) . in the shanghai rankings of universities, of the top universities are american. tens of thousands of scientists and engineers from around the world seek to come to the united states for graduate school or faculty positions (national science foundation a, pp. - , - and - , - ). how could this system be a problem? table ). moreover, that increase understates the growth of the science and engineering graduate system, as more departments within universities offered the phd, and existing doctoral programs increased in size. in american universities produced phds in science and engineering. by u.s. universities graduated , phds, growth by a factor of in a period in which the u.s. population only doubled (nsf a, table ). more doctoral programs produced constantly-growing numbers of phds, who in turn wanted to get their own research grants and fund their own phd students, all within a higher educational system that had no mechanisms for limiting the number of phds that universities produced. analysts often miss this large change in the breadth of the system because they focus on the concentration of federal dollars at the top tier of universities. federal r&d funds have indeed been concentrated in a small number of u.s. universities, the top twenty of which consists of the usual suspects: the best endowed private universities and a few flagship state universities, especially those with large medical schools (nsf a, appendix table - ). only five universities outside the top twenty in (nsb , appendix table - ) moved up into the top twenty by . although the united states has more than , four-year colleges and universities, % of academic r&d spending occurs in those top institutions and about % in the top , portions that have held steady for decades (nsb a: - and figure - ) . despite this concentration, the federal government has managed to spread the greatly-increased wealth. while membership in the top twenty r&d-spending universities has changed very little over time, universities much further down the list now receive enough funding to maintain substantial research activity, dramatically more so than they could have before the war. universities currently ranked around th in federal r&d funding still get more than $ million from federal agencies (nsf b, table ). in addition, researchers at colleges and universities that are not even among the top funding recipients receive enough money to support vibrant research programs in at least a few fields. ironically, vannevar bush's peer-reviewed project system ended up providing a wide geographic distribution of federal research funds, an outcome he fiercely opposed and that his nemesis harley kilgore favored. american universities were well-primed to take advantage of the increased federal support for r&d and the ensuing imbalance between the supply and demand for the federal r&d funds stemmed in part from institutional features of american higher education, including its rapidly growing size, its high level of fragmentation, the autonomy of individual universities, and the incentives that drive them. no central body has governed all the private and state-supported colleges and universities in the united states. all those institutions have exercised substantial autonomy in making most strategic decisions (shils : - ) , such as whether to offer graduate degrees (ben-david ) . there are some constraints on this autonomy, usually from governing boards and state legislatures. however, the largest constraint on graduate science programs has always been financial and, prior to the post-war rise of federal r&d spending, there were few opportunities for acquiring such funds. that rise in federal funding, coupled with the competitive project system of distributing the funds, suddenly created an opening for many universities to try to enter the ranks of research universities. this competitive system fit well with the ideology of the cold war, which denied the legitimacy of both inherited privilege and central planning (wolfe ) and also fit into an older cultural norm important to the u.s. education system from primary education to universities. turner ( : ) identifies what he calls "contest mobility," that is, "a system in which elite status is the prize in an open contest and is taken by the aspirants' own efforts." turner focused on individuals and how education institutions could serve them in trying to move up socially, but this cultural norm justifies, even celebrates, the efforts of universities that performed little research prior to the war to compete and acquire some of the material and status rewards from winning research grants. this growth in research took place during a rapid growth in student enrollments as well. the gi bill greatly increased university enrollments right after the war (mettler ) and the baby boom cohort came of age beginning in the s, pushing enrollments up further. in addition to public policy and demography, the united states experienced a "credential inflation" that spurred more people to seek higher education (collins [ ] ). all of this culminated in enrollments going up from about . million just before the war to . million in , after peaking at million in (u.s. department of education). universities around the country got bigger and became more research-intensive by competing for federal dollars. paul pierson ( , chap . ) emphasizes that positive feedback leads to path dependence, which makes institutions and public policies more difficult to change the longer they proceed in the same direction. as more groups and institutions both benefit from and invest in the status quo, they make it more costly to change. as more universities invested in the facilities and faculty they needed to compete successfully for increasing federal r&d funding, the larger and more geographicallyspread the constituency for such funding became. nothing pre-determined this path. instead, after the critical juncture of world war ii, well-placed political elites advocated new institutional arrangements, new structures, rules, and internalized norms, which created new beneficiaries. vannevar bush and his allies wanted to greatly increase funding for non-defense r&d while minimizing government control of such research. to operationalize that goal, they promoted the mechanism of competitive funding for individual projects, making federal extramural r&d an instance of institutions that are "distributional instruments . . . specifically intended to distribute resources to particular kinds of actors and not to others" (mahoney and thelen : , emphasis in original). even if it was not bush's intention, these policies greatly expanded the number of those "particular kinds of actors." the numbers of beneficiaries of the system grew massively, both increasing political support for the system and simultaneously undercutting its ability to function in the long run. making large changes to that system now looks very risky to its beneficiaries, even as its problems grow. these are the real roots of the financial woes that the gathering storm and other advocates for science funding decry. the post-sputnik rates of increase in r&d spending could not last long. in , the science historian derek de solla price pointed out that, before long, if the rapid growth in the r&d system continued, "we should have two scientists for every man, woman, child, and dog in the population, and we should spend on them twice as much money as we had" (price : ; see also weinberg ( weinberg ( ) . obviously that could not happen, and the first cuts to science funding followed not long after price's warning. but while analysts noticed the problems, they did not always get to their root. by late , the house science committee was sufficiently concerned about federal science funding that it commissioned studies and held hearings running to thousands of pages over two years. "an agenda for a study of government science policy" identified "funding levels" as one of the topics requiring discussion and analysis, but it did not do so with any sense of crisis or impending shortage of funding. instead, it framed the issue as one of figuring out the "optimal" level of federal funding for science and reviewed the various ways by which the government might determine such a level. these included calculating social benefits or using some percentage of gdp or the total federal budget, among other metrics. interestingly, the first method for allocating funds the agenda listed was put as the question "should all good scientists be supported?" (h.r. rpt : - , quote on ), which seems naïve now. at committee hearings, witnesses testified to the importance of scientific autonomy, to the linear model of technological innovation as a justification for funding the "best" science, and tied the importance of science to the need for productivity improvements and economic growth. as harvey brooks, a prominent science policy expert from harvard, testified, "predictions of expected payoff are, i believe, of dubious validity as a basis for allocating investments in science. . . . [more important is] scientific opportunity; that is to say, the prospect of the conceptually significant advances in knowledge independent of potential applications" (h.r. hearings b: ). despite all the expert testimony that re-affirmed the existing system, other analysts pointed to coming problems. bruce smith ( : ) pointed out that "while the project system was never the whole of the federal effort, it determined the essential character of the post-war system." when budgets were increasing rapidly, money could flow both to the well-established and the up-and-coming universities. but at some point demand had to outstrip supply: "the logic of endless growth of r&d budgets has simply collided with the fiscal realities of american politics. scientists, like any other group, will have to rethink their priorities and show that they are able to accomplish more with fewer resources" (smith : ). smith's diagnosis of the problem was certainly correct, although he left out one important factor; "scientists" do not, as a group, have the institutional means for "rethinking their priorities" any more than american higher education, as a whole, has the institutional capacity to decide which universities get to create and sustain phd programs and which do not. in an effort to address the problem of increasing competition for funds, in congress initiated a five-year doubling in current dollars of the funding for nih, a commitment they completed in (aaas ) with bipartisan support, raising the budget from $ . to $ . billion. congress achieved that doubling by reducing funding for other fields of science, particularly space and energy r&d, and increasing total non-defense r&d spending overall (aaas ; aaas ). however, even after this budget doubling, success rates for grant applications to nih soon began declining again. while about one-third of nih research grant applications were funded in the late s, slightly less than one-fifth have received funding in the last decade (nih ). similarly, funding success rates at the nsf have declined from to % in the early s to - % in the last decade (nsb , table ). in both agencies, the success rates seem to have leveled off, but they could decline further, and researchers in some areas already report anecdotally much lower success rates. nonetheless, declining success rates have not led to a drastic change in the american government's policies for funding science, despite the nas's call to arms more than a decade ago (nas ) . both government agencies and universities have muddled along, displacing most of the problems onto scientists themselves, especially those early in their careers. anecdotal stories about the toll on young scientists have circulated in such high-profile venues as science's "working life" column. in addition, a recent study of three science and engineering disciplines shows that young scientists are dropping out of scientific careers much more rapidly than cohorts that entered those disciplines in the s (milojevic and walsh ). the national academies produced a study of post-docs in that documented their growing numbers and deteriorating situation, with longer times spent in post-docs, salaries that do not keep pace with inflation, and a decreasing chance of getting an academic job when their post-docs were over (iom , ch. - ) . a major source of positive feedback that promotes the persistence of this system is the sheer amount of money the federal government provides to universities. in fy , federal funding for higher education r&d expenditures was about $ billion (nsf , table ). in addition, hundreds of universities have invested substantial funds from other sources to compete for the federal funds, deepening the "lock-in" effects (béland : ) of federal science policy. that financial commitment and the deeply entrenched norms that drive it create major barriers to disrupting this policy path. this reluctance to confront the institutional roots of these problems has led science policy elites to frame the problem as an inadequate supply of research money rather than too much demand for it. the nas study, rising above the gathering storm, depicted at length the growing problems that beset researchers. they presented numerous policy recommendations, many of them relevant and sensible. but the heart of the matter was money: they argued that the federal government should increase substantially its funding for r&d, especially for the physical sciences and mathematics. chapter of the report details a long decline after a golden age of funding in the s and s: "federal r&d as a percentage of gdp peaked in the early s and has fallen since then" (nsf : ) . the body of the report avoided stating just how much this increase should be, but a white paper in appendix d, which was not part of the official recommendations of the report, stated the numbers baldly: "increase the budget for mathematics, the physical sciences, and engineering research by % a year for the next years within the research accounts of the department of energy, the national science foundation, the national institute for standards and technology, and the department of defense (p. )." such increases would roughly double real spending in seven years, assuming % inflation. as appealing as this recommendation might be to scientists, it willfully ignores the constraints of budgetary politics. in addition, would such increases actually increase success rates over the long term or just, as in the case of increases to the nih budget, bring more proposals out of the woodwork? and what happens after the seven years are up? federal research programs cannot grow five times faster than the economy forever, as scientists discovered after the s. the gathering storm study panel reconvened in and concluded that things had gotten worse, rising above the gathering storm, revisited: rapidly approaching category . the storm had become a hurricane both because the u.s. government was not spending sufficient sums to implement the academies' recommendations and because other countries were. the result was "a system failure" (nas : ) . while the report acknowledged that there were many demands on the federal budget, its authors insisted that spending for r&d had to be treated differently than other spending because it was so important: "actions such as doubling the research budget are investments that will need to be made if the nation is to maintain the economic strength to provide for its citizens healthcare, social security, national security, and more. one seemingly relevant analogy is that a non-solution to making an over-weight aircraft flight-worthy is to remove an engine" (nas : ). one might add that another non-solution is demanding the repeal of the law of gravity. calling for ever-greater government funding is ineffectual because it ignores the distributional conflicts that constrain the federal budget. science advocates often present their claims as a special case, one that legislators and presidents should consider to be above the political fray of competing for budget resources. but no part of the budget can escape budget politics; scientists are competing for funds with dozens of other programs in the context of ever-growing mandatory expenditures, now the largest part of the budget, which bypasses congressional appropriations committees. the treasury must simply supply the funds that programs such as social security need, based on criteria set out in their authorizing legislation (omb : - ) . congress only gets to decide on the level of spending for the remainder, the defense and non-defense discretionary budget, the latter of which supplies most of the r&d funding that goes to universities. therefore, the budget politics question is how much of the non-defense discretionary budget goes to r&d. for the last years, the answer has been stable at about % (aaas , r&d as a % of discretionary spending). with only small fluctuations, the federal government has funded science at this steady portion of the discretionary budget, regardless of which party controlled congress or the white house. but a consistent fraction of the non-defense discretionary budget does not provide enough money to solve the problem of growing induced demand for research funds since, at best, it can only grow at the rate of the overall economy, assuming that federal spending remains a consistent fraction of the gdp and the domestic discretionary budget remains the same fraction of the total federal budget. and that is the optimistic scenario. for more than years total federal spending, mandatory and discretionary, has fluctuated between about % and % of the gdp, with a bump up to . % during the obama administration's stimulus program (omb , historical table . ). meanwhile, the discretionary budget has shrunk steadily as a percentage of total federal spending, displaced by mandatory spending and interest on the debt. in the discretionary budget was two-thirds of the total, but had shrunk to about % by (omb , historical table . ). these trends constrain the r&d budget even further. to imagine that r&d budgets will continue to shoot up five times faster than economic growth indefinitely, as the nas proposes, ignores everything we know about federal budgeting. in the long run such increases become arithmetically impossible, but even in the short term they encounter serious political problems. nonetheless, one can understand the appeal of these fanciful arguments for constraint-free budgets when considering the political problems that more realistic arguments for increased budgets present for science policy advocates. there are only two ways r&d funding can grow more quickly than the economy, both of them politically sensitive. if advocates for science funding try to claim an ever-larger share of the non-defense discretionary budget, they must argue that funding for r&d is more deserving of support than all the other domestic programs-the grubby business of budget politics. many of those other programs serve low-income and other disadvantaged communities or supply other important public goods like environmental protection, law enforcement, or workplace health and safety. do science policy advocates really want to argue for cuts in programs that support desperate shortterm needs and often aid the poorest segments of the population? the alternative route for r&d funding growth is for the federal budget to take a larger share of the economy, which, on its face, is a reasonable idea. compared to other wealthy countries, the united states has a relatively low percentage of its economy going into the government, even when adding together federal, state, and local taxes. of the member countries of the organization for economic cooperation and development (oecd), only ireland and mexico have public revenues that are a smaller percentage of their gdps than the united states (oecd , table . ). since other prosperous countries have government revenues that take in a much higher percentage of gdp, there is no obvious reason that the united states government could not also do so. but advocating for such an increase would put science advocates squarely in the middle of one of the oldest ideological conflicts in u.s. history, the argument over the appropriate size of the government's share of the economy. taking such a position runs sharply counter to the strategy that they have taken since world war ii of arguing that funding for science should be a bipartisan and non-ideological policy issue. therefore, if science policy elites want to leave the existing r&d funding system intact, that leaves them with politically unpalatable or substantively ineffective options. they have avoided the unpalatable options of claiming that science funding is more important than low-income housing or that the american federal government should grow from % to % (or more) of the economy. instead they have followed an ineffective strategy, arguing for more funding for science as if there were no competition for funds and no ideological disagreement over the proper size of the government, that science is special and should not be subject to the constraints that confront other recipients of federal funds. that strategy has failed to solve the problems science policy confronts precisely because science cannot get an exemption from budgetary and ideological constraints. avoiding these unpalatable and fruitless strategies means seeking larger changes to the r&d funding system. both the federal government and universities must rethink their institutional norms, rules, structures, and processes that govern the funding of research. most vexingly, who suffers from the constraints on or changes in the flow of funding? the interactions between the rapidly increasing funding after the war, the competitive project system, and the norms of higher education that prioritize research have led to the unintended result of induced demand for rapid and unceasing growth in research funding, a form of institutional friction (thelen : - ; lieberman : - ) . these interactions have unfolded over decades, with problems getting worse only gradually. for universities, one major factor is the academic norm emphasizing research and publication, which predates world war ii, as american academics sought to emulate the german model of the research university, and which found a very congenial home in a few u.s. universities (ben-david [ , ch. ). after the war, the sharp increases in federal funding led to many more colleges and universities putting a heavy emphasis on research and publications for the hiring and promotion of faculty (bok : - ) , a trend that ben-david ( [ ) noted by the early s. rapidly increasing post-war research funding made this trend of rising research standards possible, providing scientists at many more universities the opportunity for funding that such research required, which in turn created the positive feedback mechanism that strengthened path dependency. once funding leveled off, faculty faced intense pressure to maintain their research while having a more difficult time obtaining funding for it. the extraordinary events of world war ii swept away the constraints on federal funding for science, a classic critical juncture, and so created an opening for science policy elites to initiate greatly increased support for science during the war and to argue that future national security would require that the government continue supporting american scientists during peacetime at financial levels unimaginable a few years earlier. the competitive project system opened up that funding to a much larger array of universities than before the war, resulting in a huge expansion of research and doctoral programs. twelve years after the war, science advocates interpreted the launch of sputnik as another national crisis, but one that did not challenge the basic institutional rules of science policy, instead calling for even more rapid increases in funding than were already occurring. those funding increases, in turn, greatly expanded the size of the american academic scientific community, induced greater demand for funding, and deepened universities' dependence on federal funding and so their defense of the existing system. the positive feedback loops that reinforce the existing system are still operating; positive feedback can reinforce policies even if they become deeply dysfunctional (pierson ) . moreover, there are no simple criteria to evaluate what would now constitute a functional science policy. so what if senior researchers have to spend increasing amounts of their time writing grant proposals, or junior scientists spend ever more time in post-docs with diminishing prospects of getting permanent positions, or if medical school departments are in ever-more precarious financial situations, or if junior scientists are leaving the profession? the government is still funding science. people at universities are still performing research and publishing the results. universities are still producing phds. the pathologies of that system are getting worse only gradually, making it easier to avoid large-scale institutional change, always a painful process. instead, leaders of the scientific community bemoan the lack of respect that science gets in american society and make futile appeals for vastly more money. however ineffective that approach may be, it enables science policy elites to avoid directly confronting the institutional problems of science policy, which would enmesh the scientific community in difficult controversies. an assumption, usually implicit, of most political analyses is that actors in a policy conflict know which policies will advance their interests. however, the problems in science policy derive precisely from the success of the winners, the science policy elites at the end of world war ii and their successors, not the machinations of the losers. the winners created a system that avoided geographic or other formulas for distributing funds and instead made funding an open and unconstrained competition, with judgments about the most scientifically deserving projects coming from non-governmental scientists. that competitive project system created the incentives for universities around the country to expand their research portfolios, which in turn led to ever-increasing demands for research funds, the unintended higher-order consequences of this system. current science policy elites treat these features of the system as given, a deeply embedded set of norms that few people are willing to question in public. but because the existing policies are not fiscally sustainable, it is, ironically, their supporters, not their opponents, who undermine the current system by avoiding the difficult reforms that lie ahead and so increase the problems in the system. universities are already struggling to modify the norms through which they evaluate faculty. for example, as scientific projects become more complex, publications with dozens or even hundreds of authors are becoming more common. how much credit does a faculty member get for being one of those authors, but not the lead author? in addition, colleges and universities have begun creating non-publishing career tracks for faculty, in some cases replacing adjunct faculty who teach single courses for very low pay with full-time faculty who get salaries and benefits and who only teach. these processes have been anything but smooth and present their own possible set of unintended consequences, but universities are gradually changing the composition and functions of their faculty, albeit in an uncoordinated and ad hoc manner. one of the problems any reforms will confront is the sheer number of science and engineering phds the united states produces each year. should american universities reduce that number? if so, how, and what would be the consequences for the many research projects that depend on phd students to carry them out? should the federal government give universities incentives to make such reductions? or is the problem more cultural than quantitative? maybe there is a large demand, real or latent, for phds outside academia, but universities convey too much disdain about pursuing such career paths by modelling research-oriented faculty positions as the only respectable career for phds. that expectation is so deeply embedded in academic culture that one graduate student described telling her advisor about her wish to pursue a non-academic track with the same anxiety and trepidation she felt when she came out about her sexual orientation to her family (phillips ). sauermann and roach ( , figure , p. ) show that academic jobs are, by far, the most desirable career track for students starting their doctorates in the life sciences and physics, and still popular, though roughly tied with industry and government, for chemistry students. ginther ( ) elucidates the trends that have led to the decline in tenure track academic jobs in the united states that, coupled with growing numbers of phds, put them out of reach for all but a small number of new scientists. by , only . % of those who received their doctorates in the biological sciences in the previous - years held tenured or tenure-track jobs, down from . % in (nsb . federal funding agencies, as well as in universities, will need to enact long-term changes to create a fiscally sustainable r&d system, which includes adopting a different model for how science and engineering research benefits society. the core justification for the existing system, the linear model of innovation, has been thoroughly and effectively critiqued (narayanamurti and odumosu , chap. ; mowery and rosenberg , chap. ; zachary : ; sarewitz : - ) . to begin, the federal government should rethink the mechanisms it uses to distribute research funding. the existing competitive project system is not the only means for funding quality r&d and may not be the best way to fund science and technology that will have important social benefits. for example, the department of agriculture has used a portfolio of methods for distributing research funds, including block grants to universities. the defense department's advanced research projects agency has used the strong program manager model for funding (h.r. rep. b) . various oecd countries have used layers of different mechanisms, from project grants to programmatic and institutional support (paic and viros : - ) . while none of them work perfectly, all are worthy of serious analysis as partial replacements for the existing system. a new system will need to accomplish several goals at once. to be financially sustainable, such a system can grow, but its growth should not exceed the ability of the government to fund it, which over the long term means growing no faster than the economy. beyond financial sustainability, government funding should provide tangible social benefits. while the government should support some research for its own sake, the classic notion of basic science, there is a serious question about how much money can or should go into that work versus research with a more applied orientation. the nsf has already moved in that direction, requiring since an assessment of the "broader impacts" of all its research project proposals (frodeman and holbrook ) . however, requiring each individual research project to demonstrate its relevance to broad national goals puts the burden on the wrong decision makers, the project principal investigators. if the nsf wants its funding to contribute to such goals, then "[t]he nsf's capacity to meet broad national goals is best pursued through strategic design and implementation of its programmes, and best assessed at the programme-performance level" (sarewitz ) . the individual pidriven project is more than just a funding mechanism; it is a bottom-up method of setting detailed funding priorities based on proposal pressure from scientists outside of government, which may be quite different from the government's social goals. in contrast to this standard procedure, the nsf has occasionally engaged in top-down decisions to push the scientific community in particular directions of national need (sarewitz ) . nonetheless, such episodic efforts at pursing national goals leaves most distributional decisions among fields of science subject to past precedent, uncoordinated lobbying, and ad hoc policy decisions rather than any larger strategy. the project mechanism and the linear model of innovation that underlies it are inextricably bound together in this system, which means that reforming the mechanism to make the system fiscally sustainable requires replacing the model to enable strategic debates for how best to focus federal r&d funds on national needs. a new model will challenge such basic categories as the classic distinction between basic and applied research (stokes presents one promising example of an alternative). in addition to social benefits and financial sustainability, a new system should avoid freezing existing privileged positions in place. scientists and the institutions in which they work need incentives to innovate and maintain quality in their work. none of this will be easy. communities are rarely good at making brutal distributional decisions for themselves, and there is no simple alternative that solves these problems. that said, the existing system is clearly unsustainable and in fact is undergoing slow, ad hoc, and painful changes already. making those changes more deliberate, with mechanisms built in for observation, learning, and modification as new modes of funding begin to function, can save valuable resources and create more realistic expectations on the part of scientists, universities, and governments alike. those deliberations need to start with a realistic appraisal of the funding streams that the government can provide, and, just as important, with clear recognition of the institutional dysfunction at the heart of the current problems. omnibus bill completes nih doubling plan; large increases for bioterrorism r&d and facilities. r&d funding update r&d by function: nondefense only scientists against time. boston: little brown, and company reconsidering policy feedback: how policies affect politics trends in american higher education the future: steady state or new challenges? peerless science: peer review and u.s. science policy the credential society: an historical sociology of education and stratification the government's responsibilities in science science in the federal government: a history of policies and activities the usefulness of useless knowledge nsf's struggle to articulate relevance storm clouds on the career horizon for ph.d.s the politics of pure science: an inquiry into the relationship between science and government in the united states 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citizens: the g.i. bill and the making of the greatest generation changing demographics of scientific careers: the rise of the temporary workforce historical tables, table . , summary of receipts, outlays, and surpluses or deficits (-) as percentages of gdp governance of science and technology policies my second coming out politics in time: history, institutions, and social analysis the republic of science: its political and economic theory little science, big science is war necessary for economic growth? military procurement and technology development frontiers of illusion: science, technology, and the politics of progress the dubious benefits of broader impact science phd career preferences: levels, changes, and advisor encouragement the calling of education: the academic ethic and other essays on higher education american science policy since world war ii pasteur's quadrant: basic science and technological innovation historical institutionalism in comparative politics sponsored and contest mobility and the school system freedom's laboratory: the cold war struggle for the soul of science criteria for scientific choice third thoughts endless frontier: vannevar bush, engineer of the american century acknowledgments for comments on earlier drafts of this paper, i am deeply grateful to david m. hart publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -qrxoj nc authors: nagurney, anna; daniele, patrizia; nagurney, ladimer s. title: refugee migration networks and regulations: a multiclass, multipath variational inequality framework date: - - journal: j glob optim doi: . /s - - - sha: doc_id: cord_uid: qrxoj nc in this paper, we take up the timely topic of the modeling, analysis, and solution of refugee migration networks. we construct a general, multiclass, multipath model, determine the governing equilibrium conditions, and provide alternative variational inequality formulations in path flows and in link flows. we also demonstrate how governmental imposed regulations associated with refugees can be captured via constraints. we provide qualitative properties and then establish, via a supernetwork transformation, that the model(s) are isomorphic to traffic network equilibrium models with fixed demands. illustrative examples are given, along with numerical examples, inspired by a refugee crisis from mexico to the united states, which are solved using the euler method embedded with exact equilibration. the work sets the foundation for the development of additional models and algorithms and also provides insights as to who wins and who loses under certain refugee regulations. since the new millennium, the number of refugees and asylum seekers has increased from to million, constituting approximately % of the international migrants. and, according to the united nations refugee agency [ ] , the global population of forcibly displaced individuals increased by . million people in . almost . million individuals had to move due to persecution, conflict, violence, or human rights violations. now with the covid- pandemic, declared by the world health organization on march , , dolmans et al. [ ] report that covid- is likely to exacerbate what is already a humanitarian emergency in terms of a global refugee crisis. the authors argue that refugees may encounter increased difficulty in seeking asylum due to measures imposed by governments in response to the pandemic. jackson [ ] reports that the legal definition of a refugee was provided in by the united nations convention relating to the status of refugees. the convention defined a refugee as an individual living outside his or her country of nationality, who is unable or unwilling to return because of a well-substantiated fear of persecution due to race, religion, nationality, membership in a political social group, etc. here we also consider humans adversely affected by climate change, as refugees, and note that, as emphasized by hebert et al. [ ] , among the most studied causes of human migration are climate issues and conflicts, as well as economic reasons. in this paper, since the focus is on refugees, we do not emphasize the latter, but concentrate on the two former reasons for migration. the news media in recent years has been filled with reports of refugees traveling from points of origin towards destinations that they ultimately hope to reach, sometimes using challenging and even dangerous modes of transportation. for example, as emphasized in nagurney and daniele [ ] , the united nations refugee agency [ ] reported a maritime refugee crisis with , crossing the mediterranean sea to europe, in the first half of , using very risky transport modes, and with many others unsuccessfully attempting such a crossing. lost their lives in the largest refugee shipwreck on record that spring. the united nations international organization for migration notes an article by conant [ ] in the national geographic highlighting, through vivid graphical maps, several of the major mass migration routes that were then underway. the article emphasizes that those fleeing the middle east and africa to europe are not the only ones traveling along evolving and dangerous migration routes. many other countries are also being characterized by an exodus of their citizenry and/or are struggling with becoming transit points, smugglers' routes, or desired destination nodes for migrants. the routes, which may be secretive, are cutting paths through central america and mexico; the horn of africa (with almost one million somali refugees), and other countries including: bangladesh, myanmar, and malaysia, along with the headline-grabbing migrations through east africa and the mediterranean sea. governments of many nations on multiple continents are faced with the challenges associated with the migration of refugees. various strategies are being utilized to regulate the flow to various destinations. helbling and leblang [ ] eruditely emphasize that migration regulations are central to a nation's sovereignty since they directly impact the makeup of the community in a country. the united nations [ ] , in turn, reports that migration policies in both origin and destination countries play a crucial role in determining the migratory flows. we can expect refugee migratory flows to continue to increase, posing a critical need for the provision of rigorous tools for policy-makers and decision-makers for the quantification of refugee migratory flows and the impacts of various regulations. that is one of the goals of this paper. indeed, the development of computable mathematical models that can assist in the prediction of refugee flows, along with the assessment of various regulations, are sorely needed. interestingly, although there has been a growing literature on network models of human migration, certain features, alluded to above, have been missing. we first recall the relevant literature in sect. , followed by a delineation of the specific, concrete contributions in this paper. multiple disciplinary approaches, as well as perspectives, have been applied to the study of human migration, including sociological, political, economic, as well as operations research based, with associated methodologies. please refer to rahmati and tularam [ ] for a review of a spectrum of frameworks for the analysis of human migration models. recently, there has been a renewed interest in the development of network models for human migration, with an example being the work of nagurney and daniele [ ] , which is undoubtedly the first to include regulations in the modeling of international human migration networks. that work builds on the earlier contributions of nagurney [ ] , who developed a multiclass migration network model but without migration costs, and that of nagurney [ ] and nagurney, pan, and zhao [ , ] , who introduced flow-dependent migration costs, with the latter work capturing class transformations. pan and nagurney [ ] proposed a multi-stage, single class, markov chain model in order to model chain migration, which was not a feature in the above-noted research, and provided theoretical results connecting a sequence of variational inequalities and a non-homogeneous markov chain. later, pan and nagurney [ ] applied the theory of evolution variational inequalities to model the dynamic adjustment processes associated with human migration. for some background on finite-dimensional variational inequalities, we refer the interested reader to the book by nagurney [ ] , and for background on evolution variational inequalities, see the book by daniele [ ] . in the network models of human migration, migrants reflect their preferences for destination versus origin nodes through utility functions, which are distinct for each class of migrant, and the utility functions depend on the populations at the different locations. other extensions have included the inclusion of uncertainty in the utility and migration cost functions, as well as the initial populations, as in the work of causa, jadamba, and raciti [ ] . kalashnikov et al. [ ] proposed a human migration model with a conjectural variations equilibrium (cve), which extended the framework of isac, bulavsky, and kalashnikov [ ] in that the conjectural variations coefficients are continuously differentiable functions of the total population at the destination and of the group's fraction in it. cappello and daniele [ ] , subsequently, constructed a nash equilibrium model of human migration with features of conjectural variations. the utility and migration cost functions for a given class depend on the populations and flows, respectively, of that class. they also provided solutions numerical examples inspired by the refugees flows from africa through the mediterranean sea to italy in the year . nevertheless, none of the earlier models noted above include regulations, except for that of nagurney and daniele [ ] . furthermore, all the above models assumed that a path from an origin node to a destination node consists of a single link, whereas, in reality (cf. conant [ ] ), migrants, in the form of refugees, in particular, may actually be selecting paths, consisting of multiple links. moreover, different pathways even within an intermediate country may be used to their ultimate destination. some locations, in turn, may act as meeting points for refugees, signifying that there are, typically, different paths/routes that a refugee may take from an origin node to a destination node. interestingly, although having multiple path options from origins to destinations has been typical in transportation network models (cf. beckmann, mcguire, and winsten [ ] , dafermos [ , ] , sheffi [ ] , zhang and nagurney [ ] , among many others), as well as in spatial price equilibrium models, in which the flows are commodities (see dafermos and nagurney [ ] , nagurney and aronson [ ] ) and in supply chain models (cf. nagurney [ , ] ), nagurney, yu, and besik [ ] , nagurney et al. [ ] , toyasaki, daniele, and wakolbinger [ ] , and the references therein), including multiple routes has not been done in the context of human migration network models. we fill this research gap in this paper. by allowing for this important feature we then capture additional possible regulations via novel constraints. we also establish that the model without regulations is isomorphic to the well-known traffic network equilibrium (tne) problem with fixed demands (cf. beckmann, mcguire, and winsten [ ] , dafermos [ ] , dafermos and sparrow [ ] , sheffi [ ] , nagurney [ ] , patriksson [ ] ) through a supernetwork (see nagurney and dong [ ] ) equivalence. this identification, which also advances the theory of network equilibria as a unifying mechanism for many problems, enables the transferral of numerous algorithms that have been developed for tne to general migration network problems. we note that multitiered financial equilibrium problems had been transformed into fixed demand traffic network equilibrium problems (liu and nagurney [ ] ); supply chain network equilibrium problems have been as well (nagurney [ ] ), as have electric power generation and distribution network problems (nagurney et al. [ ] ). however, in this paper, the first such transformation is done for a migration equilibrium problem. moreover, the refugee migration network problem is defined over a general network topology. the refugee migration model with regulations can, hence, be transformed into a tne with side constraints (see [ ] ; larsson and patriksson [ ] ). the specific contributions to the literature of this paper are: . an international human migration network model is constructed, which allows for route choices by the migrants, which are refugees. . the routes consist of one or more links, with cost functions that capture congestion, a factor that has been seen in practice. . the model is then extended to include regulations that can be imposed by distinct multiple countries. in previous work (cf. nagurney and daniele [ ] ), it was assumed that a single country imposes the regulations on migrants. . a supernetwork transformation into a traffic network equilibrium problem with fixed demands is constructed. this identification enables the transfer of algorithmic schemes for the tne problem, which has had a long history, to the novel application domain of refugee/migration networks. . theoretical results are presented, along with an algorithm, with nice features for computations. . numerical examples illustrate the modeling and algorithmic framework and enable insights for policy-makers and decision-makers. the paper is organized as follows. in sect. , the multiclass, multipath refugee models without and with regulations are developed. in sect. , the supernetwork transformation of the problem into a traffic network equilibrium problem is presented. in sect. , we propose an algorithm, which is then applied to a series of numerical examples. in sect. , we summarize our results, present our conclusions, and provide suggestions for future research. in this section, we construct refugee migration models consisting of multiple classes of refugees and with the possibility of multiple routes/paths between an origin node and a destination node associated with refugee flows. we first present the model without regulations and then the one with. the regulations can be imposed by multiple governments. the refugee migration network consists of a graph g = [n , l], where n denotes the set of nodes and l the set of directed links representing the direction of flow. origin nodes correspond to initial locations of the refugees and there could be multiple such nodes in a country. similarly, destination nodes correspond to destinations in countries that the refugees may be interested in traveling to. we also consider the situation that the refugees may elect to stay in their own country for various reasons, including that the cost of migration may exceed the net utility gain. a typical origin node is denoted by i and a typical destination node by j, with the origin/destination (o/d) pair of nodes associated with origin i and destination j denoted by w i j . the set of routes/paths joining o/d pair w i j is denoted by p w i j , with a typical route referred to by r . the set of all routes in the refugee network is denoted by p where p = ∪ n i, j= p w i j . there are j classes of refugees, with a typical class denoted by k. according to the united nations high commissioner for refugees [ ] , a refugee has a justifiable fear of persecution because of race, religion, nationality, political opinion, or belonging to a specific social group. depending on the specific scenario and refugee application, one can define a class accordingly and even consider other identifiable attributes such as the social-economic level, professional status, etc. here we consider a class as being distinct in terms of associated utility at origin and destination nodes as well as cost associated with migration. in creating the model, for the sake of flexibility, we do not restrict ourselves to specific attributes. we see that an o/d pair of nodes corresponds to nodes in distinct countries, except in the case of a pair of nodes in the same country corresponding to the same location and with a route consisting of a single link joining such a pair of nodes, signifying the decision to stay (and not migrate). we assume, for simplicity, that there are n origin nodes and n possible destination nodes. in our models we assume that there is no repeat, that is, chain, migration. also, all vectors are column vectors. the common notation for the models is given in table . observe that, according to table , the utility functions of each refugee class can, in general, depend upon the population distribution of all the refugees in all the locations; moreover, the cost on a route/path can, in general, depend upon the vector of all the refugee flows. of course, the specific structure of these functions would be adapted to the migration scenario(s) under study. we first present the conservation of flow equations. since the route flows must be nonnegative, we have that furthermore, the refugee flows out of an origin node i must satisfy: note that eq. ( ) states that for each class of refugee at each origin node, the sum of the flows out by the class must be equal to the total initial population of that class at the origin node. remember that refugees can also elect to stay and that would correspond to o/d pairs w ii ; i = , . . . , n, with the corresponding flows on the paths consisting of single links associated with such o/d pairs. the flow of refugees of class k on route/path r . the {x k r } elements are grouped into the vector x k ∈ r n p + , where n p denotes the number of paths in the migration network. we then further group the x k vectors; the flow of refugees of class k on link a. we group the link flows for class k for all links a ∈ l into the vector f k ∈ r n l where n l is the number of links. we then group the link flows for all classes into the vector f ∈ r j n p p k i the nonnegative population of refugee class k at origin node i. we group the populations of class k; k = , . . . , j , into the vector p k ∈ r n + . we then further group all such vectors into the vector p ∈ r j n the initial fixed population of class k at origin node i; i = , . . . , n; k = , . . . , j the utility perceived by refugee class k at node i; i = , . . . , n; k = , . . . , j . we group the utility functions for each k into the vector u k ∈ r n and then group all such vectors for all k into the vector u ∈ r j n c k a ( f ) the migration cost associated with traversing link a by refugees of class k. here we interpret the migration cost as a travel cost. we group the link costs for each k into the vector c k ∈ r n l and then we group all such vectors into the vector c ∈ r j n l the cost of migration, hat is, the travel cost, encumbered by class k in migrating on route r associated with an o/d pair w i j ; i, j = , . . . , n; k = , . . . , j furthermore, the volume of population of each class k at each destination node j, after migration takes place, must satisfy the following equation: moreover, we have the following conservation of flow equations which relate the link flows to the route flows: where δ ar = , if link a is contained in route r and , otherwise. according to ( ), the flow on a link of a class is equal to the sum of flows of that class on routes that use the link. in view of the conservation of flow equations ( ), we may define link cost functions in route/path flows, such thatĉ k a =ĉ k a (x) ≡ c k a ( f ), for all links a and for all classes of refugees k. the cost on a route r is equal to the sum of costs on the links that make up the route, that is, we define the feasible set k ≡ {( p, x)|x ≥ , and ( ) and ( ) hold}. a sample refugee network is depicted in fig. . note that the direct link from an origin node to a destination node with the same numeric label will have, once the model is solved, the volume of the population that remains at that location (and does not migrate). the costs we first present the equilibrium conditions for the multiclass, multipath refugee migration model without regulations, accompanied by variational inequality formulations. we then introduce its counterpart with regulations. the equilibrium conditions are generalizations of classical migration equilibrium conditions of nagurney, pan, and zhao [ ] to include multiple possible routes. a vector of populations and refugee migration flows ( p * , x * ) ∈ k is in equilibrium if it satisfies the following conditions: for each class k; k = , . . . , j , and each pair of origin/destination nodes i, j; i, j = , . . . , n, and all routes r ∈ p w i j we have that and we assume, as noted earlier, that c k r = , for all r and k, if r consists of a route with an origin node and a destination node in the same country/location, since those who decide to stay in their origin countries and not migrate encumber a migration (travel) cost of zero. hence, according to ( ) , refugees will select routes from their origin nodes to their destinations such that the net gain in utilities for each class is maximal. also, as emphasized in nagurney and daniele [ ] , but for international human migration network models in the case of a single path/link between each pair of nodes, λ k * i is necessary since the level of the populationp k i may not be sufficiently large so that the gain in utility u k j − u k i is exactly equal to the migration cost. nevertheless, the utility gain minus the migration cost will be maximal and nonnegative, and the net gain will be equalized for all countries and classes which have a positive flow out of a node in a country (see also nagurney, pan, and zhao [ ] ). for equilibrium conditions for spatial price equilibrium problems and transportation network equilibrium problems, see beckmann, mcguire, and winsten [ ] , dafermos and sparrow [ ] , daniele [ ] , nagurney [ ] , nagurney, besik, and dong [ ] , nagurney, li, and nagurney [ ] , samuelson [ ] , takayama and judge [ ] , zhang and nagurney [ ] , and the references therein. the variational inequality formulation of the multiclass, multipath refugee migration equilibrium conditions according to definition is given in theorem below. a population and refugee flow pattern ( p * , x * ) ∈ k is a refugee migration equilibrium without regulations according to definition , if and only if it satisfies the variational inequality problem in path flows where ·, · denotes the inner product in the appropriately dimensioned euclidean space. proof see the appendix. existence of at least one solution to variational inequality ( ) follows from the standard theory of variational inequalities (see kinderlehrer and stampacchia [ ] theorem . ) under the assumption of continuity of the utility functions u and the migration cost functions c, since the feasible convex set k is compact. alternative variational inequality formulations can induce distinct algorithmic schemes. hence, for completeness, we now provide a link flow variational inequality formulation equivalent to the path flow one in ( ) . we first define the feasible set k ≡ {( p, f )|∃x such that ( )−( ) hold}. the proof is immediate by making use of the conservation of flow equations ( ), which relate the link flows to the path flows. a population and refugee link flow pattern ( p * , f * ) ∈ k is a refugee migration equilibrium without regulations according to definition , if and only if it satisfies the variational inequality problem in link flows we note that although alternative variational inequality formulations of both traffic network equilibrium problems as well as spatial price equilibrium problems have been constructed (cf. nagurney [ ] and the references therein), the above are the first such constructs for problems of human migration with multiple possible paths between o/d pairs. we now construct general constraints of relevance to regulation of refugee migratory flows. unlike in the model of nagurney and daniele [ ] , where it was assumed that only a single country was imposing regulations, here we allow for multiple countries to impose regulations. in addition, the set of constraints is of relevance to refugees in transit through a country that is neither an origin node for them nor a destination node. we denote a specific country by h, where h = , . . . , h . also, we define the set o h consisting of origin nodes of refugees from countries/locations that the country h imposes a regulation on, and we let d h denote the set of destination nodes, which lie in country h. also, c h denotes the set of refugee classes that country h imposes the regulations on and u h is the nonnegative upper bound imposed by country h on refugee migratory flows. the constraints can then be stated as follows: observe that the set of constraints ( ) is sufficiently general to capture specific, distinct migration regulations in practice. such as: an upper bound (which may be zero) of all classes from a certain country or countries; or an upper bound on a single class or several classes from a specific country or countries. furthermore-and this attests to the flexibility and generality of our multiclass, multipath framework-in the case that there are restrictions on the migratory flows on transit links, one can identify all such paths that utilize such links and restrict the total flow on them accordingly. for the refugee migration model with regulations, the equilibrium conditions ( ) and ( ) are still relevant but with a new feasible set k defined as below to include the constraints ( ): when the feasible set k is nonempty then it follows immediately (cf. nagurney [ ] ) that the variational inequality for the refugee migration model with regulations in path flows is as given in theorem below. we remark that, since we do not expect regulations to be imposed on refugees in the origin node country by the origin node country, refugees can remain in the country even if all other pathways are unavailable to them and, hence, k is nonempty. note that variational inequality ( ) differs from variational inequality ( ) in that the feasible set k is distinct from k . one can also construct the analogue to variational inequality ( ) , which is in link flows, but with regulations, by including the regulatory constraints into the expanded feasible set. we now provide a variational inequality equivalent to the one in ( ) but in path flows only (and not in the population distribution and path flows). we define a new feasible set k ≡ {x|x ∈ r j n p + , and ( ), and ( ) hold}. because of the form of the utility functions as defined in table , and using ( ), we can define utility functionsû k i (x), ∀i, ∀k, such that note that variational inequality ( ) can now be expressed solely in path flows. indeed, the first term in ( ) is: hence, it follows that variational inequality ( ) is equivalent to the variational inequality: determine x * ∈ k such that we now put variational inequality ( ) into standard form (cf. nagurney [ ] ): determine where f is a given continuous function from k to r n , k is a given closed convex set. indeed, we can set k ≡ k , x ≡ x, and n = n p . also, we can define the vector f as consisting of the elements: −û k j (x) + c k r (x), for all origin nodes i, for all destination nodes j, for all routes r ∈ p w i j , and for all classes k, and the conclusion follows. we now proceed to illustrate the above results in several simple examples. the refugee network consists of the topology depicted in fig. . there are two origin country nodes and the same two country destination nodes. according to the network in fig. , refugees residing in country are not interested in migrating to country . on the other hand, refugees residing in country are interested in the possibility of migrating to country . there are two available paths joining country with country . the links are labeled in fig. . the routes are comprised of links and are enumerated as follows: ( , ) , r = ( , , ) . we consider a single class of migrant. consequently, we suppress the superscript in the notation. the data are as follows:p = andp = with the utility functions: u ( p) = −p + and u ( p) = −p + . note that, according to these utility functions, country is more attractive to the refugees than country , under no population of refugees, because of the term of in the utility function associated with country as opposed to the fixed term of in the utility function associated with country . we see that route r consists of two legs of a journey, whereas route r is comprised on three legs. however, the fixed components of the migration cost on the legs of the former are much higher than those on the latter. we first consider the case without regulations. it is easy to compute the equilibrium solution, using simple algebra. indeed, we find that: hence, with associated utilities being: and the incurred migration costs on the routes at equilibrium: c r = , c r = , c r = c r = . moreover, λ * = λ * = . it is clear that the equilibrium conditions ( ) and ( ) hold. observe that, initially, before the refugee migration takes place, u(p ) = and u (p ) = . once equilibrium is achieved, those who have migrated from country to country more than double their utility, whereas those who remain in country experience a gain in utility of over %. those in country , because of the increase in the number of refugees and that they are not migrating, suffer a reduction in utility of approximately %. we now suppose that a regulation is imposed on destination node by country of the following form: the new equilibrium solution is: hence, with associated utilities being: and the migration costs on the routes: c r = , c r = , c r = , c r = . . moreover, λ * = λ * = . the optimal lagrange multiplier associated with the regulation constraint is: μ * = . . one can see that route r is too expensive and will not be used under the refugee migratory flow pattern. now, refugees in country , at equilibrium, enjoy a higher utility than before the regulation was imposed of versus , an increase of about %. on the other hand, refugees in country now experience a lower utility, than before the regulation was imposed. they are no longer all free to migrate because of the imposed regulatory upper bound of limiting the migration from country to country . under the regulation, those who manage to migrate enjoy a higher utility than before of , but those who are left behind in country experience a lower utility than in the case without regulations-of , revealing a drop of about %. before presenting the computational procedure that we will apply to compute solutions to larger refugee migration problems, we establish a supernetwork equivalence between the refugee model with multiple paths, but with a single class, and a traffic network equilibrium problem with fixed demands. such a connection has never been made before and enables the transfer of a plethora of algorithms from transportation science to solve refugee migration problems. we note that the multiclass transformation into a single class/mode problem readily follows by applying standard multicopy techniques as proposed by dafermos [ ] . specifically, recall, cf. fig. , that, in the refugee network, there are origin nodes where the initial populations, including the refugees, are located. moreover, in order to capture that some of the refugees may remain at their origin locations, we also have as many destination nodes in the original network as there are origin nodes. plus, in order to reflect that a volume of the population may remain at each location, we have a path consisting of a single link joining an origin node to its "companion" destination node, with an associated cost, as noted earlier, of zero. also, in the original network there are paths/routes consisting of one or more links joining origin nodes to destination nodes reflecting possible routes that the refugees may take; see, for example, multiple illustrations of this in the real world on different continents on actual maps in conant [ ] . we now construct the supernetwork representation-cf. fig. . we add a single "super" destination node d to the bottom of the original network in fig. and a link joining each original destination node to node d. the origin/destination (o/d) pairs on the supernetwork, which will be equivalent to a traffic network equilibrium problem with fixed demands (cf. dafermos [ ] , smith [ ] ) are now as follows. there are as many o/d pairs in the supernetwork as there are origin nodes, that is, n, with the o/d pairs consisting of the following pairs of nodes: w = ( , d) , . . ., w n = (n, d). note that each origin node in the supernetwork corresponds to the respective origin node in the original network. the fixed demands associated with these o/d pairs, denoted by d w , d w , . . ., d w n are set, respectively, equal to:p , p , . . .,p n . the costs on the links on the supernetwork that are the same as in the original network remain the same. the costs on the new links joining destination nodes , . . ., n, with node d capture the utility information at the respective destination and are assigned, respectively, as: −u ( p), . . ., −u n ( p). it is straightforward to verify that the flows on paths connecting each o/d pair on the supernetwork will coincide with the respective path flows on the original network and the conservation of flow equations ( ) and ( ) will hold. furthermore, the final populations (as in ( )) at the destination locations coincide with the link flows on the respective additional links in the supernetwork in fig. , terminating in node d. we now prove that the equilibrium conditions according to definition are also satisfied by the tne flow on the supernetwork in fig. with the additional link costs as defined above. observe that, from the construction of the supernetwork and the associated link costs, in equilibrium, if the flow on the path consisting of the original direct link from an origin node i to its companion node and the super demand node d is positive, then the cost on that path is precisely equal to minus the utility, −u i ( p * ). moreover, if the flow on any other path from that same origin node to d is positive, and, say, that it goes through a node j to node d, then the cost on that path is equal to c r − u j ( p * ), where c r is the cost on the original such path r and −u j ( p * ) is the cost on the final link to node d. because of the structure of the supernetwork, we know that these two costs are equalized, in the traffic network equilibrium, and, hence, we have that: or, equivalently: which is precisely the first part of the equilibrium condition ( ) (since this holds true for any such paths and nodes). clearly, the second part of ( ) also holds since any more expensive path connecting each o/d pair will not be used. the second part of the equilibrium conditions, ( ) , is easy to see will hold, as well, if the initial population at an origin location node is insufficient, in which case the corresponding λ * i may be positive. also, it is well-known that the path flow variational inequality formulation of the fixed demand traffic network equilibrium problem (cf. dafermos [ ] and nagurney [ ] ) is of the form: determinex * ∈ k such that whereĈ is the vector of path costs,x is the vector of path flows, and k is the feasible set consisting of the nonnegativity assumption on the path flows and with the demands for the o/d pairs being satisfied by the path flows. with the path flows and the path costs as defined above on the supernetwork, along with the feasible set, it is clear that variational inequality ( ) coincides with variational inequality ( ) . the supernetwork reformulation is relevant even for the refugee model with regulations since the regulations become side constraints for the former and variational inequality ( ) still applies but with the feasible set k including also the side constraints. we assume that k is nonempty. we provide the full supernetwork equivalence for the numerical example(s) in sect. . through the supernetwork equivalence, one can avail oneself of many algorithms that have been applied to solve traffic network equilibrium problems (cf. bar-gera [ ] , nagurney [ , ] , patriksson [ ] , sheffi [ ] , and the references therein), which have, also, because of the longer history of that area of application, been used effectively and efficiently to solve large-scale real world transportation networks in cities consisting of thousands of nodes, links, and origin/destination pairs of nodes (see perederieieva et al. [ ] and the references therein). our numerical examples are inspired by the refugee flows from mexico to the united states, an issue that has been receiving a lot of attention in the press. specifically, the baseline network for the numerical examples is depicted in fig. . the top nodes correspond to origin nodes, representing cities/towns, with the first four nodes being locations in the southwestern united states and the next three top nodes corresponding to locations in mexico, where refugee origin nodes have been identified. the bottom nodes in the network in fig. are the destination node locations. we consider a single class of refugee. the utility functions associated with these locations are as follows: u ( p) = −p + , , , u ( p) = − p + , , u ( p) = −p + , , , u ( p) = p + , , u ( p) = −p + , , u ( p) = −p + , , u ( p) = −p + , . from the above utility functions, one can see that the locations in the united states are more attractive than those in mexico, due to the significantly larger fixed utility term in the corresponding utility functions. we now provide the link cost data. please refer to the network in fig. for the link locations. specifically, the link costs associated with remaining at one's location at nodes through , respectively, are, as discussed earlier, all equal to . , and, hence, we have that: note that these equilibrium location populations correspond, respectively, to the equilibrium link flows on links through in the supernetwork in fig. . the associated incurred utilities at the equilibrium at the locations are: we also, for completeness, report the path costs at the computed equilibrium flows since it is easy to then verify that the equilibrium conditions, as stated in definition , hold. specifically, the incurred path costs at the equilibrium are: we now proceed to impose regulations and construct examples through , which are analogues of example , but with regulations. in example , we considered the following scenario: the us government has told the mexican government that it is restricting the flow on route r = ( , ) to zero; essentially resulting in the elimination of this path, since its processing facilities are experiencing delays due to congestion. the rest of the data remain as in example . in example , we studied the following scenario: route r = ( , ) is now unavailable to refugees, but the other routes and data remain as in example . and, in example , we investigate the scenario that the united states is concerned about the influx of refugees and both routes r and r from mexico are, in effect, banned/eliminated. in order to enable cross comparisons with the examples with regulations and with the baseline example , in table , we report the computed equilibrium path flows and in table we report the associated path costs for all four examples. in table , we report the associated computed equilibrium populations, whereas the incurred utilities at the locations are reported in table . one can see, from table , that (as occurred also in the illustrative examples in sect. ), under the regulations (as in examples through ), the utility of those subject to regulations, as in the case of those in node , is reduced. on the other hand, those in location , which now has a lower flow of refugees, experience a higher utility. also, with both refugee routes blocked to the united states, the population that remains at node is the highest in example , as compared to the value in example and example . we remark that although the examples are stylized, they nevertheless, contain features representative of refugee networks in reality. in this paper, we constructed refugee migration network equilibrium models that incorporate multiple classes of refugees, along with routes from origin to destination nodes that can consist of multiple links that capture congestion. such features have been noted in practice but, heretofore, not captured in models of human migration. moreover, we utilized a useroptimization perspective, rather than a system-optimization perspective. in the former, the refugees/migrants seek locations to migrate to that are optimal from an individual perspective as opposed to resettling refugees in a system-optimized manner. in addition, we established that the more general model, for which we also proposed constraints associated with governmental migration regulations, could be transformed, using a supernetwork construct, into a traffic network equilibrium with fixed demands. this connection expands the theory of network equilibrium problems and allows for the transferral of algorithms that have been developed over many years for the solution of traffic network equilibrium problems to problems of refugee and human migration. in addition, we noted that regulations in this context can be viewed as side constraints associated with traffic networks. we provided both small numerical examples, in order to illustrate the modeling framework, as well as larger scale examples, inspired by the refugee crisis from mexico to the united states. for the solution of the latter numerical examples, we utilized the euler method, embedded with the exact equilibrium algorithm. our examples show who may benefit from the imposition of certain regulations and who may lose. we expect that research in the future may investigate additional types of regulations of refugee networks, for which other computational schemes may be utilized, with further exploitation of network structure. origin-based algorithm for the traffic assignment problem studies in the economics of transportation a variational formulation for a human migration model a migration equilibrium model with uncertain data and movement costs the world's congested human migration routes in maps the traffic assignment problem for multi-class user transportation networks traffic equilibrium and variational inequalities the general multimodal traffic equilibrium problem with elastic demand sensitivity 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formulation of equilibrium models for end-of-life products with nonlinear constraints united nations: international migration policies: government views and priorities. department of economic and social affairs, population division population facts. department of economic and social affairs, population division united nations high commissioner for refugees united nations refugee agency. the sea route to europe: the mediterranean passage in the age of refugees united nations refugee agency. global trends. forced displacement in formulation, stability, and computation of traffic network equilibria as projected dynamical systems publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors are grateful to the anonymous reviewers for their careful reading of an earlier version of this paper and for their constructive comments and suggestions. the costs associated with the refugee migrations are, in turn, as follows:c ( f ) = . f + f + f + , c ( f ) = f + f + , c ( f ) = . f + f + f + , c ( f ) = . f + f + f + , c ( f ) = . f + f + f + , c ( f ) = f + f + , c ( f ) = f + f + , c ( f ) = . f observe that the above cost functions are nonseparable and several have flow links raised to the fourth power. the former characteristic allows one to model interactions whereas the latter captures increased congestion and, hence, cost.one can see from the network in fig. , that the refugees located at location node in mexico have three available paths to reach the united states, whereas those at node and node have a single path each, all with associated costs on the routes, which consist of multiple links. those residing at location nodes through in the united states are not interested in migrating to mexico. of course, those living at nodes , , and can also elect to remain in mexico.the routes are defined as consisting of the following respective links and enumerated as follows: for the solution of the problem, as noted earlier, we first construct the supernetwork equivalence with the supernetwork topology as in fig. and the o/d pairs, the links and paths, the link costs on the new links, the demands, and the path costs, defined accordingly.we implemented the euler method, embedded with the exact equilibrium algorithm as described in nagurney and zhang [ ] ; see also the book by nagurney and zhang [ ] . we initialized the algorithm as follows. the initial populations were equally distributed among all the paths. the sequence {a τ } in the euler method satisfied the conditions required for convergence and was set to: . { , , , , , , . . .}. the algorithm was deemed to have converged if the absolute value of the difference between each successively computed path flow differed by no more than − . the computer system utilized was a linux system at the university of massachusetts amherst.the computed equilibrium path flow pattern for example is:x * r = , , . , x * r = , . , x * r = , . , x * r = , . , x * r = . proof of theorem we first show that if a pattern ( p * , x * ) ∈ k satisfies equilibrium conditions ( ) and ( ), then it also satisfies the variational inequality in ( ) .suppose that ( p * , x * ) ∈ k satisfies the equilibrium conditions. we know, from the conservation of flow equations, that x k * r ≥ , and n j= r ∈p w i j x k * r =p k i , for all i, j, k, and routes r ∈ p w i j .for fixed class k and origin node i, it follows from ( ) that for x ∈ k :with the last equality holding because of the conservation of flow equation ( ) .hence, for all classes k and all origin nodes i, it follows that for ( p * , x * ) ∈ k :but inequality ( ) can be re-expressed as:or, equivalently, as:that is, ( ) or in vector notation:hence, necessity has been established.to prove sufficiency, we proceed as follows. clearly, from the above steps we know that we can rewrite variational inequality ( ); equivalently, ( ) , as ( ) . if we then set all path flows x r = x * r except for those associated with origin node i, we obtain ( ) , from which the conclusion follows. key: cord- -g zynbul authors: person, bobbie; sy, francisco; holton, kelly; govert, barbara; liang, arthur; garza, brenda; gould, deborah; hickson, meredith; mcdonald, marian; meijer, cecilia; smith, julia; veto, liza; williams, walter; zauderer, laura title: fear and stigma: the epidemic within the sars outbreak date: - - journal: emerg infect dis doi: . /eid . sha: doc_id: cord_uid: g zynbul because of their evolving nature and inherent scientific uncertainties, outbreaks of emerging infectious diseases can be associated with considerable fear in the general public or in specific communities, especially when illness and deaths are substantial. mitigating fear and discrimination directed toward persons infected with, and affected by, infectious disease can be important in controlling transmission. persons who are feared and stigmatized may delay seeking care and remain in the community undetected. this article outlines efforts to rapidly assess, monitor, and address fears associated with the severe acute respiratory syndrome (sars) epidemic in the united states. although fear, stigmatization, and discrimination were not widespread in the general public, asian-american communities were particularly affected. p ublic health strategies that deal with rapidly evolving disease outbreaks of new and emerging infectious diseases require a delicate balance between protecting the public's health and initiating exclusionary practices and treatments that can lead to fear and stigmatization of, and discrimination against, specific populations. the outbreak of severe acute respiratory syndrome (sars) illustrates these difficulties. sars spontaneously appeared in the southern province of guangdong, people's republic of china, in november ( , ) . by july , the epidemic, had spread to more than countries with , cumulative probable cases and deaths and was identified as a global threat to health ( ) . in the united states, cases were reported with classified as probable sars; no deaths occurred ( ) . as with many disease outbreaks, scientific information and data related to the disease changed almost hourly, as public health scientists and practitioners responded to the worldwide outbreak, which was coupled with widespread fear ( , ) . while persons, agencies, and governments sought to identify modes of transmission, strategies for disease containment, and treatment for sars, fear spread unchecked throughout the global community. fear of sars arose from the underlying anxiety about a disease with an unknown cause and possible fatal outcome ( ) . stigmatization of potential sars patients emerged early in the outbreak, as global media reported dramatic stories from asia in print media, television, and the internet. headlines from the english-language press heightened the fear. "concern is mounting over the continuing spread of the deadly sars virus. some experts say it could have a similar impact to the flu epidemic that killed million-or the current world hiv crisis," wrote the british broadcasting corporation from london, england ( ) . "china has threatened to execute or jail for life anyone who deliberately spreads the killer sars virus," stated the cable news network from beijing, china ( ) . studies have shown that during serious disease outbreaks, when the general public requires immediate information, a subgroup of the population that is at potentially greater risk of experiencing fear, stigmatization, and discrimination will need special attention from public health professionals ( ) ( ) ( ) . the recent sars outbreak was a classic example of such an outbreak. fear is further fueled when infection control techniques and restrictive practices such as quarantine and isolation are employed to protect the public's health ( , ) . while exclusionary practices based upon the best available scientific evidence may be scientifically and ethically sound for one population, those same practices may not be sound for all populations ( , ) . during the sars outbreak, some persons became fearful or suspicious of all people who fear and stigma: the epidemic within the sars outbreak looked asian, regardless of their nationality or actual risk factors for sars, and expected them to be quarantined. some americans did not understand that quarantine and isolation practices appropriate for sars-affected areas in asia, where community transmission was a concern, were practices that were not appropriate in the united states where the disease was not community acquired. for example, some persons, who had recently traveled to areas where sars was spreading, isolated themselves, even though they had no symptoms and had not been exposed to someone with sars. fear of being socially marginalized and stigmatized as a result of a disease outbreak may cause people to deny early clinical symptoms and may contribute to their failure to seek timely medical care ( ) . such fear can ultimately increase stigmatization when cases are identified at a later date ( ) . stigmatization associated with discrimination often has social and economic ramifications that intensify internalized stigmatization and feelings of fear ( ) . containing fear, which is integral to the public health management of a new and emerging disease such as sars, is best accomplished by a behavioral strategy that addresses the needs of a segment of the population at risk of becoming stigmatized and discriminated against. this strategy works best as a complement to a larger public health education and communication campaign. typically during outbreaks, initial risk communication is targeted to frontline public health professionals through vehicles such as the morbidity and mortality weekly report. initial communication provides information on case definitions and laboratory-testing strategies, as well as interim guidelines for infection control and other critical issues. communication strategies for the general public most frequently involve television sound bites, press conferences with dignitaries and health officials, and targeted release of information to mass media outlets such as newspapers and internet sites ( ) . although these risk communication activities are critical for keeping the general public informed during an outbreak, they can fail to meet the personal needs of the affected population and the general public. during the first week of april , the national center for infectious diseases (ncid) at the centers for disease control and prevention (cdc) formed a -member, multidisciplinary ncid/sars community outreach team as part of its emergency response to the global sars outbreak. while other ncid/cdc response teams dealt with laboratory investigations, surveillance, communica-tion, and clinical infection control practices, the community outreach team worked to implement rapid public health strategies to document, monitor, and assist in ameliorating specific problems associated with fear, stigmatization, and discrimination attributed to the sars outbreak in the united states. in creating a rapid public health intervention to mitigate behaviors and practices associated with sars-related fear, the team recognized the need to address the experiences of persons at greatest risk for experiencing sars-related fear, stigma, and discrimination. the team monitored stigmatizing ideas and behaviors in the general population and the media, particularly toward asian americans, who were disproportionately reporting fear, stigmatization, and discrimination compared to the general public. the team began working with asian-american communities to develop a culturally tailored intervention that ) promoted community understanding of the facts related to the transmission and prevention of sars; ) contributed to the strengthening of community resiliency and capacity to mitigate fear, stigmatization, and discrimination; and ) encouraged appropriate health-seeking behaviors for those who may have been exposed to sars and were experiencing early symptoms. the team also worked to dispel myths; keep the general public better informed; prevent discrimination against sars-affected communities; and provide guidance for institutions, agencies, and organizations hosting international visitors from sars-affected countries. during the first weeks of april , the ncid/sars community outreach team conducted a rapid situational analysis to determine the impact of sars-related fear, stigmatization, and discrimination within the asian-american community in the united states. the team carried out the following activities: ) facilitated group discussions with key opinion leaders within the asian community in the united states; ) collected and monitored the cdc public response service data; ) collected and monitored asian-language newspapers, internet sites, and other information sources; ) reviewed polling data and other communication information; ) conducted community visits, panel discussions, and media interviews; ) solicited information from state and regional minority health liaisons nationwide; ) developed ongoing relationships with the asian-american communities; particularly in major metropolitan areas throughout the united states; and ) determined new datagathering strategies as needed. the team conducted group interviews through teleconferences with national, state, and local influential leaders in the asian-american community throughout the united states. the team also conducted group interviews with chambers of commerce and trade association members, school officials and representatives, state public health department staff, academicians at universities, mental health professionals, and others. the teleconferences the team conducted reached more than persons who represented more than agencies, organizations, and communities. the goals of the group interviews were the following: ) determine the impact of sars-related fear on the asian community; ) document examples of fear, stigmatization, and discrimination; ) determine strategies for identifying and reaching "hidden populations"; ) develop partnerships with leaders and community members of the affected populations; ) determine the needs of affected populations; and ) respond appropriately to those needs through a targeted intervention with activities and asian-language materials. five major recommendations were derived from the facilitated group discussions with key informants: ) develop simple, tailored sars prevention messages; ) develop sars information materials in various asian languages; ) disseminate sars information through multiple and culturally appropriate channels, including (but not limited to) community visits, town hall meetings, and health education and communication channels to complement mass media messages; ) establish partnerships with local asian-american community-based organizations to educate the community; and ) ensure that cdc would continue to provide leadership and coordination in preventing and controlling sars. the relationships developed during these group discussions allowed team members to monitor and document ongoing stigmatizing situations related to the disease outbreak in real time and to deal more effectively with intentional and unintentional discrimination. cdc operates the public response service (cdc prs) under contract with the american social health association. this contract provides hotline service to the general public requesting information via telephone and email about bioterrorism and other disease emergencies, including sars. the ncid/sars community outreach team worked with the cdc prs to track a daily sample of incoming sars-related calls, specifically noting questions associated with fear, stigmatization, and discrimination directed toward the asian-american community. this system allowed the team to help determine specific answers to frequently asked questions for hotline staff and to develop simple, prerecorded asian-language messages. passive data collection of sars fear-related concerns began on april , . during may , , sars-related calls were received; , ( . %) of these calls were pas-sively sampled. of these sampled calls, an average of % of callers expressed concerns related to fear, stigmatization, and discrimination. a caller could express more than one concern. major concerns included the following: fear of buying asian merchandise ( calls); working with asians ( calls); living near asians ( calls); going to school with asians ( calls); and more generic issus such as being on a cruise ship or airplane ( calls); and church, school, or workplace issues ( calls). most sars calls related to transmission, symptoms, and treatment of disease and travel advisories. one critical component of the team's activities was determining where members of the asian-american community were getting sars-related information. team members monitored english-language and asian-language electronic, print, and television media coverage and informal chat rooms in the united states and other countries to stay abreast of changing information about the nature of the sars outbreak that could influence fear, stigmatization, and discrimination. the assessment showed that many people within the asian-american community were getting information from asian-language newspapers, television, and internet sites directly from china, hong kong, taiwan, and other asian areas-usually hours ahead of information providers in the united states. the information provided by these asian-language sources was often inconsistent with newspaper, television, and internet coverage in the united states, thus creating fear and suspicion that the united states government might not be telling the truth about the outbreak in this country. independent contentanalysis research conducted by intertrend communications (san francisco, ca) compared four of the most popular chinese language newspapers in the united states with two popular national mainstream english-language newspapers from march to april , ( ) . intertrend data showed that ) chinese-language newspapers were more likely to highlight sars news related to the chinese community in the united states or from china more prominently than mainstream englishlanguage newspapers; and ) chinese-language newspapers were more likely to have articles on sars, including featured in-depth articles, than mainstream english-language u.s. national newspapers ( ). these findings supported the team's initial assessment (based on an informal convenience sample of asian-language papers). general email inquiries sent to the cdc communications center and information from public health professionals, health providers, and community members led the team to sars-related internet sites that contained rumors and inaccurate information, which added to general misunderstanding, confusion, and fear. even legitimate public health internet sites from different parts of the world provided disparate information as the outbreak unfolded, furthering uncertainty and fear in the united states. the team also monitored internet sites that supported community fears as they promoted home remedies, medicinal cures, and inappropriate and unnecessary protective equipment. monitoring the information sources of the affected population was a critical activity, allowing the team to separate fact from fiction with accuracy and timeliness and address salient issues and concerns during community visits. based on its rapid situational assessment, the team was able to develop interventions to assist in mitigating fear, stigmatization, and discrimination. team members carried out the following activities: ) advised other sars emergency response teams on how to minimize the risk of stigmatizing groups in their own communications by focusing messages on the virus and the relevant behavioral risk factors; ) assisted with developing culturally tailored health education materials; and ) conducted community visits, panel discussions, and media interviews to positively influence negative behaviors occurring in communities. these visits and other contacts with the asian-american community allowed cdc to develop ongoing relationships and helped the team determine new data-gathering strategies. during a disease outbreak, information changes rapidly as scientific evidence is collected and analyzed. vital components of the team's activities were prioritizing and translating existing information and guidance documents and developing health education materials to address the specific needs of the asian-american community. an inhouse translation service did not exist, and the rapidly evolving scientific evidence challenged the turnaround time for developing, translating, and disseminating information. the team worked to identify priority documents for translation and to ensure asian-language translation for web and print products tailored to the asian-american community. to ensure accurate translations, cdc contracted with professional translation services and had all documents back-translated. web-based information on sars included documents in traditional chinese, simplified chinese, korean, vietnamese, and japanese, as well as french and spanish. the team also created brief, recorded educational hotline messages in chinese and vietnamese. the main messages for people in the united states were the following: ) the risk of sars is low; ) severe cases of sars have been uncommon, and there have been no deaths in the united states; ) methods for disease prevention in the general public are like those of other viral diseases; and ) although no evidence of community spread currently exists, continued vigilance, aggressive case management, and infection control are needed. team members conducted field visits to asian communities in boston; new york city; oakland, california; san francisco; washington, d.c.; edison, new jersey; and los angeles to respond to the direct needs of the communities and gather information. the team met with community leaders, toured the communities, informally gathered further information, and gave community sars presentations in seven cities, reaching approximately persons. through community visits, the team was able to ) provide the latest in evidence-based information on sars with asian-language education materials; ) dispel misconceptions, myths, and rumors; ) act as a catalyst for bringing together a broad spectrum of organizations and persons in the community to create local networks to promote community resiliency; and ) provide credibility and reassurance to those who felt vulnerable. speakers also presented a public health model for mitigating fear, stigmatization, and discrimination that could be instituted by public health officials, clinicians, and community members. through open discussion sessions and informal information gathering in the community, the team found that sars-related stigmatization was occurring more frequently within the asian community than from outsiders directed toward the asian community. the team also found that those persons with sars-like symptoms who used traditional herbal physicians and pharmacies were less likely to be referred to, or seek out, public health officials, suggesting that further research into strategies to reach this population is needed. conducting community visits also showed that cdc was responding to the needs of the community at risk for sars-related fear, stigmatization, and discrimination and was modeling positive behaviors to the public. other infectious disease epidemics have been associated with specific ethnic groups. fear, stigmatization, and discrimination plagued russian jewish immigrants when the outbreaks of typhus fever and cholera in new york city were traced to russian jewish immigrants from eastern europe ( ) . in the spring of , the chinatown community in san francisco was faced with extreme discrimination due to an outbreak of bubonic plague, the "black death," attributed to rats transported on a ship from hong kong ( ) . in an outbreak of hantavirus infection in the four corners area (where the borders of four states-arizona, new mexico, utah, and colorado-meet) of the united states was initially referred to by reporters as a navajo disease, which led to severe fear, stigmatization, and discrimination of native americans in the region ( ) . previous scientific studies have shown that fear associated with stigmatization and discrimination has negatively affected public health efforts with chronic conditions and diseases such as mental illness, hiv/aids, tuberculosis, leprosy, and epilepsy ( ) ( ) ( ) ( ) ( ) . more recently, stigmatization associated with fear and the aids epidemic negatively influenced voluntary testing, counseling, and treatment of those infected with the disease ( ) . health providers have also seen reluctance by recent refugees and immigrants to get tested and treated for tuberculosis because of possible social stigmatization ( ) . the potential of being labeled at-risk for having or transmitting a stigmatizing condition such as sars creates fear and anxiety, and an entire population of people can be at risk for becoming stigmatized in society ( ) . protecting the health of the public while preventing stigmatization of segments of the population during a rapidly evolving disease outbreak is complex. the team's experience during the recent sars outbreak demanded anticipatory insight, perceptive planning, and a rapid response to a targeted audience with specific cultural perspectives and influences. it also required us to recognize the distinctive features of sars in a medical, social, and cultural context. weiss states, "preventing fear and stigmatization depends on controlling or treating the target health problem, countering tendencies of those who stigmatize others, and supporting those who are stigmatized through emotional support and social policies" ( ) . the data collected during the rapid situational assessment were critical in guiding activities of the team. both the data and the data collection process assisted the team in establishing interpersonal relationships with community leaders, determining priority needs, identifying responsible intervention strategies, and developing effective communication channels. the team was able to better understand community perceptions and attitudes by identifying the communities' trusted sources of information. when conducting community visits, the team was able to address discordant information, myths, and rumors; provide simple asian-language messages and materials; and act as a catalyst to build community resiliency and prepare for the possibility of future emerging diseases. the team was also able to keep cdc/ncid leaders informed and to intervene when they identified discriminatory policies, practices, and actions that were inconsistent with evidence-based public health recommendations and guidelines. quelling fear-driven stigmatization and discrimination during the sars outbreak required tailored intervention strategies carried out by the sars community outreach team. these activities complemented traditional risk com-munication for the general public. to be effective, behavioral intervention approaches, messages, and materials had to be salient for the affected population, in this case asian-american communities within the united states. further, these interventions aimed at promoting an accurate understanding of the epidemic both in the general population and within the affected community, that is, the dynamic nature of the outbreak and its cause, treatment options, and prevention strategies. through interpersonal connections, the team members worked to promote reassurance and enhance community resiliency. public health professionals must understand the necessary balance needed to protect the public's health with appropriate exclusionary practices, while at the same time preventing fear, stigmatization, and discrimination of specific segments of the population. as we prepare for the next new or reemerging disease outbreak, we should also be preparing to deal with the fear epidemic that will likely accompany it. by developing effective behavioral and health education strategies and providing timely attention to the special needs of affected populations, we can ensure that, no matter what the infectious disease, we can limit the associated epidemic of fear and stigmatization. update: severe acute respiratory syndrome-worldwide and united states pneumonia causes panic in guangdong province managing sars amidst uncertainty fear is spreading faster than sars-and so it should. peter sandman column [serial online contagion, defect: issues in the anthropology of public health. stigma and global health: developing a research agenda sars: is global panic justified? bbc news uk edition death for sars spreaders: china east european jewish immigrants and the new york city epidemics of in search of equality: the chinese struggle against discrimination in nineteenth-century america hantavirus infection-southwestern united states: interim recommendations for risk reduction stigma interventions and research for international health. stigma and global health: developing a research agenda centers for disease control and prevention. use of quarantine to prevent transmission of severe acute respiratory syndrome-taiwan agency for toxic substances and disease registry. a primer on health risk communication principles and practices. the agency on stigma and its public health implications. stigma and global health: developing a research agenda report: sars article content analysis, comparison between chinese newspapers and mainstream newspapers in los angeles subjective experiences of stigma. a focus group study of schizophrenic patients, their relatives and mental health professionals thinking about aids and stigma: a psychologist's perspective leprosy: urgent need to end stigma and isolation tuberculosis beliefs among recent vietnamese refugees in new york state stigma in the lives of adolescents with epilepsy: a review of the literature critical delays in hiv testing and care: the potential role of stigma when tuberculosis treatment fails. a social behavioral account of patient adherence stigma: notes on the management of spoiled identity we thank the following cdc staff members who volunteered their time to translate critical information into multiple languages during the sars outbreak: feng chai, rachanee cheingsong, feng xiang gao, wenlin huang, han li, wenkai li, xiaofang li, timothy lim, gang liu, yuko mizuno, christine huong montgomery, xuanthao ngo, doan quang, yang xia, and yingtao zhou.ms. person is a senior behavioral scientist in the national center for infectious diseases, centers for disease control and prevention. her research interests focus on health and behavior, with a specific interest in cross-cultural behavioral interventions for the prevention and control of infectious disease. key: cord- -risqto authors: chu, ellen w.; karr, james r. title: environmental impact, concept and measurement of date: - - journal: encyclopedia of biodiversity doi: . /b - - - - . - sha: doc_id: cord_uid: risqto environments on earth are always changing, and living systems evolve within them. for most of their history, human beings did the same. but in the last two centuries, humans have become the planet's dominant species, changing and impoverishing the environment for all life on earth and even decimating humans' own cultural diversity. contemporary cultural worldviews that have severed humans' ancient connections with the natural world, along with consumption and population growth, have deepened this impoverishment. understanding, measuring, and managing human environmental impacts – the most important of which is the impoverishment of living systems – is the st century's greatest challenge. all organisms change their environment as they live, grow, and reproduce. over millennia, organisms evolve to contend with changes in their environment. those that do not adapt go extinct. those that survive are molded by evolution and biogeography as the environment changes. even unusual or seemingly catastrophic events, like tidal waves from earthquakes, are an integral part of the ecological contexts to which organisms adapt over long time spans. some organisms, like beavers and elephants, change their surroundings so dramatically that they have been called ecosystem engineers. beaver dams alter the flow of rivers, increase dissolved oxygen in downstream waters, create wetlands, and modify streamside zones. african elephants convert wooded savanna to open grassland by toppling trees as they browse. change brought about by living things, including ecosystem engineers, has been slow and incremental in evolutionary terms. ecosystem engineers evolve along with other inhabitants of their environments, developing ways to coexist; like other environmental components, ecosystem engineers, and their effects are part of an evolving ecological context. in contrast, human effects since the industrial revolutionincluding many that may be invisible to a casual observeroutpace the capacity of living systems to respond. in evolutionary terms, these effects are recent and outside the experience of most organisms. over the past two centuriesbarely more than two human lifetimes -humans have profoundly altered living and nonliving systems everywhere. for the first time in the earth's history, the environmental impact of one species, homo sapiens, is the principal agent of global change. understanding the environmental impacts of human actions is one of modern science's greatest challenges. understanding the consequences of those impacts, and managing them to protect the well-being of human society and other life on earth, is humanity's greatest challenge. the human evolutionary line began in africa about million years ago (ma). it took some or million years (my) for protohumans to spread from africa to asia and then to europe. these early humans, like other primates, made their living by seeking food and shelter from their environment, gathering plant foods, and hunting easy-to-kill prey. sometimes, they also experienced threats from their environment, including accidents, droughts, vector-borne diseases, and attacks from predators. at this stage, with relatively low population densities and limited technologies, humans were not ecosystem engineers. by some , years ago, however, humans had learned to use fire; developed complex tools, weapons, and language; and created art. on local scales, these modern humans were very much ecosystem engineers. sometimes their enhanced abilities to make a living outstripped their local environment's capacity to provide that living, and they caused local ecological disruptions. on several continents, for example, humans hunted large mammals to the point where many, such as the marsupial lion of australia, went extinct. as humans became more efficient at exploiting their local environments, they spread farther. by , years ago, modern humans had spread to all continents and many islands across the globe. then, about , years ago, people began to domesticate plants and animals. instead of searching for food, they began to produce food. food production changed the course of human and environmental history. domestication of plants and animals enabled people to adopt a sedentary lifestyle. as detailed by geographer and ecologist diamond ( diamond ( , , populations grew as agriculture developed, because larger sedentary populations both demanded and enabled more food production. local ecological disruptions became more numerous and widespread and more intense. with animal domestication, contagious diseases of pets and livestock adapted to new, human hosts. diseases spread more quickly in crowded conditions; inadequate sanitation compounded the effects. from agriculture, civilization followed and with it, cities, writing, advanced technology, and political empires. in just , years, these developments led to nearly billion people on earth, industrial societies, and a global economy founded on complicated technologies and fossil fuels. humans have emerged as ecosystem engineers on a global scale. the ecological disruptions we cause are no longer just local or regional but global, and we have become the principal threat to the environment. yet despite today's advanced technologies, humans are as dependent on their environments as other organisms are. history, not just ecology, has been very clear on this point. from the old kingdom of egypt more than years ago to the culture that created the huge stone monoliths on easter island between and ad to the s dust bowl of north america, civilizations or ways of life have prospered and failed by using and (mostly unwittingly) abusing natural resources. in old kingdom egypt, the resource was the valley of the nile, richly fertilized with sediment at each flooding of the river, laced with canals and side streams, blessed with a luxuriant delta. agriculture flourished and populations swelled, until unusually severe droughts brought on the civilization's collapse. on easter island, the resource was trees, which gave polynesians colonizing the island the means to build shelter, canoes for fishing the open waters around the island, and log rollers for moving the ceremonial stone monuments for which the island is famous. deforestation not only eliminated the humans' source of wood, but also further deprived the already poor soil of nutrients and made it impossible to sustain the agriculture that had sustained the island's civilization. on the dry great plains of north america, settlers were convinced that rain would follow the plow, and so they plowed homestead after homestead, only to watch their homesteads' soils literally blow away in the wind. in these cases and many others, human civilizations damaged their environments, and their actions also worsened the effects on their civilizations of climatic or other natural cycles. yet in each case, a human culture was operating precisely the way it had evolved to operate: the culture of old kingdom egypt enabled its people to prosper on the nile's natural bounty, but prolonged, unprecedented drought brought starvation and political disorder. easter islanders thrived and populated the island until its resources were exhausted. dust bowl farmers lived out their culture's view of dominating and exploiting the land for all it was worth. the inevitable outcome for all three cases was a catastrophe for the immediate environment and the people it supported -not only because the people were unprepared to cope with dramatic natural changes in their environments but because their own actions magnified the disastrous effects of those changes. quoting an apt bit of cynical graffiti, historical philosopher wright ( , p. ) sums up what he calls the hazards of human progress this way: ''each time history repeats itself, the price goes up.'' indeed, as the second decade of the st century begins, humans are ecosystem engineers on a planetary scale, and our global civilization threatens the life-sustaining capacity of all of earth's environmental ''spheres'': • geosphere (lithosphere): earth's crust and upper mantle, containing nonrenewable fossil fuels, minerals, and nutrients that plants require. the activities of plants, animals, and microorganisms weather mineral soils and rocks, create organic soils, and alter erosion and sedimentation rates. humans mine minerals, metals, and gems; extract fossil fuels including coal, oil, and natural gas; and increase erosion and sedimentation by removing or altering natural plant cover through agriculture, logging, and urbanization. • atmosphere: the thin envelope of gases encircling the planet. living systems modify the atmosphere, its temperature, and the amount of water it contains by continually generating oxygen and consuming carbon dioxide through photosynthesis and affecting the amount and forms of other gases. humans release toxic chemicals into the air and alter the climate by raising the atmospheric concentration of greenhouse gases, such as carbon dioxide and methane, through the burning of fossil fuels in motor vehicles, ships, airplanes, and power plants. • hydrosphere: earth's liquid surface and underground water; its polar ice caps, oceanic icebergs, and terrestrial permafrost; and its atmospheric water vapor. living systems alter the water cycle by modifying the earth's temperature and the amount of water plants send into the atmosphere through a process called evapotranspiration. humans build dams, irrigation canals, drinking-water delivery systems, and wastewater treatment plants. they use water to generate electricity; they mine groundwater from dwindling underground aquifers for farming as well as drinking; they alter the flows of surface waters for everything from transportation to the mining of gold; they drain wetlands to gain land area and abate waterborne diseases. modern human interference in global climate is likely to disrupt the entire planetary water cycle. • biosphere: the totality of earth's living systems, that part of the earth inhabited by living organisms. life on earth emerged . billion years ago and has sustained itself through changes in form, diversity, and detail since then. no planet yet discovered supports complex life as we know it on earth. as predators, humans have decimated or eliminated wild animal populations worldwide. as domesticators of animals and plants, humans have massively reshaped landscapes by cutting forests, burning and plowing grasslands, building cities, desertifying vast areas, and overharvesting fish and shellfish. human actions have precipitated a spasm of extinctions that today rivals five previous mass extinctions caused by astronomical or geological forces, each of which eliminated more than % of species then existing. humans themselves may be thought of as a sphere within the greater biosphere: the ethnosphere, or the sum total of all thoughts and intuitions, myths and beliefs, ideas and inspirations brought into being by the human imagination since the dawn of consciousness. in the words of anthropologist davis ( , p. ) , who coined and defined the term in , ''the ethnosphere is humanity's greatest legacy. it is the product of our dreams, the embodiment of our hopes, the symbol of all we are and all that we, as a wildly inquisitive and astonishingly adaptive species, have created.'' but, davis notes, just as the biosphere is being severely eroded, so too is the ethnosphere, but at a much faster pace. today, the scientific consensus is that h. sapiens -a single species -rivals astronomical and geological forces in its impact on life on earth. the first step in dealing with the present impact of human activity is to correctly identify the nature of humanity's environmental impact, concept and measurement of relationship with the environment and how human actions affect that relationship. many people still see the environment as something people must overcome, or they regard environmental needs as something that ought to be balanced against human needs (for example, jobs vs. the environment). most people still regard the environment as a provider of commodities or a receptacle for waste. when asked to name humanity's primary environmental challenges, people typically think of running out of nonrenewable raw materials and energy or about water and air pollution. environmental research and development institutions focus on ways technology can help solve each problem, such as fuel cells to provide clean, potentially renewable energy or scrubbers to curb smokestack pollution. even when people worry about biodiversity loss, they are concerned primarily with stopping the extinction of species, rather than with understanding the underlying losses leading up to species extinctions or the broader biological crisis that extinctions signal. these perspectives miss a crucial point: the reason pollution, energy use, extinction, and dozens of other human impacts are important is their larger impact on the biosphere. ecosystems, particularly their living components, have always provided the capital to fuel human economies. when populations were small, humans making a living from nature's wealth caused no more disruption than other species. but with nearly billion people occupying or using resources from every place on earth, humans are overwhelming the ability of other life-forms to make a living and depleting the planet's natural wealth. at this point in the planet's history, one species is compromising earth's ability to support the living systems that evolved here over millions of years. the systematic reduction in earth's capacity to support life -which woodwell ( ) termed 'biotic impoverishment' -is thus the most important human-caused environmental impact. at best, the ethics of this impact are questionable; at worst, it is jeopardizing our own survival. the connection between biotic impoverishment and extinction is intuitively obvious. by overharvesting fish, overcutting forests, overgrazing grasslands, or paving over land for cities, we are clearly killing other organisms outright or eliminating their habitats, thereby driving species to extinction and impoverishing the diversity of life. but biotic impoverishment takes many forms besides extinction. it encompasses three categories of human impacts on the biosphere: ( ) indirect depletion of living systems through alterations in physical and chemical systems, ( ) direct depletion of nonhuman life, and ( ) direct degradation of human life (table ) . identifying and understanding the biological significance of our actions -their effects on living systems, including our own social and economic systems -is the key to developing effective ways to manage our impacts. humans affect virtually all the physical and chemical systems life depends on: water, soils, air, and the biogeochemical cycles linking them. some human-driven physical and chemical changes have no repercussions on the biota; others do, becoming agents of biotic impoverishment. humans probably spend more energy, money, and time trying to control the movement and availability of water than to manage any other natural resource. in the process, we contaminate water, move water across and out of natural basins, deplete surface and groundwater; modify the timing and amount of flow in rivers, straighten or build dikes to constrain rivers, and alter natural flood patterns. we change the amount, timing, and chemistry of fresh water reaching coastal regions, and we dry up wetlands, lakes, and inland seas. our demands are outrunning supplies of this nonrenewable resource, and the scale of our transformations risks altering the planetary water cycle. physical alterations of the earth's waters, combined with massive industrial, agricultural, and residential pollution, have taken a heavy toll on nonhuman aquatic life. by as much as one-fifth of the world's coral reefs had been destroyed, and only % remained healthy. globally, the number of oceanic dead zones, where little or no dissolved oxygen exists, tripled during the last years of the th century. the biota of freshwater systems has fared no better. a -year survey of the freshwater fishes inhabiting malaysian rivers in the late s found only % of known malaysian species. some % of north america's freshwater fishes are at risk of extinction; two-thirds of freshwater mussels and crayfishes and one-third of amphibians that depend on aquatic habitats in the united states are rare or imperiled. humans use at least % of the earth's accessible water runoff, a figure that is likely to grow to % by . by then, more than a third of the world's population could suffer shortages of fresh water for drinking and irrigation. groundwater aquifers in many of the world's most important cropproducing regions are being drained faster than they can be replenished: a study published in found that the rate of groundwater depletion worldwide had more than doubled from to . natural flood regimes, as in the nile river basin, no longer spread nutrient-rich silt across floodplains to nourish agriculture; indeed, the high dam at aswan traps so much silt behind it that the nile delta, essential to egypt's present-day economy, is slumping into the sea. whole inland seas, such as the aral sea in uzbekistan, are drying up because the streams feeding them contain so little water. in addition to eliminating habitat for resident organisms, the sea's drying is bringing diseases to surrounding human populations. indeed, diseases caused by waterborne pathogens are making a comeback even in industrialized nations. in the past five or six decades, the number of large dams on the world's rivers grew more than seven times, to more than , today. the mammoth three gorges dam across china's yangtze river, completed in , created a -km-long serpentine lake behind it. the dam displaced more than million people and may force the relocation of another million from the reservoir region, which, at , km , is larger than switzerland. the dam has greatly altered ecosystems on the yangtze's middle reaches, compounding perils already faced by prized and endemic fish and aquatic mammals. the sheer weight of the water and silt behind the concrete dam raises the risk of landslides and strains the region's geological structure, while water released from the dam eats away at downstream banks and scours the bottom. and by slowing the flow of the yangtze and nearby tributaries, the dam drains the river's ability to flush out and detoxify pollutants from upstream industries. not just dirt, soil is a living system that makes it possible for raw elements from air, water, and bedrock to be physically and chemically assembled, disassembled, and reassembled with the aid of living macro-and microorganisms into the green cloak of life above ground. accumulated over thousands of years, soil cannot be renewed in any time frame useful to humans alive today, or even to their great-grandchildren. humans degrade soils when they compact it, erode it, disrupt its organic and inorganic structure, turn it too salty for life, and cause desertification. urbanization, logging, mining, overgrazing, alterations in soil moisture, air pollution, fires, chemical pollution, and leaching out of minerals all damage or destroy soils. thanks to removal of vegetative cover, mining, agriculture, and other activities, the world's topsoils are eroded by wind and water ten to hundreds of times faster than they are renewed (at roughly tons ha À year À ). soils constitute the foundation of human agriculture, yet agriculture, including livestock raising, is the worst culprit in degrading soils. agricultural practices have eroded or degraded more than % of present cropland. over the last half century, some , villages in northern and western china have been overrun by the drifting sands of desertification. besides topsoil erosion, the damage includes salting and saturation of poorly managed irrigated lands; compaction by heavy machinery and the hooves of livestock; and pollution from excessive fertilizers, animal wastes, and pesticides. living, dead, and decomposing organic matter is the key to soil structure and fertility. soil depleted of organic matter is less permeable to water and air and thus less able to support either aboveground plants or soil organisms. the linkages between soil's inorganic components and the soil biotanaturalist wilson's ( ) ''little things that run the world''are what give soil its life-sustaining capacity. a clear-cut forest patch whose soil biota has been damaged beyond recovery can no longer sustain trees, no matter how many are planted; another clear-cut patch whose soil community is intact -especially the close associations among fungi and tree rootswill support new tree growth. destroying soil biota unleashes a whole series of impoverishing biotic effects both below and above ground. in , rachel carson's landmark book, silent spring, alerted the world to the pervasiveness of synthetic chemicals produced since world war ii. as many as , synthetic chemicals are in use today. true to one company's slogan, many of these have brought ''better living through chemistry,'' providing new fabrics and lighter manufacturing materials, antibiotics, and life-saving drugs. but industrial nations have carelessly pumped chemicals into every medium. chemicals -as varied as prescription drugs flowing out of sewage plants, pesticides, heavy metals, and cancer-causing by-products of countless manufacturing processes -now lace the world's water, soil, and air and the bodies of all living things, including humans. chemicals directly poison organisms; they accumulate in physical surroundings and are passed through and, in many cases, concentrated within portions of the food web. chemicals cause cancer, interfere with hormonal systems, provoke asthma, and impair the functioning of immune systems. they have intergenerational effects, such as intellectual impairment in children whose mothers have eaten contaminated fish. what's more, over half a century of pesticide and antibiotic overuse has bred resistance to these chemicals among insects, plants, and microbes, giving rise to new and reemerging scourges. many chemicals travel oceanic and atmospheric currents to sites far from their source. sulfur emissions from the us midwest, for example, fall to earth again as acid rain in europe, killing forests and so acidifying streams and lakes that they, too, effectively die. china's burning of soft coal sends air pollution all the way to northwestern north america; the heavy haze hanging over china's chief farming regions may be cutting agricultural production by a third. chlorofluorocarbons (cfcs), once widely used as refrigerants, have damaged the atmospheric ozone layer, which moderates how much ultraviolet radiation reaches the earth, and opened ozone holes over the arctic and antarctic. but even more alarming is an unprecedented acidification of the oceans that has only recently attracted the attention of major scientific research consortiums. acid added to the world ocean by human activity has lowered the ocean's ph; it is lower now than it has been in my, which translates into a % increase in sea-surface acidity since industrialization began. the future of marine life in an ocean acidifying at this speed and intensity looks bleak. as the concentration of hydrogen ions rises, the calcium carbonate in the shells or skeletons of organisms such as tropical corals, microscopic foraminifera, and mollusks begins to dissolve; further, more hydrogen ions combine with the calcium carbonate building blocks the organisms need, making it harder for them to extract this compound from the water and build their shells in the first place. although many of the most obviously deadly chemicals were banned in the s, they continue to impoverish the biosphere. polychlorinated biphenyls -stable, nonflammable compounds once used in electrical transformers and many other industrial and household applications -remain in the environment for long periods, cycling among air, water, and soils and persisting in the food web. they are found in polar bears and arctic villagers; they are implicated in reproductive disorders, particularly in such animals as marine mammals, whose long lives, thick fat layers where chemicals concentrate, and position as top predators make them especially vulnerable. the agricultural pesticide ddt, sprayed with abandon in the s and s, even directly on children, had severely thinned wild birds' eggshells by the time it was banned in the united states. populations of birds such as the brown pelican and bald eagle had dropped precipitously by the s, although they have recovered enough for the species to be taken off the us endangered species list, the bald eagle in and the brown pelican in . reproduction of central california populations of the california condor, in contrast, continues to be threatened by ddt breakdown products, which, years after the pesticide was banned, are still found in the sea lion carcasses the birds sometimes feed on. carson's book revealed the real danger of chemical pollutants: they have not simply perturbed the chemistry of water, soil, and air but harmed the biosphere as well. the list of chemicals' effects on living things is so long that chemical pollution equals humans' environmental impact in most people's minds, yet it is just one form of biotic impoverishment. all the substances found in living things -such as water, carbon, nitrogen, phosphorus, and sulfur -cycle through ecosystems in biogeochemical cycles. human activities modify or have the potential to modify all these cycles. sometimes the results stem from changing the amount or the precise chemistry of the cycled substance; in other cases, humans change biogeochemical cycles by changing the biota itself. freshwater use, dams, and other engineering ventures affect the amount and rate of river flow to the oceans and increase evaporation rates, directly affecting the water cycle and indirectly impoverishing aquatic life. direct human modifications of living systems also alter the water cycle. in south africa, european settlers supplemented the treeless native scrub, or fynbos, with such trees as pines and australian acacias from similar mediterranean climates. but because these trees are larger and thirstier than the native scrub, regional water tables have fallen sharply. human activity has disrupted the global nitrogen cycle by greatly increasing the amount of nitrogen fixed from the atmosphere (combined into compounds usable by living things). the increase comes mostly from deliberate addition of nitrogen to soils as fertilizer but also as a by-product of the burning of fossil fuels. agriculture, livestock raising, and residential yard maintenance chronically add tons of excess nutrients, including nitrogen and phosphorus, to soils and water. the additions are often invisible; their biological impacts are often dramatic. increased nutrients in coastal waters, for example, trigger blooms of toxic dinoflagellates -the algae that cause red tides, fish kills, and tumors and other diseases in varied sea creatures. when huge blooms of algae die, they fall to the seafloor, where their decomposition so robs the water of oxygen that fish and other marine organisms can no longer live there. with nitrogen concentrations in the mississippi river two to three times as high as they were years ago, a gigantic dead zone forms in the gulf of mexico every summer; in summer this dead zone covered , km . the burning of fossil fuels is transforming the carbon cycle, primarily by raising the atmospheric concentration of carbon dioxide. with other greenhouse gases, such as methane and oxides of nitrogen, carbon dioxide helps keep earth's surface at a livable temperature and drives plant photosynthesis, but since the industrial revolution, atmospheric carbon dioxide concentrations have risen nearly % and are now widely thought to be disrupting the planet's climate. in addition, the effects of catastrophic oil spills like the one that followed the april explosion of the deepwater horizon drilling rig in the gulf of mexico -and the effects of the chemicals used to disperse the resulting plumes of oil -may reverberate for decades. in its report, written and reviewed by more than scientists, the intergovernmental panel on climate change (ipcc) concluded that climate warming was ''unequivocal'' (p. ), that most of the average global warming over the previous years was ''very likely due to anthropogenic ghg [greenhouse gas] increases'' (p. ), and that this warming has likely had ''a discernible influence at the global scale on observed changes in many physical and biological systems'' (p. ). the concentrations of heat-trapping gases in the atmosphere are at their highest level in more than , years. the th century in the northern hemisphere was the warmest of the past millennium; the first decade of the st first century, and the first months of , were the warmest on record. higher global temperatures set in motion a whole series of effects, making the study of climate change, and of humans' role in it, complex and controversial. spring arrives at least week earlier in the northern hemisphere. polar glaciers and ice sheets are receding. the arctic is warming twice as fast as the rest of the planet, and arctic sea ice melted at a near-record pace in . with the sun heating the newly open water, winter refreezing will take longer, and the resulting thinner ice will melt more easily the following summer. the large-scale circulation of global air masses is changing and, with them, the large-scale cycles in ocean currents, including the periodic warming and cooling in the tropical pacific ocean known as el niñ o and la niñ a. as a result, the distribution, timing, and amount of rain and snow are also changing, making the weather seem more unpredictable than ever. unusually warm or cold winters, massive hurricanes like those that devastated the us gulf coast in , and weatherrelated damage to human life and property are all predicted to increase with global warming. in the united states in , weather-related damage totaled nearly $ billion. where other nutrients are not limiting, rising carbon dioxide concentrations may enhance plant photosynthesis and growth. rising temperatures may shift the ranges of many plants and animals -both wild and domestic -rearranging the composition and distribution of the world's biomes, as well as those of agricultural systems. the resulting displacements will have far-reaching implications not only for the displaced plants and animals but also for the goods and services humans depend on from these living systems. from their beginnings as hunter-gatherers, humans have become highly efficient, machine-aided ecosystem engineers and predators. we transform the land so it produces what we need or want; we harvest the oceans in addition to reaping our own fields; we cover the land, even agricultural land, with sprawling cities. all these activities directly affect the ability of other life-forms to survive and reproduce. we deplete nonhuman life by eliminating some forms and favoring others; the result is a loss of genetic, population, and species diversity. we are irreversibly homogenizing life on earth, in effect exercising an unnatural selection that is erasing the diversity generated by millions of years of evolution by natural selection. one species is now determining which other species will survive, reproduce, and thereby contribute the raw material for future evolution. in the s, so many sardines were scooped from the waters off monterey's cannery row in california that the population collapsed, taking other sea creatures and human livelihoods with it; after rebounding somewhat in the first decade of the s, the species has still not recovered fully. according to the us national marine fisheries service, nearly % of commercially valuable fish of known status were overfished or fished to their full potential by . atlantic commercial fish species at their lowest levels in history include tuna, marlin, cod, and swordfish. overfishing not only depletes target species but restructures entire marine food webs. marine mammals, including whales, seals, sea lions, manatees, and sea otters, were so badly depleted by human hunters that one species, steller's sea cow (hydrodamalis gigas), went extinct; many other species almost disappeared. in the th century, russian fur traders wiped out sea otters (enhydra lutris) along the central california coast. with the otters gone, their principal prey, purple sea urchins (stronglyocentrotus purpuratus), overran the offshore forests of giant kelp (macrocystis pyrifera), decimating the kelp fronds and the habitat they provided for countless other marine creatures, including commercially harvested fishes. thanks to five decades of protection, marine mammal populations began slowly recovering -only to face food shortages as regional marine food webs continue to unravel because of fishing, changing oceanic conditions, and contamination. timber harvest has stripped vegetation from the amazonian rainforest to mountainsides on all continents, diminishing and fragmenting habitat for innumerable forest and stream organisms, eroding soils, worsening floods, and contributing significantly to global carbon dioxide emissions. in the northern hemisphere, % or less remains of old-growth temperate rainforests. the uniform stands of trees usually replanted after logging do not replace the diversity lost with the native forest, any more than monocultures of corn replace the diversity within native tallgrass prairies. a great deal of human ecosystem engineering not only alters or damages the habitats of other living things but often destroys those habitats. satellite-mounted remote-sensing instruments have revealed transformations of terrestrial landscapes on a scale unimaginable in centuries past. together, cropland and pastures occupy % of earth's land surface. estimates of the share of land wholly transformed or degraded by humans hover around %. our roads, farms, cities, feedlots, and ranches either fragment or destroy the habitats of most large carnivorous mammals. mining and oil drilling damage the soil, remove vegetation, and pollute marine areas. grazing compacts soil and sends silt and manure into streams, where they harm stream life. landscapes that have not been entirely converted to human use have been cut into fragments. in song of the dodo, writer quammen ( ) likens our actions to starting with a fine persian carpet and then slicing it neatly into equal pieces; even if we had the same square footage, we would not have nice persian rugs -only ragged, nonfunctional fragments. and in fact, we do not even have the original square footage because we have destroyed an enormous fraction of it. such habitat destruction is not limited to terrestrial environments. human channelization of rivers may remove whole segments of riverbed. in the kissimmee river of the us state of florida, for example, channelization in the s transformed km of free-flowing river into km of canal, effectively removing km of river channel and drastically altering the orphaned river meanders left behind. wetlands worldwide continue to disappear, drained to create shoreline communities for people and filled to increase cropland. the lower united states lost % of their wetlands between the s and mid- s. such losses destroy major fish and shellfish nurseries, natural flood and pollution control, and habitat for countless plants and animals. the mosaic of habitats in, on, or near the seafloor -home to % of all marine species -is also being decimated. like clear-cutting of an old-growth forest, the use of large, heavy trawls dragged along the sea bottom to catch groundfish and other species flattens and simplifies complex, structured habitats such as gravels, coral reefs, crevices, and boulders and drastically reduces biodiversity. studies reported on by the national research council of the us national academy of sciences have shown that a single tow can injure or destroy upward of two-thirds of certain bottom-dwelling species, which may still not have recovered after a year or more of no trawling. habitat fragmentation and destruction, whether on land or in freshwater and marine environments, may lead directly to extinction or isolate organisms in ways that make them extremely vulnerable to natural disturbances, climate change, or further human disturbance. ''the one process ongoing y that will take millions of years to correct,' ' wilson ( , p. ) admonishes us, ''is the loss of genetic and species diversity by the destruction of natural habitats. this is the folly our descendants are least likely to forgive us.'' both deliberately and unwittingly, humans are rearranging earth's living components, reducing diversity and homogenizing biotas around the world. the present, continuing loss of genetic diversity, of populations, and of species vastly exceeds background rates. at the same time, our global economy is transporting species worldwide at unprecedented scales. the globe is now experiencing its sixth mass extinction, the largest since the dinosaurs vanished ma; present extinction rates are thought to be on the order of - times those before people dominated earth. according to the millennium ecosystem assessment, a -year project begun in to assess the world's ecosystems, an estimated - % of the world's species will be committed to extinction over the next years. approximately % of all vertebrates, including % of sharks and rays, are at risk of extinction. at least one of every eight plant species is also threatened with extinction. although mammals and birds typically receive the most attention, massive extinctions of plants, which form the basis of the biosphere's food webs, undermine lifesupport foundations. the mutualistic relationships between animals and plants, particularly evident in tropical forests, mean that extinctions in one group have cascading effects in other groups. plants reliant on animals for pollination or seed dispersal, for example, are themselves threatened by the extinction of the animal species they depend on. not surprisingly, some scientists view extinction as the worst biological tragedy, but extinction is just another symptom of global biotic impoverishment. ever since they began to spread over the globe, people have transported other organisms with them, sometimes for food, sometimes for aesthetic reasons, and most often inadvertently. with the mobility of modern societies and today's especially speedy globalization of trade, the introduction of alien species has reached epidemic proportions, causing some scientists to label it biological pollution. aliens -zebra mussels (dreissena polymorpha) and tamarisks, or saltcedar (tamarix spp.), in north america; the red sea sea jelly rhopilema nomadica and the common aquarium alga caulerpa taxifolia now choking the mediterranean sea; and leidy's comb jelly (mnemiopsis leidyi) of northeastern america in the black sea, to name just a few -are present everywhere, and they usually thrive and spread at the expense of native species. on many islands, for example, more than half the plant species are not native, and in many continental areas the figure reaches % or more. the costs of such invasions, in both economic and ecological terms, are high. in the united states, for example, annual economic losses due to damage by invasive species or the costs of controlling them exceed $ billion per year -$ billion more than the nation's losses from weather-related damage in . furthermore, alien invasions cause extinctions and, when added to other extinctions and the deliberate monocultures of agricultural crops, homogenize biotas still more. introduced species are fast catching up with habitat fragmentation and destruction as the major engines of ecological deterioration. humans have been manipulating their crop plants and domesticated animals for , years or so -selecting seeds or individuals and breeding and cross-breeding them. the goal was something better, bigger, tastier, hardier, or all of the above; success was sometimes elusive, but the result was crop homogenization. of the myriad strains of potatoes domesticated by south american cultures, for example, only one was accepted and cultivated when potatoes first made it to europe. the new crop made it possible to feed more people from an equivalent area of land and initially staved off malnutrition. but the strain succumbed to a fungal potato blight in the s. had more than one strain been cultivated, the tragic irish potato famines might have been averted. in the last few decades of the th century, people began to manipulate genes directly using the tools of molecular biotechnology, even cloning sheep and cows from adult body cells. us farmers routinely plant their fields with corn whose genetic material incorporates a bacterial gene resistant to certain pathogens. more than genetically altered crops have been approved for sale to us farmers since , with genes borrowed from bacteria, viruses, and insects. the united states accounts for nearly two-thirds of biotechnology crops planted globally. worldwide in , . million hectares in countries on six continents were planted with genetically modified crops, as compared with . million hectares in six countries in -a -fold expansion in years. biotechnologists focus on the potential of this newmillennium green revolution to feed the growing world population, which has added almost billion people in the past decade alone. but other scientists worry about unknown human and ecological health risks; these concerns have stirred deep scientific and public debate, especially in europe, akin to the debate over pesticides in rachel carson's time. one worrisome practice is plant genetic engineers' technique of attaching the genes they want to introduce into plants to an antibiotic-resistant gene. they can then easily select plants that have acquired the desired genes by treating them with the antibiotic, which kills any nonresistant plants. critics worry that the antibiotic-resistant genes could spread to human pathogens and worsen an already growing antibioticresistance problem. another concern arises from allergies humans might have or develop in response to genetically modified foods. although supporters of genetic engineering believe that genetically altered crops pose few ecological risks, ecologists have raised a variety of concerns. studies in the late s indicated that pollen from genetically engineered bt corn can kill monarch butterfly caterpillars. bt is a strain of bacterium that has been used since the s as a pesticidal spray; its genes have also been inserted directly into corn and other crops. ecologists have long worried that genetically engineered plants could escape from fields and cross-breed with wild relatives. studies in radishes, sorghum, canola, and sunflowers found that genes from an engineered plant could jump to wild relatives through interbreeding. the fear is that a gene conferring insect or herbicide resistance might spread through wild plants, creating invasive superweeds that could potentially lower crop yields and further disturb natural ecosystems. in fact, herbicide-resistant turf grass tested in oregon in did escape and spread, and transgenic canola has been appearing throughout the us state of north dakota, which has tens of thousands of hectares in conventional and genetically modified canola. according to the scientists who discovered the transgenic escapees growing in north dakota -far from any canola field -the plants are likely to be cross-pollinating in the wild and swapping introduced genes; the plants' novel gene combinations indicate that the transgenic traits are stable and evolving outside of cultivation. genetically engineered crops do confer some economic and environmental benefits: for farmers, higher yields, lower costs, savings in management time and gains in flexibility; for the environment, indirect benefits from using fewer pesticides and herbicides. but it is still an open question whether such benefits outweigh the potential ecological risks or whether the public will embrace having genetically modified foods as staples in their diet. human biotic impacts are not confined to other species; human cultures themselves have suffered from the widening circles of indirect and direct effects humans have imposed on the rest of nature. over the past hundred years, human technology has cut both ways with regard to public health. wonder drugs controlled common pathogens at the same time that natural selection strengthened those pathogens' ability to resist the drugs. reservoirs in the tropics made water supplies more reliable for humans but also created ideal environments for human parasites. industrialization exposed human society to a remarkable array of toxic substances. although man's inhumanity to man has been both fact and the subject of discourse for thousands of years, the discussions have mostly been removed from any environmental context. few people today regard social ills as environmental impacts or humans as part of a biota. but diminished societal well-being -whether manifest in high death rates or poor quality of life -shares many of its roots with diminished nonhuman life as a form of biotic impoverishment. the intersection of the environment and human health is the core of the discipline known as environmental health. among the environmental challenges to public health are the direct effects of toxic chemicals; occupational health threats, including exposures to hazardous materials on the job; and sanitation and disposal of hazardous wastes. exploitation of nonrenewable natural resources -including coal mining, rock quarrying or other mining operations, and petroleum extraction and refining -often chronically impairs workers' health and shortens their lives. farmworkers around the world suffer long-term ills from high exposures to pesticides and herbicides. partly because of increased air pollution, asthma rates are rising, particularly in big cities. synthetic volatile solvents are used in products from shoes to semiconductors, producing lung diseases and toxic wastes. nuclear weapons production starting in world war ii, and associated contamination, have been linked to a variety of illnesses, including syndromes neither recognized nor understood at the time and whose causes were not diagnosed until decades afterward. the grayish metal beryllium, for example, was used in weapons production and was found decades later to scar the lungs of workers and people living near toxic waste sites. infectious diseases have challenged human populations throughout history, playing a significant role in their evolution and cultural development over the past , years, with % of human diseases linked to wildlife or domestic animals. the th century brought major successes in eradicating such infectious diseases as smallpox, polio, and many waterborne illnesses. but toward the century's end, emerging and reemerging diseases were again reaching pandemic proportions. infectious diseases thought to be on the wane -including tuberculosis, malaria, cholera, diptheria, leptospirosis, encephalitis, and dengue fever -have begun a resurgence. in addition, seemingly new scourges -ebola virus, hantavirus, hiv/aids, lyme disease, and west nile fever -are also spreading, often, it appears, from wild animal hosts to humans as people encroach further upon previously undisturbed regions. a number of studies over the decade before show complex connections between biodiversity and disease: biodiversity loss often increases disease transmission, as in lyme disease and west nile fever, but diverse ecosystems also serve as sources of pathogens. overall, however, the studies indicate that preserving intact ecosystems and their endemic biodiversity often reduces the prevalence of infectious diseases. human migrations -including their modern incarnation through air travel -also accelerate pathogen traffic and launch global pandemics, such as the outbreak of severe acute respiratory syndrome and the swine flu outbreak caused by the h n virus. even something as simple and apparently benign as lighting can become an indirect agent of disease. artificial lighting, especially in the tropics, for example, can alter human and insect behavior in ways that speed transmission of insect-borne diseases, such as chagas's disease, malaria, and leishmaniasis. in addition, especially in highly developed countries such as the united states, diseases of affluence and overconsumption are taking a toll. heart disease is the number one cause of death in the united states; overnutrition, obesity, and diabetes due to sedentary, technology-driven lifestyles, particularly among children, are chronic and rising. one estimate put the share of us children considered overweight or obese at one in three. this rise in obesity rates has been stunningly rapid. as recently as , just % of adults were obese; by the rate had hit %, and two-thirds of americans are now considered either overweight or obese. although not conventionally regarded as elements of biodiversity, human languages, customs, agricultural systems, technologies, and political systems have evolved out of specific regional environments. like other organisms' adaptive traits and behaviors, these elements of human culture constitute unique natural histories adapted, like any natural history, to the biogeographical context in which they arose. yet modern technology, transportation, and trade have pushed the world into a globalized culture, thereby reducing human biological and cultural diversity. linguists, for example, are predicting that at least half of the languages spoken today will become extinct in the st century. with the spread of euro-american culture, unique indigenous human cultures, with their knowledge of local medicines and geographically specialized economies, are disappearing even more rapidly than the natural systems that nurtured them. this loss of human biodiversity is in every way as troubling as the loss of nonhuman biodiversity. the effects of environmental degradation on human quality of life are another symptom of biotic impoverishment. food availability, which depends on environmental conditions, is a basic determinant of quality of life. yet according to the world health organization, nearly half the world's population suffers from one of two forms of poor nutrition: undernutrition or overnutrition. a big belly is now a symptom shared by malnourished children, who lack calories and protein, and overweight residents of the developed world, who suffer clogged arteries and heart disease from eating too much. independent of race or economic class, declining quality of life in today's world is manifest in symptoms such as increased asthma in the united states caused by environmental contaminants and the high disease rates in the former soviet bloc after decades of unregulated pollution. even with explicit legal requirements that industries release information on their toxic emissions, many people throughout the world still lack both information and the decision-making power that would give them any control over the quality of their lives. aggrieved about the degraded environment and resulting quality of life in his homeland, ogoni activist ken saro-wiwa issued a statement shortly before he was executed by the nigerian government in saying, ''the environment is man's first right. without a safe environment, man cannot exist to claim other rights, be they political, social, or economic.'' kenyan maathai ( , p. ) , winner of the nobel peace prize, has also written, ''[i]f we destroy it, we will undermine our own ways of life and ultimately kill ourselves. this is why the environment needs to be at the center of domestic and international policy and practice. if it is not, we don't stand a chance of alleviating poverty in any significant way.'' having ignored this kind of advice for decades, nations are seeing a new kind of refugee attempting to escape environmental degradation and desperate living conditions; the number of international environmental refugees exceeded the number of political refugees around the world for the first time in . environmental refugees flee homelands devastated by flooding from dam building, extraction of mineral resources, desertification, and unjust policies of national and international institutions. such degradation preempts many fundamental human rights, including the rights to health, livelihood, culture, privacy, and property. people have long recognized that human activities that degrade environmental conditions threaten not only the biosphere but also humans' own quality of life. as early as years ago in mesopotamia and south asia, writings revealed an awareness of biodiversity, of natural order among living things, and of consequences of disrupting the biosphere. throughout history, even as civilization grew increasingly divorced from its natural underpinnings, writers, thinkers, activists, and people from all walks of life have continued to see and extol the benefits of nature to humans' quality of life. contemporary society still has the chance to relearn how important the environment is to quality of life. it is encouraging that the united steelworkers of america in released a report recognizing that protecting steelworker jobs could not be done by ignoring environmental problems and that the destruction of the environment may pose the greatest threat to their children's future. it is also encouraging that the nobel peace prize was awarded to a political figure and a group of scientists for their work on climate change. making a living from nature's wealth has consistently opened gaps between haves and have-nots, between those who bear the brunt of environmental damage to their home places and those who do not, and between the rights of people alive now and those of future generations; these disparities too are part of biotic impoverishment. inequitable access to ''man's first right'' -a healthy local environment -has come to be known as environmental injustice. environmental injustices, such as institutional racism, occur in industrial and nonindustrial nations. injustice can be overt, as when land-use planning sites landfills, incinerators, and hazardous waste facilities in minority communities, or when environmental agencies levy fines for hazardous waste violations that are lower in minority communities than in white communities. less overt, but no less unjust, is the harm done to one community when unsound environmental practices benefit another, as when clear-cut logging in the highlands of northwestern north america benefits logging communities while damaging the livelihoods of lowland fishing communities subjected to debris flows, sedimentation, and downstream flooding. the plight of the working poor and the disparities between rich and poor are also examples of biotic impoverishment within the human community. according to the united nations research institute for social development, the collective wealth of the world's billionaires equaled the combined income of the poorest . billion people in . forbes magazine put the number of billionaires in early at , with a total worth of $ . trillion. in the united states during the last decade of the th century, the incomes of poor and middle-class families stagnated or fell, despite a booming stock market. the center on budget and policy priorities and the economic policy institute reported that between and , earnings of the poorest fifth of american families rose less than %, while earnings of the richest fifth jumped %. by the middle of the first decade of the st century, americans' income inequality had become the widest among industrialized nations, with the wealthiest % of the population holding % of the wealth. the wealthiest americans continued to prosper even during the global recession late in that decade, while the less well-off kept losing ground. but perhaps the grossest example of human and environmental domination leading to continued injustice is the creation of a so-called third world to supply raw materials and labor to the dominant european civilization after and the resulting schism between today's developed and developing nations. developing regions throughout the world held tremendous stores of natural wealth, some of it -like petroleum -having obvious monetary value in the dominant economies and some having a value invisible to those economies -like vast intact ecosystems. a united nations study (teeb) estimated that even today, earth's ecosystems account for roughly half to % of the source of livelihoods for rural and forest-dwelling peoples; the study calls this value the gross domestic product (gdp) of the poor. dominant european civilizations unabashedly exploited this natural wealth and colonized or enslaved the people in whose homelands the wealth was found. but the dominant civilizations also exported their ways of thinking and their economic models to the developing world, not only colonizing places but also effecting what wangari maathai has called a colonization of the mind. although dominant st century society tends to dismiss ancient wisdom as irrelevant in the modern world, perhaps the cruelest impoverishment of all is the cultural and spiritual deracination experienced by exploited peoples worldwide. exploitation of poor nations and their citizens by richer, consumer countries -and in many cases by the same governments that fought for independence from the colonists while adopting the colonists' attitudes and economic models -persists today in agriculture, wild materials harvesting, and textile and other manufacturing sweatshops. in the mid- s, industrial countries consumed % of the globe's aluminum, % of its paper, % of its iron and steel, % of its energy, and % of its meat; they are thus responsible for most of the environmental degradation associated with producing these goods. most of the actual degradation, however, still takes place in developing nations. as a result, continuing environmental and social injusticeenvironmental and social impoverishment perpetrated by outsiders and insiders alike -pervades developing nations. such impoverishment can take the form of wrenching physical dislocation like the massive displacements enforced by china's three gorges dam. it can appear as environmental devastation of homelands and murder of the people who fought to keep their lands, as in the nigerian government-backed exploitation of ogoniland's oil reserves by the shell petroleum development corporation. after saro-wiwa's execution, the ogoni were left, without a voice, to deal with a scarred and oilpolluted landscape. despite great advances in the welfare of women and children over the past century, poverty still plagues both groups. children from impoverished communities, even in affluent nations, suffer from the lethargy and impaired physical and intellectual development known as failure to thrive. poverty forces many children to work the land or in industrial sweatshops; lack of education prevents them from attaining their intellectual potential. this impoverishment in the lives of women and children is as much a symptom of biotic impoverishment as are deforestation, invasive alien organisms, or species extinctions. little by little, community-based conservation and development initiatives are being mounted by local citizens to combat this impoverishment: witness maathai's green belt movement, which began with tree planting to restore community landscapes and provide livelihoods for residents, and the rise of ecotourism and microlending (small loans made to individuals, especially women, to start independent businesses) as ways to bring monetary benefits directly to local people without further damaging their environments. ultimately, one could see all efforts to protect the ethnosphere and the biosphere as a fight for the rights of future generations to an environment that can support them. only during the last two decades of the th century did environmental issues find a place on international diplomatic agendas, as scholars began calling attention to -and governments began to see -irreversible connections between environmental degradation and national security. british scholar myers ( ) , noting that environmental problems were likely to become predominant causes of conflict in the decades ahead, was one of the first to define a new concept of environmental security. national security threatened by unprecedented environmental changes irrespective of political boundaries will require unprecedented responses altogether different from military actions, he warned. nations cannot deploy their armies to hold back advancing deserts, rising seas, or the greenhouse effect. canadian scholar homer-dixon ( ) showed that environmental scarcities -whether created by ecological constraints or sociopolitical factors including growing populations, depletion of renewable resources such as fish or timber, and environmental injustice perpetrated by one segment of a population on another -were fast becoming a permanent, independent cause of civil strife and ethnic violence. he found that such scarcity was helping to drive societies into a self-reinforcing spiral of dysfunction and violence, including terrorism. environmental and economic injustices worldwide leave no country immune to this type of threat. typically, diplomacy has stalled in conflicts over natural resources: arguments over water rights have more than once held up israeli-palestinian peace agreements; fights over fish erupted between canada and the united states, spain, and portugal. in contrast, in adopting the montreal protocol on substances that deplete the ozone layer in , governments, nongovernmental organizations, and industry successfully worked together to safeguard part of the environmental commons. the treaty requires signatory nations to curb their use of cfcs and other ozone-destroying chemicals and has been, according to former united nations secretary general kofi annan, perhaps the most successful international agreement to date. if scientists have learned anything about the factors leading to biotic impoverishment, they have learned that the factors' cumulative effects can take on surprising dimensions. as scholars like fagan ( ) and diamond ( ) have chronicled, the multiple stresses of global climatic cycles such as el niñ o, natural events like droughts or floods, resource depletion, and social upheaval have shaped the fates of civilizations. societies as far-flung as ancient egypt, peru, the american southwest, and easter island prospered and collapsed because of unwise management of their environments. the city of ubar, built on desert sands in what is now southern oman, literally disappeared into the sinkhole created by drawing too much water out of its great well. in modern sahelian africa, a combination of well digging and improved medical care and sanitation led to a threefold population increase; sedentary ways, heavy taxes imposed by a colonial government, and an impoverished people took the place of a nomadic culture evolved within the desert's realities. during the first decade of the st century, numerous natural disasters befell nations around the world: wildfires in australia, bolivia, canada, and russia; flooding in china, india, romania, and west africa; devastating hurricanes and typhoons in the caribbean, philippines, taiwan, and southeastern united states; catastrophic landslides and floods in china, guatemala, pakistan, and portugal; and destructive earthquakes in chile, china, haiti, indonesia, and pakistan. neither the rains nor the earthquakes were caused by human activity, but the cumulative effects of human land uses and management practices -from dikes separating the mississippi from its floodplain to deforestation in haiti -made the losses of human life and property much worse than they might have been otherwise. the ultimate cause of humans' massive environmental impact is our individual and collective consumptive and reproductive behavior, which has given us spectacular success as a species. but the very things that enabled humans to thrive in nearly every environment have magnified our impacts on those environments, and the technological and political steps we take to mitigate our impacts often aggravate them. too many of us simply take too much from the natural world and ask it to absorb too much waste. for most of human history, people remained tied to their natural surroundings. even as agriculture, writing, and technology advanced, barriers of geography, language, and culture kept humans a diverse lot, each group depending on mostly local and regional knowledge about where and when to find resources necessary for survival. their worldviews, and resulting economies, reflected this dependency. for example, in northwestern north america starting about years ago, a native economy centered on the abundance of salmon. at its core was the concept of the gift and a belief system that treated all parts of the earth -animate and inanimate -as equal members of a community. in this and other ancient gift economies, a gift was not a possession that could be owned; rather, it had to be passed on, creating a cycle of obligatory returns. individuals or tribes gained prestige through the size of their gifts, not the amount of wealth they accumulated. this system coevolved with the migratory habits of the salmon, which moved en masse upriver to spawn each year. because the indians viewed salmon as equals to themselves, killing salmon represented a gift of food from salmon to people. fishers were obligated to treat salmon with respect or risk losing this vital gift. the exchange of gifts between salmon and humans -food for respectful treatment -minimized waste and overharvest and ensured a continuous supply of food. further, the perennial trading of gifts among the people effectively redistributed the natural wealth brought each year by fluctuating populations of migrating fish, leveling out the boom-and-bust cycles that usually accompany reliance on an uncertain resource. in modern times, the gift economy along with the egalitarian worldview that accompanied it, has been eclipsed by a redistributive economy tied not to an exchange of gifts with nature but to the exploitation of nature and to the technologies that enhance that exploitation. nature became a resource for humans, rather than an equal to humans. in economic terms, natural resources fell under the heading of 'land' in an economic trinity comprising three factors of production: land, labor, and capital. land and resources, including crops, became commodities -expendable or easily substitutable forms of capital -whose value was determined solely by their value in the human marketplace. in adam smith published his famous inquiry into the nature and causes of the wealth of nations, in which he argued that society is merely the sum of its individuals, that the social good is the sum of individual wants, and that the market (the so-called invisible hand) automatically guides individual behavior to the common good. crucial to his theories were division of labor and the idea that all the factors of production were freely mobile. his mechanistic views created an economic rationale for no longer regarding individuals as members of a community linked by ethical, social, and ecological bonds. about the same time, fueling and fueled by the beginnings of the industrial revolution, the study of the natural world was morphing into modern physics, chemistry, geology, and biology. before the mid- century, those who studied the natural world -early century german biogeographer baron alexander von humboldt and his disciple charles darwin among them -took an integrated view of science and nature, including humans. both scientists regarded the understanding of the complex interdependencies among living things as the noblest and most important result of scientific inquiry. but this integrated natural philosophy was soon supplanted by more atomistic views, which fit better with industrialization. mass production of new machines relied on division of labor and interchangeable parts. like automobiles on an assembly line, natural phenomena too were broken down into their supposed component parts in a reductionism that has dominated science ever since. rushing to gain indepth, specialized knowledge, science and society lost sight of the need to tie the knowledge together. disciplinary specialization replaced integrative scholarship. neoclassical economics, which arose around , ushered in the economic worldview that rules today. a good's value was no longer tied to the labor required to make it but derived instead from its scarcity. a good's price was determined only by the interaction of supply and demand. as part of 'land,' natural resources therefore became part of the human economy, rather than the material foundation making the human economy possible. because of its doctrine of infinite substitutability, neoclassical economics rejects any limits on growth; forgotten are the classical economic thinkers and contemporaries of von humboldt, including thomas malthus and john stuart mill, who saw limits to the growth of human population and material well-being. consequently, the th and th centuries saw the rise to dominance of economic indicators that fostered the economic invisibility of nature, misleading society about the relevance of earth's living systems to human well-being. among the worst offenders in this regard are gross national product (gnp) and its cousin, gdp. gnp measures the value of goods and services produced by a nation's citizens or companies, regardless of their location around the globe. gdp, in contrast, measures the value of goods and services produced within a country's borders, regardless of who generates those goods and services. in effect, both gnp and gdp measure money changing hands, no matter what the money pays for; they make no distinction between what is desirable and undesirable, between costs and benefits. both indicators ignore important aspects of the economy like unpaid work or nonmonetary contributions to human fulfillment -parenting, volunteering, checking books out of the library. worse, the indicators also omit social and environmental costs, such as pollution, illness, or resource depletion; they only add and do not subtract. gdp math adds in the value of paid daycare or a stay in the hospital and ignores the value of unpaid parenting or being cared for at home by friends. it adds in the value of timber sold, but fails to subtract the losses in biodiversity, watershed protection, or climate regulation that come when a forest is cut. efforts have been made in the past few decades to create less blinkered economic indicators. social scientists herman daly and john cobb in developed an index of sustainable economic welfare, which adjusts the united states' gnp by adding in environmental good things and subtracting environmental bad things. public expenditures on education, for example, are weighted as ''goods'' while costs of pollution cleanup, depletion of natural resources, and treating environment-related illnesses are counted as 'bads.' unlike the soaring gdp of recent decades, this index of sustainable economic welfare remained nearly unchanged over the same period. still other work aims to reveal nature's worth in monetary terms by assigning dollar values to ecological goods and services. a study by ecologist david pimentel and colleagues calculated separate values for specific biological services, such as soil formation, crop breeding, or pollination; by summing these figures, these researchers estimated the total economic benefits of biodiversity for the united states at $ billion - % of us gdp at the time -and for the world at $ billion. a analysis by pimentel and colleagues reported that the approximately , nonnative species in the united states cause major environmental damage and reparation costs amounting to $ billion a year. as part of the united nations international year of biodiversity in , several studies have translated the value of the world's ecosystems into dollar values. one report estimated the worth of crucial ecosystem services delivered to humans by living systems at $ - trillion per year -comparable to a world gross national income of $ trillion in . another study reported, among other things, that as many as million people worldwide depend on coral reefs -valued between $ billion and $ billion a year -for fisheries, tourism, and protection from ocean storms and high waves, services threatened by warmer and more acidic seas. although a monetary approach does not create a comprehensive indicator of environmental condition, it certainly points out that ecological values ignored by the global economy are enormous. the us census bureau predicts that by , the global human population will top billion -having grown by nearly billion people during the decade between the first and second editions of this encyclopedia. from the appearance of h. sapiens about , years ago, it took humans until to reach their first billion, years to double to billion, and years to achieve billion. human population doubled again from to billion in about years -before most post-world war ii baby boomers reached retirement age. even with fertility rates declining in developed countries, china, and some developing countries where women are gaining education and economic power, and with pandemics like aids claiming more lives, the census bureau predicts that world population will reach billion by . humans appropriate about % of global plant production, % of earth's freshwater runoff, and enough of the ocean's bounty to have depleted % of assessed marine fish stocks. in energy terms, one person's food consumption amounts to - calories a day, about the same as that of a common dolphin. but with all the other energy and materials humans use, global per capita energy and material consumption have soared even faster than population growth over the past years. now, instead of coevolving with a natural economy, global society is consuming the foundations of that economy, impoverishing earth's living systems, and undermining the foundations of its own existence (figure ). for most of the th century, environmental measurements, or indicators, tracked primarily two classes of information: counts of activities directed at environmental protection and the supply of products to people. regulatory agencies are typically preoccupied with legislation, permitting, or enforcement, such as the numbers of environmental laws passed, permits issued, enforcement actions taken, or treatment plants constructed. resource protection agencies concentrate on resource harvest and allocation. water managers, for example, measure water quantity; they allocate water to domestic, industrial, and agricultural uses but seldom make it a priority to reserve supplies for sustaining aquatic life, to protect scenic and recreational values, or simply to maintain the water cycle. foresters, farmers, and fishers count board-feet of timber, bushels of grain, and tons of fish harvested. governmental and nongovernmental organizations charged with protecting biological resources also keep counts of threatened and endangered species. as in the parable of the three blind men and the elephanteach of whom thinks the elephant looks like the one body part he can touch -these or similar indicators measure only one aspect of environmental quality. counting bureaucratic achievements focuses on actions rather than on information about real ecological status and trends. measurements of resource supply keep track of commodity production, not necessarily a system's capacity to continue supplying that commodity. and measuring only what we remove from natural systems, as if we were taking out the interest on a savings account, overlooks the fact that we are usually depleting principal as well. even biologists' counts of threatened and endangered species -which would seem to measure biotic impoverishment directly -still focus narrowly on biological parts, not ecological wholes. enumerating threatened and endangered species is just like counting any other commodity. it brings our attention to a system already in trouble, perhaps too late. and it subtly reinforces our view that we know which parts of the biota are most important. society needs to rethink its use of available environmental indicators, and it needs to develop new indicators that represent current conditions and trends in the systems humans depend on ( table ) . it particularly needs objective measures more directly tied to the condition, or health, of the environment so that people can judge whether their actions are compromising that condition. such measures should be quantitative, yet easy to understand and communicate; they should be cost-effective and applicable in many circumstances. unlike narrow criteria tracking only administrative, commodity, or endangered species numbers, they should provide reliable signals about status and trends in ecological systems. ideally, effective indicators should describe the present condition of a place, aid in diagnosing the underlying causes of that condition, and make predictions about future trends. they should reveal not only risks from present activities but also potential benefits from alternative management decisions. most important, these indicators should, either singly or in combination, give information explicitly about living systems. measurements of physical or chemical factors can sometimes act as surrogates for direct biological measurements, but only when the connection between those measures and living systems is clearly understood. too often we make assumptionswhen water managers assume that chemically clean water equals a healthy aquatic biota, for example -that turn out to be wrong and fail to protect living systems. as environmental concerns have become more urgent -and governmental and nongovernmental organizations have struggled to define and implement the concept of sustainable development -the effort has grown to create indicator systems that explicitly direct the public's and policymakers' attention to the value of living things. moving well past solely economic indexes like gdp, several indexes now integrate ecological, social, and economic well-being. the index of environmental trends for nine industrialized countries, developed by the nonprofit national center for economic and security alternatives, incorporates ratings of air, land, and water quality; chemical and waste generation; and social system economic system natural system figure relationships among the natural, social, and economic systems on earth. human economies may be thought of as icing atop a two-layer cake. the economic icing is eroding the human social and natural layers beneath it, threatening the foundation and sustainability of all three systems. modified from karr jr and chu ew ( ) ecological integrity: reclaiming lost connections. in: westra l and lemons j (eds.) perspectives in ecological integrity, pp - . dordrecht, netherlands: kluwer academic. energy use since . by its rankings, environmental quality in the united states had gone down by % since , while denmark had declined by %. in , world leaders, supported by the united nations development programme, defined a set of eight millennium development goals to be attained by , which combine poverty, education, employment, and environmental sustainability. they include human rights and health goals -such as universal primary education, gender equality, and combating aids and other diseases -as well as ensuring environmental sustainability. in the decade since the program began, progress has been made in reducing poverty; expanding educational opportunities for children, especially in africa; slowing deforestation; and providing better water for many people, among others. but progress controlling climate change, halting biodiversity loss, and achieving gender equality has lagged. a later environmental performance index spearheaded by yale and columbia universities ranks countries on performance indicators in well-established policy categories to determine whether and how well countries are meeting established environmental goals. this index incorporates measurements addressing environmental stresses to human health plus ecosystem health and natural resource management, collectively referred to as ecosystem vitality. the categories representing environmental health include the environmental burden of disease and the effects of air and water quality on human health. those representing ecosystem vitality include air and water resources for ecosystems; biodiversity and habitat; and climate change, among others. although hampered by data gaps and the inability to track changes in countries' performance through time, the index provides a sense of countries' relative performance with regard to the environmental challenges faced by all. top performers in the rankings included iceland, switzerland, costa rica, and sweden. the united states ranked st well below japan and nations in the european union. a resource-accounting approach pioneered in the s by geographers rees and wackernagel ( ) translates humans' impact on nature, particularly resource consumption, into a metaphorical ecological footprint. this accounting estimates the area required by a city, town, nation, or other human community to produce consumed resources and absorb generated wastes; it then compares the physical area occupied by a city or country with the area required to supply that city or country's needs. the largest cities of baltic europe, for example, appropriate areas of forest, agricultural, marine, and wetland ecosystems that are at least - times larger than the areas of the cities themselves. according to the global footprint network, national ecological footprints in ranged from a high of . hectares per person for the united arab emirates to . hectares per person for timor-leste and . for afghanistan and bangladesh. the united states' ecological footprint - . hectares per person -tied for fourth among nations with populations of at least million. one-hundred and four of these nations operate under ecological deficits; that is, their . cumulative effects (frequency of catastrophic natural disasters; costs of weather-related property damage; human death tolls; government subsidies of environmentally destructive activities such as fishery overcapitalization, below-cost timber sales, water projects, and agricultural supports; replacement costs for ecological services; pricing that reflects environmental costs; ''green'' taxes; rise in polycultural agricultural practices; number of organic farms) a these indicators have been or could be used to monitor status and trends in environmental quality, including dimensions of biotic impoverishment. without a full spectrum of indicators, however, and without coupling them to direct measures of biological condition, only a partial view of the degree of biotic impoverishment will emerge. consumption exceeds the biological capacity of their lands and waters to provide needed resources and absorb their wastes. at their present rates of consumption, these nations are therefore overexploiting either their own resources or those of other nations. by ecological footprint accounting, raising the nearly billion people on earth in the early st century to living standards -and thus ecological footprints -equal to those in the united states would require four planets more than the only one we have. clearly, humans are consuming more resources, and discarding more waste, than earth's living systems can produce or absorb in a given time period. this gap is the global sustainability gap the world now faces. most environmental indexes and accounting systems are still human centered; they still do not measure the condition of the biosphere itself. we may know that biodiversity's services are worth huge sums of money and that our hometown's ecological footprint is much bigger than the town's physical footprint, but how do we know whether specific actions damage living systems or that other actions benefit them? how do we know if aggregate human activity is diminishing life on earth? to answer this question, we need measures that directly assess the condition of living systems. biological assessment directly measures the attributes of living systems to determine the condition of a specific landscape. the very presence of thriving living systems -sea otters and kelp forests off the central california coast; salmon, orcas, and herring in pacific northwest waters; monk seals in the mediterranean sea -says that the conditions those organisms need to survive are also present. a biota is thus the most direct and integrative indicator of local, regional, or global biological condition. biological assessments give us a way to evaluate whether monetary valuations, sustainability indexes, and ecological footprints are telling the truth about human impact on the biosphere. biological assessments permit a new level of integration because living systems, including human cultures, register the accumulated effects of all forms of degradation caused by human actions. direct, comprehensive biological monitoring and assessment has been done for many aquatic systems; measures are less developed for terrestrial systems. the index of biological integrity (ibi), for example, was developed in to assess the health of streams in the us midwest and has since helped scientists, resource managers, and citizen volunteers understand, protect, and restore rivers in at least countries worldwide (karr ) . borrowing from the same page as more recent sustainability indexes, ibi takes the concept behind economic indexes like gdp or the consumer price index -that of multiple indicators integrated into a multimetric index -and applies it to animals and plants in bodies of water or other environments. the specific measurements ( table ) are sensitive to a broad range of human effects in waterways, such as sedimentation, nutrient enrichment, toxic chemicals, physical habitat destruction, and altered flows. the resulting index combines the responses of biological parts such as species, as well as processes such as food web dynamics, to human actions. indexes of biological integrity have been developed for a number of aquatic and terrestrial environments; the most widely used indexes for assessing rivers examine fishes and benthic (bottom-dwelling) invertebrates. these groups are abundant and easily sampled, and the species living in virtually any water body represent a diversity of anatomical, ecological, and behavioral adaptations. as humans alter watersheds and water bodies, changes occur in taxonomic richness (biodiversity), species composition (which species are present), individual health, and feeding and reproductive relationships. sampling the inhabitants of a stream can tell us much about that stream and its landscape. biological diversity is higher upstream of wastewater treatment plants than downstream, for example, whereas, at the same location, year-toyear variation is low (figure ) . biological sampling can also reveal differences between urban and rural streams. for instance, samples of invertebrates from one of the best streams in rural king county, in the us state of washington, contain kinds, or taxa, of invertebrates; similar samples from an urban stream in the city of seattle contain only . the rural stream has taxa of mayflies, stoneflies, and caddisflies; the urban stream, only or . when these and other metrics are combined in an index based on invertebrates, the resulting benthic ibi (b-ibi) ranks the condition, or health, of a stream numerically ( table ) . a benthic ibi can also be used to compare sites in different regions. areas in wyoming's grand teton national park where human visitors are rare have near-maximum b-ibis. streams with moderate recreation taking place in their watersheds have b-ibis that are not significantly lower than those with no human presence, but places where recreation is heavy are clearly damaged. urban streams in the nearby town of jackson are even more degraded, yet not as bad as urban streams in seattle. nation-specific biological assessments also can be and are being done. the us environmental protection agency ( ), for example, performed a nationwide survey of stream condition using an ibi-like multimetric index. the survey found that % of us stream miles were in good condition in table biological attributes in two indexes of biological integrity comparison with least-disturbed reference sites in their regions, % were in fair condition, and % were in poor condition ( % were not assessed). the agency has been expanding this effort to include other water resource types, including coastal waters, coral reefs, lakes, large rivers, and wetlands. since , the heinz center ( ) has published two editions of its report on the state of us ecosystems, which seek to capture a view of the large-scale patterns, conditions, and trends across the united states. the center defined and compiled a select set of indicators -specific variables tracking ecosystem extent and pattern, chemical and physical characteristics, biological components, and goods and services derived from the natural world -for six key ecosystems: coasts and oceans, farmlands, forests, fresh waters, grasslands and shrublands, and urban and suburban landscapes. among the many conclusions of the report were that the acreage burned every year by wildfires was on the increase; nonnative fish had invaded nearly every watershed in the lower states; and chemical contaminants were found in virtually all streams and most groundwater wells, often at levels above those set to protect human health or wildlife. on the plus side, ecosystems were increasing their storage of carbon, soil quality was improving, and crop yields had grown significantly. the massive international un millennium ecosystem assessment ( ) remains the gold standard for synthesizing ecological conditions at a variety of scales. from through , the project examined the full range of global ecosystems -from those relatively undisturbed, such as natural forests, to landscapes with mixed patterns of human use to ecosystems intensively managed and modified by humans, such as agricultural land and urban areas -and communicated its findings in terms of the consequences of ecosystem change for human well-being. the resulting set of reports drew attention to the many kinds of services people derive from ecosystems, specifically, supporting services, such as photosynthesis, soil formation, and waste absorption; regulating services, such as climate and flood control and maintenance of water quality; provisioning services, such as food, wood, and nature's pharmacopoeia; creek near portland, oregon (united states), taxa richness differed little between years but differed dramatically between sites upstream of a wastewater outfall and sites downstream. (b) taxa richness also differed between two creeks with wastewater outfalls (tickle and north fork deep) and one creek without an outfall (foster). all three streams flowed through watersheds with similar land uses. fig. for graphs of selected b-ibi metrics at these sites. and cultural services from scientific to spiritual. in addition, the reports explicitly tied the status of diverse ecosystems and their capacity to provide these services to human needs as varied as food and health, personal safety and security, and social cohesion. even while recognizing that the human species is buffered against ecological changes by culture and technology, the reports highlighted our fundamental dependence on the flow of ecosystem services and our direct responsibility for the many faces of biotic impoverishment. among other findings, the assessment found that % of the services provided by ecosystems are being degraded at levels that derail efforts to stem poverty, hunger, and disease among the poor everywhere. government subsidies that provide incentives to overharvest natural resources are a leading cause of the decline in renewable natural resources. such declines are not limited to coral reefs and tropical forests, which have been on the public's radar for some time; they are pervasive in grasslands, deserts, mountains, and other landscapes as well. moreover, the degradation of ecosystem services could grow worse during the first half of the st century, effectively blocking achievement of the united nations' eight millennium development goals. the core message embodied in ecological, especially biological, assessments is that preventing harmful environmental impacts goes beyond narrow protection of clean water or clear skies, even beyond protecting single desired species. certain species may be valuable for commerce or sport, but these species do not exist in isolation. we cannot predict which organisms are vital for the survival of commercial species or species we want for other reasons. failing to protect all organisms -from microbes and fungi to plants, invertebrates, and vertebrates -ignores the key contributions of these groups to healthy biotic communities. no matter how important a particular species is to humans, it cannot persist outside the biological context that sustains it. direct biological assessment objectively measures this context and is fundamental to advancing the kinds of syntheses like those of the millennium ecosystem assessment. every animal is alert to dangers in its environment. a microscopic protozoan gliding through water responds to light, temperature, and chemicals in its path, turning away at the first sign of something noxious. a bird looking for food must decide when to pursue prey and when not, because pursuit might expose the bird to predators. the bird might risk pursuit when it is hungry but not when it has young to protect. animals that assess risks properly and adjust their behavior are more likely to survive; in nature, flawed risk assessment often means death or the end of a genetic line. humans, too, are natural risk assessors. each person chooses whether to smoke or drink, fly or take the train, drive a car or ride a motorcycle and at what speeds. each decision is the result of a partially objective, partially subjective internal calculus that weighs benefits and risks against one another. risk is a combination of two factors: the numerical probability that an adverse event will occur and the consequences of the adverse event. people may not always have the right signals about these two factors, however, and may base their risk calculus on the wrong clues. city dwellers in the united states generally feel that it is safer to drive home on a saturday night than to fly in an airplane, for example. even though the numerical odds of an accident are much higher on the highway than in the air, people fear more the consequences of an airplane falling out of the sky. human society also strives to reduce its collective exposure to risks. governments seldom hesitate to use military power to defend their sovereignty or, albeit more reluctantly, their regulatory power to reduce workplace risks and risks associated with consumer products like automobiles. but people and their governments have been much less successful in defining and reducing a broad range of ecological risks, largely because they have denied that the threats are real. policies and plans generated by economists, technologists, engineers, and even ecologists typically assume that the lost and damaged components of living systems are unimportant or can be repaired or replaced. widespread ecological degradation has resulted directly from the failure of modern society to properly assess the ecological risks it faces. like the fate of old kingdom egypt or easter island, our civilization's future depends on our ability to recognize this deficiency and correct it. risk assessment as formally practiced by various government agencies began as a way to evaluate the effects of toxic substances on human health, usually the effects of single substances, such as pollutants or drugs, from single sources, such as a chemical plant. during the s, the focus widened to encompass mixtures of substances and also ecological risks. ecological risk assessment by the us environmental protection agency ( ) asks five questions: is there a problem? what is the nature of the problem? what are the exposure and ecological effects? (a hazard to which no one or nothing is exposed is not considered to pose any risk.) how can we summarize and explain the problem to affected parties, both at-risk populations and those whose activities would be curtailed? how can we manage the risks? even though these are good questions, ecological risk management has not made any visible headway in stemming biotic impoverishment. its central failing comes from an inability to correctly answer the second question, what is the nature of the problem? our present political, social, and economic systems simply do not give us the right clues about what is at risk. none of society's most familiar indicatorswhether gdp or number of threatened and endangered species -measure the consequences, or risks, of losing living systems. if biotic impoverishment is the problem, then it only makes sense to direct environmental policy toward protecting the integrity of biotic systems. integrity implies a wholeness or unimpaired condition. in present biological usage, integrity refers to the condition at sites with little or no influence from human activity; the organisms there are the products of natural evolutionary and biogeographic processes in the absence of humans. tying the concept of integrity to an evolutionary framework provides a benchmark against which to evaluate sites that humans have altered. directing policy toward protecting biological integrity -as called for in the united states' clean water act, canada's national park act, and the european union's water framework directive, among others -does not, however, mean that humans must cease all activity that interferes with a ''pristine'' earthly biota. the demands of feeding, clothing, and housing billions of people mean that few places on earth will maintain a biota with evolutionary and biogeographic integrity. rather, because humans depend on living systems, it is in our interest to manage our activities so they do not compromise a place's capacity to support those activities in the future; that capacity can be called ecological health. ecological health describes the preferred state of sites heavily used for human purposes: cities, croplands, tree farms, water bodies stocked for fish, and the like. at these places, it is impractical to set a goal of integrity in an evolutionary sense, but we should avoid practices that damage these places to the point where we can no longer derive the intended benefits indefinitely. for example, agricultural practices that leave behind saline soils, depress regional water tables, and erode fertile topsoil faster than it can be renewed destroy the land's biological capacity for agriculture; such practices are unhealthy in both ecological and economic terms. biological integrity as a policy goal redirects our focus away from maximizing goods and services for the human economy toward ways to manage human affairs within the bounds set by the natural economy. it begins to turn our attention away from questions such as, how much stress can landscapes and ecosystems absorb? to ones such as, how can responsible human actions protect and restore ecosystems? in contrast to risk assessment, striving to protect biological integrity is more likely to lead away from mandated corrective actions in the form of technological fixes for environmental problems and toward practices that prevent ecological degradation and encourage ecological restoration. leopold ( , pp. - ) , in a sand county almanac, was the first to invoke the concept of integrity in an ecological sense: ''a thing is right when it tends to preserve the integrity, stability, and beauty of the biotic community. it is wrong when it tends otherwise.'' managing for biological integrity requires the kind of ethical commitment inherent in leopold's words. we are called to curb consumerism and limit population size, to embrace less-selfish attitudes toward land stewardship, and to understand that the biosphere matters. instead of calling on human technical and spiritual wellsprings to manage resources, we have to call on them for managing human affairs. we have to find and use appropriate measurements for all the factors contributing to biotic impoverishment, be they climate change, overharvesting, agriculture, or environmental injustice. measurement of environmental impact founded on the evolutionary idea of integrity allow us to directly assess biotic condition and to compare that condition with what might be expected in a place with little or no human influence. at least then we can make an informed choice: continue with activities that degrade biotic condition or think of an alternative. the ecological world is a complex, variable, and often unpredictable system. when managing for ecological risks, people and their governments need to expect the unexpected and develop formal, yet flexible means of coping with environmental surprises. rather than plunge ahead with projects entailing ecological risks because they can be done, decision makers should follow the precautionary principle, which holds that regulators should act to prevent potential environmental harm even in the absence of certainty. it acknowledges the existence of uncertainty rather than deny it, and it includes mechanisms to safeguard against potentially harmful effects. although inappropriate ecological risk assessment and management are more often the norm today, modern institutions are capable of recognizing ecological threats correctly and responding to them in time, as they did with the montreal protocol. a decade after the agreement's adoption, satellite measurements in the stratosphere indicated that ozone-depleting pollutants were in fact on the decline. given the treaty's success, some policy experts have suggested using it to help curb global warming. specifically, negotiators at the annual meeting of signatory parties were considering a proposed expansion of the ozone treaty to phase out the production and use of industrial chemicals called hydrofluorocarbons, which have thousands of times the global warming potential of carbon dioxide. even though the montreal protocol was not designed to fight climate change, policymakers in favor of the new proposal say that it could and should be used to achieve broader environmental objectives. early in the th century, two sciences of ''home maintenance'' began to flourish: the young science of ecology (from the greek oikos, meaning home) and a maturing neoclassical economics (also from oikos). ecology arose to document and understand the interactions between organisms and their living and nonliving surroundings -in essence, how organisms make a living in the natural economy. in fact, ernst haeckel, who coined the term in the s, defined ecology in an article as the body of knowledge concerning the economy of nature. neoclassical economics, in contrast, reinforced humans' self-appointed dominion over nature's wealth. it brought unparalleled gains in societal welfare in some places, but it also divorced the human economy from the natural one on which it stands (see figure ) . by now it is clear to economists and ecologists alike that human actions and their effects have reached scales unprecedented in the history of life. we have altered earth's physical and chemical environment, changed the planet's water and nutrient cycles, and perturbed its climate. we have unleashed the greatest mass extinction in my and distorted the structure and function of nonhuman and human communities worldwide. in trying to make our own living, we have jeopardized the earth's capacity to sustain other species and our own species as well. we are losing the bio in biosphere. now, faced with these unprecedented losses, we need to understand -not deny -the ecological consequences of what we do. we urgently need a new science and art of home maintenance, one that sees the human species' role as ecosystem engineer for what it has become and reconnects human and natural economies. this new science can help us understand and correctly interpret the consequences of human-driven change. by using indicators that measure what matters for sustaining living systems, this new science can make nature visible again and shed new light on the value of the ancient heritage we share with the larger biosphere. it can help us reunite the fragments of our worldview and re-create ethical, social, and ecological bonds that were put aside two centuries ago in the name of progress. and such a science can enable us to reengineer our own social, political, and economic institutions instead of ecosystems. this we must donow -before we impoverish the biosphere and ourselves for all time. the wayfinders: why ancient wisdom matters in the modern world guns, germs, and steel: the fates of human societies evolution, consequences and future of plant and animal domestication collapse: how societies choose to fail or succeed floods, famines, and emperors: el niño and the fate of civilizations the state of the nation's ecosystems: measuring the lands, waters, and living resources of the united states environment, scarcity, and violence intergovernmental panel on climate change (ipcc) ( ) climate change seven foundations of biological monitoring and assessment a sand county almanac: and sketches here and there the challenge for africa. new york: pantheon books. millennium ecosystem assessment ( ) ecosystems and human well-being: synthesis ultimate security: the environmental basis of political stability song of the dodo: island biogeography in an age of extinction the economics of ecosystems and biodiversity: mainstreaming the economics of nature: a synthesis of the approach, conclusions and recommendations of teeb. united nations environment programme guidelines for ecological risk assessment wadeable streams assessment: a collaborative survey of the nation's streams, epa -b- - our ecological footprint: reducing human impact on the earth the little things that run the world the earth in transition: patterns and processes of biotic impoverishment a short history of progress key: cord- -gqem bxj authors: allam, zaheer title: oil, health equipment, and trade: revisiting political economy and international relations during the covid- pandemic date: - - journal: surveying the covid- pandemic and its implications doi: . /b - - - - . - sha: doc_id: cord_uid: gqem bxj the covid- pandemic saw disruptions at an unprecedented global scale with deep societal impacts in cities, countries, and regions. moreover, in a time of global urgent need for personal protective equipment, ventilators, and other health appliances and gear, both air and sea transport were halted, disconnecting manufacturing nations with consumer nations. with steep rise in demand, and impacted supply chains, nations, which were previously hailing collaborative calls to fight the pandemic, were seen to enter into a trade war of health equipment. with borders closed, nationalist policies were on the rise coupled with fears of tech-powered surveillance states. on the commodities market, the price of oil crashed leading to uncertainties as to the future for oil producing nations as the end point of the pandemic was still unclear. altogether, the pandemic put on test not only economic structures but also geopolitical ones, where it is seen as the biggest challenge since world war ii. this chapter surveys the impacts of the pandemic on the global political landscape and outlines concerns and questions for sustaining a peaceful shared future. the covid- pandemic took the world by surprise, as it started slowly in wuhan, china, with the first known cases being only , by the time it became identified. however, in a space of months, it had transformed from being just another type of coronavirus, to a "public emergency of global concern", to a global pandemic. in the course of writing this chapter, the coronavirus responsible for the covid- had spread from wuhan, the initial epicenter, to the whole of china, to its neighbors, and finally, to countries and territories (worldometer, ) . the number of confirmed cases also increased from the first known cases to over million confirmed cases and over , casualties (spotlight, ) . during the same period, the epicenter for this virus had moved from china, to europe and to the united states, and in each of those regions; large-scale devastation, deaths, and economic disruptions have been observed. however, on the impacts, no single country has been spared since even those with few confirmed cases have experienced one or more forms of disruptions, especially due to the widespread suspension of international and local transportation, thereby interrupting supply chains of different products and services, disruption of tourism industry, manufacturing sector, schooling systems, and others. those disruptions also affected small-scale businesses, which in most countries have been offering lifelines to the majority of the population. as the pandemic spread, the whole world was seen to be collaborating in fighting the virus. for instance, when the epicenter was in china, it received personal protective equipment (ppe) and medical supplies from the united states, its immediate trade and power competitor (u.s. embassy in georgia, ). also, when the situation started to worsen in the united states, russia, its longtime foe, sent a plane full of medical supplies to help them respond to the virus as reported by seligman ( ) . besides sharing of health equipment, there have been numerous monetary aid flows between nations, organisations, and even individual contributions targeting regions and countries that were vulnerable and those that were overwhelmed by the disease. for instance, cuba showed incredible generosity by sending medical personnel to different places such as italy, south africa, and other nations that are understaffed in their hospitals (petkova, ) . despite the widespread togetherness and empathy toward those that were highly hit, when the pandemic started to become serious in almost every part of the world -with the number of confirmed cases and deaths starting to grow exponentially, countries started to close their borders and institute stringent measures. others banned entry of foreigners, and permanent residents and citizens returning from countries affected by the virus were forced to quarantine for a minimum of days. other countries imposed nationwide lockdowns and curfews, only exempting essential service providers. in other instances, countries such as russia (afp, ), germany (hodgson, ) , india (suneja, ) , and also those in the european regions (euroean commission, ) imposed strict requirements and regulations that were to guide the exportation of ppes (glöckle, ) . such actions were taken in each individual country, and region, as it became apparent that the world was experiencing a shortage of the ppes and other medical supplies, despite the increasing number of people getting infected. the shortage of those ppes was confirmed by the world health organization which was calling on countries with manufacturing capabilities to assist those struggling with to acquire those, so as to reduce exposure of health workers and other frontline personnel fighting against covid- . in some cases, for instance, in bangladesh (mahmud, ) , italy (aljazeera, ) , and the united kingdom (express & star, ) , health workers had been reported to have paid the ultimate price of life after being infected while in hospital with lack of sufficient ppes, being taunted as one of the reasons for medical personnel infection. the shortages and strains globally were prompted by the widespread lockdown that countries had imposed, thus resulting to reduce the global supply of raw materials and from the shutting down of factories that produce those products. the shortages also came due to the restriction on international travels, both air and sea, where the little available resources could not reach different parts of the globe in time or would not reach at all. these disruptions in the production/manufacturing sectors and in the supply chain also prompted countries to retreat to formulate nationalist policies that put their interests first. for instance, in most economies, especially in developed countries, there is a notable rush to provide economic stimulus and family reliefs to caution businesses, thus allowing them to continue maintaining the service of employees even during those periods when operations were almost completely grounded. the family reliefs were advanced to caution citizens and permanent residents from the harsh economic realities that covid- had exposed the global population. on this, the united states offered a $ trillion stimulus package (carney, ) , whereas germany, though it is the green light from its parliament, offered a billion euros ($ billion) to mitigate the disruptions brought by the pandemic (reuters, a) . in the united kingdom, morales et al. ( ) report that the government had announced over . billion pounds ($ . billion) to support the selfemployed. similar measures have been advanced in different other countries, which adds to the protectionism shown through border restrictions and banning of flights and exportation of medical supplies. in the united states, president donald trump went further to ban immigration to the united states (zere, ) to protect americans against competition for the few jobs available where almost million had filed unemployment claims by april , (jones, ) . those forms of protectionism, though justified, show how this pandemic has exposed economies, including developed ones. in the less developed economies, the situation was tougher and as reported by united nations world food programme, by the end of this year, the number of the hungry would double to million people (anthem, ) , and such would be brought by the numerous impacts of covid- in those economies. therefore, even as nations look inwardly, there is need for such with capacity to assist to consider doing so as the pandemic shook every social structures as well as the economic foundations of vulnerable economies. since globalization, the world's engines had been running smoothly and had never been halted, even in times of turmoil in some parts of the globe. but the unexpected has happened for the first time, where covid- pandemic was seen to have prompted the grinding halt of not a few but all of the world's engines. the unavoidable lockdowns and stringent border restrictions and travel suspensions just being a few of the underlying factors that made the running of the world engines untenable. the other factors are the morbidity levels across the globe that the disease caused and the unimaginable fear on the humanity and governments, including the most powerful ones, like in the west and in the north. the challenges that the world faced started in china, where the coronavirus started slowly, but within days, it spread widely and in unprecedented levels warranting the closure of all economic activities, including manufacturing sectors and industries. the disruptions in china immediately had ripple effects on all other parts of the world, especially noting that china has, for a long time, been the world's manufacturing capital. the disruptions came just when the consumer demand for different products in other countries from different parts of the world was on a high and rising as depicted in a "united nations conference on trade and development (unctad)" report showing that exports in grew by . % in , with china being the world's leading merchandise trader of the year (unctad, ). on this, developed economies alone exported goods worth us$ billion, whereas least developed economies also exported us$ billion worth of goods (wto, ). during the same period, it is noted that due to favorable trade, the total gross domestic product (gdp) for the entire globe rose to us$ . trillion (wto, ). this figure represents a % growth increase in the gdp from to , where there has been no disruption. surprisingly, export of pharmaceuticals has been the second best performing (a . % yearly rise since ) after the professional and management consultancy sectors. the united states was the largest exporter globally, spending over us$ . trillion in (wto, ). when the coronavirus broke in china, other countries tried to step up and fill the market gap that it left, but this was also short lived, especially to the speed at which the coronavirus spread from china to the rest of the world, especially to europe, which is exporter of manufactured goods, especially pharmaceuticals, as shown by workman ( ) . the spread of the virus prompted lockdowns, border restrictions, and travel bans, meaning that even available products would become hard to export to different parts of the world. on the same, demand for different products reduced significantly, with that of medical supplies and ppes shooting to an alltime high, as scarcity, hoarding, and export restrictions all playing a part. even after china overcame the virus, and resumed its production, it was becoming difficult to ship manufactured goods, first, because of the travel restrictions, and second, because of the deteriorating economic landscapes in different economies, with a substantial number of people losing their jobs globally. according to a report by the china's national bureau of statistics, the recovery of the country's production (purchasing manager's index of . points) has been far much better compared with the recovery in demand for the products (cnbs, ). this could be explained by the fact that apart from china, most of major exporters like the united states were still experiencing unprecedented challenges of covid- and were yet to lift lockdown restrictions, leaving alone opening their borders or suspending travel bans. the disruption in the supply chain also placed tremendous pressures on existing products on the market, with some facing an exponentially demand that could not be met, while the demand for others experienced an unimaginable plunge. those that experienced an increase demand include pharmaceuticals, ppes, ventilators, and other products required in the health sectors, especially with the ranging impacts of coronavirus. according to a who modeling, every month, there is need for million medical masks, million examination gloves, and at least . million goggles (who, ) . in most economies, there were report of exceeding shortages, prompting the who to urge those with manufacturing capacity to help in producing these items in large quantities (who, ) . in other countries such as the united states, it was reported that the government was prompted to force, through an executive order, major companies such as general motors (gm) to produce ventilators to help bridge the gap that the increasing confirmed cases for coronavirus created (haynes, ) . the motor company was later joined by other companies such as ford and tesla in helping the government by mass producing the urgently needed ventilators and other medical supplies. in europe, the carmakers joined to help build ventilators whose demand was skyrocketing, but with very little supply available (kinch et al., ) . globally, parker ( ) estimated that over , extra ventilators were required to satisfy the global hospital demand, with , of those required in the united states; hence, the interventions by those companies could not have come at a better time. in other places, such as in the oil-producing countries, including the united states, the impacts of covid- on different economic sectors such as transport and manufacturing saw the demand for oil and oil products plummeting in rates not experienced in recent history. this prompted a slump in the oil prices, as far as % in the organization of the petroleum exporting countries (opec) (turak, ) , with the prices in the united states for the first time in history going below us$ (suleymanova, ) . the fall in prices even prompted the opec to contemplate reducing their production capacity to void the losses and overproduction. this move was, however, not welcome by all partners, especially by russia, which rejected such calls (faucon and said, ) . in the succeeding section, more on the impacts of the trade disruption will be discussed, especially the consequences that ensued. while countries rushed to institute nationwide lockdowns and impose restriction on the transport sectors, leaving only a few essential service providers to operate, their actions led to an immediate effect on the energy sector. in many economies, including china, the united states, and a large number of european economies, the demand for energy plummeted rapidly, causing a subsequent crash in the oil markets as introduced earlier. with this, for the first time in history, the pressure in the oil market demanded a reduction in production to check on the losses prompted by the reduced oil prices and also by the reduced demand. according to theinternational energy agency (iea), in the month of april alone, the demand for oil across the globe fell by an average of million barrels per down, compared with demand for the same last year (iea, ). this reduction was the lowest that has been witnessed since . the price of crude oil in april was also reduced to a historical low of negative usd- , meaning that the producers were forced to pay buyers for them to take the oil away as nobody wanted to hold onto oil (ambrose, ) . following these unprecedented times, the opec and its allies reached an agreement after lengthy parlays to recommend a reduction in production of approximately . million barrels per day (mb/d) beginning as of may (stevens, ) , which is also the largest cut in production in history. in the agreement, the deal was that each member would reduce their normal daily production, such that, when accumulated, the total reduction would amount to . million barrels per day. for instance, mexico agreed to lower its daily production by , bpd, to be maintained for months (may ejune ) (stillman et al., ) . thereafter, each of the countries that were part of the meeting would taper their production, to ensure that the daily production would not be over . mb/d, as compared with a similar period last year. this would last from july to december . as from january to april , the production is expected to maintain a reduction rate of . mb/ d when another meeting will be held to review the situation market situation (opec, ). in the non-opec countries, their accumulated total of oil production reduction is expected to drop by . million b/d between may and june. also, between july and december, due to some increase in demand as some states, countries, and even region will have gradually started opening up their economies and hence, increase the demand for oil to certain levels, the reduction in these non-opec countries will improve to reach . million b/d (eia, ). but such projection will depend on whether the situation of covid- pandemic will have improved, especially in the united states, which is currently the most affected country globally. these reductions in production were necessary, especially noting that in the united states, the prices of crude oil had plunged from a high of $ per barrel to a low of -$ in just hours after there was an oversupply prompted by lack of storage facilities (ngai et al., ) . in canada, this was seen to have fell by approximately . % in a span of only month from us$ . per barrel (sönnichsen, a) to us$ . per barrel (sönnichsen, b) between march and april . since the discovery of oil, and the subsequent demand for it in different economic sectors across the globe, oil has always been a highly valued commodity, with oil-producing countries enjoying very healthy economic growth over the years. in particular, most of the countries in the gulf region can attribute their high economic growth to their oil endowment. but, the unexpected covid- outbreak and the subsequent rapid spread of the coronavirus threw into disarray those economies, as their economic lifeline was threatened by the low demand for oil. the most challenging part on this is the uncertainty as to how long the covid- crisis was to last and how far down will this have plunged the oil market. as has been discussed earlier, oil-producing nations braced themselves for further drops in demand and prepared to continue lowering their production till (eia, ). this projection could be somehow pegged on the fact that health experts and agencies have warned that the earliest a vaccine for the virus could be made available is late (cullen, ) . and with such, it means that it would be long before countries resume to their previous normal or at least adopt to "a new normal," which cannot be predicted how it will treat the oil market. for now, oil posed as one of the sectors that had supported the economy is on its knee in many economies, forcing governments to consider bailout plans for it. for instance, lefebvre ( ) reported that in the united states, president trump was planning as to how to bail the industry, before it completely collapses. according to experts, the recovery of this market is dependent on how long the industries that rely on it will be grounded and how they will also recover post-covid- (rechtsteiner, ) . and, by the look at how the opec and its allies crafted their recommendations, it may take a substantial amount of time before the industry regains its previous economic metrics. the situation would even worsen if the recession that has been projected to succeed the covid- crisis will actualize. on this, from a historical perspective, recessions have always had bad impact on the oil and energy market (mahalik and mallick, ) , and the coming one would be no different. furthermore if different nations, regions, and economies were to decide to transition out of oildependent economies by embracing renewable energy, this would mark a positive outlook toward a new global political economic landscape. but it would be a setback to the oil-producing countries, which will also be recovering from both the impacts of covid- , which have substantially affected them, and also from the recession. as the spread of covid- reached (by the time of writing) to over countries and territories, and the number of those infected continues to increase from the current figure of . million, and the deaths reaching almost , globally, the scarcity of medical supplies continues to remain one of the stumbling blocks (who, ) . at the beginning, this shortage was attributable to the reduction in the manufacturing activities, more so in china after it instituted a statewide lockdown and restricted any forms of activities except for the supply of essential supplies (bradsher and alderman, ) . later on, as from the end of march , the country's manufacturing sector gradually returned, reaching an operation capacity of almost % by mid-april (cnbs, ). but, even as they started to produce the much needed medical supplies, they faced the unprecedented challenge in the supply chain as travel across and within most countries had been suspended or banned. though the country has a robust and excellent link to almost all parts of the globe due to air and shipping routes, moving the manufactured good became a sudden challenge. as those challenges were being experienced, on local scenes, there was mounting pressure on existing stocks of health equipment, especially as the number of those needing hospitalization continues to swell. in some countries, to supplement the diminishing stocks they had, the local manufacturing sectors were put to maximum operational capacities, but still their efforts seemed not to suffice to satisfy increasing demand. for instance, in the united states, m and the prestige ameritech companies (martineau, ) , the largest producers of n masks, together with other local small competitors, initiated their full operation capacities to meet the demand for over million n masks that the health sector had estimated would be required in march, but their effort only allowed them to produce a maximum of million masks (leary and hufford, ) . this was computed even after president trump had invoked the defense production act (dpa) to force the m company to increase their production capacity and to stop exporting any mask outside of america (heilweil, ) . in europe, the same scenario of shortage was live and hurting (tsang, ) , and the potential companies such as innovatec gmbh & co.kg based in germany and bavaria-based sandler ag and others that could fill the gap were only managed to do this after june or august (burger, ) . however, even after their input, the global requirement for respirators was not expected to be met. for instance, it is estimated that europe needs at least million n masks every day, which translates to more than . billion masks a year, and this could change if the number of infections were to increase (burger, ) . local companies were not anticipating a pandemic, or such a surge in demand was insufficiently prepared to meet this demand. amid those supply shortages, governments, besides that of the united states, have set to force companies prioritize production of medical supplies and, in other cases, have seized the control of shipment and supply of those products to ensure that they remain within the boundaries of the country. for instance, in the united states, the control of production, supply, and shipment of these vital supplies was now under the federal emergency management agency (fema) (kanno-youngs and nicas, ) . it was accused of using korean war-era production tactics where the government would force companies to prioritize government orders over any other clients (kanno-youngs and nicas, ) . in the united kingdom, though in soft tone, prime minister boris johnson urged car makers in the country to prioritize manufacturing of ventilators and other supplies that could ease the pressure in the medical sphere (faulconbridge et al., ) . in czech republic, the government adopted the same approach taken by the russian, indian, and german governments by banning the exportation of medical supplies (stickings, ) . furthermore, the czech government was also gearing to control and regulate the sale of those supplies locally, to ensure that it could supply health workers and medical fraternities whenever and wherever required ( zurovec, ) . in other cases, governments have even been accused of applying underhand tactics to ensure they have supplies in their country. for instance, the us government was accused by the local government of berlin of "piracy" for redirecting over , masks en route to germany to be used locally (bbc, a). these had been exported by the m company, but the government "confiscated" the shipment and returned it to the united states. germany also lost over million masks in a kenyan airport in march in unclear circumstances (simsek, ) . in south korea, anyone implicated of hoarding masks or any other medical items in high demand in hospital was assured of a years jail term or fines/penalties reaching up to $ , (choi, ) . in indonesia, the security officers were forced to conduct a wide search after it became clear that people had purchased and stockpiled masks, with an aim of hoarding them until prices were favorable. in one warehouse, they were able to seize a consignment of , masks and arrested the owners who are facing jail terms of hefty penalties for their actions (williams, ) . these and many other actions and strategies that governments across the globe have undertaken to ensure that they secure every available medical supplies in their countries only exemplify that medical supplies have now been branded as high-value commodities and are guarded with every ounce of energy and force. such moves, coupled with border restrictions and banning of foreign citizens, and the counteraccusations on responsibility of governments on stopping or escalating the spread of coronavirus could pose serious security threats. such scenarios are uncommon and could only be traced back to situations witnessed during the world war ii (ww ) and will be expounded further in the next section. with the increased pressure on trade, which has prompted governments to take unprecedented and drastic actions such as those discussed earlier, all aimed at safeguarding local health, social, and economic stabilities, there have been little relative global governmentled action of meaningful significance. in particular, it has been noted that each government has formulated and implemented their own unique policies and measures without regard of what their neighbors, trade partners, or competitors are doing or which policies they have in place. the surprising aspect from the approaches that each government has taken is that all are meant to address a common enemy, which, as argued by guy ( ) , could be defeated in a much easier way if there was global coordination and unity. to the contrary, the solitary approach by governments has been seen to arouse local, regional, and international disagreements and disharmonies that are a threat to global security. for instance, before the emergence of coronavirus in wuhan, china, the united states and china were engaged in trade wars, which led to us banning products from china and imposing heavy taxes on others (ap, ; bbc, ) . but the rivalry between these global economic giants was awakened by the emergence of coronavirus, with the united states accusing china of hiding information, thus affecting us preparedness (sevastopulo and manson, ) . the disharmony escalated with the united states halting its funding to the world health organization (who) and accusing of the latter of collaborating with china in misinforming the world about the emergence of the virus (smith, ) . with no endpoint as to when the covid- crisis may end, plus the numerous challenges such as the shortages in the health sector, the widespread job loss, the social tension as people get tired of staying at home, and other issues, there are fears that more drastic actions may be inevitable. on this, it would not be surprising to see people, groups, or even governments use excessive force in a bid to demand some compliance on a number of pressing concerns. in fact, even such has started in china, where locals have been reported in a number of occasions to have violently attacked minority groups (mostly africans) by ejecting them from their apartments and preventing them from accessing restaurants, food store, and other basic facilities (davidson, ) . in the heilongjiang province, china, there also looms heightened discord between local government and the russian government due to suspension of the suifenhe land port over the coronavirus cases reported to be from chinese nationals returning from russia (wu, ) . suspending the port meant curtailing movement of trade within the border towns between the two countries; for this reason, the russian side threatened to deport the chinese citizens (qi and sheng, ) . while these examples exemplify the delicate situations that were live in different parts of the world, an urgent global solution and guideline were required on different issues. one of the bodies that is taking leadership on this front, especially on global collaboration on the health sector, is the who, but its soar relationship with the united states, which is also its major financier, is proving a difficult situation. on the same, its reputation was questioned when its director-general publicly accused taiwan of racism and personal attacks on him (hioe, ) , where taiwan launched a scathing counterattack accusing the who chief's accusation as "imaginary and irresponsible" (bbc, b). others who would be expected to have provided leadership included the united states, being a superpower and the largest economy, but their solitary approach to fighting the coronavirus, including suspending flights, banning noncitizens, and banning exportation of medical supplies from its land showed the contrary (fuchs, ; reuters, b; zere, ) . the european union fell short when it launched strict export regulation on health supplies, amid scarcity in other areas, especially to vulnerable nations (euroean commission, ). therefore, it is incumbent upon a global unbiased organization, to take charge and ensure that the geopolitical tensions being witnessed do not escalate to events or situations that would jeopardize global peace. and on this, the un body was rightly constituted for such a noble cause, especially noting that it was formed to ensure that world peace is maintained (un). while it is true that the un secretary general has invariably called for global unity to find a lasting solution, the powerful arm of this body, the un security council, has conspicuously been missing on the front line, especially to ensure that peace will not be threatened (gladstone, ) . with the current reluctant approach to this global crisis by the un security council, there are fears that the deepening crisis escalating to conflicts may arise. to put this into perspective, as noted earlier, the united states had already withdrawn its funding to the who, and previously, it had also halted its financial support to unesco, another un body. if the covid- crisis continues, hence causing more economic, social, and even political strains, there are possibilities that other key financiers of these international bodies may also follow the lead by the united states and withdraw their financial support, and instead, redirect the funding internally to support different sectors locally. with such a scenario, that would leave the un with limited resources; thus, it would not be in a position to undertake its responsibility or even safeguard the strides it has already made in different spheres globally. unfortunately, the actions of halting financial support for such bodies in times of the covid- pandemic impact not only on the health sector but also on other related sectors. this will also act as a dangerous international precedence in world diplomacy and international relations. on this, it is worth noting that, besides the coronavirus, the world is still under serious threats from other sever threats such as climate change and hunger. and, already, the world food programme have indicated that by the end of the year, following the emergence of coronavirus, those facing acute hunger globally would double to reaching over million people (anthem, ) . similarly, in respect to climate change, if history was to repeat itself, it would be disastrous as the gains already achieved, especially in regard to paris agreement, and others would be watered down as nations try to restore their economies. russia bans export of masks, hazmat suits to fight coronavirus one hundered italian doctors have died of coronavirus oil prices dip below zero as producers forced to pay to dispose of excess risk of hunger pandemic as covid- set to almost double acute hunger by end of trump's % tariffs on $ billion in chinese goods take effect available at trump escalates trade war with more china tariffs coronavirus: us accused of 'piracy' over mask 'confiscation coronavirus: who chief and taiwan in row over 'racist' comments the world needs masks. china makes them, but has been hoarding them europe's scramble for face masks prompts longer term rethink senate unanimously passes $ t coronavirus stimulus package face mask and hand sanitizer hoarders face $ , fine and up to years in prison under new south korean law amid coronavirus spread decline of major economic indicators significantly narrowed down in march coronavirus vaccine won't be ready until end of under "most optimistic chineseofficial: claims of racial targeting are 'reasonable concerns short-term energy outlook commission publishes guidance on export requirements for personal protective equipment the nhs workers who have died during the coronavirus pandemic russia blocks opec response to coronavirus make us ventilators to fight coronavirus, uk asks ford and rolls royce the us-china coronavirus blame game is undermining diplomacy security council 'missing in action' in coronavirus fight export restrictions under scrutiny e the legal dimensions of export restrictions on personal protective equipment coronavirus shows we are not at all prepared for the security threat of climate change trump invokes defense production act to force gm to make ventilators trump ordered more n masks. m says his tactics could make the shortage worse who director-general accuses taiwan of campaign against him involving available at: ft.com/content/ c a fc-a - -a -fe a dcc faa jobless claims climb to million in six weeks as covid- layoffs continue to rise swept up by fema': complicated medical supply system sows confusion carmakers in europe, us switch to ventilator production trump administration orders million face masks from m for coronavirus pandemic energy consumption, economic growth and financial development: exploring the empirical linkages for india hundreds of doctors in bangladesh infected with coronavirus the 'surreal' frenzy inside the us' biggest mask maker virus aid package beats financial crisis stimulus oil plunges below zero for first time in unprecedented wipeout the th (extraordinary) opec and non-opec ministerial meeting concludes more ventilators needed to cope with coronavirus outbreak cuba has a history of sending medical teams to nations in crisis ) china, russia appear to be in discord over whether to re-open land poart amid pandemic oil prices could remain depressed for at least a year. here's why factbox: germany's anti-coronavirus stimulus package portugal to treat migrants as residents during coronavirus crisis russia sends plane with medical supplies to us for coronavirus response donald trump threatens to freeze funding for who german shipment of million masks lost in kenya trump halts world health organisation funding over coronavirus 'failure western canadian select (wcs) crude oil monthly price western canadian select (wcs) crude oil weekly prices global death toll from coronavirus tops opec and allies finalize record oil production cut after days of discussion countries around the world hoard medical supplies to tackle coronavirus: germany and russia ban exports, south korea stockpiles masks and india limits paracetamol sales mexico reaches deal with u.s. to cut oil production allowing for opecþ output cuts crash! us crude futures turn negative for first time in history government bans exports of certain masks, ventilators, raw material for masks oil prices may now be at a bottom after historic opec deal coronavirus aid from u.s. groups arrives in china maintain international peace and security shortage of personal protective equipment endangering health workers worldwide police seize , face masks from indonesian warehouse after country's first coronavirus case sparks panic buying and soaring prices drugs and medicine exports by country report coronavirus cases world trade statistical review remote chinese city hit by coronavirus after weeks of feeling safe trump's travel ban: thousands of lives in limbo respirator prices will be regulated due to coronavirus key: cord- -hmii bvq authors: gostin, lawrence o.; friedman, eric a. title: health inequalities date: - - journal: hastings cent rep doi: . /hast. sha: doc_id: cord_uid: hmii bvq health inequalities are embedded in a complex array of social, political, and economic inequalities. responding to health inequalities will require systematic action targeting all the underlying (“upstream”) social determinants that powerfully affect health and well‐being. systemic inequalities are a major reason for the rise of modern populism that has deeply divided polities and infected politics, perhaps nowhere more so than in the united states. concerted action to mitigate shocking levels of inequality could be a powerful antidote to nationalist populism. a basic yet critical start to addressing health inequalities is to recognize them, which demands improving data collection and analysis. certainly, global indicators show vast progress in reducing poverty and extending life. yet aggregate health data mask a deeper reality: health gains have disproportionately benefited the well‐off, leaving the poor and middle‐class behind. t he perceived injustice of the hoarding of global wealth ( percent of it in ) by the top percent of individuals has driven both left-and right-wing political populism that is deeply suspicious of globalism, trade liberalization, and corporate wealth and influence. wealth, though, is hardly the only area where vast inequalities are manifest. socioeconomic position is also a core determinant of whether a person will be able to live a long and healthy life. health inequalities are embedded in a complex array of social, political, and economic inequalities-as the covid- pandemic is making glaringly evident. responding to health inequalities will require systematic action targeting all the underlying ("upstream") social determinants that powerfully affect health and well-being. systemic inequalities are a major reason for the rise of modern populism that has deeply divided polities and infected politics, perhaps nowhere more so than in the united states. concerted action to mitigate shocking levels of inequality could be a powerful antidote to nationalist populism. a basic yet critical start to addressing health inequalities is to recognize them, which demands improving data collection and analysis so that overall improvements in health do not disguise the dark reality of health inequalities. certainly, global indicators show vast progress in reducing poverty and ex-tending life. (the united states is an outlier, as average life expectancy ticked down three years running, mostly due to "diseases of despair," such as opioid overdoses and suicides, until edging upward in . ) globally, deaths of children under five, maternal deaths, and deaths from infectious diseases (like hiv/aids, tuberculosis, and malaria) have all been trending down for years. yet aggregate health data mask a deeper reality: health gains have disproportionately benefited the well-off, leaving the poor and middle-class behind. a baby born in a largely white, wealthy suburb of st. louis can expect to live thirty-five years longer than one born in a mostly black, lower-income suburb a few miles away. average life expectancy among black south africans is sixteen years lower than for whites. while people in japan and switzerland live an average of eighty-four years (monaco's life expectancy is eightysix ), those in the central african republic and lesotho average fiftytwo and fifty-three years, respectively, and those in chad, sierra leone, and nigeria, fifty-four. (the united states ranks twenty-sixth among organisation for economic co-operation and development countries, near the bottom, with an average of seventy-nine years. ) the circumstances of your life-where you are born, your identity, your socioeconomic position-are the greatest predictors of your future. most health gains align with the united nations millennium development goals (mdgs), which used aggregate measures of progress, thereby concealing grossly inequitable distribution. within countries, the wealthier percent of populations saw rapid reductions in hiv, for example, while the poorer percent made few gains. in paraguay, the indigenous aché people have a tuberculosis incidence seventy-five times that of the country's population overall, while tb incidence among canada's indigenous inuit people is over three hundred times that of nonnative canadians. in low-and middle-income countries, percent of communities have seen lower child mortality, but one study found that in one-quarter of sixty-four countries surveyed, the poorer percent of the population were experiencing worse mdg health outcomes as the mdg period progressed. persistent opportunity gaps mean that more than half the world's population lacks access to essential health services. in new york city, maternal deaths of black women are twelve times higher than those of white women. and even early covid- data has made clear that black americans are becoming infected and dying at considerably higher rates than white americans are. at the current rate, many countries will not close core health equity gaps this century, much less achieve the u.n.'s sustainable development agenda's pledge that "no one will be left behind" by . public discontent with these alarming health disparities is palpable. much of the anger is directed toward the very rich-the top percent-and at "greedy" corporations, especially those selling health products and services, like pharmaceutical companies and health insurers. as the costs of essential medicines and health insurance inextricably at law health inequalities by lawrence o. gostin and eric a. friedman rise, the public perceives that profit trumps health. there can be little doubt that the richest percent and mega corporations leverage their influence to gain advantage, such as lower taxes and lax regulation. we're seeing a race to the bottom, with corporations of all sorts seeking the lowest tax and weakest regulation destinations. transnational corporations are not paying their fair share for the social safety net (including health costs), and they evade more rigorous health, safety, and environmental regulations-all of which threatens people's health. in essence, this is the populist claim: advantages are going to the wealthy and bypassing middle-and lower-income people. undoubtedly, this narrative rings true, but there are other deeply consequential reasons for health inequalities. we can't fix what we don't measure t he u.s. gross domestic product was up for ten straight years before covid- , but economists were seeing a disconnect between rosy economic indicators and deep social discontent. the public is not wrong in feeling despair; the fault is with the data. the gdp is a measure of aggregate national economic growth, but wealth growth most benefits the top percent. at least before the economic ramifications of covid- , upper-income families had more wealth than they did before the great recession, while middle-and lower-income families remained well below prerecession ( ) levels, and the wealth of middle-and lower-income families is sure to fall further due to the pandemic. a new indicator, distributional accounts, would show how much of the economy's bounty is flowing to various income groups. the failure to gather, analyze, and disseminate the most pertinent data also hampers understanding of health disparities. with limited exceptions, statisticians measure overall health outcomes, so we have too little understanding of who is left behind, where they live, and why they suffer disproportionate health burdens. most importantly, if policy-makers are blithely unaware of health inequities, they are unlikely to do anything about them. thus, the first step in addressing health inequities is to measure them. by all means, continue aggregate assessments of the health of the nation, but also rigorously examine granulated data to understand better the stark variances in health outcomes. it's about public health and social determinants w hen discussing solutions to problems of health and equity, the political class almost invariably talks about health care and, specifically, about how to achieve universal health coverage. the democratic primaries feature outsized debates on "medicare for all," while tedros ghebreyesus, director-general of the world health organization, says, "all paths lead to universal health coverage." yet, as important as medical services are, they are not particularly strong drivers of population health. the more consequential health services by far are population-based public health interventions like sanitation, potable water, safe nutritious food, vector abatement, and alcohol and tobacco control. and public health measurements do not track visits to doctors or hospitals but, rather, the incidence and prevalence of injuries and diseases in the population. less than percent of all health dollars in the united states flow to public health, with the rest invested in medical and hospital services. if you ask any epidemiologist what the single biggest predictor of health outcomes is, she would point to social determinants outside the health sector, including employment, education, housing, and transportation. yet while a physician can, for example, counsel an asthmatic patient to avoid environmental triggers, if the patient lives in a neighborhood replete with indoor and outdoor pollution, or if she is homeless, no amount of medical care will prevent wheezing and breathing difficulties. deeply rooted structural factors, such as low social status or racism, are causally related to poor health. scholars observe that a history of racial segregation adversely affects health outcomes for african americans across generations. the remedies for health inequities are therefore complex, requiring action across sectors, including access to justice. intersectoral collaboration and action require new mindsets across government agencies. yet the data we collect do not account for systemic structural factors. without explicit attention to them, little progress will be made. a s important as health and economic equity are, they offer only a partial explanation for populism's rise. the united states appears separated by social class, education, and geography. working-class rural inhabitants feel that the wealthy, professional classes in the city look down at them. and many of these well-off city dwellers may, in fact, not understand concerns from the heartland; some might not even genuinely listen to them. in short, the polity feels that it is told that it must trust people they see as "the other," those who seem very different culturally and politically. voting for a plain-speaking, even vulgar and dishonest populist leader is, in part, a rebellion against a feeling of being neglected, even disrespected. and, as many rural americans see their communities becoming more diverse and see cultural norms shifting, some respond by turning to politicians who exploit their fears, and even their prejudices. there are also tangible realities undermining health and well-being in rural america. rural americans struggle to find well-paying jobs, quality education, and health services. small towns suffer the loss of the many educated young people who migrate to cities. in many communities, affordable health insurance is scarce, qualified health workers either leave or never come, and hospitals are closing. and many rural populations live in states that haven't expanded medicaid under the affordable care act, thus blocking health care access for the working poor. a combination of low socioeconomic status and a diminishing social safety net is driving deep systemic inequalities in health. the sense among less-educated, rural voters of being disrespected contributed to president trump's election in . however, he has cut supplemental nutrition assistance program benefits, undermined the affordable care act, and allowed work requirements for medicaid coverageactions that contribute to health inequalities and harm many of the very people who voted for him. just recently, the supreme court allowed the trump administration's "public charge" rule to take effect even as challenges to the rule continue to work their way through the courts. the rule is a major obstacle for legal immigrants who require public assistance, including medicaid, housing vouchers, and food stamps, and will cause many of these people to go without vital support. what can we do now? i f we want to fix health inequalities, we must focus on them. equity solutions require dedicated, sustained, prioritized, and well-resourced plans, which we call "health equity programs of action." programs of action would be systematic and systemic and would include explicit targets, costed actions, rigorous measurement, and accountability through a comprehensive national effort. every country could benefit. the united states could choose to lead, which would be a powerful political commitment to health equity and justice. the sustainable development agenda's pledge to leave no one behind will surely go unfulfilled unless we act decisively. with inequities causing millions of preventable deaths globally every year, offending the deepest values of fairness, there is no time to lose. it would be a grave injustice to see approaching and, yet again, find the world has failed to dramatically reduce health inequalities. and if we succeed, an intangible yet powerful benefit will be to restore a sense of dignity for all of society and, in turn, act collectively to elect truthful, compassionate leaders who bring us together as a nation. richest % own half the world's wealth, study finds american life expectancy rises for first time in four years forward through ferguson: a path toward racial equity (stl positive change, ferguson commission life expectancy at birth, total (years) united health foundation progress on global health goals: are the poor being left behind? us-china trade war imperils efforts to beat poverty, warns bill gates easing the dangers of childbirth for black women putting health equity at heart of universal coverage-the need for national programmes of action how wealth inequality has changed in the u.s. since the great recession, by race, ethnicity and income public health's falling share of u.s. health spending on charlottesville putting health equity at heart of universal coverage key: cord- -b qn ynk authors: baillie, l.; dyson, h.; simpson, a. title: dual use of biotechnology date: - - journal: encyclopedia of applied ethics doi: . /b - - - - . - sha: doc_id: cord_uid: b qn ynk this article addresses issues that are central to the dual use of biotechnology, such as the public perception of risk and the need for physical containment to prevent the release of potentially dangerous microorganisms. it also examines the public and media perception of the scientists who handle and manipulate these pathogens and discusses the controls that are currently in place to ensure that scientists engaged in defense-related dual-use medical research act in a transparent and ethical manner. finally, the article discusses what can be done by scientists to allay the fears of their fellow citizens. research in the area of life sciences and biotechnology has the potential to bring great benefit to humankind. in a relatively short period of time, the life sciences have evolved from a simple cataloguing exercise of the diver sity of nature to a position in which researchers are adding to that diversity through the construction of modified and potentially novel life-forms. the vast majority of this activity has had a positive impact on the quality of life of at least some of the human race. indeed, the past years have seen major advances in the fields of micro biology and biochemistry, and these have been followed by the emergence of the disciplines of immunology, molecular biology, and genetics. in practical terms, this has resulted in the introduction of sewers and clean water, the development of antibiotics and vaccines capable of eliminating infectious diseases such as smallpox, and the ability to create genetically modified organisms able to synthesize production-scale quantities of human hor mones such as insulin. indeed, on a daily basis biomedical researchers manip ulate microorganisms in an effort to understand how they produce disease and to develop better preventative and therapeutic measures against the infections they cause. the efforts of plant and animal biologists using similar techniques to improve agricultural yields have resulted in the development of disease-resistant crops and transgenic animals. some of these species have transitioned from the confines of the laboratory into mainstream agriculture in countries such as the united states and india. on first disclaimer: any views expressed are those of the authors and do not necessarily represent those of dstl, ministry of defence, or any other uk government department. inspection, these emerging technologies hold enormous potential to improve public health and agriculture, strengthen national economies, and close the develop ment gap between resource-rich and resource-poor countries. however there is also a potential dark side to this benign picture. throughout human history, every major new technology has been used for hostile purposes, and thus it would be naive to believe that the life sciences might not be similarly exploited for destructive purposes by state-sponsored biological warfare programs or by individual terrorist or doomsday groups. research with the potential to be misused for illicit purposes is said to be 'dual use.' simply stated, the techniques needed to engi neer a bioweapon are the same as those needed to pursue legitimate research. there are also concerns that rapidly advancing technological possibilities could enable the creation and production of unforeseen new biological threats with uniquely dangerous but unpredictable characteristics. a key challenge faced by regulatory authorities is the need to balance legitimate public concerns over the mis use of life sciences against the enormous potential that they have to benefit humankind. getting this balance right will be central to ensuring that governmental actions do not impose blanket restrictions and cumbersome rules on scientists that stifle legitimate research and reduce industrial competitiveness while having little impact on real security. it could be argued that any new regulations specific to dual use of biological technologies would be largely inef fective because they would only affect scientists working in government-funded laboratories, who already follow very stringent rules. indeed, even if new regulations were implemented, it is debatable as to how effective they would be. the anthrax attacks in in the united states are thought to have been undertaken by a 'regu lated' lone u.s. government scientist working in a government-controlled facility. does this mean that we need new regulations, or does it suggest that regulations alone are likely to be ineffective? it is also a fallacy to believe that life science research is limited to government-regulated facilities; indeed, the technology has reached a stage at which an individual with a graduate-level education, access to the internet, and a credit card can set up a garage laboratory anywhere in the world. the emergence of organizations such as diybio is a testament to this new movement. this spon taneously formed community of more than individuals is in the process of establishing community laboratory spaces in major cities throughout europe and the united states to enable their members to carry out their own 'hobby research.' how can these free spirits be assisted or regulated to ensure that both their own safety and that of the community in which they live and experi ment remain secure? an approach proposed by a number of advocates has been to encourage life scientists to take the lead in tack ling the issue of dual-use technology. indeed, some have stated that these scientists have a moral obligation to prevent the misapplication of their research because they are believed to be in the best position to understand the potential for misuse. although the validity of this argument is debatable, it is also extremely unlikely that the average research scientist will have more than a hazy comprehension of the factors important in developing an effective bioweapon. this view does, however, point to the need for life scientists to move more to center stage and proactively engage with both the public and the security and regulatory communities to ensure that the control systems that are ultimately adopted are both proportionate and likely to be relevant in the real world. it should not be forgotten that the reason for these control measures stems from a desire to protect the well being of the general public. although it is highly unlikely that they will understand the intricacies of the research, it is important that they support the outcome that the researchers are trying to achieve. indeed, the support and tacit consent of the general public and their elected representatives is essential in the development of propor tionate regulatory systems. unfortunately, scientists in general, and particularly those engaged in defense and industry-funded research, have a poor track record in communicating the impor tance of their research to fellow citizens. this is primarily due to the constraints imposed on them by their parent organizations, but it also flows from a lack of understand ing of science among the media industry generally, and particularly the popular press, which often results in incomplete and inaccurate reporting. as a consequence, this perceived lack of openness has created an atmosphere of suspicion in which conspiracy theorists, the media, and hollywood thrive, routinely conjuring up lurid images of evil scientists working on government-funded frankenstein projects to destroy the world. it is thus perhaps not surprising that public perception of scientists and their motives may not be as positive as it once was. this article addresses issues that are central to this theme, such as the public perception of risk and the need for physical containment to prevent the release of potentially dangerous microorganisms. it also examines the public and media perception of the scientists who handle and manipulate these pathogens and discusses the controls that are currently in place to ensure that scientists engaged in defense-related dual-use medical research act in a transparent and ethical manner. finally, this article discusses what can be done by scientists to allay the fears of their fellow citizens. although microorganisms capable of causing disease are widespread in the environment, medical, technological, and economic advances have, to a large extent, shielded individuals in the developed world from their adverse effects. notable examples include the reduction in the incidence of ( ) puerperal fever and surgical sepsis in the nineteenth century following understanding of the modes of transmission of bacterial infection, ( ) enteric fevers due to improvement in sanitation, and ( ) food poisoning due to better education and food preparation practices. while there are still intermittent outbreaks of food poisoning in the united kingdom, the real concern is that the overuse by the farming industry of powerful antibiotics to promote animal growth could result in the emergence of multi-drug resistant pathogen bacteria making them increasingly difficult to treat. the importance of a society's organizational and tech nological status in mitigating the effects of disease is well demonstrated by the contrasting fortunes of new zealand and haiti following earthquakes in . although the earthquake that hit south island at . local time on september was of a similar magnitude ( . compared to . ) to the one that struck haiti at . on january , the outcomes for the two populations have been remarkably different. there were no fatalities in new zealand (only two people were admitted to hospital in the immediate aftermath), and there have been no epidemics, despite disruption of sewage and water supply systems. this contrasts with a high initial death toll ( ), many injuries ( ), catastrophic disruption of haitian society ( million people made homeless), and an epi demic of cholera in the displaced population. aspects of a society that determine its resilience to major disasters include the general health and education of its popula tion, its technological infrastructure, the state of readiness of its societal organization to respond to the event con cerned, and its political and governance structures. new zealand and haiti appear to be at opposite ends of the spectrum for all of these criteria. a particular infection of a certain severity may have widely different impacts on an individual depending on the person's general health and specific circumstances. thus, an enteric infection in an undernourished child in the medical center of a refugee camp outside port-au-prince could well prove fatal (particularly because the child is likely to be only one of many), whereas a similar infection in a healthy child in christchurch might be overcome with little more than good nursing care from the child's parents at home. perception of the risks of such infection also varies considerably according to a society's recent experience; childhood deaths from enteric infec tions are an accepted fact of life in many poor areas of the world, whereas in richer, technologically advanced areas they are not. typically, as the prevalence of infectious disease decreases over time in a society, concern regarding rare and particularly novel infections increases. thus, fre quent but relatively mild infections (e.g., the common cold) may inflict a significant overall burden on a society in terms of general ill-health, use of health services, and loss of economic activity without arousing much outcry from the general population. in contrast, a rare but severe treatable infection such as methicillin-resistant staphylococcus aureus may cause much consternation in the media but actually inflict a much smaller overall burden on society. novel or emerging infections (e.g., severe acute respiratory syndrome (sars) and swine flu) may have major economic and societal impacts worldwide, with an actual disease burden that is a minute fraction of that caused by well-known diseases such as malaria and tuberculosis. perhaps counterintuitively, the fear engendered by rare diseases in a society appears to be inversely related to the actual disease burden that they impose. this fear will clearly be modified by experience of the disease; thus, sars was rightly to be feared and swine flu less so. by extension, an unknown infection can cause disproportion ate fear in a population, exaggeration by the media, and the risk of overreaction by the authorities. the anthrax letters episode in the united states was an exam ple of a major response to a relatively small overall disease burden ( infected and deaths in a country of million people), but it demonstrates the fact that a society's response to an unexpected human-originated event may have a much greater impact on the society than the event itself. media-dominated, internet-connected, technologically advanced, economically developed areas of the world are therefore more prone to exaggerated responses based on fear of a horrifying unknown than are those areas that are less privileged. the controversies in europe regarding genetically modified (gm) crops (feared in europe for ideological reasons but welcomed by more pragmatic societies in india and the united states for the increased yields they bring) highlight the fact that advanced societies may, for cultural reasons, have different views of the risks associated with certain technologies. although all advanced societies would be expected to have a marked fear of the sequelae of a deliberate release of infectious organisms, those with an already heightened fear of biotechnology might be more prone to extreme reactions. deliberate release of harmful biological material would provoke a number of emotions, including fear of the unknown, the ancient fear of plague or conta gion, anger and fear of malicious human action, anger directed at law enforcement agencies for failing to prevent the event, and anger at politicians for possibly provoking the event. a release of dangerous biological material from a research laboratory would provoke many similar emotions, although anger would be direc ted more at the incompetence of those operating the laboratory and at the relevant authorities for failing to prevent it. so what is the real risk of an accidental or deliberate release of dangerous biological material in the united kingdom? fortunately, escape of infectious material from laboratories is very rare; examples include a small pox outbreak in birmingham in and the foot-and mouth disease outbreak associated with faulty drainage at the animal health facility at pirbright in . the root cause of such accidental releases was a breakdown in containment (the physical control measures put in place to prevent microorganisms escaping to the environment). in fact, containment technology and practices have improved dramatically during the past years, with significant improvements often being identified by analy sis of accidents or near-misses. at the porton down site, which houses both ministry of defence and department of health microbiological containment laboratories, there have been only two cases of laboratory-acquired infec tion; these occurred in the s and both were the basis for considerable improvements in procedures. in the united kingdom, there have been no known deliberate releases of biological material. there have been deliber ate releases of infectious material in other countries -the rarity of such events has probably contributed to their celebrity status. given the extreme rarity of such events, why are they so feared? it is instructive to compare the annual inci dences of certain other commonly accepted events using headline statistics relating to work-related ill-health and accidents in the united kingdom during - : • ill-health: . million people who worked during this period were suffering from an illness (long-standing as well as new cases) that they believed to be caused or made worse by their current or past work. a total of of these instances were new conditions that started during the year. an additional . million former workers (who had last worked more than months previously) were suffering from an illness caused or made worse by their past work. a total of people died from mesothelioma in , and thousands more died from other occupational cancers and diseases. • injuries: workers were killed at work -a rate of . fatalities per workers. a total of other injuries to employees were reported -a rate of per employees. a total of reportable injuries occurred, according to the labour force survey -a rate of per workers. • working days lost: . million days were lost overall ( . days per worker), . million due to work-related ill-health and . million due to workplace injury. thus, real risk is very different from perceived threat, which may sometimes appear greater the rarer the event (and hence the lower the probability of actually experi encing that event). data for england and wales for indicated that the more common avoidable causes of death (e.g., cardiovas cular disease due to smoking and obesity) carried a risk of in compared to a risk of in for spectacular events, such as railway accidents, that generally attract media attention. these risks were calculated retrospec tively from the reported causes of death during that year. the risk of dying in england and wales from infection due to bioterrorism in that year was zero (as it was in ). however, when looking forward into an uncertain future, many more factors than likelihood affect the per ception of threat, and it may be that the very rarity of an event adds to its perceived impact, making it more inter esting to society at large and therefore much discussed in the media. it is clearly the case that if these rare events remained unreported, the public would not dread them so much, but such censorship would not be acceptable in a democratic society, and the media should take a respon sible approach to explaining real risks and suggesting appropriate and proportionate precautions to mitigating them. although past experience suggests that release of danger ous biological material, whether accidental or deliberate, from facilities is extremely rare, it is important that we consider how such an event could occur in the future. the most likely routes of escape are following an accident in a laboratory (hospital, academic, government, or commer cial research) or as a consequence of defective physical containment processes or equipment as occurred at pirbright in when foot-and-mouth virus was released to the outside world. the mainstay of preventing release of dangerous bio logical material rests on principles of biosafety, biocontainment, and biosecurity. biosafety covers the procedures needed to work safely with hazardous organ isms. biocontainment includes the measures (facilities, equipment, and apparatus) within which work on these organisms can be carried out safely without danger of release into the environment. biosecurity is the process of ensuring that the whereabouts of hazardous organisms are known and tracked and that access to them is restricted to appropriately authorized personnel. these principles actually apply more widely to other human activities, including hygienic preparation of food, supply of clean drinking water, safe processing of sewage, sterile procedures in surgery, and safe operation of hospital microbiology laboratories, as well as the more obvious situations of microbiological research laboratories. welldesigned facilities and procedures both facilitate the con duct of good science and minimize the opportunities for accidental misuse. unfortunately, although good engineering can reduce the physical risk of pathogen release, it cannot stop a researcher from deliberately removing material for his or her own use. the motives for such an action could include ideology (extremist apocalyptic, islamist, or ani mal rights philosophies), blackmail by members of an extremist group, disorders of perception (mental illness or desire for revenge against society following some real or imagined disadvantage), or severe disaffection with employers or colleagues. the u.s. anthrax mail attacks represent just such a case, in which anthrax spores alleged to have been deliberately removed from a u.s. government defense research facility by a government scientist were used to carry out indiscriminate attacks against the general population. although extremely rare, this event is likely to have had a major impact on the public perception of scientists engaged in defense-related research and their motivation. scientists have an image problem. the charming and charismatic scientist is not an image that permeates popu lar culture. although it is common for the entertainment industry (and news media should be included in this category) to portray professions such as medicine, law, and journalism as exciting and glamorous, scientists are often depicted as unattractive, reclusive, socially inept white men or foreigners working in dull, unglamorous careers on projects that could destroy the world. indeed, there is evidence that this impression may be imprinted in childhood and once established is difficult to modify. the reasons for this stereotyping are complex but can be broken down into two main areas: a failure to grasp the nature of the scientific process on the part of the public (education) and a failure to present their message in an accessible manner on the part of scientists (communica tion). these tendencies are compounded by an understandable desire on the part of the entertainment industry to produce content that is popular and profitable. the issue of how our children are taught basic science is an area of obvious concern, as highlighted by the observation that approximately % of adult americans do not understand the scientific process and have to depend on others to help them understand the signifi cance and consequences of scientific advances. in the advanced economies, the major source of information is television, whereas the internet (another unregulated environment) is increasingly used to research specific scientific issues. given the importance of these media in 'educating' and shaping public opinion, how good are scientists at ensuring that their message is getting across? it is safe to say that whatever they are doing, it is not having the desired effect. part of this failure is due to the inability or reluctance of practicing scientists to engage with the media in such a way as to convey their story in a form that is understandable by their fellow citizens. a survey com missioned and funded by the wellcome trust found that the majority of scientists believed that the public saw them as detached, poor at public relations, secretive, and uncommunicative. furthermore, they identified a lack of knowledge and/or interest in science within the general public as a major barrier to communicating concepts and ideas. most of those questioned believed that they were insufficiently trained to deal with the media; more impor tantly, the majority of scientists surveyed distrust the role of the mass media in communication of their results. the role of the mainstream media and popular press is primarily to entertain their customers and make money. in that light, it is not surprising that there is a tendency to focus on stories and issues that seize public attention. all journalists know that scares make good stories and fre quently generate a momentum of their own that does not require any facts to keep them moving forward. for example, in recent years we have seen the emergence of numerous scare stories in the media (flesh-eating bacteria, falling sperm counts, chlorofluorocarbons, bovine spongi form encephalopathy, harmful gm foods, etc.), many with little in the way of scientific evidence to support them. it is perhaps not surprising, then, that a climate has been created in which the ordinary person regards scientific developments with suspicion, having the under lying assumption that he or she is being put at risk by reckless scientists operating in an uncontrolled manner in their ivory towers. this perception is not helped by hollywood, which provides a seemingly endless diet of disaster films in which dastardly government scientists are either blowing something up or pursuing genetic experiments in a top secret government laboratory to produce new species that could escape and destroy the world. when was the last time a blockbuster film was released in which a dedicated scientist carried out an experiment that did not involve a chiseled-jawed hero saving the day? a further element that may contribute to the public distrust of science is the rise of pseudoscience, which includes topics such as astrology, alternative medicine, yogic flying, and ufos. indeed, it has been suggested that the entertainment industry (e.g., the popular x-files series) is partially responsible for the large numbers of people who now believe in astrology, esp, alien abduc tions, and other forms of pseudoscience that contribute to the scientific illiteracy of the public. against such a cultural backdrop, it is not surprising that the public has little problem in believing that government scientists employed in defense-related research are not to be trusted. as a consequence, scientists, particularly those engaged in research considered dual use, find themselves in an almost impossible position when trying to explain their research and allay understandable fears harbored by the public. so why are members of the public concerned about research sponsored by the defense community? many nations view research into the development of medical countermeasures (mcms) against biowarfare agents as an essential element of risk reduction. although civilian and military populations are equally susceptible to the same biological agents, the relative risk of exposure differs markedly. thus, although there is considerable common ality in the research priorities of each group, some biological threats, such as anthrax and plague, are cur rently seen as being more relevant to the military. in addition, the nature of the work undertaken by the mili tary and the environment in which it operates are likely to influence how and when mcms are administered. for example, the military may consider immunizing troops with a new vaccine prior to deployment as the most effective means of protecting individuals and ensuring operational effectiveness in a high-risk environment. in contrast, the civilian authorities are more likely to treat with antibiotics after an outbreak has occurred rather than vaccinate large numbers of the public against a disease with a very low likelihood of a deliberate release (albeit very high impact), such as anthrax. thus, differences in the relative risk of exposure of each target population are a major driver of the research undertaken by defense scientists. to develop mcms capable of dealing with biothreat agents such as anthrax, there is inevitably a requirement to handle and manipu late these dangerous pathogens, which in turn generates concerns, rightly or wrongly, about the possibility of their inadvertent release or potential misuse (dual use). indeed, these concerns derive partly from the fact that the government-sponsored organizations currently devel oping defensive mcms were engaged many decades earlier in the development of offensive biological weap ons. although this research was discontinued in the s in the united kingdom, there are still concerns, in some quarters at least, regarding the potential for this type of work to be resurrected. when the public's mistrust of politicians and scientists is added to this mix, it is not difficult to understand why people are willing to believe the worst. indeed, the perceived lack of 'public visibility' of defense research further stimulates the public imagination despite the fact that the results of this research are widely disseminated through peer-reviewed journals and at international conferences. the nature of modern research is such that it is rare to find a project that does not require collaboration with academic and/or industry-based part ners, thus ensuring at least some degree of scientific visibility. in addition, the regular inspection of defense research facilities by national regulatory agencies or under the auspices of international treaties is an attempt to alleviate some concerns. openness, combined with inspection by independent scrutinizers, is an important tool in tackling dual-use concerns. if one accepts that defense-related research is war ranted, then how does one justify the development of a new medical countermeasure costing millions of dollars to protect against an event that may never happen? this is particularly important given that any new mcm must first undergo clinical trials in human volunteers to demonstrate both safety and efficacy. this will require the exposure of healthy individuals to an experimental treatment that carries with it the risk of adverse reactions. given that this is a man-made risk, how can this be justified? fortunately, in countries such as the united kingdom, these decisions are taken out of the hand of the defense scientists. indeed, investigators conducting clinical trials need to justify their study to an independent research ethics committee, which determines if any potential health risks to trial participants are justified. a key element in the committee's deliberations is to determine if there is a real-world justification for the new mcm; thus, the committee represents an important reality check. once the study has received approval, it is subjected to further scrutiny at the national level in the united kingdom by the medicines and healthcare products regulatory agency (mhra). each of these layers of control has the power to stop a clinical trial if it is concerned that an ethical breach has occurred and thus plays a key role in preventing inappropriate research. although regulatory scrutiny is vital to prevent harm to volunteers, a further level of protection is provided by the financial realities of drug development. the cost of bringing new mcms to market is considerable, amount ing to hundreds of millions of dollars, and as a consequence, the engagement of the pharmaceutical industry is essential. drug companies are focused on making money and given the relatively small size of the military market will only invest significantly in the devel opment of mcms that could also be used to protect civilian populations. thus, any mcm derived from mili tary research will undergo intensive public scrutiny on route to being licensed and, as a consequence, will be exposed to intense public and financial scrutiny. even when an mcm has been approved for human use, there are still questions regarding its administration to service personnel. for example, should immunization with biodefense-specific mcms such as the anthrax vac cine be mandatory as it is the case for the u.s. army? this raises issues of military governance and consent to treat ment, which can only be dealt with by the relevant law in each country. if new mcms are being developed, there needs to be consideration of the target population in advance of likely use. it would be wasteful for defense research to develop new drugs that would not be accep table to service personnel and would therefore be effectively unusable. public concern regarding dual-use issues and the ethics of performing defense-related research has led to the instigation of a range of checks and balances in the united kingdom designed to reduce risk to a minimum. the effectiveness of these measures is rightly open to public debate, and it is hoped that future scientists, as well as members of the public, will be encouraged to make a full and active contribution to this debate to ensure that future regulatory decisions are based on evidence rather than driven by popular misconception. biological material with the capacity to cause harm can be found in a range of different institutions (hospital, aca demic, pharmaceutical, and government establishments, both civilian and military). potentially, such organisms could be released into the environment following unfore seen accidents, due to negligence, or by deliberate intent. however, experience to date shows that the actual like lihood of human infection as a result of deliberate or accidental release is vanishingly small, particularly com pared to that of contracting infections naturally or suffering harm from other types of accidents or being the victim of a criminal or terrorist assault of some kind. the disproportionate fear that the threat of such infec tions arouses in the general population reflects a lack of understanding of the nature of risk, hazard, and proba bility, coupled with an understandable tendency of the popular media to exaggerate the impact of rare or ima gined spectacular events. the research undertaken in organizations in which microorganisms can be found has produced results of enormous benefit to human society in terms of improving health outcomes (better sanitation, advances in medicines, and vaccines) and increasing safety and efficiency of food production. future developments in biotechnology hold the promise of major benefits to humanity in such diverse fields as mitigating the impact of climate change, improv ing agricultural yields in poor areas of the world, synthesis of novel materials on an industrial scale (e.g., biofuels), and the discovery of cures for major scourges such as tuberculosis and malaria. how do we balance the enormous potential for good that biotechnology offers against concerns regarding its misuse? in the united kingdom, the vast majority of microbiological research is performed in civilian organi zations, with only a very small fraction being conducted by defense laboratories. research activities in defense and civilian facilities in the united kingdom are carefully regulated by a number of statutory bodies such as the health and safety executive, which monitors studies involving genetically modified organisms, and the home office, which oversees experiments involving animals. clinical trials involving human volunteers are regulated by the mhra and are overseen by research ethics com mittees (which are themselves approved by the uk ethics committee authority). however, more regulations, such as intrusive psychological profiling of staff working in microbiological laboratories or heavy-handed, overbear ing, rigid assessment programs of scientific staff to 'ensure' reliability, are unlikely to further reduce the probability of an already extremely unlikely event. rather, they are more likely to alienate well-motivated staff, thereby sti fling research and the development of products and techniques that could bring major benefits to the united kingdom and humanity as a whole. indeed, fostering a supportive community among well-rewarded and appre ciated scientists and staff would make it much easier to detect early signs of unhappiness, social problems, or the unacceptable behavior of individual researchers. such an approach would also be expected to produce better scien tific outcomes. the role and responsibility of scientists is central to minimizing misuse of technology, and thus it is vital that life scientists are encouraged to take ownership of this problem and in doing so assume a more proactive role in regulating, communicating, and explaining their activities to the wider public. unfortunately, to date, the majority of scientists have demonstrated a marked reluctance to fill this role for the reasons outlined previously. it has been suggested that improved education of scientists, the media, and the public would go some way toward addressing this issue. improving the aware ness of scientists could take many forms, such as the inclusion of teaching material covering biosecurity and dual-use issues into the curriculum of all life science undergraduates and in seminars, conferences, and pub lications dedicated to the subject. scientists, particularly those engaged in areas of research that have the potential for misuse, must be encouraged to communicate the nature of their research as widely as possible to their fellow citizens. the most obvious vehicle through which to achieve this aim is the mass media, which is in a position to be a creative and positive influence in bring ing scientists and the public together around these issues. it has the capability to improve communication and understanding, reducing unwarranted fears and sensa tionalist reactions to imagined threats. how we achieve this utopian dream in the face of the economic realities of a / multimedia society is a question beyond our powers. the committee for skeptical inquiry uk -the health and safety executive les baillie is a professor of microbiology within the welsh school of pharmacy of cardiff university. prior to joining the university in , he was director of the biodefence medical countermeasures department based at the naval medical research center in washington, dc. in this role, he led a multidisciplinary team developing novel therapeutics to combat the threat posed by biothreat agents. this research built on previous experience gained at dstl porton down, where he led a research team working on anthrax. having worked in both government defense and academic laboratories on two conti nents, he has a unique insight into the challenges faced by life scientists engaged in research in this area.dr. hugh dyson is a principal medical officer at dstl porton down. he has previously worked in the national health service and academia, holding posts in renal medicine and pharmacology.dr. andrew simpson is a clinical microbiologist at dstl porton down. he has previously held posts in the national health service and academia, and he worked for many years in thailand at the mahidol oxford tropical medicine research unit. key: cord- -e mr kqb authors: adler, nicole; gellman, aaron title: strategies for managing risk in a changing aviation environment date: - - journal: journal of air transport management doi: . /j.jairtraman. . . sha: doc_id: cord_uid: e mr kqb abstract given the increasing volatility in the economic performance of airlines, partially reflecting the dynamics of demand for air transport and the fixed costs associated with the industry, all stakeholders need to consider appropriate strategies for better managing the risks. many risks were identified in the literature previously, some even decades ago, however most have yet to be satisfactorily addressed. urgency is growing. removal of the remaining barriers to competition at all levels, congestion management, open skies policies across continents, computer-centric air traffic management systems and increased research and development into the processes and technology needed to reduce environmental externalities remain among the top challenges for the next decade. the aviation industry is entering a new era in part due to two major issues. the first issue involves the increasing interest in the perceived environmental damage caused by transportation in general and by aviation in particular. the second issue involves the impact of multiple exogenous shocks such as the financial meltdown of as a result of which the aggregate airline industry profits of the past seventy years, which were admittedly marginal, were completely wiped out. fig. presents the data drawn from the air transport association ( ). the variability of the exogenous shocks on airline demand levels has been increasing at a rapid pace hence the need to develop strategies for all stakeholders in the aviation sector. a major risk to the sustainability of the aviation system is that legal principles rather than economic rationality will prevail such that competition and good managerial leadership are swamped by market distortions. understanding the markets, removing barriers to both entry and exit and encouraging competition on all links of the aviation sector leads to innovation and internalization of the inherent risks of volatile demand, economic cycles and climate change. deregulation in the airline sector led to the development of a new breed of carriers that has in turn increased consumer surplus. corporatization and privatization of airports led to a substantial increase in alternative revenue streams at airports which improved both producer and consumer surplus. on the other hand, distortionary subsidies given to airframe manufacturers led to the development of aircraft that are not financially viable, such as concorde and the a (gellman et al., ) . in this article we discuss potentially fruitful strategies that may aid the airlines, airports, airframe and engine manufacturers and their first tier suppliers as well as those bodies governing the industry. these strategies need to provide a cushion whereby companies can reasonably handle the risk of fuel price instability, the introduction of carbon cap and trade regulation, the need to finance airport infrastructure, air traffic management systems, aircraft and other assets, the competitive inequalities drawing from subsidies across the globe at various levels of the supply chain and the effects of increasing ad-hoc consumer protection laws. the industry is dynamic and in returned to growth. pro-active strategies are needed to ensure that further growth is viable in an economically, politically and environmentally sustainable manner since the alternative will involve regulation and a reduction in overall social welfare and mobility. most airlines provide a scheduled service over which supply and demand must be carefully balanced, especially in light of the exogenous shocks that have substantially impacted demand in the short to medium term such as the explosion of the dot-com bubble in , the security implications of september th , the severe acute respiratory syndrome outbreak in and the united states housing price bubble of that led to the current recession felt in many parts of the world. the effects of these downturns will continue to be felt at airlines that fail to adopt a plan to replenish, upgrade and perhaps increase their fleet in order to account for the longer term, underlying growth pattern that is likely to transpire over time. good management would appear to be one of the most important elements of building and maintaining a successful airline and prudent aircraft purchasing decisions are at the epicenter of this approach (tretheway and waters, ; government accountability office, ) . furthermore, management must consider direct risks to the supply side, including for example the future price of fuel as well as the pricing and/or regulation of environmental externalities such as global greenhouse gas emissions, local air pollutants and noise. this section first discusses the issues of managing a heterogeneous customer base and the life cycle of the airline market in section . , the issues of achieving profitability in section . , the approaches to handling competition in section . and the remaining supply side strategies in section . . aviation is often treated as a discretionary service in comparison to other forms of transport such as daily trips to work, which leads to volatility and seasonality of demand. however airlines do provide mobility which is unique in longer haul markets and spans heavily business oriented destinations (e.g. belgium and shanghai), almost purely touristic hotspots (e.g. hawaii and las palmas) with the majority of origin-destination pairs a mix of the two to varying degrees. overall growth in demand has been decidedly positive over the longer term in line with the different stages of maturity of the industry around the globe and the respective income levels. business travel demand appears to be shrinking which is a process that began as far back as (mason, ) and has continued as a result of the current financial crisis, with companies searching for alternative forms of communication or at the very least, economy class tickets (cobb, ) . consequently, airlines need to encourage business passengers to move to the front of the cabin by maintaining frequency where reasonable, improving frequent flyer programs and attracting long term corporate travel agent agreements. the standard scheduled carriers have lost some business demand to the business jet market, although this is obviously limited to the extremely time constrained with a substantial willingness-to-pay (mason, ) . private aircraft and related traffic have so far avoided most of the security regulations that the legacy and low cost carriers must handle, which contributes a reasonable amount of additional time to a trip particularly in the shorter haul markets. leisure travelers choose holiday purchases given their discretionary income levels which have been reduced since . this passenger type is the most price sensitive, which has encouraged airlines to unbundle their product, providing the airlines with the ability to further price discriminate whilst arguably allowing passengers greater choice (brons et al., ; clemons et al., ; bilotkach, ) . airlines must utilize their existing staffing levels and fleet of aircraft at least in the short term, which has led to a heavy reliance on revenue management technology. the heart of the airline business lies in attracting the two consumer types, namely the business passenger interested in high levels of frequency and less so the airfare as compared to the leisure passenger who places much greater emphasis on fares (proussaloglou and koppelman, ; adler, ; adler et al., c) . ignoring one type at the expense of the other would appear to be extremely perilous. despite the high margins on business travel, a scheduled airline model catering specifically to this type of consumer does not appear to be viable, see for example maxjet, eos and silverjet, pure business class airlines serving transatlantic routes, all of which filed for bankruptcy in . one of their major issues were the problems of connectivity, as none of the airlines developed a web of interline or codeshare services which is so important to beyond or behind gateway travel (holloway, ) . charter carriers serving the pure leisure market also appear to be a waning business model as the low cost scheduled carriers take their place in maturing airline markets (gillen, ) . for scheduled service, the high frequency demanded by business consumers can only be served if the remainder of the aircraft is filled with a sufficient number of passengers willing to at least cover the marginal cost of the seats. relatively high frequency ensures a disproportionately higher market share (swan, ; belobaba, ) which is only worthwhile if the yield at the very least covers the average costs of the flight, including the cost of capital. airlines in the more mature, standardized markets achieve competitive advantage through lower costs. it may also be true that on longer flights (more than five hours), passengers are more willing to pay for additional comfort which would permit the differentiation strategy to survive and prosper. strategies also need to match the life cycle of the market in which they exist. until now, airlines have placed extreme emphasis on maintaining or increasing market share rather than profit potential and origin-destination yields. it would appear that the american domestic market, currently the largest aviation market in the world, has achieved a level of maturation such that market growth is flattening out. whilst the european union is moving towards saturation, the south american, far east and intercontinental markets are all a long way from maturation. furthermore, the african and middle eastern markets have yet to begin their exponential growth rates (swelbar and belobaba, ). consequently, low cost strategies in the united states and european union domestic markets appear to be the most profitable strategy given the current market life cycle, whereas the differentiated strategy would appear to be more profitable on the intercontinental routes and in regions that have yet to develop their markets more fully. it is extremely important for airlines to analyze the markets not as short-run revenue maximizers rather as long-run profit maximizers, in which case the reasonably substantial fixed costs would be covered such that a normal return on capital could be achieved. gillen ( ) argues that the legacy carriers focus on profitability at the network level rather than individual links which has lead to managerial myopia, excessive network size and severe price discounting. tretheway ( ) argues that the low cost carrier pricing policy differs subtly but importantly from that of the legacy carrier revenue maximization procedure. whilst the low cost carriers require all flights to fully cover allocated costs thus ignoring the issue of transfer passengers, the legacy carriers separate the decision making apparatus such that in the first stage, capacity choices are made and in the second stage, yield management systems maximize revenue given the first stage decisions. this separation in decision-making reduces the pricing policies to short term decisions which has resulted in declining yields and a failure to cover the capital costs needed to replenish a fleet. proussaloglou and koppelman ( ) analyze air carrier demand and demonstrate that new carriers with limited frequent flyer programs must provide substantially lower airfares or a superior level of service in order to compete effectively with incumbents. however, the recent erosion of the gates required to ensure successful revenue management models has left the legacy carriers with a reduction in fare classes, for example as a result of the disaggregation of return fares into single unidirectional tickets that has occurred due to low cost carrier policies (cobb, ) . following porter's competitive strategy approach ( ), we argue that the likely market outcome that would permit airlines to achieve long run profitability suggests that low cost carriers should serve the domestic or regional markets whereas legacy carriers should continue with their differentiated approach on the intercontinental, longer distance routes. this would permit the legacy carriers to reduce the variety of aircraft currently required to serve greatly differing stage lengths, in turn reducing maintenance and training costs and increasing the productivity of the remaining fleet. codesharing across the two business models would be a logical next step and although low cost carriers have not generally participated in interlining or codesharing, examples do exist such as virgin blue and united ( e ) then delta (from onwards) and westjet with southwest for a short period and cathay pacific (from may ). another important set of strategies available to airline managers to better manage risk include choices with regard to interlining, codesharing, joining an alliance or merging with complementary partners or rivals, subject to government anti-trust regulation. interlining became a feature of the airline landscape as a result of the chicago conference held in which permitted an airline to sell a single ticket to a consumer despite the fact that the origin and destination were not directly connected by the carrier, rather passengers would need to change both planes and airlines on the single itinerary. this was advantageous to the consumer who would not need to carry baggage at the connection and was organized between the airlines through the international air transport association (iata). the iata conferences organized the airlines, enabling them to reach pricing decisions per region and to subsequently share interline revenues according to the geographical distance each carrier provided per itinerary. codesharing first appeared in international markets in (gellman research associates, ) . collaboration between airlines was at first designed in order to offer the international passenger a "seamless" travel experience by minimizing some of the inconveniences of traditional interline itineraries. benefits to consumers of codeshares over interline itineraries include agreements on standardized levels of service, access to airport lounges and frequent flyer programs. for the suppliers, codeshares based on block space or free sale agreements encourage the airlines to consider the issue of double marginalization but also lead to closer associations and a softening of competition, such that the agreements are a somewhat double edged sword. the transportation research board ( ) noted that % of global alliances include provisions for codesharing, % include provisions relating to sharing of frequent flyer programs and % also include agreements to share facilities such as catering, training, maintenance and aircraft purchasing. the web of codeshares that form the basis of an alliance help airlines to better handle risk, permitting a reduction in capacity during bear markets and faster response to unexpected short-term changes in demand. gillen ( ) argues that along with the development of hub-and-spoke systems, domestic feeds have contributed to the development of international alliances in which one airline feeds another hence utilizing the capacity of both to increase service and pricing. codesharing began as a pure marketing exercise but has now become an important element for both suppliers and customers. the supplier offers a greater network span and enjoys economies of scope and density. consumers avoid the issue of double marginalization that arises when required to purchase two or more tickets from different vendors, enjoy reductions in schedule delay and reduce complications arising from delays particularly on the first leg of an itinerary. adler and hanany ( ) demonstrate that consumer welfare on thin origindestination markets is higher with code-sharing airlines than purely competing carriers. consequently, codesharing increases the level of service provided to the consumer. aviation should develop into an industry in which reasonable levels of profit are achievable throughout the economic cycle. under the current regulatory regime, cross-border mergers are not permitted since foreign ownership rights are curtailed to varying degrees, except in the australasian domestic markets. however, as demonstrated in adler and smilowitz ( ) , airlines would always prefer to merge based on economic considerations, drawing from improved cost efficiency and subsequently higher profits. indeed international gateway choice would change were mergers to be permitted. adler and hanany ( ) also demonstrate this point but purely from the demand side perspective whilst the cost advantages are ignored. consumer preferences for higher frequencies and home carrier bias permit airlines to achieve their highest profits under mergers although to some extent at the expense of consumer surplus. airline competition may not always be acting on a fair playing ground which is a sign of supply side risk. airlines in the middle east, including emirates, etihad and qatar, have a growing presence in the aviation markets and enjoy a business environment to which other airlines do not have access. according to o'connell ( ) , emirates enjoys zero corporate tax under the united arab emirate's laws, extremely low airport charges at its dubai hub since the chairman of the airline is also minister in charge of civil aviation governing the airport, an uncongested hub that reduces fuel costs, low labor costs and a labor force that is not permitted to join a union or strike. altogether, this contributes to an estimated % cost advantage over british airways and a % advantage over air france/klm (o'connell, ) . were the middle east aviation market to develop alongside regional stability and liberalization, adler and hashai ( ) predict that cairo and tehran are likely to develop regional hubs with istanbul and riyadh emerging along with the prosperity of the region based on geographic and demographic considerations. current transport investments also suggest that the dubai region is succeeding in its attempt to develop a major hub system connecting the continents of north america, europe, africa, the far east and australasia via the middle east. the growing lack of trained pilots is another issue of note to both airlines and aircraft manufacturers. as the number of unmanned aerial vehicles grows globally (the economist, ), fewer fighter pilots are being trained, leaving an insufficient number to subsequently enter the civilian industry once their military careers are completed. embraer has announced that within the coming decade it plans to build a single pilot certified aircraft (flightglobal, ) and it is likely that pilotless cargo aircraft will be in use within this timeframe as well. we predict that pilotless passenger aircraft are likely to enter the skies within two decades, once the next generation of computer-centric air traffic management systems and avionics enter the market. in the meantime, the burden to push for increased funding of pilot training appears to lie on the shoulders of the pilots association and trade associations, such as the air transport association and regional airline association. finally the climate change debate is gradually pushing all sectors of society to measure, manage and subsequently reduce their carbon footprint. the aviation sector is slowly feeling this pressure too with new zealand and the european union at the vanguard of this process. the pressure on aviation has more to do with the prominence of air travel in society today than with the real contribution of aviation to global warming, since trucking and cars are a far more important contributor. new zealand introduced an emissions trading scheme (ets) in that extends only to domestic flights and can be applied to either the petroleum supplier or the airline. the new zealand government intends to reduce carbon emissions to levels. scheelhaase et al. ( ) discuss the likely impact of the european union (e.u.) emissions trading scheme currently expected to begin implementation in january , which is to be applied to both domestic and international flights. scheelhaase et al. argue that the e.u.-ets will probably provide a competitive advantage to non-e.u. carriers whose short-haul, less environmentally efficient flights are not within the e.u. jurisdiction. forsyth ( ) argues the opposite by suggesting that the free permits would provide a financial advantage to those receiving them, although the impact is not expected to be substantial. the question then remains as to whether other regions of the world will follow suit and set up emission trading schemes or introduce carbon taxes in order to internalize the environmental externalities. in addition, various individual airports have gradually introduced night flight curfews and noise charges as well as local air pollution charges covering both nitrogen oxide and hydrocarbon (scheelhaase, ) over the past decade. governments need to decide whether they are interested in dampening demand to reduce global warming or push for innovation such that each flight pollutes at lower levels hence permitting "green growth". if the latter has a greater priority, then subsidizing research and development in this area is a necessary and currently underutilized component. finally, it would probably be extremely beneficial to the various players in the aviation supply chain were the economic instruments chosen, whether restrictions, charges or taxes, to be applied equally across the globe and in a harmonized manner. airports have been changing as a result of privatization and corporatization, the deregulation of airline markets regionally and inter-continentally and the development of the low cost carrier model which demands different services from the secondary airports that they generally serve (deneufville, ) . airports in many parts of the world are no longer viewed as public utilities rather as private enterprises aiming to maximize shareholder value and profits from a fixed facility (adler et al., b) . the trend to privatize airports began in the united kingdom in with the flotation of the british airports authority, a company that owned and managed seven airports, three of which were located in london. the recent forced sale of gatwick airport has the intended aim of encouraging competition among the airports of london. within the london catchment area, baa now owns and runs heathrow and stansted, global infrastructure partners owns and runs gatwick and london city whilst luton is owned by the local council and run by a private company. as airports have required infrastructure investments beyond the budgets of local and federal governments, the airports have gradually been privatized in europe, south america, south africa, asia and australasia. perhaps surprisingly, airports in the united states are owned either at the state or local authority level and are operated by divisions of municipal governments or airport authorities. however many of the sub-processes at american airports are managed by private companies and a mere e % of the employees on the airport site are directly employed by the government authority (deneufville, ) . until the s, much of the investment in airport infrastructure drew from the airport improvement program, a federal aviation authority based fund. the fund has gradually reduced in importance, particularly at the larger hub airports, and has been replaced with direct passenger facility fees and the issuing of bonds often underwritten by the relevant hubbing airline (odoni, ) . whilst many airports remain natural or locational monopolists, for example in small countries with little to no domestic traffic, others operate in competitive markets as a result of the deregulation of both the airlines and airports (starkie, ) . tretheway and kincaid ( ) define airport competition to include local demand located in overlapping catchment areas e.g. multi-airport cities, connecting traffic served by hubs, cargo traffic, alternative modes and destinations. barrett ( ) argues airport competition is a new element of european aviation as a direct result of liberalization, whereby airports within one hour ground surface access are in direct competition for their respective catchment area, as occurs in multiple cases in france, germany and the united kingdom. hooper ( ) argues that governments in asia may rely on competition to impose a significant degree of discipline on airport managerial behavior. adler and liebert ( ) demonstrate that competition for connecting passengers and/or over catchment areas appears to be sufficient to encourage cost efficiency independent of ownership form or economic regulation. however, apart from australia and new zealand, airports around the world remain price regulated. according to fu et al. ( ) , the light handed regulatory approach of australasia in which price monitoring replaced formal regulation has not been successful, mostly due to the lack of competition inherent in a system with large distances between airports. consequently, it would appear that competition is sufficient to ensure that airports are cost efficient but without it, independent of ownership form, some form of economic regulation is necessary. such regulation would reduce the likelihood of litigation as has occurred on multiple occasions in australia with virgin blue, currently the second largest australian airline. adler and liebert ( ) also demonstrate that privatized airports operating in a competitive environment may still require economic regulation in order to avoid excessive pricing in comparison to their unregulated, public counterparts operating in a similar environment. strategies for airport managers therefore need to account for ownership form. in section . we discuss strategies for the shorter term timeframe and in section . , we discuss size and pricing policies relevant to the longer term issues identified. in the short term, airport managers may be interested in maximizing variable factor productivity, given a fixed airport capacity. this is particularly true for privatized airports and those who are price capped under an inflationary less efficiency formulation which permits the airport to retain productivity gains beyond the minimum level required by the regulator. variable factor productivity includes labor, supplies and materials and outsourcing costs and quantities, given passenger and cargo throughput, air traffic movements and non-aeronautical revenues. shorter term decision making includes searching for a balance between in-house production and outsourcing activities. partial analyses of subprocesses such as baggage handling and passenger flow through terminals may also help managers to highlight bottlenecks in the system. benchmarking good practice is crucial to effective management and public disclosure requirements, an approach adopted in britain and australia (hooper, ) , is an important missing link in encouraging productive efficiency. a uniform system of airport accounts similar to that of the international civil aviation organization (icao) airline reporting practices would be helpful to both airport managers and regulators alike. indeed, there are no generally accepted accounting practices even for airports within a single country which means that the capital input mix cannot be analyzed. the academic literature contains many potentially useful methodologies for benchmarking processes, such as stochastic frontier analysis (oum et al., ; and data envelopment analysis (sarkis and talluri, ; adler et al., b) which could be applied were comparable data to be made available. transparency in data collection would also encourage analyses of dynamic efficiency which is extremely important in an industry with lumpy and large fixed costs. in the medium term, uncongested airports with low capacity utilization need to reduce their asset base and/or increase their customer base. to attract greater output, either in terms of passengers or cargo, may require offering lower charges for new destinations served for the first couple of years of service or unbundling the airport services, thus permitting airlines to choose varying levels of service according to their desires. congested airports require different managerial policies including expanding capacity at the margin wherever bottlenecks are identified and incentivizing airlines to use off-peak slots through pricing. the icao governs the rules for landing fees on all international flights and requires that charges do not exceed the full cost including a return on capital which is needed to provide the facilities and services. a revenue neutral congestion pricing policy would remain within the guidelines of the icao and may result in negative prices for off-peak air traffic movements but this should improve capacity utilization without being discriminatory. alternatively, larger planes could attract price reductions which again would provide incentives for airlines to maximize capacity utilization in line with social welfare optimization. additional medium term strategies include actively identifying ground access improvement opportunities, such as high or higher speed train service, or improved road access which may widen an airport's catchment area. the longer term issues are the most difficult to solve since they generally require capacity expansion or reduction, both of which are very difficult to undertake. barriers to expansion include political interests, noise and environmental restrictions, the time and expense involved in receiving planning permission, not in my backyard syndrome and the lack of active management interest, likely to be more relevant at public airport authorities. in addition, there are sufficient examples of airports who undertook the risk and expense of expansion only to be underutilized afterwards, such as the city of dayton that decided to build a hub at the behest of u.s. air which then drastically reduced its services. american airlines behaved similarly at raleigh and nashville and, after acquiring reno, left san jose airport in the lurch to a large degree. in order for an airport to be cost efficient, it is necessary to utilize resources carefully, which generally leads to congestion and the need to deal with this issue fairly with respect to passengers, airlines and the environment. the toughest issue for airport managers is the lack of signals inherent in a system whereby congestion and delay are not priced. the lack of congestion pricing incentivizes airlines to increase frequency and reduce aircraft size even during peak periods. indeed, the trend in airplane size in the united states has been on the decline since because smaller aircraft achieve shorter turn-around times hence higher utilization, consumers value higher frequency which is reflected in airfares, smaller aircraft produce marginally lower levels of noise which is relevant at hub airports with aggregate noise constraints and congestion pricing which is missing from the equation (swan, ) . without peak pricing in the united states or scarcity pricing in europe under the slot allocation system, from where do the signals come to expand or define optimal capacity levels? as levine wrote in , the existing pricing system fails to guide investment so as to achieve the appropriate mix and level of output with a minimum investment of resources and the same could be said today. congestion pricing and the direct valuation of slots would appear to be strictly preferable to the current system of rationing defined in the form of slot allocation regulation in europe and department of transport brokerage in the united states (johnson and savage, ) . one could argue that were congestion fees collected for the transparent purpose of building or expanding specific bottlenecks at an airport, such charges would indeed be in line with the icao policy mandate. slot allocation policies exist to ensure that delays in air transport are not excessive and appear to be effective when comparing american and european delay outcomes (forsyth, ) . indeed, the lack of slot allocations at american airports has led to the development of a ground delay program operated by air traffic management through the federal aviation administration (faa). however, the bartering involved with this system prevents new entrants from entering congested airports hence provides an economic advantage to legacy carriers. adler et al. ( a) discuss the slot allocation issues in the greater tokyo region which permit the producers to extract surplus from consumers, to the extent that an aggressive low cost carrier is not capable of increasing competition either domestically or regionally. czerny et al. ( ) summarize much research that promotes the use of auctions as an alternative form of scarce resource allocation, however it is rather unlikely that the incumbent airlines would readily agree (see sentance, for an incumbent airline's response). the lack of clear legal ownership with respect to landing rights is an issue that needs to be solved in order to allow airports to efficiently match supply with demand. permitting slots to become a tradable asset would substantially improve the capacity allocation issue although regulation would still be necessary in order to ensure that airports are not reregulating the airline sector. whilst slot allocation is not an issue in the united states where a first come, first served policy exists, gate allocation acts as a barrier to entry instead (dresner et al., ) . gate allocations in the united states are often accompanied by a e year lease contract in order to allow airports to issue bonds that fund the expansion. despite deneufville's ( ) argument that the collaborative approach in the united states has led to a better airport system than other areas of the world, controlling access to busy airports acts as a barrier to entry for airlines, which severely curtails competition and the positive impacts of deregulation. over time, many airframe manufacturers merged, exited or failed to the point that two major markets remain; large airframe and regional jet manufacturers. the large airframe market currently consists of two firms, the european airbus and american boeing companies. the duopolists have chosen to compete headon, with each firm producing a range of aircraft in direct competition, such as the a and boeing - , the a and b and later variants of the b , and the smaller a with the b . to some extent the b is also in competition with the a over certain routes. for example, in the american-japanese market, the a may well serve the jfk-narita hub-to-hub market given the level of congestion at both airports whereas the b may serve the jfk-nagoya or newark-nagoya market as a way of avoiding at least one major hub and providing improved service to passengers through a direct itinerary. in the regional jet market, brazilian embraer and canadian bombardier are the two major players but they may be competing with manufacturers located in russia, japan and china shortly. small airframe development has benefitted from subsidies to customers in the form of low interest loans from their respective governments in order to support development of aircraft of up to seats, despite and world trade organization (wto) rulings that this should not continue. recently bombardier, which is subsidized by the canadian government, announced the development of their c series which will ultimately accommodate seats. in an unusual move, airbus and boeing joined forces and jointly argued before the wto that such financial subsidies should be limited to seat capacities, if not stopped entirely. however, both the japanese and chinese governments provide subsidies to companies developing aircraft components within their respective borders that encouraged outsourcing by both airbus and boeing. another form of subsidy occurs when new aircraft require a change in the capabilities of airports and the cost is borne by the airports rather than the relevant airframe manufacturer. in the 's, mcdonnell douglas began producing the dc - but the conditions for sale were that the new york airports could accommodate the aircraft, which required strengthening the taxiways and widening the runways. the new york airport authority argued that the costs involved were prohibitive and the mcdonnell douglas company, after reducing the costs through a radical redesign, paid for the changes necessary. multiple airports are currently under expansion in order to accommodate the a , but these costs are being borne by the airports, which represents a distortion in the airframe market. clearly, subsidies are unlikely to disappear despite wto rulings and it would appear that the more appropriate policy would be to encourage discussions and reach agreements across countries in order to limit the imbalance such distortions create. an example of the results of such discussions includes the e.u.-u.s. agreement that calls for a critical project appraisal before permitting any subsidization of the research and development of airframes. the agreement called for the repayment of direct government support over a period of years beginning from the date that the first state aid was received. however, as argued in gellman et al. ( ) , such an appraisal of the a was never undertaken and had this been the case, it is unlikely that the aircraft would have been produced. hence, it is insufficient to reach such agreements unless a legal entity exists that can uphold the clauses therein. other expensive inputs such as the engines and avionics are manufactured by various companies located in europe, south america and north east asia. in the parts market, under current american regulation, the original equipment manufacturer controls the supply of parts for aircraft still under production. alternative producers do not receive faa approval and their parts are tagged with the negative connotation of 'bogus' parts. a similar situation occurs with engine parts but in this market, alternative producers have tried to receive approval from the faa on the basis of 'functional equivalence'. to date, functional equivalence has not been approved and the spare parts market is limited, ensuring high mark-ups which inflate airline input costs. since the american policy with respect to the parts approval process is emulated globally, this issue crosses borders. we would argue that if a comprehensive functional equivalence test can be developed and the testing was undertaken by an independent agency, providing approval for these parts would break the current stranglehold in this first tier market. another major risk to the aviation sector is the continuing fluctuations in the price of oil. it is unlikely that a battery powered aircraft engine will be developed in the near future due to issues with the weight and size of the batteries available under current technological capabilities. consequently, aviation is likely to continue to be dependent on oil for the foreseeable future. two types of government action may be helpful in this regard. first, it would appear to be important to begin regulating oil speculation in order to prevent oil upside spikes that caused the massive changes in the price of oil inputs mid . second, were the united states, united kingdom, france, germany and japan to agree, it would be possible to break the stranglehold of the opec cartel on current oil prices. the current price of jet fuel has little connection to the cost of production. the relevant governments could restrict oil imports if prices were deemed unacceptably high. independently, these governments could subsidize research and development into new, cleaner technologies that would encourage universities and the private sector to explore ways of reducing greenhouse gas emissions. current promising avenues include the use of lithium aluminum or composite materials to reduce the weight of the aircraft and the development of alternative fuels, such as bio-fuels which reduce carbon dioxide based on the full life cycle approach. government funding, such as the european union's clean sky joint technology initiative, appears to be necessary at this point in time due to the high risk involved in this research. it is not yet clear whether camelina or algae have the potential to be grown in sufficient quantities to serve the market for bio-fuels without displacing land needed for food production. finally, operational research and development could encourage air traffic management systems to search for greener routings and manufacturers to further improve aerodynamics and engine efficiency. noise remains a major issue, particularly in regions with high density populations such as europe and asia but also at out of the busiest airports in the united states (girvin, ). there are examples of airports for whom capacity restrictions are defined by noise regulation rather than their physical capabilities such as schiphol. brueckner and girvin ( ) argue that continuing to limit cumulative noise at airports or equivalently, to charge a noise tax, pressures stakeholders to attempt to mitigate the issue hence maximize social welfare. swan ( ) argues that the use of smaller airplanes is preferable with respect to their noise output than an equivalent number of seats on larger aircraft. clarke ( ) calls for automated air traffic management procedures which would improve noise abatement measures beyond the impact of improvements in individual aircraft. clearly research and development needs to consider all elements of the aviation sector. two initiatives are currently being funded including nasa's 'quiet aircraft technology' program financed by the american government and the silent aircraft initiative undertaken at the cambridge-mit institute together with industrial partners, mainly funded by the british government. due to the trade-offs between reductions in local air pollution, noise in the vicinity of the airport catchment area and global greenhouse gas emissions affecting climate change, one of the major tasks of the new decade will be to strike the correct balance. in this section, we discuss the risks that exist within each of the links of the aviation industry and the potential strategies available to regulators to counteract the issues. we discuss the on-going process of deregulation of the airline markets in section . , the conditions under which airport regulation continues to be a necessity in a gradually privatized and corporatized airport industry in section . and the issues arising as a result of the changes in ownership form of the air traffic control sector in section . . over the history of the aviation industry, both airlines and airports have been heavily regulated and subsidized. in the united states, airlines have always been in private hands but until deregulation in , the civil aeronautics board chose the carriers to serve specific markets and their respective airfares. after deregulation, american carriers were free to fly wherever they chose in domestic markets but international services remain regulated according to reciprocal bi-lateral agreements. the american government has gradually opened the skies by encouraging multilaterals which led to the horizontal open skies agreement with the european union in , effective as of . however, american airlines are still protected through the standard chapter bankruptcy proceedings under which airlines restructure their debt and operations but continue to serve their markets (button, ) . whilst chapter proceedings are not specific to the aviation sector, the impact of this law is to produce an effective barrier to free exit from the market. in the european union, most airlines were defined as flag carriers up to deregulation in the third package of in which airline subsidies, which had been quite substantial up until that point, were no longer deemed acceptable. whilst there remain a few state owned airlines, such as olympic and tap, the majority of carriers are now in private hands. the european union and individual countries have permitted airlines to fail, for example sabena and swissair, however other airlines continue to survive due to either protectionist international bilateral agreements or subsidies, as has occurred in the cases of olympic and alitalia. the domestic chinese airline market has been gradually deregulated with china eastern airlines listed on three stock exchanges in , marking the beginning of the process. in there was a wave of airline consolidations resulting in the emergence of three large airline groups; air china, china eastern and china southern with major hubs in beijing, shanghai and guangzhou respectively (zhang and round, ) . however, the chinese skies remain relatively closed as the government continues to protect chinese airlines from foreign competition. southeast asian liberalization permitted a wave of new entrants in the early 's although many did not survive the regional economic crisis of (hooper, ) . the world trade organization has placed on their website a geographical tool that demonstrates the level of openness of bi-lateral agreements and awards each country a weighted air liberalization index score based on the level of air freedoms permitted, ownership restrictions, pricing and carrier designations. new zealand and australia receive relatively high scores, the united states is somewhat lower and china's score is close to the bottom of the scale currently. in order to protect airlines on the grounds of security considerations and potential job losses, the united states currently limits all foreign ownership of american carriers to % of the voting shares and at least two-thirds of the board as well as the chair must be american nationals. the european union limits foreign ownership to % of the airline's shares. a second open skies u.s.-e.u. agreement, signed in june but still requiring ratification on both sides of the atlantic, aims to loosen airline ownership and control restrictions reciprocally but as yet the details have not been revealed. in the chinese government began to permit foreign investment in chinese airlines of up to % of registered capital, which has since been increased to %, although foreign owners may not purchase more than % of the voting stock (zhang and round, ) . similar restrictions exist in south america, africa and asia. tretheway ( ) calls for the elimination of foreign ownership restrictions of air carriers and the permission for mergers across borders, arguing that national security benefits do not exceed the economic inefficiencies arising from the prevention of cross-border consolidation. the failure to permit consolidation is likely to result in either further bankruptcies or bailouts. new zealand was the first to remove foreign ownership restrictions on domestic carriers and australia followed suit in . indeed a multilateral open skies agreement (maliat) was signed in between brunei, chile, malaysia, new zealand and the united states in which the nationality clause was replaced with "the principal place of business and effective control" (hsu and chang, ) . as a result of the existing ownership restrictions, airlines currently unable to merge across borders have chosen to develop strategic alliances through the development of a web of codeshares which pools risk and increases network access. it would appear that codeshares have positive benefits for both consumers and producers alike even on parallel links and anti-trust immunity should only be necessary on thin routes (adler and hanany, ) . furthermore, bilateral agreements between two countries appear to be the worst of all worlds, limiting frequency and hiking prices at the expense of consumer surplus (gillen et al., ; adler and hanany, ) . therefore, the most important strategy from the regulators perspective should be to open up the skies through multi-laterals. cabotage, defined as the eighth and ninth freedoms of the air, would be another way to circumvent the archaic ownership rules. conservatism has ruled to date, for example the association of southeast asian nations (asean) have discussed opening the skies regionally for over a decade but still appear to be a long distance from achieving this goal (tan, ) , although the maliat agreement has shown that this is a distinct possibility. deregulation of the airline industry has served to highlight the importance of ongoing ex-post application of normal anti-trust law. to protect the lower prices and higher frequencies that strongly support the argument that the aviation market is better off without regulation (kahn, ) , it is equally important to protect the premise on which competitive markets develop. free entry and exit are the cornerstones of such a policy and prevent market distortions and inefficiencies. however, it would appear that both tenets are ignored in different geographical corners of the world. free entry only occurs if there are neither bi-laterals protecting designated carriers nor restrictions on the freedom to land and take-off at the airport level. within the far east and european union, almost all airports are slot controlled and many are highly congested, both of which present serious barriers to entry. within the united states, slot controlled airports no longer exist, however gate constraints due to high utilization or exclusive use designations are proving to be real barriers to entry (dresner et al., ) . in order to support revenue bond financing of facilities, many of the larger airport operators have required airline tenants to lease gates and counter space for a period of up to thirty years and in some instances, dominant airline carriers have built their own terminals and subsequently retain complete control whether fully utilized or not (cohen, ) . consequently, independent investment in airport gates, restrictions on minimum aircraft sizes during peaks and congestion or scarcity pricing are important policies to be considered. needless to say, the academic literature has discussed replacing the weight based landing charges with peak pricing for the last forty years but so far to no avail. levine ( ) and carlin and park ( ) were among the first to discuss this issue. daniel ( ) developed a bottleneck model and applied it to minneapolis-st. paul airport, arguing that by spreading the peak, the airport could increase air traffic movements by as much as %. a series of papers by brueckner ( brueckner ( , and brueckner and van dender ( ) argued that at least some of the congestion is internalized by hub airlines, namely that which it imposes on itself, however this does not remove the need for peak pricing nor the need to ensure access for potential new entrants. morrison and winston ( ) argue that second-best, atomistic congestion charges would improve social welfare and significantly reduce delays at congested airports in the united states even if internalized congestion is essentially charged twice. schank ( ) argued that peak pricing has so far been unsuccessful, citing three attempts at boston logan, the port authority of new york and new jersey and the british airports authority. his main line of reasoning suggests that implementation is only acceptable and likely to stand in subsequent litigation if the airlines removed from the peak timeslots have the ability to move to an alternative, efficient time, which the american carriers flying into london in the early morning successfully argued was not the case in the subsequent court proceedings, or to alternative airports, which was not available in boston. as starkie ( ) noted, most airports are not necessarily congested rather demand is peaked over the course of a day which is currently not managed efficiently through the weight-based charges but is the current basis for deciding on the need to expand. free exit is the other single most important strategy for governments to consider. ensuring that no company is 'too big to fail' is equally applicable to the airline industry. if chapter and subsidies or bailouts permit airlines to survive rather than be liquidated, the creativity and strong managerial skills that were engendered in this market apparatus will fail. it is important to permit failure and bankruptcy in order to ensure that the best survive and profit with as few market distortions as possible. reregulating the airline industry is a perennial discussion that has been highlighted once again at the initiative of oberstar and others in the united states congress recently (lowy, ) . a government accountability office report to congress in argues that such a move would likely reverse consumer benefits without saving airline pensions, such as those lost during the bankruptcy proceedings at united and us airways in . the report argues that the reduction in prices and increase in flight frequency and competition which have benefited consumers to varying degrees would be derailed by reregulation. poole and butler ( ) argue that the serious problems remaining in the aviation sector draw from the fact that although airlines were deregulated in the united states, neither the airports nor the air traffic management systems followed the same path which has led to serious distortions in the market. tretheway and waters ( ) argue that neither the civil aeronautics board nor price cap regulation would provide the stability that the political leadership is attempting to encourage. if the main aim of the politicians is to increase the levels of competition in an increasingly concentrated market, dresner et al. ( ) suggest that the construction of new gates, alternative provisions that permit gate access to new entrants during peak periods, specifying minimum aircraft size provisions during peak periods and/or peak load pricing policies may be sufficient to increase competition in congested corridors. winston ( ) argues that the use of reregulation to avoid 'destructive' competition draws from the traditional but flawed theory of regulation which assumes that perfectly informed social welfare maximizers are either managing the regulation or running the regulated firms. it is argued that the airline industry appears to oscillate between periods of excessive concentration and destructive competition. the regulator needs to help the industry to find a happy medium in which neither extreme occurs. there is sufficient anecdotal evidence that airlines use hubs, gate access and frequent flyer programs as barriers to entrance, yet the hub-spoke system allows airlines to be cost efficient and serve markets that otherwise would not be served. hubs are likely to continue for the foreseeable future because half the origin-destination traffic in the world is in markets too small to be served directly (swan, ) . however, as opposed to the discussions of excessive concentration being held in the united states congress currently, swan ( ) points out that the united states airline industry has not consolidated over the period of to according to the herfindahl index, despite numerous mergers and bankruptcies. winston ( ) argues that deregulation in multiple industries, including that of airlines, has proven to be positive for consumers, labor and producers, although not necessarily on an equal basis even within a group. consequently, the question remaining for the regulator is how to protect the advantages of deregulation whilst maintaining reasonable levels of competition in city pair markets. removing the remaining barriers to entry and exit, including the independent investment in gates and pricing of slots, will help further the impact so far achieved. finally, consumer protection rules need to be carefully balanced in order to ensure reasonable levels of service and behavior only where producers have been shown to be derelict. examples of such laws include the three hour tarmac rule that passed through congress in . this rule has increased the likelihood of canceling flights due to the maximal $ , fine per passenger were the travelers to be forced to remain onboard the aircraft whilst waiting on the tarmac for longer than the legal limit. in , the european court of justice ruled that passengers on flights delayed for more than three hours are entitled to compensation from airlines as is true for passengers on canceled flights. this begs the question as to whether these consumer rights in fact protect or harm passengers and whether there is a better way to handle congestion. we would argue that the issue of congestion and delay is better served through pricing appropriately rather than court cases or ad-hoc government restrictions imposed after a public outcry through the popular media. the aim of airport regulation is to ensure that airports do not abuse monopoly power, to incentivize airport managers to achieve productive efficiency and to provide the correct signals in the marketplace that would encourage appropriate utilization of the fixed facility. it would appear that all of these issues have yet to be resolved satisfactorily and will be discussed respectively. niemeier ( ) argues that ex-ante regulation should be limited to activities with natural monopoly characteristics. based on the premise that airports enjoy locational monopoly power, economic regulation has been undertaken in various forms ranging from cost based principles or rate of return regulation to incentive based structures. in europe, prices are capped by the relevant civil aviation authority or department of transport, generally for a period of five years, after which a new review is undertaken. the price caps are frequently based on a value that changes according to inflation, for example the retail or consumer price index, less a pre-specified level of efficiency (rpi-x). an airport that achieves levels of efficiency greater than x will reap the cost reductions at least until the next review. asymmetric information between the regulator and airport owners ensures that the review process is both time-consuming and relatively expensive but necessary where competition does not exist. furthermore, privatized airports working under competitive conditions still may require regulation in order to prevent excessive pricing relative to their public counterparts serving under similar market conditions (adler and liebert, ). an additional complication concerns the question of whether the regulation is based on a single or dual till computation because airports produce two revenue streams. on the aeronautical side airlines are charged per landing, based on maximum take-off weight, as well as a seat based fee. the non-aeronautical revenue stream draws from the terminal side in the form of concessions, car parking fees and rents from the development of airport land. niemeier ( ) argues that single till regulation, which constrains overall airport profitability, may represent a first best solution for unconstrained airports provided non-aviation rents are sufficiently high. at the london airports price caps are set per airport and specify the upper level the airports may charge for their aeronautical services, however within this calculation the british civil aviation authority takes into account the revenues that the airport realizes from the commercial side of the business, which represents a single till approach. if the british government was concerned with levels of congestion, this approach is clearly inappropriate (jones et al., ) . according to averch and johnson ( ) , if a company is prevented from fully exploiting monopoly power, there is a clear incentive to cross subsidize competitive offerings from those that are regulated. according to kahn ( ) this is precisely what occurs at a single till, regulated airport and the solution is to sever the link between the revenues and costs associated with the airside from the revenues attainable on the commercial side. in the united states, airports are viewed as notfor-profit, public utilities and their pricing mechanism is based on cost recovery using a residual, compensatory or hybrid cost pricing approach. consequently, this system does not require price regulation which appears to be advantageous. however, airports who do achieve profitability must then reinvest the revenues into the airport whether necessary or not. the residual cost approach that is more likely to arise at a hub in effect restricts airports to the equivalent of a single-till regulatory system which appears to be less appropriate for congested airports. jones et al. ( ) argue that all airport services should be regulated because the airports enjoy monopoly presence in many markets including terminal side car parking services as well as airline related services. reductions in the costs of services applicable to consumers directly, such as car parking, would stop the cross subsidization from commercial to airside activities and the consequent transfer of consumer surplus to the producers. fu et al. ( ) argue that airports enjoy substantial market power due to low price elasticity on the aeronautical side which may be moderated by the vertical relationship between the airport and hubbing airline. in summation, dual-till regulation is preferable to the single till form at congested airports both in terms of encouraging productive efficiency and ensuring sufficient investment in infrastructure (oum et al., ) . starkie ( ) argues that rpi-x price cap regulation encourages productive efficiency provided the airport acts as a profit maximizer rather than monopolist, however the same style of regulation also encourages excessive investment as defined in the averch johnson ( ) effect. consequently, we would argue that dual till economic regulation is preferable with separate price caps on aviation and commercial services, restricted to only those activities over which airports enjoy monopolistic rents. another important issue for regulators concerns the need to ensure optimal capital investment in an industry with large fixed costs. the current pricing policies at airports do not provide the signals necessary to evaluate the need for capacity expansion or reduction. barrett ( ) argues that there is no reason to assume that privatized airports are more likely to under-invest in infrastructure rather that this is more likely to occur under monopolistic regulatory conditions that restrict output below competitive levels, as indicated by the level of congestion that occurred under the traditional organization of airports prior to liberalization. however, basso ( ) argues that social welfare maximizing public airports subject to a budget constraint are strictly preferable to unregulated profit maximizing private airports because the latter would overcharge for congestion leading to excessive traffic contractions. martin and socorro ( ) argue that a private, congested airport does not require price regulation provided the regulator ensures an appropriate capacity investment under which private and public objectives coincide. cost plus regulation leads to over investment in either capacity or quality which leads to an unnecessarily expensive airport due to the spiraling regulated asset base cost issue. since governments are frequently interested in stimulating economic activity, incentives may exist that encourage over investment (forsyth, ) . whilst cost based regulation may lead to over investment, incentive based regulation may lead to under investment in which case the regulator then needs to consider an investment incentive mechanism as a counter balance. swelbar and belobaba ( ) argue that the lack of infrastructure capacity at airports and air navigation service provision enroute are two of the most critical issues facing international and national air services today. odoni ( ) argues that airport access is becoming the new form of market regulation that distorts the competitive outcome so sought after by many countries around the world. one of the major issues with regulation and optimal investment in airports lies in the mismatch between regulated price caps which are normally set every five years and the lifetime of an investment which may be closer to fifty. privatized airports will be willing to invest only if they are reasonably sure that they will cover their investment costs. carrier-served airports in the united states are defined as not-for-profits which allows them to receive infrastructure grants through the airport improvement program but as the funds are drying up, taxes on passengers, i.e. the passenger facility charge added to airfares, and bond issues cover the remaining costs. consequently, irrespective of airport ownership, the timing of capacity expansion will always be an issue unless the pricing policies change, permitting the market to signal the need for expansion through congestion and/or slot pricing mechanisms. air traffic management is another link in the system that requires change in order to prevent further restrictions on airline service. air traffic management is generally supplied by government entities although there are a few notable exceptions such as navcanada, where this control is now in the hands of a not-forprofit agency and nats, a public-private partnership in the united kingdom. weakly-led civil aviation authorities who prefer a quiet life rather than ensuring an efficient, highly utilized system have led to a mismatch between supply and demand. the dual role leads to limitations in the system that ensures neither efficiency nor productivity. around the world, air traffic management needs more rapid deployment of proven technologies and to become computer-centric rather than human-centric as is currently true. it is equally important that the individual links within the air traffic management system are understood and their respective capacities analyzed in order to set priorities for research and development to be directed specifically at the bottlenecks. prior to deregulation of the airlines, many questioned whether profit oriented companies would serve the public as safely as under the regulated era. the same is true for air traffic management. there is a visible trend towards privatization and corporatization of the air navigation service providers around the world, however the ability to introduce competition in this market is clearly suspect. separate companies, whether not-for-profit or economically regulated privatized concerns, appear to have reduced some of the inefficiency that existed previously (mcdougall and roberts, ). the departments of transport or civil aviation authorities could then promote their rightful positions as safety regulators, at arms length from the service providers. adam smith's ( ) treatise argues that competition enhances economic welfare whereas monopoly power, for example in the form of labor association restrictions or government regulation, detracts from rational pricing. multiple domestic airline markets have been deregulated over the past years, however international routes are still associated with restrictive bi-laterals for the most part, the maliat and u.s.-e.u. open skies pact being among the first to remove such restrictions. there would appear to be ample evidence of the success of deregulation in the form of business model innovation and increased consumer surplus, hence the global policy emulation. however, the volatility of demand seriously impacts the airline industry pushing the players between two extremes, excess concentration and destructive competition, which requires regulators worldwide to continue their vigilance. first, government oversight in the market should be restricted to the protection of competition rather than the protection of competitors such that no firm is too big to fail. second, in order to protect the positive impact of airline deregulation, it is necessary to remove the remaining barriers to free entry and exit including bilateral agreements between nations, restrictive slot and gate allocations that grant preferred status to incumbent airlines and the foreign ownership restrictions and controls that prevent mergers across borders. in summation, the risks to society and possible solutions are summarized in table . consequently, pricing congestion or scarcity, noise and emissions are far superior to the system of government restrictions that are currently applied to solve the bottlenecks in the aviation supply chain. pricing provides the signals necessary to identify and subsequently search for solutions to constraints based on demand rather than ad-hoc short-term solutions. specifically, one of the major limitations to the prosperity of air travel today is the ongoing regulatory regime that restricts and controls the airport and air traffic management capacities. separation of powers is necessary in both arenas in order to prevent either elements from reregulating airlines. the airports, whether private corporations or public entities, need to be separated from political pressures defining slot or gate allocations and the civil aviation authorities, who set the air traffic management levels, need to be separated from the body that operates the system. market distortions, limitations and inefficiencies will thus be removed. these strategies will enable the airlines, airframe and engine manufacturers and airports to better respond to demand and reduce the risks inherent in the existing system. for fruitful discussions that led to the development of this paper. nicole would also like to thank the recanati foundation for partial support of this work. the effect of competition on the choice of an optimal network in a liberalized aviation market with an application to western europe trading capacity and capacity trade-offs. working paper at the center for transportation studies effect of open skies in the middle eastern region the impact of ownership form, competition and regulation on 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regulation play a role economic deregulation: days of reckoning for microeconomists china's airline deregulation since and the driving forces behind the airline consolidations the authors would like to sincerely thank the organizers and participants of the hamburg aviation conference of february key: cord- -ir ywcv authors: mendes, thiago; carvalho, luís title: shifting geographies of knowledge production: the coronavirus effect date: - - journal: tijdschr econ soc geogr doi: . /tesg. sha: doc_id: cord_uid: ir ywcv this research note analyses the evolving geographies of coronavirus disease research before and during the first three months of the epidemic outbreak. an examination of global networks of scientific co‐production highlights the increasing centrality and knowledge intermediation profile of chinese organisations. it is argued that it is important to understand these global geographies and networks, as they may signal varying (and cumulative) abilities to generate, intermediate, and access relevant knowledge in the face of epidemic outbreaks. epidemic outbreaks have caused major changes throughout human history, and they have increased in frequency over the last few years (friedman ) . the worldwide impact of covid- has sounded alarms in a manner that has not been seen in recent history. in fact, since the world health organization created the public health emergency of international concern (pheic) mechanism in , it has already been activated six times. among the other social, economic, and political transformations they bring (alfani & murphy ) , large epidemic outbreaks are accompanied by fast-paced scientific and technological activity since they represent imminent threats to human life (colf et al. ) . the ebola outbreak in west africa in is illustrative of this effect. research shows that the epidemic amplified ebolarelated knowledge production on a global scale (e.g. quarcoo et al. ) , creating new interdependencies between scientists, medical practitioners, and inventors. related scientific articles and clinical trials soared, but what was more telling was the geographical reconfiguration of knowledge creation activity, placing the most affected african countries as relevant hubs in global co-authorship and collaboration networks -notwithstanding the enduring centrality of traditional science hubs in north america and europe, before and during the outbreak (e.g. hegel et al. ) . however, this shifting geography was not seen in terms of patent co-inventorship, such as in drug development and other clinical innovations. in this case, those who were able to 'anchor' knowledge networks (crevoisier & jeannerat ; vale & carvalho ; binz & truffer ) and become important co-inventors came from countries and regions endowed with scientific and technological infrastructure like universities and research labs (e.g. world intellectual property organization ). it was ultimately through these geographically nuanced networks that the development of new drugs and technologies to fight the epidemic accelerated (world health organization ). of course, it is still early to identify the effects of the covid- outbreak in this respect in detail. however, the aforementioned findings may suggest future directions in terms of the changing structure and geography of the related knowledge production systems that will emerge from -and because of -the crisis. to explore this issue, this note examines the evolving geography of coronavirus knowledge production networks, assessed through co-authorship in scientific publications indexed at the web of science. this measure is admittedly imperfect, as it primarily captures the research-driven and analytical modes of knowledge production (davids & frenken ) . it serves as a first image of the global geographies of scientific and technological efforts to understand, mitigate, and deal with coronavirus disease at a time in which complementary data such as clinical trials and patent claims are still emerging. the note concludes by hypothesising the foreseeable contours of the changing geography of coronavirus research, in which china's role as a knowledge producer and network connector will likely become heightened. moreover, it sketches several challenges for research in social and economic geography in this shifting context. methods -in order to assess the structure of coronavirus disease-related scientific co-authorship through the web of science database, search criteria included the words corona-virus, covid, and sars (i.e., severe acute respiratory syndrome) across publications titles, abstracts, and keywords. the term sars was included due to the similarities between covid- and sars-type coronaviruses (between % and % genetic similarity, according to lu et al. ) . data were collected and analysed for two periods: - (before the current outbreak) and during the first three months of (after the outbreak). since the virus responsible for covid- is new, it is not possible to directly compare recent scientific publications on the subject with those before the epidemic. however because of the structural proximity of covid- and sars coronaviruses, and considering that drug repurposing is an effective and often-followed (lower-cost) strategy (zhou et al. ) , it is reasonable to assume that new knowledge development in these fields will build upon and will be highly related to previous research efforts. the analyses included a measure of the (co-)authorship share of each country (wos weight) as well as the individual weight of co-authorship dyadic connections across countries (connection weight), as depicted in figure and figure . moreover, social network analysis was used to assess each country's centrality in the global network of coronavirus disease research. for the latter, betweenness centrality (hanneman & riddle ) was also calculated, that is, a measure assessing the number of times a certain entity (in this case, a country) represents the shortest path between two others for scientific co-production. this provided a proxy for the role of different countries as knowledge nodes and intermediation hubs in the geography of coronavirus disease research, as represented in figure and figure . results -as witnessed for previous epidemic outbreaks (e.g. quarcoo et al. ; hegel et al. ) , the current covid- outbreak boosted related scientific efforts in a very short period. the absolute number of publications increased by per cent during the first three months of , making up for an average of monthly articles (compared with an average of monthly articles during - ). in the years before the current outbreak, research organisations in the united states of america had the highest number of co-authorships ( , %), followed by organisations in china ( . %), the united kingdom ( . %), germany ( . %), saudi arabia ( . %), south korea ( . %), and the netherlands ( %), with other countries producing less than % of the global research output (figure ). the presence of saudi arabia in this rank provides an illustration of the impact of epidemic outbreaks on the geography of knowledge production; saudi arabia was the epicentre of the mers-cov epidemic in . a similar pattern occurred with the sars-cov epidemic in china and south korea in : research in those fields has endured in these countries ever since. however, significant changes have occurred as a result of the current outbreak ( figure ) . between january and march , chinese institutions began leading the ranks, taking part in . % of the global research output, followed at some distance by the united states ( . %), the united kingdom ( . %), and canada ( %). beyond its role as an increasingly important knowledge hub, this rapid change is quite naturally linked to the fact that china was the epicentre of the covid- epidemic for many weeks. the same effect can be seen in the case of italy; italian organisations became the seventh-most prevalent globally in coronavirus disease research ( . % of global research output compared to . % before the crisis). moreover, while traditional coronavirus disease research countries maintained important positions (e.g. saudi arabia, germany, the united kingdom, and south korea), others reinforced their centrality in global research networks (e.g. canada). a telling picture emerges when, beyond size, countries are assessed in relation to their ability to intermediate knowledge flows through the measure of betweenness centrality (figure and figure ). after the current outbreak, china and the united kingdom outpaced the usa, and european counties reinforced their strategic position. moreover, new countries gained centrality, notably australia, in africa (south africa and nigeria) and latin america (brazil and colombia). another important element pertains to the number of publications co-authored between pairs of countries, assessing the strength of the research links between them. before the outbreak, the link between the united states and china was the strongest ( . % of the total number of publications was co-authored by researchers in both countries), followed by co-authorship links between the united kingdom ( . %) and usa-saudi arabia ( . %). after the outbreak, the usa-china link remained the strongest ( . % of the total number of co-authorships), but china significantly intensified its research links within asia (e.g. with india, taiwan, and thailand) and with the united kingdom, australia, and canada, becoming a pivotal connector in coronavirus disease knowledge production networks. as observed, and in line with many other knowledge production systems (binz & truffer ) , the geography of coronavirus disease knowledge production, at least when assessed through scientific research, exhibits a markedly global and interconnected pattern. this geography has a deep-rooted structure that has been carved through previous collaborations and long-term relationships. however, it is also prone to being occasionally reshaped by external shocks and critical events (such as epidemic crises) that accelerate the production and diffusion of urgently needed research. on these occasions, as has been observed in other contexts (quarcoo et al. ; hegel et al. ) , locations in which the most severe epidemic episodes take place tend to enhance their role in such networks. this pattern is easily understandable. on the one hand, countries at the forefront of an epidemic outbreak have incentives -as well as social and political support -to mobilise their science systems, activate new funding vehicles, and shift research priorities. on the other hand, countries that are later in the diffusion curve may wait for the epidemic to become less urgent. although the chinese position was already very relevant before the coronavirus disease emerged -partly as a by-product of the not-sodistant sars crises -its research institutions doubled the number of related scientific productions since the recent outbreak. perhaps more significantly, this has propelled china to become a major global hub and knowledge connector for different countries and networks in coronavirus disease research. at the time of writing, the epicentre of the epidemic (now pandemic) has moved to europe and the usa, and it is thus still early to perceive the full picture of the results of the global outbreak -both in terms of science production and more applied technological development. in those geographies, although priority shifts in science and technology investments are to be expected, the vast amount of funds and policy attention channelled to fighting economic depression and keeping social security and health systems afloat render the final effect in global knowledge production systems uncertain. the unprecedented socio-economic conditions, together with the decrease of the epidemic curve in china, suggests that beyond serving as a temporary 'stage' of the epidemic, china may be on track to 'anchor' and forge new knowledge leadership on coronavirus disease, namely as it has the combined presence of technological infrastructure, a trajectory in related research, and practical experience in clinical trials. in fact, on april , the international clinical trials registry platform (ictrp) identified clinical trials related to covid- , out of which ( %) involved chinese organisations (who ), though these numbers are expected to rise in europe and the usa (covid- clinical research coalition ) . in other words, it can be hypothesised that there will be 'first-mover advantages' and lasting effects in knowledge production among the places that are firstly hit by such an epidemic, under the condition that they are endowed with relevant science and technology resources and competences. to be sure, testing this hypothesis would require following-up the analyses in this note after the pandemic. this would allow researchers to trace whether knowledge production has followed the global spread of the virus and whether newly hit countries relied on research conducted by the first movers (eventually teaming up with them). further work could also allow the disentangling of different effects and explanations behind the observed shifts -namely the relevance of the inherited network structure vis-à-vis the hypothetical 'it happened here' and 'rise of china' effects. moreover, it could also be hypothesised that the resulting knowledge production geographies will be influenced by geopolitical features, notably the attitudes of different governments towards knowledge transparency (e.g. sharing instead of closing-up information on new advances) as well as the impact of cyclical conflicts between global powers (notably the usa and china). overall, understanding the shifting geographies of knowledge production systems is likely to become an increasingly relevant research endeavour, as they may signal varying (and cumulative) abilities to generate, intermediate, and access relevant knowledge in the face of epidemic outbreaks. this is a domain to which economic and social geography scholars can largely contribute, at least in three ways. first, by paying more attention to the geographies and processes involved in neglected and epidemic-related medical innovations, namely in relation to the (now well-studied) analyses of conventional drug development, pharma, medical equipment, and biotechnology. second, instead of assuming a priori territorial boundaries and scalar approaches to knowledge and innovation, epidemic outbreaks and the networks they propel call for research that examines knowledge creation from a global perspective, in which identifying the most relevant geographies becomes an empirical question. finally, in a time in which epidemic outbreaks may have further impacts on geopolitical structures, research on the geography of knowledge and innovation may increase its relevance by articulating its research questions with issues of power imbalances and the geopolitical dimensions that co-evolve with knowledge and technological development on a global level. package (aria & cuccurullo ) . resulting networks were exported in pajek format, opened, and processed through ucinet (borgatti et al. ) . the results were georeferenced in a gis environment through esri arcgis (version . . ). . we thank one anonymous reviewer for making this remark. . we thank the two anonymous reviewers for calling our attention to these hypotheses. plague and lethal epidemics in the pre-industrial world bibliometrix: an r-tool for comprehensive science mapping analysis global innovation systems -a conceptual framework for innovation dynamics in transnational contexts ucinet for windows. software for social network analysis a role for science in responding to health crises global coalition to accelerate territorial knowledge dynamics: from the proximity paradigm to multi-location milieus proximity, knowledge base and the innovation process: towards an integrated framework we were warned. the atlantic -politics analysing published global ebola virus disease research using social network analysis genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding. the lancet ebola and its global research architecture -need for an improvement rstudio: integrated development for world health organization (who) ( ), roadmap for introduction and roll-out of merck rvsv-zebov ebola virus disease vaccine in african countries network-based drug repurposing for novel coronavirus -ncov/ sars-cov- we thank the two anonymous reviewers for their valuable insights and suggestions. thiago monteiro mendes acknowledges the support of the portuguese foundation for science and technology (doctoral scholarship sfrh/bd/ / -fct/ poch/eu). key: cord- -pa iqc authors: perrotta, d.; grow, a.; rampazzo, f.; cimentada, j.; del fava, e.; gil-clavel, s.; zagheni, e. title: behaviors and attitudes in response to the covid- pandemic: insights from a cross-national facebook survey date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: pa iqc in the absence of medical treatment and vaccination, the mitigation and containment of the ongoing covid- pandemic relies on behavioral changes. timely data on attitudes and behaviors are thus necessary to develop optimal intervention strategies and to assess the consequences of the pandemic for different demographic groups. we developed a rapid response monitoring system via a continuously run online survey (the "covid- health behavior survey") across eight countries (belgium, france, germany, italy, the netherlands, spain, the united kingdom, the united states). the survey was specifically designed to collect key information on people's health status, behaviors, close social contacts, and attitudes in response to the covid- pandemic. we developed an innovative approach to recruit participants via targeted facebook advertisement campaigns in order to generate balanced samples for post-stratification. in this paper, we present results for the period from march -april , . we estimate important differences by sex: women show a substantially higher perception of threat along with a lower level of confidence in the health system. this is paralleled by sex-specific behaviors, with women more likely to adopt a wide range of preventive behaviors. we thus expect behavior to serve as a protective factor for women. our findings also show a higher level of awareness and concern among older respondents, in line with the evidence that the elderly are at highest risk of severe complications following infection from covid- . while across all the samples respondents were less concerned for themselves than for their country or for the world, we also observed substantial temporal and spatial heterogeneity in terms of confidence in institutions and responses to non-pharmaceutical interventions. the ongoing coronavirus disease (covid- ) outbreak started in wuhan city, china, in december and quickly spread globally, soon reaching pandemic proportions [ ] . by mid-april , the virus had already caused over . million cases and over , deaths worldwide [ ] , placing a substantial burden on national healthcare systems and posing unprecedented challenges for governments and societies. as yet, governmental responses to mitigate the coronavirus epidemic have varied considerably across countries. non-pharmaceutical interventions, specifically intended to reduce sustained local transmission by reducing contact rates in the general population, have so far ranged from moderate containment measures, such as school closures and cancellations of public gatherings, to drastic measures, such as travel bans and nationwide lockdowns [ ] . in western democracies, individual behaviors, rather than governmental actions, are potentially crucial to control the spread of covid- [ ] . human behavior is in fact a key factor in shaping the course of epidemics [ ] . individuals may spontaneously modify their behaviors and adopt preventive measures in response to an epidemic when mortality or the perception of risk is high, and this may in turn change the epidemic itself by reducing the likelihood of transmission and infection [ , , ] . however, a key problem is a lack of data to assess people's behavior and reactions to epidemics. decision-making and the evaluation of non-pharmaceutical interventions require specific, reliable, and timely data not only about infections, but also about human behavior. especially in the ongoing covid- pandemic, where medical treatment and vaccination are still only remote options, mitigation and containment mainly rely on massive and rapid adoption of preventive measures [ ] . understanding how the members of different demographic groups perceive the risk, and consequently adopt specific behaviors in response to it, is therefore key to measure the effectiveness of non-pharmaceutical interventions, design more realistic epidemic models, and enable public health agencies to develop optimal control policies to contain the spread of covid- . we seek to narrow this data gap by monitoring individual behaviors and attitudes in response to the covid- pandemic in multiple countries. in march , we launched a crossnational online survey, called the "covid- health behavior survey" (chbs), to collect timely data on people's health status, behaviors, close social contacts, and attitudes related to covid- . we recruit respondents through advertisement campaigns on facebook, that we created via the facebook advertising manager (fam). this novel approach to recruiting respondents allows us to combine the flexibility of online surveys for rapid data collection, with the controlled environment of targeted advertisement. this makes it possible to recruit a balanced sample across demographic groups, that is approximately representative of the general population, after applying appropriate post-stratification weights [ , , ] . other similar online initiatives have emerged recently [ , , , ] , but to the best of our knowledge, this is the first cross-national study addressing multiple key factors, ranging from individual behaviors and attitudes to health-related indicators to social contact patterns. moreover, our sampling approach and continued data collection allows us to compare people's behaviors across countries that are at different stages of the covid- pandemic, and to assess changes in behaviors after pivotal events, such as nationwide lockdowns. in this paper, we present first results based on survey data collected over the period march to april , in belgium, france, germany, italy, the netherlands, spain, the united kingdom, and the united states. over this period, a total of , participants completed the questionnaire. our goal in this paper is to provide insights into the relation between participants' demographic characteristics and (i) the threat they perceive covid- to pose to various levels of society, (ii) the confidence they have in the preparedness of different national and international organizations to handle the current crisis, and (iii) the behavioral measures (preventive measures and social distancing measures) they have taken to protect themselves from the coronavirus. from a public health perspective, this information is key to understand the behaviors and attitudes of specific demographic groups in different countries and help guide the decision-making process to design adequate policies to contain the spread of covid- . in the following sections, we outline our methodological approach and discuss the innovative aspects of participant recruitment through facebook advertising campaigns, as well as the statistical adjustments needed to approximate a sample representative of the general population. then we describe the main features of our sample and present results of the first analyses regarding behaviors and attitudes in response to covid- . we close with a discussion and an outlook for the next steps in our broader project. the chbs is designed to collect information on respondents' health behaviors and attitudes related to covid- . participation in the survey is anonymous and voluntary. respondents can stop participating at any time and can skip questions they feel uncomfortable answering. the questionnaire consists of four topical sections: (i) socio-demographic indicators (age, sex, country of birth, country of residence, level of education, household size and composition); (ii) health indicators (underlying medical conditions, flu vaccination status, pregnancy, symptoms experienced in the previous seven days); (iii) opinions and behaviors (perceived threat from covid- , level of trust in institutions, level of confidence in sources of information, preventive measures taken, disruptions to daily routine); (iv) social contact data, i.e. the number of interactions that respondents had the day before participating in the survey in different settings (at home, at school, at work, or in other locations). to facilitate validation and warrant comparability with existing surveys, we included standard questions from several sources, such as the european social survey (ess) [ ] regarding socio-demographic characteristics, ipsos [ ] regarding opinions on the coronavirus outbreak, and the polymod project [ ] regarding social contacts. note that we ask respondents about their behavior and attitudes related to the coronavirus outbreak only if they indicated that they were aware of it. in more detail, we asked respondents how much, if at all, they had seen, read or heard about the coronavirus outbreak, with the answer options "a great deal", "a fair amount", "not very much", "nothing at all", and "prefer not to answer". respondents who indicated that they knew nothing at all, or that they preferred not to answer, were not asked any further questions related to the outbreak. we created the questionnaire first in english, and then translated it into the different official languages of the countries in our study, with support from professional translators. we considered country-level differences when adjusting the questionnaire for different countries, where applicable (e.g. differences in the educational system). in the online implementation, the questionnaire is available in both english and the national language(s) of the respective country in which respondents are located. the questionnaire was implemented in the online survey tool limesurvey (version . . + ) and hosted by the society for scientific data processing (gwdg). the full english questionnaire (as used in the united states) is reported in appendix a. the link to the questionnaire is distributed through advertisement campaigns that we created via the fam. facebook is currently the largest social media platform, with . billion monthly active users worldwide as of september [ ] . in the united states, about % of adults used facebook in [ ] , with similar penetration rates in europe, ranging from % in germany to % in denmark [ ] . the fam enables advertisers to create advertising campaigns that can be targeted at specific user groups, as defined by their demographic characteristics (e.g. sex and age) and a set of characteristics that facebook infers from their behavior on the network (e.g. interests). an increasing number of studies explore the use of facebook in demographic and health research to recruit participants for online surveys [ , , ] . two main advantages of this approach are rooted in facebook's wide reach and the possibility to directly target members of different demographic groups. two concerns that are often raised are that in online samples self-selection might lead to bias in results, and that online sub-populations may not be representative of the general population. however, there is increasing evidence that samples obtained from facebook do not significantly differ from samples obtained from more traditional recruitment and sampling techniques in central demographic and psychometric characteristics, especially if post-stratification weights are applied adequately [ , , , ] . we created one advertising campaign per country and stratified each campaign by sex (male and female), age group ( - , - , - , and + years), and region of residence (largely following the nuts classification in europe and the census regions in us; see table s in the supplementary material), resulting in to strata per country, further stratified using six different ad images. figure s in section of the supplementary material illustrates the structure of our facebook advertising campaigns in the united states. note that we aggregated the different regions of residence into larger macro-regions, to keep the number of strata in facebook manageable (see table s for the exact mapping). we launched the campaigns on march , , in italy, the united kingdom, and the united states. we added germany and france on march , spain on march , the netherlands on april , and belgium on april , . in the period - march, we were unable to recruit a significant number of participants due to technical issues with the fam which prevented the delivery of our advertisements. we select participants for our analysis in three steps. first, we include only participants who reported that they lived in the country that the respective advertising campaign and countryspecific questionnaire targeted, and who reported their sex, age, and region of residence (the central variables in our post-stratification weighting approach, see details below). second, when analysing responses to a given question, we exclude respondents who chose the options "don't know" or "prefer not to answer". in the analysis reported here, this particularly affects the question about awareness of the coronavirus outbreak (see section . ); however, as table s in the supplementary material shows, the share of respondents to whom this applies is less than % across countries. third, given that in calendar week we were only able to collect a small number of completed questionnaires in spain (less than ), we excluded these data from our analysis as the sample size would render our analysis unreliable for this period. note that all period references consider local time zones across countries and regions. after participant selection, we apply post-stratification weights to the final data set in order to correct for potential issues with non-representativeness in our sample. we use a standard procedure in survey research, in which appropriate weights are computed based on population information from more traditional data sources (e.g. census data). here we use population data from eurostat ( ) [ ] and the us census ( ) [ ] . specifically, for each stratum i (given by each combination of sex, age, and macro-region) in each country, we compute the fraction p i andp i of, respectively, the true population counts n i and the sample countsn i , compared to the total population i n i and the total sample size ini . the weights w i are then defined as w i = p i /p i , thus giving less weight to groups which are over-represented (w i < ) and more weight to groups which are under-represented (w i > ) in the sample. we provide more details about our approach to post-stratification in section of the supplementary material. in our analysis, we focus on (i) perception of threat from covid- , (ii) confidence in the preparedness of different national and international organizations to respond to this threat, and (iii) behavioral measures taken to protect oneself from the virus. all our analyses are based on the weighted sample, whereas the reported sample sizes refer to the unweighted sample. we asked respondents to rate the threat they perceived covid- to pose for different levels of society (i.e. to themselves, their family, their local community, their country, and the world) on a -point likert-type scale ( = very low threat, = very high threat), including the options "don't know" and "prefer not to answer", which are treated as missing values (table s in the supplementary material reports the corresponding sample size for each item). for comparison, we asked respondents to answer the same questions also for the seasonal flu. we normalized respondents' answers to each item to the range - , meaning that values around . correspond to moderate perceived threat, whereas and correspond to low and high perceived threat, respectively. in a similar way, we asked respondents to rate the confidence they had in the preparedness and ability of different organizations to effectively deal with the covid- pandemic (i.e. doctors and healthcare professionals in their community, hospitals in their local area, health care services in their country, the world health organization, their local government, and their national government) on a -point likert-type scale ( = not confident at all, = very confident), also including the options "don't know" and "prefer not to answer", which are treated as missing values (see table s in the supplementary material). we normalized answers to the range - , and aggregated responses related to the local health system (doctors and healthcare professionals in respondents' community and hospitals in their local area) by averaging them across items within respondents. finally, we asked respondents which measures, if any, they had taken to protect themselves from the coronavirus. for this, we showed a list of actions, from which they can choose all that apply. this list includes preventive measures (e.g. washing hand more often), measures of social distancing (e.g. avoided social events), measures of reduced mobility (e.g. avoided public transportation), panic buying (e.g. stockpiling of food), and potential discriminatory actions (e.g. avoided eating in asian restaurants). see the questionnaire in the appendix a for the full list of actions. in the analysis, we consider the shares of participants who reported having adopted specific behaviors in response to covid- , including: (i) the stockpiling of food and/or medicine; (ii) the use of a face mask; (iii) the increased use of hand sanitizer; (iv) the increased washing of hands; (v) social distancing (if participants selected at least one of the following: avoided shaking hands, avoided social activities, and avoided crowded places); and (vi) the reduced use of transportation (if participants selected at least one of the following: avoided travelling by public transportation, and avoided travelling by taxi). in our analyses, we used non-parametric tests for median comparisons (wilcoxon test to compare two groups and kruskall-wallis test to compare three or more groups) and considered p-values of less than . to be significant. data analysis was performed with the programming language python (version . ). . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint results a total of , participants completed the survey in belgium (n= , ), france (n= , ), germany (n= , ), italy (n= , ), the netherlands (n= , ), spain (n= , ), the united kingdom (n= , ), and the united states (n= , ) in the period between march , (calendar week ) and april , (calendar week ). as table shows, participation by week was high in all countries, with a median number of , participants per week in belgium, , in france, , in germany, , in italy, , in the netherlands, , in spain, , in the united kingdom, and , in the united states. table also shows the demographic characteristics of the participants in each country, based on the unweighted sample. the sex ratio is somewhat skewed towards females compared to the overall population, ranging from % female in germany to % female in france. in terms of age, older respondents tend to be over-represented, with a median age of years (iqr - ) in belgium, years (iqr - ) in france, years (iqr - ) in germany, years (iqr - ) in italy, years (iqr - ) in the netherlands, years (iqr - ) in spain, years (iqr - ) in the united kingdom, and years (iqr - ) in the united states. when it comes to education, there is some variation across countries. more specifically, in belgium ( %), france ( %), spain ( %), the united kingdom ( %), and the united states ( %) most respondents attained university-level education, whereas in germany ( %), italy ( %), and the netherlands ( %) most respondents attained secondary-level education. after applying post-stratification weights, the bias described above is reduced and the sample approximates the shares reported in nationally representative surveys in terms of sex, age, and educational attainment, as shown in figure s in the supplementary material. for more details, see section of the supplementary material. the perception of threat: higher for the elderly and for women, while everyone is less concerned for oneself than for the country as a whole in all countries, there is significant variation in threat perceptions across levels of society (p < . ). in particular, the perception of threat increases sharply from the personal sphere (oneself and the family) to more distal contexts, i.e. the local community, the country, and, ultimately, the world . considering specifically the perceived threat to oneself and to the world, the latter is on average % greater, whereas this difference ranges from % in italy to % in the united states. apart from these variations at the country level, the threat perception posed by covid- is both age-and sex-specific. as shown in figure b, . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . overall, the perceived threat increases with age, with few notable exceptions, including the perceived threat to the family in germany, the netherlands, spain, and the united states, the perceived threat to the local community in the netherlands, spain, and the united states, and the perceived threat to the country and to the world in the united states (all p > . ). importantly, as figure c shows, the perceived threat is significantly higher among women than among men . the development of threat perceptions over time shows different temporal patterns across countries, as can be seen in figure d . in particular, there is significant variation over time in germany (p < . ), and the united states (p < . ). in germany the perceived threat shows a negative trend, with the median value compared to that of week decreasing by about % in week , % in week , % in week , and % in week . in the united states the trend changes over time, with the median value compared to that of week increasing by about % in week , % in week , and % in week , but then dropping to being only % higher in week , and % higher in week . in france, italy, and the united kingdom, the temporal pattern is more mixed, with significant variation over time across levels of society (p < . ), except for the perceived threat to oneself in france (p = . ), italy (p = . ), and all p < . , except in spain for the perceived threat to oneself (p = . ), to the family (p = . ), and to the local community (p = . ) . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . finally, figure compares the threat perception for seasonal influenza (panel a) with that for covid- (panel b). the perceived threat posed by covid- is significantly higher than the perceived threat posed by influenza (all p < . ). in more detail, the perceived threat to oneself is on average % higher (ranging from % in germany to % in belgium), the threat to the family is % higher ( % in the netherlands to % in the united states), the threat to the local community is % higher ( % in france to % in the united kingdom), the threat to the country is % higher ( % in germany to % in belgium), and the threat to the world is % higher ( % in italy to % in belgium). more details about the perceived threat posed by influenza can be found in section of the supplementary material. landscape, men have higher confidence in local and national health systems in all countries, there is significant variation across organizations (all p < . ). first, respondents' confidence in the national health system tends to be lower than their confidence in the local health system . considering the median values, respondents' confidence in the national health system is about % lower than their confidence in the local health system in belgium, % lower in france, % lower in germany, % lower in all p < . , except italy (p = . ) and the united kingdom (p = . ) . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . the netherlands, % lower in spain, and % lower in the united states. second, respondents' confidence in local and national governments differs substantially in all countries (p < . ). in particular, their confidence in the national government is about % lower than their confidence in the local government in germany, it is % lower in france, % lower in spain, and % lower in the united states. by contrast, it is about % higher in belgium, % higher in italy, % higher in the netherlands, and % higher in the united kingdom. apart from this variation, several other patterns stand out in the level of confidence by age group and sex. as shown in figure b , overall the elderly tend to be more confident in the preparedness of the various organizations, with the exception of the who, in which young adults aged between and years show instead greater confidence. additionally, the level of confidence is sex-specific across organizations, as can be seen in figure c . male respondents are more confident in the local or national health systems , whereas female respondents are more confident in the who and in the local government . as for the national government, instead, confidence is higher among female respondents in germany (p < . ), and spain (p = . ), but it is higher among male respondents in the united states (p < . ). figure d shows the development of the level of confidence over time. similarly to the perceived threat shown in figure d , the temporal patterns vary across countries. in particular, all p < . , except for the netherlands, spain, and the united kingdom as for the who, all p < . , except for belgium, france, and italy, while for the local government, all p < . , except belgium, italy, and the united states . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . there is significant variation across weeks in germany (p < . ), italy (p < . ), the united kingdom (p < . ), and the united states (p < . ). while in germany and in the united kingdom, the trend is positive with the median value in week being about % and % higher compared to the first week, on the contrary, in italy this trend is negative with the median value in week being about % lower than in week . in the united states, instead, the temporal pattern is more variable, with the level of confidence in the health systems increasing, whereas the level of confidence in the different levels of government diverges. it is higher for the local government (about % higher in week than in week ), while for the national government the trend changes over time, with the median value compared to that of week decreasing by about % in week , % in week , and % in week , but then increasing to being only % lower in week , and % lower in week . on the other hand, the temporal pattern in france shows significant variation, except for the local health system (p = . ), whereas there is no significant variation in the level of confidence over time in belgium (all p > . ), the netherlands (all p > . ), and spain (all p > . ). moreover, looking at the level of confidence in the who separately, this consistently shows a negative trend in france (about % lower in week compared to week ), germany (about % lower in week compared to week ), italy (about % lower in week compared to week ), the united kingdom (about % lower in week compared to week ), and the united states (about % lower in week compared to week ). figure shows the self-reported behaviors broken down by country (panel a), age group (panel b), sex (panel c), and week (panel d). as shown in figure a , the least frequently reported behavior is the stockpiling of food and/or medicine, ranging from about % of respondents (iqr [ ] [ ] [ ] [ ] [ ] [ ] in the netherlands to about % (iqr - ) in germany. secondly, the share of participants who reported wearing a face mask ranges from about % (iqr - ) in the netherlands to about % (iqr - ) in italy. as for hand hygiene, the share of participants who increased the use of hand sanitizer ranges from about % (iqr - ) in germany to about % (iqr - ) in the united states, while the share of participants who increased washing their hands ranges from about % (iqr - ) in germany to about % (iqr - ) in spain. finally, the most frequently reported behaviors are, respectively, increased social distancing, which ranges from about % (iqr - ) in the united kingdom to about % (iqr - ) in italy, and the reduced use of transportation, which ranges from about % (iqr - ) in the united states to about % (iqr - ) in france. moreover, the share of participants adopting specific behaviors related to covid- shows a variable pattern across age groups in all countries, as shown in figure b . in particular, significant variations in the age distribution is observed in respondents who stockpiled food and/or medicine, increased the use of hand sanitizer, and reduced the use of transportation . however, there is no significant variation in the age distribution in terms of respondents who engaged in social distancing, increased hand washing, and worn a face mask . . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . fig. . proportions of participants who reported having adopted specific behaviors in response to covid- broken down by country (a), age group (b), sex (c), and week (d). behaviors include the stockpiling of food and/or medicine, wearing a face mask, increased use of hand sanitizer, increased hand washing, increased social distancing, and reduced use of public transportation. bar charts show median values and %ci as errors. weighted sample. as shown in figure c , behaviors related to covid- are sex-specific, with female respondents showing the highest adoption rates for specific behaviors . the development of behaviors over time shows different temporal patterns between countries, as can be seen in figure d . in particular, the use of a face mask substantially increased over time (all p < . , except belgium, and the netherlands), as well as hand hygiene in germany, italy, the united kingdom, and the united states (p < . ), and the reduced use of transportation in the united kingdom (p < . ), and the united states (p < . ). social distancing has increased sharply in the united kingdom (p < . ), and in the united states (p < . ), whereas it has decreased in germany (p = . ), reflecting different stages of the epidemic and different policies. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , understanding how different demographic groups perceive the risk of covid- , and thus adopt specific behaviors in response to it, is key to enable public health agencies to develop optimal intervention strategies to contain the spread of the disease. in this paper, we have presented insights from survey data collected through a cross-national online survey, the covid- health behavior survey (chbs). the survey is ongoing, and here we presented results based on data collected during the period march -april , in belgium, france, germany, italy, the netherlands, spain, the united kingdom, and the united states. in this closing section, we summarize the main findings and provide our interpretation in light of the current evidence on the covid- pandemic. first, we found that the perception of the threat that covid- poses was on average highest in italy, followed by the united kingdom, spain, belgium, france, the united states, the netherlands, and germany. conversely, respondents' confidence in the preparedness of local and national organizations to deal with covid- was on average highest in the netherlands, followed by italy, germany, spain, the united kingdom, the united states, belgium, and france. in particular, italy was the first most affected country in europe in terms of numbers of cases and deaths, as well as the first country in europe to implement a nationwide lockdown on march , . this may explain the high threat perceived by the population in this country, and, together with the high confidence in the different health systems and different levels of government, the willingness to adopt preventive behaviors and adhere to social distancing measures. after italy, nationwide lockdowns were implemented also in spain (march ), france (march ), belgium (march ), the netherlands (march ), and the united kingdom (march ) to slow the progression of the virus and to prevent overloading the healthcare system [ ] . in the united states, instead, restrictive measures were implemented at the state level, starting in california on march , . notably, regarding the united kingdom and the united states, our data collected before and after lockdown measures were implemented (considering the united states as a whole) allow to observe temporal variation in the self-reported behaviors and attitudes: the perceived threat has increased in the population, along with the adoption of social distancing measures. in the case of the united kingdom, after the lockdown was implemented, the level of confidence in the health systems and different levels of government sharply increased, possibly reflecting discontent in the population about previously announced strategies. by contrast, the results for germany are more difficult to interpret. in germany, somewhat less restrictive measures were implemented on march , including school closures, cancellations of public gatherings, and the encouragement of social distancing. however, in contrast to the united kingdom and the united states, for which we observe a change in the temporal trends only after the implementation of non-pharmaceutical interventions, we find for germany that the share of respondents who had adopted social distancing measures was already high before such measures were implemented, and did not change much after this point. furthermore, compared to other countries, the level of confidence in the health systems and different levels of government in germany was high from the beginning of our observation period, and has further increased since then, whereas the perceived threat of covid- has decreased over time. this might be interpreted as a case of spontaneous bottom-up behavioral changes emerging from the population, following high trust in decisions and preparedness of the government. also, of the european countries considered in this study, germany had the third highest number of cases (about , ), but placed only sixth in terms of deaths (about , ) as of april , [ ] , which might explain the lower perceived risk perception in the . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may , . . second, we observe a clear pattern in threat perceptions regarding different levels of society, sharply increasing from moderate threat for the personal sphere (threat to oneself and the family) to very high threat for more distal contexts (i.e. the local community, the country, and the world). yet, even though the perception of threat to oneself among our respondents was comparatively low, we found that a high share of them had increased their hand hygiene. this insight renders it uncertain as to what extent behavior can be straightforwardly linked to perceptions of personal threat. furthermore, we found that the perceived threat posed by covid- is significantly higher than the perceived threat posed by seasonal influenza. one likely explanation for this is that although seasonal influenza causes regular annual epidemics worldwide [ ] , the novelty and uncertainty that surround covid- leads risk perception to be substantially higher. third, apart from variation at the country level, we also found sex-and age-specific differences. looking at the age component, our findings suggest that younger people perceive the threat to themselves lower than older people. this is in line with the evidence that older adults are at highest risk of severe complications following infection from covid- [ ] . by contrast, the age structure in the perceived threat to the family is less pronounced, which suggests that respondents were concerned about their family members, regardless of their own age and the perceived threat to themselves. fourth, we also found sex-specific patterns in the data. specifically, female respondents perceived the threat that covid- poses substantially higher, reported a lower level of confidence in the health system, and were more willing to adopt protective behaviors. since the case fatality rate for covid- is substantially higher for men [ ] , we might expect that men are more concerned about it. our results demonstrate that this is not necessarily true, and fact may have to be considered in the design of future communication campaigns. we gained these insights by using a novel approach to collecting health behavior data in times of a pandemic. we employed facebook advertising campaigns to continuously recruit a large number of participants for our survey over a long period of time. this approach allows us to target specific demographic groups in a comparative, cross-national approach, and to collect balanced samples to which post-stratification methods can be applied. these advantages notwithstanding, our approach also has some limitations. first, online surveys potentially suffer from bias due to self-selection and non-representativeness of the sample. in the case of facebook, there is increasing evidence that samples obtained from this social media network are not significantly different in central demographic and psychometric characteristics from samples obtained by more traditional recruitment and sampling techniques [ ] . furthermore, by applying post-stratification weighting, which is a standard procedure in survey research, we can correct for non-representativeness in observable characteristics (but not necessarily for self-selection based on unobservable characteristics), at least at the level of the entire sample. ideally, in our cross-temporal comparisons, we would apply this approach at the level of the week, to warrant complete comparability of observations over time, but issues of data sparsity complicate this approach. we do not expect this to strongly affect our results, but it should be kept in mind that our weekly results might suffer from somewhat larger bias than our aggregate results. second, our data collection started at different time points across countries, and also pertains to different points in the trajectory of the pandemic across countries. this also encompasses differences in the implementation of non-pharmaceutical interventions ordered by local and national governments, and needs to be kept in mind when comparing and interpreting our results across countries. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . third, the data presented here have the form of repeated cross sections, which enables us to assess changes in the population samples over time, but does not allow us to assess changes within individuals. we are planning to address some of the limitations in the future in the following way. first, we aim to expand our post-stratification weighting scheme, by applying multilevel poststratification, which will enable us to achieve greater consistency among differently sized strata and greater precision in the estimates for population subsets, such as the weekly estimates presented here. second, we aim to carry out a follow-up survey among participants who agreed to provide their email address for this. this panel perspective offers a unique possibility to understand how the covid- pandemic affects the population in the long run and to assess the impact of loosening the lockdown measures on social contact patterns and health behaviors in a cross-national perspective. to conclude, our work reduces the gap in human behavioral data, by providing timely and accurate data on individual behaviors and attitudes across countries. our work also illustrates how social media networks, like facebook, together with appropriate survey designs and statistical methods, offer an innovative and powerful tool for rapid and continuous data collection to monitor trends in behaviors relevant for mitigation strategies of covid- . taken together, the insights gained from our survey data are particularly relevant for policy makers and help design appropriate public health strategies and communication campaigns, and to design realistic epidemic models, which can account not only for the spatio-temporal spread of the infection, but also for accurate data on individual human behaviors. . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may , . . https://doi.org/ . / . . . doi: medrxiv preprint world health organization world health organization estimating the number of infections and the impact of non-pharmaceutical interventions on covid- in european countries: technical description update how will country-based mitigation measures influence the course of the covid- epidemic? capturing human behaviour non-pharmaceutical interventions for pandemic influenza, national and community measures behavioural change models for infectious disease transmission: a systematic review towards a data-driven characterization of behavioral changes induced by the seasonal flu how behavioural science data helps mitigate the covid- crisis what's to like? facebook as a tool for survey data collection demographic research with non-representative internet data traditional versus facebook-based surveys: evaluation of biases in self-reported demographic and psychometric information are people excessively pessimistic about the risk of coronavirus infection? evaluating covid- public health messaging in italy: self-reported compliance and growing mental health concerns social psychological measurements of covid- : coronavirus perceived threat, government response, impacts, and experiences questionnaires data for good: new tools to help health researchers track and combat covid- public opinion on the coronavirus outbreak: a multi-country poll from ipsos social contacts and mixing patterns relevant to the spread of infectious diseases facebook reports third quarter results social media use : demographics and statistics measuring labour mobility and migration using big data: exploring the potential of social-media data for measuring eu mobility flows and stocks of eu movers online surveys and digital demography in the developing world: facebook users in kenya migrant sampling using facebook advertisements: a case study of polish migrants in four european countries broad reach and targeted recruitment using facebook for an online survey of young adult substance use quota sampling using facebook advertisements not by the book: facebook as a sampling frame eurostat regional yearbook annual estimates of the resident population by sex, age, race, and hispanic origin for the united states and states covid- pandemic in europe coronavirus source data world health organization people who are at higher risk: older adults covid- weekly surveillance report we would like to thank all the participants who took the time to voluntarily complete our survey, and the staff and colleagues of the max planck institute for demographic research who contributed to the realization of this project, in particular k. this study was funded through the support of the max planck institute for demographic research, which is part of the max planck society. this study was conducted in agreement with the data protection regulations valid in germany. informed consent was obtained from all participants, enabling the collection, storage, and processing of their answers. ethical approval for the study was obtained from the ethics council of the max planck society. all authors designed the questionnaire and collected the data. dp conceived the project idea, devised the idea for the manuscript, analyzed the data, and wrote the manuscript. ag developed the strategy and technical implementation for data collection and the recruitment of survey participants, and wrote the manuscript. fr supported the strategy development and the technical implementation of the data collection, and wrote the manuscript. jc and edf designed the post-stratification weighting scheme. dp, ag led the project and the implementation of the online survey. all authors provided input and edited and reviewed the manuscript. the authors declare that they have no competing interests. key: cord- -xm na as authors: hillard, paula j. adams title: pediatric and adolescent gynecology (pag) in the time of a pandemic date: - - journal: j pediatr adolesc gynecol doi: . /j.jpag. . . sha: doc_id: cord_uid: xm na as nan sometimes i struggle to decide what i will write about as a topic of editorials for the journal of pediatric and adolescent gynecology (jpag). other times, the news provides an easy choice of topics. today, i am preoccupied with the topic at the forefront of discussions, news reports, and social media postsdthe novel coronavirus covid- . as i write, on march , the situation in the united states is evolvingdas it has been for the last few weeks, and will in the weeks to come in the united states and throughout the world. admittedly, i am providing my perspective from the united states, and i recognize that your perspectives will be different. by the time you read this, we will have more information, and a different view of the situation. currently i and my family are well, but colleagues at my institution have tested positive, in-person classes for undergraduate and medical students have been cancelled, new policies for hospital visitors have been instituted, national meetings have been cancelled, and we are all washing our hands and applying hand sanitizer gel even more than we had been previouslydwhich was a lot. my travel plans have changed. as i write this piece, the annual clinical and research meeting of the north american society for pediatric and adolescent gynecology (naspag) has not officially been cancelled, but this may well happen. i had made the decision that i could not responsibly attend the meeting in person, when my county is one in which there is community spread of the virus. i felt that i did not want to be responsible for being a possible vector, bringing the virus to friends and colleagues at the meeting. not surprisingly, the annual clinical and scientific meeting of the american college of obstetricians and gynecologists (acog), which was scheduled to meet in seattle, another community where there is community spread, has been cancelled. after president trump announced a travel ban on visitors from europe last night, i received an email from a colleague in europe who was planning to attend the naspag meeting, indicating that she will be unable to attend. each of us is making individual decisions that will affect not only our own health, but that of our family members (whether young kids or elderly parents), our colleagues, and our patients. our decisions are increasing being determined by government decisions that, while they may feel coercive, are nevertheless increasingly necessary, and perhaps too little too late. the pace with which i am receiving new information that i am being asked to process and act on is escalating. i heard a term on national public radio this morning that describes how i am feeling with the barrage of information: "shock and stress." i suspect that you are experiencing some variant of this feeling, as we react to announcements and communications from our institutions; our president and vice president; the centers for disease control and prevention (cdc); our social groups; our professional organizations; our friends and our families. the world health organization (who) has declared just this week that we are experiencing a pandemic, a term that the organization had previously avoided. i searched for the definition of pandemicdand read about the highest level of public health emergency. i'm learning more about the previously identified coronaviruses as well as the novel covid- . i'm hearing and using terms that were not previously a part of my everyday vocabulary: epidemic, vectors of infection, isolation, quarantine, mitigation, incubation period. as physicians and clinicians, we are all expected to be knowledgeable about infectious diseases, and to be a source of accurate information to friends and to family; the stress of judging how much to emphasize to our neighbors that a pandemic means that we cannot proceed with business as usual vs how much to note that it is not necessary to stock up on toilet paper is tiring. we are all being impacted in a variety of ways that we could not have imagined just last week. yesterday i heard on the news that three transportation security administration (tsa) workers at the nearby san jose, california airport had tested positive. while this is not surprising, given that each tsa worker undoubtedly comes in contact with hundreds of travelers from all over the globe on a daily basis, it also means that these workers potentially exposed more individual travelers who were coming from and going to all parts of the globe. some of you have children that you are both worrying about being exposed to the virus at school and worrying about how you will be able to work when the school is closed to prevent more infections. some of you have elderly parents who are most at risk for succumbing to the infection and its pulmonary complications. some of you have had to change your vacation plans for spring break. as the one source of information in the current administration whom i trust because he is a scientist, dr. anthony fauci stated, "we can't be doing the kinds of things we were doing a few months ago" (https://youtu.be/ jfd xzrjtc). but i, and most of you, are fortunate. we have jobs that allow us to have health insurance and sick leave. if this pandemic doesn't teach us that universal health insurance is needed in the united states, i don't know what will. individuals who do not have health insurance are being faced with significant medical bills when they contract the virus and perhaps ultimately become ill with pneumonia and respiratory compromise and must be hospitalized. not only does that individual and family suffer, but we all do when the virus spreads more widely because that individual must continue to work at a minimum wage job, as she has no health insurance, no paid sick leave, and thus no access to early testing or practical ability to self-quarantine without losing her job. we all suffer because our president disbanded the unit of the national security council that was established to coordinate a government-wide response to epidemics and left leaderless the homeland security advisor position that was intended to manage complex transnational threats. we all suffer when the government's response to providing early testing for covid- is too little and too late, leading to the move from containment to mitigation. currently, while testing is more widely available, it is still difficult to prescribe or find a site where testing can be done. specific and strong steps from the white house have been suggested and would help with mitigation, but we all are now involved on a local level, as well. as a groups of colleagues from adolescent medicine discussed these current events in clinic this week, we agreed that we were assuming that we would become infected. not that we might get infected, but that we would. my biggest fear is not that i myself will have a severe infection, even though i am past the age of and thus categorized as having a higher risk of complications. my fear is that when i get infected and before i become symptomatic, i will transmit the virus to friends, family, colleagues, anddimportantlydto other patients, many of whom are immunocompromised or have multiple comorbidities. so, i am socially distancing myself to the extent possible, and washing my hands and using alcohol gel multiple times a day. sometimes it's almost comical, as we struggle to find out what is appropriate in this new age. i sing in a choral group, and we had a rehearsal early this week, but rather than sitting close to one another in the church where we rehearse, we were spread outdthree to a pew in every other row of pews. the rehearsal was videoed so that the singers who chose not to come to practice were able to view a private youtube channel and sing along at home (i marvel at what technology can do). somehow, the rehearsal worked, and we were able to sing together the choruses from mendelssohn's wonderful oratorio, elijah. what about pag in the time of a pandemic? my patients are mostly still coming to appointments, although the "noshow" rates to clinic have been higher than usual. patients are being called and offered video telehealth visits if they have symptoms. there have been changes to inpatient visitor allowances, and limitations on who can accompany outpatients. physicians are being encouraged to provide telehealth visits. in the end, we will continue to do what we have been doing: provide care to girls and adolescent young women with urgent gynecologic problems, as we always have. and so, that brings me to this issue of jpag, and as usual, i am delighted to tell you of some of the content. my stanford adolescent medicine colleague neville golden has written an excellent review on bones and birth control. for me, the biggest take-away message from this thorough and well-written review is that low-dose combined oral contraceptives (cocs), those with < mg ethinyl estradiol, are insufficient to support peak bone mass acquisition during adolescence. this is a message that i have observed is sometimes lost on the community of general pediatricians and obstetrician-gynecologists; we pag clinicians can provide that educational message. low-dose cocs can be too low for adolescents. with regard to bones and depot medroxyprogesterone acetate for contraception, the review notes that both the society for adolescent health (sahm) and acog recommend that the risks and benefits of "the shot" for contraception be discussed with adolescents. as for long-acting reversible contraceptives (larc), these methods do not appear to affect peak bone mass acquisition or fracture risk, and remain the first-line contraceptive choice for teens. other important reports in this issue include a -part report on the unmet needs of both adolescent girls with heavy menstrual bleeding and dysmenorrhea and the unmet needs of their parents, from our colleagues in australia. , these authors document what we see in our clinical practices: that menstrual problems can have a profound impact on physical and psychosocial health of adolescents, and that they and their parents have a real need for information and support. drs. dietrich and hernandez provide a report from their institution on the gynecologic problems of adolescents with ehlers-danlos syndrome, which was helpful to me in the management of a patient i saw last week. this issue also contains reports on adolescents in juvenile detention facilities, an underserved and vulnerable population in general, with significant needs for reproductive healthcare. e stay healthy, and may jpag inform your clinical care. pandemic disease is a threat to national security as coronavirus numbers rise, c.d.c. testing comes under fire steps to tackle the coronavirus bones and birth control in adolescent girls unmet needs and experiences of adolescent girls with heavy menstrual bleeding and dysmenorrhea: a qualitative study exploring the unmet needs of parents of adolescent girls with heavy menstrual bleeding and dysmenorrhea: a qualitative study gynecologic management of pediatric and adolescent patients with ehlers-danlos syndrome access to reproductive health care in juvenile justice facilities effects of an interprofessional studentled sexual education program on self-efficacy and attitudes about sexual violence in youths in juvenile detention adams hillard pj: vulnerable adolescents key: cord- -fykm ovm authors: zyoud, sa’ed h. title: global toxocariasis research trends from to : a bibliometric analysis date: - - journal: health res policy syst doi: . /s - - - sha: doc_id: cord_uid: fykm ovm background: toxocariasis is a highly prevalent parasitic disease in the tropical regions of the world, with its impact on public health being typically underestimated. to better recognise the trends and characteristics of toxocariasis research, this study is a bibliometric analysis of the global toxocariasis research. methods: searches were completed on april , , using the scopus database. a search without any language restriction was performed to extract publications dealing with toxocariasis. terms related to toxocariasis were used to perform a title keyword search. results: a total of publications comprising document types and published between and were included in the analysis. articles were the most popular document form, accounting for . % of all publications, followed by letters ( . %) and reviews ( . %). the annual number of research publications increased from in to in , indicating that the number of publications on toxocariasis has increased slowly over the past years. the united states of america and japan are the predominant countries of origin, with articles and articles, respectively, followed by brazil and the united kingdom, with ( . %) each. the h-index for all the publications was . the highest h-index were for publications from the united kingdom (h-index value = ) and the united states (h-index value = ); these two countries were also involved with the highest number of international collaborations, with and countries, respectively. conclusions: developed countries, including the united states, japan, the united kingdom, france, germany and italy, are the world’s leaders in toxocariasis research, contributing to more than % of the total published literature. in addition, developing countries, such as brazil, poland, argentina and india, showed a noticeable increase in published papers on toxocariasis research in recent years. a push for more collaboration is needed to achieve a superior research strategy related to toxocariasis at the global level from the viewpoint of epidemiological data, clinical aspects, medical ecology, molecular aspects and treatment practices associated with toxocariasis. toxocariasis is a highly prevalent parasitic disease in the tropical regions of the world, with its impact on public health being typically underestimated [ ] [ ] [ ] . human toxocariasis is acquired by ingestion of toxocara canis or toxocara cati embryonated eggs present in the soil or on hands and fomites contaminated by the faeces of infected dogs or cats; thus, it is considered to be a widespread zoonotic parasitic disease [ , ] . toxocara specimens were first illustrated by werner in ; however, the genus was not recognized until by stiles [ ] . the clinical symptoms of toxocariasis in humans may vary from asymptomatic infection to localized symptoms (ocular and neurological) or severe systemic infection (visceral larva migrans), which is commonly complicated by blood eosinophilia [ ] [ ] [ ] . several studies have concluded that the cost of human toxocariasis is underestimated and understanding of its global impact remains poor because of the inadequacy of clinical awareness and an obvious lack of efficacy of laboratory, clinical and treatment interventions [ , , , [ ] [ ] [ ] . to the author's knowledge, to date, no bibliometric studies have assessed toxocara and toxocariasis research over time at the global level. the bibliometric technique has already been applied to infectious diseases such as mayaro [ ] , zika [ ] , chikungunya [ ] , leishmaniasis [ ] , malaria [ , ] , dengue [ , ] , ebola [ ] , middle east respiratory syndrome coronavirus [ ] and giardia lamblia [ ] . bibliometric analyses based on measuring the yearly publication output, publication types, source countries with their h-index, international collaboration research, source journals with their impact factors (ifs), and citation patterns are widely used by research funders or universities to assess research performance and to shed new light on future research trends. to better recognise the trends and characteristics of toxocariasis research, this study was designed to analyse the global toxocariasis research through bibliometric analysis. the method of this study was derived from those of previous similar studies [ , [ ] [ ] [ ] . searches were completed in april , , using the scopus database. a search without any language restriction was performed to extract publications dealing with toxocariasis. scopus published by elsevier is known to be the most common source of data for bibliometric studies in the sciences [ , [ ] [ ] [ ] . compared with other databases, such as pubmed or web of knowledge, its records provide more comprehensive coverage [ ] of the toxocariasis literature. the terms "toxocar*", "nematode ophthalmitis", "visceral larva migrans", "ocular larva migrans", "nematode endophthalmitis", "dog roundworm" and "cat roundworm" were used as keywords to search titles. these keywords were based on previous review articles [ , [ ] [ ] [ ] . the asterisk (*) was applied as a wildcard and enabled the search for variations of key terms. for example, entering "toxocar*" in the scopus search engine would include the following terms: toxocariasis, toxocarabriefly, any probable word that might start with the seven letters (i.e. 'toxocar'). therefore, searching only titles would have resulted in data more related to the field of toxocariasis. no time period restriction was designated in the search concerning the start date, thus all publications prior to december , , were included. in this study, a traditional bibliometric technique that included analysis of yearly publication output, languages, publication types, countries with their h-index, international collaboration research, source journals with their ifs, citation patterns and institutes was used. documents published in or errata were excluded from the analysis. ifs were retrieved from the journal citation reports (jcr ) [ ] . the values of the h-index were extracted from the scopus database for each country. the analysis in this study is based on a retrospective bibliometric technique; therefore, no ethical approval was required. microsoft excel® and version of spss® for windows were used to perform statistical analysis. these software packages were used to generate data on frequency distribution, percentage, sum and average, and to create fig. . further analysis was introduced to obtain the top tenranked prolific countries, most prolific journals, most prolific institutions and most cited papers by using the - - - rule, which is known as the standard competition ranking. a total of publications comprising document types published between and were found. articles were the most popular type of document, accounting for . % of all the publications, followed by letters ( . %) and reviews ( . %). of the different languages identified, english ( . %), spanish ( . %), french ( . %), german ( . %) and polish ( . %) were predominant. figure concerning the country of publication, countries with publications on toxocariasis were identified. table shows the top countries in descending order of publication number. the united states of america and japan were the predominant countries, with and articles, respectively, followed by brazil and the united kingdom with ( . %) each. the h-index for all the publications was . the highest h-index were for publications from the united kingdom (h-index value = ) and the united states (h-index value = ). the united states and the united kingdom participated in the highest number of international collaborations, with and countries, respectively. in terms of the rate of publications from international collaborative research to total research for each country, the united kingdom and germany ( . % and . %, respectively) were the most active. table . medicine comprised . % articles, followed by immunology and microbiology with . %, and veterinary with . %. table presents the most commonly cited toxocariasis publications between and [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the ifs varied from . for the th most cited paper to . for the th most cited paper. the total number of citations per publication in this table ranged from to . the most frequently cited article was published in journal of clinical investigation by del prete et al. [ ] from italy, which had been cited times. table summarizes the top productive institutes. among them, two were from brazil, and one each from slovakia, ireland, the netherlands, germany, japan, the united states, the united kingdom, australia and sri lanka. the instituto de medicina tropical de sao paulo was ranked st in institutional productivity with scientific research publications, followed by the parasitological institute of the slovak academy of sciences with articles and the universidade de sao paulo with . the current bibliometric study investigated the global toxocariasis research trends from to . a bibliometric analysis of the patterns of publication outputs, publication types, journals with their ifs, source countries with their h-indexes, international collaboration research, institutional distributions and most-cited articles were conducted. as shown in the current study, the annual number of research publications increased from in to in , showing that the number of publications on toxocariasis has increased slowly in the past years. an increase in research output has also been shown in similar research related to infectious diseases such as leishmaniasis [ ] , malaria [ ] and chagas disease [ ] . in a comparison of the number of publications since concerning toxocariasis, leishmaniasis, malaria and chagas disease, more rapid growth was observed in the number of papers focusing on leishmaniasis, of which , publications were published, followed by malaria ( , publications) and chagas disease ( publications) compared with toxocariasis, on which publications were published. from this, it was concluded that, while there was a relative increase in research output in the field of toxocariasis since , there was a higher interest in leishmaniasis, malaria and chagas disease than in toxocariasis during this time period. this difference in interest between different issues can be attributed to discrepancies in the funding available for different diseases. developed countries, including the united states, japan, the united kingdom, france, germany and italy, are leading countries in toxocariasis research, contributing to more than % of the world's total publications. possible explanations for these findings may be rapid economic growth or the progress of scientific research systems in these countries. these findings were similar to those reported in earlier bibliometric studies [ ] [ ] [ ] , which found that the economic growth of a country affected the quantity of research published by its researchers. developing countries, such as brazil, poland, argentina and india, showed a noticeable increase in published papers on toxocariasis research in recent years, which may have been coincident with a high prevalence of toxocariasis in these countries [ , [ ] [ ] [ ] . the united states and the united kingdom had the highest number of collaborations. multinational collaboration can help to draw attention to toxocariasis research. another advantage of this collaboration would be that internationally collaborative publications are usually cited more often than those from individual countries [ , ] . the most cited article, by del prete et al. [ ] in , was cited times. this italian study demonstrated that, in human, the t cell response to t. canis comes from the stimulation of t-helper type cell type by the "excretory-secretory" antigens of t. canis [ ] . the second most cited article was by despommier [ ] in , and looked at epidemiology, clinical and molecular aspects of toxocariasis and the medical ecology associated with the disease. to date, this is the first bibliometric study to assess the output of peer-reviewed publications on toxocariasis at the global level. previous bibliometric studies have stated the limitations characteristic of using such an approach [ , , , , [ ] [ ] [ ] . first, the publications might not have been included in the analysis if toxocariasis or its related words were not mentioned in their titles, although these terms might have been found in the text. a second limitation was that this study did not include publications on toxocariasis that were in non-indexed journals and thus would not have been available in the scopus database, such as those published in some chinese journals. this is the first study that investigated the global toxocariasis research trends from to . the findings strategy related to toxocariasis at the global level from the viewpoints of epidemiological data, clinical aspects, medical ecology, molecular aspects, and treatment practices associated with toxocariasis. moreover, the search queries in the current area are biased toward publications in the english language. therefore, it is important to know that most publications from china may be written in a language other than english, which limits access to these publications for non-chinese speakers; this may have led to an underestimation of the research activities in non-english countries such as china. abbreviations if: impact factor human toxocariasis: current advances in diagnostics, treatment, and interventions how common is human toxocariasis? towards standardizing our knowledge knowledge gaps in the epidemiology of toxocara: the enigma remains the epidemiology and public health importance of toxocariasis: a zoonosis of global importance neuroparasitology and tropical neurology toxocariasis-associated cardiac diseases -a systematic review of the literature cutaneous manifestations of human toxocariasis toxocariasis diagnosed in international travelers at the institute of tropical medicine toxocara seroprevalence among clinically healthy individuals, pregnant women and psychiatric patients and associated risk factors in shandong province microarray gene expression analysis reveals major differences between toxocara canis and toxocara cati neurotoxocarosis and involvement of t. canis in lipid biosynthetic processes visceral larva migrans syndromes associated with toxocariasis: epidemiology, clinical and laboratory aspects of human toxocariasis bibliometric assessment of the scientific production of literature regarding mayaro a bibliometric analysis of global zika research bibliometric assessment of scientific production of literature on chikungunya bibliometric analysis of leishmaniasis research in medline ( - ) a bibliometric analysis of malaria research in china during - abu-taha as. a bibliometric analysis of literature on malaria vector resistance bibliometric assessment of the latin-american contributions in dengue dengue research: a bibliometric analysis of worldwide and arab publications during - tracing the scientific outputs in the field of ebola research based on publications in the web of science global research trends of middle east respiratory syndrome coronavirus: a bibliometric analysis a bibliometric study of international scientific productivity in giardiasis covering the period - worldwide research productivity in the field of electronic cigarette: a bibliometric analysis a scopus-based examination of tobacco use publications in middle eastern arab countries during the period - bibliometric analysis of publications on campylobacter global research productivity of n-acetylcysteine use in paracetamol overdose: a bibliometric analysis global methaemoglobinaemia research output ( - ): a bibliometric analysis comparison of pubmed, scopus, web of science, and google scholar: strengths and weaknesses toxocariasis in north america: a systematic review toxocariasis and epilepsy: systematic review and meta-analysis a systematic review of toxocariasis: a neglected but high-prevalence disease in brazil a critical look at the importance, prevalence and control of toxocariasis and the possibilities of immunological control chronic eosinophilia due to visceral larva migrans; report of three cases in vitro maintenance of toxocara canis larvae and a simple method for the production of toxocara es antigen for use in serodiagnostic tests for visceral larva migrans toxocariasis: serological diagnosis by enzyme immunoassay purified protein derivative of mycobacterium tuberculosis and excretory-secretory antigen(s) of toxocara canis expand in vitro human t cells with stable and opposite (type t helper or type t helper) profile of cytokine production toxocariasis: clinical aspects, epidemiology, medical ecology, and molecular aspects toxocara cati: an underestimated zoonotic agent evaluation of serodiagnostic tests for visceral larva migrans epidemiology and pathogenesis of zoonotic toxocariasis immunodiagnosis of toxocarosis in humans: evaluation of a new enzyme-linked immunosorbent assay kit application of the western blotting procedure for the immunodiagnosis of human toxocariasis highlights of human toxocariasis characterization of surface and excretory-secretory antigens of toxocara canis infective larvae aspects of toxocara epidemiology: human toxocarosis human toxocariasis: diagnosis, worldwide seroprevalences and clinical expression of the systemic and ocular forms toxocara larva migrans now ocular toxocariasis. a review the expanded spectrum of toxocaral disease nematode endophthalmitis scientific research in malaria: bibliometric assessment of the latin-american contributions scientific authorships and collaboration network analysis on chagas disease: papers indexed in pubmed ( - ) global trends in dem-related research from to : a bibliometric analysis ecological engineering and ecosystem restoration global biodiversity research during - : a bibliometric analysis epidemiology of human toxocariasis in poland -a review of cases - urban contamination with zoonotic parasites in the central region of argentina human toxocariasis and ascariasis: concomitant parasitism in srinagar bibliometric analysis on global parkinson's disease research trends during - bibliometric profile of the global scientific research on methanol poisoning bibliometric analysis on global catha edulis (khat) research production during the period of - the arab world's contribution to solid waste literature: a bibliometric analysis none. no funding was received for writing this study.availability of data and materials not applicable. authors' contributions sz conceptualized the study, acquired and processed the data, performed statistical analysis, and wrote and approved the final manuscript. the author declares that he has no competing interests. not applicable. the analysis in this study is based on a retrospective bibliometric technique; therefore, no ethical approval was required. submit your next manuscript to biomed central and we will help you at every step: key: cord- -brhvfsgy authors: miller, ryan s.; farnsworth, matthew l.; malmberg, jennifer l. title: diseases at the livestock–wildlife interface: status, challenges, and opportunities in the united states date: - - journal: preventive veterinary medicine doi: . /j.prevetmed. . . sha: doc_id: cord_uid: brhvfsgy abstract in the last half century, significant attention has been given to animal diseases; however, our understanding of disease processes and how to manage them at the livestock–wildlife interface remains limited. in this study, we conduct a systematic review of the scientific literature to evaluate the status of diseases at the livestock–wildlife interface in the united states. specifically, the goals of the literature review were three fold: first to evaluate domestic animal diseases currently found in the united states where wildlife may play a role; second to identify critical issues faced in managing these diseases at the livestock–wildlife interface; and third to identify potential technical and policy strategies for addressing these issues. we found that of the avian, ruminant, swine, poultry, and lagomorph diseases that are reportable to the world organization for animal health (oie), are present in the united states; ( %) of these have a putative wildlife component associated with the transmission, maintenance, or life cycle of the pathogen; and ( %) are known to be zoonotic. at least six of these reportable diseases—bovine tuberculosis, paratuberculosis, brucellosis, avian influenza, rabies, and cattle fever tick (vector control)—have a wildlife reservoir that is a recognized impediment to eradication in domestic populations. the complex nature of these systems highlights the need to understand the role of wildlife in the epidemiology, transmission, and maintenance of infectious diseases of livestock. successful management or eradication of these diseases will require the development of cross-discipline and institutional collaborations. despite social and policy challenges, there remain opportunities to develop new collaborations and new technologies to mitigate the risks posed at the livestock–wildlife interface. despite significant attention given to animal diseases in the last half-century, our understanding of disease processes, and how to manage them at the livestock-wildlife interface, remains limited (rhyan and spraker, ) . the increasing role of wildlife in the emergence of livestock fig. . the number of publications in english language journals identified in scopus database with the words "wildlife" and "parasite" or "disease" in the title, abstract, or key words. decker et al., ; rhyan and spraker, ) , potentially exacerbating pathogen transmission processes between them. globally, the role of wildlife in livestock diseases is expected to increase (siembieda et al., ) in conjunction with human population growth, which is expected to reach billion by . this will create increased demand for animal protein thereby increasing livestock populations (anonymous, ) . the demand will further increase potentially infectious contacts between livestock and wildlife leading to an increased potential for new zoonotic diseases to emerge. all of these challenges will require an improved understanding of the ecology of pathogens at the livestock-wildlife interface along with development of tools and mitigations to manage these pathogens. historically, managing diseases affecting both livestock and wildlife as a single, linked system in north america, has presented several obstacles. conflicting agency and institutional missions, program goals, and cultural differences that limit the potential for developing comprehensive mitigation of pathogen transmission contribute to hampering efforts in this area. nevertheless, research and policy at the livestock-wildlife interface has received increased attention in recent years with the number of scientific publications in english journals addressing this topic rising dramatically (fig. ) . this is driven, though not exclusively, by a rapid increase in the number of zoonotic disease events associated with wildlife in the latter part of the th century (dobson and foufopoulos, ; ostfeld and holt, ; decker et al., ) . three-fourths of all emerging infectious diseases (eids) of humans are zoonotic with most originating in wildlife (taylor and latham, ; jones et al., ) . a large proportion ( %) of livestock pathogens-and an even higher proportion ( %) of carnivore pathogens-infect multiple hosts including wildlife (cleaveland et al., ) . therefore, diseases that arise from the livestock-wildlife interface are of paramount importance and must be an area of focus for animal health authorities (siembieda et al., ) . one example, nipah virus-classified as an emerging infectious pathogen-recently moved from its natural host (fruit bats) to domestic swine, causing disease and mortality in both swine and local agricultural workers and resulting in economic losses (epstein et al., a) . the nipah virus outbreak in malaysia destroyed the malaysian swine industry while the associated human fatalities simultaneously created massive public panic (epstein et al., a) . this newly recognized virus was carried by fruit bats for decades and emerged as a result of newly occurring habitat destruction, climatic changes, and the encroachment of food-animal production into wildlife domains (epstein et al., b) . although little discussed, pathogen transmission at the livestock-wildlife interface is frequently bi-directional (bengis et al., ) . in contrast to conventional thinking, livestock have introduced several pathogens, such as bovine brucellosis and tuberculosis bacterium, to naïve wildlife populations in north america. these two pathogens are found in at least five wildlife populations (tessaro, ; sweeney and miller, ) and create significant challenges for disease control at the livestock-wildlife interface. in some instances, spillover events from livestock into wildlife impact conservation of species of concern (dobson and foufopoulos, ; nishi et al., ; joly and messier, ; cross et al., ) . an example is the transmission and introduction of bovine brucellosis and tuberculosis from livestock into native wood bison (bison bisonathabascae) populations in canada, which has created a conservation challenge for the species (tessaro et al., ; nishi et al., ) . another well-publicized example is the introduction of brucellosis into native bison and elk populations of the yellowstone ecosystem in (meagher and meyer, ; meyer and meagher, ) . this resulted in a wildlife management challenge due to conflicts between livestock and bison preservation. the presence of brucellosis poses continued risk for transmission back into livestock creating biological, social, and policy challenges (cross et al., (cross et al., , . obstacles faced by wildlife managers and livestock authorities for mitigating contact between wildlife and livestock has resulted in significant efforts to develop technology that reduces contact and is economically feasible. however, development of effective tools that can be readily deployed has been met with a host of challenges. many devices prove to be ineffective or only effective for a short duration (vercauteren et al., (vercauteren et al., , a . the most successful tools have involved fencing technology (e.g. high fence, wire mesh, electrified high-tensile steel wire, or polytape) that reduces contact between wildlife and livestock feed (vercauteren et al., b (vercauteren et al., , . however, fencing suffers from limitations such as the need for relatively frequent maintenance. more recently, research has focused on the use of historic tools such as livestock protection dogs to prevent contact between livestock and wildlife. in some cases these traditional tools have proven to be the most effective (vercauteren et al., (vercauteren et al., , . in addition to the challenges faced in developing effective mitigation tools is gaining social acceptance of their use by farmers, which is fundamental in successfully using these tools (brook and mclachlan, ) . however, there remains a need for identifying new economically feasible tools that wildlife and livestock managers can deploy to reduce contact at the livestock-wildlife interface. improving our understanding of the biological and anthropogenic processes that promote contact between wildlife and livestock is critical for limiting pathogen transmission at this interface. given the frequently bidirectional nature of pathogen transmission, cooperation is required between livestock owners, animal health officials, and wildlife managers if control efforts are to be successful. conflicts will undoubtedly continue to challenge wildlife managers and livestock authorities seeking solutions, which can only be found through the creation of new partnerships and the strengthening of existing ones that bridge the gap between wildlife and livestock agencies at all levels. here we conduct a systematic review of the english scientific literature to evaluate the status of diseases and pathogens at the livestock-wildlife interface in the united states. specifically, the goals of the literature review were three fold: first, to evaluate domestic animal diseases currently found in the united states where wildlife may play a role; second, to identify critical issues faced in managing these diseases at the livestock-wildlife interface; and third, to identify potential technical and policy strategies for addressing these issues. we highlight two examples of emerging diseases at the livestock-wildlife interface in north america, which pose management challenges and offer an opportunity for comprehensive disease management by facilitating cross-agency and state-federal partnering. in the united states, there are currently avian, ruminant, swine, and lagomorph diseases reportable to the oie. of those, are listed as present in the united states (anonymous, b) . our review of these pathogens identified ( %) which have a potential wildlife component associated with the transmission, maintenance, or life cycle of the pathogen, and ( %) are known to be zoonotic (tables and ). of these pathogens, ( %) have an arthropod vector involved in the transmission while the remaining % involve direct or indirect transmission. sixteen ( %) of the diseases present in the united states affect multiple species of livestock, all of these have a wildlife component, and % are zoonotic. of the oie reportable diseases affecting cattle, out of are present in the united states and have a wildlife component; have zoonotic potential. a wildlife component has been identified for out of ( %) oie reportable avian diseases with of these recognized as zoonotic. of the avian, ruminant, and swine diseases, are currently actively managed in the united states with of these having a federal eradication or control program (table ) . thirteen ( %) of these actively managed diseases have a wildlife component and at least (bovine tuberculosis, paratuberculosis, brucellosis, avian influenza, rabies, and cattle fever tick [vector control]) have a wildlife reservoir that is a recognized impediment to eradication due to continued spillover to domestic populations. of these diseases, (bovine tuberculosis and brucellosis) have foci of infection in wildlife as a result of spillover from livestock-further complicating eradication programs. specific estimates of direct and indirect costs to livestock and recreational hunting industries, and to governmental agencies resulting from pathogen transmission at the livestock-wildlife interface, are elusive; however, some estimates are available for specific diseases. reestablishment of bovine babesia sp. to its historic range in north america via adaptation of babesia sp. vectors to whitetailed deer would cost approximately $ . billion to the cattle industry (anderson et al., ) . in michigan, the loss of bovine tuberculosis accredited-free status is estimated to result in total agriculture and livestock losses of approximately $ million per year (horan and wolf, ) . furthermore, the michigan department of natural resources spent an estimated $ million on defining the extent of the disease in wildlife and initial management steps alone (o'brien et al., ) and to date has spent an estimated $ million on control, surveillance, and management of the disease. rabies-an important zoonotic disease with significant public health, agricultural, and ecological impacts-is known to impose a financial burden on countries around the world. the centers for disease control and prevention estimates that the united states spends in excess of $ million annually on rabies prevention, detection, and control (anonymous, a) with more than $ million spent on wildlife vaccination alone (sterner et al., ) . avian influenza, which has a well-documented wild waterfowl reservoir, continues to plague the domestic poultry (hahn et al., ; corn et al., ; kirkpatrick et al., ; spickler et al., ) direct, indirect avian chlamydiosis ducks c , turkeys c , chickens o gulls r , ducks r , herons r , egrets r , pigeons r , blackbirds r , grackles r , house sparrows r , killdeer r , raptors s , shorebirds s , migratory birds s (vanrompay et al., ; thomas et al., ; spickler et al., ) direct house finches a , american goldfinches a , purple finches a , eastern tufted titmice a , pine grosbeaks a , evening grosbeaks a , others a (thomas et al., ; luttrell et al., ; ley et al., ; spickler et al., ) direct, indirect bluetongue sheep c , goats c , cattle sc wild ovine species a , cervids a , water buffalo a , pronghorn a , (williams and barker, ; stallknecht et al., ; robinson et al., ; spickler et al., ; hoff and trainer, ) arthropod-borne bovine anaplasmosis cattle c cervids r (woldehiwet, ; kuttler, ) arthropod-borne (anonymous, ) arthropod-borne (reisen et al., ; emord and morris, ; komar et al., ; tate et al., ; schmitt et al., ; spickler et al., ) arthropod-borne equine influenza equids c wild birds r , numerous other species s (munster et al., ) direct, indirect equine piroplasmosis equids c uncertain (kellogg et al., ; spickler et al., ) arthropod-borne equine rhinopneumonitis equids c numerous species u (kinyili and thorsen, ) direct, indirect fowl cholera poultry c wild birds r (thomas et al., ; petersen et al., ; botzler, ; blanchong et al., ) direct, indirect infectious bovine rhinotracheitis/infectious pustularvulvovaginitis cattle c several implicated u (zarnke, ; kinyili and thorsen, ) (thomas et al., ; brugh and beard, ; seal et al., ; clubb and hinsch, ; spickler et al., ) direct, indirect (daszak et al., ; thomas et al., ; spickler et al., ) arthropod-borne (thomas et al., ) direct, indirect * bovine babesiosis is not present in cattle in the united states however the causative agent has been reported in wildlife and a vector eradication program exists. ** b. ovis has been found to cause poor semen quality in red deer but abortions have not been reported. the role potential role of red deer is still in doubt. *** the united states is considered free from new castle disease in poultry however new castle disease is present in free ranging species and is included here for completeness. c = clinical sc = subclinical c-sc = may be clinical or subclinical o = occasional reports r = reservoir s = spillover a = affected species (not a true reservoir, nor a spillover host) u = uncertain industry in the united states with estimated outbreak associated losses ranging from $ to $ million (capua and alexander, ; saif and barnes, ) . estimated impacts to the united states in the event of an epizootic avian influenza pandemic are at least $ billion (meltzer et al., ; arnold et al., ) . other livestock diseases with wildlife reservoirs including brucellosis, bovine viral diarrhea, and several poultry diseases are associated with significant losses in livestock production. concepts for integrated and adaptive management systems for eids at the livestock-wildlife interface are proposed by multiple authors (thirgood, ; wasserberg et al., ( s) and sweden ( s) however surveillance systems are established in norway, finland, france, united kingdom, italy, spain, switzerland, and the united states (morner et al., ; pedersen et al., ) . the united kingdom (sainsbury et al., ; lysons et al., ; hartley and gill, ; hartley and lysons, ) has developed a program to implement integrated risk management and eid monitoring systems for wildlife. these nascent emerging systems have common themes, which may be adaptable to the united states. in the existing literature, five interdependent aspects of disease management are suggested as being necessary for successfully addressing disease issues at the livestock-wildlife interface: ( ) horizon scanning (issue identification); ( ) risk analysis and assessment; ( ) risk mitigation; ( ) surveillance and monitoring; and ( ) disease control and management. these components, described as integrating sequentially with feedback loops, incorporate learning about the system. as information about the disease agent is improved, management is adapted thereby improving actions performed in the other components (fig. ) . this process of adaptive management has been well described in the ecological and wildlife management literature (kendall, ; mccarthy and possingham, ) , but concepts related to adaptive management have only recently been proposed as a method for managing disease systems (thirgood, ; wasserberg et al., ). rapid identification of new and emerging infectious diseases (horizon scanning) in wildlife is critical to protecting animal agriculture and human health. there is mounting concern over the zoonotic potential, and subsequent wide-ranging socioeconomic impacts, associated with wildlife-borne eids (jones et al., ) . recent examples of eids emerging from wildlife include nipah virus in swine (chua et al., ) , severe acute respiratory syndrome (sars) in humans (riley et al., ) , and h n hpai in domestic poultry, wild birds, and humans (ferguson et al., ) . in addition, new issues continue to emerge with well-documented disease systems, such as bovine tuberculosis and brucellosis influencing agricultural systems and wildlife management in north america (olsen, a; o'brien et al., ) . other eid's of concern to agriculture are certain to emerge in the future, some of which may disperse rapidly across broad geographic scales (cleaveland et al., ; siembieda et al., ) . the risks of existing and new eid's to disperse rapidly highlight the need for robust systems for early identification of pathogens, which may have important health, social, economic, or other management consequences. risk analysis is an often broadly used term referring to risk characterization, risk communication, and risk management, which provides support for decision making and policy in the face of uncertainty (suter, ) . in the case of animal disease, risk analysis is an important tool used to identify and characterize the potential risks posed by implementation of policy or by specific events such as importation of livestock. risk analyses form the foundation from which animal health policy is established. however, for diseases at the livestock-wildlife interface, quantitative risk assessments are often difficult. challenges for conducting quantitative risk assessments often result from incomplete information related to the disease status of wildlife or limited understanding of the potential contact between wildlife and livestock leading to pathogen transmission. in addition accurate quantitative data describing the spatial distribution, movement, population structure, and population density are typically unavailable limiting inference to the population or understanding population level risk factors. data quantifying important epidemiologic parameters necessary for describing disease risk such as contact rates, disease status of wildlife, wildlife population size, or biological process of the pathogen in wildlife are often unstudied or poorly understood. risk assessments often assess the risk of pathogen transmission from wildlife to livestock (daniels et al., ) . however, for many diseases of livestock in north america (e.g. bovine tuberculosis, brucellosis) the initial transmission event is from livestock to wildlife, which in some cases results in the establishment of a wildlife reservoir for the pathogen posing continued risks to livestock (tessaro, ; sweeney and miller, ) . for these reasons the most successful and useful risk analyses consider the bi-directional nature of transmission and address questions of risk using statistical methods to explicitly incorporate uncertainty. in addition, studies that estimate contact between livestock and wildlife to understand potential for pathogen transmission are needed. mitigating transmission risk between livestock and wildlife has received considerable attention (vercauteren et al., b (vercauteren et al., , wasserberg et al., ) . the ability to eliminate livestock pathogens from north american wildlife populations has been rare and when successful required extensive culling of wildlife. an example is the eradication of foot-and-mouth disease from the united states in which required the culling of , deer from the stanislaus national forest in california (williams and barker, ) . wildlife removal strategies can have unintended consequence, which was exemplified in the united kingdom where wildlife behavior was changed as a result of culling increasing the risk of bovine tuberculosis transmission to cattle (woodroffe et al., ). in addition protected wildlife can complicate control or eradication efforts to control disease (meyer and meagher, ) . eradication efforts requiring the culling of large numbers of wildlife are likely untenable in the united states today, thus preventing establishment of livestock diseases in wildlife populations is a central pillar of long-term risk mitigation strategies. implementing risk mitigations may offer the greatest potential for reducing economic and social impacts resulting from shared diseases. this often involves modifying animal husbandry practices to reduce contact between livestock and wildlife-including modified livestock housing, which reduces contact with peri-domestic wildlife or altered feeding practices, which reduces available forage for wildlife. other risk mitigations include tools that prevent direct contact between wildlife such as frightening devices, fencing, or livestock protection dogs (vercauteren et al., (vercauteren et al., , b (vercauteren et al., , . however, the development and implementation of these tools comes with their own set of challenges. successful implementation often includes changing social behaviors of livestock producers and developing new tools to manage risk mitigation which are cost effective and efficacious over the long term. other risk mitigations may include identifying and reducing or eliminating risky management practices-such as allowing contact between livestock and wildlife which may foster the emergence of new pathogens in the united states. these may include translocation of wildlife or domestic and international wildlife trade. the need to develop comprehensive surveillance systems that integrate livestock, wildlife, and human components has been suggested (mörner et al., ) . robust surveillance systems in wildlife and at the livestock-wildlife interface to provide early detection of newly emerging eids or spillover and spillback of pathogens between livestock and wildlife is essential. developing a comprehensive national monitoring system for eids in wildlife that is logistically and fiscally sustainable could yield economic benefits for livestock health management as a whole by reducing indemnity costs associated with spillover of disease from wildlife to livestock or by helping prevent spillover from livestock to wildlife through early detection. the objectives of such a system could be enhanced by close integration with existing livestock and wildlife health programs to guide "when", "where", and "how" surveillance is conducted. in addition, existing programs would benefit from closer working relationships between wildlife biologists, ecologists, epidemiologists, and veterinarians to improve efforts focused on reducing pathogen transmission (boadella et al., ) . one obstacle to developing long-term, comprehensive surveillance efforts at the livestock-wildlife interface is inconsistent funding for these activities (leighton et al., ; stitt et al., ) . funding has typically been in response to emergency directives (e.g. hpai h n surveillance) and focused for a short period until the threat is perceived to no longer exist. this has, predictably, generated problems for developing a comprehensive national infrastructure that can be maintained over the long-term. in addition, there are disease systems that have plagued agriculture for decades, such as bovine tuberculosis, that do not obtain sufficient levels of funding to fully address risks for introduction into new wildlife hosts such as feral swine (sweeney and miller, ) . another challenge faced by wildlife surveillance systems is that they often rely on hunter observations and reports, which are focused on game species. this increases the difficulty of identifying emergence of disease in non-game species. finally, due to challenges associated with working across agency departmental boundaries, such as reduced communication, differing priorities, perceived competition in missions, and cultural differences wildlife surveillance efforts often remain less than fully coordinated which reduces their overall benefit. once a pathogen is identified at the livestock-wildlife interface, active management and control of the disease agent is often the only method for reducing impacts to human health, agriculture, and recreational hunting industries (boadella et al., ) . integrated strategies that bring wildlife, human, and agricultural agencies together offer the greatest opportunity for success. management of diseases at the livestock-wildlife interface often requires long-term engagement using a combination of altered livestock husbandry practices, active disease suppression in wildlife, and prevention of transmission using mitigation techniques. if surveillance and risk management activities at the livestock-wildlife interface are to be successful, we must recognize the complex nature of current and emerging diseases. these diseases can involve different health jurisdictions, socio-economic dimensions, and a wide range of stakeholders (i.e. livestock industry, conservation organizations, recreational hunters, etc.). we must promote strategic collaboration and partnerships across various disciplines, sectors, departments, ministries, institutions, and organizations at country, regional, and international levels (binder et al., ; fao et al., ) . with the recent focus on "one health", which recognizes that human, animal (both domestic and wild) and ecosystems are tightly linked, successful management of disease requires an integrated approach where efforts are focused in concert across these domains (king et al., ; welburn, ) . in response to the one health focus several countries have developed specific plans to address wildlife health as it relates to human and domestic animal health (sainsbury et al., ; hartley and lysons, ) . however, obstacles still remain in developing robust systems which integrate across the domestic, wild animal, and human domains. in most countries, sector-specific institutions have clear roles, responsibilities, and budgets-but mechanisms for cross-sector collaboration typically do not exist. developing collaborations often proves difficult even mandated from the highest levels of government, as exemplified by continued outbreaks of highly pathogenic avian influenza in several countries (fao et al., ) . the united states suffers from similar limitations, due in part to the bicameral regulatory and legal authority for oversight of livestock and wildlife. states have clear ownership of wildlife; federal regulatory authorities do not always extend to control disease in livestock to manage the disease in wildlife. thus, the effective control of disease incursions from wildlife to livestock requires state and federal livestock management agencies to foster positive working relationships with wildlife agencies. unfortunately, such relationships frequently have not been developed resulting in a decision making process on livestock disease management in which wildlife appear as an afterthought, when often they are integral to disease maintenance and spread. involving all relevant stakeholders (i.e. livestock industry, wildlife conservation groups, wildlife health authorities, livestock health authorities, etc.) in the development of regional or ecosystem-level livestock disease management planning, from the beginning of the process, increases the likelihood of success (loomis, ) . one example of ongoing challenges animal health authorities face is found in the management of brucellosis in the yellowstone ecosystem. controversy has surrounded the management of brucellosis in the bison and elk within the ecosystem. these issues have often pitted federal, state, agricultural, and wildlife agencies against one another. several have noted that one of the most important constraints to managing brucellosis in yellowstone is jurisdictional inertia, or the unwillingness of agencies to relinquish their existing domains of territorial control (lavigne, ; mcbeth and shanahan, ) . this example underscores the need for wildlife, human, and agricultural agencies to develop strong working relationships prior to emergence of disease. integrated approaches to prevention before observing outbreaks in both wildlife and livestock may offer an opportunity for agencies to foster working relationships prior to a crisis. development of clear mechanisms and agreements will enhance collaboration and interaction at all levels and should include incorporation of the roles and mandates of the various institutions and agencies involved. often the agreements and working relationships that are established occur only at the highest levels of the organization resulting in little benefit to those working to implement program objectives. opportunities for professional interactions and working relationships needs to be created and supported at the field level in addition to the administrative level (fao et al., ) . historically, integrated cross-disciplinary collaboration between livestock and wildlife agencies has been a challenge. however, many programs managing animal health diseases could benefit significantly from increased communication and collaborations that combine program objectives and activities across agency jurisdictions. while challenging from a political and cultural perspective, the outcome could be beneficial and would enhance the ability to quickly identify and respond to new and emerging disease issues. integrating state and federal livestock and wildlife agencies into the disease program planning process could reap future rewards. below we illustrate the potential for crosssector collaboration using two disease eradication programs-cattle fever tick eradication and bovine tuberculosis eradication-facing challenges presented by the livestock-wildlife interface. other disease eradication and management programs that address issues associated with the diseases and pathogens listed in table would also likely benefit from increased collaboration across livestock, wildlife, and human agencies at both state and federal levels. bovine babesiosies, caused by hematoprotozoan parasites of the genus babesia, is globally among the most significant tick-borne disease of cattle (white et al., ; martinez et al., ) . in north america, the most important vectors of bovine babesiosis are rhipicephalus microplus and r. annulatus-collectively known as cattle fever ticks. cattle fever ticks were extirpated from the united states in after a nearly -year eradication campaign (graham and hourrigan, ; bram et al., ) . the eradication campaign exploited the perceived narrow host range of cattle fever ticks in combination with highly effective and now banned acaricides, which allowed the program to focus almost exclusively on the treatment of cattle (bram et al., ) . reestablishment of cattle fever ticks and bovine babesia to their historic range in north america is estimated to cost $ . billion in control efforts and cattle production losses (anderson et al., ) . as a result, animal health authorities and livestock producers consider mitigating this risk a priority. in recent years, there have been increasing infestations of cattle fever ticks on cattle along the texas-mexico border ( de león adalberto et al., ) . historically considered to be highly host specific for cattle, there is increasing evidence that white-tailed deer and other ungulates are suitable hosts for cattle fever ticks with infested deer found in locations absent of cattle (cantu et al., ) . in texas, cattle fever ticks have been recovered from free-ranging and captive-exotic ungulates including axis deer, fallow deer, elk, red deer, aoudad sheep, and nilgai antelope (mertins et al., ) . due to the potential ineffectiveness of treating tick infestations in cattle with currently approved methods, such as mandatory removal of cattle from affected pastures for a period of time (i.e. pasture vacation) and treatment of cattle with acaricides the treatment of white-tailed deer and other wildlife has become necessary. a recent study indicates that cattle fever ticks have a high degree of genetic fluidity, which may allow them to adapt to new host species and therefore provide a potential pathway for reestablishment in the united states via wildlife hosts (de meeus et al., ) . white-tailed deer are also increasingly being recognized as a potential reservoir for the babesia species (b. bigemina, b. divergens, and b. bovis) which cause clinical disease in cattle ( de león adalberto et al., ) . surveys for babesia in northern mexico and texas have identified molecular and serological evidence for the presence of b. bigemina and b. bovis in white-tailed deer and in nilgai antelope populations (cantu et al., ; cardenas-canales et al., ) . these changes in the host-pathogen system, and gaps in the understanding of cattle fever tick ecology and the host range of babesia, require the formulation of more effective control strategies that include both wildlife and livestock. to effectively address these challenges, state and federal agencies representing both livestock and wildlife authorities need to partner to develop policy that integrates surveillance and risk mitigations across both cattle and wildlife populations. an historic limitation of the program has been the nearly exclusive focus on controlling cattle fever ticks on cattle . recently the program has begun to deploy mitigations to control ticks on wildlife; however, the program is limited by a lack of operational tools to mitigate infestations on wildlife and a regulatory framework that would integrate management of the disease across wildlife and livestock authorities. while challenging, this offers an exciting opportunity to develop effective strategies and methods to address surveillance at the livestock-wildlife interface and to develop new mitigations that reduce the risk of infestation. bovine tuberculosis (btb), identified in nine geographically distinct wildlife populations in north america and hawaii, is endemic in at least four populations, including members of the bovidae, cervidae, and suidaefamilies (sweeney and miller, ) . the emergence of btb in north american wildlife poses a serious and growing risk for livestock and human health and for the recreational hunting industry. experience in many countries, including the united states and canada, has shown that while btb can be controlled when restricted to livestock species, it is almost impossible to eradicate this disease once it has spread into ecosystems with free-ranging maintenance hosts. recent epidemiological models suggest that once btb is introduced, the probability of becoming established in a wildlife population once introduced is at least % (ramsey et al., ) . spillover into wildlife-and establishment of new foci of infection in wildlife-would be costly to the cattle industry and animal health authorities. in addition, new foci of wildlife infection would complicate eradication efforts. therefore, preventing spillover of mycobacterium bovis into wildlife may be the most effective way to mitigate economic costs of btb. historically, wildlife control efforts for btb have focused solely on potential spillover into wild cervid species. however, m. bovis has been isolated from free-ranging swine (i.e. wild boar and feral swine) in at least countries (letts, ; corner et al., ; essey et al., ; o'reilly and daborn, ; aranaz et al., ; serraino et al., ; palmer, ) . new evidence from mediterranean ecosystems supports the role of wild swine as maintenance hosts of btb-sustaining infection and transmitting the pathogen to other species (aranaz et al., ; naranjo et al., ) . circumstances favoring btb transmission between wildlife and livestock in the mediterranean include artificial increases in wild game populations stimulated by a robust hunting industry, feeding and baiting of wildlife, and intensive cattle grazing in proximity to wild swine (hermoso de mendoza et al., ) . all of these characteristics likely apply to conditions in north america. particularly worrisome is the recent appearance of feral swine in the state of michigan where the potential exists for interaction with btb-infected white-tailed deer and cattle. regions of the southern united states also pose a risk where high densities of feral swine, an established hunting industry, significant baiting and feeding of wildlife, and introductions of btb infected cattle from mexico continue to occur (sweeney and miller, ) . furthermore recent evidence indicates that m. bovis may be present in free ranging white-tailed deer in northern mexico. one study report the presence of m. tuberculosis complex identified using amplification of dna from a tissue by pcr . the authors also report histopathology consistent with m. bovis infection observed in white-tailed deer. another study reported the frequent detection of antibodies against mycobacterium antigens in a cross-sectional survey of white-tailed deer in northern mexico (medrano et al., ) . while the risks posed by wildlife have been recognized, current investigations and response to potential spillover events from cattle to wildlife (cervid or swine), where disease is exceedingly more difficult to control or eradicate is inconsistently managed. few standards are in existence which establish best practices for investigating potential spillover into wildlife hosts. developing national policies and working relationships across agencies responsible for domestic and wildlife health at the state and federal level would have long-term benefits for preventing the risk of introduction of btb into new wildlife host populations. nearly % of the pathogens present in the united states have a potential wildlife component. to successfully manage and control these pathogens at the livestock-wildlife interface will require the development of cross-discipline collaborations and establishing common goals between agencies and organizations that in some cases have rarely worked together. we believe the principles of adaptive management offer the greatest opportunities to formulate a framework from which collaborations can be developed to manage diseases at the livestock-wildlife interface. eid monitoring systems for wildlife that incorporate and implement integrated risk management in an adaptive management framework offer the best opportunity for success. in addition, new and creative funding mechanisms that bring livestock and wildlife animal health authorities along with livestock industry and wildlife stakeholders together will need to be created. despite these social and policy challenges, there remain opportunities to develop new collaborations-along with the development of new technologies-to mitigate disease risks at the livestock-wildlife interface. we believe that two diseases eradication programs-bovine tuberculosis and cattle fever tick-offer the best opportunity to apply these principles and demonstrate success. seroprevalence of brucellosis, tularemia, and yersiniosis in wild boars (sus scrofa) from north-eastern germany economic impact of expanded fever tick range world population to diseases caused by the epizootic hemorrhagic disease virus serogroup. the center for food security and public health infectious bursal disease (gumboro disease). oie terrestrial manual. world organisation for animal health cost of rabies prevention status of reportable diseases in the united states united states department of agriculture spacer oligonucleotide typing of mycobacterium bovis strains from cattle and other animals: a tool for studying epidemiology of 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of managing infectious wildlife disease anthrax and wildlife rodents, rabbits and tularemia in north america: some zoological and epidemiological considerations the effect of bovine tuberculosis and brucellosis on reproduction and survival of wood bison in wood buffalo national park molecular identification and characterization of novel coronaviruses infecting graylag geese (anser anser), feral pigeons (columbia livia) and mallards (anas platyrhynchos) global trends in emerging infectious diseases arthropod parasites collected from white-tailed deer using models to facilitate complex decisions. modeling in natural resource management executive summary of the avma one health initiative task force report antigenic comparisons between herpesviruses isolated from fallow deer in alberta and the viruses of infectious bovine rhinotracheitis, equine rhinopneumonitis and dn- , a non-ibr bovine herpesvirus possible role of wild mammals in transmission of pseudorabies to swine eastern equine 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characteristics of -month-old red deer stags transmission dynamics of the etiological agent of sars in hong kong: impact of public health interventions bluetongue in the desert bighorn sheep diseases of poultry status of wildlife health monitoring in the united kingdom seroprevalence rates and transmission of plague (yersinia pestis) in mammalian carnivores. vector-borne zoonot an outbreak of eastern equine encephalitis virus in free-ranging white-tailed deer in michigan new ruminant hosts and wider geographic range identified for babesia odocoilei the avian response to newcastle disease virus monitoring transmission of tuberculosis between wild boars and cattle: genotypical analysis of strains by molecular epidemiology techniques fowl typhoid and pullorum disease the role of wildlife in transboundary animal diseases emerging and exotic diseases of animals. center for food security and public health and the institute for international cooperation in animal biologics precipitating antibodies to epizootic hemorrhagic disease and bluetongue viruses in white-tailed deer in the southeastern united states tactics and economics of wildlife oral rabies vaccination, canada and the united states modelling wildlife rabies: transmission, economics, and conservation opportunities and obstacles to collecting wildlife disease data for public health purposes: results of a pilot study on vancouver island echinococcus multilocularis identified in indiana, ohio, and east-central illinois distribution and prevalence of echinococcus multilocularis in wild predators in nebraska, kansas, and wyoming ecological risk assessment assessment of pathways for the introduction and spread of mycobacterium bovis in the united states. united states department of agriculture eastern equine encephalitis in a free-ranging white-tailed deer (odocoileus virginianus) risk factors for human disease emergence a survey of brucellosis and tuberculosis in bison in and around wood buffalo national park the existing and potential importance of brucellosis and tuberculosis in canadian wildlife: a review new perspectives on managing wildlife diseases infectious diseases of wild birds molecular and morphological characterization of echinococcus in cervids from north america north american and french caprine arthritis-encephalitis viruses emerge from ovine maedi-visna viruses chlamydia psittaci infections: a review with emphasis on avian chlamydiosis epidemiology of mycoplasma agalactiae infection in free-ranging spanish ibex (capra pyrenaica the dynamic role of livestock protection dogs in a changing world green and blue lasers are ineffective for dispersing deer at night fences and deerdamage management: a review of designs and efficacy livestock protection dogs for deterring deer from cattle and feed a fence design for excluding elk without impeding other wildlife efficacy of an animal-activated frightening device on urban elk and mule deer host culling as an adaptive management tool for chronic wasting disease in white tailed deer: a modelling study epizootic vesicular stomatitis in colorado, : some observations on the possible role of wildlife populations in an enzootic maintenance cycle one health: the st century challenge the vulnerability of the australian beef industry to impacts of the cattle tick (boophilus microplus) under climate change chronic wasting disease infectious diseases of wild mammals chronic wasting disease of deer and elk: a review with recommendations for management the natural history of anaplasma phagocytophilum bovine tuberculosis in cattle and badgers in localized culling areas serologic survey for selected microbial pathogens in alaskan wildlife we would like to acknowledge the insightful comments and critical review of early versions of this manuscript by dr. steve sweeney, dr. tom deliberto, dr. reginald johnson, dr. kathe bjork, dr. tracey lynn, and mr. allan nelson. we also would like to recognize the diligent efforts of ms. mary foley for supporting our continued literature and library science inquiries and ms. carol losapio for her editing contribution. we also thank two anonymous reviewers for their critical and insightful comments on this manuscript. key: cord- -f onp mg authors: owen, james a.; skelton, jann b.; maine, lucinda l. title: advancing the adoption of continuing professional development (cpd) in the united states date: - - journal: pharmacy (basel) doi: . /pharmacy sha: doc_id: cord_uid: f onp mg over the last four decades, the expanded patient care roles of pharmacists in the united states (u.s.) have increased focus on ensuring the implementation of processes to enhance continuing professional development within the profession. the transition from a model of continuing pharmacy education (cpe) to a model of continuing professional development (cpd) is still evolving. as pharmacists assume more complex roles in patient care delivery, particularly in community-based settings, the need to demonstrate and maintain professional competence becomes more critical. in addition, long-held processes for post-graduate education and licensure must also continue to adapt to meet these changing needs. members of the pharmacy profession in the u.s. must adopt the concept of cpd and implement processes to support the thoughtful completion of professional development plans. comprehensive, state-of-the-art technology solutions are available to assist pharmacists with understanding, implementing and applying cpd to their professional lives. pharmacists' patient care roles continue to expand in the united states. to prepare for these enhanced roles, the pharmacy profession is building the infrastructure and developing processes to support workforce development, prepare pharmacists to meet new practice opportunities, and drive practice transformation. a primary focus is the need to shift from a system of typically undirected continuing professional education (cpe) to acceptance of, and engagement in, the holistic approach of continuing professional development (cpd). the pharmacy profession in the united states represents pharmacists in substantially diverse practice environments and patient care settings who operate with variation in scope and authority in different states across the country. adoption of the principles of cpd is essential to enable pharmacists to develop, prepare, and maintain competency and proficiency in practice over time and to retool to support ongoing transformations in practice. within the profession in the united states, there is a gap in understanding and awareness of the differences between cpd and cpe, with most pharmacists believing that these concepts are interchangeable. the concept of cpd within the profession of pharmacy was initially defined by the international pharmaceutical federation (fip) as "the responsibility of individual pharmacists for systematic maintenance, development and broadening of knowledge, skills and attitudes, to ensure continuing competence as a professional, throughout their careers" [ ] . cpe is defined as: "a structured educational activity designed or intended to support the continuing development of pharmacists and/or pharmacy technicians to maintain and enhance their competence" [ ] . while cpd for pharmacists has expanded globally, the universal adoption of the concept is still illusive. over the past years, professional pharmacy organizations in the united states have pharmacists in the u.s. work in highly diverse practice settings. in the pharmacist workforce study conducted by the pharmacy workforce center, the most predominant settings are community-based and hospital practices [ ] . according to the u.s. bureau of labor statistics, % of pharmacists work in community-based settings and % work in health-systems [ ] . the diversity of community-based practice in the united states has been driven by the patient-centered focus of the u.s. health care system. patients seek to obtain care most conveniently, when and where they want it. community-based care settings serve as convenient, cost-effective, primary access points to care. the american pharmacists association (apha) has published a model of community-based pharmacy practice that describes this practice as any patient care setting outside the four walls of a hospital or health-system (see figure ). the term "community-based pharmacist practitioner" highlights the unique skillset that pharmacists use when they provide patient care services, and it brings recognition to the value community pharmacists contribute to patients, communities, and the health care system [ , ] . the complexity of pharmacy practice within the united states is driven primarily by the regulatory process. while there are some commonalities, pharmacy practice is governed by the laws, regulations, and rules set forth by each individual state or jurisdiction. what is permitted in one jurisdiction may be prohibited by another, and even states geographically close may have pharmacists in the u.s. work in highly diverse practice settings. in the pharmacist workforce study conducted by the pharmacy workforce center, the most predominant settings are community-based and hospital practices [ ] . according to the u.s. bureau of labor statistics, % of pharmacists work in community-based settings and % work in health-systems [ ] . the diversity of community-based practice in the united states has been driven by the patient-centered focus of the u.s. health care system. patients seek to obtain care most conveniently, when and where they want it. community-based care settings serve as convenient, cost-effective, primary access points to care. the american pharmacists association (apha) has published a model of community-based pharmacy practice that describes this practice as any patient care setting outside the four walls of a hospital or health-system (see figure ). the term "community-based pharmacist practitioner" highlights the unique skillset that pharmacists use when they provide patient care services, and it brings recognition to the value community pharmacists contribute to patients, communities, and the health care system [ , ] . pharmacists in the u.s. work in highly diverse practice settings. in the pharmacist workforce study conducted by the pharmacy workforce center, the most predominant settings are community-based and hospital practices [ ] . according to the u.s. bureau of labor statistics, % of pharmacists work in community-based settings and % work in health-systems [ ] . the diversity of community-based practice in the united states has been driven by the patient-centered focus of the u.s. health care system. patients seek to obtain care most conveniently, when and where they want it. community-based care settings serve as convenient, cost-effective, primary access points to care. the american pharmacists association (apha) has published a model of community-based pharmacy practice that describes this practice as any patient care setting outside the four walls of a hospital or health-system (see figure ). the term "community-based pharmacist practitioner" highlights the unique skillset that pharmacists use when they provide patient care services, and it brings recognition to the value community pharmacists contribute to patients, communities, and the health care system [ , ] . the complexity of pharmacy practice within the united states is driven primarily by the regulatory process. while there are some commonalities, pharmacy practice is governed by the laws, regulations, and rules set forth by each individual state or jurisdiction. what is permitted in one jurisdiction may be prohibited by another, and even states geographically close may have the complexity of pharmacy practice within the united states is driven primarily by the regulatory process. while there are some commonalities, pharmacy practice is governed by the laws, regulations, and rules set forth by each individual state or jurisdiction. what is permitted in one jurisdiction may be prohibited by another, and even states geographically close may have substantially different authorities in scope of practice. an example of this variability is in the laws and regulations that empower pharmacists to immunize. in some states, pharmacists can only immunize according to an established protocol, in other states by a protocol and a prescription, and still other states with no authorization, depending upon the type of vaccination and age of the patient. additionally, the restrictions on immunizations provided by pharmacists also extend to permitting immunizations of patients of various ages, ranging from greater than three years to years old [ ] . the variability of practice laws, regulations, and rules expand across many areas of practice. another emerging area of practice in the united states is the initiation of therapy via prescribing under statewide protocols, statewide standing orders, or unrestricted authority. as demonstrated in figure , data collected by the national alliance of state pharmacy associations, there is variability in practice scope across the country, with the broadest prescriptive authority provided in the state of idaho with authorization for pharmacists to prescribe medications in greater than categories [ ] . substantially different authorities in scope of practice. an example of this variability is in the laws and regulations that empower pharmacists to immunize. in some states, pharmacists can only immunize according to an established protocol, in other states by a protocol and a prescription, and still other states with no authorization, depending upon the type of vaccination and age of the patient. additionally, the restrictions on immunizations provided by pharmacists also extend to permitting immunizations of patients of various ages, ranging from greater than three years to years old [ ] . the variability of practice laws, regulations, and rules expand across many areas of practice. another emerging area of practice in the united states is the initiation of therapy via prescribing under statewide protocols, statewide standing orders, or unrestricted authority. as demonstrated in figure , data collected by the national alliance of state pharmacy associations, there is variability in practice scope across the country, with the broadest prescriptive authority provided in the state of idaho with authorization for pharmacists to prescribe medications in greater than categories [ ] . as the breadth and depth of pharmacist services increase and the scope of practice and authority for pharmacists continues to rapidly expand, there is a pressing need for pharmacists to engage in intentional, purposeful, and directed professional development focused on the specific needs of the individual pharmacist. responsibility for the quality of pharmacy education in the united states is overseen by acpe, which was initially founded in in collaboration with apha, the american association of colleges of pharmacy (aacp), the national association of boards of pharmacy (nabp), and the american council on education. acpe serves as the autonomous body for the accreditation of schools and colleges of pharmacy and providers of continuing education and is the only accreditation program recognized by the u.s. department of education to accredit pharmacy professional degree programs. nabp oversees u.s. pharmacist license requirements and administers the north american pharmacist licensure examination (naplex ® ) and the multistate pharmacy jurisprudence examination (mpje ® ). nabp facilitates the interstate/inter-jurisdiction transfer or reciprocation of a pharmacist's licensure, based upon a minimum standard for pharmacy education and uniform legislation requirements. state boards of pharmacy manage and maintain records for licensure of individual pharmacists. the established and predominant model for pharmacist re-licensure is built upon the concept of cpe, which was developed to align with continuing education requirements for other health care professionals. cpe for pharmacy was initially discussed in the united states in the s, and in , florida became the first state to mandate cpe for pharmacist licensees [ ] . from to , the as the breadth and depth of pharmacist services increase and the scope of practice and authority for pharmacists continues to rapidly expand, there is a pressing need for pharmacists to engage in intentional, purposeful, and directed professional development focused on the specific needs of the individual pharmacist. responsibility for the quality of pharmacy education in the united states is overseen by acpe, which was initially founded in in collaboration with apha, the american association of colleges of pharmacy (aacp), the national association of boards of pharmacy (nabp), and the american council on education. acpe serves as the autonomous body for the accreditation of schools and colleges of pharmacy and providers of continuing education and is the only accreditation program recognized by the u.s. department of education to accredit pharmacy professional degree programs. nabp oversees u.s. pharmacist license requirements and administers the north american pharmacist licensure examination (naplex ® ) and the multistate pharmacy jurisprudence examination (mpje ® ). nabp facilitates the interstate/inter-jurisdiction transfer or reciprocation of a pharmacist's licensure, based upon a minimum standard for pharmacy education and uniform legislation requirements. state boards of pharmacy manage and maintain records for licensure of individual pharmacists. the established and predominant model for pharmacist re-licensure is built upon the concept of cpe, which was developed to align with continuing education requirements for other health care professionals. cpe for pharmacy was initially discussed in the united states in the s, and in , florida became the first state to mandate cpe for pharmacist licensees [ ] . from to , the apha and aacp task force on continuing competency in pharmacy concluded that "cpe was the best mechanism to assure pharmacist proficiency" [ ] . in , nabp adopted a formal resolution on mandatory continuing education for re-licensure. that same year, the apha board of trustees recommended acpe develop a system for accreditation of cpe providers. in , acpe introduced the initial standards for cpe. beginning in , all states and territories in the united states now require completion of a specified amount of acpe-accredited or state-approved cpe for license renewal [ ] . as with state practice laws, regulations, and rules, requirements for cpe are also variable by individual state or jurisdiction. historically, reporting, tracking, and maintenance of cpe records were considered the responsibility of individual pharmacists. each state has requirements for submitting documentation, reporting cpe completion, or attesting to meeting the requirements established for re-licensure. in , nabp and acpe partnered on cpe monitor ® , a technology solution to help pharmacists and state boards of pharmacy track and manage the completion of cpe required for state re-licensure. the cpe monitor ® system changed the reporting requirements from pharmacists to the cpe providers and required all pharmacist users to register with and obtain an e-profile with nabp. this service enabled state boards of pharmacy to access license completion data for acpe-accredited cpe programs as a means of tracking compliance with cpe completion by licensees in the state's jurisdiction [ ] . while cpe is beneficial in contributing to the maintenance of professional competency, questions remain about the benefits of cpe alone in assuring clinical competence in practice [ ] . globally, the methods used to assure sustained professional competencies for pharmacists are diverse and variable. some countries, such as canada and japan, ensure competence through on-going and continued assessments tied to retaining or expanding the authority to practice. other countries, such as the united kingdom, ireland, and others, have adopted models of cpd with varying degrees of success [ ] . the united states has been slow to adopt cpd, with only the states of iowa and north carolina recognizing cpd, in addition to cpe, as part of their licensure requirements. all other states only recognize cpe within their licensure criteria. in the profession of medicine, the american medical association (ama) describes the responsibility for ensuring continuing professional competency in the ama code of medical ethics. the ama code of medical ethics states, "a physician shall continue to study, apply, and advance scientific knowledge, maintain a commitment to medical education, make relevant information available to patients, colleagues, and the public, obtain consultation and use the talents of other health care professionals when indicated" [ ] . in pharmacy, apha states in the code of ethics for pharmacists, adopted in , that, "a pharmacist maintains professional competence. a pharmacist has a duty to maintain knowledge and abilities as new medications, devices, and technologies become available, and as health information advances" [ ] . globally, the fip code of ethics for pharmacists, adopted in , states pharmacists have a responsibility "to ensure competency in each pharmaceutical service provided by continually updating knowledge and skills. [ ] additionally, the codes of ethics of other health care practitioners, including nurses and physician assistants, share the same perspective of protecting the care and welfare of patients in the provision of patient care by ensuring on-going, continuing professional competency maintenance and development throughout the health care practitioner's career [ , ] . in , the institute of medicine (iom) published the report redesigning continuing education in the health professions. this report stated, "all health professions should move toward requiring licensed health professionals to demonstrate periodically their ability to deliver patient care through direct measures of technical competence, patient assessment, evaluation of patient outcomes, and other evidence-based assessment methods". the iom report published the following statements [ ] : a workforce of knowledgeable health professionals is critical to the discovery and application of health care practices to prevent diseases and promote well-being the absence of a comprehensive and well-integrated system of continuing education in the health professions is an important factor of knowledge and performance deficiencies at the individual and system levels the new vision for continuing education will be based on an approach called cpd in which learning takes place over a lifetime and stretches beyond the classroom to the point of care the cpd system is a holistic approach that incorporates a broader variety of learning methods and theories than ce cpd is learner-driven and tailored to the individual learner's needs; it includes concepts such as self-directed learning and practice-based learning and teaches how to identify problems and apply solutions while cpd existed in the health professions before the iom report in , over the last decade, increased focus on the implementation of these recommendations have assisted many health professions to refocus efforts on implementing cpd to ensure the clinical competence of members in their respective disciplines. one of the earliest advancements of cpd in the pharmacy profession can be traced to work completed by fip in . the fip statement of professional standards, continuing professional development, stated, "pharmacists are health care professionals whose professional responsibilities include seeking to ensure that people derive maximum therapeutic benefit from their treatments with medicines. this requires them to keep abreast of developments in pharmacy practice and the pharmaceutical sciences, professional standards requirements, the laws governing pharmacy and medicines and advances in knowledge and technology relating to the use of medicines. this can only be achieved by an individual's personal commitment to continuing professional development." the fip model for cpd is depicted in figure . the fip model defines the following requirements for cpd [ ] : the cpd process is defined as "the responsibility of individual pharmacists for systematic maintenance, development and broadening of knowledge, skills and attitudes, to ensure continuing competence as a professional, throughout their careers" ce is an important part of a structured cpd program, personalized for each pharmacist the cpd process should be visible to ensure credibility with the public cpd must be actively managed and include all the components of the cyclical process cpd must be an on-going, cyclical process of continuing quality improvement by which pharmacists seek to maintain and enhance their competence in both current duties and anticipated future service developments in the united states, the council on credentialing in pharmacy (ccp), the body that serves to coordinate credentialing and cpd for the profession, expanded on the work published by fip and in released the council on credentialing in pharmacy resource document, continuing professional development in pharmacy. this document was aligned with the model published by fip two years earlier. ccp summarized that the need for cpd is to [ ] : ensure that pharmacists maintain (at an appropriate level) their knowledge, skills, and competence to practice through their careers in their own specific (or current) areas of practice improve the pharmacist's personal performance (i.e., develop knowledge and skills) enhance the pharmacist's career progression while aligned with the fip model, the ccp model was modified slightly to meet the identified needs of pharmacists in the united states. the ccp model is shown in figure . ensure that pharmacists maintain (at an appropriate level) their knowledge, skills, and competence to practice through their careers in their own specific (or current) areas of practice  improve the pharmacist's personal performance (i.e., develop knowledge and skills)  enhance the pharmacist's career progression while aligned with the fip model, the ccp model was modified slightly to meet the identified needs of pharmacists in the united states. the ccp model is shown in figure . ensure that pharmacists maintain (at an appropriate level) their knowledge, skills, and competence to practice through their careers in their own specific (or current) areas of practice  improve the pharmacist's personal performance (i.e., develop knowledge and skills)  enhance the pharmacist's career progression while aligned with the fip model, the ccp model was modified slightly to meet the identified needs of pharmacists in the united states. the ccp model is shown in figure . in january , acpe published the accreditation council for pharmacy education guidance on continuing professional development (cpd) for the profession of pharmacy. this guidance provided explanation and clarification of the differences between cpe and cpd and offered further refinement of the model published by ccp in . importantly, the acpe guidance provided specific categories and examples of cpd activities that helped to better explain to pharmacists and the pharmacy profession the types and scope of activities associated with cpd. the model published in the acpe guidance is shown in figure [ ] . the pharmacy profession the types and scope of activities associated with cpd. the model published in the acpe guidance is shown in figure [ ]. pharmacy in the united states is constantly changing, and the job market is extremely competitive. pharmacists must engage in lifelong learning to stay relevant, meet licensure requirements and complete activities that employers assign. pharmacists also have individual professional goals that may support seeking a promotion or changing career paths. one of the most challenging concepts for pharmacists to adopt is that cpd is broader than participation in cpe. as stated in an article published in jama in , "ce on its own, does not necessarily lead to positive changes in professional practice, nor does it necessarily improve health outcomes" [ ] . despite almost twenty years since the work conducted by fip in pharmacy, and the publication of resources and guidance by both ccp and acpe, there remains little awareness or understanding in the united states among practicing pharmacists about the differences between cpe and cpd. a study conducted by fip gathered data and reported detailed findings from countries about their experiences with cpd. this report documented the following [ ] : the cpd approach to learning is embraced more by those with a mentor or colleague demonstrating use or those that incorporated a similar approach during their undergraduate education"  "the flexibility of the cpd approach allows those with specialized practice to engage in learning that is most beneficial to their particular practice (e.g., non-pharmacy conferences, workplace learning, research, etc.)"  "there is value in focusing on an outcome in practice (i.e., applying newly-acquired knowledge to practice)"  "pharmacists support the cpd process when the impact in practice is recognized"  "the cpd cycle enables a continuous learning process and becomes a valuable platform to reinforce continuing competence within practice" the report also outlined the challenges that different countries experienced with the successful implementation of cpd. examples of these challenges detailed by fip include [ ] :  "application of the cpd cycle as an approach to lifelong learning in individual practice"  "changing the focus of cpd to meaningful learning rather than collecting ce points"  "developing the skills and knowledge to adopt the cpd process under a voluntary system" pharmacy in the united states is constantly changing, and the job market is extremely competitive. pharmacists must engage in lifelong learning to stay relevant, meet licensure requirements and complete activities that employers assign. pharmacists also have individual professional goals that may support seeking a promotion or changing career paths. one of the most challenging concepts for pharmacists to adopt is that cpd is broader than participation in cpe. as stated in an article published in jama in , "ce on its own, does not necessarily lead to positive changes in professional practice, nor does it necessarily improve health outcomes" [ ] . despite almost twenty years since the work conducted by fip in pharmacy, and the publication of resources and guidance by both ccp and acpe, there remains little awareness or understanding in the united states among practicing pharmacists about the differences between cpe and cpd. a study conducted by fip gathered data and reported detailed findings from countries about their experiences with cpd. this report documented the following [ ] : "the cpd approach to learning is embraced more by those with a mentor or colleague demonstrating use or those that incorporated a similar approach during their undergraduate education" "the flexibility of the cpd approach allows those with specialized practice to engage in learning that is most beneficial to their particular practice (e.g., non-pharmacy conferences, workplace learning, research, etc.)" "there is value in focusing on an outcome in practice (i.e., applying newly-acquired knowledge to practice)" "pharmacists support the cpd process when the impact in practice is recognized" "the cpd cycle enables a continuous learning process and becomes a valuable platform to reinforce continuing competence within practice" the report also outlined the challenges that different countries experienced with the successful implementation of cpd. examples of these challenges detailed by fip include [ ] : "application of the cpd cycle as an approach to lifelong learning in individual practice" "changing the focus of cpd to meaningful learning rather than collecting ce points" "developing the skills and knowledge to adopt the cpd process under a voluntary system" "establishing adequate assessment methods and measures for a portfolio-based system" pharmacy , , of "raising the awareness and recognition from the public on the skills and knowledge that pharmacists continuously develop" "ensuring the qualitative assessment of cpd portfolios" "lack of technical 'know-how' for implementing a robust online system to support the cpd process" "ensuring pharmacists engage with the cpd cycle that includes reflection on their practice" "minimizing cost constraints for pharmacists to undertake formal cpd programs" "making the recording or documentation of learning less onerous" "identifying those pharmacists who require additional mentoring or guidance to steer away from the hour or point collecting mentality" "ensuring relevant support for pharmacists in non-traditional roles" this report collectively demonstrated that pharmacists engaged in cpd had improved the quality of their learning, which leads to improved self-assessment of learning needs and enhancements in overall pharmacy practice. the report identifies challenges to the widespread implementation of cpd. pharmacists are often unfamiliar with the cpd process and the time commitment required for implementation. pharmacists trained on cpd and who used tools to facilitate the process were more likely to be successful. the availability of tools and resources that support pharmacist engagement in cpd is imperative to enable expanded implementation. according to the report, competency standards, pharmacist learning plans, and competency mapping of cpd activities must also be more effectively linked. finally, efforts to raise awareness of the differences between ce and cpd are required [ ] . adoption of technology solutions can help provide support to pharmacists wishing to engage in cpd and minimize the challenges associated with cpd adoption. specifically in the united states, a different approach toward implementation of cpd may be required of pharmacists, ce providers, employers/institutions, and regulators. these entities should recognize that many pharmacists will need to gain new expertise, such as identifying individual learning needs, writing smart learning objectives, and developing personal learning plans to implement cpd in practice [ , ] . infrastructure is also needed to help support workforce development and ensure that the profession is equipped to rapidly assess pharmacist readiness and retool pharmacist learning. this issue has recently been highlighted in the united states, with all organizations and individual pharmacists engaging in professional development activities to learn to care for patients with covid- . to help pharmacists better understand and embrace the tenants of cpd, several professional pharmacy organizations have developed technology solutions to support pharmacist adoption of cpd. over the last five years, acpe has undertaken substantial work to communicate the value of cpd in the united states. through acpe board of directors' directed projects, task forces and initiatives, and a partnership to develop an app called cpe monitor plus ® , acpe launched an initial technology solution called my cpd ® that permits users to create and manage a cpd plan. cpe monitor plus ® was launched in april and is available as a subscription service through purchase of the app by the individual pharmacist [ ] . my cpd ® is a web-based platform that allows pharmacists to create, record and maintain cpd details. pharmacists build and evaluate personal development plans, document learning activities, and upload supporting evidence of learning and its impact in practice. my cpd ® tracks both accredited ce as well other cpd activities undertaken in order to maintain and advance competencies in areas relevant to professional responsibilities. currently, the my cpd ® platform does not support personal assessments but encourages the development of individual goals and objectives. the my cpd ® app provides an overview of professional development and helps pharmacists create cpd cycles and review professional progress over time. according to the my cpd ® website, mycpd ® allows pharmacists to: ensure that knowledge, skills, attitudes, and values are kept current apply learning to improve practice and/or patient outcomes direct career goals or support career advancements or changes provide cv or interview templates fulfill employment, regulatory and credentialing requirements in late , apha began developing a state-of-the-art web-based technology solution, advance ® , to enable pharmacists to proactively engage in the cpd process. designed by and for pharmacists, advance ® was developed with the end-user in mind, taking a complex process and simplifying it using interactive and intuitive technology solutions. advance ® is an online professional development planner for pharmacists to easily create a personalized plan. advance ® takes the complex process of professional development planning and maintenance and simplifies and streamlines the process [ ] . the advance ® process is aligned with the fip, ccp, and acpe models and provides a pharmacist-friendly user interface that supports pharmacists through the process to complete their annual professional development plan. as shown in figure , all users complete five steps to develop a cpd plan. these steps include: evaluate-guides pharmacists through seven evaluation exercises to determine professional development needs analyze-helps pharmacists determine the meaning of the information provided in the evaluate step and provides a framework to establish smart planning goals plan-supports pharmacists by recommending activities and experiences customized to the individual, from which they can create a comprehensive professional development plan do-provides a framework to help pharmacists set priorities and deadlines for all selected activities, track accomplishments, and maintain a professional portfolio apply-prompts pharmacists to reflect on the activities they have completed, consider what they may want to focus on next, and make updates to the professional development plan the identification of personal learning needs is a core feature of this cpd platform. pharmacists are guided through assessments that help users honestly and comprehensively assess their current status and determine professional development needs. these assessments include: strengths-leveraging personal strengths can help pharmacists better understand themselves, how they work, and how they contribute to a team. professional skills-each individual has a unique set of professional skills shaped by past experiences, interests, and goals. like many aspects of life, professional skills may change or grow over time. this assessment leverages the entrustable professional activities and allows pharmacists to assess both their baseline and progress toward improving their skills. personal attributes-personal attributes are associated with how an individual's personality, emotions, and tendencies contribute to their behaviors. these attributes can significantly impact a professional's ability to interact with others and function effectively. interest areas-aligning an individual's career with their interests increases the likelihood that they will achieve professional satisfaction and maximizes the impact of cpd. growth and development-the technology platform evaluates each user's assessments and provides customized areas for growth and development focused on the improvement of professional skills and personal attributes. licensure-evaluating a summary of your licensure requirements supports pharmacists in designing a professional development plan that simultaneously keeps professional licenses active and individuals moving toward their goals. well-being-pharmacist well-being is essential to personal and professional productivity, and understanding factors that create stress or support relaxation can positively impact both the personal and professional needs of pharmacists. models and provides a pharmacist-friendly user interface that supports pharmacists through the process to complete their annual professional development plan. as shown in figure , all users complete five steps to develop a cpd plan. these steps include:  evaluate-guides pharmacists through seven evaluation exercises to determine professional development needs  analyze-helps pharmacists determine the meaning of the information provided in the evaluate step and provides a framework to establish smart planning goals  plan-supports pharmacists by recommending activities and experiences customized to the individual, from which they can create a comprehensive professional development plan  do-provides a framework to help pharmacists set priorities and deadlines for all selected activities, track accomplishments, and maintain a professional portfolio  apply-prompts pharmacists to reflect on the activities they have completed, consider what they may want to focus on next, and make updates to the professional development plan pharmacists are guided to review and analyze what they have discovered through these assessments, interpret the information, and examine each area's importance to their personal and professional development. this assessment process allows for the development of a more customized and valuable cpd plan and supports the prioritization of established goals. the cpd plan is comprised of six types of activities and experiences, which include patient care, management, leadership, community service, scholarly activity and well-being. by harmonizing skills, interests, strengths, and attributes with licensure and employer requirements, advance ® recommends specific activities and experiences that are aligned to an individual pharmacist and helps make cpd more attainable for practicing pharmacists. recommended activities might include cpe programs, books, videos, articles, community events, advocacy, or a variety of other actions. the technology allows pharmacists to prioritize and track activities and reflect on experiences and accomplishments. maintenance of a personal portfolio is stressed, with tools that allow pharmacists to attach relevant information and documents to their cpd plan. users are prompted to keep their plan current by reviewing information, documenting progress and making updates to the plan at least quarterly. simply stated, advance ® takes the complicated cpd process, which is foreign to most pharmacists, and makes cpd accessible, intentional, understandable and usable for practicing pharmacists. in the report of the - aacp academic affairs committee, the organization outlined its plans to align with other organizations and associations providing cpd initiatives focused on the large-scale pharmacist workforce. aacp also recently proposed policy to support advance ® as a novel approach to enabling workforce development [ ] . although available models of cpd may vary slightly, the published processes are similar and all provide support to a pharmacist engaging in cpd. table provides a crosswalk to the models, the steps, and the functions of the cpd models. completion of an annual self-evaluation-collect and analyze/assess relevant information and determine meaning creation of a detailed action plan specifying activities and experiences associated with each area of cpd engage in activities and experiences and track progress implement what was learned and reflect on the impact. routinely review and update information and make necessary modifications to plan. as pharmacists throughout the united states expand the nature and complexity of patient care services and push for enhanced authority within their jurisdictions, the need to maintain and demonstrate competency and proficiency remains critical. while cpd alone will not lead to improved care and outcomes, it will promote the overall growth and development of professional knowledge, skills, and abilities leading to enhanced professional competency. organizations focused on encouraging and supporting pharmacist engagement in cpd should reinforce the importance of keeping knowledge, skills and abilities current. for many pharmacists, the concept of cpd is novel, and pharmacists should be encouraged to use any process or program they find effective in supporting and advancing their cpd. lifelong learning encompasses all learning activities undertaken throughout life, with the aim of improving knowledge, skills and competencies within a personal, civic, social and/or employment related perspective [ ] . research done during the development process for advance ® reinforced the value of supporting pharmacist assessments of personal character attributes, which include skills such as leadership, management, accountability, conflict resolution and collaboration. personal character attributes contribute to a pharmacist's professional identity and are also an important component of professional development. the re-professionalization of pharmacists in the united states is needed, and adoption of cpd models with supporting technology can facilitate awareness, understanding, and uptake by pharmacists. as the roles of pharmacists continue to expand in the united states and globally, pharmacists must recommit to their personal and professional development. members of the pharmacy profession must adopt the concept of cpd and implement processes to support the thoughtful completion of professional development plans. comprehensive, state-of-the-art technology solutions are available to assist pharmacists with understanding and implementing cpd in their professional lives. additionally, systems such as advance ® provide the profession with a comprehensive solution to track the progress of individuals and populations over time, which may assist the profession in better meeting the development needs of the profession as a whole. to facilitate the adoption and acceptance of cpd in the united states, it is recommended that technolgies such as cpe monitor plus ® fip-international pharmaceutical federation. statement of professional standards on continuing professional development forty years of acpe cpe accreditation opportunities and responsibilities in pharmaceutical care accreditation council for pharmacy education. policies and procedures for acpe accreditation of professional degree programs ashp's pharmacy residency match sees continued growth community-based pharmacy residency directors and preceptors open forum perceived motivating factors and barriers for the completion of postgraduate training among american pharmacy students prior to beginning advanced pharmacy practice experiences growth of pharmacist board certification state flexibility to facilitate timely access to drug therapy by expanding the scope of pharmacy practice using collaborative practice agreements, standing orders or other predetermined protocols national governor's association. the expanding role of pharmacists in a transformed health care system patients access to pharmacists' care coalition. pharmacist scope of services national pharmacist workforce study final report recognition of community-based pharmacist practitioners: essential health care providers developing a vision and strategic action plan for future community-based residency training pharmacist administered vaccines prescribing under a statewide protocol, statewide standing order or unrestricted (category-specific) authority accreditation council for pharmacy education american association of colleges of pharmacy preliminary report of the aacp/apha task force on continuing competence in pharmacy-the continuing competence of pharmacists the benefit of continuing professional development for continuing pharmacy education continuing professional development/continuing education in pharmacy: global report code of ethics for pharmacists international federation of pharmacists. fip statement of professional standards: code of ethics for pharmacists american nurses association. code of ethics for nurses american association of physician assistants. guidelines for ethical conduct for the pa profession committee on planning a continuing health professional education institute. redesigning continuing education in the health professions international federation of pharmacists. fip statement of professional standards continuing professional development resource document on continuing professional development in pharmacy guidance on continuing professional development (cpd) for the profession of pharmacy impact of formal continuing medical education: do conferences, workshops, rounds, and other traditional continuing education activities change physician behavior or health care outcomes? continuing professional development/continuing education in pharmacy: a global report continuing professional development training program among pharmacist preceptors and non-preceptors continuing professional development: don't miss the obvious national association of boards of pharmacy. cpe monitor plans report of the - aacp academic affairs committee developing the pharmacist workforce for society's medication use needs in glossary:lifelong_learning#:~{}:text=jump% to% a% navigation% % c% search, social% or% employment% drelated% perspectives this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license the authors wish to acknowledge the previous and ongoing work of michael j. rouse, bpharm (hons), mps, ffip, and peter h. vlasses, pharmd, bcps, to advance the concept of cpd within the profession of pharmacy. pharmacy organizations that have worked to drive adoptions of cpd, including ccp, national alliance of state pharmacy associations, and fip, should also be acknowledged. the authors declare no conflict of interest. pharmacy , , of and advance ® be adopted to simplify the task of engaging in cpd by both practicing pharmacists and student pharmacists in the united states. key: cord- - g v authors: huang, qingming title: the pandemic and the transformation of liberal international order date: - - journal: j chin polit sci doi: . /s - - - sha: doc_id: cord_uid: g v in , leading international relations scholars in the united states signed a public statement in support of an urgent call to preserve the current international order, triggering heated scholarly debates. the idealized form of the liberal international order was criticized by many scholars for its chronic problems, including the contradictions between proclaimed liberal values and illiberal behaviors, the inability to reform its institutional pillars to accommodate the diverse group of emerging powers, and the tensions between the defenders of this order and its challengers. these problems became fully exposed under the external shock caused by the coronavirus pandemic. as the coronavirus spreads globally and disrupts the world’s political, economic, and social fabric, several forces that have gained momentum and strength during the last decade are now converging as a formidable force that may reconfigure the post-pandemic international order. this paper addresses three significant challenges to the foundations of the current liberal order: ( ) the entrenchment of authoritarianism, characterized by authoritarian resilience, autocratization, and the consolidation of competing authoritarian political-economic models; ( ) the exacerbation of nationalism enabled by nationalist and populist politicians; and ( ) the intensified competition among major powers. china has played mixed roles in the process of reconfiguring the current order. it challenges the mythologized liberal international order and exposes the contradictions in the dominant western model, while promoting an alternative hybrid political-economic model. the shock brought by the pandemic has provided ample opportunities for china to extend its networks and expand international space for its model. two years ago, leading international relations (ir) scholars in the united states signed a public statement in support of an urgent call to preserve the current international order, triggering heated debates among ir scholars. in the statement, prominent ir scholars reiterated the benefits provided by the liberal international order after the second world war, including economic stability and prosperity, as well as international security and peace. they warned against the potential destruction that american president donald trump would bring and the chaos that could ensue in the international arena. conversely, other scholars noted the limitations of the often-idealized liberal international order and the troubles associated with its major institutional pillars [ , ] . critics suggest that, by treating the potential change in the current international order as a crisis, the order's defenders might reflect an entrenched western-centric-and especially u.s.-centric-view of ir, ignoring the chronic problems rooted in such an idealized order. problems that have received increased scrutiny in recent years include ( ) contradictions between proclaimed liberal values and illiberal behaviors [ , ] ; ( ) an inability to reform the order's institutional pillars to accommodate the diverse group of emerging powers [ ] [ ] [ ] ; and ( ) tensions between the defenders and challengers of this order [ ] . notwithstanding their distinct positions in pre-covid- debates, there is one point on which they might agree. that is, the external shock of the novel coronavirus pandemic has generated significant pressures on the current liberal international order. the pandemic has reinvigorated debates about maintaining or restructuring the current order, and the directions of change [ ] . this paper joins the timely scholarly debates about the crisis and future of liberal international order by analyzing the changing dynamics in both domestic and global contexts during the pandemic. specifically, this paper addresses the following questions: what are the underlying tensions of the current liberal order and the sources of change to this order? how has the pandemic changed the dynamics of the current order and destabilized its major foundations? what are the implications of these changes and the roles played by challengers such as china? the current liberal international order rests upon at least three crucial foundations: ( ) the liberal ideology that emphasizes democratic values and norms; ( ) the principle of multilateralism, which emphasizes international cooperation and management of international affairs through multilateral institutions; and ( ) a group of defenders with common goals and shared commitment to preserve liberal values, norms, principles, and institutions. in this paper, i argue that, these core foundational components are under attack from all sides during the coronavirus pandemic. as the coronavirus spreads globally and disrupts the world's political, economic, and social fabric, several forces that have gained momentum and strength during the last decade are now converging as a formidable force during the pandemic. the convergence of these forces not only exposes the underlying tensions of current order but will also reconfigure the post-pandemic global order. in this paper, i focus on three significant material and ideational forces currently shaking the foundations of the existing liberal order. these mutually reinforcing domestic and international sources of change are generating immense pressure to transform the current order. first, the entrenchment of authoritarianism is eroding the popularity of liberal ideology and altering the regime landscape worldwide. this first force is characterized by authoritarian resilience, autocratization, and the consolidation of competing authoritarian political-economic models led by china and other challengers. second, the exacerbation of nationalism, enabled by nationalist and populist politicians, has damaged the popularity and authority of established westerndominated international institutions that buttress multilateralism and the seemingly unstoppable forces of globalization promoted by the liberal order. the surge of nationalism also pushes states to make choices that are most aligned with their national interests, from both material and ideological perspectives. third, the pandemic has intensified the competition among major powers, including the retreating global leader (the united states), the weakening coalition (the european union), and the rising but besieged challenger (china) . the myth about an ideal and cohesive liberal order, forged by western solidarity and a shared sense of purpose and righteousness, has been debunked during the pandemic, leaving space for challengers like china to exploit the internal division and fragmentation within the west and extend its influence globally. this paper begins by examining the literature on liberal international order and discusses the three major foundations of this order. it highlights the contrast between the ideal and the reality of liberal international order, juxtaposes the defenders and challengers' perspectives, and illustrates the underlying tensions of current order. in the next section, this paper analyzes how multiple forces during the pandemic are shaking the major foundations of the current international order and the implications of each of these changes. this paper concludes with the discussion of china's mixed roles and position in a multiplex international order with competing political-economic models. in the weeks following the public statement by ir scholars, more than scholars joined the efforts in defending the post-war liberal international order. most scholars agree that this order has produced unprecedented peace and prosperity, and u.s. leadership is essential for its success. the united states has paid a large portion of the costs of this order but has also benefited substantially [ ] . according to ikenberry, the u.s.-led post-war liberal international order is "a hierarchical order with liberal characteristics" [ : ] . on the one hand, the united states has dominated the order and served as the leading provider of rule and stability in this order. on the other hand, the order has been built on the liberal principles of governance supported by a wide array of multilateral rules and institutions. in general, the order is "relatively open, rulebased, and progressive" [ : ] . more specifically, it has been "organized around economic openness, multilateral institutions, security cooperation and democratic solidarity" and has undergone significant expansion after the end of the cold war [ : ] . the u.s.-led liberal international order was at its zenith after the downfall of the ideological and geopolitical rival-the soviet union-and the end of the cold war. according to the existing literature, the liberal international order has been solidly supported by at least three major foundations. first, in terms of ideology, it is liberal at its core. the collapse of communism and the expansion of democracy across several regions of the world was seen as the triumphant moment for western liberal democracies [ , ] . liberal ideology that emphasizes democratic values and norms has not only been consolidated in western countries but also proliferated to countries previously outside the boundary of the "free world". with the expansion of the "free world", liberal internationalism offers a set of ideas and agendas that liberal democracies use to organize the world based on their vision of "an open, loosely rules-based and progressively oriented international order" [ ] . universal values, such as the rule of law, respect for countries' sovereignty and territorial integrity, and protection of human rights, were promoted globally in an open-to-all and voluntary way. with the help of hard power, the ideals embraced by democracies are to "be applied to the entire planet", shaping the world in a single kind of order, or "whole" [ ] . in other words, alternative ideologies such as authoritarianism and exclusionary nationalism are to be cast aside to further expand the international space for liberal ideology. second, the u.s.-led liberal international order has been based on the principle of multilateralism, which emphasizes international cooperation and management of international affairs through multilateral institutions. as ruggie describes, multilateralism is an institutional form that "coordinates behavior among three or more states on the basis of generalized principles of conduct" [ : ] . multilateralism served as the foundational principle for the american post-war planners to reconstruct the international order [ : ] . the international institutions constructed under the principle of multilateralism remain robust and adaptive over time and play an essential role in sustaining the liberal international order [ ] . they act as "agents of norm construction and normative change" that could regulate and transform state behavior. they not only help to define, promote, and legitimize certain global norms but also make the transformation of international order more legitimate and peaceful [ ] . multilateral institutions and related norms helped stabilize the international system after the sudden collapse of the soviet union [ : ] . since the end of the cold war, rather than abandoning or weakening their commitment to multilateral institutions such as the north atlantic treaty organization (nato) and the european union (eu), states have invested more material and reputational resources into these institutions to realize their interests and gain from the order [ ] . moreover, along with the expansion of liberal international order and the integration of more countries into the global capitalist system, multilateral institutions and the policies forged within such institutions have enabled and promoted both political and economic globalization. lastly, the post-war liberal international order has been guarded by a group of defenders with common goals and shared commitment to preserve liberal values, norms, principles, and institutions. the dominance of the united states with economic and military superiority has helped ensure "an international system of relative peace and security," and "created and enforced the rules of a liberal international economic order" [ ] . under the auspice of this hegemonic superpower and with the support from other western powers, international institutions that weave the liberal international order together are able to sustain their vitality and respond to the changing international environment [ , ] . the united states has become a leading provider of a wide array of public goods, upholding rules and institutions, facilitating security cooperation, managing global economy, and promoting shared values and norms. as ikenberry puts it, during the cold war, the american liberal hegemony, as a distinctive type of international order, was further "'fused' to the evolving and deepening postwar liberal order" [ : ] . in other words, the united states is deeply embedded in the current order. the order is essentially structured around this dominant power and its democratic allies and clients. the united states not only serves as the primary provider of global public goods but also as the leader and unifier of the liberal order. moreover, the group of defenders rallying behind the united states have shared ideology, interest, and commitment to sustain a cohesive liberal order. considering the liberal international order in its idealized form, it seems to be trapped in a deepening crisis. the first sign of crisis is evident in the decline of the united states and its gradual disengagement from international affairs, especially after trump took office. during his first term, trump withdrew from the paris accord; the trans-pacific partnership; the united nations educational, scientific and cultural organization (unesco); and the united nations human rights council (unhrc). moreover, he has generated tensions with long-term allies in europe and tarnished the image of the liberal order. as expressed by trump in his speech at the un general assembly, "america will always choose independence and cooperation over global governance, control, and domination" [ ] . it seems that the united states is stepping back from its role as a world leader. some scholars lament that, without a broader vision as defender of the free world, and with a new focus on pursuing narrow national interest, trump's america is abandoning its "global leadership" as the "long-time champion" of the liberal international order [ ] . even worse, trump has launched a direct attack on this order-the system of multilateral trade and alliances that the united states built to serve its interests and attract others to its "way of life" [ ] . cooley and nexon's assessment further demonstrates that the unravelling of american hegemony was already underway before trump's presidency. trump only sped up america's retreat in the liberal international order [ ] . moreover, the doubt cast on america's leadership by its allies in europe, the loss of "a vision of how the world is supposed to work", and the challenge from internal fragmentation all contributed to "the eclipse of the west" [ ] . the second sign of crisis is the rise of china and russia in the international arena. scholars had already sounded alarms before trump took office. besides their military power, challengers like china and russia threaten the existing liberal order by disrupting it with their own political systems, interests, and ideologies [ ] . according to stephens, the rise of revisionist powers, including china, russia, and iran, have posed serious challenges to america's claims on "both the goodness and the success of the liberal-democratic model". as these powers become increasingly assertive and ambitious, the u.s.-led order is in deep trouble [ ] . moreover, a larger group of challengers-the emerging economies in the brics countries (brazil, russia, india, china, and south africa)-are increasingly undermining the western dominance, especially after the financial crisis in [ , ] . in particular, in recent years, china has moved from a reformist of the liberal international order to a revisionist that seeks to establish "new systems of governance and international cooperation" [ : ] . the factors behind this change include china's renewed self-confidence and awareness of a greater role in global arena, the reluctance of the west to reform, the weakening of the united states after the financial crisis, and the dominant powers' alienation of developing countries [ ] . although scholars disagree on the extent of disruption that china may bring to the liberal international order, there are evident concerns that the u.s.-led order may be replaced by a new one dominated by china [ ] [ ] [ ] . to many western scholars, these two trends-the retreat of the united states and the rise of powerful challengers-are indeed worrisome, as reflected in their warnings of a "new global disorder" [ ] or "a descent into the chaos of a world without effective institutions that encourage and organize cooperation." in stephens's words, the only alternative to pax americana would be global disorder [ ] . and it is likely to bring about "a highly competitive international environment" that may result in "unprecedented global calamity" [ ] . the main problem with this line of argument is that, the liberal international order discussed by these scholars tends to mix its normative aspect with the observed reality. their emphasis on the normative or idealized aspect of the liberal international order often leads to the assumption that this order is a unitary and cohesive whole that needs to be preserved in its original form, including perpetuating the american dominance. as such, any existing alternatives or emerging experiments are considered as disruptive to the order or sowing the seeds of disorder. in particular, an illiberal order would be considered as the opposite of all the good things brought together in the liberal order. it will be "politically and economically divided and closed, authoritarian, uncooperative, coercive, and disrespectful of rules and norms" [ : ] . however, to understand the depth of the crisis of liberal international order, it is necessary to examine the differences between the normative order and the empirically observed order. as rosenau notes, to be insensitive to their distinctions will "run the risk of either clouding sound analysis with preferred outcomes or confounding preferred outcomes with empirically faulty recommendations" [ : ] . scholars need to distinguish observations of the reality of the international order from judgments and visions of such order. in buzan's words, adopting the normative aspect of such a concept could be seen as an effort to consider what is possible and advocate what is desirable [ : ] . however, it is necessary to acknowledge that the reality on the ground may not approximate the desired ideal. regarding the current liberal international order, its advocates often offer a narrow and highly selective view of history. they tend to ignore aspects of coercion, violence, and instability in the post-war era, while emphasizing the order's unwavering support for democracy, freedom, and human rights [ ] . this tendency has led to what allison calls the "myth of the liberal order". in his words, the liberal international order is essentially "an imagined past in which the united states molded the world in its image" [ ] . moreover, the nostalgic view of the liberal order is ahistorical as it ignores the process of ordering that was marked by episodes of violence, coercion, and resistance, as well as the imperial prerogatives of the united states that had often disregarded rules and accommodated illiberal forces [ ] . beneath the surface of "stability" and "peace", the liberal international order is rife with tensions, the first of which comes from the competition between different political-economic models. that is, the liberal model, supported by dominant western powers, is challenged by the so-called illiberal models promoted by major challengers like china. these models are by no means pure in their forms and practices. there are evident contradictions within each model. just as the liberal model has elements of coercion and violence, the illiberal model also contains elements of cooperation and rule. the second tension arises between states seeking to assert their agency against the seemingly inexorable and homogenizing forces of globalization promoted by the liberal order. states refuse to be hollowed out by the globalizing forces and seek to assert their authority and legitimacy both within their territorial boundaries and in transnational processes. in the context of external shock and rising nationalism, states would prioritize their national interests and make choices that are most aligned with their material and ideological preferences. finally, the third tension lies between the defenders and challengers of the existing order. countries with increasing military and economic power may seek to transform the current international order to better reflect their own ideologies and serve their interests. the competition between major powers could be intensified by triggers like financial crisis or pandemic crisis. if the existing order rests upon widening economic discrepancies among actors, there will be growing pressure for change. if the material conditions, including the distribution of resources among actors, undergo substantial change, the current arrangement could potentially reconfigure, leading to a breakdown or restructuring of prevailing order [ ] . moreover, the image presented by the liberal world has been and will continue to be questioned by the emerging powers, further deepening the ideological divisions between them. the rising powers could also promote their images and profiles globally, provide political, economic and military goods to their clients and partners around the world, and rally support for their alternative political-economic models in the global arena. in other words, they compete with each other to sell their models in the global market of economic resources, security, aid, and ideology. by highlighting the influence of ideas on the international arena, the constructivists' account of international relations has filled in the gap left by the liberals and realists and it offers important tools for scholars to analyze the changing dynamic of the international order. according to the constructivists, ideas can generate identities and interests, help states and other actors find common solutions to problems, and shape their understandings of threats and expectations of the others' behavior [ ] . the influence of ideas can work through at least three pathways: beliefs can serve as roadmaps for decision-making; shared ideas can serve as focal points in facilitating cooperation; and ideas, enhanced by the international norms and rules and embodied in the institutional frameworks, can constrain the actors' choices [ ] . being embedded in the dense networks of international social relations, states could be "socialized to want certain things" [ : ] . in other words, states and other actors can choose to play the game in the current order, respond to the changing environments, or develop their own rules of the game to suit their purposes. the circulation of different beliefs and ideas about how the world should be organized has turned the international arena into a contested field. instead of conforming to the expectations by dominant western countries, powerful challengers may push for more space for multiple models of governance in the international order. the convergence of beliefs and ideas can reinforce the popular appeal of certain models and could serve as focal points for different actors to coordinate their actions and reshape the international norms. moreover, the creation and extension of international social networks by new institutional platforms or linkages can facilitate socialization between states and encourage state leaders to "want certain things", which could include access to alternative sources of economic power, security, aid or ideology. the rising challengers have benefited from the western-dominated order. but they also challenge the mythologized liberal international order and expose the contradictions in the dominant western model which often needs to reconcile its proclaimed liberal values with illiberal behaviors. the idealized image of liberal international order does not always align with reality, especially in the case of the order's most powerful leader. as strange [ : ] observed, there was a clear gap between america's rhetoric in preaching liberalism, internationalism, and multilateral decision-making, and its "inconsistent, fickle, and unpredictable" conduct of foreign policy. other scholars have noted that, there were plenty of illiberal behaviors by the countries that proclaimed liberal values. for instance, the united states supported authoritarian rulers throughout the cold war, and afterwards; it also dismantled the bretton woods, and invaded afghanistan and iraq, etc. [ , ] . some scholars suggest that the so-called liberal international order has "never existed". even after the end of the cold war when liberal principles were promulgated to more countries, the liberal international order only "got closer to having a liberal quality but never quite passed the threshold" [ ] . by treating the potential change in the current international order as a crisis, many prominent scholars reveal their western-centric, and especially the u.s.-centric, views of ir. as hobson points out, many ir scholars continue to reproduce the discourse of power through their own works. for instance, one prominent scholar who signed the public statement has argued on another occasion that, humanitarian interventionism and structural adjustment programs are essential for keeping the non-western world on track toward western-style liberal capitalism and democracy. without interventions by the west, these countries are denied the opportunities and "privileges" to imitate the advanced western model [ : - ] . this argument echoes the tone in the public statement, which emphasizes how the existing order has served the united states and its allies well for more than seven decades and brought unprecedented levels of prosperity and peace to the world. in the meantime, there is no mention of what kind of reform and change is needed. in the challengers' eyes, such reform has been delayed for too long. the pressure on the current international order began building during the financial crisis in . before that, advanced countries in the group of seven (g ) promised to give more voices to emerging economies in international institutions such as the international monetary fund (imf). but they failed to deliver on promised reforms. instead of embracing "the dawn of a new era of multilateralism", the world is witnessing "the last gasp of an oldfashioned concert of great powers" [ : ] . another example is the world bank, which weaver [ : ] illustrates as mired in "bureaucratic 'pathologies', dysfunctions, and legitimacy crises", unable to make substantive changes in its structures, policies, ideologies, and behaviors. as a result, a new order less reliant on these traditional international institutions, such as the imf and the world bank, may be emerging. similarly, stephen argues that existing international institutions are often too "sticky" to adapt to the new distribution of power and the preferences brought by the diverse group of emerging powers. the challenges from the brics countries may bring about an order that is "strongly contested, less universal, less liberal, and more fragmented" [ : ] . ikenberry notes that the old u.s.-led order may be in the "crisis of transition" whereby "a new configuration of global power, new coalitions of states, new governance institutions" will emerge [ : ] . as acharya observes, a key driving factor to this fragmentation is "the outdated system of privilege enjoyed by the western countries and their abuse of existing rules and norms and resistance to the lack of reform of multilateral institutions" [ : ] . in a post-hegemonic multiplex world, the united states must relinquish certain privileges and share its power and authority with emerging powers [ ] . however, the united states has already shown its reluctance to share its power and privileges, despite its gradual retreat from global leadership. in a white paper that focuses on the relation between china and the world, china criticizes the theory that assumes china will seek hegemony as it gets stronger and pose serious threat to the world. the report points out that this interpretation is driven by "cognitive misunderstanding, deep-rooted prejudice, a psychological imbalance brought about by the prospect of falling power, and deliberate distortions by vested interests" [ ] . one the one hand, the report emphasizes china's contribution to the world economy as "a stabilizing force and power source" and "an important promoter of global openness and a dynamic market". it further states that, china has benefited from the international community and in return provides it with more and better public goods. on the other hand, the report points out the dangers of blindly copying or being forced to adopt the western model, which had led to "social unrest, economic crisis, governance paralysis, and even endless civil war". the report proposes to build "a global community of shared future" that opposes "the law of the jungle, power politics and hegemonism" [ ] . as stated in the report, in a new model of international relations, there should be ) mutual respect based on equality among all countries and respect of other's political systems and developmental paths; ) equal right and equal access to opportunities and proper balancing of national interests and contribution to international community; and ) mutually beneficial cooperation. more importantly, the world should uphold the international order or global governance system with the united nations as its core, rather than the united states. according to the report, china has no intention of replacing the united states. but the united states also needs to "abandon the cold war mentality, and develop a proper understanding of itself, china, and the world", adapting to the development and prosperity of other countries and living in harmony with them [ ] . if it fails to do so and tries to maintain its strength by suppressing other countries, any serious strategic miscalculation may lead to conflict and confrontation between major countries. since the financial crisis of , tensions within the existing liberal international order have grown, especially between the defenders and challengers of the existing order and between different political-economic models. the external shock caused by the ongoing pandemic exacerbates the tensions and accelerates the reshuffling of the existing order. as the pandemic continues, several material and ideational forces, including the entrenchment of authoritarianism, the exacerbation of nationalism, and the renewed competition between the major powers, have converged to reconfigure the international order. before the pandemic, the international arena had already turned into a contested field for competing models of governance in the international order. the pandemic has intensified this competition. the entrenchment of authoritarianism allows the consolidation of alternative political-economic models proposed and promoted by powerful challengers vis-à-vis the liberal model supported and dominated by western powers. the exacerbation of nationalism not only chips away the authority and legitimacy of established western-dominated international institutions but also pushes states to make choices that are most aligned with their national interests, from both material and ideological perspectives. moreover, these two forces have laid the new ground from major actors, including the united states, the european union, and china, to engage in a renewed great power competition in the pandemic era. the myth about an ideal and cohesive liberal order, forged by western solidarity and a shared sense of purpose and righteousness, has been further debunked during the pandemic, leaving space for challengers like china to exploit the internal division and fragmentation within the west and extend its influence globally. in the following section, i examine these three sources of change and discuss how they may have changed the dynamics of the current order and shaken its foundations. the entrenchment of authoritarianism the first challenge to the current liberal order comes from the entrenchment of authoritarianism during the pandemic, as characterized by authoritarian resilience, autocratization, and the consolidation of competing political-economic models built by leading authoritarian countries. as numerous democracies test the boundaries of freedom and control, authoritarian leaders across the world exploit the coronavirus crisis to tighten control over their people even further. the sweeping measures and institutional arrangements utilized by these leaders to combat the virus will leave significant legacies on both domestic politics and foreign policies. interpreted in the path-dependence framework, the decisions made at certain "formative moments or conjunctures" can influence the long-term institutional trajectories. these institutions can be "sticky" and resistant to changes [ ] . moreover, riding the wave of autocratization, leading authoritarian countries like china have consolidated their competing political-economic models vis-à-vis the western-dominated model. as increasingly powerful and ambitious patrons in the global arena, they have provided alternative sources of economic power, security, aid, ideology, as well as institutional platforms to the autocrats and emerging autocrats, without imposing political conditionality that favors liberal values. the pandemic has provided opportunities to consolidate their positions and promote their models worldwide. the entrenchment of authoritarianism is first and foremost reflected by the durability of authoritarian regimes during the pandemic. to the disappointment of those seeking cracks in the authoritarian regimes hit hard by the pandemic, the autocrats around the world have largely survived the tests resulting from the pandemic. in particular, the resilience of communist regimes, such as china and vietnam, has provided clear examples of entrenched authoritarianism during the pandemic. in the case of china, confronted with the worst health crisis faced by the chinese communist party (ccp), the regime's capacity is questioned by many scholars and observers. pei argues that the pandemic has shown the regime's lack of capacity in responding to the health crisis and exposed the fragility of xi jinping's strongman rule. the regime will be trapped in economic stagnation and increasing social unrest domestically and in great-power competition abroad. as a result, it will start to "unravel by fits and starts" [ ] . this assessment is consistent with pei's earlier diagnosis of the ccp's serious illnesses and regime decay, as well as other scholars' observation of china's "frozen" political system [ , ] . however, the evidence so far suggests that the regime has not only managed to survive the crisis but also boosted its legitimacy. early in the outbreak, china's failure to respond was perceived as a manifestation of the breakdown of top-down governance structures [ ] . chinese people were angry at the government's handling the crisis in its initial response. the authorities chose to withhold information about the virus from the public, punished doctors for "spreading rumors," and prioritized stability over transparency. when the situation erupted beyond control, the influx of photos, videos, blogs, and diaries on social media depicting the ordeals of wuhan citizens ignited both anger and fear among the public. the ccp rushed to calm the public, started a massive machine of mobilization, and implemented extreme lockdown measures. grassroots organizations were also mobilized by the state to enforce quarantines and lockdowns, provide essential services, and collect information and monitor citizens, greatly enhancing the state's capacity at political and social control [ ] . the state soon regained control of the situation, although life was far from being back to normal. the shock caused by the pandemic was followed by the massive outbreaks in europe and later the united states, overwhelming the capacity of one country after another. chinese state media and social media produced vivid stories describing the disastrous responses in many western democracies, especially their failures to copy china's "homework" for combating the coronavirus. it looked as though china was the only haven in the world and many chinese people abroad struggled to find their way back home. both authoritarian and democratic countries have demonstrated mixed performances in responding to the pandemic. there are successful cases in democracies, such as that of south korea, which presents an effective model for combating the coronavirus. there are also failed cases among autocracies, such as iran, which struggled to contain the outbreak during its initial stage [ , ] . however, the failures of many democratic countries, especially the united states, to control the virus quickly and effectively helped reverse course in china and boost the ccp's domestic legitimacy. the comparison led many chinese to believe that an authoritarian government is a better option for china, especially in times of crisis and during the rhetorical siege by the western countries. the ccp gladly sells the idea of a better political system to its people through intensive nationwide propaganda, manipulation of social media, and spontaneous expression of national pride by its people. the success story of vietnam which shares similar political-economic model with china further contributes to the discourse of a superior political system. in a survey conducted in april, researchers asked citizens to rate their countries' performance in dealing with the pandemic. china ranked highest among countries, with a score of out of , followed by vietnam ( ) . in the rating of the political leaders' response to the crisis, both countries (china, out of ; vietnam, ) outpaced major western countries, including new zealand ( ), germany ( ), the united states ( ), the united kingdom ( ) , and italy ( ) [ ] . another report based on online surveys finds that trust in the chinese government was as high as % in april [ ] . beyond china, other authoritarian leaders exploited the crisis to further tighten control over their people. in russia, which closely monitored its neighbor's techdriven model of control, the pandemic provided an opportunity for russian authorities to develop new surveillance capabilities equipped with facial-recognition and geolocation tracking systems [ ] . in iran, the hard-liners leveraged the massive pressures from the pandemic to consolidate power. members of the revolutionary guards were dispatched to enforce strict quarantine measures, while ramping up efforts to monitor and silence citizens on the basis of "national security" [ ] [ ] [ ] . moreover, conservatives capitalized on the missteps made by the moderate, civilian-led government. they launched campaigns to undermine it, portraying the revolutionary guards as "the guardian of public health and the champion of the fight against the invisible enemy" [ ] . coupled with authoritarian resilience, a wave of autocratization has surged around the world during the pandemic. in hungary, a country already experiencing rapid erosion of freedoms and democratic norms in recent years, prime minister viktor orbán secured an indefinite state of emergency that allows him to rule by decree. journalists can be jailed for up to five years for spreading misinformation that hinders the government's response to the pandemic [ ] . similarly, in the name of maintaining order and combatting disinformation during the pandemic, extraordinary emergency powers were invoked in both thailand and the philippines. these powers allowed the thai authorities to censor or shut down media and the latter to imprison those accused of spreading false information on social media and other platforms [ , ] . by late april, more than countries had enacted emergency laws to give executives more power to handle the coronavirus [ ] . previous researches already found that states of emergency often associate with a heightened risk of autocratization [ ] . before the pandemic, more than one-third of the world's population already lived in autocratizing countries. moreover, for the first time since , the majority of countries in the world are autocracies ( in total) [ ] . the pandemic has reinforced anti-democratic trends, with countries at high risk of pandemic backsliding and others at medium risk [ ] . while the urgency and presence of the coronavirus will eventually dissipate, the effect of the authoritarian measures and the institutional legacies will likely remain, influencing both domestic politics and foreign policies. rather than witnessing "the end point of mankind's ideological evolution and the universalization of western liberal democracy as the final form of human government" [ ] , the world is now seeing a regime landscape mixed with thriving authoritarianism and democracy. to complicate the matters further, the challengers to the current order have exploited the pandemic to assert their political systems and ideologies, which are seen as incompatible with the western standards and values. ikenberry asserts that neither china nor russia has a model that is appealing to the rest of world [ ] . however, because of the ideological divergence, authoritarian political-economic models built by these two countries are increasingly welcomed by sitting dictators and emerging autocrats. china and russia have already become alternative providers of goods such as developmental assistance and military security, which used to be monopolized by major western powers [ ] . now, they are using such leverages to rival the liberal order led by the united states, building "parallel structures of global governance that are dominated by authoritarian states and that compete with older, more liberal structures" [ ] . in comparison to russia, china has maintained more extensive institutional networks. china has created, expanded, and led important international institutions (such as the asian infrastructure investment bank), regional forums (the forum for china-africa cooperation), security organizations (the shanghai cooperation organisation), and infrastructure investment projects (the belt and road initiative). these institutions have become the cornerstones of its alternative political-economic model. in this model, the powerful and ambitious patron provides alternative sources of economic power, security, aid, ideology, as well as institutional platforms for the dictators and emerging autocrats, without imposing political conditionality that favors liberal values. the pandemic allows these challengers to consolidate their positions and promote their political-economic models globally. in the case of china, it has sought to build a "health silk road" by sending medical teams and resources to numerous countries around the world. according to a report released by china's state council information office, the country had offered or provided assistance to countries and international organizations as of june [ ] . major western powers have widely criticized these efforts for their intention to capitalize on the pandemic and project china's influence globally. but china has won many hearts in the region where it has projected its economic and diplomatic influence through the belt and road initiative in recent years. countries that welcome china's growing influence include major autocratizing countries in central and eastern europe, including serbia, hungary and the czech republic [ , ] . as a result, china can utilize its reciprocating relations with the receivers of medical goods and to garner additional support for its authoritarian political-economic model vis-à-vis the western liberal model. moreover, the exacerbation of nationalism in both democracies and autocracies further reinforces the consolidation of authoritarianism and authoritarian political-economic models during the pandemic. besides the challenge brought by the entrenchment of authoritarianism, the second challenge to current order stems from the exacerbation of nationalism. one of the underlying tensions of the current order exists between states seeking to assert their agency against the seemingly inexorable and homogenizing forces of globalization promoted by the liberal order. states refuse to be hollowed out by the globalizing forces and seek to assert their authority and legitimacy both within their territorial boundaries and in transnational processes. nationalism has been a tool for modern states to legitimize their power at home and position themselves in the international arena. besides its linkage to language and symbolism, nationalism is "a sociopolitical movement and an ideology of the nation" [ ] . the pandemic provides fertile ground for nationalism to thrive in both democratic and authoritarian countries, as states reclaim their place and authority left by the retreat of globalizing forces. with help from nationalist and populist politicians, nationalism has blended with populism and authoritarianism and become stronger in both democratic and authoritarian hosts. confronted with the pandemic, many countries rushed to fend for themselves instead of joining together in multilateral efforts. state leaders worldwide unilaterally closed borders, restricted incoming travelers, grappled with solutions to meet their own soaring demands for medical supplies, and prepared to fix their damaged economies. states have reasserted their roles in responding to crises, guarding their sovereignty, and managing their own economies in the uncertain times, while the globalizing forces promoted by the current order are in the retreat. the self-serving calculations of national interests, in both political and economic spheres, have dominated many leaders' thinking since the outbreak of the pandemic and are likely to continue influencing policymaking in the post-pandemic struggle for recovery. the exacerbation of nationalism has eroded the popularity and authority of international institutions that buttress the principle of multilateralism and the seemly unstoppable forces of globalization promoted by the current order. it also pushes states to make choices that are most aligned with their national interests, from both material and ideological perspectives. as walt argues, "the pandemic will strengthen the state and reinforce nationalism" [ ] . bieber observes that even before the pandemic, exclusionary nationalism mixed with far-right politics and populism had already overshadowed major countries around the world. the pandemic reinforces nationalism in several important ways: a "marriage" between nationalism and authoritarianism, bias against others (including ethnic minorities and other marginalized groups) presumed to be associated with the pandemic, and the rise of deglobalization and anti-globalization [ ] . these changes will likely reinforce existing nationalistic dynamics. these dynamics are evident during the pandemic at both state and society levels, as well as in both democratic and autocratic settings, as exemplified by the developments in the united states and china. both countries have been involved in escalated "narrative battle" powered by nationalism [ ] . in the united states, controversial labels, from the "chinese virus" to the "kung flu", were disseminated by president trump as state leaders tried to find a scapegoat to blame for their own failures in responding to the pandemic. even after the administration wasted nearly two months responding to the crisis, many politicians were quick to defend trump: "we don't blame trump, we blame china." senator lindsey graham claimed that the chinese government was responsible for all american deaths [ ] . only a few days later, the u.s. intelligence and national security officials said that the u.s. government was exploring the possibility that the coronavirus leaked from a lab in wuhan [ ] . trump and the secretary of state mike pompeo soon joined the chorus. they ignored the assessments made by many scientists and weaponized the coronavirus for political purpose. both the republican party and the democratic party continued to blame china in an attempt to maximize their appeal to the voters and increase their odds of winning the election [ ] . while the state leaders in the us were pandering to a nationalist base, xenophobic sentiment surged across the country. within just four weeks (march -april ), at least incidents of coronavirus-related discrimination targeting chinese and other groups of asian origins were reported in the united states. these incidents included verbal harassment, refusal of services, and even physical assault [ ] . the pew research center also found that negative views of china had risen to its highest point since the center started collecting data on americans' views of china in . about two-thirds ( %) of american adults had a negative view of the country, a significant increase of percentage points since trump took office [ ] . in china, nationalist strategies were also used at the state level. early in the outbreak, the united states was blamed by china for its failure to provide sincere and substantive support toward china and for its overaction by raising its travel advisory level, bringing american citizens back, and blocking chinese visitors. later, the u.s. military was accused of intentionally spreading the virus in wuhan, a theory promoted by zhao lijian, the spokesperson for china's ministry of foreign affairs [ ] . moreover, the ministry of foreign affairs announced its decision to expel american journalists working for the new york times, the wall street journal and the washington post, further fueling nationalist sentiment in china. likewise, the chinese people's views of the united states drastically declined during the pandemic. before the united states stepped up its efforts to shift the blame toward china, a survey by the eurasia group foundation (february -march ) found that china had witnessed the starkest decline among ten countries in their views toward the united states and american democracy. favorable views of the united states decreased by nearly percent as negative views increased by %, compared to a report. positive views of american democracy also declined by %. about half of the respondents believed that the united states had made the world a worse place in the past years [ ] . an article published by a chinese nationalist tabloid reported that chinese people had seen the harm of u.s. hegemony and the darker side of democracy [ ] . politicians from both sides are playing a dangerous game by exploiting the nationalistic feelings in their respective societies to serve their own political agendas. both sides have politicized the coronavirus and related scientific researches, further rousing animosity between the two countries. beyond these two cases, many other nationalist and populist leaders around the world have sought to decry globalization and "others". the pandemic has given them the weapon they need. while trump proclaimed on twitter, "we need the wall more than ever!", france's rightist national rally party's leader le pen blamed "the religion of borderlessness" for the virus outbreak. during the pandemic, state leaders and political parties in hungary, india, germany, italy, and spain have targeted ethnic minorities and other marginalized groups [ , [ ] [ ] [ ] [ ] . foreign workers and f students were the latest victims of current u.s. administration's populist and nationalist strategies [ , ] . in the last decade, the world has witnessed the rise of nationalist and populist leaders in national and subnational politics throughout many regions [ ] [ ] [ ] . the pandemic enables these leaders to rally their supporters and attack what they see as the illusion of solidarity between nations and the failure of international institutions, including the european union and the world health organization (who). moreover, states' recalculations of national interests are likely to reinforce their appeals because the pandemic has exposed the risk and vulnerability of global dependency regarding the supply chains and strategic resources. as a result, the pandemic will likely prompt a renationalization of production and transform global integration to a more limited form that is oriented toward regional and bilateral engagements [ ] . even in europe, the region that serves as "the proof that human society was becoming transnational, transcending its national stage and moving towards a global community", confidence in globalization has declined. as we witness the "universal reversion to nationalist policies and defense of particularistic national interests at the expense of transnational solidarity", international institutions are more likely to suffer from the pandemic [ ] . the pandemic has given "a political gift for nativist nationalists and protectionists" and will have long-term impact on many aspects of globalization, including the free movement of people and goods [ ] . states are able to reclaim their place and assert their authority and legitimacy within their territorial boundaries and in transnational processes. as politicians in both democracies and autocracies exploit nationalism to serve their political agendas during the pandemic, they continue to deepen the divisions and tensions between countries, hinder multilateral cooperation, and contribute to the fragmentation of the existing international order. the exacerbation of nationalism not only chips away the authority and legitimacy of established western-dominated international institutions but also pushes states to make choices that are most aligned with their national interests, from both material and ideological perspectives. their material and ideological preferences may converge with the alternative models proposed and promoted by the challengers of the current order. challengers like china offer alternative sources of economic power, security, aid, ideology, and institutional platforms. during the pandemic, the goods on the list are extended to include medical supplies. this menu is especially attractive to state leaders who put national interest before the "western doctrines" or seek for economic opportunity or breakthrough. hungary-a member state of the eu-is one of the cases that are highly receptive to china's offers. hungary was the first european country to sign up for china's belt and road initiative (bri). it is also an active participant in the china-ceec (central and eastern european countries) summit ( + format) that helps china establish its foothold in the eu's backyard. as stated by hungarian prime minister viktor orbán, china's bri is "fully in harmony" with hungary's national interest and "offers the right response to challenges in a changing world order". hungary is ready to further cooperate with china for economic opportunities and reject "all outside ideological pressure" [ ] . during the pandemic, orbán and other ministers played down eu assistance and lashed out at those who criticized the government's autocratizing moves. as foreign minister peter szijjarto said in parliament: "all of europe, including western europe, is always extraordinarily critical and often ready to educate and lecture about the essence of democracy, (but) everyone is standing in line in china for the products needed for health protection [ ] ." the offer of alternative resources and goods, coupled with the absence of political conditionality that favors liberal values, is increasingly popular among the autocrats and emerging autocrats. as a result, china continues to extend its networks and expand international space for its model. in the process of doing so, china has faced resistance from the dominant western powers, but also successfully garnered more support around the world. the exacerbation of nationalism and the entrenchment of authoritarianism has laid the new ground for major actors, including the retreating global leader (the united states), the weakening coalition (the european union), and the rising but besieged challenger (china), to engage in a renewed great power competition in the pandemic era. the myth proliferated by the proponents of u.s.-led liberal order assumes that the order is cohesive, forged over seven decades by western solidarity and a shared sense of purpose and righteousness [ ] . under strong u.s. leadership, a group of western powers with common goals and shared commitment to preserve liberal values, norms, principles and institutions has been committed to sustaining and defending the current liberal international order. however, the perceived cohesiveness of this order was challenged during the pandemic, as the united states further retreated from its role as the leader of the order and the solidarity among the eu members states was seriously undermined. in the meantime, china had tried to fill in the gap left by the internal division and fragmentation within the west. since trump assumed office, the united states has withdrawn from many multilateral agreements and international organizations. it continues to assert america's own interests while disregarding the interests of others, including its allies. trump has continued his predecessor's trend towards global retrenchment and run on a platform that suggests "a much narrower definition of american interests and a lessening of the burdens of american global leadership" [ ] . the pandemic further reveals trump's lack of interest in carrying the burdens of global leadership and in strengthening existing alliances and institutions. the united states has been absent in leading global efforts to fight the coronavirus. after blaming china's mishandling of the pandemic, the united states found another target to blame for its own failures in handling the crisis. it announced in may that it would halt funding for the who and terminate the relationship. it formally started withdrawing from the organization in july. the u.s.centric moves have dealt serious blows to the institutional pillars of the current liberal order and undermined the principle of multilateralism. moreover, the pandemic has further tarnished its global image as the primary defender and unifier of the liberal world. as tellis notes, the pandemic threatens the u.s. position in deadly ways. it has battered the u.s. economy and weakened its economic power; discredited its state competency in times of crisis; and corroded the u.s.-led international order, as the country is questioned by allies for failing to protect shared norms, rules and institutions and to ensure shared prosperity in the face of strategic competitors [ ] . the pandemic may be the straw that breaks the camel's back. the stronghold of the liberal international order has not fared well during the pandemic. the eu was seriously questioned for its slow and bureaucratic responses to the outbreak in the region. when italy begged its european partners for masks and equipment, the latter responded by closing their borders and hoarding medical supplies for domestic use [ ] . the ethos of "every country for itself" not only spread in countries led by nationalist leaders but also other member states of the eu [ ] . solidarity among nations quickly devolved into a game of survival in which each country grappled with its own solutions. some observers have already cast doubts on the future of the eu [ ] . according to a report released in may, % of the respondents were not satisfied with the measures the eu had taken against the pandemic. among all member states, dissatisfaction was particularly high among southern european countries. in italy and spain, only % and % of respondents, respectively, were satisfied with the eu's response. fewer than a quarter of the respondents in greece ( %), spain ( %), and italy ( %) were satisfied with the solidarity between eu member states in fighting the pandemic [ ] . while the foremost defenders of the current order seem to be in disarray and the tensions within the western club are exposed in the pandemic, china sees a chance to increase its global influence, by filling in the gap left by the west's internal division and fragmentation. china already revealed its ambition in playing a more prominent role in international affairs and potentially transforming the global order by the belt and road initiative, the asian infrastructure investment bank, and other alternative institutions. the political-economic model that china has been building is oriented toward increasing economic and diplomatic influence without exporting or imposing its preference for a political system. as stated in a white paper that focuses on china's relation with the world, china "does not 'import' foreign models, nor 'export' the chinese model, and will never require other countries to replicate its practices" [ ] . nonetheless, china has been actively promoting its image and influence globally. europe is one region in which china has intensively projected its influence in recent years. during the pandemic, "health silk road" was being taunted by chinese state media as exemplifying a different kind of global leadership than trump's america [ ] . the public discontent with the eu, coupled with a distrust of the united states, has provided the opportunity for china to promote its global image, especially in countries hit hard by the coronavirus or in urgent need of help, such as italy, spain, serbia, and elsewhere. as china makes inroads into the areas traditionally dominated by the west, it has encountered strong resistance from major powers. several combined factors are pushing china to a besieged position, both politically and economically, in the global arena. these factors include the dispute over the poor quality of medical supplies sent by china; the pressure on china to be more transparent and take the responsibility for the pandemic; the call for china to compensate other countries for damages caused by the coronavirus; the strain and ramification of economic downturns in major western countries; and the possible relocation of industries for important strategic resources back to the west. before the pandemic, based on the reassessment of china's economic and political power and its ambitions to be a leading global power, the eu had labeled china as "a systemic rival promoting alternative models of governance" [ ] . the pandemic has forced the eu to reassess the challenges from china. european leaders have become increasingly concerned about the issues of supply chains and telecoms security, risks associated with closer sino-russian coordination, and china's moves to advance its ideological agenda that is hostile to european values [ ] . while the eu tries to find the middle ground in dealing with china, the united states is increasingly hostile toward china's rise. according to a report released by the white house in may, china's growing economic, political, and military power "harms vital american interests and undermines the sovereignty and dignity of countries and individuals around the world." in response to china's economic, ideological, and security challenges, the united states has adopted a competitive approach guided by "a return to principled realism," seeking to protect american interests and advance american influence [ ] . the pandemic has not only widened the division between the western powers, but also deepened the crevasse between china and the west [ ] . according to the report presented by the ministry of state security to top beijing leaders in may, the global anti-china sentiment is at its highest level since the tiananmen square incident. the report warned that this sentiment could fuel resistance to china's belt and road initiative and exasperate the security situations in asia. the growing hostility between china and the united states could lead to armed confrontation [ ] . china is eager to defend its authoritarian political system. it also relies on nationalism to boost domestic legitimacy and now sees the chance to expand its global influence. thus, china may move further toward transforming the international order as it gradually recuperates its economic strength from the destruction brought by the pandemic. since president xi jinping came to power, he has largely abandoned deng xiaoping's tao guang yang hui strategy (conceal one's ability and bide one's time) and pushed for "major country diplomacy" (da guo wai jiao). his perception of china's status in the international order also departs from previous leaders' views that positioned china at the periphery or semi-periphery of the existing western-dominated order [ : ] . xi pointed out "in explicit terms" that china is "closer than ever to the center of the global stage" and "closer than ever to fulfilling the chinese dream of national renewal" [ ] . creating and expanding alternative international institutions, regional forums, security organizations, and infrastructure investment projects-the cornerstones of the alternative political-economic model-are helping to push china to the center of the global stage. to deal with the complex and ever-changing international environment, xi consistently emphasizes the importance of "bottom-line thinking," which means always being prepared for the worst-case scenario, be it crisis or conflict. in a meeting with national legislators from the army and armed police force during the annual "two sessions" in may, xi stated that the pandemic has profoundly affected on the world's situation as well as china's security and development. as a result, he emphasized, "the chinese military must stick to bottom-line thinking, comprehensively strengthen combat training, respond effectively and in a timely way to sophisticated scenarios and firmly safeguard national sovereignty, security, development interests and its strategic stability" [ ] . in recent years, china has expanded its list of core interests to include the political system, sovereignty and territorial integrity, security, and development interests [ ] . if the international environment became too hostile, china would never allow its core interests to be undermined. the imposition of national security law in hong kong reflects this logic. the resurgence of great power competition, both in material and ideological senses, has joined the other two forces-the exacerbation of nationalism and the entrenchment of authoritarianism. as china and the western powers compete with each other at different fronts, the existing international order has become more divisive, fragmented, and confrontational. the more china feels cornered by the increasingly hostile west, particularly the united states, the more likely it will be to pursue more assertive policies regarding its political-economic model. china will likely use its institutional and ideological leverages to expand more space for its model and reconfigure the current order based on its interests and ideology. this paper examines how the pandemic could transform the liberal international order. the pandemic has generated immense pressure on the existing order that is rife with tensions. the principal foundations of the current order-the liberal ideology, the principle of multilateralism, and a group of defenders with shared commitment to preserve liberal values, norms, principles and institutions-are shaken by several powerful forces during the pandemic. the entrenchment of authoritarianism has, on the one hand, contributed to the erosion of liberal ideology. on the other hand, it has consolidated the alternative political-economic models led by china and other authoritarian challengers. the exacerbation of nationalism, by blending with populism and authoritarianism, further undermines the popularity and authority of international institutions that buttress the principle of multilateralism and the globalizing forces promoted by the liberal order. it also pushes states to make choices that are most aligned with their national interests, from both material and ideological perspectives. moreover, the pandemic has intensified internal divisions and fragmentation within the west. in the meantime, it has accelerated great power competition between china and the west as china seeks to fill in the gap left by dominant western powers. the tensions that exist in the current liberal order and the sources of change during the pandemic may reconfigure the liberal international order into an order that is more fragmented and confrontational. china, seen as a powerful challenger to the order, has played mixed roles in the process of reconfiguring the liberal international order. first, along with other challengers, china challenges the mythologized liberal international order and exposes the contradictions in the dominant western model which often needs to reconcile its proclaimed liberal values with illiberal behaviors. china also has proposed and promoted alternative authoritarian political-economic model that is hybrid in its forms, containing both the elements of authoritarian control and coercion, as well as cooperation and rule. the defining feature of this model is authoritarian. but it also incorporates the more liberal elements of the existing international order. china has essentially turned the international arena into a market of competing models, challenging the monopoly enjoyed by western powers for decades. in comparison to russia and other potential challengers, china is more ambitious and successful in promoting its model in this market and improving its global image. during the pandemic, china not only builds an image of strong authoritarian power but also an active provider of public goods that is ready to cooperate with other countries and contribute to the international community. second, china continues to utilize traditional western-dominated international institutions to benefit from the current order, showing its support for the current order. as acharya notes, "it is ironic that while the founders of liberal order are retreating (at least temporarily), and the order itself is fraying at the edges, some of the powers, especially china, that are supposed to challenge it are offering support" [ ] . but in the meantime, over the past few years, china has invested significant resources in building alternative international institutions, regional forums, security organizations, and infrastructure investment projects. both strategies help to diversify china's choices and maximize its shares in and potential rewards from the international order. moreover, by creating dense networks for international social relations, china socializes with other states, strengthens their connection, and presents them with attractive alternative choices. as a result, states are encouraged to want things including access to sources of economic power, security, aid, ideology, and institutional platforms. as a result, state leaders who put national interest first or seek for these resources are drawn closer to china's model. the offer of alternative resources and goods, coupled with the absence of political conditionality that favors liberal values, is increasingly popular in the world with mixed regime landscape. the shock brought by the pandemic has provided ample opportunities for china to extend its networks and expand international space for its model. the mixed roles played by china reflect the complex dynamics in the existing international order. instead of viewing the current international order solely by the idealized lens of the liberal world, it would be more informative to treat the existing order as a multiplex international order with competing politicaleconomic models. on the one hand, as china continues to integrate into the global market and international community, china has proposed and promoted an alternative model that asserts authoritarian control but also incorporates more liberal elements that encourage international trade and cooperation and support multilateral institutions and related rules. on the other hand, the western-dominated model proclaims liberal values but has engaged in violence and coercion in its attempts to order the world, especially when it comes to america's behavior in the world. the failed projects of "social engineering" [ ] that attempted to transform the world by violence reveal the contradictions in the western model. both china and the united states are deeply embedded in the current international order. while their models have major differences, they also overlap with each other in at least two areas: the liberal components of the authoritarian model, and the illiberal components of the liberal model. driven by the convergence of material interests and ideologies, states may locate themselves closer to the core of one model or move toward the competing model. major powers that lead the different models may attempt to draw other states closer by attracting them to their "way of life" or forcing them to integrate into their models. the competition between these powers could escalate and potentially lead to conflict and confrontation. moreover, the creation and extension of international social networks by institutional platforms or linkages can facilitate socialization between states and encourage state leaders to make certain choices. the external shock caused by the pandemic has intensified the competition between these different models as well as their major actors. it also has triggered the reshuffling of different actors' positions in the international order. the western-dominated model is confronted with internal division and fragmentation but intends to preserve 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deepgoing way and keep writing new chapters of major-country diplomacy with distinctive chinese features xi urges military combat readiness china's core interests and dilemma in foreign policy practice after liberal hegemony: the advent of a multiplex world order qingming huang is a phd candidate at the department of political science at the university of florida. his research interests include ethnicity and nationalism, state building key: cord- - q gm n authors: pearman, ann; hughes, mackenzie l.; smith, emily l.; neupert, shevaun d. title: mental health challenges of united states healthcare professionals during covid- date: - - journal: front psychol doi: . /fpsyg. . sha: doc_id: cord_uid: q gm n as covid- continues to impact global society, healthcare professionals (hcps) are at risk for a number of negative well-being outcomes due to their role as care providers. the objective of this study was to better understand the current psychological impact of covid- on hcps in the united states this study used an online survey tool to collect demographic data and measures of well-being of adults age and older living in the united states between march , and may , . measures included anxiety and stress related to covid- , depressive symptoms, current general anxiety, health questions, tiredness, control beliefs, proactive coping, and past and future appraisals of covid-related stress. the sample included hcps and age-matched controls (m(age) = . years, sd = . , range = – ) from states of the united states. a multivariate analysis of variance was performed, using education as a covariate, to identify group differences in the mental and physical health measures. hcps reported higher levels of depressive symptoms, past and future appraisal of covid-related stress, concern about their health, tiredness, current general anxiety, and constraint, in addition to lower levels of proactive coping compared to those who were not hcps (p < . , η( ) = . ). within the context of this pandemic, hcps were at increased risk for a number of negative well-being outcomes. potential targets, such as adaptive coping training, for intervention are discussed. on may , , the united states had , , confirmed covid- cases with , deaths (world health organization, ) and was considered the epicenter of the pandemic. although social distancing and quarantine guidelines have slowed the pandemic's spread, the recent relaxing of guidelines suggests continued challenges to the healthcare systems and healthcare professionals (hcps). indeed, there are calls for covid- to be considered as a new occupational hazard for h around the globe (godderis et al., ) . not only are many hcps more likely to be exposed to and, therefore, contract covid- , but providing care during a pandemic can place tremendous pressure on hcps caring for very sick and dying patients, helping the families of the sick, and dealing with the frustrations of healthcare systems, all while trying to take care of their own families and loved ones (maunder et al., ; bai et al., ) . studies out of china have examined the experiences of hcps during the height of their covid- outbreak. in a sample of , medical staff workers in china working during the covid- pandemic, . % reported stress-related symptoms, . % reported symptoms of depression, . % reported anxiety, and . % reported experiencing insomnia (liu et al., ) . lai et al. ( ) found evidence for higher rates of anxiety, depression, and distress among hcps in wuhan compared to hcps in other regions in china. other studies examined the need for and impact of services offered to healthcare workers, such as adjusting shifts to allow time for rest kang et al., ) . while there have been several well-written opinion pieces and commentaries regarding the well-being of healthcare workers in the united states during this pandemic (godderis et al., ; gold, ; greenberg et al., ) , we are aware of only one descriptive study with data from new york city (shechter et al., ) that did not include a control group. there have been several meta-analyses and reviews of the impact of this pandemic on hcps internationally (chew et al., ; pappa et al., ; rajkumar, ) , but no studies from the united states were available to be included in these studies. previous studies have shown that the mental health challenges hcps face during pandemics often impact their ability to continue to be part of the frontlines working to help treat and care for patients and their own families (maunder et al., ; shechter et al., ) . further, enduring psychological effects could negatively impact their ability to provide patient care in the future as well as impacting their quality of life (goulia et al., ) . a crucial mission for researchers during this time is enhancing our understanding of the experiences of hcps in order to plan for interventions and care both in the short-term (now) and in the long-term (over the next couple of years). the current study is designed to examine several critical outcomes such as depressive symptoms, anxiety (current general anxiety as well as anxiety about developing covid- ), covid-related stress, and health in hcps during the early months of the covid- pandemic across the entire united states. in addition, we also examine potentially beneficial indicators of resilience such as control beliefs and proactive coping. psychiatric morbidity in the forms of depression and/or anxiety not only is troubling in its own right, but is also highly correlated with burnout, higher rates of chronic diseases, reduced quality of life, and suicide (kumar, ) . during the severe acute respiratory syndrome (sars) pandemic in goulia et al. ( ) found that the pressure of the work environment combined with fears about the disease itself created negative outcomes in the form of anxiety and depression that had profound impacts on the well-being of healthcare workers during that time. additionally, follow-up studies revealed that the emotional distress from the pandemic was often long-lasting (maunder et al., ) . for instance, one to years after the sars outbreak, maunder et al. ( ) found that sars healthcare workers reported higher levels of burnout and distress, had increased smoking and alcohol consumption, were more likely to have reduced patient contact, and worked fewer hours compared to healthcare workers who did not treat sars. the sars outbreak was much more contained than the current worldwide pandemic which has even greater potential to have both ongoing and lasting consequences on society as a whole and hcps in particular. identifying opportunities for resilience will be especially critical to combat the negative consequences. control beliefs represent the subjective perceptions that one can influence what happens in one's life and include beliefs or expectations about the extent to which one's actions can bring about desired outcomes (agrigoroaei and lachman, ) . lachman and firth ( ) distinguished two main sources of control: one's own efficacy (internal control, competence, or personal mastery), and the responsiveness of the environment or other people (external control, contingency, or perceived constraints) (bandura, ) . the two control beliefs included in the present study are mastery and constraint. mastery is often described in terms of one's judgments about his or her ability to achieve a goal, while perceived constraints refers to the extent to which people believe factors exist which interfere with goal attainment (lachman and weaver, b) . pearlin and schooler ( ) suggested that personal mastery is an important psychological resource that mitigates the effects of stress and strain, and it is also associated with reduced reactivity to work-related stressors (neupert et al., ) . when faced with stressful situations, a strong sense of control has also been linked to low levels of selfreported perceived stress (cameron et al., ) and lower risk of depression (yates et al., ) . aspinwall and taylor ( ) characterized proactive coping as a series of steps one takes to preemptively modify or avoid stressful events. those who have higher levels of proactive coping compared to those with lower levels of proactive coping have more meaning in life (miao et al., ) , fewer symptoms of ptsd (vernon et al., ) , and higher levels of quality of life (cruz et al., ) . proactive coping is also associated with lower levels of depression, fewer declines in functional disability in aging, and larger systems of social support (greenglass et al., ; bokszczanin, ) . when stressors do occur, those with higher levels of proactive coping are able to maintain their emotional functioning better than those with lower levels of proactive coping (polk et al., ) . within the context of the covid- pandemic, individuals who are at high risk of exposure to the virus, hcps, could particularly benefit from engaging in proactive coping strategies in an effort to prevent exposure to future stressors. indeed, we know from our past work that older adults, who are vulnerable to the effects of the virus, had lower levels of stress when they were high in proactive coping (pearman et al., ) . this study is designed to examine the experiences of hcps in the united states during this pandemic. data collection took place between march and may , , a timeframe when the united states experienced a spike in new coronavirus cases, which limited the availability of important medical resources including appropriate personal protective equipment, and put tremendous strain on the nation's hcps. the sample is derived from a larger online study focused on individuals' psychological and behavioral responses to covid- (pearman et al., ). in the current study, we specifically examine the following variables: stress related to covid- , anxiety about developing covid- , depressive symptoms, current general anxiety, past and future appraisals of stress related to covid- , perceived health and health-related concern, tiredness, control beliefs (mastery and constraint), and proactive coping in a sample of hcps and age-matched controls. we hypothesized that hcps would show significantly more challenges on our measures of stress, mental and physical health issues, control, and coping. amazon mechanical turk (mturk.com) was used to recruit participants for a larger study on the impact of covid- . mturk is an international online crowdsourcing panel administered by amazon and used here for collecting data. potential participants responded to the description: the purpose of this study is to examine how people living across the united states are reacting to the current covid- pandemic. select the link below to complete the -min survey. participant requirements for the current study were as follows: years of age or older, living in the united states, native englishspeakers and free from a dementia diagnosis. once recruited and consented (see section "procedure"), the participants completed the survey through the qualtrics platform which is an online survey tool. the sample for the larger study consisted of , participants. participants answered "yes" or "no" to the question, "are you a hcp?" participants for the current study included all participants who answered "yes" to this question as well as age-matched controls drawn from the same dataset. because of concerns regarding age differences in our health indicators, we age-matched the controls. the final sample included hcps and age-matched controls (m age = . years, sd = . , range = - ) from states across the united states. sample characteristics, including type of hcp, are reported in table . informed consent was obtained online; participants who wished to participate in the study indicated electronically that they read and understood the study procedures. after indicating interest, participants were provided a qualtrics survey link on mturk between march , and may , , which was the time period that encompassed the majority of stay-at-home orders as well as many peaks in hospitalizations and death from covid- in the united states. human intelligence tasks (hits) were released approximately every days on mturk to promote continued enrollment and survey completion throughout the weeks of data collection. participants were compensated $ . for completing the -min survey. the study was approved by the georgia institute of technology institutional review board. participants indicated their year of birth, gender, their education from a checklist (e.g., ged, associates), and their race. hcps were also asked to report the specific profession within the healthcare field from a checklist (see table ). participants indicated their level of anxiety related to contracting coronavirus by answering the question, "how anxious are you about developing (covid- )?" on a (not at all anxious) to (very anxious) scale. on a (not at all) to (extremely) scale, participants indicated their level of stress by answering the question, "how stressed are you about the covid- outbreak?" participants completed the -item geriatric depression scale short form (gds) (yesavage, ). the gds is a self-report screening tool that examines depressive symptoms. reflecting over the past week, participants respond "yes" or "no" to other healthcare occupations include n = administration, n = facility manager, n = legal operations, n = counselor, n = exercise physiologist, n = health insurance, n = medical student, n = optometry, n = registered dental hygienist. each item. an example item includes, "do you feel that your situation is helpless?" the scale has been shown to have good diagnostic sensitivity and specificity for adults across the adult lifespan (guerin et al., ) . the scale was not used for diagnostic purposes in this study, but higher scores indicate greater depressive symptoms (α = . ). ten state anxiety items from the state-trait anxiety inventory (spielberger et al., ) were rated on a four-point scale ranging from (not at all) to (very much so). participants indicated how they were feeling in the current moment. example items include "i am tense" and "i feel frightened." five items were reverse coded. a mean was calculated across the items with higher scores indicating more state anxiety (α = . ). participants self-rated their health on a five-point scale ranging from (poor) to (excellent) by answering the question, "how would you rate your overall health?" in addition, participants rated their health concern on a (no concern) to (very serious concern) scale, responding to the question, "how much concern/distress do you feel about your health at this time?" both items were included in analyses as one focuses on current health status while the other focuses more specifically on how concerned the individual is about their health. on a five-point scale ranging from (not at all tired) to (very tired), participants were asked "in general, how tired are you right now?" control beliefs were measured using the mastery (four items, α = . ) and constraint (eight items, α = . ) scales from the sense of control scales from the midlife development inventory (lachman and weaver, a) . on a (strongly disagree) to (strongly agree) scale, participants rated their agreement with statements such as "what happens in my life is often beyond my control" (constraint) and "i can do just about anything i really set my mind to" (mastery). the proactive coping scale (aspinwall et al., ) includes six items rated on a five-point scale ranging from (strongly disagree) to (strongly agree). an example item includes, "i prepare for adverse events." one item was reverse coded. higher scores indicate more proactive coping (α = . ). on a four-point scale ranging from (not at all) to (a lot), participants rated the extent to which covid- affected different areas of their lives in the past h (past appraisal, α = . ) as well as the extent to which they expected covid- to affect their lives in the next h (future appraisal, α = . ). example items include, "your physical health or safety?" and "your plans for the future?" (lazarus, ) . items were scored so that higher scores indicate covid- having a greater impact on one's life. all data analyses were performed using spss version (ibm corp.). the significance level was set at α = . and all tests were two-tailed. a manova was conducted with education (degree) as a covariate and hcp ( = no, = yes) as the independent variable and covid- stress and anxiety, depressive symptoms, current anxiety, self-reported health, health concern, tiredness, mastery, constraint, proactive coping and appraisal (past and future) as continuous dependent variables. because healthcare positions commonly require postsecondary education, education was included as a covariate to account for group differences. significant multivariate tests were followed up with tests of between-subjects effects for each dependent variable individually. there were no significant differences between hcps and the control group on gender [χ ( , n = ) = . , p = . ] or race [χ ( , n = ) = . , p = . ]. as expected, there were significant differences on education [χ ( , n = ) = . , p = . ] such that hcps had more education than non-hcps. results from the manova ( table ) controlling for education show that hcps reported significantly higher levels of depressive symptoms, current anxiety, concern about their health, tiredness, constraint, and past and future appraisal of covid-related stress, but lower levels of proactive coping compared to non-hcps (pillai's trace = . , f( , ) = . , p < . , η = . ). of note, there were also no significant group differences on covidrelated stress or on the specific anxiety of developing covid- . this study is a timely look into the experiences of hcps across the united states during the covid- pandemic. using an age-matched comparison group, the hcps were significantly more depressed and generally anxious than the non-hcps during the first months of the pandemic. in line with shechter et al. ( ) who documented high rates of lack of control and sleep disturbances within hcps in new york city, our results show that hcps across the united states had significantly higher rates of lack of control and tiredness compared to controls. additionally, the hcp group on average fell into the clinically depressed range on the gds (guerin et al., ) . while some of the other findings (e.g., fatigue) may represent the nature of professional differences sometimes seen between hcps and other professions in non-pandemic times (dyrbye et al., ) , meeting the criteria for depressive disorder should not. we believe that the heightened level of depressive symptoms in hcps may be due to not just occupational differences but occupational differences during a pandemic. clearly, this is of concern not just for understanding and, perhaps, helping the current situation but also to look ahead to the potential lasting influence of this experience (see maunder et al., ; lee et al., ) . it is wellunderstood that the long-term consequences of depression and anxiety can create enduring negative impacts (sareen et al., ; musliner et al., ) . finding ways to intervene and support hcps, such as cognitive behavioral therapy or support groups, will be an important goal to healthcare systems and workplaces now and in the future. in addition to increased general anxiety and depressive symptoms, hcps were more tired and more concerned about their health than the age-matched controls. there are many possible reasons for the health concerns of hcps during this pandemic (centers for disease control, ). to start, hcps are more likely to be exposed to covid- which increases hcp's health risk. other health risks include long work hours and mental and physical exhaustion (shanafelt et al., ; the lancet, ) . it is not surprising therefore that the hcps also have higher perceived constraints and are more tired. the real experiences in healthcare settings during the pandemic may present hcps with what seem like insurmountable pressure when it comes to finding ways to accomplish their goals both in terms of maintaining their own health and well-being. helping hcps find ways to differentiate between immovable constraints, such as personal protective equipment deficits, and possible malleable constraints, such as feeling as though there is no opportunity to engage in self-care, may be a possible avenue for buoying the well-being of hcps (de raedt and hooley, ) . along these same lines, the hcps showed lower proactive coping and fewer resources to dedicate to adaptive coping behaviors. we know from past work that proactive coping (polk et al., ) and control beliefs (neupert et al., ) are key ingredients for resilient stress responses, representing potential targets for intervention. for instance, stauder et al. ( stauder et al. ( , found that using coping skills training with employees from work-environments that were stressful, but unchanging, helped reduce stress and improve well-being. although statistically equivalent on covid- -related stress and anxiety, the hcps in the current study scored significantly higher on both current and future stress appraisal when compared to controls. in their real-time study of work stress in nurses, johnston et al. ( ) showed that appraisals of stress were more predictive of psychological and physiological reactivity than the actual tasks being performed. in addition, the perceived reward for the work actually helped reduce stress. given the high levels of stress appraisal both current and future in our sample, it may be beneficial during this time of crisis to help hcps recognize and focus on the reward of their work as a means of managing negative stress appraisals. we acknowledge several limitations in this study. the observational design limits our ability to make causal conclusions. future longitudinal studies should examine the long-term impact of this pandemic on the mental health of hcps. we also do not know the extent to which the hcps in the sample are serving on the frontlines of the pandemic. however, given that the hcps showed significant differences on most of our measures of interest, it is likely that our effects actually underestimate the experiences of frontline workers. in addition, smereka and szarpak ( ) note that covid- is an ongoing challenge for all hcps, not just the frontline workers. another potential limitation is that the professions of the control group nor the hours worked by either group were collected so we are unable to make finer distinctions between the experiences of hcp and the others. we do know, however, that the two groups are statistically equivalent in their stress and anxiety related to the pandemic, so we are reasonably confident that the differences that we do see in our study are associated with healthcare profession status. we encourage future work that seeks to further explore potential differences between professions, but note that our results suggest that all hcps are at risk for decreased wellbeing, perceived control, and coping resources during the covid- pandemic. finally, our sample was not random or nationally representative and was restricted to those living in the united states, the current epicenter of the pandemic. hcps' experiences during the covid- pandemic could differ for those living and working in countries outside of the united states. in conclusion, our results suggest that covid- may function as an occupational hazard for hcps (godderis et al., ) because we found evidence of higher levels of anxiety and depressive symptoms, more tiredness and concern for their health, and more severe stress appraisals of covid- , along with lower levels of perceived control and coping compared to age-matched controls. across a wide array of indicators, hcps appear to be at increased risk for mental health challenges. in addition, given that previous studies during other pandemics have shown lasting impacts of service during this time, including reduced workforce participation and increased traumatic symptomatology, this is a critical issue to address. we encourage efforts to intervene that can provide relief now and in the future. the dataset presented in this article is not readily available because data sharing options were not included in consent documents. requests to access the datasets should be directed to ap, ann.pearman@psych.gatech.edu. this study involved human participants was reviewed and approved by georgia institute of technology office research integrity assurance -institutional review board (protocol # h ). written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements for exempt studies. ap designed the study and funded it out of her internal funds and a grant both from georgia tech, as well as manuscript writing. mh managed the online portion of the project and the data, wrote the methods, helped to prepare the references, and helped with primary prose. es helped with data analyses, created the tables, helped to prepare the references, and helped with primary prose. sn helped with study design, primary data analyses, as well as manuscript writing. all authors 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inventory decreasing the negative effects of work-related stress in unchanged working environments quantifying multiple work-related psychosocial risk factors: proposal for a composite indicator based on the copsoq ii covid- : protecting health-care workers proactive coping, gratitude, and posttraumatic stress disorder in college women coronavirus disease (covid- ) situation report contributors to and mediators of psychological well-being for informal caregivers geriatric depression scale key: cord- -aoz jbf authors: bartlett, john g. title: why infectious diseases date: - - journal: clin infect dis doi: . /cid/ciu sha: doc_id: cord_uid: aoz jbf infectious diseases is a broad discipline that is almost unique in contemporary medicine with its ability to cure and prevent disease, to identify specific disease causes (microbes), and to deal with diverse, sometimes massive outbreaks. the value of the infectious disease practitioner is now magnified by the crisis of antibiotic resistance, the expanding consequences of international travel, the introduction of completely new pathogen diagnostics, and healthcare reform with emphasis on infection prevention and cost in dollars and lives. infectious disease careers have great personal rewards to the practitioner based on these observations. it is unfortunate that we have been so effective in our work, but relatively ineffective in convincing the healthcare system of this value. students of medicine have multiple career options with various attractions and concerns. so it is with the discipline of infectious diseases. as with all medical specialties, infectious diseases has unique features that are important to highlight: among medical specialties, this one is consistently changing, often unpredictable, usually exciting, and incredibly rewarding for health impact. it is also often challenging and seemingly underappreciated, at least until needed. these facts appear to be relatively idiosyncratic to this discipline with a menu of priority pathogens that is in constant flux and weaponry that will change in unpredictable ways. the extraordinary kinetics and ability to intervene successfully using public health, preventive vaccines, and disease-limiting antimicrobials are its great strengths. the following are some of the highlights and unique features of a career in the science and practice of infectious diseases. the menu includes the litany of epidemics, heroic efforts to conquer disease, our expectations with antimicrobials, vaccines and public health, and challenges that may lead to transformative interventions. the field of infectious diseases is kinetic, unpredictable, and layered with surprises that sometime require heroic efforts from a diverse field of scientists and practitioners. • on october , a patient with fever and confusion was seen at a florida medical center by dr larry bush, an infectious disease physician. he examined the cerebrospinal fluid, saw boxcar gram-positive rods, diagnosed anthrax, and predicted bioterrorism [ ] . this was strong stuff at a time no one had thought much of bioterrorism anywhere in decades and especially in an obscure, small town in florida. the ensuing epidemiologic investigation showed anthrax spores in this patient's workplace, the local postal service, and a letter received by the patient. this was the index case of the anthrax bioterrorism epidemic that shook the country in .the result was a major national preparedness response to not only bioterrorism, but also preparedness for natural disasters, epidemics, and other major public health threats. • in , dr alan steere, a rheumatologist from yale school of medicine, led an investigation of an outbreak of arthritis involving children and adults in connecticut. most of the patients had asymmetric swelling and pain of large joints, especially knees, and some also had an erythematous, annular rash [ ] . it was initially called "lyme arthritis," but most physicians thought it was simply juvenile rheumatoid arthritis. dr steere was convinced it was an infection and moreover, that it was arthopod-born based on epidemiology and clinical features. his relentless pursuit of the pathogen was finally rewarded with the discovery of the newly recognized spirochete in the blood and in typical skin lesions [ ] . the specific agent was subsequently defined in a another extraordinary effort, this time by dr willie bergdorfer, who had spent much of his career studying the microbiology of the hindgut of ticks; he successfully isolated the pathogen that he considered his last and most important scientific project [ , ] . that agent is named in his honor: borrelia burgdorferi [ ] . • dr robin warren, a pathologist in australia, made the historic discovery that gastric biopsies from patients with gastritis showed a large burden of curved bacteria. no one paid attention until a young gastroenterologist, dr barry marshall, agreed to study the association. this pairing was considered an "odd couple"; dr warren was described as quiet, thoughtful, and persistent whereas dr marshall was self-described as brash and determined [ ] . subsequent studies consistently showed the association between this curved microbe with gastritis and peptic ulcer disease, but there was almost uniform opposition from both gastroenterologists and infectious disease physicians. larry altman, noted medical editor for the new york times, wrote that never in his experience had he witnessed such fierce opposition from the medical community to the possibility that peptic ulcer disease was caused by a microbe (l. altman, personal communication, may ) [ ] . this prompted proponents, drs barry marshall and alan morris, to perform the ultimate experiment-they swallowed a flask of helicobacter pylori (and suffered from the experience; l. altman, personal communication, may ) [ ] . the long-term result of this unrelenting battle is now well known: h. pylori is accepted as the cause of peptic ulcer disease and its sequela, guidelines for diagnostic testing and treatment are based on h. pylori as the pathogen, this agent is listed as a class carcinogen, and nobel prizes were awarded to drs warren and marshall [ ] . • in early september , dr april pettit, an infectious disease physician in tennessee, saw a patient with aspergillus meningitis following an epidural steroid injection [ ] . this prompted her to notify dr marion kainer at the tennessee health department, who then set up shop with a sleeping cot in the health department to facilitate a nonstop investigation [ ] . this was the beginning of the infamous national epidemic of exserohilum rostratum meningitis associated with the contaminated steroids that led to cases and deaths in states. credit here is to dr pettit for recognition and prompt notification, to dr kainer for her aggressive response on behalf of the victims, and to the centers for disease control and prevention (cdc) for the hasty intervention. (somewhat disappointing is the fact that compounding pharmacies are still unregulated.) • in , dr anthony fauci read the july edition of morbidity and mortality weekly report [ ] describing gay men with kaposi sarcoma or pneumocystis carinii pneumonia in california. for the first time in his life, dr fauci had what he called "chill pimples" ("chill bumps"), and this led to a career change to find the cause, treatment, and prevention of aids. this must be now viewed as possibly the most remarkably successful attack on an important infectious disease since fleming discovered penicillin. • in february , severe acute respiratory syndrome (sars) was a newly described, severe disease in humans that was often fatal and appeared to travel by air routes, but had no established pathogen or treatment. dr klaus stohr at the world health organization (who) identified the finest virology laboratories in the world and asked them to collaborate to define the pathogen with the condition that all information would be shared on the internet and there was no ownership of the data. the participating labs with varying skills were spread throughout the world, so the daily conference calls started with "good morning, good afternoon, and good evening." the etiologic agent was described in an unauthored "global alert" on april and in the lancet with "multicentre collaborative network" as the authors (see [ ] ). this unselfish collaboration under strong leadership is credited with the rapid solving of a global crisis that eventually showed cases with deaths in countries. • these anecdotal experiences (bioterrorism, lyme disease, peptic ulcer disease, iatrogenic fungal meningitis, human immunodeficiency virus [hiv]/aids, and sars) illustrate the unpredictable challenges and some of the unique responses that have left a major imprint on medicine. it is noteworthy that all started with strong leadership and came to closure with either elimination or successful management. epidemics of infections are predictable to occur, but largely unpredictable in time, place, microbe, and consequences. the following highlights some of the recent epidemic records and surprises in this category: • west nile virus was first reported in new york city in and reached a -year zenith for reported cases in with cases, including % with the dreaded neuroinvasive form of the disease [ ] . • coccidioidomycosis: the total number of reported cases increased -fold in years, from in to in [ ] . • malaria reported in us travelers reached a record high of cases in [ ] . • chikungunya virus reached a record number of cases in the caribbean with > reported cases, including in us travelers to st martin [ ] . this pathogen is highlighted because global warming is expected to make it endemic in the southern united states and because of its substantial morbidity with possible long-standing arthritic complications [ ] . • measles: the largest number of annual reported cases in the united states in years was noted during - . it now appears that will be worse [ ] . measles was declared eradicated in but has now become a problem, primarily in those refusing vaccination, but also in some with documented vaccination [ ] . measles continues to be an important infectious disease challenge due, in part, to the extraordinary public health issues that cost one health system $ to deal with the potential epidemiologic consequences of a single case [ ] . • pertussis: this infection is resurgent in the united states and europe, with increased cases including epidemics in children and adults and involving both vaccinated and unvaccinated individuals [ ] . this is thought to reflect waning immunity to the acellular vaccine and the need for a new vaccine [ ] . • meningitis: - reporting showed outbreaks of neisseria meningitidis meningitis, on college campuses and among gay men in new york city and los angeles [ ] . • influenza: this is a continual concern based on the everpresent threat of pandemics with devastating consequences ( - , - , - , - , - ) that seem difficult to predict or control [ , ] . limitations of current expertise were illustrated with influenza a(h n ) swine flu, as the standard concept based on historic precedent is that new influenza epidemics come from asia in the wintertime, but this one came in the eastern hemisphere in the summertime [ ] . the more recent threats that could pose serious consequences are influenza a(h n ) and influenza a(h n ) [ ] [ ] [ ] . both show high mortality rates, but little evidence so far of that single critical mutation permitting attachment to the hemagglutinin antigen to permit sustained person-to-person transmission [ ] . • middle east respiratory syndrome (mers) coronavirus: this coronavirus is a major global concern with analogies to the sars coronavirus in terms of its perceived potential to become a global epidemic with high mortality and no apparent treatment [ , ] . of immediate importance in the united states is recognition of risk with appropriate diagnostic testing, isolation, and management of persons with severe, unexplained pneumonia associated with recent travel to the arabian peninsula (mers) [ ]. • foodborne disease: widespread foodborne epidemics are now a common consequence of the massive food distribution system that permits contaminated beef or lettuce from mexico to reach stomachs in distant multistate areas, with medical consequences involving hundreds or thousands of people. this includes the more recent emergence of the gii. sydney strain of norovirus. these outbreaks seem likely to continue, with unpredictable pathogens in unpredictable places [ ] [ ] [ ] . • heartland virus: a recently encountered tick-borne disease in tennessee and missouri with cases and deaths [ ] . • polio-like virus infection with extremity paralysis has been recently reported in and possibly children in california [ ] . • ebola virus: who has reported an outbreak in guinea involving a new clade of this usually fatal infection [ ] . this listing could continue almost indefinitely. the point is that epidemics are the domain of infectious diseases and public health, with the expectation for management or prevention of outbreaks with requirements for detection, reporting, isolation, and case management. the listing here includes diverse pathogens, some life-threatening diseases, infections with important public health implications, an upsurge of pediatric infections in adults, many travel-related infections, multiple public health threats, and the continuous concerns for influenza and foodborne disease. the major weaponry of the infectious disease catalog includes antibiotics, vaccines, and public health. these categories are remedial reading, but some facets are worthy of emphasis. the value of antibiotics seems obvious. the first patient to receive penicillin was a young woman with β-hemolytic streptococcal bacteremia with fever of . °c- . °c daily for weeks. she received penicillin intravenously starting march , promptly recovered, and survived to age years [ ] . this would appear to be "evidence-based medicine" with an n = . the following statement from dr walsh mcdermott in summarizes this breakthrough especially well: "penicillin gave more curative power to a barefoot, itinerant care provider in the deepest reaches of africa than the collective powers of all physicians in new york city" [ ] . the more recent experience with bacterial resistance and sparse pipeline threatens this miracle, but antiviral development is quite different, primarily for hiv and hepatitis c virus (hcv). it now appears that patients with hiv can achieve near-normal longevity [ ] . hcv infection is even more impressive in terms of speed of progress and ability to cure. the hcv treatment story reflects the efficiency of basic science to define targets, pharmaceutical skills of industry, well-organized trial networks, and a regulatory agency (us food and drug administration [fda]) that facilitated product development [ ] . the impact of vaccines is also impressive. a comparison of annual incidence of vaccine-preventable diseases in the united states reported for the period prior to availability of the designated vaccine compared with its incidence in shows the decrease in polio as %; diphtheria, %; rubella, . %; mumps, . %; invasive type b haemophilus influenzae, . %; and pertussis, a disappointing %. a recent report concluded that the global total for lives saved by vaccines exceeds million [ ] . the impact could be substantially greater with more global access, fewer refusals, and a better pertussis vaccine. a recent cdc analysis of annual costs associated with major nosocomial infections totaled $ . billion per year in the united states with the following rank order by median cost/case: central line bacteremia, $ ; ventilator-associated pneumonia, $ ; surgical site infection, $ ; clostridium difficile infection, $ ; and catheter-associated urinary tract infection, $ . this illustrates the challenge and the priorities [ ] . another challenge is epidemics involving nosocomial pathogens, as shown with the klebsiella pneumoniae carbapenemaseproducing bacteria (kpc) in the national institutes of health (nih) clinical center. this began with a patient transferred from a new york city hospital with a kpc infection and became the source of an institutional outbreak that required extraordinary efforts to control, including a wall constructed to isolate cases, removal of plumbing (as a possible source), use of matrix-assisted laser desorption/ionization time-of-flight (maldi-tof) molecular diagnostics to detect cases and carriers, hydrogen peroxide room aerosols, and "whole house" surveillance cultures. the epidemic was finally halted, but the toll was cases and fatalities over months [ , ] . another kpc epidemiologic investigation showed widespread distribution of this microbe from a long-term acute-care facility in the chicago area [ ] , and others have demonstrated distribution of kpc by air travel from india to europe [ ] . these epidemics require extensive resources and specialized skills; they will be expected to increase substantially in the era of "bad bugs." there is no specialty field in medicine that demonstrates shifting priorities like infectious diseases. to illustrate this point, i have summarized the "hot topics" discussed in the "what's hot in infectious diseases" presentation to the annual meeting of the american college of physicians in , compared with the presentation in , to illustrate the nearly complete change of priorities in a relatively short time. avian influenza, rabies (first survival without vaccine), west nile virus, bioterrorism, transfusion-associated jacob-creutzfeldt disease, usa strain of methicillin-resistant staphylococcus aureus (mrsa), sars, and chlamydia pneumoniae and its role in coronary artery disease and influenza. carbapenemase-producing gram-negative bacilli, colistin, constant infusion of β-lactam antibiotics, molecular diagnostics, a litany of epidemics, new pathogens (mimivirus, borrelia miyamotoi, emmonsia species, and bradyrhizobium enterica), c. difficile gene sequencing, the microbiome, and hcv. note that the -year interval resulted in a completely new agenda for what was considered timely and important in the field based on rapid changes in topical microbes, new epidemics, and new diagnostics, (but not new antimicrobials). it is impossible to predict the menu for . it is now known that genes for resistance to antimicrobial agents were well established in bacteria at least million years before evidence of human life [ ] . the use of antibiotics has selected for these genes by mendelian laws, making it increasingly difficult to control previously treatable infections. this problem was predicted by the father of antibiotics, alexander fleming, who, in , wrote that ". . . the public will demand the drug and . . . then will begin an era . . . of abuses. the microbes are educated to resist penicillin and a host of penicillin-fast organisms is bred out which can be passed to another individual and perhaps from there to others until they reach someone who gets a septicemia or a pneumonia which penicillin cannot save. in such a case, the thoughtless person playing with penicillin treatment is morally responsible for the death of the man who finally succumbs to an infection with penicillin-resistant organisms. i hope this evil can be averted" [ ] . also of note is the prediction by nobel laureate joshua lederberg: "the future of humanity and microbes will likely evolve as . . . episodes of our wits vs their genes" [ ] . it now appears that fleming's prediction is a harsh reality and evolutionary microbial resistance genes are gaining the upper hand, reflecting the combination of massive antibiotic use and lack of new pharmacologic agents. the result is the alarming escalation of antibiotic resistance that is global and applies to nearly all categories of treatable pathogens, leading some to predict "the postantibiotic era." this resistance has been declared a "crisis" by the infectious diseases society of america, the cdc, who, the us congress, and the us president. a disturbing observation in the united states is the conspicuous absence of a national plan to deal with resistance, including the lack of a living record of antibiotic consumption and resistance correlated by location and trajectory. this is in sharp contrast to the european union, which includes countries with official languages and diverse cultures, but has systematically collected data on antibiotic consumption and microbial resistance patterns for years [ , ] . this has resulted in multiple publications with data reviews, studies of interventions, messages to consumers such as an ebug internet program for students, a european antibiotic awareness day, standardized methods to collect data [ ] and a recent -point plan with budget to address the issue [ ] . their data are striking in showing the dramatic association between per capita antibiotic use and national resistance patterns. for example, antibiotic consumption in greece is nearly times that of the netherlands, so we expect more resistance problems in greece, but the magnitude of this difference is alarming: bacteremic carbapenemase strains among all bacteremic k. pneumoniae isolates appear to be about times more common in greece, and mrsa as a percentage of all s aureus isolates is about times higher [ ] . the european union appears to have a mature and substantive model to learn from, with the important caveat that it functions well because there is no claimed ownership, as there are equal partners. there are also some good national programs that have successfully addressed specific problems to learn from: • eu data for showed that france had embarrassingly high antibiotic use rates, accompanied by increasing resistance by s. pneumoniae. this prompted a national campaign targeting prescribers and consumers on antibiotic abuse and its consequences. the goal was a % reduction in antibiotic prescriptions for the entire country; they achieved a % reduced resistance [ ] and also achieved the largest decrease in per capita antibiotic consumption for any nation in the history of the global antibiotic fund [ ] . • a recent report from israel showed a national campaign to reduce the incidence of kpc. analysis of their results with a prevention bundle showed a reduction from per patient-days to . per patient-days [ ] . • the united kingdom addressed the issue of the epidemic nap- strain of c. difficile through gene sequencing and aggressive antibiotic control. the result was a national % reduction in c. difficile infection rates [ ] . the examples given are based on national data addressing major challenges with impressive results. in the united states, this remains a unanswered challenge, but is also an opportunity for the skills of the infectious disease discipline in terms of data collection, evaluation, interventional trials, and policy implementation into practice, primarily in the form of antibiotic stewardship. recent reports using gene sequencing suggest that conventional methods of infection control could substantially improve this effort. examples: ( ) results from the united kingdom have largely disproven conventional teaching regarding the epidemiology of c. difficile infection [ ] ; ( ) this technology also appears to contradict some contemporary concepts about transmission patterns of s. aureus [ ] ; and ( ) it has proven to be a valuable tool in outbreak investigation of kpc infections in a hospital [ ] and in a large community outbreak of kpc involving multiple facilities [ ] . it seems clear that as this technology gets faster and cheaper, it will be embraced as an infection control standard [ ] , although there needs to be caution and skill in interpreting results [ ] . this work in developing countries is another attractive career option based on need, probability of impact, and unique special programs such as the president's emergency plan for aids relief, the bill & melinda gates foundation, and others. some of this is direct patient care, but possibly very attractive targets for impact are the development and implementation of innovative programs that deal with the vast need combined with minimal resources [ ] . the new healthcare system should value infectious disease expertise based on its important role in addressing resistance and costs associated with nosocomial infections. nevertheless, it is feared that the current structure and payment system are not constructed as a good fit to prioritize infectious disease skills. specifically, there is no code for preventing infections, conserving antibiotic use, or preventing resistant pathogens. this might be an erroneous conclusion, or the situation may change as the system matures and becomes serious about addressing the crisis. "bundles" to deal with healthcare efficiencies are in vogue and could be a strength of infectious diseases. an example is the -step central line bacteremia prevention bundle that proved effective in trials [ ] . generalized adoption of this bundle was predicted to save lives and $ . billion per year in us hospitals [ ] , and subsequent actions by clinicians, regulatory agencies, and stakeholders have resulted in an estimated % decline in central line bacteremia rates [ ] . • stewardship: solving or reducing the problem of antibiotic resistance largely depends on antibiotic development and reducing antibiotic abuse. the major on-site forces for improving smart antibiotic use at the point of care are antibiotic stewards-preferably infectious disease or pharmacy personnel trained in this skill to improve the speed of detecting resistant or epidemic pathogens. the tools are obvious to infectious diseases-trained clinicians, but often require methods that are not well inculcated into hospital or clinic practice. methodology with proven value for antibiotic conservation include shortcourse regimens (virtually always wins or ties in trials), use of procalcitonin to facilitate decisions on when to start or stop antibiotics, use of molecular diagnostics to improve pathogentargeted antibiotic decisions, outpatient infusion therapy to reduce inpatient risk (and cost), optimal use of the agents we have, waiting room with notices that the doctor will prescribe antibiotics only according to guidelines, acknowledgement of possible microbiome harm, and possible use of social network media [ , ] . nevertheless, there must be caution: the new us healthcare system represents socialized medicine largely managed by capitalists, which invites both quality and chicanery. for example, the centers for medicare and medicaid services' " -hour rule" for treating community-acquired pneumonia had improved outcome advantages, but also led to overprescribing, declined use of diagnostics, perceived antibiotic abuse, and increases in c. difficile infections. given the priority of cost containment and its relevance to infectious diseases, infectious disease training should probably include attention to the business of medicine. • molecular microbial diagnostics: these are rapidly being developed and introduced into clinical use for detection of epidemic pathogens or resistance genes with advantages of speed, precision, and sensitivity. most polymerase chain reaction (pcr)-based tests define a specific pathogen with extraordinary sensitivity within minutes. the fda has approved these pcr tests to detect at least viruses and bacteria [ ] . these tests may also be useful for early detection of epidemic pathogen or resistance genes [ ] . it seems clear that the introduction of molecular tests for general use may be difficult to interpret in the context of clinical care, so these new tests will require a substantial stewardship from the infectious disease community. this was illustrated in a trial to guide antibiotic decisions based on results of a pcr-based diagnostic to detect mrsa in purulent soft tissue infections that had no significant impact on antibiotic selection [ ] . gene sequencing will be a new and important role for the infectious diseases-trained clinician as it becomes more readily available for defining transmission patterns to inform infection control practice. • microbiome: study of the microbiome at various anatomical sites represents a major nih-sponsored initiative that could possibly translate into important opportunities to treat or prevent multiple conditions [ , ] . this work is at the dawn of development, but the early reads suggest a potential role in obesity, allergies, autoimmune disease, cancer, diabetes, heart disease, and other conditions [ , ] . it is also apparent that antibiotics have a profound and long-lasting impact on the microbiome [ ] . this field requires a transformation in our conventional understanding of infectious diseases, as the "pathogens" are communities of microbes that communicate in contrast to the koch postulate of "one microbe, one infection." an example is a recent report showing that volunteers fed steak and eggs (lecithin) have conversion by gut flora to trimethylamine-n-oxide, which is a marker of atherosclerosis [ ] . this microbial interaction could be altered with antibiotics. the long-term goal is to define associations and intervene possibly with antibiotics and probiotics; this work may also illustrate potential harm to redefine risk-benefit ratios for antibiotics. • bundles: another potentially important role for infectious diseases-trained clinicians is the development of bundles that prevent infectious disease complications. an example is central line bacteremia, as described above [ ] [ ] [ ] . that experience can now be applied to multiple iatrogenic infection risks associated with specific patients or procedures, possibly prioritizing those with the greatest healthcare consequences as described above. the role of infectious diseases is to define the bundle, design the study, and then implement them when results are convincing or even mandated. specialized skills in the management and study of infectious diseases are an increasingly important specialty in contemporary medicine. the roles of practitioners in the discipline are diverse, usually important, and sometimes critical, but commonly undervalued by contemporary priorities in healthcare systems and healthcare reform. it would be difficult to find another discipline in medicine that has such extraordinary diversity, surprises, value in patient care, and clinical relevance for both domestic and international applications. for many trained in medicine, joining the field of infectious diseases is simply the right thing to do. supplement sponsorship. this article was published as part of a supplement titled "the john bartlett festschrift: celebrating a career in medicine," sponsored solely by the department of medicine of the johns hopkins school of medicine in recognition of john bartlett's contributions to medicine. potential conflicts of interest. author certifies no potential conflicts of interest. the author has submitted the icmje form for disclosure of potential conflicts of interest. conflicts that the editors consider relevant to the content of the manuscript have been disclosed. index case of fatal inhalation anthrax due to bioterrorism in the united states lyme arthritis: and epidemic of oligoarticular articular arthritis in children and adults in three connecticut communities the spirochetal etiology of lyme disease interview with willie bergdorfer, ph.d. interview by vicki glaser lyme disease-a tick-borne spirochetosis? how the discovery of borrelia bergdorferi came about nobel prize winners robin warren and barry marshall two win nobel prize for discovering bacterium tied to stomach ailments long-term follow-up of voluntary ingestion of helicobacter pylori 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acquisition in an intensive care unit global supply of healthcare professionals an intervention to decrease catheter-related bloodstream infections in the icu vital signs: central line-associated bloodstream infections-united states preventing bloodstream infections: a measurable national success story in quality improvement a guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: recommendations by the infectious diseases society of america (idsa) and the impact of matrix-associated laser desorption ionization time-of-flight mass spectrometry on the clinical management of patients with gram-negative bacteremia: a prospective observational study introduction of rapid methicillin-resistance staphylococcus aureus polymerase chain reaction testing and antibiotic selection among hospitalized patients with purulent skin infections microbiota-targeted therapies: an ecological perspective the microbiome explored: recent insights and future challenges intestinal microbial metabolism of phosphaditylcholine and cardiovascular risk key: cord- -azkamnpa authors: ecker, david j; sampath, rangarajan; willett, paul; wyatt, jacqueline r; samant, vivek; massire, christian; hall, thomas a; hari, kumar; mcneil, john a; büchen-osmond, cornelia; budowle, bruce title: the microbial rosetta stone database: a compilation of global and emerging infectious microorganisms and bioterrorist threat agents date: - - journal: bmc microbiol doi: . / - - - sha: doc_id: cord_uid: azkamnpa background: thousands of different microorganisms affect the health, safety, and economic stability of populations. many different medical and governmental organizations have created lists of the pathogenic microorganisms relevant to their missions; however, the nomenclature for biological agents on these lists and pathogens described in the literature is inexact. this ambiguity can be a significant block to effective communication among the diverse communities that must deal with epidemics or bioterrorist attacks. results: we have developed a database known as the microbial rosetta stone. the database relates microorganism names, taxonomic classifications, diseases, specific detection and treatment protocols, and relevant literature. the database structure facilitates linkage to public genomic databases. this paper focuses on the information in the database for pathogens that impact global public health, emerging infectious organisms, and bioterrorist threat agents. conclusion: the microbial rosetta stone is available at . the database provides public access to up-to-date taxonomic classifications of organisms that cause human diseases, improves the consistency of nomenclature in disease reporting, and provides useful links between different public genomic and public health databases. thousands of different microorganisms affect the health and safety of the world's populations of humans, animals, and plants. infectious microorganisms include species of bacteria, viruses, fungi, and protozoa. many different medical and governmental organizations have created lists of the pathogenic microorganisms most relevant to their missions. for example, the centers for disease control and prevention (cdc) maintains an ever-changing list of notifiable diseases, the national institute of allergy and infectious disease (niaid) lists agents with potential for use in bioterrorist attacks, and the department of health and human services (hhs) maintains a list of critical human pathogens. unfortunately, the nomenclature for biological agents on these lists and pathogens described in the literature is imprecise. organisms are often referred to using common names, alternative spellings, or out-dated or alternative names. sometimes a disease rather than a particular organism is mentioned, and often there may be multiple organisms or co-infections capable of causing a particular disease. not surprisingly, this ambiguity poses a significant hurdle to communication among the diverse communities that must deal with epidemics or bioterrorist attacks. to facilitate comprehensive access to information on disease-causing organisms and toxins, we have developed a database known as "the microbial rosetta stone" that uses a new data model and novel computational tools to manage microbiological data [ , ] . this article focuses on the information in the database for pathogens that impact global public health, emerging infectious organisms, and bioterrorist threat agents. it provides a compilation of lists, taken from the database, of important and/or regulated biological agents from a number of agencies including hhs, the united states department of agriculture (usda), the cdc, the world health organization (who), the niaid, and other sources. we curated these lists to include organism names that are consistent with the national center for biotechnology information (ncbi) nomenclature and to provide sequence accession numbers for genomic sequencing projects (if available). important synonyms or previously used names that identify the organisms are also shown. we have organized the lists according to phylogenetic structure. this paper provides graphic representations of the phylogenetic relatedness of important pathogenic organisms. the goal of the database is to provide an informative, readily accessible, single location for basic information on a broad range of important disease causing agents. the database will help users to avoid the pitfalls of confusing nomenclature and taxonomic relationships and allow access to literature on in-depth studies. the database can be accessed at http://www.microbialrosettastone.com/. the microbial rosetta stone database was designed to link genomic sequence data, taxonomic classification, and epidemiological information in a way that facilitates searches and data updates. the intent is not to replace currently available tools, like those available from ncbi, but instead serve to resolve ambiguities and data conflicts. one of the main goals of building this informatics infrastructure was to support the rapid determination of the causative agent in the event of a bioterrorist action or emergence of a previously unknown infectious disease. the organisms listed in the additional files are represented according to phylogenetic hierarchy in the figures. the symbols used in the figures connect the organism names back to one or more of the additional files, which allows visualization of the fact that organisms are often represented in multiple additional files. figure is the symbols key. figures and show the phylogenetic relationships of cellular life forms including bacteria, fungi, protozoa, and the plants and animals that produce toxins, figure shows the phylogenetic relationships of dna viruses, and figures , , and show the phylogenetic relationships of rna viruses. for optimal utility, the genomic sequence data, taxonomic, and epidemiological information were linked in a way that facilitates searches, data updates, and data curation. the microbial rosetta stone system will serve as a translator to resolve ambiguities and data conflicts between other public databases and literature and, when unable to resolve ambiguities, provide enough context for users understand the nature of the ambiguities. the database provides links to literature on experimental protocols for pathogen identification and to the genomic and biochemical information specific to a species, strain, or isolate. the data model and query tools are described in detail in hari et al. [ ] . the following sections describe the information and literature sources used to populate in the database for globally important and emerging pathogens and potential bioterrorist agents. in the developing world, nearly % of infectious disease deaths are due to six diseases or disease processes: acute respiratory infections, diarrhea, tuberculosis, hiv, measles, and malaria [see additional file ] [ ] . in both developing and developed nations, the leading cause of death by a wide margin is acute respiratory disease [ ] [ ] [ ] . in the developing world, acute respiratory infections are attributed primarily to six bacteria: bordetella pertussis, streptococcus pneumonia, haemophilus influenzae, staphylococcus aureus, mycoplasma pneumonia, chlamydophila pneumonia, and chlamydia trachomatis [ ] . these bacteria belong to four different taxonomic classes and illustrate how similar parasitic lifestyles can evolve in parallel within unrelated bacterial species (figure ) . major viral causes of respiratory infections include respiratory syncytial virus ( figure ), human parainfluenza viruses and ( figure ), influenza viruses a and b ( figure ), as well as some adenoviruses ( figure ) [ , ] . the major causes of diarrhoeal disease in the developing and developed world have significant differences due to the great disparity of availability of pure food and water and the general nutritional and health status of the populations. important causes of diarrhoeal disease in the developing world are those that tend to be epidemic, especially vibrio cholera, shigella dysenteriae, and salmonella typhi [ ] . these organisms are gammaproteobacteria (figure ) that use many different metabolic pathways to ensure their survival in a wide range of environments. in the united states there is a much lower incidence of diarrhoeal disease overall, and a relatively greater impact of direct human-to-human infectious transmission. the most important causes of diarrhoeal disease in the united states are bacteria such as escherichia coli, campylobacter species, clostridium difficile, listeria monocytogenes, salmonella enteritidis, and shigella species ( figure ) ; viruses, such as norwalk virus ( figure ) and rotaviruses ( figure ) ; and parasites such as cryptosporidium parvum, cyclospora cayetanensis, entamoeba histolytica, giardia lamblia, while microsporidia are responsible for a smaller number of cases ( figure ). infectious disease agents important to the public health in the u.s. are monitored by the cdc and listed in additional file [see additional file ] . there are no set criteria for inclusion on the notifiable disease list; rather, the list is created by the cdc in cooperation with state health departments. as diseases occur less frequently and new diseases emerge, the notifiable disease list changes. the list provides links to case definitions of each disease, including the etiological agent(s) responsible. in cases where the etiological agent was not listed or was symbol key figure symbol key. these symbols are used in the figures through to link pathogen names to their originating additional files. figure bacterial pathogens. bacterial phylogeny is based on work by hugenholtz et al. [ ] . bacterial phyla are shown on the leaves, with the firmicutes and the proteobacteria subdivided to the class level (taxa are shown in italics). their phylogeny is further broken down to the order level with the use of smaller branches. these two phyla account for roughly three quarters of the described infectious bacterial species (with the noticeable exception of deltaproteobacteria pathogens). proteobacteria contain both important plant and animal pathogens. proteobacterial plant pathogens are not clustered, but are observed in alpha, beta, and gamma subdivisions. some plant and animal pathogen species share the same genus classification (e.g. ralstonia and pseudomonas), and for at least one species, burkholderia cepacia, different subspecies are plant and human pathogens. of the bacterial phyla currently recognized in the ncbi taxonomy, thirteen are not present in figure due to the absence of noteworthy pathogens. some of these missing phyla are relatively important, like the cyanobacteria, but most of the remaining phyla are restricted to a handful of species and/or environmental niches. also of interest is the relative weight of the infectious agents within their respective phylum: while virtually all spirochaetes and chlamydiae constitute potential infectious agents due to their parasitic lifestyle, the phylum actinobacteria has few pathogens relative to the overall diversity of the phylum. it should be cautioned that our current view of bacterial diversity is biased towards cultivatable organisms, which represent a small fraction of bacterial diversity [ ] . therefore, this compilation represents the well-recognized infectious bacterial agents, but should in no way be considered exhaustive or complete. unspecific (i.e. brucella spp.), further research was done to determine an etiological agent and this information is in additional file [see additional file ] . each year in the united states, there are approximately million cases of food-borne illness, including , hospitalizations and , deaths [ , ] . in an estimated to % of these cases, chronic sequelae develop. these sequelae include renal disease, cardiovascular diseases, gastrointestinal disorders, neural disorders, and autoim-mune disease [ ] . the estimated cost of food-borne illness in the united states is $ billion annually [ ] . mishandling of food is believed to be responsible for % of all outbreaks of food-borne disease in developed nations, primarily due to a lack of education [ , [ ] [ ] [ ] . food-borne pathogens [see additional file ] are also important because they represent one of the largest sources of emerging antibiotic-resistant pathogens. this is due in part to the administration of sub-therapeutic doses of antibiotics to food-producing animals to enhance growth. for example, certain strains of salmonella show eukaryotic pathogens figure eukaryotic pathogens. eukaryotic pathogen life forms are clearly dominated by the fungi and protists. within the fungi, the phylum ascomycota has many human, animal, and plant pathogens and is a major source of toxins. protist species are responsible for globally important diseases such as the malaria-causing plasmodium species and the leishmania and trypanosoma species that cause significant mortality in the developing world. the eukaryotic phylogeny tree is based on ribosomal and housekeeping gene sequence analysis [ ] , but different taxonomy levels are simultaneously represented as the topology has not yet been reliably determined. resistance to eight or more antibiotics [ ] . studies have shown that antibiotic resistance in salmonella cannot be traced to antibiotic use in humans, suggesting that antibiotic use in animals is the primary cause of resistance [ ] . while much is known about the major microbes responsible for diseases, there are still many undiagnosed cases of infectious disease. it has been estimated that as many as three-fifths of the deaths from acute gastroenteritis per year in the united states are caused by an infectious organism of unknown etiology [ ] . four of the major causes of food-borne infections (campylobacter jejuni, escherichia coli o :h , listeria monocytogenes, and cyclospora cayetanensis, figure ) were only recently recognized as causes of food-borne illness [ ] . zoonoses are a special class of pathogens as they co-evolve with the reservoir host, not with humans. although not always the case, when zoonotic pathogens infect humans they have a tendency to cause severe disease, much like a commensal microorganism that infects unusual areas of the body [ ] . zoonoses can be broken down into two basic groups: those spread by direct contact with the infected animal and those spread via an intermediate vector [ ] . zoonoses can infect humans through many vectors. members of the genus hantavirus are spread by rats [ ] , west nile virus by mosquitoes [ ] , and campylobacter species by family pets [ ] . in , there was an outbreak of monkeypox (figure ) in the midwestern united states, which was attributed to the importation of pet animals [ ] . viruses, protozoa, and bacteria can all be transmitted either directly or via a vector. however, these groups are clearly differentiated on a phylogenetic level. [ ] . of all the agents infectious to humans, a majority are zoonotic in origin [ ] . several viruses responsible for human epidemics have made a transition from animal host to human host and are now transmitted from human to human. human immunodeficiency virus (figure ) , responsible for the aids epidemic, is one example [ ] . although it has yet to be proven, it is suspected that severe acute respiratory syndrome (sars), caused by the sars coronavirus ( figure ) , also resulted from a species jump [ ] . for many years, robert g. webster has studied the importance of influenza viruses in wild birds as a major reservoir of influenza viruses and has clarified their role in the evolution of pandemic strains that infect humans and lower animals [ ] . intriguingly, it appears that whenever a virus (or any other pathogen or pest) is eradicated another appears to fill the environmental niche. for example, in regions where the wild-type poliovirus ( figure ) has been eliminated, nonpolio enteroviruses have been associated with outbreaks single-stranded positive strand rna viruses figure single-stranded positive strand rna viruses. the togaviridae and flaviviridae, and to a lesser extent the coronaviridae and picornaviridae, families are the most prominent human pathogens. important plant viruses affect major cereal grains causing severe crop damages worldwide and affecting the nutrition of entire populations. of paralytic disease that clinically exhibit symptoms of poliomyelitis. the most common non-polio enteroviral causes of acute flaccid paralysis (afp) are human coxsackieviruses a and a and human enterovirus (figure ) . the poliovirus epidemics that emerged in the mid th century are now believed to have arisen not due to a change in the properties of the virus, but due to an improvement of public sanitation and personal hygiene, which delayed the acquisition of enteric virus infection from infancy to childhood. since maternal antibodies protected infants, they usually underwent silent immunizing infections, whereas when older children were infected they more often suffered paralytic poliomyelitis [ ] . proteobacteria are important plant and animal pathogens, and it is interesting that proteobacterial plant pathogens are not clustered on the phylogenetic tree, but are observed in alpha, beta, and gamma subdivisions ( figure ). some plant and animal pathogen species share the same genus classification (e.g. ralstonia and pseudomonas), and for at least one species, burkholderia cepacia, different subspecies are plant and human pathogens. in viruses, plant and animal pathogens are generally found in distinct families, with the notable exception of the families rhabdoviridae ( figure ) and reoviridae (figure ) that harbor both. most plant-specific virus families are not shown in figures , , , , but for rice alone at least ten unrelated virus species have been reported to infect cultures worldwide. the overall economical effect of plant pathogens has been estimated to reduce crop production by one fifth [ ] . foot-and-mouth disease almost destroyed the beef industry in the united kingdom and losses were very high. bird flu in south east asia affected the poultry industry severely. influenza a is a bird virus that jumped from birds via pigs to humans and as a human pathogen has a large impact on the economy [ ] . bioterrorism can be defined as an attack or threat of an attack using bioweapons on humans and/or their assets to create fear, to intimidate, to inflict harm, and/or affect economic well being. such acts may be motivated by political, religious, ecological, or other ideological objectives. any microorganism or toxin capable of causing disease or harm in humans, plants, or animals has the potential for illicit use and thus the list of potential agents could be vast. however, not all organisms or toxins make useful biological weapons. displaying biological weapons from a phylogenetic perspective provides insight into how organisms that have been historically used as biowarfare agents are related to important human and agricultural pathogens and also provides insight into other similar organisms that might be considered as weapons in the future. the properties that make organisms amenable for use as biological weapons have been discussed extensively [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the most important features include: ) accessibility; ) consistent ability to cause death or disability; ) culturability; ) possibility for large scale production; ) stability and ability to retain potency during transport and storage; ) delivery potential; ) stability and retention of potency after dissemination; and ) infectivity and toxicity [ ] . the infectious agents considered by the niaid to have high potential for bioterror use are listed in additional file [see additional file ] . validated and potential bioweapons agents are listed in additional file [see additional file ] . agents that have been used to commit biocrimes [ ] are in additional file [see additional file ]. the pathogens regulated by the hhs and the usda are shown in additional file [see additional file ] and additional file [see additional file ] , respectively. in addition to infectious microbes, toxins derived from biological sources are contained on these lists. we identified the biological source of each toxin, and listed the source organism in the additional file containing the toxin. all regulated toxins can be found on the hhs select agent list [see additional file ] and five are also regulated by the usda [see additional file ] . the regulated toxins (four small molecules and seven peptides or proteins) are produced by a wide variety of organisms: five are pro-duced by bacteria [ ] [ ] [ ] , two by fungi [ , ] , two by plants [ , ] , one by an animal [ ] , and one by a protist [ ] . the bacteria that produce toxins are indicated in figure and the eukaryotic toxin producers are shown in figure . the conotoxins are a collection of five families of related peptide toxins produced by the various species of snails in the genus conus [ ] . the two fungal toxins, diacetoxyscirpenol and t- toxin, are produced by multiple species of the genus fusarium [ , ] . of the five regulated bacterial toxins, four are peptides or proteins and tetrodotoxin [ ] is a small molecule. tetrodotoxin is produced by a variety of gammaproteobacteria that colonize the puffer fish [ ] . these toxins are relevant both due to concern that they may cause outbreaks of disease through accidental food contamination and because they are potential bioweapons. according to the cdc [ ] , an average of cases of botulism, caused by a bacterial toxin (figure ), are reported each year. interestingly, numbers of cases of food-borne and infant botulism have not changed significantly in recent years, but instances of wound-botulism have increased primarily due to the use of black-tar heroin, especially in california. ricin is a toxin produced by the plant ricinus communis (figure ) [ ] . when prepared as a weapon, there are three methods of delivery: ingestion, injection, or inhalation [ ] . one of the most famous documented uses of ricin was in the assassination of georgi markov, a bulgarian defector who died three days after being shot with a ricin pellet [ , ] . pathogens that can be genetically manipulated [see additional file ] represent a unique bioterrorist threat, particularly as technology to genetically alter microbes becomes more commonplace. for the purposes of this work, viruses considered as having a high potential danger for bioterrorist engineering were derived from the literature reports and from the authors' judgment balancing the considerations of terror potential with the technical difficulty of use. dna viruses (figure ) with large genomes can be manipulated in culture, and are susceptible to engineering events such as insertion of genes not normally present in viral genomes. for example, the entire orthopoxvirus genus of the poxvirus family is considered to have high potential for bioengineering because of a much-publicized paper that describes the engineering of an orthopox member, ectromelia virus, to express mouse interleukin- , resulting in a virus with extraordinary virulence [ ] . another member of the orthopoxvirus genus, vaccinia virus, is commonly used in molecular biology research and is extensively used in vaccines and vaccine research [ ] [ ] [ ] [ ] . thus, because they are highly infectious, will tolerate inserted genes, and can be manipulated easily in culture, poxviruses must be considered high-risk agents for acts of bioengineering. mutations to create vaccine-and drug-resistant strains are also possible in other largegenome dna viruses. adeno-associated viruses are small dna viruses that are members of the family parvoviridae. they are satellite viruses that depend upon the presence of their helper dna viruses, including members of the families adenoviridae and herpesviridae, for replication. like vaccinia virus, adeno-associated viruses have been used extensively as vectors for gene therapy, and therefore represent a risk for genetic modification and subsequent terrorist use. rna-genome viruses are naturally more resistant to insertion of genes, but can be made resistant to drugs and potentially even to vaccines by introduction of mutations. most critically, rna viruses may be created in the laboratory by total chemical synthesis to generate active virus particles or reconstituted from cloned dna. total chemical synthesis was demonstrated recently for poliovirus ( figure ) [ ] . since this publication in , the technology to chemically synthesize viruses has advanced substantially. chemical synthesis of rna viruses would eliminate the need for the bioterrorist to obtain stock cultures and would allow creation of any wild-type or mutant strain of virtually any virus. other positive-strand rna viruses ( figure ) that have been reconstituted from cloned dna samples include kunjin virus [ ] , human rhinovirus [ ] , foot-and-mouth disease virus [ ] , transmissible gastroenteritis virus, a coronavirus [ , ] , all three genera of the family flaviviridae [ ] , and a variety of plant and insect viruses [ , ] . thus, the positivestranded viruses must be considered a high-risk area for bioengineering, where the relative risk for each virus must be considered roughly equivalent to the terrorist potential inherent to the virus. negative-strand rna viruses ( figure ) can also be reconstituted by total chemical synthesis or from cloned genomic dna by a reverse genetics approach [ ] . many negative-strand rna viruses, including ebolaviruses, lake victoria marburgvirus, hantaan virus and lassa virus, are important human pathogens and potential bioterrorist agents. influenza virus a is a particularly noteworthy negative-strand rna virus due to its potential to cause pandemic disease, the availability of stock cultures of many strains, and the potential for total chemical synthesis by reverse genetics techniques [ ] . for bacteria, if virulence factors have previously been modified successfully in a species, that species was considered to have a high potential for bioengineering and was included on the chart. however, numerous other methods for engineering bacterial genomes exist. bacterial genomes consist of one or more chromosomes and additional genetic information may exist in the form of plas-mids. plasmids replicate independently of the chromosomal dna and can be transferred between bacteria through transformation. genes encoding virulence factors may be found in either chromosomes or plasmids. in one example of an early bioengineering event, the selective growth of an antibiotic-sensitive species with an antibiotic-resistant species in the presence of the antibiotic resulted in transference of resistance. current techniques allow for the splicing of genes encoding virulence factors from one species followed by insertion into another. however, the complexity of the bacterial genome makes it difficult to successfully transfer a gene with a high rate of expression. this manuscript provides a visualization of the results obtained from use of the microbial rosetta stone database, a database that uses a new data model and novel computational tools to synthesize information on important human, animal, and plant pathogens [ ] . information on critical pathogens and diseases has been collected from many sources. organism names from all lists were converted to ncbi species names and diseases were linked to particular pathogens, which facilitated computational analysis and linkage to public genomic databases. this database should facilitate access to information on disease-causing organisms and toxins. the database can be accessed at http://www.microbialrosettastone.com/. agent lists were collected from various sources as described in more detail for each additional file below. government agency lists (additional files , , , , and ) were taken directly from the specified agencies, while additional tables were compiled using cited literature. organism names from all lists were converted to ncbi species names. this included changes from species synonyms to ncbi-accepted nomenclature and expansion from genus to genus species (e.g. shigella to shigella dysenteriae or shigella sonnei) to represent the most important species (when known). where possible, disease names were associated with the name of the most predominant organism that causes the disease. the additional files contain taxonomic information, the ncbi name of the agent and any well-known synonyms, and accession numbers for the complete genome of each agent (if available). names of the infectious agents listed in the additional files were placed in tree-structure drawings shown in the figures that display the biological relatedness of the organisms. cellular life forms were organized according to currently accepted phylogenetic relationships. bacterial phylogeny (figure ) is based on work by hugenholtz et al. [ ] . the eukaryotic phylogeny tree (figure ) is based on ribosomal and housekeeping gene sequence analysis [ ] . the branching order presented in figure should be considered tentative as the on-going recognition of additional protist lineages is likely to alter the topology of the eukaryotic tree in the near future [ ] . the phylogeny of dna viruses (figure ) was derived primarily from the work of iyer, aravind & koonin [ ] . the common origin of rna viruses and their tentative relationships ( figures , , ) is based on an extensive analysis of their rnadependent rna-or dna-polymerase (manuscript in preparation). the rna virus phylogenetic trees were created using maximum parsimony on protein sequences. the branching of double-stranded rna viruses is for now left unresolved in light of their apparent polyphyly [ ] . the symbol key is shown in figure and symbols are used in the other figures to link the pathogens in the figures to additional files. the agents listed in additional file [see additional file ] were taken from a list maintained by the who. the who tracks the occurrence of morbidity and mortality of global infectious diseases. because of the great disparity in infectious disease prevalence between developed and developing nations, the who divides the world into demographically developed nations (including the united states, europe, japan, australia, and nations of the former soviet union) and demographically developing nations (including india, china, other asian nations, pacific island nations, africa, latin america, and the middle east) [ ] . the who lists leading causes of death worldwide by disease categories. the disease can be caused by multiple diverse organisms or co-infections of different organisms, as is the case for acute respiratory disease, or by specific organisms, such as acquired immune deficiency syndrome (aids) or tuberculosis. in the former case, we identified the most prominent organisms responsible for the disease for display in additional file . the cdc-notifiable-disease list represents those diseases that offer the greatest threat to public health in the united states. additional file [see additional file ] lists the agents on this list. there are no set criteria for inclusion on the notifiable disease list; rather, the list is created by the cdc in cooperation with state health departments. as diseases occur less frequently and new diseases emerge, the notifiable disease list changes. an up-to-date version of the list can be found online on the cdc website [ ] . the online list provides links to case definitions of each disease, including the etiological agent(s) responsible. in cases where the etiological agent was not listed or was unspecific (i.e. brucella species), further research was done to determine an etiological agent and literature used is cited in legend for additional file . the most common causative agents of food-and waterborne illness were taken from a publication by tauxe [ ] and are listed in additional file [see additional file ] . hubálek [ ] published a list that constitutes a representative subset of emerging infectious diseases, which was used as the basis for additional file [see additional file ] . the complete list of all species classified as emerging is substantial [ , ] . the number of pathogens listed in the emerging disease table at http://www.microbialrosettas tone.com/ is significantly larger than that found in additional file . the niaid strategic plan for biodefense research, which lists agents with potential for "high morbidity and mortality; potential for person-to-person transmission, directly or by vector; low infective dose and high infectivity by aerosol, with commensurate ability to cause large outbreaks; ability to contaminate food and water supplies; lack of a specific diagnostic test and/or effective treatment; lack of a safe and effective vaccine; potential to cause anxiety in the public and in health care workers; and the potential to be weaponized [ ] ." the properties that make organisms amenable for use as biological weapons have been discussed extensively [ , ] . for the purposes of the database, we have categorized microorganisms or toxins as validated bioweapons if they have been documented as used, or prepared for use, as biological weapons [ ] . potential bioweapons are defined as agents that have some properties that are considered useful as bioweapons or agents for terrorism, or that have been the subject of serious bioweapons research and development [ , ] . greenwood et al. used a hierarchical ranking of infectious agents and toxins of biological origin [ ] to classify agents as potentially useful biological weapons. greenwood et al.'s highest scoring agents overlapped substantially with our list of validated bioweapons and these are shown in additional file [see additional file ] . the agents listed in additional file and additional agents listed in additional file [see additional file ] could be used in commission of a biocrime. biocrimes are similar to traditional crimes that harm specific individuals except that the weapon is biological in nature. a number of biological agents have been used to commit biocrimes [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , and the potential list of agents that can be used is enormous. indeed, it is impossible to anticipate the next organism that will be used for illicit purposes. documented cases and accessibility were the criteria for choice of agents in additional file . the high potential for bioengineering category [see additional file ] includes both organisms that have been actually modified in biological weapons research programs in the past, and organisms with properties that make them amenable to future engineering. placement in the latter category was based upon published reports of bioengineering for peaceful purposes [ ] [ ] [ ] [ ] [ ] [ ] and the author's (dje) analysis. the agents on the hhs list are shown in additional file . hhs regulates the possession of biological agents and toxins that have the potential to pose a severe threat to public health and safety. hhs's select agent program [ ] regularly reviews and updates the list of select agents and critical human pathogens [ ] . the usda is required by federal law to protect animal and plant health. high consequence livestock pathogens and toxins are agents that the usda considers to have the potential to pose a severe threat to animal or plant health, or to animal or plant products [ ] . these organisms are listed in additional file [see additional file ] . the pathogens on the hhs [see additional file ] and usda lists include agents that span all domains of life, including bacteria, viruses, four fungi, two protists, one prion, and toxins. a significant number of these agents appear on both the hhs and usda lists. dje conceived of the study, organized the structure and contributed to the research and writing, and was overall responsible for the development of the research and the manuscript. rs, vs, tah, kh, jam, and jrw contributed to the literature analysis, organization of written sections, and writing of the manuscript. pw conducted extensive research, analysis, and constructed and linked the tables. bb contributed the sections on biocrimes and bioterrorism. cb-o contributed the viral taxonomy components of the manuscript. cm contributed the phylogenetic organization sections, plant pathogen research, and generated the figures. the microbial rosetta stone project ii: a database system for tracking infectious microorganisms the microbial rosetta stone database: a common structure for microbial biosecurity threat agents the global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in and projected to (global burden of disease and injury epidemiology of acute respiratory infections in children in developing countries epidemiology of acute 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indicated on the phylogenetic charts when they cause at least . organisms responsible for emerging infectious diseases. literature used in conversion of disease names to pathogen responsible and in population of the table included: [ , , , , [ ] [ ] [ ] , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . key: cord- - xxc hyl authors: cuomo, raphael e.; purushothaman, vidya; li, jiawei; cai, mingxiang; mackey, timothy k. title: sub-national longitudinal and geospatial analysis of covid- tweets date: - - journal: plos one doi: . /journal.pone. sha: doc_id: cord_uid: xxc hyl objectives: according to current reporting, the number of active coronavirus disease (covid- ) infections is not evenly distributed, both spatially and temporally. reported covid- infections may not have properly conveyed the full extent of attention to the pandemic. furthermore, infection metrics are unlikely to illustrate the full scope of negative consequences of the pandemic and its associated risk to communities. methods: in an effort to better understand the impacts of covid- , we concurrently assessed the geospatial and longitudinal distributions of twitter messages about covid- which were posted between march rd and april th and compared these results with the number of confirmed cases reported for sub-national levels of the united states. geospatial hot spot analysis was also conducted to detect geographic areas that might be at elevated risk of spread based on both volume of tweets and number of reported cases. results: statistically significant aberrations of high numbers of tweets were detected in approximately one-third of us states, most of which had relatively high proportions of rural inhabitants. geospatial trends toward becoming hotspots for tweets related to covid- were observed for specific rural states in the united states. discussion: population-adjusted results indicate that rural areas in the u.s. may not have engaged with the covid- topic until later stages of an outbreak. future studies should explore how this dynamic can inform future outbreak communication and health promotion. a a a a a between the beginning of march and the end of april , the number of recorded coronavirus disease (covid- ) cases grew from under , to over million worldwide [ ] . globally, growth has not been consistent, with recorded daily cases exhibiting noticeable but relatively muted spread in january, followed by low transmission in february, rapid daily increases in march, and high but sustained levels of new cases in april [ ] . similarly, the spread of covid- has not had even geospatial distribution, with noticeably high levels of recorded cases in china, western europe, and new york; and relatively low levels of recorded cases in sub-saharan africa and central america [ ] , though the exact global burden of covid- remains unknown. current evidence suggests that covid- has an appreciable case-fatality rate when compared to other diseases of similar epidemiological characteristics and infectiousness [ ] . however, establishing even basic epidemiological data during a health emergency can be challenging, particularly in the context of lack of sufficient access to testing and diagnostic capacity, overburdened health systems, and variability in clinical protocols for testing, contact tracing, and other public health measures [ ] . a commonly-employed strategy to reduce deaths from covid- when faced with unevenness in disease reporting is to prevent especially susceptible individuals, such as the elderly and immunocompromised [ ] , from contracting the virus by implementing social distancing guidelines [ ] . despite the rapid increase in number of deaths since the beginning of the covid- pandemic, there has existed wide variability in the seriousness with which governments and local communities have pursued, implemented and enforced social distancing guidelines [ ] . concordantly, there may exist appreciable variability in the level of attention that local communities may have devoted to covid- and associated prevention measures. in addition, the covid- pandemic has numerous ramifications which extend beyond physical health, including those which are sociocultural, economic, and psychological [ ] . individuals with certain mental health conditions or occupations may be adversely impacted by social distancing measures, though they may never contract covid- . conversely, some individuals who become infected with covid- may be entirely asymptomatic [ , ] . therefore, one additional reported case may not indicate any negative utility (if that person were asymptomatic), and case counts may not reflect all negative impacts of covid- (including psychological and economic impacts). this lack of comprehensive covid- burden is likely difficult to estimate, hence, necessitating alternative methodological approaches to assess interactions between outbreak trends from both a longitudinal and localized context. the use of non-traditional forms of epidemiological data, particularly those that originate from online interaction by users, can provide additional insights how much communities pay attention to emerging public health issues, particularly when such data has resolution to geospatial location data and longitudinal data [ ] . in this study we leverage data from the popular microblogging social media platform twitter to rigorously describe the longitudinal and spatial distributions of covid- social media engagement at sub-national levels for the united states. analysis focused on longitudinal and geospatial assessments, both independently and concurrently, to better characterize community-level attention to the covid- pandemic and related opportunities to engage the public in outbreak communication. tweets related to covid- were collected prospectively from march rd to april th by using the twitter public streaming application programing interface (api) using a combination of cloud computing using virtual instances in amazon web services (aws) executed with scripts in the python programming language. tweets were included if they contained three pieces of information: ( ) geo-identifiable characteristics (e.g. geocoded metadata); and ( ) keywords related to covid- , including: "corona outbreak," "corona," "anticorona," "coronavirus," "wuhan virus," "covid," "wuhan pneumonia," and "pneumonia of unknown cause." tweets were excluded if latitude and longitude coordinates were outside of land masses or if keywords were found outside the body of the tweet text. confirmed covid- cases, deaths, and recoveries were obtained from johns hopkins university github cssegisanddata/covid- repository [ ] . these data were obtained for the united states at the secondary administrative level (i.e. counties). active covid- cases were based on diagnosed and reported cases of deaths and recoveries; specifically, active cases were calculated by subtracting a given day's deaths and recoveries from confirmed cases, following the conventional approach used to compute active covid- cases [ ] . for normalization, population estimates for secondary administrative levels for the u.s. nationally were obtained from the american community survey [ ] . in an effort to remove less relevant tweets, such as those relating to news media, machine learning was used to train a classifier to detect tweets exhibiting accounts of first-hand experience with covid- . training data was taken from another study which used tweets that were derived using the same set of keywords as this study [ ] . the classifier was computed using support vector machines (svm), utilizing a linear kernel algorithm via the e package in r, applied to a document-term matrix computed from the training set. all longitudinal and geospatial analyses utilized tweets detected using this machine learning classifier. the c method of the early aberration reporting system (ears) was used to identify statistically significant aberrations in daily change in tweets related to covid- for each of the fifty states in the united states. the ears method is derived from a separate technique, the cumulative sum control chart (cusum) for sequential analysis. furthermore, ears is a syndromic surveillance approach used by the centers of disease control and prevention (cdc) and other public health agencies to detect statistically significant aberrations in infectious diseases [ ] . all ears methods involve comparison with preceding records, and the c method is the most sensitive of the three ears methods. specifically, the first eleven days of twitter data was needed to establish a baseline for statistical comparison, and the earliest date it was possible to identify aberrations was march th. logistically, a dataframe was created in r for each state, with a factor of dates and a series of observed tweets per day, and each day following the baseline period was assessed for statistically significant longitudinal aberration via the surveillance package. geospatial analyses involved the use of arcgis to create choropleth maps with nine intervals to visualize the geospatial distribution of tweets and tweets per capita at the secondary administrative level for the united states. individual tweets were available as latitude/longitude point coordinates from the twitter api, and these point coordinates were aggregated within county spatial polygons in arcmap. for visualization of tweets per capita, the total number of tweets was divided by county-level population. equal intervals were selected as a blue-yellowred gradient in the "graduated colors" feature, thereby illustrating a consistent gradient of magnitudes. concurrent longitudinal and geospatial analysis was conducted by computing a space-time cube with -day time step intervals for , square-kilometer areas in the united states. the space-time cube is a construct whereby a record is produced for every combination of time step and space. after the space-time cube was created using built-in tools within arcmap, the emerging hot spot analysis feature was used to analyze the space-time cube to compute the getis ord gi � statistic for each area at each time point, thereby identifying of z-scores for hot spot and cold spot trends for each , square-kilometer area in the united states. specifically, this methodology utilizes the mann kendall trend test to compute z-scores for every square area, thereby relaying the degree to which the given area was becoming "hotter" or "colder." these z-scores were also visualized as a blue-yellow-red gradient so as to relay the distribution of longitudinal trends for tweets in all areas of the united states. the emerging hot spot analysis feature was also conducted on space-time cubes for active daily covid- cases per capita within the study time period. z-scores for both covid- cases per capita were then averaged for areas within each of the fifty states in the united states and the district of columbia, as were z-scores for tweets per capita in each state. ranking of average z-score was then computed for cases and tweets, and the largest discrepancies between rankings were reported. data management, statistical analysis, and geospatial visualization was conducted using r version . . and arcgis version . . from march rd through april th, , , tweets related to covid- were collected. , , of these tweets had geo-identifiable information which could be converted to point coordinates, of which , were from the united states. of these us tweets, machine learning classification selected , with evidence of first-hand experience with covid- . in an analysis to detect aberrantly high levels of tweets within the in the -day period between march th and april th, inclusive, approximately two-thirds of statistically significant aberrations at the state level were detected in the seven-day period between march th and april rd, inclusive (table ) . nearly all states with aberrantly high numbers of posts during this time period had relatively high proportions of rural populations. specifically, within this seven-day period, arkansas had four consecutive days of aberrantly high tweet volumes (march th through march st), with mississippi and missouri both having two consecutive days of high tweet volumes (march th and march th). sunday, march th was the only day to exhibit aberrantly high tweet volumes for four separate states. the number of tweets collected at the secondary administrative division in the united states were especially high in areas with high numbers of people (fig a) , with levels of tweets becoming much more evenly distributed after adjusting for population (fig b) . similarly, time-space cubes were computed for the united states at , square-kilometer units with -day time step intervals, for both tweet counts over time and population-normalized tweets per capita over time. the number of tweets over time significantly decreased (p = . ), and this trend remained consistent after normalizing for county-level population (p = . ). however, a visualization of z-scores across us spatial units revealed discrepancies in trends toward significant hot/cold spots for (fig ) data, with appreciable discrepancies in the range of the distribution. a time-space cube was computed for population-normalized us daily active cases of covid- , using county centroids with -day time step intervals. overall, a statistically significant increase in county-level population-normalized covid- cases was detected (p < . ). z-scores for trends from the resultant emerging hot spot analysis for covid- cases per capita were compared to z-scores for trends from emerging hot spot analysis for covid- tweets per capita. average values were then computed for each state and the district of columbia. the range of state-level z-scores observed for the cases per capita analysis ) , and for the tweets per capita analysis was - . (missouri) to . (alabama). furthermore, ranks were also computed for trend zscores of normalized cases and normalized tweets, with a rank of for to the highest z-score value and a rank of for the lowest z-score value. the largest discrepancies, in which a state had relatively high trend z-scores for increases in normalized cases while having relatively low trend z-scores for normalized tweets, were for new hampshire (tweet rank of , case rank of ); vermont (tweet rank of , case rank of ); and rhode island (tweet rank of , case rank of ). our analyses uncovered a relative spike in tweets about covid- around march th for predominantly rural areas within the united states. this spike in tweets immediately follows a period during which aberrantly higher number of cases of covid- were reported in the united states. it may be that the rapid acceleration of reported cases caused increased concern about the pandemic, and that communities in these areas mostly ignored the public health threat until a relatively high threshold of cases were reported elsewhere. alternatively, it is possible that the increased attention to covid- in these communities was highly influenced by the social distancing guidelines and forced suspension of businesses that occurred during this same time period. this study suggests that, across subnational areas within the united states, there exists a highly variable threshold of perceived dangerousness and/or intrusiveness required to activate outbreak-related conversations on social media platforms such as twitter, a finding that can inform future outbreak communication and health promotion strategies. both of these causal scenarios may be greatly mediated by news media commonly more consumed in certain areas, and further study should be conducted to assess media-specific roles [ ] . concurrent geospatial and longitudinal analyses also indicate that predominantly rural areas of the united states increased engagement in covid- social media conversations at later stages of the study timeframe. these analyses further suggest that there exists variability of engagement within states, as was observed for idaho, iowa, and south dakota; and that regions of increasing concern can also span across multiple states, as was the case for the montana-idaho and for the minnesota-wisconsin areas. interestingly, though several states exhibited a decline in social media engagement following relatively high points earlier in the study period, states eschewing this negative trend did not exhibit clear longitudinal patterns for recorded active covid- cases. these results suggest that increased communication in certain areas may be a reaction to conditions unrelated to reported covid- infection in their communities (such as discussion of social distancing guidelines or discussions of related government action). alternatively, increased social media messaging about covid- may result from higher numbers of people contracting covid- than have been reported in these areas, which itself may be related to insufficient testing capacity and healthcare access, as has been widely reported and remains an acute problem in rural communities [ ] [ ] [ ] . this study is unique in that it uses twitter data as a proxy measure for assessing the concurrent longitudinal and geospatial distributions of attention to covid- across local and regional communities in the united states. however, a number of studies have utilized similar methods in covid- research, although usually for covid- infection cases and/or deaths. for example, time-space methods were used to differentiate the trajectories of covid- prevalence between rural and urban counties in the united states [ ] , and sequential spatial cross-sections have been assessed to define the evolution of hot spots in subnational regions [ ] . while twitter posts related to covid- have been assessed using spatial and longitudinal techniques [ , ] , these studies have generally focused on country-level comparisons. as these analyses were ecological in nature, this study is primarily intended to generate hypotheses, and the findings in this study should be further corroborated with other sources of data that can better identify specific covid- hot and cold spots in relation to projected number of cases. other data includes the availability and volume of covid- testing kits, search engine query results (e.g. google trends data), covid- hospitalizations data, etc. tweets themselves were collected on the basis of containing certain keywords related to covid- , though the actual content of these tweets may vary in their interpretability for estimating attention to covid- or disease burden. future work by co-authors is focused on developing machine learning approaches to identify users reporting covid- -related symptoms, lack of testing access, and recovery, that could be used in a future study to better assess covid- hot spots and also used to compare against aberrations in reporting. while preliminary, this study suggests that there may exist an appreciable degree of variability in the patterns defining community attention to public health topics, particularly as pertains to online discussion of infectious disease outbreaks. further study should be conducted to characterize community-level moderators of these patterns and to understand the degree to which they may facilitate improved dissemination and impact of public health messaging. the use of ears and time-space cubes appear to have utility in identifying longitudinal trends and their discrepancies across space, and further academic research on the topic of community-level attention to public health issues may seek to leverage these analytical techniques. supporting information s data. (csv) an interactive web-based dashboard to track covid- in real time. the lancet infectious diseases novel coronavirus (covid- ) cases. github repository case-fatality rate and characteristics of patients dying in relation to covid- in italy improving epidemic surveillance and response: big data is dead, long live big data. the lancet digital health di napoli r. features, evaluation and treatment coronavirus (covid- ) scientific and ethical basis for social-distancing interventions against covid- . the lancet infectious diseases early evidence on social distancing in response to covid- in the united states. available at ssrn psychological effects of the coronavirus disease- pandemic characteristics of covid- infection in beijing clinical characteristics of asymptomatic infections with covid- screened among close contacts in nanjing, china infodemiology and infoveillance: framework for an emerging set of public health informatics methods to analyze search, communication and publication behavior on the internet covid- in india: predictions, reproduction number and public health preparedness. medrxiv american community survey -year public use microdata samples machine learning to detect self-reporting of covid- symptoms, testing access and recovery on twitter assessing the performance of the early aberration reporting system (ears) syndromic surveillance algorithms. stat med researchgate net predicting the number of covid- cases from the reported number of deaths lessons from ceos: health care leaders nationwide respond to the covid- crisis. nejm catalyst innovations in care delivery practice of interventional radiology during the covid- pandemic progression of covid- from urban to rural areas in the united states: a spatiotemporal analysis of prevalence rates. the journal of rural health covid- emergence and social and health determinants in colorado: a rapid spatial analysis a first look at covid- information and misinformation sharing on twitter an exploratory study of covid- information on twitter in the greater region key: cord- -z x stl authors: wilkening, dean a. title: combatting bioterrorism date: - - journal: encyclopedia of violence, peace, & conflict doi: . /b - - . - sha: doc_id: cord_uid: z x stl concern that a terrorist group might attack civilian populations or agriculture by releasing deadly pathogens has grown in the past decade. failed attempts by the japanese cult aum shinrikyo to release botulinum toxin and anthrax in tokyo on several occasions in the early s, and the anthrax letter attacks in the united states seem to confirm these fears. however, there were only five fatalities in the us case and none in the japanese case. the question naturally arises: how serious is this threat and, if it is serious, what strategy should states take to combat it? this article draws on us experience to outline a strategy for combating bioterrorism that is general enough to apply to most states, especially ones with well developed public health and medical infrastructures. concern that a terrorist group might attack civilian populations or agriculture by releasing deadly pathogens has grown in the past decade. failed attempts by the japanese cult aum shinrikyo to release botulinum toxin and anthrax in tokyo on several occasions in the early s, and the anthrax letter attacks in the united states seem to confirm these fears. however, there were only five fatalities in the us case and none in the japanese case. the question naturally arises: how serious is this threat and, if it is serious, what strategy should states take to combat it? this article draws on us experience to outline a strategy for combating bioterrorism that is general enough to apply to most states, especially ones with well developed public health and medical infrastructures. the nature of the threat historically, attacks using biological agents are rare. this is not surprising given the relative ineffectiveness of biological weapons as a military weapon due to the difficulty of infecting opposing forces, the availability of protective clothing (a simple mask will do in most cases), prompt medical treatment for troops, and the risk that the attacker's troops may also become infected. the centuries-old revulsion to killing people with poison or disease codified in the hague convention, the geneva protocol, and the biological and toxin weapons convention (btwc) is perhaps the best explanation for why we have not witnessed more deaths due to biological attack. norms have a powerful, albeit imperfect, influence over human behavior. finally, with respect to terrorist use, the traditional view has been that ''terrorists want lots of people watching, not lots of people dead.'' to the extent this is true, terrorists have little incentive to attack civilians indiscriminately because they would loose political support within their community and the attack would likely provoke a draconian response by the state to eliminate the group. the question is whether this trend will continue. there is reason for concern regarding bioterrorism because the knowledge, materials, and equipment to make biological weapons are spreading worldwide; the incentives for states or terrorists to acquire and use such weapons may be increasing; and civilians, as well as agricultural sectors, remain quite vulnerable to such attacks. the knowledge, materials, and equipment to manufacture biological weapons are spreading due to advances in biomedical technology, the dual-use character of this technology, the global nature of the biotechnology and pharmaceutical industries, and the pervasive access to knowledge through rapid global information sharing. unlike nuclear weapons, where - kg of fissile material is required to build a rudimentary fission bomb, no such barrier exists for biological weapons. in fact, biological weapon proliferation is governed more by the spread of knowledge than the spread of material and equipment. traditional biological agents can be found in the environment or in numerous unprotected strain collections around the world and large batches of bacteria or virus can be grown in simple fermenters. former state biological programs represent another potential source of materials, equipment and, especially, knowledge. the remnants of the former soviet biological weapon program, estimated by some accounts to have once employed over scientists and technicians, represents an avenue by which states or terrorists might acquire biological weapons without the painstaking research and development required to create them ab initio. president yeltsin declared in that the former soviet biological weapon program had been dismantled and that biopreparat, the civilian biomedical research organization that conducted much of the biological weapons research, would be converted solely to peaceful pursuits. due to a lack of transparency, concerns remain that a covert biological weapons program may still exist in russia. cuba, iran, north korea, and syria are also believed by the us government to have biological weapon programs, at various levels of development, and south africa and iraq formerly had programs from which materials or expertise could leak. in addition, numerous countries have biological weapon defense programs, which produce small quantities of pathogens for peaceful purposes (e.g., testing prophylaxis efficacy), which is allowed under the btwc, from which knowledge or materials could also leak. biological weapons of varying degrees of sophistication clearly are within a state's means to acquire covertly. the dual-use nature of the equipment and supplies make biological weapon programs easy to hide under the guise of legitimate biomedical activities. only small quantities of pathogens are required for seed stocks, and biological agents emit no detectable signal, making them virtually impossible to detect remotely. the fact that biological weapon facilities can be small and have no distinct physical features makes their identification difficult even with intrusive on-site inspections, as the un special commission charged with locating and destroying iraq's weapons of mass destruction discovered after the iraq war. it took the commission years to locate most of iraq's biological weapon facilities and then only after kamel hussein divulged the scope of the secret iraqi program after defecting to jordan in . finally, legitimate peaceful activities such as vaccine and biopesticide production can be converted to biological weapon production within weeks to months. it is less clear whether terrorists can acquire effective biological weapons without state support. terrorists operating rudimentary laboratories face challenges obtaining lethal pathogen strains, extending pathogen shelf life and, in particular, mastering the 'weaponization' hurdles -agent drying, stabilization, and aerosolization (i.e., creating a respirable aerosol of viable agent less than mm in diameter so it does not settle out of the atmosphere close to the release point and so it can penetrate the alveolar region of the lungs where pathogens are most infectious). wet pathogen slurries are relatively easy to produce but difficult to disseminate in a -mm aerosol. dry powders can be ground to less than mm prior to dispersal (although clumping and electrostatic charge can be a problem), but dry agent is more difficult to produce and handle in a safe manner. thus, each path has its hurdles. most terrorists lack the practical knowledge required to circumvent these hurdles, even if they have trained microbiologists in their ranks, unless they receive outside help. (aum shinrikyo failed to kill anyone with anthrax because they used a nonlethal vaccine (stern) strain in and attempts to aerosolize the spores failed. this led the cult to carry out its more infamous sarin gas attack on the tokyo subway in .) of course, terrorists may not strive for highly efficient weapons. causing panic, if not terror, is possible even with a rudimentary biological weapon. not only are the means for acquiring biological weapons spreading but the incentives to acquire, and possibly use, them are increasing as well. the united states emerged from the cold war as the world's unrivaled conventional military power, while the collapse of the former soviet union left its allies to fend for themselves. consequently, opponents of the united states must search for 'asymmetric' means -including, possibly, biological weapons -to counter us military might. the suicide bombings in iraq and afghanistan are a current example of this approach. terrorists' incentives to use such weapons may be changing as well. the september attack in the united states and subsequent indiscriminant attacks in bali, madrid, beslan, and london suggest that terrorists may wish to inflict mass casualties. biological attacks can also devastate sectors of the us or world economy -an attractive goal to some terrorists. still, some constraints may exist. for example, terrorists may be reluctant to use contagious agents because the subsequent contagion might spread to their home country or social group, which may have less access to public health. they may also eschew biological attacks because the operation is more likely to fail, preferring conventional explosives instead. to divinely inspired perpetrators, failure can be a deterrent because it suggests that god does not support their actions. the vulnerability of civilian populations and agriculture may encourage bioterrorism. while modern military forces are relatively invulnerable to biological attack, civilians are quite vulnerable because they do not have protective clothing, would not know when to put it on if they had it, and they do not routinely receive prophylaxis against common biological warfare agents. the agricultural sector in most countries is also vulnerable because farms, animal pens, animal feed, and even finished agricultural products (e.g., milk) typically are not very secure against malevolent actors. the sudden appearance of diseases such as foot and mouth disease, bovine spongiform encephalitis, wheat rust, or similar plant or animal diseases can shut down an agricultural sector very quickly, preventing exports if not domestic consumption, as demonstrated by natural outbreaks of these diseases in the past. the bioterrorism threat is complex and diverse. biological weapons may be toxins or living pathogens. they may target humans, livestock, or crops and, hence, be aimed at mass murder or economic impact. pathogens may be lethal or nonlethal, contagious or noncontagious, and they may infect the host via contact with openings in the skin, animal or insect vectors, ingestion of contaminated food or water, or inhalation, giving rise to a wide range of delivery mechanisms and attack outcomes that vary by many orders of magnitude in terms of their consequences. the current threat largely involves naturally occurring pathogens and toxins. in many ways, biological attacks are similar to the scourge of disease that has wrought havoc on human, animal, and plant populations for millennia, the main difference being that the consequences are greatly compressed in time if not scope. in the future, genetically altered or synthetic pathogens may be possible because the science of genetic manipulation and dna synthesis is evolving rapidly. this diversity of threats makes it difficult to comprehend bioterrorism as a singular phenomenon requiring a singular strategy. the complexity of the bioterrorism threat suggests a multifaceted approach. to simplify the remaining discussion, this article focuses on the elements of a strategy for combating bioterrorism aimed at humans, especially airborne releases because they have the potential for creating the greatest number of casualties. the strategy for protecting the agricultural sector will have similar elements but requires a separate analysis. the strategy for coping with any proliferation problem involves four complementary elements: diplomacy, deterrence, preemption, and defense. diplomatic initiatives may help prevent the spread of proscribed weapons, thereby eliminating the problem at its source. if weapons proliferate, deterrence may dissuade their use. if deterrence is about to fail, preemptive attacks may destroy the weapons before they can launch and, if preemption is not a viable option, 'active' defenses may interdict weapons before they arrive and 'passive' defenses may protect people from their effects after detonation. this framework applies to any proliferation problem -nuclear, biological, chemical, or ballistic missile. all four elements are important, with different emphasis depending on the nature of the proscribed weapon. for example, the cold war nuclear threat was principally addressed by deterrence, complemented by diplomatic (i.e., arms control) efforts to circumscribe the threat and limited efforts at preemption and defense. for biological weapons, the main emphasis should be on defense, complemented by diplomatic efforts, preemption, and deterrence. diplomatic efforts to prevent the proliferation of biological weapons include the geneva protocol, which bans the first use of biological (and chemical) weapons; the btwc, which bans the development, production, stockpiling, acquisition, and transfer of biological agents ''of types and in quantities that have no justification for prophylactic, protective or other peaceful purposes'' and their means of delivery; the australia group, which coordinates the export control policies relating to chemical and biological weapons materials and equipment among the or so member states; and un security council resolution , which calls upon states to ''refrain from providing any form of support to non-state actors that attempt to develop, acquire, manufacture, possess, transport, transfer, or use nuclear, chemical or biological weapons and their means of delivery,'' to adopt and enforce domestic legislation to prevent non-state actors from engaging in these activities, and to establish domestic controls to prevent such proliferation. the fundamental problem with monitoring biological weapon proliferation is that biological agents, material and equipment are quintessential dual use items, making it difficult to separate benevolent from malevolent applications, and covert biological weapon facilities have few unique signatures that would allow for identification without intrusive inspections. even with intrusive inspections, it can be difficult to identify covert facilities. for this reason, the btwc did not include any monitoring or verification provisions, common to most arms control treaties, because member states could not agree on inspection provisions. this difficulty is compounded by the fact that the btwc allows states to acquire small quantities of pathogens for prophylactic and other peaceful purposes. the difference between a small pathogen sample used to test antibiotics or vaccines and one used as seed stock in a biological weapon production facility is solely one of intent. attempts during the s to strengthen the btwc with an inspection protocol ended in when the bush administration withdrew its support; arguing, with some justification, that covert biological weapon programs could easily be hidden even if this protocol entered into force; that legitimate facilities could be converted to produce biological weapons in a short period of time (weeks to months); and that any inspection regime that was intrusive enough to detect covert programs could compromise proprietary information crucial to commercial companies. similarly, the australia group faces an enormous challenge distinguishing between legitimate and illegitimate end uses for exported biological material and equipment. at best, export controls may impede large-scale acquisition or activities, but it probably cannot thwart small-scale operations. future diplomatic efforts should extend beyond traditional arms control treaties and export control regimes. for example, the us-russian cooperative threat reduction program, which has focused principally on securing nuclear weapons, materials, and scientists in the former soviet union, should be expanded to cover a wider range of former soviet biological weapon facilities and activities. material protection, accounting, and control would help prevent the spread of pathogens, equipment, and materials; and funding to employ key former soviet personnel on peaceful biomedical research would discourage them from selling their expertise to foreign bidders. the latter is particularly important because biological weapon acquisition is largely an issue of acquiring the tacit knowledge, as opposed to the equipment and materials, to build such weapons. an international code of conduct for biomedical researchers could help reinforce the norm against biological weapons development. the promulgation of international standards and shared best practices for safety and security at pathogen collections or biocontainment facilities that work with deadly pathogens, for example, could reduce the risks associated with accidents or diversion and would help promote interaction among biomedical practitioners engaged in potentially dangerous research. international association and collaboration among biologists, medical professionals, and public health practitioners would help address emerging infectious diseases and the transparency produced through such collaborations would have, as a collateral benefit, the potential to detect covert activities. the soviet biological weapons program would have been more difficult to conceal had there been international collaboration with soviet biologists, medical and public health practitioners during the cold war. detecting covert biological weapon activities increasingly will be a matter of detecting the people involved, not the weapons. improving international disease surveillance, specifically improving public health laboratories in less-developed countries and their connectivity to the international health community, is a worthy objective that also has security benefits. if an attack with a contagious agent occurs in a foreign country, the sooner this is detected, the better governments will be able to limit its entry into their state by monitoring borders and ports of entry, and restricting travel. improved international disease surveillance might also detect the presence of covert biological weapon programs in the event of an accident that infects the local population. the accidental anthrax release in sverdlovsk, russia would have been readily detected if such a surveillance system were in place at that time. of course, hiding covert programs, as well as avoiding political embarrassment from natural disease outbreaks, is precisely why some states will resist disease surveillance that is not under their control. still, efforts by the world health organization (who) to implement the global outbreak alert and response network are well placed and the recently revised who international health regulations, which require reporting of any disease of international public health concern within hours, when fully implemented, will have public health and security benefits for all nations. these efforts need sustained diplomatic and financial backing. ultimately governments must recognize that the spread of disease does not respect international boundaries. hence, public health is not solely a sovereign issue, especially in an age of rapid international travel and commodity transport. however, diplomacy alone ultimately cannot prevent the spread of biological weapons. revelations about the size and scope of the covert soviet biological weapons program during the cold war, much of which existed under the guise of legitimate biomedical research, demonstrates the limited utility of diplomatic means. diplomacy's greatest benefit may be to reinforce the widely held norm against the use of disease as a weapon of war or terror. reinforcing this norm is important not because one hopes to convince malevolent actors to abide by the norms to which the status quo powers adhere, but rather for deterrence; it convinces malevolent actors of the sincerity with which the united states and other likeminded states abhor biological weapons and, hence, the resolve with which they will respond if attacked. despite the best diplomatic efforts, biological weapons may still spread. the question then becomes whether states can dissuade other states or terrorists from using them. the efficacy of deterrence against 'rogue' states or terrorists has been questioned because their leaders are believed to be irrational and, hence, cannot be dissuaded by retaliatory threats. this argument distorts the character of regional leaders. authoritarian leaders may be ruthless, unsavory characters with little regard for their civilian population; however, generally, they are not suicidal. similarly, terrorist groups often have clear strategic and tactical goals, with an infrastructure that supports their operations logistically and financially. while those who carry out acts of terror may be suicidal, the top-and mid-level leadership frequently is not. therefore, in principle, one may be able to identify targets against which retribution will dissuade some terrorist groups from acting. in practice, this often is more difficult, especially if one wants to avoid civilian casualties. effective deterrence depends upon the ability to identify the perpetrator of an attack. therefore, attribution, especially against terrorists or state-sponsored terrorists, is crucial for effective deterrence. by holding states responsible for terrorists who acquire material from them, states will have greater incentive to secure any biological agents they might possess and they will be more reluctant to provide them to terrorist groups with whom they sympathize. unauthorized acquisition is a problem and will be the obvious cover for any state that contributes to a terrorist's biological weapon capability, un security council resolution notwithstanding. deterrence relies upon clearly communicated, credible retaliatory threats whose consequences outweigh any benefits the attacker might hope to gain. credibility, in turn, depends on a state's capability and resolve to retaliate. public commitment to the geneva protocol, the bwtc, and un resolution helps convey resolve, in conjunction with statements by top government officials. however, states often lack the capability to respond, in part, because they lack biological weapons themselves with which to make tit for tat retaliatory threats. nuclear threats, for those states that can make them, are less credible because they require nuclear first use -a difficult political/strategic decision under any circumstances. the united states may be alone in having sufficient conventional military power with which to threaten retaliation, for example, to topple the regime that aided or carried out the attack. although nuclear response options cannot be ruled out, the united states clearly should emphasize conventional military capabilities to deter biological attack. such threats may help deter biological attacks by states, but they are bound to be less effective than deterrence of nuclear attacks during the cold war. deterring terrorists may have common elements with deterring states, assuming one can locate enough of the top leadership and infrastructure that supports their operations. however, terrorists have less to lose so the cost-benefit calculus is more difficult to shift in the deterring state's favor. perhaps the best way to dissuade terrorists from attacking is to deny the success of the attack. terrorists often are risk averse when it comes to the success of their mission, preferring tactics, techniques, and targets that assure success. dissuading an opponent by convincing him that his chances for success are slim is referred to as 'deterrence by denial'. however, this terminology confounds deterrence with defense. true, defenses may divert an attack to less well defended targets or dissuade a terrorist group from attacking altogether because of the reduced chance of success. however, the objective of a defense is not to influence terrorist calculations, but to protect the defender regardless of their calculations. preemptive attacks, that is, thwarting an opponent's ability to strike first when the threat is imminent by destroying his weapons before they can be launched, is frequently practiced in conventional war and was considered by both the united states and the former soviet union with respect to nuclear war. preemption will play less of a role against biological attacks because it is impractical -biological facilities and weapons are easy to conceal and, even if located, they are not easy to destroy without the risk of collateral damage, whether this is from the radioactive fallout from a nuclear blast or the dispersal of pathogens due to their incomplete destruction in a conventional strike. against terrorist attacks, preemption certainly will be attempted if a state knows where biological weapons are located but, again, this is unlikely unless intelligence or law enforcement agencies get lucky. efforts to improve intelligence on suspect groups or individuals are useful; however, there are no technical fixes in the offing that will allow intelligence agencies to improve their ability to detect covert biological weapon programs in the future. better human intelligence is imperative. therefore, while states should be alert to the opportunity to preempt state or terrorist attacks, it is impractical to rely upon preemption for coping with biological attacks because of the demands it places on accurate, timely intelligence. active defense/interdiction 'active' defenses interdict weapons before they reach their targets. interdiction frequently is cited as a preferred strategy against terrorists. however, interdiction is difficult against covert biological delivery because pathogens have no signature that allows one to detect them in transit on a person, in luggage, or in any other container. moreover, biological agents can be released in a myriad of ways, complicating surveillance efforts. again, there are no clear fixes that will allow intelligence agencies to improve their ability to determine who, when, where, and how a biological attack might occur. therefore, interdiction programs like the proliferation security initiative -a us effort to create international agreements and partnerships with other countries to allow the united states and its allies to board airplanes or ships suspected of carrying weapons of mass destruction or their components -may have some deterrent role but without accurate and timely intelligence, it will likely be of limited effectiveness against biological threats, unlike chemical, nuclear, or ballistic missile threats where the cargo is easier to detect. examples of efforts to improve border and transportation security in the united states either focus on identifying potential terrorists (e.g., the united states visitor and immigrant status indicator technology (us-visit) program) or dangerous cargo (e.g., advance electronic cargo manifests, the container security initiative, and the customs-trade partnership against terrorism program). screening travelers at ports of entry is useful because it potentially detects malevolent actors, not their weapons. screening cargo is much less useful for biological threats because, again, biological agents emit no detectable signature. not surprisingly, most cargo screening efforts focus on detecting nuclear or radiological materials. traditional forms of defense such as air and ballistic missile defense will be of limited use against bioterrorism attacks. air defenses can be effective provided air defense networks are alerted to the attack, but covert air delivery using a commercial or private airplane will be very difficult to detect without prior intelligence. ballistic missile defenses are of limited use because terrorists are unlikely to have ballistic missiles at their disposal, except possibly very short-range missiles or rockets. against the latter, defenses such as patriot advanced capability- (pac- ) interceptors or the mobile tactical high energy laser (mthel) may have some utility, assuming they can prove their effectiveness on the test range. against biological weapon attacks by a state, ballistic missile defenses also will be of limited value because biological submunitions released early in flight, a technology the united states and the former soviet union mastered in the s, can easily overwhelm missile defenses. 'passive' defenses protect a population from the effects of weapons after they detonate. against biological weapons, passive defenses can be quite effective. inhalation is the most infectious method of exposure for biological agents. therefore, a simple mask can provide considerable protection if one knows when to don it. standard, inexpensive n or n masks filter out % or %, respectively, of the submicron particles from inhaled air, thereby substantially reducing the inhaled dose. their use, for example, would substantially reduce the scale of an epidemic if donned immediately after a contagious disease outbreak is detected, thus increasing the effectiveness of any medical response because it could focus on a smaller infected population. in principle, homes could be outfitted with high-efficiency particle (hepa) filters, although this would require substantial modifications to most home heating, ventilation, and air conditioning (hvac) systems and would require positive overpressure systems to prevent infiltration through cracks. however, hermetically sealed office buildings frequently have hepa filters and positive overpressure hvac systems, making it easier to 'harden' such buildings if they are likely targets of attack or if they perform critical functions in the midst of an emergency. despite the simplicity and relatively low cost associated with most physical protection schemes, they all suffer from the fact that, to be effective, protection must either be in place at all times (e.g., hermetically sealed office buildings) or individuals must know when to seek shelter or don masks. the latter relies upon adequate warning and the ready availability of shelters and masks, both of which currently are not available in most countries. during the iraq war, most israeli citizens carried gas masks which they donned each time their ballistic missile surveillance system warned of an incoming iraqi scud missile attack. however, most countries do not have such plans or provisions and, in any case, at best they work only in war and not against covert bioterror attacks in peacetime. preattack vaccination conceptually is the simplest approach to preventing disease from a biological attack. this is the approach taken for most infectious diseases of public health concern. for example, almost all children in the united states are vaccinated against polio, measles, mumps, rubella, pertusses, and varicella; and large segments of the population who may be at risk are vaccinated against pneumococcal infection, hepatitus a, hepatitus b, tetanus, and influenza. the reason this approach has not been widely adopted as a defense against bioterrorism is twofold. first, unlike mother nature, terrorists are strategic opponents. when it becomes known that a population has been vaccinated against specific pathogens, terrorists will choose an alternate pathogen or, if sufficiently sophisticated, they may design the pathogen to circumvent the vaccine. second, some vaccines have serious medical side effects in a very small percentage of cases. vaccinating the entire population prior to an attack could produce several hundred severe reactions, possibly including death, and hence is an option of which political leaders will be chary unless the threat of attack is imminent, which as noted above will be difficult to determine. postattack medical prophylaxis, on the other hand, does not suffer from this political liability and, hence, is the preferred strategy, assuming it can be effective. if, however, postattack medical intervention is not effective against some pathogen or if the threat of attack from a particular pathogen is a clear and present danger, then a case can be made for preattack vaccination against this particular agent, assuming the vaccine exists. otherwise, preattack vaccination is contraindicated until safer vaccines become available. all biological agents, with the exception of toxins, incubate in their hosts for a period of days to weeks, depending on the pathogen and the dose to which the individual is exposed. moreover, medical interventionantibiotics and vaccines in the case of bacterial agents, and antiviral drugs and vaccines in the case of viral agentscan be very effective if administered prior to the development of symptoms in the host, or shortly thereafter under some circumstances. therefore, a window exists inside of which medical intervention can be very effective at saving lives. this is the basis for the most important element of a biodefense strategy, namely, rapid postattack medical response. postattack medical response involves three elements: biological agent detection and identification, medical logistics to deliver supplies to the exposed population, and a prophylaxis campaign that can dispense the appropriate medications to the entire exposed population in a short period of time, including to a potentially large number of people who believe they have been exposed but are not. all three steps must occur before too many people become symptomatic if this strategy is to provide a high degree of protection. the incubation period for a given disease sets the timescale on which these activities must occur. the medical efficacy of postattack antibiotic treatment against inhalation anthrax, for example, is illustrated in figure , which plots the percentage of hypothetical victims that can be saved as a function of the time at which medical intervention begins. the airborne anthrax release upon which this calculation is based is one for which the exposed population is approximately people, of which would become infected in the absence of medical treatment. the medical intervention posited here consists of antibiotic distribution to % of the exposed population over a period of hours (possibly followed by vaccination), that antibiotic treatment prior to the onset of symptoms is % effective, and that postsymptomatic antibiotic treatment is approximately % effective if delivered within days of symptom onset, assuming intensive medical care is available of the sort provided to the victims of the fall us anthrax letter attacks (i.e., multidrug regimens and pleural fluid drainage). (different curves are required for different attack sizes and different diseases, and, in the case of contagious diseases, one must account for secondary transmission.) from figure , one observes that over % of this exposed population can be saved if treatment begins within days after exposure. the maximum medical efficacy asymptotes at % due to assumptions embedded in the model. clearly, the sooner one can provide prophylaxis to the exposed population, the better. as the detection and identification time is reduced, more time is available to implement the medical response. and, some functions can overlap in time; for example, the logistics associated with activating the strategic national stockpile (warehouses in the united states that currently store medical supplies for a massive infectious outbreak) and setting up and staffing the points of distribution (pods) where people will eventually queue up to receive treatment can occur simultaneously and immediately after an attack is detected but before the agent has been identified. this figure should be interpreted with care because it is based on optimistic assumptions, given current us preparedness, regarding the detection time, the speed with which medical logistics can deliver antibiotics to the pods within the affected area, the speed with which queues can be processed at these pods, and the effectiveness of the prophylaxis regime (e.g., certain medications may be contraindicated for some subpopulations such as children, pregnant women, and immunocompromised individuals and other victims may not comply with the entire prophylaxis regimen). but, figure does represent the level of protection that, in principle, can be achieved. moreover, a % effective medical response against an attack that hypothetically infects people, still leaves people infected, which in the case of inhalation anthrax implies close to deaths, a horrific outcome compared to any bioterrorism witnessed to date. this will likely be viewed as an unacceptable outcome. thus, the tendency will be to strive for medical effectiveness well above %. to achieve levels of protection above %, it will be very important to implement policies that reduce the percentage of people who do not receive prophylaxis (assumed to be % of the exposed population in figure ) or that do not adhere to the full antibiotic regimen over timeboth of which are important social, as opposed to technical, challenges for a prophylaxis campaign. finally, it is important to note that this strategy overlaps with efforts to improve public health. consequently, some of the cost for biodefense will have benefits even if an attack never occurs. given the low, albeit uncertain, likelihood of a biological attack, emphasizing those biodefense programs and activities that have substantial public health benefits is a prudent way to proceed, although some important biodefense programs will not meet this criterion (e.g., developing an improved smallpox vaccine). moreover, given that infectious diseases are the leading cause of death in many developing countries, a strategy for coping with bioterrorism that does not address the legitimate public health concerns of the developing world will gain little sympathy, support, or cooperation. contrariwise, the developed world stands to gain tremendous good will if it helps the governments of developing countries solve their public health problems -a commodity not irrelevant in the global struggle against terrorism. two issues are important with respect to detecting a bioterrorism event: low false alarm rate and speed. false alarms quickly erode confidence in any detection system, not to mention their economic costs, and consequently should be very infrequent (e.g., on the order of one per decade for a given facility or urban area being monitored). the false positive rate depends on the detection technology, the detection threshold (lower thresholds give more false positives), and background biological aerosol levels in the environment that cannot readily be discriminated from the agents one wishes to detect. as a rule, using two or more different detection technologies, with uncorrelated noise and background signals, reduces the false alarm rate considerably. these detection methods can be sequenced in time to reduce cost, with the first detector cueing the second; however, this increases the detection time. rapid agent detection and identification is important because medical treatment is most effective if delivered prior to a victim becoming symptomatic. prophylaxis efficacy drops rapidly after symptoms appear and intensive supportive care is required to ward off death, making medical intervention more burdensome and costly and, hence, less likely to reach as many people. real-time detection is not required, unless physical protectiondonning masks or entering protected buildings -is part of the defensive strategy. detection within hours is a reasonable goal for rapidly incubating diseases such as anthrax, thus leaving - days to conduct an effective medical response. for diseases that incubate more slowly (e.g., smallpox) or for contagious diseases where preventing secondary infections is an important part of preventing a widespread epidemic, slower detection speeds are acceptable. finally, detailed dna analysis and trace element detection is important for forensic evidence; however, this can be collected and analyzed within days or weeks after an attack. the us government has funded the development of a wide range of biological agent detectors. they fall into two categories: environmental sampling and detecting the host response to infection. environmental sampling involves collecting air, water, food, or swab samples and analyzing them for the presence of pathogens using antibody tests, or matching dna sequences to known pathogens. environmental sampling has the virtue that it can, in principle, be rapid (on the order of a fraction of a day, depending on how frequently samples are taken) and it can be used to identify the pathogen, though not necessarily whether the pathogen is virulent. the us biowatch program, which currently monitors the air in approximately american cities for a range of pathogens, is an example of this approach. if a pathogen plume passes one of the biowatch air sampling stations in sufficient concentration, it would be detected within approximately day. the disadvantage of environmental sampling is that a large number of sensors, or air collection stations, must be deployed to ensure that small releases are detected with high probability. if intelligence is available, mobile sensors can be deployed to the area of concern. however, without reliable intelligence, the system costs become prohibitive if one wishes to monitor the air for small releases in hundreds of cities all the time. finally, such a sensor network provides little benefit to public health because it cannot detect contagious diseases of public health concern, for example, severe acute respiratory syndrome (sars) or influenza, because the concentration of these microorganisms in the open environment is well below any detection threshold. methods to detect the human response to infection currently involve clinical diagnosis and syndromic surveillance, the data from which would be sent over a nationwide alerting network. clinical diagnosis relies upon symptomatic patients visiting a physician or hospital emergency room. not all symptomatic victims would seek medical care immediately because the early symptoms of diseases caused by biological agents are frequently similar to those for influenza -fever, nonspecific cough, congestion, etc. physician aids can improve differential diagnosis of the relatively uncommon diseases caused by biological warfare agents, thus reducing the time for detection and identification; however, one must still wait for the first few victims to present which may take on the order of - days. moreover, laboratory cultures commonly used to confirm the infectious agent take an additional - days, although antibody tests such as enzyme linked immunosorbent assays (elisa) can reduce this to a fraction of a day if the test is conducted immediately. therefore, clinical diagnosis currently cannot warn of an attack within hours. syndromic surveillance systems monitor clinical reports, pharmacy sales, school absentee rates, and other data to detect an above-normal rate of symptoms in a geographic area. these systems, for example, biosense in the united states, have detected unusual increases in local infection levels from natural outbreaks. however, they detect events only when the number of symptomatic cases rises above the background level which, by definition, is late for effective medial intervention in the event of a biological attack. hence, while syndromic surveillance systems may have public health benefits, they cannot provide sufficient warning (i.e., within hours) of a biological attack to implement a highly effective medical response. veterinary and wild animal disease surveillance may detect disease among animal and bird populations before they become apparent in the human population, as was the case with the west nile virus natural outbreak between and in the united states. however, monitoring animal disease outbreaks benefits public health more than defense against intentional attacks, where exposure of animal and human populations would be simultaneous, because the incubation period in animals and birds frequently is comparable to that in humans, implying that animal disease detection is unlikely to precede the detection of zoonotic diseases in humans. in any case, rapid veterinary and wild animal disease detection, and its integration with human disease surveillance systems, has not occurred in the united states. future research and development in the area of attack warning should emphasize improving the detection time for the host's response to infection, as opposed to environmental sampling, because the latter will be expensive and have very limited benefits for public health. automated laboratory testing, for example, using elisa techniques or dna chips, can reduce detection and identification times to a few hours (from the time samples enter the laboratory); however, clinical diagnosis still requires the presentation of symptomatic patients. presymptomatic diagnostic techniques that detect the early host immune response to infection, for example, mrna transcription of the genes involved in the host's immune response which begins within approximately hours of exposure, would be more useful, assuming further research demonstrates that gene expression patterns are reliable fingerprints for the presence of a given pathogen or small class of pathogens. such techniques could reduce the warning time to approximately day, assuming it is used routinely in hospitals and medical clinics, by detecting asymptomatic victims who visit for other reasons. presymptomatic diagnostic methods would have tremendous benefits for routine medical diagnosis of common infectious diseases and the resulting economies of scale will reduce their cost. the united states currently can probably detect and correctly identify a bioterrorism event within approximately days of the initial release by clinical diagnosis. note, however, that it took - days to diagnose cases from the anthrax letter attacks, including the time for blood culture confirmation. diagnosis information would then be conveyed to the us center for disease control (cdc) via the public health information network in a matter of hours from most major urban areas, although this network has not been fully implemented. in the future, the us national biosurveillance integration system is being designed to provide warning of disease outbreaks of natural or terrorist origin, integrating food, agriculture, public health (clinical diagnosis and syndromic surveillance), and environmental sampling data. the speed with which this system will be able to detect an outbreak will be constrained by the abovementioned limits associated with the different detection methodologies. again, real-time detection is not required. twenty-four hour warning should be sufficient to mount an effective medical response. since medical prophylaxis should begin within approximately hours of an atmospheric release (in the case of anthrax), a -hour detection capability would leave at least one day to implement medical logistics and to begin providing prophylaxis to a large number of exposed and worried citizens. providing prophylaxis to a large number of people requires the delivery of large quantities of medical supplies to the exposed population. the suggestion that people keep supplies of the necessary medications at home, thus obviating the need for rapid distribution, have been rejected because some people will take the medications inappropriately (e.g., antibiotics when they have the flu), they may take inappropriate doses, a large selection of medications would be needed to protect against all possible biological agents, and self-vaccination would not be possible. consequently, current us plans call for stockpiling the necessary medical supplies (antibiotics, antiviral drugs, vaccines, syringes, intravenous supplies, ventilators, etc.) in central warehouses referred to collectively as the strategic national stockpile, with the intent to rapidly dispense these supplies after an attack has been detected. palletized 'push packs' of medical supplies can be delivered to any local staging area in the united states by aircraft or truck within hours of a decision to deploy them. the greater challenge is to distribute these supplies from the local staging area to the pods where people queue up to receive medications. these pods could be local schools, fire stations, or shopping malls, but not hospitals. hospitals should remain free from congestion to handle acute cases of victims who have passed into the symptomatic disease phase. the united states has little hospital surge capacity due to managed healthcare. however, hospital surge capability is important only for those victims who need intensive care. the principle challenge for effective medical response is to provide prophylaxis prior to the appearance of a large number of symptomatic cases. if hospitals become overwhelmed with acute cases, surge capacity is not the answer but rather more rapid and effective presymptomatic prophylaxis. therefore, pod surge capacity is more important, in particular, augmenting the personnel capable of servicing queues to increase pod throughput. diagnostic techniques to triage noninfected individuals will greatly reduce the number of people requiring prophylaxis because the number of people concerned about exposure will exceed the actual number of people who become infected by a factor of to , if not more. the time it takes to transfer medical supplies from the local staging area to the pods depends on the time required to repackage supplies into smaller quantities and to transport them to individual pods, most likely via small trucks. efforts clearly should be made to minimize the extent to which repackaging is necessary. helicopter backup may be required if roads are congested with people fleeing an exposed area. depending on the size of the urban area, several tens to several hundred pods will be required to minimize the time required to treat the exposed population. local officials must identify suitable pod locations, transportation, and staff for each pod, and exercise these logistics plans so they go smoothly in an emergency. this is beginning to occur in the united states. the prophylaxis campaign requires medically trained personnel to triage individuals according to their medical status and prescribe the appropriate prophylaxis regimen. paperwork is required to track individuals and the mediations they receive, and to provide information about the medications and possible side effects. security personnel will be required to ensure order. if detection occurs within hours, and it takes hours to distribute supplies from the strategic national stockpile to local staging areas, hours to distribute supplies from there to the pods, and hours to set up the pods (this can occur concurrently with stockpile dispersal), then prophylaxis can begin within hours of a release. if urban pods can process people each per hour around the clock, then such a rapid medical response can, in principle, provide prophylaxis to approximately million people within days, thereby saving over % of a population exposed to anthrax according to figure . again, these numbers do not reflect current capability but rather the level of protection that is possible with sufficient effort. effective medical treatment depends on stockpiling the appropriate medications in sufficient quantity. while antibiotics have an efficacy of approximately % for healthy individuals, they may be contraindicated for certain subpopulations (e.g., children, pregnant women, and immunosuppressed individuals) . in the united states, the immunosuppressed population is growing due to cancer treatments, human immunodeficiency virus (hiv), organ transplants, and other medical interventions, which is cause for some concern if a highly effective medical response is desired for all significant subpopulations. vaccination is an effective defense against many infectious diseases. however, vaccines often take - weeks for primary seroconversion, and may require one or more booster shots thereafter to achieve full protection. consequently, they are generally less effective for postattack prophylaxis unless antibiotic or antiviral drugs are available to control the disease until vaccination takes effect. moreover, vaccines do not exist for some biological agents and they do not exist in sufficient quantity for others because they are not routinely stockpiled for diseases that are not current public health concerns. therefore, research and development should focus on new broad spectrum antibiotics, antiviral drugs, and safe, effective vaccines against known biological agents that can be administered to most segments of the population. medical research in these areas will also have important benefits for public health as new treatments are discovered for emerging infectious diseases. concern with antibiotic or antiviral resistant pathogens is best addressed by limiting the overuse of these drugs and by having multiple medications on hand that are effective against a given pathogen strain, again highlighting the importance of medical research and development. finally, genetically engineered pathogens that have enhanced effects, circumvent detection systems, or circumvent medical countermeasures may become more widespread in the future. however, increasing the virulence of pathogens through genetic manipulation is not trivial, notwithstanding the australian mousepox experiment. nor would terrorists need to go to this trouble since natural pathogens are terrifying enough. at the current time, bioterrorism countermeasures should focus on naturally occurring pathogens. however, biotechnology is in its infancy and powerful discoveries lie ahead. hence, any defensive policy must strike a balance between developing countermeasures to current versus possible future pathogens. research on new prophylactic drugs and vaccines should be carried out largely by private biotechnology and pharmaceutical companies because they have the resources and the expertise to create new drugs, with government sponsored financial incentives to encourage them to develop countermeasures that otherwise would be unprofitable. the us bioshield act of and follow-on bioshield ii legislation currently under congressional review illustrate the kinds of incentives that may be effective, for example, tax credits, patent extension, and liability limitations. debates have also surfaced about the wisdom of censorship in biomedical publications. the world has a lot more to gain from improved public health than it stands to lose from bioterrorism by allowing unfettered access to scientific advances in biology and medicine. thus, censorship or classification schemes to keep certain information from malevolent actors should be carefully scrutinized, with open access being the norm unless a clear and present danger exists. this is the best hope for having the medical countermeasures available if and when the need arises while at the same time providing benefits to public health. the us government has established the national advisory board for biosecurity, a group of biologists, physicians, and security experts from outside the government, to help maintain the balance between scientific openness and preventing bioterrorism. in addition to developing guidelines for research and publications in the life sciences, they have helped draft a code of conduct for life science professionals and fostered international cooperation to help define these issues. decontamination is required to prevent bioterrorism from becoming a threat to physical infrastructure by rendering buildings unusable for months or years because public officials cannot certify that they are safe for occupancy. an effective decontamination policy must determine safe public exposure levels, which depend on site use and individual susceptibility to infection. little data exists on environmental background levels for common pathogens. moreover, the scientific debate regarding the effects of low-level exposure to pathogens may be as contentious as the low-level radiation debate. therefore, the seemingly simple question of how clean a site must be to ensure public safety will, in fact, be difficult to answer with existing scientific data. answering this question should be the first priority for decontamination research. pathogen levels will have to be monitored for months to years after an event, which is both expensive and complicated by the fact that some detection techniques (e.g., dna sequence matching) do not distinguish living from dead pathogens. in addition, communicating the risks associated with residual contamination to the public in a credible way is vital to allay public anxiety and the economic consequences that flow from these fears. this will be a nontrivial challenge for federal, state, and local authorities working in conjunction with the media. postattack vaccination of the local population is an important adjunct to any decontamination strategy because vaccinated individuals can live safely with much higher residual contamination. however, not everyone can be vaccinated due to health risks and vaccinating all visitors to a contaminated area will be inconvenient. decontamination strategies differ for outdoor and indoor contamination. outdoor contamination can be partially removed by washing surfaces with water and, in any case, will decrease with time due to environmental degradation of the agent (e.g., ultraviolet light reduces anthrax spore viability by -to -fold each day). locating 'hot spots' will be important but costly because all possible outdoor locations where pathogens might collect in quantity must be sampled initially and monitored thereafter. outdoor chemical decontamination is expensive and, therefore, will be feasible only for areas on the order of a few square kilometers. indoor contamination is a more serious problem because of the absence of ultraviolet light, thus slowing environmental degradation, and because of the amount of time people spend indoors, thus increasing exposure. indoor remediation can be very expensive, as demonstrated by the experience with the hart senate office building and the brentwood postal facility after the us anthrax letter attacks, the latter of which took year at a cost of approximately $ million to clean up. moreover, current decontamination chemicals (e.g., chlorine dioxide, methyl-formaldehyde, para-formaldehyde, methyl-bromide, hydrogen peroxide, and household bleach) are corrosive, carcinogenic, and/or toxic. safer, more effective decontaminants are an important area for research and development, for example, gaseous germination agents that cause anthrax spores to germinate whereupon the vegetative bacillus becomes much more vulnerable to environmental degradation. combining advanced decontamination agents with high-efficiency particulate air (hepa) vacuuming could reduce the indoor decontamination problem to a manageable level, especially when combined with vaccination of the local population. ultimately, a mixed decontamination strategy that takes advantage of environmental degradation, washing, chemical decontamination, and vacuuming where appropriate should be able to render public areas usable, but the cost may be quite high depending on the extent to which future decontamination technologies can avoid a repeat of the us anthrax decontamination experience. the logic behind the belief that bioterrorism is a serious emerging threat is sound, although reasonable people can disagree about its urgency. moreover, this threat is multifaceted and complex, owing to the range of pathogens, delivery modes, and targets for attack. substantial uncertainties exist in predicting the outcome of any hypothetical biological attack, which implies that attack outcomes can look bleak or relatively benign depending on one's assumptions. the tendency to focus on worst case scenarios, which leads one to the conclusion that biological weapons are the poor man's nuclear weapon, originate, in part, from exaggerations by those trying to move governments to action, which may have the unintended consequence of convincing some that defense against bioterrorism is too hard and others that pathogens are an ideal weapon of terror. hence, states must develop a coherent strategy for combating bioterrorism at reasonable cost. such a strategy involves diplomacy, deterrence, preemption, and defense, with the emphasis on defense. arms control and export controls may constrain largescale biological weapon programs. more importantly, they reinforce the norm against the acquisition or use of pathogens in war or as weapons of terror. this helps reinforce deterrence, which may be effective against states but is less likely to be effective against terrorist groups. attribution will be crucial to deter states from aiding terrorist groups. however, neither diplomacy nor deterrence is sufficient alone, or in combination, to reduce the biological weapon threat to a satisfactory level. in terms of limiting damage from such threats, preemption, attractive as the concept might be, will be impractical because it relies on accurate, timely intelligence. interdiction of covert biological attacks also will be very difficult because one must detect the malevolent actors since one cannot detect the biological weapons themselves. consequently, the emphasis should be placed on passive defense, which involves detecting the release of pathogens in a timely manner, rapid postattack medical intervention, and effective decontamination to restore contaminated areas to a usable state. in principle, postattack medical response can protect over % of an exposed population if pathogens can be detected within day of their release, medical logistics can deliver appropriate medical supplies to the exposed population within day, and a prophylaxis campaign can be mounted to treat the exposed population, potentially numbering into the millions, within days. while no state currently can claim to have such an effective defense in place, except possibly against small outbreaks, such a defense is possible. moreover, to the extent biodefense overlaps with efforts to improve public health, the expenditures may be justified because resources are not wasted even if a biological attack never occurs. chemical and biological warfare; health services, effects of war and political violence on; health consequences of war and political violence biohazard. new york: random house biotechnology and the challenge to arms control biological weapons threat reduction committee on research standards and practices to prevent the destructive application of biotechnology biowarrior: inside the soviet/russian biological war machine biosecurity: a comprehensive action plan biological weapons: from invention of statesponsored programs to contemporary bioterrorism responding to terrorism across the technological spectrum expression of mouse interleukin- by a recombinant ectromelia virus suppresses cytolytic lymphocyte responses and overcomes genetic resistance to mousepox will terrorists go nuclear, p- unconquerable nation: knowing our enemy, strengthening ourselves, mg- -rc investigation of bioterrorism-related anthrax confronting zoonoses, linking human and veterinary medicine the cult at the end of the world effectiveness of nuclear weapons against buried biological agents animals as sentinels of bioterrorism federal agencies face challenges in implementing initiatives to improve public health infrastructure adherence to and compliance with arms control, nonproliferation, and disarmament agreements and commitments us regional deterrence strategies, mr- -a/af hepa/vaccine plan for indoor anthrax remediation bwc protocol talks in geneva collapse following us rejection sheltering effects of buildings from biological weapons -national science advisory board for biosecurity key: cord- - ek s oe authors: wang, yun; liu, ying; struthers, james; lian, min title: spatiotemporal characteristics of covid- epidemic in the united states date: - - journal: clin infect dis doi: . /cid/ciaa sha: doc_id: cord_uid: ek s oe background: a range of near-real-time online/mobile mapping dashboards and applications have been used to track the covid- pandemic worldwide. it remains unknown about small area-based spatiotemporal patterns of covid- in the united states. methods: we obtained county-based counts of covid- cases confirmed in the united states from january to may , (n= , , ). we characterized the dynamics of covid- epidemic through detecting weekly hotspots of newly confirmed cases using spatial and space-time scan statistics and quantifying the trends of incidence of covid- by county characteristics using the joinpoint analysis. results: along with the national plateau reached in early april, covid- incidence significantly decreased in the northeast (estimated weekly percentage changes [ewpc]: - . %), but remained increasing in the midwest, south and west regions (ewpcs: . %, . %, and . %, respectively). higher risks of clustering and incidence of covid- were consistently observed in metropolitan vs rural counties, counties closest to core airports, most populous counties, and counties with highest proportion of racial/ethnic minority counties. however, geographic differences in the incidence have shrunk since early april, driven by a significant decrease in the incidence in these counties (ewpc range: - . % – - . %) and a consistent increase in other areas (ewpc range: . % – . %). conclusions: to substantially decrease the nationwide incidence of covid- , strict social distancing measures should be continuously implemented, especially in geographic areas with increasing risks, including rural areas. spatiotemporal characteristics and trends of covid- should be considered in decision-making on the timeline of re-opening for states and localities. since the first cluster of the coronavirus disease (covid- ) was reported, , the severe acute respiratory syndrome coronavirus (sars-cov- ) has triggered massive outbreaks and then evolved to a worldwide pandemic of covid- . as of may , , , , confirmed cases and , covid- related deaths have been reported worldwide. in the united states, the first covid- case was reported on january , , and national outbreak of covid- beginning in early march of had caused , , confirmed cases and , deaths from covid- as of may . it is urgent to "flatten the epidemic curve" for covid- in the united states. remarkable efforts have been made to map the coronavirus spread using near-real-time interactive online/mobile gis dashboards, websites, and applications in and out the united states. , [ ] [ ] [ ] these maps provide timely information on descriptive statistics of the outbreak situation. however, no studies have comprehensively assessed small area-based characteristics of covid- spreading in the united states. using government record-based surveillance data, we examined the spatiotemporal variations in covid- as well as its associated geographic characteristics across the country. the results would enhance our understanding of small area-based spatiotemporal dynamics of covid- outbreak, thus help inform multilevel strategies to control the spread of coronavirus and appropriate allocations of public health and healthcare resources in the united states. a c c e p t e d m a n u s c r i p t we obtained the counts of covid- cases diagnosed from january to may , in the united states from the usafacts, a not-for-profit initiative standardizing and providing the government record-based data publicly available. the daily-updated numbers were cumulated to form a time-series database of confirmed covid- cases across all the us counties. the study is exempted from the ethics review due to the use of publicly accessible data source. to identify the characteristics of counties with a high burden of covid- , we examined county-level geographic and sociodemographic factors, including rural-urban context, distance to the nearest core airport, population density, percentage of non-white minority population, percentage of population years or older, and percentage of population below the federal poverty line. using the rural-urban continuum codes of u.s. department of agriculture, rural-urban context was defined as metropolitan (codes - ), urban (codes - ), and rural areas (codes [ ] [ ] . there are core airports with the highest volume of traffic across the country. the euclidean distance from the populationweighted centroid of a given county to its nearest core airport was calculated to measure spatial relationship of that county with core airports. population density was computed as the number of population per square miles of lands. county-level information on land areas, population sizes, and other three socioeconomic variables were retrieved from combined - american community surveys to reduce potential marginal error of survey. a c c e p t e d m a n u s c r i p t statistical analysis: we first created an epidemic curve to visualize the progression of newly confirmed covid- cases by four us government-defined regions (northeast, midwest, south, and west) over distinct time periods from january through may , , including the first six epi-weeks in combination (january nd -march th ) and individual epi-weeks from march th to may th . using a spatial and space-time scan statistics (satscan), , we examined spatiotemporal clustering of confirmed covid- cases through detecting the higher-than-expected geographic hotspots across the country. the satscan applies a pre-defined circular window with varied sizes and time periods to scan the study area and identify the most likely clusters of the event of interest using a space-time permutation statistical model, and uses a monte carlo simulation approach to generate random datasets in computing the statistic for the statistical inference of a cluster. in this study, we defined the parameters of the scanning window as miles of maximum geographic radius and the day as the minimum temporal scanning unit. geographic clustering was detected in each of time periods to characterize the dynamics of geographic clustering of newly confirmed covid- cases. the most likely high-risk clusters/hotspots were captured based on the monte carlo rank with p< . . we further examined the associations of county characteristics with covid- clustering using logistic regressions. the outcome was whether a given county was identified as part of a hotspot or not. the analysis was performed separately for each of the th - th epi-weeks. considering the colinearity between county characteristics, county-level variables were not mutually adjusted for. statistical significance was tested as two-sided with p< . . as of may , , a total of , , covid- cases were confirmed in the united states over epi-weeks. figure a shows the overall temporal trend of weekly counts of newly confirmed covid- cases by four us regions. covid- had occurred sporadically until early march (first six epi-weeks); confirmed cases were reported mainly in the west region. the number of weekly confirmed covid- cases subexponentially increased across the country from the th to th epi-week, followed by a slowly decrease over recent five weeks. during the entire observation period, the largest proportion of cases was from the northeast ( . %), followed by the in the first six epi-weeks, covid- cases were reported in counties from the west coast and northeast states with the highest county-level incidence of . / , persons. starting in the th through the th epi-weeks, sars-cov- spread to broad geographic areas. as of may , . % of us counties had the confirmed covid- cases, and the median county-level cumulative incidence rate was . / , persons (interquartile range: . - . / , persons) with the highest reaching , / , persons (supplemental figure ) . the incidence of covid- reached the peak in the northeast in the th epi-week ( . / , persons), followed by a significant reduction of . % weekly until the th epi-week. however, the incidence consistently increased in the midwest, south and west regions from the th to th epi-weeks with a significant ewpc of . %, . % and . %, respectively. overall, covid- incidence reached the national plateau in the epi-week ( . / , persons), followed by a slight and insignificant decrease in recent five weeks ( figure b and table ). figure illustrates the trends in the incidence of covid- by county characteristics. over epi-weeks, the incidence was significantly higher in metropolitan vs urban/rural areas, areas closest vs farthest to core airports, most vs least populous areas, and areas with highest vs lowest percentage of minorities, and lowest vs highest percentage of population aged years and older ( figure a-e) . the incidence dramatically increased from the th epi-week and reached the peak in the th epi-week in metropolitan areas ( . / , persons), counties closest to core airports ( . / , persons), most populous counties ( . / , persons), and counties with highest percentage of minorities ( . / , persons), followed by a significant decrease thereafter (ewpc= . %, . %, . %, a c c e p t e d m a n u s c r i p t and . %, respectively) ( table ) . notably, the incidence consistently increased from epi-week - in rural ( . to . / , persons) and urban areas ( . to . / , persons) ( figure a ). unlike metropolitan areas, the incidence remained increasing in rural and urban areas after the th epi-week with a significant ewpc of . % and . %, respectively (table ) . similarly, a consistent increase in the incidence of covid- from epi-week - was also observed in counties farther from core airports and in less populous and lower minority counties ( figure b -d and table ). the incidence in counties with lowest or highest percentage of elderly people increased from epi-week - and remained steady thereafter. overall, geographic disparities in the incidence of covid- by county characteristics had decreased since the th epi-week. there was no significant difference in the incidence of covid- for highest vs lowest percentage of population below the federal poverty line ( figure f ). using a national time-series database of confirmed covid- cases, we examined the spatiotemporal patterns of covid- in the united states during the starting epi-weeks. covid- cases sporadically occurred in the west coast and northeast states in the first six epi-weeks and increased rapidly across the country thereafter until the th epi-week, and then slightly decreased since the th epi-week. despite a remarkable reduction in newly confirmed cases from the northeast in recent four weeks, the risk of covid- infection remained consistently increasing in the midwest, south and west regions. geographic clustering of covid- was first identified in southern and northern california, and then rapidly expanded nationwide. higher risks of covid- clustering and incidence were observed in metropolitan vs rural counties, counties closest to core airports, most populous counties, and counties with highest proportion of racial/ethnic minority. however, the differences have shrunk since the th epi-week, which was driven by a significant decrease in the incidence in these counties and a consistent increase in other areas in recent five weeks. it might be a result of social distancing measures well implemented recently in high-risk areas in early stage of the a c c e p t e d m a n u s c r i p t outbreak, and also suggests that recent region-to-region spreading and community transmission occurred in other areas. further studies are needed to assess the effectiveness of public health and behavioral interventions on covid- infection and implemental barriers, which is essential for promoting the strict adherence to social distancing guidelines and enhancing personal protections (including appropriately wearing face masks as needed and timely washing hands) to prevent the sars-cov- spreading and thus substantially decrease the incidence of covid- locally and nationwide. a significant association between short distance to core airports and covid- clustering suggests a critical role of air transportation in sars-cov- spreading across the country. air transportation was believed to accelerate and amplify the spread of influenza, sars-cov or mers-cov. a recent study showed that the rail transport is related to the transmission and regional outbreak of covid- in china. in the united states, the airports may contribute substantially to the early travel-related region-to-region transmission. from march to april , at least states, counties, cities, the district of columbia and puerto rico joined illinois, new york, and california in the lockdown orders. however, airlines, as one of essential transportation services, are generally exempted from the orders and still operating. we flagged the importance of airports in spreading covid- even after the lockdown of most regions in mid-march. airlines have put in place stringent safeguards for those still flying, including supercharged cleaning, reduced in-flight services, and the spacing out of passengers on flights. it is crucial to maintain strict management and monitoring of major airports to maximize the reduction of region-to-region transmission. while covid- incidence in metropolitan areas has decreased since the th epi-week, we identified a consistent increase in the incidence of covid- in rural areas over the epi-weeks. this was probably a sign of that the local spread of covid- extended beyond metro/urban enclaves and the secondary community transmissions took place around geographic hotspots and spread to rural areas. rural areas with a lower population density are not safe for this pandemic because rural residents tend to be older and have limited access to health care. , therefore, the a c c e p t e d m a n u s c r i p t restrictive social-distancing measures are necessary in rural areas, and adherence to social distancing should be enhanced for rural residents. the pandemic of covid- poses different challenges for the us states currently designing its coping strategies. the population density is a key driver for transmission of infectious disease. we observed that predominately minority counties were at higher risk of covid- . this was consistent with the reports of african americans accounting for about % of covid- related deaths but just about % of the population in chicago, milwaukee county and louisiana. the disproportionate burden of covid- in minority populations may largely result from inequities in adherence to social distancing measures. our analysis indicates that the incidence of covid- was lower in areas with higher percentage of elderly people. it could partly result from the lower mobility of older vs younger people. however, we found a comparable risk of covid- clustering in counties with highest vs lowest percentage of elderly people in recent weeks. it might be relevant to the outbreaks of covid- in nursing homes in some geographic areas. , therefore, senior-heavy areas should not be ignored in the allocation of prevention efforts on covid- because senior people typically have multiple chronic health conditions and higher risk of developing more serious complications from covid- . lack of a stable pattern in the association between poverty and the risk of covid- indicates that socioeconomic factors might not play a critical role in the risk of coronavirus infection. the study has some limitations. the confirmed cases of covid- might not reflect the actual number of persons infected with sars-cov- due to unknown/untested asymptomatic cases. 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applications to cancer rates the roles of transportation and transportation hubs in the propagation of influenza and coronaviruses: a systematic review the association between domestic train transportation and novel coronavirus ( -ncov) outbreak in china from to : a datadriven correlational report. travel medicine and infectious disease the new york times. see which states and cities have told residents to stay at home access and issues of equity in remote/rural areas. the journal of rural health : official journal of the american rural health association and the national rural health care association rural-urban differences in usual source of care and ambulatory service use: analyses of national data using urban influence codes covid- and african americans nursing home care in crisis in the wake of covid- long-term care policy after covid- -solving the nursing home crisis. the new england journal of medicine clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study transmission of -ncov infection from an asymptomatic contact in germany. the new england journal of medicine asymptomatic cases in a family cluster with sars-cov- infection. the lancet infectious diseases centers for disease control and prevention. social distancing, quarantine, and isolation: keep your distance to slow the spread how will countrybased mitigation measures influence the course of the covid- epidemic? hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease -covid-net, states can china's covid- strategy work elsewhere? governmental public health powers during the covid- pandemic: stay-at-home orders, business closures, and travel restrictions. jama. . . pan a public health interventions for covid- : emerging evidence and implications for an evolving public health crisis reopening society and the need for real-time assessment of covid- at the community level population density (quartile) we thank the gis and spatial statistics supporting from the health behavior, and communication & outreach core, which is affiliated with washington university institute of clinical translational sciences funded by the national center for advancing translational sciences, national institutes of health (ul tr ) and washington university alvin j. siteman cancer center funded by the national cancer institute, national institutes of health (p ca ). a c c e p t e d m a n u s c r i p t a c c e p t e d m a n u s c r i p t a c c e p t e d m a n u s c r i p t key: cord- -mejd blb authors: lewnard, joseph a; reingold, arthur l title: emerging challenges and opportunities in infectious disease epidemiology date: - - journal: am j epidemiol doi: . /aje/kwy sha: doc_id: cord_uid: mejd blb much of the intellectual tradition of modern epidemiology stems from efforts to understand and combat chronic diseases persisting through the th century epidemiologic transition of countries such as the united states and united kingdom. after decades of relative obscurity, infectious disease epidemiology has undergone an intellectual rebirth in recent years amid increasing recognition of the threat posed by both new and familiar pathogens. here, we review the emerging coalescence of infectious disease epidemiology around a core set of study designs and statistical methods bearing little resemblance to the chronic disease epidemiology toolkit. we offer our outlook on challenges and opportunities facing the field, including the integration of novel molecular and digital information sources into disease surveillance, the assimilation of such data into models of pathogen spread, and the increasing contribution of models to public health practice. we next consider emerging paradigms in causal inference for infectious diseases, ranging from approaches to evaluating vaccines and antimicrobial therapies to the task of ascribing clinical syndromes to etiologic microorganisms, an age-old problem transformed by our increasing ability to characterize human-associated microbiota. these areas represent an increasingly important component of epidemiology training programs for future generations of researchers and practitioners. initially submitted september , ; accepted for publication november , . much of the intellectual tradition of modern epidemiology stems from efforts to understand and combat chronic diseases persisting through the th century epidemiologic transition of countries such as the united states and united kingdom. after decades of relative obscurity, infectious disease epidemiology has undergone an intellectual rebirth in recent years amid increasing recognition of the threat posed by both new and familiar pathogens. here, we review the emerging coalescence of infectious disease epidemiology around a core set of study designs and statistical methods bearing little resemblance to the chronic disease epidemiology toolkit. we offer our outlook on challenges and opportunities facing the field, including the integration of novel molecular and digital information sources into disease surveillance, the assimilation of such data into models of pathogen spread, and the increasing contribution of models to public health practice. we next consider emerging paradigms in causal inference for infectious diseases, ranging from approaches to evaluating vaccines and antimicrobial therapies to the task of ascribing clinical syndromes to etiologic microorganisms, an age-old problem transformed by our increasing ability to characterize human-associated microbiota. these areas represent an increasingly important component of epidemiology training programs for future generations of researchers and practitioners. infectious diseases; methods; modeling; surveillance abbreviation: ebov, ebola virus. the priority afforded to infectious diseases within epidemiologic research has been fluid over the past years or longer. despite the lasting prominence of early investigations into measles, cholera, plague, typhoid fever, malaria, and yellow fever ( ) ( ) ( ) ( ) ( ) ( ) , the intellectual tradition of modern epidemiology stems largely from studies of chronic diseases dating to the post-world war ii era, when such conditions came to surpass infectious diseases in morbidity and mortality in highincome countries amid improvements in living conditions and the introduction of numerous antibiotics and vaccines. this epidemiologic transition co-occurred with a shift in focus for epidemiologic research (and training programs) toward the multifactorial etiology of chronic conditions ( ) . in parallel, early th-century work on the "dependent happenings" of communicable diseases ( ) ( ) ( ) ( ) yielded to the development of today's core biostatistical methods for chronic diseases, premised on the independence of outcomes among subjects ( ) ( ) ( ) . since the late th century, the emergence of human immunodeficiency virus and acquired immunodeficiency syndrome and other infections has renewed interest in infectious diseases and their health, economic, and security implications ( ) . outbreaks of severe acute respiratory syndrome, pandemic influenza a h n , ebola virus (ebov), and zika virus have prompted international responses, whereas influenza a h n and h n , lassa fever virus, nipah virus, and middle east respiratory syndrome coronavirus, among other agents, have been a source of regional concern. the incidence and endemic range of "neglected" infections, including dengue and cholera ( , ) , have expanded, and antimicrobial resistance has threatened to derail the control of tuberculosis, typhoid, malaria, gonorrhea, yaws, and invasive bacterial infections ( ) ( ) ( ) ( ) ( ) ( ) . although highly effective vaccines are available, measles and yellow fever have resurged on multiple continents, due to gaps in vaccine coverage ( , ) , while short-lived vaccine-induced protection has facilitated unexpected resurgences in diseases once on the path to elimination, such as pertussis and mumps ( , ) . after decades of relative obscurity in the mid- th century, infectious disease epidemiology has experienced an intellectual rebirth in response to disease emergence. repopulation of this field by scientists trained not only in clinical medicine but ecology, demography, and quantitative sciences has led to the adoption of methods scarcely addressed in traditional public health training programs. cluster-randomized trial designs, for example, have become commonplace for evaluating infectious disease interventions, quantifying indirect effects resulting from contagion ( ) . classical models of ecological dynamics have been adapted to address the transmission and control of infectious agents, while our expanding ability to integrate such models with epidemiologic data through bayesian statistics has enhanced their relevance to policymaking ( ) ( ) ( ) . most recently, sequencing and phylogenetic analysis have afforded an unprecedented view into the population structure and dynamics of pathogens ( , ) . here, we review developments in infectious disease epidemiology together with their implications for research and practice, and for the training of future epidemiologists. we first consider the role of epidemiologic surveillance in the context of pathogen emergence and the integration of surveillance data into quantitative studies of transmission. next, we discuss challenges in causal inference, including the evaluation of public health interventions against emerging pathogens and the difficulties of attributing clinical syndromes to microbial agents. surveillance justifiably has been seen as a core public health function, with its important role articulated by langmuir in ( ) . in the united states and elsewhere, surveillance for diverse infectious (and noninfectious) diseases has typically relied on an essentially passive system of reporting by healthcare providers or laboratories, often mandated by public health laws. although such passive systems of disease reporting have proven invaluable, their limitations, such as incomplete, often inconsistent detection of cases and delayed detection of outbreaks, are well documented ( ) . as a result, active surveillance systems that do not depend on providers and laboratories to report have been developed and promoted. the centers for disease control and prevention-funded emerging infections program and its components (e.g., foodnet, abcs), initiated in , is notable example of such a system, as are international versions promoted through the centers for disease control and prevention's global health security initiative ( ) . such systems, while expensive to develop and maintain, are of great value, especially when they collect biological specimens (e.g., isolates of bacterial and viral pathogens) for typing and support analytic epidemiologic studies (e.g., casecontrol studies of vaccine effectiveness ( ) ). nevertheless, these systems, too, may have limitations, particularly in their ability to detect in a timely fashion outbreaks caused by novel microbial agents, prompting interest in alternative methods. in this article, we consider proposed alternatives, highlighting their benefits and challenges. beyond efforts to quantify the incidence of infectious diseases of known etiology, disease surveillance has been advocated as a means of mitigating the threat posed by novel pathogens. large-scale efforts to identify pathogens with the potential to spill over from animals to humans have received notable investment, for instance from the us agency for international development emerging pandemic threats program ( ) . more recently, metagenomic sequencing has enabled the number of known viruses to be multiplied in such studies ( ) . the aim of those working on the global virome project, launched in , to characterize within years all . million viruses thought to exist ( ) . however, the pathway for translating data sets produced by such activities into actionable threat-reduction programs remains unclear. that only approximately viruses are known to infect humans (and an even smaller handful to cause major epidemics) may constrain the value of large-scale virus discovery for identifying high-risk pathogens, as well as viral determinants of pathogenic potential ( ) . spillover events causing recent epidemics-including h n in mexico, middle east respiratory syndrome in saudi arabia, and ebov in west africa-have been poorly predicted by factors long believed to drive disease emergence ( ) . accordingly, interest in expanding our catalogue of potential pathogens should be weighed against our persisting need to enhance the detection and control of outbreaks of known pathogens ( ) . for instance, ebov epidemics in the democratic republic of the congo in took weeks to be identified, with dozens of suspected cases having already accumulated ( , ) . serological studies have received increasing enthusiasm for monitoring emerging pathogens of significance to humans ( , ) . the prevalence of antibodies indicating previous exposure may provide valuable information about the frequency of animal-human spillover events and the potential for person-toperson spread, overcoming reporting biases that favor detection of large outbreaks under traditional surveillance. moreover, the low cost of multiplex assays makes integrated surveillance of multiple pathogens plausible. although serosurveys have bolstered recent efforts to understand the geographic range and clinical spectrum of ebov and zika virus infections ( , ) , the enhancement of dengue hemorrhagic fever risk by prior exposure ( ) , and the role of immunologic history in influenza susceptibility and vaccine response ( ) , there remain few examples of public health programs undertaking serological studies for routine surveillance, at least in civilian populations ( ) . outside of laboratory-based surveillance, the increasing availability of passively collected "big data" on the health and behaviors of individuals has prompted enthusiasm about enhancing disease surveillance through alternative data streams. initiatives such as the promed-mail network and healthmap ( , ) compile and disseminate news about outbreaks from media and other sources, aiming to trigger investigation by public health organizations. data such as emergency department visits, medication sales, online search queries, and social media postings have also been suggested as real-time indicators of outbreak activity, although their integration into public health responses remains a subject of debate ( ) ( ) ( ) . the need to overcome reporting biases is a central challenge, because observations may be too nonspecific to distinguish between meaningful and spurious signals in settings with high technological capacity while also being insensitive to even high-risk events in resource-poor settings ( , ) . although nontraditional data sources have, in some applications, supported inferences about epidemic dynamics ( ) , limited information about cases from such sources remains a barrier. for instance, models fitted from news reports of recent measles and mumps outbreaks have yielded considerable underestimates of vaccine coverage ( ) ( ) ( ) , underscoring the importance of field investigations. forecasting the incidence of diseases has been a more successful application of these emerging data streams and dataanalytic approaches. although the acknowledged failure of google flu trends-a prediction approach based on internet search behavior-yielded important lessons about nonmechanistic forecasts, approaches based on machine learning and crowdsourced human judgment have provided the most accurate within-season predictions of us influenza activity in recent comparisons ( ) ( ) ( ) . given expanding interest in forecasting among researchers, funding agencies, and other stakeholders, there is a clear and compelling need to evaluate whether such forecasts can enhance the success and efficiency of public health response efforts. mathematical modeling as a means to understanding infectious disease spread dates to studies by sir ronald ross ( ) . although the use of models to connect data such as age of infection to transmission dynamics of endemic infections has longstanding precedent ( , ) , assimilation of outbreak data for near-term assessments of control priorities is a comparatively recent phenomenon. integration of modeling with the public health response to epidemics of bovine spongiform encephalopathy and foot-and-mouth disease in the united kingdom and the severe acute respiratory syndrome epidemic ( - ) has led to expectations for near real-time modeling studies during major outbreaks. in recent experience, models of the spread of pandemic influenza a h n ( ), cholera ( ), middle east respiratory syndrome ( ), ebov ( , ) , chikungunya virus ( ), zika virus ( , ) , yellow fever ( ) , and plague ( ) have all been published within weeks of the respective outbreak notifications. although the circumstances of particular epidemics dictate what data may be available and pertinent, methods for fitting models to data have generally focused on exponential growth rates in cases ( ) or the distribution of the serial interval ( ) . methods based on the latter class of data offer the advantage of illustrating real-time changes in reproductive numbers ( ) ; however, the requisite information from patient line lists is seldom available. reliance instead on ecological data exposes models to numerous vulnerabilities, notably the inability to discern individual risk factors (and thus the population meaningfully at risk). these shortcomings may prevent models from predicting reductions in transmission before depletion of the susceptible population. a challenge thus lies ahead in determining the role of models in outbreak response and the best practices for communicating modeling results. although the ability of models to evaluate prophylactic strategies may be considered a benefit, recommendations to act against remote future risks have sometimes triggered resistance among stakeholders ( ) . during the west african ebov epidemic, for example, attention to worst-case model-based projections prompted some to question the reliability of the models ( ), reflecting an important discrepancy between public understanding of modeling as a forecasting tool and the intended uses of models for scenario-based comparisons ( , ) . this use of modeling has been better understood in attempts to communicate the impact of interventions after the fact ( ). the ease of sequencing pathogen genomes has afforded a new view into transmission during outbreaks. use of sequence data to identify transmission clusters in the presence of unsure epidemiologic links dates to the early years of the human immunodeficiency virus and acquired immunodeficiency syndrome epidemic ( ) . in recent years, sequencing has aided efforts to track the sources of unexplained epidemics of cholera in haiti ( ) and ebov in west africa ( ) , and has shown increasing utility for reconstructing the geographic spread of pathogens ( , ) . a particular advantage of phylogenetic analysis is the possibility of estimating unobserved epidemiologic quantities, such as the reporting fraction ( ) and reproductive numbers for subcritical transmission ( ) , which remain difficult to assess from traditional case-notification data. beyond reconstructing the demographic history of pathogen lineages, recent years have seen progress toward joint analysis of epidemiologic and sequencing data ( ) . such "phylodynamic" approaches have shown particular relevance for emerging infections, including distinguishing the role of repeated introductions and subsequent local transmission ( ) ( ) ( ) ( ) . whereas most applications have been tailored to specific data sets and assumptions, the development of generalized methods for joint inference of epidemiologic and phylogenetic parameters remains a priority ( ) to support real-time analysis. the ability to rapidly develop and deploy countermeasures to mitigate the threat posed by emerging infections has received increasing recognition as a component of public health preparedness. however, outbreaks are difficult environments in which to evaluate interventions. during the west african ebov epidemic, the feasibility of a new paradigm for development and evaluation of interventions in emergencies was demonstrated by accelerated vaccine safety, immunogenicity, and efficacy studies ( ) . the coalition for epidemic preparedness innovations was established in , with an initial focus on vaccines against nipah virus, middle east respiratory syndrome coronavirus, and lassa fever virus, in addition to adaptable vaccine platforms for novel threats ( ) . lessons learned in ebov vaccine trials will have an influential bearing on evaluations during future emergencies. despite efforts to accelerate evaluation of candidate vaccines, incidence had reached low levels by the time phase iii efficacy trials were ready to begin, posing a threat to their statistical power: a planned trial in liberia was canceled due to declining transmission ( ) , and no cases of disease occurred in a second trial in sierra leone ( ), preventing efficacy assessments. in a stepped-wedge trial in guinea, clusters of primary and secondary contacts of ebov disease cases were randomly assigned to immediate or delayed vaccination; no cases were reported among vaccine recipients during the trial ( ) or in subsequent field deployments of the vaccine, supporting a conclusion of near % vaccine efficacy. debates surrounding design of these trials highlight methodological questions requiring additional attention. in the guinean trial, a "ring" vaccination scheme helped maximize power by enrolling contacts of known cases ( ) . however, the choice of individual-or cluster-level randomization within rings was debated. because members of a vaccinated cluster are exposed to direct protection through vaccination and indirect protection due to reduced transmission within their clusters ( ), cluster-randomized trials have weaker statistical power than individually randomized trials of the same size ( ) . moreover, the direct effect measured in individually randomized studies may be a preferred, transportable efficacy measure ( ) . uses of simulation helped in planning vaccine trials tailored to the real-world circumstances of the ebov outbreak ( ) and enabled trialists to compare alternative designs in terms of ethical mandates ( ) . simulation-guided design further presents the opportunity for applying adaptive trial methods ( ) in the context of infectious disease outbreaks, where dynamic trends in incidence may highlight the benefits of such approaches. in addition to efficacy trials for new interventions, observational studies are needed to assess licensed interventions against evolving and re-emerging pathogens. most commonly applied in evaluations of influenza vaccines, test-negative designs have become popular in routine ( ) and exploratory ( ) studies of vaccine effectiveness. by measuring vaccine effectiveness from the exposure odds ratio of vaccination among individuals seeking care who test positive or negative for a pathogen of interest, this design seeks to overcome associations of health-care seeking with vaccination status ( ) . however, it is uncertain whether health-care seeking and other sources of confounding are appropriately controlled for, and whether measures accurately capture vaccine direct effects ( , ) . uncertainty about the validity of estimates that routinely inform vaccine policy-making demonstrates the need for formal evaluations of such studies and strategies to reduce bias. time series analyses of public health surveillance data provide another approach to measuring the real-world impact of vaccination on disease incidence, with the advantage of identifying the overall effect of a vaccination program resulting from direct and indirect protection ( ) . although the ecological nature of such designs permits the introduction of biases from changes in diagnostic practices or health-care seeking, such studies nonetheless have offered important insights where other approaches failed. limited reductions in influenza-related deaths among elderly persons amid increases in influenza vaccine coverage during the s provided an important indication that the "healthy vaccinee" effect accounted for astonishing and implausible protection against all-cause mortality among elderly influenza vaccine recipients in cohort and case-control studies ( ) ( ) ( ) . newer methods continue to improve public health inferences obtained from time-series data. in a recent evaluation of invasive pneumococcal disease incidence, trends expected under continued use of -valent pneumococcal conjugate vaccine provided a counterfactual condition for measuring the impact of the switch to a -valent vaccine targeting emerging serotypes ( ) . bayesian averaging of models encoding differing pre-and postvaccination trends and change points provides a generalized strategy for defining such counterfactual comparisons ( ) . other signals of transmission intensity in surveillance data, such as age of infection and sub-or multiannual periodicity, may provide additional insights while reducing sensitivity to fluctuations in reporting effort ( , ) . the re-emergence of pathogens against which vaccines are widely deployed, such as varicella, pertussis, and mumps in the united states, poses additional challenges for conducting vaccine effectiveness studies. situational factors may undermine researchers' ability to establish the extent to which cases owe to primary or secondary vaccine failure in all or certain vaccine recipients, and whether emerging pathogen lineages are escaping vaccine-driven immune pressure. for instance, high compliance with vaccine schedules may limit variation in individuals' vaccination status and exposures, necessitating large samples to detect factors influencing vaccine performance ( ) . because re-emergence most likely reflects the expansion of or several pathogen clades, limited pathogen diversity may hinder the application of conventional approaches to identifying microbial determinants of vaccine escape ( , ) . novel methods to distinguish null from vaccine-driven mutations in antigencoding regions ( , ) may streamline efforts to identify vaccine escape, while mathematical modeling provides a basis for comparing candidate hypotheses with observations ( , ) . because vaccine studies are typically powered for primary clinical endpoints, long-term observational studies are needed to monitor for rare vaccine-attributable adverse events. such studies have been crucial to identifying safety concerns such as intussusception after rotavirus vaccination ( ) and to refuting spurious links, such as autism onset after measles-mumpsrubella vaccination ( ) . however, unique challenges arise in vaccine safety studies; at the individual level, vaccination and adverse-event detection may be confounded due to health-careseeking behavior, whereas at the population level, age-related confounding may occur when vaccine recommendations are based on the individual's age. ecological designs taking advantage of natural experiments have proven useful in numerous studies of vaccine safety ( , ) but inconclusive for certain classes of rare events, including those that also result from the vaccine-targeted infection ( , ) . recent years have seen growing interest in case-only methods offering the ability to reduce or rule out individual-level sources of confounding. case-crossover methods are common among such approaches ( , ) and resemble matched case-control studies by sampling "control" periods from the person-time contributed by case individuals before an adverse event. self-controlled case-series methods similarly benefit from the use of cases as their own controls, following a cohort logic in estimating the relative incidence of adverse events after vaccination within specified risk periods ( ) ; with adequate sample size, researchers may be able to use such analyses to eliminate or greatly reduce potential time-or age-related confounding. in response to the growing threat posed by antimicrobial resistance, the world health organization and national governments have prioritized bringing novel antimicrobial drugs to market ( ) . these plans will necessitate phase iii trials in which the efficacy of new therapeutic agents is addressed and possibly phase iv studies, in which the optimal use of new and existing drugs, either singly or in combination, can be determined. whereas patients traditionally have been enrolled in antimicrobial treatment studies on the basis of target bacterial species infections or clinical syndromes, it is uncertain within what strata such trials may yield transportable inferences. rather than merely the infecting pathogen's baseline resistance or susceptibility phenotype, strata may be defined by factors such as pathogen lineage, mutational barriers to resistance development ( ) , and presence of horizontally transferable resistance elements in cocolonizing agents or environmental sources ( ) . stratification based on interpatient and even intrapatient tumor heterogeneity is an emerging feature of cancer therapy trials and may provide a template for such designs ( ) . in addition to clinical endpoints, carriage of susceptible and resistant bacteria, including commensal agents not purposefully targeted by treatment, can inform the impact of treatment on resistance selection in targeted and bystander species ( ) . whereas between-group differences in the absolute prevalence of colonization with resistant organisms ( ) are tested for routinely, stratified measurements (see the reports of shrag et al. ( ) and feikin et al. ( ) , for example) of the effect of treatment on acquisition and clearance of susceptible and resistant pathogens are more informative of the underlying biology ( ) and may detect signals of selection masked by simpler betweengroup comparisons ( , ) . studies are also needed to address optimal deployment of new and existing antimicrobial drugs in clinical practice. the tradeoff between maximizing a drug's impact and minimizing resistance selection has led policymakers to ration certain new drugs as last-resort treatments. however, in recent experience, such decisions have ignited ethical debates ( ) . coupling mathematical modeling with field-based studies has proven useful for understanding the effectiveness of antimicrobial use policies, as highlighted in recent evaluations of the risk of resistance under population-wide access of the tuberculosis drug bedaquiline ( , ) and antimicrobial cycling to limit resistance selection in hospital settings ( , ) . whereas certain efforts we have discussed have been made to identify novel microorganisms able to cause human infection ( , ) , most epidemics caused by emerging pathogens have been recognized first by clusters of anomalous syndromes-such as cardiopulmonary syndrome caused by new world hantaviruses, severe acute respiratory syndrome caused by a coronavirus, and congenital abnormalities caused by zika virus -before the role or even existence of the etiologic microorganism had been characterized. the problem of ascribing a clinical syndrome to an etiologic agent is among the oldest in epidemiology, dating at least to the th century, when robert koch laid out criteria for such inference (i.e., koch's, or more correctly, henle-koch's, postulates ( ) ). however, these postulates have long been recognized as inadequate, particularly for illnesses caused by viruses, and thus of largely historical interest ( ) ; for instance, the notion that a pathogen should be absent from healthy individuals is incompatible with the prominence of carriage and asymptomatic infection in the natural history of numerous pathogens. a growing appreciation of the complexity of the human microbiome, and the likelihood that intricate mixtures of microorganisms at diverse body sites may be either the cause or consequence of both detrimental and beneficial physiological states, has further highlighted the difficulty of linking a given health outcome to infection by a single microorganism. the now-recognized critically important role of persistent infection and the inflammation it can produce in diverse cancers and possibly other chronic diseases has further diminished the relevance of koch's postulates and the age-old distinction between infectious and chronic diseases, as illustrated in the well-known example of human papillomavirus causing cervical, anal, and oral cancers ( ) . the best causal understanding of such relationships has come from randomized trials demonstrating that infection-preventing interventions are efficacious against downstream chronic illness, such as peptic ulcers due to helicobacter pylori and chronic wheeze due to respiratory syncytial virus ( , ) . natural experiments following the same intuition have provided additional evidence of such relationships, such as measles-induced immunosuppression ( ) , malnutrition and stunting due to enteric infection ( ) , and complex or chronic otitis media due to tissue damage from acute early-life disease ( ) . such relationships have proven difficult to probe in the absence of a randomized or natural experiment, because of the likelihood that confounding factors influence individuals' risk for initial infection as well as chronic sequelae. new paradigms for ascribing an etiologic role to microorganisms and resulting host responses are clearly needed and may prove important in efforts to quantify the health impacts of infectious disease interventions. the recognition in the s and s that infectious diseases were not, in fact, disappearing 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years of age in resourcepoor environments prevention of early episodes of otitis media by pneumococcal vaccines might reduce progression to complex disease the authors received no specific funding for this article. conflict of interest: none declared. key: cord- - ykwwq authors: ippolito, g.; puro, v.; heptonstall, j. title: biological weapons: hospital preparedness to bioterrorism and other infectious disease emergencies date: - - journal: cell mol life sci doi: . /s - - -y sha: doc_id: cord_uid: ykwwq in the last decades, successive outbreaks caused by new, newly recognised and resurgent pathogens, and the risk that high-consequence pathogens might be used as bioterrorism agents amply demonstrated the need to enhance capacity in clinical and public health management of highly infectious diseases. in this article we review these recent and current threats to public health, whether naturally occurring or caused by accidental or intentional release. moreover, we discuss some components of hospital preparedness for, and response to, infectious disease of the emergencies in developed countries. the issues of clinical awareness and education, initial investigation and management, surge capacity, communication, and caring for staff and others affected by the emergency are discussed. we also emphasise the importance of improving the everyday practice of infection control by healthcare professionals. the global eradication of smallpox, arguably the greatest international public health achievement of the twentieth century, was certified in at a time of almost untrammelled optimism that the fight against infectious diseases had been won. in the following decades, successive outbreaks of infectious diseases caused by new, newly recognised and resurgent pathogens -which have been described as a series of 'perfect microbial storms' -amply demonstrated that such optimism was misplaced, and that, far from winding down capacity in clinical and public health management of highly infectious diseases, it was necessary to enhance it [ , ] . the risk that highconsequence pathogens, including smallpox (variola) virus, might be used as biological weapons or bioterrorism agents had been recognised, and policy makers and planners were encouraged to ensure that that health and other services were adequately prepared to deal with the threat, even before the attacks on the world trade center and the pentagon in september [ , ] . these attacks, coupled with the deliberate release of letters containing anthrax spores via the us postal service a month later [ ] , showed that the threat was real, and that work to improve preparedness and response was urgently needed at local, national, and international levels. in this article we review recent and current threats to public health in developed countries from bioterrorism and other highly infectious diseases, and discuss some of the components of hospital preparedness for, and response to, infectious disease emergencies. we also emphasise the importance of improving the every-day practice of infection control by healthcare professionals and of taking a generic, 'all-hazards' approach to hospital preparedness, integrating planning for response to infectious disease emergencies, whether naturally occurring or caused by accidental or intentional release, with planning for major incidents and natural disasters. the concepts used in developing laboratory biosafety guidelines forms the basis for categorisation of biological agents by risk group and the designation of appropriate biosafety levels. these concepts rely on expert risk assessment of the severity of human infection, the potential for transmission to exposed individuals and to the wider community or environment, and the availability of effective prophylaxis or treatment. additional assessments include likely ease of dissemination by terrorists and the estimated overall impact of any dissemination to generate lists of 'critical agents' [ , ] . the lists then rank the biological agents that might be used in deliberate release by priority, and identify measures needed to ensure public health preparedness. critical agent lists are also being used to set priorities in biodefence research, including basic research on biology and pathogenesis, and development and evaluation of molecular diagnostic assays, vaccines, antivirals, and other preventive or therapeutic interventions [ ] . although critical agent lists generally make provision for inclusion of newly recognised or recently emergent pathogens, they were developed specifically to improve preparedness for bioterror events. so though all categorise smallpox virus as a high-priority, 'category a pathogen', none accords high-priority to highly pathogenic influenza viruses, or severe acute respiratory syndrome (sars) coronavirus, despite the fact that these viruses are epidemic prone, and capable of rapid global spread and enormous public health impact. the term 'highly infectious diseases' describes infections caused by pathogens that are transmissible from person to person, cause severe or life-threatening illness; present a serious hazard in healthcare settings and in the community; and require specific control measures, which may include management of cases in a highly secure isolation unit. it thus includes some, but not all, of the infections caused by category a critical agents (including smallpox, lassa, marburg, ebola and congo crimean haemorrhagic fevers, and pneumonic plague, but excluding anthrax, bubonic plague, tularaemia and botulism because these are not transmissible from person to person), and also includes sars, influenza caused by avian influenza virus h n or other highly pathogenic influenza virus, and unusual illness of unknown, but possibly infectious, aetiology. incidents caused by the intentional release of pathogens are rare: in the last years, five such incidents have been recognised and reported. three of the first four incidents involved gastrointestinal pathogens (salmonella typhi, salmonella enteritidis, shigella dysenteriae); in the fourth a group of students developed asthma and pulmonary eosinophilia after being fed ascaris suum [ ] [ ] [ ] [ ] . in the largest of the outbreaks of gastrointestinal infection, over people developed symptoms after eating from salad bars in two restaurants in dalles, oregon, in . this was a 'covert' deliberate release: unannounced, without any warning or indication of the organism involved, or of the population affected, and it was not until late in that it was discovered that followers of baghwan shree rajneesh had deliberately contaminated the salad bars with cultures of s. enteritidis, nicely illustrating that intentional and naturally occurring outbreaks may be indistinguishable. in the united states, the intentional dissemination of anthrax through the postal service in led to cases of anthrax ( pulmonary, cutaneous) among residents of seven states along the eastern seaboard. five of the pulmonary infections were fatal [ ] [ ] [ ] [ ] [ ] [ ] [ ] . this was an example of an 'overt deliberate release', insofar as explicitly threatening notes were enclosed in the envelopes containing the anthrax spores, although the diagnosis of the first cases preceded recognition of the risk. most ( ) cases occurred in postal service employees or employees of the media companies targeted in the attacks; environmental sampling detected widespread anthrax contamination of the postal system. anthrax, along with all other infections caused by category a pathogens, is uncommon in developed countries, and lack of familiarity with the disease, coupled with failure to include it in the differential diagnosis of an unusual skin lesion or of sudden onset of serious sepsis and respiratory failure led to delays in diagnosis: the median time from onset to diagnosis of the cases of cutaneous anthrax in the first cluster was days [ ] . many of these had already occurred by the time that the index case of pulmonary anthrax was diagnosed in florida by an alert clinician who had recently undergone bioterrorism preparedness training. although the number of cases was small, the overall impact of the incident on an already stretched public health system was considerable. in new york alone, over 'suspect' cases, identified as a result of intensive case finding in hospitals and through clinician networks, or by self-referral by calls to telephone hotlines, required clinical assessment. all those who had potentially been exposed to anthrax required assessment for prophylaxis; completion of a -day course of post-exposure antibiotics was recommended for over , persons [ ] . laboratories within the laboratory response network tested over , clinical specimens. the incident highlighted the need for coordination and clear command structures at local and national levels; for stronger linkages between clinicians, clinical microbiologists, hospitals and public health departments; for information, communications and laboratory systems with inbuilt 'redundancy', readily capable of expansion to meet surges in requirements, and for coordinated and effective communication with clinicians, the media and the public [ ] . in the oregon outbreak, the organism had been obtained from a commercial source; in two of the three other outbreaks caused by gastrointestinal pathogens, the per-cell. mol. life sci. vol. , multi-author review article petrators, a bacteriologist and a laboratory worker, had access to organisms from their laboratories. the source of the b. anthracis used in the united states in remains uncertain. recent changes intended to strengthen containment of critical agents within laboratories include more stringent regulation of work on, and transfer of, high-consequence pathogens, and updated guidance that recommends that all clinical, diagnostic and research laboratories develop threat and risk assessment based site-specific biosecurity plans covering personnel selection, access and inventory control, specimen accountability, reporting of incidents, injuries and breaches, and response to an emergency [ ] [ ] [ ] . the epidemic of sars in - , with over cases in countries, illustrated how a new infection can, given the speed and reach of international air travel, spread globally within weeks [ ] . transmission was amplified within hospitals, as early cases were cared for without effective infection control measures; % of sars cases in hong kong and nearly half ( %) of sars cases in toronto and singapore ( %) occurred in healthcare workers. overall, % of hospitalised patients required mechanical ventilation, and % of hospitalised cases died. sars coronavirus, although a newly emergent virus, was transmitted in the same way as more common respiratory infections, mainly by respiratory droplet spread, and the sars epidemic was controlled by the efficient application of long-recognised public health control measures: rapid identification and early isolation of cases, and stringent adherence to infection control precautions. in canada, where sars 'paralysed the greater toronto area healthcare system for weeks' [ ] , and the toronto public health department investigated potential cases of sars, identified over , contacts as requiring quarantine and logged more than , calls on its sars hotline [ ] , a national review commission identified systemic deficiencies in response capacity, including 'inadequacies in institutional outbreak management protocols, infection control and infectious disease surveillance', and found that these deficiencies resulted at least in part from failure to implement lessons learned from earlier public health emergencies [ ] . global travel and global trade expose industrialised countries to other infectious disease threats. human monkeypox is a zoonosis, normally geographically confined to west and central africa, which is clinically similar to smallpox in that a vesiculopustular rash follows a febrile prodromal illness. the illness tends to be milder than smallpox; in contrast with smallpox, lymphadenopathy is often a prominent feature, and person-toperson transmission is uncommon. in , the first clus-ter of human cases ( confirmed, suspected) of community-acquired monkeypox in the western hemisphere occurred in the united states [ , ] . infection followed exposure to infected pet prairie dogs that had been housed or transported with african rodents imported from ghana. although pox virions were seen on electron microscopy of clinical samples from the index case, the diagnosis of smallpox was excluded because the development of pocks in the case followed, and was localised to, the site of a bite by a sick pet prairie dog. the diagnosis of monkeypox was made by specialist testing of referred samples in the national laboratory. this incident again highlighted the role of the astute clinician in outbreak recognition; the value of maintaining close working relationships between clinicians working in healthcare facilities and in public health departments, and the need for multi-level, multi-agency cooperation, including collaboration between animal and human health experts, in outbreak management. in , an outbreak of marburg haemorrhagic fever in angola, and the potential for exported cases prompted the rapid development of national guidelines for risk assessment and case management in countries that had not previously published such guidelines [ , ] . marburg viral haemorrhagic fever, and ebola, congo-crimean, and lassa haemorrhagic fevers are of particular concern in healthcare settings because there is a high risk of person-to-person transmission through percutaneous or mucocutaneous exposure to blood. lassa fever is endemic in west africa, where estimates suggest that around , cases occur each year [ ] ; congo-crimean haemorrhagic fever has a wide geographic range that includes greece, albania and pakistan; and outbreaks of the more geographically restricted ebola and marburg haemorrhagic fevers have recently occurred with apparently increasing frequency [ , ] . despite this, imported cases of viral haemorrhagic fever are uncommon: laboratory confirmed cases of lassa fever (likely to be the most frequent importation) have been reported from the united states, and fewer than from other industrialised countries since the disease was recognised in [ ] [ ] [ ] [ ] . this is perhaps because transmission and outbreaks of haemorrhagic fever viruses occur mostly in rural areas, which thus limits the opportunities of most business travellers or tourists for exposure. nevertheless, and because there have been reports of weaponisation of marburg, ebola and lassa viruses [ ] , all of which are category a pathogens, clinicians should remain alert to the possibility of these infections, maintain an awareness of current outbreaks, and should know how to conduct a risk assessment of febrile illness compatible with a diagnosis of viral haemorrhagic fever, how to safely undertake initial management and apply appropriate infection control measures, and, most important, know whom to contact for further advice on diagnosis and further management [ , , ] . infections emergencies and hospital preparedness one of the consequences of the resurgence in biodefence-related research is that more laboratories, and more laboratory workers, are now working with category a pathogens, which increases the potential for occupational exposure, for occupationally acquired infection and, for some pathogens, for onward transmission to others. laboratory workers may also be exposed to high-consequence or newly emerging pathogens whilst working on diagnostic or surveillance-related samples. since , cases of laboratory acquired glanders ( case, us military research laboratory, the first case reported in the united states since ) [ ] ; the wr strain of vaccinia ( case, research laboratory, brazil) [ ] ; recombinant vaccinia virus ( cases, research laboratories in germany, united kingdom, canada, and united states) [ ] [ ] [ ] [ ] , tularaemia ( cases, us research laboratory) [ ] ; sars ( cases, in research laboratories in taiwan, singapore, and china; all occurred after the end of the sars epidemic, infection spread from the laboratory workers in china to a further people, of whom died) [ ] [ ] [ ] ; ebola viral haemorrhagic fever ( fatal case, russia, research laboratory) [ ]; anthrax ( cutaneous case, us laboratory) [ ] ; brucellosis ( linked cases, us clinical microbiology laboratory) [ ] ; and west nile virus ( cases, us laboratories) [ ] have been reported. in several of these cases, diagnosis was delayed because the possibility of occupationally acquired infection was not considered, and/or because of difficulties in identifying the organism in the clinical microbiology laboratory. in only of these cases was the exposure that led to infection identifiable. guidelines on laboratory biosafety advise that laboratory workers should have access to expert occupational health advice, including, where appropriate, pre-exposure prophylaxis, and that those working in bsl or bsl facilities should carry 'medical contact cards' [ ] . clinicians should take an occupational history as a routine, and, if a laboratory or animal house worker presents with an unexplained febrile illness, a senior clinician should obtain further information from the laboratory director about the agents to which the patient may have been exposed, regardless of whether the worker can recall a specific exposure. since , a new, highly pathogenic strain of avian influenza virus, a/h n , has emerged, initially in se asia, but with more recent spread to countries in europe, the middle east, central asia, and africa. the first human cases were reported from vietnam in ; to date (may ), laboratory-confirmed cases, including deaths (case fatality rate %) have been reported to the world health organisation from countries (azerbaijan, cambodia, china, djibouti, egypt, indonesia, iraq, thailand and turkey) [ ] . there is limited evidence of human-to-human transmission of the virus [ ] ; most cases have followed close contact with infected birds (of-ten from household or 'backyard' flocks) or their faeces, other body fluids or carcasses. it is not known whether, and if so, when, how or where, influenza virus a/h n will evolve to become more easily transmissible between humans. nor is it known whether an increase in transmissibility would be accompanied by a change in lethality. however, the world health organisation believes that the threat of pandemic human influenza is now greater than at any time since , when the last influenza pandemic occurred [ ] . the world health organisation uses a series of six alert levels to inform the world of the seriousness of the threat, and to recommend progressively more intense preparedness activities. at present (pre-pandemic threat level ) [ ] , clinicians need to be aware of the potential for infection in travellers returning from affected countries, and in those who may have had occupational (e.g. poultry farmers, veterinarians, animal cullers) or other contact with infected domestic, commercially farmed or wild birds, a human case or virus in the laboratory. advice, algorithms and response protocols for investigation and management of possible cases or case clusters have been published, and give details of reporting mechanisms, diagnostic specimens, infection control measures and other containment responses [ ] [ ] [ ] . assessments of preparedness plans in europe and the united states suggest that, at best, most countries remain only moderately prepared for pandemic influenza; furthermore, the degree to which planning at the national level has been translated into increased preparedness at the local level within healthcare facilities remains unknown [ ] [ ] [ ] . it would be prudent, however, for planners within hospitals to review existing influenza pandemic contingency plans in conjunction with the relevant national preparedness plan, with the aim of ensuring preparedness to provide supportive medical care for influenza cases, prevent transmission of infection and at the same time continue to provide essential medical services to their community. where concerns arise about issues (e.g. criteria for hospital admission; prioritisation of antiviral use; prioritisation of admission to intensive care units; responsibility for decisions to defer elective surgical admissions; sourcing of additional supplies e.g. of personal protective equipment; use of volunteer personnel) that are not clearly dealt with within the national plan, urgent clarification should be sought from the relevant national authority. the overall aim of hospital preparedness for an infectious disease emergency is to be able to provide adequate medical care to those affected whilst at the same time continuing to provide essential medical services to the community. cell. mol. life sci. vol. , multi-author review article the phases of the traditional disaster management cycle (preparation, response, recovery and mitigation) are paralleled in infectious disease emergency management by preparedness (activities undertaken before an event, including planning, training, and undertaking practice drills and exercises to test the plans); surveillance and detection (recognising that an infectious disease emergency is occurring); and response, control and containment (the clinical, public health and other measures that minimise the health, social and economic consequences of the incident). effective preparedness planning requires a multidisciplinary approach, involving emergency planners, clinical practitioners, laboratorians, managers and administrators, emergency responders, pharmacists, voluntary agencies, mental health and occupational health services, religious and spiritual advisors, support staff including catering, housekeeping, portering and security, medical records, communications, information technology and transport/ courier services; with clear, pre-event designation of roles and responsibilities and clear chains of command, control and communication, and regular testing and evaluation of 'major incident' or emergency operations' plans by drills and exercises. hospital preparedness for infectious disease emergencies needs to be sufficiently versatile to encompass response to incidents that range from those of high/moderate probability-low/moderate consequence (e.g. a local, but severe point-source outbreak of norovirus infection), through low probability-moderate consequence (e.g. managing a single imported case of viral haemorrhagic fever or a hospital-associated outbreak of legionellosis), to low probability-high consequence (e.g. pandemic influenza; bioterrorist attack). early diagnosis and prompt institution of effective control measures are critical determinants of the eventual impact of any infectious disease emergency [ ] . nine of the cases of pulmonary anthrax in the us outbreak in presented direct to hospitals or emergency rooms. these clinicians are also likely to be the first to see cases of newly emergent highly pathogenic influenza, re-emergent sars or imported viral haemorrhagic fever. clinicians need, therefore, to maintain their awareness of current infectious disease threats by daily review of national, regional and international web-based alerting systems, or by ensuring that their department receives national cascade alerts, and to incorporate relevant epidemiological information into their daily practice (e.g. by using knowledge of areas currently affected by avian influenza h n coupled with travel and occupational histories to exclude the diagnosis in patients with febrile respiratory illness). useful and reliable open-access sources of medical intelligence include the web sites developed by the infectious diseases society of america (promed; http://www. promedmail.org) [ ] , the world health organization (http://www.who.int/csr/don/en/) [ ] ; further links to additional sources can be found at http://www.ecdc.eu.int/. all clinicians must remain open to the possibility that they may be the first person to recognise a deliberate release or other infectious disease emergency; must be prepared to consult urgently with their local infectious disease specialist, clinical microbiologist and public health department on suspicion alone, without waiting for a definitive diagnosis, and must remain alert to the unusual, the unexpected and the case that 'just doesn't fit'. examples of the unusual include unusual illness (e.g. a sudden, unexplained febrile death, critical illness or pneumonia in a previously healthy adult); an unusual number of patients with the same symptoms presenting within a short time frame; illness unusual for the time of year (e.g. 'flu in summer'); an illness unusual for the patient's age group (e.g. chicken pox in a middle-aged adult); illness in an unusual patient (e.g. cutaneous anthrax in a patient with no history of contact with animals, animal hides or products); an illness acquired in an unusual place (e.g. tularaemia acquired in the united kingdom); unusual clinical signs (e.g. mediastinal widening on chest x-ray; symmetrical flaccid paralysis of sudden onset; 'chickenpox' rash predominantly on the extremities); and unusual progression of illness (e.g. lack of response to usually effective antibiotics) [ ] . most of the illnesses caused by high-consequence pathogens are uncommon in industrialised countries (though some e.g. plague, anthrax remain endemic elsewhere) so few clinicians have direct experience of them; similarly, few of those now practising have ever seen a case of smallpox. considerable resources have therefore been invested since in training clinicians and emergency responders to recognise illnesses caused by these pathogens, and in developing web-based and other training materials, guidelines, fact sheets, and incident response check lists for health care and emergency response professionals. these can be found on, or through, national authorities' web sites (e.g. http://www.bt.cdc.gov; http://www.hpa. org.uk) and used, where formal face-to-face training programmes are not accessible, as the basis for self-directed learning. decision-based algorithms for diagnosis and clinical management pathways have also been developed, and can be used to guide initial responses to suspected cases of smallpox, sars, viral haemorrhagic fever or avian influenza [ , [ ] [ ] [ ] [ ] . effective infection control saves lives. all healthcare workers have a responsibility to ensure that their clinical infections emergencies and hospital preparedness practice prevents transmission of infection, and puts neither their own health, nor that of their patients, coworkers or others at risk. all healthcare workers should be trained in standard and transmission-based infection control precautions at induction [ ] . overall standards might be improved if an annual demonstration of competence was made a requirement for re-accreditation, and if a more stringent approach was taken to any recognised breach of infection control practice. infection control guidelines, updated after the sars epidemic, now stress the importance of incorporating 'respiratory hygiene' or 'cough etiquette' -simple measures designed to prevent transmission of respiratory infections -into standard infection control precautions [ , ] . this is particularly applicable to emergency departments, outpatient clinics and day-care centres -and includes training staff to identify and segregate or spatially separate patients with signs and symptoms of respiratory tract infection from others; offering a surgical mask to symptomatic patients; instructing all patients to cover their nose and mouth with tissues when coughing or sneezing, to dispose of used tissues safely and to clean their hands frequently, and providing tissues and tissue-disposal and hand-cleaning facilities for patients [ , ] . emergency departments should review their existing infection control practices and consider whether these are adequate to prevent intra-hospital transmission of infection, from the moment that a patient with an unrecognised but highly infectious disease arrives in the department, through the initial evaluation and investigation, to the point when the patient is admitted or transferred elsewhere. this should include identifying a space (ideally a negative pressure room) suitable for airborne infection and respiratory isolation and ensuring that staff understand when and how it should be used; review of available personal protective equipment (ppe: gloves, gowns, face and eye protection, surgical masks or other respiratory protection e.g. n -type respirators), hand-cleaning facilities, and sharps safety and disposal arrangements; assessment of staff competency in choosing, and safely using, removing and disposing of the ppe available, ensuring that, if n -type respirators are to be used, staff have been fit-tested and know how and when to perform fit checks; reinforcement of the importance of hand hygiene; arrangements for cleaning and ensuring environmental hygiene; and setting triggers for notifying the infection control team and public health department, and for seeking further expert advice. departmental competency can and should be tested by regular drills and simulation exercises. infection control planning for infectious disease emergencies should also consider the number of isolation or single rooms available, and determine when, where and how cases posing a risk of transmission to others could be cohort-nursed once the supply of single rooms is exhausted. the aim of the initial investigation and management of a patient suspected of having a highly infectious disease, or a patient who presents with an unusual, and possibly highly transmissible, illness is to provide life-sustaining medical care to the patient whilst ensuring staff safety. this implies placing the patient in a side room, limiting the number of staff exposed to the patient to the minimum necessary, evaluation of the patient by a senior clinician, using appropriate personal protective equipment during the evaluation (gloves, gown, face and eye protection, surgical mask or n -type respirator for staff, surgical mask for patient), and urgently seeking expert advice about management and diagnostic testing before taking diagnostic samples. expert advice should also be sought on the desirability and mechanism of transfer of the patient to a highly secure infectious disease unit. detailed, disease-specific national guidance on the management and investigation of highly infectious diseases has been produced by many countries, and can usually be found on the website of the relevant national authority [ ] ; planners should download this guidance, incorporate relevant points (e.g. contact details for national or regional laboratories that will undertake specialised laboratory diagnostic testing; smallpox response team) into emergency plans, and designate the task of ensuring that the locally available version is up-to-date to a specific jobholder. laboratorians should be involved in planning, and protocols for the safe collection, transport and external referral of clinical specimens should be available, and should comply with international transport regulations and international and national guidance on biosafety and biocontainment. robust systems for information management and specimen tracking should also be in place pre-event. if the event is linked to deliberate release or criminal action, or there are other forensic considerations, chain of custody (sometimes called 'chain of evidence') documentation of samples, and close liaison with the police or security forces will be required. surge capacity is the ability to expand healthcare provisions to respond to an increased number of patients that exceeds usual capacity, including the provision of specialised or unusual medical care (e.g. paediatric care; intensive care requiring mechanical ventilation; haemodialysis or haemofiltration). this is sometimes split into 'surge' capacity -the expansion of healthcare provision whilst retaining near-normal care standards, and 'supersurge' capacity -further expansion, requiring the use of alternative care facilities (e.g. schools, church halls) and/ cell. mol. life sci. vol. , multi-author review article or significant changes in standards of care, sometimes referred to as 'planned degradation of care' [ ] . infectious disease emergencies may range from providing care to a single, seriously ill, highly infectious patient, to providing care to a community affected by a bioterror event or pandemic influenza. surge requirements might include not only the ability to increase bed and personnel capacity to cope with an increased number of acute admissions, but also, for example, the ability to manage an increased number of laboratory samples, increased clinical waste for disposal, increased communication and information technology requirements (e.g. networked computers, cell phones, telephone lines connected to automatic routing systems), and increased requirements for supplies of ppe. planners need also to consider, and formalise, with nearby healthcare providers, arrangements for collaborative working and mutual aid, and to consider also how essential functions (e.g. providing ventilatory support; communications) might be maintained if utility supplies (e.g. electricity, fuel) were compromised [ , ] . modelling estimates for pandemic influenza in the united states suggest that, although many patients could be cared for at home, if the pandemic was severe, and numbers affected paralleled those of the pandemic, at the peak, hospitals would need % of available non-intensive care beds; % of available intensive care beds; and % of available ventilators for influenza alone [ , ] . thus, for influenza, the ability to provide intensive care might well be the rate-limiting step in surge capacity, and criteria for admission to intensive care and for continuation of intensive support might need to be different from those that would normally be used. this raises complex ethical and legal questions, which are best thought through, preferably at the national level, in advance of, rather than during, the event. effective communication is essential to management of infectious disease emergencies, and a communication plan is an integral part of any emergency management plan. 'communication' is a broad term that encompasses provision of accurate, timely, complete, easily understood information to the community about what the emergency is, what is being done to control it and what people can do to make themselves safer; provision of information to healthcare professionals about diagnosis, investigation, and pre-or post-exposure interventions; communication with families and others close to those affected by the emergency; communication with the media; and communication within and between all levels of all those involved in managing the emergency. recent international guidelines on risk communication, and on communicating with the media and the public during an infectious disease emergency provide greater detail, and highlight the importance of communicating in ways that build or maintain trust, of planning and testing outbreak communications strategies, and of providing media communications training for all public officials as part of professional development [ , ] . occupational health services should be involved in hospital preparedness planning. this involvement will help to ensure that staff are as well protected before the event as is possible (e.g. by ensuring uptake of seasonal influenza vaccine, pneumococcal vaccine and hepatitis b vaccine by all those who are eligible under existing national policies, and of vaccines specifically relevant to laboratory staff). occupational health services should also participate in development of systems for surveillance of infection in health care workers, which are needed both pre-event, as a means of detecting that an infectious disease emergency is occurring [ ] , and during an event, to monitor the outcome for potentially exposed workers, and of infection specific protocols for post-exposure management [ , ] . any traumatic incident, emergency or disaster, whether natural or man-made, has a psychological impact on those involved -survivors, the bereaved, witnesses, rescuers, responders and health professionals, and their families, relatives, friends and workmates. planning should ensure that, whatever the emergency, staffing levels will be sufficient for time on duty to be limited to no more than h a day, and should make provision for staff rotation from highly taxing to less taxing functions. staff will need somewhere quiet, safe and private 'off-scene' to eat, drink and rest without interruption, and facilities will also need to be such that staff are able to stay in touch with friends and family. staff should also be made aware of other sources of support (e.g. their family doctor, hospital chaplain, and other religious and spiritual advisors), and should be provided with details of how to contact confidential listening or counselling services [ , ] . it is impossible to predict when, where or how another deliberate release of a biological agent will occur, and equally impossible to predict which emergent infection will next threaten global public health, or whether the influenza pandemic will occur this year, next or in some years time. it is, however, possible to predict that infectious disease emergencies will continue to occur g. ippolito, v. puro and j. heptonstall infections emergencies and hospital preparedness with regularity, and it is possible, with appropriate planning, to be prepared to meet them in a way that ensures that they cause as little social disruption as possible. the greatest danger is complacency -the belief that 'it cannot happen', or that ' it could happen, but it will happen somewhere else'. it is not clear to what extent the efforts made at the international and national level and the long lists of lessons learned have translated into improved and sustainable hospital preparedness at the local level; we hope this article will provoke you to prepare, plan and practice, now. microbial threats to health: emergence, detection, and response the challenge of emerging and re-emerging infectious diseases 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exposures to agents of bioterrorism emergency preparedness and response. disaster mental health resources acknowledgement. this work was performed within european commission project eunid, and within ricerca finalizzata and ricerca corrente irccs projects, italian ministry of health. key: cord- -kt gt t authors: nan title: poster session abstracts date: - - journal: pediatr pulmonol doi: . /ppul. sha: doc_id: cord_uid: kt gt t nan causing mutation is ∆f , making studies of nbd essential in understanding cftr function. crystal structures have been solved of wild-type (wt) and mutant cftr nbd , including variants containing ∆f (lewis et al. embo j. ; lewis et al. j. biol. chem. ; thibodeau et al. nat. struct. mol. biol. ) . cftr nbd contains a regulatory insertion (ri) and a regulatory extension (re) that contain pka phosphorylation sites. although the nbd core is very similar in the various structures, the ri and re in some structures of human wt nbd differ by °rotations, indicating that they are mobile. we have used nmr spectroscopy to study wt and ∆f nbd in the phosphorylated (phospho) and non-phosphorylated (non-phospho) states, and bound to different regions of cftr. despite their similar structures, differences are observed in the nmr spectra of wt and ∆f nbd . these changes, possibly due to altered dynamics or interactions of the ri and re with the nbd core, will be discussed. the inherent stability and function of nbd could be affected by these changes, accounting for part of the ∆f defect. different interactions between wt and ∆f nbd with the icls could also affect channel function. to identify residues comprising the icls, we generated a homology model of cftr based on the crystal structure of sav in which nbd and nbd form a productive dimer (dawson and locher. nature. ) . our data on a peptide corresponding to the first intracellular loop (icl ) indicate that binding to nbd requires phosphorylation of the ri. our homology model shows that the icl binding site is buried when the ri is bound to the nbd core. nmr data comparing phospho and non-phospho nbd indicates that phosphorylation of the ri and re disrupts their interactions with the nbd core, likely exposing the site for icl binding. the structure of the molybdate transporter modb c , with the nbds in an open conformation, shows icl binding is cognate nbd at a different interface (hollenstein et al. nature. ) . icl in modb c interacts with the nbd near y , the analogous residue to f in cftr. we will show binding data of icl with wt and ∆f nbd in different states and also present resonance assignments of nbd to map the icl interaction sites. since the sav and modb c structures were solved in different states, the different icl interactions may represent structural changes during the reaction cycle. the ∆f mutation may thus affect intramolecular associations in certain conformations, which would account for another part of the ∆f defect. probing differences in interactions of wt and ∆f nbd is critical for understanding the molecular basis of normal cftr function and of the altered cftr function in cystic fibrosis. shsps target ∆f cftr for erad via the sumo pathway ahner, a. ; brodsky, j.l. ; frizzell, r.a. . cell biology and physiology, university of pittsburgh, pittsburgh, pa, usa; . biological sciences, university of pittsburgh, pittsburgh, pa, usa the most frequent disease-causing mutation in cystic fibrosis (cf) is a deletion of phenylalanine at position (df ) in the first nucleotide binding domain of cftr. essentially all of the mutant protein, as well as % of wild type (wt) cftr, is retained in the er and targeted for erassociated degradation (erad) by the s proteasome. key mediators of cftr folding and degradation are molecular chaperones, which help protein substrates fold, but can target them for degradation if folding efficiency is compromised. to identify factors modulating erad of cftr we performed a microarray analysis, screening for transcription profile differences between yeast expressing cftr and control strains, and identified enhanced transcript levels for the small heat shock protein hsp in yeast expressing cftr. we then demonstrated that cftr degradation was blocked in strains lacking the genes encoding the two yeast shsps, hsp and hsp ( ) . to examine whether shsps regulate cftr biogenesis in mammalian cells, we asked which of the human shsp homologues are endogenously co-expressed with cftr using rt-pcr and western blot analysis. we detected shsps, including alphaa-crystallin and hsp , in calu- and primary hbe cells. co-expression of alphaacrystallin or hsp together with wt or df -cftr in hek cells selectively decreased the steady state levels of df -cftr. pulse-chase experiments showed that the rate of df -cftr degradation was enhanced when either shsp was over-expressed, but wt cftr biogenesis was unchanged. co-immuno-precipitation experiments in hek cells revealed that alphaa-crystallin and hsp interacted preferentially with df -cftr. thus far, our results suggest that shsps selectively increase df -cftr's accessibility to proteasome-mediated degradation pathways. previously, hsp was reported to interact with ubc , the sumo (small ubiquitin-like modifier) conjugating enzyme ( ) . sumo is covalently linked to its substrates, often at sumoylation consensus sites; similarly to ubiquitin, this occurs through a series of thiol transfer reactions. we confirmed this interaction by co-immuno-precipitation and found that ubc as well as the sumo specific protease, senp , are expressed in airway epithelial cells. over-expression of ubc decreased, while over-expression of senp increased df -cftr protein levels. pulse-chase experiments indicated that these enzymes regulate selectively the degradation of df -cftr, similarly to the shsps. preliminary studies in vitro and in vivo indicate that cftr, and particularly purified nbd , is sumoylated and that hsp facilitates this process. mutational analysis of the sumoylation consensus sites within cftr suggests a cycle of sumo modification that facilitates wt cftr biosynthesis but targets df -cftr for degradation, probably because the balance between sumo addition and removal is impaired by an excessive interaction of shsps with the mutant protein. [supported by grants from the nih and the cystic young, a. physiology and biophysics, chicago medical school, north chicago, il, usa efficient retrieval of wtcftr from the cell surface is mediated by components of the clathrin mediated endocytic pathway; however many aspects of cftr endocytosis remain to be elucidated. we have previously shown that endocytosis of wtcftr is dependent upon recognition of a tyrosinebased motif in the carboxyl tail of cftr by the ap endocytic adaptor complex. in contrast to wtcftr, less is known about the mechanisms whereby mutant cftr undergoes internalization. according to one model, df cftr undergoes accelerated endocytosis compared to wtcftr, whereas others have argued that endocytic rates of df cftr are comparable to those of wild-type cftr. to further define the function of proteins involved in the initial steps of wt and mutant cftr endocytosis, we investigated the role of the gtpase dynamin. dynamin has been proposed to play a key role in endocytosis by facilitating the scission of nascent clathrin coated vesicles from the cell surface. until recently, very few tools were available to modulate clathrin mediated events. we took advantage of dynasore, a newly discovered small molecule, non-competitive inhibitor of the gtpase dynamin. dynasore acts as a potent, rapid and reversible inhibitor of endocytic pathways known to depend upon dynamin, by blocking coated vesicle formation within seconds of dynasore addition. endocytosis of wtcftr was inhibited rapidly and efficiently upon addition of dynasore. furthermore, within minutes of dynasore washout, endocytosis of wtcftr resumed completely. also upon dynamin washout, normal trafficking and recycling of wtcftr was also observed. temperature correction of df causes expression of cftr at the cell surface, however such 'rescued' df cftr is not stabilized upon returning cells to c. application of dynasore prevented such rapid loss of mutant cftr from the cell surface. since maintenance of mutant cftr at the cell surface is critical for effective therapeutic intervention in patients with cf, our results provide insight into additional potential targets for pharmacological manipulation for the treatment of cf. richardson, j.m.; thibodeau, p.h.; watson, j.; thomas, p.j. physiology, ut southwestern medical center, dallas, tx, usa protein misfolding is the basis for a multitude of human diseases; however, the mechanisms underlying misfolding are not well understood. most cases of cystic fibrosis are associated with mutations-including the most common, deletion of phenylalanine (∆f ) in nbd -that interfere with the folding of the cystic fibrosis transmembrane conductance regulator (cftr). the resulting loss of functional cftr causes the disease. thus, elucidating how ∆f , affects the folding of cftr is critical to understanding the pathology of the disease. cftr is composed of five domains: two integral membrane transmembrane domains (tmds), a regulatory domain (r), and two nucleotide binding domains (nbds). ∆f occurs in the n-terminal nbd . both the murine wildtype and ∆f nbd can be expressed in bacteria and purified to near homogeneity. while the soluble expression yield of ∆f is lower than the wild type under identical conditions, ∆f achieves a native conformation similar to wild type as monitored by a variety of hydrodynamic and spectroscopic characteristics such as analytical size exclusion chromatography, circular dichroism, and fluorescence. recently, a non-native, but folded, species has been detected under mildly denaturing conditions. far-uv cd reveals a time and temperature dependent conversion from a mixed alpha/beta native conformation to a less helical non-native conformation, while fluorescence measurements reveal a parallel blue shift in the peak emission intensity from to nm. this non-native species is in a more open conformation as determined by both limited proteolysis and the change in retention time on analytical size exclusion chromatography. the conversion to this state is inhibited by the native state ligand (atp) and by the presence of the second site suppressors (g e, r m, and r k). notably, the ∆f nbd protein populates the non-native state under milder conditions than the wild type nbd . these studies reveal the properties of the native state and its conversion to a partially folded state that is affected by the ∆f mutation. this data highlight the proximal affect of the disease causing mutation and provide a means of assessing strategies designed to correct the defect. this work is supported by the cystic fibrosis foundation through a postdoctoral training grant and by the nih we have previously demonstrated that the stability of cftr is negatively modulated by the cftr interacting protein, cal. cal competes with nherf in binding to the pdz motif at the c-terminus of cftr and directs cftr trafficking to the lysosome. recently, silencing of cal or overexpression of nherf has been shown to restore chloride transport activity in ∆f -cftr cell lines. to identify the molecular machineries involved in cal dependent degradation of cftr, we investigated the role of the cal interacting snare protein syntaxin (stx ). stx protein expression and function were manipulated by sirna silencing, over-expression, and a dominant-negative mutant. we also performed a functional study of chloride transport activity in cystic fibrosis bronchial epithelial cell line cfbe o-stably expressing either wt-cftr or ∆f -cftr. the endogenous stx and cal protein expressions were knocked down by sirna techniques in multiple human cell lines including hek , hela cell stably expressing ∆f -cftr and cfbe o-stably expressing either wt-cftr or ∆f -cftr. in hek cells, knockdown of either stx or cal augments the expression of transfected gfp-tagged cftr (gfp-cftr), which is consistent with the observation that overexpression of either stx or cal enhances the degradation of cftr. stx interaction with cal was confirmed by a co-immunoprecipitation assay. because of this interaction, we hypothesize that stx negatively regulates cftr protein stability by interacting with cal which in turn binds to the c-ter-minal pdz motif of cftr. consistent with his hypothesis, stx knockdown has no effect on protein levels of a cftr mutant lacking the pdz motif (gfp-cftr∆trl). more importantly, cal knockdown eliminates the inhibitory effect of stx overexpression on gfp-cftr. a cell surface biotinylation assay and confocal microscopy showed significant increases in plasma membrane expression of cftr in stx knockdown cells without gross changes in the expression pattern. furthermore, consistent with its trans-golgi localization, stx knockdown has no effect on gfp-∆f -cftr expression. however, ∆f -cftr increases significantly in stx knockdown, temperature-rescued cells. to assess the effect of stx in bronchial epithelial cells, stx was knocked down in cfbe o-stably expressing wt-cftr. consistent with the observations in hek and hela cells, the expression of untagged wt-cftr is also augmented. knockdown of stx increases cftr expression in a does-dependent manner, reciprocal to the expression level of stx , without changing the level of expression of cal or gapdh. furthermore, stx knockdown lead to a does-dependent increase in cftr mediated short-circuit current that is stimulated by forskolin and inhibited by cftr chloride channel inhibitor cftrinh- . more importantly, in temperaturerescued cfbe o-stably expressing ∆f -cftr, stx knockdown tripled the cftr mediated short-circuit chloride current. these results not only delineate the effect of stx on post-golgi trafficking of cftr and its dependence on cal-mediated pdz-based interaction, but also points to it as a potential therapeutic target in conjunction with the er-quality control based rescue of ∆f -cftr. supported by the cystic fibrosis foundation and the national institutes of health. seavilleklein, g. ; evagelidis, a. ; amer, n. ; chappe, f. ; hanrahan, j. ; chappe, v. . physiology & biophysics, dalhousie university, halifax, ns, canada; . physiology, mcgill university, montreal, qc, canada cftr channel activity is regulated by phosphorylation and de-phosphorylation of the r-domain. direct pkc phosphorylation at specific sites in the r domain and nbd is essential and modulates cftr activation by pka. however, the molecular mechanism by which phosphorylation of the r domain induces channel activity remains unknown. we have reported biochemical evidence for the role of phosphorylation in domain-domain association using a deltar-split construct encoding the front (tmd -nbd ) and back (nbd -tmd ) halves of cftr as separate polypeptides ( ) . in agreement with the inhibitory role of the r domain, iodide effluxes and patch-clamp experiments confirmed that deltar-split channels were functional and constitutively active without camp stimulation. co-transfecting a plasmid that directs expression of the r domain restored the pka-dependence of re-assembled channels. co-immunoprecipitations of the halves of the deltar-split with a gst-r domain fusion protein in vitro or with the cotransfected r domain in bhk cells revealed that pka phosphorylation enhances the r domain binding to the rest of the channel. we have now investigated the effect of pkc phosphorylation on the r domain binding. our data demonstrate that pkc phosphorylation also induces a strong binding of gst-r domain in vitro or co-transfected r domain in vivo when bhk cells are stimulated with pma. interestingly, the combination of pkc+pka phosphorylation induced a stronger binding than pka alone. mutation of all consensus pkc sites on the r domain to alanine ( ca) eliminated specific pkc phosphorylation but did not alter pka phosphorylation in gst-rd. western blotting and confocal microscopy experiments confirmed that expression levels of all domains of the split- ca/rd are unchanged compared to split-rd and co-localize at the plasma membrane of bhk cells. basal activity of the split- ca/rd was similar to that of the split-rd in iodide efflux experiments. however, activation by camp+ibmx was delayed and significantly reduced ( . % of split-rd and . % of wt-cftr activation). these results confirm the functional re-assembly of the ca-rd with the front and back halves of the channel and the inhibitory role of the r domain. in co-immunoprecipitation experiments, the same level of interaction was observed between the ca/rd and rd with the split halves suggesting that basal, inhibitory interaction of the r domain is independent of pkc phosphorylation. however, ca/rd binding with the split channel was not increased by pkc or pka stimulation. we conclude that pkc phosphorylation is essential for pka-dependent binding of the r domain to the rest of the channel, and that the combined effect of these kinases further strengthens the r domain interaction. these structural changes are consistent with the essential role of pkc sites for cftr activation by pka as previously reported ( ) . supported by cihr, nshrf, dmrf & ccff. g.seavilleklein was supported by nserc. ( ) the in vivo folding mechanism of multidomain membrane proteins, including the cystic fibrosis transmembrane conductance regulator (cftr), is poorly understood. cftr, a member of the abc transporter superfamily, contains two symmetrical halves, each consisting of a membrane spanning domain (msd and msd ) and a cytosolic nucleotide binding domains (nbd and nbd ), connected by the regulatory (r) domain. to address whether cftr follows the archetypical domain-wise folding of multidomain soluble polypeptides and/or the cooperative domain folding mechanism, first we determined domain combinations that are necessary and sufficient to escape the endoplasmic reticulum (er) quality control. one-, twoor three-domain assemblies failed to be processed efficiently in cells, measured by biochemical and morphological assays. the smallest folding unit that escaped the er quality control was composed of a four-domain assembly, containing msd , nbd , r or msd as linear or split polypeptide. as a second approach we showed that cf-causing point mutations in the msd , nbd or msd provoked the er retention of the full-length cftr with severe conformational defect in the nbd , measured by limited proteolysis and immunoblotting, using domain spacific antibodies. the posttranslational folding kinetics of the four-domain folding unit was comparable to that of cftr, suggesting that cooperative domain assembly is essential for the channel biogenesis. this mechanism provides an explanation for the processing defect caused by numerous cf mutations and outlines a possible paradigm for cftr folding in living cells. cftr in post-golgi compartments. our results, jointly, uncover the role of n-glycans as a critical structural determinant of cftr conformational maturation/stability in a chaperone-independent manner. karamyshev, a.l. ; patrick, a.e. ; johnson, a.e. ; thomas, p.j. . ut southwestern medical center at dallas, dallas, tx, usa; . texas a&m university, college station, tx, usa cystic fibrosis (cf) is caused by mutations in cftr (cystic fibrosis transmembrane conductance regulator). cftr, a member of the abc transporter family, is a multispanning membrane protein critical to chloride and water movement in secretory epithelia. over one thousand mutations, in all parts of the cftr sequence, have been identified, many of which disrupt the function of the protein to cause the disease. some of the disease-associated mutations in the n-terminal portion of cftr were predicted to alter cotranslational interactions with factors involved in the membrane integration of cftr required for its proper function. to test this hypothesis, a photoreactive probe was incorporated into different positions of the n-terminal portion of cftr by introducing amber stop codons and translating these messages in vitro in the presence of the amber suppressor trna n ε -( -azido- nitrobenzoyl)-lys-trna amb . ribosome-associated nascent chains of a specific length containing the modified amino acid at a defined position were produced using truncated mrnas. some of these cftr nascent chains photocrosslinked with proteins of approximately and kda molecular mass. crosslinking to the ~ kda protein was observed only after the tm span had emerged from the ribosomal tunnel. moreover, truncation analysis demonstrated that tm is necessary for this interaction. in evaluating a range of nascent chains, the extents of photocrosslinking to the ~ kda and kda proteins often varied inversely. immunochemical and knockdown/depletion studies indicate the ~ kda protein is srp , a subunit of the signal recognition particle involved in targeting ribosome nascent chain complexes to the translocon in the endoplasmic reticulum membrane. highlighting the functional relevance of this interaction, in cells with reduced srp levels, nonglycosylated forms of cftr accumulate and total cftr levels decrease. notably, some cf-causing mutations in tm also reduce crosslinking to srp. these data reveal that mutational inhibition of nascent cftr association with srp likely contributes to or mediates some types of cf. aleksandrov, l.; aleksandrov, a.a.; riordan, j.r. the initial reversible steps of atp binding to the first (nbd ) and second (nbd ) nucleotide binding sites of cftr are divalent cation independent and dependent, respectively (aleksandrov et al, j biol chem , - , ) . subsequent to the initial binding, either mg or mn drive rapid hydrolysis at the second site while promoting trapping of the nucleotide at the first site. this occlusion at the first site of functional wildtype cftr is somewhat similar to that which occurs when the catalytic glutamates in both of the hydrolytic sites of p-glycoprotein are mutated. this occluded state has been proposed to be the result of dimerization of the two nbds and represent a transient intermediate formed during atp hydrolysis (tombline and senior, j bioenerg biomembr , - , ) . to test the possible relevance of this interpretation to cftr, we have now characterized the process by which nbd occludes [ p]- n atp and [ p]- n adp. we have now found that only n atp and not n adp can be bound initially at nbd in the absence of mg. consistent with this mg requirement for the ndp binding, n adp or adp is able to compete for the n atp binding site only when the divalent ion is present. despite the lack of a requirement for mg for atp binding, retention of the nucleotide triphosphate at the binding site at °c was dependent on the cation. however, at reduced temperature ( °c), n atp remains locked in the binding pocket with virtually no reduction over a hour period even in the absence of mg. these apparently paradoxical temperature effects hint that different molecular events can contribute to the occlusion of nucleotide at nbd . that the occlusion process occurs exclusively at nbd and does not depend on its interaction with nbd , was shown by experiments in which identical behavior was exhibited by ∆nbd constructs of cftr. thus, nucleotide trapping by wild-type cftr, unlike that by mutant p-glycoprotein, is accomplished by events at a single domain (nbd ), rather than by dimerization of the two nbds. (supported by the nih and cff). cftr consists of five domains or regions, two regions that span the cell membrane (the tmds), two cytoplasmic nucleotide-binding domains (the nbds), and a regulatory (r) domain. the r domain is unique to cftr: without phosphorylation of this domain, the cftr chloride channel does not open. the tmds and the nbds of cftr are similar to those found in many atp-binding cassette proteins, the majority of which are transporters. the domains are fused in a single polypeptide chain, linked in the sequence: tmd , nbd , r domain, tmd , nbd . the first nbd is the site of the location of the mutation that is responsible for the development of cystic fibrosis in the majority of human patients (loss of phenylalanine ). although there is a structure for nbd , we are still lacking a structure for the entire cftr protein. we have employed electron microscopy to provide low-to medium-resolution structures for the complete cftr protein which was expressed in bhk cells and purified by affinity chromatography. using single particle analysis combined with site-specific labelling using . nm diameter ni-nta nanogold, we have identified the locations of nbd and the region around residue of the r-domain within the low resolution d structure. by a process of elimination, this has also allowed the identification of nbd and the region occupied by the two tmds. these low resolution studies have now enabled us to interpret medium resolution d structural data obtained for cftr. progress in obtaining two-dimensional arrays (crystals a single molecule thick) should allow higher resolution structural data to be obtained for the entire cftr protein -sufficient for the identification of the transmembrane alpha helices. these data should allow a much clearer picture of the transmembrane channel formed by cftr and will inform molecular modelling approaches aimed at the development of novel drugs for the treatment of cystic fibrosis. we explored the gating process by introducing cysteines along the entire lengths of various transmembrane domains and extra-cellular loops, and studying their ability to chemically modified. we study the changes in their reactivity in closed and open channel states to characterize the changes in transmembrane domain conformations during gating. using membrane impermeant mts-reagents, we have characterized the conformational changes in tm -ecl , ecl -tm , ecl -tm , and ecl -tm of cftr. our results suggest that atp binding induces modest changes in the transmembrane domains and extracellular loops. channel opening involves a rearrangement of the tm helices leading to decreased hydration of residues near the extracellular end. this conformational change is either a part of, or allosterically coupled to the gating mechanism. physiological role of nherf in the regulation of cftr raghuram, v.; yang, y.; yaemsiri, s. laboratory of kidney and electrolyte metabolism, nhlbi/nih, bethesda, md, usa in the apical membrane of epithelial cells, cftr seems to exist within a multiprotein complex, in which its activity is regulated by interactions with other proteins. the c-terminus of cftr contains a pdz-binding motif, which binds to several pdz domain-containing proteins, including members of na+/h+ exchanger regulatory factor (nherf) family, nherf /ebp , nherf /e karp, cap /nherf , nherf , and cal/pist/gopc. pdz domain proteins act as scaffolds to assemble signaling proteins to form signaling complexes. these signaling complexes are central to achieve specificity and efficiency of signal transduction. nherf and nherf have a c-terminal erm domain, which interacts with cytoskeleton-associated erm proteins. this interaction may anchor cftr to the actin-cytoskeleton and restrict its movement within the membrane. in addition, several functional roles have been proposed for cftr-pdz domain interactions, including as an adapter to promote efficient pka phosphorylation of cftr, apical targeting and recycling of cftr, regulation of single-channel activity, organization of β-adrenergic, and lysophosphatidic acid- receptor signaling complex, and trafficking of romk channels. our current understandings of the role of cftr-pdz interactions are mostly obtained from heterologous expression studies. very few studies have addressed the role of pdz domain proteins in native epithelial cells or in organ physiology. we have used rna interference techniques to produce a knockout or knockdown (kd) calu- cell lines using a lenti-viral vector for stable suppression. using four different shrnas, we have generated four stable nherf -kd cell lines with varying levels of nherf suppression. in these cells, nherf expression ranged from - % of calu- nt cells (control cells). in nherf -kd cells, steady-state cftr protein level was greatly reduced, whereas its apical localization was unaffected. we also found structural defects in the apical microvilli. in polarized nherf -kd epithelia, membrane-permeable camp analogs were unable to stimulate cftr mediated short-circuit currents. however, forskolin induced response was nearly normal despite reduced cftr expression. examinations of βadrenergic-, and adenosine-receptor signaling pathways suggest that nherf plays a unique role in organizing the adenosine receptor signaling pathway. abnormal retention of the df cftr mutated protein in lung epithelial cells underlies the pathology in a large proportion of individuals with cystic fibrosis. a drug discovery alliance between cfft and biofocus dpi was initiated with the aim to identify novel genes which upon shrna-mediated knockdown were able to efficiently restore df cftr activity. a high-throughput assay based on an yfp halide reporter was developed in a human cystic fibrosis bronchial epithelial cell line (cfbe o-), whereby the rate of halide influx directly correlated to df cftr activity. biofocus dpi's proprietary adenoviral shrna libraries totalling , viruses were screened in this functional assay and yielded hits. these hits were repropogated to generate new adenoviral stocks and rescreened at three concentrations on the yfp halide reporter assay. genes were eliminated due to potential cytotoxic effects, and hit calling was performed on the remaining hits. a total of duplicate hits were confirmed ( %). of the confirmed hits had more than one shrnas which targeted the respective gene. confirmed hits were stronger in restoring df cftr function than the most potent positive control: syntaxin- . in order to elucidate which of these hits induce halide influx via direct rescue and activation of df cftr, the yfp halide reporter assay was performed in the presence or absence of the cftrinh . these cftr dependent hits will move forward into subsequent validation experiments whereby hits will be categorised into potentiators and correctors. the final goal of this program is to prioritize targets for entry into drug discovery. restoring expression and/or function of mutated cftr provides a means to treat cystic fibrosis. biofocus dpi -a galapagos company -in collaboration with the cystic fibrosis foundation therapeutics (cfft) has established a drug target discovery project that will enable the selection of proteins that rescue mutated cftr. by screening biofocus dpi's proprietary adenoviral shrna libraries in a high-throughput primary functional assay for cftr activity in human cells, we have identified and confirmed hits out of , that entered the primary screen. to further validate these proteins as potential drug targets, we have set up a series of experiments and assays focused on the rescue of cftr expression and its maturation by knock-down of specific targets. ) in order to establish whether the knock-down of a specific target was able to promote df -cftr plasma membrane localization, we performed immunofluorescence stainings of df -cftr in a patient-derived human cell line carrying the df -cftr mutation (cfbe o-) grown in air-liquid interface culture. a transduction protocol to deliver shrna adenovirus to this polarized airway cell model system has been optimized and preliminary results showed increased levels of expression of df -cftr at the plasma membrane level upon knock-down of syntaxin- , our positive control. experiments performed at οc also demonstrated redistribution of df -cftr to the apical plasma membrane at low temperature. we will show the results of all the shrna hits in this assay. ) changes in the post-translational maturation levels of df -cftr upon knock-down of specific proteins were evaluated by determining the accumulation of band b and c by using a western blot approach. in this way, we can select targets able to promote post-translational maturation of df -cftr and/or its escape from er in the cfbe o-cell line. accumulation of band b and c indicates maturation of cftr and will be considered as a beneficial effect. preliminary results show increased accumulation of band b upon knock-down of specific targets and overexpression of wild-type cftr induces band c accumulation. experiments performed at οc also demonstrated increased band b expression. we will show the effect of all the shrna hits in this assay on band b and c expression. we believe that the results obtained by the combination of those two approaches will guide us in obtaining very strong drug targets for entry into a drug discovery phase. because gene therapy as a corrective measure for cf is possible in the foreseeable future, it is important to understand whether the global effects of gene introduction will have significant detrimental impact on cell function. to address this question, global gene mrna expression profiles were created with the affymetrix u a & b chip sets. wild type cftr (n= ), ∆f (n= ) and g d (n= ) were transfected in separate ib cell cultures using lipofectamine ™. control expression profiles were generated from untreated ib cells; one from this experimental set and five from previous control experiments. differential gene expression was determined by anova using a % false discovery rate threshold. genespring was used for data analysis and visualization. genego was used to determine which functional categories were over represented in the list and further assisted in interpretation of the results. rt-pcr was used to confirm differential expression of selected genes and examine the response in more detail. all transfected constructs produced very similar gene expression profiles quite distinct from the untransfected cells. probe sets representing uniquely named genes were significantly different between transfected and untransfected cells. cftr mrna expression in all forms was increased an average of -fold. transfection of ib - cells resulted in upregulation of a variety of genes involved in several basic processes: inflammation, protein folding and cytoskeleton framework regulation. genego canonical pathways with a significantly enriched number of genes from the data set involved glucocorticoid signaling and regulation, cytoskeleton remodeling and adhesion plus a variety of other signaling pathways including il , chemokines, g-protein and mapk cascades. cell processes overrepresented in the list were predominately associated with protein folding, inflammatory responses and cytoskeleton regulation. geneontology categories over represented in the list were regulation of signal transduction, receptor mediated endocytosis and protein folding. the proinflammatory interleukins il and il were upregulated . fold and fold respectively. the genes most upregulated, samd ( -fold) and oasl ( fold), are not well annotated. as controls, rt-pcr analysis of cells treated with either lipofectamine ™ alone or any form of cftr dna alone did not show upregulation of il , il , samd or oasl. in cells transfected with lipofectamine containing dna, upregulation of il (n= ), oasl (n= ) and samd (n= ) was confirmed by rt-pcr. oasl is known to interact with methyl cpg-binding protein , a dna transcription repressor acting at methylated promoter regions. thus it is possible that the global effects noted here leading to dramatic upregulation of two novel genes oasl and smad could be previously unrecognized consequences of gene therapies. cystic fibrosis (cf) is a disease which is caused by mutations of the cf gene, which codes for the cftr chloride channel. the ∆f -cftr mutation results in a mutant protein that undergoes transcription but fails to localize to the apical membrane, where it normally functions as a camp-regulated clchannel. however, clchannel activity can be detected at the plasma membrane when ∆f -cftr is overexpressed, synthesized at a reduced temperature, or in the presence of chemical chaperones. thus, strategies that facilitate the translocation of ∆f -cftr to the plasma membrane by increasing cftr transcription may be beneficial for the treat-ment of cf. previous studies performed using fluorescence halide efflux measurements and short-circuit current voltage clamp have shown that treatment with pparγ (peroxisome proliferator activated receptor gamma) agonists, such as pioglitazone and fll (fmoc-l-leucine), resulted in an increased biosynthesis and trafficking of ∆f -cftr to the cell surface. this effect was at least partially due to increased ∆f -cftr expression. further studies were designed to investigate the effect of pparγ agonists on cftr promoter activity. two firefly luciferase-conjugated cftr promoter plasmids, containing either . kb or . kb fragments, were transfected together with a control plasmid containing a renilla luciferase in human alveolar basal epithelial (a ) cells. the ratio of the firefly to renilla luminescence was used to measure cftr promoter activity. pparγ agonists increased cftr expression acting both on . kb and . kb promoter fragments. these results were confirmed in quantitative rt-pcr studies. transcription factor binding site analysis using current online programs and matrices showed three putative ppre (peroxisome proliferator response element) consensus sequences in the cftr promoter. the interaction of these sites with pparγ was shown using emsa (electrophoretic mobility shift assay). interestingly, none of these consensus sequences appear in the . kb construct, which still maintained a significant pparγ activation response. therefore, we hypothesized that a novel pparγ agonist effector site(s) is involved in transcription activation of cftr. to characterize this novel site(s), a series of deletion constructs to the promoter region were created, using mutation-introduced restriction sites in the original promoter construct. the new constructs ranged from . kb to base pairs upstream of the transcription start site. in preliminary studies we found that at least one previously uncharacterized pparγ effector site was present in the . kb promoter fragment that regulated cftr expression. additional experiments were performed using emsa to determine the proteins and cofactors which controlled the optimal conditions for cftr expression. the results of this study show that pparγ agonists, currently prescribed to treat hyperglycemia and improve peripheral insulin resistance, may also have additional benefits for the treatment of cf. our studies also show that pioglitazone and other pparγ agonists, by increasing cftr expression, are potent activators of clflux in epithelial cells expressing ∆f -cftr. this work was supported by grant from the canadian cystic fibrosis foundation decreased by µm gsno. the effect of gsno on hop expression was post-transcriptional. in cfbe o-cells transfected with sirna duplex specific for hop ( hr), hop expression was modestly inhibited; however, gsno dramatically augmented the inhibition. we next showed that knockdown of endogenous hop by sirna increased the steady-state levels of immature and mature forms of cftr. though overexpression of hop did not significantly affect cftr expression (immature and mature forms increased . ± . and . ± . fold respectively), in the presence of µm gsno, expression of both immature and mature cftr forms significantly increased in the hop overexpressing cells ( . ± . and . ± . fold respectively). next, we treated cfbe o-cells with a pulse of gsno ( µm; hr); isolated cytosol, er and golgi fractions; immunoprecipitated cftr from these fractions; and studied whether hop, co-immunoprecipitated with cftr, was s-nitrosylated (using a biotin substitution technique followed by streptavadin isolation). we found that sno-modified hop coimmunoprecipitated with ∆f cftr in the cytosol and er at baseline; and that gsno decreased the association between sno-modified hop and ∆f cftr. we speculate that the effect of gsno to decrease hop-cftr association may ) result from increased hop s-nitrosylation; and ) be permissive for ∆f cftr maturation. these data may be of relevance to the development of no donor-based therapies for cf. supported by cf foundation and the nih. mouse models for cystic fibrosis (cf) provide new possibilities to study disease pathogenesis, to correlate genotype and phenotype, and to test novel cf therapies. we use the cftr tm eu mice homozygous for the f del mutation in a congenic fvb background as a tool in pre-clinical testing of therapeutic strategies aimed at the correction of the f del folding and trafficking defect. these mice show characteristic cf ion transport abnormalities such as reduced camp-and cgmp activated intestinal chloride secretion and an increase of the amiloride-sensitive sodium absorption in nasal epithelium. we developed an ex vivo assay for the rescue studies of the f del trafficking defect in murine intestine by proteasome inhibitors based on periodical measurements of camp-activated transepithlial chloride currents in the ussing chamber. muscle-stripped ileum was incubated at c in william's e glutamax medium supplemented with insulin ( µg/ml) and dexamethasone ( µg/ml), in the presence of vehicle or proteasome inhibitor. a partial gain of chloride secretory function was achieved by incubating the tissue for - h at c in the presence of the proteasome inhibitors (pi) epoxomicin ( µm), mg ( µm), nip-(leu) -vinyl and adalys(bio)ahx l vs (both µm) and bortezomib ( nm). exposure of the tissue for h at c to alln ( µm) revealed a functional recovery up to wt levels. immunohistochemical and western blot analysis of all pitreated tissues showed the appearance of cftr positive crypt cells and mature band c cftr protein. rescue by alln remained detectable following inhibition of the er to golgi transport by brefeldin a. our ex vivo experiments demonstrate that proteasome inhibitors can enhance the amount of mature, functionally active murine f cftr mutant protein in intact tissue by preventing proteolytic degradation and increasing its expression at the cell surface. in vivo treatment of homozygous f del mice with bortezomib at a dose of . mg/kg/day for days resulted in a high morbidity. administration of a lower dose ( . mg/kg/day ) was well tolerated and no mortality or significant weight loss could be observed. as outcome parameters for the in vivo treatment with pis we used a salivary secretion assay and bioelectric measurements of intestinal and nasal epithelium in the ussing chamber. there was no difference in isoproterenol-induced salivary gland secretion or and in cftr-mediated intestinal chloride currents between control -and bortezomib-treated animals. however we found a reduction ( . fold) of the amiloride-sensitive short circuit current (isc) in the nasal epithelium of bortezomib-treated mice, indicating a moderate correction of the enacmediated sodium hyper absorption, that was not paralleled by a gain of the forskolin-mediated transepithelial chloride secretion. current in vivo experiments focus on the effects of pis upon short term ( h- h) rather than chronic treatment, to allow a direct comparison with the ex vivo treatment data. supported by grants from the cf foundation, bethesda, the sophia foundation and the dutch stomach-liver-intestine foundation. rotterdam, netherlands; . physiology and biophysics, university of alabama birmingham, birmingham, al, usa; . physiology, school of medical sciences, university of bristol, bristol, united kingdom recent progress in the development of small molecule correctors and potentiators capable of restoring cftr function have increased the need for pre-clinical test models including cultured airway epithelial cells from human cf patients as well as cf mouse models. the validity of cf mice as a surrogate for human cf patients depends on the assumption that human and mouse cftr, despite their limited sequence homology ( %) and differences in open probability (p o ) and channel subconductance state, behave similarly in their response to pharmacological correctors and potentiators. to verify this assumption, we used the iodide efflux technique to compare the cftr chloride channel activity in (i) cho cells stably transfected with mouse f del-cftr, (ii) nih- t cells stably expressing human f del-cftr, and (iii) their wt-counterparts. forskolin ( µm)-stimulated iodide efflux was very low in both mouse and human f del cftr cells ( . respectively % of wt values) and was stimulated to a similar extent ( . and . fold) by the cftr potentiator genistein ( µm). preincubation for h at c, or at c in the presence of the vertex corrector cfcor- ( µm) caused a - fold increase in forskolin-activated i-efflux in both cell types that was further enhanced by . - fold upon addition of genistein. functional correction was paralleled by the appearance of mature, complex-glycosylated mouse or human cftr on western blots. surprisingly, two other, structurally unrelated compounds known to correct the gating defect in hcftr, i.e. the vertex potentiator cfpot- ( µm) and the uncharged nppb analogue nppb-am ( µm; cf. wang w et al. ; j biol chem : ) mimicked the effect of genistein on hf del-cftr but failed to potentiate mf del-cftr in the t cells. both cfpot- and nppb-am likewise failed to potentiate forskolin-stimulated, cftr-mediated transepithelial chloride currents ex vivo in muscle-stripped ileal mucosa from homozygous f del-cftr tm eu mice (congenic fvb) mounted in ussing chambers under conditions in which genistein ( µm) enhanced the current response by - fold. in contrast, preincubation of the tissue in william's e glutamax medium for h at c, or for h at c in the presence of cfcor- ( µm) enhanced the forskolin+genisteininduced transepithelial clsecretion up to - % of the response in cftr+/+ littermates, and was associated with the appearance of band c on western blots. these results indicate that mouse and human f del-cftr ( ) respond to low temperature incubation or to a small molecule corrector with a similar gain in surface expression and function, supporting the use of cf mouse models for in vivo tests of cftr correctors; ( ) respond differently to various classes of cftr potentiators, in line with their pronounced differences in gating behaviour, and emphasizing the specificity of cftr-potentiator interaction. further studies focussing on human/mouse cftr chimera and aimed to identify the domain(s) accounting for the differential response to the cftr potentiators are in progress. cell apoptosis is a highly regulated process which is central to the maintenance of pulmonary vascular homeostasis. recent investigations implicated cftr in the regulation of intracellular sphingolipid levels. our laboratory demonstrated that an imbalance in endothelial sphingolipid levels triggers apoptotic cell death. we therefore hypothesized that a dysregulated cftr function in human lung endothelial cells inhibits programmed cell death in response to stress. methods: patch clamp analysis was used to verify the expression of cftr on human lung endothelial cells and the effect of specific inhibitors. we inhibited cftr with dpc, cftr inh - , and nppb or specific sirna followed by treatment with prototypical stressors that induce endothelial cell apoptosis, staurosporine, h o , or tnf-α. apoptosis was quantified by caspase- activity or annexin/ propidium iodide staining. lipid extraction was performed by a modified bligh and dyer method and intracellular sphingolipids were measured by tandem mass spectrometry. results: patch clamp analysis confirmed functional cftr expression on endothelial cells and a complete inhibitory effect of dpc and nppb but no effect of dids. as expected, treatment with staurosporine, a general protein kinase inhibitor and h o , as an oxidative stress stimulus resulted in significant endothelial cell apoptosis. similarly, tnf-α treatment ( ng/ml) in combination with cycloheximide caused activation of caspase- associated with a significant upregulation of the pro-apoptotic sphingolipid ceramide. knock-down with specific cftr sirna was validated with western blot and whole cell patch clamp analysis. dpc, nppb, and cftr inh - consistently and significantly inhibited apoptosis in human lung and primary mouse lung endothelial cells. caspase- activity was decreased by - % (% decrease in caspase units/µg/min) in hlmvec treated with h o after pretreatment with dpc ( %), cftr inh - ( %), and nppb ( %). however, we observed that dids, a non-specific chloride channel inhibitor also inhibited staurosporine induced caspase- activation ( %), suggesting the possible involvement of other chloride channels. in conclusion, our data suggest a role of cftr in modulating endothelial cell apoptosis in response to various stresses. the absence of functional cftr impaired stress-induced apoptosis, a process which may be mediated via alterations in sphingolipid trafficking. this abnormal cftr function in cf leading to aberrant cellular responses to stress may perpetuate an activated, pro-inflammatory phenotype of the lung vasculature. in turn, aberrant vascular activation may have a significant impact to the abnormal airway remodeling and persistence of a chronic inflammatory state characteristic of cf. supported by: cystic fibrosis foundation clinical fellowship training grant hegedus, t. , ; serohijos, a.w. , ; dokholyan, n.v. ; he, l. , ; riordan, j.r. , . department of biochemistry and biophysics, unc at chapel hill, chapel hill, nc, usa; . cystic fibrosis treatment and research center, unc at chapel hill, chapel hill, nc, usa; . department of physics and astronomy, unc at chapel hill, chapel hill, nc, usa cftr (cystic fibrosis transmembrane conductance regulator) is a camp dependent chloride channel. the phosphorylation of its amino acid r domain by protein kinase a (pka) is obligatory for channel gating under normal conditions. r domain contains multiple pka phosphorylation sites, which participate in activation, but no specific site is essential for channel function. in spite of numerous studies of the role of r domain in cftr regulation, the mechanism is largely unknown. one reason for this is the lack of information on r domain structure and its interactions with other parts of cftr. it has been shown that r domain lacks well-defined secondary structural elements and is intrinsically disordered. in this study, we used computational methods to explore the structure and function of the disordered r domain. our results show a specific disorder-order pattern in r domain, which is conserved among species even though the primary structure is not conserved. this result implies a role of the disorder-order pattern in r domain function and provides a basis of a novel working model. to gain some insight into the three dimensional structure of r domain, we per-formed ab initio folding of r-domain using discrete molecular dynamics with an all-atom force field. as disordered domains can not be characterized with a single structure, an ensemble was generated by selection of structures with the lowest energy from a large number of folding simulations. these structures were clustered to determine the dominant r domain conformations. they reveal features of secondary and tertiary structure, the positions of phosphorylation sites in d, and residue contacts within the r region that might be important for structure and function. to computationally confirm the mechanism proposed in our working model, an ensemble of phosphorylated r domain structures was also produced and characterized. supported by nih (r dk ), cff (dokhol i ), and novartis ( ). physiology system that utilises the planar patch clamp technique (finkel et al ) . this format utilises perforated patch clamp recording of wells in parallel, permitting the generation of up to data points per day. we have employed this system to develop assays to detect modulators of mutant cftr. human cftr-g d and df , over expressed in bhk and cho cells respectively, were cultured to approximately % confluence before harvesting. df cells were temperature corrected at °c for hours prior to experimentation to facilitate channel trafficking to the plasma membrane. cells were placed on the quattro system and whole cell chloride currents measured using asymmetric chloride selective solutions such that the chloride reversal potential was significantly different from that of leak currents ( mv). currents were assessed using a voltage ramp from - to + mv applied prior and min subsequent to compound addition. to validate the assays we used the prototypical cftr potentiator, genistein, which was added simultaneously to cells under study with µm forskolin. after assessing the effects of genistein, the specific cftr inhibitor glyh , was added at µm to confirm the currents were mediated via activation of cftr. the ec values determined for genistein were . ± . µm (mean ± s.e.m, n= ) for df and . ± . µm (mean ± s.e.m, n= ) for g d. these values agree with literature values (bulteau-pignoux et al ) . two alternative potentiators, phenylglycine- (pg- ) and vrt- were also tested in the presence of µm forskolin and were active against both df and g d. the ec values for pg- were . ± . µm (mean ± s.e.m, n= ) for df and . ± . µm (mean ± s.e.m, n= ) for g d. the ec values for vrt- were . ± . µm (mean ± s.d, n= ) for df and . µm (mean, n= ) for g d. these values agree with published data from ion transport studies (pedemonte et al ; van goor et al ) . in summary the ionworks quattro can be used to identify compounds which modulate the activity of cftr. this assay has a number of advantages over other formats in that it is direct, sensitive and employs voltage control of the cells under study. these assays can be used for primary screening of small to medium compound sets or as a secondary screen to triage the output from higher throughput indirect formats such as membrane potential. references it is very well agreed that ∆f cftr is recognized as a misfolded protein by the er quality control and targeted for degradation by the proteasome. during the course of experiments for aav gene therapy for cf we created an aav / vector expressing a truncated cftr insert (∆ ) driven by a chicken beta actin promoter (raav-cb-∆ -cftr). ∆ -cftr contains the normal coding sequence of wt cftr except that it is missing the first amino acids. we observed that cos cells transiently transfected with raav-cb-∆ cftr express cftr at significantly lower levels as compared to cells similarly transfected with a wt-cftr construct. to examine why, cells were transfected with raav-cb-∆ -cftr and treated for hours with µm of proteasome inhibitor, mg . in the cells treated with mg , ∆ -cftr protein expression was significantly increased. because lysosomal inhibitors did not have a significant effect, the data suggest that a large frac-tion of ∆ -cftr protein is degraded in the proteasome. to evaluate the rate of degradation, cells were treated with cycloheximide. time course experiments showed that ∆ is more rapidly degraded than ∆f -cftr. importantly, in cos cells cotransfected with ∆f and ∆ -cftr, there was a significant increase in the mature c-band of ∆f cftr compared to cells transfected with ∆f alone. this suggests that ∆ -cftr enhanced the maturation of ∆f from b to c bands. enhanced maturation of cftr from b band to c band also occurred when ∆ -cftr was transfected into hela cells stably expressing ∆ cftr (hela ∆ ) and cfbe o-cells stably expressing ∆ (cfbe o-∆ ). a number of proteins participate in the er to determine the fate of cftr. ∆f -cftr is known to associate with retrograde translocation protein complex on the er membrane containing vcp (valosin-containing protein) and derlin . vcp is also found in aggresomes containing ∆f -cftr in association with cytosolic histone deacetylase, hdac . we hypothesized that since ∆ is more efficiently degraded as compared to ∆f -cftr it may have higher affinity with vcp protein complex. we verified that ∆ -cftr interacts more readily with vcp and also has a higher degree of association with hdac as compared to ∆f -cftr. our data suggest that ∆ is more readily degraded by the proteasome as compared to ∆f -cftr and lacks biosynthetic arrest in the er. ∆ -cftr binds more readily to vcp and associates avidly with hdac , two outcomes that are expected to enhance proteasomal degradation. by engaging key quality control proteins, ∆ -cftr allows more ∆f -cftr to mature. our data suggest that truncated forms of cftr (∆ ) may be useful for cf gene therapy by affecting the maturation of endogenous cftr. ∆f , the most common disease causing cftr mutation, has impaired conformational maturation during its biosynthesis, and thus is unable to exit the endoplasmic reticulum (er). a well-defined di-acidic er exit code has been identified within the first nucleotide binding domain (nbd ) of wildtype cftr (jcb : - , ) , the disruption of which prevents cftr from efficiently exiting the er. this is consistent with the role of the diacidic code in the copii-mediated cargo concentration process. however, it is not known whether other types of er-to-golgi trafficking signals play a role in cftr trafficking in the early secretory pathway. even less is known about the trafficking signal(s) that are responsible for the rescue of ∆f cftr by a number of means. to achieve a better understanding of the trafficking signals dictating the export of cftr from the er, we constructed a series of cftr mutants to probe the potential functional targeting signals within both wild-type and ∆f cftr. it has been shown that nbd is not required for the export of wild-type cftr from the er. we further found that an internal deletion mutant lacking membrane spanning domain (msd ) and nbd -r but retaining the n-terminal cytoplasmic region, msd and nbd does not have sufficient signal to allow er export, suggesting that the signal(s) that are responsible for cftr export largely reside within the nbd -r. unlike ∆f cftr, the di-acidic code mutants are not temperature-sensitive. dissecting the di-acidic code revealed that both acidic residues contribute to er export, and that simultaneous substitution of both leads to a much decreased export of cftr. we found that the temperature-dependent export of ∆f relies on the presence of the di-acidic code within the nbd , suggesting that this code has a functional role in the temperature-dependent rescue of ∆f cftr. in our effort to further examine the role of the di-acidic code in the rescue of ∆f cftr by second site mutations, we found that ∆f cftr rescue by the simultaneous disruption of two of the arginine-framed tripeptides (afts) is also dependent upon the di-acidic code. surprisingly, we found that while nbd is not necessary for the export of wild-type cftr, it is required for the aft-mediated rescue of ∆f cftr, suggesting a role for cytoplasmic inter-domain interactions in the aft-mediated rescue of ∆f cftr. a detailed biochemical analysis of these mutants provides valuable insights into the roles of different cftr "trafficking" motifs in the er-to-golgi transport of cftr, the specific conformational defects of ∆f cftr and the potential molecular mechanism underlying the rescue of ∆f cftr. supported by cff. sonawane, n.d. ; zhao, d. ; galietta, l. ; zegarra-moran, o. ; verkman, a. . medicine, university of california san francisco, san francisco, ca, usa; . genetica molecolare, istituto gianina gaslini, genova, italy cftr inhibitors are predicted to prevent intestinal fluid secretion in enterotoxin-mediated secretory diarrheas such as cholera. cftr inhibitors that are not absorbed across the intestinal wall are attractive for diarrhea therapy because they may provide safe oral therapy. we previously discovered low affinity glycine hydrazide (glyh, ic ~ µm) cftr inhibitors that block cftr at its external pore (muanprasat et al., j. gen. physiol. ; : - ) . in order to increase inhibitor potency and prevent washout during severe secretory diarrhea, we synthesized a series of glycocalyx interactive cftr inhibitors containing a malonic acid hydrazide (malh) cftr pore blocking moiety linked to a lectin (sonawane et al., gastroenterology ; : - . lectin conjugation improved cftr inhibitory potency by ~ -fold (ic to nm). high-affinity cftr inhibition was abolished by malh-lectin heat denaturation, protease digestion, or competition by mannose or unconjugated lectin. fluorescently labeled malh-lectin remained membrane-bound for > hours after washout, whereas washout occurred in a few minutes without the lectin. malh-lectins blocked cholera toxin-induced intestinal fluid secretion in closed intestinal loops in mice with ec - pmol, and greatly reduced mortality in a suckling mouse model of cholera. we recently synthesized mono-and divalent cftr inhibitors consisting of malh coupled via a disulfonic stilbene linker to flexible mono and bifunctional polyethyleneglycols (pegs) of molecular size . , . , , , , , , and kda, with calculated solution lengths of - nm, with the larger size pegs potentially spanning cftr dimers or inducing their formation. ic for inhibition of cftr chloride current was - µm for monovalent malh-pegs, but substantially lower and size-dependent for divalent malh-pegs, decreasing from . µm to nm with increasing peg size. the mechanisms responsible for the improved and size-dependent potency of divalent malh-pegs were studied by whole cell, single-channel patch-clamp and by functional analysis of multivalent malh-conjugated dextrans and asymmetric divalent pegs. whole-cell experiments revealed reversible voltage-dependent block of cftr currents, with outward (positive) currents being more strongly blocked. in outside-out patch-clamp experiments, inhibitors caused a reduction of the mean open time. for malh-peg kda-malh ( µm) , the mean open time decreased from ± to ± ms. the effect on currentvoltage relationship and channel kinetics are consistent with a mechanism involving occlusion of the cftr pore from the extracellular side. luminally added divalent malh-pegs blocked by > % cholera toxin-induced fluid secretion in mouse intestinal loops with ic s of < pmol/loop, and greatly reduced mortality in a suckling mouse model of cholera. nonabsorbable, multivalent cftr inhibitor-macromolecule conjugates may be useful as anti-secretory agents in the treatment of enterotoxin-mediated diarrheas. supported by cff and nih. activation of the cystic fibrosis transmembrane conductance regulator (cftr) clchannel is primarily controlled by pka-dependent phosphory-lation of the r domain. once the r domain is phosphorylated, atp binding and enzymatic activity at two nucleotide-binding domains (nbds) open and close the cftr clchannel. we hypothesized that r domain phosphorylation regulates cftr activity by modulating atp interactions within two nbds. to test this hypothesis, we studied the activity of wild-type cftr and five variants with deletions of portions of the r domain between residues and . to alter atp-dependent channel gating, we tested three cftr stimulators, pyrophosphate (pp i , mm), 'deoxy-atp ( 'datp, mm) and caatp ( mm) . consistent with previous studies, pp i , 'datp and caatp all increased current of wild-type cftr about two-fold. each stimulator produced a similar increase in the r domain variants. the similar effects of stimulators on the channel activities of wild-type cftr and r domain variants suggest that the r domain does not have a major role in regulating atp-dependent channel gating. the r domain deletions did not alter the single-channel current amplitude of the r domain variants. however, r domain variants missing the sequence between residues and markedly reduced the open state probability, suggesting that this region is required for normal gating. these data suggest that the r domain does not control cftr activity by modulating atp interactions with nbd binding sites. instead, we speculate that the c-terminal part of r domain might participate in the channel-gating machinery downstream of atp regulation. supported by the cystic fibrosis foundation and howard hughes medical institute. haggie, p.m.; verkman, a. medicine and physiology, cvri, u.c.s.f., san francisco, ca, usa it was recently reported that phagolysosomes of alveolar macrophages from cf mice acidify in a cftr-dependent manner and that defective phagolysosomal acidification impairs bactericidal activity (di et al., nat. cell biol. , : - ) . these findings suggested a unifying hypothesis for cf disease progression: defective phagolysosomal acidification in cf macrophages permits the initiation and promotes progression of bacterial infection in the lungs. to reassess the central finding of that study we measured phagolysosomal ph using a fluorescent ph indicator containing oregon green® (pka ~ . ) and tetramethylrhodamine covalently bound to zymosan. phagolysosomal ph was insensitive to cftr inhibition ( µm cftrinh- ) in j macrophages (ph . ± . vs. . ± . ), alveolar macrophages from mouse lung (ph . ± . vs. . ± . ), and alveolar macrophages from human lung (ph . ± . vs. . ± . ). phagolysosomal ph in alveolar macrophages from ∆f cf mice was not significantly different from that in alveolar macrophages from wild-type mice (ph . ± . vs. . ± . ). to account for their finding of defective phagolysosomal acidification in alveolar macrophages, di et al. reported that lysosomal acidification was cftr-dependent and that fusion of lysosomes to phagosomes (at ~ min after phagocytic uptake) was responsible for phagosomal acidification. we measured lysosomal acidification in j macrophages using a dextran-conjugate containing oregon green® and tetramethylrhodamine and found that acidification was not impaired by cftr inhibition (ph . ± . vs. . ± . ) . we also measured the kinetics of phagosomal acidification using a zymosan-conjugate containing -(and- )-carboxyfluorescein (pka ~ . ) and tetramethylrhodamine. phagosomal acidification in j macrophages and murine alveolar macrophages began within min of phagocytosis and reached steady-state by - min, in agreement with prior data in murine peritoneal and bone marrow-derived macrophages. acidification kinetics in j macrophages was not altered by cftr inhibition, nor was acidification kinetics different in wild-type vs. cf alveolar macrophages. our findings do not support the conclusion that phagolysosomal acidification in alveolar macrophages is cftr-dependent, nor that it is impaired in cf. the mechanism of phagosomal acidification proposed by di et al. is not in accord with our data or precedents in the literature. because phagolysosomal acidification is central to the proposed mechanism linking defective cftr chloride channel function with cf lung disease, our results do not support the involvement of cftr in defective macrophage function in the pathogenesis of cf lung disease. supported by cff and nih. pared to that of wild-type cftr. the hsp family of molecular chaperones play important roles in the protein quality control process within the er. hsp atpase activity is regulated by multiple co-chaperones such as hsp , bag- and hspbp . hsp , a high-molecular-weight member of the hsp family was recently shown to display nucleotide exchange activity for hsp s in vitro. furthermore, hsp was identified as a component of a cftr-associated multiple protein complex using a global proteomic approach (cell : - , ) . in an attempt to explore the role of hsp in cftr conformational maturation in the er, we over-expressed the co-chaperone in hek cells and quantitatively analyzed its effect on the maturation and degradation of cftr. consistent with its role as a nucleotide exchange factor for hsp s, over-expression of hsp inhibits the er export of wild-type cftr and promotes its degradation. however, in striking contrast, over-expressing hsp stabilizes ∆f cftr and promotes its er export at reduced temperature. this effect is less pronounced at physiological temperature. the apparently opposite effects of hsp on wild-type and ∆f cftr maturation and quality control, suggests distinct conformational maturation pathways for the two cftr molecules, and reveals a specific role for hsp in regulating ∆f cftr refolding. such conclusion is reinforced by rnai experiments and further supported by quantitative co-immunoprecipitation. rnai-mediated down-regulation of hsp expression destabilizes ∆f cftr and reduces its export at reduced temperature, and hsp shows more extensive association with the er form of ∆f cftr than that of wild-type cftr. further analysis revealed that hsp not only modulates the chaperone activities of hsp s but also alters their steady state levels within the cell, creating secondary effects on cftr maturation and quality control. further studies are necessary to achieve a better understanding of the machinery, pathway and mechanism of ∆f cftr conformational maturation at reduced as well as physiological temperatures, and this in turn will provide critical insights and key factors that are of potential value to the rescue of the trafficking defect of ∆f cftr. farinha, c.m. , ; pissarra, l.s. ; amaral, m.d. , . department of chemistry and biochemistry, faculty of sciences, university of lisboa, lisboa, portugal; . ctr hum genet, nat inst health, lisboa, portugal the most frequent mutation in the cystic fibrosis (cf) gene, f del, causes retention of its protein product, f del-cf transmembrane conductance regulator (cftr) in the endoplasmic reticulum (er) as a core-glycosylated intermediate that is rapidly degraded. therefore, most f del-cftr fails to traffic to the plasma membrane, where wild-type (wt) cftr normally functions as a chloride (cl-) channel. retention, however, is not due to lack of function, since the mutant still retains some function if it reaches the membrane. instead, it results from misfolding which is recognized by the er quality control (erqc) in which many intervenients, including molecular chaperones, participate. identification of molecular partners involved in the disposal of f del-cftr to the proteasome is therefore crutial. it was recently shown that casein kinase ii (ck ), a pleiotropic constitutively active protein kinase involved in several processes, such as neoplasia, cell survival and viral infections, binds wt-cftr near the f residue, phosphorylating its first nucleotide binding domain (nbd ) at s [ ] . interestingly, deletion of f abrogates this interaction, which is the first described f del-dependent protein-protein interaction. our aim here was to identify whether ck interaction affects the early steps of cftr biogenesis, turnover and processing. to this end, novel bhk cells were produced which stably express wt-or f del-cftr in which the consensus residue s was substituted by either a neutral (alanine -s a) or an acidic residue (aspartate -s d). initial biochemical analyses of these cell lines revealed that: ) cftr proteins bearing d or a at position are processed; ) despite producing equivalent levels of cftr transcripts, s a expressing lines consistently show lower levels of cftr protein. metabolic labelling and pulse-chase experiments followed by cftr immunoprecipitation were also performed in these lines. after quantification of bands b (immature form) and c (mature form) of cftr, these preliminary results show that substitution of s (by a or d) does not affect the turnover or processing of either wt-or f del-cftr. the effect of ck inhibition on the turnover and processing of cftr was also studied, by incubating cells with µm of the ck inhibitor tetrabromobenzotriazole (tbb) for min. pulse-chase experiments under these conditions show that: ) the steady-state levels of both wt-and f del-cftr are reduced; ) the turnover of wt-cftr (but not of f del-cftr) is increased; and ) processing of wt-cftr is decreased. such data are consistent with a putative stabilizing role for ck upon wt-cftr [ ] . however, in our preliminary results this effect does not appear to be dependent on residue (nor on the putative charge added by the kinase on this residue), thus suggesting that this effect may be indirect. further studies are underway to identify the mechanism by which ck affects the turnover and processing of cftr. . treharne et al ( ) pissarra, l.s. ; xu, z. ; farinha, c.m. , ; sheppard, d.n. ; amaral, m.d. , . department of chemistry and biochemistry, faculty of sciences, university of lisboa, lisboa, portugal; . dep physiology, univ bristol, school med sciences, bristol, united kingdom; . ctr hum genet, nat inst health, lisboa, portugal g e and rk (the simultaneous mutation of four arginine-framed tripeptides (afts): r k, r k, r k and r k) are second site mutations that rescue the processing and function of f del-cftr [ , ] . these revertant mutations rescue f del-cftr from retention within the endoplasmic reticulum by distinct mechanisms: g e likely alters the conformation of the first nucleotide-binding domain (nbd ), whereas rk plausibly allows f del-cftr to escape er retention/retrieval mediated by afts [ ] . both g e and one of the afts (r k) lie close to the residue g , where a common cf-causing mutation g d occurs, generating a correctly localized clchannel with a severe gating defect. our aim here was to assess whether the revertants g e and rk influence the folding, processing and gating behaviour of the g d mutation, by employing biochemical and functional approaches. to test this idea, we introduced the g d mutation into cftr cdnas containing either g e or rk in the pnut vector and stably expressed these constructs in bhk cells. preliminary results from biochemical studies indicate that the mature fully-glycosylated form of cftr protein (band c) of both g e-g d-cftr and rk-g d-cftr were present at similar levels to those of g d-cftr. analysis of cftr-mediated iodide efflux from these cells revealed that g e is unable to rescue the functional defect of g d. however, rk generated an efflux of iodide larger than that elicited by cells expressing g d, albeit smaller than that of cells expressing wild-type (wt) cftr. consistent with these data neither rk nor g e rescued the defective channel gating of g d-cftr. however, both revertants caused a small increase in g d-cftr activity by attenuating the prolonged interburst interval of g d. we conclude that f del and g d disrupt cftr channel gating by distinct mechanisms. altogether, our data suggest that at least when in cis with the g d mutation, the afts (together or individually) might have a direct effect on cftr channel gating. this raises the possibility that rk, in addition to its well-described effect on trafficking, may act on cftr structure and/or folding, as previously suggested for r k [ ] . work supported by grant pocti/sau/mmo/ / and pluriannual funding of cigmh (fct, portugal) and the uk cf trust. l. pissarra was a recipient of bd/ / doctoral fellowship (fct, portugal) . [ ] carvalho ac, gansheroff lj, teem jl ( ) j biol chem , - . [ ] chang xb, cui l, hou yx, jensen tj, aleksandrov aa, mengos a, riordan jr ( ) mol cell , [ ] [ ] [ ] [ ] [ ] [ ] [ ] roxo-rosa m, xu z, schmidt a, neto m, cai z, soares cm, sheppard dn, amaral md ( ) proc natl acad sci usa , - . [ ] teem jl, carson mr, welsh mj ( ) improves ∆f -cftr intracellular trafficking in cf epithelial cells, although the mechanism by which this occurs is not clear. to identify gene products with atlered abundance in response to pba, we performed a differential display rt-pcr screen on rna isolated from ib - cf epithelial cells treated with pba for - hours. we isolated a cdna encoding stip- , a putative human stat- (signal transducer and activator of transcription- ) interacting protein and confirmed that pba causes transiently increased stip- mrna and protein abundance after hours of exposure. stip- was originally described as a scaffold protein that is required for ligand-dependent activation of stat- . stip- is also identical to elongator protein (elp- ), a subunit of the multicomponent elongator complex that stimulates rna polymerase ii activity. interestingly, recent data suggests that elongator may also regulate polarized secretion (rahl, et al. ( ) , mol. cell, : - ). we therefore hypothesized that stip- /elp- would regulate ∆f -cftr intracellular trafficking. in ib - cells, stip- /elp- associates with ∆f -cftr in coimmunoprecipitation experiments after pba treatment. in ib - cells overexpressing stip- /elp- , immunofluorescence experiments suggested that ∆f -cftr trafficked to the plasma membrane even in the absence of pba treatment. stip- /elp co-localized with markers of the golgi ( kda golgi protein) and exocytic vesicles (snap- ) when overexpressed in these cells. in contrast, overexpression of a deletion mutant of stip- /elp- lacking the wd domain, or stat- binding region, blocks the improvement of ∆f -cftr trafficking in response to pba in immunofluorescence and surface biotinylation experiments. this stip- /elp- deletion mutant did not co-localize with golgi or exocytic vesicle markers. furthermore, immunofluorescence experiments also suggested that pba causes colocalization of stip- /elp- and elp- , another member of the elongator complex that is often defective in familial dysautonomia. these data are consistent with stip- /elp- regulating ∆f -cftr intracellular trafficking in response to pba. this regulation may occur in the context of pba stimulating assembly of elongator, which in turn may promote trafficking of exocytic vesicles carrying ∆f -cftr to the plasma membrane. supported by grants from niddk. fold [ , ] . however, functional studies demonstrate significant differences in the gating behaviour of hcftr and mcftr [ ] . a powerful approach to investigate cftr structure and function is to examine interspecies differences and identify regions of conservation and divergence. to understand the structural basis for the functional differences between hcftr and mcftr, we generated hmcftr chimeras containing mcftr domains on an hcftr backbone. for this purpose, we replaced all or part of nbd , nbd or the rdomain of hcftr with the equivalent regions of mcftr and investigated their biochemical and functional properties. the in vivo folding of these hmcftr chimeric proteins was indirectly evaluated from their maturation status, after their stable expression in novel bhk cell lines. like wt-hcftr, most chimeric proteins were processed within the cell. however, two chimeras failed to mature: clone b (mnbd , amino acid (aa) residues - ) and clone c (mnbd , aa - ). we compared the murine sequence of these two chimeras with that of hcftr to determine the respective physico-chemical distances (pcds) of their aa changes. changes with higher pcd values were selected and in vitro mutagenesis performed to introduce these aa alterations into hcftr cdna. for clone b the selected changes were: e q, e q (pcd = ); s t (pcd = ); k q (pcd = ), i t (pcd = ) and k e (pcd = ). for clone c the changes were: p t (pcd = ), k q (pcd = ), y n (pcd = ), s k (pcd = ), c y (pcd = ), d g (pcd = ) and e d (pcd = ). biochemical analyses of these mutants stably expressed in bhk cells revealed that for clone b, e q, s t, k q and i t were processed, whereas k e was not. for clone c, p t, k q, y n, d g and e d were processed. iodide efflux showed that s t, k q, i t, e d and d g were functional, but not k e. we consider that with additional functional analyses, our approach will identify critical residues responsible for conformational changes and hence, functional differences between hcftr and mcftr. work supported by the bbsrc and grant pocti/mgi/ / (fct, portugal) and pluriannual funding of cigmh (fct, portugal) . ac dapaula is a recipient of phd fellowship sfrh/ bd/ / (fct, portugal we recently reported that the upr decreases endogenous wild-type (wt) cftr expression. as a follow up of these studies, we investigated the role of the folding deficient, ∆f cftr on upr induction and identified a mechanism by which the upr decreases cftr expression. for these studies, we developed a cell line expressing recombinant ∆f cftr on the endogenous wt background (calu- ∆f) and established individual clones with different ratios of endogenous (wt) to recombinant (∆f cftr) expression. two clones which express : (calu- ∆fc ) and : (calu- ∆fc ) ratios of wt to ∆f cftr and cfpac- cells expressing endogenous ∆f cftr were tested as models. the upr was constitutively active in calu- ∆fc cells only. in calu- ∆fc induction of ∆f cftr expression resulted in upr activation, indicating that high expression of ∆f cftr is required for upr induction. furthermore, following pharmacological induction of the upr, endogenous cftr mrna decreased to undetectable amounts both in calu- ∆f and cfpac- cells. the decrease in cftr mrna levels was not the result of shortened mrna half-life. in contrast, using a human cftr promoter driven reporter (pcftr-pluc), we demonstrate suppression of the cftr promoter when the upr is activated. considering that correction of ∆f cftr is the main therapeutic approach for cf, it is important that ∆f cftr expressed at low levels, such as in vivo, does not activate the upr. however, our results also reveal that ∆f cftr correctors have to be tested for upr activation, since transcriptional inhibition in this setting may contribute to inefficient rescue in native cells or in vivo. genistein, a naturally occurring tryrosine kinase inhibitor, at low concentrations ( µm) stimulates wt -cftr-mediated chloride secretion in a variety of cell and tissue types by an adenosine ', '-cyclic monophosphate (camp)-independent pathway. genistein has been shown to potentiate the channel function of ∆f -cftr and g d-cftr channels by prolonging channel open time (hwanget al., am j physiol cell physiol : c -c , ; illeck et al. am j physiol cell physiol : c -c , ) patch clamp studies have provided indirect evidence that genistein may bind directly to cftr and potentiate channel open probability by modifying the function of the nucleotide binding domains (weinreich et al., pflügers arch : - , ) . the goal of the present study was to determine whether genistein activated purified and reconstituted cftr protein as an initial step toward defining its molecular mechanism of action. the effect of genistein on purified and reconstituted wt-cftr was first studied following its reconstitution into planar lipid bilayers. in the presence of µm atp, phosphorylated cftr exhibited a low open probability (po= . ). the addition of µm genistein, caused a significant increase to the open probability of cftr (po= . ). using an electrogenic flux assay on a population of purified and phosphorylated cftr molecules, we determined that µm genistein caused a potentiation ( % increase) of chloride channel activity in the presence of µm atp. these results suggest that this macroscopic assay of purified cftr function is sufficiently sensitive to detect the effect of this potentiator. currently, the consequences of genistein on the channel activity and atpase activity of purified reconstituted ∆f -cftr and g d-cftr are being assessed. preliminary results suggest that in the presence of low atp concentrations ( - µm), µm genistein inhibits the atpase activity of ∆f -cftr, suggesting that it interacts directly with the nucleotide binding domains to alter their function. previous studies indicated an acute coordination between the activities of cystic fibrosis transmembrane conductance regulator (cftr) chloride channel and the amiloride sensitive epithelial sodium channel (enac) so that both these channels are either activated or deactivated in a synchronous fashion in the human sweat duct (reddy et.al, ) . however, the mechanisms responsible for such cooperativity between these ion channels are unknown. previous studies indicated that: cytoplasmic ph controls cftr activity through effects on phosphorylation (reddy et.al. ) . at ph . , cftr chloride conductance was reduced to ± ms/cm , but incresed to ± ms/cm at ph . (n=number of ducts= ). enac channel activity is also a function of cytosolic ph in heterologous expression systems (chalfant et.al, ) . the objective of this study was to test the hypothesis that the cytosolic ph may mediate the cooperative effects that occur between cftr and enac. we used basolaterally a-toxin permeabilized apical membrane preparations of native human sweat duct which expresses enac and cftr robustly as an experimental system. we showed that while luminal ph had no effect, changes in cytosolic ph acutely affected enac activity. that is, acidic ph inhibited, while basic ph activated enac activity. alkalinizing cytosolic ph from . to . increased enac conductance (genac) by ± . ms/cm (n= ). ph regulation of enac activity appears to be independent of cftr and endogenous kinase activities because basic ph stimulated enac: a.) after deactivating cftr by removing camp and atp in normal ducts, b.) in the absence of cftr in cf ducts, and c.) after blocking endogenous kinase activity with the non-specific kinase inhibitor, staurosporine. na + /h + exchanger (nhe) may mediate changes in cytosolic ph as a function of intracellular na + activity. nhe mrna is expressed in the sweat duct and cytosolic ph responds to changes in na + gradients across the basolateral membrane. conceivably, when transport conditions are favorable and intracellular na + is low, alkaline ph would allow enac and cftr to cooperatively admit na + and clthrough the apical membrane. when conditions are unfavorable and intracellular na + is excessive, acid ph would limit na + and clentry to protect the cell from disruptive changes in cell volume. thus, changes in cytosolic ph may play a crucial role in coordinating the activities of enac and cftr during transepithelial salt transport. acknowledgements: kirk taylor and sucharitha madireddi for expert technical assistance. funded by nih-ro de , nih-ro hl and the nancy olmsted trust. the cystic fibrosis transmembrane conductance regulator (cftr) is an anion channel that is normally expressed in the plasma membrane but is mislocalized in cf. to monitor trafficking we inserted super ecliptic phluorin, a ph-sensitive variant of green fluorescent protein (gfp) (miesenbock g, de angelis da, rothman je ( ) nature , - ) into the fourth extracellular loop of cftr. this construct, which we call cftr-phluor, has weak fluorescence intracellularly that increases ~ -fold when it is inserted into the plasma membrane and the phlour becomes exposed to more alkaline extracellular ph . thus cftr-phluor should be less fluorescent than cftr with the normal gfp fused to the n or c termini when situated in intracellular vesicles. despite the insertion of an entire gfp in the middle of the channel protein, cftr-phluor trafficked to the membrane and patch clamp studies revealed little change in unitary conductance or open probability compared to wild-type cftr. cftr-phluor enabled visualization of vesicle insertion events at the plasma membrane by total internal reflection fluorescence (tirf) microscopy. faintly fluorescent vesicles containing cftr were observed under the plasma membrane and eventually fusing with it to generate a burst of fluorescence. phluorin inserted at the same position in ∆f -cftr, the predominant mutant in cf, was retained in the er where the phluor remained partially quenched. when the folding defect was corrected by culturing cells at °c or treating them with known correctors, ∆f -phluor trafficking was partially restored and total cell fluorescence increased. this enabled a quantitative analysis of ∆f -cftr correction based on the increase in fluorescence in individual cells by flow cytometry. cftr-phluor may be most useful for microscope-based high-content screening studies of cftr and ∆f -cftr trafficking. support: the breathe program, canadian cf foundation, canadian institutes of health research and cf foundation therapeutics (usa). tukaye, d.n.; guggino, w.b. physiology, johns hopkins university, baltimore, md, usa type iii secretion system (t ss) toxins of p. aeruginosa are important virulence factors in p. aeruginosa infections. one of the t ss toxins, exos, has been shown to facilitate uptake and invasion of p. aeruginosa at airway surface epithelium. in mouse models of pseudomonas pneumonia, infection with p. aeruginosa exos+ strains caused increased levels of fluid in lungs as determined at autopsy in contrast to infection with p. aeruginosa exosstrains. the exact molecular mechanism underlying these observations is not known. exos is a bifunctional protein with gtpase activating protein (gap) activity at the n terminal domain and adp ribosyl transferase (adprt) activity at the c terminal domain. we found that exos-gap activity increases total cellular levels of mature (c band) wild type (wt) cftr in cfbe o-cells as measured by western blot analysis. this increase was mediated by decreased delivery of wt cftr for lysosomal degradation. in contrast, exos-gap failed to increase total levels of ∆ cftr (b band). interestingly, exos-gap increased total levels of ∆ cftr, bands c and b, following rescue with -phenylbutyrate. this indicates that targets of exos-gap exist in cftr trafficking beyond the er degradation pathway. exos-gap also brought about a corresponding increase in surface levels of mature wt cftr as measured by surface biotinylation. in conclusion, we have shown that p. aeruginosa t ss exos-gap, upregulates total and surface levels of mature wt cftr by modulating cftr trafficking beyond er, most likely by decreasing lysosomal degradation. the decrease in lysosomal degradation could be occurring in part by inactivation of small molecular weight g-proteins involved in delivery of wt cftr to lysosomes. increases in total and hence surface levels of cftr could in part explain increased amounts of fluids seen in p. aeruginosa pneumonia mouse model treated with exos+ strains. the post-maturational trafficking and localization of cftr is regulated by a wide variety of proteins. among the most prominent are several pdz domain proteins that bind to the c-terminal residues of cftr. in particular, two of these proteins, nherf and cal, have been shown to mediate opposing effects on the apical membrane levels of the disease-associated ∆f -cftr mutant, by controlling the balance between endocytic recycling and lysosomal degradation. in particular, whereas overexpression of nherf rescues ∆f -cftr at the cell surface, overexpression of cal has the opposite effect on cftr. cal-mediated downregulation of cftr requires a functional pdz binding site. we have now shown that suppression of endogenous cal cooperates with temperature rescue to stabilize functional ∆f -cftr channels at the apical membrane in polarized bronchial epithelial cells. this work supports the hypothesis that the cal pdz binding site is a therapeutic target for treatment of cystic fibrosis. a more direct test of this hypothesis will require competitive inhibitors that can efficiently block the cal:cftr interaction. in addition, given the large-number of protein-protein interactions formed by both the cal pdz domain and the cftr c-terminus, these inhibitors should ideally exhibit bidirectional selectivity, neither disrupting the favorable nherf :cftr interaction, nor strongly displacing other membrane proteins that interact with cal. using a fluorescence polarization assay and peptide-array technology, we have now identified a high-affinity, cal-selective peptide inhibitor. compared to cftr, this sequence binds cal more tightly, but nherf more weakly. furthermore, we have shown that the cal:cftr interaction is the weakest among the known cal-binding proteins, and that cftr should thus be susceptible to selective displacement from the cal binding site. finally, we have designed cell-permeable peptides that allow us to test the hypotheses (a) that such compounds will specifically disrupt the cal:cftr interaction and (b) that such targeted stereochemical inhibition will stabilize the functional cell-surface expression of ∆f -cftr in airway epithelial cells. the pathways for the endoplasmic reticulum associated protein degradation (erad) of misfolded proteins in the mammalian cells are incompletely understood. we investigated the role of molecular chaperones in erad for the cystic fibrosis transmembrane conductance regulator (cftr) and its common folding mutant, ∆f cftr. we found that hsp and its cochaperone hdj- interacted significantly with ∆f cftr and wt-cftr in airway epithelial cells. hsp interacted with the immature form of cftr while hdj- associated with both immature form and ubiquitylated cftr. structure-function studies showed that hdj- recognized ubiquitylated cftr via its zn-binding domain. immunoprecipitation and gst-fusion protein pulldown experiments revealed that hdj- interacted with ubiquitin. in steady-state, over-expression of hdj- elicited increasing both immature and mature forms of wt-cftr, but it resulted in decreasing immature form of ∆f cftr. pulse-chase studies showed that co-expression of hdj- promoted ∆f cftr degradation, reducing its half-life from to min. in contrast, hdj- expression did not significantly affect wt-cftr biogenesis. these data are consistent with our finding that hdj- shows a selective physical interaction with ∆f cftr, which translates into a functional discrimination between the mutant and its wt counterpart. the hpd motif within the j-domain of hdj- , which is necessary for the co-chaperone to bind hsp and stimulate its atpase activity, was required for hdj- mediated ∆f cftr degradation. mutation of the hpd motif retarded the degradation of ∆f cftr and increased the steady-state levels of ∆f cftr -fold. a role for hsp in hdj- mediated ∆f cftr degradation was tested in which hsp knockdown increased ∆f cftr expression - fold. hjd- regulates ∆f cftr maturation and knockdown of endogenous hdj- promoted ∆f cftr and its camp-dependent anion conductance in airway epithelial cells. in contrast, we were unable to detect maturation of ∆f cftr in hsp knockdown experiments, indicating that the maturation of ∆f cftr mediated by reduced hdj- expression may be independent of hsp function. taken together, our data demonstrate that hdj- is a molecular sensor that can detect differences in the folding related to the ∆f cftr maturation. these data also highlight a novel pathway for hdj- linked, ubiquitin-dependent degradation of ∆f cftr. reduction of hdj- expression or its association with ∆f cftr promotes maturation of this mutant and therefore represents a potential therapeutic approach for cystic fibrosis. [supported by nih and cf foundation] how the loss of cftr function results in cholesterol accumulation within the cell is currently unknown. cftr activation is driven by the camp and we propose that cf cells respond to the loss of cftr activity by increasing the camp pathway in order to increase cftr expression. to test this hypothesis, epithelial cells were treated with the phosphodiesterase- (pde ) and pde inhibitors milrinone and rolipram, respectively. inhibition of pde function with rolipram in wildtype cells leads to peri-nuclear free cholesterol accumulation identical to what is observed in cf epithelial cells as viewed by filipin staining, strongly implicating a camp-dependent pathway in the regulation of cholesterol trafficking. the pde -selective inhibitor milrinone had no effect on cholesterol trafficking suggesting specificity for the pde pathway. our preliminary data support this hypothesis in that both cf-model hteo-pcepr cells and mouse nasal epithelium (mne) from cftr -/-mice exhibit reduced protein expression of the campspecific phosphodiesterases pde compared to wt controls. the proposed consequence of a chronic amplification in camp signaling is altered cholesterol transport regulation. to address this potential role of pde in cholesterol trafficking, free cholesterol was visualized using filipin staining in wild type cells that were treated with rolipram, a pde -specific inhibitor. conversely, treatment of cf-model pcepr cells with the pka inhibitor rp-camps significantly improves cholesterol processing, further pointing to the involvement of the camp pathway. we propose that the camp pathway influences cholesterol processing through the regulation of β-arrestin- (βarr ) according to the premise that chronic increase in the camp pathway would initiate an elevation in βarr expression. βarr is an important regulator of adrenergic receptor recycling and organelle trafficking. because βarr is pivotal in regulating endocytotic recycling pathways, it could also impact cholesterol processing. this predicted increase in βarr protein expression is observed in both cf-model pcepr cells and cftr -/-mne compared to respective controls. over expression of βarr in wt epithelial cells leads to cf-like peri-nuclear cholesterol accumulation further implicating a role for βarr in the development of this phenotype. altered cholesterol trafficking in cftr would lead one to expect different βarr localization throughout the cell. further understanding of the implications of altered camp signaling and its relationship to aberrant cholesterol accumu-rationale: we recently reported that vcp (valosin containing protein) physically interacts with gp /amfr (autocrine motility factor receptor) to couple retrograde translocation of ∆f -cftr to proteasomal degradation (vij et al. jbc ) . recent studies have revealed an alternative system to the proteasome for degradation of polyubiquitinated misfolded proteins termed the aggresome. histone deacetylase- (hdac ) is a unique cytoplasmic deacetylase capable of interacting with ubiquitin and mediating the accumulation of ∆f -cftr in aggresome bodies. hypothesis: vcp competes with hdac to dissociate ∆f -cftr perinuclear aggregates. methods: ib - (∆f /w x) cf bronchial epithelial cells were transiently transfected with ∆f -cftr and vcp-gfp constructs and treated with a hdac inhibitor (tubacin), proteasome inhibitor (ps- or mg- ), lysosome inhibitor (baflomycin a ) or nil-tubacin (control) for , or hrs. the effect of these inhibitors on ∆f -cftr and vcp:∆f -cftr interactions were quantified by immunoprecipitating these protein complexes followed by immunoblotting with vcp, hdac or clathrin antibody. ∆f -cftr levels were measured by metabolic labeling using tran- s-label ( µci/ml) for a min pulse and hrs chase. the subsequent effects of these inhibitors on vcp localization was detected by fluorescence microscopy of gfp moiety. results: the co-immunoprecipitation experiments showed that hdac inhibition by µm tubacin ( hrs) promotes vcp:∆f -cftr and prevents hdac :∆f -cftr interaction. the proteasome inhibition (mg µm) resulted in maximal hdac :∆f -cftr at hrs with minimal at hrs while vcp:∆f -cftr increased overtime ( to hrs). adding tubacin ( µm; hrs) reversed the proteasomal inhibitor effects. in pulse-chase experiments, mg- increased the accumulation of cftr bform and poly-ubiquitinated-∆f -cftr as compared to the untreated control. tubacin suppressed the levels of mg- induced poly-ubiquinated-∆f -cftr as well as ∆f -cftr b-form. the vcp localization by microscopy showed the accumulation of vcp-gfp in perinuclear aggregates in the presence of proteasome inhibitor (ps- µm). the µm tubacin blocked these ps- induced perinuclear aggregates. we observed that vcp is associated with endocytic protein-complexes containing clathrin in the presence of ps- indicating cytosolic re-localization of vcp. we further confirmed the cytosolic re-localization of vcp-gfp in the presence of lysosome inhibitor (bafilomycin a µm) by fluorescent microscopy. conclusion: we found that a small molecule inhibitor of aggresome function prevents hdac :∆f -cftr interaction, promotes vcp:∆f -cftr interaction, and suppresses the accumulation of poly-ubiquinated-∆f -cftr. wang, y. ; jiang, y. ; zhu, n. ; feng, x. ; yang, h. , ; ma, t. , . membrane channel research laboratory, northeast normal university, changchun, china; . biopharmaceutical center, liaoning normal university, dalian, china deletion of the codon encoding the phenylalanine residue at position (∆f ) in the cystic fibrosis transmembrane conductance regulator (cftr) is the most common mutation causing cystic fibrosis (cf). the ∆f mutation results in a cftr protein with impaired folding, trafficking and gating in human and rodents. the consequences of ∆f -cftr mutation in other species have not been studied. the purpose of the present study was to characterize the ∆f mutant of porcine cftr in cell culture model. cdna sequence encoding full-length porcine cftr (pcftr) was cloned from the lung by rt-pcr using primers designed according to porcine genomic sequences in two bac clones (genbank accession no. ac and ac ) containing all exons of the porcine cftr. pcftr encodes a -amino-acid protein that shows . % identity to human cftr. the phenylalanine residue at position is conserved in pcftr. functional analysis of pcftr stably expressed in fisher rat thyroid (frt) epithelial cells by short-circuit current assays indicated a campactivated cl-channel similar to human cftr except that the sensitivity of pcftr to the specific cftr inhibitor cftrinh- is -fold lower than that of human cftr. a ∆f mutation of porcine cftr was generated by site-directed mutagenesis. surprisingly, ∆f -pcftr expressed as a func-tional chloride channel activated by forskolin in stably transfected frt cells. western blot analysis of cos and bhk cells transiently transfected with cmyc-tagged ∆f -pcftr indicated a protein pattern identical to that of wildtype pcftr. immunofluorescence analysis of the transiently transfected cells demonstrated similar plasma membrane expression pattern of ∆f -pcftr and wildtype pcftr. these results clearly demonstrated unimpaired cellular processing of ∆f -pcftr. however, the sensitivity of ∆f -pcftr to forskolin activation (ic ~ . µm) was dramatically lower than that of wildtype pcftr (ic ~ . µm), indicating a defect of channel gating by pka phosphorylation. the present study provided the first evidence that the ∆f mutation in mammalian cftr does not result in impaired cellular processing that is closely associated with cf phenotype. we have optimized airway epithelial cell spheroid cultures for functional measurements of cftr chloride conductance in order to screen smallmolecule activators and inhibitors. spheroids, which are sealed spheroidal monolayers of airway surface epithelial cells with diameter - micron, were generated within to days after nasal brushing and suspension culture. yields of up to spheroids were obtained from nasal brushing of a non-cf or cf subject. approximately , spheroids could be prepared from one million freshly isolated human bronchial epithelial cells. we compared several electrophysiological and fluorescence methods to assay cftr function in spheroids. whole-cell current was measured in single spheroids following pipette immobilization and micropipette puncture of the solutionexposed apical cell membrane. large, forskolin-stimulated whole-cell chloride currents were measured in non-cf spheroids. as an independent approach, transepithelial potential difference was measured by micropipette insertion into the spheroid lumen. for fluorescence detection, cell cytoplasm was stained with the halide indicators mqae or lzq. fluorescently stained spheroids were immobilized on a coated coverglass or in a custom microfluidic chamber. halide flux across the apical surface was measured in response to chloride-nitrate or iodide-chloride solution exchange, in the absence and presence of camp activators. the fluorescence assay is suitable for medium-throughput screening of ∆f correctors and potentiators, with definitive verification of cftr chloride channel function by whole-cell current analysis. an airway spheroid cultures provide a powerful approach to prioritize the efficacy of ∆f correctors because of their rapid generation without prolonged culture, and their suitability for quantitative analysis of cftr function. supported by cff and nih. background and aims: cftr has been shown to be expressed and functional in ventricular cardiomyocytes. however, to date, no physiological role for cftr in the heart has been established. the aim of this study was to determine if cftr plays a role in the regulation of cardiomyocyte contraction rate. methods: cardiomyocyte contraction rate was assessed using the neonatal mouse beating assay. ventricular myocytes were isolated from neonatal mice and cultured for - days until they formed a functional in sitium. contraction rates were captured by video imaging and analyzed by metamorph in the presence and absence of beta-adrenergic receptor stimulation by isoproteronol ( µm). assessment of cftr activity was determined by pharmacological inhibition by glibenclamide ( µm), dpc ( µm), and cftr inh- ( and µm). the role of k atp channels was assessed by -hd ( µm). results: baseline contraction rate of vehicletreated (dmso or h o) cardiomyocytes was unchanged. addition of isoproteronol caused a significant increase in contraction rate, which was sustained for at least minutes. in contrast, application of glibenclamide to beating ventricular myocytes significantly, but transiently, inhibited cardiomyocyte contraction rate, with recovery occurring within minutes. glibenclamide did not affect the initial increase in contraction rate caused by isoproteronol stimulation, but inhibited sustained increases in isoproteronol-stimulated contraction rate. to determine if this was an effect of k atp channel inhibition we examined the effect of -hd on contraction rate. in contrast to glibenclamide, -hd had no inhibitory affect on basal or isoproteronol-stimulated contraction rate, indicating glibenclamide's inhibitory effect was due to its inhibition of cftr. to further verify this, we examined the effect of two other cftr inhibitors, dpc and cftr inh- on ventricular cardiomyocyte contraction rate. both dpc and cftr inh- elicited similar responses as glibenclamide, with a quick, but transient inhibition of baseline contraction rate and inhibition of sustained isoproteronol-stimulated increases in cardiomyocyte beating. summary and conclusions: using neonatal murine ventricular myocyte cultures inhibition of cftr leads to a significant, but transient inhibition of baseline ventricular cardiomyocyte contraction rate. additionally, while inhibition of cftr did not affect initial increases in beta-adrenergic receptor-stimulated contraction rate, cftr inhibition did prevent sustained increases in contraction rate. the data suggest that cftr plays a role in modulating ventricular cardiomyocyte contraction rate during resting and adrenergic-stimulated conditions. drevillon, l. , ; tanguy, g. , ; hinzpeter, a. , ; arous, n. , ; goossens, m. , ; fanen, p. , . génétique, inserm u. , créteil, france; . faculté de médecine, université paris , créteil, france cystic fibrosis is mainly caused by mutations that interfere with the biosynthetic folding of the cftr protein. the aim of this study was to find cellular proteins capable of interacting with cftr and modifying its processing or its trafficking. we have used a genetic screen in yeast to identify such proteins and identified commd that preferentially interacted with the third cytoplasmic loop of cftr. commd is a regulator of copper transporter atp b in hepatocyte and sodium epithelial channel enac, but its exact biochemical function and physiological relevance remain elusive. here, we report that first, commd interacted with wild-type and f del-cftr in epithelial cells and second, commd subcellular distribution was not only both nuclear and cytoplasmic, but also in cytoplasmic vesicular compartments. we wondered if commd was involved in the processing and/or the trafficking of cftr protein in epithelial cells. we demonstrated that commd was not involved in cftr processing but that cell surface expression of wild-type cftr at the plasma membrane was cut by half when commd expression was % reduced by rna interference. we drew the conclusion that commd is a major component of cftr trafficking and/or recycling at the plasma membrane, precise characterization of commd in these vesicular compartments is under process to decipher its function in cftr trafficking. commd has been labelled as the prototype of a newly described protein family that plays a role in inhibiting nf-kappab signalling. moreover, subcellular distribution of commd was different in cf and non cf cells, nuclear form of commd being increased in f del cells compared to wild-type cells. thus, this opens up a new area of investigation about commd nuclear function. finally, these data indicate that commd is involved in multiple cellular processes of outstanding interest in cf pathophysiology. understanding how its modulation modifies transepithelial transport and inflammation in cf versus non cf cells should give new therapeutic clues to reduce exaggerated inflammation and improve fluid secretion in cf patients. supported ; fanen, p. ; galietta, l.j. . lab. of molecular genetics, istituto giannina gaslini, genova, italy; . inserm u. , creteil, france class iii cystic fibrosis mutations cause reduced cltransport by impairing the process of cftr channel opening. typical class iii mutations include g d, g d, and f del, all of them affecting nucleotide binding domains. it has been reported that mutations residing in other regions of the cftr protein may also reduce channel activity. we investigated the extent of loss of function caused by such mutations, in particular by missense mutations localized in cftr intracellular loops, and the sensitivity to pharmacological stimulation with cftr potentiators. to determine cftr activity, plasmids carrying the coding sequence for wild type or mutant cftr were co-transfected in cos- cells together with the halide-sensitive yellow fluorescent protein yfp-h q/i l. the rate of cftr-dependent anion transport was measured after short-term stimulation with forskolin alone or in combination with potentiators (felodipine, phenylglycine pg- , or sulfonamide sf- ). processing of cftr protein was assessed by examining glycosylation status of cftr by immunoprecipitation experiments. when stimulated with forskolin alone, cftr mutants showed the following anion transport compared to the wild type protein: i t ( %), i v ( %), q k ( %), e k ( %), g r ( %), d h ( %). interestingly, all mutants having a reduced anion transport responded to stimulation with potentiators pg- , sf- , and felodipine ( µm) with an increase in anion transport that approached the level of normal cftr protein. the correction of defective cftr activity by potentiators was confirmed in frt cells expressing e k and d h mutants using short-circuit current measurements. our results indicate that some missense cf mutations, like e k and g r, really cause a severe reduction in cftr activity. others, like d h, cause only a partial loss of function which may explain their association with a milder form of the disease. conversely, some other amino acid changes (with the extreme example of i v that seems to cause a gain of function) do not impair cftr activity and therefore may represent polymorphisms and not cf-causing mutations. interestingly, all mutants having a mild or more severe anion transport defect were sensitive to potentiators. this finding indicates that cftr potentiators have a wide efficacy on many class iii mutants and therefore may represent a promising therapeutic strategy for a significant number of cf patients. supported by cfft and telethon-italy. cftr, a cl-channel membrane protein, is a member of the atp-binding cassette (abc) super-family. mutations in cftr result in a misfolded protein which fails to mature, leading to impaired flow of cl-ions across the membrane of the epithelial cells lining the airway, and to cf. the most common mutation leading to cf is df . currently available structural information relevant to cftr modeling includes low resolution structures of cftr ( Å) and p-gp ( Å) and high resolution structures of other abc transporters as well as nucleotide binding domains (nbd) . of particular relevance is the newly published structure of the bacterial multidrug abc transporter, sav , whose topology can serve as a starting point for cftr modeling. as a first step towards the development of cf therapeutics, epix has undertaken the modeling of the d structure of cftr (excluding the r domain) in its conducting (i.e., open-channel, nbd-dimer) state, using our proprietary membrane-protein modeling technology (predicttm) in combination with other modeling tools. to date, we have modeled the cytosolic part of the receptor, namely the nbds:icls construct and work is ongoing on modeling the transmembrane (msd :msd ) region. the now available partial model has been scanned for putative binding sites for df -cftr correctors/potentiators. several potential sites have been located, and epix has initiated its in silico screening technology in order to identify potential drug candidates. this work is supported by the cfft. the deletion of a phenylalanine residue at position (f del) in the first nucleotide-binding domain (nbd ) of cftr is the principal cause of cystic fibrosis (cf). the altered interaction of f del cftr with endoplasmic reticulum (er) quality control proteins, primarily chaperones, promotes its proteasomal degradation. however, it is believed that crucial cftr-interacting proteins (cips) remain unknown [ ] . moreover, there is little information currently available on the strength of cip-cftr interactions. our goals here are two-fold: ) to quantify cftr-cip interactions; and ) to isolate and characterise unidentified cips. to address our first goal, we used surface plasmon resonance (spr; biacore tm ) to quantify real-time binding of hsc (a well-known cip) to bacterially expressed wt-and f del-nbd . hsc /hsp was covalently immobilised onto the surface of carboxymethyl dextran (cm ) sensor chips ( µm) and the real-time binding of purified nbd and control proteins quantified. in control experiments, anti-hsc antibody b ( nm; against residues - ) bound specifically to immobilised hsc with high affinity (k d , . ± . nm; n = ) whereas bovine serum albumin ( µm) did not interact (n = ). given the difficulties associated with expression of hnbd carrying the f del mutation [ ] it was not used in our spr analyses. instead, we used purified murine (m) nbd to quantify the impact of f del on the strength of the hsc -nbd binding. in the presence of low concentrations of atp (≤ um), the affinity of nbd binding to immobilised hsc was strengthened when f was deleted (wt, k d app , . ± . µm; f del, k d app , . ± . µm; n = ; p < . ). interestingly, raising the concentration of mgatp weakened the binding of nbd ( . µm) to hsc (wt, k i , µm atp; n = ). furthermore, deletion of f dramatically increased the concentration of mgatp required to destabilise the nbd -hsc interaction (f del, k i , µm atp; n = ). in summary, we used spr to demonstrate that: (i) nbd of cftr binds specifically to hsc , and (ii) the f del mutation enhances the association of nbd with hsc . we are presently investigating the effect of co-chaperones and small molecules on the interaction of hsc/hsp with wt-and f del-nbd . to identify novel cips, purified nbd was immobilised onto metalaffinity resin and used to capture cips from epithelial cell lysates. by this approach, cips were captured from human respiratory cell (calu- ) lysates and analysed by d-electrophoresis. relevant protein spots so far identified by mass spectrometry include: ) raichu x (thr/ser kinase); ) profilin isoform b; ) annexin a ; ) ifapsoriasin (intermediate filament-associated ca + regulatory protein); ) mgc (member of the er reticulon family). current analyses are underway to determine their functional roles in cftr trafficking and function. [ ] amaral ( billet, a. ; melin, p. ; norez, c. ; bilan, f. ; vandebrouck, c. ; mettey, y. ; becq, f. . physiologie, cnrs umr , poitiers, france; . gmas umr , poitiers, france; . faculté medecine et pharmacie, poitiers, france in order to gain a better insight into the structure-activity relationship (sar) of cftr protein, we have functionally characterized a cystic fibrosis mutation: the cftr-g d, identified in patients with oligospermia (vankeerberghen et al., ) . we examined cftr chloride channel activity by patch-clamp analysis, in whole cell configuration, using cos- cells transiently transfected with gfp-cftr-wt or with the mutant gfp-cftr-g d. cftr channels were activated by µm forskolin (fsk), and, after stable activation µm cftrinh- was added. as gfp-cftr-wt, g d chloride channels elicit a time and voltage independent current in presence of µm fsk. gfp-cftr-g d current density at + mv ( . ± . pa/pf) is . fold less than gfp-cftr-wt current density at + mv ( . ± . pa/pf). g d mediated currents are blocked by µm of the specific cftr-inhibitor, cftrinh- (ma et al., ) . as expected, gfp-cftr-wt channels are stimulated by µm of the potent activator -butyl- -hydroxy- -chlorobenzo[c]quinolizinium chloride (mpb- , derand et al., ) with a current density at + mv of . ± . pa/pf. interestingly, no activation of g d channels is recorded in presence of mpb- : difference between currents recorded in basal condition or in presence of mpb- is not significant. using iodide efflux experiments, we showed that cftr-g d mutant does not respond to several benzo[c]quinolizinium derivatives. however, the mutant channel can be activated by forskolin, ibmx and genistein. thus, the mechanisms of activation by xanthine and isoflavone are not affected by the mutation. these results show that: ( ) cftr-g d channels are functional: activation by camp pathway, inhibition by cftrinh- . ( ) camp chloride currents elicited by cftr-g d protein are weaker than cftr-wt. ( ) cftr-g d channels are refractory to benzo[c]quinolizinium activation. the replacement of the glycine by a negative charged amino acid in position affects cftr chloride channel activity and prevents activation by benzo [c] quinolizinium. this amino acid g , localized in the interface of nbd and r domain between two β sheets (callebaut et al., ) seems to have a crucial role in pharmacological activation of cftr by mpbs. further experiments will be performed to evaluate the role of the charge and of the nature of the amino acid at position in cftr protein. supported by vaincre la mucoviscidose and cnrs. cysteine string protein (csp) is a j-domain containing protein that regulates the extent of wild type cftr maturation. over-expression of csp blocks the formation of mature, glycosylated (band c) cftr and increases the level of immature (band b) cftr, whereas knockdown of csp elicits a marked increase in cftr maturation (zhang et al., j. biol. chem. : , ) . thus, csp appears to block the exit of cftr from the er. when the er exit of cftr is blocked by a different mechanism, i.e. the expression of mutant sar -gtp (sar h g interferes with the formation of copii vesicles), the steady-state level of immature cftr is two-fold greater than that resulting from csp over-expression. this finding suggests that csp, in addition to blocking er exit of cftr, may facilitate the degradation of the immature protein. in agreement with this concept, csp expression increased cftr ubiquitylation. a mutation within the conserved hpd motif of the j-domain (h q) disrupts the ability of csp to interact with and stimulate the atpase activity of hsp . csp h q does not block cftr maturation (above ref); in addition, the level of immature cftr was ~ % higher when h q csp was over-expressed than the level observed with mutant sar . this finding suggests that the pro-degradative effect of csp on immature cftr requires hsp binding/activation. chip (carboxy terminus of hsp -interacting protein) is an e ubiquitin protein ligase that can target wt and ∆f cftr for proteasome-mediated degradation (meacham et al., nature cell biol. : , ) . we sought to determine weather chip was involved in the csp-mediated degradation of cftr. indeed, co-immunoprecipitation (co-ip) experiments showed that chip associated with csp. also, csp h q, which has reduced interaction with hsp , showed a similar level of chip interaction by co-ip, suggesting that their association did not depend on hsp as a linker between the two proteins. a csp mutant that is truncated after the cysteine string domain, which is its site of membrane attachment, blocked cftr maturation as did wt csp; however, this mutant did not decrease cftr band b levels like wt csp did. in addition, the csp mutant missing its cterminus did not associate with chip. these findings further implicate chip in the csp-mediated degradation of immature cftr, and they suggest that the c-terminus of csp is a chip binding domain. when a dominant-negative mutant of chip, which lacks the u-box needed for chip-mediated ubiquitylation (chip∆ub), was co-expressed with cftr, csp was no longer able to facilitate the degradation of cftr in the er. these data show that it is possible to separate the effect of csp on cftr maturation from its ability to mediate the degradation of immature cftr. thus, csp blocks the exit of cftr from the er, and this requires a j-domain mediated activation of hsp but not the csp c-terminus. the action of csp on cftr degradation requires both a functional j-domain and the csp c-terminus, and this may require a trimeric complex involving csp, hsp and chip. [ the cystic fibrosis transmembrane conductance regulator (cftr) represents the main clchannel in the apical membrane of epithelial cells for camp-dependent clsecretion. mutations of this channel causes cystic fibrosis disease ; thus discovery of pharmacological activators of cftr is crucial to design future medicament for protein therapy. recently, we reported on the synthesis and screening of a small library of -phenylpyrrolo [ , b] pyrazines (named rp derivatives) evaluated as activators of wild-type cftr, g d-cftr and f del-cftr clchannels (noël et al, ) . this preliminary structure-activity relationship study identified -hydroxyphenyl and -n-butyl as determinants required for activation of cftr (rp- and rp- ). here we studied structure-function relationship of more than compounds prepared by chemical synthesis, and the subsequent activation of cftr channels. within the -phenylpyrrolo [ , -b] pyrazines family, we observed by iodide efflux technique that rp- bearing a hydroxyphenyl substituant is more potent (ec = nm) than rp- having -hydroxyphenyl substituant (ec = nm). by whole-cell patch clamp recording analysis, we confirmed that nanomolar concentrations of rp- activate linear chloride current in cho cells stably transfected with human wild-type cftr. this current was inhibited by µm of cftr inh - . we also found significant stimulation of short circuit current (i sc ) by rp- (ec = nm) on colon of cftr +/+ but not of cftr -/mice mounted in ussing chamber. stimulation of i sc by rp derivatives was inhibited by glibenclamide. the structural analogue , was less potent (ec = nm). as for rp- compound, we found that the -nbutyl chain is crucial for rp- and rp- activity, and that the -hydroxyphenyl compounds without -n-butyl chain are unactive on cftr. in this study, we showed that the presence of an hydroxyl group at position , or of the pyrrolopyrazine cycle determined the highest activity on cftr. the most potent compound is the -n-butyl- -( -hydroxyphenyl) hpyrrolo [ , b] pyrazine . the potency of these agents indicates that compounds in this class may be of therapeutic benefit in cftr-related diseases, including cystic fibrosis. the most common mutation causing cystic fibrosis (cf) is the deletion of f in the cftr gene, which results in inefficient trafficking of the cftr protein from the endoplasmic reticulum to the plasma membrane. the surface expression of the cftr is usually quantified biochemically with western blot or functionally with electrophysiological assays. however, these methods are labor intensive. we explore using fluorescence-based techniques for monitoring cftr surface expression. wild-type cftr was tagged at the amino terminus with green fluorescent polypeptides (gfp-cftr). the gfp-cftr was either transiently or stably expressed in chinese hamster ovary (cho) cells. the cells were then treated with a red fluorophore that specifically labels plasma membranes. the fluorescent images were acquired with an olympus laser scanning confocal microscope. two image channels were taken simultaneously. the green channel was excited with a nm laser, and signals within - nm were collected. the red channel was excited with a nm laser, and signals within - nm were collected. for a single focal plane, each image was composed of * pixels. threshold values were given to both green and red channels. pixels with an intensity value above the threshold were marked as green/red pixels. the green pixels in the first channel represent the signal of gfp-cftr, and the red pixels in the second channel represent the location of the plasma membrane. thus, pixels that are both green in the first channel and red in the second channel are the cftr surface expression, and denoted as yellow pixels. the percentage of successfully trafficked cftr is thus quantitatively estimated by the ratio of yellow to green pixels in the single plane. alternatively, a stack of images from the same cell at different depth was collected and analyzed. the total amount and surface portion of cftr expression are then determined by summing the correspondent pixels. the percentage of cftr surface expression was then calculated and will be verified both biochemically and functionally. the approach is modified to study deltaf cftr trafficking. we anticipate that the method can be used to screen cftr correctors from a small or intermediate sized chemical database. supported by cfft and nih. the most common mutation of the cystic fibrosis transmembrane conductance regulator (cftr) gene (deletion of phe- (∆f ) in the first nucleotide binding domain (nbd )) causes retention of the ∆f protein in the endoplasmic reticulum (er). ∆f mutation prevents conformational maturation of cftr protein without altering profoundly the local structure of nbd , but possibly by disrupting the interaction between nbd and nbd . however, the individual role of nbd and nbd in biogenesis, folding, maturation and membrane stability of a full length cftr is still under debate. using splicing by overlap extension method (soe by pcr), we generated six recombinant cftr proteins with inverted or suppressed nbds. the native boundary domains of nbd and nbd were respected for all mutants (riordan j.r. et al. ) and their c-terminal tails preserved. the constructs were transiently or stably expressed in cos- and bhk cells respectively. immmunodetection and immunolocalization assays confirmed that deletion of nbd domain (n -cftr) did not alter the trafficking or the plasma membrane expression of cftr. both processes were abolished in the presence of ∆f mutation. however, using whole cell patch-clamp configuration, we did not detect any camp-stimulated clcurrent. pulse-chase experiments established that the turnover of n -cftr is - fold faster (t / ~ h) than its wild type counterpart (t / ~ h). when we replaced nbd with nbd ( n -cftr), we could detect a faint plasma membrane expression associated with a weak cl-channel activation. more surprisingly, the t / of n -cftr coreglycosylated form was around h. when nbd was deleted (n -cftr) or substituted with nbd domain ( n -cftr), the expression and functional pattern were similar to cftr ∆f . furthermore, we showed that the n -cftr folding was not attenuated as demonstrated by protease susceptibility and sdsresistant thermoaggregation tendency, supporting the notion that n -cftr membrane stability requires nbd -nbd interaction. altogether, our results suggest that nbd domain is essential to form a foldable cftr that satisfies er quality control (erqc) but correct inter-domain assembly is mandatory for its stability at plasma membrane. the results are also in agreement with previous suggestion that ∆f mutation alters the interactions between nbds and transmembrane domains of cftr. supported . inserm u , inserm, paris, france; . inserm u , inserm, paris, france; . inserm u , inserm, paris, france; . inserm u , inserm, paris, france; . inserm u , inserm, paris, france; . inserm u , inserm, paris, france; . inserm , inserm, paris, france; . inserm u , inserm, paris, france the physiological role of cftr in renal epithelium is not known. in the proximal tubule, cftr co-localizes with the sodium-phosphate cotransporter npt a, a protein involved in phosphate (pi) reabsorption. the aim of our work is to determine if there is a functional interaction between cftr and npt a. to this end, the arnm coding for cftr and the arn coding for npt a (bearing a myc tag in c-ter) were injected in xenopus laevis oocytes. electrophysiological or biochemical experiments were performed days after arns injection. currents induced by mm pi (ipi) were measured in voltage-clamped (- mv) oocytes that expressed npt a alone, or in oocytes co-expressing cftr + npt a. for immunoprecipitation experiments, - cftrab and myc ab were used. results ipi was significantly reduced in oocytes expressing cftr + npt a compared to that measured in oocytes expressing npt a alone. using a two-bath electrodes configuration during voltage-clamping did not change this observation. this result suggests that when expressed in oocytes, cftr is in functional interaction with npt a. kinetic analysis (ipi as a function of pi concentration) of npt a showed a reduction in vmax but not in phosphate km. this suggests that npt a membrane expression and/or activity is altered when cftr is co-expressed. co-immunoprecipitation experiments performed on protein lysate derived from oocytes co-expressing cftr and npt a suggested an interaction between the transporters. using a pka activating cocktail as a pkc activator induced cftr-mediated currents in cftr+npt a expressing oocytes. in these oocytes, ipi is decreased by pkc activation (as expected from npt a regulation) but is increased shortly after exposure to the pka activating cocktail. the increase of ipi observed under this condition is at variance to that expected from classical npt a regulation. in oocytes expressing npt a alone, both pka activation and pkc activation reduced ipi. these observations suggest that in oocytes, cftr expression modifies npt a regulation. our study suggests that, after expression in xenopus laevis oocytes, cftr interacts functionally with npt a, and modifies its regulation. an interaction is also suggested by the co-immunoprecipitation of cftr and npt a. these results cannot discriminate between a direct or an indirect (via a third protein) interaction. to determine if an intracellular chloride concentration change may participate to the functional interaction, we are now measuring in cftr+npt a expressing oocytes intracellular chloride activity (using chloride-sensitive microelectrodes) during the use of the pka activating cocktail, and measuring ipi when pka is stimulated in the presence of a specific cftr inhibitor. cystic fibrosis (cf), the most commonly inherited lethal pulmonary disorder in caucasians, is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (cftr). to date, more than mutations were identified in cftr and were associated with clinical disease. a phenylalanine deletion at position accounts for % of cf genotypes in caucasian populations, and determines cftr misfolding and degradation by proteasome. consequently, limited cftr abundance leads to multiorgan disease, affecting the lung, pancreas, gut, liver, sweat glands and the reproductive organs. the past several years have witnessed an explosion of information regarding the identification and elucidation of molecules and pathways that are regulated by cftr or that regulate cftr activity. genomics and proteomics technologies now offer the opportunity to examine global alterations in the mrna and protein expression patterns of cf cells and tissues to elucidate the pathways linking defective cftr to clinical disease. here we describe systems biology methods that integrate heterogeneous datasets, including protein-protein interaction networks, gene expression and mass-spectrometry profiles, and mutation and genetic variation information, in order to identify the regulatory circuits and active subnetworks that are responsible for the progression and the severity of cf disease. the study will focus on correlations that define the key events in the cftr folding and trafficking pathways that lead to pathogenesis and dysfunctions, and could provide insights and targets for intervention and therapy. the number of cftr cl-channels in the plasma membrane, and thus the transepithelial cl-secretion is controlled, in part, by the endocytic trafficking of cftr. rab gtpases regulate the endocytic trafficking by acting as molecular switches that cycle between the gdp-bound (i.e. inactive) and the gtp-bound (i.e. active) state, associate with target membranes, and recruit downstream effectors. rab facilitates cftr endocytosis and rab a facilitates the recycling of internalized cftr to the plasma membrane. furthermore, rab and rab facilitate cftr trafficking to the lysosome. the mechanism of sorting internalized cftr for either recycling to the plasma membrane or degradation in the lysosome is not well understood. recent evidence demonstrates that protein sorting occurs in rab specific sorting endosomes. presence of cftr in rab compartment has been previously demonstrated in human airway epithelial cells by electron microscopy. yet, the role of rab in cftr trafficking has not been determined in these cells. rab did not control cftr trafficking in fibroblasts (bhk cells). however, it negatively regulated the plasma membrane expression of cftr in the colorectal cells . the goal of this study was to elucidate the role of rab in the endocytic trafficking of cftr in polarized human airway epithelial cells (calu- cells and cfbe o-cells stably expressing wt-cftr or deltaf -cftr). endogenous rab coimmunoprecipitated with cftr in calu- cell and cfbe o-cells. to determine if rab plays a role in cftr trafficking, cfbe o-cells were transfected with either the flag-tagged, dominant negative (dn) rab mutant deficient in gtp binding (gdp-locked; flag-rab -n i) or with a non-specific cdna control (gfp). if rab sorts internalized cftr to the recycling pathway, the dn rab should inhibit recycling, and, thus, should decrease the plasma membrane expression of cftr. if, on the other hand, rab sorts internalized cftr for degradation the dn rab should inhibit cftr degradation, increase cftr recycling and thus, should increase the expression of cftr in the plasma membrane. the dn rab increased cftr expression in the plasma membrane as determined by cell surface biotinylation. these data are consistent with the role of rab in sorting internalized cftr for degradation. similar to overexpression of the dn rab , silencing endogenous rab with double stranded small interfering rna specific for the human rab sequence increased the plasma membrane expression of cftr and increased the cftr mediated cl-secretion across polarized cfbe o-cells in ussing chamber experiments. the plasma membrane half-life of deltaf -cftr is decreased compared to wt-cftr. however, after silencing rab , the plasma membrane half-life of deltaf -cftr was similar to that of wt-cftr, as determined by cftr disappearance from the plasma membrane following incubation with cycloheximide. our data are consistent with the role of rab in sorting the internalized cftr for degradation and are consistent with the changing paradigm for the role of rab in protein trafficking (supported by the nih grant p rr and the cff swiate qo). the conformational changes underlying activation of phosphorylated cftr by atp remain unclear. in the present study we assessed the utility of labeling endogenous cysteine(s) in cftr using an environmentally-sensitive fluorescent probe alexa- in monitoring such changes in structure. these studies were performed using purified and functionally reconstituted wild-type cftr. we labeled pka-phosphorylated cftr with µm alexa- maleimide prior to reconstitution in phospholipids liposomes. changes in fluorescence intensity were monitored in a suspension of proteoliposomes following addition of and mm mg-atp or mm mg-amp-pnp in order to evaluate nucleotide dependent changes in conformation. in order to identify the labeled cysteines, the protein was subjected trypsin-mediated proteolysis and analysis by mass spectrometry. we have shown that cftr is labeled using alexa- maleimide. a significant increase in fluorescence emission occurred in alexa- labeled cftr of ± (au) relative to empty liposomes one minute after the addition of activating nucleotide, mm mg-atp (n = ). the non-hydrolyzable analogue, mm mg-amp-pnp, failed to cause an increase in fluorescence of alexa- -labeled cftr. however, the higher concentration of mm mg-amp-pnp evoked an increase in fluorescence similar in magnitude to that of mm mg-atp suggesting that the fluorescence response reflects structural changes relating to atp binding to cftr. analysis by mass spectrometry identified the labeled residue as c . this cysteine resides at the junction between nbd and the "r" domain in a region which has been suggested to be highly dynamic on the basis of multiple crystal structures. our studies suggest that this flexible region around c of cftr undergoes conformational change upon mg-atp binding such that it moves the alexa fluorophore into a relatively more polar environment. this finding presents a first case where conformational changes in the cftr nbds induced by atp binding could lead to changes in the conformation of the r domain. further, these studies suggest that fluorescence methods can be used to probe dynamic conformational changes in purified reconstituted cftr. acknowledgements cystic fibrosis is caused by mutations in the apical chloride channel cftr with % of patients carrying at least one allele of the ∆f mutation. this mutant form of cftr is characterized by a trafficking defect in which it fails to exit the endoplasmic reticulum (er). we have previously reported that ∆f cftr is found in complex with hsp and its co-chaperones in cell extracts suggesting that either this mutant form of the protein accumulates in on-pathway folding intermediates which result in its accumulation in the er or that these intermediates include inhibitory factors leading to retention of ∆f cftr in this compartment. we have examined the role of one of these hsp co-chaperones, fk binding protein (fkbp ), in the life cycle of cftr. fkbp is a unique member of the immunophilin family of peptidyl-prolyl isomerases (ppiases) which mediate the cis/trans interconversion of peptidyl-prolyl bonds, which is thought to represent a rate limiting step in protein folding. in order to establish a functional role for fkbp in cftr stability and trafficking, we modulated the expression level of this protein in human bronchial epithelial cells endogenously expressing either wild type or ∆f cftr. a knockdown of fkbp by sirna resulted in a destabilization of both wild type and ∆f cftr as well as a concomitant loss in channel activity of wild type and temperature corrected ∆f cftr. conversely, over expression of fkbp resulted in a stabilization of the er glycoform of ∆f cftr in both mammalian and yeast systems. these data suggest that fkbp is an essential component of the hsp -mediated folding machinery for both wild type and ∆f cftr, which supports the hypothesis that ∆f cftr accumulates in the er in an on-pathway folding intermediate. dmh cftr folding involves a series of sequential, although potentially overlapping steps that involve i) formation, orientation and integration of (tms), ii) helical packing, iii) folding of cytosolic and extracytosolic domains, and iv) establishing proper domain-domain contacts. this process begins cotranslationally and is facilitated by the sec er translocation machinery and a diverse group of lumenal and cytosolic chaperones. the most common inherited cftr mutation, deltaf , disrupts one or more early steps along this folding pathway. a major obstacle in understanding how deltaf causes cf is that the native folding environment, comprised of lipids, cytosolic and er proteins, is not amenable to traditional biochemical and biophysical approaches. to overcome this problem we are developing a flu-orescence based analytical approach that enables one to directly access nascent ribosome-attached folding intermediates at virtually any stage of synthesis. the strategy requires incorporation of fluorescent probes into the substrate protein, which provide a highly selective means to monitor structural features at sub-nanomolar concentrations in highly complex biological mixtures. polypeptides are synthesized in vitro from truncated mrna templates to generate uniform cohorts of ribosome-bound nascent chains. progressive stages of folding can then be evaluated using mrna templates of different length. as proof-of-principle we have shown that fully synthesized gfp variants can be readily trapped in an unfolded state and complete their folding only after the entire nascent peptide has exited the large ribosomal subunit. this approach enabled us to measure real-time folding kinetics of extended peptide domains following synchronous ribosome release and compare fluorophore maturation of four fluorescent protein variants with different spectral properties cfp, gfp, venus and mcherry. to extend this approach to cftr and other general protein substrates, we are employing fluorescence resonance energy transfer (fret) using "donor" and "acceptor" probes incorporated simultaneously into the substrate protein. an in frame n-terminal fusion to cfp provides the "donor" fluorophore, while the "acceptor" fluorophore is incorporated at an engineered stop codon using a synthetic modified aminoacyl-suppressor trna. we are currently developing a 'molecular ruler' to correlate the efficiency of energy transfer with changes in the relative distance between probes in ribosome-bound and ribosome-released cftr folding intermediates. fret-based experiments are underway to evaluate folding of both n-terminal ( - aa) and nbd ( - aa) domains. these studies will provide new insight into the mechanism of cotranslational cftr domain folding and provide a potential means to identify agents that correct the deltaf folding defect. relationships between hypoxia, ado release, and prostenoid production in ariway cells are not defined. in the present studies, we examined mechanisms governing hypoxia-induced production of prostenoids in cfbe o-and calu- monolayers. using elisa-based detection of prostenoid and leukotriene production, both calu- and cfbe omonolayers treated with ado ( µm) or arachidonic acid (aa, µm, the parent molecule of prostenoids and leukotrienes) for hrs led to increases in pge levels ( - ± - pg/mg of total proteins vs controls ± pg/mg in calu- cells, - ± - pg/mg vs controls ± pg/mg in cfbe o-cells, p< . in both airway cell types compared with control). in contrast, ltb and ltc release were not stimulated by both maneuvers. we next used sirna techniques to knockdown a b adenosine receptor expression, and demonstrated durable knockdown of a b ar expression to~ % of scrambled sirna-treated controls following lipid-based transfection with sirna directed against the a b ar in cfbe o-cells. following sirna knockdown of a b ar expression, cells were exposed to hypoxic conditions (mucosal volume = ml in -well plate), normoxic conditions (mucosal volume = . ml, fio = . ), and ado ( µm). hypoxic stress led to high levels of mucosal pge production ( ± . pg/mg vs controls ± . pg/mg, p< . ) that was sensitive to a b ar knockdown ( ± . pg/mg, p< . ). exogenous ado also stimulated pge production, but this effect was small relative to hypoxia. we next examined basolateral effects of ado and aa on transmucosal clsecretion in cfbe o-and calu- cells grown as monolayers on permeable supports and conducted ussing chamber analysis under voltage clamp conditions. addition of ado and aa to the basolateral membrane ( µm) activated transmucosal clsecretion [ . ± . µa/cm (ado) and . ± . µa/cm (aa) for calu- cells; and . ± . µa/cm (ado) and . ± . µa/cm (aa) for cfbe o-cells expressing wtcftr] that was sensitive to basolateral blockade with barium cl -( mm). isc by either agonist was stimulat-ed in the presence and absence of apical glybenclamide ( µm), adenosine deaminase (ada - u/ml) and hexokinase (hexo - u/ml), confirming that the effects were specific for the basolateral membrane and could be accomplished with or without cftr activity. these results demonstrate that hypoxia is sufficient to stimulate pge production through a b ars, and that both ado and aa activate basolateral k + channels to promote transepithelial clsecretion. the findings further support a model in which ado (and prostenoids) regulate cltransport through effects on both the apical and the basolateral membrane, and elucidate molecules that couple the two membranes as part of the normal clsecretory response. hypoxia would be predicted to increase local prostenoid production through ado release and stimulation of a b ars, and further highlight a unifying model by which local hypoxia promotes inflammation in airway epithelia. supported by the nih and cff. low levels of tissue oxygen -observed in lung diseases such as cystic fibrosis -initiate a signaling cascade resulting in altered transcription of genes possessing a hypoxia response element (hre). we recently used gene chip mrna array, quantitative rt-pcr, protein analysis, and functional (short circuit current) assays to show that cftr expression is strongly repressed by hypoxia in vitro and in vivo. among several thousand human mrnas suppressed by low ambient oxygen, cftr was among the most strongly inhibited (by - fold) in a cell model system. however, cftr and the vast majority of other repressed genes lack a traditional hre. because hypoxia inducible factor (hif) acts primarily as a transcriptional activator, the mechanisms underlying hypoxia mediated suppression of mammalian genes are not well understood. we therefore tested the hypothesis that micrornas play a central role during transcriptional regulation of genes such as cftr. micrornas are evolutionarily conserved, short noncoding rna sequences believed important for repression of gene expression. some reports have estimated that at least % of protein-coding genes are regulated by micrornas. thousands of micrornas have been predicted in the human genome by available algorithms (e.g. palgrade, mirscan, and promir) and several hundred experimentally validated. the cftr gene contains predicted target sites for micrornas in the 'utr, including hsa-mir- (nucleotides - of the cftr 'utr), hsa-mir- (nt - ) and hsa-mir- (nt - ). however, no study to date has examined the effect of micrornas on cftr message levels, or the influence of micrornas during the cftr response to environmental perturbations such as hypoxia. we therefore performed a global, genome-wide analyses of both mrnas and micrornas expressed during hypoxia (using air/liquid or liquid/liquid interface culture systems) in ht (colonic epithelial) cells that robustly express cftr. we found that approximately % of micrornas were significantly altered by hypoxia, as judged by mirna profiling (ambion mirvana™ bioarray v , asuragen microrna expression profiling service). comparison of these hypoxia-related micrornas with expression profiles of their predicted targets indicated a much lower level of correlation than has been previously hypothesized by others. we show that none of the micrornas predicted to regulate cftr are altered in ht (in response to hypoxia). these findings are therefore consistent with the notion that highly expressed genes in a particular tissue type are not co-expressed with their predicted regulatory micrornas. our data also indicate that micrornas do not mediate the hypoxic repression of cftr via the ' utr. supported by nih and cff. . physiology, mcgill university, montreal, qc, canada; . biochemistry, mcgill university, montreal, qc, canada the ∆f mutation impairs cftr maturation and trafficking to the plasma membrane and results in a partially functional chloride channel that is retained in the endoplasmic reticulum and degraded. using our highthroughput trafficking assay, we previously showed that the quinoline km , a structural analogue of sildenafil, corrects the ∆f -cftr processing defect and leads to a significant increase in cftr surface expression after h treatment with µm and after h treatment with nm according to detection of mature cftr in western-blots. additional studies have now been carried out with other preparations to assess the functionality of ∆f -cftr following rescue by km treatment. different time and concentration exposures were tested on the cftr function using iodide efflux assays with both bhk and human bronchial epithelial cells over-expressing ∆f -cftr. exposure to µm km for h partially restored iodide efflux responses to µm forskolin + µm genistein in both cell line. after h incubation, rescue of the mutant protein in bhk cells still required µm, whereas nm was sufficient in the human cell line cfbe. iodide efflux assays were performed at different times following km wash out to functionally assess the stability of the rescued mutant protein. camp-stimulated iodide efflux was still detectable h after removing km , but responsiveness was lost after h in both cell types. electrophysiological studies were performed to examine the channel activity of ∆f -cftr rescued by km treatment. incubation with µm km for h increased camp-responsive ∆f -cftr current density in hek whole-cell patches ~ -fold. the conductance was time-and voltage-independent, anion selective, and strongly inhibited by glibenclamide. incubating polarized cfbe monolayers with µm km increased the forskolin + genistein-stimulated short-circuit current after h, and this response was inhibited by cftrinh ( µm). permeabilization of the basolateral membrane with nystatin confirmed the apical location of the forskolin + genistein-stimulation. ussing chamber experiments also revealed trafficking correction in ileum that had been excised from cftrtm eu mice homozygous for ∆f . when the ileum was pre-incubated with µm km for - h, the forskolin + genistein-stimulation of short-circuit current was significantly increased when compared to untreated intestine. these results confirm partial correction of ∆f -cftr by km in unpolarized cells and in human polarized epithelial cell monolayers and ex-vivo intestine isolated from ∆f -cftr mice. this work was supported by the breathe program funded by the ccff and cihr, cihr, cfft, and génome québec. primary sequence and overall structure of human cftr overlaps significantly with murine, rabbit and other homologues, a feature that has limited generation of conformation specific reagents to address cftr folding. because regions of ∆f cftr exposed extracellularly may exhibit aberrant topology (jbc : - ), probes that identify cftr from the extracellular surface could be useful to ) verify plasma membrane localization of ∆f cftr, ) discriminate wild-type from mutant protein, and ) provide a means of determining whether small molecule "correctors" of the ∆f processing lead to a native (wildtype) cftr configuration. our laboratories are investigating phage-display techniques suitable for detecting properly folded extracellular domains of cftr. two large phage libraries encoding or amino acid sequences (approximately phage per library) were panned against extracellular regions of cftr in hela cells. following incubation in blocking solution containing pbs and % bsa at °c, unbound fraction was incubated with recombinant helas expressing wild-type or temperature corrected ∆f cftr (protein expression verified biochemically and functionally). bound bacteriophage was dislodged after multiple washings by exposure to an acidic elution buffer and amplified to increase copy number (five rounds of antigen selection for each library, eur j biochem : - ). supernatants from microtiter wells expressing phage were analyzed for binding to parental (no cftr), wt or ∆f cftr expressing hela cells. using this method we obtained enrichment of phage at the surface of cells expressing wt or ∆f cftr. an example using a -amino acid sequence ( phage) with specificity for ∆f cftr (representative of four repeat experiments) is shown in a binding assay with hela cells/condition. reagents such as these can be further optimized by constructing second generation libraries using core recognition sequences (derived from the initial screen) and surrounding the core epitopes with random amino acid diversity. these experiments are intended to identify peptides with high binding affinity (nm binding constants) that recognize native cftr epitopes exposed extracellularly. because there is evidence that low temperature corrected ∆f cftr in the plasma membrane is misfolded, these probes may ultimately distinguish wild-type cftr from the surface targeted ∆f mutant and be useful as drug discovery reagents. supported by cff and nih. bridges, r.; nagubadi, s.; thakerar, a.; jia, y.; bradbury, n.a. physiology and biophysics, rosalind franklin university of medicine and science, north chicago, il, usa the goal of this project was to compare several reported correctors of ∆f -cftr biosynthesis for their efficacy on chloride channel activity under a standard set of experimental conditions. fisher rat thyroid (frt) cells were transfected with ∆f -cftr and a stable cell line selected with g . cells were grown on transwell filters and studied under short circuit current (i sc ) conditions in ussing chambers. i sc measurements were performed at °c. the basolateral membrane was permeabilized with α toxin and chloride currents were measured with a serosal to mucosal chloride gradient. atp ( mm) and gtp ( µm) were added to the serosal bath. cftr channel activity was stimulated with camp ( µm), ibmx ( µm) and genistein ( µm). cells were treated with correctors or vehicle (dmso) at and hours before the i sc measurements. a subgroup of cells were temperature corrected at °c for hours for comparison. because only modest currents were observed even in the temperature corrected cells ( - µa/cm ) cells were treated for hours with mm sodium butyrate and nm dexamethasone to enhance the observed currents. under these conditions temperature corrected cells displayed stimulated chloride currents of ~ µa/cm that were - -fold greater than cells maintained at °c. correctors c (n- ' ]bithiazolyl- '-yl]-benzamide) and c ( -( h-benzomidazol- -ylsulfanylmethyl)- -( -methoxy- -methyl-quinazolin- -ylamino)pyrimidin- -ol) caused a modest rescue of ∆f -cftr chloride currents compared to cells maintained at °c (c , . -fold; c , . -fold) but far below the effect of temperature correction. rescue by c was concentration dependent with a significant observable effect at nm and a maximum effect at µm. rescue by c was observed at only µm, lower concentrations had no effect and higher concentrations caused an inhibition of the stimulated chloride currents. compounds c -piperazin- -yl]-ethyl}- -piperidin- -yl-quinazoline) ( to µm), c ( -cyclohexyloxy- -{ - [ -( - methoxy-benzensulfonyl)-piperazin- yl]-ethyl}-quinazoline) ( to µm) and phenylbutyrate ( mm) did not significantly increase the stimulated chloride currents. all four compounds c -c caused significant decreases in the transepithelial resistances at the higher concentrations ( - µm) suggesting some degree of cytotoxicity. our results indicate only c and c demonstrate efficacy in frt cells and that these effects are modest compared to temperature correction. supported by the cystic fibrosis foundation. cftr contains two membrane-spanning domains (msd), two nucleotide-binding domains (nbd), and a regulatory domain that require proper assembly for chloride channel activity. the most prevalent disease causing mutation, cftr∆f , arises from deletion of phenylalanine in the nbd domain. the cftr∆f mutant is translated and inserted into the endoplasmic reticulum (er) membrane, but is unable to attain its native state and accumulates in a kinetically trapped conformation that is degraded by the ubiquitin proteasome system ( ) . the nature of the misfolded cftr∆f intermediate that is selected for premature degradation is not clear and is a topic of great interest ( ) . recent work in the cyr lab indicate that defects in cftr and cftr∆f folding are sensed by two different e ubiquitin ligase complexes that are located in the er membrane and cytosol ( ) . the membrane-associated derlin- /rma e complex appears to recognize early folding defects of cftr that may involve assembly of msd into a complex with the amino-terminal regions of cftr. in contrast, the cytosolic hsc /chip e complex appears to sense folding defects that occur after synthesis of the nbd domain. misfolded cftrs recognized at either checkpoint are retained and degraded via the proteasomal pathway. the presence of dual protein quality control (qc) checkpoints suggests a mechanism by which the folding status of cftrs membrane and cytosolic domains are sequentially monitored prior to its escape from the er. currently little is known about how these erqc complexes sense misfolded substrates. small-molecule chemical correctors have recently been identified which rescue the folding defect of cftr∆f in model cell culture systems. in the presence of these chemical correctors a subset of cftr∆f is able to localize to the cell surface and retain channel function. however, how the chemical correctors rescue cftr∆f folding is not clear. we have examined the extent to which the molecules correct folding defects that are recognized by the derlin- /rma or hsc /chip qc checkpoints. in addition, because it is unknown at what point of cftr biogenesis that the chemical correctors act to facilitate folding, we have determined how the chemical correctors affect the folding of different biogenic intermediates. our results indicate that the correctors act in a post-translational manner to influence assembly of cftr sub-domains. interactions with members of the qc pathway have also been used to monitor the folding and assembly process of cftr in the presence of chemical correctors. ultimately the results from these studies will enhance our knowledge of how chemical correctors permit passage of the cftr mutants past different erqc checkpoints. supported by -cystic fibrosis foundation combination therapy has proven successful in treating a wide variety of human diseases, including cancer, infectious disease, and diabetes. historically, combination treatments have been discovered through trial and error using drugs with proven disease modifying effects. we have developed a combination high-throughput screening (chts™) technology to systematically and efficiently find synergistic combinations that target multiple pathways underlying disease biology, and that may be developed into new therapeutics. we are applying chts technology to discover and develop combination therapeutics for the treatment of cystic fibrosis. we have optimized two high throughput screening assays for identifying correctors and potentiators of the cftr (cystic fibrosis transmembrane protein regulator) ∆f mutation. one assay uses the flipr membrane potential dye (fmp) and the other uses genetically modified yellow fluorescent protein yfp h q/i l to measure changes in halide flux through ∆f cftr. both assays were optimized and validated on the flipr tetra using the panel of cf correctors, potentiators and inhibitors provided by the cf foundation. using our automated chts, we systematically evaluate pairwise combinations of a library of ~ , approved drugs and other bioactive molecules to identify novel disease-relevant biological interactions. candidate single agents and combinations are tested in secondary assays and prioritized for testing in animal efficacy models. combination therapies can act on multiple pathways in a coordinated way. chts may prove to be a useful tool for identifying combination therapeutic candidates with novel multi-target mechanisms and a way to enhance co-therapy regimens for the treatment of cystic fibrosis. supported the highly variable clinical phenotypes of cf airway disease suggest that a number of genetic factors, other than cftr, play a role in its pathophysiology. some of these modifier genes are expected to play a role in the endoplasmic reticulum quality control (erqc), since the major defect caused by f del is misfolding, retention and degradation of the mutant protein by this cellular surveillance system. the nematode caenorhabditis elegans is an excellent multicellular genetic model, which has been successfully used in studies of human diseases. its ~ , -genes genome has been fully sequenced, it has short life-span ( - weeks) and life cycle (~ . days) and it is easily cultured and amenable for gene disruption, both by knockout or rnai. our goal is to generate a c. elegans model for the cftr folding defect, so as to take advantage of this model for the identification of genes involved in cftr folding and/or degradation. to this end, and because no cftr orthologue has been described in c. elegans, we constructed two previously described human p-gp-/cftr chimeras (p-gp/wt-cftr and p-gp/f del-cftr) [ , ] to be used as an in vivo folding substrate in this organism. the two chimeric cdnas and intact human p-gp cdna were cloned into the c. elegans ubiquitous expression vector ps and injected into mutant nematode strains for multidrug resistance genes [ ] . the effect on the nematodes phenotype was evaluated by an assay of heavy metal sensitivity ( . mm arsenite), as described [ ] . our quantitative results show that the p-gp/wt-cftr chimera increases the resistance to arsenite when injected into the pgp- /pgp- c. elegans double mutant, whereas p-gp/f del-cftr causes no effect. these preliminary results indicate it is possible to generate two distinct nematode phenotypes caused by each of the transgenic chimeras (p-gp/wt-cftr and pgp/f del-cftr). they also suggest that the same folding defect impairing f del-cftr function in cf may be responsible for the loss of heavy metal resistance function by the p-gp/f del-cftr chimera. these chimeras are currently under test in pgp- /pgp- double and in pgp- /pgp- /mrp- triple c. elegans mutants. analysis of these strains by rt-pcr showed that the mrnas from the two p-gp/cftr chimeras have low expression levels. this led us to produce more robust constructs, including: ) to test chimera expression under the c. elegans endogenous pgp- or intestinal-specific (potent) promoters; and ) to develop p-gp chimeras with a full cftr-nbd . these c. elegans models will be used in genome-wide rnai screens to identify genes involved in the erqc of the p-gp/cftr chimeras. work channel gating of cftr is regulated by atp binding and hydrolysis at the nbds and by pka phosphorylation at multiple sites, primarily within the intrinsically disordered regulatory (r) region. phosphorylation at multiple sites is required for full activation of channel function, but no one specific phosphorylation site is required. the phospho-regulation of r region interactions with nbd likely contributes to the regulation of cftr channel function by modulating r region interactions with nbd at the nbd /nbd dimerization interface, consistent with nbd crystal structures that include the regulatory extension (re) comprising the first residues of the r region ( ). this regulation likely occurs via a dynamic complex where multiple segments of nonphosphorylated r region with αhelical propensity transiently engage nbd and are released. pka phosphorylation disrupts r region α-helical propensity and decreases binding of each interacting segment ( ) . regulation of the ∆f cftr by pka is altered, with the rate of channel activation by pka -fold slower than for wild-type ( ). we hypothesize that the dynamic interactions between the r region and nbd are affected by the ∆f mutation. to characterize the differences in r region binding between wild-type and ∆f nbd at residue-level resolution, we use nuclear magnetic resonance (nmr) techniques. experiments are performed using either r region or nbd samples labeled with nmr-active nuclei and monitoring their structural changes upon the addition of unlabeled binding partner, allowing us to confirm r region binding to nbd at the nbd /nbd dimerization interface and to identify other potential interaction surfaces on both the r region and nbd . together, these experiments will allow us to characterize the dynamic associations between the r region and nbd in order to better understand the molecular basis for the pathogenesis associated with ∆f cftr. funded by the canadian institutes for health research, the canadian cystic fibrosis foundation, and the us cystic fibrosis foundation . lewis, h.a., et al, embo j. , - ( ) . . baker, j.m.r., hudson, r.p., kanelis, v., choy, w-y, thibodeau, p.h., thomas, p.j., and forman-kay, j.d. submitted. the ∆f -cftr mutation, the most common gene mutation in cystic fibrosis (cf), results in diminished plasma membrane expression of cftr, leading to loss of functional cftr and altered mucociliary clearance. this impairment promotes chronic infection of cf patients by the opportunistic pathogen, pseudomonas aeruginosa. we previously reported that a secreted protein from p. aeruginosa (cftr inhibitory factor (cif)) reduces the wt-cftr and ∆f -cftr-mediated chloride secretion and the plasma membrane expression of cftr by decreasing endocytic recycling of cftr. the aim of the current study was to investigate the mechanism by which cif is secreted by p. aeruginosa and delivered to human airway epithelial cells (cfbe o-). in this study, we show that cif is packaged in outer membrane vesicles (omv) for secretion from p. aeruginosa. interestingly, cif secretion via omv was increased when the bacteria were exposed to airway epithelial cells. changes in cif protein level or bacterial growth did not account for the increase in cif secretion. purification and application of p. aeruginosa omv to airway epithelial cells caused a decrease in plasma membrane expression of cftr. the decreased plasma membrane cftr expression was followed by increased ubiquitination and lysosomal degradation of cftr. cif delivery to the airway epithelial cells via omv showed a more robust decrease in plasma membrane cftr expression, in comparison with cif delivery as purified protein. to investigate the mechanisms whereby cif enters epithelial cells, optiprep gradient fractionation experiments were conducted in polarized airway epithelial cells. in airway epithelial cells treated with p. aeruginosa omv, cif was associated with airway cell lipid rafts. pharmacological inhibition of lipid raft formation with filipin iii blocked the decrease in cftr plasma membrane expression upon treatment with omv. these studies demonstrate that cif is released by p. aeruginosa via omv and enters the airway epithelial cells through lipid rafts. upon entry into the epithelial cell, cif increases the ubiquitination and degradation of cftr and redirects cftr trafficking from the recycling pathway to the lysosomal-degradative pathway. these data suggest that chronic infection of p. aeruginosa in the cf lung may reduce the efficacy of therapeutics developed to increase plasma membrane expression of the mutant ∆f -cftr (supported by the nih ro hl - and t -dk - ). . physiology, dartmouth medical school, hanover, nh, usa; . microbiology and immunology, dartmouth medical school, hanover, nh, usa we have identified and cloned a secreted protein from pseudomonas aeruginosa (p. aeruginosa pa and clinical isolates), designated cftr inhibitory factor (cif). cif reduces the apical membrane expression of cftr and inhibits the cftr-mediated chloride ion secretion by human airway epithelial cells expressing wt-cftr and df -cftr. cif does not have general effects on protein trafficking, as the localization and expression of gp , na + -k + -atpase, and the transferrin receptor were not affected. cftr is a member of the atp-binding cassette (abc) transporter superfamily. abc proteins are atp-dependent transporters involved in exporting a wide variety of cytotoxic agents across the plasma membrane. p-glycoprotein (pgp; abcb , mdr gene product), also an abc transporter, is one of the major drug-efflux pumps expressed in normal tissues, as well as in many human cancers. over-expression of pgp results in reduced intracellular drug concentration and reduced cytotoxicity, conferring multi-drug resistance (mdr) to cancer cells. the aim of the current study was to examine whether cif also affects pgp expression in the plasma membrane, which could be exploited as a potential therapeutic strategy for restoring the sensitivity to pgp-transported drugs in cancer chemotherapy. cif significantly reduced the apical expression of pgp in mdck cells stably transfected with gfp-tagged pgp (mdck-gfp-mdr cells) and in caco- and calu- cells, which express endogenous pgp in the apical plasma membrane. the drug sensitivity of mdck-gfp-mdr cells to doxorubicin, a pgp substrate, was evaluated in the absence and presence of cif by measuring the ec . cif reduced the cytotoxicity of doxorubicin by -fold. neither cif nor vehicle alone had a cytotoxic effect. the drug sensitivity of the parental cell line, mdck-c , that expresses -fold less pgp than the transfected mdck cells, to doxorubicin was also increased by -fold. by contrast, cif had no effect on the ec values of cisplatin (a substrate of mrp ) and etoposide (a substrate of mrp ), suggesting that the alteration of the sensitivity to doxorubicin was due to decreased apical expression of pgp, but not other abc transporters. these results suggest that although cif may be an obstacle to therapeutic attempts to restore the apical expression of cftr in the cf lung, it could be useful for the development of a novel class of inhibitors of pgp aimed at increasing the sensitivity of tumors to chemotherapeutic drugs (supported by the nih ( ro hl )). hamai, h. ; keyserman, f. ; worgall, t.s. , . pathology, columbia university, new york, ny, usa; . pediatrics, columbia university, new york, ny, usa cystic fibrosis (cf) is characterized by an inflammatory state and susceptibility to chronic lung infections. a common clinical finding is dyslipidemia characterized by altered plasma free fatty acid patterns, low plasma hdl levels and increased phospholipase a (pla ) activity. it is not clear how cftr mutations relate to lipid abnormalities. it was shown that defective cftr is associated with decreased uptake of sphingolipids (sl). sl homeostasis is tightly regulated and metabolites are relevant to lipid metabolism and cf. sl synthesis (sls) correlates with activity of srebp, a key transcription factor of lipid metabolism; ceramide- -phosphate, a sl metabolite, is a regulator of pla that is highly activated in cf. we investigated the hypothesis that sls is increased in cf. experiments were carried out in airway epithelial cell lines that express defective cftr (c / ib ), no cftr ( hbe sense / antisense) and overexpress cftr (a cells infected with adcftr or adcontrol). sls was assessed using radioactive tracers h-serine (de-novo sls) and h-sphinganine (recycling pathways). ceramide and sphingomyelin mass were determined enzymatically. neutral and alkaline sphingomyelinase activity was assessed using h-sphingomyelin as substrate. srebp mediated gene transcription was assessed using sre-promoter assays. cholesterol synthesis was evaluated by incorporation of h-acetic and h-mevalonic acid. cholesterol mass was determined by gas-chromatography. abca- expression was determined by western blot analysis. pla activity was measured using fluorescent phospholipid substrates. sls was post-transcriptionally increased in cells expressing defective or no cftr through the de-novo pathway ( % ± % for ib ; %± % for hbe-antisense; p< . ) and the recycling pathways ( % ± % or ib ; % ± % for hbe-antisense; p< . ). ceramide mass was increased by % (± %) in hbe antisense, % ± % in ib cells. sphingomyelin mass was increased -fold in ib , up to -fold in hbe antisense cells. neutral and alkaline sphingomyelinase activity was increased up to -fold in both cell lines. sre-mediated gene expression was increased up to -fold in ib and by % in hbe-antisense cells. overexpression of cftr in a decreased sls and srebp activity up to %. free cholesterol synthesis was increased by % in ib and by % in hbe antisense. expression of the cholesterol efflux receptor abca- was decreased in ib and hbe antisense compared to controls. sl mass, sre-mediated gene transcription and pla activity were decreased following incubation with inhibitors of sls in ib and hbe antisense cells. conclusion: defective cftr or lack of cftr expression correlates with ) increased sls synthesis and sl mass; ) increased sremediated gene transcription and free cholesterol synthesis; ) decreased expression of the abca- cholesterol efflux receptor. inhibition of sls decreases sre-mediated gene transcription and pla activity. dysfunctional sls is a newly recognized pathway associated with defective cftr and a possible therapeutic target in cf. the ability to make accurate, reproducible measures of mucociliary and cough clearance (mcc/cc) in cf patients is critical to assessment of new therapies designed to improve mcc/cc function, and thus decrease pulmonary infections and decline in lung function. for example, using mcc/cc methods developed in our laboratory, we showed that -week treatment with aerosolized hypertonic ( %) saline (hs) led to a sustained increase in mcc and improved lung function in cf patients (donaldson et al, n eng j med ; : ) . the mcc/cc technique involves patient inhalation of radiolabeled particles followed by gamma camera scanning to determine the rate of particle movement from the lungs. while a few cf centers have shown the capability to measure mcc/cc, the techniques across these centers are not standardized, making comparison of results difficult. it is vital to develop standard, simplified techniques for these measures to make larger cf patient populations available for such studies. to standardize a radiolabeled particle inhalation technique that can be easily used by other cf centers, we have compared three protocols in healthy and cf subjects. protocol # was identical to that used in recent studies, and incorporates a devilbiss jet nebulizer to generate µm mmad (gsd = . ), aqueous droplets containing suspended tc m-sulfur colloid particles. tidal volume and inhaled/exhaled flow rates were guided by a volume signal displayed on an oscilloscope. protocol # was further standardized and simplified to allow use at other centers. this protocol utilized the same nebulizer, but triggered by a commercial dosimeter (spira electro , finland) during inhalation as the subject breathed in time to a metronome ( breaths/min) at flow rate of . l/sec. subjects controlled inspiratory flow rate by feedback from a digital flow readout on the dosimeter. repeat measurements of mcc/cc were made in healthy subjects and mild cf patients to compare mcc/cc variables following radioaerosol inhalation using protocols # and # . there were no differences in particle deposition (i.e. central to peripheral ratio, or "c/p"), or clearance of particles through minutes and hours in either subject group. these data suggest that the new methodology (protocol # ) will be useful and easily employed by other cf centers to test effectiveness of new therapies for cf. the third protocol (# ) was then tested in five of the healthy subjects. this protocol used a nebulizer that generated very large droplets ( . um mmad, gsd = . ) and subjects inhaled at very slow flow rates (~ ml/sec). it was designed to provide greater bronchial airway deposition and thus an "improved signal" for mcc/cc evaluation. indeed, this methodology produced a larger average c/p and significantly greater particle clearance from the lung compared to the other standardized methodology (protocol # ) (c/p = . vs. . ; min clearance = % vs. %; hr clearance = % vs. %, respectively). interestingly, the greater fraction of clearance between min and hr may also reflect heightened ability to assess clearance from smaller airways, which could be particularly important in cf. protocol # will be tested further in cf patients. supported by cf foundation. previous clinical trials in cystic fibrosis (cf) indicate that anti-inflammatory therapy probably will not result in improvement in lung function, but will slow the rate of decline. this imposes constraints on study design for new anti-inflammatory agents, requiring that they use many patients over long periods. it is highly desirable to design a strategy for evaluation of antiinflammatory agents that will allow for the selection of only the most promising agents for phase iii trials. sputum induction (si) samples lower respiratory tract secretions and permits measurement of inflammatory markers. the purpose of this study was to assess the measurement of inflammatory markers in induced sputum as one such strategy by using ibuprofen as the test agent because it has demonstrated clinical benefit in cf. if changes in inflammatory markers are detectable in ibuprofen treated patients, then si might serve as a quick, noninvasive method by which to select the most promising anti-inflammatory agents for further study. methods: in this twoarm (ibuprofen and no treatment), open-label, parallel group study, cf patients >/= years of age with mild to moderate lung disease were screened at sites. si was performed on days , , and . patients in the ibuprofen group received drug on days - . subjects met eligibility criteria. were randomized to ibuprofen and to no treatment. subjects ( ibuprofen and no treatment) completed the study through day and comprise the intent-to-treat efficacy population. a maximum of subjects ( ibuprofen and no treatment) and a minimum of subjects ( ibuprofen and no treatment) across all markers had acceptable inflammatory marker values at both days and . within group and between group comparisons were made. results: with respect to the within group comparisons (before and after ibuprofen), most inflammatory markers slightly decreased in the ibuprofen group and increased in the no treatment group. for ibuprofen patients, mean changes were most apparent for il- (- . log pg/ml, p= . ) and % neutrophils (pmns) (- %, p= . ). with respect to the between group comparisons (ibuprofen vs. no treatment), differences were strongest for il- ( . log pg/ml, p= . ), percent pmns ( %, p= . ), and absolute pmn count ( . cells/ml, p= . ). fourteen days after discontinuing ibuprofen, inflammatory mediators tended to increase. there was no difference in aes between the two groups, and si was generally safe. conclusions: . overall, si is well-tolerated in patients >/= years, . a -week treatment period may not be long enough to study anti-inflammatory drugs, . with respect to changes in inflammatory markers associated with anti-inflammatory therapy, the effect size is small and the variance of the effect is small in clinically stable patients. . measuring inflammatory markers in induced sputum has potential as a screening tool for studying anti-inflammatory drugs in cf, . further studies of si in cf are warranted. supported by cystic fibrosis foundation therapeutics, inc. in preparation for our gene therapy clinical trial programme we are currently assessing a number of sputum biomarkers including viscosity and elasticity, total solids and dna content and hr sputum weight. we tracked and correlated these biomarkers in cf patients ( years and over) during a course of iv antibiotics (ab) by collecting samples on several occasions [visit (v) : at the start of ab treatment, v : at the end of ab treatment (generally after weeks) and interim periods]. to ensure adequate reproducibility of the results viscosity/elasticity measurements were carried out in triplicate using a csl rheometer which required a comparatively large volume ( mls) of spontaneously expectorated sputum. because of this requirement paired samples could only be obtained from approximately % of the patients. there was no change in viscosity/elasticity (n= ), solid or dna (n= ) content when comparing samples at the beginning and end of iv ab. in contrast, hr sputum weight was significantly (p< . ) lower at the end of the ab treatment (visit : . ± . g, visit : . ± . g, n= ). there was a strong and significant correlation between solid content and viscosity/elasticity (r= . , p< . ) and a modest correlation between hr sputum weight and % predicted fev (r=- . , p< . ) and hr sputum weight and patient scored symptom severity (r= . , p< . ). surprisingly, sputum dna content did not correlate with viscosity/elasticity, despite being generally thought of as a contributor to viscosity, which may in part be related to the assay not being able to discriminate between free and cell-enclosed genomic dna.in summary, after a course of iv antibiotics which lead to significant subjective and objective (fev ) improvement the overall quantity of expectorated sputum was significantly reduced but, based on analysis available to date, none of the other parameters (viscosity, elasticity, solid and dna content) changed significantly. considering the difficulties we encountered in collecting sufficient sputum during this period of an exacerbation, sputum viscosity/elasticity measurements may not be feasible parameters to measure in a gene therapy trial to which stable patients re likely to be recruited. this study was funded by the cf trust. chronic neutrophilic inflammation is a feature of cystic fibrotic (cf)related inflammation and serves as a significant contributor to morbidity and mortality associated with the condition. recently, our group has described a novel collagen-derived neutrophil chemoattractant, proline-glycine-proline (pgp), in a murine model of lipopolysaccharide-induced inflammation. the purpose of this study was to explore both the presence of this peptide in sputum from cf patients and the determination of a proteolytic system involved in pgp generation. we show that lower airway secretions from cf subjects have -fold increase in pgp levels compared to normal controls and that cf sputum (p< . ) is able to generate pgp from intact type i and ii collagen -fold above that seen from normal control sputum ex vivo (p< . ). we further demonstrate that production of pgp is dependent on two specific matrix metalloproteases (mmps), mmp- and mmp- . finally, we show that the generation of pgp can be significantly inhibited ( - % inhibition) by the use of either mmp- or mmp- specific inhibitors (p< . versus no inhibitor); a nonspecific mmp inhibitor (doxycycline) also demonstrates significant attenuation of pgp production. the determination of the requirements of these proteases in pgp generation allows for the identification of logical targets for disease-modifying therapeutics in cf. . cfrc, uab, birmingham, al, usa; . cfrc, university of north carolina, chapel hill, nc, usa cystic fibrosis (cf) lung disease is characterized by chronic neutrophilic inflammation. the discrete collagen breakdown product prolineglycine-proline (pgp) is a potent neutrophil chemoattractant thought to be generated by a specific proteolytic cascade present during cf pulmonary exacerbation (nat med ( ): , ) . high-mobility group box (hmgb ) is a potent inflammatory mediator found in sepsis, rheumatoid arthritis, and other inflammatory diseases characterized by neutrophilic inflammation. the role of pgp and hmgb as pmn attractants in cf is unknown. in this study we utilized specimens derived both from humans and scnn b-transgenic mice (βenac mice) in which overexpression of the βenac subunit in the airways leads to sodium hyperabsorption and airway surface liquid depletion, mimicking the cf muco-obstructive phenotype. pgp was quantified using tandem ms. neutrophil chemotaxis was measured in vitro following preincuabtion of sputum or balf with anti-hmgb neutralizing antibody. murine balf was assayed for hmgb by western blot and elisa. human sputum was similarly evaluated after normalizing for total protein concentration. in vivo hmgb activity was measured after intratracheal instillation in wt mice. βenac mice had % higher cell counts and a greater percentage of pmns ( . % vs. . %) in bal samples than wild-type (wt) littermates (p< . , n= /genotype). pgp was elevated in balf of scnn b animals ( . vs. below limits of detection in wt controls, p< . , n= ), increased in serum from cf subjects ( vs. pg/ml normal controls, p< . , n= ), and detected at high levels in cf sputum ( , pg/ml). balf screened for hmgb by western blot revealed elevated levels in βenac mice (p< . by densitometry, n= /genotype); elisa confirmed % greater hmgb concentration ( . vs. . ng/ml, p< . ). hmgb was also detected by western blot in human cf sputum ( of ) and at higher levels than secretions from normal subjects (p< . by densitometry; n= cf, control). purified hmgb induced dose-dependent pmn chemotaxis in vitro (peak - ng/ml, p< . , n= ) and cf sputum caused potent chemotaxis ( -fold over control, p< . , n= ) that was inhibited by preincubation with hmgb antibody (p< . ). balf from βenac mice (but not wt controls) was also chemotactic ( -fold greater than media control, p< . , n= ) and inhibited by anti-hmgb antibody (p< . ). exogenous hmgb ( ng) administered intratracheally to lps resistant mice (c hej, toll- receptor mutant) and balb/c mice caused pmn influx in balf at hours (c hej: . x pmns after hmgb vs. . x after vehicle, p< . ; balb/c: . x vs. . x , p< . ), and generation of pgp ( . vs. . pg/ml in c hej, p< . , n= ) . in summary, pgp and hmgb are elevated in balf of βenac mice that present with cf-like lung pathology; in cf airway secretions, hmgb is present in vivo at concentrations that induce neutrophil chemotaxis in vitro and pgp production in vivo, and is inhibited by blocking antibody. the role of pgp and hmgb in cf deserve further evaluation as they may be potential therapeutic targets of dysregulated inflammation. esther, c.r. ; jasin, h.m. ; collins, l.p. ; boysen, g. ; boucher, r.c. . pediatric pulmonology, university of north carolina at chapel hill, chapel hill, nc, usa; . cf research center, univeristy of north carolina at chapel hill, chapel hill, nc, usa; . center for environmental health and susecptibility, univeristy of north carolina at chapel hill, chapel hill, nc, usa biomarkers of airway inflammation are needed in cystic fibrosis (cf) to aid clinical management and assess the efficacy of novel therapies. we describe a simple and non-invasive method to measure airway purines, signaling molecules previously shown to be biomarkers of neutrophilic airway inflammation. airway secretions were obtained using exhaled breath condensate (ebc) collection, a technique that was easily performed in the outpatient setting on children as young as three years. the purines adenosine and amp in ebc were measured using ultra-sensitive liquid chromatography/tandem mass spectrometry (lc/ms/ms). in addition, we used lc/ms/ms to simultaneously measure urea as a dilution marker to control for the known dilutional variability of airway secretions within ebc. detection of adenonosine, amp, and urea was optimized using positive mode ms with selected reaction monitoring, and stable isotope dilution was utilized to improve quantification. detection was linear with concentration over four orders of magnitude, with coefficients of variation < %. the method was sensitive, with limits of detection for adenosine and amp (~ . nm) and urea (~ . µm), below expected ebc concentrations. applying the methods to ebc demonstrated that detection of purines and urea was reliable, with intraclass correlation coefficients greater than . between duplicate measures (n= ). we also measured purines and urea in ebc samples collected prospectively from children with cf (n= ) and healthy controls (n= ) during regular clinic visits. all samples were lyophilized and reconstituted to increase concentration -fold. adenosine, amp, and urea were detected in all samples. neither adenosine nor amp levels differed between groups, but urea was significantly lower in cf ( . ± . µm) versus healthy control ( . ± . µm, p= . ), suggesting that airway secretions were more dilute in cf samples. when dilutional variability was controlled using purine to urea ratios, the amp to urea ratio was found to be elevated in subjects with cf ( . ± . ) compared to healthy controls ( . ± . , p= . ), consistent with previous findings. the amp to adenosine ratio was also elevated in cf ( . ± . ) compared to control ( . ± . ), although the difference did not reach statistical significance in this small sample set (p= . ). experiments are ongoing to increase sample size and assess ebc purine levels before and after treatment of a cf exacerbation. these results demonstrate that lc/ms/ms analysis of ebc provides a non-invasive method to measure purine biomarkers of cf airway inflammation. given the flexibility of ms, this methodology could also prove applicable for study of other small molecule biomarkers. importantly, we also show that dilution of airway secretions in ebc may be altered in cf, and lc/ms/ms can be used to control for this variability through measurement of urea as a dilution marker. introduction: mucociliary clearance and antimicrobial peptide activity may be affected by airway surface liquid (asl) ph, which is regulated by epithelial ion transport. asl ph is abnormal in disease states in which il- a is elevated, including cystic fibrosis (cf), and the il- a receptor is expressed at the basolateral surface of bronchial epithelium. therefore, we investigated the effects of il- a on vectorial ion transport in well-differentiated hbe cells. methods: hbe cells were grown with an apical air interface and incubated with il- a at or ng/ml in the basolateral medium for hours prior to being studied with standard short-circuit current (isc) techniques. results: il- a treated cells had a minimal increase in resting and amiloride-sensitive isc compared to control cells, and had a dosedependent, statistically significant increase in forskolin-stimulated isc. at a dose of ng/ml, il- a doubled forskolin-stimulated isc ( . ± . µa/cm for control vs. . µa/cm for il- a). the increased isc was not bumetanide-sensitive, but was sensitive to acetazolamide and dnds, and was not present in hco --free solutions, suggesting it was due to hco secretion. to investigate whether this hco secretion was cl --dependent, we studied hbe cells in cl --free solutions, and there was no difference between untreated and il- a treated hbe cells. to test the hypothesis that il- a promoted cl -/hco exchange, we performed experiments in hbe cells mounted in cl --free solutions, and after addition of amiloride and forskolin, mm nacl was added to the mucosal bath and mm nagluconate was added to the serosal bath. under these conditions, one would predict a decrease in isc due to mucosal to serosal clmovement down its electrochemical gradient. in untreated hbe cells, we saw a decrease in isc followed by a recovery. in il- a treated cells there was a sustained increase in isc, suggesting that movement of cldown its electrochemical gradient resulted in exchange of clfor an anion at the apical membrane. in the absence of hco -, both untreated and il- a treated cells responded to claddition to the mucosal bath with decreases in isc. to assess the cftr dependence of the il- a-induced isc, we stimulated primary cf hbe cells treated with il- a. in cf cells, there was a minimal increase in amiloride-sensitive isc ( . ± . µa/cm for control vs. ± . µa/cm for il- a ) and in forskolin-stimulated isc ( . ± . µa/cm for control vs. . ± . µa/cm for il- a ). conclusion: the proinflammatory cytokine il- a induces cl -/hco exchange in hbe cells. notably, the observed cl -/hco exchange appears to be cftr-independent. however, cftr activation is required for maximum cl -/hco exchange as demonstrated by the smaller isc generated in cf cells. these data suggest that the cytokine milieu of the airway epithelium can alter ion transport and potentially asl physiology. furthermore, they suggest that cftr may interact with or regulate novel proteins in the presence of inflammation. supported by cff and nih periciliary fluid balance is maintained by the coordination of sodium and chloride (cl-) channels in the apical membranes of the respiratory epithelia. in the absence of the cystic fibrosis transmembrane conductance regulator (cftr), cl-secretion is diminished and sodium reabsorption becomes exaggerated. activation of non-cftr-dependent cl-channels can provide an alternate pathway for cl-secretion in the airways and gastrointestinal tract. the ph and voltage-dependent type- cl-channel (clc- ) is expressed in airway epithelial cell luminal membranes. we hypothesize that topically applied clc- agonists may restore cl-secretion in cystic fibrosis (cf) murine airways. using in vivo nasal potential difference measurements, we quantified clc- -mediated cl-transport in both cf and wild-type mice during nasal perfusion with lubiprostone (a prostone compound and specific clc- agonist; sucampo, pharmaceuticals, inc., bethesda md) or vehicle control. wild-type (c bl , n = ) and cf knock-out (cfko; n= (jax stock# )(jackson laboratories, bar harbor, me) mice were sedated and intubated to protect the lower airways from aspiration of perfusate. nasal and subcutaneous bridges were connected to fluid-filled silver chloride electrodes. baseline (in ringer's), amiloride-inhibited, low cl-(cl-free, gluconate-substituted ringer's with amiloride), and low cl-plus lubiprostone (with increasing concentrations of lubiprostone or vehicle) mice were perfused and potential differences were measured with a high impedance voltmeter (world precision instruments, sarasota fl) and continuously recorded. a clear dose-response relationship was detected in both wild-type and cf mice. at µm lubiprostone, wild-type mice showed hyperpolarization of - . ± . mv and cf mice responded with - . ± . mv hyperpolarization. a paired t-test of low cl-perfusion and lubiprostone perfusions revealed significant (p< . ) differences in both genotypes. five clc- cfko mice were similarly tested and showed no response to lubiprostone (+ . ± / mv). cftr inhibitor- ( µmol) (calbiochem, san diego ca) added to the low cl-perfusion in additional wild-type mice eliminated the low cl-response but did not abolish the lubiprostone response, confirming that clc- is present and independent of cftr regulation. we conclude that direct application of a clc- agonist in the cf murine upper airways restores near normal levels of cl-secretion. cftr is an apical membrane chloride channel whose activity is required to maintain airway surface liquid (asl) volume and efficient mucociliary clearance. cftr is activated by camp dependent stimulation of protein kinase a. however, studies have suggested that the actin cytoskeleton may also be required for regulation of cftr, by acting as a structural element in second messenger compartmentalization ( ) . to determine whether an intact cytoskeleton is required for asl volume homeostasis, adenosine (ado), atp, or isoproterenol (iso) (all at µm) were added apically to human bronchial epithelial cultures (hbec's) before or after the cytoskeleton had been disrupted by cytochalasin d exposure ( µm for h). in control cultures ado, atp and iso all resulted in a significant increase in asl height (∆asl) within min (∆asl; ado, . ± . µm; atp, . ± . µm; iso, . ± . µm). however, in cytochalasin d exposed cultures ado was without effect while atp and iso were still able to evoke an increase in height (∆asl; ado, - . ± . µm; atp, . ± . µm; iso, . ± . µm). however, we showed that a b receptor function was not compromised by cytoskeleton disruption as camp levels were seen to increase both after addition of adenosine and adenosine in the presence of cytochalasin d. thus, the effect of cytochalasin d on asl height appeared specific for adenosine-mediated cl-secretion. to further test the effect of cytochalasin d on the relationship between adenosine and cftr, we designed a fluorescent resonance energy transfer (fret) pair of cfp-cftr (labeled at the n-terminus) and yfp-a b receptor (labeled at the c-terminus). addition of adenosine ( µm) increased fret by . times (% efficiency; control, . ± . %, ado, . ± . %) compared to the vehicle control (n= ). cytochalasin d exposure ( µm for h) completely inhibited the increase in fret that was observed after adenosine addition (p< . ). in contrast, cytochalasin d had no effect on fret between cftr and the β adrenoceptor. to determine whether cytochalasin d treatment ( µm for h) had any direct effect on cftr protein levels and localization we used a cell line stably expressed with an exotope-tagged cftr (hb cells) ( ) . cftr protein levels were found to be significantly reduced as compared to nontreated controls by both western blot analysis and chemiluminescence detection (n= ). cells were also stained with an antibody against the external cftr exotope and imaged by confocal microscopy and a significant decrease in staining at the plasma membrane was observed after cytochalasin d treatment (n= ). we conclude that cytochalasin d exposure decreases cftr protein levels and specifically inhibits adenosine-mediated regulation of cftr activity in the airways, leading to disruption of asl homeostasis and inhibition of mucociliary clearance. numerous studies have reported evidence that cftr is expressed in the apical membrane of serous cells in the airway submucosal glands. thus, it has been reasoned that ( ) cftr plays some role in normal anion and fluid secretion by airway glands and ( ) loss of this channel's function in cystic fibrosis (cf) airways plays some role in the etiology of cf lung disease. a recent study by joo et al. (jbc : - , ) indicates that cf airway glands lose the ability to secrete fluid when treated with forskolin or vip but maintain the ability to secrete when treated with muscarinic agonists. this result suggests that vip and muscarinic agonists mediate secretion by cftr-dependent and cftr-independent pathways, respectively. the present study was undertaken to explore the dynamics of fluid secretion by individual submucosal glands to determine if further differences in their responses to these two agonists could be distinguished. pig tracheas were obtained from a local slaughterhouse. after removal of the cartilage, tissues were mounted in a warm ( °c) observation chamber that permitted exposure of the submucosa to krebs solution. the mucosal surfaces of the airways were dried with a stream of warm dry air and then layered with mineral oil. liquid secreted from the gland duct openings formed spherical aqueous droplets within the oil layer, and their volumes were estimated from spatial dimensions taken from sequential digital images. liquid secretion rates were estimated for individual glands present within a . mm region of interest. rates were determined for two experimental protocols. for one group of tissues, secretion rates were determined for a control period, followed by a period of exposure to µm vip, and then a period of exposure to both vip and µm acetylcholine (ach). in the second group, the order of vip and ach treatment was reversed. these agonist concentrations were expected to produce near maximum rates of secretion. when the agonists were applied first, secretion rates were significantly (p< . ) increased from the control period by both ach ( . ± . nl/min to . ± . nl/min) and vip ( . ± . nl/min to . ± . nl/min). the secretion rates for individual glands were highly variable with both agonists (ach: . - . nl/min; vip: . - . nl/min). when ach application followed vip treatment, the mean secretion rate was significantly increased further to . ± . nl/min; however, when vip application followed ach treatment, the secretion rate was only marginally and insignificantly increased to . ± . nl/min. we conclude that both ach and vip are efficacious secretagogues for porcine airway glands and that the rate of secretion from individual glands to either agonist is very heterogenous. because vip has no effect following stimulation by ach, we speculate that ach induces secretion by activating all transporters relevant to vip-induced secretion including cftr. however, ach must also activate channels and/or transporters not induced by vip since its effects are additive to vip. this most likely includes activation of a non-cftr anion channel. ( serous cells are thought to serve as the principal anion and fluidsecreting cells of airway submucosal glands. mucous cells primarily secrete gel-forming mucins. these respective physiological roles for these two cell types imply that the mucous cells, which secrete the thick mucus gel, should lie downstream of the serous cells so that their watery secretions can flush the mucins out of the ducts and onto the airway surface. early studies indicated that such arrangements existed within glands but reports of cell distributions have been descriptive rather than quantitative. because of resurgent interest in serous cell function, we revisited this issue to formally document the distribution of these cell types within the secretory tubules of the submucosal glands as well as at the surfaces of the glands, where serous cells are most accessible for study. a piece of porcine lung, containing a mm diameter bronchus, was treated with formalin fixative, and consecutive µm sections were taken. the apices of virtually all gland epithelial cells, except the cells lining the collecting and ciliated ducts, stain positive for pas indicating that these cells are either serous or mucous cells. however, pas staining does not allow distinctions to be made between these two cell types. consequently, all slide sections were stained with hematoxylin and eosin. with these stains, mucous cells were identified as cells containing lucent granules in their apices whereas serous cells were considered to be cells where the apical cytoplasm stained a uniform dark reddish color. first, the distribution of serous and mucous cells in the secretory tubules were determined. the acini of individual tubules were located in the slide sections, and cells were identified and counted in consecutive sections that approached the collecting ducts until the tubules were no longer distinguishable as discrete tubes. secretory tubules from individual glands were studied. in the acini, serous cells accounted for . ± . % of total cells whereas mucous cells accounted for . ± . % of total cells (remaining cells were not distinguishable as either cell type). there was a significant (p<. ) negative correlation of serous cell numbers with distance from the acini so that at µm from the acinus serous cells accounted for only . ± . % of total cells. there was a coincident significant positive correlation with mucous cell numbers so that at µm from the acini mucous cells accounted for . ± . % of total cells. next, we examined the cell distribution at the adventitial and mucosal surfaces and at the lateral margins of the glands. serous cells accounted for . %, . %, and . % of the total cells at these respective locales. mucous cells represented . %, . %, and . % of total cells in these same respective regions. we conclude that serous cells are by far the dominant cell type in secretory tubules of porcine submucosal glands. mucous cells are rare in acini but increase in frequency with distance from the acini. the outer surfaces of the glands are dominated by serous cells as well. at the lateral margin of the glands, serous cells outnumber mucous cells by -to- . (supported by nih hl ) . many of the membrane transporters that participate in this process have been identified; however, the identity of the class of kchannels that maintains resting membrane potential and/or cell membrane polarization during the secretion process remains poorly characterized. liquid secretion by porcine submucosal glands is insensitive to numerous k + channel blockers including ba + , tetraethylammonium, apamin, charybdotoxin, iberiotoxin, clotrimazole, penitrem a, -aminopyridine, and quinidine. recently, a new class of k + channels, the "tandem-pore" or k p channels, have been described. potassium channels of this class are insensitive to many traditional k + channel inhibitors but are blocked by local anesthetics, such as lidocaine and bupivacaine. additionally, many k p channels are sensitive to changes in extracellular ph. in the present study, we considered whether k p channels might participate in the liquid secretion response to acetylcholine (ach). intrapulmonary bronchi, excised intact from the lungs of pigs, were cleared of accessible luminal liquid, cannulated, and treated with µm ach to induce secretion. paired airways were pretreated for h with mm bupivacaine. bupivacaine blocked . ± . % of the liquid secretion response to ach. the ic for the bupivacaine inhibition was approximately µm. the inhibitory effect of bupivacaine was not due to nonspecific toxicity since tissues exposed to bupivacaine for h and then washed with fresh inhibitor-free buffer recovered to % the control achinduced secretory rate. the bupivacaine effect was not due to inhibition of voltage-gated na + channels in intrinsic neurons since µm tetrodotoxin did not inhibit ach-induced secretion. no significant effect was seen in the secretion rate when the extracellular solution ph was lowered from . ± . (normal hco --buffered krebs gassed with % co ) to . ± . by gassing with % co gas (balance o ). while we recognize the relative nonspecificity of this agent, the inhibitory effects of bupivacaine on liquid secretion by porcine bronchi are consistent with k p channel participation in this secretory response. the failure to demonstrate inhibition with acidification of extracellular solution could signify a k p channel subtype that is insensitive to low extracellular ph. ( . novartis, horsham, united kingdom; . rosalind franklin university, chicago, il, usa; . mount sinai medical center, miami, fl, usa; . genomics institute of the novartis foundation, la jolla, ca, usa enac activity in the human airway epithelium has been reported to be partially-sensitive to the broad spectrum trypsin-like protease inhibitors aprotinin and placental bikunin (bridges et al., am j physiol :l - ; donaldson et al., jbc : - ) . a low molecular weight inhibitor of the airway channel activating protease (cap) would represent a potential therapeutic approach to attenuating enac function in cystic fibrosis (cf) lung disease. the aims of the current study were to: ( ) further characterise the in vitro efficacy of cap inhibitors in human bronchial epithelial cells (hbes), ( ) to evaluate the relevance of a cap mechanism to the regulation of enac function in vivo, and ( ) to establish whether the inhibition of the airway cap can modulate mucociliary clearance in vivo. primary cultures of hbes (normal and cf), cultured under air-liquid interface conditions, demonstrated an amiloride-sensitive short circuit current (isc), that was sensitive to aprotinin but that was insensitive to inhibition by sbti, α -anti-trypsin and α -pdx. the amiloride sensitive isc was also attenuated by the low molecular weight cap inhibitor nvp-qau (hbc ) with an ic value of approximately nm. nvp-qau caused a time dependent inhibition of the isc with a t ⁄ of approximately min and this effect could be reversed by the addition of excess trypsin. in vivo, aprotinin attenuated the guinea pig tracheal potential difference (tpd) from - . ± . mv to - . ± . mv (n= - ) with an ed value of pmoles/kg, measured at hours following intra-tracheal instillation. the tpd was unaffected by either sbti or α -anti-trypsin at doses up to pmoles/kg. the combination dosing of an enac blocker with aprotinin did not attenuate the tpd beyond the effect observed with either agent alone, consistent with aprotinin attenuating enac function in this model system. intra-tracheal instillation of nvp-qau attenuated the tpd from - . ± . mv to - . mv with an ed value of µg/kg (n= - ). in the sheep, the administration of nvp-qau into the airways by aerosolisation of a mg/ml solution resulted in a - fold enhancement of the rate of clearance of mtc sulfur colloid from the lungs compared with the vehicle control. these studies indicate that the cap mechanism of enac regulation can translate through in vitro human assays, into in vivo models. cap inhibitors can attenuate tpd in the guinea pig in vivo and enhance the rate of mucociliary clearance in the sheep, thereby representing an approach to the therapeutic regulation of enac function in cf lung disease. cotton, c. pediatrics, physiology and biophysics, case western reserve university, cleveland, oh, usa cystic fibrosis is caused by mutations in the gene that encodes cftr, a camp-activated apical membrane anion channel. loss of cftr-mediated anion conductance is a primary defect in cf but secondary defects such a sodium hyperabsorption are also implicated in cf pathophysiology. it is generally accepted that mucociliary clearance is compromised in cf airways due to reduced fluid secretion and/or increased fluid absorption. the recent generation of a transgenic mouse model with enac overexpression that exhibits cf-like lung disease highlights the importance of sodium hyperabsorption. therapies designed to reduce mucus production and viscosity, increase lumenal water content, stimulate fluid secretion, and inhibit fluid absorption are under development for treatment of cf airways. although controversial, several recent studies have demonstrated that serca pump inhibitors partially correct the trafficking defect associated with delta f mutant cftr. the goal of this work is to determine if serca pump inhibitors affect enac-mediated sodium absorption. a renal collecting duct epithelial cell line and primary cultures of well-differentiated human tracheal epithelial cells (air/liquid interface culture) were used for these studies. amiloride-sensitive short circuit current was determined as a measure of enac-mediated sodium absorption. quantitative rt-pcr was used to evaluate expression levels for each of the subunits of enac (alpha, beta, and gamma). epithelial monolayers were treated for - hours with serca pump inhibitors (thapsigargin, - nm; dbhq, - um; and curcumin, - um). treatment with serca pump inhibitors decreased amiloride-sensitive short circuit current by - %. in contrast, campstimulated short circuit current was not reduced by treatment with serca pump inhibitors. the steady-state levels of alpha, beta, and gamma enac were reduced by - % in renal epithelial monolayers treated with thapsigargin whereas beta and gamma enac were reduced by - % with no significant change in alpha enac in airway epithelial cells. the results of these studies demonstrate that sustained depletion of endoplasmic reticulum calcium stores and/or elevation of intracellular calcium by inhibition of serca pump activity reduces enac mrna expression and enac-mediated sodium absorption. thus, inhibition of serca pump activity in airway epithelial cells of cf patients that carry the delta f mutation may provide dual benefit by promoting delivery of mutant cftr to the membrane . pediatrics, national jewish medical and research center, denver, co, usa; . integrated department of immunology, national jewish medical and research center, denver, co, usa; . department of medicine, cystic fibrosis/pulmonary research and treatment center, the university of north carolina at chapel hill, chapel hill, nc, usa increased cytosolic calcium ([ca + ] i ) initiated by the release of stored ca + from the endoplasmic reticulum (er) is a key signal to elicit a wide range of essential cellular responses, including secretory functions of the respiratory epithelium that are modified in cf. serca pumps are responsible for (re)filling the er ca + stores, and serca blockers such as thapsigargin are very potent and commonly used pharmacological triggers of ca + -signals. modulation of the activity of sercas can profoundly affect ca + homeostasis. although defective calcium homeostasis is a characteristic of several pulmonary diseases including cf, the role of serca is unknown. lung tissue samples (bronchus and distal lungs) from normal (n= ) and cf subjects (n= ) were evaluated by immunohistochemistry. serca expression was decreased in the bronchial and bronchiolar epithelia of cf. non-cf and cf bronchial epithelial cell line pairs including calu- and jme/cf , c- and ib - , hbe o-( hbe), cfbe o-(cf o-) and cfbe o-(cf o-) were also probed. given certain limitations of such cells, several consistent findings still emerged. a % and % decrease in serca expression was observed in cf o-and cf ocells as compared to hbe cells. immunocytochemical studies in these cells confirmed that the serca was localized in the er and that the decreased serca expression was not associated with decreased er content. reduced serca expression and activity ( . ± . vs . ± . and . ± . pmol/min/mg protein in hbe vs. cf o-and cf ocells respectively) was observed in the purified er membranes from cf cell lines. northern blot analysis revealed a parallel reduced mrna expression as well. decreased serca was accompanied by increase in the low affinity isoform serca ( . ± . vs. . ± . and . ± . arbitrary serca intensity/b-actin in respectively) . we have also evaluated a limited number of primary airway epithelial cells isolated from lung samples of normal and cf subjects for serca expression. serca expression in polarized tracheobronchial epithelial cell lysates from cf subjects was decreased by about % as compared to those from normal subjects ( . ± . vs. . ± . arbitrary serca intensity/b-actin units in cf and normal respectively, n= ). expression of serca could also be suppressed by inhibiting cftr with cftr inh in normal human bronchial epithelial cells ( various studies indicate that the airway surface fluid possess an antibacterial system based on the combined action of lactoperoxidase, h o , and scn -(thiocyanate). the enzyme lactoperoxidase (secreted by submucosal glands) utilizes h o and scnto generate oscn -(hypothiocyanite) a molecule with antimicrobial activity. h o is produced by dual oxidases expressed on the apical membrane of airway epithelial cells whereas scnis transported across the epithelium through anion transporters and channels. in particular, scntransport seems to occur through cftr and other ca +dependent clchannels. therefore, reduced scntransport in the airways of cystic fibrosis patients may contribute to impaired antimicrobial activity. in a recent study, we have found that cytokines, in particular il- , cause a strong increase in the ability of cultured bronchial epithelia to transport scnfrom the basolateral to the apical membrane. this effect is mediated by upregulation of ca + -dependent clchannels and of the slc a (pendrin) anion transporter. these findings suggest that under proinflammatory conditions the activity of the scn -/h o /lactoperoxidase system is potentiated. we evaluated the antimicrobial activity of airway surface by seeding bacteria on the apical membrane of human bronchial epithelia grown with an air liquid interface on a porous membrane. an inoculum corresponding to , cfu of s. aureus was added to the cells in µl of saline solution with and without lactoperoxidase ( . µg/ml). experiments were performed in the presence or absence of scn -( µm) in the basolateral solution. bacteria were recovered after four hours and plated on agar plates for colony counting. our preliminary results show that simple addition of lactoperoxidase to the apical surface decreases bacterial survival. in addition, bacterial killing is strongly enhanced by prestimulation of cells for hours with il- ( ng/ml). the effect of lactoperoxidase is dependent on h o as it is prevented by addition of catalase and is absent in cell-free experiments when h o is omitted from the reaction mixture. surprisingly, the presence of scnin the basolateral compartment did not increase bacterial killing and, in some cases, appeared to generate a protective effect. our results suggest that lactoperoxidase, in the presence of h o , is an effective antimicrobial molecule. the contribution of scnand the mechanism of the potentiation caused by cytokines is less clear and requires further investigation. a possibility is that, in the absence of scn -, lactoperoxidase generates an oxidant molecule that is more toxic to bacteria than oscn -. elucidation of this mechanism and comparison between cf and non-cf epithelia is in progress to assess the role of cftr and of other anion channels. supported by cfft and telethon-italy. cf patients become infected with pseudomonas aeruginosa, which release flagellin into the airway surface liquid to activate toll-like receptor and proinflammatory signaling. flagellin has been shown to inhibit na absorption by airway epithelia. we tested flagellin on cl secretion and proinflammatory signaling (nf-κb activation) by calu cells, a cftrexpressing, serous-like airway gland cell line. calu cells were grown on filters and either mounted in ussing chambers (clamped to zero mv) in the presence of a serosa-to-mucosa gradient of [cl] for measurements of transepithelial cl secretion (i cl ) or treated with an adenovirus expressing nf-κb-controlled luciferase to assay nf-κb activation. flagellin ( - g/ml) on either the apical or basolateral surface of cells increased apparent anion secretion that began in - mins and increased over - mins by - µa/cm . this i cl was blocked by glibenclamide and glyh , indicating that it resulted at least in part from activation of cftr. flagellin also stimulated fluid secretion by intact human tracheal glands. flagellin activated nf-κb (luciferase assays) in both calu- cells and in the cf cell line cf , while i cl was stimulated in calu but not in cf cells. flagellin-stimulated i cl in calu- cells was blocked % by sb (a p mapk blocker) and by a similar amount by wortmannin (pi kinase blocker). interleukin β and the tlr -agonist pam cys also activated i cl . the effect of flagellin was not due to increases in cytosolic [ca + ] (ca i ) because flagellin did not alter ca i . in contrast to the slow effects of flagellin, pam cys and il β, atp rapidly increased i cl (within secs, up to µa/cm ) followed by slower decrease to steady i cl = - µa/cm that had a similar time signature as the increases in ca i . forskolin (to increase cytosolic [cyclic amp]) increased i cl within mins to a steady value = - µa/cm . flagellin had small or no effects on i cl following maximal stimulation with either atp or forskolin. atp and forskolin on their own had no effect on nf-κb. flagellin increased phosphorylation of p mapk and of akt (down-stream kinase phosphorylated by pi k) with a time course similar to the increase in i cl . flagellin-activated nf-κb was reduced by roughly % by either wortmannin or sb . these results indicated that tlr agonists and inflammatory cytokines stimulate both nf-κb and proinflammatory processes and also cftr-dependent cl and fluid secretion by airway gland cells. these responses are mediated in part by activation of both p mapk and pi kinase. flagellin-tlr -activated increases in cftr-mediated cl secretion and reduction in enac-mediated na absorption will increase fluid secretion into the airways, which may facilitate bacterial removal by the mucociliary escalator and thereby reduce the proinflammatory stimulus. in cf it is expected that bacteria will activate tlr signaling to trigger innate immune responses, but cl and water secretion and the resulting "bacterial flush," will be missing, leading to sustained inflammation. ( , ) . treatment with hs improved several measures of lung function including mucociliary clearance. in one study amiloride was seen to have a negative impact on the benefit of hs ( ) . the long duration of action of hs and the paradoxical effect of amiloride are surprising and require further investigation. aims: our goal was to study the effect of exposure to a hypertonic challenge (hc) on amiloride sensitive na+ transport (ina) in primary cultures of human bronchial epithelial (hbe) cells from non-cf and cf patients. methods: hbe cells were grown at an air liquid interface and studied under short circuit current conditions. cells were challenged with hs by exchange of the apical or basolateral baths. in some experiments the timedependent effect of a small ( µl) isosmotic or hs volume at the airway surface was tested on ina and apical osmolality. results: application of hypertonic nacl and mannitol solutions from either the mucosal or serosal sides of the epithelium inhibited ina. the degree of inhibition was a saturable function of the imposed hypertonicity with an ic of (mannitol) and (nacl) mosmol/kg h o and a maximal inhibition of %. the inclusion of amiloride ( - µm) did not affect the hc-induced reduction in ina. the inhibition in ina by hc was rapid in onset and accompanied by a fall in the transepithelial resistance and the total transepithelial capacitance as expected for cell shrinkage. the inhibition in ina was only partially reversible (~ %) after returning to isotonic solutions for min. exposure of the airway surface to hypertonicity ( mosmol/kg h o) inhibited ina by - % at min of exposure. as osmotically-driven water moved from the serosal to the mucosal side, the apical volume increased concomitant with a decrease in its osmolality and a recovery of ina. the osmolality declined exponentially and reached the isosmotic value after ~ hrs. the recovery of ina lagged behind the recovery of apical osmolality by , and % at . , and hrs of incubation, respectively. after hrs of airway hc exposure, the osmolality and ina recovered completely. our results demonstrate that hc causes a rapid, dramatic and prolonged decrease in na+ absorption and that continuous presence of amiloride had no effect on the inhibition of ina or the recovery of apical osmolality. hc also causes the epithelium to shrink. no appreciable differences were observed between cf and non-cf hbe cells. conclusions: we propose cell shrinkage together with the continued influx of na+ increases intracellular na+ ([na]i) and lead to an inhibition of na+ transport. elevated [na] i is a known inhibitor of epithelial na+ channels ( ). the sustained nature of the inhibition in na+ transport to a hc may help explain the longer than expected duration of action of hs in the clinical trials ( , ) . explanation of the paradoxical effects of amiloride observed in a clinical trial ( ) requires further investigation. references: . n engl j med : - , ; . n engl j med : - , ; . physiol rev : - , reduced airway surface liquid (asl) volume resulting from enac mediated na+ hyperabsorption and cftr-mediated hyposecretion plays a critical role in cf lung disease pathogenesis. however, the mechanisms involved in enac/cftr regulation are poorly understood. using human bronchial epithelial cultures (hbecs) under thick film conditions, i.e. in the ussing chamber with the asl washed away, adenosine (ado) directly stimulates cl-secretion. however, in a cl-free environment, ado has no effect on the amiloride-sensitive current, which is mediated by enac. mean change in i sc following µm ado to the apical chamber was . µa/cm from baseline compared to vehicle alone (- . µa/cm ;ns;n= ) in hbecs. mean delta amiloride ( µm) was - . and - . µa/cm respectively (ns; n= each). in contrast, under thin film conditions we have previously shown that ado stimulates sustained asl secretion via activation of cftr in the presence of the protease-inhibitor aprotinin, whereas trypsin pre-treatment abolished this secretion, likely by activating enac and abolishing the electrical driving force for cl-secretion . further, ado-mediated asl secretion is significantly increased if hbecs (thin film conditions) are left with intact asl for h, an action that is abolished by acutely washing the apical surface . thus, we hypothesised that a soluble enac inhibitor was secreted into the asl under thin film conditions, which could accumulate sufficiently to inhibit enac and provide the necessary driving force for cftr-mediated cl-secretion after ado-addition. to search for such an inhibitor, we incubated asl with trypsin-coated beads and identified bound proteins by mass spectrometry (albumin-coated beads were used as a control to exclude non-specific binding). the major identified protein was plunc, a protein that is secreted into the asl both in vivo and in vitro which has no current known function. secretion of plunc into hbec asl was confirmed by western blot. to test whether plunc could alter asl volume homeostasis, we made an anti-plunc shrna retroviral construct which we used to infect hbecs. unlike the control anti-luciferase shrna infected hbecs, anti-plunc shrna-infected hbecs exhibited > % knockdown of plunc and a failure to regulate asl volume (ctrl, . ± . µm; ± . µm; n= ) . when co-expressed with enac in oocytes, plunc inhibited enac currents by % (n= ). cftr function in contrast was unaffected by plunc expression (n= ). thus,it is likely that ado stimulates cftr mediated cl-secretion but is not involved in enac regulation. however, experiments were performed in a very simplified environment i.e. static cultures with little mucosal atp or mucus and these findings will need to be expanded and further evaluated in native tissues. we conclude that plunc, rather than ado may be the soluble mediator in the asl which regulates enac function by reducing its activity. . tarran, r. et al., j. gen. physiol., . ( ) airway surface liquid (asl) absorption is mediated by epithelial na + channels (enac), which establish an osmotic gradient that drives fluid absorption. we and others have recently reported that a protease / anti-protease balance regulates enac in normal human bronchial epithelial cells (hbe) and provides a mechanism for auto-regulation of asl volume. in cf, this balance is disturbed, leading to constitutive proteolytic activation of enac and the pathological na + hyper-absorption characteristic of the disease. to determine if channel activating protease expression is regulated by changes in asl volume and is altered in cf, we examined prostasin expression in control and cf hbe under basal and asl volume expansion conditions using western blotting. prostasin migrates as kda and kda bands in apically biotinylated proteins, apical secretions, and whole cell lysates of primary hbe. following apical aprotinin exposure, only the kda prostasin molecular species was present in the biotinylated proteins, suggesting that the proteolytic conversion of prostasin zymogen to active enzyme occurs on the cell surface. following asl volume expansion, cell surface prostasin expression increased by > % (p= . , n= tissue donors, > cultures from each). as our recent studies indicated that increased proteolytic activation of enac occurs in cf airway epithelia, we next compared prostasin expression in cf and control hbe cells. prostasin expression in the apical biotinylate of cf hbe was . fold greater than in control hbe (p= . , n= tissue donors). furthermore, the ratio of the kda (active enzyme) to kda (zymogen) prostasin molecular species was . fold greater in cf (p= . ), indicating that increased activation of prostasin occurs in cf airway epithelium. we next determined whether increased prostasin activation in cf may reflect the deficiency of a protease inhibitor. serpin e , also known as protease nexin- (pn- ), forms an ~ kda complex with prostasin and permanently inactivates its protease activity. while no significant difference in pn- expression was observed between control and cf hbe, pn- was found to contribute to prostasin regulation by (i) forming an inactive prostasin complex, (ii) inhibiting the amiloride-sensitive short-circuit current across hbe, and (iii) preventing conversion of prostasin zymogen to active enzyme. these findings demonstrate that cellular mechanisms coordinate prostasin expression and activity with asl volume. accordingly, at times when the asl volume is high, prostasin expression increases, and this presumably augments na + and asl absorption to absorb the excess luminal fluid. these regulatory mechanisms govern the apical membrane expression and processing of zymogen to active enzyme. because prostasin is incapable of autocatalysis, these findings support the existence of a proteolytic cascade that controls enac activity during asl volume homeostasis, perhaps reflecting the recently reported matriptase-prostasin cascade. furthermore, the increased expression of prostasin in cf suggests that abnormal regulation of prostasin contributes to na + hyper-absorption in cf airways. supported by the nih, cff, and ala. we report that annexin (anx )-s a forms a functional camp/pka/calcineurin (can)-dependent complex with cftr. cell stimulation with forskolin/ibmx significantly increases the amount of anx -s a that reciprocally co-immunoprecipitates with cell surface cftr and can a. pre-inhibition of the cells with pka or can inhibitors attenuates the interaction. furthermore, we find that the acetylated peptide (stvheilcklsleg, ac - ), but not the non-acetylated equivalent n - , corresponding to the s a binding site on anx , disrupts the anx -s a /cftr complex. analysis of dids and cftr inh -sensitive currents, taken as indication of the outwardly rectifying cl-channels (orcc) and cftr-mediated currents, respectively, showed that ac - , but not n - , inhibits both the camp/pka-dependent orcc and cftr activities. can inhibitors (cypermethrin, cyclosporin a) discriminated between orcc/cftr by inhibiting the cftr inh , but not the dids, sensitive currents, by more than %. furthermore, peptide ac - inhibited acetylcholine-induced short-circuit current measured across a sheet of intact intestinal biopsy. our data suggests that the anx -s a /cftr complex is important for cftr function across epithelia. the content and water (h o) mobility in airway epithelium is tighly coupled to airway function. in cystic fibrosis (cf), h o epithelial permeability is reduced in airways. the demand of noninvasively imaging techniques with high spatial resolution potential is rising because such imaging tools would expedite anatomical and functional phenotyping in the genetically altered mice. magnetic resonance microscopy (mrm) is a noninvasive, inherently three-dimensional ( d) imaging technique capable of visualizing anatomical structures in the mouse and allows for interpretation of complex spatial relationships between substructures and h o. in this study, we explore different mr contrast parameters and signal-to-noise ratios at a µm pixel size to characterize microstructure and h o mobility in ex vivo trachea of cf transmembrane conductance regulator (cftr)-deficient (cftr knockout, cftr tm unc ) mice and their aged-matched wt littermates. this study is performed using a bruker mrm system at . tesla. we demonstrate for the first time the ability of d-mrm to map the h o content and mobility in trachea epithelium. from the d-mrm videoimages, differential h o content was visualized in different levels of trachea in wt and cf mice. t mrm images depicting the h o rotational mobility which is related to environmental viscosity of trachea epithelium will be also shown. finally, this d-mrm imaging method is a valuable method for measuring h o content and permeability in airways and can serve for assessing the effects of drugs on h o mobility in cf airways. supported by grants from inserm, upmc-paris , cnrs, and the french cystic fibrosis association (vlm). cystic fibrosis (cf) is a lethal inherited disorder caused by mutations in a single gene encoding the cystic fibrosis transmembrane conductance regulator (cftr) protein resulting in progressive lung oxidative damage. in this study, we evaluated the role of cftr in the control of ubiquitin-proteasome activity (ups system) and the nf-κb / iκb-αsignaling after lung oxidative stress. we exposed cftr deficient (cftr-/-) and wild type mice for h to hyperoxia-mediated oxidative stress. cftr deficient mice exhibited significantly higher lung proteasomal activity than cftr+/+ animals after oxidative stress. this was accompagnied by a strong reduction of lung caspase- activity and an absence of degradation of nf-κb inhibitor iκb-α. in vitro, human cftr-deficient lung cells also exhibited higher proteasomal activity and a lack of increased nf-κbdependent transcriptional activity compared to cftr-sufficient lung cells after oxidative stress. furthermore, inhibition of the proteasomal activity by mg in cftr-deficient lung cells restored the nf-κb/iκb-α signaling to that of cftr-sufficient lung cells. inhibition of caspase- by z-dqmd in cftr-sufficient lung cells mimicked the response profile of increased proteasomal degradation and lowered nf-κb transcriptional activity of cftr-deficient lung cells when exposed to oxidative stress. all together, these results suggest that cftr is a crucial molecule in regulating proteasomal degradation and nf-κb activity in lung epithelium under oxidative stress. staphylococcus aureus, one of the major pathogen involved in airway infections, releases in the airway lumen virulence factors that may impair the airway epithelial functionality. to date, the effect of s. aureus virulence factors on the loss of electrolyte homeostasis of the airway epithelium has not been investigated. we have previously shown that the combination of a corticosteroid and a long-acting beta agonist attenuated the airway epithelial cell inflammatory response induced by s. aureus virulence factors. the aim of the present work was to investigate the effect of s. aureus virulence factors on the airway epithelial tightness and on the chloride efflux of airway epithelial cells incubated or not with salmeterol hydroxynaphthoate × - m and fluticasone propionate × - m (sm/fp). the airway epithelial tightness was assessed by immunocytochemistry, western blotting and transepithelial resistance measurement. the chloride efflux was evaluated by dynamic imaging using the -methoxy-n-( -sulfopropyl) quinolinium (spq) fluorescent probe. s. aureus (strain - ) virulence factors were obtained by growing bacteria at × cfu/ml for h at °c. the bacteria supernatant containing s. aureus soluble virulence factors was then centrifuged, filtered and diluted at % in cell culture medium (a concentration that did not alter cell viability). human airway epithelial cells (mm ) were incubated with % s. aureus virulence factors for h and then co-incubated or not with sm/fp for h. we observed that the incubation with % s. aureus virulence factors alone did not significantly alter the epithelial integrity assessed by the expression of tight junction proteins and transepithelial resistance measurement. however, when the cells were incubated with sm/fp alone or with % s. aureus virulence factors plus sm/fp, the expression of tight junction proteins was significantly increased (p< . ) as compared to cells incubated with s. aureus virulence factors. interestingly, the chloride efflux in airway epithelial cells was significantly decreased in a time-dependent way by s. aureus virulence factors ( fold decrease after a h incubation). the co-incubation of airway epithelial cells with s. aureus virulence factors and sm/fp prevented the s. aureus virulence factorsdependent chloride efflux decrease. our results demonstrate that bacterial virulence factors induce the loss of the electrolyte homeostasis and suggest that the treatment by the combination of a corticosteroid and a long-acting beta agonist may preserve the airway epithelial functionality. supported by association vaincre la mucoviscidose and glaxo-smithkline nilsson, h.e. ; dragomir, a. ; ahlander, a. ; johannesson, m. ; roomans, g.m. . medical cell biology, uppsala university, uppsala, sweden; . women's and children's health, uppsala university, uppsala, sweden inhalation of hyperosmotic solutions (salt, mannitol) has been used in the treatment of patients with cystic fibrosis or asthma, but the mechanism behind the effect of hyperosmotic solutions on mucociliary clearance (mcc) is unclear. one explanation has been suggested, namely that hypertonic solutions open tight junctions, which may lead to increased water transport followed by an increased airway surface liquid (asl) volume. furthermore, the role in cftr-mediated hco -conductance in regulating asl ph has led us to investigate if ph changes may have an effect on the tightness of tight junctions. the effect of osmolarity was investigated on the hbe o-cell line by the addition of nacl, nabr, licl, mannitol or xylitol ( - mosm). the effect of ph was investigated on the hbe o-, calu- and t cell lines as well as the cystic fibrosis cell line cfbe o-. transepithelial resistance was measured as indicator of the tightness of the cultures. cell-cell contacts and morphology were investigated by immuno-fluorescence and by transmission electron microscopy, with lanthanum nitrate added to the luminal side of the epithelium to investigate tight junction permeability. the electrolyte solutions caused a significant decrease in transepithelial resistance from mosm on, when the hyperosmolar exposure was gradually increased from to mosm, whereas the non-electrolyte solutions caused a decrease in transepithelial resistance from mosm on. immunofluorescence micrographs showed weaker staining for the proteins zo- , claudin- in treated samples compared to the control. the ultrastructure revealed an increased number of open tight junctions as well as a disturbed morphology with increasing osmolarity, and with electrolyte solutions opening a larger proportion of tight junctions than non-electrolyte solutions. it was noted that during the exposure of the cultured cells to the hyperosmolar solutions, the ph of the medium increased from . to . . hbe o-cells exposed to both a rise in ph and hyperosmotic stress showed an overall lower teer and a significantly reduced ability to recover from stress compared to cultures at a ph hold constant at . . without exposure to hyperosmolar solutions, a rise in ph caused a significant decrease in transepithelial resistance in hbe o-cells, calu- and t cell lines but not in the cfbe o-cell lines, where the reaction was significantly less and delayed. in conclusion, hyperosmolar solutions caused a reversible opening of the tj in hbe o-cell cultures with electrolytes having stronger effects than non-electrolytes, where one of the effects on mcc may be due to increased water transport across the leaky paracellular space. an increase in ph caused a significant decrease in teer in the healthy cell lines compared to the cfbe o-cell line. we speculated that an impaired alkalinisation of the apical fluid due to a defective cftr also will cause the tight junctions to react different to other external stimuli, such as osmolarity, compared to healthy cells, which is also indicated by preliminary experiments on the effect of nacl on teer in cfbe o-cultures. extracellular nucleotides regulate surfactant secretion in alveoli and mucociliary clearance in airway epithelia, but the mechanism(s) of their release and their regulatory pathways remain incompletely understood. previously, we showed that hypotonic swelling of a epithelial cells induces ca + -dependent secretion of several adenosine and uridine nucleotides, implicating regulated exocytosis. in this study, we examined sources of intracellular ca + ([ca + ] i ) elevation evoked by acute % hypotonic stress and the role of autocrine purinergic signaling in ca + -dependent atp release. we found that atp release does not directly involve ca + influx from extracellular spaces, but depends entirely on ca + mobilization from intracellular stores. the [ca + ] i response consisted of slowly-rising elevation representing mobilization from thapsigargin (tg)-insensitive stores and a superimposed rapid spike due to ca + release from tg-sensitive endoplasmic reticulum (er) stores. the latter could be abolished by hydrolysis of extracellular tri-and di-nucleotides with apyrase; blocking p y /p y receptors of a cells with suramin; blocking udp receptors (p y ) by ppads; emptying tg-sensitive stores downstream with µm tg or mm caffeine in ca + -free extracellular solution; or blocking the ca + -release inositol , , -triphosphate (ip ) receptor channel of the er with µm aminoethyl diphenylborinate. these results demonstrate that the rapid [ca + ] i spike results from the autocrine stimulation of ip )/ca + -coupled p y /p y receptors, which accounts for ~ % of total ca + -dependent atp release evoked by hypotonic shock. our study reveals a novel paradigm in which atp release is amplified by the synergistic autocrine/paracrine action of co-released uridine and adenosine nucleotides. we suggest that a similar mechanism of purinergic signal propagation operates in other cell types. (this study was supported in part by the canadian institutes of health research and the canadian cystic fibrosis foundation (ccff). s.t. was the recipient of a ccff studentship). the maintenance of a thin liquid layer on the airways and alveoli surfaces is essential for normal lung physiology.yet, the mechanism sensing the height of the layer remains obscure. in this study, we examined atp secretion from human lung a epithelial cell monolayers mounted in a closed, flowthrough chamber ( . mm height) and found that passage of an air bubble over the monolayer caused transient (< . min) but significant atp release ( to , pmoles/ cells). air bubble-induced atp release was reduced by~ % from cells loaded with the intracellular ca + chelator bapta-am, and was completely abolished in n-methylmalemide-treated ( mm) cells, suggesting the involvement of ca + -dependent exocytosis. fura- intracellular ca + ([ca + ] i ) imaging experiments revealed transient [ca + ] i elevation during the passage of an air bubble over the cell monolayer, but the [ca + ] i response did not involve non-specific ca + influx from the extracellular space, e.g. due to cell damage, since similar responses were observed in ca + -free extracellular solution. ethidium bromide staining did not disclose any cell damage in these experiments. confocal fluorescence microscopy study showed reversible cell deformation (flattening) of % to % in height in the monolayer part in contact with the air bubble and confirmed that cell integrity was entirely preserved. these experiments demonstrate that in close proximity to the air-liquid interface (i.e. between the air bubble and the wet cell surface), surface tension forces are transmitted directly on cells, causing their mechanical deformation, elevation of [ca + ] i and subsequent atp release. we propose that a similar mechanism may operate in vivo in the airways, where surface tension forces acting directly on exposed epithelial cell surfaces may provide a fail-proof mechanism to protect proper airway surface liquid volume via mechanosensitive, ca + -dependent atp release and purinergic modulation of fluid secretion. this mechanism may be defective in cystic fibrosis due to excessive mucus layer covering the airways. introduction : cystic fibrosis is a genetic disease that reflects the consequences of mutations in the cystic fibrosis transmembrane conductance reg-ulator (cftr) gene, affecting anionic transport in epithelia. slc family members are anionic transporters involved in cl-and hco -absorption or secretion in epithelia. in addition, the activation of some slc family members by cftr has been demonstrated (nature cell biology, , : - ) . slc a is a poorly characterized member of this family, being the solely expressed in lung. putative interaction domains with cftr are also present in the slc a protein. in this study, we have investigated the transport properties of slc a (human) to determine the functional and pharmacological characteristics of this transporter. methods : to this aim, electrophysiological studies (two-electrode voltage clamp or current clamp methods and intracellular ph measurements using ph sensitive microelectrode) were performed in xenopus laevis oocytes expressing slc a proteins. complementary ( cl) transport studies were also undertaken. results : the protein expression results in the appearance of an anionic current showing a linear current/voltage relationship. cl influxes experiments confirmed the induced cl-permeability following slc a protein expression. the sequences of conductivity, cl->i-> no -≥ gluconate > so -and selectivity (px/pcl), i-> cl-= no -> gluconate > so -are found. the hco -conductance mediated by the slc a protein expression is low. using co /hco -containing ringer solutions, no intracellular phi changes were detectable in conditions (low chloride in external medium) favoring the cl-/hco -exchange whereas phi changes (alkalinization) were observed with the expression of the ae exchanger. however, phi changes could be detected in conditions largely favoring the driving force for hco -entry. dids and ns inhibited slc a associated currents. the specific cftr inhibitor (cftrinh ) or glybenclamide had little effect. elevation of intracellular camp (a cftr activator) was also ineffective while maneuvers increasing intracellular calcium blocked the slc a associated currents. conclusions : our study demonstrates that slc a presents an electrogenic anion conductance (characteristics of an anionic channel) when expressed in xenopus oocytes (however a transporter functioning as a ncl-/hco -exchanger can not be excluded). this function (channel) has also been described for another member of this family, slc a (j biol. chem, , : - ) . the physiological role of slc a , present in the bronchial cells of airway epithelia and its potential interaction with cftr has to be precised in situ or in oocytes and in mammal expression systems. medicine, women's & children's hospital, nth adelaide, sa, australia; . cf research & treatment center, university of nth carolina at chapel hill, chapel hill, nc, usa; [ ] [ ] [ ] [ ] [ ] [ ] jasri, hyogo, japan; . physics and synchrotron science, monash university, clayton, vic, australia; . paediatrics, university of adelaide, adelaide, sa, australia non-invasive imaging of lung (e.g. hrct, mri, pet) is a valuable modality for detection and monitoring of the effects of cf in human airways, but resolution is limited; e.g. airway hrct detects airways no smaller than ~ . mm dia. detection of wall or lumen changes in smaller airways, or the detection and monitoring of induced airway disease in live rodent models, demands significantly greater resolution coupled with rapid image capture. we report substantially increased airway resolution is achievable using synchrotron phase-contrast x-ray and can produce three-dimensional reconstructions encompassing the smallest mouse lung airways. nembutal-anaesthetised c bl/ mice (~ gm) were imaged at the spring- synchrotron in hyogo, japan. -d phase-contrast airway images were obtained on ccd detectors ( . µm pixels) with a cm phase-contrast propagation distance at kev; nose and trachea were imaged at or sec intervals ( - ms exposures) over mins. mice killed with nembutal overdose were imaged in axially aligned segments to obtain dimensional ct data voume of approximately x x mm with x x um voxels of nose, trachea, and lung (hammamatsu ccd detector). volume renderings were produced using volview or osirix software. live, -d nasal or tracheal imaging revealed airway-surface activity in some live mice consistent with dynamic mucociliary clearance activity. individual ct slices revealed the fine detail in the mouse lung, with dynamic ("fly through") sequences of lung ct slices permitting visual identification and tracking of lung tree branching from trachea (~ mm dia) into small airways (approx um dia). adjustment of x-ray contrast, opacity, and range in these volume reconstructions permitted selective display of the mouse lung conducting-airway tree and airway surfaces. selected regions of the lung could be examined statically, or in rotation through different orientations in high-resolution -d. synchrotron phase contrast x-ray provides a new option for non-invasive imaging of intact mouse lung, at a resolution that permits examination of small conducting airways in mice. combined with volume-reconstruction software these ultract images can provide a powerful option for understanding the structure-function relationships produced by airway disease. ultra-ct -d studies are underway to compare lung airways at high resoltuion in normal and transgenic mice having altered airway pathophysiology. the epithelial sodium channel, enac, has a vital role in the function of the pulmonary epithelia and significantly contributes to the pathophysiology of the cf airway. thus, strategies to repair mutant cftr dysfunction must also consider the influence of such repair on enac functional expression. the ∆f trafficking repair agent -phenylbutyrate modulates the expression of the kda molecular chaperones hsc and hsp in cf epithelial cells. we therefore assessed the role of these chaperones in the regulation of enac trafficking. in xenopus oocytes, we previously observed that overexpression of hsc inhibits murine enac (menac) functional and surface expression. in contrast, hsp can either enhance or inhibit menac functional and surface expression depending on the extent of overexpression [goldfarb et al. ( ), proc. natl. acad. sci. : - ]. here, we tested the hypothesis that these differential effects of hsc and hsp on menac expression also occur in epithelial cells. mdck cell lines with stable expression of α-ha, β-v , γ-myc-menac and tetracyclineinducible expression of either hsc , atpase-deficient hsc , hsp or atpase-deficient hsp containing myc/his epitope-tags were selected. all epitopes were fused to the respective c-termini. these cells were grown as high-resistance (> Ω/cm ) monolayers on permeable supports. doxycycline-induced overexpression of hsc decreased amiloride-sensitive i sc and the whole cell content of α-haand β-v -menac. in contrast, lower amounts of tetracycline-induced hsp overexpression increased amiloridesensitive i sc and whole cell α-haand β-v -menac expression; these effects were absent at higher levels of hsp overexpression. these data are consistent with our previous data in xenopus oocytes. interestingly, the atpase-deficient chaperones had the opposite effect on menac functional expression. modest doxycycline-induced expression of atpase-deficient hsc increased amiloride-sensitive i sc in these cells, while modest overexpression of atpase-deficient hsp decreased amiloride-sensitive i sc . these effects may result from "dominant negative" interference with hsc and hsp function, respectively. these data are consistent with hsc and hsp having different effects on menac functional expression in epithelial cells, and that these effects are dependent upon the atpase activity of the respective chaperones. supported by grants from niddk. we have studied survival, airway epithelia bioelectrics and lung pathology of mice over-expressing various combinations of the epithelial na + channel (enac) subunits (α, β and γ, genes scnn a, scnn b and scnn g). we generated double-transgenic mice and crossed them with single-transgenic mice to obtain litters comprising all possible genotypes. survival analysis revealed that overexpression of βenac in combination with either αenac or γenac significantly reduced survival in comparison to wild-type (wt) littermates. strikingly, at days of age, all genotypes were represented according to the expected mendelian proportion, except for the triple transgenic αβγenac, which was significantly under represented. in utero studies are ongoing to understand if over-expression of αβγ affects the fetuses or the newborn pups during the first hours post-partum. due to the high mortality of mice over-expressing βenac subunit combinations, we studied tracheas from pups at days of age. as previously reported, mice overexpressing β, but not the α or γ enac subunits, exhibit airways hyperabsorption of na + and lung pathology (mall et all ) . the βenac tracheas exhibited na + absorption [as measured by the change in short circuit current (isc) in response to amiloride in the ussing chamber] that was ~ . fold greater (∆isc . ± . µa×cm - , n= , means±sem) than wt ( . ± . µa×cm - , n= ). over-expressing αβ or αγ enac subunits resulted in rates of na + absorption that did not differ significantly from those of βenac or γenac subunit alone, respectively. however over-expressing the β and γ enac subunits together resulted in an amiloride sensitive isc that was ~ . fold greater (∆isc . ± . µa×cm - , n= ) than wt. we also studied the tracheal bioelectrics of the few day-old αβγenac pups available. tracheas from the αbγ pups exhibited na + absorption that was ~ . fold greater (∆isc ± . µa×cm - , n= ) than wt. due to the small sample size, we cannot determine if this response is significantly different from the response of the βγenac pups. analysis of lung pathology in day-old pups revealed that all the combinations that exhibited increased airway na + absorption and decreased survival in comparison to wt littermates, e.g. αβ, βγ and αβγ, also presented with alveolar space enlargement, maybe due to postobstructive air trapping, and airway epithelia necrotic degeneration associated with ab-pas negative bronchial obstruction. from these data, it appears that the rate of airway na + absorption negatively correlates with the survival of the pups. thus, it is likely that the mucus and airway surface liquid is more dehydrated as a function of the rates of na + absorption (aβγ > βγ > αβ, β > wt) which produces gradual failure to survive due to asphyxia secondary to airway obstruction. supported by nih scor p hl choi, j. , ; joo, n. ; wu, j. ; krouse, m. ; wine, j.j. . cystic fibrosis research laboratory, , stanford, ca, usa; . otorhinolaryngology, yonsei university, seoul, south korea submucosal glands, which produce most airway mucus, are mainly controlled by parasympathetic pathways that stimulate glands via airway intrinsic neurons distributed along the airway walls. the intrinsic neurons can be stimulated via axon reflexes from receptors in the mucosa. in previous experiments, it was shown that capsaicin applied to the mucosa stimulated gland secretion in the upper tracheas of wt but not cftr -/-mice (ianowski et al., j physiol, , , ) . it seemed important to assess a possible role of capsaicin-sensitive pathways in pigs and humans. we obtained pig tracheas following acute experiments carried out for other reasons, and human airways following lung transplants from donor tracheas and from the excised lungs of the transplant recipients. secretion from individual submucosal glands was quantified optically by time-lapse digital imaging of the growth of spherical bubbles of mucus in an oil layer in humans, commercial chili oil ( µm dispersed in µm mineral oil) stimulated mucus secretion from submucosal glands from both donors (n = glands from subjects, . ± . nl/min/gland) and disease control subjects (n = glands from subjects, . ± . nl/min/gland). however, there were no responses to chili oil in submucosal glands from cf subjects (n = glands from subjects, . ± . nl/min/gland). in pigs, we determined concentrationresponse relations for gland secretion in response to purified capsaicin (sigma). the threshold was ~ µm and the ec was . ± . µm. the response to µm capsaicin was partially blocked by high dose ttx (> µm). as in humans, the capsaicin response required cftr, because it was blocked ~ % by cftrinh- , (n = glands, from pigs, p < . ). cftrinh- is presently the most specific inhibitor of cftr that can be used with glands, where we do not have access to the apical membrane. in ferrets, intrinsic airway neurons express acetylcholine, vip and sp, often colocalized within the same neurons (dey et al., am j respir cell mol biol, , , ) . in pigs, all three of these transmitter systems appear to be involved in gland secretion to capsaicin, because the response was partially blocked by the nk- receptor blocker l (oxalate salt, µm), the vip receptor inhibitor l k ( µm), and the muscarinic receptor blocker atropine ( µm); each of these blocked to % of the response (n = to glands from to pigs). indeed, most of the local pathways are probably damaged, which may account for the relatively small responses to strong stimulation. relatively few experiments have been carried out in intact airways with uninterrupted innervation and circulation, but in those experiments the glands were highly responsive to modest mucosal stimuli (reviewed in wine, auto neurosci, , , ) . hence, we hypothesize that ( ) reflex stimulation of glands plays an important role in lung innate defenses; ( ) defects in these responses is an important reason that cf airways are prone to infection, and ( ) local reflexes may assume greater importance for maintaining the mucosal defenses of transplanted lungs. supported by niddk ro - (jjw), cff and cfri. most airway mucus arises from submucosal glands, which express cftr in their ciliated ducts and in serous cells. the airway glands secrete to agonists that either increase intracellular ca + (e.g. acetylcholine) or camp (e.g. vip).substance p(sp) also stimulates airway gland liquid secretion in pig (trout l et al., am j physiol lung cell mol physiol. , ,:l ) , suggesting that sensory afferents or local neurons that express sp play a role in stimulating submucosal glands. we used pharmacological methods to dissect the secretory mechanism of sp-induced gland secretion in comparison with responses to carbachol. tracheas were obtained from pigs after acute surgeries carried out for other reasons. the ventral mucosa with underlying glands was dissected from the cartilage, pinned mucosal side up at the gas/bath interface of a physiological chamber, and covered with oil. secretions from individual glands could be visualized as spherical bubbles in the oil, and secretion rates determined by optical monitoring of bubble diameters. concentration-response relations for gland secretion were determined for sp ( - bubbles at each concentration from pigs). the threshold was ~ nm for sp and the ec was . ± . µm. the maximum secretion rate to sp was . ± . nl/min.gland, which is only ~ / of the maximal secretion rate to carbachol ( . ± . nl/min.gland). the inhibition profile for responses to sp ( µm) was quite different from those to carbachol ( nm, a value chose to mimic the secretion rate to µm sp). gland secretory responses to µm sp ( . ± . nl/min.gland, glands from pigs) were strongly inhibited by µm cftrinh- ( . ± . nl/min.gland, glands from pigs, p< . ), and by µm clotrimazole ( . ± . nl/min.gland, glands from pigs), whereas µm niflumic acid did not inhibit ( . ± . nl/min.gland, glands from pigs). in contrast, secretory response to nm carbachol ( . ± . nl/min.gland, glands from pigs) were only weakly inhibited by cftrinh- ( . ± . nl/min.gland, glands from pigs, p< . ), and by clotrimazole ( . ± . nl/min.gland, glands from pigs, p> . ), but niflumic acid, which was ineffective with sp, inhibited the carbachol response ( . ± . nl/min.gland, glands from pigs, p< . ). gland secretion to sp depends at least partially on intracellular ca + release, because the response was partially inhibited by µm bapta-am ( . ± . nl/min.gland, glands from pigs, p< . ). there was no additional effect of sp on top of µm carbachol, but a subthreshold level of sp ( nm) showed synergic response ( . ± . nl/min.gland, glands from pigs) with subthreshold level of vip ( nm). we are presently testing how sp activates cftr-dependent mucus secretion. in initial experiments to determine if pkc was being recruited, however the pkc inhibitor (gf , sigma) did not suppress sp-induced mucus secretion. in contrast, the nkcc inhibitor bumetanide ( µm) markedly suppressed secretion to sp ( . ± . nl/min.gland, glands from pigs, p< . ). supported by niddk ro - (jjw), cff and cfri. mucus obstruction of airways is considered the most vicious agent of morbidity and mortality in cystic fibrosis (cf). to provide optimal defense of the small airways the volume/thickness of airway surface fluid must be controlled according to physiological demand. to date we have no clear understandings of how these fluids are maintained in a steady state between two pathological extremes (too little or too much) in native small airways. earlier studies have attempted to measure the ion transport properties of small airways of sheep (al-bazzaz et. al. ) and pigs (ballard et. al. ), but the complicated branching structure of small airways may have compromised electrical signals. to avoid dissection trauma wang et. al. ( ) examined the electrophysiological properties of undissected intact small airways from pigs in vitro by microperfusing bronchioles (diam. - mm) embedded in the lung parenchyma; however, these studies were limited to luminal manipulations and transbronchiolar electrical potentials only. to more rigorously define small airway properties, we designed a special micro ussing chamber ( area ≈ mm ). we excised and opened small airways (diam. - mm) of pig lung that we mounted as a flat sheet over a pvc supporting filter ( - µm holes). both sides of the tissue could then be bathed with different solutions at °c. the luminal side was isolated by pressing a pipette (≈ mm diam., tip fire polished) on to the apical surface of the tissue until it sealed electrically. constant current pulses ( . - . µa) were passed across the tissue. transepithelial potential (tep) and resistance in bilateral mm nacl ringers were, - . ± . mv and . ± . Ω.cm (mean ± se) respectively. when mm naglu ringers replaced the luminal solution, tep increased significantly to - . ± . mv (n= , p< . ) and resistance increased to . ± . Ω.cm (n= , p< . . adding forkskolin (fsk, µm) plus ibmx ( . mm) hyperpolarized the tep to - . ± . mv (n= , p< . ), but decreased the resistance to . ± . Ω.cm (n= , p< . ). luminal amiloride ( µm) depolarized the tep to - . ± . mv (n= , p< . ) but significantly increased resistance to . ± . Ω.cm (n= , p< . ). these results show that this system supports measurements of ion transport properties of airways smaller than mm diameter where cf lung pathology is thought to originate. these airway epithelia express a very high constitutively active clconductance and are apparently capable of secretory as well as absorptive functions. amiloride sensitive na + conductance (≈ ms/cm ) was not significantly affected by fsk added to activate secretion. the observation that stimulation with fsk did not significantly suppress na + conductance (≈ ms/cm ) (p= . ) may suggest that separate groups of reabsorptive and secretory cells comprise small airway epithelia. mucins are class of proteins uniquely characterized by large glycosylated domains. these proteins likely play a key role in cystic fibrosis (cf) lung disease as major constituents of mucus. in airways of both humans and mice, the gel-forming secreted mucins are represented by muc ac and muc b, and the transmembrane mucins are represented primarily by muc , muc , and muc . we have been interested in the role of the transmembrane mucins in airways and have previously demonstrated that lack of muc in a knock-out mouse model (provided by s. gendler) shows increased susceptibility to adenoviral-mediated gene transfer (stonebraker, j. virology, ) . to expand upon these findings, mice deficient for muc were developed using embryonic stem cell technology by deleting exon of the mouse muc gene, which contains the atg start codon and signal peptide. rna analysis reveals loss of exon in homozygous mutant mice and immunohistochemistry using a vntr antibody indicated a loss of full length muc protein. muc homozygous mice are viable and do not develop any spontaneous, readily detectable disease phenotype. although the muc deficient mice do have reduced fertility consisting of both reduced litter size and number, all major tissue systems where the muc protein is easily detected, including the eye, respiratory tract, intestine, and reproductive tracts, appear normal in year old mice after histological analyses. in contrast to the results we reported in the muc mice, the muc deficient mice do not show an increase in adenoviral mediated gene transfer, suggesting that muc is not involved in the barrier aspect of the airway glycocalxy, at least for adenoviral infection. interestingly, quantitative real-time pcr analysis revealed up-regulation of muc protein in the trachea of the muc deficient mice, suggesting that muc may be able to compensate for loss of muc . the expression of muc in human ciliated cells as revealed by recent antibody studies prompted us to evaluate the potential role of muc in ciliary function. ciliary beat frequency (cbf) was monitored in a shear chamber using microscopy image analysis. cbf under baseline conditions for this study (low shear stress) from muc deficient trachea (c bl/ j congenic n ) was significantly lower than that for littermate controls ( . vs. . , sem ± . , p = . ). application of shear resulted in increased cbf in both groups, although the wt response to shear was smaller in magnitude. thus, muc may have a role in supporting basal cbf and may make cbf less vulnerable to stimulation by shear, perhaps by reducing the inherent friction of ciliary motion. this finding underscores the usefulness of this model for dissecting out the normal roles that the transmembrane mucins play in airway biology. supported by nih (hl ) and cff (r -cr ). enac (joo et al. jbc , and jbc , ) . in a search for a model to test the hypothesis we found that ussing chamber short-circuit current(i sc ) measurements with freshly obtained airway mucosa provided useful information about enac activity in response to various drug treatments. in these studies we observed an as yet unidentified pathway that regulates surface enac activity. airway mucosa from sheep tracheas displays a large, amiloride/benzamil-sensitive i sc prior to stimulation. when stimulated with basolateral carbachol, the enac i sc was almost abolished, as indicated by a sustained decrease ( . ± . %, n= ) in i sc after an initial increase and left a small effect to subsequent amiloride or benzamil. in contrast, when carbachol was given after benzamil, it again produced a peak response followed by a sustained increase (~ %, n= ) in the i sc . enac inhibition by carbachol was dose dependent with a minimal sensitivity between . ~ µm and was slowly reversible. apical µm atp also inhibited enac i sc by . ± . % (n= ) and carbachol on top of atp further reduced the enac i sc by . ± . % (n= ). however, u/ml of apyrase pretreatment, in attempt to breakdown atp, failed to inhibit carbachol-induced enac inhibition, indicating that atp release is not on obligatory component of carbachol inhibition of enac. carbachol inhibition of enac could result from a direct action of carbachol on the surface epithelia, by activation of airway intrinsic neurons, or by activation of the glands, which were intact in these preparations and are strongly stimulated by carbachol. rabbit tracheas, which lack airway submucosal glands, displayed large enac currents and these were not inhibited by cholinergic stimulation (n= ). carbachol-induced enac inhibition, like gland stimulation but unlike stimulation of neurons, was mediated by muscarinic receptors since it was eliminated by atropine but not by the nicotinic receptor antagonist, hexomethonium bromide (n= ). however, inhibition of gland secretion with hepes/bumetanide did not eliminate the ability of carbachol to inhibit enac. the effects of carbachol on surface na + transport in our study are consistent with previous observations in microperfused sheep bronchiole preparations (al-bazzaz, ajp-lung , ). although we do not yet know the mechanism, it would be physiologically efficient if parasympathetic, cholinergic activation of airway gland secretion was accompanied by enac inhibition, which would minimize the fluid absorption by surface epithelia and increase clearance. it will be important to determine if cholinergic inhibition of enac is present in human tissues, and if so, if it is defective in cf. supported by cff and nih. introduction: lung disease accounts for more than % of the current morbidity and mortality associated with cf. the majority of research aiming to elucidate the reason(s) of severe lung disease has focused on airway surface liquid (asl) layer homeostasis or composition. the cftr gene encodes a camp-regulated clchannel located on the apical side of the epithelium and is instrumental in maintaining a hydrated asl layer and promoting effective mucociliary clearance (mcc). in patients with class i or class ii cftr genetic mutations, normal cftr clchannel activity in the epithelium is impaired resulting in na + hyperabsorption and consequently in the generation of a thick and static overlaying asl layer creating an environment that favors progressively worsening bacterial infections. in this study we investigated the potential contributory role of altered respiratory cilia function to inefficient mcc in cf airways allowing for bacterial infestations. our ex vivo model system was the nasal airways of the cftr gene knockout (cftr tm unc ) mouse in which key aspects of the phenotype of human cf lung disease, such as dehydrated asl layer and goblet hyperplasia, are observed. methods and results: ciliary beat frequency (cbf) was measured using a dual temperature controlled perfusion chamber, differential interference contrast microscopy and high speed digital video analysis system. we evaluated the cbf of nasal septa explants from homozygote cf (affected) and non-affected littermate wild type (wt) and heterozygote mice congenic on the c bl/ background. the basal cbf of homozygote cf mice ( ± hz, n= ) was significantly lower than that of wt mice ( ± hz, n= ) and also heterozygote mice ( ± hz, n= ) (p< . , anova, snk test). to determine whether the dehydrated asl layer was still present on the surface of the cf mouse nasal airway epithelium and as such impeding normal cilial beating, we fixed nasal septa (n= ) of cf and wt mice immediately following isolation using the pfc/oso fixation method to preserve the fragile asl layer and compared the height of the asl layer to nasal septa (n= ) from cf and wt mice fixed with pfc/oso immediately following cbf analysis. electron microscopy analysis revealed that although the asl layer was present at the time of isolation, there was no asl layer following the perfusion of solutions necessary for the cbf measurements. this finding demonstrated that the activity of cilia was not impaired in the cf nasal airway epithelium due to the presence of a dehydrated asl layer. cbf frequency was also significantly reduced in three different codes of mouse ciliated nasal airway epithelial cultures derived from affected cf mice compared to those derived from non-affected wt mice. conclusion: we show that the absence of the cftr gene product in the cf knockout mouse nasal airway epithelium is associated with significantly decreased basal cbf compared to the non-affected wt and heterozygote mice. this observation potentially provides an additional mechanism as to why lung disease persists in human cf lungs. ml and mba contributed equally. clinical studies have linked increased sputum and peripheral blood neutrophil mpo activity with increased airflow obstruction in cystic fibrosis (cf) patients of the same age, gender, airway bacterial flora, and cftr genotype. variations in the tgf-β gene associated with increased tgf-β production have been linked to worse airflow obstruction in cf patients of similar age, gender and cftr genotype. we hypothesized that in the presence of mpo, tgf-β production would increase in airway epithelial cells. we obtained normal human airway epithelial cells (hae) and cultured them in trans-wells. tgf-β mrna was measured by pcr. tgf-β protein was detected by immunofluorescence staining and immunoprecipitation. we found increased tgf-β mrna after hae were exposed to mpo (at activities found in cf sputum) normalized to mrna of constitutive beta actin. under identical conditions, tgf-β protein expression was increased in hae. we conclude that neutrophil mpo present on the apical surface of cultured hae induces transcription and protein synthesis of tgf-β . these results suggest that mpo induction of airway epithelial tgf-β is one molecular system linking the chronic neutrophilic endobronchitis seen in cf and subsequent airway wall fibrosis. are more oxidatively stressed than normal. as oxidative stress (os) is a potent activator of nf-κb, these data supported our hypothesis that cftr dysfunction causes alterations in the expression and/or modification of redox related proteins thereby enhancing activation of nf-κb. delineation of this interaction will produce good therapeutic targets. in this report we examine the role of os in cf inflammation. methods: to address our hypothesis, we used both in vitro and in vivo models of cf. our airway epithelial cell models are the hteo-pcep and pcep-r cell pair; and the hbeo-sense (s) and antisense (as) cell pair. additionally, we examined whole lungs from - week old b . s -cftr tm mrc mice (r h mutants back-crossed into the c bl j background). proteins were prepared from homogenates of whole samples, run on -d gels, and their densities compared. the gel spots of differentially expressed proteins were excised, subjected to in-gel trypsin digestion, and identified by lc ms/ms. for biochemical analysis, we tested for the levels of h o , glutathione, and lipid peroxidation. we correlated these data with measurements of nf-κb activity (elisa and cytokine production), and the activity of nrf- , an antioxidant (ao) response pathway transcription factor. we studied cultured cells in the presence and absence of inflammatory stimulation (tnf-α/il- β), and compared non-stimulated cf mouse lungs to lungs from normal litter mates. results: our proteomic analysis revealed that in the absence of inflammatory stimulation, a paradoxical decrease in ao proteins exists in cf cells by or more fold compared to matched pairs. this is despite a significant increase in intracellular os, which we confirmed by different biochemical measures. activity of nrf- was decreased by ~ % in cf cells vs. normal. the data predict an increase in h o , which is a potent activator of nf-κb, and we confirmed both a significant elevation in h o (up - fold in cf) and a related significant increase in nf-κb activity, as assessed by elisa for nuclear p , and il- and il- production. when we analyzed whole lungs from cf mice for antioxidant protein levels, we similarly observed decreases vs. normal littermates. when cells were stimulated, differences in protein expression and oxidative stress between cf and normal were further enhanced, corresponding to an excessive activation of nf-κb and increased production of il- and il- . treatment with the antioxidants nac or selenium decreased the activation of nf-κb to normal levels. members of the clc family of proteins form either voltage-gated chloride channels or cl -/h + exchangers; nine subtypes are found in mammals. among these, clc- is one of the most ubiquitous variants, which is expressed in several of the types of epithelial cells that also express the cystic fibrosis transmembrane conductance regulator (cftr). it has been postulated that clc- may be a suitable alternative chloride pathway in these cells; however the contribution of clc- to chloride transport in these cells is poorly understood. this is partly due to the lack of appropriate pharmacological tools that are capable of specifically inhibiting clc- . we describe here the isolation, from venom of the scorpion leiurus quinquestriatus hebraeus, of the first peptide inhibitor of any clc channel. this toxin, which we have named gatx , specifically inhibits the clc- channel. gatx bears primary sequence identical to that of a toxin thought to serve as a k + channel inhibitor, although no molecular target for this toxin was previously known. a homology model of gatx reveals that it adopts a similar fold to other scorpion toxins. gatx was prepared via solid-phase chemical synthesis, and the synthetic toxin inhibits clc- with higher affinity than any other inhibitor of clc- or any other chloride channel. the k d for gatx mediated inhibition of clc- in multichannel patches is only pm at v m = - mv, and pm at - mv. single channel experiments show that gatx does not alter single channel amplitude, but may alter channel gating. these experiments provide the basis for developing gatx into a useful tool that can be used to define the role of clc- in airway and intestinal epithelial cells. furthermore, the high affinity and specificity of inhibition suggest that gatx interacts intimately with the channel, and thus may the exploitation of alternative chloride channels to bypass the defect in cftr-mediated chloride secretion is an established therapeutic strategy in cf. in search of such potential therapeutic targets, we assessed camp/pkadependent chloride secretion across excised nasal epithelium of cftr null mice and wildtype controls, by measuring short-circuit currents (isc) in an ussing chamber set-up. all experiments were performed in the presence of amiloride to block the contribution of epithelial sodium channels to the isc. in cftr null mice of mixed background (c bl/ ; ), the camp agonist forskolin activated a bumetanide-sensitive rise in isc that was comparable in magnitude to the cftr-mediated isc response of littermate controls ( ± vs. ± µa/cm , respectively). the forskolin-induced isc in these null mice was inhibited by the general chloride channel inhibitor dpc, but appeared insensitive to the cftr inhibitors cftrinh- and glibenclamide, the orcc and calcium-activated chloride channel inhibitor dids, and the clc- inhibitors cadmium and pre-activated omeprazol. moreover, the isc response to forskolin greatly exceeded the response to the calciumlinked agonists ionomycin and carbachol. intriguingly, in nasal epithelium of cftr null mice with a different genetic background (fvb), no such forskolin-inducible secretory pathway was evident (cftr-/-: ± vs. cftr+/+: ± µa/cm ). when, in nasal epithelium of cftr null mice (c bl/ ; ), the basolateral membrane electrical resistance was negated by nystatin treatment, and in the presence of a transepithelial chloride gradient, forskolin failed to elicit a rise in isc, suggesting that camp/pka signaling targets a basolaterally located ion transport system. indeed, in intact epithelium, addition of chromanol b, a selective inhibitor of camp/pka-activated potassium channels, to the serosal bath, blocked the forskolin-induced rise in isc. we tentatively conclude that the hyperpolarization of nasal epithelial cells, which ensues from camp/pka-induced potassium efflux across the basolateral membrane, drives chloride exit across the apical membrane via a constitutively active anion conductive pathway that is absent from fvb cftr null mice. rt-pcr and immunostaining demonstrated that, among the candidate anion channels that fit the above pharmacological profile, clc-ka, but not clc-kb, was expressed in nasal epithelium of both cftr null mice and controls (c bl/ ; ), together with the accessory protein barttin. importantly, immunostaining suggested a strong increase in clc-k protein abundance in the cftr null mice, as compared to wildtype animals. on the basis of these findings, we postulate that clc-ka channels may serve as cftr bypass channels in nasal epithelium of cftr null mice that, albeit indirectly, are responsive to camp/pka signaling. future studies aim to characterize clc-ka and barttin in the airways from cf patients and controls, and to identify the post-transcriptional mechanism resulting in the up-regulation of clc-ka protein in cftr null mice. in the disease cystic fibrosis (cf), the most common mutation f del results in endoplasmic reticulum retention of misfolded cf gene proteins (cftr). the endoplasmic reticulum (er) f del-cftr protein retention is dependent upon chaperone proteins, many of which require ca + for optimal activity. an increase in cytosolic free ca + concentration is dependent on the activity of ion channels in the membrane of er and on extracellular ca + influx. this influx, named capacitative ca + entry (cce), induced by calcium store depletion, represents the major ca + influx mechanism in cells (putney et al., ) . during the cce, ca + influx can be mediated by one or several of the isoforms of transient receptor potential canonical channels (trpc) (putney et al., ) . aims & methods: in the present work, we studied the cce in human cf tracheal gland serous cfkm cells compared to non cf human tracheal mm cells. for this, we characterized the molecular identity of trpc channels responsible of cce by rt pcr technique and we compared global ca + influx in cf and non cf cells by using fluo -am probes. moreover, we measured the single channel activity of plasma membrane trpc channels by cellattached patch-clamp configuration in cf and non cf cells. we also studied the cce in cf cells after correction of the abnormal f del-cftr trafficking by miglustat ( h at µm of n-butyldeoxynojirimycin, nb-dnj) (norez et al., ) and low temperature ( h at °c) (denning et al., ) . results: we detected by rt-pcr technique the presence of trpc and trpc in both cell lines and we observed that cce was increased -fold in cf-km cells compare to non-cf mm cells. following stimulation by histamine, we recorded elementary ca + currents with similar amplitude ( . pa at - mv) and conductance ( ps) whatever the cells tested (cf-km or mm cells). however, we observed a -fold increase of the npo (number of channels in each patch × open probability of single channel) in cf cells compare to non-cf cells. in f del-cftr corrected-cf cells, the ca + influx stimulated by the ca + stores depletion was reduced to a similar level to non cf mm cells. the permanent contact of the airway epithelium with the external milieu induces frequent injuries caused by inhaled pathogens and particles. regeneration of the wounded airway epithelium needs to respect its prior structure in order to restore its defence functions. the underlying molecular mechanisms associated with the regeneration of the human airway epithelium are poorly described. the aim of our study was to determine, using a global expression approach, the transcriptional profile of human airway cells during the epithelial regeneration process. human airway epithelial cells collected from nasal polyps were seeded on type iv collagen-coated porous membranes, cultured up to confluence in liquid-liquid(ll) conditions, then put at the air-liquid interface (ali) allowing epithelial mucociliary differentiation. rna were extracted from epithelial cells at % confluence in ll conditions (epithelial cell proliferation and migration stage, step i), after days in ali conditions (beginning of epithelial cell differentiation, step ii), when first ciliated cells appeared (step iii) and when cultures were completely differentiated (step iv). our results demonstrated that between step i and step ii, genes were significantly modulated (ratio r<- or r> , p< . ), among them were activated and were repressed. between step ii and step iii, transcripts were up-regulated (tubulin, dynein, stath, microtubule associated proteins…) and only one gene (fatty acid desaturase- ) was repressed. finally, between step iii and step iv, except stath which was~ -fold down-regulated, we observed only few genes differentially and slightly modulated. all along the regeneration process, between step i and step iv, genes were significantly modulated with % of activated and % of repressed genes, among them a family of genes encoding proteins involved in the ciliary differentiation (foxj , tektin, dynein, tubulin, …), extracellular matrix proteins (collagen, laminin, …) and inflammatory-related genes like cytokines, growth factors and their receptors (ccl , vegfc, csf , il , il ra …). by elucidating the specific transcriptome involved in each step of the human airway epithelium regeneration, our study could allow to better understand the different cellular and molecular mechanisms, as well as the chronological events involved in these processes, and will further be applied to the study of the regeneration process in cystic fibrosis airway epithelium. supported by french association vaincre la mucoviscidose. electrolytes may be transported either through cells, the transcellular pathway, or between cells, the paracellular pathway. most research has focused on the channels and transporters of the transcellular pathway, while much less is known about paracellular transport. paracellular transport is regulated by tight junctions. claudins, the main component of tight junctions, are necessary and sufficient for tight junction formation and are important in establishing ion selectivity. the goal of this study was to further investigate the role of tight junctions in human airway epithelia. real-time pcr identified claudins , , , , , and in primary human airway epithelia. immunocytochemistry localized claudins , , , and to tight junctions. to measure the relative ion selectivity of tight junctions, we studied well-differentiated human airway epithelia in ussing chambers. to minimize transcellular transport, we used cf epithelia, which lack cftr and blocked enac with amiloride. we found the pna/pcl is . ± . , suggesting tight juctions are more permeable to cations than anions. the relative cation selectivity was na+ > k+ > cs+ > tma+ > mg + and the relative anion selectivity was cl-> br-≥ i-> no -> gluconate-. we compared these in vitro results to in vivo studies in people with cf and measured nasal voltage in the presence of amiloride. we found the pna/pcl is . ± . . tight junctions were slightly more selective for cations than anions in vitro and in vivo. to determine the effect of specific claudins on the selectivity of the paracellular pathway, primary human airway epithelia were infected with adenovirus expressing claudin or gfp. epithelia overexpressing claudin had a higher transepithelial resistance (ter) and the pna/pcl was . . however, infection efficiency was only %. this lead us to investigate if transformed human airway epithelial cells lines may be a better model to study permeability. cufi cells also express claudins , , , , , and . furthermore, like the primary human airway, cufi cells are more selective for cations; pna/pcl = . ± . . future studies will investigate the effect of claudin expression on the paracellular permeability of these cells. the results will help identify the properties of a pathway critical to epithelial transport and barrier functions. altered adenosine (ado) signaling is associated with chronic lung disease and increased asl ado levels are thought to drive inflammation by stimulation of a b receptors (a b-r) in airway epithelia, which can activate nfκb. when measured by lavage, asl ado is ≤ nm. due to its relatively low affinity to ado, a b-r are thought to be inactive under normal conditions (ec is ~ . µm), and only stimulated during chronic lung disease. however, we have previously demonstrated that the ado-receptor (ado-r) antagonist -spt inhibits asl volume regulation, and that a b-r is in close proximity to cftr. thus, we hypothesized that the asl ado concentration close to the apical membrane is higher than measured by asl lavage in bulk solution. we tested this hypothesis by looking for ado-r expression and function in well-differentiated human bronchial epithelia cultures (hbecs) and in vivo. by pcr analysis, we found that a b-r was the only ado-r expressed in hbecs. we then measured asl height over h ± ado-r antagonists by xz confocal microcopy when asl height was preset to ~ µm at t= . at µm, caffeine is a non-specific ado-r antagonist, which inhibited asl volume regulation ( h asl height was . µm vs. . µm for controls, n= ). similar inhibition was observed with alloxazine, which is relatively specific for a b-r (n= ). in contrast, dpcpx, zm & mrs , which inhibit a , a a & a -r respectively had no effect on asl volume regulation. asl height regulation was also ablated by the addition of adenosine deaminase (ada) to the asl (n = ). we next attempted to recapitulate the changes in asl height seen under control conditions, i.e. increase from to µm over the initial h followed by a plateau (the remainder of the h) by adding the non-hydrolyzable ado analogue neca to the asl in the presence of ada. nm neca was insufficient to regulate asl volume and height remained at µm over h. in contrast, addition of µm neca to the asl resulted asl volume regulation that was indistinguishable from control conditions (n= ), suggesting that near-membrane asl is much higher than has been measured by lavage. to confirm that a b-r stimulates cftr chloride secretion, we measured transepithelial potential differences of hbecs mounted in ussing chambers. a dose-dependent increase in cl-secretion was observed by ado addition with an ec of . +/- . µm, similar to the concentration of neca required to regulate asl height. to demonstrate which ado-r are expressed in human airways in vivo, we used laser capture to obtain ciliated cells from frozen tissue sections of excised donor bronchi. relative expression of a b-r by qpcr was found to be . +/- . fold higher than the a , a a-r, or a receptors (n= ). to confirm that ado-r activate cftr in vivo, we measured nasal potential differences. we found that ado activated chloride secretion at similar levels to isoproterenol. the effect of ado was inhibited by pre-exposure to µm caffeine (ado, . +/- . mv; ado + caffeine, . +/- . mv). we conclude that a b-r has an important role in asl homeostasis through regulation of cftr and it is active in human airway epithelia under normal physiological conditions. through osmotic forces, hypertonic saline (hs) may increase the volume of cf airway surface liquid, restore mucus clearance, and improve lung function. the na + channel antagonist amiloride is predicted to increase the duration of action of hs. however, patients taking amiloride with hs showed less clinical benefits than patients taking placebo with hs. in vitro data suggested that amiloride inhibits transepithelial water flux (pf) in cystic fibrosis airway epithelia. we have extended this study by looking at the effects of amiloride on aquaporins in a heterologous expression system (mdck cells) and have used immunofluorescence to determine which aquaporins are expressed in human airways in vivo and in vitro. inhibition of enac by aprotinin pretreatment had no effect on hs-induced pf (n= ), suggesting that amiloride did not exert its actions on pf by inhibiting enac. however, since hs-induced pf was also inhibited with hgcl , we speculated that amiloride directly blocked an aquaporin. to test this hypothesis, we measured the rate of cell shrinkage of wild-type mdck cells, and those stably-expressing aqp or , or expressing aqp (after h exposure to a mildly hypertonic media; mosm). following mucosal exposure to a mosm hypertonic ringer solution, mdck cultures grown to confluency on permeable filters shrunk by % after s (n = ), as measured by xz confocal microscopy following staining with calcein-am. in contrast mdck/aqp or mdck/aqp cultures shrunk by % over the same period and mdck/aqp cultures shrunk by % (all n= ). a min pretreatment with µm amiloride abolished hypertonic ringer-induced cell shrinkage in mdck/aqp cultures ( % at s; n= ) but had no affect on cell shrinkage in aqp or aqp expressing cultures. amiloride is fluorescent and can be imaged in epithelia by xz confocal scanning under uv excitation. amiloride was not internalized immediately (< s) before hypertonic ringer addition and did not block aqp -mediated cell shrinkage ( % at s; n = ). however, a min pretreatment with amiloride caused it be internalized and at this time aqp -induced cell shrinkage was blocked, suggesting that amiloride blocks aqp intracellularly. to confirm that aqp is present in airway epithelia, we performed immunostaining with an aqp antibody and found that aqp is highly expressed at the apical membrane of ciliated cells in human bronchial tissue and well-differentiated bronchial cultures. we conclude that amiloride blocks aqp , which is abundantly expressed in the superficial airway epithelia. supported we have previously observed that cftr, annexin (a ) and cytosolic phospholipase a (cpla ) are partially recruited in detergent insoluble microdomains (dim) upon proinflammatory stimulation. this is prevented by specific inhibition of cftr. a participates in the regulation of inflammation by inhibiting cpla activity. we have also shown that a expression is decreased in cftr-/-mouse tissues. we postulate that cftr, a and cpla participate in the regulation of inflammation by their dynamic interaction within dim. in this study we aimed to (i) demonstrate and characterize this interaction, and (ii) identify other potential partners of this complex in dim. by coimmunoprecipitation, we examined the interaction between cftr, a and cpla in human pulmonary epithelial cells calu . to search for additional partners we developed a new proteomic approach based on double sds-page (dsds-page), which is compatible with membrane protein analysis. calu cells and human epithelial bronchial cfbe cells (expressing either wt or f delcftr) were subjected or not to proinflammatory conditions (tnfα). dim were isolated by density gradient and analyzed by dsds-page. cftr immunoprecipitated with a and cpla in calu cells. dsds-page analyses showed significant differential expression of cytokeratin , actin and protein disulfide isomerase (pdi, involved in protein folding) in dim between control and proinflammatory conditions in calu cells, and between wt and f del cfbe cells, as determined by mass spectrometry. in conclusion, cftr, a and cpla interact in basal conditions. proinflammatory treatment causes differential expression of cytoskeletal proteins and pdi depending on the expression of normal and mutated cftr. this work suggests that cftr could participate in the regulation of inflammation within a complex with a and cpla . cytoskeletal proteins and pdi could be involved in the dynamics of this complex. this could be related to the abnormal inflammatory response characteristic of cf. we acute and chronic inflammation, common features of cf airways disease, have been linked to higher atp release and changes in atp metabolic patterns in vivo, e.g., in induced sputum and exhaled breath condensate from cf patients and bronchoalveolar lavage fluid from inflamed lobes (esther, ped pulm sppl , ) . we, therefore, investigated the contribution of airway epithelia per se to the raised atp concentrations on cf airway surface during inflammation. when exposed to supernatant of mucopurulent material (smm) from cf airways for h, or infected with respiratory syncytial virus (rsv) h prior to the study, basal atp release from well-differentiated primary human bronchial epithelial (hbe) cultures did not differ from that of control cultures. however, basal atp release was increased weeks after rsv infection when inflammation had waned (as indexed by il- secretion). the increase in basal atp release correlated with increased basal udp-glucose and mucin release, and goblet cell metaplasia. these data indicate that the increased basal atp release following rsv infection reflected increased goblet cell secretion. a different pattern was observed for stimulated atp release. hbes exposed to smm for h, or infected with rsv h prior, released - times more atp following hypotonic challenge than control cultures (okada, ped pulm sppl, ) . the increase in peak atp concentrations correlated with the degree of inflammation as indexed by il- secretion and the increase in intracellular calcium (ca + i ) mobilization in response to hypotonic challenge, but not with the goblet cell number. ca + i mobilization in response to hypotonic challenge in control hbes was almost completely due to extracellular ca + i influx which was inhibited by antagonists of a transient receptor potential v (trpv ) ca + channel. in contrast, an additional component of atp-induced ca + i release from endoplasmic reticulum (er) was observed in smm-treated hbes. the increase in hypotonicity-induced atp release in smm-treated hbes compared to control hbes was almost completely sensitive to chelation of ca + i by bapta ( µm; h), or inhibition of exocytosis by brefeldin a ( µm; . h), monensin ( µm; h) or n-ethylmaleimide ( mm; min), whereas these reagents were ineffective against hypotonicity-induced atp release from control hbes. these data suggest a positive feedback loop between the increased atp release linked to ca + i -dependent exocytosis and the increase in atp-induced ca + i mobolization linked to increased er ca + i stores (ribeiro, jbc , ) in inflamed hbes. in conclusion, we propose that basal and hypotonicity-induced atp release from hbes are regulated in distinct mechanisms during inflammation. basal atp release reflects continuous exocytosis processes independent of ca + i mobilization and differs as a function of cell type (ciliated vs goblet cell), whereas acute inflammation upregulates hypotonicity-induced atp release via increased ca + i mobilization and ca + i -dependent exocytosis. we conclude that airway epithelia exhibit multiple mechanisms of increasing atp release into the lumen in response to inflammation. supported by cff grant okada i to sfo and grants from nih. the main biological role of vitamin d is in control of bone and mineral metabolism, but it has also been discovered to have many immune system functions. vitamin d, a fat soluble vitamin, is poorly absorbed in cf leading to low serum levels. we sought to investigate the involvement of vitamin d in the control of inflammation in a cf model. methods cf tracheal epithelial cells (cfte) were pretreated with vitamin d ( , [oh] d ) or control and exposed to p aeruginosa lipopolysaccharide (lps) for hrs before collecting the cell supernatants. cytokine levels in the supernatants were assessed by cytokine array and subsequent elisas specific for il- , il- and mcp- . vitamin d was measured in the plasma of children with cystic fibrosis aged months to years. neutrophil numbers, neutrophil elastase (ne) activity and il- concentrations were measured in the bronchoalveolar lavage (bal) of these children. children with cystic fibrosis were deemed to be non-colonised, intermittently colonised or chronically colonised with p aeruginosa on the basis of the leeds criteria. pretreatment with vitamin d significantly reduced secretion of il- , il- and mcp- from cftes after challenge with p aeruginosa lps in a dose dependant manner. plasma vitamin d levels were highest in the noncolonised group and lowest in the chronically colonised group with intermediate levels in the intermittently colonised group. bal neutrophil counts, ne activity and il- concentration showed a reciprocal pattern. conclusions vitamin d acts on cf lung epithelial cells to protect against excessive cytokine production in response to lps. levels of vitamin d are inversely related to both p aeruginosa colonisation status and bal markers of inflammation. low levels of vitamin d may contribute to advancing lung disease in children with cystic fibrosis. more aggressive correction of vitamin d deficiency may have a role in protecting against excessive inflammatory response to infection. sleeping in a mist tent has been used as a treatment for cystic fibrosis (cf) patients, in order to hydrate the viscous mucus and make it easier to be removed by coughing (matthews et al., ) . however, the efficiency of the method has been questioned, and its use was largely discontinued. with a new method to measure the ion content of human nasal fluid the effect of sleeping in a moisture tent on the ion content of nasal airway surface liquid (asl) in cf-patients and healthy controls was determined. the cf-patients and healthy controls spent a night ( h) in a mist tent, and samples of the nasal asl were taken before the experiment, after the period in the tent, and then at each hour during h after the persons had left the tent. samples of nasal fluid were collected on sephadex g- beads that had been mounted on strips of filter paper, which were then put into the nasal cavity of the cf patients or controls for - min. the strips were removed, and the beads were isolated, dried, and analyzed by x-ray microanalysis (vanthanouvong et al., ) . the concentration of na, cl, and k in the nasal fluid of cf patients was , , and mm, respectively, before the patient entered the tent, significantly higher than the levels in the nasal fluid of the controls (na mm, cl mm, and k mm). during the period in the tent, the ion content decreased, to levels of na mm, cl mm, and k mm (cfpatients) and na mm, cl mm, and k mm (controls) immediately after leaving the tent. after leaving the mist tent the ion levels in the nasal fluid increased, reaching after h values of na mm, cl mm, and k mm (cf-patients) and na mm, cl mm and k mm (controls), which was for both groups higher than before entering the tent. no major changes in the ion content of the asl occurred after h. the salt content of the asl may be relevant in cf, since the asl is known to contain anti-bacterial proteins, defensins, which are sensitive to the salt concentration (bals et al., ) . hence, the higher salt concentra-tions in the asl of cf-patients may have negative consequences for the anti-bacterial defense system in the lungs, and conversely, the decrease in ion concentrations, caused by spending time in a mist tent, may have positive effects. (we have previously shown that none of our patients was chronically colonized with pseudomonas aeruginosa while regularly sleeping in mist tents.) however, with currently used procedures, the effect of sleeping in a mist tent on the ion content of the nasal asl is short-lived. bals background: antibody microarrays for clinical applications have been anticipated for more than a decade but the technology has only recently become sufficiently mature for reproducible, robust detection of low abundance proteins. the advantage of this new technology is the high throughput, parallel detection of identified, known, low abundance proteins. antibody microarray results are usually given in terms of ratios between two samples (e.g., "experiment" and "control"). however, given the printing and calibration issues inherent with antibody microarrays, this ratio'ing approach precludes statistically valid inter-array comparisons of the individual protein concentrations. we have therefore developed and implemented a different calibration strategy using a benchmark mixture that is applied to every array as an internal standard, thus controlling for any differences in antibody activities as well as printing imperfections. the amount of protein bound to each spot is determined relative to the respective protein in the internal standard. since all samples in the study are compared to the same internal standard, this semi-quantitative approach permits the comparison of multiple samples. all data for the same antibody on multiple arrays can then be used to calculate the average and standard deviation for a given population (such as patients or control groups) in a parallel fashion. methods: cf lung epithelial cultured cells ib - and the cftrrepaired ib - /s were biosynthetically labeled with a hour pulse of [s]methionine, and then chased with cold methionine for , or hours. we then isolated total protein from each sample, and labeled the proteins with cy . labeled proteins were applied to clontech® antibody arrays ( antibodies printed in duplicates) according to the manufacturer's protocols. the internal standard, consisting of a mixture of cell cultures and tissue extracts known to contain the cognate protein for each antibody on the array, was labeled with cy . the data were then used to compare the cf and the corrected cells in terms of amount, biosynthesis rate and degradation half-life (t / ) for each one of the features on the array. data analysis: for each spot on the array the ratio of cy /cy (after background subtraction) was calculated, normalized and stored for further analysis. for "pulse-chase" experiments the ratio of [s] counts to cy at each time point gives a measure of the fraction of newly synthesized (radiolabeled) to total protein (dye labeled) bound to each given antibody on the array. the addition of the cy labeled internal standard enables the calibration of these totals, allowing the comparison all the spots for any given antibody on multiple arrays. furthermore, the internal standard calibration makes it possible to compare not only t / values but also to calculate the relative degradation rates in different cell lines even when the amounts of that protein are different in the "control" and "experiment" cells. the new approach quantitatively identifies and subjects to analysis the effect of the cftr mutation on protein biosynthesis and degradation of the cellular signaling proteome. supported by nih no -hv- (hbp) and ro - (hbp) in cf patients, defective apical chloride secretion, due to lack of functional cftr, leads to dehydration of airway surface liquid (asl) and mucus plugging. this defect is likely ameliorated, in part, by an alternative route of chloride conductance, the calcium activated chloride channel (cacc) . female gender appears to be associated with more rapid decline of lung function and earlier death in cf. this suggests that gender differences in hormonal environments might influence asl height regulation, thus modifying the pulmonary phenotype. we hypothesized that changes in estrogen concentrations might alter asl hydration by affecting cacc. consistent with this, we have shown that estrogen attenuates increases in intracellular calcium and asl height that follow purinergic receptor activation in primary cultures of human bronchial epithelial cells (hbecs, see accompanying abstract by hengrui sun et al). here, we report correlations between estrogen levels and nasal ion transport in vivo and further probe hormonal effects on ion transport and asl height regulation in vitro. in vivo studies: in healthy, spontaneously menstruating females, nasal potential difference (npd) was measured (both nostrils) on two occasions during a single monthly cycle. based on a history of the most recent menstrual cycles, we measured npd on a day when estrogen levels were predicted to be low (generally - days following onset of menses) and subsequently on the day when the pre-ovulatory estrogen surge was predicted. the recording electrode was positioned at the location where maximal stable basal pd was detected and changes in pd recorded continuously during sequential perfusion with ] ringer's solution, ] ringer's solution containing amiloride (to inhibit sodium absorption via enac), ] modified (low chloride) ringer's containing amiloride and finally ] a similar solution also containing utp (to activate cacc). as predicted, blood estrogen levels were higher on the "pre-ovulatory" day ( . ± . vs . ± . nm, p< . ). utp-stimulated change in pd was significantly lower on the study day when estrogen levels were elevated ( . ± . vs . ± . mvs, p< . ). further, the amiloride-sensitive component of basal pd was higher on this day ( . ± . vs . ± . mvs, p< . ). the change in pd in response to perfusion with a low chloride solution was not different. in vitro studies: expression of estrogen receptor (er) α (but not β) was confirmed in non-cf and cf hbecs by real time pcr. erα was detected in hbecs from males and female donors. in cf and non-cf hbecs mounted in modified ussing chambers, exposure to nm e was associated with a significant (~ %) reduction in utp-stimulated short circuit current. e inhibited the atp-stimulated increase in asl height in male and female hbecs and this asl regulatory phenotype was not reproduced by testosterone or progesterone. in conclusion, estrogen inhibits utp-activated chloride secretion in vivo and in vitro suggesting that elevated pre-ovulatory estrogen levels may further impair mucociliary clearance in females with cf. all data mean±sem. supported by cff leroy matthews award [ ] . data demonstrating an upregulation of caccs when cftr is absent or defective [ , ] have triggered further studies of these channels and prompted further elucidation of the functional (and possibly also physical) interactions between these two channels. although searched for long, the molecular identity of caccs is still under debate. the role of bestrophin family proteins as putative candidates for caccs is discussed controversially. bestrophin (best- ) has been proposed to form ca + activated clchannels in epithelial cells. moreover, caccs have been shown to support cell proliferation, namely in the development of cancer [ ] . here, our goal is two-fold: ) to investigate the correlation between expression levels of best- and epithelial cell proliferation; and ) to pursue a search for interacting protein partners of best- to better understand the role and function of bestrophin(s) in epithelial cells. to study the correlation between best- expression and cell proliferation, we analyzed two populations of the t colonic carcinoma cell line with very different proliferation rates: the original (t -slow) and the spontaneously transformed t cells (t -fast). we observed that t -slow cells have a small proliferation rate and express low amounts of best- , while t -fast cells express high levels of this protein. best- is spontaneously active in t -fast cells. best- -rnai inhibited ca + activated clconductance and cell proliferation, therefore establishing a novel role of bestrophins in cell proliferation, which may be of relevance for the regeneration of the epithelia in cf and also for alternative therapies for cf. for the second objective, two putative cytoplasmic domains of best , polyhistidine -tagged (phis) n-term (aa - , best -n) and c-term (aa - , best -c), were cloned into the pet-sumo bacterial expression vector. these domains were then immobilized onto metal-affinity resin to capture interacting proteins from human t whole cell and sub-cellular lysates. protein-containing fractions recovered from best -n/c-coated and blank resins were subjected to d-gel and protein identification. it is expected that functional characterization of the interaction between the captured proteins and best- will give new insights into the biological role, plausibly of relevance to cf. work supported by dfg-sfb -a grant (germany) and pluriannual funding of cigmh (feder-eu and fct, portugal extracellular nucleotides acting on epithelial cell surface purinergic receptors regulate the mucociliary clearance process that removes noxious materials from the lung. however, how epithelial cells release nucleotides into the airways remains largely unknown. cftr has been suggested to mediate atp release in airway epithelia, but conclusive demonstration remains elusive. calu- is a human airway derived cell line often described as a model of airway gland serous cells. at least % of cells in a monolayer expressed high levels of cftr protein and activity at the apical membrane. atp, adenosine, and udp-glucose, the naturally occurring agonists for the p y , a b, and p y receptors, respectively, were quantified in airway surface liquid with nanomolar sensitivity using radiolabeling and fluorescence hplc-based techniques, and real-time atp measurements. atp (and udp-glucose) was found to be released constitutively and selectively onto the mucosal surface of calu- cells. however, the specific cftr inhibitor ( µm, - min) failed to decrease atp concentration in the mucosal bath of resting calu- cells. forskolin ( µm, min) stimulated cftr channel activity, but did not affect basal levels of atp (or udpglucose) release. in contrast, elevation of intracellular calcium using ionomycin ( - µm, - min) significantly increased atp (and udp-glucose) release into the mucosal (but not serosal) bath of calu- cells. calciummediated nucleotide release enhancement was not abolished by cftr inhibitor . maneuvers like pre-incubation in nominally free-calcium solution, bapta ( µm, min), or cytochalasin d ( µm, min) to disrupt actin cytoskeleton, which inhibited regulated exocytosis in calu- cells, also reduced calcium-mediated increase in nucleotide release. calu- monolayers presented a fraction of cells (< %) exhibiting negligible cftr immunostaining signal, but displaying airway goblet cell mucin granules. remarkably, stimulation of atp and udp-sugar release with ionomycin resulted in concomitant enhanced exocytotic secretion of muc ac. these results suggest that cftr is not involved in regulation of atp release in airway epithelial cells. more likely, nucleotides and nucleotide-sugars residing in the biosynthetic pathway involved in modification of apically targeted glycoconjugates (e.g. mucins) are released to the extracellular environment via calcium-triggered exocytosis. supported although the regulation of na+ transport is relatively well described in normal and cf airway epithelial cells, the impact of inflammation and infection, two major components of cf lung disease, on na+ transport has not been studied extensively. significant amounts of evidence suggest that bacterial by-products may influence na+ transport in airway epithelium. furthermore, the secretion of exoenzyme s by pseudomonas aeruginosa is enhanced during an exacerbation of lung disease in cystic fibrosis. in the past few years, our laboratory has shown that exposition of lung epithelial cells to p. aeruginosa lps leads to a rapid decrease in activity and expression of enac channel. the aim of our study was to evaluate the mechanism involved in the modulation of enac expression and activity by lps. primary culture of lung epithelial cells grown on filters were treated with lps ( µg/ml) for different time ( min, , , h). at each time point, the total and amiloride-sensitive short circuit current (isc) was determined in ussing chamber. in parallel, the cell proteins were collected to investigate by western blot the signalling pathways involved in this response to lps. a hours lps treatment leads to a significant decrease in alpha and gamma enac mrna to % and % of control respectively. similarly, the amiloridesensitive current was decreased by % of the current in untreated cells after a min exposure to lps. by western blot, we demonstrated the strong implication of the pi k/akt pathway in response to lps in the regulation enac mrna and the potential implication of tyrosine/kinase receptors signalling pathway through mtor in the regulation of enac channel activity. in conclusion, we demonstrate that inflammatory molecules can modulate the expression and function of the na+ transport mechanism in lung epithelial cells and could contribute to the modulation of airway surface fluid in the chronic infectious process associated with cf. serous acinar cells are thought to be crucial for secretion of airway surface liquid by submucosal glands in large airways, but the molecular mechanisms of serous cell ion and fluid transport are not well understood. to address this, we isolated murine nasal serous acinar cells and studied them using simultaneous dic and quantitative fluorescence microscopy to track changes in cell volume and intracellular concentrations of ions involved in fluid secretion ([cl -] i ; spq) and its regulation ([ca + ] i ; fura- ). previous results indicated that serous acinar cell volume changes were indicative of solute efflux (shrinking) and solute influx (swelling), reflecting the secretory state of the cell. acinar cells stimulated with µm carbachol (cch) exhibited a rapid increase in [ca + ] i and subsequent ~ % cell shrinkage due to efflux of ~ % of cell clcontent and parallel loss of k + and osmotically obliged h o. because murine serous cells are sites of apical cftr expression in the airway, we tested the requirement for cftr in cch/ca +activated shrinkage/clefflux. acinar cells isolated from either cftr tm unc-/mice or wt cells pre-treated with cftr inh exhibited identical rates and magnitudes of ca + -induced cell shrinkage and clloss compared to wt control cells. resting [cl -] i was also identical in wt and cftr tm unc-/serous acinar cells ( ± and ± mm, respectively), suggesting similar levels of resting clconductance. thus, murine serous acinar cells can secrete kcl/h o by ca + -dependent mechanisms in the absence of functional cftr, in agreement with studies of intact glands suggesting cch-induced glandular fluid secretion is cftr-independent. wt serous acinar cells were stimulated with camp-agonists, including µm forskolin, µm isoproterenol, µm adenosine, and µm vip. however, no camp-induced shrinkage was observed, even in the presence of a cocktail of inhibitors to block solute uptake. to determine if cftr activation could enhance cch/ca + -induced cell shrinkage at a sub-optimal [cch], serous acinar cells were pre-treated with forskolin followed by stimulation with µm cch in the continued presence of forskolin. however, similar rates and magnitudes of cell shrinkage were observed in forskolin-treated and control cells. these results suggest that the magnitude of the cftr clconductance in murine serous acinar cells is much smaller than the ca + -activated clconductance, below the resolution of these optical assays. more sensitive electrophysiological approaches are being used to determine the molecular identity of the non-cftr clconductance(s) and the role of cftr in murine serous acinar cell ion transport. females with cf exhibit more rapid decline in fev than males, which reduces their life span. normal airway epithelia regulate airway surface liquid (asl) volume and mucus transport by secretion through both cftr and the ca +-activated cl-channel (cacc), and inhibition of either of these pathways in isolation does not abolish mucus transport. however, a loss of both pathways is predicted to result in mucus plugging which contributes to lung disease. despite a loss of cftr, cacc is functional in cf airways due to mechanical stimulation of atp release and activation of the p y pathway which serves to raise intracellular ca +. we hypothesized that e may inhibit cacc, leaving females with cf more prone to lung disease than males due to a greater depletion of asl volume. using confocal microscopy, we found that acute pre-exposure with e inhibited atp induced asl secretion in normal and cf human bronchial epithelial cultures (hbecs) from both male and female donors. the ic for e -inhibition of atp-induced asl secretion was . nm. to better understand how estrogen receptors (ers) interact with the p y pathway, we transiently transfected er-α or er-β linked to an orange fluorescent protein in an er null bhk cell line. with the co-transfection of ha tagged p y -r, we observed that e addition did not induce internalization of p y -r, neither did it alter the internalization induced by atp. we then measured total cell inositol phosphates (ip) in cf airway cells +/-e pretreatment. cell ip levels were not different between groups (n= ), suggesting that the effect of e is downstream of ip production. the investigation of the changes of the intracellular ca + (ca +i) by recording fura- emission ratio over time in er-α or er-β expressed cells provided clues. after nm e exposure, the fura- emission ratio in untransfected cells (n= ) or er-β transfected cells (n= ) increased by . following um atp addition. this increase was significantly inhibited by~ % in er-α transfected cells (n= ), providing good evidence that er-α is respon-sible for inhibiting the p y pathway. we next measured ca +i in normal hbecs. while acute nm e addition had no affect on basal ca +i levels, which were around nm, this maneuver reduced the ca +i response to nm following atp addition (both n= ), suggesting that e addition altered ca + signaling in response to atp. thapsigargin induces ca +i release from the endoplasmic reticulum, but the magnitude of ca +i release after thapsigargin addition was not altered by e pretreatment, indicating that e works further up stream to affect the p y signaling pathway. together, these results suggest that e directly interacts with the p y signaling pathway through er-α by altering ca +i. we propose that this interaction leaves females more vulnerable to infections due to a reduced asl volume during periods of high e , such as occur prior to ovulation. the nasal potential difference (or npd) is a sensitive, real time bioelectric assay of cftr-dependent and independent ion transport that is a commonly used study endpoint in early clinical stages of drug development. technical limitations of the assay must be controlled to facilitate its use in multicenter trials and limited intra-site variability. two forms of equipment are commonly employed to evaluate nasal potential difference in humans: silver-silver chloride electrodes (agcl) with saline bridges or calomel electrodes with agar bridges; however, these techniques have never been directly compared. we repeatedly evaluated (within days) the basal potential difference of five normal subjects using the two available techniques, then compared variance and repeatability of the measures. basal pd was measured during perfusion of ringer's solution, and measured at . , . , . , . , and . cm within the inferior meatus, as indicated in the cf-tdn standard operating procedures. mean basal pd were within . mv using the two techniques, with very similar coefficients of variation (cvar; . vs. . in agcl vs. calomel, respectively). maximum basal pds were also similar between the two methodologies (mean difference . mv; cvar . and . , respectively). the correlation between first and second measures of mean pd was highly reproducible, and similar between the two techniques (r= . vs. . in agcl vs. calomel, respectively); however, when each individual basal pd measure was compared, correlation between first and second pd using the agcl device appeared superior (r= . vs. . respectively; n= measures per device). comparison of values obtained in cf subjects are currently in progress and will also be reported. next, we examined diagnostic npd tracings in cf subjects for whether the effect of amiloride might influence values obtained in the contralateral nare. an effect of cross-contamination by amiloride or other agent (gene therapy vectors or other nasal administered compounds, for example) could influence accurate measure of npd values. when basal pds were performed in both nostrils prior to amiloride exposure in either nostril, mean basal pd between nares remained stable (< mv, p=ns for change). however, if the basal pd in one nostril was measured after amiloride exposure in the contralateral side, mean pd depolarized by mv (from - to - mv; p< . ), indicating the presence of a 'cross-nostril' amiloride effect that might potentially affect interpretation of this endpoint if not performed in a sequence designed to avoid amiloride exposure. in summary, we show that calomel and agcl electrodes perform similarly in repeated measures from the same normal subjects, and that improper npd sequence can adversely affect basal pd measures. other potential impediments to the pd measurement (e.g. solution temperature, tonicity, ionic content, and sources of electrical offset) will also be discussed. these findings are relevant to the optimizing the use of the npd assay in clinical trials. supported by nih, cff, and cfft. the gene defective in patients with cystic fibrosis (cf) is the cystic fibrosis transmembrane conductance regulator (cftr), a camp-activated chloride channel in the apical membrane of epithelia, but alteration of expression and function of many genes undoubtedly contributes to the pleiotropic manifestations of cf. a hallmark of cf in airway epithelia is the hyperabsorption of sodium through the epithelial sodium channel (enac) in the apical membrane followed by extrusion through the na,k-atpase in the basolateral membrane. this results in airway surface liquid (asl) dehydration, mucus buildup and bacterial infection characteristically observed in the lungs of cf patients. previous studies have shown that the na,k-atpase is increased in cf airway epithelia, consistent with increased sodium transport along the enac/na,k-atpase axis. we have previously demonstrated that fxyd , a member of a small family of proteins known to regulate the na,k-atpase, is increased in s x cf mouse lung and nasal epithelia and in primary human tracheal epithelial cells (hte) after treatment with an inhibitor of cftr ( ). recent evidence has indicated that enac activation occurs through modification of the serine protease-protease inhibitor balance in asl. thus, we hypothesized that enac-mediated increases in sodium absorption may be partially responsible for the increase in fxyd expression observed in cf airway epithelia. we now report that increasing asl volume on hte cells upregulated fxyd expression (p< . ) after hours, an effect that was further increased after trypsin addition and abrogated by the serine-protease inhibitor aprotinin. treatment of hte cells with nystatin also increased fxyd expression measured by quantitative rt-pcr (p< . ). based on these results and the observation that mice overexpressing enac beta-subunit exhibit cystic fibrosis-like lung pathophysiology, we examined fxyd expression in the lungs of mice overexpressing the scnn b-transgene. contrary to our expectations, fxyd lung expression was decreased as assessed by quantitative rt-pcr and immunoblot analysis (p< . ), indicating fxyd may be alternatively regulated in epithelia under conditions of acute versus chronic sodium hyperabsorption. therefore, we measured fxyd expression in an epithelial cell culture model using an inducible, tri-cistronic vector capable of expressing enac alpha, beta and gamma subunits. we determined that fxyd expression is decreased after chronic enac induction. we conclude that fxyd expression is coordinately regulated based on acute versus chronic enac-mediated sodium absorption and suggest that fxyd is increased in cystic fibrosis airway epithelia as a result of an imbalance between increased inflammatory signaling and altered ion transport. picher, m.; van heusden, c. cystic fibrosis center, university of north carolina, chapel hill, nc, usa airway infection by the respiratory syncytial virus (rsv) is considered an important cause of pulmonary exacerbation and hospitalization in cystic fibrosis (cf) children. this disease is characterized by functional mutations in the cf transmembrane regulator (cftr). the inability of cftr -/-mice to clear rsv is associated with exaggerated inflammatory responses. a relationship was recently established between airway inflammation and chronically-elevated airway adenosine. this signaling molecule regulates key aspects of lung defenses, including bacterial clearance and inflammatory cells. high adenosine levels measured in bronchoalveolar lavage fluid of asthmatic or cf patients cause airway inflammation, remodeling and fibrosis in animal models. the objective of this study was to investigate the longterm effects of rsv infection on adenosine regulation and inflammatory responses in human airway epithelia. methods. polarized primary cultures of bronchial epithelial cells from healthy subjects and cf patients were exposed to vehicle, uv-inactivated or active green fluorescent protein (gfp)-rsv. the cultures were monitored days for infection (fluorescence microscopy), adenosine levels (fluorescence chromatography), the release of cytokines regulating adenosine tnfα) and enzyme activities (ecto '-nucleotidase [ecto '-nt: amp Ç adenosine] and adenosine deaminase [ada : adenosine Ç inosine]). results. (a) both normal and cf cultures exhibited detectable rsv infection over days, with peak density on day - . (b) we demonstrate that rsv enhances the release of all five cytokines from normal cultures over days. in contrast, cf cultures responded to rsv by a transient decrease in il- β, il- and tnfα (peak on day ), but a sustained decrease in il- , and a sustained increase in il- , secretion. (c) on normal epithelia, rsv transiently stimulated ecto '-nt (peak on day ) but caused a sustained increase in ada activity, resulting in chronically-low adenosine levels. in cf, rsv raised adenosine levels by the combined effects of a sustained increase in ecto '-nt activity and the lack ada response. (d) chronically-elevated adenosine generated by ada inhibition [erythro -( -hydroxy- -nonyl)adenine] stimulated the secretion of all cytokines, except il- . conclusion. these data support a complex relationship between adenosine and cytokine regulation in human airway epithelia. the il- -adenosine amplification pathways identified in rsv-infected cf epithelia are in agreement with animal models and their key role in chronic airway inflammation/remodeling. on the other hand, the data also suggest that ada activity is influenced by il- , known to stimulate the expression of a major protein anchoring soluble ada to epithelial surfaces: cd . altogether, this study suggests that an rsv infection in cf children may accelerate the progression of the disease by setting the stage for airway adenosine-cytokine amplification pathways. supported by the cystic fibrosis foundation (picher g ). cystic fibrosis (cf) airway submucosal glands are defective in mucus secretion rate (jayaraman, pnas, , , ; joo, j biol chem, , , ; joo, pediatr. pulmonol., , suppl. , ; wine, proc ats, , , ; thiagarajah, faseb j, , , ; song, ajp cell, ; salinas, faseb j, , , ) . one hypothesis is that loss of cftr results in reduced secretion of electrolytes leading to underhydration of mucins, thereby altering the mucus properties. it has been generally believed that the cf mucus in response to cholinergic agonists is thicker and more viscous. however, comparisons of pure gland mucus are difficult because of variability in gland secretion rates and a decline in mucus solids with repeated stimulations (wu, pediatr. pulmonol. , suppl. , ) . in the present study, we directly compared the solid content of airway submucosal gland mucus between control and cf individuals. human donor tracheas (hn) or disease control bronchi (dc) were dissected and mounted as previously described but without mineral oil. tissue was kept warmed and humidified in a chamber with two layers of saturated degree c / % co /o water vapor. the mucosal surface was blotted dry and coated with a thin layer of dimethylpolysiloxane to prevent re-absorption by the surface epithelium. the tissue surface was covered with a cover slip, leaving minimal air space between it and the surface to further reduce evaporation. a µl droplet of % nacl was placed at the side of every tissue as a standard to assess evaporation and measurement error. any basal secretions were removed prior to stimulation with µm carbachol. mucus secretion from individual glands was pooled using forceps and then drawn into a constant bore microcapillary (drummond) that had been alcohol-cleaned, dried, and weighed. stimulation time was allowed to vary so that at least µl of mucus was collected. after mucus collection, both the standard and the bath solution were refreshed. mucus filled capillaries were weighed with a mettler microbalance before and after overnight degree c oven drying to obtain nonvolatile solid content. the average solids measured in six repeated measures of % salt solutions was ± . % with no trend over time. results for hn (n= ) and dc (n= ) did not differ and were pooled as 'control'. the initial control secretion yielded . ± . % solids (mean ± sem, n= subjects) and required ± min to produce adequate mucus. the initial cf secretion gave . ± . % solids (n= ) in ± min. the second control secretion yielded . ± . % solids (n= ) and required ± min, whereas the second cf secretion gave . ± . % solids (n= ) and required ± min. in summary, cf gland mucus solids content was % higher than control following the first stimulation (p = . ). after the second stimulation, cf solids content was % higher than the control (p = . ). solids contents of controls observed in our experiment are much higher than was found for mucus collected from airway lumens after hr stimulation (c. %, trout, am j physiol, , , l ) . supported by niddk ro - (jjw) and cff. in patients with cystic fibrosis (cf) as well as in some animal models of cf lung disease, higher levels of prostaglandin e (pge ) have been detected compared to control subjects. it is not clear whether this excess of pge contributes to the airway pathology of cf, or whether it may serve a protective function against airway constriction. inhaled pge has been tried in asthma and may be of benefit as a bronchodilator. interestingly, pge has shown benefit in aspirin-sensitive asthmatics, a population that shares some features with the cf airway phenotype including nasal polyposis. the mechanism of airway relaxation to pge is mediated primarily by ep receptors signaling through camp. in cf, beta-adrenergic bronchodilators are commonly used, but are often only partially effective at reversing bronchospasm. beta-agonists and pge both signal through g-proteins coupled to camp and pka signaling, thus pge may offer another treatment when beta-agonists are ineffective at reversing bronchospasm in cf. in mouse tracheas, the beta-agonist isoproterenol (iso) will partially relax a pre-contracted airway, but ± % of contractile force remains (n= ). in contrast to the limited relaxation with iso, constricted mouse airways demonstrate significantly greater relaxation to pge , with only ± % of force remaining (n= , p< . compared to iso). this difference in relaxation responses suggests different intracellular signals are activated by each agonist despite both signaling through pka. to investigate phosphorylation events in response to iso or pge , we developed a new method for perfusing isolated mouse lungs. using this technique, tissues were perfused with buffered solution containing p for radiolabeling. lungs were then stimulated with either iso or pge , and phosphoproteins were compared from each condition. radiolabeling was effective under all three conditions. targets were chosen from each group (unstimulated, iso, or pge treated) that showed phosphorylation or dephosphorylation, and proteins were identified by mass spectrometry. over differentially phosphorylated proteins were identified, and two of these (rho gdi and inositol-requiring protein ) were selected as candidates to be tested in the context of relaxation to pge compared to iso. by identifying signaling targets involved in airway relaxation to pge , it may be possible to activate beneficial airway relaxation responses without the limitations seen in iso relaxation and without activating pge responses other than relaxation that may link pge to the airway pathology seen in cf. the parental ∆f /∆f cf bronchial epithelial cell line (cfbe o-) was compared to clones of cfbe o-complemented with . kb wild type (wt) or . kb ∆f cftr cdna in terms of their ion transport characteristics. the transepithelial resistance (rt) (~ (cm ) observed in the parental cfbe o-was maintained in the complemented cells. two clones complemented with wt cftr cdna (c - . wt and c - . wt) demonstrated rt ~ Ωcm , while another clone (c - . ∆f) complemented with the ∆f cftr cdna showed an rt of ~ Ωcm . two stable clones expressing wt cftr were selected based on electrophysiological characteristics and stability of cftr expression. forskolin-stimulated cl secretion in clone c - . wt was on average . ± . µa/cm and . ± . µa/cm in clone c - . wt. furthermore small camp-stimulated transepithelial current of . ± . µa/cm was observed in clone c - . ∆f indicating that ∆f cftr can traffic to the plasma membrane if present at high enough levels at physiological temperatures. the role that cftr plays in ca-activated cl conductance was investigated following treatment of the cells with atp in parental cfbe o-and wtcftr . -cfbe o-monolayers. in symmetrical cl-containing solutions, mucosal application of atp ( µm) elicited a small, transient cl secretory response in the parental cfbe ocells ( . ± . µa/cm ), while the magnitude of the atp-stimulated cl current was markedly enhanced in cftr-corrected cfbe o-cells with peak currents at . ± . µa/cm . recordings done in presence of a serosal-tomucosal cl gradient to increase the driving force for cl secretion showed a transient atp-dependent activation of cl currents in parental cfbe ocells with peak cl currents of . ± . µa/cm (n= ). cftr corrected cfbe o-cells showed a sustained activation of cl currents of similar magnitude ( . ± . µa/cm ; n= ). atp-stimulated cl currents were effectively blocked by the cftr inhibitor glyh ( µm). histochemical analysis showed prominent epithelial characteristics in all clones. these observations indicate that i) the apical driving force is limiting for atp-stimulated cl secretion and that ii) cftr participates in the cl secretory response to atp. furthermore, the findings suggest that these novel clonal isolates of the cfbe o-bronchial epithelial cell line can be useful for the investigation of cf therapies. this work was supported by grants from the cff, cfri, nih, elizabeth nash foundation, and pacfi. the lactoperoxidase (lpo) system functions in normal airways to prevent infection and may be compromised in cystic fibrosis (cf) due to defective transport of its substrate thiocyanate. a computational model of normal airway surface liquid suggests that hydrogen peroxide levels regulate lpo system activity and that the lower thiocyanate in cf airways may result in elevated levels of hydrogen peroxide that is likely produced by duox the major nadph oxidase in airway epithelial cells. to investigate the regulation of duox by bacterial products, passage normal human airway epithelial cells were grown and redifferentiated at the air liquid interface and treated for , or h with either pseudomonas aeruginosa flagellin or lps, applied apically. treated and mock treated cultures were analyzed for levels of duox and lpo mrna and protein, and for hydrogen peroxide production. quantitative pcr was performed using taqman kits, protein was measured by western blots, and hydrogen peroxide was quantified using amplex red-hrp coupled fluorescence. the data showed the duox and lpo mrna but not duox mrna, were significantly upregulated at all measured time points following apical treatment of the cultures with purified flagellin compared to mock treated. at h duox was increased . +/- . fold and lpo was increased . +/- . fold (means +/-s.e.m., n = lungs, - cultures of each lung). muc ac mrna was also upregulated by flagellin treatment ( . +/- . fold, n = lungs, - cultures of each lung). apical treatment with lps had no effect on any tested mrna and induced minimal il- secretion in these cultures. western blots using anti-duox antibodies (courtesy of f. miot, brussels, belgium) showed corresponding increases in duox protein following flagellin treatments. hydrogen peroxide production by flagellin treated cultures was increased in proportion to increases in duox mrna. application of flagellin alone to the apical surface of previously untreated cultures did not increase hydrogen peroxide production. thus, pseudomonas flagellin up-regulates duox and results in higher activity in normal human airway epithelial cells perhaps serving to increase innate host defense activity of the lpo system. chloride ion in phagolysosomes is an essential substrate for neutrophils to produce hypochlorous acid (hocl), an important bactericidal agent. we have previously shown that cftr was present in the phagolysosomal membrane of neutrophils and the cftr defect led to deficient chlorination of ingested pseudomonas aeruginosa (pa) (painter et al, biochemistry, : - , ) . these results suggested that chloride accessibility to the phagolysosomal lumen might be impaired in cf neutrophils thereby affecting neutrophil-mediated bacterial killing. to understand the role of chloride ion in the process, we first assessed the effect of extracellular chloride concentration on pa killing by normal neutrophils under iso-osmotic conditions. surprisingly, bacterial killing was strongly dependent on extracellular chloride concentration. the initial rate of killing of pa was~ fold less in a chloride-free medium than a physiological chloride medium. killing efficiency increased as the chloride concentration was raised in a dosedependent fashion and plateaued at~ mm chloride concentration. to determine what percent of the chloride-dependent killing was oxidantdependent, we applied the cftr inhibitor glyh- , the myeloperoxidase (mpo) inhibitor aminobenzoic acid hydrazide (abah) and the nadph-oxidase inhibitor diphenylene iodium chloride (dpi), respectively to bacterial killing assays. the results showed that the killing of pa could be divided into three discernible components: ( ) a component accounting for about - % of the total killing rate that was inhibited by glyh- , abah or dpi; ( ) a second component amounting to~ - % that was chloride-dependent and partially sensitive to glyh- and; ( ) a third accounting for~ % of the total killing activity that was not sensitive to oxidant inhibitors, or extracellular chloride concentration. dpi and abah had no effect on killing of pa in the absence of extracellular chloride suggesting that most of the oxidant-mediated killing activity toward pa was due to hocl. none of the inhibitors had any significant effect on phagocytosis. finally, the rate of pa killing by cf neutrophils was found to be significantly lower ( - %) than that seen for normal neutrophils and was comparable to the effect of glyh- on killing of pa by normal neutrophils. the data suggest that cftr plays a significant role in killing of pa by normal neutrophils and, when defective as in cf, may compromise the ability of neutrophils to efficiently kill pa. this research was supported by a cff grant to gw. %. the cf group demonstrated a significantly higher frequency of pseudomonas respiratory infections than the non-cf group. interestingly, no significant differences were detected in any infections from other systems including blood, sinuses, skin, wounds, oral cavity, bowel, eyes, peritoneal cavity, and urinary tract. moreover, the cf lung-transplant patients had significantly less time free from pseudomonas infections in the transplanted lungs. conclusion normal lungs transplanted into cf patients had significantly higher susceptibility to pseudomonas infections than those transplanted into non-cf patients, which strongly suggests that defective host defense mechanism(s) beyond the respiratory system contribute to cf lung pathogenesis. pyocyanin (n-methyl- -hydroxyphenazine, pcn) is produced by pseudomonas aeruginosa and is found in pulmonary secretions of infected cf patients at concentrations up to µm. pcn is a redox-active compound that generates superoxide and hydrogen peroxide in the presence of cellular reductants. since cftr was reported to be modulated by h o , we hypothesized that pcn, through its ability to redox cycle and to produce h o , would affect cftr-mediated cl transport. we therefore tested pcn and h o for effects on cltransport (transepithelial short-circuit currents in ussing chambers measured with serosal-to-mucosal clgradient) and cytosolic redox potential (imaging microscopy on cells transfected with a redox sensitive gfp, rogfp ) using cftr-corrected cf bronchial epithelial cells (wtcftr . . under resting conditions, acute exposure of the apical epithelial surface to µm pcn elicited a small clsecretory response ( . ± . µa/cm , n= ) that was completely blocked by the cftr inhibitor glyh ( µm). in contrast, in presence of the camp-elevating agonist forskolin, pcn caused a time-dependent decline of forskolin-stimulated cftr clcurrents by %. exposure to h o ( µm) elicited a more pronounced clsecretory response than pcn in resting cells and h o -stimulated clcurrents peaked at . ± . µa/cm (n= ). h o was less effective than pcn at inhibiting forskolin-stimulated cftr clcurrents and currents declined by %. both pcn and h o oxidized the cytosolic redox potential from a resting value of - mv by similar amounts ( ± mv for pcn vs. ± mv for h o ), but rates of oxidation were faster for h o ( . ± . mv/min) than for pcn ( . ± . mv/min). inhibition of camp-stimulated cftr clcurrents by oxidation was a linear function of the cytosolic redox potential, but pcn ( µa×cm - ×mv - ) was more potent than h o ( . µa×cm - ×mv - ). cf bronchial epithelial cells homozygous for ∆f -cftr did not show a clsecretory response to pcn or h o . these data suggest that cftr-corrected cf bronchial epithelial cells respond acutely to oxidative stress by turning on cftr activity probably as part of the innate host defense response and this mechanism is absent in cf airways. furthermore, prolonged exposure to pcn and h o is detrimental for the proper function of the camp-regulated cftr clconductance. we conclude that oxidative stress in p. aeruginosa-infected airways is a key factor that needs to be considered for successfully correcting cftr function in cf airways. supported by nih (nccam p at ), cff (fischer g ) the lung is continually exposed to environmental agents and pathogens. the lung epithelial lining fluid (elf) is first to encounter these agents and gsh is a major antioxidant found in this apical fluid. the cystic fibrosis transmembrane conductance regulator protein (cftr) is the only known gsh transporter that maintains lung elf gsh levels. cystic fibrosis (cf) patient have low levels of gsh in their elf and have copious and viscous mucus. hypertonic saline is used in cf patient to help clear mucous and improve lung function however the mechanism(s) by which it does so are poorly understood. the purpose of these studies was to examine whether hypertonic ( . %) saline can modulate apical gsh levels and protect lung epithelial cells against the oxidant, t-butyl hydroperoxide (t-booh). we used human lung epithelial cell lines sufficient (c ) and deficient (ib ) in cftr. the cftr deficient ib cells have % lower basal levels of apical gsh as compare to cftr sufficient c cells. cells were exposed separately and in combination to % saline, and t-booh ( um) for hours. the cftr deficient ib cells were much more sensitive to t-booh-mediated oxidative injury as measured by lactate dehydrogenase (ldh) release. hypertonic saline exposure was associated with an increase in apical gsh levels in both cftr sufficient and deficient cells and decreased t-boohmediated oxidative injury in both cells lines. hypertonic saline increased gsh in the apical compartment, which appeared to be largely cftr mediated. we examined this issue in mice given a clinically used dosing regimen of % hypertonic saline nebulized twice daily and examined changes in elf gsh levels hours after last treatment. mice receiving the hypertonic saline treatment had significantly higher gsh levels in their elf than untreated controls. this data suggests that cftr and gsh adaptive responses play an important role in lung's reaction to oxidants. we propose that factors, which interfere with the lung's capability to mount and maintain an adequate adaptive apical gsh response, may compromise and sensitize the lung to oxidative injury. (supported in part from nih grant hl ). the absence of functional cftr in airway epithelia of cf patients leads to abnormal airway surface liquid, which favors chronic bacterial infection. this chronic infection in cf lungs is associated with an exaggerated inflammatory response characterized by abnormal cytokines secretion and massive lung neutrophils infiltration. we have previous recapitulated the abnormal inflammatory response in cftr-/-(cf) mice by repeated administration of pseudomonas aeruginosa lipopolysaccharide (lps) (ped. pulmonology, supp. , ) . we demonstrated that the bronchoalveolar lavage (bal) fluid of cf and heterozygous (het, cftr+/-) littermate control mice when compared to the bal from wt mice shows ) higher numbers of neutrophils and ) higher concentrations of cytokines (il- alpha, il- , kc, mcp- , gm-csf, m-csf) as assessed using multiplex analysis of selected cytokines. of note, airway epithelial cells from cf patients are known to have elevated secretion of some of these cytokines. however to date, the contribution of immune cells to these abnormal cytokine levels has not been well characterized. this study aims to investigate the contribution of cf macrophages in this altered cytokine profile/response. we examined cytokine secretion from two different macrophage populations: alveolar macrophages (am) obtained from the bal fluid and bone marrow (bm)-derived macrophages differentiated in presence of m-csf. both macrophage populations were cultured in the presence or absence of lps, and the supernatants were tested for the concentration of the cytokines that we had shown to be abnormal in vivo. these macrophage populations were examined from cf, het and wt mice. in absence of lps exposure, bm-derived macrophages from cf mice have lower levels of il- and kc compared to wt and het mice. in contrast, am of cf mice have higher levels of il- and kc than am of wt mice. this difference may be due to am's prior exposure to antigens in vivo whereas the bm-derived macrophages are a truly naïve population. interestingly, after lps stimulation, il- a, il- , mcp- , kc, g-csf and gm-csf are higher in cf macrophages compare to wt and het mice suggesting that cf affected macrophages display an altered inflammatory response when compared to wt and het. the abnormal production of these cytokines was also detected at the transcriptional level using quantitative rt-pcr analysis. in conclusion, our data support the hypothesis that cftr-null macrophages may have an impaired cytokine profile at baseline as well as after stimulation. furthermore, cftr deficient macrophages may contribute directly to the abnormal inflammatory response in cf. (supported by cff, nih, niddk) cystic fibrosis lung disease is associated with an excess of free neutrophil elastase (ne) in the airway arising from persistent neutrophil inflammation. dx- is a potent small protein inhibitor of neutrophil elastase that could be a useful therapy for diseases involving neutrophilic inflammation such as cystic fibrosis and copd. dx- effectively inhibits ne activity in cf sputum sol (ic = pm). however the physical barriers posed by cf whole sputum may prevent dx- accessing and inhibiting ne ensconced within the mucus. the mucolytic dnase acts by cleaving extracellular dna in mucus thereby reducing viscosity. however dna binds and inactivates ne and therefore dnase treatment of mucus results in an acute increase in active ne. the lipid portion of pulmonary surfactant acts as a lubricant and our group has previously shown that bovine lung extract surfactant (bles) increases the fluidity of whole sputum. ( aim we aimed to show that, by reducing the surface tension of sputum, bles would enhance the anti-elastase effect of dx- in whole sputum. methods whole sputum ( . g per well in a -well plate) was pre-incubated with µl saline as control, µl dnase ( µg/ml) or µl bovine lung extract surfactant (bles, µg/ml) for minutes at °c followed by addition of µl dx- ( µm or µm) for h at °c. the contents of each well were aspirated, added to ml nacl ( . %) and centrifuged at , g for min. the resulting sputum sol was assayed for ne activity using the colorimetric substrate n-meosuc-aapv-pna. results ne activity in whole sputum was significantly inhibited by µm dx- (p= . ) and µm dx- (p= . ). µm dx- inhibited significantly more ne when sputum was pre-treated with bles (p= . ) treatment of sputum with dnase caused a significant increase in ne activity compared to untreated sputum (p= . ) whereas treatment of sputum with bles did not have this effect. conclusion dx- effectively inhibits elastase in cf sol. pre-treatment of cf whole sputum with bles enhanced the anti-elastase effect of dx- and treatment of sputum with bles alone did not cause an increase in ne activity in contrast to treatment with dnase. dx- inhibitory capacity in whole sputum could be improved by co-treatment with surfactant which increases fluidity of sputum and could allow greater access of drugs to sputum components. bovine lung extract surfactant, bles™ was a kind gift from bles biochemicals inc., on, canada. dx- was a kind gift from dyax corp, ma who also funded part of this research. table : results are summarised as neutrophil elastase activity µg/ml and show the mean and sem of n= experiments. cystic fibrosis lung disease is associated with an excess of free neutrophil elastase (ne) in the airway arising from persistent neutrophil inflammation. dx- is a potent small protein inhibitor of neutrophil elastase that could be a useful therapy for diseases involving neutrophilic inflammation such as cystic fibrosis and copd. dx- effectively inhibits ne activity in cf sputum sol (ic = pm). however the physical barriers posed by cf whole sputum may prevent dx- accessing and inhibiting ne ensconced within the mucus. the mucolytic dnase acts by cleaving extracellular dna in mucus thereby reducing viscosity. however dna binds and inactivates ne and therefore dnase treatment of mucus results in an acute increase in active ne. pulmonary surfactant acts as a lubricant and our group has previously shown that bovine lung extract surfactant (bles™) increases the fluidity of whole sputum. ( we aimed to show that, by reducing the surface tension of sputum, bles™ would enhance the anti-elastase effect of dx- in whole sputum. methods whole sputum ( . g per well in a -well plate) was pre-incubated with µl saline as control, µl dnase ( µg/ml) or µl bovine lung extract surfactant (bles™, µg/ml) for minutes at °c followed by addition of µl dx- ( µm or µm) for h at °c. the contents of each well were aspirated, added to ml nacl ( . %) and centrifuged at , g for min. the resulting sputum sol was assayed for ne activity using the colorimetric substrate n-meosuc-aapv-pna. results ne activity in whole sputum was significantly inhibited by µm dx- (p= . ) and µm dx- (p= . ). µm dx- inhibited significantly more ne when sputum was pre-treated with bles™ (p= . ) treatment of sputum with dnase caused a significant increase in ne activity compared to untreated sputum (p= . ) whereas treatment of sputum with bles did not have this effect. conclusion dx- effectively inhibits elastase in cf sol. pre-treatment of cf whole sputum with bles™ enhanced the anti-elastase effect of dx- and treatment of sputum with bles alone did not cause an increase in ne activity in contrast to treatment with dnase. dx- inhibitory capacity in whole sputum could be improved by co-treatment with surfactant which increases fluidity of sputum and could allow greater access of drugs to sputum components. we would like to thank prof. f. possmayer, on, canada and bles biochemicals inc., on, canada for the bovine lung extract surfactant, bles™. dx- was a kind gift from dyax corp, ma who also funded part of this research. table results are summarised as neutrophil elastase activity µg/ml and show the mean and sem of n= experiments. cf patients infected with p. aeruginosa (pa) have increased levels of proinflammatory cytokines, such as tnf-α, il- β, il- , and il- ; but have low levels of the anti-inflammatory cytokine, il- in their airways. the proinflammatory mediators in the cf airway recruit a large number of polymorphonuclear neukocytes (pmns), which release high levels of neutrophil elastase and human neutrophil peptides and damage the lungs. the intense neutrophil-dominated inflammatory response associated with chronic pa infection results in progressive airway obstruction, the cause of death of over three-quarters of cf patients. recent studies highlight the significance of sphingolipid metabolism in cell growth, differentiation, membrane traffic, apoptosis, senescence, and immune regulation. acid sphingomyelinase (asm) plays a critical role in sphingolipid metabolism by hydrolyzing sphingomyelin to ceramide. ceramide self-associates to form ceramide-enriched membrane platforms(also called lipid rafts). these platforms have been shown to be involved in the internalization of pa; induction of apoptosis and immune regulation. our in vitro and in vivo studies of asm confirm that there is a loss of induction of asm after pa infection in both cf bronchial epithelial cells and cftr knock out mice as compared with controls. in vitro, we examined the asm activity in human bronchial epithelial cells with normal cftr expression (s cells) and with mutant cftr expression (ib cells ) after pa infection at , , , , , and min. asm activity was up-regulated in s cells following pa infection after min and kept increasing until min, while asm induction was lost in ib cells. asm protein and ceramide levels also increased in s cells following pa infection compared with ib cells. in our in vivo studies, cftr knock out mice and control c bl/ mice were both administered various doses of pa orally ( x cfu to x cfu) . six hours after pa infection, lung homogenates from the c bl/ mice indicated increasing asm protein and ceramide production, which corresponded to the dose of pa given. in contrast, asm protein and total ceramide production remained at baseline levels in the lung homogenates of cf mice regardless of the dose of pa given. rna interference (sirna) assays were performed by transfecting a bp pre-designed sirna specific for human asm in s cells. these cells were then infected with pa for hrs to see if they had similar il- level compared with infected ib cells. we demonstrated a significantly elevated il- expression in s cells tranfected with asm sirna compare with s cells transfected with a scramble sirna (p< . ). our results suggest that the loss of asm induction, caused by mutant cftr, is involved in pa clearance and contributes to the exaggerated proinflammatory cytokine response in cf airway. we are conducting research on defining the roles of asm and the sphingolipids in pa infection; cell signaling; as well as cytokine induction, we are also looking at the therapeutic potential of aav.asm vectors in pa-infected cf bronchial epithelial cells and cftr knock out mice. work supported by nhlbi introduction: new therapies are critically needed to treat cystic fibrosis (cf) lung disease, which is characterized by chronic infection and inflammation. novel therapies to target airway inflammation are likely to improve the clinical outcome in cf. as yet there is no consensus regarding the molecular pathway(s) mediating inflammation in the cf lung. objective: to establish whether toll-like receptor (tlr) signalling is the key molecular pathway responsible for the inflammation seen in cf lung disease and to determine whether inhibitors of tlr signalling can reduce this damaging inflammatory response. methods and results: to quantify the airway inflammatory response, we used established cf and cf-corrected lung epithelial cells (ib - and c ). since artefacts may alter the inflammatory phenotype of cell lines, we validated all findings with fresh peripheral blood mononuclear cells (pbmcs) from cf patients (n= ) and healthy controls. we measured the inflammatory response (il , il , tnfα) of these cells following stimulation with: (i) cf pathogens (p. aeurginosa, b. multivorans, b. cenocepacia); (ii) purified tlr ligands. both cf respiratory epithelial cells and cf pbmcs had a greatly increased inflammatory response compared to matched controls when stimulated with whole bacteria and purified tlr ligands (p< . ). interestingly, the cf airway cells responded most vigorously to the tlr ligand, flagellin (p< . ). to investigate tlr as a potential anti-inflammatory target, we found that tlr mrna (p< . ) and protein (p< . ) were expressed at a higher level in cf compared to cf-corrected lung epithelial cells. finally, to determine the contribution of tlr activation to cf lung inflammation we exposed the airway cells to wild-type (pak & pao ) and isogenic flagellin-deficient strains of p. aeruginosa (pak∆flic, pao ∆flic, pao ∆flge & pao ∆flim) . strikingly, the absence of the tlr -flagellin interaction significantly reduced the proinflammatory response of cf respiratory epithelial cells to p. aeruginosa (p< . ). we show that tlr-mediated innate immune responsiveness is increased in both cf respiratory epithelial cells and fresh blood cells from cf patients. moreover, inhibition of the tlr -flagellin interaction markedly reduced proinflammatory response of cf respiratory epithelial cells following exposure to predominant cf pathogen p. aeruginosa. these data suggest that tlr activation may represent a novel anti-inflammatory target for improving cf lung disease. supported by the canadian cf foundation. cf airway cells (ib - ) were stimulated with wild-type (pak) and flagellin-deficient p. aeruginosa (pak∆flic). introduction: genetic polymorphisms for tgf-β have recently been identified as a significant modifier of cf lung disease severity. however, at present little is known about protein measurements of tgf-β in bronchoalveolar lavage fluid (balf) or serum obtained from pediatric cf patients during an acute respiratory exacerbation. hypothesis: tgf-β in cf balf and serum is increased in association with markers of cf lung disease severity, and is decreased after completion of iv antibiotic (iv abx) therapy. study design and methods: in a descriptive, prospective study of children with cf presenting for hospital admission to treat a pulmonary exacerbation, balf specimens were obtained from patients undergoing clinically-indicated flexible bronchoscopy on admission. balf was immediately analyzed for total and differential cell counts with the cell-free balf supernatant stored at - °c. serum specimens were obtained at the initiation and conclusion of iv abx and similarly stored at - °c. measurement of total tgf-β utilized a commercial elisa kit. t-test statistical analysis assumed significance at p<. . results: balf was obtained from cf patients with a mean age of . ± . years (range - years). three balf cultures were pseudomonas aeruginosa positive (psa+). balf tgf-β levels ranged from - pg/ml (mean ± . pg/ml) with the highest tgf-β measured in a patient with abpa and culture positive for m. abscessus. in balf, higher neutrophil counts (greater than the median, . x pmn/ml) were associated with increased balf tgf-β ( ± . pg/ml vs. ± . pg/ml, p<. ). serum tgf-β was collected in cf patients with a mean age of . ± . years (range - years), four of whom were psa+. serum tgf-β ranged from . - . ng/ml (mean . ± . ng/ml). in both balf and serum, neither patient age nor psa culture status was associated with increased tgf-β at admission. however, previous hospitalization in the last months was significantly associated with an elevated admission tgf-β in both balf ( ± . pg/ml vs. ± . pg/ml, p<. ) and serum ( . ± . ng/ml vs. . ± . ng/ml, p<. ). after completing the clinically-indicated course of iv abx, / psa-cf patients had a reduction in serum tgf-β (mean . ± . ng/ml to . ± . ng/ml, p=ns). in contrast, / psa+ cf patients had an increase in serum tgf-β (mean . ± . ng/ml to . ± . ng/ml, p=ns) after completing iv abx therapy. conclusions: tgf-β is measurable in balf and serum from pediatric cf patients and varies in association with clinical parameters. these preliminary results support our hypothesis that increased tgf-β may be associated with more severe lung disease as evidenced by ) association of increased tgf-β in balf and serum obtained from cf patients with previous hospitalization in the last months, and ) association of increased tgf-β in balf with increased cellular inflammation. the direction of change in serum tgf-β after iv abx therapy may be influenced by the presence or absence of pseudomonas infection. acknowledgments: supported by cff (harris ao). paula murphy and cassidy henegar provided technical support. background: cystic fibrosis is one of the leading genetic causes of end stage lung disease for which the treatment is lung transplantation. however, mortality due to chronic rejection known as obliterative bronchiolitis (ob) remains high due to small airway obliteration. ob is associated with increased levels of matrix metalloproteinase- (mmp- ), an interstitial collagenase, expressed by polymorphonuclear cells (pmns). pmns are among the first inflammatory cells to be detected in ob but very little is known about the role of pmn mmp- or the mechanisms used by pmns to migrate through extracellular collagen matrices. objective: to identify the molecular mechanism for neutrophil recruitment into the airway. we hypothesize that mmp- promotes accumulation of pmns in ob lesions by promoting their migration through the extracellular matrix protein barriers by its pericellular collagenase activity. method: the heterotopic airway transplant model was used to study the role of neutrophil mmp- in promoting pmn migration through extracellular matrices. mhc-disparate balb/c tracheas were subcutaneously transplanted into c bl/ wild-type (wt) or mmp- deficient (mmp- -/-) mice. to further dissect the mechanism of pmn migration in vitro their migration through collagen gels was studied. collagen gels were made in transwells using rat-tail collagen providing a highly cross-linked thick collagen barrier. bone marrow derived pmns from wt or mmp -/-mice were fluorescently labeled and stimulated to induce the surface expression of mmp- . pmns were placed on thick collagen gels in traswells. the transwells had polycarbonate membranes at the bottom of the gels. the pore size of the membranes did not allow pmns to pass through into the lower chambers that had flmp a chemo attractant. at hours and hours the gels were fixed and the polycarbonate membrane at the bottom of the collagen gel was gently peeled off. pmns on the membrane were counted under a fluorescent microscope. results: significantly decreased migration of pmns into the airway lumen was noted in the mmp- deficient mice (p< . ) weeks post-transplantation compared to wt mice in the heterotopic airway transplant model. in addition there was more than a three-fold increase in the pmns outside the lumen in the extracellular collagen matix (p< . ). wt-pmns were able to penetrate collagen barriers in greater numbers both at and hours compared to mmp -/-pmns in vitro (p < . for hours and . for hours). in addition, mmp inhibitor gm -treated wt cells demonstrated decreased migration through collagen gels ( hours p< . and hours p< . ). conclusions: mmp- -/-mice has significantly less pmns in the airway lumen due to decreased migration through collagen matrices providing protection against ob. this has great significance for conditions such as cystic fibrosis, lung transplant rejection (obliterative bronchiolitis) and other inflammatory diseases mediated by pmns. mmp- blockade can potentially be a novel therapeutic target to decrease neutrophil efflux into the airways and thus reduce airway inflammation. background: our laboratory has demonstrated alterations in cf-related regulation of cholesterol processing. hydroxycholesterols (oxysterols) are oxygenated derivatives of cholesterol formed from autoxidation of cholesterol and from de novo synthesis. oxysterols are known to be key regulators of cholesterol metabolism and cellular signaling. the role of oxysterols in the cellular pathways involved in cholesterol processing in cystic fibrosis has not been elucidated. based on our previous findings of increased de novo cholesterol synthesis in cf tissues, we hypothesize that oxysterol production in cf would be positively impacted. increased oxysterol production may lead to abnormalities in cellular signaling associated with oxidative stress and may influence the inflammatory response in cf. the goals of this research are to investigate the effect of oxysterols on inflammation in cf and to determine if there is a difference in oxysterol production in cf compared to wild type controls. results: the goal of these studies is to determine if cf cells respond uniquely to oxysterols compared to control cells. initial studies demonstrate that cf-model /hteo-pcepr cells failed to respond to -oh cholesterol ( -oh) with regards to nfκb activation. control /hteo-pcep cells, however, exhibited a significant -fold increase in nfκb activity upon -oh stimulation ( . -fold +/- . increase from il- , tnf alpha alone). however, il- promoter activation in response to -oh was not significantly altered in either cf or wt cells ( . -fold +/- . (cf) increase from il- , tnf alpha alone, . -fold +/- . (wt) increase from il- , tnf alpha alone). in order to verify il- promoter results, il- protein production was measured directly in response to pseudomonas aeruginosa. il- protein level in response to -oh was increased in cf cells ( . -fold) and decreased in wt cells ( . -fold), although not significantly in either group. oxysterol content and de novo synthesis are currently being examined in vivo in cf and wild type mouse models. mice lacking cftr on a c bl/ background and wild type controls were obtained from our animal core and the amount of oxysterol present in these mouse models is currently being studied. conclusion: these findings suggest that endogenous oxysterol production or other components of oxidative stress are pre-stimulating nfκb activation via the oxysterol-sensitive pathway. interestingly, although oxysterols robustly activate nfκb in wt cells, oxysterol-dependent pathways are not involved in il- production. these data suggest that il- is not a primary cause for increased oxysterol mediated inflammation. elucidating the role of oxysterols in cf will be an important contribution to our understanding of the inflammatory pathways in cf and will contribute to the growing body of evidence for aberrant cholesterol regulation in cf. this work is supported by grants from the cff and the nhlbi. cystic fibrosis (cf) is a common genetic disorder caused by a mutation in the cftr, a chloride transporter of the abc transporter family. innate immunity, the first line in host defense against infectious agents, is abnormal in cf patients. cf patients are commonly colonized with bacterial pathogens, which is the major clinical problem of this disease. despite a marked difference in the clinical outcome amongst cf patients infected with pseudomonas aeruginosa and burkholderia cepacia, the mechanisms under-lying these differences remain unclear. understanding the innate immune response, specifically the role of cftr, in p. aeruginosa and b. cepacia infections will lead to new insights into mechanisms that limit these infections. our objective is to develop a cf model in the simple organism, the worm, c.elegans, and to test the role of the cftr orthologue, mrp- , in host defense. using this model, we have compared the survival of c. elegans between virulent p.aeruginosa (pa ) and b.cepacia (bc). our experiments have demonstrated that, when compared to growth on their natural food source, e.coli op , worms fed on pa and bc die prematurely. specifically, worms survive up to hours on op , whereas pa fed worms die with in hours. death on pa also requires active infection, as heat inactivation of these bacteria destroys their killing capacity. two bc strains have been tested, a virulent strain ( ) and an avirulent strain ( ). worms infected with bc show an intermediate phenotype, surviving approximately hours. our future work will define whether synergy occurs during coinfection with p.aeruginosa and b.cepacia, as would be suggested by clinical data. in addition, we will define the transcriptional changes induced in c.elegans fed on pa and bc, and use these data to identify common and pathogen specific responses to these infections. finally, mrp- knock-down worms will be generated using rna interference, and the role of the cftr orthologue in infection will be tested. in conclusion, c.elegans offers a genetically tractable model organism in which the innate immune response to pseudomonas aeruginosa and burkholderia cepacia can be studied. in addition, this simple model system will allow us to define the role of the cftr orthologue in host defense. supported serine proteases released from neutrophils are considered central to the pathogenesis of cf lung disease, and have been obvious therapeutic targets. although intracellular serine proteases are important in host defense and bacterial killing, extracellular enzymes may contribute to bacterial persistence and promote airway inflammation. neutrophil elastase (ne) digests key opsonins present in the lung and has been shown to disrupt phagocytosis, allowing the bacteria to persist in the face of established pulmonary inflammation. in addition we have found that other proteases, like cathepsin g (cg), an abundant serine protease found in human and murine neutrophils, may also have other, critical roles in development of cf lung disease. indeed, using murine models of endobronchial inflammation, cg inhibits airway defenses and interferes with the host's ability to clear pseudomonas aeruginosa from the lung with effects quite distinct from ne. to test the hypothesis that differences in bacterial killing are due to defects in innate defenses created by excess, unopposed cg at the apical surface of the airway epithelium, we have examined profiles of proteins secreted into the airway lumen by epithelial cells, which are necessary for p. aeruginosa clearance and susceptible to cg proteolysis. analysis of lavage fluid utilizing -d page indicated a total of spots which were increased in pooled lavage fluid from infected cg-deficient mice as compared to wild-type littermates. tandem mass spectrometry analysis identified several novel proteins that were cleaved by cg, including inter-alpha inhibitor protein, selenium-binding protein, sec -like protein, beta- -glycoprotein, and annexin a . another protein candidate, serum amyloid p component (sap), is a novel opsonin and may be involved in airway defenses. immunoblot analy-sis demonstrates that cg cleaves sap. these results suggest that cg, like ne, plays an important role in the pathogenesis of lung diseases. we have previously demonstrated in ∆f -cf mice that in vivo treatment with azithromycin (azm) attenuates cellular infiltration in baseline and lipopolysaccharide (lps)-induced inflammation, and inhibits proinflammatory cytokine release in induced inflammatory condition (legssyer et al, ) . this study aimed at investigating macrophages isolated from wild type (wt) or ∆f -cf mice (van doorninck et al, ) and the effect of azm on these cells. purified peritoneal and alveolar macrophages were stimulated with lps (p. aeruginosa, . µg/ml) plus ifnγ ( . µg/ml), with or without azm ( µg/ml). macrophage inflammatory status was investigated by assessing different pro-and anti-inflammatory mediators at mrna level h after stimulation. pro and anti-inflammatory markers seemed to be reduced in naive alveolar cf macrophages. by contrast, a trend to overexpression of these markers was seen in naive peritoneal cf cells. pro-inflammatory status, as assessed by il- β, was induced in stimulated alveolar and peritoneal cf macrophages and in naive peritoneal cf cells. moreover, nos- was found to be overexpressed in stimulated alveolar cf macrophages while il- was downregulated. azm significantly reduced il- β expression in stimulated alveolar macrophages. in conclusion, peritoneal and alveolar macrophages exhibit distinct phenotype. a pro-inflammatory status was more prominent in stimulated cf alveolar and peritoneal cells. interestingly, azm modulates il- β overexpression only in cf stimulated alveolar macrophages, supporting the antiinflammatory activity of this macrolide and identifying, at least partly, alveolar macrophages as possible target cells for its effects. supported it has been recently reported by perez and coll. that the inhibition of function of w/t cftr produces an inflammatory profile that resembles that observed in cf patients [am j physiol lung cell mol physiol, ] , whereas we demonstrated that correction of f del cftr function with mpb- down modulates the pseudomonas aeruginosa (p.aeruginosa) dependent expression of the pro-inflammatory mediators il- and icam- in cf bronchial cells [am. j. resp. cell. mol biology, ] . since both evidence support a direct link between cftr function and inflammatory response in respiratory epithelial cells, we extended our investigation to other f del cftr correctors, such as miglustat [norez et al, febs letters, ] , which is an approved drug for gaucher disease, in comparison with an isomer without any correcting effect, namely nb-dgj. human bronchial ib - (cftr f del/w x), cufi- (cftr f del/f del) and nuli- (cftr w/t) cells were exposed to the laboratory strain of p.aeruginosa (pao ) or tnf-alpha or il- beta and the transcription of icam- and il- were quantitated by real time rt pcr. cftr function was assayed by single-cell fluorescence imaging, using the potential-sensitive probe disbac [renier et al, hum. gene ther. ]. analysis of binding of nf-kb and ap- transcription factors to labelled dna target was performed with electrophoretic mobility shift assay (emsa) [borgatti et al, j. biol. chem. ]. miglustat significantly reduced the expression of il- by % in ib - and by % in cufi- cells and of icam- by % in ib - and by % in cufi- cells, upon infection by pao . in parallel, correction of f del cftr function was observed after miglustat treatment in both ib - and cufi- cells. miglustat had no major effects on overall binding activity of transcription factors nf-kb and ap- , activated by pao in ib - cells. the inflammatory response induced by tnf-alpha or il- beta was also significantly reduced in ib - and cufi- cells treated with miglustat. nb-dgj, which is not a corrector of function of f del cftr, down modulated the induction of il- and icam- in ib - and cufi- cells. in addition, both miglustat and nb-dgj reduced the inflammatory response to pao in non cf nuli- cells. in conclusion, miglustat and nb-dgj have an anti-inflammatory effect in bronchial cells independently of the correction of f del cftr, by interfering with the pro-inflammatory signaling downstream the receptors for pathogens and pro-inflammatory cytokines. since miglustat is already approved for the treatment of gaucher disease and other glycosphingolipidoses, it may be an interesting candidate to ameliorate lung inflammation in cf patients. background: the primary cause of mortality and morbidity in cystic fibrosis (cf) is lung disease, which is characterized as a chronic cycle of infection and inflammation dominated by a neutrophilic infiltrate and increased levels of circulating mediators such as il- . a wide variation in the rate of progression of lung disease is observed in cf. hypothesis: we postulate the presence of a brisk systemic inflammatory response in cf patients and that this systemic response reflects the magnitude and progression of lung disease. methods: lung function and clinical data were obtained from cf patients treated and followed in the adult cf clinic, st paul's hospital. forced expiratory volume at s (fev ) and forced vital capacity (fvc) values dating back to were used in regression equations to group patients into quartiles based on their decline in predicted fev %. rate of decline in lung function was compared with clinical characteristics and various systemic inflammatory biomarkers, including wbc, band cell count, crp, il- β, il- , il- , mcp- , and gm-csf results: the quartiles exemplified significantly different rates of decline in fev /fvc% values. subjects with a rapid decline in lung function were younger and were colonized/infected more commonly with methicillinresistant staphylococcus aureus (mrsa) (p< . ). in addition, altered calcium, magnesium, and albumin levels were found in subjects with increased rates of decline in lung function (p< . ). preliminary results show that patients with cf have significantly elevated levels of wbc ( . e /l), crp ( . e ng/ml), and il- ( . pg/ml) in serum when compared to control subjects (p< . ). there were trends in relationships between levels of il- , il- and mcp- and rates of decline in lung function, however none reached statistical significance. conclusion: there is a variable rate in the decline in lung function among cf patients and one factor may be a heterogeneous systemic inflammatory response. circulating pro-inflammatory mediators may not only impact progression of lung disease, but could also be novel biomarkers to monitor and assess disease severity in cystic fibrosis. nutritional status in addition effects the rate of decline in lung function perhaps by modifying the inflammatory response. this research is supported by the bc lung association. overexpression of the epithelial na + channel β subunit (protein = βenac, gene = scnn b) in transgenic mice results in cf-like lung pathology, characterized by neonatal mortality, mucus obstruction and airway inflammation (mall et al., nat. med. ) . breeding βenac mice into gene-deleted mice enables quick and efficient determination of the specific pathways relevant to the development of lung pathology. tnfα is a pleiotropic pro-inflammatory cytokine released by many different cell types, including t cells, macrophages, granulocytes, and epithelial cells. tnfα levels are significantly elevated in bronchoalveolar lavage (bal) from βenac mice in comparison to wild-type (wt) littermates. we crossbred βenac mice (heterozygous, inbred line c - ) with tnfα knockout mice, generating four types of mice: wt, tnfα +/-; wt, tnfα -/-; βenac, tnfα +/-; and βenac, tnfα -/-. all mice had comparable, high survival, ranging between - %. the lack of tnfα did not prevent neutrophil and eosinophil infiltration and did not significantly modify the lung pathology characteristic of βenac mice, namely mucus plugs, mucous secretory cell hyperplasia, airway inflammation and emphysema. the absence of tnfα in bal from βenac, tnfα -/-mice, in comparison to βenac, tnfα +/mice, was confirmed by luminex cytokine assay. the levels of kc, a potent neutrophil chemoattractant, were significantly elevated in bal fluid from βenac mice, regardless of the presence or absence of tnfα. in wt mice, no granulocytic infiltrate or morphologic changes were observed and tnfα and kc were undetectable. similarly, the pathologic changes in βenac mice were not mitigated by crossbreeding to knockout mice for tnfα receptor (tnfαr ), the major mediator of biologic responses classically attributed to tnfα. these results suggest that tnfα per se does not have a critical pro-inflammatory role in the development of inflammation in the βenac mouse model. the production of alternative cytokines may compensate for the loss of tnfα bioactivity in the tnfα and tnfαr -/-mice. since tnfα has been suggested to play a role in the regulation of enac, ussing chamber studies are underway to test whether the bioelectric features of tracheobronchial epithelia from βenac mice are altered by the absence of tnfα in vivo. these data suggest that a tnfα-independent signaling cascade links airway surface dehydration to airway inflammation in the βenac mouse model. innovative pharmacological approaches to control the excessive neutrophil infiltrates into the bronchial lumen of cf patients are thought to be beneficial to reduce the extensive airway tissue damage. the activation of expression of proinflammatory genes by p.aeruginosa with bronchial epithelial cells is a central mechanism to be targeted with novel therapies. medicinal plants from the socalled traditional asian medicine are attracting a growing interest because of their potential safety, already tested in large scale applications in human diseases. however, due to the presence of different active principles in each plant extract, whose multifunctional effects may even result contradictory, understanding the effect of each component is mandatory to pursue selective and reproducible applications. a panel of medicinal plant extracts have been firstly screened for their capacity to interfere in the binding of nuclear transcription factor proteins (tf) with dna consensus sequences identified in the promoters of the pro-inflammatory genes, thus for their potential inhibitory action on gene expression. extracts from several medicinal plants have been screened for their ability to interfere with the tf nf-kb, ap- and creb, which are induced by p.aeruginosa, and some of them, such as emblica officinalis (eo), aegle marmelos (am), polyalthia longifolia (pl), have been shown to inhibit tf/dna interactions, opening the possibility of potential applications to downregulate expression of pro-inflammatory genes. extracts from eo, am, pl were tested in ib - cf bronchial cells exposed to the p.aeruginosa laboratory strain pao . eo, am and pl strongly inhibited the pao -dependent transcription of il- in ib - cells. pyrogallol, one active principle of eo, was tested in ib - cells, where it inhibited the transcription of the neutrophil chemokines il- , gro-alpha and gamma, of the intercellular adhesion molecule icam- and the pro-inflammatory cytokine interleukin , similarly to the whole eo extract, whereas a second active principle from eo, namely hydroxy-isoquinoline, had no effect. similar results were obtained with eo and pyrogallol in the monocyte-derived macrophage cell line thp- exposed to pao . in conclusion, extracts from plants of the traditional medicine can inhibit expression of pro-inflammatory genes and screening active principles purified from medicinal plants could result useful to identify safe and innovative pharmaceutical molecules to control lung inflammation in the lung of cf patients. supported by italian cystic fibrosis research foundation and by fondazione cariverona -bando -malattie rare e della povertà. massive infiltrates of neutrophils in the mucosal wall and lumen of the conductive airways of cf patients contribute to the progressive lung func-tion decline by releasing different proteases responsible for the progressive airway tissue damage. bacterial products and pathogens themselves within the mucopurulent material of the airway surface fluid induce the activation of transcription factors such as nf-kappab, ap- , sp , nf-il , nf-at, elk- , creb resulting in expression of chemo/cytokine genes driving the recruitment of leukocytes inside the bronchial lumen. to find new treatment options focused on the reduction of neutrophil chemotaxis, without abolishing the immune response against pathogens, we are exploring the transcription factor (tf) "decoy" strategy, in which oligodeoxynucleotides (odn) mimicking the consensus sequences for the tfs proteins identified in the promoters of different chemo/cytokines are delivered inside the cell in order to interfere with gene transcription. cf bronchial epithelial cells ib - have been exposed to the (i)p.aeruginosa(/i) strain pao . a clear pao -dependent activation of tfs such as nf-κb, sp , ap- , nf-at, nf-il was confirmed by electrophoretic mobility shift assay (emsa). in parallel, transcription of genes involved in innate immune response has been quantified by real-time rt pcr. transcription factor "decoy" odns directed against the consensus sequences identified in the promoters of different genes have been designed and validated by testing their interference in tf protein/dna binding assays. transfection of ib - cells with hiv- ltr and igk chain nf-κb odn "decoys" complexed with lipofectamine, performed hrs before challenge with pao , was shown previously to inhibit strongly pao -dependent transcription of il- but not gro, il- β, il- and icam- . therefore other tf "decoy" odns have been also tested: a) odn for nf-κb from il- promoter inhibited il- , gro-gamma and il- by %, b) odn for sp from hiv- genome inhibited il- by %, c) odn for ap- from il- promoter inhibited both il- and gro-gamma by %. a tf "decoy" molecule designed as peptide-dna chimera mimicking the consensus sequence of hiv ltr nf-κb strongly and selectively inhibited il- transcription. in conclusion, transcription of chemo/cytokines induced by (i)p.aeruginosa(/i) in cf bronchial epithelial cells (i)in vitro(/i) can be inhibited with different efficiency and selectivity by tf "decoy" molecules. these results provide useful hints for a gene-targeted anti-inflammatory approach and add further information on the regulation of expression of pro-inflammatory genes induced by (i)p.aeruginosa(/i) in bronchial epithelial cells. supported by italian cystic fibrosis research foundation and by fondazione cariverona -bando -malattie rare e della povertà. background: cf is characterized by hypersecretion of the pro-inflammatory cytokine il- from airway epithelial cells. however the mechanism by which il- gene expression is dysregulated in cf is not known. the expression of cytokine and chemokine genes is known to be regulated at multiple mechanistic steps including transcription, mrna decay, translation, and various post-translational steps. sequence-specific mrna degradation is now recognized to be an important site controlling the expression of several chemokine mrnas. this selective behavior is conferred by cisacting elements in the mrna composed of au-rich sequences (ares). the regulatory function of ares is thought to be mediated via rna-binding proteins that specifically recognize the are motifs. the steps required for mrna decay is comprised of deadenylation, decapping and body decay. deadenylation or removal of the poly (a) tail by poly(a)-specific ribonuclease (parn) appears to be the first and perhaps the rate-limiting step. this is accompanied by decapping or enzymatic removal of the ' methylate guanosine cap. subsequently, exonuclease activities in the ' to ' or ' to ' direction predominate to degrade the remaining mrna. hypothesis: we have hypothesized that defects in transcription as well as modulation of the post-transcriptional stability of il- mrna might contribute to hyper-production of il- protein in the cystic fibrosis. methods: il- mrna stability was assessed in cystic fibrosis ib - lung epithelial cells and in aav-cftr-repaired ib - /s cells, by measuring residual il- mrna levels at various intervals of time after addition of actinomycin-d to the culture. protein s extracts, prepared from the cf cell line as well as the cftr-corrected cell line, were analyzed by western blot. the expression levels of the various factors known to participate in are-mediated mrna decay, including ttp (an are-binding protein), parn and the exosome were compared in the two sets of s extracts. results: we find that the levels of il- mrna in the cf cells are greater than the levels found in the cftr-repaired cells. in addition, we found that the rate of decay of il- mrna in cf cells was significantly less than that in the repaired cell line. the levels of ttp, parn and exosome proteins were significantly reduced in the cf cells compared to the cftrrepaired controls. however, expression of ttp in ib - cells causes significant destabilization of il- mrna. conclusion: we conclude that the high levels of il- protein expression in cf lung epithelial cells can be partly due to enhanced stability of the il- mrna. consistently, the actual levels of il- mrna are higher in the cf cells compared to controls. understanding the mechanism by which ttp promotes enhanced destabilization of il- mrna in cf cells may be important for developing novel therapeutic targets to alleviate the pulmonary pathophysiology of this disease manifested by hyper-secretion of il- protein. understanding the mechanism of airway remodeling could lead to the identification of novel therapeutic targets for the prevention of irreversible lung damage in cf. we have investigated transcriptional responses to epithelial injury in a mouse model of cf that was developed in our laboratory (f del, cftr tm eur fvb backcross f ). to induce transient epithelial lung injury, homozygous normal and mutant age matched littermates were treated in parallel with naphthalene ( mg/kg ip) or carrier (corn oil) as control (n= x ). naphthalene causes an almost complete selective ablation of clara cells overnight, followed by migration of resistant ciliated cells and rapid proliferation of undifferentiated progenitor cells. two and seven days after treatment, lungs were collected for histological and transcriptome analysis. based on a previous affymetrix microarray analysis (n= ), a quantitative pcr array was designed containing genes differentially expressed after naphthalene injury. as expected, naphthalene injury results in a transient increase of cell proliferation markers (mki , cdc , cdc a etc), and a strong ( %) reduction of clara cell markers (cc /scgb a ; claudin /cldn ; cyp f ). in addition, we have now identified twenty-five genes that are increased (p< . ) two-to fifty-fold after naphthalene injury in both normal and mutant mice. this includes known and novel markers of epithelial tissue injury such as timp , retlna, mmp , serpin n, and lipocalin. in particular, a group of egf receptor agonists is strongly induced: amphiregulin (areg, fold), epiregulin (ereg fold) and heparin binding egf ( fold). amphiregulin mrna can be detected by in situ hybridization only in airway epithelial cells after injury. these egfr agonists are involved in stimulating epithelial repair, but can also activate cells in the underlying mesenchyma. indeed, we observe a substantial increase of major extracellular matrix mrna's two days after injury (co a : -fold, col a : -fold, elastin: -fold). whereas expression levels were substantially reduced in normal animals seven days after injury, in cf mutant animals two to three fold higher levels were observed for these three genes at day seven (p< . ). conclusions. we have designed and validated a gene array that can be used to study distal lung injury and repair. egfr agonists produced by epithelial cells are the most prominent growth factors after injury, involved in both epithelial repair and extracellular matrix production by mesenchymal cells. ecm production in cf mouse lung is sustained compared to normal mice, suggesting an inherent tendency towards fibrosis in cf lungs. our data suggest that the mesenchymal egf receptor and regulation of its agonists are important future targets of novel therapeutic strategies. supported by eec th fw projects eurocarecf, improved precision the mucosa of the proximal airways defends itself and the lower airways from inhaled irritants, allergens, and microbial and viral infections by several mechanisms. sensory nerves monitor the luminal microenvironment and trigger reflexes in the central nervous system (cns) that alter breathing, induce cough and stimulate mucus secretion when challenged with noxious stimuli. sensory nerves also release the tachykinins substance p (sp), neurokinin a and calcitonin gene-related peptide through axon reflexes in neighboring tissues, and these locally released tachykinins stimulate mucus secretion by binding to neurokinin receptors on submucosal glands. recently we reported that local fluid secretory responses to noxious stimuli are dependent on the clchannel cftr in mouse airway submucosal glands and are defective in glands from cftr knockout mice (ianowski et al., j physiol, , , ) . we have now tested the effects of sp directly and examined the possible role of cftr in mediating these responses using tracheas from congenic wild-type and cftr knockout mice (cftr m unc /cftr m unc ) that had been bred onto c bl/ j or balb/c genetic backgrounds. we compared single gland secretion rates using optical methods as described previously. the cftr genotype of each mouse was assessed by using pcr to amplify genomic dna from tail clippings obtained at age days. after the cftr knockout mice were weaned, intestinal obstruction was minimized by supplementing their water with peglite. capsaicinoids (chili pepper oil) increased fluid secretion from glands of wild-type mice from ± pl/min (n= tracheas, glands) to ± pl/min (n= tracheas, glands, anova p< . , tukey-kramer multiple comparison test p< . ). this response was abolished by exposing the basolateral surface of the tracheas to l- , ( µmol/l), a known sp (nk- ) receptor antagonist ( ± pl/min, not different from control, tukey-kramer multiple comparison test p> . ). secretion was stimulated from ± pl/min to ± pl/min (n= tracheas, glands, student's t-test p< . ) by the direct application of sp, and this response was strongly inhibited by pre-incubation with the cftr inhibitor cftrinh (saturating concentration, nominal µmol/l; n= tracheas, glands). finally, submucosal glands from cftr knockout mice failed to secrete when exposed to sp ( µmol/l) whereas wild-type littermates were responsive. these results indicate that sp mediates local responses to capsaicinoids through a cftr-dependent mechanism. loss of this local regulation in cf may contribute to the susceptibility of cf airways. support: canadian cf foundation, canadian institutes of health research, nih (dk ), and the cff (usa). chronically infected/inflamed cf human bronchial epithelia (hbe), or normal hbe exposed to supernatant from mucopurulent material (smm) from human cf airways, exhibit expansion of the endoplasmic reticulum (er) ca + stores and amplification of ca + -mediated inflammatory responses. we have shown that infection/inflammation of hbe triggers an unfolded protein response (upr) coupled to mrna splicing of x-box binding protein- (xbp- ). spliced xbp- (xbp- s) is a transcription factor that promotes er expansion to augment the protein folding capacity during increased protein synthesis. because we have shown that hbe inflammation couples to increases in protein synthesis, we hypothesized that hbe infection/inflammation-induced er ca + store expansion is mediated by xbp- s. to test this hypothesis, we constructed four retrovirally-tranduced stable hbe o-cell lines containing empty vector (ev), xbp- unspliced (xbp- u), xbp- s, or dominant negative xbp- (dn-xbp- ). cells were grown to confluence under an air-liquid interface and er ca + store expansion and il- secretion studied in the absence or following hr mucosal pbs or smm exposure. consistent with our hypothesis, expression of xbp- s in the absence of stimulation induced er expansion and increased mucosal utp-sensitive er ca + stores ( to confirm that these effects were mediated by upr activation, cells were transfected with a upr response element luciferase reporter plasmid, and luciferase activity was measured in the absence or presence of the upr inducer tunicamycin (tm). cells expressing xbp- s exhibited higher baseline luciferase activity than cells expressing ev or xbp- u, whereas luciferase activity was decreased in the dn-xbp- expressing cells. furthermore, while tm increased luciferase activity in cultures expressing ev or xbp- u, its effect was blocked in dn-xbp- expressing cells. these findings suggest that xbp- s is the major trigger of er ca + store expansion, which mediates the amplified ca + -dependent inflammatory response in infected/inflamed airway epithelia. although it remains to be established whether upr-dependent xbp- s is a beneficial or a maladaptive response in infected/inflamed airways, therapies aimed at manipulating this upr pathway may be beneficial for patients with chronic inflammatory lung diseases. luminal exposure of well-differentiated normal human bronchial epithelia (hbe) to supernatant from mucopurulent material (smm) from human cf airways increases the secretion of inflammatory mediators and triggers an unfolded protein response (upr) mediated by the mrna splicing of the x-box binding protein- (xbp- ). spliced xbp- (xbp- s) is a transcription factor that expands the endoplasmic reticulum (er) and protein secretory pathway during er stress induced by accumulation of unfolded proteins due to increases in protein synthesis. our previous studies in primary cultures of hbe and hbe o-cells stably expressing empty vector, inactive unspliced xbp- (xbp- u), xbp- s or a dominant negative xbp- (dn-xbp- ) suggest that induction of xbp- s by smm exposure promotes er ca + store expansion, which mediates a ca + -dependent hyperinflammatory response. the present studies were designed to determine if pseudomonas aeruginosa pak strain (p.a.) would reproduce the effects of smm in both in vitro and, importantly, in vivo models. for in vitro studies, hbe were exposed to broth (tsb) or to a % p.a. extract for hr, and inflammation, xbp- s, and er ca + store expansion investigated by il- secretion, southern blots and calreticulin expression, respectively. similar to smm, p.a. induced a . fold increase in il- secretion coupled to a fold increase in xbp- s and larger er ca + stores as compared with tsbexposed hbe. these data demonstrate the link between p.a. infection, upr activation and xbp- s in vitro. we next tested the relevance of these findings in vivo. wild-type mice airways were challenged with pbs or cfu of p.a., and airway epithelial er density was assessed by calreticulin staining hr later. in comparison with pbs challenges, p.a.-challenged mice exhibited airway epithelial er expansion, which correlated with the degree of airway inflammation, based on the presence of inflammatory cells. to test whether this p.a.-induced er expansion was linked to xbp- s, we utilized "er stress activated indicator" (erai) mice expressing a fusion protein consisting of xbp- u and the fluorescent protein venus. in erai mice, upr activation-dependent xbp- splicing leads to venus expression; hence, venus fluorescence is an index of xbp- s. consistent with our hypothesis that p.a. infection-triggered inflammation would induce upr-dependent xbp- s, venus fluorescence, after hr challenge with cfu of p.a., was increased in inflamed as compared with non-inflamed airways. these findings suggest that ) airway epithelia respond to bacterial infection-induced inflammation by up-regulating the er ca + stores and ) activation of the xbp- s pathway by bacterial infection may be relevant to airway inflammatory responses in vivo. funded by the cff. we have shown that luminal exposure of well-differentiated primary cultures of normal human bronchial epithelia (hbe) to supernatant from mucopurulent material (smm) from human cf airways increases total cellular protein synthesis, which reflects the increased secretion of inflammatory factors induced by the infectious and inflammatory process. in the present studies, we first investigated whether these hbe responses to smm were linked with an increased metabolic rate by measuring lactate accumulation into the serosal media. smm increased lactate production, and this effect was maximal within hrs ( . + . vs. . + . , and . + . vs. . + . mmol/l in and hr pbs vs. smm, respectively; n= - ), suggesting that the increase in protein synthesis couples to a hyper-metabolic state in infected/inflamed hbe. in agreement with this notion, or hr smm, as compared with pbs exposure, induced the expression of genes associated with amino acid transport and metabolism (n= ). in addition, or hr smm exposure up-regulated genes involved in oxidative stress (n= ). we hypothesized that these hbe responses were linked to an unfolded protein response (upr) mediated by activation of the pkr-like er kinase/pancreatic eif α kinase (perk)-induced activating transcription factor (atf ), since this pathway has been shown to confer protection against amino acid loss and oxidative stress in other cells. we first tested whether smm induced activation of perk/atf in hbe by performing western blot analyzes of the components of this pathway. twenty-four hr smm exposure induced perk activation, as indexed by phosphorylation of perk, in comparison with pbs-exposed hbe. on the other hand, total perk protein levels were unchanged in smm-treated hbe. phosphorylation of eif α, the downstream effector of perk, and increased atf protein levels, which depend on the phosphorylated status of eif α, provided additional evidence that the perk/atf pathway was activated by smm. these data are consistent with the hypothesis that induction of atf is triggered by upr activation resulting from increased synthesis of inflammatory factors. we next utilized rna microarrays to test whether atf target genes were induced by smm. six or hr smm exposure induced atf target genes (e.g., ero , an oxido-reductase that provides protection against the accumulation of endogenous peroxides during er stress; stanniocalcin , whose expression is associated with anti-apoptotic functions; and heme oxygenase ). these findings suggest that ) activation of the upr-dependent atf pathway is a compensatory component of the airway epithelial adaptive response to luminal infection/inflammation, and ) activation of the atf pathway protects against inflammation-induced amino acid loss and oxidative stress by up-regulating genes involved in amino acid transport/metabolism and oxidative stress responses. unraveling the functions of atf should help determine if therapies targeted to manipulate pathway activity would be likely to improve lung function in patients with cf or other chronic inflammatory airway diseases. funded by the cff. miller, t.j.; perez, a.; qian, y.; davis, p. pediatrics, case western reserve university, cleveland, oh, usa fxyd is a cell surface protein originally identified in a screen for molecular markers of tumorigenesis. increased fxyd expression was found in tumors from stomach, thyroid, colon, pancreatic, breast and lung cancers and correlated with down-regulation of e-cadherin and poor patient prognosis. recent studies have shown that overexpression of fxyd promotes cell motility, decreases cell-cell attachment and increases tumor metastasis. fxyd , also known as dysadherin, is a member of small family of proteins known to regulate the na,k-atpase. we now report that fxyd is upregulated in cystic fibrosis (cf) airway epithelia and modulates wound healing. we show by immunohistochemistry and immunoblot analyses that fxyd is increased in the lungs of s x cf mice, and demonstrate an almost -fold increase in fxyd expression in the nasal epithelia of cf mice compared to wild-type littermates (p< . ). furthermore, we show that fxyd is upregulated in nasal scrapings from human cf patients compared to controls (p< . ). immunofluorescence data show that flag-tagged fxyd co-localizes with the na,k-atpase in epithelial cells, suggesting that fxyd , similar to other members of the fxyd family, may regulate na,k-atpase function. it has previously been shown that expression and localization of the na,k-atpase is required for efficient polarization and suppression of cell motility in epithelial cells. the recurrent remodeling of pulmonary epithelium as a result of bacterial infection in cf requires that airway epithelial cells polarize and migrate to wound sites in order to maintain lung integrity. thus we hypothesized that fxyd may be involved in wound healing after infection. laser-capture microdissection and microarray analysis of murine lung epithelia after hours treatment with p. aeruginosa indicated a significant, -fold increase in expression of fxyd that was confirmed by immunoblot analysis. others have shown that fxyd may mediate expression of mcp- , a critical determinant in monocyte recruitment, through activation of the nf-kb pathway. treatment of human tracheal epithelial (hte) cells with a cftr inhibitor ( ) confirmed that loss of cftr function correlated with increased fxyd expression by quantitative rt-pcr (p< . ), an effect that was abrogated with treatment of pdtc, an inhibitor of nf-kb (p< . ). we speculated that fxyd -induced increases in cell motility may be due in part to phosphorylation at serine . in a murine airway epithelial cell wound healing model, serine to alanine (s a) mutations at serine inhibited wound healing compared to wild type fxyd overexpression, whereas aspartic acid (s d) mutations increased wound healing (p< . ). immunoblot and immunofluorescence analyses of these mutants suggest phosphorylation at ser regulates membrane localization. we conclude that fxyd is increased in cystic fibrosis epithelia due to increased inflammatory mediators and suggest that fxyd may modulate airway epithelia wound healing after infection with p. aeruginosa through phosphorylation at ser . the inflammatory response to bacterial infection in the cf airway is exaggerated compared to normal, leading to the accumulation of millions of necrotic neutrophils. extracellular neutrophil elastase (ne) activity in the cf airway not only compromises innate defences by cleaving opsonins and reducing ciliary activity, but amplifies the inflammatory response by stimulating expression of the neutrophil chemoattractant il- and increases mucus production, in addition to degrading the tissue matrix leading to fatal bronchiectasis. ne therefore represents an important target for the development of new therapies. however, this strategy requires consideration of the normal physiological function of this enzyme, since previous studies in knock-out mice indicated an essential role for ne in cell migration, bacterial phagocytosis and killing. our approach was to use the intracellular neutrophil elastase inhibitor gw a to 'knock-out' ne activity in neutrophils in normal human blood and test the function of isolated cells in chemotaxis, bacterial phagocytosis and killing assays. whole normal human blood was incubated with gw a, or pbs control, for h at °c. neutrophils were isolated by sedimentation of red blood cells (rbc) on dextran , purification on lymphoprep and hypotonic lysis to remove contaminating rbc. chemotaxis towards il- was measured using a modified micro-boyden chamber. phagocytosis was assayed by the depletion of staphylococcus aureus (sa), pseudomonas aeruginosa (pa) and e. coli (ec) in supernatants following culture in a : ratio with pmn for h at °c. supernatants were diluted and remaining organisms were plated on agar and grown overnight to count viable colonies. bacterial killing was assayed by incubating bacteria and cells in a : ratio for minutes to allow phagocytosis, washing off remaining organisms, and incubating for h at °c. neutrophils were lysed with water and lysates plated on agar to test for bacterial growth overnight. results; gw a inhibited intracellular ne dose-dependently and at µm . ± . % ne activity remained (n= ). there was no significant effect of µm gw a on neutrophil chemotaxis, bacterial phagocytosis or killing of any organism compared to pbs-treated controls. phagocytosis data is shown in the table. thus, in the absence of ne activity, human neutrophils remain wellequipped with other defence molecules including myeloperoxidase and defensins to successfully maintain the role of the neutrophil in innate immunity. however, mouse neutrophils which lack defensins require ne activity for optimal intracellular bacterial killing, and mice are not a perfect model for studies of human infection. the development of novel inhibitors of ne to treat lung disease in cf therefore remains an important goal. supported by the cf trust of great britain. background: sphingolipid signalling may differ between individuals with cf and healthy controls. the response to bacterial inflammation is different, and uptake and inactivation of sphingosine- -phosphate, an intracel-lular pro-inflammatory mediator, is reduced in cf cells. it may therefore continue to act on g-protein coupled receptors in the plasma membrane. (boujaoude et al, j biol chem ) . furthermore, ceramide originating from basolateral sphingomyelin hinders augmentation of cftr-mediated anion conductance across the apical membrane, resulting in reduction of transepithelial airway anion secretion (ito et al, bbrc ) . aim of study: to determine if there is a difference in the levels of alkaline, neutral or acid sphingomyelinase (smase), or in the levels of neutral or acid ceramidase, in the intestinal or bronchial mucosa and some other tissues, between wildtype, homozygous (+/+) and heterozygous (+/-) delta-f cftr mice. methods: enzyme activities (duan and nilsson meth enzymol ) were determined in intestine (and content) divided into four regions, liver, lungs, kidney and spleen from deltaf -cftr mice (+/+) and controls (wildtype, +/-). results: there was an increased amount of neutral ceramidase in spleens from deltaf -cftr mice (+/+) in comparison to control mice (p= . ). no other significant differences were seen. conclusion: delta-f mutation did not influence the levels of alkaline smase and neutral ceramidase acting as ectoenzymes, or the levels of intracellular smases and ceramidases, which may all generate bioactive sphingolipid metabolites in intestine and lungs. the implications of the increased level of neutral ceramidase in spleen are not known. in children with cystic fibrosis (cf) there is a clear correlation between the development of chronic p aeruginosa infection and acceleration in the decline of lung function. when chronically present, p aeruginosa takes on a mucoid phenotype and is impossible to eradicate. prior to this, when colonisation is intermittent, it is possible to eradicate it with aggressive antibiotic regimes. we sought to examine the degree of inflammation and innate defence status in the lungs of children with cystic fibrosis in various stages of colonisation by looking at a range of proteases, innate defence proteins and markers of inflammation in broncho alveolar lavage (bal). children with cf were allocated to one of three groups in relation to p aeruginosa infection; chronically colonised, intermittently colonised and non-colonised, on the basis of the leeds criteria. bal was collected as per ers guidelines as part of each patient's routine clinical care. bal was collected from control patients undergoing elective non-pulmonary surgical procedures. differential cell counts in bal were performed manually. secretory leukocyte protease inhibitor (slpi), elafin, alpha- antitrypsin (a at) and lactoferrin concentrations were measured by elisa. neutrophil elastase activity and cathepsin activity were assayed by colorometric activity assays. fifty two patients were included in the study ranging in age from months to years ( chronic, intermittent, non colonised and controls). neutrophil counts, neutrophil elastase activity and cathepsin activity were markedly increased in children chronically colonised with p aeruginosa compared to those in the intermittent and non colonised groups. in contrast, levels of the antiproteases slpi and a at and the antimicrobial peptides elafin and lactoferrin were highest in the control group and decreased as colonisation progressed, with levels in the chronically colonised group markedly lower than those with intermittent colonisation. this study demonstrates that in children with chronic p aeruginosa colonisation, there is a marked decrease in antiproteases and antimicrobial factors and a marked increase in protease activity and neutrophil influx in comparison with those who are non-colonised or intermittently colonised. these findings underline the importance of careful microbiological surveillance and early aggressive treatment of p aeruginosa infection in children with cf in order to avoid chronic colonisation. background : abnormal bronchial angiogenesis is responsible for hemoptysis in cystic fibrosis (cf). expression of vegf-a in airway epithelium induces bronchial angiogenesis in animal models. we have recently found that vegf-a and egf receptors (egfr) are increased in the airway epithelium of subjects with advanced cf lung disease. aims: to examine the effects of pa bacterial products and egfr inhibition on vegf synthesis in airway epithelium. methods: culture of non cf (nci-h ) and cf (cfte o-) human airway epithelial cell lines. stimulation with pa lipopolysaccharide (lps). assessment of vegf mrna and protein by rt-pcr and elisa. use of chemical inhibitors, blocking antibodies and sirna. results: pa lps increased vegf gene expression and protein production time-and dose-dependently in both cells lines. using chemical inhibitors, we show that egfr and erk / activation are required for lpsinduced vegf production. using blocking antibodies to egfr and its ligands, we show that tgf-alpha-dependent egfr activation mediates pa lps-induced vegf gene and protein synthesis. using pharmacological inhibitors (an ros scavenger and an nadph oxidase inhibitor) and using small interfering rna of dual oxidase (duox) and tnf-alpha converting enzyme (tace),we show that lps-induced vegf upregulation is dependent on duox -mediated ros release and tace activation. thus, pa products induce vegf synthesis in airway epithelium via a duox -ros-tace-tgf-alpha-egfr-erk / cascade. conclusions: these results describe a novel pathway by which bacterial products induce angiogenic signaling in cf and non cf airway epithelium. background: unlike bronchoalveolar lavage (bal), the airway mucosa has been under-investigated in cystic fibrosis (cf), despite the fact that irreversible airway wall changes (bronchiectasis) are a feature of endstage disease. cf is characterized by a neutrophil-dominated inflammation in bal, but little is known about the pattern of inflammation in the airway mucosa, especially in children with relatively early stage disease. we aimed to assess whether the pattern of inflammation seen in cf bal was also found in the airway mucosa in cf children. methods: to date, endobronchial biopsies and bal from children ( - years) with cf and control children ( - years) without lower respiratory disease have been assessed. bal cell differential was assessed on may-grünwald-stained cytospins. endobronchial biopsies were stained for neutrophils (neutrophil elastase, ne), t-(cd ) and b-(cd ) lymphocytes, eosinophils (eg ), and macrophages (cd ). area profile counts of immunopositive cells in subepithelial tissue were performed by investigators blinded to disease group. results: all cell types were increased in cf bal compared to controls. cf bal was characterized by an abundance of neutrophils ( x /ml vs. x /ml in controls, p< . ) with moderate numbers of lymphocytes ( x /ml vs. x /ml in controls, p< . ). in contrast, cf subepithelial tissue was characterized by a lymphocytic infiltrate ( cells/mm vs. cells/mm , p< . ) with only very few neutrophils ( cells/mm vs. cell/mm , p< . ). the lymphocytic infiltrate in cf consisted mainly of t lymphocytes ( %). eosinophil counts in subepithelial tissue did not differ between cf and controls. for all cell types, there was no correlation between counts in bal and counts in subepithelial tissue. conclusions: in contrast to the neutrophil-dominated inflammation in the airway lumen, cf is characterized by a lymphocytic inflammation in the airway mucosa. the lymphocytic infiltrate consists mainly of t lymphocytes, the pathophysiological function of which may be important and is being investigated in future work. support: ers long-term fellowship and swiss national foundation grant to nr the epithelium serves as a barrier to the penetration of foreign antigens, particles, and infectious agents across the airway. the integrity of this barrier is dependent, in part, upon the apical junctional complex consisting of the tight junction (tj) and the adherens junction. alterations in tj permeability have been linked to the pathogenesis of inflammatory bowel disease and this increased intestinal permeability may actually precede the onset of chronic inflammation. in cystic fibrosis (cf), the airway lumen is filled with high concentrations of inflammatory cells, bacteria, and inflammatory mediators. since tj barrier function can be significantly reduced by inflammatory mediators, we hypothesized that measures that enhance airway tj barrier function will decrease airway responses to the continuous presence of inflammatory mediators in the lumen. to test this hypothesis, we examined the relationship between lung inflammation and epithelial permeability in vivo using a lipopolysaccharide (lps) model of lung inflammation. pseudomonas aeruginosa lps was instilled intratracheally into the lungs of c bl/ mice which were then euthanized at , and hrs. lung inflammation was assessed by total cell counts using a hemacytometer and differential counts by wrights staining of cytospin preparations of the bronchoalveolar lavage fluid (balf). lps increased total cell counts and neutrophil concentrations that peaked at hours after lps administration, compared to saline controls. measurements of the proinflammatory murine cytokine kc in balf, by a cytokine antibody bead technique, showed an increase in murine kc at hr following lps administration, which correlated with the substantial increase in neutrophil concentration. changes in lung permeability with inflammation were assessed by elisa measurements of the levels of serum protein murine albumin in balf. correlating with changes in cellular inflammation and murine kc levels, albumin concentration peaked at hr after lps administration. this increase was subsequently resolved, consistent with the restoration of barrier function. an examination of frozen sections of lung from lps-treated animals showed a redistribution of the tight junction protein zo- consistent with the disruption of barrier function. since the p map kinase signaling pathway has been implicated in lps-induced airway inflammation, and an inhibitor of this kinase, sb has been shown to reduce this inflammation, the effect of this inhibitor on barrier function is being investigated. in initial studies, sb appears to reduce total and neutrophil cell counts by % in vivo. the effect of sb on murine albumin concentrations in balf and on tj protein localization is currently being evaluated. a reduction in these parameters will be used as indices of improved barrier function with sb . these studies will determine whether a reduction in lung inflammation correlates with a restoration of barrier function. the degree of protection provided by the p map kinase inhibitor sb could have important implications for inflammatory lung diseases such as cf. background: chronic pulmonary inflammation in cf is characterized by a robust neutrophil response associated with airway damage and failure to eliminate the pathogen, p. aeruginosa (pa). pa is a highly adaptable opportunist which quickly develops resistance to antimicrobials. thus, the development of specific immunotherapy targeting the neutrophil recruitment without ablating the host's immune response to infection or promoting pathogen resistance would be ideal. our group has identified il- as a prime target for the development of immunotherapy due to the central role that the il- /il- proinflammatory axis plays in neutrophil recruitment. however il- does not mediate the early neutrophil recruitment seen in response to infection. hypothesis: il- , acting synergistically with il- , is critical to early neutrophil recruitment during pulmonary pa infection. the primary effector cells are the il- -producing antigen presenting cells: alveolar macrophages (ams) and myeloid dendritic cells (dcs). methods: wt and il- -deficient mice were infected with pa at x cfu/ ul by intratracheal (it) inoculation for hours. bal inflammatory cell counts, and cytokines and chemokines were measured. am and dc cultures were infected for hours in vitro and supernatant cytokines/chemokines were measured by luminex and elisa; il- levels were measured by taqman. these studies were designed to elucidate the role of il- in the early neutrophil peak and define am-and dc-mediated cytokine/chemokine production. recombinant murine il- , il- , and il- + il- were instilled via it into wt and il- -deficient mice. bal inflammatory cell counts and cytokines/chemokines were measured at hours. these studies were designed to elucidate the role of il- and il- in the early neutrophil peak and define am-and dc-mediated cytokine and chemokine production. results: at hours post-infection, il- deficient mice had significantly lower percent neutrophils (p< . ) and lower mip α, kc, and il- (p< . ) in the bal. il- was undetectable. there was no significant difference in bacterial load that could account for these cytokine/chemokine differences. infected wt ams elaborated significantly more mip a, gm-csf, mcp- , il- , g-csf, ip- , kc and il- than the il- -deficient ams (p< . ) and the response was inoculum-dependent (p< . ). dcs elaborated no il- and exhibited il- -dependent differences in mip- α and mcp- production (p< . ). in vivo studies of il- and il- effect demonstrated a synergistic increase in bal neutrophil recruitment (p< . ) and cytokine and chemokine induction (p< . ). conclusion: the first wave of neutrophil recruitment seen during pa infection is il- -dependent and il- -independent. ams and dcs are critical to il- and il- indcution of this neutrophil recruitment. these studies identify il- as a key mediator of neutrophil recruitment in the early stages of infection as well as the proximate mediator in the il- /il- pro-inflammatory axis and suggest il- as a potential target for anti-inflammatory therapy in the treatment of pa pulmonary infection. supported by the cystic fibrosis foundation, american lung association and the nih the airways are under constant assault from air-borne pathogenic material. despite the intake of up to , bacteria per hour, the airways are sterile below the larynx in healthy individuals. the task of maintaining this sterility falls to the airway surface liquid layer (asl), the protective twophased system consisting of the viscoelastic mucus layer and the periciliary layer (pcl) through which cilia beat, sweeping the mucus layer away from the lungs. the mucus layer, which is responsible for trapping pathogenic material, is comprised of mucins (high molecular weight glycoproteins), cellular debris, dna, neurtifils, and more than other proteins. this chemically heterogeneous mixture forms a viscoelastic gel that is thick enough to trap pathogens of various sizes and surface chemistries, while not sticking to the underling cellular / cilia layer, allowing the transport of trapped pathogenic materials away from the lungs. the performance of this trapping / transportation system is defined by the rheological properties of the mucus layer and the force imparted on the mucus. therefore, understanding how mucins and other chemical components of the mucus layer interact with each other to form a successful mucus gel (i.e. one that is cleared from the airways) is crucial to understanding airway defense. here we present the results of physical and chemical composition studies of sputum samples collected from patients with chronic obstructive pulmonary disease (copd) and cystic fibrosis (cf). the rheological properties of each sample was assayed using parallel plate rheolometry, probing the materials non-linear viscoelastic properties such as viscosity, elasticity, and yield stress. the physical properties of the sample are then correlated to the sample's chemical properties such as percents solids (divided between salts, proteins, and mucins), as well as the relative concentrations of the key airway mucins muc b and muc ac. our results indicate that the physical properties of sputum are not well predicted from the total amount of biosolids in a given sputum sample, but by the relative concentrations of muc b and muc ac and the interactions of these molecules with themselves and the other proteins present. further, we establish that the heterogeneous physical properties within a given sputum sample correlate to differences in the muc b and muc ac concentrations. the gene modifier study (gms) was established as an effort to identify potential genetic modifiers of cystic fibrosis pulmonary disease and survival. during the course of this study over delta f homozygous cf patients classified as having mild lung disease, severe lung disease, or increased survival, have submitted both clinical data and blood samples for single nucleotide polymorphism (snp) analysis. the original snp analyses have shown a significant association between variants in the endothelin receptor a (ednra) gene, and cf survival, most markedly in female cf patients. sixteen additional snps within and around the ednra gene have now been genotyped, and have implicated the ' and ' untranslated regions of the gene as having the most significant association with pulmonary disease in females (p< . ), suggesting quantitative differences as a possible mechanism for the association with pulmonary phenotype. we are in the process of saturating the ' and ' regions of ednra with an additional snps to further delineate the genetic association. ednra binds endothelin- (et- ) in airway smooth muscle cells, causing increased cell proliferation, smooth muscle contraction, and stimulation of inflammatory molecules. because each of these effects is known to be deleterious to the cf lung, we hypothesize that the ednra variants found more commonly in "severe" cf females ("severe" alleles) are marking increased ednra expression compared to alleles found more commonly in "mild" cf females ("mild" allelels). because the genetic association was strongest in cf females, we used the matinspector software to analyze kb of ednra promoter sequence and found several putative binding sites for both estrogen and progesterone. we then used a brdu assay to measure cell proliferation after stimulation with both estrogen and progesterone. these experiments showed that the asm cells with the "severe" ' ednra genotype proliferated at levels approximately twice that of the asm cells with the "mild" ' ednra genotype following stimulation with either estrogen or progesterone. using a single base extension protocol and quantitative pcr on human airway smooth muscle cells, we were also able to compare ednra expression from the "severe" allele, and the "mild" allele. these comparisons of ednra expression demonstrate that expression levels appear to be approximately % higher from alleles found more frequently in the "severe" cf females. in addition, preliminary data suggest that stimulating the asm cells with estrogen increases ednra expression by approximately fold, and like the cell proliferation experiments, these increases are most pronounced in cell lines with the "severe" genotypes. these data suggest that the "severe" genotypes are marking alleles with increased expression, perhaps due to estrogen binding, that leads to increased et- functional effects that over time are deleterious to the cf lung. cf patients do present with variable spectra of lung disease, of which infections are most life-threatening. β-defensins have an antimicrobial activity against a broad spectrum of microorganisms and are chemotactic agents for cells of the adaptive immune system, and therefore assist in combating these infections. β-defensins - are part of a repeat region. this repeat region is polymorphic between individuals and therefore the dosage of these defensin genes/proteins varies. we developed a real time pcr assay to quantify the number of βdefensin repeats in this region. appropriate controls are needed for an accurate quantitative assay. therefore we made concatemeric constructs with copy of defb and a particular number of defb copies, which ranged from to copies. using these controls as standards, the number of defensin repeats could be accurately determined in dna samples. we then tested f del homozygous cf patients from belgian ( patients), czech ( patients) and south-italian ( patients) origin. the diploid number of repeats varied between and . for each patient group, a higher number of repeats was found in the group of patients with milder disease (fev > %) compared to the group of patients with more severe disease (fev < %) (student t test, p-values of . , . and . respectively). moreover, in our cohort of belgian cf patients, cf patients of years or older have a significant higher number of repeats than the cf patient group below (p-value . ). to evaluate this at the functional level, we cultured nasal epithelial cells from individuals with a low number of repeats (i.e. or repeats) and individuals with a high number of repeats (i.e. repeats). the cells where grown in air liquid interface cultures. after differentiation, the cells were stimulated with ng tnfα. in cells with a high number of repeats, defb expression, as measured by the extent of transcription, was strongly upregulated by tnfα. in cells with a low number of repeats, defb was not upregulated (p-value = . ). we also tested the antimicrobial activity of epithelial cells. we challenged epithelial cells from individuals ( repeats) with a laboratory strain (pa ) of pseudomonas aeruginosa and a clinical isolate ( - cfu), either in combination with tnfα or without tnfα. after h, surviving bacteria were counted by a plating out method. cells that were stimulated with tnfα h prior to the bacterial challenges were more bactericidal. the clinical strain was more vulnerable to the surface liquid than the laboratory strain. in epithelial cells from individuals having a low number of repeats, these effects were very variable from individual to individual. in summary, the β-defensin region is a modulator of cystic fibrosis lung disease. the pro-inflammatory response in cultured epithelium cells strongly correlates with the number of β-defensin repeats. cells with a higher number of repeats respond to tnfα treatment, which in turn results in a better antimicrobial activity of the surface liquid. rationale: studies of affected twins and siblings demonstrate that modifier genes are major contributors to variation in cystic fibrosis (cf) lung disease severity. we performed genome wide linkage analysis to identify regions likely to contain modifier genes affecting severity of cf lung disease. methods: individuals with cf from families were analyzed. pulmonary function data were collected from patient chart review and were supplemented with data from the us cystic fibrosis foundation patient registry. to minimize environmental variation, only data obtained while subjects were living with an affected twin or sibling were analyzed. the pulmonary phenotypes were defined using the best cf-specific percentile for fev (kulich, et al) within the last year of available pft data as a crosssectional measure (maxfev cf%) and using two longitudinal measures: the lifetime average cf-specific % for fev (avgfev cf%) and the estimated percent-predicted fev at age (estfev %pred@ yrs, schluchter, et al). longitudinal measures were derived from a minimum of years of pft data. short tandem repeat markers (strs) were typed in all affected individuals and their parents (marshfield genotyping center: markers or decode genotyping center: markers). two-point and multipoint linkage analyses were performed using sequential oligogenic linkage analysis routines (solar). results: patients represented the spectrum of lung disease severity, with maxfev cf%'s ranging from to , mean . ± . and avgfev cf% ranging from . to . , mean . ± . . the maxfev cf% was predictive of avgfev cf% (r= . , p< . ) for the individuals for whom both measures were available. the two longitudinal measures were also highly correlated (r= . , p< . ). linkage was found at chromosome for all three phenotype definitions. peak multipoint lod scores on chromosome occurred at cm for maxfev cf% and avgfev cf% (lod . and lod . , respectively) and at cm for estfev %pred@ yrs (lod . ). single point lod scores on chromosome peaked at marker aaat ( . for maxfev cf%, . for avgfev cf%, and . for est-fev %pred@ yrs). the region of linkage encompasses approximately megabases near the telomere of chromosome q. conclusions: chromosome appears to contain one or more genetic modifiers of cf lung disease severity. supported by the nhlbi, cff and genome canada through the ogi. cystic fibrosis-related diabetes (cfrd) is the most common extrapulmonary complication of cf and is an increasingly important contributor to morbidity and mortality as cf patients live longer. while pancreatic fibrosis and loss of exocrine and endocrine tissue are common in cf, - % of cf adults develop defects in insulin secretion and accumulation of islet amyloid polypeptide, features typical of type diabetes (t dm) in the general population. to test whether modifier genes play a role in cfrd, we compared concordance rates for cfrd in pairs of monozygous (mz) twins, sets of dizygous (dz) twins, and sets of or more siblings ( individuals with cf). criteria for defining cfrd included physician diagnosis, treatment with insulin/oral agent, and episodes of glucose ≥ mg/dl. mz twins were highly concordant for cfrd ( of pairs, %). the young age of dz twin recruits precluded analysis of this group in isolation ( of pairs were concordant). twelve of ( %) sibling pairs were concordant for cfrd. with heritability defined as: h = *(mz concordance -dz concordance), and including siblings as a proxy for dz twins, heritability is estimated as ~ . . the same results were obtained considering only same-sex dz twins and siblings, correcting for differences in age and duration of clinical follow-up, or restricting analysis to ∆f homozygotes. these data support a significant role for one or more modifier genes in development of cfrd. we then tested whether cfrd correlated with a strong family history of adult-onset diabetes (at least first-degree or second-degree relatives on the same side of the family). of those reporting family history of diabetes, of had cfrd, compared to of with no family history (or= . [ . - . ]; p= . ). this correlation persisted after adjusting for age, sex, and pancreatic insufficiency (or= . ; p= . ). thus, family history of diabetes correlated with increased risk of cfrd. we then tested whether variants in tcf l , a transcription factor in the wnt signaling pathway, that have been reproducibly associated with t dm in the general population were associated with cfrd in our study subjects. genotyping of four single nucleotide polymorphisms associated with t dm (rs , rs , rs , rs , here termed snpa-d) and transmission disequilibrium testing (tdt) of parent-parent-child trios revealed significant overtransmission for snpb ( : , p= . ) and snpc ( : , p= . ), and possible overtransmission for snpa ( : , p= . ) and snpd ( : , p= . ). in every case, the tcf l allele overtransmitted to patients with cfrd is the same allele that confers increased risk for t dm. furthermore, individuals with cfrd who were homozygous for risk alleles were diagnosed at a significantly earlier age (average . vs. . ; p= . ). these data support a key role for modifier genes in development of cf-related diabetes, and demonstrate that cfrd and type diabetes may share disease mechanisms such as alterations in wnt signaling. supported by nih dk , hd , dk and hl , and cf foundation grant cuttin p . cystic fibrosis (cf) phenotypes and survival are highly variable among df homozygous patients, pointing to the existence of modifier genes and/or environmental factors that contribute to this disease. studies to identify genetic modifiers of cf are being carried out using dna from homozygous df cf patients. important clinical features, such as severity of lung disease, liver disease and meconium ileus (mi) status, are well defined. tgfβ has been previously identified as a modifier of cf lung disease (drumm et al., nejm, ( ) : [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] ) , but it does not explain all of the genetic heterogeneity in this population. current evidence suggests that mucus is involved in the progression of cf, making the muc genes prime candidates as modifiers of lung disease and/or other phenotypes. methods: our approach to evaluate muc genes utilizes both variable number tandem repeat (vntr) polymorphisms and single nucleotide polymorphisms (snps). vntr polymorphisms in the muc and muc ac genes (n= and n= patients, respectively) were detected by southern blotting under conditions fully optimized to maximize the allele size resolution. to minimize gel to gel variation, a genomic dna mixture with the most common muc and muc ac alleles was used as internal markers. accuracy and reproducibility were evaluated by duplicating the southern on the critical dna samples for muc and muc ac genes (n= and n= patients, respectively). fifty snps in muc ac, muc b, muc , muc and muc genes are being tested using illumina technology in cf patients. results: preliminary analysis suggests there are significant differences between cf patients with "severe" and "mild" lung disease for both muc and muc ac allele distribution, which is mainly driven by the male population; exhaustive statistical data analysis still is underway. the vntr data also suggest significant association between the larger muc allele size and cf patients with mi. the ongoing vntr analysis will be complemented by muc gene snps being genotyped. conclusions: initial results indicate that we can reproducibly characterize muc and muc ac vntr alleles. additional characterization of muc and muc ac vntr alleles, coupled to snp data, will allow us to better define the significance of muc gene variations as modifiers of different cf phenotypes. supported by cff perezv g (jpv), cff knowle a (mk), cff r -cr (wko), nih rr , r hl , and cff drumm a . reporting for the gene modifier study group (mrk). we have previously reported that βenac transgenic mice, which overexpress the beta subunit of the amiloride sensitive sodium channel (scnn b) specifically in the airways, share common features with cf, including increased enac activity, reduced airway surface liquid, mucus accumulation and obstruction, inflammation, and death. interestingly, analysis of this model also suggested the existence of potential genetic modifiers of phenotype severity, and we speculated that identification of these modifiers would provide novel insights into disease phenotype. to establish a set of reagents that could be used to uncover genetic modifiers, we have bred βenac transgenic mice from two independent founder lines ( and , b :c background) onto several strains of inbred mice, including c bl/ n, c h/hen, balb/cj, fvb/j, and /svj. these studies revealed dramatic phenotypic differences as measured by survival ( to %) among strains and between lines. all lines thus far tested show ~ - fold increases in amiloride sensitive short-circuit current as measured by ussing chambers in the trachea. complete phenotypic characterization of c bl/ n line at backcross generation reveals high survival ( ± % in comparison to ± % of the mixed b :c background), yet the mice maintain the pulmonary features of the originally reported mice, including increased mucus plugging, mucous cell hyperplasia, neutrophilic and eosinophilic inflammation peaking at early timepoints ( days - weeks). lymphocytic nodules, which are not commonly seen in - weeks-old animals with mixed strain background, are a common feature in the c bl/ n congenic line. emphysema and early airway epithelial cell necrosis, two phenotypes initially not strongly associated with transgene expression, are also observed. line on balb/cj and c h/hen backgrounds has reduced survival compared to the c bl/ n background, and generation backcross lines are now being evaluated in these two strains for other phenotypic characteristics. analysis of backcross data from line , which has low survival on all genetic backgrounds tested to date, including c bl/ n, suggested that the transgene may have integrated onto a c h locus with a dominant negative effect on survival. genetic analysis using genome-wide snp genotyping revealed a region of chromosome linked to the transgene in line (lod score > . ). further analysis of this region is underway. in summary, backcrossing onto different genetic backgrounds is revealing genetic modifiers for phenotypes in the βenac overexpressing model. characterization of these phenotypic and genetic differences should provide clues about the mechanisms relevant to disease development. furthermore, inbred lines with variable phenotype will likely be an important reagent for the cf community as the utility of this model is evaluated in future studies. supported by nih (scor p hl ) and cff (mall go, oneal go). introduction: new york state screens newborns with immunoreactive trypsinogen levels within the top % of all infants, for common cf gene mutations. infants found to be heterozygote carriers are referred to a cf center to determine sweat chloride concentration. the proposed abnormal sweat chloride value for this group of newborns is ≥ mmol/l, ≥ standard deviation (sd) above the mean (farrell, ) . this retrospective study reports on the mean sweat chloride value + sd in cf heterozygote newborns who have been referred for evaluation to suny upstate medical university cystic fibrosis center, and regarding the genotype of these infants with abnormal sweat chloride levels. method: from october, to december, , infants were referred for positive cf screening, and of these ( %) were identified as heterozygote carriers by the screening program. at our center, these patients underwent pilocarpine iontophoresis, followed by collection of sweat (≥ µl) in macroduct ® coils. sweat testing was performed successfully in of the ( %) patients. the patients' age (mean ± sd) at the time of sweat testing was . ± . days. for infants with an initial sweat chloride level ≥ mmol/l, the sweat test was repeated within a week and a complete gene sequencing was requested (quest laboratory, ca). results: the sweat chloride level (mean ± sd) in newborns who were heterozygous for a cf mutation (excluding those who were found to have an additional mutation or deletion) was . ± . mmol/l (n = ). the mean + sd was mmol/l, which defined our minimal value for an abnormal test. eleven infants had sweat chloride values of - mmol/l (table) ; of them ( %) were subsequently diagnosed with cf by complete gene sequencing. four of the remaining patients ( %) had ∆f mutation coupled to the t variant on the opposite chromosome (sweat chloride levels, - mmol/l). conclusions: the reference range for sweat chloride in cf heterozygote infants appears to be significantly lower for some centers than previously reported. thus, each cf center should consider evaluating the cutoff values for the test at their site. moreover, the t polymorphism may account for sweat chloride elevations in heterozygote infants. method: we reviewed the charts of all patients with cf who were referred as a result of the new york state newborn screening program to the suny upstate medical university cf center from october, through april, . we included the patients who were identified by the state as heterozygote carriers of one of common cf gene mutations, and whose second mutation was identified only after complete cf gene sequencing. results: seven of the patients ( %) met inclusion criteria. six of the patients ( %) were compound heterozygous for a novel or a rare cf gene mutation. one patient was compound heterozygous for a large deletion in the cf gene. the genotype and clinical status of the patients are shown in table. all patients have been pancreatic sufficient to date. conclusions:the clinical effect of compound heterozygosity as a result of novel or rare cf gene mutations appears to be mild in early childhood. prior to newborn screening (with the exception of the patient with cftr deletion), these patients may not have been diagnosed with cf in the first few years of life. these patients may have subclinical airway inflammation and thus benefit from early treatment. patients with cf manifest symptoms in the pancreas, respiratory tract, male reproductive tract and sweat gland due to mutations in cftr. patients with non-classic cf have disease in a subset of these organ systems. most non-classic cf patients have two disease-causing mutations in cftr and at least one mutation permits residual cftr function. a subset of non-classic cf patients have only one cf-causing mutation after screening for a panel of common cf-causing mutations or following mutation scanning of the coding region of cftr. these patients present a diagnostic dilemma and a challenge for genetic counseling. we evaluated cf patients with only one cf-causing mutation identified after a screen of cftr mutations ( patients) or scanning of the coding region of cftr ( patients). nine of these patients, including one set of siblings, have non-classic cf with borderline or elevated sweat [cl -] plus lung disease (table) . one patient is pancreatic insufficient and has classic cf. many of these patients have features which are consistent with cftr dysfunction including a cf-like nasal potential difference (npd),p. aeruginosa infection, or congenital bilateral absence of the vas deferens (cbavd), suggesting that they have a second cftr mutation. mutations that are not detected by screening methods include insertions or deletions, mutations outside of the cftr coding region that affect rna splicing or expression, or mutations in the coding region of cftr that were missed by screening methods. to exclude the third possiblity, dna sequencing of the exons and flanking introns of cftr was performed. a second mutation was identified in the coding region of cftr in of the patients; had screening for known cftr mutations (genzyme), while the remaining had comprehensive scanning of the coding region of cftr by modified tgge (ambry). each of the mutations identified by sequencing has been previously described in patients with cf and is predicted to cause cftr dysfunction. these results reaffirm that patients with one cftr mutation who have biochemical and clinical features of cf are likely to have a second mutation in the coding region of cftr. thus, we suggest sequencing cftr in patients with only one mutation after mutation screening before employing other more complex genotyping methods (insertion/deletion or rna analysis). diagnostic criteria for confirming cf in symptomatic individuals includes two positive sweat tests or two known disease-causing cftr mutations. accurate sweat testing is performed at accredited cf centers, while cftr testing is available through national and specialty genetic labs. most labs offer analysis of a basic panel of cftr mutations as recommended by the american college of medical genetics (acmg), while specialty laboratories may offer an expanded panel or full sequencing/scanning. we report on one center's use of these methodologies to confirm the diagnosis of cf presenting in adulthood. the charts of patients diagnosed with cf at 〉 years of age were reviewed. were sweat tested. all were genotyped. results: twelve ( %) pts had two positive sweat tests (> mmol/l). an additional five ( %) had at least one borderline result ( - mmol/l). two pts had negative results ( - mmol/l). one refused sweat testing because dna analysis through the acmg panel had confirmed the diagnosis prior to initial consultation. genotyping results for the pts are summarized in the table below. rare mutations identifiable only through gene sequencing accounted for / alleles ( %) in our population. importantly, among this group, only one pt had a negative sweat test, a suggestive mmol/l. two pts with positive sweat tests and clinical symptoms failed to reveal any cf mutations after sequencing. we continue to follow pts without genotypic confirmation, based on their clinical presentation and sweat chloride levels, and have recommended additional evaluation, including nasal potential difference studies in our series of adult-diagnosed patients, sweat test results were positive, borderline, or suggestive in all cases tested. sweat testing costs $ -$ and results are ready in a day. genotyping costs $ -$ and takes several weeks. we acknowledge that circumstances may arise where reliable sweat testing is not conveniently available; but in our series, genotyping with the acmg panel would have diagnosed % of pts; using an expanded panel would have diagnosed %. genotyping is an important tool for genetic counseling, determination of eligibility for research studies, furthering knowledge of cftr dysfunction and cf pathophysiology, and for confirming a cf diagnosis after borderline or suggestive sweat test results. based on our findings and the dramatic difference in cost, we conclude that sweat testing should remain the first approach in the diagnostic workup of adult patients with a clinical presentation suggestive of cf. in colorado, infants with cf (non-meconium ileus) have been diagnosed with cf by a two tiered immunoreactive trypsinogen (irt/irt) based newborn screening approach. the irt/irt algorithm has been recently adopted by other screening programs with two mandatory screening tests. while most infants in colorado have been successfully identified, the program has had a missed case rate of approximately %. the more common approach to cf newborn screening is the irt/dna method in which the blood spot of infants with an initial elevated irt is tested for the most common cf mutations. the initial irt cutoff is lower in the irt/dna programs than in the irt/irt programs, resulting in a lower missed case rate. the considerable number of carriers identified through the irt/dna approach puts a significant burden on the genetic counseling community, as carriers are identified at a rate of / - / of positive irts we propose an irt/irt/dna newborn screening algorithm that will maximize sensitivity and specificity while minimizing the number of identified carriers. using new database technologies in the newborn screening lab we will be able to identify those infants with an elevated first irt (> ng/ml, approximately th percentile). all infants with an irt > ng/ml will have a repeat irt on their second state mandated blood-spot. if the second screen is also elevated (> ng/ml), the blood spot will be tested using a panel of mutations, including mutations specific to the hispanic community. infants with one or two cftr mutations will have a sweat test to confirm the diagnosis, or rule out cf. we compared the projected statistics of our current method irt/irt to the new irt/irt/dna method, and to irt/dna is presented in the table, based on , births per year in colorado. four infants ( . %) identified under the current irt/irt protocol would not have been identified by the mutation panel proposed in the new algorithm, out of genotyped, non-meconium ileus infants. three of these missed cases are hispanic. two would be identified using an extreme irt cutoff of the . th percentile ( ng/ml). the projected missed case rate would be < . % ( . - . %, % ci), using the irt/irt/dna algorithm, with carriers identified, maximizing both sensitivity and specificity. this algorithm may provide a better alternative to the irt/irt screening methods in states with two mandatory screening tests, and has advantages over both the irt/irt and irt/dna methods. newborn screening for cystic fibrosis (cf) is rapidly expanding and has been implemented in at least states. although most newborn screening assays are done using biochemical testing, many laboratories screening for cf include both biochemical and molecular testing of multiple alleles in the cystic fibrosis transmembrane conductance regulator gene. in response to the growing need for proficiency testing (pt) materials for molecular testing, the centers for disease control's newborn screening quality assurance program (nsqap) in collaboration with the university of wisconsin school of medicine and public health, the johns hopkins hospital, and case western reserve university, created a repository of dried-blood spot specimens with known mutations in the cftr gene to be used in a pt program. twenty milliliters of blood was collected voluntarily from adult donors with cf and sent to the nsqap laboratory. each specimen was adjusted to a hematocrit of % before being spotted onto whatman paper ( µl per spot), dried, and stored at - °c with desiccant. proficiency testing (pt) panels consisted of to blind-coded specimens from adult donors. the panels were sent quarterly to laboratories worldwide that test specimens for cf using molecular methods. laboratories were asked to report the genotype, method used, and the presumptive clinical assessment of each specimen. twenty-two laboratories participated during both quarters and , . the laboratories used different methods ranging from in-house assays to commercially available kits. most reporting laboratories tested the following alleles -∆f , g x, and g d. another twelve alleles were detected by most participants. nine more alleles were common among commercially available kits. laboratories were evaluated based on the clinical assessments. mutations that were not detected by a particular method were not evaluated. overall, the laboratories performed well. data compiled from both quarters demonstrated that there was incorrect clinical assessment and amplification failures. developing a pt program for dna-based testing is complicated by the number of methods and different alleles each laboratory chooses to test. though molecular testing for cf may be complex, pt monitors the laboratory's ability to test multiple alleles, including uncommon alleles, the limitations of various assays, and the different algorithms used for screening. the repository will also allow storage and access to rare specimens that may be useful for future research but are not readily available. who did could not reproduce. genetic counseling focused on a patient's parents, who were counseled about their recurrence risk at the time of the child's diagnosis. today, cf is a disease of adulthood. in , > % of cf patients in the us were > ; by it will be > %. together with advances in assisted reproductive technology (art), reproduction and recurrence risk are now important issues for adolescent and young adult cf patients. methods: a item questionnaire was developed from the results of prior semi-structured interviews with cf patients age - years. knowledge based questions (medical issues, inheritance, and reproductive options/risks) as well as communication patterns (preferred resources for learning about cf and preferred people with whom to talk about reproductive issues) were addressed. recruited from the uab cf clinic population, patients age - (mean ), male ( %), female ( %), completed the questionnaire. results: regarding autosomal recessive inheritance of cf, only % knew that two carriers have a % chance of having a child with cf, and % knew that two carriers have a % chance of having a child who is a carrier. however, % knew that two carriers could have a child who did not have cf, and % knew that two carriers could have a child who did not carry cf. on their own reproductive risks, % knew that a cf patient had a % chance of having a child with cf if their partner was not a carrier, but only % knew that all their children would be carriers even if their partner was not a carrier. in the scenario of a cf patient with a cf carrier partner, % knew that a child had a % chance of having cf, and % knew that a child had a % chance of being a cf carrier. most patients knew about their reproductive potential, as % responded that cf patients are able to have children. however, when asked about whether the chance for having children was different for males and females with cf, % answered that it was more difficult for males, % that it was more difficult for females, and % answered "not sure." while % reported that they knew that there were options for male cf patients who wanted to have children, only % knew of art. conclusions: despite widespread availability, the lack of knowledge of adolescents and young adults with cf about the genetics of their disease continues. furthermore, these patients are unaware of both modern technologies that could enable them to have biological children and the risk of those children having cf. this study illustrates the changing needs of patient education as medical knowledge progresses. cf patients would benefit from further genetic knowledge and counseling to enable them to make informed decisions about reproduction as they mature into adulthood. center at the university of minnesota is one of three sites in the state providing confirmatory testing and follow up services for newborns identified by screening. while cf nbs identifies children with cf, most of the infants with positive screening results are carriers. our goal is to provide genetic counseling to every cf nbs patient seen at our center, and we believe that a protocol incorporating genetic counseling in the initial care plan for infants both with and without cf is imperative. the literature has shown that families who obtain genetic counseling through the cf nbs process recall genetic information more easily and accurately and are more likely to have testing to determine parental carrier status. for parents of a child that is determined to be a cf carrier, it is especially important to find the optimal method and timing of genetic counseling as many of these families are from several hours away and therefore less likely to return to clinic. to provide genetic information and emotional support for the families of infants screening positive on cf nbs, our center has a genetic counselor who serves as the cf nbs coordinator and clinical contact for the family. this allows many opportunities to speak with the genetic counselor and ask questions, as well as learn about their child's diagnosis or carrier status and the subsequent carrier testing recommendations for the infant's parents and families. to assess the success and impact of the minnesota cystic fibrosis center's nbs follow-up program and the incorporation of genetic counseling, an anonymous questionnaire was developed for parents of infants who were seen at our center due to a positive cf nbs result. questionnaires were mailed to parents of all infants seen at our center for a sweat test and genetic counseling due to a positive cystic fibrosis newborn screening result. as of the last mailing, this totals families. two questionnaires were returned due to incorrect address and questionnaires were returned answered, indicating a response rate of % ( / ). responses overwhelmingly indicated that parents were satisfied with our center's algorithm for the cf nbs follow-up program and found the information and support provided through genetic counseling to be a useful and recommended portion of the program. as cf nbs continues, it is critical that we learn about the patient's experience with genetic counseling and the nbs program, as well as identify areas needing improvement. genetic counseling is vital to the comprehensive success of our center's program, and we will report on the responses gathered from the families identified through cf nbs this first year, as well as discuss the lessons learned from setting up such projects on a state-wide basis. background & aims: aberrant splicing and nonsense mediated decay (nmd) lead to dysfunctional mrnas by skipping exons and to a reduced number of functional mrna respectively. both mechanisms have a strong quantitative aspect and may determine whether a cf patient develops a classic or atypical disease phenotype. in order to approach these highly important questions we wanted to establish a new quantitative real-time pcr based assay which allows allele specific quantification on cdna level. using this assay we like to determine the exact proportions of the f del and non-f del cftr mrna in cf patients compound heterozygous for the f del mutation (for example in cf patients carrying the f del and a nonsense mutation such as the r x). material & methods: materials: we used genomic dna (gdna) and total rna (extracted from white blood cells and nasal epithelial cells respectively) from cf patients with compound heterozygosity for the f del mutation, homozygosity for f del mutation and from healthy individuals (controls). methods: the lasq (ligation dependent allele specific quantification) assay comprises reactions: . reverse transcription of cftr mrna into cdna using gene specific primers (all rna specific). . overnight hybridization ( - h) of the cftr cdna with either the f del specific or the wt specific oligo probe pair provided by jan schouten (mrc holland). . ligation of the hybridized oligo pairs using the ligase enzyme from mrc holland. . quantitative real-time pcr of the allele specific ligation products on the lightcycler (roche). results: in order to establish the lasq assay we first validated it using gdna instead of cdna as template. mixing experiments were performed to verify the accuracy of the assay. in brief, gdna (c= mg/l) of a f del homozygous and a f del compound heterozygous cf patient were mixed in such a manner that . , . amplification products of the f del and the wt allele (both bp long) were analyzed by gel electrophoresis (page) and direct sequencing (abi ) to control specificity. our results using gdna and cdna showed that there occurs unspecific hybridization/ ligation for both probe pairs. the proportion of unspecific amplification products varies between . and . and increases the lower the initial number of templates is. however, the specificity of this assay can be significantly improved by increasing the hybridization temperature and/or decreasing the ligation time. conclusion: although some minor limitations concerning allele specificity the lasq assay has been proven to be an accurate, reliable and reproducible method for allele specific quantification and may be applied for several important questions in cystic fibrosis such as the exact determination of the amount of nmd of cftr mrna containing a premature termination codon (ptc) or the allele specific determination of aberrant splicing of cftr mrna . background & aims: as clinical presentation varies significantly among cf patients with the same genotype, e.g. in the f del homozygous, it is evident that factors in addition to the cftr genotype such as modifier genes, are involved in determining disease severity. however, only one of several previously postulated modifier genes, the tgfβ gene, could recently be confirmed in a large association study. hence the identification of new modifier genes is a very important task in order to find new explanations for the heterogeneity of pulmonary disease in cf patients. we decided to search for new potential modifier genes applying a quantitative proteomic approach comparing the proteomes of a wild type ( hbe o-) and a f del homozygous bronchial epithelial cell line (cfbe o-). the main goal of this study is the identification of up or down regulated proteins in the cfbe cell line which may act as modifiers of cf disease. material & methods: materials: we used two bronchial epithelial cell lines, e.g. a wild type ( hbe o-) and a f del homozygous (cfbe o-) cell line which we obtained from dr. gruenert (california, usa). additionally, we also used nasal cells from f del homozygous cf patients obtained either from nasal brushings or nasal polyps. methods: proteome analysis was performed by making d-gels using high sensitive staining protocols (ruthenium and deep purple). quantitative analysis was accomplished applying the powerful dige (difference in gel electrophoresis) method. for each dige experiment we made gels whereby each cell line was twice labelled with cy and cy (= technical replicates). finally, identification of the protein spots was done by the use of a maldi-tof mass spectrometer. results: in a first step we established the proteomes of the two bronchial epithelial cell lines. we were able to optimize protein extraction and d gel electrophoresis in such a manner that the proteomes of the two cell-lines looked very similarly and the assignment of spots could easily be done. protein spots from both cell lines were analyzed using our mass spectrometry (maldi-tof ms) and allowed the identification of more than different proteins so far. in a next step we quantitatively compared the proteome of the two cell lines using the d-dige method leading to the identification of proteins which are down regulated and proteins which are up regulated at least twofold in the cfbe cell line. out of the aforementioned differently expressed proteins could already be identified because they were among the previously determined proteins. while glutathione s-transferase p and protein s -a (s calcium binding protein) were down regulated ( . and . -fold respectively), superoxide dismutase was up regulated ( . -fold) in the cfbe cell line. conclusion: comparative quantitative proteomics using the dige method is a promising tool in search of potential new modifier genes which may unravel one of the key problems in cf: the large heterogeneity of pulmonary disease in f del homozygous patients. background: cystic fibrosis is one of the most common autosomal recessive disorders among caucasians, and manifests a wide range of disease severity. although this range of disease expression can be attributed, in part, to specific mutations within the cftr gene, much of this variability has not been adequately explained. from the gene modifier study (gms-a multicenter study of , cf patients), ten genes were tested as potential modifiers of cf, and the tgfβ codon cc genotype was associated with lung disease severity. objective: to test whether the adverse codon cc genotype is associated with higher circulating levels of tgfβ , compared to the tt genotype in cf patients and healthy controls. if true, then a link will be established between genotype, disease severity, and circulating levels of tgfβ , and have implications for novel treatment of cf patients. methods: the study includes clinically stable cf patients and healthy control subjects equally distributed between the cc and tt genotypes. the cf patients enrolled are age and older, of both genders, and all ethnicities that fulfilled the standard diagnostic criteria for cf, using the genetic information from the gms. healthy controls are age and older, caucasian males and females, obtained from the environmental polymorphism registry (epr), a dna registry of , self-reported normal volunteers. we genotyped blood samples from the epr to define healthy control subjects for each of the cc and tt cohorts. subjects have a blood draw of ml. blood is divided into tubes and each tube is used to measure a different parameter: cbc with differential; tgfβ levels in platelet poor plasma by quantikine human tgfβ elisa kit; tgfβ levels in the buffy coatwhich includes platelets; and tgfβ mrna levels in lymphocytes from the buffy coat, using real-time pcr roche light cycler. cbc with differential is performed to quantitate lymphocytes and platelets in order to reference tgfβ protein and rna levels to the number of circulating blood cells. analyses will include graphical comparisons between the two groups, chi square analysis, student's two-sample t test, and one way analysis of variance (anova). results: pilot studies show that elisa tgfβ measurements are reproducible and mrna levels can be quantified. we have currently enrolled cc genotype and tt genotype of the cf subjects and cc genotype and tt genotype of the healthy controls. blood samples have been collected and processed. conclusion: genetic variants that predispose to more severe cf disease are potential targets for new therapies. we are testing the hypothesis that the adverse (codon ) cc genotype is likely to reflect increased transcription and/ or tgfβ protein synthesis/ secretion. if true, "anti-tgfβ " therapies could provide a novel therapy in cf. *reporting for the gene modifier study group. supported by cff knowle a , cff drumm a , gcrc rr , nih r hl . aim: centralized periodic evaluations of data from the screening laboratories and cf centers by afdphe (french association for screening and prevention of infant handicaps), were analysed to optimize the efficiency of the program. methods: the strategy combined d irt assay/dna analysis (kit elucigen cf- arms) /d -fail-safe irt. revised irt-cut off levels were decided in order to maintain the percentage of positive screens around a . % target. a questionnaire yearly sent to the cf centers collected the cf false negative cases. results: from to december, , cf cases were detected through nbs ( screened infants). the i period (p) (n= ); d -irt: µg/l and d -irt: µg/l showed a) . % infant above the d cut-off, generating an excess of costly dna tests b) % had a d -irt above the cut-off leading to a very high number of st (n= ) with an extremely low rate of cf (n= ). by increasing slightly both d /d irt cutoff levels ( µg/l, µg/l) during the ii p (n= ) a) the number of positive screens decreased to . % b) . % of infants with elevated d -irt had to be referred for st (n= ) with cf diagnosis. since the risk to had true cf remained very low among infants with no detected mutations, during the iii p (n= ), d -irt concerned only the ones with d -irt> µg/l and the percentage of infants requiring a st was reduced to . % (n= , cf). the incidence of cf detected during these p did not vary significantly ( / - / - / ). another point of concern was the false negative cohort; with a follow-up period over months, cf were detected on clinical symptoms ( . %) at a mean age of months. only were directly related to the modifications of the strategy. conclusion: centralisation of data made possible changes in the flow charts of the screening strategy to limit the number of false positive cases without significant alteration of the global performance of the program. there were three infants of mixed aa/caucasian origin diagnosed with cf, all had ∆ /genotype on screening. mutation data on the additional aa cf patients followed at the cf centers in new york was collected. six patients have not been genotyped. there were patients who were homozygous for ∆ , patients had only one mutation identified and were not found to have any cf mutations. ∆ ( %) and + g>a( %) were the most common mutations. there are five cf patients (including infants diagnosed by nbs) with mixed racial origin who are not included in this analysis. mutations results: the median (range) mbl plasma level was . ( . - . ) µg/ml in cf patients, compared to . ( . - . ) µg/ml in controls. mbl genotype frequencies were similar in patients and controls. lung function level was not correlated with mbl genotype or plasma level. the frequency of colonization with pseudomonas aeruginosa was % in mbldeficient (xa/o and o/o genotype) children with cf and % in mbl-sufficient (a/a and ya/o genotypes) children (p= . ). we found a trend of a decreased age of first onset of colonization with staphylococcus aureus, haemophilus influenza and pseudomonas aeruginosa in mbl-deficient cf patients (p= . , p= . , and p= . , respectively). conclusions: mbl-deficiency was associated with an increased frequency of pseudomonas aeruginosa colonization in children. mbl deficiency was not associated with lung function deterioration. in a larger cohort we hope to confirm that mbl deficiency influences age at onset of bacterial colonization in cf patients. acknowledgments although there is some evidence that cftr gene mutations may be associated with respiratory diseases, little is known about the relationship between cftr gene mutations and idiopathic bronchiectasis (ngiam et al. ) . we have recently showed that a rare allele (- g>a) in the minimal cftr promoter, previously reported in patients with idiopathic bronchiectasis ( using supershift assays, we demonstrated that these transcription factors bind cftr promoter in vitro. a functional analysis, by using co-transfection assays with expression vectors of each transcription factor in pulmonary epithelial cells, showed that nrf , irf significantly decrease cftr expression, whereas irf and sp increase it. in an attempt to further elucidate the mechanisms involving these factors in the cftr transcriptional regulation, for instance, to determine whether these factors could interact together in order to regulate cftr transcription, we started several experiments such as co-immnoprecipitation, multiple co-transfection and rnai. taken together, these data evidence that the variant - a in cftr promoter should be considered as an important risk factor in bronchiectasis pathogenesis. furthermore, we have identified a novel regulatory complex on the minimal cftr promoter, which will enlighten the understanding of the transcriptional regulation of the cftr gene. a better knowledge of cftr cis-and trans-acting elements will allow to consider new approaches to modulate and/or control more specifically cftr expression. this work is supported in part by the association vaincre la mucoviscidose. (nat genet, ) . a recent study reports strong genetic influences for mi (blackman et al., gastroenterology, ) , but it did not replicate the modifier locus on chr. q . inconsistency of results may reflect the variability of data reporting and different classifications of mi (i.e. surgically or medically treated). we tested the accuracy of reporting of mi on case report forms (crfs), as compared to primary source documents. methods: the crf for the gms has a checklist for past medical history. for example, we requested "yes" or "no" for mi (an obstruction of the terminal ileum at birth), but did not require source documents or identification of the type of treatment. to evaluate crf reporting of mi, we requested source documents for patients with reported mi, including a surgical or medical treatment report. if a written report from the time of birth was unavailable, a clinic note, detailing mi at birth, treatment, and evidence of a surgical, abdominal scar (if applicable), was required. verbal confirmation by the patient and evidence of a surgical scar was also accepted, if no written documentation was available. results: on crfs, of patients ( %) were initially reported to have mi. to date, source documentation has been obtained for patients, and of those ( %) have been confirmed to have mi ( % by written report, % by verbal report). of the with confirmed mi, ( %) had surgery, and ( %) had medical treatment. there were false reports of mi ( . %). mi could not be confirmed or refuted for patients ( . %) because of insufficient information (n= ) or confounding circumstances (n= ). to date, documentation for patients who were reported to have no mi has been obtained, and no false negatives have been found. additional documentation for mi from other sites is expected. conclusion: at least %, and perhaps as many as %, of the reports of mi on crfs were inaccurate. gene modifier studies must include rigorous documentation of mi to ensure an accurate correlation between phenotype and genotype. studies should also characterize different classifications (i.e. surgical vs. medical treatment) to assist the detection of gene modifiers of mi. reporting for the gene modifier study group (mrk); supported by cff knowle a , cff drumm a , nih r dk , nih r hl , and gcrc rr . any mutation that disrupts or diminishes the efficiency of the splicing process will have an impact on disease manifestation. in the cystic fibrosis (cf) transmembrane conductance regulator (cftr) gene more than , mutations were identified, most of them being disease-causing [ ] . among these,~ % are classified as missense and about % are classified as splicing mutations, given that they disrupt the consensus splice sites [ ] . however, the splicing mutation concept is evolving, as it nowadays also includes mutations other than just those within or close to the consensus splice sites, rendering prediction of mutation consequences a hard task. nevertheless, it is still very important for the clinical settings to determine the functional effect of gene mutations. our aim here was to study the effect of i v, a rare cftr missense mutation in nbd (exon ), directly in native tissues of a cf patient bearing f del in the other allele, so as to gain insight on how it influence the disease outcome. to look for a possible effect at the rna level, total rna was extracted from native nasal cells and colonic tissue, and cdna producd using random primers. rt-pcr amplification was performed in the region spanning exons - , being one of the primers fluorescently labelled. the products were analysed as described before [ ] . the i v( a>g) mutation which creates both a novel acceptor and a novel donor, was found here to cause alternative spliced cftr transcripts lacking the last nucleotides of exon , thus showing that only the novel donor is used in vivo. moreover, our data show that no normal (only alternatively spliced) transcripts result from this allele. we have also analysed the i v mutation at the protein level by producing a stable bhk cell line expressing the i v-cftr, after generating the respective mutant cdna construct by site-direct mutagenesis. protein expression and function was determined by immunoblot and iodide efflux assay, respectively. results show that i v-cftr protein is processed and functional. however, given the above-described absence of normally spliced mrna coding for this cftr variant, we have to conclude that this protein is not produced in vivo. indeed, since only the mrna coding for cftr lacking the last six aminoacids of exon was detected, we are currently characterizing in vitro the proprerties of this truncated protein. altogether, our data clearly demonstrate that the functional effect of this mutation is not due to the amino acid change but to abnormal splicing. in conclusion, characterization of the consequences of mutations in native affected tissues is important, not just because this provides unexpected information about the mechanisms underlying the basic defect but also for disease diagnosis and prognosis. (darrah et al, nacfc ) . the purpose of this study was to examine the influence of common genetic variation in the endothelin pathway on the cf phenotype. methods: patients were recruited from the cf clinics in dublin, belfast and seattle. serial clinical data were abstracted from medical charts and local clinical databases. studentized residuals of maximum fev , after adjusting for age, gender and height, was the phenotype of interest. twentyone maximally informative tagsnps were identified in the edn , edn , ednra and ednrb genes using the niehs environmental genome project and were genotyped using the illumina beadarray system. genotype and haplotype analysis were carried out using helixtree genetic analysis software. results: clinical and genetic data were available on cf patients ( from seattle and from dublin/belfast). in the combined cohorts, tagsnps in the ednra gene were significantly associated with differences in cf lung disease severity (p= . ). this was observed in both the irish cohort (p= . ) and the seattle cohort (p= . ). the effects were independent of gender and cftr genotype. four common haplotypes (haplotype frequency> %) were identified in the ednra gene. there was significant association between ednra haplotypes and cf lung disease severity (table ). there was no association between genetic variants in ednrb, edn and edn and cf lung disease severity. conclusions: the ednra gene is a genetic modifier of the cf phenotype. our findings were seen in two independent cohorts and verify existing associations found in other populations. the endothelin pathway may be a novel therapeutic target for the treatment of cf lung disease. background: cystic fibrosis (cf) is a recessive "monogenetic" disorder, but there is heterogeneity of lung disease severity and survival reflecting environment and non-cftr genetic modifiers. the unc/cwru multisite gene modifier study (gms) identified patients who were "severe" or "mild" as teenagers or young adults and pertinent cross-sectional data was collected; however, we did not collect all pertinent information about early (age < years) clinical features. objective: we sought to retrospectively evaluate the early clinical features of "severe" and "young mild" patients enrolled in the gms. methods: we obtained all cff registry data available on patients. there were "severe" (worst th percentile of birth cohort, age range - ) and "mild" (best th percentile, age range - ). initial analyses focused on cross-sectional plots of patient age versus multiple clinical features, including age at diagnosis, hospitalizations, cdc height and weight percentiles, presence/absence of ps. aeruginosa from respiratory cultures, and fev (% pred). results: there were . and . years of cff registry data per patient for "severes" and "milds," respectively. preliminary results indicate "severe" patients were diagnosed earlier in life than "mild" patients (mean: . vs. . years, p= . ). this difference is greater after omitting patients who had meconium ileus (diagnosis: . vs . years, "severes" and "milds" respectively, p= . ). between and years of age, "severe" patients were hospitalized more frequently than "mild" patients and, from age onwards, the disparity in frequency of hospitalization increased. "severes" and "milds" had similar cdc height percentiles (~ th percentile) until age , at which point percentiles increased more for "mild" versus "severe" patients. by age , "severe" patients already had lower cdc weight percentiles than "milds" ( nd versus st percentile) and this disparity increased throughout adolescence. from age to , "severe" patients had a - fold higher prevalence of ps. aeruginosa than "mild" patients. as early as years of age, fev (% pred) was ~ points lower in "severes" as compared to "milds." however, some "severe" patients had normal lung function at ages - and overlapped with mild patients; thus phenotyping of lung severity for young patients is not optimal. all of these results were similar for males and females. summary: retrospective analysis of the cff registry data indicates that patients classified later in life as being "severe" experience a worse course of disease from early in life. understanding the early clinical course may prove helpful in defining surrogate phenotypes for modifier studies, and help define appropriate therapeutic targets. cystic fibrosis is mainly caused by small molecular defects of the cftr gene; despite the genotype is defined in the majority of patients, a number of cf cases still remain uncharacterised. the cf mutation database lists more than large rearrangements that may escape detection using pcrbase techniques. the innogenetics assay, the dhplc and sequencing screening showed a mutation detection rate of . % in our population. we report here the results of mlpa screening for ctfr gene rearrangements, performed on the unidentified alleles of our cf patients. our sample population consists of unrelated italian cf patients (for a total of alleles), followed at cf centres of lombardia region. mlpa analysis was performed in patients who still had one or two unidentified alleles after extensive analysis of cftr gene. all patients studied had classical clinical cf symptoms. subjects presented with persistent or recurrent respiratory symptoms, failure to thrive, salt loss syndrome and gastro-intestinal findings. we characterized different deletions and a new duplication (dup promoter-ex. ). thus, . % ( / ) tested alleles had a large gene rearrangement. the deletion of exons - ( / ) was the most frequent in our cohort. all patients had positive sweat chloride values (above meq/l), except the patient carrying duplication who has borderline sweat chloride value. out of patients, ( %) had fecal elastase levels consistent with a preserved pancreatic function: of these patients, had mild mutation, had severe, and had unknown mutation. six patients present liver involvement. the results of the present study could indicate that compound heterozygosity for large rearrangements in cftr gene, is strongly associated with severe pancreatic disease as mutations in classes i, ii, and/or iii. l f is a missense substitution which changes from leucine to phenylalanine at position , resulting from a g/c transition at position in exon a of the cftr gene. it has been described in patients with disseminated bronchiectasis, recurrent idiopathic pancreatitis, sarcoidosis, newborns with hypertripsinemia,. recently derichs et al. reported one healthy -year-old girl homozygous for l f; therefore the pathogenic role of the variant is still unclear. in this study we present subjects compound heterozygotes with l f. no other mutations have been identified after molecular analysis performed using sequencing analysis of the whole coding region of cftr gene and mlpa technique in order to search for gene rearrangements.none of them presented ivs t allele. three of them had a severe mutation in trans (r x, aa>g, and n k), while the other three had a mild mutation on the complementary allele (d h, r q, and r w). individuals with a severe mutation in trans presented a remarkably different clinical picture compared to those with a mild mutation in trans. the formers were diagnosed at a mean age of . years, had an average sweat chloride of . meq/l; besides, all of them have respiratory symptoms, staphilococcus aureus in sputum cultures (one had pseudomonas aeruginosa as well), and in two the chest x-rays was abnormal. the three l f/ps mutation individuals were diagnosed at a mean age of . years, had an average sweat chloride of . meq/l; besides none of them had respiratory symptoms, abnormal chest-xrays, or positive sputum cultures, but two had a history of pancreatitis. these data seem to suggest that l f cannot in any case be considered a neutral polymorphism. the variability of its clinical expression seems to be influenced by the mutation in trans. further studies are needed in order to support our results. expression of the cystic fibrosis transmembrane conductance regulator (cftr) is tightly regulated both spatially and temporally, yet the molecular mechanism of this regulation is not well understood. because no tissue-specific regulatory elements were recognized in the basal cftr promoter, the crucial cis-regulatory elements are likely to be located elsewhere within the cftr locus. a number of the non-coding regions of the cftr gene were found by our laboratory to contain dnase i hypersensitive sites (dhs), suggesting the presence of regulatory elements at these sites. studies presented here investigate the role of an intron dhs (dhs ) in the tissue-specific regulation of cftr gene transcription. the elucidation of molecular mechanisms underlying the temporal and spatial expression of cftr may aid in developing more specific targeted therapies for cystic fibrosis (cf). footprinting analysis of cftr intron revealed a protected region within the core of dhs at + kb. in silico analysis of this sequence uncovered a number of transcription factors binding motifs, including a consensus binding sequence for hepatocyte nuclear factor (hnf ). we have previously identified a role for this factor in the regulation of cftr expression. results of electrophoretic mobility shift assays (emsa) demonstrate that hnf α specifically binds to the motif in cftr intron in vitro. in addition, chromatin immunoprecipitation (chip) analysis of cells expressing both cftr and hnf α factor shows that this factor binds to the intron site in vivo. when cloned as an enhancer, the dhs element was found to augment minimal cftr promoter activity in a luciferase reporter based assay. this increase in luciferase activity was abolished when two nucleotides within the core hnf binding site were mutated, suggesting a functional role for hnf α in cftr gene transcription. further experiments are underway to determine whether additional transcription factors can be recruited to the core of the intron dhs regulatory element and can interact with hnf and the cftr basal promoter to modulate tissue-specific cftr gene expression. the promoter of the cftr (cystic fibrosis transmembrane conductance regulator) gene is not solely responsible for its complex pattern of expression. to identify potential regulatory elements for cftr we previously mapped dnase i hypersensitive sites (dhs) across kb spanning the locus. in addition to intronic dhs, a number of sites were observed that flank the cftr gene. we hypothesized that these may include insulator elements that establish the chromatin expression domain, within which the cftr gene is regulated. insulators are elements that shield against the effects of regulatory elements from adjacent genes, and they may also block silencing of integrated transgenes. using a well-established insulator assay, in which dna regions of interest are assayed for their ability to interfere with communication between a chicken β-globin enhancer and a neomycin resistance gene, we demonstrated that two dhs, at - . kb from the cftr translational start site, and at + . kb from the ' end of the gene, exhibit enhancer blocking activity comparable to known insulator elements. electrophoretic mobility shift assays (emsa), demonstrated in vitro binding of the well-characterized insulator protein ctcf (ccctc-binding factor) at the - . kb dhs. this was confirmed in vivo in both cftr-expressing and non-expressing cell types using chromatin immunoprecipitation (chip). in contrast, although the + . kb dhs did not bind ctcf, we obtained in vitro evidence for the interaction of other factors that may be involved in insulator activity. furthermore, chip analysis of histone modifications across the cftr locus revealed striking differences between the - . kb and + . kb dhs, again suggesting mechanistic differences between these elements. the characterization of insulator elements flanking the cftr locus may be of direct practical relevance in the design of vectors for effective cf gene therapy. one of the problems encountered in gene therapy protocols is the relatively rapid loss of expression from the cftr cdna once it is introduced into mammalian cells. incorporation of the - . kb and + . aminoglycosides, particularly tobramycin, are primary antibiotics used to treat the airway infections in cystic fibrosis patients. lifetime, systemic exposure to these antibiotics is significant and can be associated with significant nephro-and ototoxicity. these toxicities have the potential to significantly reduce the quality of life in the aging adult cf population. we previously reported an incidence of aminoglycoside ototoxicity of greater than % with sensitive audiometric studies (i.e. pure tone audiometry and distortion product otoacoustic emissions). these studies indicated considerable variability in ototoxicity in patients with similar systemic aminoglycoside exposure. the literature suggests that genetic variability in mitochondrial dna can partially explain these differences. single nucleotide polymorphisms (snps) in the mitochondrial srrna gene are associated with aminoglycoside ototoxicity. we genotyped unselected adult cf patients for four of the mitochondrial s-rrna polymorphisms associated with aminoglycoside ototoxicity by direct sequencing of dna harvested from peripheral blood. four patients exhibited polymorphisms in this gene. two patients possessed the a g transition, while another patient each revealed a polymorphism at a g and c t transitions. the patient with the a g polymorphism died prior to audiometric testing. both patients with the a g had audiometric studies consistent with moderate to severe ototoxicity. while the patient with the c t had mild aminoglycoside ototoxicity. all four patients had severe airway obstruction and at least one full course of parenteral tobramycin at mg/kg/d. there was no history of toxic serum levels aminoglycosides during this therapy. both patients with the a g polymorphism had a family history consistent with the expected maternal inheritance pattern associated with the mitochondrial s-rrna gene. we found no evidence of the delt polymorphism in this population. these studies indicate a higher than expected frequency ( %) of mitochondrial s rrna polymorphisms associated with aminoglycoside ototoxicity. these studies demonstrate that genetic screen-ing provides valuable susceptibility information and may change clinical decision-making. support: rising hope foundation/national cf foundation. cystic fibrosis is a genetic autosomal recessive disease that is caused by deleterious mutations in the cftr gene. in its most severe form, cf results in abnormal sweat electrolytes, sino-pulmonary disease, male infertility, and pancreatic exocrine insufficiency. in fact, cf is the most frequent cause of pancreatic insufficiency in humans. carriers of cf (i.e., heterozygotes) do not express any of these classic symptoms. recent studies indicate that significant numbers of non-cf patients diagnosed with congenital bilateral absence of the vas deferens (cbavd) or idiopathic chronic pancreatitis (icp) are compound heterozygotes and carry two cftr mutations of varying severity. in dogs, especially german shepherds and rough-coated collies, exocrine pancreatic insufficiency (epi) has been observed with symptoms similar to those seen in human patients. epi in dogs is most often caused by pancreatic acinar atrophy (paa), a degenerative disease of the exocrine pancreas that has been shown to be inherited as an autosomal recessive trait. the locus responsible for canine paa has not been identified to date. we considered the possibility that cftr mutations might be responsible for this disease. a dog that had been diagnosed with paa and one that was a known carrier of paa were screened for cftr mutations. our samples also included dogs diagnosed with idiopathic pancreatitis as well as healthy dogs. we have established protocols for detecting putative mutations in the canine cftr gene using temporal temperature gradient gel electrophoresis (ttge). in the dog with paa and in the carrier of paa, our screening methodology identified mutations in of the amplicons that span the exons of the cftr gene. dna sequencing revealed silent mutations in exons , and . in exons (l ) and (l ), single nucleotide polymorphisms converted ctt codons into ctc codons, both leucine codons. in exon (p ) another single nucleotide polymorphism converted a ccc proline codon into a cct proline codon. the other identified mutations (amplicons , and , , , , , and ) were found in intronic sequences and have no predicted effect on cftr expression or function. based on these findings, we conclude that cftr mutations are not responsible for paa and the epi that it causes in dogs. hypothesis: specific polymorphisms in genes of the innate immunity may modify the severity and progression of cf pulmonary disease and influence pseudomonas aeruginosa colonisation. methods: single nucleotide polymorphisms (snps) analysis of multiple genes contributing to the innate immunity ( (mbl ), masp (mbl associated serine protease) Ç , fcn (ficolin) Ç , lbp (lipopolysaccharide -binding protein), cd , tlr (toll-like receptor Ç ) ) was performed in cf patients (age - years). spirometric data and bacterial colonisation status with pseudomonas aeruginosa were collected retrospectively. a decline in fev of % over a years period and a percent predicted fev value of % were used to discriminate mild from more severe affected adult cf patients (≥ years). the frequency of single and combined snps in well-defined subgroups of the cf population was compared. results: in adult cf patients with a mean fev lower than %, the combinations of snps of cd (promoter) with tlr (promoter), fcn with tlr (exon ), and masp with tlr (promoter) were more common than in adult cf patients with mean fev > % (odds ratio (or) , ( % confidential interval (ci) : , - , ) , or , ( % ci: , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] ) and or , ( % ci: , - , ) respectively). the frequency of combination snps of masp with tlr and masp with tlr was significantly higher in cf adults with more than % decline in fev compared to cf adults with less than % decline in fev (or , ( % ci: , - , ) and or , ( % ci: , - , ) respectively). however, the single snps of masp , tlr , tlr were not more frequently found. in pseudomonas aeruginosa colonised cf patients, an increased frequency of combined snps of tlr (exon ) with tlr (exon ), lbp (exon ) with tlr (exon ) and mbl with tlr (exon ) (or , ( % ci: , - , ), or , ( % ci: , - , ), or , ( % ci: , - , ) respectively) was found. in contrast, for single snp tlr (exon ) no statistically significant differences were found between the groups (or : , ( % ci: , - , )). in general, the odds ratios for the combined snps were higher than for the single snps and remained significant when the different groups were subdivided according to cftr genotype. conclusion: certain combinations of snps of genes of the innate immunity are more frequently found in cf patients with a lower fev , a stronger decline in pulmonary function and pseudomonas aeruginosa colonisation. however, for the single snps this trend was less pronounced or absent. congenital bilateral absence of the vas deferens (cbavd) is a rare condition associated with mutations in cftr. cbavd lacks extra-genital organ system abnormalities; it has been viewed as a mild (variant) form of cf. the disease serves as an excellent model for studying the clinical and experimental ramifications of marginal cftr activity, and the functional thresholds necessary to confer a cf-related phenotype. recently, drumm et al. (nejm, ) found that the codon cc genotype of tgfβ- is associated with more severe pulmonary disease, particularly in individuals homozygous for ∆f cftr. tgfβ is also known to play a critical role during normal development and differentiation of the human vas deferens (han-nema et al., horm res, ) . because % of cbavd subjects carry at least one defective cftr allele (but millions of males worldwide are heterozygous for cftr mutations without developing cbavd), the present study was designed to test whether tgfβ polymorphism might serve as a genetic modifier underlying isolated vas deferens loss in the setting of cbavd. we sequenced the ' end of the tgfβ gene in eighty cbavd individuals possessing at least one cftr mutation, and compared genotype frequency with results previously published from demographically similar controls. when cc frequency in cbavd subjects was compared to pooled estimates from earlier trials, no significant differences were seen using a non-dominant model. compared to frequencies reported by arkwright et al. and garrote et al., a greater number of homozygous cc subjects ( . % vs. . %, p< . ) was observed. our preliminary results therefore indicate that if tgfβ- codon polymorphism is associated with cbavd penetrance, it does not represent the major modifier of disease phenotype. in order to evaluate this possibility further, we plan analysis of a larger (matched) control set of cbavd and non-cbavd individuals, studies of tgfβ- activity in vas deferens epithelial cells with and without cftr, and experiments to investigate the effects of tgfβ on cftr biogenesis and function. supported by nih and cff. newborn screening (nbs) for cf has been successful in identifying cf infants, particularly those who have positive sweat tests immediately following the positive screening result. tracking by personnel at the central nbs program facilitates resolution of diagnostic status because cf nbs presents a challenge to cf center (cfc) systems and primary care providers when apparently asymptomatic infants have inadequate (quantity not sufficient (qns)), borderline or indeterminate sweat tests. short-term follow up is more problematic when the screening algorithm requests earlier sweat tests and defines a lower cutoff for indeterminate sweat test results than is used for older infants, children and adults. the massachusetts (ma) cf nbs workgroup chose a low cutoff for indeterminate results of meq/l up to months of age, reverting to the accepted meq/l cutoff thereafter. follow up by the central nbs program identified infants whose diagnostic status remained unresolved more than weeks after a qns or borderline sweat test and eliminated the need for individual cfcs to follow infants tested at more than one cfc. the program sent informational letters and a reminder recommendation to finalize the diagnosis to primary care providers of infants with unresolved diagnoses. of the cf infants identified by ma cf nbs, had an initial sweat result that was indeterminate and another had an initial result that was qns. the central screening program has the capacity to track infant and child outcomes across cfcs; for example, we have been tracking growth outcomes of all cf infants identified by ma cf nbs, despite of the cf infants having moved from one cfc to another during their first years of life. tracking and outcomes data will be presented. when more than one cfc operates within a screening program, centralized tracking ensures capture of quality data. despite several educational campaigns cf is often not diagnosed in early infancy in poland (the mean age of diagnosis months, median is months). after several years of discussions,in september a neonatal screening for cf supported by the ministery of health was started as the third obligatory neonatal screening in poland. more than , neonates were screened in the first seven months using the existing screening infrastructure and spare blood spots after pku and congenital hypothyreosis screening. the protocol was two stage irt/dna (covering the most common mutations in the polish population). the final diagnosis was based on sweat tests (conventional pilocarpine-iontophoresis and conductometric nanoduct) as well as clinical examination. values of chloride in sweat > mmol/l and nacl > mmol/l were considered diagnostic for cf. children were confirmed as cf. although delta f is the most common mutation in the polish population, only two infants were delta f homozygotes, six were delta f heterozygotes and the remaining had different mutations ( children had + kbc>). half of the diagnosed group was still pancreatic sufficient. the children had confirmed cf diagnosis at the mean age of weeks. only children were free from any radiological changes in lungs. the most common pathogen in this group was staphylococcus aureus. at the first visit information for parents about cf was given along with physiotherapy and dietary education. anthropometric measurements, airways bacteriology and elastase - in stool were performed. psychologist consultations were available. neonatal screening for cf enabled earlier diagnosis and the introduction of complex therapy in comparision with symptomatic screening. objectives: the clinical course of cystic fibrosis (cf) varies widely among patients carrying the same cftr gene mutations supporting that additional genetic modifiers could affect the cf phenotype. as inflammation is a central contributor to the pathogenesis of cf lung disease, genes involved in the inflammatory response are potential modifier candidate genes. methods: we examined the influence of polymorphisms in genes involved in the inflammatory response (tnf, il- β, il- receptor antagonist (rn), il- , il- , il- and tgf-β ), on disease progression in a group of caucasian children with cf. the genotypes were tested for an association with changes in lung function tests, pseudomonas aeruginosa colonization and nutritional status by multivariable analysis. results: we found a significant association between tgf-β + t/c variants and decline in lung function measured as the forced expiratory volume in one second (fev ) and the forced vital capacity (fvc) (p= . and . respectively). il- gene polymorphisms (- a/t, + g/t and + t/c) were associated with the occurrence of pseudomonas aeruginosa colonization (p< . ). conclusions: this study suggest that il- variants may influence pseudomonas aeruginosa colonization in cf, however this need further confirmation. moreover, we provide additional support to the results of other trials and strongly suggest an association between tgf-β variants and lung disease phenotype in cf. if such a role of tgf-β is confirmed by functional studies, it may have important clinical impact for the identification of patients at risk to develop more severe respiratory manifestations and for the development of new therapeutic strategies aimed at adequately balancing tgf-β production and action introduction: cystic fibrosis (cf) is the most common monogenic disease in caucasian population, its frequency is about one in live born. the estimated frequency in hispanic population is about one in , with differences in mutation frequency especially for low frequent alleles. heterogeneity in pulmonary manifestations cannot be explained by the cftr mutation genotype. recent studies are focused in the study of modifier genes. these are genes different from the primary cftr gene that could influence the fq phenotype, acting trough mechanisms like inflammation, repair and remodeling, protease-anti protease balance, innate immune response, etc. this work shows some advances in cf diagnosis and modifier genes analysis in mexican population. methods: we tested the effectiveness of innolipa cftr kit (innogenetics) in clinically diagnosed cf patients. thirty six frequent mutations in cftr gene were analyzed by pcr and reverse hybridization with allele specific oligonucleotides probes in dna samples extracted from blood or oral swabs. for frequency analysis of modifier genes we tested about seventy dna samples from a dna bank of patients previously tested positive for cftr mutation. the polymorphism analysis of modifier genes was made by pcr-rflp. for alpha antitrypsin (aat), z and s alleles were analyzed according stanford and cols. ( ) . for tumor necrosis factor alpha (tnfα) - polymorphism in the promoter region was analyzed according chen and cols. ( ) . results: mutation was detected in in of patients ( % of effectiveness). df allele frequency was % (caucasian - %) followed by + g-a, s n, g x, g e and delt ( %). % of the mutant alleles remain undetected. preliminary results in modifier genes show low frequency for aat mutant alleles ( . % for aat s and z alelle respectively) and . % for tnf- . conclusions: df alelle frequency was %, and we found the low fequency alleles s n and + g-a. frequency of modifier genes mutant alleles in cf patients are low. this work is in progress of selection and recruitment of patients and controls, as well as standardization of the other genes modifiers, along with some other biomarkers that will allow to understand the physiopathology of cf and to define a possible genetic risk profile of severe pulmonary disease. over putative cystic fibrosis (cf)-causing mutations have been reported to the cf mutation database and almost half (~ ) are rare missense mutations that are predicted to substitute a single amino acid. to determine if any of these rare missense mutations cause cf by altering localiza-tion of cftr, we examined mutations in the cytosolic loops of cftr since localization signals have been identified in cytosolic loops of other ion channels. amino acids alignments comparing human cftr sequence to that of species revealed that cytosolic loop (cl ) was the most conserved loop by identity. furthermore, cl had the most naturally observed mutations: of the amino acids were found to be mutated in cf patients and sites had multiple missense mutations at the same amino acid. in addition, different substitutions of the same cl amino acid have been associated with different disease consequences, such as the missense mutations in the arginine at codon . patients with the r p mutation have pancreatic insufficient (pi)-cf, those with r w mutation have pancreatic sufficient (ps)-cf or cbavd, while patients with r q primarily had pi-cf. to determine whether the r mutations cause disease by affecting cftr localization, we used the flp-in system to create stable polarized mdck-gfp-cftr cells to produce isogenic clones with cftr expressed from the same integration site. confocal microscopy studies of stable mdck-frt-gfp-cftr-r mutant cell lines revealed that cftr-r p was cytoplasmic, cftr-r w was apical and cytoplasmic, and cftr-r q was apical. to confirm these observations, quantitative biotinylation studies were performed. biotinylation assays of mdck cells stably expressing cftr-r p confirmed that this mutant was absent from the apical surface, cftr-r w had a low level of fully glycosylated protein at the apical membrane, while cftr-r q had fully glycosylated protein at the apical membrane comparable to wild-type cftr. thus, cftr-r p and cftr-r w displayed properties in polarized cells that were distinctly different from wild-type cftr consistent with their associated cf phenotypes. however, the profile of cftr-r q (apical localization and cl-channel function (seibert et al. , mickle et al. ) appears inconsistent with a pi-cf phenotype. indeed, re-analysis of cftr genes bearing r q revealed that of carried a second mutation in cis (s x). in nine of these patients in whom cftr genotype and pancreatic status is known, presence of the nonsense mutation s x is associated with the pi-cf phenotype. since nonsense mutations are known to cause severe gene dysfunction by promoting decay of their rna transcript, we concluded that the s x mutation rather than r q is responsible for the pi-cf phenotype. the finding of s x explained the otherwise enigmatic functional studies of r q and clinical observations in patients bearing this mutation. this study also demonstrates that stable expression of cftr mutants in polarized mdck cells using the flp-in system provides a useful screen for evaluating the disease potential of rare missense mutations. the clinical course of cf is characterized by recurrent pulmonary infections and chronic inflammation. in cf patients, up-regulation of toll-like receptor- (tlr ) gene in airway epithelial cells is believed to enhance proinflammatory responses towards bacterial tlr ligands. we have recently shown that decreased methylation (demethylation) of the tlr promoter is responsible for cf-related up-regulation of tlr in bronchial epithelial cells (shuto. t. et al., faseb j, ) . however, the molecular mechanisms responsible for dna demethylation-dependent tlr gene upregulation in cf cells remain unknown. here, we identified minimum region of the tlr promoter critical for its expression at - /+ , which contains one putative binding site for sp . sp inhibitor mithramycin a treatment reduced tlr promoter activity and its expression in cf bronchial epithelial cells (cfbe o-), suggesting the importance of this sp site for the tlr gene regulation. moreover, bisulfite sequence analysis revealed the hypomethylation of adjacent this sp binding motif within tlr promoter in cfbe o-cells, implying the cf-specific demethylation of adjacent sp binding motif. although mithramycin a rarely affected basal expression of tlr gene in hbe o-cells (non-cf bronchial epithelial cells), mithramycin a inhibited tlr expression in -azacytidine (dna-demethylating agent)-treated hbe o-cells. taken together, our results suggest that sp is crucial for dna demethylation-induced gene upregulation of tlr in cf bronchial epithelial cells. mucus hypersecretion due to goblet cell metaplasia is a critical feature of cf lung disease, affecting both mucociliary clearance and drug delivery. various studies in cf lungs and cf primary cultures have shown increased expression of muc ac, the main gel-forming mucin produced by goblet cells; however, little is known about the role of muc ac in the progression of lung disease. to determine whether overexpression of muc ac alone is sufficient to induce lung pathology, we generated a mouse model overexpressing muc ac. the entire muc ac cdna (minus % of the predicted vntr sequence, final size ~ kb) was cloned and tagged with an internal gfp epitope at a site close to the vntr to preserve the integrity of mucin domains. gfp-muc ac was linked to the rat ccsp promoter to drive specific airway expression, primarily in clara cells since these cells are capable of secreting mucins. blastocyst injections were used to generate transgenic founder lines in c bl/ background. although muc ac-gfp mrnas were expressed in transgenic mice, lung histology did not show significant increases in inflammation, ab/pas-positive cells, or luminal secretion compared to wild-type littermates. gfp fluorescence from freshly excised lung was weak but immunohistochemistry showed that the distribution of gfp correlated with the expected expression pattern, with the majority of positive cells localized to the airways and few positive cells in the alveolar space. at higher magnification, gfp-positive granules were observed in dome-shaped cells that were also positive with cc antibody, suggesting proper muc ac-gfp packaging in clara cells. bronchoalveolar lavage samples separated by agarose gel western blots and probed with gfp antibody confirmed that each line secreted muc ac-gfp, with a migration pattern comparable to a mucin. to further characterize the secreted transgenic mucin, a pool of lavage samples was separated into supernatant and pellet. the pellet was resolubilized in m guanidine. both elements were passed through a s size-exclusion column. analysis by light scattering and refractometry to determine molecular weight and concentration revealed that the solubilized pellet contained an enormous but compact complex ( x g/mol and nm radius of gyration). gfp-rich fractions were pas-positive, indicating proper glycosylation of the transgenic muc ac-gfp. cscl density gradient studies revealed that the gfp-rich fractions had a high molecular weight but did not appear to be a prominent part of the megacomplex retrieved in lavages, unlike other tested mucins. in conclusion, we showed that the overexpressed muc ac-gfp was a high-molecular-weight protein that was glycosylated, packaged in clara cells and formed multimers. lack of discernable phenotype in the transgenic lungs suggests that mucin overproduction alone is not sufficient to trigger goblet cell metaplasia and mucus accumulation, supporting the protective role of mucins. currently we are crossing the muc ac-gfp with the scnn b mouse model to study muc ac-gfp under dehydrated conditions and we are conducting allergen-challenges in the transgenic mice. results of such studies will provide novel insights into the role of secreted muc ac in development of lung disease in these models. supported by grants from the cf foundation. the major characteristic in cystic fibrosis (cf) is acquirement of chronic lung infections with p. aeruginosa. once established the chronic infection can only be suppressed, not eliminated. the cf patients harbour one single strain of p. aeruginosa which only rarely is replaced by other strains. during the chronic lung infection there is a year long mutual impact of the bactaria on the host, and of the host response and antibiotics on the bacteria, resulting in a continous adaptation of the bactaria in the lungs of the cf patients with selection for different clones. in contrast, mouse models of the lung infection in cf is limited to two weeks! therefore, we introduced a new strategy infecting different groups of balb/c mice with pulsed field gel electrophoresis-(pfge) identical clones isolated from one cf patient during -years of p. aeruginosa lung infection. ) infecting the mice with non-mucoid isolate showed that the early isolates were significantly better in establishing an infection with reduced clearance of the bacteria from the lungs (p< . ), increased dissimination of the macroscopic pathology (p< . ) and a more acute type and a higher degree of inflammation (p< . ) as compared to mice infected with a late isolate. in addition, the pulmonary cytokine response was comparable with observations in cf where gm-csf and il- correlated to a milder disease, whereas g-csf, mip- (il- analog), and il- b correlated to severe disease. ) infecting the mice with the mucoid pfge-identical isolates from the same cf patient revealed a signicantly higher mortality in mice infected with the late isolates (p< . ). in addition, the pulmonary g-csf and mip- response increased in the groups of mice that were infected with the late isolates as compared to the early isolate (p< . ). moreover, the g-csf and mip- increased during the first three days of infection with the late mucoid isolates (p< . ), indicating an impairment of the host response in controlling the lung infection. ) when tobramycin treatment was initiated h after infection of mice with a mucoid isolate, the number of bacteria were cleared or reduced to a significantly lower level (p< . ), and a significant decrease of both g-csf and mip- at day one, two and three was observed (p< . ). in contrast, when treatment was initiated after h the number of bacteria did not change significantly, and the reduction in inflammatory cytokine response became significant for both late isolates only at day three of treatment (p< . ). moreover, cytokine levels were significantly lower in the h as compared to the h group (p< . ) confirming the importance of early and aggressive antibiotic treatment in cf. non-mucoid isolates were reduced during the first three days of infection independent of treatment. in conclusion, we have implemented a clinical important cf-time perspective (years) in experimental p. aeruginosa lung infection, useful for patho-physiological and treatment studies. cystic fibrosis (cf) is a complex disease that affects multiple organs and results in a wide range of phenotypes in humans. mouse models of cf display many of the phenotypes observed in human patients and provide necessary tools to dissect this multifaceted disease. however, due to the involvement of cftr in various organ systems, the ability to discern the contribution of each organ system to each phenotype of cf is unknown. for example, we have found that mouse growth is dramatically reduced compared to wildtype, and mechanisms ranging from neuroendocrine disruption, intestinal malabsorption and cacchexia have been proposed. we have found that cf mice consume more calories per gram body weight than non-cf mice and intestinal absorption of dietary lipids is similar between the two. cf animals absorb % and non-cf % (p > . ). to identify the source of the growth deficit, it would be advantageous to restrict expression of cftr in specific tissues to determine each tissue's contribution to the phenotype. to accomplish this, we have created a conditional, null murine cftr allele. a conditional null allele is one in which the gene of interest is induced to be non-functional in either a specific tissue or cell type, or at a specific developmental time. examination of cftr absence on a tissue-by-tissue basis will greatly facilitate our understanding of the disease. the conditional cftr allele was created by "floxing" exon of cftr, known to be critical for function, with flanking loxp sites that allow for the deletion of exon when bacterial recombinase cre is present. to date, mice stably transmitting the floxed allele have been created. these founder mice have been crossed with mice expressing cre from the promoter of the villin gene, which restricts transcription of cre to intestinal epithelium. first generation animals show appropriate recombination and deletion of exon in the gut. however, these first generation animals are heterozygous for the floxed allele. we are currently backcrossing these animals with the founders to generate animals with homozygous deletion of cftr in the intestinal epithelium. similar crosses are planned to target other tissues. this new animal model of cf will be available to the cf research community to further our understanding of cf pathophysiology. this work was supported by a grant from the cf foundation increased enac-mediated na+ absorption is a hallmark of cystic fibrosis (cf) airways. we demonstrated that mimicking na+ hyperabsorption by overexpression of βenac in mouse airways results in airway surface liquid (asl) depletion and reduced mucus clearance causing a spontaneous cflike lung disease with high pulmonary mortality, and airway mucus obstruction, mucous cell metaplasia and chronic airway inflammation in adult survivors (mall et al., nature med. : , ) . the aim of this study was to identify the initiating lesions and investigate the natural history of lung disease caused by asl depletion in βenac overexpressing (βenac-tg) mice. to achieve this goal, we performed longitudinal studies on lung morphology, airway mucus obstruction, bronchoalveolar lavage inflammatory cell counts, expression levels of mucins (muc ac, muc b, muc ) and proinflammatory cytokines (tnfα, kc, ifnγ, il- , eotaxin- ), lung volume, lung mechanics, and airway na+ transport in neonatal to adult βenac-tg mice and wild-type littermate controls. we show that airway mucus obstruction in βenac-tg mice originated in the trachea in the absence of mucous cell metaplasia in the first days of life, and was associated with hypoxic degeneration and necrosis of airway epithelium, and death. in surviving βenac-tg mice, mucus obstruction extended into the lungs and was accompanied by secondary mucous cell metaplasia, increased expression of muc ac, muc b and muc , and airway inflammation with transient increases in macrophages and tnfα, in eosinophils and il- , and persistent increases in neutrophils and kc in the lung. βenac-tg mice also developed emphysema with increased lung volumes, distal airspace enlargement, and increased lung compliance. several disease surrogate markers waned in parallel with βenac transcript levels and airway na+ absorption in adult βenac-tg mice indicating that the level of enac overexpression was critical in determining disease severity. in summary, our results provide several novel insights into the in vivo pathogenesis of lung disease caused by asl depletion. we show that (i) asl depletion is sufficient to initiate severe airway mucus obstruction in the absence of mucous cell metaplasia and/or mucus hypersecretion; and (ii) airway na+ hyperabsorption and mucus plugging-induced hypoxia is associated with airway epithelial necrosis constituting a mechanism that initiates airway inflammation in the absence of infection. further, our results point to a novel link between airway na+ hyperabsorption, eosinophilic inflammation, and emphysema. the high frequency of allergic airway inflammation and emphysema in cf patients warrants further studies of the mechanisms that link asl depletion with these associated pathologies. the balance of airway surface liquid (asl) at a height compatible with efficient clearance of mucus is a process regulated by two main pathways: the secretion of clvia cftr, and absorption of na + via the epithelial na + channel (enac). to study this interplay, an immortal cell line capable of growing at an air liquid interface and having properties of human bronchiolar epithelium would be desirable for its simplicity in preparation and ease of molecular manipulation. an immortal human bronchial adenocarcinoma cell line (hbac) was infected with a lcfsn retrovirus carrying either cftr cdna (hbac cftr ) or the blank vector (hbac mock ). - day monolayers, grown on transwell clear membranes, were mounted in ussing chambers and studied under open-circuit conditions. to study regulation of clsecretion, the equivalent short circuit current was calculated in the presence of amiloride (apical, µm). in hbac mock cells, forskolin ( µm, basolateral) had no effect upon i sc . in contrast, hbac cftr cells demonstrated a robust increase in i sc ; a rapid increase to a peak (∆~ µa cm ), followed by relaxation to a stable and sustained plateau. genistein ( µm) also stimulated i sc in hbac cftr (∆i sc µa cm ) but not hbac mock cells. amiloride resistant basal current was consistently higher, by - µa cm , in hbac cftr versus hbac mock cells, presumably reflecting low basal cftr activity. we next examined the ability of endogenous receptors present in hbacs to regulate transfected cftr. stimulation of i sc in response to apical adenosine ( µm) in hbac cftr was qualitatively and quantatively similar to the forskolin response. while the above experiments provided evidence to suggest that hbac cftr cells possess the bioelectric capability of sustaining anion transport via nucleoside-stimulated cftr activity, it does not guarantee a resultant vectorial flow of fluid. in the final series of experiments, we examined whether adenosine was indeed able to stimulate secretion across the hbac-cftr monolayer by assaying asl height. monolayers were loaded apically with fitc-labeled dextran ( µl), and the majority of dye was then aspirated. monolayers were then allowed to equilibrate over a hour period, and asl measured by xz scanning on a leica confocal microscope. ~ µm adenosine and ~ µm benzamil was then added apically in pfc and asl height measured after and minutes. in both hbac mock and hbac-cftr cells, the basal asl height was ~ µm. over minutes asl height of hbac mock cells did not change in response to adenosine. in contrast, adenosine stimulated hbac cftr cells demonstrated a doubling of asl height (to µm) over the same period. this response is consistent with the prolonged increase in i sc observed upon stimulation with adenosine. in summary, the hbac model which displays only absorptive currents endogenously, can be transformed into a cell line in which cftr-mediated secretion can be stimulated and sustained by endogenous receptor systems present in the apical membrane. this new model will allow us to study cftr-mediated fluid transport in a defined manipulatable system. despite the identification of the cftr channel more than years ago, many questions remain about its regulation and in vivo function. in order to better understand how cftr functions in vivo, numerous studies have searched for and identified potential interacting partners but to date, there is little evidence linking any of the known cftr interactors to its activity. during a forward genetic screen in zebrafish, aiming to identify genes regulating endodermal organ development, we identified a mutant, which we named baobab (bao), after the african tree that accumulates water during the wet season, which exhibits a dramatically enlarged fluid-filled gut tube. most interestingly, we have shown that various cftr inhibitors reduced the appearance of enlarged guts in bao mutant embryos, suggesting that the fluid accumulation phenotype resulted from an increase in cftr activity. to test whether increased cftr activity resulted from changes in cftr protein levels or localization we raised antibodies against zebrafish cftr. western-blot and immunolocalization studies revealed that the channel was expressed and localized as in wild type in bao mutant embryos indicating that the increased cftr function most likely resulted from the activation of the channel. these data, together with the recessive character of the mutation, suggest that the bao protein is a negative regulator of cftr activity. we have positionally cloned the bao locus and isolated the affected gene. bao encodes a cytosolic protein that has not been previously shown to regulate cftr. in agreement with the pharmacological data pointing to a gut-specific function of bao, in situ hybridization studies showed that bao is higly expressed in gut. we are currently investigating how the bao protein regulates cftr function. in addition, we are also investigating the function of cftr during zebrafish development. these studies lay the groundwork to take advantage of the zebrafish system to further investigate cftr biology. we establish a genetic model system for studying the regulation of the cftr channel that will contribute to the understanding of the pathophysiology of cystic fibrosis and several intestinal secretory conditions. acknowledegements: this work was supported by an embo long-term postdoctoral fellowship to mb and by nih grants to d.y.r.s.. we thank a. verkman for providing cftr inhibitors and k. brand for technical assistance. the trachea of the adult cf mouse (cftr tm unc or cftr tm kth ) expresses little cftr and exhibits neither a defect in camp-mediated clsecretion nor hyperabsorption of na + , both signature abnormalities in human cf airways. we generated a mouse exhibiting hyperabsorption of na + in the airways by over-expressing the β subunit of the epithelial na + channel (βenac, gene scnn b). βenac mice exhibit airway pathology (decreased mucociliary transport, mucus plugging, and airway inflammation) similar to human cf airways. to determine whether inactivation of cftr in βenac mice results in a more severe phenotype, we generated a cf/βenac mouse by crossing the ∆f (c bl/ n) mouse (cf mouse) with the βenac mouse (c bl/ n). survival analysis showed a drastic reduction in survival for cf/βenac mice in comparison to cf mice or βenac mice. we studied the airway bioelectrics of day-old pups of each genotype. the basal short circuit current (i sc ) was ~ fold greater in wild-type (wt) ( ± µa . cm - ; mean ± sem, n= ) vs. cf ( . µa . cm - , n= ) neonatal tracheas. as previously reported, the basal i sc in βenac preps was significantly elevated ( . ± µa . cm - , n= ) vs. wt tracheas. however, the basal i sc in the cf/βenac tracheas ( . ± µa . cm - , n= ) was intermediate between the cf and the βenac tracheas. the amiloride-sensitive i sc was elevated similarly in the tracheas of the βenac and cf/βenac pups and was ~ x greater than that exhibited by the wt or cf tracheas. the post-amiloride i sc was strikingly reduced in both cf and cf/βenac tracheas compared to the wt and βenac tracheas. we suggest that the post-amiloride i sc reflects constitutive cftr-mediated clsecretion, which may help hydrate airways in the neonate. unlike the tracheas of adult cf mice, neonatal cf tracheas exhibited the classic defect in camp-mediated clsecretion, with the forskolin response in the cf and cf/βenac tracheas being reduced ~ fold compared to the response in the wt or βenac preps. the response to utp (ca ++ -mediated clsecretion) was similar in the four genotypes. absence of cftr-mediated clsecretion does not appear to cause airway pathology in neonatal cf mice, but when this defect is coupled with na + hyperabsorption, it results in a significant increase in neonatal mortality. due to lack of cftr-mediated clsecretion, cf/βenac mice appear to experience greater mucus adhesion, producing death due to asphyxiation. in addition, the tracheas of cf mice (especially congenic c bl/ n) often appear constricted or collapsed due to a cartilaginous defect resulting in increased compliance. this anatomical defect does not appear to be detrimental to the cf mouse. however, in cf/βenac pups, that accumulate thick, sticky mucus in their tracheas, this tracheal constriction may contribute to their asphyxiation. these results demonstrate the importance of both abnormal na + absorption and decreased clsecretion in the pathogenesis of cf lung disease. supported by nih scor p hl . recently, we reported that species-specific differences in the airway biology of raav transduction exist between mice and human (am j respir cell mol biol, , : - ) . these differences significantly interfere with the use of mice as surrogate models for human lung gene therapy with certain raav serotypes. to survey which species might be an optimal animal model for raav preclinical testing, we utilized differentiated airway epithelia grown at an air-liquid interface (ali) from five species (human, non-human primate [nhp] , pig, ferret, and mouse) to test the efficiency of transduction with three serotypes of raav (type , , and ). our results demonstrated significant species-specific differences in raav transduction biology in airway epithelia. the serotype preferences of raav transduction from the apical membrane in human, ferret, and pig epithelia was raav >raav ≈raav , different from that seen in mouse epithelia (raav >>raav >>raav ). surprisingly, the profile of raav transduction with these three serotypes in nhp rhesus monkey airway epithelia (raav ≈raav >>raav ) was less similar to human than pig and ferret. additionally, raav lacked a bias in polarity of transduction in human airway epithelia, however, in nhp epithelia, raav transduced the basolateral membrane -fold more effectively than the apical membrane. furthermore, differences in the properties of raav receptors between these species was also seen. using neuraminidase treatment of the apical surface of ali cultures, we tested whether n-linked sialic acids were potential receptors for raav binding and/or transduction. these studies demonstrated removal of n-linked sialic acids inhibited raav transduction of human, nhp, and mouse airway epithelia, but not ferret and pig. however, raav binding in this setting did not correlate with changes in transduction; neuraminidase treatment dramatically reduced raav binding to nhp epithelia, but enhanced binding to human epithelia (~ fold). these findings suggest viral binding to airway epithelial cells may not be a major barrier for raav transduction. evidence that proteasome-modulating agents enhancing raav transduction - logs for all serotypes and species tested, suggest that the ubiquitin/proteasome pathway represents a common intracellular block in raav transduction of airway epithelia. these findings support the notion that viral interactions at the surface of airway epithelial cells (with co-receptors and receptors) influence intracellular processing aav virions that can alter the efficiency of productive transduction. enac surface density in cortical collecting duct (ccd) epithelial cells is established by camp/pka regulated insertion and retrieval of the channel at the apical membrane, together with the recycling of internalized enac back to the apical surface (butterworth et al. ( ) journal of general physiology : - ). ubiquitination by the nedd - ligase elicits endocytosis of surface enac, which may lead to its degradation. however, enac recycling to the apical surface requires ubiquitin removal by a deubiquitinating enzyme (dub). using a chemical probe approach, we identified ubiquitin carboxy-terminal hydrolase (uch-l ) as the predominant dub in vesicular endocytic and recycling compartments in mouse ccd epithelia. specific inhibition of uch-l ( µm of , , , -tetrachloroindan- , -dione) in filter-cultured ccd cells resulted in a rapid decline in enac currents, which was accelerated by forskolin stimulation, suggesting that uch is responsible for recycling enac to the apical surface. knockdown of uch-l significantly reduced both basal and camp-stimulated enac currents (from . ± . µa/cm in control sirna treated to . ± . µa/cm in uch-l knockdown cells). to determine whether the same dub was responsible for the regulation of enac in human bronchial epithelial (hbe) airway cells, differentiated cultures derived from cf and non-cf lung tissue were treated with the uch inhibitor. to address the possibility that protease cleaved enac may be regulated differently from unprocessed channels, differentiated hbe cultures were either maintained at air/liquid interface or were submerged under liquid/liquid conditions to alter the cleavage state of enac, as we have previously described (myerburg et al. ( ) journal of biological chemistry : - ). in all cases, no significant difference in enac-mediated na+ transport was observed between control and uch-l inhibited conditions. these data are in sharp contrast with the mechanisms of enac regulation observed in the ccd model system, and they support our previous findings that enac turnover and mode of regulation in hbe are distinct from the recycling mechanisms defined in the ccd epithelia (butterworth et al. primary human tracheobronchial epithelial (htbe) cells cultured at an air-liquid interface (ali) regulate ion transport, mucin secretion, and cilia beating to recapitulate directional mucus clearance, a key innate defense mechanism that fails in cystic fibrosis (cf). thus, ali htbe cell cultures are crucial for studying cf pathogenesis and for developing/validating novel therapies. different research centers use alternative protocols that enable reproducible creation of ali htbe cell cultures. however, limited primary htbe cell availability has driven the creation of cognate cell lines, accomplished mainly by the introduction of viral oncogenes. viral oncogenes disrupt normal cell physiology causing cellular hyperplasia, abundant apoptosis, genomic instability and, sometimes, poor polarization/differentiation, rendering the cells less useful than primary cells for assessing cftr function. furthermore, genetically unstable cell lines will continuously acquire changes independent of cftr genotype. bmi- is a polycomb group protein that controls cell cycle and cell identity via epigenetic regulation of chromatin, maintaining stem cells by suppressing expression of p , an inhibitor of cyclin dependent kinases. bmi- expression has been used to create cell lines that recapitulate normal cell structure and function better than viral oncogene-immortalized cell lines. using hiv lentiviral vectors, we introduced bmi- and the catalytic subunit of telomerase to enhance the growth of different ∆f homozygous cf and non-cf primary human airway epithelial cell preparations. all new cell lines grew for at least population doublings, while their normal counterparts senesced prior to a maximum of doublings. at passage - , the new cell lines had a diploid karyotype compared to grossly abnormal chromosomes in cells immortalized by viral oncogenes. ussing chamber analysis of ali cultures at passage (p) - revealed variable transepithelial resistances among the cell lines ranging from -> Ω*cm , but short circuit current (isc) responses stimulated by forskolin and inhibited by cftr were true to the cell's genotype and comparable to early passage primary cells, except for one non-cf cell line with relatively low cftr isc's at p . amiloride sensitive and utp-stimulated isc's were present but were more variable in magnitude in comparison to the currents observed in low passage primary cells. ali cultures exhibited a pseudostratified morphology with prominent apical membrane polarization, few apoptotic bodies, numerous mucous secretory cells and occasional ciliated cells. all cf and non-cf cell lines in culture produced similar levels of il- at baseline and cf and non-cf cells equally increased il- secretion in response to il- β, tnfα and the tolllike receptor agonist, pam cys. these novel cell lines will help fill gaps currently hindering cf research and therapeutic development. supported by cystic fibrosis foundation grant randel g . we recently considered that domestic dogs could represent a large natural reservoir to search for cftr mutations and, ultimately, to identify and breed animals with cf traits. the canine genome has been completely sequenced, and the canine cftr gene, found on chromosome , consists of exons spread over kb. an animal model that faithfully expresses human cf lung pathology is critical for the development of effective treatments for this most lethal aspect of cf disease. while transgenic mouse models of cf replicate numerous aspects of cf disease, they unfortunately do not develop the characteristic lung pathology including mucus plugging of airways, chronic bacterial infections, and bronchiectasis. the reason for this is not completely understood but it is likely related to significant differences in lung morphology between these species. to date, no non-murine genetic model of cf has been developed, and naturally-occurring, cf-causing mutations have not been identified in any non-human animal species. temporal temperature gradient gel electrophoresis (ttge), developed as a screening tool to identify sequence variations and mutations in the human cftr gene, was used to screen dogs for cftr mutations. dna was purified from whole blood received from veterinary clinics treating dogs for a variety of ailments. we have performed ttge analysis on dna from dogs, which includes dogs with pancreatitis and dogs with bronchiec-tasis, and have found hundreds of potential mutations amongst the thousands of amplicons tested. ttge can detect single base pair changes within a fragment of dna. as the temperature increases, the migrating dna becomes partially melted, creating single stranded regions (internal bubbles and branched ends) that decrease its mobility through the gel. the dna fragments have distinct melting profiles that are sequence dependent; therefore, changes in sequence of even a point mutation can alter the profile and result in a change in the rate of migration through the gel that can distinguish wild type from even a homozygous mutant. thus far exonic mutations have been sequenced but none have caused changes to cftr at the amino acid level (i.e., the mutations have all been silent). we conclude that ttge is a sensitive and effective method for screening large canine populations for cftr mutations. ( introduction: the search for "correctors" of defective protein processing of ∆f cftr has led to the development of high throughput screening assays to find compounds that promote the surface activity of the mutant protein. by necessity, primary screening assays typically use cell lines expressing recombinant ∆f cftr. however, "hits" identified in primary screening require scrutiny for false positives whose activity is either dependent on the ∆f cftr expression system or insufficiently robust to correct processing in the complex physiological setting of a native epithelium. to this end, we have developed a secondary functional assay that measures the shortcircuit current (isc) responses in organ cultures of gallbladder mucosa from ∆f cftr mice (cftr tm kth ). previous studies have shown that murine ∆f cftr recapitulates the protein processing defect including the capability to increase processing when mucosa is incubated at reduced temperature ( °c) (j. clin. invest. : invest. : , . gallbladder mucosa was chosen for this assay because the murine gallbladder can be removed aseptically for organ culture, the epithelium is essentially a monolayer, and the mucosal wall is transparent which facilitates morphological assessment. methods: using either wild-type (wt), ∆f cftr (df) mutant or cftr knockout (cftr ko) mice, excised gallbladders were opened longitudinally, rinsed and positioned on loose nylon mesh. the preparation was mounted between two halves of a polycarbonate culture cup with . mm aperture and placed in submersion culture for - days at either °c or °c using supplemented ham's f medium mixed : with nih t fibroblast-conditioned dmem containing % calf serum. after incubation, the culture cups were placed in custom designed ussing chambers for measurement of isc responses to a cocktail of µm forskolin and µm ibmx (camp isc) at °c. contribution of calcium-activated clchannels to the camp isc was eliminated by addition of the distilbene dids ( µm) to the luminal bath. results: the mean ∆camp isc responses (in µa/cm ) after two days incubation were as follows: wt at °c = . ± . (n = ); df at °c = . ± . (n = ); df at °c = . ± . (n = ); and cftr ko at °c = . ± . (n = ). in a pairwise comparison, the wt ( °c) was significantly greater than the df ( °c) and cftr ko ( °c) but not significantly different from df ( °c). conclusions: incubation of ∆f cftr mutant murine gallbladder mucosa at °c for two days in organ culture restored approximately % of the cftr-dependent isc responses to camp stimulation. the temperature-dependent effect is consistent with correction of murine ∆f cftr processing, indicating a physiological screening assay that is useful for preclinical testing of candidate drugs targeted at correcting the protein processing defect of ∆f cftr. supported by cfft and nih. the lack of a large animal model that replicates the lung disease found in humans with cystic fibrosis is a major impediment to understanding disease pathogenesis and the development of effective therapies. although cystic fibrosis is a multi-system disease, airway infection and inflammation currently cause most of the morbidity and mortality in patients. several homozygote null and missense cftr mutations have been developed in mice, but they do not exhibit the lung phenotype observed in humans. in contrast to mice, the structure and physiology of porcine lung and airways closely resemble those of humans. therefore, the goal of this project is to develop a swine model for cystic fibrosis by combining gene targeting and nuclear transfer to produce a pig with a cftr null genotype. we employed homologous recombination to disrupt exon of pig cftr with a neomycin resistance cassette. we generated primary male fetal fibroblasts that were positive for cftr-targeting at one allele as detected by multiple pcr screens. genomic southern blot analysis confirmed proper gene targeting and revealed most clones were free of random integration events. these cells were used for somatic cell nuclear transfer that resulted in the birth of ten cftr null heterozygote piglets. subsequent breeding of these male pigs to wild-type females has yielded at least female cftr null heterozygotes. breeding male and female heterozygotes will provide cftrnull homozygotes. our recent published and preliminary studies demonstrate that mouse slc a , a newly discovered member of slc family of anion exchangers, is expressed on the apical membrane of tracheal epithelial cells and gastric surface epithelial cells and in the tubulovesicle membranes of gastric parietal cells. the functional properties of mouse slc a were examined in xenopus oocytes and in stably transfected cultured cells. in xenopus oocytes injected with the slc a crna and studied with the voltage and/or ph sensitive microelectrodes, the rank order for anion selectivity at + mv was cl->i-> no ->gluconate > sulfate, and that of the selectivity (px/pcl) was i-> cl-> no -= gluconate > sulfate. inhibitor profile studies demonstrated that nppb at µm inhibited the current at min by % (p< . compared to control period, n= ). the effect of nppb was partly reversible. dids at µm had no significant effect on the slc a -mediated current (p> . compared to control period, n= ). niflumic acid at µm inhibited the current at min by ~ % (p< . compared to control period, n= ) which was partly reversible. cftr inh at µm inhibited the current at min by ~ % (p< . compared to control period, n= ) which was reversible. clamping currents in a mm k-gluconate medium and using mm k-cl or k-bicarbonate revealed very low bicarbonate conductance for slc a compared to that of cl-. no significant phi changes were observed in oocytes when favoring cl-exit by substituting perfusate cl-with gluconate in the presence of co /hco -. conversely we observed significant alkalinization in ae -expressing oocytes in the same experimental solutions. interestingly, in hek cells stably transfected with the mouse slc a , a significant intracellular alkalinization was observed upon switching to a chloride-free perfusate. the alkalization in slc a -expressing cells was inhibited by ~ % in the presence of µm dids. baseline intracellular ph was significantly increased in slc a expressing hek cells vs. non transfected cells. however, baseline phi was comparable in control and slc a -expressing cells in the presence of µm eipa, indicating the activation of endogenous nhe by slc a . in conclusion, slc a displays characteristics of an anionic channel in xenopus oocytes, with low bicarbonate permeability. in mammalian expression systems, slc a can also function in cl-/hco -exchange mode with moderate sensitivity to inhibition by dids. we propose that slc a plays an important role in anion (chloride) secretion and/or ph regulation in tracheal and gastric epithelial cells. no cell lines exist at present that robustly express endogenous wt and ∆f cftr on the same genetic background. zinc finger nucleases (zfns) allow the introduction of specific genetic changes at loci within the human genome (nature : [ ] [ ] [ ] [ ] [ ] [ ] ) . we have been using this technology in an attempt to generate human cells carrying the major cf-causing genotype -∆f -at the endogenous cftr locus. such lines could be expected to provide better understanding of the ∆f maturational processing defect, as well as new model systems for cell based assays of ∆f repair. we performed a bioinformatic analysis of cftr exon , and designed multiple distinct zfns against the ∆f dna sequence. all of these nucleases were assembled, cloned into mammalian expression vectors, and assayed for dna binding affinity and specificity. the zfns were then assayed for endogenous cftr locus editing in calu- and ht- cells using a novel, massively parallel methodology applied for the detection of genome editing events. the effort demonstrated that specific zfn pairs successfully bind to, and cleave, within exon of the endogenous cftr locus in both cell types. we will describe experiments that yielded optimized zfns for the cftr locus, and a robust viral platform to transiently deliver genome editing reagents to the human pulmonary cell line, calu- . supported by cff. the localization of slc anion transporters, as well as their function vary among members. some (slc a , slc a , slc a , slc a ) are widespread, implying specific physiological function in diverse tissues. others are expressed only in a single epithelia, e.g., slc a (prestin) in the inner ear. we have previously found that slc a is a highly electrogenic cl --hco exchanger with a large anion conductance. to determine the possible physiologic roles of slc a , we developed a chicken antibody (designed against sulfate transporter and anti-sigma domain, stas, of slc a ) to localize the protein. to test the antibody specificity for functional protein, we inject xenopus oocytes with crna for slc a , slc a or slc a and documented appropriate ph and membrane potential changes. only oocytes functionally expressing slc a were stained using our primary slc a antibody. further, specific staining was eliminated when either pre-immune serum or blocking peptide was used. slc a was only found in epithelia. in the respiratory system, slc a was in the apical membrane of nasal epithelial cells and tracheal submucosal glands. membranes of calu- cells, derived from human tracheal submucosal glands, stained indicating that our antibody also recognizes the human slc a protein. slc a is found in the proximal parts of the gastrointestinal tract (esophagus, stomach), with lesser amounts in the small intestine and colon. however, slc a is not present in liver. slc a is present in ducts of secretory epithelia such as salivary glands and pancreas. in the urinary tract, slc a is localized to the renal proximal tubule apical membrane but not in urinary bladder. in the reproductive system, we found slc a in epithelia of the uterus and seminal vesicles but not the vas deference or the prostate. finally, slc a is found on the eye surface, i.e., corneal epithelial cells. together, these results and the varied slc a physiology suggest that several epithelial function models will need to be re-evaluated to incorporate an electrogenic cl --hco exchanger and/or another apical anion channel. (support: romero- g , sindic- f ). a tgfβ- polymorphism modifies severity of cystic fibrosis lung disease in the setting of ∆f cftr homozygosity (drumm et al., nejm, ) . the mechanism(s) underlying this observation, and whether elevated or repressed tgfβ are responsible, are not known. in addition, the pathogenic role of tgfβ in other cf organs and in murine models of the disease has not been well studied. because the tgfβ codon cc genotype is associated with worsened cf pulmonary prognosis, and since high levels of tgfβ are also known to suppress cftr mrna expression and apical cftr protein expression in colonic epithelia (howe et al., exp cell res, ) , we developed a mouse model to test tgfβ/cftr interactions that may directly influence cf phenotype. we bred ∆f heterozygous mice (cftr tm kth , ∆f cftr) against the tgfβ receptor-deficient murine strain (mtrii ). mtrii mice express a dominant-negative mutant form of the tgfβ type ii receptor which lacks the intracellular (kinase) receptor domain. the receptor binds tgfβ, but fails to transmit a tgfβ dependent signal. the tgfβ receptor transgene was inserted downstream of a metallothionein-derived promoter and expressed in numerous murine tissues following induction with mm znso in drinking water. an antibody raised against active tgfβ (lc- - - , gift of dr. kathy flanders, national cancer institute) was used to establish tgfβ in murine tissues including lung and intestinal tract of the mtrii strain. rt-pcr confirmed high level transgene expression similar to gapdh internal control. nasal potential difference measurements in cftr +/+ mice expressing the tgfβ transgene indicated intact camp dependent cltransport following induction of the dominant-negative receptor. homozygous cf animals deficient for tgfβ signaling have recently been obtained and exhibit the expected litter sizes and distribution of the ∆f allele. studies of cf homozygous mice following induction with znso are in progress, and will be used to determine whether a failure to signal through tgfβ in vivo ) influences the severity of cf intestinal disease, ) alters airway or intestinal bioelectric findings characteristic of cf, or ) changes survival, histopathology or other features of the disease. these experiments are intended to provide an in vivo means of investigating tgfβ signaling and resultant cf modifier effects in vivo. supported by nih and cff. objective: to determine if the abpa phenotype observed in cftr mice was preventable by corrective gene replacement, we delivered aav cftr to the lung. in addition to further assess whether cftr-/-lymphocytes alone where responsible for the phenotype, we performed adoptive transfers of cftr-/-lymphocytes into cftr+/+ mice and proceeded to expose the mice to the abpa model. design/methods: cftr-/-mice underwent it administration of raav cftr or raav gfp. all mice were then sensitized with ug of crude af antigen via intraperitoneal route. non-injected mice were sensitized without prior virus exposure. challenges were performed on all mice, using an af solution delivered by aerosol inhalation in a closed chamber on consecutive days. serum ige levels were then obtained, as well as bronchoalveolar lavage fluid for differential cell counts, histologic and cytokine analysis. adoptive transfer experiments were done using spleens cells isolated from af sensitized delaf -/-and f +/+ mice and transfer into c /bl _rag-/-mice. after weeks post transfer c /bl _rag-/-mice with f -/-and f +/+ lymphocytes were then challenged with af. results: following challenge with af, raav -cftr mice had significantly lower total serum ige levels ( , ) as compared to raav -gfp controls ( , ) (p= . ). analysis of af-specific ige also revealed a two-fold reduction in the mice receiving the corrective gene therapy. curiously, gene transfer to the lung lowered the secretion of inflammatory cytokines from activated splenocytes of raav -cftr when compared to raav -gfp controls. these results suggest that correction of immune cells in the lung that traffic to the spleen may be partially responsible for the attenuation of the phenotype. in addition the transfer experiments showed that the hyper-ige syndrome can be partially transferred into b rag-/-by f -/-splenocytes. conclusions: correction of cftr deficiency by aav lung transfer attenuates the inflammatory phenotype associated with abpa. epithelial cells lining the vas deferens express cyclooxygenase (cox) when exposed to testosterone in vivo, although no functional link to ion transport has been established. we hypothesized that testosterone modulates cftr-mediated anion secretion across vas deferens epithelia that is stimulated via cox-dependent pathways. vas deferens epithelial cells were isolated from human and porcine tissues and cultured as monolayers on permeable supports until assayed in modified ussing chambers. rna was isolated concurrently for semi-quantitative gene expression analysis. bradykinin (bk) caused an increase in anion secretion (measured as short circuit current) and this effect was inhibited by indomethacin, which indicates cox dependency. testosterone treated monolayers exhibited a bkinduced response that is % greater than paired vehicle treated monolayers. qrt-pcr revealed that cox- mrna is times more abundant than cox- mrna in cultured vas deferens epithelial cells. the effects of bk on ion transport are inhibited by the b receptor antagonist hoe while the b receptor agonist des-arg -bk produced no effect. prostaglandin e and selective agonists of the ep ( -oh-pge ) and ep (butaprost) receptors produced concentration dependent increases in short circuit current whereas sulprostone, an agonist of ep and ep receptors, had no effect. taken together, these results suggest that testosterone plays a key permissive role for bk-stimulated anion secretion by inducing cox- expression. bradykinin acts at the b receptor to increase cox- activity and the synthesis of prostaglandins that ultimately bind to ep receptors to promote cftr-dependent hco -and cl-secretion that would be expected to modify the environment for sperm. the results further suggest that developmentally associated increases in testosterone levels during gestation and puberty will produce physiological changes in vas deferens luminal environment that are likely compromised in cystic fibrosis patients. supported by cystic fibrosis foundation schult po and ksu cobre nih rr- . background: recent studies in cystic fibrosis (cf) suggest a prominent t h profile; a facet that may interfere with normal bacterial clearance. this phenotype appears to increase secondary to infection with aspergillus fumigatus or pseudomonas aeruginosa and also, may interfere with macrophage activation. these same characteristics are present in cftr-deficient mice (cftr s x -/-fabp-hcftr (+/+), hereafter designated cf mice). as a study of pathogenesis of cf related diabetes (cfrd), we previously observed increased il- and splenocyte proliferation in cf mice subject to streptozotocin-induced hyperglycemia. herein, we hypothesized that differences in glucose concentration would increase t h profiles of splenocytes in vitro. methods: cf mice and c bl/ j mice (b mice; n= /group) were sacrificed at wk of age. splenocytes were collected and cultured at the following glucose concentrations: , , and mm. each mouse and glucose concentration was stimulated with cona, lps and cd /cd . supernatants were collected at hr and measured by luminex analysis. statistical analysis was performed by a one-way anova. results: stimulation by cona produced increased levels of il- , il- , tnf-a, gm-csf and il- in splenocytes of cf mice (p< . for all). stimulation by lps produced decreased concentrations of il- in cf mice(p< . ). stimulation of cf mice by cd /cd produced decreased concentrations of il- (p< . ). interestingly, no difference was observed in cytokine elaboration as a function of glucose concentration. data are presented in table as fold increase of cytokine concentration for cf mice compared to b mice. discussion: profound differences in cytokine production were measured in stimulated splenocyte responses of cf in comparison to b mice. the profiles did support the notion for a prominent t h response, with the potential to interference of normal macrophage activation. in addition, differences in cytokine production profiles appear related to the nature of adaptive and innate stimuli provided (cona vs. lps). the absence of influence by glucose concentration in vitro suggests that local/immediate concentration of glucose is not relevant to prolonged expression of cytokine responses to stimuli. further studies on the impact of chronic hyperglycemia and its relation to immune response are necessary. an improved understanding of these mechanisms holds hope for a better overall outcome in patients with cf and cfrd. studies from different laboratories to characterize ∆f cftr clchannel activity have yielded disparate results, likely due to variations in technique, cell type, or method of analysis. in the present study, we compared ∆f cftr activation in two well characterized polarizing cell models. fisher rat thyroid (frt) cells have been used in high-throughput drug screening to identify ∆f cftr active agents, whereas cfbe ocells have been transduced to provide robust ∆f cftr expression in an airway epithelial background. ∆f cftr biogenesis following low temperature correction was compared, indicating qualitatively similar levels of cftr transcripts and band b and c cftr. in paired studies in ussing chambers, distinct differences in isc were seen following exposure to cftr activating stimuli. in frt cell monolayers grown at °c, forskolin ( µm) or genistein ( µm) were strong stimuli of isc, producing mean isc of . +/- . (forskolin) and . +/- . (genistein) µa/cm . regardless of exposure sequence, both agents induced equivalent changes in maximal current ( % of . µa/cm by forskolin when administered prior to genistein; % of . µa/cm by forskolin in converse order). growth at °c for hours increased currents approximately . fold, but relative contributions of the two stimuli were similar to cells grown at °c ( % of total current stimulated by forskolin). in cfbe o -∆f cells grown at °c, forskolin-dependant currents were minimal and genistein-stimulated currents small ( . +/- . µa/cm , compared to zero current in parental, nontransduced cfbe ocells, p< . ). in temperature-corrected ∆f cfbe ocells, forskolin was a poor stimulus of cl-transport relative to genistein, contributing % to the total current produced by both agents (p< . ). genistein-stimulated currents did not require pre-treatment with forskolin to produce maximal effects ( . µa/cm with genistein alone vs. . µa/cm after forskolin and genistein), and forskolin did not cause further isc when added after genistein ( µa/cm ). levels of camp did not account for these differences, since forskolin markedly increased camp in both models. to determine whether excessive phosphodiesterase (pde) or phosphatase (pp) activity limited ∆f cftr activation by forskolin in the cfbe o -∆f cells, monolayers were pretreated with the nonspecific pde inhibitor papaverine ( µm) or the pp inhibitor endothall ( µm), each sufficient to activate isc in cfbe oexpressing wtcftr (papverine: . vs. . µa/cm with vehicle, p< . ; endothal: . vs. . ua/cm , p= . ). neither agent restored isc in ∆f cfbe oby forskolin ( . mv difference, p=ns). these results indicate that activity of ∆f cftr in polarizing monolayers is exquisitely dependant on the model chosen for study. substantial differences in ∆f cftr behavior in two commonly used cell models, and suggest that the failure of camp to activate ∆f cftr in cfbe ocells is due to cell-specific factors that may ) influence ∆f cftr folding and tertiary structure, or ) favor interactions of ∆f cftr with inhibitory binding partners that limit activation by camp. adverse immune responses to viral vectors or vector-encoded proteins may hinder the practical application of gene therapy. to date, little effort has been devoted to determining the immunological consequences of topically delivered lentiviral vectors to respiratory epithelia. previously, we demonstrated that an integrating feline immunodeficiency virus-based lentiviral vector pseudotyped with a baculoviral envelope glycoprotein (gp -fiv) readily transduced differentiated airway epithelia in vitro when applied to the apical surface. furthermore, using a luciferase reporter gene and bioluminescence imaging, we observed in vivo gene transfer to murine nasal epithelia following a single application of gp -fiv. longitudinal bioluminescence analysis documented persistent expression in nasal epithelia for greater than months without significant decline. by histological analysis, surface epithelial cells were transduced following a single nasal application of gp -fiv expressing beta-galactosidase. importantly, we observed that consecutive doses of gp -fiv delivered over consecutive days greatly increased the number of beta-galactosidase positive epithelial cells. using quantitative bioluminescent imaging, we observed that repeated doses given over consecutive days resulted in a linear additive increase in gene expression. in addition, we performed studies investigating gene transfer efficacy and immune responses following lentiviral vector readministration with greater intervening time periods. in control mice, we observed that giving nasally instilled doses ( weeks apart) of an e /e deleted ad vector resulted in significantly attenuated expression after the second dose. the attenuated expression correlated to the production of neutralizing antibodies. in contrast, using the same delivery protocol, doses of gp -fiv resulted in gene transfer without loss of expression of the forth dose. no significant production of neutralizing antibodies was observed following the lentiviral delivery protocol. we further report the additive increase in reporter gene expression following doses of lentiviral vector delivered over consecutive weeks ( dose/week), as well as the lack of production of systemic and local neutralizing antibodies. gp -fiv efficiently transduces and persistently expresses a transgene in respiratory epithelia and has the potential for repeat administration without eliciting adverse immune responses. these data have important implications for the application of lentiviral gene therapy to pulmonary diseases. uniform delivery of gene therapy vectors to all lung lobes is important for cf gene therapy. however, this important objective has not been achieved in large animals. to address this obstacle, we have developed an approach to specifically deliver vector into all lung lobes. in this strategy, an intracorporeal nebulizing catheter (aero-probe) is inserted into a bronchoscope to permit visual targeted aerosolization of vector specifically into each lung lobe. using this approach, ml of . % lpc (to transiently open tight junctions) containing x vp of hdad-k lacz was sequentially aerosolized into each of the six major lung lobes of a baboon. aerosolization was triggered by the ventilator upon inspiration at . ml/pulse at a rate of to pulses/min. halfway through the procedure a very slight, transient and fluctuating decrease in oxygen saturation of no more than % was noted that did not warrant supplemental oxygen. the entire procedure was otherwise uneventful and well tolerated with no clinical manifestations of toxicity. no changes in chest x-rays taken at h, h and at necropsy h post-vector were observed compared to baseline. x-gal staining of the lungs at h revealed extensive transduction of the epithelium in the large and small airways in all six major targeted lung lobes. x-gal histochemistry revealed substantial transduction that was exclusively restricted to the airway epithelial cells and submucosal glands, the target cells for cf gene therapy. assessment of the proximal major bronchi from each lung lobe revealed that~ % of the airway epithelial cells were transduced in the left upper lobe (lul), ≥ % were transduced in the lml, lll, rul, rml and rll, and~ % were transduced in the accessory lobe. approximately % of the airway epithelial cells in the tracheal sections examined were transduced. we also investigated the duration of pulmonary transgene expression. in these studies, we aerosolized a hdad expressing the baboon α-fetoprotein from the k promoter into the lungs of baboons. by measuring serum bafp levels, we found that pulmonary transgene expression from transduced airway epithelial cells can be detected for at least days post-vector. these results demonstrate for the first time that exceedingly high levels of transduction of the airway epithelial cells and submucosal glands throughout all lung lobes in a large animal can be achieved with negligible toxicity resulting in long term trangene expression and should pave the way towards successful clinical cf gene therapy. inefficient gene transfer after repeat administration of most viral vectors has limited their suitability for cf gene therapy. however, lentiviral vectors are reported to be less immunogenic. this property combined with their capacity to integrate into the genome of transduced cells and, therefore, allowing gene expression for the life-time of the cell (approximately months for airway epithelial cells and theoretically unlimited for stem cells) justify further investigation of these vectors for cf gene therapy. to ensure high transduction efficiency in the lung without the need for any pre-conditioning strategies we pseudotyped a simian immunodeficiency virus (sivagm)-based vector with the sendai virus f and hn proteins (f/hn-siv-gfp) and transduced mouse nasal epithelium ( x e tu/mouse). at this titre transduction efficiency along the nasal septum was up to % when measured and days after transduction (n= /time-point). the vast majority (approx. %) of gfp positive cells across all time-points were respiratory epithelial cells followed by neuronal and sustenticular cells (approx. %) in the olfactory epithelium. interestingly, we observed two types of duration patterns of gfp expression in mouse nose. in some mice the number of gfp positive cells decreased over time (day : ± cells/section, n= , day : ± cells/section, n= ). however, in other mice strong gfp expression persisted for up to days (day : ± cells/section, n= ), significantly longer than the proposed life-span of airway epithelial cells. in order to support the idea of f/hn-siv integration into nasal respiratory stem/progenitor cells we artificially induced cell division after siv vector transduction by damaging the nasal tissue with the detergent (polidocanol), which strips of the epithelium within a few hours, while retaining the basal cell layer. the epithelium completely regenerates over the course of a few days. seven and days after the vector transduction ( x e tu/mouse, n= ) the nasal tissue was perfused with % polidocanol ( µl/mouse) and gene expression was analyzed weeks after the last detergent treatment. gfp expression was detectable in various cell types of the regenerating epithelium including ciliated and basal cells. importantly, gfp-expressing cells were more clustered after polidocanol treatment, possibly indicating origination from a common progenitor. these data suggest that, f/hn-siv integration may have occurred into differentiated airway epithelial cells as well as into stem/progenitor cells involved in the regeneration of the airway epithelium. introduction: hypersecretion of mucus is a major cause of airway obstruction in cystic fibrosis, asthma and chronic bronchitis. though mucus is a complex, non-homogeneous mixture of secretions, one group of its constituents, the mucous glycoproteins or mucins, contributes greatly to the obstruction associated with airway diseases. currently, there are a limited number of therapeutic agents available for controlling mucin overproduction and hypersecretion. the objective of this study is to develop a sensitive, cost-effective technique for reliably quantifying total mucin concentration in a robust mucin-secreting cell line for use in high throughput screening of small molecule compounds with potential to inhibit mucin secretion. methods: an enzyme-linked lectin assay (ella) was adapted using a lectin from helix pomatia (hpa), which binds specifically to n-acetylgalactosamine residues. bovine sub-maxillary mucin was used for test development and later, as a mucin standard. the test sample was "sandwiched" between hpa pre-coated onto -well microtiter plates and biotinylated hpa lectin. the plate was developed with a fluorescent hrp substrate, and measured at nm using a standard fluorescence plate reader. using the ella, a number of carcinoma (hm , a , ls , nci-h ) and immortalized lung epithelial ( hbe, cfsme) cell lines were tested to determine their responsiveness to various secretagogues. preliminary experiments indicated that the nci-h cells, derived from a human mucoepidermoid lung carcinoma, were most suitable for adaptation to high throughput studies. nci-h cells were seeded into -plates at a density sufficient to produce confluence in approximately hours. then, individual wells were incubated for hour in either control or secretagogue-containing media. supernatants were collected and mucin concentration of individual wells was determined using the ella. results: optimization of the ella provided a sensitive calibration curve from ng/ml to . mg/ml. mucin secretory ratios (sr) were calculated by comparing mucin release from test and control wells. significant (p ≤ . ) secretory ratios were obtained following incubation with utp at µm ( . ± . ), vip at nm ( . ± . ), carbachol at . mm ( . ± . ), interleukin- β at ng/ml ( . ± . ) and heparin-binding egf-like growth factor at ng/ml ( . ± . ); all data expressed as sr ± sem, n = . histamine at µm did not result in significant mucin secretion. conclusion: a relatively simple and economical assay has been developed for high throughput screening of small molecules for detecting their effects on mucin secretion. cystic fibrosis (cf) is the most common lethal genetic disease in north america, where it occurs with a frequency of one in ~ live births. it is caused by mutations in the cystic fibrosis transmembrane conductance regulator (cftr) gene, the most common being the deletion of phenylalanine (delf ). the delf mutation causes a folding defect that inhibits maturation and trafficking to the plasma membrane, however the mutant still functions as a chloride ion channel when delivered to the plasma membrane, and partial rescue ( - %) may be sufficient to alleviate disease symptoms. thus cftr is an attractive target for the development of pharmaceutical therapies. we recently described a novel, cell-based assay for protein trafficking which directly monitors expression of delf cftr on the surface of baby hamster kidney (bhk) cells and is suitable for high throughput screening of small molecule libraries. in this study we have extended the approach to natural products by studying extracts derived from marine sponges that were collected from the coasts of indonesia and papua new guinea. sponges are a particularly rich source of novel bioactives and secondary metabolites. iterative use of our high throughput assay and chemical deconvolution of active fractions yielded four alkaloids jmcg , jmcg , jmcg and jmcg . these compounds caused a detectable increase in delf cftr trafficking to the plasma membrane within h, and after exposure to pm for h all four increased surface delf cftr expression - % and enhanced camp-stimulated halide conductance. we tested a series of analogues of the alkaloids and found three others jmcg , jmcg and jmcg that also caused trafficking correction and functional ion channels in the plasma membrane. these results were confirmed in functional studies of the human bronchial epithelial cell-line cfbe stably overexpressing delf cftr. these compounds increased surface delf cftr by - % within h when treated with nm. these results identify a promising group of delf cftr trafficking correctors that are now being actively pursued as potential pharmacotherapeutics for cystic fibrosis along with other hits from compound library screening campaigns. work supported as part of the breathe program jointly funded by the ccff and cihr, and grants from cystic fibrosis foundation therapeutics, (cfft). kim chiaw, p. , ; bear, c.e. background/rationale: biosynthetic misprocessing of the major cf mutant ∆f -cftr has been proposed to result from the disruption in domain-domain interactions (du et al. nature struct and mol biol, ) that may lead to the exposure of di-arginine (rxr) retention/retrieval motifs. simultaneous site directed mutagenesis of all four rxr motifs to rxk or kxr motifs overcame retention and promoted cell surface expression of ∆f -cftr (chang et al. mol cell, ) . we hypothesize that it is possible to compete inhibitory interactions with rxr motifs exposed in ∆f -cftr by delivering synthetically derived cftr peptides bearing one or a combination of rxr motifs (cf-rxr), each conjugated to cell penetrating peptides (cpp) to permit intracellular delivery. results: confocal immunofluorescence microscopy confirms that alexa- -tagged cpp-cf-rxr peptides can be taken up rapidly (within min) by bhk cells stably expressing recombinant human ∆f -cftr. fluorophore-conjugated peptides appear to be concentrated in vesicular compartments, consistent with the current hypothesis that cpp-peptides enter cells into endosomal vesicles via macropinocytosis from which efflux into the cytosol occurs (wadia et al. nature med, ) . we determined that treatment of cell cultures with cpp-cf-rxr peptide at a final concentration [ µm] for minutes is effective in inducing cell surface functional expression of human ∆f -cftr in bhk cells as observed by a . -fold increase in cyclic amp-mediated iodide efflux over control ∆f -cftr (n= ; p < . ). this rescue is specific to the cf-rxr peptide as controls (cpp alone or peptides bearing a kxk motif in place of rxr) show no functional rescue of ∆f -cftr (n= ; p > . ). preliminary cyclic ampmediated iodide efflux results also indicate that ∆f -cftr functional rescue by cpp-cf-rxr peptide is as effective as temperature ( o c) rescue. although we hypothesize that the peptide acts to facilitate trafficking of the major mutant to the cell surface, immunoblotting studies fail to show a clear conversion of the er-form (band b) to the fully processed, band c form of the protein. currently, we are developing more sensitive assays of cell surface expression as well as evaluating the possible efficacy of this peptide in potentiating function of ∆f -cftr. discussion: future efforts include investigating the relative efficacy of peptides corresponding to the four different rxr motifs in rescuing ∆f -cftr trafficking. the promising candidate described above is currently being evaluated with respect to functional rescue of the major mutant in primary human bronchial epithelial cells obtained from patients homozygous for ∆f -cftr (joseph zabner and phil karp, university of iowa) and in cftr-∆f mice. these studies may provide the basis for future pre-clinical studies of peptide based therapies of cystic fibrosis (supported by ccff (breathe program grant) and cihr -(strategic training program in the structural biology of membrane proteins linked to disease)). several promising methods of promoting ∆f cftr escape from er degradation increase cftr chloride channel activity at the cell surface. however, increasing data from a number of laboratories indicate that in both epithelial and non-epithelial cell lines expressing ∆f cftr, the rescued chloride channel is unstable at the cell surface compared to wild-type cftr. small molecule correctors have therefore become a widely used approach to enhance ∆f cftr function at the cell surface. in most cases, the exact mechanism of these promising compounds has not been established. in the present study, we use stably transfected, polarized cfbe o-cells to elucidate the effect of two of these compounds, cfcor- and corr- a, on the surface stability of wild type and low temperature rescued ∆f cftr. specifically, we cultured cells expressing ∆f cftr at c for hours to establish a large pool of surface-expressed ∆f cftr; we then monitored cftr internalization rates and half-life with and without small molecule treatment using surface biotinylation-based assays, performed as described previously (jurkuvenaite et al. j. biol. chem. : , ) . as a control, internalization and half-life of transferrin receptor was also followed. our results indicate that both cfcor- and corr- a slow ∆f cftr endocytosis from ~ %/ . min to ~ %/ . min, and this is similar to wild type cftr internalization rates. neither wild type cftr nor transferrin receptor internalization rates were affected by corrector treatment, suggesting that the effects of the correctors were specific for ∆f cftr. in the surface half-life studies, both correctors doubled ∆f cftr halflife from to hours, but they did not correct the half-life to wild type levels (~ h). again, the correctors had no effect on either wild type cftr or transferrin receptor surface half-lives. our results suggest that small molecule correctors may not only rescue cftr from erad during biogenesis, but can contribute to the stabilization of ∆f cftr at the cell surface, and this effect seems to be ∆f cftr-specific. the ∆f mutation in cftr causes defects in chloride channel gating and cellular processing. cell cultures models suggest the need for both a potentiator and corrector to restore ∆f -cftr channel function and processing, respectively. previously, we identified several classes of potentiators, including 'phenylglycines', which probably bind to cftr at the cell surface and restore normal channel gating (pedemonte et al., mol. pharm. ; : - . we also identified several classes of correctors, including 'bisaminomethylbithiazoles', which may bind to ∆f -cftr in the er and partially restore its folding and plasma membrane targeting (pedemonte, et al., j. clin. invest. ; : - . these compounds were identified from screening a diverse collection of , small molecules; the most active potentiator was phenylglycine pg { -[( - h-indol- -ylacetyl)-methyl-amino]-n-( -isopropylphenyl)- -phenyl-acetamide} and the most potent corrector was the bisaminomethylbithiazole corr- a {n- ( -[ -chloro- -methoxyphenylamino]- '-methyl- , '-bithiazol- 'yl) benzamide}. here we synthesized and characterized a hybrid molecule (corr- a-linker-pg ) containing both corrector and potentiator fragments. based on sar data of potentiators and correctors, a hybrid molecule was designed that incorporated an enzymatically hydrolysable linker to generate and deliver the potentiator and corrector-linker fragments. using synthetic organic chemistry we synthesized a hybrid molecule containing a pg -oh moiety and a corr- a-linker-cooh moiety, linked with an ethylene glycol spacer through an ester bond. the potentiator and corrector fragments (after cleavage) had low micromolar potency or better. however, the intact hybrid molecule was inactive, likely because of its large size ( daltons) and hence poor cell penetration. as proof-of-principle evidence that the hybrid molecule can be hydrolyzed to the active fragments, treatment with carbonic anhydrase or rodent stool specimens gave the appropriate potentiator and corrector-linker fragments identified by lcms. smallmolecule corrector-potentiator hybrids have potential utility as single drug therapy for cf caused by the ∆f mutation. supported by cff and nih. cftr is a chloride channel gated by atp binding and hydrolysis at its two nucleotide binding domains (nbd and nbd ). the two nbds may dimerize in a head-to-tail configuration, as observed in other abc transporters, forming two atp binding pockets (abp and abp ), with the atp molecules buried at the dimer interface. abp , formed by the walker a and b motifs of nbd and the signature sequence of nbd , was proposed as the site critical for the atp-dependent opening of the cftr channel, while abp (consisting of the walker a and b motifs of nbd and the signature sequence of nbd ) may contribute to the stabilization of the open channel conformation. g d, the third most common cf-associated mutation, is characterized by a very low open probability, and patients carrying this mutation present a severe phenotype. this mutation is located in the signature sequence of nbd (and thus in abp ). we have recently characterized this mutant channel and found that its low activity is atp-independent. this behavior corroborates with the idea that the occupancy of abp by atp is crucial for catalyzing the opening of the channel. interestingly, we now found that a high affinity atp analog, n -( -phenylethyl)-atp (p-atp), increases g d currents primarily by increasing the open time of the channel. this effect of p-atp is reduced when p-atp was applied together with atp, suggesting a competition between atp and p-atp for a common binding site. introducing the mutation y g (located at abp ), which reduces by more than -fold the atp-binding affinity in wild-type channels, does not alter the effect of p-atp in the g d/y g mutant. in contrast, when we introduce the mutation w g (located at abp ) in the g d background, the effect of p-atp is reduced remarkably, suggesting that abp is the binding site where p-atp binds to increase the activity of g d channels. these new results further confirm the idea that nucleotide binding at abp could stabilize the open channel conformation. since the competition experiments show that atp and p-atp are readily exchanged in the binding site, we conclude that the atp molecule is not occluded in abp , at least under the g d background. our observation that p-atp enhances the g d activity by binding at abp implicates that abp can potentially be a target for drugs to bind and increase the channel activity. supported by cff grant to s. bompadre and nih grants to t.-c. hwang (hl r , dk r ) and s. bompadre (dk k ). van goor, f.; hadida, s.; grootenhuis, p. vertex pharmaceuticals, san diego, ca, usa several cf-causing mutations, including ∆f , g d, and r h, cause gating defects in cftr that decrease the open probability (po) of the channel, resulting in decreased cl-secretion across epithelia of multiple organs, including the lung. a therapeutic strategy for the treatment of cf is to develop pharmacological potentiators that increase po leading to increased fluid transport in affected tissues. vx- was identified through cell-based screening and chemistry optimization as a potent potentiator of cftr, including ∆f -, g d-, and r h-cftr. in single-channel recordings of cftr expressed in fisher rat thyroid cells, vx- increased the po of ∆f -cftr from . ± . to . ± . . the po of g d increased from . ± . - . ± . . these levels are similar to the po of wild-type cftr, indicating that vx- restores normal gating at the single channel level. to assess the potency and efficacy of vx- in native airway cells, cl-secretion was monitored in ussing chamber studies using human bronchial epithelia (hbe) cultured from the bronchi of cf and non-cf donors. in the absence of the potentiator vx- , cftr-mediated clsecretion in ∆f /∆f or g d/∆f -hbe reached a maximum amplitude of . ± . and . ± . ua/cm , respectively. this is ~ % of that observed in wild-type-hbe ( ± ua/cm ) and consistent with the low level of residual cftr activity reported in some individuals with severe cf disease. in ∆f /∆f -hbe, vx- caused a -fold increase (peak response; . ± . ua/cm ) in cftr mediated cl-secretion with an ec of ± nm, whereas in g d/∆f -hbe, cl-secretion increased fold (peak response; ± ua/cm ) with an ec of ± nm. the improved efficacy observed in g d/∆f -hbe is consistent with a higher cell surface density of g d-cftr compared to ∆f -cftr, which has defective trafficking to the cell membrane. vx- was found to be highly selective for cftr and to have good oral bioavailability in multiple species with a half-life of - hours. the biological and pharmacokinetic data support the clinical development of vx- for the treatment of cystic fibrosis. we would like to acknowledge the cfft for their support and dr. joseph pilewski for providing cf hbe. the pari eflow ® rapid nebulizer is a member of the "soft mist" inhaler class for the administration of aerosolized antibiotics that eliminates the need for a compressor. objectives: to compare the pharmacokinetics and safety of tobramycin inhalation solution (tobi ® ) delivered via the pari eflow ® rapid electronic nebulizer vs the pari lc ® plus jet nebulizer with compressor. methods: we compared tobramycin levels in sputum and serum, incidence of bronchospasm and frequency of adverse events (ae) of mg tobi, administered twice-daily for weeks from these two delivery systems in a randomized, crossover study in cystic fibrosis patients. blood and sputum samples were collected over a dosing interval after the first and last dose on each device (days and ). tobramycin serum and sputum area under the concentration-time curves (auc) were derived and the therapeutic ratio (mean sputum auc / mean serum auc) calculated. pulmonary function tests were performed before and min after nebulization on days and , and ae were recorded. results: the total nebulization time was reduced by half for the pari eflow rapid vs pari lc plus ( . ± . min vs . ± . min [p< . ] on day , and . ± . vs . ± . [p< . ] on day , respectively). tobramycin predose serum levels > µg/ml or cmax > µg/ml, predefined as a potential for increased risk of systemic toxicity, were not exceeded in any patient during use of either nebulizer. as tabulated below, mean systemic exposure to tobramycin from the pari eflow rapid on day was slightly lower, by %, whereas mean sputum exposure was higher, by %, compared with the pari lc plus. consequently, the therapeutic ratio was nearly -fold higher for the pari eflow rapid due mainly to higher sputum concentrations. adverse events occurred in patients using the pari lc plus nebulizer (primarily headache and abdominal pain) and in patients using the pari eflow rapid nebulizer (primarily headache, cough, dyspnea). on day , no clinically relevant bronchospasm (defined as ≥ % decrease in fev ) was observed for either treatment. the mean percentage change in fev at mins from predose on day was - . % for the lc plus and - . % for the eflow rapid. conclusions: tobi delivered via the pari eflow rapid electronic nebulizer required shorter delivery times with similar safety and a higher therapeutic ratio (sputum/serum exposure) compared with the pari lc plus jet nebulizer. sponsored by novartis pharma ag which acknowledges support from pari gmbh introduction alpha- antitrypsin (aat) is a protein protecting lung tissues by inhibition of neutrophil elastase. the function of neutrophil elastase is to digest bacteria and other foreign objects in the lungs. in a person deficient of aat, the neutrophil elastase acts uncontrolled, destroying healthy tissue. the result of the damage is emphysema, which progresses if not treated. patients show a specific impaired breathing pattern of short inhalation followed by prolonged exhalation. current therapy consists of weekly i.v. infusion of aat of about - mg/kg body weight. by this method only about % of the administered dose is estimated to reach the lungs. since aat can currently be derived only from human blood serum by an expensive purification process, the worldwide supplies are limited and do not allow to treat all patients. an improvement of the delivery efficiency is highly desirable. inhaled treatment would offer a targeted therapy by delivering aat directly to the lungs and allow for a better use of the limited drug. the eflow ® , a novel electronic nebulizer, is more efficient than conventional nebulizers. it operates by means of a perforated vibrating membrane, applying no or only little stress to the nebulized substances. hence it is well suited for the pulmonary delivery of proteins. it has been shown previously, that a % aat solution can be nebulized by eflow ® without a loss of biological activity. we investigated two eflow ® configurations comparing the in-vitro delivered dose for different breathing patterns. method a highly purified % aat preparation (kamada ltd, rehovot, israel) was aerosolized with the eflow ® electronic nebulizer. initial studies were conducted using the l configuration of eflow ® . delivery performance is compared to a specially designed xl configuration, with increased aerosol chamber volume. aerosol delivery efficiency was determined by breath simulation using an emphysema breathing pattern (tidal volume ml, breaths/min, inh:exh ratio = : . ) generated by a pari compas™ breath simulator. as reference, a standardized regular breathing pattern (tidal volume ml, breaths/min, inh:exh = : ) was also investigated. the respirable fraction (drug in droplets < and . µm) was determined using the andersen cascade impactor at . l/min. samples were analysed for aat activity by an elastase inhibition assay. when the eflow ® l configuration was investigated for the standardized breathing pattern, a delivered dose (dd) of ± % of the loaded dose ( mg) was found. this value was reduced to ± % when the emphysema pattern was applied. with the new eflow ® xl configuration an improved dd of ± % was obtained. furthermore, when the emphysema pattern was applied, the dd did not drop strongly, but remained at values above %. with % of aerosol droplets in the respirable size range (< µm) and % < . µm, a high % of aat can be expected to reach both, the central and peripheral lungs of patients. conclusion inhaled aat has the potential to significantly improve the efficiency of aat replacement therapy. a customized eflow ® electronic nebulizer produced delivered doses > % even when breathing patterns of patients with impaired breathing capabilities were mimicked. the formulation is optimized for rapid aerosol administration through use of higher drug concentrations and is taste-masked. this study was conducted to evaluate the aerosol performance of novel higher dosed levofloxacin inhalation solutions in a customized eflow ® electronic nebulizer. methods two concentrations of mp- ( mg/ml and mg/ml of levofloxacin) were nebulized at fill volumes of and ml using the eflow ® l nebulizer configuration. the in-vitro delivered dose (dd) was determined by breath simulation using a standardized breathing pattern (tidal volume ml, breaths/min, inh:exh ratio = : ) generated by a pari compas™ breath simulator. the geometric droplet size distribution was determined by laser diffraction (ld). the aerodynamic droplet size distribution was determined using the andersen cascade impactor (aci). the invitro respirable dose (rd) was calculated by multiplying the respirable fraction (rf, %droplets < µm) derived from the cascade impaction experiment and the dd derived from breath simulation. nebulization time was determined by the electronic shut-off of the eflow ® control unit. all tests were conducted for three devices in duplicate, each (n= ). the eflow ® electronic nebulizer delivered mp- at both concentrations and fill volumes with equal efficiency, obtaining in-vitro dds of around ± %. the average nebulization times were between and minutes for the ml fill volume and between and minutes for the ml fill volume and were also independent of the concentration in the investigated range. determination of the mass median diameter (mmd) by ld resulted in values between . and . µm. values of the mass median aerodynamic diameter (mmad) obtained by cascade impaction were similar (between . and . µm). the average respirable fraction was in the range between % and % for both experimental methods. conclusion the eflow ® electronic nebulizer can be customized to deliver high doses of mp- . the short nebulization times achieved are patient friendly and should support high patient compliance. mp- , with the potential for once daily administration, provides significant advantages over currently avail-able aerosol antibiotics. clinical evaluation of mp- delivered by the eflow ® nebulizer in cf patients is in progress. lavange, l. ; engels, j. ; accurso, f.j. . university of north carolina, chapel hill, nc, usa; . inspire pharmaceuticals, inc., durham, nc, usa; . university of colorado, denver, co, usa introduction: percent change from baseline in a continuous outcome variable, such as lung function, is a useful descriptive measure in therapeutic clinical trials. while often favored by clinicians as the primary efficacy measure, the use of percent change as the basis for statistical comparisons raises a number of issues. defined as *(post-pre)/pre, where pre and post represent baseline and follow-up values, respectively, percent change is a ratio of random variables and as such, does not follow a normal distribution. analyzing percent change with standard methods can result in inefficiences and may be inappropriate without a suitable transformation (e.g., logarithmic). furthermore, the treatment effect estimated on the transformed scale is difficult to interpret. the purpose of this abstract is to describe an alternative method for analyzing percent change and illustrate its utility in cf clinical trials. methods: probability plots are generated to compare the distributions of percent change in fev from baseline to study endpoint among treatment groups. the plots are similar to kaplan-meier curves, with percent change on the horizontal axis in lieu of survival time. the percentage of patients on the vertical axis depicts the cumulative percentage of patients who had a percent change at least as great as the corresponding value on the horizontal axis. a log-rank test statistic provides an overall test for any difference in distributions among treatment groups. the methods are illustrated using data from a -day, phase , multicenter, randomized, double-blind, placebo-controlled clinical trial of denufosol in cf patients with a screening fev ≥ % predicted. results: a probability plot of denufosol (active doses combined, n= ) vs. placebo (n= ) is shown below. more denufosol patients ( %) experienced improvement compared to placebo ( %). the log rank test, adjusted for study site, showed that the overall distributions of percent change in fev between denufosol and placebo were significantly different (p-value= . ). conclusions: the proposed methods provide a convenient means for assessing differences in percent change and may be useful in cf clinical trials. comparisons of both a descriptive and inferential nature can be made with minimal assumptions, thereby avoiding the pitfalls in analyzing percent change with standard techniques. the methods are easy to implement with existing software packages (e.g., sas). trial supported by inspire pharmaceuticals, inc. and cf foundation therapeutics, inc. chen, x. , ; davis, p. compacted dna nanoparticles formulated with pegylated polylysine and plasmid dna transfect airway cells in vivo at high efficiency, so they have great potential for gene therapy. the mechanism by which dna nanoparticles enter the cell and get expressed is not well understood. we previously showed that rhodamine labeled dna nanoparticles enter primary human tracheal epithelial (hte) cells within min, and accumulate in the nucleus in hr, where the transgene can be expressed. dna nanoparticles do not enter via clathrin-mediated endocytosis (cme), which leads to the degradation of internalized material in lysosomes. further characterization of the kinetics and trafficking pathway may allow us to improve the formulation of the nanoparticles and facilitate its gene delivery. as they do in hte cells, rhodamine labeled dna nanoparticles enter hela and hbeo-, an immortalized human bronchial epithelial cell line, within min, and by - hr accumulate in the nucleus, especially the nucleolus, where they colocalize with nucleolin. expression of the gfp reporter gene in the nanoparticles was observed at hr, which confirms the functionality of the labeled dna nanoparticles. cellular entry is energy dependent, as little or no intracellular rhodamine was observed at °c by hr. we also applied rhodamine labeled nanoparticles and biotin-conjugated transferrin, a marker for cme, simultaneously. little colocalization was observed during a min to hr time course, so the nanoparticles do not follow this pathway. we then found a direct and strong relationship of cell surface nucleolin and the ability of the cells to take up and express dna nanoparticles. nucleolin directly binds to dna nanoparticles with kd= . nm. manipulations of cell surface nucleolin in hela cells affect transfection of dna nanoparticles with a positive correlation. we therefore costained nucleolin in both hela and hbeo-cells treated with the rhodamine labeled dna nanoparticle. the rhodamine fluorescence colocalizes with nucleolin both in the cytoplasm at early time points and in the nucleus/nucleolus at hr and hr, which further supports that nucleolin might be associated with the nanoparticles during their trafficking. to confirm this association, we performed uptake experiments with ms- , a mouse monoclonal antibody against nucleolin, alone or with rhodamine labeled nanoparticles over a min to hr time course. the ms- antibody enters hela cells at similar kinetics to the nanoparticles. at min, we observed substantial amount of cytoplasmic staining, while nuclear staining tends to increase by time until hr. it has little or no colocalization with transferrin in the cytoplasm, which suggests that this antibody also enters the cell via a pathway other than cme. in contrast, it showed extensive colocalization with dna nanoparticles in both cytoplasm and nucleus at all time points, which suggests that cell surface nucleolin and dna nanoparticles are associated or at least in close vicinity during their trafficking inside the cell. therefore, we suggest that dna nanoparticles enter the cell by binding to cell surface nucleolin and enter the cell via the same pathway as nucleolin antibody. chen, x. , ; davis, p. dna nanoparticles are non-viral gene delivery vectors in clinical trial for treating genetic disorders including cystic fibrosis. we previously discovered that cell surface nucleolin serves as a receptor for the dna nanoparticles, and is important for their gene delivery efficiency. as nucleolin has no signal sequence or membrane-spanning domain, it is not clear how nucleolin are expressed on the outer surface of plasma membrane or what signals increase its surface delivery. we initially observed that the transfection efficiency of dna nanoparticles in hela cell decreases by . % following hr serum-free medium treatment, which reduces cell surface nucleolin by . % as determined by cell surface biotinylation and streptavidin bead pulldown. since serum depletion inhibits cell proliferation and affects cell cycle progression, we examined the level of cell surface nucleolin at different stages of cell cycle. hela cells were arrested at s phase by high concentration of thymidine, and allowed to progress synchronously through cell cycle after removing this block. surprisingly, we observed substantial increase of cell surface nucleolin at the onset of m phase, about hours after release of thymidine block. it has been reported that nucleolin is phosphorylated by a cell cycle dependent kinase (cdk) cdc , and has eight consecutive cdk phosphorylation sites. therefore it is appealing to speculate that phosphorylation by cdc might increase the targeting of nucleolin to the cell surface. we then determined the potential export signal in nucleolin by serial deletions. deletion of c-terminal aa of nucleolin, including the c-terminal glycine/arginine rich (gar) domain and the four rna recognition motifs (rrm) does not affect its arrival at the cell surface. the n-terminal aa of nucleolin is sufficient to target a gfp protein to the cell surface. in contrast, when we further delete the cdk phosphorylation sites from aa to , cell surface expression of nucleolin is significantly diminished. furthermore, nucleolin lacking the n-terminal aa is not present on the cell surface. therefore, phosphorylation on the cdk sites may serve as a signal to enhance the cell surface expression of nucleolin. there has been recent interest in dry powder inhaled mannitol as a therapeutic agent in patients with cystic fibrosis (cf). it is has been shown to increase mucociliary clearance (mcc) by airway rehydration. whilst there has been one short term clinical trial of mannitol in adult subjects [ ] , to date no studies have been conducted looking at its potential as a therapy in children with cf. it could be argued that children may have the potential to benefit most from a therapeutic agent that acts relatively proximally in the cf pathogenic pathway. the aim of this study was to determine acute tolerability of inhaled mannitol in children with cf. we recruited children (aged to years) with cf. inclusion criteria were either rhdnase treatment or an fev > % and < % of mean predicted normal value. bronchial provocation challenges with incrementally increasing doses ( , , , , , , mg) of dry powder mannitol were carried out. subjects were pre-treated with bronchodilator minutes prior to the challenge ( mcg of salbutamol or mg of terbutaline). fev was measured following each dose increase up to a maximum cumulative dose of mg. oxygen saturation monitoring was carried out throughout. a positive challenge was defined by a drop in fev of > % from baseline. these subjects received bronchodilator treatment and had spirometry repeated at minute intervals until fev returned to within % of baseline. those children with a negative challenge had spirometry repeated minutes post-completion of the challenge results mean baseline fev was % predicted ( - , sd . ). / subjects ( %) had a positive challenge. mean pd (dose of mannitol required to cause a % reduction in fev ) was mg ( - , sd ). the mean time to complete the challenge was minutes ( - , sd . ) for negative challenges and minutes ( - , sd . ) to pd for those subjects with a positive challenge. we found no association between a positive challenge and age, sex, weight, height, baseline fev , pseudomonas aeruginosa colonization, bronchodilator reversibility, previous aspergillus fumigatus sen-sitization, atopy or corticosteroid use. there was a non-significant trend for lower fef - (means . versus . ; p= . ) and higher prevalence of aspergillus fumigatus cultured in sputum at baseline ( / versus / children; p= . ) amongst those children who went on to have a positive challenge. there was no significant drop in oxygen saturation in either group. although cough was common during the challenge, other adverse events were infrequent. we find that % of children with cf could not tolerate inhaled mannitol as compared with % of adult subjects as reported in the previous study [ ] . we could not identify factors predictive of a positive mannitol challenge in these patients. the most common cause of cystic fibrosis (cf) is the deletion of phenylalanine (∆f ) in the cf transmembrane conductance regulator (cftr) chloride channel [ ] . a major problem with ∆f cftr is that the protein is defective in folding so that little mature protein is delivered to the cell surface [ ] . expression of ∆f cftr in the presence of small molecules known as correctors or pharmacological chaperones can increase the level of mature protein [ ] [ ] [ ] [ ] . unfortunately, the efficiency of correctorinduced maturation of ∆f cftr is low and other approaches are needed to increase the therapeutic value of correctors. we postulated that expression of ∆f cftr in the presence of multiple correctors that bound to different sites in the protein may have an additive effect on maturation. in support of this mechanism, we found that expression of p-glycoprotein processing mutants (cftr's sister protein) in the presence of two compounds that bind to different sites (rhodamine b and hoechst ) had an additive effect on maturation. therefore we tested whether expression of ∆f cftr in the presence of combinations of three different classes of corrector molecules would increase its maturation efficiency. it was found that the combination of the quinazoline vrt- together with the thiazole corr- b or bisaminomethylbithiazole corr- a doubled the steady-state maturation efficiency of ∆f cftr (about % of total cftr was mature protein) compared to expression in the presence of a single compound. the additive effect of the correctors on ∆f cftr maturation suggests that they may directly interact at different sites of the protein. the use of multiple correctors has the potential to increase the therapeutic value of pharmacological chaperones. pharmacol. , - . the cftr protein is expressed at the surface of the airway epithelium, where it plays a critical role in maintaining airway hydration by secretion of chloride. for gene therapy of cf lung disease to be successful, it is critical that the endogenous transgene be expressed in the correct cell type and at levels sufficient to restore normal function. the expression of high levels of cftr has resulted in cftr mediated chloride secretion in a wide range of experimental systems. however, the cell type or types that need to be corrected and the level of cftr expression required to ameliorate the pulmonary manifestations of cf are not yet clear. because cftr has been localized to the ciliated cells of human airway epithelial cells, we have been investigating the use of ciliated cell-specific promoters to improve the efficiency and safety of gene therapy for cf and other airway diseases. in previous studies a fragment of the human foxj promoter was shown to target transgene expression specifically to ciliated cells. however, expression of cftr from this promoter in transgenic cf mice did not significantly improve the cf phenotype, as measured by the nasal potential difference (pd) technique (ostrowski et al, ) . this may be due to the inability of this promoter to correct the olfactory epithelium, which comprises approximately % of the mouse nasal cavity. in cf mice, the olfactory epithelium exhibits sodium hyperabsorption and an absence of cftr mediated chloride secretion, similar to the respiratory epithelium (grubb et al, ) . in this work, we used a fragment of the ciliated cell-specific promoter foxj to drive cftr expression specifically in human ciliated cells. replication deficient adenovirus expressing either egfp or cftr from the foxj promoter were used to transduce well-differentiated cultures of human cf cells following treatment with c to disrupt tight-junctions. cultures were studied hours after treatment, and those treated with ad-foxj /egfp showed strong expression of egfp that was dependant on ciliated cell differentiation. rna analysis demonstrated strong expression of cftr from the foxj promoter, and western blotting demonstrated levels of protein that were much greater than the level in normal airway cells (> -fold). immuno-localization of cftr with specific antibodies resulted in a strong signal at the apical membrane of ciliated cells. cultures treated with ad-foxj /cftr demonstrated a significant increase in forskolin-stimulated short circuit current (isc; . +/- . µa/cm , mean +/-sem, n= ), that was approximately -fold greater than the response in ad-foxj /egfp treated cultures ( . +/- . µa/cm , n= ). the increase in isc was blocked by inh , an inhibitor of cftr mediated secretion. under these conditions, ad-foxj /cftr restored approximately % of the forskolin response of normal human airway cells ( . +/- . µa/cm , n= ). because patients expressing low levels of normal cftr mrna ( - %) have mild disease symptoms, these studies demonstrate that the incorporation of the ciliated cell-specific foxj promoter into gene therapy vectors may be useful for treatment of cf. supported by nhlbi ro hl and the cff. there is a compelling need for safe and effective ai therapy for cf lung disease. low-dose methotrexate (mtx) has been used to treat inflammatory diseases and its use has been reported in cf. encouraging results previously described regarding mtx in cf prompted this study. the study objective was to determine if mtx safely reduces inflammation in the airways of cf patients. methods: this was a single-center, open label study of mtx in stable cf patients with mild to moderate lung disease. baseline levels of neutrophils, free elastase, pro-inflammatory cytokines, and bacteria were determined from an induced sputum specimen. subjects received mg/m /week of oral mtx (single dose). after weeks of treatment, a second induced sputum specimen was obtained for the same inflammatory indices. within subject comparisons (end of treatment vs baseline) were performed for the following primary endpoints: total white cell and neutrophil counts, percent neutrophils, and concentrations of free elastase, il- , il- , tnf-α, and il- β. sputum quantitative microbiology was obtained at baseline and end of therapy. routine laboratories and spirometry were performed monthly. pharmacokinetic testing was performed on the final day of treatment. results: thirteen subjects were screened with started on mtx. six completed the protocol and withdrew early secondary to adverse events (gastrointestinal [gi] complaints and pulmonary exacerbation). five of subjects completing the protocol had declines in pulmonary function: mean change in fvc was - . l (range - . to - . ); mean change in fev was - . l (range - . to - . ); change in fef - was . l (range - . to . ). mean change in weight was - . pounds (range - to . ). mean change in free elastase was . µg/ml (range - . to . ; sd . ). mean change in il- was pg/ml (range - to ; sd ). similar results were obtained for the other cytokines. analysis of cytology specimens is pending. esr and crp did not show significant changes. two subjects completing the protocol had significant gi side effects, including requiring admission for severe abdominal discomfort. quantitative microbiology specimens revealed an increase in colony counts in subjects, decreases in , and mixed results in the th. other safety laboratories were not remarkable. pharmacokinetic studies are pending. complete statistical analysis and safety assessment are also underway. conclusions: the small sample size of this study precludes definitive conclusions regarding the safety or efficacy of mtx. however, the data suggest that ) induced sputum inflammatory indices can be used to assess an ai in clinically stable patients, and ) mtx therapy may not be beneficial, and may be difficult to tolerate as along-term ai therapy for cf lung disease. additional analyses of cell counts and microbiology from this study are ongoing, and may provide additional insight into the effect of mtx in the cf lung. sponsored by the cf foundation , a cellular component of many gram negative bacteria (e.g. pseudomonas aeruginosa), is a common airway stimulus. dampening the inflammatory response in cf reduces the progressive decline in lung function, so anti-inflammatory agents have become both a cornerstone of cf clinical care and a focus of therapeutics research development. reactive oxygen species [ros] can play a role in proinflammatory signaling, including the activation of nuclear factor κb [nfκb] . research has demonstrated increased oxidative stress in cf epithelial cells, potentially highlighting one of the mechanisms responsible for the exuberant inflammation observed. we have previously shown that cddo, a novel anti-inflammatory agent, significantly limits nfκb activation in cftr deficient cell culture models at nanomolar concentrations. using cf mice, we have also shown that intra-tracheal cddo limits neutrophil accumulation and the concentrations of proinflammatory cytokines and chemokines in bronchoalveolar lavage [bal] fluid in response to lps. the synthetic triterpenoids have been shown to activate the nrf transcription factor, thereby inducing several genes involved in redox balance. we now present data demonstrating that cddo may inhibit inflammation in models of cf pulmonary disease by reducing the oxidative stress within cells. methods: b . s -cftr tm mrc cf mice received µl of µm cddo in pbs with %dmso or vehicle (control) daily. drug was administered intratracheally with an atomizer (penncentury) for three days before stimulation. in separate experiments, all mice received µg lps or free pseudomonas aeruginosa intratracheally. mice were sacrificed by co asphyxiation and cardiac puncture hours after stimulation and bal, serum and lung tissue were obtained. the lungs were incubated in lysis buffer containing protease inhibitors and immediately frozen. upon thawing, the tissue was homogenized and whole lung protein extracted. one mg of lung protein from each experimental animal was separated by two dimensional gel electrophoresis. gels were then imaged and analyzed with pdquest to identify protein spots that were differentially expressed in drugtreated mice compared with controls. spots of interest were excised from the gels, trypsin digested and analyzed by liquid chromatography/tandem mass spectroscopy. results: over proteins with greater than -fold differences in expression were identified. we categorized proteins appearing in repeated analyses and identified several affecting intracellular redox regulation; including glutathione s-transferase mu and , peroxiredoxin and , enolase (alpha non-neuron), contrapsin, alpha- antiproteinase and cu/zn superoxide dismutase. these proteins were expressed at significantly greater concentration in the lungs of mice treated with cddo rather than vehicle. conclusion: cddo exhibits anti-inflammatory effects in mouse models of cf pulmonary disease and one potential mechanism for this effect may be the upregulation of reducing proteins to combat oxidative stress. methods: lpc ( ul of . %, . % or . % (w/v) in pbs) was administered (trans-orally via a cannula) to trachea of c l/b mice. in sheep ( of completed) we targeted delivery of . ml of . % lpc dissolved in pbs to the main bronchus of the right lung at branch in a month old sheep (bronchoscope, via tracheostomy). one hour later ul (mice) or . ml (sheep) of a lv-lacz vector ( . x tu/ml) was administered in the same manner. one week post-exposure lungs were inflation-fixed in situ, removed, stained using x-gal, sectioned, and counterstained with saf-o or h/e. results: no lacz gene expression (blue cells) was found in lungs of control (pbs-treated) mice or in the left (untreated side) of sheep lung. blue cells were found in scattered punctuate groups, or in lines of stained cells in mice and sheep. mice given the highest lpc dose ( . %) had extensive gene transfer in larynx, trachea, carina, and in large, middle and small airways of most lobes of the lung, reaching % airway perimeter cell transduction in one animal. with decreasing lpc dose the distribution and number of blues cells was reduced, but transduced epithelial cells including nonciliated columnar cells, ciliated cells, and basal cells were seen in all cases. in sheep, blue cells appeared in the right main bronchus between branch and branch , and in the branch airway, and with highest expression found near branch and . cross-sections revealed that primarily ciliated columnar cells and basal cells (and no goblet cells or macrophages) were transduced. conclusions: lv gene transfer into mouse or sheep lung can be enhanced by pretreatment with lpc. in mice this early data suggests an lpc dose-dependency. for sheep, we await further results to confirm the encouraging finding in this first study; however, it does confirm that gene transfer into the airways of large animals with a lung size similar to humans can also be achieved using lpc pre-treatment and a vsv-g pseudotyped lentivirus. the transduction of both ciliated and basal lung epithelial cells in-vivo in both models is an encouraging funding for the development and understanding of our continuing efforts to produce life-long airway gene transfer suitable for a cf airway gene therapy. supported by: nh&mrc, usa cff, sa channel crf, philanthropic donations. increased airway na+ absorption is a characteristic abnormality in cystic fibrosis (cf), and is thought to play a key role in the pathogenesis of cf lung disease. we have previously demonstrated that mimicking na+ hyperabsorption by overexpression of βenac in mouse airways results in airway surface liquid (asl) volume depletion and reduced mucus clearance causing a spontaneous cf-like lung disease with high pulmonary mortality, and airway mucus plugging, mucous cell metaplasia and chronic airway inflammation in surviving βenac-transgenic (βenac-tg) mice (mall et al., nature med. : , ). in the present study, we used βenac-tg mice to test if inhibition of increased airway na+ absorption by the classic enac blocker amiloride has therapeutic effects on cf-like lung disease in vivo. specifically, we determined the effects of 'early' and 'late' enac blocker intervention on mortality, airway mucus obstruction and inflammation by starting intrapulmonary amiloride therapy in βenac-tg mice either at birth, i.e. prior to the onset of lung disease, or after mucus obstruction and inflammation had established. to achieve this goal, newborn, day, or week old βenac-tg mice and wild-type littermate controls were treated by intranasal instillation of amiloride ( mmol/l; µl/g body weight, tid) or vehicle (h o) alone for a period of days. initial deposition studies showed that this treatment protocol resulted in pulmonary amiloride concentrations sufficient for inhibition of enac. during amiloride therapy, growth and survival were monitored, and any loss in body volume due to diuretic side effects was substituted by subcutaneous injection of isotonic saline (nacl . %). after the day treatment period, mice were euthanized, bronchoalveolar lavage (bal) was performed to determine inflammatory cell counts, and lungs were processed for histology and morphometry to quantitate airway mucus obstruction and mucous cell metaplasia. we show that amiloride significantly reduced pulmonary mortality by~ % (p < . ), when therapy was started in newborn βenac-tg mice. further, early amiloride treatment significantly reduced airway mucus content (p < . ), mucous cell numbers (p < . ), and bal eosinophils (p < . ) compared to vehicle treated βenac-tg mice. in contrast, amiloride therapy had no benefits on airway mucus obstruction, mucous cell metaplasia or inflammation, if treatment was started in day, or week old βenac-tg mice with established lung disease. taken together, our results are consistent with previous human studies where amiloride lacked therapeutic benefits in cf patients with established lung disease, and demonstrate for the first time that early inhibition of na+ hyperabsorption is an effective therapy for cf-like lung disease in vivo. these results warrant an evaluation of more potent and longer acting amiloride derivatives in chronic lung disease in mice, and a clinical evaluation of preventive enac blocker therapy in human trials. supported by cff (mall g ) and ec (mext- - objective: hypertonic saline aerosol delivered intranasally is currently being studied to enhance mucociliary clearance. there is evidence of patients' reluctance to use concentrations above % due to potential discomfort. our study was performed to determine the short term tolerance of . % and % hypertonic saline versus normal saline delivered intranasally via a nebulizer/compressor system (pari sinustartm, pari respiratory equipment, midlothian, va). methods: using the sinustartm nasal aerosol delivery system, we administered concentrations of saline solution, ( . %, . %, %) to healthy, adult volunteers for minutes each. a washout period of minutes between treatments allowed volunteers to wipe their nose and cleanse their mouth with water. a question self-administered questionnaire was completed following each treatment using a point scale ( =high tolerability; =low tolerability). burning sensation, cold, cough, throat irritation, runny nose, and overall comfort were measured. the order of treatments was randomized and volunteers were blinded to the concentration. data: for all measurements . % and % were equally well tolerated compared to normal saline with burning, cough, and throat irritation measuring . or below. no variable measured more than . . out of volunteers stated they would continue this treatment on a regular basis. conclusions: our study indicates that during the time of treatment nasal aerosol delivery of hypertonic saline up to % is well tolerated in healthy adults. there appears to be no issue of discomfort associated with hypertonic saline that would prevent nasal aerosol treatment compliance. our overall research goal is to discover new drugs for clinical treatment of cystic fibrosis (cf) that will correct the biochemical defect in the predominant cf mutation, the ∆f form of the cystic fibrosis transmembrane conductance regulator (cftr) protein, which accounts for over % of all cf cases. this mutation leads to a misfolded protein which is rapidly degraded as well as changes in its function and half-life at the cell surface. however, it has been proposed that only a fraction of the normal surface expression level is needed to provide a clinically significant impact on the disease. thus, from a pharmacological standpoint, strategies that can partially but effectively correct these defects would be expected to have a clear clinical benefit to these cf patients, and these strategies may also be applicable to other cftr mutations. we previously demonstrated that several members of a particular class of related drugs, the anthracyclines, anthraquinones, and anthracenediones, significantly increased cftr cell surface expression and function in cell culture. in particular, we demonstrated that a non-cytotoxic concentration of doxorubicin (dox), a model anthracycline drug, significantly increased total cellular and membrane-associated cftr protein levels and cftr-associated chloride currents in human colon cancer t cells, and also caused a two-fold increase in ∆f cftr-associated chloride current in a canine mdck-c -derived cell line that expresses a stably transfected copy of human ∆f cftr. our previous studies also demonstrated that dox is able to impart structural integrity to ∆f cftr, increasing its half-life and decreasing its proteolytic sensitivity, which is indicative of efficient folding. additionally, two other structurally related drugs, i.e., the anthracycline, daunorubicin, and the anthraquinone, mitoxantrone, were shown to have similar effects on ∆f cftr expression. in the current work, we have extended these effects to two other related aza-anthracenedione molecules, bbr (pixantrone) which is a cancer chemotherapy drug with lower non-target toxicity than dox and which is in phase iii clinical trials, and a structurally related analog, bbr , which is essentially non-cytotoxic with a -fold lower cytotoxic potency than bbr . both compounds increased cftr-associated chloride currents to a similar extent as dox in cfbe human airway epithelial cells expressing ∆f cftr, as measured by ussing chamber experiments. the ability of the non-cytotoxic analog bbr to do so is particularly important, since it indicates that correction of the ∆f cftr defect is not directly tied to the toxicity of this class of compounds per se but rather is a result of other structural features. thus, it is likely that this and/or other non-toxic analogs in this chemical class can be developed that have potential as clinically useful agents for treatment of cf in patients. supported by a cystic fibrosis foundation (cff) grant to jwh and rm, and by the cff-supported dartmouth cf program. cystic fibrosis (cf) is caused by mutations in cystic fibrosis transmembrane conductance regulator (cftr). cftr is not only an epithelial chloride channel, but it also regulates other transporter and ion channels, including epithelial sodium channels (enac) and aquaporin water channels. in patients with cf, absent or dysfunctional cftr results in abnormal electrolyte and fluid content on the epithelial surface. treatments intended to normalize ion transport in cf airways through non-cftr dependent pathways represent attractive approaches to alleviate the underlying pathologic defect. calcium (ca +)-activated cl-channels have been proposed as rescue channel for the cyclic amp-dependent cftr cl-channels, offering a target for cf pharmacotherapy. increases in cytosolic ca + concentration activate epithelial cl-channels, but inhibit epithelial na+ channels, which is also beneficial in correcting the hyperabsorption of na+ in cf. herein we developed a high throughput screening (hts) assay for screening compound libraries with the intention of finding compounds which can increase intracellular ca +. in the pilot primary screening, we screened a mssp library which contains known bioactive compounds and natural products. compounds were classified as the real hits after the secondary screening validation with the hit percentage . %. we have found that the ec of these compounds are less than um in dose-response studies and none of those compounds were toxic to the cells. we have further discovered that those compounds stimulate cl-secretion through activating ca + dependent cl-channels in cf and non-cf human airway epithelial cells in short-circuit current experiments. in summary, our data suggest that modulation of intracellular ca + is a target for cf therapy. the compounds identified by our study will provide possible therapeutic leads in the treatment of cf. non-viral gene delivery particles with various synthetic polymer coatings have been developed for cystic fibrosis (cf). intracellular trafficking and in vivo tissue distribution of these particles must be carefully monitored to guide rational design of efficient delivery system. fluorescent semiconductor quantum dots (qds) allow sensitive, long-term and multi-target imaging in cellular environment, and so are a promising tool in tracing gene delivery materials in vitro and in vivo. however, application has been limited by the lack of efficient and reproducible techniques of qd bioconjugation. here, we describe a method of labeling dna nanoparticles with tunable qds that may enable us to study gene delivery in vitro and in vivo. highly fluorescent zns-coated cdse qds were first synthesized and encapsulated in amine-containing phospholipid micelles. the non-viral vector system we used is based on a polymer backbone consisting of lysines with a cysteine on the n-terminus (ck ) which is conjugated to polyethylene glycol (peg). this polymer vector condenses dna plasmids into stable nanoparticles that efficiently transfect airway epithelial cells in vivo. to introduce the aminecontaining qds, we utilized a hetero-bifunctional peg with an nhs ester at one end, which was first reacted with the amine groups of the qds and a maleimide group at the other end which was subsequently reacted with the thiol group in ck . excess reagents were removed from the final conjugates qd-peg-ck by filtration. conjugation was first confirmed by . % agarose gel electrophoresis. free qds were positively charged and migrated toward the cathode. pegylated qds migrated significantly slower than free qds, and qd-peg-ck conjugates migrated at still a different rate. to further demonstrate conjugation, we biotin-labeled the ck and assessed the binding of qd-peg-ck -biotin to avidin coated agarose beads by monitoring the yield of fluorescent beads. qds, pegylated qds, and physical mixture of qds and ck -biotin were also incubated with the agarose beads as controls. fluorescent beads were detected only when qd-peg-ck -biotin was present. to directly evaluate the ability of qd-peg-ck to bind double stranded dna, we also immobilized double stranded dna fragments to agarose beads. qd-peg-ck , but not unconjugated qd bound to the immobilized dna fragments as determined by the yield of fluorescent beads. qd-peg-ck was then used to compact luciferase reporter plasmids. electron microscopy images of the compacted dna showed that qds were integrated into some dna nanoparticles. we transfected hela cells with qd-labeled and unlabeled dna nanoparticles. luciferase assay and toxicity assay indicated that qd-labeled dna nanoparticles transfected hela cells, though with less reporter gene expression than unlabeled nanoparticles and more toxicity than uncompacted qd. in conclusion, we have developed a method to conjugate qd to dna nanoparticles. improvement of the quality and biocompatibility of the qd may be required for further in vitro and in vivo studies. this system is also versatile. other less toxic optical makers can be readily tested. this study was supported by dk and the cff. in cystic fibrosis (cf) the epithelial sodium channel (enac) hyperactivity plays a role in the pathogenesis of chronic lung disease. the missing enac regulation by the cf transmembrane conductance regulator (cftr) causes increased absorption of sodium ions and fluid across airway epithelia leading to the depletion of the perciliary liquid layer and to the consequent inhibition of mucus clearance. we developed a hiv-based lentiviral (lv) vector containing a sirna cassette to efficiently knockdown the expression and activity of enac in human respiratory cells. background: sildenafil has been implicated in the relocation of cystic fibrosis transmembrane conductance regulator (cftr) protein. the effect was observed in vitro and in the presence of doses roughly times larger than those commonly used for treating erectile dysfunction. aim: to evaluate in vivo therapeutic efficiency of clinical doses of sildenafil and vardenafil, two approved type v phosphodiesterase inhibitors, for correcting chloride transport defect in ∆f mice. methods: we measured transepithelial potential difference in vivo across the nasal mucosa as a readout for sodium and chloride conductance. the effect of a single intraperitoneal injection of sildenafil ( . mg/kg) or vardenafil ( . mg/kg) was investigated in df /df and normal homozygous mice. results: in df /df mice, chloride conductance, evaluated by perfusing the nasal mucosa with a chloride-free solution in the presence of amiloride and with forskolin, was corrected h after sildenafil administration. a more prolonged effect, persisting at least for h, was observed with vardenafil. the forskolin response was increased after sildenafil and vardenafil in both normal and df mutant animals. no effect on sodium conductance was detected in any group of animals. conclusion: our results provide preclinical evidence of effectiveness of both drugs for correcting chloride transport defects in the cf. acknowledgments: this work was supported by grants from the french cf association, vaincre la mucoviscidose and by an educational grant from pfizer belgium. there is a strong interest in developing small molecules able to correct the phenotypic effects of cystic fibrosis (cf) mutations. many mutations (e.g. ∆f ) impair the function of cftr protein, by altering the protein targeting to the plasma membrane and/or by causing an abnormally low open channel probability. drug-like organic compounds may restore the correct membrane localization ("correctors") or increase channel activity ("potentiators") of mutant cftr. in the last years, various research teams have identified molecules with activity as correctors (corr- a, vrt- , miglustat, curcumin) or as potentiators (tetrahydrobenzothiophenes, phenylglycines, sulfonamides, vrt- , , -dihydropyridines). however, these compounds have been tested using different assays and the results are sometimes controversial, with marked differences in declared efficacy and potency of compounds. we have tested a panel of correctors and potentiators to directly compare their effects under the same experimental conditions. for this purpose, we have used the functional assay based on the halide-sensitive eyfp-h q/i l to measure ∆f -cftr activity in frt and a cells. the assay for potentiators consisted in stimulation with the test compound ( . - µm) plus forskolin (on cells previously incubated at °c for hours). the assay for correctors consisted in hours incubation of ∆f cells with test compounds and then determination of cftr activity in the presence of forskolin plus genistein ( µm). our results indicate that all potentiators are active in our assay with a comparable maximal effect but with values of potency that vary significantly among compounds. the potency order measured in frt cells was: dhp- = pg- (ka~ nm) > sf- (ka = nm) > dhp- = dhp- (ka~ nm) > act- b (ka = nm) > felodipine (ka = nm) > vrt- (ka = . µm) > genistein (ka = . µm). a similar order of potency was found also in a cells expressing ∆f . the activity of correctors showed a more marked dependence on cell line. while the potency was comparable between frt and a cells, the maximal effects showed clear differences. in frt cells, corr- a, corr- b and corr- c generated a maximal effect that was . - -fold higher than that obtained by incubating the cells at low temperature. conversely, vrt- and vrt- were less effective (maximal correction equivalent to - % of low temperature rescue). in a cells, all compounds were instead less effective than low temperature, with vrt- being the molecule eliciting the highest activity ( - % of low temperature). our results indicate the , -dihydropyridine dhp- and the phenylglycine pg- among the most potent activators of the mutant cftr channel. the similar behavior of potentiators in two different cell lines is consistent with the assumption that all potentiators act with a similar mechanism, by interacting with the cftr protein itself. in contrast, the cell line dependence of correctors suggests that they act with indirect mechanisms, possibly by interacting with proteins involved in cftr biosynthesis and trafficking. supported by cfft and telethon-italy. we also thank cfft and rfums for providing chemical compounds. lung damage in cystic fibrosis (cf) patients is determined by mucus accumulation, pseudomonas aeruginosa infection and chronic inflammation. extracellular gsh is a scavenger of free radicals produced by neutrophils in inflamed tissues. glutathione transferases (gst) are a superfamily of dimeric proteins which conjugate glutathione to a wide range of substrates including oxidants and are involved the synthesis of leukotriens. clinical beneficial effects have been reported in cf patients following treatment with the macrolide azythromicin (azm); anti-inflammatory properties have been proposed as possible mechanism. the aim of this study is to investigate the regulation of the gstt and gstm activity and expression by azm. reductions of about % and % on gst enzymatic activity were detected in ib - and cfsmeo-cells respectively. gsts mrna expression in cf airway epithelial cell lines was analysed by quantitative pcr (qpcr). the level of gstt and gstm basal expression in cf cells ib - was significantly higher than in isogenic non-cf cells c . we found statistically significant decreases of gstt and gstm mrna of about % and % respectively in ib - cells after treatment with azm for hours, restoring the levels observed in c cells. in cfsmeo-cells after exposure to azm we observed % and % reductions in gstt and gstm mrna respectively. the macrolide jm, known to lack clinical anti-inflammatory properties, had no significant effects on gstt and gstm mrna expression in all cell lines. furthermore, azm did not alter the mrna expression levels of gstp , a glutathione-s-transferase not differentially expressed in cf and isogenic non-cf cells. decreased expression of % and % of gstt protein has been detected by immunoblotting in ib - and cfsmeo-cells, respectively, following treatment with azm. in the same conditions we found a drastic reduction of protein level of gstm in both cf cell lines. finally, gsts activity and the expression of gstt and gstm proteins in cf cells, were reduced approximately to the same level detected after treatment with interleukin (il- ), an anti-inflammatory cytokine, shedding light on a possible correlation between gsts inhibition and antiinflammatory properties of azm. the effects of azm described in this study suggest that downregulation of gstt and gstm expression may result in increased availability of intracellular gsh making cf cells less susceptible to oxidative stress induced by chronic inflammation. inhibition of gstt and gstm might provide a therapeutic approach for limiting the effects of inflammation critical for lung damage in cf patients. this study is supported by italian cf research foundation; comitato di vicenza-associazione veneta per la lotta contro la fibrosi cistica; azienda ospedaliera verona, italy. tradtrantip, l.; padmawar, p.; yangthara, b.; verkman, a. activation of cftr chloride conductance by gpcrs involves camp elevation and pka-mediated cftr phosphorylation. we developed a 'pathway screen' in which cftr-mediated iodide influx is used as a read-out of gpcr activation. the cell-based fluorescence assay utilizes multiply transfected epithelial cells expressing wildtype cftr, yfp-h q/i l and a specified gpcr. we recently used this assay to identify a new class of nanomolar-affinity, -aryl- -benzoyl- hydroxy- -( -arylethyl)- h-pyrrol- -one vasopressin- receptor antagonists (yangthara et al., mol. pharm. , in press ). additional screening of , diverse small molecules yielded novel chemical classes of inhibitors of cftr activation. the potential molecular targets of pathway inhibitors include the gpcr, gs or gi proteins, adenylyl cyclase, phosphodiesterase, pka and cftr. a series of target identification studies was done to classify the new pathway inhibitors, which involved the use of agonists acting at different sites in the activation pathway, and specific site-of-action assays. the pathway screen yielded new small-molecule cftr inhibitors that are unrelated to thiazolidinone and glycine hydrazide inhibitors. one interesting class of pathway inhibitors, thiophenecarboxylates, represent the first small-molecule phosphodiesterase activators, which strongly reduce camp and cgmp concentration in many cell types. the best thiophenecarboxylate greatly reduced intestinal fluid secretion in closed loop mouse models of cholera and travelers' diarrhea, and slowed cyst growth in a model of polycystic kidney disease. other pathway inhibitors, which are potential effectors of g-proteins and pka, are under evaluation. the gpcr-linked cftr pathway screen developed here is useful for high-throughput parallel identification of small-molecule inhibitors of multiple targets in the cftr activation pathway. potential uses of the inhibitors identified here include therapy of secretory diarrheas, polycystic kidney disease, and cyclic nucleotide-dependent tumor growth, as well as pharmacological creation of cf-phenotype in ex vivo human tissues and animal models. supported by cff and nih. inhibitors of intestinal caccs are predicted to have anti-secretory effects in certain diarrheas, and activators of airway and intestinal caccs are of potential use in cystic fibrosis therapy (activation of 'alternative' chloride channels). the purpose of this study was to identify small-molecule cacc inhibitors and activators that target caccs directly, rather than ubiquitous upstream processes such as calcium signaling. we screened a collection of , chemically diverse small molecules using a novel high-throughput screening assay involving lentiviral introduction of a yfp-based halide sensor in cacc-natively expressing human epithelial cells. cacc inhibitors were identified from iodide influx following cacc simulation by carbachol/atp. we identified five classes of cacc inhibitors with micromolar potency, including tetrahydro-cyclopentaquinolines, and -aryl- -(trifluoromethyl)-pyrazoles each of which was unrelated to known transport modulators. two classes of compounds inhibited calcium-activated halide flux following stimulation by multiple types of agonists, including thapsigargin and calcium ionophores, and by patch-clamp analysis appear to target cacc directly. structure-activity analysis of analogs of 'hits' yielded compounds with improved potency, which have been resynthesized and characterized for use in assays of antidiarrheal effiacy in rodent models of viral and drug-induced secretory diarrheas. screening for caccselective activators that act in a sustained manner (non-transiently) was accomplished using a similar cell-based fluorescence assay, but instead testing for increased halide influx. several classes of putative cacc activators with micromolar-potency were identified in screening of , small molecules, whose mechanism-of-action and specificity are under investigation. small-molecule modulators of cacc function that target caccs directly have potential clinical applications, and may be useful in defining the physiological roles and molecular identity of caccs. supported by cff and nih. introduction: inhaled hypertonic saline 〈hs〉improves lung function and decreases pulmonary exacerbations in older children and adults with cf. initiating therapeutic interventions in the youngest patients, particularly those that target the underlying cf defect of airway surface liquid volume depletion, has potential to preserve lung function and improve prognosis. subbarao et al performed baseline, post-albuterol and post-hs lung function testing in infants using the raised volume rapid thoracoabdominal compression technique 〈rvrtc〉and demonstrated no significant drop in lung function 〈 pediatric pulmonology, 〉. however, performing three sets of rvrtc maneuvers under the same sedation could prove difficult. before conducting a therapeutic trial of hs in this population, a simplified protocol must be possible at multiple centers. we sought to evaluate a simplified approach as well as to analyze changes in lung function and clinical findings after acute administration of hs. methods: in this ongoing study, clinically stable children with cf between the ages of months and years inhale . mg of albuterol prior to sedation with chloral hydrate. rvrtc and plethysmography are then performed before and after inhalation of ml of ‰ hs. fvc, forced expiratory volume in . seconds 〈fev . 〉, fef - , frc, rv/tlc ratio, respiratory rate, oxygen saturation, and chest exam findings are recorded. predefined stopping criteria include a % drop in fev . or in oxygen saturation to below ‰. results: six subjects 〈mean age . ± . years〉 have completed the protocol with ‰ hs. comparison of post-albuterol lung function to that obtained minutes after ‰ hs revealed no changes in mean fvc 〈 vs ml; p= . 〉, mean fev . 〈 vs ml; p= . 〉, mean fef - 〈 vs ml/sec; p= . 〉, frc 〈measured after each inhaled therapy in of subjects; vs ml; p= . 〉, or rv/tlc 〈measured after each inhaled therapy in of subjects; . vs . ; p= . 〉. respiratory rate, oxygen saturation and chest exam were unchanged. conclusions: results from this study demonstrate that a two-step protocol may used to evaluate the safety of hs. based on these findings, acute administration of ‰ hs is safe in children ages months to years with cf. despite the known improvement in mucociliary clearance, preliminary findings demonstrate a lack of an immediate response in lung volume measures. given the demonstrated benefits in older children and adults, a multicenter therapeutic trial of hs is warranted. supported by the cystic fibrosis foundation. methods and results: we have characterized aav serotypes - in addition to twenty novel vectors isolated from human or macaque tissues to transduce the murine airway epithelium in vivo. vectors [ e+ genome copies (gc)/mouse] expressing α- -antitrypsin (aat) and βgalactosidase (β-gal) were co-instilled into the mouse lung or nose. transgene expression levels were monitored by assaying aat concentration in serum as well as the number and cell-types positive for (β-gal) expression in lung and nasal airways. of all vectors tested aav and aav were the two most efficient vectors in conducting airways. when these aav vectors ( e+ gc) were subsequently evaluated on human ciliated airway epithelial cultures (haec), in contrast to our findings in mouse airways, aav failed to transduce haec, whereas aav resulted in~ % of the haec expressing transgene. since aav was the most efficient vector in mouse and human airway epithelium we performed structure-function analyses of the aav vector capsid and found two atypical capsid residues that were unique in otherwise conserved positions (f , k ). to generate a potentially fitter vector, residue f was mutated to its conserved state. residue k was found to confer lung tropism and was left unchanged. the resulting vector, aav . , transduced mouse lung and nasal airway with greater efficiency than all aav vectors tested. the increased transduction efficiency of this vector was also observed (~ %) in haec derived from six different human subjects. to continue our preclinical studies in a more relevant model, aav / . expressing egfp was tested in ciliated cultures derived from macaque airways and showed - % of cells expressing egfp one week after inoculation with e+ gc. confocal microscopy revealed that aav . targeted a significant number of ciliated cells: the airway cell-types that likely require cftr expression in cf patients. aav . expressing rhesus α-fetoprotein (rhafp) was then inoculated in the nasal airways of a rhesus macaque and transduction evaluated by monitoring concentration of rhafp in the nasal lavage fluid. we have found that rhafp expression remained high (~ ng/mg) and stable for at least days. conclusion: the enhanced transduction efficiency of aav / . vector in human and macaque airway cultures and its ability to stably transduce the nasal airway of a rhesus macaque in vivo demonstrates that aav / . is a good candidate gene transfer agent for the efficient expression of cftr in human cf airway epithelium. submitted for presentation at the american society of gene therapy. supported by gsk, cff, cfpo , p , mtcc. pharmacological correction of ∆f cftr cellular processing is a potential therapeutic strategy for cystic fibrosis. recent high-throughput screening has identified synthetic small molecules, such as bisaminomethylbithiazoles (corr- ), which partially restore chloride permeability in ∆f mutant cells. the purpose of this study was to examine the utility of natural compounds (chinese medicinal herbs) as ∆f correctors. a herbal compound fraction library was constructed from herbs most frequently used in traditional chinese medicine (tcm) that are believed to contain therapeutic compounds for a broad spectrum of human diseases including lung disease. for construction of the tcm fraction library, crude herbal extracts were first prepared by % ethanol extraction on soxhlet reflux apparatus followed by automated fractionation by preparative hplc. eighty fractions were collected from each of the herbs. each fraction contained to (average . ) individual compounds as determined by analytical hplc. collected fractions were dried and milligram of the material was dissolved in µl dmso to generate mg/ml solutions in -well plates. each -well plate contained fractions from one herb. high-throughout screening was done using the frt cell-based fluorescence assay developed previously (j. clin. invest. : - , . of , fractions screened, active fractions from herbs were identified, with positive fractions verified in secondary screening. the positive fraction did not increase halide transport in control non-transfected cells, and halide transport in ∆f -corrected cells was fully abolished by cftrinh- . we have fractionated some of the most active fractions by preparative hplc to identify which compound(s) conferred activity. for example, in one fraction there were single compounds, of which conferred corrector activity with ic s < µm and efficacy comparable to that of low temperature rescue. these results demonstrate the feasibility of ∆f -cftr corrector discovery from natural compounds. further fractionation, characterization and structure determination are in progress. the unexpectedly high 'hit'rate for the natural compounds suggests their further exploration in cf therapy. cystic fibrosis (cf) is the most common genetic disease affecting the caucasian population, with an incidence of approximately one in three thousand births. cf transpires as a result from a mutation in the cystic fibrosis transmembrane conductance regulator protein (cftr), which regulates ion transport across epithelial membranes. subsequently, patients afflicted with cf have an abnormally excessive incidence of chronic lung infection, with organisms such as pseudomonas aeruginosa. because cystic fibrosis is characterized by chronic bacterial infections, excessive neutrophil recruitment to the lungs, and a coinciding increase in pro-inflammatory cytokine production and nuclear factor-kappa b (nf-κb) activation, we hypothesized that exogenous addition of the nf-κb inhibitor iκbα might ameliorate this phenotype. we cloned the human iκbα gene as well as a mutated iκbα gene into plasmids with chicken-beta actin hybrid promoters. we then tested the new plasmids, paav .cb-hiκbα and paav .cb-hiκbαm, in vitro in the presence and absence of pseudomonas aeruginosa infection in the ib - and s cell lines. both plasmids produce iκbα at high levels as shown by enzyme linked immunosorbant assays (elisas). we also show that paav .cb-hiκbα transfected ib - cells, after infection with pseudomonas aeruginosa, express significantly reduced levels of interleukin (il)- β ( fold, p< . ), il- ( fold, p< . ), and tnf ( fold, p= . ) as well as nf-κb activation ( fold, p< . ) compared to p. aeruginosa-infected ib - controls as determined by human cytokine and nf-κb phosphoprotein bio-plex assays; cytokine expression and nf-κb activation levels in infected paav .cb-hiκbα transfected ib - cells were between levels found in infected ib - and s- cells, excluding il- levels which were below s- levels of expression. flavonoids are among the most potent cftr modulators known. equol [ hydroxy- -( '-hydroxyphenyl)-chroman] is a product of intestinal metabolism of dietary isoflavones such as daidzein, and has been of recent interest in studies of cancer, cardiovascular risk, and neurologic disease. equol is metabolically stable, and % circulates in the free (non-protein bound) form, which is considerably greater than the proportion of free daidzein ( %). structural differences such as modification of ring c (e.g. saturation at c- / , and absence of carbonyl group at c- ) and an absent hydroxyl at position c- distinguish equol from compounds previously reported to modulate cftr activity. in prior work by our center, we showed that equol activates wt and ∆f cftr in membrane patches excised from bhk cells and in cfbe o-monolayers studied in ussing chambers. activation by equol occurred only after r-domain phosphorylation in wt and ∆f cftr constructs, but was independent of rdomain phosphorylation in ∆r cftr, indicating activity may be related to dimerization of the nbds or other domain-domain interaction. because a molecule that alters nbd interactions might have effects on the aberrant processing of ∆f cftr, we screened equol and other flavonoids by preincubating compounds with cfbe o-cells expressing ∆f cftr for hours, and then tested for rescue of cftr dependent cl-channel activity after exchange of media solution. we found that preincubation with equol ( - µm) induced rescue of short-circuit current compared to vehicle treated cells ( vs. µa/cm , p< . , n= ). we then evaluated hour preincubation with equol ( um) for biochemical evidence of cftr processing correction in ∆f cfbe o-cells grown in polarizing conditions. immunoprecipitation and in vitro phosphorylation demonstrated minimal formation of band c compared to vehicle treated cells, but adaptation of a more sensitive avidin label/biotinylation assay specific for surface localized cftr revealed clear evidence that equol preincubation led to cftr at the plasma membrane. next, we examined equol in hela cells stably transduced with ∆f cftr. preincubation of equol led to dose-dependent increases in halide transport measured by fluorescence-based halide efflux (spq) after stimulation by genistein ( . and . fluorescence slope (∆%/sec) with equol and µm respectively, compared to . ∆%/sec in cells pretreated with vehicle alone; p< . , n= - cells/condition). immunohistochemical staining of ∆f hela cells for cftr with - c-terminus antibody showed rescue of surface localized protein with equol ( µm) preincubation for hours, while vehicle treated cells showed only perinuclear staining. in summary, we show functional, biochemical, and immunohistochemical evidence that the naturally occurring flavonoid equol corrects the ∆f processing defect in two model systems. a naturally occurring agent that both activates and corrects ∆f cftr deserves further exploration as a potential cf therapeutic, and may lead to new insights regarding domain-domain interactions that influence the activation and biogenesis of the mutant channel. supported by nih and cff. mote ∆f cftr maturation has been identified. although several small molecule agents have been described that overcome ∆f cftr processing defects in specific cellular models, few studies have directly compared the activity of temperature corrected and chemically corrected ∆f cftr in polarized cell systems. in the present study, we examined chemical and temperature corrected activity of ∆f cftr. correctors included all members of the cfft modulator library (c , c , c , and c ; rosalind franklin university, chicago, il). in a screen using ∆f cfbe omonolayers, maximal corrector activity across the two model systems exhibited a rank order of c >> c > c = c , using forskolin ( µm) and genistein ( µm) stimulated isc as a sensitive test for ∆f cftr activity at the plasma membrane. no change in isc was observed in matched control (parental) cells lacking ∆f cftr expression. based on these results, we further defined the activity of c in ∆f cfbe oand frt model systems, including dose/response and time dependence for peak isc rescue. in cfbe o-cells, exposure to µm c for hrs produced maximal reproducible correction of ∆f cftr processing, with loss of activity following prolonged or high concentration exposure; in frt cells, peak effects were seen at hours. ∆f cftr activity following small molecule treatment qualitatively mirrored temperature correction ( °c growth for - hrs) in both cell types. maximal currents produced by stimulation with forskolin ( um) and genistein ( µm) in ∆f frt monolayers following c pretreatment were % of that produced by temperature correction (p< . ). forskolin was responsible for % of maximal current in frt ∆f cells following chemical correction and % of maximal currents following temperature correction. in ∆f cfbe o-cells, maximal currents following chemical correction were % of that produced by temperature correction (p< . ). forskolin was responsible for . % of maximal currents in cfbe o -∆f cells following chemical correction and . % of maximal currents following temperature correction. these results illustrate dose and time response with a small molecule corrector in two polarizing epithelial model systems, and provide reassurance that observations based upon ∆f cftr following low temperature incubation are relevant to functional analysis after chemical correction. similarity in activation properties between chemical and low temperature correction suggest it is unlikely that the two maneuvers result in ∆f cftr with significantly different structural properties. the studies also indicate fundamental differences in ∆f cftr behavior in frt compared to cfbe ocells, and emphasize the importance of identifying an agent that can restore camp dependent regulation to bronchial epithelial cell types. supported by the nih, cff and cfft. participants: n= patients ( randomised to azm and to placebo) who had successfully completed a course of intravenous antipseudomonal antibiotics immediately before the trial (mean age: . years; mean fev : % of predicted). measurements and results: after treatment (mean dose of . mg/kg body weight once a week) pulmonary function declined in both groups compared to baseline (i.e. after cessation of iv antibiotics). the azithromycin group had signifcantly better results regarding the mean changes in serum crp (azm: + . mg/l, placebo: + . mg/l, p= . ), lipopolysaccharide binding protein in serum, lbp (azm: + . µg/ml, placebo: + . µg/ml, p= . ), serum interleukin- (azm: - . pg/ml, placebo: + . pg/ml, p= . ) and alginate in sputum (azm: + µg/ml, placebo: + µg/ml, p= . ). quality of life (german version of the cfq) showed significantly better results after azm in adolescents and adults. azithromycin was well tolerated with no increase in treatment-related adverse events. conclusion: once-weekly azithromycin ameliorated inflammatory reactions and improved quality of life. a decline of pulmonary function after cessation of intravenous antibiotics could not be prevented, however. this study has been sponsored pfizer gmbh, germany this open-label, multicenter study was conducted in the usa and australia to evaluate the clinical responsiveness of a patient-reported outcome measure, the cfq-r respiratory scale, by determining the minimal clinically important difference (mcid) following a -day course of tobramycin inhalation solution (tis). cf patients (n= [≥ to < yrs, n= ; ≥ yrs, n= ]) with pseudomonas aeruginosa and clinical symptoms predictive of a pulmonary exacerbation (increased cough, increased sputum /chest congestion, decreased exercise tolerance or decreased appetite) were enrolled. three efficacy measures were included: )change in forced expiratory volume in second (fev ) from baseline (day ) to end of treatment (day ) or end of study (day ); )one question about change in respiratory function (days and ; global rating of change questionnaire, respiratory domain, grcq rd; =no change; =maximal improvement or worsening);and )change in cfq r-respiratory scale (day , ). average change from baseline fev (mean [standard deviation, sd]) was . % ( . ) at day and . % ( . ) at day . based on grcq-rd at day , patients ( %) reported no change in respiratory symptoms (score < . ), ( %) a minimal change (≥ . to < . ), ( %) a moderate change (≥ . to < . ), and ( %) a large change (≥ . ). mean (sd) change from baseline cfq-r respiratory was . ( . ) at day and . ( . ) at day . at day , change in cfq-r was moderately correlated with change in fev and with grcq-rd; the correlation was stronger for patients with baseline fev < % of predicted fev values (see table) . mean change from baseline on the cfq-r respiratory scale was . at day for patients with grcq-rd scores indicating minimal change in symptoms (≥ . to < . ; n= ); this provided an estimate of the mcid for the cfq-r respiratory scale for those in exacerbation. this mcid value was consistent with estimates from distribution-based methods( ⁄ sd and standard error of measurement). the cfq-r was responsive to changes in pulmonary symptoms in patients in mild exacerbation following tis treatment; the mcid in this population was . points. responses on the cfq-r-respiratory scale were moderately correlated with changes in fev . funded by gilead sciences, inc. this was an open-label, multicenter study conducted in the usa. we determined the minimal clinically important difference (mcid) for the cfq-r, respiratory scale following a -day course of tobramycin inhalation solution (tis) in patients with cf and chronic pa infection (n= , children [< yrs]). patients had received ≥ courses of tis (mean = . ) within the previous year, however their respiratory symptoms were stable at study entry, with forced expiratory volume in second (fev ) between % to % of predicted values. efficacy measures included: ) percent change in fev (l) from baseline (day ) to treatment end (day ); ) a single question about change in respiratory function (day ; global rating of change questionnaire; respiratory domain, grcq-rd; =no change, =maximal improvement or worsening); ) change in cfq-r-respiratory scale (day to ); and ) change in log pa colony-forming unit (cfu) density in sputum (day to ). the mcid for cfq-r was estimated using three methods: ) change in cfq-r (day to ) for the patient subset with minimal change in respiratory function, as determined by the grcq-rd at day ; ) cfq-r standard error of measurement (sem) from a validation sample), and ) ⁄ standard deviation (sd) of the cfq-r respiratory scale scores. at day , change from baseline fev (mean [sd]) was . % ( . ), change from baseline cfq-r was - . ( . ), and change in log pa cfus was - . ( . ) . based on the grcq-rd at day , patients ( %) reported no change in respiratory symptoms (score < . ), ( %) a minimal change (≥ . to < . ), ( %) a moderate change (≥ . to < . ), and ( %) a large change (≥ . ). pearson r-values for the correlation of change in the cfq-r-respiratory scale and change in fev , log cfus and grcq-rd were . , . , and . , respectively. estimates of the mcid for cfq-r-rd ranged from . to . for adults/adolescent patients (table) . in patients with cf who had no immediate need for antipseudomonal therapy at study entry, the cfq-r-respiratory scale appeared responsive to changes in patient disease perception following days of tis treatment; the mcid for cfq-r was approximately points for the adolescent/adult patient population. funded by gilead sciences, inc. ex vivo chloride secretion measurements (intestinal current measurement, icm) in cf patients have been established over the past years to study the cftr-basic defect in more functional detail. modified micro-ussingchambers are used to registrate the transepithelial short-circuit current (isc) in freshly obtained human rectal suction biopsies as a measure of ion transport after stimulation with secretagogues. hereby, the cftr clchannel, its amount of residual function in cf and alternative cl-channels can be investigated by a standardised protocol.in the course of the development of cftr pharmacotherapeutics as well as agents activating alternative cl-channels, icm may function as an useful outcome parameter in preclinical and clinical trials. it is easy to perform repeatedly at all patients ages and comprises the safety advantages of an ex vivo method which is relevant especially for early study phases. aim of this study was to describe reference values and quantify the intraindividual variability of different icm parameters. methods: a total of n= rectal biopsies from n= individuals; with pancreatic insufficient (pi)-cf (n= ; mean age . years), pancreatic sufficient (ps)-cf (n= ; . years), excluded cf by icm diagnostics (n= ; . years) and healthy control (n= ; . years) were included into analysis. for calculation of intraindividual variability, - biopsies/patient were compared with respect to basal tissue resistance (rt basal), basal open circuit potential difference (pd basal), basal short circuit current (isc basal) and the isc responses to stimulation with carbachol ( - mol/l, serosal), -bromocyclic monophosphate (camp) ( - mol/l, mucosal+serosal) + forskoline ( - mol/l, serosal) and histamine ( x - mol/l, serosal).results:we determined icm reference values for the groups of pi-cf (isc basal . ± . µa/cm , ∆isc carbachol . ± . µa/cm ,∆isc camp/forskoline . ± . µa/cm ,∆isc histamine - . ± . µa/cm );ps-cf (isc basal . ± . µa/cm ,∆isc carbachol . ± . µa/cm ,∆isc camp/forskoline . ± . µa/cm ,∆isc histamine . ± . µa/cm ),and healthy control (isc basal . ± . µa/cm , ∆isc carbachol . ± . µa/cm , ∆isc camp/forskoline . ± . µa/cm , ∆isc histamine . ± . µa/cm ). for the total cohort, mean coefficients of variation were: rt basal %, pd basal %, isc basal %, ∆isc carbachol %, ∆isc camp/forskoline %, ∆isc histamine %. conclusion:this first comprehensive analysis of the intraindividual variability of icm basal tissue and cl-secretion parameters provides the basis for the method as an useful outcome measure for future clinical trials aiming to rescue the cftr basic defect. possible effects of pharmacological therapeutics in cf relevant human epithelia have to be adequately interpreted with respect to subject variability and laboratories reference data. ex vivo cl-secretion measurements have the potential of being an essential step in the evaluation process of cftr-correcting/potentiating agents on their way from laboratory screening to the application in human cf tissue without any risk of toxicity. center, placebo-controlled, double-blinded pilot study we assessed safety and tolerability of . mg/d moli versus placebo (normal saline) administered by inhalation (pari lc plus) once daily for days. patients included were ≥ years of age in phase i and ≥ years of age in phase ii, with a fev > % predicted and stable lung disease. overall, subjects received moli and placebo. exclusion criteria included abpa, b. cepacia infection and severe liver disease. the study involved clinic visits over a period of weeks to assess adverse events, spirometry, pulse oximetry and quality of life. a total of adverse events (aes) were observed in subjects ( ae in subjects receiving moli ), with only (productive cough) in the moli group being of severe intensity. the most frequent aes related to the study medication were (productive) cough ( x) and dry throat/throat irritation ( x), and most of these resolved within hour after inhalation. in the moli group no significant ae, defined as a decline of fev ≥ % from baseline accompanied by symptoms, a decrease in oxygen saturation to < % or a fall of % from baseline requiring therapeutic intervention, or a change in safety parameters judged to be clinically significant was observed. this trial was not primarily designed to show efficacy; however, the median change in fev from day to day was - % in the placebo group, and + % in the moli group, and this difference was significant (wilcoxon test, p= . ). similarly, there was a significant difference between the median change in fef - % from day to day in the placebo group as compared to the moli group (- % vs. + %, p= . ). no significant changes were observed for the other study days or for fvc and pulse oximetry. moli was well tolerated in this trial, with the observed aes generally being mild and of short duration. these encouraging explorative results are currently being further evaluated in explorative and confirmatory trials. introduction: results from published data elucidate that microbes found in the upper respiratory tract are similar or the same as those found in the lower airways of cf patients. inhaled, aerosolized drug delivery to the lower respiratory tract is an established treatment route. however, drug delivery systems capable of depositing drug to the paranasal cavities are not yet established and require evidence of deposition and efficacy. pari developed the vibrent™ paranasal drug delivery system to enable the aerosol and drug to penetrate into the nose and sinuses. objectives: this study was conducted to demonstrate that the pari vibrent™ pulsating drug delivery system is capable of ventilating the human paranasal sinuses of healthy volunteers. methods: mkr-gas was continuously ventilated through the nasal tract of three healthy non-smokers in front of a single-head gamma camera (diacam, siemens, germany), using the pari vibent™ pulsating drug delivery system. the nebulizer was coupled to the right nostril and a flow resistor to an output tube was inserted into the left nostril. during ventilation with the krgas (about sec) the subject closed their soft palate to transmit the pulsation and to prevent penetration into the lower respiratory tract. the gas supply of the vibrent™ was directly taken from the mkr-gas generator output channel. kr-gas ventilation imaging was performed with and without pulsation. serial images were recorded with anterior and lateral views. additionally, mri (magnetic resonance imaging) lateral slices of the subjects' head were recorded. the gamma camera images were superimposed to the mri images by adjusting the spatial resolution. with no pulsation from the vibrent™ no ventilation of sinus cavity was visualized by gamma camera images and radioactivity was detected in the nose only. when pulsation was added the maxillary sinuses can be visualized in the gamma camera images of all volunteers. conclusions: without pulsation no ventilation was observed. gas penetration to the paranasal sinuses can be demonstrated using the pulsating action of the pari vibrent™, potentially enabling drug delivery via aerosols. this confirms results of in vitro studies using a cast model. mkr-gas ventilation of the nasal cavities during sec breath holding in front of a planar gamma camera head (anterior) using the pari vibrent without (w/o, left image) and with (w, right image) the pulsation system. the delivery and the exhaust tubing of the kr-gas are shown together with the outline of the head, obtained from mri pictures. introduction: pediatric patients with cf were previously studied in clinical trial studies of denufosol, a novel selective p y agonist that enhances ciliary beat frequency and activates chloride secretion to hydrate the airways in the lung. pediatric patients are often discouraged from participation in clinical trials until later stages of drug development. aims: in order to evaluate the safety experience with denufosol in this population, we have retrospectively examined integrated data for pediatric cf patients with mild to moderate pulmonary disease that participated in three phase studies. demographic and baseline characteristics in addition to safety and tolerability results for cf patients aged - years old are reported. methods: three phase , multicenter, randomized, double-blind, placebo-controlled, parallel group studies were conducted. patients were randomized to receive either denufosol ( , or mg) or placebo (normal saline) tid for days by inhalation. only study included denufosol mg, while all studies included denufosol mg and mg. the fev predicted normal required to be eligible was > % (study ); %- %, inclusive (study ); > % (study ). all three studies included a one-week pre-randomization period during which reproducibility of fev (l) ± % was required in order to be randomized to double-blind study medication. patients were allowed to use bronchodilators, dornase alfa and corticosteroids in studies , and . patients were allowed to use oral antibiotics including macrolides and inhaled tobramycin solution in studies and . results: a total of cf patients - years old were randomized and dosed in three -day studies. eighty-one received denufosol (active doses combined) and received placebo. demographics were similar for all treatment groups -denufosol pediatric patients had a mean (sd) age of . (± . ) years old compared to placebo pediatric patients who had a mean (sd) age of . (± . ) years. denufosoltreated patients were % male and placebo-treated patients were % male. the mean (sd) percent predicted fev at baseline was similar between treatment groups [ . % (± . ) and . % (± . ) for denufosol and placebo, respectively]. the overall incidence of treatment emergent adverse events (ae) was similar between treatment groups ( % denufosol, % placebo). the most common ae was cough, reported by % and % of patients that received denufosol and placebo, respectively. seven percent of denufosol and % of placebo patients prematurely discontinued from the study due to aes. there were no differences in compliance with administration of study drug ( % in patients given denufosol and % in patients given placebo). conclusion: doses of denufosol up to mg given tid for days were well tolerated in pediatric cf patients - years old. these data demonstrate that inclusion of patients - years old is feasible regardless of administration of denufosol or placebo. a longer term phase study of denufosol in cf patients > years old in north america is currently ongoing. acknowledgements: this research was funded by inspire and the cystic fibrosis foundation. objective: pulmonary delivery of anti-infectives provides the potential to attain pk-pd indices exceeding those which can be achieved with systemic dosing. mp- is a novel formulation of levofloxacin that enables delivery of high concentrations over a short period, and provides taste masking. the objective of this study was to: i) determine the safety of aerosol doses of mp- and, ii) determine pharmacokinetics of levofloxacin in serum, urine, and sputum following aerosol doses of mp- using the pari eflow nebulizer in normal healthy volunteers (nhv) and patients with cystic fibrosis (cf). methods: nhv and patients with stable cf were enrolled in a single within-subject ascending dose study of dose levels (loaded doses of , , and mg) of inhalational mp- (levofloxacin solution for inhalation) or placebo. study participants were monitored for safety and changes in pulmonary function. serum, urine, and sputum (cf patients only) samples were collected at various times following the dose and assayed for levofloxacin concentration using hplc. in addition, each participant received a single iv dose of levofloxacin to determine the systemic bioavailability following aerosol mp- . noncompartmental and compartmental methods were used to determine serum, sputum and urinary pharmacokinetic parameters. pharmacokinetic deconvolution methods were used to determine the amount of the dose remaining in the lung over time. results: this study is ongoing. dosing in nhvs ( active mp- , placebo) has been completed. there were no serious adverse effects, and no significant changes in pulmonary function were noted. preliminary pharmacokinetic data from nhvs show a proportional increase in serum levofloxacin concentrations with increasing aerosol mp- dose; serum aucs were . , . , . , and . mg-h/l for the iv dose, low, mid, and high aerosol doses, respectively. deconvolution of the serum levofloxacin concentrations from aerosol mp- and iv dosing shows absorption of drug from lung over time. conclusion: preliminary results show that mp- is well tolerated following aerosol administration in normal volunteers. serum concentration data following aerosol dosing suggests that absorption of levofloxacin into the systemic circulation is a major route of elimination from the lung. studies in cf patients are in progress and will be presented. methods: a mg/kg aerosol dose of mp- was given using a microspray aerosol generation device. when placed just above the tracheal bifurcation, and activated, it delivers a bolus aerosol dose to the lung. a mg/kg intravenous (iv) dose of lvx was given as a slow bolus into the lateral tail vein. plasma lvx was determined in all rats up to sacrifice at , , , or hours, at which time rats were humanely euthanized and bronchialalveolar lavage (bal) performed. fluids were analyzed for lvx concentration using an hplc/ms method. results: the plasma lvx versus time profiles of both iv and aerosol doses were best described by a two compartment model. the plasma auc after an iv dose of levofloxacin and an aerosol dose mp- were similar ( . mg᭹hr/l vs. . mg᭹hr/l, respectively) suggesting near % bioavailability from the lung. after an aerosol dose, the mean residence time (mrt) was prolonged when compared to the intravenous dose ( . vs. . hours). this delay in absorption was associated with an increase in bal lvx auc - h in bal ( . mg᭹hr/l vs. . mg᭹hr/l for iv vs. aerosol dosing, respectively). conclusion: these data show that levofloxacin is highly available to plasma following a single microspray aerosol dose of mp- . the aerosol dose does produce a slightly longer mean residence time in plasma, suggesting delayed, but complete absorption from the lung; this delay in absorption was associated with increase in bal aucs. these data suggest that high concentrations of lvx can be attained in lung fluids following an aerosol dose of mp- . auc: area under the time-concentration curve; cl: clearance; cmax: maximum concentration; f: bioavailability; mrt: mean residence time. methods: animals were assigned to one of five exposure groups for all studies. for the -day toxicology studies, animals were exposed for up to four hours daily for twenty-eight consecutive days, followed by a -day recovery period. respiratory function and cardiovascular safety were conducted on the first and last day of the -day study in dogs. rats were exposed to , , or mg/kg/day, and dogs were exposed to , , or mg/kg/day. at the conclusion of the study, necropsy was performed and all respiratory tissues were harvested, weighed, and underwent gross and microscopic examination. a separate dog respiratory safety study was conducted in which dogs were exposed to , , or mg/kg. results: four week repeat dose inhalational exposure of mp- at target doses up to mg/kg/day in dogs and mg/kg/day in rats was not associated with any test article-related changes in any respiratory tissues. aerosol administration of mp- at doses of up to mg/kg in dogs was found to have no acute effects on minute volume, tidal volume, respiratory rate, or ecg. conclusion: local effects due to the inhalational administration of levofloxacin formulated as mp- were not observed in either rats or dogs. these data suggest that the risk of respiratory toxicity from nebulized doses of mp- is low. methods: bacteria were grown overnight in mueller-hinton broth (mhb) at °c and then sub-cultured into fresh mhb and allowed to reach log phase ( hours). female swiss mice were infected under anesthesia by intratracheal instillation of . ml of a x cfu/ml bacterial suspension. ip doses were selected to provide lvx exposures (as auc) comparable to that obtained with systemic dosing regimens. for the p. aeruginosa infection, treatment was initiated by either the ip or aerosol route hours post-infection. mice were euthanized and hours after the start of treatment, lungs harvested, and bacterial counts in lung determined. results: lvx plasma pharmacokinetic profiles were nearly identical following intraperitoneal or aerosol dosing. the geometric mean log cfu/lung pair (sd) for the p. aeruginosa are shown in the table below: in both the k. pneumoniae and p. aeruginosa lung infection studies, aerosol administration was more effective than systemic administration; for k. pneumoniae, the extent of bacterial killing at hrs was ca. . log cfu greater with aerosol mp- than with systemic lvx. conclusion: aerosol administration of mp- produces a greater extent of bacterial killing than systemic dosing of lvx in mouse models of pneumonia due to k. pneumoniae and p. aeruginosa. the majority of morbidity and mortality in cystic fibrosis patients is caused by chronic and persistent lung infections especially with pseudomonas aeruginosa. since galactosyl ceramide had been previously shown to be involved in pseudomonas internalization, ceramide levels in the plasma of cf patients were assessed and compared to healthy volunteers using hplc followed by mass spectrometry. the results demonstrated that cf patients displayed significantly lower levels of several ceramide species. also, cftr-knockout mice displayed diminished ceramide levels in cf related organs (lung, pancreas, and ileum) and plasma compared to wildtype controls. treatment with a semi-synthetic retinoid (fenretinide), which was previously reported to induce ceramide in neuroblastoma cell lines, was able to increase ceramide concentrations in cf related organs in cftr-knockout mice to the levels of wildtype mice. treatment also dramatically improved the ability of cftr-knockout mice to control pseudomonas infection. following infection with pseudomonas-impregnated agar beads, fenretinide treated cftr-knockout mice were able to clear bacterial infection as efficiently as wildtype mice. overall, these findings not only documented a novel deficiency of ceramide in cf patients but also demonstrated a pharmacological means to correct this defect in cftr-knockout mice. our data provides a strong rationale for clinical intervention that may benefit cystic fibrosis patients suffering from cf lung disease. recent reports show that adult bone marrow-derived stem cells can localize to and acquire phenotypic and functional markers of lung epithelium. these findings raise the novel possibility of stem cell therapy for multitude of lung diseases. however, only small numbers of adult marrowderived stem cells localize to lung and it is not clear whether these cells will be clinically useful. we investigated whether mesenchymal stem cells (mscs) obtained from human cord blood might have increased potential to participate in structural lung remodeling. cord blood was obtained from normal deliveries at the university of vermont. mononuclear cells were isolated and plastic adherent cells were expanded and characterized as mscs according to international society for stem cells research (isscr) criteria. following systemic ( x cells/mouse by tail vein) administration to sublethally irradiated ( . gy) immunodeficient (nod/scid) mice, lungs harvested day, weeks, or months later demonstrated small numbers of human b -microglobulin positive cells in the airway epithelium at all time points. small number of cells was found also stain positive for pancytokeratin (pan-ck) and rarely, we identified cells of b -microglobulin+/pan-ck+ in the airway epithelium of these mice after weeks. we are currently characterizing the phenotype of these cells with ccsp and cftr but these data suggest that cb-mscs may be a potential alternative source of stem cells for use in lung remodeling. high-throughput screening (hts) and other drug development programs have identified cftr activators and potentiators that require secondary evaluation and mechanistic confirmation. we recently evaluated the cfft modulator library (rosalind franklin university, chicago, il) and found some, but not all, cftr potentiators induced potent phosphorylation of the regulatory-domain (r-d), conventionally viewed as the first step in cftr activation. to assess whether this observation has functional significance regarding ion channel activation by these agents, we evaluated cftr potentiators in cfbe o-and fisher rat thyroid (frt) cells stabily transduced with ∆f cftr. cells were studied in modified ussing chambers under control conditions and after correction of ∆f cftr misprocessing using either low temperature ( οc x hrs) or pre-incubation with the chemical corrector c . total currents were determined following potentiator (at reported ec ), forskolin ( µm), and genistein ( µm) stimulation. in temperature corrected ∆f cfbe ocells, potentiator (p , cfpot- ), an agent that does not induce r-d phosphyorylation, caused modest activation when acutely administered ( µm) ( . vs . µa/cm in vehicle treated cells, p < . ). importantly, this agent potentiated forskolin mediated short-circuit current (isc: . vs . µa/cm , p < . ). forskolin accounted for % (vs. % with vehicle) of total current, demonstrating potent rescue of camp dependent cftr activity, an effect not previously reported in this cell type (p< . ). in contrast, two cftr potentiators that induce r-d phosphorylation, p (uccf- , a benzoflavone intermediate, µm) and p (uccf- , an isoxazole, µm) induced modest direct activation of cftr ( . and . µa/cm respectively, p= . and p< . ), but no evidence of forskolin potentiation (p : . µa/cm , % of total stimulated current p=ns; p : . µa/cm , %, p=ns). in ∆f frt cells grown at low temperate, p elicited strong potentiation of forskolin mediated currents ( . vs. . µa/cm with vehicle, p < . ), and modest direct cftr activation ( . vs. . µa/cm , p < . ). p and p were limited to minimal (not significant) activation and no evidence of forskolin potentiation. in cfbe oand frt cells pretreated with c (to chemically correct ∆f cftr processing), p again potentiated forskolin mediated current ( . vs. . µa/cm with vehicle, p< . in the frt model) but did not directly activate i sc . findings with p and p were otherwise as seen with low temperature corrected cells. in summary, in ∆f cftr polarized epithelia, p both activates and potentiates cftr activity (with potentiation being the predominant effect, a unique observation in cfbe ocells), while p and p confer activation of cftr without forskolin potentiation. given that p and p induce r-d phosphorylation while p does not, our findings suggest that agents that do not confer phosphorylation of the r-d may be better suited to rescue the endogenous camp mediated component of i sc . screening of potential therapeutic agents for effects on r-d phosphorylation may help predict utility at restoring ∆f chloride channel activity. supported by nih and cff. activation of cftr is conventionally viewed as a two step process: pka-regulated phosphorylation of multiple sites within the regulatory domain (r-domain), followed by atp dependent gating mediated by binding sites at the interface of the two nucleotide binding domains (nbds). cftr 'potentiators', small organic molecules that overcome mutant cftr gating defects at the cell surface, have been proposed as therapies for cf. although a number of these agents are advancing to the clinical testing phase, their mechanism(s) of action are not well understood. as a step towards better characterizing cftr potentiators available through the cfft modulator library or other resources, we are developing standardized biochemical and functional assays to evaluate the r-domain during cftr activation in living cells. we have previously described a gel-shift method by which phosphorylation of isolated r-domain (residues - ) can be monitored. using this method, we have confirmed that one potentiator, p (cfpot- ), does not induce phosphorylation of the r-domain ( % of forskolin response, n= , p = ns). unexpectedly, two potentiators, p (uccf- , a benzoflavone intermediate) and p (uccf- , an isoxazole), robustly confer phosphorylation of the r-domain (p : % of forskolin response, n= , p = . , p : % of forskolin response, n= , p = . ). we found the phosphorylation conferred by either p or p could be inhibited with the pka inhibitor h ( µm). maximal stimulation of phosphorylation occurs within minutes, indicating time dependence similar to forskolin. importantly, neither p nor p increased total cellular camp, a finding confirmed by a number of other laboratories. the results may therefore implicate compartmental inhibition of cftr-associated phosphotases (eg. pp a) or phosphodiestereases (eg. pde ) as an underlying mechanism by which isoxazole or certain flavone-derivative compounds stimulate cftr. to further test this hypothesis, p , p and p are being examined for effects on ∆r-cftr chloride channel activity. these studies provide a means by which novel cftr potentiators can be biochemically categorized based on r-domain phosphorylation, a measure of the first step of cftr activation. compounds working through distinct mechanisms may have particular relevance to certain cftr mutations, and could provide synergy in the clinical setting. supported by nih and cff. mucociliary clearance (mcc) is an innate defense mechanism that protects the lungs from bacteria and viruses. mcc requires maintenance of a thin layer of airway surface liquid (asl) to eliminate inhaled particles. the asl volume is tightly regulated by a balance of ion and water transport across the airway epithelia. in cf, the loss of cftr clsecretion coupled with unregulated na + absorption via enac results in asl volume depletion and impaired mcc. although significant progress has been made in the identification of the basic disease mechanism in cf, therapeutic approaches that address abnormal cftr biogenesis are not currently available. the extracellular nucleotides atp and utp are important mediators of asl volume and mcc. in the airways, secreted atp acts on the g-protein coupled p y receptors to fine-tune mcc via the regulation of apical ion transport, ciliary beating, and mucin secretion. we have previously demonstrated that atp controls asl volume by inhibiting absorption through enac and increasing secretion through apical membrane chloride channels. p y receptor agonists are good candidates to treat cf. however, the rapid hydrolysis of atp and utp on the airway surface of cf patients limits the effectiveness of this approach. consequently, inspire pharmaceuticals has developed di-nucleotide molecules which retain the ability to activate p y receptors, but are more resistant to hydrolysis by ectonucleotidases. denufosol, inspire's lead compound for cf treatment, potently activates p y receptors to stimulate cl -/water secretion, ciliary beating, and mucin release in epithelial tissues. however, the stability and potency of denufosol has not been determined using human bronchial epithelial (hbe) cells. in primary cultures of hbes, denufosol was significantly more stable than utp. under thin-film conditions, the initial hydrolysis rate of a therapeutic concentration of denufosol ( mm) was . nmol × min - × cm - with a half-life of approximately hour. by comparison, denufosol is more than times more stable than utp on the mucosal surface of hbes. importantly, the increased stability of denufosol translated into an increase in efficacy for this compound in vitro. equipotent concentrations of denufosol and utp significantly increased asl height. however, denufosol produced maximum asl height increases that were both greater ( . % versus . % maximum increase over basal asl for denufosol and utp, respectively) and longer-lasting ( . % versus . % increase over basal asl following a minute application of denufosol and utp, respectively) compared to utp. furthermore, the asl height increases are specific for denufosol as the addition of apyrase blunts the response to utp, but not denufosol. our data demonstrate that denufosol is more stable than utp on the mucosal surface of human airway epithelia, which results in larger and more sustained increases in asl volume. recent phase ii clinical trials show that administration of denufosol over days was well tolerated and associated with improved lung function in mild cf patients. taken together, these data suggest that denufosol is a promising candidate molecule for cf therapeutics. mucociliary clearance (mcc) is the primary airway host defense against chronic exposure to infectious and noxious agents. mcc is dependent upon ciliary beating and the volume and composition of the airway surface liquid (asl). asl volume is regulated via isotonic fluid transport which is dominated by na + absorption in the superficial epithelium. in cf, unregulated na + absorption through enac drives asl volume depletion and a subsequent decline in mcc. the accumulation of mucus in the airways of cf patients supports persistent and life-threatening bacterial infection. increasing airway surface hydration represents a promising therapeutic approach for treating cf. in vivo, aerosolized osmotic agents such as hypertonic saline (hs) improve mcc and lung function in cf patients. however, the benefits derived from hs treatments are transient, as nacl is relatively rapidly absorbed by airway epithelia. previously, donaldson et al. (nejm ) tested the hypothesis that blocking na + absorption with the enac inhibitor amiloride would increase the efficacy and extend the benefit of hs. surprisingly, amiloride blunted the response to hs, which resulted from a previously unrecognized property of amiloride to inhibit aquaporin-mediated water transport. while potent inhibitors of enac would likely be of great benefit to the cf treatment milieu, the compounds then available were not adequate for this purpose. parion sciences has developed novel -substituted pyrazinoylguanidine compounds that selectively inhibit enac and are > -fold more potent than amiloride. in the present study, we evaluated the ability of two compounds, - and , to increase asl volume under thin film conditions. in primary cultures of human bronchial epithelial cells (hbes), - alone produced a small, but significant increase in asl height. in cf cultures exposed to phasic motion that simulates the shear stress generated by normal tidal breathing, - alone increased asl heights by . %. additionally, we tested the effects of - pre-addition in combination with % hs. as expected, hs alone produced a rapid and substantial increase in asl height ( . % by minutes) which declined to % bỹ hour post-treatment. pre-treatment of cultures with - prior to hs was both more potent ( . % by minutes) and longer-lasting ( % initial response at ~ hours) than hs alone. on normal hbes cultures, the compound alone increased the basal asl height by . % following a hour exposure. similar to - , in combination with hs likewise extended the longevity of the hs effect (t / ~ h versus ~ h for + hs and hs, respectively). by blocking na + absorption, the parion compounds alone increased asl volume in both normal and cf hbes. strikingly, when used in combination with hs, the parion compounds enhance and sustain the increase in asl volume associated with hs alone. our data demonstrate that the parion compounds alone are sufficient to increase basal asl volume. furthermore, these data provide a proof-of-concept that combinational therapies utilizing osmotic agents and compounds that regulate ion transport will provide therapeutic benefits to cf patients. methods: a total of patients (with fev ≥ % of predicted) received mg of arikace by inhalation for days. drug was administered using the pari lc star nebulizer. laboratory parameters, adverse events and pulmonary function tests were collected for all study subjects in order to determine safety and tolerability of arikace™. sputum samples were collected to determine changes in bacterial density, and amikacin pharmacokinetic parameters were assessed at selected time points in urine, serum and sputum specimens. change in fev , fev % predicted, fef - % and fvc relative to baseline and change in log cfu on days and were assessed. results: on day , and , the observed change for fef - % was . (p < . ), . (p = . ) and . l/sec (p = . ), respectively. on day and , the observed change for fev was . (p = . ) and . l (p = . ), respectively, and was . (p < . ) and . l/sec (p = . ) for fev % predicted. significant relationships (p ≤ . ) between log cfu and serum auc:mic ratio, and between changes in log cfu and fev , fev % predicted and fvc were identified. treatment was safe and well tolerated with the most frequent adverse events being dyspnea and headache of mild to moderate severity. conclusion: inhaled arikace™ mg/ml was well tolerated and in select patients improved pulmonary function. together these clinically relevant changes from baseline likely represent drug effect and warrant further development of liposomal amikacin for inhalation in patients with cf. allergic bronchopulmonary aspergillosis (abpa) is a disease caused by hypersensitivity to aspergillus fumigatus (af). the prevalence of abpa is approximately %- % of patients with cf and can contribute to worsening of their pulmonary disease. the treatment of abpa consists of high-dose oral corticosteroids for many months and may include also antifungal antibiotic such as itraconazole. the clinical effectiveness of corticosteroids is usually shown by an improvement in clinical symptoms and radiological parameters, as well as a reduction in total ige. the prolonged period of systemic steroids may cause significant side effects such as cushingoid appearance, hypertension, glucose intolerance and more. over the past years, we have used pulse high-dose methylprednisolone in patients with cf. method:all patients were diagnosed as suffering from abpa by the standard criteria as the may have mucoid impaction or central bronchiectasis on chest radiography, an elevated ige (> iu/ml), the presence of specific ige anti af and an elevated eosinophil count. the patient may have a positive skin prick test to af allergen. they were treated once a month with iv pulse high-dose methylprednisolone ( mg/kg/a day) for days once a month for several months until the total ige decreased to normal values. three patients were treated also with itraconazole. in patients itraconazole was discontinues due to side effects. results: we treated patients age - years old ( m/ f). four patient are pancreatic insufficient and pancreatic sufficient. ige was +/- ( - ) at the time of diagnosis and decrease to +/- ( - ). fev increased from +/- to +/- . the patients also gained weight and improved their chest x-ray finding. side effect were minor and mainly during the treatment days and resolved - days after each treatment and included malaise during the infusions, glucose intolerance on infusion days in one case, and hypertension in another case. conclusion: iv pulse steroid treatment should be considered in abpa as it was found effective with fewer side effects that should be expected from prolonged oral corticosteroid treatment. lung pathology in individuals with cystic fibrosis (cf) is linked to sodium hyper-absorption. the defective regulation of the epithelial sodium channel enac is thought to be a major contributor to reduced airway surface liquid (asl) volume and impaired mucociliary clearance of the airways. thus, strategies designed to inhibit enac function may result in clinical benefit. rna interference (rnai), mediated by short, double-stranded rna molecules, can be used to target complementary rna sequences for degradation via the rna induced silencing complex (risc). we investigated the possibility of using rnai to reduce expression of enac in the mouse lung, as proof of principle for a strategy to reduce sodium hyperabsorption in the cf lung. potent sirna molecules capable of efficient knockdown of enac alpha, beta and gamma subunits were identified in an optimised cell culture system utilising mouse kidney m cells ( , cells per -well; pmol sirna complexed with lipofectamine ; hour harvest) in which enac expression was quantified using real-time rt-pcr. approximately % knockdown of each enac subunit was observed with the most potent sirna molecules in this system. subsequently, sirna molecules were delivered to the lungs of female balb/c mice via hydrodynamic tail vein injection ( µg naked sirna, n= - ). after hours, lungs were harvested, rna extracted and enac mrna measured using real-time taqman pcr. whereas, enac subunit mrna levels in mice treated with a negative control sirna were not different from untreated mice (p < . ), delivery of enac alpha and beta-specific sirna molecules resulted in a reduction to . ± . % or . ± . % of the expression levels observed in untreated mice, respectively (p < . , mann-whitney u). interestingly, despite efficient knockdown in cell culture, in vivo treatment with the most potent enac gamma-specific sirna molecule led to no reduction in enac gamma expression compared with untreated controls (p > . ). these data show proof of principle that enac expression can be reduced in the lung using sirna. further work is needed to assess the functional consequences of inhibiting enac in the lung. gene therapy for cystic fibrosis lung disease will likely require longterm transgene expression; however, in the lung, many gene transfer agents have resulted in only transient gene expression. previously we have shown that the choice of enhancer/promoter elements has a strong influence on the duration of reporter gene expression following delivery of non-viral vectors to the mouse lung (gill et al., , gene ther, , . however, it is also possible that other elements of plasmid vector design play an important role. using a clinically relevant mouse lung aerosol model, we have studied the effect of varying the plasmid cpg-dinucleotide content on the duration of expression from plasmids that had an identical enhancer/promoter sequence. firstly we constructed a cpg-free plasmid vector containing a synthetic cpg-free luciferase gene under the transcriptional control of the human cmv enhancer/ef α promoter. secondly, we constructed a similar vector containing an identical enhancer and promoter but with a small number of cpg motifs, in the luciferase gene ( cpgs) and in the backbone sequence ( cpgs). we then investigated the level and duration of transgene expression following aerosol delivery of these plasmids complexed with the genzyme lipid gl to the lungs of balb/c mice ( . mg/ml pdna, mm gl , ml, pari lc+ nebuliser). total lung extracts were assayed for luciferase activity at days , , , & (n= per time-point). the cpgcontaining plasmid initially directed approximately -fold higher levels of reporter gene expression than the cpg-free plasmid (p< . both days and post-delivery). however, while expression from the cpg-containing plasmid subsequently fell slowly to background levels, expression from the cpg-free plasmid increased -fold to day , and remained at the peak levels observed with the cpg-containing plasmid until the end of the experiment at day (cpg-free plasmid -fold, -fold and -fold higher expression at days , and post-delivery respectively; p< . for each). these data suggest that the ability of a promoter/enhancer sequence to direct long-term expression in the mouse lung is dependent by the sequence of the plasmid backbone. one explanation for this observation is that a specific, but as yet unidentified, sequence exists in the cpg containing backbone that triggers transcriptional silencing. alternatively, the well-described host inflammatory response to cpg-containing dna, may be involved and the cpg content of the vector could be responsible for these differences. we are currently evaluating the potency and duration of effect of cftr expressing, cpgfree, plasmids in late-stage pre-clinical studies prior to the initiation of a further round of clinical studies of non-viral gene transfer in cf patients. background: novel approaches to cf therapy by improving/restoring cftr chloride channel function using gene therapeutic tools or small molecules are currently undergoing phase i and phase ii clinical trials. there remains a great need for accurate and practical methods of measuring cftr function in vivo to act as primary outcome measures of efficacy. we propose that an in vivo assay measuring cftr function in sweat glands offers several potential advantages over the nasal potential difference test. objective: to develop a reliable test of sweat gland function that is capable of measuring the range of cftr function in vivo. methods: we are performing repeated measures of sweat gland function in healthy controls (n= ), obligate heterozygotes (n= ), pancreatic sufficient (cfps, n= ) and insufficient cf patients (cfpi, n= ). sweat secretion is stimulated by iontophoresis ( µa/cm ) with % pilocarpine. to elucidate the most sensitive and discriminatory parameter of sweat gland function within this study group we are performing simultaneous measurements of: a) the transglandular potential difference of a stimulated skin area using an ecg electrode (espd) and b) single sweat gland potential differences in single sweat glands (spd). using a wescor® collector cup we also measure: c) sweat secretion rate and (d) sweat chloride concentration (sweat cl-). results: we report interim results of our ongoing study (table) . sweat rate was not different between the groups, but a gender difference was observed (mean±sd; male: . ± . µl/min/cm ; female: . ± . µl/min/cm , p< . ) as previously described. our preliminary data show that espd as well as sweat cl-allow good discrimination among healthy controls, cfps and cfpi (p< . and p< . respectively). spd show similar trends to espd but with greater overlap (differences not significant). conclusion: these encouraging preliminary results, particularly the espd method and sweat cl-following stimulation with a lower iontophoretic current, justify further efforts to complete enrolment of subjects and to further refine technical challenges such as minimizing the effect liquid junction potentials across the ecg electrode. results will also be compared to the classical sweat test using higher iontophoresis current and npd measurements in these patients. this study is supported by the ccff and genome canada. ino- , a prodrug, has been demonstrated to inhibit nasal potential difference (pd)in human cf nasal airway epithelia and cf mice and this effect is more potent with repeated dosing. as such it is being developed as potential therapeutic for cystic fibrosis. ino- cell entry is facilitated by its hydrophobic propionoxy(methyl)ester protecting groups which can be hydrolyzed by intracellular carboxyesterases after the prodrug enters the cell. once the protecting groups are removed, the drug (ino- ) with the ether-linked octyl group is expected to be more slowly metabolized. however, the precise kinetics of the uptake of ino- , its conversion to its active metabolite, and methods. confluent cultures of hela or t cells were incubated for varying periods of time ranging from min to hrs with medium containing [ h] ino- ( x cpm/ml) and µm ino- cold carrier to ascertain the rate of uptake. in pulse chase experiments after cultures were incubated for hours, they were washed and incubated with media without radiolabel for varying periods of time. after the indicated times, the media was removed and the cells were washed, harvested, extracted and the aqueous and organic extracts subjected to sax and reversed phase hplc respectively. results ino- , a prodrug, has been demonstrated to inhibit nasal pd in human cf nasal airway epithelia and cf mice and this effect is more potent with repeated dosing. ino- cell entry is facilitated by its hydrophobic propionoxy(methyl)ester protecting groups which can be hydrolyzed by intracellular carboxyesterases after the prodrug enters the cell. once the protecting groups are removed, the drug (ino- ) with the ether-linked octyl group is expected to be more slowly metabolized. however, it is not known whether the mucus present in cf airways could impede its access to airway epithelia or whether ino- would cross the epithelial layer to enter the bloodstream. here, in order to address these issues we measured its uptake into human tracheal epithelial sheets in the presence and absence of mucus and compared its transepithelial permeation to mannitol. we studied the uptake and transepithelial fluxes of [ h]ino- in primary cultures of human tracheal epithelium with transepithelial resistance of from to ohms.cm . the mucosal surface of some tissues was rinsed three times with pbs to remove mucus for comparison with control cells which were not rinsed. elisa for human airway mucins performed on the rinsings confirmed that three rinses sufficed to remove the mucosal mucous blanket. the development of long-term, safe and efficacious gene therapies for lung disease will require efficient gene delivery to stem cells which produce the differentiated progeny of affected epithelial tissues. recombinant lentiviral vectors are being considered for gene therapy applications for the lung because they can efficiently transduce a wide variety of stem and progenitor cell types. however, it is of concern that strong constitutive viral promoters have produced oncogenesis in x-scid patient recipients of retroviral vectors in part due to the disregulation of proto-oncogenes by the strong viral promoter/enhancer located near the integration site. we propose that regulation of transgene expression to the tissue or cell type of interest will enhance the safety of gene therapy for respiratory disease. in this study we have investigated the potential for respiratory specific transgene expression from integrated lentiproviruses in cell lines in vitro and in mice in vivo. the lentiviral vectors constructed for this study contained regulatory elements predicted to produce lung specific transgene expression: the surfactant protein c promoter (spc) for alveolar epithelial type ii cell (aecii) expression, the clara cell kd protein (cc ) for clara cell expression in the airway, and the jaagskiete sheep retrovirus (jsrv) promoter for expression in both cell types. transgene expression from the spc and cc vectors was restricted to aecii and clara cell lines respectively, while expression from the jsrv vector was observed in multiple respiratory and non-respiratory cell types. following intra-tracheal delivery of lentivector supernatant to mice, transgene expression was observed in aecii from the spc lentivector (n= mice), and in clara cells from the cc promoted lentivector (n= mice). transgene expression was not detected in non-respiratory tissues following intravenous delivery of cc and spc lentiviral vectors to neonatal murine recipients (n= and n= respectively). in summary, incorporation of genomic regulatory elements from the spc and cc genes resulted in respiratory specific transgene expression in vitro and in vivo. these vectors will provide a useful tool for the study of lung biology and the development of gene therapies for lung disorders such as cf. cystic fibrosis (cf) is associated with chronic pulmonary inflammation and progressive lung dysfunction, associated with the formation of oxidants derived from neutrophil myeloperoxidase (mpo). indeed, respiratory tract levels of mpo are extensive, and have been found to correlate with decreases in respiratory parameters or disease severity in cf. mpo-derived oxidants thus may play a role in perpetuating the progressive lung dysfunction associated with cf. based upon these premises, we reasoned that mpo could represent a novel therapeutic target for the treatment of inflammatory diseases such as cf. herein we report that substituted urea and thiourea compounds are potent inhibitors of mpo. utilizing tetramethylbenzidine (tmb) as a classical heme peroxidase substrate, we screened a large number of structurally varied urea and thiourea derivatives. alkyl, cycloalkyl, and aromatic ureas and thioureas all proved to be effective mpo inhibitors, however, with a high degree of variability in potency. of those compounds examined, substituted phenylthioureas proved to be the most potent mpo inhibitors. various ortho-, meta-, and para-substituted phenylthioureas (ptus) were then assessed for inhibitor potency. the most potent inhibitor of mpo was -chlorophenylthiourea (ic = nm, ki = nm). the potency of ortho-ptus as mpo inhibitors showed a linear relationship with ortho sigma substituent constants (reflecting resonance, steric and inductive effects). moreover, cyclic voltametry experiments with ortho-substituted ptu compounds revealed a linear relationship between inhibitor potency and thiourea oxidation potential. this correlation is indicative of a substituent effect on the relative ease of sulfur oxidation within the thiourea moiety. this finding suggests that the redox-active sulfur plays a crucial role in mpo inhibition, perhaps via a direct interaction with the heme of mpo. thioureas proved to also inhibit the chlorinating activity of mpo, whereas sustituted ureas were not effective in this regard. both ureas and thioureas were also effective inhibitors of dityrosine formation by mpo. these findings will help facilitate the rational design and optimization of mpo inhibitors with even greater potency, which could serve as novel therapeutic agents for the treatment of cf. gene therapy is the transfer of a normal copy of the cftr gene and should, in theory, provide a long-term cure for cf. the development of prenatal screening programs for cystic fibrosis has provided an opportunity to identify cf patients in utero, and may provide an opportunity to treat the disease before birth, prior to the onset of disease symptoms. the long-term goal of our study is to investigate the therapeutic potential of delivering the normal cftr gene to epithelial stem cells in fetal cf mice by in utero administration of recombinant lentiviral vectors carrying the normal cftr gene. this would provide us with the unique opportunity to "correct" the chloride channel defect in the epithelial stem cells, which give rise to the epithelial cells in the tissues affected by cf at a very early stage. the aim of the current study is to optimize the in utero gene delivery of recombinant lentiviral vectors, carrying an egfp reporter gene to epithelial stem cells in fetal mice. mice have been used for these studies, as mouse strains with a variety of cf mutations are available. in all studies, the uterus was exteriorized following a mid-line laparotomy, and the injections were made directly into the amniotic fluid of individual fetuses. in the first studies, the survival of pregnant females and pups following saline injection at e . (n= ) and e . (n= ) was evaluated. all five females survived the procedure and an average of % ( / ) of the pups present at the time of injection were born alive. this experiment demonstrated that the surgical procedures were reasonably safe. in the next experiments, we injected . ul lentiviral supernatant (~ . x iu/pup) into the amniotic fluid of each pup and evaluated the effect of the gestational age pups on transduction efficiency. the pregnant mice were allowed to carry the fetuses to term. at p , p and p , - pups of each litter were sacrificed and skin, trachea, lung, stomach and intestines were harvested for analysis of gene transfer and egfp transgene expression. all but one pup ( / ) from the e . time point aborted prior to parturition. from the e . and e . injections, / and / pups were born naturally, respectively. at e . and e . , proviral sequences were observed in the skin, trachea and stomach, although the level of transduction varied among individual fetuses and tissues. immunofluorescence analysis on the skin of one mouse with a high proviral copy number demonstrated that some of the egfp positive cells were also positive for vimentin or f / , markers of mesenchymal cells and macrophages, respectively but negative for pancytokeratin. our preliminary studies suggest that in utero gene therapy with lentiviral gene delivery may be safe, however ongoing studies will provide more in depth analysis on safety and feasibility of delivering the normal cftr cdna to epithelial stem cells in the tissues affected by cf in utero. future studies will investigate the therapeutic potential of delivering a lentiviral vector containing the cftr gene to fetal pups in a murine model of cf. supported background & objectives: cystic fibrosis is characterized by progressive loss of lung function resulting from chronic bacterial infection and concomitant airway inflammation. while a number of bacteria are known pathogens in cf, mounting evidence suggests that the lungs of cf patients harbor numerous bacterial species, and that interactions within this ecosystem may affect outcomes. however, the composition of this community is not well characterized. we therefore initiated work to profile the bacterial diversity of the lungs of cf patients with end-stage disease by s rrna gene sequencing. methods: genomic dna was purified from snap-frozen explanted lung tissue of randomly selected cf patients undergoing transplantation in toronto between and . bacterial s rrna genes were amplified from each sample using broad-spectrum pcr primers, and pcr products used to generate s rdna libraries for each patient. s rdna profiles for each patient were generated by automated dna sequencing of up to randomly selected clones per library, and tentative species assignments made by comparison to known s rrna gene sequences using phylogenetically-based analyses. results: sequence analysis of s rdna sequences from this preliminary set of patients (avg. = sequences/patient; range = - ) demonstrates a range of complexity of the microflora in cf lungs, with some patients showing a single dominant organism and others showing multiple co-existing species. in total, over species have been identified to date in this set of patients. these include species identified previously by clinical microbiology, including pseudomonas aeruginosa (detected in / patients), and burkholderia species (detected in / patients known clinically to be infected). numerous organisms not previously reported in the lung were also identified, including several from the taxonomic order burkholderiales. interestingly, while organisms commonly associated with cf were detected in patients transplanted throughout the year, a cluster of four plant-associated species demonstrated striking seasonal variation in rates of detection. conclusions: the lungs of cf lung transplant patients harbor a diverse bacterial community. sequencing of s rrna genes is a powerful method to profile this diversity. correlation of these profiles with clinical information may help identify new patterns of infection and important interactions between species in this community. introduction and aims: pulmonary infection, primarily with pseudomonas aeruginosa, is the leading cause of morbidity and mortality in cystic fibrosis (cf) patients. we have demonstrated that anaerobic bacteria, belonging primarily to the genera prevotella, veillonella, propionibacterium and actinomyces, can be cultured from the sputum of cf patients. the aim of this study was to determine the antibiotic susceptibility of these anaerobic isolates grown planktonically and as biofilms. methods: the planktonic susceptibility of anaerobic isolates to antibiotics used in the treatment of cf (meropenem, piperacillin/tazobactam) as well as to antibiotics traditionally used to treat anaerobic infection (clindamycin, metronidazole and ampicillin) was examined using e-test® strips. selected anaerobic isolates were grown as biofilms for or hours in well trays prior to challenge with antibiotic. bacterial biofilm formation was determined using crystal violet. results: the planktonic susceptibility of anaerobic isolates ( prevotella, veillonella, propionibacterium, actinomyces and additional isolates) comprising different genera was determined. although all of the anaerobic isolates examined were sensitive to meropenem when grown planktonically, high levels of resistance to the anti-anaerobic drugs, metronidazole and clindamycin were observed. examining susceptibility by genera, the veillonella were the most resistant to piperacillin/tazobactam and the propionibacterium the most resistant to metronidazole. furthermore, several isolates, including of the prevotella isolates examined, were found to be resistant to multiple antibiotics. the susceptibility of anaerobic biofilms to antibiotics was found to be isolate and antibiotic dependent. generally antibiotic treatment of hour old biofilms was often able to eradicate biomass and prevent biofilm formation; however, antibiotic treatment after hours of biofilm formation with up to x the mic of an antibiotic often failed to eradicate the biofilm. conclusion: these results suggest that alternative antibiotic treatment regimes may be necessary to treat cf pulmonary infection if anaerobes are present. these results also suggest, based on in vitro susceptibility, that meropenem and not metronidazole or clindamycin would be the most effective antibiotic in treating any anaerobes present in cf pulmonary infection. early eradication protocols for the first appearance of pseudomonas aeruginosa (psa) have become standard practice in many cystic fibrosis (cf) clinics. the details of such protocols often vary significantly between clinics, making it important to compare efficacy from one approach to another. however, comparison of reported results is currently very difficult. this is not only because of variations in completeness of reporting, but especially because calculation of average time to regrowth cannot by definition include patients who remain free of psa regrowth at the time the "average" is calculated (nor those in whom a re-appearance of psa is found to be due to a different strain). such results would be better expressed using "time to event" (tte) statistics (analogous to "life tables") and different protocols can be better compared using this methodology. we report for the first time, results from our psa early aggressive eradication protocol for the period - , expressed using tte statistical analysis. children are seen in clinic on average times yearly for full assessment, and at each clinic visit sputum or pharyngeal cultures obtained by the physiotherapist. standard treatment for "first growth" pseudomonas aeruginosa consists of weeks of intravenous antibiotics (piperacillin mg/kg/day plus tobramycin mg/kg/day) followed by weeks of oral ciprofloxacin ( - mg/kg/day) and inhaled colymycin ( mg bid) for months. a total of treatment courses have been completed for the period - with a % clearance rate, defined as or more consecutive negative cultures for pseudomonas aeruginosa over months. since the initiation of this protocol, the percentage of patients colonized with psa in our cf pediatric clinic has declined from % in , down to % in . subsequent regrowth of psa occurred in / of patients. treatment courses may then be repeated a second, third, or fourth time. to determine whether these repeat psa isolates are newly acquired or identical to the previous isolate, rapd typing of these isolates is routinely assessed. a total of isolates have been rapd tested and have identified the same strain as the previous isolate in ( %) and a different strain in ( %)treatment courses. the average time to regrowth for those who had a recurrence of psa following this treatment protocol was months, but this does not include those patients who have had no further growth of psa for periods up to years. to reflect the results for all patients, including those who have not as yet had further regrowth of psa, we have constructed tte curves. these measures can be used to compare results using our protocol with results from other approaches to clearing pseudomonas aeruginosa in cf. retsch-bogart, g.z. inhaled antibiotics have been part of the therapeutic armamentarium for patients with cf for decades. we studied the effect of inhaled aztreonam on respiratory symptoms in cf in a phase , double blind, placebo (pl) controlled trial of azli, a novel formulation of aztreonam, which enrolled patients with cf from centers in the us, canada, australia, and new zealand. all patients have completed study participation. inclusion criteria included age ≥ years, pa in sputum or throat swab, fev ≥ % to ≤ % predicted, and no use of anti-pseudomonal antibiotics in the previous days. following a day screening period, patients were treated for days with either azli mg or pl. study drug was administered tid using the pari eflow® electronic nebulizer after pre-treatment with bronchodilator. concomitant standard cf therapies were allowed, with the exception of anti-pseudomonal antibiotics, azithromycin and hypertonic saline. the primary endpoint was change from baseline to day in scores from the cystic fibrosis questionnaire-revised (cfq-r) respiratory domain, a validated patient-reported measure of respiratory symptoms. other efficacy measures included change in pulmonary function (fev , fvc, and fef - ), number of hospital days and number of courses of iv, oral or inhaled anti-pseudomonal antibiotics. microbiological endpoints included change in pa bacterial density in sputum, change in susceptibility of pa to aztreonam, and emergence or disappearance of other pathogens. safety evaluations included adverse events, airway reactivity (defined as acute decrease in fev ≥ % at minutes after dosing) and clinical chemistry and hematology. complete efficacy and safety results from this trial will be presented. salam, a.p.; orchard, c.; wee, a.; hodson, m. introduction: oral ciprofloxacin is often used for pseudomonas aeruginosa (psa) infections in patients with cystic fibrosis (cf) not requiring intravenous antibiotics. oral chloramphenicol is commonly used at the royal brompton hospital (rbh) as an alternative to ciprofloxacin, but less so in other cf centres due to concerns about aplastic anaemia and uncertainty regarding effectiveness. this study aimed to address three questions: ) what proportion of psa is sensitive to ciprofloxacin and/or chloramphenicol? ) were there any adverse haematological effects with the use of oral chloramphenicol at rbh? ) how effective is chloramphenicol in comparison to ciprofloxacin? study design: we carried out a retrospective review from the rbh cf database ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) together with analysis of patients' notes. methods: ) psa sensitivities to ciprofloxacin and chloramphenicol were recorded from sputum samples taken in late . ) all blood dyscrasias in patients who had received chloramphenicol from to were reviewed. ) the database was searched for patients who had received a course of either oral chloramphenicol or ciprofloxacin from to . patients from each group were randomly selected. fev , fvc and oxygen saturations pre and post treatment completion were analysed, as were markers of symptom improvement. results: ) sputum samples from patients grew psa. some were sensitive to only one antibiotic, and there were some cross-sensitivities, but in total . % were sensitive to chloramphenicol and . % to ciprofloxacin. ) patients received oral chloramphenicol and oral ciprofloxacin from - . multiple courses were often given, but usually no more frequent than monthly with chloramphenicol. over years, cases of blood dyscrasia were recorded, none due to chloramphenicol, and all recovered. ) in the ciprofloxacin group: the mean oxygen saturations improved by . % (p . ), the mean fev improved by . % (p . ), and the mean fvc by . % (p . ). in the chloramphenicol group: the mean oxygen saturations improved by . % (p . ). ), the mean fev improved by % (p . ) and the mean fvc improved by . % (p . ). % of patients in the chloramphenicol group and % of patients in the ciprofloxacin group reported symptom improvement. a significant proportion of psa is sensitive to chloramphenicol and in over years there have been no documented cases of related aplastic anaemia. clinical improvements with choramphenicol comparable to ciprofloxacin were also recorded. our data shows chloramphenicol is safe and may be the oral antibiotic of choice in ciprofloxacin allergy or psa resistance to ciprofloxacin. a randomised prospective study is needed to further evaluate the efficacy of chloramphenicol in comparison to ciprofloxacin. pseudomonas aeruginosa lung infections are one of the main factors causing disease in cf patients. at present the generally recommended treatment is repeated courses of antibiotics. this has resulted in fewer infections and a markedly improved prognosis for the patients. but it has also severe drawbacks such as antibiotic resistance, disturbed normal flora and allergenicity. antibiotic resistance is an emerging problem world wide and alternatives are urgently needed. specific chicken antibodies, anti-pseudomonas igy, have potential both as an alternative and a complement to antibiotics (pediatr pulmonol ; : ) . anti-pseudomonas igy prevents p. aeruginosa from adhesion to epithelial cells and has affinity for flagellin in vitro. humans do not produce anti-igy antibodies and oral administration of igy is generally regarded as safe. the risk that bacteria should develop resistance to igy is extremely low. in total, cf patients have received antipseudomonas igy for up to years. since november, the drug is given to a group of cf patients (at present patients) on individual permissions granted by the swedish mpa and reimbursed by the swedish government. in our first study about the effect of igy there were . positive cultures/ months, compared to . / months in a control group. up to december , , nearly five years later, the effect is maintained with . / months for the whole study period. we are at present compiling the data from the control group during the same period. only two siblings in the igy-treated group have been chronically colonized (with an identical p. aeruginosa strain), which still is non-mucoid after . and . years. during the whole treatment period there have been no cultures positive for mucoid p. aeruginosa or b. cepacia and other pathogens (s. maltophilia, a. xyloxidans, atypical mycobacteria and a. fumigatus) have only appeared sporadically -possibly due to the relatively low use of antibiotics. all patients have preserved pulmonary functions and nutritional status. there have been no adverse events. thus treatment with anti-pseudomonas igy has diminished the number of positive cultures and delayed the onset of chronic infection. the need for antibiotics is reduced as well as their adverse side effects. in conclusion, igy is an important complement to antibiotics for prevention of p. aeruginosa infections in cf. introduction and aims: we have previously shown by culture that the lungs of clinically stable cystic fibrosis (cf) patients are not only colonised by commonly recognised aerobic bacteria, such as pseudomonas aeruginosa, but also by a range of potentially pathogenic anaerobic species. the aim of this study was to determine whether anaerobes are also present in the sputum of cf patients with an acute exacerbation of pulmonary infection. methods: sputum samples were collected and processed using strict anaerobic bacteriological techniques, prior to commencing and at the end of antibiotic therapy, from adult cf patients admitted for treatment of an acute exacerbation of pulmonary infection. bacteria within the samples were detected by plating on selective agars, quantified by total viable count and identified by pcr and sequencing of s ribosomal rna genes. as a control induced sputum samples were collected, using hypertonic saline, from healthy volunteers who did not have cf and processed using similar methods. results: anaerobes from a range of species including prevotella, veillonella, propionibacterium, actinomyces and gemella were detected in high numbers (up to x cfu/g of sputum) from all patients prior to commencing antibiotic therapy with the predominant primary pathogens (p. aeruginosa or b. cepacia complex) detected in similar numbers. anaerobic bacteria were also detected in sputum samples at the end of antibiotic treatment and for / ( %) patients they were present in lower numbers than detected before antibiotic treatment. moreover, in / ( %) patients there was greater than a one log reduction in the total viable count of anaerobes. similar data for detection of the predominant aerobic pathogens was also collected for of these patients. p. aeruginosa or b. cepacia complex was present in lower numbers following antibiotic treatment in / ( %) patients and in / ( %) patients there was more than a one log reduction in the total viable count. anaerobes were not detected in the induced sputum samples from volunteers and in the remaining samples they were present in much smaller numbers, ranging from to cfu/g of induced sputum, than detected in cf sputum. the most commonly isolated bacteria from the induced sputum samples were the actinomyces and streptococcus, with prevotella cultured from only samples. no veillonella and propionibacterium species were isolated from the induced sputum samples and combined with the low frequency of isolation of prevotella species, these results strongly suggests that the prevotella, veillonella and propionibacterium species recovered from cf sputum samples are not oral contaminants. conclusion: these results indicate that anaerobes are present in large numbers within the cf lung during an acute exacerbation of pulmonary infection. their presence could be of important clinical relevance to cf patients as they may contribute significantly to the inflammatory process. airway infection and inflammation cause the majority of morbidity and mortality in cystic fibrosis (cf). the microbiology of cf is complex. not only are the routinely identified pathogenic bacteria present, increasingly a number of other bacteria are associated with pulmonary disease. in addition, the normal microbiota likely contribute to airway disease in cf via intracellular signaling, but remains largely unstudied. the application of culture independent methods for bacterial identification in cf airway secretions provides for the first time the ability to characterize the bacterial communities in the cf airway comprehensively and efficiently. here we present the results of a two-year study of cf airway samples to describe the bacterial communities present by ribosomal rna sequences. we have examined airway specimens from subjects ( cf, controls). these results provide a unique perspective on cf airway microbiology. bacterial communities identified in sputum were more complex than communities identified in bronchoalveolar lavage fluid (balf). however, pulmonary status determined the level of complexity, with higher complexity observed during stable pulmonary function. we identified a collection of anaerobic bacteria that were present at high levels during pulmonary exacerbation in a subset of cf subjects. detection rates ranged from - % of cf subjects examined depending on the specific organism (table ). these organisms of interest are suspected to be involved in pulmonary exacerbation especially when cultures for standard cf pathogens are negative (~ % in our center). preliminary data will be presented from quantitative real-time pcr experiments to track these organisms. we also will present the application of new meth-ods for community comparisons. this analysis provides the ability to look at how clinical information from individuals with cf corresponds to the microbial communities that occur in the airway. overall, the results point to a much richer bacterial community associated with the cf airway than previously thought. the results also point to new opportunities to understand the differences within the cf population, and thus potentially improve individual patient outcomes. cystic fibrosis (cf) patients are characterized by persistent microbial colonization of the airways and recurrent pulmonary infection. however, due to the domination of bacterial communities present in cf sputum by a small number of species (typically pseudomonas aeruginosa), culture-independent approaches to characterize the depth of bacterial diversity in cf sputum have yielded limited information. here we describe application of a novel microarray, the s rrna phylochip to comprehensively describe the bacterial diversity present in temporal sputum samples of cf patients who experienced periods of exacerbation (defined as hospitalization) and remission. in addition, these samples permitted assessment of bacterial community dynamism during periods of antimicrobial administration in these patients. phylochip analysis identified bacterial taxa present across these patient samples, including a large number of known human pathogens. antimicrobial administration caused a profound decrease in bacterial diversity in all patients examined. despite this, a sizeable fraction of each community remained stable or proliferated during the period of antimicrobial administration, suggesting many of the bacterial taxa present were resistant to the antimicrobials administered. taxa exhibiting this behavior included p. aeruginosa, arcobacter cryaerophilus, streptococcus constellatus and burkholderia mallei amongst other pathogens. these results suggest that complex polymicrobial communities exist in cf sputum that exhibit significant antimicrobial driven dynamism and consist of multiple antimicrobial resistant pathogens. future studies will focus on whole community gene expression to determine which virulence systems are activated in response to bacterial community perturbations and contribute to pathogenic processes in cf airways. the lungs of chronically infected cystic fibrosis (cf) patients have been intensively studied. it is well documented that pseudomonas aeruginosa is the predominant pathogen in cf (høiby , baurnfeind et al. , koch , and that p. aeruginosa accumulates in heaps (aggregates), detected in cf sputum (høiby ) and intraluminal in the lung (baltimore et al. ) . the bacterial density is highest in the bronchi (potts et al ) and these p. aeruginosa microcolonies are embedded in a matrix (lam et al. ) . the morbidity of the infection is due to an extensive and ongoing pmn response which apparently does not eradicate the bacteria, instead leading to slow degradation of the lung. in addition, even highest deliverable doses of antibiotics fail to clear the bacteria completely, though survival has significantly increased the last years due to aggressive anti p. aeruginosa therapy (koch and høiby ) the present study was performed to investigate the significance of the aggressive therapy for the distribution of p. aeruginosa and how p. aeruginosa is organized and persists in the cf lung. the material used was: autopsies from dead short term colonized cf patients (n= ) obtained before today's aggressive antibiotic treatment , and explanted lungs from long term p. aeruginosa infected cf patients (n= ) (i.v. antibiotics every rd month since + inhalation of colistin daily since . histological sections of the lungs were investigated using he stain, gram stain, alcian blue, antibodies against alginate and p. aeruginosa specific pna-fish combined with bacuni pna-fish and with dapi as counter stains. due to the high specificity of the pna-fish probes employed in this study, our results provide strong evidence for that before the aggressive antibiotic therapy, p. aeruginosa infected and destroyed the cf lung due to fast spreading into the respiratory zone. today antibiotics suppress but can not eradicate the bacteria from the conductive zone, whereas the remaining respiratory zone is protected from massive biofilm infection for prolonged time. the conductive zone serves as a reservoir; here the bacteria are organized in microcolonies embedded in puss, a trait which is independent on the time course of the infection and amounts of antibiotics. these microcolonies consisted solely of p. aeruginosa. in addition, we found no bacteria adhering to the epithelial tissue. the pus consisted mainly of leukocytes, surrounding the microcolonies. a smear of dna and dead leukocytes were detected just around the microcolonies, possible due to the quorum sensing dependent rhamnolipid killing recently described by us (jensen et al. ) . we conclude that p. aeruginosa persists in the cf lung due to its ability to create microcolonies i.e. biofilms. within these biofilms the bacteria are protected against antibiotics and the host defence. respiratory viral infections, including influenza (flu) and respiratory syncytial virus (rsv) contribute to the morbidity of children with cf. additional human respiratory viruses have been identified in children such as human metapneumovirus (hmpv) and coronavirus (cov), but these have not been examined in cf patients. in our laboratory, pcr assays have been developed to identify both traditional and newer respiratory viruses in healthy and immunocompromised children. these assays are usually performed on nasal swabs or nasal wash samples. however, oropharyngeal (op) and sputum samples are routinely obtained in cf for bacterial culture. the goals of this trial are to determine whether these available samples can be used for viral pcr studies and to examine the epidemiology of respiratory viruses in cf. for this single center observational trial, cf patients, ages . to . yrs (mean . yrs), have been recruited. subjects provide op and nasopharyngeal (np) samples at quarterly clinic visits and with acute pulmonary exacerbations requiring hospitalization; sputum is also collected if patients can expectorate. np and op samples are pooled when both are available. viruses assayed are flu a and b, rsv, parainfluenza (piv) , , and , hmpv, cov, adenovirus (adv), and rhinovirus (rhv). subjects are being followed for two respiratory viral seasons. we report here the methodology of viral pcr detection in cf sputum, as well as the results of viral detection during the first respiratory viral season in the seattle community. the mean length of time subjects were followed was . yrs (median: . yrs, range: . - . yrs). overall, samples ( % of the samples analyzed) were positive. twenty-four subjects ( . %) had at least one viral infection detected and ( . %) had two viruses at different visits. both sputum and pooled op/np samples were available at visits and were concordant in % of cases. among the discordant cases, it was more common for sputum to be positive and op/np to be negative ( . %) than the converse ( . %). the most frequently identified viruses were rhv ( isolations); piv and cov were the next most prevalent with and isolations, respectively. in conclusion, sputum viral pcr shows promise for the diagnosis of both traditional and novel viral infections in cf. as part of ongoing clinical trials in cf, non-fermenting gram negative bacilli (nfgnr) identified at site laboratories are often sent to the tdn core microbiology laboratory for confirmation of identification. among nfgnr from cf patients, p. aeruginosa are the most frequently isolated and also are acknowledged to be the easiest to identify. however, in a survey of "p. aeruginosa" isolates sent to the laboratory in the past year, pcr identified ( %) as alternate species. these included: non-aeruginosa pseudomonads, stenotrophomonas maltophilia, achromobacter xylosoxidans, ralstonia spp., alcaligenes spp., brevidimonas spp., and bordetella bronchiseptica. identification of these nfgnr can be difficult; however, p. aeruginosa is an important isolate for the clinical microbiology laboratories in all cf centers to be able to identify. many methods are available including conventional biochemical testing and rapid identification kits. in the tdn core laboratory we previously demonstrated the importance of combining phenotypic identification (morphology plus a short set of biochemical tests) and genotypic identification ( s rdna sequencing of v and/or pcr using three primer sets) and developed an algorithm for testing. in this study, we examined all of the cf cultures performed in the clinical microbiology laboratory at chrmc over the past two years to determine the number of isolates for which it was necessary to perform genotypic identification in nfgnr. among this collection of nfgnr from clinical cultures sent to the microbiology laboratory from the seattle children's hospital cf center, pcr identified isolates as burkholderia cepacia complex. next most commonly identified were a. xylosoxidans ( ), p. aeruginosa ( ) and non-aeruginosa pseudomonas spp. ( ). three isolates remained unidentified, even with pcr sequencing of the v determinant. the clinical microbiology laboratory at chrmc has served as the core microbiology laboratory for tdn clinical trials for years and thousands of cf samples are processed annually. the result is that there is increased experience with cf isolates among the laboratory personnel. however, even with experienced technologists, a significant number of nfgnr required genotypic identification in the past two years. thus, it is important for clinical microbiology laboratories with less experience in the identification of cf nfgnr to utilize additional molecular techniques or send problematic isolates to a reference laboratory. based on these results we propose an algorithm for the most efficient means of identifying nfgnr from cf samples using a combination of tests including phenotypic (colony morphology, biochemical testing) and genotypic identification (pcr, sequencing). background: the epidemiology of s. aureus has been changing in both cf and non-cf patients. in non-cf patients, methicillin-resistant s. aureus (mrsa) has traditionally caused infections in patients with risk factors such as hospitalization, surgery, and anterior nares colonization. recently, community-acquired (ca-) mrsa infections have increased among patients without known risks. in cf, colonization of the anterior nares with methicillin-susceptible s. aureus (mssa) is associated with transmission between patients and household members. the prevalence of respiratory tract colonization/ infection with mrsa has increased in cf, but little is known about risk factors for mrsa, including possible transmission among families, and if strains are ca-or healthcare-acquired. methods: this is a case-control, multicenter study to investigate potential risk factors for mrsa among children with cf - years of age. subjects are enrolled from cf centers in the new york metropolitan area that have a mrsa prevalence ranging from % to %. cases are children with a positive respiratory tract culture for mrsa within the past years. controls ( age and center matched per case) are negative for mrsa. the aims of the study are: [ ] to determine the point prevalence of anterior nares colonization with s. aureus in children with cf and their household members; [ ] to assess potential risk factors for mrsa by administering a survey to the parents of subjects inquiring about factors such as crowding, pets, and participation in contact sports and by reviewing the medical record for antibiotic use, hospitalization, and surgery; [ ] to determine potential transmission of s. aureus within families and centers by assessing the molecular epidemiology of strains using pulsed field gel electrophoresis and meca type of mrsa isolates. results: to date, cf subjects ( cases, controls), mean age . years, and household members ( to per subject) have been enrolled. preliminary data demonstrate positive anterior nares cultures among cases, controls, and household members to be / ( %), / ( %), and / ( %), respectively. of the s. aureus isolates, were mssa and were mrsa ( cases, household members of cases, and household members of controls). during the past months, household members have been hospitalized and one has stayed overnight in a nursing home; had staphylococcal infections and had skin infections. data collection and molecular analysis are ongoing. conclusions: we expect this study to provide insight into risk factors for respiratory tract colonization/ infection with mrsa, the role of ca-mrsa in cf, and potential strategies to prevent mrsa. aims: . revise infection control guidelines for the institution . establish outpatient infection control policies consistent with those used for hospital inpatients . cohort young and recently diagnosed cf patients without pseudomonas or mrsa to clinic days separate from colonized patients . establish a protocol for eradication of mrsa in newly colonized patients. methods: working with representatives from hospital epidemiology, the cf center, inpatient units, outpatient clinics, respiratory therapy, and cf families, a uniform infection control policy for cf patients in all settings (inpatient, outpatient, home care) was drafted and revised. arrangements were made to cohort newly diagnosed patients and children < years free of pseudomonas and mrsa to separate clinic days from colonized patients. review of the mrsa positive patients in our pediatric population, for whom data was available, showed median age of acquisition of years (range mo to yrs). for patients the first culture obtained at diagnosis or transfer from another center was mrsa positive ( mo, yr, yr). an eradication protocol for newly acquired mrsa has been developed involving treatment with oral and topical antibiotics and phisohex or clorox washes for days, plus changing disposable respiratory care equipment at the beginning and end of the treatment period. surveillance cultures of nose, groin, and airway or sputum are done after completion of the treatment protocol and re-treatment initiated if still positive for mrsa. conclusion: using a three-tiered approach of infection control guidelines, cohorting, and mrsa eradication protocol we expect to decrease our overall rate of mrsa and protect our newly diagnosed and young cf patients from acquisition. objective: studies have shown that respiratory pathogens can be transmitted within cf centers. in a recent cross-sectional study at cf centers, we assessed the rate of bacterial shedding by cf patients during office visits and noted that % of patients carried respiratory flora on their hands. the current study was performed to assess the effectiveness of alcohol-based rubs on hand carriage of respiratory pathogens by patients during the course of office visits. methods: four bacterial organisms were chosen for study: pseudomonas aeruginosa (pa), staphylococcus aureus (sa) [including methicillin-resistant (mrsa) strains], stenotrophomonas maltophilia (sm) and burkholderia cepacia complex (bcc). at the beginning of clinic visits, hands of study patients were cultured using the "glove-juice" technique (gjt) [ ] . hand hygiene was then performed using an alcohol-based rub. at the end of the visit, hands were again sampled using the gjt. samples were sent to the microbiology laboratory at dartmouth-hitchcock medical center for culture and identification of study organisms. hand and respiratory tract isolates were compared using pulsed field gel electrophoresis (pfge). recovery experiments were also performed to assess the sensitivity of the gjt. results: samples were collected from encounters ( adult; pediatric). median encounter time was min (range . - . min). recovery experiments determined that the level of detection for each study organism using the gjt was ~ colony forming units. confirmation of matches between hand and respiratory isolates was determined by pfge. the number of patients with study organisms recovered from the respiratory tract was: pa, sa, mrsa, sm, and bcc. the overall hand contamination rate with a matched respiratory tract isolate at either culturing time was % ( % ci, . - . %). before use of the alcohol rub, hand contamination was . % ( % ci, . - . %). in those patients with hand contamination by respiratory pathogens prior to alcohol rub, . % ( % ci, - %) had negative cultures at the end of the clinic visit. however, there was strong evidence of hand contamination during the encounter, despite hand hygiene, as the overall rate at the end of visits was . % ( % ci, . - . %). there was a trend toward increased hand contamination in those suffering from pulmonary exacerbations versus clinically stable patients ( . % [ % ci, . - %] vs. . % [ % ci, . - %], p= . ). conclusions: contamination of patient hands by respiratory tract pathogens is observed in the outpatient setting in approximately % of patients. a single application of an alcohol-based hand rub, while safe and inexpensive, has limited antiseptic effectiveness during the full course of a typical cf clinic visit. repeated use of alcohol-based hand rubs during outpatient encounters would likely be more effective. these data support recent recommendations in the cf foundation consensus guidelines for infection control [ ] (nthi) is the most common initial bacterium infecting the airways in cystic fibrosis (cf). nthi infection usually precedes pseudomonas aeruginosa infection in many chronic lung diseases, including cf, emphysema, diffuse panbronchiolitis, and immotile cilia syndrome. it is hypothesized that nthi acts as a gateway organism paving the way for subsequent infection with p. aeruginosa, however, the mechanism by which this occurs remains poorly understood. we used a novel co-culture model of persistent nthi biofilm infection on airway epithelial cultures to study epithelial immune responses following nthi biofilm infections. objective: we hypothesized that prolonged exposure to nthi biofilms causes airway epithelia to become tolerant to inflammatory stimuli and show subsequent decreased innate immune responses. methods: nthi were inoculated onto the apical surface of calu air-liquid interface epithelia and grown in co-culture. rna from sets of paired airway epithelial cultures at , , and hours both with and without nthi inoculation was isolated and hybridized on custom affymetrix chips. data were normalized with rma and data biases were removed using the mixed model anova method. differentially expressed gene analyses were performed using anova, and pathways analyses were performed using gene set enrichment analysis (gsea). to test the hypothesis that prolonged nthi infection induces tolerance, epithelial cultures were pre-treated with either days of nthi or days of pbs before stimulation with pbs, il β ( ng/ml) or th cfus of live p. aeruginosa before subsequent measurement of epithelial responses. results: both rma and gsea analyses of microarray data showed many innate immune and pro-inflammatory responses at early timepoints that largely returned to baseline after days of co-culture, despite an increasing apical nthi biofilm infection. stimulation with il β or p. aeruginosa after days of nthi infection resulted in significantly decreased il production compared to uninfected controls. nthi treated cultures subsequently infected with p. aeruginosa also displayed increased tight junction integrity and resistance to cell culture death. conclusions: persistent nthi infections on airway epithelia resulted in increased tolerance to bacteria and inflammatory stimuli and increased resistance to bacterial toxicity. airway epithelial tolerance may contribute to a failure to clear subsequent bacterial infections. these phenomena would help to explain how early infections with nthi may promote chronic bacterial infections and p. aeruginosa acquisition in cf and other nthi related airway diseases. the colonization of cf airways by p. aeruginosa leads to intractable and persistent lung infections that resist permanent eradication by antibiotics. the lack of efficacy of current therapies is believed to be due to the formation of p. aeruginosa antibiotic resistant biofilms in the cf airways. however, little is known about biofilm formation on human airway epithelial cells. thus, we designed a continuous flow, live cell imaging system to grow p. aeruginosa biofilms on glass or on the apical surface of polarized human cells. cfbe ohuman airway epithelial cells homozygous for the ∆f mutation (cfbe), and cfbe o-cells complemented with wt-cftr (cfbe+wt-cftr) were grown as polarized monolayers at an air-liquid interface and gfp-labeled p. aeruginosa were applied to the apical surface of the cells. after hours biofilms did not form on glass but large bacterial macrocolonies developed on cfbe cells. surprisingly, biofilms also developed on cfbe+wt-cftr cells: however, p. aeruginosa biomass on cfbe+wt-cftr cells was significantly reduced compared to cfbe cells ( . ± . µm /µm vs . ± . µm /µm ). the minimal bactericidal concentration for tobramycin was > , µg/ml for p. aeruginosa grown on cfbe and cfbe+wt-cftr cells. these results explain why tobramycin given clinically, which is~ , µg/ml in bronchoalveolar fluid collected from cf patients, fails to eradicate the persistent infection by p. aeruginosa. p. aeruginosa also formed biofilms on human bronchial epithelial cells, which produce mucus. indeed, biomass was similar on cfbe+wt-cftr cells, which do not produce mucus, and human bronchial epithelial cells. to determine if human airway epithelial cells secrete factors that facilitate biofilm formation, conditioned medium was collected from cfbe and cfbe+wt-cftr cells and applied to p. aeruginosa grown on glass. under these conditions, biofilm formation was dramatically facilitated, with a biomass of . ± . µm /µm when p. aeruginosa was grown in conditioned medium collected from cfbe+wt-cftr cells and . ± . µm /µm when grown in conditioned medium collected from cfbe cells. the secreted factor(s) were greater than kda, as assessed by size exclusion. our results suggest that human airway epithelial cells secrete factor(s) that facilitate biofilm formation by p. aeruginosa, in the presence and absence of mucus, and that secretions from cf cells are more effective in promoting biofilms than secretions from non-cf cells. the ability of non-cf cells to facilitate biofilm formation appears to contradict the observation that non-cf lungs do not harbor p. aeruginosa. we propose that the innate immune response in the non-cf lung effectively eliminates p. aeruginosa from the lung, thus, biofilms do not form even thought the airway epithelial cells secrete factors that have the potential to facilitate biofilm formation. however, in cf when mucociliary clearance is compromised, p. aeruginosa accumulates in the lung and secretions by cf airway epithelial cells greatly enhances the formation of drug resistant biofilms (supported by the nih (ro ai , ro -hl- , p -rr , t -dk- ), and the cff (stanto ro, anders fo). ma, l. ; parsek, m.r. ; wozniak, d.j. . microbiology and immunology, wake forest university health science, winstonsalem, nc, usa; . university of washington, seattle, nc, usa bacteria in natural, industrial and clinical settings live in surface-associated communities termed biofilms, which are the source of persistent infection and resistance to antimicrobial treatment. biofilm development is initiated by the attachment of planktonic cells to a surface, followed by formation of microcolnies, and finally disperses swimming cells from microcolnies to occupy a new surface. to maintain the community structure, bacteria in a biofilm are usually enmeshed in an extracellular polymeric matrix, which consists of nucleic acids, proteins, and polysaccharides. exopolysaccharides (eps) have been known as a component of the biofilm matrix for years. however, little is know about how the eps matrix forms and develops and whether an eps can form a matrix independently. in the present report, we use lectins that specifically detect the mannose or galactose structure in pseudomonas aeruginosa psl eps. this technique allows us to visualize psl eps on the bacteria cell surface and in the biofilm matrix. our results indicate that psl eps is likely anchored on the cell surface in a helical pattern and clearly forms a matrix, which holds bacteria in the biofilm and on the surface. in a flat multiple-layer biofilm, psl eps is equally distributed in the entire biofilm. however, microcolonies reveal peripheral staining of psl eps with minimal staining of matrix in the center of the microcolonies. instead, this region has swimming cells indicating a biofilm development stage prior to dispersion. more strikingly, this area also has concentrated dead cells and/or extracellular dna, which fills up the viod spaces in the lower center of microcolonies at the stage prior to dispersion. these data provides a plausible mechanism for how p. aeruginosa sacrifices a portion of cells to make void spaces and free another portion of cells for future dispersion. in addition, our data also show that psl eps matrix and dna matrix are not overlapping, which suggests that these two components of the matrix work coordinately to encase bacteria in the biofilm. finally we show that the psl eps matrix is present in biofilms formed by mucoid p. aeruginosa, and formation of the psl eps matrix is independent of the production of alginate and pel, two eps that also contribute to p. aeruginosa biofilm formation. overall, our data indicates that psl eps functions as a primary scaffold, holding biofilm cells together in the matrix. moreover, our data along with published literature suggest a possible model for how p. aeruginosa biofilms persist in cystic fibrosis patients. . clinical microbiology, rigshospitalet, copenhagen, denmark; . biocentrum, technical university of denmark, kgs. lyngby, denmark; . department of paediatrics, copenhagen cystic fibrosis centre, rigshospitalet, copenhagen, denmark pseudomonas aeruginosa predominates chronic lung infections in patients with cystic fibrosis (cf). a hallmark of chronic p. aeruginosa lung infections in cf patients is the presence of mucoid p. aeruginosa biofilms surrounded by numerous polymorphonuclear leukocytes (pmns) in the lower airways. how p. aeruginosa escapes the bactericidal pmns is not fully understood. several virulence factors of p. aeruginosa is controlled by quorum sensing (qs); a density dependent mode of inter-bacterial communication based on signal transmitter molecules. active qs is present during chronic p. aeruginosa lung infections in cf patients and we have previously demonstrated a qs-regulated tolerance of biofilm bacteria to the antimicrobial properties of the pmns. the precise qs-regulated effect on the pmns is, however, unknown. in the present study, further elaboration using flow cytometry and microscopy revealed that qs-competent p. aeruginosa (pao and ∆rhli lasi complemented with c -hsl and -oxo-c -hsl) induces rapid necrosis of the pmns. this mechanism was also observed in in vitro biofilms and in mouse lungs infected with p. aeruginosa embedded in alginate. by using hplc fractionation the toxicity could be ascribed to a single substance. using lc-ms and d nmr this substance was identified as rhamnolipid b. in accordance, concentrations of rhamnolipid exceeding µg/ml were found in the toxic supernatants from wild-type p. aeruginosa (pao ) whereas non-toxic supernatants from qs-deficient knock-out mutants (∆rhlr lasr and ∆rhli lasi) and from ∆rhla mutants contained low amounts of rhamnolipids approaching µg/ml. our results demonstrate the potential of the qs system to facilitate infections with p. aeruginosa by utilizing rhamnolipid to disable a major first line of defense of the host -the pmns. furthermore, our study emphasizes the inhibition of qs as a target for the treatment of infections with p. aeruginosa. carlsson, m. , ; pettersson, a. ; andersson, c. ; wieslander, j. ; eriksson, l. ; segelmark, m. ; hellmark, t. . dept of microbiology, immunology, and glycobiology, university of lund, lund, sweden; . department of nephrology, lund university, lund, sweden; . heart lung division, the cystic fibrosis center, lund university hospital, lund, sweden; . wieslab analys ab, lund, sweden the clinical consequence of chronic pseudomonas (p) aeruginosa colonization in cystic fibrosis (cf) varies between individuals for unknown reasons. auto-antibodies against bactericidal/ permeability increasing protein (bpi-anca) are associated with poor prognosis in cf. we hypothesize that there is a correlation between the presence of bpi-anca, the biological properties of the colonizing bacteria and the clinical conditions of the hosts. we have compared isolates of p aeruginosa from two groups of cf patients: one with positive serum levels of bpi-anca and deteriorating lung disease, and one with negative bpi-anca levels and stable clinical conditions. epithelial cells (a ) and isolated polymorphonuclear granulocytes (pmns) were stimulated with the clinical isolates and cell death was analyzed with flow cytometry. interleukin- (il- ) released into the supernatant was measured by elisa. we found that the anca associated strains in most cases showed a pyocyanin negative phenotype. these strains also induced less inflammatory response than the non-anca associated strains as shown by the number of necrotic cells and il- release, yet elevated compared to control. we conclude that colonization with strains of p aeruginosa that induce a weak inflammatory response is associated with unfavourable outcome in cf. we speculate that inadequate control of pathogen proliferation through an insufficient inflammatory response results in a slowly increasing number of bacteria and accumulation of dying pmns in the airways, contributing to the progressive lung disease seen in many cf patients. . pulmonary critical care, northwestern university, chicago, il, usa; . microbiology/immunology, northwestern university, chicago, il, usa; . pulmonary medicine, children's memorial hospital, chicago, il, usa; . pediatrics, children's memorial hospital, chicago, il, usa purpose: most cystic fibrosis (cf) patients are infected with pseudomonas aeruginosa (pa) and have progressive loss of lung function. among individual patients, however, there are marked differences in rates of lung function deterioration. although the reasons for this variability are not completely understood, it is likely that microbiological factors play a role. type iii secretion in pseudomonas aeruginosa (pa) isolates from non-cf patients have been associated with poorer outcome. the aim of this study was to determine whether there is an association between type iii secretion properties and deterioration in lung function in cf. methods: we prospectively enrolled cf children and adults over years. demographics, clinical characteristics, spirometry and a respiratory culture were obtained at the first visit. the age at time of first postive pa culture was also determined. subsequently, spirometry and respiratory cultures were obtained and clinical characteristics recorded every months until december . from each sputum culture individual isolates were selected for evaluation and type iii secretion was evaluated for each isolate by western blot analysis. the children were subcohorted into those newly infected ( st positive pa culture) or those chronically infected (minimum sputum pa (+) > year duration). results: there were patients evaluated, of which were adults and were children. ninety percent of our population cohort was caucasian and % were female. overall % of the patients were on tobi and % on macrolides chronically. the mean age at time of a first pa positive culture was years for the chronically infected subjects(adults and children) and years for the st time infected subcohort. a total of sputum samples were collected for the current study. the prevalence of type iii secretion properties for the overall population was . %. foe adults, of ( . %) pa isolates were type iii secretion positive compared to of isolates ( . %) in chronically infected children and of isolates( . %) from newly infected children. at study entry the mean fev % predicted was +/- for the whole cohort. for the adult subcohort the fev % predicted was % +/- %, for chronically infected children it was % +/- % and newly infected children is was %+/- %. the average annual rate of fev % change was - . % for adults, - . % for chronically infected children and + . for newly infected children. analysis on the relationship between type iii secretion pa isolates and fev % decline is ongoing and will be presented at nacf. conclusion: prevalence of type iii secretion in pa isolates from cf patients decreases with age. there is a slower decline in fev % in chronically pa infected adults compared to chronically pa infected children. the relationship of type iii secretion to fev % change and pulmonary exacerbations will be presented at nacf. a limited number of bacterial species -in example pseudomonas aeruginosa, staphylococcus aureus, burkholderia cepacia complex, stenotrophomonas maltophilia -is typically found in the cf lung. these facultative anaerobic bacteria exhibit the capability to switch from aerobic to anaerobic metabolism, which enables them to survive in the hypoxic environment in the cf lung [ ] . absence of oxygen would also favour the growth of fastidious anaerobes and, indeed, sequencing of s rrna resulted in the detection of strict anaerobic species in cf sputum [ ] . thus, we identified and quantified strict anaerobes in cf sputum using conventional anaerobic microbiological methods, examined the recovery rate of identical species in sputum samples from the same patients, and determined the antibiotic susceptibilities. sputum samples were collected from cf children and cf adults (mean age . ± . yrs). samples were incubated aerobically on columbia agar, supplemented with % sheep blood, and anaerobically on brain heart infusion agar and schaedler agar supplemented with % mutton blood, for up to days. bacteria were identified (rapid ana ii identification system, remel, lenexa, ks) and cfu's were determined by dilution plate counting. fastidious anaerobes ( strains) were submitted to e-test ® susceptibility testing (ab biodisk, solna, sweden) using the anaerobically active antibiotics ceftazidime, clindamycin, meropenem, metronidazole, and piperacillin/tazobactam. in . % of the patients, the following strict anaerobes were detected with a mean of . x cfu/ml (range . x to . x cfu/ml): peptostreptococcus spp., clostridium spp., actinomyces spp., prevotella spp., wolinella spp., propionibacterium spp., streptococcus spp., lactobacillus spp., gemella spp., bacteroides spp. and eubacterium spp., whereas p. aeruginosa, s. aureus and b. cepacia revealed . x cfu/ml (range . x to . x cfu/ml). in sputum samples contaminated with p. aeruginosa together with strict anaerobes . x ± . x cfu/ml p. aeruginosa were counted, whereas in samples with p. aeruginosa without strict anaerobes only . x ± . x cfu/ml were found (p= . ). for s. aureus, no significant difference was observed. identical strict anaerobic species were detected in out of patients with two or more repeated sputum samples ( %). e-test® sensitivity testing for strict anaerobes yielded high sensitivity for meropenem (only . % resistant strains), piperacillin/tazobactam ( . %), and clindamycin ( . %), but not ceftazidime ( . %) or metronidazole ( . %). high numbers of strict anaerobes are present in the majority of cf patients. possibly, strict anaerobes promote growth of p. aeruginosa but not s. aureus. the high persistence of identical anaerobic strains reflects chronic lung infection and may be caused by their increased resistence against standard antibiotics such as ceftazidime. [ in sputum in the cf lungs bacteria such as pseudomonas aeruginosa have to metabolize anaerobically [ ] . for anaerobic energy generation, p. aeruginosa can use nitrate and arginine, but also pyruvate which is produced from glucose via anaerobic glycolysis [ ] and can be metabolized to lactate and vice versa. in order to investigate if p. aeruginosa may benefit from externally produced lactate, we measured the concentration of lactate in p. aeruginosa, staphylococcus aureus, burkholderia cenocepacia and polymorphonuclear neutrophils in vitro and in cf sputum. in sputum samples of cf patients and in neutrophils ( x /ml) from healthy donors lactate concentrations were determined. in addition, p. aeruginosa (starting with x cfu/ml in tryptone soy broth), s. aureus ( x cfu/ml), and b. cenocepacia ( x cfu/ml)were grown aerobically ( through hrs) and anaerobically ( through days). l-lactate was measured spectrophotometrically (detection limit: . mmol/l), and total lactate gaschromatographically. aerobic and anaerobic gene expression of p. aeruginosa strain pao was determined using affymetrix® microarrays. lactate concentrations in cf sputum amounted to . ± . mmol/l (range . to . mmol/l). concentrations were similar in sputum samples colonized with p. aeruginosa, s. aureus ( . ± . vs. . ± . mmol/l, p= . ) and b. cenocepacia ( . mmol/l). neutrophils produced . mmol/l. in all samples exclusively l-lactate was found. during in vitro experiments, p. aeruginosa did not generate any lactate at all, neither aerobically nor anaerobically. in contrast, anaerobically grown s. aureus produced up to . mmol/l lactate, and b. cenocepacia up to . mmol/l. a p. aeruginosa suspension [ x cfu/ml] spiked with mmol/l l-lactate did not change its concentration, indicating that p. aeruginosa does not metabolize lactate. similar results were obtained in our gene chip experiments: after three days of anaerobic growth, the genes encoding for the lactate dehydrogenases were downregulated (pa ldha - . fold, pa llda - . fold) or unchanged (pa lldd . fold). in contrast, the genes encoding for pyruvate decomposition to acetyl coa (pa and pa , both encoding for pyruvate dehygrogenase e components) were upregulated by and fold, respectively. we could demonstrate that p. aeruginosa does not benefit from externally produced lactate. we confirmed the important role of pyruvate metabolism for anaerobic p. aeruginosa energy generation. whether lactate production of neutrophils, s. aureus or b. cenocepacia contributes to cf lung pathophysiology still remains to be investigated. references: [ ] macleod, d. ; barker, l. ; gurgel, j. ; kenney, t. ; burns, j. ; baker, w. . gilead sciences, inc., seattle, wa, usa; . university of washington, seattle, wa, usa antibiotic resistance may severely limit therapeutic options in individuals with cystic fibrosis (cf) or bronchiectasis. because of frequent antibiotic treatment courses, resistance continues to emerge, even to newer agents. treatment with multiple antibiotics in a single aerosol formulation may be a promising approach to slow development of resistance. fosfomycin is a phosphonic acid antibiotic that is bactericidal against both gram positive and gram negative organisms. fosfomycin inhibits the first committed step in the synthesis of peptidoglycan, suggesting cross resistance to other cell wall acting antibiotics will not occur. the aminoglycoside tobramycin is one of the most commonly used antimicrobials in cf, with potent activity against gram negative bacteria and the majority of staphylococcus aureus isolates. a : (wt/wt) fixed combination of fosfomycin:tobramycin (gs- / ) was used to determine the in vitro susceptibilities of a panel of respiratory pathogens: cf pseudomonas aeruginosa ( ), s. aureus ( ), haemophilus influenzae ( ), stenotrophomonas maltophilia ( ) and burkholderia cepacia complex ( ), including minimal inhibitory concentration (mic) and time-kill experiments in the absence and presence of % porcine mucin. synergy was evaluated using the checkerboard method, and spontaneous resistance mutation frequencies were determined in antibiotic-containing agar ( x, x and x mic). in vivo drug efficacy was examined using a rat agar bead pneumonia model of either p. aeruginosa or s. aureus. all experiments compared gs- / to fosfomycin and tobramycin as single agents. gs- / had a lower mic than tobramycin for the s. aureus strains, % of which were methicillin resistant (mrsa). for p. aeruginosa, gs- / had a lower mic and mic than fosfomycin alone, but tobramycin was more active than either. for h. influenzae and s. maltophilia, gs- / , fosfomycin and tobramycin had similar mic and mic . b. cepacia complex were resistant to all three drugs. results in the presence of mucin were similar. time-kill studies showed a more rapid and prolonged killing of s. aureus and p. aeruginosa by gs- / compared with either agent alone at the same drug concentrations. gs- / was bactericidal and exhibited concentration-dependent killing. synergy studies showed no antagonism between fosfomycin and tobramycin, and the majority of p. aeruginosa and all of the s. aureus tested demonstrated indifference for the combination. at x mic concentrations the mutation frequency of gs- / was at least - logs lower than tobramycin and - logs lower than fosfomycin alone for s. aureus. for p. aeruginosa the mutation frequency of gs- / was - logs lower than fosfomycin and - logs lower than tobramycin. in the rat pneumonia model, gs- / and tobramycin alone demonstrated bactericidal killing of p. aeruginosa; both were more active than fosfomycin alone. in vivo killing of s. aureus by gs- / was also demonstrated. gs- / appears to have advantages over single agents for the treatment of both gram positive and gram negative bacterial lung infections in cf and bronchiectasis. britton, l.j. antibiotic resistance is becoming a major problem in the treatment of pulmonary exacerbations in cystic fibrosis (cf). organ-isms that are resistant to multiple antibiotics infect the airways of an estimated - % of adults with cf. as a result of the growing resistance in cf patients, many centers have been performing synergy testing of sputum cultures in addition to the conventional culture and sensitivity testing. the purpose of our investigation was to determine if antibiotic synergy studies and the use of synergistic combinations of antibiotics improve therapeutic outcomes in cystic fibrosis patients with acute pulmonary exacerbations. methods: this study is a retrospective chart review of cf patients who had antibiotic synergy testing performed while hospitalized for respiratory tract infections. eligibility criteria included cf patients hospitalized with respiratory tract infections from to . laboratory data from each hospital admission was reviewed for synergy among those antibiotics commonly used against pseudomonas aeruginosa. a review of medical charts ascertained each patient's pulmonary function (determined by fev before and after antibiotic therapy), weight z-score, organism cultured from sputum sample, time to next hospital admission, and the antibiotic(s) actually prescribed. primary endpoints were determined to be the change in fev and the time to next admission. results: four hundred seventy-five hospital admissions were analyzed. a total of cystic fibrosis patients, age birth to years, were included in the study. patients receiving antibiotic synergy experienced a significant decrease in mean time to next admission ( days with synergy vs. days without synergy, p= . ). no significant difference was found in the change in fev before or after antibiotic therapy, with an increase of . % with synergy vs. . % without synergy (p= . ). patients infected with non-mucoid p. aeruginosa experienced days to the next hospital admission, while patients infected with mucoid p. aeruginosa experienced days to the next hospital admission (p = . ). no statistically significant difference was observed between the synergy and non-synergy groups in regards to nutritional status and lung function prior to antibiotic therapy. speculations: antibiotic resistance in cystic fibrosis patients increases the morbidity and mortality caused by this disorder with each exacerbation the patient experiences. synergistic antibiotic therapies should improve patient outcomes through more efficient bacterial eradication and increased time to next hospital admission; however, we were unable to substantiate this assumption based on the results from this study. synergistic antibiotics did not show an improvement in the therapeutic outcomes of days to next admission or change in fev . background: expectorated sputum (es) technique is currently the most frequently used method for routine assessment of lower airway infection in patients with cystic fibrosis (cf). induced sputum (is) using hypertonic saline (hs) has been successfully used in cf patients unable to produce sputum spontaneously, but only limited data are available comparing the diagnostic yield of expectorated versus induced sputum in cf patients. while ultrasonic nebuliser have been used in the majority of studies, new high output jet nebulisers may offer a suitable alternative technique to induce sputum expectoration. aim: to assess the feasibility of sputum induction using a pari e-flow nebulizer and to compare the diagnostic yield of is and es in children with cf . methods: this is a preliminary report of an ongoing study in routine clinical care in sputum producing children with cf. es is being obtained before sputum induction. subsequently, sputum induction is performed using stepwise inhalation of nebulized ml of %, % and % hypertonic saline with an e-flow nebulizer (pari, starnberg, germany). lung function is assessed by portable spirometry before the procedure and after inhalation of each saline concentration. results: so far cf patients ( females) with a mean age of . years (range to years) and fev between - % predicted (mean %) have been included in the study. all subjects provided es samples and all produced sputum after induction. discrepancies in cultures between es and is samples were seen in cases ( . %). in cases additional cf pathogens were found in is samples, whereas in cases es yielded additional organisms compared to is. the number of distinct pathogens was similar in the remaining patient, but different bacteria were found with the techniques. in cases p. aeruginosa was detected only with one of the techniques ( es versus is). the spectrum of side effects was similar to previous reports using other nebulizer systems, with throat irritation being the most common adverse event of the is technique. all patients who had symptoms during the procedure became asymptomatic at the time of discharge from the clinic - minutes after the procedure. patients did not finish all cycles of sputum induction procedure due to symptoms of shortness of breath and/or drop in fev > % from baseline (in patients); all reversed after salbutamol inhalation. vomiting occurred in one patient. patients refused to complete the procedure due to unpleasant taste and/or throat irritation. conclusion: these preliminary results show discrepancies between expectorated sputum and induced sputum cultures in a significant proportion of cf patients. this may be explained by the previously described regional differences in lower airway infection in cf airways rather than by a higher diagnostic yield of one of the techniques. the results also demonstrate that the e-flow system is an efficient and safe device for sputum induction in sputum producing children with cf. seidler, m.j.; salvenmoser, s.; müller, f.c. dept. pediatrics iii, university heidelberg, pediatric pulmonology, cystic fibrosis centre & infectious diseases, heidelberg, germany background: the preferred growth form of bacteria is a biofilm. s. aureus, h. influenzae, and p. aeruginosa can produce an extracellular matrix (ecm) with implications in cystic fibrosis (cf) lung disease. the biofilm can protect against host defenses and antimicrobials. a. fumigatus is a frequent colonizer of the cf respiratory tract and can cause allergic bronchopulmonary aspergillosis (abpa). while antifungals in vitro are active against a. fumigatus, in vivo antifungal therapy is often complicated or resistance is observable. the aim of this study was to investigate the ability of a. fumigatus to form a biofilm-like matrix in vitro on polystyrene (ps), human bronchial epithelia cells ( hbe) and human bronchial epithelia cells with f del/f del (cfbe o-). methods: a. fumigatus atcc # was incubated in rpmi at different ph and concentrations of fbs. temperature, production time and different flow conditions were varied on ps, hbe and cfbe o-. dry weight measurement and antifungal drug susceptibility testing was performed. scanning electron microscopy (sem) and confocal scanning laser microscopy (cslm) images were analyzed. results: the thickest biofilm was produced on ps with rpmi (+ % fbs, ph= . ) at °c for h slightly rocking. biofilm dry weight on ps was . mg after h and . mg after h. the dry weight of produced biofilm exceeded . mg on hbe and . mg on cfbe o-cells after h of biofilm production. there was no significant difference in dry weight increase between the cell lines and ps. planktonic a. fumigatus was susceptible to itraconazole ( . µg/ml), voriconazole ( . µg/ml) and amphotericin b ( µg/ml). aspergillus in biofilm was resistant against all drugs (> µg/ml). the sem pictures displayed a network of hyphal structures and matrix at h. characteristic flow channels were observed at h. cslm images displayed conidia and hyphal structures embedded in matrix formations. a-alexafluor dyed polysaccharides of the cell wall and of the ecm in the biofilm. three dimensional constructs of the cslm pictures displayed biofilm on hbe and proofed viability of the cells after h co-incubation. differences in biofilm production between hbe and cfbe o-were not significant. conclusions: a. fumigatus is able to form a biofilm structure in vitro on ps, hbe and cfbe o-. a biofilm-like matrix produced by a. fumigatus was evidenced by dry weight measurement, sem, cslm and antifungal drug resist-ance in comparison to planktonic cells. potential clinical implications of a. fumigatus biofilm formation in vivo require further attention and investigations. etherington, c. ; peckham, d. ; conway, s. ; hall, m. ; denton, m. . seacroft hospital, regional adult cf unit, leeds, united kingdom; . microbiology department, leeds teaching hospitals, leeds, united kingdom susceptibility testing results are not predictive of clinical response to antibiotic therapy in chronic pseudomonas aeruginosa infections in cystic fibrosis. we assessed the impact of reducing the number of routine susceptibility tests performed on clinical outcome in these cases. in june we introduced a protocol of limiting susceptibility tests to p. aeruginosa isolates obtained from respiratory samples taken at the commencement of antibiotic therapy, when there was evidence of clinical failure, or routinely if not tested in the previous three months. at all other times, isolates were identified and reported as normal but p. aeruginosa isolates were not subjected to susceptibility tests. between st june and th november p. aeruginosa, was isolated on at least one occasion from patients attending our adult cf unit. in this six month period we reduced the number of susceptibility tests by % (from a projected , tests on samples to an actual tests on samples). this resulted in projected savings of $ , in consumables and hours (costed at $ , ) of laboratory staff time per annum, a total saving of $ , (£ , ) per annum. we assessed the response to intravenous antibiotic treatment between the study period in and the same period in . no significant differences in median change of fev , fvc, crp, white cell count, weight, or duration of intravenous antibiotics were observed. for cf units sending regular, routine sputum samples, a reduction in the number of susceptibility tests performed in cases of chronic p. aeruginosa can be carried out without impacting on clinical outcomes. we report our preliminary results for a total of strains obtained from patients ( patients harbored more than strains). these patients were classified in groups of respiratory insufficiency according to their fev : severe in patients (fev < %), moderate in patients (fev : - %) and mild in patients (fev > %). the clonal distribution was analyzed for the different strains of sa ( to ) isolated from patients sputum. these strains were analyzed for their antibiotic susceptibility and typed by pulsed-field electrophoresis gel (pfge) after smai digestion of chromosomal dna. thirty seven patients ( %) were colonized with mrsa. nine patients were both colonized with mrsa and mssa. among mrsa strains, / ( %) were also resistant to more than three other antibiotic family. strains harboring minor differences in the banding pattern (> % similarity as assessed by the dice coefficient) were considered clonal. our results show that % of the patients were colonized with a single persistent strain during the year of follow-up. consecutive isolates with different pfge profiles were obtained from only / patients ( %). pfge analysis revealed that mrsa isolated from patients were grouped in clusters. these results revealed a possible clonal relationship between mrsa isolated from different patients with cf. we did not find any difference in the distribution of sa strains in our cf patients among the groups of respiratory insufficiency. the study is ongoing in our adult cf population and in necker pediatric cf centre in paris. giusti, r. ; furfaro, s. . pediatrics, long island college hospital, brooklyn, ny, usa; . research, lumina fund, new york, ny, usa palivizumab(synagis) is a humanized monoclonal antibody to rsv. the redbook acknowledges that some patients with cystic fibrosis may be at increased risk of rsv infection but that there is insufficient data to determine the effectiveness of this therapy. the objective of this study was to assess: )practice patterns of cf physicians in the us and canada )the severity of rsv disease in cf infants during the past rsv season. )if there is a standard of care concerning the use of synagis for cf infants. methods a questionnaire was developed using a web-based commercial vendor. an embedded web link was distributed via an e-mail sent to all us and canadian pediatric cf center directors. respondents clicked on a link to respond to the survey and results were automatically tabulated in real-time. completed responses were received from center directors ( us and canadian) for a response rate of % in us and % in canada. most responders ( %) have prescribed synagis for infants with cf in the first rsv season, however only % routinely prescribed synagis for all infants with cf. only % expressed having had difficulty in obtaining insurance approval for this medication. many physicians indicated that synagis was frequently prescribed by the general pediatrician and that infants living at long distances from a cf center may be hospitalized at local hospitals. these issues may affect the accuracy of the data and result in an underestimate of actual synagis prescription and hospitalization rates. there were infants diagnosed with cf in the past year and of these infants were reported as symptomatic. there were cf infants ( %) reported as having a documented rsv infection and ( %) of these infants had received synagis. there were infants ( %) with documented rsv infection who responded to outpatient management.there were no deaths but patients were hospitalized and of these had received synagis. of the infants that required admission to an icu had received synagis. of the patients who were noted as having persistent chest x-ray changes had received treatment with synagis. there were infants with persistent wheezing and of these infants had been treated with synagis. conclusions despite the limitations of a retrospective survey, this data demonstrates that rsv can cause significant and prolonged pulmonary disease and is a significant precipitating factor resulting in hospitalization of cf infants. the data also notes that many cf infants infected during the past rsv season have a mild illness and respond to outpatient management. a surprising finding of this survey is that infants at cf care centers where synagis was prescribed for all cf infants continued to have significant rsv related hospitalizations, persistent wheezing or prolonged chest x-ray abnormalities. there are different opinions among cf physicians concerning the routine use of synagis and currently the data suggests that there is not a standard of care concerning the prophylaxis of cf infants with synagis. this results of this survey should encourage physicians to prospectively study the efficacy of synagis prophylaxis in preventing hospitalization, persistent wheezing and chest x-ray abnormalities in cf infants. milani, a. ; cisbani, g. ; macchi, r. ; vidal-aroca, f. ; bertoni, g. . biomolecular sciences and biotechnology, university of milan, milano, italy; . basilea pharmaceutica ltd., basel, switzerland with ever increasing frequency, we now observe several examples of bacteria being resistant to every clinically available drug. therefore this urgently calls for the development of novel and improved antibiotics that may escape the extant mechanisms of bacterial resistance. one recent and promising development of the genome-wide search for target functions for antibiotics led to the identification of essential genes of pathogens by interfering antisense rnas. the first step is the construction of shotgun antisense libraries (sals) as follows. genomic dna is extracted from the bacterial strain of interest, fragmented by shearing into short pieces of dna, blunt-ended and cloned in an expression vector under the control of a regulatable promoter. the library is then reintroduced into the cognate bacterial strain and screened by replica plating colonies both in the presence and the absence of an inducer of the vector promoter. by this method, insert sequencing of clones showing conditional growth phenotypes is expected to lead to the identification of essential genes that can be silenced via antisense rna activity. we adopted this technology in order to generate a panel of essential functions of the cystic fibrosis-related opportunistic pathogen pseudomonas aeruginosa. so far, we tuned the protocol for sal generation in p. aeruginosa and identified a number of sequences conferring different levels of growth inhibition we are now characterizing these putative antisense rnas in order to define the minimal sequence able to cause the toxic effect and, on the other hand, to understand the cellular role of their targets. pseudomonas aeruginosa (pa) is an extremely versatile microbe with a vast array of pathogenic and metabolic mechanisms that allow it to form persistent infections in select patient populations, especially patients with cystic fibrosis. an ineffective immune response is considered partially to blame for failure of pa eradication. we have discovered that some strains of pa express peptidylarginine deiminase (padi) activity. padi is an enzyme that post-translationally modifies peptidylarginine to peptidylcitrulline with ammonia as a byproduct. our lab has shown that human padi can modulate the immune system through downregulation of tlr and ikk-gamma signaling. characterization of the pa padi will offer insights into a completely novel method of immune modulation by pseudomonas aeruginosa. using a widely published colorimetric assay for padi activity we have found the specific activity of crude pa cell lysates is very low. however this is similar to the only other known prokaryotic padi described in porphyromonas gingivalis. a protein homology search with the porphyromonas padi has revealed the likely genetic locus of pseudomonas padi in a . kb operon that appears in the genome of the pathogenic pseudomonas isolate pa . this operon appears to contain two candidate genes for padi activity based on conserved motif searches (padi and padi ). both have been cloned into expression vectors, partially purified by affinity tag technology and tested in the colorimetric padi assay. curiously padi autocitrullinates itself while padi has not shown activity. reaction conditions and substrate specificities for pa-padi are not like either the human or porphyromonas padi. furthermore analysis of up to clinically diverse strains has demonstrated % carry the gene for padi . this work is only the second description of padi activity in any prokaryote. pa padi could clearly have a dramatic impact on the local inflammatory milieu if it can access the same targets as human padi. the description of this activity in pseudomonas will advance our knowledge of the human-pathogen relationship and give insight into new therapies. which functions by translocating toxins into the cytoplasm of host cells. these toxins cause disease by damaging the surrounding host tissue, promoting dissemination of the organism and paralyzing the phagocytic mechanism of macrophages. pcrv is a factor required for the translocation of the toxins. the bases of these studies were to evaluate pcrv as a protective antigen in "p. aeruginosa" pneumonia and cldc as a vaccine adjuvant. methods: mice were vaccinated , , or times with the pcrv antigen combined with either aluminum hydroxide (alum) or cldc by various routes of administration. efficacy of vaccination was evaluated by challenge with "p. aeruginosa" and evaluation of survival and/or measurement of various parameters associated with lung injury. results: increase in median survival time was highly significant when cldc/pcrv was compared with cldc or pcrv alone. following subcutaneous administrations cldc/pcrv showed an increase in median survival time ( hours versus hours) and overall survival benefit following intraperitoneal administrations ( % versus %). mice with anti-pcrv antibody levels above µg/ml were significantly protected. conclusion: the investigators establish the efficacy of cldc/pcrv vaccines via several parenteral routes of administration compared to no treatment as well as cldc and pcrv-only controls. differences were demonstrated between performance of cldc/pcrv and alum/pcrv in measures of lung injury, median survival, and overall survival. the results correlated with antibody levels and histological examination of the lung tissues. importantly, these studies indicate that protection can be achieved against "p. aeruginosa" infection by targeting an antigen associated with the type iii secretion system. background: there has been a recent increase in the number of reported cases of acute renal failure (arf) in cystic fibrosis (cf). our group have undertaken a national survey, which measured the incidence risk of arf in cf patients at between . and . cases / , cf patients / year. we have now conducted a case control study to determine which factors which are associated with an increased risk of arf. methods: in our initial survey we confirmed cases of arf, in cf patients from uk cf centres, presenting between & . using the uk cf database, we identified sex and age (within months) matched controls. informed consent was sought from the control patients, or their parents, for access to the case notes and clinical data were extracted. analysis of risk factors was by conditional logistic regression, using stata (version ) and by fisher's exact test. results: there were cases of arf ( male, median age y, range m- y) and controls ( male, y, m- y). in the group of patients with arf, / had received an aminoglycoside at the time of their episode of arf or in the preceding week, compared with only of the controls for the same time period (p< . ). the median number of days of aminoglycoside in the year prior to the index case developing acute renal failure was ( - ) for cases and ( - ) for controls. conditional logistic regression showed that the odds ratio for arf per each day of aminoglycoside was . ( % ci . to . , p= . it is well-known that pa senses the environment and changes its phenotype. for instance, it produces greater amounts of the extracellular polysaccharide alginate in the cf lung, characterized by a microaerobic environment. little is known about the changes in protein secretion induced by oxygen limitation in pao , the proto-typical pa laboratory strain. no data are available on this regard about pa clinical strains. our work was aimed to study the differential regulation of proteins secreted by pa strains grown in microaerobic or aerobic conditions. a pa clinical isolate and pao were grown overnight in aerobiosis and in microaerophilic conditions. the supernatants were collected and proteomic analysis was carried over by two-dimensional capillary chromatography -tandem mass spectrometry (mauri et al., faseb j ) to evaluate the differential protein expression. in the pa clinical isolate, we identified proteins down-regulated and proteins upregulated in aerobic conditions in comparison with microaerophilic culture while in pao proteins were down-regulated and were up-regulated. proteins were down-regulated and up-regulated both in the clinical and in the laboratory strain. these proteins can mediate different biological functions since they are enzymes, heat shock proteins, chaperones, proteins involved in adaptation, motility and in the transport of small molecules. among all these proteins, as the alkaline metalloproteinase is associated with tissue invasion not only by causing rupture of epithelial tight-junctions but also by degrading several chemokines, we decided to validate its up-regulation observed in aerobic conditions by zymography. we found that the proteolytic activity of the supernatants of pa grown in aerobic conditions was higher than in microaerophilic culture both for the laboratory and clinical strain, indicating the functional relevance of data obtained by proteomic analysis. the identification of proteins differentially regulated in aerobiosis and oxygen limitated conditions in pa laboratory and clinical strains might be helpful for the knowledge of the mechanisms of colonization and lung damage due to pa in cf patients. for instance, the validation of the upregulation of the alkaline metalloproteinase in aerobic condition may shed light on these mechanisms of cf lung disease. further studies are in progress to evaluate the function of other bacterial exoproducts regulated in this model and to extend the analysis to other clinical strains. supported by the italian cystic fibrosis research foundation (ffc-grant# / ), comitato di vicenza dell'associazione veneta per la lotta contro la fibrosi cistica and azienda ospedaliera di verona, italy. cystic fibrosis (cf) sufferers are subject to repeated lung infections most commonly with the bacterium pseudomonas aeruginosa. in spite of antibiotic treatment p. aeruginosa tends to become established giving rise to persistent chronic infection. in the lung environment, the bacterium grows as a highly structured biofilm consisting of a complex community of cells embedded within a self-secreted polysaccharide matrix. investigations of p. aeruginosa biofilm growth using model strains have elucidated mechanisms which appear to govern the biofilm life-cycle. our research aims to test whether observation of these mechanisms in planktonic culture can be related to the efficiency of biofilm formation. biofilm initiation has been linked to cell motility and in particular to the presence of flagella and pili, which are thought to be important for cell attachment and the formation of microcolonies. on testing a large, genetically diverse group of clinical p. aeruginosa isolates retrieved from the lungs of cf patients we found no definitive correlation between the degree of motility of an isolate in planktonic culture and its ability to form a biofilm in vitro. the development of biofilm architecture has been demonstrated in model systems to be coordinated by the production and secretion of n-acylhomoserine lactone (ahl) quorum sensing molecules. however among the clinical isolates tested we observed no obvious correlation between the amount of ahls produced in planktonic culture and the extent of biofilm formation. overall we have found observation of phenotypic characteristics in planktonic culture to be poor predictors of efficient biofilm formation. a proteomics approach was adopted to provide further insight into the physiology of biofilm growth of p. aeruginosa isolates by comparison with planktonic growth of the same isolates. two genetically unrelated clinical isolates, demonstrated as being capable of efficient in vitro biofilm formation, were selected from our culture collection on the basis of their diverse phenotypic characteristics when cultured planktonically. one displays both twitching and swimming motilities, is mucoid and expresses ahls, while the other is non-motile, non-mucoid and no ahls have been detected in planktonic culture. we have developed a simple flow-through bioreactor to provide sufficient quantities of biofilm for proteomic analysis. gel-based and gel-free techniques were employed to study protein expression patterns for both biofilm and planktonic cultures of each isolate by mass spectrometry. proteins specific for each growth phase could be detected and may prove suitable biomarkers for monitoring the physiological status of biofilm forming strains when a larger bank of clinical isolates are examined. liposomal amikacin (arikace tm ) is a liposome-encapsulated form of amikacin that is formulated to treat chronic p. aeruginosa infections in cystic fibrosis patients. these liposomes carry a zwitterionic surface charge and are composed of lipids found naturally within the lung. a key aspect of the activity of the formulation is the ability to penetrate to the sites of pseudomonas biofilm-like growth in the lung. experiments were designed to investigate the penetration of liposomes into p. aeruginosa biofilms and in vitro activity. methods and results: model liposomes of the same size and lipid composition as liposomal amikacin (arikace tm ) were prepared with membrane-associated or encapsulated fluorescent labels, a hydrophobic carbocyanine dye and calcein, respectively. a mucoid strain of pseudomonas aeruginosa (pa ) was used to establish biofilms in rectangular optical grade glass flow cells. biofilms were observed after four days of growth by confocal laser scanning microscopy using a focal plane set to view within the biofilm cluster or outside as a control. time dependent accumulation of fluorescent liposomes within the biofilms was measured by the spatial distribution of fluorescence intensity in regions within or outside of the biofilm. images indicated significant penetration of liposomes into the interior of biofilms under these conditions. the rate of penetration was considerably slower than typical rates for small molecules, consistent with the size of the liposomes. liposome concentrations were higher near the periphery than the interior. however, even the interior concentration was at least as high as the concentration of liposomes in the fluid outside of the biofilm, suggesting some binding or trapping of the liposomes within the biofilm. penetration of liposomes was observed under flow or static conditions. in a "washout" experiment, where medium is passed through the biofilms previously treated with liposomes, a significant portion of the liposomes remained associated with the biofilms for an extended period of time. the penetration of liposomes was reflected in the observation of killing of bacteria in colonies in the interior of agar beads. exposure of these cultures to liposomal amikacin resulted in a large reduction of viable bacteria throughout the beads as monitored by a fluorescent dna content assay. similar colony forming unit reductions in animal models (to be shown in other poster presentations) suggest that these principles also operate in vivo. liposomes similar to liposomal amikacin (arikace tm ) readily penetrate into biofilms of pseudomonas aeruginosa and may even have enhanced binding to biofilms. this binding along with localized release can explain the substantial efficacy observed in animal models. coates, a.l. adherence to recommended therapy in cf has always been a challenge, in part, due to the time demands of the daily therapy. while twice daily inhaled tobramycin for those infected with pseudomonas aeruginosa (pa) has become an accepted standard of care, as much as minutes a day may be consumed inhaling mg in ml of tobramycin (tobi ® ) from the pari lc plus ® breath enhanced jet nebulizer. the purpose of this study was to determine if equivalent levels of pulmonary deposition could be achieved in a much shorter time period using . ml of a more concentrated ( mg/ml) tobramycin solution delivered by a perforated vibrating membrane nebulizer (eflow ® membrane configuration l) both, developed by pari pharma; germany. methods with a goal to study children and adults, to date, the subjects are children years and older and adult males, all with an fev > % predicted, with stable cf. all were receiving inhaled tobramycin for positive sputum cultures of pa. following pretreatment with albuterol, they inhaled both preparations on two occasions with m tc-dtpa added to the tobramycin in the nuclear medicine facility. in vitro preliminary work demonstrated that the radiolabel tracked with both formulations of tobramycin. deposition was measured by a gamma camera taking both tissue attenuation and mucociliary clearance during nebulization into account (pediatric pulmonol suppl : a ; ) . in order to have a continuous rate of deposition, the pari lc plus ® was run for a timed minutes and then both the total deposition and time of nebulization "scaled up" from in vitro testing when the nebulizer was run to dryness. this was done by multiplying the deposition by the total output when run to dryness divided by the total output in minutes. (blood samples were taken for quantification of tobramycin in the serum but not yet analysed). the rate of output per minute was calculated from the minute run and the total time was total output from in vitro testing divided by the rate of output. the eflow ® pro-vides a continuous output and stops automatically at dryness. quality assurance was the agreement between total radioactivity pre nebulization (in the nebulizer) and post which included the subject, the nebulizer, the connectors and the expiratory filter. the pari lc plus ® delivered . ± . mg in . ± . minutes compared to . ± . mg in . ± . minutes for the eflow ® . only the time of delivery was significantly different with p< . (paired t-test). tolerability of the treatment was comparable for both inhalation regimes, but the shorter treatment was preferred by all patients. these results demonstrate the possibility of delivering equivalent levels of tobramycin in much shorter periods of time into the lungs of cf patients when using eflow ® , a very efficient electronic nebulizer. this time saving may improve adherence to recommended therapy. (pediatrics ; : ) . in order to properly interpret op cultures from nbs infants, especially those with non-classic cf mutations, we need to know the op flora of non-cf infants. we obtained op cultures from healthy infants under yr of age. op specimens were plated on standard cf culture media. exclusion criteria included a first degree relative with cf, respiratory illness at the time of culture, or positive newborn screen for cf. data on cigarette smoke exposure, animal exposure, and exposure to hot tubs/swimming pools was collected. samples have been collected to date. in healthy, non-cf infants, the most common finding is non-specific mixed gram negative and positive growth. however, infants have grown pa (ages months, months, and months). many infants have grown multiple organisms. the following bacteria have been found in (n) number of infants: s. aureus ( ), e. coli ( ), e. cloacae ( ) , h. flu ( ), klebsiella ( ), pseudomonas aeruginosa ( ), h. parainflu ( ), unidentified non-lactose fermenting ( ), other ( ). data on infants including correlation to environmental factors will be presented. conclusion: non-cf infants commonly have s. aureus and many gram negative organisms including pa in their oropharynx. these results may have some bearing on interpetting colonization and clearance of pa in infants identified through nbs and in epic study participants. # ) ). identification of smg by sputum cultivation represents a significant challenge because the organisms are phenotypically diverse, grow poorly on routine culture media, and are very difficult to discriminate from other members of the oropharyngeal flora. we have developed a solid media for the selective isolation of smg from sputum. the value of the media is highlighted by the identification of smg as the quantitatively dominant organism in sputum samples of three cf patients admitted to hospital for an acute pulmonary exacerbation. in all three, the smg species failed to be identified on routine or selective media currently described for the culture of cf-specific sputum pathogens. antibiotic treatment directed against the smg correlated with clinical resolution of acute symptoms as well the reduction of smg on daily serial sputum cultures during hospitalization. this novel selective media makes use of antibiotics (colistin, sulfadiazine and oxolinic acid) inhibitory to the growth of principal cf pathogens and much of the usual oropharyngeal flora. smg agar utilizes a colorimetric indicator to uniquely identify smg colonies. the sensitivity and specificity of the selective media has been evaluated by molecular methods using terminal restriction fragment length polymorphism analysis. smg organisms do not respond well to anti-pseudomonal therapy, therefore proper detection and culture-directed antibiotic therapy is paramount. we believe that smg represent significant respiratory pathogens in cf, and because of the inability to effectively culture and identify smg they have largely gone unrecognized. pseudomonas aeruginosa releases substantial amounts of the blue antibiotic pigment pyocyanin. in presence of a reductant (such as nadph), pyocyanin redox-cycles and generates superoxide and h o . in infected cf airways, pyocyanin concentrations can reach high micromolar levels and contribute to oxidative stress of the airways. the structural basis of the pyocyanin molecule that underlies the redox-cycling with reductants of the airways is not clear. we therefore investigated i) the ability of physiologically or pharmacologically relevant reductants of the airways to support the redox-cycle activity of pyocyanin, and ii) the molecular features of pyocyanin that support redox cycling. dose-and time-dependent h o production by pyocyanin was measured by amplex red oxidation in presence of horseradish peroxidase. rates of h o production by µm pyocyanin in presence of µm reductant were: nadph ( pmole/min) > l-ascorbate ( pmole/min) > reduced glutathione ( pmole/min) > α-tocopherol ( pmole/min). in contrast, lipoic acid, genistein, or resveratrol did not significantly support pyocyanin-mediated h o production. in absence of a reductant, pyocyanin showed no measurable formation of h o . to identify the structural characteristics of the pyocyanin molecule that allow for its redox-cycling activity we synthesized a number of new pyocyanins containing electron-donating or electron-withdrawing substituents. functional assays were performed in presence of l-ascorbate as reductant. molecular substituents that donated electrons to the positively charged core of pyocyanin, either by hyperconjugative or resonance effects, reduced the h o output of the corresponding pyocyanin. in contrast, a closely related analog ( -hydroxyphenazine- , dioxide) showed significantly increased activity ( . x compared to pyocyanin) suggesting that the electron-withdrawing effect of the n-oxide functionality led to an increase in the redox-cycle activity. these data indicate that the functional characteristics of pyocyanin as a redox-cycling compound are governed by its positively charged core. in the airways, pyocyanin is predicted to utilize several reductants that are present in the airway surface liquid or intracellularly, thus contributing to cf airway disease. because pyocyanin utilizes a variety of reductants, it appears prudent to test whether inhaled small-molecular cf therapeutics support pyocyanin function. supported by nih (hl- , p at ), cfri, philip morris usa inc and philip morris international, and cff (fischer g ). taccetti, g.; braggion, c.; ravenni, n.; zavataro, l.; neri, a.; festini, f.; campana, s. meyer hospital, university of florence, cf center of tuscany, florence, italy for practical purposes, after early eradication treatment, at least three consecutive negative respiratory cultures over a -month period would indicate that the organism has been eradicated (cf trust guidelines). this recommendation is based on opinion/clinical experience of respected authorities in the absence of directly applicable studies of good quality. aims: using molecular biological techniques, we evaluated whether this -month interval is really trustworthy for distinguishing between regrowth of the same strain, suppressed but not eradicated by treatment, and new pseudomonas aeruginosa (pa) colonization. patients and methods: cystic fibrosis (cf) patients were treated with oral ciprofloxacin and nebulized colistin at detection of pa. all pa colonization episodes were recorded in an appropriate database. molecular study of each bacterial isolate from each colonization episode was performed with the rapd-pcr. results: between between - of patients in follow-up in our center had repeated pa colonization. the patients' mean age at first pa colonization was ± . months. a total of episodes was observed (mean of . episodes per patient, median of , range - ). molecular typing on strains indicated that ( . %) were a different genotype from later colonization episodes while ( . %) isolates had the same genotype as those of the preceding episode. the same genotype as preceding colonization was observed in ( . %) of isolates from patients in which a successive colonization was verified in less than months, and was verified in ( . %) of strains in patients having a successive colonization in over months (or= . ). colonization was due to a genotypically diverse strain in % of cases where colonization occurred within months of eradication. during the observation period ( %) of patients acquired chronic pa infection. conclusion: re-colonization by pa following eradication therapy is mostly ( %) caused by strains with a different genotype, suggesting acquisition from an external source. a short pa-free period is mainly due to transient suppression of pa growth, and true eradication followed by acquisition of a new pa genotype occurred in most cases only after a pa-free period longer than months. those patients with a pa-free interval of less than months had a six-times higher chance that the pa was not eradicated compared to those with a germ-free interval of over months. this evidence demonstrates that the definition of successful eradication should be reconsidered, taking into account additional parameters such as molecular analysis. cystic fibrosis (cf) patients appear to have an increased risk of urolithiasis. while a number of possible explanations for this have been proposed and investigated, no definitive mechanism has yet been demonstrated. as cf patients frequently get respiratory tract infections they regularly receive ciprofloxacin treatment, often given in doses well in excess of conventional prescription regimes. there are occasional reports of ciprofloxacin crystals urine and stones in the urinary tract. here we investigate the hypothesis that ciprofloxacin excreted in urine might act as a promoter of crystallisation of calcium or magnesium salts and thereby increase the risk of kidney stone disease. the effect of ciprofloxacin was tested in artificial urine (au). in vitro crystallisation was tested using a well plate turbidity method, to identify a metastable limit of oxalate concentration (ml) and a growth and nucleation parameter, the turbidity rate index (tri). the nucleation ph of urine was examined by tritrating oxalate free au through a ph range of . to . and monitoring the solution/suspension turbidity. in au at ph . , ciprofloxacin, at , , or mg/l, had no detectable effect on initiation of calcium oxalate crystallisation (ml) or its progress (tri) (n= for each concentration). when au with mm ca, mm mg and mm po was titrated there were two distinct nucleation points; a slow event starting at about ph . and a much faster event at about ph . . omitting ca or mg confirmed that the first event was due to calcium phosphate precipitation and the second to struvite. including ciprofloxacin at , or mg/l did not alter these nucleation ph values, but the magnitude of the turbidity rise showed that the ciprofloxacin co-precipitated with the struvite. ciprofloxacin at mg/l and without ca or mg began to precipitate at ph . and could be held in solution until ph . when ca and mg were included. even at high concentrations, ciprofloxacin does not influence calcium oxalate crystallisation. nor does it promote calcium phosphate or struvite precipitation; on the contrary, while the calcium and magnesium remain in solution, they help to prevent precipitation of the ciprofloxacin itself. urinary ciprofloxacin does not appear to act as a stone or crystal promoter. pseudomonas aeruginosa is a significant cause of mortality in cystic fibrosis (cf) sufferers. cf patients were thought to acquire p. aeruginosa from the environment; however genotyping over recent years has revealed clonal strains in sputa from cf patients in the uk, australia, and canada that are transmitted person to person or from a common source. one clonal strain, australian epidemic strain- (aes- ), (formerly melbourne epidemic strain, m or pi) currently infects up to % of patients in five cf clinics on the eastern seaboard of australia. most cf clonal strains have been associated with increased virulence not fully explained by greater antibiotic resistance. both genotypic and phenotypic differences have been postulated as important in enabling transmission of clonal strains. in order to compare the expression profile of aes- to the type strain p. aeruginosa pao , the cf research group at the university of sydney compared the genome expression data of four clonal aes- isolates and pao , when grown as planktonic and as -hr biofilm cultures. in aes- , a set of significantly differentially expressed genes (all downregulated) were identified, including the quorum sensing genes lasa, lasb and rhll. in contrast, both upregulated and downregulated genes were differentially expressed in pao biofilm compared to pao planktonic culture. expression data was validated using quantitative real-time pcr. to compare biofilm growth at the phenotypic level, the four clonal strains and pao were grown as -hr biofilms in a double-blind study, and the size of ten randomly selected biofilms per isolate, stained with syto® green fluorescent stain was measured. at hr, the biofilms formed by aes- isolates were significantly larger (ca. -fold) than pao (average size: ± µm vs ± µm )(p< . ). the average thickness of three biofilms per isolate, measured by confocal microscopy, showed aes- biofilms to be approximately . -fold thicker than those formed by pao ( . ± . µm vs . ± . µm). the general gene downregulation observed in aes- biofilms suggests an adaptation to the cf host, while a larger biofilm would provide for more effective bacterial dispersal. thus the transmissibility of aes- may be linked to enhanced biofilm formation upon colonisation. background -objective: whilst influence induced by bacterial colonization in cystic fibrosis (cf) is established, risk induced by fungal colonization is less defined. prevalence of other species than aspergillus sp. or candida sp., and factors associated with fungal presence are also poorly documented. our preliminary study aimed to determine which fungal species were present in sputum collected from adult cf patients, and which factors were associated with fungal presence. methods: in a monocenter, transversal prospective study, cf adult patients were included to determine fungal presence in sputum using semi selective growing media. clinical parameters (shwachman score, respiratory function, nutritional status, gastro-oesophageal reflux, pancreatic insufficiency and diabetes); therapeutics used (including oral or intravenous antibiotics, systemic or inhaled corticosteroids or bronchodilatators, antifungal treatments); microbiological data of bacterial colonization and environmental parameters (potted plants or domestic animals presence) were determined for each patient. correlation between fungal, clinical, environmental, therapeutic or microbiological data was evaluated by mann-whitney non parametric u test. results: patients ( %) presented with fungal presence in sputum. % presented with yeasts species, % with moulds. aspergillus fumigatus and candida albicans were the predominant species in moulds and yeasts respectively, but less common mould species such as exophiala dermatidis or paecilomyces variotii were also recovered. factors associated with fungal presence were pancreatic insufficiency (p= , ); malnutrition (p= , ), bacterial colonization and inhaled corticosteroids. candida albicans was correlated with more severe shwachman score (p= , ), bacterial colonization (p= , ), notably with pseudomonas aeruginosa (p= , ) , and intravenous antibiotics use (p= , ). moulds species were significantly associated with inhaled corticosteroids (p= , ). antifungal use was associated with frequent resistance to azoles treatments ( resistant isolates out of patients treated). conclusion: fungal presence in cf appears frequent. some species could have been previously overlooked due to diagnosis difficulties. the effect of corticosteroids on moulds species, already found in other pathologies, appears important in cf. influence of fungal presence on cf course needs prospective studies, in order to establish if patients could benefit from antifungal treatments or preventive measures. dren on a ventilator without a previous diagnosis of cystic fibrosis is unknown. the aim of our study was to investigate the prevalence of these microorganisms in routine sputum cultures in young children on a ventilator in a pediatric intensive care unit (picu). methods: from all ventilated children aged - years admitted from - , sputum culture results obtained from tracheal aspirates within the first week of admission were retrospectively analysed. three patient subgroups were identified: respiratory failure due to pulmonary disease (group ), ventilation after elective surgical procedures (group ) and other ventilated children (group ). children with a previous intensive care admission or cf were excluded. the cf database was checked ( ) to identify any children with a new diagnosis of cf that were included in the study. results: . % of all ventilated children had a positive sputum culture with one of the "cf-bacteria" s. aureus, h. influenzae and p. aeruginosa these were found mainly in group (see table) . / of these children were admitted for treatment of respiratory syncytial virus (rsv) bronchiolitis. a sweat test was performed in children, all admitted with pulmonary disease and because of co-existing clinical signs or symptoms. one sweat test was positive and subsequently cf was diagnosed in this child. no other children out of the study group have since then been diagnosed with cf. as the population in the northern part of the netherlands is very stable, it is unlikely a diagnosis of cf has been missed. conclusion: s. aureus and h. influenzae are cultured frequently in ventilated children without cf, especially when ventilated because of pulmonary disease. the opportunistic pathogen p. aeruginosa causes both acute and chronic human infections. the balance between systemic infection and mortality or chronic persistence and morbidity depends on complex relationships in which the immunological status and genetic potential of the host but also the bacterial biodiversity are determinant factors. p. aeruginosa extensive genetic adaptation and microevolution have been repeatedly observed in chronic infections of cf patients in contrast to what it is documented in acute infections. whether these p. aeruginosa clonal variants differ in their pathogenic potential is not yet known. a total of clinical p. aeruginosa isolates from six cf patients which carried unique clonal lineage from the onset of colonization over - years were selected (bragonzi et al, ; montanari et al, ) . five p. aeruginosa environmental strains, which represent the source of acquisition for cf patients, and two laboratory strains pao and pa were also used as references. multiple genotypic analysis of sequential p. aeruginosa isolates which included pfge, atchip and multilocus snps showed intraclonal diversity with genome rearrangements, variations in pathogenic islands and acquisition of prothoadaptive mutations in the muc genes. the largest divergence was observed between the completely sequenced reference strains pao and pa , the latter represented in our panel by three cf isolates. p. aeruginosa virulence has been assessed by monitoring its capacity to induce bacteremia and to establish chronic infection in a murine model (bragonzi et al, ) . overall, p. aeruginosa environmental strains increased five times the risk of bacteremia when compared to clinical strains (test of proportion: p< . ). the high risk of mortality was also evidenced for p. aeruginosa cf strains isolated at the onset of the infection when compared with those isolated after years of colonization (p= . ) indicating that environmental strains or newly acquired strains were similar in their virulence. p. aeruginosa clinical strains isolated after years of colonization increased chronic persistence and reduced the risk of bacteremia (p= . ) when compared to strains isolated at the onset of the infection. the strain pa was found to be lethal in contrast to p. aeruginosa clonal strains of clinical origin that established chronic persistent infection in the murine lung. furthermore, our data showed that adaptive traits commonly associated with the chronic p. aeruginosa infections in cf patients, such as transition to the mucoid phenotype, did not confer a selective advantage to bacterial cells in colonizing the murine lung (p= . ). these results suggest that p. aeruginosa pathogenicity is independent of the strain's genotype but rather genetic adaptation to the cf airways plays an important role in the development of persistence and in the resistance to host defences. supported by telethon and italian cf research foundation. beringer, p. the combination of antipseudomonal beta-lactam and aminoglycoside antibiotics is frequently prescribed during acute pulmonary exacerbations. since the introduction of the beta-lactam compounds there has been numerous reports citing altered pharmacokinetics of several compounds (but not all) within the beta-lactam class. recently it has been suggested that substrate specificity for the renal transporter pgp may explain the variability in renal drug clearance observed in patients with cf. pgp is structurally related to cftr and evidence suggests it serves a complementary role in modulating alternative chloride channel function. in a cftr knockout model mdr expression was reported to be increased nearly four-fold. in an effort to elucidate the potential contribution of pgp to the renal clearance of drugs in patients with cf, we conducted a controlled clinical trial comparing the pharmacokinetics of fexofenadine (fx) in patients with cf and age matched healthy volunteers (hv). fexofenadine is not significantly metabolized and is a relatively specific substrate for the membrane transporters pgp and oatp. probenecid (pb) is a selective inhibitor of oatp and was used pharmacologically to block the activity of this transporter in-vivo. our hypothesis is that if pgp is upregulated within the renal tubules of patients with cf we would expect to see an enhanced renal clearance of fexofenadine in these patients when compared with control subjects. methods: (n= cf, hv) subjects underwent this prospective controlled study which fx was received alone or in combination with probenecid (pb). iothalamate was given each day to measure glomerular filtration rate (gfr). blood and urine samples were obtained at specified times over hours each study day for determination of fexofenadine and iothalamate concentrations. fexofenadine and iothalamate concentrations were assayed using liquid chromatography-tandem mass spectrometry and hplc-uv respectively. pharmacokinetic analysis was performed using a -compartment cumulative urinary excretion model with the adapt ii software. differences between groups were determined using a paired t-test or mann whitney-u. results: patients were included, cf patients were slightly older and had lower body mass index when compared to hv, (mean±sd, ± . vs. . ± years p= . , . ± . vs. . ± . p= . respectively) but did not differ in gfr ( ± . vs. ± ml/min- . m p= . respectively). no significant differences were found between cf and hv in clr of fx alone and fx in combination with pb clr ( . ± vs. . ± . ml/min- . m p= . and . ± vs . ± . ml/min- . m p= . respectively). conclusion: the results of this study indicate the enhanced clearance of certain antibiotics previously reported in patients with cf do not appear to be due to upregulation of renal tubular pgp or increased gfr. maceachran, d.p. department of microbiology and immunology, dartmouth medical school, hanover, nh, usa p. aeruginosa is the leading cause of morbidity and mortality in cystic fibrosis (cf) patients. shortly after birth cf patients are colonized by p. aeruginosa, which leads to a lifelong chronic infection. the mechanisms behind p. aeruginosa colonization of the cf lung are still poorly understood, however several secreted toxins have been associated with this phenomenon. cf is characterized by a loss of mucocilliary clearance, a key component of innate immunity in the lung, and an increase in sputum viscosity as a result of mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (cftr). we have previously shown that the novel p. aeruginosa secreted protein cif is capable of reducing apical membrane expression of cftr. we have begun to characterize cif expression and have identified a key regulator of cif transcription. mutations affecting the divergently transcribed putative tetr family repressor encoded by the pa gene result in a significant increase in cif expression. furthermore, we have demonstrated that the pa gene product is capable of binding the promoter region located immediately upstream of the cif-containing operon. this work has been supported by the nih t -dk - . ryall, b. ; davies, j.c. , ; wilson, r. ; shoemark, a. ; williams, h.d. . division of biology, imperial college london, london, united kingdom; . department of gene therapy, imperial college london, london, united kingdom; . host defence unit, royal brompton hospital, london, united kingdom; . paediatric respiratory medicine, royal brompton hospital, london, united kingdom pseudomonas aeruginosa is the most important respiratory pathogen in patients with cystic fibrosis (cf) and non-cf bronchiectasis. the factors which enable p. aeruginosa to establish chronic, debilitating respiratory infections are unclear. however p. aeruginosa is one of a limited number of bacteria that is able to synthesise hydrogen cyanide, a potent inhibitor of cellular respiration. this study examined whether hydrogen cyanide is produced by p. aeruginosa in cf and non-cf bronchiectasis airway infection. cyanide concentration was measured in fresh sputum from cf and non-cf bronchiectasis patients with and without p. aeruginosa lung infection using a cyanide ion sensing electrode. cyanide was detected in sputum from / cf and non-cf bronchiectasis patients with current p. aeruginosa infection, whereas it was not detected in any of the patients without this organism (p< . ). maximum lev-els were µm (mean ±se: ± . µm), which compares with levels of above µm which would be considered toxic in blood. concurrent lung function data were available on all p. aeruginosainfected cf patients; the group with measurable sputum cyanide (n= ) was not different from those without (n= ) on the basis of age, gender or p. aeruginosa phenotype (mucoid/ non-mucoid). however, those with detectable cyanide had significantly poorer lung function than those without (fev % predicted: . ± . % versus . ± . %, p< . ; fvc% predicted: . ± . % versus . ± . , p< . ). we have shown that cyanide is detectable at clinically significant levels in sputum from cf and non-cf bronchiectasis patients infected with p. aeruginosa and is associated with significantly impaired lung function. we have recently reported a dose regimen for once-daily tobramycin dosing in patients with cystic fibrosis which was based on a retrospective study (lam w et al., j antimicrob chemother ) . we present here an interim analysis of an ongoing prospective study to evaluate the proposed dosing in paediatric patients with cystic fibrosis. as part of this protocol pharmacokinetic parameters were determined in cystic fibrosis (cf) patients receiving intravenous antibiotic therapy for a pulmonary exacerbation. serum creatinine, audiometric testing, respiratory cultures and fev were assessed at baseline and after a week treatment period. serum tobramycin concentrations were interpreted by clinical pharmacists performing therapeutic drug monitoring (tdm) to optimize dosing. serum tobramycin levels were drawn after the first dose, repeated with each dose adjustment and weekly thereafter. the proposed sample size of this study is patients; an interim analysis was performed to identify trends for pharmacokinetic and safety outcomes from patients admitted from november through april . seven ( . %) patients achieved the target c max of - mg/l, ( . %) patients remained under the target range and patient was above the target range with the st dose. with nd, rd, and th tdm performed for either routine weekly levels or dose adjustment levels, , , and patients met the target c max respectively. the percentage of patients who achieved target c max increased to . % with the rd set of tdm levels and . % with the th set of tdm levels (p-value< . ). there were no significant changes in k e , t / and v d /kg for each patient from st to nd set of tdm levels over time. compared to the previous retrospective study the mean v d /kg was significantly higher ( . l/kg versus . l/kg, p= . ) and the mean t / was significantly shorter ( . hrs versus . hrs; p< . ). none of the patients' serum creatinine increased ≥ % from baseline. baseline audiometric tests were within normal limits in ( . %) patients. p. aeruginosa was isolated from respiratory specimens of patients on initial culture. of the patients with follow-up cultures, patients grew p. aeruginosa sensitive to tobramycin, demonstrating no decrease in sensitivity. our preliminary results suggest the pharmacokinetic data differ from the expected profile suggested by the retrospective study. all study patients treated according to the guidelines were clinically well after their course of therapy and did not experience clinically significant toxicity from once-daily tobramycin dosing. the once-daily tobramycin dosing will continue to be evaluated until the proposed sample size is achieved for final analysis. anderson, g.g.; o'toole, g.a. dartmouth medical school, hanover, nh, usa pseudomonas aeruginosa chronically colonizes the lungs of individuals with cystic fibrosis (cf). evidence suggests that this infection progresses through distinct phases, wherein initial colonizing strains undergo a switch to mucoidy that corresponds to formation of bacterial microcolonies in the airways and life-long persistence. currently, the environmental signals and mechanisms regulating conversion from the acute, highly virulent form to a less virulent biofilm state remain obscure. to investigate these issues, we developed a tissue culture model system for growth of p. aeruginosa biofilms on cf-derived human airway epithelial cells in vitro. biofilms grown on these cells appear similar to those found in cf airways as well as to abiotic biofilms. eventually, epithelial cells were killed by the p. aeruginosa biofilms. however, we discovered that addition of the antibiotic tobramycin preserved the monolayer integrity for at least hours. bacteria were not completely eliminated by this treatment, suggesting that tobramycin influenced the virulence of the biofilm bacteria. microarray analysis of cf cell grown biofilms treated with tobramycin revealed marked alterations in transcriptional profiles compared to untreated controls. two tobramycin-induced genes were identified from this screen which, when deleted, exerted altered virulence phenotypes on airway epithelial cells in culture. quantification of cytotoxicity of these mutants revealed either increased or decreased ability to kill the epithelial cells. complementation with full-length copies of these genes restored wild-type function. these studies suggest a complex relationship between acute and chronic forms of p. aeruginosa, and that antibiotic treatment may influence transitions between these modes. it is this interplay that may determine the virulence status of the microorganism upon initial infection as well as during cf exacerbations. neville, m.; sardaryan, g.; ejaz, s.; scotto, a.w.; gupta, r. transave, inc., monmouth junction, nj, usa purpose: during the course of treatment, patients with cystic fibrosis and chronic pseudomonas aeruginosa infections in their lungs may be treated with nebulized tobramycin (tobi®). reduction in treatment times or dosing frequency may improve compliance and outcome. nebulized arikace™ may offer advantages to tobramycin by producing sustained lung levels of drug, reducing dosing frequency and increasing antimicrobial efficacy. herein are presented biodistribution data and efficacy data in a chronic rat model of p aeruginosa comparing arikace™, soluble amikacin and tobramycin. method: female rats (charles river) received (~ mg / kg) of arikace™, soluble amikacin and tobramycin by inhalation. test articles were aerosolized in a pari lc star nebulizer at psi using devilbiss compressors (sunrise medical) for min. - rats were euthanized at time and hr post inhalation by co asphyxiation. blood was collected by a cardiac puncture. serum was collected from coagulated blood by centrifugation and stored at oc until analysis for drug content. in addition lungs, kidneys, intestinal contents, urine and brains were harvested. tissues and biological samples were homogenized in saline and antibiotic concentrations determined by tdx analyzer (abbott). chronic lung infections were produced in rats by intratracheal instillation of agar beads containing p. aeruginosa. three days post instillation, rats (n= /group) were treated with aerosolized saline or once daily with arikace™, or twice daily with tobramycin (total daily dose = mg /kg) for days. rats were euthanized days post final dose and the pseudomonas cfu counts per lung were determined. results: the biodistribution and pharmacokinetics of aerosolized arikace™ was significantly different from that of amikacin and tobramycin. the primary difference was the amount of antibiotic retained in the lungs. rats that inhaled soluble amikacin cleared approximately % of the amikacin from the lungs after hr with concomitant % increase in drug levels in the urine. rats that inhaled arikace™ cleared only % of the deposited amikacin from the lungs after hrs. this initial clearance of drug most likely reflected the amikacin released during nebulization. extended clearance of arikace™ from the lungs was measured by recovery of amikacin in the urine at later time points. in a separate longer-term study comparing arikace™ and tobramycin, auc ( - hr)for arikace™ in the lung was ug*hr/g while only ug*hr/ g for tobramycin which demonstrates a -fold increase in retention of antibiotic in the lung with arikace™. eradication of p. aeruginosa from the lungs of rats with arikace™ was equal to tobramycin (given equivalent daily doses). however, arikace™ reduced the number of cfu in the lungs with a single daily exposure to the same degree as inhalation of tobramycin twice a day. conclusions: inhalation of arikace™ achieved higher concentrations and increased retention time of the antibiotic in the lungs of rats when compared to inhaled amikacin or tobramycin. it is expected that these properties of arikace™ will reduce dosing frequency and improve antimicrobial efficacy in patients. nielsen, x.c. ; johansen, u.r. ; nørregaard, l. ; vandamme, p. ; høiby, n. . clinical microbiology, rigshospitalet, copenhagen, denmark; . laboratory for microbiology, university of ghent, ghent, belgium background: the burhkolderia cepacia complex (bcc) is a diverse group of bacteria with at least genomovars (gv) or species. accurate species identification is necessary for better understanding of the epidemiology and pathogenesis of bcc. species identification based on phenotypic characters is difficult when it is based on few if any differences. crossed immunoelectrophoresis (cie) has been performed routinely to identify all burkholderia and other difficult isolates in our department (høiby et al.: "taxonomic application of crossed immunoelectrophoresis." int. j. syst. bact. ( ): - .) . in this study, we compared the results obtained by cie with those obtained by the standard molecular biological method using reca gene pcr and rflp to identify bcc at the species level (golden standard). methods: between and , burkholdreia isolates were recovered from patients in the two danish cystic fibrosis (cf) centres. . cie method: immunological cross-reactivity between antigens from the reference strains and the strains isolated from our cf patients were compared by employing cie and rabbit standard-antibodies (purified igg) raised against water-soluble antigens from reference strains of the bcc. species identification was made based on matching coefficient (mc). . reca gene-based identification: bcc specific primers were used to amplify reca gene. species-specific pcr is then performed using b. multivorans specific primers to identify the b. multivorans gv ii. rflp patterns were generated for those non-multivorans bcc by digesting the bcc-specific pcr products with haeiii. the patterns were then compared with the patterns generated from reference strains in the database. pulsed field gel electrophoresis (pfge) genotyping was performed for all strains to detect patient-topatient transmission. results: / isolates were bcc-specific pcr positive. species-specific pcr identified isolates as b. multivorans (gv ii). the other three isolates were identified as b. cenocepacia (gv iii) based on rflp patterns. two isolates with negative bcc-specific pcr reactions were identified as b. gladioli by cie (confirmed by reference laboratory in belgium). results from cie showed that strains from bcc were immunologically closely related with only a few non-cross-reactive antigens. compared with the standard reca gene-based method, cie method resulted in correct identifications in isolates ( . %), misidentifications in isolates ( . %) and uncertain identifications in isolates ( . %). genotyping by pfge showed unique patterns for all isolates except for those from two sisters. this suggested that patient-to-patient transmission of bcc among the danish cf patients has remained very rare. conclusions: reca gene-based pcr and rflp is a quick and reliable method for identification of bcc at the species level. cie proved useful in initial classification of bcc strains, but additional information is obtained by the reca gene-based species identification and pfge method. background: in childhood, the cystic fibrosis airway is characterized by persistent inflammation with high quantities of neutrophils. in this setting, recurrent exposure to low numbers of pseudomonas aeruginosa occurs routinely. chronic infection by p. aeruginosa is associated with a significant increase in morbidity and mortality in cf, and is believed to occur by formation of a biofilm in the cf airway. previously, we have shown a significant neutrophil dependent enhancement of p. aeruginosa biofilm density that is greatest for low initial concentrations of p. aeruginosa. biofilm enhancement is facilitated via neutrophil-derived dna and f-actin, which form a framework that p. aeruginosa can exploit for growth. dna and factin polymerize via positively charged molecules such as histones. p. aeruginosa then associates with these polymers, which results in increased early biofilm density, displaying an increase of over fold at hours compared to p. aeruginosa in the absence of neutrophils. hypothesis: compounds that disperse dna and/or f-actin can disrupt neutrophil-enhanced biofilms. methods: poly(aspartic acid), a negatively charged amino acid chain with the capacity to disrupt f-actin, was examined singly and in combination with dnase and/or antibiotics (ciprofloxacin and tobramycin). the nunc-tsp system was used to allow for high throughput assessment of the density of biofilm formation in the presence of neutrophils and the effect of various agents in disrupting the biofilm. the biofilm assay is independent of cellular settling, as the reactor is vertically suspended in the culture. p. aeruginosa strains tested were pao , and two isogenic cf isolates recovered from an initial infection (early), and following established infection ~ years later (late). biofilms were formed by incubation of p. aeruginosa with human neutrophils for to hours in rpmi with % heat inactivated platelet poor plasma. results: antibiotics were incapable of disrupting biofilms. poly(asp) significantly disrupted neutrophil-induced biofilms. in the presence of neutrophil products this action is sensitive to proteolytic degradation, but can be protected by the presence of protease inhibitors. dnase also disrupts a biofilm formed in the presence of human neutrophils. the combination of poly(asp) + dnase resulted in an increase in biofilm disruption for a hour biofilm. biofilms allowed to form for hours were more resistant to disruption by dnase and poly(asp) as single agents, but the combination of both demonstrated a synergistic effect. similar disruption of biofilms were observed when pao was compared to early and late cf strains. conclusions: pseudomonas aeruginosa biofilms formed in the presence of neutrophils in vitro can be disrupted by agents that disperse the f-actin and dna framework. support: cff, max and yetta karasik foundation cystic fibrosis (cf) patients may suffer increased morbidity and mortality through colonisation, allergy and invasive infection from fungi. the black yeast, exophiala dermatitidis (synonym wangiella dermatitidis) has been found with increasing frequency in sputum specimens of cf patients, with reported isolation rates ranging from between . and . %. at present, no species-specific diagnostic pcr exists to aid with the clinical laboratory detection and identification of this organism. a novel species-specific pcr-based assay was developed for the detection of e. dermatitidis, based on employment of rdna operons and interspacer (its) regions between these rdna operons. two novel primers, (designated exdf & exdr) were designed in silico with the aid of computer-aided alignment software and with the alignment of multiple species of exophiala, as well as with other commonly described yeasts and filamentous fungi within cf sputum, including candida, aspergillus and scedosporium. pcr employing exdf (forward primer [ -,mer], '-ccg cct att cag gtc c- ') and exdr (reverse primer [ -mer], '-tct ctc cca ctc ccg c- '), was employed and optimized on extracted genomic dna from a well characterized culture of e. dermatitidis, as well as with high quality genomic dna template from a further unrelated fungi, including candida albicans, c. dubliniensis, c. parapsilosis, c. glabrata, scedosporium apiospermum, penicillium sp., aspergillus fumigatus, aspergillus versicolor, pichia guilliermondii, rhodotorula sp., trichosporon sp., aureobasidium pullulans, fusarium sp., mucor hiemalis, bionectria ochroleuca, gibberella pulicaris. results demonstrated that only dna from e. dermatitidis gave an amplification product of the expected size, whilst none of the other fungi were amplifiable. subsequent direct employment of this primer pair detected this yeast in the sputum of / ( %) adult cf patients, employing a nested pcr approach with panfungal outer flanking primers of the its -its region. these two patients were the only patients who were previously shown to have a cultural history of e. dermititidis from their sputum. e. dermatitidis is a slow-growing fungus, which usually takes up to two weeks to culture in the microbiology laboratory and therefore is slow to detect conventionally, with the risk of bacterial overgrowth from common co-habiting pan-and multiresistant bacterial pathogens from sputum, namely pseudomonas aeruginosa and burkholderia cepacia complex organisms, hence this species-specific pcr assay may help detect this organism from cf sputum more specifically and rapidly. overall, employment of this novel assay may help in the understanding of the occurrence, aetiology and epidemiology of exophiala dermatitidis, as an emerging fungal agent in patients with cf. cystic fibrosis patients are particularly susceptible to infection by strains of pseudomonas aeruginosa and burkholderia cepacia complex. since , the pseudomonas genome database has been a resource for peer-reviewed, continually-updated annotations for the pseudomonas aeruginosa pao reference strain's genome and, more recently, comparative analyses to several closely-related pseudomonas species. in order to facilitate better cross-strain and cross-species genome comparisons, we have developed or are incorporating methods to improve the identification of orthologs (genes diverged due to speciation) and identify genes undergoing unusual selection. our analysis of several completely sequenced pseudomonas genomes has revealed that approximately % of ortholog predictions by the classic "reciprocal best blast hit method" are likely incorrect. we have also performed an analysis of unusually large intergenic regions in p. aeruginosa pao that appear to be essential (according to saturation transposon mutagenesis) or involved in virulence (according to signature tagged mutagenesis). we identified at least new putative protein-coding regions and non-coding rnas that were not previously annotated and may play critical roles in microbial pathogenesis or viability. we are also focusing our attention on facilitating better cross-strain comparisons between recently sequenced burkholderia cepacia complex genomes through development of a new online burkholderia genome database. in addition to improved ortholog prediction, this new database will provide access to a very flexible boolean search feature that allows researchers to search and compare annotations within or between the genomes of burkholderia strains, returning annotations from multiple genomes suitable for simultaneous viewing and downstream analyses. we have also included new, very accurate protein subcellular localization predictions for the deduced proteome from each of these genomes -predictions that can aid the identification of new cell surface or secreted therapeutic targets or vaccine candidates. further comparative analyses with other newly-sequenced, related strains should provide insight into strain-specific features that may be exploited to better understand virulence and antimicrobial resistance exhibited by cf-relevant pathogens. funding provided by cystic fibrosis foundation, therapeutics (usa). popova, a.p.; verma, r.; zanni, r.l.; sembrano, e. pediatrics, monmouth medical center, long brnach, nj, usa background: cystic fibrosis (cf) is a chronic, progressive, genetic disease leading to poor lung function, chronic bronchial infection with certain bacteria and recurrent pulmonary exacerbations. despite evidence of inflammation within the airway, it is unclear which circulating inflammatory biomarker best reflects the airway inflammation and lung function in cf. objective: to determine the utility of c-reactive protein (crp) value in evaluating patients with cystic fibrosis pulmonary exacerbation. design: a retrospective chart review was carried out on patients followed at the cystic fibrosis center at the children's hospital. information about serum crp values, pulmonary function test results(pft), presence of pulmonary exacerbation as documented in the chart, sputum culture results, current medications, as well as demographic data, genetic compositions and weight percentiles between january and march was collected from the charts and was analyzed. results: of patients whose charts were reviewed, were excluded because they underwent lung transplant, were excluded because they had other mild infection, not diagnosed as pulmonary exacerbation. for patients crp was not measured and they were also excluded from the analysis. total of patients were included in the study. for patients information about crp was obtained on more than one occasion. the patients were divided into groups based on the presence of pulmonary exacerbation and elevation of crp values -in the group with pulmonary exacerbation, patients had elevated crp and had normal crp and in the nonexacerbation group had elevated crp and had normal. fisher's exact test (two -tail) was applied (p= . ) and confirmed statistically significant elevation of crp in patients with pulmonary exacerbation of cystic fibrosis. the means and standard deviations of the crp values for the patients without pulmonary exacerbation and the patients with pulmonary exacerbation were calculated and analyzed using independent group t-test (two tail). mean crp value for the exacerbation group was . with standard deviation of . and mean crp value for the non-exacerbation group of . with a standard deviation of . . statistically significant difference between the two means was noted (p= . ). conclusion: serum crp values in patients with cf pulmonary exacerbation were significantly higher than in patients without pulmonary exacerbation. serum crp may be a useful marker of pulmonary exacerbation in children. in the absence of pulmonary exacerbation, cf is not associated with elevated crp values in children. the findings of this study could aid in identifying patients with pulmonary exacerbation earlier and initiate appropriate therapy sooner. further studies are needed to determine whether crp values are associated with the severity of the underlying disease, to what extent the pft are affected, the age of the patient, the type of bacterial pathogen, and genetic factors. background pulmonary infections with nontuberculous mycobacteria (ntm) are commonly associated with structural lung diseases or airways clearance disorders such as cystic fibrosis and primary ciliary dyskinesia. we follow approximately individuals with ntm pulmonary disease who share common clinical features but have no identifiable systemic immune defect or clearly defined predisposing conditions. the pulmonary disease and clinical presentation suggest these individuals may have disorders of ion transport or ciliary function. while some cftr mutations and ciliary abnormalities are difficult to detect through standard genetic and ultrastructural analyses, in vivo physiologic tests of ion transport and measures of ciliary function may allow us to identify ion transport abnormalities in subjects with no identified cftr abnormalities, determine the functional significance of novel cftr mutations, and distinguish disorders of ciliary function from other airways clearance disorders. methods we evaluated the medical and family histories, chest and sinus ct's, sputum cultures, cftr genotypes, and sweat chloride levels of individuals with nontuberculous mycobacterial pulmonary disease and individuals with chronic airways disease and bronchiectasis. we systematically tested the pulmonary function (pft), nasal nitric oxide production (nno), and nasal potential difference (npd) of each subject. nasal mucosal scrape biopsies were performed and sent to unc-chapel hill for assessment of ciliary ultrastructure as part of the genetic diseases of mucociliary clearance consortium. pulmonary function, nno, and npd were measured on healthy controls. results all subjects had sino-pulmonary symptoms consistent with those associated with cf and pcd. subjects had low nno ( . ± . nl/min) consistent with levels reported in subjects with pcd (< nl/min, noone ). one subject with variant cf (∆f /r h) displayed low basal pd (- . mv), elevated na+ absorption ( . mv), and no cftrmediated cl-conductance (- . mv). subjects with cftr mutations, subject with isolated elevated sweat chloride ( mmol/l), and subject with isolated borderline sweat chloride ( mmol/l) displayed normal basal potential difference (- . ± . mv) and na+ absorption ( . ± . mv) but decreased cftr-mediated cl-conductance (- . ± . mv) relative to controls (- . ± . mv). conclusions ntm patients heterozygous for cftr-mutations or with elevated sweat chloride (and no identified mutations with coding region sequencing of cftr) may have detectable subtle differences in cftr clconductance, while measurement of nno may identify disease associated with ciliary abnormalities. these findings suggest subtle abnormalities in airways clearance may predispose to airway infection with environmental organisms such as ntm. support: intramural funds, national institute of allergy and infectious diseases muhlebach, m. ; goodrich, j. ; sutton-shields, t.n. ; wedd, j.p. ; henegar, c. ; miller, m.b. ; gilligan, p.h. . dept. of pediatrics, unc chapel hill, chapel hill, nc, usa; . university of north carolina hospitals, chapel hill, nc, usa; . school of public health, university of north carolina hospitals, chapel hill, nc, usa; . dept. pathology and laboratory medicine, university of north carolina hospitals, chapel hill, nc, usa introduction: proportion of methicillin resistant (mrsa) vs. susceptible sa infections increased from % in to % in in us hospitals. similarly, the prevalence of mrsa in the community has risen in recent years. these community acquired (ca) mrsa isolates are genotypically different, have different antibiotic susceptibility, and often carry the pvl virulence gene. this virulence gene is associated with more invasive, mostly skin infections in healthy individuals. reports on impact of mrsa in cf show conflicting data. , . the aim of this study was to determine the prevalence of ca-mrsa strains at our pediatric and adult cf center and to assess the impact of these infections on clinical outcome. methods: all mrsa isolates recovered from routine clinical cultures, were prospectively collected and analyzed for months ( / - / ). using molecular assays to determine the pvl status and to identify the sccmec (staphylococcal cassette chromosome) type, the organisms were classified as ca or ha. classification as ca mrsa was based on presence of pvl and sccmec iv type. clinical outcomes included lung function measurements in patients reliably performing spirometry and nutritional parameters (bmi%). patients who had undergone lung transplant were excluded as their lung functions vary depending on transplant outcome. results: of the patients identified in this month period, % had ha and % ca mrsa. neither current age (mean . yrs. in ha vs. . years in ca) nor age at acquisition of mrsa ( . vs. years) was significantly different. sixty-eight % of all mrsa infected patients had chronic p. aeruginosa infection, ( % in the ha and % in ca, relative risk . of having ha in presence of chronic p. aeruginosa infection). crosssectional comparison of patients infected with ca vs. ha acquired strains showed no difference in nutritional status (bmi vs. %). lung function (fev and fef - ) was not different in ca vs. ha patients, neither when including all mrsa infected patients or those who had no concomitant infection with other organisms (n= ). we will present further comparisons to age and gender matched children with ossa infection in the final report. conclusion: comparison to ossa in matched patients will assess clinical outcomes of infections with mrsa. initial data collected at our center did not show a significant difference in outcomes between patients infected with ca vs. ha mrsa. a multicenter study would most efficiently assess the impact on clinical outcomes and determine regional differences of mrsa patterns (ca vs. ha) in different cf centers. ref : the stringent response is a global regulatory mechanism used by bacteria to adapt to nutrient limitation and other environmental stresses, and is mediated by the signaling molecules (p)ppgpp (phosphorylated guanosine nucleotides). increases in (p)ppgpp repress metabolic processes and growth, and regulate genes involved in long-term stress and starvation survival in several species ((i)e. coli, m. tuberculosis(i)), bacterial multicellular behavior ((i)myxococcus xanthus(i)), and pathogenesis ((i)p. aeruginosa(i)). while many studies have investigated bacterial functions (such as attachment and motility) involved in biofilm development, less is known about the physiological adaptation occurring in biofilm growth. when cells grow to high densities entrapped in a polymer matrix, they must adapt to heterogeneous micro-environments where gradients in nutrients, oxygen and metabolic waste exist. nutrient may thus become depleted as they are consumed by overlying cells, and some biofilm subpopulations are likely starved. we hypothesized that the stringent response mediates adaptation to nutrient starvation in (i)p. aeruginosa(i) and is important for biofilm formation. we tested a (i)rela(i) deletion mutant unable to synthesize (p)ppgpp in response to amino acid starvation, and its isogenic wildtype parent pao . we measured the starvation survival of planktonic bacteria in phosphate buffered saline and observed that the (i)rela(i) has a to fold greater loss in viability compared to wild type after h. we also tested biofilm formation in a static biofilm assay using polystyrene peg lids and estimated biomass accumulation by crystal violet staining. in this system, the (i)rela(i) accumulates times less biomass than wild type. in a flow-cell reactor system, the wildtype strain forms complex mushroom-like biofilm structures, but the (i)rela(i) mutant forms flat, thin biofilms. we determined cell attachment to polystyrene by crystal violet staining, and to glass surfaces by direct visualization under microscopy. the attachment to both surfaces is similar in the (i)rela(i) and wildtype strains, and the strains have identical planktonic growth rates. our findings suggest that the stringent response is involved in starvation survival, a physiological condition relevant to growth in biofilm. furthermore, (i)rela(i) inactivation impairs biofilm formation, suggesting that the stringent response may be an important stress adaptation in biofilm. belfast, united kingdom; . northern ireland public health laboratory, belfast city hospital, belfast, united kingdom; . northern ireland regional adult cf unit, belfast city hospital, belfast, united kingdom; . department of respiratory medicine, queen's university, belfast, united kingdom pseudomonas aeruginosa (pa) is a clinically significant bacterial pathogen responsible for increased morbidity and mortality in patients with cystic fibrosis. small non-coding micro(mi)rna species (generally ~ nts or less) in prokaryotes are involved in numerous cellular processes as is the case with eukaryotes. as in eukaryotes, these mirnas act by base pairing with target mrnas imposing translational and stability changes of mrnas and thus culminating in the control and regulation of target mrnas, crucial for bacterial stress responses and virulence to changing environments surrounding the infected zone or host cell (e.g. human airway epithelial cells). we recruited a commercial kit (biodynamics dynaexpress mirna cloning kit av, tokyo, japan) and isolated mirnas from a variety of pseudomonas pathogens from plant, soil / agricultural environment (pseudomonas syringae -ps), type strain (pseudomonas aeruginosa -pa) and a collection of clinical isolates of pseudomonas aeruginosa (cfpa) from adult cf patients, who were chronically infected with p. aeruginosa. the results on the mirna clones obtained exhibited a wide variation in the occurrence of mirnas in this bacterium. the putative mirnas obtained, cfpa in particular, yielded small non-coding rnas of sizes from as little as nts to well over nts. an initial search using the bioinformatic tool srnapredict (www.waldorlab/tufts.edu) has not as yet, fully revealed the genomic annotations for these novel srna sequences in the inter-generic regions of the pathogenic pseudomonad group of bacteria. we present our data on these unknown cellular mirnas cloned from cfpa isolates from cf patients and discuss their significance as novel regulators to bacterial stress responses and in the context of the bacterium's involvement as the predominant pulmonary pathogen, associated with cystic fibrosis. airway function is diminished in infants with cf diagnosed clinically but whether this is true for those identified by newborn screening remains unclear. we investigated whether lung function is diminished in infants with cf diagnosed by newborn screening and if this occurs in association with pulmonary infection. methods:lung function was measured in asymptomatic infants with cf following sedation with chloral hydrate ( - mg/kg) using the raised volume rapid thoracic compression technique at an inflation pressure of cmh . we measured forced vital capacity (fvc), forced expired volume after . seconds (fev . ) and forced expired flow at % expired fvc (fef ) which were then expressed as z scores. broncho-alveolar lavage (bal) was performed under general anesthesia within forty-eight hours following infant lung function testing. three separate aliquots of ml/kg sterile saline were instilled into the right middle lobe and a further aliquot in the left lingula and the bal fluid analyzed for bacterial, fungal and viral pathogens using routine culture techniques. results: bal was successful in all infants studied aged . to . yrs (median . yrs) and lung function in infants. median (range) z scores for fvc, fev . and fef were - . (- . to . ), - . (- . to . ) and - . (- . to . ) respectively. these decrements in lung function were all significant (p< . ). bal cultures were positive in ( %) infants of whom ( %) had evidence of infection with s. aureus and ( %) with p. aeruginosa. in infants there was no growth in bal or growth only of mixed oral flora. viruses were not identified in any infants. there was no association between any of the lung function parameters and pulmonary infection detected by bal. lung function was successful in a subgroup of of infants who were less than . yrs (median age . yrs) when tested. diminished airway function was identified in this younger subgroup even though only one infant had evidence of pulmonary infection with respiratory organisms in bal. in this younger subgroup median fev . z score was - . which was significantly below that predicted ( % ci: - . ,- . and p= . ). conclusions: airway function is diminished in infants with cf diagnosed by newborn screening and occurs irrespective of infection identified by bal. lung function is abnormal in very young infants before pulmonary symptoms develop and when no evidence of pulmonary infection can be detected in bal. inhaled high-dose tobramycin appears to transiently clear p. aeruginosa (pa) from airway secretions in young children with cf, though inflammation may not be markedly reduced (am j resp crit care med ; : ) . because inhaled antibiotics may not reach some areas of infection, we hypothesized that intravenous (i.v.) antibiotics may be more effective than inhaled high-dose tobramycin for reducing lower airways inflammation in cf children with early pa infection. study design: we initiated a single-center, randomized, prospective study comparing the effects of two antibiotic treatment regimens on bronchoalveolar lavage fluid (balf) inflammatory markers. clinically stable cf children with a recent isolate of pa from surveillance cultures are randomized to receive weeks of tobi® (group ) or weeks of i.v. ceftazidime and tobramycin (group ). balf is obtained just before treatment, and repeated - weeks after completion of treatment. the primary study outcome is change in balf % neutrophils (pmn). multiple secondary outcomes are assessed including quantitative bacterial cultures and cytokines in balf. this report summarizes interim analysis at the halfway point of the study. results: to date, subjects have enrolled. five subjects ( in group , in group ) dropped out after the initial bronchoscopy due to a decision by the primary cf physician to use other treatments based on balf culture results ( ) , or because of the development of a new respiratory illness before the second bronchoscopy ( ). a total of adverse events ( significant, unrelated to protocol) were reported in subjects, none resulting in a change of protocol request by the irb or data safety monitor. of the subjects completing the protocol to date, were in group , and were in group . the groups were well matched in terms of age, pa in initial balf, and initial balf %pmn. a majority of subjects in each group were children with their first isolation of pa on surveillance cultures. there was a tendency for group , but not group , to have mild reductions in balf %pmn (- ± %) after treatment. interim efficacy analysis did not suggest a significant difference between the treatment groups at this stage. similar changes were seen in group for pmn/ml (- ± x /ml) and several cytokines including gm-csf (- ± pg/ml) and mcp- (- ± pg/ml). two group subjects were unable to have stable i.v. access established and were treated with oral ciprofloxacin and inhaled tobi® for weeks as alternative systemic antibiotics, per protocol. dropping these subjects from group data did not change data trends. conclusions: the protocol appears to have adequate safety. parents of children with first-time pa infection may be more likely to consent to treatment randomization, than those with repeated pa infection. interim data analysis suggests that continuation of the study toward the original sample estimate is appropriate. acknowledgements: supported by cff(noah a ) and nih (gcrc r ). we thank tracy callahan rn, lupe haynes rrt, justin hubbard, paula murphy, cassidy henegar, nancy lee rn, benjamin butler rn, and sheree berckmans rn for logistical and technical support. methods: our local cf database was searched for patients born - . patients were included in the analysis if they were followed in our cf center before the age of . patients were separated into two birth cohorts, born - (cohort ) and - (cohort ). yearly peak fev % predicted from ages - were obtained using knudson reference equations. yearly peak bmi% and weight-for-age% at each age were also obtained. type tests of fixed effects and repeated measures analyses were used to assess mean peak bmi%, mean peak weight-for-age%, mean peak fev % predicted at first pft, mean peak fev % predicted from ages - , and mean rate of change (slope analysis) in peak fev % predicted from ages - . chi-square test for association was used to analyze differences in demographic parameters. wilcoxon rank-sum test was used to assess differences in age at diagnosis. wilcoxon non-parametric test was used to analyze differences in mean clinic visits per year. chi-square testing with a two sided alpha of p < . was used to determine significance. results: cf patients were included in the analysis. there were no significant differences between birth cohorts and for age of diagnosis (p= . ), sex (p= . ), race (p= . ), genotype (p= . ), pancreatic insufficiency (p= . ), or the mean number of clinic visits per year from ages of - (p= . ). there was a significant difference in the mean number of clinic visits per year from ages of - (p=. ; see table ) . birth cohort had a significant effect on the rate of decline in lung function from ages - . birth cohort and age had significant effects on the mean weight-for-age%, mean fev % predicted at first pft, and mean fev % predicted from ages - . sex had a trend for significant effects on lung function parameters. adjusted for age and sex, there were significant differences between birth cohorts and in mean bmi% and mean weight-for-age% at ages and , mean fev % predicted at first pft, mean fev % predicted from ages - , and in the mean rate of decline in fev % predicted (see table ). conclusions: improvements in lung function and nutritional outcomes in our cf center are associated with an increase in the mean number of clinical visits per year for cf patients ages - . the frequency of clinical follow-up is a marker of cf care that may have positive impacts on cf outcomes. background: current management of cf airway disease includes the use of key pharmacological therapies designed to combat the chronic cycle of obstruction, infection, and inflammation. randomized controlled trials have demonstrated that maintenance therapy with azithromycin (azm), dornase alfa (dnase), and tobramycin for inhalation (tob) each improves pulmonary function and reduces the frequency of exacerbations in patients with p. aeruginosa. the purpose of this study was to determine if cf patients in an uncontrolled environment (clinical setting), experience a reduced rate of pulmonary function decline when receiving azm + dnase + tob compared to those not on all three therapies. methods: adult cf patients were selected based on positive sputum cultures for p. aeruginosa, pulmonary function test results (fev % predicted) for the past year, and receiving one of the key pharmacological therapies. in addition data was collected on cfrd, depression, medication adherence, airway clearance, and nutritional status. patients were stratified according to baseline pulmonary function: mild (fev ), moderate (fev of - %), and severe (fev < %). patients were then sub-grouped as to whether they were receiving all or ≤ of the key therapies. the annual rate of decline in % predicted fev was determined using linear regression on non-exacerbation data and was categorized as stable (< . % decline), intermediate ( . - . %) , or rapidly declining (> . %). time to intermediate or rapid decline in pulmonary function was determined using cox proportional hazard modeling. results: patients ( males/ females, median age years) were included in this study; with mild, with moderate, and with severe pulmonary disease. overall, the mild and moderate groups experienced median declines of . % and . %, while the severe group experienced a . % improvement in fev % predicted respectively. the use of regimens containing azm therapy significantly delayed time to intermediate or rapid decline in lung function in the mild group (median days vs. . days, hr= . , p= . ). similarly, regimens containing dnase + azm + tob significantly delayed time to intermediate or rapid decline in lung function in the mild group (median days vs. days, hr= . , p= . ). no significant differences were seen in the moderate or severe group for patients receiving all or individual therapies. con-clusion: administration of pharmacological regimens containing dnase + azm + tob, or azm + tob or azm + dnase significantly delay progression of pulmonary disease in cf patients with mild lung disease. sawhney, v. ; arthur, b. ; seltzer, r. ; kraynack, n.c. . internal medicine, akron general medical center, akron, oh, usa; . pediatrics, akron children's hospital, akron, oh, usa; . biostatistics, neoucom, rootstown, oh, usa; . pulmonology, akron children's hospital, akron, oh, usa early and efficient diagnosis of pulmonary exacerbations (pex) in patients with cystic fibrosis (cf) is crucial in the management of cf. in oct , we implemented a pulmonary exacerbation scoring (pes) system to uniformly and consistently identify pex in cf patients as part of a quality improvement project at the cf center at akron children's hospital. we have previously reported improved pulmonary function outcomes in pediatric patients at our center after implementation of the pes. we now describe the impact of the pes on clinical practice in the management of pex and pulmonary function in our adult cf patients. the pes was developed by our multidisciplinary cf team after an extensive literature review and was implemented in oct . the pes has been previously described and consists of clinical questions divided into three domains: systemic and pulmonary symptoms and signs, and objective measurements. these elements are scored individually and a cumulative pes of ≥ (range - ) is considered a pex and treatment with antibiotics is recommended. the course and choice of antibiotic regimen is left to the physician's discretion. we examined median percent predicted fev decline from quarterly percent predicted fev measurements obtained from port cf. we calculated this for all the patients seen in our adult cf clinic (age> ) from oct till sep during which the pes was in use. we compared this rate of decline to median percent predicted fev decline for the same cohort of patients over the preceding two years (oct till sep , during which the pes was not in use. the percent utilization of the pes was calculated individually for all adult cf care providers. the influence of individual components of pes in decision to treat was also studied. we found no significant difference between the rates of decline in percent predicted fev during the pre-pes and post-pes periods (mean = -. , sd = . vs mean = -. , sd = . , p= . ) as measured by paired samples t-test. logistic regression analysis was done to evaluate the relative importance of each pes component in predicting decision to treat a pex. we found that changes in fev (or= . ), cough (or= . ), sputum (or= . ), and chest examination (or= . ) are most likely to affect the decision to treat where as dyspnea (or= . ) has the little effect on decision to treat. we found a high degree of correlation between adult provider use of the pes and an independent chart reviewer (correlation coefficient . - . ; p< . ). in contrast to cf patients ages - years, we found no significant effect of use of the pes on pulmonary function in our adult population, despite the high frequency of use by our adult providers. it is unclear why this is the case given the robust effect of the pes on our pediatric population. this study suggests that a simplified score that includes fev , cough, sputum, and chest exam may be useful in identifying a pex in adult cf patients. special thanks to tasha capozzi for her help with chart review. this project was supported by the akron children's hospital foundation. objective chronic pulmonary infection with pseudomonas aeruginosa is the main cause for morbidity and mortality in cystic fibrosis (cf) patients. tobramycin and colistin, widely used inhaled antibiotics in cf patients, were found to affect elastase activity in vitro. we showed recently that cxcr on neutrophils mediates bacterial killing, but is cleaved in cf airways by elastase. therefore, we examined the effects of inhalation with tobramycin and colistin on cxcr expression and antibacterial capacities by airway neutrophils in cf patients in vivo. methods cxcr expression was quantified by flow cytometry on neutrophils in peripheral blood and induced sputum of cf patients without inhalation therapy, cf patients with tobramycin and cf patients with colistin inhalation therapy. the longitudinal effect of a weeks tobramycin or colistin inhalation period on cxcr expression, free elastase levels and bacterial killing by airway neutrophils was assessed. results inhalation with tobramycin increased, while inhalation with colistin decreased cxcr expression on neutrophils in induced sputum of cf patients. neutrophils isolated from sputum of cf patients after tobramycin therapy had higher, whereas patients after colistin therapy had lower bacterial killing capacity and α-defensin release as compared to neutrophils before antibiotic inhalation therapy. conclusions tobramycin and colistin differentially modulate the pulmonary host defense in cf patients in vivo via cxcr on neutrophils. these findings may have clinical implications when considering antibiotic treatment in cf patients. sharp, j. ; sheehan, d. ; ren, c.l. . pediatrics, women & children's hospital, buffalo, ny, usa; . pediatrics, university of rochester, rochester, ny, usa background: airway infection and inflammation occur early in infants with cf. the raised volume/rapid thoracoabdominal (rv/rtc) technique is more sensitive than older infant pulmonary function test (ipft) methods in detecting airflow obstruction in these patients. however, there are limited data regarding lung function measured by rv/rtc in infants with cf nbs. we hypothesized that abnormalities of lung function measured by rv/rtc are present in cf nbs infants. to test this hypothesis, we reviewed the ipft data from cf nbs infants followed at our cf centers. methods: this study was a retrospective chart review. we identified infants with cf nbs followed at our cf centers who had had at least ipft performed in the first year of life. ipfts were performed using the collins ipl. forced expiratory flows were measured using rv/rtc as described by feher et al (j appl physiol : , and fractional lung volumes were measured by whole body plethysmography (bp) as described by castile, et al (ped pulm : , ) . data from the cf infants were compared to normal data reported by jones, et al (ajrccm : , ) for rv/rtc and castile, et al for bp. results: we reviewed data from infants. their mean age was . m (range= - ). pancreatic insufficiency was present in ( %) infants, and ( . %) had been treated for pseudomonas infection. their pft findings are summarized in the table. fvc and fev . were not significantly different from the normal predicted values. however, the mean fef and fef - z scores were significantly below the mean of normal infants (p= . and . respectively). gas trapping was present, as evidenced by significantly increased frc, rv, and rv/tlc (p< . for all measures). six infants ( %) had an fef z score of < - . , and ( %) had an frc > % predicted. conclusions: infants with cf nbs have abnormal lung function early in life. our results suggest that pfts in cf nbs infants can be useful in detecting early changes in lung function. we speculate that early therapeutic interventions may improve lung function in this group of patients. table. pft findings in infants with cf nbs. forced expiratory flows are reported as z scores, while fractional lung volumes are reported as % predicted. objective: clinicians use pfts to assess effectiveness of therapy in hospitalized cf patients. however, the variability of multiple pft efforts has not been described in this group of patients. previous study of within day variation of pfts has been reported in healthy adults and children (enright, , and nickerson, ) and clinically stable outpatients with cf (nickerson, , and cooper, ) . nickerson and cooper found coefficient of variations (cv) for fvc of . - %, fev of . - . %, and fef - of . - . % for adults and children with cf. no one has studied the within day variation of pfts in cf patients during pulmonary exacerbations. our objective was to determine the within day variation of pfts during hospitalizations for cf pulmonary exacerbations. we hypothesized that within day variation would improve during treatment. methods: we retrospectively reviewed pft data for all patients admitted to childrens' hospital and regional medical center for a cf pulmonary exacerbation in . patients performed pfts under the direction of experienced pulmonary function technicians. the test was complete when the patient performed efforts that met ats/ers criteria for acceptability. if the patient was unable to produce efforts because of coughing, efforts were accepted if the fvc and fev were within % or ml of each other. for analysis, we included only those pfts: ( ) with at least - flow-volume curves that fulfilled ats/ers criteria, and ( ) were performed within days of hospital admission or discharge. for patients with multiple admissions, we used pft data for their first admission only. for patients with admission and discharge pfts available, we compared the coefficient of variation (cv) for pfts (fvc, fev , ). there were at least days between admission and discharge pfts. the wilcoxon rank-order test was used to compare the cv for admission and discharge pfts. data: sixty-one patients were admitted times in . excluding repeat hospital admissions, patients had individual pft trials available at the time of admission and patients at the time of discharge. seven admission and discharge pfts included only trials. three patients at admission, and patients at discharge, were unable to produce pft curves that met ats/ers criteria, despite previously having done so when well. nine patients had paired admission and discharge pfts from the same hospitalization. the cv for fvc at discharge was significantly better than at admission, p = . (see table) . conclusions: within day variation of pfts during hospitalizations for cf pulmonary exacerbations is comparable to published outpatient data. cv for fvc improves significantly during exacerbation. changes in fvc > %, fev > %, and fef - > % can be considered a significant spirometric response to therapy in hospitalized cf patients. background: lung clearance index (lci), a measure of ventilation heterogeneity, can be calculated from multiple breath washouts of inert gas. in cross sectional studies it is a more sensitive measure of early airway dysfunction in cf than spirometry alone. in normal subjects, the technique is reproducible, with a narrow normal range of . - . . we hypothesized that it may be helpful in detecting change longitudinally, and may have value in assessing novel therapeutic interventions such as the upcoming gene therapy by the uk cfgt consortium. methods: patients aged years and over, presenting with an exacerbation requiring intravenous antibiotics, were recruited. lci was assessed in triplicate by multiple breath washout of . % sulphur hexafluoride (sf ), using a novel gas analyser (innocor, denmark) and custom-built software within the first hours of starting treatment. the test was repeated at the end of parenteral antibiotic therapy and again - weeks later when clinically stable. patients were recruited at three sites and assessed using standardised equipment and a data analysis protocol. results: paired lci measurements were available in patients, mean age (range - ) years, male. in a further patients, technically acceptable washouts could not be obtained at one or other time point. mean (sd) lci improved from . ( . ) to . ( . ), p< . . in / patients there was an improvement in lci of > % after antibiotics. patients showed a > % deterioration in lci. mean fev was significantly greater after treatment ( . v . l/s, p< . , n= ). there was a weak correlation between percent change in fev and lci (r = . , p< . ). patients also had lci measured at the follow up. mean (sd) lci at this visit was . ( . ), p< . vs visit , no significant difference vs visit . conclusions: lci can be used to demonstrate changes in the lung after antibiotic therapy. this is the first study in cf to demonstrate a lon-gitudinal improvement after intervention in a marker of ventilation heterogeneity, and offers different but complimentary information to spirometry. the higher sensitivity of lci may make possible measurement of improvement in mild patients after novel therapies such as gene therapy. this work was funded by the cystic fibrosis trust. aim: inhaled hypertonic saline positively affects sputum production in patients with cystic fibrosis (cf) by improving mucociliary clearance. this study was conducted to compare the aerosol delivery performance of various nebulizers upon aerosolization of hypertonic saline (hyper-sal™) . % and %, available as preservative-free, sterile ml solution in single dose, patient friendly blow-fill seal vials. method: ml hypertonic saline (hyper-sal™) % was nebulized by three jet nebulizers the pari lc plus®, lc star® and hudson rci micro mist as well as the eflow® for hypertonic saline (hs) generating aerosols via a perforated vibrating membrane. hs . % was characterized in the eflow®hs. droplet size distribution patterns were assessed by laser diffraction at a flow rate of l/min and aerosol delivery performance by breath simulation tests mimicking a sinusoidal breathing pattern. the delivered dose (dd) was determined by gravimetric analysis of the inhalation filters. inhalation and exhalation filters were changed after min and the drug delivery rate (ddr) was calculated as nacl found on inhalation filters per min. respirable drug delivery rate (rddr; ddr x respirable fraction < µm) indicates how much nacl can reach the lungs per minute. results: aerosol characteristics of the different nebulizers after aerosolization of ml hs % are summarized in the table. data for hs . % nebulized by the eflow®hs were as follows: dd= . %, ddr= . %, nebulization time = . min and comparable to data for hs %. the lower recoveries for the jet nebulizers are probably associated with increased evaporation and longer nebulization times. conclusion: about - % of the charged sodium chloride from ml hs was delivered and % - % of these droplets were in a respirable size range < µm resulting in vitro respirable doses of about % - % of the label claim. ddr and rddr are about -to -fold higher for eflow®hs indicating a much higher delivery efficiency compared to conventional jet nebulizers. further studies will be needed to demonstrate that about ml hs may be sufficient to deliver a comparable dose to the lungs using an eflow®hs compared with jet nebulizers. this bears the potential to further reduce nebulization time and increase acceptance by patients. objectives: individuals with cf frequently have complicated and time consuming treatment regimens consisting of inhaled antibiotics, mucolytics, and airway clearance. patients and clinicians may have difficulty determining which specific therapies are effective for any individual patient or whether a particular treatment is causing adverse effects. this study assessed the utility of home spirometry for providing an objective measure of pulmonary status in between scheduled clinic visits. methods: consecutive adults with cf were recruited at a single academic medical center and were asked to measure fev twice daily for six months using the piko- meter (nspire health™, llc). subjects agreed to participate and completed the study. subjects were given diaries to record changes in respiratory symptoms and changes in medications during the study period. subjects were evaluated in clinic at least every three months and fev values obtained in the pulmonary function lab were compared to home fev from the same day using linear regression and bland-altman analyses. graphical displays of home fev measures were visually inspected for changing trends and these were compared with medication changes. results: the mean fev measured at home was . ± . l. the mean fev in the pulmonary lab was . ± . l. the home fev was significantly correlated with the clinic value from the same day, r = . , p< . . fev measures fell within the limits of agreement (± sd) by bland-altman plot. in of subjects ( . %) there was at least one sustained change in fev that correlated with either stopping or starting a particular treatment. the figure shows two significant changes in fev in one patient related to medication changes. there is an increase in fev at the initiation of aerosolized % saline and a fall in fev that corresponded to inhaled tobramycin use. the improvement on hypertonic saline increased this patient's enthusiasm for this treatment. conclusions: home fev monitoring is feasible and appears to provide accurate measurement of pulmonary function. it can provide clinicians with objective data to tailor treatments without necessitating a clinic visit. feedback from home monitoring may improve medication adherence and may allow treatments to be individually tailored based on patient responses to the medications. . respiratory unit, royal hospital for sick children, glasgow, united kingdom; . diagnostic imaging, nhs greater glasgow & clyde, glasgow, united kingdom; . medical statistics, royal hospital for sick children, glasgow, united kingdom; . medical physics department, gartnavel hospital, glasgow, united kingdom background: there have been calls for caution regarding the suggested use of regular chest computed tomography (ct) scans for monitoring disease progression in cf . consideration of the associations of higher ionizing radiation exposure must be made before regular chest cts are performed on the wider cf population. aim: we tested the hypothesis that higher ionizing radiation exposure from chest radiographs (cxr) and chest cts would be associated with markers of severity including gender, genotype (class i/ii or iii-v), height sds, weight sds, bmi, fev sds, length of hospital admission (days), scottish index of multiple deprivation (simd) scores and pa/bc microbiological infection (chronic or intermittent colonisation with pseudomonas aeruginosa and/or burkholderia complex). methods: effective doses of ionizing radiation (msv) from cxrs and chest cts (including hr scans) were determined for all cf children at our centre between st january and th july ( weeks). the most recent anthropometric and lung function data to july were used. simd scores report a data zone that encompasses ~ individuals and comprises indicators in six domains (current income, employment, health, education, housing and access). results: cf patients ( male: female) underwent radiation exposure procedures (mean of . procedures per patient per year). the average effective doses were calculated for of the procedures ( . %) including cxrs and chest cts. lung function data were available on patients ( %). univariate analysis revealed that higher ionizing radiation exposure was significantly associated with fev sds (p< . ), length of stay (p< . ) and pa/bc infection (p< . ). the regression line indicates that for each drop of two fev sds, each child receives an extra msv in radiation exposure from cxrs and chest cts alone. similarly, each child receives an extra msv in radiation exposure from cxrs and chest cts for every days of hospital admission. multivariate analysis with backward selection demonstrated that length of hospital admission (p< . ) and pa/bc infection (p= . ) were associated with higher ionizing radiation exposure. discussion: in cf, higher ionizing radiation exposure from cxrs and chest cts in childhood are associated with poor lung function, pa/bc infection and length of hospital admission but not other indicators of severity such as gender, severe genotype, anthropometric measures or socio-economic status. using effective doses of ionizing radiation as an outcome marker in cf is an alternative means of assessing the impact of the disease and its management on the child. background: exhaled volatile compounds have attracted attention as potential non-invasive biomarkers of chronic lung disease. early sustained airway inflammation and bacterial infection are characteristic features of pulmonary involvement in cystic fibrosis (cf). the cellular response is dominated by neutrophils, which have been shown to generate oxygen-and halogen-derived radicals as part of their host defense armamentarium. aims: to gather pilot data on the pulmonary output or uptake of selected organic trace gases in cf patients and healthy controls; and to explore the impact of pulmonary exacerbations and antibiotic treatment. methods: samples of ambient air and exhaled breath were collected from children, adolescents and young adults with cf and from healthy controls. the patients' age ranged from - years and their fev between - % predicted, were pseudomonas positive. twelve patients were studied at the start of i.v. antibiotic treatment for a pulmonary exacerbation; repeated sampling after the course was performed in subjects. all samples were analyzed on a customized gas chromatography system with flame ionization and electron capture detectors. after determining the mixing ratios of a variety of volatile organic compounds, alveolar gradients were calculated from the corresponding exhaled and ambient values. results: compared to healthy control subjects, cf patients showed a significantly lower respiratory output of methanol, ethanol, acetaldehyde and dimethylsulfide but a higher net release of benzene, methylchloride, trichloromethane and trichloroethene. these differences were most pronounced in patients with acute exacerbations. a relevant scatter and overlap between groups was noted for ethane, pentane, acetone, isoprene, toluene, and tetrachloromethane. after antibiotic treatment, the output of benzene, methylchloride and trichloromethane decreased by - %. conclusion: although important pathways remain incompletely understood, the local biochemical milieu in cf lungs may be informative and accessible through non-invasive breath testing. in this context, the diagnostic potential of exhaled organic traces gases (especially oxygenated, halogenated and aromatic compounds) should be further explored. supported by: german research foundation (dfg ba / - ). toy, e. ; weiner, j. ; sacco, p. ; duh, m.s. . health economics, novartis pharmaceuticals, east hanover, nj, usa; . analysis group, inc., boston, ma, usa objective: to review up-to-date economic outcomes data in patients with cystic fibrosis (cf), and in particular, costs related to respiratory infection by pseudomonas aeruginosa (pa), which is the leading cause of morbidity and mortality in cf patients. methods: a systematic search of the medline database from - was conducted to identify major and review articles that contained the terms "cystic fibrosis" and "cost" and which were published in english language journals. selected conference abstracts were searched, and additional articles were identified through bibliographies of retrieved articles. recent articles that contained economic data on antibiotic and mucolytic therapies were selected for in-depth review. cost estimates were converted to us dollars for comparability. results: approximately articles fulfilled the initial search criteria, and were selected for in-depth review. articles were divided into four categories: economic impact of inhaled tobramycin ( articles), the effect of home-vs. hos-pital-based antibiotic therapies for pulmonary exacerbations ( articles), economic impact of recombinant human deoxyribonuclease (rhdnase) ( articles), and cost-of-illness for cf ( articles). inhaled tobramycin (actual or recommended dose of mg/ ml) has been associated with reductions in health care costs; these cost savings offset between % and % of the cost of this therapy. antibiotic therapy for pulmonary exacerbations generally resulted in lower health care costs when administered in a home setting rather than a hospital setting. use of rhdnase led to reduction in health care costs, with higher reductions observed in patients with higher levels of use; the cost savings offset between % and % of the drug cost. cost-of-illness studies have been conducted in different countries; the economic estimates varied widely across studies due to differences in treatment patterns, health systems, methodologies, and patient populations. most cost-of-illness studies were retrospective observational studies from the perspective of a hospital or third-party payer, and the cost of cf ranged from $ , to $ , per patient per year. the largest cost categories included hospitalizations, out-patient visits, rhdnase and antibiotics, while disease severity and presence of pa infection were common determinants of cost. cost-of-illness studies have underestimated societal costs because they have rarely considered patient time costs and none have considered indirect costs (e.g., burden on lost productivity or informal caregivers). conclusions: studies show that inhaled tobramycin and rhdnase can partially offset medical costs; home-based iv antibiotic therapy is likely to reduce costs; and direct costs associated with cf can be high but vary widely across countries and analytical methodologies. areas for future research include direct comparisons of inhaled antibiotic therapies, examination of the relationship between treatment adherence and economic outcomes, and estimation of societal cost-of illness. this study was sponsored by novartis pharmaceuticals corporation, east hanover, nj. background: sputum interleukin (il ) and myeloperoxidase (mpo) are advocated as markers for infective exacerbations in cf. we have previously shown that the neutrophil protein, calprotectin, is a sputum biomarker of disease activity in cross sectional and longitudinal studies. in the present study we evaluate longitudinal measurement of sputum and serum calprotectin during infective exacerbation. methods: sputum and venous blood samples were taken at the beginning (visit ) and end of a course of iv antibiotics (visit ), and at time of clinical stability following the infective episode (visit ). processed sputum supernatant was analysed by elisa for calprotectin, il and mpo. serum calprotectin was assayed by elisa. results: paired sputum samples samples were available for visits and and paired samples for visits and . all data are presented as mean(sem). sputum calprotectin decreased from ( ) to ( ) µg/ml, p< . , from visit to . there was a non-significant increase to ( ) µg/ml at visit . sputum il did not change from visit to [ . ( . ) ( . ) ]. serum calprotectin decreased from ( . ) to . ( . ) ng/ml, p< . (n= paired samples) from visit to . at visit there was an increase to ( ) ng/ml, p< . (n= ). discussion: calprotectin appears a valuable marker both in sputum and serum for tracking changes in lung inflammation during an exacerbation of cf and may be more sensitive to change than il or mpo. on stopping antibiotic therapy sputum and serum calprotectin increase implying that this marker may be sensitive to small sub-clinical changes in lung inflammation. these data suggest that sputum and serum calprotectin might be employed to assess responses to drug therapies in cf such as gene therapy. this research was funded by the cf trust uk. chronic lung disorders are usually associated with a hypoxia driven increase in red cell mass. however, patients with cystic fibrosis often have normal or decreased haemoglobin levels. the present prospective observational study in cystic fibrosis (cf) patients was performed to determine which factors were involved in alterations in the hematopoetic response to corresponding arterial oxygen pressure. sixty adult patients (age - ) with stable cf were included. they all had vitamin a, d, e and k but no vitamin b supplementation. patients were on oral fe + ( mg/day). resting arterial blood gases, lung function, complete blood counts, parameters of iron status, crp, sputum microbiology and serum erythropoietin were measured at recruitment and after and months. patients had varying degrees of pulmonary functional impairment and % were hypoxemic (arterial oxygen pressure < mm hg). low-grade systemic inflammation (crp > . mg/dl) was present in % of the patients, who all had bacterial colonization. none of the patient had erythrocytosis and patients had anemia . there was no significant difference in iron status between patients with or without chronic iron supplementation and erythropoietin levels were normal. during the months observation period no significant changes occurred. the patients exhibited an impaired erythropoietic response to hypoxemia with normal or low hematocrit in spite of chronic lung disease. linear multivariate regression analysis (table) revealed crp and iron levels but neither iron substitution, nor erythropoietin levels nor lung function parameters as independent determinant of haemoglobin levels. cf may be associated with anemia of variable severity as expression of the chronic inflammation present in these patients. the therapeutic consequences are to treat the underlying inflammation rather than to supplement iron. variables included in initial model: background improvement in the treatment and survival of females with cf has led to many leading a normal adult lifestyle, and some can now expect to raise a family. however, pregnancy can have a profound impact on wellbeing, and caring for a young child can affect compliance with cf treatment. to look at this further, we surveyed the experience of pregnancy and motherhood in cf women attending our large adult cf centre ( patients). methods we reviewed the records of cf women who chose to remain pregnant ( babies [ male] from pregnancies), looking at changes in lung function, bmi, respiratory exacerbations during pregnancy, clinic attendance, and oral and iv antibiotic therapy (home and inpatient care) during pregnancy and also in the first year post delivery. we devised a questionnaire to examine how patients coped with pregnancy and the demands of motherhood, focussing on changes in compliance with therapy, worries regarding the effect of cf treatments on the baby, and support given by the cf team. results at conception mean fev was % predicted (range to ) and mean bmi (range to ).there were no miscarriages or neonatal mortalities and all children remain well, but the sickest mother died at years. mean fev following pregnancy was % [range to ] (p= . ), with mother losing % by one year post delivery. at one year, bmi was unchanged (mean , range to ). rates of respiratory exacerbations and iv antibiotics were similar pre and during pregnancy, although during the first year post delivery mothers avoided hospital based treatment preferring home care. six mothers' clinic attendances increased during and post pregnancy ( attended outpatients times in the first year post delivery). nine mothers worried about the effects of cf medication on their unborn child: the remaining mother was in her nd pregnancy. all managed their health differently during pregnancy: whilst increased compliance, worked harder to stay healthy, and increased clinic attendances; avoided clinic, postponed treatment, avoided any medication in the first trimester, and reduced oral antibiotic use to prevent harm to their unborn child. following delivery, mothers spent less time on their own health due to motherhood demands, and missed treatments during the first year: missed all except iv antibiotics. seven mothers ceased chest clearance and nebuliser therapy, and whilst missed oral therapies only avoided iv therapy. one mother who returned to work early felt this had contributed to her post natal depression. nine mothers indicated that cf team support was adequate, but the remaining mother felt that she should have been offered more frequent home visits post delivery due to lack of family support. conclusions the experience of pregnancy in our centre has positive outcomes for most mothers. however, compliance with treatment was affected and a number of mothers lost significant pulmonary function due to pregnancy. our study has shown that the demands of motherhood especially in the first year challenge the management of their own health. we offer a proactive service to women considering pregnancy, with early participation of the multidisciplinary team, and have increased home visit frequency to during the first year post-delivery. geller, d.e.; kesser, k.c. research, nemours children's clinic, orlando, fl, usa background: alpha- antiprotease (α- ap) is being developed as an inhaled drug in cf to inactivate excess elastase in the lungs. it is estimated that tens of milligrams of α- ap need to be deposited in the lungs to be effective. delivering a high dose with conventional jet nebulizers may be too time-consuming. we speculated that slowing and prolonging inspiration could optimize α- ap delivery. the i-neb® adaptive aerosol delivery (aad® system, respironics) is a portable, electronic, battery-powered, mesh nebulizer that uses the aad algorithms to deliver drug in the first portion of inspiration. interchangeable mouthpieces allow the i-neb to be used in a conventional tidal breathing mode (tbm) or in the target inhalation mode (tim) that guides the patient to inhale very slowly. the low residual volume after nebulization reduces drug waste and optimizes efficiency. we compared delivery efficiency of α- ap in vitro with the i-neb in the tbm vs. tim modes. methods: we studied new i-neb devices using tbm (tidal volume [vt] . l, respiratory rate [rr]= , i-time= seconds), tim- (vt . l, rr= , i-time= sec), and tim- (vt . l, rr= , i-time= sec) using a breath simulator. nebulizers were filled with . ml α- ap ( mg/ml). nebulized drug was captured on a filter and measured via spectrophotometer (inhaled dose), and particle size was measured with an insitec laser system. results: median particle sizes for the modes were similar ( . - . µm) . the dose emitted from the i-neb was very high, and similar between modes ( - % of nominal dose). predicted lung doses for these experiments were calculated from a previous scintigraphy study (nikander ) that showed % of the emitted dose deposited with tbm and % with tim. predicted lung dose of α- ap (as % of nominal) and delivery times were tbm: . % in . min, tim- : . % in . min, and tim- : . % in . min. discussion: the i-neb has a very high predicted lung dose with both tbm and tim. however, tim reduces the time of administration to as little as / that of tidal breathing. if larger predicted lung dose is necessary to see a clinical effect, either the initial drug volume or drug concentration may be increased. we conclude that slow, deep, controlled inspirations using i-neb is a very efficient method to deliver α- ap, and is faster than tidal breathing. we also speculate that tim has the additional potential advantage of better distribution of drug in the lungs because of slower flow rate and particle velocity. objective: early inflammation was observed in infants with cf regardless the occurrence of bacterial infection. lung function (lf) is a tool to assess bronchial inflammation consequences. few data are available on the pronostic value of impaired lf in infancy. methods: in infants, airflow obstruction (t ptef/te , curve shapes, tidal volume, functional residual capacity (frc, nitrogen washout technique) were assessed with the sensor medics and interpreted with stocks reference values. at y, fev and pulmonary flows (spiro , nova medical sc, zapletal reference values) and frc he , were measured. symptomatic children were defined when cough, wheeze or rattle were recurrent. all symptomatic infants have been treated with inhaled steroids as any infantile wheezer. results: screened infants ( ∆f /∆f , ∆f /other, other/other) were investigated at mean age mo and years. ( %) had respiratory symptoms (rs); the mean tidal volume was normal ( . ml/kg), ( %) had a marked obstructive curve shape, ( %) a decreased t ptef/te , and ( %) hyperinflation. then, ( %) had normal lf, ( %) ao, ( %) hyperinflation and ( %) both. at age , % had rs, and lf with mild alteration as mean flows ≥ %, and frc he = . %. accurate analyses showed that ( %) had normal lf, ( %) ao and ( %) small airway diseases (only distal ao and/or hyperinflation). frc in infancy and at age were correlated (r= . ; p= . ). conversely, no correlation between ao parameters in infancy and at age was found. the lf alteration was independent of the genotype, bacterial colonization and recurrent symptoms at both ages. conclusion: ao in infancy is frequent as found in half of the screened cf infants. the lack of correlation with the ao observed at age suggested that ao in infants might be due to a non specific inflammation (i.e viral), transient and then relevant from a treatment. hyperinflation, although mild, is conversely an early marker of the cf disease as persistent between infancy and age . we describe the efficacy of a novel system using an electronic real-time distant home monitoring of symptoms and spirometry in cf patients with the aim of early detection of p exs patients and methods: this is a month prospective observational study. all patients were provided with a set consisted of a mobile phone-palm pc (the x daii, o -uk) and with a spirometer (vitalograph) with an attachment to the pc. the pc contained a purpose-built software on which cf symptoms and spirometric values were recorded once daily. these were then sent on a real time to a computer server where the data were plotted on a time-magnitude graph. the site was accessed by a password-permitted cf physicians. patients were asked to score four symptoms (cough, sputum, breathlessness and fatigue) once a day and to record at least three attempts of spirometry. these were accepted by the software only if they met the ats criteria. preset criteria for p exs were stipulated. when the recordings met the criteria for p exs patients were invited to come to the cf clinic for review and were managed by either watchful waiting, oral or iv antibiotics. a prodrome phase is deemed to be present when a patient had an increase in one or more symptom for one week prior to the p ex. twenty one evaluable patients were included in the study. in ( %) there were an increase in one or more than one recorded symptoms throughout the study. a total of p exs median . per patient were detected within the months study period. in ( %) p exs, symptom increase and/or decline in fev met the preset criteria for p ex and in cases patients presented despite that symptom changes were not sufficient to meet the pre-set definition of p ex. prodromal phase prior to p exs were seen in ( %) patients. adherence and technical issues were the main two problems throughout the study. distant daily monitoring of patients symptom is easy and sensitive. it can be used to monitor symptoms and early detect p exs. the vast majority of our patients have an increase in their symptoms even when they perceive their disease to be stable. a prodormal phase preceded p ex is seen in the majority of patients. the pre-set criteria for defining p ex may have been too stringent. the research was funded by o telecommunication, uk the monitoring system used in the study. a combination of a mobile phone-palm computer (x daii, o uk) and a spirometer (vitalograph uk) .. the aim of this research was to examine whether systemic inflammation is present in adult patients with cf during their stable status. patients and methods: blood samples were obtained from a total of cf patients female, mean age , range( - ) males mean . range - and from control subjects, female, mean age . , range( - ) males,mean age . yrs, range( - ) all cf patients were included when they were at least weeks away from any pulmonary exacerbations. all control subjects were not known to have any pulmonary or systemic disease. venous blood samples were taken and spun at rpm.separated sera was aliquted and frozen at - degrees c. they were analysed in batches for cytokines il- b,il- ,il- , il- , ilp ,and tnf-alpa using a cba human inflammatory kit(bd bioscience). whitney-u test was used to compare values of serum cytokines between stable cf patients and control subjects.. serum il- and il- were raised in cf patients compared to control subjects. the mean value for il- was . pg/ml (sd . ) for patients and . pg/ml (sd . ) for controls, p< . . similarly, the mean value of serum il was . pg/ml (sd . ) in cf patients compared to . pg/ml (sd . ) in the control group, p< . (figure below). there was no difference between cf patients and control with regards to serum il- b, il- and il- p . conclusion: serum il- and il- were raised in cf patients compared to an agematched control subjects. inflammatory markers were raised in the sera of cf patients even during disease stability. even during disease stability, the lungs remain an inflamed organ which could explain the decline in lung function tests and the countinued daily systemic symptoms experienced by patients with cf. serum il and il in cf patients with stable disease compared to the control group (please see abstract body) we have shown that even during disease stability, an increase in inflammatory markers are present in the sera of cf patients compared to an agematched control group. this longitudinal study examines changes in serum inflammatory markers during p exs. we investigated cf patients female, mean age , range - years. their mean baseline fev was . % of predicted (range . - %). a baseline venous blood sample was withdrawn and sera were stored at - degree c from patients during disease stability. out of those there experienced p exs. blood samples were obtained at the beginning and at the end of the p exs.the following inflammatory markers were analysed: white blood counts, c -reactive protein (crp), il- , il- , il- , il- b, il- p and tnf-α. patients recorded their symptoms and their fev on a daily basis on an electronic diary and the data were beamed daily to a research centre where data were analysed. p ex was defined as ). an increase in two symptoms for successive days, or ). an increase in symptoms and % reduced fev from baseline over successive days or ). % decline in fev over successive days or ).when a patient felt that he/she was going through a p ex. paired t tests were used to analyse changes in inflammatory markers. there was no change in the number of circulating neutrophils, lymphocytes or eosinophiles at the start compared with the end of p ex. there was an increase in mean crp values at the start of p ex and reduction at the end of p ex, but this did not attain statistical significance. mean (sd) of serum il increased from . pg/ml ( . ) at baseline to . pg/ml ( . ) at the start of p ex (p= . ) and returned to base line . pg/ml ( . ) at the end of p exs (p= . compared to values at the start of p ex). (figure ) there were no changes in the values of serum il- , il- , il- b, il p or tnf-α at the start and at the end of p exs. serum il increased at the start of p ex and returned at the baseline at the end of p ex. crp was the closest inflammatory marker to follow that pattern. none of the other inflammatory markers changed with the diagnosis of p ex's. this and other studies call for the price of analysis of il- to be reduced to become available in routine clinical practice. background. abpa can be a therapeutic challenge in children with cf. aim was to describe the tolerability of voriconazole and nebulised liposomal amphotericin in the treatment of abpa in children with cf. methods. we performed a retrospective case note review of voriconazole and nebulised liposomal amphotericin use, in the treatment of abpa in children with cf, at our centre. results. children diagnosed with abpa according to the current criteria, failed to improve despite previous treatment with itraconazole and steroids, and received voriconazole as a second line agent. the dose of voriconazole was as recommended by the manufacturer's summary of product characteristics and the duration of treatment was two weeks. significant side effects noted in children. observed side effects included visual hallucinations (n= ), photopsia (n= ), sleep disturbances (n= ), severe headache (n= ), influenza like symptoms (n= ), gastrointestinal side effects (n= ) and elevation of alkaline phosphatase (n= ). of these children, one child tolerated voriconazole when concomitant treatment with omeprazole was withdrawn. a second course of voriconazole, given at a lower dose and without the loading dose was tolerated by two children. voriconazole blood levels were not measured in any patient. we used nebulised liposomal amphotericin in of these children. one child received amphotericin as a second line agent when voriconazole had to be stopped because of significant side effects. children had active abpa despite treatment with first line (itraconazole and steroids) and second line (voriconazole) agents and received amphotericin as a third line agent. amphotericin was used at a starting dose of mg nebulised twice daily, with weekly increments as tolerated, up to a maximum dose of mg twice daily for four weeks. the starting dose and all subsequent increments in dose were supervised. all children received salbutamol immediately before nebulised amphotericin. the standard formulation available for intravenous infusion was made up into single doses for nebulisation by the pharmacy. this was stored at c and diluted with water for injection for use with the nebuliser. the only side effect, experienced by all children was a dry irritant cough at the start of nebulisation that settled soon without need for discontinuation of the medication. improvement in clinical symptoms, lung function and total serum ige was noted in all children. the improvement in fev and fvc, expressed as mean (range) of percentage predicted were and respectively. the mean (range) fall in serum total ige and aspergillus specific ige were ku/l ( - ) and mg/l ( - ) respectively. conclusion. voriconazole use was associated with significant side effects. avoidance of drugs that may potentially result in interaction is important. omitting a loading dose and using a lower maintenance dose may help selected patients tolerate voriconazole. nebulised liposomal amphotericin was tolerated by our children with cf and abpa who did not tolerate or responded poorly to voriconazole. recent studies have shown that high resolution computed tomography (hrct) is a more accurate method of evaluating early lung disease in cystic fibrosis (cf) than pulmonary function tests (pfts) or chest x-rays. since young children can not perform the breathing maneuvers required for high quality hrct, lung volume control is necessary. positive pressure facemask ventilation using chloral hydrate allows full inspiration and end exhalation images, but requires special expertise. controlled ventilation can also be produced with general anesthesia (ga). ga has not been reported in children undergoing hrct for cf research. the advantages of ga over sedation include rapid onset, faster recovery and reliability of scan completion. the undesirable effects of sedation are unpredictability and the higher failure rates. additionally, failed sedation contributed significantly to parental dissatisfaction. (malviya, et al., ) . the primary outcome of our study was to examine the safety of using ga for hrct scans and the quality of images obtained. a secondary outcome was parental satisfaction. methods: participants were recruited from a larger nih/cffti funded multi-site randomized clinical trial focusing on behavior and nutrition treatment to improve growth in preschoolers with cf. hrct in subjects to years old (mean age ± months) was performed with ga. parents accompanied the child during induction and left after the child was asleep prior to the intravenous (iv) being placed. after induction of anesthesia, a proseal®, specialized laryngeal mask airway (lma), was placed which allowed ventilation with higher pressures and the ability to suction the stomach. volumetric thin section ct scans were obtained. ga using inhalation (sevoflurane) and/or iv (propofol) agents was used and out of families who were eligible ( % recruitment rate) participated in the sub-study. results: the quality of the hrct scans in all subjects were optimal. there were no anesthetic complications upon emergence and none of the patients experienced any side effects after follow-up phone calls at hours. parents also expressed that the clinical interpretation of the hrct scan provided beneficial information about their child's current lung disease status. the mean time from completion of scan to discharge was . ± minutes. conclusions: the use of ga in radiology departments is becoming more common in pediatric centers. our initial findings of this study demonstrate that ga can be safely administered for children with cf. in addition to very good quality scans being obtained, parental satisfaction was also noted. the use of the proseal® lma for hrct may improve the image quality and aid in the diagnosis of early lung disease in preschoolers with cf. supported by nih grant r dk and a cf foundation clinical research grant. whey protein is rich in sulfhydryl (sh) groups and is recognized for its ability to increase glutathione and reduce oxidative stress. hyperbaric pressure treatment of whey protein increases its digestibility, promotes the release of novel peptides for absorption, increases intracellular glutathione in healthy subjects (zavorsky et al, int j vit nutr res, ) , and reduces in vitro production of il- (vilela et al, inter immnuopharmacol, ) . we present here the initial results of a pilot study of supplementation with pressurized whey in cf patients. children and adults with cf were supplemented with hyperbaric whey protein for month ( gm/day in patients less than years of age, gm/day in older patients). anthropometric measures, pulmonary function, serum c-reactive protein (crp) and plasma lipid peroxides were measured before and after supplementation. the results of the first patients to have completed the study are reported, with further data to be presented. in / subjects weight increased and in / subjects lean body mass increased. there were no significant changes in fev or fev/fvc ratio. in / patients the crp fell ( / by more than %) and in / the crp increased. in the remaining two patients, the crp was undetectable at baseline and did not change at follow-up. plasma lipid peroxides decreased in the three patients in whom it could be measured ( / to undetectable levels). these preliminary results suggest that supplementation with pressurized whey protein can reduce systemic inflammation in cf patients and has the potential to beneficially modulate the inflammatory response in cf patients. supported by the breathe initiative of the canadian cf foundation with pseudomonas aeruginosa. soon after its introduction, the mesh technology based pari eflow® nebulizer gained preference over jet nebulization in the cf community because of its short nebulization time, portability and noiseless operation. concerns were raised about the durability of the device due to expected vulnerability of the mesh. the aim of this study was to compare the particle size distributions in the aerosol, delivered doses and output rates from the eflow and the pari lc plus®(lc+)with paritur-boboy compressor before and after use in daily practice. lc+ nebulizers in use by the adult patients taking part in the study were taken in for testing and new eflows, cleaning instructions and a disinfection device were provided. after months use ( cycles of x doses tsi: mg/ ml), the eflows were collected by the local cf center. particle size distributions were measured at a constant flow rate of l/min with a laser diffraction apparatus. because of uncertainty regarding the cleaning procedure after last use, additional e-flows were collected from the same patients after another period of months use. conclusions: new eflows produce slightly larger droplets in a narrower size range than new lc+ nebulizers. after use in daily practice, droplet size distribution changes for both devices. output rate (delivered dose per minute) decreases for both devices. for used eflows delivered dose is lower than for used lc+ nebulizers, because the eflow is programmed to switch off after min, even when nebulization is still incomplete ( out of tested eflows). this may result in a considerable reduction of delivered dose. however, when a mesh is replaced, performance is the same as that of a new device, suggesting that the changes in performance originate in the vibrating mesh. for daily practice these results indicate: ( ) the performance of both nebulizers changes during use but the changes are smaller for eflow than for lc+ ( ) changes in droplet size distribution are relatively small for both devices;in contrast with output rate and delivered dose ( ) proper functioning of eflow can be improved by timely replacement of the mesh, ultimately when eflow switches off after minutes. without replacement, the delivered dose is unpredictable. mean values for size distribution, delivered dose, nebulization time and output rate (x is volume median diameter) backgrounds: lung surfactant protein a (sp-a) belongs to the family of collagen containing, c-type lectins, called collectins. sp-a plays a critical role in the innate immune defense of the lung. sp-a binds calcium dependent to carbohydrate structures on pathogens via its carbohydrate-binding domain (crd). cystic fibrosis (cf) lung disease is characterized by chronic inflammatory and proteolytic processes in the airways, leading to destruction of the lungs and early death. aims: we hypothesized that sp-a might have a reduced function in cf. this might result from sp-a degradation by neutrophil proteases, an altered macromolecular organization of sp-a, or inhibition of crd-binding by airway components. methods: we studied bronchoalveolar lavage fluid (balf) from clinically stable patients with cf and from children suffering from bronchitis. balf samples were purified by carbohydrate-binding assay on fucose attached to sepharose resin with and without calcium. in the absence of calcium sp-a cannot bind via its crd. each fraction was analysed for sp-a and igg by immunoblotting. macromolecular organization of sp-a was determined by gel chromatography. results: only % of total sp-a of cf balf bound to the fucose column, whereas % bound from the bronchitis balf. the structural organization of the sp-a oligomers did not differ between the non-binding and the binding fractions of both groups. of the cf balf had sp-a at kd that did not bind to fucose. these balfs had a high percentage of neutrophils (> %). in vitro human leucocyte elastase decreased sp-a to less than % of its initial levels and sp-a fragments at kd were detected. conclusions: neutrophil proteases degrade sp-a in cf lungs. the carbohydrate dependent binding of sp-a is diminished due to a reduced function of the crd. these alterations contribute to the reduced ability in cf to remove specific pathogens from the lungs. chiron, r. , ; murris-espin, m. , ; crampette, l. , ; varrin, m. ; didier, a. , ; wallaert, b. , ; chanez, p. , ; leroy, s. , . crcm, chu, montpellier, france; . crcm, chu, toulouse, france; . orl, chu, montpellier, france; . iurc, chu, montpellier, france; . crcm, chu, lille, france; montpellier, france in cystic fibrosis (cf) patients, upper airways involvement is frequent but its impact and relationships on the course and severity of the disease has been rarely investigated. objective: to relate upper airways involvement with lower airways parameters and quality of life in cf patients. methods: clinical and radiological prospective study of subjects with cf at french cf centres. clinical rhino-sinusitis (rs) was defined by the presence of more than episodes of nasal symptoms during the last year, current nasal obstruction or rhinorrhea. nasal investigations included: anterior rhinoscopy, sinus ct scan analysis and rs quality of life questionnaire. lower airways were assessed using a thoracic ct scan (bhalla score), spirometry and sputum culture and a cf quality of life questionnaire (cfq +). results: ( f/ m) patients aged . ( - ) years old were enrolled. endoscopy demonstrated polyposis in % and nasal hyper secretions in . % of the patients. spirometry, bhalla score, sputum colonization did not discriminate patients with (n= ) or without rs (n= ), and regardless the presence of polyps. cfq + was significantly lower in patients with of rs (p= . ). conclusions: rs involvement altered quality of life in cf patients, although, they do not have a more severe pulmonary disease. a specific attention and treatment to rs should be paid in cf patients. the impact on different outcomes deserves to be examined in longitudinal studies. as part of the uk cystic fibrosis gene therapy consortium "tracking study", ebc was measured (ecoscreen, jaeger) in adult and paediatric patients presenting with an infective exacerbation requiring iv antibiotics. exacerbation was defined by pre-determined criteria. ebc was repeated at the end of parenteral antibiotic therapy and again - weeks later. patients were recruited at three sites and assessed using standardised equipment. samples were obtained according to ers guidelines. exhaled breath ph was assayed (shindengen ph meter, camlab, uk) immediately after collection without a de-aeration step. results: paired ebc measurements at the start and end of antibiotic therapy were available in patients. mean age was yrs (range - ). data from patients were excluded because at least one ph measurement was > , suggesting salivary contamination. for the remaining patients mean ebc (sd) ph increased from . ( . ) to . ( . ), p< . . of these patients, also had measurements available at a third visit, - weeks after completion of antibiotics. were excluded because of salivary contamination. no difference in mean(sd) ebc ph was found ( . ( . ) vs. . ( . )) conclusions: ebc ph increases after treatment with antibiotics, and may offer a non-invasive means of assessing airways inflammation in chest exacerbations. further work is required to follow the longitudinal change in ebc ph and other inflammatory markers in clinically stable patients, as ebc may be a useful tool in assessing response to novel treatments, such as gene therapy. this work was funded by the cystic fibrosis trust. background: children with cystic fibrosis (cf) undergo multiple procedures exposing them to ionizing radiation in hospital. some specialist centres have advocated regular chest computed tomography (ct) as a means of better quantifying lung pathology. the clinical benefit of this approach is unproven and previous calculations of risk have failed to account for other ionizing radiation exposure procedures . aim: to quantify the exposure of ionizing radiation in the pediatric cf population of a tertiary level children's hospital. to determine the potential difference in exposure of introducing biannual chest ct scans. methods: effective doses of ionizing radiation from chest (cxr) and abdominal (axr) radiographs, fluoroscopy and cts (sinuses and chest including hr scans) were determined for cf children at our centre between st january and th july ( weeks). the maximal effect was tested i.e. introduction of biannual chest ct scans from age years abolishing the requirement for cxrs and the assumption was made that axrs, sinus cts and fluoroscopy rates were unchanged (median exposure values calculated for age groups -< year, -< year, -< year, -< year, -< year, > year) . results: cf patients (n= , gender ratio : ) underwent a mean of . ionizing radiation exposure procedures per patient over the study period (total of procedures). the average effective ionizing radiation doses (msv) were calculated for ( . %) procedures. each cf child received a mean (median) effective radiation dose of . ( . ) msv/year with a range of . - . msv/year. the reason for the skewed distribution was identified by analysing the proportions of the procedures to the total effective dose in this population: fluoroscopy . %, chest ct . %, sinus ct . %, cxrs . %, axrs . % and hrct . %. it was calculated that these patients undergo . cxrs per patient per year. we calculated that an average patient diagnosed by newborn screening could expect to receive . msv from ionizing radiation procedures between birth and age . biannual ct chest scans in addition to median exposures for each age group from axrs, sinus cts and fluoroscopy would potentially result in . msv by age , an fold increase. discussion: there is a in lifetime risk of developing a solid or haematological cancer with each exposure to msv of ionizing radiation . although fluoroscopy forms the most significant contribution to a pediatric cf patient's ionizing radiation exposure in our centre, introducing biannual chest cts would markedly increase exposure. as cf survival improves, cf physicians must be cognisant of the potential health cost of survival. references : previous studies have used generic measures of hrqol, which are not sensitive to important changes that may occur as a result of treatment. this study assesses the impact of iv antibiotic treatment for a pulmonary exacerbation on both generic and disease-specific hrqol of children and adolescents with cf. method: participants included patients (m age = . years) from the cincinnati children's hospital and university of florida cf centers. fiftyfour percent of the sample were male. patients completed two hrqol measures, the pedsql™ (generic) and cfq-r child or teen/adult version (cf-specific), which have excellent reliability and validity. these measures were completed within hours of hospital admission (pre) and hours of discontinuation of iv antibiotics (post). note that approximately % of patients went home on iv antibiotics and % remained in the hospital for approximately weeks. results: significant improvements were found in pulmonary functioning (fev % predicted) pre to post iv antibiotic treatment (paired t ( ) = - . , p < . ), with an average of % increase in fev % predicted. paired t-tests were conducted to examine changes in hrqol scores, using holm's procedure to correct for multiple comparisons. significant improvements were found on the cfq-r respiratory (paired t ( ) = - . , p < . ) and weight scales (paired t ( ) = - . , p < . ). trends were also noted for improved emotional functioning (paired t ( ) = - . , p = . ) and vitality (paired t ( ) = - . , p = . ), and worse treatment burden (paired t ( ) = . , p = . ). on the pedsql, only emotional functioning improved significantly (paired t ( ) = - . , p < . ). conclusions: results of this study confirm the effectiveness of iv antibiotics for the treatment of pulmonary exacerbations, with significant improvements found for both pulmonary functioning and hrqol. these results also highlighted the importance of using a disease-specific hrqol instrument, which proved to be more sensitive than the generic measure. on the cfq-r, significant improvements were observed in respiratory symptoms and weight, aspects of functioning that are not assessed on generic measures. fukushima, l.k.; hsu, e.; woo, m.s. division of pediatric pulmonology, childrens hospital los angeles, los angeles, ca, usa do hispanic and caucasian cf patients share the same frequency of pulmonary exacerbations? increased frequency of pulmonary exacerbations is linked to increased risk for cf morbidity and mortality. we have previously reported that pediatric hispanic cf patients have greater mortality than our caucasian cf patients who attend the same accredited cf center. we performed a retrospective review of cf pulmonary exacerbations (defined as physician prescription of intravenous or oral antibiotic therapy) in our cf patients who routinely attended the cf clinic during the period of january , through december , . data collected included demographics, number of intravenous antibiotic courses and number of oral antibiotic courses. unpaired student's t-test was used to compare age of the groups and chi-square was used to compare use of intravenous and oral antibiotics between hispanic and caucasian cf patients as well as between males and females. during the study period, there was a total of cf patients ( males: females; mean age . ± . years). of the patients, ( %) were classified as hispanic ( males: females; mean age . ± . years) and ( %)were classified as caucasian ( males: females; mean age . ± . years; p= . , ns). hispanic cf patients ( patients had episodes; males: females) had significantly greater number of pulmonary exacerbations (received treatment with intravenous and/or oral antibiotics) than caucasian cf patients ( patients had episodes; p = . ). hispanic cf patients who required intravenous antibiotic therapy were significantly younger ( . ± . years vs . ± . years; p< . ) than the caucasian cf patients who were treated with intravenous antibiotics. there was no significant difference in age between hispanic and caucasian cf patients who received oral antibiotic courses ( . ± . years vs . ± . years; p= . , ns). gender did not have a significant impact on pulmonary exacerbation risk in our population (hispanic iv use by gender p= . ; hispanic oral use by gender p= . ; caucasian iv use by gender p= . ; caucasian oral use by gender p= . ). we conclude that hispanic cf patients had increased incidence of pulmonary exacerbations than caucasian cf patients who attend the same cf clinic. hispanic patients who were treated with intravenous antibiotics were younger than the caucasian cf patients. we speculate that hispanic ethnicity has a major impact on the incidence of pulmonary exacerbations. other factors, such as modifier genes, environmental exposures, or inflammatory responses, may play a role in the increased risk of pulmonary exacerbations in the hispanic cf population. introduction: one of the main goals of the multidisciplinary team of the cf association of minas gerais, brazil is to find strategies to preserve lung tissue from the bacterial exacerbation in cystic fibrosis patients. objective: to investigate clues on onset of bacterial exacerbation. to our knowledge, no studies were found regarding the identification of the early warning signs of bacterial exacerbation with cf patients. we wanted to know whether cf patients present early warning signs before onset of fever and/or breathing difficulties. methods: telephone interviews were carried out with the cf patients registered in the association, by a physiotherapist academic who did not know the patients and just ask two questions. the first question was about the use of antibiotics during the year of and the second was related to early signs before the onset of fever. results: from the patients, only patients replied. patients who were using antibiotics therapy during and had fever: / patients who were using antibiotics and did not have fever: / patients who had fever and did not use antibiotics: / patients who did not have fever and did not use antibiotics: / the results revealed the following warning signs and also that some patients had more than one sign. tiredness, quietness, slowness ( / ); increased cough ( / ); lack of appetite ( / ); sticky sputum ( / ); sleepiness ( / ); headache ( / ); increased excitement, nervousness ( / ); crybaby ( / ); dry mouth ( / ); clammy ( / ); difficult to walk ( / ); gastric upset ( / ); itchy throat ( / ); abdominal pain ( / ) ; itchy eyes ( / ); breathing difficulties ( / ); tremulous ( / ); paleness ( / ); burning ear ( / ); chest pain ( / ); hissing ( / ) ; and syncope( / ). conclusions: it is helpful to know these early warning sings. we assume that the earlier the diagnosis of the exacerbation is made, the easier it is to resolve the problem and the less destruction of the lung tissues. reference: lung line, national jewish center for immunology and respiratory medicine . background: cystic fibrosis patients are experiencing increasing survival and are being treated with more chronic therapies. how these changes are reflected in day to day clinical symptoms has not been evaluated. objective: we examined data from the epidemiologic study of cystic fibrosis, a large longitudinal observational study, to characterize the change in respiratory symptoms over time. for each year between and data from patients with at least one visit recorded as occurring while clinically stable were included. data from all visits, including sick as well as stable, were used for each year in which at least one clinically stable visit was recorded. patients were separated into age groups less than , to , to , and or older. note that in data collection changed, potentially confounding the results. results: the average number of patients per year was . the percent of patients with no reported cough progressively increased over time (table) . results were similar for pateints with no reported sputum production at clinically stable visits. when sick visits were added there were similar results. the frequency of cough reported at greater than percent of visits progressively decreased over time (table) . again the results for sputum production were similar. these findings were seen in all age groups although older patients are more likely to experience these symptoms. conclusions: these data suggest that cf patients are experiencing fewer respiratory symptoms of cough and sputum production over the last decade. this improvement has occurred in patients with either intermittent or chronic symptoms. how clinical care has impacted on these symptoms has yet to be determined. also, more people are being diagnosed with cf at an earlier age or with milder disease, potentially resulting in the entire cf population having fewer symptoms. lung disease in children with cf begins in early childhood, with intermittent and then chronic infection, associated with an exaggerated inflammatory response. the extent to which inflammation contributes to bronchiectasis has not yet been identified. the aim of this study was examine relationships between inflammation and early lung damage methods: twenty eight children with cf were assessed at diagnosis and annually thereafter with a bronchoalveolar lavage (bal). bal fluid was used to assess micro-organisms and inflammation, including total and differential cell counts. a three slice hrct technique (inspiration and expiration) was performed under general anesthesia at age - y, immediately preceding the annual bal. hrct scans were scored by an independent and experienced radiologist using a modification of the brody score. results. twelve children ( %) had evidence of bronchiectasis on hrct. inflammation present in bal at months of age predicted bronchiectasis at - y. total cell count at mo, predominantly neutrophils, was higher in those who developed bronchiectasis compared to those who did not ( . vs . x cells/ml bal; p= . ). the total number of infections detected in bal was not related to bronchectasis. however, children with bronchiectasis had a higher incidence of pseudomonas aeruginosa within the first years of life ( % vs. %). conclusions: bronchiectasis is evident within the first five years of life and appears to be associated with an exaggerated inflammatory response and the early acquisition of pseudomonas aeruginosa. supported by: cystic fibrosis foundation (usa), national health and medical research council (australia). fortunately the survival of patients with cystic fibrosis has improved remarkably over the last few decades. many patients can life quite "normal". therefore family planning becomes more important. several reports docu-mented the good maternal and fetal outcome in pregnant women with cystic fibrosis. besides the data from the french cf registry no longterm data about the impact of paternity of male patients with cystic fibrosis are available until now. in a retrospective analysis we gathered data about all our male patients who became father while being followed-up in our cystic fibrosis center for adults. from male patients, patients became father between and . patient no. became father twice (second time father of twins); patients no. became also father of twins .we looked at fev % year prior to childbirth, perinatal and and years after the childbirth. for the fev % one year prior to birth as well as for fev % and years after birth, we calculated the difference to the fev % at time of birth. between and , male adult patients with cystic fibrosis became fathers of a total of children, all by the assistance of reproductive techniques. their fev % are shown in table . although the male patients are not directly influenced by a pregenancy (as the pregnant women are by growth of the uterus), there seems to be more than ususal differences in this lung function parameter. there were also more fluctuations in fev per year. the biggest differences in fev % were seen year after birth of their children. further investigations in a larger group (in cooperation with other centers) are planned; especially with a focus on the frequency of infections and quality of life compared to male patients without children. intravenous (i.v) aminoglycosides are widely used in cystic fibrosis (cf) patients as treatment for pulmonary exacerbations. in an effort to reduce undesiderable effects of these antibiotics it is recommended to measure drug serum levels. recent experience suggests that tobramycin (to) may be administered as a single daily dose with equal efficacy as multiple doses but less risk of nephrotoxicity. aim: we evaluated the efficacy of once-daily i.v to treatment to improve pulmonary function expressed as forced expiratory volume in one second (fev ) in cf patients with pulmonary exacerbations compared to the same group of patients who were previously treated with to in multiple daily i.v doses, as historic control. we evaluated baseline and peak drug serum levels of to administered once daily compared to multiple dose levels. methods: all patients were treated with i.v to in combination with a beta-lactam antibiotic for two weeks. respiratory exacerbation was defined according to cff criteria. all cf patients were colonized by non-fermentative gram-negative bacteria. serum concentrations of to were measured (fluorescent polarisation immunoassays) before the fifth infusion (basal) and minutes after the fifth infusion (peak). reference to blood levels were considered to be ≤ mg/l (basal) and < mg/l (peak) for multiple daily doses, and ≤ mg/l (basal) and - mg/l (peak) for single daily dose. treatment efficacy was evaluated on the basis of improved clinical condition and increased fev values compared to the beginning of therapy. results: patients with respiratory exacerbation were evaluated, with a mean (± ds) age of . years (± . ; median . , range . - . ) . out of patients were chronically colonized by pseudomonas aeruginosa. the total mean (± sd) daily dose of to administered in multiple doses was (± . ) mg whereas the mean single dose was . (± . ) mg. of those patients given multiple doses of to, only one patient ( . %) had basal to values outside the range and patients ( . %) had peak values outside the range. of those patients given a single daily dose, no patients had basal to values outside the range whereas out of ( %) had peak values of less than mg/l and patients out of ( %) had peaks between and mg/l. the mean (± sd) increase in fev was . % (± . ) in patients treated with a single dose and % (± . ) in those treated with multiple doses. the mean (± sd) period between fev measurements before and after exacerbation was . days (± . , median , range - ) in case of monodose therapy, and . (± . , median , range - ) in case of therapy with multiple doses. conclusions: both single and multiple-dose i.v to therapy caused a comparable fev increase and were effective in resolving the respiratory exacerbation. although clinical improvement was observed, the mean i.v to dose of mg/day in patients treated with once-daily i.v to determined peak values between and mg/l in % of subjects. intravenously administered aminoglycosides are efficacious for the treatment of pulmonary infections of cystic fibrosis (cf) patients, with the principal adverse effects of these molecules being acoustic nerve damage and nephropathy. damage to the eighth cranial nerve varies from . to % in cf patients treated with multiple daily doses of aminoglycosides. recent experience suggests that tobramycin can be administered as a single daily dose, resulting in less nephrotoxicity but equal efficacy. patients and methods: we evaluated the prevalence of oto-and nephrotoxicity due to aminoglycosides administered to cf patients followed at the tuscan regional center where we are currently following patients. cochlear damage was evaluated using tonal audiometry (amplifon amplaid s). renal damage was evaluated by measuring patients' creatinine clearance. results: ( %) patients ( males and females) between the ages of and (mean age . years, median , sd ) were tested with audiometry. all these patients had been repeatedly treated with multiple daily doses of intravenous aminoglycosides. ( . %) ( males and females) out of patients between and years (mean age . , median . , sd . ) had their creatinine clearance measured. we found that patients ( . %) had an abnormal audiometry, typically attributable to aminoglycoside ototoxicity (high frequency deficit). two patients required a hearing aid. one patient with normal cochlear function had labyrinth deficit. one out of patients tested had pathological creatinine clearance values. conclusions: our data indicate that ( . %) of our patients had damage to the eighth cranial nerve due to repeated multiple daily doses of aminoglycosides. we recommend that cf patients under aminoglycoside therapy be routinely given audiometric and creatinine clearance exams in an attempt to reduce the incidence of undesirable side effects of these drugs. davies, j. , ; voase, n. , ; dewar, m. , ; mullard, k. , ; gammie, f. , ; saunders, c. , ; horsley, a. , ; gray, r. , ; macleod, k. , ; somerton, l. , ; higgins, t. , ; donovan, j. , ; cornish, n. , ; hansell, d. , ; aziz, z. , ; ashby, d. ; geddes, d. , ; greening, a. , ; cunningham, s. , ; innes, a. , ; alton, e. , . gene therapy, imperial college, london, united kingdom; . western general hospital, edinburgh, united kingdom; . royal hospital for sick children, edinburgh, united kingdom; . royal brompton hospital, london, united kingdom; . queen mary, university of london, london, united kingdom; . uk cf gene therapy consortium, edinburgh, london, oxford, united kingdom the improving clinical status of patients with cf and the slow rate of decline of conventional outcome measures such as fev necessitate the development of clinically-relevant surrogate outcome assays for use in clinical trials. in our forthcoming clinical trial of cftr gene therapy, the uk cf gene therapy consortium will use both established, clinically-available assays and more novel measures designed specifically for this purpose. both groups of assays are being subjected to rigorous testing prior to use to establish their utility as disease biomarkers. in this study, we examined their performance in the context of an infective exacerbation treated with iv antibiotics. this abstract will report the response of established, clinically-available assays; available data from novel assays will be reported separately. children ( years and above) and adults with cf were recruited from three centres at the time of a clinician-defined infective exacerbation requiring iv antibiotic treatment. exclusion criteria included fev < % predicted and requirement for supplemental oxygen. a panel of assays was performed at the start and end of treatment, which was most commonly days. data are presented as mean (sd) or median (range) and differences compared with either parametric or non-parametric paired analysis as appropriate. clinical assays included spirometry, sputum microbiology, sputum cell count and differential, serum inflammatory markers (crp, white blood cell (wbc) count,) and chest ct. patients also completed a symptom score sheet. to date, patients (mean age . [ . ] years, male) have paired data available from the start and end of the course of ivs. at baseline, were infected with p. aeruginosa, with b. cepacia complex organisms and with s. aureus ( mrsa). significant changes from baseline were observed in fev ( . [ . ] the clinical response to any novel intervention, for example, cftr gene therapy is difficult to predict. prior testing of experimental assays in a study such as this provides data on the variability of the measurements within the disease population and the degree of change observed with an intervention known to lead to clinical benefit. this should aid the design of rational, powered clinical trials. funded by the cf trust influenza can worsen cf and lead to serious complications and mortality. influenza vaccine is safe and effective in cf patients. in france, annual influenza vaccination is recommended for all cf patients aged over months and for healthcare workers in regular and prolonged contact with high-risk patients. objective: to estimate the influenza vaccination coverage rate for - season in cf patients and healthcare workers in cf care centres of the great south region of france. methods: a multicentric observational study between february and september was conducted. healthcare workers were contacted by telephone and were questioned about their - influenza vaccination status, and the reason for not getting vaccinated. for patients aged over months whose vaccination booklet was available, the physician filled in a written questionnaire. results: a total of professionals were interviewed. the survey included . % of doctors, . % of nurses, . % of dieticians, . % of physiotherapists, . % of social workers and . % of psychologists. the overall influenza vc rate was . % and varied considerably according to profession: . % of doctors, . % of physiotherapists, . % of dieticians, % of psychologists, . % of nurses and . % of social workers. the overall influenza vc rate in cf patients was . % ( . % in children (age < years old) versus . % in adults; p< . ). receiving a voucher for free vaccination from the national insurance increased the influenza vc rate. for healthcare workers, the main reason for non vaccination was that flu was considered as a benign disease (useless vaccine); for patients, it was a lack of time. conclusion methods: adult patients with cf were studied. patients completed a standardised questionnaire. the questionnaire identified which changes and duration of symptoms would cause them to contact the cf team and/or change treatment. results: all patients would contact the cf team for haemoptysis but % would wait for more than hours and % would wait for more than hours before doing so. up to % of patients would wait a week or more before contacting the cf team because of sputum purulence. % of patients would not contact the cf team if they developed new chest pain. conclusion: there appears to be a disconnect between recognizing a change in symptoms and the length of time before acting on the change. this has major implications for the delivery of cf care. supported by cystic fibrosis association of ireland. aim: to determine the efficacy of standardized desensitization protocols in treating antibiotic allergies in adults with cystic fibrosis (cf). background: dependence on high dose and multiple combination intravenous (iv) antibiotics to treat pulmonary exacerbations in adult cf patients has resulted in an increased frequency of allergic reactions when compared with the general population. ( , ) strategies to address these allergies are essential to maintain effective antibiotic treatment in this population. antibiotic desensitization is the process by which one induces immune tolerance by incremental exposure to the antibiotic, which may induce stabilization of mast cells. the mechanism remains undetermined but may be mediated via ige or memory t-cells. prior to the study period, standardized antibiotic desensitization protocols were developed by an allergist/immunologist based on published reports and were approved through the hospital's pharmacy and therapeutics committee. methods: the toronto cf database was accessed to generate a list of hospital admissions for iv antibiotics during the -year study period ( ) ( ) ( ) ( ) ( ) ( ) . patients who underwent desensitization were identified and each of their case notes underwent retrospective analysis. data were collected with respect to age, organism requiring antibiotic therapy, antibiotic allergy requiring desensitization, reactions during desensitization, reactions post desensitization, treatments required to treat these reactions, and the completeness of antibiotic therapy post desensitization. statistical analyses were performed using graph pad prism®. results: during the study period the cf unit dispensed and initiated approximately courses of iv antibiotics. a total of desensitizations were performed in patients ( female). although some patients were desensitized to only one drug or to the same drug more than once, there were patient-drug combinations with a median of (+/= . ) unique combinations per patient. of the desensitizations protocols initiated, patients developed documented reaction to the antibiotic during desensitization however only desensitization protocol was not completed due to an adverse event. there were no episodes of anaphylaxis either during or after desensitization. a total of patients developed documented reactions during the subsequent antibiotic course - required termination of the antibiotic and completed the course of iv antibiotics with management of allergic type reactions with antihistamines. conclusions: standardized desensitization protocols were initiated in patients during the study period. the success rate for desensitizations in these patients was % however when the data is analyzed for true allergic phenomenon, the success rate rises to %. this demonstrates the efficacy of these standardized protocols in the treatment of ige-mediated allergic reactions to antibiotics in the adult cf patient. references: . burrows, j., toon, m., bell, s., ( ) . antibiotic desensitization in adults with cystic fibrosis. respirology, : - . . ramesh, s. ( ) . antibiotic hypersensitivity in patients with cf. clin rev allerg immun, : - . surgery for symptomatic disease. there is a long-held suspicion that poorly-controlled chronic sinusitis negatively impacts the respiratory status of cf patients, but whether sinus surgery improves the clinical course of cf lung disease is unclear. aim: assess the impact of functional endoscopic sinus surgery (fess) on respiratory exacerbation rate and lung function in adult cf patients methods: this is a single-center, retrospective study based on chart review. during the study period, - , adult patients underwent separate fess procedures. this abstract contains results so far from the analysis of patients that underwent a total of surgeries. primary outcomes were -year change pre to post fess in pulmonary function parameters and pulmonary exacerbation rate. results: at the time of surgery, the mean fev was % of predicted (ppd), the mean fvc . ppd, and the median age was . years (range . - . ). . % of patients were female. the median number of iv antibiotic courses for respiratory exacerbations in the months prior to fess was (range - ) compared to (range - ) in the year after surgery (p = . ). further,there were fewer days on intravenous (iv) antibiotics for respiratory exacerbations in the months prior to fess than in the month post-operative period (median vs. days), but this difference was not statistically significant (p = . ). the use of oral antibiotics for respiratory flares was comparable in the months before and after fess (median vs. days, respectively, p = . ). the median number of hospital admissions and median number of days hospitalized for respiratory exacerbations did not differ in the months pre vs. post-fess (p = . and p = . , respectively). the mean fev and fvc in the months pre and post surgery did not differ significantly ( . vs. . ppd, p = . , and . vs. . ppd, p = . ). the linear rate of change in fev and fvc did not differ significantly in the months prior to and following fess (-. l/month vs. +. l/month, p = . and -. l/month vs. +. l/month, p = . , respectively). there were no significant differences (p > . ) for any of the above comparisons when the analysis was limited to months before and after fess. there were no significant differences (p > . ) in antibiotic use and hospitalizations when the analysis was limited to the surgeries in which patients were experiencing both respiratory and sinus symptoms. this latter group had lower fev and fvc ppd in the month post-fess period ( . vs. . ppd, p = . , and . vs. . ppd, p = . , respectively). however, the rate of decline in fev and fvc in the months before and after surgery did not differ significantly ( p = . and p = . , respectively). conclusion: fess did not significantly affect the rate of respiratory exacerbations or rate of decline in pulmonary function in adults with cystic fibrosis. cumulative decline in lung function as measured by fev in cystic fibrosis (cf) pulmonary exacerbation is a major cause of cf-related morbidity and mortality. high-dose extended interval aminoglycoside (hdei ag) use may be more effective in improving lung function than traditional multiple daily dosing in cf-related pulmonary exacerbation. intermittent dosing of beta-lactam antibiotics are often used with hdei ag in patients with cf pulmonary exacerbation, which does not optimize betalactam pharmacodynamics. the primary purpose of this study is to determine the effect of hdei ag plus continuous infusion beta-lactam (cibl) on patients' return to best baseline fev from the previous months. this study was conducted at university of kentucky healthcare. this was a concurrent observational trial with patients serving as their own historic controls via review of the medical record. all pediatric and adult patients with cf respiratory disease hospitalized with an acute pulmonary exacerbation between november , and may , , with pseudomonas aeruginosa in their respiratory culture and were followed for at least one year were included. excluded were patients with known hearing disability or renal insufficiency or an inability to reliably perform spirometry (ie.less than six years old). patients served as their own historic controls via conventional treatment (control) versus hdei ag plus cibl (treatment). the primary endpoint was to determine the percent of patient courses that return to best baseline fev in the last twelve months after treatment with hdei ag plus cibl. secondary endpoints included determination of patient courses that returned to mean baseline fev in the last twelve months after study treatments, and description of beta-lactam dosing characteristics. thirteen patients were included in the pilot analysis which totaled patient courses (mean . courses per patient). average patient age was ± . years with a mean fev of %; . % were female. after hdei ag plus cibl no patients showed a return to their best baseline fev in the previous months with the exception of one patient whose value was unchanged. average overall percent change in best baseline fev group was - . ± . at follow up. % of patient courses exhibited a return to their mean baseline fev . average overall percent change in mean fev baseline was . ± . at follow up. five of the ( . %) study patients who had serum beta-lactam concentrations obtained were able to achieve at least four times the mic of the target organism. more data will be collected on subsequent courses and follow up lung function. our preliminary data suggest that our patients lost % of their best fev with an acute exacerbation and returned to % above mean baseline after treatment with hdei ag and cibl therapy. this evidence suggests that this might be an alternative to intermittent beta-lactam therapy. follow up data on remaining patients may provide sufficient evidence to validate this hypothesis. respiratory exacerbation in cystic fibrosis patients is characterized by increased sputum that may become more purulent. the detection of the exacerbation is based mainly on clinical subjective parameters. fev measurements are accepted as gold standard to be used for the life-time of the patient but do not adapt fast enough after resolution of an exacerbation. we compared parameters that are affected by the uneven distribution of ventilation in the lung due to increase sputum. methods: a zen body plethysmograph was used to measure tlc, fev and dlco (co/ch mixture). tlc was also calculated by the volume of ch , the angle of the slope of phase iii was calculated in cf patients at the beginning of the respiratory exacerbation and after weeks of antibiotic treatment. patients were - years old ( m/ f). results: fev changed by . + . % at the end of the antibiotic treatment, the tlc(pleth) however was stable and changed by only . + . %. the rv/tlc decreased by . + . % and the tlc(gas) was increased by + . %. the difference between tlc (pleth) and tlc (gas) before and after the antibiotic treatment decreased from . + . % to . + . %. conclusion: the changes in the parameters affected by the unevenness of distribution of ventilation (m/p reflecting the increased sputum in the airway) are more pronounced than fev and may be used as a more sensitive parameter for assessing the course of respiratory exacerbation. fibreoptic bronchoscopy was performed in children aged - years: with cf, with non-cf bronchiectasis (bx), with asthma, and control children without lower respiratory disease. endobronchial biopsies were taken and stained with haematoxylin and eosin. asm content, myocyte number and size were quantified using stereology. results: the volume fraction of asm in subepithelial tissue (median; iqr) was . ( . - . ) in controls. by comparison, it was . ( . - . , p< . ) in cf, . ( . - . , p< . ) in bx, and . ( . - . , p< . ) in asthma. myocyte number (cells per mm of reticular basement membrane) was ( - ) in controls, ( - , ns) in cf, ( - , ns) in bx, and ( - , p< . ) in asthma. myocyte size (um , mean; sd) was ( ) in controls, ( , p< . ) in cf, ( , p< . ) in bx, and ( , p< . ) in asthma. in cf, the volume fraction of asm in subepithelial tissue was related to myocyte number (r= . , p= . ), but not to myocyte size. conclusions: asm remodeling occurs in cf children. this, however, is not disease-specific and is also found in non-cf bronchiectasis and in asthma. both myocyte hypertrophy and hyperplasia contribute to increase in asm in cf. support: ers long-term fellowship and swiss national foundation grant to nr purpose: ct scans are increasingly being ordered on a routine basis in patients with cystic fibrosis. while prior studies have investigated their clinical utility in children, there is limited and conflicting information on their utility in adults. the purpose of this study was to determine the relationship between clinical disease severity as assessed by spirometry and ct findings as well as initial ct score ability to predict change in lung function in a nonselected group of adult cf patients. methods: a retrospective review of cf patients (mean age . +/- . , male %) who had undergone a routine chest ct was performed. the ct scans were scored using the brody method by a blinded reader with the degree of bronchiectasis, mucous plugging, peribronchial thickening, parenchymal disease, and air trapping assessed individually and a composite score generated. the ct metrics were first compared with spirometric test that were temporally related to the date of the ct scan, and then with future spirometric tests. results: for the cohort the patients had a wide range of severity of disease with the average fev % . +/- . , and the average fvc% was . +/- . . no significant correlation was found between initial fev % and total ct score ( . p value . ), or initial fvc% and total ct score (- . p value . ). for ct metrics and future spirometry, the average time from ct to pft's was days +/- with median of days. predictors for a significant decline in pft's were a decreasing bmi and male sex (p-values . and . respectively). further, for patients with a low fev % (< % at baseline), the fvc% change over time was associated with total ct score, male gender, and bmi (p-values . , . , and . respectively) conclusions: in adult cf patients, ct scan findings did not correlate with lung function. however in longitudinal analysis, bmi and gender had an effect on fvc change. for patients with low lung function, total ct score did have an association with change in fvc along with bmi and gender. pulmonary exacerbations (pes) are episodes of worsening of respiratory symptoms that commonly occur in patients with cystic fibrosis (cf). in clinical trials of new therapies in cf, pulmonary exacerbation is widely used as a primary or secondary endpoint. despite its importance, no single clearly agreed upon definition exists. some are based on patient reported symptoms while others require hospitalization or antibiotic prescription. use of different definitions makes it difficult to compare the results across studies and also to plan future studies. moreover, the rate of pes (proportion of patients with at least one exacerbation over a given time-period) is affected by baseline patient characteristics such as age, fev and medication use at the start of the clinical trial; factors which also contribute to the difficulty in comparing trials. using data from the cf therapeutics development network (tdn) data bank, we examined several pe definitions and baseline characteristics for their effect on pe rates. we find that pulmonary exacerbation rates vary substantially depending on both the pe definition and the baseline characteristics. for example, in one study, the proportion of subjects hospitalized and/or prescribed antibiotics during the month treatment period was %, while the proportion who met a symptoms based criteria for pe during the same period was %. we also examined the implications of varying control group exacerbation rates on sample size requirements for clinical trials and find that the control group pe rate has a large impact. for illustration, we assume a two group study with two-sided significance level . and % power. if the control group rate is %, then approximately subjects per group are required to detect a relative rate reduction of % (corresponding to a treatment group rate of %). however, if the control group rate is %, then only approximately subjects per group are required to detect the same relative rate reduction of % (corresponding to a treatment group rate of %). thus, a pe definition that selects for a greater pe rate in the control group will require fewer study subjects to detect the same relative rate reduction given that all other variables remain equal. sample size requirements can be further reduced by analyzing the number of events or the time to first event instead of the proportion of subjects who have at least one pe during a given time period. supported by cystic fibrosis foundation therapeutics, inc. (ram-sey y ), the national center for research resources (ncrr mo -rr ) and csl behring. briglia, h.; hilliard, j.; chmiel, j.f.; krenicky, j.; konstan, m.w. pediatrics, case western reserve university, cleveland, oh, usa cystic fibrosis (cf) is characterized by a vicious cycle of obstruction, infection and inflammation. the inflammatory response, which is profound and excessive relative to the burden of bacteria, is characterized by a massive neutrophil (pmn) influx. cf patients often experience intermittent declines in lung function associated with increases in both bacterial burden and pmn influx. these pulmonary exacerbations require treatment with antibiotics. there are substantive issues in the identification of pulmonary exacerbations and the assessment of therapies. a marker which indicates the inflammatory state of the lung would be useful to identify infective/inflammatory exacerbations, as opposed to worsening due to pulmonary vascular disease, or simply upper airway infection (cold), and might guide therapy for intensity and duration. g-csf and gro-α are cytokines produced in the lung by a variety of cells, including macrophages and epithelial cells. g-csf is involved in the proliferation, differentiation and activation of pmn precursors, while gro-α has known chemotactic and activating effects on pmns. transfer of these cytokines through the basolateral membrane into the bloodstream results in increased pmn production and activation in the bone marrow. the plasma concentrations of g-csf and gro-α might serve as potential biomarkers for a pulmonary exacerbation. in this pilot study we measured g-csf and gro-α in the plasma of healthy volunteers (n= ), clinically stable cf patients (n= ) and cf patients experiencing a pulmonary exacerbation, both before (n= ) and following (n= ) - days of antibiotic (abx) therapy. cytokines were measured using commercially available elisa kits (r&d systems, minneapolis, mn) . t-tests were performed on natural log transformed cytokine data (sigmastat v . , systat software inc., san jose, ca). ᭹ the lack of a significant difference between g-csf and gro-α plasma levels in healthy and clinically stable cf patients suggests that these cytokines are not indicators of chronic inflammation. ᭹ both cytokines are increased during pulmonary exacerbations in patients with cf and decrease to baseline values following antibiotic therapy, suggesting that these cytokines might serve as potential biomarkers for cf pulmonary exacerbations. ᭹ although not statistically significant, there was a trend towards an inverse correlation between both cytokines and fev during pulmonary exacerbations in this small study (data not shown). ᭹ further studies are warranted to increase our understanding of g-csf and gro-α as potential biomarkers of pulmonary exacerbation in cystic fibrosis. this work was supported in part by the cystic fibrosis foundation through an institutional research development grant. pletcher, s.d. ; koff, j.l. ; kleinhenz, m. . otolaryngology, university of california, san francisco, san francisco, ca, usa; . medicine, university of california, san francisco, san francisco, ca, usa introduction: while sinus disease is common in adult patients with cystic fibrosis (cf), the severity of sinus symptoms and relationship of sinus disease to other manifestations of cf are relatively unknown. objectives: to evaluate the severity of sinus symptoms in adult patients with cf and correlate these findings with other cf manifestations. methods: twenty-six consecutive adult patients with cystic fibrosis were surveyed during routine clinic visits for sinus specific and overall quality of life outcomes using both the sino-nasal outcome test (snot- ) and the cystic fibrosis questionaire (cfqr). analysis of snot- and cfqr scores were compared to %fev and sputum culture growth of pseudomonas for all patients. results: snot- scores ranged from . to . with a mean of . on a - point scale. for the purpose of data analysis, the patients were divided into two patient cohorts: group with minimal sinus symptoms (snot- < . ) and group with mild to moderate sinus symptoms (snot- > . ). the mean %fev for group was significantly higher than the mean %fev for group ( . % vs. . % respectively, p< . ). patients in group were more likely to have sputum culture growth of pseudomonas although this trend did not reach statistical significance ( % vs %, p= . ). cfqr scores differed significantly among the two groups with group patients reporting more disability in the physical, role, vitality, body, eating, health, respiratory, weight, and digestion domains but not in the emotion, social, and treatment domains. conclusions: this cohort of adult cf patients show minimal to moderate symptoms of sinonasal disability. those patients with mild to moderate sinonasal symptoms have decreased pulmonary function and decreased overall quality of life compared to cf patients with minimal sinus symptoms. , . internal medicine, university of iowa hospital and clinics, iowa city, ia, usa; . translational lung imaging program, university of iowa hospitals and clinics, iowa city, ia, usa; . pulmonary and critical care medicine, mount sinai medical center, miami beach, fl, usa mucociliary transport is an important component of airway host defense against inhaled particles and microbial pathogens. mucociliary clearance is hypothesized to be defective in cystic fibrosis allowing for airway colonization and infection. current methods for measuring mucociliary transport and clearance lack the ability to measure mucociliary transport in specific proximal and distal airway segments. using a -slice high resolution ct scanner (somatom , siemens), we are developing a method to track radiopaque particle movement in the swine airway. swine were induced with ketamine/acepromazine, intubated, and then anesthesia maintained with propofol infusions. animals spontaneously breathed humidified air with the endotracheal tube cuff deflated. radiopaque teflon/bismuth trioxide disks ( mm diameter, . mm thick) were instilled via a catheter into the airways. serial ct images ( . mm slice thickness and slice increment of . mm) were obtained every minutes for a total of minutes. airway tree segmentation was performed using pulmonary workstation . (vida diagnostics, iowa city, ia). this program allows for fully automated airway tree segmentation. baseline mucociliary transport rates ( -dimensional) were . ± . mm/min. following aerosol delivery of human sputum leukocyte elastase ( mu), mucociliary transport was markedly diminished ( . ± . mm/min) at minutes. thus far, we are able to measure mucociliary transport down to the rd generation airways. future studies include more distal deposition and measurement of particle movement. in summary, this novel method measures mucociliary transport in defined airways and will allow us to examine the effect of altered airway epithelial function on mucociliary transport. lung transplant. purpose: to design a ct scoring system to quantify structural abnormalities on ct scans from cf patients with severe advanced lung disease (sald) and to investigate the correlation between ct scores and survival. materials and methods: ct scans of cf patients screened for lung transplant between and were collected from transplant centres. all scans were scored with the brody ii scoring system. to design a new scoring system sensitive for the specific changes in sald, a panel of experts reviewed a random set of ct scans on eligible items to be used in a pilot analysis. the resulting sald scoring system consisted of four items: bulla/cysts; areas with consolidation/mucous; areas with hypo perfusion/air trapping and hyper/normal perfusion. in each ct slice ( mm spacing) and for each of the items the surface area of corresponding lung tissue involved was estimated on a - % scale. total surface area for the items and each slice added up to %. the final sald score was a mean volume estimate of abnormal and normal lung tissue. results: pilot analysis of a set of ct scans showed a a spectrum of abnormalities, ranging from predominantly bronchiectasis to predominantly mosaic perfusion. a moderate correlation was found between the sald components inflammation and hypo perfusion/ air trapping and brody score (p= . , r= . and p= . , r= . ). the inter-observer variability of both scoring systems was comparable. (ri ranging from . to . ) analysis of the complete cohort with the brody ii score showed a significant correlation with survival with a hazard ratio of . ( % ci of . to . ) for dying on the waiting list for every ten point increase in brody ii score. (p= . ). the brody component scores for bronchiectasis, airway wall thickening and parenchyma showed a similar correlation with hazard ratios ( % ci's) of respectively . ( . - . ), . ( . - . ) and . ( . - . ) for every ten point increase in score. (p= . , . and . ). the preliminary results with the brody score suggest that it is useful to include ct information in prediction models. it is likely that the predictive value of the ct can for survival can be further improved using the dedicated sald-ct score. scoring of the remaining scans according to the sald system is ongoing and will be completed shortly. snell, g. . physiotherapy, the alfred, melbourne, vic, australia; . allergy, immunology and respiratory medicine, the alfred, melbourne, vic, australia; . epidemiology and preventative medicine, monash university, melbourne, vic, australia; . radiology, the alfred, melbourne, vic, australia background despite the widespread use of airway clearance (ac) techniques to clear excessive secretions and improve lung function, little is known about their efficacy following lung transplant (lt). this study aimed to compare the effects of two ac strategies (proactive vs reactive) on a range of clinical outcomes following lt. methods a prospective randomized trial design with stratification for suppurative pre-lt disease was used. consecutive patients at month post lt were eligible for inclusion. subjects were excluded if medically unstable, ventilator dependent or had a contraindication to performing positive expiratory pressure (pep) therapy. patients performed ac using pep either twice daily (proactive strategy) or only in the presence chest infection (reactive strategy). lung function (fev and fvc), chest radiography (brasfield score), exercise capacity ( minute walk) and bronchoscopic airway characteristics (anastomotic healing, patency and secretions) were assessed at , and months post lt. patient adherence and satisfaction were measured. results of consecutive patients, ( in each group) were recruited and completed the study. both groups improved lung function (fev ± % to ± % p< . ; fvc ± % to ± % p< . ), brasfield scores ( . ± . to . ± . p< . ) and minute walk ( ± m to ± m p< . ) over the study period. no significant differences between groups for any outcome were found. the vast majority had fully healed, % patent anastomoses without secretions at months. there were no significant differences between airway characteristics and incidence of chest infection. adherence to both strategies was high ( % proactive, % reactive). conclusion in the absence of significant differences in outcomes, it is recommended that ac only be performed in the presence of chest infection based on greater treatment cost and treatment time required by a proactive strategy. further studies in those with reduced anastomotic patency and in those with recurrent chest infections later post-transplant are warranted. supported by an alfred trusts grant. munro, p.e. ; button, b. , ; bailey, m. ; holland, a. , ; snell, g. . physiotherapy, the alfred, prahran, vic, australia; . allergy, immunology and respiratory medicine, the alfred, melbourne, vic, australia; . epidemiology and preventative medicine, monash university, melbourne, vic, australia; . school of physiotherapy, la trobe university, melbourne, vic, australia background the optimal duration and structure of pulmonary rehabilitation (pr) for lung transplant (lt) recipients is not known. this study aimed to describe changes in functional outcomes in lt recipients who participated in a post lt pr program at the alfred, melbourne, australia. methods prospective, repeated measures design. functional exercise capacity (six minute walk test- mwt), lung function (fev , fvc) and quality of life (sf ) were assessed at , and months following lt. following discharge, all subjects attended a hour supervised outpatient exercise training class days per week until weeks post lt and education sessions. patients with post-operative complications were excluded. data were analysed using descriptive statistics and anova with repeated measures. results consecutive lt recipients from sept to mar were assessed for inclusion. ( % male) subjects, mean age ± yrs were recruited and completed the study. % had undergone bilateral lt. % had cystic fibrosis, % chronic obstructive pulmonary disease. significant improvements were demonstrated in mwt ( ± m to ± m, p< . ), fev ( ± % to ± %, p< . ), fvc ( ± % to ± %, p< . ) and all quality of life domains, p< . . the greatest changes in mwt and lung function were seen between and months. conclusion functional exercise capacity, lung function and quality of life improved significantly over the first months in lt recipients who participated in pr at our institution. these data will allow benchmarking with other centres and program structures. supported by an alfred trusts grant. does gender play a role in perception of cf quality of life domains before and after lung transplantation? the cf quality of life (cfq-r) for patients м years of age is a disease-specific instrument. previous studies using this instrument have reported that cf females have higher scores in weight and body perception than cf males. to determine the impact of lung transplantation on gender-based perception of quality of life, we reviewed the cfq-r on all cf patients м years of age and who underwent successful lung transplantation at our center. cfq-r was administered - months prior to transplant surgery and then months after lung transplantation while the patients were in the outpatient clinic setting. domains measured: physical, role, vitality, emotion, social, body image, eating, treatment burden, health status, weight, respiratory symptoms, and digestion. the cfq-r responses were computer-scored and domain scores were then generated (score - , =better). during the ⁄ year study period, cf patients underwent successful lung transplantation ( males: females; mean age . ± . years). prior to lung transplantation, female cf patients had lower physical domain scores but higher scores in health status perceptions than the male cf lung transplant candidates (see graph). all patients had marked improvement in all domains months after lung transplantation (see graph). after transplant surgery, cf males had higher scores than cf females in emotion and in eating domains. scores for body image domain were similar for both genders before and -months after lung transplantation. we conclude that although there were differences in physical and health domain perceptions prior to lung transplantation, both male and female pediatric cf patients had marked improvement in all domains after lung transplantation. however, female cf lung transplant recipients had lower emotion and eating domain scores after transplantation. we speculate that lower scores in these domains may reflect increased post-traumatic stress and depression in female lung transplant recipients. further study on cf quality of life in pediatric lung transplant recipients is on-going. background cf liver disease (cfld) with severe cirrhosis develops in - % of patients, usually within the first decades of life. most patients with cfld suffer from complications of portal hypertension but hepatocellular function usually remains intact for many years, even decades. patients with cfld referred for lung transplantation (tx) may be offered lung tx, lung-liver tx or be excluded from lung tx. however, variceal hemorrhage due to portal hypertension can be managed by banding, sclerotherapy or shunt procedures without liver tx. the aim of this study was to examine outcome of cfld patients who underwent lung tx and the subsequent progression of cfld, particularly with the use of potentially hepatotoxic immunosuppressive drugs. we conducted a retrospective cohort study to compare cf patients undergoing lung tx with and without cfld. b. cepacia-negative cf patients undergoing lung tx at toronto general hospital from - were eligible for inclusion. liver cirrhosis was defined by histology, esophageal varices on endoscopy or imaging evidence of splenomegaly. each patient with cfld was matched for age and year of tx with cf patients without cfld. demographic data, survival and liver function tests (lfts)(ast, alt, alp, inr, albumin, protein at week , month , , , , , , , , and post tx) were obtained by chart review. results of the groups were compared using unpaired t-test (parametric data) or mann-whitney u test (non-parametric data). results b. cepacia-negative cf patients underwent lung tx over this period, ( . %) having cfld with cirrhosis. data from the cfld patients vs. matched cf patients without cfld were analyzed. no significant difference was found between the groups in pre-tx age, gender, bmi, pi status, cfrd status, fev % predicted, -minute walk distance or lfts. in the cfld group albumin was lower week post-tx ( . + . g/l vs. . + . g/l, p< . ), alp was higher month post lung tx ( . vs. . , p< . ) and alt was higher months post-tx ( . + . u/l vs. . + . u/l, p< . ). there was no significant difference in the other blood tests. azathioprine was changed to mycophenolate mofetil in cfld patients due to liver test abnormalities. cfld patient developed hepatic encephalopathy and ascites years post lung tx and is being assessed for liver tx. no difference was seen in the number of episodes of acute rejection or post-tx survival ( . % vs. . % alive at years). discussion cfld patients undergoing lung tx did not have a worse prognosis than patients without cfld. transient elevation of lfts were seen in the immediate post-tx period but settled either spontaneously or after discontinuation of azathioprine. we conclude that selected patients with cirrhosis due to cfld may be safely offered lung tx without concomitant liver tx. infectious mononucleosis, commonly called mononucleosis, or "mono," is an illness caused by the epstein-barr virus. mononucleosis has been nicknamed the "kissing disease" because the epstein-barr virus commonly is transmitted in saliva during kissing. however, sneezes and coughs also can transmit the virus occasionally. the epstein-barr virus (ebv) permanently infects more than % of the people on earth, but it causes symptomatic mononucleosis only in a small number. in developed nations, such as the united states, mononucleosis most often occurs between the ages of and . unfortunately ebv can not only infect, but can also transform, b cells after transplant and may lead to lymphoma with a resulting ~ % mortality rate. the source of ebv is presumed to be passenger lymphocytes in the donor tissue and those at greatest risk are patients who are ebv naive before transplant. since most cf patients with endstage lung disease in the developed world are now being referred for transplant given the success of this intervention, we reviewed our entire lung transplant database to determine the nature of ebv infection and the likelihood of developing lymphoma following lung transplantation. of first-time lung transplants, ( %) had cf. ebv serology was not available in ( cf, others) before transplant. of ( %) cf patients were ebv seronegative before transplant as compared to of ( %) patients with other end stage lung diseases (composed mostly of copd and ipf) in the control population (chi square p < . ). the cf ebv seronegative cohort was (sd ) years old on average, an age when most seroconversion has already occurred in our society. of the cf ebv seronegatives, survived beyond months and were thus at risk for post transplant lymphoma. of these , developed lymphoma (incidence = %) in comparison to of the ebv seronegative controls (incidence = %, p = ns). all lymphomas were stage iv at presentation and the majority ( of ) arose in the first post transplant year. the cf ebv seronegatives who developed lymphoma did not differ from those who did not with regard to levels of immunosuppression (cyclosporine, methylprednisolone or prednisone) or doses of antiviral therapy (i.e., ganciclovir which is active against both cmv and ebv). in addition, the cessation of anti-lymphocyte antibody induction therapy in the summer of , somewhat surprisingly, had no impact on the development of lymphoma. two cases of lymphoma developed in cf ebv seropositives (incidence = . %) and no cases of lymphoma developed in the control ebv seropositives (p = ns). thus ebv seronegativity raises the lymphoma risk fold in cf patients (p < . ). two of the ( %) cases of lymphoma resulted in death (one cf and one other) and one cf patient probably died of complications related to chemotherapy even though he was tumor free at that time. lymphoma outcome was not stage or clonality dependent. in conclusion, cf lung transplant recipients are at an increased risk for lymphoma largely due to their lack of exposure to ebv before transplant. kissing more before transplant may lower the risk of lymphoma afterward. university hospital uzb, brussels, belgium; . chest medicine, erasme university hospital, brussels, belgium; . dermatology, erasme university hospital, brussels, belgium; . gynaecology, erasme university hospital, brussels, belgium; . gastroenterology, erasme university hospital, brussels, belgium; . pathology, erasme university hospital, brussels, belgium hpv infection is an underestimated phenomenon in organ transplantation (tx) recipients, being unable during immunosuppression (is) to mount an adequate anti-viral immune response and risking genital/anal warts (condylomata acuminata) as well as pre-cancerous/cancerous lesions. we retrospectively assessed the incidence/treatment of genital/anal hpv-associated lesions in cystic fibrosis (cf) lung tx recipients. the files of all tx patients transplanted in the ulb center between and / ( men/ women, median age ± . , range - yrs) were reviewed. maintenance is consisted in chronic triple therapy combining a calcineurin inhibitor, a cell cycle inhibitor and corticosteroids. median survival was . ± . months (range - ). ten of sexually active patients ( %) who survived ≥ months post-tx developed hpv-associated genital/anal lesions: men ( - yrs) and women ( - yrs). genital/anal hpv-pcr proven condylomata were diagnosed between - months in the men and between - months post-tx in the women. all underwent local treatment (cryotherapy ± laser ± topical imiquimod), / patients underwent multiple treatments under general anesthesia. recurrence of the condylomata was high. one male patient presented high-grade anal dysplasia and women moderate to high-grade cervical dysplasia; underwent conization and one complete hysterectomy after conizations. one of the females presented both condylomata and a high grade cervical dysplasia. these retrospective data in a cf population indicate that ) hpv infection may cause significant morbidity in young subjects with chronic disease needing organ tx. it may even compromise life expectancy after tx. ) data on the effectiveness of treatment strategies -including topical immunomodulators -have to be collected ) the potentially protective effects of the now available hpv vaccination in females and males? with chronic disease at risk for future organ tx, when administrated before sexual activity and before tx, should be rapidly evaluated in a multi-center effort. ballmann, m. ; pfister, e. ; schlueter, k. ; becker, t. ; melter, m. ; junge, s. . pediatric pulmonology and neonatology, medical school, hannover, germany; . pediatric nephrology and hepatology, medical school, hannover, germany; . visceral and transplant surgury, medical school, hannover, germany liver disease is an important comortality and comorbidity in cf patients even in the pediatric age group. liver transplantation (ltx) is an accepted option in end stage liver disease. nevertheless the clinical outcome in cf patients is still under discussion. here we reported the clinical outcome months after isolated liver tx in pediatric cf-patients.since n= ltx were performed in children (male n= , female n= ; age (mean±sd) , ± years) . immunosuppressive therapy was done with ciclosporin ± basilixumab and steroid. we followed pulmonary function, cn-score, nutritional status (bmi z-score) and body com-position, airway cultures and igg.results:all were still alive months after ltx. before ltx all patients had a mild to moderate pulmonary disease: fvc(%pred) , ± ( , %- ), fev (%pred) , ± , ( - ), mef (%pred) , ± , ( - ) , cn-score ± , points. nutritional status: bmi(mean) , ± , % (range: , %- , %, z-score: , ± , ), upper arm circumference(cm)(mean±sd) , ± , , triceps skin fat fold(cm) , ± , . body composition: , ± , % of bodyweight were fat. one year after ltx all patients were still in a stable pulmonary situation: fvc(%pred) , ± (range: , %- %), fev (%pred) , ± , (range: %- %), mef (%pred) , ± , (range: , %- %), cn-score , ± , points. there weren't any significant changes in the airway microbiology under immunosuppressive therapy (steroid, ciclosporin±basiliximab), the serum igg levels declined significant from , ± , g/l to , ± , /l(p< . ). the growth over the year was , ± cm and the increase of weight come to , ± , kg, while the bmi didn't increase in this first year after transplantation. certainly we found an increase of the body fat mass (to , ± , % of body weight), of the upper arm circumference (to ± , cm) und of the triceps skin fat fold (to , ± , cm) .conclusion:liver transplantation is an effective therapy even in children with cf related liver disease and stabilise pulmonary function and improves nutritional status in patients with cf and mild or moderate pulmonary involvement before ltx. (neglia jp et al., n engl j med ; : - ) , and colon cancer has been described in young adults with cf (chaun h et al., can j gastroenterol ; : - ) . three of lung transplant (ltx) recipients from our center developed colon cancer after successful bilateral lung transplant for end-stage lung disease. data from these individuals are given in table below . an additional recipients with cystic fibrosis were screened via colonoscopy. colonic polyps were detected in and included lesions up to cm in diameter. five years after a colonoscopy that had shown a mm polyp, one patient underwent a nd colonoscopy that revealed multiple polyps, including a cm diameter sessile polyp in the sigmoid colon. colonic malignancies appear to arise from mucosal polyps, and screening via colonoscopy can detect and remove premalignant lesions. lung transplant recipients have an increased risk of gi malignancies and tumor surveillance is impaired by post-transplant immunosuppression, colonoscopic screening should be considered for transplant recipients with cystic fibrosis. additionally, colonic malignancy should be considered as a potential cause of unexplained gastrointestinal symptoms such as constipation. nossent, g. ; kastelijn, e. ; teding van berkhout, f. ; zanen, p. ; van den bosch, j. ; van de graaf, e. . respiratory dis, university medical centre, utrecht, netherlands; . respiratory diseases, st. antonius hospital, nieuwegein, netherlands objective: in the netherlands lung allocation is based on waiting time. to prioritize patients with a poor prognosis and to reduce waiting list mortality the high urgency (hu) status was introduced in . to be considered for hu status there has to be a limited life expectancy on clinical judgement and all three transplantation centers have to audit this decision. the aim of this study is to analyze the potential effect of las on patients with cystic fibrosis (cf) who became hu or died on the waiting list. it would be expected that patients who became hu had a higher las. methods: from till in all cf patients placed on the hu waiting list, the median las ( th, th) was calculated at the moment of listing and at the moment the patients became hu. also for the cf patients who died on the waiting list the mean las (sd) was calculated at the moment of listing. results: from the patients on the waiting list patients had cf. of these patient were placed on hu list and died on the waiting list. in the cf patients that became hu the median las on the moment of listing was . ( . ; . ) . at the moment they were placed on the hu waiting list the median las was . ( . ; . )(p= . ) . the median las of the patients who died on the waitinglist was . ( . ) . this las did not differ significantly from the las of listing of the patients that became hu (p= . ). conclusion: the las does not detect the deterioration in patients with cf as diagnosed by clinical judgement. this may be due to the exclusion of specific prognostic factors of cf in the calculation of the las. besides that, the las does not differentiate cf patients on the waiting list with a high chance of mortality. introduction: lutx recipients have one of the highest rates of ia in solid organ transplantation causing high morbidity and mortality rates. nowadays antifungal prophylaxis is extensively used but clinical trials are rare. methods: all patients who received lutx in our hospital were included in this retrospective study. aspergillus airway colonization was defined as aspergillus cultured twice from airway specimens in the absence of ia or tracheobronchitis (tb). definition of ia and tb was according to literature. after the death of cf-patients due to ia, a prophylaxis protocol was introduced containing avoidance of use of the cell saver during the operation in pretx colonized patients to avoid hematological fungal spreading and targeted prophylaxis with itraconazole or voriconazole in all pre-and posttx colonized patients during months and inhaled amphotericin during hospital admission. results: a total of lutx were performed (in patients) ( % cf patients) from - - until - - . patients ( . %) were colonized with aspergillus pretx and patients posttx. only patients were colonized before and after tx. before introduction of the protocol patients ( / = . %) ( % cf patients) developed an aspergillus infection: ( . %) patients developed a. fumigatus tb and ( . %) patient suffered from ia: cerebral a. fumigatus infection (proven ia). two patients, both cf patients, ( / = %) died due toaspergillus infection (cerebral and tb).after introduction of the protocol only one a. fumigatus tb occurred ( / = . %) but no invasive fungal infection. conclusions: the rate of fungal infections in our lutx patients was comparable with data from literature. since introduction of azole prophylaxis protocol and avoidance of use of cellsaver no ia occurred. fischer, a. ; müllinger, b. ; arendt, t. ; bernhardt, t. ; hannah, k. ; scheuch, g. . activaero gmbh, gemuenden, germany; . biological products, bayer healthcare, leverkusen, germany; . activaero gmbh, gauting, germany; . talecris biotherapeutics, research triangle park, nc, usa background patient compliance during a study is an important factor in view of assessing the clinical effect of a treatment. this is especially true when patients administer the drug at home. usually, patient records, counting of returned doses or mechanical counters are used to track compliance, which may be biased by the study subjects. this report is about an aerosol study in cf which used a device for controlled breathing (akita® inhalation system, activaero, germany). the device works with a patient-individual smart card that records every single breath during a treatment including a date/time stamp in an encrypted manner. each patient's inhalation protocol can be displayed by loading the smart card into the proprietary "compliance manager" software. methods for this report, the data set of a recent controlled study (griese et al., ) was analyzed. cf-patients were instructed to inhale with the akita inhalation system at home for days. after the study, the smart cards were returned to activaero, and the inhalation records on the chip were analysed. we analysed the compliance of patients who participated at least days ( out of patients, others deemed to be drop-outs . most of the patients showed a dsc which is lower than the tdc, indicating that they had missing treatment days, which were compensated by additional inhalations on other days. we found patients with a dsc more than % lower than their tdc (max difference: . %). conclusion this aerosol study with home treatment demonstrated a high compliance rate for tdc and dsc. this information is more reliable for compliance than study participation in days alone. for future studies it is recommended to define in the protocol not only a minimum of study participation in days but also a minimum in tdc and dsc. in addition the compliance thresholds may be defined with regard to the drug's pharmacokinetic profile. in general, the inhalation record of the akita smart card provides an unbiased view of the inhalations treatments during a study especially when the subjects perform the inhalations at home. compliance calculations as shown above may be performed and linked to other outcomes of a study for validation. compliance data like these may also be used routinely by the treating physician in order to guide and supervise his patients. introduction: adaptive aerosol delivery (the i-neb ® aad ® system) has been developed to deliver precise, reproducible doses of aerosol into inhalation. i-neb utilizes a medication chamber, which incorporates a metering chamber to deliver a preset (metered) dose of aerosol. inhalation of hypertonic ( %) saline has been shown to aid mucociliary clearance in patients with cystic fibrosis. [ ] we performed an in vitro test to determine the emitted, delivered and residual doses of hypertonic saline from the i-neb aad system with . ml metering chamber, and a conventional jet nebulizer (lc plus ® ) with a ml fill. the results were then entered into a model to predict the likely lung dose from the in vitro tests, in order to determine the equivalent i-neb dose to the ml conventional jet nebulizer fill. methods:an i-neb device configured to operate at power level (of ) was fitted with a metering chamber designed to deliver a preset dose of . ml. the i-neb was weighed, loaded with ml of % saline and run on the cen simulated breathing pattern. this process was repeated using an lc plus nebulizer loaded with ml of % saline. aerosol was collected on a filter placed between a harvard pump and the device. emitted dose and residual dose were determined by gravimetric output, and delivered dose was determined by ion analysis. all tests were conducted in triplicate. results: as shown in table , the emitted dose approximated the delivered dose for i-neb, whereas for lc plus the emitted dose was approximately twice the delivered dose, due to the wastage of aerosol upon simulated exhalation. as i-neb has a delivered dose of mg, and i-neb has been shown to deposit . % of the dose in the lung, [ ] this would result in a lung dose of mg. the pari lc plus has a higher delivered dose, but the overall lung deposition is only % of the fill volume, i.e. mg. [ ] conclusion: the results of this test suggest that two treatments would be required in order to deliver an equivalent lung dose of hypertonic saline from an i-neb device fitted with a . ml metering chamber, compared with a ml fill in an lc plus jet nebulizer. references introduction: inhaled colistimethate sodium can be used for the eradication of pseudomonas aeruginosa in patients with cystic fibrosis. the tonicity of colistimethate sodium inhalation solution has been linked to the occurrence of bronchospasm in some patients. it has been suggested that this bronchospasm can be avoided by using an isotonic solution of colistimethate sodium. [ ] this can be complicated when using conventional jet nebulizers, since evaporation during nebulization tends to change the tonicity of the solution remaining in the nebulizer. however, because very little evaporation occurs within the i-neb medication chamber during nebulization, the tonicity of the loaded solution at the beginning and end of nebulization remains almost constant. aim: we investigated the effects of various saline concentrations upon the tonicity of two concentrations of colistimethate sodium solution ( . miu/ml and miu/ml). methods: diluent containing sodium chloride concentrations of: % (water for injection), . %, . %, . %, and . % (normal saline) were used to reconstitute vials of colistimethate sodium (promixin ® , profile pharma, uk). each vial was reconstituted with either or ml of diluent to make up miu/ml or . miu/ml colistimethate sodium solution, respectively. the tonicity of each diluent concentration/colistimethate sodium concentration combination was made up and tested in triplicate using an advanced micro osmometer (advanced instruments, norwood, usa). the results were plotted on a graph along with a line of best fit, to determine the diluent concentration that gave a mean tonicity closest to that of an isotonic solution. results: tonicity increased linearly with increasing concentrations of saline solution for both miu/ml and . miu/ml concentrations. the tonicity of the miu/ml solution was approximately mosm higher than the . miu/ml solution across the range of saline concentrations tested. the best fit line passed through the isotonic solution point ( mosm) closest to the . % saline concentration point. conclusions: the diluent that produces the closest approximation of isotonicity for the mean of . miu/ml and miu/ml colistimethate sodium concentrations was . % saline. references . transave, inc., monmouth junction, nj, usa; . activaero, gmbh, gauting, germany arikace™ is an inhalation formulation of a liposomal amikacin suspension that is designed to treat chronic pseudomonas aeruginosa infections in cystic fibrosis patients. liposome encapsulation of amikacin reduces nonspecific binding of this cationic aminoglycoside drug to the negatively charged mucus and biofilm surfaces and allows penetration and delivery of packets of highly concentrated drug to the otherwise protected bacteria. as nebulized and delivered to the lungs, arikace™ comprises % liposomal amikacin and % 'free' amikacin that is not entrapped by liposomes; free drug is produced by liposome leakage during nebulization. this profile provides an initial high peak concentration of amikacin followed by a sustained level as drug leaks from the liposomes. nebulized arikace™ with this profile was evaluated previously in human clinical studies using the lc star® nebulizer. although the . µm liposomes of arikace™ are efficiently loaded with drug, the expected effective dose in humans will require relatively large volumes of drug solution to be administered. to minimize treatment time and improve patient convenience we sought to find a nebulizer that would efficiently deposit drug and produce aerosol at a high output rate, while still producing the same level of free drug during nebulization. methods: nebulization of liposomal amikacin was compared using several nebulizers, including jet nebulizers: lc star® and lc sprint® (both from pari), and electronic mesh nebulizers: microair® ne u v (omron), aeronebgo® (nektar), and eflow® (pari). additionally, meshes of different pore sizes were examined for the microair® and eflow® devices. output rates were measured by gravimetric differences. droplet size distribution was assessed by a laser light scattering method and by cascade impaction; mass median aerodynamic diameters (mmad), geometric standard deviation (gsd), and fine particle fraction (fpf) (i.e., % droplet mass < µm). amikacin association with the liposomes was measured using a centrifugation-filtration assay. results: in terms of output rate, the order of performance was eflow® (~ . g/min) > lc sprint® > lc star® > aeronebgo® > microair®. while the aeronebgo® and microair® mesh nebulizers performed well with saline, their performance declined dramatically when nebulizing the liposomal amikacin solution, and, in fact, the microair device clogged. in additional studies with the eflow® where different meshes were compared, the l mesh was selected as it provided ideal aerosol properties (mmad = . µm, gsd = . , fpf > %) with a ratio of entrapped to free amikacin of approximately %/ %. importantly, from in vitro breath simulation studies it is estimated that about twice of the nominal drug dose is expected to deposit in the lungs compared to the lc star®. conclusions: for nebulization of liposomal amikacin, the eflow® configured with a l mesh provided optimum aerosol characteristics with a high output rate and ideal size for distribution throughout the lung. the eflow® reduces dose administration time not only because of its faster output rate but also because its higher deposition factor greatly reduces the amount of drug needed. zeman, k.l.; bennett, w.d. cemalb, university of north carolina, chapel hill, nc, usa many inhaled, therapeutic drugs have their site of action in the conducting airways, but may deposit elsewhere in the respiratory tract, resulting in unwanted side effects and waste. the quantity and location of particle deposition in the respiratory tract depends on both the particles' aerodynamic size and breathing pattern. in subjects with normal lung function, we evaluated three methodologies for their ability to deliver radiolabeled particles ( mtc-labeled sulfur colloid) to the conducting airways: . inhalation of µm mmad particles (devilbiss jet nebulizer) using a resting tidal volume and flow (mean . l and . lps); . inhalation from the same nebulizer using a very large inspiratory capacity volume and higher flow rate (mean . l and . lps); and . inhalation of larger . µm mmad (heart jet nebulizer) particles with a large tidal volume and very low flow rate (mean . l and . lps). gamma scintigraphy gave an estimate of % conducting airway deposition (%cad) by multiplying the percent of activity in the lungs immediately post-deposition relative to the total deposition (i.e. lung+mouth +esophagus+stomach) times the percent of activity cleared from the lungs over hours. %cad was %, %, and % for the three methods, respectively, significantly greater for the large particle, very slow inhalation technique when compared to the other two methods. the amount deposited in the mouth and larynx was %, and %. in addition, we evaluated protocols and above in a preliminary group of cf patients. for protocol , mean inhaled volume and rate was . l and . lps. mean inhaled volume and flow were . l and . lps for protocol . the %cad for the two protocols and were % and %, respectively. the amount deposited in the mouth and larynx was % and %. higher therapeutic value of a medication delivered to the airways where the primary defect is associated with cf disease, and with fewer losses to the extrathoracic airways, can be obtained by using a "very large particle/slow inhaled flow" routine when compared to normal or higher flow breathing associated with typical nebulizers. supported by cf foundation. positive effects of physical conditioning in cystic fibrosis (cf) have been reported for quality of life (qol) in addition to effectis on fitness and lung functions. the objective of this study was to identify the effects of different modes of training on qol in cf. cf-patients (age - yr., fev > %pred.) were randomized into groups: germany: unsupervised homebased training, hours per week, free choice of training mode and means (ut, n= ) and controls (con , n= ); switzerland: aerobic training (at, n= ) or weight training (wt, n= ) in a fitness center, x min per week, or controls (con , n= ). subjects in the training groups were asked to train for months. at study entry and after and months, qol was assessed by questionnaire and maximal physical working capacity (pwc, %pred) was determined during cycle ergometry (godfrey protocol). changes from baseline values were calculated and anova for repeated measures was used to test for differences among groups. weight training resulted in a significant decrease in qol (generic dimension) at and months compared with all other training modes including controls. there was no significant difference between at or ut and controls in qol during the program. however, there was a positive association between the change in pwc and the change in qol (r= . , p< . ) in the entire sample. in conclusion, physical training may not always result in an increase in ql in cf. possibly, the decrease in qol in the wt group may have resulted from tiredness induced by the training. thus, a different outcome might have been found with less intense training. positive effects may be achieved by improving aerobic fitness. supported introduction: exercise and exercise training programs are felt to be important to improve aerobic exercise capacity, muscle strength, lung function, and quality of life in cf-patients. recent studies in children and adults with cf have demonstrated an increase of motor performance after exercise training. less is known about trainability of motor performance in younger children with cf. the aim of this study was to assess the effects of a training program on motor performance in preschool children with cf. methods: preschool children with cf ( female and male patients, mean age . yrs; range - yrs, fev %pred. , ± . rage from . - . ) participated. at baseline (t ) and at the end of the training program (t ) the "motorik test (mot)" was used to assess motor performance and to evaluate training effects. components of motor performance tested with the mot are balance, agility and flexibility, strength, coordination, fine motor skills, reactivity, accuracy of movement). lung function in patients with cf was measured by spirometric techniques. the duration of training was - weeks ( times/week, minutes per session) with different kinds of sport activities. results: at t , strength and balance had increased significantly (p< . ). no other components of the mot increased, but the increases in strength and balance were enough to cause a significant (p< . ) increase overall motor performance, as indicated by an increase of . % in mq. the mq is the sum of all test-items of the mot. no correlation was found between lung function and motor performance. discussion: to our knowledge this was the first study that examined the effects of an exercise training program on motor performance in preschool children with cf. main findings of this study were that a training program of - week of duration improved some aspects of motor performance. the improvements may be explained by different kinds of sports activities during training when compared with activities before training. classification of motor performance of the tested children was normal (mq = . ± . ). this could be the reason that only some aspects of motor performance increased. parents of the children were asked about habitual physical activity at home. all children were physically active and some of the children participated in organized sports. a recent study showed that with an increase in age lower motor performance in children and adolescent with cf was seen compared to healthy children. we speculate that time spent in physical activity in preschool children with cf is comparable to healthy children. conclusion: an exercise program offered to preschool-children with cf may lead to an improvement in motor performance. pre-school children with cf have normal motor performance. to prevent a decline of motor performance, exercise programs should be available for preschool children. gruber, w. ; braumann, k.m. ; orenstein, d.m. ; huels, g. . dept. for sports and exercise, clinic sattelduene for children and adolescent, nebel/amrum, germany; . institute for sport and exercise medicine, university of hamburg, hamburg, germany; . school of medicine, university of pittsburgh, pittsburgh, pa, usa; . dept. of medicine, clinic sattelduene for children and adolescent, nebel/amrum, germany introduction: a decline in physical activity with age is one of the main problems in patients with cf. as a consequence, lower exercise capacity and a more rapid decline in lung function may be seen in those patients who are physical inactive. furthermore, motor performance is lower in children and adolescents with cf compared to healthy children of the same age. little attention has been paid to younger children with cf and motor performance. the aim of the study was to compare motor performance in preschool-children with cf with healthy children of the same age. methods: children with cf (mean age . yrs; range - yrs) and healthy children (mean age . yrs; range - yrs) participated. the "motorik test" (mot) was used to assess motor performance. the mot consisted of test-items which evaluated seven different components of motor performance (balance, agility and flexibility, strength, coordination, fine motor skills, reactivity, accuracy of movement). lung function in patients with cf was measured by spirometric techniques results: results of the mot showed no difference either for single testitems or for parameter "motorische quotient (mq)" (p> . ). this parameter classified motor performance of all aspects tested with the mot. classification of children with cf and of healthy children was normal. mean value for parameter mq (cf: . ± . vs. healthy . ± . ) was slight higher in patients with cf than in healthy children (p> . ). differences between healthy and cf for different components of motor performance were not significant (p< . ) discussion: the mot is a reliable and valid test method in germany to determine motor performance in younger children. to our knowledge this was the first study to examine motor performance in preschool-children with cf. furthermore, we compared patients with cf and healthy children. we observed no differences between groups for motor performance. in older children with cf, lower motor performance has previously been found compared to healthy children of the same age. we do not have any information about the level of habitual activity in tested healthy children. we therefore speculate that time spent in physical activity in cf is similar to that of healthy children at this age. a recent study showed a decline in physical activity in cf when age and problems during physical activity increased. we think that motor performance is normal in children with cf up to an age of yrs. when age increased, time spent in physical activity decreases (treatment, school) and therefore motor performance decreases. conclusion: motor performance is normal in preschool-children with cf compared to healthy children. to prevent a decline or to maintain motor performance it is recommended to motivate cf-children from early infancy to participate in sports activities or other physical activities to maintain or to increase their physical fitness. . respiratory medicine, the hospital for sick children, toronto, on, canada; . respirology, st. michael's hospital, toronto, on, canada; . respiratory medicine, montreal children's hospital, montreal, qc, canada purpose: the habitual activity estimation scale (haes) questionnaire has been shown to be a feasible tool to measure physical activity however the reliability has yet to be determined in cf populations. we therefore assessed the reliability and validity of the haes questionnaire in paediatric and adult cystic fibrosis (cf) populations. methods: fourteen ( male, female) patients aged . + . yrs with cystic fibrosis from the cf clinics at the hospital for sick children and st. michael's hospital participated in this study. participants were clinically stable at the time of the study (fev > % predicted) and participating in their 'habitual' physical activity. to assess test-retest reliability, patients completed each of the haes (schneiderman-walker et al., j pediatr. ; ( ): - .), and a validated -day activity diary (bratteby et al., eur j clin nutr. ; ( ) : - ), and wore an actigraphtm tri-axial accelerometer for two consecutive weeks. validity was assessed by comparing the activity results of each of the three instruments over a single week time period. results: intra-class correlation coefficient estimates of reliability for the haes, diary and accelerometer were . (p< . ), . (p< . ), . (p< . ), respectively. validity was estimated by comparing the results from each instrument using a one-way anova with block design. there were no overall differences among the participants' activity results as estimated by the haes, diary and accelerometer. furthermore, there were no significant differences between activity measures among the instruments when broken into morning, afternoon, or evening periods, or between measures from weekday or weekend days. while there were no significant differences among the instruments when recording 'very active' intensity levels, they did detect differences during the inactive / somewhat inactive (p = . ) and somewhat active (p = . ) intensity levels. conclusion: the findings of this study suggest that the haes questionnaire is a reliable and valid instrument that can be used to assess activity levels in patients with cystic fibrosis. in agreement with others, our patients found it easiest to recall and record accurately those periods in which they are participating in vigorous activity. acknowledgement: this research was supported by the canadian cystic fibrosis foundation. . respiratory medicine, hospital for sick children, toronto, on, canada; . respiratory medicine, montreal children's hospital, montreal, qc, canada; . respirology, st. michael's hospital, toronto, on, canada objective: previous work showed a relationship between habitual physical activity (hpa) and decline of lung function (fev ) in cf females (sneiderman-walker, j peds : , ) . this study only included a small number of patients and the follow-up period was limited to months. the purpose of this study was to evaluate daily activity levels and decline in fev in a larger cohort over a longer period of time. methods: a total of (n= female) patients with cf (age - yrs) were studied over a six year period at the hospital for sick children, st. michael's hospital and montreal children's hospital. at each quarterly cf clinic visit, patients performed pulmonary function tests to determine fev and completed the habitual activity estimation scale (haes). weekday total activity (wdta), expressed as hours/day (h/day), was calculated from the sum of 'very active' (wdva) and 'somewhat active' (wdsa) categories as previously described. a repeated measures linear regression was performed to evaluate the relationship of fev and hpa over time. results: at baseline, mean fev was % predicted (range - % pred). mean baseline wdta was . h/d (wdva = . h/d and wdsa = . h/d) similar to that previously reported. subjects were divided into high and low activity groups based on the group median wdta. those in the low activity group had a significantly (p= . ) steeper rate of decline (- . % predicted per year) compared to those in the high activity group (- . % predicted per year) . unlike in the in the previous study this difference was observed in males as well as females. conclusions: six year follow-up of this patient cohort has shown that higher activity levels are clearly associated with a slower rate of decline of fev . we are currently evaluating whether strategies aimed at increasing physical activity will have an impact on lung function decline in cf patients. background: knowledge of exercise principles, benefits, and techniques has not been assessed in children with cystic fibrosis (cf) or their parents. regular exercise is a recommended cf treatment regimen that is often not followed, but one which might improve cardiovascular fitness, lung function, sputum clearance, and health-related quality of life. further, aerobic fitness, measured as peak oxygen uptake (vo ), is positively related to survival in cf. construction of a reliable and valid measure of exercise knowledge is necessary to assess level of knowledge and study its relationship to exercise behavior. the aim of this study was to develop and test a measure of exercise knowledge for pediatric patients with cf and their parents. methods: we constructed a -item exercise knowledge test (ekt) and then examined its psychometric properties. a comprehensive review of the exercise literature guided the formulation of objectives and development of items. to establish content validity, a panel of experts (cf physician, two exercise physiologists, and a clinical cf nurse) evaluated the objectives and test items for relevance, clarity, and accuracy. after feedback from the panel, we revised the ekt through an iterative process. in consultation with a reading level expert, we wrote the ekt items so that the test could be administered to children and adults. a measurement and evaluation expert also reviewed the test, and additional revisions were made. during routine clinic visits, the ekt was administered to subjects with cf and parents. the cf subjects included boys and girls, age to years, fev range: - % predicted. the parents had an average age of years and most (n= ) were female. results: the ekt includes items, true-false and multiple choice. it is self-administered, yields a single summed score, and has a flesch-kincaid rd grade reading level. the means were . + . ( % correct) and . + . ( % correct) for the cf subjects and parents, respectively; % of the parents scored between and . internal consistency reliability estimates were . for the children and . for the parents, reflecting both the multidimensionality of the material and the lack of variability in the parent scores. item difficulty ranged from . to . for the cf subjects and from . to . for the parents. in both groups, the discrimination values were positive for all items with difficulty values less than . . conclusions: we were able to develop a measure of exercise knowledge with an acceptable reading level for children with cf and their parents. this sample of cf subjects and parents showed substantial exercise knowledge. the ekt can be a useful tool to identify gaps in exercise knowledge in cf patients and their parents, develop educational programs to increase knowledge, and examine how knowledge relates to exercise behavior in children with cf. supported by cystic fibrosis foundation therapeutics, inc. purpose: although physical activity is routinely recommended for adolescents with cystic fibrosis, past research suggests that many patients do not regularly participate in physical activity. there may be a variety of reasons, both related to disease and otherwise, for this inconsistent participation. in this study, qualitative methods were used to describe factors that facilitated or served as barriers to physical activity in adolescents with cf and compared these factors to those in a healthy peer group. methods: ten subjects with cf and ten subjects without cf aged - volunteered for this study. each subject participated in two, open-ended semi-structured interviews with - weeks between each interview. subjects were questioned about their current and past physical activity as well as the benefits and barriers to participation. the adolescents with cf were also asked about their perceptions of physical activity on their own health and other adolescents with cf. interviews were transcribed and coded by three investigator groups. analysis was conducted using the grounded theory approach at two points in the study, following each interview and again at the completion of all interviews. at the first point, individual interviews were coded using line-by-line coding, and similar information was grouped into categories. in the second interview, categories were confirmed and subjects were also asked to elaborate or clarify points from the first interview. interviews were continued until themes reached a saturation point. upon completion of all interviews, data for each group were organized by question. data categories appearing throughout the interviews became major themes describing facilitators and barriers to exercise. the major themes were identified by the three researcher groups and then through collaborative group analysis. results: the central theme for both groups was perceived importance of physical activity for health benefits. for the cf group, facilitators and barriers were both psychological and physical. physical benefits were categorized as either relating to their general health (such as feeling energized) or as benefiting their disease (such as improving breathing). in the non-cf group, facilitators included social factors in addition to general health-related and psychological benefits. in the non-cf group, barriers were categorized as either internal or external, with the internal barriers being similar to the cf group (physical and psychological), however, the non-cf participants also indicated external barriers (such as time) not articulated by the cf group. conclusions: in general, we found very similar facilitators and barriers to physical activity in adolescents with cf and those without. however, the adolescents with cf strongly indicated that physical activity would have positive effects on their physical health. further work is needed to determine ways to accentuate facilitators and remove barriers to improve physical activity levels in adolescents with cf. this project was supported by a research grant from the cardiovascular & pulmonary section, apta. lloyd, e. ; dodd, m. . paediatric cystic fibrosis service, central manchester and manchester children's university hospital, manchester, united kingdom; . adult cystic fibrosis centre, wythenshawe hospital, university hospital of south manchester nhs foundation trust, manchester, united kingdom background: training in the skills of communication and self care are considered important components of transitional care . physiotherapists work to involve families and young people to encourage this independence. the cf manager training programme (cfmtp) is a recognised tool for measuring age appropriate tasks in cf care. aim: the aim of the study was to survey the current levels of autonomy in all patients with cystic fibrosis in the north west of england from birth to years to provide a baseline measure for encouraging autonomy in preparation for transition. method: three areas of the cfmtp were selected for the survey: physiotherapy (p), inhalation therapy ( it) and communication (c) for the age groups: - . , . - , - , - , - , - , - , - , - ,and + years. physiotherapists from all the north west cf clinics were invited to assess all the patients under their care. data collected were age, gender and whether the patients skills fell "below", "same" or "above" the age appropriate self management tasks as described in the cfmtp. 'not applicable' was indicated where the skills did not apply. results: / clinics responded. out of a total of patients in the nw were assessed, three patients were excluded. population by clinic ranged from - . population by age category: ( - . years) ( . - years) ( - years) ( - years) ( - years) ( - years) ( - years) ( - years) ( - years and ( + years). / ( %) were male. for p (n= ), it (n= ), c (n= ), %, %, % = below, %, %, % = same, %, %, % = above respectively. there were no gender differences. conclusions: overall scores revealed that / rd of patients were gaining age appropriate independence in all areas. there was the least autonomy with it. it was rare for a child to be setting up and cleaning equipment regularly at - years, but this continued throughout the adolescent years. overall % were 'below' for p and it; this was highest after the age of years. autonomy with physiotherapy appeared slow to develop. some categories in cfmtp were different from our practice for e.g. patients are not invited to be seen alone in our clinics until years v - years and this may account for the lower scores in communication below this age. this study has highlighted that some of our patients are not fully independent in the time up to transfer. we need to encourage independence from an early age with all aspects of care and integrate the process into our routine clinical practice. refs mcdonagh and viner bmj ; : - , . parents' guide to the cf manager training programme. children's hospital of eastern ontario planner, s. ; morrison, l. . physiotherapy, gartnavel general hospital, glasgow, united kingdom; cystic fibrosis (cf) causes a deterioration in lung function and exercise tolerance. assessing exercise capacity is therefore essential in order to monitor changes in disease severity. the -minute walk test ( mwt) and minute step test ( mst) are validated and widely used outcome measures for identifying exercise capacity in patients with cf. exercise testing is part of annual review of all patients in the west of scotland. previous studies identified that the mst was a sensitive measure of exercise tolerance, but did not successfully challenge patients with mild or moderate lung disease as defined by fev(sub) (/sub)> % (morrison ) . further analysis of the mst, where step height was increased to inches did not show any difference in sao(sub) (/sub). decline or rate of perceived exertion (rpe) in patients with mild disease. the chester step test (cst) was developed to assess aerobic fitness which is used in the uk cardiac population for exercise prescription (sykes ) . it is a minute progressive, sub-maximal test with a variable step height ( - inches) , making it suitable for those with a wide range of exercise capacities. in addition, cst results extrapolate to a mets value (oxygen utilisation: met = rate of oxygen utilisation at rest) as an outcome measure which can facilitate exercise prescription based on established values for physical activities. we aim to determine whether the cst is a more sensitive measure of exercise capacity than the mwt or mst when considering decrease in sao(sub) (/sub) and rpe. patients ( aged - mean fev(sub) (/sub) . l) with mild-moderate cf performed the cst and mwt and results were correlated with fev(sub) (/sub). decrease in sao(sub) (/sub), increase in hr and rpe scores were also compared between the cst, mwt and recent mst data. patients were exercised to a symptom limited maximum which differed from the cardiac cst where patients are exercised to % of maximal hr. the cst appears to be more challenging as only patients completed it, all with an fev(sub) (/sub)of > % predicted, whereas in the mst and the mwt all patients completed the test. mets levels for the cst were weakly correlated with fev(sub) (/sub)(r= . ) and the mwt (r= . ) . this could be explained by the narrow range of mets data available or the size of the sample population. there were significantly greater rises in hr (p= . , p= . ), decrease in sao(sub) (/sub) (p= . , p= . ) and rpe (p= . , p= . ) , between the cst, mst and mwt respectively, suggesting that the cst is a more sensitive measure of cardiorespiratory effort. conclusions the cst appears to be a more challenging exercise test for those with mild to moderate disease and therefore may be a better reflection of exercise capabilities. cst results are useful for prescribing exercise and monitoring programmes appropriately for this patient group. further study could determine whether the cst is also suitable for those with severe disease. lee, a.l. ; button, b. ; holdsworth, m. ; holland, a. . physiotherapy, the alfred, melbourne, vic, australia; . latrobe university, melbourne, vic, australia musculoskeletal pain is prevalent in cystic fibrosis (cf). while the chest and back are frequently reported regions of acute or chronic pain, it is unclear if pain in these areas is related to disease severity or respiratory symptoms. manual therapy and postural advice has been shown to alleviate pain, but the effects of a combined approach of musculoskeletal physiotherapy and massage has not been studied. the aim of this study was to identify the primary regions of musculoskeletal pain, the relationship between pain severity and respiratory symptoms and to examine the effect of musculoskeletal physiotherapy techniques and soft tissue therapy, including remedial massage on pain and ease of breathing (eob) in adults with cf. one hundred and twenty-nine adults with cf ( with acute exacerbation, post lung transplant) aged ± years (mean ±sd) with fev(sub) (/sub) of ± % participated in this study. following assessment of primary pain regions, each subject underwent a single treatment session including spinal joint / intercostal mobilisation and soft tissue therapy. pain and eob on a visual analogue scale were measured before and after treatment. changes were compared using paired-samples t-tests. pain was frequently reported in the thoracic spine region ( % of subjects), followed by the shoulder region ( %), cervical spine region ( %) and chest wall region ( %). equivalent ratings of pain and eob prior to treatment were reported for all regions of pain. eob rating prior to treatment were worse in those with low bmi (r=- . , p= . ) and low fev(sub) (/sub) (r=- . , p= . ). a single treatment session was associated with reduction in pain ( %ci . to . , p< . ) and improvement in eob ( %ci . to . , p< . ), irrespective of clinical status. improvement in pain was equivalent for all primary pain regions. however, greater improvement in eob was evident in subjects with shoulder pain compared to other regions ( %ci - . to - . , p= . ). a combination of musculoskeletal physiotherapy techniques and soft tissue therapy reduces musculoskeletal pain and improves eob in adults with stable cf, during an acute exacerbation and post lung transplantation. service cystic fibrosis is characterized by an excessive production of airway secretions responsible for bronchial obstruction and recurrent infections of the respiratory tract. the transport by ciliary activity and cough may be dependent on the unsteady rheological properties of the respiratory mucus such as thixotropy and shear-thinning properties which correspond to a decrease of viscosity with time or flow rate, respectively. we have previously shown that respiratory mucus with high shear-thinning and thixotropic properties is better transported by the cough mechanism (zahm et al, eur. respir. j., ) . to promote mucus clearance and to finally expectorate the mucus by a cough manoeuvre, an innovative device, the airhelp, has been developed and aimed to improve chest physiotherapy effectiveness. during a prolonged expiratory manoeuvre, the airhelp delivers negative pressure variations (maximal amplitude: - kpa) at an oscillatory frequency of hz. the aim of the present work was to test the effect of the airhelp device on the in vitro clearance of mucus by airflow. a plexiglass tube of mm in diameter and mm in length has been connected by one part on the airhelp and by the other part on a l thank mimicking the lung compliance. a µl drop of mucus simulant at different concentrations (viscogum at . % or . % with actigum at . % to . %) or of respiratory mucus, was deposited within the plastic tube and the distance travelled by the sample under a sec-airflow was measured. twelve respiratory mucus samples collected from cf patients were analyzed and the viscosity of the samples was measured before and after the airhelp experiment. we observed a significant (p < . ) and negative relationship (r = - . ) between the viscosity of mucus simulants and oscillatory airflow transport: the lower the viscosity, the higher the mucus transport by oscillatory airflow. using cf respiratory mucus samples, we observed that without the oscillatory airflow, no transport occurred, whereas when the samples were submitted to the oscillatory airflow, a significant increase in mucus transportability was measured. in addition, the viscosity of the cf respiratory mucus samples was significantly decreased after oscillatory airflow treatment ( ± pa.s to ± pa.s, p < . ). these results demonstrate that the mucus transport efficiency by an oscillatory airflow is dependent on mucus viscosity and that the improvement in mucus transport is related to the thixotropic and shear thinning properties of the airway mucus. we conclude that the airhelp device may improve chest physiotherapy effectiveness. potter, e. ; nufer, j. ; cullina, j. , ; quinton, h. ; jain, m. , ; mccolley, s.a. , . northwestern university feinberg school of medicine, chicago, il, usa; . children's memorial hospital, chicago, il, usa; lebanon, nh, usa; . northwestern memorial hospital, chicago, il, usa socioeconomic status (ses) significantly impacts health outcomes in cystic fibrosis (cf). the cystic fibrosis foundation (cff) is currently using median income estimated by zip code from the us census of the population for ses risk adjustment of data reported publicly from the cff patient registry. median income estimated by zip code is an "ecologic" variable that may misclassify patient and family income. in order to more fully assess the impact of ses on cf health outcomes, the cff began to ask centers to collect data on household income directly from patients and families. these data were captured for . % of patients and families in and . % in in the national registry. we report a method of collecting ses data from children and adults implemented at the children's memorial hospital and northwestern university cystic fibrosis center, and compare directly collected income to income based on zip code. methods: a short survey with the questions on household composition, income, and education level from the cff patient registry was developed. a letter from the center director and adult program director was mailed to patients and families informing them of the survey's purpose and confidentiality measures, i.e. responses would be seen only by the individual entering the data and identified by cff id number. the survey was distributed to cf patients and families in clinic by clerical staff. completed surveys were placed in an envelope and sealed by the patient or family. both directly collected income and income from zip code was classified into groups (<$ k, - k, - k, - k, - k, - k, - k, - k, and > k) . percent concordance and spearman's rank correlation were calculated. data were used for patients who provided data in ; otherwise, data were used. each patient's data was used only once in the analysis. results: unique patients were identified, pediatric and adult patients. eighteen percent of pediatric and % of adult patients preferred not to answer income questions or did not complete the survey. the mean income by zip code was $ k for patients who did not report income data and $ k for the entire group. for the responses, reported income data was moderately correlated with income by zip code (rho= . , p< . ). concordance between the categories was %. the correlation was stronger for pediatric patients (rho= . , p< . ) than for adults (rho= . , p= . ). re-classifying income as "low", "medium" and "high" (<$ k, $ - k, >$ ) led to a concordance of %. conclusion: survey methods that protect patient and family confidentiality result in good return rates of full ses data from patients and families. zip code derived median income shows moderate concordance with reported income. comparing the associations of the forms of income data with important cf outcomes needs to be done in a larger data set. we acknowledge the cystic fibrosis foundation, gerald o'connor, kathryn sabadosa, and participating patients and families. the patient registry provided a unique opportunity to assess changes in the epidemiology of respiratory pathogens in cf. while the incidence of p. aeruginosa remained stable, the prevalence decreased, suggestive of the impact of antibiotic eradication strategies. in contrast, the increasing incidence and prevalence of s. aureus and mrsa may reflect improved microbiological surveillance and laboratory techniques. the trends noted for b. cepacia complex may reflect successful implementation of infection control strategies. future studies are needed to better define the association between these observed trends and improving care for cf patients. vanderwyden, a. , ; drumm, m.l. , ; schluchter, m. . pediatrics, case western reserve university, cleveland, oh, usa; . epidemiology and biostatistics, case western reserve university, cleveland, oh, usa; . genetics, case western reserve university, cleveland, oh, usa in the genetic modifier study (gms) of lung disease of cystic fibrosis (cf), patients, homozygous for the ∆f mutation, were classified as having either severe or mild lung disease, as defined by the lowest or highest quartile of forced expiratory volume in one second (fev ) and a linear model was fit from these patients' longitudinal data (drumm , schluchter . while these models successfully dichotomized patients for the association study, we assessed whether a single slope model could be improved. here we have begun to compare models with one, two and three slopes, each representing different age ranges, for their use in this type of association study. as an example, interleukin- (il- ), a neutrophil chemoattractant, associates with the severe lung inflammation seen in cf patients. we have observed the tt genotype of the il- snp rs , correlated with severe pulmonary function in the gms sample of patients, relative to the aa and at genotypes of this snp. in a replicate study of patients, with cftr genotypes associated with exocrine insuffiency, longitudinal linear mixed models were used to further characterize the decline in lung function over time as associated with the il- snp, rs . three linear regression models of fev % predicted of patients were fit over age and compared with likelihood ratio tests. the three models differed with respect to the number of nodes. the first model had a single slope while the second and the third were piecewise linear models, with nodes at age , and ages and , respectively. age was chosen as the first node, as by this age most cf patients have reached puberty, an event believed to coincide with changes in pulmonary function. the second node, age , was arbitrarily chosen as a point in the third decade, as survivor effect becomes a significant issue during this period. when compared to the single slope and two slope models, the three slope model with nodes at age and age better explained the pulmonary function of this study (p< . , - loglikelihood chi-squared tests). when the explanatory variable, il- rs genotype, was added, the single slope model and the three slope model were again compared. the three slope with nodes at age and age again resulted in a better fit of fev % predicted over age as correlated with rs genotype (p< . , - loglikelihood chi-squared test). estimates of fev % predicted at ages , , , and for each rs genotype (aa, at/ta, or tt) were determined using the three slope model (p< . for all estimates). other explanatory variables, like gender and survival (p< . ), were added to further elucidate the relation between il- genotype and lung disease phenotype. we propose to use this piecewise three slope model with nodes at age and age to look at the pulmonary function of patients in the cf foundation registry data to better explain the decline in fev % predicted over time seen in cf patients. (supported by hl- and grants from the cf foundation) stephenson, a.l. purpose: the purpose of this study is to determine the annual incidence of hospitalizations for individuals with cf living in ontario and to examine predictors of hospitalization, specifically gender. methods: this is a retrospective cohort study from to , using newly linked clinical and administrative databases. the canadian cf foundation patient data registry (cpdr), contains detailed clinical information on all cf patients receiving care at one of accredited cf centres across canada. the institute for clinical evaluative sciences (ices), holds linked administrative databases containing information on all publicly reimbursed health care services delivered in ontario. canadian institute for health information (cihi) discharge abstracts database (dad), ontario health insurance plan (ohip), and homecare databases were used for this study. the cpdr was probabilistically linked (automatch software) to the ices administrative database using name, gender and date of birth. all individuals were then linked to the cihi dad, ohip, and homecare databases using unique numeric identifiers. with these databases, longitudinal records for each individual were created. cihi-dad, ohip, and homecare claims data were used to calculate the number of hospitalizations per year for pulmonary infections. males and females were analyzed separately to elucidate any gender disparities. other predictor variables include age, geographical location, number of clinic visits, socioeconomic status (income quintile) as well as clinical variables such as pulmonary function tests, nutritional status, diabetes mellitus, sputum bacteriology and pancreatic status. results: the cpdr contained data on individuals with cf followed within canada between - . of those individuals, could be found within the ices administrative databases using probabilistic linkage. of those individuals matched to the administrative databases, ( . % female) had hospitalizations. a total of , ohip claims were made during this -year period which represents any encounter between an individual with cf and a physician in ontario. multivariable analysis of hospitalization predictors is in progress. zhang, z.; lai, h. uw-madison, madison, wi, usa the cff practice guidelines recommend adjusting for genetic potential when evaluating height status in children with cf. however, calculation of adjusted height percentile is not recommended due to the complexity of method involved in such calculation. instead, a simple method to estimate a target height based on mid parental height was recommended. however, this target height includes a -cm confidence interval, which spans most of the channels on the growth chart. therefore, a child's unadjusted height may be considerably below the target height, yet remains above the lower bound of the target height range. in addition, there is a paucity of data on the associations between adjusted height to lung disease outcomes to justify whether adjustment for genetic potential is necessary. the objective of this study is to compare two methods of incorporating genetic potential in identifying short stature, namely, the cff's target method and the method developed by himes et al (pediatr ; : - ) , which applies positive adjustments to children with short parents and negative adjustments to those with tall parents. data from - cff registry were utilized. a total of children born between - who had complete height data from age - years and their parental height data were analyzed. short stature was defined by unadjusted height < th percentile, unadjusted height below the lower bound of cff's target height, or himes' adjusted height < th percentile. our results showed that adjusted height percentiles are consistently lower than unadjusted height percentiles, with an average difference of . z-score unit between ages - years and . z-score unit between ages - . proportionately more children were classified as short stature based on himes method compared to unadjusted height ( % vs. %, p = . ). in contrast, proportionately fewer children were below the lower bound of cff's target height ( %) compared to unadjusted height < th percentile ( %), p < . . among children with average parents, unadjusted and adjusted height percentiles were similar. however, among children with short parents (< th percentile), the percentage children with of short stature decreased from % with unadjusted height to % with himes' adjusted height and % with cff's target height method. among children with tall parents (> th percentile), the percentage of short stature increased from % with unadjusted height to % with himes method and % with cff's target height method. taken together, these results demonstrate that, without incorporating genetic height potential, - times more cf children who have short parents would be classified as short stature, while times fewer cf children who have tall parents would be classified as short stature. further analyses show that, compared to unadjusted height percentile, himes adjusted height percentile is more sensitive to, and has stronger association with, percent predicted fev- . in conclusion, our findings provide evidence that genetic potential should be incorporated in evaluating short statue in cf children, particularly for children with short or tall parents. the cff's target height method and himes method differ significantly in identifying short stature in cf children with short parents. cohort study of individuals in the cff patient registry from - . all individuals years of age or older and diagnosed before age were included. the new, persistent mrsa infection cohort was defined by having at least two cultures negative for mrsa over a two-year lead-in period followed by at least two mrsa positive cultures. individuals with only one mrsa culture (transient infection) were excluded. we developed multiple linear regression models using generalized estimating equations to assess the effect of mrsa on fev %predicted (%fev ) and rate of change of %fev . results: during the study period , individuals cultured mrsa. of these, , ( %) cultured mrsa only once (transient infection) and were excluded from subsequent analysis. , individuals met the criteria for new and persistent mrsa infection. , met the criteria for never having mrsa resulting in a total study cohort of , . participants were followed for a median of years. the median time to first isolation of mrsa in the persistent mrsa cohort was . years and the mean number of positive mrsa cultures per patient was . . a comparison of baseline characteristics between the persistent mrsa and never mrsa cohorts revealed the mrsa cohort to be younger ( . vs . years p< . ), equivalent in lung function (%fev . % vs . % p=ns), and with higher likelihood of methicillin sensitive staph aureus colonization ( % vs. . % p< . ). . years into the study period (the median time of acquisition for new mrsa), the mrsa cohort had a lower %fev ( . % vs . % p< . ), and averaged twice as many hospital admissions per year ( . vs . p< . ) and home iv courses per year ( . vs . p< . ). in an unadjusted analysis, the presence of mrsa was associated with a mean %fev that was . % lower than the mrsa cohort ( %ci . %- . %). however, after adjusting for sex, age, pancreatic status, p. aeruginosa, and b. cenocepacia, the presence of mrsa was associated with a mean %fev . % lower ( %ci . %- . %). most importantly, an analysis investigating the interaction between mrsa and time, after adjusting for confounders, indicated no statistically nor clinically meaningful difference in the mean rate of lung function decline between the two groups. conclusions: approximately one-third of patients who culture mrsa do so only once and do not subsequently develop persistent mrsa infection. mrsa infection occurs in a group with more severe structural lung disease as measured by fev , and frequent hospitalizations and iv antibiotics are strongly associated with mrsa acquisition. after adjusting for confounders, mrsa infection is not statistically significantly associated with a more rapid decline in %fev over time. simmonds, n.j. , ; macneill, s. ; cullinan, p. , ; hodson, m.e. , . department of cystic fibrosis, royal brompton hospital, london, united kingdom; . national heart and lung institute, imperial college, london, united kingdom introduction: disentangling the influence different factors have on long-term survival in cf is complex. there are a myriad of influences (including environmental, healthcare-related, psychological and socioeconomic) which may be important, as there is generally a poor genotype-phenotype correlation. the aim of this case-control study was to identify these factors. the cf database at the royal brompton hospital was used to identify long-term survivors. they were classified as cases and were patients who had reached years of age (without transplantation). each case was agematched with at least one control who died of cf (or a cf-related condition) or was transplanted before reaching years of age. late diagnosis patients were excluded. conditional logistic regression models were used to identify potential influences on survival. results: cases and controls were analysed, producing matched pairs. % of the patients were pancreatic insufficient. of the many factors investigated, those resulting in increased probabilities of survival included: increased body mass index (or= . , % ci . - . ), fev (or per % increase= . , ) at transfer to the adult clinic (after adjusting for age and sex) and the use of oral antibiotics before attending the adult clinic (or= . , . - . ) after adjusting for age at first attendance. factors associated with a reduced probability of survival included: cf diagnosis < years old (or= . , . - . ); initial presentation of chest symptoms or malabsorption (or= . , . - . and or= . , . - . , respectively); referral from a paediatric clinic in a deprived area (or= . , . - . ); pneumothorax before transfer to the adult clinic (or= . , . - . ) after adjusting for age at first attendance; and s. aureus or p. aeruginosa colonisation before years of age (or= . , . - . and . , . - . , respectively). factors not influencing survival included: sex, h. influenzae colonisation before years of age, development of diabetes before years of age, major haemoptysis before transfer to the adult clinic, parents' occupation, number of siblings (cf and non-cf) and school achievements. in a very carefully matched study we failed to identify major non-clinical determinants of long-term survival in early diagnosis cf. findings suggest that the majority of significant factors were directly related to optimal physical parameters, the use of oral antibiotics, avoiding bacterial colonisation and a low pneumothorax rate. adler, a. , ; bilton, d. ; haworth, c. ; gunn, e. ; shine, b. . addenbrooke's cambridge university hospitals, cambridge, united kingdom; . papworth hospital, papworth everard, united kingdom; . oxford centre for diabetes and endocrinology, oxford, united kingdom background and aims: although the prevalence of diabetes in patients with cf (cfrd) is high, few prospective studies exist, and even for genet-ic factors, cross-sectional studies may bias the magnitude of associations. this study sought to identify risk factors for cfrd from a predominantly white cohort of individuals with cf in the united kingdom. methods: , individuals aged - were identified from the uk cf database, a registry of patients coordinated by the uk cystic fibrosis trust with data from over specialists centres from england, scotland and wales, countries which provide medical care free of charge. of the patients, , had no diabetes at baseline ( - ) , and also had at least one follow-up annual visit. diabetes was defined as either a physician diagnosis of diabetes, a blood glucose of > . mmol/l two hours following an oral glucose tolerance test, or treatment with insulin or oral hypoglycemic drugs. follow-up was calculated as time from baseline to the first detection of new diabetes or censoring. risk factors included clinical, genetic (functional classes i,ii,iii vs iv,v), and anthropometric characteristics measured at baseline. survival analyses were limited to patients with complete data. cox proportional hazards modeling was used to estimate the magnitude of the association between potential risk factors and incident diabetes. one-way interactions with sex were tested. results: the median age of entry into the cohort was years and bmi was . kg/m . % were male, and % were white. patients developed diabetes during , person-years of follow-up (mean . years); the incidence was . % per year. patients who developed diabetes were more likely in univariate analyses to be older, have a high body mass index (bmi), bacterial pulmonary infections, liver and pulmonary function abnormalities, poor oxygen saturation, a history of organ transplantation, supplemental feeds, and take pancreatic enzymes or bile acids. in addition, patients with class iv,v genotypes were less likely to develop diabetes relative to patients with other genotypes, as were patients screened for cf at birth. not associated with incident diabetes was age at diagnosis of cf and ethnicity. in multivariate analyses (n= , ) age (hazard ratio . per year, % ci . - . ), female sex ( . ( % ci . - . ), % predicted forced expiratory volume in second ( . , . - . per % decrement), dose of pancreatic enzyme replacement ( . , . - . ), above vs below median dosage, use of bile acid supplements ( . , . - . ) , and genotype class i,ii, iii ( . , . - . ) relative to class iv/v. these associations were not confounded by bmi or history of transplantation. there were no significant interactions between sex and other risk factors. conclusions: the study confirms the high incidence of cfrd, and shows that patients with class iv/v genotypes are less likely to develop diabetes independent of other cf-related complications. females are disproportionately at risk for diabetes which is not explained by a higher prevalence of known risk factors nor by effect modification. cystic fibrosis children are at increased risk for hearing disorders due aminoglycoside exposure, mucopurulent upper respiratory tract infections, and increased inflammatory responses. pure tone audiometry is the standard instrument used to determine hearing loss. however, it can be expensive and time-consuming to use audiometry for routine hearing screening. hearing questionnaires have been used as a screening tool to assess possible hearing loss in otherwise healthy populations. what are the results of hearing questionnaires administered to pediatric cf patients? does cf patient age or ethnicity increase the likelihood of hearing loss as determined by a hearing questionnaire? a hearing questionnaire (english and spanish versions) was administered to pediatric cf patients over a week period at our accredited cf center. data collected included demographic information. inclusion criteria: age м years and in baseline health status. possible hearing loss was defined as at least "yes" responses (> ) to the quesions administered to the patients. fisher's exact test was used to perform the analyses. a total of cf patients were seen in the cf clinic during the study period. cf patients completed the hearing questionnaire. mean age was . ± . years (median . years). there were males and females; were classified as hispanic and were classified as caucasian. patients were older than . years (the median age) and patients were less than . years. patients who were older than age . years had a score of > and patients < age . years had scores > (p= . , ns). thus, of cf patients ( %) were classified as having possible hearing loss as per their questionnaire scores. of hispanic cf patients had hearing scores > and of caucasian patients had hearing score > (p= . , ns) . we found that a significant proportion ( %) of our cf children may require formal hearing evaluation. we speculate that hearing questionnaires may be useful to screen for hearing loss in the cf patient population. hispanic cf patients have increased morbidity and mortality risks compared to caucasian cf patients who attend our accredited cystic fibrosis center in southern california. is the increased morbidity/mortality risk due to decreased access to outpatient cf care? we performed a retrospective review of all patient visits to our cf clinic between january , through december , . data collected included demographic information (age, ethnicity, gender) , and the number of clinic visits during the study period. data was analyzed by unpaired student's t-test as well as by chi-square. during the study period, a total of cf patients ( males: females; mean age . ± . years; range months to years) were routinely followed in our cf clinic. these patients had a total of outpatient visits to the cf clinic ( . clinic visits/patient over the year study period). there were hispanic cf patients ( males: females; mean age . ± . years) and caucasian cf patients ( males: females; mean age . ± . years; p= . , ns). there was no difference in gender distribution between the group (p= . , ns). hispanic patients had a greater number of cf clinic visits ( . visits/patient) as compared to caucasian patients ( . vists/patient; p= . ) during the same period. we conclude that the increased morbidity and mortality of hispanic cf patients in california cannot be attributed to barriers to outpatient care. in fact, hispanic cf patients were seen more frequently in cf clinic compared to caucasian cf patients who attend the same clinic. we speculate that hispanic cf patients are seen more frequently in cf clinic due to increased severity of cf disease manifestations. duguépéroux, i. ; scotet, v. ; audrézet, m. , ; blayau, m. ; parent, p. ; journel, h. ; boisseau, p. ; férec, c. , . inserm u , brest, france; . dep. of genetics, brest, france; . dep. of genetics, rennes, france; . unit of medical genetics, brest, france; . unit of medical genetics, vannes, france; . dep. of genetics, nantes, france aim: the aim of this study was to describe -year experience of prenatal diagnosis (pd) for cf in brittany (western france) and to assess its impact on incidence. method: we registered, by the genetic laboratories of our region, all the pds performed in women living in brittany over the period - . we described the number of pds made for each reason (way by which the one-in-four risk was identified: previous affected child, family testing, echogenic bowel, etc). we reported the proportion of cf-affected fetuses and of consecutive terminations, and assessed the incidence modification due to pd. results: over the -year period, a total of pds were performed in couples living in brittany. most of them were done in couples already having cf child(ren) (n= , . %). extended testing in families -a practice largely proposed in brittany -led to the identification of new onein-four risk couples among the relatives of cf patients who opted for pd times over the study period ( . %). the other pds were made in couples without previous history of cf. the one-in-four risk was mainly identified following the detection of an echogenic bowel during pregnancy ultrasound examination ( pds were done directly following the positive ultrasound ( . %), whereas others were done for subsequent pregnancies ( . %)). the other pds were consecutive to the detection of an heterozygote through newborn screening (n= , . %) or for an other reasons (n= , . %). over the study period, the number of pds per couple varied between one and five, the mean being . . overall, a total of cf fetuses were identified, among whom were terminated ( . %). the inclusion in the incidence calculation of these pregnancy terminations led that to an incidence modification of . % over the study period. conclusion: this study shows that pd for cf is commonly used in brittany and highlights the impact of family testing and of routine ultrasound examination of pregnancies in that region. supported context: hispanics with cystic fibrosis (cf) in the united states experience an % increased annual risk of death from cf compared to non-hispanic patients. when adjusted for socioeconomic status this disparity persists. studies characterizing this at-risk population do not exist. objective: to characterize the center-reported us hispanic population with cystic fibrosis through a cystic fibrosis foundation (cff) patient registry analysis and to elucidate factors present within this hispanic population that may affect outcomes. design: retrospective cross sectional study of the cff patient registry. patients: all , patients in the cff patient registry were included in the analysis. there were no exclusion criteria. the hispanic population is defined as those who were entered by their respective care center as hispanic ethnicity regardless of race. main study measures: prior to analysis, study measures were selected to demographically and genetically characterize the hispanic cf population. genotype, state of residence, mean age and mean age of diagnosis were obtained in the entire population. maternal education (for patients < years of age) and insurance status data were captured as indicators of socioeconomic status. complication rates, fev percent predicted (under years of age) and absolute fev (over years old of age) were obtained as measures of clinical status. t-tests and logistic regression analyses were used to compare measures between hispanic and non-hispanic groups. odds ratios (or) and % confidence intervals are reported. results: center-reported hispanic patients with cf were identified. over % of hispanic patients resided in california, florida, texas or new york. the most common genotype was delta f homozygous, accounting for % of the population. mean age was . years +/- . years for hispanic patients and . years +/- . years for non-hispanic patients. hispanic patients were diagnosed at an earlier age ( . years vs. . years, p= . ). they were more likely to have mothers with education at less than a high school level (or . ( . , . ) ) and have government insurance (or . ( . , . ) ). complication patterns differed between the two groups; non-hispanics were more likely to have complications reported that were related to depression (or . ( . , . ) ), bone health (or . ( . , . ) ) and cf related diabetes (or . ( . , . )) compared to hispanics. hispanics however, were more likely to have complications reported from cf liver disease (or . ( . , . ) ). pulmonary function, as measured by fev percent predicted in children (p< . ) and absolute fev for adults (p= . ) were lower for hispanic patients. conclusions: differences exist between hispanics and non-hispanics with cf with respect to maternal education, insurance status, complications rates and pulmonary function. the lower reported rates of depression, bone complications and cf related diabetes may represent ascertainment bias. further study is needed into the etiology of health outcome disparities in this population, and to design interventions for this high-risk population. mastella, g.; baldo, e.; forneris, m.; furnari, m.; lucidi, v.; manunza, d.; marinelli, i.; messore, b.; neri, a.; raia, v.; salvatore, d.; buzzetti, r.; cairo group, italian cf research foundation, verona, italy with our work we reviewed the international scientific literature coming from cf registries worldwide. our aims were: to verify what has been produced in scientific literature thanks to the material derived from fc registries and to see which clinical problems have been tackled and which clinical questions were answered correctly and exhaustively. a search in medline and embase produced articles (our strategy was "cystic fibrosis"[mesh] and ("registry"[mesh]) or registr$) updated to the / / ). out of these articles have been selected by two independent assessors on the basis of their pertinence (primary studies that used data taken from a formally established registry, at least national, to test some hypothesis of research). each article has been examined with the help of a pre-defined form that in particular evaluated skills of different registry data, selected clinical characteristics of the study populations and statistical methods. more than one half of cases data came from usa-cff foundation patient registry, the remaining coming from canadian, uk, french, italian, german, and other european registries. the main focuses of the articles were included in the following topics: ) incidence/prevalence of the disease and survival ( studies); ) neonatal screening, growth and nutrition ( ); ) genotype/phenotype correlation/ different ethnical groups and twin/brothers ( ); ) complications and outcomes (abpa, diabetes, nasal polyposis, pregnancy and paternity, etc) ( ); ) microbiology ( ). our assessment scores were good/excellent for / studies for the relevance of the problem addressed; / for the usefulness of the outcomes and / for the usefulness of the implications for research from the italian registry. thirty-two articles gave a significant contribution to the analysis of the studied problem, but of them left a partial uncertainty, while left complete uncertainty. cf registries are a very important source of data to provide a powerful tool for clinical and research questions. however, further comparable studies have to be planned to assess registry data as a platform for improvement in clinical practice. vandenbranden, s.l. ; mcmullen, a. ; konstan, m. ; morgan, w. ; wagener, j. ; schechter, m. ; watts, k. , ; mccolley, s. , . children's memorial medical center, chicago, il, usa; . emory university, atlanta, ga, usa; . university of arizona, tuscon, az, usa; . case western reserve university, cleveland, oh, usa; . northwestern university feinberg school of medicine, chicago, il, usa; . university of colorado, denver, co, usa; . university of rochester, rochester, ny, usa background: although life expectancy in cf has dramatically improved over the last years, most of the improvement is due to improved survival during early childhood. adolescence and young adulthood continue to be a time of worsening pulmonary disease and mortality. study objective: data from a large longitudinal observational study, the epidemiologic study of cystic fibrosis (escf), was examined to characterize lung function decline in subjects with cf during the periods preceding and after the age of . design: escf data from individuals with cf collected during the period of - were analyzed. inclusion criteria required individuals to have a minimum of encounters in each of the . year time periods before and after the age of . the cohort was strati-fied by disease severity based on the best fev at the th year (+/- months). one hundred thirty seven subjects had severe lung disease (fev < % predicted), had moderate-severe lung disease (fev -< % predicted), had mild lung disease (fev -< % predicted), and had very mild disease (fev > % predicted) the study compared the annualized rate of fev decline during the adolescent period, defined as ages - . years, and in the young adult period defined as . - years. results: in the entire cohort, the annualized rate of decline was less in the young adult period than in the adolescent period (p< . ). the most dramatic improvement in slope of decline was seen in the severe group, and significant improvements were also noted in the moderate group (p< . ). the mild group demonstrated insignificant change; the very mild group was the only group that demonstrated a more negative annualized rate of the decline in young adulthood than in adolescence (p= . ). conclusions: these data suggest that, overall, young adults have a slower rate of decline in fev in the period after age . this "stabilizing" of lung function is most prominent in those individuals with moderate-to-severe lung disease. only those with very mild lung disease have a slightly more rapid rate of decline between the ages of and . overall there is less variation in the rate of fev decline across disease strata after the th birthday. further analysis is underway to better understand the factors leading to these findings. . department of paediatrics, university of florence, cystic fibrosis centre, florence, italy; . italian cystic fibrosis microbiology group, florence, italy; . institute of medical microbiology and hygiene, tübingen, germany mrsa is now a worldwide public health problem, due to the increasing rate of infection in several settings as well as in cf patients. mrsa was first recognized as being acquired from hospitalized patients (ha-mrsa), but the onset of mrsa infection outside the hospital setting, in communityassociated strains (ca-mrsa), has recently been described with increasing frequency. ha-mrsa are known to be responsible for infections in hospitalized patients, although highly virulent ca-mrsa are increasingly reported worldwide as the cause of severe outbreaks, replacing ha-mrsa strains in nosocomial infections. little evidence is available about the characterization (sccmec type) and epidemiology of community-acquired mrsa (ca-mrsa) or hospital-acquired mrsa (ha-mrsa), transmissibility, antibiotic susceptibility and virulence in the cf population. the present multicenter study investigated the susceptibility pattern, epidemiology, and sccmec type of mrsa strains isolated from nine italian cf centers. the susceptibility pattern was determined by the disk diffusion method and pulsed field gel electrophoresis (pfge) was performed for epidemiological purposes. the sccmec type in order to identify hospital-and community-acquired mrsa strains (ha-mrsa and ca-mrsa respectively) was determined with molecular methods, and the presence of gene encoding panton-valentine leukocidin (pvl) was tested. during the study period, mrsa strains were isolated from out of ( . %) patients attending these cf centers. of the sccmec type representing ha-mrsa, our data showed an high prevalence of sccmec i ( . %) while the prevalence of sccmec ii, (reported as the most represented among ha-mrsa) was only . %. furthermore a high prevalence ( . %) was found of sccmec iv (suggestive of ca-mrsa strains). epidemiological analysis showed that ( . %) out of analyzed mrsa strains belong to the same pfge clone shared among six centers, belonging to the sccmec type iv, suggestive of ca-mrsa isolates. twenty-four ( . %) out of these strains were sccmec type iv, indicative of ca-mrsa, as suggested by the good susceptibility rate to trimethoprim-sulfamethoxazole and rifampin. surprisingly all the isolates belonging to this epidemic clone were negative for the pvl genes. these results show that ca-mrsa is now spreading in the cf population, documenting the first epidemic of ca-mrsa in cf patients who are considered at risk for ha-mrsa acquisition due to frequent hospitalizations. these data show a peculiar picture of mrsa epidemiology indicating that further studies are required to clarify the role of ca-mrsa in global epidemiology, their pathogenicity and clinical impact on cf patients. we thank the fondazione per la ricerca sulla fibrosi cistica-onlus for its grant (ffc# ) . there are concerns regarding an increased risk of cancer in patients with cystic fibrosis (cf). this study aimed to review the occurrence of malignant disease in a large population of adult patients with cf. the case notes of patients attending the leeds adult cf unit were reviewed. demographics and data regarding a diagnosis of malignant disease were recorded. a total of eight patients ( male, female) were diagnosed with a malignant condition over the year period. the median (range) age of diagnosis of a malignant condition was . years ( - years). five patients were diagnosed with malignancy post-transplantation. within this group of patients there were two cases of lymphoproliferative disease, one case of basal cell carcinoma, one case of liver cancer and one case of small cell lung cancer related to the donor lung. the median (range) time to diagnosis post-transplantation was two years ( - years) with a median (range) age of years ( - years). three patients were diagnosed with a malignant condition without solid organ transplantation. this group consisted of one case of pancreatic carcinoma, one case of oesophageal carcinoma and one case of bowel carcinoma. the median age of diagnosis in this group of patients was years ( - years) . prior to transplantation we found all malignant diagnoses were related to the gastrointestinal tract. post-transplantation we found a wider variety of malignant diagnoses, with lymphoproliferative disease being most common. awareness of the increased risk of malignant disease is important and appropriate investigations should be undertaken particularly in patients with atypical symptoms. background: patient outcomes can be improved by implementing evidence-based guidelines for initiating therapies. in our cf center, practitioners have traditionally prescribed medications without a centralized database to screen patients for evidence-based criteria. goals: the primary goal of this project was to increase cf practitioner, family and patient awareness of evidence-based medication guidelines to facilitate discussions regarding therapies. the secondary goal of this quality improvement (qi) project was to determine if cf practitioner prescribing patterns would be altered by increasing awareness. methods: the cf steering committee at cincinnati children's hospital medical center (cchmc) identified oral azithromycin, inhaled tobramycin, and dornase alpha as target medications for this qi project. an evidence-based medicine committee was formed, including a parent advocate, to direct the project. a consensus was reached among cf practitioners for when to initiate therapy discussions. dornase alpha was recommended for cf patients ages six and older. inhaled tobramycin was recommended for cf patients ages six and older with chronic pseudomonas (defined as positive cultures in past months). oral azithromycin was recommended for cf patients ages six and older, with chronic pseudomonas, and a weight of kilograms or more. the cf database was screened to determine each patient's medication eligibilities. eligibilities were reviewed weekly at our cf chart conference. medication specific family and patient handouts were developed, reviewed by the parent advocate, and given to eligible families and patients on arrival to clinic. data was collected to document the number of discussions facilitated at clinic visits, the decisions regarding medications, and the number of new treatment prescriptions that were facilitated. after seven weeks of the initiative, statistical analysis was conducted using mcnemar's test for differences. a chi-square test with a two sided alpha of p < . was used to determine significance. results: of the cf patients in our center were eligible for pulmonary medications using our evidence-based criteria. there were individual prescribing opportunities in these patients (taking each medication for each patient as a unique prescribing opportunity). at the start of the project, . % ( / ) of the prescribing opportunities were fulfilled. % ( / ) of patients were prescribed all of their recommended medications. during the first seven weeks of the project, cf practitioners discussed initiating new pulmonary medications with cf families and patients. the proportion of prescribing opportunities fulfilled increased from . % ( / ) to . % ( / ) (p value < . ; % ci . %- . %). the proportion of patients prescribed all of their recommended medications increased from % ( / ) to . % ( / ) (p value < . ; % ci . %- . %). conclusions: increasing awareness of evidence-based pulmonary medication recommendations with cf practitioners, families and patients facilitates therapy discussions, increases the proportion of therapies prescribed and increases the proportion of patients on all recommended therapies. purpose: our purpose was to optimize lung function (fev ) by consistently and aggressively diagnosing and treating pulmonary exacerbations (pex) in all cf patients at our center. it was important to work on this because our families wanted standardized care and we felt our patients' fev 's were suboptimal. methods: our core llc team included two parents of cf patients and one adult patient. we met weekly, received coaching every other week, and learned and applied quality improvement techniques. physicians began monthly meetings, and monthly meetings of the entire cf team continued. the fab met every other month. we identified our specific aims, and approached them systematically. the providers, starting with criteria used by several authors, agreed upon the definition of pex and created a pulmonary exacerbation score sheet (pexss). we selected a score of as the threshold for defining a pex. after using the pexss for three months, all providers reviewed the individual pexsss and validated our original choice of . run charts were produced and reviewed periodically to display each provider's percent of pexsss used. when the use of the pexss was not standardized after a year, it was reprinted on bright yellow paper to make it stand out. to educate the families and patients about the early symptoms of pex, a refrigerator magnet was designed and distributed that included all pex criteria. results: we standardized the use of our pexss by all providers on all patients seen in cf clinic with ongoing measurement of its use and regular feedback. many patients and families gained greater knowledge about what a pex was, and the importance of early recognition and treatment. the cf nurses note that ) many patients call with milder pex symptoms than they did before, ) providers treat pex earlier, ) many patients call with their pex score as well as their symptoms. we hospitalized more patients for pex after this project began, with an average of patients/year in the years prior, and in . the median fev % predicted of our - conclusions: participating in the llc changed the culture and functioning of our cf team. limitations to our study include: ) fev change may not have been due solely to this project, ) the groups who's fev 's were averaged over the various years are different. we will continue to optimize and standardize ) prevention of pex, ) inpatient care, ) care of pex in cf providers' private offices, and ) follow up of patients with pex. patient adherence to airway clearance techniques (act) in the treatment of cystic fibrosis is known to be sub-optimal resulting in deterioration of lung function. the global aim of our project was to improve median fev . the specific aim was to improve adherence to act. we believed that these goals could be acheived by implementing a program which included re-education of airway clearance techniques (react) for our cystic fibrosis patients. methods: the initial phase of this project began with the administration of an anonymous survey to patients/families. this survey was designed to assess act practices, knowledge of the rationale for performing act and barriers that prevent patients/families from adhereing to act. the next step included an in-clinic questionnaire and patient/family demonstration of current aerosol therapy and act. based on individual results patients were identified as: adherent with correct technique, adherent with incorrect technique or non-adherent. we defined adherent as correct performance of act one to two times daily as prescribed. then all patients entered the react program which included a standardized tutorial on proper act and correction of techniques if necessary. in the non-adherent group barriers to performing act were discussed and problem solving techniques were used to overcome barriers. the patients in the non-adherent group were re-evaluated in clinic monthly while the adherent patients returned on an every two month schedule. results: analysis of our initial survey revealed that while the majority of patients/families reported performing act daily, the duration of treatments was less then medically prescribed. many patients/families reported barriers which decreased adherence to therapy. to date % ( / ) of our patients have completed the in-clinic questionnaire and entered the react program. the results of these evaluations and patient demonstrations revealed: % ( / ) were adherent with correct technique, % ( / ) were adherent with incorrect technique and % ( / ) were non-adherent. in the six months since the implementation of the react program, patients/families are self-reporting an increased adherence to act and the median fev for our center has increased form . % ( cff registry data, ages - years) to . % (cff registry, first quarter, , ages - years). conclusion: while adherence to act in our center was poor, we were able to improve adherence and ultimately improve the median fev by implementing a program of re-education for act (react). we believe re-assessment of adherence to therapy and reviewing correct technique is necessary at every clinic visit. continuous quality improvement (cqi) techniques have recently been employed in medicine to improve quality of care. although there is evidence that cqi improves efficiency in hospitals, little is known about effects of cqi on improving patient outcomes. we have previously reported creation of a unique nutritional risk pathway (nrp) to care for cystic fibrosis (cf) patients who are at nutritional risk. the goal of this study is to assess perceived impact and objective clinical efficiency of our nrp. patient data was recorded from all children attending the cf clinic over an -month observation period (between sep and mar ). bmi percentiles were assessed and nutritional risk zones -green: acceptable (bmi > %ile), yellow: at risk (bmi - %ile) or red: at urgent risk (bmi < %ile) -assigned at each visit. the visit intervals were every to weeks based on severity of nutritional risk. patients that remained in the red zone for an average of to months with no improvement were considered for gastrostomy tube (gt) placement. the cf dietitian updated the data weekly and e-mailed quarterly to cf physicians for review of their patients' status. patient/family perceptions and understanding of the nrp was assessed by questionnaire. of the children in the study, ( %) were identified to be at nutritional risk and were enrolled into the nrp: in red and in yellow zones; ( %) male, ( %) female; ( %) age < yrs, ( %) age ≥ yrs. over the -month observation period, ( %) showed improvement ( moved from red to yellow, from red to green and from yellow to green zones). thirteen ( %) females improved, whereas ( %) males improved. in the under yrs age group, ( %) improved compared to ( %) in the ≥ yrs age group. as a result of participation in the nrp, ( %) children had gt placed: six of the showed improvement with four moving from the red to green zone. from the survey responders, % stated they understood the meaning of the cf nrp. all responders were extremely to somewhat motivated to focus on their child's nutrition when asked to return for growth monitoring or follow-up visits. having specific goals for weight gain, calorie requirements and bmi were considered extremely helpful by % of families. when gt placement for their child was recommended, % felt they lacked all the necessary information to make a decision. our new cf nutrition education booklet was not received by % of families. some of the physicians who received the quarterly nutritional patient data provided positive feedback and found this information beneficial for patient care. nutritional cqi in our cf center utilizing a specific nrp and monitoring of nutritional risk status resulted in improved patient outcomes. overall perceptions of our nrp were positive from both patients and cf physicians. these results suggest that this cqi strategy improved clinical outcomes in our patient population. patients with cf require frequent healthcare visits to optimize growth, initiate early interventions and delay progression of lung disease. the cff recommends evaluation at a cf center at least quarterly. as part of a llciv quality improvement (qi) initiative, our cf team set a goal to increase the percent of cf patients attending clinic or more times a year to % or greater by developing strategies to monitor and improve adherence rates. methods: we reviewed cf patients who attended clinic times or less in to determine patterns of non-adherence in regards to age, gender, distance from center, season, physician or insurer. a patient survey was used to assess clinic attendance barriers from a patient/family perspective. a brainstorming session identified other barriers. a fishbone diagram was drafted into barrier categories: external, internal, communication, and patient/family perceptions. after reviewing all barriers, we concluded the most effective improvements could be made to internal clinic barriers. clinic processes were then assessed including making of appointments, reminder letters/calls, a time cycle analysis, and number of cf appointments available per patient per physician. our family advisory board participated by focusing on the importance of or more clinic visits in their newsletter and by assignment of a member to the llciv team. we discovered a lack of a standardized process to follow-up (fu) patients who "did not keep appointments" (dnka). a spreadsheet was created to monitor physician dnka rates. a primary fu strategy was devised to identify patients who dnka through daily auto-emails to the cf office assistant and utilization of a rescheduling decision tree for reappointment of these patients by our appointment center. two secondary fu strategies were developed. the first involves the clinical coordinator printing a monthly report off port cf entitled "patients due a visit" then emailing this list to the cf team to contact and reappoint. the second involves the cf social worker tracking patients seen per quarter on a spreadsheet and emailing the spreadsheet quarterly to the cf team as well as posting on our datawall. results: in , and , %, %, and % of our patients attended clinic or more times, respectively. in in , and , %, %, and % of our patients were at nutritional risk, respectively. in and , mean fev % predicted was . % and . %, respectively. conclusion: the number of cf patients attending clinic quarterly at our center increased by implementing processes to track dnka patients and reappoint them to clinic promptly. however, some of the early improvement in clinic attendance was partially due to an increased awareness of our qi efforts by our clinic staff, cf team and patients/families. we speculate that improvements in nutritional status and lung function are at least partially related to more frequent clinic attendance by our patients. continued monitoring of the number of dnka patients and patients who attend clinic quarterly is required to sustain these gains in improved patient outcomes. data when we first measured patient/family satisfaction in , parents and children were given questionnaires to measure their satisfaction with services provided at the clinic. at that time, responses in our survey were very positive. with regards to our new model we received very positive feedback, encouraging us to continue with the model. parents and children liked the elimination of duplication in questions and they also like having the whole team involved in the meeting and problem-solving. final results for our second satisfaction questionnaire will not be available until june of this year as the questionnaires are being given at clinics over a month period this spring. the children complete a questionnaire with the help of their parents if needed and the parents also complete a survey. results to date are very positive for both the parents and the children. of the children who have completed the survey to date, all stated they would like to continue to meet with the group as a whole as opposed to meeting individually with team members. of the parents surveyed to date, all are either very satisfied or satisfied with the group format. conclusion: we have not yet completed the survey but results to date clearly show that both the patients and their families are happy with the round table model. results will be compiled early this summer and would be ready for the poster and/or presentation in the fall. the cff clinical care guidelines recommend routine clinic visits for assessments, interventions, monitoring, education and counseling every months or more often as indicated. adherence to these guidelines is important in ensuring better clinical outcomes. in reviewing our cf center data from the cff registry report, . % of pediatric patients ( - yrs.) and . % of adults ( yrs. and older) adhered to the guidelines. national goals were not provided then; instead data was given for the top ten cf centers ( . % and . % for pediatric and adult patients respectively) as well as the national rates ( . % and . % for pediatric and adult patients respectively). our cf care center acknowledged the need to improve adherence to these guidelines and at the beginning of the year , embarked on a quality improvement project to address this issue. following the pdsa (plan-do-study-act) steps, we agreed on the objective of increasing the percentage of pediatric and adult patients adhering to the guidelines by at least % and at the same time, to exceed the national average in year or by the end of the year . the physicians and social worker obtained feedback from patients and/or families during a clinic visit regarding barriers in complying with scheduled clinic visits. suggestions were elicited to overcome these barriers. the team members then identified barriers in meeting the guidelines and implemented measures to improve compliance with clinical care guidelines. among these measures were sharing the information about clinical care guidelines and importance of adherence through our cf newsletter and at every clinic visit, reminder calls to patients or caregivers at least days prior to the visit, appointments for the next visit given prior to discharge from the clinic, and same day calls to patients who failed to keep their appointment for rescheduling. our social worker identified patients with difficulties or problems in consistently keeping appointments and helped address these problems. progress made in this endeavor was shared with parents and caregivers during the "parents' night" held in the fall of . indeed, with consistent implementation of these measures, we have seen improvement in the percentage of patients adhering to guidelines. in our cf care center data, . % of pediatric patients and . % of adult patients adhered to recommended clinical care guidelines, approximating and in fact for the adults, exceeding, our target of % increase in the percentage ( % and % increase respectively for pediatric and adult patients). these data were better than the national average for ( . % and . % for pediatric and adult patients respectively) but for pediatric patients, still % below the national goal of %. adults approximated the national goal of %. we are committed to continually engage in the process of quality improvement in further improving adherence to clinical care guidelines and to hold on to the gains. weight z-scores and height z-scores were monitored prospectively for all infants, children, and adolescents at a pediatric outpatient cf clinic during an ongoing, multidisciplinary quality improvement (qi) initiative. all cf team members participated in this qi project which emphasized the importance of good nutrition and adequate growth for optimal lung health. specific strategies for improvement included education to families at each visit with a written nutrition action plan, increased emphasis on liquid supplements and enteral feeds as needed, and a consist message from all cf clinic staff in encouraging attention to nutrition. the study objective was to determine if multidisciplinary qi interventions to improve nutritional status had any effect on weight z-scores and/or height z-scores over a -year period. the null hypothesis was that z-scores for weight and height would either not improve or worsen. inclusion criterion for this study was attendance at cf oupatient clinic during the first months of the qi initiative (time ) with a subsequent clinic visit years later (time ). patients not attending clinic at both time and time were excluded. a cohort of patients ( male, female) met the inclusion criterion. the mean time to time interval was . ± . years (range . to . years) with mean patient age at time of . ± . years (range . to . years). pancreatic enzyme replacement therapy was used for ( . %) of the cohort. paired sample t-tests indicated significant improvements for weight z-score (p <. , t ( ) = . ) and height z-score (p <. , t ( ) = . ) after the -year intervention. at time , children ( . %) were underweight or less than th percentile while children ( . %) were normal-weight, at or more than th percentile for age. mean differences in both weight and height z-scores in the initially underweight patients were greater than those for the normal-weight patients over the year interval. no significant differences were found for the initially normal weight-for-age children between time and time for weight z-score ( p = . ) or height z-score (p =. ). children who were not underweight at time grew normally, without acceleration over the yr intervention. therefore, we conclude that a longterm multidisciplinary qi project to enhance nutritional status resulted in significantly improved weight z-scores and height z-scores for those individuals who were initially underweight for age. the most common cause of morbidity and mortality for patients with cystic fibrosis (cf) is pulmonary exacerbations. these exacerbations lead to hospital admissions and treatment with intravenous (iv) antibiotics. all cf patients at our facility are admitted to a teaching service which includes house officers and students. standardized order forms are used to improve accuracy and timeliness of medications and therapies. the efficiency of this process was brought into question in / , when several parents complained about a delay in the receipt of first dose iv antibiotics after hospital admission. the objectives of this study were to determine what were the actual delivery times of the iv antibiotics to the patients (both retrospectively and prospectively), and areas where improvements could be made. our predetermined target time was < hours. two analyses were performed in order to answer the objectives. the first analysis was done in a retrospective fashion. this analysis included cf patients admitted from / / - / / . a total of patients were included. total median time from admission to receipt of first dose of iv antibiotics was analyzed. a second collection of blinded prospective data was performed between / / - / / . only the pulmonologist, pharmacist collecting data, and pharmacy clinical manager were aware of the data collection. a total of patients were included in the prospective project. each part of the process model were recorded and analyzed so that areas of improvement could be realized. the median time from hospital admission to first dose of antibiotics was hours (range - hours) (retrospective cohort). the prospective cohort median time from hospital admission to first dose of antibiotics was hours (range min- hrs). the median time from admission to order entry by pharmacy: hrs, min (range min- hrs, min). the median time from the medication order being written by medical practitioner to order entry by pharmacy: minutes (range min- hrs, min). the median turn-around time by the hospital pharmacy of order entry until reaching the nursing unit: min (range min- min). the median time required by the nursing staff to administer the antibiotic: hrs, minutes (range min- hrs). this project was initiated in response to parental concerns. from the results of the retrospective and prospective analyses, it was determined that a delay is occurring in the receipt of iv antibiotics, which translates to hours in the hospital without therapy. this is both inconvenient and uncomfortable to the family, and wasteful of medical resources. the findings of this project were presented to the pharmacy and therapeutic committee of the hospital, to the nursing directors, and to the parents of cystic fibrosis patients. the delay is greater than expected before this project was initiated. as a result of these findings a "fast track" medication order set was developed to expedite initiation of inpatient therapy. four key areas included in this order set are sputum, iv access, diet, and iv antibiotics. we speculate that time to first drug delivery will decrease and patient satisfaction with improve. the pediatric intermountain cystic fibrosis center (imcfc) provides multidisciplinary cystic fibrosis (cf) care to pediatric patients from utah and parts of idaho, wyoming, and nevada. historically the imcfc has embraced early intervention. as new therapies have been added to the cf armamentarium it has become necessary to have a method of keeping track of which patients are candidates for various therapies and also which medications have been prescribed, utilized or even should be discontinued. in order to address this quality issue, the imcfc decided to develop and implement the use of a medication tracker (mt). the imcfc decided to focus on key therapies which were felt to be at risk for variability in prescriptive practice. the five therapies included were: pulmozyme<®>, tobi<™>, hypertonic saline(hs), azithromycin and asthma medications (inhaled corticosteroids and/or leukotriene receptor antagonists). ibuprofen was intially included and later removed from the mt. prior to implementing the mt, the imcfc met to review literature, medication trackers from other centers, and develop consensus among team members. six versions of the mt have been developed between / / - / / . each mt has been tested in a pdsa cycle and revised. since initating the mt, patients have been seen at least once. there have been mt encounters. the mt is used only after the first visit to the imcfc and reflects changes to established cf care. there have been a total of changes in prescribed therapies in different patients( % of patients seen). a minority of patients were receiving therapies that did not meet our pre-determined consensus for prescription. the most common therapies in this category were tobi™ and azithromycin. primary reasons cited for prescribing were: chronic suppressive antibiotic use, pseudomonas positive and < years old, and significant changes on chest imaging. reasons patients were not prescribed clinically indicated therapies were: patient refusal, participation in clinical trials, cost, and lack of compliance with other therapies. changes in asthma therapy included the discontinuation of medication in encounters and the initiation of therapy in . the use of a specific cf patient mt allows consistent practice in selection of therapies. it can be used by all team members and helps to identify discrepancies in therapy. assuring all patients receive information and are considered for new therapies is increasingly important as our treatment options expand. the mt also highlights the need to consider discontinuing therapies. we speculate the mt will become an increasingly valuable tool over time and improve patient care. rationale: recent reports document increasing prevalence of antimicrobial resistance across a range of pathogens in patients with cf. the increase in multidrug resistance of these organisms complicates the therapeutic management of these patients. objective: to describe patterns of antibiotic use among physicians treating cf patients. methods: for the original purpose of evaluating site characteristics that act as effect modifiers on the relative efficacy or cost of novel therapies, we administered a survey to acquire information on practice patterns and characteristics of physicians participating in a clinical study of an investigational drug for patients with cystic fibrosis. chi-square and spearman rank test were used to evaluate associations between physician characteristics and patterns of reported antibiotic use. results: fifty-nine physicians, representing study sites, completed the survey. ninety percent reported a medical specialty of pulmonology and % reported practicing at a teaching hospital. on average, respondents reported that about half of their practice consisted of patients with mild cf (defined by fev ≥ % of predicted normal.). forty-two percent of respondents reported prescribing oral antibiotics and % of respondents reported prescribing inhaled antibiotics for maintenance therapy for at least % of their mild cf patients. eight-five percent and % of respondents reported prescribing iv antibiotics for pulmonary exacerbation and pulmonary 'clean out', respectively, with about a third of these cases being prescribed for outpatient iv use. physicians that prescribed iv antibiotics for pulmonary clean out were more likely to pre-scribe oral (p= . ) and inhaled antibiotics (p=. ) for maintenance therapy than physicians that did not prescribe iv antibiotics for pulmonary clean out. conclusions: antibiotic use for maintenance therapy and iv antibiotic use for pulmonary exacerbation and pulmonary clean out acted as 'complements' rather than 'substitutes' as there was a group of physicians who reported less use of antibiotics. our findings warrant further research as well as additional exploratory analyses with a larger and broader sample to examine associations between physician characteristics and patterns of antibiotic use. understanding the relationship between physician characteristics and antibiotic use has the potential to influence the approach to management of cf patients in an environment of increasing antimicrobial resistance. introduction: hypertonic saline (hs) has been shown to increase mucus clearance and improve lung function in cf, and is now increasingly being used as part of routine therapy. one of the goals of our cf center quality improvement (qi) initiative is to increase use of hs among all eligible patients. objectives: to assess adherence to treatment with hs, parental opinions on treatment, perception of side effects, and the effect of initiating hs on the use of other nebulized medications in pediatric cf patients started on hs therapy during . methods: patients under years of age were identified as initiating hs therapy during . a telephone survey of their parents using a -item multiple-option questionnaire was administered in april as part of our cf center qi initiative. results: parents ( %) completed the survey: ( %) patients were still using hs. of those still reporting use of hs, ( %) were using it twice a day; ( %) once a day; and less often than daily. among the patients who discontinued hs, ( %) stopped following recommendations from their pulmonologist; ( %) stopped due to side effects; ( %) felt hs took too long to administer; and ( %) felt hs solution was too difficult to mix. the most common side effect reported was cough in patients ( %); ( %) reported no side effects. the majority of patients ( %) spent - minutes per day on hs therapy. thirteen ( %) patients discontinued another nebulized medication when they initiated hs; ( %) of those stopped pulmozyme. reasons for stopping pulmozyme included: time to nebulize both medications was too long ( %), perception that hs was working better for their symptoms ( %); and doctor's instructions ( %). overall, ( %) parents felt hs improved their child's symptoms; ( %) saw no difference; and ( %) believed hs made symptoms worse. there was a significant difference in the proportion of patients that reported improvement of their symptoms in the group using hs twice a day ( / , %) when compared to those using it once a day ( / , %) (p= . ). discussion: the majority of patients continued to report the use of hs therapy several months after our initial intervention, with the most parents reporting improvement in their child's symptoms. physician recommendation was the most common reason cited for discontinuation of hs therapy. further study of physician opinions on hs therapy, particularly the timing of initiation and discontinuation, is warranted. one-half of patients reported using hs only once a day; however those reporting twice daily use were more likely to report subjective improvement of symptoms. since treatment complexity in cf increasing, determining the effectiveness of once daily hs therapy, either alone, in place of, or in combination with other therapies such as pulmozyme is essential. long-term follow up of these hs-initiated patients will focus on effects on exacerbations, pulmonary function, and hospitalizations. the uab/children's hospital (chs) cf center participated in learning and leadership collaborative ii. as part of the qi journey, the chs cf qi team thoroughly evaluated the current system of care in an effort to identify areas of needed improvement. one area assessed was clinic attendance. it was discovered that % of patients failed to attend clinic appointments every week. according to cff care guidelines, patients with cf should be seen a minimum of times each year at the cf center. the cff has also found that those centers that see their patients more frequently have improved outcomes for fev and nutritional status. aim to decrease the number of missed appointments at the chs cf clinic. the chs cf center administered a qi survey to identify the reasons patients and families were missing appointments. this survey was a item questionnaire that evaluated: reasons for missed appointments, if the families rescheduled missed appointments, difficulties with rescheduling, the need for reminder calls, distance traveled to the cf center, and insurance status. results completed surveys were collected. % of the families reported medicaid as their insurance provider. % of families live more than miles away from the cf center. % of the families confirmed that they had missed an appointment in cf clinic over the last months. the reasons for the missed appointments were widely variable; however, . % of those who missed appointments reported that they did not have access to transportation to get to the appointment. overall, families did not report difficulties in rescheduling appointments. % of those that missed appointments identified medicaid as their insurance which can be correlated with lower income families and . % of those that missed lived greater than miles away from the cf center. % of families reported that a reminder call would be helpful for them. interventions after evaluation of the survey data, the center quickly initiated reminder calls for cf clinics. a student employed by the cf center made these telephone calls to the patients scheduled for clinic every week. the majority of the time the student caller left a message for the family. with the implementation of this simple intervention, missed appointments have decreased from % to % which is a % improvement rate. reminder calls are now a routine part of the cf center's system of care. other ongoing interventions include increased involvement of primary care doctors for patients lost to follow up for more than months and a system for quickly rescheduling patients. next steps in addition to reminder calls, the cf team will now determine where patients who routinely miss appointments live. if there are pockets of patients in common areas of the state, the team will attempt to maximize services for those patients such as linking them with community transportation resources, community health advocates, or providing satellite clinics. this will be accomplished through geomapping of the alabama cf population based on zip code. we designed a scoring system to uniformly identify patients experiencing a pulmonary exacerbation. the elements of this pul-monary exacerbation score (pes) have been previously described. at the time this project began the median fev % predicted of the cf patients at our center - years old was below the national average ( cf registry data). our hypothesis was that greater uniformity of identification of pulmonary exacerbations, would improve pulmonary function in the pediatric age group at our center. this abstract describes continued improvement in the pulmonary function of this age group at our center now that the pes has become standardized in our clinical practice. methods: beginning in october , a pes was calculated for all patients presenting to our center age - years of age. any patient with a pes of > was defined as having a pulmonary exacerbation, and treatment with antibiotics was recommended. the patient's cf physician dictated the ultimate decision for treatment and specific course of treatment. median fev of all patients age - years was calculated quarterly to determine the effect of the pes use on pulmonary function. in october the pes was incorporated into our cf clinic medical record and its use was standardized. the use of the pes, the adherence to the recommendation for treatment, and quarterly fev of the population has continued to be monitored. results: from / to / (the duration of the original qi project), patient visits occurred, with a pes calculated on (utilization of . %). patients were treated for a pulmonary exacerbation of the patients with a pes of > (adherence of . %). . % of exacerbations were treated with oral and/or inhaled antibiotics, and . % were treated with intravenous antibiotics. since standardization of the pes in / , visits have occured. use of the score has decreased slightly ( . % utilization), however adherence to the score has increased ( . % of pes > have been treated). use of oral vs. iv antibiotics has been similar ( . % oral vs. . % iv). the median fev of our patient population has improved from an average of . % predicted during the months before implementing the pes to an average of . % predicted during the ensuing months of the original qi project (a . % improvement). since standardization of the pes in / , the average median fev of the population has continued to increase to . % predicted (an . % increase from the baseline period). this improvement in median fev is reflected in our cf registry data. summary: implementation of a pulmonary exacerbation score, designed to encourage uniform identification of pulmonary exacerbations in patients with cf, is associated with an improvement in median fev in children - years of age. standardization of the pes has resulted in continued improvement in pulmonary function of this population at our cf center. this work has been supported in part by the cff and akron children's hospital. our cf family council parent and patient advisory group has been involved in the development and implementation of this project. utilizing data from the cff patient registry, we determined that our center has had nutritional outcomes consistently below the national average for pediatric and near the average for our adult patients. as a result, we developed the global aim to improve and maintain optimal growth and nutrition in all patients at our cf center. our specific aims included: )to record growth parameters at all outpatient visits; )to identify patients at nutrition risk, categorizing them based on anthropometric data; ) to develop and implement a specific nutrition plan based on nutritional category; and ) to educate staff, patients,and families on the benefits of normal growth and nutrition. we surveyed our patients to determine their overall attitudes toward nutrition and nutritional care received at our center. we discovered that many patients and families did not feel that nutrition was addressed at every cf visit nor that they had a nutritional plan at each encounter. this led to the development of an intake form/home-going sheet for our patients to complete that included data elements necessary for assessment of nutrition and that clearly outlined a nutrition action plan. a standardized nutritional assessment score (nas) was devised that incorporated weight, height/length, bmi and weight for length percentiles as well as weight loss, failure to gain or maintain, and failure to remain in the expected growth channel. the nas was developed after examining the medical literature, reviewing work done by other qi teams, and acquiring input from our pediatric gastroenterologist and endocrinologist. we then developed nutritional algorithms to address nutritional intake, malabsorption, evaluation for cfrd, and short stature. these four algorithms were used to develop a nutrition action plan for each individual. beginning in march , a nutritional category (optimal/acceptable, concerning, at risk or failure) was assigned to each patient at each visit based on their nas. an individualized nutrition action plan was developed with each patient. at the time of project implementation, patients age - at our center had a median bmi %ile of . % with . % of our patients with a bmi < th%ile. our patients > years had a median bmi of . with . % having a bmi< th%ile. after one month of implementation of the nas, % of our patients had been categorized with % of our patients having individual nutrition action plan developed. to track our progress, we will monitor median bmi, % of patients with bmi < %ile, and % of our patients in each nutritional category quarterly using portcf. our goal is to have all our patients assessed and a nutrition action plan implemented by the end of . we have developed a nutritional assessment score and nutrition treatment algorithms for pediatric and adult patients with cf as part of a qi initiative to improve nutritional status of patients at our center. the project has been supported, in part, by akron children's hospital. we are indebted to lori lundquist, a parent of two of our cf patients, who has been an integral part of our nutriton qi team. in germany there are about , cf patients who are usually treated in special centres by a team of trained and experienced health care professionals. the result of this structured approach to patient care, including frequent clinical assessments, monitoring, and aggressive interventions is an improved mean survival and a higher quality of life of pediatric and adult cf patients. however, a recent survey showed that german reimbursement schemes cover only about % of resources used within these centres. objective to assess and evaluate direct costs of outpatient treatment of cf patients in germany. a micro-costing approach was used to record resource use data directly within representative cf centres. results of the evaluation may be used to initiate and support discussions between health care providers and insurances about adequate reimbursement schemes in germany. outpatient care was evaluated in seven different centres for pediatric and adult cf patients. patient reported outcomes, clinical patient data, resource utilisation, and physician related time consumption for treatment was recorded for every patient during one representative month in . cost data for staff, materials, medical equipment, rooms, etc. were assessed within the respective centres. data for cf patients were collected. about half of them were children and adolescents, and half of them were adults. a comparison of the resource uses to the actual remuneration of these services indicates that only about % of the costs are covered by the reimbursement system. correlation analysis identified significant cost drivers like the age of the patient, comorbidities like pancreatic insufficiency and hepatobiliary complications, lung function (% fev ), and the presence of certain pathogens in the lungs. as the actual reimbursement covers only about % of the resource usage costs in germany, the existence of the cf centres and sufficient treatment for cf patients is uncertain in the future. in order to ensure the existence of the centres it would be necessary to agree to a cost-covering reimbursement at minimum. this may be based on a lump-sum payment that could be differentiated for pediatric and adult centres or according to comorbidities or clinical parameters. the data calculated in this study could be used to trigger and support discussions between health care providers and insurances about a new cost-covering reimbursement system for the out-patient treatment of cf patients in germany. the impact of the new us cystic fibrosis foundation (cff) nutrition practice guidelines, i.e., discontinuing the use of percentage of ideal body weight (%ibw) to define "nutritional failure" and setting body mass index (bmi) below the th percentile to define "nutritional risk", on evaluating nutritional care practices is unclear. methods: data from children reported to the cff patient registry were analyzed to compare the rates of malnutrition among cf centers. results: nationally, eliminating %ibw < % as a criterion for underweight resulted in a . % reduction (from . % to . %) in "nutritional failure" rate. misclassification of "nutritional failure" by %ibw < % ranged . - . % among centers and was greater for centers having a larger proportion of tall patients. one-third of centers switched to a different tertile ranking, after correcting for misclassification by %ibw. use of bmi < th percentile led to the classification of . % of patients as "nutritional risk". more than half of the centers had different tertile rankings on "nutritional risk" compared to "nutritional failure". a total of . % ( - . % among centers) of patients who had height < th percentile but bmi ≥ percentile were not considered at nutritional risk. the cystic fibrosis questionnaire-revised (cfqr) is a disease specific quality of life measure that is currently undergoing clinical validation and may prove to be a useful adjunct to provider assessments. we proposed the routine use of the cfqr in a busy adult cystic fibrosis (cf) clinic would assist in identifying patients in need of limited clinic resources. this performance improvement project focused on new and infrequently-seen patients (i.e. fewer than three outpatient clinic visits/year) to determine the frequency of patients with domain scores that fall more than one standard deviation below our clinic mean. methods: the cfqr is routinely self-administered to all adult cf patients in clinic at least once every year. these assessments occur after vital signs are obtained and prior to any other clinical assessments. patients were deemed to be at baseline if there were no changes made to their pharmacologic or chest physiotherapy regimens. the mean and standard deviation of each domain of baseline cfqr assessments were determined. the frequency of rarely seen and new patients with domain scores less than one standard deviation below the mean was determined. results ( ). of these baseline assessments, forty five were obtained from patients who were rarely seen or new to the clinic. . % (n= ) of these patients had one or more domain scores falling more than one standard deviation below the mean. . % (n= ) of these patients had two or more domain scores below these cutoffs. % (n= ) of the rarely evaluated patients had domain composite scores (i.e. the sum of the individual domains) that fell below the standard deviation cutoff. the most common outlying domains in these infrequently seen or new patients were body ( ), weight ( ), physical ( ), health perceptions ( ) and the composite domain ( ). conclusions: the cfqr is easy to administer and score during routine adult cf clinical visits. as many as % of our infrequently evaluated patients had multiple scores that were more than one standard deviation below our clinic mean. we conclude that the cfqr is a useful adjunctive measure to provider assessments and can help focus limited personnel resources. aminoglycoside antibiotics are known to be toxic to the inner ear. however, they continue to have a leading role in the treatment of certain infections and in the treatment of pulmonary exacerbations in patients having cystic fibrosis (cf). while there is ample evidence in the literature of ototoxicity, and there are established protocols for monitoring the effects of toxic agents on hearing, less is known about the prevalence of vestibular toxicity among patients who are exposed, and there are no commonly accepted protocols for monitoring vestibular system function. oscillopsia and unsteadiness when standing and walking are the two most commonly reported and disturbing symptoms associated with bilateral loss of vestibular system function. oscillopsia is the perception that viewed stationary objects or surroundings move coincident with head movement. when it is severe, oscillopsia can prevent an individual from having clear vision with even the slightest head movement. the unsteadiness that accompanies vestibular loss can range from mild to disabling. because of the referral of a number of patients to the vestibular testing center (vtc) at the university of michigan in whom severe bilateral vestibular loss was evident secondary to apparent aminoglycoside toxicity and our concern about quality of life issues, we initiated a quality improvement clinical protocol with our cf patients. vestibular system function and hearing are evaluated at the time of admission for pulmonary exacerbations and coincident with the three month follow-up visit with the pulmonologist. our goal is to understand the incidence of ototoxicity in this patient population, and to determine how best to measure incremental changes over time. the ultimate desired outcome is to investigate the efficacy of protective agents for limiting the toxic impact of these drugs on hearing and vestibular function. to date, we have completed vestibular testing on patients with cf ranging in age from - years, some of whom were referred prior to the initiation of this monitoring program. of the sample, individuals have completely normal vestibular test results, and of the had no prior aminoglycoside exposure. of the remaining patients, have bilateral vestibular loss ranging from mild to severe, two have evidence of a unilateral vestibular loss, and each of the others has non-lateralizing evidence of vestibular involvement. we have also documented change in the three individuals we have seen for repeat testing. specifically, repeat testing has shown incremental decline in vestibular function with repeated exposure to aminoglycosides. interestingly, only individuals in the group have documented hearing loss, and although most report that they do not and have never had any problems with dizziness or balance, many patients have evidence of oscillopsia or abnormal postural control test results. it is clear from our limited data that it is important to monitor vestibular system function whenever potentially toxic agents are used. while monitoring hearing is also warranted, our data suggest that a monitoring program that includes only hearing is insufficient. background: the correlation between bmi, lung function, and longterm outcomes in cystic fibrosis patients has been well documented. based on this data the cf foundation (cff) has established adult patient care guidelines for bmi of or greater for women and or greater for men. in our cf center implementation of nutrition therapies in cf adult patients has been difficult due to lack of acceptance of proposed interventions. due to the importance of optimal nutrition to attain the cff recommendation for bmi, university of cincinnati adult cf center implemented a weight management quality improvement protocol to improve the nutritional status of patients below the cff recommended bmi. our aim is to improve to the nutritional outcomes in our center through patients' acceptance of our nutrition interventions. strategies: as part of the weight management protocol we developed a nutrition action plan, nutrition algorithm, and weight management education record and learning log. the action plan took a systematic approach to weight management, classifying patients into different risk categories based on bmi. patients were categorized as mild nutritional insufficiency (bmi - ), moderate nutritional insufficiency , and severe nutritional insufficiency . each category required a specific action to address weight loss or inability to gain weight. areas of focus for the action plan include; intake assessment through computerized dietary analysis, assessment of pancreatic function, pancreatic enzyme replacement therapy (pert) regimen assessment, hour stool collection for malabsorption, assessment of glycemic control, assessment for gerd, and enteral/parental feeding. the dietitian completed a chart review and nutrition assessment with the patients and classified them into one of the three nutritional risk categories. eleven patients with a bmi below were initially identified. nine ( %) of the eleven patients with a bmi of or less have been approached with the protocol and algorithm. patients completed a three day food journal and oral intake was assessed via computerized dietary analysis. oral enteral supplements were recommended - times per day. g-tube placement was discussed and an educational material on tube feeding was distributed. the protocol and algorithm guided identification and assessment of contributing factors to weight loss. results: of eighty patients seen in the adult center since the beginning of october, thirty-seven of the patients ( %) have a bmi below and eleven patients ( %) have a bmi below . out of the nine patients approached with the protocol % (n= ) completed and returned the three day food journal. of the patients that completed their food journal % (n= ) agreed to a peg placement, one of the patients is still contemplating peg placement while sorting through some psychosocial issues, and the other patient has had a differential diagnosis that might negate the necessity for a peg placement. conclusion: we developed a systematic approach to weight management within our adult cf program. this systematic approach to weight management, which includes patient involvement and specific education, has improved the overall acceptance of nutrition interventions in our adult population. the inpatient care of adults with cystic fibrosis can be a challenging given complicated medical regimens, specialized respiratory care orders, and unique dietary requirements. a large proportion of these patients are admitted to academic centers with rotating house staff that may have never treated an adult with cystic fibrosis. to improve the quality of care of our adult patients we have implemented a standardized electronic order set, a recurring educational program, and a "pocket card" to help the house staff. the adult cystic fibrosis program at vanderbilt cares for over patients, with - inpatient admissions per month. vanderbilt's inpatient order system is completely electronic. we have devised an order set based on our agreed standard of care for inpatients with pneumonia. the order set guides the house staff through most aspects of inpatient care including culturing, antibiotic choice and dosing, dietary consultation, nutritional recommendations, and respiratory care orders. this order set not only educates the house staff on our standard of care but also provides direct access to each order they may wish to enter. we have reiterated this educational process with a pocket sized handout that guides them through the typical issues in adults with cf as well as provide phone numbers to members of the cf team. these resources are presented in short talk given at the beginning of each month to incoming house staff. a preliminary data analysis suggests that over % of all adults with cf are admitted using some component of this order set. an informal survey of the house staff also concludes that the pocket card and lectures have been helpful. all three aspects of this quality improvement have been implemented since december of . we plan to formally test the impact of this intervention when a meaningful number of house staff have been through the service. * background: malnutrition is a common complication of cystic fibrosis (cf). the median bmi percentile in cf patients between the ages of and years is . % but ranges between various centers from . to . percent. previous research has shown a trend toward improvement of pulmonary disease and a significant improvement in weight, height, and bmi z-scores after nutritional supplementation via a gastrostomy tube ; furthermore, fev is positively correlated with bmi percentile. higher weight at three years of age predicts better pulmonary function at six years of age. the effect of gastrostomy tube feedings on pulmonary exacerbation frequency has not been well defined. hypothesis: the incidence of pulmonary exacerbations in children will decrease after the initiation of supplemental gastrostomy feedings. methods: a retrospective chart review of all pediatric patients seen at the cmh cf center, and who received gastrostomy tubes between and was performed. data was evaluated in six month time intervals for two years prior and two years after gastrostomy tube placement. we assessed weight, height and bmi percentiles, fev percent predicted, number of courses of exacerbation therapy (intravenous and oral) and microbiologic data. results: we identified patients, females and males, with ages ranging from months to years of age ( . years mean) at time of gastrostomy tube insertion. all patients had increases in their weight-forage percentile (mean of all patients of . percentile pre to . percentile post, p< . ), height-for-age percentile ( . percentile pre to . percentile post, p< . ), and bmi percentiles ( . percentile pre to . percentile post, p< . ). the mean fev percent predicted declined overall from . % to . % ( . percent predicted per year) over four years in patients. there was a trend of exacerbation reduction after gastrostomy tube placement from to total courses (p= . ). this decline in exacerbations after gastrostomy tube placement was most dramatic in those patients growing pseudomonas aeruginosa without other organisms, with a decline from total courses to total courses in patients (p= . ). discussion: weight, height and bmi percentile improved after initiation of gastrostomy tube feedings. lung function (fev % predicted) decreased at the rate predicted in spite of gastrostomy feedings. there is a trend toward decrease in exacerbation frequency after improved nutrition with gastrostomy tube feedings, especially in patients infected with pseudomonas aeruginosa. limitations of this study include the small sample size, relatively short follow-up time, and the retrospective nature of the study which did not allow assessment of adherence. conclusion: improved nutrition through gastrostomy tube placement may decrease the frequency of pulmonary exacerbations. evidence of an association of improved pulmonary function with improved nutritional status has motivated aggressive nutritional intervention. percutaneous endoscopic gastrostomies (pegs) are employed increasingly in cystic fibrosis to optimize nutritional status. we reviewed our center data over the past years to assess changes in our peg practice and effects on nutritional and pulmonary outcomes. we hypothesized that our change in practice to earlier peg intervention improved patient's nutritional and pulmonary outcomes. we conducted a case controlled retrospective study of pediatric cf patients spanning the past years divided into two periods: p (peg placed before ) and p (peg placed or later) compared with their respective age/sex matched controls. we compared peg vs. control cf patients with respect to age, nutritional and pulmonary status. we compared weight, height and bmi directly preceding peg placement and at approximately one-year post peg. we compared available data for best yearly fev and fvc before peg and at , and -years post-peg. we then compared data between the two time periods. results: peg patients in p (n= ; mean age . + . yrs.) had lower bmi ( z = - . v. - . , p< . ) pre-peg placement compared to controls. by year post peg, the bmi normalized and equaled controls (z=- . v. - . , p= . ). peg patients' fev %ile prior to placement was lower than controls ( v. , p= . ) as was their fvc %ile ( v. , p= . ) and remained lower at year post-peg. following peg placement, absolute bmi increased ( . kg/m , p= . ), as did bmi z-score ( . , p= . ). we did not see significant changes in pulmonary function tests (pft). peg patients in p , (n= ; mean age . + . yrs.) also had lower bmi (z= - . v. - . , p= . ) pre-peg than controls. at year post-peg, the peg patients still had a significantly lower bmi (z = - . v. - . , p= . ). fev was lower in peg patients compared to controls in pre-, year, and -year post-peg data (p< . ). variability in pfts and small sample size limited our analysis. pre-peg weight, height, bmi, fev and fvc were lower in p patients compared to the younger p patients. at -year post-peg, similar bmi zscores (- . , p= . ) was obtained between the two periods. variability in pfts among the patients within each period prevented valid comparisons, although p tended to have better pft values. conclusions: peg placement was effective at improving nutritional status in patients with cystic fibrosis. placement in younger patients with better pre-peg nutritional and pulmonary status allowed more complete nutritional recovery. we speculate that improved height z-scores with apparently stable fev is consistent with increased pulmonary growth. demonstration of an attenuated rate of pft decline to correlate with this earlier intervention will require a larger population and longer observation period. a multi-center longitudinal outcome study would help determine optimal timing and criteria for peg intervention. . pediatric gastroenterology and hepatology, university medical center groningen, groningen, netherlands; . biochemistery, erasmus medical center, rotterdam, netherlands background: ursodeoxycholic acid (udca) treatment is frequently applied for cystic fibrosis-related liver disease (cfld). it has been hypothesized that udca is beneficial through its choleretic activity, i.e. its capacity to induce bile flow. the hepatic expression of the cftr protein is restricted to the cholangiocytes lining the bile ducts. cholangiocytic cftr is involved in the generation of ductular bile flow. it is not known to what extent the choleretic activity of bile salt treatment depends on expression of competent cftr protein, and whether or not udca differs in this respect from other bile salts. we evaluated the role of cftr in the acute and chronic choleretic effect of bile salt treatment, through comparative studies in cftr-null, homozygous f del, and corresponding wild type control (wt) mice. methods: bile flow was determined after gallbladder cannulation. bile flow during the first minutes after acute interruption of the enterohepatic circulation was regarded as basal bile flow. after min, taurocholic acid (tca) or tauroursodeoxycholic acid (tudca) were iv administered in stepwise increasing dosages, up to nmol/min/ g bw, to cftr-null mice and wt littermates fed a standard chow diet. other cftr-null, homozygous f del mice and their respective wt littermates were fed either the standard chow, or the same diet supplemented with cholic acid (ca, . wt%) for weeks. finally, cftr-null mice and wt littermates were fed the standard chow or the same diet supplemented with ursodeoxycholic acid (udca, . wt%) for weeks. : upon a regular chow diet, the basal bile flow was similar in cftr-null and homozygous f del mice, compared to their respective wt littermates (cftr-null, . ± . vs. . ± . ; and, f del(∆/∆), . ± . vs. . ± . µl/min. g bw, resp.; ns). iv administration of tca or tudca to cftr-null mice and wt littermates increased bile flow to similar extents. dietary ca treatment increased basal bile flow significantly less in cftr-null and homozygous f del mice than in their respective wt littermates (cftr-null, . ± . vs. . ± . , p< . ; and, f del(∆/∆), . ± . vs. . ± . µl/min. g bw, p= . ; resp.). interestingly, dietary udca treatment increased basal bile flow more profoundly than ca treatment, and to similar levels in cftr-null mice and wt littermates (+~ %, . ± . vs. . ± . µl/min/ g bw, resp.; ns). conclusion: upon chronic treatment, udca is highly choleretic in mice, independently of the presence of functional cftr. the independence of functional cftr is udca specific, since the choleretic activity of chronic ca treatment is diminished in cftr-null and homozygous f del mice. we speculate that this specific, cftr-independent choleretic effect of chronic udca treatment could be therapeutically important for cystic fibrosis. most cystic fibrosis (cf) patients have mild to moderate focal portal tract changes (ductal obstruction and cholangitis) and hepatosteatosis. etiology of severe liver disease (ld)with cirrhosis and portal hypertension which occurs in - % of cf patients is unknown. the c bl/ j congenic cf mice develop progressive cf-like ld. as a useful therapeutic model, we have shown that dietary addition of docosahexaenoic acid (dha) significantly ameliorates inflammation but has little effect on ductal obstruction (am j physiol gastrointest liver physiol : g -g , ) . we hypothesized that treatment with udca,a hydrophilic bile acid will ameliorate portal tract ductal obstruction and have an additive effect with dha in preventing ld. methods: thirty-day old wild-type and cf littermates are fed peptamen and either olive oil or dha, with and without . % udca ( groups, mice/group). mice are killed following days of treatment and bile salts, serum liver enzymes and serum and tissue lipids analyzed. h&e stained liver tissues are coded and assessed blindly by an expert hepatopathologist (jp) for evidence of hepatosteatosis, inflammation, bile duct obstruction, fibrosis and other signs of liver pathology. an arbitrary scale of to is used, with representing no pathology and being the most severe. we present interim statistical analysis performed for pathology results only for untreated mice (wt, n= ; cf, n= ); treated mice with dha, (wt, n= ; cf, n= ), treated mice with udca (wt, n= ; cf, n= ) and treated mice with udca and dha (wt, n= ; cf, n= ). results: mean pathology scores from groups of mice are pooled to examine the effects of genotype, treatment and diet (table) . at present,the bile,lipid and liver biochemical test data are insufficient to perform statistical analysis. udca-treated mice have significantly increased bile duct obstructed scores compared to the untreated mice which subanalyzed (not shown) reveals increased bile duct obstruction in the wild-type littermates and no effect in cf mice. hepatosteatosis and inflammatory scores in the untreated mice (fed olive oil) are increased compared to the mice treated with dha. summary: we anticipate completing and performing final analysis within six months. however, these preliminary data confirm that dha reduces inflammation in c bl/ j mice livers and suggest that udca therapy has an adverse effect in wt mice and is not effective in ameliorating liver disease in cf mice. udca with dha therapy does not appear to have an additive effect in ameliorating cfld in this mouse model. supported by axcan pharma inc. background the cf mouse intestine has an innate response associated with small intestinal bacterial overgrowth (sibo). a previous affymetrix genechip analysis of the cf mouse intestine showed altered expression of several eicosanoid metabolic genes. eicosanoids are biologically active arachidonic acid metabolites with a variety of pro-and anti-inflammatory actions as well as effects on mucus production, electrolyte transport, and gastrointestinal motility, all of which are of potential importance to the cf phenotype of the intestine. methods wild type (wt) and cf mouse (cftr tm unc ) littermates congenic on the c bl/ j background were fed an elemental liquid diet (peptamen). intestinal rna was isolated for quantitative rt-pcr of expression levels of genes involved in eicosanoid metabolism to confirm and extend the genechip analysis. various eicosanoids were measured in small intestinal lavage fluid using specific enzyme immunoassays. results we confirmed microarray results by qrt-pcr that the following genes were differentially expressed in the cf small intestine relative to wt: cyp a (cytochrome p a ; -hete synthesis; % of wt); ltb dh (leukotriene b dehydrogenase; metabolizes prostaglandins and leukotrienes; % of wt); cyp c (cytochrome p c ; -hete synthesis; % of wt); ltc s (leukotriene c synthase; ltc synthesis; % of wt); hpgd (hydroxyprostaglandin dehydrogenase ; metabolizes prostaglandins; % of wt); and pla g (group phospholipase a ; potentiates arachidonic acid generation; % of wt). non-significant or less than -fold changes in gene expression were measured for: cyclooxygenase (cox) genes, pge synthase, pgi synthase, and -and -lipoxygenases. as measured by their stable metabolic products, pge and pgf α were significantly increased in the cf mouse intestine ( % and % of wt, respectively). the following eicosanoids were significantly decreased in the cf mice: -hete ( % of wt), -hete ( % of wt) and -hete ( % of wt). there were not significant changes in the levels of pgi , pgd , ltb , cys-lts, or lxa . the changed levels of eicosanoids are generally consistent with the differential gene expression. conclusions there are significant changes in expression of eicosanoid metabolic genes and certain eicosanoids in the cf mouse small intestine. the increase in pla g and decrease in cyp expression levels are expected to make more arachidonic acid available for eicosanoids except hetes. decreases in degradative genes (hpgd, ltb dh) will prolong availability of prostaglandins. altered levels of eicosanoids are expected to play important roles in the pathophysiology of the cf intestine. elevated pge may contribute to increased mucus secretion which is characteristic of cf. pgf α and pge regulate intestinal motility and small intestinal transit is slower in cf patients and in cf mice. the hetes are mostly known for their effects on vascular tone and electrolyte transport in the kidney but are less-well characterized in the intestine. their dramatic decrease in the cf intestine may affect blood flow, electrolyte transport, intestinal motility, or other gi functions. the specific effects of the altered eicosanoid metabolism in cf remain to be explored. supported by cff grant delisl g . for the scandinavian study consortium. background: progressive pulmonary disease, correlating with igg levels, is a major cause of morbidity and mortality in cf patients. recently, immunosuppressive effects of vitamin d and a potential role of vitamin d deficiency in the pathophysiology of autoimmune diseases have been described. we investigated whether vitamin d deficiency could contribute to the chronic proinflammatory state characterizing cf and the higher occurrence of immune-hyperreactivity-related conditions in cf patients. methods: multiple linear regression analysis, taking the confounding factor of age into account, was used to evaluate the relationship between cross-sectionally determined vitamin d variables and: lung function parameters, inflammatory parameters and immune hyperreactivity markers in patients followed at the cf centers in sweden, norway and denmark. vitamin d intake was based on a -day precoded dietary food record, calculated in the national food databases. findings: in the population of all patients included in the study (n= ), blood vitamin d positively correlated with fev (p< , ) as well as with fvc (p< , ). negative correlation was found between blood vitamin d and igg (p< , ), supplemented vitamin d per kg bw and igg (p< , ), total vitamin d intake per kg bw and igg (p< , ). additionally, lower blood vitamin d levels were related to both presence of pathological ogtt (p< , ) and occurrence of cfrdm (p< , ). correspondingly, food vitamin d (p< , ), food vitamin d per kg bw (p< , ), supplemented vitamin d (p< , ), supplemented vitamin d per kg bw (p< , ), total vitamin d intake (p< , ) and total vitamin d intake per kg bw (p< , ) all correlated negatively with hba c values. most of the studied vitamin d variables were lower in patients with endomysial antibodies positivity (n= ) and higher in patients with abpa (n= ) than in the rest of cf population studied (ns). interestingly, in children (n= ) blood vitamin d correlated negatively with transglutaminase levels (p< , ) and there was also a significant negative correlation between hba c and vitamin d intake. surprisingly, in adult cf patients (n= ) iga positively correlated with total vitamin d intake (p< . ) and total vitamin d intake per kg bw (p< . ). in the population of stockholm cf-center patients (n= ), where it was possible to allow for the influence of both age and compliance, negative correlation between blood vitamin d and igg (p< . ) was found. after allowing for age, compliance showed significant correlation only with igg (p< . ) and esr (p< . ), and with none of the rest of the studied variables. conclusions: vitamin d deficiency might contribute to the continuous shift towards inflammation as well as to the higher prevalence of dm and celiac disease in cf patients. new recommendations for vitamin d supplementation and monitoring of blood vitamin d levels are needed, in order to improve immunological balance and decrease the need for anti-inflammatory therapy in cf patients. supported by swedish heart lung foundation, stiftelsen frimurare-barnhuset i stockholm, norwegian and swedish cystic fibrosis associations, and by an unrestricted grant from solvay pharma. von drygalski, a.; biller, j.a. medical college of wisconsin, milwaukee, wi, usa anemia is associated with increased morbidity and mortality in other chronic diseases, but little is known about anemia in cf. recognition and correction of anemia in cf might lead to better outcomes. chronic inflammation, iron deficiency and malabsorption may be important mechanisms contributing to the anemia in cf patients. we hypothesized that anemia might be correlated with poor lung function. methods: clinical charts and portcf.org visit logs of patients of all ages ( m to yrs) with cf were reviewed for as many years as charts permitted (range - yrs). the following data were extracted: cbc, iron studies, pulmonary function tests (pfts), vitamins a, d, and e levels, creatinine, pertinent medical history, and current medications. anemia was defined by age-and gender-specific world health organization (who) criteria. patients were considered anemic if low hemoglobin(hb) was present on two separate occasions at least two months apart, or average annual hb met who criteria. pfts in patients (all > yrs) included forced expiratory volume (fev ) and forced vital capacity (fvc) as percent predicted of normal and were considered a reflection of patient performance. the most representative annual pft from at least annual tests was chosen for analysis since acute infection adversely influences daily performance. results: of patients were anemic (prevalence %). prevalence of anemia increased with age from . % in patients < age to % in patients > age and was significantly higher in patients with vitamin deficiencies. % vitamin-deficient patients vs. . % non-vitamin deficient patients were anemic (p= . ). mean hb was . mg/dl (range . - . ). roughly two thirds of patients had moderate and severe anemia (hb < mg/dl) with no gender difference in regard to prevalence or severity identified. complete iron studies were available in / patients. were identified as iron deficiency anemia (ida), as anemia of chronic illness(aci), and as combined; others had renal failure. in patients, iron studies were incomplete, but renal failure, hemoptysis, hematochezia and solid organ transplants were contributing factors in half. pfts obtained in patients ≥ yrs were compared in anemic and non-anemic patients. mean fev and fvc at all ages were statistically significantly poorer in the anemic patients (p < . ). complete iron studies were also available in non-anemic patients with impaired lung function. / patients had ferritins < ng/ml suggesting relative iron deficiency. conclusions: the prevalence of anemia in cf patients is high and increases with age. in patients for whom iron studies were available, ida was the prominent underlying mechanism, followed by aci or a combination of both. in addition, a group of non-anemic patients with poor lung function had relative iron deficiency. the strikingly significant association between anemia and poor pulmonary function as well as the higher prevalence of anemia in vitamin deficient patients uncover anemia as significant co-morbidity in cf. identification of iron deficiency in anemic as well as in non-anemic patients with poor lung function could be important since iron supplementation might allow hb levels to increase as an appropriate response to hypoxia. oral administration of dha to a cf mouse model corrected the lipid imbalance and reversed certain pathological manifestations in tissues affected by cf. the aim of this study was to investigate the metabolism of la through the n- pathway, and to determine the effect of dha supplementation on la metabolism in cultured cells with a cf phenotype. methods: sense (wt) and antisense (cf) cftr hbe cells were cultured in mem containing % horse serum. cells were supplemented with various concentrations of la (ranging from to µm) and dha ( , , and µm) for one week. cellular lipids were extracted from confluent monolayers, and fatty acids were methylated and analyzed by gc-ms. metabolism through the n- pathway was studied by incubating the cells with . µm [ c] la for hours, and quantitating its downstream metabolites by hplc. results: the levels of la and dha were significantly decreased in cf cells compared to wt cells (la in wt: . ± . , cf: . ± . %, p< . ; dha in wt: . ± . , cf: . ± . %, p< . , mean ± sem for each). la supplementation resulted in an increase in la and aa levels in both wt and cf cells. at most la concentrations tested, la levels were significantly lower and aa levels were significantly higher in cf cells, indicating an increased production of aa from la in cf cells. the study of [ c] la metabolites showed an increased production of multiple downstream fatty acids including : n- ( . fold), aa ( . fold), and : n- ( . fold) in cf cells compared to wt cells, further substantiating an increased metabolism through the n- pathway. supplementing hbe cells with dha for week resulted in a significant increase in la levels and a corresponding decrease in aa levels in wt and cf cells. when supplemental dha was added in combination with la, dha inhibited the la-derived increase in aa levels in cf cells and normalized them to the wt values. the formation of [ c] la metabolites was inhibited after -hour supplementation with dha. this inhibitory effect of dha was greatest on aa production, and it was more prominent in cf than in wt cells (wt: . fold, cf: . fold decrease in aa production). conclusions: decreased la levels in cf are at least in part related to increased la metabolism through the n- pathway. the fact that dha supplementation decreased the flux from la to fatty acid metabolites in the n- pathway, especially to aa, may partially explain dha's mechanism of therapeutic benefit. these data would also suggest that dha combined with la in the diet may normalize fatty acid metabolism in cf patients. background: decreased levels of linoleic acid (la) and docosahexaenoic acid (dha) have been found in the blood and tissues of cf patients. studies on cultured cf cells and cftr-/-mice have indicated that decreased la levels in cf might be related to its increased metabolism through the n- pathway. other potential mechanisms of the observed decreased la and dha levels in cf could be related to altered cellular uptake of these two essential fatty acids. the goal of this study was to investigate the uptake of la and dha into cultured cf cells, and their distribution among the major lipid classes. methods: sense (wt) and antisense (cf) cftr hbe cells were cultured in mem containing % horse serum. the uptake of la and dha into the cells was studied by incubating the cells with . µm [ c] la or [ c] dha for hour and hours, followed by measurement of radioactivity in the supernatant and cell lysate. lipid fractions from the cells (total phospholipids, triglycerides, cholesteryl esters, and free fatty acids) were separated by thin layer chromatography (tlc), and the fatty acid composition was determined by gc-ms after methylation. incorporation of la and dha into cellular lipid fractions was determined by incubating the cells with . µm [ c] la or . µm [ c] dha for hour and hours, followed by tlc separation of lipids and measurement of radioactivity associated with the various fractions. (all data are mean±sem). results: the levels of la and dha were significantly decreased in cf cells compared to wt cells (la in wt: . ± . , cf: . ± . %, p< . ; dha in wt: . ± . , cf: . ± . %, p< . ). fatty acid composition analysis of lipid fractions indicated that la levels were significantly decreased in the phospholipid and triglyceride fractions of cf cells ( . % and . % of the wt values, respectively), and dha levels were significantly decreased in the phospholipid fraction of cf cells ( . % of the wt values). the uptake of la was significantly higher into cf cells compared to wt cells at hour (wt: . ± . , cf: . ± . dpm/µg protein, p< . ) and hours (wt: . ± . , cf: . ± . dpm/µg protein, p< . ). the uptake of dha was also significantly higher in cf cells compared to wt cells at hour (wt: . ± . , cf: . ± . dpm/µg protein, p< . ) and hours (wt: . ± . , cf: . ± . dpm/µg protein, p< . ). incorporation of la and dha was increased in the phospholipid, cholesteryl ester, and free fatty acid fractions of cf cells at hours. dha, but not la, incorporation was significantly increased in the triglyceride fraction of cf cells. conclusions: low la and dha levels in cf cells are associated with a decrease in cellular lipid fractions, the largest of which is in total phospholipids. there is an increased uptake of la and dha into cf cells, and into most lipid fractions of these cells. the decreased levels of la and dha in cf cells, despite their increased cellular uptake and esterification in lipid classes, indicate that there is increased mobilization of these fatty acids in cultured cf cells. perez, a.; issler, a.; davis, p.b. pediatrics, cwru, cleveland, oh, usa even though lung disease continues to be the primary cause of death in cystic fibrosis (cf), the considerable increase in life expectancy of the cf patient over the last decades, has made management of the diverse gastrointestinal and nutritional complications in the adult cf increasingly important. malnutrition and fatty acid deficiency has been a hallmark of cf and its impact in long-term lung health has been established. data obtained by us using affymetrix mg-u av arrays from ileum and liver of pristine -week-old male mice bearing the y x cf mutation and their normal littermates, indicates that there is a profound disturbance in genes associated with lipid metabolism, many of which are regulated by the peroxisome proliferator-activated receptor-gamma (pparγ), a ligand-regulated transcription factor that regulates lipid metabolism and possess anti-inflammatory properties. we hypothesize that lack of cftr function results in altered expression of pparγ regulated genes in the gut and liver, leading to the fatty acid metabolism abnormalities observed in cf. pparγ mrna and protein levels were measured in ileum, colon, liver, and fat of week old female mice bearing the cf mutation s x and its wt littermates (c bl/ j background), and fabpcftr mice (gut corrected, mixed background) after the administration of ethanol or pioglitazone (a pparγ agonist, mg/kg) by gavage every h for days, sacrificed h after last dose. highest pparγ mrna levels were found in fat, followed by colon, liver, and lowest in ileum. at basal state, mrna levels were higher only in fabp ileum vs. wt and fabp colon vs. cf. after treatment, higher expression was seen in cf and fabp ileums and cf liver vs. controls and wt treated mice. however, there were striking differences at the protein level, especially in the colon. at basal state, pparγ was localized, mainly at the surface of the epithelia in wt, in crypts in cf, and mainly in crypts but extending towards the surface in fabp mice. upon treatment, pparγ location in wt colon moved almost exclusively to the crypts, and in the cf and fabp mice, although expression remained mainly in crypts, pparγ could now be seen at the surface. changes in pparγ protein were also seen in ileum and especially liver, between wt and cf, at basal and upon treatment, but changes were subtle and will require more sensitive methods to further examine them. we also examined mrna and protein levels for several genes involved in fat processing that could be related directly or indirectly to pparγ. mrna and protein levels for aqp and cubilin, and protein levels for megalin, apoa- , and apob- were reduced in the ileum of cf mice compared to wt. our data indicates a pparγ dysfunction in the gastrointestinal system of cf mice, which could be responsible for the gastrointestinal manifestations observed in cf. understanding the association between pparγ, cftr, and fat processing may help us to develop new therapies directed towards improving the nutritional status of cf patients that, in the long run, will influence their lung health. cf is characterized by low linoleic acid (la) and docosahexaenoic acid (dha) levels. although this could be due to a primary abnormality in fatty acid biosynthesis, this could also be explained by alterations in phosphatidylcholine (pc) formation. pc are formed by two pathways. the most utilized is the de novo conversion of choline to pc via the cdp-choline pathway, which preferentially forms pc containing saturated and monounsaturated fatty acids. in the other pathway phosphatidylethanolamine (pe) is converted to pc through three methylation steps utilizing the enzyme phosphatidylethanolamine n-methyltransferase (pemt). this pathway preferentially forms pc containing polyunsaturated fatty acids. thus decreased pemt activity would be predicted to result in decreased dha and la levels. this is supported by results seen in pemt knockout mice (watkins et al, j nutrition, ) showing decreased dha and la levels, and variable to increased levels of arachidonic acid (aa). furthermore, innis et al have shown that cf patients have decreased choline levels making them more dependent on the pemt pathway. we hypothesized that alterations in fatty acid levels in cf may be due at least in part to decreased pemt activity. methods: cftr -/mice (cf) and wt littermates were fed with either a diet containing choline (control) or, in order to mimic choline status in humans, an otherwise matched choline deficient (cd) liquid diet for days. choline levels were measured using a kit. livers were perfused and microsomes prepared. to measure pemt activity, microsomes were incubated with radioactive s-adenosylmethionine in the presence of dimethyl pe. the pc product was extracted and radioactivity measured. fatty acids from liver and pancreas were analyzed by gc/ms. results: there was no difference in choline levels in serum or liver comparing wt and cf mice. there was no difference in pemt activity in livers from cf mice compared to wt on control diet. cf mice on cd diet had decreased pemt activity in the liver compared to wt mice on cd diet (wt: ± ; cf: ± cpm/mg protein/min; p< . conclusion: induction of choline deficiency in cf mice to mimic the situation in cf patients, leads to decreased pemt activity. this resulted in low la levels compared to wt mice in both the liver and pancreas and indicates that the fatty acid abnormality in cf is at least in part due to defective pc metabolism through the pemt pathway. ( ). urolithiasis appears to be more common in adult cystic fibrosis (cf) patients than in the general population. a variety of urinary findings have been observed which could account for this, including low volumes, raised oxalate and low citrate, but not all the reports are consistent. most cf patients have pancreatic insufficiency and a plausible explanation for an elevated oxalate excretion in these patients is malabsorbed fat in the intestinal tract sequestering calcium and permitting more oxalate to be absorbed from their food. if this were the mechanism for the elevated stone risk in cf patients then we would expect to observe differences in stone incidence and oxalate excretion between cf patients with exocrine pancreatic sufficiency (ps) and pancreatic insufficiency (pi). methods diagnosis of cf is by clinical and genetic criteria and ps or pi status is based on faecal elastase measurement. patients and healthy volunteers (hv) provided h urines for analysis of volume, ph, ca, mg, na, k, po , oxalate, citrate, creatinine, urea. supersaturations were calculated using equil . there is a history of renal stone disease in out of cf patients attending our unit. patients have pi and include of the stone formers. the remaining stone former is amongst the ps patients. no significant differences in urine chemistry or derived supersaturations were found between the cf patients without a history of stones that were ps (n= ) or pi (n= ). nor were any such differences found when stone forming cf patients were included (ps, n= ; pi, n= ) or when the healthy volunteers were included in the ps group (ps, n= ; pi, n= ). amongst the cf patients, only citrate and creatinine excretions were significantly different between stone formers (n= ) and non stone formers (n= ) (medians (mmol/ h), citrate, . vs. . , p= . ; creatinine, . vs. . , p= . ) . the difference in creatinine excretion can be accounted for by the difference in body mass of these two groups (median (kg) . vs. . , p= . ) compared to the hv, the cf patients with a history of stones had significantly lower citrate excretion and higher calcium oxalate supersaturation (medians, citrate (mmol/ h), . vs. . , p= . ; . vs. . , p= . ) conclusions there is no evidence to suggest that the prevalence of stones is different in the ps and pi groups nor could we detect any difference in excretion of oxalate or any other urine variable related to pancreatic sufficiency. comparing those with and without stones, the only consistent finding was a lower citrate excretion by stone formers. between the hv and stone formers this was also associated with a significantly reduced calcium oxalate supersaturation. our evidence does not support the hypothesis that fat malabsorption by the majority of cf patients contributes to an elevated risk of renal stone disease. we undertook assessment of the use of a hypopharyngeal sensor for detection of laryngopharyngeal reflux in infants and children. gastric reflux in the airway, or supraesophageal reflux, commonly takes a gaseous form that cannot easily be measured using conventional technology. the miniaturized ph sensor at the tip of the dx-ph probe is the only sensor able to measure ph in the airway. fifteen infants and children referred to the pediatric pulmonary center for assessment of chronic cough, hoarse voice, or uncontrolled asthma unresponsive to usual medical intervention underwent - hour to placement of the dx-ph probe in supplementation of radiologic assessment of gastresophageal reflux. the probe was placed transnasally and visualzed in the hypopharynx with the red light at the tip. drops in ph < were correlated with food and symptom diaries. positive results were found in / patients, leading to surgical intervention in three patients. one patient with cystic fibrosis age months with failure to thrive underwent study for symptoms of cough. upper gi demonstrated no gross gastroesophageal reflux or anatomic obstruction.gastric emptying scan was mildly prolonged. outpatient supraesophageal ph probe demonstrated drops to ph< associated with respiratory symptoms. patient underwent nissen and g tube placement with resolution at six week follow-up.the patient returned at age six months with onset cough and underwent repeat study. there were no drops in ph and the cough responded to oral steroid burst. the device was tolerated in / patients with early removal in one young adult with endstage neuromuscular disease and in an infant with "colic" due to a hysterical parental reaction.as a result of our experience we have incorporated the use of supraesophageal ph monitoring into our practice, with particular attention to infants with persistent asthma and children with histories suggestive of gastric asthma. we have now incorporated it into our vivometrics lifeshirt, an ambulatory physiologic monitoring device which will allow us to examine supraesophageal ph and its relationship to sleep apnea, cough, tachycardia, tachypnea, and hypoxemia. aim: monitoring and adjusting dose requirements of pancreatic enzyme replacement therapy (pert) are an integral part of the dietetic assessment of patients with cf. we investigated characteristics of enzyme use in our adult clinic population and determine the extent to which inappropriate enzyme use contributed to poor nutritional and clinical state. method: information was collected using an annonymous self-administered questionnaire developed to measure patient practice, knowledge and beliefs on pert. exclusion criteria included pancreatic sufficiency, < units lipase/kg/d, and fev < %. results: out of potential clinic population of patients completed the questionnaire ( - y, % male, fev - %). % of participants reported to never miss enzymes with meals; this was considerably lower for snacks ( %). those patients who omit enzymes with meals also missed enzymes with snacks (r = %, p< . ). a more appropriate use of pert was observed in patients with lower as opposed to higher bmi. despite intensive dietetic input % of patients missed pert with foods containing fat and % took pert inappropriately with food and drink that did not contain fat. the results identified potentially better practices for measuring pert behaviour and knowledge: ) taking pert with all meals, ) taking pert with majority of snacks ) swallowing capsules intact rather than splitting them open, ) carrying enzymes around with them and ) the ability to titrate pert in accordance to the fat content of food. patients were scored on the basis of the above criteria to differentiate between prudent enzyme users and those who are compromising therapy. in conjunction with their nutritional status score (bmi and gastrointestinal symptoms) risk for intervention can be assessed. discussion:underweight patients have more optimal enzyme use, suggesting greater dietetic involvement in these patients. schall et al also found this to be the case in children. the findings emphasised the need for targeted and effective input in patients where problems are less obvious. the questionnaire has been a useful research tool, and has been adapted as a screening tool for dietitians to gain a subjective perspective of patient's enzyme management and identify patients who need support. the combination of patient's pert usage and their nutritional status could help capture and identify risk objectively and quickly and allows resources to be allocated most effectively. schall . ), nutritional failure, measured as bmi< , (p> . ), or lung transplant status (p> . ) between patients with and without colonic wall redundancy. there was no significant difference in cftr function, per sweat chloride values, between groups (p> . ). conclusion: we report a previously undescribed colonic wall abnormality seen on ct in patients with cystic fibrosis: proximal colonic wall redundancy was found in % of adults with cystic fibrosis, but not in children, appeared to be chronic, and was associated with non-∆f cftr gene mutations, particularly the g x mutation. recognition of the ct appearances will prevent erroneous diagnosis of acute colonic disease in this patient population, and stimulate investigation of a biologic basis for this finding as a recognizable feature of adult cystic fibrosis. intro: infants and children with cystic fibrosis, both pancreatic sufficient and insufficient, are at risk for developing hyponatremia due to an excess loss of salt though skin during sweating. these children should receive daily supplemental sodium. children without cf require - meq/kg of sodium daily; and one could argue children with cf need more. a historical recommendation is / tsp table salt daily for infants; this contains to meq of sodium based on the density of the table salt. parents may measure the salt inaccurately, and it may be difficult logistically to distribute the salt throughout the day. if supplementation is given as sodium chloride solutions distributed through pharmacies, as suggested in a recent consensus conference, co-pays or full payments may be required. our aim is to provide a simple, inexpensive, and more accessible method for accurately giving sodium supplementation. do pre-packaged salt packets contain a precise amount of sodium and thus could be recommended to fulfill the daily requirement of sodium in patients with cf? method: pre-packaged table salt packets were collected with permission from four national fast food restaurants and one commercial salt producer. contents (sodium chloride) of ten packets from each source were weighed individually. measurements were made using a scientific scale with the ability to measure up to / , of a gram. weights of sodium chloride from individual packets were converted to meq sodium. means, ranges and standard deviations were calculated for the data using microsoft office excel ™ program. see table conclusions: there is some variability in the content of pre-packaged salt packets, both between and within brands, though some brands have less variance than others. measurements showed that packages contained mean values of approximately to meq of sodium. there is a range in the sodium dose recommendations, and spot urine sodium can be used to determine if patients are sodium depleted. pre-packaged salt packets lack the precision of pharmacological dosing but are inexpensive, practical, and supply a reasonably predictable dose of sodium. background: ten to forty percent of people with cf have vitamin d deficiency secondary to pancreatic insufficiency. obtaining optimal vitamin d levels ( -ohd) has been a challenge. for vitamin d deficient individuals, current supplementation strategies ( , iu weekly for months) have been mostly unsuccessful. objectives: to identify individuals at risk for vitamin d deficiency and to evaluate the efficacy of a week repletion course of high dose ergocalciferol in children and young adults with cf. methods: as part of a quality improvement initiative, a prospective cohort study was performed from january to april . phase i included querying our cf practice database to identify patients who were due for annual routine blood tests or who had recently documented levels of -ohd less than ng/ml. in phase ii, , iu of daily ergocalciferol was prescribed for a day period as part of routine inpatient or outpatient care. during phase iii, a post treatment -ohd level was obtained. baseline subject characteristics were obtained at entry and included age, gender, pubertal status, pancreatic status, and fev %. post -ohd levels were classified as sub therapeutic (< ng/ml), therapeutic ( - ), high therapeutic ( - ), or potentially toxic (> ). a paired t test was performed to evaluate pre and post intervention differences. the impact of age, gender, and lung function on the response to vitamin d supplementation were also analyzed. all values are expressed as mean ± standard deviation. results: eighteen individuals with cf participated in the study. the mean age was years with a range of to years. . % were male, and % were pancreatic insufficient requiring pancreatic enzyme replacement. fev % was . ± . %. all participants had -ohd levels less than ng/dl pre-treatment. -ohd levels increased from . ± . to . ± . (p< . ). of the participants ( . %) became therapeutic over the two week interval. an increase of . ± . (ng/ml) or % was seen in the two week period. no correlation was seen on the extent of increase in -ohd and baseline lung function. pre and peri pubertal individuals had a greater increase in -ohd levels than post pubertal individuals ( . ± . vs . ± . , p< . ) although the magnitude of change did not reach significance. the degree of response also appeared related to age (r=- . ). no impact of gender was seen. seven individuals achieved normal therapeutic values while were in the high therapeutic range. no participants had toxic levels. conclusions: the results of this study demonstrate that high dosing of ergocalciferol over a day period is an effective strategy in achieving therapeutic levels of vitamin d. it is unclear whether a pubertal effect on the degree of response exists or if this response is merely age related. further research is needed to evaluate whether this strategy is able to maintain therapeutic levels after completion of the intervention. additional studies that monitor compliance and evaluate responders and non-responders are needed. foundation consensus committee established guidelines for optimizing bone health in individuals with cf, including screening for vitamin d insufficiency and a treatment protocol for achieving and maintaining normal serum vitamin d concentrations. however, since the guidelines were published, there has been additional research assessing various vitamin d treatment regimens and their effect on serum vitamin d concentrations. in addition, vitamin d assay variability has recently been well documented. the objective of this study was to evaluate variability of vitamin d surveillance methods as well as treatment protocols used to treat low vitamin d concentrations at cf centers. methods: a survey was created via survey monkey, and was sent to the cf nutrition listserv, which includes over cf healthcare providers. spss version . was used for statistical analysis. results: fifty-nine listserv members responded to the survey. the majority ( %) of respondents measured oh vitamin d concentrations, and % considered patients to be vitamin d deficient when serum concentrations were below ng/ml. however, % were monitoring only , oh vitamin d or a combination of both concentrations. there was considerable variability in vitamin d supplementation protocols for treating low oh vitamin d concentrations. only % were following the consensus guidelines of , units of ergocalciferol once/week for ages through adults. one third indicated that they followed consensus guidelines for patients less than age ; however nearly half of the remaining two thirds were not sure what is prescribed or have not observed low vitamin d concentrations in this age group. fifty-two percent of respondents were aware of vitamin d assay variability. despite this knowledge, the majority were unaware of the type of vitamin d assay used to measure serum vitamin d concentrations at their institution. conclusions: there is considerable variability in the measurement and treatment of vitamin d concentrations across cf centers despite guidelines provided via a cff consensus report. the consensus guidelines for measuring vitamin d concentrations and treatment of vitamin d insufficiency should be revisited based on recent studies and expert opinion. children with cystic fibrosis (cf) who suffer from sub-optimal growth are offered overnight enteral feeding via gastrostomy tube. this study aimed to assess the nutritional impact of overnight feeding over a year period using a retrospective study design. data, including height, weight, fev , pancreatic function were collated for all patients with cf who had a gastrostomy tube placed in the past years. data were collected at baseline and then every months for years post-gastrostomy insertion. data for height, weight and body mass index (bmi) were converted into z scores using centre for disease control reference ranges and the lms method ( , ) . a total of patients ( . % of the clinic population) were identified as having a gastrostomy tube. two were no longer receiving feeds and there were incomplete data for subjects. on placement of the tubes, there were substantial deficits in nutritional status with mean z scores for height - . (sd . ), weight - . (sd . ) and bmi - . (sd . ), with compromised lung function (mean fev %, range - ). using a repeated measures anova with fev as a co-variate, there were no significant differences in weight, height or bmi from baseline to years (at years post placement: mean z scores for height - . (sd . ), weight - . (sd . ) and bmi - . (sd . ). fev remained stable over time. these results indicate that gastrostomy feeding can potentially halt the decline in nutritional status that is a feature of cf. however, patient expectations that over night enteral feeding will lead to an increase in nutritional status need to be sensitively managed. background : cystic fibrosis (cf) is the most common life threatening autosomal recessive disorder in caucasians.following a landmark paper by corrie et al a high fat,high calorie diet has promoted a normal growth pattern.improved nutritional status together with prevention and early treatment of respiratory infections has contributed to improved survival. objective: the aim of this study was to assess the relationship between lean body mass and disease severity in children with cf. methods: the nutritional status and body composition of children with cf was measured using a harpenden stadiometer, calibrated electronic scales and a ge lunar prodigy densitometer. the following indices were calculated; body mass index (bmi), fat mass (expressed as logarithm % total body fat (ln%tbf) and fat free mass (ffm). body composition data were expressed as z-scores using dutch reference values. correlations were performed between indices of nutrition (bmi, height, ffm, tbf) z scores and markers of disease severity (percent predicted fev and shwachman kulczycki (sk) scores).the nutritional status of these children was also compared with healthy controls. statistical analyses were performed using microsoft excel . results: there was a weak but significant correlation between sk scores and height z score and ffm (r = . , p< . & r = . , p= < . respectively). there was also a weak but significant correlation between % predicted fev and bmi and ffm (r= . , p < . , r= . , p< . ). height and weight z scores were significantly lower in children with cf (- . and - . respectively) than in control subjects ( . and . respectively) with p < . in both groups. conclusion: this study demonstrates that there is an association between indices of nutrition and disease severity in children with cystic fibrosis. muscle mass (ffm), assessed by dual energy x-ray absorptiometry (dxa) correlates with lung function and with sk scores. the strongest correlation between markers of disease severity (sk scores and % predicted fev ) was with ffm. ffm may be expected to be associated with respiratory function tests.however,sk scores are a more general assessment of well being and less obviously directly related to muscle mass. ffm and growth may reflect long term nutrition and health in contrast to bmi and ln%tbf which may reflect acute deterioration or short term nutritional intervention. therefore ffm may prove to be a useful tool to assess quality of nutrition and may be predictive of respiratory and general decline. body composition assessment has an important role in chronic conditions such as cystic fibrosis, in order to identify nutritional depletion and evaluate nutritional interventions. it is important that reliable and accurate methods are used. the usefulness of non-invasive methods, such as skinfold thickness measurements (sft) to measure change in body composition has not been evaluated in cf. this study aimed to compare changes in fat-free mass (ffm) and fat mass measured using sft and dual-energy x-ray absorptiometry (dxa) in adults with cf. methods: adults with cf ( % male, % pancreatic insufficient, mean age at baseline . (sd . ) years, mean fev at baseline . (sd . ) % predicted) were studied. they underwent body composition assessment using dxa and sft, at baseline and a mean of . (sd . ) years later. durnin and womersley equations were used to estimate ffm and fat mass from sft. estimates of change in ffm and fat mass obtained using sft were compared with dxa using paired t-tests, univariate analysis and bland and altman analysis. results: at baseline, mean ffm was . (sd . ) kg; mean fat mass was . (sd . ) kg and mean bmi was . (sd . ) kg/m . mean ffm, fat mass and bmi were not significantly different at follow-up, indicating no change in nutritional status for the population overall. individual change in ffm ranged from - . to + . kg, while change in fat mass ranged from - . to + . kg. the table shows mean change (∆) in ffm and fat mass by each method, correlations (r ) between sft and dxa, and the % limits of agreements (loa) between sft and dxa for change in ffm and fat mass. mean change in ffm and fat mass estimated using sft did not differ significantly from dxa. mean bias between the methods was small, and overall correlations between sft and dxa were strong for changes in both ffm, suggesting good agreement for the overall population. however the % loa between the two methods were wide for change in both ffm and fat mass. this suggests that sft will not accurately predict changes in body composition in all cf patients. conclusion: sft measurements do not accurately estimate change in ffm or fat mass over time in individual adult cf patients compared with dxa. body composition changes measured using sft tended to more closely reflect changes detected by dxa in male patients compared with females. caution should be exercised when interpreting the results of serial measurements of body composition using sft in individuals with cf. analysed were significantly correlated with age-cml or srage levels (age, gender, bmi, presence of cf-related diabetes mellitus (cfrd) or hba c level). conclusions: serum levels of ages are elevated in adults with cf. elevation is not restricted to those with cfrd. the levels of srage reflect ability to respond to this pathway and are associated with poorer lung function. modification of the diet in cf may reduce this mediator and may have the potential to modify lung and renal injury. mouse models of cf generated by expression of improperly processed cftr (∆f ) or lacking cftr expression (ko) demonstrate selective induction of sult e in the liver (falany et al., biochem. j. : , ) . sult e is responsible for the sulfation and inactivation of β-estradiol (e ) at physiological concentrations. the increase in sult e expression is specific to the hepatocyte, whereas cftr is selectively expressed in cholangiocytes. the induction of sult e activity is associated with changes in levels of e regulated proteins in cftr (-/-) liver (li and falany, j cystic fibrosis : , ) . increased sult e activity is correlated with low body weight and decreased igf- message levels in livers of cftr(-/-). the mechanism for the induction of sult e in hepatocytes by cholanigiocytes lacking cftr expression, and the mechanism for the inhibition of igf- expression by increasing sult e expression was investigated in human cells. human mmnk- cholangiocytes in which cftr expression was inhibited by short interfering rna (sirna) induced sult e expression in human hepg hepatocytes when cocultured in a permeable membrane separated system. sult a expression was not altered in this model. the data suggests that loss of cftr function in cholangiocytes is capable of selectively modulating sult e expression in hepatocytes. to investigate the ability of increased sult e activity to modulate expression of igf- , hepg cells were stably transformed with sult e /pcdna to activity levels intermediate to the levels observed in cftr(-/-) mice. the increased sult e activity was associated with decreased igf- message expression in the hepg cells. since a major pathway for igf- regulation involves growth hormone (gh) stimulation of stat b phosphorylation, the effects of e and increased sult e activity on gh stimulated stat b phosphorylation were examined. stat b activation was identified using immunoblot analysis with a rabbit anti-tyrosine phosphorylated-stat b antibody. treatment of control hepg with nm e prior to the addition of gh increases stat b phosphorylation. in hepg cells expressing increased sult e activity, the stimulation of stat b phosphorylation by nm e was significantly decreased. e had an apparent rapid action on stat b phosphorylation that is not attenuated by the estrogen receptor antagonist, ici , . e was effective at increasing stat b phosphorylation when applied to hepg cells - min before gh. increased stat b phosphorylation was observed in control hepg cells at nm e although -fold higher e concentrations were required in the sult e -hepg cells consistent with the increased e sulfation. no differences were observed in total stat b in any of the studies. this study demonstrates that human cholangiocytes with low levels of functional cftr are capable of inducing sult e expression in human hepatocytes and the increase in e sulfation inhibits the gh stimulation of igf- expression via a decrease in stat b phosphorylation. supported by grants from the cystic fibrosis research, inc. and nih (gm ). williams, j.e. ; benden, c. ; jaffe, a. ; suri, r. ; wells, j.c. ; fewtrell, m.s. . mrc childhood nutrition unit, institute of child health, london, united kingdom; . portex respiratory medicine unit, great ormond street hospital, london, united kingdom background: patients with cystic fibrosis (cf) are at high risk of malnutrition. to our knowledge, no study so far has employed a reference fourcomponent model(sup) (/sup)( cm) to assess body composition (bc) in cf children, which allows accurate evaluation of both fat mass (fm) and the components of fat-free mass (ffm; mineral, protein, water) and most studies have been cross sectional. methods: cf subjects, aged - yrs, were compared with age-and sex-matched healthy controls for assessment of bc using a reference cm. comparison between groups was performed using paired t-tests and general linear models to adjust for age, height and pubertal status. in addition fm index (fmi; fm/height ) and ffmi (ffm/height ) standard deviation scores (sds) were calculated using measurements performed in a reference population of healthy children aged to yrs. repeat measurements were made in children with cf ( boys) after yrs and the change in fmi sds and ffmi sds investigated. results: for the initial measurement at baseline, boys with cf (n= ) were significantly shorter (mean (se) height sds: - . ( . , p< . ) compared to uk reference data; girls with cf were lighter, bmi sds (- . ( . ), p< . ). at baseline, comparison of cf children with pair-matched controls indicated that there was no difference in the boys but cf girls had less fm (cf minus control) (- . ( . )kg, p< . ) and mineral mass (- . ( . )kg, p< . ) after adjustment for age, height and puberty. fmi sds adjusted for age and puberty was also significantly lower in girls with cf (- . ( . ), p< . ) whereas ffmi sds was not. for comparison with the large reference population there was no difference in the boys at either time point for fmi sds and ffmi sds (paired t-test). for girls however, there was a significant difference at both baseline fmi sds (- . ( . ), p< . ), ffmi sds (- . ( . ), p< . ) and yrs fmi sds (- . ( . ), p< . ) and ffmi sds (- . ( . ), p< . ). paired t-test analysis between baseline and yr followup measurements indicated that fmi sds and ffmi sds were not significantly different at each point in time in either boys and girls. conclusion: at baseline, the bc of cf boys appears to be within normal range, but the cf girls already have lower fm and mineral than their healthy pair matched controls, even when adjustment for size and puberty is made. follow-up measures in cf children indicated that these descriptions of nutritional status of cf boys and girls remained consistent over the following years, with no evidence of any further deterioration in girls. however, nutritional surveillance is important in both sexes in cf at around puberty to address potential deterioration and this study suggests that the cm is a useful tool for this purpose. fuller background: although lung function (lf) in children with cystic fibrosis (cf) has been reported to be related to their nutritional status, particularly body fat, the latter has usually been assumed from anthropometric measurements and not measured using an appropriate reference method. habal, h. ; al-turkmani, m. ; freedman, s. ; laposata, m. . pathology, massachusetts general hospital and harvard medical school, boston, ma, usa; . medicine, bidmc and harvard medical school, boston, ma, usa background: increased dietary intake of fatty acids is recommended for cf patients. it is unknown if this results in increased incorporation of all fatty acids-saturated, monounsaturated, and polyunsaturated-into cells with a cf phenotype to a greater extent than into non-cf cells. docosahexaenoic acid (dha) supplementation of cftr-/-mice has been shown to reverse the pathologic cf phenotype. aim: to investigate whether the uptake of multiple predominant fatty acids and the release of membrane-bound arachidonic acid (aa) are altered in cultured epithelial cells with a cf phenotype; in addition, to determine whether fatty acid uptake is selectively inhibited by dha supplementation. methods: sense (wt) and antisense (cf) cftr hbe cells were cultured in mem containing % horse serum. aa release from membrane phospholipids (pls) was studied by incubating the cells with µm [ c] aa for min, and then with serum free medium containing . % fatty acid free human serum albumin in the presence or absence of µm adenosine for min, followed by measurement of radioactivity in the supernatant. the uptake of fatty acids into the cells was studied by incubating the cells for different time points with . µm [ c] linoleic acid (la), [ c] aa, [ c] dha, [ c] palmitic acid or [ c] oleic acid, in the presence and absence of µm or µm dha, followed by measurement of radioactivity in the cell lysate. results: basal and adenosine-stimulated aa release from membrane pls was significantly higher in cf cells compared to wt cells (basal wt: . ± . , cf: . ± . dpm/ cells, p< . ; stimulated wt: . ± . , cf: . ± . dpm/ cells, p< . ; mean±sem for each). the uptake of la, aa, dha, palmitic acid and oleic acid were significantly higher into cf cells compared to wt cells. dha significantly decreased the elevated uptake of these fatty acids into cf cells, but not into wt cells. data are shown in the table below. conclusion: in this cell culture model, these data demonstrate that aa uptake and release are increased in cf cells, which may suggest elevated mobilization of this fatty acid by cf cells. our data also show that cftr dysfunction leads to increased uptake of all tested fatty acids into the cells. downregulation of this increased uptake may be one mechanism by which dha exerts its therapeutic benefits. low bmi in cf correlates directly with worsening lung function and is an independent risk factor for mortality. the causes for this decreased bmi are incompletely understood but could be related to levels of the orexigenic peptide ghrelin, and to levels of leptin, an anorexigen. studies assessing plasma levels of leptin in cf have shown contradictory results, while the data on ghrelin in cf are scarce. we assessed both leptin and ghrelin plasma levels in mild (fev > % predicted), moderate (fev % to % predicted), and severe (fev < % predicted) adult cf patients. we compared these levels in cf subjects to age matched controls with normal bmi (range . to . kg/m ). we conclude that leptin levels are decreased, while ghrelin levels are increased only in cf patients with severe disease and low bmi. plasma levels of ghrelin and leptin did not differ from normals in those with mild and moderate disease. gastroesophageal reflux (ger) is common in cf before and after lung transplant (ltx). laparascopic fundoplication (lapf) is used when patients fail on conservative medical therapy. aims: to review longer term clinical outcomes of lapf in patients with cf in terms of lung function, body mass index (bmi), reflux symptoms, patient satisfaction with surgery and complications. method: retrospective review of patient records and patient questionnaire to gather relevant information. results:thirty-two patients with cf underwent lap.f recently; transplanted (ltxgroup), female (mean age [ - ]) years, and not transplanted (cf group), female ( ). the median time between ltx & lapf was ( ; ) days, range - . endoscopy was undertaken in patients prior to surgery and all underwent hr ph monitoring. complete (nissen) lapf was undertaken in % patients and a partial (toupet) in the other %. total median time in the operating theatre was ( - ) minutes. the average length of stay in hospital (in days) in the ltxgroup: pre-op. was . ; post-op. was . days; and in the cf group was: . and . respectively. lung function (fev and fvc in percent predicted) and bmi were measured at minus(-) , plus (+) , + and + days from lapf. patient satisfaction with lapf was a mean of % in the ltx group and % in the cf group and improvement in reflux symptoms of % in both groups. nocturnal cough reduced markedly in the cf group and there was an overall improvement in quality of life in both groups. complications consisted of port site hernias, failed lapf with re-operation months later; esophageal dilatations and patient with lower esophageal sphincter hypotonia. there were deaths on day , and post fundoplication. one was in a non-transplanted patient with recurrent episodes of hemoptysis. she succumbed to a catastrophic hemoptysis episode not related to lapf. the other were in transplanted patients. conclusions: in this relatively small series of patients there was a small but significant drop in fev in the ltx group days after lapf, but not in the cf group who remained stable throughout the review period. there was a significant drop in bmi in both groups after lapf, but the cf group returned to pre lapf values at + days. patient satisfaction with the procedure was high. fundoplication is an expensibe complicated procedure not without risk. a long term prospective study is warranted. historically this phenomenon has been attributed to intestinal malabsorption and cachexia as a consequence of chronic lung infection. however, cf mice exhibit similar growth and weight deficits but are not afflicted with malabsorption or lung infection, suggesting other mechanisms are participating as well. we hypothesize that small size is in part a result of increased β-oxidation in adipose stores. to test this we utilized a mouse model to study lipid metabolism. our study includes female cf mice with a null mutation in the cftr gene. these mice are congenic on the c bl/ j background as well as age matched with their controls (wt) to - days. liver, adipose and skeletal muscle (calf) were dissected from wt and cf mice in a fed state. tissues were immediately flash frozen in liquid nitrogen and used for rna and protein lysate harvest. quantitative pcr (qpcr) was performed using primers for the lipogenic isoform of acetyl-coa carboxylase α (acc α) in the liver and adipocytes, whereas the non-lipogenic isoform acc β was assessed in the skeletal muscle. primers for acyl coa oxidase (aox), carnitine palmitoyltransferase (cpt ) and long acyl-coa dehydrogenase (lcad) were used as gene markers for β-oxidation steps in the peroxisome, carnitine shuttle and mitochondrion, respectively. western blots were performed to detect acc (active) and phospho-acc (inactive) forms. the results show that there is a decrease in the total amount of acc protein in the fat as well as the skeletal muscle of the cf mice and the ratio of acc:phospho-acc is substantially lower in the cf tissues. phosphorylation and/or decreased expression of acc results in decreased expression of malonyl coa, leading to a cascade of events that increase β-oxidation. in addition, increased expression of aox and lcad, two downstream β-oxidation genes, is also observed. hyperactivity of the β-oxidation pathway could account for the decreased adipose stores seen in cf mice compared to the wt. such patterns of expression are reminiscent of starvation. caloric intake and intestinal absorption of dietary lipid were measured and cf animals consumed approximately % the calories of wt animals (per gram body weight) and lipid absorption was not significantly different ( % for cf, % for wt), indicating the cf animals have sufficient access to nutrition. we will continue to investigate fatty acid synthesis and degradation pathways during both the fed and fasted states to delineate the mechanism. this research was supported by grant hl . effect of gender on dha levels in p and rbc with lower values for male cf patients. acknowledgments: this work was supported by the belgian cf association (ablm), the french cf association (vlm) and by a grant from frs (ucl). data are expressed as means ± sd. * and indicate a significant difference with controls and cf ps patients respectively, p< . . background: deficit of antioxidant systems and increased oxidative stress have been demonstrated in cf patients with respect to healthy controls. the origin of this imbalance is known to be multifactorial. objective: the aim of our study was to assess changes in antioxidant systems and oxidative stress parameters in cf pediatric patients in presence or absence of pancreatic insufficiency material and methods: we recruited patients ( with pancreatic insufficiency pi and with pancreatic sufficiency ps) attending the cystic fibrosis centre of turin ( ) ( ) . during the annual routine control visit were performed antropometric measurements, pulmonary function tests (fev ), and were collected fasting blood samples and last days food record. vitamin e, a, c, selenium, glutathione (gsh, gshpx, gssg), dehydroascorbic acid, pcr were assessed. data were analysed using the two sample t-test with equal variances. results: there are not statistically significant differences between two groups for sex, age and fev . / of pi patients and / of ps patients took oral vitamin supplementation. serum levels of alpha-tocopherol and beta-carotene resulted within the local reference range either in pi or ps patients showing no significative differences. the mean serum levels were respectively suboptimal and optimal for vitamin e and a (biesalsky ' ). pi and ps patients did not show significant intergroup differences of water soluble and enzymatic antioxidants levels as well. serum levels of vitamin c, selenium, erythrocyte reduced glutathione (gsh) and glutathione peroxidase activity (gshpx) resulted within the local reference range. plasma vitamin c concentrations resulted slightly inferior to the optimal values (biesalsky ' ) in both groups. oxidative stress parameters (erythrocyte glutathione disulfide-gssg, dehydroascorbic acid) and inflammatory parameters (pcr) did not differ significantly, presenting values within the local reference range, in both groups. nutritional data revealed significantly reduced zscore for weight (p< . ) and height (p< . ) in pi patients vs ps patients. our data did not evidence significant differences in total energy (kcal/kg) and macronutrients (% of total kcal) intake in both pi and ps patients. dietary intake of antioxidant vitamins resulted slightly superior the rda (larn- ) presenting no significant intergroup differences. conclusions: this study shows that pancreatic insufficiency do not influence oxidant/antioxidant balance in cf patients at least in paediatric age. until innovative supplementation guidelines will be proposed for application, nutritional education and monitoring and correct dietary habits are useful to optimize antioxidant status in cf patients. there are more than cf mutations that are responsible for the spectrum of disease severity in cystic fibrosis (cf). the most common, f del mutation, is associated with pancreatic insufficiency (pi), and a classic phenotype. . yet even within a group of f del homozygotes, there is a small minority of patients ( . %) who are not taking pancreatic supplements, and are therefore presumably pancreatic sufficient (ps) (data from * cff registry). this observation prompted us to look more closely at enzyme use in cf patients with non-f del homozygous genotype. we reviewed enzyme use in cf patients who were fully genotyped and whose enzyme use was documented in the * cf registry. heterozygotes with one or two non-f del mutations were included in this analysis. using the assumption that the milder mutation is dominant, if the patient was ps and heterozygous with one f del mutation, the second mutation was classified as ps; if the person was pi, the second mutation was classified as pi. we also reviewed the pancreatic status and genotype of patients participating in the wisconsin newborn screening study. in this randomized control trial (rct), pancreatic status was determined by hour fecal fat analysis. enzyme use was extracted from the database for the year . there were patients in the cff registry with a total of different mutations. twenty-one of these mutations were associated with pi. this finding correlated well with the per cent of patients who were on enzyme supplements (range of per cent patients on enzymes by mutation - %). however when we looked at the six mutations associated with ps, the distribution of patients on enzymes vs. not, was much closer. see table below. possible reasons for enzyme supplement use by patients with ps mutations include a) treatment for recurrent pancreatitis, b)the fact that this is a cross-sectional analysis and patient may be on enzymes temporarily, c) patient may truly be pi, d) overuse of enzymes due to unreliable test to measure pancreatic status in patient, e) patients who are on enzymes are older, and have changed from ps to pi phenotype. this analysis suggests a need for better assessment of pancreatic status in patients with cf. * this analysis was originally done by request for the ecfs conference at garda on cftr genetics, and focused on the suggested " main mutations", and will be updated with the cff registry data. (supported by nih grants dk , dk , mo rr , mo rr ) number of patients in rct with each mutation: , , , , , respectively. dutta, a. ; woo, k. ; fitz, j.g. ; feranchak, a.p. . department of pediatrics, ut southwestern medical center/children's medical center, dallas, tx, usa; . medicine, ut southwestern, dallas, tx, usa extracellular atp is an important signaling molecule contributing to bile formation by the liver through binding biliary epithelial cell (cholangiocyte) membrane p receptors and stimulating cl-efflux. importantly, atp appears to work through cl-channels unrelated to cftr, suggesting it may be a potential way to modulate bile flow in cf liver disease. however, the signaling pathways linking receptor binding to channel activation in cholangiocytes are unknown. consequently, the aim of the present study was to identify the pathways responsible for atp-stimulated increases in [ca +]i and membrane clpermeability in a human biliary epithelial cell model. studies were performed in mz-cha- human biliary cells; [ca +]i was measured by fura- and membrane cl-currents by patch-clamp techniques. results: exposure of cells to atp ( µm) resulted in a rapid increase in [ca +]i to . ± . nm (n= ) which was abolished by prior depletion of intracellular ca + by thapsigargin ( . ± . nm; n= ), but unaffected by removal of extracellular ca + (egta, . ± . nm; n= ). in parallel studies, atp ( µm) increased current density from - . ± pa/pf to - . ± . pa/pf (n= ) . currents reversed at mv (ecl-), were outwardly rectifying, and were inhibited by the cl-channel inhibitor nppb (- . ± . pa/pf, n= ), but not the cftr inhibitor cftrinh . atp failed to activate currents after depletion of intracellular ca + stores by bapta-am (- . ± . pa/pf, n= ). the p y receptor antagonist suramin inhibited atp-stimulated increases in [ca +]i ( . ± . nm; n= ) and cl-channel activity (- . ± . pa/pf; n= ). however, the p x receptor antagonist brilliant blue g did not affect the magnitude of atp-stimulated cl-currents (- . ± . pa/pf, n= ). together these findings suggest that atp activates cl-currents primarily through p y, but not p x, receptors in human biliary cells. since p y are g-proteincoupled receptors and modulate [ca +]i by phospholipase c (plc) generation of inositol , , -trisphosphate (ip ), a series of experiments were designed to directly assess the effects of ip receptor inhibition or stimulation on atpstimulated cl-currents. first, the plc inhibitor, u blocked atp-stimulated cl-currents ( . ± . pa/pf; n= ). second, the specific ip receptor blocker -apb, inhibited both the atp-stimulated increase in [ca +]i ( . ± . nm, n= ) as well as membrane cl-currents (- . ± . pa/pf, n= ). lastly, intracellular dialysis with purified ip during whole-cell patch clamp activated cl-currents with identical properties to those activated by atp (- . ± . pa/pf, n= ). together these studies demonstrate that extracellular atp stimulates ca +-activated cl-channels in cholangiocytes primarily through p y receptor binding and plc/ip -dependent release of intracellular ca + stores. thus, the p y-ip receptor signaling complex represents a potential target to increase cholangiocyte secretion, and hence augment bile flow, in the treatment of the cholestatic liver disease associated with cf. supported by grants from the nih niddk and the cff to a. feranchak. background: supplemental pep therapy is used to treat cf patients with epi to assist with digestion, food absorption. this open-label, multipledose, single-treatment, multicenter study evaluated efficacy and safety of eur- for malabsorption treatment in young patients with cf and epi. eur- is a novel, zero-overfill, highly-stable formulation of porcinederived pancreatic enzymes, and was specifically developed for use in very young children allowing the product to be sprinkled on food. methods: eligible patients were < years with cf and epi, in acceptable nutritional status, needing peps and clinically stable. patients consumed a standard cf recommended diet, could not take drugs affecting gastric ph or motility. the trial involved a -day dose stabilization period and a -day treatment period. patients switched from their baseline enzyme treatment without washout. the optimal dose of eur- , determined during dose stabilization, was used during treatment. primary endpoint compared malabsorption of fat after eur- vs. previous treatment. clinical symptoms were also evaluated, as was physicians' and parents' judgment on the control of malabsorption signs and symptoms. safety measures included aes, physical exams, vital signs and changes in clinical laboratory findings, including cholesterol levels and fat-soluble vitamins. results: nineteen patients ( male) enrolled and completed all study phases. mean age was . years (range - ). percentage of responders (patients without steatorrhea (< % fecal fat content) and without signs and symptoms of malabsorption after and weeks of treatment) was . at baseline, . (p= . vs. base) after stabilization and . (p = . vs. base) at study end. frequency and oily stools showed a significant decrease vs. baseline at study end. the mean number of stools per day was . stools at screening and . stools during treatment (p< . ). the mean proportion of stool samples with visible oil or grease at screening was . % and . % during treatment (p= . ). a statistically significant improvement was seen in the incidence of moderate bloating. physicians characterized % of patients as "improved" in the control of epi signs and symptoms vs. previous therapies and % as "unchanged" at the end of the treatment phase, while parent assessments were % "improved" and % "unchanged." vitamin k absorption (measured through pivka) improved with eur- treatment over prior pep treatment measured at baseline. eur- was safe and well tolerated, with minimal aes. no aes led to discontinuation of study drug interruption. no incidences of uric acid toxicity or fibrosing colonopathy following eur- treatment. no trends were seen in lab parameters, physical examination, or vital signs. conclusion: eur- is effective, safe, well-tolerated in the treatment of epi in young cf patients. treatment controlled malabsorption and clinical symptoms of epi in young patients with cf. safety and efficacy of eur- in this trial is consistent with the pivotal phase iii trial. there is an association between the presence of cf and alterations in fatty acid metabolism, consisting of a decrease in linoleate ( : n- ). more recently, a deficiency of docosahexaenoate ( : n- , dha) has arisen as a prominent fatty acid abnormality in cf. an established breeding colony of exon cftr knockout (cftr-/-, cf, n= ) and wild type (wt, n= ) mice was used for this study. all mice were weaned at days of age and then raised on peptamen and water until days of age, and then continued for days with ml/day of peptamen to homogenize the nutritional status. after this period, some mice (n= per group) were subjected to dha treatment ( mg/day) for one week. after sacrifice, pancreatic tissue was collected, homogenized and extracted. lipid classes were separated by sequential elution in aminopropyl columns. the eluted fractions were transmethylated and injected into a hewlett-packard a gas chromatograph with a flame ionization detector for quantitative analysis. the vast majority of fatty acids were mainly distributed in phospholipids, except those with -carbons. wt and cf mice were studied a gender gap in the survival of cystic fibrosis (cf) is well-documented. however, little is known whether there is a gender différence in pubertal growth pattern in cf children. delayed and attenuated pubertal growth are commonly observed in adolescents with cf. however, characterizing height velocity (hv) pattern is very challenging because of errors associated with calculating hv, e.g. interpolation and extrapolation between heights measured in irregular intervals, as well as difficulties in determining the location and the magnitude of peak height velocity (phv). in this study, we applied a new statistical method, namely, the semi-parametric shape-invariant model, to characterize the hv pattern of cf children. this method is based on the assumption that all individuals' growth curves have a common shape. therefore, this method attempts to shift and stretch (squeeze) individual's growth data until they can be modeled by the common shape curve. the semi-parametric shape-invariant model has the advantage of fitting measured heights directly, thereby eliminating the errors associated with calculating hv. the study population included cf children who had height measurements between ages to years documented in the - cff registry. because fitting each individual height curve is computing-intensive, boys and girls were randomly chosen for this preliminary analysis. our results showed that girls exhibited a typical growth deceleration during late preadolescence, followed by accelerated hv and a single phv during adolescence (figure) . unexpectedly, cf boys exhibited a notable hv peak during late preadolescence in addition to the typical adolescent phv (figure) . overall, the mean magnitude and age of phv was . cm at . years for boys and . cm at . years for girls. when compared to phv of non-cf children based on tanner's reference (pediatr. , : ) , cf boys showed a greater delay in the age of phv while cf girls showed a greater attenuation in the magnitude of phv. further analyses are being performed to characterize the hv patterns of all children to confirm these results. (supported by nih-dk ). anelli, m.; foresti, r.; peloso, l.; ortenzi, g. medical affairs, eurand, pessano con bo, italy background: given their inherent instability, the dose units of all pancreatic enzyme preparations (peps) have always been "overfilled" to compensate for enzyme degradation over time and assure at least % of the label lipase content at the end of their shelf life. this overfill issue was first examined by whitehead who reported overfills ranging from to % after analyzing several commercially available peps (whitehead am. pharm weekbl sci. ) . the usp presently allows for pep overfills up to %. thus, the actual active lipase content of a pep capsule labelled at , iu might vary from , to , units according to its "freshness." as a result, patients taking peps receive a product with variable potency, which can lead to efficacy issues, increased pill burden, unnecessary drug interactions, and product switching. the fda has also noted the potential safety risk posed by overfilling and, in a recently published guidance, it imposed a zero overfill requirement for all peps to be marketed in the usa after april . methods: over a period of two years, we ran a series of tests similar to those conducted by whitehead to evaluate overfill on commercial peps currently available in the u.s. and europe. results: no finished product was formulated to % of the labelclaimed lipase enzyme activity. overfill on commercially available peps ranged from % to %, with a median value of %. the peps analyzed were to months old on average; therefore, the actual amount of overfill is likely underestimated. conclusion: our findings confirm those reported earlier by whitehead and demonstrate that none of the currently available peps complies with the zero overfill requirement of the fda guidance. these findings highlight a potential cause of suboptimal therapy with currently available peps. references: -whitehead am. study to compare the enzyme activity, acid resistance and dissolution characteristics of currently available pancreatic enzyme preparations. pharm weekbl sci. feb ; ( ): - . -food and drug administration. guidance for industry: exocrine pancreatic insufficiency drug products -submitting ndas. april . heubi, j. ; boas, s.r. ; blake, k. ; nasr, s.z. ; woo, m.s. ; graff, g.r. ; hardy, k.a. ; amaro-galvez, r. ; latino, m. ; lee, c. . children 's hospital medical center, cincinnati, oh, usa; . chicago cf care, glenview, il, usa; . nemours, jacksonville, fl, usa; . michigan u, ann arbor, mi, usa; . children's h, los angeles, ca, usa; . penn state h, hershey, pa, usa; . children's h, oakland, ca, usa; . texas u, tyler, tx, usa; . eurand, milan, italy; . eurand, vandalia, oh, usa background: supplemental pep therapy helps prevent maldigestion and malabsorption in cf patients. eur- is a novel, zero-overfill, highly-stable formulation of porcine-derived pancreatic enzymes developed to treat epi in cf patients. this phase iii, randomized, doubleblind, placebo-controlled, two-treatment, crossover, multicenter trial evaluated the efficacy and safety of eur- to treat epi in cf patients. methods: patients with confirmed cf and epi, age ≥ years, good nutritional status and weight ≤ kg were enrolled. no drugs affecting gastric ph or motility were allowed. after open-label dose titration, patients were randomized to receive eur- or placebo over a week-long period. following another open-label normalization, all patients were crossed over to the alternative treatment arm. primary endpoint was change in coefficient of fat absorption (cfa) following oral administration of eur- vs. placebo. secondary endpoints were change in coefficient of nitrogen absorption (cna), cholesterol, fat soluble vitamins, body weight, bmi and epi symptoms following oral administration of eur- vs. placebo. safety endpoints included aes, clinical laboratory parameters, physical exams and vital signs. results: thirty-four patients were enrolled ( female); were evaluated. mean age was . years (range - ). eur- treatment was associated with statistically significant (p< . ) increases in both cfa and cna vs. placebo. eur- treatment was associated with decreases in pivka ii (an indicator of vitamin k status). epi symptoms consistently improved during eur- treatment, including a statistically significant reduction in stool frequency and fewer soft and watery stools. treatment with eur- improved the signs and symptoms of malabsorption even in the small subset of patients with cfa values greater than % under placebo treatment. there were no notable changes in serum lipids, vitamin a and e values, mean weight or bmi in patients who received eur- . eur- was safe and well-tolerated. there were no unexpected or significant differences in the frequency or type of aes between eur- and placebo, and no trends were seen in lab parameters or vital signs. no patient discontinued from the study due to an ae. two serious aes were considered unrelated to the study drug and both resolved. conclusion: in this randomized, double blind, placebo-controlled study, eur- was safe, well tolerated and effective in the treatment of cf patients with epi, with clinically and statistically significant improvements in cfa, cna, and epi signs and symptoms in the absence of any concomitant treatment affecting gastrointestinal motility and ph. the therapeutic benefit of eur- was seen even in patients with very high cfa values (> %). the relative infrequency of cystic fibrosis related diabetes (cfrd), until recently, means little is known about hypoglycaemia ('hypos') associated with its treatment. insulin is frequently taken by those who have cfrd, for whom the risk of hypoglycaemia may be high due to dramatic changes in insulin sensitivity that can occur with pulmonary exacerbations and a decreased ability to secrete glucagon. a number of studies involving people with type diabetes mellitus (t dm) have reported on their experiences of hypoglycaemia, but whether results from such investigations apply to cfrd is unclear. an exploratory investigation was conducted to compare the type, frequency and severity of hypoglycaemic symptoms experienced by patients who had cfrd with patients who had t dm. method a cross sectional study was conducted, involving adults ( - years) with t dm or cfrd, recruited from two hospitals in england. a questionnaire, sent to patients with t dm and with cfrd, included investigator-developed items about knowledge and frequency of hypoglycaemia and the edinburgh hypoglycaemia scale (ehs), a standardised measure that assesses autonomic (e.g. sweating, hunger) and neuroglycopenic (e.g. confusion, poor co-ordination) symptoms associated with hypoglycaemia. questionnaire data were entered into spss for analysis. comparisons were conducted using t-tests, mann whitney tests or chi square tests as appropriate. results questionnaires were returned by patients with t dm and with cfrd. five of those with t dm were over years of age and, therefore, excluded from analysis. almost all participants had experienced a 'hypo' ( %). comparisons between the two groups are reported in table . conclusion patients with cfrd reported fewer and tended to have less severe episodes of hypoglycaemia compared to those with t dm. fewer neuroglycopenic symptoms in the former could be related to their shorter duration of diabetes or to how cfrd was managed; patients with cfrd were given shorter acting insulin, making them less prone to 'hypos' during the night, and had a high sugar diet to ensure weight maintenance. differences between the groups could also be related to specific characteristics of these two forms of diabetes. table : data from questionnaire insulin resistance. the purpose of this study was to investigate the relationship between pem and the risk of developing glucose intolerance and/or cfrd and the effect on lung function in children ≤ years of age whose history suggests pem. patients whose diagnosis of cf was suggested by failure to thrive(ftt) and whose growth parameters remain < % for weight and height for age were identified as having incurred pem. a retrospective analysis of our cf registry database was performed. cf patients ≤ years old were identified. of patients( . %) had cfrd. ( . %) of these plotted < % for weight and height (pem)and ( . %) were diagnosed with cfrd. further review of the patients showed whose diagnosis of cf was suggested by ftt and ( . %) of those had cfrd. statistical analysis did not show a clinical significance, but a strong relationship is implied. pulmonary function, fev %, was significantly lower in the pem/cfrd patients (mean fev . % ± . %) than the pem only group, (mean fev . % ± . %)(p= . ). this review provides further support that patients who have pem are at increased risk of developing cfrd. a significant risk was not established; however a strong association is suggested. assessment of a larger cohort of patients may show a stronger relationship. findings from this study would suggest that further research into the physiological relationship between pem and cfrd should be initiated. cfrd screening should be considered at a younger age than the current cff recommended age of > years. diagnosing cfrd/glucose intolerance early may contribute to improve growth parameters, preserve lung function, and improve survival. based on this review, our center is initiating cfrd screening for all patients ≥ years, and considers screening for all pem patients ≥ years. background: patients with cf are thought to have a rapid postprandial rise in plasma glucose which may be followed by a delayed and prolonged insulin response and hypoglycemia. we sought to estimate the prevalance, cumulative one year incidence, and factors associated with hypoglycemia during oral glucose tolerance testing in non-diabetic adults with cf. we also compared the prevalence of hypoglycemia to a geographically matched cohort of young adults without cf. methods: we performed a prospective study of individuals aged over years with cf followed in clinic providing population-based, specialized care in cambridgeshire, england. we excluded patients with previously-diagnosed diabetes or taking anti-diabetic medications. we evaluated individuals who underwent g hour oral glucose tolerance testing (ogtt) in . of these, individuals had neither new diabetes nor hypoglycemia in and were retested using ogtt in . we testing the association between biochemical and anthropometric factors measured in with the prevalence of hypoglycemia in , and incident hypoglycemia in . biochemical hypoglycemia was defined as a blood glucose between < . mmol/l ( mg/dl), but greater or equal to . mmol/l ( mg/dl) and severe hypoglycemia as a value lower than . mmol/l on either the fasting or post glucose challenge value. for comparison, we used data from the cambridgeshire-based young ely study of individuals age - years who underwent g ogtt testing in - . results: in , in patients with cf, the prevalence of fasting hypoglycemia was . %. no patients had fasting severe hypoglycemia. following glucose challenge, . % and . % of patients had glucose values consistent with hypoglycemia and severe hypoglycemia respectively. there were no diferrences in age, hepatic, pulmonary or renal function, but patients with hypoglycemia at two hours were five times more like to be male (odds ratio . , % ci . - . ) and more likely to have a higher bmi. the prevalence of a hours value of < . mmol/l in patients with cf at . % ( / ) was not different than in controls . % ( / ). of patients who did not have hypoglycemic readings in , at one year, patient developed fasting hypoglycemia and individuals developed post-challenge hypoglycemic for a cumulative incidence . %. of these . % ( ) had values in the range of severe hypoglycemia. there were no differences between age, sex, bmi, liver, renal, or pulmonary function in those who did and did not develop hypoglycemia. conclusions: hypoglycemia appears common in patients with cf but is also common in a healthy population. male sex and bmi were associated with post load hypoglycemia in patients with cf in cross-sectional analyses only. further research needs to assess whether these low blood glucose values are associated with symptoms. it is well recognised that cystic fibrosis related diabetes (cfrd) is a poor prognostic indicator in cf, and therefore early recognition is imperative to allow effective treatment in an attempt to prevent the associated decline in pulmonary function and nutritional status. although the oral glucose tolerance test (ogtt) is the accepted method of detecting diabetes mellitus in non cf individuals, glucose intolerance and lack of insulin can be variable in cf patients such that the reliability of ogtt in the diagnosis of cfrd has been questioned. under these circumstances, other methods of monitoring glucose intolerance, such as serial post prandial glucose monitoring (sgm), may be more appropriate. to look at this further, we prospectively compared ogtt with sgm in a group of adult cf patients. fourteen patients with no previous history of cfrd ( ], df homozygous, male) admitted for acute pulmonary exacerbations were evaluated. all were exocrine pancreatic insufficient, and was on long term oral steroids. eleven patients received mg/day oral prednisolone in addition to iv antibiotic therapy for the duration of their admission. ogtt was performed in the standard fashion (ingestion of . g glucose/kg body weight [maximum g] within minutes, after an overnight fast). sgm was performed hours post prandially and before bedtime over the period of the admission. the local ethics committee approved the study and informed consent was obtained from all patients. results sgm revealed elevated postprandial blood glucose values in all patients. there were episodes (mean per patient [ to ]) with glucose > . mmol/l (frank diabetes, who criteria) and episodes (mean per patient [ to ] ) with glucose . to . mmol/l (impaired glucose tolerance, who criteria). however, ogtt revealed impaired glucose tolerance in only one patient ( hour glucose value . mmol/l). in the remaining patients, ogtt revealed normal hour glucose values (mean . mmol/l [range . to . ]). fasting plasma glucose values were also normal (mean . mmol/l [ . to . ]) in all patients. we have shown a high prevalence of hyperglycaemia in our adult patients admitted for pulmonary exacerbations that was only detected using serial glucose monitoring. this study suggests that sgm may be more sensitive at detecting early cfrd than the ogtt. further work needs to be carried out to look at the best methods of diagnosing cfrd, to facilitate early treatment and thereby improve the prognosis. the diagnosis of cystic fibrosis related diabetes (cfrd) is associated with a decline in pulmonary function and nutritional state and is a poor prognostic indicator: the risk of its development increases with age. furthermore, the development of cfrd is due to a gradual loss of insulin production, and the disease may therefore be preceded by a period of glucose intolerance. despite this, the incidence of hyperglycaemia in cf patients is unknown. to study this further, we monitored the blood glucose profiles of adult cf patients admitted for the treatment of a pulmonary exacerbation. we looked at consecutive cf patient admissions for iv antibiotic therapy to our large adult unit. of these, had established cfrd and were excluded. the remaining patients (mean age years [range to ], male) formed the study population. none were on long term oral steroids, but received mg/day prednisolone as part of their routine exacerbation treatment. all patients underwent blood glucose measurement hours after each meal and before bedtime as part of a standard assessment protocol in our clinic. thirty patients ( %, / on steroids) demonstrated post prandial hyperglycaemia: exhibited values between . and . mmol/l (impaired glucose tolerance, who criteria) and > . mmol/l (frank diabetes, who criteria). there were no significant differences in age, genotype, fev , fvc, bmi, or duration of hospital stay between the two groups. of the hyperglycaemic patients, ( %) had abnormal glucose levels detected before bed time, significantly more than hours post breakfast ( %, p< . ), post lunch ( %, p< . ), but not post dinner ( %, p= . ). this study has shown a high prevalence of hyperglycaemia in adult cf patients treated for a pulmonary exacerbation who were not otherwise known to suffer from cfrd. nearly all our patients demonstrated glucose intolerance later in the day, when the recommended screening test for cfrd (the fasting oral glucose tolerance challenge) cannot be used. post prandial glucose monitoring of such patients during times of stress may therefore be advisable, allowing the introduction of insulin treatment at an earlier stage in the disease process. whittaker, l.a.; tilluckdharry, l.; christian, r. medicine, university of vermont, burlington, vt, usa objective: bone disease is a recognized complication of cystic fibrosis (cf). there are currently no guidelines for bone mineral density (bmd) testing or tools for fracture risk assessment in cf adults. we piloted a survey designed to identify cf-specific risk factors for low bone density and fracture. methods: a question survey was completed by patients prior to measurement of bmd at the hip, spine and radius by densitometry (dxa). the survey was comprised of questions on calcium and vitamin d intake, exercise, family history, medications, reproductive health, ultraviolet exposure, cf related diabetes (cfrd), weight loss, severity of cf lung disease and quality of life. z scores (bmd adjusted for age and gender) were used so that male and female data could be analyzed collectively. patient perceived health (pph) was rated by four questions and totaled for the pph score, which ranged from - with the highest score indicating the best health. functional status (fs) was rated by three questions that reflect the degree to which cf interferes with school, work or play. the total fs score ranged from - , with the highest score representing the least interference with life. questions on pph and fs were derived from a validated clinical assessment tool, the cf questionnaire (cfq) ( ) . results: all cf adult patients (n= , age and older) were offered participation in the study. dxa of total hip and lumbar spine was performed on patients ( %); ( %) of these patients also completed the survey. % of patients had low bone density on dxa (z score <- ). % of male cf adults had low bone density vs % of females. fracture was reported by % of patients who completed the survey ( % female and % male). lower pph score was associated with lower z score at the hip and spine. lower fs score was associated with lower z score at the hip and spine. low body mass index was associated with low z scores at both hip and spine. patients with bmi below kg/m were most likely to have osteopenia. conclusions: osteopenia and history of fracture were common in our adult cf population regardless of gender. bmi, pph and fs predicted bone density. risk stratification by a cf-specific bone health survey may guide bone density screening strategies for cf adults. prospective studies in cf adults are needed to determine whether a cf-specific survey can predict fracture risk as well as bone density. references : as life expectancy in cystic fibrosis (cf) increase, osteoporosis has become more prevalent. vitamin d status is one of many factors that contribute to optimal bone health. previous data has shown, the majority of cf patients are deficient in vitamin d despite being prescribed daily cf specific vitamin therapy. previous research has also shown that the current recommendations for vitamin d supplementation and repletion provided by the cystic fibrosis foundation bone health consensus ( ) are not sufficient to achieve optimal vitamin d levels in the majority of patients. moreover, the recommendations fail to sustain levels in the optimal range for bone health. purpose: we demonstrate a successful supplementation algorithm for individualized high dose vitamin d with continued high dose maintenance therapy which achieves and sustains appropriate levels. methods: all patients followed at the pediatric center are prescribed routine cf vitamin supplementation. vitamin d levels are obtained as part of routine clinical care via mass spectroscopy. if serum vitamin d level is < ng/dl, vitamin d therapy with ergocalciferol is initiated one time per week. patients < years of age receive iu/ dose and > years of age receive iu/dose. at the next routine quarterly visit, vitamin d levels are re-assessed via mass spectroscopy to determine efficacy of once weekly supplementation. if levels are > ng/dl, patients continue high dose supplementation time a week as maintenance therapy. however, if levels remain < ng/dl, the ergocalciferol is increased by time a week in month increments until adequate levels are obtained. once adequate serum vitamin d levels are obtained, patients remain on the level of supplementation needed to achieve levels > ng/dl as maintenance therapy. all patients are instructed to take vitamin d and their cf vitamins with enzymes and food to optimize absorption. results: after implementation of the algorithm, . % of patients, with varying levels of supplementation, had vitamin d levels > ng/dl (mean= . ng/dl). of the patients that achieved goal vitamin d levels, % were able to achieve and sustain adequate vitamin d levels without additional vitamin d supplementation while on standard cf vitamins (mean vitamin d level = . ng/dl). the remaining patients required chronic maintenance vitamin d: % required vitamin d supplementation once per week with a resulting mean vitamin d level of . ng/dl, . % required maintenance vitamin d supplementation twice per week with a resulting mean vitamin d level of . ng/dl, and, . % required vitamin d supplementation or more times per week with a resulting mean vitamin d level of . ng/dl. another % of patients take vitamin d supplements other than ergocalciferol and were not included in this study. conclusions: individualized vitamin d repletion and maintenance therapy as outlined in our algorithm is a successful mechanism to obtain optimal vitamin d levels in patients with cf. inhaled tobramycin ( %). sixty-two percent reported using at least different types of oral medications on that day including pancreatic enzymes ( %), oral antibiotics ( %), anti-reflux medication ( %), azithromycin ( %), anti-histamine ( %), and a decongestant ( %). twenty percent reported taking at least one medication for pain. forty-nine percent reported performing airway clearance at least twice during the day with % using a vest, % performing standard chest physiotherapy, and % using a flutter or acapella device. there was no difference in the reported number of medications or the reported time needed to complete therapies based on respondent age. although respondents with severe lung disease (fev < % predicted) reported a higher median number of therapies ( vs. , p= . ), the reported time for completing therapies was not associated with fev (p= . ). conclusion: daily treatment burden and complexity in all adults with cf is high, and is only marginally increased in those with worse pulmonary function. given this already high load of daily therapies, efforts to assess the treatment burden of new cf therapies are warranted. the impact of this high treatment burden on overall health related quality of life for adults with cf needs to be assessed. objective: the cystic fibrosis foundation (cff) has a network of over accredited care centers throughout the united states. data is collected from these care centers to help better understand the disease and describe changes in survival, standards of care, and health outcomes. when the cff was founded in few children survived to school age. now the predicted survival extends beyond the mid 's (cff, ) . with this change has come the need for age appropriate care in many areas including reproduction. the adult cystic fibrosis center at morristown memorial hospital presently follows adults. of those, women( %) with cf have had children affected with cystic fibrosis. each woman was diagnosed after her child. the cf data registry does not have any means of identifying if a patient has an affected child. as the average age of survival of cf patients has increased, so has the likelihood of cf patients having cf offspring. what is the estimated incidence of cf patients having cf affected children attending accredited cf centers in the united states? method: questionnaires were sent to care centers and satellite centers via standard mail or facsimile based on information from the cff directory. one month after the last questionnaire was mailed, the cf foundation sent out a reminder email to the nurse coordinators. questions asked were as follows: ) name of center ) do you presently care for any patients with cf who have given birth to, or fathered a cf affected child? ) how many patients at your center have had cf affected children? ) was the parent diagnosed before or after pregnancy was confirmed? ) if parent's diagnosis came after conception, was this after child was diagnosed? ) was the parent's diagnosis a result of prenatal testing? results: a total of questionnaires were mailed or faxed. this netted a result of responses. after email reminder, an additional questionnaires were returned for a total of responses, an % response rate. name of center was checked to remove duplicate information. the number of parents with cystic fibrosis who have had children with cf numbered . of those, ( %) were diagnosed before pregnancy; ( %) were diagnosed after pregnancy. of those diagnosed after pregnancy, the majority ( %) were diagnosed as a result of their child's diagnosis. only ( %) were diagnosed as a result of prenatal testing. conclusion: based on the responses from accredited cf care centers, patients with cf have children also affected with this disorder. prior to conceiving their child, % knew that they had cf. having cf did not appear to be a deterrent to delivering cf offspring. this study did not look at the age of the parent or child; they may have conceived their child before genetic screening was common for spouses. as the median survival of this population increases, the incidence of cf adults with cf children may also increase. the cff may choose to add a question to the cf data registry, identifying cf patients with cf offspring. the potential physical and psychosocial impact can then be tracked. anderson, a.; popli, k.; stewart, j.; heslop, k.; gascoigne, a.; bourke, s. adult cystic fibrosis centre and fertility centre, royal victoria infirmary, newcastle upon tyne, united kingdom as the outcome of patients with cf improves fertility issues become increasingly important. almost all men with cf are infertile because of azoospermia due to congenital absence of the vas deferens. these men can attain genetic paternity by sperm aspiration from the epididymis or testis with intracytoplasmic sperm injection (icsi), but few men with cf seek fertility treatment to assess their knowledge and attitude towards fertility issues a questionnaire was sent to men with cf: ( %) responded; ( %) declined to give information and ( %) replied in full. overall % thought that nearly all men with cf were infertile, % did not know how many were affected, and % could describe the exact nature of infertility. only % knew that treatment for infertility was available: % of these thought it was rarely successful and % were unsure of success rates. although % had thought of having children at some stage, only % had sought investigation of infertility. two men had children, one by icsi and one by donor insemination. overall % feared that the child could have cf and % worried that their health would affect their ability to function as a parent. in terms of receiving advice % thought that this should be given by a fertility specialist, % by a cf physician and % by a primary care physician. with regard to fertility treatment % thought that decisions should be made by the patients and their partners, % by the patient alone, and % by a doctor. the reluctance of men with cf to seek fertility treatment appears to be due to many factors including lack of knowledge of available treatments, fears about the child inheriting cf, and concerns that their health would adversely affect their role as a parent. in addiition to information provided by the cf team advice from a specialist in fertility treatment may help to improve the provision of reproductive counselling to these patients. nash, e.f. , ; coonar, a.s. ; stephenson, a.l. , ; delgado, d.h. ; singer, l.g. , ; tullis, e. , ; chaparro-mutis, c. studies have shown varying degrees of right ventricular (rv) dysfunction in adult cf patients with severe lung disease. left ventricular (lv) dysfunction is much less common with conflicting reports as to its prevalence. pulmonary hypertension (ph) is commonly seen, the severity correlating with fev . one group reported that ph was more prevalent in b. cepaciacolonized patients, albeit in a small sample. the aim of this study was to determine the true prevalence of ph and cardiac dysfunction in cf patients with severe lung disease. we carried out a retrospective cohort study of all adult cf patients referred to the lung transplant program at toronto general hospital from - . adult patients referred with non-cf bronchiectasis were included for comparison. demographic data, lung function, -minute walk, micro-biology, doppler echocardiography and resting and stress radionuclide ventriculography (muga) results were analyzed by students t-test (parametric) or mann whitney u test (non-parametric). results adult cf patients ( % non-b. cepacia, % b. cepacia) and non-cf bronchiectasis patients were included. data from these groups are summarized in the table. we found higher minute walk and bmi values and a higher percentage of males in the b. cepacia compared to non-b. cepacia group. ph was present in % of the cf patients in whom pasp could be obtained. b. cepacia patients had lower first pass rvef compared to non-b. cepacia patients. % of the b. cepacia patients had an abnormal lvef response to exercise (defined as < % increase on exercise) compared to % of the non-b. cepacia patients. we found a high prevalence of ph as well as rv and lv dysfunction in cf patients with severe lung disease. b. cepacia-colonized patients had worse rv function compared to non-b. cepacia-colonized patients on first pass radionuclide ventriculography. *non-cf bronchiectasis group older than cf groups (p< . ) b. cepacia cf group higher than non-b. cepacia cf group (p< . ) b. cepacia cf group lower than non-b. cepacia cf group (p<. ) perobelli, s. ; dorazio, c. ; assael, b. ; tamanini, a. ; castellani, c. . cystic fibrosis center, verona, italy; . molecular biology laboratory, verona, italy cf neonatal screeening (nbs) can identify neonates with elevated irt, normal or borderline sweat chloride concentrations, and one cf mutation plus an additional cftr sequence variant, or, alternatively, two cftr sequence variants. the combination of hypertrypsinogenemia and two cftr gene defects is consistent with the presence of a cftr-related disorder (cftr-rd). although these neonates are usually healthy at diagnosis, the long-term phenotypical consequences may be highly variable. such variability makes impossible to predict the clinical outcome, and provide satisfactory genetic counselling for the family. the diagnosis of such a vague condition could potentially cause considerable family stress. this study aimed at assessing how parents of infants diagnosed with a cftr-rd through nbs perceive their children's health. a questionnaire for parents was designed, consisting of three sections. the first section asked about information given to the family in the neonatal period, and about emotional reactions to the cftr-rd communication of diagnosis. the second section investigated the present perception of the child's health, and the parents level of anxiety/concern. the third section focused on the impact of the diagnosis on family planning, on relationships inside the couple and with the child, and on emotional distress; this section was concerned also with the use of carrier testing in relatives. parents were also asked to fill in a standardized form on child behaviour (achenbach child behaviour check-list). the questionnaire was distributed to two populations, the parents of children diagnosed with cftr-rd through nbs (group a), and the parents of children diagnosed with cf through nbs as the life expectancy of children with cf increases new issues arise that have not been dealt with in the past. in the past,issues related to the support and care of a young adult with cf were rarely raised because only small numbers of children with cf lived into adulthood. however, with an increasing young adult population, young adults without family support have surfaced in significant numbers and their needs should be identified and understood by the cf center care team. these young adults face the same range of issues others with cf face related to health insurance, government benefits, housing, education and employment. however, they do not have a family to help them wiht support, health insurance benefits and care needs. method in october , the cf legal information hotline ("hotline") began to provide free and confidential information to people with cf, family members and healthcare providers in the u.s. the hotline is staffed by attorneys, beth sufian and james passamano(bs and jp) and is accessed by dialing a toll free number or by e-mail. information about the hotline is available at cf care centers, in cf publications and on the web. information regarding the content of each call is recorded on an intake form and includes caller name, address, phone number, age of person with cf, cf center attended, and information related to the caller's question, attempts made to access legal information prior to calling the hotline, relation of access to information to access to care. calls and e-mails are tracked by seven major categories which are divided into subcategories. if a caller has more than one question, the call is tracked using the caller's primary issue. results from november to april the cf legal information hotline has received calls from young adults with cf who do not have family support and have issues related to obtaining health insur-ance, government benefits, educational oppornties or employment opportunities. as well as issues related to lack of support for care. the hotline has also received calls from cf care centers team members with questions related to the needs of young adults without family support. over an eight year period the cf hotline received _______calls. the categories for the calls were: social security benefits ( , ) , health insurance ( , ) , educational ( ), employment ( ), long term disability benefits ( ), family law ( ) and miscellaneous legal issues ( ). discussion people with cf face obstacles to care if they are unaware of their legal rights especially in the areas of health insurance and government benefits. healthcare providers are busy addressing the medical needs of patients and are often not well equipped to provide detailed information about the legal rights of their patients. the hotline provides important information to both patients and healthcare providers that can optimize both patient care and outcomes. access to legal information can result in individuals obtaining health insurance, medicaid, medicare or other state coverage that in turn results in better access to treatment. legal information can also lead to important modifications in the educational or employment environment for the individual with cf. these modifications can be critical in allowing those individuals access to important care and treatments. providing information that can help individuals obtain social security or long term disability benefits can result in a monthly benefit and health insurance that then allows the individual to devote more time to their healthcare. many people with cf and healthcare providers lack information about the legal rights of individuals with cf. understanding the legal rights of people with cf can reduce obstacles to obtaining care, optimize education and employment, and increase access to retirement benefits. further work needs to be done to identify ways to make individuals with cf and healthcare providers aware of the hotline. the cf hotline provides a unique service to cf patients and healthcare providers by providing information regarding the legal rights of people with cf. identification of ways to assist young adults without family support should be identified and cf center xcare teams shoudl be given the tools to allow them to help their patients access government assistance and other programs that can help make sure that the young adults have acces to care and support they need to live with cf. the dvd gives healthcare staff, patients and families a rare glimpse of ten couples with cystic fibrosis (cf) interacting at a cf care center-sponsored 'couples support group'. they discuss the impact this forum has in their daily lives for gainingo information about how cf affects their lives as individuals, and as couples, and how the 'non-cf partner' learns from others. o skills at networking and personal coping strategies. o reflections on 'family life and cf', and o observations on ways cf care centers can join them in greater health partnership. lastly, this dvd provides a 'starter kit' for ways to establish such a group. one of the realities of a life-threatening illness can be that of social isolation, and of separation from others who share the same disease. having the opportunity of participate in a support group can significantly reduce that sense of isolation and give the participants an ability to share experiences and give support to others with this disease. cystic fibrosis as an illness has growing ranks of 'survivors' who live longer, fuller lives, thanks to the advances made on multiple-research fronts. historically, adults with cystic fibrosis have not had much occasion to share person-to-person experiences within the structure of their cf care centers. justifiably, with the potential for cross-infection, the cystic fibrosis foundation has urged caution for the cf population in having face-to-face interactions. in , our cf care center recognized this need and sponsoredwith guidance from staff facilitators-an on-going adult support group. prior to the formation of the group pre-and on-site group ic protocols were developed. at the pre-group stage, the physician initially certifies that the patient is free from aggressive pathogens. each time the patient rsvp's permission to attend a group session, the physician must 'recertify' this status. on-site protocols emphasize a number of ic precautions to minimize crossinfection. the center recognized that by developing such a support group, 'patient and family centered care' could be enhanced. a goal in the group's formation was to create 'mutually beneficial partnerships among patients, families, and healthcare providers'. group structure/successes to date: the group is limited to participants. two cf care center staff act as facilitators. this is a support, not a therapy group. compliance with therapies is reported to have increased as one outcome of this forum. formal topics are purposefully not predetermined; the group's success is predicated on the personal responsibility of each participant to bring topics/issues from their daily life experiences. the group has gained identity and trust and has evolved over three years into two separate groups: an individual cf group and a couples cf group. ownership of these groups by those who attend is apparent. both the care center and the couples support group are forums for learning 'how to live with cf'. future goals will call for using identified quality of life tools to measure psychosocial and emotional growth in individuals through their participation over time in the group. sawicki, g. ; asher, d. ; dill, e. ; sellers, d. ; robinson, w. . children's hospital, boston, ma, usa; . education development center, newton, ma, usa background: advance care planning (acp) is an important tool to promote alignment of the patient's care with his or her needs, goals and values, and is particularly useful if the patient's ability to make decision becomes compromised. the purpose of acp is to develop a treatment plan promoting a high quality of life for those near the end of life. such planning is especially appropriate in persons with life limiting disease. minimal research exists on the advance care planning process of adults with cf.<p>methods: in the fifth survey wave of the project on adult care in cystic fibrosis (pac-cf), an ongoing longitudinal panel study of cf adults from cf centers in the us, participants were asked to report on their opinions and experiences with advance care planning. the survey asked about opinions on advance care planning documents, communication about advance care planning with family and clinicians and whether a directive had been completed. clinical data were obtained from the participating centers. preliminary bivariate analyses were conducted to examine factors associated with completing an advance care directive.<p>results: / ( %) surveys were completed. the mean age was ± years, % were female, and the mean fev (% predicted) was ± . % reported that they had spoken to someone about the care they would want if they became too ill to make their own decisions in the future, % had thought about whom they would want as their healthcare proxy, and % reported having specific wishes about the types of medical treatment they want or would not want if they became too ill to make decisions for themselves in the future. however, only % reported completing a healthcare proxy form, living will or any other type of written instructions concerning advance care directives. % of respondents reported feeling comfortable talking to their clinician about acp. % of subjects said that their cf clinicians have asked them about acp, and only % reported that they have discussed acp with their cf clinician. the following characteristics were significantly related (p<. ) to completion of an advance care directive: female gender ( % vs. %), age (mean years vs. years), having a college degree ( % vs. %), being married currently or in the past ( % vs. %), having children ( % vs. %), having diabetes ( % vs. %), having specific wishes about treatment decisions ( % vs. %), and reporting that a clinician had discussed acp with them ( % vs. %).<p>discussion: though the majority of cf adults report thinking about, communicating with family and deciding on their advance care wishes, only a minority report completing any legal documentation supporting their decision. additionally, very few cf adults report being asked about acp by their clinicians and even fewer report discussing acp with them. formulating specific wishes and discussing acp with a clinician are strongly associated with completing an advance care directive, suggesting that if clinicians were more active in talking to their patients about acp, patients are much more likely to complete advance care directives. efforts to improve clinician communication with cf adults around the issues of advance care planning are needed. objectives: caregiver involvement in children's cf treatments fosters better adherence and improved health outcomes. several studies have suggested that parents of children with cf report elevated symptoms of depression (quittner et al., ) , however, there is no data on the effects of caregiver depression on adherence. adherence to treatment is difficult to measure in patients with cf, and prior research has relied primarily on self-report, which is likely to be inflated. the purpose of this study was to examine the effects of caregiver depression on adherence to enzymes using both parent-reported and electronically monitored enzyme adherence over a three-month period. in addition, we examined the relationship between depression, rates of enzyme adherence and short-term changes in weight. methods: as part of a larger intervention study at cf centers, children with cf ages to and their parents were recruited. parents completed a standardized measure of depression (cesd) at enrollment and were provided with mems caps that recorded the date and time of each bottle opening. three months later, the electronic data from the pill caps was downloaded and parents completed a structured interview reporting their child's adherence to all components of the cf treatment regimen. only the section addressing enzyme adherence was included in this analysis. standard health outcomes, such as weight and height, were also assessed at enrollment and months later. results: preliminary analyses indicated that caregivers reported elevated levels of depression, with % scoring in the clinical range. rates of adherence to enzymes were poor ( % at home and % at school). caregiver depression was negatively associated with adherence, with depressed caregivers demonstrating lower rates of adherence ( percentage points). adherence to enzymes was associated with changes in weight, with a % adherence translating into percentile points of weight gain. final analyses will also include parent-reported adherence to enzymes. conclusions: a substantial number of parents scored in the clinical range on a depression screening measure. in addition, depression was associated with poorer adherence. rates of adherence to enzymes were surprisingly low, both at home and at school. furthermore, poor adherence was associated with a decrease in weight three months later. caregiver depression appears to be under-diagnosed and these results suggest that screening and intervention may be warranted. adherence to enzymes should also be targeted in clinical interventions. funding was provided by nih grant #hl of non-compliance with medical treatment and greater behavioral and emotional distress. adherence is particularly problematic during adolescence, however, few family-based interventions have been developed to target adherence behaviors in this population. the goal of this study was to compare the effects of behavioral-family systems therapy (bfst), an empirically-supported treatment, to both family education (fe) and standard care (sc). methods: as part of a larger intervention study, adolescents with cf ages to and their parents completed the conflict behavior questionnaire (cbq) and the parent-adolescent relationship questionnaire (parq) developed by robin and foster ( ) . adolescents completed these measures for each parent and both parents, if available, completed them with respect to their teen. the problem-solving, communication, and beliefs subscales from the parq were administered. participants were then randomly assigned to one of three treatment arms: bfst, fe or sc. families in the bfst group received ten -minute sessions over a month period, including family problem-solving, communication skills training, and cognitive restructuring. families assigned to the fe group received ten minute psychoeducational sessions over months aimed at increasing knowledge about cf and its management. those in the sc group received their usual care at the cf center. the cbq and parq were completed pre, post and , and months following the intervention. results: adolescents reported that the bfst intervention, relative to the other two, improved their communication with their primary caregivers (p < . ) and caregivers improved their communication with their adolescents (p < . ). in addition, caregivers reported improved problem-solving with their adolescents (p < . ). on the cbq, bfst reduced both adolescent and primary caregiver conflict and fe reduced caregiver conflict. no significant improvements were found for those in sc. conclusions: preliminary findings suggest that bfst is effective in improving communication skills and reducing conflict in adolescents with cf and their caregivers. future analyses will evaluate the effectiveness of bfst and fe on adherence and other family functioning measures over the course of the study. funding was provided by nih (hl # ) background: cases of diabetes among people with cystic fibrosis (cf) have increased as life expectancy for these patients improves, yet the impact of this additional illness on daily functioning is under-researched. to explore this issue, a study was conducted comparing the views of patients with either cystic fibrosis related diabetes (cfrd) or type diabetes mellitus (t dm) about being diagnosed and living with diabetes. methods: qualitative research was used because the study was concerned with understanding diabetes from patients' perspectives. purposive sampling was employed to achieve maximum variation in terms of duration and type of diabetes experienced by participants. data were collected via semi-structured interviews, all of which were taped and transcribed verbatim. recruitment continued until no new ideas or insights emerged from additional participants. a framework approach to analysis was adopted. this involved coding and summarising interview data into charts to explore and develop main themes. initial analysis was undertaken by two researchers (st and cd) and amended after comments from the remaining authors. results: interviews, carried out with cfrd and similarly aged t dm patients, lasted for an average of minutes (range - minutes). the following themes were derived from the data collected: evolving vs fracturing identity; diabetes in context; self-management motivators. for patients with cfrd, diagnosis represented a progression in their health status, which called on them to adapt existing treatment regimens to accommodate this additional condition. in contrast, interviewees with t dm had to re-evaluate their previous sense of self as 'healthy' and adjust to manag-ing a long-term complaint. these individuals were more likely to talk about diabetes in relation to a range of competing commitments (e.g. work or family related) and to describe feeling psychologically low due to diabetes compared to patients with cfrd, the latter depicting demands from their primary illness (cf) as a major obstacle to caring for diabetes. participants with cfrd recalled feeling lucky when told they would not face strict dietary restraints, which they associated with other forms of diabetes, and seemed less concerned about diabetic complications than those with t dm. for interviewees with t dm, a desire to reduce future health risks motivated their self-management efforts, whilst those with cfrd were driven by the negative effect poor control of diabetes had on their chest and weight. conclusions: both sets of interviewees found diabetes time consuming and, on occasions, frustrating to accommodate into daily life. findings from the study act as a reminder that patients manage their condition in the real world, against a plethora of other demands on their time and energy. in the narratives of participants with cfrd, these demands were often related to the existence of their primary illness. ing the course of development. the purpose of this study is to examine rates of medication adherence across a wide age span using an objective measure of adherence and to compare adherence to health outcomes. methods: patients with cf age years or older who are prescribed azithromycin, colistin, hypertonic saline, pulmozyme, and/or tobi for at least one year are eligible. recruitment is ongoing. the previous year's medication refill records were requested from participant-identified pharmacies. a medication possession ratio (mpr) was calculated for each drug and was defined as the sum of all days of medication supply received during the months divided by the number of days the medication was prescribed. values were truncated to % and averaged across all medications to obtain a composite score. medical records were abstracted to identify the prescribed drug regimen and health outcomes (e.g., lung function, exacerbations, bmi) over the same time period. results: thus far, patients have joined the study ( % participation rate), resulting in pharmacy records requested ( unique pharmacies). of the first participants with complete pharmacy data, the mean age was . years (sd= . ; range= - ) and % were female. the table presents mpr data for each drug and composite score overall and stratified by child, adolescent, and adult participants. the complexity of the drug regimen and age were significantly correlated with the composite score (rho= -. and rho= -. respectively; p<. ). future analyses will compare the composite score and each drug's mpr with health outcomes. con-clusions: participants had suboptimal medication adherence similar to that reported in the literature. as mpr provides the maximal possible level of adherence, actual adherence may be even lower. poor adherence spanned the age groups and was associated with regimen complexity. children had the highest adherence, but also the least complicated drug regimen. these results suggest that obtaining pharmacy records is a viable means to objectively assessing medication adherence. moreover, results suggest that interventions targeting medication adherence may be a strategy for improving health outcomes, particularly for adolescents and adults. * fewer than participants within this cell (cf) whose exchange capacities for oxygen and carbon dioxide are already diminished. lack of rem and delta sleep have significant implications for the daytime functioning of pediatric patients with cf, potentially leading to impaired memory and attention which would reduce their ability to complete typical activities, such as school work and disease-specific tasks related to self care and adherence. based on these clinic findings, the authors are beginning a prospective study on the effects of sleep on neuropsychological functioning, well-being and compliance in pediatric patients with cf. future research should examine the relationship between decreased slow wave, rem sleep and psychosocial outcomes, including attention, memory, and health-related quality of life. there are diagnostic challenges related to non-classic cf (knowles and durie, ) particularly patients presenting in adolescence or adulthood with obstructive azoospermia, chronic sinopulmonary disease and chronic or acute, recurrent pancreatitis. practitioners are often unable to provide clarity to patients about diagnosis, disease course, and prognosis. potential harms and benefits of relaying a clear or unclear diagnosis may be psychological rather than physical and have long-term implications for mental and social well-being. the aim of the current study is to assess the psychological impact of diagnostic information for adults presenting with a cf phenotype, be it confirmatory (cf or most likely not cf) or unclear. method: we administered self report measures pertaining to psychological state, cognitive appraisal and uncertainty in a welldefined cohort of adult patients. presenting symptoms of patients include chronic sinopulmonary disease, obstructive azoospermia, pancreatitis, and those presenting with more than more cf phenotype. patients completed the self-report measures on two occasions: at the time of diagnostic testing and months after being counseled and notified of the diagnostic results. at the time of the initial assessment, the subjects were unaware of the test results and had not been seen by a cf physician. results: we provide interim observations on patients (sinopulmonary (n= ), obstructive azoospermia (n= ), pancreatitis (n= ), and multiple phenotypes (n= ) who completed the initial assessment. at the time of diagnostic testing, the level of depression, hostility, anxiety and interpersonal sensitivity were elevated in each group (t score > ); male patients reported significantly greater depression, anxiety and interpersonal sensitivity than female patients. compared to published normative data of patients with mixed chronic illnesses, patients presenting with sinopulmonary or pancreatic disorders reported significantly more uncertainty(p < . ). to date, of these patients have completed the measures months after receiving the diagnostic information. preliminary review of results shows that the level of depression, hostility, anxiety and interpersonal sensitivity remained elevated while the degree of uncertainty decreased. among the patients who completed assessment at months, patients were told that it was unlikely that they had cf, were told that they had mild cf, while were given an unclear diagnosis. those who were told that they did not have cf reported more uncertainty than those who were told they had cf (p < . ). detailed analyses related to outcome diagnosis will be conducted at the time of study completion (october ) . when this study is complete, the information will assist in our understanding of the psychological impact of a genetic diagnosis at an older age, identify issues confronting those individuals and help to establish appropriate paradigms for delivering complex information about genetic diseases. supported by grants from niddk [scor] and the canadian cf foundation. ( ). in accordance with these guidelines, we report our experience in using our nutrition action plan (nap) in patients with suboptimal nutrition. objective: to determine if implementing our nap would improve the bmi of these patients. methods: our nap is a written contract between the patient, caregiver and cf team. for clarity of nutritional goals, the nap is based on the colors of a traffic light. the red zone indicates a bmi less than the th percentile and poor nutritional status. the yellow zone indicates a bmi between the th and th percentile and fair nutritional status. the green zone indicates a bmi greater or equal to the th percentile and desired nutritional status. within each color zone, specific recommendations to improve nutritional status are listed. the ultimate goal for each patient is reaching the green zone. the caregiver, patient and nutritionist review the current nutritional status and a mutually accepted weight gain goal is established. the goal is recorded on the nap which is then signed by the nutritionist and patient. this contract establishes a commitment to achieve the goal by the next clinic visit. a reward system is implemented in conjunction with the nap. for patients reaching their goal, a previously agreed upon prize is given. patients achieving some weight gain but falling short of their goal receive a gift such as candy or small toys that serve as an incentive for continued weight gain. patients chosen for inclusion into this study demonstrated a bmi less than the th percentile; those on growth hormone, appetite stimulants or chronic systemic steroids were excluded. results: twenty-one patients, male and female, with a mean age of . years (range to years) were included in this study. fifteen patients demonstrated an improvement in their bmi with use of the nap: improved by - %; improved by - %; improved by - %; improved by - %; improved by - %. six participants had a negative change in bmi which we attribute to family upheaval, missed appointments with the cf team, exacerbations of disease and non-adherence. conclusion: we intervened in patients with a bmi less than the th percentile using a nap and a reward system. the results of this pilot study suggest that our nap and reward system may be of benefit in achieving positive gains in bmi. reference: ( ) previously it was rare for women with severe cf to undertake pregnancy and doctors tended to advise against pregnancy if the forced expiratory volume in one second (fev ) was less than %. the attitudes of doctors and patients are changing and many women living their lives with cf nowadays chose to undertake pregnancy despite the severity of their health problems. over the last years females (age range - years) have attended the newcastle adult cf centre. there have been a total of pregnancies involving women with live births ( ectopic). a further women had termination of unwanted pregnancy. mean age at the time of pregnancy was years. we compared an age-matched cohort of never pregnant women to see if there were differences in key variables making successful pregnancy more likely. the mean fev was % (range - %) and % (range - %) of predicted in the pregnant and non-pregnant group respectively (p= . ); rates of chronic pseudomonas aeuriginosa infection were ( %) and ( %) respectively (p= . ). cases of burkholderia cenocepacia were identified in the non pregnant group. there were no cases in the pregnant group (p= . ); ( %) had diabetes with patients having cf related diabetes prior to pregnancy and patients developing gestational diabetes; this compared with ( %) of non pregnant women (p= . ); there was impaired nutritional status within both groups with a mean bmi of . pre pregnancy (range - ) and . in the non pregnant group (range - ) (p= . ); ( %) and ( %) patients had had previous gastrostomy feeding (p= . ). pancreatic insufficiency was present in ( %) and ( %) patients in respective groups (p= . ). no child had cf but one child had complex congenital heart disease. there were no maternal deaths but patients subsequently underwent lung transplantation and patients died leaving young children (ages and years). patients in the non-pregnant group have also died. conclusion the profile of women with cf undertaking pregnancy is now similar to the overall cf population. the woman's decision to undertake pregnancy is often not directly related to the severity of her disease. amongst those who successfully completed pregnancy maternal and fetal outcomes are generally favorable. objectives: health-related quality of life (hrqol) instruments provide important information on disease progression and are increasingly used as patient-reported outcomes (pros) for behavioral and pharmacological trials (goss & quittner, in press) . recent advances in medical care have improved the long-term stability of pulmonary functioning, which has made it more difficult to detect small improvements in fev % predicted. new outcome measures are needed; the cystic fibrosis questionnaire-revised (cfq-r; quittner et al., ) , a disease-specific hrqol measure, has shown promise in this regard. the purpose of this study was to examine the longitudinal relationships between fev % predicted, weight percentiles, and cfq-r scores for adolescents with cf. methods: as part of a larger study evaluating adherence interventions, adolescents with cf, ages to , and their parents were enrolled at six centers. parents reported on their adolescents using the cfq-parent version, and adolescents completed the cfq-teen/adult version as a selfreport. measures were completed pre and post treatment and at , , and month follow-up visits. spirometry and weight data were collected at these same time points. results: empirical bayes estimates were used to examine change over time. preliminary results indicated that adolescents' scores on the cfq-r respiratory scale were significantly and positively correlated with changes in pulmonary functioning. parents' scores on the cfq-r vitality scale were also correlated with changes in pulmonary functioning, with higher cfq-r vitality scores associated with better lung function. in addition, parents' scores on the cfq-r weight scale were significantly and positively correlated with changes in adolescents' weight. conclusions: these results support the validity and sensitivity of the cfq-r to changes in both pulmonary functioning and weight for adolescents with cf. additional analyses will be conducted to determine the relative stability of hrqol scores over time and to examine other cfq-r scales that may reflect positive changes in adolescent functioning (e.g., reduced treatment burden background: development of cf specific patient symptom tools as outcome measures is a critical step toward the development of potential new therapies for cf. we have developed a novel instrument to assess respiratory symptoms in cf patients. methods: we conducted in-depth qualitative interviews using the day reconstruction method and cognitive debriefing interviews ( adults, youth, and parents) at two cf programs, the university of washington and children's hospital and regional medical center. interviews were conducted until no new symptoms were mentioned by interviewees (i.e., data saturation). the interviews were audio-recorded, transcribed, coded and analyzed for themes. results: six pulmonary symptoms were identified in the interviews: cough, sputum production, wheeze, chest tightness, difficulty breathing/shortness of breath and fever. in addition, the most commonly cited activity and emotional impacts identified in the interviews were also included on the questionnaire. these emotions included: frustration, sadness/depression, irritability, worry, difficulty sleeping, and activities included time spent sitting or lying down, reduction of usual activities, and missing school or work. in all, eight symptom items were selected for inclusion on the self-administered questionnaire (see table) . as a result of the cognitive debriefing interviews, we changed initial language and adjusted the response options on some of the items in order to create greater distinctions between them. no important issues were felt to be omitted by patients who were interviewed. conclusions: using qualitative inductive methodology, we have created a novel patient reported outcome measure for cf. further study will be required to assess validation of the instrument. or more signs and symptoms occurred for more than two days, antibiotics were ordered with physician input and phone follow-up in days. if symptoms occurred less than two days, chest clearance was increased with phone follow-up in hours. the initial algorithm (ia) was piloted by nurses on patient calls on the emr and reviewed for adherence. subsequently, the cf phone note was revised, expanding the symptoms to include gi issues, last visit date and last hospitalization. the revised algorithm (ra) was used for a one month trial period with the entire nursing staff. a total of patient calls relating to pulmonary exacerbation were again reviewed for adherence to the algorithm. results: the review of phone notes following the ia found ( %) of the phone notes to be adherent to the assessment and treatment plan on the algorithm. several exceptions included calls received for gi issues, medications, complaints of general pediatric symptoms, and lab results. the phone follow-up within - hrs was also difficult to accomplish secondary to nursing responsibilities and difficulty locating the patient. the review of calls following the ra found ( %) notes were adherent to the algorithm. discussion: the revised algorithm and cf phone note for pulmonary exacerbation improved consistency in nursing assessment of signs and symptoms, evaluation of the current plan of care, and triggered appropriate interventions based on symptoms and length of illness. this improvement was particularly pronounced among the part-time rns who found it easier to obtain a more accurate history of patient's illnesses without asking for assistance from other cf team members. since the algorithm and cf phone note are newly implemented, tracking for consistency with the cf phone note will continue, revisions will be made as needed, and phone notes for conditions other than pulmonary exacerbation may be developed. methods: in , helen devos children's hospital integrated research coordinators (rc) from the spectrum health research department into the cf care team. this model incorporates two key aspects: . a shared resource of experienced, centrally educated and trained research coordinators (rc) with three rc's having a primary cf focus . incorporation of rc's into helen devos cf care centers' multidisciplinary team for weekly contact with patients. using the cf registry consent as a starting point of research discussion with the patients and families, the rc's present new and upcoming opportunities and answer questions about research. with attendance at local and national cf meetings, rc's have expanded their cf knowledge, networked with other rc's and explored new research trials. our site also integrated education about various aspects of research into both the clinical staff and cf family education meetings. a review of the research database was completed to assess our cf center's research program. results: over the years reviewed, participation in clinical research trials has seen significant growth and patient participation has exceeded patients enrolled into clinical studies. conclusion: utilizing a team of dedicated rc's from the research department has proven to be effective in advancing our cf center's clinical research program. discussion: to meet the growing demand of patients needed to participate in clinical trials, cf centers will need to provide research education to both the patients and families and the clinical team, improve on skills needed to identify and enroll our patients into clinical trials and include the rc's into the multi-disciplinary cf patient care team. centralized research represents an excellent model for cf centers that want to excel in clinical research. integration of rc's into the cf care team, along with education initiatives for both clinical staff and patients and families has led to successful participation and enrollment in clinical trials. further studies need to be done to better identify barriers that patients and families have with participation in research. the goal of "cystic fibrosis transition care" is to ensure that youth with cystic fibrosis (cf) are adequately prepared to participate in the management of their health condition into adulthood and as they graduate to the adult health care system. in canada, it is unknown if, or to what extent, cf transition care is practiced in individual clinics. we therefore surveyed all canadian pediatric cf clinic coordinators (n= )using a brief standardized questionnaire; surveys ( %) were completed and returned for analysis. findings: all responding clinics transfer their pediatric patients to a distinct adult cf clinic, however almost half of these share one or more team members between the two clinics. transition care is recognized and practiced by % of responding clinics: % follow a formal transition program, and % follow an "informal program". "informal" practices vary widely from one clinic to another. formal programs were created by individual clinics, and share the common properties of being based on current research, having set goals, and utilizing a tool to document the process. the average age of transfer to the adult clinic is years. most clinics have "rare exceptions only" to delaying the age of transfer, the most commonly cited reason being "very ill/palliative patient". a small number of clinics also cited "intellectually challenged patient" and "reluctant patient" as reasons to delay transfer. only % of pediatric clinics hold a formal "transition" or "graduation" clinic, which allows adult team members to be introduced to youth before the actual transfer of care takes place. conclusions: although sharing team members between pediatric and adult clinics may ease the change from pediatric to adult care, it can also create barriers to the transition process. therefore, it is encouraging to learn that the majority of canadian pediatric cf clinics view adult care as distinct from pediatric care, and that there is a consistent age of transfer across the country. transition preparedness is also recognized as an important component of care, as evidenced by the number of clinics following a formal or informal transition process. it remains undetermined, however, whether in general there is adequate preparation for adult care. with only % of clinics following a formal transition process (and % not following any type of transition program), further assessment seems warranted and may reveal inadequacies requiring remediation. future direction: to strengthen cf transition care in canada, a "patient readiness to transition" questionnaire has been developed and will be administered to canadian cf patients transferring to adult cf clinics in . analysis of this questionnaire will provide insight into how well canadian cf clinics are preparing their youth for transfer to adult life, and may provide directions for further improvement. nearly all females with cf now survive into adulthood, and advice regarding pregnancy and contraception is becoming increasingly important as part of their sexual health education. we set out to identify the level of knowledge of these issues in patients attending our large adult cf unit. using a structured questionnaire, we surveyed consecutive cf females (age range to years) attending routine cf clinics. we asked about knowledge and usage of contraception, and issues relating to pregnancy and its possible effect in cf, ensuring the opportunity for a one to one discussion with the individual on completion of the questionnaire. only ( %) claimed to have had previous advice relating to contraception and ( %) pregnancy education. of these, ( %) stated that this was from adult cf nurse specialists, ( %) from adult cf physicians and the remainder from other sources (general medical practitioners, written literature, and the internet). only patients ( %) recalled that they had been given information in the paediatric sector before transition. the majority of all advice was given verbally. of the ( %) who were using some form of contraception ( [ %] condoms, [ %] combined pill, [ %] depot injection, [ %] a coil, and [ %] the mini pill); ( %) had experienced problems, and in some cases patients had been misinformed about the reliability of their contraceptive choice. as regards pregnancy, ( %) had undergone previous termination and ( %) already had children. thirty six ( %) had considered becoming pregnant but ( %) said they would discuss this with a member of the cf team beforehand: ( %) were aware this might impact on their health. of these, ( %) believed a reduction in lung capacity to be the biggest possible problem. other problems identified were alteration of medication, tiredness, and weight loss or gain. overall, ( %) felt they did not have enough information regarding pregnancy in cf and ( %) that insufficient contraceptive advice was given, expressing a wish for further knowledge. conclusion this survey has shown that a significant number of adult females with cf require further education about contraception and pregnancy. in some cases the advice they had already been given may not have been appropriate for patients with cf. furthermore, few patients appeared to have had effective counselling in the paediatric sector, despite the risk of pregnancy. we are working with patients and paediatric colleagues to improve the education in this important area for our women with cf. the state of minnesota added cystic fibrosis to the newborn screening panel on march , . one-year follow-up to date reveals infants have screened positive, of the screen positive, have been diagnosed with cystic fibrosis, infants are pending sweat chloride tests and evaluation. of this population infants are being followed by the minnesota cf center. the university has a comprehensive, interdisciplinary team available to provide care to infants, children and adults with cystic fibrosis. in response to newborn screening for cystic fibrosis, the center has implemented a prophylactic care program to include clinical care through early intervention and education within the first two weeks of life. benefits of collaborative care have been previously identified in the literature, showing improved quality of care with increased patient satisfaction, lower mortality, and improved outcomes. infants who are identified by newborn screening and receive earlier treatment have the potential for improved physical health and development. the inclusion of comprehensive genetic consultation as an integral component of cf education, allows for informed reproductive decisions. the newborn screening intervention plan is supervised by a nurse practitioner and consists of initial evaluation, initial therapy implementation, and a teaching/consultation schedule, which covers a minimum of four appointments scheduled over weeks. follow-up visits are scheduled within hours of referral and then at one week, days and weeks post referral. the schedule is adjusted based on infant acuity and family needs. initial evaluation consists of the confirmatory sweat chloride testing and/or genetic mutation analysis, serum laboratories, chest x-ray, stool for fecal elastase, and nasopharyngeal culture. general, supportive teaching with evidence from the literature is provided. preliminary results to date demonstrate that our infants have had no pulmonary exacerbations, no pulmonary hospitalizations with pulmonary functions obtained in over half of the infants. nasopharyngeal cultures obtained at the time of ascertainment demonstrate newborn screening patients have positive cultures for staphylococcus aureus, haemophilus influenzae, escherichia coli, streptococcus pneumoniae, klebsiella pneumoniae, acinetobacter junii and alcaligenes faecalis. one infant was culture positive for pseudomonas aeruginosa at the first out-patient clinic visit. this demonstrates colonization of organisms prior to clinic exposure. through minnesota's early intervention and education plan, the families will be more adherent to prescribed care, which will result in improved cf infant outcomes as monitored by number of exacerbations, pulmonary functions and potential complications. a detailed outline of medical intervention, education, and outcomes will be presented. cf-pediatric centre we developed a malabsorption blood test (mbt) using odd-chain length fatty acids, pentadecanoic acid (pa) and heptadecanoic acid (ha), to assess fat absorption in subjects with cf. pa is a free fatty acid, while ha requires hydrolysis of triheptadecanoic acid (tha) by pancreatic enzymes for absorption. objective: to determine the mbt reproducibility in healthy subjects and subjects with cf. methods: subjects with cf ingested a liquid test meal including fats (pa and tha) on occasions at least days apart. for each subject, a standard dose of pert ( , lipase units) or the subject's usual dose (if higher) was given with each test meal. serum was analyzed for pa and ha levels at baseline and then hourly for hours. a non-compartmental pharmacokinetic analysis was performed using pa and ha concentration-time data from subjects with cf. c max was directly observed from the individual subject profiles, and auc was calculated using the linear trapezoid rule. summary statistics (mean±s.d.) were calculated for all parameters. reproducibility of the mbt was also assessed in healthy adult controls tested on occasions. between subject (bsv, %) and within subject variability (wsv, %) was calculated for pa, ha and the ha/pa ratio. results: bsv (%) and wsv (%) of pa and ha absorption are presented in the table for subjects with cf (age . ± . y, females) and healthy adult subjects (age . ± . y, females). as expected, the mbt had greater reproducibility in healthy controls than in subjects with cf. in healthy controls, the reproducibility for pa and ha absorption was comparable; there is less wsv than bsv, and the ha/pa ratio has the best reproducibility. in subjects with cf, pa and the ha/pa ratio show less wsv than ha. conclusion: wider variability in fat absorption in subjects with cf reflects the complex interactions of the biliary, pancreatic and intestinal factors background: the international, multi-center gene modifier study of cystic fibrosis liver disease (cfld) initially enrolled patients with severe liver disease (i.e. cirrhosis and portal hypertension). for the initial population despite severe liver disease with portal hypertension, many of these patients had normal liver biochemical function tests and/or inr ( - %), depending on the test. the mean age of enrollment into the study was years, with the mean age of cfld diagnosis of years. candidate gene testing revealed an increased prevalence of the alpha- antitrypsin z allele in cfld patients, particularly in females, as compared to cf patients (> yrs.) without cfld, and an association with tgfβ variants (- and codon ) in males smoothing reference centile curves: the lms method and penalized likelihood hepb) and inactivated hepatitis a (hepa) vaccines in cystic fibrosis (cf) patients chronic liver disease (cld) remains the second mortality cause in cf. we evaluated the immunogenicity of hepa-and hepb-vaccines in cf-patients because it is described lower in patients with cld. patients and methods: blood samples of cf-patients aged . - . y (mean . y) were tested twice (time interval y) by chemiluminescent microparticle immunoassay to asses the presence of hbs-ab and ha-igg, and their vaccination status was recorded. seronegative patients for hbs-ab and/or ha-igg were vaccinated in between tests with engerix®, havrix® or twinrix®. results: / ( . %) patients tested positive for hbs-ab. / cld ( steatosis and cirrhosis). / tested positive at first but negative at present data are incomplete for hbs-ab and ha-igg for and patients. conclusions: . immunogenicity of hepa-and hepb-vaccines is comparable in cf-patients and healthy subjects. . cf-patients are at risk for cld and seroconversion must be checked after vaccination. . vaccination records are important as numbers of antibodies may decline beneath the detection limit in time methods: lf was assessed in children with cf, aged - yrs, using forced expiratory volume (fev(sub) (/sub)% predicted). body composition was measured using a reference four-component model(sup) (/sup) ( cm) allowing accurate evaluation of both fat mass (fm) and the components of fat-free mass dual-energy xray absorptiometry (dxa; lunar prodigy, g.e. medical systems) was used to measure fat, lean (non mineral) and bone mass and skin-fold thicknesses (bicep, tricep, sub-scapular) were measured. strength of relationship was assessed using pearson's correlation coefficient (r) and significant body composition components were fitted into a regression model. difference in fev(sub) (/sub) between the sexes was assessed with an independent t test. results: boys with cf did not differ from the reference population conclusion: our results confirm that body fat, but not ffm or bone mass, are related to the severity of impaired lf in children with cf. it is likely that the significant association between fev(sub) (/sub)and fat in girls but not boys reflects the poor body composition of the girls with cf. longitudinal follow-up of these children should indicate whether this sex difference persists after puberty. given the fact that prognosis is worse in girls the sex difference we've identified merits more attention. fuller nj et al. four-component model for the assessment of body composition in humans: comparison with alternative methods and evaluation of the density and hydration of fat-free mass conclusions: these results show that pancreatic status plays an important role in relation with pufa status in cf patients and particularly in (the initial fatty acids in the n- and n- pathways) in neutral lipids, nonesterified fatty acids, and phospholipids this may, in some way, account for the fact that : n- is more readily metabolized, and therefore depleted, in cf animals than in wt mice. conclusion: dha supplementation increased the localization does an integrated clinical and nutritional approach prevent this case control study examines the impact of clinical approach on pre and post-cfrd clinical course. patients with cfrd (mean age . + . yrs) matched to cf controls ( . + . yrs) for age, sex and pseudomonal status had parameters of clinical status and nutritional intervention recorded annually from six years pre diagnosis of cfrd to two years post. weight and body mass index (bmi) were lower at all time points to diagnosis of cfrd (ns) but were stable as a % of control values intravenous antibiotic treatment intensified, peaking at one year post diagnosis . days/yr (cfrd) v . (cf) ns but there was no difference in nebulised antibiotic use. an aggressive clinical approach prevents nutritional decline and delays respiratory decline until the year preceding diagnosis of cfrd data show mean (sd) or % , ; battezzati with advancing age insulin secretory defects and insulin resistance cause glucose intolerance and diabetes in an increasing proportion of cystic fibrosis (cf) patients. prediction of diabetes development in cf is made difficult by unique features: many patients are normoglycemic or even hypoglycemic after overnight fast, and there are repeated changes of glucose tolerance status from normal to diabetes and vice-versa, for many years and for unclear reasons. aim of the study was to detect predictive factors of definitive cf related diabetes (cfrd) development in patients undergoing oral glucose tolerance test (ogtt) evaluations routinarily. methods. starting from , all patients followed at the cf center in milan aged > years and without established cfrd undergo ogtt yearly. among those who received their first ogtt between and , had developed definitive diabetes by µu/ml, and . ± . vs . ± . ng/ml). glucose (p= . ) and insulin aucs (p= . ) were the most important predictive variables, respectively directly and inversely related to cfrd development (pseudo r for the model: . , p< . ). glycated hemoglobin and baseline glucose concentrations were directly related with outcome at univariate analysis whereas c-peptide concentrations were inversely related. in contrast, no relationship emerged between insulin-sensitivity indexes and outcome. anthropometric (weight, height z scores, bmi) and pulmonary function indexes were also unrelated. conclusions. insulin secretory defects are an important determinant of subsequent cfrd developement response rate was / in group a and / in group b. group a included males and females, mean age was months, sd . ; group b included males and females, mean age months, sd . . followgroup b parents do ("poor-very poor" health % vs %, p< . ), but over time health perception in parents of children with cf improves, and the gap vanishes ("poor-very poor" health in last year % in group b). post-diagnosis anxiety, depressive symptoms, sleep disturbances, mood changes, and nervousness are less frequently reported in group a ( % vs % p< . ), and the diagnosis was considered to affect the parent-child relationship more in group b than in a (p< . ). the two groups did not differ in the assessment scores of internalizing, externalizing and total behavioural/emotional problems. however, group b performed worse than the general control population average (mean . sd . vs mean sd . , p< . ). thirty-five% of parents in group a and % in group b changed their family planning projects following the diagnosis physical health and anxiety symptoms: does monitoring mediate the relation? results: physical health, monitoring, and anxiety symptoms were related. children who perceived themselves to be relatively healthy were less likely to have an information processing style characterized by high levels of monitoring (r = -. , p < . ), and they reported fewer trait anxiety symptoms (r = -. , p < . ). monitoring, as hypothesized, was associated with increased trait anxiety (r = . , p = . ). low bmi, a potential indicator of poor nutritional status and physical health among youth with cf, also was related to higher monitoring (r = -. , p = . ) and trait anxiety (r = -. , p = . ). tests of mediation indicate that monitoring partially mediated the relation between poor health and trait anxiety for both child report of physical health (goodman test: z = . , p = . ) and for bmi (goodman test: z = . , p = . ), but not when parental report or fev were used to assess youth's physical health, or when parental report of youth's internalizing symptoms was used as the outcome. conclusion: youth who tend to generally scan for and are attentive to changes in their environment, which may include their internal physical environment, were found to report more anxiety. moreover, this monitoring style appears to partially mediate the relation between physical health and anxiety among youth with cf. if monitoring is found to be a risk factor leading to an increase in future anxiety symptoms among youth with cf data was analysed using a thematic analysis: "framework" results: young people say that befriending is fun, offers opportunities for new experiences, a confidant outside the family, and gives them a boost psychologically. carers see befriending as confidence building for their children, providing time out for themselves, and helping with the big questions. befrienders see their role as mentoring, broadening young people's horizons and providing a safe place physically and emotionally. challenges include: forming and ending relationships, having multiple befrienders, ongoing support and training for befrienders, maintaining boundaries, sibling rivalry, and cost. conclusions: befriending is a new innovation in cf, and has the potential to make a difference to young people's lives. careful planning at the outset, ongoing support for befrienders and regular evaluation are essential factors in ensuring its success good practice in befriending services for people with learning disabilities qualitative research practice sage london ଙ in addition, there was high use of non-cf vitamins (n= ) and protein shakes (n= ) which were not included as a cam therapies. when prayer was excluded (which was used by % of respondents), . % of the patients are still using some form of cam. the most commonly used cam therapies in cf were relaxation therapies (n= ), massage therapy (n= ), chiropractor care (n= ), herb/plant product therapies (n= ), homeopathy (n= ), and yoga (n= ). an analysis of the relaxation therapies revealed that deep breathing exercises (n= ) were the most common and frequently combined with other relaxation techniques: meditation (n= ), progressive relaxation (n= ) and guided imagery (n= ). the most common herb/plant products used were: echinacea (n= ), garlic (n= ), selenium (n= ), ragweed or chamomile (n= ) and ginseng (n= ). the use of possible cf specific cam therapies were fish oils/omega fatty acids (n= ), glutathione (n= ), docosahexaenoic acid (n= ) and curcumin (n= ). in conclusion, cam is widely used by the cf population with "prayer for health" being the most common modality, however, many patients are utilizing multiple cam therapies (data not presented) within the framework of a weighted satisfaction model of quality of life, we investigated the importance ratings of adolescent and adult patients regarding disease-specific aspects of living with cf. method: outpatients (aged - years, m= . , sd= . ; fev - %, m= . , sd= . ) repeatedly filled in the cf-specific module of the questions on life satisfaction (flz-cf) to measure satisfaction with nine cf-specific aspects of life in relation to the subjective importance of each life domain. a ranking list of the most important life domains across the study group was determined, and intra-individual changes of the importance scores were analysed. associations of importance ratings with changes of pulmonary functioning (fev %) were examined. results: the most important aspects (% of "very important" or "extremely important" answers) are sleep ( . %), integration of therapy into daily routine ( . %), breathing ( . %), gastrointestinal functioning ( . %), and eating ( . %), less important is understanding by others ( %) , ; durieu, i. , . département d'information médicale, hospices civils de lyon dr. von hauner children`s hospital helios hospital, e.v. behring, berlin, germany supported by the cystic fibrosis foundation leroy matthews physician scientist award, the national heart, lung, and blood institute cystic fibrosis foundation therapeutics inc. symptoms patient-reported respiratory symptoms in cystic fibrosis: initial validation children's hospital and regional medical center the first author is supported by a second year clinical fellowship from razvi, s. ; quittell, l.m. ; sewall, a. ; marshall, b.c. ; saiman, l. . pediatric pulmonary medicine, columbia university, new york, ny, usa; . cystic fibrosis foundation, bethesda, md, usa significance: significant improvements have been made in diagnostic and therapeutic strategies for cf patients in recent decades. we hypothesized that these changes could potentially impact cf respiratory microbiology. thus, we examined longitudinal trends in the annual incidence and prevalence of cf respiratory pathogens from to .methods: cf foundation patient registry data, estimated to include % of the cf population in the u.s., was utilized in this analysis. patients were included if results from at least one respiratory culture were in the registry from january to december . patients were excluded after organ transplantation. to avoid misclassification of incident cases, a retrospective review of registry data from to was performed to establish the culture status of included patients prior to . thus, incident cases were subjects with first detection of a given pathogen in a given year. prevalent cases were defined as subjects with at least one positive respiratory culture for a given pathogen in a given year. all submitted culture results were included.results: the number of cf patients submitting registry data increased from , in to , in . the proportion of subjects meeting inclusion criteria remained relatively constant ( % to % per year). the median age of the study cohort increased from . years in to . years in . during the study period, the incidence of hemophilus influenzae remained stable ( . % to . %) as did the prevalence ( . % to . %). the incidence of pseudomonas aeruginosa ranged from . % in to a peak of . % in . the prevalence of p. aeruginosa declined from . % in to . % in . there is a trend for both an increasing incidence and prevalence of staphylococcus aureus; the incidence increased from . % in to . % in and the prevalence increased from . % in to . % in . the age specific prevalence of s. aureus remained highest in children aged - years. the incidence of methicillin-resistant s. aureus (mrsa) increased from . % in to . % in , with a parallel increase in prevalence from . % to . %. the highest prevalence of mrsa was noted in subjects years of age and older. the incidence of burkholderia cepacia complex decreased from . % in to . % in , while the prevalence remained relatively stable (range . % to . %). both the incidence and prevalence of stenotrophomonas maltophilia increased (incidence: . % to . %, prevalence: . % to . %).this retrospective study aims at assessing the respiratory function and the cystic fibrosis (cf) co-morbid conditions according to the patients' nutritional status.method: data were collected from the french observatory (onm) (n= ) (vlm, ined). the last year data for weight (w), height (h), fev , fvc were extracted from the database (exclusion criteria: transplan-tation); were also analysed the genotype, pancreatic enzymes consumption, pseudomonas aeruginosa (pa) colonization, cirrhosis, diabetes, pulmonary transplantation and mortality (sas . ). we used international age-adjusted standards for bmi z-score for children (c) and bmi for adults (over years) (a) (cole tj bmj ) to define underw (uw), normal w (nw), overw (ow) and obesity (ob) .results: data are available for patients in the c cohort and for patients in the a cohort ( %). nutritional status subgroups prevalence (%) is: . , . , . and . in c and . , . , . and . in a for respectively uw, nw, ow and ob. mean age in a is significantly increasing with bmi (p<. ). frequency of del/ del in c and a is lower in ow/ob (p<. ) as well as the use of pancreatic enzymes (p<. ). ow/ob patients have the best fev and fvc values whatever the gender and the age, with significantly less pa colonization in a (p<. ). we could identify a positive correlation between the pulmonary function and bmi. the cf co-morbid conditions demonstrated a lower prevalence of diabetes ( / ) and cirrhosis ( / ) in ow/ob. none of the ow/ob c or a are on a transplant waiting list versus . % in uw/nw (n= / ) and none died versus % in uw/nw (n= / ).conclusion: the observed prevalence of ow and ob in cf is respectively . and % whereas the french obepi study collected and %. our results suggest that increased bmi is associated with better fev , fvc, lower prevalence of pa, cirrhosis and diabetes. the potential risks of chronically high bmi have not been studied in this population yet, but justify further investigations in this longer life expectancy cohort. materials and methods: we retrospectively identified abdominal ct scans of consecutive patients ( females, males, mean age of years) with cystic fibrosis and a control group of consecutive patients ( females, males, mean age of years) scanned as potential renal donors. three readers reviewed all scans and recorded the presence and location of colonic wall redundancy, and the wall thickness of the ascending, transverse, and descending colon. clinical information on cystic fibrosis patients, including cftr gene mutations, was queried from our cystic fibrosis patient registry database. additionally, medical records of all cystic fibrosis patients were reviewed to determine the indication for abdominal ct. results: colonic wall redundancy was seen exclusively in patients with cystic fibrosis, and was noted in of patients each for reviewers , , and (p< . ). colonic wall redundancy was seen in of adult patients with cystic fibrosis ( %), but was not seen in any children age or younger (p< . ). excellent agreement was found for the ct identification of colonic wall redundancy among readers (kappa= . , p< . ). cystic fibrosis patients with colonic wall redundancy had significantly thicker ascending colonic walls (mean . mm) vs. those without wall redundancy (mean . mm) or controls (mean . mm), (p= . ). three patients with colonic wall redundancy had follow-up ct, and all showed temporal stability (mean of months). among adult cystic fibrosis patients, cftr gene mutations were available for of patients with and of without colonic wall redundancy. while the common ∆f mutation was the predominant mutant allele among patients with normal colons at ct (only of patients, or %, had an identified mutation other than ∆f on either allele), a higher prevalence of less common non-∆f mutations was seen patients with colonic wall redundancy ( of patients, or %, p< . ). the g x mutation was seen exclusively in patients with colonic wall redundancy ( of patients, or %, p= . ). there was no significant difference in the proportion of patients with abdominal pain (> . ), pancreatic insufficiency (p> . ), diabetes mellitus (p> . ), history of meconium ileus background: airway inflammation in cf is associated with marked remodelling and bronchiectasis. pro-inflammatory mediators such as advanced glycation end-products (ages) and the soluble receptor for age (srage) may perpetuate this response in the lung and in other organs such as the kidney . the total body burden of ages reflects exogenous sources from the diet, endogenous production by the body, tissue degradation and renal clearance, which may be reduced in renal impairment. the accumulation of endogenous age is accelerated in conditions of high oxidative stress and inflammation, and ages have been implicated in the pathogenesis of diabetic nephropathy. the burden and significance of ages in cf has not been determined, but if elevated, dietary modification of ages may represent a novel anti-inflammatory approach for cf. the aim of this study was to determine serum levels of age and srage, and identify clinical correlates of age and srage levels.methods: adults with cf (n= , males, % pancreatic insufficient, mean age . ± . years (range to years), mean fev %predicted . ± . %predicted (range - )) and healthy adults (n= , male, mean age . ± . years (range - years)) were studied. cf participants provided - serum samples each over a six month period, while healthy controls provided a single sample. serum was analysed for levels of advanced glycation end-product (age-cml) and soluble receptor for age (srage) (elisa). for each cf participant, levels in the multiple samples were averaged, and the median for the study sample reported. clinical data, including bmi, presence of cf-related diabetes mellitus (cfrd) and serum hba c level were collected from the medical record. mann-whitney tests were used to compare cf and control levels, while spearman rank correlations were used to identify clinical correlates of age and srage.results: prevalence of cfrd was . %. mean bmi was . ± . kg/m and mean hba c level was . ± . %. median (iqr) levels for age-cml were ( , ) background: osteopenia is diagnosed in cystic fibrosis (cf) using dual-energy x-ray absorptiometry (dxa). areal bmd from dxa is subject to error when bones are smaller in volume than reference standards (t-scores). normalization of bone size by use of zscores in cf is controversial and not widely utilized, thus comparing to larger bone areas. reports in cftr-deficient mice (cf mice) reveal osteopenia when measured by dxa. we hypothesized that use of pqct, which eliminates bias of size, would more accurately analyze bmd.methods: femurs were collected at necropsy from cf mice and c bl/ j (b ) mice at wks, and cf mice and b mice at wks (all female) for pqct. time points were chosen to coincide with pre-pubertal and adult ages for comparison to human disease. total mineral, trabecular and cortical densities were measured. student's t-test was used to detect significant differences (p< . ).results: femur measurements from both cf mice and b mice are listed as mean ± sd in the table (below). length was greater in b mice compared to cf mice at and wks. total area at the metaphysis and diaphysis were greater in b mice at and wks. data are consistent with larger bones in b mice. total mineral density , trabecular density and cortical density , however, were greater in cf mice compared to b ( & wks, wks, wks).discussion: our study demonstrates greater bmd in cf mice when volumetric data are analyzed and size differences are accounted for by use of pqct. these findings persisted at adult age, suggesting a normal deposition of bone. in clinical management, dxa imaging is readily available compared to pqct, and can be used as a predictor of bmd and fracture risk. correct reference ranges must be utilized to minimize erroneous values secondary to size. z-scores allow correction for differences in bone area and size, even in adults. more studies into understanding bone mineral deficit and tools of measurement are needed in cf. meanwhile, bone measurements by radiographic imaging must be taken in context of overall health, pubertal progression, and size of individuals. gainesville, fl, usa; . nemours children's clinic, orlando, fl, usa; . suny upstate medical university, syracuse, ny, usa; . case western reserve university, cleveland, oh, usa; . genentech, san fancisco, ca, usa background: greater growth rates, bmi and fat-free mass are associated with improved lung function in individuals with cf (pedreira, et al. pediatr pulmonol. ) . current treatments for weight gain have focused on nutritional supplements and appetite stimulation, and not underlying issues of catabolism or chronic disease. we hypothesized that anabolic effects of gh would not only improve weight and height, but lbm as well.methods: sixty-seven prepubertal children with cf and height less than or equal to the th percentile were randomized to daily gh (n= ) or observation (n= ) for a period of year, followed by an off-treatment observation period of months. children randomized to gh received somatropin injections daily at . mg/kg/wk. height and weight were measured every three months. height was evaluated as height standard deviation score (sds) to control for differences in age and sex. lbm was measured by dexa scan at time zero, at and months, and at the end of the -month observation period. in addition, for lbm, change from baseline was calculated for subjects for whom the same dexa equipment was used at both time points. the preliminary results of the first months of the study are presented here.results: data for subjects in the observation arm and subjects in the gh arm, who completed months, are available. as shown in the table below (listed as mean ± sd), gain in height, weight and lbm were significantly greater in the gh treated group than in the observation group over the month period.discussion: gh improves growth in prepubertal children with cf as measured by height sds. in addition, gh significantly improves weight gain and this gain is, in part a result of the significantly greater increase in lbm in the gh-treated group than in the observation group. the relationship between the improvement in lbm and other outcomes in cf deserves further exploration. the national cystic fibrosis(cf) registry database notes cystic fibrosis related diabetes mellitus(cfrd) as a complication in . % of cf patients at all ages. cfrd is associated with poorer nutrition and increased pulmonary morbidity. the cause of cfrd is not completely known but insulin resistance may be associated with fibrotic damage to pancreatic islet cells due to chronic inflammation. other studies suggest protein energy malnutrition(pem) in early life leads to impairment of insulin secretion and cystic fibrosis-related diabetes (cfrd) accounts for increased morbidity and mortality in patients with cf and occurs in approximately % of patients by the age of years. cfrd net (network for epidemiology and trials) is a consortium of four large uk cf centres caring for adult patients with cf. the aim of this group is to undertake research into the diagnosis, investigation and management of cfrd. in this abstract, we estimate the prevalence of diabetes in a screened population of adults with cf. methods annual review data were collected on attending patients with cf aged and above during . g ogtts were performed after fasting for at least hours on patients without known diabetes. each ogtt was categorised as either normal ( hour glucose . - . mmol/l), impaired ( hour glucose ≥ . mmol/l and < . mmol/l) or diabetic ( hour glucose ≥ . mmol/l). all patients with a diabetic ogtt were followed up with serial bm monitoring to determine whether or not they had cfrd. fasting plasma glucose (fpg) was considered to be elevated ≥ . mmol/l, isolated impaired fasting glucose (igf) was defined as a value between . mmol/l and . mmol/l and hypoglycaemia was defined as a blood glucose < . mmol/l. in addition, we obtained information on age, sex and prescription of anti-diabetic medications subsequent to ogtt. in three of four centres, hba c was routinely performed on all patients. of patients (median age years, % male), ( %) had established diabetes and were therefore excluded from further screening. of the remaining patients, ( %) underwent formal ogtt testing. in this latter group ( %) had a diabetic ogtt, ( %) an impaired ogtt and ( %) had evidence of reactive hypoglycaemia at hours. of the patients with a diabetic ogtt, ( %) only had an abnormal hour value, ( %) only had an elevated fpg and (< %) had both. all patients with diabetic ogtts underwent blood glucose monitoring and ( %) went on to treatment with hypoglycaemic agents in the calendar year. none of the patients with an isolated elevated fpg had diabetes.hba cs were available in of newly diagnosed patients with diabetes (in the centres which performed hba c). in this group median hba c was . %. this study confirms the high prevalence of diabetes among screened patients and the growing burden of diabetes management in adult cystic fibrosis clinics. it further highlights the importance of performing screening for diabetes in this population; the majority of patients were identified on the basis of abnormal hour values. despite this only half of all suitable patients underwent ogtts in the four centres committed to screening. these patients merit further study, as previous work suggests that the decline in clinical status occurs several years before diabetes becomes apparent. cystic fibrosis related diabetes (cfrd) occurs in up to % of patients with cystic fibrosis (cf), the incidence rising with increasing age. the likelihood of developing long-term complications secondary to diabetes increases with poor glycaemic control and duration of diabetes. as survival has improved for people with cf those who develop cfrd may live with diabetes for several years. aim: to establish the frequency of diabetic complications in patients with cystic fibrosis related diabetes.method : patients with cfrd attending the adult cf service at the royal brompton hospital between april -march were screened for diabetic complications and cardiovascular risk factors. a total of patients (male/female: / ) including post transplant patients were screened. mean age was . years ( - ), mean hba c . % ( . - . % ) and average duration of diabetes was . years (< - years).as immunosuppressive therapy can also cause many of the complications associated with diabetes the results are presented separately for nontransplant and post transplant patients (table ) . patients in total had retinopathy: background retinopathy, proliferative retinopathy undergoing laser therapy and maculopathy. the average duration of diabetes in those with background retinopathy was . years with only patient having diabetes for > years. the patient with proliferative retinopathy (non-transplant) had been diabetic for years. a raised creatinine level was identified in all transplanted patients with microalbuminuria but none of the non-transplanted patients. patient (nontransplant) had macroalbuminuria. post transplant patients were on treatment for hypertension and a further patients ( post transplant and nontransplant) had elevated blood pressure (> / ) at screening requiring follow-up. none of the patients had evidence of cardiovascular disease or stroke.conclusion: macrovascular complications were not seen. microvascular complications occurred but were less common than the reported incidence in type and type diabetes. this may reflect the relatively short duration of diabetes (mean . years) of patients in this study. a further study comparing cfrd patients with a non-cf diabetic control group of similar duration of diabetes is warranted. cystic fibrosis (cf) is a disease that leads to serious disturbances in nutritional status and bone calcification. comparison of two methods for assessment of bone mineralization: dexa and hand radiograms in diagnosing osteopenia or osteoporosis. study was performed in a group of cf patients ( f, m), aged - yrs. nutritional status was assessed using bmi, cole's index and bmc. radiograms of non-dominant hand were assessed according to normalized optical density comparing to aluminum standard. bone density was also assessed using dexa. for statistical analysis, backward stepwise binary logistic regression (wald's test) was used. analysis of data revealed that using bmc, cole's index and hand radiograms markers we can diagnose bone mass disturbances (z score < sd) with precision up to . % comparing to dexa. sensitivity and specificity of this method was respectively . % and . %. false negative results were obtained in patients and false positive were also in patients. hand radiograms method could be an alternative for dexa in screening of bone density disturbances in cf patients. the study was partly supported by grant of ministry of science and higher education no p e .in a very recent publication( ) a high rate of fasting ( %) and reactive hypoglycaemia ( %) was described in a group of n= cf patients older than years who received an oral glucose tolerance test. reactive hypoglycaemia was related to the minute glucose concentration in the ogt test. we were surprised by the high percentage of asymptomatic hypoglycaemic situations in cf patients. as a part of a prospective intervention study in cf patients with cfrd, we screened more than patients years or older with cf for cfrd. in this multi-centres population ogt was performed in the morning after overnight fasting according to who standards. using the same definition for fasting hypoglycaemia (glucose < mg/dl; . mmol/l) and reactive hypoglycaemia (glucose < mg/dl; . mmol/l at minute during ogt test)as in the other study we calculated the percentage of cf patients with fasting or reactive hypoglycaemia in our cohort. results: ogt were done in patients with cf. age(mean±sd) , ± , years; bmi z-score - . ± , ;height z-score - , ± , and weight z-score - , ± , . ogt was categorised according to ada criteria. normal ogt (n= all ; fasting hypoglycaemia (fh) n= ( , %), reactive hypoglycaemia (rh)n= ( , %),ifg (n= all, fh n= , rh n= ( , %), igt(n= ,fh n= ( , %), rh n= ),fgt (n= all, fh n= ,rh n= ) and diabetes mellitus (n= all, fh n= ( , %)). fh was observed in ( , %) and rh in ( , %) out of ogt tests. there were no difference related to age, bmi z-score, height z-score and weight z-score comparing those patients with fh or rh to those without fh or rh in all categories of ogt tests.in this large multi-centres cohort of cf patients we were neither able to confirm the high percentage of fasting nor of reactive asymptomatic hypoglycaemia which was reported recently on a small group of cf patients. nutritional status measured by bmi z-scores, height and weight z-scores were unaffected by hypoglycaemia in our cohort as noticed also in the small group. as the ogt tests in the other study were done in a single centre it might by that a centre specific situation influenced the frequency of hypoglycaemia in that small group. we conclude that large numbers of investigations might be needed to come up with firm conclusions related to frequency of specific aspects of glucose disturbance in cf patients.fh does not exclude diabetes mellitus or igt. as survival from cf improves, surveillance to identify and treat complications associated with longevity is an important component of management. renal disease has been reported in adults with cf. risk factors may include cf-related diabetes mellitus (cfrd) and use of nephrotoxic medications. diabetic nephropathy has been observed in the absence of cfrd , highlighting the need for screening for renal impairment. this study aimed to measure renal function in a sample of adults with cf, and to compare estimated glomerular filtration rate (egfr) and urinary creatinine clearance (urcrcl) as markers of renal function.methods: adults with cf aged years or over (n= , % male, % pancreatic insufficient, mean age . ± . years) underwent screening for renal impairment. of these patients, ( males) had cfrd, and ( males) had no history or clinical features of cfrd. hour urine collections were analysed for urcrcl, with renal impairment being defined as < ml/min. serum creatinine level was used to calculate egfr (mdrd formula), which was classified renal function as normal or mildly impaired (> ml/min); moderately impaired ( - ml/min) or severely impaired (< ml/min). sensitivity of egfr for identification of renal function was calculated using urinary creatinine clearance as the reference method. unpaired t-tests were used to compared cfrd with non-cfrd patients.results: mean urcrcl was ± ml/min, and eight patients ( . %) had renal impairment (< ml/min). of these, only had egfr suggestive of renal impairment. the sensitivity of egfr for identifying renal impairment in this sample was %. a further patients had moderately impaired egfr, but normal urcrcl. five of the patients with impaired urcrcl had cfrd. age, gender, cfrd, fev %predicted and hba c level did not correlate with urcrcl. the table compares cfrd patients with non-cfrd patients. hba c level was higher in cfrd patients. there were no other significant differences in clinical or renal function parameters.conclusion: renal impairment, is common in the adult cf population and is not confined to patients with cfrd. screening using egfr is poorly predictive of impaired urcrcl in this population. these results suggest that surveillance to monitor renal function is indicated in the adult cf population, including in patients without cfrd, and that determination of urcrcl should be included in the screening process. cystic fibrosis (cf) patients suffer from pancreatic insufficiency resulting in malabsorption of fat soluble vitamins including vitamin d. many fac-tors contribute to low bone mass and fractures in patients with cf; however, chronic vitamin d deficiency plays a major role. the prevalence of vitamin d deficiency has been reported as high as % in some specialized care centers. in addition, reports of occult vertebral fractures have been reported as high as %. we sought to determine the prevalence of vitamin d deficiency (defined as -hydroxyvitamin d ( (oh)d) < ng/ml) and of vertebral fractures at our cf center. we obtained irb approval to review the records of all patients seen at our cf center during [ ] [ ] . we collected information related to bone health including (oh)d, bone mineral density and lateral spine or chest x-rays to examine for the presence of a vertebral fracture. we reviewed the records of subjects who were seen at our center during the study period. the mean age of the subjects was ± years. subjects had a mean bmi of . ± and an fev % predicted of . ± %. the percentage of subjects having an annual (oh)d level checked was only % and % in and , respectively. the mean (oh)d was . ± and . ± ng/ml in and . the prevalence of vitamin deficiency was % and % in and . about one quarter of the subjects had bone mineral density testing with half of the tests showing osteopenia or osteoporosis. twenty-seven percent of subjects had vertebral abnormalites detected on lateral chest x-ray. we sought to determine whether any factors were associated with vitamin d deficiency. we found that taking a multivitamin did not significantly protect against vitamin d deficiency. however, not taking a supplement containing vitamin d other than a multivitamin was associated with a % risk of vitamin d deficiency (p= . ). subjects having (oh)d levels determined in the winter or spring was associated with a % risk of vitamin d deficiency (p= . ). in summary, we found annual testing for vitamin d status was inadequate in our cf center and that when (oh)d level was determined, over % of subjects were vitamin d deficient. nearly one quarter of our adult patients already had evidence of vertebral compression fracture seen in lateral chest x-ray. we urge greater screening for vitamin d deficiency in the cf population. effective protocols to prevent and/or treat vitamin d deficiency are urgently needed in the cf population. improved vitamin d status in cf patients is one factor that may reduce the high prevalence of vetebral fractures. support for this study was provided by proctor and gamble pharmaceuticals background: more cf patients are surviving into adulthood, in part due to the increasing use of new therapies and more aggressive management of chronic respiratory and gi disease. as a result, the recommended daily treatment regimens for most cf adults are both complex and time consuming. objective: to assess the self-reported daily treatment burden of cf therapies in a cohort of adults with cf. methods: in the sixth survey wave of the project on adult care in cf (pac-cf), an ongoing longitudinal panel study of adults with cf from us cf centers, respondents were asked to report the type of medications, inhaled therapies, and airway clearance therapies they used during the day prior to completing the survey, as well as estimate the time generally required to complete each type of therapy.results: of the respondents (response rate %), the median number of therapies reported was (iqr - ) and the median reported amount of time usually spent on treatments was minutes per day (iqr - minutes). forty-eight percent reported using or more different inhaled therapies or using inhaled therapies or more times during that one day. the most commonly reported inhaled therapies were a bronchodilator ( %), pulmozyme ( %), an inhaled steroid ( %), hypertonic saline ( %), and objective: caring for a child with cf is stressful and often leads to adverse effects for both children and caregivers. support from family and friends can help reduce the adverse effects of chronic stress, however, there is little research documenting types of support provision as well as sources of support. moreover, social support may be related to important health outcomes. this study described the types of support provided to caregivers of children with cf and examined relationships between support and health outcomes.method: as part of a larger intervention study to improve adherence to medical regimens, children with cf ages to and their caregivers were enrolled across cf centers in florida: university of florida, nemours children's clinic, and all children's hospital. caregivers completed the norbeck social support questionnaire (nssq; norbeck, ) in addition to other measures at baseline and follow up. this questionnaire provides information about the number and type of people providing support, as well as its type and quality.results: caregivers received the majority of support from their families, spouses and friends and characterized these relationships as longer in duration, with more frequent provision of support. other individuals who provided support included the cf team, religious leaders, counselors or psychologists, and work associates. overall, caregivers rated family members and spouses as providing the greatest amount (i.e., "quite a bit") of emotional support. spouses received the highest ratings for tangible support; they were perceived as providing "quite a bit" of support in comparison to families (i.e., moderate) and friends (i.e., a little). in terms of size of the support network, caregivers in this study had similar networks to those of a normative sample of healthy adults. in addition, there was no difference in amount of emotional or tangible support received by these caregivers. preliminary baseline results indicated that social support was positively related to both adherence, children's growth (i.e., height and weight percentile), and family income.discussion: caregivers of young children with cf reported similar support networks as other healthy adults. however, there was variability in the amount of support provided by source, with spouses providing the greatest amount. social support appeared to be a protective factor, and lack of support was related to negative health consequences for their children. more attention should be focused on the potentially beneficial effects of social support.funding was provided by nih grant # befriending is reported to be valued by those who have been befriended, offering opportunities for social activities and new experiences and can impact positively on self confidence and self esteem . whilst government policy supports befriending, few schemes collect evidence to demonstrate the effectiveness of these services . young people with cf may suffer social isolation due to chronic illness and treatment demands and a befriend-ing service was offered to those considered socially vulnerable in the edinburgh area.this project aims to evaluate the effectiveness of this befriending service on young people with cf and their carers. methods liverpool, united kingdom; . child mental health, university of liverpool, liverpool, united kingdom; . child health, university of liverpool, liverpool, united kingdom; . psychology, university of miami, miami, fl, usa; . psychology, birkbeck college, university of london, london, united kingdom; . mathematics and statistics, university of lancaster, lancaster, united kingdom; . psychiatry, university of manchester, manchester, united kingdom introduction: existing treatments for cystic fibrosis (cf) are time-consuming and labour intensive and biomedical advances are likely to lead to further novel interventions. there is concern amongst clinicians that a high care burden associated with these interventions may compromise the wellbeing of caregivers, reduce adherence to the treatment protocol and increase the likelihood of inadvertent errors in the delivery of interventions. at present, there is no measure of 'treatment burden' and therefore no way to assess the impact of new and increasingly more complex interventions conducted by lay caregivers at home. furthermore, trials are hampered by the lack of measurable patient-reported outcomes beyond a broad quality of life assessment. to address this gap we have developed a measure of treatment burden for cf using qualitative methods (focus groups, action research, in-depth interviews) with participating parents and a working group of cf team professional staff. this measure addresses the time, effort, meaning and ease of management for caregivers of children with cf up to years and post the first year following a diagnosis. methods: we report here the pilot phase of the validation of this instrument, which involved (i) cognitive interviewing with n= caregivers; and, (ii) n= caregivers completing the clcf instrument together with a quality of life measure at time points. this yielded data for stability, reliability and coherence of the hypothesized constructs. results: the clcf takes minutes to complete. face validity and acceptability are established. for the first pilot sample the age of the child ranged from . - . years. treatments took, on average minutes per day to complete and an average of minutes of this was devoted to administering enzymes particularly for carers of infants. a prominent concern amongst these parents was their child's height and weight and their efforts were directed at optimising growth. for the child however, management of nebulised medications and physiotherapy were more frequently flagged as a concern. these data suggest this is a reliable, coherent and useful, although complex tool. conclusion: the caregiver challenge for cf cannot be understood simply in terms of time and effort involved in delivery of treatments. it also involves contextualising interventions for their meaning at multiple levels of explanation for the individual concerned. structural equation modelling would be an appropriate way to proceed with the main validation when such complex relationships occur between latent variables and would serve as a confirmatory factor analysis for the hypothesised relationships. sponsored by: royal liverpool children's nhs trust and university of liverpool. funded by: national institute for health research (nihr) research for patient benefit programme.introduction: the french cf practice recommendations, published at the end of in parallel with the creation of cf reference centres, advise that each patient should be seen at least every months at a cystic fibrosis reference centre.objective: to investigate the impact of these recommendations on the effectiveness of the follow-up of patients at the four reference centres in the rhône-alpes region.methods: all patients with cystic fibrosis attending one of the four cf centres between and were retrospectively included. the total number of visits was recorded for each patient and each year of the study period. to determine the evolution slope for each patient followed for at least years, a negative binomial regression of number of visits versus time was carried out (confirmed with a repeated model). to estimate the impact of the recommendations, the analysis was restricted to patients with at least two visits before and after and a second model was adjusted with a new intercept in to estimate the change in slope as of this point.results: a total of patients were included in the cohort. the average number of visits per patient rose from . in to . in (p< . ). the proportion of patients with at least visits per year increased from % to %. the negative binomial regression for the patients having had at least years follow-up confirmed this trend with an average slope of + . (sd= . ). a total of patients were evaluable for the change in slope. no significant change in trend was observed in : only % of patients had a higher rate of growth (this change was significant for only subjects). at the last follow-up visit, patients with increasing rates of number of visits were older ( yrs vs. yrs, p< . ), had lower %fev ( vs. , p= . ), had a similar average number of visits before ( . vs. . , p= . ), and a similar weight-for-age z-score (- . vs. - . , p= . ) .conclusion: the number of visits per patient is regularly increasing. since the publication of the practice recommendations in , the growth has tended to slow down: clinicians were already convinced by the need for closer follow-up and had begun to increase the rate of visits. methods: patients > years who presented for routine healthcare voluntarily completed four surveys: ) the revised eating attitudes test (eat), validated for cf patients by abbott and colleagues, where higher scores reflect worse attitudes towards eating; ) the rosenberg self-esteem scale (rse), where higher scores reflect better self-esteem; ) the body image scale (bis), developed for cf patients by wenninger and colleagues, where higher scores reflect better body image; ) the cystic fibrosis questionnaire (cfq), developed by quittner and colleagues, where higher scores reflect better hrqol. also, fev %, body mass index (bmi), and pancreatic sufficiency or insufficiency (based on the need for pancreatic enzymes) was recorded. regression analyses controlling for age, gender and bmi were used to examine the associations between the surveys. results: this study included patients with % males and a mean age of years. the eat was negatively associated with the rse (p= . , adjusted r = . ), bis (p= . , adjusted r = . ) and cfq (p= . , adjusted r = . ). the rse was positively associated with the cfq (p= . , adjusted r = . ). the bis was positively associated with the rse (p= . , adjusted r = . ) and cfq (p= . , adjusted r = . ). neither bmi nor pancreatic function was associated with the surveys (p=ns). fev % was positively associated with the cfq (p= . , adjusted r = . ) but was not associated with the other surveys.conclusions: more negative attitudes towards eating predict worse selfesteem and body image, while more positive body image predicts better self-esteem. also, attitudes towards eating, self-esteem and body image are significant predictors of hrqol with body image being the most important predictor.clinical importance: hrqol is an important clinical outcome measure in cf. clinicians need to be sensitive to attitudes towards eating, self-esteem and body image in cf patients, because they are important predictors of hrqol. riekert, k.a. ; mogayzel, p.j. ; bilderback, a. ; hale, w. ; boyle, m.p. . medicine, johns hopkins university, baltimore, md, usa; . pediatrics, johns hopkins university, baltimore, md, usa background: existing research suggests that self-reported adherence to all aspects of the regimen is likely suboptimal and objective measures suggest even poorer adherence. there is little empirical data on how much adherence is necessary to achieve desired health outcomes. moreover, there is limited data on how adherence changes dur-objective: cf may be associated with pain attributed to several etiologies. this study evaluates the prevalence of pain symptoms in adult cf patients and the influence on patients` lives.methods: patients of adult cf centers in germany completed a validated, self report questionnaire during a routine clinic visit assessing characteristics of chronic pain (prevalence, duration, location, quality and intensity of pain symptoms). furthermore, the impact of pain on different aspects of life was explored using a numeric scale from to with being the worst. every-day-life was divided into categories: duties at home, recreation, social activities, occupation, sexual life, autonomy, vital activities and cf-therapy. the average intensity of pain within the last weeks was correlated to fev , bmi and age.results: patients ( male) completed the questionnaire. the age was - years (mean . ± . ). patients ( %) aged - years (mean . ± . )reported pain within the last months. bmi was . - . kg/m (mean . ± . ), fev - % (mean . ± . ). if asked for pain within the last weeks ( %) reported painful episodes lasting from - days with a mean of . days (± . ). most patients described pain occurring at more than one site with the head being the most localized site, followed by chest and abdomen. concerning the quality of pain . % characterized their pain episodes as attacks whereas . % reported them as continious, . % had continious pain combined with pain attacks. patients desribed the intensity of pain as . (± . ) on a scale from to with being the most severe pain. the category of life negatively influenced most of all by pain episodes was recreation, followed by occupation and duties at home. female patients were more limited in their acitivites by pain symptoms than male patients with the highest difference being reported in sexual life. there was no correlation of the average intensity of pain within the last weeks to fev , bmi or age.conclusion: the prelevance of pain in cf is often underestimated. painful episodes can be the cause of worsening the quality of life for adult cf patients. assessment of pain should be routinely performed as part of care in cf centers. objective. sleep has been examined in a number of pediatric conditions, with impaired sleep resulting in worse neurobehavioral functioning (beebe, ) . recent research has shown that slow wave sleep is critical for memory (marshall, helgadottir, molle, & born, ) . to the authors' knowledge, no studies have examined slow wave and rapid-eye-movement (rem) sleep in pediatric patients with cystic fibrosis. methods. retrospective medical record review revealed two patients who underwent clinically indicated polysomnography (psg) who reported feeling tired and lacking energy. patients were females with cystic fibrosis, ages and years. results. psg revealed an increase in stage sleep for both patients, resulting in increased risk and observed hypopneic episodes. patient -a experienced . % in stage , . % in stage , and % in stages and combined. this patient also had no rem sleep. patient -b experienced % in stage , . % in stage , and % in delta wave sleep, with no rem sleep. respiratory disturbance index (rdi) for patients a and b were calculated at . and . , respectively. respiratory effort related arousal (rera) contributed to rdi by . and . points in patients a and b, respectively. in addition, endtidal co for patient a and b were maxed at mm hg and mmhg, respectively. their epworth sleepiness scales were scored at and for patients a and b, respectively. conclusions. structure of sleep was abnormal in both patients with decreased slow wave (delta) sleep in patient b and lack of delta sleep in patient a. neither patient experienced rem sleep. compensatory increased stage (nrem) sleep could cause respiratory related abnormalities, such as hypopnea and apnea in patients with cystic fibrosis background: understanding and advancing the application of tools to measure patients' symptoms is critical to advancing our evaluation of potential new therapies used to treat cf. we performed initial evaluation of the measurement properties of a cf-specific respiratory symptom daily questionnaire. methods: we planned to enroll cf subjects, stratified by age, at three cf programs, the university of washington medical center and children's hospital and regional medical center in seattle and mary bridge children's hospital in tacoma in a prospective assessment of a novel cf specific respiratory questionnaire. cf subjects years and older were eligible for enrollment. patients (parents for children under the age of ) completed a daily symptom questionnaire during two -day periods of clinical stability and one -day period when patients were ill for a total of days. the ill state began when patients/parents sought medical attention for respiratory symptoms. the questionnaires were completed using a secure web-based application or via paper for those patients without access to the internet. two health related quality of life measures (generic and cf specific) were completed by the subjects at the end of each -day period to assess the relationship between the novel questionnaire and health related quality of life. patients also used pedometers during the well and ill states to assess relationship between symptoms and activity level.results: cf subjects have been enrolled to date. at the time of this interim analysis, patients had completed questionnaires. of this total, only individual questionnaire entries have been missed in patients (< % of possible questionnaires). interim review of cross-sectional data suggests clear differences in symptom reporting between the ill and well periods. examples include % ( / ) noted difficulty breathing and % ( / ) noted tightness in the chest in the preceding hours during the initial well period compared to % ( / ) noting difficulty breathing and % ( / ) noting tightness in the chest during the ill period.conclusions: interim evaluation of this novel instrument demonstrates feasibility of deploying this instrument via the internet with an extremely high completion rate. using a cross-sectional analysis, the instrument can discriminate between the ill and well state. further data will be presented regarding within patient variability and discrimination of the instrument.supported by the cystic fibrosis foundation leroy matthews physician scientist award, the national heart, lung, and blood institute (hl - ), national institute of health (rr- - ), cystic fibrosis foundation therapeutics inc. background: improved communication in today's health care delivery system is a critically important aspect of patient care. nurses are in an effective position to improve communication due to their close interaction with patients. as a result, they are able to identify potential problems, communicate them to the healthcare team and improve patient care and satisfaction.hypothesis: improving communication between the patient/family and the health care team will improve patient/family satisfaction.method: as a member hospital partnering with the institute for healthcare improvement's (ihi) initiative, transforming care at the bedside (tcab), the children's hospital of philadelphia (chop) introduced the use of daily patient goal sheets (dpgs) as a vehicle to improve communication between members of the healthcare team, patients and families and the dpgs was refined to meet the needs of an inpatient medical unit to which cf patients are admitted. using rapid plan-do-study-act (pdsa) cycles, a multidisciplinary team engaged in small tests of change in different stages. initially, patient goals and discharge criteria generated in daily rounds were posted in each room on easel paper. then large "whiteboards" were placed in each patient room for documenting patient goals, discharge criteria, names of the care team members and questions from patients and families. as a final step in the process, we shifted the health care team rounds to the patient's bedside and implemented bedside shift to shift nurse report and safety checks. patient satisfaction was continuously monitored over this process using the press ganey survey.results: over an eight month period, the press ganey survey results for the unit showed an average increase of %. we attribute this increase to better information sharing among patient, family and hospital staff regarding the plan of care for the patient's hospitalization. the health care team also had an improved dialog with the patients/families. conclusion: patient/family and healthcare team communication and satisfaction were improved using an organized and stepwise pdsa process to develop daily patient goal sheets on a medical unit. background: the uab/chs pediatric cf center provides care for approximately patients. the pulmonary division has full-time rns and part-time rns who rotate phone triage for all calls (including cf) of patients seen by the faculty physicians. historically, patient calls received during office hours are taken by the receptionist and put into the emr, then returned by the rn on call. the rn contacts one of the staff md's, gives report of the patient's condition,treatment orders are received, and the patient notified. there are several issues with this phone triage system, which include inconsistencies in rn and md response as well as differences in documentation. global aim: to improve the consistency among rns in phone triage of sick cf patients.method: an algorithm for pulmonary exacerbation phone triage was developed by the cf center director and lead rns to improve consistency in symptom assessment and treatment plan. a specific list of systemic and pulmonary signs and symptoms was formed including length of illness. if three objective: patients with cf often require intravenous antibiotics for treatment of pulmonary exacerbations. patients often receive peripherally inserted central catheter (picc) lines or totally implantable venous access devices (tivads) for venous access. few studies have examined complications of tivad implantation and little published data exists concerning picc line complications in cf patients. this study sought to assess the complication rates of both tivad and picc lines as well as to identify possible risk factors for developing complications.methods: this retrospective study included patients from cf centers in northern new england. data was obtained from each patient's local medical record, port cf, and patient interviews. demographic data was recorded for all cf patients between / / - / / . for each tivad or picc line, the following information was recorded: type of line placed, history of prior line placement during the study period, patient age, history of use for blood draws, method of line flushing, and status of the line at the end of the study (if still in use). complications were defined as catheter occlusion, vascular thrombosis/stenosis, infection, or other local inflammatory reactions.results: data was collected for pediatric and adult cf patients during the defined study period. seventy-three tivads and picc lines were placed during the study period in patients. the tivad and picc line complication rates were % ( / ) and . % ( / ), respectively. in pediatric patients, % ( of ) tivads and . % ( / ) picc lines had a complication. of the tivad complications, three were systemic infections and three were catheter occlusions. of the picc line complications, there were two venous thromboses, one line occlusion, two systemic infections, and nine minor incidents of localized phlebitis. in adults, complications were recorded in % ( / ) of tivads and . % ( / ) of picc lines. of the tivad complications, there were five systemic infections, seven catheter occlusions, and four venous thromboses. of the picc line complications, there were three venous thromboses, three line occlusions, and four minor incidents of localized phlebitis. all adult patients who developed a deep venous thrombosis(dvt) associated with tivad implantation were homozygous for the deltaf mutation. the presence of diabetes or burkholderia cepacia complex(bcc) lung infection was associated with dvt with odds ratios of . ( % ci . - . ) and . ( %ci . - . ), respectively. conclusions: complications of picc lines were uncommon and usually minor. the rate of tivad complication observed was more common over the lifetime of the catheter and was similar to previously published reports. we identified potential risk factors for the development of dvt associated with tivads and picc lines, specifically cf related diabetes, bcc infection, and homozygous deltaf genotype. the mechanism by which these factors are associated with catheter complications is unclear and warrants further investigation. key: cord- -oecpqf j authors: nan title: aspho abstracts date: - - journal: pediatr blood cancer doi: . /pbc. sha: doc_id: cord_uid: oecpqf j nan myelodysplastic syndrome (mds) and frequently arise in the context of inherited bone marrow failure (bmf) syndromes, such as shwachman diamond syndrome (sds). monosomy /del( q) is associated with high grade mds and propensity to progress to acute myelogenous leukemia, a major cause of morbidity and mortality for patients with inherited bmf. development of non-transplant strategies to treat bone marrow failure without simultaneously stimulating outgrowth of malignant clones remains a major challenge. objectives: the aim of this study is to investigate the molecular consequences of del( q) in the context of bmf with the goal of developing more effective treatments. design/method: to study the biological and molecular consequences of monosomy/del( q) in bmf, induced pluripotent stem cells were generated from sds patients (sds-ipsc) . a deletion of the mds-associated region of the long arm of chromosome was then introduced using a previously published modified cre-lox approach. results: the sds ipsc phenocopied bone marrow failure with slow proliferation and impaired hematopoietic differentiation. we next explored whether deletion of q conferred a relative fitness advantage within the context of bone marrow failure. proliferation of the sds-del( q) ipscs was reduced below that of both the isogenic sds ipscs and normal controls without an increase in cell death. sds-del( q) demonstrated reduced hematopoietic differentiation compared with isogenic sds cells. these data demonstrate that deletion of q fails to confer a relative growth advantage relative to isogenic sds ipscs and results in further impairment of hematopoiesis. to gain insight into the mechanisms of del q-associated clonal evolution in sds, we performed rna sequencing (rnaseq) of sds+/-del( q) ipsc. expression of tgf pathways and their downstream targets were reduced in sds-del( q) ipscs compared to isogenic sds ipsc. single cell rnaseq analysis of primary sds bone marrow cells confirmed that the tgf pathway is hyperactivated in sds. western blot analysis showed increased phospho-smad levels in sds ipscs compared to sds-del( q) and normal controls, while total levels of smad were unchanged. pharmacological targeting of tfg with small molecule inhibitors resulted in selective improvement of sds hematopoietic colony formation and myeloid differentiation without stimulating outgrowth of the isogenic sds-del( q) cells or normal controls. these results demonstrate that del( q) reverses the tgf pathway hyperactivation of sds. furthermore, inhibition of tgf selectively rescues hematopoiesis in sds but not in isogenic del q cells, suggesting a potential strategy to treat bone marrow failure without stimulating del q clonal outgrowth. background: standard therapy of medulloblastoma consists of treatment with alkylating agents and radiation after surgical resection. although a statistically significant increase in survival is reported with this regimen, / rd recur and become resistant this class of agents ultimately leading to mortality. large numbers of somatic mutations were observed in recurrent medulloblastoma (rm) after alkylating agent and radiation treatment. high mutation rates in tumors can have twofold effect; ) a large number of non-synonymous mutations that have no role as drivers can still cause functional tumor antigens increasing the neoantigen burden and immunogenicity. moreover, ) such tumors can gain mutations in canonical or non-canonical dna repair pathways leading to a gain in the number of mutations as seen in case of glioblastoma, this can lead to even higher accelerated mutational rate. evidences suggest that high mutational load can cause higher neoantigen burden thereby making the tumor more susceptible to immune checkpoint inhibition. we propose that post therapy recurrent medulloblastoma gain mutational signature and immunophenotype of malignancies demonstrating clinical response to immune checkpoint therapy. objectives: ) rm has molecular signatures identical to tumors with high immunogenicity and clinical response to immune check point inhibition. ) rm has the immune inflammatory phenotype; harboring high percentage of tumor infiltrating lymphocytes (tils), macrophages and monocytes. design/method: to test our hypothesis, we downloaded the raw bam files of previously published data from international cancer genome consortium (icgc) . this set of about matched primaries and recurrent medulloblastoma cases forms our discovery cohort. we have called somatic variants using the gatk pipeline by the broad institute. to validate our key findings, we have procured human medulloblastoma specimens and are conducting whole exome sequencing. the primary assays utilized to assess immunogenicity are immunohistochemical (ihc) staining of formalin fixed and embedded recurrent medulloblastoma tissue to identify tils, tumor associated macrophages and other markers. mg/m had dlts of dyspnea (grade )/hypoxia (grade ) but no dlts were observed in any other cohort. adverse events were generally mild to moderate, consistent with the safety profile observed in adults. across the desc cohorts, plasma concentrations were dose-proportional and steady state concentrations were lower on day vs. day . mean systemic exposure in the mg/m cohort was ∼ -fold greater compared with the adult rp d of mg bid. a pk:pd relationship between tazemetostat exposure and h k me levels in peripheral blood monocytes and granulocytes was observed in the desc phase. consistent and significant post-dose reductions in h k me occurred at doses ≥ mg/m . further analysis of twelve patients treated at the rp d confirmed that h k me inhibition was maximally inhibited. doses - mg/m showed confirmed objective responses (cr/pr) per recist/rano in patients with es (n = ), chordoma (n = ), and atrt (n = ). background: previous studies established that the platelet/ fibrin(ogen) axis promotes metastatic potential by impeding the clearance of newly formed micrometastases by natural killer (nk) cells. however, multiple important questions remain, including the potential of fibrin(ogen) to promote metastasis through interactions with cells other than platelets (e.g., inflammatory cells), and the fundamental question of whether fibrin polymerization is required for metastasis. objectives: determine the role of fibrin polymerization and fibrin(ogen) engagement of integrins iib and m in metastasis. design/method: we performed experimental and spontaneous metastasis assays in immunocompetent mice carrying specific fibrinogen structure/function alterations. results: expression of a mutant fibrinogen lacking the binding motif for the leukocyte integrin m (fib - a) significantly decreased metastatic potential relative to wildtype fibrinogen, suggesting a role for fibrin(ogen)inflammatory cell interactions mediated by m in metastasis. to directly determine the importance of thrombinmediated fibrin polymerization in metastasis, we analyzed metastatic potential in fibaek mice, which carry a form of fibrinogen essentially "locked" in the soluble state due to a mutation in the a chain thrombin cleavage site. metastatic potential in fibaek mice was diminished relative to control mice, speaking to the importance of thrombin-mediated fibrin polymerization in the metastatic process. however, the fibaek mice retained significant metastatic potential relative to complete fibrinogen deficiency, indicating that fibrinogen monomer retains significant prometastatic properties. in order to better define the role of fibrin(ogen)-platelet interactions in metastasis, we compared metastatic potential in control and fib Δ mice, carrying a form of fibrinogen lacking the chain binding motif for the platelet integrin iib . surprisingly, this mutation had no impact on metastatic potential. together, these studies suggest fibrinogen plays a multifaceted role in metastasis. fibrin(ogen)-leukocyte interactions mediated by m appear to have a role in metastasis. previous studies showed that macrophages promote the metastatic potential of circulating tumor cells, which may represent at least one important m expressing cell type whose prometastatic behavior is influenced by fibrin(ogen) interactions. these studies show that thrombin-mediated fibrin polymerization promotes metastasis, but soluble fibrinogen retains some significant prometastatic capacity. surprisingly, loss of the fibrinogen chain iib binding motif had no impact on metastasis. given the established importance of platelets in metastasis, these findings suggest that fibrin (ogen) is capable of platelet stabilization through mechanism(s) independent of this iib binding motif. platelets may bind polymerized fibrin at other sites, and/or fibrin interactions with other matrix proteins capable of binding iib are sufficient to support platelet functions required for metastasis. the role of platelets in hemostasis and thrombosis is well defined, but it is becoming increasingly evident that platelets also assist in host defense and inflammation. platelets participate in the innate immune system through direct antimicrobial activity and interactions with effector cells (chapman , garlanda , kapur ). in the adaptive immune system, platelets recruit and costimulate t-cells, and promote b-cell differentiation and antibody class switching (kapur , morrell ). the question remains: which mechanisms influence platelet immune function and are they developmentally regulated? preliminary studies in the palis lab have revealed significant dif-ferences in embryonic versus adult platelet gene expression, including regulators of immune and inflammatory responses such as beta -microglobulin (b m) and major histocompatibility complex class i (mhc ). mhc is expressed on all cell surfaces except red blood cells and its molecular chaperone b m is a marker of inflammation highly expressed in platelet alpha granules (zufferey ). preliminary data from the morrell lab reveals a mass release of b m during platelet activation, which drives monocyte differentiation to an inflammatory phenotype through tgfb receptor signaling. we therefore sought to determine whether developmental changes in platelet b m expression mediate differences in platelet-mediated monocyte activation. with trilineage hematopoiesis with a predominance of early myeloid precursors, with full maturation. microarray, elane and sbds sequencing and deletion/duplication analyses were negative. immunologic evaluation was significant for agammaglobulinemia and an absence of memory (cd +cd +) b cells. a gene primary immunodeficiency panel revealed two variants of unknown significance-c. g>a and c. g>t in dnmt b; one previously reported in association with icf . parental testing demonstrated parental heterozygosity. centromeric instability was confirmed in mitogen stimulated lymphocytes showing characteristic, multibranched chromosomes containing at least arms of chromosome and joined near the centromere. decondensation of the qh and qh regions and triradial configuration of chromosome was noted, and a diagnosis of icf syndrome was made. the patient was started on monthly intravenous immunoglobulin (ivig). prophylaxis for pneumocystis jiroveci pneumonia and respiratory syncytial virus was initiated. a / matched sibling hsct is being planned. demonstrated the diagnosis of high grade osteosarcoma. the patient was started on multi-agent chemotherapy with planned a whole femur prosthesis at time of local control. cases of osteosarcoma have been described in the literature in patients with nf (median age; years, range - years) with slightly male predominance ( cases). the femur was the most common site of involvement ( cases). four patients died of metastatic disease despite surgery and multi-agent chemotherapy. conclusion: nf represents a major risk factor for development of malignancy and uncommonly osteosarcoma in adolescents and adults. we report a rare case of an extensive involvement of osteosarcoma of the left femur in a child with known diagnosis nf . this presentation should alert the pediatric oncologists to monitor for bone tumors in patients with nf by physical exam and detailed medical history. hasbro children's hospital, providence, rhode island, united states background: dysautonomia is a paraneoplastic syndrome most commonly described in adult malignancies. despite current therapies aimed at symptoms management, it is often debilitating. we present a case of a -year-old girl who initially presented with autonomic dysfunction and was subsequently found to have hodgkin lymphoma. objectives: describe hodgkin lymphoma presenting with dysautonomia and discuss symptom management with rituximab design/method: case report a year-old-girl presented with severe symptoms of orthostatic hypotension necessitating prone positioning to prevent syncopal episodes. additionally, she reported anhidrosis, xerostomia, urinary retention, and constipation. she had unmanageable peripheral neuropathic pain despite multiple analgesia medications. initially, it was suspected that her symptoms were caused by an atypical presentation of guillain-barre syndrome. she was treated with intravenous immunoglobulin g, without response. due to a suspicion of a paraneoplastic syndrome a positron emission test/cat scan (pet/ct) was performed and revealed widespread fdg-avid nodal and splenic disease. pathology from a thoracoscopic biopsy of a mediastinal lymph node demonstrated classical hodgkin lymphoma. she was classified as stage ivb. a paraneoplastic panel obtained during the first cycle of chemotherapy revealed elevated anti-amphiphysin antibodies and glutamic acid decarboxylase (gad) antibodies. therapy was initiated with abe-pc (doxorubicin, bleomycin, etoposide, prednisone, cyclophosphamide) ; vincristine was held given her significant neuropathy. due to persistence of autonomic symptoms following her first cycle and presence of antiamphiphysin and gad antibodies, rituximab was incorporated into her treatment. following two cycles abe-pc, she had a rapid early response by fdg-pet/ct. she completed an additional three cycles of abd-pc. end of therapy imaging demonstrated complete response with a single persistent mildly fdg-pet avid lymph node (deauville ) and her antibodies were negative. she continues treatment of maintenance rituximab with significant improvement, but not resolution, of her orthostatic hypotension. at this time, the patient can ambulate with assistance. constipation and urinary retention have fully resolved and, her peripheral neuropathy, xerostomia, anhidrosis have improved. conclusion: this is rare case of a pediatric hodgkin lymphoma patient developing dysautonomia associated with antiamphiphysin and glutamic acid decarboxylase antibodies and subsequently managed with chemotherapy and rituximab. clinicians should be suspicious of a paraneoplastic syndrome when a neurologic disorder fails to improve with standard treatment. results: labs obtained at an outside hospital one month prior to presentation showed absolute neutrophil count (anc) and hemoglobin . g/dl. she presented to our institution with days of fever, hepatomegaly cm below costal margin, a white plaque on her tongue, and circumferential perianal ulceration. labs were significant for anc and hemoglobin . g/dl. anti-granulocyte antibody testing was positive. bone marrow biopsy showed arrest of neutrophil maturation. after initiation of filgrastim ( . mcg/kg/day), her anc increased to > and repeat bone marrow biopsy demonstrated left shifted myelopoiesis. biopsy of her oral lesion demonstrated invasive actinomyces prompting a prolonged course of antibiotics. biopsies of her oral and anal lesions were reported as myeloid sarcoma without mll rearrangement. chemotherapy was not initiated due to complete resolution of both lesions within weeks of initiating filgrastim and appropriate antibiotic coverage. she has not developed any further lesions concerning for malignancy. testing for common genes associated with severe congenital neutropenia and autoimmune lymphoproliferative syndrome was negative. her immunoglobulin levels and the measurement of age-appropriate vaccine responses were normal. after her lymphocyte subpopulation analysis indicated a selective deficiency in cd positive t-lymphocytes (absolute cd cell count ), the severe combined immunodeficiency panel from genedx showed compound heterozygous mutations in results: a male infant was born with a large thigh mass. the child was clinically well aside from restricted movement of affected leg. mri showed mass expanding into pelvis without other lesions. an interventional-radiology guided core biopsy of the mass was reported as high-grade spindle cell sarcoma without etv rearrangement. surgery was deferred because of concern that it would result in excessive morbidity. the mass was treated with vincristine and dactinomycin per infantile fibrosarcoma protocols. after months of therapy, no significant change in size of the mass was noted on physical exam or imaging. repeat biopsy was obtained to confirm diagnosis and allow for expanded tumor testing. this biopsy showed triphasic distribution of adipose, fibrous and mesenchymal tissue consistent with fhi with rare sarcomatous foci. additional chemotherapy was deferred and the child was followed clinically. his tumor has remained approximately the same size and still unresectable. next generation sequencing of tumor utilizing panel based technology revealed braf-erc fusion consistent with braf activating mutation. this mutation was confirmed by fluorescent in situ hybridization (fish) probe for braf. braf and mek inhibitors have been pursued as treatments to decrease size of tumor and allow for resection. conclusion: braf mutations have been characterized in a variety of malignancies. inhibition of braf and downstream signaling components has produced promising results in a variety of patients. this is the first case report of a braf mutation in a fhi. although management of fhi is typically surgical, this does suggest a potential therapeutic target and may allow for improved surgical outcomes especially in cases where up-front surgery would result in unacceptable morbidity. genetic sequencing of fhi and other rare tumors is an important tool and has the potential to identify mutations amenable to targeted therapies. background: icf is a rare autosomal recessive disorder characterized by hypo-or agammaglobulinemia and often opportunistic infections suggesting t-cell dysfunction. it is further categorized into subtypes - based on mutations in dna methylation. mutations in the helicase-lymphoid specific (hells) gene, which is required for t-cell proliferation and participates in de novo dna methylation, are characteristic of icf type (icf ). of approximately reported cases of icf, less than percent are characterized as icf . while malignancy has been reported in icf (angiosarcoma, acute lymphoblastic leukemia), and icf (hodgkin lymphoma), here we describe the diagnosis and management of an icf patient with neuroblastoma and neutropenia, which has not been previously described. objectives: describe a novel phenotype and mutation of icf and its management to further expand our understanding of this disease. results: a month ex- week premature male with bronchopulmonary disease and failure to thrive presented with acute respiratory failure in the setting of recent viral bronchiolitis with associated chronic diarrhea. he was subsequently diagnosed with multiple infections including pjp pneumonia, norovirus, parainfluenza, rhinovirus, and pseudemonal cellulitis. he presented with profound neutropenia and agammaglobulinemia with presence of b and t cells on lymphocyte phenotyping. ct revealed a paraspinal mass that was mibg-avid on further study, strongly suggesting neuroblastoma. bone marrow was normocellular and negative for malignancy, however revealed marked granulocytic hypoplasia and maturation arrest concerning for severe congenital or, less likely, immune-mediated neutropenia. metastatic workup was negative. whole exome sequencing revealed a homozygous variant of unknown significance (c. t>c) in the hells gene, portending a working diagnosis of icf syndrome. immunoglobulin supplementation, pentamidine prophylaxis, and g-csf were initiated. he was able discontinue g-csf after months of treatment. his neuroblastoma, initially categorized as l , met criteria for observation. however, followup mri revealed interval growth nearing the spinal canal. he underwent tumor resection, confirming mycn non-amplified, favorable histology neuroblastoma. after infectious prophylaxis and immunologic support were initiated, he incurred two other hospitalizations, the first for g-tube cellulitis and the second for parainfluenza respiratory illness. he now has stable neutrophil counts off g-csf and remains in remission from neuroblastoma. current plan is to proceed with bone marrow transplantation for immunodeficiency. conclusion: icf has not previously been described with neutropenia or neuroblastoma. this report not only describes a novel mutation and phenotype of icf and the management thereof, but also reveals the potential curative role of bone marrow transplantation in such disease. staten island university hospital -northwell health, staten island, new york, united states background: desmoid tumors are rare tumors that arise from highly differentiated fibroblasts. they occur in isolation or as part of the disease spectrum of familial adenomatous polyposis (fap) . fap mutations between codons - typically correlate with increased extraintestinal disease such as desmoid tumors and upper gastrointestinal polyps. we describe a patient with a large intra-abdominal desmoid tumor who is heterozygous for a c. c>t (p.arg cys) apc gene mutation. we are not aware of any other patients reported with this germline apc mutation presenting with a desmoid tumor. objectives: to discuss a novel apc mutation and the presentation of a rare case. design/method: review of clinical presentation, genetic analysis and management of a rare tumor. a -year-old female with no significant medical history presented with abdominal asymmetry and intermittent pain. she reported urinary urgency, shortness of breath, early satiety, decreased appetite and a -pound weight loss over the course of months. ct scan of the abdomen demonstrated a × cm abdominal tumor abutting the local organs but no presence of bowel obstruction. a biopsy revealed a spindle cell neoplasm favoring fibromatosis. there was no known family history of fap, colon cancer, or desmoid tumors. apc gene mutation analysis demonstrated a c. c>t (p.arg cys) heterozygous gene variant. due to size and location of the tumor, it was initially deemed unresectable. the patient was started on a course of monthly liposomal doxorubicin. she tolerated the initial cycles well and interval ct after cycles of chemotherapy revealed a % decrease in tumor volume. variability exists in phenotypic presentation with regards to the location of the afp mutation locus. while fap mutations associated with desmoid tumors typically have changes in the - codon region, our patient presented with a heterozygous mutation resulting in a missense mutation at codon . due to the change in polarity and size, the mutation is not considered to be of conservative nature. we are only aware of one other report of this mutation, which occurred in an individual with a personal and family history of colon cancer. we are not aware of any patients with desmoid tumors who also have this germline apc gene mutation. our case report highlights an apc gene mutation that is not well-described; we are not aware of any other cases of this mutation reported in patients with desmoid tumors. future evaluation and tracking of this mutation may lead to the determination of further clinical significance. background: over time, advanced care planning for location of death has been associated with increased deaths at home rather than in the hospital. in some cases, however, complex management and symptom control can prevent families from achieving their goal of keeping their child out of the hospital and at home at the end of life. ascites is a sequelae of many conditions including malignancy that might lead to significant morbidity. increasingly, interventional procedures are being utilized. peritoneovenous "denver" shunts are placed internally with one end in the peritoneal space and the other buried within a major vessel such as the svc. a one-way valve and pump buried under the skin allows the patient to pump fluid from the peritoneal to the vascular space. the shunt is used frequently in adults, but has not seen much use in pediatric oncology patients. objectives: to describe a case of a terminally ill patient with refractory wilms tumor with ivc involvement who received symptomatic relief with denver shunt placement. results: an -year-old female was diagnosed with relapsed, refractory, metastatic wilms tumor with pulmonary and hepatic involvement, with tumor extension to the hepatic veins and ivc. multiple chemotherapeutic regimens and palliative radiation to the ivc were administered, but her disease continued to progress, leading to pressure on the portal vein and portal hypertension. the resulting ascites was causing the patient significant pain and was difficult to manage. the patient's code status was changed to dnr/dni after discussion with her mother, who identified a desire to have the child die at home as comfortably as possible. a peritoneovenous shunt was placed in order to control the patient's pain and avoid frequent medical procedures and therapies. despite initial anxiety, the patient was able to utilize the pump and achieve significant improvement in her ascites and pain. she was able to spend the remaining six weeks of her life at home. ascites is a common phenomenon of end stage disease. peritoneovenous shunts are a treatment modality that may be considered to allow for pain control at the end of life for pediatric oncology patients with ascites. the procedure is relatively low risk, allows for self-control of the pump to maintain comfort, and is easy enough to use by the patient or family. background: extraneural metastases (enm) from pediatric glioblastoma multiforme (gbm) are rare, with an estimated frequency of . %. etiologic factors include multiple neurosurgical procedures and sarcomatous dedifferentiation. their occurrence can seriously affect the patient's quality of life and survival. while enms have been well documented in adults, pediatric cases have not been previously summarized. a year old male with a cerebral gbm developed extension of disease outside of the neuraxis approximately months post initial presentation and at the time of disease progression. metastases included exracranial temporal lesions, cervical and mediastinal lymph nodes and s of s bilateral lung nodules. a large pleural-based soft tissue metastatic focus was identified on imaging when the patient presented with respiratory distress secondary to a right tension pneumothorax, which was recognized and managed promptly. we summarize the main reported cases in literature to better define risk factors for and evaluate the proposed mechanisms underlying these systemic metastases. design/method: we performed a literature review on the pubmed database using the terms gbm and enm. patients under years of age who met the weiss criteria for the diagnosis of enm from primary cns tumors were included. results: our patient fulfilled two of the three weiss criteria with confirmed gbm at the primary site with all enm in the temporal soft tissue and cervical lymph nodes displaying histopathologic features similar to the primary cns tumor. the intrathoracic adenopathy and lung nodules detected upon chest imaging during workup for respiratory distress were assumed to represent additional metastatic foci. our literature review identified pediatric patients with enm from gbm with a median age of years (range . - years) and a slight female predominance ( % females vs. % males). the most common sites of metastases reported were pleura/lungs, bones, lymph nodes and liver. in of patients, metastases were associated with csf shunting. conclusion: pediatric oncologists should have an increased index of suspicion when caring for patients with gbm, particularly those who have undergone shunting procedures and present with systemic symptoms including bony pain, respiratory changes, transaminitis or cytopenias which should prompt timely investigation for enm. although enm of cns tumors carry very poor prognosis, their diagnosis has potential therapeutic importance because treatment of metastatic lesions may alleviate symptoms and improve the quality of life. additional studies may be warranted to evaluate the incidence of enm that can provide valuable insight into the pathogenesis and biology of high-grade gliomas. nicklaus children's hospital, miami, florida, united states background: sinusoidal obstruction syndrome (sos) has been reported in patients undergoing intensive chemotherapy and as a complication post-hematopoietic stem cell transplan-tation. sos may be complicated by portal hypertension, hepatorenal disease or multi-organ failure. however, despite treatment, there may be further potential complications that can be anticipated in patients with history sos. we report two patients with history of sos presented with post-procedural bleeding after gastric tube placement. we believe that their presentations may be associated to their previous diagnosis of sos. design/method: pubmed search was done with search for terminology including "sinusoidal obstruction syndrome" "defibrotide", and "bleeding". papers relevant to our cases were selected for literature review. results: case : a year-old female with history of desmosplastic medulloblastoma status-post resection and intensive chemotherapy was diagnosed with sos one month after her second part of planned tandem transplant. she was managed with paracentesis and defibrotide. due to malnourishment, patient had a gastric tube placement months after she completed therapy and had an episode of upper gastrointestinal bleeding postoperatively from the g tube site. case : similarly, a year-old male diagnosed with anaplastic medulloblastoma status post resection and adjuvant multiagent chemotherapy. his treatment course was complicated with sos after the second cycle of induction chemotherapy which responded to -day course of defibrotide. likewise, the patient had a major bleeding event from the g-tube site approximately two months after sos diagnosis. defibrotide was discontinued in both cases before g-tube placement. both patients had no previous history of bleeding disorders or relevant family history. in addition, comprehensive laboratory evaluations were within normal limits before both procedures. in sos, there is blockage of fluid out of the liver that leads to congestion, ascites, ischemia of the liver, and post-sinusoidal portal hypertension. two related causes of sos should be considered as an explanation for g-tube bleeding. similar patients should have close monitoring postoperatively or if possible surgical intervention should be delayed until the sos process has been evolved. nicklaus children's hospital, miami, florida, united states background: the development of treatment related acute myeloid leukemia (t-aml) and myelodysplastic syndromes (t-mds) is a potential complication after cytotoxic chemotherapy or radiation therapy. the incidence of development of t-aml/t-mds varies from - % depending on the treatment regimen used. cutaneous myeloid sarcoma (ms) is a common presentation of extramedullary leukemia and usually occurs in the setting of aml. we report a rare case of cutaneous ms in an adolescent female after successful treatment for ovarian yolk sac tumor (yst) stage i with bep (bleomycin, etoposide and cisplatin) therapy. the ms was managed only with biopsy and close observation. design/method: a pubmed search was conducted for queries including t-aml/t-mds, cytotoxic agents, cutaneous myeloid sarcoma, regression. relevant papers were selected for literature review. a year-old female was diagnosed with a left ovarian yolk sac tumor, for which she underwent left salpingooophorectomy and successfully completed cycles of bep over months. during routine follow-up months after initiation of treatment for ovarian yst, she was noted to have a small, non-tender, indurated nodule on the left side of her upper back approximately cm in diameter. punch biopsy of the skin nodule was performed and pathology was positive for cutaneous myeloid sarcoma. at the time of next follow-up less than one month later, the skin lesion had resolved. two subsequent bone marrow aspirates were performed one month apart and were negative for leukemic involvement or mds. examinations and work-up including whole body pet with ct scan were negative for evidence of disease. although cutaneous ms can be regarded as the herald of systemic myeloid disease rather than a localized process, our patient was monitored periodically with physical exam and laboratory evaluations. she remains free of disease more than four years after the presentation of cutaneous ms without any further treatment. spontaneous regression ms has been previously reported. the authors would like to stress that a conservative approach with close observation could be an option in cutaneous ms even with history of chemotherapy exposure. nesreen ali, iman sidhom, sonia soliman, sherine salem national cancer institute, cairouniversity, egypt children cancer hospital egypt, egypt background: acute leukemia is the commonest malignancy in childhood. the coincidental occurrence of leukemia with hemophilia is extremely rare. hemophilia is a congenital rare x linked bleeding disorder. the main complication of the two diseases is bleeding diathesis which may be lifethreatening due to many factors, deficiency of coagulation factors in hemophilic patients, thrombocytopenia from disease and chemotherapy in leukemic patients, certain cytotoxic drugs such as asparaginase which may result in coagulation disorders and infection which may lead to disseminated intravascular coagulation. objectives: reporting such a case is imperative to set up treatment guidelines for prevention of bleeding and to optimize the therapeutic approach for these patients. design/method: seventeen years old boy, presented to children cancer hospital egypt in june with pallor and multiple ecchymoses.he was diagnosed with precursor b acute lymphoblastic leukemia, cerebrospinal fluid (csf) was free, the chromosomal analysis revealed hypodiploidy , xy. he had moderate type of hemophilia a since birth, factor viii level was . % at time of diagnosis, coagulation profile revealed prolonged partial thromboplastin time (normal - ), factor viii was low %, prothrombin concentration and prothrombin time were normal % and seconds, virology screening for hepatitis b core igg/igm, hbs ag, hiv and hc igg /igm were negative.the patient started induction total xv sjcrh protocol, factor viii unit/kg was given at presentation before doing bone marrow aspiration(bma), csf and as a prophylactic before intramuscular asparaginase injection, intrathecal and bma. it was given immediately within hours before the procedures and platelets transfusion was given regularly to maintain platelets count about , . the minimal residual disease by flow cytometry was . % and . % at d and d induction. results: our patient received his induction and reintensification chemotherapy without any major bleeding event which reveals the success of our guidelines for the prevention of bleeding. he developed very early relapse at w maintenance by the same clone. he received salvage chemotherapy but didn't achieve remission and died out of disease and resistant clone. the development of leukemia on top of hemophilia is a major problem. bleeding complication during chemotherapy can be prevented by regular prophylactic factor viii and platelets concentrate transfusion with good supportive care. life threating bleeding complication may be correlated with the severity of hemophilia. we need to collect data about the biology of leukemic cells, complications, and cause of death to optimize care for these patients. background: mucoepidermoid carcinoma (mec) is a rare malignancy that arises from exocrine glands in the upper aerodigestive tract and tracheobronchial tree. conventionally, mec diagnosis is based on histology, with prognosis based on the extent of resection and detection of metastases. mec is characterized by a translocation of chromosomes q and p resulting in a fusion between the mect and maml genes, that occurs in - % of cases. this fusion transcript has been recognized to have a favorable impact on disease features and prognosis of mec. however, recent studies indicate that high grade mec can have mect -maml fusion positivity and multiple other genomic imbalances that have not been studied in much detail. owing to the rarity of mec tumors, more definitive data related to the clinical and prognostic significance of these molecular markers are limited. objectives: . identify the presence or absence of mect -maml fusion in the tissue of our patient. . analyze the incidence of the fusion in mec cases in children and young adults retrieved from the iowa cancer registry. . determine if fusion status correlates with clinical, pathological and outcome data in our cohort. design/method: we describe the case of a year-old caucasian male who presented with recurrent pneumonia, persistent cough and radiographic evidence of right lobar collapse. bronchoscopy revealed an endobronchial lesion and the patient underwent right upper lobe sleeve resection. pathology report was consistent with low grade muco-epidermoid carcinoma. we retrieved archived formalin-fixed paraffinembedded (ffpe) specimens of pediatric and young adult mec cases (ages - ) reported in iowa from - using the iowa cancer registry. testing for the mect -maml fusion in the index case and ffpe specimens will be done using a custom-designed laboratory validated next generation sequencing (ngs) assay with the ability to detect novel fusion partners. clinical, pathological and outcome data (age, sex, tumor site, tumor size, nodal metastases, clinical stage, histologic grade, treatment and follow up) will be analyzed to correlate with fusion status. the mect -maml fusion tested positive in our index patient. we will obtain irb approval to test for the fusion in the archived ffpe specimens and correlate clinical, pathological and outcome data. conclusion: mect -maml fusion is a frequent event in mec that has prognostic and potential therapeutic applications in adults. the results of this study may enlighten the clinical management of mec in children and young adults. children 's mercy hospital, kansas city, missouri, united states background: mutations in the samd gene are associated with a rare syndrome comprising of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy (mirage syndrome). diagnosis is made through exome sequencing. in the largest reported case series, of eleven patients diagnosed with mirage syndrome, two developed loss of chromosome . given the potent growth restricting activity of samd mutants, the loss of chromosome is considered the first documentation of adaptation by aneuploidy mechanisms in humans and led to myelodysplastic syndrome (mds), with deaths occurring from related complications at and years of age. objectives: to report a case of mirage syndrome with congenital thrombocytopenia progressing to bone marrow failure, managed uniquely with bone marrow transplantation. results: male born at weeks gestation with prenatal diagnosis of iugr, two vessel cord, oligohydramnios was found to have ambiguous genitalia, adrenal insufficiency, partial panhypopituitarism and congenital thrombocytopenia with bone marrow showing absence of megakaryocytic precursors. severe thrombocytopenia was present from birth. bone marrow evaluation demonstrated a hypocellular marrow with markedly reduced megakaryocytic and myeloid precursors and no evidence of myelodysplasia. he required gastric tube placement for failure to thrive, had a laryngeal cleft repaired and developed focal segmental glomerulosclerosis. mpl gene testing for congenital amegakaryocytic thrombocytopenia was negative. testing for fanconi anemia, shwachman-diamond syndrome and dyskeratosis congenita was also negative. approximately % of cells had loss of heterozygosity on chromosome q. exome sequencing showed that he is heterozygous for a de novo gain of function variant, c. g>a (p.arg gln), identified in the samd gene, confirmed by sanger sequencing and consistent with a diagnosis of mirage syndrome. at years of age, he developed pancytopenia requiring frequent transfusions with platelets and packed red blood cells. he underwent a successful bone marrow transplant at years of age without significant complications, and remains transfusion independent without cytopenias greater than months from bone marrow transplantation. conclusion: it is imperative to pursue work up for persistent congenital thrombocytopenia in a stepwise multidisciplinary manner. to the best of our knowledge, this is the first case of mirage syndrome associated bone marrow failure treated with bone marrow transplant. due to the individual rarity of mirage syndrome and pediatric myelodysplastic syndrome, it is important to maintain an index of suspicion given their association and explore bone marrow transplant as a therapeutic option. results: the patient demonstrated disease regression, initially, and continued without disease progression for months. the regimen has been well tolerated with only minimal side effects of dry skin (ctcae grade ) and a transient episode of brief erythrodysesthesia (ctacae grade ) that resolved spontaneously. the combination of sorafenib and capecitabine was effective and well tolerated in this adolescent patient with fl-hcc. our observations, although in a single patient, lend support for further testing of this novel oral chemotherapy regimen in patients with fl-hcc, a disease for which there is no effective standard chemotherapy approach. background: epstein-barr virus (ebv) is a ubiquitous virus associated with a broad range of malignancies due to its oncogenic potential. history of organ or bone marrow transplantation, immunosuppressive therapy, and primary or acquired immunodeficiency syndromes increases the risk of ebvassociated tumors. epstein-barr virus associated smooth muscle tumors (ebv-smt) are unique and rare neoplasms typically discovered in immunocompromised patients. most information related to pathogenesis and therapeutic options is limited to case reports and case series of adult patients. there are several gene expression pathways that ebv utilizes, the most notable of which is the mammalian target of rapamycin (mtor) pathway. the mtor pathway performs a key role through integrating various cell growth signals and factors to regulate protein synthesis and metabolism related to smooth muscle proliferation. sirolimus is an immune modulating therapy that targets the mtor pathway to block activation of lymphocytes. objectives: several case reports have demonstrated shortterm clinical remission of ebv-smt in adult patients with the use of sirolimus. we report the first case of long-term background: bilateral neuroblastoma is characterized as neuroblastoma arising in both adrenal glands, a rare presentation with little data on its genetic make-up. a two-monthold patient was diagnosed with bilateral neuroblastoma in our clinic. her risk assignment was based on biopsy of the left adrenal lesion, which showed mycn amplification, an unfavorable genetic marker. treatment regimen was intensified accordingly and after courses of chemotherapy tumors were excised. patient went on to receive a stem cell transplant and immunotherapy. with no knowledge of genetic similarity between the two tumors it is unclear whether biopsy of the right lesion would have yielded similar results or whether bilateral biopsies are needed for risk assessment of bilateral neuroblastoma. objectives: utilize whole exome sequencing (wes) to characterize the genomic signature of bilateral adrenal neuroblastomas excised following chemotherapy treatment. design/method: paraffin-embedded samples from left (l) and right (r) tumors underwent wes at the broad institute. we analyzed resulting data including somatic variant calls, indel mutations, and copy number variants (cnvs) using ingenuity software to evaluate and compare differences between the two tumor samples. preliminary analysis of the data shows important descriptive information on the two tumor samples. out of somatic mutations in the r tumor cells and mutations in the l tumor cells, only two common somatic mutations were present. out of cnv calls in the r tumor and in the l tumor, cnvs were common between the two tumors, or % of each tumor's cnv calls. there was a fold higher frequency in gains versus losses. the median size of the common cnvs was , (range to , , bp). cancerrelated genes with increased copy numbers included transcription factors, receptors for signal transduction pathways, and histone methylation proteins. conclusion: preliminary analysis of the wes results of the two adrenal tumors show some genomic divergence. because the tumor tissue was exposed to chemotherapy prior to excision it is difficult to determine whether genomic divergence is a result of independently originated tumors or subsequent adaptation to chemotherapy of a clonal cell population. the high number of common cnvs in the two tumors points to a common cell of origin, however the low number of common somatic mutations does not fit that picture. a future study to help elucidate the question will be wes of the original biopsy tissue to provide information on tumor mutations prior to the effects of chemotherapy. baylor college of medicine, houston, texas, united states background: although there has been significant improvement in the overall survival rates of children with cancer many children will still die from their illness or complications secondary to treatment. research surrounding the deaths of children who succumb to their disease is warranted to ensure we are providing the best care possible for these patients. objectives: this case series aims to explore pediatric cancer deaths by focusing on perhaps the most extreme cases of high intensity end of life care. we explore those patients whom we know are dying or our very likely to die as evidence by their do not resuscitate (dnr) orders. in all of these cases despite the patients very grim prognosis, their great likelihood of death and limitations placed of resuscitation methods all patients continued end of life care in the pediatric intensive care unit (picu). the primary medical records of all children with a cancer diagnosis who died between february , and january , in the picu with a dnr order seven days or earlier prior to death. each medical history included disease-directed treatment history and response with particular attention to the events surrounding the terminal admission. results: eight patients met criteria for this study representing . % of all cancer patients who died during this time period and . % of those who died in the icu. the average time between dnr and death is . days ( days - days). the average length of terminal admission was . days ( day - days). the average time between diagnosis and dnr is . months ( months - months). the average time between diagnosis and death is . months ( months - months). conclusion: these cases highlight the journey that patients, families and providers endure leading up to death. medical care is complex, there are very few absolutes that are encountered when caring for patients and decisions around limiting or withdrawing medical care are made in a context of the prior journey. . these cases help to understand the complexity of death and how two seemingly opposite ideals can be congruent in the event of an anticipated death. most of these cases show the need for improved anticipatory guidance surrounding death and greater consideration for de-escalation of care when death is expected. the hospital for sick children, toronto, ontario, canada background: rhabdomyosarcoma (rms) is the most common soft tissue sarcoma in children, with embryonal (erms) and alveolar (arms) representing the most common subtypes. arms tumors are associated with inferior outcome when compared to erms, and they are characterized in about % of the cases by a t ( ; ) or t( ; ) chromosomal translocation with creation of a pax -foxo or pax -foxo fusion gene, respectively. it is increasingly clear that the pax-foxo fusion status is an important poor prognostic factor, thus the histological classification tends to be replaced by the fusion status, particularly in terms of risk stratifica-tion in contrast to arms, there are no recurrent chromosome alterations in erms; however, there are multiple numerical chromosome changes that are frequent in these tumours: gain of chromosome , , and have been found in to % of emrs karyotypes. moreover, erms tumors show frequently allelic loss, the .p . chromosomal region being the most frequently involved. recently, novel gene fusions have been described also in erms tumours. these fusions involved mainly the ncoa and or the vggl genes. the rearrangement partners are variable, and include, i.e. pax ( q ), srf ( q ) and tead ( p ). objectives: to present a patient who died as a consequence of brain metastases while on therapy in the setting of an foxo negative rms and the identification of a new translocation t( ; )(q ;q ). design/method: case report and retrospective review of the literature. we report a case of pelvic embryonal rhabdomyosarcoma in a -month old boy. he was treated as per cog arst intermediate risk group, but unfortunately was found to have a large cerebellar tumour during the course of his chemotherapy treatment and he subsequently passed away. a novel translocation between chromosomes and was observed in of metaphase cells by g-band analysis in the autopsy sample of the brain lesion. breakpoints of the translocation were estimated to be at q and q . there were no additional clonal chromosome abnormalities in the tumour cells. conclusion: erms tumors with fusion genes involved have been exclusively described in patients less than months of age; they seem to be associated with spindle cell histology and, a favorable outcome. in our patient, a novel ( ; ) translocation was found and clinically, the patient had a dismal outcome. further studies are indicated to inquire whether this finding is of significance in term of prognosis for these patients. children 's national medical center, washington, district of columbia, united states background: iatrogenic immunodeficiency-associated lymphoproliferative disorders (lpds) are a group of lymphoid s of s proliferations or lymphomas that are well known to be associated with an immunosuppressed state. these disorders most commonly occur following hematopoietic or solid organ transplantation (called post-transplant lymphoproliferative disorders or ptld), but cases have also been described during the treatment of autoimmune and rheumatologic disorders by immunosuppressive and immunomodulatory medications. these disorders are strongly associated with infection by the epstein-barr virus (ebv) as a result of impaired immune function in the immunosuppressed state. while this phenomenon has been well documented in autoimmune conditions, cases affecting pediatric patients while on antileukemia chemotherapy are lacking. background: atypical teratoid/rhabdoid tumor (at/rt) of the central nervous system (cns) in children younger than years old has a prevalence of % to % and accounts for . % of all pediatric cns tumors. only - % of patients have leptomeningeal dissemination. rhabdomyosarcoma is the most common soft tissue tumor in childhood, but represent only - % of all pediatric cancers. rarely, it can metastasize or even directly extend into the cns, but typically, cases of cns involvement arise either from parameningeal areas or other primary sites. primary spinal or meningeal rhabdomyosarcoma is extremely rare. objectives: our objective is to describe two unique cns malignancies presenting as rare, primary leptomeningeal disease. design/method: case a -month-old female presented with vomiting, fatigue and listlessness, despite a normal head ct and brain mri. csf showed hypoglycorrhachia and mild pleocytosis. ceftriaxone was started, but she developed nuchal rigidity and cranial nerve vii palsy. repeat brain mri showed evolving leptomeningeal enhancement concerning for meningitis. she gradually developed worsening opisthotonus and ultimately a brain biopsy of the temporal lobe was consistent with at/rt. case a -year-old male presented with new generalized tonic-clonic seizure activity and intermittent headaches with photophobia, phonophobia, and vomiting. brain mri was significant for enhancement of interpenducular and suprasellar cisterns extending to the optic nerves and chiasm most consistent with meningitis. neurosurgery ultimately placed a lumbar drain for hydrocephalus, and a tissue biopsy demonstrated primary meningeal rhabdomyosacroma. results: in case , our patient's temporal lobe biopsy demonstrated grade iv malignant tumor cells consistent with atypical teratoid/rhabdoid tumor. fish demonstrated a homozygous deletion of smarcb ( q . ). she was started on chemotherapy per the dana farber at/rt protocol but ultimately was discharged home on hospice. in case , our patient's lumbar arachnoid biopsy demonstrated cellular tumor consistent with group iiia embryonal rhabdomyosarcoma. immunostaining was positive for cd , desmin, myogenin, and myo-d with neural markers ema and gfap highlighting the meninges but without a neural component to the tumor. he completed craniospinal radiation to gy total with lumbar boost to . gy total. he is currently receiving chemotherapy per arst protocol. conclusion: these two cases are particularly instructive because of their similar initial presentations and neuroimaging, but with very different and unique diagnoses. university of iowa, iowa city, iowa, united states background: ebf -pdgfrb fusion causes ph-like b-cell acute lymphoblastic leukemia (b-all), which has a philadelphia positive phenotype without the bcr-abl translocation. this is one of several mutations associated with ph-like b-all and leads to downstream overexpression of tyrosine kinase. ebf -pdgfrb fusion accounts for about % of children with ph-like b-all. patients with ph-like b-all previously had poorer outcomes with conventional chemotherapy. the addition of tyrosine kinase inhibitors (tki), like imatinib, has improved the outcome for many patients predicted to have tki sensitive mutations. objectives: to review clinical characteristics and outcomes of two cases of ph-like b-all at the university of iowa stead family children's hospital and to compare these outcomes to similar cases reported in the literature. design/method: a retrospective chart review was performed for two cases of ph-like b-all diagnosed and treated at the university of iowa stead family children's hospital. results: both patients were males diagnosed at years of age with high wbc count ( , and , ) and positive for ebf -pdgfrb gene fusion. patient (pt ) was cns b at presentation while patient (pt ) was cns negative; neither had testicular involvement. both started treatment according to cog protocol aall . peripheral blasts cleared by induction day for pt and induction day for pt . at end of induction, pt had m bone marrow and pt had m bone marrow but mrd %. dasatinib was started induction day for pt and induction day for pt . pt was still not in remission at end of consolidation; bone marrow cell culture for tki resistance showed best response to dasatinib. pt proceeded to anti-cd car t-cell therapy followed by tbi-based matched unrelated donor bone marrow transplant. pt had negative mrd at the end of consolidation and continues chemotherapy according to aall , dasatinib arm. both patients are currently clinically well. our patients had the same tyrosine kinase gene fusion and similar initial clinical courses. while both patients had persistent disease at end of induction, pt had almost % blasts while pt had significant reduction of disease burden before starting tki. pt showed good response with the addition of dasatinib while pt did not. these findings suggest that response to conventional chemotherapy may potentiate the effect of tki and may predict overall outcome. there are likely additional factors which must be taken into account when determining response to tki for patients with ph-like b-all which have not yet been identified. background: medulloblastoma is the most common malignant brain tumor of childhood. classically, medulloblastoma presents as a well-defined mass lesion in the cerebellum, with a high rate of metastatic dissemination. primary leptomeningeal medulloblastoma (plmb) is an exceedingly rare type of medulloblastoma presentation with a dismal prognosis in which patients present with isolated leptomeningeal disease without an associated mass. to our knowledge, only three pediatric and three adult cases of plmb (ages - years) have been reported, all of which died within months of diagnosis. this is the first case of plmb to report a molecular classification. objectives: to report the case of a pediatric patient with plmb in which histopathologic and molecular characterization was performed and to describe the patient's treatment and clinical course. design/method: retrospective review of the patient's electronic medical record and review of the literature. a -year-old boy presented with headache, vomiting, diplopia, and fatigue. physical examination revealed upward gaze palsy, left-sided extremity and facial weakness, and ataxia. magnetic resonance imaging (mri) of the brain revealed diffuse cerebellar leptomeningeal enhancement and edema without an identifiable mass and moderate hydrocephalus. mri of the spine and cerebral spinal fluid analysis were normal. a diagnosis of cerebellitis was rendered, and the patient underwent placement of a ventriculoperitoneal shunt. an extensive infectious, neurologic, rheumatologic, and oncologic workup did not identify an etiology. empiric antibiotics, high-dose steroids, and intravenous immunoglobulin therapy yielded minimal improvement. two months later, repeat mri of the brain performed for declining mental status demonstrated progressive thickening of cerebellar leptomeningeal disease. a suboccipital craniectomy with decompression and cerebellar biopsy were performed. pathologic examination revealed a diagnosis of plmb, classic histology, non-wnt/non-shh, without gain/amplification of myc/mycn, and p wild type pattern. craniospinal radiation to cgy with a cgy boost to the posterior fossa was delivered with concurrent carboplatin/vincristine over six weeks. two months following chemoradiation, mri of s of s the brain demonstrates significantly reduced pathological leptomeningeal enhancement of the cerebellum, and the patient is awaiting initiation of systemic chemotherapy while recovering from a surgical wound infection. conclusion: plmb is extremely rare but should be considered in patients with cerebellitis and diffuse leptomeningeal involvement who are refractory to medical management or in whom an etiology has not been identified. cerebellar biopsy is recommended early to enable timely treatment and improved outcomes. molecular classification should be performed in cases of plmb to further characterize this disease, inform treatment decisions, and improve clinical outcomes. background: primary intracerebral osteosarcoma is extremely rare and limited to case reports. ptpn gain of function is associated with noonan syndrome, which has increased risk of multiple cancer types including brain tumors, but osteosarcoma has never been described. ptpn mutations have been reported in many cancers as both oncogenes and tumor suppressors, however no ptpn mutations have been described in osteosarcoma. pdgfr-a is a growth factor receptor whose activation is implicated in several malignancies. pdgfr-a and ptpn concurrent mutations are described in glioblastoma. there is no known link between holoprosencephaly, noonan syndrome, and osteosarcoma. we report a case of multifocal intracerebral osteosarcoma in a child with lobar holoprosencephaly and chronic subdural hemorrhage and discuss the genetic changes found in the tumor. design/method: a seven-year-old caucasian female, with a known diagnosis of lobar holoprosencephaly, chronic subdural hemorrhage and well controlled seizure disorder presented with status epilepticus shortly after completing antibiotic therapy for infection of subdural hematoma. mri showed diffuse dural thickening with mass lesions in the frontal lobe, temporal lobe, and the parasagittal region, the largest of which was contiguous with the subdural space but none of the lesions were associated with bone on mri or by direct neurosurgical visualization. tissue obtained for concern for recurrent infec-tion resulted in a diagnosis of high grade osteosarcoma. dna analysis was performed to help guide treatment choice. results: standard metastatic work-up was negative for skeletal primary tumor or metastatic lesions outside of the brain. she was treated with high dose methotrexate for two cycles per modified aost . despite maximal supportive care, she quickly developed rapid tumor growth as well as intratumoral hemorrhage with resultant herniation and death from respiratory failure just three months after diagnosis. tumor gene sequencing discovered three mutations with described roles in cancer: pdgfra d >vr, kdm a loss of exons - , and ptpn a v. conclusion: to our knowledge, primary multifocal extraosseus intracerebral osteosarcoma has not been previously described. despite known cns penetration of high dose methotrexate, this tumor proved resistant and aggressive. holoprosencephaly is associated with a multitude of known genetic drivers, but none are found in this case. furthermore, the genetic changes in this tumor are not typical for osteosarcoma. pdgfr-a over-expression is described in osteosarcoma, but is not clearly correlated with worse overall survival. further research is required to determine the role of ptpn in osteosarcoma. background: anaplastic lymphoma kinase (alk) encodes a receptor tyrosine kinase whose activation induces pathways associated with cell proliferation, angiogenesis, and cell survival. alk rearrangements are rare in neuroblastoma, while alk mutations and gene amplification occur more frequently. alk mutations have been found to be associated with increased alk protein expression that is associated with a worse prognosis. alk is commonly mutated in neuroblastoma at three hotspots (f , r , and f ). the eml -alk rearrangement has mostly been associated with lung adenocarcinomas, with only a few cases of non-lung cancers found. it has never been reported in neuroblastoma. multimodal therapy and to report the successful management of treatment related iron overload. results: a -year old male presented with abdominal swelling and ct showed a right kidney mass and bilateral lung nodules. he underwent right radical nephrectomy with lymph node sampling. pathology was reviewed centrally and revealed wilms tumor with diffuse anaplasia with rhabdomyosarcoma arising within the stromal component and of nodes positive. he received adjuvant intensive chemotherapy and radiation to the hemiabdomen and whole lungs. the -week chemotherapy regimen was vincristine, doxorubicin, cyclophosphamide (per cog arst ) alternating with carboplatin and etoposide (per cog aren revised uh- ). treatment was complicated by multiple episodes of fever and neutropenia and anorexia requiring g-tube placement. post-therapy, he had persistent neutropenia and thrombocytopenia without related complications. every months for evaluations he underwent a bone marrow which revealed normocellular marrow with maturing trilineage hematopoiesis. evaluation for a bone marrow failure syndrome was unrevealing. starting at months into therapy and all posttherapy imaging showed splenomegaly. he received units of packed red blood cells through the duration of therapy. he was diagnosed with iron overload based on serum ferritin and imaging, including t *mri. he received therapeutic phlebotomy for years with normalization of serum iron studies, t * of the heart, and liver iron concentration. he is more than years from completing therapy with no evidence of recurrent disease. asymptomatic cytopenias persist and he has no evidence of iron overload. conclusion: though a rare development, clonal sarcomatous transformation can occur in wilms tumor. our patient's tumor was successfully treated with intensive multimodal therapy targeting the diffusely anaplastic wilms and the rhabdomyosarcomatous component. treatment-related iron overload in a pediatric patient with a solid tumor was successfully treated with phlebotomy. consideration should be given to screen patients with solid tumors who receive multiple packed red cell transfusions for iron overload at the completion of cancer therapy. primary children's hospital, university of utah, salt lake city, utah, united states background: malignant solid tumors are less frequently encountered in infants. primitive myxoid mesenchymal tumors of infancy (pmmti) are a myofibroblastic malignancy and cases are rarely reported in the literature. cure is achieved in the majority of cases with surgical resection, however treatment for unresectable cases remains an enigma. recently published literature postulates that the newly discovered bcor duplication found in pmmti is tumorigenic via an epigenetic pathway. this molecular signature resembles that of clear cell sarcoma of the kidney (ccsk) and the growing number of bcor mutated sarcomas. a similar chemotherapeutic backbone and local control used for ccsk, has been proposed for the unresectable subset of pmmti. utilizing this approach a month-old with relapsed disease has remained disease free for months. however, given the rarity of this disease and the lack of published literature, there is no known standard of care treatment for unresectable and/or recurrent ppmti. we report a case of unresectable recurrent pmmti, a rare infant tumor, with less than cases reported. design/method: medical record, radiological studies, pathology and literature was reviewed. results: our patient is a now month-old female who presented with constipation and lower extremity weakness in the first weeks of life. an mri demonstrated a large lumbar epidural mass with spinal cord impingement. given prolonged (> days) neurological symptoms and location, emergent chemotherapy was initiated. biopsy showed a bcor positive, primitive myxoid mesenchymal tumor of infancy (pmmti). she was treated with ifosfamide, carboplatin and etoposide, and demonstrated clinical and radiographic response. we gave two additional cycles of cyclophosphamide, carboplatin and etoposide until surgical resection was feasible followed by two post-surgical cycles of chemotherapy. unfortunately, four month post-therapy mri demonstrated two new lesions; an unresectable paraspinal soft tissue mass and a left iliopsoas groove mass. given bcor association and reported successful therapy with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide, we elected to incorporate vinca-alkaloid and anthracycline into her regimen. she is being treated with vdc/ie with plan for radiation consolidation. conclusion: pmmti is a locally aggressive tumor, for which surgical resection is curative. for those not amendable to resection, best care practices are still being determined. we report a case of pmmti initially responsive to chemotherapy, but not curative. this is the second case to conclusively demonstrate chemo-responsiveness. bcor mutation seems to be a common feature of this cancer; its role in the pathogenesis and as a target is an area of investigation. medical college of wisconsin, milwaukee, wisconsin, united states background: atypical teratoid/rhabdoid tumors (atrt) are central nervous system (cns) tumors that most commonly occur in very young children. there is no widely accepted standard of care for atrt patients, and while survival rates are improving they are historically poor. patients with metastatic disease to the spine at diagnosis have a worse prognosis, and for patients > years old, the presence of metastatic disease often results in the use of craniospinal radiation. the importance of correctly identifying metastatic disease at diagnosis aids in decision making and can have both prognostic and therapeutic implications. mr imaging at diagnosis is used to identify metastatic disease; however, here we present a case of diffuse leptomeningeal enhancement that spontaneously resolved after resection of a primary supratentorial atrt. objectives: to describe the resolution of diffuse leptomeningeal enhancement after resection of a primary atrt tumor in a -month-old prior to any adjuvant therapy. results: a -month-old male presented with a month history of vomiting and weight loss, regression of gross motor developmental milestones, and left hemiparesis. a brain mri demonstrated a × . × . cm solid and cystic right atrial mass with diffusion restriction and post-contrast enhancement. smooth diffuse enhancement was noted along the surface of the brainstem and within the interpeduncular fossa. a spine mri demonstrated diffuse circumferential post-contrast enhancement along the surface of the entire spinal cord. the patient underwent a successful near total surgical resection of the primary mass. pathology confirmed the loss of ini- staining in tumor cells, consistent with a diagnosis of atrt. no immediate adjuvant radiation or chemotherapy was given. repeat imaging was completed days after resection. brain mr demonstrated expected post-operative changes within the surgical cavity without definitive residual mass or leptomeningeal enhancement. spine mr demonstrated complete resolution of the previously seen circumferential enhance-ment along the entire spinal cord. csf evaluation at that time was negative for tumor cells. after recovery from surgery, chemotherapy treatment was initiated. conclusion: leptomeningeal enhancement at the time of diagnosis of atrt has historically been considered clear evidence of metastatic disease. this case raises questions about the previously accepted etiology of these imaging changes and suggests that widespread leptomeningeal enhancement should be carefully interpreted in future patients with similar imaging findings. in this setting, clinicians should consider repeat imaging following primary surgical resection in order to provide appropriate prognostic information and inform therapeutic decisions. poster # primary ewings sarcoma of cervical cord mimicking cauda equina syndrome sucharita bhaumik, joshua chan nyu winthrop hospital, mineola, new york, united states background: ewing's sarcoma (es) is a malignant primary bone tumor usually involving long bones. primary es of spine is quite uncommon ( . %) and its location in the cervical spine is even more rare. cauda equina syndrome (ces) is symptoms due to damage to the bundle of nerves below the end of the spinal cord known as the cauda equina (low back pain, radiating shooting pain down the legs, paraplegia, and loss of bowel or bladder control). it often occurs with lesions of lumbosacral spine. treatment with high-dose steroids may provide pain relief and improved neurologic function (by reducing edema) while awaiting diagnostic studies objectives: to demonstrate an unusual clinical presentation and emergent management of cervical es presenting with ces like symptoms. : year old male presented with a left sided posterior neck mass. soon after, he developed weakness of left arm, urinary and stool retention and inability to walk or bear weight in both legs. on physical exam a left tempero-occipital × cm fixed, non-tender, non-fluctuant mass was noted as well as motor and sensory impairment of left upper extremity, bilateral spastic paraplegia and loss of sphincter control. mri cervical spine showed a left cervical tumor with moth eaten appearance involving the vertebral bodies of c -c , adjacent muscles, displacing vital structures of the neck and compressing the cervical spinal cord. the thoracic and lumbosacral spine had no disease involvement. due to rapidly worsening spinal cord compression he was emergently treated with high dose steroids. he gained back all function in his extremities and regained bowel and bladder control. this eliminated need for urgent neurosurgical intervention. results: biopsy of the neck mass showed small blue round cells consistent with es with ewsr gene rearrangement. staging work up revealed no additional metastatic involvement. he then initiated treatment for localized es with systemic chemotherapy and radiotherapy and has had excellent response to treatment so far. conclusion: this is the first known case of non metastatic primary cervical es mimicking ces where an acutely enlarging mass presented with rapidly progressive neurologic deficits due to compression of anterior spinothalamic tract. in these unusual presentations of ces without lumbodorsal involvement it is important to consider cervical lesions. early rapid steroid initiation should be considered while awaiting biopsy results to prevent worsening cord compression followed by es focused treatments. this increases the chance of a successful outcome. the initial improvement with steroids may confuse the tumor with being a lymphoma children 's mercy hospital, kansas city, missouri, united states background: von willebrand disease (vwd) is a relatively common bleeding disorder with a high degree of genotypic and phenotypic variation. bleeding is usually mucocutaneous but can be severe and include muscle and joint bleeds especially in type vwd patients. most common bleeding management consists of desmopressin, anti-fibrinolytics, and/or plasma-derived antihemophilic factor/von willebrand factor (ahf/vwf) complex. a recombinant vwf has become available in the last few years. anaphylaxis and inhibitor development in vwd are rare. objectives: to describe the rare clinical manifestation of anaphylaxis to factor concentrate in a patient with severe type vwd. results: a -year-old female with severe type vwd [baseline vwag %, activity < %, factor viii (fviii) %] originally presented with heavy menstrual bleeding (hmb) leading to anemia requiring blood transfusion. she underwent placement of a levonorgestrel-releasing intrauterine device (lngiud) and began norethindrone. her hmb continued despite the lngiud and an increase in norethindrone dosing. plasma derived ahf/vwf complex was administered, which she had previously received. following the infusion, the patient developed anaphylaxis with hives, wheezing, tachycardia, and itching requiring doses of diphenhydramine and dose of hydrocortisone with resolution of symptoms. subsequently, she received recombinant vwf without incident. however, due to her low fviii level, she also required treatment with a full length recombinant fviii product. she again developed hives and itching after this infusion. she has since received recombinant vwf with recombinant fviii/fc fusion protein without further allergic reaction. there was no evidence of an inhibitor with her most recent post-infusion vwf level was %, factor viii %. conclusion: anaphylaxis to plasma derived factor products has been documented far less frequently within the vwd population compared to those with hemophilia and is typically seen in those with large gene deletions, usually with type disease. therefore, similar type vwd patients with severe disease may benefit from gene sequencing. it is unclear in this patient's case to which aspect of her treatment she is allergic, as she reacted to plasma-derived ahf/vwf and full length recombinant fviii, but not recombinant vwf or recombinant fviii/fc fusion protein. we hypothesize that she may be allergic to an epitope in the fviii b domain, or that the presence of fc fusion may have had a protective effect. further investigation including genetic analysis is planned. nodules. biopsies were consistent with neuroendocrine carcinoma, large cell type (g ). next generation sequencing revealed a khdrbs -braf fusion. he received conventional cytotoxic chemotherapy regimens both with cisplatin/doxorubicin, capecitabine/temozolomide, and doxorubicin/etoposide, but achieved a minimal response followed by rapid disease progression, massive ascites, and renal failure secondary to bilateral ureteral obstruction. results: based on his prior genomic testing, therapy with single agent mek inhibitor (trametinib) was initiated. this produced a rapid, dramatic response with greatly reduced disease burden at all sites, resolution of ascites and return to completely normal activity within months. this response lasted for approximately months before the tumor again progressed. further therapy with an erk inhibitor was ineffective, and the patient expired from progressive disease. located on the chromosome q , the braf oncogene, as part of the ras/mapk pathway, is involved in cellular proliferation, differentiation, migration, and apoptosis. braf mutations are recognized in a wide range of adult malignancies: thyroid cancers, non-small cell lung cancer, cholangiocarcinoma, ovarian cancers, and multiple myeloma. braf mutations have also been described in adult neuroendocrine carcinoma of the colon. trametinib is a highly specific inhibitor of mek /mek , a downstream mediator in the braf pathway. it has demonstrated activity in a number of tumors including advanced melanoma and gliomas. trametinib was chosen for this patient based on his atypical braf fusion. we believe this is the first documented case of its successful use in neuroendocrine carcinoma in the pediatric population. conclusion: this case demonstrates the presence of braf fusion in a case of pediatric neuroendocrine carcinoma and significant response to single agent mek inhibition in this context. this cases raises the question as to whether the combination of a targeted inhibitor, in addition to either conventional chemotherapy or other braf inhibitors, might offer a better approach to therapy than current treatment options. albany medical center, albany, new york, united states background: warm autoimmune hemolytic anemia (waiha) is characterized by autoantibody, and occasional complement binding of protein antigens, on the surface of red blood cells at temperatures ≥ oc resulting in targeted destruction. we describe the case of a year old male with a history of evan's syndrome, poor immune response to vaccines and lymphoid hyperplasia, presenting with altered mental status and severe anemia, found to have a warm igg pan agglutinin with evidence of both intra and extravascular hemolysis. his course was complicated by respiratory failure requiring intubation, pulmonary emboli, enterococcus bacteremia and hypertension. he received multiple transfusions with only transient increases in hemoglobin. the aiha was refractory to multiple rounds of treatment with high dose steroids, ivig, rituximab, cyclophosphamide, bortezomib, plasma exchange and mycophenolate mofetil (mmf). objectives: given the refractory nature of our patient's aiha the decision was made to trial eculizumab, a monoclonal antibody targeting c complement, preventing its cleavage and activation, and shown to be effective in treatment of atypical hemolytic uremic syndrome and hemolysis due to an igm cold agglutinin. prior to eculizumab infusion, ch and sc b- assays were significantly elevated. design/method: the patient was given two doses of eculizimab days apart. results: his hemoglobin steadily rose independent of red cell transfusions with a corresponding decrease in reticulocyte count, ldh and ch levels. the patient has remained stable with a normal hemoglobin ( - g/dl) on maintenance steroids and mmf. although we cannot definitively conclude that eculizumab directly caused his recovery, the clinical course post-eculizumab suggests this may be an efficacious treatment for aiha. genetic testing showed monoallelic frameshift mutation of the nfkb gene and monoallelic missense mutation of the dock gene. given the role of nfkb in both immunodeficiency and autoimmunity, it is thought that the patient's phenotype is due to nfkb haploinsufficiency and he is currently considering hematopoietic stem cell transplant. st. joseph's regional medical center, paterson, new jersey, united states background: heterozygous -thalassemia typically manifests as thalassemia minor, characterized by mild microcytic hypochromic anemia with minimal clinical ramifications. coinheritance of -globin gene triplication has been reported to exacerbate the clinical and hematological phenotype ofthalassemia trait, due to increase in the alpha/non-alpha-chain imbalance. reported phenotypes range from asymptomatic thalassemia minor to moderate thalassemia intermedia, usually diagnosed in adulthood without transfusion dependence. this combination has been described in mediterranean, european and asian populations, but rarely reported in hispanics. objectives: to report two cases of unusually severethalassemia intermedia in hispanic patients with heterozygosity for triplicated -globin gene and a ( )-thalassemia allele. results: case : sixteen-month-old male of mexican descent presented with persistent microcytic anemia and jaundice. peripheral smear showed nucleated rbcs with basophilic stippling and target cells. hemoglobin electrophoresis revealed: hba- %, hbf- %, hba - . %. -globin gene testing revealed heterozygosity for ( ) mutation (ivsi-i, g→a). given the unusually severe anemia, -gene testing was performed which showed -globin gene(anti . ) triplication ( / ). at four years, he had splenomegaly and bilateral maxillary prominence. head ct showed irregular contour of the parieto-occipital region due to medullary expansion. due to significant persistent anemia ( - g/dl) and progressive bony deformities of the skull, patient began chronic transfusions at age eight after family declined splenectomy.case : fifteen-year-old female, of peruvian and honduran descent, presented for evaluation prior to cholecystectomy for gallstones and recurrent ruq pain. father had known thalassemia trait. her hb was . g/dl with hypochromia, microcytosis, and target cells. electrophoresis indicated -thalassemia trait (hba- %, hba - . %, hbf- . %), confirmed by gene testing (heterozygous for a ( ) mutation in codon c>t). given jaundice and gallstones, -globin gene analysis was ordered showing triplication ( / ). ruq pain resolved post-cholecystectomy, but she developed persistent painful splenomegaly. she began hydroxyurea to increase gamma-globin production and decrease excess alpha chains, but it was discontinued due to hematological toxicity. due to recurrent luq pain and progressive splenomegaly, she underwent laparoscopic splenectomy at age with resolution of symptoms and improved hemoglobin. conclusion: -globin gene testing should be considered in -thalassemia carriers with an atypical clinical presentation including hispanic patients. the wide variability in the phenotypic expression of (anti . ) mutation andthalassemia trait suggest interplay of other genetic factors which remain undefined. the clinically significant presentation amongst certain subjects, as in our two cases, makes it imperative to identify these factors to aid in phenotype prediction and genetic counseling. ashley bonheur, shivakumar subramaniyam, jogarao vedula, sucharita bhaumik nyu winthrop hospital, mineola, new york, united states background: wilms tumor (wt) is one of the most common solid malignant neoplasms in children. a diverse range of genes and mechanisms are implicated in wt pathogenesis. predisposing syndromes result from a disruption of wt gene, crucial for renal and gonadal embryogenesis. another gene is wt gene locus at p , an area of imprinting. the p tumor suppressor gene on chromosome p . is seen in patients with anaplastic histology. in addition to these genes, whole and partial chromosome gains of q, , q, , , & and losses of p, p, q, q, as well as loss of heterozygosity (loh) are commonly seen. some genetic markers appear to be predictive of outcome and are now incorporated into the assigning of risk-directed therapy. patients with loh at chromosome p and q are treated with more intensive chemotherapy, as they have been associated with increased risk of relapse and mortality. objectives: to describe a new complex translocation involving chromosome , , and in a case of pediatric wt. design/method: a four-year old female presented with abdominal pain and emesis. on exam, patient had a firm and large abdominal mass. radiologic studies revealed a complex lobulated right renal mass. right radical nephrectomy was performed. histopathologic studies showed wt with triphasic histologic features with blastema predominance, invasion of the lymphovascular and perinephric adipose tissues, perinephric lymph node involvement and no anaplasia. chest ct scan showed bilateral lung metastases. tumor cytogenetics showed an abnormal karyotype, a complex translocation of , , and . the rearrangement occurred due to translocation between chromosomal bands q and q , with an insertion of q - on the q region. pcr based genotyping using microsatellite markers additionally identified loh for chromosome p and q . the patient was treated for high risk stage iv wilms tumor with favorable histology and received intensive chemotherapy and radiation therapy to the flank and the lungs. she is now in remission months after, with no evidence of recurrence on surveillance scans. complex translocations associated with wt have not been rigorously studied. a question for further study is whether there is any relationship between recurrence potential with a complex translocation compared to common chromosomal abnormalities. further knowledge of the molecular pathology and genetic changes in wt will help the development of new targeted therapies, as well as new biomarkers to aid diagnosis, risk stratification, and monitoring of treatment and relapse. results: a week-old girl was referred for evaluation of an abnormal newborn screen. mother was a known carrier of hb khartoum trait while father was a known carrier of thalassemia trait. patient's hemoglobin quantification performed by capillary zone electrophoresis showed hbf %, hb variant %, and no detectable hba. the hb variant ran in the d zone, a pattern consistent with mother's hb. alkaline agarose gel electrophoresis banding pattern showed f/s. acid agarose gel electrophoresis pattern showed v/f. later testing revealed abnormal isopropanol stability with + precipitation at minutes. this electrophoresis pattern is consistent with the pattern previously reported of hb khartoum. clinically, the patient is a healthy, active child whom we have followed for two years. she has not had any significant anemia outside of her physiologic nadir. she has not had any hemolytic episodes, and her bilirubin levels have always been within the normal range conclusion: to the best of our knowledge, this is the only reported case of hb khartoum/ thalassemia. the proline to arginine substitution of hb khartoum introduces a charged group on the chain at the site of contact. the resulting unstable chains can dissociate into monomers and favor the formation of methemoglobin, leading to hemoglobin instability. we had wondered if this unstable hemoglobin might result in clinical hemolysis when challenged with oxidative stress, such as in periods of infection. however, in the two years we have followed this patient, she has never had a hemolytic episode. at two years of age, she has hbf . %, hb khartoum . %, and hba . %. whether hbf elevation is protective from oxidative stress remains to be determined as we continue to follow this child. university of puerto rico -medical science campus, san juan, puerto rico, united states background: gm gangliosidosis is a lysosomal disorder caused by -galactosidase deficiency due to mutations in the glb gene. it is a rare autosomal recessive neurodegenerative disorder with an incidence of about : , - : , live births worldwide. this neurological disorder has three clinical forms. gm type , or infantile form is characterized by psychomotor regression by the age of months, visceromegaly (hepatosplenomegaly), macular cherry red spot, facial and skeletal abnormalities, seizures, and profound intellectual disability. we present a -year-old female with gm type and acute lymphocytic leukemia (all). design/method: she was diagnosed with gm type at the st months of age and family history was remarkable for an older sister with gm type . diagnostic studies reveal homozygous exon of the glb gene for a sequence variant defined as c. c>t, predicted to an amino acid substitution p.aarg cs. results: patient presented to our hospital with petechiae in lower extremities, pallor and intermittent tracheal bleeding. physical examination shows a hemodynamically stable girl that is chronically ill dependent of mechanical ventilation, severe mental retardation and scatter petechiae at upper and lower extremities. laboratory workup revealed severe normocytic anemia (hgb: . g/dl) with immature peripheral cells and thrombocytopenia ( × /l). serum chemistry revealed increase ldh ( u/l), increase hepatic enzymes (ast: u/l), normal uric acid level. there was no evidence coagulopathy. chest x ray was unremarkable except for evidence of chronic pulmonary illness. abdominal sonogram hepatosplenomegaly. during hospitalization, bone marrow aspirate and biopsy was performed which was diagnostic of b cell acute lymphoblastic leukemia (all) with . % lymphoblast and orderly myeloid/erythroid maturation. flow cytometry: % b lymphoblast with aberrant phenotype c/w b-acute lymphoblastic leukemia. karyotype revealed hyperdiploid female of favorable prognosis. cytogenetic by fish: hyperdiploid all with extra copies of runx and igh (no bcr-abl translocation). family was oriented about the new diagnosis and the dismal prognosis in conjunction to her primary condition. parents agree on no chemotherapy treatment for all with only supportive treatment. to this date, there is no evidence in literature that has previously described association of gm and leukemia. life expectancy of patient's primary condition is null therefore, correlation with leukemia might not be a coincidental finding. this patient opens the possibility of malignancy as part of gm type thus, malignancy diagnosis should be considered as part of their medical lifetime course. university of south florida, tampa, florida, united states background: hematological manifestations related to hiv infection are not uncommon, with thrombocytopenia having an estimated prevalence of - %. the pathophysiology is likely multifactorial. studies suggest that the primary mechanism may be immunologic resulting in accelerated platelet destruction. additional theories suggest that infection of megakaryocytes may also play a role causing inadequate platelet production. treatment of hiv-related thrombocytopenia is challenging. first-line treatments include initiation and optimization of antiretroviral therapies, immunoglobulin (ivig), and glucocorticoids. however, this approach is not effective in all patients and second line treatment options are less well studied, particularly in the pediatric population. objectives: we aim to present and discuss the case of a year old patient with perinatally acquired hiv- infection and persistent thrombocytopenia who, after failing first line therapies, showed normalization of platelet count on the novel thrombopoietin receptor agonist, eltrombopag. design/method: a retrospective chart review of the case patient's medical record was conducted. additionally, a thorough literature review was performed on this topic including the pathophysiology of hiv related thrombocytopenia and its treatment modalities. the patient required monthly ivig infusions for about year, but did not show a sustained response, often with platelet count dropping to less than , in between infusions. after initiation of mg eltrombopag daily the patient showed a sustained increase in platelet count (range , - , ). during a brief week lapse in eltrombopag treatment his platelet count dropped to , . upon re-initiation of therapy his count increased to , . the patient has remained asymptomatic, off of ivig for over one year, with undetectable hiv viral load and greater than cd t cell counts. no side effects or grade laboratory abnormalities were reported. conclusion: treatment of hiv-related thrombocytopenia can be challenging. first line therapies, including ivig and glucocorticoids, are not effective in all patients. several other treatment modalities have been utilized, including anti-d immunoglobulin, dapsone, danazol, interferon alfa, vincristine, thrombopoetic growth factors including romiplostim and eltrombopag, or splenectomy, but these are less well studied. this represents the first reported case of a pediatric patient with hiv who showed a positive response to eltrombopag with a sustained improvement in platelet count and no adverse effects from treatment. eltrombopag may be a safe alternative to first line therapies in those patients with hiv and refractory thrombocytopenia, however additional studies are needed. university of illinois college of medicine at peoria, peoria, illinois, united states background: achromobacter xylosoxidans is a gram negative rod with peritrichous flagella which causes rare opportunistic infections most commonly encountered by immunocompromised patients. it is primarily associated with uncomplicated bacteremia, cather-associated infections, and pneumonia. most reports of bacteremia associated with a. xylosoxidans are nosocomial, associated with neoplasm, and occurring mainly in adults. most reported infections with a. xylosoxidans in children are associated with cystic fibrosis. there are very few reported cases of septic shock from a. xylosoxidans bacteremia and pneumonia in the pediatric oncology population. objectives: to describe a rare case of a. xylosoxidans septic shock in a pediatric patient with relapsed neuroblastoma results: a -year old boy with history of stage iv highrisk neuroblastoma underwent standard frontline therapy with chemotherapy, hematopoietic stem cell transplant, radiation therapy, and immunotherapy, followed by a dfmo trial for maintenance. his -month follow-up scans demonstrated relapse and he was subsequently treated with additional chemotherapy, surgical resection, and mibg therapy, crizotinib for an eml -alk fusion and finally ifosfamide, carboplatin and etoposide (ice). he developed neutropenic fevers and was started on cefepime, vancomycin and fluconazole. blood cultures were initially negative. on the th day of fever, his previously scheduled pet scan was performed during hospitalization and showed new pulmonary opacities. he did not have respiratory symptoms, but therapy was escalated to meropenem, vancomycin and amphotericin. emergent bronchoscopy was performed the same day, with all bacterial and fungal cultures remaining negative. overnight, he developed tachypnea and saturations in the upper s, requiring nasal cannula. ir-guided lung biopsy was performed the next day, a flexible bronchoscopy was done to remove blood clots in the airway, the patient was placed on a ventilator, femoral lines were placed, granulocytes ordered and pressors were started for deterioration to presumed septic shock. arterial and femoral lines were placed but patient continued to have hemodynamic instability on multiple pressors. the following day, blood and respiratory cultures returned positive for results: at days after the start of iti, the inhibitor was < . bu and continued undetectable months after initiation of iti therapy. in this patient, iti with high-dose plasma-derived factor viii and von willebrand factor (vwf) complex was well tolerated and effective. genetic analysis confirmed a large factor viii gene duplication of exons to . we believe our patient developed inhibitor so quickly ( exposure days) due to the possibility of this mutation causing a frameshift that introduces a premature termination codon. this might be functionally similar to a deletion in the factor viii gene which poses the highest risk for inhibitor development in patients with severe hemophilia a. this variant has only been identified previously in two unrelated patients diagnosed with severe hemophilia a. this duplication is not listed in dbsnp variant database, nor observed in the general population database. our case proves the effectiveness of this method for patients with severe hemophilia a and an inhibitor. it also shows that more research is needed to identify patients at risk for inhibitor development. background: mercaptopurine ( -mp) is a prodrug that is a core component of maintenance chemotherapy for patients with a diagnosis of acute lymphoblastic leukemia (all). suppression of the neutrophil count is used to demonstrate adequate dosing of -mp during this phase of therapy. bone marrow suppression is mediated by the active metabolite -thioguanine ( -tgn), whereas the metabolite -methylmercaptopurine nucleotides ( -mmpn) has been shown to cause hepatotoxicity. allopurinol has been used infrequently in all maintenance therapy in the setting of skewed metabolism when adequate myelosuppression is difficult to achieve due to excessive hepatic toxicity. when given in combination with allopurinol a reduced dose of -mp may result in both increased -tgn levels and decreased -mmpn levels. objectives: describe the characteristics and clinical course of patients treated with allopurinol and reduced dose -mp during maintenance chemotherapy for all. we performed a retrospective chart review of patients at aflac cancer and blood disorders center of children's healthcare of atlanta with new diagnoses of b or t-cell all who received allopurinol during maintenance chemotherapy. we identified eleven patients with b-cell or tcell all who received allopurinol adjunctive therapy during maintenance chemotherapy at a single institution between - . these patients received adjunctive allopurinol for - weeks (median weeks) with reduced -mp ( - % of full dose). all ten patients with genetic testing for thiopurine s-methyltransferase (tpmt) had wildtype genotype associated with normal enzyme levels. indications for allopurinol use were most commonly unfavorable -mp metabolite levels, transaminitis (n = ), pancreatitis (n = ) and hyperbilirubinemia (n = ). favorable metabolite shift was achieved in all patients. liver enzymes improved in of patients with transaminitis after initiation of allopurinol/reduced -mp. three patients who experienced pancreatitis during maintenance did not have recurrence after initiation of allopurinol ( of these patients previously reported). six patients developed pancytopenia while on allopurinol, and two of those patients developed pancytopenia severe enough to require allopurinol cessation. four patients developed isolated anemia (hgb < . g/dl) without thrombocytopenia or severe neutropenia. no patient has experienced a recurrence of leukemia. overall, treatment with allopurinol and reduced dose -mp was successful in producing a favorable -mp metabolite distribution and reducing toxicity. therapy was generally tolerated; however a major and notable side effect was pancytopenia, in two cases severe enough to stop allopurinol treatment. anemia may be more prominent with allopurinol usage. allopurinol effect is variable among individual patients despite normal tpmt genotypes. baylor college of medicine, houston, texas, united states background: congenital sideroblastic anemia, b-cell immunodeficiency, periodic fevers and developmental delay syndrome (sifd) is a rare inherited sideroblastic anemia syndrome, first described in with clinically similar cases. genetic variations of trnt were identified as causative. objectives: to present an unusual presentation of a patient with sifd complicated by diagnosis of concomitant alpha thalassemia trait. design/method: retrospective chart review. a five month old male infant was referred to our hematology center for evaluation of elevated hemoglobin barts identified on newborn screen. despite numerous attempts, blood work was unable to be collected. at seven months of age he had microcytic anemia (hemoglobin . g/dl, mean corpuscular volume fl) more severe than what would be expected with alpha thalassemia trait. no variant hemoglobin was identified with isoelectric focusing or high performance liquid chromatography. by nine months of age he developed growth failure, intermittent emesis with fevers, developmental delays (predominantly gross motor), hearing loss, a disproportionally large head and coarse, thinning hair. over the next ten months, he was seen by numerous specialists for seemingly unconnected problems including sensorineural hearing loss, elevated liver enzymes and growth hormone deficiency. alpha globin analysis revealed deletion of two alpha globin genes. at months of age, he was admitted with one week of fevers, jaundice, and emesis. peripheral blood smear showed microcytic hypochromic anemia with marked anisopoikilocytosis including target cells, elliptocytes, tear drops, spherocytes, poikilocytes, marked polychromasia, and coarse basophilic stippling. given the inconsistency of his laboratory findings with the diagnosis of alpha thalassemia trait and clinical syndromic findings, bone marrow biopsy was performed which revealed rare ringed sideroblasts. one month later whole exome sequencing revealed trnt splicing variant c. - c>g and novel missense variant c. a>t consistent with sifd. hemoglobin barts on newborn screen with moderate to severe microcytic anemia directed initial diagnostic work-up towards variant alpha thalassemia. as additional medical conditions developed the focus shifted to a unifying syndrome. compared to previously described cases, our patient was diagnosed at an older age, presented with anemia rather than episodes of febrile illnesses, and had rare sideroblasts on bone marrow examination. diagnosis in this case led to identification of the novel c. a>t variant in his sister who had similar, but milder, features. sifd is a rare disease with variable phenotypic severity making diagnosis challenging without high index of suspicion which is crucial for appropriate management. wiseman, blood, . chakraborty, blood, background: cholelithiasis is uncommon in childhood. cholelithiasis is known to occur more frequently in children with predispositions, including female sex, obesity, parenteral nutrition, previous abdominal surgery, use of oral contraceptives, family history of gallstones, chronic hemolytic anemias, hepatobiliary disease, or exposure to specific drugs. although there have been occasional case reports linking cholelithiasis to childhood leukemia or leukemia therapy, the prevalence and risk factors of cholelithiasis in patients with childhood leukemia remain unclear. objectives: to estimate the prevalence of cholelithiasis in patients diagnosed with childhood acute lymphoblastic leukemia (all), and to evaluate possible risk factors for the development of cholelithiasis in patients with childhood all. we performed a computer-assisted review of the electronic medical records of patients diagnosed for b or t-cell all at children's healthcare of atlanta in the period from to . patients with diagnoses of cholelithiasis, cholecystitis or who had a cholecystectomy were identified. possible risk factors of age, sex, bmi, history of abdominal surgery and parenteral nutrition use were abstracted. patients with underlying chronic hemolytic anemia or pre-existing gallbladder disease were excluded. results: seventeen cases of cholelithiasis and cases of cholecystitis without documented cholelithiasis were identified. among patients with cholelithiasis, were female. median age at diagnosis of cholelithiasis was . (range . - . ) years. seven patients had no symptoms referable to cholelithiasis at the time of diagnosis. the median age of leukemia diagnosis among these patients was . (range . - . ) years. the median interval from diagnosis of leukemia to gallbladder disease was . years. four patients had bmi over the th percentile for age. two patients had a prior history of intraabdominal surgery. no patient received oral contraceptive pills. six patients received parenteral nutrition for more than days. there was no documented family history of cholelithiasis. seven patients did not receive any cholelithiasis directed therapy. two patients were managed with medical management only, with endoscopic retrograde cholangiopancreatogram with stone extraction, and with cholecystectomy. our study estimates the prevalence of cholelithiasis in childhood lymphoblastic leukemia to be . %, higher than the reported prevalence in the general pediatric population of . - . %. although our cohort size is small, it appears that all therapy and supportive care modalities associated with all are likely to play a larger role in the development of cholelithiasis than known predisposing factors in the general population. further studies are warranted. background: an uncommon side effect of intravenous immunoglobulin (ivig) administration is clinically apparent, sometimes severe hemolysis. we describe a severe case of coombs-positive hemolytic anemia secondary to ivig administration. ivig is a blood derivative manufactured from pools of , to , individual plasma donations. ivig is not abo-type restricted, so anti-a, anti-b and anti-a,b isoagglutinins are detectable. objectives: to describe a rare but serious type of transfusion reaction leading to gross hemolysis after ivig administration. results: a -year-old male with a past medical history of obstructive sleep apnea and obesity was admitted to the pediatric intensive care unit for adenoviral pneumonia and subsequent respiratory failure requiring mechanical ventilation. he had a complex hospital course with many complications including acute respiratory distress syndrome (ards), septic-shock, and coombs-positive hemolytic anemia. the patient was treated with commercial ivig (baxter/baxalta) -mg/kg daily for five days. he had two isolated episodes of severe hemolysis in relation to ivig administration requiring multiple transfusions of packed red blood cells (prbc). examination of pre-transfusion peripheral blood smear showed spherocytosis with rouleaux formation and large clumped rbc aggregates. the patient's blood type was classified as blood group a, rh-negative and his initial prbc transfusions were of this type. subsequently, the patient's coombs test was found to be positive using polyspecific and anti-igg typing sera. the patient's antibody screen against reagent group o screening cells was negative ruling out autoimmune hemolytic anemia. however, type specific anti-a antibodies were detected in his plasma as well as the acid eludate prepared from the coombs-positive red blood cells. it was concluded that the patient's hemolysis was due to anti-a antibodies presumed to arise from ivig. the patient's rbc transfusions were changed to o-negative blood and the hemolytic process resolved. the patient ultimately died due to complications of ards. although hemolysis is a known side effect of ivig, it is rarely considered when deciding to administer ivig. in addition, it has rarely been described in the pediatric population. ivig is used in the treatment of a growing number of medical conditions. due to the critical nature of many of these patients, hemolysis secondary to ivig may not be considered and continued blood transfusions with the patient's specific blood type may be used. it is crucial to remember that severe hemolysis can occur from ivig, and the importance of transfusing with blood group o, rh-negative blood when applicable. university of maryland medical center, children's hospital, baltimore, maryland, united states background: coagulopathy is a well-described complication of acute promyelocytic leukemia (apml), and remains a leading cause in induction failure. with treatment, coagulopathy associated with apml has been shown to rapidly improve. multiple organ dysfunction syndrome (mods) in apml, including acute respiratory distress syndrome (ards), has been associated with infection, traumatic injury, malignant infiltration, and cytokine release syndrome. when mechanical ventilation is no longer sufficient, extracorporeal membrane oxygenation (ecmo) can be considered; however, coagulopathy, severe end-organ damage, and malignancy are all relative contraindications to initiation of treatment. we report the case of a -year-old female presenting in respiratory failure, disseminated intravascular coagulopathy (dic), with intracranial hemorrhage, and mods, diagnosed with apml, successfully treated with ecmo therapy. design/method: retrospective case analysis and literature review. our patient, a -year-old female was admitted in respiratory failure and altered mental status, following a fall shortly prior to presentation. initial laboratory values were notable for pancytopenia, dic, and acute renal failure. a non-contrast head ct showed left temporal lobe intraparenchymal hemorrhage. she was diagnosed with apml by peripheral smear, later confirmed by fish for t( : ), and was started immediately on high-risk induction chemotherapy as per cog protocol aaml , including all-trans retinoic acid, arsenic trioxide, idarubicin, and dexamethasone. cvvhd was required for acute renal failure. despite maximal respiratory support, she remained hypoxemic, with oxygenation index of , pao /fio ratio of . ecmo was initiated hours after start of induction, hours after admission. coagulopathy resolved on day of induction, ecmo was discontinued after days, mechanical ventilation and cvvhd were stopped after days and she continued to improve, eventually achieving remission with few neurologic side effects. despite relative contraindications to ecmo, this patient was successfully treated with ecmo without significant neurologic side effects. the correction of her coagulopathy was multifactorial: ) restoration of adequate oxygen delivery via ecmo improving endothelial function; ) successful organ support to allow sufficient response to induction chemotherapy with atra leading to the terminal differentiation of leukemic blasts; ) complement and contact system activation through contact with ecmo circuitry. this case illustrates that ecmo can still be considered in patients despite coagulopathy and end organ damage. sinai hospital of baltimore, baltimore, maryland, united states background: primary polycythemia vera is an extremely rare diagnosis in the pediatric patient and is defined by a marked elevation of red blood cells due to erythropoietin-independent mechanisms. presentations of this disorder range from the asymptomatic person to severe thrombotic events, such as budd-chiari syndrome or cerebrovascular stroke. mutations in the jak gene are found in adult and pediatric patients with polycythemia vera; however, the jak v f mutation is less commonly identified in pediatric patients. we describe an otherwise healthy -year-old female who presented with a significantly elevated total erythrocyte count, hemoglobin, and platelets, incidentally discovered upon routine annual blood work obtained by her pediatrician. design/method: this is a report and discussion of a rare case. demonstrated cellular marrow with trilineage hematopoiesis and no dysplasia. cytogenetics were not assessed. his hemoglobin and platelet count recovered but leukopenia and neutropenia persisted. follow-up evaluation at three months revealed fevers, ongoing cytopenias, a one-month of a nodular skin rash on the trunk and extremities resembling erythema nodosum, and hepatitis (peak alt and ast of , and , , respectively). following clinical evaluation, a skin biopsy was performed and was remarkable for atypical lymphocytes within the subcutis with t-cell markers, a high ki- , and positive tia- , perforin, and -f immunoperoxidase stains. negative stains for cd , cd , and ebv were noted. these results are consistent with sptcl. additional evaluation did not support a diagnosis of hlh. a staging evaluation was performed. pet-ct showed widespread hypermetabolic subcutaneous activity in the legs, trunk and skull and diffuse marrow hyperplasia. bone marrow demonstrated involvement with precursor b-cell acute lymphoblastic leukemia, with a mll gene rearranagement. his skin biopsy was retrospectively stained with tdt, cd , pax- , cd a, and cd with negative results, and a blood smear taken at the time of the skin biopsy did not demonstrate leukemic cells. conclusion: this is the first report of a patient with sptcl having a synchronous malignancy. the patient is doing well, currently in the maintenance phase of treatment for his all, and his skin disease has resolved on pet-ct. while it is possible that his presentation was a function of chance, the possibility of an underlying immune dysfunction or cancer predisposition warrants further investigation. cincinnati children's hospital medical center, cincinnati, ohio, united states background: hereditary xerocytosis (hx) is a rare red blood cell (rbc) dehydration disorder, characterized by variable hemolysis and propensity to iron overload. hx is often misdiagnosed as hereditary spherocytosis (hs). while splenectomy is curative for hs, it is relatively contraindicated in hx due to a substantial thromboembolism risk, signifying the importance of delineating these diseases. blood smear abnormalities are variable and often insufficient to make an accurate diagnosis. osmotic-gradient ektacytometry and genetic confirmation are critical in distinguishing these overlapping disorders. objectives: describe a family with hx, initially misdiagnosed as hs. discuss the importance of distinguishing these disorders and the utility of ektacytometry in making this distinction. design/method: a -year-old caucasian male was diagnosed with hs after presenting with prolonged neonatal jaundice starting on the first day of life. he described mild scleral icterus and history of intermittent jaundice and dark urine, without need for transfusions. his father, paternal uncle and paternal grandmother were all diagnosed with hs during childhood and underwent cholecystectomy. additionally, his father underwent splenectomy for abdominal pain. the child's blood counts revealed compensated anemia (hb . gm/dl) and reticulocytosis (arc × /mcl) with increased mcv ( . fl) and mchc ( . gm/dl). blood smear showed increased polychromasia and poikilocytosis with rare spherocytes and few stomatocytes. while the child had normal ferritin, his father had iron overload (ferritin ng/ml) despite no prior transfusions. osmotic-gradient ektacytometry profile of the child and father's rbcs showed a characteristic left-shifted, bell-shaped curve with decreased omin and ohyp, diagnostic of hx. the family is currently undergoing genetic studies. despite clinical similarities between hs and hx, distinguishing these diseases has significant management implications. hx is a disorder of rbc permeability, causing shortened rbc survival. stomatocytes on blood smear can raise suspicion for hx, but are insufficient to make an accurate diagnosis. identifying characteristic biomechanical membrane properties using osmotic-gradient ektacytometry is the gold standard for clinical diagnosis, which can then be confirmed by molecular studies. hs and hx can be easily and reliably distinguished using ektacytometry, as both disorders have very distinctive curves representing different rbc deformability patterns. after hx diagnosis was made, we counseled the family against splenectomy, as the risk of thromboembolism is significantly increased in hx compared to hs, and the father was diagnosed with iron overload. conclusion: hx is commonly misdiagnosed as hs. this case highlights the importance of making this distinction, and the utility of osmotic-gradient ektacytometry in reliably distinguishing these conditions. penn state health children's hospital, hershey, pennsylvania, united states background: relapsed acute myeloid leukemia (aml) presenting as an isolated central nervous system myeloid sarcoma (cns ms) is very rare and its treatment is not well-defined. thiotepa, vinorelbine, topotecan and clofarabine (tvtc) has been successful for re-induction therapy to induce remission prior to hematopoietic stem cell transplant (hsct). objectives: to describe our experience in utilizing tvtc therapy in two children with no extramedullary disease at initial diagnosis who presented with relapsed aml as intracranial myeloid sarcomas. results: case : month-old female was diagnosed with flt negative aml and completed treatment per the children's oncology group (cog) aaml study on the low risk arm without bortezomib. cerebral spinal fluid (csf) negative at diagnosis. fish testing positive for tcf gene deletion of unknown significance. mrd was undetectable after induction i and remained undetectable after each cycle. nine months off therapy, recurrent headaches prompted mri imaging which revealed two posterior fossa masses. csf and bone marrow testing were negative. stereotactic biopsy of the larger mass confirmed recurrence of aml. patient underwent two cycles of tvtc with a total of seven doses of intrathecal cytarabine with almost near resolution of the cns ms. completed cranial radiation and proceeded to allogeneic stem cell transplant with unrelated cord marrow donor and is disease free at approximately day + .case : year-old female diagnosed with flt and mll negative aml and completed treatment per cog aaml study on the low risk arm without bortezomib. csf negative at diagnosis. mrd was undetectable after induction i and completed therapy without complications. two months off therapy, a retrospective analysis of her diagnostic bone marrow by the cytogenetic laboratory to test a new panel identifying novel q partners revealed a cryptic insertional : (mllt /mll(kmt a) translocation. at four months off therapy, acute mental status changes prompted mri imaging which revealed two intracranial ms and lumbar spine involvement. resection of the larger lesion for symptomatic relief confirmed the mllt /mll(kmt a) fusion. csf positive for blasts and marrow negative for relapsed disease. patient completed two cycles of tvtc with a total of seven doses of it cytarabine with near resolution of cns disease (only mm contrast enhancement in the medulla). she received craniospinal radiation and is awaiting improvement in her cardiac function before proceeding to hsct. conclusion: tvtc is a successful reinduction regimen for relapsed aml with cns ms prior to hsct. background: acute severe anemia can be a life-threatening medical condition. the differential is quite broad for possible etiologies of acute severe anemia, including autoimmune hemolytic anemia (aiha) and atypical hemolytic uremic syndrome (ahus). autoimmune hemolytic anemia is an antibody-mediated process that targets the protein antigens located on the surface of red blood cells. treatment options for aiha include corticosteroids, with up to % of patients being responsive, with some requiring splenectomy. atypical hemolytic uremic syndrome is a medical urgency, defined as the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. the etiology is usually due to genetic causes, or less commonly, due to autoantibodies or idiopathic reasons. prognosis is very poor. objectives: differentiating between autoimmune hemolytic anemia and atypical hemolytic uremic syndrome can be a time-sensitive diagnostic dilemma while the patient is in critical condition, but this important delineation can vastly alter therapeutic options. design/method: here we discuss two cases highlighting the diagnostic workup involved in differentiating between atypical hemolytic uremic syndrome and autoimmune hemolytic anemia. patient a is a -year-old male who presented in extremis with severe anemia, uremic encephalopathy, and severe acute renal injury requiring hemodialysis and multiple blood transfusions. patient b is a -month-old male, who also presented in extremis with respiratory failure secondary to adenovirus/rhinovirus/enterovirus, with acute progressive renal failure and microangiopathic hemolytic anemia, requiring hemodialysis and cardiorespiratory support. : patient a underwent a full hematologic and infectious disease workup. subsequent laboratory studies confirmed enteropathogenic e.coli (epec) in the patient's stool; blood cultures remained negative. renal biopsy results were consistent pigment nephropathy. bloodwork indicated positive direct coombs. patient a was ultimately treated with steroids mg/kg/day, with significant improvement. patient b also included a full hematologic work-up, including adamts activity and ahus genetic panel, as well as full infectious disease work-up. subsequent laboratory test-ing revealed blood cultures growing streptococcus pneumoniae, with adamts activity at % (adult ref range: >/ = %), and normal complement levels. imaging findings also supported diagnosis of ahus. the management of a critically ill patient with acute severe anemia requires a thorough hematologic and infectious disease work-up. while molecular and genetic are helpful in definitive diagnosis of ahus, the utility of such results is limited by time. overlapping clinical presentation of a patient in extremis due to acute severe hemolytic anemia with progressive renal failure presents a rather broad differential, with time-sensitive treatment and prognostic implications. the favorable response to steroids delineates aiha from hus. background: d- -hydroxyglutaric aciduria (d- -hga) is a rare metabolic disorder characterized by developmental delay, hypotonia, and bi-allelic mutations in d- hydroxyglutarate dehydrogenase (d hgdh) or isocitrate dehydrogenase (idh ). metaphyseal chondromatosis with d- -hydroxyglutaric aciduria (mc-hga) is a type of d- -hga that has been previously reported in seven patients (omim ; pmid ), three of whom had somatic mosaicism for r variants in isocitrate dehydrogenase (idh ). we describe a -year-old boy with mc-hga who subsequently developed acute myeloid leukemia (aml) and was found to have a r variant in idh in a leukemic bone marrow sample. we report the first case of aml with this metabolic disorder. design/method: a -year-old hispanic boy presented with short stature, developmental delay, abnormal skin pigmentation, and unilateral congenital cataract. workup revealed multiple skeletal enchondromatosis and elevated urine d- -hydroxyglutaric acid levels. he was diagnosed with mc-hga. no pathogenic variants in d hgdh, idh and idh were identified in peripheral blood. germline testing with biopsies of skin lesions was declined by the family. two years later, he presented with streptococcal sepsis and pancytopenia. blasts were noted on peripheral smear. bone marrow morphology was consistent with acute myelomonocytic leukemia (∼ % blasts). chromosome analysis showed normal xy, and molecular testing by pyrosequencing idh and idh revealed a r c variant in idh ( % mosaicism). the patient is being treated as per the cog study aaml . end of induction i bone marrow aspirate was hemodiluted, but there was no obvious residual disease by flow cytometry ( . - . % sensitivity) or morphology. the previously identified idh variant was no longer detectable (limit of detection < %). although targeted therapy for aml with idh mutation is currently in phase i clinical trials in adults, there is no safety or efficacy data for using idh inhibitors in children. treatment with ivosidenib is therefore not currently an option for our patient. conclusion: this is the first case of aml reported with this rare metabolic disorder. somatic r variants in idh have been identified in three other mc-hga cases. this same mutation leads to the accumulation of d- -hydroxyglutarate in gliomas and aml. without any confirmed germline mutation or somatic mosaicism testing of multiple specimen sources, we can only speculate that the patient has an underlying somatic idh mutation associated with mc-hga which subsequently led to leukemogenesis. we present the first case of this association, to increase index of suspicion for development of aml in children with metabolic disorders associated with variants in idh . background: congenital combined deficiency of the vitamin k-dependent coagulating factors (vkcfd) is a rare heterogeneous autosomal recessive bleeding disorder. vkcfd is caused by mutations in the genes of either gamma-glutamyl carboxylase (ggcx) or vitamin k epoxide reductase complex (vkorc), which are responsible for the gammacarboxylation of vitamin k dependent proteins (vkdps) allowing for their activation. the clinical presentation ranges from no bleeding to intracranial hemorrhage. to date, vkcfd has been reported in few patients worldwide. objectives: we report a case of a girl with novel homozygous mutation of the ggcx gene, highlighting her clinical and biochemical characteristics with a review of the literature. a -month-old girl of consanguineous emirati parents, presented to our hospital with a history of bleeding from puncture site after receiving her second-month vaccine. that was associated with episodes of mild mucosal bleeding. review of systems was negative for jaundice, steatorrhea and failure to thrive and physical exam was unremarkable. investigations revealed markedly prolonged pt and aptt with high inr. fibrinogen, hemoglobin and platelets were always normal. activities of vitamin k-dependent factors including fii, fvii, fix, fx, protein c and s were all low. a measurement of proteins induced by vitamin k absence (pivka-ii) was done and came very high. this was associated with a mild elevation in liver enzymes but normal liver function test. the picture was supporting vitamin k deficiency, and as a result, she was started on oral vitamin k supplements of mg/day. she responded partially to vitamin k and required higher doses to stabilize her inr. after excluding acquired causes and due to her requirement of high doses of vitamin k, a mutation in either ggcx or vkorc genes was suspected. genetic analysis was conducted for her which revealed a novel missense homozygous mutation in the ggcx gene (c. a>t) confirming the diagnosis of combined deficiency of vitamin k-dependent clotting factors type . the asymptomatic parents were both heterozygous for the same mutation. results: she is currently stable on mg/day of vitamin k supplements. conclusion: vkcfd is a rare bleeding disorder with an overall good prognosis due to the availability of several effective therapeutic options. the function of the mutated gene is unknown. our patient demonstrated a partial response to vitamin k supplements suggesting presence of a residual carboxylation capacity and a possible role of this gene in the enzymesubstrate interactions. university of alabama at birmingham, birmingham, alabama, united states s of s background: gata is a zinc finger transcription factor that plays a critical role in the regulation of hematopoiesis and lymphatic angiogenesis. mutations leading to gata deficiency (gd) have been linked to a variety of clinical conditions. patients with gd have a striking predisposition to develop myelodysplastic syndrome (mds), acute myeloid leukemia (aml), or chronic myelomonocytic leukemia (cmml). acute lymphoblastic leukemia (all) has not been associated with gd, although the association of bcell all and gd has been previously reported. objectives: to describe a unique association of gata deficiency and t-cell all in a young child. results: an -year-old female presented with a one-week history of fever and malaise. she had a significant past medical history of verruca plantaris and self-resolving leukopenia associated with febrile illnesses. significant family history included sister with neutropenia and human papilloma virus (hpv) infection, and mother with neutropenia, monocytopenia, atypical mycobacterial infections, and hpv infection. peripheral blood revealed hemoglobin . g/dl, hematocrit . %, platelets , /ul, and white blood cell , /ul (neutrophils /ul, lymphocytes /ul, monocytes /ul). patient underwent a bone marrow biopsy demonstrating lymphoblast infiltration. flow cytometry analysis demonstrated monoclonal lymphoid blast population that co-expressed cd , cd , cd , nuclear tdt, cd , however, lacked expression of cd , cd , cd , cd , hla-dr, or myeloperoxidase. findings were consistent with tcell all with aberrant myeloid markers. cytogenetics analysis revealed ,xx,dic( ; )(p . ;p . ). patient began treatment as per children's oncology group aall and achieved remission at the end of induction. course of therapy was complicated by episodes of fever, reciprocating junctional tachycardia, asparaginase-associated thrombosis, viral meningitis, recurrent episodes of verruca plantaris, and resistant streptococcus pneumoniae or haemophilus parainfluenza infections causing chronic cough. later, she was also found to have low igm levels; after completion of therapy, she developed monocytopenia. lymphocyte subset panel revealed absent b cells, decreased number of natural killer (nk) cells, and cd /cd inversion. further work-up included gata sequence analysis that showed heterozygous nonsense mutation (c. c > t/c; reference nm_ ) likely resulting in gata haploinsufficiency. patient continues to be in remission, is receiving monthly immunoglobulin replacement and is on azithromycin for atypical mycobacterial prophylaxis. surveillance bone marrow biopsies have shown no evidence of mds or leukemia, however, have demonstrated persistent hypocellularity. the possibility of undergoing an allogeneic bone marrow transplant is actively being discussed given its curative potential. clinicians should be aware that t-cell all may be associated with gata deficiency. cincinnati children's hospital medical center, cincinnati, ohio, united states background: treatment for severe hemophilia a is centered on factor viii (fviii) replacement therapy. development of an alloantibody (inhibitor) against fviii is a significant treatment complication occurring in as many as - % of patients. high titer inhibitors render treatment with factor viii ineffective, necessitating the use of bypass agents that may not achieve hemostasis with the same efficacy. considering the substantial ramifications of inhibitor development on treatment, eradication of inhibitors is of great importance to achieve adequate hemostasis in this patient population. desensitization by immune tolerance induction (iti) is the primary method of inhibitor elimination. however, not all patients respond to iti. immunomodulation may be considered as the next line of therapy, although controversy remains in regards to agent selection and use. objectives: there is incomplete data on the use of immunomodulation therapy for inhibitor eradication in severe hemophilia a. we present a case of a pediatric patient with severe hemophilia a and high titer inhibitor who failed initial iti therapy to better illustrate potential treatment options for the future. design/method: a retrospective chart review was performed on a patient with severe hemophilia a at cincinnati children's hospital medical center. results: an -year-old caucasian male with severe hemophilia a secondary to intron inversion, was initially diagnosed following extensive bleeding after circumcision at birth. he was identified as having an inhibitor ( bethesda units (bu)) at months of age after exposure days of treatment. he failed multiple attempts of iti, with recombinant and plasma-derived (pd) fviii. he was advanced to immunomodulation therapy in combination with pdfviii, however demonstrated anaphylaxis to rituximab and ofatumumab. he underwent tolerization to rituximab, and received a six month course with a partial response (nadir of . bu). months following last dose of rituximab, a rising inhibitor titer ( . bu) was found. mycophenolate mofetil (mmf) was initiated with subsequent inhibitor stabilization and a decreasing titer ( . bu) over the course of the following year. mmf has been well tolerated without major side effects or infection throughout therapy. conclusion: development of an inhibitor against fviii is a considerable complication in patients with severe hemophilia a. use of immunomodulatory therapies following iti failure remains controversial. mmf has not been well studied in this patient population. we report a case of a patient who is being successfully treated with mmf with minimal side effects. further prospective studies should be considered to further define the role of mmf immunomodulation therapy. background: down syndrome (ds) children with aml (ds aml) have higher cure rates than their non-ds counterparts. outcomes for refractory/relapsed cases, however, remain dismal. somatic mutations of the gene encoding the transcription factor gata in ds aml patients are responsible for the observed hypersensitivity of ds aml blasts to cytosine arabinoside (ara-c). in view of excellent survival rates (approaching %) of ds aml patients, the ongoing children's oncology group (cog) aaml study seeks to determine the feasibility of treating standard risk (minimal residual disease/mrd negative) ds aml patients using a reduced dose ( -fold decrease) ara-c backbone. although results from japanese trials with this approach are promising, north american and european data are conflicting. although chromosome rearrangements in ds aml do not appear to carry the same adverse prognostic significance as in non-ds aml, monosomy in ds aml patients has been associated with a moderately worse outcome. isochromosome q, however, is rare and has only been reported in previous cases of ds aml. objectives: to report our institutional experience of very early relapse involving cases of ds aml patients treated per the reduced dose ara-c arm ( . g/m ) of the aaml study. design/method: we hereby report the disease course and cytogenetics of the above ds aml patients. : patient is a month old caucasian female who had gata mutation negative aml. patient is a -year old caucasian male whose chromosomal analysis revealed isochromosome q ( copies of the long arm of chromosome ). both patients achieved negative mrd (< . %) after induction i chemotherapy with thioguanine, low-dose ara-c and daunorubicin and proceeded per the reduced dose ara-c arm of aaml . patient relapsed immediately after completion of chemotherapy. salvage chemotherapy with mitoxantrone/high dose ara-c (hidac) failed to induce a second remission and the patient subsequently died of disease. patient relapsed within months from end of therapy. the patient underwent salvage chemotherapy utilizing a hidac backbone and remains in disease remission. the noted very early relapse following a reduced dose ara-c regimen in our above ds aml children suggests that testing for gata mutation and chromosome rearrangements may play a useful role in the development of future risk-stratified treatment strategies for ds aml. university of rochester, rochester, new york, united states background: in developed countries in the st century, severe nutritional deficiency is not an often considered differential diagnosis of unexplained childhood anemia. aside from iron deficiency anemia, vitamin deficiency severe enough to impact hematopoiesis is uncommon in the general pediatric population. here we present the unique case of a -monthold infant who presented with intermittent emesis, failure to thrive (ftt), developmental delay, macrocytic anemia, and neutropenia which was initially concerning for a congenital bone marrow failure syndrome. instead, she was discovered to have an underlying, potentially familial deficiency of b . objectives: . to describe the unique case of an infant with b deficiency. . to outline the importance of including b deficiency in the differential diagnosis of unexplained megaloblastic anemia in children. a -month-old exclusively breastfed infant presented for gastroenterology evaluation due to persistent emesis and poor weight gain over the course of months. her history was notable for delayed developmental s of s milestones and hypoactivity. marked pallor prompted hematologic evaluation, which revealed concern for macrocytic anemia (hemoglobin . g/dl, mcv ), reticulocytopenia ( . × ^ / l), and neutropenia (anc . × ^ /l). an otherwise reassuring physical examination and laboratory evaluation was notable only for the discovery of an undetectable b level and marked hyperhomocysteinemia ( mol/l). her hemoglobin (hgb) continued to decline (to . g/dl) over the first few days after presentation, and she required red blood cell (rbc) transfusion. within only a few days of initiation, daily cyanocobalamin injections resulted in a robust reticulocytosis response, improved hgb, immediate normalization in the neutrophil count, and resolution of hyperhomocysteinemia. additional history and laboratory evaluation from the patient's mother revealed a concurrent, asymptomatic maternal b deficiency as well as a history of a need for b supplementation in the maternal grandfather, raising concern for an inherited etiology. despite the rarity of vitamin-deficient hematologic abnormalities in the general pediatric population, b deficiency should be considered as a potential cause of an otherwise unexplained megaloblastic anemia, especially in the setting of concurrent ftt and neurodevelopmental delay. a detailed family history should be obtained in such cases and may have helped to prevent this patient's clinical sequelae had the deficiency been discovered sooner. our patient has experienced a favorable clinical response to b supplementation, attesting to the importance of vitamin b in early childhood growth and development. background: peg-asparaginase is universally utilized in the treatment of pediatric acute lymphoblastic leukemia (all). despite its high efficacy in this disease, it is associated with hypersensitivity and allergy in - % of patients. protracted anaphylaxis has been described in circumstances such as severe food allergy with ongoing allergen exposure; however, it has not yet been described in relation to peg-asparaginase. we describe the first reported case of protracted anaphylaxis after peg-asparaginase administration, provide guidance as to time course and management of protracted anaphylaxis, as well as evidence that erwinia asparaginase may be safely administered even in this high risk population. objectives: to provide guidance regarding the duration, course and management of protracted, severe anaphylaxis after peg-asparaginase therapy. a year old male with very high risk all presented for consolidation therapy with peg-asparaginase (intramuscular) and vincristine. one hour after administration, he developed generalized hives and angioedema, for which he was given diphenhydramine. he then quickly developed progressive hives, angioedema, subjective throat and chest tightness, and wheezing. he was treated with diphenhydramine, epinephrine, albuterol, and methylprednisolone with resolution of symptoms. one hour later, symptoms recurred and the patient became hypotensive; he was retreated with methylprednisolone and epinephrine, and was transferred to the pediatric intensive care unit (picu). in the picu, he was placed on an epinephrine drip, and continued on methylprednisolone, diphenhydramine, cetirizine, albuterol, and ranitidine. the epinephrine drip was successfully discontinued after hours, and his other medications were gradually weaned over the course of two weeks. of note, the patient did have st segment changes in his electrocardiogram during the first hours of anaphylaxis. these were associated with normal ventricular function as per echocardiogram, and resolved within one week. this patient has subsequently tolerated multiple doses of erwinia asparaginase (intramuscular) without premedication. this patient was acutely managed in the pediatric intensive care unit with steroids, anti-histamines, and continuous infusion epinephrine. symptoms consistent with severe anaphylaxis including hives, angioedema, throat and chest tightness, wheezing, and hypotension persisted for a total of four days before finally resolving. he has thus far tolerated multiple doses of erwinia asparaginase without any symptoms of allergy, hypersensitivity, or anaphylaxis. protracted severe anaphylaxis after peg-asparaginase therapy can be successfully managed with multi-agent therapy, including antihistamines, steroids, and continuous infusion epinephrine. re-challenge with an alternate form of asparaginase may be tolerated, even in a patient with protracted anaphylaxis to peg-asparaginase. ucsf benioff children's hospital oakland, oakland, california, united states background: vincristine (vcr) is widely used in pediatric cancers. unlike most cytotoxic agents, hematopoietic toxicity is uncommon. vcr-induced anemia has been observed but its mechanism has not been well studied. vinca alkaloid-induced membrane changes were seen in early studies of hereditary spherocytosis (hs) and anecdotal cases suggest vcr may increase hemolysis in such patients. here we describe a case involving severe vcr-induced anemia in a patient with hs and an explanation as to the mechanism. objectives: to describe the mechanism of vcr-induced anemia in hs. design/method: case report. a year-old female with hs was diagnosed with t-lymphoblastic lymphoma. she had required packed red blood cell (prbc) transfusions as a neonate and thereafter had done well without episodes of acute hemolysis or aplasia. complete blood counts (cbc's) demonstrated a compensated hemolysis, and she did not require further transfusions until she commenced chemotherapy. by the start of maintenance she had received many more prbc transfusions than the average patient. intermittent drops in hemoglobin (hb) did not correlate with any particular agent, and she had stable, mild splenomegaly. a clear pattern emerged during maintenance. her hb was - g/dl at monthly clinic visits, when she received vcr, intermittent intrathecal methotrexate, and corticosteroids. within - days, her hb dropped to . ± . g/dl, and reticulocyte count decreased from . to . ± . %. transfusion at day corrected hb, and the reticulocytes and hb returned to baseline. white blood cell and platelet counts did not change after vcr. blood samples from pre, immediately post, and days post vcr were analyzed and rbc characteristics and markers of hemolysis were not significantly different. ektacytometry showed identical curves, indicating no change in rbc deformability. in vitro incubation of patient blood samples with vcr also did not affect the osmotic deformability, confirming that a change in rbc rigidity was unlikely the reason for the drop in hb. these data indicate that a dysregulation of erythropoiesis was responsible for the anemia after vcr, rather than damage of peripheral rbc's. in most patients, maintenance therapy for lymphoblastic lymphoma does not cause severe anemia, likely because a temporary reduction in erythropoiesis in patients with a normal rbc survival and low reticulocyte count is not noticed. however, in a patient with decreased rbc survival and a brisk reticulocytosis, a disruption in rbc generation is more apparent. in conclusion, vcr administration to patients with an rbc disorder warrants close observation for potentially severe vcr-induced anemia. background: the addition of tyrosine kinase inhibitors (tki) to conventional chemotherapy has improved outcomes for pediatric patients with philadelphia chromosome-positive (ph+) acute lymphoblastic leukemia (all), however there remains an increased risk of relapse compared to other types of childhood all. typically, in relapsed disease the philadelphia chromosome persists and several mechanisms of resistance involving acquired mutations of the bcr-abl chimeric oncoprotein have been reported. objectives: describe a unique case of a pediatric patient with ph+ b-precursor all relapsing with b-precursor all without the philadelphia chromosome. results: an -year-old boy was diagnosed with ph+ bprecursor all with the presence of the t( ; )/bcr-abl translocation by cytogenetics and fluorescence in situ hybridization (fish), respectively. additional abnormalities included gains of runx and loss of one copy of etv . a remission bone marrow with negative minimal residual disease (mrd) was achieved at the end of induction with dasatinib and the esphall chemotherapy backbone. duration of tki therapy was two years post diagnosis. nearly one year after the completion of therapy, cytopenias prompted a bone marrow investigation. relapsed b-precursor all was established by immunophenotyping, however fish analysis did not identify the bcr-abl rearrangement. moreover, quantitative reverse transcriptase pcr was negative for the bcr-abl fusion transcript. again fish analysis of the bone marrow revealed multiple additional copies of runx and mono-allelic loss of etv , similar to the initial diagnostic sample. the patient was re-induced per aall anticipating a ph+ all relapse. however, with confirmation of the loss of the ph+ clone, tki therapy was not re-initiated. due to positive mrd of . % at the end of re-induction therapy, the patient was salvaged with blinatumomab therapy and subsequently underwent an allogenic stem cell transplant with a sibling donor. conclusion: this is the first known report of a pediatric patient with ph+ b-precursor all who developed recurrent b-precursor all without the philadelphia chromosome. the persistent findings of gain of runx and loss of etv makes it unlikely that a second unrelated b-precursor all developed following successful treatment of the original disease. this case highlights the possibility of a genetically distinct subclone present at the onset of disease that shared abnormalities of runx and etv but did not contain the philadelphia chromosome. nevertheless, the subclone harbored leukemogenic potential in the absence bcr-abl expression. it is plausible that the predominant clone present at diagnosis was effectively treated with dasatinib and extinguished, but the bcr-abl -negative clone persisted in the face of tki therapy. background: ligneous conjunctivitis is a rare form of pseudomembranous conjunctivitis that develops specifically in patients with type plasminogen deficiency. lack of plasmin activity in those patients result in defective fibrinolysis and formation of fibrin-rich membranous material/ masses that develops on the palpebral conjunctiva as well as other sites in the body.current management involve surgical excision of the masses that is usually complicated by multiple recurrences. recently, use of topical plasminogen concentrates helped delaying recurrence, but currently, those concentrates are not commercially available. we report on a -year-old omani girl, with hypoplasminogenemia who required optimization of plasminogen level at the time of surgery to delay/ prevent recurrence. objectives: case report on the peri-operative use of ffp versus cryopricipitate transfusion as an alternative replacement of plasminogen during surgical excision of ligneous conjunctivitis. design/method: pharmacokinetic study was performed to assess plasminogen recovery after ffp ( ml/kg) and precipitate ( bag/ kg) transfusion results: plasminogen levels remained subnormal after either ffp or cryoprecipitate administration. with ffp, the maximum concentration reached was almost % of normal. although half-life of plasminogen is known to be - . days, the patient seemed to have a high catabolic rate after receiv-ing cryoprecipitate, with plasminogen levels reaching basal levels within hours. because of the better recovery profile with ffp, we opted to give ffp before and after surgery. peri-operative management included ffp transfusion at ml/kg/ hours one day before and for days post operatively, followed by ml/kg once daily from day - , then ml/kg on th post-operative day. topical treatment was initiated using antibiotic and steroids ed on the day of surgery, followed by heparin ed on the second day. on follow up, she used topical heparin, cyclosporine, prednisolone, and topical lubricant eye drops for variable duration. clinical picture remained stable for almost year post operatively, when she started to develop recurrence of ligneous lesions again. background: ponatinib (inclusig®, ariad pharmaceutical) is a rd generation multi-targeted tyrosine kinase inhibitor (tki) approved for treatment of adults with chronic myeloid leukemia (cml) and philadelphia chromosomepositive acute lymphoblastic leukemia (ph+ all) resistant to or intolerant of other tkis. ponatinib has numerous drug-drug interactions and a black box warning for associated serious adverse vascular events and hepatotoxicity. for this reason, ponatinib use has been confined to specific high-risk populations. however, in patients who prove refractory to other therapies, the potential benefits of ponatinib may outweigh risks. to date, ponatinib has not been studied in the pediatric/adolescent and young adult (aya) population. furthermore, literature describing the use of ponatinib alone or in combination with other agents in pediatric oncology patients is scarce. objectives: to describe a single institutional experience using ponatinib in the pediatric patients with ph+ all. design/method: two cases of ponatinib use in pediatric ph+ patients resistant to other tkis were identified at our institution and are described. peripheral blood samples obtained from both patients identified bcr-abl p fusion transcripts and sanger sequencing was used to identify resistant mutations. results: our first case is a -year-old female who received upfront multi-agent chemotherapy plus dasatinib for ph+ all. relapse was confirmed on end-of-therapy bone marrow evaluation, thus bcr-abl mutation testing was performed and revealed a t i mutation. ponatinib was initiated then discontinued after one week due to clinically significant fluid retention with peripheral edema and bilateral pleural/pericardial effusions. the second case is a lateadolescent female with ph+ all who relapsed -years after stem cell transplant (sct). following relapse, tki therapy included both imatinib and dasatinib. due to persistence of bcr-abl fusion transcript despite tki therapy she was switched to ponatinib. shortly following initiation of ponatinib she developed a diffuse, maculopapular rash, which persisted despite dose reduction, resulting in ultimate discontinuation of the drug. bcr-abl mutation testing identified f l and f v resistance-conferring mutations. to date, there is scant existing literature detailing the use of ponatinib in pediatric patients. appropriate dosing is undefined and side effect profile not well described, particularly when used concurrently with other chemotherapeutic agents. thus, this case series reporting the response to and toxicity of ponatinib in pediatric ph+ all patients has important clinical implications. additionally, this is the first report of a pediatric ph+ all patient with documented t i mutation underscoring the importance of bcr-abl mutational testing, particularly at the time of relapse. cooper university hospital, camden, new jersey, united states background: myh -related disorder is a rare autosomal dominant disease, encompassing several subtypes: may hegglin anomaly, epstein syndrome, fechtner's syndrome, and sebastian syndrome. heterozygous mutations are seen in the gene encoding non-muscle myosin heavy chain iia (nmmhc-iia) which is involved in cell motility as well as functions to maintain cellular shape and integrity. the presentation of myh -rd is mainly characterized by macrothrombocytopenia, but various related expressions exist: nephritis often leading to renal failure, cataracts and sensorineural deafness ( ). a -year-old girl with history of extensive dental caries, hyperactivity, and speech delay due to suspected hearing loss was incidentally found to have thrombocytopenia at the time of genetic evaluation. she did not have any bruising or excessive bleeding. she did not respond to observation, immunoglobulins, or steroid therapy. her platelet count remained persistently low ( - k/ul). she underwent extensive evaluation to rule out platelet disorder vs. coagulation defect. her peripheral smear showed enlarged platelets by giemsa stain but no inclusion bodies were noted in granulocytes. her platelet aggregation and platelet surface glycoprotein by flow cytometry were negative. her coagulation profile was also normal. objectives: this case report summarizes the complexity in diagnosing myh -rd in a pediatric patient. design/method: since a unifying diagnosis for her clinical presentation was not apparent, whole exome sequencing (wes) was undertaken. results: wes revealed the r c heterozygous pathogenic variant, located in exon in the myh gene. myh gene alteration explained the patient's clinical features of macrothrombocytopenia and hearing loss. this mutation was paternally inherited, and her father demonstrates mosaicism. he was asymptomatic with normal platelet count but his morphology showed enlarged platelets with no inclusion bodies in granulocytes. when dealing with patients who have mild or no symptoms of bleeding diathesis but evidence of persistent macrothrombocytopenia, considering a platelet disorder belonging to myh -rd can help delineate certain predisposing syndromes and guide clinical management. patients are likely to benefit from early genetic testing while receiving supportive therapy. wes can highlight syndromes and provide information on recurrence risk for families. the renal and hearing abnormalities are indistinguishable between epstein and fechtner's syndromes, but the pathogenic variants differ ( ). the genotype-phenotype correlation implies that our patient may have either syndrome, although clinical features compatible with nephritis have yet to manifest. patients should be monitored closely for long-term progression of myh disease, and treatments should be initiated accordingly. we present an -year old female evaluated by genetics at birth due to prenatal microcephaly. chromosomes and microarray were normal. at age she developed standard risk pre-b-cell acute lymphoblastic leukemia (all). she completed treatment in and has been doing well in the interim, remaining in complete clinical remission. during and after treatment she exhibited developmental delay and neurocognitive deficits. at age her height and weight were at or below the th centile and head circumference was below the nd centile (approximately standard deviations below the mean and corresponding to the th centile for a -month-old girl). bone age was appropriate. she had a distinctive triangular face with micrognathia and a pointed nose resembling a seckel-like syndrome. the patient also had clinodactyly of the th toes, zygodactylous triradius involving the nd and rd left toes, tendency to sydney line in the right palm and a radial loop in the left middle finger. the patient's unique clinical presentation prompted a more thorough genetic evaluation, which led to a novel finding we feel is clinically significant with regard to the development of malignancy. design/method: whole exome sequencing (wes) was performed on the patient as well as her biological parents (trio). a de novo heterozygous mutation in the gene pcdh with potential relation to the phenotype was discovered. this c. dupa variant causes a frameshift starting with codon asparagine , changing this amino acid to a lysine residue and creating a premature stop codon at position of the new reading frame denoted p.asn lysfsx . this variant is predicted to cause loss of normal protein function via protein truncation or nonsense-mediated mrna decay. conclusion: pcdh is a member of the protocadherins family which is important in cell-to-cell adhesion and synaptic function in the central nervous system and is highly expressed in areas of the brain involved in higher cortical function and speech. aberrant expression of protocadherins has been associated with the development of malignancies in many organ systems. with regards to leukemia, the methylation status of this gene at diagnosis has been implicated in the prognosis of all and could be used as a biomarker to predict relapse. this patient's de novo mutation and clinical presentation are unique to what has been previously presented in the literature. we feel that this mutation is a clinically significant finding that may shed light on the role of this gene in the development of hematopoeitic malignancies. background: acquired hemophilia a (aha) is an uncommon and potentially life-threatening hemorrhagic disease characterized by sudden onset of bleeding in patients with neither personal nor family history of bleeding dyscrasia. it is usually seen in adults with autoimmune diseases, solid tumors, lymphoproliferative diseases, pregnancy or during the postpartum period; occurrence in the pediatric population has rarely been reported. we report a case of an otherwise healthy teenager who was found to have aha when he presented with acute onset of atraumatic soft tissue hematoma. results: a -year old male of middle eastern descent with history of congenital absence of the right external ear, but otherwise in good general health, presented to our emergency department with a three day history of progressive worsening of right lower leg pain, swelling, and paresthesia, without preceding history of trauma. evaluation by the pediatric orthopedics service documented significantly elevated compartment pressures, necessitating immediate four-compartment fasciotomy. pre-operative labs were significant for prolonged activated partial thromboplastin time (aptt) of . ( . - . ) seconds with normal prothrombin time (pt) and international normalized ratio (inr). ptt did not correct on mixing studies, suggesting the presence of a circulating anticoagulant. factors xii and xi were in the normal range; factor ix was elevated, ( - ). factor viii level was % and fviii inhibitor level was . bethesda units (< . ), confirming the diagnosis of aha. work up for autoimmune disease was negative. his bleeding and surgical hemostasis were managed with recombinant factor vii (novoseven) mcg/kg every hours for hours post operatively, with gradual interval prolongation. factor viii antibody eradication was managed with prednisone mg/kg/day. factor viii and inhibitor levels normalized by day of hospitalization. recombinant factor vii was discontinued; steroids were gradually tapered and discontinued at discharge (hospital day ). conclusion: acquired hemophilia is likely an underdiagnosed condition in pediatrics. while it is typically seen in adults with underlying autoimmune disease, solid tumors, lymphoproliferative disease, or during pregnancy or the postpartum period, pediatric cases may have no identifiable etiology. this case highlights the importance of considering this diagnosis in any patient with unexplained bleeding regardless of their age, so as to intervene early and prevent adverse consequences. university of oklahoma, oklahoma city, oklahoma, united states background: myeloid neoplasms associated with eosinophilia is a rare subtype of chronic leukemia characterized by clonal eosinophilia. the true incidence is unknown due to its rarity and possible classification as idiopathic hypereosinophilia syndrome. the most common chromosomal aberrations involve platelet-derived growth factor receptors (pdgfrs). we report one such rare case in a pediatric patient. most of the pediatric management of this entity is derived from adult case reports and case series. objectives: to describe a case of chronic leukemia presenting as eosinophilia results: a previously healthy year old caucasian male presented with a several week history of migrating joint pain, splenomegaly, and abnormal blood counts with leukocytosis, thrombocytopenia and absolute eosinophilia. white blood cell differential showed myeloid precursors suggestive of chronic myeloid leukemia. bone marrow evaluation showed % blasts and % eosinophils. bcr-abl testing was negative, ruling out cml. fish analysis for eosinophilic clonality revealed deletion of chic gene, resulting in fip l /pdgfra fusion gene, diagnostic for myeloid neoplasm with eosinophilia associated with pdgfr abnormalities. treatment was started with tyrosine kinase inhibitor (tki), imatinib mg daily. within months, fish analysis for fusion gene was negative. after approximately months of daily imatinib, he was switched to maintenance dose of mg weekly. he is approximately months since diagnosis and doing well on maintenance imatinib. in , the who revised its classification of some chronic eosinophilic leukemias to myeloid and lymphoid neoplasms associated with eosinophilia and rearrangement of pdgfra, pdgfrb, fgfr . the most common abnormality is the fip l /pdgfra fusion gene. other less common abnormalities include fusion genes kif b-pdgfra and etv -pdgfrb and point mutations in pdgfra . some features of chronic eosinophilic leukemia include absolute eosinophilia, splenomegaly, elevated vitamin b and tryptase levels, and organ damage from eosinophil infiltrates and cytokine release. patients with rearrangements or mutations involving pdgfra are usually very responsive to imatinib. starting doses have not been well studied or established. experts recommend co-administration of corticosteroids during the first few days of imatinib therapy in patients with a history of cardiac involvement and/or elevated serum troponin levels to prevent myocardial necrosis, a rare complication of imatinib therapy in eosinophilic patients. fortunately our patient did not have cardiac involvement and to date has not exhibited signs of chronic tki toxicity. conclusion: myeloid neoplasms with eosinophilia constitute a rare form of chronic leukemias. they are often associated with pdgfr abnormalities and are usually very responsive to tyrosine kinase inhibitor therapy. walter reed national military medical center, bethesda, maryland, united states background: germline samd l mutation is a rare cause of constitutional bone marrow failure with a unique propensity for clonal evolution to monosomy and mds. objectives: previous case series have demonstrated diverse clinical outcomes in patients with a germline samd l mutation. our case presents a novel samd l mutation (p.val leu). additionally, the case highlights the challenges in clinical decision making for a patient with a gene mutation that is known for clonal evolution towards monosomy with risk of progression to myeloid malignancy, but also known for self-correction through uniparental disomy or inactivating mutations which results in disease remission. design/method: a retrospective chart review and review of the literature was performed. dna was isolated from peripheral blood and used for whole exome sequencing. a peripheral blood sample from the patient's mother and father showed no samd l mutation. skin biopsies of the patient and parents were evaluated for uniparental disomy or new mutations. to determine the pathogenicity of this novel mutation, the specific samd l mutant dna was transfected into the human embryonic kidney cell line to assess its role in inhibiting cell proliferation. our patient presented at months of age with pancytopenia and hypocellular bone marrow in the setting of s of s sepsis. he had evidence of dysfunctional immune activation with hemophagocytosis and elevated soluble il with simultaneous severe hypogammaglobulinemia. analysis of the peripheral blood showed no increase in chromosomal breakage, normal telomere length, and normal flow cytometry. gene testing for primary hemophagocytic lymphohistiocytosis and inherited bone marrow failure were negative. after the patient recovered from his presenting illness, a repeat bone marrow biopsy demonstrated improved cellularity with myelodysplasia and cytogenetics significant for monsomy .whole exome testing demonstrated a novel samd l mutation. the patient continued to require intermittent ivig and failed to demonstrate appropriate leukocytosis with intermittent infections. on repeat bone marrow evaluation over the course of months, the patient demonstrated no evidence of evolution towards self-correction and had a persistent monosomy clone. the patient is scheduled to undergo a matched unrelated donor bone marrow transplant. our case highlights the unique clinical picture associated with constitutional marrow failure and clonal evolution secondary to a novel samd l mutation which is thought to cause pancytopenia by inhibiting cellular proliferation and often results in the development of monosomy which rescues hematopoiesis but with a risk for malignancy. background: notable labs developed a flow cytometricbased assay with a custom robotic platform to test fdaapproved drugs for anti-cancer activity against individual patient's tumor cells. this personalized assay is a potential method for identifying novel agents and drug combinations to treat aml patients who have failed standard therapies. objectives: to present the case of a teen who underwent successful treatment of relapsed aml post-sct with bortezomib, panobinostat, and dexamethasone-a regimen selected based upon results of notable lab testing. results: a -year-old male with m -aml had an isolated bone marrow relapse months after completion of scheduled therapy. at relapse, his aml was flt -itd positive. he achieved a second remission with negative mrd and underwent matched sibling donor bmt after busulfan/cyclophosphamide conditioning. bma performed on day + was mrd positive ( . %). repeat bma done on day + showed . % mrd. he started sorafenib on day + . he received donor lymphocyte infusion (dli) on day + , then received cycles of azacitadine (aza) followed by dli. marrow mrd by flow after sorafenib alone, sorafenib with dli, and sorafenib with aza/dli were %, . %, and . %, respectively. treatment was complicated by varicella meningitis, grade i skin agvhd, febrile neutropenia and c. difficile colitis, and metapneumovirus pneumonia. despite extremely low levels of leukemia (marrow mrd . %), notable lab testing performed on the patient's leukemia cells from marrow collected after aza/dli/sorafenib revealed sensitivity of his leukemic blasts to a combination of bortezomib, panobinostat, and dexamethasone. because of prolonged cytopenias, multiple infectious complications, and persistently positive mrd, he discontinued aza/dli/sorafenib and on day + started bortezomib . mg/m iv on days , , , and ; panobinostat mg po on days , , , , , ; and dexamethasone mg po on days , , , , , , , and . chemotherapy cycle started days later. he tolerated treatment without side effects and with resolution of rash and cytopenias. he achieved full donor chimerism, negative flt -itd, and complete remission by morphology and flow after two cycles. notable lab testing is a powerful tool for evaluating the sensitivity of small populations of leukemic blasts to novel drug therapy. results from notable lab testing may serve as a useful guide for treatment selection after failure of standard aml therapy. this patient achieved morphologic and mrd remission post-sct with bortezomib, panobinostat, and dexamethasone-a regimen predicted to be efficacious based upon notable lab results. maria ahmad-nabi, christine knoll, sanjay shah, esteban gomez, lori wagner phoenix children's hospital, phoenix, arizona, united states background: development of inhibitors in patients with factor ix deficiency (fixd) is a well-recognized complication occurring in - % of patients. within this subset a small percentage can develop anaphylaxis to factor. desensitization with cyclophosphamide, an alkylating agent used in the management of various oncologic malignancies, and reported for use in factor viii desensitization has been previously unreported for use in desensitization in patients with fixd. rituximab, an anti-cd antibody, however has been used. objectives: to induce immune tolerance (it) in patients with inhibitors to factor ix with either novel or under reported methods using cyclophosphamide and/or rituximab. we report a case series of patients at phoenix children's hospital with fixd who achieved it with cyclophosphamide and/or rituximab. results: patient one was a year old male with severe fixd, who at the time of desensitization had inhibitor levels of bu. he was desensitized with cyclophosphamide, then admitted for infusion of recombinant factor ix. he experienced a few minor symptoms of intolerance including an urticarial rash which was self-limited, and hemarthrosis of the right elbow on day which responded to novo . he tolerated the remainder of his infusion without issues. he continued recombinant factor ix daily, and returned to clinic for monthly cyclophosphamide for months. he did develop urticaria with hemarthrosis and spontaneous muscle bleeds which were tempered with zantac, zyrtec, solumedrol, and benadryl. he remained without a recurrence of inhibitors, however did have intermittent hemarthrosis of his ankles thereafter requiring prophylactic twice daily dosing recombinant factor ix. patient two was a year old male with severe fixd and a family history of anaphylaxis to factor causing early death in all male relatives with the disease. he had never received factor ix and did not have a detectable inhibitor prior to desensitization. he successfully underwent desensitization to recombinant factor ix with rituximab in the icu, and returned to clinic for weekly infusions x . he experienced no adverse reactions concerning for anaphylaxis. he continued to tolerate factor ix products without evidence of intolerance, development of inhibitors, and continues on as prophylactic dosing of recombinant factor ix every other day. our experience at a single institution proves cyclophosphamide as a novel agent for inducing it in those with fixd and anaphylaxis. it also provides further evidence that rituximab can desensitize patients with severe fixd. differences include longer duration for cyclophosphamide therapy ( months vs month). background: cartilage-hair hypoplasia (chh) is an autosomal recessive chondrodysplasia associated with defective cell-mediated immunity caused by mutations in the ribonuclease mitochondrial rna processing (rmrp) gene. cancer incidence is -fold higher in patients with chh than in the general population, especially non-hodgkin lymphoma. the use of rituximab, an anti cd antibody, results in decreased host b-cell number and impaired humoral function for - months. the safety of rituximab in pediatric patients with cancer and immunodeficiency is not well documented. a diagnosis of underlying immunodeficiency may discourage physicians from using rituximab due to the risk of severe bacterial infection or viral re-activation. objectives: to report a case of burkitt lymphoma in a young adult female with chh and defective cellular immunity successfully treated with rituximab. results: an -year old amish female with disproportionate short stature presented to our center for management of stage iv biopsy proven burkitt lymphoma with myc rearrangement. she had presented a week earlier with cervical, occipital, and submandibular lymphadenopathy, splenomegaly; fevers, night sweats, and weight loss for - weeks. on exam, her height was three feet associated with brachydactyly, mild bowing of the legs, normal size head without frontal bossing, fine and sparse hair. she had normal intelligence. her pattern of dysmorphisms was suggestive of chh (genetic testing not performed at time of diagnosis). pet-ct scan showed stage iv disease with involvement of cervical lymph nodes, spleen, iliac bone and bone marrow. treatment with standardintensity fab/lmb therapy (group c) with the addition of rituximab was initiated. she had an incomplete response to cop (∼ % reduction of tumoral masses) but achieved complete remission after copadam . her course was complicated with severe varicella zoster but she completed therapy and remains in complete disease remission for months after treatment completion. genetic testing subsequently performed proved homozygosity for chh with a n. a>g variant. she had no other opportunistic infections during or after therapy. conclusion: the use of rituximab was both safe and beneficial in our patient despite defective cell mediated immunity secondary to chh suggesting that rituximab may be safe to use in patients with cellular immune deficiencies. background: hemophilia a and b are bleeding disorders characterized by deficiency in factor viii or ix, respectively. spontaneous or provoked hemarthrosis is a known complication of hemophilia. repetitive episodes of hemarthrosis can lead to debilitating hemophilic arthropathy. lyme disease is a tick-born infection which is endemic to increasing parts of the united states. chronic lyme disease, the phase in which lyme arthritis typically develops, occurs months to years after initial infection and is characterized by swelling of one or more large joints generally in the absence of systemic symptoms. objectives: review cases of hemophilia a and b patients with episodes of provoked hemarthrosis refractory to intensive recombinant factor replacement therapy found to have concurrent lyme arthritis. design/method: we report two clinical cases and review relevant literature. results: first, we report a year-old male with moderate hemophilia a with a provoked knee hemarthrosis which failed to improve despite months of intense factor replacement therapy requiring multiple hospitalizations. factor replacement regimens included twice daily standard half-life recombinant factor viii products or daily to every other day extended half-life recombinant factor viii products with trough levels aimed as high as - %. factor viii pk studies were obtained for dosing, to confirm adherence, and to evaluate for subclinical inhibitors (inhibitor testing was negative). given protracted symptoms additional workup for hemarthrosis was pursed. lyme titers were positive for ( )igg, though negative for igm. he was treated with days of doxycycline during which time hemarthrosis greatly improved on examination and imaging, and he was able to recover function through physical therapy. second, we report a year-old male with moderate hemophilia b who required multiple hospital admissions for a provoked knee hemarthro-sis with no improvement in symptoms despite weeks of daily or twice daily factor replacement with standard halflife recombinant factor ix products aiming for % correction. we performed inhibitor testing (which was negative) and pk studies to assess for non-detectable inhibitors, dosing and adherence. lyme testing was positive for ( )igg, though negative for igm. he was treated with amoxicillin for days during which time hemarthrosis significantly improved on examination and imaging. diagnosis and follow-up imaging studies for both patients included mri and serial bedside ultrasounds performed as per uc san diego school of medicine mskus guidelines. background: relapse/refractory aml following allogeneic hematopoietic stem cell transplant (hsct) holds a high mortality rate. current relapse/refractory therapy modalities for younger patients may include re-induction with a clofarabinebased regimen followed by second allogeneic hsct. even for patients who undergo second hsct, the five-year survival rate is dismal. new therapies, including small molecule inhibitors, are being studied in the post-hsct relapse setting or those unfit for hsct with promising results. venetoclax is a small molecule inhibitor that has received breakthrough designation for aml treatment in elderly patients objectives: to report a young adult aml patient with relapse post hsct who was successfully re-induced with topotecan, vinorelbine, thiotepa, clofarabine (tvtc) and has sustained remission with venetoclax maintenance therapy. this approach appears to be unique in terms of reported literature. results: our patient is now a -year-old female noted to have mll rearranged aml at initial diagnosis when she was years old. she underwent chemotherapy consisting of cytarabine/daunorubicin according to standard + . due to persistent disease, she was re-induced with g-csf, clofarabine, and high-dose cytarabine (gclac) which put her in cr. her course was complicated by sepsis, colitis, gastrointestinal bleed, deep venous thrombosis, and transfusionassociated circulatory overload. given her co-morbidities, she received another cycle of clofarabine/cytarabine, and then proceeded to reduced intensity allogeneic hsct, according to bmt ctn . the patient tolerated hsct well and experienced no transplant-related complications, including no acute or chronic gvhd. unfortunately, she relapsed about month's post-hsct. initial salvage therapy consisted of another course of g-clac, but due to persistent disease the decision was made to re-induce her with topotecan, vinorelbine, thiotepa, and clofarabine (tvtc). during this time however, she was found to have extensive infection with a fusarium species requiring a course of anti-fungal therapy. bone marrow evaluation showed no residual disease with an mrd of < . %. once the absolute neutrophil count recovered, the patient was started on single-agent venetoclax for maintenance therapy, which has been well-tolerated. she remains in morphologic remission for over months. we describe herein a young adult with multiply relapsed aml wherein tvtc re-induction, followed by maintenance with venetoclax were safely used in the post-hsct setting. venetoclax therapy in the relapsed aml setting warrants further study. background: vitamin b deficiency is uncommon in children in developed countries, especially in the absence of risk factors like malabsorption or inadequate dietary intake. it often presents with non-specific symptoms and signs and can elude diagnosis. the recognition and treatment of vitamin b deficiency is critical as it can lead to bone marrow failure as well as severe neurological and developmental problems in children. to increase index of suspicion of vitamin b deficiency anemia in children. we report a rare case of vita-min b deficiency anemia in a child who presented with a severe macrocytic anemia, with signs of hemolysis and concern of malignancy. design/method: an almost three-year-old previously healthy girl presented with a few day history of fever, emesis, fatigue and pallor. she had no dysmorphic features, hepatosplenomegaly or lymphadenopathy on exam, growth and development were normal. laboratory findings showed severe macrocytic anemia (hemoglobin . grams/dl; mcv . fl) with reticulocytopenia. signs of intravascular hemolysis were present with elevated lactate dehydrogenase ( , units/l) and haptoglobin below assay limit. immune-mediated hemolysis was ruled out. initial picture of a hemolytic anemia was compounded by other findings of moderate neutropenia, mild thrombocytopenia and peripheral smear showing occasional blasts. further workup was done with a broad differential diagnosis that included leukemias, hemolytic anemias, bone marrow failure syndromes, and specific deficiencies. results: workup revealed abnormally low vitamin b levels along with significantly elevated homocysteine and methylmalonic acid levels indicating functional vitamin b deficiency. bone marrow evaluation showed megaloblastic anemia and dyserythropoiesis consistent with vitamin b deficiency, and ruled out leukemia. vitamin b deficiency can cause a hemolytic anemia like picture secondary to intramedullary hemolysis due to ineffective erythropoiesis. myeloid precursors are also affected which can lead to neutropenia, thrombocytopenia, and abnormal peripheral blood cells. in our patient, initial symptomatic anemia was treated with blood transfusion, followed by intramuscular vitamin b injections with normalizing lab values. so far, workup for an etiology for vitamin b deficiency is negative except for an equivocal range of anti-parietal cell antibodies raising concerns for pernicious anemia; however it is rare in this age group. another rare condition is an inborn error of the cobalamin transporter. she is currently on oral vitamin b supplementation and further workup will be planned based on response. conclusion: this case highlights the importance of early consideration and thorough evaluation of vitamin b deficiency in children with unclear etiology of anemia, so that prompt treatment can be initiated. memorial hospital/ university of miami, miami, florida, united states background: despite great success in the treatment of acute lymphoblastic leukemia (all), the outcomes for patients with relapsed all remain poor. prognostic indicators include timing and site of relapse. blinatumomab, is the first agent in its class that simultaneously binds cd -positive cytotoxic t cells to cd -positive b cells resulting in lysis of malignant cells. however, mechanisms of leukemia resistance to blinatumomab are unclear. objectives: to describe a case with multiple sites of extramedullary (em) relapse during blinatumomab therapy. results: a -year-old hispanic male with philadelphia positive, cd -positive b-precursor cell all refractory to chemotherapy, had failed a bone marrow (bm) and was placed on blinatumomab and imatinib. he achieved minimal residual disease (mrd)-negative systemic remission, but during his fifth cycle developed bilateral periorbital masses. biopsies confirmed cd -negative isolated em relapsed disease, which was treated with radiation therapy (rt). there was notable resolution of em disease and he continued systemic therapy. subsequently, he presented with a painful left scapular swelling. imaging showed muscle and lung parenchymal em relapse with cd -positivity confirmed on histology. he continued on blinatumomab with localized rt while awaiting car-t cell therapy. his bm mrd remained negative until he developed systemic mrd-positivity with cd -positive blasts following the sixth cycle. primary resistance to blinatumomab is poorly understood. it is proposed that expansion of cd -negative clones or downregulation of cd following blinatumomab may play a role. this was observed in our patient's periorbital relapse; but subsequent em and systemic relapses were cd -positive, consistent with the co-existence of multiple clones in relapsed all. it has also been postulated that em relapse could be linked to the failure of blinatumomab or t cells to migrate to em sites of disease or drug inactivation by the microenvironment. the second em relapse in our patient, with cd -positive disease suggests this as a possible mechanism of relapse. this was reported in patients with cd positive non-hodgkin lymphoma (nhl), and higher doses of blinatumomab however, have shown promising results in this population. despite blinatumomab's effectiveness in inducing remissions in patients with refractory/relapsed all, it appears to have limitations in patients with em disease. these may arise either from the multiclonality associated with relapsed all or due to the emergence of resistance to blinatumomab, including failure to migrate to em sites. background: cyclic neutropenia is a rare hereditary disorder, characterized by recurrent neutropenia, cycling at about week intervals, with variable associated symptoms including oral ulcers and fever. there are reported cases of cyclic neutropenia associated with chronic inflammation leading to development of reactive aa amyloidosis. one patient also presented with amyloid goiter. we report a new case of cyclic neutropenia with associated renal and thyroid amyloid. design/method: a -year-old female presented with a month history of thyromegaly, and recurrent aphthous ulcers associated with fevers. laboratory workup showed severe neutropenia, anemia, azotemia, and abnormal thyroid function, with an absolute neutrophil count - / l, hemoglobin - . g/dl, serum creatinine - . mg/dl, and uric acid - . mg/dl. thyroid stimulating hormone was elevated - . iu/ml, and normal free t . urinalysis showed + protein, + blood, and - urine red blood cells/hpf. chest radiograph showed mild narrowing of the trachea from thyroid compression. bone marrow biopsy showed a hypocellular marrow, with tri-lineage hematopoiesis, left shifted myeloid maturation with very rare mature neutrophils. both renal biopsy and thyroid fine needle aspiration revealed abundant amyloid. of note, her father had aa amyloidosis, resulting in end-stage renal disease (esrd) requiring hemodialysis, and recurrent aphthous ulcers. the family history suggested a familial predisposition. genetic testing revealed a pathogenic elane c. a>t gene mutation with autosomal dominant inheritance confirming the diagnosis of cyclic neutropenia. we treated our patient with daily granulocyte colony stimulating factor to reduce the burden of chronic inflammation induced by cyclic neutropenia, and to preserve renal and other end organ function affected by further amyloid deposition. results: proband with elane gene mutation positive cyclic neutropenia, amyloidosis of thyroid and kidney, with a positive paternal history of aa amyloidosis resulting in esrd. cyclic neutropenia may result in chronic inflammatory states leading to secondary amyloidosis. university of kentucky, lexington, kentucky, united states background: overall survival of burkitt lymphoma (bl), regardless of stage, is greater than % in the pediatric population when treated with multi-agent chemotherapy. adenovirus is a common, usually self-limited infection within the pediatric population; however, findings can vary within an immunocompromised host. hepatitis is a rare complication, with very few reports of radiologic findings in this patient population. we discuss a three year old male with history of bl who presented with clinical and radiographic evidence of relapse but was found to have adenovirus hepatitis. design/method: a case report of a patient with bl in complete remission after completion of standard of care chemotherapy, who presented with return of high fever, elevated ldh, transaminitis and hepatic lesions. we describe the hepatic imaging and pathology consistent with adenovirus hepatitis in this immunocompromised host. our patient presented at three years old with a six week history of worsening abdominal pain and fevers. he was found to have a right sided pleural effusion, multiple lesions of the liver, and diffuse abdominal lymphadenopathy; biopsy of lymph tissue was consistent with bl. he completed therapy per anhl arm b and was in a complete remission at the end of planned therapy. one month after completion of therapy, he returned with high fever, abdominal pain and transaminitis, similar to his initial presentation. ct scan showed multiple hypodense discrete lesions throughout the liver and re-accumulation of right sided pleural effusion. ldh peaked at u/l (uln u/l). uric acid remained within normal limits. bilirubin peaked at . mg/dl, conjugated . mg/dl. liver biopsy was performed, showing smudgy nuclei with immunohistochemical staining positive for adenovirus. there was no evidence of lymphomatous involvement. resolution of hepatic lesions and transaminitis, with normalization of ldh and fever, occurred with symptomatic treatment alone. adenovirus is known to cause systemic disease in immunocompromised patients and rarely hepatitis. no pediatric patients with discrete hepatic lesions secondary to adenovirus have been reported in the literature. three cases of discrete hepatic lesions have been reported in adult immunocompromised patients, two with fatal fulminant liver failure and one who required cidofovir. this case demonstrates that a common pediatric viral infection can present with lesions concerning for metastatic disease in a pediatric lymphoma patient. prompt diagnosis is vital in the management of these patients when recurrent lymphoma is in the differential. background: heparin induced thrombocytopenia (hit) is an immunologic process in which antibodies bind a heparin complex and cause a paradoxical hypercoagulable state. ramifications of this process may include a multitude of thrombotic events and bleeding complications secondary to platelet consumption. in our patient, hit manifested as increased bruising, an acute decrease in platelet count, and continual clotting of her crrt circuit. hit, although rare in pediatrics, should be included in the differential for children with thrombocytopenia who have received heparin products. to present a unique case report of a critically ill pediatric patient who developed hit in the presence of multiorgan system failure and to discuss the challenges encountered with identification of an alternative anti-coagulant. results: a yo obese, caucasian female child presented to our facility with bilateral pulmonary emboli (of unclear etiology). initially, she was started on a continuous heparin infusion, but was transitioned to enoxaparin within days without issue. five days after enoxaparin was initiated, the patient developed acute kidney injury (evidenced by increasing creatinine) attributable to her biventricular heart failure. due to her need for continuous renal replacement therapy (crrt), she was transitioned back to a continuous heparin infusion. whereas her initial platelet count on transition was normal, she developed severe thrombocytopenia ( , ul) within hours. due to intermediate risk but low suspicion for hit, pf antibodies were sent which were positive. after much discussion, she was transitioned to an argatroban infusion which was titrated according to ptt levels. within hours, her platelet count normalized. at discharge, she was prescribed apixaban for anti-coagulant management. conclusion: hit is an uncommon presentation in the pediatric population. given its rarity, there is often a delay in diagnosis which increases risk of complications such as bleeding, stroke, and limb ischemia. even if the diagnosis is suspected or proven, there may be challenges in initiating alternative agents as limited data exists on pediatric options. as argatroban remains the treatment of choice for patients with hit, experience in pediatric patients is limited, and dosing recommendations have been extrapolated from adult studies. anecdotal data exists for use of bivalirudin in children, although studies, primarily, focus on use in specific cardiac cases. in our patient's case, choice was further complicated by renal failure. this case study highlights the need for further research regarding the identification of a secondary anti-coagulant agent for use in pediatric patients with hit. background: subcutaneous panniculitis-like t-cell lymphoma (sptl) is a rare form of non-hodgkin's lymphoma characterized by infiltration of cytotoxic t-cells into subcutaneous tissue. sptl occurs in both adults and children and can present in both patient populations as either alpha/beta or gamma/delta subtypes. patients with the gamma-delta phenotype have an overall poorer survival, although the exact etiology is unclear. interestingly, both subtypes of sptl can present with secondary hemophagocytic lymphohistiocytosis (hlh), and this is associated with a worse prognosis. currently, there are no standardized treatment protocols for sptl, and clinical management includes watchful waiting, corticosteroids/immunosuppression, chemotherapy, and stem cell transplant. the primary objective was to compare how two patients with the same diagnosis responded acutely to therapy. we performed a retrospective chart review of two pediatric patients at our institution who were diagnosed with alpha/beta sptl and secondary hlh. we examined each presentation, treatment course, and outcome. we then completed a brief review of the current literature describing treatment of and outcomes for sptl with secondary hlh. results: these two patients presented in a similar manner with signs and symptoms of hlh. each was then subse-quently diagnosed with alpha/beta sptl after biopsy of cutaneous nodules and each had diffuse disease, as measured by pet. however, they demonstrated vastly different acute responses to therapy. one patient was pre-treated with systemic glucocorticoids before receiving definitive chemotherapy and tolerated therapy well as an outpatient. the other patient started systemic chemotherapy without steroid pretreatment and developed severe cytokine storm characterized by hypotension, cardiac dysfunction, multi-organ failure and cytokine elevation. both patients achieved complete remission (cr) after treatment with chop chemotherapy and remain disease-free - months off therapy. in patients presenting with sptl and secondary hlh, we propose that initial treatment with antiinflammatory or anti-cytokine therapy can decrease, or even prevent, the possibility of life threatening cytokine release as a result of cytotoxic chemotherapy. background: congenital dyserythropoietic anemia type ii (cda ii) is a rare autosomal recessive disorder, rarely presenting in the neonatal period. iron overload often occurs as a late sequela of ineffective erythropoiesis and intramedullary hemolysis. objectives: to report the novel use of iron chelation in an infant with cda ii associated with severe iron overload. the patient is a -month-old, former -week infant with prenatal non-immune hydrops and transfusion-dependent fetal anemia who presented with persistent anemia, reticulocytopenia, hyperbilirubinemia, liver dysfunction, and hyperferritinemia. his initial ferritin was . ng/ml, tibc ug/dl, and transferrin mg/dl. his bone marrow biopsy showed trilineage hematopoiesis and erythroid dyspoiesis characterized by binucleation of late-stage precursors. genetic testing revealed a compound heterozygous missense mutation and splice site mutation in the sec b gene, confirming the diagnosis of cda ii. initial liver biopsy revealed mild portal fibrous expansion, and abundant hepatic iron deposition. his ferritin continued to increase, peaking at , ng/ml, along with liver enzymes peaking at an alanine aminotransferase (alt) of u/l and aspartate aminotransferase (ast) of u/l. ferriscan showed an elevated estimated liver concentration of . mg/g dry tissue. repeat liver biopsy months later showed giant cell hepatitis with worsening mild portal fibrosis and hemosiderosis. additionally, tissue liver iron concentration was mcg/g dry weight. cardiac t * mri revealed mild cardiac iron deposition. given his significant degree of iron overload, deferoxamine was used to reduce hemosiderosis and liver morbidity in preparation for bone marrow transplantation. the patient received deferoxamine mg/kg/day iv x days/week for three months, without any clinically significant adverse events. blood counts and hepatic and renal function were monitored weekly without any abnormalities. growth parameters and liver enzymes significantly improved while receiving chelation therapy. as a noninvasive, cost-effective method, serum ferritin levels were monitored monthly to gauge response to treatment. despite receiving blood transfusions every - weeks, serum ferritin decreased to ng/ml and liver enzymes decreased to alt u/l and ast u/l prior to bone marrow transplantation. we report the use of deferoxamine in a patient with cda ii less than years of age, for treatment of iron overload. our patient tolerated deferoxamine well without significant adverse events or organ toxicity. deferoxamine may be a well-tolerated method of reducing iron burden in young patients with iron-loading pathologies. background: low grade gliomas with kiaa- -braf fusions typically have a favorable prognosis with infrequent rates of high grade transformation, low rates of metastasis and even lower rates of extra cns metastasis. while highgrade transformation has been reported for tumors with braf v e mutations and cdkn a deletions, it has not been pre-viously reported in gliomas with kiaa- -braf fusions. while there are case reports of high-grade cns malignancies metastasizing through a ventriculo-peritoneal (vp) shunt, low-grade gliomas metastasizing in this manner are extremely rare. objectives: to describe a unique case of peritoneal tumor dissemination of a braf fusion positive high grade neuroepithelial tumor in a child with a vp shunt placed for multifocal braf fusion positive low grade astrocytomas results: an eight-year-old male was initially diagnosed with multifocal low-grade astrocytomas of the hypothalamus and c -c spinal cord. initial testing revealed the kiaa- -braf fusion, but no cdkn a or braf v e mutation. initial surgical management included a vp shunt and resection of the cervical spinal lesion. he received vincristine and carboplatin, followed by transition to vinblastine given new thoracic metastatic lesions after months of therapy. at months after diagnosis, scans were concerning for diffuse leptomeningeal progressive disease and new intracranial lesions, necessitating craniospinal radiation. following a near cr, he presented months later with acute onset of abdominal pain. a ct scan revealed peri-renal and perirectal soft tissue masses, confirmed by exploratory laparotomy to be peritoneal tumor dissemination of high grade neuroepithelial tumor. a kiaa -braf fusion was noted and confirmed by rt-pcr, identical to that seen in the original cns tumors. additional findings included deletion of chromosome p (without q loss) and heterozygous and homozygous deletion of cdkn a found by fish. brisk mitotic activity justified a high-grade designation. salvage chemotherapy consisted of cycles of ice with subsequent resolution of pet-avid disease and only minimal peri-nephric tissue remaining. given the favorable response, surgical resection and multiple tissue biopsies were performed which documented no residual active disease. the shunt was revised and he started trametinib for maintenance. we present a unique case of peritoneal dissemination of high grade neuroepitheial tumors with the same kiaa- -braf fusion as multifocal low grade astrocytomas in a child with a vp shunt. this raises suspicion for tumor metastasis and transformation to a higher grade malignancy versus two distinct diseases, which may be indicative of an underlying cancer predisposition. texas children's hospital, houston, texas, united states background: polycythemia is a common referral to hematology. it is important to evaluate for a high oxygen affinity hemoglobinopathy, ensuring appropriate testing is performed for early diagnosis and avoidance of additional tests and procedures. a year old mexican female presented with an elevated hemoglobin and hematocrit, symptoms of plethora of her hands and feet, chest pain, palpitations, and fatigue. further confounding the picture, she also had significant menorrhagia and iron deficiency. she was diagnosed with the rare high oxygen affinity hemoglobin new mexico variant, only previously described once in the literature in a year old black boy. objectives: the patient initially presented at age with a hemoglobin of . g/dl and a hematocrit of . %. initial work up consisted of a hemoglobin electrophoresis which diagnosed sickle cell trait, a co-oximetry panel which was normal, and erythropoietin level of mu/ml, also normal. she was then lost to follow up and re-referred at age . she is a competitive basketball athlete, and at that time, she presented with a hemoglobin of . g/dl, and hematocrit of %. erythropoietin level continued to be normal at mu/ml. design/method: cardiology was consulted regarding chest pain and palpitations with a normal evaluation. chest x-ray was also normal. a bone marrow aspirate and biopsy was performed with results significant for mild erythroid hyperplasia and mild reticulin fibrosis. jak mutation, von hippel lindau, bpgm, and hereditary erythrocytosis mutations including phd , hif a, and epor mutation analysis were sent, all of which were normal. testing to mayo clinic for p rbc oxygen dissociation returned low at mmhg ( - mmhg normal range) and subsequently a hemoglobin electrophoresis identified a hemoglobin variant leading to beta globin gene sequencing. results: patient found to be heterozygous for hemoglobin new mexico, with . % hb new mexico and . % hba, and . % hba . there was no evidence of hbs. when evaluating patients with polycythemia, maintaining a high index of suspicion for high affinity hemoglobinopathies may eliminate further unnecessary and invasive testing for patients. caution should be used when using hemoglobin electrophoresis testing since hb new mexico is known to migrate similarly to hbs on hplc with minimal change that may not be detected in regular laboratories. most high affinity hemoglobinopathies are reported to not have significant symptoms. in this case, our patient complains of fatigue, occasional palpitations and plethora of hands and feet. we will need to further follow this patient for possible attributable symptomatology. divya keerthy, simone chang, warren alperstein, patricia delgado, claudia rojas, ofelia alvarez, matteo trucco university of miami jackson memorial hospital, miami, florida, united states background: improved technology is enabling detection of previously unidentified translocations and mutations in otherwise unclassified sarcomas. one such mutation is the bcl- co-repressor -internal tandem duplication (bcor-itd) allowing for the new classification of bcor positive undifferentiated round cell sarcomas (urcs). this sarcoma has a similar appearance to clear cell sarcoma of the kidney (ccsk), potentially representing an extra-renal manifestation of this tumor, but their clinical pathologic features are not identical. objectives: this case highlights how recombinant polymerase chain reaction (rt-pcr) and bcor immunohistochemical staining can ease the diagnosis of this rare sarcoma. results: a month-old female presented for right sided pre-septal cellulitis and a temporal subcutaneous mass. the detection of multiple other subcutaneous nodules on exam raised the concern for malignancy and she was admitted for evaluation. she had two subcutaneous masses on her abdomen, with more cutaneous masses on her legs, back, shoulder, cheek and submandibular areas. she lacked spontaneous lower limb movement and had bilateral clonus. imaging confirmed multiple masses throughout the body including paravertebral area from t to l , bilateral adrenal glands, left kidney and muscles of upper and lower extremities. initial differential included neuroblastoma, infantile myofibromatosis, rhabdomyosarcoma or atypical presentation of a renal tumor. however, synaptophysin and chromogranin stains were negative. with standard immunohistochemistry, the tumor could be only broadly classified as "undifferentiated sarcoma" maintaining the diagnostic challenge. using rt-pcr in the setting of a morphologically primitive round cell neoplasm with strong bcor expression, two external institutes simultaneously diagnosed the tumor as bcor-urcs. the primary lesion is unknown but potentially may have arose from the kidney. bcor-urcs has a heterogeneous histology with tumor cells appearing monomorphic in nests of - cells separated by septa with uniform nuclei. there is frequently an "orphan annie eye" appearance and sparse cytoplasm to the cells. diagnosis cannot be made solely on evaluation of this nonspecific histology. rt-pcr uses the genetic abnormality in undifferentiated sarcomas to narrow the differential and bcor immunohistochemical staining provides further context. bcor has significant diagnostic value given its sensitivity and specificity in urcs. another potential marker includes ywhae-nutm b fusions, which occur in smaller subset of cases, but requires further study. rt-pcr has helped further classify tumors leading to the diagnosis of a rare undifferentiated sarcoma with bcor overexpression. while this technology is beneficial, its availability is limited. if accessibility improves, earlier identification and treatment may be possible maximizing the chance for a positive outcome. background: hematohidrosis is a rare condition that mimics bleeding disorders. cases present with oozing blood tinged fluid from various sites like eyes, ears, nose, skin, etc. reported causes of this condition were stress or fear, physical activity, psychological disorders. the condition is self-limited and don't affect the general condition of the patients, but it may contributes to psychosocial problems and may increases their stress and anxiety. so this condition needs to be promptly treated. to test the response of this disease and the associated headache to propranolol treatment. design/method: our case female patient years old st offspring of non consanguineous marriage, was admitted with recurrent episodes of oozing blood tinged fluid from eyes, ears and nose months before admission, about . - ml from each orifice, lasted - minutes and subsided spontaneously. it could involve the sites simultaneously or - sites. the number of attacks was - times per day then gradually increased to - times per day. later on the patient developed a bleeding attack from umbilicus. these attacks were aggravated by stress and physical activity and decreased with rest and sleep. the condition was associated with severe headache involving the whole head, throbbing in nature of gradual onset, increased by physical activity and relieved by analgesics. the condition was not associated with vomiting, blurring or diminution of vision, ocular pain, eye discoloration. no earache, tinnitus or diminution of hearing. there was no other form of discharge from eyes, ears or nose. no history of ecchymotic patches, bleeding from other orifices or blood product transfusion. no history of trauma, drug intake, fever or rash. no symptoms of other system affection. past history of recurrent attacks of epistaxis and two operations were done that passed without remarkable bleeding. no similar condition in the family physical examination was free, no evidence of psychological problems. complete blood count, coagulation profile, platelets function, factor and c.t brain were normal. oozing fluid from the patient was analyzed showed the same components as blood. results: our case started oral propranolol . mg/kg/day based on its use in similar cases in literature. the frequency of attacks and headache reduced then stopped after months of treatment and didn't recur after stoppage of propranolol. propranolol can treat this condition successfully. further investigations are needed to determine the link between this condition and severe headache our case was suffering from. background: wilms tumor is the most common renal solid tumors of childhood and is derived from primitive metanephric cells located in the kidney. primary extra-renal wilms tumors (erwt) are extremely rare, estimated to comprise . - % of all wilms tumors. despite similar histologic appearance intrarenal and erwts differ in embryologic tissues of origin. erwts arise from the more primitive mesonephric or pronephric origin and, therefore, can develop anywhere along the craniocaudal migration pathway of these primitive tissues, most often retroperitoneal, inguinal/genital, lumbosacral/pelvic and mediastinal. these tumors are typically staged and treated per national wilms tumor study (nwts) guidelines, and, by definition, are stage ii or greater due to location beyond the kidney borders. based on the cases reported in the literature, outcomes for erwt are comparable to renal wilms tumors with an % local recurrence rate and an % two-year event-free survival. we report the first case of a stage iii testicular extrarenal wilms tumor in an -month-old male with an intrabdominal undescended testis who underwent complete surgical excision followed by chemotherapy and inguinal radiation. results: a full term -month old male underwent orchipexy for an undescended left testicle. the testicle was noted to be grossly abnormal with a pea-sized thickened tissue adherent to the upper pole and a separate mass outside of the scrotum on the superior epididymis. both masses were removed, and s of s pathology demonstrated wilms tumor with favorable histology and negative margins. ct imaging of the chest, abdomen and pelvis were negative for a primary renal tumor, local residual disease, pathologic lymph node enlargement or distant metastases. the tumor was classified per nwts as stage iii due to tumor removal in multiple pieces. the patient completed dd- a treatment with vincristine, doxorubicin and dactinomycin per aren with cgy left inguinal radiation. he is currently months off therapy without clinical or radiographic evidence of recurrent disease. primary erwt is an extremely rare malignant neoplasm associated with challenges in diagnosis, staging and treatment. based on the cases reported in the literature, outcomes are similar to that of intrarenal wilms tumor. there are four pediatric paratesticular wilms tumors reported in the literature and, to the best of our knowledge, this is the first case of stage iii testicular wilms tumor successfully treated with dd- a chemotherapy and radiation. in erwt, nwts guidelines for staging and treatment should be applied with evaluation of both kidneys to exclude an intrarenal primary tumor. background: patient is a yo f, with esrd secondary to atypical hus versus ttp, who presented with thrombotic microangiopathy, aki, thrombocytopenia and anemia after a living unrelated donor kidney transplant. patient initially had downtrending creatinine. on post-op day , hematology was consulted for an increasing ldh and drop in platelets. peripheral smear was notable for an absence of schistocytes. yet, biopsy of the kidney revealed microthrombi. the patient was diagnosed with a thrombotic microangiopathy. plasmapharesis was initiated on day # , at which time ms r was noted to have significantly elevated creatinine. plasmapharesis did not yield any correction in labs and significant bruising developed. patient was started on eculizimab; plasmapharesis was stopped. shortly after, creatinine, anemia and thrombocytopenia corrected to levels at which she was discharged. overall, patient was found to have progressive anemia, thrombocytopenia, an increasing creatinine and ldh ( s) concerning for atypical hus, despite absence of schistocytes on peripheral smear. she responded well to eculizimab, with correction of hematologic changes during induction. she was discharged on eculizimab and continued to respond with normalizing platelet counts and hemoglobin. the differential in light of patient's thrombotic microangiopathy and thrombocytope-nia also included ttp. yet, adamts remained normal. dic was unlikely given normal fibrinogen level and d-dimer. objectives: presentations of atypical hus vs ttp. discuss eculizumab as a treatment of atypical hus. highlight atypical presentations of illness in transplant patients. results: despite absence of schistocytes by smear, pt was diagnosed with atypical hus based on presentation and after failing plasmapharesis, she responded well to eculizumab. though her presentation was abnormal, her response to this antibody that blocks the complement cascade suggests that she was experiencing a complement-mediated process. there are rare documented cases in the literature of atypical hus without schistocytes. hemolytic uremic syndrome (hus) is characterized by hemolytic anemia, thrombocytopenia and acute kidney injury. atypical hus is a diagnosis of exclusion, not due common etiologies such as shiga toxin. among atypical causes are complement-mediated forms, caused by an antibody to complement factor. in addition to plasmapharesis, renal transplant and supportive care, the mainstay of treatment for atypical hus is eculizumab (an antibody that blocks the complement terminal cascade). this case describes a patient unique in that, she was diagnosed with atypical hus without any schistocytes by smear. secondly, she responded to eculizumab, with unremarkable gene studies. finally, this case highlights that transplant patients often have unique presentations. nicklaus children's hospital, miami, florida, united states background: synovial sarcoma is a spindle cell tumor categorized as a soft tissue sarcoma. the chromosomal translocation t(x; ) leading to the ss -ssx fusion protein is unique to this sarcoma. it is a slow growing tumor with common recurrences and often, at presentation, with evidence of metastatic disease. if resection is not feasible, then neoadjuvant with adjuvant chemotherapy is recommended. metastasis carries an unfavorable prognosis given synovial sarcoma historically does not respond well to chemotherapy. trabectedin is a well-tolerated alkylating agent currently indicated for the treatment of liposarcoma and leiomyosarcoma. we present a -year-old male with metastatic synovial sarcoma to the lungs that progressed and was refractory to chemotherapy. he was administered trabectedin as a form of palliative chemotherapy, with significant clinical and radiographic response. design/method: pubmed search was done with search for terminology including "synovial sarcoma" and "trabectedin". papers relevant to our case were selected for literature review. a -year-old male patient presented with a large right axillary mass. initial imaging showed a heterogeneous multiseptated mass invading the subscapularis and teres major muscles along with innumerable lung nodules. biopsy confirmed diagnosis of monophasic synovial sarcoma. the patient was started on protocol arst with ifosfomide, mesna, doxorubicin. he completed cycles followed by radical resection and sessions of radiation. due to progression of disease multiple chemotherapy regimens were tried including topotecan and cyclophosphamide, protocol advl with lorvotuzumab, and pazopanib. imaging of the chest continued to show significant progression of metastasis. the patient's clinical status deteriorated with worsening respiratory status, requiring l of oxygen therapy, and inability to ambulate. he was started on trabectedin . mg/m for palliative care. after cycles of treatment patient was no longer requiring oxygen and was ambulating without assistance. radiological imaging showed significant reduction in number and size of lung nodules. trabectedin is a recently approved alkylating agent for the management of sarcomas resistant to first line treatment. response in synovial sarcoma is scarcely documented in the pediatric population. epidemiology places the most common age group in the young adults and children. our case opens the doors to further consideration of the use of trabectedin in the pediatric patient with metastatic synovial sarcoma. background: gata is an x-linked gene that plays critical role in hematopoiesis. mutations of gata gene can be associated to various blood disorders including diamond blackfan anemia, cytopenia, congenital dyserythropoietc anemia and acute megakaryoblastic leukemia. we report a patient with macrocytic anemia and platelet dysfunction who carries a novel gata mutation that has not been reported. results: a now -month-old male with complex medical history including prematurity at weeks, dysmorphic features, global developmental delay, hyperinsulinism, hypogonadotropic hypogonadism, growth hormone deficiency, micropenis, failure to thrive, patent ductus arteriosus status post ligation, and severe hypotonia, was referred to hematology at months old for resolved, transient thrombocytopenia and macrocytic anemia since month of age. chromosomal microarray showed chromosome deletion of q . , which is the rps gene. he doesn't have a family history of diamond blackfan anemia (dba), despite mom having the same rps mutation. he was then diagnosed with dba. his lab workup showed mild macrocytic anemia (hgb . g/dl, mcv fl), normal to inappropriately low reticulocyte count, normal white blood cell and platelet counts, hgf %, erythroid ada . eu/gm hgb (elevated). he has abnormal pfa- , with prolonged closure time of both adp and epinephrine. he had low von willebrand antigen and ristocetin cofactor activity. he has severe pancreatic insufficiency. bone marrow biopsy showed normocellular marrow with trilineage hematopoietic maturation, without ringed sideroblasts. since mother has the same rps gene mutation, maternal labs were done and showed no evidence of macroytosis or anemia. the diagnosis of dba was questioned. whole exome sequencing did not identify any pathogenic sequence changes in the coding regions of rps gene, but detected a gata mutation r w, which was reported variant of uncertain significance. his mother shares the same mutation and is asymptomatic, but she may not be affected since gata iis xlinked. his father doesn't harbor the gata mutation. conclusion: gata gene encodes zinc finger dna binding hematopoietic transcription factor, which is important during erythroid differentiation. gata mutation r w has not been reported in literature and is a novel variant of gata mutation, which might be contributing to this patient's clinical picture. further studies are warranted to confirm gata mutation r w to be a pathogenic sequence change. alexander boucher, tomoyuki mizuno, alexander vinks, greg tiao, stuart goldstein, james geller cincinnati children's hospital medical center, cincinnati, ohio, united states background: hepatoblastoma (hb), the most common pediatric primary hepatic malignancy, can be associated with specific congenital syndromes. recently, chronic kidney disease and genitourinary anomalies have been linked to hb. cisplatin is a key chemotherapeutic agent in treating hb but its renal clearance and toxicity profile can limit its use for those with end-stage renal disease (esrd). objectives: using an institutional case series, we present data using cisplatin for hb in dialysis-dependent esrd and define recommended dosing for future use. design/method: a chart review of patients with concurrent hb and esrd on dialysis treated with cisplatin at our institution was undertaken. demographic data, diagnostic history, tumor pathology, alpha fetoprotein (afp), hearing assessments, dosing schema, treatment outcomes, and therapyrelated toxicities were reviewed. total cisplatin levels were collected at time points within days after each infusion. free cisplatin levels were also collected for infusions, as were dialysate cisplatin levels. pk parameters were generated using bayesian estimation with a published population pk model as a priori information. results: three patients meeting these criteria were identified. each had "low risk" (non-metastatic resectable) disease at presentation and underwent upfront resections. all had congenital renal anomalies with esrd prior to their hb diagnosis. all cisplatin infusions were given over hours, followed hours later by hemodialysis. patients and received cisplatin at % of children's oncology group's ahep weight-based dosing ( . mg/kg). patient received % of ahep body surface area-based dosing ( mg/m ) during cycle but required a second dose reduction ( mg/m ) for cycle due to prolonged cisplatin exposure (total area under the curve mg⋅h/l; average for all seven evaluable cycles mg⋅h/l) and early sensorineural hearing loss at - hz. no other hearing loss in any patient was identified; mild toxicities also included grade - emesis and grade neutropenia and thrombocytopenia. the median (range) of clearance, volume of distribution at steady-state, and elimination half-life at terminal phase for total platinum were . ( . - . ) l/hour/ kg, . ( . - . ) l/ kg and ( - ) hours, respectively. patients and received cycles with rapid afp normalization. patient required an additional cycles, for a likely second primary hb year after initial therapy. cisplatin can be used successfully in pediatric patients with esrd on hemodialysis to treat hb with minimal morbidity using % standard mg/kg-based dosing ( . mg/kg), achieving pharmacologically appropriate cisplatin exposures. background: treatment for immune thrombocytopenia (itp) has been grouped into rescue and maintenance therapy and often is reserved for patients with bleeding, severe thrombocytopenia, or for improvement in quality of life. splenectomy is considered one of the more invasive but definitive treatments with success rates of - %. treatment of itp can be more difficult in the setting of previous treatment with immune modulation or when the patient is immunocompromised and not a candidate for splenectomy. objectives: present an interesting case of a patient with an autoimmune disease that presented with severe thrombocytopenia, un-responsive to rescue therapy, and requiring emergent splenectomy in the setting of acute intracranial hemorrhage (ich). a year old female with a history of juvenile dermatomyositis presented with a fine purpuric rash on her extremities, wet purpura, and a platelet count of k/ l. bone marrow evaluation at that time was consistent with itp. she was on cyclosporine and plaquenil for dermatomyositis. platelets failed to increase after three doses of intravenous immunoglobulin and high dose steroids. following a two week course of oral prednisone and eltrombopag, she presented with persistent severe thrombocytopenia of k/ l, anemia of . g/dl, and a lower gi bleed. she was started on amicar, novo-seven, rituximab, and given platelet transfusions with no improvement in bleeding. subsequently, she developed a subdural hematoma with midline shift. surgery performed an emergent open splenectomy with concurrent continuous platelet transfusion. results: she was monitored closely post operatively and, due to ich, transfused to maintain platelets greater than k/ l. by week post-op she had normal platelet counts off transfusions. all medications were stopped within three days of discharge. she represented eight days later with abdominal pain and thrombocytosis and was found to have a portal vein, splenic vein and mesenteric vein thrombosis. she was started on lovenox therapy and admitted for monitoring due to her history of ich. it is unknown whether our patient's underlying immune dysregulation and history of treatment with immunosuppressive medications may have contributed to her unresponsiveness to multiple therapeutic agents. in addition, her significant bleeding did not allow us to fully evaluate her response to second tier therapy. this adds to the scarcity of literature of itp response in pediatric patients with autoimmune disease, and may support more aggressive therapy upfront in these patients. background: multivisceral organ transplantation involves concurrent transplantation of the stomach, pancreas, liver, and intestine with splenectomy, and has been classically used in the pediatric population for infants with intestinal failure from disorders affecting foregut integrity. while there is some data demonstrating its efficacy in adults with low-grade abdominal malignancies, it has not been traditionally used for hepatocellular carcinoma treatment. to describe a unique pediatric case of multivisceral organ transplantation as definitive therapy for refractory fibrolamellar hepatocellular carcinoma in an adolescent male. a year old male presents with a history of fibrolamellar hepatocellular carcinoma, tumor invasion of the portal vein, severe portal hypertension complicated by bleeding esophageal varices and hypersplenism. he had two treatments with yttrium- radioembolization, without significant response. he completed six cycles of traditional chemotherapy in combination with sorafenib with resolution of petavidity, but minimal decrease in tumor size and continued portal hypertension. since his disease remained relatively stable for over years, he was evaluated and listed for multivisceral organ transplantation. at approximately years and months after diagnosis, he underwent en bloc liver, pancreas, stomach, small bowel, and colon transplant with splenectomy. a single lymph node was positive for malignancy at the time of resection. in addition to expected post-transplant complications, he also developed skin only acute graft versus host disease at weeks after transplant, treated successfully with a thymoglobulin course. he clinically improved and was back to his baseline activity level, on full oral feedings within months post-transplantation. at three and six month post-transplantation, there is no concern for relapsed hepatocellular carcinoma on comprehensive imaging and evaluation. he is maintained on protocol immunosuppression and posttransplant support. we present the first known case of successful multivisceral organ transplantation in the treatment of refractory pediatric fibrolamellar hepatocellular carcinoma. background: hematohidrosis is a rare disorder that presents with spontaneous excretion of whole blood from intact skin or mucosa. diagnosis is based on clinical observation of the occurrence with the proven presence of erythrocytes and other blood components, without other abnormalities to account for the phenomenon. the existing literature is scarce and consists of primarily case studies. most reports describe bleeding from facial sites around the eyes, ears, and nose. the available literature suggests anxiety and physical or emotional stress reactions as the most common inciting events. little evidence exists regarding the ideal therapeutic approach, however propranolol has been used successfully to reduce bleeding frequency and severity in multiple case reports. a specific genetic etiology has not been elucidated, and no familial cases have previously been reported. we present a pair of half-siblings, both of whom presented with spontaneous cutaneous and mucosal bleeding before two years of age, and report on preliminary results of propranolol therapy. tanzania. at months of age, he became ill and developed spontaneous bleeding from his ears, nose, and scalp. he continued to have frequent bleeding episodes, usually related to illness or physical distress. a bleeding diathesis work-up was unremarkable, however some episodes were severe enough to require transfusions. the patient was subsequently diagnosed with hiv and hepatitis b, presumably acquired via unscreened blood product transfusions. patient b is an infant female born to the same mother as patient a, with a different father. she was healthy until two months of age when she developed spontaneous bleeding from the hairline, eyelids, ears and genital/rectal area. bleeding episodes were nearly always associated with irritability and crying. extensive coagulation workup was unremarkable. results: propranolol therapy was started in both patients, titrated to a goal of mg/kg/day. in both patients, the frequency and duration of bleeding episodes significantly improved. patient b continues to have milder occasional bleeding episodes from her eyes, ears and scalp but has significantly less discomfort and irritability during the episodes. conclusion: to our knowledge, there are no prior reports involving two related patients with hematohidrosis. this case series suggests that there may be a genetic predisposition which has yet to be identified. propranolol has shown effectiveness in reducing symptom frequency and severity. background: gliomas are the most common central nervous system tumors in children. they are classified into different grades based on genotype (idh, braf, tsc, etc.). lowgrade gliomas such as oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas are classified as grades i and ii. of the molecular level alterations this case report focuses on the braf v e mutation. braf is a member of the raf family of serine/threonine protein kinases and it plays an important role in cell survival, proliferation and terminal differentiation. objectives: here we discuss two cases where dabrafenib, a braf kinase inhibitor, was utilized in the management of gliomas. the cases focus on the use of dabrafenib late versus early in disease course. design/method: patient jl is a year old female who was diagnosed with a low-grade glioneuronal tumor (c -t with a metastatic lesion to the brain) in . jl was treated with chemotherapy, radiation, and surgical resection. despite treatment, the patient's disease progressed. she developed lower extremity dysfunction, urinary incontinence, poor truncal control, and hydrocephalus. dabrafenib was started after the braf v e mutation was confirmed. patient lg is a year old female who presented in november with left facial and upper extremity weakness. ct and mri scans demonstrated a mixed solid and cystic lesion extending from the optic chiasm and hypothalamus to the right thalamus and posterior basal ganglia with additional involvement of the right cerebral peduncle. neurosurgical intervention was undertaken and dabrafenib was started after the braf v e mutation was confirmed. results: patient jl's mri scans have demonstrated improvement of the spine with diminished areas of enhancement along thecal margins, decreased volume and enhancement within the trigeminal plate cistern and resolution of ependymal enhancement within the right ventricle. the patient's most recent mri exhibits no disease progression in head or spine. jl has shown improvement clinically since starting dabrafenib. patient lg has shown improvement in strength and recent mri of the brain has shown resolution of enhancement along surgical resection margins, decreased hyperintensity along the inferomedial aspect of the right basal ganglia and no new enhancements. conclusion: low grade gliomas can alter a person's quality of life and even lead to life threatening complications. often the standard chemotherapy, radiation and surgery don't prevent these complications. genetic analysis can help clinicians target therapy towards certain mutations such as braf v e. dabrafenib has shown to decrease tumor burden, early utilization as therapy can help prevent morbidity and mortality. children's hospital of pittsburgh of upmc, pittsburgh, pennsylvania, united states background: copper is an essential cofactor in enzymatic reactions essential to proper hematologic, skeletal, neurologic and vascular function. copper requirements in children over the age of are mg/day, which is readily acquired in a typical diet. copper deficiency is known to occur in patients with the rare x-linked mutation and in older individuals with gastrointestinal bypass surgery; however, it is rarely reported in other conditions. objectives: to highlight individuals with autism spectrum disorders or developmental delay with a limited dietary repertoire are at risk for copper deficiency, thus a high index of suspicion must exist in order to diagnose the disorder. design/method: a y/o boy with a prior diagnosis of global developmental delay and oral aversion presented with slowly progressive fatigue, weakness, gait instability, and weight loss. his longstanding feeding difficulties were refractory to intensive feeding programs. his daily diet consisted of - oz of milk and - individual servings of butterscotch pudding ( - calories/day, . mg iron/day). initial complete blood count demonstrated white blood cell count of . , absolute neutrophil count of , hemoglobin of . , mean corpuscular volume of < , reticulocyte count of . , platelet count of . review of his peripheral blood smear revealed microcytic, hypochromic red cells without marked fragmentation, anisopoikilocytosis and ringed sideroblasts; there were no morphologic abnormalities of his leukocytes or platelets. iron studies demonstrated ferritin of , total iron binding capacity of , and % iron saturation. he had no evidence of b , folate deficiency or blood loss. additional evaluation revealed a serum copper level of (range - ), and cerulosplasmin of . (range - ). results: once a diagnosis of copper deficiency was made, the patient promptly began a course of parenteral copper repletion. he received iv copper mcg/kg/day x days then weekly intravenous infusions. given his malnutrition, a gtube was placed to begin oral copper repletion and enteral nutrition. within weeks his copper level improved as well as his blood counts. unfortunately, although his blood counts and copper levels normalized, his neurologic status remains below his old baseline although, he has made gains in his gross and fine motor abilities. conclusion: acquired copper deficiency in the pediatric population is a rare event but given the hematologic and neurologic consequences, prompt recognition and treatment is important. this patient's clinical course demonstrates the need to have a high index of suspicion of concomitant nutritional deficiencies other than those routinely evaluated such as iron, b and folate. background: lymphoepithelioma-like thymic carcinoma (lelc) is a rare, aggressive neoplasm with a high rate of invasion, metastasis and recurrence. there are no known curative therapies for metastatic lelc. we report the case of a -year-old male who presented with metastatic ebv positive lelc. sites of disease included a large primary anterior mediastinal mass and metastases to hilar lymph nodes, lungs and liver. he was initially treated with cisplatin and fluorouracil followed by mediastinal radiation. he had a partial response to therapy but his end of therapy scans showed disease progression in lungs, liver, and hilar, supraclavicular and axillary lymph nodes. objectives: molecularly targeted therapies tailored to the patient's genetic profile offer a novel approach to obtain improved survival outcomes. design/method: the patient enrolled on a precision medicine trial, nmtrc : molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancer (nct ). in this study, tumor/normal whole exome sequencing and tumor rna sequencing were performed and a molecular report detailing the results of genomic and gene expression analysis was generated. a treatment plan was designed within a molecular tumor board comprising oncologists, pharmacists, genomicists, and molecular biologists with domain expertise. results: exome sequencing revealed somatic coding point mutations and no structural mutations (focal copy number changes or translocations). candidate somatic driver mutations included tp s x and r w as well as kit n k. both genes have been previously implicated in thymic carcinoma. rna expression analysis demonstrated aberrant activation of biological pathways, including overexpression of kit, hdac , and , tyms, and dhfr. the molecular tumor board selected the combination of pemetrexed ( mg/m ) on day of a day cycle, imatinib ( mg daily), and vorinostat ( mg days - , - , and - ) . on day of cycle , he was admitted with a herpes zoster infection and imatinib was discontinued in order to reduce risk of herpes zoster recurrence. imaging after cycles showed a complete metabolic response on f- fdg pet and a partial response by ct size criteria. as of december , the patient had received cycles of pemetrexed and vorinostat. scans in december showed an increase in the size and metabolic activity of two right lower lobe pulmonary nodules. there were no new sites of disease and imatinib was re-started. background: systemic lupus erythematosus (sle) is a chronic autoimmune disease that affects multiple organ systems and is associated with many different autoantibodies. patients can present with vague constitutional symptoms including fever, rash, fatigue, and weight loss. some of the various hematologic manifestations of sle include anemia of chronic disease, leukopenia, autoimmune hemolytic anemia (aiha), and idiopathic thrombocytopenic purpura (itp). these can be the presenting signs of sle. evans syndrome (es), a disease characterized by itp and aiha, is a rare hematologic manifestation of sle. neurofibromatosis (nf ) is a relatively common neurocutaneous disorder. these patients are at risk of developing benign and malignant tumors. its association with autoimmune disorders, including sle, remains rare. objectives: there are few cases in the literature that have patients with the combination of sle and nf . this is the only case that has a patient with sle, nf , and es. results: a -year-old caucasian female presents with two months of vaginal bleeding, weight loss and petechiae. her exam is remarkable for petechiae and café au lait macules. laboratory findings show severe anemia and thrombocytopenia. she receives blood and platelet transfusions during stabilization, and a bone marrow aspirate is performed to rule out a malignancy which is negative. based on the presence of thrombocytopenia and a positive coombs test, an autoimmune process such as es is considered. screening tests for sle reveal positive antinuclear and anti-double stranded dna antibodies as well as low complement. she receives intravenous immunoglobulin and methylprednisolone and eventually her vaginal bleeding slows and her counts recover. she begins sle therapy with hydroxychloroquine and azathioprine. due to the presence of café au lait macules on her exam, a genetics evaluation is performed and the patient is also diagnosed with nf . to date, there are seven cases of sle with nf reported in the literature, only two of which are pediatric cases. there are no reports of the combination of sle, nf , and es. conclusion: es is a rare hematologic manifestation of sle but can be the initial presentation of this disease. one large study estimates % of childhood-onset sle cases are observed to have es. screening for sle should be considered in all es patients even in the absence of typical clinical findings. association of nf and sle has been rarely described. whether this association reflects a causal relationship or is coincidental needs more investigation. (lube, ped blood & cancer, ) . university of california san diego, la jolla, california, united states background: high grade glioma (hgg) has poor outcomes in adults and children. extraneural metastases are very rare in hgg, and poorly characterized with only a few small case series in adults and only isolated case reports in pediatrics. no genomic data has previously been published for any children with hgg who develop extraneural metastases. objectives: our objective is to describe the natural history of two children with hgg and bony extraneural metastases, comparing their clinical characteristics as well as whole exome sequencing data for both tumors. this information would suggest similar patients should be monitored closely for extraneural metastasis and may benefit from more systemic therapy. design/method: we present a case series of two patients who presented with hgg and had development of bony metastases less than six months after initial diagnosis. both patients had molecular profiling with whole exome sequencing (wes). the first patient was an -year-old male with a tumor found in the left lateral ventricle invading into the fornices, hypothalamus, and left midbrain, who had subtotal resection. bony metastasis were found at . months after diagnosis, and he died months after diagnosis. he initially received radiation, followed by nivolimuab. the second was a -year-old female with a tectal/pineal tumor and multiple spinal cord metastases, who had subtotal resection. she developed bony metastasis at . months after diagnosis and died months after diagnosis. her histologic diagnosis was pineoblastoma, revised to hgg after whole exome sequencing. she received craniospinal radiation followed by chemotherapy per acns (cisplatin, vincristine, and cyclophosphamide) for cycles. when she failed to respond satisfactorily to this therapy, wes of tumor was performed and the findings were consistent with hgg. treatment was transitioned to temodar and lomustine after hgg diagnosis was given. she had ongoing progressive disease despite this therapy as well as trials of nivolumab, everolimus, and vorinostat. neither patient had extraneural metastasis at presentation. in both tumors, whole exome sequencing identified the h f a k m mutation. both tumors also had additional known mutations associated with hgg but no other overlapping mutations. this case series represents the first description of the genetic alterations of pediatric hgg patients who developed extraneural metastases. while h f a k m is a common mutation in pediatric midline hgg, especially dipg, and is associated with more aggressive disease, there has not been an association with extraneural metastasis prior to this series. background: deferiprone-induced agranulocytosis is a well -known albeit rare side effect of the drug. incidence of agranulocytosis varies from . - . %, while milder neutropenia is reported in . % of patients treated with deferiprone. deferasirox is unknown to cause such a complication. clinical trials and post marketing side effect monitoring studied possible correlations between different risk factors and development of agranulocytosis. unfortunately, no studies directly addressed a special risk in a community with background of ethnic neutropenia, like oman. objectives: to report on the incidence of neutropenia among omani children with b thalassemia using different iron chelators design/method: a retrospective study conducted on patients < year-old with b thalassemia treated with different iron chelators. electronic patients records were reviewed to detect episodes of neutropenia either mild (anc . -< . /cmm), moderate (anc . -< ), severe < . , or agranulocytosis anc = ). data were collected including sex, age, personal or family history of ethnic neutropenia, iron chelating agent, infective complications, management and outcome. detailed clinical, laboratory ± radiological information were reported for patients who developed life-threatening agranulocytosis. among young patients with b thalassemia, treated between - in squh, neutropenia, was reported in patients ( . %).severe neutropenia was encountered on occasions in patients ( / : . %) ( on deferiprone including episodes of agranulocytosis, on defersirox, on combined chelation, and off chelation). moderate neutropenia was encountered in patients ( / : . %), on occasions: deferiprone ( ), deferasirox ( ), combined chelation ( ), and episodes off chelation. mild neutropenia was more prevalent, encountered in patients ( . %) on occasions ( on deferiprone, on defersirox, on combined chelation, and off chelation) of patients exposed to deferiprone, patients had neutropenia ( %), higher than previously reported. deferiproneinduced agranulocytosis was encountered in patients ( / = . %). three of them had life threatening complications. one patient developed pneumonia complicated by rupture of pulmonary artery aneurysm-massive hemoptysis, who recovered fully after catheter embolization. the second had facial cellulitis and treatment with gcsf was complicated by frequent ventricular extrasystoles. the third had sepsis, disseminated herpes simplex and required admission to icu for inotropic support. in a community with background ethnic neutropenia, neutropenia is more common to be encountered among thalassemic patients, both on and off chelation therapy. careful monitoring of anc and rational choice/modification of chelating agents is required for optimal management of iron overload and to avoid life threatening complications. objectives: this case control study aimed to evaluate the systolic and diastolic cardiac function in groups of children with ti: non transfused group and a group that received early regular blood transfusion comparing them to healthy controls. design/method: thirteen regularly transfused patients with ti with a mean age of . + . years were compared with eight patients who are non-transfused or minimally transfused (< rbcs transfusion/year); mean age . + . years and healthy controls with a mean age of . ± . years. clinical parameters and standard echocardiographic and tissue doppler imaging (tdi) were compared. results: young non-transfused ti patients had a statistically significant higher peak late diastolic velocity of the left ventricular inflow doppler, a mitral valve a wave duration over the pulmonary vein a wave duration ratio and the pulmonary s of s vein s/d velocities ratio compared to the transfused group with p values of . , . , . respectively. in addition, they have a lower e/a ratio of the mitral valve inflow and a larger left atrial to aortic diameter ratio compared to the control group with p values of . and . respectively. the diameters of the right and left outflow tract were significantly larger in the non transfused group with a trend to have a higher cardiac index compare to the transfused group. systolic function was similar in the studied groups and none of the patients had evidence of pulmonary hypertension. young patients with ti who are receiving early regular blood transfusion have normal systolic function. diastolic function assessment revealed indicators of an abnormal relaxation of the left ventricle in the non transfused group which indicate diastolic dysfunction. the abnormalities affected multiple diastolic function parameters which give an indication that the changes are clinically significant. a statistically significant increase in the diameters of the outflow tracts are likely attributed to high cardiac output status in nontransfused ti patients as they had a trend to have a higher cardiac index. these findings support the early commencing of regular blood transfusion therapy for ti patients to prevent serious cardiac complications in adult life. background: in the -week sustain study, crizanlizumab . mg/kg significantly reduced the frequency of scpcs versus placebo ( . vs . , p = . ) and increased the time to first on-treatment scpc ( . vs . months, p = . ) in patients with sickle cell disease (scd). to evaluate time to first scpc in sustain study subgroups and the likelihood of not experiencing scpc for the duration of the trial using post hoc analyses. design/method: sustain was a randomized, double-blind, placebo-controlled, phase study (nct ). inclusion criteria were: scd patients aged - years; - scpcs in previous months; concomitant hydroxyurea use permitted if ≥ months and stable dose for ≥ months. patients were randomized : : to receive intravenous crizanlizumab . mg/kg, . mg/kg, or placebo. study treatments were administered on days and , then every weeks to week , with the final assessment at week . median time to first scpc after first dose was summarized for crizanlizumab . mg/kg or placebo in these subgroups: - or - scpcs in previous months; scd genotype; and hydroxyurea use at baseline. hazard ratios (hrs) for crizanlizumab . mg/kg versus placebo were calculated based on cox regression analysis, with treatment as a covariate. descriptive statistics were used to summarize the frequency of patients who were scpc event-free for the duration of the study by prior scpc events, scd genotype, and hydroxyurea use at baseline. : patients received crizanlizumab . mg/kg and received placebo. there was a meaningful delay in time to first scpc with crizanlizumab . mg/kg versus placebo observed in the entire study population. the effect was present in both scpc subgroups, and the largest treatment difference was observed in hbss scd versus other genotypes ( . vs . months; hr: . ). in patients taking hydroxyurea who experienced - scpcs in the previous year, time to first onstudy scpc was longer with crizanlizumab . mg/kg versus placebo ( . vs . months; hr: . ). a greater proportion of patients treated with crizanlizumab . mg/kg were scpc event-free versus placebo in each of the analyzed subgroups. one third of patients who were taking hydroxyurea and treated with crizanlizumab . mg/kg were scpc event-free during the study versus . % with placebo, possibly suggesting an additive effect. with crizanlizumab . mg/kg, there was a clinically meaningful delay in time to first scpc and an increased likelihood of being scpc-free versus placebo in all subgroups investigated. cincinnati children's hospital medical center, cincinnati, ohio, united states background: shwachman-diamond syndrome (sds) is an inherited marrow failure syndrome associated with increased risk of myelodysplasia (mds) and acute myeloid leukemia (aml). objectives: this multi-institutional retrospective study investigated clinical features, treatment, and outcomes of sds patients who developed mds or aml by central pathology review. design/method: nine individuals presented with aml ( male, female), mds-eb / ( males, females, with mds ( male and female), and one male with isolated persistent somatic tp mutation. one mds-eb and mds patient progressed to aml. median age (years) at diagnosis of mds was (range . - ), mds-eb / was (range . - ) and aml was . (range . - ). complex cytogenetics were noted in / aml cases, with one having normal cytogenetics. complex clonal cytogenetic abnormalities were noted in of mds-eb /eb patients and clonal abnormalities in of mds patients. follow up was available for aml patients; are deceased. received chemotherapy with intent to proceed to hematopoietic stem cell transplant (hsct). four failed to achieve remission and died with disease without proceeding to transplant. one patient proceeded to hsct without prior chemotherapy. four of six transplanted subjects died with relapsed disease. treatment related mortality was largely infectious or gvhd. the sole surviving aml patient had normal cytogenetics, achieved remission with chemotherapy and underwent hscts with separate stem cell infusions due to two primary graft failures. he remains alive in remission more than years after diagnosis. of the mds-eb / patients, underwent ric hsct, three of whom are alive, one died of infection. the fifth patient has stable disease on continued decitabine monotherapy for . years. of mds patients with treatment data, had upfront hsct therapy, upfront chemotherapy and had no therapy. three patients required ≥ hscts all due to graft failure. follow up is available for , of whom are deceased, with relapsed disease. treatment related mortality was largely infectious or graft failure. one individual died of hepatic failure unrelated to mds. seven mds patients are alive in remission. in summary, prognosis is poor for patients with sds who develop aml due to resistant disease and treatment-related complications. better markers for risk stratification are needed to identify patients who would benefit from early transplant. novel therapeutic strategies are urgently needed to improve outcomes of sds patients with mds or aml. background: unlike primary myelofibrosis (pmf) in adults, which is associated with somatic mutations in jak , mpl, or calr, myelofibrosis in children is rare and the underlying genetic mechanisms remain elusive. here we describe families with autosomal recessive congenital macrothrombocytopenia with focal myelofibrosis (cmtfm) due to germline mutations in the megakaryocyte-specific immune receptor tyrosine-based inhibitory motif (itim) receptor g b-b. objectives: to characterize the clinical phenotype, histological features and identify the causative gene for cmtfm. we performed affymetrix snp . genotyping on the index family to identify shared regions of homozygosity by descent. whole exome sequencing (ws) was performed on all three pedigrees to identify potentially causative mutations. we studied affected children from families, with macrothrombocytopenia, anemia, mild leukocytosis and a distinctive pattern of bone marrow (bm) fibrosis centered around clusters of atypical megakaryocytes. affected children had mild to moderate bleeding symptoms and required platelet and red cell transfusions. none showed evidence of extramedullary hematopoiesis, and all were negative for mutations in jak , mpl, and calr. snp genotyping identified multiple statistically non-significant genomic loci, including the region of the major histocompatibility locus (mhc) on chromosome p (lod = . ). we focused on this region because affected individuals in two families shared a common homozygous human leukocyte antigen (hla) type and had congenital adrenal hyperplasia (cah) due to -hydroxylase (cyp a ) mutation; the cyp a and hla loci are located at p . and p . - p . . wes revealed homozygous frameshift mutations in the megakaryocyte and platelet inhibitory receptor g b-b, encoded within the candidate linkage region. we identified two distinct g b-b frameshift mutations (c. _ + dup; p. fs and c. inst; p. fs) in individuals within these three families. no other mutations that segregated with the phenotype were identified. to validate g b-b as a potential disease-causing gene, we evaluated g b-b expression in bm biopsy specimens from affected patient and control samples by immunohistochemical staining using a monoclonal antibody. g b-b was strongly s of s and selectively expressed in megakaryocytes of control samples, but completely absent in clinically affected individuals. a murine knockout that lacks g b-b has a strikingly similar phenotype with macrothrombocytopenia, myelofibrosis and aberrant platelet production and function, further affirming the causality of g b-b mutations. we showed that autosomal recessive loss-offunction mutations in g b-b cause cmtfm, uncovering the molecular basis of this rare disease. loss of g b-b-dependent inhibition of megakaryocyte activation likely underlies the distinctive focal myelofibrotic phenotype and might be important in other forms of marrow fibrosis. cardinal glennon, saint louis, missouri, united states background: intrauterine transfusion is the method of choice for management of fetal anemia due to red blood cell alloimmunization. despite the decrease in prevalence of anemia due to rhesus d alloimmunization with prophylactic administration of anti-rhd immunoglobulin in rh d negative patients, maternal red red blood cell alloimmunization with other type of red blood cell antigens remains an important cause of fetal anemia. newborn who received intrauterine transfusion for hemolytic disease may have prolonged postnatal transfusion requirement. objectives: -to evaluate clinical outcome of fetuses and newborns who received intrauterine transfusions. -to determine the need of packed red blood cell transfusions until months of age. we conducted a retrospective case series study of all intrauterine transfusions due to anemia secondary to red blood cell alloimmunization performed in our regional center ssm in st louis missouri, between april and january . we evaluated the indications, diagnosis, gestational age, and frequency of intrauterine transfusions, along with the infant's gestational age at birth, duration of admission, timing of blood transfusion and monitoring of hemoglobin. results: intrauterine transfusions were performed in patients. the most common causes of alloimmunization were due to d antibodies (n = , %) and kell antibodies (n = , . %). the median gestational age of the first intrauterine transfusion was . weeks, and the median pre-transfusion hemoglobin was . g/dl. the gestational age at the first intrauterine transfusions was found to be significantly correlated with the number of postnatal transfusions (r = . . p = . ). the median gestational age at birth was found to be weeks ( . - . weeks), with a hemoglobin of . ( . - . ). in our population, patients ( %) received postnatal transfusions, of which were during the first weeks of life, and close monitoring follow up with a hematologist was established in patients at their discharge from the nursery/nicu. one neonatal death occurred and severe morbidity due to severe anemia occurred in one infant. despite the continuing risk factor for persistent anemia, only patients had follow up hemoglobin monitored by their primary care provider. conclusion: infants with anemia due to red blood cell alloimmunization treated with intrauterine transfusion should be monitored closely via regular complete blood count for persistent anemia due to suppression of fetal erythropoiesis. sebastian hesse, piotr grabowski, juri rappsilber, christoph klein dr. von hauner childen's hospital, lmu university hospital, munich, munich, germany background: neutrophil granulocytes are the most abundant leukocytes in the peripheral blood. validated diagnostic options for these cells are limited, leaving many patients with functional neutrophil defects without a defined diagnosis. objectives: here we evaluate proteomics as a new diagnostic tool to investigate defects of neutrophil granulocytes. we analyzed neutrophil granulocytes from children with severe congenital neutropenia (scn) associated with elane mutations, children with chronic granulomatous disease (cgd) with cyba ( ) or cybb ( ) mutations and children with leukocyte adhesion deficiency (lad) due to itgb mutations. in addition we collected samples of children with genetically undetermined neutrophil defects. neutrophils from healthy individuals served as controls. cells were isolated from fresh venous blood using negative selection (purity > %). whole cell proteome analysis was done by data-independent acquisition. showed a correlation coefficient of ∼ . . principal component analysis demonstrated unequivocal separation of the proteome of healthy and diseased cells. differential expression analysis showed minimal proteome aberrations in lad with deficiency in cell surface receptors and upregulation of alpl (total downregulated proteins: / total upregulated proteins: ). analysis of neutrophils from cgd patients also showed limited proteome aberration. cyba and cybb were both diminished independent of genotype, whereas protein clusters around a stat / centered network were increased (total down: / up: ). neutrophils with elane mutations showed the gravest proteome disturbance (total down: / up: ) with an upregulated translational apparatus (srpdependent ribosomes and protein folding complexes) and increased mitochondrial proteins. proteins of each granule subset were dysregulated and metabolic pathways upregulated. a detailed analysis of the proteome from patients with genetically undefined diseases is currently ongoing. one patient with clinical phenotype of cgd was found to have no mutations of nadph oxidase members in whole exome sequencing but critically low levels of ncf on protein level. heterozygosity mapping showed autozytocity in the ncf region warranting current efforts to sequence promoters and intronic regions of the gene. mass spectrometry based proteomics promises exciting new insights into monogenic disease of neutrophil granulocytes and may offer new diagnostic options, in particular in synergy with genome sequencing. by virtue of our international care-for-rare alliance, open to new partners, we hope that our proteome focus may lead to better delineation of as yet unknown disease of neutrophil granulocytes. background: warm autoimmune hemolytic anemia (aiha) is an igg mediated disease. although it can be post-viral, it is often idiopathic and can also be a forme fruste for malignancy or an autoimmune disease. initial management includes steroids. it often relapses on steroid wean and can be refractory to the use of second line treatment such as rituximab. objectives: abatacept (ctla- -ig fusion protein, ctla- mimetic) has been used to ameliorate autoimmune manifestation associated with ctla- haploinsufficiency. we used abatacept as a novel therapeutic agent to manage patients with refractory aiha. design/method: a retrospective case series of two patients at phoenix children's hospital with severe refractory aiha. results: patient , a previously healthy year old female, presented with weeks of icterus, fatigue, and hemoglobinuria. spleen was enlarged cm below the costal margin. laboratory evaluation demonstrated: hemoglobin . g/dl, mild leukopenia /microliter, platelets , /microliter, reticulocytosis . %, positive direct coombs' test, mycoplasma igm and igg positive. bone marrow evaluation showed a hypercellular marrow. she continued to need packed red blood cell (prbc) transfusions despite receiving high dose steroids, ivig and rituximab from may-july . in august, she started sirolimus decreasing her transfusion requirement. after starting abatacept ( mg/kg/dose bi-monthly for three doses and then monthly) in october, she maintained hemoglobin of - g/dl without transfusion. patient , a previously healthy month old male, presented with one week of progressive fatigue, jaundice, and poor feeding. splenomegaly was absent. laboratory evaluation revealed hemoglobin . g/dl, leukocytosis , /microliter, platelets , /microliter, reticulocytosis . %, negative direct coombs' test, and non-specific reactivity on antibody screen. evaluation for inherited hemolytic anemia including a next generation sequencing panel was negative. further evaluation by blood bank showed + positive coombs' for c d due to a warm antibody. cold agglutinin disease was ruled out. bone marrow evaluation was normal. he received high dose ivig as a steroid sparing agent but continued to require prbc transfusions weekly. when prednisone did not seem to slow down hemolysis, treatment with abatacept was initiated and he has not required transfusions for two months. steroids are being weaned. we present successful treatment of two refractory aiha cases with abatacept. patient is steroid and transfusion free and continues on monthly abatacept and sirolimus. patient is also transfusion free and continues on a steroid taper. ctla- is crucial for suppressive function of treg cells. abatacept by binding to cd / seems to enhance treg activity ameliorating autoimmune hemolysis. children's minnesota, minneapolis, minnesota, united states s of s background: transfusional iron overload is common in patients receiving chronic red cell transfusions. as a result, iron chelation is required to minimize toxicity from iron overload. chelation with a single agent can be inadequate at controlling or reducing iron burden. when combination therapy is required deferoxamine may be added to oral chelation. deferoxamine is generally given subcutaneous over - hours for - days a week at - mg/kg/day. many patients struggle to remain compliant with this schedule which has prompted trials of intravenous high-dose (hd) deferoxamine. prior reports of short-term hd deferoxamine have shown minimal side effects however, prolonged use of hd deferoxamine has known toxicity. when compliance is a concern, our center has used hd deferoxamine infusions at mg/kg/hr x hours every to weeks. objectives: evaluate the safety and efficacy of hd deferoxamine at our institution to help guide future therapy. design/method: a retrospective review was completed of patients previously treated with hd deferoxamine between april and september at children's minnesota. final sample included patients ages to years with underlying diagnosis of thalassemia ( ) and diamond-blackfan anemia ( ). deferoxamine infusions were given for hours every - days with a mean length of treatment of days. results: all patients were on combination therapy with deferasirox, however deferasirox was held during deferoxamine infusion. mean pre-deferoxamine liver iron concentration (lic) was . mg/g and mean post lic was . mg/g (p = . ). ferritin mean pre-deferoxamine was ng/ml compared with mean post ng/ml (p = . ). two patients had possible allergy, leading to deferoxamine discontinuation. one patient developed hives, eye swelling and cough while the other had emesis and cough. another patient experienced facial nerve palsy of unclear etiology, which did not recur with resumption of deferoxamine. no respiratory complications were seen. results showed significant decrease in iron burden following combination therapy with high dose deferoxamine and deferasirox. no significant pulmonary, liver, renal, vision, or hearing toxicities were observed. three patients reported reactions to deferoxamine infusions. however, one of these was able to successfully continue deferoxamine without further incident. short-term, hd deferoxamine was effective at reducing lic in combination with oral chelation but requires further evaluation to assess for potential increased risk of toxicity. short-term hd deferoxamine may be considered in the setting of poor compliance of subcutaneous administration or inadequate chelation with single agent therapy. further studies are needed to clarify ideal dosing, timing and risk of toxicity. background: immune thrombocytopenia (itp) is the most common cause of symptomatic thrombocytopenia in childhood but remains a diagnosis of exclusion warranting further evaluation if atypical findings are present. two male children ( months and years old) with newly diagnosed immune thrombocytopenia (itp) were found on initial evaluation to have persistent elevations of lactate dehydrogenase (ldh), alanine aminotransferase (alt), and aspartate aminotransferase (ast). these serum enzyme abnormalities cannot be attributed to itp. in the setting of thrombocytopenia, elevated transaminases and ldh create diagnostic complexity for the hematology/oncology provider as their elevation raises concern for malignancy, hemolytic disease, and other systemic diseases. to raise awareness about an unexpected pattern of duchenne muscular dystrophy in patients undergoing evaluation for itp. to expand the differential of a hematologist/oncologist when abnormal labs support a nonhematologic diagnosis design/method: this case-series of two patients with their clinical and laboratory findings were discovered with retrospective chart review. results: after a thorough evaluation for hemolytic anemias, liver disease and infectious etiologies was negative, bone marrow and liver biopsies were considered. eventually, both children were found to have severely elevated serum creatine kinase (ck). skeletal muscle has the highest concentration of ck of any tissue. thus, significant ck elevation is almost exclusively attributable to muscle injury and is the most sensitive and specific enzyme for diagnosis of muscle disease. referral to a neuromuscular specialist and further genetic testing confirmed the diagnosis of duchenne muscular dystrophy in both children allowing initiation of appropriate interventions. to date, there is no clear genetic predisposition to itp in patients with muscular dystrophy although further investigation may be needed. hematology/oncology providers should consider obtaining a serum ck to rule out muscle disease in any male child with unexplained elevations of serum ldh and/or aminotransferases, as it provides an easy and inexpensive, non-invasive approach to screening. additionally, clinical history and physical examination can aid in the diagnosis of muscular dystrophy, with gross motor delay, abnormal muscle bulk, gower's sign, and proximal muscle weakness all possible findings. objectives: to identify the range of cbcs in patients with ds without infections, hematologic or immune disorders and to create more accurate reference ranges for total white blood count; hemoglobin; hematocrit; mcv; platelet count and absolute neutrophils (anc), lymphocytes, monocytes, eosinophils, and basophils. design/method: a retrospective investigation of healthy pediatric patients with ds who received a cbc between and as part of their medical care at a single, large, pediatric teaching hospital. the study group consisted of children with ds (male = , . %; mean age = . years, sd = . ) at time of blood draw. initially children were reviewed for possible participation in the study; however, patients were excluded due to not meeting the study's inclusion criteria. descriptive statistics were performed on demographic and clinical characteristics. kruskal-wallis h tests, anova, and t-tests were run to determine the significant associations between independent means. results: a significant difference in absolute neutrophils between racial groups, f( , . ) = . , p = . , was observed. there was an increase in anc from . +/- . with african americans to . +/- . in the other racial groups and to . +/- . with caucasians. differences were also found in anc in hispanics/latinos versus non-hispanic/latinos. the results were higher in non-hispanics and latinos, a significant difference of -. ( % ci, -. to -. ), t( ) = . , p = . . preliminary kruskal-wallis h tests run determined that there were significant differences between age groups for total white blood cell, hemoglobin, hematocrit, platelets, lymphocytes and anc. further studies are being run to evaluate in which age groups these differences lie and create reference ranges by age, race and sex. conclusion: among patients with ds, there are differences between racial groups and age groups. this data has been compared to previously established reference ranges for cbcs, but we are currently establishing healthy cbc controls which we will use to validate the reference ranges. these ranges will be published to help guide providers in workup and management of patients with ds. background: transfusion is a critical part of the care provided in the neonatal intensive care unit, but it is not without risks. low birth weight and premature infants can become anaemic from an immature haematopoietic system and frequent phlebotomy. these infants often receive multiple red blood cell transfusions. identifying infants more likely to require such intervention is important in ensuring the appropriate usage of this scarce resource. to determine whether birth weight, gestational age, gender, length of stay and mode of delivery can predict red cell concentrate (rcc) transfusion, units required, donor exposure and time to exposure. design/method: a retrospective chart review of all infants born below weeks gestation and/or birth weight less than , g who received a red blood cell transfusion between july and july in the cork university maternity hospital neonatal unit. results: infants met the inclusion criteria, ( . %) received a rcc transfusion. our study showed lower gestational age (p< . ) and lower birth weight (p< . ) infants are more likely to be transfused. donor exposure increases with a lower birth weight (p = . ). multivariate analysis showed infants with a lower gestational age (or - . per day; p< . ); lower birth weight (or - . per g; p< . ) and a longer length of stay (or . per day; p< . ) are more likely to receive a higher number of rcc transfusions. the time to first rcc transfusion is shorter in those with lower birth weight (or . per g; p< . ) and lower gestational age (or . per day; p< . ). gender and mode of delivery were not found to be predictors of red blood cell transfusion in this study. conclusion: low birth weight and premature infants are more likely to receive a rcc transfusion during admission to the neonatal unit. our study highlights predictors of rcc transfusion, donor exposure and time to transfusion. these can be used in identifying at risk infants, counselling parents and in anticipating transfusion requirements. emily southard, r. grant rowe, david williams, akiko shimamura, taizo nakano children's hospital colorado, aurora, colorado, united states background: the mecom locus encodes transcription factors that regulate hematopoietic stem cell self-renewal and maintenance. overexpression of mecom has been noted in - % of acute myeloid leukemia, several solid tumors, and denotes a poor prognosis. mutations that reduce mecom expression or that disrupt protein function, however, have been implicated in the development of bone marrow failure (bmf) through undefined pathways. an association between mecom mutations and radioulnar synostosis with amegakaryocytic thrombocytopenia (rusat) syndrome has been reported, however further characterization of this phenotype has yet to be explored. to characterize the phenotypic spectrum of a cohort of pediatric patients with novel mecom mutations. we performed a retrospective review of five patients with mecom mutations who were referred to hematology at children's hospital colorado or boston children's hospital. clinical, laboratory, and genetic data was collected on subjects and available family members. results: four of subjects were identified in infancy presenting with congenital cytopenias or physical dysmorphisms that prompted broad genetic screening. platforms for genetic detection included microarray, targeted genetic panels, and whole exome sequencing. three of subjects with cytopenias presented with congenital thrombocytopenia, of whom rapidly progressed to severe aplastic anemia. four of subjects presented with congenital anomalies, of whom demonstrated radioulnar synostosis. additional dysmorphic features identified include craniofacial (low set ears x ), cardiac (pda x , vsd x , aortic root dilation x ), pulmonary (pulmonary hypertension x , arteriovenous malformations x ), and developmental delay. one subject presented at age years with acute pancytopenia, hypocellular marrow, no dysmorphisms, and a mecom variant of unknown signif-icance. the identified mecom mutations include one . mb deletion involving several genes including mecom, one variant affecting a splice acceptor consensus sequence predicted to disrupt splicing, and three novel missense mutations, tyr cys, arg thr, and tyr cys, all of which were absent from public databases and were predicted in silico to be deleterious. we describe the phenotypic spectrum of patients with novel mecom variants. a subset of patients lacked radio-ulnar synostosis and had presence of additional systemic anomalies, demonstrating a varied clinical phenotype that is not isolated to rusat syndrome. a centralized publically accessible database to share clinically annotated mecom variants, together with analysis by experts in mecom function would advance our understanding of the clinical interpretation of mecom variants. mecom should be considered in the differential diagnosis of bone marrow failure and we advocate for the inclusion of mecom in targeted sequencing panels. cairo university, cairo, egypt background: beta thalassemia is regarded as a serious public health problem in the mediterranean region, southeast asia, and the middle east. however, very few studies have been conducted to assess the quality of life (qol) among thalassemia major patients. objectives: to assess the quality of life among b-thalassemia major patients using short form (sf)- questionnaire and to determine the factors associated with their quality of life. design/method: a cross-sectional study was conducted among thalassemia major patients who were attending the hematology outpatient clinic at cairo university hospital, during the study period. data were collected between october and march . the quality of life was assessed for patients aged ≥ years. the mean age of the studied group was . ± . years. the majority ( . %) had one monthly blood transfusion. the mean total score of sf- was . ± . . general health perception domain was the most affected domain with mean score, while vitality was the least affected one. there was no statistically significant difference between males and females regarding different quality domains except for vitality where the mean score was significantly higher in males than females (p = . ). age at onset of disease, and at first blood transfusion were the most documented factors positively correlated with the quality of life among the enrolled thalassemia patients. conclusion: the quality of life in thalassemia major patient was found to be compromised. all thalassemia patients should undergo assessment of the quality of life so that interventions focusing on the affected domains can be implemented. background: international adoption of children with special needs has become more prevalent in recent years leading to tremendous growth in the number of u.s. thalassemia patients adopted from foreign countries. currently % of the , thalassemia patients registered in the cooley's anemia foundation (caf) patient database have been adopted from foreign countries, primarily china. as this population continues to grow, further information is needed in order to provide these families with best supportive care. the primary goal of this study is to characterize the socio-demographics and health statuses of adopted children with thalassemia and their families. a secondary goal is to describe adoptive families' motivations, experiences, challenges, and support resources. design/method: a redcap survey was accessed by families of adopted children with thalassemia through the caf website and caf social media from january to august . following a four-question screen, eligible subjects were directed to complete an adoption questionnaire. families who had at least one adopted child with thalassemia receiving care at a participating thalassemia treatment center or hematology office in the u.s. were considered eligible. descriptive statistics were analyzed using sas . . respondents who were ineligible or who provided incomplete data were removed from the dataset prior to analysis. of survey respondents, qualified and completed the survey. these households had adopted a total of children with thalassemia ( . % male), most from china ( . %), where they had been living in orphanages ( . %). legal guardians identified primarily as christian ( . %). the majority had completed post-secondary education ( . %) with reported household incomes greater than $ , ( . %). most adoptive families were connected to an adoption group or community including online groups, local support groups, and adoption networks ( . %). commonly cited challenges were: ) volume of frequent medical appointments, ) insufficient support from their local care centers, and ) financial burdens. the reality of care for the population of adopted patients with thalassemia in the u.s does not seem to match the expectations set by their providers. we are hopeful this data will be used to assist adoptive families navigating the complexities of thalassemia care. the findings suggest that this population would benefit from additional outreach, education, guidance, and advocacy resources -especially in the early stages of adoption and during initiation of post-adoption medical care. background: in many higher-income countries, thalassemia major has become a chronic disorder; many outcomes are different in emerging countries with more limited resources. most analyzes of health-related quality of life (qofl) in thalassemia have been conducted in high-income settings. objectives: to assess the impact of health status on qofl in thalassemia patients in an emerging country. we assessed qofl in randomly-selected patients ( thalassemia major; with hemoglobin e thalassemia; five thalassemia intermedia) at the national thalassemia center in kurunegala, sri lanka where approximately patients are managed. treatment is free, but compared to north america/europe, access to tertiary staff and other resources are limited. overall, control of body iron as estimated by serum ferritin concentration (mean± sem, ± g/l) was not optimal in many patients. to understand the impact of health status on qofl, we used the sf v health survey, analyzing scores of physical function, pain, general health, social functioning, emotional and mental health, to generate overall physical and mental component scores. results: compared to reports from higher-income countries (american journal of hematology ; : - ), physical function scores (mean±sd, . ± . ) were similar in sri lankan patients; indeed, in three categories (physical role, social function, emotional role), sri lankan scores were slightly higher. by contrast, compared to scores from higherincome settings, those estimating bodily pain, general health, and mental health were significantly lower, resulting overall in a significantly lower physical component score in sri lankan patients. male sri lankan patients reported higher scores than females, and somewhat surprisingly, in four categories (physical function, physical role, social function and emotional role) reported higher scores than those obtained in higher-income settings. lower scores in physical functioning, leading to an overall lower physical component score, were recorded by females. patients with hemoglobin e thalassemia reported generally poorer qofl than those with thalassemia major. the lack of differences in qofl in patients with "high" and "low" hemoglobins was likely related to low pre-transfusion hbs (mean±sem, . ± . g/dl) in nearly all patients. these early data in a small cohort of thalassemia patients in an emerging setting suggest that in many patients bodily pain, reduced mental health, and poorer views of general health affect overall qofl. prospective studies in larger cohorts including evaluation of adequacy of transfusions and chelation therapy, complications, and overall accessibility of care may guide approaches to improve qofl in lower-income settings of thalassemia care. geetanjali bora, anand prakash dubey, tarun sekhri, mammen puliyel, aparna roy maulana azad medical college, new delhi, delhi, india background: in the last two decades, the presence of osteopenia has been described in optimally treated patients with transfusion dependent thalassemia, the pathogenesis of which seems to differ from osteopenia in non-transfused patients. the prevalence rate of low bone mineral density (bmd) in pediatric population is highly variable amongst studies done worldwide. furthermore, the role of metabolic and endocrine factors in determining bone mass in this population is not well understood. objectives: to assess bmd in subjects with transfusion dependent beta thalassemia by dual-energy-x rayabsorptiometry and find its co-relation with clinical, biochemical and hematological parameters. design/method: this is a comparative cross-sectional study and includes patients with transfusion dependent beta thalassemia between ages to years enrolled from a thalassemia day care center in the year - . at the time of enrollment age, sex, bmi z scores, pubertal staging, duration and type of chelation therapy were noted. enrolled subjects were scanned for bmd at lumbar spine l - and left femoral neck using dexa scan. the bmd was expressed in mean values and z scores. age, bmi, ethnicity and gender matched historic controls were used to generate z scores. ml of pre transfusion fasting venous blood samples were obtained to test for serum calcium, phosphate, alkaline phosphatase, pth, thyroid function panel, serum ferritin and serum igf- levels. mean values for pretransfusion hemoglobin and serum ferritin over last months were calculated. results: total no of subjects , median age . years, male ( %), female ( %), ethnicity % asian, bmi < rd centile ( %), pre pubertal %, all receiving transfusion and chelation therapy. prevalence of low (z score < - sd) and very low (< - . sd) bmd was %, % at l -l respectively and %, % at left femoral neck respectively. there was trend of lower bmd z scores with advancing age. statistically significant co-relation (p value < . ) was found between low bmd and low mean pretransfusion hemoglobin, serum phosphate, igf - and vitamin d levels conclusion: a sizable proportion of children and adolescents with transfusion dependent thalassemia have suboptimal bone mineral density and this decline may start as early as - years of age despite being on transfusion regimen highlighting the importance of yearly dexa screening and optimization of pre-transfusion hemoglobin, vitamin d and igf levels. vanderbilt university medical center, nashville, tennessee, united states background: it is well described that iron deficiency anemia (ida) can co-present with thrombocytosis or thrombocytopenia, though cases of thrombocytopenia are less frequent than thrombocytosis. prior reports of thrombocytopenia have included adult and pediatric patients with menorrhagia ( - ), menorrhagia due to uterine fibroids ( ), or other gynecologic abnormalities ( ). our cases highlight the pattern of ida, thrombocytopenia, and menorrhagia in the setting of significant menstrual clotting without observed gynecologic abnormalities in african-american adolescents. objectives: to describe the clinical course of three adolescent females with severe ida, menorrhagia, and thrombocytopenia. results: our cases included three female african-american patients ages - who presented with severe anemia and concurrent thrombocytopenia in the setting of menorrhagia. all three patients reported heavy and prolonged menstrual cycle bleeding with significant clots. two of the three were admitted for transfusions at presentation and noted to have significant menstrual bleeding with continued blood loss requiring additional transfusions until bleeding was controlled with estrogen therapy. these two patients were evaluated with pelvic ultrasounds revealing a prominent endometrium in both patients and hyperechoic material consistent with a clot in one patient. average hemoglobin on presentation was . gm/dl ( . - . ), average platelet count was , /mcl ( , - , ), and average mcv was ( - ). all had severe iron deficiency with an average ferritin of ng/ml ( - ) subsequently treated with oral iron. one patient had a prior history of ida that required transfusion and had subsequent normalization of her complete blood count. two patients had subsequent thrombocytosis before normalization of their platelet counts. two patients received platelet transfusions: one due to recent neurosurgical intervention with a higher goal platelet count and the other to help control menstrual bleeding after a nadir platelet count of , . a review of the clinical history and red cell indices pointed to ida and ongoing blood loss from menorrhagia as the reason for the bicytopenias. the thrombocytopenia in these cases may have been exacerbated by consumption of platelets in the significant clots all three patients reported. it is reasonable to treat with iron supplementation and supportive care which may include transfusions or management of menorrhagia with oral contraceptives or other hormonal methods. background: sickle cell disease is one of the most common inherited red blood cell disorders, yet many are not aware of their carrier status. the american college of obstetricians and gynecologists' guidelines recommend that pregnant women of african, mediterranean and southeast asian descent be screened for hemoglobinopathies with a cbc and hemoglobin electrophoresis . however, adherence to this practice and frequency of improper screening with sickledex is unknown. proper screening and counseling can impact families' knowledge, allowing for establishing relationships with pediatric hematology providers earlier. objectives: we sought to assess prenatal hemoglobinopathy screening practice patterns and methods of obstetrics & gynecology (obgyn) and family medicine providers in the nyc regional area. design/method: a cross-sectional electronic survey was administered to obgyn and family medicine practitioners from four nyc institutions. questions focused on prenatal hemoglobinopathy screening practices using case scenarios with variations on parental trait status and ethnicities. chisquare analyses were used to compare the two provider groups on categorical variables. there were total responses; surveys were complete, of which were obgyn and family medicine providers. respondents were mainly from academic medical centers, with the majority being faculty ( % of the obgyns and % of family medicine). no significant difference was found in frequencies of screening patients with a positive family history of a hemoglobinopathy. when asked about screening practices for patients without a personal/family history of a hemoglobinopathy, % of obgyns versus % of family medicine providers "always" screened for hemoglobinpathies (p = . ). when analyzed by ethnic background, there were significant differences by group in screening patients of white ( % vs %), black ( % vs %), mediterranean ( % vs %), and asian descent ( % vs %) (p≤ . for all). however, in cases where the hemoglobinopathy carrier status of both parents was known, there was no difference in screening with a hemoglobin electrophoresis. furthermore, > % of all respondents use sickledex for screening in the case scenarios. conclusion: this pilot survey highlights a difference in the methods and likelihood of prenatal hemoglobinopathy screening based on the type of prenatal care provider. screening differences can lead to variations in prenatal guidance, diagnostic procedures, informed decision-making and knowledge of families referred to pediatric hematology clinics. this is the first study analyzing prenatal screening for hemoglobinopathies in obgyn and family medicine. improving prenatal screening practices by collaborating with hematologists may decrease health care disparities and allow for earlier relationship building with pediatric hematology. . acog, opinion# , poster # hermansky-pudlak syndrome: spectrum in oman background: hermansky-pudlak syndrome (hps) is a rare autosomal recessive disorder, characterized by the triad of oculocutaneous albinism, a hemorrhagic diathesis resulting from storage pool-deficient platelets, and accumulation of ceroid/lipofuscin-like material in various tissues. before , nine different types of hermansky-pudlak syndrome were identified, which can be distinguished by their signs and symptoms and underlying genetic cause. in , a tenth type was defined based on mutations in the ap d gene. hps type is characterized in addition by severe neutropenia and recurrent sinopulmonary infection. the disease is more common in puerto rico, and this is the first report from oman. to describe the clinical, laboratory and genetic characteristics of hps sub-types in oman, including the first cases of hps type . design/method: this is a retrospective study, including cases with hps that had been suspected clinically and confirmed through genetic mutation analysis. clinical data included sex, age at presentation, initial clinical presentation (skin, eyes, development, neurological involvement, bleeding tendency, recurrent infections) and course of disease. laboratory data (complete blood counts, platelet and absolute neutrophil counts, coagulation screening, platelet function tests by platelet function analyzer, and platelet aggregation studies using different agonist had been recorded. pcr and next generation sequencing for genetic confirmation by testing mutations in hps , ap b , hps , hps , hps , hps , dtnbp ,, bloc s , bloc s genes had been done. results: seven omani cases with hps have been identified ( males and females). their age ranged between (at birth) to years. two patients had hps type , patient had type , while the other cases had hps type . no other sub-types were encountered in oman. all patients were products of consanguineous marriage. one patient had adrenal hge, while the others had mild hemorrhagic phenotype, characterized by recurrent bruising and mild epistaxis. laboratory testing confirmed variable platelet aggregation defects with different platelet agonists. all patients had characteristic hypopigmentation, iris transillumination, nystagmus, and foveal hypoplasia. both patients with hps type had the same homozygous mutation in the ap b gene (c. _ delta), and presented with severe neutropenia. early diagnosis and initiation of gcsf on one of them improved outcome and prevented the development of complications. late diagnosis in the other patient resulted in the development of bronchiectasis as a result of recurrent sinopulmonary infections. background: sickle cell disease (scd), a genetic disorder characterized by defective sickle hemoglobin (hbs), triggers red blood cell sickling, hemolysis, vaso-occlusion, and inflammation. ischemic injury from scd starts in infancy and accumulates over a lifetime, causing pain, fatigue, and progressive end-organ damage that culminates in early mortality. voxelotor (gbt ) is an oral, once-daily therapy that modulates hemoglobin's oxygen affinity, thereby inhibiting hemoglobin polymerization. objectives: to assess the safety, pharmacokinetics, and efficacy of voxelotor in pediatric patients with scd. design/method: this ongoing study is being conducted in parts: part a: a single dose of voxelotor mg in pediatric and adolescent patients; part b: multiple doses of voxelotor mg/d or mg/d for weeks in adolescents. part b's primary objective is to assess the effect of voxelotor on modifying anemia. secondary objectives include measuring other markers of disease modification, such as hemolysis; daily scd symptoms, using a patient-reported outcome (pro) measure; and safety. results: as of november , , patients ( females) had received voxelotor mg and patients ( females) had received voxelotor for ≥ weeks. the median age for the patients was years, % were receiving hydroxyurea (hu), and % had ≥ painful crises in the past year. data for hemolysis measures are available for patients who received voxelotor for weeks. six of the patients achieved a hemoglobin (hb) response of > g/dl increase. laboratory markers of hemolysis improved concordantly; the median reductions in reticulocytes and indirect bilirubin were % and %, respectively. ten of patients showed reduction in total symptom scores (tss) at week , with a % median reduction in tss from baseline. there were no treatmentrelated serious adverse events (aes) or drug discontinuations due to aes. voxelotor mg for weeks in adolescents with scd, the majority receiving hu, demonstrated consistent, sustained efficacy on hb levels and measures of hemolysis; > % of patients showed a > g/dl improvement in hb. improvement in tss in mildly symptomatic patients suggests that the pro is sensitive to treatment effect and supports use in the ongoing hope phase study. voxelotor's reassuring safety profile is consistent with results in adults. these interim results support ongoing clinical evaluation of voxelotor as a potential disease-modifying therapy for adults and children with scd. supported by global blood therapeutics. background: acute kidney injury (aki) is a common complication in sickle cell disease (scd), and a potential risk factor for sickle nephropathy. aki is associated with acute decline in hemoglobin (hb) during vaso-occlusive pain crisis and acute chest syndrome (acs). it is unclear which pathologic factor plays a stronger role in aki development during hb drop: increase in free heme during vaso-occlusive events secondary to hemolysis or hb decline itself. objectives: to investigate if hb decline alone is associated with aki, we tested if the renal function of patients with scd worsened during parvovirus b -induced transient aplastic crisis (tac), in the absence of accentuated hemolysis. design/method: with irb approval, a retrospective study of patients who had laboratory confirmed parvovirus-b was conducted. serum creatinine (scr), both during and within months from the tac event, was collected. comparisons of the clinical and laboratory characteristics were analyzed using the wilcoxon test for continuous variables. aki was defined as an increase in scr by ≥ . mg/dl or a % increase in scr from baseline. to evaluate differences in change in hb on aki risk, changes in scr during tac were compared to those during pain crisis or acs admissions by fitting a generalized linear mixed model for binary outcome. a comparative sample of acs events and vaso-occlusive pain crisis were used to estimate rates of aki according to hb levels. results: three ( %) of the patients with scd developed aki during tac. no association was identified between change in hb from baseline to tac event (p = . ). no cases of aki were identified until hb decreased < . g/dl or the change in hb was ≥ . g/dl from baseline. next, we developed a model to evaluate the impact of change in hb from baseline for patients admitted with tac, pain crisis or acs on aki. with a g/dl decrease in admission hb from baseline, patients with tac had a % probability of developing aki, while acute chest syndrome and pain crisis would have a % and % probability, respectively. our data suggest that aki is still prevalent during parvovirus b -induced tac. however, the risk of aki during a tac event is and times lower than that from severe anemia induced by acute chest syndrome and vasoocclusive pain events, respectively. hemolysis-induced anemia during scd crisis appears to have a more significant role in the development of aki as compared to agenerative anemia. background: the natural history of hemoglobin e beta thalassemia (hbethal), the commonest form of severe beta thalassemia worldwide, has been examined in very few longterm studies. previously, we reported findings in hbethal patients in sri lanka. objectives: to evaluate longterm requirements for transfusion and splenectomy, complications and death in hbethal patients. design/method: all available patients were reviewed - times annually over years. results: patients ( %) died, aged (mean ± sem) . ± . years; the (known) causes commonly included iron overload ( ) and infection ( ); patients surviving patients are aged . ± . years. of patients originally classified by severity (group the mildest, and group the most severe, phenotypes), ( %) were assessed as mild (groups and ), of whom transfusions had been discontinued in . ultimately, / ( %) resumed transfusions, often following shifts to increasingly severe phenotypes including increasing intolerance to anemia. age at resumption of transfusions (following a transfusion-free interval of . ± . years) was . ± . years; in the more severe groups and , regular transfusions were stopped in / patients and resumed in / ( %), at younger ages ( . ± . years) and after shorter transfusion-free periods ( . ± . years) than in "milder" patients. mid-parental height (mph) was ultimately achieved in %. patients ( %) were splenectomized; updated analysis of responses to splenectomy (originally "group " patients), showed that splenectomy (at . ± . years) was followed by an extended, but impermanent, transfusion-free interval ( . ± . years); % patients resumed transfusions, usually related to exercise intolerance or poor growth. in groups and , complications of anemia and ineffective erythropoiesis, including leg ulcers (in % and %) and gallstones ( % and %), were more frequent than in groups and ; fractures were observed ( - %) across all groups, except for regularly-transfused group patients ( %). pulmonary artery pressures > mm were recorded in % patients. evaluation of patients with hbethal requires observations over years, without which definition of patients as "mild" or "severe" may be misleading. while in many patients transfusions may be withheld or reduced in frequency, troublesome complications may surface with advancing age even in "milder" patients. although individual consideration of transfusion requirements is critical, the availability of effective chelation, where this can be provided without prohibitive cost, may alter the balance of risks and benefits of regular transfusions in hbethal. (premawardhena a. lancet ). background: social determinants of health (sdh) are environmental and socioeconomic factors, such as access to food and housing that affect health outcomes. pediatricians are increasingly screening for sdh as part of primary care visits, however less is known about screening for sdh in pediatric hematology. evidence suggests that sdh play a role in disease severity for children with scd, who face significant socio-economic and racial disparities. the goal of our quality improvement (qi) project was to increase the percentage of patients with scd who were connected to community resources for unmet social needs. design/method: we based our intervention on the successful implementation of wecare in our institution's pediatric primary care clinic. eligible patients were identified at the start of each clinic session. on arrival the parent was given a self-reported screening tool for six sdh (childcare, education, employment, food, utilities and housing). results were entered in the electronic health record by the physician or social worker who then printed a pre-existing resource list for patients with a positive screen. we used a series of plan-do-study-act (pdsa) cycles to study tests of change. we tracked process measures (percentage of patients screened, percentage of patients with an unmet social need who received a resource sheet), outcome measures (percentage of patients with an unmet social need who connected with a community resource) and balancing measures (staff, patient and provider satisfaction). run charts were reviewed weekly and then monthly to inform further tests of change. examples of pdsa cycles include who gave the paper survey to patients (social worker or physician versus medical assistant) and length of time between surveys ( to months). results: between august and december screening rates improved from % to %. of the patients screened, % report at least one unmet social need; of those % received a targeted list of community resources in the first month of the project, and % in the fifth month. finally, % of patients reached by phone had connected with a community resource within weeks of the clinic visit. we have successfully implemented universal screening for sdh for patients with scd in our urban pediatric hematology clinic without requiring extra staff. next steps include further pdsa cycles to connect more patients to appropriate resources, and tracking improvement in health care utilization outcomes from addressing sdh in this vulnerable patient population. background: the clinical manifestations of sickle cell disease (scd), chronic hemolytic anemia, and vaso-occlusion occur as a direct result of sickle hemoglobin (hbs) polymerization. voxelotor (gbt ) is a first-in-class, oral, oncedaily investigational agent designed to modulate hemoglobin's oxygen affinity in a targeted approach to inhibit hbs polymerization. objectives: to examine the pharmacokinetics (pk), safety, and dosing of voxelotor in children (aged - years) and adolescents (aged - years) with scd from part a of the gbt - study. design/method: gbt - is an ongoing, open-label, phase a study in patients aged - years with scd (sickle cell anemia or sickle beta zero thalassemia). part a of this study (the focus of this abstract) is examining pk of singledose ( mg) voxelotor. pk samples to measure whole blood and plasma voxelotor concentrations were collected up to days following single-dose administration. separate population pk (ppk) models were developed to describe the concentration versus time profiles of voxelotor in whole blood and plasma using nonlinear mixed effects modeling (non-mem, version . ). ppk modeling and physiologically based pk (pbpk) modeling were used to simulate voxelotor pk parameters and support dose selection for future evaluation in younger children. : part a included adolescents ( females; median age years [range - ]) and children ( females; median age . years [range - ]). mean weight was . kg (range - kg) and . kg (range - kg) in adolescents and children, respectively. voxelotor was well tolerated with no drugrelated grade ≥ adverse events (ae) or serious aes. a compartment model with first-order absorption best described the pk of voxelotor (and was the same model structure used for adults with scd). voxelotor pk exposures in adolescents were comparable to those observed in adults, but higher exposures were observed in children. ppk and pbpk modeling support the use of a weight-based dosing strategy in younger children (aged < years) in future trials. adult voxelotor doses can be used in adolescents. however, based on higher pk exposures, a lower weight-based dosing strategy is recommended in children. ppk and pbpk modeling provides an innovative approach to minimize experimental dosing in children and accelerate dose selection of voxelotor in ongoing and future clinical studies. this abstract is supported by global blood therapeutics. background: hydroxyurea (hu) reduces rates of acute complications, and improves long term outcomes in patients with sickle cell disease (scd) and is now fda approved for children. through previous work we have increased the number of eligible patients on hu in our clinic, however accessing a compounding pharmacy remained a significant barrier to hu adherence for infants and children who cannot swallow capsules. objectives: the objective of our quality improvement project was to improve adherence to hu among pediatric patients with scd at our urban safety net hospital by addressing barriers to obtaining liquid hu. design/method: to begin we met with the leadership of our outpatient pharmacy which offers mail order delivery. however, like most retail pharmacies, they do not have the necessary protective equipment to compound liquid hu. through a series of discussions, we began a unique partnership with our institution's inpatient chemotherapy pharmacy who compounds the liquid hu and delivers it to the outpatient s of s pharmacy, who then dispenses liquid hu to families. using a series of plan-do-study-act (pdsa) cycles we tracked adherence by calculating the medication possession ratio (mpr), defined as the percentage of days in a given period of time that each patient had their medication on hand. the mpr for liquid hu mpr among enrolled patients was tracked by pharmacy staff and reviewed monthly. additional pdsa cycles included adding automatic refills and reminder calls by pharmacy staff and improving communication about delivery. we also tracked patient satisfaction. results: between march and december , a total of thirty pediatric patients were enrolled in our program for on-site compounding and free mail order delivery of liquid hu. mpr for liquid hu is currently . % among enrolled patients, significantly higher than the mpr of % reported in the literature, and has risen steadily since the beginning of the project. families are highly satisfied with the program, specifically appreciating the convenience of mail order delivery, saving on delivery fees, and reminder calls when refills were due. by compounding and dispensing liquid hu directly from our institution's outpatient pharmacy we have significantly improved adherence to this hu therapy in our high-risk population. next steps include analysis of change in clinical outcomes for patients enrolled in this program. as adherence to hydroxyurea is associated with decreased acute care utilization and cost, programs such as ours could play a crucial role in reducing the excessive costs and ed utilization among this patient population. background: experience with the iron-chelator deferasirox is reported widely in higher-income settings. by contrast, real-life experiences in emerging countries are infrequently reported. objectives: to evaluate, in a non-trial setting, the real-life response to deferasirox in an emerging country. design/method: in sri lanka's national thalassemia center which manages patients without tertiary staff, quantitative evaluations of body iron or estimates of extra-hepatic iron, the records of patients who began deferasirox in / were retrospectively reviewed. results: baseline assessments (mean±sem) indicated substantial iron loading [serum ferritin (sf) , ± ug/l; serum alt ± . u/l (normal ≤ u/l)]. deferasirox was introduced at low doses ( . ± . mg/kg/day); many patients started at < mg/kg and, after months, doses remained ≤ mg/kg/day in % patients. after months, sf in % patients remained > , ug/l; only by months had (mean) sf declined to < , ug/l ( ± ; p< . ). similarly, mean alt normalized (to ± u/l) only by months. death and complications were not systematically recorded by staff who had been charged, without provision of additional resources, with the introduction of this new drug in hundreds of patients. these results contrast to those in sri lanka's tertiary thalassemia center where, in patients following the introduction of deferasirox ± . mg/kg/day, sf declined rapidly, even in relatively less ironloaded patients (from , ± to , ± g/l after months; p = . ). these findings underscore the importance, during the implementation of new drug regimens in lowerincome centers with marginal resources, for investments in methods to quantitate body iron burden, hands-on educational initiatives to guide day-to-day management by competent but non-expert staff, and data systems to record efficacy, effectiveness, toxicity and compliance. such investment is critical to optimising therapy and improving complications in thalassemia patients worldwide: even in sri lanka, where resources directed to thalassemia management are greater than in most of asia, results in the oldest living cohort (born - ) indicate under-treatment [elevated iron burdens (sf , ± ug/l) and high prevalences of diabetes ( %) and hypothyroidism ( %)]. even in a younger cohort (born - ) which has benefitted from improved treatments, the prevalence of many complications exceeds those reported from high-income settings. over the next decade, and two decades after the who declaration that the impact of thalassemia on global mortality and morbidity is underrecognized, increased investments by governmental and nongovernmental sources will be necessary to improve outcomes for asian patients with thalassemia. background: a major barrier to success in hydroxyurea (hu) treatment of patients with sickle cell disease (scd) is non-adherence. objectives: to optimize hu adherence in patients with scd. design/method: a care model was designed by the sickle cell (qi) team at children's hospital to improve hu adherence among scd patients. the original model included bimonthly family phone contact, monthly dispensing pharmacy phone contact and lab monitoring. adherence measures included obtaining hu from pharmacy monthly, completion of monthly labs, hb f percentage and mcv, and mtd achievement. from / - / , several pdsa cycles refined our care model. a one-year follow-up survey gathered feedback on the care model. the first-year data involved ∼ patients. the biggest improvements resulted from making pharmacy calls before patient/family calls, shipping liquid hu to outlying patients, and tracking call time/content. the qi goal was % hu adherence by / . the % baseline adherence rate increased to % by / , and has remained in that range. the completion rate of patient/parent phone calls increased from % the first month to % at six months. pharmacy prescription pick-up has increased from % to % per month. lack of liquid hu availability was overcome by shipping the medication to the patient's home. parental hesitance to share information by phone, especially with qi team members with whom they had no established relationship, was overcome by having the longtime sickle cell nurse do many of the early calls. however, survey feedback showed families became comfortable with several clinic personnel calling. the calls gave families the opportunity to ask questions about their child and/or get additional information about scd. the calls also provided an opportunity for seasonal flu shot or tcd testing reminders. the surveys gave information on the optimal time of day to reach each family, providing individualization and further increasing the percentage of completed calls. two families surveyed said they no longer needed two calls a month because they were now able to remember to pick up hu, administer it, and get labs on their own. this qi project has not only improved hu adherence, but also fostered health education/counseling, increased patient/parent satisfaction, and enhanced service utilization. medical team member and patient/family comments demonstrate that it has helped build relationships and trust between families and the medical care system. based on survey feedback, we will further individualize care to increase adherence rate and sustain improvements. cincinnati children's hospital medical center, cincinnati, ohio, united states background: the thalassemias are a heterogeneous group of genetic blood disorders caused by mutations that decrease or eliminate the synthesis of the -and/or -globin subunits of hemoglobin. the phenotype of thalassemia depends on the interaction of the -and -globin gene clusters, because both loci determine the -/ -chain balance. for example, a -thalassemia phenotype can be more severe than expected when coinherited with -globin gene triplication (copy number gain), which exacerbates the -/ -globin imbalance. objectives: describe four individuals with an incorrect diagnosis of -thalassemia trait who were later properly diagnosed by comprehensive genetic testing to have -thalassemia intermedia caused by heterozygous -thalassemia mutations coinherited with triplicated -globin loci. design/method: sequence analysis of the -globin (hba /hba ) and -globin (hbb) genes, and copy number variation analysis of the -and -globin gene clusters by multiplex ligand-dependent probe amplification. results: four unrelated individuals of northern european ancestry were evaluated for signs and symptoms not explained by a diagnosis of -thalassemia trait (previously made by a pediatric hematologist), including growth delay, splenomegaly, moderate anemia, marked elevation of hemoglobin f, thalassemic facies, reticulocytosis, and/or indirect hyperbilirubinemia. genetic testing revealed that all were heterozygous ( / ) for the same, single -globin mutation [hbb.c. c>t (p.q *)] and also heterozygous for an -globin triplication ( / anti- . ). their previous diagnoses of thalassemia trait had been made by complete blood counts, hemoglobin electrophoresis, and/or sequence analysis of the -globin genes only. these individuals' phenotypes ranged from moderate anemia only to multiple stigmata of thalassemia, demonstrating the phenotypic variation of a thalassemia genotype. correct diagnosis was made at an average age of . years. a trial of chronic transfusions was initiated for one patient for growth failure. all were educated about the potential for exacerbations of anemia, gallstones, osteoporosis, and iron overload (even without transfusions). parental genetic testing was recommended to assess reproductive risk, because inheritance of this complex genotype can be apparently autosomal dominant. conclusion: heterozygosity for a -thalassemia mutation does not necessarily indicate -thalassemia minor or "trait". when coinherited with -globin gene triplication, a symptomatic form of -thalassemia can occur. correct and timely diagnosis of thalassemia requires careful consideration of the degree of anemia and examination for organomegaly, bony changes, and jaundice. sequence analysis and copy number variation analysis of both the -and -globin gene clusters is key. hematologists need to be aware of this diagnostic possibility and how to test for it to prevent inaccurate or delayed diagnosis. background: the burden of healthcare costs for sickle cell disease (scd) is nationally estimated at over $ billion. the major components of these costs are inpatient and emergency center (ec) visits, many of which are potentially avoidable. in several chronic conditions, a subset of patients account for most of the avoidable encounters. identifying these patients is the first step in targeted care delivery. objectives: to measure and analyze scd patient utilization patterns in the ec and inpatient at texas children's hospital (tch). we identified all individuals under years old with any encounter at tch associated with an international classification of disease (icd)- or code for scd, including hgb ss, hgb sc, and hgb s/beta thalassemia. for each patient, we identified all inpatient and ec encounters in the days prior to their most recent encounter. finally, each encounter was classified as associated with pain, acute chest syndrome (acs), or "other" using an algorithm of discharge diagnosis codes and pharmaceutical delivery. the total number of scd-associated ec and inpatient encounters over the prior year was calculated for each patient. we stratified each patient according to their utilization patterns: low ( - encounters), intermediate ( - encounters), and high (≥ encounters). we identified unique patients with scd that had at least one encounter from july until june . there were , scd-related encounters in the days prior to their most recent encounter. most ( %, n = ) patients exhibited low-utilization patterns and % (n = ) were intermediate. finally, a small subset ( %, n = ) demonstrated high-utilization patterns and accounted for % of all encounters. high-utilization was associated with older age and public payment mechanisms. pain encounters were predominantly in pre-adolescents and teenagers with high-and intermediate-utilization patterns. acs was most frequent in pre-teens and younger teens in the intermediate-utilization group. finally, the youngest-aged high and intermediate users presented for other reasons such as febrile episodes and splenic sequestration. our findings reflect national trends in that a significant portion of encounters are attributed to a small subset of patients exhibiting a high-or "super-" utilization pattern. at our institution, scd super-utilization is associated with older age and pain. we also identified a group of infants and toddlers with frequent encounters for fever. to comprehensively address this burden, it will be important to design interventions targeted toward age and specific medical needs. background: background: the rarity of diamond blackfan anemia (dba) has hindered describing the spectrum of disease, identifying predictive correlations, and guiding datadriven recommendations. long-term toxicities from steroid or transfusion therapy that start in childhood remain the major clinical problems in patients with dba who do not receive stem cell transplant. objectives: objective: to define the dba patient population at st. jude children's research hospital including treatment responses and toxicities to help inform recommendations on treatment and monitoring. design/method: method: medical records were reviewed for all patients with dba treated at st. jude between and for diagnostic testing, treatment types and regimens, and outcomes. two-sample t-test or wilcoxon rank sum test was used to compare continuous variables in two groups depending on the normality of the data tested by shapiro-wilk test. results: a total of patients with dba were identified with a median age of . years (range months - years) at last follow up. a ribosomal protein gene mutation was identified in / patients ( %) with an rps mutation / ( %). thirteen different congenital malformations were described in / patients ( %). fourteen of twenty ( %) patients treated with corticosteroids had an initial response and of those achieved full remission. three patients became steroid-refractory and were unable to wean to an acceptable dose. five of twenty patients continue on lower-dose steroids. five patients currently require no therapy. univariate analysis revealed no statistically significant genetic predictors of response or remission, however, / rpl patients responded to steroids with / ( %) in long-term remission. ten patients are maintained on chronic transfusions and have undergone successful hematopoietic stem cell transplant. nineteen of treated patients ( %) had a treatment-related toxicity. patients on steroids were more likely to have short stature than patients on transfusions or in remission (p = . ). severe bone mineral density deficit occurred in / ( %) patients, in before age years. eight patients had hepatic iron overload, in one documented by age years. other severe toxicities included restrictive cardiomyopathy from iron overload, pathologic fracture, diabetes mellitus, and premature ovarian failure in one patient each. this genotypically and phenotypically heterogeneous dba cohort had a high rate of treatment-related toxicities, notably growth retardation, bone density loss, and hepatic iron overload even in very young children. these findings underscore the need for early standardized monitoring. background: patients with sickle cell disease (scd) face worsening morbidity and mortality between ages and , when they must transition from pediatric to adult healthcare.( ) an effective curriculum addressing disease knowledge, educational and vocational skills, self-efficacy, and social supports is critical to a successful transition. traditional didactic approaches have not led to durable knowledge retention. ( ) technology-based methods have been attempted, but the best educational approach remains unknown. objectives: . to understand how adolescent and young adult (aya) patients with scd view existing transition education. . to include patient preferences in improving our transition curriculum. we developed a qualitative survey to assess patient views of existing approaches for learning about scd and their opinions about preferred transition topics. thirty patients with scd aged to years old were recruited between january and december . responses were managed using redcap electronic data tools hosted at the university of rochester.( , ) qualitative and quantitative data analyses were performed, including independent t-testing to compare responses between age groups. results: approximately % of subjects were under years of age, while % were or older. seventy-one percent had a computer, and . % had a cell phone, with most reporting daily use. subjects reported greatest satisfaction with learning from their doctor during clinic visits ( . % agree or strongly agree) and websites on a cell phone ( . % agree or strongly agree); the least popular methods were online chat rooms and microsoft® powerpoint presentations. satisfaction was similar across age groups. recommended transition topics were viewed positively, with subjects ranking highest understanding their bloodwork ( . % agree or strongly agree) and understanding laws protecting students with chronic disease ( . % agree or strongly agree). older subjects ( - years old) agreed more strongly with learning about opioid addiction and understanding differences between adult and pediatric doctors than did younger subjects ( - years old) (p < . ). this pilot study was successful in helping us to understand the educational needs of aya patients with scd. preliminary data underscore the importance of education provided by the pediatric hematologist. our results also suggest that the optimal use of technology-based methods requires further investigation and that tailoring transition education by age group may be useful. background: similar to patients with transfusion-dependent beta-thalassemias (tdt-beta), survivors of hemoglobin barts hydrops fetalis (homozygous alpha- -thalassemia, tdtalpha) will require lifelong transfusions of erythrocytes. we have previously shown that a transfusion strategy that is based on the guidelines developed for tdt-beta (conventional transfusion) is suboptimal for these patients owing to the differences in the pathophysiology of anemia in the two conditions: in tdt-alpha, conventional transfusion strategy will lead to a gradual increase in non-functional hbh with subsequent tissue hypoxia and hemolysis. an aggressive transfusion strategy that was based on reduction of hbh and increase in "functional" hemoglobin level resulted in improvement of tissue oxygenation and reduction of hemolysis but was associated with significant increase in transfusional iron burden [amid et al, blood ] . objectives: to define the optimal chronic blood transfusion targets for hbh% and functional hemoglobin in patients with tdt-alpha. design/method: following research ethics board approval, longitudinal data of patients with tdt-alpha ( males, median age . ( . - . ) were retrospectively collected. variables of interest included total pre-transfusion hemoglobin, hbh%, and "functional" hemoglobin [measured as total hemoglobin x ( -hbh/ )]. outcome variables were lactate dehydrogenase (ldh, marker of hemolysis), and soluble transferrin receptor (str, marker of erythropoiesis). hemoglobin analysis was done using high-performance liquid chromatography and capillary zone electrophoresis. we examined the association of "functional" hemoglobin with str, and hbh% with ldh, using repeated-measures anova to adjust for the effect of multiple testing. we constructed receiver operating characteristic curve and calculated the area under the curve to define the best cut-off values for variables of interests. there was a strong association between functional hb and str, as well as hbh and ldh. the optimal cut-off for "functional" hemoglobin that was associated with str < . mg/l was g/l (auc = . , sensitivity and specificity of . % and % respectively). the optimal cut-off for hbh to supress ldh to < u/l was % (auc = . , sensitivity and specificity of . % and % respectively). the optimal pre-transfusion hbh% for reduction of hemolysis was % and the optimal "functional" hemoglobin to adequately supress erythropoiesis was g/l. to meet these hbh% and functional hb targets by simple blood transfusions, patients with tdt-alpha would require a hypertransfusion regimen with a minimum pre-transfusion total hb of g/l and consequently high transfusional iron burden. an alternative approach using exchange transfusion to reduce hbh% and improve functional hemoglobin would be associated with less volume of transfusion and potentially better long-term outcome. hospital sacre coeur, milot, haiti background: initial results of work developing a pediatric sickle cell disease (scd) clinic at the hôpital sacré coeur (hsc) in milot, northern haiti were presented at aspho . the purpose of this clinic is for a pediatrician with a special interest in scd to provide scd care, advising on trait and managing disease with penicillin prophylaxis (pcn) and hydroxyurea therapy (hu) for select patients. this clinic was started in collaboration with a us based hematologist and support from yale-new haven hospital. objectives: to describe the success and challenges of providing pcn and hu in the scd clinic at hsc through a review of patient records. design/method: since this clinic's inception, a database of patients, with basic clinical information has been kept and made accessible, through 'drop-box', to the us hematologist. the records of those that presented to the clinic were reviewed. the hemoglobin diagnosis was made either by clinical history and sickle cell prep or by hemoglobin electrophoresis through alpha laboratory, port-au-prince, haiti. results: ninety-nine individuals were seen in the first years of the program. fifty-six underwent a hemoglobin electrophoresis. of these , are ≤ years old. thirty-two were started on pcn vk, of which / ( %) were ≤ years old. eleven patients were started hu therapy. all patients on hu have shown progressive increases in hemoglobin. there have been no clinical complications of hu therapy. none of the patients taking hu have required hospitalization or transfusion in . three patients (not on hu) were hospitalized in for complications of scd (osteomyelitis, pain). in , with less than half the numbers in the program, there were admissions for severe anemia, pain, stroke and splenic sequestration. with ongoing external support and a local reputation for excellence in sickle cell care, the clinic at hsc has been able to expand services and improve the health of a growing number of patients with scd. early data suggests that pcn and hu therapies are helping to reduce complications and improve quality of life. challenges to date have included lack of funding for transportation to clinics, for hospitalizations and to cover the cost of electrophoreses. at the same time as continuing providing excellent care and gathering data, it is crucial to explore opportunities for collaboration and cooperation in ways that will assure that the clinic can become independently sustainable while continuing to improve the quality of life for the individuals it serves. background: ykl- is an inflammatory glycoprotein expressed by infiltrating macrophages in various inflammatory conditions. it has been found to be elevated in patients with different pathological conditions like acute and chronic inflammations, increased remodeling of the extracellular matrix (ecm), development of fibrosis and cancer. several studies have found elevated ykl- concentrations in sera of patients with liver diseases such as hepatic fibrosis by hepatitis c virus. it has been suggested that ykl- concentrations reflect the degree of liver fibrosis. to evaluate serum ykl- levels in patients with -thalassemia and its relation to viral hepatitis, liver stiffness as assessed by transient elastography (fibroscan, fs) and hepatic iron concentration. design/method: a prospective study included patients with -tm ( males and females) with mean age . ± . years (range: - years). serum ferritin level, liver enzymes (alt and ast), hbs ag, anti hcv ab and serum ykl- using elisa kit were evaluated. all patients were subjected to liver mri t * to detect liver iron content by the sequence and transient elastography (fibroscan, fs) to assess degree of liver stiffness. results: mean fibroscan value was ( . ± . ) kpa with a median . (range . to ) kpa. ( %) patients were categorized as f - and ( %) were stage f - , ( %) patients had severe fibrosis. their median serum ferritin was ng∖ml, with ( %) patients had values exceeding g/l. median cardiac t * was . with patients had values below ms, and the median lic was . mg/g dw with patients showed readings above mg/g dw. nyl- was evaluated as a marker of inflammation and liver fibrosis and showed mean value . (± . ) pg/ml, and range from to pg/ml. mean ykl- was significantly higher among males (p = . ), patients on chelation therapy (p = . ), patients on dfs (p≤ . ), in those with abnormal liver enzymes, splenectomised patients, patients with hbv sero-positivity, those with moderate elevation of t * and patients with high grades of liver fibrosis (p< . ). ykl- showed positive correlation with the rate of transfusion, lic, ferritin, alt and ast but negative correlation with weight, height and t *. roc curve analysis revealed that the cutoff value of ykl- at pg/ml could differentiate -tm patients with and without viral hepatitis with . % sensitivity and specificity of . %, area under the curve (auc) . , positive predictive value . and negative predictive value . (p< . ). roc curve analysis revealed that the cutoff value of ykl- at pg/ml could detect -tm patients with liver cirrhosis with . % sensitivity and specificity of . %, area under the curve (auc) . , positive predictive value . and negative predictive value . (p< . ). conclusion: serum ykl- levels are elevated in patients with -thalassemia and can detect patients with active viral hepatitis and liver stiffness. background: the most common splenic complication in pediatric patients with sickle cell disease (scd) is acute splenic sequestration (ass), which has often been managed with splenectomy. although splenectomy has been a treatment of choice for years, long-term vascular complications have not been thoroughly evaluated. pulmonary hypertension (phtn) is a severe complication of scd. in adults with scd, phtn has been associated with a -month mortality rate of approximately %. it has been reported that splenectomized patients with hemolytic disorders are at even greater risk of phtn. several medications exist to treat phtn, but with few studies of their efficacy or toxicities in patients with scd. additionally, these patients are often treated with either chronic prbc transfusions or hydroxyurea (hu) to raise hemoglobin, reduce hemolysis, and prevent vaso-occlusive events. objectives: to evaluate effect of chronic prbc or hu vs. no intervention, on tricuspid regurgitant jet velocities (trv) in pediatric patients with scd and history of splenectomy. design/method: retrospective chart review of splenectomized patients with hbss followed at marian anderson center at st. christopher's hospital for children, philadelphia, between and . we analyzed trvs ( hu, prbc, and from control group receiving neither treatment) from patients ( hu, prbc, neither). mean age at echo was . +/- . . data was analyzed with linear correlations and analysis of variance (anova), including the post hoc test of least significant difference (lsd) for all pairs of treatment groups. results: trv was not significantly correlated with age at time of assessment or with time between splenectomy and trv. univariate anova among groups yielded trv means of: . +/- . cm/s (hu), . +/- . (prbc), . +/- . (neither). we found a notable difference as the mean of the hu group was almost cm/s lower than the others, but no overall statistically significant association for any of the groups exists. however, when we performed post hoc tests to adjust for multiple comparisons and looked at all pairings within the anova, we found that the lsd between the hu and the prbc groups was statistically significant (p = . ), and that a trend exists between the hu group and the neither treatment group (p = . ). our data suggests that treatment with hu is correlated with a reduction in trv in pediatric patients with scd who underwent splenectomy. given these promising results, we believe our data warrants further study with larger treatment groups. nancy olivieri, gaurav sharma, susmita nath, rajib de, tuphan kanti dolai, prakas kumar mandal, abhijit phukan, amir sabouhanian, robert yamashita, angela allen, david weatherall, prantar chakrabarti background: hemoglobin e thalassemia (hbethal), which accounts for % of all severe beta thalassemia worldwide, has an estimated prevalence of . / , in west bengal, from which little information about clinical findings has been reported. objectives: to document clinical and laboratory findings in patients with hbethal, ultimately to improve resources for clinical management. design/method: we reviewed records from: a database recording patient names; clinic charts; "special" charts containing additional details; and, in transfused patients, transfusion day-care records. additionally, because in india's public hospitals original lab/imaging reports are commonly retained at home, % of families were interviewed to provide additional information. we excluded records of patients aged < years and patients aged < years who had not been reviewed since . results: while at least one visit had been recorded in , hbethal patients at nrs hospital, most patients are not regularly reviewed there. we examined charts [ ( %) aged ≥ years; ( %) aged - years; % male], representing approximately % of regularly-reviewed patients. most families ( . %) reported monthly incomes (< , indian rupees), below the monthly cost of living ( , rupees) in kolkata. mean (±sem) hemoglobin was . ± . g/dl. % patients were receiving eight or more transfusions per year; from , % had been treated with deferasirox, . ± . mg/kg/day. iron control estimated by serum ferritin concentration ( . ± g/l) was highly variable. a total of % patients were splenectomized. a substantial obstacle to documenting complications was the lack of recording, in any of the five sources, of many relevant parameters: for example, the status of sexual maturation (normal, delayed, or absent) was documented in less than %, and measurements of fasting blood glucose in less than %, of records. where recorded, complication rates were high: delayed/abnormal sexual maturation was recorded in % patients aged > years; in the patients aged > years and those aged - years, respectively, hypothyroidism was recorded in % and %, and elevated serum alt in % and %. in most evaluable patients > years, height was measured between the rd- th percentiles. cardiac findings, rarely documented, included pulmonary hypertension and reduced left ventricular ejection fractions in a few patients. despite dedicated attention to many aspects of thalassemia care, insufficient documentation limited a clear understanding of the current morbidity in hbethal patients. investment in personnel and technology will be critical to record relevant information, ultimately to improve clinical management, over the next decade. children's hospital of richmond at vcu health, richmond, virginia, united states background: sepsis is a common cause of death in children with sickle cell disease (scd). recommendations for care of fever in children with scd include immediate medical evaluation including blood culture and initiation of broad-spectrum antibiotic therapy. the increasing availability of pcr-based respiratory pathogen panels (rpp) provide the opportunity to rapidly identify viral causes of fever. the role for rpps in identifying the source of fever in children with scd and how it affects provider practice is not well studied. ( ) to determine the epidemiology of respiratory virus-associated fever in children with scd and ( ) to determine whether a positive rpp is associated with reduced risk of bacteremia in this population. this was a single-center, retrospective cohort study. we identified and reviewed the medical records of all children with scd seen in our emergency department (ed) with temperature ≥ . oc at home or in the ed from january , , through september , , as well as, all febrile children for whom rpps were sent since the introduction of rpps april . we reviewed the results of blood cultures, rpps, chest radiographs, and ed notes and discharge summaries to identify sources of infections. independent t test and chi-square analysis were used as appropriate to compare results using spss©. overall, the rate of bacteremia was %. there were no cases of bacteremia among children with positive rpps. % of children with negative rpps had true bacteremia. a positive rpp did not reduce the likelihood of bacteremia (p . ). patients with bacteremia had higher presenting temperatures than those without bacteremia ( . oc vs . oc, p . ). the most common rpp findings were rhinovirus/enterovirus ( %), human metapneumovirus ( %), and influenza a ( %). sending an rpp did not affect admission rate ( % and % respectively, p . ); however, likelihood of admission was lower in patients with positive rpps ( % vs %, or . [ . - . ], p . ). length of stay (los) was shorter in patients for whom an rpp was not sent ( . vs . days, p . ). as previously reported, bacteremia in febrile children with scd is very low, but remains a serious concern, particularly in the setting of high fever (> oc). a positive rpp did not reduce the odds of bacteremia, but did have a sta-tistically significant impact on both admission rate and los. more work is needed to understand how rpp results impact provider decision-making and care for children with scd. cincinnati children's hospital medical center, cincinnati, ohio, united states background: diffuse myocardial fibrosis is a common, if not defining, feature of the heart in sickle cell anemia (sca) that is strongly associated with diastolic dysfunction. we found diffuse myocardial fibrosis in every patient in a sca cohort (n = ) ranging in age from to years (niss ). the treatment and prevention of this complication of sca has not been studied before. objectives: because diffuse myocardial fibrosis must begin in early childhood, we hypothesized that early initiation and uninterrupted use of disease-modifying therapy for sca can prevent it. design/method: we use cardiac magnetic resonance imaging (cmr) to measure the myocardial extracellular volume fraction (ecv) to quantify diffuse myocardial fibrosis in individuals with sca who have been treated, uninterrupted, with hydroxyurea or chronic transfusion therapy since ≤ years of age. two comparison groups were used: individuals with sca who have not been treated with disease-modifying therapy since ≤ years of age (n = ) and controls without sca (n = ). results: we studied individuals ( m/ f) with a mean age of . years (range - ). mean age at the start of diseasemodifying therapy was . ± . years (range - ). only had evidence of mild diffuse myocardial fibrosis (ecv . ); the other had no detectable diffuse fibrosis (all had ecv < . , the upper limit of normal). mean ecv was . ± . , which was significantly lower than the ecv of individuals with sca who have not received early uninterrupted therapy ( . ± . ; p = . ) and not statistically different from normal controls ( . ± . ; p = . ). none had macroscopic fibrosis by late gadolinium enhancement or evidence of myocardial hemosiderosis by t * imaging. no patient had diastolic dysfunction by echocardiographic classification, right heart catheterization, or both. disease-modifying therapy for sca can prevent diffuse myocardial fibrosis, and possibly diastolic dysfunction, if started in early childhood. prospective trials of disease-modifying and anti-fibrotic therapy are planned to prevent diffuse myocardial fibrosis, which can be monitored noninvasively by cmr, and improve outcomes in sca. (niss, blood, ) . background: a statewide sickle cell surveillance system (sscss) was developed with the goal of determining the prevalence of sickle cell disease (scd) in indiana and the level of care that patients receive throughout the state. persons with scd are at high risk of infection, especially with encapsulated organisms, as well as at increased complications from influenza. utilizing sscss data, the relationship between vaccination status and mortality was explored. to determine if vaccination status is associated with mortality in persons with scd. the project was granted a waiver of consent by the st. vincent irb. death certificates were obtained to identify cause of death. deceased patients (cases) were matched by age, gender, and sickle genotype to living patients (controls). vaccination data were collected from the medical record and the children and hoosier immunization registry program (chirp) through the date of death for each case. cases and controls were assigned a point for completion of the pneumococcus, meningococcus and haemophilus influenza type b (hib) vaccine series and one point if the influenza vaccine was given within a year prior to death of the cases [max vaccine status score (vss): ]. total points were compared between the cases and controls. two tailed t-tests to compare means of continuous data and wilcoxon signed-rank test to compare ordinal data. one thousand forty-eight individuals were included in the sscss. six hundred and seven ( . %) were seen at one institution and included in this analysis (mean age = years). thirty-three of the ( . %) were deceased at the time of analysis. six point one ( . )% of controls and . % of cases received a vss of . the mean vss for cases was . ± . and . ± . for controls. thirty point three ( . ) % of controls had a vss of one or more, compared to % of cases (p = . ). patients who died of infection [streptococ-cus (n = ), pseudomonas (n = ) and unidentified organisms (n = )] were not up to date on vaccination against encapsulated organisms, but two had received the influenza vaccine in the year prior to death. in this sample, mortality occurred exclusively among adult patients, which is consistent with current patterns in developed countries. among these adults, vss and mortality rates were not related. limitations to the study include small sample size and potential incompleteness of vaccine records. vaccination rates and other standard of care indicators should be explored in a larger cohort of patients to determine associations with mortality. background: sickle cell disease (scd) is a genetic disorder resulting in acute and chronic complications, including delayed puberty. delayed puberty can have adverse physical and psychosocial effects on affected children and families. there are no published reports from ghana on pubertal timing in children with scd. the aim of this cross-sectional study was to describe pubertal changes in children with scd at korle bu teaching hospital (kbth), accra, and compare these findings to those in a control group without scd. design/method: children with scd and children with hb aa, ages - years, were consecutively recruited and matched for age, sex and socioeconomic status. investigator-administered questionnaires were used to obtain demographic data for all participants and information on menarche (girls only). pubertal status was assessed by physical examination using tanner staging. testicular volumes were determined in boys using a prader orchidometer. body mass index (bmi) and socioeconomic status (ses) of participants were analyzed to determine if there were any associations with tanner stage. of the with scd, ( . %) were hb ss and ( . %) hb sc. females comprised . % (cases and controls). mean age at onset of breast development was significantly delayed in girls with scd ( . ± . years) compared to controls ( . ± . years) but there was no significant age difference at onset of pubic hair development. mean age at menarche was significantly delayed in girls with hb ss ( . ± . years) and hb sc ( . ± . years), compared to those with hb aa ( . ± . years). in boys, the mean ages at onset of puberty were significantly delayed in those with scd ( . ± . years, for genital development and . ± . years, for pubic hair development), compared to those without scd ( . ± . years and . ± . years, respectively). mean testicular volumes were significantly lower in cases compared to controls, across all age ranges (p< . ). mean bmi in both cases and controls were similar at onset of breast development in girls. however, in boys with and without scd, mean bmi values were significantly different at pubertal onset. in univariate analysis, ses was not associated with tanner stage for both genital and breast development. mean ages at pubertal onset were significantly delayed in children with scd. longitudinal studies are needed to further characterize any associations with bmi and determine potentially modifiable risk factors affecting pubertal onset in scd. background: sickle-cell disease (scd) is a life-threatening genetic disorder associated with multiple chronic and acute complications. specific monitoring and treatment for children is a major part of the medical focus, but there remains a lack of real-world evidence of the disease burden and practice patterns among the pediatric scd population. objectives: to examine the clinical burden and management of scd among pediatric patients. design/method: a retrospective claims study was conducted using the medicaid analytic extracts database from jan - dec . pediatric patients (aged < years) with scd were identified using icd- -cm diagnosis codes ( . - . , . - . ). the first observed scd diagnosis during the identification period was designated as the index date. patients were required to have continuous medical and pharmacy benefits for at least months pre-and months post-index period. patient data were assessed until the earliest occurrence of the following events: disenrollment, death, or the end of the study period. patient demographic and baseline clinical characteristics, clinical outcomes (mortality, incidence of pain crisis, complications), scd management, and healthcare utilization were examined. all variables were analyzed descriptively. results: a total of , patients met the study inclusion criteria, with a mean age of . years. most patients were black ( . %) and had a charlson comorbidity index score of ( . %). mortality during follow-up was . in personyears, and the event rate of pain crisis in the inpatient setting was . in person-years. the three most common complications after pain crisis (highest rates in person-years) were fever ( . ), infectious and parasitic diseases ( . ), and asthma ( . ). rates of life-threatening complications were also examined in person-years, including acute chest syndrome ( . ), stroke ( . ), splenic sequestration ( . ), pulmonary hypertension ( . ), and pulmonary embolism ( . ). . % of patients were prescribed antibiotics during the one-year post-index period. other frequent medications utilized among children were folic acid ( . %), nonsteroidal anti-inflammatory drugs ( . %), opioids ( . %), and hydroxyurea ( . %). . % of patients had a blood transfusion within one year post-index date. patients had frequent health care utilizations in the inpatient ( visit), emergency room ( visits), office ( visits), and pharmacy ( visits) settings during the one-year follow-up period. pediatric scd patients are burdened with a high rate of complications including pain crisis. in addition, patients utilized a substantial amount of health care resources including outpatient office care and acute care visits. background: novel use of hydroxyurea in an african region with malaria (noharm, nct ) is a randomized controlled trial of hydroxyurea for very young children with sickle cell anemia living in uganda. during year , study participants received blinded study treatment of hydroxyurea or placebo; those receiving hydroxyurea had no increased risk of malaria, but had both laboratory and clinical benefits. during year , all study participants received openlabel hydroxyurea treatment. to assess the effects of open-label hydroxyurea treatment in a very young population of children with sickle s of s cell anemia living in uganda. study endpoints included the rates and severity of malaria infections, clinical sickle-related events, and laboratory effects. design/method: all children in the noharm trial were enrolled at mulago hospital sickle cell clinic in kampala uganda. during year , all children received open-label fixeddose hydroxyurea ( mg/kg/day) for months, after previously receiving either hydroxyurea or placebo for months. results: a total of children entered year of the noharm trial and received fixed-dose hydroxyurea, including males and females, at an average age of . ± . years. among children previously on placebo, there were malaria events in children, including with severity grade ≥ , and three deaths (two acute chest syndrome, one sepsis). clinical adverse event rates dropped from . to . per patient year, and hospitalizations were reduced from to . expected hematological benefits of increased hemoglobin, mcv, and fetal hemoglobin, along with decreased neutrophils and reticulocytes, were rapidly achieved. laboratory adverse events were infrequent at . events per patient-year, and only half of those were dose-limiting hematological toxicities. among children previously on hydroxyurea, there were malaria events in children, including with severity grade ≥ , and two deaths (one acute chest syndrome, one sepsis). clinical adverse event rates and hospitalizations were maintained at low rates, the hematological benefits of hydroxyurea continued throughout the extended treatment period, and dose-limiting toxicities remained infrequent. fixed-dose hydroxyurea treatment of young children with sickle cell anemia living in uganda is associated with no increased risk for malaria. clinical and laboratory benefits occur, including children previously on placebo who crossed-over to hydroxyurea treatment. future studies should focus on the optimal dosing and monitoring strategies, in an effort to determine the overall feasibility and safety of introducing hydroxyurea therapy across sub-saharan africa. background: acute chest syndrome (acs) is the second most common cause of hospitalization in patients with sickle cell disease and is a leading cause of morbidity and mortality. in mid- , an algorithm was implemented at cohen children's medical center to initiate transfusions within four hours of diagnosis of acs in order to improve patient outcomes. objectives: the aim of this project was to analyze the effect of early blood transfusion on the outcomes of patients with acs. we focused on the number of total transfusions, need for exchange transfusion, need for intensive care unit (icu) stay, and length of hospitalization. design/method: a retrospective chart review was completed on patients admitted to ccmc with a primary diagnosis of sickle cell disease and a secondary diagnosis of either acs or pneumonia during the years of - . data from the three years directly prior to implementation of the algorithm was compared to data from the three years directly after implementation of the algorithm. a total of patients were analyzed, of which belonged to the pre-algorithm group and to the postalgorithm group. patients from the post-algorithm group had a higher incidence of transfusions ( % with a mean transfusion number of . pre versus % with a mean of . post) as well as exchange transfusion ( % pre versus % post). the post-algorithm group had a shorter overall length of stay (mean of . days pre versus . days post). while the overall percentage of patients requiring an icu admission was similar in each group ( % pre versus % post), the post-protocol group had a lower likelihood of requiring an icu admission for reasons outside of line placement for exchange transfusion, most commonly for icu-level respiratory support ( % pre versus % post). despite a higher total number of transfusions, early recognition and transfusion for acs can lead to decreased lengths of hospitalization as well as decreased need for icu-level respiratory support. further studies comparing different center's clinical practice guidelines are necessary to improve the standard of care. background: novel use of hydroxyurea in an african region with malaria (noharm) was the first placebocontrolled randomized clinical trial of hydroxyurea in sub-saharan africa. in noharm, young children with sca received either hydroxyurea or placebo during year , followed by open-label hydroxyurea for all study participants during year . an ancillary noharm project was designed to determine if hydroxyurea treatment lowers transcranial doppler (tcd) velocities and possibly reduces stroke risk in this very young cohort. objectives: to perform tcd screening on the noharm cohort, measuring the time-averaged mean velocity (tamv) at the end of both year and year . we hypothesized that the maximum tamv would be lower for noharm study participants receiving hydroxyurea compared to those receiving placebo, and that key clinical and laboratory parameters would also influence tcd velocities. design/method: all children enrolled in noharm were eligible to undergo tcd examination at two study time points: month - when they were completing the blinded treatment phase, and again at month - at the end of the open-label treatment phase. tcd measurements included tamv readings from the main intracranial arteries: middle cerebral artery, distal internal carotid artery, and bifurcation on tcd. all tcd examinations were scored and classified as normal (less than cm/sec), conditional ( - cm/sec) or abnormal (greater than or equal to cm/sec), with higher scores correlating to greater risk of stroke. results: at the end of year , tcd exams were conducted of which were suitable for analysis ( hydroxyurea, placebo). based on the maximum tamv, the median velocity was cm/sec (iqr - ) for children on hydroxyurea and cm/sec (iqr - ) on placebo, p = . . maximum tamv values had negative correlations with hemoglobin concentration (- . ), fetal hemoglobin (- . ), and oxygen saturation (- . ); positive correlations were noted with age ( . ) and absolute neutrophil count ( . ). at the end of year , tcd exams were conducted and all were suitable for analysis; the median velocity was cm/sec on open-label hydroxyurea treatment, regardless of previous blinded treatment. all correlations with tamv were maintained except for age. conclusion: compared to placebo, hydroxyurea treatment for young children with sca living in uganda was associated with lower tcd velocities, which have been correlated in other studies with lower risk of primary stroke. tcd velocities were correlated with hematological and clinical parameters that can be improved by hydroxyurea therapy. children's hospital of richmond at virginia commonwealth university, richmond, virginia, united states background: acute chest syndrome (acs), defined by respiratory symptoms and a new pulmonary infiltrate, is a serious complication of sickle cell disease (scd). acs can occur during hospitalization for non-pulmonary conditions, such as a vaso-occlusive crisis or after surgery. nih clinical practice guidelines encourage incentive spirometry (is) which decreases the incidence of acs. it is additionally widely accepted that early, frequent ambulation in post-operative and pneumonia patients decreases the length of stay (los). to decrease acs events in children with scd at our children's hospital, we aimed for is use in % of ageappropriate pediatric sickle cell admissions. design/method: a multidisciplinary team examined inpatient acs prevention practices, including is, at children's hospital of richmond. key drivers were identified, including educational awareness of patients and healthcare staff, order placement, and documentation. we aimed for all scd patients ≥ months of age hospitalized with any admission diagnosis to participate in is with the use of a traditional incentive spirometer or similar age-and ability-appropriate devices (e.g. positive expiratory pressure devices, bubbles, and pinwheels). we secondarily aimed to increase activity events, specifically ambulation and out of bed time. educational and outreach tools included patient informational brochure and incentive program, and staff informational sessions and reference materials at workstations. a disease-specific order set was implemented including desired is and activity orders. data were collected prospectively may through november , during which pdsa cycles were conducted. admissions during the corresponding months of the previous year were reviewed for comparison. independent t-test analysis was performed using graftpad prism statistical analysis software. results: improvements reaching statistical significance included increase in is order placement from % to % of admissions (p < . ), and admissions with documented is use increased from % to % (p < . ). los decreased from a mean of . days to . days (p . ). post-admission development of acs also decreased from % to % of admissions, but did not reach statistical significance (p . ). there was an additional increase in appropriate activity order placement and documentation of activity events. conclusion: improving education and outreach to patients and staff, including implementation of a disease-specific order set, can improve is use and activity events. the decline seen in incidence of acs development during hospitalization, though not statistically significant, and the decreased los are encouraging, and efforts continue to improve on these trends. background: painful vaso-occlusive crises (voc) are a frequent and debilitating complication of sickle cell disease (scd) and are thought to occur due to progressive blockage of the microvasculature with rigid sickle shaped red blood cells. any trigger that decreases the microvascular blood flow (mbf) can promote entrapment of sickled cells in the microvasculature and progression to voc. exposure to cold wind and changes in weather are common triggers of voc and are associated with increased frequency of hospitalizations for pain in patients with scd. there is limited experimental data on the physiologic effects of these factors on peripheral perfusion in scd. to study the effect of graded thermal stimuli on the peripheral mbf in scd. design/method: scd and control (healthy or sickle trait) subjects aging to years were exposed to their individual threshold temperatures for heat and cold detection, heat and cold pain via tsa-ii thermode that was placed on the thenar eminence. mbf was measured on the contralateral thumb using photo-plethysmography (ppg). the vasoconstriction response within the complex ppg signal was detected using cross-correlation technique. mean mbf was derived from the ppg amplitude during each of these stimuli and compared to baseline mbf. cross correlation analysis showed that cold pain caused significant vasoconstriction response in % of the subjects, followed by heat pain ( %), cold detection ( %) and heat detection ( %).there was a significant drop in the mbf during cold pain (p < . ), heat pain (p < . ), heat detection (p = . ) and cold detection (p = . ) when compared to baseline mbf, with cold pain causing the greatest drop in mbf. thermal sensitivity and mbf responses were comparable between scd and controls. conclusion: exposure to graded thermal stimuli causes a progressive drop in mbf with exposure to cold pain eliciting the strongest vasoconstriction response. vasoconstriction occurred in the contralateral hand at an average of seconds after the stimuli, suggesting a neurally mediated mechanism. although there was no significant difference in vasoconstriction responses between scd and controls, the drop in mbf in patients with sickle cell disease can increase the likelihood of entrapment of the sickled red blood cells, leading to vaso-occlusion. these findings are consistent with extensive reports in literature that exposure to cold weather is associated with a higher frequency of voc. this suggests that neurally mediated vasoconstriction is likely an important factor in the pathophysiology behind cold exposure leading to voc in scd. background: vaso-occlusive crisis (voc) is a major cause of hospital admissions in children with sickle cell disease (scd). although the use of clinical biomarkers in voc has been studied, especially with regards to acute chest syndrome (acs), there is less data regarding overall voc severity prediction. in addition new biomarkers such as platelet to lymphocyte ratio (plr), neutrophil to lymphocyte ratio (nlr), and lymphocyte to monocyte ratio (lmr) have been little studied with regards to scd. objectives: to identify whether admission laboratory values, changes from well baseline laboratory values, and new biomarkers such as plr, nlr, and lmr could predict severity of vaso-occlusive crisis in children with sickle cell disease admitted with voc. design/method: this was a retrospective single center observational study of admissions of voc in children aged - years with hbss or hbs-b thal from september to november excluding those on hyper-transfusion protocol or having an admission diagnosis of acs. univariate analysis was done using student's t-test, mann-whitney non parametric test, or fischer's exact test as appropriate depending on the distribution between admission laboratory data of complete blood count (cbc), reticulocyte count, comprehensive metabolic panel, lactate dehydrogenase (ldh), change from well baseline cbc values within months previously, plr, nlr, lmr, and the development of complicated voc. complicated voc was defined as the development of secondary acute chest syndrome, prolonged admission duration > days ( hours), requirement of blood transfusion, and readmission within days. results: a total of admissions were studied. fifty-nine ( . %) were female. of the , ( . %) were complicated with no significant differences in sex (p . ) or age (p . ). univariate analysis revealed significant elevations in total bilirubin (p . ), ldh (p . ), and platelet count (p . ) in those with complicated voc. there is also significant difference in the percentage change of platelet count from baseline with greater decline in uncomplicated voc (p . ). there were no significant differences in plr (p . ), nlr (p . ), or lmr (p . ). conclusion: elevations in total bilirubin, ldh, and platelet count in admission laboratory values are associated with developing complicated voc. in addition, those with complicated voc present with significantly less decline in platelet count from baseline well cbc. plr, nlr, and lmr do not seem to be useful predictive biomarkers for severity of voc. background: sickle cell disease (scd) causes health problems of varying frequency and severity. the only validated biomarker for children with scd is transcranial doppler. if reliable predictors existed for scd severity, children with scd could be treated according to risk category. many patients with scd face psychosocial or economic hardships, but these factors have not been evaluated as risk markers for medical or functional severity of scd. objectives: the goal of this project was to develop and stratify a preliminary list of psychosocial risk factors for health outcomes that could be used as scd severity predictors. st. vincent institutional review board. a list of potential psychosocial risk factors for adverse health outcomes was compiled based on assessment materials utilized by the sickle safe program (indiana's hemoglobinopathy newborn screening follow-up program). this list of items was distributed to child abuse prevention ( ) and scd ( ) experts, who ranked each item on a likert scale of (least important) to (most important). mean scores were calculated using spss version ; assessments were retrospectively analyzed to determine psychosocial risk factor frequency. risk factors occurring in ≥ % of homes were considered high frequency events. overall, there was high agreement among experts on the risk factors that were considered the most important predictors of severe scd outcomes. the risk factor with the highest frequency ( %) was eligibility for public assistance programs. fifteen risk factors were rated ≥ by the experts. four ( . %) were high frequency events occurring in ≥ % of homes: a child with hbss or hbs thalassemia not taking hydroxyurea ( %); parent report that they had treated a fever (> ®f) at home in the past months ( %); tobacco use by someone in the household ( %); and the family reporting significant psychosocial stressors in the past year ( %). tobacco use in the home was significantly correlated with several other risk factors (smoking during pregnancy [r = . ], other health concerns in the child [r = . ], and child having health insurance [r = - . ]), suggesting that it is part of a constellation of health risk. in general, the risk factors that were rated as most important for health outcomes occurred less frequently in the sample. this study represents important progress toward identifying a group of psychosocial risk factors for scd severity, which is a necessary first step for future investigation of empirical relationships between candidate risk factors and scd outcomes. unitversity of cartagena, cartagena, bolivar, colombia s of s background: sickle cell disease is an autosomal recessive disorder characterized by a mutation in the -globin chain, which produces hbs. acute and chronic complications as aplastic crisis, acute chest syndrome, priapism, stroke, leg ulcers and primary/secondary prevention of stroke can be treated with simple transfusion or exchange transfusion. the latter offers advantages as lower iron overload, post-treatment hbs goal control, lower viscosity and improved microvascular circulation. but it is not a widely-used option because is associated with technical difficulties. objectives: standardization of a new partial exchange transfusion protocol in a group of patients with sickle cell disease, within the framework of a chronic transfusion program. design/method: this is a prospective descriptive study, which included patients under years with sickle cell disease ( hbss, hbs-tal), with indication of partial exchange transfusion in a chronic transfusion program, according to the institutional protocol; patients who fulfilled the inclusion criteria were enrolled in the study between february and december . a registry of the medical and technical complications was made in each of the procedures. a database was constructed in excel, and the graph-pad prism® version oc software was used for statistical analysis. the sequence is as follows: isovolemic phlebotomy and transfusion of packed red cells. depending of the recent hemoglobin level ( hrs), we do the phlebotomy there: hb: - . : cc/kg, hb: - . : cc/kg, hb> : cc/kg; isovolemic solution (ns , %) there: hb: - . : cc/kg, hb: - . : cc/kg, hb> : cc/kg and packed red cell transfusion there: hb: - . : cc/kg, hb: - . : cc/kg, hb> : cc/kg. the safety of this exchange transfusion protocol was analyzed in patients with sickle cell disease ( procedures). there were no differences in the sex distribution, and the median age was years. % of the population was homozygous. the indication of transfusion was . %( / ) primary stroke prevention, . %( / ) secondary stroke prevention and . %( / ) was other reason. a low percentage of complications was found ( . %); of which, those of medical origin (hypotension and nausea/vomiting) were only presented in . % of the total procedures. the standardization of this protocol was safe and its use could be extended to other low-income centers that treat patients with sickle cell disease that need chronic transfusion program including patient with hemoglobin level until gr/dl. we suggest do studies for measure the security and efficacy of this protocol in patients with acute complications. background: clinical trials that aim to achieve pain reduction have challenges achieving clinical endpoints as pain has no quantifiable biomarkers and may be unrelated to scd. furthermore, the threshold of seeking medical care differs between patients and vocs that occur at home are missed. we present a non-interventional, longitudinal study to identify vocs in patients with scd. objectives: to examine the longitudinal relationship between pros and biomarkers in subjects with scd before, during, and after a self-reported voc event, in order to build a model of in-home and clinical voc and to collect longitudinal pros and biomarker data from subjects that span voc events in the home, clinic and the hospital. design/method: longitudinal measures of pain, fatigue, function, activity, and biomarkers from scd patients in steady state and voc were studied over a six month period. patients self-reported pain, fatigue, function, and medication use using a novel epro tool. voc was reported in real-time, triggering a mobile phlebotomy team. blood was collected sequentially after self-reported voc (at home or hospital). blood samples were drawn two days after resolution of voc, as reported by the patient. during non-voc periods, blood was drawn every weeks to establish a baseline. biomarkers included leukocyte-platelet aggregates and circulating microparticles, cell and soluble adhesion molecules, cytokines, inflammatory mediators and coagulation factors. patients wore an actigraphy device to track sleep and activity and rest. results: twenty-seven of thirty-five patients experienced a total of days with voc > hr, of which only days resulted in healthcare utilization. voc days had significantly higher pain and fatigue scores. voc days were associated with significantly decreased functional scores, with significantly greater decreases during vocs requiring medical contact compared to at-home vocs. different activity profiles were identified for non-voc, at-home voc and medical contact voc days by actigraphy monitoring. at-home voc days exhibited increased daytime resting compared to non-voc days. medical contact vocs had decreased average and peak activity, and increased daytime resting compared to non-voc days. a sleep fragmentation index trended up for both at-home ( %) and medical contact voc days ( %). significant changes during voc days were observed in: c-reactive protein ( % increase), nucleated rbc ( % increase), monocyte-platelet aggregates ( % increase) and neutrophil-platelet aggregates ( % increase), interleukin- ( % increase), interleukin- ( % increase) and tnfalpha ( % increase). the identification and assessment of at-home vocs through use of epros, actigraphy and biomarkers is feasible as demonstrated by this innovative at-home study design. background: risk-stratifying sickle cell disease (scd) patients and demonstrating response to disease-modifying therapies is challenging due to the phenotypical heterogeneity of scd. a pathogenic role for procoagulant von willebrand factor (vwf) via excess vwf high molecular weight multimers (hmwm) has been proposed, with variable reports of increased vwf and hmwm in crisis vs. steady-state in adults, but less so for vwf in children with scd. moreover, vwf and multimers have not been studied in sickle trait. objectives: our pilot study evaluated the potential for vwf antigen (vwf:ag) and hmwm on densitometric tracings to serve as biomarkers for disease severity or treatment response in children and young adults with scd compared to sickle trait (hbas) siblings. design/method: we evaluated vwf:ag, vwf multimers and retrospective clinical data from hbss, hbsc and hbas subjects at steady state. one hbsc subject also had a crisis sample. median scd age was years ( . - . years). % were female. scd severity was judged by annual vasoocclusive and acute chest events, or stroke/elevated tcd. eight of ( hbss and hbsc) took hydroxyurea. four hbss subjects had severe scd, all of whom were chronically transfused. results: mean vwf:ag (normal - iu/dl) was higher for hbss ( +/- . ) and severe hbss ( +/- . ) compared to hbsc ( +/- . , p = . and . , respectively); however, lacked statistical significance when compared to hbas ( +/- . , p = . and . , respectively). vwf:ag was elevated in / ( %) steady-state, including / ( %) with "severe" disease on chronic transfusion and / ( %) taking hydroxyurea, in hbsc crisis but no hbsc / ( %) at baseline. vwf:ag was high in / ( %) hbas siblings. four ( %) had increased hmwm at baseline: hbss/severe disease/chronic transfusion, hbss/hydroxyurea and hbsc untreated. hmwm were increased only during vaso-occlusive crisis in hydroxyureatreated hbsc subject. no ultra-large hmwm were observed. in this preliminary study, in young scd subjects, vwf:ag trended higher in hbss vs. hbsc and in severe hbss participants at a single time-point, but serial evaluations at baseline, in crisis and with optimized diseasemodifying therapy are needed to determine the potential of vwf:ag and hmwm as biomarkers for severity or treatment response. surprisingly, vwf:ag was high in some sickle trait subjects. since hbas is associated with some health challenges such as increased thrombosis risk, further examination of vwf and endothelial dysfunction in sickle trait may provide novel insights into its role as a biomarker. background: the national heart lung & blood institute(nhlbi) guidelines for acute management of voe recommends rapid evaluation and treatment of pain, including administration of a parenteral opioid within -minutes of triage or -minutes from registration, pain reassessment & repeat opioid delivery within - -minutes. inf use has been increasing in peds due to its rapid onset and ease of administration. objectives: to evaluate ped utilization of inf & its effect on intravenous (iv) opioid administration and pain control for the treatment of voe. design/method: a retrospective review of emr was performed on children with scd± years presenting to a ped with voe (pain scores on a - scale) from jan-june . variables studied were median time (iqr, %ci) from ped arrival to first-parenteral-opioid-administration, time-to-first-iv-opioid, first & final pain score, disposition and readmission rate. time-to-first-iv-opioid was also compared to historical data (jan-dec ,n = ) prior to inf protocol initiation. . additionally, % patients received iv opioids within minutes of ed arrival in the inf+iv opioid vs. % in the iv opioids alone group (p< . ). no differences in -hour-returnrates were found in any of the groups, including inf alone group. conclusion: use of inf in the ped for voe is an excellent strategy to shorten time-to-first-parenteral-opioidadministration, improve pain scores & improve adherence to the nhlbi guidelines. however we had distinct unexpected findings: ( ) delays in iv opioid delivery after inf use & ( ) inf alone appeared to provide sufficient pain control without iv opioids for disposition home in % of voe patients. whether the latter reflects insufficient pain management or that there is a milder subgroup for whom inf alone is sufficient, requires further investigation. this study illustrates our experience with a ped-based inf protocol in terms of unanticipated delays in iv opioids and also discharges after inf alone. efforts are underway to further improve use of inf in voe management. st. christopher's hospital for children, philadelphia, pennsylvania, united states background: folate supplementation is commonly included as standard management in patients with sickle cell disease. however, clear evidence supporting the clinical benefits of this practice is lacking. a single study demonstrated improvement on the occurrence of repeat dactylitis at a higher dose of folic acid. to compare clinical outcomes in pediatric patients with sickle cell disease treated with folate supplementation versus those who were not. design/method: this study was a retrospective chart review that included patients to years old with sickle cell disease type ss and s followed at st. christopher's hospital for children. data collected included information about folate supplementation, red cell indices and the presence or absence of clinical outcomes including vaso-occlusive crisis requiring hospitalization in the last six months, acute chest syndrome, infections, asthma, sleep apnea, nephropathy, cerebral vascular disease, stroke and avascular necrosis. analysis of variance (anova) was used to evaluate mean differences between age, number of infections, number of voc events, hemoglobin, reticulocyte count, and mean corpuscular volumes. additionally, chi square analysis was implemented to evaluate differences in folate and non-folate groups for left ventricular remodeling (lvr), sickle cell nephropathy, asthma, obstructive sleep apnea (osa), nocturnal hypoxia, and avascular necrosis (avn). mean differences between the folate and non-folate groups were compared for patients on and off hydroxyurea therapy. one hundred and seven patients met inclusion criteria following review of clinical data. of the patients included in the study, patients were found to be taking folate ( %), while patients were not ( %). statistical analysis showed that there were no significant differences in the incidence of clinical outcomes between patients on folate versus those who were not on folate. of the patients who were not on hydroxyurea, hemoglobin levels were significantly higher in patients on folate versus those who were not (p = . ), but not significantly different for the patients on hydroxyurea. this study suggests that folate supplementation makes no significant impact on the red blood cell indices of anemia nor on the incidence of adverse clinical outcomes in children with sickle cell disease. however, a larger prospective study is needed to guide future considerations for folate supplementation in sickle cell patients in the clinical setting. background: tanzania ranks rd globally for the number of infants born annually with sickle cell disease (scd) but lacks a national newborn screening program. the prevalence of sickle cell trait (sct) and scd is highest in the northwestern regions around lake victoria served by bugando medical centre (bmc) a teaching and consultancy hospital in mwanza. bmc also houses the hiv early infant diagnosis (eid) laboratory that tests dried blood spots (dbs) from hivexposed infants. dbs can be tested for hiv and then retested for sickle cell trait and disease. to determine the prevalence of sickle trait and disease by region and district in northwestern tanzania using existing public health infrastructure. secondary objectives explored associations between sct, scd, malaria and hiv. design/method: the tanzania sickle surveillance study (ts ) is a prospective year-long cross-sectional study of hivexposed infants born in northwestern tanzania, whose dbs collected by the eid program are tested at bmc and available for further testing of sct and scd. samples from children ≤ months of age were tested by isoelectric focusing (ief) and scored independently by two tanzanian staff as normal, sct, scd, variant, or uninterpretable. dbs samples scored as disease or variant were repeated. over the course of months, ief gels have been run. a total of , dbs samples have been scored, including , from children less than -months old. the overall prevalence of sct is . % and the prevalence of scd is . %, along with . % hemoglobin variants. quality of the laboratory results is extremely high, with only . % dbs samples yielding an uninterpretable result. geospatial mapping of the first , samples revealed a regional scd prevalence ranging from . % up to . % among the regions served by bmc. the prevalence of sct and scd is very high in northwestern tanzania. geospatial mapping will identify high prevalence areas where targeted newborn screening can be started using existing public health infrastructure with minimal start-up cost and training. further data will enhance the accuracy of the map to the district level. background: pediatric patients with sickle cell disease (scd) could develop obstructive, restrictive or mixed abnormalities of pulmonary function (pf). several publications report progressive worsening of pf over time, which could lead to severe morbidity in adult patients with sickle cell disease. in adults with sickle cell anemia up to - % of mortality is related to lung disease. early intervention aimed at improvement of lung function could significantly decrease morbidity and possibly improve life expectancy. among disease modifying approaches commonly used in scd are hydroxyurea (hu) and chronic prbc transfusions. both interventions lead to increase of hemoglobin, decrease of hbs fraction, leading to decreased hemolysis. reports of effect of hu on pulmonary function are conflicting with some suggesting no effect and others proposing a slower decline of pulmonary function. the goal of our study is to evaluate effect of disease modifying therapies, like hu and chronic prbc on change of pulmonary function in pediatric patients with sickle cell disease. design/method: this study utilized a retrospective chart review of children with scd who had multiple pfts. we analyzed pfts from patients done during clinic visits. scd patients were divided into three treatment groups: hydroxyurea, chronic transfusions or neither. data was analyzed with linear correlations and analysis of variance (anova). comparison were made between the three groups specifically observing the changes in absolute numbers on pfts over time using the first and last pft the patient had. results: there were a total of patients with multiple pfts (ranging from - ); control ( ), hydroxyurea ( ) and chronic transfusion ( ). the mean changes of the control, and hydroxyurea for the pft parameters fev (- . the chronic transfusion group demonstrated a small improvement in pfts over time for fev ( . ), fvc ( . ), fef - ( . ), however there was a decline in fev /fvc (- . ). however, there was no statistically significant (p-value < . ) in the difference in any pfts parameters between any of the groups. in children with scd there is a decline of pf parameters over time. although no significant differences were seen between the three groups it appears chronic transfusion may improve or limit the decline in pfts. larger studies need to be done to evaluate difference in pf decline in patients with scd patients. background: the use of mobile technology in health care has been a growing trend. patients with chronic diseases such as sickle cell disease (scd) require close monitoring to provide appropriate treatment recommendations and avoid complications. we conducted a feasibility study for patients with scd hospitalized for pain using our self-developed mobile application (tru-pain: technology resources to better understand pain) and a wearable activity tracker. subjective symptoms such as pain and objective data such as heart rate (hr) were measured. we aimed to ) correlate nursing recordings with mobile technology recordings; ) get feedback from patients about usability. design/method: we enrolled patients with scd > years old and < hours from admission for uncomplicated vasoocclusive crisis, excluding patients admitted to icu. patients were given an ipad and a wearable device. they were instructed to record in the application at least once per day and to keep the wearable on, removing only to charge. prior to discharge, patients completed a feasibility questionnaire. we enrolled patients, % females, median age . (range to ) who were admitted for a median days (range to ) for uncomplicated pain crisis. patients used the application throughout hospitalization and made one entry/day (range to ). pain scores recorded via tru-pain correlated well (r = . , p< . ) with pain scores recorded in emr. there was an average of , data points recorded per day, by the wearable, with a maximum of , data points/day. the median amount of hours of wearable data per day was . (maximum of . ). the hr recorded via the wearable correlated significantly with the hr recorded in emr (r = . , p-value < . ). as for usability, % of patients indicated never having a problem with the technology, % found tru-pain 'very easy' or 'somewhat easy' to use, and % were 'very satisfied' with their participation in the study, indicating that it helped them track their pain. our pilot study during hospitalization shows strong potential for using tru-pain for patients with scd. pain data from application and hr from wearable correlated well to the emr data. according to the feedback received, our application was easy to use and helped patients track their pain. despite limitations of battery life, the use of wearable technology is feasible, providing additional data such as activity. we are optimistic that we can continue to improve our tru-pain system to help improve care in patients with scd. background: hydroxyurea, chronic blood transfusion, and bone marrow transplantation can reduce complications, and improve survival in sickle cell disease (scd), but are associated with a significant decisional dilemma because of the inherent risk-benefit tradeoffs, and the lack of comparative studies. these treatments are underutilized leading to avoidable morbidity and premature mortality. there is a need for tools to provide patients high-quality information about their treatment options, the associated risks, and benefits, help them clarify their values, and allow them to share in the process of informed medical decision making. objectives: to develop a health literacy sensitive, web-based, decision aid (ptda) to help patients with scd make informed choices about treatments, and to estimate in a randomized clinical trial the acceptability and effectiveness of the ptda in improving patient knowledge, involvement in decisionmaking and decision-making quality. design/method: we conducted qualitative interviews of scd patients, caregivers, stakeholders, and healthcare providers for a decisional needs assessment to identify decisional conflict, knowledge, expectations, values, support, resources, decision types, timing, stages, and learning, and personal clinical characteristics, and to guide the development of a ptda. transcripts were coded using qsr nvivo . stakeholders completed alpha and beta testing of ptda. we conducted a randomized clinical trial of adults, and of caregivers of pediatric patients to evaluate the comparative efficacy of the ptda, vs. standard of care. results: ptda (www.sickleoptions.org) was developed per decisional needs described by stakeholders and finalized following alpha testing, and beta testing by and stakeholders respectively. in a randomized trial of subjects considering various treatment options, qualitative interviews revealed a high level of usability, acceptability, and utility in education, values clarification, and preparedness for decision making of the ptda. a median % rated the acceptability of ptda as good or excellent and provided narrative comments endorsing the acceptability, ease of use, and utility in preparation for decision making. the ptda met international standards for content, development process, and efficacy with the exception of having a full range of positive and negative experiences in patient stories. compared to baseline ptda group had statistically significant improvement in preparedness for decision making (p = . ) and informed subscale of decisional conflict (p = . ) but not for decisional self-efficacy, knowledge, choice predisposition, or stages of decision-making. a ptda for patients with scd developed following extensive engagement of key stakeholders was found to be acceptable, useful, easy to use, to improve preparedness for decision making, and decrease decisional conflict. background: painful vaso-occlusive crisis (voc) accounts for the majority of emergency department (ed) visits and hos-pitalizations in sickle cell disease (scd). we are interested in studying mental stress and associated autonomic nervous system (ans) imbalance that cause vaso-constriction as possible triggers of scd pain. to this end, we developed a mobile phone application (app) to record daily pain frequency and intensity as clinical endpoints that might be predicted by ans parameters measured in the laboratory. in particular, we think that the aura may represent ans instability that precedes or even triggers change in blood flow and voc. objectives: to assess the feasibility of using an app to evaluate frequency and severity of voc and its potential association with mental stress and presence of aura. design/method: an app was developed for both ios and android systems to allow patients to track pain, stress, and aura. the idea was to create an app that was easy to use with the intent to only capture pain episodes, rather than detailed description of the pain. all scd patients were eligible and a parent version was available for younger children. de-identified data was automatically transferred to a hipaa compliant database via a cloud-based server interfaced to the main research project database. a feedback questionnaire was implemented after at least a month of utilization to assess usability. of the scd patients enrolled, participants utilized the app and of the participants that provided feedback indicated the app was easy to navigate. the mean pain scale was out of (standard deviation . ) for those that entered they had pain that day. although the mean stress level was out of , there was a statistically significant correlation between increasing stress levels and increasing pain scores (p < . ). aura was reported by patients, with patients reporting more than episodes. moreover, on days aura was present there was greater incidence that pain was present as well (p < . ). however, there was no statistically significant association between pain intensity and presence of an aura (p = . ). conclusion: consistent with prior research, reported pain intensity is significantly associated with reported stress intensity. although there was an association between presence of aura and pain, it did not seem to correlate with pain intensity. this uniquely designed app can monitor scd pain clinically and help understand the role of sickle dysautonomia in the genesis of scd pain. university of florida college of medicine, gainesville, florida, united states background: evidenced-based guidelines recommend the emergent evaluation of fever in children with sickle cell disease (scd). as the prevalence of bacteremia has decreased, outpatient management has become more common. however, fever can sometimes herald other complications of scd, such as acute chest syndrome, vaso-occlusive pain crisis, splenic sequestration, or aplastic crisis. institutional practices regarding fever management in scd remain variable, and little is known about the clinical outcomes of children hospitalized for uncomplicated fever. objectives: the primary objective was to determine the rate of bacteremia or scd-related complications per febrile episode in children with scd admitted to a single institution between january and june for uncomplicated fever. this was a retrospective cohort study of febrile patients up to years of age with scd, any genotype, admitted to the university of florida during the defined study period. eligible patients were identified by a database search using admitting diagnosis codes for scd and fever based on the international classification of diseases th and th revisions. encounters were manually reviewed to confirm eligibility. patients were excluded if they had other indications for hospitalization apparent at the time of admission, such as an acute vaso-occlusive episode requiring parental narcotics, asthma exacerbation, or additional complications of scd. the database search identified encounters, of which were excluded based on confounding indications for hospitalization. sixty-three eligible patients accounted for hospitalizations. the median age was years (range weeks- years); . % were male. mean duration of hospitalization was . days (range - days). eight positive blood cultures were identified; six of these were classified as contaminants. bacteremia or the development of a scd-related complication was identified in ( . %) admissions. these included acute chest syndrome (n = ), bacteremia (n = ), splenic sequestration (n = ), and red cell transfusion (n = ). exploratory analyses of potential predictors of bacteremia or scd-related complications showed no association with the presenting white blood cell count or degree of fever (p = . ). of the patients classified as having a scd-related complication, % had hemoglobin ss disease and % had at least one prior documented complication. % of the patients transfused had at least one prior transfusion. conclusion: while improvements in preventative care have substantially lowered rates of bacteremia in children with scd, fever warrants careful evaluation for other acute scdrelated complications. providers should consider inpatient observation in select cases. additional studies are warranted to define subsets of patients suitable for outpatient fever management. background: children with sickle cell disease (scd) exhibit lower neurocognitive functioning than healthy peers, even in the absence of stroke. among the domains commonly affected, working memory (wm) seems particularly affected by disease processes and wm deficits have significant implications for academic achievement and disease selfmanagement. few interventions to improve working memory in pediatric scd have been evaluated. to determine the effects of cogmed, a homebased computerized wm training intervention, in children with scd using a randomized controlled trial design. design/method: participants (ages - ) with scd completed a baseline neuropsychological assessment and those with wm deficits were randomized to either begin cogmed immediately or enter an -week waitlist. cogmed is a homebased intervention completed on an ipad that consists of increasingly challenging exercises targeting visual-spatial and verbal wm, practiced over sessions. at the end of training, participants completed a post-intervention neuropsychological assessment, including tests of visual-spatial and verbal wm from the wechsler intelligence scale for children-fifth edition (wisc-v). results: ninety-one participants (m age = . , sd = . ; % female; % hbss) enrolled in the study; % (n = ) exhibited wm deficits and were randomized to either begin cogmed immediately or wait - weeks before starting cogmed. among those that have received the intervention and reached the end of their training period (n = ), participants ( %) completed at least cogmed sessions, ( %) finished at least sessions, and finished at least sessions ( %). the mean number of completed cogmed sessions was . (sd = . ). paired samples t-tests revealed significant improvements on the working memory index (t[ ] = - . , p = . ) and on the digit span (t[ ] = - . , p = . ), and spatial span-backward (t[ ] = - . , p = . ) subtests. improvements were especially pronounced for participants completing at least sessions. partial correlations controlling for respective baseline scores indicated that the number of cogmed sessions completed was positively correlated with post-test scores on digit span (r = . , p = . ) and spatial span-backward (r = . , p = . ) subtests. among participants who completed at least cogmed sessions, % scored in the average range or higher on the working memory index at the post-intervention assessment, compared to % at baseline. results support the efficacy of cogmed in producing significant improvements in wm. a dose-effect was observed such that participants who completed more cogmed sessions had greater improvements in wm. home-based cognitive training programs may ameliorate scd-related wm deficits but methods for motivating and supporting patients as they complete home-based interventions are needed to enhance adherence and effectiveness. background: sickle cell disease is associated with myriad complications that lead to significant morbidity and early mortality. hydroxyurea has been used successfully to reduce the incidence of these complications and has led to significant improvements in quality and duration of life. at children's minnesota we recommend hydroxyurea in all patients with hb ss/s thalassemia as early as months of age with a goal of starting all patients before months of age. objectives: the purpose of this study was to evaluate the use of hydroxyurea therapy in young patients with sickle cell disease, with particular attention to those children less than one year of age. design/method: a retrospective chart review was conducted on patients less than years of age with sickle cell disease who began hydroxyurea therapy between january , and december , . the study population was divided into three cohorts based upon age at hydroxyurea initiation: cohort ( - year), cohort ( - years), and cohort ( - years). outcomes included laboratory data, clinical events (hospitalization, dactylitis, pain crisis, transfusion, splenic sequestration, acute chest syndrome), and toxicity occurring in the first years of life. results: a total of patients were included in cohorts (n = , mean age . months), (n = , mean age . months), and (n = , mean age . months). patients in cohort had higher hemoglobin (p = . ) and mcv (p = . ) and lower absolute reticulocyte count (p = . ) when compared to cohort . the wbc (p = . , < . ) and anc (p = . , . ) were significantly lower compared to both older cohorts. however, no patient had therapy held because of neutropenia. the mean baseline hemoglobin f in cohort was . % compared to . % and . % in cohorts and respectively (p = . , p< . ). the mean duration of therapy in cohort was . months, compared to . months in cohort (p = . ) and . months in cohort (p = . ). during this time, hb f levels remained higher in cohort (mean . %) compared to cohorts and (mean . %, p = . and mean . %, p = . ). patients in cohort experienced fewer hospitalizations (p = . ), pain crises (p = . ), and transfusions (p = . ). there was no difference in toxicity between groups. hydroxyurea was used safely in infants to months of age and resulted in more robust hematologic responses and a decrease in sickle-related complications when compared with patients starting hydroxyurea later in life. children's national health system, washington, district of columbia, united states background: children with sickle cell disease (scd) have a significantly greater risk of silent or overt cerebral infarction than the general population. infarcts are associated with declines in cognitive functioning and academic achievement. while infarcts are reliably identified using mri, scans are expensive and occasionally necessitate sedation. moreover, mri's are not recommended for routine monitoring of cerebral infarcts. additional tools are needed for discriminating the presence of a cerebral infarct that are brief, noninvasive, inexpensive, and repeatable. objectives: to evaluate differences in performance on cogstate, a computerized neurocognitive assessment, in patients with scd with and without history of cerebral infarct. design/method: participants included children with scd ages - (m = . , sd = . ; % female; % s of s hbss) enrolled in a cognitive intervention trial. participants completed the cogstate pediatric battery, which measures processing speed, sustained attention, verbal learning, working memory, and executive functioning. history of silent or overt infarct was determined via health record review. participants also completed measures of intelligence (iq) and math fluency. results: participants' standard scores across most neurocognitive measures were lower than expected compared to the standardization sample (mean iq = . , sd = . ). thirty percent of participants (n = ) had a documented history of cerebral infarct. participants with a history of cerebral infarct scored lower on cogstate tasks measuring sustained attention (t[ ] = . , p = . ) and executive functioning (t[ ] = . , p = . ), as well as on a measure of math fluency (t[ ] = . , p = . ). receiver operating characteristic (roc) analyses demonstrated that the cogstate task measuring sustained attention was a fair discriminant of patients with and without a history of infarct (auc = . , ci = . - . , p = . ), whereas iq score was not (auc = . , ci = . - . , p = . ). cogstate processing speed and sustained attention tasks fairly discriminated between patients with at least average or below average intelligence (auc = . , ci = . - . , p = . and auc = . , ci = . - . , p = . , respectively). finally, the cogstate processing speed task was good at discriminating between at least average or below average math fluency (auc = . , ci = . - . , p< . ). multiple tasks in the cogstate pediatric battery appear to adequately identify patients with a history of cerebral infarcts. in addition, cogstate tasks appear to be fair predictors of impairments in iq and academic achievement outcomes. cogstate is inexpensive and can be easily administered in a medical setting with minimal training in approximately minutes. results support the potential for cogstate to be used as a screening tool for medical and neuropsychological abnormalities in children with scd. st. christopher's hospital for children, philadelphia, pennsylvania, united states background: cardiovascular disease contributes to the morbidity and mortality of patients with sickle cell disease (scd). hydroxyurea therapy in scd has known clinical efficacy including improving anemia, decreasing episodes of vasoocclusive crisis and acute chest syndrome, and decreasing mortality. effect of hydroxyurea on cardiac function in children with scd is not well studied. an earlier study suggested the protective effect of hydroxyurea on left ventricular (lv) hypertrophy in scd. we hypothesized that hydroxyurea use would be associated with decreased lv remodeling and improved cardiac function. we aimed to evaluate the association between hydroxyurea use and lv remodeling and cardiac dysfunction in children with scd. design/method: we completed a retrospective study of patients with scd who were to years old, followed at st. christopher's hospital for children and had an echocardiogram completed in the past months. data collected included gender, bmi, scd genotype, hydroxyurea use, chronic transfusion use, and d and doppler echocardiographic parameters. cardiac structure, geometry, systolic function, and diastolic function echocardiogram parameters were included. analysis of variance (anova) tests were performed to assess for statistical significance of differences in cardiac parameters between patients with and without hydroxyurea use. analysis of covariance (ancova) tests were performed to control for age. results: demographic and echocardiogram data was collected on all patients who met inclusion criteria. of the patients included, ( %) were on hydroxyurea therapy. patients on hydroxyurea had significantly lower mean relative wall thickness (p = . ) and significantly higher mean peak early lv filling velocities (p = . ) and peak early lv filling/septal annuli early peak (e/ea) velocities (p = . ); however, only the e/ea velocities remained significant when controlling for age (p = . ). mean peak early lv filling velocities approached significance when controlling for age (p = . ). hydroxyurea therapy resulted in a significantly higher e/ea velocity, suggesting that these patients had worse diastolic function. it is possible that the patients initiated on hydroxyurea already had worse disease manifestations than those not on hydroxyurea, possibly accounting for the decreased diastolic function. when controlling for age, hydroxyurea use did not result in significant differences in cardiac structure parameters, systolic function parameters or cardiac geometry. prospective studies and larger sample size are needed to validate our findings, examine for additional statistically significant differences, and develop preventive strategies for cardiovascular disease in children with scd. background: acute chest syndrome (acs) is now the leading cause of death in children with sickle cell disease; mortality in the u.s. is reported to be - % and is mostly due to respiratory failure. early transfusion improves clinical outcomes. although patients with concurrent asthma are considered at increased risk for poor outcomes, risk factors for respiratory failure in pediatric acs have not been well-defined. to determine whether specific epidemiological and clinical features of children hospitalized with acs are predictive of the need for mechanical ventilation. design/method: data from the kids' inpatient database were reviewed to identify patients age < years with a discharge diagnosis of acs for the years , , , and . outcomes were defined by the international classification of diseases, ninth revision, clinical modification code. data were weighted to estimate total annual hospitalizations according to hospital characteristics in the united states. trends in healthcare costs, length of hospital stay, transfusion, and mechanical ventilation use were analyzed using multivariable linear regression. in addition, multivariable logistic regression was used to ascertain specific clinical or epidemiologic factors associated with mechanical ventilation use after adjusting for patient and hospital characteristics. the total hospitalizations for acs were , in ; , in ; , in ; and , in . reported use of mechanical ventilation ranged from . % to . % and was associated with non-black compared to black children (or, . ; %ci, . to . ) and the fall season (or, . ; %ci, . to . ), but not with age, preexisting asthma or hb-genotype. comorbidities of obesity (or, . ; %ci, . to . ), obstructive sleep apnea (or, . ; %ci, . to . ) and heart disease (or, . ; %ci, . to . ) were associated with mechanical ventilation use. the use of simple and exchange transfusion during all acs admissions ranged from . % to . % and . % to . %, respectively. among pediatric acs patients, those with obesity, obstructive sleep apnea or heart disease were at increased risk for respiratory failure and might benefit from early intervention (e.g., transfusion). surprisingly, asthma in children with acs does not appear to be a distinct risk factor for respiratory failure, and further studies are needed to clarify whether differences in treatment approach (e.g., addition of corticosteroids, bronchodilators) might impact on acs progression and/or severity even in high risk patients without asthma. objectives: to compare pulmonary functions between aa and k children with scd and to assess if a high hb f level contributes to better function. design/method: a cross sectional study was done on children with scd (hb ss disease) followed in comprehensive sickle cell programs. aa patients were followed at brookdale hospital, ny and k patients were followed in mubarak hospital, kuwait. children between the ages of and years who had pulmonary function tests (pft) done as a routine screening were enrolled. pft was done using spirometer and plethysmography. patients with congenital or anatomical lung abnormality, heart disease, pulmonary disease such as acute chest syndrome, acute asthma or pneumonia within weeks were excluded. results: there were children ( in each group) with scd,. restrictive pattern on pft was seen in / ( %) of aa vs. / ( %) of k (p> . ). obstructive pattern was seen in / ( %) of aa vs. / ( %) of the k group (p> . ). in both groups, children ( %) had normal pft. three/ ( %) in the aa group had a hb f> % as compared to / ( %) in the k group (p< . ). abnormal pft was noted in / children ( %) in each group. hbf was > % in / ( %) in the aa group vs. / ( %) in the s of s k group (p< . ). in patients with abnormal pft, mean hbf was . ± . in aa group, compared to . ± in k group (p< . ). conclusion: abnormal pft is highly prevalent among children with scd in both groups. aa children are more likely to have restrictive disease and k to have an obstructive pattern. level of hbf did not seem to protect k patients from abnormalities on pft. this finding should emphasize the importance of performing pft as part of the initial evaluation of all children with scd. background: sickle cell disease (scd) is a life-threatening disease with varied clinical spectrum and severity leading to premature death. there is a lack of validated prognostic marker in scd. recent evidence suggests that inflammation and platelet adhesion plays a critical role in the pathophysiology of vaso-occlusion in scd. elevated mean platelet volume(mpv) values are associated with a higher degree of inflammation in many disease states but it's effect on sickle cell disease or it's severity is unknown. objectives: to analyze the role of mpv in predicting disease severity/mortality in pediatric patients with scd. design/method: this is a single center retrospective study and included patients with sickle cell disease between months and years of age during a -year period ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . demographic information, lab data and clinical information including acute chest syndrome (acs), priapism, transfusions, sepsis, pain crisis, avascular necrosis were collected. all laboratory data were collected in steady state with no crisis in the recent past months. the disease severity score/probability of death was calculated using a validated model to predict risk of death in sickle cell disease (sebastiani et al. blood ) . pearson test was used to analyze correlation between mpv and probability of death. results: total no. of patients = ; male ( . %); female ( . %). median age is . years. all patients were of african-american origin. disease severity, hb ss - ( %); hb sc - ( . %) and sickle-beta thalassemia ( . %). patients on hydroxyurea has significantly lower mpv, p = . and this is independent of hb f levels. mpv has a significant positive correlation with the probability of death, p = . and correlation coefficient, r = . . on subgroup analysis, the correlation is even more significant in the age group between and years, p = . , r = . . using linear regression model, with probability of death as a dependent variable and hydroxyurea, mpv as independent variables, mpv maintains a significant association with probability of death (p = . ). conclusion: mpv is an independent biomarker predicting disease severity and probability of death in pediatric patients with sickle cell disease. hydroxyurea a known disease ameliorating agent is associated with lower mpv values. this effect is independent of the levels of fetal hemoglobin and may be due to anti-inflammatory effect of hydroxyurea or effect on the platelets. background: major success with initial qi projects by the sickle cell care team at children's hospital has precipitated ongoing inclusion of the qi approach to many other aspects of patient care. objectives: to optimize scd patient care utilizing qi processes. design/method: success of the scd qi team's initial project on transcranial doppler studies (tcds) and a second more complex project on hydroxyurea (hu) adherence, led to additional projects on completion of key immunizations, rbc phenotyping, and vitamin d level testing. using similar processes and principles from the hu adherence project, plan-do-study-act (pdsa) cycles were used to conduct smallscale tests of change. patient chart prep sheets, created for bi-monthly pre-appointment chart prep meetings, were significantly modified to include these focused care qi objectives. because of difficulty with emr database capability, data collected from the emr was tracked in excel spreadsheets or other unique tracking vehicles for the various parameters. for example, due to the clinic's diffuse, geographically scattered population, many separate non-shared primary care emrs, and lack of a mandatory state immunization registry; immunization records needed to be retrieved from pcps, outlying hospitals, public health departments, and fqhcs, and added to the emr and excel database. starting in / , all such data was collected and updated monthly. in one year's time ( - ) , the average immunization completion rate for seven key immunizations (pcv , pcv , hepatitis a, hepatitis b, meningococcal a, meningococcal b, and hpv) has increased by %. the biggest improvements were a % and % increase in completion for meningococcal a and meningococcal b, respectively. completion rate for rbc phenotyping rose from . % to . %. patients with at least one vitamin d lab test increased from . % to . %. since starting the tcd project in , the percent of patients who have completed their annual tcd has gone from a baseline of % to a sustained value of > %. conclusion: these qi projects have not only increased adherence to national recommendations for care of scd patients, they have helped establish a scd clinic methodology to create and implement sustainable processes. having the focused care initiatives prominently displayed on the patients' chart prep sheet serve as a reminder to medical team members to check the status of that item. this methodology is currently being used to formulate additional qi projects on annual renal function parameters and specialty visits, such as annual eye and dental exams. background: dominican republic has a high burden of sickle cell disease, and - % of children with homozygous hbss (sickle cell anemia, sca) will develop primary stroke. transcranial doppler (tcd) ultrasonography is an effective screening tool for primary stroke risk, but is not routinely available in dominican republic. hydroxyurea and blood transfusions are available, but no prospective screening and treatment program for stroke prevention has been implemented to date. ( ) to screen a large cohort of children with sca living in dominican republic, using tcd to identify elevated stroke risk; ( ) to determine the effects of treatments for stroke prevention (hydroxyurea for conditional velocities and transfusions for abnormal velocities). we hypothesized that both hydroxyurea and blood transfusions will decrease elevated tcd velocities and help prevent primary stroke. design/method: stroke avoidance for children with república dominicana (sacred, nct ) features a research partnership between cincinnati children's hospital and robert reid cabral children's hospital in dominican republic. the protocol, consent forms, and redcap database were prepared collaboratively and translated into spanish, and then irb approval was obtained at both institutions. in the initial prospective phase, children receive tcd screening over a -month period; those with conditional tcd velocities (maximum time-averaged velocity - cm/sec) receive fixed-dose hydroxyurea at mg/kg/day, followed by dose escalation to maximum tolerated dose, while those with abnormal tcd velocities (≥ cm/sec) receive monthly transfusions for stroke prevention. results: a total of children were enrolled in sacred, with an average age of . ± . years. initial tcd screening revealed ( . %) normal, ( . %) conditional, ( . %) abnormal, and ( . %) inadequate velocities. among children ( males, females, average age . ± . years) who initiated hydroxyurea at mg/kg/day for conditional tcd velocities, completed six months of treatment with expected hematological benefits including significant increases in hemoglobin concentration ( . to . g/dl) and fetal hemoglobin ( . to . %). no clinical strokes have occurred in the treatment group. repeat tcd examination after -months of hydroxyurea treatment revealed % ( / ) with previous conditional velocities had normal tcd velocities. the prevalence of conditional tcd velocities in the dominican republic is high, indicating an elevated stroke risk among children with sca. hydroxyurea treatment is associated with improved hematological parameters, lower tcd velocities, and probable decreased stroke risk. sacred is an important prospective and collaborative research trial providing epidemiological data regarding tcd screening, stroke risk, and hydroxyurea effects among children with sca. background: red blood cell aggregation is a rheologic property that explains the shear-thinning behavior of blood. at lower shear rate blood flow, red cells tend to aggregate, s of s whereas in higher shear rate blood flow, these aggregates are dispersed. this property is especially important in the venous system, where low shear rate blood flow predominates. there is inconsistent data in the literature concerning aggregation and aggregability in sickle cell disease (scd). objectives: because the lorrca and myrenne instruments have been shown to be similarly effective methodologies in red cell aggregation measurements, we aimed to determine whether the measurement of aggregation indices in scd, by myrenne and by lorrca, is consistent in our lab. design/method: we measured aggregation in blood samples corrected to % hematocrit. aggregability was measured using kda dextran in the myrenne but not the lor-rca. aggregation index using lorrca was measured in patients with scd and healthy subjects enrolled in a study of blood flow between and . aggregation and aggregability using the myrenne was measured in patients with scd and healthy subjects enrolled in a separate study of blood flow between and . results: using lorrca, we found that aggregation index in patients with scd was less than that of healthy subjects (p< . ). in the myrenne, aggregation at stasis was slightly higher in patients with scd compared to healthy subjects (p = . ) but aggregation at low shear rotation was not different. aggregability was higher in the patients with scd compared to healthy subjects at both stasis and low shear rotation (p< . ). red cell aggregation is an important determinant of low shear blood flow. deoxygenated venous blood is particularly important to low shear blood flow in patients with sickle cell disease. we found that two different aggregometers predict different aggregation results for scd. it is unclear why there is a systematic difference between the two methods, but there are some possibilities. first, the syllectogram in the lorrca is generated by the backscatter of light from the laser, while the myrenne measures transmitted light. second, the distance between the bob and cup in the lorrca is microns, while the gap between plates in the myrenne is microns, which might affect the disaggregation of red cells. further work is needed to understand the differences in red cell aggregation and aggregability when using these instruments, particularly when using aggregation as a predictor of blood flow and tissue perfusion. background: children with sickle cell disease (scd) are at risk of acute splenic sequestration crisis (assc). assc is a life-threatening complication characterized by splenomegaly, pain and severe anemia. assc most often occurs in young children with the most severe forms of scd and one-third of patients will have more than one episode. treatment is based primarily on expert opinion and includes blood transfusion and surgical splenectomy. objectives: we plan to assess the clinical practice patterns of physicians treating children with assc. design/method: a survey study was performed. the survey included six scenarios of severe scd with variation in age, hydroxyurea-use, and episode number of assc; questions focused on the acute and chronic management of assc. the survey was disseminated on three occasions over a six-month period, using an online survey tool, surveymonkey, to pediatric hematologist-oncologists participating in the american society of pediatric hematology-oncology hemoglobinopathy special interest group. the survey had a response rate of % ( / ). most respondents were recent graduates ( %; / ) practicing in academic urban centers with greater than sickle-cell patients. seventy-nine percent ( / ) recommended hydroxyurea initiation in - m/o with severe scd. prophylactic penicillin after surgical splenectomy was continued by % ( / ) after years. for the acute management of assc results did not vary despite patient age, hydroxyurea use, and the number of previous assc episodes. simple transfusion was preferred by % ( / ), with % ( / ) recommending slow transfusion and % ( / ) recommending routine simple transfusion. for the chronic management of assc, results varied based on patient age and the number of previous assc episodes. for a m/o after the first episode, % ( / ) recommended observation and % ( / ) hydroxyurea initiation. for a m/o with any prior episode of assc, % ( / ) recommended chronic transfusion therapy and % ( / ) surgical referral for splenectomy. for a y/o after the first episode, % ( / ) recommended surgical splenectomy and % ( / ) increasing hydroxyurea dose. for a y/o with any prior assc episode, % ( / ) recommended referral for surgical splenectomy. in this survey, we found most providers continue to recommend simple transfusions for assc and surgical splenectomy after two episodes. the majority of providers continue to delay referral for surgical splenectomy until age two, but earlier referral in children under two and use of chronic transfusion therapy were also reported. variability in chronic management highlights the need for further research of splenic sequestration. background: developing therapies for sickle cell disease (scd) is challenging in part because the accepted endpoint, vaso-occlusive crisis (voc), occurs infrequently, does not measure full disease burden, and is a measure of healthcare utilization. in phase / studies of patients with scd, voxelotor (gbt ) has demonstrated increased hemoglobin (hb) levels and reduced hemolysis and has been safe and welltolerated. voxelotor is being evaluated in the ongoing hope phase trial. objectives: to report the innovative phase / hope trial design with novel primary and secondary outcomes to accelerate drug development. design/method: hope (nct ) is a phase , randomized, placebo-controlled, multicenter study of oral voxelotor in patients with scd (aged - years) with baseline hb . - . g/dl and - episodes of voc in the prior year. to accelerate clinical trials to support drug development, the study combines a phase exploratory, dose-selection phase (group ) with a pivotal phase (groups / ). patients in group will be randomized : : to voxelotor or mg/day or placebo. analysis for dose selection will occur when the final patient has received weeks of treatment. group will continue enrollment with randomization : : until dose selection based on analysis of the group cohort. group will allow for a seamless transition into group , which will randomize patients : to the selected dose or placebo. the final data analysis set will include group patients who received placebo or the selected dose and all group patients. the primary endpoint is an objective laboratory measure and surrogate of clinical benefit, increase in hb > g/dl, from baseline to weeks based on voxelotor mechanism of action (inhibition of hb polymerization). this trial is the first to use a patient-reported outcome (pro), the -item sickle cell disease severity measure, as a secondary endpoint. this novel electronic pro, developed specifically for the hope study following fda guidance, will evaluate changes in scd symptom exacerbation and total symptom score from baseline to weeks. additional secondary endpoints include measures of hemolysis, rates of voc, transfusions, and opioid use. the study was designed to enable selection of pro-defined symptom exacerbations or traditionally defined voc as the key secondary endpoint after the group analysis. results: this study is ongoing. the hope trial, expected to complete enrollment by late , will evaluate the efficacy and safety of voxelotor compared with placebo in patients with scd. supported by global blood therapeutics. background: inflammation, coagulation activation, oxidative stress and blood cell adhesion are elements of sickle cell disease (scd) pathophysiology. patients with scd have low levels of the omega- fatty docosahexaenoic acid (dha) and eicosatetraenoic acid (epa) in plasma and blood cell membranes. dha is a bioactive fatty acid with anti-inflammatory, anti-blood cell adhesion and anti-oxidant properties. altemi-atm is a novel dha ethyl ester formulation with a proprietary delivery platform (advanced lipid technology® (alt®)) that enhances oral dha bioavailability. the scot trial investigated the effects of altemiatm in children with scd. objectives: to demonstrate the effects of altemiatm on blood cell membrane omega- index and selected biomarkers of inflammation, coagulation, adhesion and haemolysis associated with scd. s of s design/method: children with scd, aged - years (n = ), were enrolled. subjects were randomized to receive either placebo or one of three daily oral doses of altemiatm ( - , - or - mg/kg/day dha) for two months. the effects of altemiatm on red blood cell (rbc), white blood cell and platelet membrane omega- fatty acids index (total dha + epa levels) were assessed after four weeks of treatment. the effects of altemiatm on markers of inflammation, adhesion, coagulation, and hemolysis were assessed after eight weeks of treatment. cell membrane dha and epa concentration was determined by using lc-ms/ms method. the percent changes from baseline on blood cell membrane omega- index and select scd biomarkers were compared between the three dose groups and placebo using a mixed-model repeatedmeasures (mmrm) analysis with baseline blood cell membrane omega- index, hydroxyurea use, and treatment as fixed effects and patient as a random effect. after four weeks of treatment, blood cell membrane dha and epa levels were significantly increased in all altemiatm doses (p< . ). after eight weeks of treatment, significant reductions were observed in se-selectin (p = . ), and d-dimer (p = . ) in patients exposed to altemiatm dose level vs. placebo. hemoglobin was significantly increased at altemiatm dose level versus placebo. plasma high-sensitivity c-reactive protein, lactate dehydrogenase, soluble vascular cell adhesion molecule- and white blood cell count showed improvement after weeks of treatment in all three altemiatm doses levels but did not reach significance. conclusion: treatment with altemiatm enriches dha and epa in blood cell membranes of patients with scd and improves select sickle cell disease biomarkers of blood cell adhesion and thrombin generation. these findings provide insight into the mechanisms of action of altemiatm in sickle cell disease. brown university -hasbro children's hospital, providence, rhode island, united states background: despite clinical advances in the treatment of sickle cell disease (scd) in pediatric and young adult patients, pain remains a significant source of disease-related morbidity. physical therapy has been shown to be useful for the treatment of pain in children and young adults with various chronic illnesses of which pain is a significant component, however no data exists regarding potential benefits of physical therapy in pediatric and young adult patients with scd. objectives: to query healthcare providers and others involved in the care of pediatric and young adult scd patients regarding possible benefits of and barriers to physical therapy as a potential treatment modality. design/method: we conducted a web-based survey of healthcare providers within the new england pediatric sickle cell consortium (nepscc) in an attempt to identify potential benefits of and barriers to outpatient physical therapy in this patient population. results: nearly % of survey participants felt that physical therapy had the potential to be "somewhat beneficial" or "very beneficial" in pediatric and young adult patients with scd. a majority of physicians reported having referred patients with scd for physical therapy in the past. the most frequently identified perceived potential benefits included improved functional mobility, improvement of chronic pain symptoms, decreased use of opiates, improved mood symptoms, improved acute pain symptoms, and improved adherence with medications and clinic visits. significant perceived barriers identified included lack of transportation, time constraints, patient lack of understanding, and difficulty with insurance coverage. our study indicates that healthcare providers have an overwhelmingly positive view of the use of physical therapy in the management of pediatric and young adult patients with scd. significant barriers exist which need to be addressed. future research should focus on patient and parent perspectives regarding physical therapy, as well as a randomized controlled trial of a physical therapy intervention in this patient population. background: vitamin-d deficiency is fast becoming increasingly recognized in patients with sickle cell disease (scd). while it is estimated that these patients are five times more likely to develop vitamin-d deficiency, the exact clinical significance of this is largely unknown. given that this deficiency can be inexpensively and easily treated, our study sought to establish the prevalence of vitamin-d deficiency in our patient population and its relationship with disease severity. objectives: to estimate the prevalence of vitamin-d deficiency in patients with scd in our institution and to analyze their disease severity in relation to their vitamin-d level. design/method: through retrospective chart review we analyzed subjects that represent a cohort of patients followed at the adult and pediatric hematology services at university of miami with known diagnosis of scd that had a vitamin-d level drawn between january st, and august st, . we conducted a cross-sectional study and recorded the first vitamin-d level during this period. patient demographics, medical and social history information were collected along with laboratory data. the number of admissions for vaso-occlusive crisis (voc) and acute chest syndrome within one year preceding the collection the vitamin-d level was also recorded. results: a total of charts were reviewed, adult charts and pediatric charts. after exclusion, patients were enrolled. subclinical vitamin-d deficiency is only evident on laboratory blood testing of vitamin-d ( -hydroxy) and according to this laboratory result patients were classified as sufficient (≥ ng/ml), insufficient (< to ng/ml) and deficient (< ng/ml). out of the cases, . % ( / ) were deficient, . % ( / ) were insufficient and . % ( / ) were optimal. after statistical analysis two negative correlations were identified, increasing vitamin-d levels with decreasing white blood cell count (ci %- . (- . , - . )and decreasing incidence voc (ci %- . (- . , - . ). conclusion: this study confirms that there is a significant prevalence of vitamin-d deficiency in patients with scd. furthermore, the results of this investigation proved that vitamin-d deficiency is associated with acute pain and leukocytosis in patients with scd. given the multitude of confounding factors that affect vitamin-d absorption and intake, multivariate analyses are required to truly further investigate this relationship. texas children's hospital, houston, texas, united states background: hemophagocytic lymphohistiocytosis (hlh) is a rare but life-threatening condition of hyper-inflammation that is characterized by splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia, hemophagocytosis and coagulopathy. although timely diagnosis is imperative, it is often challenging as these individual signs and symptoms may occur in a variety of clinical conditions. to report a case of undiagnosed sickle cell anemia presenting with severe ebv viremia and associated hemophagocytic lymphohistiocytosis results: a -month-old previously healthy male presented with respiratory distress, increased fatigue, and a focal seizure following a two-week history of cough and lowgrade fevers. physical exam was consistent with hypovolemic shock and revealed significant splenomegaly. laboratory testing revealed severe hypoglycemia, acidosis and electrolyte disturbances including hyperkalemia, hyperphosphatemia, and hyperuricemia. labs showed a leukocytosis (wbc , ), severely low hemoglobin ( . ), and platelets of , . coagulation testing revealed prolonged pt/inr and ptt, hypofibrinogenemia and a highly elevated d-dimer. additional workup was completed to determine etiology of acute presentation, given broad differential diagnosis. infectious studies were consistent with an acute ebv infection (plasma ebv pcr > , ). elevated levels of soluble il- and ferritin completed / criteria for the diagnosis of hlh. bone marrow evaluation showed trilineage hematopoiesis with no abnormal blast population or hemophagocytosis. results from hemoglobin electrophoresis sent from the initial cbc sample were notable for hbs . %, hbf . %, and hba of %, confirming the diagnosis of sickle cell disease. the patient was started on hydroxyurea and penicillin and splenomegaly resolved. with supportive care, he demonstrated gradual improvement in symptoms and laboratory abnormalities, including normalization of soluble il- , ferritin, cd , il- levels, immunoglobulins, and declining ebv titers. nk cell function has remained abnormally low, not eliminating the possibility of acquired hlh despite spontaneous improvement. conclusion: splenic sequestration associated with sickle cell disease in combination with acute infectious mononucleosis could have explained many of the presenting symptoms including anemia, thrombocytopenia, and splenomegaly. however, it does not explain the unusually high ebv titer and degree of inflammation meeting diagnostic criteria for hlh, which raises concern for an underlying immunologic abnormality such as x-linked lymphoproliferative disorder (xlp). although testing for xlp was negative, he will require s of s continued monitoring in the future for signs of relapse. this case illustrates the complexity of diagnosing lymphohistiocytic disorders and the significant overlap in presentation between these disorders and other medical conditions. background: vaso-occlusive crisis (voc) is one of the most distressing occurrences in patients with sickle cell disease (scd). patient controlled analgesia (pca) is recommended by nih and expert opinions favor its early use. we aim to review the use of pca in patients with voc and to evaluate if its early use is associated with faster pain control and reduced length of stay (los). design/method: this retrospective single center study included all pediatric patients admitted and treated with pca for a severe voc from to . "early" use was defined as start of pca within hours of arrival in the emergency department (ed) and "late" use after hours. time to reach adequate analgesia was defined as oucher, verbal scale or faces pain scale < / obtained twice consecutively in a -hours interval. time to reach adequate analgesia and los were compared between early-pca and late-pca groups. results: a total of patients presented episodes of voc treated with pca during the study. sixty-one episodes ( %) were treated with early-pca and ( %) with late-pca. both groups were comparable in terms of age ( . vs . years old), gender ( . % female vs . %), hemoglobin phenotype ( . % hbss vs . %), but median pain score at admission was higher in early-pca than in late-pca ( / vs / , median difference ( % ci , ). early-pca was associated with a median reduction in los of . days ( % ci . , . ) (median early-pca los . vs late-pca . days). time to reach analgesia could be evaluated only in a subset of patients ( in early-pca and in late-pca group). although time to reach adequate analgesia tended to be shorter in the early-pca group, it was not statistically different: median . hours vs . hours, difference of . ( % ci - . , . ). side effects were observed during ( . %) pca treatments ( / ( . %) episodes in early-pca, / ( . %) in late-pca group) among which ( . %) were significant adverse events. these were observed in patients who required interventions: desaturations requiring oxygen without intubation, neurologic abnormalities (hallucinations, visual abnormalities, no stroke), urinary retentions. conclusion: early use of pca for severe voc was associated with a reduced length of hospital stay despite that these patients had higher pain score on admission. prospective studies are needed to support these positive outcomes. background: acute chest syndrome is one of the leading causes of death in children with sickle cell disease - . while the cause of acute chest syndrome most commonly is not identified, fat embolism and infectious causes are believed to be most common. with an extremely high mortality rate, rapid identification and initiation of therapy is essential for survival. case presentation: we describe the case of an -year-old female with sickle cell sc disease who was admitted for vasoocclusive pain crisis and quickly progressed to multi-system organ failure due to fat embolism syndrome and parvovirus b infection objectives: the case highlights the presentation and diagnosis so other providers can optimize outcomes for those with this under-recognized syndrome design/method: her parvovirus studies returned after days which showed: parvovirus b dna pcr detected; parvo igg . (positive > . ); and igm . (positive > . ). the patient experienced an approximately . g/dl drop in hemoglobin( . to . g/dl/ hrs) with progressive thrombocytopenia (from , to , /ul) and a peripheral smear showed microcytic,normochromic red cells with nucleated rbcs and occasional nuclear budding, slight polychromasia, schistocytes, and polymorphic cells with toxic granules that suggested leukoerythroblastosis. she was emergently transferred to the regional quaternary care hospital for ongoing ecmo therapy where she experienced a change in her pupillary exam prompting a stat ct scan that showed severe, diffuse cerebral edema with transtentorial herniation. the decision was made to withdraw life-sustaining therapies and her family refused a post-mortem autopsy examination. fat embolism syndrome is a severe and uncommonly recognized complication of sickle cell disease, seen most commonly in those with a non-ss phenotype and previous mild disease course who present with severe, unrelenting vaso-occlusive pain episode and/or acute chest syndrome that progresses to respiratory distress with altered mental status and cutaneous changes. rapid identification and initiation of exchange transfusion therapy should be initiated with clinical suspicion because of the extremely high mortality rate. although previously considered rare, it needs to be considered in the differential diagnosis of more commonly encountered complications of sickle cell disease. background: patients with sickle cell disease (scd) experience vaso-occlusive crisis (voc), which results in extreme pain, often requiring opioids and admission. genetic and environmental factors affect the frequency and severity of these episodes. previous research has born conflicting evidence on whether environmental temperature is contributory. edmonton, alberta is the northern most city with a population over a million in north america. there is an increasing sickle cell population which is exposed to extreme winter conditions. this provides a suitable population and atmosphere to study the influence on cold external temperatures in scd. this study sought to identify if pediatric patients with scd, experience greater morbidity in cold external temperatures. board approved retrospective case control series. patients were identified through a clinical database, and emergency visit, phone call and admission data was collected over a fiveyear period. the average, minimum and change in temperature on day of presentation, and hours prior, was collected from the government of alberta, and was statistically analyzed using descriptive statistics, to determine the relation to vaso-occlusive events. results: one-hundred and eighteen patients were identified, and voc events reviewed. the mean patient age was . years of age with a range from . - years old. the female to male ratio was equivalent with female ( . %) and male ( . %) voc events. eight records ( %) had docu-mented cold exposures. the analysis between the temperature and the frequency of events did not yield significant correlation. average and minimum temperature on day of admission had the largest percentage of voc events occur at mild temperatures, from - . to • c and - . to respectively. change in temperature on day of admission, and hours had the largest percentage of voc events at a mild to moderate change in temperature of - degrees. data at & hours prior to admission showed similar results. secondary data analysis accounting for the lower proportion of extreme weather days in comparison to moderate temperate days showed no significant impact. there was no correlation of average, minimum or change in temperature on day of admission, or hours prior. multiple cofounding factors likely contribute to these results. as it was a retrospective study many confounding and precipitant factors may not be recorded or identified. a prospective study to better record specific cold exposure is warranted. children's national health system, washington, district of columbia, united states background: achieving optimal anticoagulation with unfractionated heparin (ufh) in pediatric patients receiving extracorporeal membrane oxygenation (ecmo) is often challenging due to antithrombin (at)-mediated heparin resistance (hr). intermittent at dosing during pediatric ecmo support does not maintain adequate at levels. continuous at infusion (cati) presents an alternative strategy to achieving consistent goal at levels and optimizing heparinization. however, cati during pediatric ecmo has not been adequately studied. objectives: to describe our center's experience with an ecmo cati protocol. design/method: in , we modified our ecmo anticoagulation protocols to include ufh titration according to anti-factor xa (anti-fxa) levels and cati in patients with at-mediated hr. the cati rate was calculated using baseline and goal at levels while accounting for the circuit volume. cati was administered with ufh into the circuit via a s of s y-infusion set. at and anti-fxa levels were monitored every hours. recombinant at (r-at) concentrate was used at our center until with subsequent transition to a plasmaderived at (pd-at) concentrate. due to the longer half-life of pd-at concentrate, the protocol was modified so cati is stopped once target at and anti-fxa levels are achieved. we conducted a retrospective study of all patients who received cati during ecmo support at our center. data are reported as median and interquartile range and compared using the mann-whitney u test. two-tailed p-value < . was considered statistically significant. since , patients [ males, age month ( . - )] on ecmo support received catis ( rat, pd-at) per our protocol ( patients received pd-at infusions during one ecmo run). the duration of cati was hours ( - ). cati administration led to significant increases in at and anti-fxa levels from baseline of % ( - ) and . units/ml ( . - . ) to the first level within goal of % ( - ) and . units/ml ( . - . ), respectively (p< . ). the respective times to achieve goal at and anti-fxa levels were hours ( - ) and hours ( - ). the respective peak at and anti-fxa levels were % ( - ) and . units/ml ( . - . ). during cati, no patient required circuit change, patient developed cannula thrombosis and patients experienced non-fatal major bleeding. conclusion: cati in pediatric patients receiving ecmo support with close monitoring of at and anti-fxa levels was associated with significant rapid increase in at, optimization of heparin effect, and reduction in thrombotic complications without increase in major bleeding compared to prior reports. a prospective study of this at dosing strategy is warranted. children's hospital of orange county, orange, california, united states background: inherited factor xiii (f ) deficiency is a rare bleeding disorder with wide heterogeneity in clinical manifestations ranging from mild bruising, and mucosal and umbilical stump bleeding to spontaneous, severe intracranial bleeding. the bleeding phenotype is influenced not just by zygosity of the fxiii mutation alone, but also by co-inheritance of variants in other clotting protein genes that also play a major role in clot formation and stability. we present a series of three siblings found with f a gene variant and platelet dysfunction linked to bleeding phenotype. design/method: retrospective chart review of the index case, coagulation studies and whole gene sequencing. the index patient presented at two years of age with a subdural hematoma after a fall, requiring emergent craniotomy. a week after initial evacuation, she re-bled, prompting an extensive work-up for potential bleeding disorders, including f activity, von willebrand profile, comprehensive fibrinolysis panel, pai- antigen level, platelet mapping thromboelastogram (plt-teg), and f genetic analysis. the patient's identical twin and older sibling, who had symptoms of bruising, underwent a similar evaluation. the index patient demonstrated consistently low f activity ( - %), and platelet function testing revealed decreased response to adp agonists. the twin and older sibling had normal f levels, and only slightly decreased response to adp in platelet studies. whole gene analysis of f and other genes on our next generation panel, revealed several intronic deletions in the index patient that were not shared by her siblings, which likely account for her decrease in circulating f levels. her symptoms have responded well to monthly treatment with factor concentrate. all three children shared the f variant, pro leu, previously described as a risk factor for intracranial hemorrhage. the f mutation, pro leu, has been associated with intracranial hemorrhage in young women, but the presence of the variant alone may not be enough to cause a severe bleeding phenotype. family studies identified novel deletions in the index patient which may account for her decreased f levels, which would have been overlooked with standard sequencing. future studies, including evaluation of 'platelet' f levels, should be performed when platelet dysfunction is detected. further laboratory and clinical evaluation is required to delineate the long term implications of the interaction of even mild f deficiency if present with additional clotting disorders such as the platelet function defect in these siblings. background: acquired hemolytic anemia can occur due to mechanical shearing of red blood cells and is classically seen in patients with prosthetic heart valves. there are reports of this same traumatic effect with other repairs, including annuloplasty. following valvular procedures flow disturbances can exist across the valve that lead to shear stress and hemolysis. although von willebrand disease (vwd) is typically seen due to an inherited disorder in the pediatric population, flow disturbances in the setting of valve abnormalities can lead to acquired von willebrand syndrome (avws). von willebrand factor multimers become unfolded and elongated in the setting of shear stress resulting in increased susceptibility to cleavage by adamsts- . specifically, loss of high molecular weight multimers (hmwms) can lead to a syndrome akin to type a vwd. objectives: to describe a case of mechanical hemolysis with acquired type a vwd design/method: a -month-old girl with history of hypoplastic left heart syndrome and severe tricuspid valve insufficiency underwent norwood procedure, blalok-taussig shunt placement and subsequently a bidirectional glenn and tricuspid valve annuloplasty. during the following month she requires weekly red blood cell (rbc) transfusions due to intermittent anemia. she also experienced bloody stools and dark urine. laboratory evaluation was notable for normocytic anemia, reticulocytosis, elevated lactate dehydrogenase, and low haptoglobin consistent with hemolytic process. immune-mediated hemolysis from transfusion reaction or presence of autoimmune or alloimmune antibodies testing was negative. to investigate gi bleeding, work up for vwd revealed normal vw activity and antigen but with loss of high molecular weight multimers consistent with acquired type a vwd. in consultation with cardiology, it was felt her tricuspid valve insufficiency jet could be leading to mechanical hemolysis and avws. a repeat echo showed persistent moderate tricuspid insufficiency but no other significant changes. due to the patient's continued need for weekly rbc transfusions she was subsequently trialed on pentoxifylline which is used in adult patients to decrease blood viscosity and increase erythrocyte flexibility in patients with mechanical hemolysis. her transfusion needs remained the same and the medication was discontinued after two weeks. she required one transfusion a week later but no transfusions since that time. although not commonly seen in pediatric patients, the diagnosis of mechanical hemolysis accompanied by avws should be pursued in a patient with congenital heart disease with significant anemia and/or bleeding. the work up in these patients is difficult as echocardiograms can be inconclusive thus an extensive hematologic evaluation is usually necessary. objectives: our aim was to assess incidence of and potential risk factors for central line-related dvt at our institution between - . additionally, our goal was to analyze if that incidence differed between the three central line types and identification of line-specific risks. design/method: a retrospective chart review of central line placements in pediatric patients at cleveland clinic between - was conducted. data included demographics, potential risk factors, line characteristics and any related thrombotic events. the study cohort consisted of lines in pediatric patients aged - years of age. there were . thrombi ( % ci . - . ) per , line days. statistically significant risk factors for thrombus include diagnosis group (liquid tumor highest rate of %, solid tumor lowest at %), type of line (picc %, broviac %, and mediport %), location of line, greater number of lines per patient, peg asparaginase ( % vs %), sepsis, and history of procoagulant state. line characteristics such as lumen size and number of lumens were not identified as a significant risk. there was a significantly higher rate of thrombus in than in the previous years when pooled ( % in vs . % from - , p = . ). the incidence of dvt in pediatric patients at our institution was highest with broviac lines, and significant risk factors in our patient population included liquid tumor, femoral vein location, peg asparaginase, sepsis, and history of a procoagulant state. the incidence of thrombi was highest in , and therefore highlights the urgent need for improvement in nationwide hospital practices to minimize risk of thrombi formation and early detection in the higher-risk s of s populations. there is still much to be learned regarding the characteristics specific to different central lines, which would influence thrombi formation. nyu winthrop hospital, mineola, new york, united states background: pediatric immune thrombocytopenic purpura (itp) is an autoimmune disorder with platelet counts < causing increased risk for significant hemorrhage. there is increased immunologic platelet destruction due to production of specific autoantibodies along with inhibition of platelet production. few randomized trials exist to guide management and ultimately each patient requires an individualized treatment plan. itp may be acute (diagnosis to m) or chronic (> months). one of the treatments of chronic itp is laparoscopic splenectomy (ls), which is very well tolerated. a rare complication of ls is splenosis, an autotransplantation or implantation of ectopic splenic tissue within the abdominal cavity or in any other unusual body compartment. splenosis is sometimes associated with relapsed itp due to preserved immune activity. the usual management of symptomatic splenosis is surgical resection. objectives: to describe medical management in a young patient with itp relapsed due to extensive unresectable splenosis following ls design/method: our patient was originally diagnosed at years with itp and was treated with ls at years of age for chronic severe thrombocytopenia and persistent bleeding not responding to first line therapies. she tolerated it well and had a complete response (cr) defined as a platelet count of > measured on occasions > days apart and absence of bleeding. she maintained a normal platelet count for twelve years after which she relapsed (loss of response after cr) with severe thrombocytopenia and hematuria necessitating high dose steroids. ct scans showed multiple wellcircumscribed soft tissue masses in the left lower quadrant adjacent to uterus and left ovary, involving left omentum and the anterior abdominal wall partly. findings were confirmed by damaged rbc nuclear scan to be splenosis. during laparoscopy the splenosis lesions were deemed too extensive and were not resected completely to avoid postoperative morbidity. she was started on sirolimus around the same time for treatment of her relapsed itp and steroids were weaned off. results: eight months since beginning sirolimus with therapeutic levels she remains in cr with no bleeding and has not required any steroids, immunoglobulins or anti d immunoglobulin. conclusion: sirolimus is a safe and effective steroid-sparing agent in treatment of chronic itp. this is the first instance of a patient with poorly resectable splenosis responding well to medications for itp. more data is needed regarding the longterm efficacy of such an intervention and whether it will eliminate the need for a second surgery in relapsed itp patients with extensive splenosis. background: storage pool disorders affecting platelets result in bleeding symptoms related to a deficiency or defect in alpha granules or delta granules. in delta-storage pool disorders (dspd,) there is a deficiency of the delta granules and their constituents, which results in the inability of platelets to properly activate as well as lack of proper constriction of blood vessels during bleeding episodes. amongst patients with dspd, females most commonly present with menorrhagia, while males tend to present with epistaxis and easy bruising. the international society on thrombosis and hemostasis (isth) developed a screening bleeding assessment tool (bat) for mild bleeding disorders, shown to be a validated tool in children. diagnosis of dspd is classically made with a platelet electron microscopy (pem) value < . delta granules per platelet (dg/pl), but recently lower diagnostic thresholds of dg/pl or even . dg/pl have been suggested. objectives: evaluate the correlation between pem and bleeding scores, and also examine various cut-off values used to diagnose and risk stratify patients with dspd. design/method: retrospective chart review of pediatric patients followed by hematology with a diagnosis of dspd was performed. clinicians obtained bleeding scores for each patient as standard of care in the hemostasis clinic. quartile ranges were established to appropriate three stages of severity based upon bleeding scores. statistical analysis was performed using software r and exploratory data analysis to evaluate for a correlation. results: amongst all patients, the average bat score was . and pem was . dg/pl. the average bleeding score for pem between . dg/pl and dg/pl was . , while the average bleeding score for pem below dg/pl was . . the correlation coefficient between pem and bleeding scores is . . using a threshold of dg/pl, % of patients would have met diagnostic criteria. quartile ranges for the bleeding scores are as follows: st quartile was - , nd quartile was - , and rd quartile was > . conclusion: patients with a more marked granule deficiency do not exhibit a more severe bleeding phenotype, suggesting proper platelet function is not solely determined by granule quantity in these patients. bleeding severity may be more appropriately assessed with bleeding scores rather than pem values, and using quartile ranges may aide in risk stratification and therapeutic interventions for dspd patients. further work remains to determine the optimal diagnostic threshold of pem dspd in pediatric populations. texas children's hospital, houston, texas, united states background: warfarin management has many challenging aspects including pharmacogenomics, food and drug interactions, lack of standardized dosing, patient compliance, tracking lab results from multiple lab locations, and the potential for significant bleeding or thrombotic complications. a literature review revealed limited data highlighting anticoagulation monitoring workflow and emr documentation and specifically, no data in the pediatric population. historically, the texas children's hospital cardiology and hematology centers were each documenting anticoagulation data within the epic tm system differently. epic's tm original design for anticoagulation documenting resulted in the necessity to duplicate documentation in order to see at-a-glance critical anticoagulation monitoring information. objectives: the objective of this project was to standardize inr documentation across departments to reduce the risk of patient safety events and improve workflow. design/method: a workgroup assembled consisting of nurses from the cardiology and hematology departments, along with staff members from the epic tm is support group. the workgroup identified current documentation practices, available epic tm tools, and brainstormed ideas to streamline and improve both documentation with the current epic tm tools. physician partners were identified in cardiology, hematology and coagulation laboratory to gain their input. a new anti-coag (ac) encounter was developed and first made available in an epic tm practice environment, then once approved, epic tm written education and training session were completed by both departments' staff. results: surveys were sent to health care providers in the cardiology and hematology centers prior to the new ac encounter, and also to health care providers six months after implementing the ac encounter. six responses were received for each survey. the pre-implementation survey showed the most problematic part of the documentation system for anticoagulation was no single place in the emr to find a complete anticoagulation picture. post ac encounter implementation survey results revealed more health care providers using the epic tm inr reminder pool, less time needed to compile a report of three months of anticoagulation information, less time needed to document individual encounters, less locations needed to document ac information and decreased amount of types of documentation used. standardized ac encounters improves workflow with less time needed to document and compile information, less types of documentation utilized and easier access to patients ac information. next steps include retrospective review of patients' inr time in therapeutic range to determine if there was an impact on patient compliance and continue to evaluate and modify the ac encounter to enhance user friendliness. caitlin tydings, jennifer meldau, christine guelcher, carole hennessey, eena kapoor, michael guerrera, yaser diab s of s children's national health system, washington, district of columbia, united states background: venous anatomic abnormalities (vaas) are considered a risk factor for developing deep vein thromboses (dvts) that occur as a result of significant alterations in venous blood flow. identification of predisposing vaas can be challenging. hence, diagnosis can be delayed or overlooked especially in pediatric patients. dvts in children or adolescents with predisposing vaas have been only described in sporadic case reports and small case series. objectives: to describe characteristics and outcomes of dvts in pediatric patients with underlying vaa treated at our center. design/method: we conducted a retrospective chart review of all pediatric patients with objectively confirmed extremity dvt treated at our institution over a -year period from to and identified all patients with underlying vaas. patients were managed according to standardized institutional protocols based on published guidelines. post-thrombotic syndrome (pts) was assessed at our center using the manco-johnson instrument. relevant data were collected and summarized using descriptive statistics. during the study period, of pediatric patients ( %) [ females, median age years (range - )] diagnosed with extremity dvt at our center were found to have an underlying vaa. vaas included may-thurner anomaly ( patients), venous thoracic outlet obstruction ( patients) and inferior vena cava (ivc) atresia ( patients). additional provoking factors were identified in patients at time of presentation. dvt locations included upper extremity veins ( patients), lower extremity veins ( patients) and lower extremity veins and ivc ( patients). the majority of dvts [ patients, ( %)] were completely occlusive. high risk thrombophilia (defined as inherited deficiency of antithrombin, protein c, or protein s, or antiphospholipid antibody syndrome) was present in patients ( %). all patients were treated with therapeutic anticoagulation with patients continuing indefinite anticoagulation. endovascular interventions were performed in patients and included percutaneous pharmacomechanical thrombectomy and/or catheter-directed thrombolysis ( patients), balloon angioplasty ( patients) and stent angioplasty ( patients). surgical interventions included thoracic decompressive surgery ( patients) and surgical thrombectomy ( patient vvas represent an important risk factor for developing extensive extremity dvt in adolescents. this special population is at risk for short-term and long-term com-plications. early identification and correction of vaas may improve outcomes. however, multicenter, prospective studies are needed for developing optimal evidence-based treatment approaches. alexander glaros, roland chu, sureyya savasan, meera chitlur, madhvi rajpurkar, yaddanapudi ravindranath children's hospital of michigan, detroit, michigan, united states background: acute budd-chiari syndrome (bcs) is a rare thrombotic emergency in children, and etiologies/treatment are less well-defined than in adults. in adults, a systematic approach including anticoagulation, relief of venous obstruction, and treatment of the underlying cause has proven successful. more recently treatment has tilted towards aggressive surgical interventions, which carry significant risk and are often not feasible. objectives: review our experience with three different patients with bcs and suggest a mechanistic based approach to treatment. the records of three patients with bcs were reviewed and their presentations, etiologies, treatment, and outcomes were reported. results: patient a was a -year-old female with paroxysmal nocturnal hemoglobinuria who presented with recurrent worsening abdominal pain over several months. narrowing of inferior vena cava (ivc) and hepatic veins was noted on imaging. liver transplant was not considered surgically feasible. she was treated with eculizumab, steroids, and anticoagulation with restoration of hepatic venous flow in weeks. patient b was a -year-old male with several weeks of right upper quadrant pain, fatigue, and pre-syncopal episodes, with a history of blunt abdominal trauma from football scrimmage weeks earlier. he was found to have near complete occlusion of the ivc and hepatic veins. liver transplant was not considered feasible. he was successfully treated with anticoagulation alone. patient c was a -yearold male with acute myeloid leukemia in induction cycle who developed severe pancytopenia; typhlitis was diagnosed and managed medically. days later he acutely decompensated, arrested, and was placed on extra corporeal membrane oxygenation, and imaging showed complete occlusion of the portal vein, hepatic veins, and ivc to the level of the atrium, with bilateral pulmonary emboli. emergency liver transplant or catheter based interventions was deemed not feasible. treatment with eculizumab was considered for presumed inflammation induced complement activation (c mg/dl [normal - ]; ch was u/ml [normal - ]) as a trigger for thrombosis, but the patient progressed quickly and died before it could be initiated. our experience with bcs shows that invasive interventional options and liver transplant may not be feasible in most patients for multiple reasons. rapid diagnosis and aggressive etiology-based medical management are paramount to successful treatment of this rare complication. eculizumab may be considered in treating bcs with complement activation not only due to innate disorders, but also secondary to acute inflammation when proper laboratory evidence is present. background: platelet aggregation studies are the gold standard for the diagnosis of platelet function defects during the evaluation of a patient with bleeding problems. the platelet aggregation test measures how well platelets clot in response to different concentrations of epinephrine, adenosine diphosphate (adp), collagen, arachidonic acid and ristocetin. because platelet function defects are often under-recognized and under-diagnosed in the pediatric patient, the true incidence is unknown. we report our experience in the diagnosis of platelet defects at our institution over a -year period in order to add some clarity to the limited pediatric data available. objectives: our primary objective is to document correlations/trends between less well-known platelet function abnormalities and clinically significant bleeding at our institution over a -year period. design/method: after appropriate irb approval obtained, we performed a retrospective chart review of all children who had platelet aggregation testing done from to . data collected included demographics (age, sex, race), personal and family history of bleeding, screening for coagulation defects and platelet aggregation test results. symptoms examined in our data were limited to epistaxis and heavy menstrual periods. for each of these symptoms, results were further analyzed to those with abnormal responses to adp and epinephrine. patients with existing bleeding diagnoses and those with incomplete medical records were excluded. we identified patients. of the patients with epistaxis, % had abnormal platelet aggregation testing while only % of those with heavy menstrual periods had abnormal results. within our population, abnormal platelet function assay (pfa- ) results or race did not appear to correlate with abnormal platelet aggregation testing. in the cases of epistaxis, sex was also noncontributory. our preliminary results suggest that platelet aggregation testing was more useful in predicting platelet defects in those with a clinical bleeding history of epistaxis as opposed to heavy menstrual periods. for other presenting symptoms, platelet aggregation testing did not offer diagnostic benefit. abnormal response to adp in the platelet aggregation test was the most common finding in our population; the clinical significance of which is not well understood. going forward, we plan to document whether abnormal results correlated significantly with the subsequent final diagnoses of our patients. background: decision making for severe hemophilia a in previously untreated patients (pups) has recently become a significant ethical debate. recombinant factor viii (rfviii) products previously were recommended to avoid transmission of blood borne pathogens associated with plasma-derived fviii (pdfviii) products. however, the increased incidence of fviii alloantibody inhibitors with rfviii products compared to pdfviii products has challenged this former standard of care. despite the support of the medical and scientific advisory council, recommendations considering pdfviii products for a pup remains controversial. design/method: we used a modified utilitarian approach involving clinical, public health, and research ethics. shared decision making permeates the framework to maximize understanding, minimize bias, respect informed consent or dissent, and provide care that aligns with patient and family values when medically and practically feasible. the framework has three tiers. first, it evaluates whether resources are scarce or abundant for equitable resource allocation. if fviii products are scarce, we s of s recommend developing a central supply for emergency use and then evaluating the needs of the severe hemophilia a patients. prioritization of who receives the factor products would be decided by a designated team based on the availability of the factor products and clinical scenarios, with no preference given to those on research trials. however, if resources are abundant, treatment for acute bleeding and standard of care prophylaxis measures, including primary prophylaxis, could continue. the second tier accounts for whether there is a new infectious epidemic or concern where a pathogen cannot be eliminated. if there is, healthcare and public health workers may limit the use of pdfviii products. if not, pdfviii and rfviii products are to be equally considered. the third tier evaluates whether the clinical scenario is emergent or not. if there is acute, emergent bleeding, the immediately available resource should be used, along with bypassing and/or adjuvant resources as needed until the bleeding has resolved or improved. to align with patient and family preferences, attempts to have both pdfviii and rfviii products available at similar costs in institutions would be ideal. this ethical framework endeavors to balance autonomy, beneficence, nonmaleficence and justice in helping guide discussions among providers, pups with severe hemophilia a, and their families. disclaimer: findings and conclusions are those of the author(s) and do not necessarily represent the official position of the centers for disease control and prevention, emory university, or children's healthcare of atlanta. background: von willebrand disease (vwd) is a common bleeding disorder which affects up to % of the population without gender predilection. bleeding associated with this condition results from a deficiency or abnormality in von willebrand factor interfering with formation of primary hemostasis. ehlers-danlos syndrome (eds) is a group of rare inherited connective tissue disorders which may have an associated bleeding manifestation without abnormalities in coagulation testing. bleeding symptoms reported in eds result from capillary and tissue fragility. joint hypermobility syndrome (jhs) is an inherited condition which is nearly indistinguishable from eds iii. reports of coinheritance of vwd and eds or jhs are infrequent. the objective of this retrospective study was to review patients with coexisting vwd and eds or jhs at the indiana hemophilia and thrombosis center in order to describe the type and severity of bleeding symptoms, physical examination findings, and pertinent laboratory data. design/method: the electronic medical record database of the indiana hemophilia and thrombosis center was queried for patients with a diagnosis of vwd and one of the following descriptors: hypermobility syndrome, hypermobility, hypermobile joints, or ehlers-danlos syndrome. the records of identified patients were reviewed for demographics, type and severity of bleeding symptoms, beighton scores (bs), vwd antigen, ristocetin cofactor, factor viii levels, vwd multimer pattern, vwd subtype, genetic testing for eds, and family history of eds. results: a total of patients with dual diagnoses of vwd and eds and patients with vwd and hypermobility were identified with this query. two patients had completed genetic testing for eds, and one had a col a gene mutation identified. significant bleeding symptoms in the vwd and eds group included hematuria and postoperative hemorrhage. two of these patients had delayed wound healing postoperatively. seven of the patients identified to have type i vwd and jhs had moderately severe and somewhat unusual bleeding episodes reported including hematuria, hematemesis, and hemoptysis; of these patients had significant perioperative bleeding. females composed % of the vwd and eds group and % of the vwd and jhs group. conclusion: coinheritance of vwd and eds is an uncommon phenomenon. patients with vwd and eds or jhs may have atypical and moderately severe bleeding, especially with procedural intervention. incorporation of bs into the assessment of patients with bleeding disorders is useful to identify potential inherited collagen disorders, as diagnosis of these conditions may impact clinical management. in the year-long phase ii study (ro fd ), / khe patients responded. patients were followed for years after study completion, collecting data on growth and development, complications of therapy, unexpected toxicities, and need for continuing sirolimus. objectives: after study therapy treatment of one year, objectives include: . assess long term toxicity over the - year period after study therapy completion . assess unexpected toxicity . assess overall condition of the patient . assess need for restart or continuation of sirolimus therapy design/method: prospective follow-up of patients with a diagnosis of khe from institutions. inclusion criteria: follow-up for - years post-study. results: follow-up included data at year (n = ) and - . year (n = ) time points. average age at the start of treatment was months. of patients were available for follow up. four patients are no longer on sirolimus: one patient completed study therapy and remains off treatment (ot) ( years), required years of treatment and is now . years ot and required an additional treatment course prior to successful discontinuation now and months ot. of the patients still on sirolimus, all restarted medication for symptoms of pain, swelling and/or edema interfering with quality of life and have made an average of . attempts to discontinue sirolimus. no patient had reoccurrence of kmp. all patients had improvement in clinical and radiologic appearance of khe but all have residual lesions noted on imaging and/or clinical exam. no unexpected toxicity, growth delay, developmental issues or other long term toxicity of sirolimus was noted. conclusion: this is the first prospective data on long-term follow up of khe patients treated with sirolimus. although numbers are small, sirolimus is well tolerated; however, over half the patients were still on medication at - year follow up. this stresses the need for continued long term follow up in these young patients and investigation of the mechanism of sirolimus effect. nationwide children's hospital, columbus, ohio, united states background: recent studies have identified that adult persons with hemophilia (pwh) have a higher prevalence of hypertension and renal disease than the general population. while hematuria is a known complication of hemophilia a and b (ha, hb), its long-term impact on pwh is not currently known. by annually screening our patients with urinalysis, our pediatric center identified that just under half of our patients demonstrated hematuria over a four-year period. motivated by a desire to identify early markers of hypertension and renal disease, we sought to determine if this finding is reflected in the pediatric hemophilia population as a whole. objectives: establish the population-wide prevalence of hematuria in pediatric pwh. design/method: we used the pediatric health information system (phis) database, which contains clinical and resource utilization data for inpatients from hospitals nationwide, to analyze the prevalence of hematuria, hypertension, renal disease and related diagnosis codes in pediatric pwh who were admitted from january to september . results: during the five-year period, , unique pediatric pwh accounted for , admissions. while the majority of admissions were for bleeding or infectious concerns, ( . %) patients had an affiliated admission code for hematuria. for admissions as a whole, the median age was years with % of those admitted being infants, % toddlers, % children, % adolescents, % older than . we identified % of admissions were for ha with the remaining % were for hb. there were ( %) admits in which a bypassing agent was administered. the median length of stay for persons with hematuria was days compared to days for nonhematuria/other bleeding. there were ( . %) admissions with hypertension reported; though, only patients received an antihypertensive medication during that admission. additionally, only ( . %) admissions reported a diagnosis code of renal disease. our study demonstrated that pediatric pwh are experiencing hematuria. in general, only patients with persistent hematuria require hospital admission so we suspect this data underrepresents the numbers of pwh experiencing hematuria that is managed in the outpatient setting. we also suspect that hypertension is grossly underreported and undertreated in pediatric pwh. additionally, there are a low number of patients experiencing renal disease requiring hospital admission among this cohort. given that there is little research into the long-term impact of hematuria in hemophilia, we feel these findings support the need for further vigilance of our pediatric pwh. background: gla and gsd can aggressively destroy bone, with significant impact on morbidity and mortality. the mtor inhibitor, sirolimus has been shown to be effective in the treatment of these diseases. based on the addition of mtor inhibition to bisphosphonate therapy in metastatic cancer therapy, regimens have been used for refractory or high risk gla and gsd but there is heterogeneity of diagnosis, and variability of drug regimens and assessment of effectiveness. objectives: . assess the variability of clinical features of gla and gsd . assess the heterogeneity of diagnosis . assess drug regimens and response assessment across multiple institutions design/method: we conducted a retrospective review from institutions of cases of gla and gsd treated with sirolimus and a bisphosphonate for at least months with assessment of clinical features, treatment protocols, response regimens and side effects. results: patients included gla (n = ) and gsd (n = ). the average age at diagnosis was years. clinical features included effusions: gla (n = ), soft tissue lymphatic malformations: gla (n = ), gsd (n = ), multiple splenic lesions: gla (n = ), and soft tissue swelling at the site of bony lesion: gsd (n = ). the presenting symptom in patients was pain with patients (gla) presenting with shortness of breath. fracture was noted in patients: gla ( ), gsd ( ). diagnostic and/or response imaging included mri, ct, bone scan, skeletal survey and dexa scan. treatment consisted of: initial sirolimus use with the addition of bisphosphonate secondary to worsening disease (n = ), initial therapy with other agents (interferon, chemotherapeutic agents, radiation) and change to sirolimus and bisphosphonate secondary to toxicity (n = ), sirolimus and bisphosphonates (n = ) and sirolimus, bisphosphonates and interferon (n = ). seventeen patients had stable disease and patients had improvement of disease. sirolimus protocol was standard; however, bisphosphonate protocol varied in dosing and frequency. side effects were tolerable and expected with no grade iii or iv toxicity. sirolimus and bisphosphonates are a safe and effective therapy for gsd and gla. a consistent medication regimen, redefined response and an improved radiologic classification will be important for the development of a prospective clinical trial. background: hemophilia a is a bleeding disorder from the deficiency of clotting factor viii. the most significant sequelae of hemophilia a is the tendency to develop hemarthrosis that incites joint destruction. the prevalence of overweight and obesity has been increasing in the general and hemophilia population and leads to several morbidities including arthropathy. this is a particular concern for hemophilia a as arthropathy is a consequence of joint bleeding. objectives: the purpose of this study was to detect the relation between body mass index (bmi) and joint health endpoints in a pediatric hemophilia population. design/method: participants in this study included patients from the hemostasis and thrombosis center at children's hospital los angeles. participants were pre-screened and approached for this study during routine follow-up appointments. patients aged - years old who have been diagnosed with hemophilia a, including mild, moderate, and severe, qualified for the study. informed consent was obtained from the patients or parents before enrollment. joint health was objectively measured by physical therapists from children's hospital los angeles using the hemophilia joint health score (hjhs). an hjhs total score is calculated by assessing: swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, and muscle strength in major joints. subjective data was also obtained by patients recording their annual bleed rate within the past year. of the patients, ( %) were normal weight, ( %) overweight, and ( %) obese. we used chi-square analysis to compare joint scores across bmi classifications (chi square = . , df = , p-value = . ). although, this did not approach statistical significance, the average hjhs score in patients who had a hjhs > shows an increasing trend among bmi classifications: . in normal bmi patients, . in overweight bmi patients, and . in obese bmi patients. the average number of annual bleeds in those with positive values show: in normal bmi patients, in overweight bmi patients, and in obese bmi patients. although a positive effect of adiposity was found in the joints of hemophilia a pediatric patients, the effect shows there was not enough evidence to conclude a difference. future studies are needed to address whether obesity has an effect on hemophilia and to determine whether overweight/obesity can lead to further complications in hemophilic joints. background: stagnant blood flow in slow-flow vascular malformations (vm), particularly in their venous components, can lead to localized intravascular coagulation (lic) that is characterized by elevated d-dimer levels, low fibrinogen and decreased platelet count this coagulation derangement can lead to localized thrombosis or bleeding which can result in pain, functional limitations, and possible progression to disseminated intravascular coagulopathy (dic). the treatment of vm and their associated coagulopathy has proven difficult. patients with complex vm are frequently managed with sirolimus, an mtor inhibitor, and have clinical benefits, including reduction of pain and improvement in functional impairment. it is possible that some of these improvements from sirolimus could be secondary to improvement in the coexisting lic. objectives: this study assessed the use of sirolimus to manage the coagulopathy seen in slow-flow vm. design/method: we reviewed charts of patients with vm who are followed in the vascular anomalies center at arkansas children's hospital and were started on sirolimus. efficacy was objectively assessed through improvement of ddimer, fibrinogen and platelet count. three sets of lab values (pre-sirolimus, - months post-sirolimus, and most recent) were obtained for each patient when available. we identified a total of patients who had been prescribed sirolimus. eighteen were excluded based on underlying condition other than slow-flow vascular malformation and for inadequate medical records. a total of patients ( combined vascular, venous) were included in the study. all had elevated d-dimer levels (mean . mcg/ml feu, median . mcg/ml feu, range ( . - . )) prior to treatment. two patients had an associated low fibrinogen (below mg/dl), indicating severe lic. with treatment, ( . %) patients showed an overall decrease in d-dimer levels with an average decrease of . mcg/ml feu between pre-and post-sirolimus labs, and an average decrease of . mcg/ml feu between pre-sirolimus and most recent values. the two patients with low fibrinogen prior to treatment showed a decrease in d-dimer levels (mean decrease of . mcg/ml feu) and an increase and normalization in fibrinogen (mean increase . mg/dl) after beginning sirolimus. no patient had thrombocytopenia. we report that treatment with sirolimus was effective in improving coagulopathy associated with slowflow vm as evidenced by decreased d-dimer levels and increased fibrinogen and/or platelets. long-term use of this medication in this population may decrease the bleeding and thrombotic complications that these patients experience, especially following invasive vascular procedures. background: safety and efficacy of bay - , a sitespecifically pegylated b-domain-deleted recombinant factor viii, in previously treated adolescents and adults aged - years with severe hemophilia a was demonstrated in the phase / protect viii study and ongoing extension. objectives: this subanalysis examines the efficacy and safety of bay - in adolescents in protect viii and the ongoing extension study (data cutoff, january ). design/method: in protect viii, patients (including adolescents) received bay - on demand or as prophylaxis for weeks. prophylaxis regimens for weeks - were twice-weekly ( - iu/kg), every- -days ( - iu/kg), or once-weekly ( iu/kg) infusions based on bleeding during a -week run-in period of iu/kg twice-weekly prophylaxis. patients continued their prophylaxis regimens in the extension or changed regimens at any time. results: twelve patients aged - years were included in the protect viii intent-to-treat population; s of s additional patient discontinued after dose (included in safety population). for patients receiving prophylaxis before study enrollment, median (range) number of total and joint bleeds in the months before study entry was . ( - ) and . ( - ), respectively. ten patients ( . %) had target joints at baseline (median [range], [ - ] per patient). during weeks - of protect viii for the entire time patients remained on their designated prophylaxis dosing frequency, the median (quartile [q] ; q ) annualized bleeding rate (abr) for patients receiving twice-weekly (n = ), every- -days (n = ), and once-weekly prophylaxis (n = ) was ( ; . ), . ( ; . ), and . ( ; . ), respectively (overall prophylaxis [n = ], . [ . ; . ]). two patients switched from once-weekly to twice-weekly (n = ) or every- -days prophylaxis (n = ), and number of bleeds decreased from to in one patient and to in the other. all patients from the main study continued in the extension; mean abr in the extension was . and varied by dosing regimen (twice weekly [n = ], . ; every days [n = ], . ; once weekly [n = ], . ). two patients changed from every- -days to once-weekly prophylaxis during extension (mean abr, . ). one patient had a nonneutralizing antibody to bay - at baseline; end-of-study titers were negative. no patient developed anti-peg antibodies or factor viii inhibitors or experienced a serious adverse event related to bay - during the main study or extension. in previously treated adolescents with severe hemophilia a, bay - prophylaxis was effective in prevention of bleeds, with less bleeding overall versus prestudy, and was generally well tolerated. funded by bayer. cincinnati children's hospital medical center, cincinnati, ohio, united states background: vascular malformations (vms) consist of a heterogeneous group of congenital disorders characterized by the abnormal development of blood and/or lymphatic vessels, which cause a broad spectrum of clinical manifestations. although considered benign, vms are frequently associated with cutaneous complications that can cause significant morbidity such as nodular overgrowth, skin thickening, pruritus, oozing or bleeding of lymphatic blebs and secondary infection. oral sirolimus has shown to be effective in the treatment of complicated vascular malformations but has known side effects and need for frequent laboratory monitoring. currently, there are limited studies on the use of topical sirolimus for the treatment of cutaneous manifestations of vascular malformations. objectives: to evaluate the efficacy and safety of topical sirolimus in vms with cutaneous complications and propose indications for use. design/method: this is a retrospective review of medical records of patients with vascular malformations treated with topical sirolimus from january to december . response was determined by subjective and objective improvement. results: twenty-four patients, ( %) females and ( %) males, with vascular malformations and cutaneous manifestations were treated with topical sirolimus. age ranged from - years. indications for treatment were: blebs ( %, n = ) causing either leaking, bleeding, pain, pruritus, swelling or recurrent infection; nodular overgrowth % (n = ); pyogenic granuloma % (n = ); bleeding % (n = ) and cosmetic % (n = ). treatment course ranged from - months. no major side effects were reported. one patient reported burning and itching sensation. regarding clinical response: % (n = ) patients had improvement in cutaneous lesions; % (n = ) had a stable lesions; and % (n = ) stopped treatment due to side effects. for prior/concomitant treatment: % (n = ) had prior surgery, laser or sclerotherapy; % (n = ) had concomitant oral sirolimus. of the patients not receiving concomitant systemic sirolimus, only % (n = / ) had been on oral sirolimus. of these patients, % (n = / ) had a very good response to topical treatment. : topical sirolimus appears to be beneficial and well-tolerated with a minimal side effect profile for the treatment of cutaneous manifestations of vascular malformations as a single agent or as adjuvant therapy with systemic sirolimus when symptoms are not adequately controlled. further studies are needed to prospectively analyze efficacy and safety of topical sirolimus in this patient population. objectives: to evaluate the safety and efficacy of long-term romiplostim in children with itp. design/method: all patients received weekly sc romiplostim from - g/kg to target platelet counts of - × ( )/l. median (min-max) treatment for the patients was ( - ) weeks for a total of patient-years, or . years per patient. at baseline, median (min-max) age was ( - ) years; % were female; . % had prior splenectomy. median (min-max) average weekly dose was . ( . - . ) g/kg, including escalation to a stable dose; patients started on g/kg. reasons for discontinuing romiplostim (n = , %) included consent withdrawn (n = ), required other therapy (n = ), and ae (n = ) (asthenia, headache, dehydration, and vomiting in one patient and anxiety in the other; none treatment related). fifty four serious aes occurred in patients but were treatment related in one (concurrent grade thrombocytopenia, grade epistaxis, and grade anemia). anti-romiplostim neutralizing antibodies were detected in one patient who discontinued to receive other therapy; antibodies were absent on retesting. from week on, median platelet counts remained > × ( )/l; median platelet counts were > × ( )/l from weeks - . nearly all ( %, / ) patients had ≥ platelet response (platelet counts ≥ × ( )/l, excluding ≤ weeks after rescue medication). most ( %, / ) patients had a platelet response ≥ % of the time and % ( / ) did ≥ % of the time. sixty ( %) patients (or caregivers) self-administered romiplostim. fifteen ( %) patients had treatment-free periods of platelet counts ≥ × ( )/l for ≥ weeks (ie, remission); these patients ( girls, boys) had had itp for a median (min-max) of . ( . - ) years, none had prior splenectomy, and had received romiplostim for . ( . - ) years. all had platelet counts > × ( )/l for ≥ months and / for ≥ months; the median (min-max) duration of being ≥ × ( )/l was ( - ) weeks. of baseline characteristics such as sex, platelet counts, itp duration, and number of past itp treatments ( , , , > ), only age < years was predictive of developing treatment-free periods ≥ weeks (p = . ). in this seven-year open-label extension, > % of children with itp achieved a platelet response and romiplostim was well tolerated. importantly, % of patients were able to discontinue all itp medications for ≥ months. funded by amgen inc. background: sirolimus is an immunosuppressive drug that is widely used in solid organ and bone marrow transplantation, and more recently for the treatment of vascular and lymphatic anomalies. sirolimus has been associated with decreased immunity in the transplant setting in patients that have received other immunosuppressive drugs or were immunosuppressed from previous chemotherapy. the effects of sirolimus on the immune system in chemotherapy naïve children who have not received other immunosuppressive agents are not well understood, and there is variability in the approach to fever and pcp prophylaxis. to understand the effects of sirolimus on the immune system of patients with non-complicated vascular or lymphatic anomalies by evaluating anc, alc prior to and after sirolimus therapy. design/method: multi-institutional retrospective review was done to include patients with non-complicated vascular or lymphatic anomalies. those with effusions/ascites, multiorgan involvement, or history of vascular-anomaly-related infections prior to treatment were excluded. results: twenty patients with kaposiform hemangioendothelioma (n = ), generalized lymphatic anomaly (n = ), cloves syndrome ( ), and simple vascular malformation (n = ) were included. age at initiation of sirolimus treatment ranged from . - years. male to female ratio was : . sirolimus was initiated due to extensive disease, lack of response to steroids or bisphosphonates, pain, dment, lymphatic drainage, and prevention of ongoing overgrowth. prior to the start of sirolimus (sir- ) the mean anc was and alc was . the target level of sirolimus varied by indication and patient, and ranged from to . after the st steady state level, month after sirolimus (sir- ) the mean anc decreased to and alc was . at months after sirolimus (sir- ) the mean anc was and alc was . the first sirolimus levels (sir- ) mean was . ; and sir- level was . . nine patients were placed on pcp prophylaxis at the start of sirolimus. none of these patients had an infectious complication while on sirolimus at a median f/u of months. one patient had mild neutropenia (anc > ) which normalized after discontinuation of pjp prophylaxis. conclusion: in this small cohort of patients we found that the anc and alc level in patients with non-complicated vascular or lymphatic anomalies at sir- was not different from the sir- or sir- . prospective studies that specifically track anc, alc, igg, and lymphocyte function should be conducted to better understand the effects of sirolimus in the immune system. this data will allow for uniform recommendations regarding prophylaxis and management of febrile episodes. background: acute infections and the associated systemic inflammation can increase the risk of venous thromboembolism (vte) and in certain well-defined clinical scenarios may be the primary trigger of vte in pediatric patients. pediatric data on vte in the setting of acute infection are sparse. objectives: to describe characteristics and outcomes of vte in pediatric patients with acute infections. we conducted a retrospective chart review of all pediatric patients with objectively confirmed vte treated at our institution since and identified all patients in whom an acute infection was identified as a vte trigger. patients were managed according to standardized institutional protocols based on published guidelines. relevant demographic, clinical and laboratory data were collected and summarized using descriptive statistics. since , acute infection was identified as a trigger in of vtes ( %) diagnosed at our center. the median age at time of vte diagnosis in this group was . years (interquartile range . - ). males were more commonly affected than females, representing % of cases. neonatal vte events accounted for % of cases. sepsis was the most common acute infection to be identified as a vte trigger [ / cases ( %)]. most vte events ( %) associated with acute infections were considered hospital-associated vtes. at time of vte diagnosis, % of patients were critically ill. extensive vte (defined as completely occlusive thrombosis involving > venous segment) occurred in % of patients. acute infection was deemed to be the primary trigger for vte in / patients ( %). infection-associated vtes in this cohort included cerebral sinus venous thrombosis due to sinus or cns infection ( patients, %), septic throm-bophlebitis ( patients, %), lemierre's or lemierre's-like syndrome ( patients, %) and osteomyelitis-associated deep vein thrombosis ( patients, %). systemic anticoagulation was prescribed in / patients ( %). anticoagulationrelated major bleeding occurred in / patients ( %). vte complications included vte recurrence ( patients, %), vte progression ( patient), acute pulmonary embolism ( patients) and arterial ischemic stroke ( patients). our study indicates that acute infection is a common risk factor for pediatric vte, especially in critically ill children, and can be the primary trigger in a significant proportion of vte cases associated with acute infections. anticoagulation appeared to be overall safe in this population and was associated with low rates of serious vte-related acute complications. however, our study also suggests that this population may be at increased risk for vte recurrence and anticoagulation-related major bleeding. background: epithelioid hemangiomas (eh) are rare benign vascular tumors that occur in soft tissues and bone and present between the third and sixth decades of life. a subset ( %) of eh harbor fos rearrangement. eh has been described in children, but little is known about the long-term outcomes of pediatric eh. the main objective is to obtain data to be used for improved understanding of this rare disease in order to provide standardization of care and development of future research studies. board-approved retrospective review of clinical, pathologic, and radiographic characteristics, and treatment outcomes in patients diagnosed with eh between and . results: eight patients were male; mean age at diagnosis was . years (range: - ). lesions involved the lower extremities (n = ), cranium (n = ), pelvis (n = ), and spine (n = ). multifocal disease was identified in five patients. the most common presentations involved significant localized pain and neurologic symptoms: headache, cranial nerve injury, loss of consciousness. radiographic studies identified variable features, such as multifocal lytic bony lesions with sclerotic margins, enhancing soft tissue component, and surrounding inflammatory edema. histologically, all specimens were composed of vascular channels lined by epithelioid endothelial cells without significant cytologic atypia; solid cellular areas (n = ). endothelial cells were positive for cd and egr, and negative for camta . fos rearrangement was assessed in only one specimen and detected. mean follow-up time was days (range: - ). patients were treated with surgical resection, intravascular embolization, bisphosphonates, propranolol, interferon, and sirolimus. one patient treated with interferon and one with sirolimus exhibited partial response for mean follow-up of . days. although eh is a benign neoplasm, it is difficult to manage without standard protocols and portends considerable morbidity. our findings suggest medical management, particularly sirolimus, may benefit these patients; however, long-term follow-up is needed in treated children. novel fos inhibitors are in development and may benefit patients with fos rearrangement. penn state health children's hospital, hershey, pennsylvania, united states background: central venous catheters (cvc) are often required in critical care settings in order to provide a secure point of access for life sustaining care. clinical studies identify cvc presence as the single most important risk factor for deep vein thrombosis (dvt) in children. venous thromboembolic event (vte) incidence rates in critically ill children with a cvc range from . - % and . - . per catheter days depending on the population studied. per institutional protocol, the penn state health children's hospital picu (hershey, pa) utilizes a low dose continuous infusion of unfractionated heparin (ldufh) at units/kg/hr as prophylaxis against cvc-related vte and to maintain line patency. the efficacy of this approach has never been evaluated. to determine if ldufh for prophylaxis results in lower incidence of cvc-related vte, catheter dysfunction and central line associated blood stream infection (clabsi) without increasing morbidities. to determine if the incidence of catheter related vte is lower than historical published data, a retrospective chart review was conducted utilizing the institutional electronic medical record for all patients in , aged - . years, who had a cvc during a picu admission. secondary objectives such as the incidence of catheter dysfunction, clabsi, and any associated bleeding complications are also being analyzed. results: interim data analysis revealed cvcs ( nontunneled cvc, totally implantable devices, tunneled lines, peripherally inserted central catheters [picc] ) in total patients with a median age of . years. overall vte incidence was . % ( / ) with vtes associated with non-tunneled cvc and with piccs. sixty one percent of non-tunneled cvcs received ldufh and % ( / ) of the patients with vtes associated with non-tunneled cvcs did receive ldufh prophylaxis. vte incidence rate of nontunneled cvcs with ldufh was . % ( / ) and . per picu catheter days. the only other vte events identified within our study cohort were in the picc group where two patients experienced vte, one of which was receiving ldufh. clabsi incidence was . % ( non-tunneled cvc, tunnel cvc, picc). no major bleeding complications were associated with ldufh. preliminary data demonstrates ldufh is efficacious in preventing cvc-related vte in comparison to published reports. further analysis will compare another similar sized and acuity level picu which does not practice the same method. background: fibroadipose vascular anomaly (fava) is a rare, challenging disorder associated with pik ca mutations. fava often causes painful replacement of muscle and soft tissues with fibrotic and adipose tissue and is associated with ectatic draining veins. treatments for focal lesions are surgical excision, cryoablation or sclerotherapy and the role of medical therapy is unclear. some fava lesions are too extensive or directly involve neurovascular structure, resulting in refractory pain. objectives: to retrospectively evaluate the efficacy of sirolimus in patient with residual symptoms after procedural therapies for fava design/method: retrospective review of individual cases from institutions of fava refractory to other therapies treated with sirolimus for at least months. cases were s of s identified by polling member of the aspho vascular anomalies special interest group. results: all seven patients report improvement on sirolimus therapy. all patients had received prior procedures, including sclerotherapy ( patients), cryoablation ( patients) and/or resection ( patients). mean age at sirolimus initiation was y (range - y). mean length of therapy is . months (range - months). six patients were treated with bid dosing and one adult received daily dosing. goals of sirolimus were improvement in pain or musculoskeletal dysfunction. pain and function improved in all patients, including discontinuation of narcotic use and resumption of participation in sports. time to symptom improvement ranged from - weeks. in four patients for whom dose was lowered, pain recurred in all four and responded to restarting or increasing sirolimus dose. while all patients do not have pre-and postsirolimus imaging, decrease in fava lesion size is seen in cases with available imaging. sirolimus side effects are similar to prior reports, most commonly mouth sores, elevated lipids and acne. we report the first known data supporting a role of sirolimus in refractory fava cases. sirolimus is welltolerated and initial improvement is rapid, within weeks of initiation. whether sirolimus has a role in upfront therapy to reduce lesion size prior to procedures deserves further study. objectives: to assess platelet responses in children with itp receiving romiplostim. design/method: eligible children had itp for ≥ months, ≥ prior therapy, and screening platelet counts ≤ × ( )/l or uncontrolled bleeding. weekly dosing was from - g/kg to target platelet counts of - × ( )/l. bone marrow biopsies were evaluated in europe at baseline and after or years (cohorts and ). as of mar , patients received ≥ dose. at baseline, median (min-max) age was ( - ) years, itp duration was . ( . - . ) years, and platelet count was ( - ) × ( )/l; patients ( %) had had prior splenectomy. the median (q , q ) % time with a platelet response (platelet count ≥ × ( )/l, no rescue medications past weeks) in months - was % ( %, %) (primary endpoint). over the course of the study, % ( / ) of patients had a platelet response. four patients maintained platelet counts ≥ × ( )/l with no itp medications for ≥ weeks. median (min-max) treatment duration was ( - ) weeks for patient-years in total. median (min-max) average weekly romiplostim dose over the course of the study was . ( . - . ) g/kg; the median dose was g/kg at year (n = ) and g/kg at years (n = ). most ( %) patients initiated self-administration. sixty-four patients ( %) discontinued treatment, most frequently for lack of efficacy (n = ), patient request (n = ), and adverse event (ae) (n = ). fortyone ( %) patients had serious aes (saes) including epistaxis ( %) and decreased platelet count ( %). five patients had treatment-related saes: headaches, abdominal pain, and each of presyncope and neutralizing antibodies (ab). there were cases of neutralizing ab to romiplostim (of patients tested), but none to tpo; / had continued elevated platelet counts and in / cases ab were not found on retesting. for cohort , of patients with baseline bone marrow biopsies, had evaluable on-study biopsies scheduled for year; patient had an increase from grade to . there were no findings of collagen or abnormalities. in this interim datacut of a romiplostim openlabel study in children with itp, % of children had a platelet response. overall, the median dose was . g/kg; the median romiplostim dose over time reached g/kg. no new safety signals were observed over patient-years. funded by amgen inc. background: hepatic hemangiomas are benign vascular tumors without a medical home, managed by multiple specialties. the diagnosis has been assigned historically to various vascular lesions affecting the liver with completely different clinical presentations, resulting in difficult standardized management. objectives: the consensus steering committee identified an acute need of clear definitions and evaluation guidelines using the updated international society for the study of vascular anomalies (issva) classification. the goal was to formulate recommendations that will be adopted by all specialties involved in the care of children with hepatic hemangiomas. design/method: we used a rigorous, transparent consensus protocol, with input from multiple pediatric experts in vascular anomalies from hematology-oncology, surgery, pathology, radiology and gastroenterology. in the first section, we precisely define the subtypes of hepatic hemangiomas seen in children (congenital and infantile) using clinical course, histology and radiologic characteristics. inclusion and exclusion limits to the diagnosis are noted. the following two sections describe these subtypes in further detail, including complications to be considered during monitoring and respectively recommended screening evaluations. conclusion: while institutional variations may exist for specific clinical details, a clear understanding of the diagnosis of hepatic hemangiomas affecting the pediatric population and the possible complications that require screening during the monitoring period should be standard. as patients with hepatic hemangiomas are managed by different medical and surgical specialties, a multidisciplinary consensus based on current literature, on the data extracted from the liver hemangioma registry and on expert opinion was required and was accomplished by this manuscript. objectives: to investigate the association between routine prophylaxis with bay - and bleeding outcomes after adjusting for key patient and pharmacokinetic (pk) characteristics. design/method: the leopold kids study evaluated safety and efficacy of bay - prophylaxis in previously treated boys aged ≤ years with severe hemophilia a. patients received bay - - iu/kg x/wk (n = ) or > x/wk (n = ) and were followed up for - months. prophylaxis dose and frequency were assigned by investigators. pk parameters, including area under the curve (auc), half-life, and clearance, were derived from a population pk model and reflect predicted pk values with a -iu/kg dose. patient characteristics were compared between the x/wk and > x/wk groups using wilcoxon rank sum or chi-square tests. negative binomial regression was used to model the association between prophylaxis frequency and annualized bleeding rate (abr) for total bleeds, first without adjustment and then adjusting for age, pk parameters, and bleed history. results: mean ± sd age for patients in this analysis was . ± . years. patients receiving prophylaxis x/wk had more bleeding episodes in the months before study entry (mean ± sd, . ± . [median, . ] for x/wk vs . ± . [ . ] for > x/wk; p = . ) and were more likely to have been treated on demand ( % vs %; p = . ). pk parameters were similar between the x/wk and > x/wk groups. without adjustments, abr during the study was % higher in the x/wk group compared with the > x/wk group (rate ratio [rr], . ; % ci, . - . ; p = . ). abr was % lower in the x/wk group (rr, . ; % ci, . - . ; p = . ) after adjusting for age, auc, and number of bleeds in the prior months. conclusion: abr was numerically lower but not significantly different between the x/wk and > x/wk groups after adjusting for age and pk parameters. these findings suggest that even among patient groups that are homogeneous with respect to age, pk, and bleed history, further individualization of bay - prophylaxis based on other characteristics may help reduce bleeding episodes even at a lower treatment frequency. larger real-world studies are needed to verify these findings. funded by bayer. stanford, palo alto, california, united states s of s background: vascular malformations may be of lymphatic, arterial, venous or capillary endothelial origin. they may be simple or complex, with complex malformations being a combination soft tissue and skeletal overgrowth. although likely present at birth, these malformations often become symptomatic with puberty or infection, and range from little or no clinical impact to life threatening symptoms. in malformations primarily of venous origin, pain may be significant and hypothesized to be caused by phlebolith development (intra-malformation thrombi), inflammation, consumptive coagulopathy, vascular engorgement, and endothelial proliferation. anti-angiogenic and anti-platelet therapies have been reported to relieve pain. however, the use of anticoagulation for pain is not well described. objectives: to report clinical features and outcomes of patients with vascular malformations of venous origin treated with anticoagulation for pain. we performed a retrospective review of patients with vascular malformations followed by the hematology service between january and december who were treated for pain with anticoagulation. pain relief was determined both by wong-baker pain scales and patient report. clinical data were extracted from electronic medical records. we identified five patients with venous malformations (vm) who had received anticoagulation for pain. four patients were female and median age was years old (range to years old) at time of initiation of anticoagulation. all five patients had vm of the extremity, two with vm of the lower extremity, and three patients had vm of the upper extremity. two patients had concomitant coagulopathy and demonstrated decreased d-dimer after initiation of anticoagulation. four patients received enoxaparin, and one adult patient received rivaroxaban. all patients reported improvement in pain after administration of anticoagulation. one patient exhibited mild epistaxis and bruising at the injection site. there was no significant bleeding or other complications. pain is a significant complication in patients with venous malformations. our case series suggests that anticoagulation is a safe and effective therapy for pain relief in this population. further investigation is indicated to compare the effect of anticoagulation to other therapeutic interventions such sclerotherapy, surgery, and sirolimus in the treatment of pain associated with venous malformation. maria ahmad-nabi, christine knoll, sanjay shah, lucia mirea phoenix children's hospital, phoenix, arizona, united states background: estimates of the incidence of dvt in patients with osteomyelitis range widely from %- %, however risk factors and outcomes of dvt in this cohort have not been thoroughly established. objectives: this study aims to estimate the incidence of dvt in patients with osteomyelitis, and to assess risk factors and outcomes of dvt in this cohort. design/method: after irb approval, a retrospective chart review was conducted for patients aged - years seen at phoenix children's hospital between - with icd / codes for osteomyelitis. exclusion criteria included chronic recurrent multifocal osteomyelitis, and chronic dvt. demographics, clinical factors and outcomes were compared between osteomyelitis patients with and without dvt using the fisher-exact and wilcoxon-rank sum tests, as appropriate for the data distribution. results: a total of study subjects with osteomyelitis had a mean (standard deviation) age of . ( . ) years. dvt was present in ( % of ) patients, and ( %), ( %) and ( %) patients received anticoagulation for < , - and ≥ weeks, respectively. patients with vs without dvt were more likely to be male ( % vs %; p-value = . ), and had significantly higher rates of bacteremia ( % vs %; p-value = . ). rates of central lines were comparable between dvt and non-dvt patients ( % vs %; p-value = . ); however patients with dvt vs without dvt had significantly longer mean length of stay ( vs days; p-value < . ) and higher rates of icu admission ( % vs %; p-value < . ). the incidence of dvt among osteomyelitis pediatric patients was estimated at %, with risk increased by male sex and bacteremia. patients with dvt had significantly higher rates of icu admission and longer length of hospital stay. many of these patients had standard practice management of their dvt with - weeks of anticoagulation. our data highlights the need for recognition of high risk patients, and the need for future efforts targeting dvt prophylaxis. baylor college of medicine, houston, texas, united states background: lymphatic malformations (lm) frequently occur in the head and neck and can often be disfiguring and even life-threatening. management options include observation, surgery, sclerotherapy, and sirolimus. the optimal sequence of therapeutic interventions has not been determined due to the lack of comparative clinical trials or established guidelines. thus, prenatal planning with a multidisciplinary team is beneficial. we present a case series of ten children with head and neck lms evaluated in at our multidisciplinary vascular anomalies center. a chart review was performed to assess treatment modalities and recent trends. results: seven of patients ( %) with head and neck lms were diagnosed prenatally. six patients required an ex utero intrapartum treatment procedure. all patients were started on sirolimus at a median age of . months (range days - years). four patients most recently started on sirolimus were less than months of age at the time of initiation. six patients underwent partial excision of lm during the first year of life; none of whom received sirolimus prior to surgery. sirolimus was discontinued in one patient given chronic clostridium difficile infections, and non-compliance in another patient. five patients received sclerotherapy. tracheostomy was necessary in six patients; one patient was de-cannulated after months on sirolimus. all patients have had radiographic and clinical improvement of lm with varying treatment modalities. current clinical observations show improved response with sirolimus and demonstrate tolerability of sirolimus at a young age. conclusion: treatment of pediatric head and neck lms is challenging and a multidisciplinary approach is necessary. as the majority of patients are diagnosed prenatally, prenatal planning and discussion of potential use of sirolimus is beneficial. availability of vascular anomalies experts in the prenatal/neonatal period offers the best management results, and early initiation of sirolimus should be considered for complex lesions. long-term follow up is warranted to investigate the efficacy and timing of treatment options. yale school of medicine, new haven, connecticut, united states background: to mitigate transfusion of pathogencontaminated platelets, amotosalen, a synthetic psoralen compound, is added to sdp components. exposure to uv-a light activates amotosalen and crosslinks dna/rna base pairs, preventing replication of a broad spectrum of viral, bacterial, and other pathogens that may contaminate platelets. pr-sdps were fda approved for clinical use with no age restrictions in . we initiated use of pr-sdps in november of for all patients. we retrospectively analyzed usage of pr-sdp vs conventional (non-pr) platelets (cp) in neonatal and pediatric patients with thrombocytopenia to compare hemostatic efficacy and the incidence of transfusion reactions (tr) for these products, after one year of a dual platelet inventory. design/method: since pr-sdp were fda-licensed, no irb approval was required; pr-sdp and cp were both considered standard of care. we evaluated transfusions for all pediatric patients age - years who received any platelet transfusion between november and november . we determined the volume (mean ml ± sd) of each type of platelet component transfused, the number of platelet transfusion episodes, and reported trs based on cdc hemovigilance guidelines. a subgroup analysis was performed for thrombocytopenic neonates ( - months). results: patients - years who received only cps (n = ) received a total of , ml of platelets ( ± ml/patient) over transfusions ( . ± . episodes/patient). for comparison, in patients who received only pr-sdp, a total of , ml of platelets ( ± ml/patient, p = . ) were infused over transfusions ( . ± . episodes/patient, p = . ). for neonates ( - months, n = ) who received only cps, , ml of cps ( ± ml/ patient) were transfused over episodes ( . ± . episodes/patient). for comparison, those who received only pr-sdp (n = ), received , ml of pr-sdp ( ± ml/patient, p = . ), transfused over episodes ( . ± . episodes/patient, p = . ). for all recipients - years (n = ), including additional patients who received both cp and pr-sdp, there were three reported allergic trs over transfusion episodes, while no allergic reactions were reported with pr-sdp transfusions. one febrile tr was reported to cp transfusion, while three were reported for pr-sdp. in conclusion, pr-sdps, in our pediatric population age - years, were comparable to cp products in regards to volume and episodes of platelet transfusions, and incidence/type of transfusion reactions. pr-sdp were safe and effective for use in this pediatric patient population. background: vascular anomalies are classified as either vascular tumors or vascular malformations. fibro-adipose vascular anomaly (fava) is a newly described entity which presents with distinct clinical, radiographic and histopathologic findings. we present a case in which the diagnosis of fava was complicated by a persistent low platelet count secondary to immune thrombocytopenia (itp). to describe a challenging diagnosis of a novel vascular anomaly (fava) complicated by severe thrombocytopenia. a year old male presented to hospital with bruising and left thigh pain related to a remote sports injury. blood work revealed a platelet count of × /l, but with an otherwise normal complete blood count. the following were also normal: aptt and fibrinogen; d dimer levels were slightly increased. he was treated with one dose of ivig ( . mg/kg) for presumed itp and responded well with his platelet count increasing to × /l. he returned to hospital weeks later with recurrent thrombocytopenia and worsening leg pain. an ultrasound of the left thigh revealed a . cm x . cm x . cm lesion within the vastus medialis. the diagnosis of an intramuscular hematoma secondary to persistent thrombocytopenia was made. the patient presented with multiple episodes of thrombocytopenia over the next several months. his itp did not respond to oral prednisone ( mg/day for days). he continued to have short-lived responses to ivig requiring infusions every other week as his platelet count would fall below × /l. his leg pain progressed, restricting him to a wheelchair. further imaging by mri brought into question the diagnosis of a hematoma and a biopsy of the thigh lesion was performed. the results were consistent with a diagnosis of fava; this was subsequently excised. conclusion: this is a unique case where a vascular anomaly was misdiagnosed as a hematoma due to a patient's persistent thrombocytopenia and history of an injury. fava is a newer entity which, unlike other vascular anomalies, has not been linked to thrombocytopenia or a localized consumptive coagulopathy. after excision of the fava, the patient's chronic pain, and mobility resolved, though his itp persisted. objectives: this preliminary, exploratory analysis of realworld administrative data was conducted to determine units dispensed and factor replacement product-related direct expenditures associated with a currently marketed shl or ehl rfix product. design/method: de-identified claims data from the commercially available truven health marketscan® research u.s. claims database were used to identify direct expenditures and number of international units (ius) dispensed for all patients aged - years with a diagnosis code of icd- . /icd- d who used nonacog alfa or eftrenonacog alfa during the study period (june , to july , ). reference weight measurements from the centers for disease control and prevention national center for health statistics' (cdc nchs) anthropometric data were used to estimate product dispensation on an iu per kg basis. the nonacog alfa and eftrenonacog groups comprised and patients, respectively. the median [iqr] age in the two groups was . [ . ] and . [ . ] years, respectively. while of the patients in the eftrenonacog alfa group had > calendar quarter of available data, only of the patients in the nonacog alfa group had > available quarter. the median rfix product dispensation per quarter was , ius (iqr, , ius) in the nonacog alfa group and , ius (iqr, , ius) in the eftrenonacog alfa group. incorporating attributed weight values, the median rfix product iu dispensation per kg per week was . iu/kg/wk (iqr, . iu/kg/wk- . iu/kg/wk) in the nonacog alfa group, and . iu/kg/wk (iqr, . - . iu/kg/wk) in the eftrenonacog alfa group. applying wac prices (eftrenonacog alfa = $ . /iu; nonacog alfa = $ . /iu), the calculated estimates of $/kg/week were $ and $ in the nonacog alfa and eftranonacog alfa groups, respectively. conclusion: preliminary real-world data derived from a large u.s. claims database revealed differences in product dispensation and factor product-related expenditures among pediatric patients with any severity of hemophilia b to whom an shl or ehl rfix product was prescribed. refinements of these data, potentially to exclude instances of sporadic usage, may shed light on real-world dispensation of rfix products among pediatric hemophilia b patients. background: vascular malformations can be classified as simple (including capillary, venous, lymphatic, arteriovenous), combined, malformations of major named vessels or associated with other anomalies. multiple modalities including laser treatments, sclerotherapy, embolization, surgery and pharmacological intervention (with mtor inhibitors like sirolimus) have been used for treatment of vascular malformations. these interventions have been used alone or in combination with varied outcomes. we present our institution's experience with a multimodal approach to simple and combined vascular malformations. design/method: we performed a retrospective chart review of patients with vascular malformations who were referred to our center for an interventional radiology evaluation from june -july . we included patients (age at presentation: months - years), referred initially for interventional radiology procedures (irp) for vascular malformations. all patients had symptoms of pain and/or swelling/deformity. diagnosis of was based on vascular imaging (doppler ultrasound, mri/a/v). nine patients had venous malformations (vm), five had macrocystic lymphatic malformations (lm), six had lymphatic-venous malformations (lvm), and two arteriovenous malformations (avm). patients initially underwent interventional radiology procedures. all the vm patients responded to sclerotherapy alone. three patients with lm responded to sclerotherapy alone, remainder required surgical intervention. one avm patient responded well to embolization, the other needed surgical resection after embolization. four lvm patients underwent irp with minimal improvement in symptoms ( - procedures attempted), surgical resection was attempted in patients with poor response and patients were started on sirolimus ( . mg/m /dose twice a day). all lvm patients started on sirolimus have responded well (decreased pain and swelling); time to initial symptom response ranged from weeks - month from starting medication. in this case series, patients with simple vm responded well to sclerotherapy alone, avm and lm patients needed irp and/or surgery for complete response. complex lvm did not respond well to surgery or irp; . % had improvement in clinical symptoms with addition of sirolimus to the treatment regimen. response to various modalities of treatment varied based on the type of vascular malformation. a multidisciplinary approach to management of vascular malformations is essential to provide multimodal therapeutic options for rapid symptom relief and improve the quality of life of these fragile patients, especially those with complex malformations. background: von willebrand disease (vwd) is the most common bleeding disorder in humans, affecting ∼ % of the united states' population. desmopressin (ddavp) is a longacting vasopressin analog that induces vasoconstriction and release of vwf. ddavp is used in patients with vwd and as a surgical prophylaxis, but carries anti-diuretic properties. to avoid electrolyte imbalance and hyponatremia, fluid restrictions are recommended in the hours post-ddavp administration. objectives: this study sought to examine perioperative practices and outcomes following ddavp administration and a fluid restriction protocol in a population of pediatric patients with von willebrand disease. design/method: a retrospective chart review was conducted for patients with von willebrand disease who underwent surgical procedures at children's hospital of pittsburgh of upmc between january , and december , . patient age, sex, weight, diagnosis, surgical procedure, total fluids administered, and post-operative sodium level were recorded. the primary outcomes noted were the proportion of patients exceeding % of the recommended fluid consumption for the -and -hour periods post-ddavp s of s administration, as defined by local guidelines. secondary outcomes were the presence of any bleeding requiring an er visit or readmission or hyponatremic seizures within hours of ddavp administration. results: data was compiled for patients ( females, males). the mean age was . years (sd . years), median age was years (range to years). procedures included dental ( ), otolaryngology ( ), orthopedics ( ), gastrointestinal ( ), plastics ( ), neurosurgery ( ), ophthalmology ( ), dermatology ( ), general surgery ( ) and gynecology ( ). % of patients exceeded % of the fluid volume recommended for the first -hour period post-ddavp administration while still in the surgical setting. no patients exceeded % of the fluid volume recommended for the total -hour period post-ddavp administration. post-operative sodium levels were obtained in only of patients. no patients returned to the er or were admitted for bleeding in the hours post-ddavp administration. no patients returned to the er or were admitted for hyponatremia or seizures in the hours post-ddavp administration. maintenance of a fluid restriction protocol effectively deterred negative outcomes in this cohort. however, a significant fluid volume was administered in nearly a third of patients despite the restrictions. given the risk of hyponatremia, and limited compliance with fluid restrictions, postoperative sodium levels should be recorded in following ddavp administration to assess the possibility of a hyponatremia and to reinforce the importance of fluid restrictions and their communication. results: a male fetus required in utero insertion of a pleuroamniotic shunt for bilateral pleural effusions diagnosed antenatally by ultrasound. shortly after delivery at term, he developed respiratory distress and was found to have reaccumulation of the pleural effusions. blood work on day of life showed a platelet count of , / l, which then decreased precipitously. he demonstrated schistocytes on blood-smear, signs of consumptive coagulopathy with hypofibrinogenemia and high d-dimers, and compensatory reticulocytosis. he required multiple transfusions and admissions to the intensive care unit for respiratory support. investigations ruled out congenital ttp, neonatal alloimmune thrombocytopenia, and noonan syndrome. given high clinical suspicion for an underlying vascular lesion causing kmp, a full body mri without contrast was undertaken. this showed a focal area of suspicious signal intensity in the upper paraspinal musculature. an ultrasound and mri with contrast demonstrated an extensive infiltrative vascular lesion involving the paraspinal musculature, prevertebral space, posterior extrapleural space, mediastinum, and neck. the child was commenced on prednisone ( mg/kg/day) and rapamycin ( . mg/m twice/day). there was no clinical or laboratory improvement after one month. a biopsy was performed which confirmed khe. in the second month of rapamycin therapy, the platelet count gradually normalized and the patient was discharged from hospital at . -months of life. prednisone was weaned off at . months of life. a repeat mri at months showed significant reduction in the khe. he is now almost years into therapy and doing well. conclusion: this is a unique case of khe with kmp that initially presented with extensive and recurrent pleural and pericardial effusions. this case demonstrates the importance of suspecting an underlying vascular malformation in the presence of kmp. our patient had a delayed but overall good response to rapamycin. further studies investigating duration of rapamycin therapy is key for the optimal management of these patients. rosa diaz, donald mahoney, lakshmi srivaths, donald yee texas children's hospital, houston, texas, united states background: since von willebrand disease (vwd) is the most common inherited bleeding disorder, it must co-exist with other less common bleeding disorders in some dually affected patients. however, reports of combined deficiencies in factor viii (fviii) and von willebrand factor (vwf) are rare. objectives: to study the prevalence and bleeding phenotype of combined deficiencies of fviii and vwf in males with hemophilia a in a hemophilia treatment center. design/method: we retrospectively reviewed the electronic medical records of males with hemophilia a followed at our institution during the past years. the primary and secondary outcomes for the study were ( ) the prevalence of combined fviii and vwf deficiencies and ( ) the bleeding phenotype of these patients. we identified vwf deficiencies in % (n = ) of the patients with hemophilia a. most (n = , %) patients were tested for vwf deficiency as part of the initial hemostatic evaluation, but one-third were tested due to clinical concern for inadequate response to fviii concentrate. the median duration of follow up was . years (range . to . ). patients were referred to our clinic at a median age of months (range to years) for evaluation of easy bruising (n = , %), mucosal (n = , %) and surgical bleeding (n = , %). primary diagnoses included with severe, moderate and mild discrepant hemophilia a. secondary diagnoses included with low vwf activity, type vwd and with type unclassified. patients experienced episodes of musculoskeletal (n = , %), mucocutaneous (n = , %) and cns bleeding (n = , %). a total of patients received factor prophylaxis. half of the patients were initially treated with fviii concentrates but subsequently changed to combined fviii/vwf products due to the frequency of breakthrough bleeding despite good compliance. all patients are on combined fviii/vwf products at the time of this review. a total of ( %) of this cohort developed chronic joint disease manifest as decreased range of motion and/or abnormal mri findings. combined deficiencies of fviii and vwf were present in % of our center's hemophilia patients. these patients exhibited a severe bleeding phenotype as evidenced by the high frequency of hemarthrosis, need for prophylaxis and high prevalence of chronic joint disease. while the optimal treatment strategy remains to be elucidated, early recognition of a combined deficiency may have important clinical implications, particularly in patients who demonstrate a suboptimal response to fviii concentrate alone. background: childhood neutropenia is heterogeneous and may be congenital or acquired. cerebral cavernous malformation (ccm ) is a neurovascular malformation disorder where lesions consist of low flow, dilated capillary endothelial channels with increased permeability, predisposing to hemorrhage and thrombosis. programmed cell death protein (pdcd ) activity has been implicated in glia and neuron migration, and recently linked to the dysregulation of the actin and microtubule cytoskeleton, thereby affecting cellular morphology and migration. variants of pdcd encoding pdcd have been associated with ccm . ccm causes a greater and earlier disease burden than other ccms, with % presenting younger than years. some patients have associated extra-neuronal manifestations, suggesting that pdcd plays a role in other tissues. we describe a patient with significant blood cytopenias associated with ccm . design/method: retrospective chart review to obtain patient data. results: an -month old female presented with seizure and was found to have multiple intracranial cystic lesions and abscesses due to s. pneumonia serotype f. during her treatment, she developed anemia (hemoglobin . - . g/dl), thrombocytopenia (platelets , - , cells/l), and profound neutropenia (absolute neutrophil counts of zero). initial bone marrow evaluation revealed a normocellular marrow but with marked granulocytic hypoplasia and % hematogones on flow cytometry. florescent in situ hybridization excluded cytogenetic changes characteristic of myelodysplastic syndrome. further evaluation included testing for neutrophil antibodies, chromosome breakage, and telomere length and results were normal. whole exome sequencing excluded mutations affecting congenital neutropenia genes, but detected a de novo pdcd variant (c. + g>a), thereby diagnosing ccm . the neutropenia has responded well to granulocyte colony stimulation factor (gcsf), which is still needed at months of age. moreover, the thrombocytopenia has progressed, requiring periodic platelet transfusions. over time, the bone marrow hematogone population has decreased to % at months of age, though the granulocytic hypoplasia persists. conclusion: our case describes the first patient with neutropenia and thrombocytopenia associated with ccm . we hypothesize the pdcd variant is the etiology of bone marrow dysfunction due to its role in actin and microtubule cytoskeleton formation, akin to the pathophysiology of xlinked neutropenia. supportive features of an underlying genetic cause of marrow dysfunction include the persistence of cytopenias beyond infection resolution as well as presence of hematogones. hematogones were previously reported to occur in patients with other congenital neutropenia disorders, indicating they could be a feature of congenital neutropenia and may be reactive to surrounding cell apoptosis. further testing of pdcd role in hematopoiesis should be explored. background: - % of adult women will suffer from heavy menstrual bleeding (hmb) during their lifetime. % of women with inherited bleeding disorders suffer from hmb. there is a paucity of data about hmb among adolescents and young adults (aya), a population in which hmb may have large social and educational effects. objectives: to study the social and academic implications of hmb in an aya population. design/method: this is a questionnaire based survey conducted in a medium-sized city in california. we recruited females - years of age from one high school and from local university. the questionnaire was set up in research electronic data capture (redcap) at our institute which allowed us to obtain objective data about the respondents' menstrual cycles. a link was sent to the high school students via their online portal schoolloop and to the university students via social media and word of mouth. data was collected over weeks from may to august . we received replies, some were not complete. using regression analysis, data was analyzed from respondents in the age group of - (with a mean age of ) years. we developed a composite score for hmb based on factors including saturation levels, number of pads, duration of bleeding, soaking of a pad within two hours, passage of clots, size and number of clots, and gushing sensation. we conducted statistical analysis of the drivers and implications of hmb based on the composite score. results indicate that having a relative with hmb, having other bleeding problems, and having anemia are drivers of higher hmb score. the results also indicate that hmb adversely affects quality of life as measured by participation in sports, social activities, after-school activities, tiredness, absenteeism, and gpa. hmb is also associated with increased rates of anemia and use of anti-depressants. hmb-driven anemia further adversely affects gpa. under-represented minorities are more likely to have a higher hmb score, as well as an increased adverse effect of hmb on gpa. the results suggest that the social costs of hmb are pervasive in the aya population, and especially pronounced among minorities. a relative with hmb is a significant driver of heavy menstrual bleeding. a hemostatic screen should be included when assessing the aya population with hmb. johns hopkins all children 's hospital, st. petersburg, florida, united states background: propranolol is a non-cardioselective beta blocker medication frequently prescribed for hemangiomas and hyperthyroidism. propranolol inhibits types i and ii iodothyronine deiodinases, enzymes that convert bioinactive thyroxine (t ) into bioactive triiodothyronine (t ). hypothyroidism is a well-recognized complication of diffuse hepatic hemangiomas that produce type iii deiodinase, an enzyme that converts t into bioinactive reverse t and t into diiodothyronine. thyroxine is typically selected for replacement in this population, even though doses up to % above physiologic may be necessary. we hypothesized that low dose, nearly physiologic t would be safer and equally effective because it bypasses propranolol's impact on the pituitarythyroid axis. we report an infant with diffuse hepatic hemangiomatosis and acquired hypothyroidism successfully treated with propranolol, prednisone, and triiodothyronine. design/method: a mo healthy female presented with abdominal distension, poor oral intake, and hepatomegaly. mri confirmed diffuse hepatic hemangiomatosis, the largest lesion measuring . cm by . cm. thyrotropin (tsh) was elevated at . (reference range* . - mcgiu/ml), total t # (rr - ng/dl), and total t ^ . (rr - mcg/dl). treatment was started with prednisone ( mg/kg/day) for three weeks, propranolol ( mg/kg/day) and t ( . mcg/kg/day). the t dose was slowly titrated to a maximum of . mcg/kg/day. thyroid hormone levels rapidly improved on t replacement. after two weeks, the tsh was . , tt , and tt . . after eight months, the tsh was . , tt , and tt . . at twelve months, the tsh dropped to . , tt , and tt . , suggesting decreased tumor production of type iii iodothyronine deiodinase. liver mri confirmed fewer hemangiomas, largest being . cm by . cm. the patient's t dose was reduced. both propranolol and t were discontinued after twenty-four months of treatment. one year off all therapy, this child has normal growth and development, only two < . cm hepatic hemangiomas and no evidence of hypothyroidism (tsh . ; tt ; tt . ). conclusion: t at near physiologic doses corrects the consumptive hypothyroidism associated with diffuse hepatic hemangiomas. t replacement is preferable to thyroxine due to its lower risk of rebound hyperthyroidism as the hemangiomas involute and type iii deiodinase production declines. there are two prior case reports describing t use without t , one employing propranolol and the other utilizing steroids for hemangioma management. this is the first case report with long term follow-up of a child treated with multimodal therapy including propranolol, prednisone, and triiodothyronine. *rr = reference range; #tt = total t ;^tt = total t background: multifocal lymphangioendotheliomatosis with thrombocytopenia (mlt) is a rare congenital disorder first described in that is characterized by multiple vascular abnormalities commonly involving the skin and gastrointestinal tract as well as consumptive coagulopathy often resulting in gi bleeding in infancy( ). to describe an unusual presentation and successful management of mlt in a neonate. design/method: baby h was born at full term after a pregnancy complicated by maternal sinus venous thrombosis requiring anticoagulation beginning at weeks. at birth, she was diagnosed with multiple hemangiomas based on clinical exam. at two weeks of age, she developed melena and hematemesis. cbc revealed platelet count of and she was referred to the ed. abdominal ultrasound was concerning for abnormal hepatic waveform; cxr showed multiple pulmonary nodules. workup revealed no other lesions and no further hematologic abnormalities. biopsy of presumed hemangioma ultimately revealed a smooth muscle-lined vascular proliferation without glut- immunoreactivity, consistent with mlt. her early course was complicated by an acute hemodynamically significant gi bleed; esophagogastroduodenoscopy identified six bleeding vascular malformations within the stomach that were injected with epinephrine and sclerosed with successful hemostasis. she received multiple prbc and platelet transfusions. central access was obtained and she was started on oral sirolimus based on previous reports of successful use in management of vascular malformations given its antiangiogenic and immunosuppressive effects ( ). she has tolerated it well with no evidence of toxicity and has achieved a partial response with stable of hemoglobin > and platelet count > . cutaneous lesions have diminished in intensity and she has had no further signs of gi bleeding. she receives pentamidine for pcp prophylaxis. she continues to have appropriate growth and development. we describe here an unusual presentation of an already rare disease. while cutaneous and gi lesions are typical of mlt, pulmonary involvement is not well-described in the literature. early identification of tissue-based diagnosis enabled timely stabilization and treatment of the patient. five months later, she continues to tolerate sirolimus and has shown significant response with diminished coloration of cutaneous lesions, stable blood counts, and no further bleeding. mlt is a relatively newly-recognized disorder with significant phenotypic variability. given that bleeding secondary to a kasabach-merritt-type consumptive thrombocytopenia is the major cause of morbidity and mortality in the first year of life in children with mlt, it is essential to recognize the diagnosis and initiate appropriate treatment as early as possible. north, arch background: patients with generalized joint hypermobility (jhm) may experience easy bruising or bleeding given the association between these symptoms and abnormalities in collagen, a required component of primary hemostasis. heavy menstrual bleeding (hmb) is a common initial presentation for females with underlying hemostatic defects and may be the sole manifestation of a bleeding disorder. however, limited reports describe jhm as a cause of hmb, leading to under recognition. objectives: to describe the clinical characteristics and management of young women presenting with hmb in the setting of jhm. design/method: this study utilized our hmb research registry. we included subjects - years, seen in the nationwide children's young women's hematology clinic between february and november with both hmb and jhm. medical records were retrospectively reviewed for history of presentation, menorrhagia impact questionnaire (miq): a validated quality-of-life tool for females with hmb, medication profiles and relevant laboratory studies. results: twenty-five patients met inclusion criteria (median age years, range - ) with an average beighton score of . (range to ). participants presented an average of . years (range months to years) after menarche despite % of patients reporting heavy to very heavy menses since menarche. according to the miq responses, most participants expressed hmb-associated limitations in physical activities ( %), social activities ( %), and work or school activities ( %). of the participants, % reported bleeding symptoms in addition to hmb, most commonly easy bruising ( %), epistaxis ( %) and cutaneous bleeding ( %). forty percent of young women presented with anemia due to chronic blood loss. results of hemostatic testing were unremarkable, with the exception of one patient who was also found to have type von willebrand disease. additionally, % of females reported arthralgia, with knees and ankles the most commonly affected joints. at time of presentation, % of participants reported failure of initial therapies and most patients ( %) were managed long-term with oral hormone therapy. in a small population of young women found to have jhm who initially presented with hmb, patients were likely to have prior bleeding symptoms as well as substantial delays from menarche to timing of presentation at our young women's hematology clinic despite limitations in activities of daily life. greater awareness of the associations between bleeding symptoms and jhm, despite typically normal hemostatic laboratory results, is necessary so that patients can more easily be identified and receive appropriate therapy. the objective is to determine the impact of cl care practices involving the home environment on ambulatory clabsi rates. design/method: information for the pi was collected through a comprehensive survey that was completed annually by the ccbdn member hospitals. responses to the questions about cl care practices involving the home environment were selected from the pi for . ambulatory clabsi rates and ambulatory total bloodstream infection (bsi) rates were obtained from another ccbdn database. the proportion of hospitals that did or did not employ a particular cl care practice was tallied. the mean ambulatory clabsi rate and mean ambulatory total bsi rate of the hospitals that did or did not employ a particular cl care practice were compared using generalized linear model techniques assuming an underlying negative binomial distribution. results: twenty-five hospitals submitted responses to the questions about cl care practices involving the home environment. one hospital was excluded for lack of bsi data. sixty-three percent of the hospitals programmatically educated parents about all aspects of the cl care bundle. the mean ambulatory clabsi rate for the hospitals that educated parents was significantly lower than that of the hospitals that did not ( . infections/ cl days vs. . infections/ cl days; p = . ). the mean ambulatory total bsi rate was also significantly lower ( . infections/ cl days vs. . infections/ cl days; p = . ). the mean ambulatory clabsi rates and mean ambulatory total bsi rates were not significantly different for the other cl care practices. conclusion: an analysis of cl care practices involving the home environment reveals that parental education of all aspects of the cl care bundle is associated with a lower ambulatory clabsi rate and lower ambulatory total bsi rate. this finding highlights the importance of systematically teaching family members the proper method of handling cl. background: children undergoing chemotherapy are at a high risk for developing nausea. dr. amy baxter in collaboration with pediatric oncology patients and nurses, developed and validated a pictorial nausea rating scale for children aged - years, called the baxter retching faces (barf) nausea scale. staff nurses at a large, academic, pediatric hospital located within washington, d.c., have identified variability in nursing assessment and documentation of chemotherapy induced nausea and vomiting (cinv) in pediatric oncology patients. the purpose of this quality improvement project was to utilize the barf scale to standardize assessment and documentation of nausea in pediatric oncology patients receiving chemotherapy. the primary aims of this project were to: assess feasibility of the barf scale in clinical practice; increase nursing knowledge about cinv through education sessions; increase documentation of nausea assessments through the use of the scale. the secondary aim of this project was to: increase the recognition of nausea through the use of a standardized assessment tool. design/method: the pdsa model was used to guide the design and implementation plan. in the first phase of the project data was collected to identify the prevalence of nausea in patients admitted for chemotherapy in the prior three months. education sessions discussing cinv and the utilization of the barf scale were conducted. pre and post assessment of nurses' knowledge of cinv and documentation were assessed. in the second phase the barf scale was implemented into practice. nurses were asked to utilize the barf scale to assess and document nausea scores in patients, aged to years, receiving chemotherapy. at the end of the implementation period nurses were surveyed about the feasibility of the scale. post data was collected to identify the prevalence of nausea documented in the electronic health record. this project was undertaken as a quality improvement initiative at children's national and it does not constitute as human subjects research. as such it was not under the oversight of the institutional review board. results: all data has been collected; however complete data analysis will be conducted in the upcoming weeks. background: sickle cell disease (scd) is the most common inherited blood disorder in the united states (us); however, there are few quality measurements to evaluate scd practice. in , the nhlbi published guidelines that include two key interventions for children with sickle cell anemia (sca): the use of transcranial doppler (tcd) screening for stroke prevention and hydroxyurea (hu) to prevent scd pain crisis. we conducted a national survey of scd management sent to providers in over institutions in the us to better assess knowledge of the guidelines and barriers to hu counseling and tcd screening guideline implementation. it was hypothesized that the barriers to tcd screening are different than barriers to hu counseling and prescribing. a -question anonymous survey was sent to providers by mail (follow-up by email). survey themes included nhlbi guidelines knowledge and comfort with understanding and implementing both tcd screening and hu use. the response rate was % ( / ) however one survey was incomplete. thus, were analyzed in the final data set. all of the respondents are in active practice, % s of s in academics and all care for children with scd. the majority of providers ( %) felt "very" or "extremely" confident in their knowledge of tcd screening and interpretation. similarly, % of providers felt "very" or "extremely" familiar with hu dosing and management. for tcd screening, % of providers estimated their screening rates were > % and % providers felt their annual screening rates were - %. the two biggest barriers to tcd screening noted by providers (of moderate to extreme significance) included: lack of support staff ( %) and lack of time during a patient visit ( %). regarding hu prescribing practices, % of providers offered hu to at least % of children with sca over nine months of age. the biggest barrier to hu prescribing noted by % of providers was concerns about patient adherence or access to the medication. only % providers felt that lack of support staff was a moderately significant barrier to hu prescribing. the pediatric scd providers surveyed all have access to the nhlbi guidelines. despite widespread guideline knowledge, there are different barriers for tcd screening versus hu prescribing, which prevent optimal implementation. as a result, although both recommendations are from the same nhlbi guideline, they likely will require different implementation strategies (systems-based interventions for tcd screening; interventions to improve patient adherence for hu counseling) to improve outcomes. background: invasive fungal disease (ifd) is a major cause of mortality and morbidity among pediatric immunocompromised patients such as those who receive chemotherapy or hematopoietic stem cell transplantation. the current diagnostic 'gold standard' of ifd remains culture of infected tissue obtained by biopsy. noninvasive biomarker testing for galactomannan or , -beta-d-glucan (bg) can have low sensitivity and does not provide species-level identification. nextgeneration sequencing (ngs) of cell-free plasma is a promis-ing noninvasive approach to providing species-level identification of ifd via a blood test and can further guide specific treatment. objectives: describe the incidence of positivity for fungal specific pathogens on ngs analysis in a high-risk immunocompromised pediatric population and correlate results with other 'standard' infectious studies if performed. design/method: immunocompromised pediatric patients with suspected ifd were enrolled and plasma was collected at time of enrollment. ngs was performed on extracted dna in cell-free plasma (karius, redwood city, ca). after removing human reads, remaining sequences were aligned to a curated database including pathogens. organisms present at a significance-level above a predefined threshold were reported. results: twenty-seven samples from enrolled patients have been processed thus far. of these subjects, were enrolled for prolonged febrile neutropenia (≥ hours) despite broad-spectrum antibiotics, for recrudescent febrile neutropenia, for abnormal imaging, and with other findings. after evaluation of routine studies performed, patients met criteria for proven ifd, for probable ifd, and for possible ifd using eortc/msg guidelines. the ngs plasma test identified the same pathogen as cultured from infected tissue or blood in % ( / ) of the proven cases. in the probable cases, pneumocystis jirovecii was identified in a patient with a positive bg ( pg/ml) and pneumonia. among the possible cases, toxoplasma gondii was detected in a patient with prolonged febrile neutropenia and lung imaging suggestive of ifd. additionally, candida glabrata was isolated in a patient with prolonged febrile neutropenia but no other criteria for ifd. numerous pathogens were also identified that could explain the above clinical parameters, including hsv , cmv, vzv, hhv , ebv, bk polyoma virus, and ureaplasma parvum. the cell-free plasma ngs test can detect invasive fungal infections from blood. the test identified fungi from proven ifd, detected pathogens in both probable and possible ifd cases, and is a useful diagnostic tool in the evaluation of ifd. supplies and sample shipment and processing supported by karius, inc. baylor college of medicine, texas children's hospital, houston, texas, united states background: practicing medicine is a lifelong learning process. as noted in the institute of medicine's seminal report, 'to err is human,' adverse outcomes do not typically result from individual recklessness; rather, they result from faulty systems, processes, or conditions that provide an environment conducive to making a mistake, or failing to prevent one. learning to systematically review errors and translate lessons learned into quality improvement (qi) initiatives is a critical component of practice-based learning and improvement for practitioners at all career levels. objectives: to develop a methodical, self-reflective and nonthreatening approach to incident analysis and translation of lessons learned into qi initiatives. design/method: we used a validated, structured case audit approach, modified from szostek et al: ) review all documentation relating to the case and identify all health care providers involved; ) interview stakeholders, including those who directly provided and supported care; ) use a qi tool to conduct a root-cause analysis; ) identify a systems issue that contributed to the outcome; and ) propose systems-level interventions and prioritize initiatives based on effort-yield projections. results: pdsa cycle : plan: establish a committee to ) identify potential cases, ) triage cases for conference presentation, ) determine timing and frequency of conferences, ) develop a training manual, ) record identified qi initiatives. do: we established a quarterly section-wide meeting to which all members of the pediatric hematology/oncology service are invited, including administrative and nursing leadership. we developed a training manual and structured presentation template. prioritized cases were discussed in advance during multidisciplinary case review sessions, and presented by senior fellows who were instructed to focus discussion on potential opportunities for qi. study: we identified cases, meeting criteria for mmi presentation. qi initiatives identified from this conference resulted in a number of systemic practice changes; however, we encountered challenges to sustaining these changes over time. act: objectives for the next pdsa cycle are to ) establish a method for tracking the adherence to recommended changes in practice, ) maximize sustainability by integrating qi initiatives into institutional qi leadership and practice standardization committees. we have successfully implemented an mmi conference that meets out of institute of medicine quality domains: safety, effectiveness, patient-centeredness, timeliness, and efficiency. a standardized, consistent approach to mmi presentations that includes identification of contributing factors and specific qi implications has the potential for improving both provider education and patient care/safety. johns hopkins university, baltimore, maryland, united states background: receiving a cancer diagnosis is a life-changing event for patients and caregivers, although little is known about the experience. while some oncologists receive dedicated training in delivering this bad news, the initial conversation is often with a primary pediatrician, and these providers often feel they do not receive adequate training in the communication of a cancer diagnosis. objectives: our objectives were two-fold: first, to better define the experiences of caregivers/patients when told of a cancer diagnosis, and to query how caregivers/patients believe providers can improve the disclosure of this bad news. secondly, to assess what, if any, training primary pediatricians received in this skill, and to assess how comfortable providers in various settings and stages of training are with communicating cancer diagnoses. design/method: from november - , semistructured, in-depth interviews were conducted with pediatric oncology patients and caregivers of patients (n = ) diagnosed in the past year regarding their experiences receiving the diagnosis at our institution. in addition, pediatric residents (n = ), outpatient pediatric primary care physicians and pediatric emergency medicine physicians (n = ) were interviewed regarding their experiences delivering cancer diagnoses. interviews were analyzed following principles of thematic analysis. interviewers with patients and caregivers had two common themes: ) all emphasized their wish for direct and thorough information; ) both patients and caregivers emphasized the gratitude they felt for physicians who gave them hope by emphasizing the good prognosis of their child's cancer. lack of training in this area, as well as lack of comfort delivering this news was common will all providers. additionally, providers report variable approaches to giving bad news, including ) whether to tell caregivers separately or tell the child and parents together, and ) whether to give favorable prognostic information. additionally, attending physicians also differed significantly in their approaches to teaching residents. while some believed residents should give the news to gain experience, others felt that this is not appropriate if residents are inexperienced. only one resident reported ever receiving feedback on his communication skills in this type of discussion. conclusion: we plan to build on these interviews to develop a national survey of patients, caregivers, and providers to better understand the issues surrounding this discussion. we will use the findings to develop a communication curriculum for pediatric residents, focusing on the discussions that occur in the outpatient setting by primary pediatricians. background: human papilloma virus (hpv), common in both females and males, is responsible for pathologies ranging from benign genital warts to cervical and penile cancer. hpv strains and are responsible for , malignancies each year in the united states, and one third of them arise in men. pharmaceutical companies have now developed a vaccine that will help prevent the virus-associated malignancies. the cdc initially recommended that females ages - years receive the vaccine series, then starting in they expanded the eligibility to males ages - years. despite being widely available and highly publicized, only % of eligible females receive the full vaccine series. objectives: this study aims to assess the knowledge of hpv, the attitudes towards the hpv vaccine, and identify barriers preventing its full utilization. once identified, we aim to overcome the barrier(s) in order to improve vaccination rates in eligible adolescents. we distributed a standardized questionnaire to the parents of eligible female and male patients in our pediatric hematology-oncology clinic. it assessed the parents' knowledge of hpv and the vaccine, their views of the vaccine, and reasons why they may oppose it. results: approximately % of parents claim they have been educated about hpv, mostly by their primary care physician. however, % did not know what disorders hpv caused; % felt the vaccine should not be added to the typical vaccine schedule; % of parents do not intend to vaccinate their child. of those that opposed the vaccine, one-third were concerned about potential side effects and nearly % feel they do not have enough information. additionally, % of parents are not aware that the vaccine is available at their child's doctor and only % of parents have discussed the hpv vaccine with their child's doctor. the largest barrier to the utilization of the hpv vaccine that we have identified appears to be lack of educa-tion. as a result, we have begun distributing the cdc's hpv and vaccine patient guide to our patients' families as an intervention. we are currently in the process of re-administering our survey to these families after implementing the intervention to assess its success in increasing both knowledge and utilization of the hpv vaccine. cancer institute, chennai, chennai, tamilnadu, india background: rasburicase is a recombinant urate oxidase enzyme approved for use in tumor lysis syndrome (tls) and it acts by reducing serum uric acid levels. using rasburicase at the recommended dose of . mg/kg/day for days is expensive and it is not known whether this extended schedule is clinically beneficial compared to a single fixed dose of . mg. the aim of the present study was to evaluate the efficacy of single dose rasburicase . mg in prevention and management of tls. design/method: rasburicase is available as single use . mg vial. at our institution a single dose of rasburicase . mg irrespective of bodyweight has been used in adults and in children a dose of . mg/kg (maximum . mg) has been used since for prevention and management of tls and subsequent doses are given based on biochemical response and clinical condition. we retrospectively analysed the case records of patients who had received rasburicase from january to january . the study included patients with hematological malignancies who received rasburicase. children accounted for . % (n = ) patients and males comprised % (n = ). rasburicase was used prophylactically in ( . %) patients, for laboratory tls in patients ( . %) and for clinical tls in ( . %) patients. single fixed dose rasburicase prevented laboratory/clinical tls in % of the prophylactic group and prevented clinical tls in % of the laboratory tls group. none of the patients in prophylactic and laboratory tls group developed clinical tls. however, majority of the patients with clinical tls required more than one dose rasburicase. single dose of . mg ( vial) rasburicase is efficient in preventing and managing laboratory tls and is economically viable in resource constrained settings. nicole wood, lauren amos, nicholas clark, chris klockau, karen lewing, alan gamis children's mercy kansas city, kansas city, missouri, united states background: medication reconciliation for newly diagnosed oncology patients is complicated and cumbersome. these patients are often admitted on no medications, and leave on multiple. chemotherapy and supportive medications are crucial. despite numerous individuals overseeing this process, prescribing errors or omissions still occur. when reviewing the literature, improvement occurs when there is an interprofessional and standardized process to medication reconciliation. objectives: this project's aim was to improve the accuracy of the discharge medication reconciliation process from % to % from february -august . the process measure was the percentage of patients discharged with an accurate checklist. additional time for staff spent in completing the checklist and avoiding an increased error rate by changing the prescribing process were followed as balancing measures. we created a discharge medication checklist which included a list of required home medications prescribed by the resident, ideally hours prior to discharge. it required fellow or attending review and pharmacy to review the list and educate the family. checklists were collected monthly and reviewed against the electronic medical record (emr) for accuracy. results: six pdsa cycles were completed. there were errors during the data collection time frame. in pdsa cycle , a patient received acetaminophen for pain control which is avoided at home. in addition, this patient received diphenhydramine instead of ondansetron, which is preferred as an antiemetic. in pdsa cycle , a patient with a pending diagnosis was sent home with acetaminophen. of note, this patient did not have a checklist completed upon discharge. this project provides a novel and important method to standardize the discharge medication reconciliation process in a complex patient population. it clarifies which types of medications these patients need, provides pharmacy teaching to families which was not done previously, and prescribes discharge medications to families sooner. after the first medication reconciliation error, the checklist was revised. no further errors were made following revision, with the exception of one patient without a completed checklist at dis-charge. our accuracy rate increased from % at baseline to % following implementation. we are in the process of making the checklist electronic and accessible in the emr. in the interim between the end of data collection and implementation into the emr, a leukemia patient was sent home without an epinephrine pen, further demonstrating the importance of this standardized discharge process. for this reason, we have re-instituted the checklist until the electronic version is available. background: survivors of pediatric cancer are at risk of losing pre-existing protective antibodies to vaccine preventable diseases. in a prior study, % of children < years lost humoral immunity to measles as a result of chemotherapy induced alterations in immune system. measles in recipients of immunosuppressive chemotherapy has mortality rates up to %. because of volitional vaccine refusal, there has been a dramatic increase in measles infection from cases in to in , including several statewide outbreaks. small pediatric oncology practices frequently share floor/clinic space with the general pediatric patients putting them at risk for measles since virulence starts hours prior to symptoms. there is no standard protocol for revaccinating post-chemotherapy patients. to assess measles risk based on serial humoral immune status in a cohort of pediatric oncology patients receiving intensive chemotherapy design/method: patients < years age with known vaccination status receiving intensive chemotherapy between july -june at our institution's pediatric oncology practice were included in this prospective study. serial measles igg antibodies were measured at diagnosis, months and months after initiation of chemotherapy using elisa. measles immunity was defined per lab standards. a comparison of pre-chemotherapy and serial post-chemotherapy immunization titers was made for all patients by diagnosis. the study population consisted of children ( male); patients had all, non-hodgkin lymphoma, sarcoma and other solid tumors. two patients ( . %), both unvaccinated had non-protective measles antibody levels at s of s baseline. of the remaining patients, . % patients ( leukemia, lymphoma and sarcoma) lost protective antibody titers at months after initiation of chemotherapy and . % ( leukemia, lymphoma and sarcoma) at months after initiation of therapy. % of the remaining patients who retained measles antibody titers within protective range at months also demonstrated a steady decline in antibody titers at and months from therapy initiation. the loss of protective measles humoral immunity occurred significantly more often in patients with leukemia compared to other malignancies. oncology patients in our practice undergoing intensive chemotherapy demonstrated progressive waning of protective measles igg titers. our data suggests that it should be standard practice to check all patients for measles humoral immunity prior to starting chemotherapy and at completion. larger studies need to be performed to establish guidelines for revaccinating post-chemotherapy pediatric patients, an intervention that is easily applicable and of low cost. background: the accurate determination of glomerular filtration rate (gfr) is important to screen for acute kidney injury, to dose chemo-therapy, and to identify risk for chronic kidney disease.being correlated with inulin clearance, measured gfr by iohexol plasma disappearance (igfr) is a new gold standard for measurement of gfr in pediatric cohort studies. igfr is based on the clearance of an exogenous marker and is unaffected by endogenous compounds or a patient's muscle mass. we compared igfr with -hour urine creatinine clearance ( crcl) and gfr estimating equations using serum creatinine (scr) and serum cystatin c (cystc) in pediatric patients with cancer. we recruited participants who were ages to yrs, continent of urine, and diagnosed with a malignancy in the past years. eligible subjects had stable kidney function for at least two weeks prior to the assessment of igfr. consented subjects had baseline assessments including height, weight and vital signs. blood samples were obtained for serum chemistry, and time zero iohexol. igfr determined by ml iohexol solution infused over - minutes followed by ml of sterile saline. blood was drawn at , , and minutes.at the same time of igfr, the crcl was collected. igfr was calculated using a two-compartment model and area under the curve. we compared igfr to published gfr equations (schwartz et al, kidney int ). results: ten subjects ( female/ male) agreed to participate. the distribution of diagnoses for the subjects: all = , lymphoma = , brain tumors = and hepatocellular carcinoma = . six patients were off therapy. the lower gfrs are noted in patients who had malignancies other than leukemia, likely due to the use of cisplatin based therapy. the average igfr was ml/min/ . m^ whereas crcl was . ml/min/ . m^ ; demonstrating the crcl overestimates gfr compared to igfr. comparing igfr to univariate equations using scr, cystc, and the multivariate equation with both, the univariate cystc equation correlated well with igfr; the others overestimated igfr. we found that crcl overestimated igfr. the univariate cystc equation better correlated to igfr than equations with scr. the poor performance of scr based methods to assess gfr might be due to decreased muscle mass and inadequate nutritional status. creatinine-based determinations of gfr alone, may not be accurate in this population. further study is needed to determine if igfr should be a standard of care to assess gfr in children with cancer particularly who are receiving nephrotoxic medications and incontinent of urine. background: pediatric oncology patients undergoing chemotherapy through indwelling venous catheters are at increased risk for severe sepsis especially when neutropenic due to chemotherapy. rapid triage and early recognition are essential because delayed initiation of antibiotics and fluids in these patients or delayed transfer to higher level of care after initial stabilization is associated with poor clinical outcome. our pediatric oncology out-patient clinic is designated as an article unit whereby the providers can initiate and give treatment such as intravenous fluid, antibiotics, chemotherapy and blood products. objectives: global aim-optimize management of early sepsis and decreased morbidity, mortality and hospital length of stay in the high risk pediatric oncology patients. smart aim-improve timely management with initiation of fluids and antibiotics and transfer of septic patients to higher levels of care by % in months in above patients design/method: multidisciplinary team with physicians and nurses was created. retropective chart review of sepsis patients treated at the clinic from april to october was done using an audit sheet to identify the barriers in the delivery of care. three patients were identified and data analyzed prior to intervention; two were analyzed post interventions. a key driver diagram was created by the group to drive intervention. a process map was designed to identify the different steps in the care of these patients to pinpoint areas needing improvement. different timed data points were used starting from time of arrival to clinic, time to antibiotics and fluids and time to transfer to higher level of care. rapid pdsa cycles were done to improve the processes and delivery of care. run charts were created. there was an improvement close to the goal of % for all data points used. pdsa cycles for improvement included conducting frequent mock codes with appropriate feedback real time coaching and process planning with nursing staff. we partnered with pharmacy for close loop communication with clinic staff and we improved communication between physicans at different levels. conclusion: sepsis in neutropenic pediatric oncology patients is deadly and can be reversed with timely management at different levels. given the promising results of the above project, we want re-inforcement of the processes to be a part of the daily practice of first line clinical staff. eventually we will extend the principles learnt in management and triage of sepsis to other outpatient emergencies chemotherapy related anaphylaxis background: chemotherapy-induced nausea and vomiting (cinv) is a common side effect in children receiving antineoplastic chemotherapy. recommended prophylactic antiemetic medications are based on the classification of chemotherapy emetogenicity. however, despite appropriate use of these antiemetic agents, some patients will still experience nausea and/or vomiting. children's oncology group clinical practice guidelines recommend the addition of olanzapine to prophylactic regimens for management of breakthrough cinv. objectives: our pediatric hematology oncology center implemented a quality improvement (qi) project aimed to increase the use of olanzapine in pediatric cancer patients years of age and older receiving moderately or highly emetogenic chemotherapy and experiencing breakthrough cinv over a month period. design/method: this qi project was conducted utilizing plan-do-study-act (pdsa) cycles. for the first pdsa cycle, baseline data was collected through chart review to determine the rate of olanzapine use for breakthrough cinv over a month period from july to december . breakthrough cinv was defined as use of or more doses of antiemetic agents other than those given for cinv prophylaxis. guidelines for treatment of breakthrough cinv were reviewed with pediatric hematology/oncology attending physicians and fellows. flyers were created that listed chemotherapy regimens considered moderately and highly emetogenic. if a patient experienced breakthrough cinv, a flyer was to be placed in the patient's roadmap binder to signal olanzapine should be added to the next chemotherapy block. data was collected over a month period in september following this first intervention. the second pdsa cycle consisted of didactic education and training of pediatric oncology nurses as well as pediatric residents regarding the addition of olanzapine for breakthrough cinv. rates of olanzapine use were then collected from october through november . results: olanzapine use increased from . % at baseline to . % after the first pdsa cycle ( = . , p = . ). after the second pdsa cycle, olanzapine use increased another . % to . % ( = . , p = . ). the administration of olanzapine was successfully increased by modifying patients' roadmaps after patients experienced breakthrough cinv as well as with education and training of pediatric oncology staff, fellows, residents, and nurses. background: venous thromboembolism (vte) is increasingly affecting children. according to an administrative database study, there was a % increase in the incidence of vte among children admitted to free-standing children's hospitals in the united states from to . risk factors for hospital-acquired vte are well-known and well-studied in adults, with evidence-based preventative measures available. similar guidelines are lacking for children. objectives: there is an ongoing national-initiative to develop and institute methods for screening and preventing hospitalacquired vte in children. in / , nationwide children's hospital instituted an electronic screening form required for all patients admitted ≥ hours. patients were scored and riskstratified based on eight risk-categories. a summated score was used to determine the vte risk level, and used to make prophylaxis recommendations for patients ≥ years; as well as patients ≥ years who were admitted to an intensive care (icu), surgical, or trauma unit. the purpose of this irb exempt, quality improvement initiative was to retrospectively review our experience with this risk-stratification tool. results: hospital-acquired vte events occurred in unique subjects. median age at vte diagnosis was years. only ( %) vte occurred in children ≥ years of age. ( %) vte were deep vein thrombosis (dvt), and ( . %) involved pulmonary embolism. vte was most common in subspecialty units including the pediatric and cardiac icus ( . %); neonatal icu, ( . %); and hematologyoncology, ( . %). ( %) vte were associated with central venous catheters (cvc) and events ( %) were associated with altered mobility. congenital heart disease/heart failure was the most common chronic medical condition associated with vte ( ( . %) events); whereas infection and trauma/surgery were the most common acute medical conditions associated with vte ( ( . %) and ( %) events, respectively). during ( %) events, subjects scored a summated score ≥ . in summary, in this single institution, prospectively maintained database, cvc remains the most common risk factor for vte, followed by cardiac disease, infection and trauma/surgery. most subjects who developed vte scored high (score ≥ ) on our screening tool. only a small proportion of vte occurred in patients older than years and thus eligible for thromboprophylaxis. our results indicate that future vte prevention endeavors should include these age groups in addition to exploring more aggressive prophylactic modalities including pharmacological prophylaxis. background: pediatric fellows are required to have active engagement in quality improvement (qi) activities, and yet a national acgme review found most trainees had "limited knowledge of qi methods" and "limited participation in interprofessional qi teams". the twenty fellows in our pediatric hematology/oncology training program identified blood culture utilization as their qi priority. our institution recently introduced a hospital-wide decision algorithm to guide providers regarding when to obtain blood cultures. there is often a low threshold to obtain blood cultures in immunocompromised pediatric oncology patients, but these are often low-yield or result in falsepositives. our fellows spearheaded a project to implement the algorithm in the inpatient pediatric oncology population and improve the proportion of appropriately drawn blood cultures. we investigated how appropriately the algorithm was being utilized on the inpatient pediatric oncology floor prior to and after several educational steps aimed at disseminating the algorithm to members of the care team. our primary endpoint was to quantify the proportion of culture episodes drawn "inappropriately", with a goal of reducing inappropriate episodes to ≤ %. the algorithm was initially introduced to the nursing staff and residents covering the twenty-bed inpatient unit in september . qi project planning took place with upper level fellows in january . fellows and faculty received intensive training on the algorithm in july-august . we then conducted a retrospective chart review of blood culture episodes drawn between august and november . upper level fellows scored ∼ culture episodes as to whether the decision to culture and number of cultures drawn were "appropriate" or "inappropriate", and catalogued the indications for culture episodes and if applicable, why the episode was found to be inappropriate. additionally, fellows discussed inappropriate culture episodes with the team onservice, to provide direct feedback on where the algorithm failed. results: between august -december on average cultures/ patient-days were drawn. forty-nine percent of culture episodes were inappropriate. from january -october , following targeted education on the algorithm, the rate of blood cultures drawn decreased to cultures/ patient-days. the average proportion of inappropriate culture episodes fell to . %, representing a % decrease in inappropriate culture utilization. correct application of a decision algorithm for blood culture utilization can reduce total cultures drawn on an inpatient pediatric oncology unit. fellow-led education of the multi-disciplinary team decreases the rate of inappropriate culture episodes as well as provides active engagement in qi. background: inadequate understanding of sickle cell disease (scd) is common and can affect patients' compliance and therefore their morbidity and mortality, especially after transition to adult care. optimal clinical care for scd includes disease education, which can be difficult given the breadth of possible topics and limited time in clinic. it is unclear how best to provide personalized, efficient education for adolescents with scd. this quality improvement (qi) study aimed to implement a questionnaire-based system to improve patients' knowledge of their scd and documentation of education by the nurse or physician. the study objective was to improve provider documentation and patient knowledge about their scd by identifying patients' gaps in comprehension. by january , the study aimed to increase education documentation from % to %. by april , the study aimed to increase use of a smart phrase for education documentation from % to %. by june , the study aimed to increase patients' knowledge about their disease by %. design/method: twenty-one scd patients enrolled on an irb approved qi study, with twenty active patients. our comprehensive team generated a questionnaire with knowledgebased questions for two age groups: - and - years old. at each comprehensive visit, a questionnaire was distributed, with at least -month intervals. the provider scored questionnaires and reviewed two educational topics, with wrong answers taking priority. plan-do-study-act (pdsa) cycles included pdsa# : patients completed questionnaire. pdsa# : a smart phrase addressing questionnaire topics was created and shared with providers. pdsa# : patients received education handouts during clinic education. documentation in clinic notes was the process measure and questionnaire scores was the outcome measure. results: pdsa# is complete, pdsa# has four patients remaining, and pdsa# is ongoing. due to variable visit frequency, there are multiple concurrent cycles. after pdsa# , free text documentation was completed an average of % over the course of months. after pdsa # documentation increased to % within months and questionnaire scores increased from an average of % to %. of the questions that patients got wrong on their first visit, they were significantly more likely to improve on retesting if the topic was taught to them than if it was not addressed ( % vs. %, p = . ). we are currently completing pdsa# and collection of post pdsa# data. questionnaire-based scd education coupled with standardized smart phrases improves patients' scd knowledge and documentation by providers. further improvement in knowledge is expected with the addition of handouts. background: exposure to suffering can have a profound impact on the wellness of caregivers, often referred to as the "cost of caring". this cost is especially high in pediatric hematology/oncology. repeated exposure to suffering has the potential to negatively impact resilience and increases the risk of burnout, thus impacting quality of care and patient satisfaction. we have developed a peer support team utilizing the critical incident stress management (cism) model. this model has been successfully used in other professions that frequently face traumatic events such as fire fighters, police and emergency medical technicians. the h.o.p.e.s. team (helping our peers endure stress) consists of volunteer multidisciplinary staff members who have received training to provide both group and peer support following any 'critical incident' that may impact one or more staff members. we hypothesize that implementation of the h.o.p.e.s. team will improve staff resilience, decrease overall rates of burnout and improve compassion satisfaction. s of s design/method: we are using both empiric metrics and anecdotal reports to assess the impact of the h.o.p.e.s. team. prior to the activation of the team, all pediatric hematology/oncology clinical staff members were surveyed using validated tools to assess their levels of resilience, burnout, secondary trauma and compassion satisfaction (proqolv and brief resilience scale). they were also asked to rate the number of times they had experienced critical incidents, as well as their perceived level of distress after dealing with traumatic events. after the h.o.p.e.s. team has been functional for months, we will send the same survey to staff members to measure changes, paying special attention to resilience and rates of burnout and compassion satisfaction. results: enthusiasm for development of the team has been high. of people approached to volunteer their time to participate in the multidisciplinary team agreed, including attending physicians, fellows, nurses, nurse practitioners, child life specialists, social workers, clergy and psychologists. all volunteers participated in a -day training conducted by an instructor from the international critical incident stress foundation. engagement in the first staff survey has been high, with of responding to date. data collection is ongoing. clinical staff in pediatric hematology/oncology may be particularly vulnerable to burnout and decreased resilience by repeatedly witnessing suffering and trauma. peer support interventions following critical incidents may lead to increased resilience and compassion satisfaction while decreasing rates of burnout. enthusiasm for the development of a peer support team has been high. background: monthly blood transfusions are an indicated therapy for pediatric patients with sickle cell disease with certain complications. maximizing transfusion efficiency in a busy infusion clinic requires: ensuring that appropriate blood units are available in the hospital blood bank; laboratory specimens are obtained from patients in advance; and coordination of clinic appointment and nursing availability. we sought to improve clinic efficiency through identifying ways to better communicate with patients/families regarding upcoming laboratory and transfusion appointments, and to assess the efficacy of implementing a web-based personalized text reminder (pinger.com). we measured the baseline frequency with which transfusion appointments were missed by families, moved to later within the week, or delayed due to late labs. a convenience sample of patients receiving monthly transfusions received a questionnaire about patient/parent preferences for appointment reminders and barriers to keeping appointments. those patients/parents who did not opt-out of an additional text reminder received personalized texts from their care team reminding them of lab and transfusion appointments. rates of missed/moved/delayed appointments were compared between the group receiving the additional text messages and the group only receiving standard, hospitalgenerated appointment reminders (telephone call). results: forty-one families ( patients) responded to the survey, capturing information on % of patients receiving chronic transfusion therapy. thirteen families ( %) declined the additional text reminders. families reported a preference for text reminders ( %), more often than email ( %) or telephone ( %), and % of families wanted to receive reminders for both transfusion and laboratory appointments. the majority ( %) of families reported competing work/life priorities as the reason for missed/late appointments. other families noted transportation/travel ( %), fear/illness/pain ( %), and lack of reminders ( %) as the reason for missed appointments. at baseline (twelve weeks), . % of appointments were missed on a weekly basis (range - of available per week), . % were moved, and % of appointments were delayed. during our intervention period (twelve weeks), % were missed, . % were moved, and . % were delayed (combined, both groups). there was no difference in missed ( . % texted vs . % standard), moved ( . % texted vs . % standard) or delayed ( . % text vs . % standard) appointments. though families at our center reported a preference for a text-based reminder, personalized text reminders for appointments did not improve clinic efficiency as measured by missed, moved or delayed transfusion appointments. there was no improvement in appointment adherence in the group receiving personalized texts in addition to standard hospital reminders. university of utah, salt lake city, utah, united states background: childhood cancer outcomes have improved significantly, in large part due to multi-institution collaborative clinical trials run by the children's oncology group (cog). approximately half of eligible children with cancer will enroll on a therapeutic trial, but little is known about the factors affecting caregiver decision-making regarding enrollment or how well the required elements of informed consent are conveyed during the consent process. objectives: . assess coverage of ten of the required elements of informed consent for cog therapeutic trials. . describe factors affecting caregiver decision-making regarding therapeutic trial enrollment. we surveyed families of children who were offered enrollment onto a phase cog therapeutic study for an initial cancer diagnosis in the previous months. fisher's exact or wilcoxon rank-sum tests were utilized to compare demographic and other motivating factors related to enrollment decision-making. results: seventy participants were surveyed. regarding of the basic required elements of informed consent, % knew the trial involved research, % knew consent was required, % knew the enrollment length for the trial, % knew they could continue care independent of enrollment, % knew who to contact with questions, % knew there were options besides enrollment, % knew they could withdraw at any time, % knew the information was confidential, % knew there were risks associated with the trial, and % knew there were benefits. of all participants, % (n = / ) enrolled onto a therapeutic study. among enrollees, % (n = / ) of the primary caregivers had completed college compared to % (n = / ) of those not enrolled (p = . ). when asked about factors impacting their decision, % (n = / ) of those enrolled said they felt there were no risks or did not know if there were risks associated with the study compared to % (n = / ) of those choosing not to enroll (p = . ). of those enrolled, % (n = / ) reported the physician recommendation "somewhat" or "strongly" affected their decision to enroll compared to % (n = / ) of those not enrolling (p = . ). of those who enrolled, % (n = / ) reported feeling pressured to enroll while % (n = / ) of those not enrolled reported pressure (p = . ). of enrollees, % (n = / ) reported they did not have enough time to decide compared to % (n = / ) of those not enrolled (p = . ). failure to convey all required elements of informed consent highlights possible deficiencies in the consent process for cog therapeutic trials. caregivers' perception of being pressured and lack of time to make an informed decision may impact clinical trial enrollment. background: abnormal uterine bleeding (aub) is a frequent adolescent gynecologic complaint. however, limited research exists to guide management, and acute care varies. we sought to improve emergency care for adolescents with aub by developing a clinical effectiveness guideline (ceg) and assessing its impact on quality of care. design/method: a stakeholder engagement group consisting of members from the departments of hematology/oncology, adolescent medicine, general pediatrics, and emergency medicine designed a ceg algorithm for emergency aub management. pediatric residents received ceg training and their knowledge and attitudes were assessed using pre and post intervention surveys. icd- and codes identified electronic health record data for patients presenting to the pediatric emergency department (ed) for aub months before and after ceg implementation. pre-pubertal patients and those with vaginal bleeding from trauma were excluded. a weighted, -point scoring system consisting of prioritized aspects of history, laboratory studies and management was developed to quantify the quality of care provided. t-test, chi square test, wilcoxon rank sum test, and a run chart were used for analysis. of the patients identified, met inclusion criteria. there were % of patients currently using some form of contraception, while . % had bleeding related to a current or recent pregnancy. median aub quality care scores were pre-and post-intervention (p = . ). run chart data showed no shifts or trends (overall median score, -points). both pre and post-implementation, points were deducted most frequently for not assessing personal/family clotting disorder history and inappropriate use/dosing of oral contraceptives. we successfully designed and implemented a ceg and educational intervention for aub management in a pediatric ed. these data suggest our ceg may be an effective tool to improve emergency aub care for adolescents, though additional cycles are needed. background: high-dose methotrexate (hd-mtx) is a common chemotherapy administered inpatient at most centers. its administration is particularly susceptible to error due to the need for frequent drug levels with resulting changes in supportive care. errors can prolong patient stay and cause patient harm. objectives: global aim-to reduce the length of stay (los) of hd-mtx admissions. smart aims-to increase the percentage of patients whose pre-hydration fluids are started by am from % to % by / / , and to increase the percentage of patients who receive hd-mtx by pm from % to % by / / . we used rapid process improvement methods to target earlier methotrexate administration. a key driver of prolonged los was hypothesized to be drug levels returning overnight rather than in the day time due to delayed hd-mtx start. changes implemented have included scheduling hd-mtx patients as the first patients of the day for their exam in clinic and scheduling labs to pass for hd-mtx on the day prior to admission. there are ongoing pdsa cycles to change the location of pre-hydration start from the inpatient room to the clinic exam room in order to meet hd-mtx administration time goals. we are piloting two different education materials to improve patient experience. one explains hd-mtx levels in a red/yellow/green stoplight format and the other reminds patients how to prepare for the admission. other interventions regarding how we test urine ph and safety checks in the ordering process for history of delayed clearance are in the planning stage. the project is ongoing, but as of / / , we start methotrexate by pm % of the time which is improved from a baseline of %. when the project was started, pre-hydration was never started before am. now, fluids are started by am % of the time. pdsa cycles are ongoing and we have yet to sustain reductions in los, but some months have shown decreased los by as much as hours from baseline measurements. rapid cycle improvement can be utilized to decrease los hd-mtx admissions. this has important financial implications as well as the potential to reduce secondary harm from unnecessary time in the hospital. pediatric cancer centers should schedule hd-mtx admissions first thing in the morning so that data regarding kidney injury and drug clearance can be interpreted by the day team and children are not cleared for discharge in the middle of the night. background: education and training for interdisciplinary pediatric oncology providers requires training in principles of palliative and end-of-life (eol) care. the experiences of bereaved parents can inform and enhance palliative care educational curricula in uniquely powerful and valuable ways. the objective of this study is to present an innovative palliative care educational program for oncology providers facilitated by trained bereaved parents who serve as volunteer educators in local and national palliative care educational forums and to describe how incorporation of bereaved parents in these educational forums affects participant comfort with communication and management of children at the eol. design/method: survey tools were adapted to determine how bereaved parent educators affected participant experiences in different educational forums: institutional seminars on pediatric palliative and eol care, role-play based communication training sessions, and an international symposium on pediatric palliative oncology. pre-and post-session surveys with incorporation of retrospective pre-program assessment item to control for response shift were used in the evaluation of institutional seminars and communication training sessions. results from feedback surveys sent to all attendees were used to appraise the participants experience in the international oncology symposium. results: involvement of trained parent educators across diverse, interdisciplinary educational forums improved attendee comfort in communicating with, and caring for, patients and families with serious illness. importantly, parent educators also derive benefit from educational with interdisciplinary clinicians. integration of bereaved parents into palliative and eol care education is an innovative and effective model that benefits both interdisciplinary clinicians and bereaved parents. background: poorly controlled chemotherapy-induced nausea and vomiting (cinv) significantly impairs patients' quality of life and contributes to ongoing medical costs through increased length of stay in the hospital or readmissions and outpatient visits for control of nausea, vomiting or dehydration. lack of adherence to national evidenced-based guidelines that dictate antiemetic prescribing for variably emetogenic chemotherapy leaves patients vulnerable to increased cinv and its ensuing complications. objectives: to review our institution's antiemetic prescribing practices and their consistency with the antiemesis guidelines from the national comprehensive cancer network (nccn) and children's oncology group (cog)-endorsed supportive care guidelines and to further develop tools to increase adherence to these national-based guidelines to improve control of cinv. we performed a retrospective chart review of inpatient chemotherapy encounters. we evaluated emetogenicty of chemotherapy (high, medium, low), initial antiemetic regimen ordered, number of as needed medications required and adherence to national evidenced based guidelines tailored to each level of emetogenicity in the prescription of antiemetics. results: fifty-five total inpatient chemotherapy encounters were reviewed over months. eighteen of these encounters were considered to have been highly emetogenic chemotherapy (hec) with the remaining of these considered to be moderately emetogenic. only out of hec encounters completely included all guideline-recommended agents. there was a demonstrable lack of consistency across providers with dosing of aprepitant and most as needed medications. there was significant variation in order of first, second and third line anti-emetics ordered -with lorazepam and promethazine being used most frequently. with an aim of improving antiemetic prescribing practices for our patients, we are currently rebuilding chemotherapy treatment plans in our electronic medical record to incorporate antiemetic drug order sets that follow evidenced-based guidelines for variably emetogenic chemotherapy. this will be used in conjunction with an education initiative about best practices in supportive care for all prescribers of antiemetics. review of our department's recent inpatient chemotherapy encounters show we are falling short in following nationally recommended standards for appropriate antiemetic coverage during chemotherapy. identification of these deficiencies allows for implementation of quality initiatives to improve prescriber adherence to evidenced-based guidelines for better control of cinv. background: there are currently no consensus guidelines for the management of pediatric oncology patients presenting with fever without neutropenia. historically, these patients had been treated similarly to neutropenic patients with empiric antibiotics. while there has been a shift towards reducing unnecessary empiric treatment, there has been limited research into the outcomes associated with withholding empiric iv antibiotics in this patient population. we assessed the safety and efficacy of our institution's current protocol of observing well-appearing patients who present with fever without neutropenia and compared the outcomes of the patients who did and did not receive empiric iv antibiotics. design/method: this was a prospective, single-institution cohort study. patients were included if they were currently undergoing chemotherapy for an oncologic diagnosis and presented initially as an outpatient with fever and nonneutropenia (defined as anc ≥ cells/mm ). for each episode we recorded lab and blood culture results, signs and symptoms of initial presentation, and clinical outcomes, including antibiotic administration and hospital admission. results: a total of episodes of well-appearing patients with fever without neutropenia were identified. compliance with the institutional protocol was high; . % of patients were observed without receiving empiric iv antibiotics. the majority of patients were discharged home and there were no serious complications or infectious deaths. the incidence of positive blood cultures was low ( . % including several likely contaminants), despite the presence of central venous catheters in the majority ( . %) of patients. there were no significant differences in age, oncologic diagnosis, central s of s line access, anc value, or incidence of bacteremia between patients who did and did not receive empiric iv antibiotics. patients who were admitted to the hospital were significantly more likely to have received iv antibiotics (p < . ) despite documentation of a reassuring exam. however, admitted patients who initially received iv antibiotics were just as likely to discharge within hours compared to patients who were observed. we propose that empiric iv antibiotic administration in febrile, non-neutropenic, otherwise well-appearing patients is unnecessary. our study demonstrated no adverse consequences of observation and no significant differences in clinical outcomes between patients who did and did not receive iv antibiotics aside from rate of hospitalization. this supports the practice of observation without empiric antibiotics for such patients. background: children with hepatoblastoma (hb) undergo repetitive computed tomography (ct) scans to determine response to treatment and assess for relapse. this imaging exposes children to radiation, anesthesia, and imposes financial and emotional burden. objectives: review our institutional experience to determine if afp measurements are sufficient to assess response to treatment and detect relapse. we conducted a retrospective chart review of all patients diagnosed with hb at our institution between - . data collected included serum afp, total number and type of imaging studies during and post treatment, and how relapse or progressive disease was detected. results: thirty-one patients were diagnosed with afp positive hb. during therapy, ct scans were performed: to assess for response to therapy or surgical planning (average scans/patient) and due to concern for progression with rising afp. off therapy, surveillance ct scans were performed (average of . scans/patient) and ( %) included the chest in patients with no lung metastasis at diagnosis. relapsed patients averaged . surveillance scans, . of which were done before relapse was noted on imaging. there were no cases of radiographic evidence of relapse without a prior increase in afp. during treatment, response to therapy based on imaging correlated with a decline in afp in all patients, arguing that repetitive scans are not needed in this setting unless required for surgical planning. only of scans performed during off therapy surveillance displayed evidence of relapse, all of which were preceded by rise in afp. our study represents the largest cohort of hb patients. prior studies suggest similar results, but included fewer patients, lower stage of disease and less than years of surveillance monitoring. at our institution, the cost of a ct c/a/p is $ , with reimbursement varying from - %. in comparison, the cost of an afp measurement is $ . . many scans also require anesthesia and result in emotional toil for families concerned about this procedure as well as the results. thus, afp demonstrates greater sensitivity, with significant cost savings and decreased emotional burden, and should be used for monitoring both during and off therapy, replacing routine serial imaging. background: we observed that our practice of drawing daily blood cultures in hospitalized patients with fever and neutropenia was wasteful; it resulted in excessive negative cultures that did not add to patient care. the smart aim of this quality improvement project was to reduce the number of negative blood cultures drawn on hospitalized patients with fever and neutropenia by % in months. design/method: after reviewing published evidence suggesting drawing daily blood cultures in febrile neutropenic patients was unnecessary, a new blood culture guideline was implemented: cultures were drawn at presentation for fever with neutropenia and, if negative at hours, repeat cultures were not drawn except for clinical change, new fever after being afebrile > hours, or antimicrobials were being changed/broadened. to impact key drivers, we educated staff and changed blood culture order sets to require providers to select a reason for ordering the culture and to eliminate a nursing order to draw daily cultures with fever. we compared the number of blood cultures drawn per central linedays (/ -cld) and the proportion of positive versus negative cultures pre-guideline (july -may ) and postguideline (june -december ). we calculated the cost savings from reducing cultures. to assess patient safety, potential septic events without a corresponding positive blood culture were reviewed. data were analyzed by service (oncology and stem cell transplant). a chi-square test was used to compare rates. in stem cell transplant patients, pre vs. postguideline, there were vs. total cultures drawn/ -cld; vs. positive ( % decrease, p = . ) and vs. negative cultures/ -cld ( % decrease, p< . ). in oncology patients, pre vs. post-guideline, there were vs. total cultures drawn/ -cld; vs. positive ( % decrease, p = . ) and vs. negative cultures/ -cld ( % decrease, p< . ). the decreased positive culture rate among oncology patients may be due to decreased culture contaminants and/or the effect of a concurrent initiative to decrease clabsi in that group. there were safety concerns; however, chart review concluded that the guideline did not lead to missed infections in these patients. for the first months of the guideline, the total cost savings in blood cultures was $ , . . the implementation of our new blood culture guideline successfully led to a substantial reduction in the collection of negative cultures and a cost savings without compromising the detection of bacteremia in hospitalized pediatric patients with fever and neutropenia. background: there are various evidence-based guidelines for treatment of adult cancers, such as the nccn guidelines. previously, care was standardized for most new diagnosis pediatric cancer patients through enrollment on a clinical trial. with decreasing clinical trial availability and enrollment and few, if any, evidence-based guidelines for pediatric cancer, care standardization is challenging for pediatric cancers. objectives: to assess consistency of care, as determined by plan of treatment by diagnosis, for pediatric patients receiving chemotherapy for newly diagnosed cancer at a single center. design/method: patients with a new cancer diagnosis at a large, tertiary care pediatric oncology center in calendar year were identified through reports from the chemotherapy order entry (coe) system. reports included diagnosis (recorded through standardized options) and the plan of treatment. chart review was used to exclude patients who started treatment elsewhere and patients being treated for relapse, to clarify diagnosis if the standardized options in coe were unclear, and to clarify treatment plan if needed. data was entered and analyzed in a redcap database. specific diagnoses were clustered into higher level disease groups and the distribution of treatment plans for patients within each was determined. this project was deemed exempt from irb approval for human subject research as a qualifying quality improvement project. of the patients with a first chemotherapy order in , were excluded due to one or more reasons: stem cell transplant ( ), transfer of care ( ), relapse ( ), and other ( ). an additional patients were excluded because < patients/year/diagnosis. there was no cns tumor disease group with > patients. thus, patients with hematologic malignancies or non-cns solid tumors are the focus of this analysis. for patients with intermediate risk rhabdomyosarcoma, the plan of treatment was the standard arm of a cog protocol, arst for patients and arst for subsequent patient after protocol activation. for all other diseases including lymphoblastic leukemia/lymphoma (excluding infants), classical hodgkin lymphoma, aml (excluding trisomy and apml), stage iii/iv burkitt lymphoma/diffuse large b-cell lymphoma, posttransplant lymphoproliferative disease, wilms tumor, rhabdomyosarcoma, ewings sarcoma, osteosarcoma, neuroblastoma, and retinoblastoma, only one treatment plan per risk category was used. conclusion: this analysis demonstrates highly consistent chemotherapy treatment at a single center for patients with hematologic malignancies and non-cns solid tumors. next steps include exploring strategies to group diagnoses for cns tumors and assessing the quality of evidence supporting the treatments given. background: rapid initiation of empiric antibiotics in patients with fever and neutropenia has been shown to reduce morbidity and mortality. current practice guidelines call for the initiation of antibiotics in these patients within sixty minutes and time-to-antibiotic (tta) has been suggested as a quality-of-care measure. many institutions, including our own, face barriers to meeting this time limit. objectives: utilizing a quality improvement model, determine barriers and implement an intervention to reduce the time-to-antibiotics for pediatric febrile patients with suspected neutropenia who present to the emergency department (ed) at our institution. we have identified and implemented an intervention utilizing the plan-do-study-act model for quality improvement. a twelve-month retrospective review was conducted to evaluate the efficacy of the current practice algorithm at our large, academic tertiary-care hospital. subjects identified were pediatric oncology patients undergoing active chemotherapy who presented to the ed with febrile neutropenia. we identified two specific barriers, triage level assignments and delay in ordering antibiotics. to address these barriers, we have created a wallet sized "fever card" that patients were instructed to show upon arrive to the ed. in collaboration with the ed staff, efforts were also made to educate all pediatric staff on the use of the fever card. post-intervention data collection is currently underway and pre-and post-intervention antibiotic delivery times will be compared. the pre-intervention cohort consisted of thirty-three encounters with a mean time-to-antibiotic delivery of minutes, or seventy-five minutes greater than the accepted standard of care. only one patient received antibiotics within sixty minutes of arrival. post-intervention data collection is currently underway. since identifying two barriers to meeting the standard of care at our institution, we have implemented a quality improvement measure that empowers patient families to direct appropriate triage in the ed as well as simplifying the treatment protocol for ed providers. we expect to identify an improvement in time-to-antibiotics from the pre-intervention to the post-intervention period. background: sickle cell disease (scd) is a genetic disorder in which sickle hemoglobin (hbs) triggers multiple downstream effects, including red cell sickling, hemolysis, vaso-occlusion, and inflammation. scd, a lifelong disease initiated at birth with injury that accumulates over time, causes significant end-organ damage and clinical complications that are undertreated and associated with early death. homozygous mutation (hbss) causes the severe form of scd. individuals with scd are at increased risk of infection, stroke, and retinopathy. clinical guidelines for pediatric patients with scd recommend prophylactic penicillin use (ages - ), annual screening for stroke with transcranial doppler (tcd) imaging (ages - ), and annual ophthalmology exams to assess for retinopathy (ages ≥ ). there are limited real-world data on implementation of these nhlbi-based recommendations. objectives: to describe utilization of penicillin, tcd screening, and ophthalmology care in children with hbss disease. medicaid administrative claims databases were used to identify us patients aged - years at first indication of hbss recorded in each calendar year from to . patients were required to have medical and pharmacy benefits for the calendar year in which they were identified and for months prior to their first recorded hbss indication. prior year utilization of penicillin, tcds, and ophthalmologist visits was measured for each annual cohort. annual cohorts included - commercial (mean age . years, % female) and - medicaid (mean age . years, % female) patients with hbss disease. fewer than half of all patients had received a tcd scan in the previous year, with similar rates seen across all age groups for both payers. ophthalmologist visits increased as patients aged, and while patients aged - years had the highest proportion with an ophthalmologist visit in both payer populations, the overall implementation remained low. in contrast to the low use of tcd and ophthalmology visits, penicillin use was highest in the - year age group: > % use in any given year for both payers. conclusion: although our data demonstrated high penicillin use in the - year age group, consistent with guidelines there is an opportunity to improve implementation of other guidelines-based recommended screening. for example, tcd screening can identify children at risk of scd-related stroke in order to initiate preventive therapies. further research to understand potential barriers to proper screening and to evaluate strategies to improve awareness, adherence, and implementation of recommended screenings in children with scd is warranted. supported by global blood therapeutics. background: childhood cancer therapy has improved where there are many long-term survivors. while psychosocial difficulties in pediatric cancer survivors are recognized, the prevalence of these problems at initial survivorship presentation is unclear. objectives: to examine the prevalence of overall internalizing symptoms (e.g., depression/anxiety) in pediatric cancer survivors presenting to a survivorship clinic and to examine how this is mitigated by receiving psychological services and by evidence of parental depression/anxiety. design/method: pediatric cancer survivors attending their first visit at the reach for survivorship clinic at vanderbilt (ages - ) were included. survivors' parents ( % female) completed the child behavior checklist (cbcl), beck depression inventory-ii, and beck anxiety inventory. survivors > years completed a self-report. the wilcoxon rank-sum and pearson's test were used for univariate analyses. the effect size and % confidence intervals (ci) estimated from the multivariable linear regressions were reported. results: childhood cancer survivors a median of years old and . years off therapy were included. thirty one survivors ( %) showed at least borderline clinical internalizing problems (t score > ) on the cbcl, but only of these patients ( %) reported receiving psychological services. nine other survivors with normal t score ≤ also reported receiving psychological services. parental depressive and anxiety symptoms were correlated to the parental report of survivor overall internalizing symptoms (spearman = . , p = < . and = . , p = < . respectively), however they were not correlated to survivor selfreports. furthermore, parents with mild to severe depressive symptoms or mild to severe anxiety symptoms were more likely to rate their child as having higher overall internalizing symptoms (p = . ; p = . , respectively). multivariable linear regression showed that when adjusted for age, gender, cancer diagnosis and time off treatment, reported utilization of psychological services ( = . , % ci [ . , . ],p = . ), and parent depressive symptoms ( = . , [. , . ],p< . ) were significantly associated with child overall internalizing symptoms. in an otherwise identical alternate model substituting parental anxiety for parental depression, parental anxiety was also a significant risk factor ( = . , [. , . ], p< . ). alternatively, parent anxiety/depressive symptoms were not significantly associated with child self-report of internalizing symptoms. childhood cancer survivors have an elevated prevalence of experiencing internalizing symptoms but seldom report receiving psychological services. childhood cancer survivors' parents with anxious/depressed symptoms are more likely to rate their children as having more internalizing problems, compared to patient self-reports. ongoing longitudinal analyses will help clarify the best timing for potential interventions. background: life expectancy for adults with sickle cell disease (scd) has remained unchanged over the past years despite improvements in pediatric scd survival. at greatest risk are the adolescents and young adults (ayas) transitioning from pediatric to adult care. allen county ranks rd in scd incidence among the counties in indiana, and has board certified pediatric hematologist-oncologists. when children "age out" of the pediatric system, there are few providers knowledgeable about managing adults with scd in the region. a novel partnership between hematologists and the family medicine residency program in allen county was initiated to educate family medicine residents (fps) about scd, hydroxyurea (hu), and management of scd-related complications with the goal to increase the number of knowledgeable providers to care for adults with scd. to determine the effectiveness of online learning modules in educating fps about hu, best practices for aya scd care and transition. three online learning modules about scd (comprehensive care of ayas with scd, hu, best practices in aya transition) were developed and cme-accredited. electronic pre-and post-tests were distributed to fps with five questions for each module covering: contraception; screening tests; hu indications, dosing and monitoring; developmental milestones and scd knowledge assessments. the st vincent irb reviewed the protocol and granted a waiver of consent. results: twenty-six fps ( %) completed the pre-and posttests. over two-thirds correctly identified the clinical benefits of hu on both assessments. knowledge about the rationale for hu therapy increased after the completion of the hu module ( % correct on pre-test vs. % on post-test, p = . ). the proportion of correct responses increased for all comprehensive aya scd care post-test questions, but only the leading cause of death and the priapism-related questions reached statistical significance ( % vs. %, p = . ; % vs. %, p = . , respectively). the proportion of correct responses for of the transition-focused questions was unchanged ( % for both), while the proportion of correct post-test responses on the self-care assessment question significantly increased ( % vs. %, p = . ). after module completion, fps were able to correctly identify common scd complications and why hu is an effective treatment for individuals with scd. the best practices of transition clinic module may need modification to improve physician understanding of the intricacies in establishing and maintaining a scd transition clinic. overall, online training is effective at educating fps and could be used to increase the number of providers knowledgeable about scd care. background: survival rates for pediatric hodgkin lymphoma (hl) exceed % with contemporary therapy. studies of pediatric hl survivors treated in the s- s have shown increased risk for treatment-related chronic health conditions. risk-adapted therapy, including tailored radiotherapy, has been developed to reduce long-term morbidity while maintaining excellent survival. little is known about chronic conditions associated with contemporary therapy presenting during the first years from therapy completion (early outcomes). objectives: to analyze survival and early outcomes of pediatric hl patients treated with contemporary therapy. we conducted a retrospective review of hl patients diagnosed < years of age at our institution from - . three-year overall (os) and event-free (efs) survival were calculated with kaplan meier statistics using sas . . results of standardized screening for targeted toxicities that developed between - years from therapy completion were identified and graded per ctcae criteria. censoring occurred at date of death, years from therapy completion, or december , . data from the last collection point were used for prevalence calculations in cases with multiple evaluations. we identified patients ( % male; % non-hispanic white; mean age at diagnosis . ± . years) with a median time since therapy completion of . years (range . - . ). initial treatment included: ( %) chemotherapy only and ( %) multimodality treatment. all patients received anthracyclines (median dose mg/m ) and % received alkylating agents (median cyclophosphamide equivalent dose [ced] mg/m ). the -year os was % with an efs of % ( % chemotherapy only, % multimodality treatment; p = . ). patients with relapsed/refractory disease received salvage treatment including chemotherapy only (n = ), multimodality therapy (n = ), or multimodality treatment including stem cell transplant (autologous n = ; autologous+allogeneic n = ). no patients developed thyroid dysfunction, cardiac dysfunction, subsequent neoplasm, or male gonadal dysfunction during the study period. pulmonary dysfunction was limited to ctcae grade . anti-mullerian hormone (amh) below the normal range was found in / pubertal females who received ced ≥ mg/m compared to / females who received ced < mg/m . two of the females with low amh also had follicle stimulating hormone > iu/ml. this study is the first to evaluate early outcomes in pediatric hl survivors. the results indicate contemporary chemotherapy and a lower rate of radiotherapy utilization lead to excellent -year survival rates with minimal early toxicities. females exposed to ced ≥ mg/m are at increased risk for gonadal dysfunction and should be prioritized for fertility preservation approaches prior to initiation of cancer therapy. background: cancer is one of the leading disease-related causes of death among individuals aged < years in the united states. recent evaluations of national trends of pediatric cancer used data from before , or covered ≤ % of the us population. objectives: this study describes pediatric cancer incidence rates and trends by using the most recent and comprehensive cancer registry data available in the us. design/method: data from us cancer statistics were used to evaluate cancer incidence rates and trends among individuals aged < years during - . data were from states and covered % of the us population. we assessed trends by calculating average annual percent change (aapc) in rates using joinpoint regression. rates and trends were stratified by sex, age, race/ethnicity, us census region, county-based economic status, and county-based rural/urban classification, and cancer type, as grouped by the international classification of childhood cancer (iccc). we identified , cases of pediatric cancer during - . the overall cancer incidence rate was . per million; incidence rates were highest for leukemia ( . ), brain tumors ( . ), and lymphoma ( . ). rates were highest among males, aged - years, non-hispanic whites, the northeast us census region, the top % of counties by economic status, and metropolitan counties. the overall pediatric cancer incidence rate increased (aapc = . , % ci, . - . ) during - and contained no joinpoints. rates increased in each stratum of sex, age, race/ethnicity (except non-hispanic american indian/alaska native), region, economic status, and rural/urban classification. rates were stable for most individual cancer types, but increased for non-hodgkin lymphomas except burkitt lymphoma (iccc group ii(b), aapc = . , % ci, . - . ), central nervous system neoplasms (group iii, aapc = . , % ci, . - . ), renal tumors (group vi, aapc = . , % ci, . - . ), hepatic tumors (group vii, aapc = . , % ci, . - . ), and thyroid carcinomas (group xi(b), aapc = . , % ci, . - . ). rates of malignant melanoma decreased (group xi(d), aapc = - . , % ci, - . -- . ). this study documents increased rates of pediatric cancer during - , in each of the demographic variables examined. increased overall rates of hepatic cancer and decreased rates of melanoma are novel findings using data since . next steps in addressing changing rates could include investigation of diagnostic and reporting standards, host biologic factors, environmental exposures, or potential interventions for reducing cancer risk. increasing pediatric cancer incidence rates may necessitate changes related to treatment and survivorship care capacity. background: while childhood cancer treatment modalities have improved, the delayed effects of cancer treatment continue to compromise the quality of life in survivors. metabolic syndrome (ms) is diagnosed based on the presence of three of the following findings -obesity, dyslipidemia, hypertension and insulin resistance per the world health organization (who) criteria. the increased risk of ms among childhood cancer survivors was first reported in the 's and is known to increase the incidence of cardiovascular disease in these individuals. objectives: assess the frequency of ms in childhood cancer survivors at our institution. . we conducted a retrospective chart review on pediatric cancer survivors, - years of age, who had been treated at sri ramachandra medical institute and research foundation between august and august . patients who received at least one year of treatment with s of s chemotherapy and/or radiation and surgery were included. medical history, family history of diabetes, cardiovascular diseases, and hypercholesterolemia, tanner staging, weight for height (< y per who criteria), bmi (> y per indian academy of pediatrics iap), blood pressure (nhlbi criteria), fasting blood sugar levels and lipid profile were obtained from the charts. statistical analysis of the data was done using ibm spss statistical software (version ). results: patients were studied, . % were male. . % were under years of age, . % between - years and . % above years. leukemia survivors comprised . % of the sample and non-leukemic's were . %. . % were treated with chemotherapy alone, . % with radiotherapy and chemotherapy, and . % underwent surgery with radiotherapy and chemotherapy. hypertension was found in . % of the study group, dyslipidemia in %, impaired fasting blood glucose in . % and . % were found to be obese. % of the study group was diagnosed with ms based on who criteria. conclusion: % of our study population was found to have ms per who criteria. individual metabolic complications were detected in % of the population. acute lymphoblastic leukemia (all) survivors appeared to be at high risk in our population. ms has been known to increase cardiovascular complications in cancer survivors. a multidisciplinary team approach to management of these patients is important to closely monitor and manage the long-term complications related to ms such as type diabetes and atherosclerosis. such an approach is essential to decrease long term morbidity and mortality from ms in this vulnerable population. background: the -year survival rate for childhood cancer exceeds %. however, up to % of these children require admission to the pediatric intensive care unit (picu) within three years of diagnosis. these children account for approximately % of all picu deaths, with mortality being higher for those post-hematopoietic stem cell transplant (hsct). national guidelines recommend that providers share informa-tion regarding prognosis and treatment options within the first hours of icu admission. these prognostic goals of care conversations (pgocc) are critical to the care of children with malignancies, a subpopulation at risk for increased mortality. to determine the frequency of pgocc as well as describe differences in patient characteristics and critical care therapies by pgocc status. design/method: a retrospective cohort study was conducted using the university of michigan virtual picu system database. picu admissions lasting longer than hours for patients ages to years between july , and june , with an oncologic diagnosis and/or hsct were identified. data on pgocc, patient demographics, diagnoses, picu interventions, and outcomes were recorded and compared between children with pgocc and those without using chi square test for categorical variables and kruskal-wallis test for continuous data. of picu admissions, % were male; the mean age was . years. the leading diagnoses were acute lymphoblastic leukemia ( %), acute myeloid leukemia ( %), lymphoma ( %), neuroblastoma ( %), and brain tumors ( %), and % of patients were post-hsct. pgocc was documented in ( %) patients. in comparison with patients who did not have a pgocc, children with a pgocc were more likely to be readmitted to the picu ( % vs. %, p < . ) and more likely to have had relapse of disease ( % vs. %, p< . ). patients with a pgocc had higher severity of illness scores (p = . ), higher use of non-invasive ( . % vs. . %, p = . ) and invasive conventional ventilation ( . % vs. . %, p< . ), and high frequency ventilation ( . % vs. . %, p < . ). also, patients with pgocc were more likely to receive continuous renal replacement therapy ( . % vs. . %, p< . ), arterial catheterization ( . % vs. . %, p< . ), and cardiopulmonary resuscitation ( . % vs. . %, p< . ). in only in critically ill children with hematologic-oncologic disease is pgocc held. children with pgocc were sicker and received more critical care interventions. future research is needed to evaluate the content of pgocc. background: central nervous system (cns) tumors and autism spectrum disorder (asd) represent significant disease cohorts in the pediatric population. asd diagnoses in children have a prevalence of %, in every children in the united states. additionally, more than , cns tumors are reported in children age to years in the united states with brain tumors being the most common solid tumor and the leading cause of death among all childhood cancers. the genetic etiology of autism and cns tumors is complex. specific gene alterations present in certain cancers have similarly been described and suspected to play a role in asd subtypes. targeted therapy panels, like foundation one (fo), have been beneficial in guiding treatment for some cancers based on distinct gene alterations. given the genetic overlap, the potential for therapeutic benefit and crossover from such actionable gene target panels merit further exploration in asd and cns tumors. we aim to identify and describe genetic alterations with known actionable targets in cancer therapy from fo as potential diagnostic, therapeutic and research targets for neurodevelopmental diseases. we plan to discuss the common genetic alterations between our cancers and neurodevelopmental diseases described in the literature. fo data was extracted and compared to the literature. each reported gene alteration from fo plus the keywords "autism", "psych" were used on pubmed to search for a suspected association if any with a neurodevelopmental disorder. results: twenty-one patients representing a cohort of six unique (astrocytoma-five, ependymoma-six, gbm-four, glioma-three, nerve sheath tumor-one, etmr-two) cns tumors were investigated. fo produced eighty total with sixty unique gene alterations. thirty-one ( %) of these yielded at least one published, suspected association to a neurodevelopmental disorder. the most common gene alterations were tp -four, cdkn a/b-five and braf-four. the main functional categories were cellular: proliferation, structure, differentiation and degradation; chromatin modeling; histone transcriptional modification; dna methylation and repair; strna; and neural signaling. sixty unique gene alterations were found in our cns tumor set using foundation one. thirty-one ( %) of these discrete alterations paired with at least one description in the literature as having been similarly altered in an asd subtype. many of these alterations have actionable targeted therapies presented through foundation one for our cns tumors and may be a relevant guide in the future of targeted therapy and research in asd subtypes. monoclonal antibody therapy usage is associated with significantly improved survival in b-cell nhl aya patients. although the usage has increased in the aya population from to , the magnitude of the increase is low. factors that affect the use of mab include race and insurance s of s type. further research is warranted to identify why privately insured patients are less likely to receive these drugs. background: prevention of chemotherapy-induced nausea and vomiting (cinv) remains a challenge despite advances in pharmacotherapy and the development of cinv clinical practice guidelines by the pediatric oncology group of ontario (pogo) that have been endorsed by the children's oncology group. achieving control of cinv in pediatrics further is complicated by the difficulty young children have vocalizing their symptoms. use of a validated nausea-assessment tool in conjunction with improved adherence to evidence-based guidelines may result in better quantification of symptoms and reduction of both nausea severity and vomiting frequency for pediatric patients undergoing chemotherapy. the pediatric nausea assessment tool (penat) has been validated for children ages - , and its integration into clinical practice may help optimize cinv control. objectives: this single-institution study sought to improve control of cinv in patients admitted for chemotherapy by standardizing the antiemetic regimens prescribed by all providers according to an institutional cinv algorithm developed from the pogo guidelines. we hypothesized that treatment using a standardized guideline would improve cinv control in patients admitted for chemotherapy. a baseline cohort of admissions for chemotherapy completed penat assessments and cinv diaries prior to receiving chemotherapy, four times daily during each admission, and daily for days following completion of chemotherapy from may , to january , . providers then were provided an institutional cinv treatment algorithm based on the pogo guidelines and received education at departmental meetings on appropriate implementation of this algorithm. a second cohort of admissions completed penat assessments and cinv diaries in a similar fashion from july , to december , . results: complete control of vomiting markedly improved following cinv guideline implementation ( % vs %, p <. ) with treatment failure also significantly reduced ( % vs %, p <. ). after controlling for the degree of emetogenicity of chemotherapy received, a patient was . times more likely to vomit prior to guideline implementation (or . , ci . - . ). there was no difference in nausea control, even after adjusting for the emetogenicity of chemotherapy. conclusion: control of chemotherapy-induced vomiting (civ) improved following widespread implementation of an institutional cinv treatment algorithm at a single institution. the severity of nausea reported remained unchanged which may reflect the difficulty of assessing nausea or an inadequate sample size. future research may focus on cinv treatment management through the use of guidelines specifically for breakthrough cinv and delayed cinv. background: aspho's professional development committee (pdc) recognized pediatric hematologists-oncologists (phos) serving in the united states (us) military have unique professional development needs that may not be addressed by aspho or a similar professional society. these individuals may also encounter challenges when transitioning to a civilian career. however, barriers to professional development have not been systematically characterized. the objectives were to characterize the number of phos with current or prior military service (mphos) and to identify any unmet professional development needs. design/method: a working group consisting of pdc members and both senior and early career mphos was formed. initial comments were solicited by email from known mphos regarding potential gaps in professional development and interest in working with aspho to improve support of mphos. a survey was developed and piloted with four members of the advisory group, questions were revised based on their feedback, and a final version was distributed via the aspho website and online community forum. targeted emails were sent to mphos identified through aspho and military databases. eligibility to complete the survey included ) completion of a fellowship in pediatric hematologyoncology, and ) current or prior service as an active duty military provider. quantitative and qualitative information were collected, including demographic data and perceived barriers to professional development. responses were summarized using descriptive statistics. results: sixty-five mphos were identified and surveys were completed for a % response rate. respondents were engaged in a variety of professional activities; % were male, % were serving active duty commitments, and % felt there were professional development gaps. areas of concern were categorized into nine themes with the most concerning being ) limited civilian knowledge of mpho practices ( % of participants), ) inability to attend professional society meetings ( %), and possibility of deployment ( %). participants expressed a desire for educational products to meet their specific needs and for networking opportunities with civilian colleagues. qualitative analyses identified concerns about low patient numbers and practice size. a subset of mphos perceive significant gaps in professional development. additional research is needed to better define areas for intervention, but many of the concerns align with those of similarly sized civilian programs and may be addressed through professional society networking opportunities, such as an aspho special interest group. background: infertility is an established cause of distress and has a negative impact on quality of life among childhood cancer survivors. the american society of clinical oncology has established guidelines on fertility counseling for individuals of reproductive age diagnosed with cancer, with the goal of improving reproductive and psychosocial outcomes. studies have shown that instituting a fertility team that can provide counseling and discuss fertility preservation (fp) options results in improved patient satisfaction in patients with cancer. objectives: the goal of this study was to examine predictors of referrals to the multidisciplinary fertility team, and documented fp interventions among these patients. design/method: an irb-approved retrospective medical record review was performed at a large pediatric academic center. all patients with new cancer diagnoses receiving chemotherapy were included from january (when the fertility team was established) to present. a standardized abstraction form was used to collect information about: age at diagnosis, gender, cancer type, whether a fertility consult was placed, and documented fp interventions. data were summarized descriptively and comparisons were made using nonparametric statistical methods. results: patients met inclusion criteria, of which ( %) were male. cancer types were as follows: leukemia/lymphoma, cns tumors, sarcomas, embryonal tumors, and langerhan's cell histiocytosis (lch). the mean age was . years, (range < - years). overall, % of all patients had a consultation with the fertility team. patients were significantly less likely to have a fertility consult if they were younger (p< . ). further, there were differences in the consultation rate between diagnoses, with % of sarcoma patients completing a consult, compared to % of those with cns tumors, % of those with embryonal tumor, % of those with leukemia/lymphoma and none of the patients with lch. our findings show that many children, adolescents, and young adults newly diagnosed with cancer are still not receiving fertility counseling despite: ) an expanding body of literature supporting the need to provide this counseling, ) guidelines published by several organizations recommending discussions about infertility risk and fp options, and ) presence of a multidisciplinary fertility team. specific strategies need to be developed to improve access for younger children, and for disease groups in whom fertility consults are underutilized, such as youth with cns tumors, embryonal tumors, and leukemia/lymphoma. background: socioeconomic status (ses) has on impact on overall survival in the pediatric oncology population. unfortunately, data are insufficiently detailed to explain the mechanism behind this phenomenon. how parents handle the health management demands placed on them at the time of a child's cancer diagnosis may represent a point of differentiation in health outcomes. objectives: determine the association between socioeconomic factors, cancer literacy, and parents' understanding of home emergency management and their responses to instances of pain, nausea, and fever. in a prospective observational study of parents whose children were newly diagnosed with cancer, we obtained demographic information and, using a validated instrument, (dumenci, ) we evaluated cancer literacy. we tested understanding of the education parents received about home emergency management with a -item multiple-choice vignette-based questionnaire focused on actions needed in home scenarios. we then followed parents' actual behavior through periodic phone calls assessing instances of nausea, pain, and fever and their responses to these episodes. results: preliminary analysis of participants showed an average score of on the -item parental understanding questionnaire (range - ). variables associated with increased score were college-level education by . points ( % ci [. to . ]), private insurance by . points [. to . ] and adequate cancer literacy by . points [. to . ]. actual behavior reported by families indicated that married parents and those with income above $ , were less likely to treat instances of pain by % ( % ci [ to ]) and % [ . to ], respectively. white parents, those with college-level education, and those with adequate cancer literacy were less likely to treat instances of nausea by % [ to ], % [ to ] and % [ to ], respectively. no associations were found between socioeconomic markers and parental responses to instances of fever. our findings suggest an association between demographic and socioeconomic markers and improved parental understanding of home emergency management. paradoxically, the same markers show a decrease in treatment response to pain and nausea. larger prospective studies are needed to link this behavior pattern to health outcomes, and help inform the extent of ses impact on home emergency management. emory university/children's heathcare of atlanta, atlanta, georgia, united states background: cardiovascular disease is a leading cause of morbidity and mortality in childhood cancer survivors (ccs). previous research showed wide practice variation in referral patterns to cardiology from the survivor clinic and in recommendations from cardiologists about the need for further testing or exercise restrictions. to develop a cardio-oncology algorithm in order to standardize referrals to cardiology and provide guidelines for cardiologists evaluating pediatric ccs. design/method: survivorship and cardiology experts developed a weighted scoring system for pediatric ccs who received cardiotoxic therapy based on time since treatment and risk factors identified by the children's oncology group (cog) and american heart association (aha). the cardiooncology algorithm assigned a score of - . the score range was categorized to guide cardiology referral: screening echo only ( - ), consider cardiology referral ( - ), recommend cardiology referral ( - ), and regular cardiology follow-up (≥ ). the algorithm also provides recommendations to cardiologists for screening and exercise modifications based on the score. after establishment of the algorithm, a convenience sample of institutional survivor clinic patient charts were retrospectively reviewed from the first month of each quarter from april -march to validate the algorithm, evaluate referral patterns to cardiology, and assess cardiology recommendations. the retrospective chart review evaluated patients ( % male; % non-hispanic white; % leukemia survivors; median age at diagnosis . years [range - . ]; median time off-therapy . years [range . - . ]). patients ( %) received anthracyclines (median dose mg/m , range - ) and ( %) received cardiac radiation. assigned cardio-oncology scores resulted in: % echo only, % consider cardiology referral, % recommend cardiology referral, and % regular cardiology followup. when evaluating detection rates of late effects by cardiooncology score, survivors ( %) had an abnormal echo: / echo only, / consider referral, / recommend referral, and / regular cardiology follow-up. assessing referral patterns prior to initiation of the algorithm revealed forty-two survivors ( %) referred to cardiology: / echo only, / consider referral, / recommend referral, and / regular cardiology follow-up. of the patients seen by a cardiologist at our institution, had further diagnostic testing ordered (i.e., stress test) and received exercise restrictions. a cardio-oncology algorithm and guidelines will standardize cardiac care for survivors by assigning a score to guide referral and cardiology practice after referral. prospective clinical use has begun and review will occur in one year to determine changes in detection rates of cardiac late effects, referrals, and recommendations from cardiologists. oregon health and science university, portland, oregon, united states background: delirium affects - % of patients (pts) in pediatric intensive care units (picu) and is associated with increased length of stay, decreased attention in school, and post-traumatic stress disorder. the diagnostic and statistical manual of mental disorders (dsm v) defines delirium as a "disturbance of consciousness […] with reduced ability to focus, sustain or shift attention" due to an underlying medical condition. despite the medical complexity of the hospitalized pho population, there are no published prospective studies looking at delirium in these pts. hypothesizing that delirium is under recognized in the pho population, we designed a year-long prospective study using a validated screening tool to determine the frequency of delirium in hospitalized pho pts and to identify associated clinical factors. design/method: baseline frequency of pts with symptoms suggestive of delirium was determined through retrospective chart review using a data mining program of electronic medical records (emr). for the prospective study, pho and picu nurses were trained to use the cornell assessment for pediatric delirium and to record scores within the emr on all pho pts once every -hour shift. predetermined demographic and clinical variables were entered daily into a red-cap database on all hospitalized pho pts. results: baseline frequency of delirium, without active screening, was determined to be . % of hospitalized pho pts. in the first months of the prospective study, consecutive admissions occurred among unique pho pts: oncology, hematology, and stem cell transplant pts. pts had at least positive delirium screen, for a prevalence per admission of . %. statistically significant variables associated with delirium, at p < . by univariate logistical regression, included prolonged length of stay, pt location (picu vs pho unit), and fever. adjusting for length of stay, administration of benzodiazepines and opiates were also significantly associated with delirium, p = . and . , respectively. on average, nurses completed delirium screening in % of each pts' -hour shifts. study accrual ends in jan and final data analyses will be reported in the abstract presentation. conclusion: delirium does occur in the pho hospitalized population and screening by trained nursing staff is feasible. pts at highest risk appear to be pts with prolonged hospital stays, picu admissions, or frequent use of benzodiazepines/opioids. routine screening should improve our recognition of delirium and allow us to promptly intervene, or prevent delirium in an effort to avoid potential acute and long term consequences. background: with high survival rates for children and adolescents with hodgkin lymphoma (hl), treatment regimens are now designed to maximize cure while decreasing risk of long-term health outcomes associated with chemotherapy and radiation therapy. within contemporary treatment regimens, the comparison of toxicities experienced by patients receiving chemotherapy plus radiotherapy (crt) versus only chemotherapy (co) has not been studied extensively. objectives: this study examines select self-reported adverse health outcomes in survivors of contemporarily-treated pediatric hl to better understand the balance between efficacy and toxicity associated with chemotherapy and radiation therapy. (cog) ahod that evaluated a response-based treatment paradigm in pediatric hl. patient who received initial chemotherapy were randomized based on early response to continued chemotherapy, chemotherapy plus radiotherapy or augmented chemotherapy plus radiotherapy. patients completed self-report questionnaires on health problems at , , , and years following therapy. we examined selected patient-reported pulmonary, gastrointestinal (gi), cardiac and endocrine outcomes. kaplan-meier survival curves were used to determine probability of survival without the selected adverse health outcome. log-rank tests were used to compare the co versus the crt group. results: a total of , enrolled patients, patients in the co group and patients in the crt group, completed , questionnaires at a median of . years after s of s completion of therapy (q , q : . , . ) which were analyzed. the cumulative -year incidence of endocrine dysfunction was significantly greater in the crt group versus those in the co group ( % versus %; p< . ), driven by the incidence of hypothyroidism ( % versus %; p< . ). there were no significant differences in cardiac ( % versus %; p = . ), pulmonary ( % versus % p = . ), and gastrointestinal dysfunction ( % versus %; p = . ) between the co and crt patients. conclusion: this study demonstrates low cumulative incidence overall of organ dysfunction early post completion of contemporary therapy for hl. the addition of radiation therapy significantly increased risk for hypothyroidism, but with no higher risk noted for cardiac, pulmonary or gi dysfunction. limitations include self-report status, potential selection bias, and relatively short latency period following end of therapy. longer follow-up is needed to determine more delayed risks for organ dysfunction in order to best define the balance between therapeutic efficacy and long-term adverse health outcomes related to chemotherapy and/or radiation therapy. background: identification of an organism via bronchoalveolar lavage (bal) or respiratory tract biopsy (rtb) has historically been considered the gold standard for diagnosis of invasive fungal infection (ifi); however, data previously published by our group showed that these procedures infrequently lead to a change in management in children with an oncological diagnosis or undergoing hematopoietic stem cell transplant (hsct). there is also a paucity of data on the cost of ifi in this population. to compare the costs of work-up and management of pulmonary ifi diagnosed based on ct scan alone versus ct scan or chest x-ray prompting a bal or rtb. design/method: we collected cost data on patients at ann & robert h. lurie children's hospital of chicago undergoing chemotherapy or within months of hsct who were suspected of having an ifi between and . in order to include sufficient time to account for post-procedure compli-cations but avoid including costs unrelated to ifi, data were included for days from the day of their diagnostic scan or procedure. cost data was available for of the patients previously studied. thirty-six of these patients were diagnosed with suspected ifi based on ct only and patients underwent bal or rtb. when evaluating specific costs, inpatient beds costs were higher in the bal and rtb group (median $ , versus $ , , p = . ), yet there was only a trend towards higher costs for antifungal agents (median $ , versus $ , , p = . ) and respiratory support (median $ versus $ , p = . ). many of the initial ct scans were not captured in the -day evaluation period for the bal or rtb group based on the study design; however, even when accounting for ct scans up to a week prior these procedures, the total cost of ct scans was higher in the ct only group (median $ versus $ , p = . ), as they had more scans. despite this, total costs were significantly higher for patients who underwent bal or rtb versus ct scan only (median $ , versus $ , , p < . ). combined with our previous data that bal and rtb infrequently leads to a change in management in children with an oncological diagnosis or undergoing hsct suspected to have an ifi, the significantly higher costs associated with these procedures makes these invasive diagnostic techniques even less desirable. batra, pediatr blood cancer, . background: while infants > months of age with acute lymphoblastic leukemia (all) have a poor prognosis, infants with acute myeloid leukemia (aml) fare better despite more intensive therapy. there are limited data on this difference, particularly differences in supportive care requirements during induction therapy for infants. objectives: to compare induction mortality and resource utilization in infants relative to non-infants aged < years, separately for all and aml. design/method: we used previously established cohorts of children treated for new onset all or aml at children's hospitals in the us contributing to the pediatric health information system. patients with down syndrome were excluded. follow-up started on the first day of induction chemotherapy and continued until the earliest of: days after commencement of chemotherapy, start of the subsequent course, or death. high acuity of presentation, defined as icu requirements involving or more organ systems within the first hours following initial admission were compared using log binomial regression. -day inpatient mortality was compared using cox regression. resource utilization rates (days of use per inpatient days) were compared using poisson regression. results: a total of all ( infants, non-infants) and aml ( infants, non-infants) were included in the analyses. infants were more likely to present with high acuity compared to non-infants for both all ( % and %, rr = . , % ci: . , . ; p< . ) and aml ( % vs %; rr = . , % ci: . , . ; p = . ). infants with all had higher inpatient mortality compared to non-infants even after accounting for differences in acuity of presentation ( . % vs . %, adjusted hr = . % ci: . , . ; p = . ). in contrast, inpatient mortality was more similar for infants and noninfants with aml ( . % vs . %, adjusted hr = . % ci: . , . ; p = . ) and comparable to rates among infants with all. infants with all and aml had higher rates of utilization of fresh frozen plasma, cryoprecipitate, diuretics, supplemental oxygen, and ventilation relative to non-infants. infants with all also had higher rates of total parenteral nutrition, ecmo, and patient controlled analgesics compared to noninfants. infants with all experienced significantly higher induction mortality compared to noninfants, a difference not entirely explained by acuity at presentation. differences in ru among infants may reflect higher presentation acuity and greater treatment related toxicity. further work is needed to elucidate the contribution of treatment related toxicity to early mortality in infants with all. background: fever in a child with cancer is a medical emergency due to the significant risk of a serious bacterial infection. many attempts have been made to risk stratify these patients. the respiratory pathogen panel (rpp) is a panel of polymerase chain reaction tests that identify seventeen common respiratory viruses and three bacterial infections. samples are taken via nasopharyngeal swab. rpps are frequently sent, but we do not have data to determine whether a positive result can lead to stratification to a lower risk of bacterial infection. ( ) to determine the epidemiology of respiratory virus-associated fever in pediatric oncology patients ( ) to determine whether a positive rpp is associated with reduced risk of bacteremia in this population. this was a single-center, retrospective cohort study. we identified and reviewed the medical records of all pediatric oncology patients seen in our emergency department (ed) with fever from the introduction of the rpp in april to september , . we reviewed the results of blood cultures, rpp, chest radiographs, and discharge summaries to identify sources of infection. we also identified the patients' cancer diagnosis, age, absolute neutrophil count (anc), and absolute lymphocyte count (alc). results: positive rpps were found among pediatric oncology patients who presented to the ed with fever. the most common positive rpp findings were rhinovirus/enterovirus (rev) ( %), parainfluenza ( %), influenza ( %), coronavirus ( %), and polyviral ( %). among patients with a positive rpp, % had bacteremia compared to % bacteremia among all pediatric oncology patients with fever (or . [ . - . ], p . ). all cases of bacteremia were associated with rev. there was no bacteremia identified in patients with rpps positive for other viruses (or . [ . - . ], p . ). rev positivity did not confer a lower risk of bacteremia than rpp negative patients ], p . ). anc (p = . ) and alc (p = . ) less than , and number of patients with severe neutropenia (p = . ) were not statistically different between the rev and non-rev positive rpp groups. rpps positive for viruses other than rev reduced the likelihood of bacteremia in febrile pediatric oncology patients in the ed setting. patients with bacteremia may have concurrent infection with rev. a larger study is warranted to determine if positive rpp results can inform clinical management of a child with febrile neutropenia. emily mueller, anneli cochrane, seethal jacob, aaron carroll s of s background: the usage of mobile health (mhealth), which refers to the application of mobile or wireless communication technologies to health and healthcare, has grown exponentially in recent years. mhealth tools have been used by caregivers of other vulnerable populations, but little has been focused on caregivers of children with cancer. objectives: to conduct a survey to understand the mobile technology usage, barriers, and desired mhealth tools by caregivers of children with cancer. we conducted a mailed cross-sectional paper survey of caregivers of all children who were diagnosed with cancer at riley hospital for children between june, and june, . the survey contained questions, both fixed and open-ended, in both english and spanish. up to three rounds of surveys were sent to those who did not respond. of the respondents, they were primarily parents ( . %), median age was . years (range - ), and most were white ( . %) and non-hispanic/latino ( . %). the top three annual household income brackets included $ , to $ , ( . %), $ , to $ , ( . %) and under $ , ( . %). the majority had an education: . % college graduates, % graduate degree, and . % high school education or ged. nearly all respondents owned a smart phone ( . %) and . % owned a tablet. the majority used an ios operating system ( . %), while . % reported use of a device with an android operating system. all caregivers reported use of at least one mobile website/app regularly for their personal use. while . % of respondents reported no barriers to mobile technology use, the top barrier selected was "data limitations" ( . %). overall, . % wanted at least one medical managementrelated website/app: medical knowledge ( . %), healthcare symptom tracking/management ( . %), and medication reminders ( %). healthcare system-related desires were high, as . % wanted access to their child's medical record and . % wanted a website/app to facilitate better communication with medical providers. there were no significant associations between socioeconomic status (income or education) with barriers or types of websites/apps desired by caregivers. since the vast majority of caregivers use mobile technology with minimal barriers, future research should focus on designing an mhealth tool to address the medical management needs by caregivers of children with cancer. by supporting caregivers through this type of mhealth tool, it could positively impact patient clinical outcomes through greater adherence to medications and treatment protocols. background: in children with fever and neutropenia, early initiation of targeted antibiotic therapy improves outcomes, yet there are no standards for choice of empiric antibiotics. in our institution implemented an early empiric ceftriaxone (eec) protocol to reduce time to antibiotic administration in febrile hematology-oncology patients who are potentially neutropenic when the absolute neutrophil count is not yet know. ceftriaxone is given immediately after obtaining blood for culture and lab studies. in patients found to be neutropenic, ceftriaxone is discontinued and cefepime is initiated. the purpose of this retrospective study was to evaluate our eec protocol in neutropenic patients by assessing ceftriaxone sensitivity of positive blood cultures and comparing rates of adverse outcomes with a cohort of patients treated prior to implementation of the protocol. we are now conducting a prospective study to more thoroughly investigate antibiotic sensitivities of organisms isolated from blood cultures of neutropenic patients. design/method: hematology-oncology patients with at least one positive blood culture between january and december were identified. patient demographics, neutrophil count, antibiotic treatment, isolated organisms and sensitivities, and adverse outcomes (increased respiratory support, hypotension requiring intervention, and icu admission) were obtained by retrospective chart review. fisher exact test was used to compare dichotomous variables between patient groups. we are now prospectively identifying febrile neutropenic patients with positive blood cultures and performing antibiotic sensitivity testing to several antibiotics commonly used as empiric therapy for febrile neutropenia. results: retrospectively, we identified neutropenic patients with a total of bacterial isolates from blood cultures. of organisms isolated, were tested for sensitivity to ceftriaxone and ( %) were not sensitive, / ( %) of gram-positive cultures and / ( %) of gram-negative cultures. ten of ( %) eec patients had an adverse outcome versus / ( %) of non-eec patients (p = . ). notably, % of eec patients required icu admission versus % of non-eec patients (p = . ). thus far our data obtained prospectively is revealing similar rates of ceftriaxone resistance with / cultures not sensitive to ceftriaxone ( %, ci . %- . %). in our retrospective study, no statistically significant difference was seen in overall adverse outcome rate between the two cohorts, though icu admission rates were significantly higher in eec patients. ceftriaxone resistance rates were high in tested isolates, which is further supported by preliminary data from our ongoing prospective study. given these data, eec may not be effective at improving outcomes in febrile neutropenic pediatric hematology-oncology patients. background: approximately in children diagnosed with cancer will die of their disease, despite advances in treatment. results: two focus groups of six parents each met in june . the parents were predominantly female ( female, male) and had lost their children an average of . years prior (range - . years). two parents were in the same family. nearly all patients were offered palliative care ( / ), all were offered hospice and most died at home ( at home, in the icu). parent discussion uncovered six broad themes: beneficial provider qualities, optimal communication, helpful systematic supports, struggles to feel like a good parent, struggles with a loss of control and unmet needs. parents appreciated providers who were consistent, reliable and honest. parents desired communication that was sensitive to the needs of the patient and family with a balance of hope and realism. parents appreciated the tangible supports pro-vided by social work and the emotional support of child life both for the patient and their siblings. some parents struggled to define and advocate for their child's quality of life, especially when it led to disagreeing with the medical team. several parents expressed frustration with unfamiliar caregivers in the hospital, especially trainees. they expressed a strong desire for more anticipatory guidance about the end of life including how to discuss it with their children. they also wished for a cancer-specific support group for bereaved parents. conclusion: bereaved parents of pediatric oncology patients in our focus groups appreciated consistent, reliable providers who communicated with a balance of realism and hope. they appreciated the tangible and emotional support they received and wanted more anticipatory guidance at the end of their child's life. these results can help guide clinical care, especially in communities without strong palliative care support. further research is needed to develop interventions to improve end of life care. background: clinical trials involving human subjects depend on informed consent (ic) to ensure ethical protections for participants. parents of children with cancer often lack full understanding of the basic elements of ic for clinical trials. additionally, the stress of their child's cancer diagnosis may affect their decision-making capabilities. this is especially problematic as these children rely on parents to fully comprehend clinical trials and weigh their benefits and risks. physician communication is critical for effective family-centered care. the acgme mandates that training programs teach and assess trainees' communication skills. however, there are currently no published curricula aimed at training pediatric hematology/oncology fellows to deliver ic effectively for cancer clinical trials. to develop and pilot-test a simulation-based curriculum to enhance communication skills of pediatric s of s hematology/oncology fellows in the delivery of ic for cancer clinical trials. we developed, tested, and implemented the curriculum from to in two phases. in phase- , we reviewed literature on simulation-based curricula and completed a needs assessment to create a clinical scenario and full curriculum using standardized patients. using miller's pyramid model, fellows' assessments included: immediate de-brief, surveys to assess pre/post confidence and knowledge of the basic ic elements ("knows" and "knows how"), and -degree summative assessments compiled from fellow self-assessments, faculty, and standardized patients ("shows how"). after initial testing and refinements done with fellow, in phase- , we implemented the curriculum with our fellows. likert scale ( strongly disagree- strongly agree) and basic p values are reported. results: fellows gave high mean ratings for training relevance ( . ) and standardized patients' preparedness ( ). almost all ( . ) reported they have used the knowledge gained in their clinical practice. increase in self-reported confidence (pre/post) was noted in all domains: general -describing possible benefits of the clinical trial . / vs. . / (p = . ), risks and potential side effects . / vs. . / (p = . ), and explaining alternatives . / vs. . / (p = . ); research -discussing purpose of the clinical trial . / vs. . / (p = . ), and randomization . / vs. . / (p = . ); and family-centered -addressing emotions during ic . / vs. . / (p = . ), and delivering bad news . / vs. . / (p = . ). summative evaluation mean ratings for all fellows were . (range . - . ). our novel simulated-based ic curriculum, significantly increased fellows' self-reported confidence and skills during ic delivery. importantly, our ic curriculum addressed not just research-related content but also management of parental emotional needs during the ic discussion. next phase includes kirkpatrick model program evaluation and dissemination across other training programs in our institution. national kaohsiung normal university, kaohsiung, taiwan, province of china background: taiwan's childhood cancer foundation reported in that the -year survival rate of childhood cancer was %. as a result, many childhood cancer survivors were back in school after treatment. however, childhood cancer survivors' educational outcomes suffered because of their long-term absence from school and late effects of cancer and cancer treatment. a few school reentry protocols have been developed by the nursing professionals in taiwan to facilitate students' return to school but remained experimental in nature and hardly accessible. parents, students, and teachers were left to their own devices to make individual school reentry plans. objectives: this study aimed to examine and uncover the commonalities among three middle school students' successful school reentry experiences from their teachers' perspectives and to analyze the factors contributing to their success. design/method: this is a qualitative interview study. indepth semi-structured interviews were conducted with three middle school teachers in december about their perceptions, observations, and experiences working with adolescent childhood cancer survivors. the students were two boys with leukemia and one girl with bone cancer. they were diagnosed in the first year of middle school when they were - years old and returned to school for the third and the final year. these students met the following criteria for successful school reentry: regular school attendance, average/above average academic performance, friendship maintenance, and high school diploma. the theme -bring the class to the hospital was found to be the key to the adolescents' successful return to school. without a prescribed school reentry protocol and in the face of limited bedside education services, the homeroom teachers, as links between school, home, and hospital, brought the class to their hospitalized students. they doubled as bedside teachers conducting lessons at the hospital or students' homes, became friends with the parents, witnessed firsthand the students' pain and triumph during treatment, brought the students back to school for visits and celebrations, delivered the classmates' wishes and news to the students, encouraged and welcomed classmates' visits to the hospital, and, together with parents and other teachers, developed flexible school reentry schedules for the students. this on-going study demonstrated the critical roles and functions of homeroom teachers in successfully bringing the students back to school during and/or after cancer treatment. further analysis will be focused on how and why these three homeroom teachers were able to carry out this unexpected task on top of their already full workload. jennifer kesselheim, shicheng weng, victoria allen, collaborative group fellowship program directors dana-farber/boston children's cancer and blood disorders center, boston, massachusetts, united states background: a novel, -module, case-based curriculum entitled "humanism and professionalism for pediatric hematology-oncology" (hp-pho) aims to foster pho fellows' reflection on grief and loss, competing demands of fellowship, difficult relationships with patients and families, and physician well-being and burnout. in small group facilitated sessions, fellows work to identify coping strategies and explore how the challenges of fellowship influence both their own doctoring and the patient experience. objectives: to administer the hp-pho curriculum in a prospective, cluster-randomized trial, measuring whether exposure to this educational intervention, compared to standard conditions, fosters humanism and professionalism and improves satisfaction with training. design/method: pho fellowship programs (n = ) were cluster-randomized to deliver usual training in humanism and professionalism (control) or the novel curriculum (intervention) during the - academic year. the primary outcome measure was the pediatric hematology-oncology self-assessment in humanism (phosah). secondary measures included a -point satisfaction scale, the maslach burnout inventory (mbi), the patient-provider orientation scale, and the empowerment at work scale. participating fellows were pre-tested in summer and post-tested in spring . a change score was calculated for each study instrument. we compared each outcome between arms using mixed effect models adjusted for pre-test score as a fixed effect and site as a random effect. results: randomization yielded intervention and control fellows. the two arms did not significantly differ in distribution of fellow age, gender, or post-graduate year. the intervention sites successfully administered of ( %) modules. change scores on the phosah were not significantly different between the control and intervention arms (adjusted mean difference = . ; % confidence interval [ci] - . , . ; p = . ). compared to the control arm, fellows' exposed to the curriculum gave significantly higher ratings on several items within the satisfaction scale including satisfaction with their training on "physician burnout" (adjusted mean difference = . ; % ci . , . ; p< . ), "physician depression" (adjusted mean difference = . ; % ci . , . ; p< . ), "balancing professional duties and personal life" (adjusted mean difference = . ; % ci . , . ; p = . ), and "humanism overall" (adjusted mean difference = . ; % ci . , . ; p = . ). change scores on other secondary measures were not significantly different between study arms. conclusion: exposure to the hp-pho curriculum did not alter fellows' self-assessed humanism and professionalism. however, the curriculum proved feasible to administer and intervention fellows expressed higher levels of satisfaction in their humanism training, indicating the curriculum's positive impact both for fellows and their learning environment. background: recent work has documented significant levels of unmet needs among adolescents and young adults with cancer, particularly psychosocial challenges during the transition to adulthood, (e.g., abrupt disruption to school and social life, and social isolation). given that adolescents and young adults drive mobile app use, a mobile-phone may be an ideal way to deliver a psychosocial intervention to adolescents and young adults with cancer. to use a patient-centered approach to inform a mobile-based mindfulness and social support intervention for adolescent and young adult patients with cancer. design/method: participants were ten aya with sarcoma ( % female; % adolescents); parents of the five adolescents, and six healthcare providers (n = ). formative research involved three steps: ( ) in-depth interviews were conducted with ten aya with sarcoma; parents of the five adolescents, and six healthcare providers (n = ). ( ) adaptations were made to an existing mindfulness app which offers a program for youth. modifications included creating a -week "mindfulness for resilience in illness" program, with relaxation exercises, and the addition of videos featuring two sarcoma survivors as program hosts. content was informed by the mindfulness curriculum for adolescents, learning to breathe. ( ) a private facebook usability group was organized to (i) elicit beliefs about the mindfulness app and potential future enhancements, and (ii) promote social support. results of the in-depth interviews revealed themes around adolescents' functioning and coping, including body image concerns; recurrence-related anxiety; anger over loss; and being overwhelmed by medical information. themes from the interviews were incorporated into a demonstration version of the mobile app. a patient-centered approach is widely recommended in the development of mobile-based health behavior change interventions and may be a useful way to inform development of a mobile-based mindfulness and social support intervention for adolescents and young adults with cancer. background: medical trainees consistently report suboptimal instruction and poor self-confidence in communication skills. despite these deficits, few training programs provide comprehensive pediatric-specific communication education, particularly in the provision of "bad news." an in-depth survey to examine the historical experience and communication needs of pediatric fellows was conducted at a large academic pediatric center as the first step towards the development of a comprehensive communication curriculum. to determine the previous educational and clinical experiences of pediatric subspecialty fellows, assess their levels of comfort in the context of various communication topics, and query potential modalities and topics for future communication training. design/method: the needs assessment survey was developed using previously developed and validated questions and review of the literature. the survey was reviewed by internal and external pediatric oncology and palliative experts and pre-tested with a subset of trainees to enhance content validity. results: thirty-two out of a total of fellows completed the survey ( % completion rate), of which % were pediatric hematology-oncology or subspecialty fellows. most fellows had participated in previous teaching sessions ( %), including those involving role play or simulation ( %). however, few fellows had received feedback from senior clinicians on their communication skills ( % of fellows had received feedback ≤ times). on a scale of -x, with indicating "not well prepared," the mean score for of communication items was < . fellows felt least prepared to lead discussions around informed consent for experimental therapies, end of life care, and autopsy. fellows indicated that didactic educational sessions and additional coursework were less useful strategies for improving their communication skills, whereas small group role play sessions with faculty and/or bereaved parent educators were most useful. fellows' overall communication preparedness score was not correlated with post-graduate year but was positively associated with the number of times they previously had delivered bad news to patients and families. fellows requested additional training on many topics, with greatest interest in learning skills to optimize communication with an angry patient or family. additional topic requests included placing limitations on resuscitation, withdrawing/withholding further therapy, and ageappropriate inclusion of patients in difficult discussions. despite self-report of prior communication skills training, pediatric subspecialty fellows felt underprepared to participate in difficult discussions with patients and families. learners identified role-playing and coaching with real-time feedback from other physicians and bereaved parents as more useful training strategies as compared to didactic sessions. background: when children die of cancer, parents must adjust to their child's absence amidst the lingering turmoil of what preceded their death: witnessing their child undergo painful treatments, making difficult decisions, and anticipating a devastating loss, all the while hoping for a recovery. adjustment to a child's death, as depicted by current bereavement literature, necessitates making meaning of one's loss. professional care staff can help parents make sense of their child's illness, and in turn, of their own parental experience during treatment. however, the extent to which relationships with professional care team members influence parents' ability to make sense of, and successfully cope with, their loss has not been examined. objectives: to examine how bereaved parents' interactions with their deceased child's pediatric oncology professional care team have impacted their grief symptoms design/method: to better understand how interactions with professional care staff relate to parents' grief outcomes, we conducted a mixed-methods study examining staff impact on parental grief. thirty participants whose children died of cancer one to three years ago completed an in-depth interview and psychometrically validated surveys measuring meaningmaking, depression, and grief symptoms. results: correlational analyses of the measures found that an increase in meaning making was associated with lower depressive and grief symptoms. a content analysis of the interviews found that many participants regarded staff "like family," had on-going relationships with staff after their child died, and described various ways staff interactions during treatment and after the child's death helped them make sense of their loss. in particular, participants described how interactions with staff have helped them find benefits in their loss and learn to create a new relationship with their child despite their physical absence. quantifying the interview data and statistically analyzing it along with the measures found that participants' increased frequency of describing staff's positive impact on their grief correlated with higher meaning-making scores and lower grief symptom scores. our study found that bereaved parents who lost their children to cancer were articulate in sharing their experiences of staff engagement and communication during treatment, offering numerous examples of how staff aided them in making meaning of their loss that were reliably associated with their subsequent grief. we hope the results of this mixed methods research encourage further study of the importance of staff interaction with families during the critical period of their children's care, and the lasting impact this can have regardless of the treatment outcome. memorial sloan kettering cancer center, new york, new york, united states background: although resiliency has been recognized as necessary for healthcare professionals, trainees feel unprepared for the emotional challenges inherent in caring for sick and dying patients. compounded by long hours, challenging work environments, and lack of formal training on handling emotionally difficult situations, many institutions are recognizing the need for interventions to reduce trainee distress. the goals of this fellow-led quality improvement initiative were: ) to determine whether there is a need for emotional support amongst pediatric hematology and oncology fellows, ) to provide formal resiliency and debriefing sessions, and ) to measure feasibility, acceptability and effectiveness of implemented curriculum. design/method: an anonymous survey to determine need for resiliency and debriefing sessions following a traumatic event was distributed to active pediatric hematology & oncology fellows at memorial sloan kettering cancer center in january . once need was established, an intervention consisting of a formal curriculum was developed and initiated in june , involving: ) scheduled and ad hoc debriefing sessions in response to traumatic events (including patient death, codes, interpersonal conflicts, end-of-life care); led by a psychiatrist and social worker with fellows and a pediatric oncologist mentor in attendance, and ) a resiliency didactic curriculum, led by a palliative medicine specialist, focused on skills such as contesting cognitive distortions and mindfulness. the effectiveness of these sessions will be measured using follow-up anonymous surveys at months (currently underway) and months post-initiation of intervention. the initial survey demonstrated most trainees ( / ) were present at or more deaths during their training, while less than half of respondents had attended a post-event debriefing session. % of respondents felt there was not sufficient emotional support from the institution for physicians caring for dying patients. a separate pre-intervention survey found all respondents ( / ) expressed a need for regular debriefings, and nearly all anticipated that they would benefit from such debriefings. concerns identified by trainees that would preclude participation in the curriculum included preference to deal with emotional situations privately and time constraints. trainees identified a need for formal debriefings and resiliency skill development. the program was easily implemented, and is both feasible and acceptable with good attendance. feedback received at the -month mark will determine deficits and possible improvements to the curriculum. the -month survey will measure effectiveness of the program and whether it should be continued. background: acute kidney injury (aki) is a common but under-recognized complication among patients with leukemia. it is associated with prolonged hospital stays, increased mortality, progression to chronic kidney disease, and delays or changes in cancer therapy which may affect a patient's prognosis. however, data on aki in pediatric patients with cancer is still lacking overall. we investigated the incidence of aki in patients who were newly diagnosed with all at our center from january to september . we performed a retrospective chart review of all patients who were newly diagnosed with all from neonate to years in our facility. we determined the incidence of aki in our population using the kidney disease: improving global outcomes (kdigo) diagnostic criteria. we also assessed for nephrotoxic exposures, nci all risk stratification and risk of aki, and tumor lysis syndrome (tls). we identified patients diagnosed during the study period who met inclusion criteria. median follow-up time was . months (range . - . ). the cohort was predominantly male ( . %) and hispanic ( . %). our analysis showed . % had aki by kdigo criteria ( % grade , . % grade , and % grade ), . % had aki on presentation, and % had multiple aki episodes during the study period. older age and longer length of hospitalization were associated with aki (p = . and p = . , respectively). there was no association between aki and nci all risk classification, contrast exposure, hyponatremia, elevated white blood cell count, uric acid levels, antimicrobial therapy, or diuretic use in this study. conclusion: aki was a common finding in our study population. the majority had grade aki by kdigo criteria. however, aki was associated with older age and a longer length of stay. further study is needed to determine the short-and long-term impact of aki on pediatric patients with all. st. jude children's research hospital, memphis, tennessee, united states background: in some regions, the availability of trained pediatric oncologists is a limiting barrier for the care of children with cancer. in , the unidad nacional de oncología pediátrica (unop) and the universidad francisco marroquín school of medicine in guatemala established a pediatric hematology/oncology fellowship program sponsored by st jude children's research hospital to provide central america and the caribbean with well-trained specialists. a systematic analysis of the impact of fellowship programs in pediatric oncology has never been done, especially in the context of a regional education program. objectives: this study sought to analyze the impact of the unop fellowship program based on the regional number of providers, pediatric cancer centers and patient volume. in addition, it sought to characterize the jobs and scientific output of the graduates. the impact will be evaluated in the context of a cost analysis. to define the volume of providers, pediatric cancer centers and patients, the directors of pediatric cancer centers in central america were sent an online survey to obtain these data. all the centers contacted maintain an updated hospital-based patient registry. in addition, the graduates of the fellowship program were also sent an online survey, asking about their job at graduation, current role and scientific productivity. the cost analysis will include assessment of direct costs including salaries and stipends for away rotations, as well as the indirect costs of faculty time spent teaching. since the establishment of the unop fellowship program, the region has more providers for pediatric cancer (p< . ) and centers treat a larger volume of patients (p< . ). two new centers have opened with graduates of the program. all but one graduate practice pediatric oncology ( / ) and the majority do it in their country of origin ( / ). no graduate practices outside of this region. almost half of the graduates ( %) hold a leadership role at their institution. the majority of their time is spent in the public sector (> %). the majority of graduates participate in clinical research ( %) and have participated in the creation or implementation of therapeutic protocols ( %). on average, the graduates have published peer-reviewed articles since completion of training. the unop fellowship program has had a favorable impact on pediatric cancer care in the region, contributing to the capacity to treat a larger volume of patients. graduates practice pediatric oncology in the region in the public sector, frequently hold leadership roles and are scientifically productive. background: abandonment of treatment is a major cause of treatment failure and poor survival in children with cancer in low-and middle-income countries. the incidence of abandonment in peru has not been reported. objectives: the aim of this study was to examine the prevalence and associated factors of treatment abandonment in pediatric patients with cancer of peru. we retrospectively reviewed the sociodemographic and clinical data of children referred between january and december to the two main tertiary centers for childhood cancer, located in lima, peru. definition of treatment abandonment was used from the siop (international society of paediatric oncology) podc (paediatric oncology in developing countries) abandonment of treatment working group recommendation. results: data of children diagnosed with malignant solid tumors and lymphomas were analyzed, of which ( . %) abandoned treatment. univariate logistic regression analysis showed significant higher abandonment rates in children living outside the capital city, lima (p< . ); prolonged travel time to a tertiary center (> hours; or . , p = . ); living in a rural setting (or . ; p< . ) and lack of parental formal job (or . ; p = . ). according to cancer diagnosis, children with retinoblastoma were more likely to abandon compared with other solid tumors. in multivariate regression analyses, rural origin and lack of formal parental employment were independently predictive of abandonment. conclusion: treatment abandonment prevalence in our country is high and closely related to socio-demographical factors. treatment outcomes could be substantially improved by strategies that help prevent abandonment of therapy based on these results. st. jude children's research hospital, memphis, tennessee, united states background: to improve the quality of a pediatric hematology/oncology fellowship program, a systematic assessment must be performed that can evaluate its current state and identify areas of opportunity, as well as modifications over time. unfortunately, widely agreed-upon metrics of quality for pediatric hematology/oncology fellowship programs currently do not exist. this is particularly important in this field due to the global shortage of specialists. for this reason, an assessment instrument that is applicable throughout the world must be created. objectives: the st. jude global education program assessment tool (epat) is a novel instrument that seeks to evaluate pediatric hematology/oncology fellowship programs around the world in systematic and objective way. epat will help determine key performance indexes that are relevant for quality education in pediatric hematology/oncology fellowship programs and establish the framework for improvement. design/method: firstly, key domains to be evaluated for program assessment were identified a priori based on the continuum of pediatric hematology/oncology fellowship programs in the context of geography and educational structure. subsequently, questions were formulated to evaluate these key domains, seeking to assess elements involved in ensuring competence in clinical practice, academic productivity and regional impact. due to the novelty of this tool and the lack of defined metrics of quality, epat relies on expert opinion in a two-step process: internally in the department of global pediatric medicine at st. jude children's research hospital and, subsequently, from a panel of experts in global pediatric oncology and medical education from around the world. ten key domains were identified to evaluate all aspects relevant to training programs around the world, regardless of educational and geographic context. questions have been created to assess these domains and, to make epat quantitative, these have assigned weights with a value reflective of their relative importance. this grading system allows for a score in each key domain, permitting monitoring of changes over time. epat is currently at the stage of external expert review, and subsequently will be piloted in five fellowship programs around the world to provide different geographical and patient care contexts for its validation. once epat is finalized, it will be distributed to pediatric hematology/oncology fellowship programs around the world to be applied. epat proposes a novel strategy to assess training programs in a systematic way that includes all aspects relevant for a training program in a global context. this tool will help guide improvements in pediatric hematology/oncology fellowship programs and assure a well-trained workforce. background: with the improvement in pediatric oncology patient survival and outcomes in the past several decades, monitoring for recurrence and long-term effects of therapy has become even more important. the utilization of personalized treatment summaries and survivorship care plans (scps) is one way to communicate this information with patients and families. the american college of surgeons commission on cancer (coc) created a standard regarding provision of scps to % of eligible patients by december , as a metric for accreditation of all cancer centers. the standard applies to all patients with stage i, ii, and iii cancer diagnoses and requires creation of the scp within one year of diagnosis or six months of completing treatment. during implementation at our pediatric cancer center, we identified barriers to use of the guidelines in the childhood cancer setting. objectives: define eligibility for an scp for pediatric oncology patients to include all patients with curative intent and to deliver scps within six months of finishing therapy. design/method: using chart review and a cancer center registry query, we identified childhood cancer patients potentially eligible for an scp by collecting stage, goal of therapy, and dates of treatment. all patients with curative intent were deemed eligible for an scp regardless of stage i-iv. patients being followed in the oncology clinic for posttreatment surveillance and care were included even if they had received an scp in the survivorship program or were greater than six months off therapy at time of implementation. as expected in the pediatric oncology population, acute lymphoblastic leukemia (all) was the most common diagnosis comprising . % of patients. all is stratified into risk groups instead of surgical staging categories, and treatment duration is greater than one year, unlike many adult-onset malignancies. these differences required interpretation of the guidelines to apply to our pediatric population for all and other pediatric diagnoses with non-surgically based staging. our pediatric oncology clinic has to date provided scps to of eligible patients by adapting the guidelines to focus on patients with curative intent to receive an scp by six months off therapy. cancer staging guidelines and goals for curative intent as well as lengths of treatment vary between the pediatric and adult populations. the coc guidelines require adaptation for optimal applicability to the pediatric oncology population. background: education in communication for fellows in fields that require difficult discussions with families are few in nature. adult learning pedagogies such as role play are under-utilized in medical education, and have been shown to be as effective as traditional teaching methods such as lecture. an -module course for fellows in hematology/oncology, hospice and palliative medicine, radiation oncology, and pediatric hematology/oncology was implemented in january/february . fellows participated in the program. topics covered including fundamentals of communication, coping and spirituality, delivery of bad news, communicating with families, sexual dysfunction during treatment, palliative care/death and dying, and burnout. objectives: overall goal of this course is to foster holistic physicians who views their patients as people with cancer, not cancer patients, and physicians that can communicate effectively with their patients throughout the disease continuum. by the end of the course, learners should be able to practice the fundamental principles of good communication. design/method: fellows initially participated in a pre-course osce to establish baseline skills. osce was facilitated by the center for learning and innovation at northwell, and included actors portraying a pediatric patient and family member to whom the fellow had to break bad news. two months later, the course was carried out over the span of eight weeks and included didactic sessions followed by minutes of role play scenarios. five of the eight modules included role play, with faculty members serving as simulated patients. after the course, a second breaking bad news osce was held. both osces were filmed, and feedback was given by the on-site actors. additionally, faculty members were given access to the videos in an on-line format and were given an evaluation tool to assess the fellows' performance pre-and post-intervention. fellows were given subjective surveys pre-and post-course as well. results: subjective data from participants showed a noticeable increase in comfort level in all areas on the pre-and post-course survey. data obtained from osce videos showed improvement in communication skills as assessed by sps and faculty members using a new evaluation tool developed by faculty. initial first-run data shows that this course is successful in improving communication skills as well as increasing fellows' comfort level across several domains of communication. future directions for our course include improving and validating our assessment tool, expanding our topic base to include more aya and pediatric scenarios, faculty development for improved role play, and investigating impact on practice after course completion. background: acute lymphoblastic leukemia (all) is the most common form of childhood cancer with approximately children diagnosed each year. survival rates have improved significantly over the past several years. children with all are at risk for developing musculoskeletal complications during and after completion of treatment, which can contribute to impaired activity, elevated body mass index (bmi), and risk for complications. interventions involving physical activity could improve musculoskeletal strength as well as overall health in these children. the aims of this study are to examine the feasibility of a directed physical activity program for children with newly diagnosed all during the initial intensive phase of therapy and to evaluate the overall health and quality of life of children participating in the directed physical activity program. design/method: all subjects will receive education materials about the importance and safety of physical activity and a nutrition handout. all subjects will also participate in the directed physical activity program under the supervision of a trained physical therapist for at least minutes every week for weeks. the program will entail four stations including a cardiovascular, balance/proprioception, strength and flexibility, and coordination and cardio. feasibility will be assessed by tracking the participation rate throughout the study period. other assessments will be made at study entry, at the end of weeks of physical activity initiative and months after completion of the intervention. assessments include overall strength and flexibility, weight, height, bmi, blood pressure and performance scores. descriptive statistics will be used for this study. results: a total of patients, male and female, enrolled in the study over a . month period. patient ages ranged from - years. half of the patients enrolled have completed the week program and all patients had stability or improvement of their physical functioning scores. further data collection and analysis is ongoing. patients in the early intensive phase of all therapy are at risk for complications that can affect their physical functioning. a directed physical activity protocol may improve their overall physical functioning. patients may not need specific physical therapy; however a directed physical activity program appears to be beneficial for these patients. the main roadblocks to successful completion of the program were difficulty with scheduling, strain on the parents and patient from treatment, unplanned admissions for fever, as well as nausea and fatigue at time of visit. albany medical center, albany, new york, united states background: communication skills are a core competency highlighted by the acgme. increasing resident confidence in delivering difficult news has been shown to lead to more s of s effective communication. currently, the majority of residency programs lack formal training in communication skills. our objective was to demonstrate feasibility and efficacy of integrating a standardized-patient based training program for communication skills into the curriculum of pediatric residents design/method: to date, pediatric and medicine/pediatric residents have participated in the program during the intern year. the program consists of three, two-hour long sessions, in which each resident is given several opportunities to act out case scenarios with a standardized patient. scenarios included informing a parent of their child's new cancer diagnosis and disclosure of a positive hiv test to a teenager. residents received post hoc peer to peer, and preceptor to learner feedback. pre and post-program surveys were completed by residents. results: following course completion residents reported an increase in confidence in multiple areas of communication including giving a difficult diagnosis (p< . ), discussing a poor prognosis (p< . ), responding to different patient/family member emotional responses i.e. crying or anger (p< . ), and organizing vital information to be relayed (p< . ). in conclusion, communication skills training of pediatric residents is feasible and provides a platform for developing valuable skills not taught elsewhere within the curriculum. background: for children with cancer, transitioning back to school during or after treatment can be challenging. literature supports the need for school re-entry programs to ease this transition. however, these programs vary widely among pediatric cancer institutions with little data addressing their program components. data from this study provides information on current school re-entry programs across these institutions. objectives: one objective of this study was to assess for correlation between the presence of a school re-entry program and other factors, such as geographic location and institution size. a second objective was to establish a list of differences between institutions' school re-entry program components. finally, we aimed to describe current school reentry practices, as well as program benefits and perceived areas for improvement. states with membership in the children's oncology group were offered enrollment in this study. a member of each institution was invited to participate in a survey established by the research team. this person was closely associated with the institution's school re-entry practices. each interview queried institution demographics, as well as program components (e.g., participants, target audience, resources). comment was also collected on program benefits and potential for improvements. analysis of transcripts was performed using pearson's correlation to assess for relationships between institution size, geographic location, and program presence. grounded theory was used for analysis of benefits and improvements. results: thirty-nine of forty-one pediatric institutions who were offered enrollment participated in this study. twentynine institutions ( %) indicated the presence of a school reentry program, and ten ( %) stated they had none. no correlation was found between institution size and the presence of a school re-entry program (p = . , ns). there was also no correlation found between institution location and the presence of a school re-entry program (p = . , ns). a major theme surrounding the benefits of having a program included education for the returning student's peers. for those with programs, perceived improvements included increasing staffing and the ability to offer more services. the results do not support the hypothesis that the presence of a school re-entry program is influenced by the size and geographic location of the treating institution. however, data seem to suggest that available staffing may influence the presence of a program. future studies are needed to address other potential influences, as well as to take an evidence-based approach to determine the effectiveness of the interventions present in these programs. cohen children's medical center/ zucker school of medicine at hofstra-northwell, new hyde park, new york, united states background: genetics/genomics is evolving at an extremely rapid pace. current advances lead to individual algorithms toward disease treatment for each disease with multiple branch points. fellows learn only a fraction of the knowledge and there is no formal approach to teaching critical analysis of information and application algorithms toward disease. additionally, as knowledge evolves extremely rapidly, any approach must teach self-acquisition and application of evolving discoveries. objectives: to create, implement and evaluate a novel curriculum for genetics/genomics targeted toward pediatric hematology/oncology fellows design/method: the curriculum includes four components: ) genetic and genomic medical knowledge, with one initial team-based learning session and weekly online multiple choice questions; ) essential pathways, which will teach molecular pathways common in oncogenesis and relevant to targeted therapy in microteaching sessions with using auditory, visual and tactile learning; ) knowledge acquisition and clinical judgment, to allow learners to gain experience into researching data available, then developing and prioritizing potential treatment plans using problem-based learning sessions in which they will stage a patient, research treatment options, prioritize and present findings; and ) synthesis to demonstrate independent ability to research and recommend therapy through an independent project in which the learner, given a case, will present the case and research findings, genetics/genomics, molecular pathways and make recommendations for therapy in molecular tumor board for faculty and fellows. to evaluate, we plan to recruit to institutions, match for size of programs and implement in half and evaluate nd and rd year fellows in both groups by mcq exam and satisfaction surveys. the creation of a multi-module, adult-learning based curriculum for genetics and genomics in pediatric oncology is feasible. implementation and evaluation are necessary to demonstrate efficacy. background: neuroblastoma is the most common extracranial solid tumor in children. chimeric anti-gd antibody ch . (dinutuximab) therapy has improved the survival of children with newly diagnosed high-risk, neuroblastoma patients as well at the time of first relapse/progression. acute neuropathic pain is a well-documented side effect of dinutuximab administration. however, additional adverse effects including sensorimotor neuropathy, ocular symptoms, and behavioral changes have been described. the incidence and severity of these effects are currently not well-documented in pediatric patients. with improved long term survival of patients receiving this modality, it is important to look for the potential late effects of dinutuximab. objectives: to determine the incidence and severity of neurologic, ophthalmologic, or behavioral changes after dinutuximab administration at our institution. we performed a retrospective chart review using our electronic medical record. we included all patients with high-risk neuroblastoma between the ages of and years at our institution diagnosed between and who received dinutuximab. patients with history of opsoclonus-myoclonus syndrome or gross sensorimotor neuropathy prior to receiving dinutuximab were excluded. we examined clinical documentation for subjective reports and objective exam findings of neurologic, ophthalmologic, or behavioral changes. we also looked for referrals made to neurology, ophthalmology, physical medicine & rehabilitation (pm&r), and psychology. : twenty-two patients met inclusion criteria. at the time of chart review, patients were alive and were deceased. eighteen patients received dinutuximab per anbl ; patients received dinutuximab per anbl . of these patients, patients reported symptoms of interest and reported multiple symptoms. six patients reported symptoms that began at least months after completing dinutuximab. nine patients had objective findings on exam, including decreased deep tendon reflexes, abnormal pupils, and nearsightedness. for patients, referrals were made to ophthalmology, pm&r for neuropsychologic testing, or neurology. two patients who reported symptoms of interest were not referred to a specialist. conclusion: neurologic, ophthalmologic, and behavioral symptoms were commonly reported and demonstrated on exam among pediatric patients with high-risk neuroblastoma who received dinutuximab. it is important to identify these effects so that appropriate specialist referrals can be placed for adequate management of these changes. we recognize that these symptoms may not be solely due to dinutuximab as these patients receive other agents including opioids, so a prospective trial is needed to further evaluate the long-term effects of dinutuximab and to determine how best to screen for these effects. akron children's hospital, akron, ohio, united states background: pediatric cancer is the leading cause of diseaserelated death in children in the united states (u.s.). in , over fifteen thousand children were diagnosed with cancer in the u.s. this population is at high risk for malnutrition due to the multimodal therapies they receive: surgery, chemotherapy, radiation therapy, antibody therapy, and/or bone marrow transplant. adverse effects of these therapies include taste changes, loss of appetite, diarrhea, vomiting, and/or mucositis, making it difficult for the children to be able to consume adequate amounts of nutrition during therapy. there is no "gold standard" measurement tool for identifying patients at risk for malnutrition. nutritional status is not frequently evaluated as a component of clinical trials. assessment of anthropometric measurements (weight, height, z-scores) at diagnosis, as well as over the duration of treatment, can assist in the early identification of malnutrition. the incidence and prevalence of malnutrition in this population is unknown at akron children's hospital. the purpose of this study is to describe the nutritional status and provision of nutritional support therapies in pediatric patients during their first year post new oncologic diagnosis. objectives: identify the incidence and prevalence of malnutrition across oncologic diagnostic categories over the first twelve months post diagnosis. we performed a retrospective records review of all patients newly diagnosed with cancer in at akron children's hospital. demographic and anthropometric data was collected at time of diagnosis and nutritional status categorized by z score. anthropometric and nutrition support data was then collected every two months for the first year after diagnosis along with incidence of unplanned inpatient admissions. results: a total of patients were included in the analysis, with . % malnourished at time of diagnosis; . % developed malnutrition the first year. patients with solid tumors represented % of patients with pre-existing or acquired malnutrition. overall, % of patients received at least one nutritional support modality. patients with pre-existing or acquired malnutrition had a non-significant increase in unplanned admissions (p = . ). our study demonstrated that patients with solid tumors were found to be at increased risk of pre-existing and acquired malnutrition, followed by leukemias, and experienced higher incidence of unplanned admissions in the time period observed. prospective, multi-center replication of this study, including detailed collection of nutrition therapies is recommended to guide development of diagnosis specific nutrition support guidelines. background: pediatric and young adult oncology patients treated with intense chemotherapy have a high incidence of transfusional iron overload. iron deposition can lead to heart failure/arrhythmias, liver abnormalities, endocrine dysfunction, ineffective erythropoiesis, and increased cancer and mortality risk. however, there is a paucity of data regarding recommendations for management of transfusional iron overload in these cancer survivors. consequently, long-term complications of transfusional iron overload specific to these patients have not been assessed. objectives: to assess screening and phlebotomy-based treatment algorithms for this population. design/method: a retrospective chart review of pediatric and young adults who completed oncology management, had iron overload, and initiated phlebotomy treatment was conducted. tiered screening occurred in patients that received at least packed red blood cell (prbc) transfusions. patients were recommended for evaluation and possible phlebotomy if: ( ) liver iron concentration (lic) > mg of iron/gram dry weight liver tissue by ferriscan and/or ( ) cardiac mri t * < ms. during phlebotomy, iron status was assessed quarterly and phlebotomy discontinued with lic < or normalization of ferritin/imaging lic verification. descriptive statistics were employed to report the characteristics of the study population. spearman correlations were utilized to describe associations between transfusions, lic, ferritin, iron saturation and number of phlebotomy sessions. results: twenty five survivors underwent phlebotomy. the mean age was . years (sd . ) and ( %) were female. oncologic diagnoses: all ( %), aml ( %), nhl ( %), ewing sarcoma ( %), osteosarcoma ( %), neuroblastoma ( %) and cns ( %). patients received a median of . (iqr - ) transfusions. median number of phlebotomy sessions was (iqr - ) over . years (iqr . - . ). prior to phlebotomy, median lic was . mg/g (iqr . - . ) and ferritin was . ng/ml (iqr - ) . no patients demonstrated abnormal cardiac t * mri (n = ). ( %) patients completed phlebotomy. one discontinued due to poor vascular access. no patients developed iron deficiency. lic was reduced by a median of . mg/g (iqr . - . ) and ferritin by ng/ml . correlation between number of transfusions and phlebotomy sessions was poor (r = . ). conclusion: management guidelines are lacking for transfusional iron overload in pediatric and young adult survivors of cancer. we demonstrate a phlebotomy algorithm that is effective and tolerated. correlation between number of transfusions received and phlebotomy treatments was poor, necessitating serial assessments. using this management algorithm, prospective studies can evaluate the effect of iron removal on iron overload complications in this patient population. penn state children's hospital, hershey, pennsylvania, united states background: cancer therapy leads to an impaired immune system that takes time to recover. it is important to ensure that these survivors have adequate immunity to prevent common yet potentially severe childhood illnesses. no validated guidelines currently exist for surveillance testing or re-immunization in this population. retrospective analysis involving a small cohort of pediatric cancer patients treated at penn state children's hospital showed % of patients screened for varicella immunity after therapy completion did not have adequate disease titers. to determine the proportion of pediatric cancer survivors who have lost humoral immunity to previously received vaccines; to determine the rate of response to single dose boosters or full vaccine series in seronegative subjects after one booster. design/method: pediatric cancer survivors treated at the children's hospital who are at least months from completion of cancer therapy are prospectively tested for antibody levels to hepatitis b, tetanus, varicella, measles, and strains of pneumococcus ( , b, v, c, f, and f). samples are analyzed by the cdc for measles and varicella avidity. seronegative subjects by commercial studies, are eligible to receive booster vaccines. titers are rechecked at least weeks after boosters to re-evaluate immunity; if still seronegative, subjects will receive the entire vaccine series. titers are finally tested at least weeks after the final dose of the vaccine series. immunity analyzed after therapy, after boosters, and after vaccine series. results: of pediatric cancers survivors who completed therapy, % were non-immune to hepatitis b, % nonimmune to > % of pneumococcal strains tested, % nonimmune to measles, % non-immune to varicella, and % non-immune to tetanus. of subjects who received mmr vaccine after therapy and prior to study enrollment did not have protective antibodies to measles. of the subjects who received varicella vaccine after end of therapy and prior to study enrollment, did not maintain protective antibody levels. cdc results for measles and varicella are pending, as well as repeat studies after vaccine boosters and series. conclusion: a significant percentage of pediatric cancer survivors do not retain immunity to hepatitis b, pneumococcus, measles, and varicella. after one booster, a high percentage of subjects did not develop protective immunity to varicella. only subject did not have immunity to tetanus, which is consistent with the high immunogenicity of tetanus toxoid. formal guidelines are needed to protect this population from vaccine-preventable illness post-therapy. children's hospital of richmond at virginia commonwealth university health system, richmond, virginia, united states background: childhood cancer survivors are at risk for being overweight. diet and physical exercise are important in maintaining a healthy lifestyle and weight; however, it has been reported that cancer survivors are less active than their peers. one reason for this may be that there are no clearly established risk-based exercise recommendations for cancer survivors. another reason may be that providers tend to focus s of s recommendations for exercise more towards patients who are overweight. objectives: to describe changes in physical fitness of childhood cancer survivors who exercise. design/method: 'moving forward' is a wellness and physical fitness program that the center for care beyond the cure at chor offers in partnership with the ask childhood cancer foundation and the ymca. the program is available for any childhood cancer survivor between y and y age, being seen at our center. survivors define their fitness or wellness goals and then work with a trainer once a week (at least) for min sessions throughout the year to achieve these goals. baseline and ongoing measurements for core strength, endurance, overall strength and balance were collected. the average of each of the parameters of all participants were compared from the beginning to the end of the program. over the year, there was a % increase in endurance as measured by the average of the miles walked in minutes, % increase in core strength as measured by the average number of sit-ups in secs, an % and % increase in overall strength as measured by the average weight lifted by leg press and the average weight lifted by chest press, and a % increase in balance as measured by the average number of seconds balancing on a single leg. in addition, each child had actually gained weight in the process with an approximately % increase in the average of the weights of all children. there are benefits to regular exercise beyond weight control, and improvements in physical fitness can be seen even without weight loss. regular physical exercise results in improved physical fitness and should be universally advocated to all patients. determining insulin resistance, measuring changes in fatigue and wellness perception following exercise are future directions that we intend to explore. dana-farber cancer institute, boston, massachusetts, united states background: improvements in adolescent and young adult cancer patient (aya) survival rates and quality of life outcomes have lagged behind those of children and older adults, highlighting a need for research targeting this unique population. current literature supports the value of strong ayaclinician communication, notably in facilitating therapeutic alliance, however little is known about aya communication priorities during cancer care and barriers to optimal ayaclinician communication. objectives: to explore aya and oncology clinician communication priorities and to identify barriers and facilitators to aya-oncology clinician communication. design/method: semi-structured interviews were held with aya cancer patients and survivors (ages - years) from a single large academic institution and oncology clinicians (physicians and nurse practitioners) from academic institutions in the northeastern united states. interviews were conducted in english by phone or in person. all interviews were audio-recorded and transcribed verbatim. analyses were aided by nvivo software. ayas identified a wide range of topics as important to discuss with clinicians. the most frequently identified topics were ) side effects of treatment (with an emphasis on physical appearance and function, n = ), ) social issues (including friendship, family, and school, n = ), ) looking ahead to the future (n = ), and ) sexual & reproductive health (including future fertility, contraception, and romantic relationships, n = ). clinicians prioritized ) cancer treatment and side effects (n = ), ) emotional and psychological health (n = ), and ) sexual and reproductive health with a focus on fertility risk and fertility preservation (n = ). aya reported facilitators to good communication including an open and long-established relationship with the clinician (n = ) and clinician engagement in age-appropriate and patient-directed conversations (n = ). barriers included parental presence during visits (n = ). clinicians reported barriers including ) clinician discomfort (not feeling wellequipped to discuss psychosocial topics such as sexual health, spirituality, and relationships with peers, n = ), ) presence of parents/family (n = ), and ) perceived patient discomfort discussing specific topics (such as sexual health, n = ). clinicians acknowledged the need for collaborative efforts with additional team members (i.e. nurses, psychosocial providers) to assist in meeting aya communication needs. conclusion: aya and clinician-reported communication priorities are largely aligned. however, ayas emphasize some topics, such as social function, appearance, and sexual health that are not highly prioritized by clinicians, which may result in gaps in care for ayas in treatment and in survivorship. these data identify opportunities for intervention, including clinician education, patient and family education, clinic-based intervention, and systems-based changes that can be developed and tested. background: primary care physicians (pcps) cite lack of knowledge and inadequate communication with the oncology team as major barriers to providing recommended surveillance for late effects of treatment to childhood cancer survivors. a standardized telephone handoff to pcps posttherapy is a potential strategy to increase survivorship care by pcps through interactive communication. to determine the feasibility of a structured telephone communication using the situation, background, assessment, and recommendation (sbar) communication tool delivered by a trained oncology nurse to increase pcp knowledge and willingness to provide survivorship care. design/method: from / / to / / , a registered nurse expert in childhood cancer survivorship attempted to contact by telephone the pcps of the most recent patients attending yale's childhood cancer survivorship clinic that were < years old, english-speaking, and ≥ years posttreatment. all pcps had been previously sent an individualized survivorship care plan (scp) that listed the patient's previous treatment history and recommended surveillance tests. upon successful contact and after confirming receipt of the scp, the nurse explained the definition of late effects, description of patient's diagnosis and treatment history, and associated potential late complications and schedule of recommended surveillance tests. the pcp was also asked about his/her ability and willingness to provide needed surveillance for late effects in the future. overall, of pcps were successfully contacted with a median of phone call (range: - ) that lasted a median of minutes (range: - ) after a median of business day (range: - ). no pcps ended the call mid-conversation. all pcps were receptive and expressed appreciation for the call. twenty-five of ( %) pcps expressed an understand-ing of the material discussed and endorsed belief in their ability and willingness to provide late effects surveillance for their patients. no pcps questioned discussing their patient's care with a nurse versus a physician. interactive, structured communications between nurses and pcps by telephone are feasible and are associated with high-levels of pcp confidence in providing survivorship care. background: childhood cancer (cc) admissions account for % of non-newborn pediatric hospitalizations. these hospitalizations are longer and more expensive than other hospitalizations. admission payer (medicaid or commercial) reflects both health policy and sociodemographic status. the objective of this study was to determine if length of stay (los) or cost of cc admissions differed by payer. we used the kids inpatient database, a sampling of all pediatric hospital discharges in the united states. analysis for this study was limited to admissions containing a cancer diagnosis in any discharge icd- codes. admissions were further subcategorized by discharge codes according to diagnosis (leukemia, lymphoma, solid tumor and brain tumor) and reason for admission (chemotherapy, procedure, infection, non-infectious toxicity or "other"). charges were converted to costs using cost-to-charge ratios. multivariable linear regression models were performed to control for age, gender, race, reason for admission, and diagnosis. results: there were , weighted admissions for children with a cancer diagnosis in . of these admissions, . % had medicaid, . % had commercial insurance, and less than % had other payers. the mean los for medicaid admissions was . days ( % ci . - . ), compared with . days ( % ci . - . ) for commercial insurance. surgical admissions accounted for the largest difference in length of stay with medicaid admissions being . days longer than those covered by commercial insurance ( . days vs . days), however, the difference was significantly different for all reasons for admission. in multivariable analysis admissions associated with commercial insurance were % shorter s of s (p< . ), accounting for approximately one hospital day, than admissions associated with medicaid after controlling for other variables including race. the mean overall cost for medicaid admissions was $ , ( % ci - ), compared with $ , ( % ci - ) for commercial insurance. in the multivariable model, cost was collinear with race. conclusion: los and cost of admissions associated with medicaid differed from those associate with commercial payers. medicaid admissions were % longer on average than commercial insurance, accounting for a difference in length of stay of approximately one day although the difference varied with the reason for hospitalization (chemotherapy, surgical procedure, infection, other toxicity, other). costs of admissions were not independent of race. further investigation into potential explanations for this difference including differential access to home care needs, outpatient reimbursement differences, social indications for prolonged hospitalization, and provider biases, is warranted. background: pediatric cancer is a major cause of morbidity and mortality among children surpassed only by accidents. despite improved outcomes in high income countries (hic) survival rates remain poor in the developing word. there are various diagnostic and therapeutic limitations contributing significantly for the survival gap. the main objective of the study is to to evaluate the outcomes of pediatric cancer in armenia and identify diagnostic and therapeutic limitations in the country. we conducted a retrospective study among (≤ years old) children with cancer (solid tumors and hematological malignancies), who were diagnosed and treated at the clinic of chemotherapy of muratsan hospital complex of yerevan state medical university between and . those patients, who didn't receive chemotherapy for any reason were not included in the study cohort. epidemiological, social, medical information was collected through the patient charts review. this included patient age at diagnosis, sex, place of residence (city vs village), the educational level and employment status of parents, type of cancer, stage, presentation of symptoms, first medical specialty consulted and the time consulted, initial work-up, the type of treatment received, information on the diagnosis/treatment received abroad. results: at our clinic during the mentioned period of time the majority of patients presented with hematologic malignancies- %. ( . %) patients had information on diagnosis delay. average delay in diagnosis was about days. in % of cases the first contact with "healthcare system" was through pediatrician, and in % with surgeon. out of relapsed patients received salvage treatment in armenia and abroad. from those who stayed for treatment in armenia patients survived. majority of relapsed patients had acute lymphoblastic leukemia. from leukemia patients immunophenotyping and cytogenetics were available for ( . %) patients; the majority of missing cases were between and , when these diagnostic modalities were not available or affordable in the country. ( %) patients received part of diagnosis and/or treatment abroad. the most frequent reason for going abroad was bone marrow transplantation, otherwise none available in armenia. out of patients were lost to follow-up, patients had a fatal outcome. patients were in remission at a median follow up of . years. conclusion: unavailability of cancer registry and several essential diagnostic/treatment modalities, luck of multidisciplinary care and palliative support, high rate of out-of-pocket expenses were among the main challenges of pediatric cancer care in armenia. background: adverse drug reactions (adrs) are increasingly recognized as important and sometimes irreversible complications of cancer treatment. anthracyclines and cisplatin are effective chemotherapeutic agents, but their use can be limited by cardiotoxicity (anthracyclines) and ototoxicity (cisplatin) in up to % of patients. genetic variants that can be used to predict who is most at risk of developing these adrs have been discovered and replicated. objectives: to create pharmacogenetic risk prediction models for anthracycline and cisplatin toxicities and discuss results with oncologists to facilitate incorporation into treatment decision-making when appropriate. design/method: risk prediction models were developed from the linear regression of strongly-predictive genomic variants (odds ratios ≥ ) discovered and replicated in at least three patient populations. these models were used to assess an individual patient's genomic risk of developing cardiotoxicity from anthracyclines or hearing loss from cisplatin. risk results were returned to oncologists showing where the specific patient's genetic risk of toxicity lies on a continuum between the lowest and highest risk groups across all studied patients using a multi-gene model. interviews were conducted with patients, families, and oncologists to determine how results were valued and utilized. results: patients have been genotyped and had their genetic risk results returned to their oncologists. the first patients have been characterized to determine the impact these test results have had on their clinical care. results were described as being useful in decision-making by patients and/or oncologists in % of cases. additionally, for patients in the most extreme risk groups (highest and lowest risk), a change in treatment plan was ordered % of the time for cisplatin patients and % of the time for anthracycline patients. this included increased cardiac and audiological monitoring, the addition of a protective agent, or choosing an alternative treatment protocol if the risk outweighed the benefits of remaining on the current treatment plan. in interviews, patients indicated that they felt more involved in decision making, and felt reassured by understanding their genetic risk of toxicities. genetic risk prediction models for anthracycline cardiotoxicity and cisplatin ototoxicity were highly utilized by patients and oncologists in decision-making. results were found to be an important tool for informing patients of the risk of adrs during cancer treatment, and resulted in patients and their families feeling more involved in decision-making. background: childhood cancer survivors are at increased risk of developing executive dysfunction, and low socioe-conomic status (ses) has been identified as one of the mediators of executive functioning. previous studies have used traditional measures of ses, such as parents' education level, family annual income and occupation. but more recently, area based socioeconomic measures like block group poverty status are deemed to be more useful in monitoring of social inequalities in health in the united states. block groups are statistical divisions of census tracts and generally contain between and , people. the current study aims to understand the association of block group poverty status (percentage of households in family's block group of residence living below the federal poverty level) with executive functioning among cancer survivor children. design/method: we used a retrospective cohort of childhood cancer survivors. relevant information was collected from the medical record, administrative data sets and parent-filled surveys. address information was geocoded using arcgis . to obtain data on the block group poverty status. a priori cut-points were set to represent block groups with families living below poverty level at %, . % to . %, and ≥ . %. executive functioning were assessed through a parent-rated instrument, the behavior rating inventory of executive functions (brief). multiple linear regressions were used to determine the relationship between block group poverty status and the brief scores. results: data was examined from families of childhood cancer survivors, ranging in age from to years. in this sample, . % families reported an annual income <$ , , . % reported income between $ , and $ , while . % reported annual income ≥$ , . primary care giver of . % of cancer survivors had more than more high school education, and . %, . % and . %, of families were living in a block groups with %, . - . % and ≥ % poor households respectively. block group poverty level was not significantly associated with annual income levels (spearman's rho = . , p = . ), or parental education level (spearman's rho = - . , p = . ). in a step-wise multiple linear regression, there was no statistically significant association seen between block group poverty status and executive functioning after adjusting for co-variables in the final model. future prospective study with a bigger sample size, longer follow up period and more robust measures of the executive functioning like a clinician administered test are needed to understand the effect of block group poverty status on executive functioning. to d completion was . days (range - ). all parents strongly agreed/agreed that d was helpful and would recommend d participation to another family. ten parents ( %) reported time spent on d was "just right." no parent felt more worried due to the intervention, though parent found d participation stressful. this interim analysis suggests that parents have a favorable d experience and recommend the intervention. to date, < % of enrolled parents fail to participate. d shows promise as an acceptable interdisciplinary communication intervention targeted to the early treatment period for childhood cancer. children 's hospital and research center oakland, oakland, california, united states background: screening echocardiograms are recommended by children's oncology group (cog) guidelines to assess for anthracycline-induced left ventricular (lv) systolic dysfunction. the yield of screening echocardiograms during chemotherapy and in the immediate post-therapy period is uncertain. objectives: to assess the incidence of lv dysfunction detected by screening echocardiograms during chemotherapy and in the immediate post-therapy period, defined as - months off-therapy. design/method: children diagnosed with cancer between january -march who received anthracycline chemotherapy were identified. echocardiograms were performed as per protocol, institutional and cog guidelines, and were reviewed retrospectively. lv dysfunction was defined as fractional shortening (fs) < % or ejection fraction (ef) < % ( ) results: in this cohort (n = , median age years), the most common diagnosis was all ( . %), followed by aml ( . %). of echocardiograms, ( . %) were performed during treatment and in the immediate posttreatment period. thirty-eight ( . %) patients had a > % decrease in fs compared to their pre-treatment echocardiograms. none of these patients required any treatment modification or cardiac medications. only patient ( . %) had echocardiogram-proven lv dysfunction discovered on a screening echocardiogram during her treatment course. she eventually died due to multi-organ failure following septic shock. this patient was receiving treatment for aml and had received mg/m of doxorubicin-equivalent anthracyclines at the time of the abnormal echocardiogram. one patient with metastatic ewing sarcoma had borderline lv dysfunction with a fs of % detected a month before completion of therapy. she had received mg/m of doxorubicin equivalent anthracyclines at the time of the abnormal echocardiogram. she did not require any therapy modification or additional cardiac medications. serial echocardiograms done on this patient have shown stable ventricular function. no off-therapy screening echocardiograms identified lv dysfunction. in our experience, the yield of echocardiograms to detect anthracycline-related cardiac dysfunction during treatment and in the immediate post-therapy period is very low. one patient developed lv dysfunction during treatment and one had borderline fs, while no lv dysfunction was identified within months of completing chemotherapy. though fs decreased in % of patients, none required intervention. further study is needed to optimize the use of echocardiography screening in children treated with anthracyclines. references: . landier w et al. jco . background: platinum-based chemotherapy increases the risk of sensorineural hearing loss in children with cancer. little is known about the impact of hearing loss on cognitive and emotional functioning in survivors. to determine the association of severe/profound hearing loss after platinum-based chemotherapy with ) cognitive impairment and ) emotional distress (i.e. anxiety and/or depression). cross-sectional study of all patients attending yale's childhood cancer survivorship clinic ≥ years off therapy for cancer diagnosed at < years and treated with cisplatin and/or carboplatin, but with no history of cns tumor, cranial radiation, congenital hearing loss, or developmental delay. hearing loss severity and hearing aid data were abstracted from audiograms and detailed clinical history. cognitive impairment was defined as behavior rating inventory of executive function t score ≥ , assessment by neuropsychologist, and/or history of special education. emotional distress was determined by brief symptom inventory t score ≥ (global or two subscales) or behavioral and emotional screening system t score ≥ , psychologist interview, and/or history of psychotropic medication/psychotherapy. the most recent available patient data were used. logistic regression with sas software, version . was performed. results: overall, patients ( % female, % white) met eligibility criteria with a median age of . years (iqr = . ) at diagnosis and . years at evaluation (iqr = . ) after a diagnosis of sarcoma ( %), neuroblastoma ( %), or other ( %) for which % received cisplatin and % received carboplatin. fifteen patients ( %) had severe/profound hearing loss in at least one ear. patients with severe/profound hearing loss had a significantly increased risk of cognitive impairment (or = . ; % ci = . - . ), but not emotional distress, compared to patients without severe/profound hearing loss. there was no significant association between age at diagnosis, current age, time since diagnosis, sex, race, ethnicity, or diagnosis with either cognitive impairment or emotional distress. similarly, there was no significant interaction between ) age at diagnosis and hearing loss or ) sex and hearing loss with either cognitive impairment or emotional distress. ten of the ( %) patients with severe/profound hearing loss in at least one ear were recommended hearing aids, of which ( %) reported compliance most of the time. we conclude that severe/profound hearing loss is significantly associated with cognitive impairment, but not emotional distress, in childhood cancer survivors. our data supports the need for interventions to improve hearing in these patients, including compliance with hearing aids. background: who grade anaplastic astrocytoma is a high grade glioma dependent on vascular endothelial s of s growth factor (vegf) mediated angiogenesis for its growth and infiltration. bevacizumab is a recombinant humanized monoclonal antibody which binds vegf-a and inhibits angiogenesis. common adverse effects of bevacizumab are hypertension, proteinuria, thrombosis and bleeding. while animal model based studies have shown that bevacizumab may impair ovarian function the effects of bevacizumab therapy on human fertility are not clear. since the physiology of pregnancy involves neovascularization/angiogenesis it is recommended that conception be avoided for at least months following exposure to bevacizumab. to describe the course of a young adult who became pregnant after receiving bevacizumab and radiation therapy for treatment of an anaplastic astrocytoma. a year old woman diagnosed with a localized hemispheric who anaplastic astrocytoma was treated with chemotherapy and radiation (temozolomide/ . gy) followed by cycles of bi-weekly bevacizumab/temozolomide. patient opted not to pursue fertility preservation prior to initiation treatment. she experienced bevacizumab-associated proteinuria and hypertension during treatment but received all protocol mandated doses (cumulative doses: bevacizumab = mg/kg; temozolomide = . gm/m ). she had a spontaneous unassisted pregnancy months after completing treatment. her pregnancy was uneventful and she was normotensive throughout. fetal ultrasonography at , , , weeks revealed no abnormality of the brain, heart, great vessels, kidney, extremities, placenta and umbilical cord. at weeks she delivered a female infant via cesarean section (birth weight: grams, apgars: and ) excessive post-partum hemorrhage was not reported. placenta was bi-lobed and weighed g. histological analysis revealed normal placental villous development and maturation and two small infarcts. conclusion: exposure to bevacizumab in our patient had no detrimental effect on fertility and on placental/fetal vascular development. we hope this report will add to the existing data on the effects of bevacizumab therapy on fertility. children's healthcare of atlanta, emory university school of medicine, atlanta, georgia, united states background: reports of malnutrition incidence and prevalence in young cancer patients are variable and not well established. previous research suggests children, especially less than years old, treated with intensive cancer-directed therapy are at higher risk for malnutrition. however, no standardized assessment has been used to evaluate risk in this population. objectives: we aim to assess the trends of weight-for-age for patients following cancer diagnosis. this study will be the first to use a standardized measure of treatment intensity (intensity treatment rating scale, itr- ) and will assist in targeting interventions for identification and treatment of malnutrition. design/method: this observational, retrospective study obtained data through the center's pediatric cancer registry and electronic medical record. patients were classified by tumor type (brain or non-brain tumor) and treatment intensity (itr- ). itr- incorporates diagnosis, chemotherapy, radiation, and surgery, beginning with lowest intensity ( ) to highest intensity ( ). inclusion criteria included new cancer diagnosis - at less than years old, with weight obtained and available within days of therapy start date. incomplete data, alternate growth charts, or treatment intensity of , were excluded. weight was obtained at start of therapy and through years after treatment initiation (approximately days) and converted to z-scores adjusted for age and sex. weight trajectories were modeled using generalized linear mixed models with subject-specific random intercepts and spline functions. separate functions were constructed for subgroups of interest (tumor type and itr). results: there were patients included: patients with brain tumors ( . %) and with non-brain tumors ( . %). of included patients, had treatment intensity of ( . %), of ( . %) and of ( . %). over the observation period, , valid weights were recorded. at initiation of treatment, no difference existed between z-score by tumor type (p = . ) or by intensity ( vs. , p = . ; vs. , p = . ; vs. , p = . ). tumor type did not affect z-score through the follow up period. z-scores were higher for intensity rating vs. and vs. (p = < . and p = . respectively) at days after the start of treatment and persisted through days (p = . and p< . respectively). higher treatment intensity is associated with decline in z-score and failure to return to baseline. future directions include further analysis on specific risk factors and timing of weight loss, longer-term follow-up of weight trends, and targeted interventions for identification, prevention, and treatment of malnutrition. objectives: asses the pt requirements for bleeding episodes in a prospective cohort of pcp using a < × e threshold compared to a < × e /l threshold in a historical cohort. we collected pt data in all pcps treated at our center between january/ through december/ . diagnosis, prescription for pt (prophylaxis vs bleeding disorder), plt count and transfused units were assessed for each pt. pcps treated from january/ through june received prophylactic pt with a < × e threshold (cohort a), and pts treated from july/ through december/ received prophylactic pt with a < × e threshold. pts done for procedures and pts with concomitant hemorrhagic pathology were excluded. we compared the number of pts prescribed as prophylaxis vs bleeding episode between cohorts. data analyzed: graphpad prims . ®. statistical analysis: percentages with confidence interval (ci); t-student test (parametric variables) and mann-whitney test (nonparametric variables). statistical significance: p< . . we reviewed pts ( in cohort a, cohort b) in patients. % had acute leukemia, % received and auto or allo hsct. diagnoses and the proportion of patients undergoing hsct was comparable in both cohorts. the average number of pts per patient was , in cohort a and , in cohort b (p = ns), but a significant difference was found when hsct patients were excluded from this comparison ( , pt per patient in cohort a vs , in cohort b, p = , ), which resulted in an estimated , % reduction in pts prescription. furthermore ( , %) pts were prescribed for bleeding episodes in cohort a versus ( , %) in cohort b (p = ns). patients receiving hsct in the entire group ver-sus those not receiving hsct had similar pt requirements for bleeding episodes ( % vs , % p = ns) conclusion: a < × e plt count threshold for prophylactic pts is safe in pcp in chemotherapy and hsct. it can result in a significant reduction in pt usage. key words: platelets, transfusions, prophylaxis, cancer, childhood. ucsf benioff children's hospital oakland, oakland, california, united states background: transition of care for adolescent and young adult (aya) survivors of childhood cancer from pediatric to adult-oriented long-term follow-up (ltfu) is complex. loss to follow-up is common, and little is known about the success rates among different models. the survivors of childhood cancer program (sccp) at ucsf benioff children's hospital oakland employs a community-based model for transitional care. our multidisciplinary team provides aya survivors a comprehensive treatment summary and recommendations, then facilitates transition to primary care or adult oncology ltfu programs. evaluate the success rate for transition of care among aya survivors of childhood cancer in our ltfu program, and identify barriers to successful transition. design/method: aya patients seen from november to august in the sccp with intent to transition were asked by email or telephone if they had followed up with their designated provider. the primary outcome was successful transition, defined as establishing care within months of their visit. patients were also asked about barriers to transition and to rate the new provider's familiarity with their cancer history and ltfu needs. results: transition was intended for patients. eightyseven were contacted and responded. of these, ( %) successfully transitioned, while ( %) were lost to followup. ages ranged from to years, at to years since completion of therapy. ten ( %) transitioned to a primary care provider, ( %) to an adult oncology ltfu program, and ( %) to a pediatrician. patients rated their new provider's knowledge above average ( . ) on a -point scale from poor ( ) to excellent ( ). survivors lost to follow up indicated the following barriers to transition: loss/change of insurance ( ), inability to find a provider ( ), too busy/forgot ( ), problems with transportation ( ), concerns about cost/copay ( ), and s of s other ( ). twelve patients requested further assistance with transition. conclusion: two-thirds of responding patients successfully transitioned. more work is needed to overcome various barriers to transition for one third of aya survivors. albany medical center, albany, new york, united states background: the transition from active treatment, to offtherapy follow-up, is a stressful event for parents of children with cancer. the psychosocial needs of parents after therapy have received limited attention in the united states with only published quantitative studies, the largest with parents. we have secured funding for and recruited a transition care coordinator (tcc) to investigate this further. objectives: our objective is to assess and screen parents at the end of their child's treatment, and to develop interventions to support parents during this time and thereafter. design/method: after informed consent, a standardized questionnaire, the psychosocial assessment tool (pat . ), was administered to parents at end of therapy (t ), months later (t ) and year later (t ). the tcc provided "universal" intervention to all families with an end of therapy binder containing a treatment summary, follow-up roadmaps, information on late effects, and survivor scholarships. based on their pat . scores, some parents were provided intervention specific to symptoms (targeted intervention for scores - . ) or referred to a behavioral health specialist through the clinic social worker for counseling (for scores > ). results: analysis of pat data showed that % of parents (n = ) scored in the targeted or clinical ranges; % of parents scored in those ranges at pat . significant gender differences were revealed with the mean score for men of . and for women of . . this was confirmed by showing statistical significance (p = . ) when analysis was conducted for only a subgroup of data composed of couples (n = ). analysis of pat data by couples (n = ) showed the mean score for men was . and for women was . (p = . ). gender differences were most apparent in caregiver stress reaction questions that focused on ptsd symptoms. when the subgroup of couples' scores (n = ) for caregiver stress reaction at pat was analyzed, there was a significant difference (p = . ) in caregiver stress reaction with a mean of . for men versus . for women. [note: subcategory scores range from to ]. this study was initiated in october using a tcc and the pat . screening tool. the results suggest greater stress on mothers after therapy, with a substantial proportion of parents having symptoms of ptsd after therapy. background: hodgkin lymphoma (hl) is a common childhood cancer characterized by an inflammatory microenvironment. chemotherapy and radiation may exacerbate this inflammation and contribute to the development of late effects (pneumonitis or pulmonary fibrosis). in a heterogeneous cohort of childhood cancer survivors exposed to pulmonarytoxic therapy, no association between pro-inflammatory cytokines and late pulmonary dysfunction was observed. our objective was to test this association in a relatively uniform cohort of survivors of hl, given the well-recognized proinflammatory background of this disease. objectives: to characterize off-therapy pulmonary function in survivors of hl treated with contemporary therapy, and to investigate its association with persistent systemic inflammation. design/method: blood samples, clinical data, and pulmonary function tests were obtained from survivors of hl ≥ months off therapy. lung function score (lfs), a validated method for assessing degree of pulmonary dysfunction on a scale of i to iv, was determined from diffusion capacity and forced expiratory volume in one second (fev ). for a control group, blood samples from patients with benign, noninflammatory hematologic conditions were used. plasma concentrations of inflammatory cytokines were measured on a luminex platform (emd millipore). associations between clinical features or cytokine levels and lfs i (normal) vs. ii-iv were evaluated using logistic regression or wilcoxon rank sum tests, respectively. results: of survivors (mean age at diagnosis: years, range: - ; mean time off therapy: . years, range: . - ), % were categorized as lfs ii (mild dysfunction), % as lfs iii (moderate dysfunction), and no survivors as lfs iv (severe dysfunction). higher lfs was associated with female sex (p = . ) but not other demographic, disease, or treatment factors. forty-eight survivors had blood samples collected at a mean age of . years (range: - ) with a mean time since treatment completion of . years (range: . - . ). of controls, the mean age at time of blood collection was years (range: - ). survivors did not have significantly elevated cytokine levels compared to controls. female survivors of hl ≥ months off therapy are at increased risk of pulmonary dysfunction. neither evidence for pulmonary dysfunction, as measured by lfs, nor duration of time off therapy were related to systemic inflammation in this study. pulmonary function deterioration and clinical pulmonary symptoms are rarely observed immediately following therapy but increase over time. future studies may consider exploring the contribution of systemic inflammation to pulmonary late effects in survivors farther off therapy, when risk for this late effect is greater. background: thyroid carcinoma is a very rare tumor in pediatrics, accounting for . - % of childhood carcinomas in the united states and europe. we aim to detect the risk of second malignancies among pediatric thyroid cancer survivors. the cohort analysis consisted of pediatric cancer patients aged less than years diagnosed with a primary thyroid cancer and identified by site code icd- - : c , reported to a seer database between and . they were followed up by death or the end of the study period (december , ) . out of patients diagnosed primarily with thyroid carcinoma, there were patients who had incidences of subsequent malignancies. the mean age of patients at initial diagnosis of thyroid cancer was years. females ( . %) had significantly higher incidence of second malignancies (sm) than males ( . %). the overall standardized incidence ratio (sir) of sm in thyroid pediatric patients was higher than expected (sir = . ). some specific sites showed significantly higher incidences: salivary gland (sir = . ), gum and other mouth (sir = . ) and kidney (sir = . ). the overall risk of sm in patients received radioactive iodine was higher than expected (sir = . ). the cumulative inci-dence of sms from the initial diagnosis of thyroid cancer was calculated with the survival methodology of competing risk, death treated as a competing event. cumulative incidence of sm was . % [ % ci ( . , . %)] at years and substantially expanded after years, reaching . % [ % ci ( . , . %)] at years. the cumulative incidence of each tumor type at years was . % [ % ci ( . , . %)] for breast cancer, . % [ % ci ( . , . %)] for salivary gland, . % [ % ci ( . , . %)] for each one of kidney and cervix uteri and . % [ % ci ( , . %)] for each one of ovary and melanoma of the skin. cumulative incidence of sm was stratified based on race, gender and radiotherapy exposure, but there was no statistical difference in each of them. conclusion: race, gender, histological subtypes, and radioactive iodine may play an important role as prognostic factors for developing sm among pediatric thyroid cancer survivors. identification of underlying mechanisms that raise the risk of sm is important for both treatment and follow-up strategy. background: the ethical practice of informed consent requires it be both voluntary and understood by the research participant. in pediatric oncology, parents must undergo informed consent to enroll their child with cancer into clinical trials, but often it can be difficult to understand especially for parents with low english proficiency. previous research has shown that parents of children with cancer have difficulty understanding voluntariness, and that parental satisfaction with informed consent does not always correlate with adequate comprehension. objectives: to examine socio-demographic and contextual correlates of comprehension of informed consent, voluntariness, and satisfaction in parents who consented to participation of their child in a cancer clinical trial. we focused on characterizing differences between non-hispanics and hispanics, the fastest growing ethnic group in the u.s. design/method: parents/guardians (n = ) of children aged - years with newly diagnosed cancer, who had consented to participation of their child in a clinical trial for cancer treatment at rady children's hospital-san diego were s of s prospectively recruited. parents completed questionnaires assessing comprehension, voluntariness, satisfaction, health literacy, socio-demographics, and acculturation level, if hispanic. comprehension was surveyed at baseline and longitudinally at months. comprehension, voluntariness and satisfaction outcomes were analyzed by socio-demographics, health literacy, and acculturation level using logistic regression. results: of the participants surveyed, ( . %) were hispanic and ( . %) were non-hispanic. we found that higher health literacy was associated with greater objective comprehension (p< . ), voluntariness (p< . ), socioeconomic status (p< . ), and acculturation (p< . ). hispanics reported lower objective comprehension (p = . ), voluntariness (p = . ), health literacy (p< . ) and ses (p = . ) compared to non-hispanics. spanish-speakers reported lower voluntariness (p = . ), health literacy (p< . ), and acculturation (p< . ) compared to englishspeakers. at the -month follow-up, comprehension in hispanics significantly improved (p = . ) compared to their baseline comprehension. satisfaction was moderately high across all subgroups and was not significantly impacted by socio-demographics, health literacy, or acculturation. in this study, with equivalent numbers of hispanic and non-hispanic participants, we found that hispanic and spanish-speaking parents of children with newly diagnosed cancer had inadequate informed consent comprehension, voluntariness and health literacy despite high satisfaction. our study suggests that hispanics and individuals with limited english proficiency are not making truly informed decisions for their child with cancer. to ensure the ethical practice of research in pediatric oncology, the informed consent and decision-making process must be improved with culturally and linguistically interventions for these underserved populations. memorial sloan kettering cancer center, new york, new york, united states background: pediatric oncology patients undergo repeated bone marrow aspirations and biopsies (bma/bx). these potentially painful procedures can exacerbate anxiety and distress. standard practice at memorial sloan kettering (msk) department of pediatrics is to use propofol, which has amnestic but no analgesic properties. we sought to evaluate whether the addition of local anesthetic would improve patient experience with bma/bx. the purpose of reppair: reducing procedural pain and improving recovery of quality of life (qol) (nct ) is to evaluate the efficacy of local anesthesia with ropivacaine in reducing procedural pain and improving post-procedure qol in pediatric neuroblastoma patients undergoing bma/bx with general anesthesia. reppair is a prospective, randomized, crossover clinical trial that opened for enrollment october . eligible patients were - years old with neuroblastoma. participants were observed on trial for two sequential bm procedures; one procedure with intervention a: propofol alone (pa), and the other with intervention b: propofol plus ropivacaine (p+r). participants were randomized to intervention sequence ab or ba and were blinded to the order of interventions. participants and recovery room (rr) nurses, who were also blinded, followed a standardized postprocedure pain management algorithm. the primary endpoint was percentage of participants requiring opioid analgesia in the hours post-procedure. secondary endpoints included total opioid in hours, non-opioid analgesia use, pain scores, time to first opioid, and short-term qol. qol was assessed by a parent-proxy metric that evaluated pain interference with sleep, physical, emotional, and social recovery. as of january , patients were assessed for eligibility and patients were randomized ( have completed both procedures). for the primary endpoint, a slightly higher proportion of participants required opioid for pa than p+r ( % versus %, p = . ). pain scores in the rr were significantly higher for pa than p+r (median [ th, th percentile]: [ , ] versus [ , ], p = . ). there were no statistically significant differences in total opioid or non-opioid analgesia, -and -hour pain scores, median time to first opioid, or pain interference scores. there were no adverse events. conclusion: preliminary findings of the reppair trial suggest that local anesthesia does not reduce the need for opioid analgesia or improve short-term qol in pediatric patients undergoing bma/bx with general anesthesia. local anesthesia did improve pain scores in the immediate recovery period. final results of this study will help establish evidence-based guidelines and optimize the experience of pediatric patients with bone marrow procedures at our center. background: children with advanced cancer experience a range of symptoms throughout treatment or at end of life, some of which are poorly controlled. minimizing suffering, including effective symptom management, in children with advanced cancer is a central value for pediatric oncology clinicians. patient-reported outcomes have been used in symptomrelated research in pediatric oncology patients; however the majority of literature specific to symptoms during palliative care and end of life for children and adolescents with advanced cancer is based primarily upon medical record reviews and to a lesser extent, patient self-report. the purpose of this study was to prospectively describe symptom frequency, severity, and level of distress in children/adolescents with advanced cancer using patient selfreport and parent proxy. design/method: a prospective cohort design was used for this study. five pediatric oncology institutions from across the united states participated. children and adolescents were eligible to participate if they were - years of age, englishspeaking, and had a diagnosis of advanced cancer, defined as a -week history of progressive, recurrent, or non-responsive disease or a decision not to pursue curative-focused therapy. a modified version of the memorial symptom assessment scale (msas) was used to measure symptom frequency, severity, and level of distress and was administered to child/parent dyads electronically via smartphones every two weeks. information regarding disease status and cancer treatment was collected concurrently. data was analyzed using descriptive statistics and univariate logistic regression analysis. results: a total of children and adolescents and parents participated in the study. the median age of child participants was years, with half being male. the median age of parents was years. the child participants had a variety of primary diagnosis, including: leukemia/lymphoma (n = , %), solid tumor (n = , %), and brain tumor (n = , %). the most frequently reported symptoms by children with advanced cancer and parents were pain (n = / , . %), lack of energy (n = / , . %), and nausea (n = / , . %). presence of disease (p = < . ), recent disease progression (p = . ), and receiving cancer therapy (p = . ) were significant factors on the presence of pain. high intensity cancer therapy was a significant factor on pain frequency (p = . ) and level of distress (p = . ). it is feasible to collect data prospectively in children with advanced cancer regarding symptom frequency, severity, and level distress. clinicians' increased understanding of the symptom experience may promote communication with children and adolescents and timely intervention. more research is needed to understand symptom clusters in children with advanced cancer. vanderbilt children's hospital, nashville, tennessee, united states background: febrile neutropenia (fn) is a frequent occurrence in children undergoing chemotherapy. though guidelines recommend adding a second antibiotic to broad-spectrum antipseudomonal coverage in specific scenarios, augmenting empiric therapy with a second antibiotic is common practice. additional empiric antibiotic (aea) use increases the risk of antibiotic toxicity and future antimicrobial resistance. data clarifying the indications for aea are limited in pediatric patients. objectives: to identify risk factors for gram-positive (gp) and gram-negative (gn) bacteremia in patients presenting with fn to determine situations in which aea use is warranted. design/method: a retrospective chart review was conducted of pediatric severe fn with absolute neutrophil count < / l occurring at a single institution between and . potential a priori risk factors based on clinical reasons for antibiotic expansion were chills, hypotension, mucositis, skin or soft tissue infections (sstis), recent administration of highdose cytarabine (hdac), and a diagnosis of acute myeloid leukemia (aml). potential factors for gn bacteremia were chills, hypotension, mucositis, and abdominal pain. the association between each potential risk factor and gp or gn s of s bacteremia was identified. logistic regression was used for multi-variable analysis. the review yielded episodes. gp bacteremia was isolated in cases ( . %) and gn bacteremia in episodes ( . %). in multivariable analysis, hypotension (or . ( % ci . , . ), p = . ) and sstis (or . ( . , . ) , p = . ) were independently associated with increased risk of gp bacteremia, while mucositis (p = . ), recent administration of hdac (p = . ) and chills (p = . ) were not. ten patients with aml didn't receive hdac, thus the association between aml and gp bacteremia could not be reliably estimated. hypotension (or . ( . , . ), p< . ) and chills (or . ( . , . ), p< . ) were independently associated with a higher risk of gn bacteremia, while mucositis (p = . ) and abdominal pain (p = . ) were not. of the gn infections, ( %) were resistant to cefepime, the empiric agent of choice at our institution. patients with fn with sstis, hypotension, or recent hdac had increased risk of gp bacteremia indicating potential benefit of empiric vancomycin in these settings, while mucositis and chills were not associated with gp bacteremia. hypotension and chills were associated with gn bacteremia, potentially warranting empiric antibiotic expansion, while mucositis and abdominal pain were not. identifying specific indications for aea use in pediatric severe fn use may improve antimicrobial utilization, decrease unnecessary antibiotic use, and improve patient outcomes. background: for children/young adults with incurable high grade gliomas (hggs), like diffuse intrinsic pontine glioma (dipg) or glioblastoma multiforme (gbm), oncologists endeavor to align therapy with patient/family goals of care, but may be influenced by providers' preferences or limited resources. ethical challenges can arise around the perceived purpose, risks and benefits of therapy options, provider conflicts of interest, access to care, deciding decisional priority between patients and families, and conflicts around end-oflife care. objectives: evaluate factors that play into longitudinal decision making for children and young adults with hggs, their families and oncologists using a qualitative approach with ethnographic elements. design/method: eligible patients were aged - with dipg, gbm, or secondary hgg. patient exclusions included: non-english speaking, in state custody, death prior to diagnosis, seen by oncology once, or an oncologist declined participation. key decision making visits (e.g. mri reviews) were serially audio-recorded, along with subsequent : semistructured interviews with patients and/or parents about the decision making process. field notes from clinician meetings, chart notes, and oncologist questionnaires were obtained. discussions and interviews were transcribed and independently coded by three investigators. inter-rater reliability was assessed during code book development. discrepancies were discussed until consensus met. constant comparison analysis with maxqda software continued until thematic saturation. results: twenty-two of eligible patients were approached; agreed to participate. one withdrew upon transferring care. mean age was . years (sd . ); % male, % caucasian, % african american, % hispanic, and % asian. four encounters, ( . hours), were recorded on average per patient. parent/patient interview themes included: ) hope (for a cure, prolonged life, and quality of life), ) importance of physician recommendations, ) importance of support systems (family, community, social media), ) food (as cancer etiology, intervention) ) finances (personal, research funding), ) communication (with medical providers, family, community), ) death, and ) god (beliefs, prayer, existential questions). oncologists desired prolonged quality of life, while patients/families transitioned to that hope from hope for a cure. decisions made in the setting of hggs are multi-factorial, ultimately reflecting the competing values of decision makers. optimism about treatment efficacy is held in tension with poor prognosis, allowing for functional hope. acknowledging patients' and families' shifting hopes allows for changes in goals of care and shared decision making. future work is needed to ) develop preference tools for pediatric patients and families to inform medical providers and ) provide training in communication and shared decision making with oncologists. emory university, atlanta, georgia, united states background: bone marrow transplantation (bmt) is a potentially curative but underutilized treatment for scd. our previous work has shown that there is variation in physician philosophy and practice in considering bmt as a treatment option for patients with scd, and physicians may not discuss this with patients and families as a potential treatment option. in a randomized clinical trial to test the effectiveness of a decision aid for disease modifying therapies for sickle cell disease, adult patients with scd as well as caregivers of adult/pediatric patients were interviewed about how they seek or have sought information related to scd, made decisions about treatments for scd, and identified a treatment option they were interested in learning more about using the decision aid tool. we performed a secondary analysis of these baseline data to understand patient information needs and attitudes regarding bmt as a treatment option for scd. the goals of this analyses was to understand patient and caregivers' attitudes and perceived information needs regarding bmt as a treatment option for scd. we performed an analysis of baseline interviews from caregivers of patients with scd or adult patients from a randomized control trial for a decision aid tool for scd. of the interviews belonged to caregivers of patients with scd. in addition to reviewing interviews for discussion of bmt, we interrogated for mention of terms such as 'bone marrow transplant' or 'cure' or 'stem cell transplant'. interviews were coded using nvivo and analyzed for emerging themes. results: of the baseline interviews, interviews met selection criteria. thirteen of the interviews were with caregivers of pediatric patients, and the remainder were with adult patients, including young adult patients with scd. the majority of participants want to learn about bmt or curative options. in many participants, this was expressed despite knowledge that they were not a likely candidate for transplant. desired information about bmt included eligibility, benefits, risks, long-term effects, quality of life and financial aspects related to bmt. of the patients who discussed how they learnt about bmt, approximately half mentioned that their healthcare provider had not previously mentioned this to them. we then examined knowledge of bmt and attitudes with demographic and clinical variables. patients and caregivers of pediatric patients with scd want to learn about bmt as a treatment option. healthcare providers should consider discussing bmt with their patients with scd. natasha frederick, anna revette, alexis michaud, jennifer mack, sharon bober dana-farber cancer institute, boston, massachusetts, united states background: adolescents and young adults (ayas) consistently identify the need for improved patient-clinician communication on sexual and reproductive health (srh) issues. however, oncology clinicians do not routinely integrate srh conversations with ayas through disease treatment and survivorship. little is known about why these conversations do not take place. objectives: explore aya perceptions of and receptiveness to srh communication with oncology clinicians and to identify barriers and facilitators to these conversations. design/method: semi-structured interviews were held with aya cancer patients and survivors (ages - years, men, women). twelve participants were on active treatment and were within years of treatment completion. interviews were conducted in english by phone or in person. the interview transcript underwent pre-testing with ayas. all interviews were audio-recorded and transcribed verbatim. transcripts were analyzed and summarized by two trained qualitative researchers according to standard comprehensive thematic qualitative analysis methods. analyses were aided by nvivo software. results: ayas perceived existing srh communication between ayas and oncology providers as inadequate. all ayas reported a need for improved srh communication with oncology providers, and three key areas of need emerged: ) general education; ) addressing specific srh issues experienced during treatment and survivorship; and ) understanding the long-term impact of cancer and treatment on srh. ayas felt that current srh discussions are limited and too narrow in scope and scale. ayas reported that most srh conversations focus exclusively on fertility (n = ), usually taking place at the start of treatment. other additional yet limited communication reported was about sexual activity (n = ), contraception (n = ), sexual function (n = ). no ayas reported conversations about potential treatment complications related to sexuality other than infertility. key barriers to srh conversations include patient discomfort initiating conversation (n = ) and presence of family members (n = ), with additional reported barriers including perceived provider discomfort (n = ), lack of rapport with provider (n = ), and age/gender differences (n = ). ayas felt that s of s communication tools such as handouts, brochures, and websites would be helpful facilitators to direct communication from the oncology clinician, and wanted conversations to start before treatment initiation and to continue through treatment and survivorship conclusion: ayas identify a key role for pediatric oncology providers in srh care from diagnosis through survivorship, however multiple barriers interfere with discussions about srh on a regular basis. identified barriers suggest that future efforts should focus on provider education and training in srh and srh-related communication in order to optimize care provided to this unique patient population. background: peripherally inserted central venous catheters (picc) provide secure vascular access in pediatric patients for the delivery of necessary therapies. the ease of placement in the inpatient and outpatient settings has expanded their utilization. however, recent data analyses show a significant increase in venous thromboembolism (vte) risk with the use of picc lines. with its rising use, modifiable risk factors need to be understood for preventative measures. objectives: in this study we aim to understand patient and catheter specific characteristics in relation to the development of vte. design/method: with irb approval, a retrospective interrogation of the electronic medical record and a picc database, at rainbow babies and children's hospital, was completed. the study cohort contained patients < years of age who had a picc line placed between january of and december of . data collected included indication for line placement, line dwell time, location of insertion including blood vessel and extremity, number of attempts at line placement, lumen size and indwelling line length. in addition, we collected number of days to vte formation, associated symptoms and location of vte. chi-squared analyses and fischer's exact test were used where appropriate for statistical analysis. we analyzed ( neonatal) newly placed picc lines. fifty line-associated vte events were found, for an incidence of . %. all vte occurred with the placement of the first picc line. intravenous therapies were the most common reason for line placement. no statistical significance was found between various indications for placement. the most common symptom of vte manifestation was extremity swelling, follow by extremity pain. right extremity picc was found to have a higher incidence of vte. larger catheter lumen sizes (> french) had a higher incidence of vte. we found a mean time of . days to vte detection. we were unable to find any clinical, patient or line specific factors leading to increased vte formation after statistical analysis. special consideration should be given to the duration of picc line use as this may reduce the incidence and comorbities associated with vte. there is still much to be understood about catheter associated vte formation as our analyses indicates the need for prospective data collection on a larger scale in hopes to create guidelines related to catheter use in pediatrics. background: the decision to transfuse a patient is a complex one and is never based solely on a number; however, certain hemoglobin or platelet count thresholds have been proposed in aiding physicians make transfusion decisions. in our hospital, the thresholds for packed red blood cell (prbc) and platelet transfusion in pediatric oncology patients are hemoglobin levels below . g/dl and platelet counts below , /mm (< , for brain tumors), respectively. recently, these thresholds have been questioned and we were asked whether we could safely lower the thresholds to < . g/dl of hemoglobin and < , /mm platelet count objectives: to investigate platelet and hemoglobin transfusion thresholds for oncology patients at children hospital of michigan design/method: retrospective chart review over a -month period, examining platelet and hemoglobin pretransfusion levels for each prbc and platelet transfusion given to oncology patients results: over the course of months, eligible oncology patients (median age years) received transfusions ( prbc transfusions and platelet transfusions). the mean pretransfusion hemoglobin level was . ± . g/dl (range . - . ) (n = ) for total prbc transfusions and this was not different among disease categories (p = . ). patients who had anemia symptoms and signs (n = ) had a slightly lower hemoglobin level compared to those who did not (n = ): . ± . vs . ± . g/dl (p = . ). the mean pretransfusion platelet count was , ± , /mm (range , - , ) for total platelet transfusions (n = ); , ± , /mm in patients with brain tumors (n = ); , ± , in patients with leukemia (n = ); and , ± , in patients with solid tumors (n = ). the mean pretransfusion platelet count was significantly higher in transfusions for brain tumors compared to that in the other disease groups (p< . for both). the mean pretransfusion platelet count was not different among those patients who had bleeding/bruising symptoms ( , ± , , n = ) versus those who did not ( , ± , , n = ) (p = . ). the bleeding/bruising rate was slightly but insignificantly higher in those who had platelet counts < , vs those who had ≥ , ( . % vs . %, p = . ). since most patients develop symptoms of anemia at hemoglobin above g/dl and about / of patients develop bleeding/bruising symptoms at platelet counts above , /mm , our current policy so far reflects a safe threshold for transfusion, and further lowering of the thresholds should be investigated in prospective studies. background: renal impairment is an important complication of childhood cancer and its treatment. serum creatinine level is frequently used as a screening test to monitor renal function; however, patients can have significantly decreased glomerular filtration rate (gfr) with normal serum creatinine. to determine the prevalence of chronic kidney disease (ckd) among children with cancer diagnosis, based on calculated gfr. to compare the difference between using serum creatinine value alone versus gfr in detecting ckd. design/method: retrospective review of medical records of patients, age - years, diagnosed between / - / with solid tumors were analyzed. serum creatinine and calculated gfr using schwartz formula were recorded. ckd as classified by the foundation of kidney disease and outcome quality initiative was used: ckd stage : gfr ( to ml/min per . m ) ckd stage : gfr ( to ml/min per . m ) statistical analysis using spss software v. . chi-squared test for proportions within group, and pearson chi-squared and fisher exact tests for statistical differences between groups. p-value < . was considered to indicate significance results: out of the records reviewed, ( %) were males and ( %) females, with mean age of . ± . years. ( . %) patients received one or more of nephrotoxic chemotherapy drugs; cisplatinum, carboplatinum, or ifosphamide mainly in the non-wilms solid tumors group ( . %) compared to ( . %) in the wilms tumor (wt) group. based on calculated gfr (by schwartz formula) ckd stage /or was diagnosed in ( %) patients with overwhelming majority ( %) were in the mild stage ckd, only ( . %) of those patients had abnormally high serum creatinine levels (p = . ). . % of patients who received nephrotoxic chemotherapy developed ckd, compared to . % in those who did not receive it, (p = . ). despite that only / ( %) of wt group patients received nephrotoxic chemotherapy, yet this group had higher percentage of ckd ( . %) compared to non-wt group ( . %) p = . . significantly lower mean gfr . ± was noticed in the wt group compared to . ± in non-wt group (p = . ) conclusion: high prevalence of mild ckd was found among solid tumor patients. using serum creatinine alone as measure of renal function significantly under estimates renal impairment in those patients. early identification of ckd is easily achieved by using calculated gfr, which can helps providers and care givers to avoid potential nephrotoxic antibiotics, contrast media, nsaids and dehydration that may further deteriorate renal function the university of texas southwestern medical center, dallas, texas, united states background: children with down syndrome (ds) have increased risk of developing leukemia. pediatric patients with ds-associated acute lymphoblastic leukemia (ds-all) are known to have significant toxicities with reinduction chemotherapy and historically poor outcomes with stem cell transplant (sct). anti-cd chimeric antigen receptor (car) t-cell therapy, tisagenlecleucel, demonstrated high rates of durable complete remission (cr) and a manageable safety profile in children with r/r b-cell acute lymphoblastic leukemia (b-all). objectives: characterize the efficacy and safety of tisagenlecleucel in pediatric/young adults with ds-all. design/method: pooled data from single-arm, multicenter, phase trials of tisagenlecleucel in pediatric/young-adult patients with r/r b-all (eliana, nct ; ensign, nct ) were analyzed. eight patients with ds-all were enrolled (data cutoff: eliana, november ; ensign, february ). seven were infused with tisagenlecleucel; patient died from all progression and intracranial hemorrhage before infusion. no manufacturing issues occurred during production. / infused patients were male, / had prior sct (age range, - years). / patients achieved cr or cr with incomplete blood count recovery (cri) by day (d) (cr+cri, %); died before d and was not evaluable. analysis of minimal residual disease was negative in bone marrow in responding patients. two patients had cd negative relapses at and months. ongoing remissions in patients without relapse ranged from to months. the safety profile (n = ) appears similar to that in patients without ds in the same trials (n = ). grade (g) / cytokine release syndrome occurred in % ( / ) of patients with ds and in % without ds. rates of other g / adverse events of special interest did not appear to favor a consistent trend between patients with/without ds (febrile neutropenia: % vs %; neurological events: % vs %; tumor lysis syndrome: % vs %). g / infections were not observed in patients with ds ( % vs %). one patient died after infusion due to intracranial parenchymal hemorrhage on d associated with ongoing coagulopathy. time and extent of tisagenlecleucel expansion and long-term persistence were similar between groups. conclusion: this is the first analysis of car t-cell therapy in pediatric patients with r/r b-all and ds. these data suggest that toxicities appear similar to those in patients with b-all without ds, remission rates in ds-all are high, and longterm outcomes with sustained persistence appear promising. further exploration of tisagenlecleucel as an alternative to sct in children with r/r ds-all is warranted. sponsored by novartis. background: hispanic adolescence and young adults are twice as likely to develop acute lymphoblastic leukemia (all) with high risk features as non-hispanic whites. they also have poor prognosis and % higher death rate. b-all with crlf overexpression caused by genetic alteration of the cytokine receptor, crlf is five times more common in this subgroup. approximately % of crlf b-all cases also have ikzf genetic alterations. ikaros is involved in transcriptional regulation of several important genes involved in leukemogenesis. overexpressed casein kinase ii (ck ) impairs functions of ikaros. objectives: understand the molecular mechanisms that regulate crlf expression in crlf b-all. here we present evidence that ikaros-mediated repression of crlf transcription in b-all in hispanic children is regulated by ck . design/method: primary b-all patient samples from hispanic children were used. ikaros retroviral transduction, ikaros shrna transfection, real time-pcr, luciferace assay, quantitative chromatin immunoprecipitation (qchip) coupled with the next-generation sequencing (chip-seq), cytotoxicity assay and western blot. results: ikaros binding to promoter of crlf was confirmed using quantitative chip. functional experiments such as overexpression of ikaros in b-all primary cells results in transcriptional repression of crlf whereas ikaros silencing using shrna resulted in increased transcription. these results suggest that ikaros negatively regulates crlf expression. molecular inhibition of ck with shrna targeting the ck catalytic subunit, as well as pharmacological targeting of ck with cx resulted in transcriptional repression of crlf . ck inhibition was associated with increased ikaros dnabinding to the promoter of crlf . however, the ability of cx to repress crlf is lost or severely reduced, in cells with shrna silencing of ikaros, as compared to cells with intact ikaros. moreover, similar results were noted following treatment with cx in leukemia cells obtained from high risk b-all patients with deletion of one ikzf allele. ikaros binds poorly to promoters of crlf gene in these cells. treatment with cx restores ikaros dnabinding to the promoters of crlf , which is associated with its strong repression. serial qchip analysis of the epigenetic signature at the crlf promoter showed that increased ikaros binding to the crlf promoter, following ck inhibition, is associated with enrichment for the h k me histone modification, which is a marker of repressive chromatin. results demonstrate that crlf expression is epigenetically regulated by the ck -ikaros axis .cx show antileukemic effect via restoration of ikaros tumor suppressor function, resulting in crlf repression suggesting advantage of using ck inhibitors as potential therapeutic approach in crlf altered b-all. results: hypodiploid all (modal chromosome number < and/or di < . ) was identified in patients ( . % of all patients; . % of nci standard risk (sr) and . % of nci high risk (hr)), who were removed from frontline protocol therapy post-induction. overall -year efs and os were . %± . % and . %± . %. transplant status was retrospectively available for / ( %), of whom underwent hsct in cr . five-year efs with hsct was . %± . % vs. . %± . % without (p = . ). -year os with and without hsct was . %± . % vs. . %± . % (p = . ). when corrected for the median time to hsct ( days), there were no significant differences in -year efs or os rates with and without hsct: . %± . % and . %± . % vs. . %± . % and . %± . %. no nci risk group or mrd subset benefitted significantly from cr hsct. sr patients (n = ) had -year efs and os of . ± . % and . %± . % with hsct (n = ) vs. . %± . % and . %± . % without. hr patients (n = ) had -year efs and os of . %± . % and . %± . % with hsct (n = ) vs. . %± . % and . %± . % without. for those with end-induction mrd < . % (n = ), -year efs and os were . %± . % and . %± . % with hsct (n = ) vs. . %± . % and . %± . % without. end-induction mrd-positive patients (n = ) fared poorly with both year efs and os of . %± . % with hsct (n = ) vs. . %± . % and . %± . % without. multivariate regression analysis including nci risk group, mrd, and cr hsct, showed only mrd negativity was significantly associated with efs (hr . , p< . ) and os (hr . , p< . ). patients with hypodiploid all fare poorly, particularly those with end-induction mrd ≥ . %. while cr hsct is a standard treatment approach, it does not confer significant benefit. we were unable to assess bridging therapy prior to hsct, and comparator groups are small. taken together, however, new strategies are urgently needed for these patients. background: ras-pathway mutations are known to play a pivotal role in a significant proportion of myeloid malignancies, including upwards of % of pediatric aml cases. ras-pathway mutations in myeloid malignancy commonly co-occur with mutations of epigenetic regulators, suggesting cooperative leukemogenesis. among the epigenetic modifiers most frequently mutated in myeloid malignancy are regulators of dna methylation. this indicates that the alteration of dna methylation contributes to leukemogenesis. the ten-eleven translocation (tet ) is an epigenetic regulator that plays an important role in regulation of dna methylation through its action of hydroxylation of -methylcytosine, which ultimately leads to passive de-methylation of dna cytosines. in myeloid malignancy, loss of function tet mutation is one of the most frequently co-occurring lesions in ras mutated malignancy. how specifically the altered methylation patterns in ras-pathway driven diseases promotes leukemogenesis is unclear. objectives: we hypothesize in mice with a ras-pathway mutation, that when an epigenetic modifier co-occurs, such as loss of function of tet , this primes stem cells and/or early differentiating progenitors for transformation by preventing the repression of stem cell self-renewal genes, inhibiting differentiation, enhancing ras signaling and leading to leukemogenesis. we have generated a novel murine model with constitutive deletion of tet (tet -/-) combined with an inducible activating krasg d mutation (krasg d/wt). mice have been tracked for evidence of hematologic malignancies and compared to mice with corresponding single genetic lesions. cooperative leukemogenesis will be demonstrated by decreased latency to disease onset, impact on malignancy lineage, in addition to investigating mechanistically through which pathways leukemogenesis may be promoted. results: krasg d/wt/ tet -/-mice demonstrate statistically significant differences in peripheral white blood cell count, hemoglobin, and platelet levels as early as -weeks post ras-pathway activation. peripheral cell lineage analysis demonstrates early skewing toward myeloid differentiation and marked splenomegaly in mice harboring both genetic lesions compared to wild type or mice with single genetic lesions. phospho-flow cytometric analysis reveals increased perk and ps activation in krasg d/wt/ tet -/-sca- enriched bone marrow cells compared to either genetic lesion alone. our study utilizing a murine model to examine how in ras-pathway mutations the addition of a co-occurring epigenetic lesion demonstrates that these lesions appear to cooperate to promote early myeloid differentiation with attendant changes in signaling pathways. this exploration to elucidate the mechanics of ras-pathway mediated disease lay the foundation for identification of patients who may benefit from existing therapies, such as dmtis, or identify new signaling targets for therapeutic exploration. background: the humoral immunogenicity of car , a chimeric antigen receptor (car) with a murine scfv domain developed for treatment with tisagenlecleucel in relapsed/refractory (r/r) pediatric/young-adult acute lymphoblastic leukemia (all), was evaluated in studies. little is known about the presence/impact of preexisting/treatmentinduced anti-murine car (mcar ) antibodies in patients treated with car therapy. objectives: patients from eliana (nct ; n = ) and ensign (nct ; n = ) were evaluated before and after tisagenlecleucel infusion to determine the impact of anti-mcar antibodies on cellular kinetics, efficacy, and safety. design/method: anti-mcar antibodies were determined by flow cytometry and reported as median fluorescence intensity. assay validation included evaluation of the interferences of intravenous immunoglobulin (ivig) treatment with the anti-mcar antibody assay. impact of preexisting and treatment-induced immunogenicity on cellular kinetics, efficacy, and safety was determined. treatment-induced immunogenicity was defined by a positive increase in anti-mcar antibody levels over baseline and was assessed by calculating the fold-change between preexisting (ie, baseline) and postinfusion levels. results: % of patients displayed preexisting anti-mcar antibodies; a similar incidence was detected in healthy volunteer samples during method validation. % of patients developed treatment-induced anti-mcar antibodies. no relationship was identified between tisagenlecleucel expansion (auc - d) and preexisting/treatment-induced anti-mcar antibodies (r < . and r = . , respectively); similar results were seen for cmax. presence of treatment-induced anti-mcar antibodies did not appear to impact transgene persistence or response. kaplan-meier estimates showed that preexisting/treatment-induced anti-mcar antibodies did not appear to impact duration of response or event-free survival. strip plots showed consistent levels of preexisting/treatment-induced anti-mcar antibodies across patients with safety events, including cytokine release syndrome, neutropenia, thrombocytopenia, and neurological events. there was no apparent relationship between treatment-induced anti-mcar antibodies and b-cell recovery categories (≤ months, > and ≤ months, > months, and ongoing sustained aplasia). no association existed between time of b-cell recovery and presence of treatment-induced anti-mcar antibodies. b-cell aplasia requiring ivig occurred following tisagenlecleucel in the majority of patients. the tisagenlecleucel concentration-time profiles in patients with treatment-induced anti-mcar antibodies were categorized by time following ivig administration. time of ivig administration had no impact on in vivo transgene expansion and persistence. we report the first comprehensive assessment of the impact of anti-mcar antibodies on clinical endpoints with car therapy. pediatric/young-adult patients with r/r all had a high frequency of baseline anti-mcar antibodies, and preexisting/treatment-induced anti-mcar antibodies did not impact the cellular kinetics, safety, and efficacy of tisagenlecleucel. cell-mediated immunity studies are ongoing. sponsored by novartis. background: adoptive immunotherapy, using cd engager (cd -eng) t-cells, has shown success in preclinical studies, recognizing and killing acute myeloid leukemia (aml) blasts in vitro and in vivo. cd -eng t-cells secrete bispecific molecules that recognize cd (t-cells) and cd (aml blasts), and are able to direct transduced t-cells and recruit bystander t-cells to kill cd -positive blasts. however, cd -engs do not provide costimulation and have not shown the capability for sequential killing of targets in vitro. we are seeking to improve the expansion, persistence and sequential killing capabilities of cd -engs by genetically modifying these cells with an inducible costimulatory molecule, which can be activated by a chemical inducer of dimerization (cid). we generated a retroviral vector encoding cd -eng and the inducible costimulatory molecule myd .cd linked by a a sequence (cd -eng. a.imc). cd -eng and cd -eng.imc t-cells were generated by retroviral transduction, and their effector function was compared with and without cid. we used flow cytometric analysis to assess transduction efficiency, chromium release assays to evaluate cytolytic activity, and elisa to determine cytokine production. we successfully generated cd -eng.imc tcells and achieved a mean initial transduction efficiency of % that was maintained above % throughout our study period. cd -eng.imc t-cells +/-cid and cd -eng t-cells readily killed cd -positive aml blasts (molm and kg a) in cytotoxicity assays when compared to the cd -negative control (k ). in co-culture assays, cd -eng.imc t-cells secreted increased il- and ifn-gamma in the presence of cid and cd -positive targets (kg a and molm ) when compared to co-culture with cd -positive targets in the absence of cid. in addition, cd -eng.imc t-cells displayed enhanced sequential killing capabilities and ifn-gamma secretion when stimulated weekly with cid and tumor cells at a : ratio when compared to cd -eng t-cells. conclusion: cd -eng.imc t-cells are able to recognize and kill cd -positive aml blasts in an antigen dependent manner. cd -eng.imc t-cells have improved effector function in the presence of cid as judged by cytokine production and their ability to sequentially kill cd -positive target cells. thus, inducible myd and cd costimulation is a promising strategy to improve the effector function of cd -eng t-cells, and warrants further active exploration in preclinical studies. background: eliana (nct ; n = ) is a pivotal multicenter study testing the efficacy of tisagenlecleucel, anti-cd car-t, in children/young adults with r/r b-all. tocilizumab (toci) has been used for management of moderate/severe (grade / ) crs in ≈ % of patients treated with tisagenlecleucel at equivalent doses used in approved nononcological pediatric indications (< kg received mg/kg; ≥ kg received mg/kg [ mg max dose]).( ) crs onset, as graded by the penn grading scale, generally occurred at a median of days (range, - ) after infusion, requiring administration of - toci doses in some patients via a protocol-specific treatment algorithm. toci is a humanized monoclonal antibody that inhibits il- receptor (il- r) signaling. the pharmacokinetics (pk) and pharmacodynamics (pd) of toci in pediatric patients with b-all with carassociated crs have not previously been described. objectives: characterize toci pk/pd for crs management following tisagenlecleucel infusion and describe its impact on cellular kinetics. design/method: toci pk and levels of soluble il- r (sil- r) were determined from serum and quantified using validated assays. maximum toci concentration (cmax) was derived using noncompartmental methods. sil- r, proinflammatory cytokines, and crs resolution time were characterized to describe toci pd. summary statistics and graphical analyses of tisagenlecleucel exposure by number of doses were performed to describe the impact of toci on tisagenlecleucel kinetics in patients responding to tisagenlecleucel infusion. : / patients with crs received the first toci dose at a median of days (range, - ) after crs onset. seventeen patients received dose (range, . - mg/kg); received doses ( - mg/kg); received doses ( - mg/kg), per the crs treatment algorithm. first-dose mean cmax (sd) was ≈ ( . ) g/ml; second dose, ≈ ( ) g/ml. individual patient pd concentration-time profiles showed increased sil- r levels after the first toci dose which remained elevated following the second dose. following toci administration, median time to crs resolution (including fever resolution) was days (range, - ). crs onset coincided with tisagenlecleucel expansion, followed by a peak in serum cytokines, including il- . the geometric mean auc - day and cmax of tisagenlecleucel transgene (by pcr) were % and % higher in tisagenlecleucel-responding toci-treated patients. conclusion: crs symptoms resolved within a median of days after toci administration. toci levels achieved in patients with b-all were similar to reported pediatric nononcological indications (tocilizumab label) and resulted in concentration/time-dependent sil- r increases. transgene continued to expand and persist following toci administration. these data support treatment with toci for crs management. ( ) buechner, eha, . sponsored by novartis. background: in acute myeloid leukemia (aml), mesenchymal stem and stromal cells (mscs) in the bone marrow microenvironment contribute to extrinsically mediated chemo-resistance and are therefore important potential therapeutic targets. the study of patient-derived mscs is at a competitive disadvantage, however, because traditional means of isolating mscs from a bone marrow aspirate interferes with isolating the more highly prioritized leukemic cells. many opportunities to study mscs are therefore missed. objectives: to develop a novel method of isolating mscs using the otherwise discarded portion of a bone marrow aspirate, thereby de-coupling the isolation of primary mscs from the isolation of leukemia cells. design/method: aml patient bone marrow aspirates were obtained prospectively from the children's oncology group. healthy patient marrow was purchased. experimental mscs were isolated from the bottom-most layer (rbc-layer) produced by density-gradient separation of a bone marrow aspirate, which is typically discarded. control mscs were isolated from the buffy coat (mnc layer). non-adherent cells were removed after hours, and adherent cells were cultured at % co with mem-alpha containing % fbs. growth curves were obtained by seeding -well plates with , cells per well. cells were stained using oil red o to observe adipocyte differentiation. results: rbc-layer mscs grow successfully following overnight shipment of the aspirate. identical to mnc-layer mscs, rbc-layer mscs exhibit a fibroblastic morphology and are adherent to plastic. rbc-layer mscs persist in culture up to passages before senescence. they exhibit a slower growth curve relative to mnc-layer mscs, but their overall doubling time is similar at approximately hours. surprisingly, mscs from the rbc-layer exhibit adipocyte differentiation on stimulation, revealing their stem-cell like qualities. we present a method of isolating mscs from the discarded portion of a bone marrow aspirate that does not interfere with the isolation of leukemia cells from the same patient. this portion of the aspirate can be shipped, or can sit for at least hours, without sacrificing its mscs. rbclayer mscs are nearly identical to mscs obtained conventionally. perhaps most importantly, rbc-layer mscs retain a stem-cell like capacity, showing them to be a highly valuable cell population in aml research. future plans include investigating potential selective enrichment of stem-cell mscs in the rbc-layer, which could explain the unexpected difference in growth kinetics. aml researchers now have the opportunity to study this exciting component of the bone marrow microenvironment without sacrificing valuable leukemic cells in the process. background: neutropenia is one of the most frequent side effect of chemotherapy associated with an increase in the risk of infection, especially in the cases when the depth and duration of neutropenia are extended. some genes, as variations of darc, gsdma and cxcl are known to influence white blood cell and neutrophil counts. our previous study conducted in children with acute lymphoblastic leukemia (all), showed that polymorphisms in these genes might play a role in the onset of chemotherapy complications during consolidation and maintenance treatment. objectives: in order to support our previous finding, we have expanded the study to the induction period in a cohort of all children treated at the sainte-justine university health center between july and july . design/method: previous associated single nucleotide polymorphisms (snps) in darc, gsdma and cxcl genes were analyzed for an association with the complications occurring during induction including the duration of low neutrophil count (pnn) and low absolute phagocyte count (apc), proven infections and delay between induction and consolidation phases. results: significant effect was found for all studied polymorphims. minor alleles of darc rs , cxcl rs and gsdma rs were all associated with higher risk of complications during induction treatment, whereas that of darc rs (particularly gg genotype) had a protective effect. the gg genotype of rs was associated with a lower risk of post-induction delay (p = . or = . , %ci . - . ), less frequent febrile episodes (p = . ) and lower number of days with apc/pnn count reduction (p = . for apc< . and p = . for pnn< . ). in contrast, the minor t allele of another darc polymorphism (rs ), was associated with longer apc/pnn count reduction (p = . for apc< . and p = . for pnn < . ), as it was the tt genotype of gsdma rs (p = . for apc< . and p = . for pnn< . ). the patients with the gsdma rs had also a higher risk of documented febrile episodes (p = . or = . %ci - . ). the aa genotype of rs cxcl was associated with a higher risk of post-induction delay due to infection (p = . , or = . , % ci . - . ). conclusion: this complementary study confirmed our previous results, showing overall that variations in darc, gsdma and cxcl genes influence the onset of chemotherapy complications in pediatric all, regardless of treatment phases. these polymorphisms might be useful pharmacogenetics markers possibly guiding an adjustment of chemotherapy intensity. background: pediatric acute myeloid leukemia (aml) has a poor survival rate of about % and there is an urgent need for newer targeted therapies. car t-cell based therapies are effective against all but similar therapies against aml are still under development. recent clinical trials have highlighted the concerns about toxicity and therapy related deaths from car t-cells. antigen selection is the key factor determining the specificity, efficacy and toxicity of car t-cells. while contemporary adoptive t-cell therapies use monoclonal antibodies against tumor associated antigens we employed the naturally occurring flt ligand (fl) to target aml cells expressing flt receptors. flt receptor is expressed on multipotent and myelomonocytic progenitors as well as myeloid leukemia cells. to generate fl containing chimeric tlymphocytes designated flcar t-cells and to evaluate their efficacy against aml cells. design/method: flcar was constructed by fusing the coding sequences of the human fl, cd costimulatory domain, and cd -zeta chain (intracellular region) in series. it was then cloned into the phiv-egfp lentiviral vector for expression in cell lines and primary t cells obtained from healthy donors. the empty phiv-egfp vector was used as a negative control. flcar was expressed on both cd + and cd + t-lymphocytes, confirmed by western blot. cell cytoxicity was evaluated by co-culturing flcar t-cells and aml cells followed by flow cytometric analyses. cytokine production was assessed by analyzing expression of interleukin- using quantitative rt-pcr. results: flcar t-cells were generated from cd + jurkat and cd + tk- cell lines with up to % lentiviral transduction efficiency. the efficiency for primary t cells was lower ( - %). flcar was expressed as a ∼ kda protein in cells and was partially phosphorylated on tyrosine. the expression of flcar on lymphocytes lead to increased basal il- expression in the cells. this was further augmented (by > folds) upon co-incubating flcar t-cells with flt expressing target cells. jurkat cells, tk- cells and primary human t cells expressing flcar suppressed the growth of flt -expressing aml cell lines and primary aml cells in vitro. notably, flcar t-cells generated from healthy donors caused strong inhibition of aml cells even at a lower transduction efficiency. in vivo experiments using nsg-sgm mice xenografted with human aml cells are underway. our data demonstrate that flcar can be effectively expressed on t-lymphocytes and mediate potent cytotoxicity against flt -expressing aml cells in vitro. being a completely human derived chimeric protein, it represents a promising candidate for further therapeutic development. holly pacenta, kelly sullivan, ahwan pandey, kelly maloney, joaquin espinosa children's hospital colorado, denver, colorado, united states background: individuals with down syndrome (ds) have a -fold higher risk of developing acute lymphoblastic leukemia (all) than the typical population. there are several important differences between all in individuals with ds (ds-all) and all in individuals without ds (nds-all): first, patients with ds-all have a lower percentage of favorable cytogenetic features compared to nds-all. second, patients with ds-all are more likely to have activating mutations in jak , crlf overexpression, and ikzf deletions. despite these clear genotypic differences, this knowledge has not yet been exploited for therapeutic purposes in ds-all. when outcomes for ds-all are compared to nds-all with similar cytogenetic features, the survival rates are similar. however, individuals with ds-all have an increased risk of treatment-related mortality (trm). current therapy for ds-all is similar to that for nds-all, with the exception of small changes to decrease toxicities that are more prevalent in ds-all. it was recently identified that interferon signaling is constitutively activated in healthy individuals with t . we hypothesize that aberrant interferon signaling could play a role in the unique leukemias observed in ds patients. objectives: to identify differences in gene expression and intracellular signaling cascades that are unique to individuals with ds-all, relative to both nds-all and healthy individuals with ds that can be exploited for therapeutic use. design/method: bone marrow samples were obtained from ds-all patients and matched nds-all patients based on clinical characteristics and genetic features. rna sequencing of these samples was performed and a total of samples were used for the transcriptome analysis ( ds-all vs. nds-all). the differential expression data was generated by deseq and analyzed using ingenuity pathway analysis. the analysis revealed that the chromosome genes that have been implicated in leukemogenesis are not differentially expressed in the ds-all samples, relative to nds-all. an inflammatory signature was identified, which included interferon gamma as an upstream regulator with predicted activation in ds-all. this finding is consistent with prior observations from healthy individuals with ds. other examples of results with potentially actionable targets include the upregulation of several genes in the ras pathway and genes involved in histone methylation. the increased interferon signaling seen in healthy individuals with ds was also identified in ds-all. this may contribute to the development of mutations in inflammatory pathways such as jak and crlf in ds-all. targeting these common pathways with small molecule inhibitors may have a therapeutic benefit in ds-all. cincinnati children's hospital medical center, cincinnati, ohio, united states background: next-generation sequencing (ngs) guides precision medicine approaches in oncology using therapies targeting molecular alterations found within an individual cancer. increased availability of ngs coupled with a proliferation of targeted drugs in development heightens the need for reliable pre-clinical animal models. here we report a patientderived xenograft (pdx) system with integrated molecular profiling for pre-clinical testing of conventional cytotoxic and novel targeted agents. objectives: to utilize ngs from patients with pediatric leukemia to guide rational pre-clinical trials in pdx leukemia avatars, and to determine pdx mice tolerance of and response to cytotoxic and targeted therapies. pediatric acute lymphoblastic leukemia (all) samples were obtained in adherence to an irb-approved protocol and xenografted into nod/rag/interleukin- (il- )rg (nrg) mice. ngs was performed clinically using the foundationone® heme panel. a de novo all sample bearing mutations involving jak , crlf , ntrk , cdkn a/b, ptpn and wt was used for pre-clinical testing. thirty-seven nrg mice were transplanted with million patient cells/mouse via iv injection. standard -drug induction chemotherapy was administered consisting of vincristine, dexamethasone, pegaspargase, and daunorubicin [vxpd, n = mice], in comparison to vehicle control [n = ]. parallel pdx cohorts were treated with single agent targeted therapies based on ngs findings, including ruxolitinib [n = ], crizotinib [n = ] and loxo- [n = ]. the four-week treatment period began on day + from transplant after confirmation of engraftment. following completion of therapy, residual disease burden was analyzed by flow cytometry (hcd +, mcd -cells) in the bone marrow [bm] . to date, pdx models have been established using over thirty ngs-profiled pediatric all samples, including six samples bearing philadelphia (ph) chromosome or phlike mutations. pre-clinical testing was performed in a repre- conclusion: ngs reveals concomitant mutations in ph-like all that may represent additional targets for therapy, or predict tyrosine kinase inhibitor (tki) resistance. we show that all xenograft nrg mice can tolerate a -week multi-agent cytotoxic chemotherapy induction regimen, as well as rational targeted agents, and serve as a robust pre-clinical model for precision medicine trials. background: osteonecrosis is a well-characterized all therapeutic toxicity attributed to glucocorticoids, asparaginase, and methotrexate that disproportionately affects adolescents. in ccg- , alternate-week dexamethasone during double delayed intensification (di) reduced osteonecrosis vs continuous dexamethasone with single di in rapid early responders (rer) ≥ y. to compare efs and os between hr-all patients with vs without osteonecrosis. design/method: hr-all patients - y on aall ( - ) received cog augmented therapy with a × randomization to: ( ) induction dexamethasone ( mg/m d - ) vs prednisone ( mg/m d - ), and ( ) interim maintenance (im) high-dose methotrexate (hdm) vs escalating-dose methotrexate/pegaspargase (ema). rer received single, and slow early responders (ser) double, im/di. initially, all received monthly dexamethasone maintenance pulses, patients ≥ y received di alternate-week dexamethasone, and patients ≤ y received di continuous s of s dexamethasone. there were osteonecrosis-related amendments: after / all patients ≥ y received di alternateweek dexamethasone; after / all patients ≥ y were assigned to induction prednisone, and all patients received di alternate-week dexamethasone and maintenance prednisone pulses. results: osteonecrosis was confirmed in / patients. the y cumulative incidence (ci) was . % overall and increased with age: - y . %, - y . % (alternateweek dexamethasone . % vs continuous dexamethasone . %; p< . ), ≥ y . % (p< . ). among randomized rer patients ≥ y, ci differed by glucocorticoid (dexamethasone . % vs prednisone . %; p = . ) but not methotrexate assignment (hdm . % vs ema . %; p = . ). among randomized ser patients ≥ y, ci was . % with no difference by regimen. results were similar for patients ≥ y. in the entire study population, patients with osteonecrosis had superior y efs ( . % vs . %; p< . ) and os ( . % vs . %; p< . ) than those without osteonecrosis. y efs was significantly higher among randomized patients ≥ y with vs without osteonecrosis ( . % vs . %; p< . ); this finding was present in different age ranges (≥ y, ≥ y, ≥ y) and rer/ser subsets within each, especially in the ≥ y rer ( . % vs . %; p = . ) and ser ( . % vs . %; p< . ) cohorts. across groups, asparaginase allergy was significantly associated with reduced osteonecrosis risk (≥ y: hr . ; p = . ). patients who develop osteonecrosis have significantly increased efs and os, suggesting host differences that increase sensitivity to develop osteonecrosis and render all cells more chemo-responsive. pennsylvania state university, hershey, pennsylvania, united states background: cdc (cell division cycle protein ) belongs to rho family of small gtpases in ras-oncogene superfamily. pro-oncogenic role of overexpressed cdc in ras driven solid tumors are well known. however, role of cdc in leukemia is yet to be established. ikzf encodes ikaros protein which has important role in regulation of lymphoid development and tumor suppression in leukemia. casein kinase ii (ck ) oncogene is overexpressed in leukemia. ck impairs ikaros function which can be restored by using ck inhibitors. objectives: to investigate role of cdc in leukemia and regulation of cdc by ikaros and ck in b-cell acute lymphoblastic leukemia (b-all). shrna transfection, real time-pcr, luciferace assay, quantitative chromatin immunoprecipitation (qchip) coupled with the next-generation sequencing (chip-seq), cytotoxicity assay and western blot. results: cdc is identified as one of the ikaros target genes by analysis of genome-wide dna binding of ikaros using chip-seq and qchip in b-all primary cells. expression of cdc was also noted to be higher in all patient samples compared to normal bone marrow. functional experiments showed that ikaros overexpression via retroviral transduction results in transcriptional repression of cdc . ikaros silencing using shrna resulted in increased expression of cdc . these data suggest that ikaros negatively regulates transcription and expression of cdc . ck directly phosphorylates ikaros and impairs its function as transcription factor. we noted that molecular inhibition of ck via sirna as well as treatment with specific ck inhibitor, cx also decreases expression of cdc . treatment with cx of primary b-all with ikaros haploinsufficiency restores ikaros binding to cdc promoter and represses cdc expression. however, this effect is evident only in presence of ikaros. treatment with cx in ikaros silenced (ikaros shrna) cells showed no change in expression of cdc . these results emphasizes the importance of ikaros in regulating cdc expression. furthermore, we analyzed the changes in epigenetic signature at the cdc promoter following treatment with cx . results show that loss of histone marker of open chromatin (h k ac) and increased histone marker for repressive chromatin (h k me ), at the cdc promoter. these data suggest that ikaros transcriptionally represses cdc via chromatin remodeling. a specific cdc inhibitor, ml showed cytotoxic effects on primary b-all cells. conclusion: cdc may have important role in hematologic malignancies. expression of cdc in b cell all is regulated by ikaros and ck . these results suggest that targeting cdc could be a potential therapeutic strategy in leukemia. caitlyn duffy, laura hall, justin godown, koyama tatsuki, scott borinstein monroe carell jr. children's hospital at vanderbilt, nashville, tennessee, united states background: systemic corticosteroids are widely used as treatment of acute lymphoblastic leukemia (all) and lymphoblastic lymphoma. there are anecdotal reports of bradycardia in pediatric patients receiving corticosteroids, but a more extensive analysis of this effect is needed. objectives: the aim of this study was to describe the incidence, severity, and timing of steroid-induced bradycardia and document any adverse events associated with bradycardia. design/method: we performed a retrospective review of all newly diagnosed patients at our center ( - ) with all/lymphoblastic lymphoma who received corticosteroids (dexamethasone - mg/m /dose or prednisone mg/m /dose) during induction chemotherapy. patients were excluded if they had a pre-existing cardiac abnormality or if they received prior corticosteroids. the average hour heart rate (hr) was assessed for the period prior to initiating steroid therapy and for the hour period surrounding the nadir following steroid administration. the degree and time of steroid induced bradycardia was assessed. adverse patient events and concomitant medication use was documented to identify other contributing factors to bradycardia. a total of children ( females, males, months- years) were included in the analysis with demonstrating a decrease in mean hr following steroid administration. median hr decrease was . beats per minute (quartiles . - ) from prior to initiating steroids to surrounding nadir. sixty one percent developed bradycardia less than or equal to the st percentile for their age range. nadir occurred doses (range - ) into treatment, which corresponded to hours ( - ) after initiation of therapy. of patients who experienced bradycardia, % were associated with dexamethasone rather than prednisone. hr nadir was not associated with other vital sign abnormalities. after completion of induction chemotherapy, % of patients had documented resolution of bradycardia with hr greater than the th percentile for age. it was observed that the children who continued to have relatively low hr were often younger ( months- years old). examination of nadir hr during subsequent hospitalizations in which steroids were not being administered (excluding hr during procedural sedation) did not demonstrate a significant incidence of bradycardia. concomitant opioid, beta-blocker, or other medication exposure did not contribute to the incidence of bradycardia. corticosteroid-induced bradycardia is extremely common in children, teenagers, and young adults with all receiving induction chemotherapy. bradycardia was not associated with clinical adverse events and resolved after completion of corticosteroid treatment. therefore, further cardiac assessment may not be warranted in the presence of bradycardia suspected to be secondary to steroid administration. baylor college of medicine, houston, texas, united states background: survival in newly diagnosed pediatric acute myeloid leukemia (aml) is approximately %; however survival falls dramatically if a patient relapses. currently, approximately one-third of patients with pediatric aml relapse on standard chemotherapy regimens. aml cells are exposed to proteotoxic stress at baseline due to their rapid and inefficient metabolism; proteotoxic stress increases after chemotherapy due to accumulation of reactive oxygen species resulting in misfolded proteins. this leads to activation of cell stress pathways, such as the unfolded protein response (upr) in the endoplasmic reticulum. because an activated upr can make cells more sensitive to proteotoxic stress, we hypothesize that upr activation correlates with response to chemotherapy. objectives: determine the status of upr in pediatric aml and its correlation with chemosensitivity; design/method: peripheral blood samples from pediatric patients with aml were collected at the start of induction chemotherapy, - hours (h) and h post initiation of systemic chemotherapy. tumor cells were sorted from peripheral blood mononuclear cells. expression of upr proteins was determined by chemiluminescence using an automated capillary electrophoresis system. clinical correlations were performed using an annotated database. we measured five upr proteins: grp (glucose regulated protein kda), phospho-eif , inositol-requiring enzyme (ire ) and activating transcription factor (atf ). patients with aml had - times higher expression of upr proteins (except atf ) at baseline than normal controls. grp -the key upr driver-had the highest level of protein expression in myeloid blasts. there was a wide variability in the level of baseline upr expression. eight out of samples expressed > fold increase in grp above those with the lowest grp levels. similarly, and patients respectively, had a > fold increase in peif and ire , compared to patients with low basal expression of these upr proteins. in our limited sample set, there was a trend towards lower overall survival (os) and event-free survival in patients with low baseline grp and ire . conclusion: upr has a variable expression at baseline in pediatric aml, with a trend towards lower os in patients with a low basal grp and low ire expression, suggesting less chemosensitivity in this subgroup. conversely, it is possible that blasts with an upregulated upr prior to chemotherapy manage proteotoxic stress less effectively, having faster apoptosis and hence a better response to chemotherapy in patients with a high basal upr. we are currently expanding our findings in a larger cohort of patients enrolled in the children's oncology group aaml protocol. background: children with newly diagnosed acute lymphoblastic leukemia (all) undergo chest x-ray (cxr) evaluation during initial diagnostic workup to ensure safe airway management. however, to our knowledge, no systematic assessment of cxr findings has been reported. objectives: to evaluate cxr findings at diagnosis of all and their associations with clinical characteristics. we reviewed the cxr findings at diagnosis of all in patients treated on the total xv and xvi protocols at st. jude children's research hospital. findings were evaluated for associations with clinical characteristics at presentation, and the clinical management of mediastinal masses was reviewed. mediastinal masses were seen in ( . %) of patients evaluated and were more common in older patients (mean age, . years) than in younger patients (mean age, . years) (p = . ), in males than in females (p = . ), and in patients with t-all than in those with b-all (p< . ). also associated with mediastinal masses were a higher white blood cell count (wbc) at diagnosis (mean, . × /l) (vs. a lower wbc; mean, . × /l) (p< . ), cns involvement (vs. no involvement) (p = . ), and standard/high-risk disease (vs. low-risk disease) (p< . ). other cxr findings included pulmonary opacity ( patients [ . %]), bronchial/perihilar thickening ( patients [ . %]), cardiomegaly ( patients [ . %]), and osteopenia/fracture/periosteal lesions ( patients [ . %]). pulmonary opacity was more common in younger patients (mean age, . years) than in older patients (mean age, . years) (p = . ) and in those with t-all (vs. b-all) (p = . ). bronchial/perihilar thickening, cardiomegaly, and osteopenia/fracture/periosteal lesions were also more common in younger patients than in older ones (p< . , p = . , and p< . , respectively) and in those with low-risk disease (versus standard/high-risk disease) (p< . , p = . , and p = . , respectively). of the patients with a mediastinal mass on cxr, underwent a confirmatory chest ct scan, and ( . %) were confirmed to have a mediastinal mass. notably, patients ( . %) had airway compression, and compression of venous structures was identified in of patients ( . %) who received iv contrast. the clinical course was evaluated for patients with mediastinal masses detected by cxr. fifty patients ( . %) required icu admission (mean stay, . days). general anesthesia was used for only patients ( . %), and patients ( . %) had a less invasive peripherally inserted central catheter. no deaths occurred in the acute phase. conclusion: cxr at the time of all diagnosis can detect various intrathoracic lesions and is helpful in planning initial diagnostic workup and management. background: mertk is a receptor tyrosine kinase that is aberrantly expressed in % of pediatric primary aml samples. mertk inhibition with the small molecule tyrosine kinase inhibitor (tki) mrx- decreases tumor burden and prolongs survival in aml xenografts. while treatment with mrx- reduces leukemia in the peripheral blood, it is less effective in the bone marrow, suggesting a role for the marrow microenvironment in therapeutic resistance. the jak/stat pathway has been implicated as a mediator of bone marrow derived resistance to tkis and inhibitors of this pathway are in clinical development for the treatment of aml. to determine the role of the bone marrow stromal niche in mediating resistance to mertk inhibition and to evaluate the efficacy of combined mertk and jak/stat inhibition. design/method: aml cell lines were cultured with or without the hs stromal cell line or hs conditioned medium, then treated with mrx- +/-the jak/stat inhibitor ruxolitinib, or control. induction of apoptosis and cell cycle arrest in aml cells was measured by flow cytometry. expression of h ax and total and phosphorylated stat were determined by immunoblot. results: co-culture with stromal cells significantly reduced aml cell death and g /m phase arrest in response to treatment with nm mrx- compared to no co-culture (cell death: . % versus . %, p< . ; g /m arrest: . % versus . %, p< . ). g /m arrest was accompanied by an increase in h ax expression which was similarly abrogated in co-culture. conditioned medium did not provide protection from mrx- induced apoptosis, g /m arrest, or h ax induction. mrx- inhibited stat phosphorylation but direct co-culture and conditioned medium potently increased basal stat phosphorylation which was not inhibited by mrx- . to determine whether the observed induction of stat phosphorylation was functionally relevant, cocultures were treated with both mrx- and ruxolitinib. while ruxolitinib potently inhibited the phosphorylation of stat in the presence of co-culture, combination treatment did not overcome stromal mediated protection from mrx- induced apoptosis. similarly, the addition of exogenous gm-csf induced stat phosphorylation but did not yield protection from mrx- functional effects in the absence of co-culture. together these data support a model whereby direct cell-cell contact with stromal cells in the bone marrow niche protects leukemia cells from mrx- induced apoptosis, cell cycle alterations, and dna damage. while co-culture potently induces phosphorylation of stat in leukemia cells, this is neither necessary nor sufficient for stromal-cell mediated protection from mertk inhibition and combined treatment with jak/stat inhibitors is unlikely to be therapeutically efficacious. background: mercaptopurine ( -mp) is an immunosuppressive thiopurine drug that is a key component of acute lymphoblastic leukemia (all) treatment. -mp is metabolized into -thioguanine ( -tgn), which is responsible for anti-leukemic effects, as well as -methylmercaptopurine nucleotides ( -mmpn/ -mmp), which are associated with hepatotoxicity. some patients preferentially metabolize -mp to -mmpn/ -mmp, increasing their risk for hepatotoxicity and potentially reducing anti-leukemic effects. hepatotoxicity can cause interruptions or delays in therapy that may jeopardize cure rates. allopurinol has been increasingly used in patients with inflammatory bowel disease (ibd) to shunt -mp metabolism toward -tgn and away from -mmpn to minimize hepatotoxicity and preserve therapeutic effects. objectives: this retrospective chart review expands upon our previously published case series of three patients with all in whom allopurinol was successfully used to redirect -mp metabolism. twelve additional patients have subsequently received allopurinol and -mp combination therapy at texas children's hospital. data from this larger patient sample, with longer follow up, is being analyzed to increase knowledge of the effectiveness and longitudinal effects of adding allopurinol to -mp to reduce risk of hepatotoxicity. design/method: data were abstracted from the electronic medical records of patients with all treated at texas children's hospital from to present, who had been found to have evidence of altered -mp metabolism and in whom allopurinol was added to -mp therapy due to concern for risk or recurrence of hepatotoxicity. metabolite levels, -mp dose, and alanine transaminase (alt) prior to initiation of allopurinol and approximately weeks later were compared. wilcoxon signed-rank test was applied for statistical analysis. : after the addition of allopurinol, patients experienced a significant decrease in mean levels of -mmpn (p = . ), correlating with a significant decrease in mean alt (p = . ). with the initiation of allopurinol, the mean -mp dose was decreased from to mg/m /day over an -week period. mean -tgn levels increased (p = . ). in follow up beyond weeks, no patients had further holds in -mp due to hepatotoxicity. addition of allopurinol appears to shift metabolism from -mmpn toward -tgn, with increases in mean -tgn levels despite a decrease in mean -mp dose. this may limit negative side effects, thus resulting in fewer gaps in therapy and possible improved outcomes. further analysis of -mp dose titration and effects on anc over time as well as effects on overall survival is ongoing. prospective background: alterations in epigenetic patterning are a fundamental feature in acute myeloid leukemia (aml). treatment with dna methyltransferase inhibitors (dnmti) yields responses in aml, but the molecular mechanisms underlying this effect are poorly understood. in prior work, we demonstrated induction of genes involved in the pirna rna (piwi) silencing pathway as a common gene feature of aml cell lines treated with decitabine. the piwi pathway is an rna silencing system, distinct from classical small rna transcriptional silencing, responsible for transposon-silencing in gametogenesis; emerging data suggest a role for this system in somatic cells. based on these data, we postulate that piwi induction plays a crucial role in aml recovery following demethylation and that disruption of this pathway would modulate response and/or recovery from decitabine treatment. to assess the effect contribution of the pirna pathway response following dnmti treatment in aml. design/method: to choose target genes in the pirna pathway for disruption, molm cells were first treated with escalating doses of decitabine. using quantitative rt-pcr, the dose-dependent expression of several pirna-associated genes were analyzed. two genes, mael and piwil , were selected for disruption experiments based on preliminary data suggesting decitabine dose-dependent responses. molm cells were transduced with shrna targeting these genes using a lentivirus delivery system with selection in puromycin. knockdown efficiency was assessed by rt-qpcr. to determine how gene disruption affected cell growth, knockdown cells were treated with decitabine nm. proliferation was assessed by celltiter glo assay following decitabine treatment. clonogenic potential was assessed by colony forming assays of transduced cells after treatment with decitabine at nm and nm. results: following decitabine exposure in molm , there was a markedly increased expression of mael and piwil compared to untreated cells ( : and : , respectively) . thus, these were the candidate genes chosen for disruption. of mael shrna constructs, two resulted in a % relative expression of mael compared to controls. of the piwil shrna constructs, the best knockdown showed % relative expression. there were no significant differences in proliferation or clonogenicity of stably selected mael or piwil knock-down molm cells following decitabine treatment. using gene knockdown procedures, mael and piwl do not appear to have a marked effect on growth and response to decitabine treatment in molm . however, these results may be limited by inefficient knockdown using shrna targeting methods. further work using a cas /crispr based inactivation of these genes is ongoing. children cancer hospital cairo, egypt background: hypodiploidy < chromosomes is very uncommon and have particularly poor outcomes in childhood acute lymphoblastic leukemia (all). it is subdivided into: near-haploid ( - chromosomes), lowhypodiploid ( - chromosomes) and high-hypodiploid ( - chromosomes). to determine if minimal residual disease (mrd) can identify a group of patients with better prognosis in the hypodploid population who can be treated with intensive chemotherapy alone. design/method: a retrospective study that included all patients under age of diagnosed as hypodiploid b-precursor all during the period between january -december and treated at children's cancer hospital egypt on sjcrh total study-xv for ir/hr all. sixteen patients had < chromosomes ( nearhaploid and low-hypodiploid), constituting % of all pediatric patients with b-precursor all during the study period. patients with near-haploid all had a median age of years (range - ), initial leukocyte count (wbc) median of . × /l (range . - . ), ( . %) were males and / ( . %) had hr-nci criteria. four patients ( . %) are alive in complete remission(cr) (range - months, median ), one died in induction and ( . %) had hematological relapse (range . - months, median ). patients with low-hypodiploid all had significantly older age (median years, range - ), median wbc . × /l (range . - . ), / ( . %) were males. one patient ( . %) is alive in cr, one died in induction, one failed to achieve cr post-induction and patients( %) had hematological relapse (range . - . months, median . ). mrd< . % by flow-cytometry on day- and end of induction was achieved in / ( . %) and / patients( %) with near-haploid, compared with / ( . %) and / patients( %) with low-hypodiploid; respectively (p = . , p = . ;respectively). allogeneic transplantation was performed during initial remission only in mrd negative patients (one relapsed and one is in cr) and in the patient with induction failure (relapsed post-transplant). five of the total six patients who had negative mrd on day- and end of induction are alive in cr ( / with chemotherapy alone). all patients with negative mrd at end of induction but with mrd levels≥ . % on day- (range . - . %) relapsed as well as all patients with detectable mrd at the end of induction. the difference in relapse was statistically significant in relation to negative-mrd on day- (p = . ), but not at end of induction(p = . ). conclusion: children with hypodiploid all and negative mrd on day- of induction are highly curable with intensive chemotherapy alone, while patients with negative mrd at the end of induction and detectable mrd on day- had dismal outcome. background: overall survival in pediatric acute myeloid leukemia (aml) has plateaued between - %, with death during induction chemotherapy seen in - % of patients. respiratory complications contribute to morbidity and mortality in pediatric aml induction, however the incidence, patterns, and predictors of respiratory adverse events (aes) during this period are unknown. to estimate the incidence of respiratory aes during induction therapy for de novo pediatric aml, to characterize and grade these respiratory aes, and to identify predictors of respiratory ae development. we conducted a retrospective longitudinal study from presentation to day in institutional de novo pediatric aml patients (≤ years) between march and december . outcomes included any nci ctcae grade - respiratory ae or death from another cause. demographic, disease, and treatment-related data were abstracted. the most specific, best-fitting ctcae category and grade for each ae was determined. descriptive statistics, survival analysis, multivariable logistic regression analysis, and time-toevent distributions were performed (sas v . , cary, nc) . among eligible patients, . % (n = ) experienced discrete respiratory aes. incidence of grade - aes was . % (n = ). a bimodal time-to-event distribution demonstrated peaks at treatment days and . induction death occurred in . % (n = ) including deaths from respiratory failure associated with disseminated fungal disease. in univariate analysis, those experiencing aes differed significantly in regards to older age at diagnosis (p< . ), higher initial wbc (p = . ), higher initial peripheral blast percentage (p = . ), coagulopathy at diagnosis (pt (p = . ), d-dimer (p = . )), fluid overload status (p< . ), occurrence of infection (p = . ), and occurrence of tumor lysis syndrome (tls) (p = . ). patients with hyperleukocytosis (p = . ), fluid overload (p< . ), and fab m morphology (p = . ) each had a significantly decreased probability of completing the follow up period without experiencing a respiratory ae. on multivariable analysis, fluid overload (aor . [ % ci: . - . ) and older age (aor . [ % ci: . - . ) were significantly associated with ae occurrence when gender, hyperleukocytosis, tls, and infection status were held constant. we describe a high incidence of respiratory aes during pediatric aml induction. fluid overload and older age at diagnosis are independently associated with ae development when controlling for other proposed risk factors. interventions focused on conservative fluid management and offset of fluid overload should be explored in newly diagnosed pediatric aml in an effort to reduce respiratory complications during induction. overall, all survival rates are outstanding and have continued to improve with risk-adapted therapy. the most striking improvement occurred in t-all where -year os rates now exceed % and parallel b-all. survival improvements, however, have not been observed uniformly across all subgroups. while the gap in outcome differences narrowed among blacks, outcomes for hispanics have remained static. further, no improvements in survival were observed in infants or ayas and new treatment approaches have been implemented for these populations. background: acute myeloid leukemia (aml) accounts for approximately % of new childhood leukemia cases. chest x-ray (cxr) is performed in all newly diagnosed aml cases to evaluate the safety of airway management for anesthesia during diagnostic procedures; however, cxr results in pediatric patients with aml have not been described. objectives: the primary objective was to evaluate cxr findings at diagnosis in patients with aml. the secondary objectives included assessing associations between cxr findings and clinical characteristics, with the overall goal of aiding in the evaluation of the use of cxrs as an initial diagnostic study in pediatric patients with aml. design/method: cxr findings and clinical characteristics were evaluated in patients with newly diagnosed aml who were enrolled in one of three protocols at st. jude children's research hospital (aml , aml , and aml ). the findings were categorized based on radiologic reports. further, the associations of these findings and clinical characteristics were evaluated. we evaluated cxr findings in a total of patients: from aml ; from aml ; and from aml . common cxr findings were pulmonary opacity (n = , . %), bronchial/perihilar thickening (n = , . %), splenomegaly (n = , . %), mediastinal mass and lymph nodes (n = , . %), pleural effusion/thickening (n = , . %), demineralization/fracture/periosteal lesions (n = , . %), scoliosis (n = , . %), and granulomatous disease (n = , . %). three cxr findings were associated with younger age at diagnosis: pulmonary opacity (median age, . years in patients with positive findings vs. . years in those with negative findings, p< . ), bronchial/perihilar thickening (median age, . years vs. . years, p< . ), and demineralization/fracture/periosteal lesions (median age; . years vs. . years, p = . ). two cxr findings were associated with older age at diagnosis: scoliosis (median age, . years vs. . years, p< . ) and granulomatous disease (median age, . years vs. . years, p = . ). higher white blood cell counts (wbcs) at diagnosis were associated with cxrs showing pulmonary opacity (median wbc; . × ^ /l vs. . × ^ /l, p = . ) or splenomegaly (median wbc; . × ^ /l vs. . × ^ /l, p = . ). french-american-british (fab) m /m subtypes were more frequently associated with pulmonary opacity compared with others (p< . ). we did not find significant differences between female and male patients. conclusion: cxr in patients with newly diagnosed aml showed a variety of thoracic, abdominal, and bony lesions that are important for the initial evaluation and management. pulmonary opacity was the most common finding and was frequently seen in patients who were younger or had higher wbcs at diagnosis or fab m /m . background: children diagnosed with acute lymphoblastic leukemia (all) require a central venous catheter (cvc) to administer chemotherapy safely. both external and internal cvcs carry risks of complications including thrombosis, infection, and possible replacement. internal catheters, such as a port, are generally used for the majority of patients for the duration of treatment since therapy lasts for several years. many institutions place a port at the time of diagnosis. other institutions prefer to start induction therapy via placement of a peripherally inserted central catheter (picc) and defer port placement until the completion of induction therapy due to concerns of increased risk of infectious complications with port placement. objectives: to compare rates of common cvc associated complications by type of cvc placed at start of induction therapy in children treated for newly diagnosed all at the jimmy everest center (jec) at the university of oklahoma health sciences center. design/method: a retrospective chart review analyzed data from newly diagnosed all patients treated at the jec between - . data was collected on complications including thrombosis, bacteremia, insertion site infection, cvc malfunction and need for removal. data collection began at the start of induction and was completed at the end of induction therapy. statistical analysis used a univariate and multivariate logistic regression model to compare complication rates between those who had a port versus those who had a picc placed at start of induction. results: data was collected on patients. fifty-six patients had a port placed at start of therapy while had a picc placed. fourteen percent of patients had a cvc associated complication. univariate analysis showed no statistically significant difference in rates of cvc associated complications between the groups (port %, picc . % p = . ). the rates of hospitalization for cvc associated complications were similar between both groups (port %, picc % p = . ). rates of cvc removal were also similar between both groups (port %, picc % p = . ). multivariate model that included baseline patient characteristics including type of all, patient body surface area, gender, ethnicity and age continued to demonstrate no significant difference in cvc associated complications between both groups. conclusion: this single institution study showed that there was no significant difference in cvc associated complications between port and picc line placement at the start of childhood all induction therapy. port placement can be considered as a safe option at the start of induction therapy. complete remission [cr] or cr with incomplete blood count recovery [cri]) within treatment cycles - . interim data are reported (nct ). results: seventeen patients were enrolled and received ≥ dose of lenalidomide; median age was years (range - ); patients were female. patients received median prior regimens (range - ). nine patients had previously undergone bone marrow transplantation (bmt). four patients had relapsed aml and were refractory to immediate prior treatment. median duration of study treatment was weeks (range - ); patients completed a median of treatment cycle (range - ). all patients were evaluable for primary outcome; achieved morphologic cri after cycles (no patients achieved cr). the responder was a -year-old male with history of r/r aml after first-and second-line treatment, bmt, and salvage chemotherapy. at baseline, he had a complex cytogenetic karyotype (monoallelic − q . , − q, − q . , − p ) with no identifiable molecular mutation; he was also positive for del( q) (− q , − q ). his post-treatment karyotype showed no abnormalities. sixteen patients experienced treatment failure; due to resistant disease, of indeterminate cause, and had treatment failure before a post-baseline assessment was performed. all patients experienced ≥ grade - treatment-emergent adverse event (teae). the most commonly reported were thrombocytopenia (n = ), anemia (n = ), febrile neutropenia (n = ), and hypokalemia (n = ). fifteen patients experienced ≥ teae related to lenalidomide. all patients discontinued treatment; remain in follow-up. the study is now closed to enrollment. ten patients died on study: during treatment, during follow-up. all deaths were attributed to aml or complications due to aml. conclusion: third-line lenalidomide monotherapy was associated with clinical response in of pediatric patients with r/r aml; however, treatment exposure was limited. safety data are consistent with the known profile of lenalidomide. lenalidomide was not an efficacious treatment for r/r pediatric aml. funding: celgene corporation, summit, nj, usa. cook children's medical center, fort worth, texas, united states background: it is well documented that pediatric patients with acute lymphoblastic leukemia (all) often experience significant weight gain during induction therapy and later struggle with obesity. however, some patients experience unintended weight loss during induction therapy; since this issue is not well reported, it often goes undertreated. although malnutrition is reported to be associated with decreased survival, increased risk of infection, and loss of lean body mass, there remains a scarcity of in-depth analysis of prevalence and risk factors that contribute to this problem. our study attempts to address this critical yet unmet need. objectives: our aim was to identify the clinical risk factors and outcomes associated with weight loss during induction therapy for pediatric all. design/method: this was a retrospective chart review of patients between and years of age diagnosed with all at cook children's medical center from / / to / / . for each patient, we collected height, weight, age, body mass index (bmi) z-scores at diagnosis and end of induction therapy, risk stratification, and whether consolidation was delayed. patients with a bmi > th percentile at diagnosis were categorized as being overweight or obese. using logistic regression analyses, we examined which variables predicted whether the patient had an increase or decrease in bmi z-score throughout induction. a critical alpha level of . indicated statistical significance. results: ninety-six patients met our inclusion criteria. of these, % experienced a decrease in bmi during induction therapy. compared to patients whose bmi increased during induction, patients with a decrease in bmi were more likely to be overweight or obese at diagnosis ( % vs. %; p< . ), to be ≥ years of age ( % vs. %; p< . ), to have a high-or very-high-risk stratification ( % vs. %; p< . ), and to experience a delay in the start of consolidation therapy ( % vs. %; p< . ). conclusion: this research highlights a risk not previously identified in the literature that may impact outcomes. patients treated on high-or very-high-risk protocols, who are overweight or obese at diagnosis, and who are ≥ years of age at diagnosis should be monitored closely for weight loss during induction therapy. patients who experience weight loss should receive prompt intervention. it is our hope that this information can be used for future prospective studies and to help develop evidence-based guidelines. background: p abnormalities have been observed in some patients with hematologic malignancies. loss of p function as a tumor suppressor gene in the chromosome plays an important role for development of leukemia. these patients usually have poor outcome due to the chemotherapy and are associated with poor prognosis. objectives: this study aimed to identify frequency of p abnormalities between iranian children and adult patients with aml (acute myeloid leukemia) malignancy. design/method: the p abnormalities were analyzed via bone marrow karyotyping and fish method in acute myeloid leukemia patients. in this study, p abnormalities were observed in ( %) patients out of diagnosed cases. a significant strong correlation between p abnormalities and other high risk factors (poor risk cytogenetic) were observed. from patients with aml malignancy ( p abnormalities), ( %) patients have complex karyotype, ( %) patients monosomal karyotype and ( %) patients have monosomal karyotype accompanied with a complex karyotype. overall, p abnormalities are independent risk factor in acute myeloid leukemia and evaluation of these abnormalities by fish or other complementary techniques prior to treatment, might help for better risk stratification of high risk aml patients. background: hepatotoxicity in treatment of acute lymphoblastic leukemia (all) is well studied and transiently affects most patients receiving antimetabolite therapy. rarely, patients develop liver injury severe or prolonged enough to undergo a liver biopsy. little is known about how these patients differ from patients that develop transient hepatotoxicity. we sought to describe disease and treatment characteristics for all patients that developed hepatotoxicity severe enough to undergo liver biopsy. we also looked for pre-dictive factors for liver biopsy, including signs of early hepatic injury from the initial treatment protocol. design/method: pathology reports of all patients from the liver biopsy database at children's healthcare of atlanta were collected. controls were matched : for age, all subtype, and treatment protocol. demographics, treatment protocols, and overall outcomes were collected through the electronic health record. hepatic lab results for transaminases, coagulation, and albumin were collected for induction, consolidation, interim maintenance, delayed intensification, and maintenance. results: sixteen patients diagnosed between - (median age at diagnosis years, range - ; % male; % pre-b all) were included in the case series. the median time from diagnosis to liver biopsy was . years (range - ). eight patients ( %) were in maintenance at the time of biopsy; none had active disease. eight ( %) were postbone marrow transplant. biopsy results included: steatosis ( ), acute inflammatory/infectious ( ), liver infiltration ( ), fibrosis ( ) and graft-vs-host disease (gvhd) ( ). six patients were deceased; -year all-cause mortality from diagnosis was %. thiopurine methyltransferase (tpmt) status was known in % cases and % controls. all cases had intermediate or wildtype status, which did not differ from controls (p > . ). patients requiring liver biopsy did not have evidence of acute hepatotoxicity (ast/alt > × normal values) during their initial treatment protocol. hepatotoxicity requiring liver biopsy is a rare outcome of all treatment. these patients had elevated rates of relapse, bmt, and -year all-cause mortality, suggestive of a more severe disease process. however, it is difficult to sort out the temporality of relapse, bmt, and hepatoxicity requiring biopsy in this limited sample. additionally, patients with bmt preceding liver biopsy have other confounding factors that makes them difficult to include in the analysis. finally, our limited descriptive data show no notable correlation between early hepatotoxicity and later indication for liver biopsy. future cohort or case-control studies with larger sample sizes are required to further explore early predictive factors for severe hepatotoxicity requiring liver biopsy. nathan gossai, joanna perkins, michael richards, yoav messinger, bruce bostrom background: the majority of chemotherapeutic agents used to treat hodgkin lymphoma are teratogenic. pregnancy screening prior to the start of chemotherapy is supported by clinical guidelines and baseline testing is a standard component in therapeutic trials. there is limited data available on the incidence of pregnancy screening prior to the start of hodgkin therapy but previous studies suggest that pregnancy screening, especially at pediatric institutions, is not consistently completed. objectives: the objective of this study is to evaluate the incidence of pregnancy screening and contraceptive counseling prior to the start of therapy in females diagnosed with hodgkin lymphoma. design/method: a retrospective chart review was performed for all female patients newly diagnosed with hodgkin lymphoma from to at the hospital for sick children in toronto, ontario. all patients who were intended to receive multi-agent chemotherapy were included, regardless of age. data collected included demographic and disease information, chemotherapy regimen and enrollment on clinical trial. all pregnancy testing within two weeks prior to the start of therapy was captured, as well as type of pregnancy test performed, documentation of menstrual status, contraceptive counseling and contraceptive provision. univariate and multivariate analyses were used to describe factors influencing the incidence of pregnancy testing. results: a total of female patients with newly diagnosed hodgkin lymphoma between the ages of and years were identified. sixty patients ( %) had pregnancy testing done prior to the start of therapy. testing modalities included serum and urine screens as well as quantitative beta-hcg measures. older age (p = . ), documentation of menstrual status at diagnosis (p = . ) and diagnosis between and (p = . ) were associated with higher incidence of screening. enrollment on a therapeutic trial was not associated with a higher incidence of screening (p = . ). contraceptive counseling was documented for patients ( %) and patients ( %) were prescribed contraceptive medications during therapy. pre-chemotherapy pregnancy testing was completed on % of females with newly diagnosed hodgkin lymphoma. improvement is required and interventions, including clarification of institutional standards, modification of chemotherapy order sets and staff education, are planned. (rao et al., cancer, ) . university of louisville, louisville, kentucky, united states background: granulocytic sarcomas (also known as chloromas or leukemia cutis) were first described by a. burns in . they are solid tumors comprised of immature granulocytic cells and represent extramedullary manifestations of underlying leukemia. chloromas are most commonly associated with acute myeloid leukemia. they may arise in other myeloproliferative disorders but are rarely seen in b or t cell acute lymphoblastic leukemia (all). objectives: although patients with all rarely have chloromas, it should remain on the differential for patients with unusual swelling or masses. design/method: we present a case series of two patients from our institution diagnosed with b cell all who had a chloroma as the presenting symptom. the first patient is a yo who presented to his primary provider with nasal congestion and a one-week history of bilateral eye swelling and was referred to an allergist when the symptoms did not resolve with anti-histamines. his review of systems was otherwise negative. he was referred urgently to ent two months later for a × cm mass palpated along the medial border of the left eye. an mri showed a left facial mass surrounding the zygoma and extending into the anterior inferior left orbit. biopsy revealed b cell acute lymphoblastic lymphoma, and bone marrow aspirate and biopsy confirmed the diagnosis as b cell all. the second patient is a yo who presented to his primary doctor for rapid growth of a scalp nodule that had been present for about months. he was referred to dermatology and treated for a supposed kerion from tinea capitis. the lesion continued to grow and became more irritated with this treatment. punch biopsy revealed a complicated phenotype of lymphoblastic lymphoma. however, after a lymph node biopsy and bone marrow aspirate and biopsy, the diagnosis was confirmed as b all. his only other positive point on review of systems was a questionably pathologic -pound weight loss and an area of matted cervical lymph nodes. for both of our patients, the chloromas completely disappeared during induction therapy. it is worth noting that both of these patients presented with the chloroma as the only symptom of the underlying leukemia. this led to initial misdiagnosis and delay in identifying their leukemia. therefore, while it is very rare for a patient with b all to present with a chloroma, our experience shows that all should be on the differential for patients presenting with unusual swelling or masses. background: hodgkin lymphoma (hl) is a lymphoproliferative neoplasm that commonly presents with history of adenopathy and a predictable pattern of disease involvement with or without systemic symptoms of fever and/or weight loss. in the hands of an experienced oncologist the diagnosis of hl is usually not a challenge. occasionally a diagnostic challenge is presented by a patient who has an atypical presentation which is suggestive of an alternative diagnosis. we describe a case series of patients diagnosed with hl whose initial clinical presentations lead to a diagnosis different form hl. honduras, nicaragua and the united states. results: six pediatric oncology centers from the american continent conducted a retrospective review of patients diagnosed with hl since . patients that had an initial presentation not suggestive of hl or who were initially diagnosed with a disease other that hl were included for a total of patients. argentina n = , guatemala n = , honduras n = , nicaragua n = , united states n = . five patients were female and male. patient's ages ranged from to years. most patients (n = ) were older than years. three patients ( %) presented with non-immune cytopenias without overt lymphadenopathy, of those one had active hemophagocytic syndrome. five patients ( %) were suspected to have localized solid tumors: ewing sarcoma n = , rhabdomyosarcoma n = , hepatocellular carcinoma n = , and soft tissue tumor of the cheek n = . two ( %) metastatic solid malignancy as they presented with disseminated pulmonary nodules. five ( %) with autoimmune disorders: hashimoto thyroiditis n = , autoimmune hemolytic anemia n = , nephrotic syndrome n = . ten ( %) with chronic infectious processes: brucella n = , tonsillar abscess n = , splenic abscess n = , and tuberculosis (tb) n = . patients with suspected tuberculosis were diagnosed outside of the united states. six of patients were ultimately diagnosed as having both tb and hl. seventeen patients had ann-arbor stage iii or iv, seven patient had stage ii with either b symptoms or bulky disease. patients were treated with various chemotherapy regimens according to the treating center: abvd, abve-pc oepa-copdac, avpc, beacopp. two patients had recurrent disease, one died of disease progression and one died from causes not related to hl conclusion: a small proportion of hl patients have atypical or unusual presentations. hl should be included in the differential diagnosis of solid tumors, autoimmune disorders, infections or cytopenias. the most common atypical presentation is an infectious process. background: acute lymphoblastic leukemia (all) represents the largest group of pediatric malignancies. the high cure rate of childhood all represents one of the most remarkable success stories in the war on cancer. in a lower middle income country (lmic) like the philippines, we reviewed the five year survival in a tertiary referral center. objectives: this retrospective cohort study aims to determine the survival of children - years old with all treated at a tertiary referral center for childhood cancer in the philippines from january to december . design/method: this is a retrospective cohort study that reviewed medical charts of newly diagnosed all ages to years old from january to december . a total of subjects were included in the study. the year overall survival (os) and event free survival (efs) were . % and . %, respectively. the year os for standard risk all was . % and for high risk patients was %. the year os for the patients on remission was . % and for those who relapsed was . %. univariate and multivariate by cox proportional hazards regression revealed wbc count at diagnosis, risk classification, immunophenotyping, and development of relapse showed significant prognostic impact for mortality. age and gender were reported with no prognostic significance. the -year os and efs were lower compared to developed countries but are comparable with other lmics. the prognostic factors for relapse and mortality were compatible with the literature. overall, the adopted treatment protocols for childhood all in this institution showed acceptable results. relapse has a significant prognostic impact for mortality. development of accessibility to care, increase awareness, early detection and resources at hand should be achieved. improvement in the follow up protocol to prevent delays in the treatment, patient education to prevent non-compliance and psychosocial support, to developed better supportive care, and expand facilities should be given emphasis to further improve survival and prevent relapse. objectives: here, we seek to further characterize this entity by describing the pathologic and clinical features of pediatric cases of burkitt-like lymphoma with q aberration. we collected pathologic and clinical data from the medical record on all pediatric high grade b-cell lymphoma (hgbcl) cases diagnosed at our institution over a -year period ( - ) . for those cases classified as neither burkitt lymphoma nor diffuse large b-cell lymphoma (dlbcl), fish for myc, bcl- and bcl- , as well as array comparative genomic hybridization (acgh), were performed. we identified cases of hgbcl, including cases of burkitt lymphoma presenting as purely leukemic phase. of the hgbcl cases, had burkitt lymphoma as defined by myc rearrangements, and had dlbcl. collectively, the majority of these patients had primary disease outside of the head/neck, and most patients presented with advanced stage (iii-iv) disease. of the remaining cases, q aberration was identified in cases using acgh. all cases histologically and immunophenotypically resembled burkitt lymphoma but lacked myc rearrangement, instead showing proximal gains in q -q and telomeric losses in q . qter. all cases involved primary disease in the cervical lymph node and/or tonsil. three of these cases were localized (stage ii), and the fourth case involved a few metabolically active but non-enlarged lymph nodes in the chest and abdomen (stage iii). all patients achieved complete remission with standard therapy for mature b-cell lymphoma, and were alive with no clinical evidence of disease at a median follow-up of months. although the number is small, our results suggest that the majority of non-burkitt, non-dlbcl cases of pediatric hgbcl carry q aberrations. in addition, patients with q aberrations appear to be more likely to present with lower stage disease, thus requiring less intensive therapy, and also tend to have primary disease in the head/neck. these findings further support the classification of burkitt-like lymphoma with q aberration as a distinct pathologic and clinical entity, and we propose that all pediatric non-burkitt, non-dlbcl cases of hgbcl regularly undergo further workup for possible q aberrations. marie claire milady auguste, joseph bernard st damien hospital, port-au-prince, port-au-prince, haiti background: hodgkin lymphoma (hl) and non-hodgkin lymphoma (nhl) account for % of cancers in the united states pediatric population ( , ). in central america and the caribbean, they are in second position among all types of pediatric cancers ( ). a previous study on pediatric cancers in haiti showed that the lymphomas were in fifth place after the leukemias, wilms tumor, retinoblastoma and the sarcomas ( ). the main objective of this study is to present the epidemiological profile of lymphomas managed at a haitian pediatric hospital. design/method: this is a retrospective study conducted on the cases of lymphoma diagnosed and managed at st damien hospital from january to december . key variables such as age, gender, stage at diagnosis, histopathological types and outcome were collected to present the characteristics of this retrospective cohort. of the cases of cancer diagnosed during the study period, ( . %) had the diagnosis of lymphoma. the sex ratio was . ( males for females) and the average age was . years [ - years]. there were cases of hl ( . %) and cases of nhl ( . %). . % of the patients were diagnosed at stages iii and iv. among the hl cases, ( . %) were nodular sclerosis lymphoma, ( . %) with mixed cellularity and ( . %) with lymphocytic predominance. for the nhl cases, ( . %) were burkitt's lymphoma and ( . %) lymphoblastic t-cell lymphoma. among the patients for who immunohistochemistry was found, the cases of hl were cd -positive and out of cases of nhl were cd -negative. only patient was hiv-positive, and patients had a confirmed exposure to epstein-barr virus. patients ( . %) were lost to follow-up, ( . %) were in remission, ( %) relapsed, ( . %) were still in treatment and ( %) were deceased. university of chicago, chicago, illinois, united states background: due to the adoption of risk-adapted therapy, pediatric and adolescent acute lymphoblastic leukemia (all) is associated with high cure rates. despite excellent outcomes in most children, patients with certain blast cytogenetic features do not fare as well. furthermore, african american, native american, and hispanic patients have worse outcomes than caucasian patients. while the outcome discrepancies are certainly multifactorial, and blast cytogenetics are related to age, it remains unclear whether ethnicity and blast cytogenetics correlate. the diverse patient population at the university of chicago provides an opportunity to evaluate for such a correlation. objectives: to describe cytogenetic findings in a racially and ethnically diverse population of patients of all age groups diagnosed with all at university of chicago from to and determine if there is a correlation between race/ethnicity and blast cytogenetics. results: a total of newly diagnosed patients with all between the ages of - from - were included in this study. of those, patients ( . %) had b-all, had t-all ( . %), one had early t-cell precursor all and one had mixed phenotype all (b/t). caucasians accounted for % of patients, african americans (aa) %, hispanics . %, asians . %, and % were of other races. age distribution had a bimodal pattern, with a peak in incidence at and another at years of age, consistent with published data. cytogenetic categories included: t( ; )(p ;q ), q rearrangements (kmt a), iamp , t( ; )(q ;p . ), t( ; ) (q ;q ), hypodiploidy, hyperdiploidy and double trisomy of chromosomes and . aa and hispanic patients with b-all presented more frequently between the ages of - years compared to caucasians (p = . and . , respectively). in aa patients, t( ; ) (q ;p . ) was overrepresented (p = . when compared to caucasians), and was mainly observed in patients between - years. caucasian patients were more likely than non-caucasians to have hyperdiploidy (p = . ), especially in patients aged - years. the rate of t( ; )(q ;p . ) was significantly higher in aa patients in our cohort, in particular in patients between the ages of - years. hyperdiploidy was more likely in caucasians aged - years. these findings may suggest that varying blast cytogenetics could contribute to outcome differences between races. ahmed elgammal, yasser elborai, mohamed fawzy, asmaa salama, eman d el-desouky, lobna shalaby national cancer institute, cairo, cairo, egypt background: hodgkin lymphoma (hl) in children is one of the malignancies that have a high chance of cure. stage iv hl remains a challenge for getting good clinical outcome as in other stages. many treatment protocols used to give combination chemotherapy while combined modality treatment is the mainstay in other treatment protocols. objectives: we aimed in to assess the outcome using consolidation radiotherapy to chemotherapy (combined modality treatment) versus combination chemotherapy alone in treatment of stage iv hl. design/method: we included patients with stage iv hl and whose data were retrieved from the medical records of the pediatric oncology department, national cancer institute, cairo university, egypt from till june and were followed till august . treatment was either to give cycles of abvd (adriamycin, bleomycin, vinblastine, dacarbazine) only or to give cycles of abvd followed by consolidation radiotherapy. the study included cases; were males and were females. mean age was . years ranging from to years. the histopathology subtype was nodular sclerosis in the majority of cases ( cases) followed by mixed cellularity ( cases) then only one case of lymphocyte rich. nine cases were initially bulky while cases were not. constitutional manifestations were present in cases while it was absent in cases. bone marrow was involved in only cases. radiotherapy was given after completion of chemotherapy to cases while cases received chemotherapy only. the -year overall survival for patients who received radiotherapy was superior to those who received chemotherapy alone; % versus . % respectively with statistical significance (p = . ). the -year progression free survival was also higher with radiotherapy than others; % versus . % (p = . ). patients with stage iv hl who received consolidation radiotherapy apparently had a better outcome than those who received chemotherapy only. this suggests that radiotherapy contributes significantly with chemotherapy to the cure rate for those patients. the feinstein institute for medical research, manhasset, new york, united states background: microrna (mirnas) are short non-coding rnas that play a decisive role in cancer biology, including leukemia. exosomes are microvesicles ( - nm) produced by most cells in biological fluids. exosomes represent the fingerprint of the parental tumor and are loaded with bioactive markers such as mirnas, which may regulate tumor growth. exosomal cargo can be transferred into target cells changing their biological properties. our study investigates a functional role for exosomal mir- a in pediatric acute lymphoid leukemia (p-all). objectives: / to demonstrate that p-all exosomes induce cell proliferation / to confirm that exosome-induced cell proliferation is disease-stage specific / to analyze exosomal mir- a expression profiles in p-all / to authenticate that inhibition of exosomal mir- a reduces leukemia proliferation design/method: exosomes were isolated by ultracentrifugation from healthy donors (hd) & p-all serum and conditioned medium (cm) of sup-b , jm , and cl- (control) human cell lines. cell lines were exposed to different sources of leukemia-derived exosomes in a paracrine or autocrine fashion for hrs in triplicates. proliferation was assessed by microscopic cell counting and confirmed by gene expression for proliferation, pro-survival and pro-apoptotic genes. mirna profiling was performed with the human cancer pathway finder microarray (qiagen). silencing of exosomal mir a was carried out by a mir- a inhibitor (qiagen), utilizing exo-fecttm exosome transfection reagent (sbi, system biosciences). further, exosomal mir- a silencing was confirmed by q-pcr. cellular uptake of texred-sirna (sbi, system biosciences) was confirmed by flow cytometry. transfer of exosomal mir a to the target cells was evaluated by q-pcr. we elucidated that cm-derived exosomes from sup-b and jm cell lines induce cell proliferation in sup-b , jm (autocrine and paracrine) and cl- cells (paracrine) (p< . ). serum p-all exosomes promote paracrine cell proliferation in all cell lines compared to hdderived exosomes (p< . ). heatmap analysis of mirna profiles of leukemia exosomes (all cell lines and p-all) identified mir- a significantly upregulated in leukemia exosomes compared to controls. mir- a was also upregulated in all cell lines after exposure to leukemia exosomes that induced proliferation. moreover, exosomal mir- a inhibition reduces leukemic proliferation in pediatric all. our data suggest that all exosomes induce cell proliferation of leukemic cell lines in both paracrine and autocrine fashion. exosomes regulate these phenomena in a highly orchestrated way, by transfer of functional exosomal mirnas such as mir- a. the results of this study suggest s of s that exosomal mir- a inhibition can act as a novel way for growth-suppression of pediatric leukemia. results: a total of disease sites were detected at pet/ct, while sites were detected at contrast-enhanced ct and bone marrow biopsy (bmb). pet/ct showed improved detection of nodal lesions (p < . ) (kappa value = . ), extranodal lesions (p < . ) (kappa value = . ) and bone marrow (p < . ) (kappa value = . ) compared to contrast enhanced ct and bmb. pet/ct had upstaged cases ( %) and down-staged cases ( . %) (p < . ) (kappa value = . ). among the upstaged cases, patients ( . %) were upstaged from stage ii to iii, based on residual in pet/ct not seen in contrast enhanced ct after abdominal mass excision. four patients ( . %) were upstaged from stage iii to iv based on bone marrow uptake in fdg-pet without positivity in bma or bmb.regarding response assessment, sensitivity was % for pet and % for contrastenhanced ct (p = . ). specificity was % for pet and % for ct (p< . ). positive predictive value for pet was %, while was % for ct scan (p< . ). negative predictive value for both pet and ct was % (p = . ). five patients had nd biopsy to confirm viability of the residual lesions, lesions were negative in pathological examination (all of them were metabolic negative in pet/ct; deauville score below ). one lesion was positive in pathological examination (was positive in pet/ct; deauville score of ). conclusion: pet/ct detected additional sites compared with contrast-enhanced ct and resulted in changing stage of disease. pet scan is significantly more specific than ct in the management of children with burkitt lymphoma. background: deep sequencing of the immunoglobulin heavy chain (igh) locus indicates that each b all is composed of innumerable subclones. in many cases, subclones exhibit differing phenotypic qualities. however, it remains unclear whether subclones demonstrate distinct tissue distribution within a patient. objectives: . to quantify the extent of clonal heterogeneity in diagnostic b all specimens; . to identify variability in clonal composition between bone marrow (bm) and peripheral blood (pb) disease sites. design/method: igh sequencing was performed on purified dna from pairs of matched bm and pb patient specimens. multiplex pcr was used to globally amplify the igh locus; next generation sequencing (ngs) was performed using illu-mina® miseq. index clones (defined as ≥ % of all sequence reads in a specimen) and their subclone progeny (defined by shared nucleotide bases immediately upstream of a common jh, or n_jx) were identified using igblast-determined vh and jh alignments (http://www.ncbi.nlm.nih.gov/igblast/) and an established in-house computational pipeline. results: up to index clones per specimen were discovered in of the samples. in the remaining ( bm/pb pairs), pair did not reveal a clonal igh and was eliminated from analysis; in the other, clone frequency did not reach the % index threshold, but predominant clonal precursors were inferred by the prevalence of their subclone progeny. subclone counts ranged from to , per index clone. a combined , subclones derived from pb index clones were observed; in contrast, bm index clones gave rise to only subclones. subclone heterogeneity was observed between all paired specimens. in bm/pb pairs, index clones existed in equivalent proportions between disease sites. in contrast, bm/pb pair demonstrated high-frequency index clones in the bm ( . % & . %) with limited representation of these clones in the pb ( . % & . %, respectively); in this case, the most prevalent clone in the pb ( . %) matched the least frequent index clone in the bm ( . %). similarly, another pair showed a predominant index clone in the pb ( . %) which was below index threshold ( . %) in the bm. in paired patient specimens, index clone predominance was discovered to be overtly distinct between bm and pb. among all pairs, the extent of subclone progeny derived from each index clone showed marked variability, with far higher subclone frequency in the pb than in the bm. our data indicate that b all clonal composition differs between disease sites. valley children's healthcare, madera, california, united states background: tuberculosis (tb) presenting with hodgkin lymphoma (hl) is rare. their coexistence could lead to delay in diagnosis of both tb and hodgkin lymphoma due to the similarities in signs and symptoms of presentation. most cases have been reported in the adult literature. we describe a case series of children that were suspected to have tb and were found to have coexisting tb and hl. results: a retrospective review of hl patients in guatemala and argentina over six years, uncovered patients with simultaneous diagnosis of tb and hl. eight patients were from guatemala (incidence of . %) and from argentina (incidence of . %). there were females and males. age ranged from - years (mean . years, media years). nine patients were suspected to have tb at presentation by the referring physician. two patients were found to have tb at the time of relapse through routine tissue culture. initial systemic symptoms included fever (n = ), weight loss (n = ), and night sweats (n = ). six patients had a second systemic symptom in addition to fever. time for referral to oncology center ranged from weeks to months. nine patients were diagnosed with tb and hl through a tissue cultures and with serum quantiferon. one patient was found to have hl without tb. two patients had no systemic symptoms and the diagnosis of tb came to light through routine tissue culture. five patients had stage iiib and ivb, two stage iia and one iib at diagnosis. hl treatment was given according to the insti-tutional standards depending on stage and risk with abvd, oepa/copdac +/-radiation therapy, and ice for relapse. five patients started anti tb treatment (isoniazid, rifampin, pyrazinamide +/-ethambutol for months followed by isoniazid and rifampin for - weeks) simultaneously with chemotherapy, and three others after completing cycles. the two relapsed patients started tb treatment after cycles of chemotherapy. seven patients are alive and have been followed for months - years. one patient died during therapy, another died for causes not related to tb or hl and one is currently receiving treatment. conclusion: tuberculosis can coexist with hl. in areas were the prevalence of tb is high, microbiology investigations of biopsy specimen should be strongly considered. therapy for tb can be given simultaneously with chemotherapy. coexistence of tb and hl does not appear to affect outcomes. the children's hospital affiliated to the capital institute of pediatrics, united states background: the pi k/akt signaling pathway plays a central role in cell growth, proliferation and survival in physiological conditions. this signal pathway is considered to be an innovative targeted therapy of cancer, and its abnormal activation has been proved to be related to t-cell acute lymphoblastic leukemia (t-all). despite improved treatment strategies, such as multi-drug combination, high-dose chemotherapy and all kinds of application and popularization of hematopoietic stem cell transplantation, children with drug resistance or relapse t-all are still rather worse and its overall outcome and prognosis are much poorer than the more common b-lineage all. objectives: to explore the relationship between the pi k/akt pathway and the pediatric t-all, so as to probe the exact molecular mechanisms of t-all and provide more directions for its treatment. design/method: cases of new or recurrent acute t lymphocyte leukemia children with clinical information were collected in the children's hospital affiliated to the capital institute of pediatrics from dec. to oct. , with age and gender matched healty children as control (all was informed consent). the expressions of key genes in pi k pathway were s of s analyzed by western blot rt-pcr analysis, the pi k enzyme activities were detected by elisa,and the ccrf -cem's proliferation and its apoptosis were tested by mtt and flow cytometry technology on t-all cell lines ccrf-cem in different treatment group. the results of t-all children in clinical showed that pi k protein and gene expression level were higher apparent than the control group (p< . ), and pi k enzyme activity increased as well (p< . ); pi k inhibitor ly made a significant inhibition of cell proliferation and promoted cell apoptosis. ly also enhanced the effectiveness of clinical commonly used chemotherapeutic drug dnr. in combination ly and dnr treatment group cell viability dramatically declined, apoptosis and the apoptosis relation protein casepase expression in t-all patients was obviously higher than the control and the single drug group; pi k/akt signaling pathway related proteins and gene expression level, pi k, akt, gsk transcription in ccrf-cem were significantly higher than the control (p< . ), while pten transcription was significantly lower than the control (p< . ). the abnormal activation of pi k/akt signaling pathway might play an important role in pediatric t-all patients, especially in the cell proliferation or apoptosis. the results might provide new train of thought and direction in targeted suppress this signal pathway or in combination with other chemotherapy drugs therapy in looking for the more effective and less cytotoxic treatment of pediatric t-all. cleveland clinic children's hospital, cleveland, ohio, united states background: non-hodgkin lymphomas (nhls) are a heterogeneous group of lymphoproliferative diseases which comprise % of all childhood malignancies. nhls can be divided in to b cell lymphomas and t cell/natural killer (nk) cell lymphomas depending on immunophenotype, molecular biology, and clinical response to treatment. although nk/t cell lymphomas occurring in childhood and adolescence comprise a small portion of all lymphomas, they present many diagnostic and therapeutic challenges. the role of angiogenesis in lymphoma pathogenesis is becoming more evident. high molecular weight kininogen (hk) is a central compo-nent of the kallikrein-kinin system. it has been previously reported that cleaved hk (hka) induces apoptosis of proliferating endothelial cells and inhibits angiogenesis in matrigel plug and corneal angiogenesis models. however, the role of endogenous kininogen in regulation of angiogenesis is in tumor microenvironment is unknown. objectives: to elaborate the role of hk in lymphoma angiogenesis, we used a murine t-cell lymphoma model and compared angiogenesis and tumor growth between wild-type and kininogen deficient (mkng -/-) mice. we also evaluated the effect of hka on lymphoma cell proliferation. design/method: el- murine t-cell lymphoma cells ( × ^ ) were implanted into wild-type and mkng -/-mice. tumor size was measured using calipers and tumor volume was calculated using the formula volume = length × width^ × . . seventeen days after cell implantation, tumors were harvested and processed by immunoblotting and immunofluorescent staining. cell proliferation assays (mts) were performed to investigate any possible inhibitory effect of hka on el- cell growth, with human umbilical vein endothelial cells (huvec) were used as a positive control. results: el- lymphomas grew more rapidly and to larger sizes in mkng -/-mice compared to wild-type mice, with significant differences apparent by day after tumor implantation (p< . ). by day , the volume of tumors in mkng -/-mice was approximately . -fold larger than in wild-type mice (mean volume ± standard deviation; ± vs. ± mm , respectively, p< . ). mts assays showed that hka does not directly inhibit the proliferation of el- cells in vitro, though it does significantly impair the viability of ecs studied simultaneously. conclusion: these findings suggest that hk is an important endogenous regulator of angiogenesis and tumor growth in this t-cell lymphoma model, and suggests that hka specifically modulates endothelial proliferation in tumor microenvironment. further work is needed to understand the mechanisms underlying these findings and provide future anti-angiogenic approaches to increase the therapeutic options for patients with nhl. bruce bostrom, jack knudson, nathan gossai, joanna perkins, michael richards, jawhar rawwas, susan sencer, julie chu, nancy mcallister, yoav messinger children's minnesota, minneapolis, minnesota, united states background: osteonecrosis causes significant pain and morbidity in older patients treated for acute lymphoblastic leukemia. besides altering the schedule of dexamethasone in delayed intensification there is no other intervention known to reduce the incidence of symptomatic osteonecrosis. pamidronate has been shown to reduce bone pain from osteonecrosis but not to prevent joint collapse when advanced. objectives: to compare the incidence of symptomatic osteonecrosis in patients who received prophylactic pamidronate compared with concurrent controls. to describe any increase in side effects from the use of pamidronate. design/method: patients age to years at time of all diagnosis were given intravenous pamidronate monthly for one year at the discretion of the primary oncologist starting in the first year of therapy. concurrent controls were patients age to who did not receive pamidronate. all patients were treated according to the concurrent cog protocols and received intermittent dexamethasone during delayed intensification. patients with bcr-abl all were excluded as the use of imatinib may increase the risk of osteonecrosis. imaging was only done if osteonecrosis was suspect based on clinical symptoms. patients were censored at the time of relapse. data were analyzed as of / / . this retrospective study was approved by the children's minnesota irb. of the patients evaluated % were male and % female, % had b-cell and % t-cell. the median followup is . years with a range of . to years. pamidronate was given to patients with developing symptomatic osteonecrosis. there were concurrent controls with developing osteonecrosis. there was no significant difference in the leukemia lineage, gender distribution or body mass index (bmi) at diagnosis between groups. for all patients the median bmi was with a range of to . the age at diagnosis was significantly higher in the pamidronate group with a median of . years vs. . in the controls (p = . ). by kaplan-meier analyses the incidence of symptomatic osteonecrosis was significantly lower in the pamidronate group at % vs. % in controls. the log-rank p-value was . and the breslow p-value, which is more sensitive to early events, was . . there were no untoward side-effects from pamidronate. pamidronate infusions significantly reduced the incidence of symptomatic osteonecrosis in patients over the age of compared to concurrent controls who did not receive pamidronate. arahana awasthi, dina edani, janet ayello, christian klein, mitchell cairo new york medical college, valhalla, new york, united states background: mature b-nhl, including bl and pmbl express cd +/cd b+ and have an excellent prognosis, however, subset of patients relapse secondary to chemoimmunotherapy resistant disease and have a dismal prognosis (≤ % yr. efs, cairo et al. blood. ; gerrard/cairo et al., blood, , goldman/cairo et al. leukemia, . pv has been demonstrated to possess significant preclinical activity against indolent cd b+nhl (polson et al. can. res. ). we previously observed that obinutuzumab (anti-cd mab) significantly enhanced cell death and increased overall survival against bl (awasthi/cairo et al., bjh ) in xenografted nsg mice. however, additive/synergistic effects of pv with obinutuzumab against mature pmbl/bl are unknown. to determine the efficacy of the pv or obinutuzumab/rtx alone or in combination against pmbl and rituximab (rtx) sensitive/resistant bl cell lines. design/method: raji rh (provided by m. barth, md, roswell park cancer institute) and raji/ karpas p (atcc, usa) were cultured in rpmi. tumor cells were incubated with pv, and/or anti-cd b, mmae (generously supplied by genentech inc.) with obinutuzumab /rituximab ( ug/ml) for hr with nk cells at : e: t ratio and cytotoxicity was determined by delfia cytotoxicity assay. six to week old female nsg (nod.cg-prkdcscid il rgtm wjl/szj), were divided into groups: pbs, isotype control, pv, anticd b mab and mmae ( mg/kg). mice were xenografted with intravenous injections of luc+ bl and pmbl cells and tumor burden was monitored by ivis spectrum system. results: os of mice receiving pv alone was significantly increased compared to anticd b ab or isotype control in raji ( . vs. vs. . our preliminary data indicates that pv significantly increased survival in bl and pmbl nsg xenografts compared to anti-cd b ab alone. furthermore, pv in combination with obinutuzumab significantly enhances in-vitro cytotoxicity in bl and pmbl compared to obinutuzumab or pv alone. results: maximal grades (g) / , , and crs occurred in , , and patients, respectively. median lowest fibrinogen levels were . , . , and . g/l in patients with maximal g - , , and crs, respectively. %, %, and % of patients with maximal g - , , and crs had lowest reported fibrinogen levels of ≥ to < . g/l. eight patients (all with g crs) had very low fibrinogen levels (< g/l), which occurred before (n = ) or during (n = ) maximal crs grade or at time of improvement (n = ). no patients with maximal g - crs had < g/l fibrinogen levels. at the onset of < g/l fibrinogen levels, patient had concurrent g , and had g - increased international normalized ratio and activated partial thromboplastin. cryoprecipitate was the primary treatment in the us, and fibrinogen concentrate (fc) guidelines for tisagenlecleucel-associated coagulopathy were developed for other countries because administration of fresh frozen plasma can be problematic. fc was available at / sites for infused patients: / (g crs) and / (g - crs). cryoprecipitate was available at / sites for infused patients: / (g crs), / (g crs), and / (g - crs). risk of bleeding increases in pediatric patients with comorbid thrombocytopenia and anticoagulant treatments. / patients had g / decreased platelets within day of < g/l fibrinogen levels. fatal case of intraparenchymal cranial hemorrhage occurred during resolving crs with g hypofibrinogenemia, ongoing thrombocytopenia, and continuous veno-venous hemofiltration with citrate. hypofibrinogenemia was observed more frequently in patients with higher crs grades during/when crs was improving or resolving. fc and cryoprecipitate treatment guidelines were developed. frequent monitoring and fibrinogen replacement are needed in patients with g / crs. sponsored by novartis. its prolonged cns half-life, may allow a reduction in the number of intrathecal injections. objectives: to safely reduce the burden of therapy by reducing the number of it injections and reducing the total dose of doxorubicin with the addition of liposomal cytarabine and rituximab. design/method: patients ( - years) with cd + b-nhl with fab group b good risk (=stage i/ii and stage iii with ldh < xuln), fab group b intermediate risk (=stage iii ldh ≥ xuln and stage iv {bm blasts < %}) and fab group c high risk were eligible. patients received fab backbone therapy with the addition of six rituximab ( mg/m ) doses; two doses prior to each of two induction courses and one dose prior to each of two consolidation courses. cumulative doxorubicin was reduced from to mg/m in gr patients. after systemic methotrexate clearance, patients received age based dosing of it liposomal cytarabine. it injections were reduced from nine to five. the primary outcome is safety and toxic deaths among evaluable patients with an estimated -year survival above %, monitored by an independent dsmb. results: to date, evaluable patients, fab group b and group c ( cns positive), median age years (range - ), males, burkitt/ dlbcl with gr, ir and hr have enrolled. there has been one grade anaphylactic reaction to rituximab and one grade facial nerve palsy. no other serious adverse events were attributable to protocol therapy. there has been death from progressive disease and relapse at a median follow up of months. efs and os are % and %, respectively. our initial results show excellent efs and os, consistent with published standard of care outcomes, with the addition of rituximab and intrathecal liposomal cytarabine despite the reductions in therapy. further enrollment is ongoing and continued long term outcomes are needed to confirm early results. future randomized studies are needed to examine both short term (mucositis, infections, hospitalization days) and long term (late cardiac toxicity) endpoints. . goldman etal, leukemia, . cairo etal, jco st. jude children's research hospital, memphis, tennessee, united states background: bereaved parents identify significant spiritual needs around time of death and throughout their bereavement journeys. spirituality has been identified as a primary means by which bereaved parents can find meaning in their losses, and this ability to find meaning is associated with lower maladaptive grief symptoms. the use of spiritual coping strategies has been associated with improved coping and mental health outcomes among bereaved parents. objectives: to better understand how bereaved parents' experiences with spirituality throughout bereavement effects objective measures of grief, depression, and meaning-making. design/method: thirty participants whose children died of progressive cancer or related complications one to three years prior to participation completed an in-depth semi-structured telephone interview about their experiences with grief. participants were prompted to describe the impact of their spirituality on their bereavement processes. additionally, participants completed surveys related to grief (prolonged grief disorder questionnaire, pg- ), depression (beck depression inventory, bdi), and meaning-making (integration of stressful life experiences scale, isles). results were analyzed using a mixed methods approach including semantic content analysis of qualitative content and kruskal-wallis h test and post-hoc analyses of quantitative data. results: correlation analyses demonstrated significant differences between participants with positive and negative spiritual experiences of bereavement. participants with negative experiences of bereavement had a statistically significant increase in scores on the pg- compared to those with positive spiritual experiences signifying greater symptoms of prolonged grief. participants with negative spiritual experiences with grief had significantly lower scores on the isles, suggesting a lesser degree of adaptive integration of their losses. there were no significant differences in depression scores between groups. conclusion: bereaved parents that have a negative spiritual experience of bereavement are at increased risk for prolonged grief symptoms and are less likely to find meaning in their children's deaths than bereaved parents that describe a positive spiritual experience of bereavement. providers should consider exploration of spiritual beliefs and provision of spiritual care for parents of children facing life-limiting illnesses during treatment and bereavement. background: langerhans cell histiocytosis (lch) is an inflammatory myeloid neoplasia characterized by frequent relapse, with treatment failure associated with higher risk of death and neurodegenerative disease (lch-nd). activating somatic mutations in mapk pathway genes have been identified in almost all cases, with braf-v e in approximately % of lesions. targeted therapies have been successful in treating other refractory cancers with braf v e mutations (such as melanoma). given the central role of mapk pathway activation in lch, mapk pathway inhibition may be an effective therapeutic strategy for children with lch. objectives: the purpose of this study was to report the efficacy and toxicity profile of a retrospective cohort of patients with lch treated with mapk pathway inhibitors. design/method: medical records from pediatric patients with lch (systemic and/or lch-associated neurodegeneration) who were treated with a mapk pathway inhibitor were retrospectively reviewed from five institutions. all patients had failed at least one prior systemic therapy and had a proven mapk pathway mutation. results: all patients in this series were less than years old (median = . years; range: - years) with a median of three prior treatments (range: - ). at the time of initial mapk inhibitor use, nine of the patients had lch-nd diagnosed clinically and/or by radiographic imaging; the remaining three patients had systemic disease. patients were treated for a median of months (range: - months) with various reasons for discontinuation. three patients received combination mapk inhibitor therapies and three patients received other concurrent lch-directed therapies. four of the twelve patients had a grade or toxicity reported and three of these patients required dose reduction in order to be able to successfully resume therapy. overall survival was % with median month follow-up (range: - months) with only one patient achieving transient complete response. the remaining ten patients had partial response or stable disease and four of these patients developed progressive disease while on therapy. conclusion: mapk pathway inhibitors may be a relatively safe salvage therapy for refractory systemic lch and lch-nd but the efficacy and durability of this strategy remains to be defined. combination with cytotoxic chemotherapies may be required in order to eradicate the disease-causing cell. future prospective trials of mapk pathway inhibitors for patients with refractory lch are needed in order to directly compare their efficacy and toxicity relative to other current salvage strategies. cincinnati children's hospital medical center, cincinnati, ohio, united states background: medication adherence during maintenance therapy has been shown to have a direct relationship with disease relapse in pediatric leukemia. previous research determined that patients who are ≤ % adherent to mercaptopurine ( mp) have a greater risk for relapse. the primary aim of the present study is to examine the relationship between metabolite profiles of mp with behavioral adherence rates obtained via electronic monitoring at , , and days. it is hypothesized that patients demonstrating low levels of thioguanine (tgn) and methylated mercaptopurine (mmp) will have lower behavioral adherence rates prior to the blood draw. design/method: in a multisite, prospective study of patients ages - years diagnosed with acute lymphoblastic leukemia (all) or lymphoblastic lymphoma (lbl), mp adherence was measured across months of maintenance therapy using behavioral adherence (electronic monitoring) and pharmacological (metabolites) measures of mp. mp is metabolized into mmp and tgn. cluster analysis was used to generate three mutually-exclusive profiles of mp adherence. behavioral adherence rates were calculated for , , and days prior to the blood draw. results: this study identified three metabolite profiles of mp across months. previous research indicated that low levels of both metabolites suggest nonadherence to medication. low levels of one metabolite with high levels of another metabolite indicate adherence to mp. in this study, . % of the low tgn-low mmp group had -day behavioral adherence rates ≥ % (mean = %); . % had adherence rates < % (mean = . %). in the high tgn-low mmp group, . % had a mean -day adherence of %; . % had adherence rates < % (mean = . %). the low tgn-high mmp group had % of patients with a mean -day adherence level of %; % had adherence rates < % (m = . %). at and -days, to % of patients in the low tgn-low mmp group had adherence rates < %. conclusion: these findings suggest that electronic monitoring and metabolite concentrations can be used to monitor mp medication adherence during maintenance therapy. it is notable that there is a sub-sample of pediatric patients who are identified as being nonadherent to mp based on electronic monitoring, however, metabolite levels indicate adherence to mp. similarly, a sub-sample of patients were identified as being adherent based on electronic monitoring, but metabolite profiles indicated sub-therapeutic levels of mp. our findings underscore the clinical significance of using both objective measures of medication adherence to inform clinical decision making. cincinnati children's hospital medical center, cincinnati, ohio, united states background: hemophagocytic lymphohistiocytosis (hlh) is a life-threatening hyperinflammatory syndrome characterized by non-remitting fevers, rash, hepatosplenomegaly, cytopenias, liver dysfunction and coagulopathy, and can include central nervous system involvement. several genetic diseases cause hlh by impairing normal lymphocyte or macrophage function. the hlh panel at the cincinnati children's genetics laboratories includes genes associated with hlh and other lymphoproliferative diseases, including the genes that cause primary hlh (prf , unc d, stxbp , stx , rab a), x-linked lymphoproliferative diseases (sh d a, xiap), itk deficiency (itk), hermansky-pudlak syndrome types and (ap b and bloc s ), chediak-higashi syndrome (lyst), cd deficiency (cd ), xmen syndrome (magt ) and lysinuric protein intolerance (slc a ). deletion/duplication analysis is available as a reflex test for all genes, as copy number variations (cnvs) are not directly assessed by sequencing. objectives: the prevalence of cnvs among large groups of patients with hlh in north america is unknown. we assessed the frequency of cnvs in the genes on the hlh panel through a retrospective review of orders for deletion/duplication analysis performed after next-generation or sanger sequencing: orders for all genes on the panel, and orders of - genes from the panel. deletion/duplication analysis was performed on a custom × k microarray annotated against ncbi build (ucsc hg , march ). deletion/duplication analysis resulted in a confirmatory diagnosis in of cases ( . %). pathogenic or likely pathogenic cnvs were most common in the three x-linked genes: sh d a ( deletions), xiap ( deletions, duplication), and magt ( deletions). hemizygous deletions in xlinked genes in male patients were typically suspected after amplification failure during previous sequencing. of the autosomal recessive genes, pathogenic cnvs were observed once in each of three genes: rab a (heterozygous), lyst (heterozygous), and stxbp (homozygous). in the two heterozygous cases, a second change was not identified by sequencing, so deletion/duplication analysis did not offer a confirmatory diagnosis. in patients, deletion/duplication analysis was performed after a pathogenic or likely pathogenic variant was identified in an autosomal recessive gene during sequencing; however, in no case was a second mutation uncovered by cnv analysis. we recommend that deletion/duplication analysis be routinely performed in all male patients with hlh who lack a genetic diagnosis after sequencing of hlh-associated genes, especially if any regions failed to amplify. deletion/duplication analysis may be performed in female patients after sequencing if a genetic form of hlh is highly suspected, but the yield is expected to be low. cleveland clinic children's hospital, cleveland, ohio, united states background: the development of post-transplant neoplasia, typically from lymphoproliferative disease (ptld), is a severe complication in transplant recipients and affects approximately % of pediatric solid organ recipients. rates of lymphoma in adult heart transplantation patients are comparatively low, at less two percent at ten years. there are few published reports of the long-term outcomes of neoplasia after pediatric heart transplantation. we aimed to identify the subsequent malignancies that occurred in pediatric heart transplantation patients in a large single institution, and describe their treatment and subsequent clinical course. we performed a retrospective chart review of all pediatric heart transplant recipients followed at the cleveland clinic children's hospital from january to october . we excluded patients who died within days of heart transplantation. we reviewed in depth the history and clinical course of subjects who developed neoplasms. results: between and , patients underwent heart transplantation and survived at least days post transplantation. nine patients ( . %) developed a subsequent malignancy. in this case series, the median age at heart transplant was years old and the median time to develop neoplasia was . months. primary neoplasia included monomorphic ptld ( ), polymorphic ptld ( ), burkitt lymphoma ( ), hodgkin's lymphoma ( ), plasmacytoma-like lymphoma ( ) and epstein-barr virus-associated smooth muscle tumor (ebv-smt) ( ). one patient with hodgkin lymphoma subsequently developed monomorphic ptld, one patient with polymorphic ptld subsequently developed ebv-smt and later, an undifferentiated gastric cancer. one patient with monomorphic ptld developed an ebv-smt. evidence of epstein-barr virus was present in six of nine patients at diagnosis of first malignancy. four of nine patients received reduction in immunosuppression as a primary intervention for the initial malignancy, with two complete responses (cr), one partial response, and one with progressive disease. five patients were treated with chemotherapy, with four cr and one with progressive disease. three patients died of malignancy (recurrent ebv-smt, undifferentiated gastric cancer, and monomorphic ptld post-hodgkin disease) and two patients died of other transplant related complications. conclusion: secondary malignancies represent a significant disease burden to survivors of cardiac transplantation. as expected, much of the malignancy burden is driven by ebv. despite aggressive histology, many malignancies can be successfully cured in this setting with a multidisciplinary approach. stanford university school of medicine, palo alto, california, united states background: current treatment of langerhans cell histiocytosis (lch) is based on extent of organ system involvement and if high risk systems are affected. gastrointestinal (gi) involvement is diagnosed in about % of lch patients, and classically presents in children under years of age with malabsorption, failure to thrive, bloody diarrhea and anemia. although the gi system is considered standard risk, a mortality rate over % occurring within years of diagnosis has been reported. this study was performed due to this discrepancy and the limited number of published cases. objectives: to review the clinical course and outcomes of patients diagnosed with gi lch. design/method: a retrospective chart review of patients with histologically confirmed gi lch diagnosed in the last years identified from the bass center histiocytosis clinical database was performed. two other pediatric hematology/oncology centers (ucsf benioff children's hospital oakland and san francisco) were queried for additional cases. results: four patients with biopsy proven gi lch [ subjects ( . %) from database records and l from center queries] were identified. failure to thrive, hypoalbuminemia, bloody diarrhea and rash were the most common presenting symptoms. lch of the skin was found in all patients. risk organ systems were involved in patients. of note, subjects were of african racial background. the median age at diagnosis was . months ( . months to years), mean albumin . g/dl ( . - . g/dl), mean esr of mm/hr ( - mm/hr). all patients initially received combination therapy per lchiii protocol (vinblastine, prednisone, and mercaptopurine). two patients had recurrent disease and received second line therapy (cytarabine, cda, and local radiation therapy). all patients are alive without active disease at last follow-up ( to months after completion of therapy). a systematic approach to evaluate gi involvement should be performed in children diagnosed with lch. from our experience, combination chemotherapy for patients with lch involving the gi tract is an effective intervention for active disease. cincinnati children's hospital medical center, cincinnati, ohio, united states background: bhatia indicated that rates of mp adherence ≥ % have better clinical outcomes. those with adherence rates ≤ % have an increased risk for disease relapse. the present study investigated patterns of mp medication adherence using group-based trajectory modeling in a large sample of pediatric patients. to describe patterns of behavioral adherence during the maintenance phase of therapy for a cohort of pediatric patients ages - years who were diagnosed with acute lymphoblastic leukemia or lymphoblastic lymphoma (n = ). previous research has documented the relationship between optimal levels of medication adherence with positive health outcomes. it was hypothesized that three groups would be identified: optimal adherence, deteriorating adherence, and chronic nonadherence. it was hypothesized that patients in the optimal adherence group would have adherence rates ≥ %. those with poor adherence would have adherence rates ≤ %. design/method: the present study was a longitudinal, multisite study investigating adherence to -mercaptopurine in a pediatric cohort of patients using electronic monitoring devices. daily adherence rates (electronic monitoring of mp) were examined across -months. health outcomes were measured at quarterly intervals through medical chart reviews. results: unconditional growth curve modeling indicated that the mean percentage of behavioral adherence was . % at baseline and declined to . % at -months. three trajectories of mp behavioral adherence were identified: ) optimal adherence ( % of patients): averaging % behavioral adherence across months; ) moderate adherence ( %): relatively stable nonadherence with rates of % across months; and, ) chronically nonadherent ( %): adherence decreased from % to %. with respect to patterns of medication adherence and relationship to clinically-relevant health outcomes, there were no significant differences in health outcomes between patients in the adherent versus nonadherent trajectories, including mean absolute neutrophil counts (anc), risk for infection as measured by anc, healthcare utilization, or risk for disease relapse. although longitudinal patterns of mp behavioral adherence were not related to health outcomes, it is notable that only % of the current sample had adherence rates ≥ %. in fact, % of the current sample demonstrated adherence rates ≤ %. our findings are important for development of future adherence promotion studies in pediatric cancer. our findings underscore the relative significance of tailoring adherence promotion interventions to subgroups of patients, including those with problematic patterns of adherence. patients who demonstrate adequate levels of adherence could still benefit from less intensive, preventative interventions to sustain and improve adherence. sophie gatineau-sailliant, pascale grimard, marie-claude miron, guy grimard, anne-sophie carret, jean-marie leclerc chu sainte-justine, montreal, quebec, canada background: vertebral involvement in langerhans cell histiocytosis (lch) is still a subject of interest, due to its low frequency and the absence of management's guidelines. objectives: to provide additional information on presentation, treatment and morbidity of pediatric lch vertebral lesions, we report cases of children with vertebral lesion of biopsy-proven lch, between january st and december st , at sainte-justine university health center (montreal, quebec, canada). we conducted a retrospective study by reviewing charts and imaging of vertebral lch in a population of children (median age of . years at lch diagnosis), followed for a median duration of months. symptoms at presentation, treatment modalities and morbidities were collected. results: vertebral lesions were present at lch diagnosis in of cases. they were usually diagnosed secondary to back pain in of cases and were asymptomatic in only one case. despite an epidural extension in of cases, no child developed neurological symptoms. lesions frequently involved vertebral body ( of cases) and were rarely unstable ( of cases). out of vertebral lesions, most of them had a dorsal localization ( of lesions) and of patients had lch in multiple vertebrae. at diagnosis, median vertebral height loss was . % compared to % at last imaging control. most used imaging modalities were pet-scan and plain x-rays. treatments were diverse and consisted in chemotherapy in all children but three and bisphosphonates in only cases. radiation therapy was not used in any patient. six out patients did benefit of an orthosis. a lch recurrence was observed in patients and involved vertebrae in cases. one patient with treatment-resistant lch disease had relapses, and required multiple lines of treatment. all children were alive and disease-free at their last follow-up, patients having radiological vertebral sequelae and only had clinical sequelae. our study is consistent with the epidemiological data described in larger cohorts of children with vertebral lesions of lch and the favorable prognosis associated with such lesions. nevertheless, aggressive treatment and long term follow-up seemed to be essential as recurrences are s of s not rare and spontaneous bone regeneration often incomplete. plain x-rays appears to be a good follow-up tool for vertebral lesions as it allows reliable measures, less exposure to radiation at lower cost. national cancer institue, giza, giza, egypt background: acute lymphoblastic leukemia (all) is the most common type of childhood cancer and also the most complicated in the treatment, so it requires many interventions for both treatment and to alleviate suffer form side effects. pancreatitis is one of the toxicities, which is more common in all as it appears in about % of the patients. it occurs in many drug combinations which induce pre-pancreatitis and even direct destruction of pancreatic tissues. pancreatitis can be induced by many drugs used in the treatment such as chemotherapeutic agents or supportive treatment. lasparaginase is the backbone drug of the treatment of all in which to doses are required to achieve complete remission status in the induction phase of treatment and to doses in the maintenance phase.it is an enzyme that destructs the l-asparagine amino acid into aspartic acid and ammonia thus deplete the asparagine from the extracellular matrix . many drugs are investigated for their effect on treatment of induced pancreatitis such as interleukin- , nsaid as antiinflammatory, glycerin tri nitrates as improvement of microcirculation, tnf-alpha antibody, paf inhibitor as specific anti-inflammatory and low molecular weight heparin .none of the drugs was investigated for their ability to prevent the occurrence of pancreatitis. objectives: this study was designed to evaluate the protective effect of enoxaparin and diclofenac against l-asparaginase induced pancreatitis design/method: acute pancreatitis was induced in rats by intra-muscular injection of l-asparaginase ( i.u/kg) given daily for five days. enoxaparin was given subcutaneous ( i.u/kg) and diclofenac was given intra-peritoneal ( mg/kg) daily for five days. then, markers of pancreatic injury, lipids, immune cell infiltration and oxidative stress were analyzed with histo-pathological examination of the pancreatic tissue results: during acute pancreatitis, oxidative stress markers were significantly changed as indicated by reduced tis-sue glutathione and increased malondialdehyde levels. this was accompanied with significant increase in immune cells infiltration as indicated by high levels of myeloperoxidase and pro-inflammatory cytokine tnf-alpha. triglyceride only showed increase level. treatment with enoxaparin and/or diclofenac restored levels of biochemical markers including serum alpha-amylase, reduced glutathione, malondialdehyde, pro-inflammatory cytokine tnf-alpha, myeloperoxidase and triglyceride. histological injuries of pancreatic tissues as vacuolation and necrosis of epithelial lining pancreatic acini, inflammatory cells infiltration and focal pancreatic hemorrhage were also reduced by treatment with enoxaparin and/or diclofenac. the present study emphasizes the potential protective effect of enoxaparin and diclofenac against l-asparaginase induced pancreatitis background: rosai dorfman disease (rdd), or sinus histiocytosis with massive lymphadenopathy (shml), is a rare condition of immune dysregulation of unknown etiology arising from the massive accumulation of non-langerhans type histiocytic cells inside lymph nodes. the disease classically presents as bulky, painless lymphadenopathy often associated with infection showing distension of lymph node sinuses by abundant histiocytic cells (cd a(-), s- (+)/cd (+)). in some cases, the disease can be self-limiting, but in cases with a prolonged chronic course of exacerbations and remissions, those with extranodal involvement, or disease that threatens vitals structures, treatment may be necessary. there is no treatment consensus. to describe a case of life-threatening, unresectable, recurrent rdd successfully treated with langerhans cell histiocytosis (lch) -inspired therapy. design/method: we compared this case to the current literature on chemotherapeutic treatments for rdd. we searched pubmed, ovid, and google scholar for similar cases. we believe this to be the first reported case of using lch therapy to successfully treat rdd. an -year-old male presented to an outside hospital with two years of massive neck swelling causing torticollis. biopsy confirmed rdd. he was intermittently treated with courses of antibiotics with partial response. surgical removal of the affected lymph nodes was unsuccessful due to proximity to the spinal cord. two years later, the patient presented to our institution. he was initially treated with prednisone with a fast tapering dose, but after a second relapse the decision was made to try chemotherapy following the lch- protocol of weekly vinblastine ( mg/m ), -mp ( mg/m ), and high dose steroid bursts. he experienced two additional relapses off therapy at ages and years old, including cmv(+) associated septic shock and cytokine storm requiring rapid response, picu admission, and ionotropic support. this last episode was treated with a more prolonged induction and maintenance therapy. an extended and slowly tapered maintenance therapy regimen of . years of daily -mp, monthly vinblastine and steroids with a slowly tapered dose during his fourth remission has resulted in -months of continuous complete remission-the longest stretch of his life. no similar cases were found. literature search demonstrated no consensus regarding the most effective treatment of rdd, with no previous cases being successfully treated following lch chemotherapy protocols. we hypothesize that the multi-agent relatively mild lch- therapy mitigates the immune dysregulation of rdd. this case suggests that lch- therapy can be used to treat cases of rdd that is not amendable to surgery or observation. nicklaus children's hospital, miami, florida, united states background: central venous catheters (cvc) are necessary in the management of patients with malignancies, especially children. patients with acute leukemia (al) have higher rates of central line associated complications such as bloodstream infections compared with other malignancies. objectives: to examine the choice of placement of cvc and the differences in outcome between peripherally inserted central catheters (picc) and ports in patients with leukemia during induction. design/method: retrospective chart review of patients with newly diagnosed leukemia at nicklaus children's hospital between and . results: ninety four patients with a new diagnosis of leukemia undergoing induction chemotherapy were identified. the average age was . years. overall, ( . %) patients had a port placed and ( . %) had a picc placed. the decision for picc or port was subjective and physician based. the main outcome measures were local inflammation/infection, bacteremia, thrombophlebitis, blocked catheter and premature removal. the most common complication was bacteremia ( . %). in a multiple logistic regression analysis for predicting whether patients had at least one complication, results showed that having at least one complication is . times the odds in patients with aml compared to patients with all (p = . ). when comparing picc vs. ports, patients with picc had more frequent episodes of blocked catheters ( . %) and premature removal ( . %) compared to the patients with ports ( . % and . %) (p = . and p = . respectively) during induction. local inflammation, bacteremia and thrombophlebitis were not statistically different (p = . , p = . and p = . respectively). the most common place for port placement was the right subclavian vein ( %). there was no significant association between port location and having at least one complication (p = . ). acute lymphocytic leukemia subgroup analysis: fourteen patients ( %) in the picc group had at least one complication and ( %) in the port group but that was not statistically significant (p = . ). our series showed a higher incidence of blocked catheters and premature removals with picc compared to ports in patients with leukemia during induction. the choice of placement of picc vs port was subjective and physician based. patients with all, despite receiving steroids and asparaginase during induction, did not show a statistically significant increase risk in thrombosis or infection but larger numbers may be needed in future studies. university of california, san francisco, san francisco, california, united states background: hemophagocytic lymphohistiocytosis (hlh) is classically a disorder of young children meeting systemic hyperinflammation criteria. presentation in late adolescence is uncommon. furthermore, though cns signs occur in - % of cases, initial isolated neurologic presentation is rare, frequently resembling encephalitis or demyelinating disorders. these cns signs can be isolated or precede systemic disease, delaying hlh diagnosis. hlh declaring in adolescence with predominant psychiatric features has not been well documented. objectives: to describe a case of cns hlh presenting with neuropsychiatric features in absence of classic hlh criteria. design/method: retrospective review of clinical, radiologic, histologic, immunophenotypic, and molecular features of a patient with cns hlh. a -year-old female presented with acute-onset headaches following nine months of progressive anxiety, short-term memory loss, emotional lability, perceptual disturbances, and hypomania. brain mri demonstrated numerous enhancing t hyperintense supratentorial and infratentorial white matter lesions in the left thalamus and caudate head. brain biopsy showed histiocyte-rich inflammation and associated demyelination. extensive evaluation including universal microbial pcr failed to reveal underlying infection or malignancy. past medical history was notable for presumptive pulmonary sarcoidosis diagnosed months prior with progressive respiratory failure with associated granulomatous pulmonary nodules which responded to systemic immunosuppression. at presentation of her neuropsychiatric symptoms, she had normal sil- r, ferritin, fibrinogen, and triglycerides. there was no pancytopenia, coagulopathy, bone marrow hemophagocytosis, fevers, or splenomegaly. given the possibility of partial immune suppression of systemic symptoms and the prominent neurologic symptoms, hlh screening labs were sent and notable for decreased natural killer and cytotoxic t lymphocyte function, normal granzyme expression and cd a mobilization, and absent perforin expression. genetic testing confirmed compound heterozygous mutations in prf (c. g>a, c. a>c) and familial hlh type . she was treated with low-dose dexamethasone and intrathecal chemotherapy per hlh- . due to lack of evidence of systemic inflammation, vp- and high-dose steroids were held. within one week of initiating therapy, she had decreased anxiety and improved cognition, with sustained, incremental neuropsychiatric improvement with additional intrathecal treatments. she tolerated dexamethasone tapering without symptom flare. mri also demonstrated parenchymal lesion improvement. for definitive treatment, she underwent unrelated allogeneic hematopoietic cell transplantation and remains at neurologic baseline as of eight months post-transplant with ongoing imaging improvement. conclusion: this case of familial hlh with compound heterozygous perforin mutations in an adolescent with isolated neuropsychiatric symptoms illustrates that cns hlh may be an underrecognized phenomenon in absence of systemic signs. standard hlh therapy may effectively reverse these symptoms with associated radiologic responses. rush university children's hospital, chicago, illinois, united states background: posterior reversible encephalopathy syndrome (pres), a recognized complication of pediatric leukemia treatment has been reported in up to % patients in various series. hypertension, chemotherapy and cortical spreading depression have been implicated in the pathophysiology. due to the combinations used, it is difficult to identify the offending drug, several have been implicated. since delay of chemotherapeutic treatment in children with high risk leukemia is unfavorable, it is important to recognize the characteristic radiologic findings, manage appropriately and reintroduce the treatment as soon as possible. pharmacoethnicity is now recognized as an important factor for variation in neurotoxicity in children with all. ethnic differences in reported pres events in pediatric patients with all has not been well described in literature. to describe the factors associated with pres in a cohort of high risk pediatric all patients at a single institution. design/method: a total of children with an average age of years ( - years) diagnosed with all between - were retrospectively reviewed for the occurrence of pres. various demographic factors, therapy received, clinical features, radiology related findings and management were reviewed. a search for all published articles on pres in leukemia was conducted using pubmed databases. results: five ( %) children (average age . years) developed pres during days - of induction. % of the patients that developed and % of those that did not develop pres were hispanic. all the patients that developed pres and % of those that did not were diagnosed with high risk all. all patients received vincristine, % received daunomycin and intrathecal methotrexate and % received asparaginase in the week prior to the event. mri findings confirmed pres in all patients with no evidence of methotrexate related leukoencephalopathy or leukemia. at the time of pres all patients were in remission based on mrd and spinal fluid cytology. two-thirds of the patients had seizures and hypertension at the time of the event with no prior history of either. all patients had complete recovery of normal mental status after resolution of pres. a higher incidence of pres than previously reported was noted in our series. hispanic ethnicity, high-risk all and exposure to vincristine, daunomycin and intrathecal methotrexate in induction were associated with pres in our cohort. a new association that emerged was that of hispanic ethnicity with pres .larger studies to understand the importance of pharmacoethnicity in pres may help in individualization of chemotherapy based on ethnic differences. children's hospital of illinois, peoria, illinois, united states background: hyper ige syndrome is a primary immunodeficiency characterized by susceptibility to skin and lung infections as well as increased propensity for malignancy. hemophagocytic lymphohistiocytosis (hlh) is a syndrome characterized by overwhelming activation of t lymphocytes and macrophages occurring as either primary hlh caused by genetic abnormalities or secondary hlh associated with infectious, malignant, metabolic, or immunodeficiency causes. we describe the first case to our knowledge of hlh in a patient with hyper ige syndrome. to describe a case of hlh in a pediatric patient with hyper ige syndrome. results: a -year old caucasian male with known autosomal dominant hyper ige syndrome (stat mutation) was transferred to the pediatric intensive care unit secondary to concern for septic shock. the patient had persistent slow bleeding from oral lesions and central catheter sites despite the addition of aminocaproic acid and recombinant factor viia. he also required numerous blood product transfusions sec-ondary to anemia and thrombocytopenia. clinical suspicion was high for hlh and the patient met criteria for diagnosis of hlh with the following: ferritin > , ng/ml, triglycerides mg/dl, decreased nk cell function with the sample only containing % nk cells, elevated soluble il- receptor at u/ml, splenomegaly, and fever. infectious workup was remarkable for a positive ebv qpcr with , copies/ml suggestive of ebv driven secondary hlh. familial hlh testing was unable to be completed. therapy was initiated based upon the hlh- study. the addition of ruxolitinib and anakinra were considered but the patient declined rapidly prior to treatment. ct of the head was concerning for a stroke with signs of edema and increased intracranial pressure likely leading to the development of symptoms consistent with brain stem herniation. the decision was then made to withdraw care. conclusion: to our knowledge, this is the first report of hlh in a patient with hyper ige syndrome. diagnosing hlh requires a high index of suspicion in critically ill patients, and prompt initiation of therapy is essential. this challenging case of hlh in a patient with hyper ige syndrome highlights the diagnostic challenge, variable presentation, and need for effective therapy in this vulnerable patient population. background: adolescents and young adults (ayas) with cancer are at risk for psycho-social as well as physical symptom burden during cancer therapy. the purpose of this study is to explore psychological and physical symptoms endorsed by aya while receiving therapy for cancer design/method: surveys were given in both inpatient and outpatient settings during cancer therapy. symptom screening in pediatrics tool (sspedi) and memorial symptom assessment scale (msas). symptoms severity was rated by teens on a point likert scale. spss , used for statistical analysis. results: : a total of aya on cancer therapy (age range - . years) % female, % male, . % acute leukemia, . % solid tumors, and . % diagnosis was not reported. % of aya on cancer therapy reported at least or more symptoms, % reported > symptoms cluster. of the physical symptoms that were reported as most distressing to the teens, mouth sores and headaches were the top causes. of the physical symptoms that were most frequently endorsed; fatigue was on the top ( %), followed by change in appetite %, vomiting %, and pain %., the least was bowel habit changes. aya rated sadness as the most frequent psychological symptom %, followed by feeling angry %, and scared %. statistically significant difference was noticed based on gender difference with more females reported symptoms (p = . ), while type of cancer (acute leukemia versus solid tumors) was not statistically different. conclusion: aya with cancer reported multiple physical and psychological symptoms with significant distress. females seem to report more symptoms compared to males. screening aya for cancer therapy related symptoms is feasible during routine visits and adds important information about the aya well-being. background: sinus histiocytosis with massive lymphadenopathy (shml), also known as rosai-dorfman disease, is a rare histiocytic proliferative disorder of unknown etiology. many treatment modalities have been employed; however, no uniform guidelines exist. objectives: literature review of treatment options for shml. design/method: chart review was performed on pediatric patients diagnosed with shml at the children's hospital at montefiore between and after irb approval. inclusion criteria included children between the ages of and years with shml. exclusion criteria included children with cutaneous shml. four cases of shml seen at montefiore are described. a comprehensive review of the literature identified additional cases published between and . manuscripts that did not include the treatment modality or outcome were excluded. results: many of the patients with shml responded to observation alone. of patients, patients were observed, with ( %) having resolution of disease, five having stable disease, and five being lost to follow-up. one patient received subsequent systemic therapy. surgical management was con-ducted upfront in patients. of those, ( %) had resolution of disease, one had stable disease, and one had recurrence with no further therapy noted. of the remaining nine patients, % were successfully treated with systemic therapy, consisting of either steroids ( ) or steroids and chemotherapy ( ). systemic therapy was used as first-line therapy in patients. steroids alone or in conjunction with chemotherapy resulted in resolution of disease in / and / patients ( / , %), respectively, with four patients having stable and three with progressive disease. chemotherapy without steroids resulted in resolution of or stable disease in / patients. radiation was ineffective. conclusion: shml is a rare disease with no published guidelines for treatment. from the results of the cases and a detailed review of the literature, it can be suggested that observation may be considered as first line management in patients providing there are no significant symptoms. for patients who are symptomatic or have significant progression, surgery may be considered. in patients with recurrence or refractory disease, steroids and/or chemotherapy may be used. the presence of nodal or extra-nodal disease did not seem to have a significant impact on the course of treatment. given the rarity of the disease, it is difficult to conduct a randomized control trial. further work, involving collaboration between centers and cooperation with the international rare histiocytic disorders registry would be helpful. boston children's hospital, boston, massechusettes, united states background: increasing census and intensified work compression on the inpatient oncology service at our institution was identified as leading to resident dissatisfaction, impaired resident learning and decreased perceived quality of patient care. objectives: to evaluate the impact of a redesign of a pediatric inpatient hematologic malignancy (ihm) service on resident perceptions of the educational value of the rotation and safety of patient care. design/method: during the - academic year, we initiated a bundled intervention on the ihm service. modifications included ) decreased patient volume: the ihm service was divided into two teams, utilizing an extra attending -a teaching service consisting of residents and fellows and a team comprised of nurse practitioners. ) intentional patient team assignment: patients were deliberately assigned to a care team based on educational opportunities and provider skill sets. ) intentional attending faculty selection: attending faculty with deeper clinical and teaching experience were selected to supervise on the teaching team. ) increased weekend staffing. after completing the service, junior residents completed an electronic survey to evaluate their perceptions of the educational value of the rotation, as well as their ability to deliver safe care while on the rotation. fisher's exact tests were used to compare responses from residents in who experienced the redesign to residents in , whose experience results: survey completion rates were % ( / ) in and % ( / ) in . intervention residents were significantly more likely than comparison group residents to choose the answers "very good" or "excellent" to describe both the overall quality of the rotation ( % intervention vs. % comparison, p< . ) and the educational experience on rounds ( % intervention vs. % comparison, p< . ). intervention residents also reported caring for fewer average primary patients daily on weekdays as compared to comparison residents ( . vs . patients, p< . , % ci - . to - . ). furthermore, intervention residents were more likely than comparison residents to "agree" or "strongly agree" that they could provide safe patient care on weekend days ( % intervention vs. % comparison, p< . ) and on nights ( % intervention vs. % comparison, p< . ) while on the oncology service. a redesign initiative of an oncology service with the development of a new teaching service led to improved resident perceptions of the educational value of the rotation and ability to provide safe care to patients. this approach could be useful to other services and institutions to promote similar outcomes in resident education and patient care. background: alk-positive histiocytosis is a rare histiocytic proliferative disorder that has been reported in three infants presenting primarily with hepatosplenomegaly, anemia, and thrombocytopenia. given the rarity of this disease, there are no standard treatment algorithms for this diagnosis and the disease course and outcomes remain largely unknown. the published series describes treatment ranging from monitoring alone to multi-drug chemotherapy regimens. there was ulti-mately resolution of presenting symptoms in all three cases despite varying treatment strategies. objectives: to report a newly diagnosed case of alkpositive histiocytosis that was treated with a novel approach using cytarabine monotherapy. results: a full term male infant presented at birth with difficulty feeding and hyperbilirubinemia. over the first few weeks of his life, he subsequently developed thrombocytopenia, transaminitis, and profound hypoalbuminemia. by six weeks of life, he was experiencing significant abdominal ascites requiring repeat paracenteses, massive hepatosplenomegaly, respiratory distress secondary to abdominal distension, anemia, and coagulopathy. he underwent numerous diagnostic tests, including a liver biopsy followed by a bone marrow biopsy that showed alk-positive histiocytic infiltrates in both sites. treatment was initiated with cytarabine mg/kg/day x days, repeating every weeks. throughout his course of five cycles of treatment, he experienced intermittent fevers and mild nausea with no other adverse events. by the end of five cycles, his hepatosplenomegaly resolved, his blood counts normalized, he demonstrated weight gain on oral feeds, and his liver enzymes normalized. he is currently months post completion of therapy and remains well with a normal physical exam and laboratory values. conclusion: treatment of alk-positive histiocytosis with lose dose cytarabine resulted in complete resolution of our patient's symptoms with minimal treatment related adverse effects, and few long-term treatment related risks. given the rarity of the diagnosis, the reporting of effective novel treatment options is important for future patient care. background: adult patients with melanoma or lung cancer harboring braf v e have benefitted from the development and subsequent approval of specific braf inhibitors. as such, delineating the subset of similarly targetable pediatric oncology patients may spur development and rational use of these inhibitors in children. importantly, other point mutations and fusions of braf may also be targetable in s of s children analogous to recent emerging data in adult cancer patients. objectives: to define the genomic landscape of known and novel braf alterations and raf fusions in pediatric malignancies and report index cases with clinical response to braf or mek inhibitors. design/method: dna was extracted from microns of ffpe sections of , tumors from pediatric (< years of age) oncology patients, and cgp was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of x for up to cancer-related genes plus introns from genes frequently rearranged in cancer. genomic alterations (ga) included base substitutions, indels, copy number alterations and fusions/rearrangements. a total of ( . %) braf-altered pediatric malignancies were identified. ( . %) harbored a single kinaseactivating braf short variant, indel, or fusion. an alteration resulting in reduced braf kinase activity was identified in ( . %) tumors while ( . %) tumors harbored multiple braf alterations, of which contained at least a single activating short variant. the remaining tumors ( . %) contained functionally uncharacterized variants. kinaseactivating braf alterations were identified in diverse tumor spectra comprised of brain tumors ( . %; subtypes), carcinomas ( . %; subtypes, with melanoma constituting % of cases), hematological malignancies ( . %; subtypes), sarcomas ( . %; subtypes), and extracranial embryonal tumors ( . %; subtypes). seventy-two ( . % of braf-altered cases) braf fusions were identified, ( . %) of which were kiaa -braf; involved the novel fusion partners: stard nl and khdrbs . seven ( . %) raf fusionpositive cases, predominantly brain tumors ( ), were identified; involved the novel fusion partners: tmf and sox . index cases of response to therapy of intracranial tumors will be presented. we describe a population of pediatric patients with targetable braf alterations predominantly enriched in primary intracranial tumors, but spanning diverse solid tumor types and hematologic malignancies. we additionally report a cohort of raf fusion-positive patients. an index case and multiple previous reports suggest raf or mek inhibitors may benefit pediatric patients with either intracranial or extracranial disease, and development of such drugs in pediatric indications is strongly warranted. background: diffuse midline gliomas (dmg) with h k m mutation, including diffuse intrinsic pontine glioma (dipg), are the leading cause of brain tumor-related deaths in children. there are no effective therapeutic strategies and the median survival remains dismal. genomic studies have identified a recurrent mutation in the majority of dmgs involving a lysine to methionine substitution (k m) in histones . and . , resulting in changes in the epigenetic landscape that dysregulate gene expression and promote gliomagenesis. panobinostat, a multiple histone deacetylase (hdac) inhibitor, was found to be one of the most effective agents against dipg patient-derived cell cultures and xenograft models in previous studies and is presently in clinical trial for dipg. hdac inhibition with panobinostat may also exhibit activity against h k m+ diffuse midline gliomas of the thalamus and spinal cord. to evaluate the effect of panobinostat as a single agent against patient-derived thalamic and spinal cord h k m+ diffuse midline glioma cell cultures and in an orthotopic xenograft murine model of h k m+ spinal cord glioma. design/method: patient-derived thalamic and spinal cord h k m+ diffuse midline glioma cell cultures were treated with single agent panobinostat at a range of concentrations. cell viability was evaluated using the celltiter-glo assay. panobinostat was systemically administered to orthotopic xenograft murine models of luciferase-expressing spinal cord h k m+ diffuse midline glioma. response to panobinostat was evaluated with ivis in vivo imaging. results: hdac inhibition with panobinostat significantly decreases cell proliferation with an ic of nm and nm in the spinal cord and thalamic glioma patient-derived cell cultures respectively. panobinostat slowed tumor growth in murine models of spinal cord glioma by . -fold in the brain (p = . , n = ) and -fold in the spinal cord (p = . , n = ) when compared to vehicle controls after week of administration. panobinostat is in clinical trials for dipg. this study suggests that hdac inhibition with panobinostat may also be beneficial for patients with thalamic and spinal cord diffuse midline glioma h k m mutants. background: brain tumors are the most common solid tumor of childhood and the leading cause of childhood cancer deaths. while medulloblastoma is the most common malignant brain tumor of childhood with a -year survival - %, children with high-grade gliomas (hggs) such as glioblastoma multiforme (gbm) fare much worse with a -year survival of - %. implicated in this poor outcome is the presence of treatment resistant brain tumor stem-like cells. gbm stem-like cells (gscs) have been implicated in tumor growth, treatment resistance and patient relapse, making them a key therapeutic priority. antipsychotic drugs (apds) have been used for decades in various psychiatric clinical settings and are associated with a lower incidence of cancer, including malignant brain tumors. currently, atypical apds are being evaluated for their potential to alleviate cancer and treatment induced side effects. furthermore these drugs may have direct anti-tumor effects, potentially via inhibition of dopamine d receptors (drd ). objectives: determine the anti-cancer effects of atypical apds on gbm stem-like cells design/method: the anti-cancer effects of apds (quetiapine and risperidone) were evaluated on gbm stem-like cell lines developed in our laboratory (glio and ) and the group medulloblastoma cell line hdmbo . cell proliferation/viability was determined using trypan blue exclusion and mts assays. the effect of apds on cancer stem cell self-renewal was determined by neurosphere assay. receptor expression and apds effect on cell cycle proteins were examined by western blot analysis. results: western blot analysis of gscs and hdmbo demonstrated robust drd expression indicating a viable therapeutic target. both apds induced dose dependent cell death of all cell lines tested. treatment with only um of either apd for days significantly reduced cell proliferation by % (hdmbo ) and - % (gscs). consistent with these findings, we observed an increase in cell cycle inhibitors p and p . furthermore at day both apds induced a robust increase in gsc death, approximately % compared to only % in non-treated controls. lastly, um apds significantly reduced gsc neurosphere formation compared to untreated controls by up to % suggesting inhibition of gbm stem cell self-renewal. our data indicates that clinically relevant concentrations (low micromolar) of these apds induce anticancer effects in both gscs, which are enriched with tumor initiation/propagation properties, and in the group (myc amplified) medulloblastoma cell line. these apds represent strong candidates as potential adjuvant therapies for the treatment of these brain tumors. background: while the poor prognosis for high risk neuroblastoma (hrnb) underscores the need for new treatment strategies, the elucidation of specific biologic subsets of neuroblastoma suggests a way to improve disease management. the identification of agents that target specific molecular pathways associated with the development or progression of diseases holds promise. dfmo, an inhibitor of odc, has been shown to decrease lin and mycn and target cancer stem cells in preclinical studies. currently % of patients undergoing immunotherapy relapse. dfmo is in studies to prevent relapse after immunotherapy and may be helpful during immunotherapy as well. the hypotheses for this study were that: ) the incorporation of a targeted therapy, selected based upon upfront tumor genomic interrogation, into standard induction chemotherapy for hrnb is safe, feasible and may increase the pr/cr/vgpr response rate at the end of induction therapy; and ) the addition of dfmo as maintenance during immunotherapy is safe and feasible and may decrease the relapse rate for hrnb. a multicenter feasibility pilot trial in subjects with newly diagnosed hrnb within the beat childhood cancer consortium. at diagnosis, patients' tumors underwent dna exome and rna sequencing which were analyzed within a molecular tumor board to identify the single best drug of targeted agents to be added to cycles - of induction chemotherapy. after consolidation with asct and radiation, the patients received dfmo along with standard dinutuximab and retinoic acid and dfmo for years after immunotherapy. patients were evaluated for additional toxicities with the addition of targeted agents and dfmo in addition to induction response. results: the pilot study of eligible patients has shown this process to be feasible. all patients have completed induction portions of the study. the combination of targeted agent with chemotherapy was shown to be safe without any unexpected toxicities. delays between induction cycles were < weeks and related to surgery, infection, or thrombocytopenia. the induction response demonstrated % cr/vgpr/pr rate, which suggests improvement over historical %. in addition, patients were eligible for the combination of dfmo with dinutuximab and retinoic acid was well tolerated and safe without additional toxicities due to dfmo. the pilot study of patients has shown the process of genomic sequencing and addition of a targeted agent to upfront chemotherapy and addition of dfmo to dinutuximab and retinoic acid maintenance therapy in newly diagnosed hrnb patients and is feasible and safe without any unexpected toxicities. background: identifying sub-populations of medulloblastoma tumors with stem cell-like properties holds promise for reducing disease recurrence, but there is no known unifying marker of medulloblastoma cancer stem cells. the granulocyte stimulating factor receptor (gcsf-r or cd ) is well understood in the context of hematopoiesis, but its role in solid tumor pathogenesis is less clear. neuroblastoma and melanoma subpopulations expressing gcsf-r have cancer stem cell properties of chemoresistance and increased tumorigenicity, and are enriched in tumors after chemotherapy. gcsf-r activation leads to signaling through the jak-stat pathway, suggesting a potential therapeutic target. we hypothesized that a subpopulation of medulloblastoma cells would express the gcsf-r and that this subpopulation would demonstrate chemoresistance and response to inhibitors of the jak/stat pathway. objectives: our objective was to identify a subpopulation of medulloblastoma cells expressing the gcsf-r and determine their relative growth rates, tumorigenicity, and responses to chemotherapy and jak/stat inhibition. design/method: medulloblastoma cell lines were sorted via flow cytometry for gcsf-r surface expression. subpopulations of gcsf-r-positive and -negative medulloblastoma cells were then monitored for growth by continuous live cell imaging. responses to chemotherapy were measured in subpopulations of gcsf-r-positive and -negative medulloblastoma cells using continuous live cell imaging to measure percent cell confluence and cell viability assays. ic values were calculated for each cell line and each agent. parental medulloblastoma cell lines and isolated gcsf-r-positive and -negative subpopulations were also treated with the jak / inhibitor ruxolitinib and growth rates, viability, and ic values were calculated. results: gcsf-r surface expression was identified on . - . % of medulloblastoma cell lines. isolated gcsf-r positive cells demonstrate a slower growth rate compared to gcsf-rnegative or parental unsorted medulloblastoma cells. gcsf-r positive cells are more resistant in vitro to vincristine, etoposide, and carboplatin, when compared to the gcsf-r negative population and an unsorted population of the same cell line. ruxolitinib is cytotoxic to medulloblastoma cells in vitro, with higher ic values noted in gcsf-r positive cells compared to unsorted and gcsf-r negative cells. we show that a subpopulation of gcsf-r positive cells are present in multiple medulloblastoma cell lines via flow cytometry, and that isolated gcsf-r-positive cells have a slower growth rate than gcsf-r-negative or unsorted populations. we also show that ruxolitinib has in vitro activity against medulloblastoma cell lines. we propose that jak inhibition may represent an adjunct therapy targeting overall tumor burden and specifically targeting the gcsf-r-positive subpopulation of medulloblastoma cells that may drive tumor recurrence. we investigated the efficacy of intensified adjuvant chemotherapy in osteosarcoma patients. design/method: we retrospectively analyzed the medical records of children with osteosarcoma treated at asan medical center between and . all patients received a -drug induction consisting of cycles of cisplatin and doxorubicin along with cycles of methotrexate (map), and proceeded to surgical resection. adjuvant ct was map or map with the additional ifosfamide and etoposide (mapie), and mapie was mainly considered for poor responders (tumor necrosis below %) or patients with metastases. results: among patients, patients had metastases at diagnosis. surgery was conducted in patients who responded to induction ct, and showed over % tumor necrosis. among patients who proceeded to adjuvant ct, and patients received to map and mapie protocols. with a median follow-up of months, the -year overall survival (os) and event-free survival (efs) rates of all patients were % and . %. of those patients, patients recurred, and of them died of disease progression. relapsed patients received salvage ct and/or surgery, and were rescued after autologous stem cell transplantation (sct). three patients developed treatment-related acute myeloid leukemia, and they are alive after allogeneic sct. according to the response to neoadjuvant ct, the os rates of good responders (n = ) and poor responders (n = ) were % and . % (p = . ), and efs rates were . % and . % (p = . ). of the poor responders, patients received map as adjuvant ct, and the other received mapie. the os rates of map and mapie group were . % and . % (p = . ), and efs rates were . % and . % (p = . ), respectively. when patients were classified into three groups: . localized disease & necrosis ≥ % (n = ), . localized disease & necrosis < % (n = ), . metastatic disease (n = ), survival rates were in the order of group > > (os = %: . %: . %, efs = . %: . %: %). in each group, intensified adjuvant ct by mapie did not improve survival outcomes. conclusion: initial metastatic disease and poor histological response to neoadjuvant ct were major risk factors for poor survival in osteosarcoma patients. we found that adding ifosfamide and etoposide to map did not improve survival outcomes of patients with adverse risk factors. more effective adjuvant therapy for these patients is needed. background: circulating cell-free dna (cfdna) that shed from tumors into circulation have been used for noninvasive molecular profiling in adult cancers but little is known about its utility in pediatric cancers. pediatric patients with metastatic and refractory solid tumors are known to have poor survival rates, and a key challenge in their management is obtaining biopsy samples especially at times when disease is widely spread or the patient is physically unfit for sampling. the development of a noninvasive profiling strategy is critical for optimizing molecularly guided therapy and assessing response to treatment. in this study, we want to determine the utility of cfdna to noninvasively analyze the molecular profiles of pediatric solid tumors such as neuroblastoma (nb), osteosarcoma (os), and wilms tumor (wt). design/method: tumor, plasma, and matched controls were collected from patients with nb, wt, and os, at diagnosis or time of disease progression. cfdna was extracted from the plasma and analyzed through multiple methodologies including a targeted next generation sequencing panels and shallow whole genome sequencing (swgs). results: fifteen nb patients, os patients, and wt patients had tumor molecular profiles known from different targeted next-generation sequencing platforms. in the cfdna of / nb patients, somatic mutations and copy number alterations previously reported in the tumors were detected, including recurrent nb drivers such as mycn amplification, alk, and atrx mutations. mutations not detected in the original tumor were also found in / nb patients including nras, mll , arid b, some of which are potentially actionable. in os, mutations known from the tumor were found in the cfdna of of patients, including atrx and notch mutations, as well as copy number alterations such as cdk amplification, which has targetable therapeutics available. of the two wt patients analyzed, cfdna revealed the same mutations as tumor in one patient, however in a cohort of patients where tumor was not available, cfdna revealed recurrent driver mutations such as amer , dicer . it is feasible to noninvasively identify somatic mutations and copy number alterations in cfdna of patients with pediatric solid tumors. establishing a platform using cfdna to identify molecular profiles of these tumors can serve as a powerful tool for guiding treatment and monitoring response to treatment. background: despite multi-modality therapy, the prognosis for patients with metastatic osteosarcoma remains poor necessitating development of novel targeted therapies. immunotherapy can be exploited to target osteosarcoma with exquisite specificity but remains limited by insufficient tumor specific targets. objectives: to overcome the dearth in tumor specific antigens, we have explored the use of tumor derived mrna (representing a tumor specific transcriptome) for development of personalized nanoparticle vaccines. design/method: rna-nanoparticles (rna-nps) can be amplified from limited amounts of biopsied tissue for induction of tumor specific t cells against osteosarcoma. since local vaccination strategies are mired by poor overall immunogenicity, we assessed the feasibility, immunogenicity and antitumor activity of intravenously administered rna-nps (tumor mrna complexed to dotap nanoliposomes) in pre-clinical murine and canine tumor models. we identified a clinically translatable np formulation for the delivery of rna to antigen presenting cells (apcs) that induces in vivo gene expression and preserves rna stability over time. tumor derived rna-nps induced antigen specific t cell immunity and mediated anti-tumor efficacy in several pre-clinical solid tumor models (i.e. b f , kr b). when administered intravenously, rna-nps increased expression of co-stimulatory molecules (i.e. cd , cd , cd , ccr ) and pd-l on cd c+ cells throughout reticuloendothelial organs (i.e. spleen, liver, bone marrow) and within the tumor microenvironment; this phenotype was strictly dependent on type i interferon. targeted inhibition of type i interferon signaling (via infar mabs) abrogated anti-tumor efficacy mediated by rna-nps. we enhanced the immunogenicity of this platform by simply combining mrnas encoding for immunomodulatory molecules (i.e. hcv-pamps, gm-csf) or by combining rna-nps with immune checkpoint inhibitors. addition of checkpoint inhibitors (pd-l mabs) to rna-nps increased tumor infiltrating lymphocytes, and intratumoral mhc class i/ii expression, and mediated synergistic anti-tumor activity in settings where pd- or pd-l inhibition alone did not confer therapeutic benefit. we then explored the feasibility of rna-nps in a large animal osteosarcoma model. in ongoing studies for canines with osteosarcomas, we have shown that sufficient amounts of rna can be extracted, amplified, and manufactured into personalized rna-np vaccines. conclusion: rna-nps reprogram systemic immunity and mediate anti-tumor activity providing near immediate immune induction without the complexity of cellular immunotherapy. the immune correlate of preclinical response to rna-nps is hallmarked by interferon dependent pd-l expression on activated apcs (cd c+ mhcii+ cd + cells). based on these findings, we are exploring the preclinical safety, efficacy and immunologic effects of rna-nps targeting canine osteosarcoma before first in-human evaluation. background: ewing sarcoma is an aggressive bone tumor affecting mainly adolescent and young adults. treatments are based on compressed schedule chemotherapy combined with local control (surgery and/or radiation). prognosis is poorer for patients with metastatic disease, older age and central primaries. survival when disease recurs within two years of diagnosis is < %. the ews-fli fusion gene t( ; ) (q ; q ) has been well characterized as a dominant ews driver-gene. the most common variation is ews exon with fli exon ( % of fusion positive patients). we designed a novel pbi-shrna tm ews/fli type lpx which has demonstrated, safety and efficacy in animal model (rao et all). the pbi-shrna strategy silences target gene expression by concurrently inducing translational repression and p-body sequestration as well as post-transcriptional mrna cleavage. to determine the safety and maximum tolerated dose of intravenous administration of pbi-shrna tm ews/fli type lipoplex in patients advanced ews. design/method: phase i study × escalation cohort. testing pbi-shrna tm ews/fli type lpx (starting iv dose of . mg/kg) on patients (≥ age ) with advanced ewing's sarcoma, all with a type translocation. intravenous infusion was given twice a week for weeks with the following escalation schema: % → % → % → % → %. required kps > % and adequate organ function. cytokines induction pre and post-infusion was analyzed (il- , il- , tnf-alpha, il ra). first cohort of patients has been enrolled (ages between - years). three relapsed patients had > lines of therapy and patient had refractory disease, patients received a complete cycle of pbi-shrna tm ews/fli type lpx with twice a week infusions. a total of doses were given. the most prominent related toxicity has been hematological, patient developed transient g neutropenia, another patient developed g anemia that required prbc transfusion, and of note this patient had significant bone and bone marrow involvement. one patient only received two lpx infusions; she developed a fatal rsv pneumonia. other reported grade toxicity includes fatigue and headache. evaluable patients (n ) had stable disease between and months before progression. one patient had sustained response for month before progression, two patients are still alive. our preliminary experience supports the safety and potential efficacy of pbi-shrna tm ews/fli type lpx as novel treatment for advanced ews with limited toxicity. il- increase correlates with higher bi-shrnai ews/fli lpx infusion rate and clinical symptoms. further clinical testing is indicated. background: as more children with cns malignancies (bt) are surviving, the late effects of the therapies they receive are better described. studies show that radiation therapy is particularly harmful to neurocognitive functioning, specifically processing speed, working memory, and attention span. these deficits have negative effects on quality of life, especially in academic and professional settings. a large proportion of s of s adult survivors of bt are unable to reach adult milestones such as living on their own, holding a steady job, and getting married. proton beam radiation therapy (pbrt), is touted for the potential to have fewer and less severe side effects than traditional photon radiation therapy (xrt). because of the properties of protons, the amount of damaging energy released in non-target healthy tissue is reduced when compared to xrt. although a study comparing iq testing between pbrt and xrt found no difference between the two therapies, no studies have compared the specific neurocognitive domains. it would be valuable to evaluate full neurocognitive testing scores (nct) since the specific domains, particularly processing speed (psi), appear to be most vulnerable to radiation therapy. objectives: our primary aim was to assess differences in psi for patients with bt who underwent pbrt versus xrt. a secondary aim was to assess differences in iq (fsiq) and working memory (wmi). we retrospectively evaluated all patients treated for bt at the jimmy everest cancer center within the past years who received rt and had nct post radiation. we examined the full nct results for both subsets of participants to evaluate differences in the specific domains of processing speed, working memory, and iq by measuring percentiles scored in these domains. objectives: we report our experience on imaging children with mm treated uniformly on an institutional melanoma trial. we retrospectively reviewed the clinical and imaging findings of patients with ajcc stage iic-iv cutaneous mm treated on our institutional mel protocol. brain mri/ct, pet/ct, ct chest, abdomen, and pelvis (ctcap) were performed at diagnosis in all patients. on treatment, stratum a patients (peg-interferon; ajcc iic, iiia, iiib) (n = ) had the same imaging repeated every months; stratum b (peg-interferon and temozolomide; unresectable measurable disease metastatic, or recurrent) (n = ) had pet scans every months and brain imaging every months; those in stratum b (peg-interferon and temozolomide; unresectable non-measurable, metastatic, or recurrent) (n = ) had the same imaging performed every months. off therapy all patients continued same imaging every months for years. results: there were patients ( female; median age years). eleven had spitzoid and conventional melanoma. primary sites included head/neck (n = ), trunk (n = ), and extremities (n = ). patients with spitzoid melanoma had imaging studies ( pet, ctcap, ct chest, ct brain, and mri brain) with a median of , , , and studies/patient respectively. median cost per patient was $ , . thirteen studies ( . %) showed suspicious lesions with additional scans and diagnostic biopsies of which one only was positive stratum a with tert promoter mutation and died from disease). for conventional mm, studies ( pet, ctcap, ct chest, ct brain, and mri brain) were performed with a median of , . , , , studies/patient respectively. median cost per patient was $ , . twenty ( %) showed suspicious lesions with additional scans and diagnostic biopsies; four were positive (two at diagnosis); both died of disease; the other two recurred locoregionally and were detected clinically; both are alive and disease free; one patient had diffuse metastases and died shortly after enrollment. after a median follow up of . years (range . - . ) patients are alive and disease free. children with spitzoid melanoma should have minimal imaging at diagnosis and follow-up given the low risk of recurrence and low yield and high cost of aggressive imaging protocols. patients with conventional mm should be imaged according to the adult guidelines. nationwide children's hospital, columbus, ohio, united states background: the role of infections in the long term outcome of patients with bone tumors is controversial. two retrospective studies have shown increased survival in osteosarcoma patients who had a post-operative wound infection, while another showed no changes in overall survival. to determine the relationship between wound infections and/or bloodstream infection (bsi) on survival in pediatric and young adult patients with osteosarcoma and ewing sarcoma treated at a tertiary children's hospital. design/method: a retrospective chart review was performed for patients with diagnosis of osteosarcoma or ewing sarcoma from - . patients received standard chemotherapy regimens for their disease type and stage. local control included surgical resection and/or radiation therapy. presence of infection was determined by bsi or wound cultures while receiving treatment for primary tumor. the median age of patients was (range - years) at diagnosis. % had a diagnosis of osteosarcoma and % had ewing sarcoma. of these, % of patients developed an infection during treatment; % had bsi, % had wound infections, and % had both. patients with bsi had a year os of . %, compared to % in those without bsi (p = . ). those with both bsi and wound infections had the poorest overall survival of %, compared to . % for patients without any infection. patients with wound infections alone had a year os of . %, compared to % of patients without a wound infection. our analysis revealed decreased os in patients with bsi; however, this could be due to other confounding factors in the presence of bsi. those with bsi or bsi and wound infections had the poorest survival. wound infections without bsi were associated with a slight increase in survival; however, this study was limited by the number of patients that had local wound infections. with the use of newer surgical techniques, availability of antimicrobials and routine use of prophylactic antibiotics, the incidence of infections while undergoing treatment is low. however, the importance of this clinical observation indicates a likely enhanced immune system associated with infection, supporting the role of immunotherapy for treatment of these aggressive tumors. background: hypoalbuminemia is a well-recognized effect of cancer and other chronic illnesses and is often regarded as a marker of malnutrition. in adults, hypoalbuminemia has been associated with adverse outcomes in patients with cancers of the lung, pelvis, head and neck, gastrointestinal tract, and bone marrow, as well as in some pediatric patients with ewing sarcoma and hodgkin lymphoma. hypoalbuminemia has not been well studied in children with cancer. to determine the incidence of hypoalbuminemia (using age-specific references) in children with cancer receiving chemotherapy at baseline (prior to starting chemotherapy) and to determine whether hypoalbuminemia is associated with inferior -year overall survival. design/method: we performed a single institution, irbapproved, retrospective review of pediatric oncology patients diagnosed between and . five-year survival was estimated using the kaplan-meier method; groups were compared using cox regression. we identified pediatric patients with a first diagnosis of cancer, brain tumor, or other condition possibly requiring chemotherapy. of these patients, were excluded for reasons including not receiving chemotherapy and missing data, leaving patients who had a serum albumin level within days prior to starting chemotherapy. the mean age was . years (sd . years); % were male; % were non-hispanic. the most common diagnosis was acute lymphoblastic leukemia ( of ; %). one hundred thirty nine of ( %) had hypoalbuminemia prior to starting chemotherapy. there was no statistically significant difference in -year overall survival between those with and without hypoalbuminemia ( % vs. %, respectively; hazard ratio . , % c.i. . - . ). conclusion: hypoalbuminemia at baseline in pediatric oncology patients requiring chemotherapy is common (one in five), and was not associated with inferior -year overall survival in this cohort. leptomeningeal metastases at diagnosis. standard treatment for completely resected, non-anaplastic supratentorial ependymomas is close observation. treatment for anaplastic or incompletely resected non-anaplastic ependymomas is maximal safe surgical resection followed by focal radiation. however, up to % of localized ependymomas recur. the role of chemotherapy in treating ependymomas is under investigation. extraneural metastases of anaplastic ependymomas have rarely been reported and the outcome is dismal. objectives: to report extraneural cervical node metastases of a non-anaplastic ependymoma and successful treatment with surgical resection, radiation, and systemic chemotherapy. design/method: retrospective review of patient medical records, including radiographic imaging and tumor tissue pathology, and comprehensive literature review. results: a previously healthy -year-old girl underwent gross total resection (gtr) of an isolated right parietal lobe ependymoma (who grade ii). at age years, magnetic resonance imaging (mri) revealed an isolated localized recurrence. she underwent gtr followed by observation. at age years, she again experienced isolated localized recurrence and underwent gtr followed by . gy focal conformal photon radiation. at each recurrence, pathology revealed a non-anaplastic ependymoma, and cerebral spinal fluid (csf) cytopathology and spine mri were negative. at age years, she developed an enlarged right posterior cervical chain lymph node. subsequent mri revealed a large rim-enhancing, t hyperintense lymph node and multiple abnormally enhancing regional nodes consistent with metastases. biopsy revealed a non-anaplastic ependymoma. mri of the brain and spine, computed tomography of the chest, abdomen, and pelvis, and csf and marrow evaluations were unremarkable. chemotherapy according to acns was initiated. mri after course demonstrated significant node size reduction. she underwent right neck node dissection. only one right level ii lymph node showed metastases. she was treated with . gy irradiation to the neck and additional courses of chemotherapy. she remains in remission months and months after diagnosis of metastatic disease and end of therapy, respectively. literature review reveals rare reports of extraneural metastatic disease of anaplastic ependymomas to bone, lung, or liver, and only involving lymph nodes, all associated with a poor outcome despite multimodal therapy. to our knowledge, this is the first report of extraneural metastases of a non-anaplastic ependymoma. extraneural metastases should be considered in children previously treated for non-anaplastic ependymomas who experience systemic symptoms, even in absence of cns relapse. multimodal treatment offers potential long-term disease control with acceptable toxicity. arun gurunathan, joel sorger, andrew trout, joseph pressey, rajaram nagarajan, brian turpin cincinnati children's hospital medical center, cincinnati, ohio, united states background: pigmented villonodular synovitis (pvns) is a benign neoplasm of the synovium. standard treatment is surgery, but post-operative recurrence rate is as high as %. radiation therapy can be used for local control, but is associated with late effects. while pvns is rarely fatal, aggressive disease and/or extensive surgery can result in substantial functional impairment. colony stimulating factor- (csf ) overexpression, often due to chromosomal translocation involving csf , drives pvns through recruitment of synovial-like mononuclear cells expressing the csf -receptor. tyrosine kinase inhibitors such as imatinib are active against the csf -receptor, and have shown benefit in the post-surgical relapse setting. however, questions remain regarding the broader application of imatinib and regarding optimal response assessment. to present three patients with pvns, each with different clinical scenarios, who demonstrate clinical response to imatinib monitored by changes in metabolic activity (maximum suv) on pet/ct. results: three patients with pvns demonstrate pet/ct response to imatinib, guiding management of their challenging clinical scenarios. patient is a year-old female with left hip pvns and high grade articular cartilage loss, with decrease in metabolic activity (suvmax . to . in months) on neoadjuvant imatinib, enabling total hip replacement surgery planning. patient is a year-old female with left knee pvns with recurrences after synovectomies, spared subsequent surgical control attempts after clinical improvement correlating with pet/ct response to imatinib (suvmax . to . in months). patient is a year-old male with right knee pvns that recurred after total knee replacement, now with clinical improvement correlating with pet/ct response to imatinib (suvmax . to . in months). all patients would have been characterized as stable disease by response evaluation criteria in solid tumors (recist). in each of these patients, imatinib has been tolerated well, with no therapy interruptions and absent or easily managed side effects (one patient takes dronabinol for decreased appetite, one patient takes prn immodium for diarrhea). all patients are currently still taking imatinib, with therapy length ranging from five to eleven months. in our series of three patients with pvns, imatinib shows promise for disease management in neoadjuvant and adjuvant settings with a tolerable side effect profile. imatinib should be considered in the treatment of pvns to spare surgical and radiotherapy related morbidity, and treatment effect can be monitored by pet/ct. background: metastatic rhabdomyosarcoma (rms) carries a poor prognosis with three-year event free survival rates ranging between %- % (depending on oberlin risk factors) due to the lack of significantly effective breakthroughs in the recent past. there is an urgent and unmet need for new treatment strategies against this disease. metastatic rms cell lines exhibit increased expression of the erm family membrane-cytoskeleton linker protein ezrin. knockdown of ezrin expression using sirnas decreases the metastatic potential of these cells, whereas forced expression of ezrin results in increased degree of metastasis. the activity of ezrin is controlled by its phosphorylation at the threonine (thr ) residue at the c-terminus of the protein, suggesting that alteration of ezrin phosphorylation may control rms growth and metastasis. our goal was to determine if pharmacological inhibition of thr phosphorylation in ezrin affects the growth, survival and metastasis in rms in vitro as well as in vivo. design/method: rms cell lines representative of the alveolar and embryonal histological subtypes were used. rms cells were treated with a small molecule inhibitor of ezrin, nsc , which specifically dephosphorylates ezrin at the thr residue. baseline expression of ezrin and perm levels as well as the effect of nsc on perm levels in the rms cell lines was determined by western blotting of cell lysates. viability of cells was assessed by trypan blue exclusion, and morphology visualized by bright field microscopy. the extent of apoptosis was detected by imaging caspase / activation using fluorescent microscopy. motility of rms cells was examined by performing a wound-healing assay. subcutaneous and orthotopic xenografts were established in nsg mice using rd cells (embryonal rms). mice harbor-ing xenografts were treated with intraperitoneal injections of nsc or dmso. results: ezrin is constitutively phosphorylated at the thr residue in a majority of the rms cell lines examined. nsc dephosphorylates ezrin at the thr residue in these cell lines. treatment with nsc inhibits growth, induces apoptosis and inhibits the migration of rms cell lines in vitro. further, treatment of nsg mice bearing subcutaneous or orthotopic embryonal rhabdomyosarcoma xenografts with nsc significantly impedes tumor progression without any obvious adverse effects. our findings suggest that dephosphorylation of ezrin at the threonine residue may have the potential to be a novel therapeutic strategy for rms patients. all india institute of medical sciences, new delhi, new delhi, delhi, india background: the role of laparoscopy in the management of pediatric intra-abdominal solid tumors is yet to be established. the safety of laparoscopic management of pediatric intra-abdominal tumors is still questionable. we study the results of the initial case series of pediatric intraabdominal tumors managed laparoscopically at our institute from july onwards. design/method: total children ( -males, females) who presented to us with pediatric intra-abdominal tumors were included. the tumors included wilms tumor (n = ), neuroblastoma(n = ), adrenal cortical tumor(n = ), ovarian teratoma(n = ).children were between months - years and received neo-adjuvant chemotherapy. a -port laparoscopic nephrectomy and lymph node sampling for wilms tumor and adrenalectomy for adrenal tumors was performed. the tumors were removed in-toto with no rupture (except in one). specimens were retrieved through a lumbar incision (n = ) or an inguinal incision(n = ). all the children are under regular follow up. two children with wilms tumor had recurrence. the neuroblastoma child underwent open surgery for recurrence later. conclusion: laparoscopy/laparoscopic assisted removal of pediatric intra abdominal tumor is a feasible and safe option. it has the advantage of less postoperative pain, shorter hospital stay and a better cosmetic result. proper patient selection, port placement and laparoscopic experience are contributory. background: targeting of proteins and cell surface antigens specific to cancer cells with monoclonal antibodies has proven to be an effective form of treatment in many forms of cancer. gd is a cell surface disialoganglioside that is expressed on the cell surface of some normal tissues including nerve cells, melanocytes, and mesenchymal stromal cells and is overexpressed in some pediatric cancers like neuroblastoma and osteosarcoma. dinutuiximab is a chimeric monoclonal antibody that is fda approved for the treatment of patients with high risk neuroblastoma and under investigation for the treatment of relapsed osteosarcoma. little is known about the patterns of gd expression in other pediatric malignancies. objectives: we sought to describe the patterns of gd expression in the following pediatric sarcomas: synovial sarcoma, rhabdomyosarcoma and ewing sarcoma. design/method: synovial sarcoma (n = ), rhabdomyosarcoma (n = ) and ewing's sarcomas (n = ) formalin fixed, paraffin embedded cores were obtained from the seattle children's research institute tissue microarray (tma) biorepository. tma blocks consisting of melanoma cores stained with and without gd antibody were used as positive and negative controls, respectively. slides were incubated with anti-ganglioside gd antibody clone q (ab from abcam) diluted : in % normal goat serum and % bsa in tbs overnight at ˚c. the negative control of human melanoma section was incubated in % normal goat serum and % bsa in tbs without primary antibody. the expression of gd was indicated by characteristic brown diaminobenzidine staining. the intensity and location of tissue staining were assessed and compared to positive and negative controls. staining was considered positive (+++) if the intensity of the staining was consistent with that of the positive control with - % of cells staining positive. classification of intermediate gd expression (++) was assigned to slides in which - % of cells stained positive. slides were classified as sporadic staining (+) if - % of cells stained positive. tissue was considered (-) if there was complete absence of staining, similar to the negative control. objectives: to evaluate the clinical presentation, management and treatment outcomes of children with malignant germ cell tumor at our institute design/method: a prospective study was conducted from june to dec in the department of pediatric surgery in a tertiary care institute in a developing country. all patients were evaluated for local disease and metastatic disease by imaging and tumor markers. risk stratified chemotherapy was used with low risk tumor receiving no chemotherapy, intermediate risk: courses of peb chemotherapy and high risk: courses of peb + courses of pe. upfront resection of the primary or the residual disease after neoadjuvant chemotherapy if feasible was performed. follow up was done with monthly tumor markers for months and imaging studies every - months for initial years. five year overall survival and disease free survival was calculated. results: during the study we treated children who formed the study group. of these ( %) were gonadal ( ; % testicular and ; % ovarian) and the remaining ( %) were extragonadal with sacrococcygeal (sct) being the most common site ( %). one hundred and thirteen children ( %) presented to us primarily while the remaining had received treatment elsewhere. stage or stage disease at presentation was present in ( %) children. recurrence was noted in ( %) patients. respectively. patients with testicular mgct and children with age - years and males had significantly poor rfs rates. conclusion: patients with mgct should be staged correctly and adjuvant chemotherapy is advisable to all patients except stage i endermal sinus tumor of testis. awareness regarding the same is still lacking in our country. meticulous follow up is needed as more than % of will recur. cure rates are dismal in children with recurrent mgct especially those who are not chemotherapy naïve. nemours children's specialty care, jacksonville, florida, united states background: radiotherapy for pediatric head and neck tumors often results in mucositis, limiting oral intake and compromising patients' nutritional status. this may be reduced through the improved conformality offered by proton therapy. despite widespread use of enteral tube feeding through a percutaneous gastrostomy (peg) or nasogastric tube (ngt), there is little data available regarding overall incidence of ngt/peg placement and perspectives of pediatric patients and caregivers. objectives: to (a) estimate the need for ngt/peg support and (b) characterize patient and caregiver perceptions surrounding enteral feeding in children with head and neck tumors undergoing proton therapy. design/method: dependent on development stage, patient (n = ) or parents (n = ) filled out a series of customized surveys according to a prospective irb approved study. seventythree percent of patients also received concurrent chemotherapy. questions addressed their current feeding route and perception, for example, "what aspect(s) of tube feedings are beneficial to you?" and "what aspect(s) of tube feeding worry or scare you?" fifty-five surveys were distributed before and after radiation, and with any change in feeding route. results: at the start of proton therapy, patient had a ngt and patients had peg. of these, patients ( %) had a ngt/peg in place exclusively for the administration of medication; only patient ( %) needed a ngt/peg for nutrition. in those patients without ngt/peg, % would "consider" enteral feeds. in patients without ngt/peg, the most commonly cited benefit was "maximizing my nutrition" ( %) and the most common negative aspect was "fear" of tube placement ( % of patients). all sub-populations ( % of patients) cited change in appearance as a negative aspect. in patients without ngt/peg at the start of proton therapy, % of patients/caregivers felt enteral feeding to be "unnecessary," and % of these patients would not "consider" ngt/peg even if their "physician advised it." over the course of proton therapy, the patients/caregivers who deemed enteral feeding "unnecessary" decreased from % to %. at completion of treatment, patients ( %) were using a ngt/peg tube for nutritional support but only one ( %) patient relied exclusively on their enteral feeds. two patients (without ngt/peg) ( %) required parenteral support. our data does not support prophylactic placement of ngt/peg in of children with head and neck tumors undergoing proton therapy. ongoing research is needed to identify which patients will need ngt or peg to supplement their diet. in this cohort, anticipatory counseling should focus on pain, cosmesis, and utility. children's national medical center, washington, district of columbia, united states background: ovarian sex cord-stromal tumors (osct) are rare neoplasms that typically present with signs/symptoms of an adnexal mass and signs of hormonal production approximately % of ovarian sex cord-stromal tumors in children are sertoli-leydig cell tumors (slct) with median age of presentation years overall. to our knowledge the youngest reported case in the literature describes a -month old female in china with a slct that was treated with oophorectomy alone. some studies have found an association in families between pleuopulmonary blastoma and osct with a germline mutation leading to dicer syndrome, which has been associated with a younger age at diagnosis. , objectives: to describe an unusual case presentation of slct in an infant results: -month old, twin female, ex- week premature infant presented to the emergency department on multiple occasions for abdominal distention and feeding intolerance initially thought to be related to previous omphalocele repair and umbilical hernia. an ultrasound demonstrated an × cm mass arising from the right ovary with large volume ascites. she required admission to the intensive care unit due to s of s respiratory distress from her significant ascites. serum tumor marker including hcg, afp and ldh were negative. patient underwent right oophorectomy with tumor capsule noted to be open at time of surgery. further imaging post operatively demonstrated no other sites of disease. the patient was classified as figo stage ic due to the presence of her significant abdominal ascites that was presumed to be malignant pre-operative tumor rupture. the pathological diagnosis was challenging and eventually resulted as a mixed germ cell sex cord stromal tumor with pattern of sertoli cell tumor with neuroendocrine differentiation. based on the staging of figo ic with pre-operative rupture, the decision was made to treat with a standard platinum based regimen as there is a higher incidence of relapse in stage ic patients when compared to ia treated with observation alone. our patient tolerated four cycles of chemotherapy well and end of therapy scans showed no evidence of disease. interestingly, her dicer mutation genetics performed by ion torrent tm next generation sequencing was negative in germline and tumor studies. to our knowledge, our patient is the youngest described with slct. she will continue to be followed with serial imaging alone as she had no evidence of elevated tumor markers at diagnosis. , due to young age and unusual diagnosis, she was referred to cancer genetics team. background: approximately % of patients with wilms tumor (wt) have metastatic disease at diagnosis and often have a grave prognosis. limited cell lines are available for the study of metastatic wt and long-term passaged cell lines do not always recapitulate the human condition. focal adhesion kinase (fak) is a non-receptor tyrosine kinase that controls cellular pathways involved in the tumorigenesis of pediatric renal tumors. using a novel patient-derived xenograft (pdx) model from a patient's primary wt (coa ) and matched isogenic metastatic wt (coa ), we previously demonstrated that fak is expressed and its inhibition led to decreased tumorigenicity of both the primary and metastatic pdxs. kinomic profiling is an innovative, high-throughput method used to investigate kinase signaling to identify potential therapeutic targets. to date, the kinomic profile of primary and metastatic wt has not been examined. objectives: investigate baseline kinomic differences between primary and metastatic wt and evaluate kinases upstream and downstream of fak as potential targetable therapies. design/method: cells from coa and coa were treated with pf- , (pf), a small molecule fak inhibitor. protein from cell lysates of treated and untreated coa and coa were combined with kinase buffer, atp, and fluorescently labeled antibodies and loaded into a phosphotyrosine kinase or serine-threonine kinase pam-chip® per the uab kinome core protocol. phosphopeptide substrate analysis with the pamstation® kinomics workstation (pamgene® international), pamchip® protocol using evolve software, and bionavigator v. . were used to analyze kinases upstream and downstream of fak. the primary wt had increased epha , ror sgk and decreased pdgfrb relative to the paired metastatic wt at baseline. treatment with pf increased ron, pdgfrb, p s kb, mak, camk g, vacamkl, camk d, ck a and pskh in the primary wt. treatment with pf decreased tnk , lmr , cck , epha , pdk , sgk , lkb and increased pskh in the paired metastatic wt. primary wt displayed a different kinomic profile compared to metastatic wt in a matched isogenic pdx model. these data reveal that alternative therapies to specifically target metastases are needed. furthermore, fak inhibition resulted in diverse kinomic alterations between primary and metastatic wt. inhibitors targeting many of these pathways, such as pdgfrb inhibitors, are currently available and potentially could be combined with fak inhibitors in the treatment of wt. the results of the current study indicate that kinases upstream and downstream of fak in primary and metastatic wt warrant further investigation. background: use of high-dose methotrexate (hd-mtx, g/m^ ) is a mainstay of standard therapy for pediatric osteosarcoma (os) in north america. in pediatric os, there is a narrow therapeutic window for hd-mtx, with decreased tumor response rate with mtx concentrations < m and decreased survival due to severe toxicity with concentrations > m. risk factors for hd-mtx toxicity have been defined in adults, including body mass index (bmi) and male gender, but such studies have not been conducted in children. we sought to examine the relationship between mtx levels and toxicities during hd-mtx infusion for pedi-atric os, thereby identifying risk factors for increased toxicity and providing a framework for therapeutic drug monitoring. design/method: this retrospective chart review included patients treated at texas children's hospital with hd-mtx as first-line therapy for os from - . data abstracted from electronic records included patient characteristics, bmi and body surface area (bsa), baseline and post-treatment laboratory values, mtx levels and hours after dose given ( h, h), hour mtx cleared (mtx < . um), grade / mucositis, myleosuppression, persistent lft elevation (ctace v . ), and % tumor necrosis. correlation between h mtx level and other covariates was summarized using descriptive statistics. we reviewed hd-mtx infusions corresponding to patients. bmi was found to significantly impact h mtx level (p< . ). female gender was also significantly associated with higher h mtx level (p< . ). percent necrosis (available in patients) was associated with h mtx levels at near-statistical significance (p = . ). h mtx level was not found to contribute to toxicities or associate significantly with mtx clearance. analysis in a larger cohort is ongoing. we have identified at least one patient factor (bmi) that significantly impacts h mtx levels and is of potential use for future modeling, as current models incorporate bsa only. our findings concord with studies in adult os in that bmi significantly impacts h mtx level but diverge in that female gender is associated with higher h levels. importantly, these data support targeting h mtx levels to ensure that minimum concentration for adequate tumor necrosis is reached. these results do not suggest that monitoring h levels would prevent toxicities, thus necessitating further characterization of any intrinsic patient factors that associate with toxicity. overall, our definition of the clinical factors that associate with h mtx levels contributes to a framework for therapeutic drug monitoring in pediatric os. children 's mercy hospital kansas city, kansas city, missouri, united states background: post consolidation immunotherapy with dinutuximab, aldesleukin (il- ), granulocyte macrophage colony stimulating factor (gmcsf) and isotretinoin is standard of care for children with high risk neuroblastoma. dinutuximab is combined in alternating cycles with s of s gmcsf or il , followed by a th cycle with isotretinoin alone. il- is administered as a hour continuous infusion on days - at miu/m /day followed by a higher infusion dose, . miu/m /day, in combination with dinutuximab on days - of cycles and . the miu/m /day dose may be administered inpatient or in the ambulatory setting. objectives: to retrospectively compare the incidence of inpatient and outpatient side effects and complications associated with low dose ( miu) il to provide the tolerability data necessary to evaluate these venues for future administration options. design/method: this study was a descriptive, singlecentered definitive study utilizing a retrospective convenience sample population of children with high risk neuroblastoma who received low dose il either as an inpatient or an outpatient without exclusion from may to june . subjects were identified by a tumor registry query post irb approval. electronic and paper medical records were reviewed for the dates and location of the infusions, the home health company used if applicable and all documentation regarding clinical status, side effects and toxicity. demographics was limited to age and gender. results: infusion venue was chosen by provider preference. twenty-six infusions, inpatient and outpatient via separate home health companies were all administered in entirety and without interruption. there were males and females ranging from - years of age. two children received a single outpatient infusion due to intolerance of il when combined with dinutuximab and received therapy in both settings. fever, inpatient and outpatient was the only common side effect. no source of infection was ever identified. there was one incidence of diarrhea and one patient with pruritus in both the outpatient and inpatient settings respectively. no planned outpatient infusions required subsequent admission however the outpatient fever did necessitate an er evaluation. conclusion: low dose il can successfully be administered outpatient. the medication has minimal side effects with fever occurring in %, none of which were associated with infection. no outpatient infusion required a subsequent admission. no patients who received cycle infusions outpatient opted to receive the next cycle inpatient. baylor college of medicine, houston, texas, united states background: metastatic ewing sarcoma (es) has an extremely poor overall survival, necessitating investigations into molecular mechanisms to identify novel targets and develop new therapies. we previously performed an in vivo study, using our mouse model, designed to provide insights into transcriptomic and proteomic signatures for metastatic es to identify potential therapeutic targets. comparing profiles of primary tumors to corresponding metastatic lesions, we identified aberrant expression of integrin ß (itgb ) and downstream activation of integrin-linked kinase (ilk) in metastatic lesions compared to primary tumors, implicating this pathway as a key regulator in the ability of es to establish and enhance metastasis. our hypothesis is that upregulation of itgb and its downstream signaling events play a key role in es metastasis and are viable therapeutic targets. objectives: to investigate the role of itgb and its downstream signaling pathways in driving the establishment and enhancement of metastasis in es and to investigate this pathway as a potential therapeutic target. to investigate the role of itgb and ilk in es metastasis, we used sirna to knock down itgb and ilk expression in established es cell lines and then performed functional assays in vitro, including cell proliferation and invasion/migration assays. we also tested inhibition of this itgb signaling pathway using available small molecule inhibitors targeting itgb , ilk and the downstream target ap- , using cilengitide, compound and sr , respectively. we are currently using these small molecule inhibitors as treatment in vivo and assessing rates of metastatic tumor formation. we generated stable itgb and ilk overexpression and knockdown cell lines, which we are using for similar in vitro and in vivo investigations. knockdown of itgb and ilk in our sirna cell lines resulted in decreased cell proliferation and decreased invasion and migration compared to controls. we also found significantly decreased cell proliferation using each of the small molecule inhibitors in vitro. our preliminary studies using compound in vivo established a safety profile and dose escalation is underway to assess the effectiveness of inhibiting es metastasis. these results support our hypothesis that itgb and its downstream signaling events play a key role in the ability of es to establish metastatic foci and may serve as a potential therapeutic target. we continue to investigate this pathway in vitro. we are also using our small molecule inhibitors and itgb and ilk overexpression and knockdown approaches to study these effects on metastatic tumor development in vivo using our mouse model. background: neuroblastoma (nbl) is characterized by phenotypic heterogeneity. outcome is excellent for patients with low-(lr) and intermediate-risk (ir) disease, whereas only % of high-risk (hr) patients will survive. -hydroxymethylcytosine ( hmc) is an epigenetic marker of active gene transcription, and hmc profiles are prognostic in many types of adult cancers. we hypothesized that hmc profiles will serve as robust biomarkers in children with nbl tumors, refining current risk stratification. objectives: analyze genome-wide hmc in nbl tumors and correlate hmc deposition with chromosomal copy number and gene expression. design/method: hmc was quantified by nano-hmc-seal-seq from the dna extracted from hr, ir and lr nbl tumors. read counts and clinical data were analyzed with deseq to identify genes with differential hmc patterns between risk groups. chromosomal copy number was assessed by chromosomal microarray analysis (cma) in a subset of samples ( lr and hr). expression of genes located on chromosome p was evaluated using publically available microarrays (e-mtab- ) of hr nbl tumors with known p loh status. results: globally, lr tumors had more hmc peaks ( , ) than ir ( , , p = . ) tumors, or hr tumors ( , , p = . ). , genes had different patterns of hmc deposition in hr versus lr tumors. ( %) of these genes mapped to chromosome p and had decreased hmc in hr versus lr tumors (padj < . ). in the cma analysis p deletion was detected in of the tumors tested. in the tumors with p loss, genes that map to p showed decreased hmc deposition compared to the hr tumors without p loss (p< . ). further, compared to the tumors without p loss, the expression of of the p genes was decreased (p< × - ), including chd , camta , and arid a, known and proposed tumor suppressor genes in nbl. conclusion: different patterns of hmc accumulation are associated with neuroblastoma risk classification. nano-hmc-seal-seq is sensitive to copy number variations and has the potential to identify these changes in patient tumors. our results suggest that hmc deposition contributes to the silencing of tumor suppressor genes in p and may also regulate the transcription of other genes that drive tumor phenotype. background: metastatic osteosarcoma has a -year survival rate of - %. pulmonary metastases remain a major treatment challenge in osteosarcoma. current treatment with conventional chemotherapy shows inadequate activity towards metastases and has toxic systemic side effects. chloroquine is a widely used anti-malarial drug and has been shown to have promising anti-cancer and anti-metastatic activity. polymeric drugs have been shown to have multiple advantages over their small molecular parent drugs, including enhancing the therapeutic efficacy, an improved pharmacokinetics profile and decreased systemic toxicity. we hypothesized that by developing chloroquine into a polymeric drug and combining it with conventional chemotherapy it will improve the treatment of metastatic osteosarcoma. objectives: to identify the optimal combination of polymeric chloroquine (pcq) with conventional chemotherapy active in osteosarcoma as a new means of treating metastatic disease in a murine osteosarcoma model. we synthesized and developed pcq and evaluated its anti-invasive activity using an osteosarcoma cell migration and invasion assay. we evaluated the efficacy of cell killing using combination drug therapies with pcq and a panel of conventional chemotherapy agents (doxorubicin, docetaxel, cisplatin and paclitaxel) using celltiter blue cell viability assay. to develop the murine osteosarcoma model, we intravenously injected luciferase-expressing human osteosarcoma cells b into nsg mice. we administered the drug combination that showed the strongest in vitro synergy to the mice and evaluated their anti-cancer and anti-metastatic effects in vivo. tumor growth and suppression were evaluated using whole body bioluminescence imaging. results: we successfully synthesized pcq that contains . % chloroquine with a molecular weight of . kd. pcq was also found to decrease the toxicity of the parent chloroquine. pcq showed strong inhibition of osteosarcoma cell migration with % inhibition compared to % by chloroquine. we screened the combination drug therapies and found the combination of pcq and doxorubicin to show the strongest synergism. the pcq/doxorubicin combination is currently being evaluated in the murine model. combination drug therapy using pcq and doxorubicin showed synergistic cell killing and inhibition of cell migration in vitro. the combination represents a promising treatment strategy for pulmonary metastatic osteosarcoma. emory university/children's healthcare of atlanta, atlanta, georgia, united states background: survival for relapsed high-risk neuroblastoma (rnb) is < %, underscoring the critical need for novel therapies. rnbs have increased ras/raf/mapk mutations and increased yes-associated protein (yap) transcriptional activity. yap is a transcriptional co-activator that binds with tea-domain (tead) transcription factors to regulate cellular proliferation, self-renewal, and survival. we found that shrna inhibition of yap decreases nb cell proliferation and sensitizes ras-mutated nbs to mek inhibitors, supporting yap as a tractable therapeutic target. verteporfin (vp), a photodynamic drug used for macular degeneration, is the only drug found to inhibit yap expression or yap:tead binding to kill tumor-derived cells. peptide is a mer yap peptidomimetic that also disrupts yap:tead interactions. we sought to determine whether these compounds are potent in nb via yap direct effects. design/method: yap expressing (nlf, sk-n-as) or yap null (ngp, lan , sk-n-as-shyap) human-derived nbs were incubated with vp, with and without direct light exposure, or with peptide . celltiter-glo and immunoblots were used to assess for cell death and yap-downstream protein expression, respectively. results: without direct light exposure, vp inhibits yap expression at nm dosing, yet no nb cell death was observed at equal or higher concentrations. egfr and erk / were inhibited along with yap, confirming yap/ras pathway coregulation. when vp was exposed to direct incandescent light for minutes, > % nb cell death occurred in all nbs tested, even those lacking yap. peptide caused no cell death or yap inhibition up to um. neuroblastomas are resistant to vp at doses sufficient to inhibit yap expression. in macular degeneration, light-activated vp produces reactive oxygen species, which we hypothesize is the off target mechanism killing nbs independent of yap. given the off target effects and the need for light activation, vp is not an ideal preclinical or clinical yap inhibitor. accordingly, peptide has poor cell permeability and low tead affinity, leading to its lack of efficacy. given the relevance of yap in rnb and other cancers, we are chemically optimizing a yap peptidomimetic with enhanced permeability, nuclear localization, and tead affinity to create a bonafide yap inhibitor for preclinical and clinical application. kayeleigh higgerson, aaron sugalski, rajiv rajani, josefine heim-hall, jaclyn hung, anne-marie langevin ut health san antonio, san antonio, texas, united states background: osteosarcoma is the most common bone malignancy in children, adolescents, and young adults. most study cohorts have to % hispanic patients that encompass many different hispanic backgrounds. the university of texas health science center at san antonio (uthscsa) sarcoma team serves a latino population that is predominantly mexican american, thus providing a unique opportunity for evaluation this population. this study expands on previous data collected from january to december from the same institution, providing increased insight into outcomes of mexican american children, adolescents, and young adults with osteosarcoma. objectives: to further understanding of osteosarcoma in latino children, adolescents and young adults. design/method: a retrospective analysis of demographics, tumor characteristics, response to treatment, and survival outcome of all localized osteosarcoma of the extremity patients below years of age diagnosed and treated by the uthscsa sarcoma team between january and june was performed. results: in our original cohort from january to december , we observed a significantly decreased -year eventfree survival (efs) in patients diagnosed before age (preadolescent) relative to patients diagnosed between ages and ( % vs. %, p< . ). patients had a -year overall survival (os) and event-free survival of % and % respectively. in our expanded cohort from january to june we evaluated sixty-six patients with a median age of (range, to y) with localized high-grade osteosarcoma of the extremity. the expanded cohort was % mexican american, with a median follow-up of months (range, to ). the analysis of our expanded cohort is ongoing and we postulate that the findings will hold true, as we increase the cohort size and length of follow-up. conclusion: analysis of our previous cohort, predominantly of mexican american ethnicity, showed that preadolescent patients had an increased rate of relapse when compared with previous large studies. we also showed a trend towards decreased efs for the entire cohort. we hypothesize that we will further validate these findings with this expanded cohort and this will support further investigation into potential causes of poor outcome in this vulnerable latino population. background: neuroblastoma in infants has the potential to regress or mature spontaneously. growing literature showed that some cases subjected to initial observation didn't show inferior outcome compared to actively treated similar categories. objectives: we investigated whether early active treatment can be safely avoided/deferred in selected favorable cases at the children's cancer hospital-egypt (cche). design/method: patients enrolled on the watch and see strategy (w&s) at cche had small primary tumor; inss stage - , uncomplicated stage s or stage infants (< days). tissue biopsy was not mandatory for infants below months of age with localized adrenal mass (stage - ). on progression, immediate intervention took place according to stage and risk of disease after biological characterization. results: thirty four nbl patients were enrolled on w&s strategy; m/f: . / . eighteen patients had stage s disease, patients had stage - and were stage . primary adrenal site was reported in patients ( . %), patients ( . %) had small mass measuring ≤ cm in its largest diameter. the -year os & efs were . ± . % and . ± %, respectively, with months median follow-up (range: - months). spontaneous total/near total resolution of mass occurred in / patients ( %). median time to eliciting regression was . months (range: . - . months), and . months (range: - months) till complete resolution. only / patients ( . %) witnessed progression ( local, distant and combined local and distant progression); median time to progression was months (range: - months) with / deaths after starting chemotherapy. watch and see strategy is a safe approach in localized and uncomplicated stage s neuroblastoma. progressive cases could be rescued. baylor college of medicine, houston, texas, united states background: ga- dotatate binds to somatostatin receptor expressed in neuroendocrine tumors (nets). it was approved by fda in for use with pet/ct scan for localization of somatostatin receptor positive nets in adult and pediatric patients. pediatric approval was based mainly on extrapolation of data from adults. objectives: to describe the use of ga- dotatate pet/ct scan in children with neuroendocrine tumors and compare with other imaging modalities. design/method: patients with nets enrolled in texas children's rare tumor registry between february and october were reviewed and those patients who underwent ga- scan were included. results: four patients with nets underwent ga- scans without any adverse reactions. first patient was a -yearold female with small bowel net with multiple liver metastases. mri abdomen and fdg pet at diagnosis showed s of s multiple liver metastases but could not identify the primary lesion. ga- scan was able to accurately identify the enlarged lymph nodes in the small bowel and was better than fdg pet in delineating the liver metastases. second patient was a -year-old female with recurrent small bowel net with liver, lung and paraspinal metastases. the lesions were initially detected by ct scan. octreotide scan failed to show any uptake in the identified lesions while ga- was taken up by the liver lesions, lung lesions > cm in size and the paraspinal lesion. third patient is an year-old male with pancreatic net with peripancreatic lymphadenopathy, multiple liver metastases and cardiophrenic lymph node involvement. the primary lesion in the pancreas could not be identified by ct scan, ct angiogram, mibg scan, or octreotide scan. in addition, there was uncertainty about involvement of the enlarged cardiophrenic lymph node. in addition to clearly identifying the primary lesion, ga- scan was able to detect multiple peripancreatic lymph nodes not detected by other scans and revealed uptake in the cardiophrenic lymph node confirming its involvement by the tumor. fourth patient is a -year-old female with malignant abdominal paraganglioma with solitary lung metastasis. both mibg scan and ga- scan were able to identify the primary lesion. ga- scan was performed after the lung metastasis was removed and thus its ability to detect it could not be confirmed. background: neuroblastoma is the most common extracranial solid tumor of childhood, with overall survival for high-risk patients (hrnbl) near %. the outcomes of hrnbl have improved with high dose chemotherapy followed by autologous stem cell rescue (abmt). data about factors influencing the rate of hematopoietic recovery following abmt in hrnbl is lacking in the literature. our objective was to identify factors influencing the rate of hematopoietic recovery following abmt in hrnbl. design/method: this was a retrospective chart review of patients with hrnbl treated at texas children's hospital from to . neutrophil engraftment was considered the first of three consecutive days with post-transplant neutrophil count greater than cells/ul. red blood cell and platelet engraftment were considered at a hemoglobin greater than g/dl and platelets greater than , /ul three days after the last transfusion. race and conditioning regimen were analyzed using one-way anova; amount of infused cells was analyzed using pearson correlation coefficients; chemotherapy delay and bone marrow (bm) involvement after cycle of induction chemotherapy were analyzed using independent sample t-tests. the study included males and females with a median age at diagnosis of . years. thirtyeight patients were caucasian, african-american, hispanic, asian, and did not have race documented. the mean dose of infused cd + cells was . × ^ cells/kg. forty-five patients received conditioning therapy with carboplatin/etoposide/melphalan (cem), received busulfan/melphalan (bu/mel), and received thiotepa/cyclophosphamide (thiotepa/cpm). the conditioning regimen administered was significant (p = . ) for time to engraftment of neutrophils, with bu/mel at . days, cem at . days, and thiotepa/cpm at days. a delay of chemotherapy during induction (n = ) was significant (p = . ) for time to platelet engraftment of greater than , /ul and trended towards significance (p = . ) for time to neutrophil engraftment. bm involvement at diagnosis and after cycle of induction was not significant for time to engraftment. dose of stem cells infused was the only variable significant for hemoglobin engraftment. background: osteosarcoma (os) is the most prevalent aggressive primary malignancy of the bone affecting children and young adults. approximately % to % of patients have metastatic disease at initial presentation, and % of those patients have isolated pulmonary metastases. although overall survival in patients with os has improved with advances in therapy, there have been no significant improvements in survival outcome in patients with metastatic disease. recent studies suggest that tumor-associated vascular cell adhesion molecule (tvcam- or cd ) plays a critical role in the metastatic progression of various tumors. indirect evidence from these studies suggest that vcam- / integrin signaling promotes tumor survival and metastatic progression by changing the tumor niche and associated immune response. to determine if interfering vcam- / signaling between pulmonary metastatic osteosarcoma (pos) and macrophages (macs) by down-regulating vcam- , depleting macs or blocking vcam- / signaling will reduce pos and improve overall disease-free survival. design/method: we used a pair of spontaneous, high-grade murine os cell lines from balb/c mouse (h- d), k and k m (derived from in vivo k metastasis). we used lentiviral shrnas to knockdown vcam- mrna and protein expression in k m (vcam- kd). we introduced luciferase into k , k m and various k m shrna cell lines to follow lung metastasis by bioluminescence (bli). we depleted macs by intranasal administration of liposomal clodronate formulation. we tested the ability of k and k m supernatants to polarize m macs into m or m phenotype in vitro. we also administered anti- monoclonal antibody (anti- mab) intranasally to assess the outcome of functional blockade of vcam- / signaling. results: k m over-expressed vcam- compared to k . mac depletion in k m -bearing animals exhibited reduced pos. weekly administration of anti- mab resulted in % tumor-free rescue among mice with established k m pos. interestingly, supernatant from k m but not k preferentially induced m -like macs, suggesting a novel integrin-mediated mechanism of m differentiation. validation data with additional os cell lines will be presented. despite aggressive multimodal therapy, overall outcome for patients with pos remains dismal at - %. for this reason, novel and directed therapy approaches are desperately needed. molecular targeted approaches for therapy are challenging, due to the complex genetic heterogeneity of os. immune-modifying therapy is a promising new alternative approach for pos. university of chicago, chicago, illinois, united states background: only half of all patients diagnosed with high-risk neuroblastoma achieve long-term survival. imetaiodobenzylguanidine (mibg) scans are routinely used to evaluate disease at diagnosis and following treatment, and the extent of disease is quantified using the curie scoring system. a previous study by yanik et al., has shown that for high-risk patients with mycn non-ampliified tumors, scores less than versus greater than following cycles chemotherapy are associated of superior survival, whereas scores less than versus greater than were prognostic in patients with mycn-amplified tumors. however, the prognostic significance of specific sites of metastatic disease at diagnosis is not known. to determine if site of metastatic disease determined by i-metaiodobenzylguanidine (mibg) imaging in high-risk patients at the time of diagnosis was associated with outcome design/method: we performed a retrospective chart review of high-risk neuroblastoma patients treated at comer children's hospital and lurie children's hospital in chicago between and with positive mibg scans at the time of diagnosis. we collected imaging data as well as other clinical data including bone marrow status. sites of disease were defined as curie regions with any positive value. kaplan-meier analysis was performed to evaluate the association with disease sites and survival. pearson correlation coefficients were calculated to compare bone marrow disease to sites of positivity on mibg scan. the cohort consisted of high-risk patients. had skull disease, and had pelvic disease. the presence of mibg positive disease in the skull and in the pelvis trended toward worse efs. efs at years for patients with disease in the skull at diagnosis was ± % and for patients without skull disease was ± % (p = . ). efs at years for patients with and without pelvic disease was ± % and ± % (p = . ). consistent with prior data, we found that the presence of bone marrow disease was associated with worse survival with year efs of ± % and ± % with and without marrow disease at diagnosis (p = . ). there is the highest correlation between pelvic disease on mibg scan and bone marrow disease with pearson coefficient . . pelvic disease noted on mibg scan likely reflects underlying bone marrow disease. in patients with high-risk neuroblastoma, skull disease and pelvic disease on mibg scan at diagnosis may predict worse event free survival. background: osteosarcoma is one of the deadliest cancers in the pediatric population with little progress in morbidity and recurrence rates since the 's. oncolytic herpes simplex- virus (ohsv) is an attenuated virus that has shown encouraging results against certain solid tumors. programmed cell death protein (pd)- -mediated t cell suppression via engagement of its ligand, pd-l , is also of particular interest due to recent successes in selected cancers, especially those with high genetic mutational loads. most pediatric cancers do not have a wide variety of mutations; however, osteosarcoma has a chaotic genome, prone to genetic mutations. it has been shown through numerous other studies that pd- inhibition alone is not sufficient to result in statistically significant tumor growth delays in osteosarcoma models and patients. we hypothesize the addition of ohsv therapy as an immunologic stimulus to pd- inhibition is efficacious for osteosarcoma. ( ) to determine whether ohsv therapy enhances response to pd- inhibition in immunocompetent murine models of osteosarcoma and ( ) to quantify and characterize the anti-tumor t-cells infiltration after treatment with ohsv and pd- inhibition individually and in combination. we utilized an immunocompetent transplantable murine model using a cell line derived from a spontaneous metastatic osteosarcoma (k m , balb/c background). we transplanted established tumor wedges subcutaneously and monitored tumor volume by caliper measurement. once tumors reached - mm , we administered intratumoral injections of hsv ( × plaque-forming units) every other day for a total of injections. we then gave intraperitoneal injections of ug anti-pd- or control antibody twice weekly, up to weeks, starting from the last dose of virus treatment. we monitored tumor growth via calipers twice weekly until tumors reached mm or cm diameter. we quantified and characterized innate and adaptive immune cell infiltrates in tumors using flow analysis. we found significantly prolonged survival with our combination therapy group compared to all other groups. we found that anti-pd- by itself had little impact on t cell recruitment while the combination group had higher influx of cd + cells with a reduced amount of t-regulatory cells (cd +foxp +cd +). we also found an increase in cd + effector memory cells. osteosarcoma is a deadly cancer with therapeutics remaining unchanged for the last years. here, we describe prolonged murine survival after treatment with combination of pd- inhibition and ohsv injection. the combination treatment changed the microenvironment to be more inflammatory. our data support further preclinical and clinical studies. background: neuroblastoma is the second most common cause of cancer related death in children. treatment for high-risk neuroblastoma has improved significantly over the past twenty years, however cure rates remain below %. immunotherapy has emerged as an effective therapy for neuroblastoma, however new modalities and targets are needed to improve outcomes. objectives: our lab has developed a chimeric antigen receptor (car) that targets b -h (cd ), an immune checkpoint molecule overexpressed on many cancers, including neuroblastoma. we hypothesized that b -h would be a good target for car based immunotherapy for neuroblastoma. design/method: neuroblastoma tissue microarrays of primary patient samples were screened for b -h expression by immunohistochemistry and cell lines were screened using flow cytometry. b -h car t cells were tested in vitro by measuring tumor cell killing and cytokine production after coculture with tumor cell lines and in vivo in an orthotopic model of neuroblastoma. results: b -h expression was detected by ihc on % of the screened neuroblastoma patient samples. b -h was expressed at high levels ( + or +) in more than half of these samples ( %). almost all cell lines screened were homogeneously positive for b -h by flow cytometry. retrovirally transduced b -h . - bb. car t cells were cocultured with three b -h positive neuroblastoma cell lines (sk-n-be , kcnr, and chla ) and robust tumor cell killing was demonstrated using an incucyte assay. supernatant from the co-cultures was harvested after hours and both interferon gamma and il- production were detected by elisa.in an orthotopic subrenal capsule xenograft model of neuroblastoma, mice treated with b -h car t cells show significant reductions in tumor growth and prolonged survival compared to those treated with untransduced control t cells. however, the treatment is not always curative.b -h car t cells express high levels of exhaustion markers (pd , tim , and lag ) when compared to cd car controls. in order to overcome inhibition from exhaustion, b -h car t cells were co-cultured with neuroblastoma cell lines and pd- blocking antibody. nivolumab significantly increased the production of il- and interferon-gamma by b -h car t cells. further studies are underway to determine if b -h car t cell activity is enhanced in vivo by treating animals with pd- blockade along with car t cells. conclusion: b -h is expressed on a majority of neuroblastoma samples and appears to be a promising candidate for car t cell therapy. b -h car t cells demonstrate activity against neuroblastoma xenografts that may be enhanced by the addition of pd inhibitors. helen devos children's hospital, michigan state university, grand rapids, michigan, united states background: osteosarcoma is the most common bone tumor in children. it is often metastatic at diagnosis and in this scenario less than % of children survive. polyamines, small molecules found in all cells, are involved in many cell processes including cell cycle regulation, immune modulation, cell signaling and apoptosis. they are also involved in tumor development, invasion and metastasis. in neuroblastoma, inhibition of the polyamine biosynthesis pathway with odc inhibitor alpha-difluoromethylornithine (dfmo) results in decreased cell proliferation and differentiation. these finding have led to multiple phase i and phase ii multicenter clinical trials in pediatric neuroblastoma patients. dfmo is an attractive drug as it is oral, well-tolerated, can be given for prolonged periods and is already used in pediatric patients. the polyamine pathway has not been evaluated in osteosarcoma. objectives: evaluate effect of inhibition of polyamine biosynthesis with dfmo on osteosarcoma proliferation and cell differentiation. design/method: up to three osteosarcoma cell lines were used: mg- , u- os and saos- . cells were exposed to mm dfmo for days with replacement of media and dfmo on day . intracellular polyamine levels were measured by high performance liquid chromatography (hplc). cell numbers were obtained with a hemocytometer using trypan blue. flow cytometry cell cycle distribution (facs) and propidium iodide were used to evaluate for cell cycle arrest. the protein expression of several osteosarcoma differentiation markers was measured by sds-page and western blot using differentiation specific antibodies. a bioluminescent cell viability assay was used to measure cell recovery over several days after dfmo was removed and replaced with standard media. results: dfmo exposure resulted in significantly decreased cell proliferation in all cell lines. after treatment, intracellular spermidine levels were nearly eliminated in all cells. cell cycle arrest at g was observed in u- os. cell differentiation was most pronounced in mg- and u- os cells as determined by increased osteopontin levels. remarkably, cell proliferation continued to be suppressed for several days after removal of dfmo. conclusion: based on our findings dfmo is a promising new adjunct to the current osteosarcoma therapy for high risk patients. it is a well-tolerated oral drug that is currently in phase ii clinical trials in pediatric neuroblastoma patients as a maintenance therapy. the same type of regimen may also improve outcomes in metastatic or recurrent osteosarcoma patients for whom there have been essentially no medical advances in the last years. background: recent studies demonstrate that lower levels of the ews-fli fusion oncoprotein are associated with enhanced metastatic capability in ewing sarcoma. the nf-kb transcription factor is a critical mediator of cxcr and cxcr -driven metastasis in multiple cancers, and increased cxcr and cxcr expression have each been associated with increased metastasis and poor prognosis in ewing sarcoma. we thus sought to investigate the impact of ews-fli on cxcr /cxcr -dependent nf-kb signaling in ewing sarcoma. objectives: the goals of this study are ) to determine the impact of cxcr /cxcr signaling on metastasis-associated nf-kb target gene expression in ewing sarcoma and then ) to investigate how the ews-fli fusion oncoprotein modulates this response . design/method: we utilized multiple ewing sarcoma cells lines including a , chla , chla , tc and tc . cxcr /cxcr cell surface expression was determined by flow cytometry. ews-fli level was modulated using sirna and expression levels were confirmed by western blot and rt-pcr. p dna binding was measured via elisa. nf-kb target gene expression was assessed via rt-pcr. results: consistent with ihc analysis of primary and metastatic patient tumor samples, the paired primary and metastatic ewing sarcoma cell lines chla and chla showed dramatic differences in cxcr and cxcr expression, with the metastatic chla line demonstrating much higher expression of both receptors. other cell lines (nonpaired) showed variable cxcr /cxcr expression. genetic knock-out of cxcr lead to significant decrease in expression of both cxcl /sdf- and il- , two nf-kb transcriptional targets known to play a key role in tumor metastasis. knock-out of cxcr did not alter endogenous ews-fli mrna levels. conversely, lowering the level of ews-fli using sirna lead to enhanced nf-kb signaling, indicated by an increase in p dna binding. consistent with this observation, treating ewing cell lines with ews-fli sirna also resulted in significantly increased nf-kb target gene expression compared to control cells and target gene expression was then further enhanced upon cxcr /cxcr receptor stimulation with the receptor ligand cxcl /sdf- . our findings indicate that the ews-fli oncoprotein negatively modulates cxcr /cxcr -dependent nf-kb signaling. this suggests that ews-fli low, cxcr /cxcr high cells, which are associated with enhanced metastasis and poor prognosis, would be anticipated to exhibit enhanced expression of key nf-kb target genes. importantly, the nf-kb pathway is a druggable target that could potentially serve as an "achilles heel" in this subset of high risk tumors. current work is evaluating nf-kb inhibition as an approach to treating metastatic and refractory ewing sarcoma. background: acute graft versus host disease (agvhd) is a major cause of morbidity and mortality following allogeneic bone marrow transplant (bmt) in pediatric patients. gastrointestinal (gi) agvhd is the most serious manifestation. recently, decreased paneth cell (pc) in a predominantly adult cohort was shown to correlate with agvhd clinical grading and response to treatment. we aim to demonstrate the relationship between pc counts and gi agvhd stage and response to therapy. design/method: charts of patients who underwent endoscopy following bmt between - were reviewed. for repeated biopsies during the course of agvhd, only the first was included for analysis. one pathologist retrospectively reviewed the biopsies and counted pcs in high powered fields; the average pc count was analyzed. twenty-six percent of biopsies were reviewed by a second blinded pathologist. statistical associations between pc counts and day (d ) response, agvhd stage, and other study covariates of interest were gauged using general linear regression. agreement in pathologist pc counts was quantified by intraclass correlation (icc). the research was approved by the children's healthcare of atlanta irb. results: seventy-eight biopsies were included in the analysis. mean age at transplant was . years ± . (range: months - years). most patients underwent transplant for hematologic malignancies ( , %). the majority of transplants used a matched unrelated donor graft -including cords ( , %) and myeloablative conditioning regimens ( , %) - % received total body irradiation. of these, % were diagnosed clinically with gi agvhd (stage , %; stage , %; stage , %; stage , %). icc showed good agreement ( . ) between the pathologists. mean pc was . for patients with no gut agvhd, . for stage , . for stage , . for stage and . for stage (p = . ). on multivariate analysis pc was strongly associated with gi agvhd stage (p< . ) after controlling for age, preparative regimen intensity, and diagnosis (malignant vs. non-malignant). mean pc counts were significantly lower in patients with no response to steroid therapy at d (complete response (mean . ) vs. persistent disease ( . ) vs. partial response ( . ) (p = . )). patients diagnosed with gi agvhd with pc counts less than had a higher risk of mortality (hr . , % ci: . , . ; p = . ). lower pc count correlated with stage gi agvhd, refractory disease at d , and mortality. incorporating pc count in pathology review during gi agvhd work-up may help in agvhd risk stratification. background: there have been increasing discussions pressuring health care teams and institutions for potentially bearing the cost of clostridium difficile infections (cdi) as a health care-associated infection in the recent years. the pediatric oncology patient population, though small, accounts for significant portion of all cdi with - -fold increased risk. hematopoietic stem cell transplant (hsct) recipients constitute a unique subset with distinct risk factors, such as severe immune deficiency state and graft versus host disease (gvhd). although there is ample data on cdi in adult hsct recipients, reports on pediatric experience are limited. objectives: to evaluate the incidence and patterns of cdi among pediatric hematology, oncology and hsct inpatients at our institution. a retrospective review of all clostridium difficile (cd) stool tests performed using toxin enzyme immunoassay and later, polymerase chain reaction targeting toxin genes between and in a large, urban academic children's hospital was performed. the data were analyzed for hematology, oncology, hsct inpatient population and all the other cases separately and statistical comparisons were performed. results: a total of samples were submitted to the microbiology laboratory for cd testing during the study period. while hematology patients constituted . %, oncology . %, hsct . % and others . % of the cases on whom cd testing was done; per patient average test number was . , . , . , and . , respectively. of all the cd tests per-formed, . % were positive. test positivity was higher in hsct ( . %) and oncology ( . %) cases tested compared with hematology ( . %) and other cases ( . %) with statistical significance (p< . ). overall recurrence rate was . %; hsct patients had the highest recurrence with a rate of % followed by oncology ( . %), hematology ( . %) and other ( . %) cases, again reaching statistical significance (p< . ). again, hsct patients had the highest average number of recurrences at . ( - ) followed by oncology . ( - ), general . ( - ) and hematology . ( - ) groups. there was no seasonal variability in the incidence of cdi among populations analyzed. prolonged hospital stay/antibiotic use and persistent diarrhea due to gvhd are the likely reasons for higher rate of cd testing in hsct as a result of increased monitoring and thus might have even caused underrepresentation of positive cd test frequency. higher incidence and frequencies of recurrence underscores the inevitable nature of cdi in hsct population as a consequence of the current therapies and may lead to future radical treatment approaches like fecal implantation. background: viral infections remain a challenge to treat post hct in children, and significantly contribute to morbidity and mortality. virus specific t cells (vsts) have shown tremendous clinical efficacy in treating viral infections post-hct, with minimal toxicity and long term efficacy. we have used donor-derived vsts in individual patients, however not all donors are agreeable to the process, and numerous patients may benefit from vsts who do not have an identified donor/have other disease indications objectives: we sought to actively build a third-party vst bank, for "off the shelf" use in eligible patients. design/method: vsts targeting cmv, adenovirus and ebv were manufactured using one of techniques. initially ebv transformed b cells were genetically modified with an ad f pp vector and used as antigen presenting cells (apc) to stimulate and expand ebv, ad and cmvpp specific t cells. more recently, vsts were expanded using s of s apc pulsed with commercially available peptide pools (pep-mixes) to expand ebv/cmv/ad specific t cells. products were entered into the "bank" via two mechanisms: a) left over products from our "donor-derived" protocol when patients no longer required vsts or were not at risk of developing viral infections, or b) by targeting regular blood donors based on their hla typing to ensure an appropriate mix of high frequency hla types for optimal patient matching and antigen presentation based on current knowledge of antigen presentation. results: a total of products are currently in the thirdparty vst bank ready for use. twenty seven of these are from our donor derived protocol, and three from targeted donors. all vst products met safety and in vitro efficacy testing. thirteen vst infusions have been given to patients. eleven infusions have been given for cmv and two for adenovirus. five out of seven patients responded to thirdparty vst infusions, with a median of vst infusions per patient (range - ). the median hla matching was out of per patient (range to ) no patients experienced adverse reactions, gvhd or other toxicity related to the vst infusion. a third-party vst bank is feasible and produces clinically appropriate vsts for use in patients with viral infections. hla typing and matching of vst products is essential to reduce toxicity and promote appropriate antigen presentation and expansion of vsts in vivo. further work is underway to further characterize the vsts using epitope mapping to better define the hla restriction and immunogenicity of each vst product. akron children's hospital, akron, ohio, united states background: acute graft-versus-host disease (agvhd) is a well-known complication of hematopoietic stem cell transplant (hsct) and a major cause of post-transplant related morbidity and mortality. first line therapy of agvhd involves corticosteroids and calcineurin inhibition. in patients with severe refractory gvhd, mortality can reach up to %. currently, there is no standard of care for the treatment of steroid refractory agvhd. many centers have looked at the use of antibody mediated control of agvhd to competitively inhibit the inflammatory cascade. basiliximab, a chimeric monoclonal antibody against the t-cell il- receptor, has been used in adults with steroid refractory agvhd. patients receiving this medication have demonstrated complete and partial responses to therapy with minimal toxicities. objectives: report the successful use of basiliximab in the treatment of agvhd in a -year-old following matched unrelated (mud) hsct. design/method: a -year-old male underwent mud transplant for high risk aml with monosomy . conditioning regimen included busulfan, fludarabine and equine atg. his clinical course was complicated by fever, mucositis and agvhd (stage skin; stage gi-biopsy proven). gvhd prophylaxis included tacrolimus and methotrexate, however with progressive skin rash, diarrhea, and early satiety, gvhd treatment with corticosteroids was initiated. as the patient continued to have worsening symptoms, basiliximab therapy was started. the patient received doses ( mg) iv basiliximab on two consecutive days and then received weekly therapy for a total of doses leading to initial improvement. the patient further developed acute on chronic gvhd on day + , and subsequently received a second course of basiliximab. after initial administration of basiliximab, the patient had near complete resolution of symptoms. however, with a small wean in his tacrolimus dose, the patient experienced another skin gvhd flare prompting the second basiliximab course. the patient was subsequently weaned off all immunosuppression by day + . the only acute complication the patient experienced while receiving basiliximab was right toe paronychia and asymptomatic low ebv titer. the patient is currently off all immunosuppression at the time of report without evidence of cgvhd. conclusion: this single case report, in a young pediatric patient, demonstrates the use of basiliximab may be a safe and efficacious treatment for pediatric patients with agvhd. university of california, san diego, la jolla, california, united states background: clinical outcomes after allogeneic hematopoietic stem cell transplantation (hsct) depend on restoration of t lymphocyte populations. association between recovery of cd +foxp + regulatory t cells (tregs) and protection from chronic graft versus host disease (cgvhd) has been described in adult hsct. in adults, t cell recovery is driven by expansion of donor t cells and treg reconstitution is hypothesized to result from peripheral conversion. restoration of t cells in pediatric patients has a larger contribution from thymopoiesis, however, the relationship between thymopoiesis and treg recovery is undefined. objectives: we hypothesized that effective thymopoiesis is important for restoration of treg populations and protection from cgvhd in pediatric hsct patients. design/method: we performed longitudinal flow cytometry of peripheral blood t cells from pediatric hsct patients and age-matched healthy donors. laboratory data were correlated with clinical outcomes to evaluate impact. recovery of tregs occurred in / ( . %) patients by post-transplant day . day treg frequency in patients that developed cgvhd ( . ± . % of cd + t cells) was reduced compared to cgvhd-free patients ( . ± . %). failure to restore tregs to > . % of cd + cells by day was associated with increased risk of cgvhd in the first year post-hsct (rr = . , p = . ). a majority ( . ± . %) of tregs from patients recovering the peripheral treg compartment expressed helios, a marker of thymic-derived tregs; only . ± . % of tregs expressed helios in patients failing to restore adequate tregs. this prompted examining the relationship between defects in thymopoiesis and inability to restore tregs. we evaluated thymic function by flow cytometry quantification of cd ra+cd +ptk + recent thymic emigrant (rte) cd + cells (confirmed by qpcr for trec content). most ( / , . %) hsct patients had detectable rtes by day post-hsct. thymic production of rtes was persistently absent in patients that developed cgvhd (< / ^ cd + cells in / patients), compared to cgvhd-free patients ( / patients > rte/ ^ cd + cells by day , average . ± . / ^ cd + cells). post-hsct thymic activity as measured by rte enumeration correlated with treg restoration; / ( %) rte+ patients restored tregs, compared to / ( %) of rte-patients. conclusion: failure to restore tregs after allogeneic hsct results in increased risk for cgvhd. in pediatric patients thymic generation of new t cells is an important contributor to restoration of the treg compartment. this data supports further investigation into mechanisms impairing post-hsct thymopoiesis and suggests peripheral blood tregs may be a prognostic biomarker for cgvhd. background: haploidentical stem cell transplantation (haplo sct) is riddled with unique challenges. objectives: we present our experience in the use of haplo sct with post-transplant cyclophosphamide (ptcy) and the adaptations required for each disorder for optimal outcome. design/method: we performed a retrospective study at the pediatric blood and marrow transplant unit, apollo cancer institutes, chennai, india. children up to years of age, diagnosed to have benign disorders and underwent haplo sct with ptcy from to july were included. results: ptcy was used in i.e. % haplo transplants for children with benign disorders. the underlying conditions included fanconi anemia , severe aplastic anemia , mds , jmml , hemoglobinopathy , prca , xld and primary immunedeficiency disorders (pid) . source of stem cells was peripheral blood in %, bone marrow in %. conditioning included fludarabine with treosulphan or cyclophosphamide for pids and aplastic anemia respectively. neutrophil engraftment by day+ - with a durable graft was noted in % transplants with graft versus host disease in %, cmv reactivation in %. mortality rate was % with infants less than months of age developing severe fatal cytokine release syndrome. the median follow up is year with years being the longest. no significant late effects have been noted with chronic skin gvhd in children. survival rate was superior among children with pids with survival of % in this group. haplo sct with ptcy is a feasible and costeffective option for cure in children with life-threatening benign disorders with no compatible family or matched unrelated donor. careful patient selection, reducing cyclophosphamide related free radical toxicity with the use of n acetylcysteine, limiting t cell numbers by capping cd at × /kg, post-transplant viral monitoring protocols are required to reduce morbidity and mortality. we have been working on universal access to care for children from s of s all socioeconomic background and incorporating innovations to reduce the cost of hsct without compromising outcomes. haploidentical hsct using tcr / depletion costs usd as compared to ptcy priced at usd. children with severe aplastic anemia and pids can be transplanted using reduced intensity conditioning and ptcy. in hemoglobinopathies, pretransplant immunosuppression is required to prevent graft rejection. graft versus host disease remains the main cause of mortality in children with fanconi anemia. mortality in infants less than months after ptcy has been high, tcr / depletion would be superior in this cohort. cincinnati children's hospital medical center, cincinnati, ohio, united states background: fanconi anemia (fa) is a congenital bone marrow failure syndrome with hsct the only curative option for associated bone marrow failure. patients with fa undergoing hsct may experience increased toxicity related to either their underlying disease, or the effects of medications, resulting in the inability to tolerate prophylactic medications or sideeffects from anti-microbial therapy. objectives: we postulated that increased cd cell dose would be associated with a rapid immune reconstitution and therefore early withdrawal of anti-infective prophylactic medications. design/method: patients with fa transplanted at cchmc from an unrelated donor had peripheral blood stem cell grafts collected and cd selection performed. where possible, patients had serial measurements of their immune system performed at varying intervals post hsct. we defined immune reconstitution as normalization of lymphocyte subsets-cd , cd , cd and cd cells, as well as a normal response to mitogen stimulation including phytohemagglutinin, concanavalin a and pokeweed. the first measurement of either normal cell number or mitogen response was recorded for each patient. results: a total of patients underwent hsct for fa at cchmc between and . patient demographics included a median age of years at hsct, the vast majority of patients having a fully matched or one anti-gen mismatched donor, and the majority of patients transplanted for bone marrow failure. there was a statistically significantly decreased time post-transplant to immune cell recovery in patients receiving > × /kg cd cells (median . ) compared to those receiving < × /kg cd cells (median . ). the median time to normalization of cd count was days (cd count > /kg) versus days (cd count < /kg), cd count days (cd count > /kg) versus days (cd count < /kg), cd count days (cd count > /kg) versus days (cd count < /kg) and cd count days (cd count > /kg) versus days (cd count < /kg). time to normalization of mitogen response was decreased posttransplant in those patients receiving increased cd cell dose at time of transplant, though this was not significant, reflecting low number of patients with evaluable responses. no patients in either group experienced gvhd or graft failure. patients with fa who are transplanted with higher cd cell doses have quicker immune reconstitution than those who receive lower cell doses. along with benefit to patients including less risk of infection and early termination of immune-prophylaxis medications, this supports the use of high dose cd selected grafts in this vulnerable population. background: parvovirus b (pvb ) infection after transplantation was first reported in . since then, numerous cases of pvb infections after hematopoietic stem cell transplantation (hsct) and solid organ transplantation (sot) have been reported. most report anemia as the predominant clinical manifestation. however, pvb has been associated with pancytopenia, hepatitis, myocarditis, and allograft rejection. we present a patient with acute lymphoblastic leukemia who developed bone pain and pancytopenia following hsct in the setting of pvb infection. to describe an unusual presentation of pvb in a patient with acute lymphoblastic leukemia following hsct. design/method: a search of the english-language medical literature was performed using pubmed and medline databases. a review of the patient's medical history was performed. a year old male with relapsed b-cell all and history of "fifth disease" in infancy presented four months after hsct with focal left arm pain and difficulties fully extending the arm. bone mri showed enhancement of the medullary space centered within incomplete transverse cortical fracture interpreted as pathologic fracture due to neoplastic involvement of the ulna with no history of inciting injury. subsequently, peripheral blood counts decreased from low normal values to wbc . k/microl, anc /microl, plt k/microl, and hemoglobin . g/dl. the patient's chimerism remained % donor. a bone marrow biopsy and aspirate were performed to assess for recurrent leukemia given persistence of bone pain and developing pancytopenia. marrow findings included morphologic cytopathic effects with erythroid precursors and strong parvovirus staining with no signs of red cell aplasia or recurrent b-cell disease by morphology or flow cytometry. pvb was detected in blood by pcr and immunoglobulins with resolution of cytopenia and bone pain. this case highlights an unusual constellation of symptoms following hsct in a child with all. unexplained bone pain and medullary infiltrates with pancytopenia suggestive of recurrent leukemia were likely triggered by pvb infection. the question remains if he had reactivation of pvb , a primary infection by a new strain, or the virus was aquired through stem cells. bone biopsy could not be justified in light of clinical improvement. so far, bone lesions have only been described with congenital pvb infection. pvb appears to be uncommon after hsct, with a review of literature yielding pediatric cases. however, it may be underestimated due to lack of routine screening. our patient's presentation supports that evaluating for pvb may be warranted in hsct patients presenting with symptoms suggestive of relapsed leukemia. background: cardiac injury may occur during hematopoietic stem cell transplant (hsct) in pediatric patients and can be asymptomatic for many years. recommendations for screening are available for patients who received anthracyclines or chest irradiation, but no guidelines exist for unexposed longterm survivors. we sought to define the prevalence of echocardiographic abnormalities in long-term survivors of pediatric hsct and determine the need for screening in asymptomatic patients. design/method: we analyzed echocardiograms performed on long-term survivors (≥ five years) who underwent hsct at cincinnati children's hospital between and . we analyzed echocardiograms for left ventricular ejection fraction (ef), end-diastolic dimension (lvedd), septal thickness, posterior wall thickness, and global longitudinal strain (gls). we normalized linear measurements for age and patient body surface area. we included for further analysis patients who had echocardiogram obtained for routine surveillance. results: a total of patients underwent hsct and were alive more than years after transplant in , with having an echocardiogram obtained ≥ five years postinfusion. those with an echocardiogram were transplanted more recently (median vs. ). however, no difference between screened and unscreened individuals was noted for age at transplant, sex, transplant indication, anthracycline exposure, chest irradiation, or cyclophosphamide based preparative regimen. indications for echocardiograms included: cardiac symptoms ( . %), congenital cardiac anomalies ( . %), hypertension ( . %), known cardiac or pulmonary disease ( . %), routine post-hsct surveillance ( . %), and unknown ( . %). the mean time post-hsct was . years. among routine surveillance echocardiograms, the mean ef z-score was - . . mean lvedd zscore was - . , mean septal thickness z-score - . , mean posterior wall thickness z-score - . , and mean gls - . %. for patients that had echocardiogram performed for routine surveillance, / patients ( . %) had ef measured, and / ( . %) had ef z-scores ≤ - . (abnormally low). patients exposed to anthracyclines had a mean z-score ef of - . vs. unexposed patients - . (p = . ). among individuals who received neither anthracyclines nor tbi only / ( . %) was found to have an abnormal ef, . % (z-score - . ) or gls (- . %). only one patient who had a normal ejection fraction (z-score - . , ef . %) had an abnormal gls, - . % (normal ≤ - . ). long-term survivors of pediatric hsct who are asymptomatic and did not receive radiation or anthracyclines likely do not require surveillance echocardiograms, unless indicated by clinical symptoms. patients exposed to anthracyclines or tbi require close echocardiographic s of s screening and clinical monitoring for the development of cardiac complications. duke children's hospital, durham, north carolina, united states background: children undergoing pediatric blood and marrow transplants (pbmt) experience significant symptom distress. mobile health (mhealth) technologies can be leveraged to collect and monitor patient generated health data, and subsequently enhance our understanding of pbmt symptom clusters, patterns, and trajectories. better understanding of symptom complexity can foster development of precision health strategies to improve patient outcomes. however, limited research exists in integrating mhealth technology into pbmt management. we aimed to explore the feasibility, acceptability, and usability of using a pbmt specific mobile application to collect and monitor symptoms and wearable technology (apple watch) to measure objective data such as heart rate (hr) and activity. design/method: an exploratory mixed method design began in october to monitor pbmt symptoms for patients using real-time data from: ) a self-developed mhealth application (app) to collect subjective symptom data; and ) apple watch to collect physiologic measures such as heart rate and number of daily steps. data is collected pre-transplant through days. acceptability will be assessed through satisfaction surveys at study completion. we have enrolled patients to date who are all currently using the app and watch. patients' average frequency of daily charting in the app %. the wearable average daily recorded measurements are for hr and for step count. most common symptoms recorded within the app include fatigue and pain. we have noted trends in data including a decrease in activity following transplant and gvhd and an increase following engraftment. patients have stated "the app is helpful to keep track of how my pain is doing day to day" and "i try to take more steps each day than the day before". patients often remove the watch for charging, then forget to put it back on, but consistently put it on upon reminder. finally, parents often were required to make app entries with patients too sick to record. we continue to enroll patients with enthusiasm from both patients and parents to use mhealth during pbmt. preliminary findings suggest feasibility of using the mhealth devices is strongly correlated to the patient's post-transplant stage and is facilitated by caregiver participation with device management (charging devices, reminders to wear watch and record in app). patients reported satisfaction and ease of use with devices, but found it difficult to keep up with charging and charting. these findings indicate using mobile devices may be useful methods to collect patient generated health data. cincinnati children's hospital medical center, cincinnati, ohio, united states background: bacterial bloodstream infections (bsi) are a common complication following hematopoietic stem cell transplantation (hsct) in both pediatric and adult populations, and are associated with poor outcomes. there is limited data describing the outcomes and characteristics of patients who develop three or more bsi after hsct. objectives: to describe the characteristics and outcomes of pediatric patients who develop three or more blood stream infections in the first-year post hsct. design/method: we performed a retrospective chart review of consecutive patients who underwent hsct at our institution from through to compile this case series. data were collected through the first year post-hsct including: patient demographics, underlying disease and therapy characteristics; and transplant complications such as thrombotic microangiopathy (tma), graft versus host disease (gvhd) and overall survival. bsis were classified according to current center of disease control guidelines. results: of patients, ( %) developed or more bsi in the first-year post transplant (total bsi cases = including all patients). of the cases, the majority underwent allogeneic hsct (n = / ; %). most cases were from unrelated donor (n = / , %). more than half of patients had grade - gvhd (n = / , %). sixteen ( %) had tma. of these cases, tma preceded the first bsi in n = / ( %). the majority of bsis were classified as central line-associated bloodstream infections (clabsis, n = / , %), followed by mucosal barrier injury laboratory-confirmed bloodstream infections (n = / , %) and secondary bsi (n = / , %). the majority of isolated organisms ( %) were associated with mucosal barrier injury pathogens. one-year overall survival in the cohort was % (n = / ). pediatric patients undergoing hsct who develop or more bsis in the first-year post transplant demonstrated an increased rate of tma compared to the overall institutional incidence of roughly %. tma diagnosis preceded the first bsi in over half of patients, suggesting that tma may predispose to recurrent bsi. improved strategies for early detection and treatment of tma as well as prevention of clabsis may help reduce the number of bsis ultimately leading to decreased morbidity and mortality in this patient population. background: in neutropenic pediatric patients, infection remains a significant cause of morbidity and mortality. while granulocyte transfusions have been utilized for decades to treat infections, including in the pediatric population, the efficacy of this intervention remains poorly described. previous guidelines have primarily utilized information from adult populations. furthermore, recruitment of donors typically involves friends or relatives of the patient with periodic involvement of community donors. the use of a readily available local donor population to improve availability has yet to be well described. as the immunocompromised population is particularly susceptible to worsening infection and clinical deterioration, the ability to rapidly harvest and deliver granulocytes warrants further investigation. to investigate the efficacy, safety, and outcomes of severely immunocompromised patients receiving granulocyte transfusions from a local altruistic granulocyte program in a pediatric tertiary care center. design/method: a retrospective review was performed to evaluate the context for receiving a transfusion as well as primary outcomes including infection clearance, survival to discharge, and overall mortality. the indiana blood bank assisted with timing the interval from initial order placement to onset of first granulocyte infusion. results: among the patient population reviewed, patients received separate granulocyte regimens. ages ranged from - years with a mean neutrophil count of at time of first transfusion. indications for transfusions included bacteremia (n = ), fungal pneumonia (n = ), and fungemia (n = ). primary outcomes included clearing infection ( %) and surviving to discharge ( %). the median time from initial order placement to infusion was hours, although there was no significant difference between responders who cleared the infection and non-responders who did not. however, additional investigation found that ward patients had a % chance of surviving to discharge while patients in the icu at time of initial transfusion had a % chance of survival to discharge. the readily available granulocyte transfusion program allows patients to quickly receive therapy in neutropenic settings. this is beneficial for patients as transfusion prior to clinical decompensation correlates with increased likelihood of infection clearance, and subsequently improved mortality. further investigation is needed, likely as a prospective study, to better explore circumstances that are beneficial for granulocyte transfusions. background: donor lymphocyte infusions (dli) are composed of immune cells to treat relapse after hematopoietic cell transplantation (hct). to date, data regarding its efficacy is limited in pediatric populations. furthermore, while outcomes related to cd content have been characterized, to our knowledge, the relationship between outcomes and other cellular content in dli has never been reported. objectives: determine whether the primary hematological malignancy, presence/absence of graft-versus-host disease s of s (gvhd), and unique phenotypic content of each dli impact overall survival (os) in pediatric patients with hematological malignancies. design/method: irb-approved, retrospective study investigating all consecutive dlis given to patients at the children's hospital of wisconsin. analyses were conducted using mann-whitney, fisher's exact, and chi-square. from from - patients ≤ years old with hematologic malignancies [myeloid (aml/ mds/cml/jmml),n = ; lymphoid (all),n = ] underwent dlis ( %% ≥ dlis). the median time between hct and dli was . (range, . - . ) years. there were significant differences between the lymphoid and myeloid groups, respectively, in regard to median age at hct ( . vs . yrs, p = . ) and at first dli ( vs years, p = . ). ultimately, there were no statistically significant differences in gvhd or os in products with either higher or lower cd , cd , cd , cd , or cd cellular content. however, the median cd /kg content was more than double in the patients who developed gvhd as compared to patients who exhibited no gvhd after dli ( . × vs . × , p = . ). patients receiving one dli had a -year os of ± % vs those receiving + dli of ± % (p = . ). with a median follow-up of . (range, . - . ) years, the year estimated os of patients in the lymphoid group was higher at ± % vs ± % in the myeloid group, although not significant (p = . ). our results indicate a survival benefit when using dli in a subset of patients who relapse after hct. unlike adult studies demonstrating little effect of dli in lymphoid diseases, many children with all achieved durable remission. while our analysis did not demonstrate that dli cellular content had a statistically significant effect on gvhd or os, it is possible that differences could be found if a larger population and more targeted cell doses were studied. more data will be needed to further define these relationships and identify patients who stand to benefit most. cincinnati children's hospital medical center, cincinnati, ohio, united states background: many arabic speaking muslim parents of children requiring bone marrow transplantation (bmt) receive medical care in the united states. providers may not understand the impact of islamic parents' religious beliefs and practices on their health care experience. objectives: to explore how islamic parents used religion in decision making and to understand the impact of their religious beliefs and practices on their overall health care experience. design/method: we used grounded theory, an inductive method gathering data from interviews and analyzing text, to identify core themes. ten caregivers of bmt children from middle eastern countries were interviewed by an arabicspeaking provider; interviews were coded by an interdisciplinary team. we identified key themes: . patience is a core belief in islam. patience results from the acceptance of allah's will. behaviors showing patience include praying rather than questioning and crying. . al qur'an provides comfort, healing, and protection. families listen to recitations of al qur'an in the patient's room because they feel that this practice not only comforts them but promotes healing as well. for some, certain portions of the qur'an were especially meaningful such as surat al-baqara, which explains that while we may think something is bad for us, allah will know it is good for us. . religious care in the medical center helped families feel respected. religious care in the medical center included interactions with chaplains, who were understood to be "religion experts," and provision of space for prayer and religious resources. . seeking religious consultation. religious consultation from imams or religious scholars (muftis or sheikhs) provides interpretations of the qur'an applied to the family's specific situation helps families make difficult decisions and follow allah's plan. . muslim beliefs guided decision making; muslim practices brought comfort, strength, and peace. drawn from the parents' understanding of islam. parents who addressed this topic said they would only do what islam allowed. they did indicate that most aspects of healthcare were understood to be allowed within islam. additionally, muslim practices of prayer, reading/listening to qur'an, and giving alms all provided comfort, strength and peace. we identified several recurring themes through our interviews that allowed us to understand how families use their muslim faith to deal with their children's illnesses and how it influences their decision making. we believe this better understanding will allow for more informed conversations about patients' health care and decision making, and shows respect for religious beliefs and practices. nemours/dupont hospital for children, wilmington, delaware, united states background: virtually all children will be infected with human herpesvirus (hhv- ) by the age of two. hhv- reactivation after stem cell transplantation causes multiorgan toxicities, including encephalitis, with inflammation and destruction of the temporal lobes and hippocampi, memory loss, and seizures. catatonia is characterized by posturing, immobility, mutism, and autonomic instability, and it's associated with various psychiatric and medical conditions. we describe a patient with hhv- encephalitis and unusual neurologic sequelae, including cognitive and neurobehavioral dysfunction and catatonia, which may impact our understanding of the pathophysiology of hhv- reactivation encephalitis. objectives: describe a case of hhv encephalitis with practice implications for stem cell transplantation. results: our patient was diagnosed with acute myeloid leukemia at age . within years, he relapsed and received two stem cell transplants. on the th day after his second transplant, he developed hyponatremia and refractory seizures. brain mri showed edema in the medial right temporal lobe with linear ischemic change. eeg showed diffuse encephalopathy. cerebrospinal fluid (csf) demonstrated white blood cells, red blood cells, and hhv- by pcr. his prophylactic antiviral was switched to foscarnet and ganciclovir. repeat mri showed abnormal signals in bilateral medial temporal lobes and the right insula. three months later he developed episodes of diaphoresis, hypothermia, agitation, mutism, and unusual posturing, recurring almost daily, recognized as catatonia. mri showed improvement of the abnormalities in the bilateral medial temporal lobes and hippocampi. eegs showed diffuse slowing. after months of antiviral therapy, csf was negative for hhv- . over the ensuing years, he had numerous episodes of diaphoresis, hypertension, hypothermia, pruritis, confusion, agitation, cogwheel rigidity, and bizarre posturing. dopamine blocking agents did not help. clonazepam helped reduce their frequency, and hot showers helped break acute episodes. further mris showed generalized cortical volume loss. he suffered from depression and severely impaired sleep and cognitive function. we describe a novel, debilitating outcome of hhv encephalitis which may provide diagnostic considerations as we continue to improve our understanding of the breadth of possible neurologic sequelae in transplant patients. hhv- is understood to infect and destroy the temporal lobes and hippocampi, but our patient's autonomic dysfunction indicate involvement of the hypothalamus and basal ganglia. antidopaminergic agents may worsen catatonia, and they were not effective for our patient. treatment of catatonia includes benzodiazepines; electroconvulsive therapy was not attempted in this case but may also be useful. background: epstein-barr virus (ebv)-related posttransplant lymphoproliferative disorder (ptld) is a lifethreatening complication in patients following hematopoietic stem cell transplantation, with a frequency estimated at . % and a cumulative incidence of mortality estimated as high as %. studies of ebv have hypothesized that the tonsils are critical for propagating this infection, as tonsillar epithelial cells have been shown to be the site of primary viral infection and continued viral shedding; however, to date no studies have been performed assessing the role of tonsillectomy in patients with ebv ptld. objectives: identify patients with localized ebv ptld treated with tonsillectomy to identify prognostic factors that may be able to help guide future treatment decisions. design/method: patients treated at memorial sloan kettering cancer center who had received hematopoietic stem cell transplantation and had billing codes for both ebv and tonsillectomy were eligible for inclusion in this study. a retrospective chart review was performed, assessing patient demographics, transplant characteristics, laboratory values, tonsillar pathology, and clinical course. any patient who did not have unilateral or bilateral tonsillectomy performed or who had non-localized disease (defined as disease involvement outside of the oropharynx and neck) was subsequently immunodeficiency; % (n = / ) fanconi anemia (fa); % (n = / ) hemoglobinopathy; % (n = / ) non-fa marrow failure and % (n = / ) a metabolic disorder. seventy one percent (n = / ) had normal amh for age pre-transplant, % (n = / ) had low amh for age pre-transplant; of these, % (n = / ) had an oncologic diagnosis; % (n = / ) had fa; % (n = / ) had previously treated hlh; % (n = / ) had non-fa marrow failure; one had a metabolic disorder and one a hemoglobinopathy. of the patients with post-transplant amh measurement % (n = / ) had low levels. of the patients with previously normal pre-transplant amh % (n = / ) underwent myeloablative conditioning (mac) regimen with a % (n = / ) having low amh levels post-transplant compared to %(n = / ) who underwent reduced intensity conditioning (ric) regimen with % (n = / ) having low amh levels post-transplant (p . ). fifteen percent (n = / ) had low levels pre-transplant and underwent mac regimen with % (n = / ) remaining low; % of these patients (n = / ) had fa. nine percent (n = / ) had low levels and underwent a ric regimen with % (n = / ) of amh levels remaining low; % (n = / ) of these patients had hlh treated prior to transplant. conclusion: amh levels can be used for detection of premature ovarian failure and fertility counseling. there is a higher risk of premature ovarian failure with mac regimens and prior chemotherapy vs ric regimens. follow up of this cohort will provide more information to understand the effects of hsct in ovarian function and the usefulness of amh as a predictor of fertility potential. background: there are no proven strategies to prevent blood stream infections (bsi) secondary to oral mucosal barrier injury after hematopoietic stem cell transplant (hsct). additionally, we recently reported progressive gingivitis and dental plaque accumulation in hsct recipients despite our current oral standard of care (three times daily oral rinse). xylitol is a non-fermentable sugar alcohol that reduces dental caries, plaque accumulation, and oral disease progression by inhibiting bacterial growth. we hypothesized that the addition of xylitol to standard oral care will decrease dental plaque accumulation, gingivitis and bacteremia from oral flora. objectives: identify a clinically effective strategy to improve oral health and prevent bsi secondary to bacterial translocation through the oral mucosa in patients undergoing hsct. we are conducting a prospective randomized control study to test our hypothesis. those in the intervention arm receive our current standard of care (three times daily oral rinse) in addition to daily xylitol wipes; controls receive oral standard of care alone. oral exams are performed at baseline and weekly for the first days post hsct. metagenomic shotgun sequencing (mss) of gingival samples is performed at all time points to evaluate microbiome diversity and pathogenic bacterial load. finally, we performed whole genome sequencing of pathogenic bacterial isolates causing bacteremia to assess for genetic relatedness to corresponding strains present within the patient's oral microbiome preceding the infection. : preliminary interim analysis of patients demonstrates improved oral health in patients receiving xylitol (n = ) over those receiving standard of care (n = ), measured by the oral hygiene index (p = . ) and gingivitis index (p = . ). in the nine patients having complete oral mss analysis, xylitol appeared to be associated with decreased streptococcus mitis/oralis domination in the oral microbiome. finally, patients receiving xylitol had no incidence of streptococcus mitis/oralis bacteremia through the first days compared to three patients ( %) in standard of care arm. interestingly, streptococcus mitis/oralis comprised % of the oral microbiome in one child who subsequently developed a streptococcus mitis/oralis bsi. we expect to complete this study in the next months (n = ). the addition of xylitol to oral standard care appears to decrease dental plaque and gingivitis in patients undergoing hsct. xylitol may also impede streptococcus mitis/oralis dominance in the oral microbiome with potential reduction in blood stream infections. (range: - days). twenty-one mdli ( %) were administered because of lymphopenia, fourteen of them ( %) in patients with concomitant viral/opportunistic infections. mixed chimerism/graft failure was the motive of % of the mdli (n = ) and six ( %) were administered to accelerate immune reconstitution. all infusions were well tolerated without appearance or worsening of gvhd. an increase in t-cell counts was observed following six mdli ( . %), although it was a transitory response ( - weeks) in five cases. viral/opportunistic infections were controlled in five cases ( . %), requiring a median of mdli to achieve this response. none of the mdli administered in cases of mixed chimerism/graft failure were effective in reverting this situation. our preliminary data suggests that mdli, is a safe adoptive immunotherapy strategy even with high dose of t-cells without infusion side effects or gvhd complications. some efficacy has been observed in patients with lymphopenia and opportunistic infections, with no positive results in patients with mixed chimerism/graft failure, up to date. however, to determine the real efficacy of this strategy, prospective studies are required. jun zhao, kristen beebe, lucia mirea, alexandra walsh, shane lipskind, alexander, ngwube phoenix children's hospital, phoenix, arizona, united states background: male adolescents undergoing myeloablative hematopoietic stem cell transplantation (hsct) develop infertility with impaired spermatogenesis with reported rates ranging from % to %. in nonmalignant diseases, myeloablative regimens have been replaced with reduced intensity conditioning (ric) with the hopes of better survival rate, less organ toxicity and improved quality of life. despite the increased use of ric regimens for hsct, the effects of ric on fertility remain unknown. objectives: to assess fertility following ric hsct in young adult males. we assessed gonadal function and semen characteristics in adolescent males (> years) who received a single ric hsct at phoenix children's hospital for nonmalignant diseases during - . male patients who were a minimum of year from ric hsct and had postpubertal development at tanner stage iii or above were eligible for this study. gonadal status was assessed by measuring fsh, lh, testosterone, and inhibin b levels, and semen anal-yses assessed fertility indicators (semen volume, sperm concentration, motility, viability, forward progression, morphology, and total count). results: hormone levels and semen analysis have been obtained for patients thus far. the median time between transplant and semen analysis was years. post hsct, ( %) patients showed abnormally elevated lh levels, but fsh, testosterone (total and free), and inhibin b levels were within normal range for all patients. sperm morphology and viability testing were not able to be performed due to low concentrations and volumes. as a result, the total motile sperm count, the most useful estimate for fertile potential, is essentially for all patients. conclusion: recruitment is ongoing, but so far our limited results suggest that ric hsct may have detrimental longterm effects on male fertility. a multi-institutional trial may be appropriate due to small patient numbers at each institution. we are currently exploring options to expand to other centers. further consideration is warranted regarding decisions made by providers, ways to improve anticipatory counseling provided to patients and their families prior to transplant, and how to augment the preventive care of these patients in longterm follow-up. currently all male patients being considered for ric transplant should be counseled to sperm bank prior to transplant. background: a previous systematic literature review identified all published studies of defibrotide treatment for patients of all ages with vod/sos. to assess day+ survival for defibrotidetreated pediatric patients (≤ or ≤ years, per study) all patients exhibited infectious complications with at least viral infection. four patients also had bacterial infections. of note, no patient developed evidence of fungal infections. conclusion: early institution of ecp in patients with high risk acute gvhd (grade - ) was very effective at treating agvhd, allowed for an aggressive steroid taper and contributed to excellent overall survival rates ( %). infectious complications were primarily viral and bacterial, with no fungal infections in this very high risk population. background: vod/sos is a life-threatening complication of hsct conditioning. vod/sos with multi-organ dysfunction (mod) may be associated with > % mortality. defibrotide is approved to treat hepatic vod/sos with renal/pulmonary dysfunction post-hsct in the us and severe hepatic vod/sos post-hsct patients aged > month in the eu. there are few published data on survival of neuroblastoma patients with vod/sos post-hsct. objectives: to report day+ survival and safety post hoc for patients with neuroblastoma and vod/sos post-hsct in the defibrotide t-ind trial. design/method: vod/sos was diagnosed by baltimore or modified seattle criteria or biopsy, with/without mod, after hsct or chemotherapy. defibrotide treatment ( mg/kg/day) was recommended for ≥ days. this post hoc analysis is based on adult and pediatric patients receiving ≥ dose of defibrotide, including with mod. results: among patients with neuroblastoma, developed vod/sos after hsct. for these post-hsct patients, . % were male and . % were female, median age was years (range - years): . % aged - months, . % - years, . % - years, and patient > years. day+ survival data were available for / of these neuroblastoma patients ( with mod and without mod); had autologous and had allogeneic transplants. kaplan-meier estimated day+ survival for the neuroblastoma group was . % ( % confidence interval [ci] , . %- . %). for the mod and no mod subgroups, kaplan-meier estimated day+ survival was . % ( % ci, . %- . %) and . % ( % ci, . %- . %), respectively. in the overall t-ind hsct population aged ≤ years (n = ) and pediatric autologous hsct subgroup (n = ), kaplan-meier estimated day+ survival was . % and . %, respectively. treatment emergent adverse events (teaes) occurred in . % (n = / ), with serious teaes in . % ( / ; most common: multi-organ failure, . % [ / ]). teaes lead to treatment discontinuation in . % (n = ; most common: pulmonary hemorrhage, n = ); death occurred in . % (n = ; > %: multi-organ failure, . %; vod/sos, . %). treatment-related adverse events, as assessed by investigators, occurred in . % (n = ; most common: pulmonary hemorrhage, . %). this post hoc analysis found kaplan-meier estimated day+ survival of . % in patients with neuroblastoma and vod/sos post-hsct, which was consistent with outcomes in pediatric patients after autologous hsct. the safety profile of defibrotide in neuroblastoma patients was consistent with the overall hsct population in this study and other defibrotide studies in pediatric patients. cincinnati children's hospital medical center, cincinnati, ohio, united states background: blood stream infections occur in nearly % of patients undergoing hematopoietic stem cell transplant (hsct) and fever is often the first symptom. timely administration of antibiotics is associated with improved outcomes, thus, early recognition of fever is paramount. current standard of care (soc) includes episodic monitoring of temperature in hospitalized patients, which may delay fever detection. therefore, continuous real-time body temperature measurement may detect fever prior to the current soc. temptraq is a food and drug administration cleared class ii medical device and consists of a soft, comfortable, disposable patch that results: of patients, were started on a pca in the days post hct. % were male with median age of y. % had all, and % aml. matched related donors were used in % and % received tbi. pca was initiated median d+ . oral mucositis alone was the most common indication ( %). a majority of patients were started on hydromorphone ( %); % started on morphine and % started on fentanyl. % started on continuous infusion. pca was used for a median of days (range - days). median pain score was highest d+ of pca use, however, there was inconsistency in charting of numerical pain scores. on d+ , patients had insufficient data to determine efficacy of pain control; of the remaining patients, % had good pain control while % had moderate and % had poor pain control using our devised scale. the most common toxicity observed was respiratory depression (∼ %), however, etiology was often multifactorial and not due to opiates alone. analysis is ongoing to assess variables predicting pca use as well as efficacy of pain control and correlation between current reporting scales and patient perception. conclusion: pca use is common in pediatric hct yet pain control remains inadequate. there's a need for better evaluation of pca management, especially uniform assessment of pain, thereby improving quality of life post hct. children's national health system, washington, district of columbia, united states background: actinomycosis is a rare invasive anaerobic gram-positive bacterial disease caused by actinomyces spp. that may colonize the oropathynx, gastrointestinal tract and urogenitial tract and can lead to abscesses. respiratory tract actinomycosis is characterized by pulmonary cavities, nodules, consolidations and pleural effusions. although actinomyces are nearly always sensitive to penicillin they are frequently resistant to cephalosporins and variable sensitives to fluoroquinolones. although rare in children, immunosuppressed patients are at increased risk for actinomycosis. to describe a case of next-generation sequencing identification of actinomycosis. a -year-old male with a history of very high risk b-cell acute lymphoblastic leukemia who was months status post a / matched unrelated donor bone marrow transplant complicated by prolonged fevers, persistent weight loss, and splenic lesions, treated with posaconazole and levofloxacin developed fever and cough in the setting of neutropenia. blood cultures demonstrated staphylococcus epidermidis. ct showed micronodules and effusion not consistent with s. epi, prompting bronchoscopy. all bacterial cultures were negative. patient was prescribed a three-week course of vancomycin with rapid improvement. design/method: s next generation sequencing (ngs) from bronchoalveolar levage sample was performed at the university of washington laboratory results: ngs assay from bronchoalveolar lavage showed major abundance of actinomyces most closely related to meyeri or oodontolyticus. demonstrated actinomyces. the patient was started on a six month course of amoxicillin with continued clinical improvement. in retrospect, the splenic nodules that were presumed fungal disease were likely actinomycosis, partially treated with levofloxacin. this case highlights the potential utility of ngs in the diagnosis of rare diseases in immunocompromised patients. actinomycosis was only demonstrated through ngs and led to a change in treatment regimen and durable clinical improvement. because actinomyces often mimics malignancy, tuberculosis or nocardiosis, the use of this novel test both targeted appropriate therapy and reduced the exposure to unnecessary medications to treat the differential diagnosis. finally, we highlight that actinomyces should be considered in patients who present with unexplained fevers, weight loss, and night sweats. haneen shalabi, cynthia delbrook, maryalice stetler-stevenson, constance yuan, bonnie yates, terry j. fry, nirali n. shah center for cancer research, national cancer institute, national institute of health, bethesda, maryland, united states background: car-t therapy, while effective, may not be durable for all, and antigen negative escape is a growing problem. hct, in relapsed/refractory all, can be curative, particularly for those in an mrd negative remission. we demonstrated that cd directed car-t therapy effectively rendered patients into mrd negative remissions (by flow cytometry) and the leukemia free survival post-hct was high . in pastorek, jesssica bruce, michael a. pulsipher, chloe anthias, peter bader, andre willasch, jennifer sees, jennifer hoag, wendy pelletier, brent logan, pintip chitphakdithai, lori wiener university of pittsburgh, pittsburgh, pennsylvania, united states background: more than , pediatric hscts are performed in north american and europe each year. the ethics of exposing a healthy child to donation procedures which have some risks and no direct medical benefits continue to be a topic of debate. pediatric donors may experience psychological distress and poorer quality-of-life during and after donation compared to healthy controls. although there are fact/jacie requirements related to the management of pediatric donors, it is unclear what standardized practices exist for psychosocial assessment/management of this group. objectives: to describe transplant center practices for psychosocial evaluation/ management of pediatric donors (< years) and to examine differences in practices by location (cibmtr/ebmt) and number of harvests (volume). design/method: data were collected via a single crosssectional survey distributed electronically to cibmtr and ebmt centers between / / and / / . : / ( %) of cibmtr and / ( %) of ebmt centers completed the survey. most centers had written eligibility guidelines for pediatric donors ( %). most also had a process for ensuring that donors were freely assenting to donate ( %), managed by a transplant physician ( %). a single physician often jointly managed donor/recipient care ( %). half of centers had a pediatric donor advocate ( %), who was most often a physician ( %) or social worker ( %). cost was the largest barrier to having a donor advocate ( %). most centers performed psychosocial screening of donors ( %) but rarely declined donors based on psychosocial concerns ( %). less than half of centers provided post-donation psychosocial follow-up ( %). comparisons by center location indicated that ebmt centers were more likely to have a physician doing joint donor/recipient care ( % vs. %; p = . ), less likely to have a psychosocial assessment policy ( % vs. %; p = . ), less likely to have a donor advocate ( % vs. %; p = . ), but marginally more likely to do post-donation psychosocial follow-up ( % vs. %; p = . ). large volume centers were more likely to have a psychosocial assessment policy than their medium/smaller counterparts ( % vs. %, %; p = . ) â€"there were no other differences on key psychosocial management variables by volume. although most centers have written guidelines for pediatric donor eligibility and mechanisms for ensuring assent, substantial numbers of donors do not undergo psychosocial assessment, are jointly managed with the recipient by a single physician without an assigned donor advocate, and do not receive psychosocial follow-up. the field would benefit from guideline development for the psychosocial management of pediatric donors. background: germline mutations in samd and samd l genes cause mirage (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy) and ataxia-pancytopenia syndromes, respectively, and are associated with chromosome deletions, mds and bone marrow failure (bmf). there are limited data on outcomes of hct in these patients. to describe outcomes of allogeneic hct in patients with hematologic disorders associated with samd /samd l mutations. results: seven patients underwent allogeneic hct for primary mds (n = ), congenital amegakaryocytic thrombocytopenia (camt)(n = ), and dyskeratosis congenita (n = ). retrospective exome sequencing revealed gain-of-function mutations in samd (n = ) or samd l (n = ) genes. constitutional mosaic monosomy was present in cases. two samd patients had features of mirage syndrome. unusual findings of panhypopituitarism, laryngeal cleft, and glomerulosclerosis were noted in one case. in another case with a samd mutation hypospadias & bifid scrotum were the only findings. the remaining patients had no phenotypic abnormalities. median age at hct was y (range: . - . ). patients received transplants from bone marrow (matched unrelated (n = ) & hla identical sibling (n = )), or unrelated cord blood (ucb) (n = ). five mds patients received myeloablative s of s conditioning (busulfan-based (n = ) or tbi-based (n = )); patients (mds (n = ); camt (n = )) received reducedintensity conditioning (ric) (fludarabine, cyclophosphamide, with ratg or alemtuzumab). syndrome-related comorbidities (diarrhea, infections, malnutrition, electrolyte imbalance, lung disease and hypoxia) were present in both patients with mirage syndrome. one patient with a familial samd l mutation, mds and morbid obesity failed to engraft following ric double ucbt. she died one year later from refractory aml. all other patients achieved neutrophil and platelet engraftment, at a median (range) of ( - ) and ( - ) days, respectively. posttransplant complications included severe hypertension (n = ), pericardial effusions (n = ), veno-occlusive disease of liver (n = ), and recurrent aspiration pneumonias (n = ). one patient developed grade iii agvhd which resolved with treatment. one patient developed mild skin cgvhd and suffers from chronic lung disease. all surviving patients had resolution of hematological disorder and sustained peripheral blood donor chimerism ( - %). overall survival was % with a median follow-up of years (range: . - . y). patients with hematological disorders associated with germline samd /samd l mutations tolerated transplant conditioning without unusual, or unexpectedly severe toxicities. allogeneic hct led to successful resolution of mds or bmf, with excellent overall survival. more data is needed to refine transplant approaches in samd /samd l patients with significant comorbidities, and develop guidelines for their long-term follow-up. shyamli singla, tiffany simms-waldrip, andrew y. koh, victor m. aquino background: steroid-refractory acute graft versus host disease (agvhd) is a potentially fatal complication of allogeneic hematopoietic stem cell transplantation (hsct). basiliximab (anti-il -r monoclonal antibody) as a single agent or in combination infliximab (anti-tnf-monoclonal antibody) has demonstrated efficacy in adult cohorts with steroid-refractory agvhd, but has not been well studied in the pediatric population. we adopted the use of basiliximab and infliximab as our institutional standard of care for steroid-refractory agvhd in pediatric hsct patients. to determine the response and survival of hsct children who received basiliximab and infliximab for the treatment of steroid-refractory agvhd. design/method: we retrospectively reviewed children who received basiliximab and infliximab for steroid-refractory agvhd refractory between september and december . complete response (cr) was defined as resolution of all clinical signs of agvhd. partial response (pr) was defined as at least one grade reduction in one target organ (e.g. skin, gut or liver) without increased grade in another target organ. no response was defined as either no improvement or progressive worsening of agvhd in at least one organ. baseline demographics, transplant details, laboratory findings, and treatment outcomes were also evaluated. results: of the evaluable hsct patients, children (median age yrs, range mo- yrs) with steroid-refractory agvhd received combination monoclonal antibody (mab) therapy. the median time from the start of steroid therapy to initiation of mab was days. the overall glucksberg grade of agvhd at the time of initiating mab therapy was grade i (n = , . %) ii (n = ; %), iii (n = ; %) or iv (n = ; %). the overall response rate was %, with ( %) patients achieving cr, ( . %) patients achieving pr, and ( . %) patients with no response at days following the start of mab therapy. the median overall survival was , , and days for patients who exhibited cr, pr, and no response, respectively. the overall survival at year following start of mab therapy was %. background: the role of high dose chemotherapy (hdc) and autologous stem cell rescue (ascr) in patients with high risk (advanced metastatic or relapsed) soft tissue sarcomas is controversial. despite multimodal chemotherapy, radiotherapy, and local control measure advancements, prognosis of patients with advanced metastatic or unresectable and relapsed sarcomas remains poor, with less than % years disease free survival. objectives: to determine if consolidation with myeloablative hdc and ascr improves relapse free (rfs) and overall survival (os) outcomes in a high risk patient subgroup. we performed retrospective review of all high risk soft tissue sarcoma patients who underwent hdc and ascr at the children's hospital at montefiore, bronx, ny between october and january . the protocol was approved by albert einstein college of medicine institutional review board. results: patients ( primary metastatic high risk disease, relapsed or recurrent disease) received hdc with ascr. primary diagnoses were rhabdomyosarcoma (rms) (n = , alveolar histology), primary site nasopharynx (n = ) and lower extremity (n = ). ewing's sarcoma (ews) (n = ), axial site (pelvic) in patients ( %). median age years (range - years), ( %) were male. all patients were in complete metabolic remission before transplant. median pre transplant comorbidity index was (range - ). patients ( rms and ews) received conditioning with carboplatin, etoposide and melphalan. remaining patients with ews received conditioning with busulfan, melphalan and topotecan. all patients received peripheral blood mobilized hematopoietic stem cell transplantation. stem cell mobilization achieved with high dose filgrastim in all patients except one who required addition of plerixafor. median cd +/kg s of s recipient body weight cell dose infused was . × ^ (range . - . × ^ ). median times to neutrophil and platelet (> , / l) engraftment were (range - ) and ( - ) days respectively. patients ( %) developed bk viuria (one with grade iii hemorrhagic cystitis); ( %) developed cmv viremia; and one patient ( %) had asymptomatic ebv viremia. there was no graft failure, sinusoidal obstruction syndrome or transplant related mortality. median follow up post-transplant was days (range - days). year probability of os and rfs were % and % respectively. hdc with ascr is a promising therapeutic strategy to consolidate remission and improve survival in select high risk soft tissue sarcoma patient subgroups. prospective clinical trials will inform the impact of disease status prior to hdc and ascr on outcome, optimal conditioning and long term relapse free and overall survival. background: absence of minimal residual disease is paramount for cure of pediatric acute lymphoblastic leukemia (all). the testis may harbor occult leukemia and this disease may result in treatment failure. objectives: the purpose of this study was to assess the longterm outcomes of boys with or without testicular leukemia pre-hematopoietic stem cell transplantation (hsct). design/method: retrospective analysis of boys with high-risk de novo ( with hypodiploidy all) or recurrent/refractory all was conducted. flow cytometry of bone marrow mononuclear cells was used to determine remission status. testicular evaluations were performed by physical examination and wedge biopsy pre-hsct. the median age at time of transplant was . years. all patients were in remission by flow cytometry of bone marrow mononuclear cells at the time of transplant and none had evidence of clinically apparent testicular disease. testicular leukemia was detected in patient and he underwent bilateral orchiectomy. he developed acute graft versus host disease (gvhd) of the duodenum and sigmoid colon which resolved, and the leukemia remains in second complete remission and he is free of hsct-related morbidity . months post-hsct. of the patients without testicular leukemia died a median of . months (range, . to . ) post-hsct ( with adenovirus infection and each with thrombotic microangiopathy and aspergillus pneumonia); experienced infection (staphylococcus species, corynebacterium, enterococcus, klebsiella, citrobacter, e. coli, epstein barr virus, adenovirus, bk virus, human herpesvirus- , candida albicans, fusarium, aspergillus, yeast, and other fungus); experienced gvhd ( of the gi tract, of the skin, of the liver, of the eyes, of the mouth, and of the lungs); and developed a second neoplasia (right lower leg leiomyosarcoma). one patient developed bone marrow minimal residual disease ( . % phenotypically abnormal cells detected months after / matched sibling hsct). reinduction therapy comprised weekly doses of rituxan, courses of blinatumomab and donor lymphocyte infusions with il- . two subsequent bone marrow evaluations were minimal residual disease negative. thirteen months post-hsct residual disease recurred ( . %) and he will receive inotumumab. overall median survival post-transplant of the boys is . months (range, . to . ) and of the surviving boys is . months (range, to . ). conclusion: testicular biopsy can detect occult leukemia pre-hsct. testicular leukemia pre-hsct does not appear to increase the risk of subsequent relapse or other hsct-related adverse events compared to those without it. yaya chu, nang kham su, sarah alter, emily k. jeng, peter r. rhode, mathew barth, dean a. lee, hing c. wong, mitchell s. cairo new york medical college, valhalla, new york, united states background: rituximab has been widely used in frontline treatment of b-nhl including burkitt lymphoma (bl), however, some patients retreated with rituximab relapse, which limit patient treatment options. novel therapies are desperately needed for relapsed/refractory b-nhl patients. several strategies for overcoming rituximab-resistance are currently being evaluated, including engineering immune cells with chimeric antigen receptors (car), as well as second-generation anti-cd antibodies. nature killer (nk) cells play important roles in the rejection of tumors. however, nk therapy is limited by small numbers of active nk cells in unmodified peripheral blood, lack of tumor targeting specificity, and multiple mechanisms of tumor escape of nk cell immunosurveillance. our group has successfully expanded functional and active peripheral blood nk cells (expbnk). b t m was generated by fusing alt- , an il- superagonist, to four single-chains of rituximab. b t m displayed tri-specific binding activity through its recognition of the cd molecule on tumor cells, activated nk cells to enhance adcc, and induced apoptosis of b-lymphoma cells. objectives: to examine if b t m significantly enhances the cytotoxicity of expbnk against rituximab-sensitive and -resistant bl cells. design/method: expbnks were expanded with lethally irradiated k -mbil - bbl and isolated using miltenyi nk cell isolation kit. alt- and b t m were generously provided by altor bioscience. nk receptors expression and cytotoxicity were examined as we previous described. ifng and granzyme b levels were examined by elisa assays. equal doses of rituximab, alt- , rituximab+alt- , obinutuzumab (obinu) were used for comparison. igg was used as controls. anti-cd car expbnk cells were generated as we previously described by mrna electroporation. rituximab-sensitive raji andresistant bl cells raji- r and raji- rh, were used as target cells. results: b t m significantly enhanced expbnk cytotoxicity against rituximab-sensitive raji cells, rituximab-resistant raji- r cells and resistant raji- rh cells compared to the controls igg, rituximab, alt- , rituximab+alt- , obinu (p< . , e:t = : ). furthermore, we confirmed the enhanced cytotoxicity by measuring ifn-g and granzyme b production. b t m significantly enhanced ifn-g and granzyme b production from expbnk against raji, raji- r and raji- rh compared to igg (p< . ), rituximab (p< . ), alt- (p< . ), rituximab+alt- (p< . ), and obinutuzumab (p< . ). when compared to anti-cd car expbnk cells, b t m + expbnk had the similar cytotoxicity against raji, raji- r and raji- rh as anti-cd car expbnk cells did (p> . ). conclusion: b t m significantly enhanced expbnk activating receptor expression and in vitro cytotoxicity against rituximab-sensitive and -resistant bl cells. the in vivo functions of b t m with expbnk against rituximab-sensitive and -resistant bl cells using humanized nsg models are under investigation. background: cardiac dysfunction, including left ventricular systolic dysfunction (lvsd), is a known complication in stem cell transplant (sct) survivors. while detection of lvsd by echocardiography is important in this population, there has been minimal research to determine if subclinical cardiac dysfunction exists in sct patients. cardiopulmonary exercise testing (cpet) is a valuable tool to assess cardiac function, and to determine how the heart responds to the stress of exercise. no studies have been performed to determine if sct patients with normal lvsd on standard echocardiography may have abnormal cpet. to determine the feasibility of cpet, as well as additional echocardiographic parameters, to detect dysfunction in sct patients with a normal ejection fraction on echocardiogram. design/method: we performed a cross-sectional analysis of sct survivors who were at least years post sct, years of age or older and with an ejection fraction > % (low end of normal range) on echocardiogram. we assessed the exercise capacity of all patients with cpet, and sub-clinical cardiac dysfunction through tissue doppler and strain analysis from the echocardiogram. results: seven patients ( male) have qualified and completed this study so far with an average age of . ± . years. the median time from transplant is . ± . years. all seven patients had a normal ejection fraction, however four patients had abnormalities on their cpet. these abnormalities included abnormal predicted peak oxygen consumption (vo ) ( %± . , normal > %) (the best predictor of functional capacity), predicted oxygen pulse ( %± . , normal > %) (measure of cardiac stroke volume) and ventilatory efficiency (ve/vco slope) ( ± . , normal < ). submaximal exercise data, used when patients are unable to complete a maximal effort test, demonstrated low-normal predicted vo at anaerobic threshold ( . %± . %, normal > % of was . days while patients who received autologous infusions had a mean number of days to engraftment of . . engraftment after hsct needs to be prompt to minimize duration of neutropenia and maximize survival rates . our data demonstrates that the infusion of hematopoietic stem cell products with a syringe or iv pump is an effective method of delivery for stem cell products and does not delay the time to engraftment. the median days to neutrophil engraftment was . days. this is comparable to data from the nmdp, which reports engraftment occurs within - days. the main limitation to this study was its small sample size due to the number of transplants done at our center. however, it does provide evidence to support that infusion of stem cell products via pump mechanism is a safe alternative to the infusion by gravity method in the process of the hematopoietic stem cell administration. johns hopkins all children 's hospital, st. petersburg, florida, united states background: leukemic relapse remains the most common cause of treatment failure after allogeneic hematopoietic cell transplant (allohct) for myeloid malignancies. most children who relapse post-allohct will die of their disease, making interventions to minimize this risk a high priority. objectives: to evaluate the safety and efficacy of posttransplant azacitidine for relapse prevention in children undergoing allohct for myeloid malignancy. design/method: we retrospectively reviewed the charts of children undergoing allohct for myeloid malignancies between february and november at johns hopkins all children's hospital. results: during the study period, children (ages to years, median ) underwent allohct for myeloid malignancies: de novo acute myeloid leukemia (aml), ; mixed phenotype acute leukemia, ; treatment-related aml, ; juvenile myelomonocytic leukemia with aml transformation, ; and myelodysplasia/aml, . thirteen were in first complete remission, were in cr or greater. most patients ( / ) received fludarabine/melphalan/thiotepa conditioning; received hla-identical related or unrelated donors, and received haploidentical bone marrow grafts with post-transplant cyclophosphamide. three patients never received planned azacitidine ( early relapse; early trm), leaving evaluable patients. azacitidine ( mg/m /dose for days, in -day cycles for up to cycles) was started at a median of days post-transplant (range - ). two-thirds ( / ) of patients received eight or more cycles. of five patients who stopped therapy early, only one was due to toxicity; other reasons included severe gvhd ( ), parental preference ( ), and relapse ( ). cycle delays occurred in patients, with a median cycles delayed per patient, mostly for mild myelosuppression with early cycles. no patient required blood product transfusion during therapy, but g-csf was used in three patients to maintain anc> / l. dose-modifications were made in patients (renal tubular acidosis, acute kidney injury, and myelosuppression). there were relapses ( %), two of which occurred in patients in cr , for a relapse incidence of % in patients in cr , with a median follow-up of months (range . to ). no patients who received azacitidine died of transplant-related mortality. conclusion: administration of azacitidine in children undergoing allohct for myeloid malignancies is safe and feasible, with most patients successfully receiving all planned cycles. toxicity was acceptable and there was no trm or secondary graft failure. despite the limitations of a small cohort, relapse incidence-particularly in patients transplanted in cr suggests a potential benefit in disease control that warrants investigation in follow-up studies. background: despite significant improvements in the success rate of hematopoietic cell transplantation (hct), graft failure remains an important complication in patients transplanted for severe aplastic anemia (saa). second allogeneic hct can salvage patients, but -year overall survival (os) rates have been reported as low as % . objectives: identify patients who developed dropping donor chimerism, graft rejection, and/or graft failure after first hct for saa, necessitating additional hcts or cellular boosts (defined as stem cell products infused without preceding chemotherapy), and evaluate treatment-related complications and os. with vod/sos with and without multi-organ dysfunction (mod) pubmed and embase databases were searched for "defibrotide and retrospective chart reviews; excluded publication types were: case reports (< cases); meta-analyses; reviews; animal, modeling, pharmacokinetic, chromatography, and adult-only studies; guidelines; articles; and letters. resulting reports were screened for exclusion criteria. full-text articles were then reviewed for eligibility. study characteristics of selected publications were summarized, and publications were categorized by patients' mod status. when necessary, additional data tables were requested. a random effects model was used for pooling data for efficacy. interstudy heterogeneity was assessed with cochran's q-test. percentage of total variation across studies due to heterogeneity (i ) was evaluated we quantified ∼ proteins in each sample. reproducibility for one donor at different time points children 's minnesota, minneapolis, minnesota, united states background: pediatric and young adult hodgkin lymphoma (hl) has five-year survival rates > %. chemotherapy required to achieve this rate is associated with a lifetime risk of cardiac deaths, second malignancies, pulmonary disease and infertility. as effective salvage therapy exists, outcomes may be improved by de-intensifying initial therapy to lessen toxicity.objectives: we piloted a regimen in low and intermediate risk hl patients using agents without known association to significant late effects. this retrospective chart review was approved by children's minnesota irb.design/method: the bvg(p) regimen incorporated bortezomib ( . mg/m day , , , ); vinorelbine ( mg/m day , ); gemcitabine ( mg/m day , ) every days and prednisone ( mg/m /dose bid x days). we treated newly diagnosed patients, ages - years, with non-bulk stage iia (n = ) or iib (n = ) hl. two patients received bvg and received bvgp with the addition of prednisone.results: newly diagnosed patients were all pet negative after the first or second cycle and remained pet negative at end of therapy, cycles. nausea was well controlled with -ht antagonists and scopolamine. pegfilgrastim was not necessary due to the high absolute neutrophil count nadir [median . and minimum . × /l]. there were no episodes of febrile neutropenia, infection or transfusion need. no patients experienced alopecia. one patient developed sensory neuropathy after the eighth dose of bortezomib that was controlled with gabapentin and a switch to subcutaneous bortezomib administration. of the five newly diagnosed patients, four remain in remission at , , , days; relapsed at previous disease sites at days and subsequently achieved remission with bvgp with the addition of brentuximab. this series provides early evidence to stimulate expansion of this pilot experience and subsequent multiinstitutional study leading to a randomized trial of bvgp and current chemotherapy for low and intermediate hl. st jude affiliate clinic at st francis hospital, tulsa, oklahoma, united states background: symptoms suggestive of morning hypoglycemia has been noticed in children receiving all chemotherapy. only few small studies looked at this therapy related complication. factors increase risk of hypoglycemia in all patients include accelerated starvation, steroid induced adrenal suppression, mercaptopurine therapy and prolonged fasting for procedures.objectives: to study the prevalence and risk factors for hypoglycemia during all therapy design/method: medical records of of children (up to years old) treated for all between - ( patients) were studied for evidence of morning hypoglycemia defined as blood sugar (bs) < mg/dl. statistical mean differences between the subgroups were analyzed with spss using a nonparametric mann-whitney u test.results: fifty two percent ( %) of patients developed hypoglycemia during all treatment, with an average of . episodes/patient. % were males and % females. almost / ( %) of patients with hypoglycemia were in maintenance phase of therapy. % of hypoglycemic episodes occurred in % of patients. majority of hypoglycemic episodes ( . %) occurred on the day of procedure when patients were fasting overnight. . % of hypoglycemic episodes occurred in children ≤ years, with . % in ≤ years. patients who developed hypoglycemia were significantly younger (mean age at time of diagnosis of all was . ± . at the hypoglycemia group versus the non-hypoglycemia ( . ± . ) p< . . no statistically significant difference was found regarding sex, or tpmt genotype. % of hypoglycemic children-all < years of age-presented with life threatening hypoglycemia symptoms including seizure and loss of consciousness. this study showed high prevalence of hypoglycemia during childhood all therapy. younger age, especially ≤ years, is associated with higher risk of hypoglycemia as well as life-threatening episodes. to decrease fasting hypoglycemia during therapy for childhood all, we recommend that children under the age of years receive bed time snack high in proteins and complex carbohydrates, and to get them up early the day of procedure to take clear sugary drink. hospital for sick children, toronto, ontario, canada ann & robert h. lurie children's hospital of chicago, chicago, illinois, united states background: childhood brain tumors are the most common solid malignancy and the leading cause of cancer-related mortality in children. the most aggressive type of pediatric central nervous system (cns) tumors is diffuse intrinsic pontine glioma (dipg). despite decades of clinical trials, there has been no substantial improvement with respect to therapeutic outcomes with most children eventually succumbing to the disease. research on adult high-grade gliomas has shown a targetable pathway through the inflammationinduced expression of indoleamine , dioxygenase (ido ) and its recognized ability to suppress the anti-tumor immune response. a limited understanding into the role of ido in pediatric central nervous system tumors serves as the foundation of this research project. furthermore, the integration of nanotechnology is a fundamental step for the investigation and targeting of ido . spherical nucleic acids (snas) composed of nanoparticles have been shown to transverse cellular membranes, exhibit stability in physiological environments, escape from degradation, and create precise targeting in brain tumors.objectives: the purpose of our project is to delineate the role of ido in pediatric dipg, and develop small inhibitory (si)rna oligonucleotides and snas aimed at therapeutically inhibiting the gene expression of immunosuppressive ido . our specific aims are to: ( ) confirm the gene expression ido in different human dipg cell lines; ( ) generate and characterize sirna oligonucleotides targeting human ido in vitro; and ( ) generate and characterize gold nanoparticles for targeted inhibition of ido .design/method: unique patient-derived dipg cell lines were grown in culture, stimulated with increasing concentrations of the proinflammatory cytokine, ifn , and analyzed for mrna levels. sirna specific to ido was transfected into cells. sna generation is in progress.results: ido is expressed in multiple human pediatric dipg cell lines. sirna targeting ido among exons and results in a significant decrease in overall ido expression by dipg cells. sna generation for targeting ido with improved penetration & stability is ongoing, with preliminary results demonstrating a robust ability to inhibit ido expression. the grim prognosis of children with dipg, the lack of effective therapies, and the expression of ido by human dipg cells emphasize the importance of developing the treatment capability to inhibit ido gene expression, as a excluded from this study. the remaining patients were analyzed using descriptive statistics.results: a total of patients meeting inclusion criteria were identified. of these, patients ( . %) received tonsillectomy alone, ( . %) underwent tonsillectomy and decreased immunosuppression, ( . %) received tonsillectomy and rituximab, and another ( . %) received tonsillectomy with additional therapy (including ebv-specific cytotoxic tlymphocytes, donor leukocyte infusion, and chemotherapy). of the patients who received tonsillectomy with or without a decrease in immunosuppression, all were diagnosed with high-grade lymphoma and achieved clinical remission following tonsillectomy with no evidence of relapse to date. on further analysis looking at ptld risk factors, all patients were under years of age, all received t-cell depleted grafts, and none had significant graft-versus-host disease (gvhd) at the time of ptld diagnosis. we have identified a population of patients with localized ebv ptld that achieved clinical remission with no evidence of recurrence following tonsillectomy, suggesting that tonsillectomy alone may be an adequate treatment for localized ebv ptld in a specific subgroup of patients. further analysis is needed to identify characteristics of this subgroup to determine which patients would be most likely to respond to this treatment. university of rochester, rochester, new york, united states background: malignant central nervous system (cns) tumors in young children have a poor prognosis and pose a significant therapeutic challenge. consolidation therapy with carboplatin and thiotepa was piloted in ccg- , cog acns , and cog acns with the goals of intensifying therapy and omitting or delaying radiation.objectives: to document outcomes for patients undergoing carboplatin/thiotepa consolidation with autologous stem cell rescue (ascr) and to demonstrate the feasibility and toxicity of this regimen.design/method: patients up to years old (median age: months) with malignant cns tumors treated at the university of rochester from - with at least one cycle of carboplatin ( mg/kg/day x days) and thiotepa ( mg/kg x days) followed by peripheral blood ascr were included in retrospective analysis. data were recorded on time to engraftment (defined by absolute neutrophil count (anc) recovery to > . × ^ /l), length of hospitalization, toxicity with each consolidation cycle, progression free survival (pfs) and overall survival (os). stem cell harvest data were also collected.results: eleven patients with malignant cns tumors ( atypical teratoid/rhabdoid tumor, primitive neuroectodermal tumor, glioblastoma multiforme, and pineoblastoma) received a total of cycles of carboplatin/thiotepa. of these, underwent stem cell harvest at our institution, with complications limited to procedure-related hypotension for patient with known autonomic instability, and catheter-associated deep vein thrombosis (dvt) for patient. four patients were in complete remission (cr) /status-post gross total resection, was in cr , and had residual tumor at the time of consolidation. nine patients received planned consolidation cycles, patient (of ) planned cycles, and patient of an anticipated cycles thus far. average time to engraftment for these cycles was . (+/- . ) days, with a mean hospital length of stay of (+/- . ) days. fever occurred in of cycles ( %); infectious toxicity included documented bacterial infection in cases (enterococcus faecalis bacteremia in , klebsiella pneumoniae in ). there were no regimenrelated deaths. with a mean follow-up of months, survivors have not yet completed all therapies, and patients have relapsed ( have died of disease). of the survivors, have been disease-free for > months. background: autologous hematopoietic stem cell transplantation (auto-hsct) has resulted in improved survival for patients with high-risk neuroblastoma. treatment intensification is however associated with greater complications. data on early infectious complications in low-and-middle income countries are limited.objectives: to review the early infectious complications following auto-hsct in patients with high-risk neuroblastoma.design/method: a retrospective chart review of pediatric patients with high-risk neuroblastoma who underwent auto-hsct at the american university of beirut medical center between and was conducted. infectious complications during the first days post-transplant were reviewed.results: forty-three patients ( males and females) with a median age at diagnosis of . years [range: . - . ] years underwent auto-hsct during the above-mentioned period. conditioning regimen consisted of melphalan, etoposide and carboplatin. all patients received antiviral and antifungal prophylaxis. median time for neutrophil engraftment was days [range: - ]. bacteremia and clostridium difficile infections occurred in ( %) and ( %) patients respectively. seven ( %) patients developed enterocolitis diagnosed by imaging, were adenovirus induced. cmv viremia was diagnosed in ( %) patients, of whom required treatment. varicella zoster reactivation, parvovirus viremia, toxoplasmosis encephalitis, bk virus cystitis ( patients) and central nervous system ebv related post-transplant lymphoproliferative disorder were diagnosed in different patients. there was no invasive fungal infection. sixteen ( %) patients have died, of whom died in the early post-transplant period, due to disease progression and ( . %) due to infectious complications. among the patients who died due to infection, developed toxoplasmosis encephalitis, developed severe enterocolitis, of which were adenovirus related. the mean igg level within one week post-transplant was lower in patients with clinically significant viral infection compared to others ( vs . mg/dl, p: . ). the mean igg level at the time of clinically significant bacterial infection was lower in infected patients compared to others ( . vs . mg/dl, p: . ). neither absolute lymphocyte count nor absolute neutrophil count at day post-transplant affected the incidence of clinically significant infections. our results show that the rate of infections during the early post auto-hsct period is higher than what has been described in developed countries and has a significant impact on mortality. prevention, early detection and improvement in the treatment is required to improve outcome. university of miami, miami, florida, united states background: allogeneic hematopoietic stem cell transplantation (allo-hsct) is a curative treatment for many malignant and non-malignant (bone marrow failure, immunodeficiency, or metabolic diseases) in pediatrics. despite advances in medicine, graft-versus-host-disease (gvhd) remains a significant cause of non-relapsed morbidity and mortality, specifically in those with malignant diseases.objectives: to highlight the complexity to acute gvhd management and seldom-described treatment approach. a year male with a history of high risk acute myeloid leukemia (aml) due to failed induction therapy. he received a matched ( / ) unrelated donor hsctmarrow product-conditioned with busulfan, fludarabine, and anti-thymoglobulin (atg). his post-transplant course was complicated by hhv- viremia, pres (prompting a change from prograf to cyclosporine), mucositis, and grade iii acute gvhd (skin s , gut s , liver s ) around post transplant day , which later morphed to ocular involvement by d+ . he was started on mg/kg steroids with good response but flared up with each attempt to taper steroid dose. a course of rituximab and later atg were tried without success in weaning off steroids. switching cyclosporine to sirolimus did not provide any additional benefit either. extracorporeal photopheresis (ecp) was started times a week. he initially responded well, yet was not able to wean off steroids. in addition, he developed a flare when ecp session was reduced to days per week. ecp was therefore increased to days per week, which appeared to stabilize skin lesions. a trial of weekly methotrexate was attempted to wean off steroids and photopheresis, which provided no response. finally, a trial of bortezomib on days , , , and of a day cycle as published in a case series of multiple myeloma patients who developed post hsct gvhd. skin lesions improved remarkably however dose had to be reduced due to related pancytopenia. given the response to therapy, he was continued on a weekly dose of bortezomib, receiving a total doses, which has permitted the slow taper of prednisone that has since been discontinued without a major flare. he however is currently maintained on ecp times per week, which is now been slowly withdrawn.conclusion: management of acute gvhd in pediatric patients after hsct can be challenging with no definite options for those who fail steroids or become steroid dependent after initial response. in these situations, bortezomib could be a valid therapeutic option. background: neuroblastoma (nbl) is the second most common solid tumor in children and despite recent treatment advances, overall survival for high risk nbl remains < %. the addition of immunotherapy has improved survival and includes anti-gd antibody therapy. the success of antibody therapy in neuroblastoma is primarily due to natural killer (nk) cell mediated antibody dependent cellular cytotoxicity. we previously demonstrated that nk cells from patients with high risk nbl can be successfully isolated and expanded to large numbers and exhibit potent anti-tumor effects against nbl ( ). thus, infusions of autologous expanded nk cells in high risk nbl in combination with anti-gd antibody are being studied in clinical trials. toll-like receptors (tlr) present on the surface of leukocytes are responsible for pathogen recognition, and activation of these receptors stimulate the production of cytokines that critically link innate and adaptive immune responses. the tlr agonist, poly(ic) is a synthetic analog of dsrna that has previously been shown to directly stimulate cytokine production and improve cytotoxicity in primary nk cells through activation of genes regulated by interferon-response elements (ire) ( ). we hypothesized that ex vivo activation of tlr pathways in nk cells during our normal -day expansion using k feeder cells expressing membrane bound il- would enhance their function.design/method: nk cells were isolated from peripheral blood mononuclear cells and expanded with our previously described expansion protocol in media containing il- and ug/ml poly(ic) ( ). at the end of the -day expansion, nk cells expanded with poly(ic) were compared to controls using a calcein cytotoxicity assay to measure cytotoxicity against high risk neuroblastoma and cytometric bead array to measure cytokine production. : surprisingly, the addition of poly(ic) during nk cell expansion did not improve proliferation, cytokine production or cytotoxicity compared to our standard expansion method. rnaseq demonstrated that our standard expansion method results in a modest decrease in tlr expression at the transcriptional level, but significant upregulation of several ireregulated genes. we conclude that either our standard approach interferes with tlr signaling or saturates the innate immune response pathway such that co-stimulation with poly ic does not produce an additive effect. we are performing expression analysis on nk cells receiving poly(ic) during expansion to further explore this hypothesis. background: gonadal dysfunction leading to infertility is a complication after hematopoietic stem cell transplant (hsct). anti-müllerian hormone (amh) is a marker of ovarian reserve; it is not controlled by gonadotropins and has minimal inter-cycle variations, therefore, it can be used as a marker of ovarian reserve and aid in fertility counseling.objectives: assess ovarian reserve in hsct patients utilizing amh levels. background: tgf beta is an immune suppressive cytokine frequently elevated in the tumor microenvironment causing tumor immune evasion. acute tgf beta treatment potently inhibits nk cell cytotoxicity, cytokine secretion, and proliferation. however, tumor infiltrating nk cells receive chronic inhibitory tgf beta signals in conjunction with activating signals from tumor cells. objectives: to this end, we hypothesized that long-term tgf beta-cultured nk cells would induce functional and phenotypical changes on nk cells that differ from short-term tgf beta treatment.design/method: to explore this, primary human nk cells were cultured with the leukemia cell line, k , alone or with exogenous tgf beta for weeks. : surprisingly, nk cells cultured in tgf beta proliferated faster, and upon challenge with a variety of cell line targets they secreted much greater quantities of ifnÎ ( -to -fold increase against / cell lines) and tnf ( -to -fold increase against / cell lines). further, the high cytokine secretion induced in these nk cells was no longer inhibited by adding additional tgf beta. degranulation was also increased ( / cell lines), however cytotoxicity was not enhanced in a -hour cytotoxicity assay. after resting in il- , the cytokine hypersecretion of tgf betacultured nk cells was maintained for several weeks suggesting this functional change might involve cellular reprogramming. we investigated the mechanism behind these functional changes and profiled genes involved in tgf beta signaling. we found significant reduction of smad transcription which corresponded to a striking decrease in smad chromatin accessibility. we also found significantly increased smad and decreased tgfbr expression. phenotypic analysis revealed that tgf beta also induced remodeling of the nk receptor repertoire with decreased nkp , cd , and klrg and upregulation of trail. the functional consequences of these tgf beta-induced changes on in vitro and in vivo nk cell function are currently under investigation. background: the use of t-cell depleted grafts in haploidentical stem cell transplantation (hsct) has been associated with a delay in early t-cell recovery which increases the risk of viral infections, relapse or graft rejection. conventional donor lymphocyte infusion (dli) after hsct transplantation is effective but conditioned because of a high prevalence of gvhd. the infusion of selected lymphocyte subpopulations with low aloreactivity is emerging as an effective strategy to rectify this issue. the depletion of cd ra+ naive lymphocytes, preserving cd ro+ memory t-cells, could provide a safe source of functional lymphocytes with anti-infection, antileukemic and anti-rejection properties, and lower rates of adverse effects. our objective is to present data of patients that have received cd ro+ memory t-cells dli (mdli) and assess its safety and outcome. we present data of mdli performed after hsct in cases of mixed chimerism, persistent lymphopenia, viral/opportunistic infections or as a strategy to accelerate immune reconstitution.results: fifteen patients with diagnosis of all (n = ), aml (n = ), mds (n = ), saa (n = ), sideroblastic anemia (n = ) and cgd (n = ), received mdli after hsct. a total of forty-three mdli were infused. the median dose of cd ro+ memory t-cells infused was . × /kg (range: . × - . × /kg), with a median dose of cd ra+ naive t-cells of . × /kg (range: - . × /kg). the mdli were infused at a median of seventy-seven days after hsct (range: - days), with a median interval between mdli of thirty-four days results: eight published studies reported survival outcomes for pediatric vod/sos patients (n = ), across all defibrotide doses. estimated day+ survival ( % confidence interval) was % ( %- %). for vod/sos with mod, studies were identified (n = ) with pooled estimated day+ survival of % ( %- %). only one openlabel expanded-access study, the treatment-ind, reported outcomes separately for pediatric vod/sos patients without mod (n = patients aged ≤ years). the day+ kaplan-meier estimated survival for those patients was % ( %- %). safety results were not pooled due to differences in reporting methodology; however, study results were consistent with the safety profile of the phase historicallycontrolled trial in vod/sos patients with mod ( % pediatric), in which / defibrotide-treated patients and all controls experienced ≥ ae. hypotension was the most frequent ae ( %, defibrotide; %, controls); common hemorrhagic aes (ie, pulmonary alveolar and gastrointestinal hemorrhage) occurred in % of defibrotide-treated patients and % of controls. in this pooled analysis of studies with defibrotide-treated pediatric patients with vod/sos, estimated day + survival was % (without mod, %; with mod, %). safety results in individual studies were generally consistent with the known safety profile of defibrotide. taken together, these results show a largely consistent defibrotide treatment effect in pediatric patients treated with defibrotide for vod/sos, with or without mod. results: six patients met inclusion/exclusion criteria. all patients were started on ecp while concurrently receiving . to mg/kg steroid therapy for agvhd plus a calcineurin inhibitor. patients had initiation of ecp within a maximum of weeks from initial diagnosis of agvhd (range - days). patients had grade - agvhd ( / patients with grade ) with skin, liver, and gi gvhd represented. patients received ei-ecp - times per week for the first weeks and then had ei-ecp frequency tapered based on initial response.after weeks of therapy patient had a decrease in overall gvhd grade by grade. all patients were able to have steroids tapered, with doses decreased by an average of % ( % - % decrease).at weeks of therapy, one patient with grade agvhd died of mof associated with infections. three patients had complete resolution of agvhd and patients decreased by grade. steroid doses were decreased by an average of % ( % - % decrease). continuously measures axillary temperature and wirelessly transmits real time-time data. the primary aim of the study was to evaluate the feasibility, safety and tolerability of continuous temperature monitoring in hsct patients using temptraq. we are performing a prospective observational study of pediatric patients ( - years of age) undergoing hsct at cincinnati children's hospital in cincinnati, ohio. enrolled patients wore a temptraq patch for days. a - rating scale survey was completed by the parent/guardian at the end of the study to determine tolerability, ease of use, satisfaction and desire for future use in the inpatient and outpatient setting. temperature data from the temptraq patch was compared to the standard episodic temperature monitoring to determine detection of febrile episodes. seven of ten patients have completed screening. we anticipate completion of the study in early february. the temptraq patch was well tolerated by study subjects (mean tolerability rating of . / ). one patient developed skin breakdown at the site of the temptraq patch attributed to recent thiotepa. the patch was easy to apply with an easy of application rating of . / . parents were overall satisfied (rating . / ) and would like to use the temptraq patches in future hospitalizations (rating . / ) and at home (rating . / ). temptraq patch identified fever (≥ . • f) in patients. the fever was never detected by episodic monitoring (soc) in patients and significantly delayed in the other patients (> hours). temptraq was well tolerated in pediatric hsct patients. timely fever detection was improved in temptraq over the current soc. background: serotherapy is commonly used in patients undergoing hematopoietic stem cell transplant (hsct) to reduce the incidences of engraftment failure and graft versus host disease. however, one well-known side effect is fever. as children undergoing hsct have compromised immune defenses, fever may also be an early indicator of bloodstream infection, which would warrant prompt use of broad-spectrum antibiotics. in a subset of patients with serotherapy-associated fever, antibiotics, which may induce antibiotic resistance and increase costs, may be unnecessary. we aimed to determine the incidence and characteristics of serotherapy-related fever, as well as the likelihood of concomitant bacteremia, in our institutional experience. a -year retrospective chart review was conducted of pediatric patients who received serotherapy as part of hsct conditioning at the university of minnesota. one-hundred sixty eight consecutive hsct patients who received serotherapy -either atg (n = ) or alentuzumab (n = ) -were identified. the median age at hsct was -years (range, . - years). a total of patients ( %) developed fever while on serotherapy (atg = , alentuzumab = ). one-hundred sixteen patients presented fever following the first infusion, and the median onset of fever was hours after commencing infusion (range, . - hours). fever resolved at a median hours (range, - hours). one hundred and fourteen patients ( %) underwent blood cultures. only seven patient were not started on ( %) empiric antibiotics, while % (n = ) were on antibiotic treatment prior to serotherapy for previously known or suspected infections. nine patients ( % of febrile patients, % of all patients) had positive blood cultures (atg = ; alentuzumab = ). no infection-associated deaths were observed.conclusion: while fever is common during serotherapy conditioning in children undergoing sct, episodes of concomitant bloodstream infection are rare. ongoing analysis identified potential risk factors for bacteremia as recent history of infection, first episode of fever following second or subsequent infusions, and previous central line placement. further analysis is being conducted to identify subgroups of patients for whom close monitoring alone may be safe. background: hsct is potentially curative for caya with high-risk leukemias; however, most lack an hla-matched aspho abstracts related donor. the risk of gvhd is increased with unrelated (urd) or partially matched related (pmrd) donors. selective t-cell depletion based on the elimination of t cells carrying and chains of the t-cell receptor may greatly reduce the gvhd risks, while allowing the maintenance of mature donor-derived alloreactive nk cells and / (+) t cells, which may augment the anti-leukemia effect.objectives: this is a prospective study of caya with acute leukemia who underwent hsct with mmrd or urds and tcr / /cd depletion. outcomes included engraftment, toxicities, viral reactivation, and relapse.design/method: this study included caya with acute leukemia transplanted between october and may . all received a myeloablative preparative regimen with targeted busulfan (n = ) or tbi ( cgy/ fractions) (n = ), with thiotepa ( mg/kg) and cyclophosphamide ( mg/kg). atg ( mg/kg x ) was given to those receiving haploidentical grafts and to the first who received urd grafts. immune suppression was not given post-hsct. the stem cell source was mobilized peripheral blood stem cells (pscs), which then underwent tcr / /cd depletion utilizing the clinimacs device under gmp conditions in the chop cellular immunotherapy lab.results: median age was (range . - . ). diagnoses included all ( -b-cell, -t-cell) and aml ( ; -secondary aml). urd were used for ; were / allele matched and were / matched. haploidentical donors were used for . median cd (+) dose - . × , / (+) cd (+) cells - . × , and b cells - . × . all patients achieved an anc at a median of d+ ( - ), and % had platelet engraftment at median d+ ( - ). nine patients ( %) developed acute gvhd (all skin, grades i-iv). five developed chronic gvhd (skin, gut, lung): limited in , extensive in . viral reactivations included: adenovirus ( , %), bk virus ( , %), cmv ( , %), and hhv ( , %). nine ( %) patients relapsed at a median of days (range - ) post-hsct, including aml patients ( . %) and all patients ( . %). transplant-related mortality was %; causes included sepsis ( ) and ards ( ). os was %; efs was % (gvhd-free efs %, lfs %). hsct with tcr / /cd depletion demonstrates excellent engraftment kinetics with limited gvhd without immune suppression. elimination of post-hsct immunosuppression may offer an excellent platform to augment anti-leukemic immune therapy or to enhance immune reconstitution. background: hematopoietic cell transplantation (hct) is the only curative treatment available for patients with sickle cell disease (scd). low bone mineral density (bmd) has been described in scd, but little is known about the impact of curative hct on this outcome. to determine the prevalence of low bmd and variables associated with low bmd in scd patients after hct. we conducted a retrospective chart review of scd patients who underwent hct at children's healthcare of atlanta (choa) between / and / and survived ≥ year post-hct. transplant characteristics, post-hct dual-energy x-ray absorptiometry (dexa) scan results, vitamin d levels, graft-versus-host-disease (gvhd) status, and fsh levels were reviewed. for patients - years of age, height corrected z-scores were calculated using a nihvalidated calculator, with t-scores used for older patients. bmd was categorized as low if between - and - sd below the mean and clinically significantly low if >- sd, in accordance with the children's oncology group long-term follow-up guidelines. vitamin d levels < ng/mol were considered deficient, and fsh levels > miu/ml suggestive of premature ovarian failure. fisher's exact test was used to compare variables in those with normal versus abnormal dexa scan results, with p< . considered significant.results: hct was performed on patients with scd, with surviving ≥ year post-hct. dexa scans were obtained in patients ( % female), with mean time from hct to dexa scan being years ( . - . years) and mean age at time of dexa . years ( . - . years). patients with and without dexa scans did not differ by sex, donor source, age at transplant, or vitamin d status. low bmd was noted in patients ( . %), with these patients more likely to be > years (pubertal; . versus . %, p = . ). acute gvhd was more common in patients with low bmd ( . versus . %), but not statistically significant (p = . ). clinically significant low bmd was noted in patients ( . % of those with dexa scans). these patients were older ( . years at testing), were more likely to be male ( . %), and all had acute and chronic gvhd, while none had evidence of gonadal failure.conclusion: clinically significant low bmd is uncommon after hsct for scd. patients at risk for low bmd include older patients and likely those with gvhd. this preliminary data suggests routine dexas may not be indicated for all patients who undergo hct for scd, but further data is needed. background: causes of renal dysfunction after hematopoietic cell transplantation (hct) include damage from radiation, nephrotoxic medications, graft vs. host disease (gvhd), hepatorenal syndrome, viral infections, or transplant associated microangiopathy. we sought to investigate the incidence of, and risk factors for, acute kidney injury in pediatric hct patients and associated risk with mortality.design/method: data from patients who underwent hct between and at a single institution were sequentially retrospectively captured on irb approved protocol. acute kidney injury (aki) was defined at multiple time points post-hct using the standardized criteria: kidney disease: improving global outcomes (kdigo). interval differences between values were analyzed using wilcoxon rank sum testing and categorical variables were analyzed using chi-square analysis.results: ninety-eight patients were included in the study: allogeneic (n = ) and autologous (n = ), mean age . years, of whom % were african american, % asian, % caucasian, % latino, and % mixed race. forty-seven percent of patients developed aki within the first years of hct. increased risk for aki was associated with a lower pre-transplant creatinine level (p = . ), abnormal pretransplant bun (p = . ) and an unrelated donor (p = . ) while preparative regimen intensity, race, or primary disease were not. twenty-six percent of patients developed aki within days of hct. of those with aki, % were exposed to either cidofovir, aminoglycosides, and/or ambisome for at least days versus % without aki and % were exposed to vancomycin compared to % without aki. evaluating outcomes at year after hct, of those with stage aki: % had reduced gfr and % died, while % had reduced gfr and % had died for patients with aki stage or . the absence of aki by day was associated with % reduced gfr and % death at -year after hct. overall, those with aki at any time in the first year post-hct had a . fold increased risk of death compared to those without. for patients who required renal replacement therapy (rrt, n = ), the risk of death was . fold greater compared to those who did not. in the % of patients who survived rrt, both recovered renal function within years.conclusion: acute kidney injury is common after pediatric hct, and may be associated with low creatinine, abnormal bun, unrelated donor pre-hct, and renal toxic medications. early-onset aki post hct is associated with an increased risk of mortality. these data should be validated in a larger prospective study but may offer opportunities to intervene and enhance outcomes. background: myeloablative hematopoietic stem cell transplant (hct) for pediatric malignant disease is associated with significant morbidity with % patients experiencing mucositis. patient controlled analgesia (pca) utilizing opioids is an effective strategy for pain management. we sought to describe and analyze pca use in d+ days post myeloablative hct for malignancies at lurie children's hospital of chicago from - .design/method: utilizing retrospective chart review, pca details were collected: indication, initiation day, pca duration, team managing pca (anesthesia or palliative), medication and dose in morphine equivalents, and pca toxicities. efficacy of pca was evaluated on pca day + , + , + , + using demands %, maximum pain score (rflacc, faces, vas) and subjective patient, parent and/or pain team perception of pain control. we devised a scale based on the above to designate pain control as good, moderate or poor. variables being analyzed include recipient age, sex, donor type, source, diagnosis, tbi use, gvhd/trm. this analysis, we analyze the depth of remission, car-t persistence, and post-transplant gvhd on our phase i anti-cd car-t protocol (nct ) to better understand the role of car-t in the peri-hct setting.design/method: children and young adults with relapsed/refractory cd + all treated on our phase i anti-cd car-t protocol were analyzed. mrd was assessed by flow cytometry (fc) in all, with pcr-based mrd analysis using igh or tcr testing assessed in select patients. hcts were performed at each patient's local institution based on standard of care and included varying conditioning regimens, donor types, stem cell source, and gvhd prophylaxis.results: on our cd car trial, patients were treated, the majority of patients (n = ) having relapsed following a prior hct. / patients ( %) attained a cr, of whom were mrd negative by fc. concurrent pcr based mrd analysis available in patients demonstrated that all patients achieved pcr based negativity. in , this was simultaneous with the month mrd negative fc, and in , pcr negativity was achieved over time (fc remained negative). patients proceeded to hct at a median time of days (range: - days) post-car-t, which was a first hct in . these two patients remain in an mrd negative cr, year post-car-t. no patients developed acute or chronic gvhd. car persistence was seen in patients who had detectable car-t cells on the pre-hct marrow suggesting the possibility of ongoing anti-leukemia surveillance prior to initiation of the conditioning regimen.conclusion: by inducing pcr negativity, car-t therapy may have a synergistic role with hct to improve leukemia free survival, prior to emergence of antigen negative leukemia, without an increased risk of gvhd. while the sample size is small, car-t therapy may offer an effective bridge to hct, particularly for those who are pcr negative, and those who have not had a previous transplant. given the underlying risk of hct related trm, pre-hct car may potentially allow for hct conditioning de-intensification as it may not be needed to eradicate residual disease. lee dw, ash abstract , background: post-transplant lymphoproliferative disease (ptld) is a complication after solid organ transplantation (sot) that is frequently due to epstein -barr virus (ebv) as a decrease in ebv-specific t cell immunity due to immune suppression allows for uncontrolled proliferation of ebv-infected b cells. outcomes for ptld are suboptimal with relapse rates approaching %. however, ebv-infected b cells in ptld express the ebv antigens lmp and lmp that can be targeted with immune therapy.objectives: we hypothesize that third party "off the shelf" lmp-specific t cell products may improve outcomes and decrease associated co-morbidities for patients with ptld by not only target the lymphoproliferating ebv-infected b cells but also restoring ebv-specific immunity.design/method: lmp-specific t cells (lmp-tcs) are manufactured from eligible donors with a broad range of hla types in our gmp facility to be used in a children's oncology group (cog) trial (anhl ) for patients with ptld after sot. lmp-tc products are manufactured from healthy donors using autologous monocytes and lymphoblastoid cell lines (lcl) transduced with an adenoviral vector expressing Δlmp and lmp as antigen presenting cells. lmp-tc products undergo comprehensive characterization by ifn-elispot assay to determine lmpspecific epitopes, class i and/or ii response, and hla restriction to guide selection of lmp-tc product for each patient.results: thus far, lmp-tc products have been manufactured. lmp-tcs were active against lmp (mean: sfu/ × ^ cells; range: - ), lmp ( ; - ), and lcl ( ; - ) as determined by ifn-elispot assay. at the time of cryopreservation, the lmp-tc products comprised a mean of % cd + t-cells, % cd + t-cells, and % nk cells. no b cells or monocytes were detected in the final products. thus far, we have identified novel lmp epitopes (lmp specific: n = ; lmp specific: n = ). approximately % of the lmp-tc products have lmp-specific activity through multiple hla alleles, and % have a mixed class i and class ii response. conclusion: thus, lmp-specific t cell products can be expanded from healthy donors to creat a third party bank, and identifying epitopes and hla alleles with lmp activity will facilitate selecting the most appropriate product for patients. while lmp-specific t cells have previously demonstrated safety and efficacy in phase i studies, anhl is the first trial using cellular therapy within a cooperative group setting. children's cancer hospital at the university of texas md anderson cancer center, houston, texas, united states background: in , the united states food and drug administration (fda) approved the first chimeric antigen receptor t cell (car-t) therapy; tisagenlecleucel. this cd -directed genetically modified autologous t cell immunotherapy has shown response rates of almost % among children and young adults with b-cell precursor acute lymphoblastic leukemia (all) that are refractory or in second or later relapse. cytokine release syndrome (crs) and car-t cell related encephalopathy syndrome (cres) are well described toxicities associated with car-t therapy. crs is a systemic inflammatory response and is typically characterized by fever, hypoxia, tachycardia, hypotension and multi-organ toxicity. cres may occur concurrently or following crs, or without any associated crs symptoms and is characterized by encephalopathy, delirium, seizures and rarely cerebral edema. almost half of patients who receive tisagenlecleucel may require pediatric intensive care unit (picu) support. crs and cres are generally reversible but may be associated with fatal outcomes. pediatric specific management guidelines, comprehensive training of multidisciplinary staff, effective communication and phased infrastructure ensure that adequate resources are available to facilitate early diagnosis and appropriate management of pediatric patients with crs and cres and allow for optimal patient outcomes and accreditation by the foundation for accreditation of cellular therapy (fact).objectives: develop a comprehensive program to ensure safe administration of immune effector cell (iec) therapy to pediatric patients.design/method: an inter-disciplinary pediatric cartox (car t cell therapy associated toxicity) committee consisting of cell therapy and picu physicians, neurologists, fellows, nursing leadership, advanced practice practitioners, pharmacists, registered nurses and social workers was created to monitor patient toxicity and establish specific clinical guidelines and diagnostic and treatments algorithms for pediatric patients receiving iec therapy. educational modules were developed as (i) live in-services and (ii) an online module with a competency based assessment. electronic medical record (emr) order sets and documentation and warning systems were also developed by the committee. the pediatric cartox committee developed a diagnostic and treatment algorithm for patients receiving iec therapy. emr orders and flowsheets were developed to support adherence to the algorithm. inter-disciplinary staff training and competency assessments were closely tracked. almost % of identified staff have completed training and achieved competency including, pediatric cell therapy staff, emergency center, picu, outpatient clinic/triage, neurology and sub-specialty staff and nocturnalists.conclusion: an inter-disciplinary approach can assist in institutional readiness for an iec program, promote quality assurance and perhaps fact iec accreditation. future directions include a program for ongoing staff competency assessments. predicted peak vo ) and abnormal oxygen uptake efficiency slope at the anaerobic threshold ( . ± . . , normal ± ). additionally, on echocardiogram three patients had evidence of diastolic dysfunction as evidenced by an elevated e/a ratio ( . ± . ) on tissue doppler. three patients demonstrated depressed longitudinal peak systolic strain (- . ± . ), indicating dysfunction not captured by ejection fraction. in this feasibility study, sct patients without evidence of lvsd on standard measures by resting echocardiogram can demonstrate abnormal exercise capacity. additionally, they can demonstrate systolic and diastolic dysfunction by measures not always included in standard echocardiography. these data suggest the need for a more thorough screening of survivors, and will be further validated as additional patients are recruited for this study. background: in hematopoietic transplantation, the t lymphocytes of the inoculum play a determining role in promoting hematopoiesis, transferring immunity to pathogens and acting as mediators of the graft-versus-leukemia effect (gvl). however, they are also responsible for graft-versus-host disease (gvhd), the main cause of post-transplant morbidity and mortality. the depletion of cd ra lymphocytes, by eliminating naive t lymphocytes from the inoculum, aims to conserve the gvl without producing gvhd.design/method: since april , patients ( boys and girls), with a median age of years, have undergone an allogeneic hematopoietic transplant from an hla donor identical with cd ra/cd depletion. the indication for transplant was: acute lymphoblastic leukemia ( ), acute myeloblastic leukemia ( ), myelodysplasia ( ) and medullary aplasia ( ). the donor was familiar in cases and unrelated in . the conditioning regimen was with fludarabine, busulfan and thiotepa. the median of cd + cells infused was . × / kg. on the day , + and + a programmed infusion of × / kg lymphocytes cd ra-was performed.results: all the patients grafted with a median leukocyte (> . × / l) and platelet (> × / l) engraftment time of and days, respectively. only one patient has developed acute gvhd grade i and no patient has developed chronic gvhd. immune reconstitution was early and rapid in all t cell subsets no patient has relapsed so far and only patient with myelodysplasia has developed an aml. she has received a nd transplant and has died of relapse. there was no case of toxic mortality. the event-free survival (sle) was ± % with a median follow-up of months. at present, patients are alive, out of immunosuppressive treatment and doing well. allogeneic transplantation with cd lymphocytes ra depletion resulted on very encouraging results, with a very low incidence of acute and chronic gvhd, but preserving the gvl effect by infusing cd ra-donor lymphocytes. miami children's health system, miami, florida, united states background: hematopoietic stem cell transplantation (hsct) using autologous or allogeneic progenitor cells is a potentially curative treatment for patients with high-risk malignancies and nonmalignant conditions. the american society for blood and marrow transplantation developed a task force to establish consensus guidelines for defining patient care in hsct and advocated for further studies to delineate safe procedural steps as an increasing amount of hsct are being offered to patients. there is limited evidence to support engraftment in recipients who receive their infusions via iv or syringe pump. we present novel data from patients who achieved neutrophil engraftment following hsct by a pump mechanism.objectives: to provide evidence supporting the use of pump (intravenous or syringe) infusion method in hematopoietic stem cell transplantations.design/method: a retrospective review was completed for patients who underwent hsct between and . inclusion criteria included patients who had received hematopoietic stem cell transplants between and and who were ages months to years old. the main outcome measure was days to neutrophil engraftment (defined as the first of three consecutive days with an anc > × /l).results: among patients who received infusion of hematopoietic stem cell products via pump mechanism, patients ( . %) received autologous products and ( . %) received stem cells from allogeneic donors. neutrophil engraftment (anc > × /l) occurred in a median of . days after stem cell infusion. the mean number of days to engraftment for patients who received allogeneic infusions s of s design/method: a retrospective chart review was performed at the children's hospital of wisconsin. statistical analyses included kaplan-meier estimate for os, mann-whitney test for comparing outcomes between subjects, and descriptive analyses.results: from - , patients with a median age of . ( . - . ) years at st hct were identified. patients were conditioned with cy/atg (n = ), cy/flu/atg (n = ), or cy/flu/atg/tbi (n = ) and received marrow (n = ) or cord blood (n = ) with median cd /kg dose of . ( . - . ) × . two patients developed grade i acute graftversus-host disease (gvhd); none developed chronic gvhd. due to dropping chimerism, graft rejection, or graft failure, nd hct (n = ) or boost (n = ) was offered. the median cd chimerism prior to hct/boost was ( - )%. median time between st hct and nd hct or boost was days ( days- . years). in patients receiving nd hct, used the same donor, of which used the same stem cell source (marrow) and switched to peripheral blood stem cells (pbsc). in patients who switched donors, used pbsc and used cord blood. most patients receiving nd hct underwent a uniform conditioning regimen of cy /flu /equine atg/ gy tli (n = ) or cy /flu /rabbit atg/ gy tbi (n = ); one received cy/atg. acute and chronic gvhd (limited seen in %) developed in % and % of patients, respectively. four patients required additional boosts and additional hct. after final intervention, cd and whole-blood chimerism at last follow-up was between - % (n = ) and - % (n = ), respectively. with a median follow-up of . ( . - . ) years, of patients are alive with an estimated -year os of . ± . %, having performance status ≥ % (n = ) or % (n = ). one patient developed chronic extensive gvhd and died of fungal infection . years after nd hct. our single-center experience demonstrates excellent ability to salvage patients who develop graft failure after initial hct. transplant-related complications such as gvhd and infections remain significant concerns.